Facile coupling of 2-(1-ethylthioethenyl)pyrroles with amines: A route to 2-(1-aminoethenyl)pyrroles and 1-amino-3-iminopyrrolizines

Article abstract of DOI:10.1002/jhet.5570440301

(Chemical Equation Presented) 2-(2-Cyano-1-ethylthioethenyl)pyrroles are readily coupled (50-55°) with primary and secondary amines at the position 1 of the ethenyl moiety to eliminate ethanethiol and afford 2-(1-amino-2- cyanoethenyl)pyrroles and/or thei

Full text of DOI:10.1002/jhet.5570440301

May-Jun 2007
505
Facile Coupling of 2-(1-Ethylthioethenyl)pyrroles with Amines:
A Route to 2-(1-Aminoethenyl)pyrroles and 1-Amino-3-
iminopyrrolizines
Boris A. Trofimov,* Lyubov’ N. Sobenina, Al’bina I. Mikhaleva, Ol’ga V. Petrova,
Vladislav N. Drichkov, Igor A. Ushakov, Ol’ga A. Tarasova, Darya-Suren D.
Toryashinova, Yuriy Yu. Rusakov, and Leonid B. Krivdin
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian
Academy of Sciences, 1 Favorsky St, Irkutsk 664033, Russian Federation
boris_trofimov@irioch.irk.ru
Received November 18, 2006
R3
R3
R3
NR4R5
X
SEt
X
R4R5NH
NR4R5
R2
R2
R2
N
N
R1
+
N
R1
NC
NC
HN
R1 = H
65- 93%
X
65-87%
R1 = H, Me; R2 = H, Alk, Ph; R3 = H, Alk; R4 = H, Me; R5 = H, Me, n-Bu
X = CN, CONH2
2-(2-Cyano-1-ethylthioethenyl)pyrroles are readily coupled (50-55°) with primary and secondary
amines at the position 1 of the ethenyl moiety to eliminate ethanethiol and afford 2-(1-amino-2-
cyanoethenyl)pyrroles and/or their cyclic isomers – functionalized 1-amino-3-iminopyrrolizines, in
good to high yields.
J. Heterocyclic Chem., 44, 505 (2007).
Scheme I
INTRODUCTION
R3
R3
R3
R2
Functionalized vinylpyrroles are important building
blocks in heterocyclic chemistry [1-3]. Among them,
there are just a few [4] representatives with amino
function at the double bond. Meanwhile, such pyrroles
offer wide opportunities in design of new drugs and
materials for optoelectronics, including porphyrine-like
systems [3]. Their close derivatives and, in certain cases,
cyclic isomers, pyrrolizines, are a scaffold of numerous
alkaloids and some pheromones, though still remain a
synthetic challenge [5].
a
b
SEt
S
R2
R2
N
R1
N
R1
N
R1
SR4
X
NC
1a-h
a: for 1a-f: CS2, KOH, DMSO (20-25°, 2 hours), then EtI (20-25°, 2
hours) [6]; for 1g,h: n-BuLi, CS2, MeI [7]
b: XCH2CN, KOH, DMSO (110°, 1.5 hour), then EtI (20-25°, 2 hours) [8]
Pyrrole
R1
R2
R3
X
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
Me
Me
(CH2)4
CN
CN
Herein, we describe an approach to the synthesis of 2-
(1-aminoethenyl)pyrroles and their cyclic isomers, 1-
amino-3-iminopyrrolizines, by a non-catalyzed unusually
mild coupling of 2-(2-cyano-1-ethylthioethenyl)pyrroles
with primary and secondary amines.
Ph
n-Pr
H
Et
n-Pr
CONH2
CONH2
CONH2
CONH2
CN
n-Bu
(CH2)4
Ph
H
H
H
H
H
1g
1h
We focus on the peculiarities and general features of
this reaction and its further development to an expedient
synthesis of so far inaccessible and mostly unknown but
highly synthetically attractive 2-(1-aminoethenyl)pyrroles
with strong electron-withdrawing substituents at the
double bond and their cyclization products, functionalized
pyrrolizines.
CONH2
RESULTS AND DISCUSSION
We found that 2-(2-carbamoyl-2-cyano-1-ethylthio-
ethenyl)-5-phenylpyrrole 1f with aqueous methylamine
(50-55°, 0.5 hour) exchanges the ethylthio group for
methylamine moiety to give 2-(2-carbamoyl-2-cyano-1-
methylaminoethenyl)-5-phenylpyrrole 2f in 74% yield
(Scheme II).
Starting 2-(2-cyano-1-ethylthioethenyl)pyrroles 1a-h,
including previously unknown 1g,h, are available through
2-pyrrolecarbodithioates (Scheme I) [6-8].

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B. A. Trofimov, L. N. Sobenina, A. I. Mikhaleva, O. V. Petrova, V. N. Drichkov, I. A. Ushakov,
O. A. Tarasova, D.-S. D. Toryashinova, Y. Yu. Rusakov, and L. B. Krivdin
Vol 44
pyrrolizinone-2-carbonitrile 6e from corresponding 1-
ethylthio-3-pyrrolizinone-2-carbonitrile 7 (Scheme V),
available from 4,5,6,7-tetrahydroindole-2-carbodithioate
and ethyl cyanoacetate [10].
Scheme II
NHMe
MeNH2
Ph
N
1f
H
CONH2
NC
Scheme V
2f 74%
Meanwhile, pyrroles 1b-d, as well as preliminarily
reported [9] pyrroles 1a,e, under the same conditions form
1-methylamino-3-iminopyrrolizines 4a-e in 77-93% yield
(Scheme III). The TLC monitoring (Silufol, eluent – diethyl
ether) of the reaction indicates that its first stage is the
cyclization of ethenylpyrroles 1a-e to 1-ethylthio-3-imino-
pyrrolizines 3a-e. The second step is the coupling of
pyrrolizines 3a-e with methylamine to eliminate ethan-
ethiol. Correspondingly, 1-aminopyrrolizines 4a-e are
synthesized from 1-ethylthio-3-iminopyrrolizines 3a-e,
readily prepared by cyclization of pyrroles 1a-e in the
presence of triethylamine [10], under the above conditions
in 78-83% yield (Scheme III).
NMe2
Me2NH
SEt
N
N
-(EtSH)
O
CN
O
CN
6e 85%
7
Pyrrolizine 3e, when allowed to react with dimethyl-
amine, undergoes ring-opening (50-55°, 0.5 hour)
affording aminoethenylpyrrole 5e and aminopyrrolizinone
6e in the same ratio (7:1) as in the reaction of pyrrole 1e
with dimethylamine (Scheme VI).
Scheme VI
Scheme III
Me2NH
-(EtSH)
NMe2
CONH2
R3
R3
NMe2
1e, 3e
+
N
H
N
MeNH2
MeNH2
-(EtSH)
R2
R2
NC
NHMe
SEt
N
O
CN
1a-e
N
6e
5e
HN
X
HN
X
3a-e
4a-e
from 1a-e - 77-93%
from 3a-e - 78-83%
Thus, pyrroles 1c-e react with aqueous methyl- and
dimethylamine differently: with the former first the
cyclization to 1-ethylthiopyrrolizines 3c-e takes place and
afterwards the exchange with amine occurs, whereas with
the latter the ring-closure is not the case. Evidently, there
are two competing pathways of the coupling: the direct
ethylthio-amino exchange in ethenylpyrroles 1c-e to form
aminoethenylpyrroles 2c-e, 5c-e (A) and intramolecular
cyclization of ethenylpyrroles 1c-e to 1-ethylthio-3-
iminopyrrolizines 3c-e followed by the ethylthio-amino
exchange (B) (Scheme VII).
With dimethylamine, the major (or in the case of
pyrrole 1f exclusive) pathway is the coupling to yield 2-
(1-amino-2-carbamoyl-2-cyanoethenyl)pyrroles 5c-f along
with minor amount of 3-pyrrolizinones 6c-e (the 5c-e:
6c-e ratio is ~3-19:1, 1H NMR) (Scheme IV).
Scheme IV
R3
R3
NMe2
Scheme VII
Me2NH
-(EtSH)
R2
NMe2
R2
+
1c-f
N
H
N
MeNH2 (Me2NH)
CONH2
NC
O
CN
3c-e
1c-e
5c-f
68-87%
6c-e
B
MeNH2 (Me2NH)
-(EtSH)
MeNH2 (Me2NH)
-(EtSH)
The latter result from the intramolecular cyclization of
pyrroles 5c-e, that follows from the fact that the content of
3-pyrrolizinones 6c-e in the reaction mixture increases.
Thus, percentage of 3-pyrrolizinone 6d in 15, 30 and 90
minutes changes from 0 to 5 and 25%, respectively.
Apparently, the coupling of the intermediate 1-ethylthio-
3-pyrrolizinones, which are products of intramolecular
cyclization of pyrroles 1c-e with dimethylamine, is not
ruled out. The ease of such an exchange (35°, 5 minutes)
is demonstrated by the synthesis of 1-dimethylamino-3-
A
B
R3
R3
NHMe (NMe2)
R2
R2
NHMe (NMe2)
N
N
CN
H
O
HN
CONH2
NH2
4c-e (8c-e)
2c-e (5c-e)

May-Jun 2007
Facile Coupling of 2-(1-Ethylthioethenyl)Pyrroles with Amines
507
R3
Pyrroles 2c-e are capable of cyclization to pyrrolizines
4c-e in their tautomeric form (Scheme VIII).
SEt
CN
NH2
R2
N
H
Scheme VIII
O
R3
R2
R3
Me
1c-f
N
H
NHMe
NH
O
R2
4c-e
N
H
N
H
2-(2-Carbamoyl-2-cyano-1-ethylthioethenyl)pyrroles 1c-f
cyclize not as easy as the corresponding dicyanoethenyl-
pyrroles 1a,b [10].
CN
NC
O
NH2
2c-e
The fact that pyrrole 1f couples with both methyl- and
dimethylamine to furnish only corresponding 2-(1-
aminoethenyl)pyrroles 2f, 5f indicates its lower reactivity
in the intramolecular cyclization. Actually, it does not
cyclize on reflux in methanol with triethylamine (under
these conditions pyrroles 1a,c-e are converted to
pyrrolizines within 0.5-4 hours).
Pyrroles 1a,b with dimethylamine form 1-dimethyl-
amino-3-iminopyrrolizines 8a,b in 90 and 85% yield,
respectively (Scheme XI).
The most likely mechanism of the coupling observed
seems to be zwitter-ion formation in the first step by the
nucleophilic attack of amine at the electron-deficient site of
the vinyl group, i.e. position 1, and the further intramolecular
thiol elimination via four-membered transition state or in an
intermolecular manner with the participation of another
molecule of the zwitter-ion or/and with electrophilic
assistance of the solvent (alcohol, water) (Scheme IX).
Scheme IX
Scheme XI
R4
R3
R3
R2
H
N
R5
DMSO
Me2NH
-(EtSH)
R2
1a-h R4R5NH
SEt
+
1a,b
NMe2
N
r.t.
N
R1
-(HSEt)
R3
2 days
R2=Ph, R3=H
X
NC
HN
CN
8a,b
NR4R5
X
NMe2
CN
Ph
N
R2
N
R1
H
NC
NC
5b 100%
R4, R5 = H, alkyl
Interestingly, pyrrolizine 8b, which is stable upon storage
in crystalline state, when dissolved in DMSO-d6, undergoes
the ring-opening to 2-(1-dimethylamino-2,2-dicyanoethenyl)-
pyrrole 5b (2 days, r.t., 100% conversion). A partial ring-
opening 8bꢁ5b is also observed on recrystallization of
8b from ethanol, while pyrrolizine 8a is stable under
analogous conditions. Evidently, the role of DMSO in the
complete conversion of 8b to 5b is the H-bonding with
pyrrole and the stabilization of highly polar [11] open
form 5b by dipole-dipole interaction with the polar
solvent (Scheme XII).
A similar mechanism may be operative in the coupling
of amines with 1-ethylthio-3-pyrrolizines 3a-e to yield
pyrrolizines 4a-e (Scheme X).
An obvious driving force of the coupling is a known
stronger p-ꢀ-conjugation of the lone electron pare of the
amine nitrogen with the double bond than that of the
sulfide sulfur.
Scheme X
R3
H
NR4R5
R4R5NH
R2
3a-e
+
4a-e
Scheme XII
SEt
N
-(HSEt)
HN
X
NMe2
Ph
Ph
NMe2
DMSO
N
H
N
The difference in behavior of 2-(2,2-dicyanoethenyl)-
pyrroles 1a,b and 2-(2-carbamyl-2-cyanoethenyl)pyrroles
1c-f is due to the existence of the latter solely in E-
configuration with syn-disposition of the carbamoyl and
NH groups (1H NMR) stabilized by the intramolecular H-
bond, which is unfavorable for cyclization:
CN
NC
Me
HN
CN
ꢀꢁ
O
S
8b
ꢀ+
Me
5b

508
B. A. Trofimov, L. N. Sobenina, A. I. Mikhaleva, O. V. Petrova, V. N. Drichkov, I. A. Ushakov,
O. A. Tarasova, D.-S. D. Toryashinova, Y. Yu. Rusakov, and L. B. Krivdin
Vol 44
Incomplete transformation 8bꢀ5b in ethanol is
explained by a lower basicity and polarity of the latter as
compared to DMSO. A better stabilization of the 2-
phenyl-substituted 5b than 5a (Schemes XI, XII) agrees
with a higher acidity of its pyrrole NH function (stronger
H-bonding) [12].
Z-isomer only, probably due to stabilization by the
intramolecular hydrogen bonding which can not be
formed in pyrrole 5h:
Me
N
H
2-(2-Cyano-1-ethylthioethenyl)-1-methylpyrroles 1g,h
with aqueous methyl- and dimethylamine (50-55°, 0.5
hour) afford 2-(1-amino-2-cyanoethenyl)-1-methylpyrroles
2h, 5g,h in 65-73% yield (Scheme XIII).
N
O
Me
NC
NH2
2h
1
Scheme XIII
The isomers of 2h and 5h were assigned using the H
NMR spectra: in Z-5h, signals of H-3 and the pyrrole Me
are downfield shifted due to the CN bond anisotropy and
their values are close to those of the same hydrogen in
pyrrole 5g:
NMeR
RMeNH
N
1g,h
-(EtSH)
Me
X
NC
2h, 5g,h
H
H
NC
2h: R = H, X = CONH2;
5: R = Me; X = CN (g), CONH2 (h)
NMe2
CONH2
N
N
NMe2
CONH2
Me
Me
In the case of pyrrole 1g, the reaction is accompanied
by hydrolysis of one of the nitrile groups to yield 2-(2-
carbamoyl-2-cyano-1-methylaminoethenyl)-1-methyl-
pyrrole 2h.
The reaction of pyrroles 1a,e with n-butylamine in
aqueous ethanol (1:1, v/v) is slower (reflux, 2-4 hours)
and less selective than that with methylamine. Thus,
pyrrole 1a and its cyclic isomer, pyrrolizine 3a, give a
mixture of 1-n-butylaminopyrrolizine 9a and 2-(1-n-
NC
Z-5 h
In E-1h, a downfield shift due to CN bond anisotropy is
observed for the CH2 hydrogens of the ethylthio group.
Their chemical shift (2.70 ppm) corresponds to that of
pyrrole 1g.
Aminoiminopyrrolizines 4a-e, 9a,e were isolated in the
form of the individual isomers with the unknown
configuration at the C=N bond. In view of the further
synthetic interest to iminopyrrolizines, the potential
building blocks capable of stereo-dependendent hetero-
cylization to highly condensed heterocycles, it was a
rewarding task and a structural challenge to determine the
configuration of 9e as an illustrative representative of this
series.
butylamino-2,2-dicyanoethenyl)pyrrole
(Scheme XIV).
10a,
19:1
Scheme XIV
NHBu-n
n-BuNH2
NHBu-n
1a,e
3a,e
N
N
+
-(EtSH)
H
X
NC
To solve this problem we used a method [13] based on
the measurement of the one-bond 13C-13C spin-spin
coupling constants, 1J(C,C), showing marked stereo-
chemical dependence upon the orientation of the nitrogen
lone pair in azomethines.
Experimental measurement of 1J(C,C) involving the
ꢁ-imino carbon of the individual isomer of 9e has been
carried out from the INADEQUATE spectrum
accumulated overnight while calculations of this coupling
in the four possible forms of 9e were performed at the
HN
X
9a,e
10a,e
When the reaction is carried out in ethanol, only
pyrrolizine 9a is formed (80% yield). Likewise (ethanol-
water, 1:1,v/v, 4 hours), pyrrole 1e gives aminopyrrolizine
9e (65% yield) and aminoethenylpyrrole 10e, 5:1
(Scheme XIV)
Di(n-butyl)amine, due to its bulky substituents, does not
couple neither with ethenylpyrrole 1e nor with imino-
pyrrolizine 3e. Its reaction with pyrrole 1e (ethanol-water,
1:1, v/v, reflux, 4 hours) results in pyrrolizine 3e, i.e. this
amine acts just as a basic catalyst. Under the same
conditions, when reacting with di(n-butyl)amine, pyrrol-
izine 3e is recovered almost quantitatively.
SOPPA
(Second-Order
Polarization
Propagator
Approach) level [14] taking into account all four coupling
contributions, namely, Fermi contact, JFC, spin–dipolar,
JSD, diamagnetic spin–orbital, JDSO, and paramagnetic
spin–orbital, JPSO (Table 1). The model structure of 9e was
used since the original molecule is too large for the high-
level ab initio calculations.
Pyrroles 1h and 5h consisted of E- and Z-isomers (1:5,
and 1:3 respectively), while pyrrole 2h was isolated as the

May-Jun 2007
Facile Coupling of 2-(1-Ethylthioethenyl)Pyrroles with Amines
509
Table 1
Spin-spin coupling constants 1J(C,C) of the model of 2-carbamoyl-3-iminopyrrolizines calculated at the SOPPA level [a]
NH2
O
NH2
NH2
O
NH2
N
N
N
N
NH2
H
N
NH2
H
N
N
N
H2N
O
H
H
H2N
O
Z-s-trans
Z-s-cis
E-s-trans
E-s-cis
Relative
energy,
kcal/mol
0.0
12.4
2.9
Isomer
Conformation
JDSO
JPSO
JSD
JFC
J
J experimental
71.0
s-cis
s-trans
s-cis
0.4
0.4
0.4
0.4
-2.4
-1.9
-2.2
-1.9
0.5
0.5
0.5
0.5
74.2
79.9
61.9
63.4
72.7
78.9
60.6
62.4
Z
E
s-trans
4.5
1
[a] All couplings and their contributions are in Hz. In the calculations of J(C,C) the coupled carbons were specified with the cc-
pVDZ-Cs basis set [15-17] while the rest of the elements were assigned with cc-pVDZ [15] with no polarization p-functions on
hydrogens. The equilibrium HF/6-311G** geometries were used throughout. All calculations were performed without symmetry
constraints assuming the C1 symmetry point group.
It is obvious from the data presented in Table 1 that
calculated 1J(C,C) expectedly show marked stereo-
specificity in respect to the orientation of the nitrogen
lone pair being 10-15 Hz larger in Z-isomer. On the other
amines has been developed. No obvious limitation are
envisaged for this approach to be valid for coupling of the
functionalized ethenylpyrrole moiety with molecules of
pharmacologically and synthetically important function-
alized amines, including aminoacids and amino-substi-
tuted heterocycles.
1
hand, J(C,C) also depends upon the orientation of the
C=O bond of the CONH2 group in different confor-
mations of both isomers being 2-6 Hz larger in s-trans
conformations. Comparison of these theoretical results
with experiment leaves no doubt that 1-n-butylamino-
pyrrolizine 9e obtained as shown in Scheme XIV is the
individual isomer with Z configuration at the C=N bond
adopting predominant s-cis conformation of the CONH2
moiety. These results are in line with the thermodynamic
reasoning based on the fact that it is this form, Z-s-cis,
which is most favorable, i.e. having the lowest total
energy calculated at the MP2//HF/6-311G** level (see
Table 1). It is noteworthy that predominant Z-s-cis form is
ideally planar while the higher-energy other three, Z-s-
trans, E-s-cis and E-s-trans, show noticeable out-of-plane
deviations (ca 15-30°). The stabilization of the Z-s-cis
form is likely due to the following multiple H-bonding:
EXPERIMENTAL
IR spectra of compounds synthesized (400-4000 cm-1) were
recorded on a Bruker IFS-25 instrument in potassium bromide
pellets. 1H and 13C NMR spectra were taken on Bruker DPX 250
[250.13 (1H) and 62.9 (13C) MHz, respectively] and Bruker DPX
400 [400 (1H) MHz] spectrometers in dimethylsulfoxide-d6 and
deuteriochloroform with HMDS as internal reference.
1
Structure of compounds synthesized was determined by H
and 13C NMR spectroscopy with the use of 2D NMR techniques.
Assignment of 13C resonances was done using 2D heteronuclear
HSQC [18] and HMBC [19] correlation methods.
In 2D HMBC pulse sequence, the delays optimized for the
direct coupling constant 1J(H,C) = 145 Hz and long-distance
coupling constant nJ(H,C) = 5 Hz were used.
Methyl- and dimethylamines were used as 2 M aqueous
solutions.
Analyses of reaction mixtures and purity control of
compounds obtained were carried out using TLC on Silufol UV-
254 plates, eluent: diethyl ether:ethanol, 10:1. Carbon–carbon
coupling constants were measured at 25° in deuteriochloroform
using the INADEQUATE [20] pulse sequence adjusted for J =
70 Hz on a Bruker AVANCE 400 MHz spectrometer in a 10
mm broadband probe at 300 K in deuteriochloroform with
HMDS as an internal standard. Settings for the INADEQUATE
experiments were as follows: 90° pulse length, 12–14 μs;
spectral width, 10–15 kHz; acquisition time, 4–6 s; relaxation
delay, 6–10 s; characteristic delay ꢀ = 1/4J, 3.6 ms; digital
resolution 0.05–0.1 Hz/pt; accumulation time, 12 h.
H
N
N
H
O
N
H
N
H
H
CONCLUSION AND OUTLOOK
Thus, an efficient route to earlier inaccessible
aminoethenylpyrroles and aminopyrrolizines through a
facile non-catalyzed coupling of available 2-(2-cyano-1-
ethylthioethenyl)pyrroles with primary and secondary
Geometrical optimizations were performed with the
GAMESS code [21] while calculations of spin–spin coupling

510
B. A. Trofimov, L. N. Sobenina, A. I. Mikhaleva, O. V. Petrova, V. N. Drichkov, I. A. Ushakov,
O. A. Tarasova, D.-S. D. Toryashinova, Y. Yu. Rusakov, and L. B. Krivdin
Vol 44
constants have been carried out using the DALTON package
[22] as described in the text.
ethenylpyrroles 1a-e (Rf 0.90) turn to red spots of 1-ethylthio-3-
iminopyrrolizines 3a-e (Rf 0.95 for pyrrolizines 3a,b and Rf 0.15
for pyrrolizines 3c-e)]. Then red spots (eluent – diethyl ether :
ethanol, 10:1 (v/v) of 1-ethylthio-3-iminopyrrolizines 3a-e turn to
orange spots of 1-amino-3-iminopyrrolizines 4a-e (Rf 0.5-0.6).
2-(2-Carbamoyl-2-cyano-1-methylaminoethenyl)-5-phenyl-
pyrrole (2f). This compound was obtained as white solid, 79 mg
(74%), mp 176-177°; ir (potassium bromide): 3483, 3382, 3248,
2185, 1651, 1599, 1357, 790, 759 cm-1; 1H nmr (400 MHz,
deuteriochloroform): ꢀ 3.15 (d, 3H, NMe, J = 4.9 Hz), 5.49 (br s,
2H, CONH2), 6.60 (dd, 1H, H-3, J = 3.7, 2.1 Hz), 6.70 (dd, 1H,
H-4, J = 3.7, 2.1 Hz), 7.30 (m, 1H, Ph-Hp), 7.40 (m, 2H, Ph-Hm),
7.55 (m, 2H, Ph-Ho), 9.18 (br s, 1H, NHMe), 10.78 ppm (br s,
1H, NH); 13C nmr (62.5 MHz, dimethylsulfoxide-d6): ꢀ 32.0,
70.9, 106.9, 114.7, 121.1, 122.2, 124.4, 126.8, 128.8, 131.8,
134.8, 161.9, 170.2 ppm. Anal. Calcd for C15H14N4O: C, 67.65;
H, 5.30; N, 21.04. Found: C, 67.51; H, 5.14; N 20.82.
2-(2,2-Dicyano-1-ethylthioethenyl)-1-methylpyrrole (1g).
To a suspension of malononitrile (600 mg, 9 mmoles) and KOH
(500 mg, 9 mmoles) in DMSO (30 ml) stirred at room
temperature for 0.5 hour, methyl 1-methyl-2-pyrrolecarbo-
dithioate (1030 mg, 6 mmoles) was added. The reaction mixture
was heated at 110° for 1.5 hour, cooled to room temperature,
then ethyl iodide (940 mg, 6 mmoles) was added. The mixture
was stirred for 2 hours, diluted with brine (100 ml) and extracted
with ether. After removal of ether, the residue was recrystallized
from ethanol to give 1110 mg (85%) of pyrrole 1g as yellow
solid, mp 68°; ir (potassium bromide): 2217, 1533, 1481, 1472,
1454, 1402, 1374, 1306, 1267, 1246, 1054, 945, 750, 688, 605
cm-1; 1H nmr (400 MHz, deuteriochloroform): ꢀ 1.22 (t, 3H, Me,
J = 7.3 Hz); 2.79 (q, 2H, SCH2, J = 7.3 Hz), 3.75 (s, 3H, NMe),
6.30 (dd, 1H, H-4, J = 3.9, 2.6 Hz), 6.69 (dd, 1H, H-3, J = 3.9,
1.7 Hz), 7.00 ppm (dd, 1H, H-5, J = 2.6, 1.7 Hz); 13C nmr (62.5
MHz, deuteriochloroform): ꢀ 14.4, 29.7, 35.4, 76.3, 110.8,
113.4, 114.0, 118.9, 125.2, 131.8, 168.6 ppm. Anal. Calcd. for
C11H11N3S: C, 60.80; H, 5.10; N, 19.34; S, 14.76. Found C,
60.52; H, 5.06; N, 19.02; S, 14.81.
3-Imino-1-(methylamino)-5,6,7,8-tetrahydro-3H-pyrrolo-
[1,2-a]indole-2-carbonitrile (4a). This compound was obtained
as yellow solid, 80 mg (88%), mp 215-216°; ir (potassium
bromide): 3276, 3292, 2190, 2205, 2179, 1653, 1576, 1536,
1
1297, 791, 760 cm-1; H nmr (400 MHz, deuteriochloroform): ꢀ
2-(2-Carbamoyl-2-cyano-1-ethylthioethenyl)-1-methyl-
pyrrole (1h). To a suspension of cyanoacetamide (660 mg, 9
mmoles) and KOH (500 mg, 9 mmoles) in DMSO (30 ml)
stirred at room temperature for 0.5 hour, methyl 1-methyl-2-
pyrrolecarbodithioate (1030 mg, 6 mmoles) was added. The
reaction mixture was heated at 110° for 1.5 hour, cooled to room
temperature, then ethyl iodide (940 mg, 6 mmoles) was added.
The mixture was stirred for 2 hours and then diluted with brine
(100 ml). The crystals formed were collected by filtration, dried
and recrystallized from ethanol to give 1060 mg (75%) of
pyrrole 1h (E/Z, 1:5) as yellow solid, mp 192°; ir (potassium
bromide): 3394, 3296, 3176, 2210, 1681, 1617, 1546, 1501,
1.75 (m, 2H, CH2-6), 1.82 (m, 2H, CH2-7), 2.49 (m, 2H, CH2-8),
2.85 (m, 2H, CH2-5), 3.23 (br s, 3H, NMe), 6.09 (br s, 1H,
=NH), 6.26 (s, 1H, H-3), 7.66 ppm (br s, 1H, NHMe). Anal.
Calcd. for C13H14N4: C, 69.00; H, 6.24; N, 24.76. Found: C,
68.78; H, 6.15; N, 24.96.
3-Imino-1-(methylamino)-5-phenyl-3H-pyrrolizine-2-carbo-
nitrile (4b). This compound was obtained as yellow solid, 76 mg
(77%), mp 202-203°; ir (potassium bromide): 3375, 3292, 2206,
1
2189, 2179, 1651, 1615, 1536, 1297, 1157, 758 cm-1; H nmr
(400 MHz, dimethylsulfoxide-d6): ꢀ 3.27 (br s, 3H, NMe), 6.60
(d, 1H, H-4, J = 4.0 Hz), 6.85 (d, 1H, H-3, J = 4.0 Hz), 7.31 (m,
1H, Ph-Hp), 7.40 (m, 2H, Ph-Hm), 7.55 (m, 2H, Ph-Ho), 7.80 (br
s, 1H, NHMe), 9.54 ppm (br s, 1H, =NH); 13C nmr (100 MHz,
deuteriochloroform): ꢀ 32.84, 81.70, 108.13, 117.4, 124.1,
124.9, 127.6, 128.9, 131.2, 137.4, 159.5, 166.8 ppm. Anal.
Calcd. for C15H12N4: C, 72.56; H, 4.87; N, 22.57. Found: C,
72.47; H, 4.79; N, 22.62.
1
1382, 1306, 1236, 939, 793, 732 cm-1; E-isomer: H nmr (400
MHz, deuteriochloroform): ꢀ 1.17 (t, 3H, Me, J = 7.5 Hz), 2.70
(q, 2H, SCH2, J = 7.5 Hz), 3.55 (s, 3H, NMe), 5.46 (br s, 2H,
CONH2), 6.28 (dd, 1H, H-4, J = 3.8, 2.6 Hz), 6.42 (dd, 1H, H-3,
J = 3.8, 1.7 Hz), 6.90 ppm (dd, 1H, H-5, J = 2.6, 1.7 Hz); 13C
nmr (62.5 MHz, deuteriochloroform): ꢀ 14.6, 28.5, 34.5, 102.5,
112.1, 114.7, 116.7, 124.5, 128.4, 161.3, 162.8 ppm. Z-isomer:
1H nmr (400 MHz, deuteriochloroform): ꢀ 1.13 (t, 3H, Me, J =
7.5 Hz), 2.38 (q, 2H, SCH2, J = 7.5 Hz), 3.61 (s, 3H, NMe), 5.65
(br s, 1H, CONH2), 6.17 (br s, 1H, CONH2), 6.23 (dd, 1 H, H-4,
J = 3.8, 2.7 Hz), 6.29 (dd, 1H, H-3, J = 3.8, 1.7 Hz,), 6.80 ppm
(dd, 1H, H-5, J = 2.7, 1.7 Hz); 13C nmr (62.5 MHz, deuterio-
chloroform): ꢀ 13.6, 28.1, 34.2, 101.7, 109.0, 112.1, 117.3,
125.6, 126.0, 163.9, 168.4 ppm. Anal. Calcd. for C11H13N3OS: C,
56.15; H, 5.57; N, 17.86; S, 13.62. Found: C, 56.12; H, 5.60; N,
17.68; S, 13.41.
General procedure for coupling of 2-(2-cyano-1-ethylthio-
ethenyl)pyrroles 1a-f with methylamine. A suspension of 2-(2-
cyano-1-ethylthioethenyl)pyrrole 1a-f (0.40 mmoles) in aqueous
methylamine solution (5 ml) was heated at 50-55° for 0.5 hour.
The suspension turned homogeneous and then crystalline
precipitate formed. The crystals were collected by filtration,
washed with water and dried. Recrystallization from ethanol gave
3-imino-1-methylaminopyrrolizine 4a-e and 2-(2-carbamoyl-2-
cyano-1-methylaminoethenyl)-5-phenylpyrrole (2f). The TLC
monitoring (Silufol, eluent – diethyl ether) of the reaction
indicates that its first stage is the cyclization of ethenylpyrroles
1a-e to 1-ethylthio-3-iminopyrrolizines 3a-e [yellow spots of
6-Ethyl-3-imino-1-(methylamino)-5-n-propyl-3H-pyrrol-
izine-2-carboxamide (4c). This compound was obtained as
yellow solid, 97 mg (93%), mp 191-192°; ir (potassium
bromide): 3358, 3263, 1653, 1625, 1589, 1570, 1426, 1280,
1
1153, 821, 797, 769 cm-1; H nmr (400 MHz, deuteriochloro-
form): ꢀ 1.00 (m, 3H, CH3 of propyl), 1.16 (m, 3H, CH3 of
ethyl), 1.65 (m, 2H, CH2-2 of propyl), 2.39 (m, 2H, CH2 of
ethyl), 2.71 (m, 2H, CH2-1 of propyl), 3.21 (d, 3H, NMe, J = 5.4
Hz), 5.10 (br s, 1H, CONH2), 6.23 (s, 1H, H-3), 7.15 (br s, 1H,
=NH), 8.12 (br s, 1H, CONH2), 8.96 ppm (br s, 1H, NHMe); 13
C
nmr (100 MHz, deuteriochloroform): ꢀ 14.0, 15.4, 18.7, 21.2,
26.7, 31.8, 89.5, 110.9, 126.6, 129.4, 131.9, 157.1, 157.8, 168.8
ppm. Anal. Calcd. for C14H20N4O: C, 64.59; H, 7.74; N, 21.52.
Found: C, 64.47; H, 7.56; N, 21.62.
5-n-Butyl-3-imino-1-(methylamino)-6-n-propyl-3H-pyrrol-
izine-2-carboxamide (4d). This compound was obtained as
yellow solid, 104 mg (90%), mp 154-155°; ir (potassium
bromide): 3364, 3268, 1623, 1584, 1571, 1425, 1273, 1153, 773
1
cm-1; H nmr (400 MHz, deuteriochloroform): ꢀ 0.95 (m, 6H,
CH3 of butyl and propyl), 1.41 (m, 2H, CH2-3 of butyl), 1.58 (m,
4H, CH2-2 of butyl and propyl), 2.33 (m, 2H, CH2-1 of propyl),
2.72 (m, 2H, CH2-1 of butyl), 3.20 (d, 3H, NMe, J = 5.1 Hz),
5.07 (br s, 1H, CONH2), 6.21 (s, 1H, H-3), 7.15 (br s, 1H, =NH),

May-Jun 2007
Facile Coupling of 2-(1-Ethylthioethenyl)Pyrroles with Amines
511
8.17 (br s, 1H, CONH2), 8.94 ppm (1H, br s, NHMe); 13C nmr
(100 MHz, deuteriochloroform): ꢀ 13.8, 14.0, 22.7, 24.1, 24.6,
27.6, 30.0, 31.7, 89.6, 111.5, 126.6, 127.5, 132.7, 157.1, 157.9,
168.9 ppm. Anal. Calcd. for C16H24N4O: C, 66.64; H, 8.39; N,
19.43. Found: C, 66.42; H, 8.23; N, 19.65.
3-Imino-1-(methylamino)-5,6,7,8-tetrahydro-3H-pyrrolo-
[1,2-a]indole-2-carboxamide (4e). This compound was
obtained as orange solid, 89 mg (91%), mp 210-211°; ir
(potassium bromide): 3330, 3149, 1636, 1620, 1589, 1574,
1523, 1478, 1427, 1272, 1137, 787, 738 cm-1; 1H nmr (400 MHz,
deuteriochloroform): ꢀ 1.76 (m, 2H, CH2-6), 1.88 (m, 2H, CH2-
7), 2.49 (m, 2H, CH2-8), 2.77 (m, 2H, CH2-5), 3.19 (d, 3H,
NMe, J = 5.1 Hz), 5.09 (br s, 1H, CONH2), 6.17 (s, 1H, H-3),
7.12 (br s, 1H, =NH), 8.03 (br s, 1H, CONH2), 8.90 ppm (br s,
1H, NHMe); 13C nmr (100 MHz, deuteriochloroform): ꢀ 22.5,
22.7, 22.9, 23.1, 31.8, 89.4, 110.5, 124.7, 126.2, 130.5, 156.9,
158.2, 168.8 ppm. Anal. Calcd. for C13H16N4O: C, 63.92; H,
6.60; N, 22.93. Found: C, 63.57; H, 6.34; N, 22.62.
164-165°; ir (potassium bromide): 3391-3183, 2190, 2172,
1651, 1630, 1605, 1538, 1485, 1389, 1377, 1269, 1009 cm-1; 1H
nmr (400 MHz, deuteriochloroform): ꢀ 0.95 (m, 6H, CH3 of
butyl and propyl) 1.32 (m, 2H, CH2-3 of butyl), 1.55 (m, 4H,
CH2-2 of butyl and propyl), 2.38 (m, 2H, CH2-1 of propyl), 2.60
(m, 2H, CH2-1 of butyl), 3.18 (s, 6H, NMe2), 5.37 (br s, 2H,
CONH2), 6.46 (d, 1H, H-3, J = 2.7 Hz), 9.00 ppm (br s, 1H,
NH); 13C nmr (62.5 MHz, dimethylsulfoxide-d6): ꢀ 13.9, 22.4,
24.1, 25.8, 27.9, 31.9, 44.0, 68.8, 118.5, 120.5, 123.3, 123.8,
137.0, 161.0, 167.5 ppm. Anal. Calcd. for C17H26N4O: C, 67.52;
H, 8.67; N, 18.53. Found: C, 67.39; H, 8.49; N, 18.23.
5-n-Butyl-1-(dimethylamino)-3-oxo-6-n-propyl-3H-pyrrol-
1
izine-2-carbonitrile (6d). H nmr (400 MHz, deuteriochloro-
form): ꢀ 0.95 (m, 6H, CH3 of butyl and propyl), 1.32 (m, 2H,
CH2-3 of butyl), 1.55 (m, 4H, CH2-2 of butyl and propyl), 2.38
(m, 2H, CH2-1 of propyl), 2.76 (m, 2H, CH2-1 of butyl), 3.38 (s,
3H, NMe2), 3.59 (s, 3H, NMe2), 6.25 (s, 1H, H-3).
2-(2-Carbamoyl-2-cyano-1-dimethylaminoethenyl)-4,5,6,7-
tetrahydroindole (5e). This compound was obtained as white
solid, 70 mg (68%), mp 219-220°; ir (potassium bromide): 3360,
3231, 3173, 2184, 1644, 1611, 1541, 1490, 1362, 1155, 1103,
General procedure for coupling of 2-(2-carbamoyl-2-
cyano-1-ethylthioethenyl)pyrroles 1c-e with dimethylamine.
A
suspension of 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl)-
1
812 cm-1; H nmr (400 MHz, deuteriochloroform): ꢀ 1.77 (4H,
pyrrole 1c-e (0.40 mmoles) in aqueous dimethylamine (5 ml) was
heated at 50-55° for 0.5 hour. The suspension turned homo-
geneous and then gave crystalline precipitate. The crystals were
immediately collected by filtration, washed with water and dried,
then washed with ether and recrystallized from ethanol to produce
3-pyrrolizinones 6c,e. This procedure was invalid to isolate pure
3-pyrrolizinone 6d, so it was characterized in the reaction mixture
by its 1H nmr. The filtrate was extracted with chloroform, washed
with water and dried over MgSO4. The residue after chloroform
removal was recrystallized from aqueous acetone (1:1, v/v) to give
2-(1-dimethylaminoethenyl)pyrrole 5c-e.
2-(2-Carbamoyl-2-cyano-1-dimethylaminoethenyl)-4-ethyl-
5-n-propylpyrrole (5c). This compound was obtained as cream-
colored solid (acetone:H2O, 1:1, v/v), 73 mg (68%, purity 98%),
mp 135-136°; ir (potassium bromide): 3423, 3201, 2185, 1630,
1609, 1549, 1386, 835, 772 cm-1; 1H nmr (400 MHz,
deuteriochloroform): ꢀ 0.95 (t, 3H, CH3 of propyl, J = 7.1 Hz),
1.15 (t, 3H, CH3 of ethyl, J = 7.5 Hz), 1.62 (m, 2H, CH2-2 of
propyl), 2.40 (q, 2H, CH2 of ethyl, J = 7.5 Hz), 2.56 (t, 2H, CH2-
1 of propyl, J = 7.1 Hz), 3.17 (s, 6H, NMe2), 5.34 (br s, 2H,
CONH2), 6.44 (d, 1H, H-3, J = 2.4 Hz), 8.89 ppm (1H, br s,
NH); 13C nmr (62.5 MHz, deuteriochloroform): ꢀ 13.8, 15.3,
18.8, 23.1, 27.9, 43.9, 69.1, 117.6, 120.4, 123.2, 125.4, 136.7,
161.0, 167.9 ppm. Anal. Calcd for C15H22N4O: C, 65.67; H,
8.08; N, 20.42. Found: C, 65.33; H, 8.00; N 20.21.
m, CH2-5,6), 2.51 (m, 2H, CH2-4), 2.65 (m, 2H, CH2-7), 3.21 (s,
6H, NMe2), 6.42 (d, 1H, H-3, J = 2.4 Hz), 8.56 ppm (br s, 1H,
NH); 13C nmr (62.5 MHz, dimethylsulfoxide-d6): ꢀ 21.7, 21.9,
22.3, 22.4, 41.6, 43.5, 71.5, 115.8, 116.9, 118.5, 121.7, 133.6,
160.0, 166.3 ppm. Anal. Calcd. for C14H18N4O: C, 65.09; H,
7.02; N, 21.69. Found: C, 65.39; H, 6.89; N, 21.44.
1-(Dimethylamino)-3-oxo-5,6,7,8-tetrahydro-3H-pyrrolo-
[1,2-a]indole-2-carbonitrile (6e). A suspension of 3-pyrroli-
zinone 7 (103 mg, 0.40 mmoles) in aqueous dimethylamine (5
ml) was heated for 5 min at 30-35° and then cooled to room
temperature. Crystals formed were filtered off, washed with
water, dried and recrystallized from aqueous acetone (1:1) to
give 82 mg (85%) of 6e as yellow crystals, mp 185-186°; ir
(potassium bromide): 3116, 2201, 2190, 1710, 1611, 1505,
1429, 1289, 742 cm-1; 1H nmr (400 MHz, deuteriochloroform): ꢀ
1.75 (m, 4H, CH2-6,7), 2.43 (m, 2H, CH2-8), 2.79 (m, 2H, CH2-
5), 3.35 (s, 3H, NMe2), 3.57 (s, 3H, NMe2), 6.19 ppm (s, 1H, H-
3); 13C nmr (100 MHz, deuteriochloroform): ꢀ 21.5, 21.9, 22.2,
22.4, 42.1, 43.4, 68.2, 116.1, 117.1, 124.4, 125.6, 134.5, 158.7,
164.0 ppm. Anal. Calcd. for C14H15N3O: C, 69.69; H, 6.27; N,
17.41. Found: C, 69.48; H, 6.19; N, 17.19.
2-(2-Carbamoyl-2-cyano-1-dimethylaminoethenyl)-5-phenyl-
pyrrole (5f). A suspension of 2-(2-cyano-1-ethylthioethenyl)-
pyrrole 1f (119 mg, 0.40 mmoles) in aqueous dimethylamine (5
ml) was heated for 0.5 hour at 50-55°. The suspension turned to
a homogeneous solution, from which crystals were then formed.
The latter were filtered off, washed with water and dried to give
77 mg (69%) of pyrrole 5f as white solid, mp 228-229°; ir
(potassium bromide): 3364, 3248, 3169, 2184, 1642, 1611,
1538, 1517, 1477, 1366, 1134, 799, 759 cm-1; 1H nmr (400 MHz,
dimethylsulfoxide-d6): ꢀ 2.96 (br s, 6H, NMe2), 6.69 (br s, 4H,
H-3,4, CONH2), 7.26 (m, 1H, Ph-Hp), 7.41 (m, 2H, Ph-Hm), 7.79
(m, 2H, Ph-Ho), 11.79 ppm (br s, 1H, NH); 13C nmr (62.5, MHz,
dimethylsulfoxide-d6): ꢀ 43.2, 73.47, 107.8, 117.9, 122.8, 124.6,
127.1, 128.8, 131.6, 136.3, 159.1, 165.9 ppm. Anal. Calcd. for
C16H16N4O: C, 68.55; H, 5.75; N, 19.99. Found: C, 68.39; H,
5.49; N, 20.18.
1-(Dimethylamino)-6-ethyl-3-oxo-5-n-propyl-3H-pyrrol-
izine-2-carbonitrile (6c). This compound was obtained as
yellow solid, 10 mg (10%), mp 174-175°; ir (potassium
1
bromide): 2194, 1716, 1617, 1506, 1409, 1299, 747 cm-1; H
nmr (400 MHz, dimethylsulfoxide-d6): ꢀ 0.86 (t, 3H, CH3 of
propyl, J = 7.1 Hz), 1.10 (t, 3H, CH3 of ethyl, J = 7.5 Hz), 1.66
(m, 2H, CH2-2 of propyl), 2.33 (q, 2H, CH2 of ethyl, J = 7.5 Hz),
2.67 (t, 2H, CH2-1 of propyl, J = 7.1 Hz), 3.33 (s, 3H, NMe2),
3.47 (s, 3H, NMe2), 6.71 ppm (s, 1H, H-3); 13C nmr (62.5 MHz,
deuteriochloroform): ꢀ 13.6, 15.2, 18.0, 21.7, 25.5, 41.6, 43.4,
66.1, 117.2, 117.5, 124.0, 129.9, 134.3, 157.2, 164.1 ppm. Anal.
Calcd. for C15H19N3O: C, 70.01; H, 7.44; N, 16.33. Found: C,
69.78; H, 7.39; N, 16.69.
5-n-Butyl-2-(2-carbamoyl-2-cyano-1-dimethylaminoethenyl)-
4-n-propylpyrrole (5d). This compound was obtained as
cream-colored solid (acetone:H2O, 1:1, v/v), 105 mg (87%), mp
General procedure for coupling of 2-(2-cyano-1-ethylthio-
ethenyl)pyrroles 1a,b with dimethylamine. A suspension of 2-
(2-cyano-1-ethylthioethenyl)pyrrole 1a,b (0.40 mmoles) in

512
B. A. Trofimov, L. N. Sobenina, A. I. Mikhaleva, O. V. Petrova, V. N. Drichkov, I. A. Ushakov,
O. A. Tarasova, D.-S. D. Toryashinova, Y. Yu. Rusakov, and L. B. Krivdin
Vol 44
aqueous dimethylamine solution (5 ml) was heated for 0.5 hour
at 50-55°. During that time, the suspension turned to a
homogeneous solution, from which a crystalline precipitate was
then formed. The crystals were collected by filtration, washed
with water and dried. Recrystallization from ethanol gave
1-dimethylamino-3-iminopyrrolizine 8a,b.
1-(Dimethylamino)-3-imino-5,6,7,8-tetrahydro-3H-pyrrolo-
[1,2-a]indole-2-carbonitrile (8a). This compound was obtained
as yellow solid, 87 mg (90%), mp 197-198°; ir (potassium
bromide): 3248, 2201, 2195, 1641, 1609, 1511, 1439, 1418,
1278, 1184, 1002, 901, 885, 713 cm-1; 1H nmr (250 MHz,
deuteriochloroform): ꢀ 1.72 (m, 4H, CH2-6,7), 2.46 (m, 2H,
CH2-8), 2.78 (m, 2H, CH2-5), 3.28 (s, 3H, NMe2), 3.41 (s, 3H,
NMe2), 6.15 (s, 1H, 3-H), 7.95 ppm (br s, 1H, NH); 13C nmr
(62.5 MHz, deuteriochloroform): ꢀ 22.4, 23.1, 23.4, 41.8, 42.8,
68.1, 112.4, 118.2, 125.1, 126.1, 133.2, 155.6, 159.3 ppm. Anal.
Calcd for C14H16N4: C, 69.97, H, 6.71; N, 23.31. Found: C,
69.78; H, 6.65; N, 23.66.
nmr (400 MHz, deuteriochloroform): ꢀ 2.99 (br s, 3H, NMe2),
3.43 (br s, 3H, NMe2), 3.67 (s, 3H, NMe), 6.25 (dd, 1H, H-4, J =
3.9, 2.7 H,), 6.49 (dd, 1H, H-3, J = 3.9, 1.7 Hz), 6.88 ppm (dd,
1H, H-5, J = 2.7, 1.7 Hz); 13C nmr (62.5 MHz, deuteriochloro-
form): ꢀ 34.6, 43.1, 53.1, 109.8, 116.5, 116.6, 117.2, 123.4,
128.6, 163.1 ppm. Anal. Calcd. for C11H12N4: C, 65.98; H, 6.04;
N, 27.98. Found: C, 65.79; H, 6.23; N, 28.14.
2-(2-Carbamoyl-2-cyano-1-dimethylaminoethenyl)-1-methyl-
pyrrole (5h). This compound was obtained as white solid, 60
mg (69%), mp 174-175°; ir (potassium bromide): 3427, 3140,
2181, 1659, 1608, 1554, 1534, 1437, 1394, 1341, 1205, 1122,
1
1058, 779, 732, 642, 608 cm-1; E-isomer: H nmr ( deuterio-
chloroform): ꢀ 3.19 (br s, 6H, NMe2), 3.57 (s, 3H, NMe), 5.19
(br s, 2H, CONH2), 6.24 (dd, 1H, H-4, J = 3.8, 2.6 Hz), 6.37 (dd,
1H, H-3, J = 3.8, 1.4 Hz), 6.85 ppm (1H, dd, H-5, J = 2.6, 1.4
Hz); 13C nmr (deuteriochloroform): ꢀ 34.6, 43.3, 75.9, 109.4,
115.3, 122.3, 125.1, 128.1, 160.4, 167.2 ppm. Z-isomer: 1H nmr
(deuteriochloroform): ꢀ 3.08 (s, 6H, NMe2), 3.69 (s, 3H, NMe),
5.53 (br s, 2H, CONH2), 6.24 (dd, 1H, H-4, J = 3.8, 2.6 Hz),
6.50 (dd, 1H, H-3, J= 3.8, 1.7 Hz), 6.87 ppm (dd, 1H, H-5, J =
2.6, 1.7 Hz); 13C nmr ( deuteriochloroform): ꢀ 34.6, 43.9, 74.5,
109.5, 117.0, 120.4, 126.1, 128.4, 160.4, 165.5 ppm. Anal.
Calcd. for C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C,
60.29; H, 6.33; N, 25.36.
General procedure for coupling of 2-(2-cyano-1-ethylthio-
ethenyl)pyrroles 1a,e and 1-ethylthio-3-iminopyrrolizines
3a,e with n-butylamine. A mixture of 2-(2-cyano-1-ethylthio-
ethenyl)pyrrole 1a,e or 1-ethylthio-3-iminopyrrolizine 3a,e (0.39
mmoles) and n-butylamine (142 mg, 1.94 mmoles) in 20 ml of
ethanol (or in a water-ethanol solution, 1:1, v/v) was heated at
70° for 4 hours. After cooling, the crystals that formed were
collected by filtration, dried and recrystallized from benzene to
give pyrrolizine 9a,e.
1-(Dimethylamino)-3-imino-5-phenyl-3H-pyrrolizine-2-
carbonitrile (8b). This compound was obtained as yellow solid,
89 mg (85%), mp 167-168°; ir (potassium bromide): 3254, 2190,
1642, 1609, 1470, 1447, 1421, 1166, 896, 788, 756, 714, 694
1
cm-1; H nmr (250 MHz, dimethylsulfoxide-d6): ꢀ 3.39 (s, 3H,
NMe2), 3.47 (s, 3H, NMe2) 6.57 (d, 1H, H-4, J = 4.0 Hz), 6.81
(d, 1H, H-3, J = 4.0 Hz), 7.35 (m, 3H, Ph-Hm,p), 7.90 (m, 2H, Ph-
Ho), 8.19 ppm (br s, 1H, NH); 13C nmr (62.5 MHz, dimethyl-
sulfoxide-d6): ꢀ 42.1, 42.8, 69.9, 112.9, 116.2, 117.8, 124.9,
127.7, 129.0, 130.4, 131.2, 138.1, 154.6, 159.3 ppm. Anal.
Calcd for C16H14N4: C, 73.26; H, 5.38; N, 21.36. Found: C,
73.09; H, 5.49; N, 21.69.
2-(2,2-Dicyano-1-dimethylaminoethenyl)-5-phenylpyrrole
1
(5b). H nmr (400 MHz, dimethylsulfoxide-d6): ꢀ 3.15 (s, 6H,
NMe2); 6.39 (m, 1H, H-3), 6.71 (m, 1H, H-4), 7.32 (m, 1H, Ph-
Hp), 7.45 (m, 2H, Ph-Hm), 7.78 (m, 2H, Ph-Ho), 11.98 ppm (br s,
1H, NH); 13C nmr (62.5 MHz, dimethylsulfoxide-d6): ꢀ 43.4,
69.9, 108.4, 118.0, 118.8, 119.2, 122.3, 128.0, 128.6, 128.9,
131.2, 137.8, 162.4 ppm.
1-(n-Butylamino)-3-imino-5,6,7,8-tetrahydro-3H-pyrrolo-
[1,2-a]indole-2-carbonitrile (9a). This compound was obtained
as yellow solid, 84 mg (80%), mp 148°; ir (potassium bromide):
1
3255, 2205, 2188, 1646, 1610, 1575, 1408, 1182, 805 cm-1; H
nmr (400 MHz, deuteriochloroform): ꢀ 0.97 (m, 3H, Me), 1.45
(m, 2H, CH2-3 of butyl), 1.69 (m, 2H, CH2-2 of butyl), 1.71 (m,
2H, CH2-6), 1.82 (m, 2H, CH2-7), 2.48 (m, 2H, CH2-8), 2.85 (m,
2H, CH2-5), 3.50 (m, 2H, NCH2), 5.54 (br s, 1H, =NH), 6.22 (s,
1H, H-3), 7.70 ppm (br s, 1H, NHBu); 13C nmr (400 MHz,
deuteriochloroform): ꢀ 13.7, 20.0, 22.4, 23.1, 23.2, 23.4, 31.5,
45.8, 95.5, 111.9, 124.8, 125.3, 133.8, 157.5, 158.4 ppm. Anal.
Calcd for C16H20N4: C, 71.61; H, 7.51; N, 20.88. Found: C,
71.49; H, 7.67; N, 20.62.
General procedure for coupling of 2-(2-cyano-1-ethylthio-
ethenyl)-1-methylpyrroles 1g,h with aqueous methyl- and
dimethylamine.
A
suspension of 2-(2-cyano-1-ethylthio-
ethenyl)-1-methylpyrrole 1g,h (0.40 mmoles) in aqueous amine
solution (5 ml) was heated for 0.5 hour at 50-55°. Then the
reaction mixture was cooled to room temperature and extracted
with chloroform. After removal of chloroform, the residue was
recrystallized from ethanol to give 2-(2-cyano-1-aminoethenyl)-
1-methylpyrrole 2h, 5g,h.
1-(n-Butylamino)-3-imino-5,6,7,8-tetrahydro-3H-pyrrolo-
[1,2-a]indole-2-carboxamide (9e). This compound was
obtained as yellow solid, 73 mg (65%), mp 184°; ir (potassium
bromide): 3326, 3157, 1634, 1617, 1586, 1569, 1520, 1471,
1272, 1167, 1146, 973, 952, 780 cm-1; 1H nmr (400 MHz,
deuteriochloroform): ꢀ 0.95 (3H, m, Me) 1.44 (2H, m, CH2-3 of
butyl), 1.68 (2H, m, CH2-2 of butyl), 1.76 (2H, m, CH2-6), 1.86
(2H, m, CH2-7), 2.46 (2H, m, CH2-8), 2.82 (2H, m, CH2-5), 3.42
(2H, m, NCH2), 5.01 (1H, br s, CONH2), 6.12 (1H, s, H-3), 7.12
(1H, br s, =NH), 8.00 (1H, br s, CONH2), 9.05 ppm (1H, br s,
NHBu); 13C nmr (100 MHz, deuteriochloroform): ꢀ 13.8, 20.1,
22.5, 22.6, 22.9, 23.1, 31.9, 45.1, 89.2, 110.0, 124.3, 126.1,
129.9, 156.7, 157.1, 168.7 ppm. Anal. Calcd for C16H22N4O: C,
67.11; H, 7.74; N, 19.56. Found: C, 66.73; H, 7.92; N, 19.48.
Reaction of 1e, 3e with di(n-butyl)amine. A mixture of
pyrrole 1e or pyrrolizine 3e (107 mg, 0.39 mmoles) and di(n-
2-(2-Carbamoyl-2-cyano-1-methylaminoethenyl)-1-methyl-
pyrrole (2h). This compound was obtained as white solid, 60 mg
(73%), mp 212-213°; ir (potassium bromide): 3469-3185, 2189,
1635, 1583, 1488, 1461, 1417, 1401, 1354, 1334, 1290, 870, 835,
736 cm-1; 1H nmr (400 MHz, deuteriochloroform): ꢀ 2.85 ppm (d,
3H, NHMe, J = 5.0 Hz), 3.64 (s, 3H, NMe), 5.23 (br s, 1H,
CONH2), 5.78 (br s, 1H, CONH2), 6.23 (dd, 1H, H-4, J = 3.8, 2.7
Hz), 6.35 (dd, 1H, H-3, J = 3.8, 1.7 Hz), 6.79 (dd, 1H, H-5, J =
2.7, 1.7 Hz), 10.48 (br s, 1H, NHMe) ppm; 13C nmr (62.5 MHz,
deuteriochloroform): ꢀ 31.9, 34.5, 73.9, 109.0, 112.5, 120.4,
122.9, 125.6, 163.2, 170.2 ppm. Anal. Calcd. for C10H12N4O: C,
58.81; H, 5.92; N, 27.43. Found: C, 59.09; H, 5.79; N, 27.41.
2-(2,2-Dicyano-1-dimethylaminoethenyl)-1-methylpyrrole
(5g). This compound was obtained as white solid, 52 mg (65%),
mp 116-117°; ir (potassium bromide): 2206, 2193, 1556, 1535,
1
1480, 1465, 1444, 1403, 1304, 1114, 1058, 750, 716 cm-1; H

May-Jun 2007
Facile Coupling of 2-(1-Ethylthioethenyl)Pyrroles with Amines
513
[11] Murzina, N. M.; Vokin, A. I.; Sobenina, L. N.; Turchaninov,
V. K. Russ. J. Gen. Chem. 2002, 72, 793; Zh. Obshch. Khim. 2002, 72,
848. [b] Murzina, N. M.; Vokin, A. I.; Fedorov, S. V.; Demenev, A. P.;
Sobenina, L. N.; Mikhaleva, A. I. Russ. J. Gen. Chem. 2002, 72, 945;
Zh. Obshch. Khim. 2002, 72, 1011.
[12] Trofimov, B. A.; Shatenshtein, A. I.; Petrov, E. S. Khim.
Geterotsikl. Soedin. 1980 632.
[13] Krivdin, L. B.; Kalabin, G. A.; Nesterenko, R. N.; Trofimov,
B. A. Tetrahedron Lett. 1984, 25, 4817.
butyl)amine (251 mg, 1.94 mmoles) in 20 ml of ethanol (or in a
water-ethanol solution, 1:1, v/v) was heated at 70° for 4 hours.
After cooling, the reaction mixture was diluted with water and
extracted with chloroform. The extracts were washed with water
and dried over CaCl2. The residue left after chloroform removal
had 1H nmr spectra identical to those of 1-ethylthio-3-
iminopyrrolizine 3e [10].
[14] [a] Nielsen, E. S.; Jorgensen, P.; Oddershede, J. J. Chem.
Phys. 1980, 73, 6238. [b] Packer, M. J.; Dalskov, E. K.; Enevoldsen, T.;
Jensen, H.; Oddershede, J. J. Chem. Phys. 1996, 105, 5886. [c]
Enevoldsen, T.; Oddershede, J.; Sauer, S. P. A. Theor. Chem. Acc.
1998, 100, 275. [d] Bak, K. L.; Koch, H.; Oddershede, J.; Christiansen,
O.; Sauer, S. P. A. J. Chem. Phys. 2000, 112, 4173.
REFERENCES
[1] Trofimov, B. A. in The Chemistry of Heterocyclic
Compounds. Pyrroles, Part 2; Jones, R. A. Ed, Wiley, New York, 1992,
Vol 48, pp 131-298.
[15] [a] Dunning, T. H., Jr.; J. Chem. Phys. 1989, 90, 1007. [b]
Kendall, R. A. Dunning, T. H., Jr.; Harrison, R. J. J. Chem. Phys. 1992, 96,
6796. [c] Woon, D. E.; Dunning, T. H., Jr.; J. Chem. Phys. 1993, 98, 1358.
[16] Woon, D. E.; Dunning, T. H., Jr.; J. Chem. Phys. 1995, 103,
4572.
[17 ] [a] Krivdin, L. B.; Sauer, S. P. A.; Peralta, J. E.; Contreras, R.
H. Magn. Reson. Chem. 2002, 40, 187. [b] Sauer, S. P. A.; Krivdin, L. B.
Magn. Reson. Chem. 2004, 42, 671. [c] Krivdin, L. B. Magn. Reson.
Chem. 2004, 42, 168. [d] Krivdin, L. B. Magn. Reson. Chem. 2005, 43,
101.
[2] Sobenina, L. N.; Demenev, A. P.; Mikhaleva A. I.; Trofimov
B. A. Usp. Khim. 2002, 71, 641; Russ. Chem. Rev. 2002, 71, 563.
[3] Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.;
Mikhaleva, A. I. Chem. Rew. 2004, 104, 2481.
[4] [a] Hartke, K.; Radau, S. Liebigs Ann. Chem. 1974 2110. [b]
Tominaga, Y.; Matsuoka, Y.; Oniyama, Y.; Uchimura, Y.; Komiya, H.;
Hirayama, M.; Kohra S.; Hosomi, A. J. Heterocycl. Chem. 1990, 27,
647.
[5] Ong, C. W.; Lai, M. C.; Chang, Y. A. Heterocycles, 2002,
57, 1303.
[18] Wagner, G.; Wüthrich, K. J. Mol. Biol. 1982, 155, 347.
[19] Bodenhausen, G.; Ruben, D. J. Chem. Phys. Lett. 1980, 69,
185.
[20] Bax, A.; Freeman, R.; Kempsell, S. P. J. Am. Chem. Soc.
1980, 102, 4849.
[21] Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.;
Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K.
A.; Su, S. J.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comp.
Chem. 1993, 14, 1347.
[22] Agren, H.; Angeli, C.; Bak, K. L.; Bakken, V.;. Christiansen,
O.; Cimiraglia, R.; Coriani, S.; Dahle, P.; Dalskov, E. K.;
Enevoldsen, T.; Fernandez, B.; Haettig, C.; Hald, K.; Halkier, A.;
Heiberg, H.; Helgaker, T.; Hettema, H.; Jensen, H. J. A.; Jonsson, D.;
Joergensen, P.; Kirpekar, S.; Klopper, W.; Kobayashi, R.; Koch, H.;
Ligabue, A.; Lutnaes, O. B.; Mikkelsen, K. V.; Norman, P. ; Olsen, J.;
Packer, M. J.; Pedersen, T. B.; Rinkevicius, Z.; Rudberg, E.; Ruden, T.
A.; Ruud, K.; Salek, P.; Sanchez de Meras, A.;. Saue, T.; Sauer, S. P.
A.; Schimmelpfennig, B.;. Sylvester-Hvid, B.; Taylor, K. O.; Vahtras,
P. R.; Wilson, O.; Dalton, D. J. A Molecular Electronic Structure
Program, Release 2.0 (2005), see http://www.kjemi.uio.no/softw
[6] [a] Trofimov, B. A.; Sobenina, L. N.; Mikhaleva, A. I.;
Sergeeva, M. P.; Golovanova, N. I.; Polovnikova, R. I.; Vavilova, A. N.
Khim. Geterotsikl. Soedin. 1992 1176. [b] Trofimov, B. A.; Sobenina, L.
N.; Mikhaleva, A. I.; Sergeeva, M. P.; Polovnikova, R. I. Sulfur Lett.
1992, 15, 219. [c] Sobenina, L. N.; Protasova, L. E.; Sergeeva, M. P.;
Petrova, O. V.; Aksamentova, T. N.; Kozyreva, O. B.; Polovnikova, R.
I.; Mikhaleva, A. I.; Trofimov, B. A. Chem. Heterocycl. Compd. 1995
47; Khim. Geterotsikl. Soedin. 1995 47. [d] Trofimov, B. A.; Sobenina,
L. N.; Mikhaleva, A. I.; Demenev, A. P.; Tarasova, O. A.; Ushakov, I.
A.; Zinchenko, S. V. Tetrahedron 2000, 56, 7325.
[7] Verkruijsse, H. D.; Brandsma, L. J. Organomet. Chem. 1987,
332, 95.
[8] Sobenina, L. N.; Mikhaleva, A. I.; Sergeeva, M. P.; Petrova,
O. V.; Aksamentova, T. N.; Kozyreva, O. B.; Toryashinova, D.-S. D.;
Trofimov, B. A. Tetrahedron 1995, 51, 4223.
[9] Sobenina, L. N.; Mikhaleva, A. I.; Toryashinova, D.-S. D.;
Kozyreva, O. B.; Trofimov, B. A. Sulfur Lett. 1997, 20, 205.
[10] Sobenina, L. N.; Mikhaleva, A. I.; Sergeeva, M. P.;
Toryashinova, D.-S. D.; Kozyreva, O. B.; Trofimov, B. A. Chem.
Heterocycl. Compd. 1996 919; Khim. Geterotsikl. Soedin. 1996 919.