Transcript
Page 1: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Diastereoselective multicomponent [3+2] and [4+2] cycloadditions

Verónica Selva Martínez

Page 2: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Departamento de Química Orgánica

Instituto de Síntesis Orgánica (ISO)

Facultad de Ciencias

DIASTEREOSELECTIVE MULTICOMPONENT

[3+2] AND [4+2] CYCLOADDITIONS

Verónica Selva Martínez

Tesis presentada para aspirar al grado de

DOCTORA POR LA UNIVERSIDAD DE ALICANTE

MENCIÓN DE DOCTORA INTERNACIONAL

Doctorado en Síntesis Orgánica

Dirigida por:

Carmen Nájera Domingo José Miguel Sansano Gil

Catedrática de Química Orgánica Catedrático de Química Orgánica

Alicante, Abril de 2018

Page 3: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

2

Page 4: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

3

Table of contents

PREFACE 7

SUMMARY 9

GENERAL INTRODUCTION 11

1,3-DIPOLAR CYCLOADDITIONS 13

Azomethine ylides 15

1,3-Dipolar cycloadditions of azomethine ylides 18

CHAPTER 1: Multicomponent synthesis of indolizidines 27

BIBLIOGRAPHIC BACKGROUND 27

Multicomponent reactions 27

Synthesis of indolizidines 27

Synthesis of indolizidines using multicomponent 1,3-DC 31

OBJECTIVES 35

RESULTS AND DISCUSSION 37

CONCLUSIONS 53

EXPERIMENTAL SECTION 55

General methods 55

General procedure for the synthesis of indolizidines 72-73 56

Characterization of indolizidines 72-73 56

General procedure for the synthesis of indolizidine 74 61

Characterization of indolizidine 74 61

General procedure for the synthesis of indolizidine 75 62

Characterization of indolizidine 75 62

Page 5: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

4

General procedure for the synthesis of indolizidines 77 and 79

63

Characterization of indolizidines 77 and 79 63

CHAPTER 2: Thermal 1,3-DC of unactivated azomethine ylides

71

BIBLIOGRAPHIC BACKGROUND 71

Synthesis of substituted pyrrolidines 71

OBJECTIVES 77

RESULTS AND DISCUSSION 79

CONCLUSIONS 97

EXPERIMENTAL SECTION 99

General methods 99

General procedure for the synthesis of pyrrolidines 98, 101

and 103 99

Characterization of pyrrolidines 98, 101 and 103 99

General procedure for the synthesis of 104 113

Characterization of 104 113

CHAPTER 3: Multicomponent periselective cycloadditions of

nitroprolinates 115

BIBLIOGRAPHIC BACKGROUND 115

Diversity-oriented synthesis 115

OBJECTIVES 119

RESULTS AND DISCUSSION 121

CONCLUSIONS 135

EXPERIMENTAL SECTION 137

General methods 137

General procedure for the synthesis of pyrrolizidines 116 137

Page 6: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

5

Characterization of pyrrolizidines 116 137

General procedure for the synthesis of compounds 119 146

Characterization of compounds 119 146

General procedure for the synthesis of pyrrolizidines endo-

120-123 153

Characterization of pyrrolizidines endo-120-123 154

LIST OF ABBREVIATIONS 157

RESUMEN EN CASTELLANO 159

INTRODUCCIÓN GENERAL 161

1,3-Cicloadiciones dipolares 161

Cicloadiciones 1,3-dipolares de iluros de azometino 164

CAPÍTULO 1: SÍNTESIS MULTICOMPONENTE DE

INDOLIZIDINAS 167

Antecedentes bibliográficos: Reacciones multicomponente 167

Antecedentes bibliográficos: Síntesis de indolizidinas 167

Resultados y discusión 168

CAPÍTULO 2: 1,3-DC LIBRE DE METALES DE ILUROS DE

AZOMETINO DESACTIVADOS 175

Antecedentes bibliográficos: Síntesis de pirrolidinas

sustituidas 175

Resultados y discusión 176

CAPÍTULO 3: CICLOADICIONES MULTICOMPONENTE

PERISELECTIVAS DE NITROPROLINATOS 187

Antecedentes bibliográficos: Síntesis de orientación diversa

187

Resultados y discusión 188

REFERENCES 199

Page 7: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

6

Page 8: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

7

PREFACE

In this thesis, the main projects in which I have been involved during my

Ph.D. studies are described. The research concerns the study of 1,3-dipolar

cycloaddition, where an azomethine ylide is generated as intermediate, in both

their diastereoselective and non diastereoselective version. This work has been

carried out under the supervision of Prof. Carmen Nájera Domingo and Prof. José

Miguel Sansano Gil in the Organic Chemistry Department and the Organic

Synthesis Institute at the University of Alicante (Spain). Another research line was

developed during my three months stay in Tokyo at Gakushuin University under

the supervision of Prof. Takahiko Akiyama where many good results were

obtained, but the diffussion of these results is not authorized till publication.

The thesis is divided into a general introduction and three chapters. In

General introduction, the mechanism of the 1,3-dipolar cycloaddition involving

azomethine ylides is explained. Chapter 1 is focused on the synthesis of

substituted indolizidine derivatives through a multicomponent 1,3-dipolar

cycloaddition. Chapter 2 covers the study of multicomponent thermal 1,3-dipolar

cycloaddition reaction between unactivated azomethine ylides, generated in situ

from amines, aromatic aldehydes, and electrophilic alkenes. Finally, in Chapter 3

it is described the diverse oriented synthesis of diastereomerically enriched

pyrrolizidines from enantiomerically enriched nitroprolinates through a

multicomponent 1,3-dipolar cycloaddition and also the cyclohex-2-en-1-

ylprolinate cores by means of an amine-aldehyde-dienophile reaction.

Most of the results described herein have been published in the following

international peer reviewed journals:

“Multicomponent diastereoselective synthesis of indolizidines via 1,3-

dipolar cycloadditions of azomethine ylides”.

Castelló, L. M.; Selva, V.; Nájera, C.; Sansano, J. M. Synthesis 2017, 49, 299–309.

Page 9: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Preface

8

“Diastereoselective [3 + 2] vs [4 + 2] cycloadditions of nitroprolinates with

α,β-unsaturated aldehydes and electrophilic alkenes: an example of total

periselectivity”.

Selva, V.; Larranaga, O.; Castelló, L. M.; Nájera, C.; Sansano, J. M.; de Cozar, A. J. Org.

Chem. 2017, 82, 6298–6312.

“Sequential metal-free thermal 1,3-dipolar cycloaddition of unactivated

azomethine ylides”.

Selva, V.; Selva, E.; Nájera, C.; Sansano, J. M. Org. Lett. accepted. DOI:

10.1021/acs.orglett.8b01292.

These studies have been supported by Spanish Ministerio de Economía y

Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-

REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia

Estatal de Investigación (AEI) and Fondo Europeo de Desarrolo Regional (FEDER,

EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat

Valenciana (PROMETEO2009/039 and PROMETEOII/2014/017) and by the

University of Alicante.

I also thank Prof. Fernando P. Cossío, Dr. Abel de Cózar and Dr. Olatz

Larrañaga from the University of the Basque Country for their suggestions and

ideas about the elucidation of the mechanisms of these reactions, as well as for the

realization of computational calculations. I thank Dr. Tatiana Soler from Research

Technical Services of the University of Alicante for her work performing X-ray

diffraction analyses.

Page 10: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

9

SUMMARY

In this Doctoral Thesis the synthesis of substituted indolizidine,

pyrrolizidine, pyrrolidine and prolinate derivatives, from stabilized azomethine

ylides in situ generated, through different methodologies which involve a 1,3-

dipolar cycloaddition, multicomponent or multicomponent sequencial, in both

their diastereoselective and no diastereoselective way, is described.

In Chapter 1, the multicomponent free-metal synthesis of indolizidine

derivatives by intermediancy of iminium intermediate form by alkyl pipecolinates

or pipecolic acid with aldehydes reacting afterwards with dipolarophiles in both

thermal and decarboxylative way, are depicted.

In Chapter 2, it is described the one-pot synthesis of different pyrrolidine

derivatives through a sequencial 1,3-dipolar cycloaddition in a thermal free-metal

version of CH activation from unactivated azomethine ylides, generated in situ, and

dipolarophiles.

Page 11: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Summary

10

In Chapter 3, the multicomponent [3+2] 1,3-dipolar cycloaddition of

enantiopure exo-4-nitroprolinates with aldehydes and dipolarophiles giving the

corresponding pyrrolizidines is described. The same three components using

isomerizable aldehydes experiment a [4+2] cycloaddition (Amine-Aldehyde-

Dienophile reaction) giving the corresponding cyclohexenes.

Finally, at the end of each chapter the corresponding conclusions are

detailed. And after Chapter 3 references, abbreviations and biography are added

in this order.

Page 12: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

11

GENERAL INTRODUCTION

Nitrogen-containing compounds such as alkaloids or amino acids have an

important role in medicinal chemistry, pharmaceutical industry and in synthetic

organic chemistry due to their bioactivity or their catalytic properties. For this

reason, organic chemists have increased their attention in synthesizing this type

of organic compounds.1

The development of synthetic methods for the construction of five-

membered heterocycle derivatives has been focused towards the obtention of

natural and unnatural compounds2 through reactions with greater atomic

economy and less number of steps. Prolines and alkaloids such as pyrrolidines,

pyrrolizidines and indolizidines are examples of (at least) a five-membered ring

compounds containing a nitrogen atom, and their skeleton is present in many

biologically active compounds and natural products.

Proline-derivative compounds have applications in the synthesis of

natural products, biologically active structures and also have been employed as

organocatalysts in many useful transformations.3 For example, proline-scaffold 1

is an antiviral agent against the hepatitis C virus,4 kainoid-derived 2 has

neuroexcitatory activity5 and (-)-dysibetaine 3 is a neuroexcitotoxin6 (Figure 1a).

Pyrrolidine alkaloids are five-membered N-heterocycles mainly extracted from

the plants and can be used for pharmaceutical purposes thanks to their biologically

activity.2,7 A big amount of natural pyrrolidine alkaloids are known, hygrine 4 is

the simplest representative which has anesthetic and analgesic activity,8 or more

complex substituted pyrrolidine derivatives like broussonetine K 5 which has

antifungal, anti-inflammatory and antihyperglycemic activity, among others8,9

(Figure 1b). Pyrrolizidine alkaloids are a group of alkaloids, that contain an

azabicyclo[3.3.0]octane structural motif, produced by plants as self defense

mechanism against herbivore insects10 and are currently of special interest

because several of them have shown toxic, genotoxic and carcinogenic reactions in

humans;11 although some families of pyrrolizidines possess interesting

therapeutic and medicinal applications.12 (-)-Isoretronecanol 6, (-)-

Page 13: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

General introduction

12

trachelantamidine 7 and (+)-laburnine 8 exhibit potent glycosidase inhibitory

activities7,11a,13; (+)-crotanecine (9), madurensine (10) and anacrotine (11) are

hydroxylated alkaloids with pyrrolizidine moiety, widely used for the treatment of

bacterial and viral infections as well as for cancer14 (Figure 1c).

Figure 1. a) Some biologically active proline derivatives and structure of some naturally occurring

alkaloids with b) pyrrolidine skeleton or c) pyrrolizidine and d) indolizidine cores.

Indolizidine alkaloids present an azabicyclo[4.3.0]nonane core being the

most important scaffold in the structure of numerous bioactive natural and

unnatural compounds.15 These alkaloids, which can be isolated from plant or

Page 14: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

1,3-Dipolar cycloadditions

13

animal sources, have attracted a great deal of attention because of their structural

diversity and varied biological activity.7,15e-f,16 Polyhydroxylated indolizidines,

such as (-)-swainsonine 12, (+)-castanospermine 13 and 6-epicastanospermine

14, are very interesting compounds from the pharmaceutical point of view due to

their anticancer and anti-HIV properties, and also is known their ability to act as

glycosidase inhibitors.17 On the other side, indolizidine structures with alkyl

substitution can block the neuromuscular transmission, like the family of

pumiliotoxins (15, 16, 17) which are isolated from the skin of Central and South

American dart poison frogs18 (Figure 1d).

To prepare these nitrogen-containing compounds the 1,3-dipolar

cycloaddition reaction (1,3-DC) is commonly employed due to the regio- and

diastereoselective control.19 In this Doctoral Thesis, we will focus our attention on

the 1,3-DC of azomethine ylides (as 1,3-dipoles) and different electrophilic alkenes

as dipolarophiles for the synthesis of highly substituted pyrrolidines,

pyrrolizidines and indolizidines.

1,3-Dipolar cycloadditions

The concept of 1,3-dipolar cycloaddition emerged for the first time in

1963 in the laboratory of Organic Chemistry of Professor Rolf Huisgen at the

University of Munich.20 This type of cycloadditions are reactions [π4s + π2s]

between a species called 1,3-dipole and a dipolarophile that evolve through an

aromatic transition state of 6π electrons, where a five-membered ring is generated

with different substituents and up to four stereogenic centers in just one step (this

last featured only in the case of enantioselective approaches) (Scheme 1).

Scheme 1. General mechanism of 1,3-dipolar cycloaddition.

Page 15: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

General introduction

14

A dipole is a zwitterionic system with 4π electrons delocalized on three

atoms where one of them at least is a heteroatom, meanwhile the dipolarophile

(alkene or alkyne are the most used) is a 2π electron system. There is a great

diversity of 1,3-dipoles formed from various combinations of carbon atoms and

heteroatoms (azides, nitrile oxides, nitrile ylides, nitrones, carbonyl ylides,

azomethine ylides…), which can be classified into two main groups: a) propargyl-

allenyl type such as azides, nitrile oxides or nitrile ylides, which have linear

structure and are present in the two resonance forms, propargyl type and

cumulene type, and b) allyl type such as azomethine ylides, nitrones, carbonyl

ylides or ozone, among others, whose structure is angular and has a single and a

double bond (Scheme 2).21

Scheme 2. Classification of dipole structures.

The group of Huisgen studied the mechanism of this reaction, proposing a

concerted pathway,22 on the other hand the group of Firestone proposed a radical

mechanism.23 After years of research in this area it was concluded that the

mechanism of the 1,3-DC reaction is a concerted [3+2] pericyclic cycloaddition24

and a radical trap did not inhibit the process. However, the reaction can proceed

through a stepwise pathway if the dipole is stabilized by resonance.21b,25

Page 16: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Azomethine ylides

15

As mentioned before, the 1,3-dipolar cycloaddition reaction involves a

total of 6π electrons (π4s + π2s) and takes place thermally in a suprafacial process

according to the rules of Woodward and Hoffmann.26 Thanks to that fact this

cycloaddition generally takes place through a concerted process, and a high regio-

and stereospecificity is obtained.27

The application of the frontier molecular orbital theory (FMOT)28 to this

type of process allows us to explain the high regiochemistry and stereoselectivity

of the 1,3-DC reaction which is controlled by the energies of HOMO (highest energy

occupied molecular orbital) and LUMO (lowest energy unoccupied molecular

orbital) of the two components, that means, the interaction between a

HOMOdipole/LUMOdipolarophile or LUMOdipole/HOMOdipolarophile is crucial for the reaction

course. When the FMOT overlapping is maximum the reactions are faster because

the difference of the energy between the HOMO/LUMO levels are low.

The 1,3-dipoles most employed in organic synthesis are nitrones29 and

azomethine ylides,19a,b,d,30 whose structures are shown in Scheme 2. These dipoles

give rise to interesting five-member heterocycles that appears in nature after

reacting with a dipolarophile. Next, we will pay attention to azomethine ylides and

their use in the 1,3-dipolar cycloaddition.

Azomethine ylides

Azomethine ylides can be generated from diverse routes30b,31 and are

widely used in the synthesis of natural products by 1,3-DC. They are very reactive

species due to they have an electron rich allyl type structure with 4π electrons

distributed over three C-N-C atoms, being the most common resonance structure

that has the positive charge on the nitrogen and the negative charge on one of the

atoms of carbon, depending on the nature of the molecule (Scheme 3). This planar

structure becomes optimal for the use of these intermediates in 1,3-DC with

electron-deficient alkenes.

Page 17: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

General introduction

16

Scheme 3. Resonance structures of azomethine ylides.

Azomethine ylides are unstable intermediate species which are generated

in situ. Two types of azomethine ylides are known: a) those that are stabilized by

an electron-withdrawing group attached to the carbon atom that bears the

negative charge and b) those that are not stabilized by any functional group. This

second group can be generated for example through a desilylation reaction of N-

benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)amine 18 in acidic

conditions,32 by deprotonation of iminium salts 1933 or amine oxides 20, 34

through decarboxylations of N-alkylamino acids 21,35 by the use of N,N-

bis(sulfonylmethyl)alkylamines 22 in the presence of samarium iodide,36 as well

as by thermal opening of N-lithioaziridines 2337 and another possibility is the

decarboxylation of pyridinium salts 24-2538 (Scheme 4).

Scheme 4. General formation of non stabilized azomethine ylides.

Page 18: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Azomethine ylides

17

On the other hand, azomethine ylides with groups which can stabilize the

negative charge can be carried out in different ways, being via aziridine route 2639

or by iminum route 27, the two most common routes (Scheme 5). The problem to

generate the dipole from aziridines is the high temperature required (>170 °C). In

addition, the preparation of the appropriate aziridines is a difficult task. However,

azomethine ylides generated by iminum route from α-imino esters 27 can be

prepared thermally at lower temperatures in a process known as 1,2-prototropy,40

and it is even possible to carry out the formation of a metallo-dipole 28 assisted

by a Lewis acid with a weak base at room temperature (rt)27b,30b,41 (Scheme 5).

Scheme 5. Usual generation of azomethine ylides from aziridines and α-imino esters.

Given the complexity involved in preparing aziridines to give rise to the

1,3-dipoles, it is commonly preferable to work with α-imino esters, either by

conventional heating40b,e,42 or microwave irradiation30b,43 or by generating the

corresponding metallo-dipole 28 under milder reaction conditions (Scheme 5). In

the last case, the activating atom during the formation of the azomethine ylide is a

metal cation while in the case of the 1,2-prototropic route is a hydrogen atom. The

tautomeric route 1,2-prototropy needs a higher temperature than the other one,

so it is more difficult to control the dipole geometry during the key stage.

The carbonyl group contained in the azomethine ylide structure, derived

from α-imino esters 27, acts as an electron-withdrawing group (EWG) stabilizing

Page 19: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

General introduction

18

the ylide. Thanks to that effect azomethine ylides become excellent 1,3-dipoles,

widely employed in the synthesis of five membered N-heterocycle derivatives

through a 1,3-DC.

1,3-Dipolar cycloadditions of azomethine ylides

The 1,3-dipolar cycloaddition carried out thermally with stabilized

azomethine ylides and electrophilic olefins is a type 1-cycloaddition, according

with Sustmann,44 that means the predominant interaction is given by HOMOdipole

(azomethine ylide) and LUMOdipolarophile (olefin)19a,21a,27b,28e,41,45 (Figure 2). The main

features of this cycloaddition are the high regioselectivity, total stereospecificity,

high diastereoselection and extraordinary enantioselection when a chiral catalyst

is employed.

Figure 2. Type 1-cycloaddition.

This process is highly regioselective,27b,39 because only one of the two

possible regioisomers is preferentially obtained. This high regioselectivity

respond to the fact that the major overlapping of coefficients between frontier

orbitals occurs. Favouring the first Michael-type addition followed by the

cyclization (Mannich reaction) when is a stepwise process. A detailed example is

shown in Scheme 6, describing on it the energy differences between HOMO/LUMO

levels, the calculated values of coefficients and the ratio of final products.

Page 20: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

1,3-Dipolar cycloadditions of azomethine ylides

19

Scheme 6. Regiochemistry of the 1,3-DC between an azomethine ylide and methyl acrylate.

The total stereospecificity refers to the configuration of the dipolarophile,

thus, a 1,2-disubstituted E-alkene will maintain a trans-arrangement of these two

substituent in the five membered ring and the corresponding 1,2-disubstituted Z-

alkene will afford the cis-relative configuration.

The most appropriate dipolarophiles used in the reaction with stabilized

azomethine ylides are those that have a low LUMO energy, which means,

electrophilic olefins. However, other alkenes with higher LUMO energy react badly

or do not, such is the case of styrene or methyl vinyl ether, among others. These

electron-rich alkenes react under hard conditions employing azaallyl anions.46

Furthermore, the presence of electron-donating group (EDG) in the ylide increases

the energy of the HOMOdipole.

It is well known that the presence of metal-based Lewis acids can modify

the orbital coefficients of the reacting spices and the energy levels of the frontier

orbitals, lowering the LUMO level, of the 1,3-dipole and the dipolarophile, (Figure

3)21a allowing a faster reaction. In order to reach high diastereoselection as well as

a quick reaction in the 1,3-DC is necessary the coordination of the Lewis acid,

which plays a catalytic role, to one or both of the reagents.47 It has been observed

an improvement of the diastereoselectivity when the metal coordinates the

dipolarophile, because it guides the dipolarophile in a specific direction due to

Page 21: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

General introduction

20

stereo-electronic effects. On the other hand, once the metal is coordinated with a

chiral ligand it is possible to control the regio-, diastereo- and enantioselectivity,21

which converts this reaction in an important asymmetric synthetic tool.

Figure 3. Effect on the dipolarophile (left) or on the dipole (right) frontier orbitals of a Lewis acid.

The formation of azomethine ylides is sensitive to the pKa of the hydrogen

atom in α position to the carbonyl group, as well as to the basicity of the nitrogen

atom of the imine.40b The α-imino ester 27 (Scheme 7), under thermal conditions,

works through 1,2-prototropy which controls kinetically the dipole reaching the

E,E-(syn)-32 configuration or also called W-32 conformation. In the 1,3-DC of this

azomethine ylide with a dipolarophile a mixture of endo-30 (relative configuration

4,5-cis) and exo-30 (relative configuration 4,5-trans) cycloadducts is obtained

from the transition states endo and exo, respectively, both with a relative

configuration of 2,5-cis (Scheme 7).

Regarding the diastereoselectivity of the cycloaddition, the terms endo

and exo refers to the orientation of the electron-withdrawing group (EWG) from

the double bond with respect of the dipole during the approximation of both

reagents. Thus, when the EWG substituent approaches the dipole during the

formation of the transition state we refer as an endo-approach, whereas in an exo

approximation this substituent is oriented away from the dipole (Scheme 7). The

possibility of both endo- or exo-approach produces cycloadducts that are

diastereoisomers to each other. Many steroelectronic effects control the

diastereoselectivity of these cycloadditions being the endo-approach the most

favourable to occur.

Page 22: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

1,3-Dipolar cycloadditions of azomethine ylides

21

The geometry of the dipole must be controlled during all the process. The

initial formation of the most stable E,E-dipole 32 may undergo stereomutation to

produce the E,Z-32 or Z,E-32 dipoles, also called dipoles with S-shape 32, which

can react with the same dipolarophile to achieve the corresponding cycloaddition

producing endo-30, exo-30, endo’-30 and exo’-30 products with 2,5-trans relative

configuration in all cases (Scheme 7).

This kinetic progression of the ylide E,E-32 is generally controlled by

various factors such as: structure of the imine, solvent, reaction temperature and

reactivity of the dipolarophile employed.40b,48

Page 23: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

General introduction

22

Scheme 7. Possible cycloadducts formed in the 1,3-dipolar cycloaddition by 1,2-prototropy and

transition states with the W- and S-shape ylide conformation.

Page 24: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

1,3-Dipolar cycloadditions of azomethine ylides

23

When the 1,3-DC reaction is carried out under mild reaction conditions

using a Lewis acid and a weak base the products are obtained through a metallo-

azomethine ylide intermediate (Scheme 8).49 In these transformations the atom

involved in the formation process of the corresponding ylide is a metal ion

coordinated to the nitrogen atom instead of the hydrogen atom in the 1,2-

prototropy. The first examples that involve these metallo-azomethine ylides were

studied in the early eighties.49,50 These studies show that the coordination between

the metal and both nitrogen and oxygen of the ester group 33 increases the acidity

of the α hydrogen to the carbonyl group making easier the deprotonation by a

weak base. This fact allows the formation of the kinetically favored W-34 shape

azomethine ylide, and lower quantities of the S-34 conformation. In this way, the

metallo-azomethine ylide W-34 evolves from two possible transition states, endo

and exo, to give rise to the corresponding cycloadducts 30 with a relative

configuration of 2,5-cis (Scheme 8). So, the high diastereoselectivity depends on

the coordinative power and the compatibility of the catalyst with the reagents in

order to achieve a major or minor diastereoselection. At the same time, if this

catalyst or Lewis acid is coordinated with a chiral ligand the cycloadducts can be

also obtained with excellent enantioselectivities.

Page 25: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

General introduction

24

Scheme 8. The most probable products for the Lewis acid-catalyzed 1,3-DC.

Several Lewis acids can be used for this purpose, such as salts of AgI, TlI,

LiI, CaII, MgII, CoII, TiIV, ZnII, CuI, CuII and SnIV, together with organic bases such as

Hünig or N,N-diisopropylethylamine (DIPEA), Et3N, 1,8-diazabicyclo[5.4.0]undec-

7-ene (DBU), N,N,N’,N’-tetramethylethylenediamine (TMEDA), guanidine

derivatives and phosphazenes, as well as inorganic bases.41,51 This reaction can

also occur in the absence of base, but more slowly and higher temperatures are

necessary.

Page 26: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

1,3-Dipolar cycloadditions of azomethine ylides

25

The major advantage of the metallo-azomethine ylides compared to the

1,2-prototropy is the greatest control of the dipole geometry that results in the

high stereoselectivity of the obtained pyrrolidines, especially when starting from

imines formed from aromatic aldehydes and α-amino esters. In this case, the

cycloaddition is very selective towards the formation of the endo product, although

it may depend on the structural properties of the dipolarophile. This process can

be avoided with the choice of Lewis acid and the appropriate solvent. In addition,

thanks to the mild reaction conditions and the metallo-azomethine ylide

generated, imines derived from aliphatic aldehydes can be used; while, under

thermal conditions (1,2-prototropy), these imines undergo an imine-enamine

isomerization, resulting in low yields in the cycloaddition.

This high stereochemical control of the reaction and the generation of up

to four stereogenic centers simultaneously make this cycloaddition one of the most

useful routes for the asymmetric synthesis of highly polysubstituted five-

membered heterocycles.19f,h,31b-c,52

On the following pages, the results obtained in the study of 1,3-DC to

synthesize different cycloadducts bearing a N as main heteroatom, such as

pyrrolidine, pyrrolizidine, indolizidine and proline derivatives, through both 1,2-

prototropic reaction or Lewis acid catalyzed reaction, are going to be developed

and discussed divided in three different chapters.

Page 27: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

26

Page 28: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

27

CHAPTER 1: Multicomponent synthesis of

indolizidines

Bibliographic background

Multicomponent reactions

Multicomponent reactions (MCRs) are reactions in which three or more

different substrates are used at the same time to form a new product which

contains at least partial units of each components. They are also considered as

cascade reactions in which multiple carbon-carbon and carbon-heteroatom bonds

and multiple stereocenters are formed in only one process (Figure 4).53

Multicomponent transformations have important advantages over other

kind of reactions because of the high atom economy level, avoiding the

employment/removal of protecting groups as well as the isolation of

intermediates. 54 These synthetic advantages correspond with less synthetic steps,

which means, less amount of waste residues and less amount of solvent required,

bringing the reaction to “green” chemistry.55

These processes usually generate complex structures through a simple

process with good yield and stereoselectivity.56

Synthesis of indolizidines

Due to the biological and pharmaceutical importance of this type of

compounds, and the frequency of appearing in nature, the synthesis of

indolizidines is a very attractive field from the synthetic organic chemistry point

of view. As it was described before, indolizidine alkaloids have shown important

biological properties and medicinal applications,7,16b-c they can be isolated from

plant or animal sources and also there are numerous works in which the final

Page 29: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

28

scaffold of indolizidine is successfully reached. The synthetic approaches to obtain

this heterocyclic skeleton can be classified according to the cyclization order, that

means, six-member ring followed by five-membered ring construction (6→5) and

vice versa (5→6). The most important drawback of the synthesis of indolizidines is

that it is necessary several reaction steps to obtain the desired product.15f

Interesting 6→5 sequences have been studied, such as the case of the work

published by the group of Mariano, where they synthesized natural products (-)-

swaisonine 12, (+)-castanospermine 13 and uniflorine-A 38. To get the

indolizidines, firstly they performed a ring rearrangement metathesis, as key

reaction step with the aim to obtain six-membered ring 37 (Scheme 9).57 Once they

had the N-heterocycle 37 and after the corresponding hydroxylation, followed by

a cyclization, they could obtain the desired indolizidines.

Scheme 9. Synthesis of polyhydroxylated indolizidines.

Alkyl indolizidines are also very interesting due to their wide biological

activities, most of them detected from amphibian skin,15f,58 for this reason many

research groups have studied the synthesis of this compounds. Toyooka and

Nemoto synthetized (-)-(5R,9S)-5-epi-indolizidine 167B 42 in 29% yield59 from

Page 30: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Bibliographic background: Synthesis of indolizidines

29

starting material 39. After several steps, the obtained product (-)-40, which is the

precursor of an internal lactam (-)-41, was generated through a cyclization. After

a reduction step, desired product (-)-42 is reached (Scheme 10a). Toyooka,

Nemoto and co-workers continued developing new synthetic pathways to get alkyl

indolizidines (Scheme 10b), making valuable contributions to the total synthesis

of 5,8-disubstituted indolizidine alkaloids such as (-)-43, (-)-44 and (-)-45.60

Scheme 10. Synthesis of alkylated indolizidines.

Another synthetic strategy is the 5→6 ring sequence, actually this is the

most employed due to the high accessibility to indolizidines from

polyfunctionalized pyrrolidines or proline derivatives.7 An example of this

sequence is the synthesis of natural products using the work of Overman where

they could obtain the pumiliotoxin 251D 17 from methyl prolinate derivatives

(Scheme 11),61 and also they obtained the pumiliotoxin B 16 introducing changes

into the alkyl chain. 62

Page 31: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

30

Scheme 11. Synthesis of alkylated indolizidine Pumiliotoxin 251D 17.

On the other hand, several works were focused on the synthesis of

indolizidine derivatives through routes which can offer better results. This is the

case, for example, of the work published by Waters’ group in 2012. They have

developed a domino 2-aza-Cope-1,3-DC protocol,63 where the condensation of a

homoallylic amines 50 with ethyl glyoxylate 51 allows to reach intermediate

imines 52, which after subsequent 2-aza-Cope rearrangement, generated the

imine 53. This imine underwent a 1,3-DC affording the 2-allylpyrrolidines 54

employed in the synthesis of functionalized indolizidines 56 through aza-Prins

cyclization (Scheme 12).

Scheme 12. Synthesis of indolizidine derivatives via domino 2-aza-Cope-1,3-DC.

Page 32: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Bibliographic background: Synthesis of indolizidines using multicomponent 1,3-DC

31

The common synthesis of indolizidines usually required too many steps

and final overall yields were very low. To hamper these disadvantages, MCR could

be employed because higher yields would be obtained as well as saving time,

solvents, reagents and waste, due to few steps needed.

Synthesis of indolizidines using multicomponent 1,3-DC

In the last decade, the thought of pharmaceutical industry has undergone

a major change, focusing on multicomponent reaction for the advantages it offers.

Especially for its efficiency, the facility to automate the synthesis, and obtain

enormous batteries of compounds with high structural complexity. According to

the topic of this work, 1,3-DC reactions can be employed as MCRs and is

extensively demonstrated that this reaction is an important tool for the

construction of complex alkaloid structures.19,30b-c Here are shown few examples

of cycloadditions between azomethine ylides and electrophilic alkenes through

this synthetic pathway to the synthesis indolizidine derivatives.

In 1985, Hamelin’s group used this methodology to obtain indolizidine

derivatives 59 from ethyl 2-pipecolinate 57 in combination with benzaldehyde 58

and a dipolarophile, yielding a mixture of stereoisomers.64 They used dimethyl

fumarate, dimethyl maleate and N-methylmaleimide (NMM) as dipolarophiles and

in all these examples the chemical yield was almost quantitative (95%), however,

the mixture of diastereoisomers was notable (Scheme 13).

Page 33: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

32

Scheme 13. Multicomponent reaction to synthesize indolizidine derivatives from ethyl 2-

pipecolinate, benzaldehyde and dipolarophile.

An example of 1,3-dipolar cycloaddition in the synthesis of more complex

indolizidines is the one published by Grigg,65 where the multicomponent reaction

from cyclic secondary α-amino acid 60 takes place through decarboxylation of the

iminium salt, generated in situ at higher temperatures, followed by reaction with

a dipolarophile (Scheme 14a). Later on, they performed the same reaction

changing the α-amino acid 60 for the secondary α-amino ester 62 and they

obtained indolizidine derivatives 64 without the decarboxylation process. To

prove the independence of the aryl ring, they tested the reaction with 2-

methoxybenzaldehyde 63 and significative differences were not observed in the

mixture of endo:exo diastereoisomers (45:55 dr) (Scheme 14b).66

Page 34: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Bibliographic background: Synthesis of indolizidines using multicomponent 1,3-DC

33

Scheme 14. a) MCR to synthesize complex indolizidines through the decarboxylation route. b)

Synthesis of complex indolizidines without previous decarboxylation.

Grigg's group continued exploring the multicomponent reaction 1,3-

dipolar cycloaddition with secondary amines, in this occasion with the carbonyl

group at the 1 position of 65. Due to this change, the stereoselectivity of the dipole

formation is noticeably less and the double bond of the azomethine ylide can

isomerize yielding up to 4 different products in the same crude reaction (Scheme

15).67 Thus when the reaction was carried out with benzaldehyde 58 and N-

methylmaleimide it was obtained a 21:29:17:33 mixture of exo-66:endo-66:exo’-

66:endo’-66 different indolizidine derivatives, respectively.

Page 35: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

34

Scheme 15. 1,3-DC between 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, benzaldehyde and

NMM to give the corresponding decarboxylated indolizidines 66.

More recently, our research group, in collaboration with Attanasi’s group,

have described the synthesis of indolizidine derivatives with an azo moiety into

the structure. This is possible to perform a multicomponent 1,3-DC between ethyl

2-pipecolinate 57, paraformaldehyde 67 and using 1,2-diaza-1,3-dienes 68 as

dipolarophiles.68 Despite the low yields achieved, only one diastereoisomer 69 of

each reaction was isolated (Scheme 16).

Scheme 16. 1-(Phenyldiazenyl)octahydroindolizine-2,8a-dicarboxylates 69 synthetized by

multicomponent 1,3-DC.

Page 36: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

35

Objectives

According to the precedents found in the literature and combining our

experience in multicomponent 1,3-dipolar cycloaddition, it was decided to set the

following objectives to expand the study of new substituted indolizidines:

1 To perform the synthesis of indolizidines from alkyl esters of

pipecolinic acid by multicomponent 1,3-dipolar cycloaddition

involving azomethine ylides, using different cyclic six-membered ring

amino acids alkyl esters, several aldehydes and various dipolarophiles.

2 To carry out the decarboxylative multicomponent 1,3-dipolar

cycloaddition using pipecolinic acid as amino acid and different

aldehydes and dipolarophiles to prepare the corresponding

indolizidines.

Page 37: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

36

Page 38: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

37

Results and discussion

Following the methodology of multicomponent 1,3-dipolar cycloadditions

studied by our group in the synthesis of unnatural pyrrolizidine alkaloids,12d,69 it

was decided to apply, directly, this strategy for the synthesis of substituted

indolizidines 72 from methyl pipecolinate hydrochloride 70 and trans-

cinnamaldehyde 71 generating the corresponding azomethine ylide in situ, and

further cyclization with dipolarophiles (Scheme 17).

Scheme 17. Multicomponent synthesis of indolizidine derivativatives and their mechanistic details of

the iminium route.

As it was mentioned in the General Introduction, the 1,3-dipolar

cycloaddition exhibits high diastereocontrol over the cycloadducts obtained.

Specifically, in the case of Scheme 17 the reaction proceeded when the dipole had

S-shape conformation because it had less steric problems, and in agreement with

previous works of our group12d,69 and Maiti’s group,70 we can assume that the

cycloaddition took place by the attack of the α position to the carbonyl group

toward the dipolarophile. The proton in α position to the ester group has lower

pKa, which means, it is more reactive than the other option. All these features

explained the reason of the final 2,5-trans relative configuration of the obtained

indolizidines 72 and also explained the most favourable endo-approach of the

Page 39: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

38

dipolarophile to the intermediate ylide. This endo-approach allows, mainly, the

formation of the product with 2,4-trans configuration (Scheme 18).

Scheme 18. Relative configuration of diastereoisomers obtained from endo- or exo-approach by the

α-attack of the S-dipole.

To study the optimal conditions for the synthesis of the desired

indolizidines 72, toluene was selected as solvent attending the good results

obtained in similar works by our group in multicomponent 1,3-DC. As reagents for

the optimization methyl pipecolinate hydrochloride 70, trans-cinnamaldehyde 71

and methyl acrylate were selected in presence of 1 equiv. of Et3N (Scheme 19),

affording the scaffold, formed by the α-attack of the S-conformation, 2,5-trans-2,4-

trans endo-72 as major one (Scheme 17).

Scheme 19. Multicomponent 1,3-DC between methyl pipecolinate hydrochloride 70, trans-

cinnamaldehyde 71 and methyl acrylate to yield substituted indolizidine 72a.

Page 40: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

39

A screening of the temperature (T) of the reaction was carried out without

any catalyst in an overnight reaction (Scheme 19 and Table 1). Refluxing toluene

(110 °C) was selected for the first attempt, and a conversion higher than 95% was

achieved (Table 1, entry 1). Then, the reaction was tested at 90 °C, and again the

reaction proceed with a conversion upper than 95% (Table 1, entry 2). In order to

study the optimal temperature, 70 °C was explored, and the same result as above

was obtained (Table 1, entry 3). When the temperature was set at 50 °C the

reaction did not take place (Table 1, entry 4).

Then, two different silver catalysts were tested with the aim to observe if

they could improve the results. AgOAc and AgOBz were chosen for the

optimization process in a 5 mol% of catalyst loading. The selected temperature

was 70 °C and the results, in terms of conversion, for both silver salts were higher

than 95% (Table 1, entries 5 and 6). It was also tested both silver catalyst at 50 °C

in order to see their efficiency, but unfortunately the reaction did not occur (Table

1, entries 7 and 8). Because of the results with and without silver were practically

the same, it is possible to assume that silver salts did not play any role in the

reaction.

Table 1. Optimization of the multicomponent 1,3-DC between methyl pipecolinate hydrochloride 70,

trans-cinnamaldehyde 71 and methyl acrylate to yield substituted indolizidine 72a.

Entry T (°C) Reaction Conversion (%)a

Without AgI salts With AgOAcb With AgOBzb

1 110 >95 ----- -----

2 90 >95 ----- -----

3 70 >95 ----- -----

4 50 0 ----- -----

5 70 ----- >95 -----

6 70 ----- ----- >95

7 50 ----- 0 -----

8 50 ----- ----- <5

a Determined by 1H NMR of the crude reaction.

b 5 mol% of catalyst.

Page 41: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

40

Once the optimal reaction conditions were set, 70 °C, toluene as solvent, 1

equiv. of Et3N and 17 h, the scope of the reaction was studied keeping constant the

methyl pipecolinate hydrochloride 70 and trans-cinnamaldehyde 71, and

modifying the dipolarophile (Scheme 20). When methyl acrylate was employed,

the corresponding product endo-72a was achieved with high diastereoselection

(endo:exo 95:5 dr) in 57% yield (Scheme 20). This good result regarding the

diastereoselectivity could be explained because it is the less sterically hindered

dipolarophile. The highest diastereoselection of the series (98:2 dr) was

accomplished with maleic anhydride affording the corresponding indolizidine

endo-72b in 93% yield (Scheme 20). Then, N-methylmaleimide (NMM) and N-

phenylmaleimide (NPM) were used affording the same diastereomeric ratio

(70:30 dr) and almost the same yield for each of the separable diastereoisomers

(Scheme 20). Thus, with NMM endo-72c was achieved in 59% yield, meanwhile

exo-72c was isolated in 22% yield after flash chromatography (Scheme 20). For

NPM the yield for endo-72d was 55% and for exo-72d was 20% (Scheme 20). With

methyl fumarate the product was generated in 70% yield for the endo-72e and

11% yield for the exo-72e with a 84:16 dr, slightly lower than the obtained for

indolizidine 72a, but higher than the achieved with both maleimides.

Later on, chalcone and trans-β-nitrostyrene, as suitable dipolarophiles for

multicomponent thermal reactions, were submitted to study. For both reagents

unexpected exo-product was the major one, instead of the endo observed in the

previous examples (Scheme 20). Working with chalcone, an inseparable mixture

of both diastereoisomers 72f was obtained in a 66% overall yield with an

inversion of diastereoselectivity endo:exo of 25:75 dr (Scheme 18), meanwhile for

trans-β-nitrostyrene, endo-72g was reached in 17% yield and the regioisomer exo-

73g in 55% yield (23:77 dr) (Scheme 20). Finally, other dipolarophiles such as

trans-1,2-bis(phenylsulfonyl)ethylene, diethyl benzylidenemalonate, trans-

cinnamaldehyde and allyl methacrylate could not afford the corresponding

indolizidine (Scheme 20).

Page 42: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

41

Scheme 20. Multicomponent cycloaddition of methyl pipecolinate hydrochloride 70 with trans-

cinnamaldehyde 71 and different dipolarophiles.

Page 43: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

42

The relative configuration observed in the obtained indolizidines

was determined by analysis of 1H NMR of the reaction crudes, where only a

mixture of two diastereoisomers were identified. Thus, it was possible to affirm

that the reaction proceeds through a mechanism with high to excellent

diastereoselectivity. This high diastereocontrol is due to the S-type dipole

generated by the iminium salt (Scheme 17) which reacts with the dipolarophile by

the α-position to the carbonyl group (Scheme 18). The 2,4-trans-2,5-trans

arrangement of the five-membered ring, observed in compounds 72a-e, is due to

the favourable endo-approach of the S-type dipole (Scheme 18). This relative

configuration is in agreement with the results obtained by Maiti’s group70 and by

our group12d,69 in the synthesis of pyrrolizidines employing the same methodology.

It was also confirmed by nOe experiments performed over the most stable

conformation of endo-72a. Such as it is depicted in Figure 5, where an

unambiguous nOe is represented, an interaction between protons Ha and Hb is

detected as well as a small effect between methyl group and proton Hb, so

according with this data the relative configuration of the major endo-cycloadducts

72a-e was proposed. Moreover, this configuration is in agreement with the

structural arrangement of pyrrolizidines performed by multicomponent 1,3-DC

involving prolinates.12d,69,70

Figure 5. Representative nOe detected for the major endo-72a adduct.

As it was mentioned above, the example run with chalcone (72f) was

obtained mainly as exo-cycloadduct, probably due to the high steric interaction

between the substituent of the cyclic dipole and the phenyl group closer to the

ketone group,71 so 2,5-trans-2,4-cis arrangement was generated (Scheme 18).

Page 44: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

43

It is also important to notice that when trans-β-nitrostyrene is employed

the reaction takes place as a result of the γ-attack of the S-dipole (Scheme 21). This

is possible thanks to the ability of trans-β-nitrostyrene to trap all kind of resonance

forms due to be an excellent Michael acceptor. Thus the compound 73g was

synthesized by a more feasible exo-attack of the dipolarophile. This behaviour was

explained in the multicomponent synthesis of pyrrolizidines because of

steroelectronic effects of the nitroalkene.12d,69,70

Scheme 21. Relative configuration of diastereoisomers obtained from endo- or exo-approach by the

γ-attack of the S-dipole.

The obtention of regioisomer exo-73g was confirmed by the proton shift

and coupling constants of the 1H NMR where the α proton respect to the nitro

group (Hc) appears as a doublet meanwhile for the endo-72g appears as doublet of

doublets (Hb). Besides, it was also confirmed by nOe experiments carried out to

both products (Figure 6), where for endo-72g exists a visible interaction between

Ha and Hb, and between Hb and the phenyl group and a small one with the methyl

group. On the other hand, for exo-73g, Hb cannot interact with the phenyl group

but Hc does, meanwhile, as well as for endo-72g, Ha and Hb interact one to each

other and Hb with methyl group, which did not happen if the product was exo-72g.

Page 45: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

44

Figure 6. 1H NMR and representative nOe detected for the endo-72g and exo-73g adducts.

At this point, a different scope of the reaction keeping constant the

dipolarophile and testing different aldehydes was surveyed (Scheme 22). The first

attempt was done with benzaldehyde 58 and maleic anhydride as dipolarophile

because of the good results exhibited in terms of diastereoselection in the previous

scope. An excellent diastereomeric ratio was observed (>99:1 endo:exo) for the

product endo-72h (Scheme 22) but in poor yield (27%). Other aldehydes such as

ethyl glyoxylate, isovaleraldehyde and furfural were taken under study but none

of the products were generated. So, the dipolarophile was moved to NMM, which

is one of the most reactive dipolarophiles, but again all the aldehydes tested

(benzaldehyde, ethyl glyoxylate, formaldehyde, crotonaldehyde,

hydrocinnamaldehyde and (2E,4E)-hexa-2,4-dienal) showed very poor reactivity.

According to our experience, aldehydes in general, but unsaturated aldehydes in

particular, are very sensitive to elevated temperatures (>70 °C) affording

decomposition products.

Page 46: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

45

Scheme 22. Multicomponent cycloaddition methyl pipecolinate hydrochloride 70, different

aldehydes and dipolarophiles.

Surprisingly, when ethyl pipecolinate 57, furfural and NMM were mixed

together the reaction took place affording endo-cycloadduct 74 as major

compound in 82:18 dr (endo:exo) and 48% overall yield (Scheme 22). In this

example, it was possible to obtain and isolate a crystalline major diastereoisomer

endo-74 which was submitted to an X-ray diffraction experiment72 (Figure 7) to

confirm the proposed structure (Scheme 23).

Page 47: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

46

Scheme 23. 1,3-DC between ethyl pipecolinate 57, furfural and NMM.

Figure 7. Different perspectives of the X-Ray diffraction analysis of endo-74 cycloadduct

(CCDC number: 1496416).

The third reagent of the reaction, the amine, was also evaluated. The

reaction was carried out with NPM and methyl 1,2,3,4-tetrahydroisoquinoline-3-

carboxylate 62, as amine source, synthesized from phenyl alanine methyl ester.73

Tetracyclic complex skeleton endo-75 was obtained as major compound in 65%

yield, and exo-75 in 11% yield with 86:14 dr (Scheme 24).

Page 48: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

47

Scheme 24. Multicomponent cycloaddition between 62, trans-cinnamaldehyde 71 and NPM.

The possibility to perform the 1,3-DC starting from pipecolic acid 76,

aldehydes and dipolarophiles it was also studied. To carry out this reaction it was

necessary the decarboxylation of the iminium salt generated in situ, which

requires a higher temperature (refluxing toluene) than the pipecolic ester (Scheme

26). For pipecolic acid 76 thanks to the high temperature and the less steric

hindrance, in compare with pipecolic ester, higher diastereomeric ratio could be

achieved. Besides, the four intermediates generated after decarboxylation, two of

them as a S-shape dipole and the other two as a U-shape dipole, can attack the

diapolarophile through a α or γ direction, affording 8 different products. When S-

shape dipole goes through α-attack products endo-77 and exo-77 were obtained,

whereas the same attack of the U-shape dipole afford pyrrolizidine derivatives

endo’-77 and exo’-77 (Scheme 25). On the other hand, N-heterocyles endo-78 and

exo-78 are synthesized by the γ-attack of the S-shape dipole, meanwhile γ-attack

of the U-shape dipole provide products endo’-78 and exo’-78 (Scheme 25).

Page 49: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

48

Scheme 25. Multicomponent synthesis of indolizidine derivatives 77 and 78 after decarboxylation

and their mechanistic details of the iminium route and endo- or exo-approach by α- and γ-attack.

The compound 76, trans-cinnamaldehyde, and NMM were diluted in

toluene and the mixture was heated in a sealed tube at 120 °C (bath temperature)

obtaining a mixture of four different stereosiomers 77a in 89% overall yield

(Table 2, entry 1 and Figure 8). Both the diastereomeric ratio observed in the crude

1H NMR spectra and the observed after separation of each isomer by column

chromatography were similar. When NPM was used it was possible to reach the

Page 50: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

49

maximum endo-diastereoselection of the series of decarboxylative reaction

yielding the product 77b in 78% (Table 2, entry 2 and Figure 8). Dimethyl and

diisobutyl fumarates gave both identical chemical yields (75%) and mixtures of

diastereoisomers of products 77c and 77d (Table 2, entries 3 and 4 and Figure 8).

tert-Butyl acrylate and trans-β-nitrostyrene were the two last examples tested and

both products 77e and 77f were isolated in low yields, 52% and 40% respectively

(Table 2, entries 5 and 6 and Figure 8).

Table 2. Multicomponent 1,3-DC between pipecolic acid 76, trans-cinnamaldehyde 71 and different

dipolarophiles to yield substituted indolizidines 77.

Entry Dipolarophile Product dra (endo:exo’:endo’:exo) Yield (%)b

1 NMM 77a 35:23:20:22 89

2 NPM 77b 45:20:18:17 78

3 dimethyl

fumarate 77c 33:20:18:29 75

4 diisobutyl

fumarate 77d 35:16:19:30 75

5 tert-butyl

acrylate 78e 39:16:17:28 52

6 trans-β-

nitrostyrene 77f 43:21:11:25 40

a Determined by 1H NMR of the crude reaction mixture.

b Overall isolated yield after purification (flash silica gel) of 4 diastereoisomers.

Page 51: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

50

Figure 8. Structures and purified yields obtained for polysubstituted indolizidines 77.

Page 52: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

51

In this decarboxylative way was not observed any of the products 78 who

come from the γ-attack whereas it was possible to synthesized four different

indolizidines derivatives 77 by the α-attack of the dipole to the dipolarophile,

which was observed, after careful analyses of selective nOe experiments of each

product and the chemical shifts and coupling constants that endo-cycloadduct is

always the most abundant stereoisomer. nOe experiments revealed clear all-cis-

arrangement in C2, C3, C4, and C5, for the endo-cycloadduct 77a (Figure 9).

Moreover, a small interaction was detected between hydrogens Ha and Hd in

compounds endo-77a and exo-77a that in contrast was not observed in endo’-77a

and exo’-77a (Figure 9).

Figure 9. Representative nOe detected for the 77a adducts.

Finally, the synthesis of indolizidine derivatives was performed with

benzaldehyde, pipecolic acid 76 and NPM affording the desired product 79 in very

high overall yield (95%) as a mixture of four stereoisomers (Scheme 26). However,

starting materials such as NMM or tert-butyl acrylate only provided

decomposition products. When other aldehydes (crotonaldehyde,

isovaleraldehyde and furfural) were mixed with NMM or NPM the reaction failed.

Page 53: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

52

Scheme 26. Synthesis of substituted indolizidines 79 after decarboxylation.

Page 54: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

53

Conclusions

1 In this work it has been studied the synthesis of new polysubstituted

indolizidines by reaction of alkyl pipecolinate or methyl 1,2,3,4-

tetrahydroisoquinoline-3-carboxylate, in a multicomponent 1,3-DC, with

aldehydes and different dipolarophiles at 70 °C.

2 It could be isolated new products in moderate to good yields and good to

high diastereoselection towards the endo-stereoisomer for

cinnamaldehyde, in contrast worst results were obtained employing other

aldehydes.

3 The diastereoselectivity of the reaction is oriented by the attack of the

reactive S-shape dipole, prepared via the iminium route, by its α-position

leading the formation of endo-products with relative configuration 2,5-

trans-2,4-trans.

4 Whereas, for chalcone and trans-β-nitrostyrene the major

diastereoisomer is the exo-one demonstrating the existence of a

stereodivergency on the basis of the dipolarophile employed.

5 Meanwhile, for pipecolic acid, due to the high temperature and the less

steric hindrance, it was observed the transformation of the S-type dipole

into unstable U-type dipole through stereomutation, because a mixture of

endo-, exo-, endo’- and exo’-77 products was detected with the relative

configuration proper of an α-attack. Thus, new decarboxylated

indolizidines could be isolated in moderate to good yields.

6 The thermal process has much more stereocontrol that the

decarboxylative route.

Page 55: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

54

Page 56: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

55

Experimental section

General methods

All commercially available reagents and solvents were used without

further purification, only aldehydes were also distilled prior to use. Analytical TLC

was performed on Schleicher & Schuell F1400/LS 254 silica gel plates, and the

spots were visualised under UV light (λ = 254 nm). Flash chromatography was

carried out on handpacked columns of Merck silica gel 60 (0.040-0.063 mm).

Melting points (mp) were determined with a Reichert Thermovar hot plate

apparatus and are uncorrected. Optical rotations were measured on a Perkin

Elmer 341 polarimeter with a thermally jacketed 5 cm cell at approximately 25 °C

and concentrations (c) are given in g/100 mL. The structurally most important

peaks of the IR spectra (recorded using a Nicolet 510 P-FT) are listed and

wavenumbers are given in cm-1. NMR spectra were obtained using a Bruker AC-

300 or AC-400 and were recorded at 300 or 400 MHz for 1H NMR and 75 or 100

MHz for 13C NMR, using CDCl3 as solvent and TMS as internal standard (0.00 ppm).

The following abbreviations are used to describe peak patterns where

appropriate: s = singlet, d = doublet, t = triplet, q = quartet, hept = heptet, m =

multiplet or unresolved, app = apparent and br s = broad signal. All coupling

constants (J) are given in Hz and chemical shifts in ppm. 13C NMR spectra were

referenced to CDCl3 at 77.16 ppm. DEPT-135 experiments were performed to

assign CH, CH2 and CH3. 19F NMR were recorded at 282 MHz using CDCl3 as solvent.

The techniques to assign the spectra were H,H-COSY, H,H-nOe and H,H-NOESY.

Low-resolution electron impact mass spectra (LRMS) were obtained at 70 eV using

a Shimadzu QP-5000 by injection or DIP; fragment ions in m/z are given with

relative intensities (%) in parentheses. High-resolution mass spectra (HRMS) were

measured on an instrument using a quadrupole time-of-flight mass spectrometer

(QTOF) and also through the electron impact mode (EI) at 70 eV using a Finnigan

VG Platform or a Finnigan MAT 95S.

Page 57: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

56

General procedure for the synthesis of indolizidines 72-73

To a solution of the pipecolic acid methyl ester hydrochloride 70 (40 mg,

0.22 mmol) in toluene (1 mL), Et3N (1 equiv., 30.5 μL, 0.22 mmol), the

corresponding aldehyde (1 equiv., 0.22 mmol) and the dipolarophile (1 equiv., 0.22

mmol) were added. The resulting mixture was stirred at 70 °C for 17 h. EtOAc

(5mL) and H2O (5 mL) were added and the organic phase was separated, dried

(MgSO4), and evaporated to obtain the crude heterocycle, which was purified by

flash chromatography (silica-gel) to yield the desired indolizidines 72-73.

Characterization of indolizidines 72-73

Dimethyl (2S*,3S*,8aR*)-3-[(E)-

styryl]hexahydroindolizine-2,8a(1H)-dicarboxylate

(endo-72a): yellow solid (43 mg, 57% yield), mp 189-190

°C (Et2O), IR (neat) 𝜈max: 2977, 2946, 1745, 1474 cm-1. 1H

NMR δ: 1.11–1.17 (m, 1H, NCH2CH2CH2), 1.33–1.51 (m, 2H,

NCH2CH2, NCH2CH2CH2), 1.52–1.60 (m, 1H, NCH2CH2), 1.65 – 1.75 (m, 1H, CCH2),

2.15 (dd, J = 12.4, 8.0, Hz, 1H, CHCH2), 2.24 (dd, J = 12.4, 10.8, Hz, 1H, CHCH2), 2.40

(dtd, J = 12.4, 3.3, 1.2 Hz, 1H, CCH2), 2.68 (td, J = 11.7, 3.3 Hz, 1H, NCH2), 2.80 (dd, J

= 11.7, 3.9 Hz, 1H, NCH2), 3.20 (td, J = 10.5, 8.0 Hz, 1H, NCHCH), 3.53 (s, 3H,

CHCO2CH3), 3.70 (s, 3H, CCO2CH3), 4.10 (ddd, J = 10.8, 8.8, 8.0 Hz, 1H, NCH), 5.91

(dd, J = 15.8, 8.8 Hz, 1H, PhCHCH), 6.53 (d, J = 15.8 Hz, 1H, PhCH), 7.15–7.21 (m,

1H, ArH), 7.23–7.30 (m, 2H, ArH), 7.31–7.38 (m, 2H, ArH). 13C NMR δ: 22.0

(NCH2CH2CH2), 25.3 (NCH2CH2), 34.6 (CCH2CH2), 39.0 (CCH2CH), 43.4 (NCH2), 45.5

(CHCO2Me), 51.2 (OCH3), 51.6 (OCH3), 65.2 (NCH), 68.6 (CCO2Me), 126.4, 127.5,

128.5, 129.7, 132.9, 136.9 (ArC, C=C), 173.3 (CO2Me), 175.6 (CO2Me). LRMS (EI)

m/z: 343 (M+, 2%), 285 (20), 284 (100), 224 (12). HRMS calculated for C20H25NO4:

343.1784; found: 343.1800.

Page 58: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of indolizidines 72-73

57

Methyl (3aS*,4S*,9aR*,9bR*)-1,3-dioxo-4-[(E)-

styryl]octahydro-3H,9aH-furo[3,4-a]indolizine-9a-

carboxylate (endo-72b): colorless prisms (72 mg, 93% yield),

mp 146-148 °C (Et2O), IR (neat) 𝜈max: 1774, 1734, 1226 cm-1.

1H NMR δ: 1.15–1.25 (m, 1H, NCH2CH2CH2), 1.50 (ddt, J = 12.9,

8.4, 3.9 Hz, 1H, NCH2CH2CH2), 1.58–1.69 (m, 1H, NCH2CH2),

1.67–1.85 (m, 2H, CCH2, NCH2CH2), 2.45 (ddd, J = 12.7, 4.5, 1.9 Hz, 1H, CCH2), 2.90

(d, J = 2.7 Hz, 1H, NCH2), 2.93 (d, J = 2.7 Hz, 1H, NCH2), 3.54 (dd, J = 8.5, 8.3 Hz, 1H,

NCHCH), 3.71 (d, J = 8.5 Hz, 1H, CCH), 3.79 (s, 3H, OCH3), 4.27 (dd, J = 9.3, 8.3 Hz,

1H, NCH), 5.98 (dd, J = 15.7, 9.3 Hz, 1H, PhCHCH), 6.73 (d, J = 15.7 Hz, 1H, PhCH),

7.26–7.36 (m, 3H, ArH), 7.39–7.44 (m, 2H, ArH). 13C NMR δ: 21.3 (NCH2CH2CH2),

24.3 (NCH2CH2), 31.5 (CCH2), 44.1 (NCH2), 48.4 (NCHCHCO), 52.0 (CCHCO), 52.4

(OCH3), 66.0 (NCH), 70.6 (CCO2Me), 125.5, 127.1, 128.4, 128.8, 136.2, 136.4 (ArC,

C=C), 169.0, 169.4 (2xNCO), 172.4 (CO2Me). LRMS (EI) m/z: 355 (M+, 5%), 297

(20), 296 (100), 225 (10), 224 (50). HRMS calculated for C20H21NO5: 355.1420;

found 355.1426.

Methyl (3aS*,4S*,9aR*,9bR*)-2-methyl-1,3-dioxo-4-[(E)-

styryl]decahydro-9aH-pyrrolo[3,4-a]indolizine-9a-

carboxylate (endo-72c): colorless prims (36 mg, 59% yield),

mp 134-135 °C (Et2O), IR (neat) 𝜈max: 1734, 1698, 1213 cm-1.

1H NMR δ: 1.18 (dt, J = 13.3, 3.5 Hz, 1H, NCH2CH2CH2), 1.27–

1.48 (m, 1H, NCH2CH2CH2), 1.45–1.63 (m, 2H, NCH2CH2), 1.74

(dt, J = 13.2, 3.4 Hz, 1H, CCH2), 2.48 (ddd, J = 13.2, 2.9, 1.4 Hz, 1H, CCH2), 2.81, 2.84

(2xd, J = 2.7 Hz, 2H, NCH2), 3.01 (s, 3H, NCH3), 3.25 (dd, J = 8.0, 7.9 Hz, 1H, NCHCH),

3.35 (d, J = 7.9 Hz, 1H, CCH), 3.76 (s, 3H, OCH3), 4.18 (dd, J = 9.2, 8.0, Hz, 1H, NCH),

5.88 (dd, J = 15.6, 9.2 Hz, 1H, PhCHCH), 6.68 (d, J = 15.6 Hz, 1H, PhCH), 7.22–7.35

(m, 3H, ArH), 7.36–7.45 (m, 2H, ArH). 13C NMR δ: 21.7 (NCH2CH2CH2), 24.7

(NCH2CH2), 25.1 (NCH3), 32.0 (CCH2), 43.8 (NCH2), 47.9 (NCHCHCO), 51.4 (CCHCO),

51.8 (OCH3), 65.2 (NCH), 69.9 (CCO2Me), 126.7, 127.8, 128.6, 128.7, 134.5, 136.8

(ArC, C=C), 173.6, 175.3 (2xNCO), 175.9 (CO2Me). LRMS (EI) m/z: 368 (M+, 3%),

310 (20), 309 (100), 224 (3). HRMS calculated for C21H24N2O4: 368.1746; found

368.1750.

Page 59: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

58

Methyl (3aS*,4S*,9aR*,9bR*)-1,3-dioxo-2-phenyl-4-[(E)-

styryl]decahydro-9aH-pyrrolo[3,4-a]indolizine-9a-

carboxylate (endo-72d): pale yellow oil (52 mg, 55% yield),

IR (neat) 𝜈max: 2933, 1710, 1498, 1448, 1375, 1179, 1309,

1192 cm-1. 1H NMR δ: 1.17–1.23 (m, 1H, NCH2CH2CH2), 1.28–

1.35 (m, 1H, NCH2CH2CH2), 1.38–1.48 (m, 1H, NCH2CH2),

1.62–1.68 (m, 1H, NCH2CH2), 1.78 (dt, J = 13.1, 3.2 Hz, 1H, CCH2), 2.53 (dd, J = 13.1,

1.5 Hz, 1H, CCH2), 2.82–2.93 (m, 2H, NCH2), 3.41 (t, J = 8.0, Hz, 1H, NCHCH), 3.51

(d, J = 8.0 Hz, 1H, CCH), 3.79 (s, 3H, OCH3), 4.29 (dd, J = 8.9, 8.0, Hz, 1H, NCH), 6.01

(dd, J = 15.7, 8.9 Hz, 1H, PhCHCH), 6.72 (d, J = 15.7 Hz, 1H, PhCH), 7.16–7.35 (m,

5H, ArH), 7.37–7.50 (m, 5H, ArH). 13C NMR δ: 21.8 (NCH2CH2CH2), 24.9 (NCH2CH2),

32.1 (CCH2), 44.0 (NCH2), 48.0 (NCHCHCO), 51.4 (CCHCO), 51.9 (OCH3), 65.5

(NCH), 70.4 (CCO2Me), 126.7, 126.9, 127.7, 127.9, 128.6, 128.8, 129.3, 132.0, 134.4,

136.8 (ArC, C=C), 173.6 (CO), 174.2 (CO), 175.0 (CO2Me). LRMS (EI) m/z: 430 (M+,

3%), 372 (26), 371 (100), 224 (6). HRMS calculated for C26H26N2O4: 430.1893;

found 430.1911.

Trimethyl (1S*,2S*,3S*,8aR*)-3-[(E)-

styryl]hexahydroindolizine-1,2,8a(1H)-tricarboxylate

(endo-72e): pale yellow oil (62 mg, 70% yield), IR (neat)

𝜈max: 1732, 1201, 1167 cm-1. 1H NMR δ: 1.24 (tdd, J = 13.5,

8.8, 3.9 Hz, 1H, NCH2CH2CH2), 1.46–1.65 (m, 3H, NCH2CH2,

NCH2CH2CH2), 1.68–1.79 (m, 1H, CCH2), 2.40–2.72 (m, 2H, NCH2, CCH2), 2.76–2.85

(m, 1H, NCH2), 3.43 (d, J = 10.8 Hz, 1H, CCH), 3.55 (s, 3H, CHCO2CH3), 3.68 (s, 3H,

CHCO2CH3), 3.69 (dd, J = 10.8, 10.5 Hz, 1H, NCHCH), 3.70 (s, 3H, CCO2CH3), 4.19 (dd,

J = 10.5, 9.1 Hz, 1H, NCH), 5.87 (dd, = 15.8, 9.1 Hz, 1H, PhCHCH), 6.55 (d, J = 15.8

Hz, 1H, PhCH), 7.19–7.37 (m, 5H, ArH). 13C NMR δ: 21.8 (NCH2CH2CH2), 25.1

(NCH2CH2), 34.5 (CCH2), 43.8 (NCH2), 48.2 (CCH), 51.7 (NCHCH), 52.1 (OCH3), 52.3

(OCH3), 55.0 (OCH3), 64.4 (NCH), 70.9 (CCO2Me), 126.6, 127.8, 128.7, 128.9, 133.7,

136.8 (ArC, C=C), 171.0 (CCO2Me), 172.3 (CHCO2Me), 172.8 (CHCO2Me). LRMS (EI)

m/z: 401 (M+, 5%), 343 (21), 342 (100), 310 (13), 282 (38), 250 (23). HRMS

calculated for C22H27NO6: 401.1838; found 401.1849.

Page 60: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of indolizidines 72-73

59

Methyl (1R*,2S*,3S*,8aR*)-2-benzoyl-1-

phenyl-3-[(E)-styryl]hexahydroindolizine-

8a(1H)-carboxylate (endo-72f) and Methyl

(1S*,2R*,3S*,8aR*)-2-benzoyl-1-phenyl-3-

[(E)-styryl]hexahydroindolizine-8a(1H)-

carboxylate (exo-72f): colorless sticky oil (68 mg, 66% yield), IR (neat) 𝜈max:

1718, 1682, 1447, 1207 cm-1. 1H NMR δ (mixture of endo:exo 0.33:1): 1.13–1.19

(m, exo-2H, NCHCHCH2), 1.20–1.24 (m, endo-2H, NCHCHCH2), 1.49–1.56 (m, endo-

2H, NCHCH2, exo-2H, NCHCH2), 1.68–1.81 (m, endo-1H, CCH2, exo-1H, CCH2), 1.88–

1.93 (m, endo-2H, NCH2, CCH2), 2.36 (dt, J = 12.3, 3.4 Hz, exo-1H, CCH2), 2.49 (td, J

= 11.4, 4.0 Hz, exo-1H, NCH2), 2.87 (dd, J = 15.3, 3.8 Hz, exo-1H, NCH2), 2.96–2.92

(m, endo-1H, NCH2), 3.42 (s, exo-3H, OCH3), 3.90 (dd, J = 8.5, 6.3 Hz, endo-1H,

NCHCH), 3.93 (s, endo-3H, OCH3), 4.03 (d, J = 11.2 Hz, exo-1H, CCH), 4.13 (dd, J =

8.5, 8.3 Hz, endo-1H, NCH), 4.26 (d, J = 6.3 Hz, endo-1H, CCH), 4.58 (dd, J = 10.2, 8.8

Hz, exo-1H, NCH), 4.85 (dd, J = 11.2, 10.2 Hz, exo-1H, NCHCH), 5.71 (dd, J = 15.7, 8.8

Hz, exo-1H, PhCHCH), 6.20 (dd, J = 15.9, 8.3 Hz, endo-1H, PhCHCH), 6.30 (d, J = 15.7

Hz, exo-1H, PhCH), 6.37 (d, J = 15.9 Hz, endo-1H, PhCH), 7.04–7.23 (m, endo-9H,

exo-9H, ArH), 7.28–7.46 (m, endo-4H, exo-4H, ArH), 7.83–7.92 (m, exo-2H, ArH),

8.01–8.08 (m, endo-2H, ArH). 13C NMR δ (major diastereoisomer): 22.3

(NCH2CH2CH2), 25.4 (NCH2CH2), 33.8 (CCH2), 44.0 (NCH2), 50.8 (CCHPh), 51.9

(CHCO), 55.2 (OCH3), 65.8 (NCH), 73.6 (CCO2Me), 126.5, 126.6, 127.4, 127.5, 128.1,

128.1, 128.3, 128.4, 128.4, 128.5, 128.5, 128.6, 128.7, 128.9, 129.9, 133.0, 133.0,

136.7, 137.0, 138.1 (ArC, C=C), 174.6 (CO2Me), 198.5 (CO). LRMS (EI) m/z: 465 (M+,

3%), 407 (30), 406 (100), 360 (8). HRMS calculated for C31H31NO3: 465.2324;

found 465.2334.

Methyl (1S*,2S*,3S*,8aR*)-2-nitro-1-phenyl-3-[(E)-

styryl]hexahydroindolizine-8a(1H)-carboxylate (endo-

72g): brown sticky oil (15 mg, 17% yield), IR (neat) 𝜈max: 1544,

1355, 1083, 767, 749 cm-1. 1H NMR δ: 1.08–1.32 (m, 2H,

NCH2CH2CH2), 1.47–1.65 (m, 2H, NCH2CH2), 1.69–1.82 (m, 1H,

CCH2), 2.21–2.56 (m, 2H, NCH2, CCH2), 2.86–2.93 (m, 1H, NCH2), 3.43 (s, 3H, OCH3),

4.09 (d, J = 10.0 Hz, 1H, CCHPh), 4.69 (dd, J = 9.6, 8.4 Hz, 1H, NCH), 5.74 (dd, J =

10.0, 9.6 Hz, 1H, CHNO2), 5.90 (dd, J = 15.8, 8.4 Hz, 1H, PhCHCH), 6.72 (d, J = 15.8

Page 61: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

60

Hz, 1H, PhCH), 7.08–7.21 (m, 2H, ArH), 7.27–7.34 (m, 6H, ArH), 7.35–7.42 (m, 2H,

ArH). 13C NMR δ: 21.9 (NCH2CH2CH2), 25.1 (NCH2CH2), 33.6 (CCH2), 44.6 (CCHPh),

51.1 (NCH2), 57.9 (OCH3), 65.7 (NCH), 73.4 (CCO2Me), 91.1 (CHNO2), 126.0, 127.0,

127.9, 127.9, 128.2, 128.4, 128.6, 128.8, 133.5, 136.3 (ArC, C=C), 173.6 (CO2Me).

LRMS (EI) m/z: 406 (M+, <1%), 361 (15), 360 (57), 348 (20), 347 (80), 301 (33),

300 (100), 210 (17), 198 (16), 91 (18). HRMS calculated for C24H26NO2 [M–NO2]:

360.1983; found: 360.1974.

Methyl (1S*,2R*,3S*,8aR*)-1-nitro-2-phenyl-3-[(E)-

styryl]hexahydroindolizine-8a(1H)-carboxylate (exo-73g):

colorless prisms (62 mg, 55% yield), mp 146-148 °C (Et2O), IR

(neat) 𝜈max: 1734, 1556, 1363, 1265, 1223, 1154, 737 cm-1. 1H

NMR δ: 1.21–1.38 (m, 2H, NCH2CH2CH2), 1.50–1.70 (m, 2H,

NCH2CH2), 1.74–1.87 (m, 1H, CCH2), 2.24–2.31 (m, 1H, CCH2), 2.96–3.02 (m, 2H,

NCH2), 3.86 (s, 3H, OCH3), 3.93 (dd, J = 8.4, 5.2 Hz, 1H, NCHCHPh), 4.08 (t, J = 8.4

Hz, 1H, NCH), 5.22 (d, J = 5.2, 1H, CHNO2), 6.15 (dd, J = 15.8, 8.4 Hz, 1H, PhCHCH),

6.40 (d, J = 15.8 Hz, 1H, PhCH), 7.06–7.12 (m, 2H, ArH), 7.22–7.39 (m, 8H, ArH). 13C

NMR δ: 21.6 (NCH2CH2CH2), 24.6 (NCH2CH2), 31.5 (CCH2), 43.7 (NCHCHPh), 52.4

(NCH2), 54.5 (OCH3), 71.5 (NCH), 72.0 (CCO2Me), 97.9 (CHNO2), 126.7, 127.7, 128.0,

128.2, 128.7, 129.1, 129.5, 134.7, 136.5, 138.1 (ArC, C=C), 172.8 (CO2Me). LRMS

(EI) m/z: 406 (M+, <1%), 361 (25), 360 (91), 347 (51), 302 (25), 301 (100), 300

(39), 224 (18), 210 (45), 111 (26), 91 (18). HRMS calculated for C24H26NO2 [M–

NO2]: 360.1983; found: 360.1974.

Methyl (3aS*,4R*,9aR*,9bR*)-1,3-dioxo-4-

phenyloctahydro-3H,9aH-furo[3,4-a]indolizine-9a-

carboxylate (endo-72h): yellow sticky oil (20 mg, 27% yield),

IR (neat) 𝜈max: 2927, 2856, 1781, 1733, 1209, 922, 734 cm-1. 1H

NMR δ: 1.53–1.39 (m, 2H, NCHCHCH2), 1.55–1.65 (m, 1H,

NCH2CH2), 1.83 (dt, J = 13.8, 3.5 Hz, 1H, NCH2CH2), 1.96 (td, J = 13.4, 3.9 Hz, 1H,

CCH2), 2.45–2.55 (m, 1H, CCH2), 2.65 (dd, J = 11.9, 4.3 Hz, 1H, NCH2), 2.78 (td, J =

11.9, 3.3 Hz, 1H, NCH2), 3.61 (dd, J = 9.4, 8.3 Hz, 1H, PhCHCH), 3.69 (d, J = 8.3 Hz,

1H, CCHCO), 3.79 (s, 3H, OCH3), 4.75 (d, J = 9.4 Hz, 1H, PhCH), 7.22–7.28 (m, 2H,

ArH), 7.29–7.40 (m, 3H, ArH). 13C NMR δ: 21.4 (NCH2CH2CH2), 24.6 (NCH2CH2),

Page 62: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of indolizidine 74

61

31.0 (CCH2), 44.1 (NCH2), 49.6 (NCHCHCO), 52.2 (OCH3), 52.1 (CCHCO), 67.7

(NCH), 70.9 (CCO2Me), 127.8, 128.6, 128.8, 128.9, 130.2, 136.5 (ArC, C=C), 169.0,

169.2 (2xNCO), 172.9 (CO2Me). LRMS (EI) m/z: 329 (M+, <1%), 271 (18), 270

(100), 220 (8), 198 (67). HRMS calculated for C16H16NO3 [M–CO2Me]: 270.1130;

found 270.1132.

General procedure for the synthesis of indolizidine 74

To a solution of the ethyl pipecolinate 57 (0.22 mmol) in toluene (1 mL),

the corresponding aldehyde (1 equiv., 0.22 mmol) and the dipolarophile (1 equiv.,

0.22 mmol) were added. The resulting mixture was stirred at 70 °C for 17 h. The

solvent was evaporated to obtain the crude product which was purified by flash

chromatography (silica-gel) in good chemical yields.

Characterization of indolizidine 74

Ethyl (3aS*,4R*,9aR*,9bR*)-4-(furan-2-yl)-2-methyl-1,3-

dioxodecahydro-9aH-pyrrolo[3,4-a]indolizine-9a-

carboxylate (endo-74): white prisms (30 mg, 39% yield), mp

121-124 °C (Et2O), IR (neat) 𝜈max: 2936, 1699, 1432, 1377,

1281, 1230, 1148, 1006, 755 cm-1. 1H NMR δ: 1.21 (dt, J = 13.3,

3.8 Hz, 1H, NCH2CH2CH2), 1.32 (t, J = 7.2 Hz, 3H, CH2CH3), 1.44

(ddd, J = 12.4, 5.3, 4.1 Hz, 1H, NCH2CH2CH2), 1.51–1.61 (m, 1H, NCH2CH2), 1.78 (dd,

J = 13.9, 6.0 Hz, 1H, NCH2CH2), 1.87 (td, J = 13.2, 3.7 Hz, 1H, CCH2), 2.53 (ddt, J =

13.2, 4.6, 2.1 Hz, 1H, CCH2), 2.56–2.65 (m, 1H, NCH2), 2.79 (td, J = 11.7, 3.5 Hz, 1H,

NCH2), 2.93 (s, 3H, NCH3), 3.28–3.40 (m, 2H, NCHCH, CCH), 4.23 (q, J = 7.2 Hz, 2H,

CH2CH3), 4.80 (d, J = 8.2 Hz, 1H, NCH), 6.24 (dd, J = 3.2, 0.8 Hz, 1H, OCHCHCH), 6.33

(dd, J = 3.2, 1.9 Hz, 1H, OCHCH), 7.38 (dd, J = 1.9, 0.8 Hz, 1H, OCH). 13C NMR δ: 14.5

(CH2CH3), 21.6 (NCH2CH2CH2), 24.7 (NCH2CH2), 25.1 (NCH3), 30.9 (CCH2), 44.3

(NCH2), 47.0 (NCHCHCO), 51.3 (CCHCO), 61.0 (CH2CH3), 61.2 (NCH), 69.9 (CCO2Et),

109.2 (OCHCH), 110.3 (OCCH), 142.8 (OCH), 151.1 (OCCH), 173.1, 175.0 (2xNCO),

Page 63: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

62

175.8 (CO2Et). LRMS (EI) m/z: 346 (M+, <1%), 274 (16), 273 (100). HRMS

calculated for C18H22N2O5: 346.1529; found: 346.1519.

General procedure for the synthesis of indolizidine 75

To a solution of the amine 62 (40 mg, 0.21 mmol) in toluene (1 mL), the

corresponding aldehyde (1 equiv., 0.21 mmol) and the dipolarophile (1 equiv., 0.21

mmol) were added. The resulting mixture was stirred at 70 °C for 17 h. The solvent

was evaporated and the heterocycles were separated by flash chromatography

(silica-gel) in good chemical yields.

Characterization of indolizidine 75

Methyl (3aS*,4S*,11aR*,11bR*)-1,3-dioxo-2-phenyl-

4-[(E)-styryl]-1,2,3,3a,4,6,11,11b-octahydro-11aH-

pyrrolo[3',4':3,4]pyrrolo[1,2-b]isoquinoline-11a-

carboxylate (endo-75): white solid (68 mg, 65% yield),

mp 209-212 °C (Et2O), IR (neat) 𝜈max: 1703, 1494, 1396,

1203 cm-1. 1H NMR δ: 2.98 (d, J = 16.8 Hz, 1H, CCH2), 3.44

(d, J = 8.0 Hz, 1H, CCHCO), 3.52 (d, J = 16.8 Hz, 1H, CCH2), 3.55 (dd, J = 8.2, 8.0 Hz,

1H, NCHCH), 3.72 (s, 3H, OCH3), 3.88 (dd, J = 8.6, 8.2 Hz, 1H, NCH), 3.95 (d, J = 18.1

Hz, 1H, NCH2), 4.31 (d, J = 18.1 Hz, 1H, NCH2), 6.22 (dd, J = 15.7, 8.6 Hz, 1H,

PhCHCH), 6.62 (d, J = 15.7 Hz, 1H, PhCH), 6.94–7.06 (m, 1H, ArH), 7.09–7.21 (m,

3H, ArH), 7.23–7.32 (m, 5H, ArH), 7.37–7.48 (m, 5H, ArH). 13C NMR δ: 30.2 (CCH2),

45.4 (NCH2), 47.4 (NCHCHCO), 52.8 (CCHCO), 53.7 (OCH3), 64.8 (NCH), 68.8

(CCO2Me), 126.2, 126.5, 126.6, 126.9, 127.1, 128.2, 128.7, 128.8, 129.0, 129.2,

130.6, 131.9, 135.2, 136.3 (ArC, C=C), 170.9 (CO), 174.2 (CO), 174.6 (CO2Me). LRMS

(EI) m/z: = 478 (M+, <1%), 420 (31), 419 (100), 180 (4). HRMS calculated for

C30H26N2O4: 478.1893; found 478.1883.

Page 64: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of indolizidines 77 and 79

63

General procedure for the synthesis of indolizidines 77 and 79

To a solution of the pipecolinic acid 76 (40 mg, 0.31 mmol) in toluene (1

mL), the corresponding aldehyde (1 equiv., 0.31 mmol) and the dipolarophile (1

equiv., 0.31 mmol) were added. The resulting mixture was stirred in a pressure

tube at 120 °C for 17 h. The solvent was evaporated and the mixture was separated

by flash chromatography affording the corresponding cycloadducts.

Characterization of indolizidines 77 and 79

(3aS*,4S*,9aR*,9bR*)-2-Methyl-4-[(E)-

styryl]octahydro-1H-pyrrolo[3,4-

a]indolizine-1,3(2H)-dione (endo-77a) and

(3aR*,4R*,9aR*,9bS*)-2-Methyl-4-[(E)-

styryl]octahydro-1H-pyrrolo[3,4-

a]indolizine-1,3(2H)-dione (endo’-77a):

brown sticky oil (57 mg, 59% yield), IR (neat) 𝜈max: 2938, 1697, 1433, 1382, 1281,

1239, 1138, 1039, 965, 749, 694 cm-1. 1H NMR δ (mixture of endo:exo’ 1:0.9): 1.11–

1.28 (m, endo-2H, NCHCH2, exo’-1H, NCHCH2), 1.34–1.45 (m, endo-1H, NCH2CH2,

exo’-1H, NCHCH2), 1.50–1.66 (m, endo-1H, NCH2CH2, exo’-1H, NCH2CH2), 1.69–1.90

(m, endo-1H, NCH2CH2CH2, exo’-2H, NCH2CH2CH2, CH2CH2), 1.97–2.12 (m, endo-1H,

NCH2CH2CH2, exo’-1H, NCH2CH2CH2), 2.18–2.36 (m, J = m, endo-1H, NCH2, exo’-1H,

NCH2), 2.79–2.93 (m, endo-2H, NCHCH2, NCH2, exo’-1H, NCHCH2), 2.98–3.02 (m,

endo-3H, NCH3, exo’-4H, NCH3, NCHCH), 3.03–3.08 (m, endo-1H, NCHCH, exo’-1H,

NCH2), 3.10–3.32 (m, endo-1H, CH2CHCH, exo’-2H, NCHCH, CH2CHCH), 4.13 (d, J =

9.6 Hz, endo-1H, NCHCH), 6.12 (dd, J = 15.7, 9.2 Hz, exo’-1H, PhCHCH), 6.26 (dd, J =

15.7, 9.6 Hz, endo-1H, PhCHCH), 6.61 (d, J = 15.7 Hz, exo’-1H, PhCH), 6.64 (d, J =

15.7 Hz, endo-1H, PhCH), 7.46 – 7.21 (m, endo-5H, exo’-5H, ArH). 13C NMR δ

(mixture of endo:exo’): 24.4, 24.4 (2xNCH2CH2CH2), 24.8, 25.0 (2xNCH2CH2), 25.0,

25.1 (2xNCH3), 28.0, 28.9 (2xNCHCH2), 47.1, 47.6, 48.2 (3xCHCO), 48.5 (NCH2),

50.0 (CHCO), 51.8 (NCH2), 60.5, 65.9, 67.8, 70.5 (4xNCH), 125.0, 126.5, 126.8,

127.9, 128.0, 128.2, 128.6, 128.7, 134.3, 134.5, 136.3, 136.7 (ArC, 2xC=C), 176.4,

176.7, 176.9, 178.7 (4xCO). LRMS (EI) m/z: 310 (M+, 18%), 309 (17), 220 (14), 219

Page 65: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

64

(100), 199 (20), 198 (17), 115 (10). HRMS calculated for C19H22N2O2: 310.1681;

found: 310.1668.

(3aR*,4S*,9aR*,9bS*)-2-Methyl-4-[(E)-styryl]octahydro-

1H-pyrrolo[3,4-a]indolizine-1,3(2H)-dione (exo-77a):

yellow sticky oil (21 mg, 22% yield), IR (neat) 𝜈max: 2919,

2850, 1698, 1435, 1283, 1122, 1074, 1010, 966, 732, 694 cm-

1. 1H NMR δ: 1.21–1.30 (m, 1H, NCHCH2), 1.44–1.53 (m, 4H,

NCH2CH2, NCHCH2), 1.55–1.69 (m, 1H, NCH2CH2), 1.78–1.89

(m, 2H, NCH2CH2CH2), 2.62–2.75 (m, 1H, NCH2), 2.88 (dd, J = 8.2, 2.1 Hz, 1H,

CH2CHCH), 2.91–2.98 (m, 1H, NCH2), 3.00 (s, 1H, NCH3), 3.38 (dd, J = 8.2, 8.0 Hz,

1H, NCHCHCO), 3.44–3.51 (m, 1H, NCH2), 4.10 (dd, J = 9.5, 8.0 Hz, 1H, NCHCHCO),

5.93 (dd, J = 15.7, 9.5 Hz, 1H, PhCHCH), 6.64 (d, J = 15.7 Hz, 1H, PhCH), 7.23–7.42

(m, 5H, ArH). 13C NMR δ: 19.2 (NCH2CH2CH2), 24.5 (NCH2CH2), 25.2 (NCH3), 27.0

(NCHCH2), 45.5 (NCH2), 48.7 (NCHCHCO), 50.5 (NCHCHCO), 62.1, 62.1 (2xNCH),

126.5, 126.8, 127.9, 128.6, 134.6, 136.6 (ArC, C=C), 176.5, 178.8 (2xNCO). LRMS

(EI) m/z: 310 (M+, 18%), 309 (16), 220 (14), 219 (100), 199 (9), 198 (12), 115 (9).

HRMS calculated for C19H22N2O2: 310.1681; found: 310.1668.

(3aS*,4S*,9aR*,9bR*)-2-Phenyl-4-[(E)-styryl]octahydro-

1H-pyrrolo[3,4-a]indolizine-1,3(2H)-dione (endo-77b):

yellow sticky oil (31 mg, 27% yield), IR (neat) 𝜈max: 2941,

1708, 1498, 1381, 1185, 968, 849, 734 cm-1. 1H NMR δ: 1.15–

1.29 (m, 2H, NCHCH2CH2), 1.38–1.47 (m, 1H, NCH2CH2), 1.54–

1.63 (m, 1H, NCH2CH2), 1.77–1.85 (m, 1H, NCH2CH2CH2), 2.02–

2.13 (m, 1H, NCH2CH2CH2), 2.34 (td, J = 11.5, 3.0 Hz, 1H, NCH2), 2.85–2.92 (m, 1H,

NCH2), 2.96 (ddd, J = 10.8, 8.4, 2.7 Hz, 1H, NCHCH2), 3.22 (dd, J = 7.9, 0.8 Hz, 1H,

NCHCHCO), 3.43 (dd, J = 8.4, 7.9 Hz, 1H, CH2CHCH), 4.25 (d, J = 9.5 Hz, 1H,

NCHCHCO), 6.30 (dd, J = 15.7, 9.5 Hz, 1H, PhCHCH), 6.67 (d, J = 15.7 Hz, 1H, PhCH),

7.19–7.52 (m, 10H, ArH). 13C NMR δ: 24.5 (NCH2CH2CH2), 25.2 (NCH2CH2), 29.3

(NCHCH2), 47.6 (NCHCHCO), 48.6 (NCH2), 50.2 (NCHCHCO), 60.8 (NCH), 68.2

(NCH), 124.8, 126.2, 126.9, 128.1, 128.6, 128.8, 129.1, 132.3, 134.4, 136.4 (ArC,

C=C), 176.0, 177.8 (2xNCO). LRMS (EI) m/z: 372 (M+, 23%), 371 (16), 282 (19),

Page 66: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of indolizidines 77 and 79

65

281 (100), 199 (32), 198 (18), 115 (10). HRMS calculated for C24H24N2O2:

372.1838; found: 372.1828.

(3aR*,4S*,9aR*,9bS*)-2-Phenyl-4-[(E)-styryl]octahydro-

1H-pyrrolo[3,4-a]indolizine-1,3(2H)-dione (exo-77b):

white prisms

(17 mg, 15% yield), mp 133-137 °C (Et2O), IR (neat) 𝜈max:

2930, 1705, 1498, 1384, 1189, 974, 749 cm-1. 1H NMR δ: 1.25–

1.34 (m, 2H, NCHCH2), 1.46–1.62 (m, 2H, NCH2CH2), 1.69–1.76

(m, 1H, NCH2CH2CH2), 1.79–1.95 (m, 1H, NCH2CH2CH2), 2.66–2.79 (m, 1H, NCH2),

2.93–3.02 (m, 1H, NCHCH2), 3.06 (dd, J = 8.4, 2.4 Hz, 1H, CH2CHCH), 3.56 (dd, J =

8.4, 8.2 Hz, 1H, NCHCHCO), 3.53–3.59 (m, 1H, NCH2), 4.21 (dd, J = 9.1, 8.2 Hz, 1H,

NCHCHCO), 6.05 (dd, J = 15.7, 9.1 Hz, 1H, PhCHCH), 6.69 (d, J = 15.7 Hz, 1H, PhCH),

7.23–7.46 (m, 10H, ArH). 13C NMR δ: 19.7 (NCH2CH2CH2), 24.5 (NCH2CH2), 27.4

(NCHCH2), 45.8 (NCH2), 48.7 (NCHCHCO), 50.6 (NCHCHCO), 62.5 (NCH), 62.8

(NCH), 125.9, 126.6, 126.9, 128.0, 128.6, 128.7, 129.2, 132.1, 134.7, 136.6 (ArC,

C=C), 175.5, 177.8 (2xNCO). LRMS (EI) m/z: 372 (M+, 23%), 371 (13), 282 (19),

281 (100), 199 (15), 198 (14). HRMS calculated for C24H24N2O2: 372.1838; found:

372.1828.

Dimethyl (1S*,2S*,3S*,8aR*)-3-[(E)-

styryl]octahydroindolizine-1,2-

dicarboxylate (endo-77c) and dimethyl

(1R*,2R*,3R*,8aR*)-3-[(E)-

styryl]octahydroindolizine-1,2-

dicarboxylate (endo’-77c): yellow oil (37 mg, 35% yield), IR (neat) 𝜈max: 2934,

2853, 1733, 1436, 1300, 1196, 1168, 1011, 968, 749, 693 cm-1. 1H NMR δ (mixture

of endo:exo’ 1:0.75, difficult assignment): 1.04–1.41 (m, 4H), 1.49 (tt, J = 7.1, 3.6 Hz,

3H), 1.64–1.71 (m, 1H), 1.78 (td, J = 9.2, 7.4, 4.2 Hz, 2H), 1.87–1.96 (m, 1H), 2.36–

2.50 (m, 2H), 2.80–2.96 (m, 3H), 3.08 (dd, J = 7.8, 7.1 Hz, 1H), 3.15 (ddd, J = 11.5,

8.9, 2.9 Hz, 1H), 3.27 (dd, J = 7.1, 4.2 Hz, 1H), 3.55 (s, 2H), 3.71 (s, J = 1.0 Hz, 5H),

3.75 (s, 2H), 3.88 (t, J = 8.1 Hz, 1H), 4.03–4.15 (m, 2H), 6.09 (dd, J = 15.7, 9.8 Hz,

1H), 6.28 (dd, J = 15.7, 9.5 Hz, 1H), 6.54 (d, J = 15.7 Hz, 1H), 6.57 (d, J = 15.7 Hz, 1H),

7.22–7.35 (m, 7H), 7.36–7.42 (m, 2H). 13C NMR δ (mixture of endo:exo’ 1:0.75,

Page 67: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

66

difficult assignment): 23.4, 23.7, 24.0, 24.3, 27.3, 30.5, 47.6, 48.0, 48.1, 49.4, 51.5,

51.9, 52.0, 52.3, 52.3, 61.3, 63.3, 66.3, 67.2, 124.8, 126.6, 127.8, 127.8, 128.4, 132.2,

134.7, 136.6, 172.2, 173.1, 173.7, 173.8. LRMS (EI) m/z: 343 (M+, 33%), 284 (35),

282 (19), 253 (15), 252 (100), 250 (17), 199 (39), 198 (24), 115 (17). HRMS

calculated for C20H25NO4: 343.1784; found: 343.1785.

Dimethyl (1S*,2S*,3R*,8aR*)-3-((E)-

styryl)octahydroindolizine-1,2-

dicarboxylate (exo’-77c) and Dimethyl

(1R,2R,3S,8aR)-3-[(E)-

styryl]octahydroindolizine-1,2-

dicarboxylate (exo-77c): yellow oil (43 mg, 40% yield), IR (neat) 𝜈max: 2944,

2854, 1733, 1436, 1196, 1167, 1005, 969, 746, 693 cm-1. 1H NMR δ (mixture of

endo’:exo 0.65:1, difficult assignment): 1.06–1.25 (m, 2H), 1.43 (tdd, J = 12.4, 10.8,

3.6 Hz, 2H), 1.58 (q, J = 3.4 Hz, 2H), 1.76–1.91 (m, 4H), 1.98–2.07 (m, 1H), 2.19 (td,

J = 10.4, 2.5 Hz, 1H), 2.43 (ddd, J = 10.8, 8.3, 2.3 Hz, 1H), 2.95–3.05 (m, 1H), 3.12 (d,

J = 10.9 Hz, 1H), 3.18–3.32 (m, 3H), 3.37 (dd, J = 8.5, 4.9 Hz, 1H), 3.43 (dd, J = 10.0,

7.8 Hz, 1H), 3.59 (s, 3H), 3.66 (s, 2H), 3.70 (s, 3H), 3.73 (s, 2H), 5.95 (dd, J = 15.8,

8.6 Hz, 1H), 6.21 (dd, J = 15.8, 8.5 Hz, 1H), 6.55 (dd, J = 15.8 Hz, 1H), 6.57 (dd, J =

15.8 Hz, 1H), 7.16–7.45 (m, 9H). 13C NMR δ (mixture of endo’:exo 0.65:1, difficult

assignment): 24.0, 24.3, 24.7, 24.9, 28.4, 30.5, 49.5, 49.8, 50.7, 51.2, 51.2, 51.7, 51.9,

51.9, 52.0, 52.1, 66.4, 66.7, 69.3, 72.0, 126.5, 126.6, 127.2, 127.7, 127.8, 128.6,

128.6, 129.1, 134.0, 134.1, 136.7, 173.8, 173.1, 173.3, 173.8. LRMS (EI) m/z: 343

(M+, 34%), 284 (36), 253 (15), 252 (100), 199 (66), 198 (36), 192 (12), 157 (13),

156 (13), 122 (13), 115 (18). HRMS calculated for C20H25NO4: 343.1784; found:

343.1785.

Diisobutyl (1S*,2S*,3S*,8aR*)-3-[(E)-

styryl]octahydroindolizine-1,2-

dicarboxylate (endo-77d) and

diisobutyl (1R*,2R*,3R*,8aR*)-3-[(E)-

styryl]octahydroindolizine-1,2-

dicarboxylate (endo’-77d): yellow oil (49 mg, 37% yield), IR (neat) 𝜈max: 2961,

2935, 1731, 1469, 1379, 1169, 1002, 967, 748, 693 cm-1. 1H NMR δ (mixture of

Page 68: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of indolizidines 77 and 79

67

endo:exo’ 1:0.5, difficult assignment): 0.79 (s, 1H), 0.80 (s, 1H), 0.82 (s, 1H), 0.83

(s, 1H), 0.90 (s, 3H), 0.92 (s, 3H), 0.94 (s, 3H), 0.96 (s, 3H), 1.07–1.15 (m, 1H), 1.16–

1.29 (m, 2H), 1.41–1.31 (m, 1H), 1.48 (dtt, J = 9.2, 6.3, 3.6 Hz, 2H), 1.69 (dd, J = 12.1,

3.3 Hz, 0H), 1.73–1.87 (m, 1H), 1.89–2.03 (m, 2H), 2.36–2.53 (m, 1H), 2.78–2.96

(m, 2H), 3.07 (t, J = 7.7 Hz, 1H), 3.16 (ddd, J = 11.3, 8.8, 2.8 Hz, 1H), 3.27 (dd, J = 7.4,

4.3 Hz, 1H), 3.62–3.81 (m, 1H), 3.82–3.99 (m, 4H), 4.03–4.19 (m, 1H), 6.09 (dd, J =

15.7, 9.8 Hz, 1H), 6.30 (dd, J = 15.7, 9.5 Hz, 1H), 6.52 (d, J = 15.6, Hz, 1H), 6.57 (d, J

= 15.7, Hz, 1H), 7.16–7.47 (m, 8H). 13C NMR δ (mixture of endo:exo’ 1:0.5, difficult

assignment): 19.1, 19.2, 19.3, 23.9, 24.0, 24.4, 27.3, 27.7, 27.8, 27.9, 30.6, 47.7, 47.9,

48.2, 49.4, 51.8, 52.7, 61.3, 63.4, 66.2, 67.2, 71.1, 71.2, 125.1, 126.6, 127.7, 127.8,

128.6, 128.8, 129.2, 133.1, 134.6, 136.6, 136.7, 171.9, 172.8, 173.3. LRMS (EI) m/z:

427 (M+, 27%), 354 (15), 337 (22), 336 (100), 326 (39), 324 (13), 224 (22), 199

(38), 198 (21), 122 (15). HRMS calculated for C26H37NO4: 427.2723; found:

427.2720.

Diisobutyl (1S*,2S*,3R*,8aR*)-3-[(E)-

styryl]octahydroindolizine-1,2-

dicarboxylate (exo’-77d) and diisobutyl

(1R*,2R*,3S*,8aR*)-3-[(E)-

styryl]octahydroindolizine-1,2-

dicarboxylate (exo-77d): yellow oil (50 mg, 38% yield), IR (neat) 𝜈max: 2960,

1729, 1469, 1383, 1168, 1002, 968, 738, 692 cm-1. 1H NMR δ (mixture of endo’:exo

0.65:1, difficult assignment): 0.74 (s, 1H), 0.75 (s, 1H), 0.76 (s, 1H), 0.77 (s, 1H),

0.85 (d, J = 0.8 Hz, 2H), 0.87 (d, J = 0.8 Hz, 2H), 0.92 (d, J = 0.6 Hz, 3H), 0.94 (d, J =

0.6 Hz, 3H), 0.95 (s, 2H), 0.97 (s, 2H), 1.12–1.31 (m, 2H), 1.37–1.67 (m, 3H), 1.71–

2.03 (m, 7H), 2.04–2.11 (m, 1H), 2.20 (td, J = 10.4, 2.5 Hz, 1H), 2.43 (ddd, J = 10.7,

8.2, 2.4 Hz, 1H), 2.92–3.07 (m, 1H), 3.11 (d, J = 10.9 Hz, 1H), 3.18–3.48 (m, 4H),

3.69–3.82 (m, 2H), 3.84–3.95 (m, 4H), 5.97 (dd, J = 15.8, 8.7 Hz, 1H), 6.22 (dd, J =

15.8, 8.5 Hz, 1H), 6.55 (d, J = 15.8 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 7.20–7.43 (m,

8H). 13C NMR δ (mixture of endo’:exo 0.65:1, difficult assignment): 19.1, 19.2, 19.3,

24.1, 24.4, 24.8, 25.0, 27.6, 27.7, 27.8, 28.6, 30.6, 49.5, 49.9, 50.9, 51.2, 51.4, 51.7,

66.5, 66.6, 69.3, 71.0, 71.1, 71.2, 72.0, 126.6, 127.4, 127.7, 128.6, 129.6, 133.9,

134.1, 136.7, 136.8, 172.5, 172.9, 173.5. LRMS (EI) m/z: 427 (M+, 34%), 354 (23),

Page 69: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

68

337 (22), 336 (100), 326 (47), 252 (17), 224 (24), 199 (80), 198 (35), 122 (17).

HRMS calculated for C26H37NO4: 427.2723; found: 427.2720.

tert-Butyl (2S*,3S*,8aR*)-3-[(E)-

styryl]octahydroindolizine-2-carboxylate (endo-77e):

yellow sticky oil (20 mg, 19% yield), IR (neat) 𝜈max: 2931,

1723, 1366, 1148, 966 cm-1. 1H NMR δ: 1.23–1.39 (m, 2H,

NCHCH2CH2), 1.43 (s, 9H, t-Bu), 1.47–1.78 (m, 5H, CH2CHCO2,

NCH2CH2, NCH2CH2CH2), 2.28 (ddd, J = 12.5, 10.3, 6.3 Hz, 1H, CH2CHCO2), 2.58 (td,

J = 12.3, 3.3 Hz, 1H, NCH2), 2.72 (ddd, J = 10.3, 7.4, 5.9 Hz, 1H, CHCO2), 2.86–3.01

(m, 2H, NCHCH2, NCH2), 3.98 (dd, J = 9.2, 5.9 Hz, 1H, NCH), 6.17 (dd, J = 15.7, 9.2

Hz, 1H, PhCHCH), 6.54 (d, J = 15.7 Hz, 1H, PhCH), 7.18–7.43 (m, 5H, ArH). 13C NMR

δ: 22.4 (NCH2CH2CH2), 24.4 (NCH2CH2), 28.3 (CH3), 29.9 (NCHCH2CH2), 34.7

(CH2CHCO2t-Bu), 46.8 (NCH2), 49.6 (CHCO2t-Bu), 59.8 (NCH), 66.0 (NCH), 80.6

(CMe3), 126.5, 127.6, 128.7, 130.3, 132.7, 137.0 (ArC, C=C), 174.0 (CO). LRMS (EI)

m/z: 327 (M+, 18%), 271 (27), 270 (100), 254 (16), 226 (18), 180 (74). HRMS

calculated for C21H29NO2: 327.2198; found: 327.2199.

(1S*,2R*,3S*,8aR*)-1-Nitro-2-phenyl-3-[(E)-

styryl]octahydroindolizine (endo-77f): brown sticky oil (19

mg, 18% yield), IR (neat) 𝜈max: 2938, 2855, 1717, 1549, 1496,

1449, 1362, 1264, 1144, 967, 736, 694 cm-1. 1H NMR δ: 1.25–

1.36 (m, 2H, NCHCH2), 1.51–1.62 (m, 1H, NCHCHCH2), 1.70–

1.78 (m, 1H, NCHCHCH2), 1.84–1.93 (m, 2H, NCHCHCH2), 2.44 (ddd, J = 11.9, 8.9,

6.5 Hz, 1H, NCH2), 2.90–3.03 (m, 1H, NCH2), 3.30–3.42 (m, 1H, NCHCH2), 4.25 (dd,

J = 10.1, 7.8 Hz, 1H, NCHCHPh), 4.59 (dd, J = 7.8, 7.2 Hz, 1H, NCHCHPh), 5.54 (dd, J

= 8.4, 7.2 Hz, 1H, CHNO2), 5.89 (dd, J = 15.6, 10.1 Hz, 1H, PhCHCH), 6.32 (d, J = 15.6

Hz, 1H, PhCH), 7.06–7.38 (m, 10H, ArH). 13C NMR δ: 23.8 (NCH2CH2CH2), 23.9

(NCH2CH2), 26.0 (NCHCH2), 48.4 (NCH2), 51.7 (NCHCH), 62.3 (NCH), 69.2 (NCH),

93.0 (CNO2), 124.8, 126.5, 127.4, 127.8, 128.6, 128.7, 128.8, 135.2, 136.6, 136.8

(ArC, C=C). LRMS (EI) m/z: 348 (M+, 1%), 303 (25), 302 (100), 300 (11), 257 (10),

219 (15), 143 (11), 117 (20), 115 (21). HRMS calculated for C22H24N2O2: 348.1838;

found: 348.1825.

Page 70: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of indolizidines 77 and 79

69

(3aS*,4R*,9aR*,9bR*)-2,4-Diphenyloctahydro-1H-

pyrrolo[3,4-a]indolizine-1,3(2H)-dione (endo-79): white

solid (58 mg, 54% yield), mp 151-154 °C (Et2O), IR (neat)

𝜈max: 2934, 2854, 1712, 1496, 1376, 1173, 734, 698 cm-1. 1H

NMR δ: 1.29–1.39 (m, 2H, NCH2CH2CH2), 1.47–1.64 (m, 2H,

NCHCH2), 1.82–1.97 (m, 2H, NCH2CH2), 2.22–2.41 (m, 2H, NCHCH2, NCH2), 2.84 (d,

J = 11.0 Hz, 1H, NCH2), 3.17 (dd, J = 9.3, 8.5 Hz, 1H, CH2CHCH), 3.27 (dd, J = 9.3, 6.9

Hz, 1H, PhCHCH), 3.49 (d, J = 6.9 Hz, 1H, NCHPh), 7.28–7.42 (m, 6H, ArH), 7.44–

7.53 (m, 4H, ArH). 13C NMR δ: 24.1 (NCH2CH2CH2), 25.0 (NCH2CH2), 31.3 (NCHCH2),

50.2 (NCHCHCO), 50.9 (NCH2), 53.0 (NCHCHCO), 67.8 (NCH), 72.0 (NCH), 126.6,

127.8, 127.9, 128.1, 128.7, 128.9, 129.2, 131.9 (ArC), 176.1, 176.6 (2xNCO). LRMS

(EI) m/z: 346 (M+, 73%), 345 (56), 269 (23), 198 (20), 173 (55), 172 (100), 115

(15). HRMS calculated for C22H22N2O2: 346.1681; found: 346.1668.

(3aR*,4R*,9aR*,9bS*)-2,4-Diphenyloctahydro-1H-

pyrrolo[3,4-a]indolizine-1,3(2H)-dione (exo-79): yellow

oil (26 mg, 24% yield), IR (neat) 𝜈max: 2943, 2850, 1701, 1497,

1393, 1189, 848, 755, 693 cm-1. 1H NMR δ: 0.98–1.12 (m, 1H,

NCH2CH2CH2), 1.18–1.29 (m, 1H, NCHCH2), 1.33–1.56 (m, 2H,

NCH2CH2CH2, NCHCH2), 1.60–1.84 (m, 2H, NCHCH2, NCH2CH2), 1.99–2.10 (m, 1H,

NCH2), 2.82-2.92 (m, 2H, NCH2, NCHCH2), 3.54 (dd, J = 8.0, 1.0 Hz, 1H, PhCHCH),

3.61 (t, J = 8.0 Hz, 1H, CH2CHCH), 4.69 (d, J = 1.0 Hz, 1H, NCHPh), 7.07–7.19 (m, 2H,

ArH), 7.30–7.54 (m, 8H, ArH). 13C NMR δ: 24.2 (NCH2CH2CH2), 24.9 (NCH2CH2),

29.1 (NCHCH2), 48.5 (NCH2), 48.7 (NCHCHCO), 50.3 (NCHCHCO), 59.9 (NCH), 69.4

(NCH), 126.7, 128.0, 128.4, 128.6, 128.7, 132.3, 136.6 (ArC), 176.1, 178.1 (2xNCO).

LRMS (EI) m/z: 346 (M+, 61%), 345 (48), 269 (22), 198 (12), 173 (57), 172 (100),

115 (14). HRMS calculated for C22H22N2O2: 346.1681; found: 346.1668.

Page 71: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 1: Multicomponent synthesis of indolizidines

70

Page 72: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

71

CHAPTER 2: Thermal 1,3-DC of unactivated

azomethine ylides

Bibliographic background

Synthesis of substituted pyrrolidines

Such as it was mentioned in the general introduction, the scaffold of the

pyrrolidine is present in many natural and unnatural products with biological and

pharmaceutical properties.8,9,74 An easy way to synthesize polysubstituted

pyrrolidines is through 1,3-DC19,30,31,52 employing azomethine ylides as dipoles and

dipolarophiles under mild conditions.

In almost all metal-free 1,3-DC the generation of the 1,3-dipole occur via

1,2-prototropy shift or through the iminium route. In the first case, the 1,2-

prototropy is produced upon heating an imine, generated by an N-alkyl amino acid

and an aldehyde, affording the stabilized dipole at low temperature. Otherwise

strong bases or higher temperatures are necessary to form the non-stabilized

azomethine ylide from arylidene(alkyl)amines, which reacts with the

dipolarophile (Scheme 27).30b,40b,48

Scheme 27. Formation of the pyrrolidine from metal free 1,3-DC.

For a long time the change of functional groups in carbons 2 and 5 in the

synthesis of new pyrrolidines has been studied, looking for economic synthetic

Page 73: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

72

pathways, milder conditions, improvement of the results or reactions with less

waste generation such as multicomponent reactions.

Simple amino acids such as glycine, alanine or leucine are widely used in

the synthesis of pyrrolidine derivatives, providing alkyl or ester functional group

in C2 of five-membered ring.19,31b-c,52,75 In order to obtain different functionalities

in this kind of products and extend their applicability, many groups had been

studied different reagents that could suit the reaction as well.

Kauffmann and coworkers, in 1970, introduced by the first time an

aromatic ring in C2 using olefins bearing an aromatic group such as styrene and

trans-stilbene. They employed a strong base as LDA at low temperatures (-60 °C)

as optimal reaction condition generating a lithium azaallyl anion in the transition

state (Scheme 28).76 Since then, many groups had been following working in the

synthesis of pyrrolidines generated from imine 81 and strong bases as LDA and

BuLi at very low temperature to force the HOMO-LUMO approach and promote the

1,3-DC with non-activated dipolarophiles.77 Thus, reactions with 81 had been

extended to do a cyclization with alkenyl arenes78 or dienes79 or hetero-

substituted olefins80 as a dipolarophiles.

Scheme 28. Reactivity of lithium azaallyl anions generated from strong bases with aromatic olefins.

Later, in 1983, Grigg worked with benzylamine derivative 81 as reagent

to introduce the new functionality in C2 position but the 1,2-prototropy failed,

however they had good results when they introduced an alkoxy group or amino

group at the orto-position in the aromatic moiety and heated the mixture in

refluxing xylene.40d Also, they got the desired compounds when they introduced a

2-pyridyl group instead of the phenyl ring, rising the temperature with a reflux of

Page 74: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Bibliographic background: Synthesis of substituted pyrrolidines

73

toluene (Scheme 29).81 More recently, the group of Carretero have performed the

enantiomeric version of this cycloaddition between N-(2-pyridylmethyl)imines

and a variety of activated olefins using a Cu(CH3CN)4PF6/bisoxazoline catalyst

system to obtain high to excellent enantioselectivities.82

Scheme 29. 1,3-Dipolar cycloaddition between imines 83 with 2-pyridyl group and maleimides.

The group of Grigg continued studying the 1,2-prototropy shift in other

systems. For instance, several new functional groups at C2 position could

successfully attached employing another precursors such as aminoacetophenone

or diethyl aminomethylphosphonate, obtaining pyrrolizidines 86 with a ketone

moiety with endo-epimer as major one coming from aminoacetophenone (Scheme

30). In contrast, they obtain exo-88 as the major one when the group PO(OEt)2 was

introduced through diethyl aminomethylphosphonate (Scheme 31).83

Page 75: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

74

Scheme 30 and 31. Dicomponent cycloadditions introducing a ketone moiety or phosphonate group

in C2 position.

Trying to going deeper in the study of this issue Grigg et al. in 2002

combined three different reagents in a multicomponent reaction, where the C2

functional group is provided by a substituted propargyl amine alongside with a

maleimide and aromatic aldehyde obtaining the products 91 in good to excellent

yields but very poor diastereoselectivities (1:1) (Scheme 32).84 In this example, the

dipole was generated through the iminium route.

Scheme 32. Multicomponent cycloaddition to give a 1:1 mixture of diastereoisomers 91.

Page 76: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Bibliographic background: Synthesis of substituted pyrrolidines

75

However, to the best of our knowledge, it does not exist any research

involving the C-H activation of unactivated arylidene(allyl)amines through 1,2-

prototropic shift. In this case imines derived from allylamine would permit the

incorporation of a vinyl group in C2 position in the pyrrolidine scaffold. There is

one example reported by Waters and coworkers where a dicomponent reaction

catalyzed by metals from glyoxylimine affording the desired product with the vinyl

group at C5 instead of C2 93 was reported (Scheme 33).85

Scheme 33. Dicomponent metal-catalyzed 1,3-DC to provide 5-alkenyl pyrrolidine cycloadducts.

Page 77: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

76

Page 78: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

77

Objectives

According to the precedents found in the bibliographic background the

aims for this work are:

1 The study the direct CH activation of imines derived from alkylamines

in the generation of non-stabilized dipoles through thermal 1,2-

prototropy for the synthesis of pyrrolidine derivatives bearing an alkyl

group at C2 position different to the ester moiety.

2 To study the diastereoselective version of this thermal metal-free 1,3-

dipolar cycloaddition using chiral dipolarophiles.

Page 79: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

78

Page 80: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

79

Results and discussion

Such as it has been mentioned above, this work was started with the aim

to study the formation of pyrrolidines from unactivated azomethine ylides through

1,3-dipolar cycloaddition. To address this study it was decided to use imines from

amines such as benzylamine, allylamine and 1-butylamine and aromatic

aldehydes, using NMM as electron deficient alkene, which is a good hunter of the

resulting high energy azomethine ylide intermediate (Scheme 34). Taking into

account the recently thermal investigation of our group,68 the results of the

Chapter 1 and 1,3-DC performed by other groups for the synthesis of pyrrolidine

derivatives,40d,48c,84 it was chosen toluene as solvent. So, with all the background in

hand, it was carried out a study of the temperature, the time of the reaction and

the benefits of adding additives or not (Scheme 34 and Table 3).

Scheme 34. Optimization of the 1,3-DC between unactivated azomethine ylides and NMM.

Imines 81, 94 and 95 synthesized from benzylamine, 1-butylamine and

allylamine, respectively with benzaldehyde 58 were taking under study (Scheme

34, Table 3). As initial conditions were taking those employed by Grigg in his work

where azomethine ylides from arylidene benzylamines were studied in a

dicomponent reaction at 110 °C (toluene reflux).40d However, any cycloadduct

could be isolated because none of them gave conversion (CNV) (Table 3, entries 1-

3). Next, a weak base in combination with a Lewis acid at 90 °C was used, but the

Page 81: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

80

reaction did not proceed whit imines 81 and 94 (Table 3, entries 4 and 5), although

slightly reaction conversion was observed to pyrrolidine 98 (Table 3, entry 6). In

this point, it was proposed the use of strong acids such as benzoic acid (BzOH) and

trifluoroacetic acid (TFAA). With benzoic acid only the reaction took place with

imine 95 (Table 3, entries 7-9), on the other hand, TFAA afforded decomposition

products (Table 3, entries 10-12). Continuing the study with benzoic acid which

yielded the best results, the temperature was raised in order to study if the

reaction time could be decreased. As it was expected using a toluene reflux the

reaction was nearly completed in only one night (Table 3, entry 15). Total

conversion was observed when the reaction was carried out at 150 °C for imine 95

in the presence or in the absence of benzoic acid (Table 3, entries 18 and 19).

Meanwhile for the other couple of imines, 81 and 94, the reaction was not

successful neither at 110 °C nor at 150 °C (Table 3, entries 13-14 and 16-17). With

this thermal conditions in hand, 150 °C, it was studied if benzoic acid is really

necessary, and it was observed that at high temperatures the reaction yielded the

product without using the acid as additive (Table 3, entry 19). Therefore, that

means that the reaction occurred after a 1,2-prototropy at high temperatures.

Then, one reaction was carried out just in 7 hours, but the conversion was less than

60% (Table 3, entry 20), so leaving the reaction overnight (16 h) was needed. In

order to set more precisely the temperature, 130 °C was selected, but the reaction

failed (Table 3, entry 21), so higher temperature is necessary. At this moment, it

was decided to perform the multicomponent version between allylamine 99,

benzaldehyde 58 and NMM, but instead of the desired product, the product of the

Michael addition could be isolated (Table 3, entry 22). Finally, trying to solve this

problem it was studied a sequential reaction where allylamine 99 and

benzaldehyde 58 reacted during 1 h at rt and later NMM is added and stirred for

16 h at 150 °C (Table 3, entry 23). With this one-pot sequential methodology it was

possible to observe the desired product and save time and waste.

Page 82: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

81

Table 3. Study the 1,3-DC between azomethine ylide 81 and NMM.

Entry Imine Additive T (°C) t (h) CNV (%)a

1 81 ----- 110 48 0

2 94 ----- 110 48 0

3 95 ----- 110 48 0

4 81 Et3N (5 mol%),

AgOBz (5 mol%) 90 48 0

5 94 Et3N (5 mol%),

AgOBz (5 mol%) 90 48 0

6 95 Et3N (5 mol%),

AgOBz (5 mol%) 90 48 15

7 81 BzOH (30 mol%) 90 48 0

8 94 BzOH (30 mol%) 90 48 0

9 95 BzOH (30 mol%) 90 48 95

10 81 TFAA (30 mol%) 90 48 0

11 94 TFAA (30 mol%) 90 48 0

12 95 TFAA (30 mol%) 90 48 11

13 81 BzOH (30 mol%) 110 16 0

14 94 BzOH (30 mol%) 110 16 0

15 95 BzOH (30 mol%) 110 16 90

16 81 BzOH (30 mol%) 150 16 0

17 94 BzOH (30 mol%) 150 16 0

18 95 BzOH (30 mol%) 150 16 100

19 95 ----- 150 16 100

20 95 ----- 150 7 58

21 95 ----- 130 16 0

22b 95 ----- 150 16 0

23c 95 ----- 150 1+16 100

a Determined by 1H NMR of the crude reaction mixture.

b Multicomponent reaction: allylamine 99, benzaldehyde 58 and NMM were added at the same time

and reacted 16 h at 150 °C.

c Sequential reaction: allylamine 99 and benzaldehyde 58 reacted during 1 h at rt, then NMM was

added and stirring continued 16 h at 150 °C.

Page 83: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

82

With the optimal conditions in hand, where imine 95 was prepared in situ

stirring the solution of allylamine 99 and benzaldehyde 58 in toluene at rt during

1 h, the diastereoselectivity of the 1,3-DC reaction was studied such as the different

endo-or exo-approach of the dipolarophiles, the geometry of the 1,3-dipole and its

two possible α- or γ-attacks (Scheme 35). For the α-attack of the W-shape

conformation endo-98 and exo-98 pyrrolidines are obtained. When the α-attack is

from S-shape conformation products endo’-98 and exo’-98 are formed (Scheme

35). However, cycloadducts endo-100 and exo-100 were observed for the γ-attack

of the W-shape conformation, and endo’-100 and exo’-100 for the γ-attack of the

S-shape conformation (Scheme 35).

Page 84: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

83

Scheme 35. Optimized reaction 1,3-DC conditions between allylamine 99, benzaldehyde 58 and the

dipolarophile in a sequential reaction and their stereochemical analysis.

The scope of the 1,3-DC was performed between in situ generated imine

95 and maleimides, N-alkyl and N-arylmaleimides affording the corresponding

compounds 98a-98i as a mixture of endo’:endo diastereoisomers 98 (Scheme 36

and Table 4), coming from the α-attack of the S- and W-shape conformation

yielding 2,5-trans-2,4-trans and 2,5-cis-2,4-cis relative configuration, respectively.

Page 85: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

84

Scheme 36. Sequential one-pot reaction to yield the pirrolidine derivatives 98.

In all the reactions just two diastereoisomers could be observed, the major

diastereomer, endo’-98, could be isolated and characterized, meanwhile the minor

endo-diastereomer could not. NMM was the first dipolarophile tested yielding the

corresponding product 98a with high diastereoselectivity (71:29) and good yield

for endo’-98a (67%) (Table 4, entry 1). Almost equal results as 98a were reached

in compound 98b from maleimide (Table 4, entry 2). Then N-benzylmaleimide

afforded the product endo’-98c in 64% yield and 65:35 dr (Table 4, entry 3). N-

Arylmaleimides were tested, starting with N-phenylmaleimide obtaining the

desired product endo’-98d in high yield (69%) and high diastereoselection (72:28)

(Table 4, entry 4). The most hindered maleimide [N-(2-

methoxyphenyl)maleimide] furnished the best chemical yield, 70% for endo’-98e,

and best diastereomeric ratio (92:8) (Table 4, entry 5). The meta- and para-chloro

substituted N-arylmaleimides afforded the corresponding products 98f and 98g

in moderate to good yields, and high diastereoselectivity for the endo’-one (Table

4, entry 6 and 7). As well as product 98g, pyrrolidine derivative 98h, which bears

a bromine atom at the para-position in the aromatic ring instead of a chlorine, was

obtained in high diastereoselectivity (74:26) but moderate yield (55%) (Table 4,

entry 8). Finally, para-fluorobenzylmaleimide was evaluated furnishing a good

diastereoselectivity, 73:27 towards the endo’-98i adduct as major one in good

yield, 68% (Table 4, entry 9).

Page 86: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

85

Table 4. Thermal 1,3-DC between allylamine 99, benzaldehyde 58 and different maleimides to yield

pyrrolidine derivatives 98.

Entry R Product dra

(endo’:endo)

Yield (%)b

(endo’, endo)

1 Me 98a 71:29 67, 6

2 H 98b 69:31 62, 9

3 Bn 98c 65:35 64, 8

4 Ph 98d 72:28 69, 5

5 2-(OMe)C6H4 98e 92:8 70, 0

6 3-ClC6H4 98f 83:17 41, 0

7 4-ClC6H4 98g 76:24 68, 0

8 4-BrC6H4 98h 74:26 55, 5

9 4-FC6H4-CH2 98i 73:27 68, 9

a Determined by 1H NMR of the crude reaction mixture.

b Isolated yield after purification (flash silica gel) of major, minor diastereoisomer.

The obtention of regioisomer endo’-98 as major one was confirmed by the

proton shift and coupling constants of the 1H NMR where the coupling constant

between Hc and Hd is 1.0 to 1.4 depending of the cycloadduct, being the standard

value for a coupling between two protons in trans relative position. Moreover, the

relative configuration of these products has been confirmed by nOe experiments

performed to endo’-98a, where it could be observed a strong interaction between

Ha, Hb and Hc, but a weak one with Hd (Figure 10).

Figure 10. Representative nOe detected for the endo’-98a adduct.

Page 87: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

86

More symmetric dipolarophiles were tested beyond maleimides such as

maleic anhydride, dimethyl acetylenedicarboxylate and tetracyanoethylene giving

all of them decomposition products due to the high temperature required by the

reaction. To know if the reaction proceeds through α- or γ-attack of the dipole a

series of non symmetric dipolarophiles to obtain more information of the

regiochemistry of the reaction were tested. Acrylates such as methyl acrylate, tert-

butyl acrylate, methyl 2-acetamidoacrylate, 1,1,1,3,3,3-hexafluoroisopropyl

acrylate (HFiPA) and allyl methacrylate were assayed providing in some cases

products of polymerization of the dipolarophile. Trying to figured out the reason

for that, the reaction was carried out with other different dipolarophiles. When

acrylonitrile, 2-chloroacrylonitrile and methyl vinyl ketone were used some

decomposition product was observed in the crude of the reaction. And the

corresponding starting material was recovered after 16 h reacting when methyl

fumarate, methyl cinnamate, trans-4-phenyl-3-buten-2-one, chalcone, dimethyl

itaconate, N,N-dimethylacrylamide, diethyl vinylphosphonate, trans-β-

nitrostyrene or phenyl vinyl sulfone were assayed in this reaction. Only with trans-

1,2-bis(phenylsulfonyl)ethylene and 1,1-bis(phenylsulfonyl)ethylene reacted

under these conditions. So, it was possible to direct the cycloaddition giving

moderate yields of the corresponding cycloadduct 98. Surprisingly, both

bis(phenylsulfonyl)ethylene (BPSE) afforded the same relative configuration

endo’-98j of the major diastereoisomer in different proportion in the crude

mixture (endo’:endo 56:44 dr was obtained with 1,1-BPSE and 70:30 when 1,2-

BPSE was try it, Scheme 37). After purification just the major diastereoisomer

endo’-98j was isolated in 40% yield for 1,1-BPSE and 60% for 1,2-BPSE.

Page 88: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

87

Scheme 37. Sequential 1,3-DC involving non isolated 95 and 1,1- or 1,2-BPSE as dipolarophiles.

The presence of product endo’-98j was confirmed after detecting the same

chemical shifts of the protons in 1H NMR experiments, with same constant

couplings. Also both reagents 1,1-BPSE and 1,2-BPSE offered the same 13C NMR

and DEPT spectra. The synthesis of diastereoisomers 98j from 1,1-BPSE could be

accomplished thanks to its thermal β-elimination generating ethynyl phenyl

sulfone, which reacted with the phenylsulfinic acid affording 1,2-BPSE in the

reaction media.86 The relative configuration endo’ was confirmed by nOe

experiments where two strong interactions were found, one between Ha and Hb

and the other one between Hc and Hd (Figure 11).

Figure 11. Representative nOe detected for the endo’-98j adduct.

The obtention of product 98j and the confirmed relative configuration of

the major diastereomer endo’-98j suggested that the mechanism of this reaction

proceeded through an α-attack of azomethine ylide intermediate in S-shape

Page 89: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

88

conformation to the dipolarophile (Scheme 35). The thermal CH activation is more

stable when the negative charge is at the allylic position (α-attack) rather than in

the benzylic position (γ-attack) (Scheme 35). The endo-cycloadducts 98 were

obtained from the endo-approach of the dipolarophile to the W-dipole and in this

thermal conditions the dipole underwent a stereomutation generating the

thermodynamically more stable S-dipole following the analogous endo-approach

by the dipolarophile that gave access to the endo’-98 cycloadducts (Scheme 35).

Next, the scope of the reaction using allylamine 99, NMM and selecting

different kind of aldehydes was studied (Scheme 38 and Table 5). In contrast to

what was observed in the study of the scope (see above), when aldehydes such as

2-naphthaldehyde, p-nitrobenzaldehyde, p-bromobenzaldehyde, 2-

pyridinecarboxaldehyde and 3-pyridinecarboxaldehyde were employed the minor

endo-diastereoisomer could be isolated in more than 11% yield (Table 5, entries

1, 7, 8, 9 and 10). When 2-naphthaldehyde was used the major product endo’-98k

was obtained in 60% yield and low diastereomeric ratio (Table 5, entry 1). The

comparison between ortho-, meta- and para-methyl substituted benzaldehyde was

done but no significant differences in terms of both dr and yield of endo’-98l-n

compounds were found (Table 5, entries 2-4). On the other hand, the ortho-, meta-

and para-nitro substituted benzaldehydes afforded the corresponding products

98o-q in moderate to good diastereoselection and moderate to good yields (Table

5, entries 5-7). Product 98r (Table 5, entry 8) was isolated in 62% yield and good

dr (69:31). For 2- and 3-pyridinecarboxaldehydes the corresponding products

98s-t were isolated with good dr and moderate yield for major 98s-t and low yield

for endo-98s-t (Table 5, entries 9 and 10). Finally 2-thiophenecarboxaldehyde was

evaluated and again good diastereoselection and moderate yield was achieved for

the corresponding product 98t (Table 5, entry 11).

Scheme 38. Sequential reaction to yield the pyrrolidine derivatives 98 changing the aldehyde.

Page 90: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

89

Table 5. Scope of 1,3-DC between allylamine 99, different aldehydes and NMM to yield pyrrolidine

derivatives 98.

Entry Ar Product dra

(endo’:endo)

Yield (%)b

(endo’, endo)

1 2-Naphthyl 98k 58:42 60, 24

2 2-MeC6H4 98l 73:27 38, 0

3 3-MeC6H4 98m 80:20 31, 0

4 4-MeC6H4 98n 77:23 40, 0

5 2-(NO2)C6H4 98o 76:24 41, 0

6 3-(NO2)C6H4 98p 66:34 62, 11

7 4-(NO2)C6H4 98q 59:41 56, 37

8 4-BrC6H4 98r 69:31 62, 23

9 2-Pyridyl 98s 67:33c 44, 23

10 3-Pyridyl 98t 62:38 53, 24

11 2-Thienyl 98u 71:29c 55, 8

a Determined by 1H NMR of the crude reaction mixture.

b Isolated yield after purification (flash silica gel) of major, minor diastereoisomer.

c Exo’:endo ratio.

From compound 98q, synthesized from p-nitrobenzaldehyde, it was

possible to isolate both diastereoisomers and analyse their relative configurations

through nOe experiments. It is important to confirm, firstly, the proposed

structure in the previous study of the scope of the major endo’-isomer, and

secondly the relative configuration of the minor ones, endo-98. In this last

cycloadduct, it was possible to observe the interaction between all protons of the

five-membered all-cis-ring (Figure 12). Besides, from endo’-98t an appropriate

crystal was separated and submitted to an X-ray diffraction experiment87 (Figure

13) confirming the proposed endo’-structure.

Page 91: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

90

Figure 12. Representative nOe detected for the major endo’-98q and minor endo-98q adducts.

Figure 13. X-Ray diffraction analysis of endo’-98t cycloadduct (CCDC number: 1820733).

The pyrrolidines synthesized from aldehydes bearing a heteroatom at 2

position of the cycle were submitted to the study as well. In those examples (98s

and 98u, Table 5, entries 9 and 11, respectively) both products could be isolated

in a good dr isolating both diastereoisomers for each product. The presence of the

minor endo-diastereoisomer was confirmed by 1H NMR and by nOe experiments.

Major diastereoisomer exo-98 was identified according to a high nOe interaction

between Hd and Hc as well as Hc with Hb, but a very small one with Ha (Figure 14).

Besides, it was found a constant coupling between Ha and Hb around 1.0 and 1.5

Hz in both cases, typical coupling constant for protons in trans-relative

configuration. According to Scheme 35 the relative configuration 4,5-trans is due

to the exo-approach of the dipolarophile and the 2,5-trans relative configuration is

due to the thermal stereomutation to S-shape dipole of the azomethine ylide

before the attack onto the dipolarophile. Moreover, to have more information

about this feature a brief simulation of the minimum energy for those examples

Page 92: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

91

was performed using MM2 basic calculations88. When benzaldehyde is used the

endo’-98a is more favoured than the corresponding exo’-98a cycloadduct (Figure

15), but in the case of imines incorporating a heterocycle with a heteroatom at

position 2 (2-thiophene surrogate) the reaction proceeded through an exo-

approach giving exo’-98u rather than endo’-98u. These differences of energies

could be explained due to the presence of lone pairs of electrons in the heteroatom

(S or N) of the heterocycle causing a stereoelectronic effect which hamper the

endo-approach of the dipolarophile onto the S-shape dipole yielding exo’-

cycloadducts (Figure 15). This explanation can be extended to the result obtained

employing the imine derived from 2-pyridylcarbaldehyde (Table 5, entry 9).

Figure 14. Representative nOe detected for the major exo’-98u cycloadduct.

Figure 15. Simulation of the minimum energy for the endo’- and exo’-diastereoisomers of compounds

98a y 98u.

More aldehydes were evaluated in the reaction, such as 2-

thiazolecarboxaldehyde, which provided a complex mixture in the crude of the

reaction, which was difficult to purify. With p-methoxybenzaldehyde traces of

products endo’ y endo were observed, being the conversion very low. Alkylic

aldehydes, such as phenylacetaldehyde, hydrocinnamaldehyde and sorbaldehyde

Page 93: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

92

were tested and none of them provide the desired compound. Curiously, a strange

product was obtained as major one when crotonaldehyde and trans-

cinnamaldehyde were used. For trans-cinnamaldehyde it was possible to isolate

the major product in 38% yield. After exhaustively studies of the 1H NMR, 13C NMR,

DEPT, COSY and NOESY experiments and the data obtained of HRMS a new spiro-

compound was identified as 101 (Scheme 39).

Scheme 39. Sequential multicomponent reaction to synthesis new spiro-cycloadduct 101.

To go deeper in the study of the synthesis of spiro-101 it was carried out

the reaction between allylamine 99, trans-cinnamaldehyde 71 and 2 equivalents

of N-methylmaleimide in order to see whether the final yield is improved

according to the fact that the final product 101a has two units of maleimide in its

structure. Indeed the yield was increased to 59% (Scheme 40). It can be only found

in the literature two contributions where similar products were synthesized, both

of them from imines and maleimides reacting at high temperatures. Zirngibl et. al.

obtained the same final relative configuracion in the major diastereoisomer from

N-methylbenzaldimines and maleimides in xylene in low yields,89 and one year

later, the group of Hanaoka obtained the same scaffold from N-

cinnamylidenemethylamine and N-methylmaleimide at refluxing of benzene in

very low yields (20%).90 With our results and with the data of the literature we

could propose the following reaction mechanism described in Scheme 40: the very

slow 1,3-DC competes with the faster Michael addition from the in situ generated

imine 102 to 1 equivalent of NMM yielding intermediate-I, followed for a 1,2-

prototropy to generate intermediate-II, which is a stabilized 1,3-dipole. The

process ends with a 1,3-DC between this dipole II and NMM (Scheme 40).

Page 94: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

93

Scheme 40. Proposed mechanism for the synthesis of the spiro compound 101a.

After the study of the scope with aldehydes, the effect of the amine was

assessed. Only two reagents, 2-methylallylamine and propargylamine could be

tested. When 2-methylallylamine was used in the reaction the conversion obtained

was very poor (<20%). On the other hand, with propargylamine 102 the reaction

with benzaldehyde 58 and NMM gave high diastereoselections (89:11 endo’:endo

dr) and good yield (69%) for the major diastereoisomer endo’-103 which was the

only diasteroisomer that could be isolated after the purification (Scheme 41). The

unique similar work found in the literature was from Grigg,84 where they could

only reached a diastereomeric mixture 1:1 endo’:exo’ from a secondary N-alkyl

propargylamine but employing the iminium route to generate the corresponding

fleeting dipole.

Page 95: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

94

Scheme 41. Sequential reaction to yield the new 2-ethynylpirrolidine derivative 103.

As a direct application of this methodology, the synthesis of the tricyclic

thrombin inhibitor 105b was envisaged (Scheme 42).91 Thrombin is a serine

protease and one of the key enzymes in the process of blood-coagulation cascade.

It catalyses the conversion of the soluble fibrinogen into insoluble and

polymerizable fibrin and activates platelet aggregation92. It is therefore the

inhibition of this enzyme is an important pharmaceutical target for prevention and

treatment of thrombotic disorders.

For this purpose, we started from allylamine 99 and benzaldehyde 58, and

the 1,3-DC was carried out with NMM and N-(4-fluorobenzyl)maleimide yielding

compounds 98a and 98i in good diastereomeric ratio and good yield of the major

isomer (Table 4, entries 1 and 9). The major endo’-diastereoisomer was next

allylated at the nitrogen atom using allyl bromide and sodium carbonate in

acetonitrile. Next, a ring closing metathesis using the 2nd generation Hoveyda-

Grubbs’ catalyst93 providing the tricyclic intermediate 104 in good overall yield

(69% two combined steps from 98). After hydrogenation of the double bond under

very mild conditions in the presence of Pd/C in methanol, compound 105 was

isolated in good yield (90%). Hence it has been described a synthetic pathway of

three steps starting from allylamine 99, benzaldehyde 58 and N-(4-

fluorobenzyl)maleimide achieving the tricyclic-105 in 52% overall yield (Scheme

42).

Page 96: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

95

Scheme 42. Synthesis of tricyclic thrombin inhibitor 105.

Finally, taking advantage of this synthetic route the diastereoselective

version was evaluated. In this study, a commercially available enantiomerically

enriched maleimide such as (R)-N-(1-phenylethyl)maleimide, was selected to

react with the imine 95 generated in situ from allylamine 99 and benzaldehyde 58

under the optimal reaction conditions. Two diastereomers endo’-98v:endo-98v

were obtained with good diastereomeric ratio (70:30) in the crude of the reaction

(analyzed by 1H NMR) and only the major diastereoisomer endo’-98v, with

Page 97: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

96

absolute configuration 2,5-trans-2,4-trans, was isolated after purification in good

yield (63%) as unique enantiopure diastereoisomer (Scheme 43).

Scheme 43. Diastereoselective 1,3-DC using chiral maleimide to synthesis diastereoenriched

pyrrolidine derivative 98v.

Page 98: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

97

Conclusions

1 New pyrrolidines with a vinyl substituent at the 2 position have been

synthesized through a multicomponent metal-free pathway employing

unactivated azomethine ylides derived from imines of allylamine where a

C–H activation was successfully promoted at high temperature.

2 Almost total endo-approach dipole-dipolarophile was observed. The S-

shape dipole (2,5-trans) was much more stable (and abundant) than the

corresponding W-shape dipole (2,5-cis) affording high

diastereoselections despite the high temperature used.

3 The presence of heterocycles in the imino moiety containing a heteroatom

at the 2 position difficult the endo-approach due to steroelectronic effects

favouring the generation of exo-cycloadducts (2,5-trans-2,4-cis).

4 The higher steric hindrance of the dipolarophile the better diastereomeric

ratio in the final cycloadduct was obtained. For example, N-(2-

methoxyphenyl)maleimide afforded the corresponding adduct in a 92:8

dr in crude mixture of product 98e.

5 This methodology can be implemented as an alternative synthesis of

tricyclic compound 105, which shows thrombin inhibitor activity, in good

overall yield.

6 The diastereoselective version was very noticeable because

enantiomerically enriched products were obtained. Here, up to five

stereogenic centres can be generated in just one step from a thermal

allylic C–H activation without using catalytic complexes and metals.

Page 99: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

98

Page 100: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

99

Experimental section

General methods

(See general methods shown in the experimental section of Chapter 1).

General procedure for the synthesis of pyrrolidines 98, 101

and 103

In a pressure tube the corresponding amine 99 (0.3 mmol) and aldehyde

(0.3 mmol) were added in toluene (1 mL). The solution were stirred 1 hour at room

temperature and later, the corresponding dipolarophile (1.5 equiv.) were added

with toluene (1 mL). The resulting mixture was stirred overnight at 150 °C. The

solvent was evaporated under reduced pressure and the crude mixture was

purified by flash column chromatography over silica gel (30% EtOAc in hexane as

the eluent) to furnish the corresponding product.

Characterization of pyrrolidines 98, 101 and 103

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-phenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98a): yellow solid (51.3 mg, 67% yield), mp 68-69 °C

(Et2O), IR (neat) 𝜈max: 1693, 1435, 1384, 1284, 748, 703 cm-1. 1H

NMR δ: 2.87 (s, 3H, CH3), 3.20 (dd, J = 7.6, 1.1 Hz, 1H,

CH2=CHCHCHC=O), 3.26 (br s, 1H, NH), 3.37 (dd, J = 8.6, 7.8 Hz, 1H, PhCHCH), 4.39

(dd, J = 5.9, 1.3 Hz, 1H, NCHCH=), 4.70 (d, J = 8.7 Hz, 1H, PhCH), 5.15-5.39 (m, 2H,

CH=CH2), 6.02 (ddd, J = 17.3, 10.4, 5.9 Hz, 1H, CH=CH2), 7.21-7.52 (m, 5H, ArH). 13C

NMR δ: 25.0 (CH3), 49.3, 50.8 (2xCHC=O), 61.5 (CHCH=), 62.1 (PhCH), 115.7

(CH=CH2), 127.2, 128.1, 128.4, 128.5, 137.7, 138.1 (ArC, CH=CH2), 175.7, 178.5

(2xC=O). LRMS (EI) m/z: 256 (M+, 12%), 255 (24), 254 (22), 170 (13), 153 (15),

Page 101: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

100

152 (33), 145 (57), 144 (100), 143 (21), 117 (13), 116 (12), 115 (31), 104 (13), 68

(22), 67 (12). HRMS calculated for C15H16N2O2: 256.1212; found: 256.1196.

(3aS*,4R*,6S*,6aR*)-4-Phenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98b): yellow solid (45.1 mg, 62% yield), mp 97-99 °C

(Et2O), IR (neat) 𝜈max: 1702, 1347, 1329, 1178, 730, 697 cm-1. 1H

NMR δ: 2.17 (br s, 1H, NHCH), 3.25 (dd, J = 7.7, 1.0 Hz, 1H,

CH2=CHCHCHC=O), 3.38 (dd, J = 8.7, 7.7 Hz, 1H, PhCHCH), 4.40 (dd, J = 6.0, 1.3 Hz,

1H, NCHCH=), 4.71 (d, J = 8.7 Hz, 1H, PhCH), 5.22-5.31 (m, 2H, CH=CH2), 6.00 (ddd,

J = 17.2, 10.4, 5.9 Hz, 1H, CH=CH2), 7.28-7.39 (m, 5H, ArH), 8.38 (br s, 1H, NHC=O).

13C NMR δ: 50.5, 52.0 (2xCHC=O), 61.6 (CHCH=), 62.2 (PhCHN), 115.9 (CH=CH2),

127.3, 128.3, 128.5, 137.6, 137.8 (ArC, CH=CH2), 175.8, 178.7 (2xC=O). LRMS (EI)

m/z: 242 (M+, 14%), 241 (15), 170 (12), 149 (11), 146 (11), 145 (100), 144 (68),

143 (11), 117 (11), 115 (18), 104 (11), 68 (16). HRMS calculated for C14H14N2O2:

242.1055; found: 242.1036.

(3aS*,4R*,6S*,6aR*)-2-Benzyl-4-phenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98c): brown sticky oil (64.1 mg, 64% yield), IR (neat)

𝜈max: 1696, 1395, 1341, 1168, 743, 696 cm-1. 1H NMR δ: 2.16 (br

s, 1H, NH), 3.21 (dd, J = 7.8, 1.0 Hz, 1H, CH2=CHCHCHC=O), 3.35

(dd, J = 8.7, 7.7 Hz, 1H, PhCHCH), 4.41 (dd, J = 5.9, 1.3 Hz, 1H, NCHCH=), 4.51 (d, J =

14.0 Hz, 1H, PhCH2N), 4.56 (d, J = 14.0 Hz, 1H, PhCH2N), 4.68 (d, J = 8.7 Hz, 1H,

PhCHN), 5.21-5.30 (m, 2H, CH=CH2), 6.01 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H, CH=CH2),

7.09-7.34 (m, 10H, ArH). 13C NMR δ: 42.7 (PhCH2N), 49.2, 50.8 (2xCHC=O), 61.7

(CHCH=), 62.3 (PhCHN), 115.9 (CH=CH2), 127.4, 128.0, 128.1, 128.3, 128.6, 129.2,

135.9, 137.6 (ArC, CH=CH2), 175.2, 178.1 (2xC=O). LRMS (EI) m/z: 332 (M+, 20%),

331 (13), 228 (17), 170 (11), 146 (11), 145 (100), 144 (61), 143 (12), 115 (14),

104 (12), 91 (24), 68 (14). HRMS calculated for C21H20N2O2: 332.1525; found:

332.1523.

Page 102: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolidines 98, 101 and 103

101

(3aS*,4R*,6S*,6aR*)-2,4-Diphenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98d): yellow solid (65.8 mg, 69% yield), mp 143-145 °C

(Et2O), IR (neat) 𝜈max: 1704, 1497, 1391, 1207, 1182, 737, 692

cm-1. 1H NMR δ: 2.19 (br s, 1H, NH), 3.35 (dd, J = 7.7, 1.1 Hz, 1H,

CH2=CHCHCHC=O), 3.50 (dd, J = 9.1, 7.5 Hz, 1H, PhCHCH), 4.52 (dd, J = 5.8, 1.3 Hz,

1H, NCHCH=), 4.81 (d, J = 8.9 Hz, 1H, PhCH), 5.22-5.35 (m, 2H, CH=CH2), 6.05 (ddd,

J = 17.3, 10.4, 5.8 Hz, 1H, CH=CH2), 7.10-7.51 (m, 10H, ArH). 13C NMR δ: 49.2, 51.1

(2xCHC=O), 61.9 (CHCH=), 62.5 (PhCH), 115.9 (CH=CH2), 126.2, 126.3, 126.6,

127.4, 128.3, 128.5, 129.0, 129.1, 129.2, 132.0, 137.7, 138.2 (ArC, CH=CH2), 174.6,

177.4 (2xC=O). LRMS (EI) m/z: 318 (M+, 14%), 317 (12), 316 (13), 214 (23), 213

(18), 170 (12), 145 (70), 144 (100), 143 (17), 130 (11), 117 (11), 115 (22), 68 (20),

67 (15). HRMS calculated for C20H18N2O2: 318.1368; found: 318.1358.

(3aS*,4R*,6S*,6aR*)-2-(2-Methoxyphenyl)-4-phenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98e): yellow sticky oil (73.4 mg, 70% yield), IR (neat)

𝜈max: 1708, 1504, 1384, 1252, 1184, 1023, 747, 734, 697 cm-1.

1H NMR δ (mixture of two rotamers): 2.25 (br s, 1H, NH), 3.43

(td, J = 8.1, 1.1 Hz, 1H, CH2=CHCHCHC=O), 3.56 (q, J = 8.2 Hz, 1H,

PhCHCH), 3.72, 3.86 (2s, 3H, OMe, two rotamers), 4.53 (dd, J = 5.3, 1.3 Hz, 1H,

NCHCH=), 4.76, 4.82 (2d, J = 8.4 Hz, 1H, PhCH, two rotamers), 5.24-5.38 (m, 2H,

CH=CH2), 6.01-6.12 (m, 1H, CH=CH2), 6.91-7.47 (m, 9H, ArH). 13C NMR δ: 49.5, 51.2

(2xCHC=O), 55.8 (OCH3), 61.7 (CHCH=), 62.4 (PhCH), 112.2 (CH=CH2), 115.8,

115.9, 121.0, 127.4, 127.6, 128.1, 128.3, 128.5, 129.1, 129.3, 130.7, 137.4, 137.7,

138.0, 138.1 (ArC, CH=CH2), 154.7 (ArCOMe), 174.3, 177.3 (2xC=O). LRMS (EI)

m/z: 348 (M+, 8%), 243 (21), 170 (11), 149 (13), 146 (13), 145 (100), 144 (58),

115 (11), 104 (10), 68 (13). HRMS calculated for C21H20N2O3: 348.1474; found:

348.1461.

Page 103: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

102

(3aS*,4R*,6S*,6aR*)-2-(3-Chorophenyl)-4-phenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98f): brown sticky oil (43.3 mg, 41% yield), IR (neat)

𝜈max: 1710, 1372, 1172, 747, 698 cm-1. 1H NMR δ: 3.42 (dd, J =

8.0, 1.2 Hz, 1H, CH2=CHCHCHC=O), 3.58 (dd, J = 8.9, 7.9 Hz, 1H,

PhCHCH), 4.60 (dd, J = 5.7, 1.2 Hz, 1H, NCHCH=), 4.88 (d, J = 9.0

Hz, 1H, PhCH), 5.30-5.38 (m, 2H, CH=CH2), 6.10 (ddd, J = 17.2, 10.4, 5.8 Hz, 1H,

CH=CH2), 6.65-7.47 (m, 9H, ArH). 13C NMR δ: 49.1, 50.7 (2xCHC=O), 61.9 (CHCH=),

62.6 (PhCH), 117.0 (CH=CH2), 123.9, 124.6, 126.6, 127.4, 128.5, 128.7, 128.8,

129.1, 129.4, 130.1, 132.9, 134.6 (ArC, CH=CH2), 173.9, 176.5 (2xC=O). LRMS (EI)

m/z: 352 (M+, 14%), 170 (12), 146 (12), 145 (100), 144 (65), 143 (15), 117 (11),

115 (17), 104 (12), 68 (15), 66 (11). HRMS calculated for C20H17ClN2O2: 352.0979;

found: 352.0984.

(3aS*,4R*,6S*,6aR*)-2-(4-Chorophenyl)-4-phenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98g): brown sticky oil (72.0 mg, 68% yield), IR (neat)

𝜈max: 1707, 1492, 1377, 1168, 1090, 822, 735, 698 cm-1. 1H NMR

δ: 2.16 (br s, 1H, NH), 3.36 (dd, J = 7.8, 0.9 Hz, 1H,

CH2=CHCHCHC=O), 3.51 (dd, J = 8.9, 7.8 Hz, 1H, PhCHCH), 4.53

(dd, J = 5.9, 1.2 Hz, 1H, NCHCH=), 4.83 (d, J = 8.9 Hz, 1H, PhCH),

5.25-5.35 (m, 2H, CH=CH2), 6.05 (ddd, J = 17.3, 10.4, 5.9 Hz, 1H, CH=CH2), 7.09-7.42

(m, 9H, ArH). 13C NMR δ: 49.2, 51.0 (2xCHC=O), 61.9 (CHCH=), 62.4 (PhCH), 116.0

(CH=CH2), 127.3, 127.4, 128.4, 128.5, 129.3, 130.4, 134.2, 137.6, 138.1 (ArC,

CH=CH2), 174.4, 177.2 (2xC=O). LRMS (EI) m/z: 352 (M+, 6%), 146 (12), 145 (100),

144 (48), 115 (12), 68 (12). HRMS calculated for C20H17ClN2O2: 352.0979; found:

352.0952.

Page 104: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolidines 98, 101 and 103

103

(3aS*,4R*,6S*,6aR*)-2-(4-Bromophenyl)-4-phenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98h): brown solid (66.0 mg, 55% yield), mp 75-77 °C

(Et2O), IR (neat) 𝜈max: 1707, 1488, 1375, 1166, 1070, 1011, 819,

734 cm-1. 1H NMR δ: 2.06 (br s, 1H, NH), 3.37 (dd, J = 7.8, 1.1 Hz,

1H, CH2=CHCHCHC=O), 3.52 (dd, J = 8.9, 7.8 Hz, 1H, PhCHCH),

4.51 (dd, J = 5.9, 1.3 Hz, 1H, NCHCH=), 4.82 (d, J = 8.9 Hz, 1H,

PhCH), 5.26-5.35 (m, 2H, CH=CH2), 6.05 (ddd, J = 17.3, 10.4, 5.8 Hz, 1H, CH=CH2),

7.03-7.53 (m, 9H, ArH). 13C NMR δ: 49.2, 51.0 (2xCHC=O), 61.9 (CHCH=), 62.4

(PhCH), 116.1 (CH=CH2), 122.3, 127.1, 127.2, 127.7, 128.4, 128.5, 130.9, 132.2,

137.4, 138.0 (ArC, CH=CH2), 174.5, 177.2 (2xC=O). LRMS (EI) m/z: 397 (M+, 5%),

293 (15), 291 (14), 146 (12), 145 (100), 144 (59), 143 (11), 115 (12), 68 (13).

HRMS calculated for C20H17BrN2O2: 396.0473; found: 396.0453.

(3aS*,4R*,6S*,6aR*)-2-(4-Fluorobenzyl)-4-phenyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98i): yellow sticky oil (71.4 mg, 68% yield), IR

(neat) 𝜈max: 1697, 1509, 1396, 1341, 1221, 1167, 1159, 745,

699 cm-1. 1H NMR δ: 3.23 (dd, J = 7.8, 1.1 Hz, 1H,

CH2=CHCHCHC=O), 3.38 (dd, J = 8.7, 7.8 Hz, 1H, PhCHCH),

4.43 (dd, J = 5.9, 1.4 Hz, 1H, NCHCH=), 4.47 (d, J = 14.0 Hz, 1H, ArCH2N), 4.53 (d, J =

14.0 Hz, 1H, ArCH2N), 4.70 (d, J = 8.7 Hz, 1H, PhCHN), 5.24-5.32 (m, 2H, CH=CH2),

6.03 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H, CH=CH2), 6.94-7.01 (m, 2H, ArH), 7.11-7.32 (m,

7H, ArH). 13C NMR δ: 42.0 (ArCH2N), 49.0, 50.6 (2xCHC=O), 61.6 (CHCH=), 62.2

(PhCHN), 115.5 (d, 2JC-F = 21.4 Hz, CHCF), 116.4 (CH=CH2), 127.4, 128.3, 128.4 (ArC,

CH=CH2), 131.2 (d, 3JC-F = 8.2 Hz, CHCHCF), 131.7 (d, 4JC-F = 3.4 Hz, CCHCHCF), 137.1

(ArC), 162.5 (d, 1JC-F = 246.5 Hz, CF), 175.0, 177.8 (2xC=O). 19F NMR δ: -114.2. LRMS

(EI) m/z: 350 (M+, 21%), 349 (17), 246 (11), 170 (12), 146 (12), 145 (100), 144

(65), 143 (11), 117 (11), 115 (16), 109 (45), 104 (12), 68 (15). HRMS calculated

for C21H19FN2O2: 350.1431; found: 350.1429.

Page 105: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

104

(2S*,3R*,4R*,5S*)-2-Phenyl-3,4-bis(phenylsulfonyl)-5-

vinylpyrrolidine (endo’-98j): brown sticky oil (81.5 mg, 60%

yield), IR (neat) 𝜈max: 1446, 1306, 1144, 1082, 751, 721, 686

cm-1. 1H NMR δ: 2.98 (br s, 1H, NH), 4.07 (dd, J = 4.2, 3.1 Hz,

1H, CH2=CHCHCHSO2Ph), 4.24 (dd, J = 6.2, 4.2 Hz, 1H, PhCHCH), 4.46-4.51 (m, 1H,

NCHCH=), 4.80 (d, J = 6.2 Hz, 1H, PhCH), 5.13-5.22 (m, 2H, CH=CH2), 5.90 (ddd, J =

16.8, 10.3, 6.3 Hz, 1H, CH=CH2), 7.17-7.87 (m, 15H, ArH). 13C NMR δ: 63.5 (CHCH=),

64.8 (PhCHN), 71.0, 72.3 (2xCHSO2Ph), 117.6 (CH=CH2), 126.9, 127.3, 127.6, 128.2,

128.6, 128.8, 128.9, 129.0, 129.4, 129.6, 129.7, 134.3, 134.6, 135.5, 137.2, 137.5,

138.5 (ArC, CH=CH2). LRMS (EI) m/z: 453 (M+, >1%), 312 (20), 171 (49), 170

(100), 169 (13), 144 (12), 143 (19), 128 (12), 125 (13), 115 (27), 77 (25). HRMS

calculated for C18H18NO2S [M–SO2Ph]: 312.1058; found: 312.1050.

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-(naphthalen-2-yl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98k): brown needles (55.6 mg, 60% yield),

mp 199-201 °C (Et2O), IR (neat) 𝜈max: 1689, 1433, 1282,

1284, 1270, 1129, 822, 761 cm-1. 1H NMR δ: 2.63 (br s, 1H,

NH), 2.87 (s, 3H, CH3), 3.25 (dd, J = 7.6, 0.9 Hz, 1H, CH2=CHCHCHC=O), 3.48 (t, J =

8.2 Hz, 1H, ArCHCH), 4.47 (dd, J = 6.0, 1.0 Hz, 1H, NCHCH=), 4.88 (d, J = 8.7 Hz, 1H,

ArCHN), 5.24-5.35 (m, 2H, CH=CH2), 6.06 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H, CH=CH2),

7.38-7.48 (m, 3H, ArH), 7.75-7.83 (m, 4H, ArH). 13C NMR δ: 25.2 (NCH3), 49.2, 50.8

(2xCHC=O), 61.6 (CHCH=), 62.3 (ArCHN), 116.2 (CH=CH2), 125.5, 125.9, 126.3,

127.9, 128.0, 128.1, 133.4, 135.2, 137.4 (ArC, CH=CH2), 175.5, 178.3 (2xC=O).

LRMS (EI) m/z: 306 (M+, 35%), 305 (19), 195 (100), 194 (95), 167 (19), 165 (27),

155 (60), 154 (19), 152 (19), 128 (35), 127 (16). HRMS calculated for C19H18N2O2:

306.1368; found: 306.1353.

(3aS*,4R*,6R*,6aR*)-2-Methyl-4-(naphthalen-2-yl)-

6-vinyltetrahydropyrrolo[3,4-c]pyrrole-

1,3(2H,3aH)-dione (endo-98k): white solid (21.6 mg,

24% yield), mp 196-198 °C (Et2O), IR (neat) 𝜈max: 1689,

1432, 1381, 1285, 1078, 826, 750 cm-1. 1H NMR δ: 2.11

(br s, 1H, NH), 2.88 (s, 3H, CH3), 3.30 (dd, J = 7.7, 7.4 Hz, 1H, CH2=CHCHCHC=O),

Page 106: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolidines 98, 101 and 103

105

3.46 (dd, J = 8.1, 7.7 Hz, 1H, ArCHCH), 3.95 (t, J = 7.4 Hz, 1H, NCHCH=), 4.63 (d, J =

8.1 Hz, 1H, ArCHN), 5.30-5.48 (m, 2H, CH=CH2), 6.17 (ddd, J = 17.1, 10.2, 7.5 Hz, 1H,

CH=CH2), 7.42-7.49 (m, 3H, ArH), 7.77-7.84 (m, 4H, ArH). 13C NMR δ: 25.0 (NCH3),

49.2, 49.9 (2xCHC=O), 63.2 (CHCH=), 64.4 (ArCHN), 117.9 (CH=CH2), 125.6, 125.8,

126.0, 126.2, 127.9, 128.0, 128.1, 133.4, 135.5, 135.6 (ArC, CH=CH2), 175.5, 176.1

(2xC=O). LRMS (EI) m/z: 306 (M+, 16%), 196 (15), 195 (100), 194 (61), 165 (17),

152 (12), 128 (22). HRMS calculated for C19H18N2O2: 306.1368; found: 306.1367.

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-(o-tolyl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98l): yellow solid (31.1 mg, 38% yield), mp

118-120 °C (Et2O), IR (neat) 𝜈max: 1691, 1425, 1279, 1089,

921, 755, 735 cm-1. 1H NMR δ: 2.07 (br s, 1H, NH), 2.42 (s, 3H,

CCH3), 2.83 (s, 3H, NCH3), 3.35 (dd, J = 7.6, 1.0 Hz, 1H,

CH2=CHCHCHC=O), 3.47 (dd, J = 8.6, 7.6 Hz, 1H, ArCHCH), 4.44 (dd, J = 5.9, 1.1 Hz,

1H, NCHCH=), 4.85 (d, J = 8.6 Hz, 1H, ArCHN), 5.23-5.33 (m, 2H, CH=CH2), 6.05 (ddd,

J = 17.2, 10.4, 5.8 Hz, 1H, CH=CH2), 7.10-7.21 (m, 3H, ArH), 7.38-7.42 (m, 1H, ArH).

13C NMR δ: 19.6 (CCH3), 25.0 (NCH3), 46.8, 50.7 (2xCHC=O), 58.4 (CHCH=), 61.1

(ArCHN), 115.9 (CH=CH2), 125.2, 126.1, 127.7, 130.2, 136.1, 137.7 (ArC, CH=CH2),

175.4, 178.5 (2xC=O). LRMS (EI) m/z: 270 (M+, 70%), 269 (15), 255 (16), 159 (94),

158 (75), 153 (22), 152 (21), 144 (66), 143 (20), 142 (23), 131 (73), 130 (100),

129 (19), 128 (19), 119 (49), 118 (34), 117 (23), 116 (31), 115 (26), 104 (18), 91

(26), 68 (25). HRMS calculated for C16H18N2O2: 270.1368; found: 270.1361.

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-(m-tolyl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98m): yellow solid (25.1 mg, 31% yield), mp

40-41 °C (Et2O), IR (neat) 𝜈max: 1692, 1432, 1380, 1281, 1126,

781, 759 cm-1. 1H NMR δ: 2.33 (s, 3H, CCH3), 2.90 (s, 3H,

NCH3), 3.22 (dd, J = 7.6, 0.9 Hz, 1H, CH2=CHCHCHC=O), 3.39

(dd, J = 8.6, 7.6 Hz, 1H, ArCHCH), 4.43 (dd, J = 6.0, 1.0 Hz, 1H, NCHCH=), 4.69 (d, J =

8.7 Hz, 1H, ArCHN), 5.23-5.33 (m, 2H, CH=CH2), 6.04 (ddd, J = 17.2, 10.4, 5.8 Hz, 1H,

CH=CH2), 7.08-7.25 (m, 4H, ArH). 13C NMR δ: 21.6 (CCH3), 25.1 (NCH3), 49.3, 50.9

(2xCHC=O), 61.6 (CHCH=), 62.3 (ArCHN), 116.1 (CH=CH2), 124.4, 128.4, 129.1,

Page 107: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

106

137.5, 138.1 (ArC, CH=CH2), 175.6, 178.3 (2xC=O). LRMS (EI) m/z: 270 (M+, 34%),

269 (26), 268 (22), 255 (13), 159 (100), 158 (77), 157 (21), 152 (21), 144 (33),

118 (17), 115 (16), 91 (15), 68 (18), 67 (13). HRMS calculated for C16H18N2O2:

270.1368; found: 270.1360.

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-(p-tolyl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98n): yellow solid (32.4 mg, 40% yield),

mp 72-74 °C (Et2O), IR (neat) 𝜈max: 1692, 1433, 1381,

1282, 1128, 926, 813, 761 cm-1. 1H NMR δ: 2.15 (br s, 1H,

NH), 2.33 (s, 3H, CCH3), 2.90 (s, 3H, NCH3), 3.21 (dd, J = 7.7, 1.2 Hz, 1H,

CH2=CHCHCHC=O), 3.47 (dd, J = 8.7, 7.7 Hz, 1H, ArCHCH), 4.40 (dd, J = 5.9, 1.2 Hz,

1H, NCHCH=), 4.69 (d, J = 8.7 Hz, 1H, ArCHN), 5.22-5.33 (m, 2H, CH=CH2), 6.03 (ddd,

J = 17.2, 10.4, 5.8 Hz, 1H, CH=CH2), 7.11-7.22 (m, 4H, ArH). 13C NMR δ: 21.4 (CCH3),

25.1 (NCH3), 49.3, 50.8 (2xCHC=O), 61.5 (CHCH=), 62.1 (ArCHN), 116.0 (CH=CH2),

127.1, 129.2, 134.7, 137.6, 137.9 (ArC, CH=CH2), 175.8, 178.5 (2xC=O). LRMS (EI)

m/z: 270 (M+, 26%), 269 (19), 268 (14), 255 (14), 159 (100), 158 (74), 157 (15),

152 (14), 144 (41), 143 (13), 119 (20), 118 (17), 115 (14), 91 (15), 68 (12). HRMS

calculated for C16H18N2O2: 270.1368; found: 270.1349.

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-(2-nitrophenyl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98o): yellow sticky oil (37.2 mg, 41% yield), IR

(neat) 𝜈max: 1692, 1520, 1433, 1344, 1282, 1071, 738 cm-1. 1H

NMR δ: 1.91 (br s, 1H, NH), 2.83 (s, 3H, CH3), 3.23 (dd, J = 7.8,

1.0 Hz, 1H, CH2=CHCHCHC=O), 3.90 (t, J = 8.1 Hz, 1H, ArCHCH), 4.41 (dd, J = 6.3, 1.2

Hz, 1H, NCHCH=), 5.17 (d, J = 8.4 Hz, 1H, ArCHN), 5.15-5.32 (m, 2H, CH=CH2), 6.05

(ddd, J = 17.0, 10.4, 6.4 Hz, 1H, CH=CH2), 7.42-7.48 (m, 1H, ArH), 7.53-7.61 (m, 1H,

ArH), 7.80-7.85 (m, 1H, ArH), 8.05-8.10 (m, 1H, ArH). 13C NMR δ: 25.0 (CH3), 48.0,

50.2 (2xCHC=O), 57.6 (CHCH=), 61.5 (ArCHN), 116.2 (CH=CH2), 125.0, 128.3,

128.6, 133.6, 137.5, 148.7 (ArC, CH=CH2), 175.7, 178.4 (2xC=O). LRMS (EI) m/z:

301 (M+, >1%), 284 (24), 283 (100), 198 (14), 181 (15), 170 (12), 169 (40), 168

(19), 143 (16), 115 (21). HRMS calculated for C15H15N3O4: 301.1063; found:

301.1043.

Page 108: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolidines 98, 101 and 103

107

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-(3-nitrophenyl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98p): yellow solid (56.0 mg, 62% yield), mp 80-

81 °C (Et2O), IR (neat) 𝜈max: 1694, 1524, 1435, 1347, 1285,

732 cm-1. 1H NMR δ: 2.28 (br s, 1H, NH), 2.88 (s, 3H, CH3), 3.26

(dd, J = 7.7, 1.0 Hz, 1H, CH2=CHCHCHC=O), 3.46 (t, J = 8.1 Hz,

1H, ArCHCH), 4.42 (dd, J = 6.0, 1.2 Hz, 1H, NCHCH=), 4.82 (d, J = 8.5 Hz, 1H, ArCHN),

5.25-5.34 (m, 2H, CH=CH2), 6.04 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H, CH=CH2), 7.48-7.53

(m, 1H, ArH), 7.64-7.69 (m, 1H, ArH), 8.10-8.20 (m, 2H, ArH). 13C NMR δ: 25.1

(CH3), 49.2, 50.4 (2xCHC=O), 61.1 (CHCH=), 61.6 (ArCHN), 116.0 (CH=CH2), 122.2,

123.1, 129.2, 133.6, 137.4, 140.8, 148.3 (ArC, CH=CH2), 175.4, 178.0 (2xC=O).

LRMS (EI) m/z: 301 (M+, 27%), 284 (57), 254 (27), 191 (12), 190 (100), 189 (54),

152 (28), 151 (27), 143 (31), 115 (27), 68 (33). HRMS calculated for C15H15N3O4:

301.1063; found: 301.1054.

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-(4-nitrophenyl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98q): yellow prisms (51 mg, 56% yield),

mp 175-176 °C (Et2O), IR (neat) 𝜈max: 1693, 1683, 1524,

1513, 1342, 1282, 1086, 882, 827, 745 cm-1. 1H NMR δ:

2.89 (s, 3H, CH3), 3.35 (dd, J = 7.9, 1.1 Hz, 1H, CH2=CHCHCHC=O), 3.47 (t, J = 8.1 Hz,

1H, ArCHCH), 4.44 (dd, J = 6.0, 1.4 Hz, 1H, NCHCH=), 4.82 (d, J = 8.6 Hz, 1H, ArCHN),

5.27-5.35 (m, 2H, CH=CH2), 6.04 (ddd, J = 17.2, 10.4, 6.0 Hz, 1H, CH=CH2), 7.48-7.55

(m, 2H, ArH), 8.16-8.22 (m, 2H, ArH). 13C NMR δ: 25.2 (CH3), 49.2, 50.4 (2xCHC=O),

61.3 (CHCH=), 61.7 (ArCHN), 116.4 (CH=CH2), 123.7, 128.2, 137.1, 147.8 (ArC,

CH=CH2), 175.1, 177.9 (2xC=O). LRMS (EI) m/z: 301 (M+, 56%), 300 (16), 254 (13),

191 (12), 190 (100), 189 (54), 152 (28), 151 (25), 143 (36), 115 (28), 68 (33).

HRMS calculated for C15H15N3O4: 301.1063; found: 301.1052.

(3aS*,4R*,6R*,6aR*)-2-Methyl-4-(4-nitrophenyl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo-98q): yellow needles (33.0 mg, 37% yield),

mp 164-167 °C (Et2O), IR (neat) 𝜈max: 1691, 1519, 1510,

1433, 1340, 1282, 1077, 930, 856, 825, 750 cm-1. 1H

Page 109: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

108

NMR δ: 1.96 (br s, 1H, NH), 2.89 (s, 3H, CH3), 3.35 (t, J = 7.7 Hz, 1H,

CH2=CHCHCHC=O), 3.49 (t, J = 7.9 Hz, 1H, ArCHCH), 4.00 (t, J = 7.5 Hz, 1H,

NCHCH=), 4.62 (d, J = 8.0 Hz, 1H, ArCHN), 5.31-5.48 (m, 2H, CH=CH2), 6.10 (ddd, J

= 17.7, 10.2, 7.5 Hz, 1H, CH=CH2), 7.55-7.60 (m, 2H, ArH), 8.17-8.23 (m, 2H, ArH).

13C NMR δ: 25.0 (CH3), 48.6, 49.8 (2xCHC=O), 63.0 (CHCH=), 63.2 (ArCHN), 118.2

(CH=CH2), 123.6, 128.1, 134.9, 145.6, 147.7 (ArC, CH=CH2), 175.2, 175.6 (2xC=O).

LRMS (EI) m/z: 301 (M+, 14%), 191 (12), 190 (100), 189 (25), 143 (15), 115 (12),

68 (16). HRMS calculated for C15H15N3O4: 301.1063; found: 301.1052.

(3aS*,4R*,6S*,6aR*)-4-(4-Bromophenyl)-2-methyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98r): yellow prisms (62.3 mg, 62% yield),

mp 141-142 °C (Et2O), IR (neat) 𝜈max: 1689, 1432, 1383,

1283, 1071, 1009, 926, 812 cm-1. 1H NMR δ: 1.86 (br s, 1H,

NH), 2.89 (s, 3H, CH3), 3.35 (dd, J = 7.6, 1.1 Hz, 1H, CH2=CHCHCHC=O), 3.47 (dd, J =

8.6, 7.6 Hz, 1H, ArCHCH), 4.39 (dd, J = 6.0, 1.2 Hz, 1H, NCHCH=), 4.66 (d, J = 8.6 Hz,

1H, ArCHN), 5.22-5.32 (m, 2H, CH=CH2), 6.02 (ddd, J = 17.2, 10.4, 6.0 Hz, 1H,

CH=CH2), 7.16-7.21 (m, 2H, ArH), 7.42-7.47 (m, 2H, ArH). 13C NMR δ: 25.1 (CH3),

49.2, 50.7 (2xCHC=O), 61.5 (CHCH=), 61.6 (ArCHN), 115.9 (CH=CH2), 122.0, 128.9,

131.6, 137.3, 137.6 (ArC, CH=CH2), 175.6, 178.4 (2xC=O). LRMS (EI) m/z: 334 (M+,

32%), 336 (22), 335 (19), 333 (16), 255 (16), 224 (54), 223 (100), 222 (45), 184

(19), 182 (15), 153 (23), 152 (62), 144 (31), 143 (43), 116 (19), 115 (47), 89 (17),

68 (31), 67 (23). HRMS calculated for C15H15BrN2O2: 334.0317; found: 334.0236.

(3aS*,4R*,6R*,6aR*)-4-(4-Bromophenyl)-2-methyl-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo-98r): yellow solid (22.9 mg, 23% yield), mp

105-106 °C (Et2O), IR (neat) 𝜈max: 1690, 1431, 1379, 1281,

1072, 1010, 814, 730 cm-1. 1H NMR δ: 2.02 (br s, 1H, NH),

2.89 (s, 3H, CH3), 3.27 (t, J = 7.5 Hz, 1H, CH2=CHCHCHC=O), 3.35 (t, J = 7.8 Hz, 1H,

ArCHCH), 3.90 (dd, J = 7.4, 1.0 Hz, 1H, NCHCH=), 4.43 (d, J = 7.9 Hz, 1H, ArCHN),

5.27-5.43 (m, 2H, CH=CH2), 6.10 (ddd, J = 17.5, 10.2, 7.4 Hz, 1H, CH=CH2), 7.21-7.26

(m, 2H, ArH), 7.44-7.48 (m, 2H, ArH). 13C NMR δ: 25.0 (CH3), 48.9, 49.8 (2xCHC=O),

63.0 (CHCH=), 63.6 (ArCHN), 117.9 (CH=CH2), 122.0, 129.0, 131.5, 135.3, 137.0

Page 110: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolidines 98, 101 and 103

109

(ArC, CH=CH2), 175.4, 175.8 (2xC=O). LRMS (EI) m/z: 334 (M+, 10%), 226 (11),

225 (93), 224 (38), 223 (100), 222 (28), 182 (15), 144 (21), 143 (24), 116 (11),

115 (26), 89 (11), 68 (21), 67 (15). HRMS calculated for C15H15BrN2O2: 334.0317;

found: 334.0276.

(3aR*,4R*,6S*,6aS*)-2-Methyl-4-(pyridin-2-yl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (exo’-98s): brown sticky oil (33.9 mg, 44% yield), IR

(neat) 𝜈max: 1687, 1433, 1382, 1281, 1126, 993, 750, 729 cm-

1. 1H NMR δ: 3.03 (s, 3H, CH3), 3.45 (dd, J = 8.0, 7.9 Hz, 1H,

CH2=CHCHCHC=O), 3.84 (dd, J = 8.0, 1.5 Hz, 1H, ArCHCH), 4.21 (t, J = 7.9 Hz, 1H,

NCHCH=), 4.88 (d, J = 1.5 Hz, 1H, ArCHN), 5.23-5.38 (m, 2H, CH=CH2), 5.96 (ddd, J

= 17.3, 10.3, 7.2 Hz, 1H, CH=CH2), 7.21-7.28 (m, 1H, ArH), 7.43-7.48 (m, 1H, ArH),

7.70-7.76 (m, 1H, ArH), 8.54-8.59 (m, 1H, ArH). 13C NMR δ: 25.4 (CH3), 49.3, 51.3

(2xCHC=O), 61.7 (CHCH=), 64.4 (ArCHN), 118.2 (CH=CH2), 122.1, 123.0, 134.2,

137.2, 149.3, 159.3 (ArC, CH=CH2), 176.1, 178.6 (2xC=O). LRMS (EI) m/z: 257 (M+,

42%), 256 (35), 179 (28), 171 (23), 165 (33), 146 (28), 145 (100), 130 (36), 119

(18), 118 (19), 117 (24), 94 (24), 93 (54), 92 (15), 79 (19), 78 (16). HRMS

calculated for C14H15N3O2: 257.1164; found: 257.1151.

(3aS*,4R*,6R*,6aR*)-2-Methyl-4-(pyridin-2-yl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo-98s): yellow sticky oil (18.0 mg, 23% yield), IR

(neat) 𝜈max: 1691, 1433, 1380, 1280, 1126, 994, 777, 757, 732

cm-1. 1H NMR δ: 3.04 (s, 3H, CH3), 3.38 (dd, J = 9.3, 7.5 Hz, 1H,

CH2=CHCHCHC=O), 3.74 (dd, J = 9.4, 6.4 Hz, 1H, ArCHCH), 4.04 (dd, J = 7.5, 6.4 Hz,

1H, NCHCH=), 4.61 (d, J = 6.3 Hz, 1H, ArCHN), 5.29-5.54 (m, 2H, CH=CH2), 6.07 (ddd,

J = 16.9, 10.4, 6.4 Hz, 1H, CH=CH2), 7.26-7.33 (m, 1H, ArH), 7.53-7.57 (m, 1H, ArH),

7.72-7.80 (m, 1H, ArH), 8.57-8.61 (m, 1H, ArH). 13C NMR δ: 25.3 (CH3), 52.2, 52.7

(2xCHC=O), 64.9 (CHCH=), 65.4 (ArCHN), 119.4 (CH=CH2), 123.4, 123.8, 134.9,

137.7, 149.5, 156.5 (ArC, CH=CH2), 176.0, 176.7 (2xC=O). LRMS (EI) m/z: 257 (M+,

20%), 179 (14), 146 (100), 145 (37), 131 (18), 130 (99), 119 (23), 118 (14), 117

(20), 94 (18), 92 (14), 79 (19), 78 (14). HRMS calculated for C14H15N3O2: 257.1164;

found: 257.1151.

Page 111: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

110

(3aS*,4R*,6S*,6aR*)-2-Methyl-4-(pyridin-3-yl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-98t): yellow needles (41.0 mg, 53% yield), mp

150-151 °C (Et2O), IR (neat) 𝜈max: 1693, 1427, 1386, 1285,

1141, 1075, 997, 900, 765, 716 cm-1. 1H NMR δ: 2.43 (br s, 1H,

NH), 2.90 (s, 3H, CH3), 3.24 (dd, J = 7.7, 1.1 Hz, 1H, CH2=CHCHCHC=O), 3.42 (dd, J =

8.5, 7.8 Hz, 1H, ArCHCH), 4.40 (dd, J = 6.1, 1.3 Hz, 1H, NCHCH=), 4.74 (d, J = 8.5 Hz,

1H, ArCHN), 5.25-5.34 (m, 2H, CH=CH2), 6.04 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H,

CH=CH2), 7.24-7.31 (m, 1H, ArH), 7.60-7.66 (m, 1H, ArH), 8.51-8.58 (m, 2H, ArH).

13C NMR δ: 25.2 (CH3), 49.1, 50.5 (2xCHC=O), 59.8 (CHCH=), 61.7 (ArCHN), 116.1

(CH=CH2), 123.4, 134.1, 135.4, 137.4, 148.7, 149.1 (ArC, CH=CH2), 175.4, 178.1

(2xC=O). LRMS (EI) m/z: 257 (M+, 60%), 256 (25), 171 (20), 146 (96), 145 (100),

119 (15), 118 (52), 117 (21), 107 (18), 106 (26), 105 (19), 79 (20), 68 (35). HRMS

calculated for C14H15N3O2: 257.1164; found: 257.1158.

(3aS*,4R*,6R*,6aR*)-2-Methyl-4-(pyridin-3-yl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo-98t): brown sticky oil (18.7 mg, 24% yield), IR

(neat) 𝜈max: 1687, 1430, 1380, 1282, 1127, 1078, 1026, 800,

711 cm-1. 1H NMR δ: 2.60 (br s, 1H, NH), 2.90 (s, 3H, CH3), 3.31

(t, J = 7.7 Hz, 1H, CH2=CHCHCHC=O), 3.42 (t, J = 7.8 Hz, 1H, ArCHCH), 3.94 (dd, J =

7.6, 7.4 Hz, 1H, NCHCH=), 4.42 (d, J = 7.9 Hz, 1H, ArCHN), 5.28-5.45 (m, 2H,

CH=CH2), 6.09 (ddd, J = 17.5, 10.2, 7.4 Hz, 1H, CH=CH2), 7.28-7.34 (m, 1H, ArH),

7.67-7.74 (m, 1H, ArH), 8.53-8.63 (m, 2H, ArH). 13C NMR δ: 25.0 (CH3), 48.8, 49.8

(2xCHC=O), 61.8 (CHCH=), 63.0 (ArCHN), 118.0 (CH=CH2), 123.4, 134.0, 135.1,

135.74, 148.5, 148.9 (ArC, CH=CH2), 175.3, 175.6 (2xC=O). LRMS (EI) m/z: 257

(M+, 21%), 256 (13), 255 (11), 171 (11), 149 (12), 147 (11), 146 (100), 145 (52),

144 (10), 118 (31), 117 (13), 105 (10), 79 (11), 68 (21). HRMS calculated for

C14H15N3O2: 257.1164; found: 257.1156.

Page 112: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolidines 98, 101 and 103

111

(3aR*,4R*,6S*,6aS*)-2-Methyl-4-(thiophen-2-yl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(exo’-98u): yellow solid (43.0 mg, 55% yield), mp 75-77 °C

(Et2O), IR (neat) 𝜈max: 1689, 1432, 1381, 1281, 1126, 834, 703

cm-1. 1H NMR δ: 2.22 (br s, 1H, NH), 3.01 (s, 3H, CH3), 3.41 (dd,

J = 8.3, 7.9 Hz, 1H, CH2=CHCHCHC=O), 3.52 (dd, J = 7.8, 1.3 Hz, 1H, ArCHCH), 4.19

(dd, J = 8.4, 7.0 Hz, 1H, NCHCH=), 5.07 (d, J = 1.0 Hz, 1H, ArCHN), 5.20-5.34 (m, 2H,

CH=CH2), 5.88 (ddd, J = 17.2, 10.3, 6.9 Hz, 1H, CH=CH2), 6.95-7.01 (m, 2H, ArH),

7.24-7.27 (m, 1H, ArH). 13C NMR δ: 25.0 (CH3), 48.7, 53.4 (2xCHC=O), 59.5

(CHCH=), 61.0 (ArCHN), 117.7 (CH=CH2), 124.5, 125.0, 127.3, 134.8, 146.1, (ArC,

CH=CH2), 175.9, 177.8 (2xC=O). LRMS (EI) m/z: 262 (M+, 57%), 261 (31), 176 (12),

152 (14), 151 (100), 150 (45), 149 (17), 136 (11), 122 (10), 121 (12), 118 (34),

110 (11), 67 (10). HRMS calculated for C13H14N2O2S: 262.0776; found: 262.0770.

(3aR,4S,6R,6aS)-4-Phenyl-2-((R)-1-phenylethyl)-6-

vinyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

(endo’-98v): yellow sticky oil (65.2 mg, 63% yield), [𝜶]𝐷20 = +44.5

(c 1.0, CHCl3), IR (neat) 𝜈max: 1694, 1387, 1357, 1221, 1186, 735,

696 cm-1. 1H NMR δ (mixture of two rotamers): 1.67, 1.74 (2d, J

= 7.3 Hz, 3H, CH3, two rotamers), 2.59 (br s, 1H, NH), 3.26, 3.28 (2dd, J = 8.7, 7.4 Hz,

1H, PhCHCH, two rotamers), 4.13, 4.14 (2dd, J = 7.4, 1.0 Hz, 1H, CH2=CHCHCHC=O,

two rotamers), 4.41 (dd, J = 5.6, 1.1 Hz, 1H, NCHCH=), 4.65, 4.69 (2d, J = 8.7 Hz, 1H,

PhCH, two rotamers), 5.20-5.27 (m, 2H, CH=CH2), 5.28 (q, J = 7.3 Hz, 1H, CHMe),

6.00 (ddd, J = 17.2, 10.4, 5.8 Hz, 1H, CH=CH2), 7.06-7.46 (m, 10H, ArH). 13C NMR δ:

16.7 (CH3), 48.7, 50.4 (2xCHC=O), 50.9 (PhCHMe), 61.6 (CHCH=), 62.2 (PhCHN),

116.0 (CH=CH2), 127.3, 127.4, 127.8, 128.0, 128.3, 128.4, 137.5, 139.8 (ArC,

CH=CH2), 175.1, 178.0 (2xC=O). LRMS (EI) m/z: 346 (M+, 19%), 242 (14), 241 (20),

146 (14), 145 (100), 144 (54), 105 (33), 104 (13), 77 (11), 68 (12). HRMS

calculated for C22H22N2O2: 346.1681; found: 346.1676.

Page 113: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 2: Thermal 1,3-DC of unactivated azomethine ylides

112

(3R*,3'S*,3a'S*,6a'R*)-2'-allyl-1,5'-dimethyl-3'-((E)-

styryl)tetrahydro-4'H-spiro[pyrrolidine-3,1'-

pyrrolo[3,4-c]pyrrole]-2,4',5,6'(5'H)-tetraone (101):

white solid (69.6 mg, 59% yield), mp 173-175 °C (Et2O),

IR (neat) 𝜈max: 1684, 1434, 1385, 1277, 1132, 1068, 985,

752 cm-1. 1H NMR δ: 2.64 (d, J = 19.4 Hz, 1H, CCH2C=O),

2.98 (s, 3H, CH3), 3.04 (s, 3H, CH3), 3.05-3.11 (m, 1H, NCH2CH=CH2), 3.25 (d, J = 8.1

Hz, 1H, NCCHC=O), 3.36 (ddt, J = 15.7, 6.4, 1.6 Hz, 1H, NCH2CH=CH2), 3.63 (dd, J =

8.8, 8.1 Hz, 1H, NCHCHC=O), 4.02 (d, J = 19.4 Hz, 1H, CCH2C=O), 4.46 (dd, J = 9.5,

8.8 Hz, 1H, PhCH=CHCH), 4.93-5.06 (m, 2H, NCH2CH=CH2), 5.72-5.84 (m, 1H,

NCH2CH=CH2), 5.87 (dd, J = 15.7, 9.5 Hz, 1H, PhCH=CH), 6.69 (d, J = 15.7 Hz, 1H,

PhCH=CH), 7.28-7.41 (m, 5H, ArH). 13C NMR δ: 24.4, 25.4 (2xCH3), 35.2 (CCH2C=O),

47.6, 48.1 (2xCHC=O), 50.0 (NCH2CH=), 65.3 (NCHCH=CH), 69.2 (NCC=O), 117.8

(CH=CH2), 126.6, 127.0, 128.2, 128.7, 133.9, 135.3, 136.4, (ArC, CH=CH, CH=CH2),

174.7, 175.4, 176.0, 178.5 (4xC=O). LRMS (EI) m/z: 393 (M+, 2%), 353 (21), 352

(100), 302 (14), 115 (16). HRMS calculated for C22H23N3O4: 393.1689; found:

393.1679.

(3aR*,4R*,6R*,6aS*)-4-Ethynyl-2-methyl-6-

phenyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-

dione (endo’-103): yellow prisms (52.7 mg, 69% yield), mp

161-162 °C (Et2O), IR (neat) 𝜈max: 1693, 1386, 1328, 1285, 1093,

993, 894, 745 cm-1. 1H NMR δ: 2.42 (br s, 1H, NH), 2.45 (d, J =

2.2 Hz, 1H, C≡CH), 2.87 (s, 3H, CH3), 3.37 (dd, J = 7.6, 0.9 Hz, 1H, CH≡CCHCHC=O),

3.43 (dd, J = 8.2, 7.6 Hz, 1H, PhCHCH), 4.60 (dd, J = 2.2, 1.0 Hz, 1H, NCHC≡), 4.89

(d, J = 8.2 Hz, 1H, PhCH), 7.28-7.37 (m, 5H, ArH). 13C NMR δ: 25.1 (CH3), 48.4, 50.3

(2xCHC=O), 52.1 (NCHC≡), 62.7 (PhCH), 72.9 (C≡CH), 83.3 (C≡CH), 127.3, 128.3,

128.5, 137.3 (ArC), 175.2, 176.9 (2xC=O). LRMS (EI) m/z: 254 (M+, 22%), 253 (14),

168 (11), 151 (19), 144 (16), 143 (100), 142 (45), 116 (22), 115 (42), 104 (11).

HRMS calculated for C15H14N2O2: 254.1055; found: 254.1046.

Page 114: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of 104

113

General procedure for the synthesis of 104

In a pressure tube the compound endo’-98 (0.2 mmol) was dissolved in

acetonitrile (1.5 mL). Sodium carbonate (1.2 equiv., 25.5 mg) and allyl bromide

(1.1 equiv., 19.0 µL) were added and the solution was refluxed overnight. Next, the

solvent was evaporated under reduced pressure and the reaction mixture was

washed with water and brine. The organic layer was separated and dried over

anhydrous Na2SO4. Later in a pressure tube the product was solved in dry toluene

(20 mL) and the 2nd generation Hoveyda-Grubbs’ catalyst (2 mol%, 2.5 mg) was

added. The reaction was refluxed for 2 hours, filtered with celite and concentrated

in vacuo. The crude product was purified by flash column chromatography over

silica gel (30% EtOAc in hexane as the eluent) to give the corresponding product

104.

Characterization of 104

(3aS*,4R*,8aS*,8bR*)-2-(4-Fluorobenzyl)-4-phenyl-

3a,6,8a,8b-tetrahydropyrrolo[3,4-a]pyrrolizine-

1,3(2H,4H)-dione (104b): brown sticky oil (50.0 mg, 69%

yield), IR (neat) 𝜈max: 2923, 2853, 1699, 1509, 1395, 1338,

1221, 1170, 1088, 752, 731, 697 cm-1. 1H NMR δ: 3.20 (app d,

J = 15.8 Hz, 1H, NCH2CH=), 3.55 (br s, 2H, 2xCHC=O), 3.59 (app

d, J = 15.8 Hz, 1H, NCH2CH=), 4.40-4.51 (m, 3H, PhCHN and

ArCH2N), 5.78-5.89 (m, 2H, CH=CH), 6.84-6.93 (m, 2H, ArH), 7.16-7.26 (m, 7H,

ArH). 13C NMR δ: 41.8 (ArCH2N), 48.5, 50.3 (2xCHC=O), 59.5 (NCH2CH=), 71.0

(NCHCH=), 73.9 (PhCHN), 115.5 (d, 2JC-F = 21.5 Hz, CHCF), 128.2, 128.3 (CH=CH),

129.3, 130.5 (ArC), 130.9 (d, 3JC-F = 8.5 Hz, CHCHCF), 131.7 (d, 4JC-F = 3.2 Hz,

CCHCHCF), 138.1 (ArC), 162.5 (d, 1JC-F = 246.5 Hz, CF), 175.1, 177.9 (2xC=O). 19F

NMR δ: -114.3. LRMS (EI) m/z: 362 (M+, 29%), 158 (14), 157 (100), 156 (63), 115

(13), 109 (16). HRMS calculated for C22H19FN2O2: 362.1431; found: 362.1453.

Page 115: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

114

Page 116: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

115

CHAPTER 3: Multicomponent

periselective cycloadditions of nitroprolinates

Bibliographic background

Diversity-oriented synthesis

Diversity-oriented synthesis (DOS) concept described by Schreiber94 has

been interestingly applied in many methodologies for the synthesis of complex

molecules. The formation of molecular frameworks, just by modifying functional

group arrangements, reaction parameters, etc., are key features of divergent

synthesis. In this concept, the addition of operational simplicity and atom (and

step) economy provided by multicomponent reactions (MCRs)53,54,95 constitutes a

very important strategy. Particularly, 1,3-dipolar cycloadditions (1,3-DC)19,30,31,52

and amide-aldehyde-dienophile (AAD)96 are attractive and versatile

multicomponent processes that can generate organic molecules with very

different skeletons.

Recently have been described that 1,3-DC of in situ generated cyclic

azomethine ylides could be used for the generation of highly substituted

pyrrolizidines,12d,56,69 and indolizidines (see Chapter 1).11 Namely, pyrrolizidine

alkaloids are currently of special interest because they have wide and interesting

biological properties. The pyrrolizidines 107 can be obtained by multicomponent

reaction of proline derived esters 106 with aromatic, aliphatic, and α,β-

unsaturated aldehydes, and the corresponding dipolarophiles.12d,30a,d,56,69,70,97 Mild

reaction conditions were required for all type of electrophilic alkenes affording

diastereoselectively bicyclic alkaloids 107 in good yields (Scheme 44a).

On the other hand, the MCR known as AAD has been widely studied for the

synthesis of 3-aminocyclohexenes and other interesting structures.98 Amides,

carbamates and sulfonamides reacted with aldehydes and dienophiles in the

presence of p-toluenesulfonic acid (TsOH) through a [4+2] process, to yield the

Page 117: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

116

corresponding cycloadducts 108 (Scheme 44b). Apart from amides, a few

examples of AAD using pyrrolidine, morpholine, proline derivatives99,100 or

diallylamine100 have been reported. In the last case only nitrostyrenes were used

as dienophiles.100 These AAD reactions have provided the access to several hetero-

and carbocycles as well as key structural cores of the natural product pumiliotoxin

C.98a

Scheme 44. a) General multicomponent 1,3-DC of prolinates, aldehydes and dipolarophiles affording

pyrrolizidines 107. b) General multicomponent [4+2] cycloaddition of amides-aldehydes-dienophiles

(AAD processes) providing 3-aminocyclohexenes 108.

Concerning the presence of a nitro group in cyclic structures101 not only

allows a series of synthetic transformations but also enhances/modifies the

biological properties of such molecules. Thus, optically active polysubstituted

nitroprolinates have emerged as promising therapeutic agents. For example,

molecules 109 (Figure 15) are important inhibitors of α4,β1-integrin-mediated

hepatic melanoma and in a murine model of colon carcinoma metastasis, as well

as potent antiadhesive properties in several cancer cell lines.102 Bicyclic

heterocycles 110, containing an atropane scaffold have been found as novel

inhibitors of skin cancer.103 Spiroxindoles 111 increased the mortality of zebrafish

Page 118: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Bibliographic background: Diversity-oriented synthesis

117

embryos,104 whilst molecules 112 with benzopyran skeleton were successfully

tested as antimycobacterials against M. tuberculosis H37Rv strain. 4-Nitroprolines

exo-113, and endo-113 have been recently used as chiral organocatalysts in aldol

reactions.105 Michael-type addition of ketones to nitroalkenes was successfully

organocatalyzed by exo-113b (X=H),106 providing good to excellent

diastereoselections and high enantiomeric ratios. In addition, the NH-D-EhuPhos

ligand 114 has been efficiently employed in the 1,3-DC to yield nitroprolines and

structurally rigid spirocompounds from chiral γ-lactams.105,107 A family of

enantiomerically enriched spironitroprolinates 115 were obtained by our group

from imino lactones and nitroalkenes which are currently tested as anticancer

agents.108

Figure 15. Interesting nitroprolinates with biological properties and with useful synthetic

applications.

Page 119: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

118

Page 120: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

119

Objectives

Taking into account the precedent works and researches, the objectives

for this investigation were set as follows:

1 To perform the diastereoselective multicomponent 1,3-DC employing

enantiopure nitroprolinates, α,β-unsaturated aldehydes and

electrophilic alkenes to afford enantiomerically enriched

polysubstituted pyrrolizidines.

2 The evaluation of the diastereoselective multicomponent AAD process

using enantiopure nitroprolinates, α,β-unsaturated aldehydes and

electrophilic alkenes to afford enantiomerically enriched 3-

aminocyclohexene derivatives.

Page 121: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

120

Page 122: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

121

Results and discussion

Keeping the focus on the research of the synthesis of pyrrolizidines using

multicomponent 1,3-DC as this group have been done lately12d,69 it was thought to

expand the study to a multicomponent and diastereoselective version of the 1,3-

DC starting from enantioenriched nitroprolinates exo-113a described by our

group (Scheme 45).109

Scheme 45. Multicomponent synthesis of pyrrolizidines endo- or exo-116 via 1,3-DC.

As well as in previous works toluene was selected as solvent due to the

good results provided with its uses in multicomponent 1,3-dipolar cycloaddition

involving azomethine ylides. trans-Cinnamaldehyde 71 was chosen as aldehyde

because of the high diastereoselection shown in pyrrolizidine derivatives

synthesis (up to 99:1),12d,69 and methyl nitroprolinate exo-113a was selected as

nitrogen source, using a conventional iminium route for the 1,3-DC. The starting

reaction conditions were those optimized by our group where optically active

nitroprolinate exo-113a and 5 mol% of AgOAc are stirring in toluene at 70 °C to

obtain complete conversion in only one night (Scheme 46).110

Scheme 46. Optimized reaction conditions for the 1,3-DC to synthetize pyrrolizidines 116.

Page 123: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

122

To study the scope of this 1,3-dipolar cycloaddition for the synthesis of

enantiomerically enriched pyrrolizidines 116 a large serie of dipolarophiles were

selected (Scheme 47). N-Methylmaleimide gave the best result with an overall

yield of 116a (96%) in a good diastereomeric ratio (62:38 endo:exo in the crude of

the reaction, Table 6, entry 1). Other maleimides are well tolerated such as

maleimide and N-phenylmaleimide. giving very high overall yields (95% and 90%

for 116b and 116c, respectively) and good diastereoselections (Table 6, entries 2

and 3). The best diasteroselectivity of the series is observed with methyl acrylate

(96:4 dr in the crude of the reaction) isolating after the chromatographic column

just the major isomer endo-116d in 88% yield (Table 6, entry 4). Methyl fumarate

furnished a 65:35 mixture of endo:exo diasteroisomers in a 74% overall isolated

yield being the endo-116e diastereoisomer the major one (Table 6, entry 5). In

order to expand the study, reagents bearing a triple bond were surveyed, obtaining

low conversions because at 70 °C large quantities of the product from Michael

addition between nitroprolinates and dialkyl acetylenedicarboxylates are formed.

So, the products 116f and 116g were obtained as unique products in moderate

yields (Table 6, entries 6 and 7). Unfortunately, dipolarophiles such as chalcone,

trans-β-nitrostyrene, trans-1,2-bis(phenylsulfonyl)ethylene or phenyl vinyl

sulfone did not afford any product when the reaction was performed under the

optimal conditions (Table 6, entries 8-11).

Scheme 47. Multicomponent cycloaddition between exo-113a, trans-cinnamaldehyde 71 and

different dipolarophiles to synthetize pyrrolizidines endo- or exo-116.

Page 124: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

123

Table 6. Multicomponent 1,3-DC between exo-113a, trans-cinnamaldehyde 71 and different

dipolarophiles to yield pyrrolizidine derivatives 116.

Entry Dipolarophile Product CNV

(%)a

dra

(endo:exo)

Yield (%)b

(endo, exo)

1

116a >95 62:38 70, 26

2

116b >95 66:34 65, 30

3

116c >95 25:75 23, 67

4 116d >95 96:4 88, 0

5 116e >95 61:39 48, 26

6 116f >95 >99:1 31

7 116g >95 >99:1 35

8

-- <10 -- --

9 -- <10 -- --

10 -- <10 -- --

11 -- 0 -- --

a Determined by 1H NMR of the crude reaction mixture.

b Isolated yield after purification (flash silica gel) of major, minor diastereoisomer.

The cycloadducts obtained through multicomponent 1,3-DC from highly

enantioenriched exo-nitroprolinates 113a are enantiopure diastereoisomers and

they present optical activity, thus the configuration presented corresponds to the

absolute configuration. The structure of the major endo-diastereoisomer was

confirmed by nOe experiments performed to compound endo-116a. Besides, these

assignments are in perfect agreement with the absolute configuration revealed by

X-ray diffraction analysis of molecule endo-116a111 (Figure 16).

Page 125: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

124

Figure 16. X-Ray diffraction analysis of endo-116a cycloadduct (CCDC number: 1538328).

The structure of the minor exo-diastereoisomer was also confirmed by a

nOe experiment, in this product. Thanks to the performed nOe experiments, the

proton shifts and coupling constants of 1H NMR the structures of the remaining

products could be confirmed. Compound 116b performed with NPM was the only

one of the entire series where the exo-diastereoisomer was the major one. The

explanation for that could be a lower destabilizing stereoelectronic interaction,

mainly consisted of electrostatic repulsion between the nitro group of the dipole

and the phenyl group of the dipolarophile, compared with the endo-approach.

Pyrrolidine scaffold which acts as amine source was also submitted to

study employing trans-cinnamaldehyde 71 and NPM as dipolarophile (Scheme

48). When the optically active compound exo-117 was used with the optimal

conditions, good diastereomeric ratio and high overall yield purified from two

diastereoisomers 116h was obtained (88%, Table 7, entry 1). As well as for

compound 116b, where NPM was employed as dipolarophile, exo-ismoer is

isolated as major one. endo-Nitroprolinates are also tested in this reaction,

unfortunately very low conversion was obtained when endo-113a was used as

amine source in this multicomponent reaction (Table 7, entry 2). However, when

racemic endo-118 was employed high conversion was achieved and the major exo-

Page 126: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

125

diastereoisomer 116i could be isolated in good yields (72%, Table 7, entry 3).

Yields represented in Table 7 obey to the overall yields obtained after purification.

Scheme 48. Pyrrolizidines obtained form multicomponent cycloaddition between different

nitroprolinates, trans-cinnamaldehyde 71 and NPM.

Table 7. Multicomponent 1,3-DC between different nitroprolinates, trans-cinnamaldehyde 71 and

NPM.

Entry Amine Product CNV

(%)a

dra

(endo:exo)

Yield (%)b

(endo, exo)

1

116h >95 32:68 60, 28

2

-- <20 50:50 --

3

116i >95 1:99 --, 72

a Determined by 1H NMR of the crude reaction mixture.

b Isolated yield after purification (flash silica gel) of major, minor diastereoisomer.

Page 127: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

126

The switch of the aldehyde moiety was also evaluated (Scheme 49),

obtaining good results when β-phenylcinnamaldehyde was used in combination

with NPM and the quiral secondary amine exo-113a. Both observed

diastereoisomers 116j in the crude reaction mixture were isolated, thanks to the

good dr, after purification process in 80% yield. The endo-diastereoisomer was the

major isomer with 71:29 dr in the crude of the reaction (Table 8, entry 1). This fact

could be due to the presence of an additional phenyl moiety of β-

phenylcinnamaldehyde which implies a higher Pauli repulsion in the exo-

approach, which makes this approximation less favourable. In consequence, endo-

116j adduct was the major diastereoisomer obtained. Unfortunately, other

aldehydes such as isovaleraldehyde, formaldehyde, benzaldehyde or ethyl

glyoxylate were tested in the same optimized conditions for the multicomponent

reaction, failing in the formation of the desired heterocycle.

Scheme 49. Multicomponent cycloaddition between exo-113a, NPM and different aldehydes.

Page 128: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

127

Table 8. Synthesis of pyrrolizidines 116 from exo-113a, NPM and different aldehydes via 1,3-DC.

Entry Aldehyde Product CNV (%)a dra

(endo:exo)

Yield (%)b

(endo, exo)

1

116j >95 71:29 59, 21

2

-- 0 -- --

3

-- 0 -- --

4

-- <5 -- --

5

-- 0 -- --

a Determined by 1H NMR of the crude reaction mixture.

b Isolated yield after purification (flash silica gel) of major, minor diastereoisomer.

However, when crotonaldehyde was used in the reaction of the Scheme 49

only one product was detected, and it was very different from the series of the

pyrrolizidines 116. The presence of hydrogen atoms at the γ-position afforded an

amine (instead of amide)-aldehyde-dienophile (AAD) multicomponent process

through the intermediate 1-pyrrolidine-1,3-diene formed by a previous

isomerization of the iminium ion. A new enantiopure compound in excellent

diastereomeric ratio (>99:1 in the crude of the reaction) and high isolated yield

(86%) was obtained (Scheme 50), which absolute configuration was confirmed

thanks to a X-ray diffraction analysis performed over compound 119a (Figure

17).112

Page 129: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

128

Scheme 50. Divergent multicomponent synthesis of polysubstituted cyclohexenes 119a via AAD

process from prolinate exo-113a, crotonaldehyde and NPM.

Figure 17. Different perspectives of the X-Ray diffraction analysis of 119a cycloadduct (CCDC

number: 1481758).

Page 130: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

129

Going deeper in the reaction conditions of AAD process, it was found that

silver catalyst was not necessary to achieve full conversion and neither was

necessary rise the temperature until 70 °C (Scheme 51).

Scheme 51. Optimized reaction conditions of AAD process between prolinate exo-113a,

crotonaldehyde and NPM.

AAD reactions of compound exo-113a (>99:1 er, >99:1 dr) with aldehydes

and dipolarophiles were carried out at room temperature. The reaction with NMM

(2 equiv) gave compound 119b in a very high yield (94%) and also N-

benzylmaleimide, maleimide and maleic anhydride gave satisfactory yields (89%,

80%, and 71% respectively) of products 119c-e (Figure 18). 1,4-Benzoquinone

afforded compound 119f in 65% yield (determined by 1H NMR spectra of the

crude product) at room temperature. Higher temperature (70 °C) was needed to

accomplish the reaction with 1,2-bis-(phenylsulfonyl)ethylene (BPSE) giving

compound 119g in 78% yield (Figure 18). Diisopropyl azodicarboxylate also

promoted the multicomponent AAD reaction giving 119h in a lower yield (57%,

also determined by 1H NMR spectra of the crude product). Diastereomeric

compounds 119f and 119h could not be neither purified by column

chromatography due to partial decomposition nor recrystallized in order to obtain

pure samples to accomplish the full characterization. Next, α,β-unsaturated

aldehydes with hydrogen atoms at the γ-position such as 3-methyl-2-butenal, 2-

pentenal and 2-hexenal were appropriate aldehydes for the success of the name

AAD multicomponent reaction furnishing with NPM adducts 119i-k in 62%, 89%,

and 72%, respectively (Figure 8). In all these examples, aminocyclohexenes 119

were isolated as unique diastereoisomers. However, the reaction with geranial,

Page 131: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

130

NPM and nitroprolinate exo-113a gave a complex crude mixture containing the

major adduct 119l and various unidentified compounds. After purification, only a

53% yield of the product 119l could be isolated.

Figure 18. Scope of the multicomponent [4+2] AAD process changing the dipolarophiles and the

aldehydes.

Two nitroprolinates, exo-117 and rac-endo-118 were tested as

precursors in this AAD domino reaction with NPM and crotonaldehyde. The

reaction of the exo-117 gave 119m in 81% yield, whereas rac-endo-118 afforded

compound 119n as a 1:1 mixture of two inseparable diastereoisomers in 79%

overall yield (Scheme 52).

Page 132: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

131

Scheme 52. Products 119m and 119n obtained from AAD sequence employing different exo- and

endo-nitroprolinates with crotonaldehyde and NPM.

Noteworthy, no AAD multicomponent reaction was observed during the

reaction of L-proline methyl ester 120 or proline ester derivatives 121, 122 and

123. In these cases, the 1,3-DC occurred instead and the corresponding endo-

pyrrolizidines 124-127 were formed in 61%, 69%, 67% and 68% yield,

respectively (Scheme 53).

Page 133: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

132

Scheme 53. Products endo-124-127 obtained from 1,3-DC employing different methyl prolinates

with crotonaldehyde and NPM.

According to these described results, the presence of the nitro group is

crucial in the origin of the periselectivity in these multicomponent reactions. The

initial step in the proposed mechanism consists in the formation of the iminium

cation A, derived from the condensation between the proline derivative and

crotonaldehyde (Scheme 54). This intermediate has two acidic protons. Therefore,

in presence of a base, A can evolve into the azomethine ylide B by abstraction of

the hydrogen atom located in α-position of the methoxycarbonyl group, that leads

to pyrrolizidines 116, 124-127 or to a dienamine intermediate C by abstraction of

the hydrogen atom in γ-position of crotonaldehyde, thus forming

cyclohexenylpyrrolidines 119.

Page 134: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Results and discussion

133

Scheme 54. General scheme of the reaction of prolinates, aldehydes and dipolarophiles.

Page 135: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

134

Page 136: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

135

Conclusions

1 An example of total periselectivity has been demonstrated in the

multicomponent 1,3-DC or AAD of enantiopure methyl exo- or endo-4-

nitroprolinates in the presence of a dipolarophile and an α,β-unsaturated

aldehyde. The crucial presence of a nitro group in the heterocycle and the

existence or not of hydrogen atoms at the γ-position of the aldehyde

determines the periselectivity towards AAD or 1,3-DC, respectively.

2 The diastereomeric control was notable in the [3+2] process when

cinnamaldehyde was used and was excellent in [4+2] cycloadditions when

isomerizable α,β-unsaturated aldehydes were used affording in this last

case enantiopure polysubstituted 3-aminocyclohexenes.

3 DFT calculations supported these conclusions and gave us information

and confirmation about the mechanism through 1,3-dipolar cycloaddition

or AAD reaction. On the basis of the DFT calculations here presented, it

was supported that the dienamines derived from 4-nitroproline and

crotonaldehyde are in general more reactive than its azomethine ylide

counterparts, being the AAD reaction preferred over the 1,3-DC. High

Pauli repulsions between the nitro group and the dipolarophile difficult

the [3+2] process.

4 In contrast, DFT calculations also supported the different behavior

observed when various proline derivatives (without nitro group) were

used with crotonaldehyde yielding corresponding pyrrolizidines, by

means of 1,3-DC, more than 3-aminocyclohexene derivatives through AAD

cycloaddition in analogous reaction conditions.

Page 137: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

136

Page 138: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

137

Experimental section

General methods

(See general methods shown in the experimental section of Chapter 1).

General procedure for the synthesis of pyrrolizidines 116

To a stirred solution of the chiral nitroprolinate (0.1 mmol) in toluene (1

mL) the aldehyde (0.1 mmol) and the dipolarophile (0.1 mmol) were added. Then

a 5 mol% of AgOAc (0.005 mmol, 0.84 mg) was added and the reaction was stirred

overnight at 70 °C in the dark. Then the reaction was filtered through a celite path

and the solvent was evaporated under reduced pressure. The crude mixture was

purified by flash column chromatography over silica gel (hexane/EtOAc) to

furnish the corresponding product 116.

Characterization of pyrrolizidines 116

Methyl (3aS,4S,6S,7R,8R,8aR,8bR)-2-methyl-7-nitro-

1,3-dioxo-6,8-diphenyl-4-((E)-

styryl)octahydropyrrolo[3,4-a]pyrrolizine-8a(6H)-

carboxylate (endo-116a): colorless prisms (38.6 mg, 70%

yield), mp 194-197 °C (Et2O), [𝜶]𝐷28 = +160.3 (c 1.0, CHCl3),

IR (neat) 𝜈max: 1742, 1697, 1552, 1208, 1037, 968 cm-1. 1H NMR δ: 3.19 (s, 3H,

NCH3), 3.30 (s, 3H, OCH3), 3.53 (t, J = 8.0 Hz, 1H, NCHCHC=O), 4.20 (dd, J = 10.2, 8.0

Hz, 1H, NCHCH=), 4.34 (d, J = 8.0 Hz, 1H, CCHC=O), 4.69 (d, J = 8.4 Hz, 1H, CCHPh),

4.86 (d, J = 9.9 Hz, 1H, NCHPh), 5.41 (dd, J = 9.9, 8.4 Hz, 1H, CHNO2), 5.89 (dd, J =

15.5, 10.2 Hz, 1H, CH=CHPh), 6.31 (d, J = 15.5 Hz, 1H, =CHPh), 6.82-6.91 (m, 2H,

ArH), 7.13-7.49 (m, 13H, ArH). 13C NMR δ: 25.6 (NCH3), 52.0 (CCHPh), 52.1 (OCH3),

52.7, 52.8 (2xCHC=O), 64.9, 67.9 (2xNCH), 82.7 (CCO2Me), 96.7 (CHNO2), 122.6,

126.7, 126.9, 128.1, 128.3, 128.4, 128.8, 128.9, 129.0, 134.8, 135.8, 136.0, 139.0

Page 139: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

138

(ArC, C=C), 171.4 (CO2Me), 175.6, 176.8 (2xC=O). LRMS (EI) m/z: 551 (M+, <1%),

505 (41), 492 (59), 446 (32), 445 (100), 256 (29), 193 (61), 115 (58), 91 (25).

HRMS calculated for C32H29N3O6: 551.2056; found: 551.2057.

Methyl (3aR,4S,6S,7R,8R,8aR,8bS)-2-methyl-7-nitro-

1,3-dioxo-6,8-diphenyl-4-((E)-

styryl)octahydropyrrolo[3,4-a]pyrrolizine-8a(6H)-

carboxylate (exo-116a): colorless plates (14 mg, 26%

yield), mp 88-90 °C (Et2O), [𝜶]𝐷29 = +76.1 (c 0.5, CHCl3), IR

(neat) 𝜈max: 1737, 1700, 1551, 1434, 1372, 1279, 1131, 1084, 968 cm-1. 1H NMR δ:

3.04 (s, 3H, NCH3), 3.23 (s, 3H, OCH3), 3.82 (dd, J = 9.9, 6.6 Hz, 1H, NCHCHC=O), 4.15

(d, J = 9.9 Hz, 1H, CCHC=O), 4.48 (dd, J = 7.9, 6.6 Hz, 1H, NCHCH=), 4.56 (d, J = 8.9

Hz, 1H, CCHPh), 4.83 (d, J = 7.6 Hz, 1H, NCHPh), 5.44 (dd, J = 8.9, 7.6 Hz, 1H, CHNO2),

5.90 (dd, J = 15.7, 7.9 Hz, 1H, CH=CHPh), 6.53 (d, J = 15.7 Hz, 1H, =CHPh), 6.83-6.99

(m, 2H, ArH), 7.12-7.50 (m, 13H, ArH). 13C NMR δ: 25.3 (NCH3), 52.3 (CCHPh), 53.0

(OCH3), 56.0, 58.0 (2xCHC=O), 65.7, 68.2 (2xNCH), 82.9 (CCO2Me), 97.3 (CHNO2),

125.4, 126.7, 127.2, 128.1, 128.2, 128.5, 128.8, 129.0, 129.2, 134.8, 135.5, 135.8,

139.4 (ArC, C=C), 169.2 (CO2Me), 174.5, 175.8 (2xC=O). LRMS (EI) m/z: 551 (M+,

<1%), 506 (19), 505 (55), 492 (18), 446 (17), 445 (48), 256 (19), 194 (18), 193

(100), 115 (57), 91 (21). HRMS calculated for C32H29N2O4 [M–NO2]: 505.2127;

found: 505.2129.

Methyl (3aS,4S,6S,7R,8R,8aR,8bR)-7-nitro-1,3-dioxo-

6,8-diphenyl-4-((E)-styryl)octahydropyrrolo[3,4-

a]pyrrolizine-8a(6H)-carboxylate (endo-116b): pale

pink prisms (35.0 mg, 65% yield), mp 249-252 °C (Et2O),

[𝜶]𝐷26 = +179.2 (c 1.0, CHCl3), IR (neat) 𝜈max: 1711, 1554,

1356, 1192, 750 cm-1. 1H NMR δ: 3.33 (s, 3H, OCH3), 3.57 (t,

J = 8.3 Hz, 1H, NCHCHC=O), 4.21 (dd, J = 10.3, 8.5 Hz, 1H, NCHCH=), 4.37 (d, J = 8.2

Hz, 1H, CCHC=O), 4.91 (d, J = 8.4 Hz, 1H, CCHPh), 5.01 (d, J = 10.2 Hz, 1H, NCHPh),

5.50 (dd, J = 10.2, 8.4 Hz, 1H, CHNO2), 5.93 (dd, J = 15.4, 10.3 Hz, 1H, CH=CHPh),

6.28 (d, J = 15.4 Hz, 1H, =CHPh), 6.84-6.91 (m, 2H, ArH), 7.10-7.50 (m, 13H, ArH),

8.67 (br s, 1H, NH). 13C NMR δ: 51.7 (CCHPh), 52.8 (OCH3), 52.9, 54.0 (2xCHC=O),

64.4, 67.6 (2xNCH), 82.5 (CCO2Me), 96.3 (CHNO2), 122.4, 126.7, 126.9, 128.1,

Page 140: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolizidines 116

139

128.2, 128.3, 128.4, 128.8, 128.9, 129.0, 134.3, 135.9, 136.1, 138.8 (ArC, C=C),

171.4 (CO2Me), 175.3, 176.9 (2xC=O). LRMS (EI) m/z: 538 (M+, <1%), 491 (39),

479 (19), 478 (58), 440 (15), 432 (34), 431 (100), 256 (31), 193 (65), 191 (19),

178 (15), 157 (18), 141 (16), 128 (15), 115 (70), 91 (28). HRMS calculated for

C31H27N2O4 [M–NO2]: 491.1971; found: 491.1963.

Methyl (3aR,4S,6S,7R,8R,8aR,8bS)-7-nitro-1,3-dioxo-

6,8-diphenyl-4-((E)-styryl)octahydropyrrolo[3,4-

a]pyrrolizine-8a(6H)-carboxylate (exo-116b): yellow

prisms (16.2 mg, 30% yield), mp 108-111 °C (Et2O), [𝜶]𝐷26 =

+81.3 (c 1.0, CHCl3), IR (neat) 𝜈max: 1712, 1552, 1340, 1180,

737 cm-1. 1H NMR δ: 3.27 (s, 3H, OCH3), 3.83 (dd, J = 9.9, 7.6 Hz, 1H, NCHCHC=O),

4.14 (d, J = 9.9 Hz, 1H, CCHC=O), 4.51 (d, J = 8.6 Hz, 1H, CCHPh), 4.50-4.56 (m, 1H,

NCHCH=), 4.76 (d, J = 7.7 Hz, 1H, NCHPh), 5.37 (dd, J = 8.6, 7.7 Hz, 1H, CHNO2), 5.84

(dd, J = 15.7, 7.7 Hz, 1H, CH=CHPh), 6.51 (d, J = 15.7 Hz, 1H, =CHPh), 6.81-6.92 (m,

2H, ArH), 7.11-7.46 (m, 13H, ArH), 8.36 (br s, 1H, NH). 13C NMR δ: 52.3 (CCHPh),

53.5 (OCH3), 57.3, 57.8 (2xCHC=O), 65.9, 68.4 (2xNCH), 83.0 (CCO2Me), 97.2

(CHNO2), 125.1, 126.7, 126.8, 127.3, 128.1, 128.2, 128.3, 128.4, 128.5, 128.8, 129.0,

129.2, 134.6, 135.8, 139.2 (ArC, C=C), 169.1 (CO2Me), 174.2, 175.9 (2xC=O). LRMS

(EI) m/z: 538 (M+, <1%), 492 (17), 491 (49), 431 (34), 256 (15), 194 (18), 193

(100), 191 (12), 115 (52), 91 (18). HRMS calculated for C31H27N2O4 [M–NO2]:

491.1971; found: 491.1968.

Methyl (3aS,4S,6S,7R,8R,8aR,8bR)-7-nitro-1,3-dioxo-

2,6,8-triphenyl-4-((E)-styryl)octahydropyrrolo[3,4-

a]pyrrolizine-8a(6H)-carboxylate (endo-116c):

colorless prisms (14.3 mg, 23% yield), mp 209-212 °C

(Et2O), [𝜶]𝐷26 = -131.2 (c 1.0, CHCl3), IR (neat) 𝜈max: 1707,

1549, 1379, 1184, 739 cm-1. 1H NMR δ: 3.36 (s, 3H, OCH3), 3.72 (t, J = 8.1 Hz, 1H,

NCHCHC=O), 4.27 (dd, J = 10.3, 7.9 Hz, 1H, NCHCH=), 4.58 (d, J = 8.2 Hz, 1H,

CCHC=O), 4.86 (d, J = 8.6 Hz, 1H, CCHPh), 5.01 (d, J = 10.6 Hz, 1H, NCHPh), 5.55 (dd,

J = 10.6, 8.6 Hz, 1H, CHNO2), 6.01 (dd, J = 15.4, 10.3 Hz, 1H, CH=CHPh), 6.35 (d, J =

15.4 Hz, 1H, =CHPh), 6.86-6.93 (m, 2H, ArH), 7.11-7.58 (m, 18H, ArH). 13C NMR δ:

51.9 (CCHPh), 52.2 (OCH3), 53.0, 53.1 (2xCHC=O), 65.1, 68.3 (2xNCH), 82.9

Page 141: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

140

(CCO2Me), 96.2 (CHNO2), 122.5, 126.6, 126.7, 127.0, 128.2, 128.3, 128.4, 128.8,

128.9, 129.0, 129.3, 129.6, 131.7, 134.0, 135.9, 138.5 (ArC, C=C), 171.4 (CO2Me),

174.4, 175.8 (2xC=O). LRMS (EI) m/z: 613 (M+, <1%), 568 (16), 567 (36), 555

(24), 554 (61), 508 (40), 507 (100), 440 (36), 394 (22), 256 (44), 219 (18), 194

(20), 193 (97), 191 (26), 178 (20), 157 (19), 141 (25), 115 (94), 91 (40). HRMS

calculated for C37H31N2O4 [M–NO2]: 567.2284; found: 567.2278.

Methyl (3aS,4S,6S,7R,8R,8aR,8bR)-7-nitro-1,3-dioxo-

2,6,8-triphenyl-4-((E)-styryl)octahydropyrrolo[3,4-

a]pyrrolizine-8a(6H)-carboxylate (exo-116c): colorless

prisms (40.9 mg, 67% yield), mp 161-164 °C (Et2O), [𝜶]𝐷24

= -31.5 (c 0.6, CHCl3), IR (neat) 𝜈max: 1707, 1552, 1387,

1192, 742 cm-1. 1H NMR δ: 3.25 (s, 3H, OCH3), 3.94 (dd, J =

10.1, 6.6 Hz, 1H, NCHCHC=O), 4.22 (d, J = 10.1 Hz, 1H, CCHC=O), 4.51-4.70 (m, 2H,

CCHPh and NCHCH=), 4.88 (d, J = 7.7 Hz, 1H, NCHPh), 5.47 (dd, J = 9.0, 7.7 Hz,

CHNO2), 5.92 (dd, J = 15.7, 8.0 Hz, 1H, CH=CHPh), 6.54 (d, J = 15.7 Hz, 1H, =CHPh),

6.83-6.97 (m, 2H, ArH), 7.12-7.51 (m, 18H, ArH). 13C NMR δ: 52.4 (CCHPh), 53.1

(OCH3), 55.9, 57.9 (2xCHC=O), 65.9, 68.3 (2xNCH), 83.3 (CCO2Me), 97.1 (CHNO2),

125.3, 126.5, 126.7, 127.2, 128.1, 128.2, 128.5, 128.7, 128.8, 129.0, 129.2, 129.3,

132.1, 134.8, 135.3, 135.9, 139.3 (ArC, C=C), 169.3 (CO2Me), 173.4, 174.9 (2xC=O).

LRMS (EI) m/z: 613 (M+, <1%), 568 (18), 567 (44), 507 (23), 440 (10), 394 (11),

256 (15), 193 (100), 115 (48), 91 (19). HRMS calculated for C37H31N2O4 [M–NO2]:

567.2284; found: 567.2277.

Dimethyl (2S,3S,5S,6R,7R,7aS)-6-nitro-5,7-diphenyl-3-

((E)-styryl)tetrahydro-1H-pyrrolizine-2,7a(5H)-

dicarboxylate (endo-116d): sticky yellow oil (46.4 mg,

88% yield), [𝜶]𝐷26 = +40.2 (c 1.5, CHCl3), IR (neat) 𝜈max:

1715, 1690, 1543, 1266 cm-1. 1H NMR δ: 2.68 (t, J = 12.8 Hz,

1H, CH2), 3.07 (dd, J = 12.8, 6.0 Hz, 1H, CH2), 3.47 (s, 3H,

CCO2CH3), 3.58 (s, 3H, CHCO2CH3), 3.59-3.67 (m, 1H, CHCO2CH3), 4.09 (dd, J = 9.8,

7.2 Hz, 1H, NCHCH=), 4.32 (d, J = 11.5 Hz, 1H, CCHPh), 5.00 (d, J = 8.5 Hz, 1H,

NCHPh), 5.98 (dd, J = 11.5, 8.5 Hz, 1H, CHNO2), 6.28 (dd, J = 15.5, 9.8 Hz, 1H,

CH=CHPh), 6.38 (d, J = 15.5 Hz, 1H, =CHPh), 7.21-7.45 (m, 15H, ArH). 13C NMR δ:

Page 142: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolizidines 116

141

35.7 (CH2), 51.2 (CCHPh), 52.2 (OCH3), 60.0 (CCH2CH), 65.0, 66.5 (2xNCH), 79.1

(CCO2Me), 96.0 (CHNO2), 125.0, 126.9, 127.2, 128.5, 128.9, 129.0, 132.7, 136.1,

137.3, 139.3 (ArC, C=C), 171.1, 172.9 (2xCO2Me). LRMS (EI) m/z: 526 (M+, <1%),

480 (25), 467 (38), 232 (89), 193 (100), 169 (18), 141 (28), 128 (15), 115 (50), 91

(22). HRMS calculated for C31H30N2O6: 526.2104; found: 526.2104.

Trimethyl (1S,2S,3S,5S,6R,7R,7aR)-6-nitro-5,7-

diphenyl-3-((E)-styryl)tetrahydro-1H-pyrrolizine-

1,2,7a(5H)-tricarboxylate (endo-116e): sticky colorless

oil (27.9 mg, 48% yield), [𝜶]𝐷26 = +80.9 (c 0.8, CHCl3), IR

(neat) 𝜈max: 1717, 1700, 1549, 1251 cm-1. 1H NMR δ: 3.37

(s, 3H, CCO2CH3), 3.59 (s, 3H, OCH3), 3.61 (s, 3H, OCH3),

3.89-3.98 (m, 2H, 2xCHCO2Me), 4.17 (ddd, J = 9.8, 5.5, 2.1 Hz, 1H, NCHCH=), 4.39

(d, J = 11.4 Hz, 1H, CCHPh), 4.99 (d, J = 8.3 Hz, 1H, NCHPh), 5.80 (dd, J = 11.4, 8.3

Hz, 1H, CHNO2), 6.22 (dd, J = 15.4, 9.8 Hz, 1H, CH=CHPh), 6.31 (d, J = 15.4 Hz, 1H,

=CHPh), 7.27-7.41 (m, 15H, ArH). 13C NMR δ: 51.7 (CCHPh), 52.4, 52.5, 52.9

(3xOCH3), 53.7 (CCHCO2Me), 61.5 (NCHCHCO2Me), 63.0, 66.0 (2xNCH), 79.6

(CCO2Me), 97.6 (CHNO2), 124.6, 127.0, 128.2, 128.6, 128.7, 128.9, 129.0, 129.5,

132.1, 137.4, 139.0 (ArC, C=C), 169.6, 170.5, 171.0 (3xCO2Me). LRMS (EI) m/z: 584

(M+, <1%), 538 (12), 440 (5), 394 (7), 290 (15), 193 (100), 193 (100), 115 (25).

HRMS calculated for C33H32N2O8: 584.2159; found: 584.2155.

Trimethyl (1R,2R,3S,5S,6R,7R,7aR)-6-nitro-5,7-

diphenyl-3-((E)-styryl)tetrahydro-1H-pyrrolizine-

1,2,7a(5H)-tricarboxylate (exo-116e): sticky colorless

oil (15.1 mg, 26% yield), [𝜶]𝐷26 = +31.8 (c 0.5, CHCl3), IR

(neat) 𝜈max: 1712, 1699, 1547, 1250 cm-1. 1H NMR δ: 3.60

(s, 3H, OCH3), 3.68 (s, 6H, 2xOCH3), 3.84 (dd, J = 11.0, 10.9

Hz, 1H, NCHCHCO2Me), 4.07-4.13 (m, 1H, NCHCH=), 4.14 (d, J = 11.0 Hz, 1H,

CCHCO2Me), 4.37 (d, J = 11.6 Hz, 1H, CCHPh), 4.82 (d, J = 8.9 Hz, 1H, NCHPh), 5.42

(dd, J = 11.6, 8.9 Hz, CHNO2), 5.84 (dd, J = 15.9, 7.4 Hz, 1H, CH=CHPh), 6.46 (d, J =

15.9 Hz, 1H, =CHPh), 6.90-6.94 (m, 2H, ArH), 7.15-7.30 (m, 11H, ArH), 7.43-7.48

(m, 2H, ArH). 13C NMR δ: 51.2 (CCHPh), 52.5, 52.6, 52.8 (3xOCH3), 53.4

(CCHCO2Me), 54.5 (NCHCHCO2Me), 66.2, 67.7 (2xNCH), 79.5 (CCO2Me), 95.6

Page 143: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

142

(CHNO2), 123.5, 126.6, 127.3, 128.2, 128.5, 128.6, 128.7, 128.9, 132.4, 133.5, 134.8,

136.0, 139.6 (ArC, C=C), 171.4, 171.6, 172.4 (3xCO2Me). LRMS (EI) m/z: 584 (M+,

4%), 538 (28), 525 (49), 314 (18), 290 (72), 258 (19), 230 (25), 194 (19), 193

(100), 115 (62), 91 (22). HRMS calculated for C33H32N2O8: 584.2159; found:

584.2154.

Trimethyl (1R,2R,3S,5S,7aR)-2-nitro-1,3-diphenyl-5-

((E)-styryl)-2,3-dihydro-1H-pyrrolizine-6,7,7a(5H)-

tricarboxylate (116f): sticky yellow oil (17.8 mg, 31%

yield), [𝜶]𝐷27 = +131.2 (c 1.0, CHCl3), IR (neat) 𝜈max: 1734,

1555, 1435, 1265, 1227 cm-1. 1H NMR δ: 3.51 (s, 3H,

OCH3), 3.60 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.59 (d, J =

11.5 Hz, 1H, CCHPh), 5.01 (d, J = 8.4 Hz, 1H, NCHPh), 5.08 (d, J = 9.3 Hz, 1H,

NCHCH=), 5.55 (dd, J = 11.5, 8.4 Hz, 1H, CHNO2), 6.05 (dd, J = 15.7, 9.3 Hz, 1H,

CH=CHPh), 6.44 (d, J = 15.7 Hz, 1H, =CHPh), 7.14-7.45 (m, 15H, ArH). 13C NMR δ:

52.2 (CCHPh), 52.6, 52.7, 59.1 (3xOCH3), 66.4, 69.6 (2xNCH), 85.4 (CCO2Me), 97.3

(CHNO2), 126.3, 122.4, 126.9, 127.0, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 129.5,

132.9, 135.6, 137.2, 137.9, 139.4, 143.1 (ArC, C=C), 163.2, 163.9, 170.6 (3xCO2Me).

LRMS (EI) m/z: 582 (M+, <1%), 523 (14), 194 (17), 193 (100), 115 (23). HRMS

calculated for C33H30N2O8: 582.2002; found: 582.2010.

6,7-Diethyl 7a-methyl (1R,2R,3S,5S,7aR)-2-nitro-1,3-

diphenyl-5-((E)-styryl)-2,3-dihydro-1H-pyrrolizine-

6,7,7a(5H)-tricarboxylate (116g): colorless needles

(21.9 mg, 35% yield), mp 87-90 °C (Et2O), [𝜶]𝐷28 = +141.9

(c 0.7, CHCl3), IR (neat) 𝜈max: 1744, 1722, 1555, 1286, 1270,

1227 cm-1. 1H NMR δ: 1.04 (t, J = 7.1 Hz, 3H, CH2CH3) 1.22

(t, J = 7.1 Hz, 3H, CH2CH3), 3.49 (s, 3H, OCH3), 3.98-4.25 (m, 4H, 2xCH2CH3), 4.61 (d,

J = 11.5 Hz, 1H, CCHPh), 5.02 (d, J = 8.4 Hz, 1H, NCHPh), 5.08 (d, J = 9.4 Hz, 1H,

NCHCH=), 5.56 (dd, J = 11.5, 8.4 Hz, 1H, CHNO2), 6.07 (dd, J = 15.7, 9.4 Hz, 1H,

CH=CHPh), 6.45 (d, J = 15.7 Hz, 1H, =CHPh), 7.14-7.19 (m, 2H, ArH), 7.25-7.45 (m,

13H, ArH). 13C NMR δ: 13.8, 14.2 (2xCH2CH3), 52.4 (CCHPh), 59.2 (OCH3), 61.4, 61.8

(2xOCH2CH3), 66.4, 69.7 (2xNCH), 85.4 (CCO2Me), 97.3 (CHNO2), 122.7, 126.9,

127.0, 128.4, 128.6, 128.7, 128.8, 129.6, 133.0, 135.64, 137.0, 137.7, 139.5, 143.0

Page 144: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolizidines 116

143

(ArC, C=C), 162.8, 163.5 (2xCO2Et), 170.6 (CO2Me). LRMS (EI) m/z: 610 (M+, <1%),

551 (11), 194 (17), 193 (100), 115 (22). HRMS calculated for C35H34N2O8:

610.2315; found: 610.2323.

Methyl (3aR,4S,6S,7R,8R,8aR,8bS)-8-(4-

methoxyphenyl)-7-nitro-1,3-dioxo-2,6-diphenyl-4-

((E)-styryl)octahydropyrrolo[3,4-a]pyrrolizine-

8a(6H)-carboxylate (endo-116h): yellow prisms (17.9

mg, 28% yield), mp 181-184 °C (Et2O), [𝜶]𝐷26 = -100.4 (c

0.9, CHCl3), IR (neat) 𝜈max: 1710, 1554, 1514, 1495, 1377,

1252, 1178, 1032, 756 cm-1. 1H NMR δ: 3.43 (s, 3H,

CO2CH3), 3.71 (dd, J = 8.3, 7.9 Hz, 1H, NCHCHC=O), 3.78 (s, 3H, COCH3), 4.25 (dd, J

= 10.2, 7.9 Hz, 1H, NCHCH=), 4.57 (d, J = 8.3 Hz, 1H, CCHC=O), 4.84 (d, J = 8.5 Hz,

1H, CCHPh), 4.92 (d, J = 10.7 Hz, 1H, NCHPh), 5.49 (dd, J = 10.7, 8.5 Hz, 1H, CHNO2),

6.01 (dd, J = 15.4, 10.3 Hz, 1H, CH=CHPh), 6.35 (d, J = 15.4, Hz, 1H, =CHPh), 6.81-

6.91 (m, 4H, ArH), 7.09-7.24 (m, 3H, ArH), 7.38-7.59 (m, 12H, ArH). 13C NMR δ:

51.9 (CCHPh), 53.1, 53.2 (2xOCH3), 55.4 (CHC=O), 65.1, 68.2 (2xNCH), 82.9

(CCO2Me), 96.5 (CHNO2), 114.2, 114.4, 122.5, 125.5, 126.6, 126.7, 127.0, 128.2,

128.3, 129.0, 129.3, 129.6, 129.7, 131.7, 135.9, 138.5 (ArC, C=C), 159.6 (ArCOMe),

171.6 (CO2Me), 174.5, 175.9 (2xC=O). LRMS (EI) m/z: 644 (M+, <1%), 224 (17),

223 (100), 115 (13). HRMS calculated for C38H33N2O5 [M–NO2]: 597.2389; found:

597.2363.

Methyl (3aS,4S,6S,7R,8R,8aR,8bR)-8-(4-

methoxyphenyl)-7-nitro-1,3-dioxo-2,6-diphenyl-4-

((E)-styryl)octahydropyrrolo[3,4-a]pyrrolizine-

8a(6H)-carboxylate (exo-116h): yellow prisms (38.5 mg,

60% yield), mp 98-101 °C (Et2O), [𝜶]𝐷27 = -48.3 (c 1.0,

CHCl3), IR (neat) 𝜈max: 1711, 1552, 1517, 1496, 1373, 1254,

1180, 735 cm-1. 1H NMR δ: 3.31 (s, 3H, CO2CH3), 3.75 (s, 3H,

COCH3), 3.93 (dd, J = 10.1, 6.5 Hz, 1H, NCHCHC=O), 4.19 (d, J = 10.1 Hz, 1H,

CCHC=O), 4.52-4.58 (m, 2H, CCHPh and NCHCH=), 4.88 (d, J = 7.7 Hz, 1H, NCHPh),

5.45 (dd, J = 9.3, 7.7 Hz, 1H, CHNO2), 5.93 (dd, J = 15.7, 8.0 Hz, 1H, CH=CHPh), 6.53

(d, J = 15.7, Hz, 1H, =CHPh), 6.84-6.93 (m, 4H, ArH), 7.16-7.49 (m, 15H, ArH). 13C

Page 145: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

144

NMR δ: 52.5 (CCHPh), 53.3, 55.3 (2xOCH3), 55.8, 57.6 (2xCHC=O), 65.8, 68.1

(2xNCH), 83.3 (CCO2Me), 97.3 (CHNO2), 114.3, 125.3, 126.2, 126.5, 126.7, 126.8,

128.2, 128.5, 128.6, 128.7, 128.8, 129.1, 129.2, 132.1, 134.3, 134.8, 135.9, 139.3

(ArC, C=C), 159.3 (ArCOMe), 169.4 (CO2Me), 173.4, 175.0 (2xC=O). LRMS (EI) m/z:

644 (M+, <1%), 224 (17), 223 (100). HRMS calculated for C38H34N3O7 [M+H]:

644.2397; found: 644.2394.

Methyl (3aS*,4S*,6S*,7S*,8S*,8aR*,8bR*)-8-cyclohexil-

7-nitro-1,3-dioxo-2,6-diphenyl-4-((E)-

styryl)octahydropyrrolo[3,4-a]pyrrolizine-8a(6H)-

carboxylate (exo-116i): sticky yellow oil (45.0 mg, 72%

yield), IR (neat) 𝜈max: 1712, 1550, 1371, 1184, 908, 729 cm-

1. 1H NMR δ: 1.10-1.25 (m, 4H, CyH), 1.54-1.76 (m, 4H,

CyH), 2.06-2.27 (m, 2H, CyH), 3.07 (t, J = 9.8 Hz, 1H, CCHCy), 3.54 (s, 3H, OCH3),

3.83 (dd, J = 9.9, 5.1 Hz, 1H, NCHCHC=O), 3.92 (d, J = 9.9 Hz, 1H, CCHC=O), 4.53

(ddd, J = 8.8, 5.1, 1.0 Hz, 1H, NCHCH=), 4.71 (d, J = 6.7 Hz, 1H, NCHPh), 5.11 (dd, J =

9.7, 6.7 Hz, 1H, CHNO2), 6.03 (dd, J = 15.6, 8.8 Hz, 1H, CH=CHPh), 6.55 (d, J = 15.6

Hz, 1H, =CHPh), 7.08-7.13 (m, 2H, ArH), 7.20-7.53 (m, 13H, ArH). 13C NMR δ: 25.9,

26.0, 26.2 (CH2CH2CH2), 30.5, 32.4 (2xCHCH2), 39.3 [CHCH(CH2)2], 52.6 (CCHCy),

53.9 (OCH3), 54.9, 61.6 (2xCHC=O), 66.1, 68.3 (2xNCH), 81.8 (CCO2Me), 99.0

(CHNO2), 125.9, 126.5, 126.8, 128.2, 128.3, 128.6, 128.7, 128.9, 129.2, 132.2, 135.5,

135.7, 140.4 (ArC, C=C), 170.1 (CO2Me), 173.9, 174.8 (2xC=O). LRMS (EI) m/z: 619

(M+, 2%), 574 (40), 573 (100), 561 (18), 560 (48), 514 (16), 513 (40), 446 (14),

432 (17), 431 (53), 317 (24), 284 (18), 258 (20), 180 (43), 157 (20), 141 (27), 117

(44), 115 (44), 91 (35). HRMS calculated for C37H37N2O4 [M–NO2]: 573.2753;

found: 573.2753.

Methyl (3aS,4S,6S,7R,8R,8aR,8bR)-4-(2,2-

diphenylvinyl)-7-nitro-1,3-dioxo-2,6,8-

triphenyloctahydropyrrolo[3,4-a]pyrrolizine-8a(6H)-

carboxylate (endo-116j): colorless prisms (40.5 mg, 59%

yield), mp 239-242 °C (Et2O), [𝜶]𝐷27 = +25.1 (c 1.0, CHCl3),

IR (neat) 𝜈max: 1710, 1552, 1497, 1372, 1265, 1215 cm-1. 1H NMR δ: 3.31 (s, 3H,

OCH3), 3.55 (dd, J = 8.3, 8.2 Hz, 1H, NCHCHC=O), 4.19 (dd, J = 10.9, 8.3 Hz, 1H,

Page 146: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolizidines 116

145

NCHCH=), 4.46 (d, J = 8.2 Hz, 1H, CCHC=O), 4.94 (d, J = 8.6 Hz, 1H, CCHPh), 5.09 (d,

J = 10.7 Hz, 1H, NCHPh), 5.60 (dd, J = 10.7, 8.6 Hz, 1H, CHNO2), 5.93 (d, J = 10.9 Hz,

1H, NCHCH=C), 6.74-6.78 (m, 2H, ArH), 7.00-7.55 (m, 23H, ArH). 13C NMR δ: 51.8

(CCHPh), 52.0 (OCH3), 52.7, 52.9 (2xCHC=O), 60.5, 68.2 (2xNCH), 82.8 (CCO2Me),

95.9 (CHNO2), 121.1, 126.6, 127.1, 127.7, 127.8, 127.9, 128.0, 128.2, 128.3, 128.5,

128.6, 128.8, 129.0, 129.1, 129.3, 129.4, 129.7, 131.7, 133.8, 138.4, 138.5, 141.3,

146.6 (ArC, C=C), 171.4 (CO2Me), 174.7, 175.9 (2xC=O). LRMS (EI) m/z: 689 (M+,

1%), 630 (28), 583 (24), 517 (27), 516 (74), 471 (16), 470 (43), 256 (18), 193 (61),

191 (100), 178 (19), 115 (41), 91 (20). HRMS calculated for C43H35N2O4 [M–NO2]:

643.2597; found: 643.2628.

Methyl (3aR,4S,6S,7R,8R,8aR,8bS)-4-(2,2-

diphenylvinyl)-7-nitro-1,3-dioxo-2,6,8-

triphenyloctahydropyrrolo[3,4-a]pyrrolizine-8a(6H)-

carboxylate (exo-116j): yellow prisms (14.7 mg, 21%

yield), mp 111-113 °C (Et2O), [𝜶]𝐷26 = +66.9 (c 0.5, CHCl3),

IR (neat) 𝜈max: 1711, 1552, 1495, 1375, 1259, 1182, 1028 cm-1. 1H NMR δ: 3.17 (s,

3H, OCH3), 3.93 (dd, J = 10.2, 6.6 Hz, 1H, NCHCHC=O), 4.25 (d, J = 10.2 Hz, 1H,

CCHC=O), 4.55 (dd, J = 10.5, 6.6 Hz, 1H, NCHCH=), 4.60 (d, J = 9.4 Hz, 1H, CCHPh),

5.07 (d, J = 7.7 Hz, 1H, NCHPh), 5.47 (dd, J = 9.4, 7.9 Hz, 1H, CHNO2), 5.84 (d, J =

10.5 Hz, 1H, NCHCH=C), 6.69-6.80 (m, 2H, ArH), 6.92-6.99 (m, 2H, ArH), 7.13-7.56

(m, 21H, ArH). 13C NMR δ: 52.3 (CCHPh), 54.7 (OCH3), 56.4, 57.9 (2xCHC=O), 61.3,

67.9 (2xNCH), 83.2 (CCO2Me), 96.9 (CHNO2), 124.0, 126.6, 126.7, 127.1, 127.5,

127.6, 127.7, 128.0, 128.1, 128.2, 128.3, 128.7, 128.8, 128.9, 129.0, 129.2, 129.3,

129.4, 129.6, 132.1, 134.7, 138.2, 139.3, 141.3, 147.5 (ArC, C=C), 169.1 (CO2Me),

173.2, 174.5 (2xC=O). LRMS (EI) m/z: 689 (M+, <1%), 643 (14), 517 (13), 516 (37),

471 (12), 470 (32), 256 (13), 194 (16), 193 (100), 192 (26), 191 (68), 178 (17),

167 (17), 115 (42), 91 (16). HRMS calculated for C43H35N2O4 [M–NO2]: 643.2597;

found: 643.2628.

Page 147: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

146

General procedure for the synthesis of compounds 119

To a stirred solution of the chiral nitroprolinate (0.1 mmol) in toluene (1

mL) the aldehyde (0.1 mmol) and the dienophile (0.1 mmol) were added. The

reaction mixture was stirred overnight at room temperature and the solvent was

evaporated under reduced pressure. The crude mixture was purified by flash

column chromatography over silica gel (hexane/EtOAc) to furnish the

corresponding product.

Characterization of compounds 119

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7aS)-1,3-dioxo-2-

phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl]-4-

nitro-3,5-diphenylpyrrolidine-2-carboxylate (119a):

colorless prisms (47.4 mg, 86% yield), mp 249-251 °C

(Et2O), [α]D26 = +40.2 (c 1.0, CHCl3), IR (neat) 𝜈max: 1700,

1555, 1387 cm-1. 1H NMR δ: 1.89-2.06 (m, 1H, CH2), 2.79

(ddd, J = 15.7, 7.1, 1.7 Hz, 1H, CH2), 3.17 (ddd, J = 9.0, 7.4, 1.7 Hz, 1H, CH2CHC=O),

3.29 (s, 3H, OCH3), 3.60 (dd, J = 9.0, 6.9 Hz, 1H, NCHCHC=O), 3.71 (dd, J = 6.9, 3.0

Hz, 1H, NCHCH=), 4.44 (d, J = 9.3 Hz, 1H, NCHCO2Me), 4.97 (dd, J = 12.1, 9.3 Hz, 1H,

NCHCHPh), 5.24 (d, J = 8.5 Hz, 1H, NCHPh), 5.61 (dd, J = 12.1, 8.5 Hz, 1H, CHNO2),

5.84 (dt, J = 9.7, 3.0 Hz, 1H, NCHCH=), 5.98 (ddt, J = 9.7, 7.1, 3.0 Hz, 1H, NCHCH=CH),

7.18-7.32 (m, 6H, ArH), 7.39-7.57 (m, 7H, ArH), 7.65-7.71 (m, 2H, ArH). 13C NMR δ:

23.8 (CH2), 39.0, 39.6 (2xCHC=O), 50.9 (NCHCH=), 51.8 (NCHCHPh), 53.3 (OCH3),

66.0 (NCHPh), 68.3 (CHCO2Me), 92.5 (CHNO2), 126.7, 127.7, 128.0, 128.3, 128.7,

128.9, 129.0, 129.1, 129.4, 131.9, 132.8, 137.7 (ArC, C=C), 174.3 (CO2Me), 177.0,

178.5 (2xC=O). LRMS (EI) m/z: 551 (M+, <1%), 332 (13), 279 (22), 278 (100), 272

(23), 220 (37), 219 (25), 193 (12), 115 (21), 91 (12). HRMS calculated for

C32H29N2O4 [M–NO2]: 505.2127; found: 505.2121.

Page 148: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of compounds 119

147

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7aS)-2-methyl-1,3-

dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl]-4-

nitro-3,5-diphenylpyrrolidine-2-carboxylate (119b):

colorless prisms (46.1 mg, 94% yield), mp 205-209 °C

(Et2O), [𝜶]𝐷26 = 95.5 (c 1.0, CHCl3), IR (neat) 𝜈max: 1739, 1697,

1551, 1436, 1200, 1155 cm-1. 1H NMR δ: 1.81-1.99 (m, 1H,

CH2), 2.70 (ddd, J = 15.7, 7.1, 1.7 Hz, 1H, CH2), 3.01 (td, J = 8.9, 7.1 Hz, 1H,

CH2CHC=O), 3.04 (s, 3H, NCH3), 3.29 (s, 3H, OCH3), 3.43 (dd, J = 8.9, 6.2 Hz, 1H,

NCHCHC=O), 3.62 (dd, J = 6.1, 3.1 Hz, 1H, NCHCH=), 4.39 (d, J = 9.4 Hz, 1H,

NCHCO2Me), 5.06 (dd, J = 12.1, 9.4 Hz, 1H, NCHCHPh), 5.21 (d, J = 8.5 Hz, 1H,

NCHPh), 5.61 (dd, J = 12.1, 8.5 Hz, 1H, CHNO2), 5.72 (dt, J = 9.7, 3.1 Hz, 1H,

NCHCH=), 5.87 (ddt, J = 9.8, 7.1, 3.0 Hz, 1H, NCHCH=CH), 7.28-7.32 (m, 5H, ArH),

7.40-7.44 (m, 3H, ArH), 7.63-7.68 (m, 2H, ArH). 13C NMR δ: 23.5 (CH2), 25.3 (NCH3),

38.9, 39.4 (2xCHC=O), 51.0 (NCHCH=), 51.8 (NCHCHPh), 53.1 (OCH3), 66.0

(NCHPh), 68.3 (CHCO2Me), 92.5 (CHNO2), 127.7, 128.0, 128.3, 128.6, 128.7, 129.4,

133.0, 137.8 (ArC, C=C), 174.4 (CO2Me), 178.0, 179.5 (2xC=O). LRMS (EI) m/z: 489

(M+, 2%), 430 (13), 383 (22), 279 (22), 278 (100), 272 (24), 220 (57), 219 (36),

193 (19), 115 (29), 91 (14), 79 (28). HRMS calculated for C27H27N2O4 [M–NO2]:

443.1971; found: 443.1965.

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7aS)-2-benzyl-1,3-

dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl]-4-

nitro-3,5-diphenylpyrrolidine-2-carboxylate (119c):

colorless prisms (50.1 mg, 89% yield), mp 72-75 °C (Et2O),

[𝜶]𝐷27 [α]D

26= +63.7 (c 1.0, CHCl3), IR (neat) 𝜈max: 1738, 1697,

1551, 1398, 1350, 1201, 1159 cm-1. 1H NMR δ: 1.87 (ddd, J =

15.6, 6.7, 3.0 Hz, 1H, CH2), 2.75 (ddd, J = 15.6, 7.2, 1.8 Hz, 1H, CH2), 2.97-3.09 (m,

1H, CH2CHC=O), 3.23 (s, 3H, OCH3), 3.41 (dd, J = 8.9, 6.9 Hz, 1H, NCHCHC=O), 3.61

(dd, J = 6.9, 3.0 Hz, 1H, NCHCH=), 3.99 (d, J = 9.4 Hz, 1H, NCHCO2Me), 4.63 (d, J =

14.2 Hz, 1H, NCH2Ph), 4.81 (d, J = 14.2 Hz, 1H, NCH2Ph), 4.94 (dd, J = 12.1, 9.4 Hz,

1H, NCHCHPh), 5.22 (d, J = 8.5 Hz, 1H, NCHPh), 5.66-5.51 (m, 2H, CHNO2 and

NCHCH=), 5.88 (ddt, J = 10.1, 6.7, 3.0 Hz, 1H, NCHCH=CH), 7.07-7.15 (m, 2H, ArH),

7.20-7.47 (m, 11H, ArH), 7.58-7.68 (m, 2H, ArH). 13C NMR δ: 23.3 (CH2), 39.2, 39.8

(2xCHC=O), 42.8 (NCH2Ph), 50.7 (NCHCH=), 51.7 (NCHCHPh), 53.2 (OCH3), 65.8

VS81

Page 149: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

148

(NCHPh), 68.2 (CHCO2Me), 92.3 (CHNO2), 127.7, 127.9, 128.0, 128.2, 128.4, 128.6,

128.9, 129.0, 129.4, 132.9, 135.7, 137.9 (ArC, C=C), 174.3 (CO2Me), 177.4, 179.0

(2xC=O). LRMS (EI) m/z: 565 (M+, <1%), 332 (9), 279 (21), 278 (100), 272 (17),

220 (33), 219 (23), 115 (15), 91 (26), 79 (18). HRMS calculated for C33H31N2O4 [M–

NO2]: 519.2284; found: 519.2266.

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7aS)-1,3-dioxo-

2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl]-4-nitro-3,5-

diphenylpyrrolidine-2-carboxylate (119d): colorless

prisms (37.8 mg, 80% yield), mp 87-91 °C (Et2O), [𝜶]𝐷26

[α]D26= +90.5 (c 1.0, CHCl3), IR (neat) 𝜈max: 1699, 1551, 1353,

1199, 1162 cm-1. 1H NMR δ: 1.89 (ddd, J = 15.6, 7.2, 2.9 Hz,

1H, CH2), 2.68 (ddd, J = 15.6, 7.0, 1.7 Hz, 1H, CH2), 3.09 (ddd,

J = 9.0, 7.2, 1.7 Hz, 1H, CH2CHC=O), 3.30 (s, 3H, OCH3), 3.49 (dd, J = 9.0, 7.0 Hz, 1H,

NCHCHC=O), 3.63 (dd, J = 7.0, 3.0 Hz, 1H, NCHCH=), 4.46 (d, J = 9.3 Hz, 1H,

NCHCO2Me), 5.01 (dd, J = 12.1, 9.3 Hz, 1H, NCHCHPh), 5.19 (d, J = 8.5 Hz, 1H,

NCHPh), 5.62 (dd, J = 12.1, 8.5 Hz, 1H, CHNO2), 5.79 (dt, J = 9.8, 3.0 Hz, 1H,

NCHCH=), 5.94 (ddt, J = 9.8, 7.0, 2.9 Hz, 1H, NCHCH=CH), 7.19-7.36 (m, 5H, ArH),

7.35-7.49 (m, 3H, ArH), 7.62-7.70 (m, 2H, ArH), 9.06 (br s, 1H, NH). 13C NMR δ: 23.3

(CH2), 40.3, 40.6 (2xCHC=O), 51.0 (NCHCH=), 51.9 (NCHCHPh), 53.1 (OCH3), 66.0

(NCHPh), 68.3 (CHCO2Me), 92.5 (CHNO2), 127.7, 127.8, 128.1, 128.4, 128.6, 128.8,

129.4, 132.8, 137.8 (ArC, C=C), 174.4 (CO2Me), 178.5, 180.1 (2xC=O). LRMS (EI)

m/z: 475 (M+, <1%), 429 (11), 428 (16), 416 (17), 378 (19), 369 (44), 332 (28),

279 (24), 278 (100), 272 (50), 221 (16), 220 (96), 219 (79), 193 (21), 115 (43), 91

(20), 79 (42), 77 (19). HRMS calculated for C26H25N2O4 [M–NO2]: 429.1814; found:

429.1804.

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7aS)-1,3-dioxo-

1,3,3a,4,7,7a-hexahydroisobenzofuran-4-yl]-4-nitro-

3,5-diphenylpyrrolidine-2-carboxylate (119e, isolated as

1:0.6 mixture of diastereoisomers): sticky yellow oil (33.9

mg, 71% yield). Data for the major isomer: IR (neat) 𝜈max:

1774, 1739, 1552, 1203, 910, 731 cm-1. 1H NMR δ: 1.93-2.04

(m, 1H, CH2), 2.71 (ddd, J = 16.1, 7.0, 2.0 Hz, 1H, CH2), 3.28 (s, 3H, OCH3), 3.34-3.38

Page 150: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of compounds 119

149

(m, 1H, CH2CHC=O), 3.63-3.70 (m, 2H, NCHCHC=O and NCHCH=), 4.40 (d, J = 9.2

Hz, 1H, NCHCO2Me), 4.89 (dd, J = 12.1, 9.2 Hz, 1H, NCHCHPh), 5.11 (d, J = 8.5 Hz,

1H, NCHPh), 5.62 (dd, J = 12.1, 8.5 Hz, 1H, CHNO2), 5.77-5.86 (m, 1H, NCHCH=),

6.01 (ddt, J = 12.4, 6.8, 2.7 Hz, 1H, NCHCH=CH), 7.04-7.51 (m, 13H, ArH), 7.58-7.77

(m, 2H, ArH). 13C NMR δ: 23.4 (CH2), 39.9, 40.3 (2xCHC=O), 51.1 (NCHCH=), 52.0

(NCHCHPh), 52.6 (OCH3), 65.6 (NCHPh), 68.3 (CHCO2Me), 92.2 (CHNO2), 127.2,

127.7, 127.8, 128.0, 128.5, 128.7, 128.8, 129.3, 129.5, 129.6, 130.1, 132.4, 137.4

(ArC, C=C), 172.1 (CO2Me), 173.7, 174.1 (2xC=O). LRMS (EI) m/z: 476 (M+, <1%),

378 (10), 280 (16), 279 (18), 221 (19), 220 (100), 219 (19), 193 (56), 117 (20),

115 (43), 91 (16). HRMS calculated for C24H20NO3 [M–NO2, –HCO2Me]: 370.1443;

found: 370.1451.

(2S,3S,4R,5S)-1-((1R,5R,6R)-5,6-

bis(phenylsulfonyl)cyclohex-2-en-1-yl)-2-

((methylperoxy)-λ2-methyl)-4-nitro-3,5-

diphenylpyrrolidine (119g): yellow prisms as a 1:0.5

endo/exo-mixture (53.5 mg, 78% yield), mp 94-97 °C (Et2O),

IR (neat) 𝜈max: 1737, 1551, 1447, 1308, 1204, 1146, 1081,

756 cm-1. 1H NMR δ [mixture of endo/exo (1:0.5), difficult assignment]: 2.27-2.42

(m, 1H), 2.43-2.52 (m, 1.5H), 2.71-2.78 (m, 0.5H), 3.01-3.05 (m, 0.5H), 3.24 (s,

1.5H), 3.25 (s, 3H), 3.72-3.77 (m, 0.5H), 3.80-3.85 (m, 1.5H), 4.15 (br s, 1H), 4.24-

4.27 (m, 0.5H), 4.61 (dd, J = 12.0, 9.2 Hz, 1H), 4.68-4.73 (m, 0.5H), 4.81 (d, J = 8.6

Hz, 0.5H), 4.89 (d, J = 9.3 Hz, 1H), 5.03 (d, J = 8.3 Hz, 1H), 5.10 (d, J = 8.4 Hz, 0.5H),

5.59 (dd, J = 12.0, 8.4 Hz, 2H), 5.71-5.83 (m, 1.5H), 5.99 (ddq, J = 10.7, 5.4, 2.7 Hz,

1H), 6.20 (d, J = 2.7 Hz, 0.5H), 6.93-6.97 (m, 0.5H), 7.20-7.86 (m, 35H). 13C NMR δ

[mixture of endo/exo (1:0.5), data of the major endo-diastereoisomer]: 20.7 (CH2),

48.3 (NCHCHS), 51.7 (NCHCHPh), 52.5 (CH2CHS), 55.9 (OCH3), 58.7 (NCHCHS),

64.7 (NCHPh), 68.6 (CHCO2Me), 92.6 (CHNO2), 126.1, 126.6, 127.4, 127.8, 128.1,

128.4, 128.7, 128.8, 129.0, 129.5, 129.8, 129.9, 130.1, 132.8, 134.5, 134.6, 136.3,

138.6, 138.7 (ArC, C=C), 174.0 (CO2Me). LRMS (EI) m/z: 687 (M+, <1%), 404 (24),

403 (89), 296 (27), 221 (20), 220 (100), 219 (41), 193 (31), 164 (21), 141 (43),

125 (57), 115 (46), 104 (19), 91 (20), 79 (33), 78 (24), 77 (87). HRMS calculated

for C36H35N2O8S2 [M+H]: 687.1835; found: 687.1837.

Page 151: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

150

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7aS)-6-methyl-1,3-

dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-

yl]-4-nitro-3,5-diphenylpyrrolidine-2-carboxylate

(119i): colorless prisms (35.2 mg, 62% yield), mp 228-232

°C (Et2O), [𝜶]𝐷29 = +73.1 (c 1.0, CHCl3), IR (neat) 𝜈max: 1746,

1705, 1548, 1500, 1384 cm-1. 1H NMR δ: 1.75 (s, 3H, CCH3),

2.02 (dd, J = 15.2, 7.3 Hz, 1H, CH2), 2.62 (dd, J = 15.3, 2.1 Hz, 1H, CH2), 3.17 (ddd, J

= 9.0, 7.0, 2.0 Hz, 1H, CH2CHC=O), 3.30 (s, 3H, OCH3), 3.54 (dd, J = 9.0, 6.9 Hz, 1H,

NCHCHC=O), 3.68 (br s, 1H, NCHCH=), 4.40 (d, J = 9.3 Hz, 1H, NCHCO2Me), 4.95 (dd,

J = 12.0, 9.3 Hz, 1H, NCHCHPh), 5.24 (d, J = 8.5 Hz, 1H, NCHPh), 5.44 (br s, 1H,

NCHCH=), 5.60 (dd, J = 12.0, 8.5 Hz, 1H, CHNO2), 7.12-7.35 (m, 7H, ArH), 7.37-7.58

(m, 6H, ArH), 7.64-7.71 (m, 2H, ArH). 13C NMR δ: 23.6 (CH2), 28.8 (CCH3), 39.3, 39.7

(2xCHC=O), 50.9 (NCHCH=), 51.8 (NCHCHPh), 54.0 (OCH3), 66.0 (NCHPh), 68.5

(CHCO2Me), 92.5 (CHNO2), 121.0, 126.6, 127.8, 128.1, 128.3, 128.7, 129.0, 129.4,

132.0, 133.0, 138.0, 138.3 (ArC, C=C), 174.5 (CO2Me), 177.1, 178.4 (2xC=O). LRMS

(EI) m/z: 566 (M+, <1%), 346 (33), 286 (14), 279 (25), 278 (100), 220 (45), 115

(16), 93 (35), 91 (18). HRMS calculated for C33H31N3O6: 565.2213; found:

565.2199.

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7S,7aS)-7-methyl-1,3-

dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-

yl]-4-nitro-3,5-diphenylpyrrolidine-2-carboxylate

(119j): colorless plates (50.6 mg, 89% yield), mp 244-247

°C (Et2O), [𝜶]𝐷26 = +104.3 (c 1.0, CHCl3), IR (neat) 𝜈max: 1699,

1552, 1385, 1192, 1032, 762 cm-1. 1H NMR δ: 1.44 (d, J = 7.3

Hz, 3H, CCH3), 2.20-2.30 (m, 1H, CHMe), 3.06 (dd, J = 8.7, 6.5

Hz, 1H, MeCHCHC=O), 3.31 (s, 3H, OCH3), 3.58 (dd, J = 8.7, 6.9 Hz, 1H, NCHCHC=O),

3.67-3.73 (m, 1H, NCHCH=), 4.48 (d, J = 9.3 Hz, 1H, NCHCO2Me), 4.97 (dd, J = 12.1,

9.3 Hz, 1H, NCHCHPh), 5.24 (d, J = 8.5 Hz, 1H, NCHPh), 5.61 (dd, J = 12.1, 8.5 Hz, 1H,

CHNO2), 5.73-5.87 (m, 2H, CH=CH), 7.19-7.28 (m, 7H, ArH), 7.41-7.56 (m, 6H, ArH),

7.62-7.71 (m, 2H, ArH). 13C NMR δ: 16.7 (CCH3), 30.6 (CCH3), 40.4, 44.0 (2xCHC=O),

50.9 (NCHCH=), 51.9 (NCHCHPh), 53.9 (OCH3), 66.2 (NCHPh), 68.3 (CHCO2Me),

92.6 (CHNO2), 126.8, 127.4, 127.7, 128.1, 128.3, 128.7, 129.0, 129.4, 129.5, 131.9,

132.9, 135.5, 137.7 (ArC, C=C), 174.3 (CO2Me), 176.3, 176.7 (2xC=O). LRMS (EI)

Page 152: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of compounds 119

151

m/z: 566 (M+, <1%), 393 (12), 392 (45), 346 (21), 286 (44), 279 (21), 278 (100),

220 (36), 219 (17), 115 (23), 93 (34), 91 (24). HRMS calculated for C33H31N2O4 [M–

NO2]: 519.2284; found: 519.2275.

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7S,7aS)-7-ethyl-1,3-

dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-

yl]-4-nitro-3,5-diphenylpyrrolidine-2-carboxylate

(119k): yellow prisms (41.7 mg, 72% yield), mp 201-204 °C

(Et2O), [𝜶]𝐷26 = +84.3 (c 1.0, CHCl3), IR (neat) 𝜈max: 1699,

1552, 1385, 1188, 1030, 758 cm-1. 1H NMR δ: 0.99 (t, J = 7.0

Hz, 3H, CH2CH3), 1.79-2.02 (m, 3H, CHCH2CH3), 3.17 (dd, J =

8.7, 5.4 Hz, 1H, EtCHCHC=O), 3.31 (s, 3H, OCH3), 3.57 (dd, J = 8.7, 7.1 Hz, 1H,

NCHCHC=O), 3.71 (d, J = 7.1 Hz, 1H, NCHCH=), 4.46 (d, J = 9.4 Hz, 1H, NCHCO2Me),

4.98 (dd, J = 12.1, 9.4 Hz, 1H, NCHCHPh), 5.27 (d, J = 8.5 Hz, 1H, NCHPh), 5.61 (dd,

J = 12.1, 8.5 Hz, 1H, CHNO2), 5.81-5.90 (m, 2H, CH=CH), 7.16-7.31 (m, 6H, ArH),

7.38-7.58 (m, 7H, ArH), 7.63-7.73 (m, 2H, ArH). 13C NMR δ: 12.7 (CH2CH3), 24.1

(CH2CH3), 37.9 (CHCH2), 40.3, 42.4 (2xCHC=O), 50.9 (NCHCH=), 51.9 (NCHCHPh),

54.1 (OCH3), 66.3 (NCHPh), 68.3 (CHCO2Me), 92.6 (CHNO2), 126.8, 127.6, 127.8,

128.0, 128.1, 128.3, 128.7, 129.0, 129.4, 129.5, 131.9, 132.9, 134.5, 137.8 (ArC,

C=C), 174.3 (CO2Me), 176.2, 176.7 (2xC=O). LRMS (EI) m/z: 580 (M+, <1%), 407

(15), 406 (53), 360 (21), 300 (37), 279 (21), 278 (100), 220 (39), 193 (16), 115

(26), 107 (18), 91 (19), 79 (27). HRMS calculated for C34H33N2O4 [M–NO2]:

533.2440; found: 533.2429.

Methyl (2S,3S,4R,5S)-1-[(3aS,4R,7aS)-6-(4-methylpent-

3-en-1-yl)-1,3-dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-

1H-isoindol-4-yl]-4-nitro-3,5-diphenylpyrrolidine-2-

carboxylate (119l): yellow plates (33.8 mg, 53% yield), mp

117-120 °C (Et2O), [𝜶]𝐷24 = +34.3 (c 0.6, CHCl3), IR (neat)

𝜈max: 1743, 1703, 1549, 1375, 1163, 750 cm-1. 1H NMR δ:

1.54 (s, 3H, CCH3), 1.64 (s, 3H, CCH3), 1.93-2.10 (m, 5H,

=CCH2CH and 2xCH2), 2.67 (dd, J = 15.0, 1.9 Hz, 1H,

=CCH2CH), 3.18 (ddd, J = 9.0, 7.2, 1.9 Hz, 1H, CH2CHC=O), 3.30 (s, 3H, OCH3), 3.56

(dd, J = 9.0, 6.8 Hz, 1H, NCHCHC=O), 3.69 (br s, 1H, NCHCH=), 4.44 (d, J = 9.4 Hz,

Page 153: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

152

1H, NCHCO2Me), 4.97 (dd, J = 12.0, 9.4 Hz, 1H, NCHCHPh), 4.97-5.03 [br s, 1H,

CH=C(CH3)2], 5.25 (d, J = 8.5 Hz, 1H, NCHPh), 5.45 (br s, 1H, NCHCH=), 5.61 (dd, J =

12.0, 8.5 Hz, 1H, CHNO2), 7.20-7.33 (m, 7H, ArH), 7.41-7.56 (m, 6H, ArH), 7.66-7.71

(m, 2H, ArH). 13C NMR δ: 17.8 (CH2), 25.8 (CCH3), 25.9, 27.9, 37.2 (3xCH2), 39.2,

39.6 (2xCHC=O), 50.9 (NCHCH=), 51.9 (NCHCHPh), 54.0 (OCH3), 66.0 (NCHPh),

68.4 (CHCO2Me), 92.5 (CHNO2), 120.6, 123.2, 126.6, 127.8, 128.1, 128.7, 129.0,

129.4, 129.5, 132.0, 132.5, 133.0, 137.9, 142.0 (ArC, C=C), 174.5 (CO2Me), 177.2,

178.4 (2xC=O). LRMS (EI) m/z: 634 (M+, <1%), 279 (27), 278 (100), 240 (13), 220

(37), 115 (15), 91 (18), 69 (17). HRMS calculated for C38H39N2O4 [M–NO2]:

587.2910; found: 587.2895.

Methyl (2R,3S,4R,5S)-1-[(3aS,4R,7aS)-1,3-dioxo-2-

phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl]-3-(4-

methoxyphenyl)-4-nitro-5-diphenylpyrrolidine-2-

carboxylate (119m): orange prisms (47.2 mg, 81% yield),

mp 208-211 °C (Et2O), [𝜶]𝐷25 = +86.3 (c 1.0, CHCl3), IR (neat)

𝜈max: 1745, 1702, 1550, 1517, 1388, 1254, 1156, 1024, 796,

761 cm-1. 1H NMR δ: 1.93-2.04 (m, 1H, CH2), 2.80 (ddd, J =

15.7, 7.0, 1.7 Hz, 1H, CH2), 3.18 (ddd, J = 9.0, 7.5, 1.7 Hz, 1H,

CH2CHCO), 3.36 (s, 3H, CO2CH3), 3.60 (dd, J = 9.0, 7.0 Hz, 1H, NCHCHCO), 3.71 (dd,

J = 6.6, 3.0 Hz, 1H, NCHCH=), 3.75 (s, 3H, COCH3), 4.40 (d, J = 9.3 Hz, 1H,

NCHCO2Me), 4.90 (dd, J = 12.1, 9.3 Hz, 1H, NCHCHPh), 5.23 (d, J = 8.5 Hz, 1H,

NCHPh), 5.54 (dd, J = 12.1, 8.5 Hz, 1H, CHNO2), 5.84 (dt, J = 9.7, 3.0 Hz, 1H,

NCHCH=), 5.98 (ddt, J = 10.0, 6.6, 3.0 Hz, 1H, NCHCH=CH), 6.76-7.31 (m, 6H, ArH),

7.39-7.56 (m, 6H, ArH), 7.65-7.69 (m, 2H, ArH). 13C NMR δ: 23.9 (CH2), 39.0, 39.6

(2xCHC=O), 50.4 (NCHCH=), 52.0 (NCHCHPh), 53.4, 55.3 (2xOCH3), 66.0 (NCHPh),

68.2 (CHCO2Me), 93.0 (CHNO2), 114.1, 124.7, 126.7, 127.7, 128.8, 128.9, 129.0,

129.2, 129.4, 131.9, 137.8 (ArC, C=C), 159.5 (ArCOMe), 174.5 (CO2Me), 177.0, 178.6

(2xC=O). LRMS (EI) m/z: 582 (M+, >1%), 362 (13), 309 (23), 308 (100), 302 (22),

250 (29), 249 (37), 223 (25), 115 (13), 79 (24). HRMS calculated for C33H31N2O5

[M–NO2]: 535.2233; found: 535.2222.

Page 154: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of compounds 119

153

Methyl (2S*,3R*,4S*,5S*)-3-cyclohexyl-1-

[(3aS*,4R*,7aS*)-1,3-dioxo-2-phenyl-2,3,3a,4,7,7a-

hexahydro-1H-isoindol-4-yl]-4-nitro-5-

phenylpyrrolidine-2-carboxylate (119n): colorless

prisms (26.5 mg, 79% yield), mp 76-80 °C (Et2O), IR (neat)

𝜈max: 1705, 1551, 1380, 1166 cm-1. 1H NMR δ [mixture of

diastereoisomers (1:1)]: 0.75-0.94 [m, 4H, 2xCH2(CH2CH2)2],

0.98-1.18 [m, 8H, 2xCH(CH2CH2)2], 1.51-1.81 [m, 12H,

2xCHCH(CH2CH2)2], 1.96-2.14 (m, 1H, 2x=CHCH2), 2.69-2.93 (m, 1H, 2x=CHCH2),

3.07-3.22 (m, 1H, 0.5H CH2CHC=O), 3.30 (dd, J = 10.8, 4.3 Hz, 1H, NCHCHC=O), 3.44

(ddd, J = 11.3, 9.7, 5.8 Hz, 1H, CH2CHC=O), 3.60 (dd, J = 9.1, 8.0 Hz, 1H, NCHCHC=O),

3.80-4.00 (m with 2s at 3.82 and 3.90, 9H, 2xNCHCH=, NCHCO2Me and 2xCH3), 4.29

(d, J = 9.6 Hz, 1H, NCHCO2Me), 4.75 (d, J = 9.4 Hz, 1H, NCHPh), 5.21 (d, J = 9.1 Hz,

1H, NCHPh), 5.34 (dd, J = 9.1, 8.3 Hz, 1H, CHNO2), 5.58-5.66 (m, 2H, CHNO2 and

NCHCH=), 5.71-5.80 (m, 1H, NCHCH=CH), 5.85 (dt, J = 10.0, 2.8 Hz, 1H, NCHCH=),

5.90-5.99 (m, 1H, NCHCH=CH), 7.21-7.65 (m, 20H, ArH). 13C NMR δ [mixture of

diastereoisomers (1:1), difficult assignment]: 22.8, 23.4, 26.1, 26.4, 29.8, 30.1, 30.4,

30.7, 38.6, 38.8, 39.2, 39.4, 40.6, 48.4, 51.5, 52.5, 52.7, 54.7, 55.1, 64.0, 66.1, 68.0,

89.3, 90.5, 126.5, 127.6, 128.3, 128.5, 128.7, 128.9, 129.1, 129.2, 129.5, 137.17,

140.6, 173.6, 175.9, 176.7, 177.1, 178.4. LRMS (EI) m/z: 557 (M+, <1%), 512 (35),

511 (100), 498 (22), 451 (22), 384 (38), 337 (37), 331 (40), 286 (57), 284 (26),

278 (46), 226 (45), 225 (32), 202 (67), 196 (48), 144 (64), 143 (24), 117 (27), 115

(18), 91 (24), 79 (87). HRMS calculated for C32H35N2O4 [M–NO2]: 511.2597; found

511.2602.

General procedure for the synthesis of pyrrolizidines endo-

124-127

To a stirred solution of methyl prolinate 124-127 (0.1 mmol) in toluene

(1 mL) crotonaldehyde (0.1 mmol, 8.3 µL) and N-phenylmaleimide (0.1 mmol, 17.3

mg) were added. The reaction mixture was stirred overnight at room temperature

and the solvent was evaporated under reduced pressure. The crude mixture was

VS61

Page 155: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

154

purified by flash column chromatography over silica gel (hexane/EtOAc) to

furnish the corresponding product.

Characterization of pyrrolizidines endo-124-127

Methyl (3aS*,4S*,8aR*,8bR*)-1,3-dioxo-2-phenyl-4-

((E)-prop-1-en-1-yl)octahydropyrrolo[3,4-a]-

pyrrolizine-8a(6H)-carboxylate (endo-124): sticky

yellow oil (21.6 mg, 61% yield), IR (neat) 𝜈max: 1707, 1498,

1376, 1215, 1176, 967, 733 cm-1. 1H NMR δ: 1.78 (dd, J =

6.5, 1.6 Hz, 3H, =CHCH3), 1.80-1.98 (m, 1H, NCH2CH2), 1.99-2.15 (m, 1H, NCH2CH2),

2.36-2.44 (m, 1H, CCH2), 2.59-2.72 (m, 2H, CCH2 and NCH2), 3.18 (ddd, J = 10.4, 8.1,

3.0 Hz, 1H, NCH2), 3.52 (t, J = 8.4 Hz, 1H, NCHCHC=O), 3.81 (s, 3H, OCH3), 4.04 (d, J

= 8.4 Hz, 1H, CCHC=O), 4.13 (t, J = 8.9 Hz, 1H, NCHCH=), 5.71 (ddd, J = 15.0, 9.5, 1.6

Hz, 1H, NCHCH=), 5.86-6.02 (m, 1H, =CHCH3), 7.18-7.34 (m, 2H, ArH), 7.35-7.54

(m, 3H, ArH). 13C NMR δ: 18.1 (=CHCH3), 24.8 (NCH2CH2), 30.3 (CCH2), 48.9 (NCH2),

51.2 (OCH3), 51.6, 53.3 (2xCHC=O), 65.5 (NCH), 79.4 (CCO2Me), 124.2, 126.1, 126.6,

128.8, 129.2, 129.3, 131.8, 133.4 (ArC, C=C), 173.9 (CO2Me), 175.5, 176.0 (2xC=O).

LRMS (EI) m/z: 354 (M+, <1%), 296 (19), 295 (100), 148 (14). HRMS calculated

for C20H22N2O4: 354.1580; found: 354.1578.

Methyl (3aS,4S,7R,8aR,8bR)-7-hydroxy-1,3-dioxo-2-

phenyl-4-((E)-prop-1-en-1-yl)octahydropyrrolo[3,4-

a]-pyrrolizine-8a(6H)-carboxylate (endo-125): sticky

yellow oil (25.6 mg, 69% yield), [𝜶]𝐷26 = -42.4 (c 0.6, CHCl3),

IR (neat) 𝜈max: 1705, 1377, 1178, 731 cm-1. 1H NMR δ: 1.79

(dd, J = 6.5, 1.6 Hz, 3H, =CHCH3), 2.43 (d, J = 15.4 Hz, 1H, CCH2), 2.82 (dd, J = 10.4,

4.2 Hz, 1H, NCH2), 2.96 (dd, J = 15.4, 6.2 Hz, 1H, CCH2), 3.03-3.32 (br s, 1H, CHOH),

3.14 (d, J = 10.4 Hz, 1H, NCH2), 3.61 (t, J = 8.4 Hz, 1H, NCHCHC=O), 3.86 (s, 3H,

OCH3), 4.09 (d, J = 8.4 Hz, 1H, CCHC=O), 4.18 (t, J = 9.0 Hz, 1H, NCHCH=), 4.40 (t, J

= 5.2 Hz, 1H, CHOH), 5.59 (ddd, J = 15.0, 9.6, 1.7 Hz, 1H, NCHCH=), 5.88-6.02 (m,

1H, =CHCH3), 7.17-7.23 (m, 2H, ArH), 7.37-7.54 (m, 3H, ArH). 13C NMR δ: 18.2

(=CHCH3), 40.5 (CCH2), 50.7 (OCH3), 52.1, 53.8 (2xCHC=O), 57.4 (NCH2), 64.7

Page 156: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Experimental section: Characterization of pyrrolizidines endo-120-123

155

(NCH), 72.4 (CHOH), 77.9 (CCO2Me), 123.5, 126.1, 129.0, 129.4, 131.6, 134.2 (ArC,

C=C), 173.5 (CO2Me), 175.0, 175.6 (2xC=O). LRMS (EI) m/z: 370 (M+, 1%), 312

(21), 311 (100). HRMS calculated for C20H22N2O5: 370.1529; found: 370.1516.

Methyl (3aR,3bR,3cR,6aS,7S,9R,9aS)-2-methyl-1,3,4,6-

tetraoxo-5,9-diphenyl-7-((E)-prop-1-en-1-

yl)dodecahydro-3bH-dipyrrolo[3,4-a:3',4'-

f]pyrrolizine-3b-carboxylate (endo-126): colorless

prisms (34.3 mg, 67% yield), mp 223-227 °C (Et2O), [𝜶]𝐷25

= +96.1 (c 0.9, CHCl3), IR (neat) 𝜈max: 1705, 1436, 1379,

1177, 1060, 963, 733 cm-1. 1H NMR δ: 1.22 (dd, J = 6.5, 1.7

Hz, CCH3), 2.77 (s, 3H, NCH3), 3.41-3.46 (m, 1H, NCHCHC=ONPh), 3.48 (dd, J = 10.4,

8.2 Hz, PhCHCH), 3.93 (s, 3H, OCH3), 4.19-4.26 (m, 1H, NCHCH=), 4.30 (d, J = 8.2 Hz,

1H, CCHC=ONPh), 4.47 (d, J = 10.4 Hz, 1H, CCHC=ONMe), 4.53 (d, J = 8.3 Hz, 1H,

NCHPh), 5.16 (ddd, J = 14.9, 9.9, 1.7 Hz, 1H, NCHCH=), 5.55 (ddd, J = 14.9, 6.5, 0.6

Hz, 1H, =CHCH3) 7.20-7.25 (m, 4H, ArH), 7.30-7.60 (m, 6H, ArH). 13C NMR δ: 17.4

(=CHCH3), 25.1 (NCH3), 48.6, 50.2, 50.5, 52.5 (4xCHC=O), 53.6 (OCH3), 66.3, 66.9

(2xNCH), 81.1 (CCO2Me), 123.4, 125.8, 127.4, 128.3, 129.3, 129.8, 131.7, 133.8,

138.9 (ArC, C=C), 170.6 (CO2Me), 173.7, 174.8, 175.1, 176.1 (4xC=O). LRMS (EI)

m/z: 513 (M+, 6%), 455 (26), 454 (86), 341 (21), 340 (100), 193 (100), 282 (14),

281 (72), 228 (16), 115 (15). HRMS calculated for C29H27N3O6: 513.1900; found:

513.1896.

7,8-Diisobutyl 8a-methyl (3aS,4S,6R,7S,8S,8aS,8bR)-

1,3-dioxo-2,6-diphenyl-4-((E)-prop-1-en-1-

yl)octahydropyrrolo[3,4-a]-pyrrolizine-7,8,8a(6H)-

tricarboxylate (endo-127): colorless prisms (42.9 mg,

68% yield), mp 132-135 °C (Et2O), [𝜶]𝐷26 = +4.1 (c 1.0,

CHCl3), IR (neat) 𝜈max: 2960, 1381, 1223, 1178, 748 cm-1.

1H NMR δ: 0.77 (dd, J = 6.7, 2.4 Hz, 6H, 2xCH2CHCH3), 0.92 (d, J = 6.7 Hz, 6H,

2xCH2CHCH3), 1.61 (dt, J = 6.5, 1.8 Hz, 1H, =CHCH3), 1.62 (hept, J = 6.7 Hz, 1H,

CH2CHCH3), 1.97 (hept, J = 6.7 Hz, 1H, CH2CHCH3), 3.18 (dd, J = 10.6, 6.6 Hz, 1H,

CO2CH2CH), 3.49 (dd, J = 10.6, 6.6 Hz, 1H, CO2CH2CH), 3.65 (d, J = 10.6 Hz, 1H,

CCHC=O), 3.73 (dd, J = 10.6, 8.4 Hz, 1H, NCHCHC=O), 3.95 (dd, J = 12.2, 10.9 Hz, 1H,

Page 157: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Chapter 3: Multicomponent periselective cycloadditions of nitroprolinates

156

NCHCHCO2), 3.91 (s, 3H, OCH3), 3.95 (dd, J = 10.4, 6.7 Hz, 1H, CO2CH2CH), 4.06 (dd,

J = 10.4, 6.7 Hz, 1H, CO2CH2CH), 4.31 (ddt, J = 8.4, 4.7, 1.9 Hz, 1H, NCHCH=), 4.64 (d,

J = 10.9 Hz, 1H, NCCHCO2), 4.77 (d, J = 12.2 Hz, 1H, NCHPh), 5.40 (ddq, J = 15.5, 4.7,

1.5 Hz, 1H, NCHCH=), 5.95 (dqd, J = 14.9, 6.5, 1.9 Hz, 1H, =CHCH3), 7.17-7.51 (m,

10H, ArH). 13C NMR δ: 18.1 (=CHCH3), 19.0, 19.1, 19.2 [2xCH2CH(CH3)2], 27.4, 27.6

[2xCH2CH(CH3)2], 49.9, 50.1 (2xCHCO2), 50.9, 51.0 (2xCHC=O), 53.5 (OCH3), 63.2,

66.6 (2xNCH), 71.3, 72.0 (2xCO2CH2), 80.0 (CCO2Me), 126.2, 126.8, 127.7, 128.1,

128.6, 129.2, 131.0, 132.3, 140.9 (ArC, C=C), 169.2, 169.9, 170.3 (3xCO2R), 173.8,

175.0 (2xC=O). LRMS (EI) m/z: 630 (M+, <1%), 572 (17), 571 (45), 498 (15), 497

(48), 396 (28), 395 (100), 369 (30), 367 (16), 356 (12), 222 (12). HRMS calculated

for C36H42N2O8: 630.2941; found: 630.2942.

Page 158: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

157

LIST OF ABBREVIATIONS

1,3-DC 1,3-dipolar cycloaddition

1H NMR proton nuclear magnetic resonance

13C NMR carbon nuclear magnetic resonance

AAD amide/amine-aldehyde-dienophile

Ac acetyl group

app apparent

BPSE bis(phenylsulfonyl)ethylene

Boc tert-butoxycarbonyl protecting group

Bn benzyl group

br s broad signal

Bz benzoyl group

BzOH benzoic acid

cat. catalyst

CCDC Cambridge crystallographic data centre

CNV reaction conversion

COSY homonuclear correlated spectroscopy

conc. concentrated

d doublet

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DEAD diethyl azodicarboxylate

DEPT distortionless enhancement by polarization transfer

DEtAD diethyl acetylenedicarboxylate

DFT density functional theory

DIBAL diisobutylaluminum hydride

DIP direct injection process

DIPEA N,N-diisopropylethylamine

DMAD dimethyl acetylenedicarboxylate

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DOS diversity-oriented synthesis

Page 159: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

List of abbreviations

158

dr diastereomeric ratio

EDG electron-donating group

EI electron impact mode

equiv. equivalents

EWG electron-withdrawing group

FMOT frontier molecular orbital theory

hept heptet

HFiPA 1,1,1,3,3,3-hexafluoroisopropyl acrylate

HIV human immunodeficiency virus

HOMO highest energy occupied molecular orbital

HRMS high resolution mass spectrometry

LDA lithium diisopropylamide

LUMO lowest energy unoccupied molecular orbital

m- meta-substitution

MCPBA m-chloroperbenzoic acid

MCRs multicomponent reactions

NMM N-methylmaleimide

nOe nuclear Overhauser effect

NOESY nuclear Overhauser effect spectroscopy

NPM N-phenylmaleimide

o- ortho-substitution

OBz benzoate group

p- para-substitution

PG protecting group

pKa negative decadic logarithm of the dissociation constant K

of an acid (pKa = –logKa)

rt room temperature

T temperature

t time

TFAA trifluoroacetic acid

THF tetrahydrofuran

TMEDA N,N,N',N'-tetramethylethylenediamine

TOS target-oriented synthesis

TsOH para-toluenesulfonic acid

Page 160: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

159

RESUMEN EN CASTELLANO

En la presente memoria se describe el trabajo realizado durante mis

estudios de doctorado en el periodo de tiempo que comprende los años de 2015 a

2018. Todos los proyectos realizados han estado dedicados al estudio de de iluros

de azometino generados in situ en reacciones de cicloadición 1,3-dipolar y

diferentes dipolarófilos, todo ello bajo la supervisión de los Profesores Carmen

Nájera Domingo y José Miguel Sansano Gil en el Departamento de Química

Orgánica e Instituto de Síntesis Orgánica de la Universidad de Alicante (España).

Esta tesis se divide en una introducción general y tres capítulos:

En la Introducción General, se explica el mecanismo de la cicloadición 1,3-

dipolar que involucra iluros de azometino.

El Capítulo 1 se centra en la síntesis multicomponente libre de metal de

derivados de indolizidina a partir de pipecolinatos, aldehídos y

dipolarofilos de forma térmica, y también a partir de ácido pipecólico de

forma descarboxilada.

El Capítulo 2 cubre el estudio de la reacción de cicloadición 1,3-dipolar

térmica multicomponente entre iluros de azometino no activados

generados in situ a partir de aminas y aldehídos aromáticos, y alquenos

electrofílicos para generar derivados de pirrolidina.

En el capítulo 3 se describe la síntesis de pirrolizidinas

diastereoméricamente enriquecidas a partir de nitroprolinatos

enantioméricamente puros a través de una cicloadición 1,3-dipolar

multicomponente catalizada por una sal de plata y, por otro lado, una

reacción de Amina-Aldehído-Dienófilo (AAD) para sintetizar estructuras

ciclohex-2-en-1-ilprolinato como diastereoisómero enantiopuro único de

forma multicomponente y libre de metales.

La mayoría de los resultados aquí descritos han sido objeto de las

siguientes publicaciones:

Page 161: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

160

“Multicomponent diastereoselective synthesis of indolizidines via 1,3-

dipolar cycloadditions of azomethine ylides”.

Castelló, L. M.; Selva, V.; Nájera, C.; Sansano, J. M. Synthesis 2017, 49, 299–309.

“Diastereoselective [3 + 2] vs [4 + 2] cycloadditions of nitroprolinates with

α,β-unsaturated aldehydes and electrophilic alkenes: an example of total

periselectivity”.

Selva, V.; Larranaga, O.; Castelló, L. M.; Nájera, C.; Sansano, J. M.; de Cozar, A. J. Org.

Chem. 2017, 82, 6298–6312.

“Sequential metal-free thermal 1,3-dipolar cycloaddition of unactivated

azomethine ylides”.

Selva, V.; Selva, E.; Nájera, C.; Sansano, J. M. Org. Lett. aceptado.

Page 162: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Introducción general

161

Introducción general

Los compuestos que contienen nitrógeno, como alcaloides o aminoácidos,

tienen un papel importante en la química médica, la industria farmacéutica y la

química orgánica sintética debido a su bioactividad o sus propiedades catalíticas.

Por esta razón, los químicos orgánicos están aumentando su atención al sintetizar

este tipo de compuestos orgánicos.1

El desarrollo de métodos sintéticos para la construcción de derivados

heterocíclicos de cinco miembros se ha enfocado hacia la obtención de compuestos

naturales y no naturales2 a través de reacciones con una mayor economía atómica

y un menor número de pasos. Prolinas y alcaloides tales como pirrolidinas,

pirrolizidinas e indolizidinas son ejemplos de (al menos) compuestos con un anillo

de cinco miembros que contienen un átomo de nitrógeno, y su esqueleto está

presente en muchos compuestos biológicamente activos y productos naturales.

Para preparar estos compuestos que contienen nitrógeno, se emplea

comúnmente la reacción de cicloadición 1,3-dipolar (1,3-DC) debido al control

regio y diastereoselectivo.19 En esta Tesis Doctoral, enfocaremos nuestra atención

en la 1,3-DC de los iluros de azometino (como 1,3-dipolos) y diferentes alquenos

electrofílicos como dipolarófilos para la síntesis de pirrolidinas, pirrolizidinas e

indolizidinas altamente sustituidas.

1,3-Cicloadiciones dipolares

El concepto de cicloadición 1,3-dipolar surgió por primera vez en 1963 en

el laboratorio de Química Orgánica del Profesor Rolf Huisgen en la Universidad de

Munich.20 Este tipo de cicloadiciones son reacciones [π4s + π2s] entre una especie

llamada 1,3-dipolo y un dipolarófilo que evolucionan a través de un estado de

transición aromática de 6π electrones, donde se genera un anillo de cinco

miembros con diferentes sustituyentes y hasta cuatro centros estereogénicos en

Page 163: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

162

un solo paso (este último aparece solo en el caso de aproximaciones

enantioselectivas) (Esquema I).

Esquema I. Mecanismo general de la cicloadición 1,3-dipolar.

Un dipolo es un sistema zwitteriónico con 4 electrones π deslocalizados

en tres átomos donde uno de ellos es al menos un heteroátomo, mientras que el

dipolarófilo (el alqueno o el alquino son los más utilizados) es un sistema de 2

electrones π. Existe una gran diversidad de 1,3-dipolos formados a partir de varias

combinaciones de átomos de carbono y heteroátomos (azidas, óxidos de nitrilo,

iluros de nitrilo, nitronas, iluros de carbonilo, iluros de azometino...), que se

pueden clasificar en dos grupos principales: a) tipo propargil-alenilo tales como

azidas, óxidos de nitrilo o iluros de nitrilo, que tienen estructura lineal y están

presentes en las dos formas resonantes, tipo propargilo y tipo cumuleno, y b) tipo

alílico tales como iluros de azometino, nitronas, iluros de carbonilo u ozono, entre

otros, cuya estructura es angular y tiene un enlace simple y un enlace doble

(Esquema II).21

Page 164: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Introducción general

163

Esquema II. Clasificación de las estructuras dipolo.

El grupo de Huisgen estudió el mecanismo de esta reacción, proponiendo

una vía concertada,22 por otro lado el grupo de Firestone propuso un mecanismo

radicalario.23 Después de años de investigación en esta área, se concluyó que el

mecanismo de la reacción de 1,3-DC es una cicloadición pericíclica concertada [3

+ 2]24 y una trampa de radicales no inhibe este proceso. Sin embargo, la reacción

puede avanzar a través de una vía por pasos si el dipolo se estabiliza mediante

resonancia.21b, 25

Como se mencionó anteriormente, la reacción de cicloadición 1,3-dipolar

implica un total de 6 electrones π (π4s + π2s) y se produce térmicamente en un

proceso suprafacial de acuerdo con las reglas de Woodward y Hoffmann.26 Gracias

a esto, esta cicloadición se realiza a través de un proceso concertado, y se obtiene

una alta regio y estereoespecificidad.27

La aplicación de la teoría de orbitales moleculares frontera (FMOT) a este

tipo de proceso nos permite explicar la alta regioquímica y estereoselectividad de

la reacción 1,3-DC que está controlada por las energías de HOMO (orbital

Page 165: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

164

molecular ocupado de mayor energía) y LUMO (orbital molecular desocupado de

menor energía) de los dos componentes, es decir, la interacción entre un

HOMOdipolo/LUMOdipolarófilo o LUMOdipolo/HOMOdipolarófilo es crucial para el curso de

la reacción. Cuando la superposición de FMOT es máxima, las reacciones son más

rápidas porque la diferencia de energía entre los niveles de HOMO/LUMO es baja.

Cicloadiciones 1,3-dipolares de iluros de azometino

La cicloadición 1,3-dipolar llevada a cabo térmicamente con iluros de

azometino estabilizados y olefinas electrofílicas es una cicloadición tipo 1, de

acuerdo con Sustmann,44 lo que significa que la interacción predominante está

dada por HOMOdipolo (iluro de azometino) y LUMOdipolarófilo (olefina)19a,21a,27b,28e,41,45

(Figura I). Las principales características de esta cicloadición son la alta

regioselectividad, la total estereoespecificidad, alta diastereoselección y

extraordinaria enantioselección dependiendo del catalizador quiral empleado.

Figura I. Cicloadición tipo 1.

Este proceso es altamente regioselectivo,27b,39 porque solo uno de los dos

posibles regioisómeros se obtiene preferentemente. Esta alta regioselectividad

responde al hecho de que se produce la mayor superposición de coeficientes entre

orbitales de frontera. Favoreciendo la primera adición de tipo Michael seguida de

la ciclación (reacción de Mannich). Un ejemplo detallado se muestra en el Esquema

Page 166: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Introducción general

165

6, que describe en él las diferencias de energía entre los niveles de HOMO/LUMO,

los valores calculados de los coeficientes y la relación de los productos finales.

Esquema III. Regioquímica de la 1,3-DC entre un iluro de azometino y acrilato de metilo.

Es bien sabido que la presencia de ácidos de Lewis basados en metales

puede modificar los coeficientes orbitales de las especias que reaccionan y los

niveles de energía de los orbitales frontera, disminuyendo el nivel de LUMO, del

1,3-dipolo y el dipolarófilo, (Figura II)21a que permite una reacción más rápida.

Para alcanzar una alta diastereoselección así como una reacción rápida en el 1,3-

DC, es necesaria la coordinación del ácido de Lewis, que desempeña un papel

catalítico, con uno o ambos reactivos.47 Se ha observado una mejora de la

diastereoselectividad cuando el metal coordina al dipolarófilo, ya que guía al

dipolarofilo en una dirección específica debido a los efectos estereoelectrónicos.

Por otro lado, una vez que el metal se coordina con un ligando quiral, es posible

controlar la regio-, diastereo- y enantioselectividad,21 que convierte esta reacción

en una importante herramienta sintética asimétrica.

Page 167: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

166

Figura II. Efecto en los orbitales frontera del dipolarófilo (izquierda) o del dipolo (dererecha) de un

ácido de Lewis.

Con respecto a la diastereoselectividad de la cicloadición, los términos

endo y exo se refieren a la orientación del grupo atractor de electrones del doble

enlace con respecto al dipolo durante la aproximación de ambos reactivos. Por lo

tanto, cuando el sustituyente atractor de electrones se acerca al dipolo durante la

formación del estado de transición, se habla de una aproximación endo, mientras

que en una aproximación exo este sustituyente está orientado lejos del dipolo.

Muchos efectos esteroelectrónicos controlan la diastereoselectividad de estas

cicloadiciones siendo la aproximación endo el más favorable para que suceda.

Varios ácidos de Lewis se pueden usar para este propósito, tales como

sales de AgI, TlI, LiI, CaII, MgII, CoII, TiIV, ZnII, CuI, CuII y SnIV, junto con bases orgánicas

tales como Hünig o N,N-diisopropiletilamina (DIPEA), Et3N, 1,8-

diazabiciclo[5.4.0]undec-7-eno (DBU), N,N,N',N'-tetrametiletilendiamina

(TMEDA), derivados de guanidina y fosfacenos, así como bases inorgánicas.41,51

Esta reacción también puede ocurrir en ausencia de base, pero más lentamente y

son necesarias temperaturas más altas.

Este alto control estereoquímico de la reacción y la generación de hasta

cuatro centros estereogénicos simultáneamente hacen que esta cicloadición sea

una de las rutas más útiles para la síntesis asimétrica de heterociclos de cinco

miembros altamente polisustituidos.19f,h,31b-c,52

Page 168: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

167

CAPÍTULO 1: Síntesis multicomponente de indolizidinas

Antecedentes bibliográficos: Reacciones multicomponente

Las reacciones multicomponentes (MCR) son reacciones en las que se

utilizan tres o más sustratos al mismo tiempo para formar un nuevo producto. Se

consideran reacciones one-pot o en cascada en las que se forman múltiples enlaces

carbono-carbono y carbono-heteroátomo y múltiples estereocentros en un solo

proceso.

Las transformaciones multicomponente tienen importantes ventajas

sobre otro tipo de reacciones debido al alto nivel de economía atómica, evitando

el empleo/eliminación de grupos protectores, así como el aislamiento de

compuestos intermedios. Estas ventajas sintéticas corresponden a menos pasos

sintéticos, es decir, menos cantidad de residuos de desecho y menos cantidad de

disolvente requerido, lo que lleva la reacción a la química "verde".

Estos procesos generalmente generan estructuras complejas a través de

un proceso simple con buen rendimiento y estereoselectividad.

Antecedentes bibliográficos: Síntesis de indolizidinas

Las aproximaciones sintéticas para obtener este esqueleto heterocíclico

se pueden clasificar de acuerdo con el orden de ciclación, es decir, el anillo de seis

miembros seguido de la construcción del anillo de cinco miembros (6 → 5) y

viceversa (5 → 6). El inconveniente más importante de la síntesis de indolizidinas

es que son necesarios varios pasos de reacción para obtener el producto

deseado.15f

La síntesis común de indolizidinas generalmente requiere demasiados

pasos y los rendimientos globales finales son muy bajos. Para obstaculizar estas

desventajas, se podría emplear MCR porque se obtendrían mayores rendimientos

Page 169: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

168

y se ahorrarían tiempo, disolventes, reactivos y residuos, debido a los pocos pasos

necesarios.

Resultados y discusión

Siguiendo la metodología de cicloadiciones 1,3-dipolares

multicomponente estudiadas por nuestro grupo en la síntesis de alcaloides

pirrolizidínicos no naturales,12d,69 se decidió aplicar, directamente, esta estrategia

para la síntesis de indolizidinas sustituidas 72 a partir de clorhidrato de

pipecolinato de metilo 70 y trans-cinamaldehído 71 que genera el iluro de

azometino correspondiente in situ, y posterior ciclación con dipolarófilos

(Esquema IV).

Esquema IV. Síntesis multicomponente de derivados de indolizidina y su mecanismo por la ruta de

iminio.

Para estudiar las condiciones óptimas (T y MX) para la síntesis de las

indolizidinas deseadas 72a, se seleccionó tolueno como disolvente atendiendo los

buenos resultados obtenidos en trabajos similares de nuestro grupo en

multicomponentes 1,3-DC. Como reactivos para la optimización se seleccionaron

Page 170: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 1

169

el clorhidrato de pipecolinato de metilo 70, el trans-cinamaldehído 71 y el acrilato

de metilo en presencia de 1 equiv. de Et3N (Esquema V).

Esquema V. 1,3-DC multicomponente entre clorhidrato de pipecolinato de metilo 70, trans-

cinamaldehído 71 y acrilato de metilo para producir la indolizidina sustituida 72a.

Una vez que se establecieron las condiciones de reacción óptimas, 70 °C,

tolueno como disolvente, 1 equiv. de Et3N y 17 horas, se estudió el alcance de la

reacción modificando los diferentes reactivos (Esquemas VI, VII, VIII y IX)

obteniendo resultados variados en función de los reactivos, donde las

diastereoslectividades obtenidas fueron elevadas mientras que los rendimientos

fueron de bajos a muy elevados.

Page 171: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

170

Esquema VI. Cicloadición multicomponente de clorhidrato de pipecolinato de metilo 70, trans-

cinamaldehído 71 y diferentes dipolarófilos.

Page 172: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 1

171

Esquema VII. Cicloadición multicomponente de clorhidrato de pipecolinato de metilo 70, diferentes

aldehídos y dipolarófilos.

Page 173: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

172

Esquema VIII. 1,3-DC entre pipecolinato de etilo 57, furfural y NMM.

Esquema IX. Cicloadición multicomponente entre 62, trans-cinamaldehído 71 y NPM.

También se estudió la posibilidad de realizar la 1,3-DC a partir de ácido

pipecólico 77, aldehídos y dipolarófilos. Para llevar a cabo esta reacción es

necesaria la descarboxilación de la sal de iminio generada in situ, que requiere una

temperatura elevada (reflujo de tolueno) (Esquema X).

Esquema X. Síntesis multicomponente de los derivados de indolizidina 78 después de la

descarboxilación.

Page 174: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 1

173

Una vez que se establecieron las condiciones de reacción óptimas, se

estudió el alcance de la reacción modificando el dipolarófilo (Tabla I).

Tabla I. Reacción 1,3-DC multicomponente entre ácido pipecólico 77, trans-cinamaldehído 71 y

diferentes dipolarófilos para producir las indolizidinas sustituidas 78.

Entrada Dipolarófilo Producto dra (endo:exo:endo’:exo’) Rto (%)b

1 NMM 78a 35:22:20:23 89

2 NPM 78b 45:17:18:20 78

3 fumarato de

dimetilo 78c 33:29:18:20 75

4 fumarato de

diisobutilo 78d 35:30:19:17 75

5 acrilato de

terc-butilo 78e 39:28:17:16 52

6 trans-β-

nitrostireno 78f 43:25:11:21 40

a Determinado por 1H NMR del crudo de reacción.

b Rendimiento aislado después de purificar (silice flash) de 4 diastereoisómeros.

Finalmente, la síntesis de derivados de indolizidinas se realizó con

benzaldehído, ácido pipecólico 77 y NPM proporcionando el producto 80 deseado

con un rendimiento muy alto (95%) como una mezcla de cuatro diastereoisómeros

(Esquema XI).

Page 175: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

174

Esquema XI. Síntesis de indolizidinas sustituidas 80 después de la descarboxilación.

Page 176: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

175

CAPÍTULO 2: 1,3-DC libre de metales de iluros de

azometino desactivados

Antecedentes bibliográficos: Síntesis de pirrolidinas sustituidas

La estructura de la pirrolidina está presente en muchos productos

naturales y no naturales con propiedades biológicas y farmacéuticas.8,9,77 Una

forma fácil de sintetizar pirrolidinas polisustituidas es a través de 1,3-DC19,30,31,52

empleando iluros de azometino como dipolos y dipolarófilos bajo condiciones

suaves.

En casi todas las 1,3-DC libres de metales, se necesita una imina generada

por un (N-alquilo)aminoácido y un aldehído para formar el dipolo a baja

temperatura. De lo contrario, se necesitan bases fuertes o altas temperaturas para

formar el iluro de azometino que reacciona con el dipolarófilo (Esquema

XII).30b,40b,48

Esquema XII. Formación de la pirrolidina a partir de 1,3-DC libre de metal.

Durante mucho tiempo se ha estudiado el cambio de grupos funcionales

en los carbonos 2 y 5 en la síntesis de nuevas pirrolidinas, buscando vías sintéticas

económicas, condiciones más leves, mejora de los resultados o reacciones con

menos generación de residuos como reacciones multicomponente.

Sin embargo, hasta donde tenemos conocimiento, no existe ninguna

investigación con un grupo vinilo en posición C2 en estructuras de pirrolidina. Solo

Page 177: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

176

apareció en la literatura el estudio llevado a cabo por Waters en el que realizaron

una reacción dicomponente catalizada por metales utilizando glioxilimina que

proporciona el producto deseado con el grupo vinilo en C5 en lugar de C2 93

(Esquema XIII).88

Esquema XIII. Reacción 1,3-DC dicomponente catalizada por metal para proporcionar 5-

alquenilpirrolidinas.

Resultados y discusión

Tal como se ha mencionado anteriormente, este trabajo se inició con el

objetivo de estudiar la formación de pirrolidinas a partir de iluros de azometino

no activados a través de la cicloadición 1,3-dipolar. Para abordar este estudio, se

decidió utilizar iminas formadas a partir de aminas tales como bencilamina,

alilamina y 1-butilamina, y aldehídos aromáticos, usando NMM como alqueno

deficiente en electrones, que resulta ser un buen cazador del intermedio de alta

energía resultante, el iluro de azometino (Esquema XIV). Teniendo en cuenta la

reciente investigación térmica de nuestro grupo,68 los resultados del Capítulo 1 y

las investigaciones sobre la reacción 1,3-DC realizadas por otros grupos para la

síntesis de derivados de pirrolidina,40d,48c,87 se eligió tolueno como disolvente. Por

lo tanto, con todos los antecedentes en la mano, se llevó a cabo un estudio de la

temperatura, el tiempo de la reacción y las ventajas de agregar aditivos o no

hacerlo (Esquema XIV).

Page 178: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 2

177

Esquema XIV. Optimización de la reacción 1,3-DC entre iluros de azometino no activados y NMM.

Las iminas 81, 94 y 95 sintetizadas a partir de bencilamina, 1-butilamina

y alilamina, reaccionando respectivamente con benzaldehído 58 se sometieron a

estudio. Las condiciones iniciales que se tomaron fueron las empleadas por Grigg

en su trabajo en el que se estudiaron iluros de azometino en una reacción

dicomponente a 110 °C (reflujo de tolueno).40d Sin embargo, no se pudo aislar

ningún cicloaducto porque en ninguna reacción se observó conversión alguna.

Después del proceso de optimización se encontró que las mejores

condiciones de la reacción (100% de conversión) fueron llevar a cabo la misma de

una manera secuencial, dejando reaccionar primero la alilamina 99 junto con el

benzaldehído 58 durante 1 h a temperatura ambiente utilizando tolueno como

disolvente para generar la imina 95, para una vez transcurrido ese tiempo añadir

el dipolarófilo escogido y dejar reaccionar el conjunto a 150 °C durante 16 h.

Una vez obtenidas las condiciones óptimas, se pasó a estudiar el efecto

sobre la diastereoselectividad que producen tanto el diferente tipo de

aproximación de los dipolarófilos, pudiendo ser endo o exo, la geometría del dipolo

y las dos posibles direcciones de ataque, α o γ (Esquema XV).

Page 179: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

178

Esquema XV. Condiciones de la reacción 1,3-DC optimizadas entre alilamina 99, benzaldehído 58 y el

dipolarófilo en una reacción secuencial y su análisis estereoquímico.

El alcance de la 1,3-DC se realizó entre la imina 95 generada in situ y

diferentes maleimidas, N-alquil y N-arilmaleimidas proporcionando los

compuestos correspondientes 98a-98i como una mezcla de diastereoisómeros

endo':endo 98 (Esquema XVI y Tabla II). En todas las reacciones solo se pudo

observar dos diastereoisómeros, el diastereoisómero principal, endo'-98,

pudiendo aislarlo y caracterizarlo, mientras que el diastereoisómero minoritario

endo no pudo aislarse. Como se puede observar en la tabla II todos ellos fueron

aislados con elevada diastereoselectividad y de moderado a buen rendimiento

Page 180: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 2

179

(entradas 1 a 8). Además, se llevó a cabo un último ejemplo utilizando para-

(fluorobencil)maleimida que proporcionó una buena diastereoselectividad, 73:27

hacia el aducto endo'-98i con un buen rendimiento, 68% (Tabla II, entrada 9).

Esquema XVI. Reacción secuencial para producir los derivados de pirrolidina 98.

Tabla II. Reaccion 1,3-DC térmica entre alilamina 99, benzaldehído 58 y diferentes maleimidas para

producir derivados de pirrolidina 98.

Entrada R Producto dra

(endo’:endo)

Rendimiento

(%)b

(endo’, endo)

1 Me 98a 71:29 67, 6

2 H 98b 69:31 62, 9

3 Bn 98c 65:35 64, 8

4 Ph 98d 72:28 69, 5

5 2-(OMe)C6H4 98e 92:8 70, 0

6 3-ClC6H4 98f 83:17 41, 0

7 4-ClC6H4 98g 76:24 68, 0

8 4-BrC6H4 98h 74:26 55, 5

9 4-FC6H4-CH2 98i 73:27 68, 9

a Determinado por 1H RMN de la mezcla de reacción cruda.

b Rendimiento aislado después de la purificación (sílice flash) de los diastereoisómero mayor y

menor.

Page 181: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

180

La obtención del regioisómero endo'-98 como producto principal se

confirmó por el desplazamiento químico y las constantes de acoplamiento

observadas en el 1H RMN donde la constante de acoplamiento entre Hc y Hd es de

1.0 a 1.4 dependiendo del cicloaducto, siendo este el valor estándar para un

acoplamiento entre dos protones en posición relativa trans. Además, la

configuración relativa de estos productos ha sido confirmada por experimentos

nOe realizados para el endo'-98a, donde se pudo observar una fuerte interacción

entre Ha, Hb y Hc, pero una interacción débil con Hd (Figura III).

Figura III. Representación del nOe detectado para el aducto endo'-98a.

Se probaron dipolarófilos más simétricos más allá de las maleimidas,

como el anhídrido maleico, el acetilendicarboxilato de dimetilo y el

tetracianoetileno, dando todos ellos productos de descomposición debido a la alta

temperatura requerida por la reacción. Para saber si la reacción procede a través

del ataque α o γ del dipolo, se probaron una serie de dipolarófilos no simétricos y

así obtener más información sobre la regioquímica de la reacción. Se probaron

acrilatos como el acrilato de metilo, acrilato de terc-butilo, 2-acetamidoacrilato de

metilo, acrilato de 1,1,1,3,3,3-hexafluoroisopropilo (HFiPA) y metacrilato de alilo,

proporcionando en algunos casos productos de polimerización del dipolarófilo.

Tratando de descubrir la razón de eso, la reacción se llevó a cabo con otros

dipolarófilos diferentes. Cuando se usaron el acrilonitrilo, 2-cloroacrilonitrilo y la

metil vinil cetona, se observó algo de producto de descomposición en el crudo de

la reacción. Y el material de partida correspondiente se recuperó después de 16 h

reaccionando cuando se emplearon el fumarato de metilo, cinamato de metilo,

trans-4-fenil-3-buten-2-ona, chalcona, itaconato de dimetilo, N,N-

dimetilacrilamida, dietil vinilfosfonato, trans-β-nitrostireno o fenil vinil sulfona.

Solo con el trans-1,2-bis(fenilsulfonil)etileno y 1,1-bis(fenilsulfonil)etileno la

Page 182: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 2

181

reacción tuvo lugar bajo las condiciones óptimas. Por lo tanto, fue posible dirigir

la cicloadición dando rendimientos moderados del correspondiente cicloaducto

98. Sorprendentemente, ambos bis(fenilsulfonil)etileno (BPSE) proporcionaron la

misma configuración relativa endo'-98j del diastereoisómero principal en

diferente proporción en el crudo de la mezcla (se obtuvo endo':endo 56:44 dr con

1,1-BPSE y 70:30 cuando se utilizó 1,2-BPSE, Esquema XVII). Después de purificar

la mezcla inicial, se aisló solo el diastereoisómero principal endo'-98j con un

rendimiento del 40% para el 1,1-BPSE y un 60% para el 1,2-BPSE.

Esquema XVII. Reacción 1,3-DC secuencial que involucra la imina generada in situ 95 y los

dipolarófilos 1,1- o 1,2-BPSE.

La presencia del producto endo'-98j se confirmó después de detectar los

mismos desplazamientos químicos en el experimento de 1H RMN, con las mismas

constantes de acoplamiento. Además, ambos reactivos 1,1-BPSE y 1,2-BPSE

ofrecen los mismos espectros 13C NMR y DEPT. La síntesis de los

diastereoisómeros 98j a partir de 1,1-BPSE podría lograrse gracias a su β-

eliminación térmica que genera etinil fenil sulfona, que reacciona con el ácido

fenilsulfínico produciendo 1,2-BPSE en el medio de reacción. La configuración

relativa endo’ fue confirmada por un experimento nOe donde se encontraron dos

interacciones fuertes, una entre Ha y Hb y la otra entre Hc y Hd (Figura IV).

Page 183: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

182

Figura IV. Representación del nOe detectado para el aducto endo'-98j.

La obtención del producto 98j y la configuración relativa ya confirmada

del diastereómero principal endo'-98j sugieren que el mecanismo de esta reacción

procede a través de un ataque α del intermedio, el iluro de azometino en

conformación S sobre el dipolarófilo (Esquema XV). La activación térmica de CH es

más estable cuando la carga negativa está en la posición alílica (S-dipolo) en lugar

de en la posición bencílica (W-dipolo) (Esquema XV). Los cicloaductos endo-98 se

obtuvieron de la aproximación endo del dipolarófilo al W-dipolo y en estas

condiciones térmicas el dipolo sufre una estereomutación generando el S-dipolo

termodinámicamente más estable siguiendo la aproximación endo análoga por el

dipolarófilo que da acceso a los cicloaductos endo'-98 (Esquema XV).

A continuación, se decidió ampliar el alcance de la reacción usando

alilamina 99, NMM y seleccionando diferentes tipos de aldehídos (Esquema XVIII

y Tabla III). A diferencia de lo que se observó en el estudio del alcance anterior,

cuando se emplearon aldehídos tales como 2-naftaldehído, p-nitrobenzaldehído,

p-bromobenzaldehído, 2-piridinacarboxaldehído y 3-piridinacarboxaldehído, el

diastereoisómero minoritario endo pudo aislarse cuando el rendimiento fue

superior al 11% (Tabla III, entradas 1, 7, 8, 9 y 10). Para todos los productos se

obtuvieron relaciones diastereoméricas de moderadas a elevadas y rendimientos

de moderados a buenos (Tabla III).

Page 184: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 2

183

Esquema XVIII. Reacción secuencial para producir los derivados de pirrolidina 98 modificando el

aldehído.

Tabla III. Alcance de la reacción 1,3-DC entre alilamina 99, diferentes aldehídos y NMM para producir

derivados de pirrolidina 98.

Entrada Ar Producto dra

(endo’:endo)

Rendimiento

(%)b

(endo’, endo)

1 2-Naphthyl 98k 58:42 60, 24

2 2-MeC6H4 98l 73:27 38, 0

3 3-MeC6H4 98m 80:20 31, 0

4 4-MeC6H4 98n 77:23 40, 0

5 2-(NO2)C6H4 98o 76:24 41, 0

6 3-(NO2)C6H4 98p 66:34 62, 11

7 4-(NO2)C6H4 98q 59:41 56, 37

8 4-BrC6H4 98r 69:31 62, 23

9 2-Pyridyl 98s 67:33c 44, 23

10 3-Pyridyl 98t 62:38 53, 24

11 2-Thienyl 98u 71:29c 55, 8

a Determinado por 1H RMN de la mezcla de reacción cruda.

b Rendimiento aislado después de la purificación (sílice flash) del diastereoisómero mayor y menor.

c Exo’:endo ratio.

Page 185: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

184

A partir del producto endo'-98t se separó un cristal adecuado y se sometió

a un experimento de difracción de rayos X (Figura V) que confirma la estructura

endo’ propuesta.

Figura V. Análisis por difracción de rayos X del cicloaducto endo’-98t. (CCDC number: 1820733).

Cuando se probó con 2-tiazolcarboxaldehído, p-metoxibenzaldehído,

phenilacetaldehído, hidrocinamaldehído o sorbaldehído la reacción no funcionó.

Sin embargo, curiosamente se obtuvo un extraño producto cuando se utilizó

crotonaldehído y trans-cinamaldehído. Para el trans-cinamaldehído fue posible

aislar el producto principal con un rendimiento del 38%. Después de exhaustivos

estudios de los experimentos 1H RMN, 13C RMN, DEPT, COSY y NOESY y los datos

obtenidos de HRMS, se identificó un nuevo compuesto spiránico identificado como

101 (Esquema XIX).

Esquema XIX. Reacción secuencial multicomponente para la síntesis de nuevo spiro-cicloaducto 101.

Page 186: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 2

185

Tras los aldehídos se estudiaron las aminas, aunque solo los dos pudieron

ser probadas, la 2-metilalilamina y la propargilamina. Solo con la segunda amina

se obtuvieron buenos resultados (Esquema XX).

Esquema XX. Reacción secuencial para producir el nuevo derivado de 2-etinilpirrolidina 103.

Finalmente, como una aplicación directa de esta metodología, se decidió

intentar la síntesis del inhibidor de trombina tricíclico 105 (Esquema 42).94 La

trombina es una serina proteasa y una de las enzimas clave en el proceso de la

cascada de la coagulación sanguínea. Por lo tanto, la inhibición de esta enzima es

un objetivo farmacéutico importante para la prevención y el tratamiento de los

trastornos trombóticos.

Se comienza a partir de la alilamina 99 y benzaldehído 58, y la 1,3-DC se

llevó a cabo con N-(4-fluorobencil)maleimida produciendo el compuesto 98i en

buena relación diastereomérica y buen rendimiento del isómero principal. El

diastereoisómero mayor endo'-98i se aliló a continuación en el átomo de nitrógeno

usando bromuro de alilo y carbonato de sodio en acetonitrilo. A continuación, a

través de una metátesis se cierra el anillo usando el catalizador de segunda

generación de Hoveyda-Grubbs proporcionando el intermedio tricíclico 104 con

buen rendimiento global (69% de dos etapas combinadas a partir de 98i). Después

de la hidrogenación del doble enlace en condiciones muy suaves en presencia de

Pd/C en metanol, se aisló el compuesto 105 con buen rendimiento (90%).

(Esquema XXI).

Page 187: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

186

Esquema XXI. Síntesis del inhibidor de la trombina tricíclico 105.

Page 188: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

187

Capítulo 3: Cicloadiciones multicomponente

periselectivas de nitroprolinatos

Antecedentes bibliográficos: Síntesis de orientación diversa

El concepto de síntesis orientada a la diversidad (DOS, en inglés) descrito

por Schreiber97 se ha aplicado de manera interesante en muchas metodologías

para la síntesis de moléculas complejas. La formación de estructuras moleculares,

simplemente modificando la disposición de los grupos funcionales, los parámetros

de reacción, etc., son características clave de la síntesis divergente. En este

concepto, la adición de la simplicidad operacional y la economía atómica (y de

pasos) proporcionada por las reacciones multicomponente (MCR)53,54,98

constituye una estrategia muy importante. Particularmente, las cicloadiciones 1,3-

dipolares (1,3-DC)19,30,31,52 y el amida-aldehído-dienófilo (AAD)99 son procesos

multicomponentes atractivos y versátiles que pueden generar moléculas

orgánicas con esqueletos muy diferentes.

Recientemente se ha descrito que la reacción 1,3-DC de iluros de

azometino cíclicos generados in situ podría usarse para la generación de

pirrolizidinas altamente sustituidas,12d,56,69 e indolizidinas (véase el Capítulo 1).11

A saber, los alcaloides de pirrolizidina son actualmente de especial interés porque

tienen propiedades biológicas amplias e interesantes. Las pirrolizidinas 107 se

pueden obtener por reacción multicomponente de ésteres 106 derivados de

prolina con aldehídos aromáticos, alifáticos y α,β-insaturados, y los

correspondientes dipolarófilos.12d,30a,e,56,69,70,100 Se requieren condiciones de

reacción suaves para todo tipo de alquenos electrofílicos, proporcionando

diastereoselectivamente alcaloides bicíclicos 107 con buenos rendimientos

(Esquema XXIIa).

Por otro lado, el MCR conocido como AAD ha sido ampliamente estudiada

para la síntesis de 3-aminociclohexenos y otras estructuras interesantes. Las

amidas, carbamatos y sulfonamidas reaccionaron con aldehídos y dienófilos en

presencia de ácido p-toluenosulfónico (TsOH) a través de un proceso [4+2], para

Page 189: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

188

producir los correspondientes productos de cicloadición 108 (Esquema XXIIb).

Estas reacciones AAD han proporcionado el acceso a varios heterociclos y

carbociclos, así como núcleos estructurales clave del producto natural

pumilotoxina C.101a

Esquema XXII. a) Reacción multicomponente 1,3-DC general de prolinatos, aldehídos y dipolarófilos

que producen pirrolizidinas 107. b) Cicloadición multicomponente [4+2] general de amidas-

aldehídos-dienófilos (procesos AAD) que proporcionan 3-aminociclohexenos 108.

Resultados y discusión

Manteniendo el foco en la investigación de la síntesis de pirrolizidinas

usando la reacción multicomponente 1,3-DC, como nuestro grupo ha realizado

últimamente,12d,69 se pensó ampliar el estudio a una versión multicomponente y

diastereoselectiva de la 1,3-DC a partir de nitroprolinatos enantioenriquecidos

exo-113a descritos por nuestro grupo (Esquema XXIII).110

Page 190: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 3

189

Esquema XXIII. Síntesis multicomponente de pirrolizidinas endo- o exo-116 via 1,3-DC.

Al igual que en trabajos anteriores, se seleccionó tolueno como disolvente

debido a los buenos resultados proporcionados cuando se utiliza en la cicloadición

1,3-dipolar multicomponente que involucra iluros de azometino. El trans-

cinamaldehído 71 se eligió como aldehído debido a la alta diastereoselección

mostrada en la síntesis de derivados de pirrolizidina (hasta 99:1),12d,69 y el

nitroprolinato de metilo exo-113a se seleccionó como fuente de nitrógeno, usando

una ruta de iminio convencional a través de 1,3-DC para su síntesis. Para ampliar

los ejemplos a estudio se utilizaron diferentes dipolarófilos. Las condiciones de

reacción de partida fueron las optimizadas por nuestro grupo en el que el

nitroprolinato, ópticamente activo, exo-113a y AgOAc al 5% en moles se agitan en

tolueno a 70 °C para obtener la conversión completa en una sola noche de las

pirrolizidinas deseadas 116 (Esquema XXIV).111

Esquema XXIV. Cicloadición multicomponente entre exo-113a, trans-cinnamaldehído 71 y diferentes

dipolarófilos para sintetizar pirrolizidinas endo o exo-116.

Page 191: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

190

Los resultados obtenidos para los diferentes dipolarófilos se muestran en

la tabla siguiente (Tabla IV):

Tabla IV. Cicloadición multicomponente entre exo-113a, trans-cinnamaldehído 71 y diferentes

dipolarófilos para sintetizar pirrolizidinas endo o exo-116.

Entrada Dipolarófilo Producto CNV

(%)a

dra

(endo:exo)

Rendimiento

(%)b

(endo, exo)

1

116a >95 62:38 70, 26

2

116b >95 66:34 65, 30

3

116c >95 25:75 23, 67

4 116d >95 96:4 88, 0

5

116e >95 61:39 48, 26

6 116f >95 >99:1 31

7 116g >95 >99:1 35

8

-- >10 -- --

9 -- >10 -- --

10

-- >10 -- --

11 -- 0 -- --

a Determinado por 1H RMN de la mezcla de reacción cruda.

b Rendimiento aislado después de la purificación (sílice flash) del diastereoisómero mayor y menor.

Page 192: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 3

191

El esqueleto de pirrolidina, que actúa como fuente de amina, también se

sometió a estudio empleando trans-cinamaldehído 71 y NPM como dipolarophile

(Esquema XXV) Se probaron 3 pirrolidinas con diferentes sustituyentes en la

posición 3, cuyos resultados se muestran en la Tabla V.

Esquema XXV. Pirrolizidinas obtenidas de la cicloadición multicomponente entre diferentes

nitroprolinatos, trans-cinamaldehído 71 y NPM.

Page 193: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

192

Tabla V. Reacción multicomponente 1,3-DC entre diferentes nitroprolinatos, trans-cinamaldehído 71

y NPM.

Entrada Amina Producto CNV

(%)a

dra

(endo:exo)

Rendimiento

(%)b

(endo, exo)

1

116h >95 32:68 60, 28

2

-- <20 50:50 --

3

116i >95 1:99 --, 72

a Determinado por 1H RMN de la mezcla de reacción cruda. b Rendimiento aislado después de la purificación (sílice flash) del diastereoisómero mayor y menor.

También se evaluó el aldehído (Esquema XXVI), obteniendo resultados

solo cuando se utilizó β-fenilcinnamaldehído (Tabla VI).

Esquema XXVI. Cicloadición multicomponente entre exo-113a, NPM y diferentes aldehídos.

Page 194: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 3

193

Tabla VI. Síntesis de pirrolizidinas 116 a partir de exo-113a, NPM y diferentes aldehídos a través de

1,3-DC.

Entrada Aldehído Producto CNV

(%)a

dra

(endo:exo)

Rendimiento

(%)b

(endo, exo)

1

116j >95 71:29 59, 21

2

-- 0 -- --

3

-- 0 -- --

4

-- <5 -- --

5

-- 0 -- --

a Determinado por 1H RMN de la mezcla de reacción cruda. b Rendimiento aislado después de la purificación (sílice flash) del diastereoisómero mayor y menor.

Sin embargo, cuando se usó crotonaldehído en la reacción del Esquema

XXVII, solo se detectó un producto, y fue muy diferente de la serie de las

pirrolizidinas 116. Se obtuvo un nuevo compuesto enantiopuro en excelente

relación diastereomérica (> 99:1 en el crudo de la reacción) y alto rendimiento

(86%) (Esquema XXVIII), cuya configuración absoluta se confirmó gracias a un

análisis de difracción de rayos X realizado sobre el compuesto 119a (Figura VI).116

Page 195: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

194

Esquema XXVIII. Síntesis multicomponente divergente de ciclohexanos polisustituidos 119a a través

del proceso AAD a partir de prolinato exo-113a, crotonaldehído y NPM.

Figura VI. Análisis de difracción de rayos X del compuesto 119a.

Al profundizar en las condiciones de reacción del proceso de AAD, se

descubrió que el catalizador de plata no era necesario para lograr la conversión

Page 196: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 3

195

completa y tampoco era necesario elevar la temperatura hasta 70 °C (Esquema

XXIX).

Esquema XXIX. Condiciones de reacción optimizadas del proceso AAD entre prolinato exo-113a,

crotonaldehído y NPM.

Las reacciones de AAD del compuesto exo-113a (> 99:1 er,> 99:1 dr) con

aldehídos y dipolarophiles se llevaron a cabo a temperatura ambiente, pudiendo

obtenerse los productos deseados en altos rendimientos (Figura VII).

Page 197: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Resumen en castellano

196

Figura VII. Alcance del proceso de AAD multicomponente [4+2] al cambiar los dipolarófilos y los

aldehídos.

De acuerdo con estos resultados descritos, la presencia del grupo nitro es

crucial en el origen de la periselectividad en estas reacciones multicomponentes.

El paso inicial en el mecanismo propuesto consiste en la formación del catión A de

iminio, derivado de la condensación entre el derivado de prolina y el

crotonaldehído (Esquema XXX). Este intermedio tiene dos protones ácidos. Por lo

tanto, en presencia de una base, A puede evolucionar hacia el iluro de azometina

B mediante la abstracción del átomo de hidrógeno localizado en la posición α del

grupo metoxicarbonilo, que conduce a las pirrolizidinas 116, 124-127 o a una

dienamina intermedia C por abstracción del átomo de hidrógeno en la posición γ

de crotonaldehído, formando así ciclohexenilpirrolidinas 119.

Page 198: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

Capítulo 3

197

Esquema XXX. Esquema general de la reacción de prolinates, aldehídos y dipolarophiles.

Page 199: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

198

Page 200: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

199

REFERENCES

1 Chemistry of Natural Products; Bhat, S. V.; Nagasampagi, B. A.; Sivakumar, M.; Ed.

Springer: Narosa, 2005; p 317.

2 Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213–7256.

3 Nájera, C.; Retamosa, M. d. G.; Sansano, J. M.; de Cózar, A.; Cossío, F. P. Tetrahedron:

Asymmetry 2008, 19, 2913–2923, and references cited therein.

4 a) Burton, G.; Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky, R. T.; Lin-Goerke, J.; Baker,

A.; Earnshaw, D. L.; Hofmann, G. A.; Keenan, R. M.; Dhanak, D. Bioorg. Med. Chem.

Lett. 2005, 15, 1553–1556. b) Chabour, I.; Castelló, L. M.; Mancebo-Aracil, J.;

Martín-Rodríguez, M.; Retamosa, M. d. G.; Nájera, C.; Sansano, J. M. Tetrahedron:

Asymmetry 2017, 28, 1423–1429.

5 a) Parsons, A. F. Tetrahedron 1996, 52, 4149–4152. b) Baldwin, J. E.; Fryer, A. M.;

Pritchard, G. J.; Spyvee, M. R.; Whitehead, R. C.; Wood, M. E. Tetrahedron 1998, 54,

7465–7484.

6 Wardrop, D. J.; Burge, M. S. Chem. Commun. 2004, 1230–1231.

7 Bhat, C.; Tilve, S. G. RSC Adv. 2014, 4, 5405–5452.

8 a) IPCS, International Programme on Chemical Safety (WHO). Pyrrolizidine

alkaloids. Environmental Health Criteria 80. Geneva; http://www.

inchem.org/documents/ehc/ehc/ehc080.htm; 1988. b) Matyas, M.; Abranyi-

Balogh, P.; Keglevich, G. Curr. Org. Synth. 2014, 11, 889–901.

9 Wang, G. W.; Huang, B. K.; Qin, L. P. Phytother. Res. 2012, 26, 1–10.

10 Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773–781.

11 a) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.

Phytochemistry 2001, 56, 265–295. b) Cramer, L.; Schiebel, H.-M.; Ernst, L.;

Beuerle, T. J. Agric. Food Chem. 2013, 61, 11382–11391. c) Roeder, E.; Wiedenfeld,

H. Pharmazie 2013, 68, 83–92.

12 a) Naturally Occurring Pyrrolizidine Alkaloids, Rizk, A. M., Ed. CRC Press, Boca

Ratón, 1991. b) Harborne, J. B. Nat. Prod. Rep. 2001, 18, 361–379. c) Liddell, J. R.

Nat. Prod. Rep. 2001, 18, 441–447. d) Mancebo-Aracil, J.; Nájera, C.; Sansano, J.

Chem. Commun. 2013, 49, 11218–11220.

Page 201: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

References

200

13 a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077–3092. b) Asano,

N.; Kato, A.; Watson, A. A. Mini-Rev. Med. Chem. 2001, 1, 145–154.

14 a) Denmark, S. E.; Thorarensen, A. J. Am. Chem. Soc. 1997, 119, 125–137. b)

Felluga, F.; Pitacco, G.; Visintin, C.; Valentin, E. Helv. Chim. Acta 1997, 80, 1443–

1456. c) Rao, M. S.; Rao, P. S. Fitoterapia 1999, 70, 449–450. d) Le Roux, K.; Hussein,

A. A.; Lall, N. J. Ethnopharm. 2011, 138, 748–755. e) Mancebo-Aracil, J.; Nájera, C.;

Castelló, L. M.; Sansano, J. M. Larrañaga, O.; de Cózar, A.; Cossío, F. P. Tetrahedron

2015, 71, 9645–9661.

15 a) Hagan, D. O. Nat. Prod. Rep. 2000, 17, 435–446. b) Lewis, J. R. Nat. Prod. Rep.

2001, 18, 95–128. c) Daly, J. W. J. Med. Chem. 2003, 46, 445–452. d) Daly, J. W.;

Garraffo, H. M.; Spande, T. F. J. Nat. Prod. 2005, 68, 1556–1575. e) Michael, J. P. Nat.

Prod. Rep. 2007, 24, 191–222. f) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165.

16 a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603–626. b) Gerber-Lemaire, S.;

Juillerat-Jeanneret, L. Chimia 2010, 64, 634–639. c) Bronner, S. M.; Im, G.-Y. J.; Garg,

N. K. Heterocycles in Natural Product Synthesis 2011, 221–265.

17 a) Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause, B. L.; Oredipe, O. A.;

Newton, S. A.; White, S. L. Pharmacol. Ther. 1991, 50, 285–290. b) Michael, J. P. Nat.

Prod. Rep. 1997, 14, 21–41.

18 a) Franklin, A. S.; Overman, L. E. Chem. Rev. 1996, 96, 505–522. b) Michael, J. P.;

Gravestock, D. Eur. J. Org. Chem. 1998, 865–870, and references cited therein.

19 a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Towards

Heterocycles and Natural Products, Padwa, A.; Pearson, W. H. Eds. John Wiley &

Sons; New Jersey, 2003. b) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–

2810. c) Pellissier, H. Tetrahedron 2007, 63, 3235–3285. d) Nair, V.; Suja, T. D.

Tetrahedron 2007, 63, 12247–12275. e) Nájera, C.; Sansano, J. M. in Topics in

Heterocyclic Chemistry, vol. 12 (Ed.: A. Hassner), Springer: Verlag. Berlin-

Heidelberg, 2008, pp. 117. f) Nájera, C.; Sansano, J. M. J. Organomet. Chem. 2014,

771, 78–92. g) Baunach, M.; Hertweck, C. Angew. Chem. Int. Ed. 2015, 54, 12550-

12552. h) Singh, M.S.; Chowdhury, S.; Koley, S. Tetrahedron 2016, 72, 1603–1644.

i) Nájera, C.; Sansano, J. M. Chem. Rec. 2016, 16, 2430–2448. j) Pandey, G.; Dey, D.;

Tiwari, S. K. Tetrahedron Lett. 2017, 58, 699–705.

20 a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565–598. b) Huisgen, R.

Angew. Chem., Int. Ed. Engl. 1963, 2, 633–645.

Page 202: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

References

201

21 a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863–910. b) Pellissier, H.

Tetrahedron 2015, 71, 8855–8869.

22 a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1968, 7, 321–328. b) Huisgen, R. J. Org.

Chem. 1968, 33, 2291–2297. c) Huisgen, R. J. Org. Chem. 1976, 41, 403–419.

23 a) Firestone, R. A. J. Org. Chem. 1968, 33, 2285–2290. b) Firestone, R. A. J. Chem.

Soc. A 1970, 1570–1575. c) Firestone, R. A. J. Org. Chem. 1972, 37, 2181–2191. d)

Firestone, R. A. Tetrahedron 1977, 33, 3009–3039.

24 Houk, K. N.; González, J.; Li, Y. Acc. Chem. Res. 1995, 28, 81–90.

25 Huisgen, R.; Mloston, G.; Langhals, E. J. Am. Chem. Soc. 1986, 108, 6401–6402.

26 a) Hoffmann, R.; Woodward, R. B. J. Am. Chem. Soc. 1965, 87, 2046–2048. b)

Hoffmann, R.; Woodward, R. B. Acc. Chem. Res. 1968, 1, 17–22. c) Woodward, R. B.;

Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 781–853.

27 a) Grigg, R.; Kemp, J.; Malone, J.; Tangthongkum, A. J. Chem. Soc., Chem. Commun.

1980, 648–650. b) Grigg, R. Chem. Soc. Rev. 1987, 16, 89–121. c) Annunziata, R.;

Benaglia, M.; Cinquini, M.; Raimondi, L. Tetrahedron 1993, 49, 8629–8636. d)

Tatsukawa, A.; Kawatake, K.; Kanemasa, S.; Rudzinski, J. J. Chem. Soc. Perkin Trans.

2 1994, 2525–2530. e) Ayerbe, M.; Arrieta, A.; Cossío, F. J. Org. Chem. 1998, 63,

1795–1805. f) Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.;

Cossío, F. J. Am. Chem. Soc. 2000, 122, 6078–6092.

28 a) Houk, K. N.; Sims, J.; Duke, R. E.; Strozier, R. W. Jr.; George, J. K. J. Am. Chem. Soc.

1973, 95, 7287–7301. b) Frontier Orbitals and Organic Chemical Reactions, Eds:

Fleming I., Wiley: Chichester, 1976. c) Houk, K. N.; Yamaguchi, K. in 1,3-Dipolar

Cycloaddition Chemistry, Padwa, A., Ed.; Wiley: New York, 1984; Vol. 2, p 407. d)

Pericyclic Reaction, Eds: Fleming, I., Oxford Science Publications, Oxford, 1994. e)

Fleming, I. in Peryciclic Reaction, Oxford Science Publications: Oxford, 1994. f) Anh,

G. T. in Frontiers Orbitals a Practical Manual; Wiley & Sons: Chichester, England,

2007.

29 a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 718–719. b)

Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887–2902. c) Stecko, S.; Jurczak,

M.; Urbanczyk-Lipkowska, Z.; Solecka, J.; Chmielewski, M.; Carbohydrate

Research 2008, 343, 2215–2220. d) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F.

M.; Goti, A. Chem. Eur. J. 2009, 15, 7808–7821.

30 a) Grigg, R.; Jordan, M.; Malone, J. F. Tetrahedron Lett. 1979, 20, 3877–3878. b)

Nájera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105–1150. c) Padwa, A.; Bur, S.

Page 203: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

References

202

K. Tetrahedron 2007, 63, 5341–5378. d) Hashimoto, T.; Maruoka, K. Handbook of

Cyclization Reactions, Ma, S. Ed. Wiley-VCH: Weinheim, 2010. e) Codelli, J. A.;

Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2012, 134, 1930–1933.

31 a) Yoo, E. J. Synlett 2015, 26, 2189–2193. b) Döndas, H. A.; Retamosa, M. d. G.;

Sansano, J. M. Synthesis 2017, 49, 2819–2851. c) Bdiri, B.; Zhao, B.-J.; Zhou, Z.-M.

Tetrahedron: Asymmetry 2017, 28, 876–899.

32 Karlsson, S.; Han, F.; Högberg, H.-E.; Caldirola, P. Tetrahedron: Asymmetry 1999,

10, 2605–2616.

33 Deyrup, J. A.; Szabo, W. A. J. Org. Chem. 1975, 40, 2048–2052.

34 a) Bengelmans, R.; Negron, G.; Roussi, G. J. Chem. Soc., Chem. Commun. 1983, 31–

32. b) Chastanet, J.; Roussi, G. J. Org. Chem. 1985, 50, 2910–2914. c) Chastanet, J.;

Roussi, G. J. Org. Chem. 1988, 53, 3808–3812.

35 a) Grigg, R.; Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984, 180–181. b)

Grigg, R.; Aly, M. F.; Sridharan, V.; Thianpatanagul, S. J. Chem. Soc., Chem. Commun.

1984, 182–183. c) Alker, D.; Harwood, L. M.; Williams, C. E. Tetrahedron 1997, 53,

12671–12678.

36 Katritzky, A. R.; Feng, D.; Fang, Y. Synlett 1999, 590–592.

37 Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. in Comprehensive Heterocyclic

Chemistry II, Eds: Katritzky, A. R.; Rees, C. W.; Scriven, E. F. Pergamon Press. 1996,

Vol. 1A, Cap. 1.01, pp 2-60.

38 Ratts, K. W.; Howe, R. K.; Phillips, W. G. J. Am. Chem. Soc. 1969, 91, 6115–6121.

39 a) Deshong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem. 1985, 50, 2309–2315. b)

Deshong, P.; Kell, D. A. Tetrahedron Lett. 1986, 27, 3979–3982. c) Danielsson, J.;

Toom, L.; Somfai, P. Eur. J. Org. Chem. 2011, 607–613. d) Khlebnikov, A. F.; Novikov,

M. S. Chem. Heterocycl. Comp. 2012, 48, 179–190.

40 a) Grigg, R.; Kemp, J.; Sheldrik, G.; Trotter, J. J. Chem. Soc., Chem. Commun. 1978,

109–111. b) Grigg, R.; Donegan, G.; Gunaratne, H. Q. N.; Kennedy, D. A.; Malone, J.

F.; Sridharan, V.; Thianpatanagul, S. Tetrahedron 1989, 45, 1723–1746. c) Grigg, R.;

Sridharan, V.; Suganthan, S.; Bridge, A. W. Tetrahedron 1995, 51, 295–306. d)

Grigg, R.; McMeekin, P.; Sridharan, V. Tetrahedron 1995, 51, 13331–13346. e)

Mancebo-Aracil, J.; Muñoz-Guillena, M. J.; Such-Basáñez, I.; Sansano-Gil, J. M. Chem.

Plus. Chem. 2012, 77, 770–777.

41 Grigg, R.; Sridharan, V. in Advances in Cycloaddition, JAI Press Inc.: Greenwich,

1993, Vol. 3, pp 161–204.

Page 204: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

References

203

42 a) Grigg, R.; Gunaratne, H. Q. N.; Henderson, D.; Sridharan, V. Tetrahedron 1990,

46, 1599–1610. b) Grigg, R.; McMeekin, P.; Sridharan, V. Tetrahedron 1995, 51,

13347–13356.

43 Arrieta, A.; Otaegui, D.; Zubia, A.; Cossío, F. P.; Díaz-Ortiz, A.; de la Hoz, A.;

Herrero, M. A.; Prieto, P.; Foces-Foces, C.; Pizarro, J. L.; Arriortua, M. a. I. J. Org.

Chem. 2007, 72, 4313–4322.

44 a) Sustmann, R. Tetrahedron Lett. 1971, 12, 2717–2720. b) Sustmann, R. Pure

Appl. Chem. 1974, 40, 569–593.

45 a) Fleming, I. in Frontier Orbitals and Organic Chemical Reactions, Wiley:

Chichester, 1976. b) Cycloaddition Reactions in Organic Synthesis, Eds: Carruthers,

W., Pergamon Press: Oxford, 1990, pp 269.

46 Otero-Fraga, J.; Montesinos-Magraner, M.; Mendoza, A. Synthesis 2017, 49, 802–

809.

47 a) Broggini, G.; Molteni, G.; Terraneo, A; Zecchi, G. Heterocycles 2003, 59, 823–

858. b) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887–2902. c) Álvarez-

Corral, M.; Muñoz-Dorado, M; Rodríguez-García, I. Chem Rev. 2008, 108, 3174–

3198. d) Naodovic, M.; Yamamoto, H. Chem Rev. 2008, 108, 3132–3148. e) Nájera,

C.; Sansano, J. M.; Yus, M. J. Braz. Chem. Soc. 2010, 21, 377–412.

48 a) Grigg, R.; Kemp, J. Tetrahedron Lett. 1980, 21, 2461–2464. b) Armstrong, P.;

Grigg, R.; Jordan, M. W.; Malone, J. F. Tetrahedron 1985, 41, 3547–3558. c) Tsuge,

O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull. Chem. Soc. Jpn. 1986, 59, 1809–1824. d)

Van Es, J. J. G. S.; Jaarsveld, K.; van der Gen, A. J. J. Org. Chem. 1990, 55, 4063–4069.

e) Van Es, J. J. G. S.; Wolde, A. T.; van der Gen, A. J. J. Org. Chem. 1990, 55, 4069–

4079.

49 a) Barr, D.; Grigg, R.; Gunaratne, H. Q. N.; Kemp, J.; McMeekin, P.; Sridharan, V.

Tetrahedron 1988, 44, 557–570. b) Tsuge, O.; Kanemasa, S.; Yoshioka, M. J. Org.

Chem. 1988, 53, 1384–1391.

50 a) Casella, L.; Gulloti, M.; Pasini, A.; Pasaro, R. Synthesis 1979, 150–151. b)

Casella, L.; Gulloti, M.; Melani, E. J. Chem. Soc., Perkin Trans. 1 1982, 1827–1831. c)

Grigg, R.; Sridharan, V.; Thianpatanagul, S. J. Chem. Soc., Perkin Trans. 1 1986,

1669–1675.

51 a) Casas, J.; Grigg, R.; Nájera, C.; Sansano, J. M. Eur. J. Org. Chem. 2001, 1971–

1982. b) Kanemasa, S. Synlett 2002, 1371–1387, and references cited therein.

Page 205: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

References

204

52 a) Randjelovic, E.; Simic, M.; Tasic, G.; Husinec, S.; Savic, V. Curr. Org. Chem. 2014,

18, 1073–1096. b) Hashimoto, T.; Maruoka, K. Chem. Rev. 2015, 115, 5366–5412.

53 a) Choudhury, L. H.; Parvin, T. Tetrahedron, 2011, 67, 8213–8228. b)

Multicomponent Reactions: Concepts and Applications for Design and Synthesis,

Pérez-Herrera, R.; Marqués-López, E. Eds. Wiley-VCH: Weinheim, 2015.

54 a) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237–294. b) van der Heijden, G.;

Ruijter, E.; Orru, R. V. A. Synlett 2013, 24, 666–685.

55 a) Trost, B. M. Science 1991, 254, 1471–1477. b) Anastas, P. T.; Warner, J. C. in

Green Chemistry: Theory and Practice, Oxford University Press, Oxford, 2000, p.

135. c) Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem. 2007, 9, 438–440.

56 Mancebo-Aracil, J.; Nájera, C.; Sansano, J. M. Org. Biomol. Chem. 2013, 11, 662–

675.

57 a) Song, L.; Duesler E. N.; Mariano, P. S. J. Org. Chem. 2004, 69, 7284–7293. b)

Zhao, Z.; Song L.; Mariano, P. Tetrahedron, 2005, 61, 8888–8894.

58 Daly, J. W.; Garraffo, H. M.; Spande, T. F. in Alkaloids: Chemical and Biological

Perspectives, ed. S. W. Pelletier, Pergamon Press, Amsterdam, 1999, vol. 13, pp. 1–

161.

59 Toyooka, N.; Nemoto, H. Heterocycles 2005, 66, 549–555.

60 a) Toyooka, N.; Dejun, Z.; Nemoto, H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W.

Tetrahedron Lett. 2006, 47, 577–580. b) Toyooka, N.; Dejun, Z.; Nemoto, H.;

Garraffo, H. M.; Spande, T. F.; Daly, J. W. Tetrahedron Lett. 2006, 47, 581–582.

61 Overman, L. E.; Bell K. L. J. Am. Chem. Soc. 1981, 103, 1851–1853.

62 Overman, L. E.; Bell, K. L.; Ito, Fumitaka J. Am. Chem. Soc. 1984, 106, 4192–4201.

63 a) Liu, X.; McCormack, M. P.; Waters, S. P. Org. Lett. 2012, 14, 5574–5577. b)

McCormack, M. P.; Waters, S. P. J. Org. Chem. 2013, 78, 1176–1183.

64 Joucla, M.; Mortier, J.; Hamelin, J. Tetrahedron Lett. 1985, 26, 2775–2778.

65 Grigg, R.; Surendrakumar, S.; Thianpatanagul, S.; Vipond, D. J. Chem. Soc., Chem.

Commun. 1987, 47–49.

66 Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Somasunderam, A. Tetrahedron 1993,

49, 8679–8690.

67 Grigg, R.; Surendrakumar, S.; Thianpatanagul, S.; Vipond, D. J. Chem. Soc., Perkin

Trans. 1 1988, 2693–2701.

68 Mantenuto, S.; Cayuelas, A.; Favi, G.; Attanasi, O. A.; Mantellini, F.; Nájera, C.;

Sansano, J. M. Eur. J. Org. Chem. 2016, 4144–4151.

Page 206: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

References

205

69 Mancebo-Aracil, J.; Nájera, C.; Castelló, L. M.; Sansano, J. M.; Larrañaga, O.; de

Cózar, A.; Cossío, F. P. Tetrahedron 2015, 71, 9645–9661.

70 Sengupta, T.; Khamarui, S.; Samanta, S.; Maiti, D. K. Chem. Commun. 2013, 49,

9962–9964.

71 Gayen, B.; Banerji, A.; Dhara, K. Synth. Commun. 2016, 46, 293–308.

72 The X-ray structures has been deposited in CCDC with reference 1496416.

73 Chaulet, C.; Croix, C.; Alagille, D.; Normand, S.; Delwail, A.; Favot, L.; Lecron, J. C.;

Viaud-Massuard, M.-C. Bioorg. Med. Chem. Lett. 2011, 21, 1019–1022.

74 a) Paderes, M. C.; Chemler, S. R. Org. Lett. 2009, 11, 1915–1918. b) Coppola, M.;

Mondola, R. Toxicol. Lett. 2012, 212, 57–60.

75 Grigg, R.; Kemp, J.; Trotter, J. J. C. S. Chem. Commun. 1978, 109–111.

76 Kauffmann, T.; Berg, H.; Köppelmann, E. Angew. Chem. Int. Ed. 1970, 9, 380–381.

77 Otero-Fraga, J.; Montesinos-Magraner, M.; Mendoza, A. Synthesis 2017, 49, 802–

809.

78 a) Kauffmann, T. Angew. Chem., Int. Ed. 1974, 13, 627–639. b) Kauffmann, T.;

Habersaat, K.; Koeppelmann, E. Chem. Ber. 1977, 110, 638–644. c) Pandiancherri,

S.; Lupton, D. W. Tetrahedron Lett. 2011, 52, 671–674.

79 a) Kauffmann, T.; Eidenschink, R. Angew. Chem., Int. Ed. 1971, 10, 739–740. b)

Kauffmann, T.; Eidenschink, R. Chem. Ber. 1977, 110, 645–650. c) Pearson, W. H.;

Mans, D. M.; Kampf, J. W. Org. Lett. 2002, 4, 3099–3102. d) Pearson, W. H.; Mans,

D. M.; Kampf, J. W. J. Org. Chem. 2004, 69, 1235–1247.

80 a) Popowski, E. Z. Chem. 1974, 14, 360–367. b) Kauffmann, T.; Ahlers, H.;

Hamsen, A.; Schulz, H.; Tilhard, H. J.; Vahrenhorst, A. Angew. Chem., Int. Ed. 1977,

16, 119–119. c) Kauffmann, T.; Ahlers, H.; Echsler, K. J.; Schulz, H.; Tilhard, H. J.

Chem. Ber. 1985, 118, 4496–4506. d) Pearson, W. H.; Mi, Y.; Lee, I. Y.; Stoy, P. J. Am.

Chem. Soc. 2001, 123, 6724–6725.

81 Grigg, R.; Gunaratne, H. Q. N.; Sridharan, V.; Thianpatanagul, S. Tetrahedron Lett.

1983, 24, 4363-4366.

82 Padilla, S.; Tejero, R.; Adrio, J.; Carretero, J. C. Org. Lett. 2010, 12, 5608–5611.

83 Grigg, R.; Donegan, G.; Gunaratne, H. Q. N.; Kennedy, D. A., Malonw, J. F.;

Sridharan, V.; Thianpatanagul, S. Tetrahedron 1989, 45, 1723–1746.

84 Grigg, R.; Sridharan, V.; Thornton-Pett, M.; Wang, J.; Xu, J.; Zhang, J. Tetrahedron

2002, 58, 2627–2640.

85 Machamer, N. K.; Liu, X.; Waters, S. P. Org. Lett. 2014, 16, 4996–4999.

Page 207: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

References

206

86 Prilezhaeva, E. N.; Laba, V. I.; Snegotskii, V. I.; Shekhtman, R. I. Izv. Akad. Nauk

SSSR, Ser. Khim. 1970, 7, 1602–1608.

87 The X-ray structures has been deposited in CCDC with reference 1820733.

88 The MM2 basic calculations has been done it with the software “ChemBioDraw

Ultra 14.0”.

89 Zirngibl, L.; Wagner-Jauregg, T.; Pretsch. E.; Stage, D. J.; Hales, N. J.; Paris, C. W.

Tetrahedron 1971, 27, 2203–2209.

90 Sakamoto, M.; Tomimatsu, Y.; Momose, T.; Iwata, C.; Hanaoka, M. Yakugaku

Zasshi 1972, 92, 1431–1434.

91 a) Olsen, J.; Seiler, P.; Wagner, B.; Fischer, H.; Tschopp, T.; Obst-Sander, U.;

Banner, D. W.; Kansy, M.; Müller, K.; Diederich, F. Org. Biomol. Chem. 2004, 2, 1339–

1352. b) Schweizer, E.; Hoffmann-Röder, A.; Schärer, K.; Olsen, J. A.; Fäh, C.; Seiler,

P.; Obst-Sander, U.; Wagner, B.; Kansy, M.; Diederich, F. ChemMedChem 2006, 1,

611–621.

92 a) Furie, B.; Furie, B. C. Cell 1988, 53, 505–518. b) Scully, M. F. in Essays in

Biochemistry, Ed. K. F. Tipton, Portland Press, London, 1992, pp. 17–36.

93 Iza, A.; Carrillo, L.; Vicario, J. L.; Badía, D.; Reyes, E.; Martínez, J. I. Org. Biomol.

Chem. 2010, 8, 2238–2244.

94 Schreiber, S. L. Science 2000, 287, 1964–1969.

95 Biggs-Houck, J.-E.; Younai, A.; Shaw, J. T. Curr Opin Chem Biol. 2010, 14, 371–382.

96 a) Fang, X.; Jackstell, R.; Beller, M. Chem. Eur. J. 2014, 20, 7939–7942. b) Hübner,

S.; Jiao, H.; Michalik, D.; Neumann, H.; Klaus, S.; Strübing, D.; Spannenberg, A.;

Beller, M. Asian J. Chem. 2007, 2, 720–733, and articles cited therein.

97 a) Felluga, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E.; Zangrando, E. J.

Heterocyclic Chem. 2010, 47, 664–670. b) Cui, P.; Xu, L.; Shi, Z.; Gan, L. J. Org. Chem.

2011, 76, 4210–4212. c) Kang, T.-R.; Cheng, Y.; He, L.; Ye, J.; Liu, Q.-Z. Tetrahedron

Lett. 2012, 53, 2552–2555. d) Lu, Q.; Song, G.; Jasinski, J. P.; Keeley, A. C.; Zhang, W.

Green Chem. 2012, 14, 3010–3012. e) Lim, A. D.; Codelli, J. A.; Reisman, S. E. Chem.

Sci. 2013, 4, 650–654.

98 a) Overman, L. E.; Jessup, P. J. J. Am. Chem. Soc. 1978, 100, 5179–5185. b)

Neumann, H.; Strübing, D.; Lalk, M.; Klaus, S.; Hübner, S.; D.; Spannenberg, A.;

Lindequist, U.; Beller, M. Org. Biomol. Chem. 2006, 4, 1365–1375.

99 Bertelsen, S.; Marigigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc.

2006, 128, 12973–12980.

Page 208: rua.ua.es · 3 Table of contents PREFACE 7 SUMMARY 9 GENERAL INTRODUCTION 11 1,3-DIPOLAR CYCLOADDITIONS 13 Azomethine ylides 15 1,3-Dipolar cycloadditions …

References

207

100 Weber, A. K.; Jacobi, A.; van Wangelin, A. J. Org. Biomol. Chem. 2014, 12, 5267–

5277.

101 a) Parry, R.; Nishino, S.; Spain, J. Nat. Prod. Rep. 2011, 28, 152–167. b) Nájera,

C.; Sansano, J. M. Curr. Top. Med. Chem. 2014, 14, 1271–1282.

102 a) Zubia, A.; Mendoza, L.; Vivanco, S.; Aldaba, E.; Carrascal, T.; Lecea, B.; Arrieta,

A.; Zimmerman, T.; Vidal-Vanaclocha, F.; Cossío, F. P. Angew. Chem. Int. Ed. 2005,

44, 2903–2907. b) San Sebastián, E.; Zimmerman, T.; Zubia, A.; Vara, Y.; Martin, E.;

Sirockin, F.; Dejaegere, A.; Stote, R. H.; López, X.; Pantoja-Uceda, D.; Valcárcel, M.;

Mendoza, L.; Vidal-Vanaclocha, F.; Cossío, F. P.; Blanco, F. J. J. Med. Chem. 2013, 56,

735–747.

103 Narayan, R.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew.

Chem. Int. Ed. 2013, 52, 12892–12896.

104 Puerto-Galvis, C. E.; Kouznetsov, V. V. Org. Biomol. Chem. 2013, 11, 7372–7386.

105 Conde, E.; Bello, D.; de Cózar, A.; Sánchez, M.; Vázquez, M. A.; Cossío, F. P. Chem.

Sci. 2012, 3, 1486–1491.

106 Ruíz-Olalla, A.; Retamosa, M. d. G.; Cossío, F. P. J. Org. Chem. 2015, 80, 5588–

5599.

107 a) Conde, E.; Rivilla, I.; Larumbe, A.; Cossío, F. P. J. Org. Chem. 2015, 80, 11755–

11767. b) Yang, W.-L.; Liu, Y.-Z.; Luo, S.; Yu, X.; Fossey, J. S.; Deng, W.-P. Chem.

Commun. 2015, 51, 9212–9215.

108 Cayuelas, A.; Ortiz, R.; Nájera, C.; Sansano, J. M.; Larrañaga, O.; de Cózar, A.;

Cossío, F. P. Org. Lett. 2016, 18, 2926–2929.

109 a) Castelló, L. M.; Nájera, C.; Sansano, J. M.; Larrañaga, O.; de Cózar, A.; Cossío, F.

P. Adv. Synth. Catal. 2014, 356, 3861–3870. b) Castelló, L. M.; Nájera, C.; Sansano J.

M.; Larrañaga, O.; de Cózar, A.; Cossío, F. P. Synthesis 2015, 47, 934–943.

110 L. M. Castelló, Doctoral Thesis. University of Alicante. 2015.

111 The X-ray structures has been deposited in CCDC with reference 1538328.

112 The X-ray structures has been deposited in CCDC with reference 1481758.


Top Related