3-Alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)-acrylonitriles as masked 1,3-dipoles

Article abstract of DOI:10.1016/j.tet.2009.06.114

Reaction of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles with maleimides, dimethyl maleate and dimethylacetylene dicarboxylate were carried out to give octahydro-pyrrolo[3,4-a]pyrrolizin-4-ylidenes, hexahydro-pyrrolizines and 6,7-dihydro-5H

Full text of DOI:10.1016/j.tet.2009.06.114

Tetrahedron 65 (2009) 7662–7672
Contents lists available at ScienceDirect
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3-Alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)-acrylonitriles as masked 1,3-dipoles
,
a
b
a
Nataliya P. Belskaya a , Vasiliy A. Bakulev , Tatyana G. Deryabina , Julia O. Subbotina ,
*
Mikhail I. Kodess b, Wim Dehaen c, Suzanne Toppet c, Koen Robeyns c, Luc Van Meervelt c
a Urals State Technical University, Mira Str. 19, Ekaterinburg 620002, Russia
b I. Ya. Postovsky Institute of Organic Synthesis of the Ural Branch of Russian Academy of Sciences, S. Kovalevskaya Str. 20, Ekaterinburg 620219, Russia
c Department of Chemistry, K.U. Leuven, Celestijnenlaan 200F, B-3001, Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles with maleimides, dimethyl mal-
eate and dimethylacetylene dicarboxylate were carried out to give octahydro-pyrrolo[3,4-a]pyrrolizin-4-
ylidenes, hexahydro-pyrrolizines and 6,7-dihydro-5H-pyrrolizines. The formation of the synthesized
compounds is explained by a 1,3-dipolar cycloaddition of an in situ generated azomethine ylide. The
mechanisms of the formation of these active intermediates were discussed with the aid of density
functional theory methods with the B3LYP functional 6-31Gþ calculations using the STQN method and
chemical experiments.
Received 10 March 2009
Received in revised form 9 June 2009
Accepted 25 June 2009
Available online 2 July 2009
Keywords:
1,2-Diazadiene
Thioaminal
Ó 2009 Elsevier Ltd. All rights reserved.
Azomethine ylides
Dipolarophile
1. Introduction
molecules,6 that have found wide applications as chiral ligands and
organocatalysts in asymmetric synthesis7 and for the construction
1,2-Diazabutadienes are very useful reagents in organic syn-
thesis. The chemistry of the 1,2-diazabutadiene system mainly
deals with the nucleophilic interaction of the terminal carbon atom
with a large series of C- and hetero-nucleophiles.1 In the case of the
reactions of functionalized azadienes, the formation of various
types of heterocyclic compounds occurs via a Michael type addition
followed by cyclization with participation of either one of the ni-
of new materials in nanoscience and nanotechnology.8 Several
methods have been developed for the synthesis of azomethine
ylides: ring opening of aziridines,9 decarboxylation of arylidene
a
-amino acids,10 1,2-prototropy11 or metallotropy12 of iminoesters,
deprotonation of iminium salts,13 desilylation of imines14 or
destannylation of (2-azaallyl)stannates.15 At the same time, the use
of diazabutadienes with a terminal conjugated S,N-thioaminal
function as starting compounds to generate azomethine ylides was
not known except for our preliminary publication.4
trogen atoms of the diene system or of the functional group.2
A
variety of azoles (pyrroles, pyrazoles, imidazoles, thiazoles, thia-
diazoles) and azines (pyrazines, piperazines and triazines) were
prepared based on the reactions of 1,2-diazadienes.1,2 Tetrahy-
dropyridazines and N-aminopyrroles were synthesized by [4þ2]
cycloadition of diazadienes with alkenes and enamines.3 Before our
preliminary report there were no data in the literature on the
chemical properties of 1,2-diazadienes bearing an S,N-acetal
group.4 It was shown there that these compounds reacted with
N-phenyl- and N-methyl maleimides to form [3þ2] adducts via
initally formed azomethine ylides.
We report here the study of the mechanism of generation of
azomethine ylides from 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-
1-yl)acrylonitriles and their interaction with dipolarophiles.
2. Results and discussion
In terms of frontier molecular orbital (FMO) theory, in which
a reaction takes place by maximizing overlap of the HOMO and the
LUMO, azomethine ylides can be considered to be electron-rich,
and the dominant interaction involves the HOMO of the azome-
thine ylide with the LUMO of the dipolarophile. This is borne out by
the general preference for the reaction of azomethine ylides with
electron-poor alkenes and alkynes. Thus, we investigated the
cycloaddition of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acry-
lonitriles 1 and 2 with substituted maleimides, dimethyl maleate
and dimethyl acetylenedicarboxylate (DMAD).
It is worth noting that the chemistry of azomethine ylides re-
mains the subject of intensive research of organic chemists for the
preparation of various heterocyclic compounds including those
that contain fragments of natural products5 and other bioactive
* Corresponding author. Tel.: þ7 343 375 4135.
E-mail address: belska@mail.ustu.ru (N.P. Belskaya).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.114

N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
7663
3
2.1. Reaction of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-
yl)acrylonitriles with maleimides
4.7–5.10 ppm corresponding to the 3a proton with J3a–8b¼8.2–
3
8.9 Hz and two doublet of doublet signals with J8b–3a¼8.2–8.9;
3J8b–8a¼9.8–10.5 Hz and the shift of the doublet of multiplet signal
of H8a (4.5–4.7 ppm) for 0.6–0.8 ppm downfield in comparison
with the starting material. We can assume the all-cis-H structure by
analogy with similar tricyclic compounds reported by Viehe et al.16
that have coupling constants in the same range. Thus, cycloaddition
of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles 1 and
2 with maleimides 3 takes place in a stereoselective manner to
form endo-products.
The starting S,N-ketenacetals 1,2a–k were obtained by the
reaction of arylhydrazonoacetothioamides with the corresponding
haloalkanes as reported earlier.4 Reactions of 3-alkylsulfanyl-2-
arylazo-3-(pyrrolidin-1-yl)acrylonitriles 1,2 a–k with N-methyl-
and N-phenylmaleimides 3a–b have been carried out in benzene
at reflux in the presence of 5 equiv of dipolarophile for 0.5–10 h
resulting in solid products in good yields (71–98%) (Scheme 1,
Table 1). The IR-, mass-, 1H and 13C NMR spectra are in good
agreement with the structures of the tricyclic pyrrolo[3,4-a]pyr-
rolizines 4 and 5 and refute the structure of the initially proposed
pyridazines.4a The IR spectra of all prepared compounds exhibit
an absorption band corresponding to the cyano group at
The assignment of the signals in the 1H and 13C NMR spectra was
made on the base of DEPT, 2D COSY, HSQC, HMBC, NOESY experi-
ments. Cross-peaks between the aromatic proton and the C3a pro-
ton in the E-isomer and the aromatic proton with the proton at
position C6 are found in the NOESY spectra. The spin–spin couplings
of C4 and C40 with the C3a proton were confirmed by 2D COSY ex-
2200 cmꢀ1
.
Scheme 1.
periments. The signals of C40 are displayed at 102.8 and 103.9 ppm
as two doublets with coupling constants 3J¼1.3 and 0.6 Hz, and the
signals of C4 at 158.9 and 154.3 ppm with coupling constants with
H3a 2J¼6.4 and 3.4 Hz. The data of the NMR spectra confirm the
formation of two new bonds, namely, C4–C3a and C8b–C8a.
It is interesting to note that the measurement of the 1H NMR
spectra of compounds 4a has shown the degeneration of two dou-
blets for proton 3a and for the ortho-proton of the aromatics; first
they becamewiderandcloserandthen coalescencewasachieved for
the compound 4a at 120 ꢁC. This confirms the existence of two iso-
mers in equilibrium. The ratio of isomers at 25 ꢁC depends on the
nature of the substituent at the aromatic ring (Supplementary data).
The equilibrium is shifted in favor of the Z-isomer for compounds
with electron-withdrawing substituents and it is in favor of the E-
isomer for compounds with electron-releasing substituents.
Table 1
The time of conversion and yields of cycloadducts 4 and 5 for the reaction cyclo-
addition of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles 1 and 2 with
N-methyl- and N-phenylmaleimides 3
Entry Compounds 1 and 2
Reaction with 3a
(R1¼Me)
Reaction with 3b
(R1¼Ph)
N
Ar
R
Time of
conversion cycloadduct conversion cycloadduct
1 and 2 (h) 4 (%) 1 and 2 (h) 5 (%)
0.5
Yielda of
Time of
Yielda of
1
1a 4-NO2C6H4
Me
85
92
99
95
90
89
65
68
75
95
97
95
80
75
83
78
85
75
73
71
83
80
0.5
0.3
1.0
0.5
1.1
90
85
98
95
87
95
78
83
81
78
84
80
90
85
80
85
75
71
78
80
78
71
2
2a
Allyl 0.3
Me 1.0
Allyl 0.5
1.0
Allyl 0.5
Me 2.0
Allyl 1.5
Me 0.7
Allyl 0.5
Me 3.0
Allyl 0.5
3.5
Allyl 1.0
Me 3.0
Allyl 1.1
Me 5.5
3
1b 4-CF3C6H4
4
2b
5
1c 4-EtOOCC6H4 Me
6
2c
0.5
2.0
1.5
1.5
0.5
2.5
0.7
2.5
1.0
3.0
1.0
5.0
4.0
10.0
6.0
10.0
7.0
7
1d 2-CF3C6H4
8
2d
9
1e 2,4-Cl2C6H3
10
11
12
13
14
15
16
17
18
19
20
20
22
2e
2.2. Theoretical study of interaction of S,N-ketene acetals 1
and 2 with maleimide: generation of azomethine ylide and its
cycloaddition
1f 4-ClC6H4
2f
1g 2-Cl-4-MeC6H3 Me
2g
1h Ph
2h
1i 4-MeC6H4
2i
1j 4-EtOC6H4
2j
1k 4-MeOC6H4
2k
Depending on whether elimination of thiols take place either
from cycloaddition products or from starting compounds, in-
termediates for the reactions of thioaminals 1 and 2 with mal-
eimides can be presented as ylides A or B, respectively (Scheme 2).
Other mechanisms initiated by electrophilic/nucleophilic attack
were rejected since observed reaction proceeds in non-polar ben-
zene media.
Allyl 4.0
Me 10.0
Allyl 6.5
Me 10.0
Allyl 7.0
a
Yield after isolation and putification.
In path 1 the first step is a 1,6-hydrogen shift occuring in
compounds 1 and 2 yielding the intermediate A. In path 2 the
formation of the azomethine ylide is accomplished by elimination
It should be noted that compounds 4 and 5 are present as
a mixture of two isomers due to the fact that the intermediate
azomethine ylides can isomerize. Indeed, two sets of signals are
present in the NMR spectra. The most typical for the structures of
pyrrolopyrrolizine-4-ylidines is the presence of two doublets at
of HSR. Using the B3LYP density functional17 within a 6-31G
basis
*
set we explored two possible mechanisms of generation of azo-
methine ylides A and B. The structure of substrates was simplified:
no aryl substituent on nitrogen was taken into account (Scheme 3).

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N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
CN
R
S
number of references with a detailed explanation of this concept is
CN
R
S
CN
R
S
H
N
available elsewhere.20 To answer the question if there is a change of
mechanism one has to monitor the evolution of electron density
localization within the reaction coordinate interval. Moreover, the
aromaticity of the transition state should be determined, since
pseudopericyclic transition states should not exhibit any aroma-
ticity oppositely to the pericyclic transition states.
H
N
N
Ar
N
H
H
Ar
N
H
Ar
N
H
N
N
H
H
N
1,2
dipole A
-HSR
CN
The evolution of the orbitals interaction with the flow of the
reaction coordinate was done within a natural bond orbital (NBO)
localization scheme. This method in regard to this problem was
extensively tested and recognized as a powerful tool to distinguish
the participation of orbitals. NBO analysis was performed for the
points along the reaction pathway from 6 to dipole A. The pathway
was reconstructed in both directions starting at TSHshift by instrict
reaction coordinate (IRC) methodology. The screenshot presented
CN
N
Ar
N
N
Ar
N
N
N
dipole B
Scheme 2. The two proposed mechanisms for the generation of azomethine ylides.
in Figure 2 depicts the involvement of LP(N1) and
p
(N1¼N2) into
simultaneous of the new (N1–H7)-bond. The second order per-
s
turbation theory analysis of the Fock matrix in the NBO basis has
shown that both orbitals, the lone pair of electrons of nitrogen
*
LP(N1) and p(N1]N2), interact with the s (C6–H7) orbital, but the
contribution of LP(N1) was somewhat more significant. Also, the
decrease of orbital occupancy for the lone pair of electrons LP(N1)
was more than the lack of electron occupancy from the
orbital (1.972/1.857 vs 1.964/1.877).
p
(N1¼N2)
Although a number of aromaticity criteria has been described in
the literature,21 the screening of anisotropy of the induced current
density (ACID)21a,22 should be the preferred one in this case due to
the nonplanar geometry of the transition state. The calculated ACID
profile gave some more insights into the nature of the located
transition state for the transfer of hydrogen atom. This profile vi-
sually supports the evidence of the pericyclic nature of the transi-
tion state since the disconnection in the cyclic loop of the ACID
function was located only at the isocontour line of 0.061 a.u. (Fig. 3)
and not at the critical isocontour value less than 0.002 a.u. The
absence of a disconnection confirms the pericyclic nature of the
transition states as predicted for pseudopericyclic reactions by
Herges et al.21a
Scheme 3. The mechanism of cycloaddition via the dipole A.
According to calculations, the formation of dipole A is thermo-
dynamically more preferable than formation of dipole B. Dipole B
was located 31.8 kcal/mol above the dipole A (Supplementary data).
Therefore we concentrated our further efforts on the way leading to
ylide A only.
The transition state of the hydrogen transfer TSHshift from carbon
to nitrogen was successfully located at the B3LYP/6-31G level of
*
theory using the STQN method18 (Fig. 1). Distances between re-
action centers were r(C6/H7)¼1.497 Å and r(N1/H7)¼1.169 Å.
The activation barrier for the process of dipole formation was cal-
culated to be 14.9 kcal/mol.
The cycloaddition transition state TScycloadd of maleimide 7 to
dipole A was located 1.35 kcal/mol above the reactants energy level
(Fig. 1); distances between reaction centers were r(C6C30)¼2.251 Å
and (C4C40)¼2.745 Å. NBO analysis of TScycloadd confirms that in that
point two separate fragments are presented. The bonds C4C40 and
This located transition state has attracted our special attention.
Previously it was proposed by Lemal and later developed by
a number of authors, that if there is a lone pair of electrons in the
C6C30 are not formed yet. The stabilization provided by
p
(C30C40)/
(N5C6) interaction is more than the one given by the LP(C4)/
(C30C40) electron density shift, 16.66 kcal/mol versus 9.09 kcal/
p
*
plane orthogonal to the
p-system, the reaction mechanism for
p
*
a sigmatropic shift and other pericyclic reactions can switch from
pericyclic to pseudopericyclic.19
mol. No other remarkable secondary interactions were listed.
Concerning the energetics of this reaction, the cycloaddition of
maleimide 7 to 3-methylsulfanyl-2-azo-pyrrolidin-1-yl-acrylonitrile
So the reaction can proceed comparably easy due to reduction of
electron–electron repulsion thus lowering the activation barrier. A
Figure 1. Stationary points 6, TSHshift, dipole A, TScycloadd, 9 and energy profile for the reaction of 3-methylsulfanyl-2-azo-(pyrrolidin-1-yl)acrylonitrile 6 with maleimide 7 at the
B3LYP level.

N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
7665
Figure 2. The screenshot for orbital picture based on NBO analisis during the hydrogen shift.
CN
1
CN
3
2
3
2
N
S
S
N
1
Ar
N
Me
Me
4
4
N
Ar
N
N
6
6
H
7
H
7
5
5
1a,h,k
Conformer I
Conformer II
Scheme 4.
accordance with the experimental data for the time of conversion
of starting compounds 1 and 2 to final compounds 4 and 5.
We propose that the introduction of electron-withdrawing
substituents to the aromatic ring enhances the 1,6-proton shift. This
is in accordance with a 0.1 ppm downfield a
-CH2 shift of in the 1H
NMR spectra that should enhance its dissociation, when the
methoxy group at the aryl was replaced by nitro group. Within our
theoretical study we have determined atom charges, bond lenghts
of the azadiene system and occupancies of bonds in electrons to-
gether with the charges on the nitrogen atom and
the pyrrolidine ring in compounds 1a,h,k by the NBO method
(MP2/6-31G ) (Supplementary data). According to these data the
a-carbon atom of
*
charge on the nitrogen atom of the azo group N1 turns more
negative in the series of substituents at the aromatic ring 1a(4-
NO2C6H4)>1h(Ph)>1k(4-MeOC6H4). Hence, the hydrogen shift
should be enhanced in the same order.
As it is outlined above (Fig. 1) the activation barrier for hydrogen
shift is higher than for cycloaddition step. So any factor like de-
crease of relative thermodynamic stability of starting compounds
and increasing electron density, e.g., negative charge on N1 would
increase the rate of this reaction. This supports our theory that the
introduction of electron-withdrawing groups increases the conju-
gation of the nitrogen electron pair of the pyrrolidine ring with the
aromatic ring via the diene system. Remarkably, the N1–H7 bond
distance is shorter for the compounds that react faster (Supple-
mentary data).
To determine the role of the azo group in the interaction process
of S,N-acetals with maleimides, we have studied interaction of
ketene S,N-acetal 10, where the azo group is absent, with
N-methylmaleimide 3a (Scheme 5). We have shown that com-
pound 10 does not react with maleimide under any conditions
studied. It confirms the participation of the azo group in the gen-
eration process of the azomethine ylides from 1,2-diazadienes.
Figure 3. The ACID profile for transition state TSHshift at the CIV¼0.050 a.u.
6 was calculated to be exothermic by 20.45 kcal/mol (B3LYP/6-
31G ). The activation energy for the general process calculated in the
*
gas phase, is about 15 kcal/mol, which is consistent with experi-
mental conditions for the reaction of compounds 1 and 2 with
maleimides 3 in benzene at 80 ꢁC.
Experiments have shown that the time of conversion for com-
pounds 1 and 2 mainly depends on their structure (Table 1). The
introduction of electron-withdrawing substituents to the aryl
group and replacement of methyl by allyl in the alkylsulfanyl
moiety increase the rate of reaction.
We have carried out a number of estimations of the relative
stability of two of the possible conformers for compounds 1
(Scheme 4). A 1,6 hydrogen-shift can take place only in conformer
II. According to calculations in vacuum the difference in energy of
the conformers decreases in the following order: 1k(Ar¼4-
MeOC6H4)>1h(Ar¼Ph)>1a(Ar¼4-NO2C6H4) (Supplementary data).
In part, decreasing the relative stability of conformers is in
CN
NC
N
CN
S
O
O
N
NC
Me
+
X
N
N
benzene
Me
O
Me
O
11
10
3a
Scheme 5.

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N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
Indeed, the experimental and theoretical studies for the reaction
stereoselectivity for the cycloaddition with dimethyl maleate in
comparison to the same reaction with maleimide might be due to
the increased dipolarophile activity of dimethyl maleate and the
spatial hindrance between two COOCH3-groups in transition state.
The cycloaddition of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-yl)-
acrylonitriles 1 with DMAD was carried out in benzene at reflux
(Scheme 7). It should be noted that the complete conversion of
reaction is reached after 0.5–2.0 h and accompanied by the for-
mation of a mixture of quite a few products that were difficult to
separate to single components. Only in the case of compound 1a,
we managed to isolate a single product that was identified by
spectroscopic data as 6,7-dihydro-5H-pyrrolizine 14a.
of thioaminals 1 and 2 with maleimides 3 is consistent with the
mechanism outlined in the Scheme 2. First the generation of azo-
methine ylide A occurs via 1,6-sigmatropic shift of hydrogen from
pyrrolidine ring to N1 of the azo group. During the second step,
ylide A reacts with the double bond of the maleimides to give
cycloadducts 8. The latter looses a thiole molecule to give final
products 4 or 5.
The process proceeds stereoselectively via an endo-transition
state and the formation of two isomers can be explained by ster-
eomutation of the 1,3-dipole.
2.3. Reaction of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-
yl)acrylonitriles with dimethyl maleate and dimethyl
acetylenedicarboxylate
Ar
NC
E
N
CN
R
N
H
E
H
N
3'
2
R=Allyl
1
benzene
80 °C
E
N
3
Ar
S
E
N
+
1,2
N
7a
7
5
E
HSAllyl
Heating of ketene-S,N-acetals 1 with dimethyl maleate in ben-
zene followed by column chromatograpy allowed us to prepare
hexahydro-pyrrolizines 12 as an inseparable mixture of four ste-
reoisomers that are crystalline compounds of yellow or orange
color (Scheme 6).
H
E
14 a-g
6
E = COOMe
Ar=4-NO2C6H4
R=Me
13
HSMe
14
Ar
Yield, %
60
a 4-NO2C6H4
b 4-CF3C6H4
E
NC
63
H
N
c 4-EtO2CC6H4 41
E
d 2,4-Cl2C6H3
e 4-ClC6H4
36
46
N
COOMe
COOMe
NC
N
N
N
+
N
f
4-Me-2-ClC6H3 45
Ar
g
Ph
46
SMe
O2N
14a 40%
benzene
60 °C
1a-c,e
Scheme 7.
CN
5
H
COOMe
COOMe
H
CN
H
6
7
N
N
N
1
Ar
The use of compounds 2 bearing an S-allyl group allowed us to
prepare other derivatives of this series, compounds 14 a–g. The
mass-spectra of dihydropyrrolizines 14 exhibit peaks of molecular
ions with intensity of 9–36%.
N
Ar
N
+
2
N
7a
H
MeOOC
COOMe
12a-d
E
Z
IR spectra of these compounds contain bands at 2220, 1700 and
1740 cmꢀ1 corresponding to the cyano and two carbonyl groups,
respectively (Fig. 4).
12
a
b
c
d
Ar
4-NO2C6H4 4-CF3C6H4 4-EtOOCC6H4 2,4-Cl2C6H3
51 68 35
Scheme 6.
Yield,% 88
Their structures are consistent with their elemental analysis
and spectroscopic data. Thus mass-spectra of the prepared com-
pounds 12 contain peaks corresponding to their molecular masses.
IR spectra of all prepared compounds exhibit an broad absorption
bands corresponding to the cyano groups at 2200 cmꢀ1 and broad
absorption bands at 1715 and 1710 cmꢀ1 corresponding to car-
bonyl groups. The 1H NMR and 13C NMR spectra are complicated.
Several signals were combined, which hampered their assignment.
At the same time we have registered four doublet signals in the
range of 4.6–5 ppm corresponding to C2H with coupling constants
3J1–2¼8.5–9.5 Hz in the 1H NMR spectra and four singlets of C7a at
70 ppm in the 13C NMR spectra 12. 2D TOCSY and 1D TOCSY with
selective excitation allowed us to separate the 4 sets of signals for
protons of bicyclical fragments of four stereo isomers. Those are
resulted from the cis-, trans-isomerism for two double bonds
(C]C and N]N) combined with inversion occurred on the N1
atom.
Although relatively large coupling constants were observed
between H2 and H1, H1 and H7a (J¼8.3–10.5 Hz), the formation of
the exo/endo isomers should be taken into account. We admit that
all sets of signals are not typical for protons in trans position,
though analogously large coupling constants have also been ob-
served between a trans hydrogen atom in cyclopentane derivatives
bearing an electron-deficient substituent.23 The observed lack of
Figure 4. The X-ray data of 3-[cyano-(phenylhydrazono)methyl]-6,7-dihydro-5H-
pyrrolizine-1,2-dicarboxylic acid dimethyl ester 14g.
The formation of pyrrolizidines 14 was proposed to be a three-
step process. Firstly, the generation of azomethine ylides of dipole A
type occurred, followed by cycloaddition with DMAD. The elimi-
nation of methyl- or allylthiol from adducts 13 finalized the whole
process.
3. Conclussion
In conclusion, we have demonstrated a new approach leading to
the generation of azomethine ylides under mild conditions. A series
of new pyrrolo[3,4-a]pyrrolizin-4-ylidenes
4
and
5
were

N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
7667
synthesized efficiently by 1,3-dipolar cycloaddition of 3-alkylsul-
fanyl-2-arylazo-3-(pyrrolidin-1-yl)acrylonitriles and with
s, 3H, NMe), 3.75 (dd, 1H, J¼8.5, 9.9 Hz, CH), 3.77–3.89 (m, 2H, CH2),
4.51–4.82 (m, 1H, CH2), 4.87 and 5.17 (d and d, 1H, J¼8.5 Hz, CH),
7.68 and 7.94 and 8.25 (AA0XX0 and AA0XX0, 4H, J¼9.1 Hz, Ar)
(mixture of Z- and E-isomers in ratio 58:42). MS m/z (%) 380 (Mþ,
51). Anal. Calcd for C18H16N6O4: C, 56.84; H, 4.24; N, 22.09. Found:
C, 56.72; H, 4.19; N, 21.97%.
1
2
maleimides. Experimental and theoretical investigation of the
mechanisms of these reactions by DFT calculations allowed us to
conclude that although the azo group is not included into the cyclic
products it effects the mechanism of the generation of the azo-
methine ylides. The process depends on the type of the structural
fragments on the sulfur and at the aromatic ring. The 1,3-dipolar
cycloaddition reaction of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-
1-yl)acrylonitriles could be expanded to other electron-poor
dipolarophiles such as dimethyl maleate and dimethyl
acetylenedicarboxylate. 3-Alkylsulfanyl-2-arylazo-3-(pyrrolidin-
1-yl)acrylonitriles 1 and 2 are shown to be masked azomethine
ylides that react with dipolarophiles via a concerted mechanism.
Investigations of the scope of these reactions are in progress.
4.2.2. (4-Trifluoromethylphenylazo)-(2-methyl-1,3-dioxo-
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (4b)
Yellow powder; yield 200 mg (99%) from 1b and 191 mg (92%)
from 2b; mp 313–315 ꢁC; IR (KBr) nmax 2955 (CH2), 2200 (CN),
1710 (CO) cmꢀ1 1H NMR dH 1.37–1.49 (m, 1H, CH), 1.94–2.05 (m,
;
1H, CH2), 1.12–2.25 (m, 2H, CH2), 2.85 and 2.87 (s and s, 3H, Me),
3.70–3.88 (m, 3H, CH), 4.55–4.64 (m, 1H, CH), 4.85 and 5.18 (d and
d, 1H, J¼8.6 Hz, CH), 7.69 (d, 1H, J¼8.1 Hz, Ar), 7.79 (d, 2H,
J¼7.6 Hz, Ar), 7.93 (d, 1H, J¼8.1 Hz, Ar) (mixture of Z- and E-iso-
mers in ratio 57:43). MS m/z (%) 403 (Mþ, 20.4). Anal. Calcd for
C19H16F3N5O2: C, 56.58; H, 4.00; N, 17.36. Found: C, 56.52; H, 3.96;
N, 17.29%.
4. Experimental
4.1. General considerations
The IR data (potassium bromide) were obtained with an UR-20
spectrometer. The 1H NMR and 13C NMR spectra were recorded on
Bruker DRX-400 instrument (400 MHz for 1H and 100 MHz for 13C)
in DMSO-d6 solvent with TMS as a standard. Chemical shifts and
coupling constants were expressed in ppm and Hz. Mass spectra
were recorded on a Varian MAT 311A mass spectrometer using the
electron impact ionization technique (40–200 ꢁC, 70 eV). Single
crystal X-ray diffraction analyses were performed on a Bruker
SMART APEXIICCD area-detector diffractometer.
Column chromatography was performed on silica gel (0.035–
0.070, 60 Å) with chloroform/acetone (30:1). Routine monitoring of
reactions was made using thin layer chromatography monitored by
TLC was performed on Sorbfil UV–254. Solvents were dried and
distilled according to the common procedure.
4.2.3. 4-[Cyano-(2-methyl-1,3-dioxooctahydropyrrolo-[3,4-
a]pyrrolizin-4-ylidene)-methyl]-azobenzoic acid ethyl ester (4c)
Yellow powder; yield 183 mg (90%) from 1c and 181 mg (89%)
from 1c; mp 255–257 ꢁC; IR (KBr) nmax 2950 (CH2), 2200 (CN), 1705
(CO) cmꢀ1
;
1H NMR dH 1.37 and 1.38 (t and t, 3H, J¼7.0 Hz, Me),
1.43–1.59 (m, 1H, CH2), 1.97–2.12 (m, 1H, CH2), 2.15–2.36 (m, 2H,
CH2), 2.89 and 2.91 (s and s, 3H, Me), 3.63–3.92 (m, 3H, CH2), 4.32
and 4.33 (q and q, 2H, J¼7.0 Hz, CH2), 4.48–4.67 (m, 1H, CH2), 4.83
and 5.14 (d and d, 1H, J¼8.5 Hz, CH), 7.58 (d, 1H, J¼8.8 Hz, Ar), 7.83
(d, 1H, J¼8.8 Hz, Ar), 8.0 (d, 2H, J¼8.8 Hz, Ar) (mixture of Z- and E-
isomers in ratio 57:43). MS m/z (%) 407 (Mþ, 35.9). Anal. Calcd for
C21H21N5O4: C, 61.91; H, 5.20; N, 17.19. Found: C, 61.85; H, 5.16; N,
17.03%.
3-Alkylsulfanyl-2-arylazo-3-pyrrolidin-1-yl-acrylo-nitriles 1 and
4.2.4. (2-Trifluoromethylphenylazo)-(2-methyl-1,3-dioxo-
2 were prepared by the procedure reported in our previous articles.4
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (4d)
Dark yellow powder; yield 131 mg (65%) from 1d and 137 mg
(68%) from 2d; mp 245–247 ꢁC; IR (KBr) nmax 2980 (CH2), 2200
4.1.1. Computational details
All calculations were carried out using the Gaussian03W pack-
age.24 Geometries were completely optimized using Becke’s hybrid
HF density functional theory method17 with the Lee–Yang–Parr
correlation functional25 and the 6-31G(d) basis set [B3LYP/6-
31G(d)]. The nature of the various critical points was established by
performing frequency computations. IRC calculations24 were also
performed for transition-state structures. The NBO analysis25 was
performed to explore the electronic structure of located stationary
points [MP2/6-31G(d)]. ACID calculations were performed at
B3LYP/6-31G(d) level. To estimate the energetic of isomerism for of
1a,h,k, both possible conformers have optimized at MP2/6-31G(d)
level of theory. All visualization was done with the gOpenMol
program.26
(CN), 1710 (CO) cmꢀ1 1H NMR dH 1.36–1.50 (m, 1H, CH2), 1.94–
;
2.04 (m, 1H, CH2), 1.13–2.25 (m, 2H, CH2), 2.85 and 2.87 (s and s,
3H, Me), 3.68–3.85 (m, 3H, CH), 4.54–4.63 (m, 1H, CH), 4.84 and
5.19 (d and d, 1H, J¼8.3 Hz, CH), 7.42–7.48 (m, 1H, Ar), 7.68 (dd,
1H, J¼7.7, 0.8 Hz, Ar), 7.77 (dd, 1H, J¼7.7, 0.8 Hz, Ar), 7.51 and
8.03 (d and d, 1H, J¼8.1 Hz, Ar) (mixture of Z- and E-isomers in
ratio 60:40). MS m/z (%) 403 (Mþ, 17.9). Anal. Calcd for
C19H16F3N5O2: C, 56.58; H, 4.00; N, 17.36. Found: C, 56.55; H,
3.94; N, 17.14%.
4.2.5. (2,4-Dichlorophenylazo)-(2-methyl-1,3-dioxo-
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (4e)
Yellow powder; yield 151 mg (75%) from 1e and 175 mg (92%)
from 2e; mp 304–306 ꢁC; IR (KBr) nmax 2965 (CH2), 2190 (CN),
4.2. Reaction of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-
yl)acrylonitriles with maleimides
1700 (CO) cmꢀ1 1H NMR dH 1.53–1.40 (m, 1H, CH), 1.99–2.07 (m,
;
1H, CH2), 2.08–2.38 (m, 2H, CH2), 2.89 and 2.92 (s and s, 3H, Me),
3.62–3.83 (m, 3H, CH), 4.51–4.67 (m, 1H, CH2), 4.83 and 5.13 (d and
d, 1H, J¼8.2 Hz, CH), 7.22–7.32 (m, 2H, Ar), 7.48 (dd, 1H, J¼7.1,
2.4 Hz, Ar), 7.91 (d, 1H, J¼8.7 Hz, Ar) (mixture of Z- and E-isomers
in ratio 66:34). MS m/z (%) 403 (Mþ, 33.2). Anal. Calcd for
C18H15Cl2N5O2: C, 53.48; H, 3.74; N, 17.32. Found: C, 53.41; H, 3.68;
N, 17.30%.
General procedure: A solution of 0.5 mmol 1 or 2 and 2.5 mmol
corresponding maleimide 3a,b was refluxed in 5 mL benzene (TLC).
The reaction mixture was evaporated and purified by column
chromatography.
4.2.1. (4-Nitrophenylazo)-(2-methyl-1,3-dioxo-octahydro-
pyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (4a)
4.2.6. (4-Chlorophenylazo)-(2-methyl-1,3-dioxo-octa-
Yellow crystals; yield 162 mg (85%) from 1a and 175 mg (92%)
from 2b; yield 162 mg (85%); mp 278–280 ꢁC; IR (KBr) nmax 2965
(CH2), 2200 (CN), 1710 (CO) cmꢀ1; 1H NMR dH 1.34–1.62 (m, 1H, CH),
1.92–2.13 (m, 1H, CH2), 2.14–2.40 (m, 2H, CH2), 2.88 and 2.90 (s and
hydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (4f)
Yellow powder; yield 178 mg (97%) from 1f and 175 mg (95%)
from 2f; mp 278–180 ꢁC; IR (KBr) nmax 2960 (CH2), 2200 (CN), 1710
(CO) cmꢀ1 1H NMR dH 1.32–1.55 (m, 1H, CH2), 1.94–2.11 (m, 1H,
;

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N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
CH2), 2.12–2.31 (m, 2H, CH2), 2.88 and 2.90 (s and s, 3H, Me), 3.61–
3.88 (m, 3H, CH), 4.45–4.63 (m, 1H, CH), 4.78 and 5.11 (d and d, 1H,
J¼8.4 Hz, CH), 7.39 and 7.52 and 7.75 (AA0XX0, 4H, J¼8.8 Hz, Ar)
(mixture of Z- and E-isomers in ratio 57:43). MS m/z 368 (Mþ, 27.1).
Anal. Calcd for C18H16ClN5O: C, 58.62; H, 4.10; N, 18.94. Found: C,
58.57; H, 4.08; N, 18.83%.
17.9). Anal. Calcd for C20H21N5O3: C, 63.31; H, 5.58; N, 18.46. Found:
63.27; H, 5.52; N, 18.42%.
4.2.11. (4-Methoxyphenylazo)-(2-methyl-1,3-dioxo-octa-
hydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (4k)
Yellow powder; yield 151 mg (83%) from 1k and 146 mg (80%)
from 2k; mp 259–261 ꢁC; IR (KBr) nmax 2965 (CH2), 2195 (CN), 1705
(CO) cmꢀ1; 1H NMR dH 1.27–1.52 (m, 1H, CH), 1.95–2.11 (m, 1H, CH),
2.12–2.32 (m, 2H, CH2), 2.89 and 2.91 (s, 3H, NMe), 3.62–3.93 (m,
3H, CH and CH2), 3.82 (s, 3H, OMe), 4.43–4.58 (m, 1H, CH), 4.74 and
5.10 (d and d, 1H, J¼8.8 Hz, CH), 7.70 and 7.92 (AA0XX0, 4H, J¼8.8 Hz,
Ar); 13C NMR dC 25.15, 25.2, 26.4, 26.6, 26.7, 26.9, 40.3, 40.5, 46.1,
48.9, 55.3, 56.7, 56.8, 69.3, 69.8,102.4,103.4,114.0,114.4,114.8,115.1,
122.7, 123.1, 146.7,147.0, 153.4, 158.2, 159.2, 159.4, 172.0, 172.8, 174.5,
174.6 (mixture of Z- and E-isomers in ratio 46:54). MS m/z (%) 365
(Mþ, 17.9). Anal. Calcd for C19H19N5O3: C, 62.46; H, 5.24; N, 19.17.
Found: C, 62.39; H, 5.32; N, 19.09%.
4.2.7. (2-Chloro-4-methylphenylazo)-(2-methyl-1,3-dioxo-
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (4g)
Yellow powder; yield 153 mg (80%) from 1g and 144 mg (75%)
from 2g; mp 301–303 ꢁC; IR (KBr) nmax 2955 (CH2), 2200 (CN), 1710
(CO) cmꢀ1 1H NMR dH 1.35–1.55 (m, 1H, CH2), 1.97–2.13 (m, 1H,
;
CH2), 2.15–2.2 (m, 2H, CH2), 2.36 (s, 3H, Me), 2.89 and 2.92 (s and s,
3H, Me), 3.7–3.8 (m, 3H, CH2), 4.48–4.63 (m, 1H, CH), 4.80 and 5.12
(d and d, 1H, J¼8.4 Hz, CH), 7.07 (d, 1H, J¼7.7 Hz, Ar), 7.18–7.30 (m,
1.5H, Ar), 7.77 (d, 0.5H, J¼8.1 Hz, Ar); 13C NMR dC 20.3, 25.2, 25.3,
26.2, 26.4, 26.7, 26.9, 40.0, 40.4, 45.9, 48.9, 55.1, 57.2, 69.9, 70.3,
103.3, 104.6, 114.3, 114.7, 117.3, 118.7, 128.1, 128.5, 130.0, 130.4, 130.5,
130.8, 138.8, 139.2, 146.6, 146.8, 154.7, 159.2, 172.5, 171.9, 174.4, 174.5
(mixture of Z- and E-isomers in ratio 56:44). MS m/z (%) 383 (Mþ,
25.8). Anal. Calcd for C19H18ClN5O2: C, 59.45; H, 4.73; N, 17.51.
Found: C, 59.37; H, 4.64; N, 17.47%.
4.2.12. (4-Nitrophenylazo)-(1,3-dioxo-2-phenyl-octa-
hydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (5a)
Yellow powder; yield 198 mg (90%) from 1a and 188 mg (85%)
from 1b; mp 273–275 ꢁC; IR (KBr) nmax 2950 (CH2), 2200 (CN),
1720 (CO) cmꢀ1 1H NMR dH 1.53–1.69 (m, 1H, CH2), 2.13–1.99 (m,
;
4.2.8. Phenylazo-(2-methyl-1,3-dioxo-octahydropyrrolo-
[3,4-a]pyrrolizin-4-ylidene)acetonitrile (4h)
1H, CH2), 2.40–2.16 (m, 2H, CH2), 4.06–3.73 (m, 3H, CH and CH2),
4.79–4.66 (m, 1H, CH), 5.04 and 5.36 (d and d, 1H, J¼8.4 Hz, CH),
7.28–7.59 (m, 5H, Ar), 7.72 (d, 1H, J¼8.8 Hz, Ar), 7.89 (d, 1H,
J¼8.7 Hz, Ar), 8.27 (d, 1H, J¼8.7 Hz, Ar), 8.29 (d, 1H, J¼8.7 Hz, Ar);
13C NMR dC 26.2, 26.4, 26.8, 27.0, 30.7, 35.7, 46.2, 49.5, 57.8, 57.9,
70.9, 71.4, 104.0, 105.3, 114.1, 114.4, 121.8, 122.1, 124.8, 125.0, 127.3,
127.5, 128.7, 128.8, 132.2, 132.5, 145.5, 145.6, 156.3, 156.8, 157.2,
160.5, 162.3, 170.8, 171.5, 173.6, 173.7 (mixture of Z- and E-isomers
in ratio 59:41). MS m/z (%) 442 (Mþ, 95.2). Anal. Calcd for
C23H18N6O4: C, 62.44; H, 4.10; N, 18.99. Found: C, 62.36; H, 4.00; N,
18.76%.
Yellow powder; yield 140 g (83%) from 1h and 131 mg (78%)
from 2h; mp 314–316 ꢁC; IR (KBr) nmax 2965 (CH2), 2200 (CN), 1710
(CO) cmꢀ1; 1H NMR dH 1.30–1.52 (m, 1H, CH), 1.94–2.10 (m, 1H, CH),
2.12–2.30 (m, 2H, CH2), 2.88 and 2.90 (s and s, 3H, N–Me), 3.62–3.92
(m, 3H, CH and CH2), 4.45–4.62 (m, 1H, CH), 4.78 and 5.13 (d and d,
1H, J¼8.8 Hz, CH), 7.21–7.32 (m, 1H, Ar), 7.35–7.45 (m, 2H, Ar), 7.40
(d, 4H, 1H, J¼7.8 Hz, Ar), 7.55 (d, 4H, 1H, J¼7.8 Hz, Ar) (mixture of Z-
and E-isomers in ratio 50:50). MS m/z (%) 335 (Mþ, 25). Anal. Calcd
for C18H17N5O2: C, 64.47; H, 5.11; N, 20.88. Found: C, 64.26; H, 5.05;
N, 20.96%.
4.2.13. (4-Trifluorophenylazo)-(1,3-dioxo-2-phenyl-
4.2.9. (2-Methyl-1,3-dioxo-octahydropyrrolo[3,4-a]pyrrolizin-4-
ylidene)-p-tolylazoacetonitrile (4i)
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)acetonitrile (5b)
Yellow powder; yield 228 mg (98%) from 1b and 220 mg (95%)
from 2b; mp 281–283 ꢁC; IR (KBr) nmax 2955 (CH2), 2200 (CN), 1710
(CO) cmꢀ1; 1H NMR dH 1.55–1.65 (m, 1H, CH), 1.99–2.08 (m, 1H, CH),
2.17–2.34 (m, 2H, CH2), 3.75–3.97 (m, 3H, CH), 4.63–4.74 (m, 1H,
CH), 5.0 and 5.34 (d and d, 1H, J¼8.6 Hz, CH), 7.34 (dd, 2H, J¼6.3,
8.2 Hz, Ar), 7.40–7.55 (m, 3H, Ar), 7.69–7.83 (m, 3H, Ar), 7.88 (d, 1H,
J¼8.9 Hz, Ar) (mixture of Z- and E-isomers in ratio 58:42). MS m/z
(%) 465 (Mþ, 23.9). Anal. Calcd for C24H18F3N5O2: C, 61.93; H, 3.90;
N, 15.05. Found: C, 61.86; H, 3.86; N, 14.96%.
Yellow powder; yield 148 g (85%) from 1i and 130 mg (75%)
from 2i; mp 305–307 ꢁC; IR (KBr) nmax 2955 (CH2), 2190 (CN), 1710
(CO) cmꢀ1 1H NMR dH 1.30–1.52 (m, 1H, CH2), 1.93–2.11 (m, 1H,
;
CH2), 2.12–2.31 (m, 2H, CH2), 2.37 (s, 3H, Me), 2.88 and 2.91 (s and
s, 3H, Me), 3.60–3.93 (m, 3H, CH), 4.40–4.62 (m, 1H, CH), 4.76 and
5.10 (d and d, 1H, J¼8.6 Hz, CH), 7.19 and 7.42 and 7.20 and 7.65
(AA00XX0, 4H, J¼8.4 Hz, Ar); 13C NMR dC 20.8, 25.2, 25.3, 26.4, 26.6,
26.8, 26.9, 39.9, 40.1, 46.1, 48.9, 56.9, 57.0, 69.5, 70.0, 102.5, 103.6,
114.8, 115.1, 121.2, 121.6, 129.4, 129.7, 137.5, 137.9, 150.6, 150.9,
154.1, 158.7, 172.0, 172.8, 174.6, 174.7 (mixture of Z- and E-isomers
in ratio 48:52). MS m/z (%) 349 (Mþ, 20.9). Anal. Calcd for
C19H19N5O2: C, 65.32; H, 5.48; N, 20.04. Found: C, 65.25; H, 5.43;
N, 19.89%.
4.2.14. 4-{[Cyano-(1,3-dioxo-2-phenyl-octahydro-pyrrolo[3,4-
a]pyrrolizin-4-ylidene)-methyl]-azo}-benzoic acid ethyl ester (5c)
Yellow powder; yield 205 mg (87%) from 1c and 223 mg (95%)
from 1c; mp 235–237 ꢁC; IR (KBr) nmax 2950 (CH2), 2200 (CN), 1715
(CO) cmꢀ1
;
1H NMR dH 1.36 and 1.38 (t and t, 3H, J¼7.3 Hz, Me),
4.2.10. (4-Ethoxyphenylazo)-(2-methyl-1,3-dioxo-octa-
hydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (4j)
1.51–1.73 (m, 1H, CH2), 2.02–2.17 (m, 1H, CH2), 2.17–2.41 (m, 2H,
CH2), 3.83 (dd, 1H, J¼8.8, 10.5 Hz, CH), 3.85–4.03 (m, 2H, CH2), 4.30
and 4.32 (q and q, 2H, J¼7.3 Hz, CH2), 4.57–4.75 (m, 1H, CH2), 4.98
and 5.29 (d and d, 1H, J¼8.8 Hz, CH), 7.24–7.54 (m, 5H, Ar), 7.60 (d,
1H, J¼8.7 Hz, Ar), 7.79 (d, 1H, J¼8.7 Hz, Ar), 7.98 (d, 1H, J¼8.7 Hz,
Ar), 8.02 (d, 1H, J¼8.7 Hz, Ar) (mixture of Z- and E-isomers in ratio
60:40). MS m/z (%) 469 (Mþ, 63.7). Anal. Calcd for C26H23N5O4: C,
66.51; H, 4.94; N, 14.92. Found: C, 66.48; H, 4.89; N, 14.86%.
Yellow powder; yield 138 g (73%) from 1j and 135 mg (71%) from
2j; mp 259–261 ꢁC; IR (KBr) nmax 2955 (CH2), 2200 (CN), 1710 (CO)
cmꢀ1; 1H NMR dH 1.29–1.43 (m, 1H, CH2), 1.35 and 1.34 (t and t, 3H,
J¼7.0 Hz, Me), 1.90–2.01 (m, 1H, CH), 2.09–2.23 (m, 2H, CH), 2.84
and 2.86 (s and s, 3H, Me), 3.61–3.84 (m, 3H, CH), 4.06 and 4.07 (q
and q, 2H, J¼7.0 Hz, CH2), 4.46–4.55 (m, 1H, CH), 4.75 and 5.11 (d
and d, 1H, J¼8.7 Hz, CH), 6.93 and 6.98 (d and d, 2H, J¼8.8 Hz, Ar),
7.51 and 7.71 (d and d, 2H, J¼8.8 Hz, Ar); 13C NMR dC 14.59, 14.6,
25.2, 25.3, 26.4, 26.6, 26.8, 26.9, 40.3, 40.6, 46.1, 48.9, 56.7, 56.8,
63.2, 63.3, 69.4, 69.8, 102.4, 103.5, 114.5, 114.8, 114.9, 115.2, 122.8,
123.1, 146.6, 146.9, 153.5, 158.2, 158.6, 158.8, 172.1, 172.9, 174.6, 174.7
(mixture of Z- and E-isomers in ratio 35:65). MS m/z (%) 379 (Mþ,
4.2.15. (2-Trifluoromethylphenylazo)-(1,3-dioxo-2-phenyl-
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (5d)
Orange powder; yield 181 mg (78%) from 1d and 193 mg (83%)
from 1d; mp 258–260 ꢁC; IR (KBr) nmax 2980 (CH2), 2200 (CN), 1720
(CO) cmꢀ1; 1H NMR dH 1.51–1.63 (m, 1H, CH), 1.99–2.08 (m, 1H, CH),

N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
7669
2.17–2.34 (m, 2H, CH2), 3.75–3.98 (m, 3H, CH), 4.63–4.72 (m, 1H,
CH), 4.99 and 5.35 (d and d, 1H, J¼8.9 Hz, CH), 7.34 (dd, 2H, J¼6.4,
7.6 Hz, Ar), 7.39–7.56 (m, 4.4H, Ar), 7.62–7.81 (m, 2H, Ar), 7.94 (d,
J¼8.3 Hz, 0.6H, Ar) (mixture of Z- and E-isomers in ratio 61:39). MS
m/z (%) 465 (Mþ, 20.8). Anal. Calcd for C24H18F3N5O2: C, 61.93; H,
3.90; N, 15.05. Found: C, 61.88; H, 3.87; N, 14.89%.
(CO) cmꢀ1; 1H NMR dH 1.49–1.61 (m, 1H, CH), 1.98–2.07 (m, 1H, CH),
2.14–2.30 (m, 2H, CH2), 2.33 and 2.32 (s, 3H, Me), 3.71–3.90 (m, 2H,
CH), 3.90 and 3.94 (dd and dd, 1H, J¼8.7, 10.5 Hz, CH), 4.58–4.69 (m,
1H, CH), 4.95 and 5.31 (d and d, 1H, J¼8.7 Hz, CH), 7.25–7.36 (m,
3H,Ar), 7.38–7.54 (m, 5H, Ar), 7.76 and 7.57 (d and d, 1H, J¼8.2 Hz,
Ar), 7.51 and 7.21 (AA0XX0, 2H, J¼8.1 Hz, Ar); 13C NMR dC 20.7 (dt,
J¼126.4, 4.3 Hz, Me), 20.8 (dt, J¼126.6, 4.4 Hz, Me), 26.7 (m, C(8)),
26.5 (m, C(8)), 26.9 (m, C(7)), 26.8 (m, C(7)), 40.6 (m, C(8b)), 40.3
(m, C(8b)), 46.4 (t, C(6), J¼146.3 Hz), 49.2 (t, C(6), J¼147.5 Hz), 56.9
(dd, C(3a), J¼148.6, 2.1 Hz), 57.1 (dd, C(3a), J¼147.1, 2.1 Hz), 69.8 (d,
C(8a), J¼150.1 Hz), 70.3 (d, C(8a), J¼150.7 Hz), 102.8 (d, C(4), J¼0.6
Hz), 103.9 (d, C(40), J¼1.2 Hz), 114.8 (CN), 115.2 (CN), 121.2 (dd,
J¼161.0, 5.1 Hz, C(Ar)), 121.6 (dd, J¼161.0, 5.4 Hz, C(Ar)), 127.3 (d,
J¼163.1 Hz, C(Ar)), 127.5 (d, J¼163.6 Hz, C(Ar)),128.6 (d, J¼158.3 Hz,
C(Ar)), 128.7 (d, J¼158.0 Hz, C(Ar)), 128.8 (d, J¼157.1 Hz, C(Ar)),
128.8 (d, J¼157.3 Hz, C(Ar)), 129.4 (d, J¼158.0 Hz, C(Ar)), 129.7 (d,
J¼158.1 Hz, C(Ar)), 132.2 (dd, J¼10.1, 9.2 Hz, C(Ar)), 132.5 (ddd,
J¼9.3, 7.7, 1.5 Hz, C(Ar)), 137.46 (dddd, J¼8.9, 6.8, 5.2, 4.1 Hz, C(Ar)),
137.9 (ddd, J¼6.5, 7.7, 6.5 Hz, C(Ar)), 150.6 (C(Ar)), 150.9 (C(Ar)),
154.3 (ddd, J¼3.4, 1.7, 1.7 Hz, C(4)), 158.9 (d, J¼6.4 Hz, C(4)), 171.9
(dd, J¼7.5, 4.1 Hz, CO), 171.1 (dd, J¼7.4, 4.3 Hz, CO), 173.8 (m, CO),
173.9 (m, CO) (mixture of Z- and E-isomers in ratio 46:54). MS: m/z
(%) 411 (Mþ, 21). Anal. Calcd for C24H21N5O2: C, 70.06; H, 5.14; N,
17.02. Found: C, 69.91; H, 5.05; N, 16.84%.
4.2.16. (2,4-Dichlorophenylazo)-(1,3-dioxo-2-phenyl-
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)acetonitrile (5e)
Yellow powder; yield 189 mg (81%) from 1e and 182 mg (78%)
from 2e; mp 243–245 ꢁC; IR (KBr) nmax 2960 (CH2), 2215 (CN), 1725
(CO) cmꢀ1 1H NMR dH 1.58–1.69 (m, 1H, CH2), 2.05–2.17 (m, 1H,
;
CH), 2.17–2.38 (m, 2H, CH2), 3.80–3.99 (m, 3H, CH2), 4.72–4.60 (m,
1H, CH), 4.98 and 5.28 (d and d, 1H, J¼8.9 Hz, CH), 7.22–7.50 (m,
7H, Ar), 7.84 (d, 1H, J¼8.6 Hz, Ar) (mixture of Z- and E-isomers in
ratio 70:30). MS m/z (%) 466 (Mþ, 10.1). Anal. Calcd for
C23H17Cl2N5O2: C, 59.24; H, 3.67; N, 17.19. Found: C, 59.19; H, 3.61;
N, 17.03%.
4.2.17. (4-Chlorophenylazo)-(1,3-dioxo-2-phenyl-
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)acetonitrile (5f)
Yellow powder; yield 181 mg (84%) from 1f and 172 mg (80%)
from 2f; mp 217–219 ꢁC; IR (KBr) nmax 2955 (CH2), 2195 (CN), 1718
(CO) cmꢀ1 1H NMR dH 1.49–1.62 (m, 1H, CH2), 1.98–2.07 (m, 1H,
;
CH2), 2.14–2.31 (m, 2H, CH2), 3.90 and 3.94 (dd and dd, 1H, J¼8.7,
9.8 Hz, CH), 3.73–3.87 (m, 2H, CH2), 4.59–4.69 (m, 1H, CH), 4.98 and
5.29 (d and d, 1H, J¼8.7 Hz, CH), 7.30–7.36 (m, 2H, Ar), 7.42–7.53 (m,
2H, Ar), 7.47 (d, 1H, J¼8.8 Hz, Ar), 7.50 (d, 1H, J¼8.8 Hz, Ar), 7.57 (d,
1H, J¼8.8 Hz, Ar), 7.73 (d, 1H, J¼8.8 Hz, Ar). MS m/z (%) 431 (Mþ,
32.4). Anal. Calcd for C23H18ClN5O2: C, 63.97; H, 4.20; N, 16.22.
Found: C, 63.92; H, 4.17; N, 16.14%.
4.2.21. (1,3-Dioxo-2-phenyl-octahydropyrrolo[3,4-a]pyrrolizin-4-
ylidene)-(4-ethoxyphenylazo)acetonitrile (5j)
Yellow powder; yield 172 mg (78%) from 1j and 176 mg (80%)
from 2j; mp 254–256 ꢁC; IR (KBr) nmax 2955 (CH2), 2200 (CN),
1720 (CO) cmꢀ1
;
1H NMR dH 1.33 and 1.34 (t and t, 3H, J¼7.0 Hz,
Me), 1.45–1.59 (m, 1H, CH2), 1.95–2.06 (m, 1H, CH2), 2.10–2.31 (m,
2H, CH2), 3.70–3.86 (m, 2H, CH2), 3.89 and 3.93 (dd and dd, 1H,
J¼8.5, 10.6 Hz, CH), 4.05 and 4.07 (q and q, 2H, J¼7.0 Hz, CH2),
4.56–4.67 (m, 1H, CH), 4.93 and 5.28 (d and d, 1H, J¼8.5 Hz, CH),
7.30–7.36 (m, 2H, Ar), 7.42–7.56 (m, 3H, Ar), 6.95 and 7.68 and 7.00
and 7.73 (AA0XX0 and AA0XX0, 4H, J¼9.0 Hz, Ar); 13C NMR dC 14.6,
26.6, 26.7, 26.8, 26.9, 40.4, 40.7, 46.5, 49.2, 56.8, 59.9, 63.2, 63.3,
69.6, 70.1, 102.7, 103.7, 114.5, 114.8, 114.9, 115.3, 122.8, 123.1, 127.3,
127.5, 128.6, 128.7, 128.8, 128.9, 132.2, 132.5, 146.6, 146.9, 153.6,
153.7, 158.5, 158.8, 171.2, 172.0, 173.9, 174.0 (mixture of Z- and E-
isomers in ratio 36:64). MS m/z (%) 441 (Mþ, 1.9). Anal. Calcd for
C25H23N5O3: C, 68.01; H, 5.25; N, 15.86. Found: C, 67.98; H, 5.21; N,
15.81%.
4.2.18. (2-Chloro-4-methylphenylazo)-(1,3-dioxo-2-phenyl-
octahydropyrrolo[3,4-a]pyrrolizin-4-ylidene)-acetonitrile (5g)
Yellow powder; yield 200 mg (90%) from 1g and 189 mg (85%)
from 2g; mp 281–283 ꢁC; IR (KBr) nmax 2955 (CH2), 2200 (CN), 1720
(CO) cmꢀ1; 1H NMR dH 1.51–1.70 (m, 1H, CH), 2.03–2.16 (m, 1H, CH),
2.18–2.34 (m, 2H, CH2), 2.34 and 2.36 (s and s, 3H, Me), 3.76–3.99
(m, 3H, CH), 4.96 and 5.28 (d and d, 1H, J¼8.6 Hz, CH), 7.06 (dd, 1H,
J¼7.3, 7.8 Hz, Ar), 7.20–7.37 (m, 3H, Ar), 7.37–7.54 (m, 2.4H, Ar),
7.57–7.72 (m, 1H, CH), 7.70 (d, 0.6H, J¼7.8 Hz, Ar) (mixture of Z- and
E-isomers in ratio 58:42). MS m/z (%) 445 (Mþ, 26.2). Anal. Calcd for
C24H20ClN5O2: C, 64.65; H, 4.52; N, 15.71. Found: C, 64.61; H, 4.48;
N, 15.68%.
4.2.22. (1,3-Dioxo-2-phenyl-octahydropyrrolo[3,4-a]pyrrolizin-4-
ylidene)-(4-methoxyphenylazo)acetonitrile (5k)
4.2.19. (1,3-Dioxo-2-phenyloctahydropyrrolo[3,4-a]pyrrolizin-4-
ylidene)-phenylazoacetonitrile (5h)
Yellow powder; yield 167 mg (78%) from 1k and 151 mg (71%)
from 2k; mp 237–239 ꢁC; IR (KBr) nmax 2950 (CH2), 2200 (CN), 1720
(CO) cnꢀ1; 1H NMR dH 1.52–1.55 (m, 1H, CH), 1.95–2.06 (m, 1H, CH),
2.12–2.30 (m, 2H, CH2), 3.78 and 3.80 (s and s, 3H, OMe), 3.74–3.87
(m, 2H, CH and CH2), 3.89 and 3.73 (dd and dd, J¼8.7, 10.1 Hz, 1H,
CH), 4.65–4.55 (m, 1H, CH), 5.28 and 4.91 (d and d, J¼8.7 Hz, 1H,
CH), 7.30–7.35 (m, 2H, Ar), 7.42–7.53 (m, 3H, Ar), 7.55 and 7.02
(AA0XX0, J¼7.7 Hz, 2H, Ar), 7.69 and 7.97 (AA0XX0, J¼8.8 Hz, 2H, Ar)
(mixture of Z- and E-isomers in ratio 30:70); MS m/z (%) 427 (Mþ,
27). Anal. Calcd for C24H21N5O3: C, 67.44; H, 4.95; N,16.38. Found: C,
67.29; H, 4.81; N, 16.15%.
Dark yellow powder; yield 159 mg (80%) from 1h and 169 mg
(85%) from 2h; mp 202–204 ꢁC; IR (KBr) nmax 2950 (CH2), 2200
(CN), 1715 (CO) cmꢀ1 1H NMR dH 1.49–1.61 (m, 1H, CH), 1.98–2.07
;
(m, 1H, CH), 2.14–2.30 (m, 2H, CH2), 3.71–3.90 (m, 2H, CH), 3.90 and
3.94 (dd and dd, 1H, J¼8.7, 10.5 Hz, CH), 4.58–4.69 (m, 1H, CH), 4.95
and 5.31 (d and d, 1H, J¼8.7 Hz, CH), 7.25–7.36 (m, 3H,Ar), 7.38–7.54
(m, 5H, Ar), 7.76 and 7.57 (d and d, 1H, J¼8.2 Hz, Ar), 7.71 and 7.72 (d
and d, 1H, J¼8.2 Hz, Ar); 13C NMR dC 26.5, 26.7, 26.8, 26.9, 46.3, 49.3,
57.1, 57.2, 69.9, 70.4, 102.9, 103.9, 114.7, 115.0, 121.3, 121.6, 126.8,
127.3,127.5,127.7,127.8,128.2,128.3,128.6,128.7,128.8,129.1,132.2,
132.5, 134.6, 152.6, 152.9, 154.7, 159.3, 169.9, 171.1, 171.9, 173.9
(mixture of Z- and E-isomers in ratio 51:49). MS m/z (%) 397 (Mþ,
24.7). Anal. Calcd for C24H21N5O2: C, 69.51; H, 4.82; N, 17.02. Found:
C, 69.47; H, 4.78; N, 16.96%.
4.3. Reaction of 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-1-
yl)acrylonitriles 1 and 2 with dimethyl maleate
4.2.20. (1,3-Dioxo-2-phenyl-octahydropyrrolo[3,4-a]-pyrrolizin-4-
ylidene)-p-tolylazo-acetonitrile (5i)
Yellow powder; yield 154 mg (75%) from 1i and 146 mg (71%)
from 2i; mp 224–226 ꢁC; IR (KBr) nmax 2950 (CH2), 2195 (CN), 1715
General procedure: A solution of 0.5 mmol 1 or 2 and 2.5 mmol
dimethyl maleate in 5 mL benzene was heated at 60 ꢁC (TLC). The
reaction mixture was evaporated and purified by column
chromatography.

7670
N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
4.3.1. 3-[Cyano-(4-nitrophenylazo)-methylene]-hexa-
J¼7.7 Hz, 2H, CH2); 13C NMR dC 25.1 (C(7)H2), 25.9 (C(6)H2), 48.8
(C(5)H2), 51.1 (OMe), 51.9 (OMe), 105.9 (C(1)), 108.9, 110.1 (C(2)),
114.2 (Corto), 120.1 (C(3)), 120.3 (CN), 125.6 (Cmeta), 141.9 (Cpara),
146.8 (C(7a)), 148.6 (Cipso), 162.7 (CO), 164.2 (CO). MS m/z (%) 411
(Mþ, 21.3). Anal. Calcd for C19H17N5O6: C, 55.48; H, 4.17; N, 17.02.
Found: C, 55.42; H, 4.15; N, 16.93%.
hydropyrrolizine-1,2-dicarboxylic acid dimethyl ester (12a)
Yellow powder; yield 182 mg (88%) from 1a; mp 90–92 ꢁC; IR
(KBr) nmax 2200 (CN), 1740 (CO), 1680 (CO) cmꢀ1; 1H NMR dH 1.58–
1.82 (m, 1H, CH), 2.42–2.46 (m, 1H, CH2), 2.25–2.43 (m, 2H, CH2),
3.61, 3.69, 3.68, 3.72 (s, s, s, s, 3H, OMe), 3.64, 3.71, 3.72, 3.75 (s, s, s,
s, 3H, OMe), 3.78–3.94 (m, 2H, CH), 4.50–4.58 and 4.7–4.81 (m and
m, 1H, CH), 4.72, 4.96, 5.20 (d, d, d, 1H, J¼8.5, 10.2, 8.9 Hz, CH), 7.60–
7.78 (m, 1H, Ar), 7.60 and 7.75 (d and d, 1H, J¼9.0 Hz, Ar), 8.34–8.26
(m, 2H, Ar) (mixture of isomers). MS m/z (%) 413 (Mþ, 27.64). Anal.
Calcd for C19H21N5O4: C, 55.20; H, 4.63; N, 18.27. Found: C, 55.12; H,
4.56; N, 18.24%.
4.4.2. [Cyano-(4-trifluoromethylphenylhydrazono)-methyl]-6,7-
dihydro-5H-pyrrolizine-1,2-dicarboxylic acid dimethyl ester (14b)
Yellow powder; yield 137 mg (63%) from 2b; mp 238–240 ꢁC; IR
(KBr) nmax 3240 (NH), 2955 (CH2), 2215 (CN), 1710 (CO) cmꢀ1 1H
;
NMR dH 2.51–2.54 (m, 2H, CH2), 3.05 (t, 2H, J¼7.2 Hz, CH2), 3.07 (t,
J¼7.7 Hz, 2H, CH2), 3.08 (dt, J¼6.9, 14.7 Hz, 2H, CH2), 3.71 (s, 3H,
OMe), 3.77 (s, 3H, OMe), 4.28 (t, 2H, J¼7.2 Hz, CH2), 7.49 and 7.67
(AA0XX0, 4H, J¼8.7 Hz, Ar), 11.55 (s, 1H, NH). MS m/z (%) 434 (Mþ,
36.7). Anal. Calcd for C20H17F3N4O4: C, 55.30; H, 3.94; N, 12.90.
Found: C, 55.19; H, 3.86; N, 12.78%.
4.3.2. 3-[Cyano-(4-trifluorophenylazo)methylene]hexahydropyr-
rolizine-1,2-dicarboxylic acid dimethyl ester (12b)
Yellow powder; yield 111 mg (51%) from 1b; mp 108–110 ꢁC; IR
(KBr) nmax 2220 (CN), 1750 (CO), 1660 (CO); 1H NMR dH 7.83–7.77
(m, 2H, Ar), 1.58–1.78 (m, 1H, CH), 2.24–2.13 (m, 1H, CH2), 2.42–2.25
(m, 2H, CH2), 3.63, 3.68, 3.69, 3.72 (s, s, s, s 3H, OMe), 3.59, 3.69,
3.71, 3.75 (s, s, s, s, 3H, OMe), 3.79–3.89 (m, 2H, CH), 4.44–4.54 and
4.67–4.77 (m and m, 1H, CH), 4.69, 4.92 and 5.18 (d, d, d, 1H, J¼8.3,
10.4, 9.1 Hz, CH), 7.59 (d, 1H, J¼8.5, Ar), 7.65 and 7.76 (d and d, 1H,
J¼9.0 Hz, Ar) (mixture of isomers). MS m/z (%) 436 (Mþ, 31.90).
Anal. Calcd for C20H19F3N4O2: C, 55.05; H, 4.39; N, 13.85. Found: C,
55.00; H, 4.37; N, 13.83%.
4.4.3. 3-[Cyano-(4-ethoxycarbonylphenylhydrazono)-methyl]-6,7-
dihydro-5H-pyrrolizine (14c)
Yellow powder; yield 90 mg (41%) from 2c; mp 235–237 ꢁC; IR
(KBr) nmax 3270 (NH), 2950, 2860 (CH2), 2200 (CN), 1700 (CO)
cmꢀ1
;
1H NMR dH 1.36 (t, J¼7.1 Hz, 3H, Me), 25.1 (CH2-7), 2.58 (dt,
J¼7.1,19.5 Hz, 2H, CH2), 3.07 (t, J¼7.3 Hz, 2H, CH2), 3.74 (s, 3H, OMe),
3.80 (s, 3H, OMe), 4.28 (q, J¼7.1 Hz, 2H, CH2), 4.29 (t, J¼7.1 Hz, 2H,
CH2), 7.38 and 7.89 (AA0BB0, J¼8.9 Hz, 4H, Ar), 11.35 (s, 1H, NH); 13C
NMR dC 14.1 (Me), 25.9 (C(6)H2), 48.6 (C(5)H2), 51.1 (OMe), 51.8
(OMe), 60.2 (CH2O), 105.7 (C(1)), 106.9, 110.3 (C(2)), 114.0 (Corto),
120.6 (C(3)), 119.5 (CN), 123.1 (Cpara), 130.7 (Cmeta), 146.4 (C(7a)),
146.9 (Cipso), 162.8 (CO), 164.3 (CO), 165.3 (CO). MS m/z (%) 438 (Mþ,
8.6%). Anal. Calcd for C22H22N4O6: C, 60.27; H, 5.06; N,12.78. Found:
C, 60.23; H, 5.01; N, 12.56%.
4.3.3. 3-[Cyano-(4-ethoxyphenylazo)methylene]hexahydropyr-
rolizine-1,2-dicarboxylic acid dimethyl ester (12c)
Yellow powder; yield 150 mg (68%) from 1c; mp 132–134 ꢁC; IR
(KBr) nmax 2220 (CN), 1740 (CO), 1640 (CO); 1H NMR dH 1.30–1.37
(m,1H, Me),1.58–1.79 (m,1H, CH), 2.13–2.23 (m,1H,CH2), 2.26–2.40
(m, 2H, CH2), 3.59, 3.69, 3.71 and 3.74 (s, s, s, s, 3H, OMe), 3.64, 3.68,
3.72 and 3.75 (s, s, s, s, 3H, OMe), 4.28 and 4.35 (m, 2H, CH2), 4.54–
4.45 and 4.76–4.66 (m and m, 1H, CH), 4.69, 4.92 and 5.18 (d, d, d,
1H, J¼8.5, 9.2, 8.9 Hz, CH), 7.53–7.62 (d and d, 1H, J¼7.9 Hz, Ar), 7.76
(d, 1H, J¼8.9 Hz, Ar), 7.99–8.04 (m, 2H, Ar). MS m/z (%) 440 (Mþ,
18.33%). Anal. Calcd for C21H22N4O3: C, 59.99; H, 5.49; N, 14.80.
Found: C, 59.97; H, 5.46; N, 14.77%.
4.4.4. 3-[Cyano-(2,4-dichlorophenylhydrazono)-methyl]-6,7-
dihydro-5H-pyrrolizine (14d)
Yellow powder; yield 72 mg (36%) from 2e; mp 187–189 ꢁC; IR
(KBr) nmax 3300 (NH), 2950 (CH2), 2210 (CN), 1740, 1700 (CO) cmꢀ1
;
1H NMR dH 2.55 (dt, J¼7.4, 20.1 Hz, 2H, CH2), 3.08 (t, J¼7.4 Hz, 2H,
CH2), 3.73 (s, 3H, OMe), 3.79 (s, 3H, OMe), 4.31 (t, J¼7.5 Hz, 2H, CH2),
7.33 (dd, J¼8.8, 2.1 Hz, 1H, Ar), 7.45 (d, J¼5.1 Hz, 1H, Ar), 7.46 (d,
J¼6.1 Hz, 1H, Ar), 9.50 (s, 1H, NH). MS m/z (%) 434 (Mþ, 8.8). Anal.
Calcd for C19H16Cl2N4O4: C, 52.43; H, 3.71; N, 12.87. Found: C, 52.34;
H, 3.65; N, 12.80%.
4.3.4. 3-[Cyano-(2,4-dichlorophenylazo)-methylene]-
hexahydropyrrolizine-1,2-dicarboxylic acid dimethyl ester (12d)
Yellow powder; yield 76 mg (35%) from 1e; mp 124–126 ꢁC; IR
(KBr) nmax 2220 (CN), 1740 (CO), 1660 (CO) cmꢀ1; 1H NMR dH 1.59–
1.79 (m,1H, CH), 2.13–2.40 (m,1H, CH2), 2.24–2.42 (m, 2H, CH2), 3.56,
3.68,3.70and3.72(s, s, s,s, 3H,OMe), 3.63, 3.69,3.71and3.74(s,s, s, s,
3H, OMe), 3.78–3.92 (m, 2H, CH), 4.46–4.53 and 4.67–4.76 (m and m,
1H, CH), 4.68, 4.92 and 5.17 (d, d, d, 1H, J¼8.5, 10.4, 8.8 Hz, CH), 7.41–
7.44 (m,1H,Ar), 7.49and7.69(dandd,1H,J¼2.0 Hz,Ar), 7.71–7.73(m,
2H, Ar). MS m/z (%) 436 (Mþ, 7.2%). Anal. Calcd for C19H18Cl2N4O2: C,
52.19; H, 4.15; N, 13.82. Found: C, 52.18; H, 4.11; N, 13.80%.
4.4.5. 3-[Cyano-(4-chlorophenylhydrazono)-methyl]-6,7-dihydro-
5H-pyrrolizine (14e)
Yellow powder; yield 92 mg (46%) from 2f; mp 273–275 ꢁC; IR
(KBr) nmax 3270 (NH), 2950, 2850 (CH2), 2210 (CN), 1710 (CO) cmꢀ1
;
1H NMR dH 2.54 (dt, J¼6.7, 16.2 Hz, 2H, CH2), 3.05 (t, J¼7.3 Hz, 2H,
CH2), 3.73 (s, 3H, OMe), 3.77 (s, 3H, OMe), 4.27 (t, J¼7.4 Hz, 2H, CH2),
7.24 and 7.32 (AA0BB0, J¼9.2 Hz, 4H, Ar), 11.05 (s, 1H, NH); 13C NMR
dC 25.1 (C(7)H2), 25.9 (C(6)H2), 48.5 (C(5)H2), 51.0 (OMe), 51.7
(OMe),105.6 (C(1)), 110.6 (C(2)), 116.0 (Corto), 118.9 (CN), 120.8 (C-3),
129.0 (Cmeta), 126.0 (Cpara), 146.1 (C(7a)), 142.0 (Cipso), 162.8 (CO),
164.3 (CO). MS m/z (%) 400 (Mþ, 33.2). Anal. Calcd for C19H17ClN4O4:
C, 56.94; H, 4.28;N, 13.98; Found: C, 56.86; H, 4.22; N, 13.85%.
4.4. Reaction of the 3-alkylsulfanyl-2-arylazo-3-(pyrrolidin-
1-yl)acrylonitriles with dimethyl acetylenedicarboxylate
General procedure: A solution of 0.5 mmol 1 or 2 and 2.5 mmol
dimethyl acetylenedicarboxylate in 5 ml benzene was refluxed
(TLC). The reaction mixture was evaporated and purified by column
chromatography.
4.4.6. 3-[Cyano-(2-chloro-4-methylphenylhydrazono)-methyl]-6,7-
dihydro-5H-pyrrolizine (14f)
4.4.1. [Cyano-(4-nitrophenylhydrazono)-methyl]-6,7-dihydro-5H-
pyrrolizine-1,2-dicarboxylic acid dimethyl ester (14a)
Yellow powder; yield 93 mg (45%) from 2g; mp 264–265 ꢁC; 1H
NMR dH 2.31 (s, 3H, Me), 2.57 (dt, J¼7.0, 13.9 Hz, 2H, CH2), 3.08 (t,
J¼7.6 Hz, 2H, CH2), 3.73 (s, 3H, OMe), 3.79 (s, 3H, OMe), 4.30 (t,
J¼7.2 Hz, 2H, CH2), 7.12 (d, J¼9.4 Hz, 1H, Ar), 7.22 (s, 1H, Ar), 7.34 (d,
J¼7.9 Hz, 1H, Ar), 9.37 (s, 1H, NH); 13C NMR dC 25.1 (C(7)H2), 25.9
(C(6)H2), 48.8 (C(5)H2), 51.2 (OMe), 51.9 (OMe), 80.0 (Me), 108.5
(C(1)), 103.4, 109.9 (C(2)), 116.2 (Corto), 119.0 (CN), 120.1 (C(3)), 129.2
Yellow powder; yield 82 mg (40%) from 1a and 123 mg (60%)
from 2a; mp 256–258 ꢁC; IR (KBr) nmax 3230 (NH), 2950 (CH2), 2200
(CN), 1710 (CO) cmꢀ1 1H NMR dH 11.61 (s, 1H, NH), 8.15 and 7.47
;
(AA0BB0, J¼9.2 Hz, 4H, Ar), 4.32 (t, J¼6.9 Hz, 2H, CH2), 3.80 (s, 3H,
OMe), 3.73 (s, 3H, OMe), 3.08 (dt, J¼6.9, 14.7 Hz, 2H, CH2), 3.07 (t,

N.P. Belskaya et al. / Tetrahedron 65 (2009) 7662–7672
7671
Giorgi, G.; Mantellini, F.; Mazzanti, A. Synlett 2006, 2403–2406; (g) Rossi, E.;
Abbiati, G.; Attanasi, O. A.; Rizzato, S.; Santeusanio, S. Tetrahedron 2007, 63,
11055–11065.
(Cmeta), 129.8 (Cmeta), 136.2 (Cpara), 136.2 (Cipso), 146.7 (C(7a)), 163.0
(CO), 164.3 (CO). MS m/z (%) 414 (Mþ, 10.0%). Anal. Calcd for
C20H19ClN4O4: C, 57.91; H, 4.62; N, 13.51; Found: C, 57.84; H, 4.52;
N, 13.22%.
3. (a) South, M. S. J. Heterocycl. Chem. 1999, 36, 301–319; (b) Sande, M.; Gais, H.-J.
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4.4.7. 3-[Cyano-(phenylhydrazono)-methyl]-6,7-dihydro-5H-
pyrrolizine (14g)
Yellow powder; yield 84 mg (46%) from 1h; mp 264–265 ꢁC; IR
(KBr) nmax 3250 (NH), 2950, 2850 (CH2), 2210 (CN), 1710 (CO) cmꢀ1
;
1H NMR dH 3.06 (t, J¼7.3 Hz, 2H, CH2), 2.58 (dt, J¼7.3, 13.3 Hz, 2H,
CH2), 3.72 (s, 3H, OMe), 3.76 (s, 3H, OMe), 4.28 (t, J¼7.5 Hz, 2H, CH2),
6.95 (dt, J¼8.3, 1.4 Hz, 1H, Ar), 7.29–7.36 (m, 4H, Ar), 11.21 (s, 1H,
NH); 13C NMR dC 25.1 (C(7)H2), 25.9 (C(6)H2), 48.5 (C(5)H2), 51.0
(OMe), 51.9 (OMe), 105.6 (C(1)), 104.3, 110.8 (C(2)), 114.4 (Corto),
121.1 (C(3)), 118.6 (CN), 129.2 (Cmeta), 122.4 (Cpara), 143.0 (Cipso),
146.0 (C(7a)), 162.9 (CO), 164.3 (CO). MS m/z (%) 366 (Mþ, 18.8%).
Anal. Calcd for C19H18N4O4: C, 62.29; H, 4.95; N, 15.29; Found: C,
62.21; H, 4.92; N, 15.17%.
4.4.7.1. X-ray Structure analysis of 14g. Crystaldata:C19H18N4O4 was
crystallized from ethanol. Crystal dimensions 0.32ꢂ0.26ꢂ0.1 mm,
monoclinic, P21/n, a¼7.6737(4) Å, b¼9.4134(5) Å, c¼24.0540(13) Å,
a
¼90.00ꢁ,
b
¼90.876ꢁ,
g
¼90.00ꢁ,
V¼1737.35(16) Å3;
Z¼4,
Dc¼1.401 g cmꢀ3
,
m
¼0.835 cmꢀ1, Bruker SMART 6000 detector,
CuK
a(l¼1.54178 Å), crossed Go¨bel mirrors, T¼100 K, 9077 measured
reflections, 2371 independent reflections. The datawere corrected for
Lorentz, absorption, and polarization effects. The structurewas solved
by directs methods. Full matrix least-squares refinement based on
F2ꢃ2
s,257parameters, hydrogenatomsplacedatcalculatedpositions
with temperature factors 20% higher than parent atom and the hy-
drogen bond distances were free to refine, R1¼0.0581.
Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation no. CCDC-677317. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements
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The authors thank the Russian Foundation for Basic Research
for financial support (grant RFBR # 08-03-00376_a, RFBR/NNSF #
08-03-92208_a). J.S. acknowledges Michail-Lomonosov-For-
schungsstipendien (DAAD). J.S. is greatly appreciate useful dis-
cussion with Prof. R. Herges and F. Koehler (Otto-Diels-Institut fu¨r
Organische Chemie, Christian Albrecht University of Kiel, Ger-
many) and their advises about ACID application. We also thank the
FWO-Vlaanderen and the University of Leuven for the financial
support.
Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.06.114.
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