Cyclic α-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones and their spiro derivatives

Article abstract of DOI:10.1007/s00706-012-0727-3

α-Aminoisobutanoic acid and some representatives of cyclic α-amino acids were converted to corresponding 1-phthalimido- and N-trifluoroacylated acid chlorides. Treatment of 2-(1H-benzimidazol-2-yl) acetonitrile with 1-phthalimidoacid chlorides in DMF unexpectedly gave 2-(1H-benzimidazol-2-yl)-3-(dimethylamino)-2-propenenitrile. On the other hand, the reaction of hetarylacetonitriles with N-trifluoroacylated acid chlorides gave the desired (3-cyano-2-oxo-3-hetarylpropyl)-2,2,2-trifluoroacetamides that upon detrifluoroacetylation provided the target 2-amino-3-hetarylpyrrolin-4- ones. The acylation of benzoimidazolylamino-pyrrolinones by benzoyl chloride leads to formation of 3-benzoyl-2,3-dihydro-5-phenyl-1H-benzo[4,5]imidazo[1,2-c] pyrrolo[3,2-e]pyrimidin-1-ones. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-012-0727-3

Monatsh Chem (2012) 143:779–789
DOI 10.1007/s00706-012-0727-3
ORIGINAL PAPER
Cyclic a-amino acids as precursors for synthesis of 2-amino-3-
hetarylpyrrolin-4-ones and their spiro derivatives
•
Alexey V. Dobrydnev Tatyana A. Volovnenko
•
•
•
Yulian M. Volovenko Gennady V. Palamarchuk
Oleg V. Shishkin
Received: 28 July 2011 / Accepted: 22 January 2012 / Published online: 11 February 2012
ꢀ Springer-Verlag 2012
Abstract a-Aminoisobutanoic acid and some representa-
tives ofcyclica-aminoacids wereconverted tocorresponding
1-phthalimido- and N-trifluoroacylated acid chlorides.
Treatment of 2-(1H-benzimidazol-2-yl)acetonitrile with
1-phthalimidoacid chlorides in DMF unexpectedly gave
2-(1H-benzimidazol-2-yl)-3-(dimethylamino)-2-propenenitrile.
On the other hand, the reaction of hetarylacetonitriles with
N-trifluoroacylated acid chlorides gave the desired (3-cyano-
2-oxo-3-hetarylpropyl)-2,2,2-trifluoroacetamides that upon
detrifluoroacetylation provided the target 2-amino-3-hetar-
ylpyrrolin-4-ones. The acylation of benzoimidazolylamino-
pyrrolinones by benzoyl chloride leads to formation of
3-benzoyl-2,3-dihydro-5-phenyl-1H-benzo[4,5]imidazo[1,2-c]
pyrrolo[3,2-e]pyrimidin-1-ones.
Introduction
Aminopyrroles have received great attention as materials
of choice for preparation of pharmacological drugs [1–11]
because of their possibility to activate the potassium
channels [1, 2], inhibit phosphodiesterase VII [3, 4], pre-
vent urinary incontinence [5, 6], inhibit HIV replication
[7], and have fungicidal activity [8]. These beneficial bio-
logical activities continue to make aminopyrroles attractive
targets for both synthetic and medicinal chemists.
Among the many methods available for constructing
aminopyrroles, the cyclization of 4-aminobutanenitriles has
proven to be a very powerful tool [12–34]. The interaction
of nitriles containing an active methylene group with
a-aminocarbonyl derivatives was found to proceed smoothly,
providing the required 4-aminobutanenitriles.
Keywords Pyrroles ꢀ Cyclization ꢀ Spiro compounds ꢀ
Acylation ꢀ Vilsmeier reaction ꢀ
Recently, we have introduced a strategy [12, 13] for the
construction of the 2-amino-3-hetarylpyrrolin-4-one system
through an acylation of hetarylacetonitriles with 1-phtha-
limidoacetic and 1-phthalimidopropanoic acid chlorides in
the presence of pyridine in dioxane or DMF. The isolated key
intermediates undergo a cyclization reaction (hydrazine
hydrate in dioxane) to 2-amino-3-hetarylpyrrolin-4-ones
through an intramolecular condensation mechanism.
Given these results, we hypothesized that cyclic
a-amino acids subjected to the same chemical reactions and
conditions might yield the corresponding spiro-2-amino-3-
hetarylpyrrolin-4-ones.
X-ray structure determination
A. V. Dobrydnev (&) ꢀ T. A. Volovnenko ꢀ Y. M. Volovenko
Chemistry Department, Kiev National Taras Shevchenko
University, Vladimirskaya Street, 60, Kiev 01033, Ukraine
e-mail: pierrot@gala.net
G. V. Palamarchuk
Division of Functional Materials Chemistry, SSI ‘‘Institute for
Single Crystals’’ National Academy of Science of Ukraine,
Lenina Avenue, 60, Kharkiv 61001, Ukraine
Results and discussion
O. V. Shishkin
The purpose of this study was to use a-aminoisobutanoic
acid (1a) as a model substance for developing of amino-
pyrrolinones. The cyclic a-amino acids were shown to
Department of Inorganic Chemistry, V.N. Karazin Kharkiv
National University, Svobody Square, 4, Kharkiv 61202,
Ukraine
123

780
A. V. Dobrydnev et al.
behave like disubstituted a-amino acids, thus presumably
yielding corresponding spiro-aminopyrrolinones in similar
reaction sequences. Therefore, a-aminoisobutanoic acid
(1a), 1-aminocyclopropane (1b), 1-aminocyclopentane
(1c), and 1-aminocyclohexanecarboxylic acids (1d) were
converted into the corresponding phthalimidoacid chlorides
3a [35–37], 3b [38], 3c [39], and 3d [40, 41].
were obtained, and the products were readily isolated
(Scheme 3). It was found to be advantageous to allow the
reaction mixture to remain warm at least overnight to
ensure completion of the acylation process.
The structure of compounds 8a–8r was established based
on the spectral data. Thus, the IR showed the presence of a
strong conjugate carbonyl band at 1,630–1,619 cm-1 as
well as a carbonyl stretching vibration at 1,731–1,697 cm-1
from the trifluoroacetamide fragment. The nitrile group
The subsequent reaction of 1-phthalimidoisobutanoic
acid chloride (3a) or 1-phthalimidocyclic acid chlorides
(3b, 3c, 3d) with 2-(1H-benzimidazol-2-yl)acetonitrile (4a)
in DMF unfortunately yielded the acids 2a–2d and 2-
(1H-benzimidazol-2-yl)-3-(dimethylamino)-2-propenenitrile
hydrochloride (5) via a Vilsmeier reaction (Scheme 1).
However, treatment of other hetarylacetonitriles 4b–4e
(Scheme 3) with acid chlorides 3a–3d failed to undergo
reaction. Likewise, the reaction of nitriles 4a–4e with acid
chlorides 3a–3d in dioxane or DMSO also failed to react
even in the presence of pyridine or Et3N bases.
1
absorption is situated at 2,207–2,184 cm-1. The H NMR
spectrum indicated the absence of methylene proton signals.
The presence of NH protons at 8.83–10.05 ppm and
12.62–13.72 ppm was confirmed by exchange with D2O.
Also, the mass spectrum revealed molecular ion peaks that
correspond to the molecular formulae. These data were all
consistent with the desired structures and agree with the
conclusion described in Ref. [12, 13].
The elaboration of acylated nitriles into the target am-
inopyrrolinones was achieved without difficulty. Thus,
treatment of these precursors with a solution of NaOH in
1-propanol produces the saponification of the trifluoroac-
etamide fragment and the subsequent intramolecular
addition of the primary amino group in the intermediate to
the nitrile group followed by consequent pyrrolinone ring
formation.
2-Methyl-2-(trifluoroacetylamino)propanoic acid (6a)
[42] and 1-(trifluoroacetylamino)cyclopropanecarboxylic
acid (6b) [43] were prepared according to known proce-
dures. The trifluoroacylation of cyclic a-amino acids 1c, 1d
was carried out with satisfactory yields using the modified
Weygand’s [44] method. The corresponding acid chlorides
of N-trifluoroacylated a-amino acids were prepared in the
following pathway by interaction with thionyl chloride
(Scheme 2) using several modifications of the conditions
described in Ref. [45, 46]. The best yields of acid chlorides
7a–7d were achieved with 1.1-fold excess of freshly dis-
tilled SOCl2 as required by stoichiometry, considering that
the extra equivalent of thionyl decreased the yield on the
following reaction stage. The only difficulty found in this
study was due to cyclopropane derivative 7b, which
required less time and careful performance during the
course of the reaction. The crude acid chlorides were not
isolated or purified, but were used in the following reaction
sequences.
The structures of pyrrolinones 9a–9r were confirmed by
NMR, IR, and mass spectral data. Particularly, presence of
the amino group signals observed at 7.13–8.67 ppm,
absence of nitrile absorption both in IR and 13C NMR
spectra, and absence of signals from the trifluoroacetamide
fragment in 13C, 19F NMR, and IR spectra clearly indicated
the ring closure.
Acylation of pyrrolinones 9a, 9j, and 9n by benzoyl
chloride proceeds both at the amino group and NH group of
the pyrrolinone ring. However, this reaction does not
stop at the dibenzoyl derivative, but rather proceeds
with dehydration and closure of the pyrimidine ring,
leading to a heterocyclic system, namely 2,3-dihydro-1H-
benzo[4,5]imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine (10a–10c,
Scheme 4).
However, when acetonitriles 4a–4e were forced to react
with chlorides 7a–7d in the presence of pyridine, satis-
factory yields of corresponding acylated nitriles 8a–8r
R1
O
Scheme 1
R2
H
R1 COCl
N
N
DMF, 50 °C
+
NPhth
R2 NPhth
3a-3d
N
CN
N
CN
+
H
H
4a
Me
N
Me
Cl
H+
N
R1 CO2H
R2 NPhth
2a, 3a: R1= R2 = Me
2b, 3b: R1+ R2 = (CH2)2
2c, 3c: R1+ R2 = (CH2)4
2d, 3d: R1+ R2 = (CH2)5
N
H
CN
5
2a-2d
123

Cyclic a-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones
781
1
2
Scheme 2
1
2
1
2
1
2
a: R = R = Me
R
R
CO H
2
R
R
CO H
2
R
R
COCl
TFAA
TFA
SOCl
2
1
2
b: R + R = (CH )
2 2
NH
2
NHCOCF
DMF
NHCOCF
3
1
2
3
c: R + R = (CH )
2 4
1
2
1a-1d
6a-6d
7a 7d
-
d: R + R = (CH )
2 5
R1
R4
R3
O
H
N
R1 COCl
R4
R3
R2
NHCOCF3
N
DMF
+
CN
R2 NHCOCF3
Pyridine, 40 °C
X
CN
X
4a-4e
7a-7d
8a-8r
NaOH, 1-propanol,
reflux
R1
O
O
R1
R2
NH
NH2
H
N
R2
R4
N
R4
R3
NH2
CN
R3
X
X
9a-9r
8g, 9g: R1+ R2 = (CH2)2, R3 + R4 = -CH=CH-CH=CH-, X = NMe
8h, 9h: R1+ R2 = (CH2)2, R3 + R4 = -CH=CH-CH=CH-, X = NCHF2
8i, 9i: R1+ R2 = (CH2)2, R3 + R4 = -CH=CH-CH=CH-, X = S
8j, 9j: R1+ R2 = (CH2)4, R3 + R4 = -CH=CH-CH=CH-, X = NH
8k, 9k: R1+ R2 = (CH2)4, R3 + R4 = -CH=CH-CH=CH-, X = NMe
8l, 9l: R1+ R2 = (CH2)4, R3 + R4 = -CH=CH-CH=CH-, X = NCHF2
8m, 9m: R1+ R2 = (CH2)4, R3 + R4 = -CH=CH-CH=CH-, X = S
8n, 9n: R1+ R2 = (CH2)5, R3 + R4 = -CH=CH-CH=CH-, X = NH
8o, 9o: R1+ R2 = (CH2)5, R3 + R4 = -CH=CH-CH=CH-, X = NMe
8p, 9p: R1+ R2 = (CH2)5, R3 + R4 = -CH=CH-CH=CH-, X = NCHF2
8q, 9q: R1+ R2 = (CH2)5, R3 + R4 = -CH=CH-CH=CH-, X = S
8r, 9r: R1+ R2 = (CH2)5, R3 = R4 = H, X = NCH2Ph
4a: R3 + R4 = -CH=CH-CH=CH-, X = NH
4b: R3 + R4 = -CH=CH-CH=CH-, X = NMe
4c: R3 + R4 = -CH=CH-CH=CH-, X = NCHF2
4d: R3 + R4 = -CH=CH-CH=CH-, X = S
4e: R3 = R4 = H, X = NCH2Ph
8a, 9a: R1= R2 = Me, R3 + R4 = -CH=CH-CH=CH-, X = NH
8b, 9b: R1= R2 = Me, R3 + R4 = -CH=CH-CH=CH-, X = NMe
8c, 9c: R1= R2 = Me, R3 + R4 = -CH=CH-CH=CH-, X = NCHF2
8d, 9d: R1= R2 = Me, R3 + R4 = -CH=CH-CH=CH-, X = S
8e, 9e: R1= R2 = Me, R3 = R4 = H, X = NCH2Ph
8f, 9f: R1+ R2 = (CH2)2, R3 + R4 = -CH=CH-CH=CH-, X = NH
Scheme 3
O
R1
R2
NH
NH2
O
R1
R2
N
N
N
PhCOCl
Pyridine, reflux
N
N
H
O
N
Ph
Ph
9a, 9j, 9n
10a: R1= R2 = Me
10b: R1+ R2 = (CH2)4
10c: R1+ R2 = (CH2)5
Scheme 4
In order to confirm the structure of product 10c in the
solid state, a X-ray crystal structure determination was
carried out. Figure 1 shows the molecular structure toge-
ther with the atomic numbering scheme of 10c. The most
interesting feature of molecule 10c is some non-planarity
of the pyrimidine ring adopting a flattened boat confor-
mation. The C(16) and N(4) atoms deviate from the plane
Fig. 1 Molecular structure together with the atomic numbering
scheme of 10c
˚
of the remaining ring atoms by 0.06 and 0.04 A,
123

782
A. V. Dobrydnev et al.
Evaporation of combined filtrates led to the respective
crude acid 2. Yield: 79% (from 3a), 75% (from 3b), 83%
(from 3c), 86% (from 3d); m.p.: 236 ꢁC; 1H NMR:
d = 3.77 (s, 2 Me), 7.33 (m, H-4 and H-7), 7.52 (m, H-5
and H-6), 8.86 (s, CH) ppm; 13C NMR: d = 38.84, 47.81,
61.49, 112.67, 116.88, 124.78, 131.54, 150.80, 156.25
ppm; IR: m = 3,412 (N–H), 2,202 (C:N) cm-1; MS (CI):
m/z = 213.2 ([MH]?).
respectively. This leads to some bending of the tetracyclic
fragment where the angle between planes of two lateral
planar rings is 10.0ꢁ. This non-planarity of the aromatic
ring is caused by strong repulsion between atoms of the
benzene ring of the polycyclic fragment and the phenyl
substituent at C(24) (shortened intramolecular contact
˚
H(22A)…C(26) 2.50 A, van der Waals radii sum [47] is
˚
2.87 A). Out-of-plane deformation is one of the easiest
ways for relaxation of the geometry of a pyrimidine ring
under steric strain due to its high conformational flexibility
[48–50].
General method for the trifluoroacylation of amino
acids 1c, 1d
Thus, a facile route for the synthesis of spiro-pyrrolinones
and spiro-2,3-dihydro-1H-benzo[4,5]imidazo[1,2-c]pyrrolo
[3,2-e]pyrimidines has been developed. General and con-
venient methods for preparation of trifluoroacylated amino
acid chlorides and further acylation were elaborated. Further
studies for this reaction extension and preparation of new
N-substituted cyclic amino acids and spiro-pyrrolinones
substituted at position 1 are currently in progress.
Amino acid 1c or 1d (100 mmol) was dissolved in 80 cm3
TFA and cooled in an ice water bath. Trifluoroacetic
anhydride (28 cm3, 200 mmol) was added dropwise to the
stirred solution. The ice water bath was allowed to melt,
and the mixture was stirred at room temperature overnight.
The solvent was removed in vacuum, and 15 cm3 water
was added to the residue. The N-trifluoroacylated amino
acid was collected on a suction filter and washed with
water (2 9 4 cm3). The material thus obtained was pure,
and no further purification was required. The evaporation
of combined water filtrates led to crude trifluoroacetate salt
of the amino acid, which could be reused after drying in a
vacuum desiccator.
Experimental
Reactions requiring anhydrous conditions were performed
with the usual precautions for rigorous exclusion of air and
moisture. N,N-Dimethylformamide was dried by distilla-
tion from phosphorus pentoxide. The other chemicals were
from Aldrich or Fluka and, when necessary, chemicals
1-(Trifluoroacetylamino)cyclopentanecarboxylic acid
(6c, C8H10F3NO3)
1
Yield: 62%; m.p.: 163 ꢁC; H NMR: d = 1.71–2.14 (m,
cyclopentane), 9.28 (s, NH), 12.45 (s, CO2H) ppm; 13C
1
were purified according to reported procedures [52]. H,
1
13C, and 19F NMR spectra were recorded on a Varian
Mercury 400 spectrometer at 400.45, 100.61, and
376.73 MHz, respectively, using DMSO-d6 as solvent and
TMS (1H, 13C) or CFCl3 (19F) as internal standards. NH
protons were generally identified by exchange with D2O.
IR spectra were obtained on a Perkin-Elmer BX II spec-
trometer in KBr pellets and are reported in cm-1. Mass
spectra were recorded on an Agilent 1100 Series with an
Agilent LC/MSD SL detector by chemical ionization (CI).
Melting points were determined on a Mel-Temp capillary
apparatus.
NMR: d = 25.17, 36.99, 66.86, 116.61 (q, JC,F
=
287.7 Hz), 156.97 (q, JC,F = 36.2 Hz), 174.75 ppm; 19F
NMR: d = -74.43 (s, CF3) ppm; IR: m = 3,319 (N–H),
1,710 (C=O) cm-1; MS (CI): m/z = 226 ([MH]?).
2
1-(Trifluoroacetylamino)cyclohexanecarboxylic acid
(6d, C9H12F3NO3)
1
Yield: 67%; m.p.: 194 ꢁC; H NMR: d = 1.30–2.08 (m,
cyclohexane), 8.95 (s, NH), 12.43 (s, CO2H) ppm; 13C
1
NMR: d = 22.10, 25.71, 32.14, 60.52, 116.59 (q, JC,F
=
288.8 Hz), 156.97 (q, JC,F = 36.2 Hz), 174.88 ppm; 19F
NMR: d = -74.26 (s, CF3) ppm; IR: m = 3,312 (N–H),
1,715 (C=O) cm-1; MS (CI): m/z = 240.2 ([MH]?).
2
(E)-2-(1H-Benzimidazol-2-yl)-3-(dimethylamino)-2-
propenenitrile hydrochloride (5, C12H13ClN4)
General method for the preparation of acylated
hetarylacetonitriles 8a–8e and 8j–8r
Acid chloride 3a, 3b, 3c, or 3d (10.5 mmol) was dissolved
in 10 cm3 dry DMF, and the resulting solution was added
in one portion to the stirred solution of 1.57 g 2-(1H-
benzimidazol-2-yl)acetonitrile (4a, 10 mmol) in 5 cm3
DMF. After being kept at 50 ꢁC for 5 min, the formation
of an obvious precipitate occurred, and then the mixture
was allowed to stand at a warm temperature overnight. The
solvent was removed in vacuum, and the residue was
recrystallized from 2-propanol. Filtration and washing with
2-propanol afforded enaminonitrile 5 as hydrochloride.
The corresponding N-(trifluoroacetyl)amino acid 6a, 6c, or
6d (16 mmol) was dissolved in 5 cm3 dry DMF, and
1.3 cm3 SOCl2 (18 mmol) was added in one portion. The
resulting mixture was allowed to stand at room temperature
with stirring for 3 h. After this period the mixture was
added gradually to a stirred solution of the corresponding
hetarylacetonitrile 4a–4e (15 mmol) and 3.3 cm3 pyridine
123

Cyclic a-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones
783
9.59 (s, NHCOCF3), 13.66 (s, NH-3) ppm; 13C NMR:
(40 mmol) in 10 cm3 dry DMF and left overnight at 40 ꢁC.
The solvent with excess of pyridine was evaporated in
vacuum, and 15 cm3 water was added. The resulting pre-
cipitate was triturated, filtered off, and recrystallized from
the corresponding solvent.
1
d = 24.01, 63.49, 73.28, 112.88, 115.23 (q, JC,F
=
287 Hz), 118.04, 123.23, 124.05, 126.90, 127.30, 138.56,
155.38 (q, 2JC,F = 36 Hz), 170.12, 190.27 ppm; 19F NMR:
d = -74.25 (s, CF3) ppm; IR: m = 3,441 (NH-3), 3,277
(NHCOCF3), 2,185 (C:N), 1,701 (NHCOCF3), 1,620
(C=O) cm-1; MS (CI): m/z = 356.2 ([MH]?).
N-[3-Cyano-3-(1,3-dihydro-2H-benzimidazol-2-ylidene)-
1,1-dimethyl-2-oxopropyl]-2,2,2-trifluoroacetamide
(8a, C15H13F3N4O2)
N-[3-Cyano-3-[1,3-dihydro-1-(phenylmethyl)-2H-
imidazol-2-ylidene]-1,1-dimethyl-2-oxopropyl]-
Yield: 28%; m.p.: 270 ꢁC (EtOH); 1H NMR: d = 1.60 (s, 2
Me), 7.17 (m, H-4 and H-7), 7.49 (m, H-5 and H-6), 9.38
2,2,2-trifluoroacetamide (8e, C18H17F3N4O2)
Yield: 32%; m.p.: 204 ꢁC (2-propanol); 1H NMR: d =
1.56 (s, 2 Me), 5.49 (s, NCH2Ph), 7.08 (s, H-5), 7.19
(s, H-4), 7.28–7.35 (m, CH2C6H5), 9.26 (s, NHCOCF3),
13.19 (s, NH-3) ppm; 13C NMR: d = 24.01, 49.53, 58.33,
59.61, 115.67 (q, 1JC,F = 289 Hz), 115.91, 119.74, 121.68,
(s, NHCOCF3), 12.71 (s, NH-1 and NH-3) ppm; 13C NMR:
1
d = 24.02, 59.82, 60.59, 111.79, 115.65 (q, JC,F
=
287 Hz), 119.74, 123.11, 130.31, 152.54, 154.92 (q,
2JC,F = 36 Hz), 190.93 ppm; 19F NMR: d = -73.45 (s,
CF3) ppm; IR: m = 3,434 (NH-1 and NH-3), 3,255
(NHCOCF3), 2,190 (C:N), 1,698 (NHCOCF3), 1,625
(C=O) cm-1; MS (CI): m/z = 339.2 ([MH]?).
127.35, 127.75, 128.49, 136.12, 145.22, 154.44 (q, 2JC,F
=
36 Hz), 188.89 ppm; 19F NMR: d = -74.56 (s, CF3) ppm;
IR: m = 3,406 (NH-3), 3,232 (NHCOCF3), 2,196 (C:N),
1,712 (NHCOCF3), 1,583 (C=O) cm-1; MS (CI): m/z =
379.2 ([MH]?).
N-[3-Cyano-3-(1,3-dihydro-1-methyl-2H-benzimidazol-2-
ylidene)-1,1-dimethyl-2-oxopropyl]-2,2,2-trifluoro-
acetamide (8b, C16H15F3N4O2)
Yield: 41%; m.p.: 256 ꢁC (2-propanol); 1H NMR:
d = 1.61 (s, 2 Me), 3.98 (s, NMe), 7.28 (m, H-5 and
H-6), 7.52 (d, J = 7.6 Hz, H-7), 7.68 (d, J = 7.6 Hz, H-4),
9.46 (s, NHCOCF3), 13.39 (s, NH-3) ppm; 13C NMR:
d = 24.02, 31.78, 59.85, 60.02, 109.90, 112.25, 115.66 (q,
1JC,F = 287 Hz), 120.45, 123.10, 123.50, 129.00, 131.83,
151.12, 154.73 (q, 2JC,F = 36 Hz), 191.85 ppm; 19F NMR:
d = -73.42 (s, CF3) ppm; IR: m = 3,524 (NH-3), 3,244
(NHCOCF3), 2,190 (C:N), 1,709 (NHCOCF3), 1,625
(C=O) cm-1; MS (CI): m/z = 353.2 ([MH]?).
N-[1-[2-Cyano-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)acetyl]cyclopentyl]-2,2,2-trifluoroacetamide
(8j, C17H15F3N4O2)
Yield: 36%; m.p.: 243 ꢁC (toluene); 1H NMR: d =
1.65–2.39 (m, cyclopentane), 7.12 (m, H-4 and H-7), 7.47
(m, H-5 and H-6), 9.56 (s, NHCOCF3), 12.62 (s, NH-1 and
NH-3) ppm; 13C NMR: d = 25.02, 35.14, 68.33, 73.42,
114.00, 115.03 (q, 1JC,F = 287 Hz), 121.59, 123.17, 133.25,
149.98, 156.16 (q, 2JC,F = 36 Hz), 190.44 ppm; 19F NMR:
d = -74.59 (s, CF3) ppm; IR: m = 3,434 (NH-1 and NH-3),
3,266 (NHCOCF3), 2,190 (C:N), 1,695 (NHCOCF3),
1,622 (C=O) cm-1; MS (CI): m/z = 365.2 ([MH]?).
N-[3-Cyano-3-[1-(difluoromethyl)-1,3-dihydro-2H-
benzimidazol-2-ylidene]-1,1-dimethyl-2-oxopropyl]-2,2,2-
trifluoroacetamide (8c, C16H13F5N4O2)
N-[1-[2-Cyano-2-(1,3-dihydro-1-methyl-2H-benzimidazol-
2-ylidene)acetyl]cyclopentyl]-2,2,2-trifluoroacetamide
(8k, C18H17F3N4O2)
1
Yield: 35%; m.p.: 273 ꢁC (1-butanol); H NMR: d = 1.56
(s, 2 Me), 7.34 (m, H-5 and H-6), 7.60 (d, J = 6.8 Hz,
Yield: 20%; m.p.: 252 ꢁC (toluene); 1H NMR: d =
1.62–2.39 (m, cyclopentane), 3.94 (s, NMe), 7.25 (m,
H-5 and H-6), 7.50 (d, J = 7.6 Hz, H-7), 7.64 (d,
J = 7.6 Hz, H-4), 9.59 (s, NHCOCF3), 13.32 (s, NH-3)
ppm; 13C NMR: d = 24.93, 30.99, 32.32, 61.04, 64.28,
2
H-7), 7.71 (d, J = 6.8 Hz, H-4), 8.19 (t, JH,F = 57.2 Hz,
CHF2), 9.67 (s, NHCOCF3), 13.68 (s, NH-3) ppm; 13C
1
NMR: d = 23.98, 60.27, 61.10, 109.04 (t, JC,F
248 Hz), 112.67, 113.22, 115.61 (q, JC,F = 287 Hz),
=
1
119.56, 124.41, 125.40, 126.85, 130.10, 151.97, 155.17
2
1
(q, JC,F = 36 Hz), 192.32 ppm; 19F NMR: d = -73.35
(s, CF3), -100.30 (d, JH,F = 56.4 Hz, CHF2) ppm; IR:
110.13, 112.43, 115.23 (q, JC,F = 287 Hz), 121.20,
2
122.88, 124.00, 129.18, 132.07, 151.49, 156.03 (q,
2JC,F = 36 Hz), 191.12 ppm; 19F NMR: d = -74.14 (s,
CF3) ppm; IR: m = 3,417 (NH-3), 3,244 (NHCOCF3),
2,190 (C:N), 1,715 (NHCOCF3), 1,622 (C=O) cm-1; MS
(CI): m/z = 379.3 ([MH]?).
m = 3,415 (NH-3), 3,266 (NHCOCF3), 2,190 (C:N),
1,717 (NHCOCF3), 1,631 (C=O) cm-1; MS (CI): m/z =
389.1 ([MH]?).
N-[3-(Benzothiazol-2(3H)-ylidene)-3-cyano-1,1-
dimethyl-2-oxopropyl]-2,2,2-trifluoroacetamide
(8d, C15H12F3N3O2S)
N-[1-[2-Cyano-2-[1-(difluoromethyl)-1,3-dihydro-2H-
benzimidazol-2-ylidene]acetyl]cyclopentyl]-2,2,2-
trifluoroacetamide (8l, C18H15F5N4O2)
Yield: 49%; m.p.: 222 ꢁC (1-butanol); 1H NMR: d =
1.64–2.40 (m, cyclopentane), 7.33 (m, H-5 and H-6), 7.59
1
Yield: 40%; m.p.: 267 ꢁC (1-butanol); H NMR: d = 1.54
(s, 2 Me), 7.27 (t, J = 8.0 Hz, H-5), 7.41 (t, J = 8.0 Hz,
H-6), 7.68 (d, J = 8.0 Hz, H-4), 7.82 (d, J = 8.0 Hz, H-7),
123

784
A. V. Dobrydnev et al.
(d, J = 6.8 Hz, H-7), 7.70 (d, J = 6.8 Hz, H-4), 8.16 (t,
2JH,F = 56.5 Hz, CHF2), 9.81 (s, NHCOCF3), 13.12 (s,
NH-3) ppm; 13C NMR: d = 25.09, 36.10, 62.25, 71.42,
1,709 (NHCOCF3), 1,625 (C=O) cm-1; MS (CI): m/z =
393.2 ([MH]?).
N-[1-[2-Cyano-2-[1-(difluoromethyl)-1,3-dihydro-2H-
benzimidazol-2-ylidene]acetyl]cyclohexyl]-2,2,2-
1
110.03 (t, JC,F = 249.5 Hz), 113.57, 114.18, 116.65 (q,
1JC,F = 287.7 Hz), 120.51, 125.29, 126.31, 127.88,
trifluoroacetamide (8p, C19H17F5N4O2)
2
131.17, 152.95, 156.53 (q, JC,F = 36.2 Hz), 192.87 ppm;
Yield: 34%; m.p.: 219 ꢁC (1-butanol); 1H NMR: d =
1.26–2.06 (m, cyclohexane), 7.33 (m, H-5 and H-6), 7.60
(d, J = 6.8 Hz, H-7), 7.73 (d, J = 6.8 Hz, H-4), 8.20 (t,
2JH,F = 57.2 Hz, CHF2), 9.34 (s, NHCOCF3), 13.70 (s,
NH-3) ppm; 13C NMR: d = 21.39, 24.83, 31.05, 61.43,
2
19F NMR: d = -73.94 (s, CF3), -96.85 (d, JH,F
=
56.5 Hz, CHF2) ppm; IR: m = 3,434 (NH-3), 3,266
(NHCOCF3), 2,190 (C:N), 1,717 (NHCOCF3), 1,631
(C=O) cm-1; MS (CI): m/z = 415.0 ([MH]?).
1
63.17, 109.03 (t, JC,F = 248 Hz), 112.67, 113.23, 115.60
1
(q, JC,F = 287 Hz), 119.90, 124.37, 125.36, 126.83,
N-[1-[2-(Benzothiazol-2(3H)-ylidene)-2-cyanoacetyl]-
cyclopentyl]-2,2,2-trifluoroacetamide
2
130.09, 152.21, 155.44 (q, JC,F = 36 Hz), 192.62 ppm;
(8m, C17H14F3N3O2S)
19F NMR: d = -72.82 (s, CF3), -96.29 (d,
2JH,F = 56.4 Hz, CHF2) ppm; IR: m = 3,439 (NH-3),
3,260 (NHCOCF3), 2,202 (C:N), 1,712 (NHCOCF3),
1,626 (C=O) cm-1; MS (CI): m/z = 429.2 ([MH]?).
Yield: 45%; m.p.: 236 ꢁC (toluene-MeCN 10:1); 1H NMR:
d = 1.65–2.33 (m, cyclopentane), 7.27 (t, J = 8.0 Hz,
H-5), 7.40 (t, J = 8.0 Hz, H-6), 7.65 (d, J = 8.0 Hz, H-4),
7.81 (d, J = 8.0 Hz, H-7), 9.74 (s, NHCOCF3), 13.10 (s,
NH-3) ppm; 13C NMR: d = 24.01, 34.98, 69.90, 72.19,
N-[1-[2-(Benzothiazol-2(3H)-ylidene)-2-cyanoacetyl]-
cyclohexyl]-2,2,2-trifluoroacetamide
(8q, C18H16F3N3O2S)
1
113.69, 115.52 (q, JC,F = 287 Hz), 117.50, 122.23,
123.73, 126.91, 127.16, 138.15, 155.45 (q, 2JC,F = 36 Hz),
168.22, 189.81 ppm; 19F NMR: d = -73.31 (s, CF3) ppm;
IR: m = 3,529 (NH-3), 3,227 (NHCOCF3), 2,202 (C:N),
1,715 (NHCOCF3), 1,631 (C=O) cm-1; MS (CI): m/z =
382.0 ([MH]?).
1
Yield: 61%; m.p.: 239 ꢁC (EtOH); H NMR: d = 1.23-
2.08 (m, cyclohexane), 7.27 (t, J = 8.0 Hz, H-5), 7.40 (t,
J = 8.0 Hz, H-6), 7.66 (d, J = 8.0 Hz, H-4), 7.81 (d,
J = 8.0 Hz, H-7), 9.32 (s, NHCOCF3), 13.09 (s, NH-3)
ppm; 13C NMR: d = 21.12, 24.63, 30.79, 62.61, 72.23,
1
N-[1-[2-Cyano-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)acetyl]cyclohexyl]-2,2,2-trifluoroacetamide
(8n, C18H17F3N4O2)
113.70, 115.44 (q, JC,F = 288 Hz), 117.51, 122.22,
123.74, 126.94, 127.16, 138.09, 155.38 (q, 2JC,F = 38 Hz),
168.45, 190.71 ppm; 19F NMR: d = -72.85 (s, CF3) ppm;
IR: m = 3,546 (NH-3), 3,221 (NHCOCF3), 2,196 (C:N),
1,715 (NHCOCF3), 1,620 (C=O) cm-1; MS (CI): m/z =
396.2 ([MH]?).
Yield: 39%; m.p.: 302 ꢁC (EtOH); 1H NMR: d =
1.35–2.06 (m, cyclohexane), 7.17 (m, H-4 and H-7), 7.48
(m, H-5 and H-6), 9.05 (s, NHCOCF3), 12.63 (s, NH-1 and
NH-3) ppm; 13C NMR: d = 22.51, 26.02, 32.16, 62.06,
N-[1-[2-Cyano-2-[1,3-dihydro-1-(phenylmethyl)-2H-
imidazol-2-ylidene]acetyl]cyclohexyl]-2,2,2-
1
64.06, 112.89, 116.78 (q, JC,F = 288.8 Hz), 120.94,
2
124.28, 131.41, 153.96, 156.47 (q, JC,F = 36.2 Hz),
trifluoroacetamide (8r, C21H21F3N4O2)
192.47 ppm; 19F NMR: d = -73.59 (s, CF3) ppm; IR:
m = 3,434 (NH-1 and NH-3), 3,294 (NHCOCF3), 2,207
(C:N), 1,715 (NHCOCF3), 1,631 (C=O) cm-1; MS (CI):
m/z = 379.2 ([MH]?).
Yield: 22%; m.p.: 236 ꢁC (1-butanol); 1H NMR: d = 1.25–
2.09 (m, cyclohexane), 5.47 (s, NCH2Ph), 7.03 (s, H-5), 7.14
(s, H-4), 7.30–7.33 (m, CH2C6H5), 8.83 (s, NHCOCF3),
13.23 (s, NH-3) ppm; 13C NMR: d = 21.50, 25.02, 31.16,
1
N-[1-[2-Cyano-2-(1,3-dihydro-1-methyl-2H-benzimidazol-
2-ylidene)acetyl]cyclohexyl]-2,2,2-trifluoroacetamide
(8o, C19H19F3N4O2)
49.42, 58.43, 62.84, 115.71 (q, JC,F = 289 Hz), 118.08,
119.14, 123.09, 127.52, 127.62, 128.34, 136.84, 146.04,
2
154.91 (q, JC,F = 36 Hz), 189.43 ppm; 19F NMR: d =
Yield: 58%; m.p.: 277 ꢁC (1-butanol); 1H NMR: d = 1.25-
2.10 (m, cyclohexane), 3.94 (s, NMe), 7.25 (m, H-5 and
H-6), 7.49 (d, J = 7.6 Hz, H-7), 7.66 (d, J = 7.6 Hz, H-4),
9.07 (s, NHCOCF3), 13.41 (s, NH-3) ppm; 13C NMR:
d = 21.44, 24.93, 31.12, 31.98, 60.26, 63.13, 109.99,
-73.86 (s, CF3) ppm; IR: m = 3,440 (NH-3), 3,238
(NHCOCF3), 2,190 (C:N), 1,712 (NHCOCF3), 1,578
(C=O) cm-1; MS (CI): m/z = 419.2 ([MH]?).
General method for the preparation of acylated
hetarylacetonitriles 8f–8i
1
112.37, 115.67 (q, JC,F = 287 Hz), 120.61, 123.19,
123.59, 129.10, 131.98, 151.49, 155.15 (q, 2JC,F = 36 Hz),
192.29 ppm; 19F NMR: d = -72.83 (s, CF3) ppm; IR:
m = 3,434 (NH-3), 3,238 (NHCOCF3), 2,196 (C:N),
1-(Trifluoroacetylamino)cyclopropanecarboxylic acid (6b,
3.15 g, 16 mmol) was dissolved in 5 cm3 dry DMF,
123

Cyclic a-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones
785
-73.83 (s, CF3), -100.13 (d, 2JH,F = 60.2 Hz, CHF2) ppm;
IR: m = 3,434 (NH-3), 3,249 (NHCOCF3), 2,190 (C:N),
1,731 (NHCOCF3), 1,625 (C=O) cm-1; MS (CI): m/z =
387.0 ([MH]?).
1.3 cm3 SOCl2 (18 mmol) was added in one portion, and
the resulting mixture was allowed to stand at room tem-
perature with stirring for 30 min. After this period the
mixture was added gradually to a stirred solution of the
corresponding hetarylacetonitrile 4a–4e (15 mmol) and
3.3 cm3 pyridine (40 mmol) in 10 cm3 dry DMF and left
overnight at 40 ꢁC. The solvent and the excess of pyridine
were evaporated in vacuum, and 15 cm3 water was added.
The resulting precipitate was triturated, filtered off, and
recrystallized from the corresponding solvent.
N-[1-[2-(Benzothiazol-2(3H)-ylidene)-2-cyanoacetyl]-
cyclopropyl]-2,2,2-trifluoroacetamide
(8i, C15H10F3N3O2S)
1
Yield: 62%; m.p.: [300 ꢁC (HOAc); H NMR: d = 1.11
(m, CH2), 1.55 (m, CH2), 7.28 (t, J = 8.0 Hz, H-5), 7.41 (t,
J = 8.0 Hz, H-6), 7.68 (d, J = 8.0 Hz, H-4), 7.81 (d,
J = 8.0 Hz, H-7), 10.11 (s, NHCOCF3), 13.17 (s, NH-3)
ppm; 13C NMR: d = 17.81, 39.04, 74.26, 114.14, 115.58
N-[1-[2-Cyano-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)acetyl]cyclopropyl]-2,2,2-trifluoroacetamide
(8f, C15H11F3N4O2)
1
(q, JC,F = 286 Hz), 117.91, 122.36, 124.03, 127.13,
2
127.32, 138.36, 158.78 (q, JC,F = 36.2 Hz), 168.53,
Yield: 44%; m.p.: [300 ꢁC (1-butanol); 1H NMR:
d = 1.07 (m, CH2), 1.56 (m, CH2), 7.16 (m, H-4 and
H-7), 7.48 (m, H-5 and H-6), 9.96 (s, NHCOCF3), 12.70 (s,
NH-1 and NH-3) ppm; 13C NMR: d = 16.49, 38.25, 65.12,
186.97 ppm; 19F NMR: d = -74.00 (s, CF3) ppm; IR:
m = 3,503 (NH-3), 3,294 (NHCOCF3), 2,185 (C:N),
1,703 (NHCOCF3), 1,620 (C=O) cm-1; MS (CI): m/z =
354.0 ([MH]?).
1
108.54, 115.12 (q, JC,F = 287 Hz), 120.00, 122.03,
2
131.15, 150.73, 155.11 (q, JC,F = 36 Hz), 188.63 ppm;
General method for the preparation
of aminopyrrolinones 9a–9r
19F NMR: d = -74.18 (s, CF3) ppm; IR: = 3,434 (NH-1
and NH-3), 3,266 (NHCOCF3), 2,185 (C:N), 1,701
(NHCOCF3), 1,622 (C=O) cm-1; MS (CI): m/z = 337.2
([MH]?).
The corresponding acylated hetarylacetonitrile 8a–8r
(1 mmol) and 50 mg NaOH (1.3 mmol) were dissolved in
5 cm3 1-propanol, and this mixture was refluxed for 3 h.
The resulting solution was evaporated to dryness and trit-
urated with 2 cm3 water. The precipitate was filtered off,
washed with water (2 9 0.5 cm3), and, if necessary, re-
crystallized from the corresponding solvent.
N-[1-[2-Cyano-2-(1,3-dihydro-1-methyl-2H-benzimidazol-
2-ylidene)acetyl]cyclopropyl]-2,2,2-trifluoroacetamide
(8g, C16H13F3N4O2)
Yield: 56%; m.p.: 257 ꢁC (2-propanol); 1H NMR:
d = 1.11 (m, CH2), 1.52 (m, CH2), 3.94 (s, NMe), 7.26
(m, H-5 and H-6), 7.51 (d, J = 7.6 Hz, H-7), 7.64 (d,
J = 7.6 Hz, H-4), 9.90 (s, NHCOCF3), 12.70 (s, NH-3)
ppm; 13C NMR: d = 11.82, 16.08, 31.98, 40.39, 61.97,
5-Amino-4-(1H-benzimidazol-2-yl)-1,2-dihydro-2,2-
dimethyl-3H-pyrrol-3-one (9a, C13H14N4O)
1
Yield: 93%; m.p.: 294 ꢁC; H NMR: d = 1.26 (s, 2 Me),
1
6.97 (m, H-50 and H-60), 7.35 (d, J = 7.6 Hz, H-70), 7.43
(d, J = 7.6 Hz, H-40), 7.75 (s, NH-1 and NH2), 8.19 (s,
NH2), 11.33 (s, NH-10) ppm; 13C NMR: d = 24.33, 62.32,
82.51, 110.69, 116.01, 119.81, 120.44, 132.94, 142.44,
149.66, 165.63, 193.67 ppm; IR: m = 3,377 (NH2, asym),
3,335 (NH-10), 3,235 (NH-1), 3,159 (NH2, sym), 1,678
(C=O) cm-1; MS (CI): m/z = 243.2 ([MH]?).
110.18, 112.40, 115.66 (q, JC,F = 287.7 Hz), 120.29,
2
123.73, 129.07, 131.96, 150.96, 157.21 (q, JC,F
=
36.2 Hz), 187.93 ppm; 19F NMR: d = -74.55 (s, CF3)
ppm; IR: m = 3,429 (NH-3), 3,232 (NHCOCF3), 2,185
(C:N), 1,723 (NHCOCF3), 1,625 (C=O) cm-1; MS (CI):
m/z = 351.2 ([MH]?).
N-[1-[2-Cyano-2-[1-(difluoromethyl)-1,3-dihydro-2H-
benzimidazol-2-ylidene]acetyl]cyclopropyl]-2,2,2-
trifluoroacetamide (8h, C16H11F5N4O2)
5-Amino-1,2-dihydro-2,2-dimethyl-4-(1-methyl-1H-
benzimidazol-2-yl)-3H-pyrrol-3-one (9b, C14H16N4O)
1
1
Yield: 38%; m.p.: 273 ꢁC (1-butanol); H NMR: d = 1.17
Yield: 82%; m.p.: 280 ꢁC; H NMR: d = 1.24 (s, 2 Me),
3.96 (s, NMe), 7.06 (m, H-50 and H-60), 7.30 (d,
J = 7.6 Hz, H-70), 7.41 (d, J = 7.6 Hz, H-40), 7.50 (s,
NH2), 7.69 (s, NH-1), 8.38 (s, NH2) ppm; 13C NMR:
d = 24.56, 31.60, 61.49, 81.95, 108.86, 116.62, 120.21,
120.89, 135.45, 142.43, 151.20, 167.12, 192.09 ppm; IR:
m = 3,401 (NH2, asym), 3,294 (NH-1), 3,255 (NH2, sym),
1,653 (C=O) cm-1; MS (CI): m/z = 257.2 ([MH]?).
(m, CH2), 1.54 (m, CH2), 7.34 (m, H-5 and H-6), 7.61 (d,
J = 6.8 Hz, H-7), 7.71 (d, J = 6.8 Hz, H-4), 8.20 (t,
2JH,F = 57.2 Hz, CHF2), 10.05 (s, NHCOCF3), 13.70 (s,
NH-3) ppm; 13C NMR: d = 16.21, 39.73, 63.13, 108.96 (t,
1
1JC,F = 248 Hz), 112.72, 113.30, 115.63 (q, JC,F
=
287 Hz), 119.38, 124.47, 125.41, 126.89, 130.04, 151.56,
2
157.41 (q, JC,F = 36 Hz), 188.54 ppm; 19F NMR: d =
123

786
A. V. Dobrydnev et al.
5-Amino-4-[1-(difluoromethyl)-1H-benzimidazol-2-yl]-
1,2-dihydro-2,2-dimethyl-3H-pyrrol-3-one
(9c, C14H14F2N4O)
32.74, 46.96, 86.01, 110.14, 117.95, 121.55, 122.16,
133.61, 143.54, 151.97, 168.73, 188.05 ppm; IR:
m = 3,401 (NH2, asym), 3,300 (NH-1), 3,227 (NH2,
sym), 1,648 (C=O) cm-1; MS (CI): m/z = 255.2 ([MH]?).
1
Yield: 75%; m.p.: 226 ꢁC; H NMR: d = 1.26 (s, 2 Me),
7.14 (t, J = 7.6 Hz, H-60), 7.20 (t, J = 7.6 Hz, H-50), 7.48
(d, J = 7.6 Hz, H-70), 7.67 (d, J = 7.6 Hz, H-40), 7.85 (s,
5-Amino-6-[1-(difluoromethyl)-1H-benzimidazol-2-yl]-4-
azaspiro[2.4]hept-5-en-7-one (9h, C14H12F2N4O)
2
NH2), 7.99 (s, NH-1), 8.67 (s, NH2), 9.15 (t, JH,F
=
Yield: 78%; m.p.: 284 ꢁC dec. (MeCN); 1H NMR:
d = 1.13 (m, CH2), 1.21 (m, CH2), 7.14 (t, J = 7.6 Hz,
H-60), 7.19 (t, J = 7.6 Hz, H-50), 7.49 (d, J = 7.6 Hz,
H-70), 7.57 (d, J = 7.6 Hz, H-40), 8.01 (s, NH-1 and NH2),
59.2 Hz, CHF2) ppm; 13C NMR: d = 25.25, 65.10, 81.90,
110.50 (t, JC,F = 245 Hz), 112.03, 117.38, 122.03,
1
124.10, 130.27, 143.34, 150.16, 167.07, 191.81 ppm; 19F
2
NMR: d = -95.83 (d, JH,F = 59.4 Hz, CHF2) ppm; IR:
2
8.93 (s, NH2), 9.37 (t, JH,F = 57.6 Hz, CHF2) ppm; 13C
m = 3,412 (NH2, asym), 3,339 (NH-1), 3,227 (NH2, sym),
1
1,653 (C=O) cm-1; MS (CI): m/z = 293.2 ([MH]?).
NMR: d = 12.57, 45.92, 84.07, 110.71 (t, JC,F
=
244 Hz), 111.84, 117.63, 122.05, 123.41, 130.02, 143.00,
148.52, 166.86, 187.26 ppm; 19F NMR: d = -95.68 (d,
2JH,F = 60.2 Hz, CHF2) ppm; IR: m = 3,401 (NH2, asym),
3,328 (NH-1), 3,171 (NH2, sym), 1,645 (C=O) cm-1; MS
(CI): m/z = 291.2 ([MH]?).
5-Amino-4-(benzothiazol-2-yl)-1,2-dihydro-
2,2-dimethyl-3H-pyrrol-3-one (9d, C13H13N3OS)
Yield: 91%; m.p.:[300 ꢁC; 1H NMR: d = 1.26 (s, 2 Me),
7.15 (t, J = 7.6 Hz, H-50), 7.31 (t, J = 7.6 Hz, H-60), 7.67
(d, J = 7.6 Hz, H-40), 7.82 (d, J = 7.6 Hz, H-70), 7.93 (s,
NH-1 and NH2), 7.27 (s, NH2) ppm; 13C NMR: d = 25.25,
63.22, 89.53, 120.44, 122.25, 123.22, 126.36, 132.31,
152.63, 162.57, 165.23, 194.72 ppm; IR: m = 3,356 (NH2,
asym), 3,270 (NH-1), 3,165 (NH2, sym), 1,650 (C=O)
cm-1; MS (CI): m/z = 260.2 ([MH]?).
5-Amino-6-(benzothiazol-2-yl)-4-azaspiro[2.4]hept-5-en-
7-one (9i, C13H11N3OS)
Yield: 72%; m.p.:[300 ꢁC; 1H NMR: d = 1.15 (m, CH2),
1.23 (m, CH2), 7.15 (t, J = 7.6 Hz, H-50), 7.31 (t, J =
7.6 Hz, H-60), 7.68 (d, J = 7.6 Hz, H-40), 7.81 (d, J =
7.6 Hz, H-70), 8.07 (s, NH-1 and NH2), 8.31 (s, NH2) ppm;
13C NMR: d = 12.04, 46.03, 91.05, 119.49, 121.21,
122.21, 125.32, 131.31, 151.56, 161.09, 164.44, 188.62
ppm; IR: m = 3,378 (NH2, asym), 3,305 (NH-1), 3,266
(NH2, sym), 1,650 (C=O) cm-1; MS (CI): m/z = 258.2
([MH]?).
5-Amino-1,2-dihydro-2,2-dimethyl-4-[1-(phenylmethyl)-
1H-imidazol-2-yl]-3H-pyrrol-3-one (9e, C16H18N4O)
1
Yield: 68%; m.p.: 208 ꢁC; H NMR: d = 1.13 (s, 2 Me),
5.68 (s, NCH2Ph), 6.80 (s, H-50), 6.87 (s, H-40), 7.06–7.23
(m, CH2C6H5), 7.13 (s, NH-1 and NH2), 7.82 (s, NH2)
ppm; 13C NMR: d = 24.40, 49.50, 64.80, 83.95, 119.13,
126.74, 127.06, 127.32, 128.15, 139.01, 143.85, 167.59,
189.92 ppm; IR: m = 3,451 (NH2, asym), 3,322 (NH-1),
3,221 (NH2, sym), 1,662 (C=O) cm-1; MS (CI): m/z =
283.2 ([MH]?).
2-Amino-3-(1H-benzimidazol-2-yl)-1-azaspiro[4.4]non-2-
en-4-one (9j, C15H16N4O)
1
Yield: 94%; m.p.: 261 ꢁC; H NMR: d = 1.65-1.97 (m,
cyclopentane), 6.96 (m, H-50 and H-60), 7.34 (d, J = 7.6 Hz,
H-70), 7.42 (d, J = 7.6 Hz, H-40), 7.58 (s, NH2), 7.97 (s, NH-
1), 8.18 (s, NH2), 11.35 (s, NH-10) ppm; 13C NMR:
d = 26.73, 34.15, 67.89, 81.30, 113.04, 118.51, 121.04,
123.10, 134.02, 145.83, 153.27, 169.35, 191.28 ppm; IR:
m = 3,580 (NH-10), 3,368 (NH2, asym), 3,341 (NH-1), 3,125
(NH2, sym), 1,656 (C=O) cm-1; MS (CI): m/z = 269.2
([MH]?).
5-Amino-6-(1H-benzimidazol-2-yl)-4-azaspiro[2.4]-
hept-5-en-7-one (9f, C13H12N4O)
1
Yield: 89%; m.p.: 297 ꢁC; H NMR: d = 1.18 (m, CH2),
1.24 (m, CH2), 6.99 (m, H-50 and H-60), 7.38 (d,
J = 7.6 Hz, H-70), 7.45 (d, J = 7.6 Hz, H-40), 7.85 (s,
NH-1 and NH2), 8.24 (s, NH2), 11.37 (s, NH-10) ppm; 13C
NMR: d = 13.14, 44.56, 85.01, 110.82, 115.69, 117.81,
121.26, 133.14, 140.98, 150.10, 166.37, 186.05 ppm; IR:
m = 3,406 (NH2, asym), 3,373 (NH-10), 3,322 (NH-1),
3,232 (NH2, sym), 1,642 (C=O) cm-1; MS (CI): m/z =
241.2 ([MH]?).
2-Amino-3-(1-methyl-1H-benzimidazol-2-yl)-1-
azaspiro[4.4]non-2-en-4-one (9k, C16H18N4O)
1
Yield: 86%; m.p.: [300 ꢁC; H NMR: d = 1.67–1.96 (m,
cyclopentane), 3.97 (s, NMe), 7.06 (m, H-50 and H-60), 7.28
(d, J = 7.6 Hz, H-70), 7.41 (d, J = 7.6 Hz, H-40), 7.92 (s,
NH-1 and NH2), 8.42 (s, NH2) ppm; 13C NMR: d = 25.11,
36.54, 72.20, 89.45, 119.47, 121.29, 122.22, 125.39,
131.30, 151.66, 161.35, 164.67, 193.27 ppm; IR:
m = 3,328 (NH2, asym), 3,204 (NH), 3,154 (NH2, sym),
1,650 (C=O) cm-1; MS (CI): m/z = 283.3 ([MH]?).
5-Amino-6-(1-methyl-1H-benzimidazol-2-yl)-4-
azaspiro[2.4]hept-5-en-7-one (9g, C14H14N4O)
1
Yield: 90%; m.p.: 265 ꢁC; H NMR: d = 1.10 (m, CH2),
1.17 (m, CH2), 3.98 (s, NMe), 7.07 (m, H-50 and H-60), 7.30
(d, J = 7.6 Hz, H-70), 7.42 (d, J = 7.6 Hz, H-40), 7.84 (s,
NH-1 and NH2), 8.13 (s, NH2) ppm; 13C NMR: d = 13.22,
123

Cyclic a-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones
787
2-Amino-3-[1-(difluoromethyl)-1H-benzimidazol-2-yl]-
1-azaspiro[4.4]non-2-en-4-one (9l, C16H16F2N4O)
J = 6.8 Hz, H-40), 8.29 (s, NH-1), 8.93 (s, NH2), 9.17 (t,
2JH,F = 57.6 Hz, CHF2) ppm; 13C NMR: d = 21.63,
24.44, 32.03, 64.80, 82.09, 110.67 (t, JC,F = 244 Hz),
1
1
Yield: 92%; m.p.: 259 ꢁC; H NMR: d = 1.66–1.97 (m,
cyclopentane), 7.14 (t, J = 7.6 Hz, H-60), 7.20 (t,
J = 7.6 Hz, H-50), 7.48 (d, J = 7.6 Hz, H-70), 7.57 (d,
J = 7.6 Hz, H-40), 7.66 (s, NH2), 8.24 (s, NH-1), 8.88 (s,
111.82, 117.49, 122.02, 123.40, 129.96, 142.95, 148.78,
167.09, 192.09 ppm; 19F NMR: d = -95.56 (d, JH,F
2
=
60.2 Hz, CHF2) ppm; IR: m = 3,371 (NH2, asym), 3,226
(NH-1), 3,187 (NH2, sym), 1,645 (C=O) cm-1; MS (CI):
m/z = 333.2 ([MH]?).
2
NH2), 9.18 (t, JH,F = 56.5 Hz, CHF2) ppm; 13C NMR:
1
d = 26.20, 37.90, 72.81, 83.42, 111.79 (t, JC,F
245.5 Hz), 112.90, 118.60, 123.06, 124.47, 131.08,
=
144.08, 149.74, 167.99, 193.21 ppm; 19F NMR: d =
2-Amino-3-(benzothiazol-2-yl)-1-azaspiro[4.5]dec-2-en-4-
one (9q, C16H17N3OS)
2
-96.30 (d, JH,F = 56.5 Hz, CHF2) ppm; IR: m = 3,412
(NH2, asym), 3,350 (NH-1), 3,143 (NH2, sym), 1,653
Yield: 80%; m.p.: [300 ꢁC (EtOH); 1H NMR:
d = 1.25–1.81 (m, cyclohexane), 7.14 (t, J = 7.6 Hz,
H-50), 7.30 (t, J = 7.6 Hz, H-60), 7.34 (s, NH2), 7.66 (d,
J = 7.6 Hz, H-40), 7.81 (d, J = 7.6 Hz, H-70), 8.19 (s, NH-
1), 8.26 (s, NH2) ppm; 13C NMR: d = 23.15, 26.40, 34.86,
68.27, 89.60, 119.53, 121.87, 122.73, 124.38, 130.12,
151.94, 162.43, 165.10, 189.25 ppm; IR: m = 3,367 (NH2,
asym), 3,262 (NH-1), 3,116 (NH2, sym), 1,648 (C=O)
cm-1; MS (CI): m/z = 300.2 ([MH]?).
(C=O) cm-1; MS (CI): m/z = 319.2 ([MH]?).
2-Amino-3-(benzothiazol-2-yl)-1-azaspiro[4.4]-
non-2-en-4-one (9m, C15H15N3OS)
1
Yield: 88%; m.p.: [300 ꢁC; H NMR: d = 1.66–1.97 (m,
cyclopentane), 7.15 (t, J = 7.6 Hz, H-50), 7.30 (t,
J = 7.6 Hz, H-60), 7.66 (d, J = 7.6 Hz, H-40), 7.77 (s,
NH2), 7.81 (d, J = 7.6 Hz, H-70), 8.19 (s, NH-1), 8.26 (s,
NH2) ppm; 13C NMR: d = 26.44, 35.18, 65.22, 90.09,
121.35, 122.89, 124.37, 126.45, 133.69, 154.11, 165.19,
167.05, 193.56 ppm; IR: m = 3,350 (NH2, asym), 3,266
(NH-1), 3,148 (NH2, sym), 1,648 (C=O) cm-1; MS (CI):
m/z = 286.2 ([MH]?).
2-Amino-3-[1-(phenylmethyl)-1H-imidazol-2-yl]-1-
azaspiro[4.5]dec-2-en-4-one (9r, C19H22N4O)
Yield: 77%; m.p.: 160 ꢁC (toluene); 1H NMR: d =
1.24–1.76 (m, cyclohexane), 5.68 (s, NCH2Ph), 6.81 (s,
H-50), 6.87 (s, H-40), 7.06–7.23 (m, CH2C6H5), 7.66 (s,
NH-1 and NH2), 8.13 (s, NH2) ppm; 13C NMR: d = 21.98,
24.68, 33.21, 49.41, 64.36, 83.81, 119.24, 126.66, 126.84,
127.16, 128.10, 138.85, 143.71, 167.68, 190.63 ppm; IR:
m = 3,451 (NH2, asym), 3,345 (NH-1), 3,210 (NH2, sym),
1,645 (C=O) cm-1; MS (CI): m/z = 323.2 ([MH]?).
2-Amino-3-(1H-benzimidazol-2-yl)-1-azaspiro[4.5]-
dec-2-en-4-one (9n, C16H18N4O)
1
Yield: 90%; m.p.: 278 ꢁC; H NMR: d = 1.12–1.81 (m,
cyclohexane), 6.96 (m, H-50 and H-60), 7.16 (s, NH2), 7.34
(d, J = 7.6 Hz, H-70), 7.42 (d, J = 7.6 Hz, H-40), 7.99 (s,
NH-1), 8.22 (s, NH2), 11.35 (s, NH-10) ppm; 13C NMR:
d = 22.86, 25.64, 33.95, 66.43, 84.23, 111.76, 117.03,
120.93, 121.52, 133.96, 143.42, 150.56, 167.13,
194.40 ppm; IR: m = 3,423 (NH2, asym), 3,384 (NH-10),
3,322 (NH-1), 3,120 (NH2, sym), 1,653 (C=O) cm-1; MS
(CI): m/z = 283.2 ([MH]?).
General method for the preparation of 10a–10c
A mixture of hetarylaminopyrrolinones 9a, 9j, or 9n
(10 mmol), 5 g benzoyl chloride (35 mmol), and 10 cm3
pyridine was refluxed for 6 h. The excess pyridine was
evaporated in vacuum, and 10 cm3 water was added. The
resulting precipitate was triturated, filtered off, and re-
crystallized from the corresponding solvent.
2-Amino-3-(1-methyl-1H-benzimidazol-2-yl)-1-
azaspiro[4.5]dec-2-en-4-one (9o, C17H20N4O)
1
Yield: 69%; m.p.: [300 ꢁC; H NMR: d = 1.25–1.82 (m,
cyclohexane), 3.93 (s, NMe), 6.90 (s, NH2), 7.08 (m, H-50
and H-60), 7.31 (d, J = 7.6 Hz, H-70), 7.43 (d, J = 7.6 Hz,
H-40), 7.97 (s, NH-1), 8.50 (s, NH2) ppm; 13C NMR:
d = 21.50, 25.69, 31.60, 33.12, 65.40, 85.39, 110.46,
115.78, 119.89, 121.54, 134.19, 141.08, 154.12, 169.71,
190.66 ppm; IR: m = 3,362 (NH2, asym), 3,256 (NH-1),
3,138 (NH2, sym), 1,645 (C=O) cm-1; MS (CI): m/z =
297.2 ([MH]?).
3-Benzoyl-2,3-dihydro-2,2-dimethyl-5-phenyl-1H-pyrrolo-
[20,30:4,5]pyrimido[1,6-a]benzimidazol-1-one
(10a, C27H20N4O2)
Yield: 87%; m.p.: 276 ꢁC (aqueous MeOH); 1H NMR:
d = 1.75 (s, 2 Me), 6.72 (d, J = 8.4 Hz, H-7), 7.06 (t,
J = 8.0 Hz, H-8), 7.29 (d, J = 7.6 Hz, HPh-2,6), 7.43
(t, J = 8.0 Hz, H-9), 7.45 (t, J = 7.6 Hz, HPh-3,5), 7.47 (t,
J = 7.2 Hz, HBz-3,5), 7.58 (t, J = 7.6 Hz, HPh-4), 7.60 (d,
J = 7.2 Hz, HBz-2,6), 7.64 (t, J = 7.2 Hz, HBz-4), 7.82
(d, J = 8.0 Hz, H-10) ppm; 13C NMR: d = 22.73, 70.45,
96.94, 114.37, 119.61, 122.18, 126.87, 127.58, 128.09,
128.43, 128.60, 128.74, 131.46, 132.25, 132.40, 136.99,
144.63, 145.91, 156.76, 162.92, 167.66, 194.95 ppm; IR:
2-Amino-3-[1-(difluoromethyl)-1H-benzimidazol-2-yl]-1-
azaspiro[4.5]dec-2-en-4-one (9p, C17H18F2N4O)
Yield: 66%; m.p.: 288 ꢁC (MeCN); 1H NMR: d =
1.22–1.80 (m, cyclohexane), 7.20 (m, H-50 and H-60),
7.27 (s, NH2), 7.47 (d, J = 7.2 Hz, H-70), 7.57 (d,
123

788
A. V. Dobrydnev et al.
m = 3,059, 2,975, 2,936 (C–H), 1,712 (C=O), 1,670
(NCOPh) cm-1; MS (CI): m/z = 433.2 ([MH]?).
coordinates, geometrical parameters, and crystallographic
data have been deposited with the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge, CB2
1EZ, UK (fax: ?44 1223 336033; e-mail: depos-
it@ccdc.cam.ac.uk). CCDC dep. number of compound 10c
is 856035.
30-Benzoyl-50-phenylspiro[cyclopentane-1,20-[2H]pyrrolo-
[20,30:4,5]pyrimido[1,6-a]benzimidazol]-10(30H)-one
(10b, C29H22N4O2)
Yield: 92%; m.p.: 300 ꢁC (1-butanol); 1H NMR: d =
1.98–2.45 (m, cyclopentane), 6.72 (d, J = 8.4 Hz, H-7),
7.05 (t, J = 8.0 Hz, H-8), 7.29 (d, J = 7.6 Hz, HPh-2,6),
7.44 (t, J = 7.6 Hz, HPh-3,5), 7.46 (t, J = 7.2 Hz, HBz-3,5,
H-9), 7.58 (t, J = 7.6 Hz, HPh-4), 7.60 (d, J = 7.2 Hz,
HBz-2,6), 7.64 (t, J = 7.2 Hz, HBz-4), 7.81 (d, J = 8.0 Hz,
H-10) ppm; 13C NMR: d = 31.78, 40.35, 82.99, 101.39,
119.00, 124.24, 126.78, 131.48, 132.22, 132.71, 133.07,
133.22, 133.36, 136.07, 136.84, 137.07, 141.79, 149.12,
150.58, 161.13, 168.09, 171.97, 201.40 ppm; IR: m =
3,048, 2,936, 2,868 (C–H), 1,706 (C=O), 1,681 (NCOPh)
cm-1; MS (CI): m/z = 459.3 ([MH]?).
Acknowledgments Alexey Dobrydnev acknowledges Olga Nefe-
dova for a fellowship. The authors also thank Prof. Olexander Turov
for technical support.
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30-Benzoyl-50-phenylspiro[cyclohexane-1,20-[2H]pyrrolo-
[20,30:4,5]pyrimido[1,6-a]benzimidazol]-10(30H)-one
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d = 1.41–2.70 (m, cyclohexane), 6.72 (d, J = 8.4 Hz,
H-7), 7.04 (t, J = 8.0 Hz, H-8), 7.22 (d, J = 7.6 Hz, HPh-
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X-ray diffraction study of compound 10c
Crystals of compound 10c are monoclinic, C60H48N8O4, at
˚
293 K, a = 26.255(2) A, b = 13.272(1) A, c = 13.602(1)
˚
3
˚
˚
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,
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reflections with F [ 4r(F), S = 0.778). Final atomic
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Cyclic a-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones
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123