1,3-Dipolar cycloaddition of difluoro-substituted azomethine ylides. Synthesis and transformations of 2-fluoro-4,5-dihydropyrroles

Article abstract of DOI:10.1007/s11178-005-0373-x

2-Fluoro-4,5-dihydropyrrole-3,4-dicarboxylic acid derivatives were obtained by reaction of difluorocarbene with N-substituted ketone imines in the presence of fumaronitrile, maleonitrile, or dimethyl maleate. The reaction involves intermediate formation of azomethine ylides and their subsequent cycloaddition at the double bond. 11H-Dibenz[b,e]azepine and 3,4-dihydroisoquinolines react with difluorocarbene in the presence of fumaronitrile to give fluoro-substituted dibenzo[c,f]pyrrolo[1,2-a]azepine and pyrrolo[2,1-a]-isoquinoline derivatives. Treatment of 2-fluoro-4,5-dihydropyrrole-3,4-dicarbonitrile with amines and alkoxides affords the corresponding 2-amino- and 2-alkoxy derivatives, while its reactions with hydrazine hydrate and benzimidamide lead to formation of substituted pyrrolo[2,3-c]pyrazole and pyrrolo[2,3-d]-pyrimidine derivatives.

Full text of DOI:10.1007/s11178-005-0373-x

Russian Journal of Organic Chemistry, Vol. 41, No. 10, 2005, pp. 1496–1506. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 10, 2005,
pp. 1527–1537.
Original Russian Text Copyright © 2005 by Novikov, Khlebnikov, Shevchenko, Kostikov, Vidovic.
1,3-Dipolar Cycloaddition of Difluoro-Substituted
Azomethine Ylides. Synthesis and Transformations
of 2-Fluoro-4,5-dihydropyrroles
M. S. Novikov1, A. F. Khlebnikov1, M. V. Shevchenko1, R. R. Kostikov1, and D. Vidovic2
1 St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: Mikhail.Novikov@pobox.spbu.ru
2 Institut für anorganische Chemie, Georg-August-Universität, Göttingen, Germany
Received November 24, 2004
Abstract—2-Fluoro-4,5-dihydropyrrole-3,4-dicarboxylic acid derivatives were obtained by reaction of
difluorocarbene with N-substituted ketone imines in the presence of fumaronitrile, maleonitrile, or dimethyl
maleate. The reaction involves intermediate formation of azomethine ylides and their subsequent cycloaddition
at the double bond. 11H-Dibenz[b,e]azepine and 3,4-dihydroisoquinolines react with difluorocarbene in the
presence of fumaronitrile to give fluoro-substituted dibenzo[c,f]pyrrolo[1,2-a]azepine and pyrrolo[2,1-a]-
isoquinoline derivatives. Treatment of 2-fluoro-4,5-dihydropyrrole-3,4-dicarbonitrile with amines and
alkoxides affords the corresponding 2-amino- and 2-alkoxy derivatives, while its reactions with hydrazine
hydrate and benzimidamide lead to formation of substituted pyrrolo[2,3-c]pyrazole and pyrrolo[2,3-d]-
pyrimidine derivatives.
Pyrrole derivatives are widely used in synthetic and
medical practice [1]. In the recent years, much atten-
tion was given to fluorinated pyrroles as potential
biologically active substances. Several synthetic ap-
proaches to fluoropyrroles have been reported. Among
these, direct fluorination of pyrrole derivatives [2, 3],
transfunctionalization according to Schiemann [4],
heterocyclization of fluorinated linear precursors [5],
and 1,3-dipolar cycloaddition with participation of
either fluorine-containing azomethine ylides [6–8] or
fluorinated dipolarophiles [9, 10] must be noted.
cesium fluoride resulted in formation of only 4% of
2-fluoro-1-methyl-2,3-dihydropyrrole-3-carbonyl
fluoride [12].
We recently found that reactions of difluorocarbene
with Schiff bases in the presence of 2-butenedioic acid
derivatives could lead to 2-fluoro-4,5-dihydropyrroles
in good yields [13]. The present article reports the
results of our detailed study on the reactions of various
ketone imines with difluorocarbene in the presence of
fumaric and maleic acid derivatives as a method of
synthesis of substituted 2-fluoro-4,5-dihydropyrroles
and building up of a 2-fluoro-4,5-dihydropyrrole frag-
ment as a part of a polycyclic system. Difluorocarbene
was generated in situ by reduction of dibromodifluoro-
methane with lead in the presence of tetrabutylammo-
nium bromide.
2-Fluoro-4,5-dihydropyrroles attract interest not
only as potential biologically active substances but
also as useful building blocks having a labile fluorine
atom in the Į-position with respect to nitrogen. How-
ever, there are no convenient methods for the prepara-
tion of such compounds. Only two kinds of trans-
formations are known to produce 2-fluoro-4,5-dihydro-
pyrrole systems [11, 12]. Photolytic ring contraction
in N-substituted perfluoroazepines to give perfluoro-
(3a,5a-dihydrocyclobuta[b]pyrroles) cannot be re-
garded as an acceptable synthetic route to 2-fluoro-4,5-
dihydropyrroles, for its scope is limited to perfluorinat-
ed derivatives [11]. The reaction of N-methylpyr-
rolidone with carbonyl fluoride in the presence of
The reactions of Schiff bases Ia–Id with difluoro-
carbene in the presence of fumaronitrile, maleonitrile,
or dimethyl fumarate afforded dihydropyrroles IIa–IId
and III which were isolated in good yields by column
chromatography. The reaction mechanism includes
attack by difluorocarbene on the lone electron pair on
the nitrogen atom in Schiff base Ia–Id to give azo-
methine ylide IVa–IVd, cycloaddition of the latter at
the double C=C bond of 2-butenedioic acid derivative,
1070-4280/05/4110-1496 © 2005 Pleiades Publishing, Inc.

1,3-DIPOLAR CYCLOADDITION OF DIFLUORO-SUBSTITUTED AZOMETHINE YLIDES.
1497
Scheme 1.
Pb/Bu4NBr
CF2Br2
CF2
R2
R2
R3
R1
R1
R2
R1
R1
R2
R1
F
F
R1
R1
R3
CF2
N
N
F
N
N
R1
R3
Va–Ve, VI
–HF
CF2
R3
R3
R3
Ia–Ie
IVa–IVe
IIa–IIe, III
I, IV, R1 = Ph, R2 = H (a), PhCH2 (b), MeOCO (c); R1R1 = 2,2'-biphenylene, R2 = H (d); R1R1 = 2,2'-(C6H4OC6H4), R2 = H (e);
II, V, R1 = Ph, R2 = H, R3 = CN (a), R2 = PhCH2, R3 = CN (b), R2 = MeOCO, R3 = CN (c); R1R1 = 2,2'-biphenylene, R2 = H, R3 =
CN (d); R1R1 = 2,2'-(C6H4OC6H4), R2 = H, R3 = CN (e); III, VI, R1 = Ph, R2 = H, R3 = MeOCO.
and dehydrofluorination of difluoropyrrolidine Va–Vd
or VI thus formed (Scheme 1). The isolated fluorodi-
hydropyrroles are fairly stable: they can be stored for
a long time below 5°C. However, they undergo slow
hydrolysis to the corresponding lactams in chloroform
solution.
The reaction of Schiff base Ic with difluorocarbene
in the presence of fumaronitrile is the only example of
intermolecular cycloaddition in iminiodifluorometha-
nide, in which the primary adduct, intermediate 2,2-di-
fluorodihydropyrrole, was isolated. This reaction pro-
vides a convenient model for studying stereoselec-
tivity in the cycloaddition of geminal difluoro-substi-
Compound III formed by addition of ylide IVa to
dimethyl maleate is less stable. We succeeded in isolat-
ing this product by chromatography using an eluent
containing anhydrous triethylamine. Dihydropyrrole
III can be stored for several months at –18°C. It was
obtained in a good yield (64%) when activated lead
was used instead of lead filings [7], presumably due to
shortened reaction time. The primary adducts, com-
pounds V and VI are extremely unstable, and we failed
to isolate or detect them by chromatography. An ex-
ception was compound Vc. It was obtained as an ana-
lytically pure substance in 38% yield (together with
18% of dihydropyrrole IIc) from Schiff base Ic and
fumaronitrile. When the reaction mixture was treated
with anhydrous triethylamine before chromatographic
treatment, the yield of IIc increased to 63%.
1
tuted azomethine ylides. According to the H and 13C
NMR data, the reactions of ketone imine Ic with
difluorocarbene in the presence of fumaronitrile and
maleonitrile give different isomeric dihydropyrroles:
trans-Vc and cis-Vc, respectively (Scheme 2). The
1H NMR spectrum of trans-Vc contains a doublet at
į 4.63 ppm (JHH = 12.4 Hz) from the 3-H proton, while
the corresponding signal of cis-Vc is located at
į 4.64 ppm (JHH = 8.2 Hz). The 4-H signal of trans-Vc
appears as a double doublet of doublets at į 3.74 ppm
(JHH = 12.4, JHF = 8.8, 5.3 Hz), while isomer cis-Vc is
characterized by a doublet of doublets at į 4.16 ppm
(4-H, JHH = 8.2, JHF = 15.4 Hz). Compounds trans-Vc
and cis-Vc in CDCl3 undergo gradual hydrolysis with
traces of water to give lactams trans-VII and cis-VII.
Scheme 2.
COOMe
F
COOMe
O
NC
Ph
Ph
Ph
Ph
N
N
H2O
CN
F
NC
CN
NC
CN
Ph
Ph
COOMe
Ph
Ph
COOMe
CF2
trans-Vc
trans-VII
N
N
CF2
COOMe
COOMe
Ic
IVc
Ph
Ph
F
Ph
Ph
N
N
H2O
NC
CN
O
F
NC
CN
NC
CN
cis-VII
cis-Vc
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

NOVIKOV et al.
1498
Scheme 3.
F
Me
Me
CF2
Me
N
N
N
F
CF2
O
O
O
Ie
IVe
X
Me
N
Me
F
N
O
NHMe
·
F
Pb
H2O/SiO2
O
O
O
XI
XII
Me
N
Me
N
Me
Me
F
O
N
N
F
X
H2O/SiO2
XI
O
O
O
O
IX
VIII
Thus the addition of ylide IVc to fumaronitrile and
maleonitrile occurs with retention of the configuration
of the double bond, which is typical of concerted
processes.
of the reaction mixture, we succeeded in isolating pre-
cursor of VIII, difluoride IX (using benzene–chloro-
form–ethyl acetate as eluent). Spirocyclic pyrrolidi-
none VIII is likely to be formed by hydrolysis of IX
over silica gel. In fact, compound VIII was obtained in
42% yield when difluoride IX was applied to silica gel
9-Methyliminoxanthene (Ie) also revealed a spe-
cific behavior under conditions of difluorocarbene
generation, and the corresponding dihydropyrrole
derivative Ve was isolated in only 7% yield. The other
product was compound VIII (26%) (Scheme 3). In the
absence of fumaronitrile, the yield of VIII was 72%.
By varying conditions for chromatographic treatment
13
and kept for 12 h. The C NMR spectrum of IX con-
tained triplet signals from C5 at įC 125.3 ppm (JHF
=
255 Hz) and C4 at įC 60.2 ppm (JHF = 18.5 Hz).
A probable scheme of formation of geminal difluoro
derivative IX (Scheme 3) includes successive genera-
Scheme 4.
R2
R2
R2
CF2
N
N
R2
CF2
R1
XIIIa–XIIId
R1
R2
R2
R2
MeO
MeO
NC
N
N
H2O
R1 = H, R2 = MeO
N
CN
R2
F
F
O
+
R1
R1
NC
XVa–XVd
H
NC
XVI
–HF
NC
CN
CN
CN
XIVa–XIVd
R1 = Ph, R2 = MeO (a), H (b); R1 = 3,4-(CH2O2)C6H3, R2 = H (c); R1 = H, R2 = MeO (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

1,3-DIPOLAR CYCLOADDITION OF DIFLUORO-SUBSTITUTED AZOMETHINE YLIDES.
1499
tion of ylide IVe and its transformation into ketene
imine XI through aziridine X. Some analogies of the
transformation X ĺ XI are known from the literature.
For example, reductive opening of the three-membered
C16
C15
ring in 2,2-dichloroaziridines by the action of zinc dust
was reported [14] to produce ketene imines. Taking
into account our previous data on the stability of
fluorine- and chlorine-containing 1,2-diaryl-3,3-di-
haloaziridines [15], we anticipated that aziridine X
should be extremely unstable due to the presence of
strong ʌ-donor substituents in the benzene rings and of
a fluorine atom at C3 in the aziridine ring. Both these
factors favor opening of the aziridine ring at the C–N
bond opposite to the CF2 group. Apart from com-
pounds VIII and IX, we isolated a small amount of
amide XII whose structure was proved by the X-ray
diffraction data (see figure). It is known that ketene
imines readily undergo hydrolysis to the corresponding
amides [16]; therefore, the presence of compound XII
among the products is a strong evidence in support of
inter-mediate formation of ketene imine XI.
C17
C14
C18
C13
C5
N2
O12
C3
O4
C1
C11
C6
C7
C10
C9
C8
Structure of the molecule of N-methyl-9H-xanthene-9-car-
boxamide (XII) according to the X-ray diffraction data.
spondingly, the 1-CN and 10b-Ph substituents in XIVa
are arranged cis. Compounds XIVa–XIVd are charac-
terized by smaller hydrogen–fluorine coupling con-
stants for the 10b-H proton (JHF = 2.5–3.1 Hz) than
those for stereoisomers XVa–XVd (JHF = 4.4–4.6 Hz).
It should be emphasized that the behavior of ylide
IVe is not typical of geminal difluoro-substituted azo-
methine ylides [17] which as a rule readily react with
electron-deficient unsaturated compounds according to
the cycloaddition pattern rather than undergo intra-
molecular ring closure to aziridines. Presumably, the
reason for the anomalous reactivity of ylide IVe is
considerable rotation of the xanthene ring system with
respect to the plane of the C–N(Me)–CF2 ylide frag-
ment (53°, PM3), which facilitates conrotatory closure
of aziridine ring, on the one hand, and increases steric
hindrances to cycloaddition to a dipolarophile, on the
other. For comparison, the corresponding dihedral
angle in C,C-diphenyl-substituted ylide IVa is 17°
(see also [18]).
Fluorodihydropyrroles derived from aldehyde
imines are less hydrolytically stable than the corre-
sponding ketone derivatives, and they cannot be syn-
thesized by the above method [19, 20]. On the other
hand, cyclic analogs of such Schiff bases can be con-
verted into fused fluoropyrrole systems provided that
no traces of acids are present at the stage of chromato-
graphic treatment of the reaction mixture. From
6,7-dimethoxy-3,4-dihydroisoquinoline (XIIId) and
fumaronitrile we obtained a mixture of stereoisomeric
pyrroloisoquinolines XIVd and XVd in an overall
yield of 39% (Scheme 4), which were isolated by chro-
matography using an eluent containing triethylamine.
1-Phenyl-3,4-dihydroisoquinolines XIIIa–XIIIc re-
acted with difluorocarbene in the presence of fumaro-
nitrile in a way similar to acyclic Schiff bases Ia–Id,
but the products were mixtures of stereoisomeric
pyrroloisoquinolines XIVa–XIVc/XVa–XVc (overall
yield 59–69%, Scheme 4). The relative configuration
of the chiral centers in molecules XIVa and XVa was
determined by NOE experiments. Irradiation of the
1-H proton in XIVa gave a response on the 10-H
signal which increased in intensity by 14%. Irradiation
of the same proton in XVa did not change the 10-H
signal intensity, but an 11% response was observed
on the ortho proton in the benzene ring. These data
indicate that the cyano group on C1 in XVa is oriented
trans with respect to the benzene ring on C10b; corre-
1
According to the H NMR data, the isomer ratio
XIVd:XVd was 3:1. Compound XIVd was isolated in
the pure state as a stable crystalline substance and was
1
characterized by the H and 13C NMR and IR spectra;
its elemental composition was consistent with the as-
sumed structure. We failed to isolate compound XVd
as individual substance (it was characterized only by
1
the H NMR spectrum), for it readily underwent hy-
drolysis to lactam XVI upon attempted purification by
crystallization or chromatography. Lactam XVI showed
in the 13C NMR spectrum a signal at įC 160.3 ppm
from the carbonyl carbon atom, and its mass spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

NOVIKOV et al.
1500
Scheme 5.
CF2
N
N
CF2
XVII
NC
CN
N
N
H
H
+
–HF
NC
F
NC
F
CN
CN
XVIII
XIX
contained the molecular ion peak [M]+ with m/z 297
(50%). On the basis of spin–spin coupling constats in
the 1H NMR spectra, isomer XIVd was assigned trans
configuration with respect to the substituents on C1 and
C10b (JHH = 4.2 Hz), and compound XVd, cis con-
figuration (JHH = 10.1 Hz) [21]. 3-Oxo-1,2,3,5,6,10b-
hexahydropyrrolo[2,1-a]isoquinoline-1,2-dicarbo-
nitrile XVI was isolated in 9% yield.
this reaction (36%) was considerably lower than in
analogous reactions with ketone imines Ia–Id.
Compounds IIa–IIe, III, XIVa–XIVd, XVa–XVd,
XVIII, and XIX contain several functional groups
which make them promising from the viewpoint of
further transformations, in particular those leading to
polyheterocyclic systems. By treatment of fluorodi-
hydropyrrole IIa with aqueous ammonia, methyl-
amine, and 2-phenylethylamine we obtained the corre-
sponding 2-amino-, 2-methylamino-, and 2-(2-phenyl-
ethylamino)-4,5-dihydropyrroles XX–XXII (Scheme 6).
The reaction of IIa with methanol in the presence of
potassium carbonate afforded 2-methoxy derivative
XXIII which was isolated in 72% yield. Compound
IIa reacted with hydrazine hydrate to give 74% of
Under analogous conditions, the reaction of 11H-di-
benz[b,e]azepine (XVII) with difluorocarbene in the
presence of fumaronitrile gave stereoisomeric fluoro-
dihydropyrroledinitriles XVIII and XIX (Scheme 5).
Compounds XVIII and XIX are more stable to hy-
drolysis than XIVd and XVd, and they can be isolated
as analytically pure substances. The overall yield in
Scheme 6.
Me
N
Ph
Ph
NH3 (aq.)
NH2
NHR
OMe
Me
Me
H
N
N
Ph
Ph
N
NC
CN
Ph
Ph
NHNH2
NH2NH2
N
XX
Me
N
Me
N
NH2
NC
CN
XXIV
NC
XXV
Ph
Ph
Ph
Ph
RNH2
F
Me
NC
CN
NC
CN
N
Ph
N
PhC(=NH)NH2
Ph
Ph
XXI, XXII
IIa
N
Me
N
Ph
Ph
O
NH2
XXVI
MeOH/K2CO3
NC
CN
XXIII
XXI, R = Me; XXII, R = PhCH2CH2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

1,3-DIPOLAR CYCLOADDITION OF DIFLUORO-SUBSTITUTED AZOMETHINE YLIDES.
1501
2-hydrazino-1-methyl-5,5-diphenyl-4,5-dihydropyr-
role-3,4-dicarbonitrile (XXIV) which underwent intra-
molecular ring closure to pyrrolo[2,3-c]pyrazole XXV
on heating at 100°C in toluene (yield 84%). The reac-
tion of IIa with benzimidamide involved both cyano
groups of the former, leading to formation of pyrrolo-
[2,3-d]pyrimidine XXVI (Scheme 6).
XIIIa–XIIId, or XVII, 0.41 g (5.2 mmol) of fumaro-
nitrile, and 1.72 g (8.3 mmol) of dibromodifluoro-
methane. The flask was hermetically plugged with
a cap and was placed in an ultrasonic bath (160 W).
The mixture was irradiated at 45°C until lead filings
disappeared completely. When the reaction was com-
plete, 5.4 g of silica gel (a double amount with respect
to tetrabutylammonium bromide, by weight) was
added to the mixture, the solvent was evaporated to
dryness under reduced pressure, and the residue was
applied to a column charged with silica gel. The col-
umn was eluted with solvent systems indicated below,
and the isolated products were additionally purified by
recrystallization.
Thus difluorocarbene generated in situ by reduction
of dibromodifluoromethane with lead is a convenient
synthon for the preparation of 2-fluoro-4,5-dihydropyr-
roles via three-component reaction with 2-butenedioic
acid derivatives and Schiff bases. The reaction follows
a domino pattern involving intermediate formation of
azomethine ylides and is characterized by good yields
of the final products. Analogous derivatives are also
available from cyclic aldehyde imine analogs, but the
products are as a rule less stable, and their yields are
lower.
The physical constants and spectral parameters of
compounds IIa–IIc, III, XIVa, XIVd, XVa, XVI,
XVIII, and XIX were reported previously [13].
5-Fluoro-1-methyl-2,2-diphenyl-2,3-dihydropyr-
role-3,4-dicarbonitrile (IIa) was obtained from 0.51 g
(2.6 mmol) of N-(diphenylmethylidene)-N-methyl-
amine (Ia) and 0.41 g (5.2 mmol) of fumaronitrile
according to the general procedure (reaction time
7 h) with the use hexane–ethyl acetate as eluent. Yield
0.66 g (84%).
The 1,3-dipolar cycloaddition of difluoro azo-
methine ylides to fumaronitrile and maleonitrile is
stereoselective, indicating a concerted mechanism of
the process. 2-Fluoro-4,5-dihydropyrroles thus obtain-
ed are convenient intermediate products for the pre-
paration of various 4,5-dihydropyrrole, pyrrolo[2,3-c]-
pyrazole, and pyrrolo[2,3-d]pyrimidine derivatives.
5-Fluoro-2,2-diphenyl-1-(2-phenylethyl)-2,3-di-
hydropyrrole-3,4-dicarbonitrile (IIb) was obtained
from 0.7 g (2.45 mmol) of N-(diphenylmethylidene)-
N-(2-phenylethyl)amine (Ib) and 0.38 g (4.9 mmol) of
fumaronitrile according to the general procedure (reac-
tion time 14 h) with the use of hexane–ethyl acetate as
eluent. Yield 0.62 g (64%).
EXPERIMENTAL
The melting points were determined on a Boetius
melting point apparatus and are uncorrected. The IR
spectra were recorded on a Carl Zeiss UR-20 spec-
trometer using 400-μm cells. The NMR spectra were
obtained on a Bruker DPX 300 instrument at 300 MHz
for 1H and 75 MHz for 13C. The mass spectra (electron
impact, 70 eV) were run on an MKh-1303 mass spec-
trometer. The elemental compositions were determined
using a Hewlett–Packard HP-185B CHN analyzer. The
progress of reactions was monitored by TLC on Silufol
UV-254 plates. Silica gel LS (5–40 μm, Chemapol)
was used for column chromatography.
Reaction of Schiff base Ic with difluorocarbene
in the presence of fumaronitrile and maleonitrile.
The reaction was carried out according to the general
procedure with 1 g (3.95 mmol) of compounds Ic and
0.48 g (6.14 mmol) of fumaronitrile; chromatographic
separation of the product mixture using hexane–ethyl
acetate as eluent gave 0.274 g (18%) of methyl 2-(3,4-
dicyano-5-fluoro-2,2-diphenyl-2,3-dihydro-1H-pyr-
rol-1-yl)acetate (IIc) and 0.596 g (38%) of methyl
(3RS,4SR)-2-(3,4-dicyano-5,5-difluoro-2,2-diphenyl-
pyrrolidin-1-yl)acetate (Vc, trans isomer).
Compounds Ia, Ib, Id, Ie [22], Ic [23], XIIIa–
XIIId [24], and XVII [25] were synthesized according
to published procedures.
Compound Vc. mp 144–150°C (decomp., from
hexane–ethyl acetate). IR spectrum (CHCl3), Ȟ, cm–1:
1760 (C=O), 2270 (CŁN). 1H NMR spectrum (CDCl3),
į, ppm: 3.32 s (3H, CH3), 3.57 d.d (1H, CH2, J = 18.1,
3.1 Hz), 4.16 d.d.d (1H, 4-H, J = 12.8, 8.8, 5.3 Hz),
3.88 d.d (1H, CH2, J = 18.1, 3.1 Hz), 4.63 d (1H, 3-H,
J = 12.4 Hz), 7.28–7.33 m (10H, H, Harom). 13C NMR
spectrum (CDCl3), įC, ppm: 39.0 d.d (C4, J = 29.3,
Reactions of compounds Ia–Ie, XIIIa–XIIId, and
XVII with difluorocarbene in the presence of
fumaronitrile (general procedure). A 50-ml flask was
filled with argon and charged in succession with 15 ml
of methylene chloride, 1.7 g (8.2 mmol) of freshly pre-
pared lead filings, 2.7 g (8.4 mmol) of tetrabutylam-
monium bromide, 2.64 mmol of Schiff base Ia–Ie,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

NOVIKOV et al.
1502
26.0 Hz); 40.0 (C3); 42.0 d (CH2, J = 1.7 Hz); 51.6
(CH3); 74.3 (C2); 111.4 (CN); 113.3 (CN); 121.5 d.d
(C5, J = 252, 247 Hz); 128.3, 128.4, 128.5, 128.6,
129.2, 129.4, 135.5 d (J = 6.1 Hz), 136.0 d (J =
2.2 Hz) (Carom); 168.2 (C=O). Found, %: C 66.18;
H 4.60; N 11.03. C21H17F2N3O2. Calculated, %:
C 66.14; H 4.49; N 11.02.
8.2 Hz), 7.20–7.46 m (10H, Harom). 13C NMR spectrum
(CDCl3), įC, ppm: 39.9 d.d (C4, J = 35.4, 26.0 Hz),
122.3 t (C5, J = 250 Hz).
1
Compound cis-VII. H NMR spectrum (CDCl3), į,
ppm: 3.35 d (1H, CH2, J = 18.4 Hz), 3.43 d (1H, CH2,
J = 18.4 Hz), 4.07 d (1H, 4-H, J = 6.2 Hz), 4.47 d (1H,
3-H, J = 7.1 Hz), 7.20–7.46 m (10H, Harom).
A solution of 45 mg of trans isomer Vc in 0.5 ml of
CDCl3 was kept for 24 h; the solution turned dark, and
hydrogen fluoride evolved. By column chromatog-
raphy on silica gel we isolated 17 mg (40%) of methyl
(3RS,4SR)-2-(3,4-dicyano-2-oxo-5,5-diphenylpyrroli-
din-1-yl)acetate (VI, trans isomer). mp 187–189°C
(from CH2Cl2–Et2O). IR spectrum (CHCl3), Ȟ, cm–1:
5-Fluoro-1-methyl-2,3-dihydro-9'H-spiro[pyr-
role-2,9'-fluorene]-3,4-dicarbonitrile (IId) was
obtained from 0.5 g (2.59 mmol) of N-methyl-
fluorenylideneamine (Id) and 0.403 g (5.16 mmol) of
fumaronitrile according to the general procedure (reac-
tion time 32 h) with the use of hexane–diethyl ether as
eluent. Yield 0.49 g (63%), mp 124–127°C (from
EtOAc). IR spectrum (CHCl3), Ȟ, cm–1: 2215 (CŁN).
1H NMR spectrum (CDCl3), į, ppm: 2.36 s (3H, CH3),
4.46 d (1H, 3-H, ȳ = 2.8 Hz), 7.28–7.78 m (8H, Harom).
13C NMR spectrum (CDCl3), įC, ppm: 27.0 (CH3);
40.0 d (C3, ȳ = 3.9 Hz); 52.1 d (C4, ȳ = 15.5 Hz); 74.1
(C2); 113.2 d (CH, ȳ = 3.8 Hz); 115.0 d (CH, ȳ =
2.2 Hz); 120.5, 122.7, 125.2, 128.3, 128.7, 130.8,
131.0, 138.3, 139.7, 140.1, 142.1 (Carom); 165.9 d (C5,
1ȳCF = 287 Hz). Found, %: C 75.71; H 4.03; N 13.90.
C19H12FN3. Calculated, %: C 75.74; H 4.01; N 13.95.
1
1760, 1730 (C=O); 2265 (CŁN). H NMR spectrum
(CDCl3), į, ppm: 3.36 s (3H, CH3), 3.56 d (1H, CH2,
J = 17.2 Hz), 3.87 d (1H, 4-H, J = 11.9 Hz), 4.50 d
(1H, CH2, J = 17.2 Hz), 4.69 d (1H, 3-H, J = 11.9 Hz),
7.20–7.39 m (10H, Harom). 13C NMR spectrum (CDCl3),
įC, ppm: 35.9 (C4); 39.7 (C3); 42.8 (CH2); 51.9 (CH3);
72.4 (C5); 113.1 (CN); 113.8 (CN); 127.8, 128.5,
128.6, 129.7, 128.8, 129.7, 129.9, 134.3, 134.7 (Carom);
162.9 (C=O, lactam); 166.3 (C=O, ester). Found, %:
C 70.10; H 4.83; N 11.74. C21H17N3O3. Calculated, %:
C 70.18; H 4.77; N 11.69.
Reaction of 9-methylimino-9H-xanthene (Ie)
with difluorocarbene in the presence of fumaro-
nitrile. The reaction was performed according to the
general procedure with 0.5 g (2.38 mmol) of com-
pound Ie and 0.372 g (4.76 mmol) of fumaronitrile
(reaction time 10 h). The product mixture was
separated by column chromatography using hexane–
methylene chloride as eluent to isolate 0.053 g (7%) of
5-fluoro-1-methyl-2,3-dihydro-9'H-spiro[pyrrole-2,9'-
xanthene]-3,4-dicarbonitrile (IIe) and 0.14 g (26%) of
1'-methyl-5'-methylimino-9H,9''H-dispiro[xanthene-
9,3'-pyrrolidine-4',9''-xanthene]-2'-one (VIII).
Following an analogous procedure, the reaction was
performed with 0.51 g (2.01 mmol) of Schiff base Ic
and 0.24 g (3.07 mmol) of fumaronitrile. When the
reaction was complete, 0.5 ml of anhydrous triethyl-
amine was added, and the mixture was stirred for 0.5 h
and was then treated as described above. Yield of IIc
0.45 g (63%).
Following an analogous procedure, the reaction was
performed with 1 g (3.95 mmol) of Schiff base Ic and
0.48 g (6.14 mmol) of maleonitrile. When the reaction
was complete, the mixture was subjected to column
chromatography using hexane–ethyl acetate as eluent.
The fraction with an Rf range corresponding to com-
Compound IIe. mp 124–127°C (from EtOAc). IR
1
spectrum (CHCl3), Ȟ, cm–1: 2215 (CŁN). H NMR
1
pounds IIc and Vc was examined by H NMR spec-
spectrum (CDCl3), į, ppm: 2.69 s (3H, CH3), 4.34 d
(1H, 3-H, ȳ = 3.4 Hz), 7.26–7.50 m (8H, Harom).
13C NMR spectrum (CDCl3), įC, ppm: 27.6 (NCH3),
48.6 d (C3, ȳ = 3.3 Hz); 49.2 d (C4, ȳ = 12.7 Hz); 63.3
(C2); 113.1 d (4-CN, ȳ = 3.8 Hz); 114.5 (3-CN, ȳ =
2.2 Hz); 115.2, 117.5, 117.6, 124.1, 124.5, 125.0,
126.6, 130.9, 131.4, 149.9, 150.4 (Carom); 164.9 d (C5,
ȳCF = 286 Hz). Found, %: C 71.74; H 3.86; N 13.20.
C19H12FN3O. Calculated, %: C 71.92; H 3.81; N 13.24.
troscopy. It contained methyl (3RS,4RS)-2-(3,4-di-
cyano-5,5-difluoro-2,2-diphenylpyrrolidin-1-yl)acetate
(Vc, cis isomer) and methyl (3RS,4RS)-2-(3,4-dicyano-
2-oxo-5,5-diphenylpyrrolidin-1-yl)acetate (VII, cis iso-
mer) at a ratio of ~2:1. Difluoride cis-Vc in CDCl3
completely decomposed in a few hours with evolution
of hydrogen fluoride.
1
Compound cis-Vc. H NMR spectrum (CDCl3), į,
ppm: 3.39 s (3H, CH3), 3.66 d.d (1H, CH2, J = 17.4,
3.1 Hz), 3.89 d.d (1H, CH2, J = 17.4, 3.1 Hz), 4.16 d.d
(1H, 4-H, J = 15.4, 8.2 Hz), 4.64 d (1H, 3-H, J =
Compound VIII. mp 229–231°C (from hexane–
EtOAc). IR spectrum (CHCl3), Ȟ, cm–1: 1720 (C=O),
1
1680 (C=N). H NMR spectrum (CDCl3), į, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

1,3-DIPOLAR CYCLOADDITION OF DIFLUORO-SUBSTITUTED AZOMETHINE YLIDES.
1503
2.71 s (3H, CH3), 3.65 s (3H, CH3), 6.64–6.83 m (12H,
Harom), 7.02–7.07 m (4H, Harom). 13C NMR spectrum
(CDCl3), įC, ppm: 26.5 (CH3); 37.8 (CH3); 59.0 (C4);
63.4 (C3); 115.8, 116.1, 119.6, 120.2, 122.2, 122.3,
127.5, 128.0, 128.1, 128.3, 151.1, 152.3 (Carom); 156.9
(C=N); 174.2 (C=O). Found, %: C 78.73; H 4.80;
N 6.04. C30H22N2O3. Calculated, %: C 78.59; H 4.84;
N 6.11.
was evaporated, and the residue was recrystallized
from hexane–ethyl acetate to obtain 6 mg (42%) of
compound VIII.
Reaction of Schiff base Ia with difluorocarbene
in the presence of dimethyl maleate. Following the
general procedure, but using activated lead instead of
lead filings, from 0.64 g (3.3 mmol) of N-(diphenyl-
methylidene)-N-methylamine (Ia) and 0.41 g
(5.2 mmol) of dimethyl maleate (reaction time 3 h) we
obtained 0.77 g (64%) of dimethyl 5-fluoro-1-methyl-
2,2-diphenyl-2,3-dihydropyrrole-3,4-dicarboxylate
(III) which was isolated by column chromatography
using hexane–ethyl acetate as eluent.
Following the general procedure, from 1 g
(4.76 mmol) of Schiff base Ie we obtained [after chro-
matographic separation using first benzene–chloroform
(4:1) and then benzene–chloroform–ethyl acetate
(3:1:0.01) as eluents] 0.041 g (3.6%) of N-methyl-N-
(5',5'-difluoro-1'-methyl-9H,9''H-dispiro[xanthene-9,3'-
pyrrolidine-4',9''-xanthene]-2'-ylidene)amine (IX),
0.37 g (34%) of compound VIII, and 1.5 mg of
N-methyl-9H-xanthene-9-carboxamide (XII).
(1RS,10bSR)-3-Fluoro-8,9-dimethoxy-10b-
phenyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquino-
line-1,2-dicarbonitrile (XIVa) and (1RS,10bRS)-3-
fluoro-8,9-dimethoxy-10b-phenyl-1,5,6,10b-tetra-
hydropyrrolo[2,1-a]isoquinoline-1,2-dicarbonitrile
(XVa) were obtained from 0.8 g (3.0 mmol) of 6,7-di-
methoxy-1-phenyl-3,4-dihydroisoquinoline (XIIIa)
and 0.94 g (12.0 mmol) of fumaronitrile according to
the general procedure (reaction time 25 h); by column
chromatography using hexane–ethyl acetate as eluent
we isolated 0.35 g (31%) of compound XIVa and
0.31 g (28%) of compound XVa; the latter contained
35% of XIVa as an impurity
Compound IX. mp 193–195°C (from hexane–
EtOAc). IR spectrum (CHCl3), Ȟ, cm–1: 2200 (CŁN).
1H NMR spectrum (CDCl3), į, ppm: 2.61 s (3H, CH3),
3.41 s (3H, CH3), 6.76–6.84 m (10H, Harom), 7.10–
7.21 m (6H, Harom). 13C NMR spectrum (CDCl3), įC,
ppm: 25.3 (CH3); 37.4 (CH3); 60.2 t (C4, J = 18.5 Hz);
61.0 (C3); 116.0, 116.8, 119.4, 121.4, 122.1 (Carom);
125.3 t (C5, J = 255 Hz); 128.2, 128.3, 128.5, 129.5 t
(Carom, J = 7.2 Hz); 151.7, 151.8 (Carom); 155.9 (C2).
Mass spectrum, m/z (Irel, %): 480 (100) [M – HF]+, 387
(1.3), 230 (3), 206 (68), 199 (39), 181 (42). Found, %:
C 74.83; H 4.78; N 5.79. C30H22 F2N2O2. Calculated,
%: C 74.99; H 4.61; N 5.83.
Following the general procedure, from 0.8 g
(3.86 mmol) of 1-phenyl-3,4-dihydroisoquinoline
(XIIIb) and 0.6 g (7.72 mmol) of fumaronitrile (reac-
tion time 30 h) we obtained 0.26 g (21%) of
(1RS,10bSR)-3-fluoro-10b-phenyl-1,5,6,10b-tetra-
hydropyrrolo[2,1-a]isoquinoline-1,2-dicarbonitrile
(XIVb) and 0.58 g (48%) of (1RS,10bRS)-3-fluoro-
10b-phenyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]iso-
quinoline-1,2-dicarbonitrile (XVb) which were isolat-
ed by column chromatography using hexane–ethyl
acetate as eluent.
Compound XII. X-Ray diffraction data: C15H13NO2.
M 239.26. Unit cell parameters: a = 15.4459(3), b =
9.4460(19), c = 16.339(3) Å; Į = ȕ = Ȗ = 90°; V =
2386.0(8) Å3; Z = 8; d = 1.332 mg/mm3. Orthorhombic
crystals, space group Pbca; MoKĮ irradiation, Ȝ =
0.71073 Å, 133 K; RAll = 0.046, wR2 = 0.0884. Total of
6900 reflections were measured, 2040 of which were
independent (Rint = 0.0658).
Compound XIVb. mp 143–145°C (from EtOAc–
CH2Cl2). IR spectrum (CHCl3), Ȟ, cm–1: 2217 (CŁN).
1H NMR spectrum (CDCl3), į, ppm: 2.59–2.68 m (1H,
CH2), 2.96–3.07 m (1H, CH2), 3.31–3.40 m (1H, CH2),
3.70–3.78 m (1H, CH2), 4.78 d (1H, 1-H, ȳ = 2.7 Hz),
Following an analogous procedure, but in the
absence of fumaronitrile, from 0.5 g (2.48 mmol) of
Schiff base Ie (reaction time 20 h) we obtained 0.39 g
(72%) of compound VIII (which was isolated by
column chromatography using hexane–methylene
chloride as eluent).
13
7.22–7.41 m (9H, Harom). C NMR spectrum (CDCl3),
3
įC, ppm: 26.6 (C6); 38.2 (C5); 43.8 d (C1, ȳCF
=
A mixture of 15 mg (0.031 mmol) of compound IX
and 0.5 g of silica gel in 1 ml of methylene chloride
was kept for 0.5 h under reduced pressure (20 mm) and
then for 9 h under atmospheric pressure. The resulting
material was transferred to a Schott filter and was
washed with 30 ml of methylene chloride. The solvent
4.5 Hz); 52.6 d (C2, ȳ = 13.8 Hz), 70.5 (C10b); 112.9 d
(CH, ȳ = 3.8 Hz); 115.5 d (CH, ȳ = 3.5 Hz); 125.8,
126.8, 127.2, 128.5, 128.6, 129.2, 129.6, 133.3, 135.8,
137.1 (Carom); 165.4 d (C3, ȳCF = 286 Hz). Found, %:
1
C 76.21; H 4.40; N 13.25. C20H14FN3. Calculated, %:
C 76.18; H 4.47; N 13.32.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

NOVIKOV et al.
1504
Compound XVb. mp 190–192°C (from EtOAc–
(1RS,10bSR)-3-Fluoro-8,9-dimethoxy-1,5,6,10b-
tetrahydropyrrolo[2,1-a]isoquinoline-1,2-dicarbo-
nitrile (XIVd) and (1RS,10bRS)-3-fluoro-8,9-di-
methoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]iso-
quinoline-1,2-dicarbonitrile (XVd) were obtained
from 0.53 g (2.8 mmol) of 6,7-dimethoxy-3,4-dihydro-
isoquinoline (XIIId) and 0.44 g (5.6 mmol) of fumaro-
nitrile according to the general procedure (reaction
time 47 h). By column chromatography using hexane–
ethyl acetate as eluent we isolated 0.22 g (26%)
of compound XIVd. Compound XVd was detected by
1H NMR spectroscopy as a mixture with XIVd. Re-
peated chromatographic treatment resulted in hydrol-
ysis of XVd to (1RS,10bSR)-8,9-dimethoxy-3-oxo-
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-
1,2-dicarbonitrile (XVI) (0.075 g, 9%).
CH2Cl2). IR spectrum (CHCl3), Ȟ, cm–1: 2217 (CŁN).
1H NMR spectrum (CDCl3), į, ppm: 2.84–2.89 (1H,
CH2), 3.11–3.22 (1H, CH2), 3.25–3.35 (1H, CH2),
3.81–3.86 m (1H, CH2), 4.73 d (1H, 1-H, ȳ = 4.4 Hz),
13
7.15–7.45 m (9H, Harom). C NMR spectrum (CDCl3),
įC, ppm: 28.3 (C6); 37.8 (C5); 44.3 d (C1; ȳ = 2.8 Hz);
53.4 d (C2, ȳ = 14.4 Hz); 68.7 (C10b); 113.1 d (CH,
ȳ = 4.4 Hz); 115.8 d (CH, ȳ = 1.7 Hz); 125.7, 126.7,
128.5, 128.6, 128.7, 129.0, 129.1, 132.9, 133.6, 141.7
(Carom); 163.2 d (C3, ȳ = 286 Hz). Found, %: C 76.31;
H 4.48; N 13.23. C20H14FN3. Calculated, %: C 76.18;
H 4.47; N 13.32.
Following the general procedure, from 0.505 g
(2 mmol) of 1-(1,3-benzodioxol-5-yl)-3,4-dihydroiso-
quinoline (XIIIc) and 0.31 g (4 mmol) of fumaronitrile
(reaction time 64 h) we obtained 0.29 g (40%) of
(1RS,10bSR)-10b-(1,3-benzodioxol-5-yl)-3-fluoro-
1,5,6,10b-tetrahydropyrrolo-[2,1-a]isoquinoline-1,2-
dicarbonitrile (XVc) and 0.21 g (29%) of a mixture of
XVc and (1RS,10bRS)-10b-(1,3-benzodioxol-5-yl)-3-
fluoro-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinoline-
1,2-dicarbonitrile (XIVc) at a ratio of 1.3:1. The prod-
ucts were isolated by column chromatography using
hexane–ethyl acetate as eluent, followed by recrystal-
lization from diethyl ether–methylene chloride.
5-Amino-1-methyl-2,2-diphenyl-2,3-dihydro-1H-
pyrrole-3,4-dicarbonitrile (XX). A mixture of 0.3 g
(0.99 mmol) of dihydropyrrole IIa and 5 ml of 25%
aqueous ammonia was stirred for 7 days at room tem-
perature. The mixture was poured into 25 ml of water,
and the precipitate was filtered off, washed with water,
dried in air, and recrystallized from ethanol. Yield
0.224 g (53%), colorless crystals with mp 189°C
(decomp.). IR spectrum (CHCl3), Ȟ, cm–1: 3500, 3410
1
(N–H); 2250, 2190 (CŁN). H NMR spectrum
1
(DMSO-d6), į, ppm: 2.46 s (3H, CH3), 4.97 s (1H,
3-H), 7.02 s (2H, NH2), 7.21–7.45 m (10H, Harom).
13C NMR spectrum (DMSO-d6), įC, ppm: 30.9 (CH3);
45.9 (C4); 46.9 (C3); 77.3 (C2); 119.8 (CN); 121.2
(CN); 128.3, 128.9, 129.1, 129.2, 129.3, 140.2, 140.6
(Carom); 163.6 (C5). Found, %: C 75.64; H 5.54; N 17.91.
C19H16N4. Calculated, %: C 75.98; H 5.37; N 18.68.
Compound XIVc. H NMR spectrum (CDCl3), į,
ppm: 2.62–2.71 m (1H, CH2), 2.95–3.06 m (1H, CH2),
3.34–3.44 m (1H, CH2), 3.66–3.77 m (1H, CH2),
4.77 d (1H, 1-H, ȳ = 3.1 Hz), 6.01 (OCH2O), 6.72–
6.83 m (3H, Harom), 7.15–7.27 m (4H, Harom). 13C NMR
spectrum (CDCl3), įC, ppm: 26.5 (C6); 38.1 (C5);
43.8 d (C1, ȳ = 5.7 Hz); 52.3 d (C2, ȳ = 13.8 Hz); 70.2
(C10b); 101.4 (OCH2O); 107.6, 107.8 (Carom); 113.0 d
(CH, ȳ = 4.6 Hz); 115.6 d (CH, ȳ = 3.5 Hz); 118.1,
121.5, 125.7, 126.8, 129.5, 131.1, 133.2, 136.0, 147.9,
148.0 (Carom); 165.2 d (C3, ȳ = 286 Hz).
1-Methyl-5-methylamino-2,2-diphenyl-2,3-dihy-
dro-1H-pyrrole-3,4-dicarbonitrile (XXI). A mixture
of 0.2 g (0.66 mmol) of compound IIa, 0.045 g
(0.67 mmol) of methylamine hydrochloride, 0.2 g
(1.45 mmol) of calcined potassium carbonate, and 3 ml
of anhydrous 1,2-dimethoxyethane was stirred for 1 h
at room temperature. The mixture was poured into
25 ml of water, and the precipitate was filtered off,
dried in air, and recrystallized from methanol. Yield
0.157 g (75%), colorless crystals with mp 212–215°C
(decomp.). IR spectrum (CHCl3), Ȟ, cm–1: 3460 (N–H);
Compound XVc. mp 192–194°C (from Et2O–
CH2Cl2). IR spectrum (CHCl3), Ȟ, cm–1: 2217 (CŁN).
1H NMR spectrum (CDCl3), į, ppm: 2.81–2.89 m (1H,
CH2), 3.09–3.20 m (1H, CH2), 3.24–3.33 m (1H, CH2),
3.79–3.86 m (1H, CH2), 4.66 d (1H, 1-H, ȳ = 4.63 Hz),
6.01 (OCH2O), 6.72–6.77 m (3H, Harom), 7.15–7.40 m
(4H, Harom). 13C NMR spectrum (CDCl3), įC, ppm:
28.3 (C6); 37.6 (C5); 44.5 d (C1, ȳ = 2.8 Hz); 53.2 d
(C2, ȳ = 14.4 Hz); 68.7 (C10b); 101.4 (OCH2O); 106.4,
107.8 (Carom); 113.1 d (CH, ȳ = 5.0 Hz); 115.7 (CH);
119.8, 126.8, 128.6, 128.7, 129.2, 133.1, 133.6, 135.8,
148.0, 148.1 (Carom); 163.1 d (C3, ȳ = 285 Hz). Found,
%: C 70.26; H 4.00; N 11.67. C21H14FN3O2. Calcu-
lated, %: C 70.19; H 3.93; N 11.69.
1
2250, 2185 (CŁN). H NMR spectrum (CDCl3), į,
ppm: 2.44 s (3H, 1-CH3), 3.14 d (3H, 5-NHCH3, J =
5.1 Hz), 4.57 s (1H, 3-H), 5.09 q (1H, NH, J = 5.1 Hz),
7.29–7.40 m (10H, Harom). 13C NMR spectrum
(CDCl3), įC, ppm: 29.8 (CH3); 30.3 (CH3); 46.6 (C4);
46.9 (C3); 76.5 (C2); 117.7 (CN); 121.0 (CN); 127.0,
128.0, 128.2, 128.3, 128.4, 128.5, 138.4, 139.7 (Carom);
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

1,3-DIPOLAR CYCLOADDITION OF DIFLUORO-SUBSTITUTED AZOMETHINE YLIDES.
1505
160.8 (C5). Found, %: C 76.44; H 5.79; N 17.84.
C20H18N4. Calculated, %: C 76.41; H 5.77; N 17.82.
ppm: 31.4 (CH3); 46.9 (C3); 48.3 (C4); 67.2 (OCH2);
77.2 (C2); 119.8 (CN); 121.7 (CN); 128.4, 128.9,
129.0, 129.1, 129.2, 129.3, 140.4, 140.5 (Carom); 163.8
(C5). Found, %: C 70.18; H 5.62; N 20.47. C19H17N5·
0.5C4H8O2. Calculated, %: C 70.18; H 5.89; N 19.48.
1-Methyl-2,2-diphenyl-5-(2-phenylethylamino)-
2,3-dihydro-1H-pyrrole-3,4-dicarbonitrile (XXII).
A mixture of 0.2 g (0.66 mmol) of compound IIa,
0.16 g (1.32 mmol) of 2-phenylethylamine, and 5 ml of
anhydrous DMF was stirred for 1 h at room tempera-
ture. The mixture was poured into 30 ml of water and
extracted with 5 ml of ethyl acetate, and the extract
was washed with water (3×20 ml) and a saturated
solution of NaCl and dried over Na2SO4. Removal of
the solvent gave 0.258 g (96%) of compound XXII as
a glassy material. IR spectrum (CHCl3), Ȟ, cm–1: 3440
(N–H); 2250, 2185 (CŁN). 1H NMR spectrum (CDCl3),
į, ppm: 2.34 s (3H, CH3), 2.98 t (2H, CH2Ph, J =
6.9 Hz), 3.75–3.85 m (2H, CH2N), 4.58 s (1H, 3-H),
7.17–7.43 m (15H, Harom). 13C NMR spectrum (CDCl3),
įC, ppm: 29.6 (CH3); 35.5 (PhCH2); 44.1 (NCH2); 46.7
(C3); 47.4 (C4); 76.5 (C2); 117.4 (CN); 120.3 (CN);
126.5, 127.0, 127.9, 128.3, 128.3, 128.4, 128.5, 128.6,
137.3, 138.2, 139.6 (Carom); 159.5 (C4).
3-Amino-6-methyl-5,5-diphenyl-2,4,5,6-tetra-
hydropyrrolo[2,3-c]pyrazole-4-carbonitrile (XXV).
A solution of 50 mg (0.159 mmol) of compound XXIV
in 0.5 ml of anhydrous toluene was heated for 3 h at
100°C. The solvent was removed under reduced pres-
sure, and the residue was recrystallized from THF–
Et2O. Yield 42 mg (84%), mp 126–130°C (decomp.,
1
from EtOH). H NMR spectrum (DMSO-d6), į, ppm:
2.23 s (3H, CH3), 4.78 s (1H, 4-H), 5.34 s (2H, NH2),
7.12–7.44 m (10H, Harom), 10.19 s (1H, NH). 13C NMR
spectrum (DMSO-d6), įC, ppm: 31.7 (CH3); 31.8 (C4);
84.5, 85.5 (C3a, C5); 119.5 (CN); 128.4, 128.6, 128.8,
128.9, 129.0, 141.0, 141.8, 143.6 (Carom). Found, %:
C 72.38; H 5.49; N 22.20. C19H17N5. Calculated, %:
C 72.36; H 5.43; N 22.21.
4-Amino-7-methyl-2,6,6-triphenyl-6,7-dihydro-
5H-pyrrolo[2,3-d]pyrimidin-5-one (XXVI). A mix-
ture of 0.4 g (1.32 mmol) of compound IIa, 0.2 g
(1.66 mmol) of benzimidamide, 0.25 g (2.45 mmol) of
anhydrous triethylamine, and 4 ml of anhydrous DMF
was stirred for 5 days at room temperature. The mix-
ture was poured into 25 ml of water, and the precipitate
was filtered off, washed with water, dried in air, and
recrystallized from DMF. Yield 0.245 g (47%), color-
less crystals with mp 320–322°C (from DMF). IR spec-
trum (KBr), Ȟ, cm–1: 3510 (OH), 3380 (N–H). 1H NMR
spectrum (DMSO-d6), į, ppm: 7.20–7.53 m (14H,
5-Methoxy-1-methyl-2,2-diphenyl-2,3-dihydro-
1H-pyrrole-3,4-dicarbonitrile (XXIII). A mixture of
0.3 g (0.99 mmol) of compound IIa, 0.3 g (2.18 mmol)
of potassium carbonate, and 3 ml of methanol was
stirred for 1 h at room temperature. The mixture was
poured into 25 ml of water, and the precipitate was
filtered off and recrystallized from methanol. Yield
0.227 g (72%), colorless crystals with mp 195–197°C
(from MeOH). IR spectrum (CHCl3), Ȟ, cm–1: 2250,
1
2200 (CŁN). H NMR spectrum (CDCl3), į, ppm:
2.49 s (3H, NCH3), 4.31 s (3H, OCH3), 4.67 s (1H,
3-H), 7.31–7.48 m (10H, Harom). 13C NMR spectrum
(CDCl3), įC, ppm: 29.9 (NCH3); 46.1 (C3); 49.7 (C4);
60.2 (OCH3); 75.0 (C2); 116.5 (CN); 117.5 (CN);
126.9, 127.9, 128.3, 128.5, 128.7, 137.6, 139.22 (Carom);
166.7 (C5). Found, %: C 76.21; H 5.40; N 13.24.
C20H17N3O. Calculated, %: C 76.17; H 5.43; N 13.32.
H
arom, NH), 8.15 s (1H, NH), 8.43 d (2H, Harom, J =
7.3 Hz). 13C NMR spectrum (DMSO-d6), įC, ppm:
27.9 (CH3); 79.7 (C6); 90.3 (C4a); 129.0, 129.1, 129.1,
129.6, 132.4, 138.1, 138.2 (Carom); 160.6 (C2); 169.7
(C4); 172.4 (C7a); 195.5 (C5). Mass spectrum, m/z
(Irel, %): 394 (3) [M + 2]+, 393 (27) [M + 1]+, 392 (100)
[M]+, 365 (3), 264 (27), 393 (99), 315 (32), 287 (44),
244 (10), 157 (7), 118 (11), 104 (14). Found, %:
C 76.69; H 5.16; N 14.43. C25H20N4O. Calculated, %:
C 76.51; H 5.14; N 14.28.
5-Hydrazino-1-methyl-2,2-diphenyl-2,3-dihydro-
1H-pyrrole-3,4-dicarbonitrile (XXIV). A solution of
0.8 g (2.64 mmol) of compound IIa in 4 ml of 1,4-di-
oxane was added dropwise under stirring to 10 ml of
hydrazine hydrate. The mixture was stirred for 30 min
and poured into 30 ml of water. The precipitate was
filtered off, washed with water, and dried in air. The
product was isolated as a solvate with dioxane,
C19H17N5·0.5C4H8O2, yield 0.705 g (74%), mp 116°C
(decomp., from EtOH). 1H NMR spectrum (DMSO-d6),
į, ppm: 2.39 s (3H, CH3), 3.57 s (3H, dioxane), 4.62 m
(2H, NH2), 4.93 s (1H, 3-H), 7.22–7.44 m (10H, Harom),
This study was performed under financial support
by the program “Universities of Russia” (project
no. ur.05.01.316) and by the Russian Foundation for
Basic Research (project no. 05-03-33257).
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