impregnated cobalt, nickel, copper and palladium oxides on...

Impregnated Cobalt, Nickel, Copper and Palladium Oxides on Magnetite: Nanocatalysts

for Organic Synthesis

Juana Pérez Galera

http://www.ua.es/

http://www.eltallerdigital.com/

Instituto de Síntesis Orgánica

Facultad de Ciencias

Impregnated Cobalt, Nickel, Copper and Palladium

Oxides on Magnetite: Nanocatalysts for

Organic Synthesis

Manuscript thesis submitted for the degree of PhD at the University of

Alicante by:

JUANA M. PEREZ GALERA

Alicante, 27th

May 2016

INTERNATIONAL MENTION IN THE TITLE OF DOCTOR

Scientific advisor:

DIEGO J. RAMÓN

Instituto de Síntesis Orgánica

Institute of Organic Synthesis

FRANCISCO ALONSO VALDÉS, Director del Instituto de Síntesis Orgánica de

la Facultad de Ciencias de la Universidad de Alicante,

CERTIFICA:

Que la presente memoria titulada “Impregnated Cobalt, Nickel, Copper and

Palladium Oxides on Magnetite: Nanocatalysts for Organic Synthesis”

presentada por la Licenciada Dña. Juana M. Pérez Galera para aspirar al grado de

Doctora en Química (mención internacional), ha sido realizada en este Instituto

bajo la dirección del catedrático Diego J. Ramón.

Alicante, 27 de Mayo de 2016

Francisco Alonso Valdés

PROLOGUE

3 Prologue

Part of the results reported on this thesis has been already published:†

“Cobalt-Impregnated Magnetite as General Heterogeneous Catalyst for the

Hydroacylation Reaction of Azodicarboxylates” J. M. Pérez, D. J. Ramón, Adv. Synth.

Catal. 2014, 356, 3039-3047.

“Copper-Impregnated Magnetite as a Heterogeneous Catalyst for the Homocoupling of

Terminal Alkynes” J. M. Pérez, R. Cano, M. Yus, D. J. Ramón, Synthesis 2013, 45,

1373-1379.

“Straightforward Synthesis of Aromatic Imines from Alcohols and Amines or

Nitroarenes Using an Impregnated Copper Catalyst” J. M. Pérez, R. Cano, M. Yus, D. J.

Ramón, Eur. J. Org. Chem. 2012, 4548-4554.

“Cross-Dehydrogenative Coupling Reaction using Copper Oxide Impregnated on

Magnetite in Deep Eutectic Solvents” X. Marset, J. M. Pérez, D. J. Ramón, Green Chem.

2016, 18, 826-833.

“Impregnated Copper(II) Oxide on Magnetite as Catalyst for the Synthesis of

Benzo[b]furans from Alkynes and 2-Hydroxyarylcarbonyl derivatives” J. M. Pérez, D. J.

Ramón, to be submitted.

“Multicomponent Azide-Alkyne Cycloaddition Catalysed by Impregnated Bimetallic

Nickel and Copper on Magnetite” J. M. Pérez, R. Cano, D. J. Ramón, RSC Adv. 2014, 4,

23943-23951.

“Impregnated palladium on magnetite as catalyst for direct arylation of heterocycles” R.

Cano, J. M. Pérez, D. J. Ramón, G. P. McGlacken, Tetrahedron 2016, 72, 1043-1050.

“Palladium(II) Oxide Impregnated on Magnetite as Catalyst for the Synthesis of 4-

Arylcoumarins via a Heck-arylation/cyclization process” J. M. Pérez, R. Cano, G. P.

McGlacken, D. J. Ramón, RSC Adv. 2016, DOI: 10.1039/C6RA01731B.

“Synthesis of 3,5-Disubstituted Isoxazoles and Isoxazolines in Deep Eutectic Solvents”

J. M. Pérez, D. J. Ramón, ACS Sustainable Chem. Eng. 2015, 3, 2343-2349.

† This research has been generously supported by the Spanish Ministerio de Economía y

Competitividad (MICINN; CTQ2011-24151) and the University of Alicante.

RESUMEN

SUMMARY

RESUM

7 Resumen

En la siguiente memoria se describe la aplicación de diferentes

nanocatalizadores derivados de óxidos metálicos impregnados sobre la superficie

de la magnetita en varias reacciones de interés general en Química Orgánica.

En el Primer Capítulo, un catalizador derivado de cobalto fue usado en la

reacción de hidroacilación de azodicarboxilatos con aldehídos.

En el Segundo Capítulo, un catalizador derivado de cobre fue usado para

llevar a cabo diferentes reacciones, incluidas la reacción de homoacoplamiento

de alquinos terminales y la subsecuente reacción de hidratación para obtener los

correspondientes benzofuranos 2,5-disustituidos, la reacción de alcoholes y

aminas (o nitroarenos) para la obtención de las correspondientes iminas

aromáticas, el acoplamiento deshidrogenante cruzado de tetrahidroisoquinolinas

usando mezclas eutécticas y aire como oxidante final y, por último, la formación

de benzofuranos a partir de aldehídos y alquinos a través de una reacción tándem

de acoplamiento-alenilación-ciclación.

En el Tercer Capítulo, un catalizador bimetálico derivado de niquel y

cobre fue usado en el estudio de la reacción de cicloadición multicomponente

entre bromuros bencílicos, azida de sodio y alquinos para la obtención de los

correspondientes triazoles.

En el Cuarto Capítulo, un catalizador derivado de paladio fue usado en la

arilación directa de heterociclos usando sales de iodonio y en la síntesis de 4-

arilcumarinas a través de una arilación mediante reacción Heck seguida de

ciclación.

En el último Capítulo, se estudió el uso de mezclas eutécticas como

medios alternativos para llevar a cabo en un único recipiente la reacción de

ciclación de cloruros de N-hidroxi imidoilo y alquinos, sin ningún tipo de

catalizador y en condiciones oxidantes.

Summary 8

In this manuscript, the application of different nanocatalysts derived

from metal oxides impregnated on the surface of the magnetite in different

reaction of general interest in Organic Chemistry is described.

In the First Chapter, a cobalt derived catalyst was used to study the

hydroacylation reaction of azodicarboxylates with aldehydes.

In the Second Chapter, a catalyst derived from copper was used to

perform different reactions, including homocoupling of terminal alkynes and the

subsequent hydration reaction to obtain the corresponding 2,5-disubstituted

benzofurans, the reaction of alcohols and amines (or nitroarenes) to obtain the

corresponding aromatic imines, the cross-dehydrogenative coupling reaction of

N-substituted tetrahydroisoquinolines using deep eutectic solvents and air as final

oxidant. Finally, the formation of benzofurans from aldehydes and alkynes

through a tandem coupling-allenylation-cyclization process has been performed.

In the Third Chapter, a bimetallic catalyst derived from nickel and

copper was used to study the multicomponent reaction between benzyl bromides,

sodium azide and alkynes to obtain the corresponding triazoles.

In the Fourth Chapter, a catalyst derived from palladium was used in the

direct arylation of heterocycles using iodonium salts. Also the synthesis of 4-aryl

coumarins through the Heck arylation reaction and subsequent cyclization using

the same catalyst is described.

In the last Chapter, the use of different eutectic mixtures were studied as

alternative media to perform in a single vessel the cyclation reaction of N-

hydroxy imidoyl chlorides and alkynes, without any type of catalyst under

oxidizing conditions.

9 Resum

En aquest treball es descriu la aplicació de diferents nanocatalitzadors

derivats d’òxids metàl·lics impregnats sobre la superfície de la magnetita en

diverses reaccions d’interès general en Química Orgànica.

En el Primer Capítol, es va usar el catalitzador de cobalt en la reacció de

hidroacilació de azodicarboxilats amb aldehids.

En el Segon Capítol, es va usar un catalitzador derivat de coure per a

portar a cap diferents reaccions, incloses el homoacoplament d’alquins terminals

amb la subseqüent reacció de hidratació per a obtindre els corresponents

benzofurans 2,5-disubstituits, la reacció d’alcohols i amines (o nitroarens) per a

obtindre les corresponents imines aromàtiques, l’acoblament deshidrogenant

creuat de tetrahidroisoquinolines N-substituïts usant mescles eutèctiques i aire

com oxidant final i, per últim, s’ha realitzat la formació de benzofurans a partir

de aldehids y alquins a través d’un procés tàndem d’acoblament-allenylation-

ciclació.

En el Tercer Capítol, un catalitzador bimetàl·lic de níquel i coure

impregnats en magnetita va ser emprat per a l’estudi de la reacció de cicloaddició

multicomponent entre bromurs benzílics, azida de sodi i alquins per a obtindre

els corresponents triazols.

En el Quart Capítol, es va usar un catalitzador de pal·ladi en la arilació

directa de heterocicles emprant sals de iodoni i en la síntesis de 4-arilcumarines a

partir de una arilació mitjançant una reacció Heck seguida de una ciclació.

En l’últim Capítol, es va estudiar l’ús de mescles eutèctiques com medis

alternatius per a realitzar en un únic recipient la reacció de ciclació de clorurs

d’hidroxil imidoil i alquins, sense cap catalitzador en condicions oxidants.

PREFACE

13 Preface

At the Department of Organic Chemistry (Alicante University), the

group of Prof. Ramón has been developing a new research idea inside the area of

heterogeneous catalysts since 2007, using magnetite as non-innocent support.

The final aim of this study is the development of a new series of metal oxide

catalysts impregnated on magnetite and their use in Organic Synthesis.

Heterogeneous catalysis presents obvious advantages, from the

environmental point of view compared to the homogeneous one, being one of

them their easy recycling and reuse. The magnetic systems present an extra

advantage, as it is the possibility of their confinement, or their isolation through

magnetic fields (magnetic decantation). Despite the obvious advantages, the

impregnation is the simplest method to support different metallic oxides on

magnetite and had not been extensively prepared and studied.

The present research work is inspired by this central idea and on this

basis, some metal oxides impregnated on magnetite have been employed as

catalysts in different Organic Chemistry reactions.

The results and conclusions of this research work would be presented

following this structure:

I. GENERAL INTRODUCTION

II. RESULTS

CHAPTER I: “Reactions performed using nanoparticles of

impregnated cobalt(II) oxide on magnetite”

CHAPTER II: “Reactions performed using nanoparticles of

impregnated copper(II) oxide on magnetite”

CHAPTER III: “Reactions performed using the impregnated

bimetallic nickel(II) oxide/copper(0) on magnetite”

CHAPTER IV: “Reactions performed using nanoparticles of

impregnated palladium(II) oxide on magnetite”

CHAPTER V: “Reactions without catalyst”

Preface 14

III. EXPERIMENTAL PART

IV. CONCLUSIONS

V. BIOGRAPHY

VI. INDEX*

* The references have been included as footnote.

GENERAL INTRODUCTION

17 General Introduction

1. MAGNETITE

Magnetite,1 Fe3O4, is a mixed iron(II) and (III) oxide having a cubic

inverse spinel structure where the oxygen atoms form a unit cell cubic centered

on their faces and the iron atoms occupy the interstitial places. The octahedral

holes are occupied by ions of Fe3+

, while the tetrahedral ones are occupied by

ions of Fe2+

and Fe3+

equally.2 Electrons can move between the cations of Fe

2+

and Fe3+

on the octahedral holes at room temperature, providing magnetite

properties of semimetal (Figure 1).

Fe+3

Fe+2

Oxygen

Figure 1. Cristal structure of Fe3O4.

Magnetite can act as Brönsted base through the oxygen atoms and as

Lewis acid through the Fe atoms. The nature of the surface of magnetite3 hs been

analysed by Low Energy Electron Diffraction (LEED) and Scanning Tunnelling

Microscope (STM), demonstrating that the surface of magnetite (Figure 2)

present ¼ of monolayer of tetrahedral iron atoms forming a 2 x 2 structure with a

unit cell of 5.94 Å, with oxygen atoms (marked with X) that are not totally

coordinated. Due to this fact, both active places are present at the surface and are

accessible to substrates.

1 P. Majewski, B. Thierry, Crit. Rev. Solid State Mater. Sci. 2007, 32, 203-215. 2 M. Ritter, W. Weiss, Surf. Sci. 1999, 432, 81-94. 3 a) Y. Joseph, M. Wühn, A. Niklewski, W. Ranke, W. Weiss, C. Wöll, R. Schlögl, Phys. Chem.

Chem. Phys. 2000, 2, 5314-5319; b) K. T. Rim, D. Eom, S.-W. Chan, M. Flytzani-

Stephanopoulos, G. W. Flynn, X.-D. Wen, E. R. Batista, J. Am. Chem. Soc. 2012, 134, 18979-

18985.

General Introduction 18

Figure 2. Magnetite surface.

Nanoparticles of magnetite, among other iron oxides, present

superparamagnetism at room temperature due to their small size (ranging

between 1-100 nm). Therefore, these nanoparticles do not have a permanent

magnetic moment and can be only magnetised when an external magnetic field is

applied. This transient magnetization of the nanoparticles stops as soon as the

external field is ceased. The superparamagnetism phenomenon is not only

beneficial because it partially avoids the agglomeration but also because it can be

applied for purification purposes. For this reason, magnetite can be easily

removed from the reaction4 mixture or confined through the application of an

external magnetic field, greatly facilitating its reuse and making the whole

process more sustainable.5

A wide variety of metals and molecules can be easily immobilised and

supported on the magnetite surface. When compared with other nanosupports, the

differences between the rest of metal oxides and nanomagnetite are evident.

Nanoparticles possess different physical and chemical properties compare to their

bulk oxides. They have obvious advantages in terms of the activity, especially in

terms of the higher surface area of the active specie and the higher dispersability.

This fact favours a closer contact with the reactants. Therefore, they have being

4 G. M. Whitesides, C. L. Hill, J.-C. Brunie, Ind. Eng. Chem., Process Des. Dev. 1976, 15, 226-

227. 5 S. Shylesh, V. Schünemann, W. R. Thiel, Angew. Chem. Int. Ed. 2010, 49, 3428-3459.


considered for many authors as a bridge between homogeneous and

heterogeneous catalysis.6

For catalysts that consist of metal nanoparticles supported on a reducible

oxide, like magnetite, an oxygen spill over from the oxide to the metal may also

occur, which possibly induces the formation of an oxide film on the active metal

surface.7 As a result of this so-called strong metal-support interaction, in extreme

cases, the metal can be incorporated and then covered by a thin layer of the

support oxide. This ultra-thin oxide films may alter the catalytic activity of the

metal phase considerably. In several cases, it has been found that these native

oxides enhance the whole reactivity.

1.1. SYNTHETIC METHODS

Magnetite nanoparticles are readily accessible by different synthetic

methodologies,8 as follows:

Co-precipitation:9 It is the simplest way to gain access to magnetite

nanoparticles. It consists in the addition, under an inert atmosphere, of a base to

an aqueous solution containing Fe(II)/Fe(III) salts. The size and the shape of the

particles depend on different factors, such as pH, salt precursor, Fe(II)/Fe(III)

molar ratio, temperature, etc. However, once the conditions are fixed, the

synthesis is highly reproducible. Moreover, those features (especially the size)

can be controlled by using organic additives such as, polyvinylalcohol (PVA),

oleic acid, etc.

Thermal Decomposition:10

This methodology allows the synthesis of

magnetic nanoparticles with a narrow size distribution and high shape control

6 D. Astruc, F. Lu, J. R. Aranzaes, Angew. Chem. Int. Ed. 2005, 44, 7852-7872. 7 a) L. Giordano, G. Pacchioni, C. Noguera, J. Goniakowski, ChemCatChem 2014, 6, 185-190;

b) K. Zhang, S. Shaikhutdinov, H.-J. Freund ChemCatChem 2015, 7, 3725-3730. 8 A.-H. Lu, E. L. Salabas, F. Schüth, Angew. Chem. Int. Ed. 2007, 46, 1222-1244. 9 a) J. Lee, T. Isobe, M. Senna, Colloids Surf. A 1996, 109, 121-127; b) D. K. Kim, Y. Zhang, W.

Voit, K. V. Rao, M. Muhammed, J. Magn. Magn. Mater. 2001, 225, 30-36; c) B. L. Cushing,

V. L. Kolesnichenko, C. J. O’Connor, Chem. Rev. 2004, 104, 3893-3946; d) A. K. Gupta, A. S.

G. Curtis, Biomater. 2004, 25, 3029-3040; e) A. L. Willis, N. J. Turro, S. O’Brien, Chem.

Mater. 2005, 17, 5970-5975. e) A. K. Gupta, M. Gupta, Biomaterials 2005, 26, 3995-4021. 10 a) S. Sun, H. Zeng, D. B. Robinson, S. Raoux, P. M. Rice, S. X. Wang, G. Li, J. Am. Chem.

Soc. 2004, 126, 273-279; b) F. X. Redl, C. T. Black, G. C. Papaefthymiou, R. L. Sandstrom, M.

Yin, H. Zeng, C. B. Murray, S. P. O’Brien, J. Am. Chem. Soc. 2004, 126, 14583-14599; c) Z.

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from organometallic iron precursors, using the above mentioned additives (fatty

acids, polyalcohols, among others). To be successful, the control of high

temperatures (ranging between 100 and 320 ºC depending on the iron precursor),

as well as the use of inert atmosphere, is mandatory.

Microemulsion:11

It could be regarded as a co-precipitation methodology

variation which permits a better control of size and morphology, although with

notably poorer yields and rather complicated manipulation.

Hydrothermal Synthesis:12

It is also a variation of the thermal

decomposition method, but using high pressure and temperature. The size and

shape control obtained is as high as in the aforementioned methodology but the

process itself can be considered fairly simple. Conversely, the yields are lower.

1.2. APPLICATIONS

Iron-based catalysts are becoming very popular in the Organic Synthesis

community, since iron is abundant, eco-friendly, relatively non-toxic, and

inexpensive element.13

However, these catalysts have also some drawbacks, in

comparison with other commonly employed supports, such as silica, titania,

ceria, etc. On the one hand, magnetite, like most of the iron oxides, is dissolved

in strong acid media. This could be a limitation for the use of magnetite

nanoparticles supports under those conditions. However, in Organic Synthesis,

the use of such extreme reaction media is not very common.14

On the other hand,

the main problem associated with ‘naked’ magnetite nanoparticles, Fe3O4, is their

tendency to slowly oxidize to the more stable maghemite (γ-Fe2O3) or even to the

most stable iron oxide hematite (α-Fe2O3). This oxidation processes affect the

properties of the support and can lead to morphologic changes, which could

result in loss of magnetism and dispersability.

Even though, and as a consequence of the interesting properties that it

presents, in the last years the number of applications of the magnetite has

11 M. Igartua, P. Saulnier, B. Heurtault, B. Pech, J. E. Proust, J. L. Pedraz, J. P. Benoit, Int. J.

Pharm. 2002, 233, 149-157. 12 a) H. Deng, X. Li, Q. Peng, X. Wang, J. Chen, Y. Li, Angew. Chem. Int. Ed. 2005, 44, 2782-

2785; b) X. Wang, J. Zhuang, Q. Peng, Y. Li, Nature 2005, 437, 121-124. 13 B. Plietker in Iron Catalysis in Organic Chemistry; Wiley VCH, Wienheim, 2008. 14 a) P. S. Sidhu, R. J. Gilkes, R. M. Cornell, A. M. Posner, J. P. Quirk, Clays Clay Miner. 1981,

29, 269-276; b) J. Tang, M. Myers, K. A. Bosnick, L. E. Brus, J. Phys. Chem. B. 2003, 107,

7501-7506.


increased in a wide range of fields such as magnetic fluids,15

data storage,16

and

biomedicine.17

Iron oxide compounds have been traditionally used, by the chemical

industry, as heterogeneous catalysts or as promoters of several chemical

transformations of global importance due to its natural occurrence. Thus, iron

oxides have been involved in the Haber-Bosch process for producing ammonia,18

in the Fischer-Tropsch process for producing synthetic fuel,19

and in the water-

gas shift reaction, among others.20

However, during this century, more efficient

transition metal catalysts have been discovered, with iron compounds being used

not so often. However, during the last decade, iron species have suffered a new

renaissance. This is due to the discovery of new reactivity modes,21

and also to

the use of iron oxides, such magnetite, as magnetically recoverable support for

other metal species.

15 a) R. Hiergeist, W. Andrä, N. Buske, R. Hergt, I. Hilger, U. Richter, W. Kaiser, J. Magn.

Magn. Mater. 1999, 201, 420-422; b) A. Jordan, R. Scholz, K. Maier-Hauff, M. Johannsen, P.

Wust, J. Nadobny, H. Schirra, H. Schmidt, S. Deger, S. Loening, W. Lanksch. R. Felix, J.

Magn. Magn. Mater. 2001, 225, 118-126; c) L.-Y. Zhang, H.-C. Gu, X.-M. Wang, J. Magn.

Magn. Mater. 2007, 311, 228-233. 16 G. Reiss, A. Hütten, Nat. Mater. 2005, 4, 725-726. 17 a) Q. A. Pankhurst, J. Connolly, S. K. Jones, J. Dobson, J. Phys. D: Appl. Phys. 2003, 36, 167-

181; b) D. L. Graham, H. A. Ferreira, P. P. Freitas, Trends Biotechnol. 2004, 22, 455-462; c) T.

Neuberger, B. Schöpf, H. Hofmann, M. Hofmann, B. V. Rechenberg, J. Magn. Magn. Mater.

2005, 293, 483-496; d) J. Gao, H. Gu, B. Xu, Acc. Chem. Res. 2009, 42, 1097-1107; e) A.

Akbarzadeh, M. Samiei, S. Davaran, Nanoscale Res. Lett. 2012, 7, 144. 18 a) G. Ert, Chem. Rec. 2001, 1, 33-45; b) T. Kandemir, M. E. Schuster, A. Senyshyn, M.

Behrens, R. Schlögl, Angew. Chem. Int. Ed. 2013, 52, 12723-12726; c) L. C. A. Oliveira, J. D.

Fabris, M. C. Pereira, Quim. Nova 2013, 36, 123-130; d) K. Grubel, W. W. Brennessel, B. Q.

Mercado, P. L. Holland, J. Am. Chem. Soc. 2014, 136, 16807-16816; e) N. Cherkasov, A. O.

Ibhadon P. Fitzpatrick, Chem. Eng. Process. Process Intensif. 2015, 90, 24-33. 19 a) L. S. Glebov, G. A. Kliger, T. P. Popova, V. E. Shiryaeva, V. P. Ryzhikov, E. V.

Marchevskaya, O. A. Lesik, S. M. Loktev, V. G. Beryezkin, J. Mol. Catal. 1986, 35, 335-348;

b) M. M. Khalaf, H. G. Ibrahimov, E. H. Ismailov, Chem. J. 2012, 2, 118-125; c) A. Y.

Krylova, Kinet. Catal. 2012, 53, 742-746; d) D. W. Lee, B. R. Yoo, J. Ind. Eng. Chem. 2014,

20, 3947-3959. 20 a) C. R. F. Lund, J. E. Kubsh, J. A. Dumesic in Solid State Chemistry in Catalysis, Vol. 279

(Eds.: R. K. Grasselli, J. F. Brazdil), ACS, Washington DC, 1985, pp. 313-338; b) Q. Liu, W.

Ma, R. He, Z. Mu, Catal. Today 2005, 106, 52-56; c) A. Patlolla, E. V. Carino, S. N. Ehrlich,

E. Stavitski, A. I. Frenkel, ACS Catal. 2012, 2, 2216-2223; d) D.-W. Lee, M. S. Lee, J. Y. Lee,

S. Kim, H.-J. Eom, D. J. Moon, K.-Y. Lee, Catal. Today 2013, 210, 2-9; e) X. Yan, H. Guo, D.

Yang, S. Qiu, X. Yao, Curr. Org. Chem. 2014, 18, 1335-1345. 21 a) C. Bolm, J. Legros, J, Le Paih, L. Zani, Chem. Rev. 2004, 104, 6217-6254; b) S. Enthaler, K.

Junge, M. Beller, Angew. Chem. Int. Ed. 2008, 47, 3317-3321; c) A. Correa, O. García

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2730-2744.

http://www.sciencedirect.com/science/article/pii/S0255270115000409




Magnetite nanoparticles have been employed as catalyst in different

reduction reactions overcoming the traditional non catalytic process (Béchamp

reduction), where nitroarenes are treated with stoichiometric amounts of Fe metal

under acidic conditions, generating large amounts of waste. Nitroarenes have

been efficiently transformed to the corresponding anilines employing 20 mol% of

catalyst and hydrazine as hydrogen source.22

This transformation has been further

expanded by implementing an in situ formation of magnetite nanoparticles in a

continuous flow reaction under microwave radiation (Scheme 1). Thus, making

the whole process highly attractive from the environmental point of view, since

the only by-products were N2 and H2O.23

In this case, the magnetite particles

were unambiguously identified as a single phase cubic Fe3O4 by means of XRD

(X-Ray Diffraction) analysis, being the particle size 6±2 nm according to

HRTEM images.

Scheme 1. Reduction of nitroarenes catalysed by in situ formed Fe3O4.

Magnetite nanoparticles have been also employed as recoverable

catalysts for different oxidation reactions.24

The magnetite-catalysed styrene

oxidation to afford benzaldehydes has been studied by different groups. The

particle sizes of magnetite in all the cases ranged from 16 to 22 nm.25

However,

the reactions were not very selective. Other oxidation products, such as the

corresponding epoxide, alcohol and carboxylic acid, among others, were also

obtained. Better results, in terms of yield and selectivity, were achieved for the

oxidation of aldehydes to carboxylic acids.26

In this case, ethyl acetoacetate was

used as 1,3-dicarbonyl compound additive and 20 mol% of Fe3O4 was needed to

obtain good results, with the catalyst being recyclable up to four times without a

decrease in the reaction yield (Scheme 2).

22 S. Kim, E. Kim, B. M. Kim, Chem. Asian. J. 2011, 6, 1921-1925. 23 a) D. Cantillo, M. Baghbanzadeh, C. O Kappe, Angew. Chem. Int. Ed. 2012, 51, 10190-10193;

b) D. Cantillo, M. M. Moghaddam, C. O. Kappe, J. Org. Chem. 2013, 78, 4530-4542. 24 S. Zhang, X. Zhao, H. Niu, Y. Shi, Y. Cai, G. Jiang, J. Hazard. Mater. 2009, 167, 560-566. 25 a) M. J. Rak, M. Lerro, A. Moores, Chem. Commun. 2014, 50, 12482-12485; b) J. Liang, Q.

Zhang, H. Wu, G. Meng, Q. Tang, Y. Wang, Catal. Commun.2004, 5, 665-669; c) D. Guin, B.

Baruwati, S. V. Manorama, J. Mol. Catal. A: Chem. 2005, 242, 26-31. 26 R. Villano, M. R. Acocella, A. Scettri, Tetrahedron Lett. 2014, 55, 2242-2245.


Scheme 2. Oxidation of aldehydes using Fe3O4.

It should be also pointed out that the dehydrogenation of ethylbenzene

derivatives to give the corresponding styrenic compounds has been reported with

little success. Probably, as pointed out by the authors, this was due to a blockage

of the Fe3O4 (111) surface by both the product and the starting material.3a,27

during the last years, numerous multicomponent transformations, in

which the nucleophilic addition to an in situ formed imine represents a key step,

have been published using magnetite as catalyst. One of the first examples

reported was a four-component aza-Sakurai type reaction yielding the

corresponding N-protected amines. After 15th catalytic cycles (Scheme 3), similar

yields were achieved. The remaining magnetite particle was almost the same that

the fresh sample, as revealed by TEM, XRD and BET surface measurements.28

Scheme 3. Four-component aza-Sakurai reaction.

27 A. Schüle, U. Nieken, O. Shekhah, W. Ranke, R. Schlögl, G. Kolios, Phys. Chem. Chem. Phys.

2007, 9, 3619-3634. 28 R. Martínez, D. J. Ramón, M. Yus, Adv. Synth. Catal. 2008, 350, 1235-1240.


Different three-component reactions involving the formation of imines

have been reported. Some examples are the phosphite addition to imines29

(Pudovik-type reaction), Strecker reaction30

and alkyne addition to imines,31

among others.32

In all these cases, the catalyst was recycled several times without

a substantial loss of activity. More recently, the one-pot synthesis of β-acetamido

carbonyl compounds in a four-component reaction has been reported employing

magnetite as catalyst (Scheme 4).33

Scheme 4. Synthesis of β-acetamido carbonyl compounds.

The successful application of magnetite as catalyst for the synthesis of

quinoxalines34

by condensation of 1,2-dicarbonyl compounds and 1,2-diamine

derivatives has been recently published (Scheme 5). Remarkably, the highest

yield was obtained when water was employed as solvent, with the catalyst being

recycled up to five times. It is also important to note that the XRD pattern

confirmed the magnetite structure before and after recycling experiments, with

the particle size being around 20 nm.

Scheme 5. Synthesis of quinoxalines by condensation reaction.

29 B. V. Subba-Reddy, A. Siva-Krishna, A. V. Ganesh, G. G. K. S. Narayana-Kumar,

Tetrahedron Lett. 2011, 52, 1359-1362. 30 M. M. Mojtahedi, M. Saed-Abaee, T. Alishiri. Tetrahedron Lett. 2009, 50, 2322-2325. 31 T. Zeng, W.-W. Chen, C. M. Cirtiu, A. Moores, G. Song, C.-J. Li, Green Chem. 2010, 12, 570-

573. 32 J. Deng, L.-P. Mo, F.-Y. Zhao, L.-L. Hou, Z.-H. Zhang, Green Chem. 2011, 13, 2576-2584. 33 B: Movassagh, F. Talebsereshki, Helv. Chim. Acta 2013, 96, 1943-1947. 34 H.-Y. Lü, S.-H. Yang, J. Deng, Z.-H. Zhang, Aust. J. Chem. 2010, 63, 1290-1296.


The related synthesis of imidazoles35

has also been described. The

reaction has been accomplished in the absence of solvent, being the magnetite

recycled ten times with a slight decrease on the reaction yield.

The aldol condensation followed by a Michael-type addition has been

catalysed by microparticles of magnetite.36

The subsequent dehydration has led to

the synthesis of 4-substituted-4H-pyrans, in a cascade process (Scheme 6).

Scheme 6. Synthesis of 4H-pyrans.

The reaction proceeds smoothly at room temperature in the presence of

acetyl chloride as dehydrating agent. Although a rather high amount of catalyst

was employed (65 mol%) and its recyclability was not possible, it should be

pointed out that the protocol is simple and applicable to a broad range of

substrates. This protocol reduced the previously described reaction times from

weeks to hours. Remarkably, similar results were obtained when Fe2O3 was

employed as catalyst, not discarding Fe(III) species acting as the real catalyst of

the reaction. Shortly after this pioneer report, different research groups have

published the synthesis of several heterocycles with a Knoevenagel condensation

as starting step.37

The C(sp3)-C(sp

2) coupling between terminal alkynes and aryl iodides

(Sonogashira-Hagihara reaction) has been alsodescribed. Only 5 mol% of

recoverable magnetite in ethylene glycol as solvent was required in this late-

transition metal-free process.38

More recently, the synthesis of alkynyl

chalcogenides by reaction between terminal acetylenes and diorganyl

dichalcogenides has been also reported.39

35 N. Montazeri, K. Pourshamsian, H. Rezaei, M. Fouladi, S. Rahbar, Asian J. Chem. 2013, 25,

3463-3466. 36 R. Cano, D. J. Ramón, M. Yus, Synlett, 2011, 14, 2017-2020. 37 a) B. Karami, S. J. Hoseini, K. Eskandari, A. Ghasemi, H. Nasrabadi, Catal. Sci. Technol.

2012, 2, 331-338; b) M. Nikpassand, L. Zare, T. Shafaati, S. Shariati. Chin. J. Chem. 2012, 30,

604-608; c) M. Kidwai, A. Jain, S. Bhardwaj, Mol. Divers. 2012, 16, 121-128. 38 H. Firouzabadi, N. Iranpoor, M. Gholinejad, J. Hoseini, Adv. Synth. Catal. 2011, 353, 125-132. 39 M. Godoi, D. G. Liz, E. W. Ricardo, M. S. T. Rocha, J. B. Azeredo, A. L. Braga, Tetrahedron

2014, 70, 3349-3354.


The reaction between different acyl chlorides and acetylenic compounds

using nanoparticles of magnetite as catalyst has been studied, producing in one

hour the corresponding β-chlorovinyl ketones in good yields and moderate to

excellent Z-selectivity (Scheme 7). The reaction products were further elaborated

to the corresponding furans using iridium oxide impregnated on magnetite (IrO2-

Fe3O4) catalyst. In addition, cyclopenten-2-ones and cyclopenta[a]naphtalen-1-

ones can be obtained in high yields in a Nazarov-type cyclization, by choosing

the appropriate acyl chloride. Unfortunately, the catalyst could not be recycled.40

Scheme 7. Addition of acyl chlorides to alkynes using Fe3O4 NPs.

The hydrogen autotransfer process is a high selective, environmentally

friendly and atom-economic process for the synthesis of monalkylated amines.41

However, the employed catalysts are normally based on expensive transition

metals, which are sometimes toxic and difficult to handle. The use of magnetite

nanoparticles for the monoalkylation of anilines, and other electron-poor

heteroaromatic amines, using benzylic alcohols as electrophiles has been reported

(Scheme 8). The catalyst was recycled eight times with only slight variations in

yields.42

This high recyclability could arise from the fact that no apparent

sinterization occurred in the process, since no significant differences were

observed between the fresh catalyst and the recycled one, according to TEM

images and BET area measurement experiments.

40 R. Cano, M. Yus, D. J. Ramón, Tetrahedron 2013, 69, 7056-7065. 41 For different reviews , see: a) G. Guillena, D. J. Ramón, M. Yus, Angew. Chem. Int. Ed. 2007,

46, 2358-2364; b) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth. Catal.

2007, 349, 1555-1575; c) T. D. Nixon, M. K. Whittlesey, J. M. J. Williams, Dalton Trans.

2009, 753-762; d) K.-I. Fujita, R. Yamaguchi in Iridium Complexes in Organic Synthesis (Eds.:

L. A. Oro, C. Claver), Wiley-VCH, Weinheim, 2009, pp 107-143; e) G. E. Dobereiner, R. H.

Crabtree, Chem. Rev. 2010, 110, 681-703; f) G. Guillena, D. J. Ramón, M. Yus, Chem. Rev.

2010, 110, 1611-1641; g) R. Yamaguchi, K.-I. Fujita, M. Zhu, Heterocycles 2010, 81, 1093-

1140; h) F. Alonso, F. Foubelo, J. C. González-Gómez, R. Martínez, D. J. Ramón, P. Riente,

M. Yus, Mol. Divers. 2010, 14, 411-424; i) A. J. A. Watson, J. M. J. Williams, Science 2010,

329, 635-636; j) H. Kimura, Catal. Rev. Sci. Eng. 2011, 53, 1-90; k) S. Bähn, S. Imm, L.

Neubert, M. Zhang, H. Neumann, M. Beller, ChemCatChem 2011, 3, 1853-1864; l) D.

Hollmann, ChemSusChem 2014, 7, 2411-2413; m) Y. Obora, ACS Catal. 2014, 4, 3972-3981;

n) K.-I. Shimizu, Catal. Sci. Technol. 2015, 5, 1412-1427. 42 R. Martínez, D. J. Ramón, M. Yus, Org. Biomol. Chem. 2009, 7, 2176-2181.


Scheme 8. Amine alkylation by a hydrogen autotransfer.

Finally, it is also worth mentioning that magnetite has been used in

several studies as reusable initiating system for living cationic or radical

polymerizations.43

2. MAGNETITE AS CATALYST SUPPORT

Magnetite has been employed not only as an excellent catalyst, as it has

been mentioned previously, but also as a support for a great variety of catalysts.

Numerous approaches in order to introduce metal on a solid support surface have

been reported.44

The first advantage to use magnetite as support it is the facility

of isolation that this material shows due to the superparamagnetic behaviour.

Different methodologies have been developed to support metals as catalysts on

the magnetite surface.8

2.1. COATED CATALYST

Coating45

of metal nanoparticles is a commonly employed procedure in

material science. Silica has been chosen from all the different oxide-based

coatings to support magnetite nanoparticles due mainly to economy reasons, as

well as its high stability under different conditions. The procedure is based on the

formation of a SiO2 layer on the magnetite surface, which is normally generated

employing the sol-gel strategy, and subsequent formation of a second layer

containing particles of the active metal specie onto the SiO2 coating (Figure 3).

43 a) A. Kanazawa, S. Kanaoka, S. Aoshima, J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 916-

926; b) A. Kanazawa, S. Kanaoka, N. Yagita, Y. Oaki, H. Imai, M. Oda, A. Arakaki, T.

Matsunaga, S. Aoshima, Chem. Commun. 2012, 48, 10904-10906; c) A. Kanazawa, K. Satoh,

M. Kamigaito, Macromolecules 2011, 44, 1927-1933. 44 a) J.-F. Lambert, M. Che, J. Molec. Catal. A 2000, 162, 5-18; b) Supported Metals in Catalysis

(Eds.: J. A. Anderson, M. Fernández-García), Imperial College Press, London, 2005; c)

Catalyst Preparation, Science and Engineering (Eds.: J. Regalbuto), CRC Press, Taylor &

Francis Group, Boca Ratón, 2007. 45 M. B. Gawande, Y. Monga, R. Zboril, R. K. Sharma, Coord. Chem. Rev. 2015, 288, 118-143.


This procedure has been developed in order to prevent the problems associated

with the use of ‘naked’ magnetite, especially regarding the oxidation issues.

Figure 3. General scheme for a coated catalyst: Cat-SiO2@Fe3O4.

Different metal catalysts have been prepared through this methodology

and the obtained recoverable materials have been used in a wide range of

catalytic reactions, including oxidation,46

hydrogenation,47

asymmetric

synthesis,48

hydration,49

Knoevenagel condensation,50

reductions,51

and

biocatalytic reactions.52

For instance, the Pd-SiO2@Fe3O4 catalyst53

has been used in the Suzuki

type cross-coupling reaction of organoboronic acids with alkynyl bromides. The

C-C bond formation54

could be performed with only 0.5 mol% of palladium

loading and it could be recycled up to 16 times without significant loss of

catalytic activity (Scheme 9).

46 a) M. J. Jacinto, O. H. C. F. Santos, R. F. Jardim, R. Landers, L. M. Rossi, Appl. Catal. A: Gen.

2009, 360, 177-182; b) J. Wegner, S. Ceylan, C. Friese, A. Kirschning, Eur. J. Org. Chem.

2010, 4372-4375. 47 a) D. Guin, B. Baruwati, S. V. Manorama, Org. Lett. 2007, 9, 1419-1421; b) L. M. Rossi, F. P.

Silva, L. L. R. Vono, P. K. Kiyohara, E. L. Duarte, R. Itri, R. Landers, G. Machado, Green

Chem. 2007, 9, 379-385. 48 B. Panella, A. Vargas, A. Baiker, J. Catal. 2009, 261, 88-93. 49 R. B. N. Baig, R. S. Varma, Chem. Commun. 2012, 48, 6220-6222. 50 R. K. Karma, Y. Monga, A. Puri, Catal Commun. 2013, 35, 110-114. 51 K. S. Shin, Y. K. Cho, J.-Y. Choi, K. Kim, Appl. Catal. A: Gen. 2012, 413-414, 170-175. 52 S. Wang, Z. Zhang, B. Liu, J. Li, Catal. Sci. Technol. 2013, 3, 2104-2112. 53 X. Zhang, P. Li, Y. Ji, L. Zhang, L. Wang, Synthesis, 2011, 2975-2983. 54 Z. Wang, P. Xiao, B. Shen, N. He, Colloid Surface A 2006, 276, 116-121.


Scheme 9. Suzuki cross-coupling catalysed by Pd-SiO2@Fe3O4.

2.2. GRAFTED CATALYSTS

Another widespread strategy to support metals on magnetite is based on

the grafting of active metal species, using tailored ligands which are able to bind

effectively to the magnetite surface. In addition, when this procedure is used, the

ligands are supposed to protect the magnetite surface against oxidation,

conferring stability to the iron oxide particles (Figure 4).

Figure 4. General scheme for a grafted catalyst.

A great variety of catalysts, using different metals, have been prepared

with this methodology. These catalysts have been used to perform some reactions

such as, atom transfer radical polymerization,55

hydration,56

oxidations,57

C-C

bond formation through Suzuki coupling58

or o-allylation,59

amoung others.60

55 S. Ding, Y. Xing, M. Radosz, Y. Shen, Macromolecules 2006, 39, 6399-6405. 56 V. Polshettiwar, R. S. Varma, Chem. Eur. J. 2009, 15, 1582-1586. 57 V. Polshettiwar, R. S. Varma, Org. Biomol. Chem. 2009, 7, 37-40. 58 Y.-Q. Zhang, X.-W. Wei, R. Yu, Catal. Lett. 2010, 135, 256-262. 59 A. Saha, J. Leazer, R. S. Varma, Green Chem. 2012, 14, 67-71. 60 U. Laska, C. G. Frost, P. K. Plucinski, G. J. Price, Catal. Lett. 2008, 122, 68-75.


For instance, the hydrogenation reaction of alkyne and the transfer

hydrogenation of ketones could be carried out using nickel grafted catalyst,61

obtaining high yields. Due to the magnetic properties of the catalyst, it could be

recycled five times without any change in its activity (Scheme 10).

Scheme 10. Ni grafted catalyst for hydrogenation and hydrogen transfer

reaction.

2.3. COATED-GRAFTED CATALYST

A third way of immobilizing ctalysts over magnetite is preferred by

many other research groups. This procedure can be considered as a combination

of the two aforementioned methods. Thus, onto a SiO2-coated magnetite, metal

species are grafted by using a ligand bearing a triethoxysilane derivative, capable

to bind the silica (Figure 5). In this way, an effective protection of the magnetite

is obtained, along with the introduction of specific anchoring metal points.62

61 V. Polshettiwar, B. Baruwati, R. S. Varma, Green Chem. 2009, 11, 127-131. 62 a) A. Schätz, O. Reiser, W. J. Stark, Chem. Eur. J. 2010, 16, 8950-8967; b) K. V. S. Ranganath,

F. Glorius, Catal. Sci. Tehcnol. 2011, 1, 13-22; c) V. Polshettiwar, R. Luque, A. Fihri, H. Zhu,

M. Bouhrara, J.-M. Basset, Chem. Rev. 2011, 111, 3036-3075; d) D. Zhang, C. Zhou, Z, Sun,

L.-Z. Wu, C.-H. Tung, T. Zhang, Nanoscale 2012, 4, 6244-6255; e) S. Liu, S.-Q. Bai, Y.

Zheng, K. W. Shah, M.-Y. Han, ChemCatChem 2012, 4, 1462-1484; f) R. B. Baig, R. S.

Varma, Chem. Commun. 2013, 49, 752-770; g) H.-J. Xu, X. Wan, Y. Geng, X.-L. Xu, Curr.

Org. Chem. 2013, 17, 1034-1050; h) M. B. Gawande, A. K. Rathi, P. S. Branco, R. S. Varma,

Appl. Sci. 2013¸ 3, 656-674; i) L. M. Rossi, N. J. S. Costa, F. P. Silva, R. Wojcieszak, Green

Chem. 2014, 16, 2906-2933; j) M. B. Gawande, R. Luque, R. Zboril, ChemCatChem 2014, 6,

3312-3313; k) Q. M. Kainz, O. Reiser, Acc. Chem. Res. 2014, 47, 667-677.


Figure 5. General scheme for a coated-grafted catalyst.

Using the aforementioned coated-grafted catalysts, important catalytic

applications have been performed including hydroformylation,63

reduction,64

hydrogenations,65

CO oxidation,66

C-C bond formation,67

water gas shift

reaction,68

CO2 and biomass conversion,69

amoung others.

For instance, the cross-coupling reaction between acrylic acid and

iodobenzene has been performed using coated and grafted Pd catalyst70

affording

good yields (Scheme 11). The catalytic activity decreased after five cycles due to

the aggregation into big particles of the catalyst.

63 R. Abu-Reziq, H. Alper, D. Wang, M. L. Post, J. Am. Chem. Soc. 2006, 128, 5279-5282. 64 a) J. Ge, T. Huynh, Y. Hu, Y. Yin, Nano Lett. 2008, 8, 931-934; b) Y. Deng, Y. Cai, Z. Sun, J.

Liu, C. Liu, J. Wei, W. Li, C. Liu, Y. Wang, D. Zhao, J. Am. Chem. Soc. 2010, 132, 8466-8473. 65

a) R. Abu-Reziq, D. Wang, M. Post, H. Alper, Adv. Synth. Catal. 2007, 349, 2145-2150; b) M.

J. Jacinto, P. K. Kiyohara, S. H. Masunaga, R. F. Jardim, L. M. Rossi, Appl. Catal. A-Gen.

2008, 338, 52-57; c) M. J. Jacinto, F. P. Silva, P. K. Kiyohara, R. Landers, L. M. Rossi,

ChemCatChem 2012, 4, 698-703. 66 H.-P. Zhou, H.-S. Wu, J. Shen, A.-X. Yin, L.-D. Sun, C.-H. Yan, J. Am. Chem. Soc. 2010, 132,

4998-4999. 67 a) G. Lv, W. Mai, R. Jin, L. Gao, Synlett 2008, 9, 1418-1422; b) Q. Du, W. Zhang, H. Ma, J.

Zheng, B. Zhou, Y. Li, Tetrahedron, 2012, 68, 3577-3584. 68 M. Shekhar, J. Wang, W.-S. Lee, W. D. Williams, S. M. Kim, E. A. Stach, J. T. Miller, W. N.

Delgass, F. H. Ribeiro, J. Am. Chem. Soc. 2012, 134, 4700-4708. 69 D. Preti, C. Resta, S. Squarcialupi, G. Fachinetti, Angew. Chem. Int. Ed. 2011, 50, 12551-

12554. 70 Z. Wang, B. Shen, Z. Aihua, N. He, Chem. Eng. J. 2005, 113, 27-34.


Scheme 11. Coated and grafted Pd-catalysed cross-coupling reaction.

2.4. CO-PRECIPITATION AND DUMBELL-LIKE COMPOSITES

Although they differ in the synthesis and structure, co-precipitation and

dumbell-like composites can be considered as a magnetite possessing a metal

catalyst domain in its structure. For the co-precipitation strategy, two metal salts

are precipitated together at basic pH. A spinel structure is formed after

evaporation of the solvent and treatment at high temperatures. The spinel

structure has different metal oxide domains normally located in a multiple region

within the nanoparticles. In the extreme case, all positions of Fe(II) are

substituted by different transition metal cation(II), leading to the ferrites.71

For

the dumbell-like cases, the domain is perfectly located in a specific region, and

can be conceived as a metal nanoparticle which has grown onto the magnetite

surface. In fact, most of the dumbbell-like metal nanoparticles are produced by

precipitation of a metal salt onto the surface of a preformed magnetite

nanoparticle (Figure 6).

Figure 6. General scheme of a co-precipitation or dumbbell-like catalyst

M/Fe3O4.

Different metal catalysts have been prepared through this methodology.

Catalyst Fe0/Fe3O4

72 has been used in the treatment of waste-water using the

71 a) J. Lee, S. Zhang, S. Sun, Chem. Mater. 2013, 25, 1293-1304; b) A. S. Burange, S. R. Kale,

R. Zboril, M. B. Gawande, R. V. Jayaram, RSC Adv. 2014, 4, 6597-6601; c) D. Gherca, A. Pui,

V. Nica, O. Caltun, N. Cornei, Ceram. Int. 2014, 40, 9599-9607; d) A. Goyal, S. Bansal, S.

Singhal, Int. J. Hydrogen Energy 2014, 39, 4895-4908. 72 a) F. C. C. Moura, M. H. Araujo, R. C. C. Costa, J. D. Fabris, J. D. Ardisson, W. A. A.

Macedo, R. M. Lago, Chemosphere 2005, 60, 118-1123; b) F. C. C. Moura, G. C. Oliveira, M.

H. Araujo, J. D. Ardisson, W. A. A. Macedo, R. M. Lago, Appl. Catal. A-Gen. 2006, 307, 195-

204.


Fenton oxidation process. On the other hand, catalyst Ni/Fe3O473

has been used in

the synthesis of different N-substituted carbamates (Scheme 12). This catalyst

could be recycled five times with stable activity.

Scheme 12. Synthesis of N-substituted carbamates.

Magnetic Cu/Fe3O4 nanoparticles have been used in the Huisgen

cycloaddition in water yielding triazoles.74

The catalyst could be recycled five

times with no appreciable decrease in yield.

Using this methodology different Pd/Fe3O475

and Pt/Fe3O476

catalysts

have been prepared. The first one was used to perform the thermal decomposition

of methanol to give CO/CO2 and CH4, and in the Suzuki-Miyaura coupling

reaction. The second one was used in the hydrogenation reaction of nitroarenes

and alkenes. To perform the hydrogenation reaction, other catalysts like

Au/Fe3O477

and Rh/Fe3O478

were used, using siloxanes and hydrazine as source of

hydrogen, respectively. In both cases, the catalyst was recycled without any loss

of activity.

73 a) Z. Li, Y. Deng, B. Shen, W. Hu, Mater. Sci. Eng. 2009, 164, 112-115; b) J. Shang, X. Guo,

F. Shi, Y. Ma, F. Zhou, Y. Deng, J. Catal. 2011, 279, 328-336. 74 R. Hudson, C.-J. Li, A. Moores, Green Chem. 2012, 14, 622-624. 75 a) Y. Usami, K. Kagawa, M. Kawazoe, Y. Matsumura, H. Sakurai, M. Haruta, Appl. Catal. A:

Gen. 1998, 171, 123-130; b) K. Mori, Y. Kondo, H. Yamashita, Phys. Chem. Chem. Phys.

2009, 11, 8949-8954. 76 a) A. Figuerola, A. Fiore, R. D. Corato, A. Falqui, C. Giannini, E. Micotti, A. Lascialfari, M.

Corti, R. Cingolani, T. Pellegrino, P. D. Cozzoli, L. Manna, J. Am. Chem. Soc. 2008, 130,

1477-1487; b) C. Wang, H. Daimon, S. Sun, Nano Lett. 2009, 9, 1493-1496; c) K. Mori, N.

Yoshioka, Y. Kondo, T. Takeuchi, H. Yamashita, Green Chem. 2009, 11, 1337-1342. 77 a) H. Yu, M. Chen, P. M. Rice, S. X. Wang, R. L. White, S. Sun, Nano Lett. 2005, 5, 379-382;

b) H. Yin, C. Wang, H. Zhu, S. H. Overbury, S. Sun, S. Dai, Chem. Commun. 2008, 4357-

4359; c) Y. Lee, M. A. García, N. A. F. Huls, S Sun, Angew. Chem. Int. Ed. 2010, 49, 1271-

1274; d) J. S. Beveridge, M. R. Buck, J. F. Bondi, R. Misra, P. Schiffer, R. E. Schaak, M. E.

Williams, Angew. Chem. Int. Ed. 2011, 50, 9875-9879; e) S. Park, I. S. Lee, J. Park, Org.

Biomol. Chem. 2013, 11, 395-399. 78 Y. Jang, S. Kim, S. W. Jun, B. H. Kim, S. Hwang, I. K. Song, B. M. Kim, T. Hyeon, Chem.

Commun. 2011, 47, 3601-3603.


Furthermore, the Au/Fe3O4 catalyst has been used in the oxygen

reduction reaction79

and CO oxidation.80

The epoxidation of alkenes was performed with the Ag/Fe3O481

catalyst

obtaining after 13 hours of reaction full conversion of the starting material and 84

% yield of styrene epoxide. After five reaction cycles no deactivation was

observed.

The Ru/Fe3O482

catalyst was obtained through the co-precipitation

methodology and after that was used in the coupling reaction between alcohols

and sulphonamides through the hydrogen autotransference mechanism.

2.5. IMPREGNATED CATALYST

The impregnation method83

is one of the oldest ways employed to deposit

metal catalysts on the surface of inorganic materials. From all the possible ways

to immobilize or support a metal in the surface of a particle,44

the impregnation is

the most straightforward, simple and less expensive protocol. It consists either in

the evaporation or in the precipitation of a solution which contains the metal salt

or metal oxide precursors and the desired support, followed by an ulterior drying

process. Although the procedure is simple, the particle distribution and

morphology of the supported catalyst is governed by various factors such as the

possible interactions between the support and the metal specie, the porosity of the

support, the pH, the viscosity of the solution and the drying rates (Figure 7).

Metal-support interactions are frequently invoked to explain the

enhanced catalytic activity of metal nanoparticles dispersed over reducible metal

oxide supports, for some cases the atomic surface scale pathway is known.84

79 Y. Lee, A. Loew, S. Sun, Chem. Mater. 2010, 22, 755-761. 80 B. Wu, H. Zhang, C. Chen, S. Lin, N. Zheng, Nano Res. 2009, 2, 975-983. 81 a) D.-H. Zhang, G.-D. Li, J.-X. Li, J.-S. Chen, Chem. Commun. 2008, 3414-3416; b) S. Peng,

C. Lei, Y. Ren, R. E. Cook, Y. Sun, Angew. Chem. Int. Ed. 2011, 50, 3158-3163. 82 F. Shi, M. K. Tse, S. Zhou, M.-M. Pohl, J. Radnik, S. Hübner, K. Jähnisch, A. Brückner, M.

Beller, J. Am. Chem. Soc. 2009, 131, 1775-1779. 83 M. B. Gawande, P. S. Branco, R. S. Varma, Chem. Soc. Rev. 2013, 42, 3371-3393. 84 R. Bliem, J. van der Hoeven, A. Zavodny, O. Gamba, J. Pavelec, P. E. de Jongh, M. Schmid, U.

Diebold, G. S. Parkinson, Angew. Chem. Int. Ed. 2015, 54, 13999-14002.


Figure 7. General scheme for an impregnated catalyst: Cat-Fe3O4.

Different metal oxides derived from cobalt, nickel, copper, niobium,

molybdenum, rhodium, palladium, cerium, tungsten, osmium, iridium, platinum,

gold, amoung others,85

have been impregnated on magnetite surface and used to

perform a great variety of organic transformations. In this chapter, only a few

examples of them will be discussed. In order to avoid avoid a too long chapter,

we will focus this section on the catalysts which are related to the ones used in

the thesis studies.

2.5.1 COBALT CATALYST

The use of cobalt in organic synthesis has been traditionally linked to

reactions involving carbonylations, π-bonds activation and radicals. However,

recently, the use of cobalt catalysts in organic transformations such as coupling

reactions, C-H bond activations, among others, has experimented a significant

growth. This is an alternative to other noble transition metals. However, despite

the multiple applications of cobalt complexes in organic synthesis and their

general instability, there are few examples in literature of impregnated cobalt

species onto magnetite as catalysts as far as we know.

One of the interesting reports deals with the use of a Co3O4-Fe3O4

obtained by wet impregnation in basic media and subsequent reduction of the

corresponding oxide. This catalyst was used for the oxidation of alcohols, mainly

benzylic ones, to the corresponding carbonyl compounds (Scheme 13). For this

transformation, TBHP was the chosen oxidant, with products being obtained, at

80 ºC and after six hours of reaction, with yields between 79 and 94 %. Notably,

the catalyst was recycled up to seven times with a slight loss of activity and

85 a) D. J. Ramón, Johnson Matthey Technol. Rev. 2015, 59, 120-122; b) A. Baeza, G. Guillena,

D. J. Ramon, ChemCatChem 2016, 8, 49-67.


negligible metal leaching.86

The TEM image of the catalyst presented a spherical

morphology of the nanoparticles with an average diameter ranging from 10 to 30

nm. The active catalytic specie was identified by XPS as Co3O4, excluding the

existence of CoO and Co(OH)2.

Scheme 13. Oxidation of alcohols catalysed by Co3O4-Fe3O4.

2.5.2 NICKEL CATALYST

Despite the number of applications of nickel complexes in homogeneous

catalysis, there are only a two studies where the use of impregnated nickel

species onto magnetite surfaces has been reported so far.

A NiO-Fe3O4 catalyst hs been applied to the reduction of nitroarenes and

carbonyl compounds using glycerol as the hydrogen-transfer reagent. Different

nitroarenes and aromatic carbonyl compounds have been successfully

hydrogenated using Ni-Fe3O4 magnetic nanoparticles (8.85 mol%) in glycerol

and in basic media at 80 ºC. The corresponding amines and alcohols have been

obtained in high yields with short reaction times (Scheme 14). Remarkably, even

halogen substituted arenes are hydrogenated without observing any

dehalogenation process. The study of the surface composition by XPS revealed

that the impregnated Ni species on the magnetite correspond to NiO, despite the

authors claimed to obtain Ni(0) nanoparticles by using a reducing agent after the

impregnation methodology. The morphology observed by TEM images revealed

spherical particles with an average size range of 15-30 nm. Finally, the catalyst

has shown high performance even after eight cycles. Applying the hot filtration

method, metal leaching was discarded.87

86 M. B. Gawande, A. Rathi, I. D. Nogueira, C. A. A. Ghumman, N. Bundaleki, O. M. N. D.

Teodoro, P. S. Branco, ChemPlusChem 2012, 77, 865-871. 87 M. B. Gawande, A. Rathi, P. S. Branco, I. D. Nogueira, A. Velhinho, J. J. Bundaleski, O. M. N.

Teodoro, Chem Eur. J. 2012, 18, 12628-12632.


Scheme 14. Transfer hydrogenation of nitroarenes and carbonyl compounds

catalysed by NiO-Fe3O4.

2.5.3 COPPER CATALYST

Copper salts and complexes are one of the most employed catalysts in

Organic Synthesis. This is due to the availability of copper compounds and their

versatility. They have proven to be high efficient catalysts for a wide variety of

organic transformations. Therefore, copper impregnated magnetite could be a

recyclable catalyst, prone to be tested in a large variety of organic reactions.

In 2010, the first study about the use of impregnated copper on magnetite

as catalysts for a three-component acetylene-Mannich reaction to give

propargylamines was reported (Scheme 15). The reaction took place in only three

hours at 120 ºC, giving the expected amines in quantitatively yields. The catalyst

was recycled up to ten-fold without losing its initial activity. Studies about a

possible degradation of the catalyst under the reaction conditions, by means of

the determination of BET surface area and TEM images, concluded that no

significant sinterization process occurred.88

Scheme 15. Acetylene-Mannich reaction catalysed by CuO-Fe3O4.

88 M. J. Aliaga, D. J. Ramón, M. Yus, Org. Biomol. Chem. 2010, 8, 43-46.


The borylation of double bonds could be carried out using the same

catalyst. After an exhaustive search for the optimal reaction conditions, it was

observed that only 2.5 mol% for the recyclable catalyst was enough to effectively

promote the addition of alkoxy diboron reagents to both electron-rich and

electron-poor olefins (Scheme 16). As expected, the obtained yields with

electron-poor olefins were higher. The performance of the catalyst remained high

(ranging between 88-99 %) after eight recycling experiments.89

Scheme 16. Borilation of olefins catalysed by CuO-Fe3O4.

The same impregnated CuO on magnetite catalyst was subsequently used

for other organic transformations. The synthesis of benzofurans through a

domino Sonogashira-cyclization protocol, by reaction of 2-iodophenol and

different alkynes has been reported. The corresponding heterocycles were

synthetized in good to excellent yields (Scheme 17). The catalyst employed was

reused up to ten times with the results remaining almost constant. In addition, the

hot test filtration experiment excluded a possible metal leached catalysed

process. Importantly, neither the reaction catalysed by Fe3O4, nor by CuO took

place. These results can also reveal the importance of the CuO nanoparticles size,

which are far more active than the bulk oxide, as well as the presence of a

possible synergistic effect between both metal oxides.90

89 R. Cano, D. J. Ramón, M. Yus, J. Org. Chem. 2010, 75, 3458-3460. 90 R. Cano, M. Yus, D. J. Ramón, Tetrahedron 2012, 68, 1393-1400.


Scheme 17. Domino Sonogashira-cyclization reaction catalysed by CuO-Fe3O4.

A similar catalyst has been successfully applied for the arylation of

phenols with aryl halides. Good to high yields were achieved using bromo or

iodoarenes. However, poor yields were obtained using chloroarenes as reagents

(Scheme 18). These results were maintained for 3 cycles. Although the activity of

the catalyst decreased notably after the third cycle, the spherical shape remained

almost unaltered.91

Scheme 18. Arylation of phenols catalysed by CuO-Fe3O4.

2.5.4 PALLADIUM CATALYST

The enormous amount of applications and organic transformations in

which homogeneous palladium species are involved, together with the high cost

of the palladium compounds has led to a plethora of scientific work about the

synthesis and use of supported palladium nanoparticles.

It is not surprising that several studies dealing with the synthesis and use

of supported palladium species on magnetite nanoparticles have been reported.

The first one describes the use of a palladium(0) supported nanoparticles for the

carbonylative Sonogashira coupling reaction of aryl iodides with terminal

alkynes in a phosphine-free transformation. The employed catalyst was prepared

by the classical impregnation methodology. The process normally rendered the

91 Y.-P. Zhang, A.-H. Shi, Y.-S. Yang, C.-L. Li, Chin. Chem. Lett. 2014, 25, 141-145.


coupling products in high yields using only 0.2 mol% of catalyst. Its recycling

was possible up to seven times with a slight loss of activity.92

Later on, in 2010, an important breakthrough in the use of impregnated

metal species on magnetite was reported. The work describes the use of chiral-

carbene decorated Pd-Fe3O4 catalyst for the asymmetric α-arylation of cyclic

ketones (Scheme 19).93

Scheme 19. Enantioselective arylation of ketones catalysed by Chiral NHC-Pd-

Fe3O4.

Although the reached yields and enantiomeric excess were moderate to

good, this challenging transformation represents the first and unique example in

which impregnated metal specie has been employed in an enantioselective

process.94

The heterogeneous nature of the catalyst was demonstrated by XPS,

ATR-IR, SEM-EDX and TEM analyses. The catalyst was recycled five times

without a significant decrease in yield and enantioselectivity.

Shortly after, the use of PdO-Fe3O4 catalyst for the multicomponent

reductive amination reaction was also reported. Under the optimised reaction

conditions, several primary amines were obtained in high yields at room

temperature independently of the nature of the amine employed. The reaction

became sluggish when poor nucleophilic amines were employed, being necessary

harsh reaction conditions and longer reaction times (Scheme 20). Notably, this

catalytic system also turned out to be effective in the reductive amination process

92 J. Liu, X. Peng, W. Sun, Y. Zhao, C. Xia, Org. Lett. 2008, 10, 3933-3936. 93 K. V. S. Ranganath, J. Kloesges, A. H. Schäfer, F. Glorius, Angew. Chem. Int. Ed. 2010, 49,

7786-7789. 94 R. B. N. Baig, M. N. Nadagouda, R. S. Varma, Coord. Chem. Rev. 2015, 287, 137-156.


when employing secondary amines. However, the catalyst recycling was

unsuccessful and after the third use the yield dropped dramatically. A possible

explanation arises from the fact that the exposure of the catalyst to a reducing

media produces a Pd(II) reduction to the less active and more prone to leach

Pd(0) nanoparticles.95

Scheme 20. Reductive amination reaction catalysed by PdO-Fe3O4.

The same impregnated catalyst has been also reported for the ligand-free

Suzuki-Miyaura cross-coupling reaction.96

The reaction works especially well for

electron-rich aryl iodides and a wide variety of boronic acids. However, the

catalyst recycling was not possible probably due to the poisoning as consequence

of the different salt adsoption on the metal surface.

Finally, PdO-Fe3O4 or Pd-Fe3O4 catalysts have been also employed for

other interesting transformations such as, the Buchwald-Hartwing amination

reaction,97

the hydrogenation of acetylenic derivatives,98

or nitrocompounds,99

and the selective dehalogenation of organic compounds from aqueous wastes.100

95 R. Cano, M. Yus, D. J. Ramón, Tetrahedron 2011, 67, 8079-8085. 96 R. Cano, D. J. Ramón, M. Yus, Tetrahedron 2011, 67, 5432-5436. 97 S. Sá, M. B. Gawande, A. Velhinho, J. P. Veiga, N. Bundaleski, J. Trigueiro, A. Tolstogouzov,

O. M. N. D. Teodoro, R. Zboril, R. S. Varma, P. S. Branco, Green Chem. 2014, 16, 3494-3500. 98 F. Parra da Silva, L. M. Rossi, Tetrahedron 2014, 70, 3314-3318. 99 K. Jiang, H.-X. Zhang, Y.-Y. Yang, R. Mothes, H. Lang, W.-B. Cai, Chem. Commun. 2011, 47,

11924-11926. 100 H. Hilderbrand, K. Mackenzie, F.-D. Kopinke, Appl. Catal. B: Env. 2009, 91, 389-396.

RESULTS

CHAPTER I

Reactions performed using

nanoparticles of impregnated

Cobalt(II) Oxide on Magnetite

47 Chapter I. Reactions performed by nanoparticles of Cobalt

1. HYDROACYLATION REACTION OF AZODICARBOXYLATES

1.1 INTRODUCTION

The C-N bond formation is one of the most important reactions in

Organic Synthesis, which has found a wide application in the synthesis of many

organic substances, including natural products.101

This type of bond has been constructed using polar, radical and transition

metal-catalysed reactions,102

with dialkyl azodicarboxylate compounds being

used during the last few decades to perform this type of transformations.

The synthesis of dialkyl azodicarboxylate compounds, that normally are

orange liquids, can be carried out using the corresponding chloroformate and

hydrazine followed by oxidation of the resulting substituted hydrazine

dicarboxylate with chlorine. (Scheme 21).103

Scheme 21. Synthesis of azodicarboxylates.

These reagents are sensitive to heat and light and should be stored in a

dark container under refrigerated conditions. Azodicarboxylates contain a vacant

orbital and a strong electron-withdrawing group which contributes to make them

good nucleophilic acceptors, favouring their reaction. Several types of reactions

(Scheme 22), such as the zwitterion intermediate reaction, the electrophilic α-

amination of carbonyl compounds, the C-H activation at the α-position of amines

101 a) O. Mitsunobu in Comprehensive Organic Synthesis, Vol 6 (Eds.: B. M. Trost), Pergamon

Press, Oxford, 1991, pp. 65-101; b) O. Mitsunobu in Comprehensive Organic Synthesis, Vol 6

(Eds.: B. M. Trost), Pergamon Press, Oxford, 1991, pp. 381-411; c) C. M. Manson, A. D.

Hobson in Comprehensive Organic Functional Group Transformations, Vol 2 (Eds.: A. R.

Katritzky, O. Meth-Cohn, C. W. Rees), Pergamon, Cambridge, 1995, pp. 297-332; d) P. D.

Bailey, I. D. Collier, K. M. Morgan in Comprehensive Organic Functional Group

Transformations, Vol 5 (Eds.: A. R. Katritzky, O. Meth-Cohn, C. W. Rees), Pergamon,

Cambridge, 1995, pp 257-307. 102 a) J. F. Hartwig, Science 2002, 297, 1653; b) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew.

Chem. Int. Ed. 2004, 43, 3368-3398; c) V. Nair, R. S. Menon, A. R. Sreekanth, N. Abhilash, A.

T. Biju, Acc. Chem. Res. 2006, 39, 520-530; d) R. Matsubara, S. Kobayashi, Acc. Chem. Res.

2008, 41, 292-301. 103 N. Rabjohn, Org. Syntheses, Coll. 1955, 3, 375.

Chapter I. Reactions performed by nanoparticles of Cobalt 48

and ethers, and the ene-type reaction with olefins have been extensively studied

using these compounds.104

However, the hydroacylation reaction with aldehydes

has been less considered.105

Azodicarboxylates

hydroacylation of

aldehydes

α-amination carbonilic

compounds

C-H activation α-position

amine and ethers

Scheme 22. Reaction involving azodicarboxylates.

104 V. Nair, A. T. Mathew, B. P. Babu, Chem. Asian J. 2008, 38, 810-820. 105 a) C. González-Rodríguez, M. C. Willis, Pure Appl. Chem. 2011, 83, 577-585; b) P. W. N. M.

van Leeuwen in Science of Synthesis: Stereoselective Synthesis, Vol. 1 (Eds.: J. G. de Vries),

Thieme, Stuttgart, 2011, pp. 409-475; c) S. Brase, Nachr. Chem. 2012, 60, 265-299; d) J. C.

Leung, M. J. Krische, Chem. Sci. 2012, 3, 2202-2209.


The first example of hydroacylation of azodicarboxylates using an excess

of formaldehyde106

was introduced in 1914 and after that, the scope of aliphatic

aldehydes for the reaction was increased, affording in all cases moderate yields

after several days of reaction time.107

Recently, the use of unusual solvents, such

as ionic liquids108

or water109

has been introduced in order to increase the reaction

scope, as well as to overcome other previous drawbacks. However, the reaction

using arenecarbaldehydes is still very challenging and unsuccessful.

The first metal-catalysed process was introduced in 2004 using

[Rh(OAc)2]2 (2 mol%), but still arenecarbaldehydes were not reacting under this

conditions.110

The use of copper(II) acetate,111

as well as zinc112

catalyst, allowed

to carry out the reaction with aliphatic and aromatic aldehydes with similar yields

for both substrates, but increasing the reaction time for 10 h for aliphatic

aldehydes to several days for arenecarbaldehydes.

It should be pointed out that there was only one example of a

heterogeneous catalyst performing the hydroacylation of azodicarboxylate

derivatives.113

The reaction using CuO nanoparticles supported on silica (10

mol%) as catalyst, gave similar results, in terms of yields and reaction times (12-

30 h), independently of the nature of the used aldehyde. With these protocol in

hand, we believed that heterogeneous catalysts derived from copper, iridium or

any other transition metal with two closed oxidation states could be a catalytic

alternative for this process.

106 O. Diels, E. Fisher, Ber. Dtsch. Chem. Ges. 1914, 47, 2043-2047. 107 a) K. Alder, T. Noble Ber. Dtsch. Chem. Ges. 1943, 76B, 54-57; b) R. Huisgen, F. Jakob Justus

Liebigs Ann. Chem. 1954, 590, 37-54; c) G. O. Schenck, H. Formaneck Angew. Chem. 1958,

70, 505; d) M. E. González-Rosende, O. Lozano-Lucia, E. Zaballos-García, J. Sepúlveda-

Arques J. Chem. Res., Synop 1995, 260-261; e) E. Zaballos-García, M. E. González-Rosende,

J. M. Jorda-Gregori, J. Sepúlveda-Arques, Tetrahedron 1997, 53, 9313-9322. 108 B. Ni, Q. Zhang, S. Garre, A. D. Headley, Adv. Synth. Catal. 2009, 351, 875-880. 109 a) Q. Zhang, E. Parker, A. D. Headley, B. Ni, Synlett 2010, 2453-2456; b) V. Chudasama, J. M.

Ahern, D. V. Dhokia, R. J. Fitzmaurize, S. Caddick, Chem. Commun. 2011, 47, 3269-3271; c)

V. Chudasama, A. R. Akhbar, K. A. Bahou,, R. J. Fitzmaurice, S. Caddick, Org. Biomol. Chem.

2013, 11, 7301-7317. 110 a) D. Lee, R. D. Otte, J. Org. Chem. 2004, 69, 3569-3571; b) Y. J. Kim, D. Lee, Org. Lett.

2004, 6, 4351-4353. 111 Y. Qin, Q. Peng, J. Song, D. Zhou, Tetrahedron Lett. 2011, 52, 5880-5883. 112 Y. Qin, D. Zhou, M. Li, Lett. Org. Chem. 2012, 9, 1875-1876. 113 S. M. Inamdar, V. K. More, S. K. Mandal, Chem. Lett. 2012, 41, 1484-1486.


1.2 RESULTS

The hydroacylation reaction of diisopropyl azodicarboxylate (DIAD, 1a)

using benzaldehyde (2a) catalysed by impregnated iridium on magnetite was

selected as the model for the optimization of the reaction conditions (Table 1).

Table 1. Optimization of the reaction conditions.a

Entry T (ºC) Solvent Yield 3a (%)

b Yield 4a (%)

b

1 25 CH3CN 2 0

2 40 CH3CN 18 0

3 50 CH3CN 32 0

4 60 CH3CN 65 5

5 70 CH3CN 15 0

6 100 CH3CN 9 0

7 60 - 54 7

8 60 THF 7 92

9 60 H2O 70 21

10 60 PhMe 30 4

11 60 (ClCH2)2 69 2

12 60 CHCl3 24 9

13 60 CCl4 25 4

14 60 Cl3CCH3 12 5

15c 60 Cl2C=CHCl 80 10

a Reaction carried out using compounds 1a (1mmol), and 2a (1.2 mmol) in 1 mL of

solvent. b Isolated yield after column chromatography.

c Reaction carried out during 24 h.

Benzaldehyde was chosen for its limited success in previous protocols,

and the iridium catalyst for its tendency to have an easy electronic state change.

Initially, the effect of temperature on the results was examined (entries 1-6),

achieving the best result at 60 ºC (entry 4). Then, different solvents were tested

(entries 4 and 7-15), with the reaction affording similar results in water and


dichloroethane and best results being reched in trichloroethylene. It should be

pointed out that the hydrazine by-product 4a was obtained as the main compound

in THF (entry 8).

In order to establish the hydrogen donor for the process, the reaction was

repeated using THF-d8. After quenching the reaction by addition of toluene and

magnetic decantation, the GC-MS of the crude mixture showed the

corresponding deuterated by-product 4a, with the incorporation of the second

deuterium being lower than 25 %. Then, the reaction was conducted with α-

deuterobenzaldehyde and THF, with the mono-incorporation of deuterium to the

by-product 4a being negligible.

Once the optimal conditions were determined, the reaction was repeated

with a variety of catalysts prepared by the simple impregnation protocol (Table

2). The reaction without a catalyst gave a poor yield (entry 1). Then, the activity

of the support was evaluated using magnetite as the unique catalyst.

Nanoparticles (size < 50 nm) or microparticles (size < 5 μm) of magnetite

(entries 2 and 3) were used with the results showing the inactivity of the support,

reaching the same yield as that obtained without catalyst.

Once the activity of magnetite was tested, different metal oxides

impregnated on magnetite (entries 4, 7, 10-18) were evaluated as catalyst,

achieving surprisingly the best result using the cobalt catalyst in only 3 h (entry

4). To the best of our knowledge, this is the first time that a cobalt catalyst has

shown its great activity in the hydroacylation reaction. This reaction time is the

shortest ever reported for this type of reaction. Molecular oxygen seems to have

an important role in the initial radical acyl formation the in non-catalysed

processes.109c

In order to clarify this aspect, the reaction was repeated but in an

inert atmosphere, obtaining similar result (entry 4, footnote d). Then, the reaction

was carried out with different bimetallic catalysts (entries 19 and 20), obtaining

worse results. Different amounts of catalyst were tested (entries 5, 6, 8, and 9)

finding that increasing the amount of nickel or cobalt, the amount of by-product

4a was increased, whereas the decrease of the catalyst amount, decreased the

yield of 3a.

Reactions using cobalt oxide or nickel oxide alone, gave moderate yields

(entries 21 and 22), with these results pointing out the high activity of these

nanostructured catalysts. It should be highlighted that the optimal amount of

catalyst is the lowest one ever reported for this type of transformations.


Table 2. Optimization of the catalyst.a

Entry Catalyst (mol%) Yield 3a (%)

b Yield 4a (%)

b

1c - 42 7

2 Micro-Fe3O4 (21.6) 45 7

3 Nano-Fe3O4 (21.6) 52 8

4 CoO-Fe3O4 (1.42) 90 (93)d 6

5 CoO-Fe3O4 (2.8) 78 18

6 CoO-Fe3O4 (0.28) 60 8

7 NiO-Fe3O4 (1.03) 83 6

8 NiO-Fe3O4 (2.06) 70 27

9 NiO-Fe3O4 (0.21) 66 6

10 CuO-Fe3O4 (0.91) 40 10

11 Ru2O3-Fe3O4 (1.03) 51 7

12 Rh2O3-Fe3O4 (0.42) 50 7

13 PdO-Fe3O4 (1.22) 69 8

14 Ag2O/Ag-Fe3O4 (1.25) 49 8

15 WO3-Fe3O4 (0.57) 51 7

16 OsO-Fe3O4 (0.51) 38 9

17 PtO/PtO2-Fe3O4 (0.54) 49 8

18 Au2O3/Au-Fe3O4 (0.14) 43 9

19 NiO/Cu-Fe3O4 (0.91/0.88) 43 12

20 PdO/Cu-Fe3O4 (1.53/0.90) 4 11

21 CoO (1.42) 46 9

22 NiO (1.03) 46 8 a Reaction carried out using compounds 1a (1mmol), and 2a (1.2 mmol).

b Isolated yield after column chromatography.

c Reaction carried out during 5 h.

d Reaction performed in argon atmosphere.

Having established the similar catalytic activity for cobalt and nickel

derivatives, the problem of recycling was faced (Figure 8). When the catalyst was

recovered from the reaction mixture by magnetic decantation, washed with

toluene, and reused under the same reaction conditions, the expected product 3a

was obtained in good yields with both catalysts. These catalysts could be


recycled up to 10 times with only a slight loss of their activity for the case of

NiO-Fe3O4 in which the yield decreased to 53 %. However, the CoO-Fe3O4

catalyst kept its activity practically constant and only in the last reaction cycle the

yield decreased slightly.

Figure 8. Recycling of the NiO-Fe3O4 and CoO-Fe3O4 catalyst.

In order to study the effect of the reaction conditions on the cobalt

catalyst, the nanosize distribution of the cobalt catalyst was measured through

Transmission Electron Microscopy (TEM) images (Figure 9), before, after only

one reaction process, and after ten runs, observing a small sinterization process of

the nanoparticles.

Figure 9. TEM images: a) before and b) after 10 times of recycling cobalt

catalyst.

a) b)


Before the reaction, the size of 77 % of the cobalt oxide particles on the

surface of the catalyst was between 1 and 4 nm. After the first recycling of the

catalyst, the average of the cobalt oxide particles was practically the same, as the

fresh one. However, after ten reactions, the recycled catalyst suffered a small

sinterization process, with the 73 % of cobalt oxide particles measuring between

2 and 6 nm (Figure 10).

0

10

20

30

40

50

0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-1010-15

Par

ticl

es

Particle size (nm)

Ten-fold recycled catalyst

First recycled catalyst

Fresh catalyst

Figure 10. Cobalt particle size distribution.

The X-Ray Photoelectron Spectroscopy (XPS) study of catalyst showed

the transformation of cobalt(II) oxide to the corresponding cobalt(II) hydroxide

(Figure 11). These small changes in particle size as well as the initial cobalt

species seemed not to affect the activity of the catalyst, since it could be reused

ten times with similar results.

0

2000

4000

6000

8000

10000

12000

14000

16000

770 775 780 785 790

Inte

nsi

ty/

arb.

Un

its

Binding energy (eV)

Fit

CoO 2p3/2

CoO 2p3/2

-50

50

150

250

350

450

550

650

750

770 775 780 785 790 795

Inte

nsi

ty/

arb

. U

nit

s

Binding energy (eV)

Fit

Co(OH)2 2p3/2

Co(OH)2 2p3/2

Figure 11. XPS of cobalt catalyst: a) before and b) after ten reactions.

a) b)


To know if the reaction took place by the leached cobalt species to the

organic medium, we performed the standard reaction (Table 3, entry 1). After

that, the catalyst was removed carefully by a magnet at high temperature, and

washed with trichloroethylene. The solvents of the above solution, without

catalyst, were removed under low pressure, and DIAD (1a) and 3-

methylbenzaldehyde (2c), as well as 1 mL of Cl2CCHCl, were added to the above

residue. The resulting solution was heated again at 60 ºC for 3 h. The analysis of

the crude mixture, after hydrolysis, revealed the formation of compound 3a in 93

% (catalysed process) and product 3c in 72 % yield by GC analysis (compare

with entry 3 in Table 3). It seems that the reaction takes place under

homogeneous conditions. Finally, Inductively Coupled Plasma-Mass

Spectroscopy (ICP-MS) analysis of the crude reaction solution showed the

leaching of a small amount of cobalt (1.4 % of the initial amount) and iron

(0.17% of the initial amount).

All these data seem to point out that the initial cobalt-impregnated

magnetite catalyst is only a reservoir for homogeneous cobalt species at high

temperatures, and after the reaction has taken place in the homogeneous solvent

phase, the cobalt species is efficiently re-adsorbed by the magnetite surface at

low temperatures, keeping its activity.

The evolution of the yield for compound 3a with the time at different

catalyst and reactive loadings is depicted in Figure 12. Assuming that the

equation rate is simple and that the reaction conditions permit a pseudo-first

order approximation for all reagents, with [A] being the initial concentration of

catalyst or reagents, the equation rate could be expressed as Ln roi=a Ln [A]oi +

constant. The estimation of the initial reaction rate for each trial and their

representation allowed us to estimate the value of the reaction order for the

catalyst and for both reagents, with the obtained value being very close to 1/2 for

both reagents and 3/4 for the cobalt catalyst. These results pointed out that the

mechanism is not very simple and could be an indirect indication of a previously

reported radical mechanism. To verify this fact, a radical scavenger (TEMPO)

was added to the initial reaction solution, recovering the starting reagents

unchanged after 6 h. In order to know if the sun light had some impact on the

possible radical reaction pathway, the reaction was performed in a light protected

tube, affording a similar result (88 %) to that presented in Table 2, entry 4.


0

10

20

30

40

50

60

70

80

90

100

0 50 100 150 200

Yie

ld (

%)

t (min)

2 mol% Co

1.42 mol% Co

0.6 mol% Co

Ln roi = 0,7306 Ln [Catlyst]o + 0,376

R² = 0,9996

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

-0,6 -0,4 -0,2 0 0,2 0,4 0,6 0,8

0

10

20

30

40

50

60

70

80

90

100

0 50 100 150 200

Yie

ld (

%)

t (min)

1 mmol DIAD

0,5 mmol DIAD

0,1 mmol DIAD

Ln roi = 0,4991 Ln [DIAD]o + 0,8435

R² = 0,9995

-0,4

-0,2

0

0,2

0,4

0,6

0,8

1

-2,5 -2 -1,5 -1 -0,5 0

0

10

20

30

40

50

60

70

80

90

100

0 50 100 150 200

Yie

ld (

%)

t (min)

1,2 mmol aldehyde

0,5 mmol aldehyde

0,1 mmol aldehyde

Ln roi = 0,5055 Ln [aldehyde]o + 0,5902

R² = 0,9995

-0,8

-0,6

-0,4

-0,2

0

0,2

0,4

0,6

0,8

-2,5 -2 -1,5 -1 -0,5 0 0,5

Figure 12. Plot-time yield and correlation between initial rates and the

corresponding catalyst and reagents.

With the best conditions in hands, the scope of the reaction was

evaluated using cobalt and nickel catalysts (Table 3). The reaction gave excellent

and consistent results when diisopropyl azodicarboxylate reagent was employed

using different arenecarbaldehydes bearing electron-withdrawing groups (Table

3, entries 7–10). However, the presence of electron-donating groups at the aryl

moiety decreased somehow the yields (entries 2-5), with the reaction using 3,4,5-

trimethoxybenzaldehyde giving the worse result (entry 6).


Table 3. Preparation of hydroacylation products.a

Entry R

1 R

2 No Yield 3 (%)

b

1 i-Pr Ph 3a 89 (83)

2 i-Pr 2-MeC6H4 3b 86 (75)

3 i-Pr 3-MeC6H4 3c 79 (99)

4 i-Pr 4-MeC6H4 3d 72 (78)

5 i-Pr 4-MeOC6H4 3e 67 (41)

6 i-Pr 3,4,5-(MeO)3C6H2 3f 26 (8)

7 i-Pr 4-FC6H4 3g 90 (86)

8 i-Pr 2-ClC6H4 3h 95 (38)

9 i-Pr 3-ClC6H4 3i 97 (88)

10 i-Pr 4-ClC6H4 3j 87 (65)

11 i-Pr 1-naphthyl 3k 87 (79)

12 i-Pr 1-thienyl 3l 60 (60)

13 i-Pr C6H5CH=CH 3m 74 (82)

14c i-Pr CH3(CH2)2 3n 99

15c i-Pr CH3(CH2)7 3o 99

16c i-Pr (CH3CH2)2CH 3p 99 (99)

17c i-Pr (CH3)3C 3q 75 (88)

18 i-Pr (Z)-EtCH=CH(CH2)5 3r 99

19 Et Ph 3s 99 (99)

20 t-Bu Ph 3t 40 (62)

21 i-Pr Me2N 3u 0 a Reaction carried out using compounds 1 (1mmol), and 2 (1.2 mmol).

b Isolated yield after column chromatography. In brackets the yield obtained using

NiO-Fe3O4 catalyst (1.03 mol%). c Reaction carried out during 30 min.

Interestingly, the reaction using cobalt catalyst led to higher yields than

using nickel. The reaction reached good results when other aromatic aldehydes,

including heteroaromatic (entry 12) or α,β-unsaturated aldehydes (entry 13), were

used. The reaction with aliphatic aldehydes also gave excellent results

independently of the substitution at the α-position or the presence of an isolated

carbon-carbon double bond (entries 14-18). It should be pointed out that the


reaction using diethyl azodicarboxylate (entry 19), gave practically the same

result as the diisopropyl derivative. However, when the steric hindrance of the

azoderivative was increased the final yield decreased (compare entries 1, 19 and

20). Finally, the reaction was performed using N,N-dimethylformamide (2u)

(entry 21) recovering the starting material unchanged after 3 h.

CHAPTER II



Copper(II) Oxide on Magnetite

61 Chapter II. Reactions performed by nanoparticles of Copper

1. HOMOCOUPLING OF TERMINAL ALKYNES

1.1 INTRODUCTION

The homocoupling of terminal alkynes114

to give 1,3-diynes has attracted

great deal of attention in Organic Chemistry due to of their role as building

blocks in the synthesis of many natural products115

or for pharmaceuticals with

anti-inflammatory, antibacterial, antitumor, or antifungal activities. Furthermore,

1,3-diynes have attracted the attention of chemists as interesting material that are

useful as precursors of polymers,116

macrocycles,117

or supramolecular

structures.118

The symmetric coupling of simple terminal acetylenes,119

known as the

Glaser-Hay reaction, was discovered over a century ago, and the methodology

for this reaction was improved shortly afterwards.120

Among the various metallic

salts that were used, copper emerged as the best metal for catalysing this

transformation. In fact, the number of copper complexes that have been identified

as being capable of successfully inducing this transformation continues to

increase.121

However, homogeneous catalysts have some important drawbacks,

114 a) Modern Acetylene Chemistry, (Eds.: P. J. Stang, F. Diederich), VCH, Weinheim, 1995; b) L.

Brandsma in Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques;

Elsevier Academic Press, Amsterdam, 2004; c) Acetylene Chemistry, (Eds.: F. Diederich, P. J.

Stang, R. R. Tykwinski), Wiley-VCH, Weinheim, 2005. 115 A. L. K. S. Shun, R. R. Tykwinski, Angew. Chem. Int. Ed. 2006, 45, 1034-1057. 116 a) T. X. Neenan, G. M. Whitesides, J. Org. Chem. 1988, 53, 2489-2496; b) J. M. Tour, Chem.

Rev. 1996, 96, 537-553; c) U. H. F. Bunz, Y. Rubin, Y. Tobe, Chem. Soc. Rev. 1999, 28, 107-

119. 117 a) M. Ladika, T. E. Fisk, W. W. Wu, S. D. Jons, J. Am. Chem. Soc. 1994, 116, 12093-12094; b)

M. Ohkita, K. Ando, T. Suzuki, T. Tsuji, J. Org. Chem. 2000, 65, 4385-4390; c) J. A. Marsden,

M. M. Haley, J. Org. Chem. 2005, 70, 10213-10226. 118 J. D. Crowley, S. M. Goldup, A.-L. Lee, D. A. Leigh, R. T. McBurney, Chem. Soc. Rev. 2009,

38, 1530-1541. 119 a) P. Siemsen, C. Livingston, F. Diederich, Angew. Chem. Int. Ed. 2000, 39, 2632-2657; b) H.

A. Stefani, A. S. Guarezemini, R. Cella, Tetrahedron 2010, 66, 7871-7918; c) F. Alonso, M.

Yus, ACS Catal. 2012, 2, 1441-1451. 120 a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422-424; b) A. S. Hay, J. Org. Chem. 1962, 27,

3320-3321. 121 a) J. S. Yadav, B. V. S. Reddy, K. B. Reddy, K. U. Gayathri, A. R. Prasad, Tetrahedron Lett.

2003, 44, 6493-6496; b) X. Lu, Y. Zhang, C. Luo, Y. Wang, Synth. Commun. 2006, 36, 2503-

2511; c) H.-F. Jiang, J.-Y. Tang, A.-Z. Wang, G.-H. Deng, S.-R. Yang, Synthesis 2006, 1155-

1161; d) V. Kumar, A. Chipeleme, K. Chibale, Eur. J. Org. Chem. 2008, 43-46; e) K. Yin, C.

Li, J. Li, X. Jia, Green Chem. 2011, 13, 591-593; f) S. Zhang, X. Liu, T. Wang, Adv. Synth.

Catal. 2011, 353, 1463-1466; g) R. Schmidt, R. Thorwirth, T. Szuppa, A. Stolle, B.

Ondruschka, H. Hopf, Chem. Eur. J. 2011, 17, 8129-8138.

Chapter II. Reactions performed by nanoparticles of Copper 62

such the need of high metal loadings and the inability to recycle the catalyst. A

homogeneous copper acetate-poly(ethylene glycol) catalyst system121b

has been

recycled up to five times, although this was accompanied by a decrease in

activity after each reactivation step of treatment with acetic acid.

Heterogeneous catalysts have been designed to perform this

transformation and to facilitate their removal, recovery, and recycling of the

catalysts. Although, there are several examples of insoluble copper derivatives

that are able to induce the Glaser-Hay reaction,122

the most widely used strategy

has involved the use of copper salts supported on various inert oxides, such as

hydrotalcite,123

alumina,124

zeolites,125

titania,126

silicotungstate complexes,127

molecular sieves,128

or mesoporous silica.129

However, the use of such catalysts

entails some drawbacks that require elimination, such as the need for a high

metal loading,122-129

and high temperatures.125,126a,127,128

Furthermore, most

procedures used non-environmentally benign solvents,122,123b,c,125,126a,127-129

and

pressurized oxygen.123a,b,126a,127,128

Moreover, in some cases, the lack of

recyclability of the catalyst.122a,b,123b,124,125,126a

An interesting cooperative effect was observed when the reaction was

carried out in the presence of homogeneous mixtures containing a copper and an

iron salts.130

In this case, the loading of the copper salt could be reduced to 0.1

mol% in the presence of 10 mol% of iron(III) acetylacetonate. For all these

reasons, we thought that impregnated copper on magnetite would be an

alternative to known catalysts.

122 a) F. Toda, Y. Tokumaru, Chem. Lett. 1990, 987-990; b) F. Nador, L. Fortunato, Y. Moglie, C.

Vitale, G. Radivoy, Synthesis 2009, 4027-4031; c) D. Wang, J. Li, N. Li, T. Gao, S. Hou, B.

Chen, Green Chem. 2010, 12, 45-48. 123 a) S. M. Auer, M. Schneider, A. Baiker, J. Chem. Soc., Chem. Commun. 1995, 2057-2058; b) S.

M. Auer, R. Wandeler, U. Göbel, A. Baiker, J. Catal. 1997, 169, 1-12; c) B. C. Zhu, X. Z. Jiang,

Appl. Organometal. Chem. 2007, 21, 345-349. 124 A. Sharifi, M. Mirzaei, M. R. Naimi-Jamal, Monatsh. Chem. 2006, 137, 213-217. 125 P. Kuhn, A. Alix, M. Kumarraja, B. Louis, P. Pale, J. Sommer, Eur. J. Org. Chem. 2009, 423-

429. 126 a) T. Oishi, T. Katayama, K. Yamaguchi, N. Mizuno, Chem. Eur. J. 2009, 15, 7539-7542; b) F.

Alonso, T. Melkonian, Y. Moglie, M. Yus, Eur. J. Org. Chem. 2011, 2524-2530. 127 K. Kamata, S. Yamaguchi, M. Kotani, K. Yamaguchi, N. Mizuni, Angew. Chem. Int. Ed. 2008,

47, 2407-2410. 128 T. Oishi, K. Yamaguchi, N. Mizuno, ACS Catal. 2011, 1, 1351-1354. 129 R. Xiao, R. Yao, M. Cai, Eur. J. Org. Chem. 2012, 4178-4184. 130 X. Meng, C. Li, B. Han, T. Wang, B. Chen, Tetrahedron 2010, 66, 4029-4031.


1.2 RESULTS

The homocoupling of ethynylbenzene (5a) in the presence of piperidine

as a base, was selected as a model reaction for optimising the reaction conditions

(Table 4). Initially, the reaction was examined in various solvents (Table 4,

entries 1-9), and the best results were found in the absence of any solvent.

Increasing the temperature of the reaction did not improve the results (entry 10),

whereas the reaction at room temperature only gave traces of product 6a (entry

11). The reaction failed in the absence of the base (entry 12).

The effects of changing the base was also examined by using various

amines (entries 13-15), and similar yields were obtained in only four hours with

various similar amines; however, the corresponding amides were also obtained as

by-products. When other organic or inorganic bases were used (entries 16-20),

lower yields were obtained. The product 6a was obtained in quantitative yield

only when potassium tert-butoxide was used as base (entry 21).

When the reaction was carried out in the presence of 50 mol% of base,

the yield decreased (entry 22). Therefore, we concluded that a stoichiometric

amount of the base was mandatory for the homocoupling (entries 21 and 22).

Increasing the amount of base did not reduce the reaction time further (entry 23).

When the reaction was performed under an argon atmosphere, the yield

decreased to 38 % (entry 24). This confirmed that the oxygen present in the air

played an important role in the process and that it acted as the ultimate source of

oxidant reagent.

Then, the effect of the amount of catalyst used was evaluated (entries 25-

27). Decreasing the amount of catalyst to 0.26 mol% gave 6a in 99 % yield of 6a,

although a longer reaction time (48 hours) was needed (entry 25). Reactions with

higher or lower loading of the metal did not improve the results (entries 26 and

27). Finally, when the reaction was repeated under the optimised conditions but

in the absence of catalyst, the starting material was recovered after one week

(entry 28). Note that performing the reaction under an atmosphere of pure

oxygen did not change the results (entries 21 and 29).



Entry Base (mol%) Solvent T (ºC) t (h) Yield (%)

b

1 Piperidine (100) THF 60 24 84

2 Piperidine (100) PhMe 60 24 85

3 Piperidine (100) MeCN 60 24 57

4 Piperidine (100) 1,4-Dioxane 60 24 87

5 Piperidine (100) DMF 60 24 54

6 Piperidine (100) H2O 60 24 6

7 Piperidine (100) DMSO 60 24 14

8 Piperidine (100) EtOH 60 24 0

9 Piperidine (100) - 60 24 90

10 Piperidine (100) - 90 24 73

11 Piperidine (100) - 25 24 2

12 - - 60 24 0

13c

BuNH2 (100) - 60 4 87

14 Et3N (100) - 60 24 5

15 DABCO (100) - 60 24 79

16 KOAc (100) - 60 24 0

17 t-BuONa (100) - 60 24 16

18 MeONa (100) - 60 24 2

19 CsOH·H2O (100) - 60 24 60

20 KOH (100) - 60 24 88

21 t-BuOK (100) - 60 24 99

22 t-BuOK (50) - 60 24 75

23 t-BuOK (200) - 60 24 99

24d

t-BuOK (100) - 60 24 38

25e

t-BuOK (100) - 60 48 99

26f

t-BuOK (100) - 60 48 26

27g

t-BuOK (100) - 60 24 99

28h

t-BuOK (100) - 60 168 0

29i

t-BuOK (100) - 60 24 99 a Reaction carried out using compound 5a (2 mmol) under air atmosphere.

b Isolated yields after column chromatography.

c N-Butyl-2-phenylacetamide was isolated in 13 % yield.

d Reaction carried out under argon atmosphere.

e Reaction carried out with 0.26 mol% of catalyst.

f Reaction carried out with 0.13 mol% of catalyst.

g Reaction carried out with 2.6 mol% of catalyst.


Table 4. Continuation.

h Reaction carried out in the absence of the catalyst.

i Reaction carried out under O2.

Having determined the optimal conditions, other catalysts prepared by a

simple impregnation protocol were explored (Table 5). First, the activity of the

support by using magnetite as the sole catalyst was tested. Nanoparticles (size <

50 nm) or microparticles (size < 5 μm) of magnetite were used, and the results

showed that ‘naked’ magnetite had a lower activity than the copper-impregnated

form, needing longer reaction times and giving lower yields (Table 5, entries 1,

2, and 3).

Table 5. Optimization of catalyst.a

Entry Catalyst (mol%) t (d) Yield (%)

b

1 CuO-Fe3O4 (0.26) 2 99

2 Micro-Fe3O4 (0.13) 7 68

3 Nano-Fe3O4 (0.13)

7 78

4 Ru2O3-Fe3O4 (0.28) 2 0

5 CoO-Fe3O4 (0.35) 2 0

6 IrO2-Fe3O4 (0.03) 2 0

7 NiO-Fe3O4 (0.20) 2 41

8 PdO-Fe3O4 (0.24) 2 1

9 PtO/PtO2-Fe3O4 (0.12) 2 1

10 PdO/Cu-Fe3O4 (0.30/0.16) 2 89

11 NiO/Cu-Fe3O4 (0.18/0.22) 2 99

12 CuO (0.26) 2 89

13 CuO (0.26) + Fe3O4 (0.13) 2 88 a Reactions were carried out by using compound 5a (2 mmol) under air atmosphere.


Ruthenium,131

cobalt,131

iridium,132

palladium,95

and platinum133

did not

show any activity in this transformation (entries 4-6, 8 and 9). The nickel

catalyst131

showed a moderate activity, giving the expected product in 41 % yield

(entry 7). Reactions using bimetallic catalysts gave the expected product in high

131 R. Cano, D. J. Ramón, M. Yus, J. Org. Chem. 2011, 76, 5547-5557. 132 R. Cano, M. Yus, D. J. Ramón, Chem. Commun. 2012, 48, 7628-7630. 133 R. Cano, M. Yus, D. J. Ramón, ACS Catal. 2012, 2, 1070-1078.


yields (entries 10 and 11), with the copper-nickel95

catalyst attaining a

quantitative yield. Reactions using copper oxide alone or together with magnetite

gave slightly lower yields than those obtained with the impregnated catalyst

(compare entries 1, 12 and 13), but we do not have any clear explanation for this

cooperative effect.

Having established the optimal reaction conditions, the problem of

recycling was examined (Figure 13). When the catalyst was recovered from the

reaction mixture by using a magnet, washed with methanol, and reused under the

same conditions, the expected product 6a was obtained in 99 % yield. However,

in the fourth cycle, the yield was only 75 %, indicating that there is a small

decrease in the activity of the catalyst. In the fifth cycle, the yield fell sharply to

20 %.

0

20

40

60

80

100

12

34

5

Yie

ld (

%)

6a

Cycle

Figure 13. Yields obtained with recycled CuO-Fe3O4.

The nanosize distribution of the catalyst, as measured from TEM images,

remained about the same before and after the reaction. Before the reaction, 73 %

of the copper oxide particles on the surface of the catalyst measured between 2

and 6 nm, whereas the corresponding particle size distribution after the reaction

was 68 % (Figure 14).


0

20

40

60

0-1

1-2

2-3

3-4

4-5

5-6

6-7

7-8

8-9

9-1

0

10

-11

11

-12

12

-13

13

-14

14

-15

15

-20

20

-25

Par

ticl

es

Particle size (nm)

Recycled catalyst

Fresh catalyst

Figure 14. TEM images: a) before and b) after recycling copper catalyst. c)

Copper particle size distribution.

XPS and Auger Electron Spectroscopy (AES) studies on the used catalyst

showed that copper was partially reduced from an initial 4:1 mixture of Cu(II)

and Cu(0) to a 2:1 mixture of these oxidation states (Figure 15 and 16).

b) a)

c)


0

1000

2000

3000

4000

5000

6000

7000

8000

9000

927 932 937 942 947 952

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Fit

Cu 2p3/2

CuO 2p3/2

75000

80000

85000

90000

95000

100000

903 908 913 918 923

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Cu L3VV

Figure 15. a) XPS of fresh catalyst; b) Auger spectroscopy of fresh catalyst.

0

2000

4000

6000

8000

10000

12000

926 931 936 941 946

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Fit

Cu 2p3/2

CuO 2p3/2

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

904 909 914 919 924

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Cu L3VV

Figure 16. a) XPS of recycled catalyst; b) Auger spectroscopy of recycled

catalyst.

The ICP-MS analysis of the reaction solution showed the presence of

copper (6.2 % of the initial amount) and iron (0.22 % of the initial amount). A

similar result was obtained when the catalyst was removed before the mixture

was cooled. These results seems to show that not all copper on the surface of

magnetite has the same activity, and that the most-active species leach fastest.

The optimized conditions were applied to other substrates. Reaction

using various substituted alkynes 5 gave the expected products 6 (Table 6). The

reaction seem to be more affected by the presence of chelating groups at the aryl

moiety of substituted alkyne than by the electronic nature of the substrates, and

reactants with the strongest chelating ability gave the lowest yields (entries 1-5).

The presence of steric hindrance in the aryl moiety decreased the yield (entry 6).

Finally, the reaction could also be performed by using less-reactive aliphatic

alkynes, and the expected products 6 were obtained in all the cases, albeit in

slightly lower yields (entries 10-14).

a) b)

a) b)


Table 6. Preparation of various 1,3-diynes.a

Entry R Product t (d) Yield (%)

b

1 Ph 6a 2 99 (99)c

2 4-Me2NC6H4 6b 6 20

3 4-MeOC6H4 6c 7 57

4 4-MeC6H4 6d 2 (1)c

91 (99)c

5 4-ClC6H4 6e 4 99

6 2-ClC6H4 6f 2 32

7 4-F3CC6H4 6g 2 99

8 4-BrC6H4 6h 7 26 (17)c

9 3-MeC6H4 6i 3 99

10 c-Hex 6j 3 70 (88)c

11 (CH2)5Me 6k 3 92

12 (CH2)7Me 6l 7 (3)c

50 (74)c

13 (CH2)9Me 6m 7 31

14 (CH2)3Cl 6n 2 99 a Reactions were carried out by using compound 5 (2 mmol) under air atmosphere.


c With NiO/Cu-Fe3O4 (0.18/0.22 mol%) catalyst.

Encouraged by the success that was achieved in homocoupling of

terminal alkynes, the hydration reaction of 1,3-diynes to afford the corresponding

2,5-disubstituted furans was examined. This reaction is catalysed by various

copper salts.134

The reaction was performed with compound 6a in dimethyl

sulfoxide in the presence of potassium hydroxide and the impregnated copper

oxide on magnetite as catalyst at 80 ºC. To our delight, the desired furan 7a was

obtained in quantitative yield. However, it should be pointed out that the

hydration reaction performed in the absence of the catalyst also, surprisingly,

gave furan 7a in the same yield.

Then, a direct, two-step, one-pot transformation of various alkynes into

the corresponding 2,5-disubstituted furans 7 was attempted (Table 7). Having

obtained the diyne in the first reaction step, the catalyst with a magnet was

removed, and without purification of the reagents, dimethyl sulfoxide and

aqueous potassium hydroxide were added. Excellent results were obtained for

134 H. Jiang, W. Aeng, Y. Li, W. Wu, L. Huang, W. Fu, J. Org. Chem. 2012, 77, 5179-5183.


various types of 4-substituted aryl diynes (entries 1-4). Unfortunately, when a

cycloaliphatic diyne was used, the reaction failed (entry 5) and the substrate was

recovered unchanged.

Table 7. One-Pot preparation of 2,5-Furans.a

Entry R Product t (d) Yield (%)

b

1 Ph 7a 3 99

2 4-MeOC6H4 7b 8 59

3 4-MeC6H4 7c 3 90

4 4-F3CC6H4 7d 3 99

5 c-Hex 7e 5 0 a Reaction carried out by using compound 5 (1 mmol) under an air atmosphere.


Finally, the decarboxylative coupling reaction135

of 3-phenylprop-2-ynoic

acid (8) was examined. The copper catalyst gave only a 21 % yield of the

expected diyne 6a. However, this product was obtained quantitatively when we

used NiO/Cu-Fe3O4 as catalyst (Scheme 23).

Scheme 23. Decarboxylative coupling reaction of 3-phenylprop-2-yonic acid.

135 M. Yu, D. Pan, W. Jia, W. Chen, N. Jiao, Tetrahedron Lett. 2010, 51, 1287-1289.


2. SYNTHESIS OF AROMATIC IMINES FROM ALCOHOLS AND

AMINES OR NITROARENES

2.1 INTRODUCTION

Imines are crucial intermediates and their reactions are fundamental and

ubiquitous in the synthesis of biologically active nitrogen compounds, such as β-

lactams, dyes, fragances, pharmaceuticals, fungicides, and agricultural

chemicals.136

Generally, imines, including Schiff bases, are produced from the

condensation of primary amines with carbonyl compounds. However, several

new synthetic strategies have been developed in recent years, including the

metal-catalysed oxidation (or dehydrogenation) of primary amines to give the

corresponding imines.137

Imines have also been prepared from symmetrical secondary amines.138

However, the variety of compounds obtained in this manner was very limited; the

136 a) R. W. Layer, Chem. Rev. 1963, 63, 489-510; b) K. A. Tehrani, N. De Kimpe in Science of

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Joiner, J. F. Stoddart, Chem. Soc. Rev. 2007, 36, 1705-1723; d) S. F. Martin, Pure Appl. Chem.

2009, 81, 195-204. 137 a) R. E. Miller, J. Org. Chem. 1960, 25, 2126-2128; b) S. Minakata, Y. Ohshima, A. Takemiya,

I. Ryu, M. Komatsu, Y. Ohshiro, Chem. Lett. 1997, 311-312; c) B. Zhu, M. Lazar, B. G.

Trewyn, R. J. Angelici, J. Catal. 2008, 260, 1-6; d) L. Aschwanden, B. Panella, P. Rossbach, B.

Keller, A. Baiker, ChemCatChem 2009, 1, 111-115; e) S. Komada, J. Yoshida, A. Nomoto, Y.

Ueta, S. Yano, M. Ueshima, A. Ogawa, Tetrahedron Lett. 2010, 51, 2450-2452; f) A. Prades,

E. Peris, M. Albrecht, Organometallics 2011, 30, 1162-1167; g) R. D. Patil, S. Adimurthy, Adv.

Synth. Catal. 2011, 353, 1695-1700; h) S. Furukawa, Y. Ohno, T. Shishido, K. Teramura, T.

Tanaka, ACS Catal. 2011, 1, 1150-1153. 138 a) F. Porta, C. Crotti, S. Cenini, G. Palmisano, J. Mol. Chem. 1989, 50, 333-341; b) A. J.

Bailey, B. R. James, Chem. Commun. 1996, 2343-2344; c) K. Mori, K. Yamaguchi, T.

Mizugaki, K. Ebitani, K. Kaneda, Chem. Commun. 2001, 461-462; d) Y. Maeda, T. Nishimura,

S. Uemura, Bull. Chem. Soc. Jpn. 2003, 76, 2399-2403; e) B. Zhu, R. J. Angelici, Chem.

Commun. 2007, 2157-2159; f) L. Aschwanden, T. Mallat, J.-D. Grunwaldt, F. Krumeich, A.

Baiker, J. Mol. Cal. A: Chem. 2009, 300, 111-115; g) L. Aschwanden, T. Mallat, F. Krumeich,

A. Baiker, J. Mol. Cal. A: Chem. 2009, 309, 57-62; h) A. Grirrane, A. Corma, H. García, J.

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4568-4571; j) L. Aschwanden, T. Mallat, M. Maciejewski, F. Krumeich, A. Baiker,

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Chem. Soc. Jpn. 2011, 84, 588-599.


use of secondary arylamine derivatives circumvented this restriction enabling

access to a wider range of products.139

The in situ oxidative imine formation process, starting from alcohols and

amines, by manganese oxides and molecular sieves, formally permitted access to

several types of imines.140

It should be pointed out that the same intermediates

have been detected in the alkylation41a,b,c,e,h

of amines by alcohols through the

hydrogen autotransfer reaction.41f,g,j,k

The use of stoichiometric amounts of

manganese oxidants is highly undesirable from both economical and

environmental points of view. Therefore, much attention has been paid to the use

of other catalysts to effectively carry out this transformation. In fact, some

complexes and compounds derived from transition metals of the second and third

row, such as ruthenium,131,141

palladium,142

osmium,143

iridium,144

platinum,145

and gold146

have shown promise for this imine synthesis strategy. However, the

toxicities, pricing, and stability of these metals prohibit their general use for

industrial purposes. We thought that impregnated copper on magnetite could be a

catalyst capable to overcome the aforementioned problems.

139 a) K. Yamaguchi, N. Mizuno, Angew. Chem. Int. Ed. 2003, 42, 1480-1483; b) K. Yamaguchi,

N. Mizuno, Chem. Eur. J. 2003, 9, 4353-4361; c) J.-R. Wang, Y. Fu, B.-B. Zhang, X. Cui, L.

Liu, Q.-X. Guo, Tetrahedron Lett. 2006, 47, 8293-8297; d) S.-I. Murahashi, Y. Okano, H. Sato,

T. Nakae, N. Komiya, Synlett 2007, 1675-1678; e) R. Yamaguchi, C. Ikeda, Y. Takahashi, K.-i.

Fujita, J. Am. Chem. Soc. 2009, 131, 8410-8412; f) M.-H. So, Y. Liu, C.-M. Ho, C.-M. Che,

Chen. Asian J. 2009, 4, 1551-1561. 140 a) L. Blackburn, R. J. K. Taylor, Org. Lett. 2001, 3, 1637-1639; b) S. Sithambaram, R. Kumar,

Y.-C. Son, S. L. Suib, J. Catal. 2008, 253, 269-277. 141 a) J. W. Kim, J. He, K. Yamaguchi, N. Mizuno, Chem. Lett. 2009, 38, 920-921; b) B.

Gnanaprakasam, J. Zhang, D. Milstein, Angew. Chem. Int. Ed. 2010, 49, 1468-1471; c) H. Li,

X. Wang, F. Huang, G. Lu, J. Jiang, Z.-X. Wang, Organometallics 2011, 30, 5233-5247. 142 a) M. S. Kwon, S. Kim, S. Park, W. Bosco, R. K. Chidrala, J. Park, J. Org. Chem. 2009, 74,

2877-2879; b) W. He, L. Wang, C. Sun, K. Wu, S. He, J. Chen, P. Wu, Z. Yu, Chem. Eur. J.

2011, 17, 13308-13317; c) L. Jiang, L. Jin, H. Tian, X. Yuan, X. Yu, Q. Xu Chem. Commun.

2011, 47, 10833-10835. 143 M. A. Esteruelas, N. Honczek, M. Oliván, E. Oñate, M. Valencia, Organometallics 2011, 30,

2468-2471. 144 a) H. Aramoto, Y. Obara; Y. Ishii, J. Org. Chem. 2009, 74, 628-633; b) C. Xu, L. Y. Goh, S. A.

Pullarkat, Organometallics 2011, 30, 6499-6502. 145 Y. Shiraishi, M. Ikeda, D. Tsukamoto, S. Tanaka, T. Hirai, Chem. Commun. 2011, 47, 4811-

4813. 146 a) H. Sun, F.-Z. Su, J. Ni, Y. Cao, H.-Y. He, K.-N. Fan, Angew. Chem. Int. Ed. 2009, 48, 4390-

4393; b) S. Kegnæs, J. Mielby, U. V. Mentzel, C. H. Christensen, A. Riisager, Green Chem.

2010, 12, 1437-1441.


2.2 RESULTS

The first process evaluated using the impregnated copper on magnetite as

catalyst was the reaction between benzyl alcohol (9a) and aniline (10a) under an

argon atmosphere to give the corresponding imine 11a as depicted in Table 8,. It

should be pointed out that simple copper(II) acetate gave, in similar process,147

the typical monoalkylated amine, rendering, in this case, N-benzylaniline.

However, using the new copper catalyst, imine could be isolated after a few days

of reaction in the absence of oxygen. Thus, the reaction using NaOH as base gave

the expected imine 11a with a small amount of the corresponding N-

benzylaniline, which came from the aforementioned hydrogen autotransfer

process.

Studying of the influence of base, as well as its absence, showed that

NaOH rendered the best results (Table 8, compare entries 1-7). The effect of

reaction temperature was also investigated. Temperatures below 130 ºC were

found to minimize the formation of by-product N-benzylaniline and to the

enhance imine formation; ideal yields routinely resulted from reactions run at

100 ºC (Table 8, entries 1 and 8-10). Choice of solvent was also found to

influence the reaction yield (Table 8, entries 10-12), with toluene providing the

best results. In addition, increasing the amount of base had a significantly

negative effect (Table 8, entries 13 and 14); an increase in the amount of benzyl

alcohol (Table 8, entry 15) also had a negative effect, whereas an increase in the

amount of aniline had a beneficial effect on the yield, being practically

quantitative (Table 8, entry 16).

The influence of catalyst concentration was also studied. While lower

catalyst concentrations, led to lower reaction yields, higher catalyst

concentrations produced only marginal increment of the yield (Table 8, entries 17

and 18). The reaction was repeated in the presence of air to see if this might be

the actual source of oxidant in these reactions. However, no difference in yield or

the required reaction time between the reactions performed with or without air

(Table 8, entries 16 and 19) was found. The reaction was performed also using

the commercial micro-magnetite support, giving the expected imine 11a in

moderate yield (Table 8, entry 20), whereas the use of the most active nano-

powder magnetite42

afforded a comparable yield (63 %).

147 a) A. Martínez-Asencio, D. J. Ramón, M. Yus, Tetrahedron Lett. 2010, 51, 325-327; b) A.

Martínez-Asencio, D. J. Ramón, M. Yus, Tetrahedron 2011, 67, 3140-3149.



Entry Base (mol%) Solvent T (ºC) t (d) Yield (%)

b

1 NaOH (140) PhMe 130 4 65c

2 KOH (140) PhMe 130 4 2d

3 LiOH (140) PhMe 130 4 39

4 Na2CO3 (140) PhMe 130 4 3

5 K2CO3 (140) PhMe 130 4 27

6 NaOAc (140) PhMe 130 4 1

7 - PhMe 130 7 2

8 NaOH (140) PhMe 25 7 27

9 NaOH (140) PhMe 70 7 71

10 NaOH (140) PhMe 100 4 91

11 NaOH (140) 1,4-Dioxane 100 6 61

12 NaOH (140) MeCN 100 6 18e

13 NaOH (300) PhMe 100 4 59f

14 NaOH (500) PhMe 100 4 25

15g

NaOH (140) PhMe 100 4 20

16h NaOH (140) PhMe 100 4 98

17h,i

NaOH (140) PhMe 100 4 81

18h,j

NaOH (140) PhMe 100 4 98

19h,k

NaOH (140) PhMe 100 4 95

20h,l

NaOH (140) PhMe 100 4 57

a Reaction carried out using compounds 9a (1.3mmol), and 10a (1.0 mmol) in solvent

(3 mL) and under an Ar atmosphere, unless otherwise stated. b Isolated yield after bulb-to-bulb distillation.

c N-Benzylaniline was isolated in 14 % yield.

d N-Benzylaniline was isolated in 89 % yield.

e N-Benzylaniline was isolated in 51 % yield.

f N-Benzylaniline was isolated in 19 % yield.

g Reaction carried out using compounds 9a (2.6 mmol), and 10a (1.0 mmol).

h Reaction carried out using compounds 9a (1.0 mmol), and 10a (2.0 mmol).

i Reaction carried out using 0.3 mol% of catalyst.

j Reaction carried out using 2.3 mol% of catalyst.

k Reaction carried out under air atmosphere.

l Reaction performed using only magnetite support (powder < 5μm; 65 mol%).


The standard catalyst89

was routinely prepared from copper dichloride.

To know the possible effect of anion on catalyst activity, similar catalysts were

prepared from copper(II) dibromide or nitrate. The X-Ray Fluorescence (XRF)

analysis revealed that the total incorporation of copper was 1.26 and 1.35 % for

bromide- and nitrate-derived catalyst, respectively; both incorporations were

similar to the observed for the standard chloride-derived catalyst (1.12 %).

Through XPS and Auger analysis we could obtain that the relationship between

Cu(0):Cu(II) was 1:1 in both catalysts (Figure 17).

-100

4900

9900

14900

19900

24900

925 930 935 940 945 950 955 960 965

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Cu 2p 3/2

CuO 2p 3/2

Cu 2p 1/2

CuO 2p 1/2

19000

21000

23000

25000

27000

29000

31000

33000

905 910 915 920 925 930

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Cu L3VV

-100

1900

3900

5900

7900

9900

11900

13900

925 935 945 955 965

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Cu 2p 3/2

CuO 2p 3/2

Cu 2p 1/2

CuO 2p 1/2

18000

19000

20000

21000

22000

23000

24000

25000

26000

27000

907 912 917 922 927 932

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Cu L3VV

Figure 17. a) XPS catalyst prepared from CuBr2; b) Auger spectroscopy of

catalyst prepared from CuBr2; c) XPS of catalyst prepared from

Cu(NO3)2·5/2H2O; d) Auger spectroscopy of catalyst prepared from

Cu(NO3)2·5/2H2O.

TEM images were analysed obtaining similar particle size distribution

than the previously prepared with copper(II) chloride (compare Figure 14c with

Figure 18). When these catalysts were used under the reaction conditions

presented in Table 8, entry 16, similar yields were obtained (95 and 99 % using

bromide- and nitrate-derived catalysts, respectively), indicating only a marginal

effect of the counterion of the catalyst on catalytic activity.

a) b)

c) d)


0

20

40

60

80

Par

ticl

es

Particle Size (nm)

Cu(NO3)2·5/2H2O

CuBr2

Figure 18. a) TEM image of catalyst prepared from CuBr2. b) TEM image of

catalyst prepared from Cu(NO3)2·5/2H2O. c) Copper particle size distribution of

both catalysts.

Once the optimal reaction conditions were established, the prospect of

catalyst recycling was examined (Figure 19). The catalyst was recovered using a

magnet, washed with toluene and re-used under the same reaction conditions, to

render the expected product 11a but in only 72 % yield. A third cycle of

recovered catalyst provided a modest yield of 11a (44 %).

c)

a) b)


0

20

40

60

80

100

12

3

Yiel

d1

1a

(%)

Cycle

Figure 19. Recycling of the CuO-Fe3O4 catalyst.

The phenomenon of leaching was studied by ICP-MS analysis of the

resulting reaction solution mixture, 17 % of the initial amount of copper was

detected (0.002 % for iron), which could be due to the formation of different

soluble imine-copper complexes. To validate this hypothesis, the process was

repeated in the absence of amine. After 4 days of reaction with benzyl alcohol

and NaOH in toluene at 100 ºC, the solution obtained after trapping the catalyst

by a magnet was analysed by ICP-MS which revealed the presence of only 9.8 %

of the initial amount of copper, lower than that obtained under typical reaction

conditions involving the presence of amine.

In another trial, quinoline (100 mol%) was heated at 100 ºC in toluene

with the catalyst. A subsequent ICP-MS analysis showed an incorporation of 18

% of copper to the final solution which is similar to that obtained from typical

reaction conditions and substantially higher than that obtained in the absence of

amines. These data support our hypothesis of a leaching process. Moreover, the

TEM images of the recycled catalyst showed a drastic change in the copper

particle size from 7.0 ± 6 nm (maximum at 3 nm) of freshly prepared catalyst to

13.0 ± 6 nm for the recycled catalyst (Figure 20).

This change in particle size may affect the reactivity of the recycled

catalyst. However, the BET surface area did not suffer a great change, from 6.2

m2g

-1 for the initial catalyst, to 11.4 m

2g

-1, for the used catalyst, which is

practically the same specific area.


0

20

40

60

Par

ticl

es

Particle size (nm)

Recycled catalyst

Fresh catalyst

Figure 20. a) TEM image of fresh CuO-Fe3O4 catalyst. b) TEM image of

recycled CuO-Fe3O4 catalyst. c) Copper particle size distribution.

It should be pointed out that the TEM images of the recycled catalyst

from the aforementioned treatment without amine showed a similar particle size

distribution (3.7 ± 1.5 nm) to that of the initial catalyst. However, the results

obtained from treatment with quinolone were slightly different (9.2 ± 1.9 nm),

indicating that nitrogen-containing compounds may not only favour the leaching

process but may also facilitate the sinterization of CuO-nanoparticles (Figure 21).

a) b)

c)


0

30

60

90

0-1

1-2

2-3

3-4

4-5

5-6

6-7

7-8

8-9

9-1

0

10

-11

11

-12

12

-13

13

-14

14

-15

Par

ticl

es

Particle size (nm)

Without amine

Quinoline

Figure 21. a) TEM image of CuO-Fe3O4 catalyst after reaction without amine. b)

TEM image of CuO-Fe3O4 catalyst after reaction with quinoline. c) Copper

particle size distribution of with different conditions reactions.

The optimised protocol was then applied to other substrates in order to

study the scope of the reaction (Table 9). The protocol gave excellent results in

the case of aromatic alcohols, independently of the presence of electron-

withdrawing or electron-donating groups; even the relative position of this

substituent had no influence on the reaction efficiency. However, the reaction

failed when aliphatic 3-methyl-1-butanol was used as a substrate (Table 9, entry

19). The methodology could be applied to aromatic amines, with different

functional groups as well as to aliphatic amines. However, the use of aliphatic

amines rendered slightly lower yields than those obtained for aromatic ones

(compare, for instance, Table 9, entries 1 and 5-7).

c)

a) b)


Table 9. Preparation of imines derivatives.a

Entry Ar R Product Yield (%)

b

1 Ph Ph 11a 98

2 Ph 3-ClC6H4 11b 71

3 Ph 4-MeOC6H4 11c 73

4 Ph 2,5-Me2C6H3 11d 41

5 Ph n-Bu 11e 75

6 Ph t-BuCH2 11f 45

7 Ph Me(CH2)11 11g 77

8 4-ClC6H4 Ph 11h 80

9 4-ClC6H4 3-ClC6H4 11i 98

10 4-MeC6H4 Ph 11j 69

11 4-MeOC6H4 Ph 11k 97

12 4-MeOC6H4 3-ClC6H4 11l 30

13 3-MeC6H4 Ph 11m 99

14 3-MeOC6H4 Ph 11n 62

15 3,5-Me2C6H3 Ph 11o 74

16 3,5-Me2C6H3 3-ClC6H4 11p 86

17 3,5-(MeO)2C6H3 Ph 11q 93

18 3,5-(MeO)2C6H3 3-ClC6H4 11r 89

19 i-PrCH2 Ph 11s 0 a

Reaction carried out using compounds 9 (1.0 mmol), and 10 (2.0 mmol) in 3 mL of

toluene. b Isolated yield after bulb-to-bulb distillation.

The success obtained in preparing imines using our impregnated copper

on magnetite catalyst inspired us to formulate a process to synthetise aldehydes

from alcohols (Table 10). Thus, the above standard reaction of arylmethanol

derivatives 9 with aniline catalysed by impregnated copper on magnetite was

followed by treatment with aqueous HCl, following by catalyst removal with a

magnet. The whole process provided an organic layer in which the aldehyde

could be isolated in good yields and with excellent purity simply by solvent

removal under low pressure. Addition of Na2CO3 to the aqueous solution and

extraction of the resulting mixture rendered the pure aniline (10a) in good yields

(76-96 %), showing the possible recyclability of the integrated process. The


reaction was found to proceed with excellent yields regardless of the presence of

electron-donating or electron-withdrawing groups on the aromatic ring. Only in

the case of the 2,6-dichlorophenyl derivative the yield of the corresponding

arenecarbaldehyde 2t was significantly lower (Table 10, entry 7). This is perhaps

due to the steric hindrance of the starting reagent, since the related 3,4-

dichlorophenyl derivative gave the corresponding aldehyde 2u in good yield

(Table 10, entry 8).

Table 10. Preparation of arenecarbaldehydes.a

Entry Ar Product Yield (%)

b

1 Ph 2a 99

2 4-ClC6H4 2j 93

3 4-MeC6H4 2d 88

4 4-MeOC6H4 2e 96

5 3-MeC6H4 2c 85

6 3-MeOC6H4 2s 95

7 2,6-Cl2C6H3 2t 32

8 3,4-Cl2C6H3 2u 88

9 3,5-Me2C6H3 2v 98

10 3,5-(MeO)2C6H3 2w 94

11 3,4,5-(MeO)3C6H2 2f 81 a

Reaction carried out using compounds 9 (1.0 mmol), and 10a (2.0 mmol) in 3 mL of

toluene for the first step; and HCl (2 mL) and Et2O (2 mL) for the second step. b Isolated yield after extraction.

Very recently, a new entry to the synthesis of imines has been

accomplished using nitroarenes as the nitrogen-containing moiety and an excess

of alcohol as the source of both the aldehyde and the reducing agent of the nitro

moiety. The reaction of nitrobenzene (12a) with four equivalents of alcohol 9

catalysed by the impregnated copper catalyst gave the expected imines 11 with

reasonable yields, independently of the used alcohols and of the substitution at

the aromatic ring (Table 11). Although the process using simple amines is more

effective than the one using nitroarenes, it is interesting to note that the same


copper catalyst could be used for both processes and demonstrated similar

activities in both scenarios.

Table 11. Preparation of N-phenyl imine derivatives.a


b

1 Ph 11a 70

2 4-MeC6H4 11j 61

3 4-MeOC6H4 11k 84

4 3-MeC6H4 11m 58 a

Reaction carried out using compounds 9 (4.0 mmol), and 12 (1.0 mmol) in 3 mL of

toluene. b Isolated yield after bulb-to-bulb distillation.

Finally, we studied the possible catalytic activity of the impregnated

copper on magnetite for the preparation of imines starting from primary amines

(13). Thus, the treatment of arylmethylamines with a base and substoichiometric

amounts of the copper catalyst under the same reaction conditions gave the

expected imines 14 in good yields (Table 12); the apparent discrepancy of yield

in the formation of 14b was more a matter of isolation difficulties rather than of

the product formation.

Table 12. Preparation of aryl imine derivatives.a


b

1 Ph 14a 95

2 4-MeC6H4 14b 49

3 3-MeC6H4 14c 71 a Reaction carried out using compound 13 (2.0 mmol) in 3 mL of toluene.

b Isolated yield after bulb-to-bulb distillation.


3. CROSS-DEHYDROGENATIVE COUPLING REACTION IN DEEP

EUTECTIC SOLVENTS

3.1 INTRODUCTION

Tretrahydroisoquinolines are widely present in Nature.148

The synthesis

of these compounds has been payed much attention in industrial and academic

research due to their biological and pharmaceutical applications, such as

anticancer149

and anticonvulsant agents,150

enzyme inhibitors,151

ligand

receptors152

and therapeutic agents.153

The C-C bond formation via C-H activation154

is one of the most

challenging reactions in organic synthesis. Various strategies for transition-

metal-catalysed C-H bond activation have been of significant interest, as they are

environmentally friendly processes, and no functionalization step is needed.

The C(sp3)-H bond activation at the α-position of nitrogen has been

broadly used in different transformations. The key step, in this transformation, is

the generation of an iminium intermediate assisted by the lone pair of nitrogen

atom, via a single-electron transfer (SET) mechanism.155

For this purpose an important number of different methods have been

developed, with metal-catalysed protocols being well stablished. Different

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iron,157

copper,158

ruthenium,159

rhodium,160

palladium,161

antimonium,162

iridium163

or gold,164

among others have been

recently introduced. In all cases, the protocols needed a highly reactive oxidising

agent such as peroxides or high oxygen pressure. Moreover, the lack of

recyclability, and the high catalyst loading (5-20 mol%) made these protocols

unsustainable for large chemical production.

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Wang, M. Wu, X. Jia, X. Wang, Y. Yuan, H. Xie, Org. Biomol. Chem. 2014, 12, 3123-3128. 163 a) A. G. Condie, J. C. González-Gómez, C. R. J. Stephenson, J. Am. Chem. Soc. 2010, 132,

1464-1465; b) Z.-J. Feng, J. Xuan, X.-D. Xia, W. Ding, W. Guo, J.-R. Chen, Y.-Q. Zou, L.-Q.

Lu, W.-J. Xiao, Org. Biomol. Chem. 2014, 12, 2037-2040. 164 T. Amaya, T. Ito, T. Hirao, Heterocycles 2012, 86, 927-932.


The metal-free version using organic radical promoters, recently

published, has similar drawbacks.165

Within the framework of green chemistry, solvents occupy a strategic

place. In order to be qualified as a green medium, the components of the solvent

have to meet different criteria such as availability, non-toxicity, biodegradability,

recyclability, inflammability, renewability and low price, among others. DES

(Deep Eutectic Solvent) is an environmentally benign alternative to hazardous

(organic) solvents and, in many cases, might replace them. DESs are liquid

systems formed from a eutectic mixture of a solid Lewis or Brønsted acids and

bases which can contain a variety of anionic and/or cationic species.166

These two

components are capable of self-association, often through a strong bond

interaction, to form a eutectic mixture with a melting or phase transition point

lower than that of each individual component.167

The properties of a solvent, such as conductivity, viscosity, vapour

pressure and thermal stability can be fine-tuned by the choosing appropriately the

mixture components, with the large-scale preparation being feasible. Besides

these interesting advantages, the application of DES in organic synthesis is in its

infancy,168

with the related metal-catalysed process being nearly unknown.169

Only, very recently, the superparamagnetic CuFeO2 has been used as catalyst for

the multicomponent synthesis of imidazo[1,2-a]pyridines in DMU-citric acid

165 a) A. S.-K. Tsang, P. Jensen, J. M. Hook, A. S. K. Hashmi, M. H. Todd, Pure Appl. Chem.

2011, 83, 655-665; b) W. Fu, W. Guo, G. Zou, C. Xu, J. Fluorine Chem. 2012, 140, 88-94; c) J.

Dhineshkumar, M. Lamani, K. Alagiri, K. R. Prabhu, Org. Lett. 2013, 15, 1092-1095; d) G.

Zhang, Y. Ma, S. Wang, W. Kong, R. Wang, Chem. Sci. 2013, 4, 2645-2651; e) A. Tanoue,

W.-J. Yoo, S. Kobayashi, Org. Lett. 2014, 16, 2346-2349; f) L. Huang, J. Zhao, RSC Adv.

2013, 3, 23377-23388; g) H.-M. Huang, Y.-J. Li, Q. Ye, W.-B. Yu, L. Han, J.-H. Jia, J.-R. Gao,

J. Org. Chem. 2014, 79, 1084-1092; h) J. F. Franz, W. B. Kraus, K. Zeitler, Chem. Commun.

2015, 51, 8280-8283. 166 E. L. Smith, A. P. Abbot, K. S. Ryder, Chem. Rev. 2014, 114, 11060-11082. 167 a) C. Ruβ, B. König, Green Chem. 2012, 14, 2969-2982; b) Q. Zhang, K. D. O. Vigier, S.

Royer, F. Jérôme, Chem. Soc. Rev. 2012, 41, 7108-7146; c) Y. Dai, J. van Spronsen, G.-J.

Witkamp, R. Verpoorte, Y. H. Choi, Anal. Chim. Acta 2013, 766, 61-68; d) M. Francisco, A.

van den Bruinhorst, M. C. Kroon, Angew. Chem. Int. Ed. 2013, 52, 3074-3085; e) B. Tang, K.

H. Row, Monatsh Chem. 2013, 144, 1427-1454; f) A. Paiva, R. Craveiro, I. Aroso, M. Martins,

R. L. Reis, A. R. C. Duarte, ACS Sustainable Chem. Eng, 2014, 2, 1063-1071. 168 a) P. Liu, J.-W. Hao, L.-P. Mo, Z.-H. Zhang, RSC Adv. 2015, 5, 48675-48705; b) D. A. Alonso,

A. Baeza, R. Chinchilla, G. Guillena, I. M. Pastor, D. J. Ramón, Eur. J. Org. Chem. 2016, 612-

632. 169 a) J. García-Alvarez in Green Technologies for the Environment, (Ed.: R. Luqie, O. Obre),

ACS Books, New York, 2015, pp. 37-53; b) J. García-Alvarez, Eur. J. Inorg. Chem. 2015, 31,

5147-5157.


medium.170

With this in hand, we thought that impregnated copper on magnetite

could be an interesting catalyst for this transformation.

3.2 RESULTS

To start with this study, 2-(4-fluorophenyl)-1,2,3,4-

tetrahydroisoquinoline (15a) and phenylacetylene (5a) using impregnated copper

on magnetite as catalyst was selected as the model reaction for the optimization

of the conditions (Table 13).

Initially, the reaction was performed using different DES (entries 1-6),

obtaining the best result (entry 4) with the mixture choline chloride

(ChCl):ethylene glycol (1:2), with the only by-product observed being the

corresponding lactam 17a. Then, the influence of the amount of catalyst was

evaluated, obtaining similar results when the catalyst loading decreased (entry 7).

However, a further decrease of catalyst loading to 0.37 mol% (entry 8) led to

lower yield. Increasing the amount of copper to 3.64 mol% (entry 9), the yield

could be improved. It should be pointed out that even this high amount of copper

catalyst is one of the lowest metal catalyst loadings reported so far in the

literature for this type of transformations.

The addition of only one equivalent of alkyne led to a decrease of the

reaction yield (entry 10), and the addition of an excess of alkyne did not improve

it (entry 11). The study of the temperature of the reaction was carried out

obtaining, after seven days of reaction at room temperature, a full conversion of

the starting material (entry 12). Increasing the temperature up to 100 ºC,

decreased the yield (entry 13). The reaction was carried out under an argon

atmosphere (entry 14) obtaining a very low yield, highlighting the capital role of

oxygen in the air as the final oxidising agent. To finish with the optimization of

the reaction conditions, the reaction was tested using LED irradiation

(photoredox conditions), microwave irradiation and an ultrasound bath (entries

15-17), but the yield did not improved. Finally, the reaction was repeated in only

ethylene glycol obtaining a modest result (entry 18).

170 J. Lu, X.-T. Li, E.-Q. Ma, L.-P. Mo, Z.-H. Zhang, ChemCatChem 2014, 6, 2854-2859.



Entry Catalyst (mol%) DES (molar ratio) T

(ºC) 16a (%)

b

17a (%)

b

1 CuO-Fe3O4 (1.82) ChCl:urea (1:2) 50 55 29

2 CuO-Fe3O4 (1.82) AcChCl:urea (1:2) 50 50 13

3 CuO-Fe3O4 (1.82) ChCl:glycerol (1:2) 50 59 11

4 CuO-Fe3O4 (1.82) ChCl:ethylene glycol (1:2) 50 83 2

5 CuO-Fe3O4 (1.82) Ph3P+MeBr

-:glycerol (1:2) 50 60 11

6 CuO-Fe3O4 (1.82) ChCl:resorcinol (1:1) 50 10 21




10c CuO-Fe3O4 (1.82) ChCl:ethylene glycol (1:2) 50 75 2

11d

CuO-Fe3O4 (1.82) ChCl:ethylene glycol (1:2) 50 92 2

12 CuO-Fe3O4 (3.64) ChCl:ethylene glycol (1:2) RT 57e 0


14f


15g


16h


17i


18 CuO-Fe3O4 (3.64) Ethylene glycol 50 40 9 a

Reaction carried out using compounds 15a (0.5 mmol), and 5a (1 mmol) in 1mL of

DES. b Conversion determined by

1H-NMR.

c Reaction carried out using compounds 15a (0.5 mmol), and 5a (0.5 mmol) in 1mL of

DES. d Reaction carried out using 15a (0.5 mmol), and 5a (2.5 mmol) in 1mL of DES.

e 99 % of conversion after 7 days of reaction.

f Reaction carried out under an Argon atmosphere.

g Reaction carried out using visible LED light irradiation.

h Reaction carried out under microwave irradiation during 10 h at 80W.

i Reaction carried out under ultrasound bath during 8 h.


To prove the essential role of DES [ChCl:ethylene glycol], other VOC

solvents were tested as reaction medium (Figure 22). In all cases, a mixture of

products 16a and 17a were obtained in a ratio close to 1:1, highlighting the role

of DES to minimise the lactam formation. It should be pointed out that when the

reaction was performed in 1,4-dioxane as solvent the main product was 17a.

0

50

100

Yie

ld (

%)

16a

17a

Figure 22. Yield obtained yield in different volatile organic solvents.

We also found an interesting correlation between DES conductivity and

the yield of the desired product (Figure 23), in such a way that a higher

conductivity affords a better yield. Since an iminium intermediate is generated in

the reaction media, a better conductivity means an easier movement of ions that

could explain the increase in the yield. Nevertheless, the correlation between

obtained yields and conductivities of VOC solvents and of water did not fit with

the aforementioned plot. It should be pointed out that the reaction using

ChCl:1,2-propanediol:water (1:1:1, conductivity 12.09 mS/cm) or

ChCl:glycerol:water (1:2:1, conductivity 13.78 mS/cm) gave the product 16a in

46 and 53 % yield respectively. Although these two mixtures have higher

conductivity than the previous DES used, the presence of water changed the

direct proportion between yield and conductivity, probably due to the highly

nucleophilic character of water.


0

10

20

30

40

50

60

70

80

90

0 2 4 6 8

Yie

ld 1

6a

(%

)

Conductivity (mS/cm)

Yield (%) = 4,0·Conductivity + 52,6

R2 = 0,9915

H2O

ChCl:urea

(1:2)

ChCl:(CH2OH)2

(1:2)

ChCl:glycerol (1:2)

Ph3PMeBr:glycerol

(1:2)

Figure 23. Relationship between solvent conductivity and yield.

Once the optimal conditions were determined, the reaction was repeated

with a variety of catalysts prepared by the simple impregnation protocol85a

(Table

14). The reaction without a catalyst gave a poor yield (entry 2). Then, the activity

of the support was evaluated using magnetite as the unique catalyst.

Microparticles and nanoparticles of magnetite (entries 3 and 4) were used with

the results showing the inactivity of the support, reaching a low conversion of

product and highest amount of compound 17a, as the only by-product detected

by CG-MS. Once the activity of magnetite was tested, different metal oxides

impregnated on magnetite (entries 5-17) were evaluated as catalysts, observing

that none of them gave better results than the copper catalyst (entry 1). After that,

different copper salts were tested (entries 18-20), obtaining from moderate to

good results, but poorer results than the one obtained by the heterogeneous

copper oxide impregnated on magnetite.

After, that, the addition of a mixture of CuO and Fe3O4 was evaluated

(entry 21), obtaining a decrease in the conversion compared to the impregnated

catalyst, which seems to be related with a synergic effect between the metal

oxide and support in the catalyst.



Entry Catalyst (mol%) 16a (%)

b 17a (%)

b

1 CuO-Fe3O4 (3.64) 95 3

2 - 6 20

3 Micro-Fe3O4 (259.15) 15 48

4 Nano-Fe3O4 (259.15) 0 34

5 CoO-Fe3O4 (2.83) 4 31

6 NiO-Fe3O4 (2.06) 30 30

7 Ru2O3-Fe3O4 (2.64) 8 28

8 Rh2O3-Fe3O4 (0.84) 0 45

9 PdO-Fe3O4 (2.43) 46 7

10 Ag2O/Ag-Fe3O4 (2.5) 13 0

11 OsO2-Fe3O4 (1.03) 5 21

12 IrO2-Fe3O4 (0.26) 33 47

13 PtO/PtO2-Fe3O4 (1.08) 33 7

14 Au2O3/Au-Fe3O4 (0.28) 13 4

15 PdO/Cu-Fe3O4 (3.05/1.79) 35 28

16 NiO/Cu-Fe3O4 (1.82/1.76) 78 2

17 WO3-Fe3O4 (1.13) 37 8

18 CuCl2 (8.5) 88 5

19 CuO (4.04) 46 10

20 Cu(OAc)2 (3.64) 80 6

21 CuO (3.64) + Fe3O4 (255.26) 51 9 a

Reaction carried out using compounds 15a (0.5 mmol), and 5a (1 mmol) in 1mL of

DES. b Conversion determined by

1H-NMR.

Once the best conditions were established, the scope of the reaction was

evaluated. First of all, different pro-electrophiles were tested by modifying the

nitrogen substituent at the tetrahydroisoquinoline ring (Table 15). The reaction

was carried out with different N-substituted substrates. When the substituent was

an aryl group, bearing both, electron-withdrawing or electron-donating groups

(entries 1 and 3), the results were excellent. In the case of phenyl derivatives, the


yield was moderate. On the other hand, when the reaction was carried out with

the free amine or with a strong electron-withdrawing group such as tosyl, the

reaction did not take place at all (entries 4 and 5), recovering the starting material

unchanged.

Table 15. Scope of the reaction with different pro-electrophiles.a

Entry R Product Yield (%)

b

1 4-FC6H4 16a 94

2 Ph 16b 63

3 4-MeOC6H4 16c 90

4 Ts 16d 0/0c

5 H 16e 0 a

Reaction carried out using compounds 15 (0.5 mmol), and 5a (1 mmol) in 1mL of

DES. b Isolated yield after bulb-to-bulb distillation.

c Yield obtained after 7 days of reaction at room temperature.

Having studied the scope of pro-electrophiles, we tested a variety of

alkynes as pro-nucleophiles (Table 16). Once again, the reaction took place

obtaining from moderate to good yields when the alkyne had an electron-rich

(entry 1) or electron-poor (entries 2-5) aryl substituents. Not only aryl

substituents were tested, but also olefinic and aliphatic ones (entries 6-9) and the

reaction still worked smoothly. It has to be pointed out that, in the case of using a

dialkyne, the reaction was selective in such a way that only one of the two

alkynes reacted (entry 8).


Table 16. Scope of the reaction using different alkynes.a

Entry R

2 Product Yield (%)

b

1 4-MeOC6H4 16f 57

2 4-BrC6H4 16g 61

3 4-CF3C6H4 16h 68

4 3-ClC6H4 16i 58

5 2-BrC6H4 16j 64

6 1-C6H9 16k 37

7 C6H11 16l 83

8 HC≡CC5H10 16m 71

9 THPOCH2c

16n 65 a

Reaction carried out using compounds 15a (0.5 mmol), and 5 (1 mmol) in 1mL of

DES. b Isolated yield after distillation.

c THPO stands for 2-(tetrahydro-2H-pyran-2-yl)oxy.

After the study of alkynes as pro-nucleophiles was completed, we

decided to check other types of reagents (Table 17), such as nitroalkanes (entry

1), heterocycles (entry 2), phosphonates (entry 3), silyl enol ethers (entry 4),

ketones (entries 5 and 6) and fluoroborates (entry 7), proving that this

methodology can be applied to a wide range of substrates with very different

properties and obtaining similar results. It should be noted that both, silyl enol

ether and ketone (entries 4 and 5) afford the same product 16r but with different

diastereomeric ratios. Only the starting material alongside a small amount of by-

product 17a was detected from the crude of the reaction, when a moderate or low

yield of product was obtained.


Table 17. Scope of the reaction with different pro-nucleophiles.a

Entry Nu-H Product Yield (%)

b

1 MeNO2 16o 95/15c

2

16p 84

3

16q 45

4

16r 50d

5

16r 38e

6

16s 24

7 16t 51 a

Reaction carried out using compounds 15a (0.5 mmol), and 18 (1 mmol) in 1mL of

DES. b Isolated yield after bulb-to-bulb distillation.

c Yield after 7 days at room temperature.

d Mixture of isomers syn:anti (1:1.25).

e Mixture of isomers syn:anti (1.4:1).

In order to stablish the reusability of the catalyst and DES, the reaction

with nitromethane (Table 17, entry 1) was repeated under standard conditions

(Figure 24). When the reaction was completed, the mixture was extracted with

cyclopentyl methyl ether, recently reported as a potential green alternative


solvent.171

All organic compounds were removed and the mixture of DES and

catalyst, lower phase in the decantation, was reused under the same reaction

conditions. This catalytic mixture could be recycled up to ten times without any

decrease of the yield.

When only the catalyst was recovered by magnetic decantation, and fresh

solvent was used, the obtained yield showed an important decrease, pointing out

the sharp decrease of the catalyst after four reaction cycles. In fact, the ICP-MS

analysis of crude reaction solution showed the leaching of a small amount of

copper (14.2 ppm; 3.6 % of the initial amount) and iron (0.30 ppm; 0.001 % of

the initial amount), these values were completely different from the reported

solubility of these metal oxides in this DES (3.68 ppm for CuO and 10.85 ppm

for Fe3O4).172

The higher solubility in DES of copper species seems to show that

the heterogeneous catalyst is only a reservoir of highly active copper clusters.

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10

Yie

ld 1

6o

(%)

Cycle

CuO-Fe3O4

CuO-Fe3O4 + DES

Figure 24. Recycling of the CuO-Fe3O4 catalyst and CuO-Fe3O4 + DES.

171 a) K. Watanabe, N. Yamagiwa, Y. Torisawa, Org. Processs Res. Dev. 2007, 11, 251; b) A.

Kadam, M. Nguyen, M. Kopach, P. Richardson, F. Gallou, Z.-K. Wan, Green Chem. 2013, 15,

1880. 172 A. P. Abbot, G. Gapper, D. L. Davies, K. J. McKenzie, S. U. Obi, J. Chem. Eng. Data 2006,

51, 1280-1282.


To try to understand more this effect, the standard reaction was

performed as usual (Table 14, entry 1) and, after 36 h, only the catalyst was

removed by magnetic decantation, with the yield of 16a being estimated in 40 %

by CG-MS. The mixture was heated again for 36 h, and after the usual work up

the yield of compound 16a increased up to 65 %, with the oxidised by-product

17a reaching 25 %. This fact seems to indicate that a partial copper catalyst

specie solubilisation took place during the reaction. However, at the end of the

first cycle, the catalyst was removed, by magnetic decantation, as well as the

organics by cyclopentyl methyl ether extraction (yield of compound 16a 93 %).

Then, the used DES medium was employed alone in other cycles (without

catalyst) and the final product 16a was obtained in 52 % (29 % for by-product

17a). These two experiments showed that there was a partial leaching of active

species, capable of performing the oxidative step. However, and due to the great

amount of by-product, these leached species seemed to be less effective to

catalyse the final nucleophilic addition.

In order to study the effect of the reaction conditions on the copper

heterogeneous catalyst, TEM images of the catalyst were analysed to obtain the

nanosize distribution of the copper nanoparticles before and after one reaction

cycle (Figure 25). A uniform size distribution was found, 60 % of nanoparticles

have an average size between 2-4 nm on the recycled catalyst. In the fresh

catalyst, 63 % of nanoparticles have an average size between 2-6 nm, showing a

small overall decrease in the particle size with the reaction cycles which is in

concordance with a partial solubilization-readsoption of copper species.


0

20

40

60

80

Par

ticl

es

Particle size (nm)

Recycled catalyst

Initial catalyst

Figure 25. a) TEM image of fresh CuO-Fe3O4 catalyst. b) TEM image of

recycled CuO-Fe3O4 catalyst. c) Particle size distribution of fresh and recycled

catalyst.

a) b)

c)


The XPS and Auger Electron Spectroscopy (AES) studies of the catalyst

showed the transformation of the initial Cu(0) (Figure 15), onto the

corresponding copper(I) oxide and Cu(OH)2 in the recycled catalyst (Figure 26)

with CuO being the main species in both cases. These changes in particle size as

well as in the initial oxidation state did not seem to affect the activity of the

catalyst, since it could be reused ten times without losing its activity.

-50

450

950

1450

1950

2450

2950

3450

926 931 936 941 946

Inte

nsi

ty/a

rb. unit

s

Binding energy (eV)

After reactionFit

Cu2O 2p3/2

CuO 2p3/2

Cu(OH)2 2p3/2

CuO 2p3/2 sat.

CuO 2p3/2 sat.

11400

11600

11800

12000

12200

12400

12600

12800

13000

13200

13400

899 904 909 914 919 924

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Cu3LVV

Figure 26. a) XPS of recycled copper catalyst. b) AES of recycled copper

catalyst.

a) b)


4. SYNTHESIS OF BENZO[b]FURANS FROM ALKYNES AND 2-

HYDROXYARYLCARBONYL DERIVATIVES

4.1 INTRODUCTION

Heterocycles are important structural motifs of a wide range of natural

substrates, compounds of pharmaceutical interest and commodity chemicals.

Benzo[b]furan173

core is present in a large number of natural products and has

attracted a great deal of interest due to its biological activity like anticancer,

antimicrobial, antiviral or anti-inflammatory activity among others, and its

potential applications as pharmacological agents.174

These compounds are

important intermediates for the synthesis of a variety of useful and novel

heterocyclic systems that are otherwise difficult to obtain synthetically.175

The synthesis of these heterocyclic compounds has attracted enormously

the attention of synthetic organic chemists, which has been developed through

different methodologies,176

but the most common route used is the cyclization

through different mechanism starting from phenols.177

An interesting alternative,

involves the formation of a C-C bond through a Sonogashira type process using

2-iodophenol derivatives and the subsequent cyclization to give the

corresponding benzo[b]furan.90,178

173 R. Benassi in Comprehensive Heterocyclic Chemistry II, Vol. 2, ch. 2.05, (Eds.: A. R.

Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 259-295. 174 a) B. A. Keay in Comprehensive Heterocyclic Chemistry II, Vol. 2, ch. 2.08, (Eds.: A. R.

Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 395-435; b) A.

Radadiya, A. Shah Eur. J. Med. Chem. 2015, 97, 356-376; c) H. Khanam, Shamsuzzaman, Eur.

J. Med. Chem. 2015, 97, 483-504. 175 a) H. Heaney, J. S. Ahn in Comprehensive Heterocyclic Chemistry II, Vol. 2, ch. 2.06, (Eds.: A.

R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 297-348; b) A.

A. Abu-Hashem, H. A. R. Hussein, A. S. Aly, M. A. Gouda, Synth. Commun. 2014, 44, 2899-

2920. 176 a) W. Friedrichsen in Comprehensive Heterocyclic Chemistry II, Vol. 2, ch. 2.07, (Eds.: A. R.

Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 352-392; b) C. P.

Dell in Science of Synthesis, Vol. 10, ch. 1, (Eds.: E. J. Thomas), Georg Thieme Verlag,

Stuttgart, 2002, 1. pp. 11-86; c) A. A. Abu-Hashem, H. A. R. Hussein, A. S. Aly, M. A. Gouda,

Synth. Commun. 2014, 44, 2285-2312; d) S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Biomol.

Chem. 2011, 9, 641-652. 177 a) E. J. Guthrie, J. Macritchie, R. C. Hartley, Tetrahedron Lett. 2000, 41, 4987-4990; b) T. Pei,

C.-Y. Chen, L. CiMichele, I. W. Davies, Org. Lett. 2010, 12, 4972-4975; c) S. Ghosh, J. Das,

Tetrahedron Lett. 2011, 52, 1112-1116; d) J. Liu, Z. Liu, P. Liao, X. Bi, Org. Lett. 2014, 16,

6204-6207. 178 a) C. G. Bates, P. Saejueng, J. M. Murphy, D. Venkataraman, Org. Chem. 2002, 4, 4727-4729;

b) M. Nagamochi, Y.-Q. Fang, M. Lautens, Org. Lett. 2007, 9, 2955-2958; c) C. Rossy, E.

Fouquet, F.-X. Felpin, Beilstein J. Org. Chem. 2013, 9, 1426-1431.


Alternatively, it has been demonstrated that the addition of ortho-

hydroxy arylalkynes to N-tosylhydrazones179

catalysed by copper salts gave

directly the corresponding benzo[b]furans. An alternative route, was designed

avoiding the high cost of the ortho-functionalised arylalkynes, starting from the

corresponding N-tosylhydrazone, using terminal alkynes, acetonitrile as solvent

and the homogeneous CuBr (10 mol%) as catalyst.180

We anticipated that our copper catalyst could be the promoter in the

heterogeneous approach to their synthesis. Moreover, we expected that using this

catalyst the mandatory hydrazone synthesis could be overcome.

4.2 RESULTS

The coupling of 2-hydroxybenzaldehyde (19a) with phenylacetylene (5a)

using impregnated copper(II) oxide on magnetite, in the presence of 4-

methylbenzenesulfonohydrazide, was selected as the model for the optimization

of the reaction conditions (Table 18). Initially, the reaction was studied with

different solvents (entries 1-8) and in its absence (entry 9), obtaining only good

yield when EtOH was used.

Some organic and inorganic bases were examined (entries 10-18)

obtaining traces of the product with organic bases and moderate yields when

some inorganic hydroxide salts were used. The reaction failed in the absence of

base (entry 19). Furthermore, the decrease of the temperature on the reaction was

tested (entries 20 and 21) obtaining lower yields. The reaction with only one

equivalent of base (entry 22) was tested obtaining a decrease in the reaction

yield. Moderate results were obtained using three equivalents of terminal alkyne

(entry 23) or using different amounts of solvent (entries 24 and 25).

179 T. Xiao, X. Dong, L. Zhou, Org. Biomol. Chem. 2013, 11, 1490-1497. 180 L. Zhou, Y. Shi, Q. Xiao, Y. Liu, F. Ye, Y. Zhang, J. Wang, Org. Lett. 2011, 13, 968-971.



Entry Solvent Base T (ºC) Yield (%)

b

1 THF Cs2CO3 100 26

2 PhMe Cs2CO3 100 0

3 CH3CN Cs2CO3 100 0

4 1,4-Dioxane Cs2CO3 100 3

5 DMF Cs2CO3 100 0

6 H2O Cs2CO3 100 0

7 DMSO Cs2CO3 100 0

8 EtOH Cs2CO3 100 91

9 - Cs2CO3 100 0

10 EtOH KOAc 100 0

11 EtOH MeONa 100 3

12 EtOH Et3N 100 0

13 EtOH DABCO 100 0

14 EtOH KOH 100 56

15 EtOH NaOH 100 43

16 EtOH CsOH·H2O 100 58

17 EtOH t-BuOK 100 34

18 EtOH K2CO3 100 0

19 EtOH - 100 0



22c

EtOH Cs2CO3 100 35

23d

EtOH Cs2CO3 100 63

24e

EtOH Cs2CO3 100 58

25f

EtOH Cs2CO3 100 44 a

Reaction carried out using compounds 19a (0.4 mmol), 5a (0.5 mmol), and 1.2 mmol

of base in 2 mL of the corresponding solvent. b Yield calculated by GC using tridecane as an internal standard.

c Reaction carried out using 19a (0.4 mmol), 5a (0.5 mmol), and 0.4 mmol of base in 2

mL of the corresponding solvent. d

Reaction carried out using 19a (0.4 mmol), 5a (1.2 mmol), and 1.2 mmol of base in 2

mL of the corresponding solvent. e

Reaction carried out using 19a (0.4 mmol), 5a (0.5 mmol), and 1.2 mmol of base in 1

mL of the corresponding solvent.


Table 18. Continuation.

f Reaction carried out using 19a (0.4 mmol), 5a (0.5 mmol), and 1.2 mmol of base in 6

mL of the corresponding solvent.

Having stablished the optimal reaction conditions, different catalysts

prepared by simple impregnation protocol were tested on the reaction (Table

19).85a

First of all, the reaction was tested without catalyst (entry 1) and only with

the support of the catalyst (entries 2 and 3), but failed. After that, different

supported metal catalysts were tested (entries 4-16), obtaining traces of the

product with some of them. In the case of the palladium catalyst, the reaction

took place with moderate results. Having stablished that the impregnated

copper(II) oxide on magnetite was the best catalyst to perform this reaction (entry

6), different amounts of them were used (entries 17 and 18). Trying to decrease

the metal loading led to moderate results. Then, a variety of copper(I) and

copper(II) salts were used obtaining moderate yields (entries 19-25), and

confirming the higher activity of the supported catalyst.



Entry Catalyst (mol%) Yield (%)

b

1 - 5

2 Micro-Fe3O4 (162) 4

3 Nano-Fe3O4 (162) 4

4 CoO-Fe3O4 (3.54) 4

5 NiO-Fe3O4 (2.58) 3

6 CuO-Fe3O4 (2.40) 91

7 Ru2O3-Fe3O4 (3.30) 4

8 Rh2O3-Fe3O4 (1.05) 4

9 PdO-Fe3O4 (3.04) 32

10 Ag2O/Ag-Fe3O4 (3.13) 0

11 OsO2-Fe3O4 (1.28) 3

12 PtO/PtO2-Fe3O4 (1.34) 4

13 Au2O3/Au-Fe3O4 (0.35) 4

14 PdO/Cu-Fe3O4 (3.82/2.24) 6

15 NiO/Cu-Fe3O4 (2.28/2.20) 2

16 WO3-Fe3O4 (1.41) 2

17 CuO-Fe3O4 (1.2) 56

18 CuO-Fe3O4 (0.50) 44

19 CuO (2.40) 46

20 Cu(OAc)2 (2.40) 43

21 CuBr2 (2.4) 46

22 Cu2O (2.40) 36

23 CuCN (2.40) 49

24 CuBr (2.40) 61

25 Cu (powder) (2.40) 9 a Reaction carried out using 19a (0.4 mmol), and 5a (0.5 mmol).

b Yield calculated by GC using tridecane as an internal standard.

Once the optimal conditions were obtained, the problem of recycling was

examined. When the catalyst was recovered from the reaction mixture by using a

magnet, washed with ethanol and reused under the same reaction conditions only

traces (12 %) of the expected product 20a were obtained (Figure 27).


0

20

40

60

80

100

01

2

Yie

ld 2

0a

(%)

Cycle

Normal

recycling

Recycling by

bubbling up O2

Recycling using

t-BuOOH

Figure 27. Catalyst recycling.

To explain these phenomena some studies were carried out. First of all,

XPS and AES analysis before and after reaction (Figure 15 and 28), showing that

before the reaction the catalyst was formed by a mixture 4:1 of Cu(II):Cu(0)

nanoparticles, and after the reaction only Cu(0) was detected in the catalyst.

-100

400

900

1400

1900

2400

2900

3400

3900

4400

925 930 935 940 945 950 955 960 965

Inte

nsi

ty/a

rb. u

nit

s

Binding energy (eV)

Fit

Cu 2p3/2

Cu 2p1/2

5400

5500

5600

5700

5800

5900

6000

6100

6200

6300

6400

900 905 910 915 920 925

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Cu L3VV

Figure 28. a) XPS of recycled catalyst. b) AES of recycled catalyst.

TEM images were analysed before and after the reaction completion.

Before the reaction, 73 % of the copper oxide nanoparticles had an average size

between 2-6 nm, while after completion of the reaction, nanoparticles were not

detected and only a sheet of copper(0) were observed (Figure 29).

a) b)


0

10

20

30

40

50

0-1

1-2

2-3

3-4

4-5

5-6

6-7

7-8

8-9

9-1

0

10

-11

11

-12

12

-13

13

-14

14

-15

15-2

0

20

-25

25

-30

30

-35

Par

ticl

es

Particle size (nm)

Figure 29. a) TEM image of fresh copper catalyst. b) TEM image of recycled

copper catalyst. c) Particle size distribution of fresh copper catalyst.

The ICP-MS analysis of the reaction solution showed the presence of

copper (20.5 % of the initial amount). With these results in hand we could

speculate that the heterogeneous CuO-Fe3O4 catalyst could serve as a reservoir of

copper and when the copper goes to the reaction solution181

catalyses the

reaction, after that it is reduced by ethanol to give a Cu(0) sheet. In fact, the

obtained result using Cu(0) powder (entry 25, Table 19) was the same as the one

using the recycled catalyst.

181 For an example were recyclable impregnated cobalt oxide on magnetite acts as heterogeneous

reservoir for the homogeneous reaction see results from Chapter I.

a) b)

c)


The hot filtration experiment was performed to confirm that

nanoparticles of copper were leached to the homogeneous solution. After

completion of the standard reaction, the catalyst was removed and the reaction

was performed using 1-ethynyl-4-methoxybenzene as a substrate. After 6 h, the

reaction was quenched and only traces of the corresponding product 20j were

observed by 1H-NMR, recovering the starting alkyne unchanged.

Due to the inability of the catalyst to be reused after completion of the

reaction, re-oxidation was tried using different methodologies. In order to re-

oxidise the Cu(0) sheet formed, O2 was bubbled up during 4 h using THF as

solvent. However, only 22 % of yield of the product 20a was obtained when the

reaction was repeated . Another method used to re-oxidise the catalyst was to add

t-BuOOH in decane to the catalyst, which was previously washed with ethanol to

remove the reaction products. When the reaction was carried out using this re-

oxidised catalyst, heating the reaction at 70 ºC overnight, higher yield of product

20a compared to the aforementioned protocol, was achieved. However, the yield

was not good enough to consider this protocol the appropriate method for the

catalyst recycling (see Figure 27).

The mechanism for the formation of the final product are similar to the

previously introduced,180

as shown in Scheme 24. First of all, 2-

hydroxybenzaldehyde reacts with 4-methylbenzenesulfonohydrazide to give the

corresponding hydrazone, which in turn reacts with the base (Cs2CO3) to form 2-

(diazomethyl)phenol derivative. At the same time, phenylacetylene reacts with

the base giving copper phenyl acetylide. Having formed these two species, they

react with each other through a dediazotization reaction giving a copper carbene

intermediate that through a migratory insertion forms [1-(2-hydroxyphenyl)-3-

phenylprop-2-yn-1-yl]copper intermediate. The subsequent protonation of this

intermediate gives the corresponding allene, and finally it cycles generating the

corresponding benzo[b]furan.

To check if the reaction took place through the formation of the N-

tosylhidrazone, the reaction was performed starting from the previously prepared

4-methylbenzenesulfonohydrazine obtaining the product 20a with the same yield

than under standard reaction conditions. Moreover, when only 30 mol% of

TsNHNH2 was used in the reaction, only 29 % of conversion to product 20a was

obtained. These results seem to indicate that the formation of hydrazone is

fundamental in the reaction pathway.


Scheme 24. Proposed mechanism for the synthesis of benzo[b]furan.


The optimised reaction conditions were applied to other substrates (Table

20). Different substituted o-hydroxybenzaldehydes were used (entries 2 and 3)

obtaining good results. After that, some arylalkynes with electron-withdrawing

substituents in different positions at the aromatic ring were tested (entries 4-7),

obtaining good results.

Table 20. Scope of the reaction.a

Entry R

1 R

2 R

3 Product Yield (%)

b

1 H H Ph 20a 91 (58)c

2 t-Bu t-Bu Ph 20b 71

3 Br OMe Ph 20c 75

4 H H 2-BrC6H4 20d 70

5 H H 3-ClC6H4 20e 82

6 H H 4-BrC6H4 20f 90

7 H H 4-CF3C6H4 20g 92

8 H H 2-MeC6H4 20h 67

9 H H 3-MeC6H4 20i 67

10 H H 4-MeOC6H4 20j 68

11 H H CH3(CH2)4 20k 54

12 H H C6H11 20l 39

13 H H Cl(CH2)3 20m 70

14 H H CH2OC5H10O 20n 90

15 H H 3-(CH≡C)C6H4 20o 17

16 t-Bu t-Bu 4-BrC6H4 20p 69 a Reaction carried out using 19 (0.4 mmol), and 5 (0.5 mmol).


c Reaction carried out using 19a (8 mmol), and 5a (10 mmol).

Slightly lower yields were obtained when the reaction was performed

using arylalkynes with electron-donating groups at the aromatic ring (entries 8-

10). Then, some aliphatic alkynes were tested (entries 11-14) obtaining moderate

to good yields. The reaction could be performed selectively using a diyne, giving

the mono-benzofuran 20o in low yield (entry 15). To finish with the reaction

scope a combination of substituted o-hydroxybenzaldehyde and a substituted


alkyne was used to obtain compound 20p with good yield (entry 16). The

reaction could be scaled up to 20 fold obtaining product 20a in good yield (entry

1, footnote c).

The same reaction could be carried out with different o-

hydroxybenzofenones, reaching good yields of the corresponding substituted

benzo[b]furan in both cases, showing the great versatility of the reaction (Scheme

25).

Scheme 25. Reaction with o-hydroxyacetophenone.

CHAPTER III

Reactions performed using the

impregnated bimetallic Nickel(II)

Oxide/Copper(0) on Magnetite

111 Chapter III. Reactions performed by nanoparticles of Nickel and Copper

1. MULTICOMPONENT AZIDE-ALKYNE CYCLOADDITION

REACTION

1.1 INTRODUCTION

Although the 1,3-dipolar cycloaddition of azide derivatives and alkynes

dates back to the nineteenth century,182

the pioneer and seminal works of the

Medal183

and Sharpless184

groups on the copper-catalysed process were the

definitive push for the blossoming of this process.

The process allowed access to different 1,2,3-triazoles of great interest to

different areas of chemistry and pharmacy, in short reaction times, under mild

conditions, and as only one regioisomer.185

The tremendous success of the homogeneous copper(I) complexes as

catalysts has eclipsed the activity of others, such as those derived from

ruthenium, platinum, palladium,186

silver,187

or nickel,188

as well as the use of

other heterogeneous catalysts.

182 A. Michael, J. Prakt. Chem. 1893, 48, 94-95. 183 C. W. Tornøe, C. Christensen, M. Medal, J. Org. Chem. 2002, 67, 3057-3064. 184 V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41,

2596-2599. 185 a) V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem. 2006, 51-68; b) M.

Medal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952-3015; c) F. Amblard, J. H. Cho, R. F.

Schinazi, Chem. Rev. 2009, 109, 4207-4220; d) J. E. Hein, V. V. Fokin, Chem. Soc. Rev. 2010,

39, 1302-1315; e) L. Liang, D. Astruc, Coord. Chem. Rev. 2011, 255, 2933-2945; f) S. Díez-

González, Catal. Sci. Technol 2011, 1, 166-178; g) T. Jin, M. Yan, Y. Yamamoto,

ChemCatChem 2012, 4, 1217-1229. 186 C. Schilling, N. Jung, S. Bräse, in Organic Azides: Syntheses and Applications; Eds.: S. Bräse,

K. Banert, Wiley-VCH, Weinheim, 2010, pp 269-284. 187 a) J. McNulty, K. Keskar, R. Vemula, Chem. Eur. J. 2011, 17, 14727-14730; b) J. McNulty, K.

Keskar, Eur. J. Org. Chem. 2012, 5462-5470. 188 a) P. Paul, K. Nag, Inorg. Chem. 1987, 26, 2969-2974; b) R. Nasani, M. Saha, S. M. Mobin, S.

Mukhopadhyay, Polyhedron 2013, 55, 24-36.

Chapter III. Reactions performed by nanoparticles of Nickel and Copper 112

However, very recently some heterogeneous catalysts have emerged as

an alternative. Thus, the particles of copper,189

or its oxide derivatives,190

different copper salts supported on charcoal,191

on organic materials,192

as well as

on inorganic supports193

have been tested for this transformation, with copper

loading of these catalysts ranging from 0.5 to 12 mol%. Interestingly, some of the

inorganic supports were based on iron, permitted the development of magnetic

catalyst and separation, as it was for the case of copper supported iron (5

mol%),194

copperferrite (5 mol%),195

or ligand-grafted copper on magnetite (2

mol%).196

189 a) F. Alonso, Y. Moglie, G. Radivoy, M. Yus, Tetrahedron Lett. 2009, 50, 2358-2362; b) F.

Alonso, Y. Moglie, G. Radivoy, M. Yus, Eur. J. Org. Chem. 2010, 1875-1884; c) T. Jin, M.

Yan, Menggernbateer, T. Minato, M. Bao, Y. Yamamoto, Adv. Synth. Catal. 2011, 353, 3095-

3100; d) T. L. Cook, J. A. Walker, J. Mack, Green Chem. 2013, 15, 617-619. 190 a) J. Y. Kim, J. C. Park, H. Kang, H. Song, K. H. Park, Chem. Commun. 2010, 46, 439-441; b)

C. Shao, R. Zhu, S. Luo, Q. Zhang, X. Wang, Y. Hu, Tetrahedron Lett. 2011, 52, 3782-3785; c)

F. Alonso, Y. Moglie, G. Radivoy, M. Yus, Synlett 2012, 23, 2179-2182; d) H. Woo, H. Kang,

A. Kim, S. Jang, J. C. Park, S. Park, B.-S. Kim, H. Song, K. H. Park, Molecules 2012, 17,

13235-13252. 191 a) B. H. Lipshutz, B. R. Taft, Angew. Chem. Int. Ed. 2006, 45, 8235-8238; b) C-T. Lee, S.

Huang, B. H. Lipshutz, Adv. Synth. Catal. 2009, 351, 3139-3142; c) M. Fuchs, W. Goessler, C.

Pilger, C. O. Kappe, Adv. Synth. Catal. 2010, 352, 323-328; d) F. Alonso, Y. Moglie, G.

Radivoy, M. Yus, Adv. Synth. Catal. 2010, 352, 3208-3214; e) F. Alonso, Y. Moglie, G.

Radivoy, M. Yus, Org. Biomol. Chem. 2011, 9, 6385-6395; f) F. Alonso, Y. Moglie, G.

Radivoy, M. Yus, J. Org. Chem. 2011, 76, 8394-8405. 192 a) U. Sirion, Y. J. Bae, B. S. Lee, D. Y. Chi, Synlett 2008, 2326-2330; b) L. Bonami, W. van

Camp, D. van Rijckegem, F. E. Du Prez, Macromol. Rapid Commun. 2009, 30, 34-38; c) H.

Hagiwara, H. Sasaki, T. Hoshi, T. Suzuki, Synlett 2009, 643-647; d) Y. Wang, J. Liu, C. Xia,

Adv. Synth. Catal. 2011, 353, 1534-1542; e) M. Liu, O. Reiser, Org. Lett. 2011, 13, 1102-1105;

f) B. Kaboudin, Y. Abedi, T. Yokomatsu, Org. Biomol. Chem. 2012, 10, 4543-4548; g) A.

Kumar, S. Aerry, A. Saxena, A. de, S. Mozumdar, Green Chem. 2012, 14, 1298-1301; h) Y. M.

A. Yamada, S. M. Sarkar, Y. Ouzumi, J. Am. Chem. Soc. 2012, 134, 9285-9290. 193 a) S. Chassaing, M. Kumarraja, A. S. S. Sido, P. Pale, J. Sommer, Org. Lett. 2007, 9, 883-886;

b) S. Chassaing, A. S. S. Sido, A. Alix, M. Kumarraja, P. Pale, J. Sommer, Chem. Eur. J. 2008,

14, 6713-6721; c) K. Namitharan, M. Kumarraja, K. Pitchumani, Chem. Eur. J. 2009, 15, 2755-

2758; d) P. Veerkumar, M. Velayudham, K.-L. Lu, S. Rajogopal, Catal. Sci. Technol. 2011, 1,

1512-1525; e) J. C. Park, A. Y. Kim, J. Y. Kim, S. Park, K. H. Park, H. Song, Chem. Commun.

2012, 48, 8484-8486; f) M. N. S. Rad, S. Behrouz, M. M. Doroodmand, A. Movahediyan,

Tetrahedron 2012, 68, 7812-7821; g) S. Mohammed, A. K. Padala, B. A. Dar, B. Singh, B.

Sreedhar, R. A. Vishwakarma, S. B. Bharate, Tetrahedron 2012, 68, 8156-8162; h) L. Wan, C.

Cai, Catal. Lett. 2012, 142, 1134-1140. i) J. M. Collinson, J. D. E. T. Wilton-Ely, S. Díez-

González, Chem. Commun. 2013, 49, 11358-11360. 194 a) S. Kovács, K. Zih-Perényi, Á. Révész, Z. Novák, Synthesis 2012, 44, 3722-3730; b) R.

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Green Chem. 2012, 14, 625-632.


The intrinsic instability of organic azides, mainly those of low molecular

weight, has been an important drawback in the generalization of this approach for

the synthesis of interesting polyvalent structures. However, the use of a

multicomponent approach, generating the azide derivative in situ by reaction of

sodium azide and the corresponding organic reagent,190c,191b,d-f,192d,f,h,193h,195,196b,197

has permitted us to overcome this problem. With these antecedents in hands, we

thought that impregnated copper on magnetite could be a good catalyst for this

click process.

1.2 RESULTS

Although our ultimate goal was to get a heterogeneous and recyclable

catalyst for the multicomponent version of azide-alkyne cycloaddition, the study

was started with the standard two-component reaction between ethynylbenzene

(5a) and (azidomethyl)benzene (23a) catalysed by impregnated copper on

magnetite (Table 21).

The initial reaction was conducted in absence of catalyst at 110 ºC in

water, obtaining after 7 days a 1:1 mixture of both possible isomers. Then, the

reaction was repeated in the presence of copper catalyst in toluene at 70 ºC

giving exclusively 1-benzyl-4-phenyl-1H-1,2,3-triazole (24a) in modest yield

(entry 2). Both, the decrease and the increase of temperature, led to the formation

of a mixture of regioisomers (entries 3 and 4).

Then, the influence of solvent was examined (entries 5-11), finding that

the highest yield was reached in water (entry 10). Under these conditions, the

role of magnetite support was studied and high activity of the supposed inert

material was found (entry 12).

197 a) A. K. Feldman, B. Colasson, V. V. Fokin, Org. Lett. 2004, 6, 3897-3899; b) P. Appukkuttan,

W. Dehaen, V. V. Fokin, E. van der Eycken, Org. Lett. 2004, 6, 4223-4225; c) Z.-X. Wang, A.-

G. Zhao, J. Heterocycl. Chem. 2007, 44, 89-92; d) J. T. Fletcher, J. E. Reilly, Tetrahedron Lett.

2011, 52, 5512-5515; e) R. B. N. Baig, R. S. Varma, Chem. Commun. 2012, 48, 5853-5855; f)

S. Koguchi, K. Izawa, Synthesis 2012, 44, 3603-3608.


Table 21. Optimization of cycloaddition reaction conditions.a

Entry Solvent T (ºC) t (d) Yield 24a (%)

b Yield 25a (%)

b

1c H2O 110 7 46 49

2 PhMe 70 2 58 0

3 PhMe 25 2 35 7

4 PhMe 110 2 73 25

5 THF 70 2 43 7

6 CHCl3 70 2 52 6

7 MeCN 70 2 15 6

8 DMSO 70 2 33 8

9 MeOH 70 2 50 0

10 H2O 70 1 94 0

11 - 70 2 73 12

12d

H2O 70 1 82 1 a Reaction carried out using compounds 5a (1 mmol), and 23a (1 mmol) in 2 mL of

solvent. b Isolated yield after column chromatography.

c Reaction carried out in absence of catalyst.

d Reaction performed using only nanomagnetite (21 mol%).

Once the activity of copper catalyst was examined, its recycling was

studied. After the first trial, the magnetite was collected with a magnet, washed

with toluene and ethanol, and dried. The recycled catalyst could be re-used three

fold with similar results (82-78 %). However, the yield dropped to 35 % in the

fourth use, keeping this level of results during the following five cycles (Figure

30).


0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10

Yie

ld 2

4a (%

)

Cycle

Figure 30. Recycling of CuO-Fe3O4 catalyst for the cycloaddition.


resulting reaction solution mixture, and 1.1 % of the initial amount of copper was

detected (0.007 % of iron), explaining the loss of activity. Moreover, the TEM

images of the recycled catalyst showed a small change in the copper particle size

from 7.1 ± 6.5 nm of the fresh prepared catalyst to 6.4 ± 5.2 nm for the recycled

one, which would not affect the reactivity of the recycled catalyst. Finally, it

should be pointed out that the BET surface area did not suffer a great change,

from 6.2 m2g

-1 for the initial catalyst to 8.4 m

2g

-1 for the used one, being is

practically the same specific area.

After finding that copper catalyst was effective in the cycloaddition

between azides and terminal alkynes, the problem of the multicomponent

version,190c,191d,e,192d,h,193h,195,196b,c

using benzyl bromide (26a), sodium azide (27)

and ethynylbenzene (5a) as reaction model (Table 22) was faced. The reaction in

water gave a mixture of the expected heterocycle 24a together with its

regioisomer 25a (compare entry 1 in Table 22 and entry 9 in Table 21). This

initial trial showed that the change from simple cycloaddition to the

multicomponent reaction one was not so straightforward. Thus, a new

optimization process on this multicomponent reaction was carried out, starting by

studying the effect of solvent (entries 1-8 in Table 22).


The best result was obtained in absence of solvent, but a small amount

of the product arising from homocoupling of terminal alkyne was found (see

Chapter II.1). The optimal temperature seemed to be 50 ºC (entries 8-11), since at

higher temperatures different by-products were formed, while lower temperatures

gave a modest yield for product 24a.

Table 22. Optimization of multicomponent cycloaddition process.a

Entry Solvent T (ºC) t (d) Yield 24a (%)

b Yield 25a (%)

b

1 H2O 70 3 57 13

2 PhMe 70 3 33 0

3 THF 70 3 21 4

4 CHCl3 70 3 19 1

5 MeCN 70 3 16 0

6 DMSO 70 3 25 3

7 MeOH 70 3 32 25

8 - 70 3 69c 0

9 - 50 2 71 0

10 - 25 3 38 0

11 - 110 2 53c 6

a Reaction carried out using compounds 5a (1 mmol), 26a (2 mmol), and 27 (2 mmol) in

2 mL of solvent. b Isolated yield after column chromatography.

c 1,4-Diphenylbuta-1,3-diyne was isolated in a 10 % yield.

Although copper catalysts have been the most used, other metal

catalysts have also shown some activity for this reaction. For this reason, a series

of impregnated metal catalyst in this multicomponent version were tested (Table

23), studying also the uncatalysed reaction (entry 1).


Table 23. Optimization of catalyst for multicomponent cycloaddition.a


b

1 - 0

2 Micro-Fe3O4 (21) 0

3 Nano-Fe3O4 (21) 0

4 CoO-Fe3O4 (1.4) 0

5 NiO-Fe3O4 (1.0) 5

6 CuO-Fe3O4 (0.9) 83

7 Ru2O3-Fe3O4 (1.3) 0

8 Rh2O3-Fe3O4 (0.4) 0

9 PdO-Fe3O4 (1.2) 0

10 Ag2O/Ag-Fe3O4 (1.3) 0

11 OsO2-Fe3O4 (0.5) 0

12 IrO2-Fe3O4 (0.1) 0

13 PtO/PtO2-Fe3O4 (0.5) 0

14 Au2O3/Au-Fe3O4 (0.1) 0

15 PdO/Cu-Fe3O4 (1.5/0.9) 42

16 NiO/Cu-Fe3O4 (0.9/0.9) 98

17 NiO/Cu-Fe3O4 (0.2/0.2) 15

18 NiO/Cu-Fe3O4 (1.8/1.8) <99e

19 NiO-Fe3O4 (1.0) + CuO-Fe3O4 (0.9) 87

20 CuO (0.9) 78

21 NiO (0.9) 12

22 Cu(OH)2 (0.9) 58

23 Ni(OH)2 (0.9) 11

24 NiO (0.9) + CuO (0.9) 76

25 Ni(OH)2 (0.9) + Cu(OH)2 (0.9) 62 a Reaction carried out using compounds 5a (1 mmol), 26a (2 mmol), and 27 (2 mmol).


e Reaction performed during 24 h.


From all ductile metal oxide, only nickel and copper catalysts showed

activity (Table 23, entries 2-14). Then, a series of bimetallic derivatives were

studied, finding that Pd/Cu system90

could render the expected product 24a (entry

15). Very recently, different bimetallic Ni-Cu/C composite catalysts198

have been

tested in the simple cycloaddition of azides and terminal alkynes and these results

prompted us to prepare the corresponding impregnated bimetallic catalyst. Its

reaction gave the expected product with an excellent result (entry 16). The

decrease of the amount of Ni-Cu catalyst had an important detrimental effect,

meanwhile its increase had a marginal benefitial effect (compare entries 16-18).

Faced with the excellent result obtained with the bimetallic nickel-

copper catalyst, we wondered if the yield was the result of the simple addition of

two independent catalytic sites or if there was some type of synergic effect. To

answer that question, the reaction was repeated using both catalysts (the copper

and the nickel one) with almost the same loading. The achieved results seemed to

be due to the addition of the activity of both catalysts (compare entries 5 and 6

with entry 19 in Table 23). Therefore, we believe that the bimetallic catalyst

(entry 16) develops a synergetic effect that makes it superior to the addition of

both parts, although the nature of this positive interaction is unknown.

Finally, the unsupported metal catalysts were tested. Thus, the reaction

using CuO alone gave the expected product 24a with a good result (Table 23,

entry 20), meanwhile the related nickel oxide gave a worse result (entry 21).

When the reaction was repeated with the corresponding metal hydroxide

derivatives the yields were slightly lower (entries 22 and 23).

The equimolecular mixture of both metallic catalysts did not show any

improvement of the result obtained by the copper derivative (compare entries 20,

22 and 24, 24, respectively).

198 a) B. H. Lipshutz, D. M. Nihan, E. Vinogradova, B. R. Taft, Ž. V. Bošković, Org. Lett. 2008,

10, 4279-4282; b) J. Gong, J. Liu, L. M. Ma, X. Wen, X. Chen, D. Wan, H. Yu, Z. Jiang, E.

Borowiak-Palen, T. Tang, Appl. Catal.,B 2012, 117-118, 185-193.


The bimetallic Ni-Cu catalyst could be recycled and reused ten-fold,

just by collection of the catalyst with a magnet, washing with toluene and

ethanol, and drying, without any depletion in its activity (Figure 31).

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10

Yie

ld2

4a

(%

)

Cycles

Figure 31. Recycling of NiO/Cu-Fe3O4 catalyst for the multicomponent reaction.


resulting reaction solution mixture, and 1.1 and 0.2 % of the initial amount of

copper, and nickel, respectively, was detected (0.006 % of iron). The TEM

images of the recycled catalyst showed a small change in the particle size from

3.1 ± 1.7 nm of the freshly prepared catalyst to 4.7 ± 2.4 nm for the recycled one

(Figure 32).


0

20

40

60

80

Par

ticl

es

Particle size (nm)

before reaction

after reaction

Figure 32. TEM images: a) before and b) after recycling bimetallic

nickel/copper catalyst. c) Nickel/Copper particle size distribution before and

after reaction.

Moreover, XPS data analysis of bimetallic catalyst showed only NiO,

CuO and Cu2O species, which was confirmed by Auger spectroscopy (Figure

33). However, the recycled one showed the presence of Ni(OH)2 as well as

Cu(OH)2. These small changes, in particle size and the nickel species seemed not

to affect the activity of the bimetallic catalyst, since it could be reused several

times with similar activity.

a) b)

c)


-100

900

1900

2900

3900

4900

5900

928 933 938 943 948

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

fit

Cu 2p3/2

CuO 2p3/2

-100

400

900

1400

1900

2400

2900

3400

3900

4400

847 852 857 862 867

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Fit

NiO 2p3/2

NiO 2p3/2

-100

100

300

500

700

900

1100

1300

926 931 936 941 946 951

Inte

nsi

ty/a

rb. u

nit

s

Binding Energy (eV)

Fit

Cu(OH)2 2p3/2

Cu(OH)2 2p3/2 sat.

-100

400

900

1400

1900

2400

2900

3400

3900

4400

845 850 855 860 865 870

Inte

nsi

ty/a

rb. unit

s

Binding Energy (eV)

Fit

Ni(OH)2 2p3/2

Ni(OH)2 2p3/2

Figure 33. XPS of the a) fresh and b) recycled NiO/Cu-Fe3O4 catalyst.

To know if the reaction took place by the leached copper or nickel

species to the organic medium, the standard multicomponent reaction was

performed (Table 23, entry 16). After that, the catalyst was removed carefully by

a magnet at high temperature, and washed with toluene. The solvents of the

above solution, without catalyst, were removed under low pressure and alkyne

5a, sodium azide (27) and 4-bromobenzyl bromide were added to the above

residue. The resulting mixture was heated again at 50 ºC for 24 h. The analysis of

crude mixture, after hydrolysis, revealed the formation of compound 24a in 95 %

(catalysed process) and product 24b in less than 1 % yield by GC-analysis

(compare with entry 2 in Table 24). Therefore, we could exclude that the final

leached copper-nickel species were responsible for the reaction results under the

standard conditions.

Once the catalytic activity and the recyclability of bimetallic catalyst

were proved, the scope of the reaction was tested (Table 24). The reaction gave

excellent results independently of the substituent at the aromatic ring. Also the

position of the substituent at the aromatic ring of the bromide 26 seemed not to

have influence on the results (compare entries 1-7). The reaction with 2-

(bromomethyl)isoindoline-1,3-dione gave the expected compound 24h in modest

yield (entry 8). Also, the reaction was accomplished with alkynes 5 with different

groups at the aromatic ring, with no clear correlation of the reached yields with

the electronic nature of the substituents (entries 9-17). However, it should be

pointed out that the reactions using less electrophilic reagents such as aliphatic

a)

b)


bromide (1-bromododecane) or benzyl chloride, failed after seven days under

standard conditions, recovering unchanged the starting alkyne, as well as in the

case of using an aliphatic substituted alkyne (oct-1-yne).

Table 24. Multicomponent cycloaddition.a

Entry R

1 R

2 Nº Yield (%)

b

1 Ph Ph 24a 98

2 Ph 4-BrC6H4 24b <99

3 Ph 3-BrC6H4 24c <99

4 Ph 2-BrC6H4 24d <99c

5 Ph 2-MeC6H4 24e 59c

6 Ph 3-MeC6H4 24f 50

7 Ph 3,5-(MeO)2C6H4 24g 89

8 Ph C6H4(CO)2N 24h 37c

9 4-ClC6H4 Ph 24i 80c

10 4-ClC6H4 4-BrC6H4 24j <99

11 2-ClC6H4 Ph 24k 45c

12 4-BrC6H4 Ph 24l 42c

13 4-BrC6H4 3-MeC6H4 24m 90

14 4-MeOC6H4 Ph 24n 42c

15 3-MeC6H4 Ph 24o 55b

16 3-MeC6H4 3-BrC6H4 24p 86

17 3-MeC6H4 3-MeC6H4 24q 49 a Reaction carried out using compounds 5 (1 mmol), 26 (2 mmol), and 27 (2 mmol).


c Reaction performed during 4 days.

Then, the initial source of benzyl azide was tested (Scheme 26). The

reaction with benzylic alcohols failed after 6 days, recovering unchanged the

initial alkyne. The reaction also failed using the silyl ether 28b. However, the

reaction using benzyl mesylate gave a modest yield (35 %) after 2 days reaction

time. When the reaction time was increased up to 6 days a reasonable yield was

isolated (75 %). When the reaction was performed with benzyl tosylate (28d) the

result was very modest.


Scheme 26. Multicomponent cycloaddition with benzyl derivatives.

The multicomponent reaction with symmetrical internal alkynes 29

gave the expected compound 30 with very modest yield (Scheme 27). This result

highlighted the possible selectivity of the catalyst. In order to confirm this, the

reaction of benzyl bromide (26a, 2 eq.), sodium azide (27, 2 eq.), ethynylbenzene

(5a, 1 eq.) and 1,2-diphenylethylene (29a, 1 eq.) was performed under standard

conditions, finding exclusively the compound 24a (94 %) from the analysis of

crude mixture, and the internal alkyne unchanged.

Scheme 27. Multicomponent cycloaddition with internal alkynes.

Once the scope of the reaction was studied, we faced the problem of

reaction sequentiality was faced. For this proposal, we carried out the reaction

with the dibromide derivative 31, and a double amount of sodium azide (27),

obtaining after six days the azide 32 with a moderate yield (Scheme 28).


Scheme 28. Sequential multicycloaddition process.

The CG-MS analysis of crude mixture did not show the presence of the

symmetrical bis-triazole, with the relate bis-azide derivative being the main by-

product. The isolated azide 32 was re-submitted to another cycloaddition process,

yielding the unsymmetrical bis-triazole derivative 33 in good yield. This

approach highlights the possibilities of the catalyst in the synthesis of different

substituted triazoles.

CHAPTER IV†



Palladium(II) Oxide on Magnetite

† The results presented in this Chapter were performed in collaboration with the

research group of Prof. Dr. McGlacken from the University of Cork in Ireland

127 Chapter IV. Reactions performed by nanoparticles of Palladium

1. DIRECT ARYLATION OF HETEROCYCLES

1.1 INTRODUCTION

The formation of aryl-aryl (Ar-Ar’) bonds and heteroaryl (Ar-Het and

Het-Het') analogues is an important transformation in compounds used in in

Organic Synthesis due to number of compounds containing these moieties in the

pharmaceutical and other industries.199

Traditional methods200

for the

introduction of the Ar-Ar' bond (e.g. Suzuki-Miyaura, Stille, Negishi and other

named reactions) suffer from drawbacks, as they require the installation of

activating groups on both coupling partners. The associated waste (B, Sn, Zn-

based) is also a major problem in the pharmaceutical and other industries. A

modern, efficient and environmentally friendly alternative is termed Direct

Arylation (DA).201

Through catalytic C–H activation,154,202

DA avoids the

preactivation steps, establishing a convenient pathway for the synthesis of

arylated compounds in terms of atom economy and environmental impact.41a,f,203

In the last decade a broad number of catalytic systems have been used

for the DA of heterocycles.204

However, most of these methodologies are based

on homogeneous catalysis and needed harsh reaction conditions. Homogeneous

catalysis suffers from a number of drawbacks. Deactivation due to metal

aggregation and precipitation205

and separation of the catalyst from the API

product206

seriously impede scale-up of many potentially useful transformations.

199 D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103, 893-930. 200 E. Negishi in Handbook of Organopalladium Chemistry for Organic Synthesis, Wiley, New

York, 2003. 201 a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174-238; b) L. Ackermann, R.

Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792-9826; c) G. P. McGlacken, L. M.

Bateman, Chem. Soc. Rev. 2009, 38, 2447-2464. 202 K. Godula, D. Sames, Science 2006, 312, 67-72. 203 a) B. M. Trost, Science 1991, 254, 1471-1477; b) Green Chemistry: Designing Chemistry for

the Environment; (Eds.: P. T. Anastas, T. C. Williamson), American Chemical Society:,

Washington DC, 1996; c) B. M. Trost, Acc. Chem. Res. 2002, 35, 695-705; d) R. A. Sheldon, I.

Arends, U. Hanefeld, Green Chemistry and Catalysis, Wiley–VCH, Weinheim, Germany,

2007. 204 For recent reviews see: a) J. J. Mousseau, A. B. Charette, Acc. Chem. Res. 2013, 45, 412-424;

b) F. Shibahara, T. Murai, Asian J. Org. Chem. 2013, 8, 624-636; c) K. Yuan, H. Doucet,

ChemCatChem 2013, 5, 3495-3496; d) R. Rossi, F. Bellina, M. Lessi, C. Manzini, Adv. Synth.

Catal. 2014, 356, 17-117; e) R. Rossi, F. Bellina, M. Lessi, C. Manzini, L. A. Perego, Synthesis

2014, 46, 2833-2883; f) S. El Kazzouli, J. Koubachi, N. El Brahmi, G. Guillaumet, RSC Adv.

2015, 5, 15292-15327; g) Y. Liang, S. F. Wnuk, Molecules 2015, 20, 4874-4901. 205 J. G. de Vries, Dalton Trans. 2006, 421-429. 206 C. E. Garret, K. Prasad, Adv. Synth. Catal. 2004, 346, 889-900.

Chapter IV. Reactions performed by nanoparticles of Palladium 128

Heterogeneous catalysis,207

on the other hand, offers a more attractive approach.

Heterogeneous catalysts possess good thermal stability and can usually be

removed from the reaction media and can, in principle, be recycled.

Recently notable progress has been made in the search of

heterogeneous systems for DA.208

Palladium has been the most employed

transition-metal to accomplish this transformation. Examples include Pd

supported on zeolite,209

modified silica,210

metal organic frameworks,211

carbon212

and mesocellular foam.213

Palladium has been incorporated within a bimetallic

heterodimer with magnetite using thermal decomposition.214

Discerning whether

the catalyst behaves in a homogeneous or heterogeneous manner is difficult and

complex.208

In many cases, heterogeneous catalyst precursors are used, but

leaching to homogeneous species215

(e.g. soluble nanoparticles) is likely,

although both in some cases212b,213

have good evidence for a heterogeneous

pathway in Pd-catalysed DA reactions. However, in both cases, recycling of the

catalyst was not possible (Pd/C and PD/mesocellular foam respectively). Other

heterogeneous systems used are based on copper,216

nickel217

and TiO2.218

Even a

transition-metal-free arylation methodology has been reported with similar

overall objectives.219

We thought that impregnated palladium on magnetite

catalyst fitted all requirements.

207 J. Ross in Heterogeneous Catalysis Fundamentals and Applications, Elsevier, Amsterdam,

2012. 208 R. Cano, A. F. Schmidt, G. P. McGlacken, Chem. Sci. 2015, 6, 5338-5346. 209 a) L. Djakovitch, V. Dufaud, R. Zaidi, Adv. Synth. Catal. 2006, 348, 715-724; b) G. Cusati, L.

Djakovitch, Tetrahedron Lett. 2008, 49, 2499-2502. 210 a) L. Wang, W.-B. Yi, C. Cai, Chem. Commun. 2011, 47, 806-808.; b) J. Areephong, A. D.

Hendsbee, G. C. Welch, New J. Chem. 2015, 39, 6714-6717. 211 Y. Huang, Z. Lin, R. Cao, Chem. Eur. J. 2011, 17, 12706-12712. 212 a) D.-T. D. Tang, K. D. Collins, F. Glorius, J. Am. Chem. Soc. 2013, 135, 7450-7453; b) D.-T.

D. Tang, K. D. Collins, J. B. Ernst, F. Glorius, Angew. Chem. Int. Ed. 2014, 53, 1809-1813; c)

K. D. Collins, R. Honeker, S. Vásquez-Céspedes, D.-T. D. Tang, F. Glorius, Chem. Sci. 2015,

6, 1816-1824; d) S. Hayashi, Y. Kojima, T. Koizumi, Polym. Chem. 2015, 6, 881-885. 213 J. Malmgren, A. Nagendiran, C.-W. Tai, J.-E. Bäckvall, B. Olofsson, Chem. Eur. J. 2014, 20,

13531-13535. 214 J. Lee, J. Chung, S. Moon Byun, B. Moon Kim, C. Lee, Tetrahedron 2013, 69, 5660-5664. 215 C. G. Baumann, S. De Ornellas, J. P. Reeds, T. E. Storr, T. J. Williams, I. J. S. Fairlamb,

Tetrahedron 2014, 70, 6174-6187. 216 a) W. Zhang, Q. Zeng, X. Zhang, Y. Tian, Y. Yue, Y. Guo, Z. Wang, J. Org. Chem. 2011, 76,

4741-4745. b) W. Zhang, Y. Tian, N. Zhao, Y. Wang, J. Li, Z. Wang, Tetrahedron 2014, 70,

6120-6126; c) S. Keshipour, A. Shaabani, Appl. Organometal. Chem. 2014, 28, 116-119; d) H.

T. N. Le, T. T. Nguyen, P. H. L. Vu, T. Truong, N. T. S. Phan, J. Mol. Catal. A: Chem. 2014,

391, 74-82. 217 N. T. S. Phan, C. K. Nguyen, T. T. Nguyen, T. Truong, Catal. Sci. Technol. 2014, 4, 369-377. 218 J. Zoeller, D. C. Fabry, M. Rueping, ACS Catal. 2015, 5, 3900-3904. 219 H. Liu, B. Yin, Z. Gao, Y. Li, H. Jiang, Chem. Commun. 2012, 48, 2033-2035.


1.2 RESULTS

1.2.1 DIRECT ARYLATION OF HETEROCYCLES

To start with the arylation study, benzothiophene (34a) and diphenyliodonium

tetrafluoroborate (35a) in bio-renewable ethanol as solvent was chosen as a

model for the optimization of the reaction conditions (Table 25). Our first

attempt gave the corresponding arylated heterocycle (36a) after 24 h, and

arylation occurred selectively at C3-position but in low yield (entry 1). Increasing

the equivalents of 35a, gave a small increase in yield (entries 2 and 3). A

reduction of palladium loading (3 mol%), led to a lower conversion (entry 4) and

an increase of catalyst (10 mol%) improved the yield (entry 5).


Entry 35a (mol%) Solvent T (ºC) Pd (mol%) Yield (%)

b

1 110 EtOH 80 6 22

2 220 EtOH 80 6 45

3 300 EtOH 80 6 31

4 220 EtOH 80 3 11

5 220 EtOH 80 10 59

6 300 EtOH 80 10 62

7 300 EtOH 100 10 65

8 300 EtOH 60 10 71

9 300 EtOH 40 10 39

10 300 EtOH 25 10 0

11 300 1,4-Dioxane 60 10 0

12 300 H2O 60 10 0

13 300 PhMe 60 10 0

14c

300 EtOH 60 0 0 a

Reaction carried out using compound 34a (0.5 mmol), 35a (0.6 mmol), in 1.5 mL of

solvent, unless otherwise stated. b Isolated yield after column chromatography.

c Reaction performed in absence of catalyst.

With the optimised catalyst loading in hand, the amount of iodonium salt was

modified (entry 6). The yield of 36a was increased to 62 % with the addition of 3


equivalents of the salt. The temperature effect was evaluated at this point.

Increasing the temperature to 100 ºC only gave a slightly higher yield (entry 7).

However, the best yield was obtained at 60 ºC (entry 8). Unfortunately, it was not

possible to reduce the temperature without a significant reduction in yield

(entries 9 and 10). The impact of the solvent was evaluated (entries 11-13). The

reaction failed in 1,4-dioxane, water and toluene. Finally, with the best

conditions in hand, the reaction was performed in the absence of catalyst (entry

14). Only starting material was recovered, confirming the catalytic role of the

palladium on magnetite.

Once the best reaction conditions for this process were found, a number of

impregnated metal catalysts were tested (Table 26). Only the palladium on

magnetite showed high activity. However, the bimetallic palladium-copper

catalyst did give a small amount of arylated product (entry 10). Finally, the

reaction was also performed using Pd-free magnetite nanoparticles to confirm the

role of Pd, and no product was observed.

Table 26. Optimization of catalyst.a


b

1 Micro-Fe3O4 (259) 0

2 Nano-Fe3O4 (259) 0

3 CoO-Fe3O4 (5.7) 0

4 NiO-Fe3O4(4.1) 0

5 CuO-Fe3O4 (3.5) 0

6 Rh2O3-Fe3O4 (1.7) 0

7 Ag2O/Ag-Fe3O4 (5.0) 0

8 OsO2-Fe3O4 (2.1) 0

9 Au2O3/Au-Fe3O4 (0.6) 0

10 PdO/Cu-Fe3O4 (6.1/3.5) 8

11 NiO/Cu-Fe3O4 (3.6/3.5) 0

12 WO3-Fe3O4(2.3) 0 a Reaction carried out using 34a (0.5 mmol), and 35a (1.5 mmol).


The optimised protocol was then applied to other prominent heterocycles

(Table 27). When benzofuran was used as substrate, the arylated product was


isolated in an excellent yield (99 %, entry 1). The reaction was completely

regioselective at the C2 position. Indoles containing electron-withdrawing

substituents coupled well (entries 2-4), affording the arylated products in yields

from 58 to 83 % and there was no problems associated with the presence of free

NH groups in this compounds. For all the indoles tried, the arylation took place at

the C-2 position selectively.

Table 27. Substrate scope: arylation of different heterocycles.a

Entry X R Product Yield (%)

b

1 O H 36b 99

2 NH 7-CO2Me 36c 83

3 NH 5-F 36d 79

4 NH 4-Br 36e 58 a

Reaction carried out using the corresponding heterocycle 34 (0.5 mmol), and 35a (1.5

mmol). b Isolated yield after column chromatography.

The use of other iodonium salts was also studied (Table 28). Chemoselective

arylation could be performed by introducing a non-transferable aryl group such

as 2,3,5-triisopropylphenyl (TRIP).212b,213

Table 28. Substrate scope: use of different diaryliodonium salts.a

Entry X Ar

1 Ar

2 Ar

2 position Product Yield (%)

b

1 S TRIP 4-MeC6H4 C3 36f 38

2 O TRIP 4-MeC6H4 C2 36g 71

3 O TRIP 2-MeC6H4 C2 36h 66

4 O TRIP 4-ClC6H4 C2 36i 55

5 O 4-MeOC6H4 4-MeOC6H4 C2 36j 84 a

Reaction carried out using the corresponding heterocycle 34 (0.5 mmol), and 35 (1.5



Using this approach, an arylated benzothiophene was isolated in low yield

(entry 1). Better yields were obtained using benzofuran and methyl phenyl

groups (entries 2 and 3). An electron-poor aryl group was also shown to be a

suitable substrate (entry 4). Finally, and electron-rich aryl moiety was

transferred, this time using a symmetrical iodonium salt (entry 5). The catalyst

gave excellent regioselectivity in all the cases (arylation of benzofuran at C2-

position and thiophene at C3-position).

The protocol was then extended to the arylation of simple thiophenes under

the same reaction conditions (Table 29). Using thiophenes, the process was not as

high yielding or selective as with previous substrates and a mixture of the mono-

and di-arylated heterocycles was obtained in 39 % overall yield (entry 1).

Table 29. Substrate scope: arylation of thiophenes.a


b

1 H 38a 39

2 2-Cl 38b 34

3 2-Br 38c 18

4 3-Br 38d 51

5

38e 48

a Reaction carried out using the corresponding heterocycle 37 (0.5 mmol), 35a (1.5


Using 2-chlorothiophene the reaction reached 34 % of the mono-arylated

product (entry 2, Table 29). With 2-bromothiophene, only 18 % of the mono-

arylated heterocycle was recovered, (entry 3). Better yield was obtained with the

3-bromothiophene (entry 4). In both cases the bromine remained intact, allowing

for further functionalisation. Finally, 2,2’-bithiophene gave the corresponding

monoarylated product selectively in 48 % yield (entry 5).

Once the substrate scope was evaluated, the recyclability of the catalyst was

tested. After a standard reaction using benzofuran as heterocycle, the catalyst was

retained in the reaction vessel using a magnet and washed several times with


ethanol. The vessel was then charged with a new set of reagents and the standard

conditions applied. The corresponding product 36b was obtained in 49 % yield

after the second cycle, and 18 % after third. These results show deactivation of

the catalyst. While others have shown that heterogeneous catalysis and

recyclability can prove mutually exclusive, no examinations of the reasons for

deactivation have been proposed in these systems. We sought to examine the

catalyst structure before and after the reaction. TEM analysis showed that fresh

(Figure 34a) and recycled (Figure 35a) particles displayed a similar appearance.

Also no sinterization of the particles could be observed after the reaction.

Additionally, both fresh and recycled catalyst particles showed an identical

particle-size distribution (Figures 34b and 35b).

0

5

10

15

20

25

30

Par

ticl

es

Particle size (nm)

Figure 34. a) TEM image of fresh palladium catalyst. b) Palladium particle size

distribution of fresh catalysts.

a)

b)


0

50

100

Par

ticl

es

Particle size (nm)

Figure 35. a) TEM image of recycled palladium catalyst. b) Palladium particle

size distribution of recycled catalysts.

XPS analysis of the catalyst did not show any change in the oxidation state of

the palladium on the magnetite surface. The XPS spectra of the recycled catalyst

showed, after deconvolution, two peaks at 337.0 and 342.1 eV, which correspond

to the binding energies of PdO 3d5/2 and PdO 3d3/2, respectively. The spectra

were identical to that taken from the catalyst before reaction (Figure 36). Thus

we cannot attribute deactivation of the catalyst to an oxidation change at the

surface.220

220 G. Collins, M. Schmidt, C. O’Dwyer, J. D. Holmes, G. P. McGlacken, Angew. Chem. Int. Ed.

2014, 53, 4142-4145.

a)

b)


-100

1900

3900

5900

7900

9900

11900

330 335 340 345

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Fit

3d 5/2 PdO

3d 3/2 PdO

-100

900

1900

2900

3900

4900

5900

6900

7900

8900

330 332 334 336 338 340 342 344 346 348

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Fit

PdO 3d 5/2

PdO 3d 3/2

Figure 36. XPS of a) fresh catalyst and b) recycled catalyst.

We then hypothesised that leaching of the Pd from the support might be

occurring, rendering the insoluble catalyst framework inactive, when reused. The

phenomenon of leaching was studied by ICP-MS. Here, the reaction mixture was

filtered hot after the reaction and the homogeneous solution was tested by

dissolved Pd. Only 1.95 % of the initial amount of palladium was detected. This

amount seems insufficient to explain the deactivation given the lower turnover

numbers observed when lower Pd loading was used (Table 25). The inability of

the solution phase to catalyse the arylation of benzofuran was confirmed by

observation of the reaction progress after filtration. Thus, after two hours, the

catalyst was filtered hot. No reaction progress was observed after this point

confirming that no active species were solubilised under the reaction conditions.

The above tests point strongly to heterogeneous catalysis, in line with the

conclusion previously reported in the arylation of 2-butylthiophene.212b

Clearly, if leaching is ruled out, some change, which deactivates the catalyst,

must occur at the surface.221

XRF was then used to gain further insight at the

catalyst surface. More specifically, 5.4 % of iodine was detected at the catalyst

surface. The adsorbance of halides on the surface of Pd catalysts has previously

been shown to affect the activity of heterogeneous catalysts and we believe this

to be this case here also.222

221 J. Pal, T. Pal, Nanoscale 2015, 7, 14159-14190. 222 a) E. J. A. X. van de Sandt, A. Wiersma, M. Makkee, H. van Bekkum, J. A. Moulijn, Appl.

Catal. A Gen. 1998, 173, 161-173; b) F. J. Urbano, J. M. Marinas, J. Mol. Catal. A Chem. 2001,

173, 329-345; c) P. Kar, B. G. Mishra, J. Clust. Sci. 2014, 25, 1463-1478.

a) b)


1.2.2 INTRAMOLECULAR DIRECT ARYLATION

Encouraged by the success that obtained in the direct arylation of

heterocycles, we decided to apply palladium on magnetite to an intramolecular

arylation.204d,223

A different mechanism is operative here and thus application to

this reaction would give a good indication of the broad utility of the catalyst. The

intramolecular arylation of haloether 39a to obtain the corresponding chromene

40a (Table 30) as a suitable reaction was chosen for this study.


Entry Base (mol%) Solvent T (ºC) Pd (mol%) Yield (%)

b

1 KOAc (200) DMA 140 0.1 5

2 KOAc (200) DMA 140 1 9

3 KOAc (200) DMA 140 2 20

4 KOAc (200) DMA 140 5 61

5 KOAc (200) DMA 140 10 85

6 KOAc (200) DMA 140 15 77

7 KOAc (100) DMA 140 10 64

8 KOAc (300) DMA 140 10 71

9 KOH (200) DMA 140 10 5

10 NaOH (200) DMA 140 10 0

11 NaOAc (200) DMA 140 10 56

12 K2CO3 (200) DMA 140 10 0

13 KOAc (200) PhMe 140 10 0

14 KOAc (200) DMF 140 10 74

15 KOAc (200) t-BuOK 140 10 25

16 KOAc (200) DMA 160 10 75

17 KOAc (200) DMA 120 10 63

18c

KOAc (200) DMA 140 0 0 a

Reaction carried out using compounds 39a (0.5 mmol), and KOAc (1 mmol), in 2 mL

of solvent, unless otherwise stated. b Isolated yield after column chromatography.

c Reaction performed in absence of catalyst.

223 L. Campeau, K. Fagnou, Chem. Commun. 2006, 1253-1264.


Firstly, the optimum catalyst loading was established (entry 1-6). Again 10

mol% of Pd was needed to obtain the best chemical yield (entry 5). Then the

effect of the base was tested (entries 7-12). When one equivalent of base was

used the yield of 40a was reduced (entry 7). The addition of 3 equivalents was

not beneficial for the cyclisation process (entry 8). Different bases were tried, but

none were as efficient as KOAc (entries 9-12). The impact of the solvent was

studied (entries 13-15). Only DMF gave a comparable yield, but was slightly

lower to the one obtained with N,N-dimethylacetamide (DMA). Finally, the

temperature was modified. Neither a higher, nor lower temperature gave better

yields (entries 16 and 17). As a control test, the reaction was performed in the

absence of catalyst under the optimised conditions (entry 18). Only starting

material was recovered confirming the role of palladium in this process.

The best reaction conditions were then applied to different substrates to

evaluate the reaction scope (Table 31). First we studied the tolerance of

substituents on the phenoxy group. The presence of a methoxy group was

tolerated with only a small detriment in yield (entry 2).


Entry R

1 R

2 R

3 Product Yield (%)

b

1 H H H 40a 85

2 H H 4-MeO 40b 75

3 H H 4-Me 40c 86

4 H H 4-Cl 40d 93

5 H H 4-F 40e 92

6 H H 3-F 40f 89c

7 H H 2-F 40g 87

8 H CF3 H 40h 84

9 F H H 40i 77 a Reaction carried out using compounds 39 (0.5 mmol), KOAc (1 mmol).


c A mixture of isomers was obtained: 1-Fluoro-6H-benzo[c]chromene (40f) and 3-

Fluoro-6H-benzo[c]chromene (40f’) (45:55).

Good yield was obtained with methyl substituent at the 4-position of the ring

(entry 3). The introduction of electron-withdrawing groups had a beneficial effect


on the process, and excellent yields were achieved (entries 4 and 5). Then, the

effect of substitution on the benzyloxy group was evaluated. Similarly good

results were obtained using electron-withdrawing groups (entries 5-7), although a

mixture of regioisomers was obtained when a F substituent at the meta-position

was presented. Little impact on the yield was observed on substitution on the

halo-aryl either, and very good yields were observed (entries 8 and 9).

The recyclability of the catalyst was also investigated in this case. In a similar

way to the intermolecular reaction, the catalyst was removed using a magnet and

reused using the standard reaction conditions (see Table 30, entry 5). Again

deactivation of the catalyst was observed. This time no product was detected

after the second cycle of reaction. ICP-MS analysis of the reaction solution

showed 3.3 % of the initial palladium was leached.

XPS analysis also showed a distinctive change and four peaks were observed

(Figure 37). Two peaks at 336.9 and 342.2 eV, correspond to the binding

energies of PdO 3d5/2 and PdO 3d3/2, respectively. The two other peaks at 334.9

and 340.1 eV, correspond to the binding energies of PdO 3d5/2 and PdO 3d3/2,

respectively. The ratio between the two oxidation states was Pd:PdO 2:1. Clearly

some reduction of the PdO species had occurred perhaps forming inactive Pd-

black aggregates.

-100

400

900

1400

1900

2400

330 332 334 336 338 340 342 344 346

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Fit

Pd 3d 5/2

PdO 3d 5/2

Pd 3d 3/2

PdO 3d 3/2

Figure 37. XPS of recycled catalyst.


Recycled TEM analysis revealed that a substantial sintering of palladium

nanoparticles had occurred (compare Figure 34 and Figure 38).

0

20

40

60

Par

ticl

es

Particle size (nm)

Figure 38. a) TEM image of recycled palladium catalyst. b) Palladium particle

size distribution of recycled catalysts.

The hot filtration test determined that no reaction progress occurred after

filtration. Thus, we believe that changes in the oxidation state of Pd during the

reaction renders the recovered Pd/magnetite unable to catalyse subsequent

reactions. Thus in an attempt to recycle the catalyst, recycled particles of

palladium were subjected to oxygen (bubbling O2). Using this protocol, the re-

generation of the palladium(II) oxide nanoparticles was impossible. Other

oxidants like I2 or t-BuOOH were tested giving the same result.

a)

b)


2. SYNTHESIS OF 4-ARYLCOUMARINS THROUGH THE HECK-

ARYLATION/CYCLIZATION REACTION

2.1 INTRODUCTION

The Heck reaction224

is a powerful and general synthetic method used in

Organic Chemistry to construct compounds by C-C bond formation. Its synthetic

flexibility and compatibility with most organic functional groups makes it one of

the most explored reaction promoted by palladium.225

Some efforts have been

devoted to improve the efficiency of this reaction, and recently, iodonium salts226

have been extensively studied as arylation agent to replace aryl halides or triflates

in the Heck reaction. They are appealing coupling partners as they display

different reactivity profiles to halides, are highly reactive yet air- and moisture-

stable, and can be easily prepared in one step from commercially available

starting materials.227

Coumarins228

are important structural motifs in natural compounds and

exhibit broad biological activity. Particularly, 4-aryl derivatives constitute a

subgroup of flavonoids that have received considerable attention, as they display

important biological activities such as anti-HIV, antimalarial, antibacterial and

cytotoxic properties. Classical synthetic approaches for the synthesis of 4-

arylcoumarins are based on Knoevenagel condensation,229

cross-coupling

reactions,230

C-H bond activation,154,208,231

von Pechman condensation,232

among

224 a) R. F. Heck, Acc. Chem. Res. 1979, 12, 146-151; b) A.-L. Lee, Org. Biomol. Chem. 2016,

DOI: 10.1039/c5ob01984b. 225 a) P. Prediger, A. R. da Silva, C. R. D. Correia, Tetrahedron Lett. 2014, 70, 3333-3341; b) D.

H. Ortgies, A. Hassanpour, F. Chen, S. Woo, P. Forgione, Eur. J. Org. Chem. 2016, 408-425. 226 a) R. M. Moriarty, W. R. Epa, A. K. Awasthi, J. Am. Chem. Soc. 1991, 113, 6315-6317; b) M.

Zhu, Y. Song, Y. Cao, Synthesis 2007, 853-856; c) J. Aydin, J. M. Larsson, N. Selander, K. J.

Szabó, Org. Lett. 2009, 11, 2852-2854; d) R. J. Phipps, L. McMurray, S. Ritter, H. A. Duong,

M. J. Gaunt, J. Am. Chem. Soc. 2012, 134, 10773-10776; e) J. Li, L. Liu, Y.-Y. Zhou, S.-N. Xu,

RSC Adv. 2012, 2, 3207-3209; f) N. Gigant, L. Chausset-Boissarie, M.-C. Belhomme, T.

Poisson, X. Pannecoucke, I. Gillaizeau, Org. Lett. 2013, 15, 278-281. 227 a) R. J. Phipps, N. P. Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130, 8172-8174; b) R. J.

Phipps, M. J. Gaunt, Science 2009, 323, 1593-1597; c) M. Bielawski, M. Zhu, B. Olofsson,

Adv. Synth. Catal. 2007, 349, 2610-2618; d) M. Bielawski, D. Aili, B. Olofsson, J. Org. Chem.

2008, 73, 4602-4607; e) E. A. Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48, 9052-

9070. 228 F. Boeck, M. Blazejak, M. R. Anneser, L. Hintermann, Beilstein J. Org. Chem. 2012, 8, 1630-

1636. 229 J. Crecente-Campo, M. P. Vázquez-Tato, J. A. Seijas, Eur. J. Org. Chem. 2010, 4130-4135. 230 W. Gao, Y. Luo, Q. Ding, Y. Peng, J. Wu, Tetrahedron Lett. 2010, 51, 136-138. 231 Y. Li, Z. Qi, H. Wang, X. Fu, C. Duan, J. Org. Chem. 2012, 77, 2053-2057. 232 H. Wang, Monatsch Chem. 2013, 144, 411-414.


others.233

In many cases, the reactions were performed under harsh reaction

conditions and high temperatures. The loading of transition metal was, in many

cases, very high (5-20 mol%).

Another methodology to obtain 4-arylcoumarins, that has been less

studied, is the arylation/cyclization of o-hydroxylcinnamates. Initially, this

approach was reported in 2005 using aryl halides in a molten n-Bu4NOAc/n-

Bu4NBr mixture.234

Later on, the approach was modified by the use of aryl

diazonium salts in methanol.235

Finally, diaryliodonium(III) salts have been

successfully used to perform this transformation using dimethylformamide as

solvent.236

In all cases the reaction was performed with the help of high amounts

of the homogeneous Pd(OAc)2 catalyst (5-10 mol%), giving moderate to good

yields. For this reason we thought that impregnated palladium catalyst could be a

promising candidate for the heterogeneous version of the aforementioned

approach.

2.2 RESULTS

To start the study, (E)-ethyl 3-(2-hydroxyphenyl)acrylate (41a) and

diphenyliodonium tetrafluoroborate (35a), using impregnated palladium on

magnetite as catalyst, was selected as the reaction model for the optimization

(Table 32). Initially, the reaction was performed using different equivalents of

compound 35a (entries 1-3). Full conversion of the starting material was

observed after 5 hours when 2 equivalents of the salt were used. This result could

not be improved by increasing the amount of iodonium salt. After that, different

loadings of palladium catalyst were tested (entries 4-7). Good yields were

obtained with 2.5 mol% Pd, with the yield being slightly improved using higher

233 a) B. M. Trost, F. D. Toste, K. Greenman, J. Am. Chem. Soc. 2003, 125, 4518-4526; b) J.

Ferguson, F. Zeng, H. Alper, Org. Lett. 2012, 14, 5602-5605; c) K. Sasano, J. Takaya, N.

Iwasawa, J. Am. Chem. Soc. 2013, 135, 10954-10957; d) P. Shah, M. D. Santana, J. García, J.

L. Serrano, M. Naik, S. Pednekar, A. R. Kapdi, Tetrahedron 2013, 69, 1446-1453; e) M.

Khoobi, F. Molaverdi, M. Alipour, F. Jafarpour, A. Foroumadi, A. Shafiee, Tetrahedron 2013,

69, 11164-11168; f) J. Li, H. Chen, D. Zhang-Negrerie, Y. Du, K. Zhao, RSC Adv. 2013, 3,

4311-4320; g) M. L. N. Rao, A. Kumar, Tetrahedron 2014, 70, 6995-7005; h) P. Niharika, B.

V. Ramulu, G. Satyanarayana, Org. Biomol. Chem. 2014, 12, 4347-4360; i) S. K. Gadekh, S.

Dey, A. Sudalai, J. Org. Chem. 2015, 80, 11544-11550; j) A. M. Escobar, D. M. Ruiz, J. C.

Autino, G. P. Romanelli, Res. Chem. Intermed. 2015, 41, 10109-10123. 234 G. Battistuzzi, S. Cacchi, I. D. Salve, G. Fabrizi, L. M. Parisi, Adv. Synth. Catal. 2005, 347,

308-312. 235 D. A. Barancelli, A. G. Salles Jr., J. G. Taylor, C. R. C. Correia, Org. Lett. 2012, 14, 6036-

6039. 236 Y. Yang, J. Han, X. Wu, S. Xu, L. Wang, Tetrahedron Lett. 2015, 56, 3809-3812.


amounts of metal. Then, a study of the solvent was performed (entries 8-15). A

moderate yield was obtained in H2O, but best results were observed in bio-

renewable ethanol (entry 5). When the reaction was performed without solvent

(entry 16) only traces of the product could be detected. To complete the

optimization, different temperatures were tried (entries 17 and 18). Only traces of

product were detected at room temperature and full conversion of the starting

material was observed at 80 ºC.


Entry Pd (mol%) Solvent T (ºC) Yield (%)

b

1 10 EtOH 60 99

2c

10 EtOH 60 54

3d

10 EtOH 60 99

4 1 EtOH 60 46

5 2.5 EtOH 60 86

6 5 EtOH 60 90

7 7.5 EtOH 60 99

8 2.5 PhMe 60 0

9 2.5 THF 60 0

10 2.5 H2O 60 64

11 2.5 1,4-Dioxane 60 0

12 2.5 DCM 60 0

13 2.5 CH3CN 60 34

14 2.5 DMF 60 48

15 2.5 DMSO 60 10

16 2.5 - 60 15

17 2.5 EtOH 25 7

18 2.5 EtOH 80 99 a Reaction carried out using compounds 41a (0.25 mmol), and 35a (0.5 mmol).

b Yield determined by GC using 0.25 mmol of tridecane as internal standard.

c Reaction carried out using compounds 41a (0.25 mmol), and 35a (0.25 mmol).

c Reaction carried out using compounds 41a (0.25 mmol), and 35a (0.75 mmol).

Once the optimal conditions were determined, the reaction was submitted

to a variety of catalysts, prepared by a simple impregnation protocol85

(Table 33).

The reaction without catalyst did not give any product (entry 2). The partial


inactivity of the support was confirmed (entries 3 and 4), the role of magnetite is

only to facilitate the easy separation of the reaction media through magnetic

decantation. The inactivity of the support was confirmed (entries 3 and 4). Then,

different metal oxides impregnated on magnetite (entries 5-17) were evaluated as

catalyst, but the high activity displayed by the palladium catalyst could not be

surpassed. With these results in hand, the reaction was carried out using different

sources of palladium, (entries 18-20). All catalysts tested (homogeneous, as well

as heterogeneous) failed to give similar or improved activities relative to

palladium on magnetite (entry 1).


Entry Catalyst (mol %) Yield (%)

b

1 PdO-Fe3O4 (2.5) 99

2 - 0

3 Micro-Fe3O4 (129.9) 10

4 Nano-Fe3O4 (129.9) 11

5 CoO-Fe3O4 (2.8) 17

6 NiO-Fe3O4 (2.1) 0

7 CuO-Fe3O4 (2.3) 0

8 Ru2O3-Fe3O4 (2.6) 25

9 Rh2O3-Fe3O4 (2.5) 25

10 Ag2O/Ag-Fe3O4 (2.5) 4

11 OsO2-Fe3O4 (2.1) 8

12 IrO2-Fe3O4 (2.1) 10

13 PtO/PtO2-Fe3O4 (2.2) 17

14 Au2O3/Au-Fe3O4 (2.3) 0

15 PdO/Cu-Fe3O4 (3.1/1.8) 18

16 NiO/Cu-Fe3O4 (1.8/1.8) 7

17 WO3-Fe3O4 (2.3) 25

18 PdO (2.5) 79

19 PdCl2 (2.5) 83

20 Pd(OAc)2 (2.5) 76 a Reaction carried out using compounds 41a (0.25 mmol), and 35a (0.5 mmol).

b Yield determined by GC using 0.25 mmol of tridecane as internal standard.


In order to stablish the reusability of the catalyst, the standard reaction

was repeated (Figure 39). When the reaction was completed, the catalyst was

retained in the reaction vessel using a magnet and washed several times with

ethanol. The vessel was then charged with a new set of reagents and the standard

conditions were applied. The corresponding product was obtained with a 39 %

yield after the first cycle indicating that the catalytic activity of the catalyst has

been affected by the first reaction.

0

50

100

01

2

Yiel

d 4

2a

(%)

Cycle

Normal recycling

Re-used catalystafter regenerationby O2 treatment

Figure 39. Recycling of the PdO-Fe3O4 catalyst.

As a consequence of the non-recyclability of the catalyst, some studies

were performed. XPS analysis of the catalyst showed a change in the oxidation

state [Pd(II) to Pd(0)] after completion of the reaction. The XPS spectra of the

recycled catalyst showed, after deconvolution, four peaks at 334.9, 335.7, 340.3

and 341.3 eV, which correspond to the binding energies of Pd 3d5/2 and Pd 3d3/2,

and two more peaks, that have the same binding energy as the starting PdO

nanoparticles, with a relative area of 4 % (Figure 40).


-50

450

950

1450

1950

2450

2950

330 335 340 345

Inte

nsi

ty/a

rb. U

nit

s

Binding energy (eV)

Fit

Pd 3d 5/2

Pd 3d 5/2

PdO 3d 5/2

Pd 3d 3/2

Pd 3d 3/2

PdO 3d 3/2

Figure 40. XPS of recycled catalyst.

TEM analyses were carried out. A high sinterization of the palladium

nanoparticles as well as dissociation of the palladium particles from the support

after completion of the reaction was observed (Figure 41). The initial size range

of the starting PdO nanoparticles was 2-4 nm but increased to 14-16 nm after the

reaction.

Figure 41. TEM images of recycled palladium catalyst.

The phenomenon of leaching was studied by ICP-MS. Here, the reaction

mixture was filtered at high temperature after completion of the reaction and the

catalytic activity of the homogeneous solution was tested. Only 3.64 % of the


initial palladium was present in solution. More importantly, no progress of the

reaction was observed in the filtrate after the filtration, providing further

evidence of the heterogeneous nature of the reaction.

Finally, a modified hot filtration test was performed. Thus, after the

standard reaction, the mixture was decanted with the aid of a magnet, while hot,

and a mixture of 41c (0.25 mmol) and 35a (0.5 mmol) dissolved in 0.75 mL of

ethanol, was added to the filtrate. After five hours at 80 ºC, the product 42a

(heterogeneous catalysed system), as well as the aforementioned starting

reagents, were detected.

The TPR and TPO analyses of Fe3O4, fresh and recycled catalyst

were carried out (Figure 42). Previously to analyses, the samples were pre-treated by heating at 200 ºC under Argon atmosphere to be sure that all the organic material was removed. Then, the samples were heated to 900 ºC at 10 ºC/min in the corresponding atmosphere [TPR was performed with a mixture Ar/H2 (1.8 %), and TPO with a mixture Ar/O2 (3%)].

Figure 42. a) TPR and b) TPO analysis. In the case of differential thermogravimetric analysis under

reductive atmosphere (Figure 43a), when the temperature reached 100 ºC only the fresh catalyst sample showed a consumption of hydrogen and an emergence of H2O (Figure 44), what it could be assigned to the reduction from PdO to Pd(0). At 300 ºC a new consumption of H2 could be observed and it seems to be due to the reduction of superficial magnetite. In the case of both magnetite support and recycled catalyst, only this last consumption of hydrogen was detected. It should be pointed out that in the case of the supported catalyst the reduction of superficial magnetite took places at lower temperatures, probably by the influence of the supported palladium.

0 200 400 600 800 1000

%

T (ºC)

Fe3O4

Fresh PdO-Fe3O4

Recycled PdO-

Fe3O4

a) b)


Figure 43. a) DTPR and b) DTPO analysis. From the data of differential thermogravimetric analysis under

reductive atmosphere it could be calculated the expected weight losing due to a PdO to Pd(0) transformation, with this figure being slightly higher than the nominal palladium. This could be due to the reduction through a spill-over of hydrogen to the support of magnetite units that are in intimate contact with palladium.

Figure 44. MS analysis on fresh catalyst under reductive conditions.

In the case of differential thermogravimetric analysis under oxidative

atmosphere (Figure 43b), only the recycled sample showed a weight losing at

about 400 ºC. The analysis showed the loss of CO2 and then iodine in the case of

recycled catalyst (Figure 45). The emergence of CO2 should be associated to

organic compounds strongly bounded to the catalyst surface; meanwhile the

emergence of iodine could be a hindered proof of the poisoning of palladium

species by this element.

-0,00005

0,00045

0,00095

0,00145

0,00195

0,00245

0 200 400 600 800 1000

mg·s

-1

T (ºC)

Fe3O4

Fresh PdO-Fe3O4

Recycled PdO-Fe3O4

-9,00E-04

-6,00E-04

-3,00E-04

0,00E+00

3,00E-04

6,00E-04

0 200 400 600 800

mg·s

-1

T (ºC)

Fe3O4

Fresh PdO-Fe3O4

Recycled PdO-Fe3O4

0 50 100 150 200 250 300 350

Ms

sign

al (

arb

. U

nit

s)

T (ºC)

H2O

0 50 100 150 200 250 300 350

MS

sig

nal

(ar

b. U

nit

s)

T (ºC)

H2

a) b)


Figure 45. MS analysis on recycled catalyst under oxidative conditions.

Guided by the previously mentioned XPS, as well as TPR and TPO

analysis, we attribute the deactivation of the catalyst to an almost complete

reduction of the nanoparticles of palladium(II) oxide to palladium(0), and/or the

associated morphologic changes and the poisoning by iodine species. Thus, in an

attempt to recycle the catalyst, the recycled catalyst was subjected to oxygen

(bubbling O2, see Figure 39). Using this protocol, the results obtained for the

recycling of the catalyst were improved but did not reach the initial catalyst

activity. Other oxidants tested (e.g. t-BUOOH or I2) gave poorer results.

Once the best conditions were established, the scope of the reaction was

evaluated (Table 34). Moderate yields could be obtained using symmetrical

bis(4-fluorophenyl)iodonium tetrafluoroborate (entry 2). Better results were

observed, with symmetrical bis(4-methoxyphenyl)iodonium tetrafluoroborate

giving 77 % yield (entry 3). Chemoselective Heck-arylation/cyclization reactions

were performed by introducing a non-transferable aryl group such as 1,3,5-

triisopropylphenyl (TRIP). Good results were observed with substrates bearing

electron-withdrawing and sterically hindered electron-donating groups (entries 4

and 5).

Then various substituted o-hydroxyphenylacrylates were tested (entries

6-8). Better results were found with the sterically hindered (E)-ethyl 3-(3,5-di-

tert-butyl-2-hydroxyphenyl)acrylate. The presence of electron-withdrawing

groups at the 5-position in the aromatic ring of the acrylate seemed to affect

negatively the reaction. The use of substituted acrylates and diaryliodonium

tetrafluoroborates gave very good yields in all cases (entries 9-11). To finish with

the study, different diaryliodonium trifluoromethanesulfonates were tested,

which gave moderate to good results (entries 12-14). In the case of phenyl(2,4,6-

triisopropylphenyl)iodonium trifluoromethanesulfonate (entry 12), the expected

product 42a was obtained with lower yield than that obtained with the previously

0 200 400 600 800 1000

MS

sig

nal

(ar

b. U

nit

s)

T (ºC)

Iodine

0 200 400 600 800 1000

MS

sig

nal

(ar

b. U

nit

s)

T (ºC)

CO2


tested diphenyliodonium tetrafluoroborate (entry 1). Others aryl sources were

ineffective under similar reaction conditions.237


Entry R

1 R

2 X Ar

1 Ar

2 Product Yield (%)

b

1 H H BF4 Ph Ph 42a 98

2 H H BF4 4-FC6H4 4-FC6H4 42b 40

3 H H BF4 4-MeOC6H4 4-MeOC6H4 42c 77

4 H H BF4 4-ClC6H4 TRIP 42d 64

5 H H BF4 2-MeC6H4 TRIP 42e 55

6 F H BF4 Ph Ph 42f 72

7 t-Bu t-Bu BF4 Ph Ph 42g 97

8 Br OMe BF4 Ph Ph 42h 56

9 F H BF4 4-MeOC6H4 4-MeOC6H4 42i 70

10 t-Bu t-Bu BF4 4-FC6H4 4-FC6H4 42j 79

11 Br OMe BF4 4-FC6H4 4-FC6H4 42k 95

12 H H OTf Ph TRIP 42a 66

13 H H OTf 4-MeC6H4 4-MeC6H4 42l 52

14 Br OMe OTf 4-MeC6H4 4-MeC6H4 42m 91 a Reaction carried out using compounds 41 (0.25 mmol), and 35 (0.5 mmol).

bIsolated yield after column chromatography.

Once the scope of the reaction was evaluated, the possible pathway of the

process was studied. The reaction could occur through a cyclization reaction

followed by an arylation238

or through a Heck-arylation reaction and a subsequent

cyclization. To check if the reaction took place following the first process, the

cyclization reaction of (E)-ethyl 3-(2-hydroxyphenyl)acrylate (41a) using ethanol

at 80 °C was tested. Here, the starting material was recovered unchanged. We

237 Reaction performed using 2 equivalents of other arylation agents (phenyl boronic acid, 4-

bromoanisole, 4-methoxybenzenediazonium tetrafluoroborate) under the standard conditions

failed to give the corresponding product. 238 a) M.-T. Nolan, J. T. W. Bray, K. Eccles, M. S. Cheung, Z. Lin, S. E. Lawrence, A. C.

Whitwood, I. J. S. Fairlamb, G. P. McGlacken, Tetrahedron 2014, 70, 7120-7127; b) M.-T.

Nolan, L. M. Pardo, A. M. Prendergast, G. P. McGlacken, J. Org. Chem. 2015, 80, 10904-

10913; c) L. M. Pardo, A. M. Prendergast, M.-T. Nolan, E. Ó. Muimhneacháin, G. P.

McGlacken, Eur. J. Org. Chem. 2015, 3450-3550.


gained access to the cyclised product using an n-Bu3P mediated reaction.228

When the resulting 2H-chromen-2-one was treated with salt 35a and PdO-Fe3O4

under standard conditions, only starting chromenone was recovered. These

results suggest that the cyclization/arylation pathway is unlikely. To further study

if the Heck-arylation reaction took place first, followed by cyclization (Scheme

29), some acrylates 43, no longer possessing the required hydroxyl group needed

for cyclization, were tested under the optimal reaction conditions (Table 35).

Scheme 29. Possible mechanism of the reaction.

Using two equivalents of 35a, a 3:1 mixture of the mono- and di-

substituted products 44 were obtained in good yield (entry 1). With these results

in hand, the reaction was repeated with only one equivalent of the salt 35a. A

lower amount of the di-substituted product 44b was obtained, along with

concomitant improvement in the yield of 44a (entry 2). Then, methyl cinnamate

(43b) was tested and 68 % yield of 44c was obtained (entry 3). To finish with the

study of the Heck-arylation, different substituents at the 4-possition of the

aromatic ring of starting cinnamate were used, obtaining a ca. mixture 1:1 of Z/E

isomers in good yields (entries 4 and 5).


Table 35. Heck-arylation reaction.a

Entry R

1 R

2 Product Yield (%)

b

1 H Et 44a 76 (23)c

2d

H Et 44a 86 (13)c

3 Ph Et 44b 68

4 4-MeC6H4 Me 44c 71 (Z/E 0.95/1)

5 4-MeOC6H4 Me 44d 69 (Z/E 1/0.8) a Reaction carried out using compounds 43 (0.25 mmol), and 35a (0.5 mmol).

b Isolated yield after bulb-to-bulb distillation.

c Isolated yield of compound 44b.

d Reaction carried out using compounds 43 (0.25 mmol), and 35a (0.25 mmol).

All these findings seem to suggest that the mechanism follows the

pathway described in Scheme 29. Thus, the initial Heck reaction favors the final

cyclization process.

CHAPTER V

Reactions without catalyst

155 Chapter V. Reactions without catalyst

1. SYNTHESIS OF 3,5-DISUBSTITUTED ISOXAZOLES AND

ISOXAZOLINES IN DEEP EUTECTIC SOLVENTS

1.1 INTRODUCTION

Isoxazoles and related 4,5-dihydroisoxazoles are a valuable and well

established239

class of heterocyclic compounds240

with broad applications,241

as

pharmaceutical and agricultural compounds due to their activities.242

Numerous synthetic approaches for the construction of the isoxazole

and 4,5-dihydroisoxazole framework have been reported. There are two main

methodologies: the first approach involves the condensation of hydroxylamine

with 1,3-dicarbonyl compounds or their three-carbon 1,2-electrophilic variants,

such as α,β-unsaturated ketones, enamino ketones, β-alkylthioenones, and

ynones. The second one is the 1,3-dipolar cycloaddition reaction between alkynes

or alkenes with nitrile oxides, generated in situ from aldoximes or nitroalkanes.243

239 a) A. Padwa in Comprehensive Organic Synthesis, ch. 4.9; Vol. 4 (Eds.: B. M. Trost, I.

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Cecchi, F. De Sarlo, C. Faggi, F. Machetti, Eur. J. Org. Chem. 2006, 3016-3020; f) L. Cecchi,

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Chapter V. Reactions without catalyst 156

In turn, these heterocycles can be transformed into β-functionalised carbonylic

compounds,244

by cleavage of the labile N-O heterocyclic bond.

Different metallic derivatives have been used to perform the

regioselective cycloaddition reaction, including aluminium,245

magtrieve

(CrO2),246

cobalt247

and copper248

complexes, AgBF4,249

SnPh4,250

triscetylpyridiniumtetrakis(oxodiperoxotungsto)phosphate,251

gold compounds,252

and Pb(OAc)2.253

Conversely, in the case of cyclopentadienyl ruthenium

derivatives,254

the regioselective formation of the related 4,5-disubstituted

heterocycles was observed.

It should be pointed out that for many applications the use of toxic

transition metals is undesirable, if not prohibited. Therefore, there is a clear

necessity for metal-free protocols. This green approach has been conducted by

different oxidative reagents such as oxone,255

iodine,256

iodobenzene

244 B. Raghava, G. Parameshwarappa, A. Acharya, T. R. Swaroop, K. S. Rangappa, H. Ila, Eur. J.

Org. Chem, 2014, 1882-1892. 245 O. Jackowski, T. Lecourt, L. Micouin, Org. Lett. 2011, 13, 5664-5667. 246 a) S. Bhosale, S. Kurhade, U. V. Prasad, V. P. Palle, D. Bhuniya, Tetrahedron Lett. 2009, 50,

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H. Togo, J. Org. Chem. 2014, 79, 2049-2058.


trifluoroacetate,257

iodobenzene diacetate,258

tert-butyl hypoiodite,259

or

chloramine-T.260

However, these new protocols have several inconveniencies

such as stability, price, and manipulation of reagents. The importance of the

solvents used as reaction media has been recently addressed by the use of

aqueous biphasic protocols,261

ionic liquid,262

and aqueous polyethylene glycol.263

Within the framework of green chemistry, solvents occupy a strategic place. To

be qualified as a green medium, the components of this solvent have to meet

different criteria such as availability, non-toxicity, biodegradability, recyclability,

inflammability, renewability, and low price, among others.

Deep eutectic solvents167b,c,e,264

(DES), as it has been previously

reported (Chapter II), are an environmentally benign alternative to hazardous

(organic) solvents and, in many cases, might replace them. DESs are liquid

systems formed from an eutectic mixture of solid Lewis or Brønsted acids and

bases, which can contain a variety of anionic and/or cationic species.166

These

two components are capable of self-association, often through a strong bond

interaction, to form an eutectic mixture with a melting point lower167a,d,265

than

that of each individual component. The typical green characteristic properties of

a solvent, such as conductivity, viscosity, vapour pressure and thermal stability

can be fine-tuned by the appropriate choosing of the mixture components, with

the large-scale preparation being feasible.

The applications of DES in organic synthesis have notable advantages.

As most of the components are soluble in water, addition of water to the reaction

257 A. M. Jawalckar, E. Reubsaet, F. P. J. T. Rutjes, F. L. van Delft, Chem. Commun. 2011, 47,

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Gonçalves, M. D. Santos, G. Bernadat, D. Bonnet-Delpon, B. A. Crousse, Beilstein J. Org.

Chem. 2013, 9, 2387-2394. 259 S. Minakata, S. Okumura, T. Nagamachi, Y. Takeda, Org. Lett. 2011, 13, 2966-2969. 260 M. Koufaki, T. Fotopoulou, M. Kapetanou, G. A. Heropoulos, E. S. Gonos, N. Chondrogianni,

Eur. J. Med. Chem. 2014, 83, 508-515. 261 a) A. P. Kozikowski, M. Adamczyk, J. Org. Chem. 1983, 48, 366-372; b) Y. Koyama, M.

Yonekawa, T. Takata, Chem. Lett. 2008, 37, 918-919. 262 H. Valizadeh, M. Amiri, H. Gholipur, J. Heterocyclic Chem. 2009, 46, 108-110. 263 R. G. Chary, G. R. Reddy, Y. S. S. Ganesh, K. V. Prasad, A. Raghunadh, T. Krishna, S.

Mukherjee, M. Pal, Adv. Synth. Catal. 2014, 356, 160-164. 264 A. P. Abbott, R. C. Harris, K. S. Ryder, C. D’Agostino, L. F. Gladden, M. D. Mantle, Green

Chem. 2011, 13, 82-90. 265 a) A. P. Abbott, G. Capper, D. L. Davies, R. K. Rasheed, V. Tambyrajah, Chem. Commun.

2003, 70-71; b) M. A. Kareem, F. S. Mjalli, M. A. Hashim, I. M. AlNashel, J. Chem. Eng. Data

2010, 55, 4632-4637.


mixture dissolves the reaction medium, and the organic products either form a

separate layer or precipitate. Moreover, the solvent and the catalyst may be

recycled by the adequate quenching of the reaction.

DES have been used as an ideal medium in biocatalysed,266

organocatalysed267

reactions as well as in reactions using homogeneous268

and

heterogeneous170

catalysts. Although there are several misconceptions about their

uses in organic synthesis due to the high reactivity of the intermediate, this kind

of eutectic mixture has a promising future.

1.2 RESULTS

To start our study we decided to examine the three step one pot synthesis

of 3,5-disubstituted isoxazoles, similar to those previously reported,248f

using

benzaldehyde (2a) and phenylacetylene (5a) as the starting materials, and our

impregnated copper(II) oxide on magnetite as catalyst. After dissolving reagents

in DMF (1 mL) at room temperature, hydroxylammonium chloride and solid

NaOH were added, which should lead to the formation of the corresponding

oxime after 1 h of reaction. Then NCS was added to the basic reaction mixture,

which should result in the formation of hydroxyiminoyl chloride derivative after

3 h at room temperature. To obtain the corresponding isoxazole 45a in 60 %

yield, the addition of phenylacetylene (5a) and 0.44 mol% of CuO-Fe3O4 at 100

ºC was needed. Once the protocol was checked using our catalyst, the reaction

was repeated changing the solvent by the same amount of slightly basic eutectic

mixture ChCl:urea (1:2), obtaining better results (72 % yield). After that, the

reaction was repeated without the addition of CuO-Fe3O4 catalyst, surprisingly,

reaching a similar yield.

With these results in hand, the reaction was performed in a similar way

but changing the common organic volatile solvent by different DES in absence of

catalyst (Table 36). The reaction conditions were modified slightly, performing

all the steps at 50 ºC. Initially, the effect of DES in the reaction was examined

(entries 1-6). In first place, the reaction was performed in the DES formed by

ChCl:glycerol (1:2) and although the yield was not satisfactory, it proved that the

concept may work (entry 1). Then, other DESs were examined as medium for the

266 Z. Maugeri, P. Domínguez de María, ChemCatChem. 2014, 6, 1535-1537. 267 a) C. R. Müller, I. Meiners, P. Domínguez de María, RSC Adv. 2014, 4, 46097-46101; b) R.

Martínez, L. Berbegal, G. Guillena, D. J. Ramón, Green Chem. 2016,

DOI:10.1039/C5GC02526E. 268 L. Gu, W. Huang, S. Tang, S. Tian, X. Zhang, Chem. Eng. J. 2015, 259, 647-652.


reaction, finding that DES containing urea gave better results. The initial mixture

ChCl:urea (1:2) led to the best yield (entry 6).


Entry DES (molar ratio) t (h) Yield (%)

b

1 ChCl:glycerol (1:2) 8 20

2 ChCl:trifluoroacetamide (1:2.5) 8 0

3 ChCl:ethylene glycol (1:2) 8 0

4 Ph3P+MeBr

-:glycerol (1:2) 8 0

5 AcChCl:urea (1:2) 8 40

6 ChCl:urea (1:2) 8 71

7 ChCl:urea (1:2) 1 46

8 ChCl:urea (1:2) 2 64

9 ChCl:urea (1:2) 4 73 (70)c

10d

THF 8 4

11d

THF (urea)e

8 13

12d

THF (ChCl)e

8 11

13 ureaf

8 34

14 ChClf

8 15 a

Reaction carried out using compounds 2a (203 μL, 2mmol), NH2OH·HCl (138 mg, 2

mmol), NaOH (80 mg, 2 mmol), NCS (400 mg, 3 mmol) and 5a (110 μL, 2 mmol) in

1mL of DES. b Isolated yield after column chromatography.

c Reaction carried out using compounds 2a (2.03 mL, 20 mmol), NH2OH·HCl (1,38 g, 20

mmol), NaOH (800 mg, 20 mmol), NCS (4g, 30 mmol) and 5a (2.2 mL, 20 mmol) in 10

mL of DES. d Reaction carried out using 1 mL of THF.

e 2 equivalents of additive was added.

f Reaction carried out in the absence of solvent using 2 equivalents of additive.

It should be pointed out that this renewable solvent is a good medium for

different reactions, including the deprotonation of aromatic hydroxylammonium

chloride with solid sodium hydroxide, condensation of amine derivative with

benzaldehyde, and chlorination of the formed oxime with N-chlorosuccinimide to

give the corresponding hydroximinoyl chloride, which is stable enough into the


highly functionalized medium, to allow the final [3+2] cycloaddition by slow

HCl elimination.

Then, the reaction time was evaluated for the last cycloaddition step

(entries 6-9), finding that after 4 h the increase of the yield was marginal. The

reaction was scaled up to grams using 10 mL of DES (entry 9, footnote c), and

after completion of the reaction 10 mL of NaOH 1 M and 10 mL of hexane were

added. The resulting mixture was stirred during 30 minutes and after that, the

obtained solid was filtered off, obtaining the corresponding pure product with

good yield. This purification protocol is easier and greener than that employed in

the milligram scale.

In order to clarify the role of different components or the solvent, the

reaction was performed in THF adding 2 equivalents of urea or chlorine chloride

(Table 36, entries 10-12), obtaining slightly better results using these additives.

When the reaction was repeated in absence of solvent but in the presence of the

aforementioned additives (Table 36, entries 13 and 14), the best result was

obtained in the presence of urea. These facts highlight the beneficial role of urea

in the reaction mechanism, probably by stabilising the ionic intermediates

through hydrogen bonds.

With the best conditions in hand, the scope of the reaction was evaluated

(Table 37). The reaction gave excellent results for substituted benzaldehydes

independently of the nature of the substituent at the aromatic ring of the aldehyde

(entries 1-3) as well as of the relative position (compares entries 3 and 4). The

reaction was tested using aliphatic (entry 5) and heterocyclic (entries 6 and 7)

aldehydes, obtaining good yields.

The reaction was also accomplished with different substituted

ethynylbenzenes, using electron-donating substituents as well as electron-

withdrawing groups, obtaining good yields (entries 8 and 9). Heterocyclic (entry

10) and aliphatic (entry 11) alkynes were also tested leading to good results. The

combination of substituted aldehydes and alkynes was not problematic, obtaining

the corresponding product with a similar good yield (entry 12).


Table 37. Preparation of Isoxazoles.a

Entry R

1 R

2 Product Yield (%)

b

1 Ph Ph 45a 73

2 4-ClC6H4 Ph 45b 83

3 4-MeC6H4 Ph 45c 96

4 2-MeC6H4 Ph 45d 81

5 C6H11 Ph 45e 86

6 2-Quinolyl Ph 45f 82

7 2-Thienyl Ph 45g 86

8 Ph 3-ClC6H4 45h 80

9 Ph 4-MeOC6H4 45i 76

10 Ph 2-Pyridyl 45j 63

11 Ph C6H11 45k 84

12 4-MeC6H4 4-MeOC6H4 45l 70 a

Reaction carried out using compounds 2 (2mmol), NH2OH·HCl (138 mg, 2 mmol),

NaOH (80 mg, 2 mmol), NCS (400 mg, 3 mmol) and 5 (2 mmol) in 1mL of ChCl:urea

(1:2). b Isolated yield after column chromatography.

The recycling of ChCl:urea medium was evaluated once the compound

45a was obtained. The simple decantation of DES mixture with toluene permitted

the partial isolation of all organic products and by-products. The lower DES layer

was reused in a second cycle, but the yield decreased from 73 to 32 %. The high

solubility of initial reagents (NH2OH·HCl, NaOH, NCS), as well as the

stoichiometric by-product formed (H2O and succinimide) presented in the second

cycle might modify the initial DES structure, decreasing the initial beneficial

solvent effect.

Once the study of this reaction was finished, a similar process was

performed but using alkenes269

(Table 38). The yields were similar to the

previously obtained with alkynes allowing either the use of aromatic (entries 1-3)

and heterocyclic (entry 4) aldehydes or the use of aromatic (entry 5), heterocyclic

(entry 6), and aliphatic (entries 7 and 8) alkenes. The combination of aromatic

269 L. Han, B. Zhang, C. Xiang, J. Yan, Synthesis 2014, 46, 503-509.


aldehydes and aliphatic alkenes gave the corresponding product with moderate

yield (entry 9).

Table 38. Preparation of Isoxazolines.a

Entry R

1 R

2 Product Yield (%)

b

1 Ph Ph 47a 54

2 4-ClC6H4 Ph 47b 91

3 4-MeC6H4 Ph 47c 51

4 2-Thienyl Ph 47d 79

5 Ph 4-ClC6H4 47e 70

6 Ph 2-Pyridyl 47f 84

7 Ph C6H13 47g 74

8 Ph 4-MeOC6H4CH2 47h 47

9 4-NO2C6H4 CH2Br 47i 42 a

Reaction carried out using compounds 2 (2mmol), NH2OH·HCl (138 mg, 2 mmol),

NaOH (80 mg, 2 mmol), NCS (400 mg, 3 mmol) and 46 (2 mmol) in 1mL of DES. b Isolated yield after column chromatography.

Once the scope of the reaction was studied, a ring opening reaction270

was carried out using 0.5 equivalents of Mo(CO)6 and starting from the

previously obtained isoxazoles 45 (Table 39). The reaction took place with good

yields when the substituents of the isoxazole were aromatic, independently of the

electronic nature of the substituents at the rings (entries 1-3). However, when the

reaction was performed with aliphatic substituents, the yield decreased (entry 4).

270 a) C. Kashima, S. Tobe, N. Sugiyama, M. Yamamoto, Bull. Chem. Soc. Jpn. 1973, 46, 310-313;

b) C. Kashima, J. Org. Chem. 1975, 40, 526-527; c) D. P. Curran, J. Am. Chem. Soc. 1983,

105, 5826-5833; d) M. Nitta, T. Kobayashi, J. Chem. Soc., Perkin Trans. 1985, 1, 1401-1406;

e) C.-S. Li, E. Lacasse, Tetrahedron Lett. 2002, 43, 3565-3568; f) R. Saxena, V. Singh, S.

Batra, Tetrahedron 2004, 60, 10311-10320; g) S. I. Sviridov, A. A. Vasil’ev, S. V. Shorshnev,

Tetrahedron 2007, 63, 12195-12201; h) L. Zhu, G. Wang, Q. Guo, Z. Xu, D. Zhang, R. Wang,

Org. Lett. 2014, 16, 5390-5393.


Table 39. Synthesis of β-amino enones.a

Entry R

1 R

2 Product Yield (%)

b

1 Ph Ph 48a 90

2 4-ClC6H4 Ph 48b 92

3 Ph 4-MeOC6H4 48c 89

4 Ph C6H13 48d 55 a

Reaction carried out using compounds 45 (1 mmol), H2O (1 mmol), Mo(CO)6 (0.5

mmol) in 20 mL of CH3CN. b Isolated yield after column chromatography.

Our next goal was to examine if a similar dipolar cycloaddition is

feasible also with activated nitroalkenes. So, the simple approach for the

synthesis of ethyl 5-substituted isoxazole-3-carboxylates by reaction of the

corresponding nitrocompounds using DES was tested (Table 40). Ethyl 2-

nitroacetate (49) and phenylacetylene (5a) were selected as the model for the

optimization of the reaction conditions. Initially, the effect of different DES was

examined (entries 1-5). The reaction was performed in some of the previously

tested DES, with only those containing urea giving the expected product 50a.

With these results in hand, the reaction was repeated increasing the

temperature (entries 6 and 7) observing that, in the mixture acetyl choline

chloride (AcChCl):urea the reaction took place with good yield after 24 h. The

reaction was tested using 2 equivalents of compound 49, obtaining good yield

after only 4 h of reaction (entry 8), with the yield not being improved by an

increasing the reaction time. To prove the beneficial effect of the DES media, the

reaction was repeated in absence of solvent, under the best reaction conditions,

and the starting material was recovered unchanged (entry 9).



Entry DES (molar ratio) T (ºC) t (h) Yield (%)

b

1 ChCl:glycerol (1:2) 50 48 0

2 ChCl:ethylene glycol (1:2) 50 48 0

3 Ph3P+MeBr

-:glycerol (1:2) 50 48 0

4 AcChCl:urea (1:2) 50 48 42

5 ChCl:urea (1:2) 50 48 35

6 ChCl:urea (1:2) 100 24 40

7 AcChCl:urea (1:2) 100 24 85

8c AcChCl:urea (1:2) 100 4 79 (80)

d

9 - 100 24 0 a

Reaction carried out using compounds 49 (0.5 mmol) and 5a (0.5 mmol) in 1mL of

DES. b Isolated yield after column chromatography.

c Reaction carried out using compounds 49 (1 mmol) and 5a (0.5 mmol) in 1mL of DES.

d After 8 h of reaction.

Once the optimization was performed and with the best conditions in

hand, the scope of the reaction was evaluated using AcChCl:urea (1:2) at 100 ºC

(Table 41).



b

1 Ph 50a 79

2 3-ClC6H4 50b 91

3 3-MeC6H4 50c 85

4 4-MeOC6H4 50d 78

5 C6H13 50e 63 a Reaction carried out using compounds 49 (1 mmol) and 5 (0.5 mmol) in 1mL of DES.



The reaction gave excellent results with different substituted

ethynylbenzenes 5, independently of the relative position or the electron nature of

the substituent. However, the reaction with a related aliphatic alkyne gave the

expected product 50e with a slight decrease in yield (entry 5).

Once the positive effect of the DES on the reaction was proved, the

recycling of the media was evaluated. After performing the reaction and

generating compound 50a in AcChCl:urea (1:2), the product was isolated by

extraction with toluene and the DES media was reused for the next process

(Figure 46). The DES solvent could be reused five times obtaining similar yields

compared to the freshly prepared one.

0

10

20

30

40

50

60

70

80

90

100

12

34

5

Yie

ld 5

0a

(%)

Cycle

Figure 46. Yields obtained with recycled DES (AcChCl:urea).

Finally, a possible picture of the hypothetic mechanism is described in

Scheme 30. In both protocols, only DES containing urea gave the expected

product in a reasonable yield. This fact might be due to the high hydrogen-bond

donating character of this component. In the first approach, we believe that urea

favours the release of chloride from the imidoyl chloride compound. In fact, this

interaction is the responsible for the formation of DES. In the second approach, a

similar interaction would favour the nitrotautomerization. Finally, the nitrile

oxide intermediate formed in both cases could be stabilised by both component

of DES, through hydrogen bonding with urea and through electronic interaction

with the choline derivative.


Scheme 30. Possible mechanism pathway.

EXPERIMENTAL PART

169 Experimental Part

1. GENERAL

1.1. SOLVENTS AND SUBSTRATES

All reagents listed in the present research work, whose preparation has

not been described, were purchase with the best commercial grade and were used

without purification (Acros, Aldrich, Alfa Aesar, Fluka, Fluorochem, Merck).

The solvents used in the reactions that required anhydrous conditions were dried

under standard conditions before the use. Other solvents employed (hexane, ethyl

acetate, diethyl ether, methanol, ethanol) were the best grade commercially

available.

1.2. INSTRUMENTATION

The X-ray fluorescence analyses (XRF) were carried out on the units of

Technical Services Research at the University of Alicante on a PHILIPS MAGIX

PRO (PW2400) X-ray spectrometer equipped with a rhodium X-ray tube and a

beryllium window.

The gas adsorption analysis were carried out on the units of Technical

Services Research at the University of Alicante with an automatic volumetric

equipment of physical adsoption gas and degassing AUTOSORB-6 and

AUTOSORB DEGASSER, both from Quantachrome. N2 was used as gas.

The X-ray photoelectron spectroscopy (XPS) analyses were carried out

on the units of the Technical Services of Investigation at the University of

Alicante in a VG-Microtech Multilab 3000 equipped with a hemispheric electron

analyser with 9 channeltrons (pass energy between 2 and 200 eV) and an X-ray

tube with Mg and Al anodes.

The transmission electron microscopy (TEM) analyses were carried out

on the units of the Technical Services of Investigation at the University of

Alicante on a JEOL JEM-2010 microscope, equipped with a X-ray detector

OXFORD INCA Energy TEM 100 for microanalysis EDS.

TG-DTA analysis were carried out on a METTLER TOLEDO

equipment, model TGA/SDTA851e/LF/1600, and EM analysis on a PFEIFFER

VACUUM, model THERMOSTAR GSD301T.

Melting points were obtained with a Reichert Thermovar apparatus.

Experimental Part 170

The purity of volatile compounds and the chromatographic analysis

(GLC) was performed with a Younglin 6100GC equipped with a flame ionization

detector (FID) and a capillary column HP-5 (5 % crosslinking PH ME siloxane)

30 m length, 0.25 mm internal diameter and 0.25 μm thick sheet, using nitrogen

(2 mL/min) as carrier gas, 10 psi pressure in the injector block temperature 270

°C injection volume 0.75 μL sample injected and 5 mm/min speed recording. The

selected program was 60 °C initial temperature for 3 minutes 15 °C/min heating

rate to 270 °C, where the temperature is held for ten minutes. The retention times

(tr) are given in minutes under these conditions.

Thin layer chromatography (TLC) was carried out on Schleicher &

Schuell F1400/LS 254 plates coated with a 0.2mm layer of silica gel; detection

by UV254 light, staining with phosphomolybdic acid [25 g phosphomolybdic acid,

10 g Ce(SO4)2·4H2O, 60 mL of concentrated H2SO4 and 940 mL H2O].

IR spectra (cm-1

) were obtained with a spectrophotometer Nicolet Impact

400 D-FT spectrophotometer or with a spectrophotometer attenuated total

reflectance (ATR) JASCO 4100LE (Pike Miracle). Samples were prepared on

glass capillary film on sodium chloride in the case of oils. For solid samples, the

corresponding potassium bromide pellets were prepared, in a proportion of 0.5-1

% by mass. In the case of ATR spectrometer, the samples were analyzed directly.

Proton nuclear magnetic resonance spectra (1H-NMR), carbon (

13C-

NMR) and fluorine (19

F-NMR) were performed in the unit of Nuclear Magnetic

Resonance of the Technical Services Research at the University of Alicante with

a Bruker AC-300 or Bruker Avance-400, using deuterated chloroform as solvent

(unless otherwise is indicated) and tetramethylsilane (TMS) as an internal

standard (if not indicated otherwise). The spectra of proton nuclear magnetic

resonance were performed at 300 or 400 MHz, while the carbon became 75 or

100 MHz and 282 MHz for fluorine. Chemical shifts (δ) are given in parts per

million (ppm) and coupling constants (J) in Hz.

The mass spectrometric analysis was performed using a spectrometer

Agilent GC / MS-5973N, performing studies in the form of electron impact (EI) at

70 eV ionization source and helium as the mobile phase. Samples were

introduced by injection through a gas chromatograph Hewlett-Packard HP-6890,

equipped with a HP-5MS column 30 m length, 0.25 mm internal diameter and

0.25 μm film thickness (crosslinking 5 % PH ME siloxane). Ions derived from

the breaks are given as m/z with brackets relative percent intensities.


The mass spectrometry analyses of high resolution (HRMS) were

performed in units Mass Spectrometry of the Technical Services Research at the

University of Alicante with a spectrometer Finnigan MAT95-S.

Elemental analyses were carried out on the units of the Technical

Services of Investigation at the University of Alicante with an elemental

microanalyser Thermo Finningan Flash 1112.

Column chromatography was performed on pre-packed columns (12 mm

7.5 to 15 cm) using a pump chromatography type Büchi Pump (C-610

Controller Module C-601). The sample was introduced into the column prior

preparation of slurry with the apolar eluent, eluting with mixtures of the solvents

indicated in the purification of each particular compound and increasing in

polarity (hexane, ethyl acetate and methanol). They were also made with glass

columns, using as stationary phase silica gel Merck 60, with a particle size of

0.040 to 0.063 mm (flash silica), or 0.063 to 0.2 mm. This was introduced into

the column prior preparation of slurry with the initial eluent, eluting with

mixtures of hexane and ethyl acetate of increasing polarity, unless otherwise

specified.

The analysis of mass spectrometry with inductively coupled plasma

(ICP-MS) were performed in units of Technical Services Research at the

University of Alicante with a mass spectrometer with inductively coupled plasma

THERMO ELEMENTAL, model VG PQ.ExCell.

2. PREPARATION OF CATALYSTS

To a stirred solution of the metal salt MClx (1 mmol) in deionized water

(120 mL) was added commercially available Fe3O4 (17 mmols, 4g, powder

<5μm, BET area: 9.86 m2/g). After 10 min at room temperature, the mixture was

slowly basified with NaOH (1M) until pH around 13. The mixture was stirred

during one day at room temperature in air. After that, the catalyst was filtered and

washed several times with deionized water (3 x 10 mL). The solid was dried at

100 ºC during 24 h in a standard glassware oven, obtaining the expected catalyst.

In the case of the palladium catalysts, 13 mmol of KCl were added

initially to increase the solubility of the palladium salt (PdCl2) and the usual

procedure was followed.

For the preparation of the bimetallic catalysts, 1 mmol of each metallic

salt was dissolved in 120 mL and the usual procedure was carried out.


3. REACTIONS CATALYSED BY NANOPARTICLES OF

IMPREGNATED COBALT(II) OXIDE ON MAGNETITE

3.1. HYDROACYLATION OF AZODICARBOXYLATE COMPOUNDS

General Procedure: To a stirred solution of the corresponding aldehyde

(2, 1.2 mmol) in trichloroethylene (1 mL) were added the catalyst (50 mg) and

the corresponding substituted azodicarboxylate (1, 1 mmol). The resulting

mixture was stirred at 60 ºC until the end of the reaction. The catalyst was

removed by a magnet and the resulting mixture was quenched with water and

extracted with AcOEt (3 x 5 mL). The organic phases were dried over MgSO4,

followed by evaporation under reduced pressure to remove the solvent. The

product was usually purified by chromatography on silica gel (hexane/ethyl

acetate) to give the corresponding products 3:

Diisopropyl 1-benzoylhydrazine-1,2-

dicarboxylate (3a):113

white solid; m.p. = 120-121

ºC (hexane); tr = 15.8; Rf = 0.1 (hexane/ethyl

acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.69

(m, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.40-7.45 (m,

2H), 6.87 (s, br, 1H), 4.85-5.10 (2m, 1 and 1H,

respectively), 1.30 (d, J = 6.0 Hz, 6H), 1.07 (d, J =

5.4 Hz, 6H); 13

C NMR (75 MHz, CDCl3): δ 171.1,

155.2, 152.8, 135.1, 131.8, 128.0 (4C), 72.3, 70.5, 21.8 (2C), 21.2 (2C); IR

(ATR): ν 3275, 1756, 1740, 1684, 1251, 1047 cm-1

; MS (EI) m/z (%): 222 (8),

105 (100), 77 (17).

Diisopropyl 1-(2-methylbenzoyl)hydrazine-1,2-

dicarboxylate (3b): pale yellow solid; m.p. = 64-66


acetate: 3/2); 1H NMR (300 MHz, CDCl3): δ 7.30-

7.40 (m, 2H), 7.15-7.30 (m, 2H), 6.97 (s, br, 1H),

5.03 (heptet, J = 6.2 Hz, 1H), 4.84 (heptet, J = 6.2

Hz, 1H), 2.39 (s, 3H), 1.30 (d, J = 6.2 Hz, 6H), 1.00

(d, J = 6.2 Hz, 6H); 13

C NMR (75 MHz, CDCl3): δ

170.4, 155.1, 152.2, 136.1, 135.2, 130.2, 129.9, 126.2, 125.3, 72.3, 70.6, 21.9

(2C), 21.1 (2C), 19.1; IR (ATR): ν 3294, 2984, 1754, 1734, 1687, 1252, 1505

cm-1

; MS (EI) m/z (%): 322 (M+, 0.1), 120 (9), 119 (100), 91 (17); Elemental

analysis calcd. for C16H22N2O5: C = 59.61, H = 6.88, N = 8.69; found: C = 59.65,

H = 6.93, N = 8.59.


Diisopropyl 1-(3-methylbenzoyl)hydrazine-1,2-

dicarboxylate (3c): white solid; m.p. = 96-98 ºC

(hexane); tr = 16.3; Rf = 0.7 (hexane/ethyl acetate:

3/2); 1H NMR (300 MHz, CDCl3): δ 7.50 (s, br,

2H), 7.25-7.35 (m, 2H), 6.96 (s, br, 1H), 5.01

(heptet, J = 6.2 Hz, 1H), 4.89 (heptet, J = 6.2 Hz,

1H), 2.38 (s, 3H), 1.29 (d, J = 6.2 Hz, 6H), 1.07 (d,

J = 6.2 Hz, 6H); 13


171.3, 155.2, 152.9, 137.9, 135.1, 132.6, 128.9, 128.0, 125.2, 72.3, 70.6, 21.9

(2C), 21.3 (2C), 21.2; IR (ATR): ν 3273, 2985, 1741, 1689, 1519, 1252; MS (EI)

m/z (%): 236 (8), 120 (9), 119 (100), 91 (18) cm-1

; Elemental analysis calcd. for

C16H22N2O5: C = 59.61, H = 6.88, N = 8.69; found: C = 59.68, H = 7.01, N =

8.75.

Diisopropyl 1-(p-tolyl)hydrazine-1,2-

dicarboxylate (3d):113




(s, br, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.86 (s, br,

1H), 4.90-5.10 (2m, 1 and 1H, respectively), 2.40

(s, 3H), 1.29 (d, J = 5.6 Hz, 6H), 1.11 (d, J = 5.6

Hz, 6H); 13

C NMR (75 MHz, CDCl3): δ 171.1, 155.2, 153.0, 142.7, 132.1, 128.7

(2C), 128.4 (2C), 72.3, 70.6, 21.9 (2C), 21.6, 21.3 (2C); IR (ATR): ν 3281, 1753,

1736, 1685, 1250, 1044 cm-1

; MS (EI) m/z (%): 236 (9), 120 (14), 119 (100), 91

(22).

Diisopropyl 1-(4-methoxyphenyl)hydrazine-

1,2-dicarboxylate (3e): white solid; m.p. = 85-

87 ºC (hexane); tr = 17.4; Rf = 0.57

(hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,

CDCl3): δ 7.73 (m, 2H), 7.05 (s, br, 1H), 6.91

(d, J = 8.8 Hz, 2H), 4.85-5.05 (m, 2H), 3.85 (s,

3H), 1.28 (d, J = 6.0 Hz, 6H), 1.13 (d, J = 6.0

Hz, 6H); 13

C NMR (75 MHz, CDCl3): δ 170.6, 163.9, 163.0, 153.4, 153.2, 132.3,

131.0, 113.4 (2C), 72.2, 70.5, 55.4, 21.9 (2C), 21.4 (2C); IR (ATR): ν 3258,

1748, 1719, 1698, 1251, 1024 cm-1

; MS (EI) m/z (%): 136 (10), 135 (100).


Diisopropyl 1-(3,4,5-

trimethoxybenzoyl)hydrazine-1,2-

dicarboxylate (3f):113

white solid; m.p.= 92-

94 ºC (hexane); tr = 18.9; Rf = 0.3

(hexane/ethyl acetate: 3/2); 1H NMR (300

MHz, CDCl3): δ 7.01 (s, 2H), 6.93 (s, br, 1H),

4.85-5.05 (m, 2H), 3.89 (s, 3H), 3.88 (s, 6H),

1.30 (d, J = 6.3 Hz, 6H), 1.14 (d, J = 6.3 Hz,

6H); 13

C NMR (75 MHz, CDCl3): δ 170.8, 155.3, 153.0, 152.9 (2C), 141.7,

129.9, 106.0 (2C), 72.4, 70.6, 60.9, 56.2 (2C), 21.9 (2C), 21.4 (2C); IR (ATR): ν

3283, 2979, 1746, 1719, 1699, 1587, 1248 cm-1

; MS (EI) m/z (%): 398 (M+, 5%),

196 (11), 195 (100).

Diisopropyl 1-(4-fluorobenzoyl)hydrazine-1,2-

dicarboxylate (3g):109b

white solid; m.p. = 98-99 ºC


1/1); 1H NMR (300 MHz, CDCl3): δ 7.70-7.75 (m,

2H), 7.12 (t, J = 7.1 Hz, 2H), 6.95-7.00 (m, 1H),

4.90-5.05 (m, 2H), 1.31 (d, J = 5.9 Hz, 6H), 1.14 (d,

J = 5.9 Hz, 6H); 13


170.2, 164.9 (d, 1JC-F = 253.3 Hz), 152.8, 152.2,

131.1, 130.8 (d, 3JC-F = 6.8 Hz, 2C), 115.3 (d,

2JC-F = 22 Hz, 2C), 72.6, 70.7, 21.9

(2C), 21.4 (2C); IR (ATR): ν 3282, 1745, 1723, 1698, 1283 cm-1

: MS (EI) m/z

(%): 240 (10), 154 (10), 124 (12), 123 (100), 95 (20).

Diisopropyl 1-(2-chlorobenzoyl)hydrazine-1,2-

dicarboxylate (3h): yellow oil; tr = 16.4; Rf = 0.63


CDCl3): δ 7.30-7.50 (m, 4H), 6.99 (s, 1H), 4.85-

5.05 (2m, 1 and 1H, respectively), 1.05-1.35 (2m, 6

and 6H, respectively); 13

C NMR (75 MHz, CDCl3):

δ 167.5, 154.9, 151.6, 136.1, 130.8, 130.2, 129.3,

127.9, 126.6, 72.6, 70.6, 21.8 (2C), 21.2 (2C); IR (ATR) ν 3312, 2983, 2937,

1739, 1257 cm-1

; MS (EI) m/z (%): 256 (10), 141 (34), 139 (100), 111 (12);

Elemental analysis calcd. for C15H19ClN2O5: C = 52.56, H = 5.59, N = 8.17;

found: C = 52.42, H = 5.49, N = 8.23.



dicarboxylate (3i): white solid; m.p. = 108-110



7.65 (m, 3H), 7.30-7.40 (m, 1H), 7.04 (s, br, 1H),

4.90-5.10 (m, 2H), 1.30 (d, J = 6.2 Hz, 6H), 1.11

(d, J = 5.9 Hz, 6H); 13


δ 169.8, 155.1, 152.5, 136.8, 134.2, 131.7, 129.5, 128.0, 126.1, 72.8, 70.8, 21.9

(2C), 21.3 (2C); IR (ATR): ν 3286, 2985, 2940, 1744, 1757, 1527, 1518, 1254

cm-1

: MS (EI) m/z (%): 256 (12), 214 (11), 170 (17), 141 (39), 139 (100), 111

(20); Elemental analysis calcd. for C15H19ClN2O5: C = 52.56, H = 5.59, N = 8.17;

found: C = 52.59, H = 5.48, N = 8.08.


dicarboxylate (3j):110a



acetate: 3/2); 1H NMR (300 MHz, CDCl3): δ

7.65-7.70 (m, 2H), 7.30-7.40 (m, 2H), 6.95 (s, br,

1H), 4.90-5.05 (m, 2H), 1.30 (d, J = 5.2 Hz, 6H),

1.13 (d, J = 5.2 Hz, 6H); 13

C NMR (75 MHz,

CDCl3): δ 170.2, 155.1, 152.7, 138.2, 133.4, 129.6 (2C), 128.4 (2C), 72.7, 70.8,

21.9 (2C), 21.4 (2C); IR (ATR): ν 3310, 2989, 1735, 1712, 1596, 1486, 1264 cm-

1; MS (EI) m/z (%): 256 (8), 141 (33), 139 (100), 111 (14).

Diisopropyl 1-(1-naphthoyl)hydrazine-1,2-

dicarboxylate (3k): white solid; m.p. = 102-104 ºC


3/2); 1H NMR (300 MHz, CDCl3): δ 8.15-8.20 (m,

1H), 7.93 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 7.9 Hz,

1H), 7.60-7.65 (m, 1H), 7.45-7.55 (m, 3H), 7.10 (s,

1H), 5.05-5.10 (m, 1H), 4.65-4.70 (m, 1H), 1.34 (d,

J = 6.2 Hz, 6H), 0.65-0.75 (m, 6H); 13

C NMR (75

MHz, CDCl3): δ 170.4, 155.3, 152.0, 134.1, 133.1, 130.5, 129.9, 128.2, 127.3,

126.4, 124.7, 124.6 (2C), 72.3, 70.7, 21.9 (2C), 20.8 (2C); IR (ATR): ν 3278,

1760, 1743, 1514, 1251 cm-1

; MS (EI) m/z (%): 358 (M+, 6), 156 (26), 155 (100),

127 (61); Elemental analysis calcd. for C19H22N2O5: C = 63.67, H = 6.19, N =

7.82; found: C = 63.8, H = 6.25, N = 7.9.


Diisopropyl 1-(thiophene-2-carbonyl)hydrazine-

1,2-dicarboxylate (3l):111

colorless oil; tr = 16.0; Rf

= 0.47 (hexane/ethyl acetate: 3/2); 1H NMR (300

MHz, CDCl3): δ 7.89 (dd, J = 3.9, 1.3 Hz, 1H), 7.60

(dd, J = 5.0, 1.3 Hz, 1H), 7.22 (s, br, 1H), 7.09 (dd, J

= 5.0, 3.9 Hz, 1H), 4.95-5.10 (m, 2H), 1.25-1.35 (m,

12H); 13

C NMR (75 MHz, CDCl3): δ 162.6, 155.3, 154.8, 152.6, 135.5, 133.5,

127.1, 72.6, 70.8, 21.8 (2C), 21.5 (2C); IR (ATR): ν 3299, 1736, 1234 cm-1

; MS

(EI) m/z (%): 228 (12), 186 (8), 142 (10), 111 (100).

Diisopropyl 1-cinnamoylhydrazine-1,2-

dicarboxylate (3m):111

colorless oil; tr = 17.9; Rf

= 0.53 (hexane/ethyl acetate: 3/2); 1H NMR (300

MHz, CDCl3): δ 7.72 (d, J = 15.7 Hz, 1H), 7.45-

7.50 (m, 3H), 7.25-7.30 (m, 3H), 6.81 (s, br, 1H),

5.01 (heptet, J = 6.3 Hz, 1H), 4.93 (heptet, J = 6.3

Hz, 1H), 1.27 (d, J = 6.3 Hz, 6H), 1.15-1.25 (m, 6H); 13

C NMR (75 MHz,

CDCl3): δ 166.5, 155.1, 152.8, 145.8, 134.6, 130.4, 128.8 (2C), 128.4 (2C),

118.8, 72.3, 70.4, 21.8 (2C), 21.7 (2C); IR (ATR): ν 3311, 1732, 1236 cm-1

; MS

(EI) m/z (%): 132 (10), 131 (100), 103 (16).

Diisopropyl 1-butyrylhydrazine-1,2-

dicarboxylate (3n):109b

colorless oil; tr = 13.01; Rf =

0.6 (hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,

CDCl3): δ 6.84 (s, br, 1H), 4.85-5.00 (m, 2H), 2.80-

2.85 (m, 2H), 1.62 (m, 2H), 1.20-1.25 (m, 12H),

0.90 (t, J = 7.4 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 173.7, 155.1, 152.6, 71.9,

70.2, 38.7, 21.8 (2C), 21.6 (2C), 18.0, 13.5; IR (ATR): ν 3311, 1719, 1235 cm-1

;

MS (EI) m/z (%): 204 (48), 173 (10), 162 (28), 146 (13), 120 (33), 118 (46), 103

(13), 102 (20), 76 (51), 71 (100), 59 (11).

Diisopropyl 1-nonanoylhydrazine-1,2-

dicarboxylate (3o):109a

colorless oil; tr = 16.2. Rf =


CDCl3): δ 6.66 (s, br, 1H), 4.90-5.10 (m, 2H), 2.85-

2.90 (m, 2H), 1.60-1.70 (m, 2H), 1.2-1.35 (m, 22H),

0.87 (t, J = 6.7 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 173.9, 155.1, 152.6, 71.9,

70.2, 36.9, 31.7, 29.2, 29.0 (2C), 24.6, 22.5, 21.8 (2C), 21.6 (2C), 14.0; IR

(ATR): ν 3314, 2981, 2925, 1720, 1244 cm-1

; MS (EI) m/z (%): 205 (12), 204


(100), 162 (44), 160 (12), 141 (52), 120 (24), 118 (70), 76 (32), 71 (26), 57 (28),

55 (13).

Diisopropyl 1-(2-ethylbutanoyl)hydrazine-1,2-

dicarboxylate (3p): colorless oil; tr = 13.6; Rf =

0.73 (hexane/ethyl acetate: 3/2); 1H NMR (300

MHz, CDCl3): δ 7.01 (s, br, 1H), 4.95-5.10 (2m, 1

and 1H, respectively), 3.45-3.50 (m, 1H), 1.65-1.80

(m, 2H), 1.50-1.60 (m, 2H), 1.32 (d, J = 6.3 Hz,

6H), 1.25-1.30 (m, 6H), 0.91 (t, J = 7.4 Hz, 6H); 13

C NMR (75 MHz, CDCl3): δ 177.0, 155.1, 152.6, 71.8, 70.0, 47.3, 24.7 (2C),

21.7 (2C), 21.5 (2C), 11.4 (2C); IR (ATR): ν 3311, 2970, 2937, 2878, 1719, 1230

cm-1

; MS (EI) m/z (%): 302 (M+, <0.1%), 204 (16), 162 (9), 120 (15), 99 (46), 98

(22), 76 (11), 71 (100); Elemental analysis calcd. for C14H26N2O5: C = 55.61, H =

8.67, N = 9.26; found: C = 55.57, H = 8.60, N = 9.19.

Diisopropyl 1-pivaloylhydrazine-1,2-

dicarboxylate (3q):109b



MHz, CDCl3): δ 6.81 (s, br, 1H), 4.95-5.10 (m, 2H),

1.20-1.35 (m, 21H); 13


179.6, 155.7, 153.2, 72.1, 70.5, 42.0, 27.4 (3C),

21.8 (2C), 21.6 (2C); IR (ATR): ν 3295, 2981, 1720, 1227 cm-1

; MS (EI) m/z

(%): 204 (37), 162 (30), 120 (43), 118 (15), 103 (11), 85 (17), 76 (31), 57 (100).

(Z)-Diisopropyl 1-(dec-7-enoyl)hydrazine-

1,2-dicarboxylate (3r):

colorless oil; tr =

16.7; Rf = 0.47 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 6.72 (s, br,

1H), 5.25-5.40 (m, 2H), 4.90-5.10 (m, 2H),

2.90 (t, J = 6.8 Hz, 2H), 1.95-2.05 (m, 4H),

1.60-1.70 (m, 2H), 1.20-1.40 (m, 16H), 0.95 (t, J = 7.5 Hz, 3H); 13

C NMR (75

MHz, CDCl3): δ 173.0, 155.1, 152.6, 131.7, 128.9, 72.0, 70.3, 36.9, 29.4, 28.7,

26.9, 24.5, 21.8 (2C), 21.6 (2C), 20.4, 14.3; IR (ATR): ν 3313, 1736, 1502, 1237

cm-1

; MS (EI) m/z (%): 356 (M+, 0.08), 205 (14), 204 (100), 163 (11), 162 (49),

153 (54), 152 (32), 135 (13), 123 816), 121 (13), 120 (27), 118 (74), 109 (11), 83

(15), 76 (43), 71 (10), 69 (37), 67 (16), 55 (31); Elemental analysis calcd. for

C18H32N2O5: C = 60.65, H = 9.05, N = 7.86; found: C = 60.67, H = 9.03, N =

7.87.


Diethyl 1-benzoylhydrazine-1,2-dicarboxylate (3s):

271 colorless oil; tr = 15.5; Rf = 0.5


CDCl3): δ 7.68 (d, J = 7.1 Hz, 2H), 7.35-7.55 (m,

3H), 7.24 (s, br, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.15

(q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.07 (t,

J = 7.1 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 172.1, 155.7, 153.4, 133.7, 132.0,

130.1, 128.4, 128.1, 64.0 (2C), 14.3 (2C); IR (ATR): ν 3312, 2921, 1705, 1222

cm-1

; MS (EI) m/z (%): 106 (8), 105 (100), 77 (21).

Di-tert-butyl 1-benzoylhydrazine-1,2-

dicarboxylate (3t): white solid; m.p. = 118-120 ºC


3/2); 1H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 7.7

Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.4

Hz, 2H), 6.84 (s, br, 1H), 1.50 (s, 9H), 1.23 (s, 9H); 13

C NMR (75 MHz, CDCl3): δ 171.6, 154.5, 151.7, 135.8, 131.7, 128.1 (4C),

84.4, 82.2, 28.1 (3C), 27.4 (3C); IR (ATR): ν 3336, 1760, 1721, 1703, 1280,

1063 cm-1

; MS (EI) m/z (%): 180 (13), 163 (22), 136 (37), 105 (100), 77 (47), 59

(10), 57 (94), 51 (15); Elemental analysis calcd. for C17H24N2O5: C = 60.7, H =

7.19, N = 8.33; found: C = 60.65, H = 7.23, N = 8.32.


IMPREGNATED COPPER(II) OXIDE ON MAGNETITE

4.1. SYNTHESIS OF 1,3-DIYNES

General Procedure: t-BuOK (224 mg, 2 mmol) and CuO-Fe3O4 (10 mg,

0.26 mol%) or NiO/Cu-Fe3O4 were added to a stirred solution of the appropiate

alkyne 5 (2 mmol) under air, and the mixture was vigorously stirred at 60 ºC until

the reaction was complete. The catalyst was collected by using a magnet and

washed successively with EtOAc (2 x 5 mL) and H2O (2 x 5 mL). The collected

organic phases were dried over MgSO4 and concentrated under reduced pressure.

The crude product was purified by column chromatography on silica gel

(hexane/ethyl acetate) to give the corresponding products 6.

271 T. Osikawa, M. Yamashita, Rep. Fac. Eng. Shizuoka Univ. 1984, 35, 37-40.


1,1’-Buta-1,3-diyne-1,4-diyldibenzene

(6a):126b

white solid; m.p. = 83-85 °C (hexane);

tr = 15.8 min; Rf = 0.67 (hexane/ethyl acetate:

4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-7.50 (m, 4 H), 7.25-7.30 (m, 6 H);

13C

NMR (75 MHz, CDCl3): δ 132.5 (4C), 129.2 (2C), 128.4 (4C), 121.8 (2C), 81.5

(2C), 73.9 (2C); IR (ATR): ν 3050, 1593, 1485 cm-1

; MS (EI) m/z (%): (M+

+ 1,

17), 202 (M+, 100), 201 (11), 200 (22), 101 (8).

4,4’-(Buta-1,3-diyne-1,4-

diyl)bis(N,N-dimethylaniline)

(6b):122b

pale brown solid; m.p.

= 215-217 ºC (hexane); tr = 13.4

min; Rf = 0.43 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.35-

7.40 (d, J = 8.8 Hz, 4H), 6.65-6.70 (d, J = 8.8 Hz, 4H), 3.00 (s, 12H); 13

C NMR

(75 MHz, CDCl3): δ 150.4 (2C), 133.2 (4C), 111.7 (4C), 108.8 (2C), 84.8 (2C),

74.7 (2C), 40.2 (4C); IR (ATR): ν 1598, 1358, 1225 cm-1

; MS (EI) m/z (%): 298

(M+, 10), 269 (10), 229 (19), 208 (14), 207 (60), 203 (22), 202 (100), 201 (70),

183 (12), 155 (19), 78 (11), 77 (40), 51 (15).

1,4-Bis(4-methoxyphenyl)buta-

1,3-diyne (6c):272

pale yellow

solid; m.p. = 131-133 ºC

(hexane); tr = 20.7 min; Rf = 0.37

(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-7.50 (d, J = 8.8

Hz, 4H), 6.80-6.85 (d, J = 8.8 Hz, 4H), 3.82 (s, 6H); 13


δ 160.2 (2C), 134.0 (4C), 114.1 (4C), 113.9 (2C), 81.2 (2C), 72.9 (2C), 55.3

(2C); IR (ATR): ν 3004, 2939, 2837, 1598, 1502 cm-1

; MS (EI) m/z (%): 263 (M+

+ 1, 19), 262 (M+, 100), 248 (11), 247 (58), 219 (14), 176 (15), 131 (13).

1,4-Di-p-tolylbuta-1,3-diyne (6d):128

pale yellow solid; m.p. = 118-120 ºC

(hexane); tr = 17.5 min; Rf = 0.8

(hexane/ethyl acetate: 4/1); 1H NMR

(300 MHz, CDCl3): δ 7.35-7.40 (d, J = 8.0 Hz, 4H), 7.10-7.15 (d, J = 8.0 Hz,

4H), 2.34 (s, 6H); 13

C NMR (75 MHz, CDCl3): δ 139.5 (2C), 132.4 (4C), 129.2

(4C), 118.8 (2C), 81.5 (2C), 73.4 (2C), 21.6 (2C); IR (ATR): ν 3032, 1501 cm-1

;

272 X. Feng, Z. Zhao, F. Yang, T. Jin, Y. Ma, M. Bao, J. Org. Chem. 2011, 696, 1479-1482.


MS (EI) m/z (%): 231 (M+

+ 1, 19), 230 (M+, 100), 229 (22), 228 (12), 226 (13),

215 (17).

1,4-Bis(4-chlorophenyl)buta-1,3-

diyne (6e): 128

pale yellow solid; m.p.

= 165-167 ºC (hexane); tr = 18.0 min;

Rf = 0.77 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-7.50 (d, J = 8.7 Hz, 4H), 7.30-7.35 (d, J =

8.7 Hz, 4H); 13

C NMR (75 MHz, CDCl3): δ 134.0 (2C), 133.7 (4C), 128.9 (4C),

119.3 (2C), 80.8 (2C), 76.6 (2C); IR (ATR): ν 1483, 1395, 1092 cm-1

; MS (EI)

m/z (%): 274 (M++4, 11), 273 (M

++3, 11), 272 (M

++2, 65), 271 (M

++1, 18), 270

(M+, 100), 200 (28).

1,4-Bis(2-chlorophenyl)buta-1,3-diyne

(6f):122c


(hexane); tr = 18.4 min; Rf = 0.5 (hexane/ethyl


7.55-7.60 (dd, J = 7.6, 1.7 Hz, 2H), 7.40-7.45

(dd, J = 8.0, 1.2 Hz, 2H), 7.30-7.35 (td, J =

7.5, 1.7 Hz, 2H), 7.20-7.25 (td, J = 7.5, 1.2 Hz, 2H); 13


δ 136.9 (2C), 134.4 (2C), 130.3 (2C), 129.4 (2C), 126.5 (2C), 121.8 (2C), 79.4

(2C), 78.3 (2C); IR (ATR): ν 3068, 1463, 1433, 1053 cm-1

; MS (EI) m/z (%): 274

(M+

+ 4, 12), 273 (M+

+ 3, 12), 272 (M+

+ 2, 64), 271 (M+

+ 1, 18), 270 (M+, 100),

200 (34).

1,4-Bis((4-

trifluoromethyl)phenyl)buta-1,3-

diyne (6g):273

pale yellow solid;

m.p. = 165-168 ºC (hexane); tr =

15.0 min; Rf = 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ

7.60-7.65 (m, 8H); 13

C NMR (75 MHz, CDCl3): δ 132.8 (4C), 131.1 (q, 2JC-F = 33

Hz, 2C), 125.4 (q, 3JC-F = 3.8 Hz, 4C), 125.3 (2C), 123.7 (q,

1JC-F = 272.4 Hz,

2C), 80.9 (2C), 75.6 (2C); IR (ATR): ν 1610, 1407 cm-1

; MS (EI) m/z (%): 339

(M+

+ 1, 22), 338 (M+, 100), 319 (17).

273 K. Kude, S. Hayase, m. Kawatsura, T. Itoh, Heteroat. Chem. 2011, 22, 397-404.


1,4-Bis(4-bromophenyl)buta-1,3-

diyne (6h):274


= 140-141 ºC; tr = 20.7 min; Rf = 0.73


(300 MHz, CDCl3): δ 7.45-7.50 (d, J = 8.5 Hz, 4H), 7.35-7.40 (d, J = 8.5 Hz,

4H); 13

C NMR (75 MHz, CDCl3): δ 133.8 (4C), 131.8 (4C), 131.7 (2C), 120.6

(2C), 81.0 (2C), 77.2 (2C); IR (ATR): ν 1480, 1066 cm-1

; MS (EI) m/z (%): 361

(M+

+ 1, 18), 360 (M+, 100), 358 (52), 281 (12), 207 (19), 200 (34), 199 (11), 174

(10).

1,4-Di-m-tolylbuta-1,3-diyne (6i):128

pale

yellow solid; m.p. = 65-67 ºC (hexane); tr =

17.3 min; Rf = 0.67 (hexane/ethyl acetate:

4/1); 1H NMR (300 MHz, CDCl3): δ 7.30-

7.35 (m, 4H), 7.15-7.25 (m, 4H), 2.33 (s,

6H); 13

C NMR (75 MHz, CDCl3): δ 138.1

(2C), 132.9 (2C), 130.1 (2C), 129.6 (2C), 128.3 (2C), 121.6 (2C), 81.6 (2C), 73.6

(2C), 21.1 (2C); IR (ATR): ν 3035, 1479 cm-1

; MS (EI) m/z (%): 231 (M+

+ 1,

19), 230 (M+, 100), 229 (10), 228 (10).

1,4-Dicyclohexylbuta-1,3-diyne (6j):126b

pale

yellow solid; m.p. = 77-82 ºC (hexane); tr =


4/1); 1H NMR (300 MHz, CDCl3): δ 2.35-2.40

(m, 2H,), 1.60-1.75 (m, 8H), 1.35-1.45 (m, 6H), 1.15-1.25 (m, 6H); 13

C NMR (75

MHz, CDCl3): δ 81.9 (2C), 65.1 (2C), 32.3 (4C), 29.5 (2C), 25.7 (2C), 24.8 (4C);

IR (ATR): ν 2925, 2852, 1447 cm-1

; MS (EI) m/z (%): 215 (M+

+ 1, 15), 214 (M+,

84), 207 (18), 185 (16), 171 (35), 158 (11), 157 (21), 145 (27), 144 (14), 143

(39), 141 (14), 133 (11), 132 (15), 131 (62), 130 (20), 129 (63), 128 (47), 127

(14), 119 (17), 118 (28), 117 (82), 116 816), 115 (55), 105 (33), 104 (32), 103

(16), 102 (11), 95 (17), 93 (15), 92 (23), 91 (100), 89 (15), 80 (26), 79 (43), 78

(17), 77 (33), 76 (14), 75 (10), 67 (39).

Hexadeca-7,9-diyne (6k):272

colorless oil; tr =

14.1 min; Rf = 0 .87 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 2.20-2.25 (t, J =

274 N. Mizuno, K. Kamata, Y. Nakagawa, T. Oishi, K. Yamaguchi, Catal. Today 2010, 157, 359-

363.


6.8 Hz, 4H), 1.45-1.55 (m, 4H), 1.25-1.45 (m, 12H), 0.85-0.95 (m, 6H); 13

C

NMR (75 MHz, CDCl3): δ 77.5 (2C), 65.2 (2C), 31.3 (2C), 28.5 (2C), 28.3 (2C),

22.5 (2C), 19.2 (2C), 14.0 (2C); IR (ATR): ν 1465, 1459, 1378, 724 cm-1

; MS

(EI) m/z (%): 218 (M+, 0.3), 161 (10), 147 (16), 133 (25), 121 (12), 119 (43), 117

(15), 107 (26), 106 (12), 105 (63), 95 (26), 93 (43), 92 (20), 91 (100), 81 (41), 80

(12), 79 (56), 78 (31), 77 (37), 76 (10), 69 (14), 67 (46), 65 (17), 63 (11), 55 (37),

51 (13).

Icosa-9,11-diyne (6l):272

colorless oil; tr =


4/1); 1H NMR (300 MHz, CDCl3): δ 2.20-

2.25 (t, J = 6.9 Hz, 4H), 1.45-1.55 (m, 4H),

1.25-1.40 (m, 20H), 0.85-0.90 (t, J = 6.5 Hz, 6H); 13


77.5 (2C), 65.2 (2C), 31.8 (2C), 29.1 (2C), 29.0 (2C), 28.8 (2C), 28.4 (2C), 22.6

(2C), 19.2 (2C), 14.1 (2C); IR (ATR): ν 2924, 2854, 1464, 722 cm-1

; MS (EI) m/z

(%): 274 (M+, 0), 175 (14), 161 (25), 149 (12), 148 (10), 147 (32), 135 (20), 134

(12), 133 (45), 131 (10), 121 (41), 120 (15), 119 (55), 117 (21), 115 (13), 109

(15), 108 (10), 107 (41), 106 (14), 105 (60), 103 (12), 95 (38), 94 (17), 93 (52),

92 (22), 91 (100), 82 (12), 81 (57), 80 (15), 79 (61), 78 (25), 77 (32), 69 (19), 67

(50), 65 (13), 57 (14), 55 (38).

Tetracosa-11,13-diyne (6m):275

pale yellow

oil; tr = 19.5 min; Rf = 0.8 (hexane/ethyl


2.20-2.25 (t, J = 7.1 Hz, 4H), 1.45-1.55 (m,

4H), 1.25-1.30 (m, 28H), 0.85-0.90 (m, 6H); 13

C NMR (75 MHz, CDCl3): δ 77.5

(2C), 65.2 (2C), 31.9 (2C), 29.6 (2C), 29.5 (2C), 29.3 (2C), 29.1 (2C), 28.8 (2C),

28.3 (2C), 22.7 (2C), 19.2 (2C), 14.1 (2C); IR (ATR): ν 2953, 2923, 2853, 1464,

721 cm-1

; MS (EI) m/z (%): 330 (M+, 0), 189 (15), 175 (21), 163 (11), 162 (11),

161 (35), 149 (15), 148 (17), 147 (38), 135 (30), 134 (21), 133 (54), 131 (14),

123 (11), 122 (16), 121 (67), 120 (19), 119 (60), 117 (25), 115 (12), 109 (25),

108 (15), 107 (48), 106 (17), 105 (59), 103 (11), 96 (12), 95 (57), 94 (24), 93

(55), 92 (25), 91 (100), 83 (20), 82 (20), 81 (71), 80 (21), 79 (66), 78 (24), 77

(27), 69 (33), 67 (65), 65 (11), 57 (27), 55 (50).

275 T.-P. Cheng, B.-S. Liao, Y.-H. Liu, S.-M. Peng, S.-T. Liu, Dalton Trans. 2012, 41, 3468-3473.


1,10-Dichlorodeca-4,6-diyne (6n):272

pale

yellow oil; tr = 13.5 min; Rf = 0.67


MHz, CDCl3): δ 3.60-3.65 (t, J = 6.3 Hz, 4H), 2.45-2.50 (t, J = 6.8 Hz, 4H), 1.95-

2.00 (p, J = 6.5 Hz, 4H); 13

C NMR (75 MHz, CDCl3): δ 75.8 (2C), 66.0 (2C),

43.4 (2C), 31.0 (2C), 16.6 (2C); IR (ATR): ν 2960, 2927, 1288 cm-1

; MS (EI) m/z

(%): 206 (M+

+ 4, 10), 204 (M+

+ 2, 61), 202 (M+, 88), 176 (16), 174 (20), 167

(20), 141 (15), 139 (42), 131 (39), 130 (10), 129 (20), 128 (10), 127 (20), 125

(47), 117 (45), 116 (38), 114 (61), 112 (26), 111 (11), 105 (33), 104 (33), 103

(93), 102 (14), 91 (100), 89 (29), 79 (12), 78 (25), 77 (86), 76 (25), 74 (16), 65

(22), 64 (12), 63 (36), 62 (10), 53 (11), 51 (29).

4.2. HYDRATION OF 1,3-DIYNES TO AFFORD 2,5-DISUBSTITUTED

FURANS

General Procedure: CuO-Fe3O4 (5 mg, 0.26 mol%) and t-BuOK (112

mg, 1 mmol) were added to a stirred solution of the appropiate alkyne 5 (1 mmol)

and the resulting mixture was stirred at 60 ºC until the reaction was complete.

The catalyst was then removed by using a magnet and washed with DMSO (5

mL). The DMSO washings were combined with the original reaction solution,

and KOH (280 mg, 5 mmol, 500 mol%) and H2O (4 mmol, 400 mol%) were

added under air. The resulting solution was stirred at 80 ºC for 1 day, then the

reaction was quenched by addition of H2O (5 mL). The resulting mixture was

extracted with EtOAc (2 x 5 mL) and the combined organic phases were dried

with MgSO4 and concentrated under reduced pressure. The residue was purified

by column chromatography to give the corresponding products 7.

2,5-Diphenylfuran (7a):134


= 47-52 ºC (hexane); tr = 15.8 min; Rf = 0.73


CDCl3): δ 7.70-7.75 (m, 4H), 7.40-7.45 (m, 4H),

7.25-7.30 (m, 2H), 6.75 (s, 2H); 13

C NMR (75

MHz, CDCl3): δ 153.3 (2C), 130.7 (2C), 128.7 (4C), 127.3 (2C), 123.7 (4C),

107.2 (2C); IR (ATR): ν 3022, 1259, 1023, 927 cm-1

; MS (EI) m/z (%): 221 (M+

+ 1, 18), 220 (M+, 100), 191 (20), 115 (32), 105 (16), 77 (29), 51 (10).


2,5-Bis(4-methoxyphenyl)furan

(7b):276


(hexane); tr = 17.5; Rf = 0.20


(300 MHz, CDCl3): δ 7.65-7.70 (d, J =

9.0 Hz, 4H), 6.90-6.95 (d, J = 9.0 Hz, 4H), 6.58 (s, 2H), 3.85 (s, 6H); 13

C NMR

(75 MHz, CDCl3): δ 158.8 (2C), 152.8 (2C), 124.0 (2C), 125.0 (4C), 114.1 (4C),

105.5 (2C), 55.3 (2C); IR (ATR): ν 2839, 1600, 1509, 1018 cm-1

; MS (EI) m/z

(%): 281 (M+

+ 1, 20), 280 (M+, 100), 266 (16), 265 (87), 140 (14).

2,5-Di-p-tolylfuran (7c):276

white solid; m.p. =

114-117 ºC (hexane); tr = 17.9 min; Rf = 0.73


CDCl3): δ 7.60-7.65 (d, J = 8.1 Hz, 4H), 7.20-

7.25 (d, J = 8.1 Hz, 4H), 6.70 (s, 2H), 2.40 (s,

6H); 13

C NMR (75 MHz, CDCl3): δ 153.0 (2C), 136.9 (2C), 129.2 (4C), 128.0

(2C), 123.4 (4C), 106.3 (2C), 21.2 (2C); IR (ATR): ν 3020, 2914, 2856, 1605,

1503, 1021 cm-1

; MS (EI) m/z (%): 249 (M+

+ 1, 20), 248 (M+, 10), 129 (9).

2,5-Bis(4-(trifluoromethyl)phenyl)furan

(7d):134

pale yellow solid; m.p. = 139-141

ºC (hexane); tr = 15.5; Rf = 0.57


MHz, CDCl3): δ 7.85-7.90 (d, J = 8.1 Hz,

4H), 7.65-7.70 (d, J = 8.1 Hz, 4H), 6.9 (s, 2H); 13


152.8 (2C), 133.4 (2C), 129.4 (q, 2JC-F = 33.2 Hz, 2C), 125.8 (q,

3JC-F = 3.7 Hz,

4C), 124.1 (q, 1JC-F = 271.8 Hz, 2C), 123.9 (4C), 109.4 (2C); IR (ATR): ν 1617

cm-1

; MS (EI) m/z (%): 357 (M+

+ 1, 20), 356 (M+, 100), 337 (10), 183 (21), 173

(11), 145 (17).

4.3. DECARBOXYLATIVE COUPLING OF 3-PHENYLPROP-2-YONIC

ACID

General Procedure: Et3N (0.07 mL, 138 mol%), DMF (1.5 mL), and

CuO-Fe3O4 (50 mg, 2.1 mol%) or NiO/Cu-Fe3O4 (50 mg, 1.5/1.83 mol%) were

added to a stirred solution of alkynoic acid 8 (0.6 mmol) under air, and the

276 P. Nun, S. Dupuy, S. Gaillard, A. Poater, L. Cavallo, S. P. Nolan, Catal. Sci. Technol. 2011, 1,

58-61.


resulting mixture was stirred at 130 ºC for 2 days. The catalyst was removed by

using a magnet and washed with EtOAc (2 x 5 mL) and H2O (2 x 5 mL). The

collected organic phases were dried with MgSO4 and concentrated under reduced

pressure. The residue was purified by column chromatography giving the

corresponding product 6a.

4.4. SYNTHESIS OF ARYL IMINES DERIVATIVES FROM ALCOHOLS

AND AMINES

General Procedure: To a stirred solution of the corresponding alcohol (9,

1 mmol) in toluene (3 mL) under an Ar atmosphere was added CuO-Fe3O4 (50

mg, 1.3 mol%), NaOH (56 mg, 1.4 mmol) and the corresponding amine (10, 2

mmol). The resulting mixture was stirred at 100 ºC for 4 days. The catalyst was

removed by a magnet and washed with EtOAc (2 x 5 mL). The collected organic

phases were dried with MgSO4, and the solvents were removed under reduced

pressure. The product was purified either by bulb-to-bulb distillation or

crystallization to give the corresponding pure products 11.

(E)-N-Benzylideneaniline (11a):277

pale yellow oil; tr =

13.3; Rf = 0.37 (hexane/ethyl acetate: 4/1); 1H NMR

(300 MHz, CDCl3): δ 8.46 (s, 1H), 7.90-7.95 (m, 2H),

7.2-7.5 (m, 8H); 13

C NMR (75 MHz, CDCl3): 160.4,

152.0, 136.2, 131.4, 129.1 (2C), 128.8 (4C), 125.9,

120.9 (2C); IR (ATR): ν 1621, 1597 cm-1

; MS (EI) m/z (%): 182 (M+

+ 1, 11),

181 (M+, 100), 104 (8), 77 (35), 51 (12).

(E)-N-Benzylidene-3-chloroaniline (11b):278

pale

yellow oil; tr = 14.8; Rf = 0.87 (hexane/ethyl acetate:

4/1); 1

H NMR (300 MHz, CDCl3): δ 8.4 (s, 1H),

7.85-7.90, 7.40-7.50, 7.30-7.35, 7.15-7.20, 7.05-7.10

(5m, 1, 2, 1, 3 and 2H, respectively); 13

C NMR (75

MHz, CDCl3): δ 161.3, 153.3, 135.8, 134.7, 131.7, 130.0, 128.9 (2C), 128.8 (2C),

125.8, 120.9, 119.4; IR (ATR): ν 1622, 1582, 1067 cm-1

; MS (EI) m/z (%): 217

(M+

+ 1, 31), 216 (M+, 45), 215 (93), 214 (100), 111 (26), 89 (10), 75 (15).

277 L. C. da Silva-Filho, V. L. Júnior, M. G. Constantino, G. V. J. da Silva, Synthesis 2008, 16,

2527-2536. 278 H. Naeimi, H. Sharghi, F. Salimi, K. Rabiei, Heteroat. Chem. 2008, 19, 43-47.


(E)-N-Benzylidene-4-methoxyaniline (11c):139c

white solid; m.p. = 66-68 ºC (hexane); tr = 15.4; Rf

= 0.53 (hexane/ethyl acetate: 4/1); 1

H NMR (300

MHz, CDCl3): δ 8.51 (s, 1H), 7.90-7.95 (m, 2H),

7.45-7.50 (m, 3H), 7.25-7.30 (m, 2H), 6.95-7.00

(m, 2H), 3.85 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 158.3, 158.2, 144.8, 136.4,

131.0, 128.7 (2C), 128.5 (2C), 122.1 (2C), 114.3 (2C), 55.4; IR (ATR): ν 1609,

1581, 1247 cm-1

; MS (EI) m/z (%): 212 (M+

+ 1, 14), 211 (M+, 88), 210 (15), 197

(15), 196 (100), 167 (22).

(E)-N-Benzylidene-2,5-dimethylaniline (11d):279

orange solid; m.p. = 86-90 ºC (hexne); tr = 14.5; Rf =


CDCl3): δ 8.36 (s, 1H), 7.90-7.95 (m, 2H), 7.45-7.50

(m, 3H), 7.11 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6

Hz, 1H), 6.75 (s, 1H), 2.34 (s, 3H), 2.31 (s, 3H); 13


159.4, 151.1 (2C), 136.7, 136.4, 131.3, 130.2, 128.8 (4C), 126.4, 118.5, 21.2,

17.5; IR (ATR): ν 3019, 1629, 1573 cm-1

; MS (EI) m/z (%): 210 (M+

+ 1, 19),

209 (M+, 100), 208 (96), 194 (13), 193 (33), 132 (100), 131 (12), 130 (13), 117

(16), 105 (12), 103 (16), 79 (14), 77 (27).

(E)-N-Benzylidenebutan-1-amine (11e):142c

brown

oil; tr = 10.1; Rf = 0.56 (hexane/ethyl acetate: 4/1); 1H

NMR (300 MHz, CDCl3): δ 8.30 (s, 1H), 7.40-7.70

(m, 5H), 3.60 (t, J = 6.4 Hz, 2H), 1.35-1.70 (2m, 4H),

0.95 (t, J = 6.6 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 160.9, 136.4, 130.6,

128.7 (2C), 128.1 (2C), 61.6, 33.1, 20.6, 14.0; IR (ATR): ν 3026, 1645, 1451 cm-

1; MS (EI) m/z (%): 161.1 (M

+, 8) 160.1 (21), 132 (31), 119 (29), 118 (100), 117

(10), 105 (10), 104 (30), 91 (93), 90 (9), 89 (13), 84 (19), 83 (14), 77 (15).

(E)-N-Benzylidene-2,2-dimethylpropan-1-amine

(11f):280

yellow oil; tr = 9.9; Rf = 0.63 (hexane/ethyl

acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 8.23 (s,

1H), 7.75-7.80 (m, 2H), 7.35-7.45 (m, 3H), 3.37 (s,

2H), 0.98 (s, 9H); 13

C NMR (75 MHz, CDCl3): δ 160.9, 136.6, 130.5, 128.7 (2C),

128.2 (2C), 74.1, 32.8, 28.1 (3C); IR (ATR): ν 3027, 1742, 1645 cm-1

; MS (EI)

279 R. Nagarajan, P. T. Perumal, Synth. Commun. 2001, 31, 1733-1736. 280 W. D. Jones, E. T. Hessell, Organometallics 1990, 9, 718-727.


m/z (%): 175 (M+, 9) 174 (21), 160 (16), 119 (37), 118 (100), 117 (10), 91 (100),

90 (9), 89 (10).

(E)-N-Benzylidenedodecan-1-amine (11g):143

yellow

oil; tr = 16.4; Rf = 0.6 (hexane/ethyl acetate: 4/1); 1H

NMR (300 MHz, CDCl3): δ 8.26 (s, 1H), 7.70-7.75,

7.25-7.40 (2m, 3 and 2H, respectively), 3.60 (t, J = 6.7

Hz, 2H), 1.65-1.75 (m, 2H), 1.20-1.50 (m, 18H), 0.88 (t, J = 5.4 Hz, 3H); 13

C

NMR (75 MHz, CDCl3): δ 160.6, 136.3, 130.3, 128.5 (2C), 128.0 (2C), 61.8,

31.9, 30.9, 29.6 (3C), 29.5, 29.4, 29.3, 27.3, 22.6, 14.0; IR (ATR): ν 3021, 1647,

1466 cm-1

; MS (EI) m/z (%): 273 (M+, 2), 174 (16), 161 (12), 160 (100), 132

(25), 119 (16), 118 (35), 104 (11), 91 (29).

(E)-N-(4-Chlorobenzylidene)aniline (11h):146a

yellow solid; m.p. = 51-54 ºC (hexane); tr = 14.8; Rf

= 0.7 (hexane/ethyl acetate: 4/1); 1

H NMR (300

MHz, CDCl3): δ 8.37 (s, 1H), 7.75-7.85, 7.35-7.40,

7.15-7.20 (3m, 3, 4 and 2H, respectively); 13

C NMR

(75 MHz, CDCl3): δ 158.6, 151.5, 137.2, 134.6, 129.8 (2C), 129.3, 129.1 (2C),

128.9 (2C), 120.8 (2C); IR (ATR): ν 1621, 1578, 1092 cm-1

; MS (EI) m/z (%):

217 (M+

+ 1, 32), 216 (M+, 46), 215 (95), 214 (100), 104 (10), 77 (43), 51 (13).

(E)-3-Chloro-N-(4-

chlorobenzylidene)aniline (11i):281

brown

oil; tr = 16.1; Rf = 0.67 (hexane/ethyl acetate:

4/1); 1H NMR (300 MHz, CDCl3): δ 8.39 (s,

1H), 7.82 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5

Hz, 2H), 7.20-7.35 (m, 4H); 13

C NMR (75

MHz, CDCl3): δ 159.9, 152.9, 137.8, 134.8, 134.3, 130.2, 130.1 (2C), 129.2 (2C),

126.1, 120.9, 119.4; IR (ATR): ν 3060, 1596, 1485 cm-1

; MS (EI) m/z (%): 253

(M+

+ 4, 10), 252 (M+

+ 3, 18), 251 (M+

+ 2, 64), 250 (M+

+ 1, 74), 249 (M+, 100),

248 (99), 138 (19), 113 (20), 112 (13), 111 (63), 89 (26), 77 (10), 76 (12), 75

(45), 51 (10).

281 S. S. Karki, S. R. Butle, R. M. Shaikh, P. K. Zubaidha, G. S. Pedgaonkar, G. S. Shendarkar, C.

G. Raiput, Res. J. Pharm. Biol. Chem. Sci. 2010, 1, 707-717.


(E)-N-(4-Methylbenzylidene)aniline (11j):277


4/1); 1

H NMR (300 MHz, CDCl3): δ 8.40 (s, 1H),

7.78 (d, J = 8.0 Hz, 2H), 7.10-7.25 (m, 7H), 2.40 (s,

3H); 13

C NMR (75 MHz, CDCl3): δ 160.4, 145.3,

141.8, 133.5, 129.5 (2C), 128.7 (2C), 120.8, 118.4 (2C), 115.0 (2C), 21.6; IR

(ATR): ν 3027, 1602, 1498 cm-1

; MS (EI) m/z (%): 196 (M+

+ 1, 20), 195 (M+,

100), 194 (100), 91 (19), 77 (58), 51 (16).

(E)-N-(4-Methoxybenzylidene)aniline (11k):139c

yellow solid; m.p. = 45-48 ºC (hexane); tr = 15.4;

Rf = 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300

MHz, CDCl3): δ 8.32 (s, 1H), 7.75-7.85, 7.30-

7.35, 7.15-7.20, 6.90-6.95 (4m, 2, 3, 2 and 2H,

respectively), 3.78 (s, 3H); 13

C NMR (75 MHz,

CDCl3): δ 161.7, 159.1, 151.8, 130.0, 128.7 (2C), 128.6 (2C), 125.0, 120.4 (2C),

113.6 (2C), 54.8; IR (ATR): ν 1679, 1600, 1245 cm-1

; MS (EI) m/z (%): 213 (M+,

1), 212 (13), 211 (88), 210 (100), 167 (12), 77 (20).

(E)-3-Chloro-N-(4-

methoxybenzylidene)aniline (11l):282

brown oil; tr = 16.7; Rf = 0.57 (hexane/ethyl

acetate: 4/1); 1

H NMR (300 MHz, CDCl3): δ

8.33 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.15-

7.30 (m, 6H), 3.86 (s, 3H); 13

C NMR (75

MHz, CDCl3): δ 162.4, 160.6, 159.5, 153.5, 134.7, 130.2, 130.1 (2C), 118.3,

114.2, 113.8 (2C), 113.1, 55.2; IR (ATR): ν 1621, 1597, 1243, 1027 cm-1

; MS

(EI) m/z (%): 247 (M+

+ 2, 32), 246 (M+

+ 1, 45), 245 (M+, 96), 244 (100), 111

(23), 77 (10), 75 (17).

(E)-N-(3-Methylbenzylidene)aniline (11m):277

brown oil; tr = 14.3; Rf = 0.7 (hexane/ethyl acetate:

4/1); 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 7.75

(s, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.20-7.40 (m, 7H),

2.41 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 160.6,

152.1, 138.5, 136.1, 132.2, 129.1 (2C), 128.9, 128.6,

126.4, 125.8, 120.8 (2C), 21.3; IR (ATR): ν 3030,

282 S. Oumar, M. Righezza, Anal. Chim. Acta 1997, 356, 187-193.


1627, 1584 cm-1

; MS (EI) m/z (%): 196 (M+

+ 1, 15), 195 (M+, 100), 194 (100),

104 (11), 91 (14), 77 (52), 51 (15).

(E)-N-(3-Methoxybenzylidene)aniline (11n):277


4/1); 1H NMR (300 MHz, CDCl3): δ 8.40 (s, 1H), 7.40

(s, 1H), 7.20-7.35 (m, 8H), 3.83 (s, 3H); 13

C NMR (75

MHz, CDCl3): δ 160.3, 159.8, 151.8, 137.4, 129.5,

129.1 (2C), 125.9, 122.3, 120.8 (2C), 118.3, 111.6,

55.1; IR (ATR): ν 3005, 1601, 1584, 1265, 1037 cm-1

;

MS (EI) m/z (%): 212 (M+

+ 1, 24), 211 (M+, 100), 210 (100), 182 (11), 181 (26),

180 (13), 168 (10), 167 (24), 104 (18), 77 (63), 51 (16).

(E)-N-(3,5-Dimethylbenzylidene)aniline (11o):283


4/1); 1H NMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.5

(s, 2H), 7.35-7.40 (m, 2H), 7.15-7.25 (m, 4H), 2.40

(s, 6H); 13

C NMR (75 MHz, CDCl3): 161.0, 152.3,

138.1 (2C), 136.2, 133.3, 129.2 (2C), 126.7 (2C),

125.9, 124.9 (2C), 21.3 (2C); IR (ATR): ν 3014, 1625, 1588 cm-1

; MS (EI) m/z

(%): 210 (M+

+ 1, 44), 209 (M+, 100), 208 (100), 194 (14), 193 (13), 165 (12),

105 (11), 104 (25), 103 (13), 91 (26), 78 (13), 77 (100), 51 (25).

(E)-3-Chloro-N-(3,5-

dimethylbenzylidene)aniline (11p): brown oil; tr

= 16.1. Rf = 0.7 (hexane/ethyl acetate: 4/1); 1H

NMR (300 MHz, CDCl3): δ 8.33 (s, 1H), 7.84 (d, J

= 8.6 Hz, 2H), 6.95-7.10 (m, 5H), 3.80 (s, 6H); 13

C

NMR (75 MHz, CDCl3): δ 161.9, 147.6, 138.1

(2C), 135.6, 134.7, 130.2, 129.8, 126.0 (2C), 118.2, 114.8, 113.0, 21.1 (2C); IR

(ATR): ν 3019, 1597, 1485 cm-1

; MS (EI) m/z (%): 245 (M+

+ 2, 31), 244 (M+

+

1, 48), 243 (M+, 96), 242 (100), 109 (23), 91 (12), 76 (11), 75 (13); HRMS calcd.

(%) for C15H14ClN: 243.0815; found: 243.0800.

283 A. M. Voutchkova, R. H. Crabtree, J. Mol. Catal. A 2009, 312, 1-6.


(E)-N-(3,5-Dimethoxybenzylidene)aniline

(11q):284

brown oil; tr = 16.7; Rf = 0.5


CDCl3): 8.40 (s, 1H), 7.35-7.40 (m, 2H), 7.20-

7.25 (m, 3H), 7.05 (d, J = 2.3 Hz, 2H), 6.58 (t, J

= 2.3 Hz, 1H), 3.84 (s, 6H); 13

C NMR (75 MHz,

CDCl3): 161.1 (2C), 160.4, 152.0, 138.3, 129.2 (2C), 126.1, 121.0 (2C), 106.5

(2C), 104.3, 55.6 (2C); IR (ATR): ν 3004, 1627, 1587, 1151 cm-1

; MS (EI) m/z

(%): 242 (M+

+ 1, 37), 241 (M+, 100), 240 (100), 226 (10), 212 (23), 211 (56),

210 (19), 196 (12), 183 (10), 182 (18), 167 (12), 154 (12), 104 (24), 78 (10), 77

(78), 51 (18).

(E)-3-Chloro-N-(3,5-

dimethoxybenzylidene)aniline (11r): red oil;

tr = 17.9; Rf = 0.5 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 8.31 (s, 1H),

7.20-7.30 (m, 3H), 7.05-7.10 (m, 4H), 3.84 (s,

6H); 13

C NMR (75 MHz, CDCl3): δ 161.2,

160.9 (2C), 153.0, 147.6, 137.7, 130.2 (2C),

130.1, 125.8, 120.8, 119.3, 104.4, 55.6 (2C); IR (ATR): ν 3004, 1593, 1484,

1204, 1064 cm-1

; MS (EI) m/z (%): 277 (M+

+ 2, 32), 276 (M+

+ 1, 47), 275 (M+,

100), 274 (99), 246 (12), 245 (21), 138 (11), 111 (20); HRMS calcd. (%) for

C15H14ClNO2: 275.0713; found: 275.0730.

4.5. SYNTHESIS OF ARENECARBALDEHYDES

General Procedure: To a stirred solution of the corresponding alcohol (9,

1 mmol) in toluene (3 mL) under an Ar atmosphere was added CuO-Fe3O4 (50

mg, 1.3 mol%), NaOH (56 mg, 1.4 mmol) and the corresponding aniline (10a,

0.18 mL, 2 mmol). The resulting mixture was stirred at 100 ºC for 4 days. The

catalyst was removed by a magnet and then HCl (2 mL) and ether (2 mL) were

added. The resulting mixture was stirred for 2 h at room temperature, and then it

was quenched with water (2 mL) and extracted with EtOAc (3 x 5 mL). The

organic phases were dried with MgSO4, followed by evaporation under reduced

pressure to remove the solvent. The product was purified by vacuum distillation

at 120 ºC to give the corresponding products 2.

284 D. Blanco-Ania, P. H. H. Hermkers, L. A. J. M. Sliedregt, H. W. Scheeren, F. P. J. T. Rutjes,

Tetrahedron 2009, 65, 5393-5401.


Benzaldehyde (2a):285

colorless oil; tr = 6.1; Rf = 0.6

(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ

10.01 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.50-7.65 (m, 3H); 13

C

NMR (75 MHz, CDCl3): δ 192.2, 136.5, 134.3, 129.6 (2C),

128.8 (2C); IR (ATR): ν 3060, 1697 cm-1

; MS (EI) m/z (%): 106

(M+, 100), 105 (96), 78 (17), 77 (98), 51 (37).

4-Chlorobenzaldehyde (2j):286


ºC (hexane); tr = 8.3; Rf = 0.53 (hexane/ethyl acetate:

4/1); 1H NMR (300 MHz, CDCl3): δ 9.99 (s, 1H), 7.83

(d, J = 7.9 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H); 13

C NMR

(75 MHz, CDCl3): δ 190.9, 141.0, 134.7, 130.9 (2C),

129.5 (2C); IR (ATR): ν 1687, 1574 cm-1

; MS (EI) m/z (%): 142 (M+

+ 2, 35),

141 (M+

+ 1, 56), 140 (M+, 100), 139 (100), 113 (27), 112 (13), 111 (87), 77 (22),

76 (11), 75 (39), 74 (21), 51 (16).

4-Methylbenzaldehyde (2d):285


0.53 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3):

δ 9.94 (s, 1H), 7.75-7.80 (m, 2H), 7.30-7.35 (m, 2H), 2.40 (s,

3H); 13

C NMR (75 MHz, CDCl3): δ 191.8, 145.3, 133.9,

129.6 (2C), 129.5 (2C), 21.6; IR (ATR): ν 1700, 1603 cm-1

;

MS (EI) m/z (%): 121 (M+

+ 1, 12), 120 (M+, 100), 119 (100),

92 (16), 91 (100), 89 (16), 65 (38), 63 (20), 51 (11).

4-Methoxybenzaldehyde (2e):285

yellow oil; tr = 9.7; Rf

= 0.37 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,

CDCl3): δ 9.87 (s, 1H), 7.80-7.85 (m, 2H), 7.00-7.05 (m,

2H), 3.87 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 190.5,

164.3, 131.7 (2C), 129.6, 114.0 (2C), 55.3; IR (ATR): ν

1681, 1509, 1255, 1022 cm-1

; MS (EI) m/z (%): 137 (M+

+ 1, 14), 136 (M+, 100), 135 (100), 107 (34), 92 (35), 77 (59), 65 (17), 64 (16),

63 (19), 51 (11).

285 P. Paraskevopoulu, N. Psaroudakis, S. Koinis, P. Stavropoulos, K. Mertis, J. Mol. Catal. A

2005, 240, 27-32. 286 K. Fujita, T. Yoshiba, Y. Imori, R. Yamaguchi, Org. Lett. 2011, 13, 2278-2281.


3-Methylbenzaldehyde (2c):285

brown oil; tr = 7.6; Rf = 0.57

(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 9.95

(s, 1H), 7.65 (s, 2H), 7.40 (s, 2H), 2.40 (s, 3H); 13

C NMR (75

MHz, CDCl3): δ 192.3, 138.7, 136.3, 135.0, 129.7, 128.6,

127.0, 20.9; IR (ATR): ν 1699, 1587 cm-1

; MS (EI) m/z (%):

121 (M+

+ 1, 14), 120 (M+, 100), 119 (100), 92 (19), 91 (100),

89 (17), 65 (42), 63 (22), 51 (11).

3-Methoxybenzaldehyde (2s):285

yellow oil; tr = 9.1; Rf = 0.57

(hexane/ethyl acetate: 4/1); 1

H NMR (300 MHz, CDCl3): δ 9.98

(s, 1H), 7.40-7.45 (m, 3H), 7.15-7.20 (m, 1H), 3.87 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 192.0, 160.1, 137.8, 130.0, 123.5,

121.4, 112.0, 55.4; IR (ATR): ν 1699, 1585, 1260, 1037 cm-1

;

MS (EI) m/z (%): 136 (M+, 100), 135 (96), 107 (35), 92 (16), 77

(35), 65 (18), 64 (11), 63 (14).

2,6-Dichlorobenzaldehyde (2t):287


ºC (hexane); tr = 10.5; Rf = 0.6 (hexane/ethyl acetate: 4/1); 1H

NMR (300 MHz, CDCl3): δ 10.50 (s, 1H), 7.40 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 188.8, 136.8 (3C), 133.6, 129.7

(2C); IR (ATR): ν 3092, 1697, 1576 cm-1

; MS (EI) m/z (%): 178 (M

+ + 4, 8), 177 (M

+ + 3, 16), 176 (M

+ + 2, 49), 175 (M

+ + 1, 85), 174 (M

+,

76), 173 (100), 147 (20), 146 (12), 145 (29), 111 (21), 110 (20), 109 (15), 75

(38), 74 (26).

3,4-Dichlorobenzaldehyde (2u):288

white solid; m.p. = 39-

41 ºC (hexane); tr = 10.1; Rf = 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 9.95 (s, 1H), 7.96 (d, J = 1.8

Hz, 1H), 7.73 (dd, J = 8.2, 1.8 Hz, 1H), 7.64 (d, J = 8.2 Hz,

1H); 13

C NMR (75 MHz, CDCl3): δ 189.6, 139.1, 135.8,

133.9, 131.2, 131.1, 128.3; IR (ATR): ν 3063, 1698, 1561

cm-1

; MS (EI) m/z (%): 178 (M+

+ 4, 6), 177 (M+

+ 3, 13),

176 (M+

+ 2, 41), 175 (M+

+ 1, 69), 174 (M+, 64), 173 (100), 147 (27), 145 (41),

111 (19), 109 (18), 75 (34), 74 (30), 73 (11).

287 P. Zheng, L. Yan, X. Ji, X. Duan, Synth. Commun. 2011, 41, 16-19. 288 S. Rani, B. R. Bhat, Tetrahedron Lett. 2010, 51, 6403-6405.


3,5-Dimethylbenzaldehyde (2v):289

yellow oil; tr = 8.78; Rf =

0.63 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3):

δ 9.94 (s, 1H), 7.48 (s, 2H), 7.25 (s, 1H), 2.38 (s, 6H); 13

C

NMR (75 MHz, CDCl3): δ 192.7, 138.7 (2C), 136.5, 136.1,

127.5 (2C), 21.0 (2C); IR (ATR): ν 1696, 1608 cm-1

; MS (EI)

m/z (%): 135 (M+

+ 1, 12), 134 (M+, 100), 133 (100), 106 (11),

105 (100), 103 (20), 91 (28), 79 (23), 78 (10), 77 (34), 63 (11), 51 (12).

3,5-Dimethoxybenzaldehyde (2w):

286 white solid; m.p.

= 46-48 ºC (hexane); tr = 11.3; Rf = 0.43 (hexane/ethyl

acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 9.91 (s,

1H), 7.01 (d, J = 2.5 Hz, 2H), 6.71 (t, J = 2.5 Hz, 1H),

3.85 (s, 6H); 13

C NMR (75 MHz, CDCl3): δ 192.0, 161.2

(2C), 138.3, 107.2, 107.1 (2C), 55.6 (2C); IR (ATR): ν

3060, 1697, 1590, 1206, 1064 cm-1

; MS (EI) m/z (%): 167 (M+

+ 1, 17), 166 (M+,

100), 165 (68), 137 (30), 135 (46), 122(28), 109 (21), 107 (22), 95 (14), 79 (13),

77 (17), 63 (19), 51 (10).

3,4,5-Trimethoxybenzaldehyde (2f):290

white solid; m.p.

= 71-73 ºC (hexane); tr = 12.7; Rf = 0.20 (hexane/ethyl

acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 9.88 (s, 1H),

7.14 (s, 2H), 3.95 (s, 3H), 3.94 (s, 6H); 13

C NMR (75

MHz, CDCl3): δ 191.1, 153.6 (2C), 131.6 (2C), 106.6

(2C), 61.0, 56.2 (2C); IR (ATR): ν 1682, 1585, 1123, 990 cm

-1; MS (EI) m/z (%): 197 (M

+ + 1, 11), 196 (M

+, 100), 181 (41), 125 (22), 110

(17), 95 (11), 93 (10).

4.6. SYNTHESIS OF ARYL IMINES DERIVATIVES FROM PRIMARY

AMINES

General Procedure: To a stirred solution of the corresponding amine (13,

2 mmol) in toluene (3 mL) under air was added CuO-Fe3O4 (50 mg, 2.6 mol%)

and NaOH (120 mg, 2 mmol). The resulting mixture was stirred at 100 ºC for 3

days. The catalyst was removed by a magnet and washed with EtOAc (2 x 5 mL).

The collected organics phases were dried with MgSO4, and the solvents were

289 M. Zahmakiran, S. Akbayrak, T. Kodaira, S. Özkar, Dalton Trans. 2010, 39, 7521-7527. 290 L. J. Gooβen, B. A. Khan, T. Fett, M. Tren, Adv. Synth Catal. 2010, 352, 2166-2170.


removed under reduced pressure. The product was purified either by bulb-to-bulb

distillation or crystallization to give the corresponding pure products 14.

(E)-N-Benzylidene-1-phenylmethanamine (14a):137g


4/1); 1H NMR (300 MHz, CDCl3): 8.39 (s, 1H),

7.78 (d, J = 3.3 Hz, 2H), 7.20-7.50 (m, 8H), 4.82 (s,

2H); 13

C NMR (75 MHz, CDCl3): 162.0, 139.2, 136.1, 130.7, 128.6 (2C), 128.5

(2C), 128.2 (2C), 127.9 (2C), 126.9, 65.0; IR (ATR): ν 3061, 3027, 1643, 1579

cm-1

; MS (EI) m/z (%): 196 (M+

+ 1, 7), 195 (M+, 45), 194 (44), 117 (12), 92

(33), 91 (100), 89 (15), 65 (14).

(E)-N-(4-Methylbenzylidene)-1-(p-

tolyl)methanamine (14b):137g

white solid; m.p.

= 51-53ºC (hexane); tr = 15.4; Rf = 0.6


CDCl3); 8.34 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H),

7.10-7.25 (m, 6H), 4.77 (s, 2H), 2.34 (s, 6H); 13

C NMR (75 MHz, CDCl3);

161.7, 140.9, 136.5, 136.3, 133.6, 129.3 (2C), 129.1 (2C), 128.2 (2C), 127.9

(2C), 64.8, 21.5, 21.1; IR (ATR): ν 3015, 1646, 1558 cm-1

; MS (EI) m/z (%): 223

(M+, 27), 222 (12), 106 (20), 105 (100), 77 (12).

(E)-N-(3-Methylbenzylidene)-1-(m-

tolyl)methanamine (14c):291

yellow oil; tr = 15.2;

Rf = 0.5 (hexane/ethyl acetate: 4/1); 1H NMR (300

MHz, CDCl3); 8.35 (s, 1H), 7.64 (s, 2H), 7.25-

7.60 (m, 6H), 4.77 (s, 2H), 2.37 (s, 3H), 2.33 (s,

3H); 13

C NMR (75 MHz, CDCl3): 162.1, 139.1, 138.4, 138.3, 138.0, 132.6,

131.5, 128.7, 128.1, 127.7, 125.8, 125.0, 124.2, 65.1, 21.3, 21.2; IR (ATR): ν

1652, 1568 cm-1

; MS (EI) m/z (%): 223 (M+, 35), 222 (22), 208 (15), 106 (54),

105 (100), 103 (15), 91 (14), 79 (13), 77 (19).

291 S. M. Landge, V. Atanassova, M. Thimmaiah, B. Torök, Tetrahedron Lett. 2007, 48, 5161-

5164.


4.7. SYNTHESIS OF N-ARYLATED 1,2,3,4-

TETRAHYDROISOQUINOLINES.

General Procedure: Copper(I) iodide (200 mg, 1.0 mmol) and potassium

phosphate (4.25 g, 20.0 mmol) were placed into a 50 mL two-neck flask. The

flask was evacuated and back filled with Ar. 2-Propanol (10.0 mL), ethylene

glycol (1.11 mL), 1,2,3,4-tetrahydroisoquinoline (2.0 mL, 15 mmol) and the

corresponding iodoaryl (10.0 mmol) were added successively by syringe at room

temperature. The reaction mixture was heated at 90 °C for 24 h and then allowed

to cool to room temperature. Et2O (20 mL) and water (20 mL) were then added to

the reaction mixture. The organic layer was extracted with diethyl ether (2 × 20

mL). The combined organic phases were washed with brine and dried over

sodium sulphate. The solvent was removed and the residue was purified by

column chromatography on silica gel using hexane/ethyl acetate (20:1) as an

eluent giving the corresponding products 15.

2-(4-Fluorophenyl)-1,2,3,4-

tetrahydroisoquinoline (15a):292

white solid;

m.p. = 69-71 ºC (ethanol); tr= 15.3; Rf= 0.6


CDCl3): δ 7.10-7.20 (m, 4H), 6.90-7.00 (m, 4H),

4.33 (s, 2H), 3.48 (t, J = 5.9 Hz, 2H), 2.98 (t, J =

5.9 Hz, 2H); 13

C NMR (75 MHz, CDCl3): δ 156.7 (d, 1JC-F = 238.0 Hz), 147.4

(d, 4JC-F = 1.5 Hz), 134.5, 134.3, 128.6, 126.5, 126.4, 126.0, 117.1 (d,

3JC-F

= 7.5 Hz, 2C), 115.5 (d, 2JC-F = 22.0 Hz, 2C), 51.9, 47.8, 29.0; IR (ATR): ν

1505, 1205 cm-1

; MS (EI) m/z (%): 228 (M+

+ 1, 14), 227 (M+, 95), 226 (100),

104 (72), 103 (15), 95 (12), 78 (12).

2-Phenyl-1,2,3,4-tetrahydroisoquinoline (15b):165a

pale yellow solid; m.p. = 45-47 ºC (ethanol); tr = 15.4;

Rf = 0.8 (hexane/ethyl acetate : 4/1); 1H NMR (300

MHz, CDCl3): δ 7.25-7.30 (m, 2H), 7.10-7.20 (m,

4H), 6.96 (d, J = 8.0 Hz, 2H), 6.82 (t, J = 7.3 Hz,

1H), 4.39 (s, 2H), 3.53 (t, J = 5.8 Hz, 2H), 2.96 (t,

J = 5.8 Hz, 2H); 13

C NMR (75 MHz, CDCl3): δ 150.5, 134.8, 134.4, 130.2 (2C),

129.2, 126.5, 126.3, 126.0, 118.6, 115.1 (2C), 50.7, 46.5, 29.1; IR (ATR): ν

292 J.-J. Zhang, Q.-Y. Meng, G.-X. Wang, Q. Liu, B. Chen, K. Feng, C.-H. Tung, L.-Z. Wu, Chem.

Eur. J. 2013, 19, 6443-6450.


3058, 3023, 1598, 1500, 1386 cm-1

; MS (EI) m/z (%): 210 (M+

+ 1, 10), 209 (M+,

82), 208 (M+-1, 100), 104 (56), 78 (10), 77 (17).

2-(4-Methoxyphenyl)-1,2,3,4-

tetrahydroisoquinoline (15c):293

pale orange

solid; m.p. 92-94 ºC (ethanol); tr = 18.6; Rf = 0.5

(hexane/ethyl acetate : 4/1); 1H NMR (300

MHz, CDCl3): δ 7.10-7.20 (m, 4H), 6.95-7.00

(m, 2H), 6.80-6.90 (m, 2H), 4.29 (s, 2H), 3.77

(s, 3H), 3.44 (t, J = 5.8 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H); 13

C NMR (75

MHz, CDCl3): δ 153.6, 145.5, 134.7 (2C), 128.8, 126.6, 126.4, 126.0, 118.1 (2C),

114.7 (2C), 55.8, 52.8, 48.6, 29.2; IR (ATR): ν 2808, 1509, 1239, 1036 cm-1

; MS

(EI) m/z (%): 240 (M+

+ 1, 16), 239 (M+, 100), 238 (M

+ - 1, 93), 224 (22), 135

(27), 120 (20), 104 (24).

General Procedure for the preparation of 2-Tosyl-1,2,3,4-

tetrahydroisoquinoline (15d):294

To a mixture of 1,2,3,4-tetrahydroisoquinoline

(0.2663 g, 2 mmol) and pyridine (0.5 mL), p-toluenesulfonyl chloride (0.46 g,

2.4 mmol) in dry dichloromethane (5 mL) was added slowly and stirred at room

temperature for 1 h. The reaction mixture was then washed with aqueous 1N HCl

(10 mL) and extracted with diethyl ether (2 x 10 mL). The combined organic

phases were washed with water (10 mL), brine solution (10 mL) and dried over

anhydrous sodium sulphate. The filtered solution was concentrated and purified

by column chromatography. Pale yellow solid;

m.p. 132-134 ºC (ethanol); tr = 15.6; Rf = 0.4

(hexane/ethyl acetate : 4/1); 1

H NMR (300

MHz, CDCl3): δ 7.70-7.75 (m, 2H), 7.30-7.40

(m, 2H), 7.14 (dd, J = 5.6, 3.5 Hz, 2H), 7.00-

7.10 (m, 2H), 4.24 (s, 2H), 3.35 (t, J = 5.9 Hz,

2H), 2.93 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 143.8,

133.3, 133.1, 131.7, 129.8 (2C), 129.0, 128.9, 127.8 (2C), 126.8, 126.4, 47.6,

43.8, 28.9, 21.6; IR (ATR): ν 3064, 1489, 1338, 1163 cm-1

; MS (EI) m/z (%): 287

(M+, 5), 286 (M

+ - 1, 14), 132 (100), 131 (29), 130 (32), 105 (26), 104 (53), 103

(15), 91 (29), 77 (16).

293 M. Brzozowski, J. A. Forni, P. G. Savage, A. Polyzos, Chem. Commun. 2015, 51, 334-337. 294 S. O’Sullivan, E. Doni, T. Tuttle, J. A. Murphy, Angew. Chem. Int. Ed. 2014, 53, 474-478.


4.8. SYNTHESIS OF 1-SUBSTITUTED-N-ARYLATED 1,2,3,4-

TETRAHYDROISOQUINOLINES.

General Procedure: To a stirred solution of the corresponding

tetrahydroisoquinoline 15 (0.5 mmol) and catalyst (100 mg, 3.64 mol%) in 1 mL

of DES were added and the corresponding nucleophiles 5 or 18 (1 mmol). The

resulting mixture was stirred at 50 ºC during 3 days until the end of the reaction.

The mixture was quenched with water and extracted with AcOEt (3 x 5 mL). The

organic phases were dried over MgSO4, followed by evaporation under reduced

pressure to remove the solvent. The product was usually purified by

chromatography on silica gel (hexane/ethyl acetate) and/or distillation to give the

corresponding product 16.

2-(4-Fluorophenyl)-1-(phenylethynyl)-1,2,3,4-

tetrahydroisoquinoline (16a): brown oil; tr = 21.0;

Rf = 0.6 (hexane/ethyl acetate : 4/1); 1

H NMR (300

MHz, CDCl3): δ 7.35-7.40 (m, 1H), 7.20-7.30

(m, 8H), 7.05-7.10 (m, 2H), 7.00-7.05 (m, 2H),

5.54 (s, 1H), 3.60-3.65 (m, 2H), 3.10-3.20 (m,

1H), 2.96 (dt, J = 16.3, 3.6 Hz, 1H); 13

C NMR

(75 MHz, CDCl3): δ 157.4 (d, 1JC-F = 239.3 Hz),

146.4, 135.1, 134.0, 131.7 (2C), 129.0, 128.1 (3C), 127.4, 127.2, 126.2, 122.8,

119.4 (d, 3JC-F = 7.7 Hz, 2C), 115.5 (d,

2JC-F = 22.2 Hz, 2C), 88.1, 85.3, 53.7,

44.0, 29.0; IR (ATR): ν 3056, 3026, 1506, 1489 cm-1

; MS (EI) m/z (%): 328 (M+

+ 1, 9), 327 (M+, 50), 326 (M

+-1, 100), 222 (10), 207 (14), 204 (27), 203 (33),

202 (36), 102 (22); HRMS calcd. (%) for C23H18FN: 327.1423; found: 327.1412.

2-Phenyl-1-(phenylethynyl)-1,2,3,4-

tetrahydroisoquinoline (16b):158i



H NMR (300

MHz, CDCl3): δ 7.35-7.40 (m, 1H), 7.25-7.35 (m,

4H), 7.20-7.25 (m, 6H), 7.12 (dd, J = 8.7, 0.9 Hz,

2H), 6.88 (dd, J = 7.7, 6.8 Hz, 1H), 5.64 (s, 1H),

3.8-3.9 (m, 1H), 3.67 (ddd, J = 12.4, 10.2, 4.0 Hz,

1H), 3.14 (ddd, J = 16.1, 10.2, 6.1 Hz, 1H), 2.97

(dt, J = 16.1, 4.0 Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 149.5, 135.4, 134.4,

131.7 (2C), 129.1 (2C), 128.9, 128.0 (2C), 128.0, 127.4, 127.2, 126.2, 123.0,

119.6, 116.7 (2C), 88.6, 84.7, 52.3, 43.4, 28.9; IR (ATR): ν 3059, 3024, 1596,

1501, 1490 cm-1

; MS (EI) m/z (%): 310 (M+

+ 1, 13), 309 (M+, 63), 308 (100),

204 (27), 203 (21), 202 (27), 77 (8).


2-(4-Methoxyphenyl)-1-(phenylethynyl)-

1,2,3,4-tetrahydroisoquinoline (16c):158i

brown

oil; tr = 25.1; Rf = 0.5 (hexane/ethyl acetate : 4/1);

1H NMR (300 MHz, CDCl3): δ 7.35 (dd, J =

5.0, 3.9 Hz, 1H), 7.15-7.35 (m, 8H), 7.05-7.15

(m, 2H), 6.85-6.95 (m, 2H), 5.51 (s, 1H), 3.78

(s, 3H), 3.45-3.70 (m, 2H), 3.15 (ddd, J =

16.4, 6.2, 3.4 Hz, 1H), 2.93 (dt, J = 16.4, 3.4

Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 154.3, 144.1, 135.4, 134.0, 131.7 (2C),

129.0, 128.0 (2C), 127.9, 127.5, 127.1, 126.1, 123.1, 120.2 (2C), 114.4 (2C),

88.4, 85.5, 54.6, 54.4, 44.2, 29.0; IR (ATR): ν 1509, 1242, 1035 cm-1

; MS (EI)

m/z (%): 339 (M+, 82), 338 (M

+ - 1, 100), 291 (29), 283 (35), 281 (51), 218 (28),

208 (47), 207 (95), 204 (31), 203 (33), 202 (31), 133 (28), 115 (28), 102 (40), 92

(31), 78 (33), 61 (36).

2-(4-Fluorophenyl)-1-((4-

methoxyphenyl)ethynyl)-1,2,3,4-

tetrahydroisoquinoline (16f): pale yellow oil; tr =

26.4; Rf = 0.4 (hexane/ethyl acetate : 4/1); 1

H

NMR (300 MHz, CDCl3): δ 7.30-7.35 (m, 1H),

7.20-7.25 (m, 3H), 7.15-7.20 (m, 2H), 7.05-

7.10 (m, 2H), 7.00-7.05 (m, 2H), 6.70-6.75 (m,

2H), 5.52 (s, 1H), 3.75 (s, 3H), 3.55-3.65 (m,

2H), 3.10-3.20 (m, 1H), 2.94 (dt, J = 16.2, 3.6

Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 159.4,

157.4 (d, 1JC-F = 238.8 Hz), 146.4, 135.4, 133.9,

133.1 (2C), 128.9, 127.4, 127.2, 126.2, 119.3 (d, 3JC-F = 7.6 Hz), 115.4 (d,

2JC-F =

22.1 Hz, 2C), 114.9, 113.7 (2C), 86.6, 85.2, 55.2, 53.7, 44.0, 28.9; IR (ATR): ν

3050, 1604, 1506 cm-1

; MS (EI) m/z (%): 357 (M+, 82), 356 (M

+ - 1, 100), 283

(10), 208 (11), 207 (54), 191 (19), 190 (10), 189 (29), 133 (15), 73 (12), 65 (10);

HRMS calcd. (%) for C24H20FNO: 357.1529; found: 357.1517.


1-((4-Bromophenyl)ethynyl)-2-(4-fluorophenyl)-

1,2,3,4-tetrahydroisoquinoline (16g): brown oil;

tr = 26.5; Rf = 0.6 (hexane/ethyl acetate : 4/1); 1H

NMR (300 MHz, CDCl3): δ 7.30-7.40 (m, 3H),

7.15-7.25 (m, 3H), 6.95-7.15 (m, 6H), 5.52 (s, 1H),

3.60 (dd, J = 8.6, 3.7 Hz, 2H), 3.13 (dt, J = 16.3,

8.6 Hz, 1H), 2.95 (dt, J = 16.3, 3.7 Hz, 1H); 13

C

NMR (75 MHz, CDCl3): δ 157.6 (d, 1JC-F = 239.3

Hz), 146.6, 135.0, 134.1, 133.2, 131.5, 129.2,

127.5 (2C), 126.4, 122.4, 121.9, 119.5 (d, 3JC-F =

7.7 Hz, 2C), 115.7 (d, 2JC-F = 22.2 Hz, 2C), 89.5,

84.4, 53.9, 44.2, 29.1; IR (ATR): ν 3058, 3025, 1657, 1507 cm-1

; MS (EI) m/z

(%): 408 (M+

+ 2, 11), 407 (M+

+ 1, 54), 406 (M+, 100), 404 (M

+-2, 94), 284 (26),

282 (27), 350 (15), 226 (10), 224 (25), 207 (10), 203 (23), 202 (83), 201 (16),

200 (12), 122 (15), 95 (17); HRMS calcd. (%) for (C23H17BrFN - H): 404.0450;

found: 404.0437.

2-(4-Fluorophenyl)-1-((4-

(trifluoromethyl)phenyl)ethynyl)-1,2,3,4-

tetrahydroisoquinoline (16h). orange oil, tr = 20.2;


H NMR (300

MHz, CDCl3): δ 7.45-7.50 (m, 2H), 7.30-7.40

(m, 3H), 7.20-7.25 (m, 3H), 6.95-7.15 (m, 4H),

5.56 (s, 1H), 3.61 (dd, J = 8.5, 3.6 Hz, 2H), 3.10-

3.20 (m, 1H), 2.96 (dt, J = 16.2, 3.6 Hz, 1H); 13

C

NMR (75 MHz, CDCl3): δ 157.5 (d, 1JC-F = 239.5

Hz), 146.2, 134.6, 134.0, 131.9 (2C), 129.8 (q, 2JC-F

= 32.6 Hz), 129.0, 127.4 (2C), 126.6, 126.3, 125.0

(q, 3JC-F = 3.6 Hz, 2C), 123.8 (q,

1JC-F = 271.1 Hz), 119.4 (d,

3JC-F = 7.7 Hz, 2C),

115.6 (d, 2JC-F = 22.1 Hz, 2C), 90.8, 84.0, 53.8, 44.0, 28.9; IR (ATR): ν 3065,

1614, 1507 cm-1

; MS (EI) m/z (%): 396 (M+

+ 1, 12), 395 (M+, 64), 394 (M

+-1,

100), 272 (46), 203 (10), 202 (31), 95 (12); HRMS calcd. (%) for C24H17F4N:

395.1297; found: 395.1287.


1-((3-Chlorophenyl)ethynyl)-2-(4-fluorophenyl)-

1,2,3,4-tetrahydroisoquinoline (16i): yellow oil; tr

= 23.6; Rf = 0.7 (hexane/ethyl acetate : 4/1); 1H

NMR (300 MHz, CDCl3): δ 7.30-7.35 (m, 1H),

7.20-7.30 (m, 5H), 7.10-7.15 (m, 2H), 6.95-7.10

(m, 4H), 5.52 (s, 1H), 3.60 (dd, J = 8.3, 3.6 Hz,

2H), 3.05-3.20 (m, 1H), 2.95 (dt, J = 16.2, 3.4 Hz,

1H); 13

C NMR (75 MHz, CDCl3): δ 157.7 (d, 1JC-F

= 239.3 Hz), 146.4, 134.9, 134.1 (2C), 131.7, 130.0,

129.5, 129.2, 128.5, 127.5 (2C), 126.5, 124.7, 119.5

(d, 3JC-F = 7.6 Hz, 2C), 115.7 (d,

2JC-F = 22.2 Hz, 2C), 89.6, 84.1, 53.8, 44.2, 29.1;

IR (ATR): ν 3061, 2924, 2832, 1591, 1507 cm-1

; MS (EI) m/z (%): 362 (M+

+ 1,

42), 361 (M+, 67), 360 (M

+ - 1, 100), 238 (35), 208 (13), 207 (56), 203 (21), 202

(52), 136 (13); HRMS calcd. (%) for (C23H17ClFN - H): 360.0955; found:

360.0966.

1-((2-Bromophenyl)ethynyl)-2-(4-fluorophenyl)-

1,2,3,4-tetrahydroisoquinoline (16j): brown oil; tr =

25.4; Rf = 0.4 (hexane/ethyl acetate : 4/1); 1H NMR

(300 MHz, CDCl3): δ 7.48 (dd, J = 7.9, 1.3 Hz, 1H),

7.35-7.40 (m, 1H), 7.29 (dd, J = 7.6, 1.8 Hz, 1H),

7.15-7.25 (m, 3H), 6.95-7.15 (m, 6H), 5.59 (s, 1H),

3.55-3.75 (m, 2H), 3.15 (m, 1H), 2.97 (dt, J = 16.3,

3.7 Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 157.6 (d, 1JC-F = 239.1 Hz), 146.4, 134.9, 134.2, 133.5, 132.4,

129.4, 129.1, 127.7, 127.5, 126.9, 126.4, 125.7, 125.1, 119.6 (d, 3JC-F = 7.6 Hz,

2C), 115.7 (d, 2JC-F = 22.1 Hz, 2C), 93.1, 84.1, 53.9, 44.3, 29.2; IR (ATR): ν

3063, 2920, 1507, 1468 cm-1

; MS (EI) m/z (%): 407 (M+

+ 1, 5), 406 (M+, 12),

405 (M+

- 1, 5), 404 (M+-2, 12), 281 (20), 209 (36), 207 (100), 202 (11); HRMS

calcd. (%) for (C23H17BrFN - H): 404.0450; found: 404.0451.


1-(Cyclohex-1-en-1-ylethynyl)-2-(4-fluorophenyl)-

1,2,3,4-tetrahydroisoquinoline (16k): brown oil; tr

= 21.0; Rf = 0.6 (hexane/ethyl acetate : 4/1); 1H

NMR (300 MHz, CDCl3): δ 7.25-7.30 (m, 1H),

7.15-7.20 (m, 4H), 6.95-7.05 (m, 3H), 5.90-5.95

(m, 1H), 5.42 (s, 1H), 3.50-3.60 (m, 2H), 3.05-

3.15 (m, 1H), 2.91 (dt, J = 16.2, 3.6 Hz, 1H),

1.95-2.00 (m, 4H), 1.50-1.55 (m, 4H); 13

C NMR

(75 MHz, CDCl3): δ 157.3 (d, 1JC-F = 238.7 Hz),

146.4, 135.6, 134.6, 133.8, 128.9, 127.4, 127.0, 126.1, 120.2, 119.2 (d, 3JC-F = 7.6

Hz, 2C), 115.4 (d, 2JC-F = 22.1 Hz, 2C), 87.1, 85.2, 53.5, 43.9, 29.2, 28.9, 25.5,

22.2, 21.4; IR (ATR): ν 3050, 3023, 2927, 2857, 1507 cm-1

; MS (EI) m/z (%):

331 (M+, 18), 330 (M

+ - 1, 34), 281 (15), 208 (14), 207 (100); HRMS calcd. (%)

for C23H22FN: 331.1736; found: 331.1719.

1-(Cyclohexylethynyl)-2-(4-fluorophenyl)-1,2,3,4-

tetrahydroisoquinoline (16l): yellow oil; tr = 19.9;

Rf = 0.3 (hexane/ethyl acetate 9/1); 1

H NMR (300

MHz, CDCl3): δ 7.25-7.30 (m, 1H), 7.10-7.20 (m,

3H), 6.95-7.05 (m, 4H), 5.32 (s, 1H), 3.52 (dd, J

= 8.5, 3.6 Hz, 2H), 3.05-3.10 (m, 1H), 2.89 (dt, J

= 16.2, 3.6 Hz, 1H), 2.25-2.30 (m, 1H), 1.50-1.65

(m, 4H), 1.40-1.45 (m, 1H), 1.15-1.30 (m, 5H); 13

C NMR (75 MHz, CDCl3): δ 157.3 (d, 1JC-F = 238.6

Hz), 146.6, 136.0, 133.7, 128.8, 127.3, 126.9, 126.0, 119.3 (d, 3JC-F = 7.6 Hz,

2C), 115.3 (d, 2JC-F = 22.1 Hz, 2C), 89.9, 78.6, 53.2, 43.8, 32.5 (2C), 29.0, 28.8

(2C), 25.8, 24.4; IR (ATR): ν 3061, 3024, 2927, 2852, 1507 cm-1

; MS (EI) m/z

(%): 334 (M+

+ 1, 11), 333 (M+, 74), 332 (M

+ - 1, 100), 250 (30), 224 (12), 167

(16), 165 (13), 153 (11), 141 (13), 128 (17), 115 (12), 95 (13); HRMS calcd. (%)

for C23H24FN: 333.1893; found: 333.1885.

2-(4-Fluorophenyl)-1-(nona-1,8-diyn-1-yl)-1,2,3,4-

tetrahydroisoquinoline (16m): pale yellow oil; tr =


H NMR

(300 MHz, CDCl3): δ 7.25-7.30 (m, 1H), 7-10-7.20

(m, 3H), 6.95-7.05 (m, 4H), 5.31 (s, 1H), 3.50-3.60

(m, 2H), 3.09 (dt, J = 16.4, 8.3 Hz, 1H), 2.90 (dt, J =

16.4, 3.6 Hz, 1H), 2.15-2.00 (m, 4H), 1.92 (t, J = 2.6

Hz, 1H), 1.15-1.50 (m, 6H); 13

C NMR (75 MHz,

CDCl3): δ 157.4 (d, 1JC-F = 238.8 Hz), 146.6, 136.1,


133.9, 129.0, 127.5, 127.2, 126.3, 119.2 (d, 3JC-F = 7.6 Hz, 2C), 115.5 (d,

2JC-F =

22.1 Hz, 2C), 85.7, 84.6, 79.1, 68.4, 53.8, 43.9, 29.1, 28.3, 28.1, 27.9, 18.7, 18.4;

IR (ATR): ν 3303, 2937, 2859, 1508 cm-1

; MS (EI) m/z (%): 345 (M+, 38), 344

(M+

- 1, 100), 302 (12), 276 (27), 264 (13), 262 (31), 250 (27), 226 (12), 224

(19), 207 (18), 155 (13), 153 (13), 142 (11), 141 (23), 95 (13); HRMS calcd. (%)

for C24H24FN: 345.1893; found: 345.1877.

2-(4-Fluorophenyl)-1-(3-((tetrahydro-2H-

pyran-2-yl)oxy)prop-1-yn-1-yl)-1,2,3,4-

tetrahydroisoquinoline (16n): colourless oil; tr =

22.3; Rf = 0.4 (hexane/ethyl acetate : 4/1); 1H

NMR (300 MHz, CDCl3): δ 7.15-7.30 (m, 4H),

6.95-7.05 (m, 4H), 5.39 (s, 1H), 4.56 (t, J = 3.2

Hz, 1H), 4.18 (d, J = 1.9 Hz, 2H), 3.65-3.80 (m,

1H), 3.50-3.60 (m, 2H), 3.35-3.45 (m, 1H), 3.10

(ddd, J = 16.3, 9.7, 7.0 Hz, 1H), 2.90 (dt, J = 16.3, 3.5 Hz, 1H), 1.70-1.80 (m,

1H), 1.40-1.65 (m, 5H); 13


Hz), 146.5, 135.0, 134.0, 129.1, 127.5, 127.4, 126.3, 119.3 (d, 3JC-F = 7.7 Hz,

2C), 115.6 (d, 2JC-F = 22.1 Hz, 2C), 96.4, 84.8, 81.2, 62.1, 54.3, 53.3, 43.9, 30.3,

29.0, 25.5, 19.2; IR (ATR): ν 2923, 2849, 1230, 1021 cm-1

; MS (EI) m/z (%): 365

(M+, 16), 364 (M

+ - 1), 281 (16), 280 (16), 264 (56), 263 (37), 262 (100), 250

(19), 248 (29), 235 (12), 226 (22), 224 (21), 207 (27), 141 (21), 140 (12), 139

(13), 129 (14), 128 (14), 122 (15), 115 (26), 95 (18), 85 (17), 84 (46), 83 (24), 57

(12), 56 (25), 55 (60), 54 (12); HRMS calcd. (%) for C23H24FNO2: 365.1791;

found: 365.1781.

2-(4-Fluorophenyl)-1-(nitromethyl)-1,2,3,4-

tetrahydroisoquinoline (16o):293



H NMR (300

MHz, CDCl3): δ 7.05-7.30 (m, 4H), 6.85-6.95 (m,

4H), 5.42 (dd, J = 8.6, 5.9 Hz, 1H), 4.82 (dd, J = 12.0,

8.6 Hz, 1H), 4.55 (dd, J = 12.0, 5.9 Hz, 1H), 3.55-

3.60 (m, 2H), 2.95-3.05 (m, 1H), 2.70 (dt, J = 16.5, 4.2 Hz, 1H); 13

C NMR (75

MHz, CDCl3): δ 157.1 (d, 1JC-F = 239.1 Hz), 145.3, 135.2, 132.5, 129.4, 128.0,

126.9, 126.7, 117.8 (d, 3JC-F = 7.6 Hz, 2C), 115.8 (d,

2JC-F = 22.2 Hz, 2C), , 78.7,

58.6, 42.7, 25.7. IR (ATR): ν 2913, 2843, 1547, 1506 cm-1

; MS (EI) m/z (%): 286

(M+, 5), 227 (23), 226 (100), 225 (29), 224 (68), 128 (10), 104 (13), 95 (12).


2-(4-Fluorophenyl)-1-(1-methyl-1H-indol-3-yl)-

1,2,3,4-tetrahydroisoquinoline (16p): white solid;

m.p. 137-139 ºC (ethanol); tr = 24.6; Rf = 0.5

(hexane/ethyl acetate : 4/1); 1H NMR (300 MHz,

CDCl3): δ 7.42 (dt, J = 8.0, 0.9 Hz, 1H), 7.10-7.25

(m, 6H), 7.0 (ddd, J = 8.0, 6.8, 1.3 Hz, 1H), 6.85-6.95

(m, 4H), 6.43 (s, 1H), 6.00 (s, 1H), 3.61 (s, 3H), 3.40-

3.60 (m, 2H), 3.02 (ddd, J = 16.1, 9.8, 5.8 Hz, 1H),

2.79 (dd, J = 16.1, 4.3 Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 156.7 (d, 1JC-F =

237.7 Hz), 146.9, 137.6, 137.4, 135.4, 129.0 (2C), 128.3, 127.2, 126.7, 125.9,

121.8, 120.2, 119.3, 118.6 (d, 3JC-F =7.5 Hz, 2C), 117.5, 115.6 (d,

2JC-F = 22.0 Hz,

2C), 109.3, 57.7, 43.4, 32.8, 26.9; IR (ATR): ν 3047, 2957, 1505 cm-1

; MS (EI)

m/z (%): 355 (M+

- 1, 1%), 262 (20), 186 (13), 170 (37), 169 (14), 168 (23), 142

(10), 141 (26), 115 (12), 104 (12), 94 (66), 78 (100), 77 (43), 76 (16), 66 (16), 65

(16), 52 (13), 51 (22), 50 (17); HRMS calcd. (%) for C24H21FN2: 356.1689;

found: 356.1692.

(Diethyl(2-(4-fluorophenyl)-1,2,3,4-

tetrahydroisoquinolin-1-yl)phosphonate

(16q):295

pale pink oil; tr = 17.52; Rf = 0.3

(hexane/ethyl acetate : 4/1); 1

H NMR (300 MHz,

CDCl3): δ 7.30-7.40 (m, 1H), 7.10-7.25 (m, 3H),

6.85-7.00 (m, 4H), 5.06 (d, J = 20.2 Hz, 1H), 3.8-

4.3, 3.45-3.60 (2m, 1 and 5H, respectively), 2.85-3.10 (m, 2H), 1.24 (t, J = 7.07,

3H), 1.14 (td, J = 7.07, 0.28, 3H); 13


237.7 Hz), 146.3 (dd, JC-P = 6.4, 1.9 Hz), 136.4 (d, 4JC-F = 5.5 Hz), 130.5, 128.9

(2C), 127.6, 126.0, 116.7 (d, 3JC-F = 7.4 Hz, 2C), 115.6 (d,

2JC-F = 22.1 Hz, 2C),

63.4 (d, 2JC-P = 7.3 Hz), 62.4 (d,

2JC-P = 7.7 Hz), 59.4 (d,

1JC-P = 158.4 Hz), 44.4,

26.6, 16.5 (d, 3JC-P = 5.9 Hz), 16.4 (d,

3JC-P = 5.9 Hz); IR (ATR): ν 1508, 1234,

1018 cm-1

; MS (EI) m/z (%): 363 (M+, 1), 227 (21), 226 (100), 224 (13).

2-(2-(4-Fluorophenyl)-1,2,3,4-

tetrahydroisoquinolin-1-yl)cyclohexanone

(16r):165d


(hexane/ethyl acetate : 4/1); 1H NMR (300 MHz,

CDCl3): δ 6.75-7.25 (4m, 1, 7, 7 y 1H,

respectively), 5.56 (d, J = 8.5 Hz, 1H, anti), 5.47

(d, J = 5.2 Hz, 1H, syn), 3.50-3.70 (2m, 2 y 2H,

295 M. Rueping, S. Zhu, R. M. Koenigs, Chem. Commun. 2011, 47, 8679-8681.


respectively), 2.80-2.90 (m, 6H), 2.15-2.45 (2m, 2 y 2H, respectively), 1.25-1.90

(m, 12H); 13

C NMR (75 MHz, CDCl3): δ 212.1 (anti), 211.9 (syn), 156.3 (d, 1JC-F

= 237.5 Hz, syn), 155.2 (d, 1JC-F = 235.3 Hz, anti), 146.2 (2C, anti, syn), 140.1

(anti), 135.8 (syn), 135.0 (syn), 134.5 (anti), 128.9 (syn), 128.1 (anti), 128.0

(syn), 127.3 (anti), 126.8 (2C, anti, syn), 126.4 (anti), 125.8 (syn), 117.1 (d, 3JC-F

= 7.3 Hz, syn, 2C), 115.5 (d, 2JC-F = 22.0 Hz, syn, 2C), 115.4 (d,

2JC-F = 22.0 Hz,

anti, 2C ), 113.6 (d, 3JC-F = 7.3 Hz, anti, 2C), 59.4 (anti), 56.5 (syn), 55.8 (syn),

54.7 (anti), 44.1 (anti), 43.5 (syn), 43.2 (anti), 41.4 (syn), 32.8 (anti), 30.5 (syn),

28.8 (anti), 27.5 (syn), 27.4 (anti), 26.8 (syn), 25.7 (anti), 23.8 (syn); IR (ATR): ν

2938, 2862, 1703, 1507 cm-1

; MS (EI) m/z (%): 323 (M+, 0.5%), 227 (19), 226

(100), 55 (14).

1-(2-(4-Fluorophenyl)-1,2,3,4-

tetrahydroisoquinolin-1-yl)but-3-en-2-one

(16s): yellow oil; tr = 17.51; Rf = 0.4 (hexane/ethyl

acetate : 4/1); 1H NMR (300 MHz, CDCl3): δ 7.10-

7.20 (m, 4H), 6.80-7.00 (m, 4H), 6.29 (dd, J =

17.6, 10.5 Hz, 1H), 6.10 (dd, J = 17.6, 1.1 Hz,

1H), 5.76 (dd, J = 10.5 Hz, 1.1 Hz, 1H), 5.37 (t, J

= 6.3 Hz, 1H), 3.45-3.65 (m, 2H), 3.19 (dd, J = 16.1, 6.3 Hz, 1H), 3.04 (m, 1H),

2.94 (dd, J = 16.1, 6.3 Hz, 1H), 2.80 (dt, J = 16.2, 4.5 Hz, 1H); 13

C NMR (75

MHz, CDCl3): δ 199.1, 156.5 (d, 1JC-F = 237.3 Hz), 145.8, 138.2, 136.9, 134.3,

128.9, 128.7, 127.1, 127.0, 126.4, 116.9 (d, 3JC-F = 7.4 Hz, 2C), 115.8 (d,

2JC-F =

22.1 Hz, 2C), 55.9, 46.1, 42.6, 27.1; IR (ATR): ν 3052, 1676, 987, 956 cm-1

; MS

(EI) m/z (%): 295 (M+, 6), 227 (19), 226 (100), 225 (11), 207 (17), 55 (11);

HRMS calcd. (%) for C19H18FNO: 295.1862; found: 295.1845.

(E)-2-(4-Fluorophenyl)-1-styryl-1,2,3,4-

tetrahydroisoquinoline (16t): orange oil; tr =


H

NMR (300 MHz, CDCl3): δ 7.10-7.45 (m, 9H),

6.75-7.05 (m, 4H), 6.40 (d, J = 15.9 Hz, 1H), 6.30

(dd, J = 15.9, 4.7 Hz, 1H), 5.25 (d, J = 4.7 Hz 1H),

3.63 (ddd, J = 12.2, 7.3, 5.1 Hz, 1H), 3.45-3.55 (m,

1H), 2.85-3.10 (m, 2H); 13

C NMR (75 MHz,

CDCl3): δ 156.4 (d, 1JC-F = 237.0 Hz), 146.5 (2C),

136.9, 136.5, 135.4, 131.0, 130.4, 128.6 (2C),

127.8, 127.6, 127.0, 126.6 (2C), 126.4, 116.6 (d, 3JC-F = 7.4 Hz, 2C), 115.7 (d,

2JC-F = 22.1 Hz, 2C), 62.4, 43.9, 28.4; IR (ATR): ν 3025, 2904, 2834, 1735, 1507

cm-1

; MS (EI) m/z (%): 329 (M+, 52), 328 (M

+ - 1, 38), 252 (10), 238 (30), 237


(20), 226 (100), 224 (17), 128 (12), 115 (14), 95 (11), 91 (24); HRMS calcd. (%)

for C23H20FN: 329.1580; found: 329.1577.

2-(4-Fluorophenyl)-3,4-dihydroisoquinolin-

1(2H)-one (17a): yellow solid; m.p. 112-114 ºC

(ethanol); tr = 16.56; Rf = 0.5 (hexane/ethyl acetate

: 3/2); 1H NMR (300 MHz, CDCl3): δ 8.14 (dd, J =

7.7, 1.2 Hz, 1H), 7.47 (td, J = 7.4, 1.5 Hz, 1H),

7.30-7.40 (m, 3H), 7.20-7.30 (m, 1H), 7.00-7.15

(m, 2H), 3.95 (t, J = 6.5 Hz, 2H), 3.14 (t, J = 6.5 Hz, 2H); 13

C NMR (75 MHz,

CDCl3): δ 164.5, 160.8 (d, 1JC-F = 245.6 Hz), 139.2, 138.3, 132.3, 130.1, 129.6,

128.8, 127.3 (d, 3JC-F = 6.7 Hz, 2C), 127.1, 115.8 (d,

2JC-F = 22.6, 2C), 49.7, 28.7;

IR (ATR): ν 1650, 1500 cm-1

; MS (EI) m/z (%): 242 (M+

+ 1, 16), 241 (M+, 91),

240 (M+

- 1, 25), 122 (20), 119 (13), 118 (100), 95 (18), 90 (46), 89 (24); HRMS

calcd. (%) for C15H12FNO: 241.0903; found: 241.0907.

4.9. SYNTHESIS OF BENZO[b]FURANS.


19 (0.4 mmol) in EtOH (2 mL), was added 4-methylbenzenesulfonohydrazine

(74 mg, 0.4 mmol) and the reaction was stirred at 100 ºC during 1 h. After that

time, Cs2CO3 (390 mg, 1.2 mmol), tridecane (73.7 mg, 0.4 mmol as an internal

standard), CuO-Fe3O4 (50 mg, 2.4 mol%) were added to the reaction solution

followed by the corresponding terminal alkyne 5 (0.5 mmol). The resulting

mixture was stirred at 100 ºC during 5 h. The catalyst was removed by magnetic

decantation and the solvent was removed under reduce pressure. The resulting

mixture was quenched with deionised water and extracted with AcOEt (3 x 5

mL). The organic phases were dried over MgSO4, followed by evaporation under

reduced pressure to remove the solvent. The product was usually purified by

column chromatography on silica gel (hexane/ethyl acetate) to give the

corresponding product 20.

2-Benzylbenzofuran (20a):180

colorless oil; tr= 14.2;

Rf= 0.6 (hexane/ethyl acetate: 4/1); 1H NMR (300

MHz, CDCl3): δ 7.40-7.45 (m, 1H), 7.35-7.40 (m, 1H),

7.15-7.30 (m, 7H), 6.33 (s, 1H), 4.06 (s, 2H); 13

C

NMR (75 MHz, CDCl3): δ 157.8, 154.9, 137.2, 128.9

(2C), 128.8, 128.6 (2C), 126.7, 123.4, 122.5, 120.4,


110.9, 103.3, 35.0; IR (ATR): ν 3029, 1454, 1252, 952 cm-1

; MS (EI) m/z (%):

208 (M+, 88), 207 (M

+ - 1, 100), 178 (22), 131 (36), 77 (8).

2-Benzyl-5,7-di-tert-butylbenzofuran (20b):

colorless oil; tr= 17.0; Rf= 0.7 (hexane/ethyl


(d, J = 1.9 Hz, 1H), 7.20-7.30 (m, 5H), 7.17 (d, J =

1.9 Hz, 1H), 6.31 (s, 1H), 4.10 (s, 2H), 1.47 (s,

9H), 1.35 (s, 9H); 13


156.8, 151.3, 145.2, 137.7, 133.4, 128.8 (3C),

128.4 (2C), 126.5, 118.0, 114.5, 103.1, 35.1, 34.8, 34.4, 31.9 (3C), 29.9 (3C); IR

(ATR): ν 2955, 2905, 1603, 1479, 1242, 1030 cm-1

;. MS (EI) m/z (%): 321 (M+

+

1, 11), 320 (M+, 49), 306 (31), 305 (100), 153 (9), 91 (17), 57 (12); HRMS calcd.

(%) for C23H28O: 320.21402; found: 320.2137.

2-Benzyl-5-bromo-7-methoxybenzofuran (20c):

yellow solid; m.p. = 52-54ºC (Hexane); tr= 17.6;


MHz, CDCl3): δ 7.20-7.35 (m, 5H), 7.18 (d, J =

1.7 Hz, 1H), 6.83 (d, J = 1.7 Hz, 1H), 6.24 (t, J =

0.94 Hz, 1H), 4.09 (s, 2H), 3.95 (s, 3H); 13

C NMR

(75 MHz, CDCl3): δ 159.3, 145.2, 142.9, 136.7, 131.6, 128.9 (2C), 128.6 (2C),

126.8, 115.6 (2C), 109.3, 103.2, 56.2, 34.8; IR (ATR): ν 1597, 1472, 1207 cm-1

;

MS (EI) m/z (%): 319 (M+

+ 3, 17), 318 (M+

+ 2, 96), 317 (M+

+ 1, 57), 316 (M+,

100), 315 (21), 281 (19), 241 (10), 237 (19), 222 (16), 209 (11), 208 (19), 207

(41), 206 (91), 194 (19), 181 (37), 166 (19), 165 (64), 89 (14), 82 (12), 78 (44);

HRMS calcd. (%) for C16H13BrO2: 316.0099; found: 316.0109.

2-(2-Bromobenzyl)benzofuran (20d): pale yellow

oil; tr= 16.0; Rf= 0.6 (hexane/ethyl acetate: 4/1); 1H

NMR (300 MHz, CDCl3): δ 7.55-7.60 (m, 1H), 7.45-

7.50 (m, 1H), 7.40-7.45 (m, 1H), 7.10-7.30 (m, 5H),

6.38 (s, 1H), 4.24 (s, 2H); 13

C NMR (75 MHz,

CDCl3): δ 156.0, 154.9, 136.8, 132.9, 130.9, 128.7,

128.5, 127.6, 124.6, 123.5, 122.6, 120.5, 110.9, 104.0, 35.2; IR (ATR): ν 1601,

1585, 1453, 1251, 1025 cm-1

; MS (EI) m/z (%): 289 (M+

+ 3, 15), 288 (M+

+ 2,

98), 287 (M+

+ 1, 54), 286 (M+, 100), 285 (M

+-1, 39), 208 (11), 207 (63), 206

(17), 105 (41), 178 (73), 177 (16), 176 (24), 152 (16), 151 (12), 131 (82), 89


(33), 88 (11), 77 (14), 76 (26), 63 (12); HRMS calcd. (%) for C15H11BrO:

285.9993; found: 285.9985.

2-(3-Chlorobenzyl)benzofuran (20e):179

pale yellow


NMR (300 MHz, CDCl3): δ 7.45-7.50 (m, 1H), 7.35-

7.40 (m, 1H), 7.29 (br s, 1H), 7.15-7.25 (m, 5H), 6.40

(s, 1H), 4.06 (s, 2H); 13


156.7, 155.0, 139.2, 134.4, 129.8, 129.0, 128.6, 127.0

(2C), 123.6, 122.6, 120.5, 110.9, 103.7, 34.6; IR

(ATR): ν 1596, 1585, 1574, 1453, 1252, 1008 cm-1

; MS (EI) m/z (%): 244 (M+

+

2, 34), 243 (M+

+ 1, 37), 242 (M+, 100), 241 (M

+-1, 69), 208 (10), 207 (77), 205

(13), 179 (22), 178 (44), 131 (67), 77 (13), 76 (14).

2-(4-Bromobenzyl)benzofuran (20f):296

white solid;

m.p. = 47-49 ºC (Hexane); tr= 16.2; Rf= 0.7


CDCl3): δ 7.40-7.50 (m, 4H), 7.10-7.20 (m, 4H), 6.36

(dd, J = 1.1, 0.9 Hz, 1H), 4.03 (s, 2H); 13

C NMR (75

MHz, CDCl3): δ 156.9, 154.9, 136.2, 131.7 (2C),

130.6 (2C), 128.6, 123.6, 122.6, 120.7, 120.5, 110.9,

103.6, 34.4; IR (ATR): ν 1599, 1584, 1488, 1452, 1250, 1010 cm-1

; MS (EI) m/z

(%): 289 (M+

+ 3, 19), 288 (M+

+ 2, 78), 287 (M+

+ 1, 69), 286 (M+, 75), 285

(M+-1, 66), 208 (19), 207 (100), 205 (24), 179 (25), 178 (56), 177 (16), 176 (14),

152 (14), 151 (11), 131 (52), 103 (12), 102 (13), 89 (25), 77 (17), 76 (32), 63

(12).

2-(4-Trifluoromethyl)benzyl)benzofuran (20g):180

pale yellow oil; tr= 14.0; Rf= 0.6 (hexane/ethyl


(d, J = 7.8 Hz, 2H), 7.45-7.50 (m, 1H), 7.40-7.45

(m, 3H), 7.15-7.25 (m, 2H), 6.41 (s, 1H), 4.16 (s,

2H); 13

C NMR (75 MHz, CDCl3): δ 156.4, 155.0,

141.3, 129.2 (2C), 129.2 (q, 2JC-F = 32.3 Hz), 128.1,

126.0 (q, 1JC-F = 272.4 Hz), 125.5 (q,

3JC-F = 3.8 Hz, 2C), 123.7, 122.7, 120.5,

110.9, 103.8, 34.8; IR (ATR): ν 1454, 1322, 1252 cm-1

; MS (EI) m/z (%): 277

296 J. Barluenga, M. Tomás-Gamasa, F. Aznar, C. Valdés, Nat. Chem. 2009, 1, 494-499.


(M+

+ 1, 16), 276 (M+, 100), 275 (M

+-1, 84), 207 (59), 179 (11), 178 (26), 131

(57).

2-(2-Methylbenzyl)benzofuran (20h):179

pale yellow


NMR (300 MHz, CDCl3): δ 7.42 (ddd, J = 8.2, 1.8, 0.7

Hz, 2H), 7.10-7.25 (m, 6H), 6.23 (d, J = 0.9 Hz, 1H),

4.09 (s, 2H), 2.34 (s, 3H); 13

C NMR (75 MHz,

CDCl3): δ 157.5, 154.9, 136.6, 135.4, 130.4, 129.8,

128.8, 127.1, 126.2, 123.3, 122.5, 120.3, 110.9, 103.2, 32.7, 19.4; IR (ATR): ν

1599, 1585, 1454, 1253, 1008 cm-1

; MS (EI) m/z (%): 223 (M+

+ 1, 18), 222 (M+,

100), 221 (M+

- 1, 31), 207 (37), 178 (23), 131 (27), 116 (11), 115 (10), 110 (10),

107 (48), 104 (22), 77 (11).

2-(3-Methylbenzyl)benzofuran (20i):180

colorless oil;

tr= 14.7; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR

(300 MHz, CDCl3): δ 7.45-7.50 (m, 1H), 7.40-7.45

(m, 1H), 7.15-7.25 (m, 3H), 7.05-7.10 (m, 3H), 6.37

(s, 1H), 4.06 (s, 2H), 2.33 (s, 3H); 13

C NMR (75 MHz,

CDCl3): δ 157.9, 154.9, 138.2, 137.1, 129.6, 128.8,

128.5, 127.5, 125.9, 123.3, 122.5, 120.4, 110.9, 103.3, 34.9, 21.4; IR (ATR): ν

3065, 3026, 1601, 1586, 1454, 1251, 954 cm-1

; MS (EI) m/z (%): 222 (M+, 100),

221 (M+

- 1, 81), 207 (54), 179 (11), 178 (25), 131 (34).

2-(4-Methoxybenzyl)benzofuran (20j):180



7.50 (m, 1H), 7.35-7.40 (m, 1H), 7.15-7.25 (m,

4H), 6.85-6.90 (m, 2H), 6.34 (dd, J = 1.9, 0.9 Hz,

1H), 4.04 (s, 2H), 3.79 (s, 3H); 13

C NMR (75 MHz,

CDCl3): δ 158.5, 158.3, 154.9, 129.9 (2C), 129.3,

128.8, 123.3, 122.5, 120.4, 114.0 (2C), 110.9, 103.1, 55.3, 34.1; IR (ATR): ν

1612, 1584, 1509, 1245 cm-1

; MS (EI) m/z (%): 238 (M+, 59), 237 (M

+ - 1, 56),

207 (100), 131 (13).


2-Hexylbenzofuran (20k):90

colorless oil; tr= 12.6;


MHz, CDCl3): δ 7.35-7.40, 7.45-7.50 (2m, 1H and

1H respectively), 7.10-7.20 (m, 2H), 6.34 (s, 1H),

2.74 (t, J = 7.5 Hz, 2H), 1.73 (quin-, J = 7.5 Hz,

2H), 1.25-1.40 (m, 6H), 0.89 (t, J = 7.14 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 159.8, 154.7, 129.1, 123.0, 122.4, 120.2, 110.7,

101.8, 31.6, 28.9, 28.5, 27.7, 22.6, 14.1; IR (ATR): ν 1600, 1587, 1252, 1009,

738 cm-1

; MS (EI) m/z (%): 202 (M+, 24), 132 (29), 131 (100), 95 (13), 77 (13).

2-(Cyclohexylmethyl)benzofuran (20l): colorless oil;


(300 MHz, CDCl3): δ 7.35-7.50 (m, 2H), 7.10-7.20 (m,

2H), 6.35 (s, 1H), 2.63 (d, J = 6.8 Hz, 2H), 1.60-1.80

(m, 6H), 1.10-1.30 (m, 3H), 0.90-1.05 (m, 2H); 13

C

NMR (75 MHz, CDCl3): δ 158.5, 154.7, 129.0, 122.9,

122.3, 120.1, 110.7, 102.8, 37.0, 36.3, 33.2 (2C), 26.4, 26.2 (2C); IR (ATR): ν

2921, 2850, 1601, 1586, 1453, 1253, 1008 cm-1

; MS (EI) m/z (%): 214 (M+, 50),

133 (12), 132 (90), 131 (100), 83 (10), 77 (10); HRMS calcd. (%) for C15H18O:

214.1357; found: 214.1351.

2-(4-Chlorobutyl)benzofuran (20m):297



7.45-7.50 (m, 1H), 7.40-7.45 (m, 1H), 7.15-7.25

(m, 2H), 6.40 (s, 1H), 3.58 (t, J = 6.2 Hz, 2H),

2.81 (t, J = 7.1 Hz, 2H), 1.85-1.95 (m, 4H); 13


158.6, 154.6, 128.8, 123.2, 122.5, 120.2, 110.7, 102.2, 44.6, 31.9, 27.7, 25.0; IR

(ATR): ν 2922, 2853, 1603, 1584, 1455, 1252, 948 cm-1

; MS (EI) m/z (%): 208

(M+, 18), 132 (15), 131 (100), 77 (10).

2-(2-(Tetrahydro-2H-pyran-2-

yl)oxy)ethyl)benzofuran (20n): colorless oil;

tr= 15.0; Rf= 0.5 (hexane/ethyl acetate: 4/1); 1H

NMR (300 MHz, CDCl3): δ 7.45-7.50 (m, 1H),

7.35-7.40 (m, 1H), 7.15-7.25 (m, 2H), 6.47 (d, J

= 0.9 Hz, 1H), 4.60-4.65 (m, 1H), 4.09 (dt, J =

297 M. Yamaguchi, H. Katsumata, K. Manabe, J. Org. Chem. 2013, 78, 9270-9281.


9.8, 6.8 Hz, 1H), 3.75-3.85 (m, 2H), 3.45-3.55 (m, 1H), 3.08 (td, J = 6.8, 0.8 Hz,

2H), 1.45-1.85 (m, 6H); 13

C NMR (75 MHz, CDCl3): δ 156.4, 154.6, 128.9,

123.2, 122.4, 120.3, 110.7, 103.0, 98.8, 65.0, 62.2, 30.6, 29.3, 25.4, 19.4; IR

(ATR): ν 2941, 2871, 1602, 1587, 1455, 1252, 1030 cm-1

; MS (EI) m/z (%): 246

(M+, 1), 162 (28), 145 813), 144 (50), 132 (16), 131 (100), 85 (26), 77 (14), 55

(12); HRMS calcd. (%) for C15H18O3: 246.1256; found: 246.1264.

2-(3-Ethylbenzyl)benzofuran (20o): pale yellow oil;


(300 MHz, CDCl3): δ 7.35-7.50 (m, 4H), 7.25-7.30 (m,

2H), 7.15-7.20 (m, 2H), 6.39 (d, J = 0.9 Hz, 1H), 4.08

(s, 2H), 3.06 (s, 1H); 13


157.0, 155.0, 144.9, 137.5, 132.5, 130.6, 129.5, 128.6,

123.6, 122.6, 120.5, 110.9, 103.6, 83.5, 77.3, 34.7; IR

(ATR): ν 3291, 1599, 1584, 1454, 1251, 1008 cm-1

; MS (EI) m/z (%): 233 (M+

+

1, 18), 232 (M+, 100), 231 (M

+-1, 87), 203 (14), 202 (31), 131 (36), 101 (11);

HRMS calcd. (%) for C17H12O: 232.0888; found: 232.0886.

2-(4-Bromobenzyl)-5,7-di-tert-

butylbenzofuran (20p): white solid; m.p. =

104-106 ºC (Hexane); tr= 15.0; Rf= 0.8


MHz, CDCl3): δ 7.40-7.45 (m, 2H), 7.32 (d, J =

1.9 Hz, 1H), 7.15-7.20 (m, 3H), 6.32 (s, 1H),

4.05 (s, 2H), 1.46 (s, 9H), 1.35 (s, 9H); 13

C

NMR (75 MHz, CDCl3): δ 155.9, 151.4, 145.4,

136.7, 133.5, 131.5 (2C), 130.5 (2C), 126.7,

120.4, 118.2, 114.6, 103.4, 34.8, 34.5, 34.4, 31.9 (3C), 29.9 (3C); IR (ATR): ν

2959, 2950, 1607, 1478 cm-1

; MS (EI) m/z (%): 401 (M+

+ 2, 39), 400 (M+

+ 1,

10), 399 (M+, 39), 386 (22), 385 (99), 384 (24), 383 (100), 281 (10), 227 (12),

207 (28), 169 (16), 152 (10), 138 (56), 57 (46); HRMS calcd. (%) for C23H27BrO:

398.1245; found: 398.1251.


acetophenone 21 (0.4 mmol) in EtOH (2 mL) was added 4-

methybenzenesulfonohydrazine (74 mg, 0.4 mmol) and the reaction was stirred at

100 ºC during 1 h. After that time, Cs2CO3 (390 mg, 1.2 mmol), CuO-Fe3O4 (50

mg, 2.4 mol%) were added to the reaction solution followed by the

corresponding terminal alkyne 5 (0.5 mmol). The resulting mixture was stirred at


ºC during 5 h. The catalyst was removed by magnetic decantation and the solvent

was removed under reduce pressure. The resulting mixture was quenched with

deionised water and extracted with AcOEt (3 x 5 mL). The organic phases were

dried over MgSO4, followed by evaporation under reduced pressure to remove

the solvent. The product was usually purified by column chromatography on

silica gel (hexane/ethyl acetate) to give the corresponding product 22.

2-Benzyl-3-methylbenzofuran (22a):298

colorless oil;


(300 MHz, CDCl3): δ 7.45-7.50 (m, 1H), 7.20-7.40

(m, 8H), 4.09 (s, 2H), 2.23 (s, 3H); 13

C NMR (75

MHz, CDCl3): δ 154.0, 152.1, 138.0, 130.2, 128.6

(2C), 128.5 (2C), 126.5, 123.4, 122.0, 118.9, 110.8,

32.6, 8.0; IR (ATR): ν 1494, 1454, 1088, 744 cm-1

; MS (EI) m/z (%): 223 (M+

+

1, 19), 222 (M+, 94), 221 (M

+ - 1, 49), 208 (23), 207 (100), 178 (20), 145 (48),

131 (10), 115 (19).

2-Benzyl-3-methylbenzofuran (22b): colorless

oil; tr= 16.5; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.56 (d, J = 1.9

Hz, 1H), 7.25-7.30 (m, 3H), 7.20-7.25 (m, 4H),

4.07 (s, 2H), 2.18 (s, 3H); 13

C NMR (75 MHz,

CDCl3): δ 153.6, 152.8, 137.5, 132.3, 128.6

(2C), 128.4 (2C), 126.6, 126.2, 121.7, 115.2,

112.2, 110.5, 32.6, 7.9; IR (ATR): ν 1602, 1494, 1445, 1262, 1089, 799 cm-1

; MS

(EI) m/z (%): 302 (M+

+ 2, 72), 301 (M+

+ 1, 38), 300 (M+, 80), 299 (M

+ - 1, 28),

287 (85), 285 (100), 281 (33), 225 (37), 223 (27), 207 (99), 205 (27), 193 (29),

191 (18), 115 (28), 110 (18), 103 (27), 89 (21), 88 (16), 78 (17), 74 (17), 73 (16),

63 (19), 61 (23). HRMS calcd. (%) for C16H13BrO: 300.0150; found: 300.0143.

298 R. Stoermer, R. Wehln, Ber. Dtsch. Chem. Ges. 1902, 35, 3549-3560.



BIMETALLIC IMPREGNATED NICKEL(II) OXIDE AND

COPPER(0) ON MAGNETITE

5.1. SYNTHESIS OF 1,4-DISUBSTITUTED-1H-1,2,3-TRIAZOLES

General Procedure: To a stirred solution of sodium azide (27, 2 mmol)

and benzyl halide 26 (2 mmol) were added NiO/Cu-Fe3O4 (50 mg, 0.9 mol% of

Ni and 0.9 mol% of Cu) and the corresponding alkyne 5 or 29 (1 mmol). The

resulting mixture was stirred at 50 ºC until the end of the reaaction. The catalyst

was removed by magnetic decantation and the resulting mixture was quenched

with deionized water and extracted with AcOEt (3 x 5 mL). The organic phases

were dried over MgSO4, followed by evaporation under reduced pressure to

remove the solvent. The product was usually purified by chromatography on

silica gel (hexane/ethyl acetate) to give the corresponding produts 24 and 30.

1-Benzyl-4-phenyl-1H-1,2,3-triazole (24a):191e

white

solid; m.p. 104-108 °C (hexane/ethyl acetate); tr=

17.9; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR

(300 MHz, CDCl3): δ 7.75-7.80 (m, 2H), 7.66 (s, 1H),

7.30-7.45 (m, 8H), 5.57 (s, 2H); 13

C NMR (75 MHz,

CDCl3): δ 148.2, 134.7, 130.5, 129.1 (2C), 128.8

(3C), 128.1, 128.0 (2C), 125.7 (2C), 119.4, 54.2; IR (ATR): ν 3021, 2920, 1450,

1223 cm-1

; MS (EI) m/z (%): 235 (M+, 22%), 207 (14), 206 (71), 180 (13), 179

(11), 116 (100), 104 (21), 91 (84), 89 (29), 65 (20), 63 (11).

1-(4-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (24b):

299 white solid; m.p. 150-152 °C (hexane/

ethyl acetate); tr= 21.2; Rf= 0.2 (hexane/ethyl


7.85 (m, 2H), 7.70 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H),

7.40-7.45 (m, 2H), 7.30-7.35 (m, 1H), 7.17 (d, J =

8.4 Hz, 2H), 5.50 (s, 2H); 13

C NMR (75 MHz,

CDCl3): δ 148.4, 133.6, 132.3 (2C), 130.3, 129.6

(2C), 128.8 (2C), 128.3, 125.7 (2C), 122.9, 119.4, 53.5; IR (ATR): ν 3082, 1489,

1221, 1073 cm-1

; MS (EI) m/z (%): 315 (M+

+ 2, 9%), 313 (M+, 10%), 286 (16),

284 (17), 206 (20), 171 (24), 169 (25), 116 (100), 90 (19), 89 (28).

299 J. Albadi, M. Keshavarz, M. Abedini, M. Vafaie-Nezhad, Chinese Chem. Lett. 2012, 23, 797-

800.


1-(3-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (24c):

195 white solid; m.p. 85-87 °C (hexane/ethyl

acetate); tr= 21.0; Rf= 0.1 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 2H),

7.71 (s, 1H), 7.45-7.50 (m, 2H), 7.40-7.45 (m, 2H),

7.30-7.35 (m, 1H), 7.20-7.25 (m, 2H), 5.54 (s, 2H); 13

C NMR (75 MHz, CDCl3): δ 148.3, 136.8, 131.9,

130.9, 130.7, 130.2, 128.8 (2C), 128.3, 126.5, 125.7 (2C), 123.1, 119.5, 53.4; IR

(ATR): ν 3084, 1460, 1432, 1222, 1046 cm-1

; MS (EI) m/z (%): 315 (M+

+ 2,

8%), 313 (M+, 8%), 286 (14), 284 (14), 206 (21), 171 (22), 169 (23), 116 (100),

90 (20), 89 (29).

1-(2-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (24d):


acetate); tr= 21.3; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.82 (d, J = 7.3 Hz,

2H), 7.78 (s, 1H), 7.62 (dd, J = 7.9, 1.0 Hz, 1H), 7.40-

7.45 (m, 2H), 7.30-7.35 (m, 2H), 7.15-7.25 (m, 2H),

5.70 (s, 2H); 13

C NMR (75 MHz, CDCl3): δ 148.1,

134.2, 133.2, 130.4, 130.2, 130.1, 128.8 (2C), 128.2 (2C), 125.7 (2C), 123.4,

119.8, 53.8; IR (ATR): ν 3051, 1459, 1430, 1220, 1043 cm-1

; MS (EI) m/z (%):

315 (M+

+ 2, 12%), 313 (M+, 11%), 208 (12), 207 (59), 206 (93), 184 (11), 171

(31), 169 (32), 117 (11), 116 (100), 103 (13), 91 (21), 90 (24), 89 (34), 63 (10).

1-(2-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole (24e):

193h white solid; m.p. 98-99 °C (hexane/ethyl


7.54 (s, 1H), 7.35-7.45 (m, 2H), 7.30-7.35 (m, 2H),

7.20-7.25 (m, 3H), 5.60 (s, 2H), 2.31 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 148.0, 137.0, 132.5, 131.1,

130.5, 129.4, 129.2, 128.8 (2C), 128.1, 126.7, 125.6 (2C), 119.2, 52.5, 19.0; IR

(ATR): ν 3096, 1462, 1216 cm-1

; MS (EI) m/z (%): 249 (M+, 22%), 220 (35), 207

(17), 206 (11), 118(31), 117 (39), 116 (100), 105 (63), 104 (10), 103 (15), 89

(23), 79 (14), 77 (21).


1-(3-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole (24f):



7.66 (s, 1H), 7.25-7.45 (m, 4H), 7.10-7.20 (m, 3H),

5.52 (s, 2H), 2.34 (s, 3H); 13

C NMR (75 MHz,

CDCl3): δ 148.1, 139.0, 134.5, 130.5, 129.5, 129.0, 128.8 (2C), 128.7, 128.1,

125.6 (2C), 125.1, 119.5, 54.2, 21.3; IR (ATR): ν 3089, 1464, 1222 cm-1

; MS

(EI) m/z (%): 249 (M+, 29%), 221 (13), 220 (61), 206 (36), 179 (20), 118 (14),

117 (17), 116 (100), 105 (66), 103 (14), 89 (24), 79 (13), 77 (20).

1-(3,5-Dimethoxybenzyl)-4-phenyl-1H-1,2,3-

triazole (24g): 193h

white solid; m.p. 90-92 °C

(hexane/ethyl acetate); tr= 22.8; Rf= 0.4


MHz, CDCl3): δ 7.75-7.80 (m, 2H), 7.68 (s,

1H), 7.35-7.40 (m, 2H), 7.30-7.35 (m, 1H),

6.44 (s, 3H), 5.49 (s, 2H), 3.76 (s, 6H); 13

C

NMR (75 MHz, CDCl3): δ 161.2 (2C), 148.2, 136.7, 130.5, 128.8 (2C), 128.1,

125.6 (2C), 119.5, 106.0 (2C), 100.4, 55.4 (2C), 54.2; IR (ATR): ν 3086, 1610,

1197 cm-1

; MS (EI) m/z (%): 296 (M+

+ 1, 13%), 295 (M+, 74%), 281 (14), 266

(41), 252 (10), 239 (32), 236 (19), 209 (21), 208 (15), 207 (61), 164 (36), 152

(13), 151 (100), 117 (12), 116 (100), 91 (19), 89 (21), 78 (11), 77 (18), 65 (11).

2-((4-Phenyl-1H-1,2,3-triazol-1-

yl)methyl)isoindoline-1,3-dione (24h): white

solid; m.p. 186-188 °C (hexane/ethyl acetate);


NMR (300 MHz, CDCl3): δ 8.11 (s, 1H), 7.90-

7.95 (m, 2H), 7.75-7.85 (m, 4H), 7.25-7.40 (m,

3H), 6.26 (s, 2H); 13


δ 166.5 (2C), 148.4, 134.9 (2C), 131.4 (2C), 130.1, 128.8 (2C), 128.3, 125.8

(2C), 124.1 (2C), 120.5, 49.7; IR (ATR): ν 1715 cm-1

; MS (EI) m/z (%): 304 (M+,

31%), 281 (11), 248 (10), 208 (10), 207 (40), 161 (11), 160 (100), 133 (15), 116

(31), 104 (16), 77 (15), 76 (14); Elemental analysis calcd. for C17H12N4O2: C =

67.10; H = 3.97; N = 18.41; found: C = 67.11; H = 3.96; N = 18.42.


1-Benzyl-4-(4-chlorophenyl)-1H-1,2,3-triazole (24i):

196b white solid; m.p. 125-127 °C

(hexane/ethyl acetate); ); tr= 19.6; Rf= 0.1


CDCl3): δ 7.72 (d, J = 8.7 Hz, 2H), 7.65 (s, 1H),

7.30-7.40 (m, 7H), 5.57 (s, 2H); 13

C NMR (75

MHz, CDCl3): δ 147.1, 134.5, 133.9, 129.2 (2C),

129.0 (2C), 128.8, 128.1 (2C), 126.9 (2C), 119.5, 60.4, 54.3; IR (ATR): ν 3060,

1481, 1222, 1069 cm-1

; MS (EI) m/z (%): 271 (M+

+ 2, 9%), 269 (M+, 26%), 242

(23), 241 (15), 240 (70), 207 (14), 206 (27), 179 (29), 152 (36), 151 (10), 150

(100), 125 (10), 123 (25), 104 (20), 102 (11), 91 (93), 65 (22).

1-(4-Bromobenzyl)-4-(4-chlorophenyl)-1H-

1,2,3-triazole (24j): white solid; m.p. 146-150

°C (hexane/ethyl acetate); tr= 24.9; Rf= 0.2


MHz, CDCl3): δ 7.72 (d, J = 8.5 Hz, 2H), 7.66

(s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.36 (d, J =

8.5 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.53 (s,

2H); 13

C NMR (75 MHz, CDCl3): δ 147.3, 133.9, 133.5, 132.3 (2C), 129.6 (2C),

129.0 (2C), 128.8, 126.9 (2C), 123.0, 119.5, 53.5; IR (ATR): ν 1487, 1456, 1227,

1092, 1072 cm-1

; MS (EI) m/z (%): 349 (M+

+ 2, 17%), 347 (M+, 13%), 320 (19),

318 (14), 240 (26), 207 (10), 171 (27), 169 (29), 152 (33), 151 (10), 150 (100),

123 (16), 90 (19), 89 (16); HRMS (ESI): m/z calcd for C15H11BrClN3: 346.9825;

found: 346.9828.

1-Benzyl-4-(2-chlorophenyl)-1H-1,2,3-triazole (24k):


acetate); tr= 18.7; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 8.22 (dd, J = 7.8, 1.8

Hz, 2H), 8.12 (s, 1H), 7.20-7.45 (m, 7H), 5.61 (s,

2H); 13

C NMR (75 MHz, CDCl3): δ 144.4, 134.6,

131.1, 130.1, 129.8, 129.2, 129.1 (2C), 129.0, 128.7,

127.9 (2C), 127.1, 123.1, 54.2; IR (ATR): ν 3083, 1461, 1227, 1056 cm-1

; MS

(EI) m/z (%): 271 (M+

+ 2, 6%), 269 (M+, 17%), 242 (12), 240 (36), 206 (40),

179 (30), 152 (28), 150 (87), 123 (14), 104 (26), 102 (10), 91 (100), 65 (19).

300 X. Meng, X. Xu, T. Gao, B. Chen, Eur. J. Org. Chem. 2010, 5409-5414.


1-Benzyl-4-(4-bromophenyl)-1H-1,2,3-

triazole (24l):187b




MHz, CDCl3): δ 7.65-7.70 (m, 3H), 7.50-7.55

(m, 2H), 7.30-7.40 (m, 5H), 5.56 (s, 2H); 13

C

NMR (75 MHz, CDCl3): δ 147.1, 134.4, 131.9 (2C), 129.4, 129.1 (2C), 128.8,

128.1 (2C), 127.2 (2C), 122.0, 119.5, 54.3; IR (ATR): ν 3070, 1477, 1449, 1222,

1050 cm-1

; MS (EI) m/z (%): 315 (M+

+ 2, 23%), 313 (M+, 24%), 287 (10), 286

(54), 285 (11), 284 (53), 207 (12), 206 (40), 204 (11), 196 (73), 194 (75), 179

(32), 178 (12), 169 (13), 167 (13), 115 (11), 104 (18), 102 (12), 91 (100), 88

(14), 65 (19).

4-(4-Bromophenyl)-1-(3-methylbenzyl)-

1H-1,2,3-triazole (24m): white solid; m.p.

127-128 °C (hexane/ethyl acetate); tr= 22.4;

Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR

(300 MHz, CDCl3): δ 7.67 (d, J = 8.6 Hz,

2H), 7.65 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H),

7.28 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.3 Hz, 2H), 5.53

(s, 2H), 2.35 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 147.1, 139.1, 134.3, 131.9

(2C), 129.6, 129.5, 129.0, 128.8, 127.2 (2C), 125.2, 122.0, 119.5, 54.3, 21.3; IR

(ATR): ν 3016, 1450, 1225, 1069 cm-1

; MS (EI) m/z (%): 329 (M+

+ 2, 24%), 327

(M+, 22%), 300 (34), 298 (36), 286 (27), 284 (26), 220 (21), 207 (22), 196 (70),

194 (76), 193 (27), 178 (12), 169 (12), 167 (12), 118 (18), 117 (11), 115 (15),

105 (100), 103 (20), 102 (14), 88 (15), 79; Elemental analysis calcd. for

C16H14BrN3: C = 58.55; H = 4.30; N = 12.80; found: C = 58.50; H = 4.29; N =

12.69.

1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-

triazole (24n):196b




MHz, CDCl3): δ 7.72 (d, J = 8.9 Hz, 2H), 7.58

(s, 1H), 7.25-7.40 (m, 5H), 6.93 (d, J = 8.9 Hz,

2H), 5.55 (s, 2H), 3.82 (s, 3H); 13

C NMR (75

MHz, CDCl3): δ 159.5, 148.0, 134.7, 129.1 (2C), 128.7, 128.0 (2C), 127.0 (2C),

123.2, 118.6, 114.2 (2C), 55.3, 54.1; IR (ATR): ν 1455, 1250 cm-1

; MS (EI) m/z

(%): 266 (M+

+ 1, 6%), 265 (M+, 35%), 237 (21), 236 (100), 222 (17), 210 (10),


209 (20), 206 (19), 194 (10), 193 (10), 179 (16), 160 (11), 146 (82), 119 (29), 91

(63), 89 (15), 76 (13), 65 (24).

1-Benzyl-4-(m-tolyl)-1H-1,2,3-triazole (24o):300

white solid; m.p. 145-146 °C (hexane/ethyl acetate);


NMR (300 MHz, CDCl3): δ 7.65-7.70 (m, 2H), 7.58

(d, J = 7.6 Hz, 1H), 7.25-7.45 (m, 6H), 7.12 (d, J =

7.6 Hz, 1H), 5.58 (s, 2H), 2.38 (s, 3H); 13

C NMR

(75 MHz, CDCl3): δ 148.3, 138.5, 134.7, 130.3,

129.1 (2C), 128.9, 128.8, 128.7, 128.0 (2C), 126.3, 122.8, 119.4, 54.2, 21.4; IR

(ATR): ν 3031, 1454, 1220 cm-1

; MS (EI) m/z (%): 249 (M+, 25%), 221 (13), 220

(58), 206 (10), 179 (12), 131 (11), 130 (100), 104 (13), 103 (14), 91 (70), 77

(14), 65 (14).

1-(3-Bromobenzyl)-4-(m-tolyl)-1H-1,2,3-triazole (24p):

187a white solid; m.p. 90-93 °C (hexane/ethyl

acetate); tr= 22.3; Rf= 0.3 (hexane/ethyl acetate:

3/2); 1H NMR (300 MHz, CDCl3): δ 7.70 (s, 1H),

7.65 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.40-7.45 (m,

2H), 7.10-7.30 (m, 4H), 5.48 (s, 2H), 2.35 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 148.3, 138.4, 136.8,

131.7, 130.7, 130.5, 130.1, 128.9, 128.6, 126.4, 126.2, 122.9, 122.6, 119.5, 53.2,

21.3; IR (ATR): ν 3036, 1429, 1223, 1084 cm-1

; MS (EI) m/z (%): 329 (M+

+ 2,

11%), 327 (M+, 12%), 300 (18), 298 (17), 220 (18), 207 (39), 171 (24), 169 (22),

131 (11), 130 (100), 103 814), 90 (14), 89 (13).

1-(3-Methylbenzyl)-4-(m-tolyl)-1H-1,2,3-triazole (24q): white solid; m.p. 127-128 °C (hexane/ethyl

acetate); tr= 19.5; Rf= 0.2 (hexane/ethyl acetate:

4/1); 1H NMR (300 MHz, CDCl3): δ 7.66 (s, 1H),

7.64 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.25-7.30 (m,

2H), 7.10-7.20 (m, 4H), 5.52 (s, 2H), 2.37 (s, 3H),

2.34 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 148.2,

139.0, 138.4, 134.6, 130.4, 129.5, 129.0, 128.8, 128.7, 128.6, 126.3, 125.1,

122.7, 119.4, 54.2, 21.4, 21.3; IR (ATR): ν 3017, 1446, 1220 cm-1

; MS (EI) m/z

(%): 264 (M+

+ 1, 7%), 263 (M+, 35%), 235 (14), 234 (62), 220 (41), 207 (18),

193 (18), 131 (10), 130 (100), 118 (15), 105 (62), 103 (22), 79 (10), 77 (25);

HRMS (ESI): m/z calcd for C17H17N3 263.1422; found: 263.1414.


1-Benzyl-4,5-diphenyl-1H-1,2,3-triazole (30a):

301 white solid; m.p. 109-110 °C



MHz, CDCl3): δ 7.55-7.60 (m, 2H), 7.40-7.50

(m, 3H), 7.20-7.30 (m, 6H), 7.10-7.15 (m, 2H),

7.00-7.05 (m, 2H), 5.41 (s, 2H); 13

C NMR (75

MHz, CDCl3): δ 144.5, 135.3, 133.9, 130.9,

130.1 (2C), 129.6, 129.1 (2C), 128.7 (2C), 128.4 (2C), 128.1, 127.8, 127.7, 127.5

(2C), 126.7 (2C), 52.0; IR (ATR): ν 3058, 1449, 1246 cm-1

; MS (EI) m/z (%):

311 (M+, 17%), 193 (16), 192 (100), 165 (23), 91 (75), 89 (16).

1-Benzyl-4,5-bis(4-butylphenyl)-1H-

1,2,3-triazole (30b): pale yellow oil; tr=

19.3; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-7.50

(m, 2H), 7.20-7.25 (m, 5H), 7.00-7.10 (m,

6H), 5.39 (s, 2H), 2.67 (t, J = 7.6 Hz, 2H),

2.55 (t, J = 7.6 Hz, 2H), 1.50-1.70 (m,

4H), 1.25-1.45 (m, 4H), 0.97 (t, J = 7.3

Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); 13

C

NMR (75 MHz, CDCl3): δ 144.5, 144.4,

142.4, 135.5, 133.6, 129.9 (2C), 129.1

(2C), 128.6 (2C), 128.4 (2C), 128.0, 127.5 (2C), 126.5 (2C), 125.1, 51.9, 35.5,

35.3, 33.4, 33.3, 22.3 (2C), 14.0, 13.9; IR (ATR): ν 3030, 1455, 1245 cm-1

; MS

(EI) m/z (%): 423 (M+, 0%), 361 (16), 360 (69), 359 (24), 328 (13), 283 (18), 282

(20), 281 (72), 209 (13), 208 (18), 207 (100); Elemental analysis calcd. for

C29H33N3: C = 82.23; H = 7.85; N = 9.92; found: C = 82.26; H = 7.75; N = 9.89.

1-(3-Bromobenzyl)-4,5-diphenyl-1H-1,2,3-

triazole (30c): white solid; m.p. 70-73 °C



MHz, CDCl3): δ 7.35-7.60 (m, 6H), 7.20-7.30

(m, 3H), 7.10-7.15 (m, 4H), 6.97 (d, J = 7.7 Hz,

1H), 5.37 (s, 2H); 13


δ 144.6, 137.3, 133.8, 131.4, 130.7, 130.3,

130.0 (2C), 129.9, 129.3 (2C), 128.4 (2C),

301 D.-R. Hou, T.-C. Kuan, Y.-K. Li, R. Lee, K.-W. Huang, Tetrahedron 2010, 66, 9415-9420.


127.8, 127.6 (2C), 126.6 (2C), 126.2, 122.7, 51.4; IR (ATR): ν 3054, 1572, 1241

cm-1

; MS (EI) m/z (%): 391 (M+

+ 2, 6%), 389 (M+, 6%), 193 (15), 192 (100),

165 (28), 89 (15); Elemental analysis calcd. for C21H16BrN3: C = 64.63; H = 4.13;

N = 10.77; found: C = 64.65; H = 4.17; N = 10.69.

1-((2’-(Azidomethyl)-[1,1’-biphenyl]-2-yl)-4-

phenyl-1H-1,2,3-triazole (32): colorless oil; tr=

14.8; Rf= 0.7 (hexane/ethyl acetate: 1/1); 1H

NMR (300 MHz, CDCl3): δ 7.70-7.80 (m, 2H),

7.35-7.50 (m, 8H), 7.20-7.30 (m, 3H), 7.15-7.20

(m, 1H), 5.25-5.35 (m, 2H), 3.95-4.05 (m, 2H); 13

C NMR (75 MHz, CDCl3): δ 147.5, 139.1 (2C),

133.5, 132.9, 130.1, 129.9, 129.6, 128.9, 128.7

(2C), 128.6, 128.5, 128.4 (2C), 128.0, 125.5 (2C),

119.7, 52.3, 51.7; IR (ATR): ν 2092, 1242 cm-1

;

MS (EI) m/z (%): 194 (M+

- 172, 16%), 193 (100), 192 (28), 166 (14), 165 (56),

164 (10), 163 (10); Elemental analysis calcd. for C22H18N6: C = 72.11; H = 4.95;

N = 22.94; found: C = 72.12; H = 4.98; N = 22.98.

4-(4-Methoxyphenyl)-1-((2’-((4-phenyl-1H-

1,2,3-triazol-1-yl)methyl)-[1,1’-biphenyl]-2-

yl)methyl)- 1H-1,2,3-triazole (33): pale yellow

oil; Rf= 0.6 (hexane/ethyl acetate: 1/1); 1H NMR

(300 MHz, CDCl3): δ 7.70-7.75 (m, 2H), 7.60-

7.65 (m, 2H), 7.47 (s, 1H), 7.30-7.45 (m, 9H),

7.25-7.30 (m, 3H), 6.90-6.95 (m, 2H), 5.30-5.35

(m, 2H), 5.10-5.25 (m, 2H), 3.83 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 159.6, 147.4 (2C),

138.6 (2C), 133.3 (2C), 130.3, 130.1, 130.0,

129.9, 129.1, 128.8, 128.7 (2C), 128.6 (2C),

128.1, 126.9 (2C), 125.6 (2C), 123.0, 120.4,

119.5, 114.5, 114.2 (2C), 60.3, 55.3, 51.8; IR

(ATR): ν 1245 cm-1

; MS (EI) m/z (%): 499 (M+

+

1, 5%), 498 (M+, 14%), 339 (11), 325 (15), 324

(13), 309 (11), 295 (16), 294 (15), 292 (10), 283 (14), 282 (62), 180 (27), 179

(100), 178 (61), 166 (10), 165 (36), 146 (16), 133 (12), 132 (11), 116 (19), 89

(10); Elemental analysis calcd. for C31H26N6O: C = 74.68; H = 5.26; N = 16.86;

found: C = 74.69; H = 5.28; N = 16.87.


6. REACTIONS CATALYSED BY NANOPARTICLES OF PALLADIUM

6.1. SYNTHESIS OF DIARYLIODONIUM SALTS

Diphenyliodonium tetrafluoroborate (35a):227d

m-CPBA (5.120 g, 24 mmol)

was dissolved in CH2Cl2 (80 mL). To the solution was added iodobenzene (2.48

mL, 21.6 mmol) followed by slow addition of BF3·OEt2 (6.8 mL, 54.4 mmol) at

room temperature. The resulting yellow solution was stirred at room temperature

for 30 min and then cooled to 0 ºC and PhB(OH)2 (2.960 g, 24 mmol) was added.

After 15 min of stirring at room temperature, the crude mixture was applied on a

silica plug (20 g) and eluted with CH2Cl2 (2 x 100 mL) followed by

CH2Cl2/MeOH (2 x 100 mL). The latter solution was concentrated and diethyl

ether (40 mL) was added to the residue to induce precipitation. The solution was

allowed to stir for 15 min, and then the solid was filtered and washed several

times with diethyl ether and then dried in vacuo. White

solid; m.p. = 133-135 ºC (Et2O); 1H NMR (300 MHz,

DMSO-d6): δ 8.25 (d, J = 7.3 Hz, 4H), 7.68 (t, J = 7.4

Hz, 2H), 7.54 (t, J = 7.6 Hz, 4H); 13

C NMR (75 MHz,

DMSO-d6): δ 135.1 (4C), 132.0 (2C), 131.7 (4C), 116.4

(2C); 19

F NMR (282 MHz, DMSO-d6): δ -148.3 (dd, J =

2.3, 1.2 Hz), -148.2 (br. s); IR (KBr): ν 1559, 1471, 1443, 1287, 1167, 1053, 740

cm-1

.

The appropriate iodoarene (5 mmol) was added to a stirred solution of m-

CPBA (1.6 g, 7.5 mmol) in acetic anhydride (10 mL) and the solution was stirred

for 1 h at room temperature after which 1,3,5-triisopropyl benzene (1.32 mL, 6.5

mmol) was added and the solution cooled to 0 ºC. Tetrafluoroboric acid (50 %

aqueous, 1.25 mL, 10 mmol) was added over 15 min via syringe pump and the

solution stirred at 0 ºC for 30 min before being allowed to warm to rt. After 6 h

the solution was recooled to 0 ºC and water (100 mL) was slowly added with fast

stirring. The solution was extracted with CH2Cl2 (2 x 50 mL) and the combined

organic extracts dried (MgSO4) and evaporated. The pure iodonium

tetrafluoroborate salts were precipitated with Et2O from a concentrated solution

of hot CH2Cl2 and obtained by filtration followed by washed with generous

amounts of Et2O on the filter


p-Tolyl(2,4,6-trisopropylphenyl)iodonium

tetrafluoroborate (35b): white solid; m.p. =

189-191 ºC (Et2O); 1H NMR (300 MHz,

DMSO-d6): δ 7.82 (d, J = 8.4 Hz, 2H), 7.35 (d,

J = 8.2 Hz, 2H), 7.30 (s, 2H), 3.40 (heptet, J =

6.8 Hz, 2H), 2.97 (heptet, J = 6.8 Hz, 1H), 2.33

(s, 3H), 1.22 (app. t, J = 6.8 Hz, 18H); 13

C

NMR (75 MHz, DMSO-d6): δ 154.1, 151.1

(2C), 142.2, 134.0 (2C), 132.5 (2C), 124.5 (2C), 123.2, 111.3, 38.6 (2C), 33.3,

24.0 (4C), 23.5 (2C), 20.7; 19

F NMR (282 MHz, DMSO-d6): δ -148.3 (dd, J =

2.3, 1.2 Hz), -148.3 (br. s); IR (KBr): ν 1585, 1571, 1480, 1463, 1057, 1023, 998,

985 cm-1

; HRMS calcd. (%) for C22H30I: 421.1387; found: 421.1368.

o-Tolyl(2,4,6-trisiopropylphenyl)iodonium

tetrafluoroborate (35c): white solid; m.p. = 154-

155 ºC (Et2O); 1H NMR (300 MHz, DMSO-d6): δ

7.77 (d, J = 7.9 Hz, 1H), 7.50-7.60 (m, 2H), 7.25-

7.35 (m, 3H), 3.31 (heptet, J = 6.9 Hz, 2H), 2.98

(heptet, J = 6.9 Hz, 1H), 2.63 (s, 3H), 1.21 (2 x d,

J = 6.7 and 6.9 Hz respectively, 18H); 13

C NMR

(75 MHz, DMSO-d6): δ 154.2, 151.1 (2C), 140.4,

135.4, 132.3, 132.0, 129.6, 124.8 (2C), 123.0, 119.4, 38.9 (2C), 33.3, 24.4, 24.0

(4C), 23.5 (2C); 19

F NMR (282 MHz, DMSO-d6): δ -148.3 (br. s), -148.3 (dd, J =

2.3, 1.1 Hz); IR (KBr): ν 1586, 1572, 1560, 1467, 1426, 1058, 979 cm-1

; HRMS

calcd. (%) for C22H30I: 421.1387; found: 421.1368.

(4-Chlorophenyl)(2,4,6-

triisopropylphenyl)iodonium

tetrafluoroborate (35d):212b

white solid;

m.p. = 180-181 ºC (Et2O); 1H NMR (300

MHz, CDCl3): δ 7.64 (d, J = 8.9 Hz, 2H),

7.42 (d, J = 8.9 Hz, 2H), 7.20 (s, 2H), 3.26

(heptet, J = 6.7 Hz, 2H), 2.79 (heptet, J = 6.9

Hz, 1H), 1.29 (d, J = 7.0 Hz, 6H), 1.26 (d, J = 6.8 Hz, 12H); 13

C NMR (75 MHz,

CDCl3): δ 156.1, 152.7 (2C), 139.0, 133.9 (2C), 132.6 (2C), 125.5 (2C), 119.7,

108.6, 39.7 (2C), 32.4, 24.3 (4C), 23.6 (2C); 19

F NMR (282 MHz, CDCl3): δ -

146.8 (dd, J = 3.3, 1.6 Hz), -146.7 (br. s); IR (KBr): ν 1585, 1570, 1471, 1427,

1389, 1369, 1087, 1055, 1011, 817 cm-1

.


Bis(4-methoxyphenyl)iodonium tetrafluoroborate (35e): 227d

. m-CPBA (1.280

g, 6 mmol) was dissolved in CH2Cl2 (20 mL). To the solution was added 1-iodo-

4-methoxybenzene (1.264 g, 5.4 mmol). The mixture was placed then on a pre-

heated oil bath at 80 ºC and stirred for 10 min. The mixture was cooled at -78 ºC.

A 0 ºC cooled mixture of BF3·OEt2 (1.7 mL, 13.6 mmol) and 4-

methoxybenzeneboronic acid (912 mg, 6 mmol) in 20 mL of CH2Cl2 was added

dropwise. The resulting solution was stirred at -78 ºC for 30 min Then was

allowed to warm to room temperature and was applied on a silica plug (12 g) and

eluted with CH2Cl2 (2 x 50 mL) followed by CH2Cl2/MeOH (2 x 50 mL). The

latter solution was concentrated and diethyl ether (40 mL) was added to the

residue to induce precipitation. The solution was allowed to stir for 15 min, and

then the solid was filtered and washed several times with diethyl ether and then

dried in vacuo. Grey solid; m.p. = 177-180 ºC (Et2O); 1H NMR (300 MHz,

DMSO-d6): δ 8.13 (d, J = 9.1 Hz, 4H), 7.07

(d, J = 9.2 Hz, 4H), 3.80 (s, 6H); 13

C NMR

(75 MHz, DMSO-d6): δ 161.8 (2C), 136.8

(4C), 117.3 (4C), 105.9 (2C), 55.7 (2C); 19

F

NMR (282 MHz, DMSO-d6): δ -148.3 (dd, J

= 2.3, 1.1 Hz), -148.2 (br. s); IR (KBr): ν

1572, 1487, 1441, 1406, 1302, 1258, 1177, 1062, 1022, 825 cm-1

.

Phenyl(2,4,6-triisopropylphenyl)iodonium trifluoromethanesulfonate (35f):

227a 1,3,5-triisopropylbenzene (2.38 mL, 10 mmol) was added to a solution

of iodobenzene (1 mL ,9 mmol) and m-CPBA (2.64 g, 10 mmol) in CH2Cl2 (40

mL). The solution was cooled to 0ºC. Trifluoromethanesulfonic acid (1.31 mL,

15 mmol) was added dropwise over 5 min and the mixture allowed to slowly

warm to room temperature over 2 hours. The latter solution was concentrated and

diethyl ether (40 mL) was added to the residue to induce precipitation. The

solution was allowed to stir for 15 min, and then the solid was filtered and

washed several times with diethyl ether and then dried in vacuo. White solid;

m.p. = 169-170 ºC (Et2O); 1H NMR (300 MHz,

DMSO-d6): δ 7.93 (d, J = 7.3 Hz, 2H), 7.64 (t, J

= 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H), 7.32 (s,

2H), 3.35-3.45 (m, 2H), 2.90-3.05 (m, 1H), 1.15-

1.25 (m, 18H); 13

C NMR (75 MHz, DMSO-d6): δ

154.2, 151.2 (2C), 133.9 (2C), 131.9 (2C), 131.7,

124.6 (2C), 123.0, 114.9, 38.6 (2C), 33.3, 23.9

(4C), 23.4 (2C); 19

F NMR (282 MHz, DMSO-d6):

δ -148.3 (dd, J = 2.3, 1.2 Hz), -77.8 (br. s); IR (KBr): ν 1580, 1588, 1566, 1465,

1279, 1240, 1162, 1029, 881, 756 cm-1

.


Di-p-tolyliodonium trifluoromethanesulfonate (35g):227c

m-CPBA (285 mg,

1.65 mmol) and 1-iodo-4-methylbenzene (327 mg, 1.5 mmol) were dissolved in

CH2Cl2 (7 mL). Toluene (176 μL, 1.65 mmol) was added to the solution at room

temperature followed by dropwise addition of TfOH (2 equiv.). The reaction

mixture was stirred at room temperature during 10 minutes and subsequently

concentrated under vacuum. Et2O was added and the mixture was stirred at room

temperature for 10 minutes to precipitate out an off-white solid. To ensure

complete precipitation, the flask was stored in the freezer for at least 30 minutes

before the solid was filtered off, washed with Et2O

and dried under vacuum. Grey solid; m.p. = 121-

123 ºC (Et2O); 1H NMR (300 MHz, DMSO-d6): δ

8.05-8.10 (m, 4H), 7.30-7.35 (m, 4H), 2.33 (s,

6H); 13

C NMR (75 MHz, DMSO-d6): δ 142.4 (2C),

135.0 (4C), 132.3 (4C), 113.0 (2C), 20.8 (2C); IR

(ATR): ν 1481, 1242, 1156, 1024, 812, 796 cm-1

.

Bis(4-fluorophenyl)iodonium tetrafluoroborate (35h):236

m-CPBA (610 mg,

2.9 mmol) was dissolved in CH2Cl2 (10 mL). To the solution was added 1-fluoro-

4-iodobenzene (300 μL, 2.6 mmol) followed by slow addition of BF3·OEt2 (802

μL, 6.5 mmol) at room temperature. The resulting solution was stirred at room

temperature for 30 minutes and then cooled at 0 ºC, and 4-(fluorophenyl)boronic

acid (406 mg, 2.9 mmol) was added. After 15 min of stirring at room

temperature, the crude mixture was applied on a silica plug (20 g) and eluted

with CH2Cl2 (2 x 100 mL) followed by CH2Cl2/MeOH (2 x 100 mL). The latter

solution was concentrated and diethyl ether (40 mL) was added to the residue to

induce precipitation. The solution was allowed to stir for 15 min, and then the

solid was filtered and washed several times with diethyl ether and then dried in

vacuo. White solid; m.p. = 97-98 ºC (Et2O); 1H

NMR (300 MHz, DMSO-d6): δ 8.30-8.35 (m, 4H),

7.40-7.45 (m, 4H); 13

C NMR (75 MHz, DMSO-

d6): δ 164.0 (d, 1JC-F = 251.4 Hz, 2C), 138.0 (d,

3JC-

F = 9.0 Hz, 4C), 119.4 (d, 2JC-F = 22.8 Hz, 4C),

111.2 (2C); IR (ATR): ν 1576, 1479, 1232, 1034,

996, 827 cm-1

.


6.2. SYNTHESIS OF ARYLATED HETEROCYCLES


heterocycle 34 or 37 (0.5 mmol) in ethanol (1.5 mL) were added the

corresponding diaryliodonium tetrafluoroborate 35 (1.5 mmol) and PdO-Fe3O4

(180 mg, 10 mol% Pd). The mixture was stirred at 60 ºC for 24 h. The catalyst

was removed by a magnet and the solvent evaporated under reduced pressure.

The corresponding products 36 or 38 were usually purified by column

chromatography on silica gel (hexane/ethyl acetate).

3-Phenylbenzo[b]thiophene (36a):212b

colorless oil; 1H

NMR (300 MHz, CDCl3): δ 7.90-8.00 (m, 2H), 7.60-7.65

(m, 2H), 7.50-7.55 (m, 2H), 7.40-7.50 (m, 4H); 13

C NMR

(75 MHz, CDCl3): δ 140.7, 138.1, 137.9, 136.0, 128.7

(4C), 127.5, 124.4, 124.3, 123.4, 122.90, 122.90, IR (KBr):

ν 1600, 1524, 1484, 1442, 1425, 1348, 834 cm-1

; HRMS

calcd. (%) for C14H11S: 211.0581; found: 211.0573.

2-Phenylbenzofuran (36b):212b

white solid; m.p. =

122-124 ºC (hexane/ethyl acetate); 1H NMR (300

MHz, CDCl3): δ 7.85-7.90 (m, 2H), 7.55-7.60 (m,

1H), 7.52 (d, J = 8.1 Hz, 1H), 7.40-7.50 (m, 2H),

7.15-7.40 (m, 3H), 7.02 (d, J = 0.7 Hz, 1H); 13

C

NMR (75 MHz, CDCl3): δ 155.9, 154.9, 130.4, 129.2, 128.8 (2C), 128.5, 124.9

(2C), 124.2, 122.9, 120.9, 111.2, 101.3; IR (KBr): ν 1605, 1562, 1491, 1471,

1455, 1259, 1020 cm-1

.

Methyl 2-phenyl-1H-indole-7-carboxylate (36c):

white solid; m.p. = 72-74 ºC (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 10.11 (br s, 1H),

7.80-7.90 (m, 2H), 7.70-7.75 (m, 2H), 7.40-7.50

(m, 2H), 7.30-7.35 (m, 1H), 7.14 (t, J = 7.7 Hz,

1H), 6.85 (d, J = 2.4 Hz, 1H), 3.99 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 168.0, 139.0, 136.9,

131.9, 130.3, 129.0 (2C), 128.0, 126.1, 125.3 (2C), 124.2, 119.4, 112.2, 99.5,

51.9; IR (ATR): ν 3435, 1699, 1438, 1268 cm-1

; HRMS calcd. (%) for

C16H13NO2: 251.0946; found: 251.0951.


5-Fluoro-2-phenyl-1H-indole (36d):302

white

solid; m.p. = 175-177 ºC (hexane/ethyl acetate); 1H

NMR (300 MHz, CDCl3): δ 8.30 (br s, 1H), 7.60-

7.65 (m, 2H), 7.40-7.45 (m, 2H), 7.25-7.40 (m,

3H), 6.93 (m, 1H), 6.77 (dd, J = 2.0, 0.6 Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 158.2 (d, 1JC-F = 235.0 Hz), 139.6, 133.3, 132.0,

129.6 (d, 3JC-F = 10.4 Hz), 129.1 (2C), 128.0, 125.2 (2C), 111.5 (d,

3JC-F = 9.7

Hz), 110.6 (d, 2JC-F = 26.4 Hz), 105.4 (d,

2JC-F = 23.6 Hz), 100.0 (d,

4JC-F = 4.7

Hz); IR (ATR): ν 3434, 1624, 1586, 1472, 1457 cm-1

.

4-Bromo-2-phenyl-1H-indole (36e):303

white solid;

m.p. = 100-102 ºC (hexane/ethyl acetate); 1H NMR

(300 MHz, CDCl3): δ 8.40 (br s, 1H), 7.60-7.65 (m,

2H), 7.40-7.45 (m, 2H), 7.25-7.50 (m, 3H), 7.01 (t, J =

7.9 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H); 13

C NMR (75

MHz, CDCl3): δ 138.4, 136.8, 131.6, 130.0, 129.0

(2C), 128.1, 125.2 (2C), 123.1 (2C), 114.5, 110.0, 100.1; IR (ATR): ν 3443,

1597, 1568, 1456, 1452 cm-1

.

3-(p-Tolyl)benzo[b]thiophene (36f):212a

colourless oil; 1H

NMR (300 MHz, CDCl3): δ 7.85-8.95 (m, 2H), 7.48 (d, J =

8.0 Hz, 2H), 7.35-7.40 (m, 3H), 7.29 (d, J = 7.8 Hz, 2H),

2.43 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 140.7, 138.1,

138.0, 137.3, 133.1, 129.4 (2C), 128.6 (2C), 124.3, 124.2,

123.0, 122.94, 122.89, 21.2; IR (NaCl): ν 1532, 1495, 1456,

1425, 1344, 1060, 1021, 819 cm-1

.

2-(p-Tolyl)benzofuran (36g):304

white solid; m.p.

= 115-117 ºC (hexane/ethyl acetate); 1H NMR

(300 MHz, CDCl3): δ 7.75 (d, J = 7.9 Hz, 2H),

7.55 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H),

7.15-7.30 (4H, m), 6.94 (1H, s), 2.38 (3H, s); 13


156.2, 154.8, 138.6, 129.5 (2C), 129.3, 127.8, 124.9 (2C), 124.0, 122.8, 120.7,

111.1, 100.5, 21.4; IR (KBr): ν 1613, 1587, 1504, 1451, 1257, 1033, 801 cm-1

.

302 K. Funaki, T. Sato, S. Oi, Org. Lett. 2012, 14, 6186-6189. 303 V. Guilarte, M. P. Castroviejo, P. García-García, M. A. Fernández-Rodríguez, R. Sanz, J. Org.

Chem. 2011, 76, 3416-3437. 304 M. L. N. Rao, D. N. Jadhav, P. Dasgupta, Eur. J. Org. Chem. 2013, 781-788.


2-(o-Tolyl)benzofuran (36h):305

colorless oil; 1H

NMR (300 MHz, CDCl3): δ 7.75-7.90 (m, 1H), 7.58

(d, J = 6.7 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.15-

7.35 (m, 5H), 6.87 (s, 1H), 2.56 (s, 3H); 13

C NMR (75

MHz, CDCl3): δ 155.7, 154.4, 135.8, 131.2, 129.9,

129.2, 128.5, 128.2, 126.1, 124.2, 122.8, 120.9, 111.1, 105.1, 21.9; IR (NaCl): ν

1605, 1575, 1489, 1473, 1454, 1259, 1019, 921, 805 cm-1.

2-(4-Chlorophenyl)benzofuran (36i):304

white

solid; m.p. = 135-138 ºC (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 8.7

Hz, 2H), 7.55-7.60 (m, 1H), 7.45-7.50 (m, 1H),

7.40 (d, J = 8.8 Hz, 2H), 7.29 (td, J = 7.7, 1.6 Hz,

1H), 7.22 (td, J = 7.4, 1.2 Hz, 1H), 6.99 (d, J = 0.8 Hz, 1H); 13

C NMR (75 MHz,

CDCl3): δ 154.9, 154.8, 134.3, 129.05, 129.02 (2C), 128.98, 126.1 (2C), 124.5,

123.1, 121.0, 111.2, 101.7; IR (KBr): ν 1602, 1581, 1487, 1450, 1404, 1256,

1104, 1094, 1031, 1010, 836, 804 cm-1

.

2-(4-Methoxyphenyl)benzofuran (36j): 304

white solid; m.p. = 147-148 ºC (hexane/ethyl

acetate); 1H NMR (300 MHz, CDCl3): δ 7.78

(d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.1 Hz, 1H),

7.49 (d, J = 7.6 Hz, 1H), 7.15-7.30 (m, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.85 (s,

1H), 3.82 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 160.0, 156.0, 154.7, 129.5,

126.4 (2C), 123.7, 123.3, 122.8, 120.5, 114.2 (2C), 111.0, 99.7, 55.3; IR (KBr): ν

1610, 1593, 1505, 1453, 1440, 1248, 1180, 1023, 835, 799 cm-1

.

3-Phenylthiophene (38a):212b


(hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 7.60-

7.65 (m, 2H), 7.40-7.50 (m, 4H), 7.25-7.40 (m, 2H); 13

C

NMR (75 MHz, CDCl3): δ 142.4, 135.9, 128.8 (2C), 127.2,

126.4 (2C), 126.3, 126.2, 120.3; IR (ATR): ν 3059, 3033,

1597, 1530, 1493 cm-1

.

305 S. E. Denmark, R. C. Smith, W.-T. T. Chang, J. M. Muhuhi, J. Am. Chem. Soc. 2009, 131,

3104-3118.


3,4-Diphenylthiophene (38a’):212b

white solid; m.p. =

112-114 ºC (hexane/ethyl acetate); 1H NMR (300 MHz,

CDCl3): δ 7.31 (s, 2H), 7.15-7.25 (m, 10H); 13

C NMR

(75 MHz, CDCl3): δ 141.7 (2C), 136.5 (2C), 129.0 (4C),

128.1 (4C), 126.9 (2C), 124.0 (2C); IR (ATR): ν 3049,

3023, 1670, 1598, 1508 cm-1

.

2-Chloro-4-phenylthiopehene (38b): white solid; m.p. =


CDCl3): δ 7.50-7.55 (m, 2H), 7.35-7.45 (m, 2H), 7.30-7.35

(m, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 141.7, 135.1, 130.7, 128.9

(2C), 127.6, 126.1 (2C), 125.5, 118.5; IR (ATR): ν 3065,

3038, 1598, 1493 cm-1

; MS (EI) m/z (%): 196 (M+

+ 2, 37),

194 (M+, 100), 158 (9), 115 (39), 79 (9).

2-Bromo-4-phenylthiophene (38c):302

white solid; m.p. =


CDCl3): δ 7.50-7.55 (m, 2H), 7.35-7.40 (m, 2H), 7.30-7.35

(m, 3H); 13

C NMR (75 MHz, CDCl3): δ 142.8, 134.9,

129.2, 128.9 (2C), 127.6, 126.2 (2C), 121.4, 112.9; IR

(ATR): ν 3082, 3057, 1596, 1492, 1446 cm-1

.

3-Bromo-4-phenylthiophene (38d):306

white solid; m.p. =


CDCl3): δ 7.45-7.50 (m, 2H), 7.40-7.45 (m, 3H), 7.35 (d, J

= 3.5 Hz, 1H), 7.24 (d, J = 3.5 Hz, 1H); 13

C NMR (75 MHz,

CDCl3): δ 142.0, 135.1, 129.0 (2C), 128.2 (2C), 127.8,

124.0, 123.4, 111.0; IR (ATR): ν 3058, 3030, 1600, 1523,

1482 cm-1

.

306 I. Schnapperelle, T. Bach, ChemCatChem 2013, 5, 3232-3236.


4-Phenyl-2,2’-bithiophene (38e):307

pale brown solid;

m.p. = 72-74 ºC (hexane/ethyl acetate); 1H NMR (300

MHz, CDCl3): δ 7.55-7.65 (m, 2H), 7.44 (d, J = 1.4

Hz, 1H), 7.35-7.40 (m, 2H), 7.30-7.35 (m, 2H), 7.20-

7.25 (m, 2H), 7.02 (dd, J = 5.0, 3.7 Hz, 1H); 13

C NMR

(75 MHz, CDCl3): δ 142.9, 138.0, 137.3, 135.5, 128.8

(2C), 127.8, 127.3, 126.3 (2C), 124.5, 123.9, 122.9, 119.1; IR (ATR): ν 3063,

3029, 1596, 1491 cm-1

.

6.3. SYNTHESIS OF HALOETHERS

General Procedure: To a mixture of potassium carbonate (690 mg, 5

mmol) and the apropriate phenol (5 mmol), was added acetone (5 mL). To the

stirring mixture was added the required benzyl bromide (2.5 mmol) followed by

heating to 50 ºC overnight. The reaction mixture was then cooled to room

temperature, poured into a solution of NaOH (2M), and extracted three times

with ether. The organic extracts were dried over MgSO4 and concentrated under

reduced pressure. Purification was done by column chromatography using

hexane/ethyl acetate (9:1) mixtures to afford the haloethers 39.

1-Bromo-2-(phenoxymethyl)benzene (39a):308

white

solid; m.p. = 39-40 ºC (hexane/ethyl acetate); 1H NMR

(300 MHz, CDCl3): δ 7.55-7.60 (m, 2H), 7.25-7.35 (m,

3H), 7.15-7.20 (m, 1H), 6.95-7.00 (m, 3H), 5.14 (s,

2H); 13

C NMR (75 MHz, CDCl3): δ 158.4, 136.4,

132.6, 129.5 (2C), 129.1, 128.8, 127.5, 122.2, 121.2,

114.9 (2C), 69.3; IR (KBr): ν 1597, 1585, 1570, 1497, 1482, 1447, 1437, 1379,

1303, 1245, 1171, 1154, 1056, 1044, 1024, 750 cm-1

.

1-Bromo-2-((4-

methoxyphenoxy)methyl)benzene (39b):309

colorless oil; 1H NMR (300 MHz, CDCl3): δ

7.56 (app. t, J = 7.3 Hz, 2H), 7.32 (dd, J = 7.5,

1.2 Hz, 1H), 7.17 (dd, J = 7.9, 1.7 Hz, 1H), 6.92

(d, J = 9.3 Hz, 2H), 6.84 (d, J = 9.3 Hz, 2H),

307 S. Varello, S. T. Handy, Synthesis 2009, 1, 138-142. 308 C.-L. Sun, Y.-F. Gu, W.-P. Huang, Z.-J. Shi, Chem. Commun. 2011, 47, 9813-9815. 309 L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581-590.


5.08 (s, 2H), 3.76 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 154.2, 152.6, 136.6,

132.6, 129.1, 128.9, 127.5, 122.3, 115.9 (2C), 114.7 (2C), 70.1, 55.7; IR (NaCl):

ν 1593, 1570, 1506, 1465, 1455, 1441, 1381, 1230, 1108, 1042, 823, 749 cm-1

.

1-Bromo-2-((p-tolyloxy)methyl)benzene (39c):308

colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.50-

7.60 (m, 2H), 7.30 (dd, J = 7.6, 0.8 Hz, 1H), 7.15

(dd, J = 7.7, 1.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H),

6.87 (d, J = 8.5 Hz, 2H), 5.09 (s, 2H), 2.28 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 156.3, 136.6, 132.5,

130.4, 129.9 (2C), 129.1, 128.8, 127.5, 122.2, 114.7 (2C), 69.5, 20.5; IR (NaCl):

ν 1586, 1570, 1510, 1441, 1380, 1297, 1239, 1044, 1025, 817, 747 cm-1

.

1-Bromo-2-((4-chlorophenoxy)methyl)benzene (39d):

308 colorless oil;

1H NMR (300 MHz, CDCl3):

δ 7.58 (dd, J = 7.9, 1.1 Hz, 1H), 7.51 (1H, d, J = 7.7

Hz, 1H), 7.32 (td, J = 7.6, 1.1 Hz, 1H), 7.24 (d, J =

9.1 Hz, 2H), 7.18 (td, J = 7.9, 1.7 Hz, 1H), 6.90 (d,

J = 9.0 Hz, 2H), 5.10 (s, 2H); 13

C NMR (75 MHz,

CDCl3): δ 157.0, 135.9, 132.7, 129.41 (2C), 129.36, 128.8, 127.6, 126.1, 122.3,

116.2 (2C), 69.7; IR (NaCl): ν 1599, 1493, 1439, 1291, 1249, 1174, 1096, 1044

cm-1

.

1-Bromo-2-((4-fluorophenoxy)methyl)benzene (39e):

308 pale yellow oil;

1H NMR (300 MHz,

CDCl3): δ 7.57 (dd, J = 7.9, 1.1 Hz, 1H), 7.52 (d, J

= 7.7 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.18

(td, J = 7.9, 1.7 Hz, 1H), 6.85-7.05 (m, 4H), 5.09 (s,

2H); 13


238.8 Hz), 154.6 (d, 4JC-F = 2.1 Hz), 136.1, 132.6, 129.3, 128.9, 127.6, 122.3,

116.0 (d, 3JC-F = 10.0 Hz, 2C), 115.9 (d,

2JC-F = 21.2 Hz, 2C), 70.1; IR (NaCl): ν

1602, 1571, 1505, 1469, 1440, 1381, 1298, 1247, 1220, 1097, 1044, 1025, 827

cm-1

; 19

F NMR (282 MHz, CDCl3): -123.3 (tt, 3JH-F = 8.0 Hz,

4JH-F = 4.5 Hz).

1-Bromo-2-((3-fluorophenoxy)methyl)benzene (39f):

309 pale yellow oil;

1H NMR (300 MHz,

CDCl3): δ 7.55-7.65 (m, 2H), 7.32 (td, J = 7.6, 1.2

Hz, 1H), 7.17 (td, J = 7.9, 1.7 Hz, 1H), 6.85-7.15


(m, 4H), 5.18 (s, 2H); 13

C NMR (75 MHz, CDCl3): δ 152.9 (d, 1JC-F = 246.0 Hz),

146.5 (d, 3JC-F = 10.6 Hz), 135.9, 132.5, 129.3, 128.8, 127.6, 124.3 (d,

3JC-F = 3.9

Hz), 122.1, 121.7 (d, 2JC-F = 6.9 Hz), 116.3 (d,

2JC-F = 18.2 Hz), 115.7 (d,

4JC-F =

1.6 Hz), 70.6; IR (NaCl): ν 1611, 1595, 1490, 1440, 1280, 1263, 1166, 1136,

1027, 748 cm-1

; 19

F NMR (282 MHz, CDCl3): -133.9 (m).

1-Bromo-2-((2-fluorophenoxy)methyl)benzene (39g):

310 colorless oil;

1H NMR (300 MHz, CDCl3): δ

7.58 (dd, J = 7.9, 1.1 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H),

7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.15-7.25 (m, 2H), 6.60-

6.80 (m, 3H), 5.11 (s, 2H); 13


δ 163.6 (d, 1JC-F = 245.5 Hz), 159.8 (d,

2JC-F = 10.9 Hz),

135.8, 132.7, 130.3 (d, 3JC-F = 10.0 Hz), 129.4, 128.9, 127.6, 122.3, 110.6 (d,

4JC-

F = 2.9 Hz), 108.1 (d, 3JC-F = 21.4 Hz), 102.8 (d,

2JC-F = 24.9 Hz), 69.6;

19F NMR

(282 MHz, CDCl3): -111.4 (m); IR (NaCl): ν 1591, 1571, 1504, 1456, 1442,

1380, 1313, 1284, 1260, 1206, 1110, 1024, 745 cm-1

.

1-Bromo-2-(phenoxymethyl)-4-

(trifluoromethyl)benzene (39h): white solid; m.p.

= 70-72 ºC (hexane/ethyl acetate); 1H NMR (300

MHz, CDCl3): δ 7.86 (s, 1H), 7.67 (d, J = 8.3 Hz,

1H), 7.41 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 7.8 Hz,

2H), 6.95-7.05 (m, 3H), 5.10 (s, 2H); 13

C NMR (75

MHz, CDCl3): δ 158.1, 137.7, 133.1, 130.2 (q, 2JC-F = 33.0 Hz), 129.6 (2C),

125.74 (q, 3JC-F = 3.8 Hz), 125.73, 125.5 (q,

3JC-F = 3.8 Hz), 123.8 (q,

1JC-F =

272.4 Hz), 121.6, 114.9 (2C), 68.8; 19

F NMR (282 MHz, CDCl3): -62.6 (s); IR

(KBr): ν 1600, 1586, 1498, 1484, 1459, 1449, 1417, 1342, 1304, 1248, 1173,

1154, 1128, 1060, 1022, 904, 831 cm-1

.

2-Bromo-4-fluoro-1-(phenoxymethyl)benzene (39i): colorless oil;

1H NMR (300 MHz, CDCl3): δ

7.52 (dd, J = 8.6, 6.0 Hz, 1H), 7.25-7.35 (m, 3H),

6.90-7.10 (m, 4H), 5.08 (s, 2H); 13

C NMR (75 MHz,

CDCl3): δ 161.9 (d, 1JC-F = 250.6 Hz), 158.3, 132.3

(d, 4JC-F = 3.5 Hz), 130.0 (d,

3JC-F = 8.5 Hz), 129.6

310 J. Barluenga, F. J. Fañanás, R. Sanz, Y. Fernández, Chem. Eur. J. 2002, 8, 2034-2046.


(2C), 122.4 (d, 3JC-F = 9.6 Hz), 121.3, 119.9 (d,

2JC-F = 24.6 Hz), 114.9 (2C),

114.7 (d, 2JC-F = 21.0 Hz), 68.8;

19F NMR (282 MHz, CDCl3): -112.5 (m); IR

(NaCl): ν 1601, 1496, 1457, 1304, 1238, 1171, 1054, 1032, 812, 752 cm-1

.

6.4. SYNTHESIS OF SUBSTITUTED BENZO[c]CHROMENE

DERIVATIVES

General Procedure: To a stirred solution of the corresponding arene 39

(0.5 mmol) in N,N-dimethylacetamide (2 mL) were added KOAc (98 mg, 1

mmol) and PdO-Fe3O4 (180 mg, 10 mol% Pd). The mixture was stirred at 140 ºC

for 48 h. The catalyst was removed by a magnet and the mixture was quenched

with water and extracted with AcOEt (3 x 10 mL). The organic phases were dried

over MgSO4, followed by evaporation under reduced pressure to remove the

solvent. The corresponding products 40 were usually purified by column

chromatography on silica gel (hexane/ethyl acetate).

6H-Benzo[c]chromene (40a):311

colorless oil; 1H NMR (300

MHz, CDCl3): δ 7.71 (dd, J = 7.7, 1.6 Hz, 1H), 7.67 (d, J =

7.5 Hz, 1H), 7.34 (td, J = 7.6, 1.4 Hz, 1H), 7.20-7.25 (m, 2H),

7.11 (d, J = 7.4 Hz, 1H), 7.03 (td, J = 7.5, 1.3 Hz, 1H), 6.98

(dd, J = 8.1, 1.2 Hz, 1H), 5.09 (s, 2H); 13

C NMR (75 MHz,

CDCl3): δ 154.8, 131.4, 130.1, 129.4, 128.4, 127.6, 124.6,

123.3, 122.9, 122.1, 122.0, 117.3, 68.4; IR (NaCl): ν 2842, 1607, 1594, 1487,

1440, 1245, 1198, 1018, 755 cm-1

.

2-Methoxy-6H-benzo[c]chromene (40b):309

colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J = 7.5 Hz, 1H),

7.38 (td, J = 7.6, 1.3 Hz, 1H), 7.25-7.30 (m with td at 7.30, J

= 7.4, 1.2 Hz, 2H), 7.16 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 8.8

Hz, 1H), 6.81 (dd, J = 8.8, 2.9 Hz, 1H), 5.07 (s, 2H), 3.84 (s,

3H); 13

C NMR (75 MHz, CDCl3): δ 154.8, 148.9, 131.9,

130.2, 128.4, 127.8, 124.7, 123.6, 122.1, 118.0, 115.0,

108.3, 68.6, 55.8; IR (NaCl): ν 2835, 1614, 1572, 1496, 1450, 1219, 1194, 1049,

1037 cm-1

.

311 M. Parisien, D. Valette, K. Fagnou, J. Org. Chem. 2005, 70, 7578-7584.


2-Methyl-6H-benzo[c]chromene (40c):308

colorless oil; 1H

NMR (300 MHz, CDCl3): δ 7.68 (d, J = 7.6 Hz, 1H), 7.53

(d, J = 1.7 Hz, 1H), 7.36 (td, J = 7.6, 1.1 Hz, 1H), 7.26 (td, J

= 7.4, 1.2 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.03 (dd, J =

8.2, 2.0 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.08 (s, 2H), 2.36

(s, 3H); 13

C NMR (75 MHz, CDCl3): δ 152.6, 131.6, 131.3,

130.3, 130.1, 128.3, 127.5, 124.6, 123.6, 122.6, 121.9, 117.1, 68.5, 20.9; IR

(NaCl): ν 2840, 1607, 1593, 1573, 1498, 1449, 1246, 1199, 1021 cm-1

.

2-Chloro-6H-benzo[c]chromene (40d):308

colorless oil; 1H

NMR (300 MHz, CDCl3): δ 7.67 (d, J = 2.5 Hz, 1H), 7.64

(d, J = 7.5 Hz, 1H), 7.38 (td, J = 7.6, 1.4 Hz, 1H), 7.30 (td, J

= 7.4, 1.3 Hz, 1H), 7.17 (dd, J = 8.6, 2.5 Hz, 1H), 7.14 (d, J

= 7.5 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.10 (s, 2H); 13

C

NMR (75 MHz, CDCl3): δ 153.3, 131.3 (2C), 129.1, 128.6,

128.3, 127.1, 124.7, 124.3, 123.1, 122.1, 118.7, 68.5; IR

(NaCl): ν 2842, 1591, 1487, 1445, 1408, 1249, 1259, 1247, 1200, 1093, 1020,

815 cm-1

.

2-Fluoro-6H-benzo[c]chromene (40e): 308

colorless oil; 1H

NMR (300 MHz, CDCl3): δ 7.60 (d, J = 7.7 Hz, 1H), 7.35-

7.40 (m, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.3 Hz,

1H), 6.85-6.95 (m, 2H), 5.08 (s, 2H); 13

C NMR (75 MHz,

CDCl3): δ 158.2 (d, 1JC-F = 238.9 Hz), 150.7 (d,

4JC-F = 2.0

Hz), 131.5, 129.4 (d, 4JC-F = 2.2 Hz), 128.5, 128.3, 124.7,

124.1 (d, 3JC-F = 8.1 Hz), 122.2, 118.4 (d,

3JC-F = 8.3 Hz),

115.8 (d, 2JC-F = 23.5 Hz), 109.6 (d,

2JC-F = 24.2 Hz), 68.5;

19F NMR (282 MHz,

CDCl3): -121.5; IR (NaCl): ν 2842, 1619, 1577, 1495, 1448, 1426, 1285, 1247,

1173, 1021, 902, 867, 815 cm-1

.

1-Fluoro-6H-benzo[c]chromene (40f)

and 3-Fluoro-6H-benzo[c]chromene

(40f’) (45:55): colorless oil; 1H NMR

(300 MHz, CDCl3): δ 8.04 (d, J = 7.8

Hz, 1H), 7.67 (dd, J = 8.6, 6.4 H, 1H),

7.63 (d, J = 7.8 Hz, 1H), 7.25-7.45 (m,

4H), 7.10-7.20 (m, 3H), 6.65-6.85 (m,

4H), 5.12 (s, 2H), 5.07 (s, 2H); 13


247.3 Hz), 160.7 (d, 1JC-F = 250.7 Hz), 156.6 (d,

3JC-F = 6.6 Hz), 156.0 (d,

3JC-F =


12.1 Hz), 131.5, 130.4, 129.5, 129.0 (d, 3JC-F = 11.1 Hz), 128.5, 127.9 (d,

4JC-F =

1.1 Hz), 127.5, 127.0 (d, 4JC-F = 3.0 Hz), 126.3, 126.2, 124.7, 124.6, 124.4 (d,

3JC-

F = 10.0 Hz), 121.7, 119.2 (d, 4JC-F = 3.2 Hz), 113.1 (d,

4JC-F = 3.2 Hz), 112.3 (d,

3JC-F = 13.7 Hz), 109.7 (d,

2JC-F = 23.3 Hz), 109.3 (d,

2JC-F = 22.0 Hz), 104.8 (d,

2JC-F = 24.3 Hz), 68.8, 68.7;

19F NMR (282 MHz, CDCl3): 115.1 (m), -111.5

(m); IR (NaCl): ν 2842, 1618, 1591, 1508, 1486, 1459, 1440, 1262, 1144, 1039,

1025, 966, 793, 763 cm-1

;HRMS calcd. (%) for C13H8FO: 199.0559; found:

199.0551.

4-Fluoro-6H-benzo[c]chromene (40g): colorless oil; 1H

NMR (300 MHz, CDCl3): δ 7.68 (d, 3JH-H = 7.5 Hz, 1H),

7.49 (dt, 3JH-H = 7.8 Hz,

5JH-F = 1.3 Hz, 1H), 7.39 (td,

3JH-H

= 7.4 Hz, 4JH-H = 1.3 Hz, 1H), 7.31 (td,

3JH-H = 7.4 Hz,

4JH-H

= 1.3 Hz, 1H), 7.17 (d, 3JH-H = 7.4 Hz, 1H), 7.04 (ddd,

3JH-F

= 10.1 Hz, 3JH-H = 8.1 Hz,

4JH-H = 1.6 Hz, 1H), 6.97 (td,

3JH-H = 8.0 Hz,

4JH-F = 5.1 Hz, 1H), 5.19 (s, 2H);

13C NMR

(75 MHz, CDCl3): δ 152.1 (d, 1JC-F = 245.5 Hz), 142.6 (d,

2JC-F = 11.5 Hz), 131.1,

129.3 (d, 3JC-F = 3.2 Hz), 128.6, 128.2, 125.4 (d,

4JC-F = 2.1 Hz), 124.8, 122.3,

121.6 (d, 3JC-F = 7.2 Hz), 118.4 (d,

4JC-F = 3.5 Hz), 115.9 (d,

2JC-F = 18.2 Hz),

68.7; 19

F NMR (282 MHz, CDCl3): -136.0 (ddd, 3JH-F = 10.2 Hz,

4JH-F = 5.2 Hz,

5JH-F = 1.1 Hz); IR (NaCl): ν 2843, 1617, 1593, 1575, 1488, 1467, 1438, 1299,

1279, 1258, 1221, 1014, 900, 753 cm-1

. HRMS calcd. (%) for C13H8FO:

199.0559; found: 199.0559.

8-(Trifluoromethyl)-6H-benzo[c]chromene (40h):312

white solid; m.p. = 68-70 ºC (hexane/ethyl acetate); 1H

NMR (300 MHz, CDCl3): δ 7.77 (d, J = 9.0 Hz, 1H),

7.74 (dd, J = 8.0, 1.5 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H),

7.41 (s, 1H), 7.30 (td, J = 7.8, 1.5 Hz, 1H), 7.08 (td, J =

7.6, 1.2 Hz, 1H), 7.02 (dd, J = 8.1, 0.9 Hz, 1H), 5.14 (s,

2H); 13

C NMR (75 MHz, CDCl3): δ 155.1, 133.7, 131.8, 130.7, 129.5 (q, 2JC-F =

32.6 Hz), 125.3 (q, 3JC-F = 3.8 Hz), 124.1 (q,

1JC-F = 272.1 Hz), 123.8, 122.4,

122.3, 121.7 (q, 3JC-F = 3.8 Hz), 121.6, 117.6, 68.0;

19F NMR (282 MHz, CDCl3):

-62.5; IR (NaCl): ν 2851, 1607, 1483, 1424, 1333, 1246, 1164, 1076, 757 cm-1

.

312 D. W. Manley, R. T. McBurney, P. Miller, J. C. Walton, J. Org. Chem. 2014, 79, 1386-1398.


9-Fluoro-6H-benzo[c]chromene (40i):313

colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.63 (dd,

3J = 7.7 Hz,

4J

= 1.5 Hz, 1H), 7.35 (dd, 3JH-F = 9.9 Hz,

4J = 2.5 Hz,

1H), 7.20-7.30 (m, 1H), 6.90-7.15 (m, 4H), 5.07 (s, 2H); 13


Hz), 154.7, 132.3 (d, 3JC-F = 8.3 Hz), 130.1, 127.0 (d,

4JC-F = 2.9 Hz), 126.2 (d,

3JC-F = 8.5 Hz), 123.5, 122.3, 122.1 (d,

4JC-F = 2.5 Hz),

117.5, 114.3 (d, 2JC-F = 22.1 Hz), 109.0 (d,

2JC-F = 23.2 Hz), 67.9;

19F NMR (282

MHz, CDCl3): δ -113.5 (m); IR (NaCl): ν 2846, 1598, 1574, 1504, 1455, 1422,

1246, 1180, 1040, 1015, 757 cm-1

.

6.5. SYNTHESIS OF ACRYLATES

General Procedure: To a solution of the corresponding 2-

hydroxybenzaldehyde (5 mmol) in THF (30 mL) was added ethyl 2-

(diethoxyphosphoryl)acetate (1.03 mL, 5.2 mmol) and DBU (0.77 mL, 5.1

mmol). The solution was stirred at room temperature overnight. The resulting

mixture was quenched with water and extracted with AcOEt (3 × 5 mL). The

organic phases were dried over MgSO4, followed by evaporation under reduced

pressure to remove the solvent. The corresponding products 41 were usually

purified by column chromatography on silica gel (hexane/ethyl acetate).

(E)-Ethyl 3-(2-hydroxyphenyl)acrylate (41a):235

white

solid; m.p. = 83-86 ºC (hexane/ethyl acetate); tr= 13.9;

Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,

CDCl3): δ 8.02 (d, J = 16.2 Hz, 1H), 7.45-7.50 (m, 1H),

7.20-7.25 (m, 1H), 6.85-6.95 (m, 3H), 6.62 (d, J = 16.2

Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13

C NMR (75 MHz,

CDCl3): δ 168.0, 155.6, 140.9, 131.4, 129.2, 121.6, 120.5, 118.1, 116.4, 60.8,

14.3; IR (ATR): ν 3375, 1675, 1601, 1459, 1249, 1036 cm-1

; MS (EI) m/z (%):

192 (M+, 7), 147 (15), 146 (69), 118 (100), 91 (20), 90 (18), 89 (21).

(E)-Ethyl 3-(5-fluoro-2-hydroxyphenyl)acrylate (41b): white solid; m.p. = 114-115 ºC (hexane/ethyl

acetate); 1H NMR (300 MHz, CDCl3): δ 8.03 (d, J =

15.7 Hz, 1H), 7.10-7.20 (m, 2H), 6.94 (ddd, 3JH-H =

8.8 Hz, 3JH-F = 7.8 Hz,

4JH-H = 8.8 Hz, 1H), 6.82 (dd,

313 H. Xie, F. Lin, Q. Lei, W. Fang, Organometallics 2013, 32, 6957-6868.


3JH-H = 8.9 Hz,

4JH-F = 4.6 Hz, 1H), 6.59 (d, J = 16.2 Hz, 1H), 4.30 (q, J = 7.1 Hz,

2H), 1.35 (t, J = 7.1 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 168.5, 156.7 (d, 1JC-F

= 238.4 Hz), 151.7 (d, 4JC-F = 1.9 Hz), 139.8 (d,

4JC,F = 2.2 Hz), 122.6 (d,

3JC-F =

7.5 Hz), 119.1, 118.1 (d, 2JC-F = 23.5 Hz), 117.4 (d,

3JC-F = 8.0 Hz), 114.3 (d,

2JC-F

= 23.3 Hz), 61.0, 14.2; 19

F NMR (282 MHz, CDCl3): -123.9 (m); IR (KBr): ν

3431, 1685, 1629, 1508, 1445, 1372, 1335, 1264, 1199 cm-1

.

(E)-Ethyl 3-(3,5-di-tert-butyl-2-

hydroxyphenyl)acrylate (41c):236

pale yellow

solid; m.p. = 120-122 ºC (hexane/ethyl acetate); Rf=


CDCl3): δ 8.09 (d, J = 15.8 Hz, 1H), 7.36 (d, J = 2.4

Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 6.44 (d, J = 15.8

Hz, 1H), 5.84 (br s, 1H), 4.27 (q, J = 7.1 Hz, 2H),

1.44 (s, 9H), 1.33 (t, J = 7.1 Hz, 3H), 1.30 (s, 9H); 13


167.5, 151.4, 142.7, 140.6, 136.5, 126.6, 122.3, 121.8, 118.7, 60.7, 34.8, 34.3,

31.4 (3C), 29.9 (3C), 14.3; IR (ATR): ν 1684, 1621, 1471, 1441, 1289, 1186 cm-

1; MS (EI) m/z (%): 304 (M

+, 7), 244 (16), 243 (100).

(E)-Ethyl 3-(5-bromo-2-hydroxy-3-

methoxyphenyl)acrylate (41d): white solid; m.p. =

97-99 ºC (hexane/ethyl acetate); tr= 16.5; Rf= 0.3


CDCl3): δ 7.85 (d, J = 16.2 Hz, 1H), 7.22 (d, J = 2.2

Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.55 (d, J = 16.2

Hz, 1H), 6.11 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.91

(s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 167.1, 147.4,

144.3, 137.9, 123.0, 122.2, 120.3, 114.8, 111.5, 60.5, 56.4, 14.3; IR (ATR): ν

1734, 1701, 1630, 1359, 1260, 1172 cm-1

; MS (EI) m/z (%): 302 (M+

+ 2, 18),

300 (M+, 21), 281 (18), 257 (17), 256 (100), 255 (24), 254 (98), 226 (16), 208

(69), 148 (16), 133 (13), 105 (27), 77 (15), 76 (11); HRMS calcd. (%) for

C12H13BrO4: 299.9997; found: 299.9990.

6.6. SYNTHESIS OF 2H-CHROMEN-2-ONE DERIVATIVES

General Procedure: To a stirred solution of the corresponding acrylate

41 (0.25 mmol) in ethanol (0.75 mL) were added the corresponding

diaryliodonium salt 35 (2 equiv) and PdO-Fe3O4 (25 mg, 2.5 mol% Pd). The

mixture was stirred at 80 ºC for 5 h. The catalyst was removed by a magnet and


the solvent was evaporated under reduced pressure. The corresponding products

42 were usually purified by column chromatography on silica gel (hexane/ethyl

acetate).

4-Phenyl-2H-chromen-2-one (42a):236

white solid; m.p.

= 98-100 ºC (hexane/ethyl acetate); tr= 16.1; Rf= 0.4

(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3):

δ 7.35-7.60 (m, 8H), 7.20-7.30 (m, 1H), 6.38 (s, 1H); 13

C

NMR (75 MHz, CDCl3): δ 160.7, 155.6, 154.2, 135.2,

131.9, 129.6, 128.8 (2C), 128.4 (2C), 127.0, 124.1, 118.9,

117.3, 115.1; IR (KBr): ν 1737, 1607, 1558, 1444, 1367,

1247, 1181, 1115, 941, 884, 773, 744, 699 cm-1

; MS (EI)

m/z (%): 222 (M+, 100), 221 (M

+ - 1, 50), 194 (89), 166 (11), 165 (69), 164 (13),

163 (10), 139 (11); HRMS calcd. (%) for C15H11O2: 223.0759; found: 223.0762.

4-(4-Fluorophenyl)-2H-chromen-2-one (42b):236

white


(300 MHz, CDCl3): δ 7.57 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H),

7.40-7.50 (m, 4H), 7.20-7.30 (m, 3H), 6.37 (s, 1H); 13

C

NMR (75 MHz, CDCl3): δ 163.5 (d, 1JC-F = 250.2 Hz),

160.5, 154.6, 154.1, 132.0, 131.2 (d, 4JC-F = 3.5 Hz), 130.4

(d, 3JC-F = 8.4 Hz, 2C), 126.7, 124.2, 118.9, 117.4, 116.1

(d, 2JC-F = 21.8 Hz, 2C), 115.3; IR (ATR): ν 1724, 1605,

1507, 1190, 1158, 943, 840, 830 cm-1

; MS (EI) m/z (%):

241 (M+

+ 1, 11), 240 (M+, 72), 239 (10), 213 (15), 212 (100), 207 (27), 184 (13),

183 (82).

4-(4-Methoxyphenyl)-2H-chromen-2-one (42c):236

white solid; m.p. = 123-126 ºC (hexane/ethyl acetate); 1H

NMR (300 MHz, CDCl3): δ 7.50-7.60 (m, 2H), 7.35-7.45

(m, 3H), 7.20-7.30 (m, 1H), 7.00-7.05 (m, 2H), 6.35 (s,

1H), 3.90 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 160.9,

160.8, 155.3, 154.2, 131.8, 129.9 (2C), 127.5, 127.0,

124.1, 119.2, 117.3, 114.6, 114.3 (2C), 55.4; IR (KBr): ν

1731, 1605, 1509, 1451, 1367, 1296, 1245, 1176, 1030,

929, 831, 752 cm-1

; HRMS calcd. (%) for C16H13O3:

253.0865; found: 253.0863.


4-(4-Chlorophenyl)-2H-chromen-2-one (42d):236

white


(300 MHz, CDCl3): δ 7.50-7.60 (m, 3H), 7.35-7.45 (m, 4H),

7.15-7.30 (m, 1H), 6.36 (s, 1H); 13

C NMR (75 MHz,

CDCl3): δ 160.4, 154.4, 154.2, 136.0, 133.6, 132.1, 129.8

(2C), 129.2 (2C), 126.7, 124.3, 118.7, 117.4, 115.4; IR

(KBr): ν 1733, 1606, 1557, 1482, 1445, 1404, 1365, 1253,

1191, 1093, 945, 842, 750 cm-1

; HRMS calcd. (%) for

C15H10O2Cl: 257.0369; found: 257.0371.

4-(o-Tolyl)-2H-chromen-2-one (42e):236

colorless oil; 1H

NMR (300 MHz, CDCl3): δ 7.53 (ddd, J = 8.6, 7.2, 1.6 Hz,

1H), 7.35-7.45 (m, 2H), 7.30-7.35 (m, 2H), 7.15-7.20 (m,

2H), 7.07 (dd, J = 7.9, 1.6 Hz, 1H), 6.32 (s, 1H), 2.16 (s,

3H); 13

C NMR (75 MHz, CDCl3): δ 160.8, 156.1, 153.8,

135.3, 134.7, 131.9, 130.5, 129.2, 128.4, 126.9, 126.1,

124.3, 119.4, 117.1, 115.7, 19.7; IR (KBr): ν 1731, 1604,

1564, 1483, 1451, 1365, 1276, 1254, 929 cm-1

; HRMS

calcd. (%) for C16H13O2: 237.0916; found: 237.0908.

6-Fluoro-4-phenyl-2H-chromen-2-one (42f):314

white


(300 MHz, CDCl3): δ 7.50-7.60 (m, 3H), 7.35-7.50 (m, 3H),

7.20-7.30 (m, 1H), 7.10-7.20 (m, 1H), 6.42 (s, 1H); 13

C

NMR (75 MHz, CDCl3): δ 160.2, 158.6 (d, 1JC-F = 243.9

Hz), 154.7 (d, 4JC-F = 2.7 Hz), 150.3 (d,

4JC-F = 2.0 Hz),

134.6, 129.9, 129.0 (2C), 128.2 (2C), 119.9 (d, 3JC-F = 8.6

Hz), 119.3 (d, 2JC-F = 24.5 Hz), 118.8 (d,

3JC-F = 8.4 Hz),

116.0, 112.5 (d, 2JC-F = 25.2 Hz);

19F NMR (282 MHz, CDCl3): δ -116.9 (m); IR

(KBr): ν 1732, 1564, 1481, 1446, 1428, 1360, 1263, 1247, 1179, 971, 826 cm-1

;

HRMS calcd. (%) for C15H10O2F: 241.0665; found: 241.0668.

314 J. Wu, L. Zhang, Y. Luo, Tetrahedron Lett. 2006, 47, 6747-6750.


6,8-Di-tert-butyl-4-phenyl-2H-chromen-2-one (42g):

236 white solid; m.p. = 181-183 ºC (hexane/ethyl

acetate); Rf= 0.4 (hexane/ethyl acetate: 4/1); 1H NMR

(300 MHz, CDCl3): δ 7.61 (d, J = 2.3 Hz, 1H), 7.50-

7.55 (m, 3H), 7.40-7.45 (m, 2H), 7.32 (d, J = 2.3 Hz,

1H), 6.35 (s, 1H), 1.56 (s, 9H), 1.26 (s, 9H); 13

C NMR

(75 MHz, CDCl3): δ 160.6, 156.8, 150.9, 146.1, 137.5,

136.1, 129.4, 128.7 (2C), 128.4 (2C), 127.1, 121.5,

118.6, 114.4, 35.2, 34.7, 31.3 (3C), 30.0 (3C); IR

(ATR): ν 1720, 1568, 1362, 1250, 869, 766, 704 cm-1

; MS (EI) m/z (%): 334

(M+, 22), 320 (23), 319 (100), 207 (55).

6-Bromo-8-methoxy-4-phenyl-2H-chromen-2-one (42h): white solid; m.p. = 181-183 ºC (hexane/ethyl


7.40-7.45 (m, 2H), 7.20 (d, J = 2.3 Hz, 1H), 7.16 (d, J =

2.3 Hz, 1H), 6.40 (s, 1H), 3.98 (s, 3H); 13

C NMR (75

MHz, CDCl3): δ 159.4, 154.8, 148.3, 143.1, 134.8,

129.9, 129.0 (2C), 128.3 (2C), 120.7, 120.6, 116.8,

116.5, 116.4, 56.6; IR (ATR): ν 1726, 1554, 1461,

1443, 1358, 1259, 1209, 1167, 1085, 865, 699 cm-1

; MS (EI) m/z (%): 332 (M+

+

2, 91), 331 (M+

+ 1, 19), 330 (M+, 92), 304 (32), 302 (35), 281 (29), 208 (22),

207 (100), 163 (12), 152 (83), 151 (24), 150 (15), 102 (17), 76 (23), 73 (10);

HRMS calcd. (%) for C16H11BrO3: 329.9892; found: 329.9883.

6-Fluoro-4-(4-methoxyphenyl)-2H-chromen-2-one (42i):

315 white solid; m.p. = 162-164 ºC (hexane/ethyl

acetate); 1H NMR (300 MHz, CDCl3): δ 7.35-7.45 (m

with d at 7.40, J = 8.8 Hz, 3H), 7.20-7.30 (m, 2H), 7.06

(d, J = 8.8 Hz, 2H), 6.39 (s, 1H), 3.90 (s, 3H); 13

C NMR

(75 MHz, CDCl3): δ 161.0, 160.5, 158.6 (d, 1JC-F =

243.4 Hz), 154.5 (d, 4JC-F = 2.7 Hz), 150.3 (d,

4JC-F = 2.0

Hz), 129.8 (2C), 126.9, 120.1 (d, 3JC-F = 8.5 Hz), 119.2

(d, 2JC-F = 24.5 Hz), 118.8 (d,

3JC-F = 8.4 Hz), 115.5,

114.5 (2C), 112.6 (d, 2JC-F = 25.2 Hz), 55.4;

19F NMR (282 MHz, CDCl3): δ -

117.1 (m); IR (KBr): ν 1718, 1610, 1565, 1510, 1478, 1431, 1361, 1253, 1176,

315 Y. Luo, J. Wu, Tetrahedron Lett. 2009, 50, 2103-2105.


1120, 1036, 824 cm-1

; HRMS calcd. (%) for C16H12O3F: 271.0770; found:

271.0758.

6,8-Di-tert-butyl-4-(4-fluorophenyl)-2H-chromen-2-

one (42j): white solid; m.p. = 112-114 ºC (hexane/ethyl

acetate); tr= 18.0; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 2.3 Hz, 1H),

7.40-7.50 (m, 2H), 7.20-7.30 (m, 3H), 6.33 (s, 1H), 1.56

(s, 9H), 1.26 (s, 9H); 13


163.3 (d, 1JC-F = 250.0 Hz), 160.4, 155.7, 150.9, 146.2,

137.7, 132.1 (d, 4JC-F = 3.1 Hz), 130.4 (d,

3JC-F = 8.3 Hz,

2C), 127.3, 121.2, 118.6, 115.9 (d, 2JC-F = 21.8 Hz, 2C),

114.6, 35.3, 34.8, 31.3 (3C), 30.0 (3C); IR (ATR): ν

1727, 1601, 1507, 1223 cm-1

; MS (EI) m/z (%): 330

(M+, 23), 338 (23), 337 (100); HRMS calcd. (%) for C23H25FO2: 352.1839;

found: 352.1830.

6-Bromo-4-(4-fluorophenyl)-8-methoxy-2H-

chromen-2-one (42k): white solid; m.p. = 178-180 ºC

(hexane/ethyl acetate); tr= 19.1; Rf= 0.3 (hexane/ethyl

acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.40-7.45

(m, 2H), 7.25-7.30 (m, 2H), 7.21 (d, J = 2.0 Hz, 1H),

7.11 (d, J = 2.0 Hz, 1H), 6.39 (s, 1H), 3.98 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 163.6 (d, 1JC-F = 250.7 Hz),

159.2, 153.7, 148.3, 143.1, 130.7 (d, 4JC-F = 3.5 Hz),

130.3 (d, 3JC-F = 8.4 Hz, 2C), 120.6, 120.3, 116.9, 116.6,

116.5, 116.2 (2C, d, 2JC-F = 21.9 Hz), 56.6; IR (ATR): ν

1719, 1601, 1558, 1507, 1262, 1091, 835 cm-1

; MS (EI) m/z (%): 351 (M+

+ 3,

18), 350 (M+

+ 2, 100), 349 (M+

+ 1, 21), 348 (M+, 99), 323 (10), 322 (45), 321

(10), 320 (43), 279 (10), 277 (12), 184 (14), 181 (11), 171 (11), 170 (94), 169

(22), 120 (21), 85 (19); HRMS calcd. (%) for C16H10BrFO3: 347.9797; found:

347.9786.


4-(p-Tolyl)-2H-chromen-2-one (42l):236

pale yellow solid;

m.p. = 108-110 ºC (hexane/ethyl acetate); tr= 16.8; Rf= 0.4


7.50-7.60 (m, 2H), 7.35-7.45 (m, 5H), 7.20-7.25 (m, 1H),

6.36 (s, 1H), 2.46 (s, 3H); 13


160.8, 155.7, 154.1, 139.9, 132.2, 131.8, 129.5 (2C), 128.4

(2C), 127.0, 124.0, 119.0, 117.3, 114.8, 21.3; IR (ATR): ν

3068, 1727, 1605, 1189, 940 cm-1

; MS (EI) m/z (%): 237

(M+

+ 1, 10), 236 (M+, 92), 235 (M

+ - 1, 26), 221 (54), 209

(17), 208 (100), 207 (25), 179 (14), 178 (30), 176 (10), 165 (35), 152 (13), 89

(11), 76 (10), 63 (10).

6-Bromo-8-methoxy-4-(p-tolyl)-2H-chromen-2-one (42m): white solid; m.p. = 186-188 ºC (hexane/ethyl


7.15-7.30 (m, 2H), 6.38 (s, 1H), 3.98 (s, 3H), 2.46 (s,

3H); 13

C NMR (75 MHz, CDCl3): δ 159.5, 154.9,

148.3, 143.1, 140.1, 131.9, 129.7 (2C), 128.3 (2C),

120.9, 120.7, 116.8, 116.4, 116.1, 56.6, 21.4; IR (ATR):

ν 1726, 1558, 1460, 1261, 1091 cm-1

; MS (EI) m/z (%):

347 (M+

+ 3, 24), 346 (M+

+ 2, 100), 345 (M+

+ 1, 17),

344 (M+, 95), 329 (13), 318 (32), 316 (36), 222 (12), 207 (22), 194 (10), 166

(35), 165 (56), 164 (13), 163 (10), 139 (10), 115 (16); HRMS calcd. (%) for

C17H13BrO3: 344.0048; found: 344.0029.

6.7. SYNTHESIS OF CINNAMATE DERIVATIVES

General Procedure: To a stirred solution of the corresponding α,β-

unsaturated ester 43 (0.25 mmol) in ethanol (0.75 mL), was added the

corresponding diaryliodonium salt 35 (2 equiv) and PdO-Fe3O4 (25 mg, 2.5

mol% Pd). The mixture was stirred at 80 ºC for 5 h. The catalyst was removed by

a magnet and the solvent was evaporated under reduced pressure. The

corresponding products 44 were usually purified by bulb-to-bulb distillation.


Ethyl cinnamate (44a):316

colorless oil; tr= 11.2; Rf= 0.3


7.69 (d, J = 16.0 Hz, 1H), 7.50-7.55 (m, 2H), 7.35-7.40 (m,

3H), 6.43 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H),

1.33 (t, J = 7.1 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 166.9, 144.5, 134.4,

130.1, 128.8 (2C), 127.9 (2C), 118.2, 60.4, 14.2; IR (ATR): ν 1707, 1637, 1450,

1165, 1036, 765 cm-1

; MS (EI) m/z (%): 176 (M+, 31), 148 (13), 147 (16), 132

(11), 131 (100), 103 (44), 102 (12), 77 (28), 51 (10).

Ethyl 3,3-diphenylacrylate (44b):317

brown oil; tr= 14.5;

Rf= 0.6 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,

CDCl3): δ 7.20-7.40 (2m, 2H and 8H respectively), 6.36 (s,

1H), 4.05 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.1 Hz, 3H); 13

C

NMR (75 MHz, CDCl3): δ 166.1, 156.4, 140.8, 139.0, 129.3, 129.1 (2C), 128.3

(2C), 128.2 (2C), 128.0, 127.8 (2C), 117.5, 60.0, 13.9; IR (ATR): ν 1719, 1617,

1574 cm-1

; MS (EI) m/z (%): 253 (M+

+ 1, 15), 252 (M+, 83), 251 (M

+ - 1, 18),

223 (15), 211 (28), 208 (12), 207 (73), 180 (45), 179 (60), 178 (100), 177 (16),

176 (21), 165 (20), 152 (27), 151 (13), 105 (18), 77 (18).

(E/Z)-Methyl 3-phenyl-3-(p-tolyl)acrylate (44c):225

pale yellow oil; tr= 15.0/15.1; Rf= 0.6 (hexane/ethyl


7.40 (m, 18H), 6.35 (s, 1H), 6.32 (s, 1H), 3.63 (s,

3H), 3.60 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 166, 157.4, 157.1, 141.1, 139.7, 139.0, 138.1, 137.9,

135.7, 129.4, 129.1 (2C), 129.0 (4C), 128.6 (2C), 128.4 (2C), 128.3 (2C), 128.8

(2C), 128.1, 128.0, 127.8 (2C), 116.4, 115.8, 51.2 (2C), 21.3, 21.2; IR (ATR): ν

1721, 1608, 1509, 1492, 1263, 1160, 1150, 815 cm-1

; MS (EI) m/z (%): 253 (M+

+ 1, 17), 252 (M+, 100), 251 (M

+ - 1, 35), 222 (16), 221 (97), 194 (13), 193 (29),

192 (14), 191 (19), 189 (15), 179 (16), 178 (57), 165 (17), 115 (23).

316 B. Zhang, C. Lu, W. Li, Z. Cui, D. Chen, F. Cao, F. Miao, L. Zhou, Chem. Pharm. Bull. 2015,

63, 255-262. 317 S. K. Guchhait, G. Priyadarshani, J. Org. Chem. 2015, 80, 6342-6349.


(E/Z)-Methyl 3-(4-methoxyphenyl)-3-

phenylacrylate (44d):318

pale yellow oil; tr=

16.0/16.2; Rf= 0.5 (hexane/ethyl acetate: 4/1); 1H

NMR (300 MHz, CDCl3): δ 7.15-7.40 (m, 14H),

6.91 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H),

6.32 (s, 1H), 6.28 (s, 1H), 3.85 (s, 3H), 3.81 (s,

3H), 3.64 (s, 3H), 3.60 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 166.6 (2C), 160.8,

159.8, 157.1, 156.9, 153.9, 141.5, 139.0, 133.1, 130.9 (2C), 129.8 (2C), 129.4

(2C), 129.0 (2C), 128.6 (2C), 128.3 (2C), 128.1 (2C), 127.9 (2C), 116.2, 114.6,

113.8, 113.2, 55.4, 55.2, 51.2 (2C); IR (ATR): ν 2843, 1719, 1601, 1509, 1247,

1160, 1147, 1031, 831 cm-1

; MS (EI) m/z (%): 269 (M+

+ 1, 12), 268 (M+, 100),

267 (M+

- 1, 13), 238 (13), 237 (71), 210 (16), 209 (15), 195 (11), 194 (16), 178

(10), 166 (16), 165 (50), 135 (21).

7. REACTIONS WITHOUT CATALYST

7.1. SYNTHESIS OF 3,5-DISUBSTITUTED ISOXAZOLES

General Procedure: To a stirred solution of the corresponding aldehyde 2

(2 mmol) in ChCl:urea (1:2) (1 mL) were added hydroxylamine hydrochloride

(138 mg, 2 mmol) and sodium hydroxide (80 mg, 2 mmol). The resulting mixture

was stirred at 50 ºC during one hour. After that N-chlorosuccinimide (400 mg, 3

mmol) was added to the mixture and it reacted during three hours at 50ºC. Then,

the corresponding alkyne 5 (2 mmol) was added, and the mixture reacted during

four hours at 50ºC, after this time the reaction was quenched with water and



product 45 was usually purified by column chromatography on silica gel

(hexane/ethyl acetate).

3,5-Diphenylisoxazole (45a):248g

white solid; m.p. =

117-120 ºC (hexane/ethyl acetate); tr= 16.4; Rf= 0.5


CDCl3): δ 7.80-7.90 (m, 4H), 7.45-7.50 (m, 6H),

6.83 (s, 1H); 13

C NMR (75 MHz, CDCl3): δ 170.4,

163.0, 130.2, 130.0, 129.1, 129.0 (2C), 128.9 (2C),

318 Z. She, Y. Shi, Y. Huang, Y. Cheng, F. Song, J. You, Chem. Commun. 2014, 50, 13914-13916.


127.4, 126.8 (2C), 125.8 (2C), 97.5; IR (ATR): ν 3050, 1593, 1572 cm-1

; MS (EI)

m/z (%): 222 (M+

+ 1, 10), 221 (M+, 61), 220 (16), 144 (15), 105 (100), 89 (10),

77 (51), 51 (13).

3-(4-Chlorophenyl)-5-phenylisoxazole (45b):

248f pale yellow solid; m.p. = 112-113 ºC



CDCl3): δ 7.80-7.90 (m, 4H), 7.45-7.55 (m, 5H),

6.83 (s, 1H); 13


170.7, 162.0, 136.0, 130.4, 129.2 (2C), 129.0 (2C), 128.1 (2C), 127.6, 127.3,

125.8 (2C), 97.3; IR (ATR): ν 1488, 1092 cm-1

. MS (EI) m/z (%): 257 (M+

+ 2,

17), 256 (M+

+ 1, 10), 255 (M+, 53), 105 (100), 77 (35).

5-Phenyl-3-(p-tolyl)isoxazole (45c):252

white

solid; m.p. = 130-132 ºC (hexane/ethyl acetate);


NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 2H),

7.76 (d, J = 8.0 Hz, 2H), 7.45-7.50 (m, 3H), 7.29

(d, J = 8.0 Hz, 2H), 6.81 (s, 1H), 2.41 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 170.2, 162.9, 140.1, 130.1, 129.6 (2C), 129.0 (2C),

127.5, 126.7 (2C), 126.2, 125.8 (2C), 97.4, 21.4; IR (ATR): ν 1568, 1494 cm-1

.

MS (EI) m/z (%): 236 (M+

+ 1, 16), 235 (M+, 90), 234 (14), 220 (16), 207 (10),

158 (23), 105 (100), 77 (43).

5-Phenyl-3-(o-tolyl)isoxazole (45d):319

pale orange


NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 2H),

7.50-7.55 (m, 1H), 7.40-7.50 (m, 3H), 7.20-7.35 (m,

3H), 6.67 (s, 1H), 2.51 (s, 3H); 13

C NMR (75 MHz,

CDCl3): δ 169.4, 163.6, 136.8, 131.0, 130.1, 129.4,

129.3, 128.9 (2C), 128.7, 127.4, 125.9, 125.7 (2C), 100.1, 21.0; IR (ATR): ν

3061, 1614 cm-1

; MS (EI) m/z (%): 236 (M+

+ 1, 13), 235 (M+, 83), 234 (M

+ - 1,

94), 209 (13), 208 (22), 207 (100), 206 (11), 191 (14), 158 (35), 130 (34), 117

(12), 105 (48), 103 (10), 90 (10), 89 (12), 77 (48), 51 (11).

319 R. L. N. Harris, J. L. Huppatz, Aust. J. Chem. 1977, 30, 2225-2240.


3-Cyclohexyl-5-phenylisoxazole (45e):248a

pale

yellow solid; m.p. = 52-54 ºC (hexane/ethyl

acetate); tr = 16.0; Rf = 0.5 (hexane/ethyl acetate:

4/1); 1H NMR (300 MHz, CDCl3): δ 7.75-7.80 (m,

2H), 7.40-7.45 (m, 3H), 6.4 (s, 1H), 2.75-2.85 (m,

1H), 2.00-2.05 (m, 2H), 1.75-1.85 (m, 3H), 1.25-

1.55 (m, 5H); 13

C NMR (75 MHz, CDCl3): δ 169.3, 169.0, 129.9, 128.9 (2C),

127.8, 125.7 (2C), 97.8, 36.0, 32.1 (2C), 26.0 (2C), 25.9; IR (ATR): ν 2927,

2852, 1447 cm-1

; MS (EI) m/z (%): 227 (M+, 37), 226 (77), 208 (11), 207 (15),

199 (16), 198 (36), 186 (16), 185 (10), 173 (11), 172 (100), 159 (41), 150 (17),

122 (16), 105 (52), 94 (11), 91 (10), 82 (11), 81 (14), 80 (10), 77 (45), 67 (14),

56 (13), 55 (18), 54 (20), 51 (11).

5-Phenyl-3-(quinolin-2-yl)isoxazole (45f):


acetate); tr = 20.9; Rf = 0.6 (hexane/ethyl


8.25-8.30 (m, 2H), 8.15-8.20 (m, 1H), 7.90-

7.95 (m, 2H), 7.85 (m, 1H), 7.75-7.80 (m, 1H),

7.60-7.65 (m, 1H), 7.45-7.55 (m, 3H), 7.40 (s, 1H); 13


δ 170.6, 164.2, 148.7, 148.0, 136.9, 130.3, 129.9, 129.7, 129.0 (2C), 128.4,

127.7, 127.5, 127.3, 125.9 (2C), 119.1, 98.6. IR (ATR): ν 1591, 1573, 1562 cm-1

;

MS (EI) m/z (%): 273 (M+

+ 1, 18), 272 (M+, 100), 271 (18), 246 (19), 244 (21),

154 (14), 128 (53), 105 (31), 101 (11), 77 (19); HRMS calcd. (%) for C18H12N2O:

272.0950; found: 272.0941.

5-Phenyl-3-(thiophen-2-yl)isoxazole (45g):256a

pale orange solid; m.p. = 84-86 ºC (hexane/ethyl


4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.85 (m,

2H), 7.52 (dd, J = 3.6, 1.1 Hz, 1H), 7.45-7.50 (m,

3H), 7.43 (dd, J =5.1, 3.6 Hz, 1H), 7.14 (dd, J = 5.1, 3.6 Hz, 1H), 6.76 (s, 1H); 13

C NMR (75 MHz, CDCl3): δ 170.3, 158.1, 130.8, 130.3, 129.0 (2C), 127.6

(2C), 127.4, 127.2, 125.8 (2C), 97.5; IR (ATR): ν 3050, 1593, 1572 cm-1

; MS

(EI) m/z (%): 228 (M+

+ 1, 12), 227 (M+, 76), 105 (100), 77 (42).


5-(3-Chlorophenyl)-3-phenylisoxazole (45h):247



4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.90 (m,

3H), 7.70-7.75 (m, 1H), 7.40-7.50 (m, 5H), 6.86 (s,

1H); 13

C NMR (75 MHz, CDCl3): δ 168.9, 163.1, 135.1, 130.4, 130.2 (2C),

129.0, 129.0 (2C), 128.8, 126.8 (2C), 125.9, 123.9, 98.3; IR (ATR): ν 1561, 1079

cm-1

. MS (EI) m/z (%): 257 (M+

+ 2, 30), 256 (M+

+ 1, 20), 255 (M+, 78), 254

(28), 207 (11), 144 (35), 141 (20), 139 (100), 113 (13), 111 (30), 103 (34), 89

(10), 77 (20), 76 (10), 75 (18).

5-(4-Methoxyphenyl)-3-phenylisoxazole

(45i):252


(hexane/ethyl acetate); tr = 18.3; Rf = 0.5


MHz, CDCl3): δ 7.85-7.90 (m, 2H), 7.75-7.80

(m, 2H), 7.45-7.50 (m, 3H), 6.95-7.05 (m, 2H), 6.71 (s, 1H), 3.87 (s, 3H); 13

C

NMR (75 MHz, CDCl3): δ 170.4, 162.9, 161.1, 129.9, 129.3, 128.9 (2C), 127.4

(2C), 126.8 (2C), 120.3, 114.4 (2C), 96.1, 55.4; IR (ATR): ν 2839, 1613, 1465,

1248 cm-1

; MS (EI) m/z (%): 251 (M+, 82), 207 (21), 136 (12), 135 (100), 103

(26), 77 (14).

3-Phenyl-5-(pyridin-2-yl)isoxazole (45j):257

white

solid; m.p. = 78-80 ºC (hexane/ethyl acetate); tr =

15.9; Rf = 0.3 (hexane/ethyl acetate: 4/1); 1H NMR

(300 MHz, CDCl3): δ 8.70-8.75 (m, 1H), 7.80-8.00

(2m, 3H and 1H respectively), 7.45-7.50 (m, 3H),

7.35-7.40 (m, 1H), 7.28 (s, 1H); 13

C NMR (75 MHz, CDCl3): δ 169.9, 163.2,

150.0, 146.5, 137.2, 130.1, 128.9 (2C), 128.4, 126.8 (2C), 125.4, 120.9, 100.3; IR

(ATR): ν 3059, 1699, 1576, 1560 cm-1

; MS (EI) m/z (%): 223 (M+

+ 1, 14), 222

(M+, 100), 221 (M

+ - 1, 36), 194 (12), 193 (16), 145 (11), 144 (94), 116 (22), 103

(67), 78 (20), 77 (32), 76 (15), 51 (17).

5-Cyclohexyl-3-phenylisoxazole (45k):256c

pale


4/1); 1H NMR (300 MHz, CDCl3): δ 7.75-7.80 (m,

2H), 7.40-7.45 (m, 3H), 6.25 (d, J = 0.8 Hz, 1H),

2.70-2.85 (m, 1H), 2.10-2.15 (m, 2H), 1.80-1.85 (m,

2H), 1.25-1.55 (m, 6H); 13

C NMR (75 MHz, CDCl3): δ 178.4, 162.1, 129.7,


129.5, 128.8 (2C), 126.7 (2C), 97.0, 36.4, 31.2 (2C), 25.8, 25.7 (2C); IR (ATR):

ν 2928, 2853, 1596, 1577 cm-1

; MS (EI) m/z (%): 199 (M+

- 28, 30), 197 (99),

195 (100), 124 (16), 97 (10).

5-(4-Methoxyphenyl)-3-(p-

tolyl)isoxazole (45l):248h

white solid; m.p.

= 130-131 ºC (hexane/ethyl acetate); tr =

19.2; Rf = 0.3 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.75-7.80

(m, 4H), 7.28 (d, J = 7.9 Hz, 2H), 6.95-7.05 (m, 2H), 6.68 (s, 1H), 3.87 (s, 3H),

2.41 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 170.2, 162.9, 161.1, 140.0, 129.6

(2C), 127.4 (2C), 126.7 (2C), 126.4, 120.4, 114.4 (2C), 96.1, 55.4, 21.4; IR

(ATR): ν 1614, 1568, 1505, 1250, 1047 cm-1

; MS (EI) m/z (%): 266 (M+

+ 1, 11),

265 (M+, 53), 135 (100), 117 (14), 116 (10), 77 (8).

7.2. SYNTHESIS OF 3,5-DISUBSTITUTED ISOXAZOLINES


2 (2 mmol) in ChCl:urea (1:2) (1 mL) were added hydroxylamine hydrochloride

(138 mg, 2 mmol) and sodium hydroxide (80 mg, 2 mmol). The resulting mixture

was stirred at 50 ºC during one hour. After that N-chlorosuccinimide (400 mg, 3

mmol) was added to the mixture and it reacted during three hours at 50ºC. Then,

the corresponding alkene 46 (2 mmol) was added, and the mixture reacted during

four hours at 50ºC, after this time the reaction was quenched with water and



product 47 was usually purified by column chromatography on silica gel

(hexane/ethyl acetate).

3,5-Diphenyl-4,5-dihydroisoxazole (47a):255a

pale

yellow solid; m.p. = 67-69 ºC (hexane/ethyl


4/1); 1H NMR (300 MHz, CDCl3): δ 7.65-7.70 (m,

2H), 7.30-7.45 (m, 8H), 5.74 (dd, J = 11.0, 8.3 Hz,

1H), 3.78 (dd, J = 16.7, 11.0 Hz, 1H), 3.35 (dd, J = 16.7, 8.3 Hz, 1H); 13

C NMR

(75 MHz, CDCl3): δ 156.1, 140.9, 130.1, 129.4, 128.7 (4C), 128.2, 126.7 (2C),

125.8 (2C), 82.5, 43.2; IR (ATR): ν 3027, 1492, 1446 cm-1

; MS (EI) m/z (%):

224 (M+

+ 1, 13), 223 (M+, 40), 222 (11), 117 (12), 115 (17), 106 (70), 105 (87),

104 (67), 103 (37), 91 (12), 78 (23), 77 (100), 75 (13), 52 (13), 51 (42).


3-(4-Chlorophenyl)-5-phenyl-4,5-

dihydroisoxazole (47b):255a

white solid; m.p. =

117-119 ºC (hexane/ethyl acetate); tr = 17.6; Rf =


MHz, CDCl3): δ 7.60-7.65 (m, 2H), 7.30-7.40

(m, 7H), 5.75 (dd, J = 11.0, 8.4 Hz, 1H), 3.75 (dd, J = 16.6, 11.0 Hz, 1H), 3.31

(dd, J = 16.6, 8.4 Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 155.2, 140.6, 136.1,

129.0 (2C), 128.8 (2C), 128.3, 128.0, 127.9 (2C), 125.8 (2C), 82.8, 43.0; IR

(ATR): ν 1589, 1491 cm-1

; MS (EI) m/z (%): 259 (M+

+ 2, 27), 258 (M+

+ 1, 22),

257 (M+, 81), 256 (27), 240 (15), 192 (18), 153 (10), 151 (22), 137 (11), 115

(11), 111 (11), 106 (13), 105 (26), 104 (100), 103 (17), 91 (12), 78 (17), 77 (25),

75 (13), 51 (12).

5-Phenyl-3-(p-tolyl)-4,5-dihydroisoxazole

(47c):255a




CDCl3): δ 7.58 (d, J = 8.1 Hz, 2H), 7.30-7.40

(m, 5H), 7.21 (d, J =8.1 Hz, 2H), 5.72 (dd, J = 10.9, 8.2 Hz, 1H), 3.77 (dd, J =

16.6, 10.9 Hz, 1H), 3.33 (dd, J = 16.6, 8.2 Hz, 1H), 2.38 (s, 3H); 13

C NMR (75

MHz, CDCl3): δ 156.0, 141.0, 140.4, 129.4 (2C), 128.7 (2C), 128.2, 126.7 (2C),

126.6, 125.9 (2C), 82.4, 43.3, 21.4; IR (ATR): ν 3035, 1560, 1515 cm-1

; MS (EI)

m/z (%): 237 (M+, 73), 236 (20), 220 (11), 207 (29), 133 (13), 132 (17), 131 (13),

119 (15), 117 (45), 116 (20), 115 (18), 106 (100), 105 (98), 104 (50), 103 (17),

91 (31), 78 (36), 77 (99), 74 (20), 65 (13), 52 (12), 51 (44), 50 (24).

5-Phenyl-3-(thiophen-2-yl)-4,5-dihydroisoxazole

(47d):256a



CDCl3): δ 7.30-7.40 (m, 6H), 7.18 (d, J = 3.6 Hz,

1H), 7.00-7.05 (m, 1H), 5.72 (dd, J = 10.8, 8.4 Hz,

1H), 3.77 (dd, J = 16.5, 10.8 Hz, 1H), 3.33 (dd, J = 16.5, 8.4 Hz, 1H); 13

C NMR

(75 MHz, CDCl3): δ 151.9, 140.5, 131.9, 128.7 (2C), 128.4, 128.2 (2C), 127.3,

125.8 (2C), 82.7, 43.9; IR (ATR): ν 1671, 1438 cm-1

; MS (EI) m/z (%): 230 (M+

+ 1, 12), 229 (M+, 87), 212 (29), 166 (10), 165 (28), 125 (13), 123 (10), 115 (26),

109 (24), 107 (10), 106 (99), 105 (100), 104 (56), 103 (12), 78 (33), 77 (92), 74

(15), 52 (10), 51 (45).


5-(4-Chlorophenyl)-3-phenyl-4,5-

dihydroisoxazole (47e):255a

white solid; m.p. =

97-99 ºC (hexane/ethyl acetate); tr = 17.6; Rf =


MHz, CDCl3): δ 7.7-7.65 (m, 2H), 7.45-7.4 (m,

3H), 7.30-7.35 (m, 4H), 5.72 (dd, J = 11.0, 8.0 Hz, 1H), 3.79 (dd, J = 16.7, 11.0

Hz, 1H), 3.3 (dd, J = 16.7, 8.0 Hz, 1H); 13

C NMR (75 MHz, CDCl3): δ 156.0,

139.5, 134.0, 130.3, 129.2, 128.9 (2C), 128.8 (2C), 127.2 (2C), 126.8 (2C), 81.8,

43.2; IR (ATR): ν 3056, 1599, 1491, 1091 cm-1

; MS (EI) m/z (%): 259 (M+

+ 2,

14), 257 (M+, 38), 256 (15), 192 (10), 142 (21), 141 (37), 140 (95), 139 (100),

138 (88), 125 (10), 117 (16), 13 (18), 112 (14), 111 (52), 104 (13), 103 (41), 89

(10), 77 (40), 76 (16), 75 (38), 74 (19), 51 (23), 50 (27).

3-Phenyl-5-(pyridin-yl)-4,5-dihydroisoxazole

(47f):320

brown oil; tr = 16.2; Rf = 0.3 (hexane/ethyl


8.60 (m, 1H), 7.65-7.75 (m, 3H), 7.55-7.60 (m, 1H),

7.35-7.40 (m, 3H), 7.20-7.30 (m, 1H), 5.88 (dd, J =

11.1, 6.8 Hz, 1H), 3.86 (dd, J = 16.8, 11.1 Hz, 1H), 3.69 (dd, J = 16.8, 6.8 Hz,

1H); 13

C NMR (75 MHz, CDCl3): δ 159.6, 156.3, 149.1, 136.8, 129.9, 129.0,

128.5 (2C), 126.6 (2C), 122.7, 120.4, 82.2, 41.2; IR (ATR): ν 3057, 1590, 1570

cm-1

; MS (EI) m/z (%): 224 (M+, 5), 195 (21), 194 (86), 193 (100), 192 (12), 146

(13), 79 (15), 77 (11), 51 (10).

5-Pentyl-3-phenyl-4,5-dihydroisoxazole

(47g):321

yellow solid; m.p. = 36-38 ºC



CDCl3): δ 7.65-7.70 (m, 2H), 7.35-7.45 (m, 3H),

4.73 (dddd, J = 10.3, 8.2, 6.9, 6.0 Hz, 1H), 3.39

(dd, J = 16.4, 10.3 Hz, 1H), 2.96 (dd, J = 16.4, 8.2 Hz, 1H), 1.55-1.85 (m, 2H),

1.25-1.55 (m, 6H), 0.85-0.95 (m, 3H); 13

C NMR (75 MHz, CDCl3): δ 156.4,

129.9, 129.8, 128.6 (2C), 126.5 (2C), 81.5, 39.9, 35.3, 31.6, 25.2, 22.5, 13.4; IR

(ATR): ν 3051, 2920, 2854, 1446 cm-1

; MS (EI) m/z (%): 217 (M+, 17), 147 (13),

146 (100), 144 (11), 119 (16), 118 (58), 117 (20), 104 (26), 103 (36), 91 (17), 77

(45), 76 (18), 57 (26), 56 (22), 55 (14), 51 (14).

320 D. Maiti, P. K. Bhattacharya, Synlett 1998, 4, 385-386. 321 S. Auricchio, A. Ricca, Heterocycles 1988, 27, 2395-2402.


5-(4-Methoxybenzyl)-3-phenyl-4,5-

dihydroisoxazole (47h): white solid; m.p.

= 69-71 ºC (hexane/ethyl acetate); tr =

18.5; Rf = 0.3 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.65-7.70

(m, 2H), 7.40-7.45 (m, 3H), 7.20-7.25 (m, 2H), 6.85-6.90 (m, 2H), 4.90-5.05 (m,

1H), 3.82 (s, 3H), 3.33 (dd, J = 16.6, 10.2 Hz, 1H), 3.11 (dd, J = 13.9, 6.1 Hz,

1H), 3.06 (dd, J = 16.6, 7.8 Hz, 1H), 2.86 (dd, J = 13.9, 7.2 Hz, 1H); 13

C NMR

(75 MHz, CDCl3): δ 158.4, 156.4, 130.3 (2C), 129.9, 128.9, 128.6 (2C), 126.6

(2C), 114.0 (2C), 82.1, 55.3, 40.1, 39.3; IR (ATR): ν 3035, 2839, 1609, 1582,

1242, 1034 cm-1

; MS (EI) m/z (%): 267 (M+, 7), 122 (19), 121 (100), 91 (10), 78

(11), 77 (18). HRMS calcd. (%) for C17H17NO2: 267.1249; found: 267.1247.

5-(Bromomethyl)-3-(4-nitrophenyl)-4,5-

dihydroisoxazole (47i):322

pale yellow solid;

m.p. = 166-168 ºC (hexane/ethyl acetate); tr =

16.6; Rf = 0.2 (hexane/ethyl acetate: 4/1); 1H

NMR (300 MHz, CDCl3): δ 8.29 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H),

5.05-5.15 (m, 1H), 3.60-3.80 (m, 2H), 3.45-3.60 (m, 1H), 3.30-3.45 (m, 1H); 13

C

NMR (75 MHz, CDCl3): δ 154.7, 148.6, 135.0, 127.5 (2C), 124.0 (2C), 80.7,

44.7, 37.9; IR (ATR): ν 1574, 1515, 1336, 853, 693 cm-1

; MS (EI) m/z (%): 286

(M+

+ 2, 1), 284 (M+, 5), 207 (17), 148 (16), 128 (33), 117 (100), 105 (10), 77

(11), 76 (51), 64 (12).

7.3. SYNTHESIS OF β-AMINO ENONES

General Procedure: To a stirred solution of the corresponding isoxazole

45 (1 mmol) in CH3CN (20 mL), were added H2O (1 mmol) and Mo(CO)6 (0.5

mmol). The resulting mixture was stirred at 81 ºC during four hours. After this

time, the reaction was quenched with water and extracted with AcOEt (3 x 5

mL). The organic phases were dried over MgSO4, followed by evaporation under

reduced pressure to remove the solvent. The product 48 was usually purified by

column chromatography on silica gel (hexane/ethyl acetate).

322 N. Dorostkar-Ahmadi, M. Bakavoli, F. Moeinpour, A. Davoodnia, Spectrochim Acta A 2011,

79, 1375-1380.


(Z)-3-Amino-1,3-diphenylprop-2-en-1-one

(48a):270d



CDCl3): δ 10.43 (br s, 1H), 7.80-7.90 (m, 2H),

7.60-7.65 (m, 2H), 7.45-7.50 (m, 6H), 6.15 (s, 1H),

5.48 (br s, 1H); 13

C NMR (75 MHz, CDCl3): δ 190.1, 162.9, 140.3, 137.6, 131.0,

130.7, 129.0 (2C), 128.3 (2C), 127.2 (2C), 126.3 (2C), 91.8; IR (ATR): ν 3453,

3348, 1598, 1563 cm-1

; MS (EI) m/z (%): 223 (M+, 29), 222 (M

+ - 1, 100), 209

(11), 208 (10), 207 (68), 191 (11), 146 (22), 117 (11), 104 (11), 103 (16), 89

(11), 79 (10), 78 (27), 77 (15), 50 (12).

(Z)-3-Amino-3-(4-chlorodiphenyl)-1-

phenylprop-2-en-1-one (48b):248g

yellow oil;

tr = 18.7; Rf = 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 10.38 (br s,

1H), 7.90-7.95 (m, 2H), 7.55-7.60 (m, 2H),

7.40-7.50 (m, 5H), 6.11 (s, 1H), 5.42 (br s,

1H); 13

C NMR (75 MHz, CDCl3): δ 190.3, 161.4, 140.1, 136.7, 136.0, 131.2,

129.3 (2C), 128.3 (2C), 127.7 (2C), 127.2 (2C), 92.0; IR (ATR): ν 3454, 3342,

1595, 1557, 1523, 1475 cm-1

; MS (EI) m/z (%): 258 (M+

+ 2, 43), 257 (M+

+ 1,

49), 256 (M+, 100), 207 (20), 180 (27), 77 (13).

(Z)-3-Amino-1-(4-methoxyphenyl)-3-

phenylprop-2-en-1-one (6c):323

yellow oil; tr =

19.6; Rf = 0.4 (hexane/ethyl acetate: 1/1); 1H

NMR (300 MHz, CDCl3): δ 10.34 (br s, 1H),

7.90-7.95 (m, 2H), 7.60-7.65 (m, 2H), 7.45-

7.50 (m, 3H), 6.90-6.95 (m, 2H), 6.12 (s, 1H),

5.36 (br s, 1H), 3.86 (s, 3H); 13

C NMR (75 MHz, CDCl3): δ 189.2, 162.3, 162.0,

137.8, 133.0, 130.6, 129.1 (2C), 129.0 (2C), 126.3 (2C), 113.4 (2C), 91.5, 55.3;

IR (ATR): ν 3463, 3354, 2837, 1593, 1560, 1524, 1507 cm-1

; MS (EI) m/z (%):

253 (M+, 26), 252 (M

+ - 1, 100), 209 (10), 207(25).

323 X. Yu, L. Wang, M. Bao, Y. Yamamoto, Chem. Commun. 2013, 49, 2885-2887.


(Z)-3-Amino-1-cyclohexyl-3-phenylprop-2-en-1-

one (48d): yellow oil; tr = 16.5; Rf = 0.5


CDCl3): δ 9.98 (br s, 1H), 7.55-7.60 (m, 2H), 7.40-

7.45 (m, 3H), 5.47 (s, 1H), 5.20 (br s, 1H), 2.31 (tt,

J = 11.6, 3.4 Hz, 1H), 1.65-1.90 (m, 5H), 1.15-1.50 (m, 5H); 13

C NMR (75 MHz,

CDCl3): δ 203.8, 161.3, 137.6, 130.4, 128.9 (2C), 126.2 (2C), 93.6, 50.8, 29.8

(2C), 26.1 (2C); IR (ATR): ν 3342, 3171, 2924, 2850, 1603, 1572, 1524, 1485

cm-1

; MS (EI) m/z (%): 229 (M+, 12), 207 (60), 146 (100), 104 (20); HRMS

calcd. (%) for C15H19NO: 229.1466; found: 229.1473.

7.4. SYNTHESIS OF ISOXAZOLES FROM ETHYL 2-NITROACETATE

General Procedure: To a stirred solution of the corresponding ethyl 2-

nitroacetate (49, 0.5 mmol) in 1 mL of AcChCl:urea (1:2), was added the

corresponding alkyne 5 (0.5 mmol). The mixture was stirred at 81 ºC during four

hours. After this time, the reaction was quenched with water and extracted with

AcOEt (3 x 5 mL). The organic phases were dried over MgSO4, followed by

evaporation under reduced pressure to remove the solvent. The product 50 was

usually purified by column chromatography on silica gel (hexane/ethyl acetate).

Ethyl 5-phenylisoxazole-3-carboxylate (50a):263

pale

yellow solid; m.p. = 50-52 ºC (hexane/ethyl acetate); tr

= 14.1; Rf = 0.5 (hexane/ethyl acetate: 4/1); 1H NMR

(300 MHz, CDCl3): δ 7.80-7.85 (m, 2H), 7.45-7.50

(m, 3H), 6.93 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.45 (t,

J = 7.1 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 171.7,

160.0, 156.9 130.8, 129.1 (2C), 126.6, 125.9 (2C), 99.9, 62.2, 14.1; IR (ATR): ν

1728, 1480 cm-1

; MS (EI) m/z (%): 218 (M+

+ 1, 10), 217 (M+, 68), 172 (24), 145

(36), 105 (100), 78 (11), 77 (36), 51 (16).

Ethyl 5-(3-chlorophenyl)isoxazole-3-carboxylate

(50b):241a


acetate); tr = 12.1; Rf = 0.4 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 1H),

7.65-7.70 (m, 1H), 7.40-7.45 (m, 2H), 6.96 (s, 1H),

4.48 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H); 13

C

NMR (75 MHz, CDCl3): δ 170.2, 159.8, 157.0, 135.3, 130.8, 130.5, 128.2, 126.0,

124.0, 100.7, 62.3, 14.1; IR (ATR): ν 1721, 1247, 1081, 1020 cm-1

; MS (EI) m/z


(%): 253 (M+

+ 2, 28), 251 (M+, 69), 207 (25), 206 (31), 181 (11), 179 (29), 141

(29), 139 (100), 114 (12), 113 (17), 111 (23), 75 (24).

Ethyl 5-(m-tolyl)isoxazole-3-carboxylate (50c):

colorless oil; tr = 15.0; Rf = 0.4 (hexane/ethyl acetate:

4/1); 1H NMR (300 MHz, CDCl3): δ 7.60-7.65 (m,

1H), 7.61 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H),

7.29 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 4.47 (q, J = 7.1

Hz, 2H), 2.43 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H); 13


171.9, 160.1, 156.9, 139.0, 131.6, 129.0, 126.5 (2C), 123.1, 99.8, 62.2, 21.4,

14.2; IR (ATR): ν 1725, 1579, 1249, 1049 cm-1

; MS (EI) m/z (%): 232 (M+

+ 1,

14), 231 (M+, 91), 186 (21), 159 (14), 119 (100), 92 (12), 91 (32); HRMS calcd.

(%) for C13H13NO3: 231.0895; found: 231.0882.

Ethyl 5-(4-methoxyphenyl)isoxazole-3-

carboxylate (50d):241b


ºC (hexane/ethyl acetate); tr = 16.2; Rf = 0.3


CDCl3): δ 7.70-7.75 (m, 2H), 6.95-7.00 (m, 2H),

6.8 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.87 (s. 3H), 1.44 (t, J = 7.1 Hz, 3H); 13

C

NMR (75 MHz, CDCl3): δ 171.7, 161.5, 160.1, 156.9, 127.6 (2C), 119.4, 114.5

(2C), 98.5, 62.1, 55.4, 14.1; IR (ATR): ν 2839, 1726, 1609, 1508, 1243, 1024 cm-

1; MS (EI) m/z (%): 248 (M

+ + 1, 12), 247 (M

+, 78), 202 (14), 136 (10), 135

(100).

Ethyl 5-cyclohexylisoxazole-3-carboxylate

(50e):324

pale yellow oil; tr = 10.8; Rf = 0.5


CDCl3): δ 6.37 (d, J = 0.7 Hz, 1H), 4.43 (q, J = 7.1

Hz, 2H), 2.80-2.85 (m, 1H), 2.05-2.10 (m, 2H), 1.65-

1.85 (m, 4H), 1.35-1.50 (m, 7H); 13

C NMR (75 MHz, CDCl3): δ 179.7, 160.3,

156.1, 99.8, 62.0, 36.3, 31.0 (2C), 25.6, 25.5 (2C), 14.1; IR (ATR): ν 2929, 2855,

1730, 1588, 1229, 1020 cm-1

; MS (EI) m/z (%): 223 (M+, 20), 179 (12), 178 (76),

150 (37), 125 (18), 124 (95), 122 (14), 110 (16), 109 (20), 108 (19), 97 (17), 96

(69), 95 (16), 83 (32), 82 (10), 91 (30), 90 (19), 79 (11), 78 (10), 69 (18), 68

(100), 67 (17), 55 (48), 54 (15), 53 (13).

324 C. Mioskowski, S. D. L. Marin, M. Maruani, M. Gill, US Pat. 0199853A1, 2006.

CONCLUSIONS

255 Conclusions

From the results of these studies, we can conclude that magnetite can be

used as an adequate support showing reasonable stability and it can be easily

remove from the reaction media throught a magnetic decantation.

Furthermore, magnetite is a good support for the anchoring metal oxides,

including cobalt, copper, nickel and palladium. The protocol for the preparation

of these impregnated catalysts is very easy and reproducible.

Also, depending on the reaction conditions the catalyst could be recycled

several times without lose of their initial catalytic activity.

The applicability of these heterogeneous catalysts in reactions previously

reported with similar homogeneous catalysts seems to be factible in most cases,

without major changes.

BIOGRAPHY

259 Biography

I was born in Baza (Granada) on 15th March 1988.

I conducted my primary studies at school "Salesianos" and secundary

ones at I. E. S. "Barrachina" in Ibi (Alicante).

During 2006-2011, I realized the degree in Chemistry on the Science

Faculty at the University of Alicante.

In September 2011 I joined the research group of Prof. Ramón at the

Organic Chemistry Department of the University of Alicante, where I performed

the Máster in Medicinal Chemistry.

Since 2012 to the present, I have been working in my Doctoral Thesis.

Part of results are presented this manuscript.

Since December 2012, I hold a FPI grant from the Spanish Ministerio de

Economía y Competitividad (MICINN).

From 1st June 2014 to 1

st September 2014, I performed an internship at

presitigious research group of Prof. Dr. Silvia Díez-González, at the Imperial

College of London, working in click chemistry.

ACKNOWLEDGMENTS

263 Acknowledgments

I would like to thank all people and institutuions which helped and

permitted to reach the current situation, including the Spanish Ministerio de

Economía y Competitividad (MICINN, CTQ2011-24151 and fellowship) and

University of Alicante for their continuous economical support.

I would like to express my gratitude to all people who kindly welcomed

and helped me during my stay at the Imperial College in London. In particular,

Prof. Dr. Silvia Díez-González, thank you for your hospitality and the perfect

working atmosphere in the lab.

I am also very grateful to Dr. Rafael Cano, thank you for transmitting

your knowledge during my first time in the lab, when I was an absolut beginner,

for your patient and for all your advices.

Last but not least, I do not want to forget my family, my ‘little kid’, Xavi,

and my lab partners. Thank you for your patient and for all the good moments we

have lived together in the lab.

PROLOGUE 1

RESUMEN/SUMMARY/RESUM 5

PREFACE 11

GENERAL INTRODUCTION 15

1. MAGNETITE 17

1.1 SYNTHETIC METHODS 19

1.2 APPLICATIONS 20

2. MAGNETITE AS CATALYST SUPPORT 27

2.1 COATED CATALYST 27

2.2 GRAFTED CATALYST 29

2.3 COATED-GRAFTED CATALYST 30

2.4 CO-PRECIPITATION AND DUMBELL-LIKE

COMPOSITES

32

2.5 IMPREGNATED CATALYST 34

2.5.1 COBALT CATALYST 35

2.5.2 NICKEL CATALYST 36

2.5.3 COPPER CATALYST 37

2.5.4 PALLADIUM CATALYST 39

RESULTS 43

CHAPTER I. Reactions performed using nanoparticles of

impregnated Cobalt(II) Oxide on Magnetite

45

1. HYDROACYLATION REACTION OF

AZODICARBOXYLATES

47

1.1 INTRODUCTION 47

1.2 RESULTS 50

CHAPTER II. Reactions performed using nanoparticles of

impregnated Copper(II) Oxide on Magnetite

59

1. HOMOCOUPLING OF TERMINAL ALKYNES 61

1.1 INTRODUCTION 61

1.2 RESULTS 63

2. SYNTHESIS OF AROMATIC IMINES FROM

ALCOHOLS AND AMINES OR NITROARENES

71

2.1 INTRODUCTION 71

2.2 RESULTS 73

3. CROSS-DEHYDROGENATIVE COUPLING

REACTION IN DEEP EUTECTIC SOLVENTS

83

3.1 INTRODUCTION 83

3.2 RESULTS 86

4. SYNTHESIS OF BENZO[b]FURANS FROM ALKYNES

AND 2-HYDROXYARYLCARBONYL DERIVATIVES

98

4.1 INTRODUCTION 98

4.2 RESULTS 99

CHAPTER III. Reactions performed using the impregnated

bimetallic Nickel(II) Oxide/Copper(0) on

Magnetite

109

1. MULTICOMPONENT AZIDE-ALKYNE

CYCLOADDITION REACTION

111

1.1 INTRODUCTION 111

1.2 RESULTS 113

CHAPTER IV. Reactions performed using nanoparticles of

impregnated Palladium(II) Oxide on Magnetite

125

1. DIRECT ARYLATION OF HETEROCYCLES 127


1.2 RESULTS 129

1.2.1 DIRECT ARYLATION OF HETEROCYCLES 129

1.2.1 INTRAMOLECULAR DIRECT ARYLATION 136

2. SYNTHESIS OF 4-ARYLCOUMARINS THROUGH

THE HECK-ARYLATION/CYCLIZATION REACTION

140


2.2 RESULTS 141

CHAPTER V. Rections without catalyst 153

1. SYNTHESIS OF 3,5-DISUBSTITUTED ISOXAZOLES

AND ISOXAZOLINES IN DEEP EUTECTIC

SOLVENTS

155


1.2 RESULTS 158

EXPERIMENTAL PART 167

1. GENERAL 169

1.1 SOLVENTS AND SUBSTRATES 169

1.2 INSTRUMENTATION 169

2. PREPARATION OF CATALYSTS

171


IMPREGNATED COBALT(II) OXIDE ON

MAGNETITE

172

3.1 HYDROACYLATION OF AZODICARBOXYLATE

COMPOUNDS

172

4. REACTION CATALYSED BY NANOPARTICLES OF

IMPREGNATED COPPER(II) OXIDE ON

MAGNETITE

178

4.1 SYNTHESIS OF 1,3-DIYNES 178

4.2 HYDRATION OF 1,3-DIYNES TO AFFORD 2,5-

DISUBSTITUTED FURANS

183

4.3 DECARBOXYLATIVE COUPLING OF 3-

PHENYLPROP-2-YONIC ACID

184

4.4 SYNTHESIS OF ARYL IMINES DERIVATIVES

FROM ALCOHOLS AND AMINES

185

4.5 SYNTHESIS OF ARENECARBALDEHYDES 190

4.6 SYNTHESIS OF ARYL IMINES DERIVATIVES

FROM PRIMARY AMINES

193

4.7 SYNTHESIS OF N-ARYLATED 1,2,3,4-

TETRAHYDROISOQUINOLINES

195

4.8 SYNTHESIS OF 1-SUBSTITUTED-N-ARYLATED

1,2,3,4-TETRAHYDROISOQUINOLINES

197

4.9 SYNTHESIS OF BENZO[b]FURANS 205


BIMETALLIC IMPREGNATED NICKEL(II) OXIDE

AND COPPER(0) ON MAGNETITE

212

5.1 SYNTHESIS OF 1,4-DISUBSTITUTED-1H-1,2,3-

TRIAZOLES

212


PALLADIUM

220

6.1 SYNTHESIS OF DIARYLIODONIUM SALTS 220

6.2 SYNTHESIS OF ARYLATED HETEROCYCLES 224

6.3 SYNTHESIS OF HALOETHERS 228

6.4 SYNTHESIS OF SUBSTITUTED 231

BENZO[b]CHROMENE DERIVATIVES

6.5 SYNTHESIS OF ACRYLATES 234

6.6 SYNTHESIS OF 2H-CHROMEN-2-ONE

DERIVATIVES

235

6.7 SYNTHESIS OF CINNAMATE DERIVATIVES 240

7. REACTIONS WITHOUT CATALYST 242

7.1 SYNTHESIS OF 3,5-DISUBSTITUTED

ISOXAZOLES

242

7.2 SYNTHESIS OF 3,5-DISUBSTITUTED

ISOXAZOLINES

246

7.3 SYNTHESIS OF β-AMINO ENONES 249

7.4 SYNTHESIS OF ISOXAZOLES FROM ETHYL 2-

NITROACETATE

251

CONCLUSIONS 253

BIOGRAPHY 257

ACKNOWLEDGMENT 261

EPILOGUE

273 Epilogue

La magnetita, Fe3O4, es un óxido mixto de Fe(II) y Fe(III), que posee una

estructura cúbica de espinela inversa, en la que los átomos de oxígeno se

encuentran formando una celdilla unidad cúbica centrada en las caras y los

cationes de hierro ocupan los huecos intersticiales. Más concretamente, los

huecos tetraédricos están ocupados por iones de Fe(III) y los octaédricos por

iones de Fe(II) y Fe(III) por igual.

El interés de la magnetita en el campo de la Química Orgánica ha

aumentado en los últimos años gracias a las propiedades peculiares que presenta,

ya que puede ser fácilmente separada del medio de reacción mediante la

aplicación de un campo magnético externo, facilitando así su reutilización.

Debido a lo anteriormente expuesto, el número de aplicaciones de la

magnetita en los últimos años ha ido en aumento en campos como la catálisis.

Recientemente, la impregnación con metales de transición en su superficie, ha

sido considerada como una metodología muy poderosa y alternativa para la

preparación de nuevos catalizadores.

El protocolo de impregnación de prácticamente todos los metales de

transición en la superficie de la magnetita, ha dado lugar a una primera

generación de catalizadores. Estos catalizadores han sido usados en un gran

rango de transformaciones orgánicas, incluyendo reacciones conocidas como la

simple formación de derivados de iminas, oxidación, adición, autotransferencia

de hidrogeno y reacciones multicomponentes, o reacciones desconocidas como la

β-alquilación cruzada directa de alcoholes primarios mediante deshidrogenación.

En muchos de los casos, el estudio de la superficie del catalizador por

medio de diferentes técnicas superficiales ha permitido determinar las especies

involucradas en el proceso y los cambios estructurales por culpa de los ciclos de

reacción. Además, la posterior modificación de los catalizadores mediante

reducción u oxidación de los metales inmovilizados en la superficie, o mediante

la adición de ligandos, ha engrandecido la aplicabilidad de este tipo de

catalizadores.

En la presente memoria, se han desarrollado algunas de las reacciones

que han sido llevadas a cabo con este tipo de catalizadores durante los últimos

años, y que han sido incluidas como trabajo experimental de mi tesis doctoral.

Los catalizadores de óxido de cobalto(II) y óxido de niquel(II)

impregnados en magnetita fueron preparados, caracterizados y usados en la

Epilogue 274

reacción de hidroacilación de diferentes azodicarboxilatos con aldehídos, usando

para ello cantidades casi equimoleculares de ambos reactivos y en solo tres horas

de reacción. Además, esta reacción fue realizada con la menor cantidad de

catalizador jamás reportada. Los correspondientes productos de reacción fueron

obtenidos generalmente con buenos rendimientos, incluso cuando se usaron

aldehídos alifáticos. El catalizador de cobalto fue lo suficientemente estable

como para poder ser reciclado hasta diez veces sin pérdida de actividad catalítica.

Tras realizar el estudio del catalizador mediante XPS y TEM se pudo comprobar

que las nanopartículas de óxido de cobalto(II) iniciales se transformaron en

hidróxido de cobalto(II) y que hubo un pequeña sinterización de las mismas tras

los diez ciclos de reacción, pero sin ningún efecto en la actividad del catalizador.

Hidroacilación de azodicarboxylatos.

El catalizador de óxido de cobre(II) impregnado en magnetita fue usado

para llevar a cabo diferentes reacciones en síntesis orgánica como:

1) La síntesis de 1,3-diinos mediante el homoacoplamiento de alquinos

terminales. En este caso, no fue necesario el uso de oxigeno presurizado como

oxidante, así como de disolvente o condiciones enérgicas de reacción para llevar

a cabo la misma. Además, la reacción tuvo lugar con la menor cantidad de

catalizador jamás comunicada con catalizadores heterogéneos, pudiéndose

eliminar el mismo del medio de reacción con el simple uso de un imán. Además,

la síntesis 2,5,-furanos tras la formación de dichos 1,3-diinos, pudo ser llevada a

cabo obteniendo muy buenos resultados con los sustratos aromáticos.

275 Epilogue

Homoacoplamiento de alquinos terminales usando CuO-Fe3O4.

2) La síntesis de iminas partiendo de alcoholes y aminas, o nitroarenos,

también pudo ser llevada a cabo usando el catalizador de óxido de cobre(II)

impregnado en magnetita. Dicho catalizador no requiere el uso de ligandos

orgánicos caros o difíciles de manipular, obteniendo rendimientos buenos con

condiciones suaves de reacción. El reciclado del catalizador se intentó llevar a

cabo sin éxito debido a la siterización de las nanopartículas de cobre facilitada

por la presencia de especies nitrogenadas en el medio de reacción. La reacción de

deshidrogenación de alcoholes en presencia de anilina en un solo recipiente,

seguido de hidrólisis acuosa, dio los aldehídos puros con excelentes

rendimientos. También pudieron ser usados nitroarenos como reactivos que

contienen átomos de nitrógeno, para la formación de las correspondientes iminas.

Por último, se llevó a cabo la reacción con aminas primarias, obteniéndose con

éxito las correspondientes iminas y usando condiciones de reacción similares.

Síntesis de iminas partiendo de alcoholes y aminas.

Epilogue 276

3) La síntesis de diferentes tetrahidroisoquinolinas pudo ser llevada a

cabo con éxito usando la mezcla cloruro de colina:etilenglicol (1:2), evitando así

la presencia de disolventes orgánicos volátiles, junto con el catalizador de óxido

de cobre(II) impregnado en magnetita, siendo la cantidad de cobre utilizada la

más baja comunicada hasta el momento. La presencia de DES fue esencial

debido a que la reacción en ausencia del mismo no tuvo lugar. Una relación

directamente proporcional fue encontrada entre la conductividad del medio

eutéctico y el rendimiento obtenido. La recuperación del catalizador se llevó a

cabo usando dos metodologías diferentes. Por una parte, la mezcla de DES y

catalizador pudieron ser reutilizados mediante simple extracción y posterior

decantación, hasta diez veces sin un descenso en el rendimiento de la reacción.

Las condiciones estrictamente aeróbicas de la reacción hacen que el protocolo

sea sostenible debido a que el único residuo generado es agua. Sin embargo,

cuando solo el catalizador fue recuperado del medio de reacción, mediante

decantación magnética, se produjo un descenso importante en el rendimiento de

la reacción después del cuarto ciclo. Esta diferencia puede ser atribuida a la alta

disolución irreversible de las nanopartículas de cobre en la mezcla eutéctica. De

hecho, la mezcla eutéctica reciclada pudo ser usada para llevar a cabo el

acoplamiento deshidrogenante después de haber eliminado el catalizador, que

permanecía sobre la magnetita

Reacción de acoplamiento cruzado deshidrogenante.

4) La síntesis de benzo[b]furanos a través de un proceso de

acoplamiento-alenilación-ciclación entre alquinos y derivados de 2-

hidroxiarilcarbonilo en presencia de hidracida de p-toluenosulfonilo, fue llevada

a cabo usando el catalizador de óxido de cobre(II) impregnado en magnetita y

etanol como disolvente no tóxico y biorenovable. La cantidad de cobre utilizada

en este caso fue muy pequeña y el catalizador pudo ser eliminado del medio de

reacción mediante el simple uso de un imán. La reutilización del catalizador se

intentó llevar a cabo sin éxito debido a la reducción del cobre(II) inicial a

cobre(0), lo cual fue comprobado mediante estudios del catalizador con técnicas

277 Epilogue

como XPS o TEM. Posteriormente, se intentó llevar a cabo la re-oxidación de

dichas nanopartículas mediante burbujeo del catalizador con oxígeno, o usando

oxidantes como t-BuOOH, pero ninguno de los procedimientos utilizados fue

efectivo para la regeneración de las nanopartículas de cobre(II).

Síntesis de benzo[b]furanos usando CuO-Fe3O4.

El catalizador bimetálico de nanopartículas de óxido de niquel(II) y

cobre(0) impregnadas sobre magnetita pudo ser preparado, caracterizado y usado

en la reacción multicomponente entre alquinos terminales, azida de sodio y

bromuro de bencilo (Esquema 36). Tras probar diferentes condiciones de

reacción, el producto deseado fue obtenido con un 83 % de rendimiento, sin el

uso de disolvente. Con este catalizador, se pudieron sintetizar diferentes triazoles

con rendimientos que oscilaban entre buenos y moderados. La presencia de

ambas especies metálicas en la superficie de la magnetita mostró tener un efecto

positivo y sinérgico en la reacción, pudiéndose reciclar el mismo hasta en diez

ocasiones sin pérdida de actividad catalítica. Tal y como cabría esperar, tras

llevar a cabo el reciclado del catalizador, la disolución irreversible de las

nanopartículas metálicas de cobre y níquel que forman el catalizador fue

despreciable. Tras el estudio del mismo, mediante XPS y TEM, se pudo

comprobar una pequeña sinterización de las nanopartículas, así como una

transformación de las especies metálicas iniciales en los correspondientes

hidróxidos, los cuales parecen no afectar en la actividad catalítica del catalizador.

Epilogue 278

Reacción multicomponente catalizada por NiO/Cu-Fe3O4.

El catalizador de óxido de paladio(II) impregnado sobre magnetita pudo

ser usado en diferentes reacciones como:

1) La arilación directa de compuestos heterocíclicos usando el

catalizador de paladio mencionado con anterioridad. Dicha reacción fue llevada a

cabo usando etanol como disolvente no tóxico y renovable, bajo condiciones de

reacción relativamente suaves. Una gran variedad de sustratos pudieron ser

utilizados obteniendo rendimientos de moderados a buenos. En la gran mayoría

de los casos, el catalizador se mostró selectivo obteniendo los productos arilados

en la posiciones 2 ó 3 dependiendo del heterociclo utilizado. Dicha metodología

se extendió a la síntesis de cromenos a través de una reacción de arilación directa

intramolecular. En ambas reacciones el catalizador es desactivado tras llevar a

cabo la reacción siendo imposible la reutilización del mismo. Tras llevar a cabo

diferentes estudios del catalizador reciclado, se descartó la disolución irreversible

de las especies de paladio en el medio, así como la sinterización de las mismas o

el cambio de estado de oxidación, ya que el catalizador permanecía igual tras la

reacción. Tras llevas a cabo el estudio del catalizador mediante fluorescencia de

rayos X pudimos comprobar que lo que parece inactiva el catalizador es la

presencia de haluros en la superficie del mismo.

Arilación directa de heterociclos con PdO-Fe3O4.

2) La síntesis de 4-arilcumarinas, a través de una reacción de arilación

tipo Heck seguida de una ciclación, pudo ser llevada a cabo usando un

catalizador de óxido de paladio(II) impregnado sobre magnetita y etanol como

disolvente no tóxico y biorenovable. La reacción pudo ser aplicada a una gran

279 Epilogue

variedad de sustratos obteniendo buenos resultados. El reciclado del catalizador

no pudo llevarse a cabo con gran éxito debido a la prácticamente total reducción

del paladio(II) inicial a paladio(0). Dicha reducción fue comprobada realizando

estudios del catalizador, como XPS o TEM, observando una gran sinterización de

dichas nanopartículas al igual que una disociación del metal del soporte tras

completar la reacción. Habiendo observado dicha reducción, se intentó llevar a

cabo la oxidación del paladio(0) generado, a través de diferentes técnicas como el

burbujeo del catalizador con oxígeno o la adición de oxidantes como el t-BuOOH

o I2, siendo imposible la regeneración de la actividad inicial del catalizador.

Síntesis de 4-arilcumarinas.

Por último, la síntesis de isoxazoles 3,5-disustituidos, así como las

correspondientes isoxazolinas relacionadas, usando cloruro de colina:urea (1:2)

como medio de reacción, en un solo recipiente y mediante tres pasos de reacción,

pudo ser llevada a cabo con éxito (Esquema 39). El uso de mezclas eutécticas

(DES) nucleofílicas altamente funcionalizadas no afectó en el proceso donde

reactivos altamente electrofílicos, o intermedios estaban involucrados. La

presencia de DES parece ser esencial debido a que la reacción sin este medio de

reacción no tuvo lugar. El DES pudo ser reciclado hasta en cinco ocasiones sin

obtener un descenso en el rendimiento de la reacción. Dicha reacción fue

escalada para la obtención de gramos del correspondiente producto sin ningún

problema. Para finalizar, diferentes isoxazoles fueron fácilmente transformados

en β–amino enonas con buenos rendimientos mediante el uso de Mo(CO)6 como

catalizador.

Epilogue 280

Síntesis de isoxazoles e isoxazolinas usando DES.

impregnated cobalt, nickel, copper and palladium oxides on...

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