Diastereoselective multicomponent [3+2] and [4+2] cycloadditions
Verónica Selva Martínez
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
2
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
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
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
6
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.
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.
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.
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.
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, (-)-
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
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.
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
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.
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.
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
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.
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
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.
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
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.
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.
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.
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.
26
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
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
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
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.
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).
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
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.
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.
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.
36
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
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.
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.
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).
Results and discussion
41
Scheme 20. Multicomponent cycloaddition of methyl pipecolinate hydrochloride 70 with trans-
cinnamaldehyde 71 and different dipolarophiles.
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).
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.
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.
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).
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).
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).
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
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.
Chapter 1: Multicomponent synthesis of indolizidines
50
Figure 8. Structures and purified yields obtained for polysubstituted indolizidines 77.
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.
Chapter 1: Multicomponent synthesis of indolizidines
52
Scheme 26. Synthesis of substituted indolizidines 79 after decarboxylation.
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.
54
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.
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.
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.
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.
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
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),
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),
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.
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
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),
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,
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
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),
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.
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.
Chapter 1: Multicomponent synthesis of indolizidines
70
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
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
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
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.
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.
76
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.
78
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
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.
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.
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).
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.
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).
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.
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.
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
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.
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.
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
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
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).
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.
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).
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
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.
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.
98
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),
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.
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.
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.
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.
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),
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,
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.
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
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
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.
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.
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.
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.
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.
114
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
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
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.
118
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.
120
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.
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.
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).
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-
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.
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.
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
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).
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,
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).
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).
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.
Results and discussion
133
Scheme 54. General scheme of the reaction of prolinates, aldehydes and dipolarophiles.
134
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.
136
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
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,
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
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:
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
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
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
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,
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.
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.
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
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
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.
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)
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,
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.
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
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
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,
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.
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
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
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:
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.
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
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
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
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
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.
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
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
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
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.
Resumen en castellano
170
Esquema VI. Cicloadición multicomponente de clorhidrato de pipecolinato de metilo 70, trans-
cinamaldehído 71 y diferentes dipolarófilos.
Capítulo 1
171
Esquema VII. Cicloadición multicomponente de clorhidrato de pipecolinato de metilo 70, diferentes
aldehídos y dipolarófilos.
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.
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).
Resumen en castellano
174
Esquema XI. Síntesis de indolizidinas sustituidas 80 después de la descarboxilación.
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
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).
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).
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
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.
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
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).
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).
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.
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.
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).
Resumen en castellano
186
Esquema XXI. Síntesis del inhibidor de la trombina tricíclico 105.
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
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
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.
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.
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.
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.
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
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
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).
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.
Capítulo 3
197
Esquema XXX. Esquema general de la reacción de prolinates, aldehídos y dipolarophiles.
198
199
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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.