Synthesis of spiro 2-(5-amino-2,3-dihydro-3-oxopyrrol-4-yl)-1,3-dialkylbenzimidazolium chlorides

Article abstract of DOI:10.1007/s00706-015-1438-3

The interaction of 1,3-dialkyl-2,3-dihydro-1H-benzo[d]imidazol-2-ylidenemethyl cyanides with N-trifluoroacylated acid chlorides gave the desired (3-cyano-2-oxo-3-hetarylpropyl)-2,2,2-trifluoroacetamides that upon detrifluoroacetylation provided the target

Full text of DOI:10.1007/s00706-015-1438-3

Monatsh Chem
DOI 10.1007/s00706-015-1438-3
ORIGINAL PAPER
Synthesis of spiro 2-(5-amino-2,3-dihydro-3-oxopyrrol-4-yl)-1,3-
dialkylbenzimidazolium chlorides
Alexey V. Dobrydnev
Alexandr V. Turov Volodymyr V. Medviediev
Oleg V. Shishkin Tatyana A. Volovnenko
•
Yulian M. Volovenko
•
•
•
•
Received: 6 November 2014 / Accepted: 17 February 2015
Ó Springer-Verlag Wien 2015
Abstract The interaction of 1,3-dialkyl-2,3-dihydro-1H-
benzo[d]imidazol-2-ylidenemethyl cyanides with N-tri-
fluoroacylated acid chlorides gave the desired (3-cyano-2-
oxo-3-hetarylpropyl)-2,2,2-trifluoroacetamides that upon
detrifluoroacetylation provided the target 2-(5-amino-2,3-
dihydro-3-oxopyrrol-4-yl)-1,3-dialkylbenzimidazolium
chlorides.
Keywords Pyrroles Á Cyclization Á Spiro compounds Á
Antitumor agents Á Lanthanide shift reagent Á
X-ray structure determination
Introduction
Graphical abstract
As a part of a program designed to study the antitumor
properties of 2-amino-3-hetarylpyrrolin-4-ones [1], certain
corresponding quaternary salts were required as pre-pro-
duction models with significant water solubility.
Me
N
N
Me
N
O
R1
Cl Me
N
O
2
CN
R1
R2
NHCOCF3
R3
In our previous works [2–6], a facile route to
aminopyrroles 1, bearing a benzoazole substituent at the
suitable position, has been developed. Continuing our re-
search in this field the corresponding quaternary salts 2
were also obtained [3] (Fig. 1). In light of these results, we
prepared previously unreported spiro derivatives of
pyrrolinones with quaternary benzoazole substituent 3.
Among the many methods available for constructing
the aminopyrroles, the cyclization of 4-aminobuta-
nenitriles has proven to be a very powerful tool [2–12]. It
is known that the reaction of 4-halobutanenitriles with
primary amines is a convenient method for aminopyrrole
preparation [7]. This approach, although reasonably ef-
fective, suffers from several drawbacks and not very
efficient for the amination of tertiary halogenides. Con-
sequently, our synthetical pathway includes the
interaction of nitriles containing an active a-carbon atom
with a-aminocarbonyl derivatives to proceed smoothly
providing the required 4-aminobutanenitriles.
DMF
Pyridine
1) NaOH
2) HCl
R2
+
NH
R1 COCl
N
R3
CN
N
R3
H N
R2 NHCOCF3
R1
R3 = Me, Et, CHF2
=
R
2 = Me; R1 + R2 = (CH ) , (CH )
2 4
2 5
A. V. Dobrydnev (&) Á Y. M. Volovenko Á
A. V. Turov Á T. A. Volovnenko
Chemistry Department, Taras Shevchenko National University
of Kiev, Vladimirskaya street 60, Kiev 01601, Ukraine
e-mail: alexey.pierrot@gmail.com
A. V. Dobrydnev
State Centre of Innovation Biotechnologies,
Donetska Street 30, Kiev 03151, Ukraine
V. V. Medviediev Á O. V. Shishkin
Division of Functional Materials Chemistry, SSI ‘‘Institute for
Single Crystals’’ National Academy of Science of Ukraine,
Lenina avenue 60, Kharkiv 61001, Ukraine
Recently we have introduced a strategy [13] for the
construction of spiro-2-amino-3-hetarylpyrrolin-4-one
system through an acylation of hetarylacetonitriles with
acid chlorides of N-trifluoroacylated cyclic a-amino acids
in the presence of pyridine in DMF. The isolated key
O. V. Shishkin
Department of Inorganic Chemistry, V. N. Karazin Kharkiv
National University, Svobody square 4, Kharkiv 61202, Ukraine
123

A. V. Dobrydnev et al.
intermediates undergo a cyclization reaction (NaOH in
-propanol) to spiro-2-amino-3-hetarylpyrrolin-4-ones
using several modifications of the conditions described in
References [15, 16].
1
through an intramolecular condensation mechanism.
However, when nitriles 4a–4c were forced to react with
chlorides 7a–7c in the presence of pyridine, satisfactory
yields of corresponding acylated nitriles 8a–8g were ob-
tained, and the products were readily isolated (Scheme 2).
It was found to be advantageous to allow the reaction
mixture to remain warm at least overnight to ensure com-
pletion of the acylation process.
Results and discussion
Given these results, we hypothesized that hetarylylide-
neacetonitriles subjected to the same chemical reactions
and conditions might yield the corresponding quaternary
salts of spiro-2-amino-3-hetarylpyrrolin-4-ones 3.
An unforeseen result was obtained during the course of
reaction. A single products, either the (Z)- or the (E)-iso-
mers, 8d–8g, were obtained by acylation of isomer mixture
4b and 4c with the acid chlorides 7. The configurations of
To apply such a reaction for our purpose, the readily
available nitriles 4a–4c [14] and amino acids 5a–5c were
selected as starting materials. The cyclic a-amino acids
were shown to behave like disubstituted a-amino acids,
thus presumably yielding corresponding spiro-aminopy-
rrolinones in similar reaction sequences. Therefore, a-
aminoisobutanoic acid (5a) was used as a model substance
for developing of aminopyrrolinones.
1
acylated nitriles 8f and 8g were established through H
NMR spectroscopy using lanthanide shift reagent (LSR).
Thus the use of Eu(FOD) showed that in compound 8f the
3
CN group is in a trans position relative to the NMe frag-
ment, while in compound 8g the CN group and NMe
fragment are in a cis position (Fig. 2). The similarity in
structure of compounds 8f and 8d, 8e respectively permits
the supposition that the latter have similar configurations.
The only alternative interpretation of the observed data
evident to the authors was that, perhaps, the electrostatic
repulsion between the negative charges created on CN and
CHF groups, which forced CHF group to exist in trans
The trifluoroacylation of a-amino acids 5a–5c was car-
ried out with satisfactory yields using the noted method
[
13]. The corresponding acid chlorides of N-trifluoroacy-
lated a-amino acids were prepared in the following
pathway by interaction with thionyl chloride (Scheme 1)
2
2
position with respect to Me group.
The reaction was assumed to proceed via initial addition
of acyl chloride across the exocyclic double bond in 4a–4c
yielding an intermediate (Fig. 3), followed by loss of
proton, which was accompanied by the charge transfer
from the benzoazole moiety and exocyclic double bond
reconstruction.
Cl
N
Cl
N
Me
Me
N
X
O
X
O
N
O
R
H N
2
H2N
H N
2
(CH )
2 n
N
R
N
N
The structure of compounds 8a–8g was established
based on the spectral data. Thus, the IR showed the pres-
ence of strong conjugate carbonyl band at
H
Ar
1
2
3
-
1
1
2
3
: X = NH, S; R = H, Ar
1619–1601 cm as well as carbonyl stretching vibration
-
at 1714–1703 cm from the trifluoroacetamide fragment.
1
: X = NAlk, S
: R = Me, Et; n = 4,5
The nitrile group absorption is situated at
-
183–2168 cm . The H NMR spectrum indicated the
1
1
Fig. 1 The structure of pyrrolinone derivatives 1, 2, and 3
2
Scheme 1
1
23

Synthesis of spiro 2-(5-amino-2,3-dihydro-3-oxopyrrol-4-yl)-1,3-dialkylbenzimidazolium chlorides
Scheme 2
=
0.65 ppm
Eu(FOD)3
= 1.07 ppm
Eu(FOD)3
The elaboration of the acylated nitriles 8a–8g into the
target aminopyrrolinones 3 was achieved without difficul-
ty. Thus, treatment of these precursors with the solution of
NaOH in 2-propanol, produces the saponification of the
trifluoroacetamide fragment and the subsequent in-
tramolecular addition of the primary amino group in the
intermediate to the nitrile group followed by consequent
pyrrolinone ring formation (Scheme 3).
CH3
CHF
2O
O
N
N
NHCOCF3
NHCOCF3
N
CN
N
CN
CH2
CH3
Me
=
0.47 ppm
= 0.55 ppm
8
f+ Eu(FOD)3
8g+ Eu(FOD)3
The quaternary salts could be isolated as either chlorides
3a–3f or trifluoroacetates 9a–9f. However, pyrrolinones
with chloride counterion exhibits higher usability, water
solubility, and stability upon storage.
Fig. 2 Values of lanthanide induced shifts of the signals of N-
1
aliphatic substituents in H NMR spectra of compounds 8f and 8g in
the presence of Eu(FOD)
3
The structures of pyrrolinones 3a–3f were confirmed by
1
13
19
H, C, F NMR, IR, and mass spectral data. Particularly,
presence of the amino group signals observed at
.55–8.05 ppm, absence of nitrile absorption both in IR
R3
N
R1
O
H
R2
7
1
3
NHCOCF3
and C NMR spectra and absence of signals from tri-
13
CN
N
Me
19
fluoroacetamide fragment both in C, F NMR, and IR
spectra clearly indicated the ring closure.
Cl
In order to confirm the structure of product 9c in the
solid state, a X-ray crystal structure determination was
carried out. Figure 4 shows the molecular structure to-
gether with the atomic numbering scheme of 9c.
Fig. 3 The structure of intermediate with single bond between CN
and heterocyclic fragment
absence of exocyclic CH proton signals. The presence of
NH protons at 9.04–9.97 ppm was confirmed by exchange
According to XRD data compound 9c is a salt of organic
-
cation with CF COO anion. Almost equal values of the
3
with D O. Also, the mass spectrum revealed molecular ion
2
C–N bond lengths within imidazole ring (Table 1) and
peaks that correspond to the molecular formulae. These
data were all consistent with the desired structure.
rotation of two planar heterocycles with respect to each
o
other [the N1–C7–C8–C9 torsion angle is -46.4(4) ] agree
123

A. V. Dobrydnev et al.
Scheme 3
Me
R1
Me
R1
O
O
R2
R2
N
N
NaOH
NHCOCF3
NH2
i-PrOH
reflux
N
R3
N
R3
CN
CN
8a-8f
CF CO2
Me
3
Me
Cl
O
R1
O
R1
N
R2
N
R2
HCl
NH
- TFA
NH
N
N
R3 H N
R3 H2N
2
3a-3f
9a-9f
1
2
3
1
2
3
3
3
3
a, 8a, 9a: R = R = R = Me
3d, 8d, 9d: R = R = Me, R = Et
1
2
3
1
2
3
b, 8b, 9b: R + R = (CH ) , R = Me
3e, 8e, 9e: R + R = (CH ) , R = Et
2
4
2 4
1
2
3
1
2
3
c, 8c, 9c: R + R = (CH ) , R = Me
3f, 8f, 9f: R + R = (CH ) , R = Et
2
5
2 5
Fig. 4 Molecular structure
together with the atomic
numbering scheme of 9c
according to X-ray diffraction
data
well with chemical formula of cation 9c depicted in
Scheme 3. However, detailed analysis of bond lengths
demonstrates considerably more complex and stronger
delocalization of electron density within cation. Besides
imidazole ring equalization of bonds is observed for the C–
C and C–N bonds within the C7–C8–C9 and N3–C9–N4
fragments, respectively (Table 1). This indicates strong
delocalization of electron density within these fragments
either it is caused by delocalization of positive charge due
to protonation or induced by polar environment in the
crystal phase as it was found recently for derivatives
aminoiminoisoindole [17] containing similar amidine
fragment. Quantum-chemical calculations of structure of
cation 9c by the M06-2X/6-311G(d,p) method demon-
strated good agreement between calculated and
experimental values of bond lengths (Fig. 6; Table 1).
Some differences are observed only for C8–C10=O1
fragment which probably are induced by polar environment
in the crystal. Thus, it is possible to suggest that strong
(
Fig. 5).
Based on XRD data it is impossible to understand rea-
sons of highly delocalized conjugated system in cation 9c
1
23

Synthesis of spiro 2-(5-amino-2,3-dihydro-3-oxopyrrol-4-yl)-1,3-dialkylbenzimidazolium chlorides
˚
Table 1 Values of bond lengths/A for cation and neutral deprotonated tautomers A–C of compound 9c according to X-ray diffraction data and
quantum-chemical calculations by M06-2X/6-311G(d,p) method
Bond
Cation
Exp
Neutral
A
Calc
B
C
O1–C10
N1–C7
N2–C7
N3–C9
N4–C9
C7–C8
C8–C9
C8–C10
1.226(3)
1.349(3)
1.356(3)
1.329(3)
1.333(3)
1.428(3)
1.417(3)
1.434(3)
1.209
1.355
1.344
1.345
1.338
1.429
1.405
1.452
1.220
1.373
1.365
1.393
1.283
1.395
1.460
1.447
1.223
1.361
1.362
1.281
1.397
1.405
1.458
1.430
1.221
1.369
1.361
1.282
1.388
1.399
1.465
1.435
N-substituted cyclic amino acids and spiropyrrolinones
Me
O
substituted at position 1 are currently in progress.
N
NH
N
+
Experimental
Me HN
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
Fig. 5 The graphic illustration of wide delocalization of electron
density within cation 9c
delocalization of electron density in cation 9c is caused by
protonation of molecule.
1
were purified according to the reported procedure [18]. H,
Analysis of calculated values of bond lengths in de-
protonated tautomers A–C of the cation 9c (Fig. 6) shows
absence of considerable delocalization of electron density
within molecule (Table 1). Values of the C–N bond lengths
within amidine fragment are usual for single and double
bonds (Table 1). It is observed only some elongation of the
13
19
C, and F NMR spectra were recorded on a Varian
Mercury 400 spectrometer at 400.45, 100.61, and
76.73 MHz, respectively, using DMSO-d as solvent and
3
6
1
13
19
Me Si ( H, C) or CFCl ( F) as internal standarts. IR
4
3
spectra were obtained on a Perkin Elmer BX II spec-
-1
trometer in KBr pellets and are reported in cm . Mass
˚
C7–C8 bond up to 1.395–1.404 A which may be explained
spectra were recorded on an Agilent 1100 Series with an
Agilent LC/MSD SL detector by chemical ionization (CI).
All melting points were determined in open capillary tubes
in a Thiele apparatus.
by strong conjugation within planar enone fragment
C7=C8–C10=O1. It is accompanied by shortening of the
C8–C10 bond (Table 1). Thus, it is possible to conclude
that strong delocalization of electron density in cation 9c is
caused by protonation of molecule.
Analysis of changes of atomic charges due to protona-
tion of one of the nitrogen atom of neutral tautomers A–
C indicates that positive charge in cation is mainly local-
ized within the amidine fragment N3–C9–N4 (Dq = ?0.6
e). Probably this leads to complete delocalization of elec-
tron density within this fragment creating suitable
conditions for charge transfer to enone and imidazole
fragments of cation.
General method for the preparation of acid chlorides
7a–7c
To a magnetically stirred suspension of the N-trifluoroa-
3
cylated amino acid 6a–6c (0.05 mol) in 50 cm of CH Cl
containing two drops of dry pyridine was added 4.04 cm
2
2
3
SOCl (0.056 mol). The mixture was heated under reflux
2
for 4 h and allowed to cool to room temperature. Then
CH Cl with excess of SOCl were removed by rotary
Thus, a facile route to the quaternary salts of spiro
pyrrolinones has been developed. General and convenient
methods for preparation of trifluoroacylated amino acid
chlorides and further acylation were elaborated. Further
studies for this reaction extension and preparation of new
2
2
2
evaporation maintaining the temperature below 40 °C,
yielding the crude acid chloride as solidify yellow oil. The
material thus obtained was used without further
purification.
123

A. V. Dobrydnev et al.
Fig. 6 Tautomers of
deprotonated cation 9c
Me
N
Me
N
O
O
N
NH
N
N
Me H N
Me
N
B
2
A
H
Me
N
O
NH
N
Me
N
C
H
General method for the acylation of nitriles 4a–4c
N-[2-Cyano-2-(1,3-dimethyl-2,3-dihydro-1H-benzo-
d]imidazol-2-ylidene)acetyl]cyclohexyl-2,2,2-
trifluoroacetamide (8c, C H F N O )
[
The corresponding acid chloride 7a, 7c, 7d (0.016 mol)
was added gradually to stirred solution of nitrile 4a–4c
2
0 21 3 4 2
1
Yield 88 %; m.p.: 273–275 °C (n-BuOH); H NMR:
d = 1.33 (m, 1H, cyclohexane), 1.61 (m, 5H, cyclohex-
ane), 1.98 (m, 2H, cyclohexane), 2.08 (m, 2H,
3
3
0.015 mol) and 3.3 cm pyridine (0.04 mol) in 10 cm dry
(
DMF, and left overnight at 40 °C. The solvent with excess
of pyridine was evaporated in vacuum and 15 cm water
3
cyclohexane), 3.74 (s, 6H, NCH ), 7.44 (m, 2H, H-5 and
3
was added. The resulting precipitate was triturated, filtered
off, and recrystallized from the corresponding solvent.
H-6), 7.71 (m, 2H, H-4 and H-7), 9.09 (br. s, 1H,
3
1
NHCOCF ) ppm; C NMR: d = 21.41, 25.01, 31.22,
3
1
2.75, 54.23, 62.85, 111.60, 115.73 (q, J = 288 Hz),
3
1
1
C,F
N-[3-Cyano-3-(1,3-dimethyl-2,3-dihydro-1H-benzo-
2
20.76, 124.64, 131.68, 153.86, 155.22 (q, J = 36 Hz),
C,F
[
d]imidazol-2-ylidene)-1,1-dimethyl-2-oxopropyl]-
,2,2-trifluoroacetamide (8a, C H F N O )
1
9
89.29 ppm; F NMR: d = -70.88 (s, CF ) ppm; IR:
3
2
1
7 17 3 4 2
m = 3238 (NHCOCF ), 2179 (C:N), 1703 (NHCOCF ),
1
3
3
Yield 74 %; m.p.: 257 °C (HOAc); H NMR: d = 1.57 (s,
6
-
620 (C=O) cm ; MS (CI): m/z = 407.2 ([M?H] ).
1
?
1
H, CH ), 3.76 (s, 6H, NCH ), 7.55 (m, 2H, H-5 and H-6),
3 3
7
.73 (m, 2H, H-4 and H-7), 9.45 (br. s, 1H, NHCOCF )
3
N-[3-Cyano-3-(1-ethyl-3-methyl-2,3-dihydro-1H-benzo-
[d]imidazol-2-ylidene)-1,1-dimethyl-2-oxopropyl]-
2,2,2-trifluoroacetamide (8d, C H F N O )
1
3
ppm; C NMR: d = 24.28, 32.75, 54.01, 59.84, 111.60,
1
15.74 (q, JC,F = 287 Hz), 120.76, 124.66, 131.67,
1
18
19 3 4 2
2
53.51, 154.81 (q, JC,F = 36 Hz), 188.98 ppm;
19
1
1
F
Yield 83 %; m.p.: 220–221 °C (n-BuOH); H NMR:
d = 1.45 (t, J = 7.2 Hz, 3H, NCH CH ), 1.58 (s, 6H,
NMR: d = -74.56 (s, CF3) ppm; IR: m = 3232
2
3
(
NHCOCF ), 2179 (C:N), 1712 (NHCOCF ), 1606
CH ), 3.72 (s, 3H, NCH ), 4.40 (q, J = 7.2 Hz, 2H,
3 3
3
3
-
1
?
C=O) cm ; MS (CI): m/z = 367.2 ([M?H] ).
(
NCH CH ), 7.46 (m, 2H, H-5 and H-6), 7.75 (m, 2H, H-4
2 3
1
and H-7), 9.42 (br. s, 1H, NHCOCF ) ppm; C NMR:
3
3
N-[2-Cyano-2-(1,3-dimethyl-2,3-dihydro-1H-benzo-
d]imidazol-2-ylidene)acetyl]cyclopentyl-2,2,2-
trifluoroacetamide (8b, C H F N O )
d = 13.27, 24.21, 32.80, 40.61, 53.08, 59.80, 111.73,
[
1
11.89, 115.75 (q, JC,F = 287 Hz), 121.10, 124.72,
1
1
1
1
9
19
3
4
2
2
24.85, 130.46, 131.99, 152.76, 154.82 (q, J = 36 Hz),
1
C,F
Yield 85 %; m.p.: 272 °C (n-BuOH); H NMR: d = 1.64
1
9
89.03 ppm; F NMR: d = -74.59 (s, CF ) ppm; IR:
3
(
(
(
m, 2H, cyclopentane), 1.75 (m, 2H, cyclopentane), 2.06
m, 2H, cyclopentane), 2.33 (m, 2H, cyclopentane), 7.41
m, 2H, H-5 and H-6), 7.65 (m, 2H, H-4 and H-7), 9.62 (br.
m = 3234 (NHCOCF ), 2171 (C:N), 1715 (NHCOCF ),
3
3
-
1
612 (C=O) cm ; MS (CI): m/z = 381.2 ([M?H] ).
?
1
1
3
s, 1H, NHCOCF ) ppm; C NMR: d = 24.20, 32.78,
N-[2-Cyano-2-(1-ethyl-3-methyl-2,3-dihydro-1H-benzo-
[d]imidazol-2-ylidene)acetyl]cyclopentyl-2,2,2-
trifluoroacetamide (8e, C H F N O )
3
1
5.44, 54.46, 70.12, 111.40, 115.81 (q, J = 286 Hz),
3
1
1
C,F
2
20.79, 124.48, 131.67, 153.74, 155.26 (q, J = 35 Hz),
C,F
20 21 3 4 2
1
9
1
88.69 ppm; F NMR: d = -74.14 (s, CF ) ppm; IR:
Yield 79 %; m.p.: 263 °C (n-BuOH); H NMR: d = 1.44
(t, J = 7.2 Hz, 3H, NCH CH ), 1.64 (m, 2H, cyclopen-
3
m = 3223 (NHCOCF ), 2186 (C:N), 1705 (NHCOCF ),
1
3
3
2
3
-
603 (C=O) cm ; MS (CI): m/z = 393.2 ([M?H] ).
1
?
tane), 1.75 (m, 2H, cyclopentane), 2.07 (m, 2H,
1
23

Synthesis of spiro 2-(5-amino-2,3-dihydro-3-oxopyrrol-4-yl)-1,3-dialkylbenzimidazolium chlorides
cyclopentane), 2.33 (m, 2H, cyclopentane), 3.69 (s, 3H,
pyrrolinones 9a–9c. It was filtered off, washed with water
3
3
NCH ), 4.39 (q, J = 7.2 Hz, 2H, NCH CH ), 7.44 (m, 2H,
3
(2 9 2 cm ) and dissolved in 15 cm of 4 N HCl. Evapo-
ration of the solution and subsequent recrystallization (if
necessary) from aq. i-PrOH led to 2-(5-amino-2,3-dihydro-
3-oxopyrrol-4-yl)-1,3-dimethylbenzimidazolium chlorides
3a–3c.
2
3
H-5 and H-6), 7.72 (m, 2H, H-4 and H-7), 9.61 (br. s, 1H,
3
1
NHCOCF ) ppm; C NMR: d = 13.29, 24.14, 32.85,
3
3
5.36, 40.54, 53.51, 70.09, 111.59, 111.77, 115.80 (q,
1
JC,F = 287 Hz), 121.11, 124.61, 124.74, 130.50, 132.02,
2
19
53.00, 155.27 (q, J = 36 Hz), 188.73 ppm; F NMR:
C,F
1
2-(5-Amino-2,2-dimethyl-3-oxo-2,3-dihydro-1H-4-
d = -74.18 (s, CF ) ppm; IR: m = 3247 (NHCOCF ),
3
3
pyrrolyl)-1,3-dimethyl-3H-benzo[d]imidazol-1-
-
1
2
168 (C:N), 1711 (NHCOCF ), 1610 (C=O) cm ; MS
?
3
ium chloride (3a, C H ClN O)
4
15 19
(
CI): m/z = 407.2 ([M?H] ).
N-[2-Cyano-2-(1-ethyl-3-methyl-2,3-dihydro-1H-benzo-
d]imidazol-2-ylidene)acetyl]cyclohexyl-2,2,2-
trifluoroacetamide (8f, C H F N O )
1
Yield 64 %; m.p.: [300 °C; H NMR: d = 1.32 (s, 6H,
CH ), 3.85 (s, 6H, NCH ), 7.58 (m, 2H, H-5 and H-6), 7.89
3
3
[
(m, 4H, H-4 and H-7, NH ), 8.57 (br. s, 1H, NH-pyrroline)
2
1
3
2
1 23 3 4 2
ppm; C NMR: d = 24.27, 32.46, 63.09, 74.11, 112.38,
125.34, 131.80, 147.43, 164.71, 194.04 ppm; IR: m = 3451
(NH , asym), 3401 (NH , sym), 3294 (NH-pyrroline), 1690
1
Yield 88 %; m.p.: 249–250 °C (n-BuOH); H NMR:
d = 1.34 (m, 1H, cyclohexane), 1.44 (t, J = 7.2 Hz, 3H,
NCH CH ), 1.62 (m, 5H, cyclohexane), 1.97 (m, 2H,
2
2
-
1
?
2
3
(C=O) cm ; MS (CI): m/z = 271.2 ([M–Cl] ).
-(3-Amino-1-oxo-4-azaspiro[4.4]non-2-en-2-yl)-1,3-
dimethyl-3H-benzo[d]imidazol-1-ium chloride
3b, C H ClN O)
cyclohexane), 2.09 (m, 2H, cyclohexane), 3.71 (s, 3H,
2
NCH ), 4.40 (q, J = 7.2 Hz, 2H, NCH CH ), 7.46 (m, 2H,
3
2
3
H-5 and H-6), 7.74 (m, 2H, H-4 and H-7), 9.04 (br. s, 1H,
1
(
3
17 21
4
NHCOCF ) ppm; C NMR: d = 13.26, 21.46, 25.03,
3
1
Yield 60 %; m.p.: [300 °C; H NMR: d = 1.84 (m, 6H,
cyclopentane), 1.95 (m, 2H, cyclopentane), 3.85 (s, 6H,
3
1.27, 32.78, 40.53, 53.31, 62.79, 111.73, 111.91, 115.75
1
q, JC,F = 287 Hz), 121.11, 124.73, 124.86, 130.47,
(
NCH ), 7.56 (m, 2H, H-5 and H-6), 7.87 (m, 4H, H-4 and
3
2
32.00, 153.12, 155.23 (q, J = 36 Hz), 189.32 ppm;
1
C,F
13
H-7, NH ), 9.03 (br. s, 1H, NH-Pyrroline) ppm; C NMR:
1
9
2
F NMR: d = -73.86 (s, CF ) ppm; IR: m = 3222
3
d = 25.00, 32.53, 36.69, 72.92, 75.04, 112.37, 125.30,
(
(
NHCOCF ), 2178 (C:N), 1706 (NHCOCF ), 1618
3
-1 ?
C=O) cm ; MS (CI): m/z = 421.2 ([M?H] ).
3
1
31.80, 147.37, 165.20, 193.54 ppm; IR: m = 3361 (NH2,
asym), 3293 (NH , sym), 3266 (NH-pyrroline), 1636
2
-
1
?
N-[2-Cyano-2-[1-(difluoromethyl)-3-methyl-2,3-dihydro-
(C=O) cm ; MS (CI): m/z = 297.4 ([M–Cl] ).
-(3-Amino-1-oxo-4-azaspiro[4.5]dec-2-en-2-yl)-1,3-
dimethyl-3H-benzo[d]imidazol-1-ium chloride
3c, C H ClN O)
1
2
H-benzo[d]imidazol-2-ylidene]acetyl]cyclohexyl-
2
,2,2-trifluoroacetamide (8g, C H F N O )
2
0 19 5 4 2
1
Yield 90 %; m.p.: 281 °C (n-BuOH); H NMR: d = 1.37
m, 1H, cyclohexane), 1.62 (m, 5H, cyclohexane), 2.03 (m,
H, cyclohexane), 3.84 (s, 3H, NCH ), 7.52 (m, 2H, H-5
(
1
8
23
4
(
1
Yield 75 %; m.p.: [300 °C; H NMR: d = 1.31 (m, 1H,
cyclohexane), 1.55 (m, 3H, cyclohexane), 1.63 (m, 3H,
cyclohexane), 1.78 (m, 3H, cyclohexane), 3.84 (s, 6H,
NCH ), 7.57 (m, 2H, H-5 and H-6), 7.73 (br. s, 2H, NH ),
4
3
2
and H-6), 7.56 (t, 1H, J = 56.4 Hz, CHF ), 7.75 (d,
H,F
2
1
H, J = 7.6 Hz, H-7), 7.81 (d, 1H, J = 7.6 Hz, H-4), 9.52
3
1
3
2
(
br. s, 1H, NHCOCF ) ppm; C NMR: d = 21.40, 24.94,
3
7
.88 (m, 2H, H-4 and H-7), 9.37 (br. s, 1H, NH-pyrroline)
13
1
1.15, 33.16, 56.23, 62.79, 110.67 (t, JC,F = 247 Hz),
3
ppm; C NMR: d = 21.78, 24.57, 32.45, 32.89, 66.25,
1
12.60, 112.84, 115.62 (q, JC,F = 286 Hz), 119.21,
1
74.71, 112.37, 125.33, 131.80, 147.42, 165.51,
1
25.81, 125.90, 126.83, 132.46, 153.42, 155.76 (q,
19
1
93.50 ppm; IR: m = 3339 (NH , asym), 3277 (NH ,
2
2
2
JC,F = 36 Hz), 191.30 ppm; F NMR: d = -73.94 (s,
3
-1
sym), 3204 (NH-pyrroline), 1631 (C=O) cm ; MS (CI):
2
F, CF ), -97.15 (d, 2F, J = 56.5 Hz, CHF ) ppm; IR:
3 H,F 2
?
m/z = 311.2 ([M–Cl] ).
m = 3246 (NHCOCF ), 2184 (C:N), 1706 (NHCOCF ),
3
3
-
1
?
619 (C=O) cm ; MS (CI): m/z = 443.1 ([M?H] ).
1
General method for the preparation
General method for the preparation
of aminopyrrolinones 3d-3f
of aminopyrrolinones 3a–3c
The corresponding acylated hetarylylideneacetonitrile 8a–
8c (0.005 mol) and 0.26 g NaOH (0.007 mol) were dis-
The corresponding acylated hetarylylideneacetonitrile
a–8c (0.005 mol) and 0.26 g NaOH (0.007 mol) were
3
solved in 20 cm i-PrOH and this mixture was refluxed for
8
dissolved in 20 cm i-PrOH and this mixture was refluxed
3
3 h. The resulting solution was evaporated to dryness and
3
diluted with 5 cm water. The bottom phase was separated,
for 3 h. The resulting solution was evaporated to dryness
3
and triturated with 8 cm water. The precipitate thus
3
3
washed with water (2 9 2 cm ) and dissolved in 8 cm i-
PrOH. An addition of fresh saturated solution of HCl in i-
obtained was the corresponding trifluoroacetate of
123

A. V. Dobrydnev et al.
PrOH produced the crystallization of 2-(5-amino-2,3-di-
hydro-3-oxopyrrol-4-yl)-1-ethyl-3-methylbenzimidazolium
chlorides 3d–3f. This quaternary salt was collected on a
suction filter and washed with i-PrOH. The products thus
obtained were pure and no further purification was
required.
a = 103.550(12)°, b = 105.966(12)°, c = 102.068(12)°,
3
˚
V = 1000.3(2) A , space group Pm, Z = 2, D =
c
-
3
-1
1.409 g cm , l(MoKa) = 0.115 mm , F(000) = 444;
11,108 reflections measured up to 2hmax = 60.0°, 6238
unique (Rint = 0.0448) which were used in all calculations.
Refinement was converged at wR2 = 0.1979 (all data),
R1 = 0.0680 [2968
GoF = 1.01.
reflections
with I [ 2r(I)],
2
-(5-Amino-2,2-dimethyl-3-oxo-2,3-dihydro-1H-4-
pyrrolyl)-1-ethyl-3-methyl-3H-benzo[d]imidazol-1-
Intensities of reflections were measured on an automatic
Xcalibur 3 diffractometer (graphite monochromated MoKa
radiation, CCD-detector x-scaning). All structures were
solved by direct method using SHELX97 package [19].
Positions of the hydrogen atoms were located from electron
density difference maps and refined by ‘‘riding’’ model
with Uiso = nUeq of carrier non-hydrogen atom (n = 1.5
ium chloride (3d, C H ClN O)
1
6
21
4
1
Yield 56 %; m.p.: [300 °C; H NMR: d = 1.33 (s, 6H,
CH ), 1.41 (t, J = 6.8 Hz, 3H, NCH CH ), 3.83 (s, 3H,
3
2
3
NCH ), 4.36 (m, 2H, NCH CH ), 7.57 (m, 2H, H-5 and
3
2
3
H-6), 7.91 (m, 2H, H-4 and H-7), 7.97 (br. s, 2H, NH ),
2
1
3
8.66 (br. s, 1H, NH-pyrroline) ppm; C NMR: d = 14.06,
24.28, 32.23, 41.06, 63.07, 73.73, 112.52, 112.79, 125.38,
125.47, 130.66, 132.15, 146.62, 164.86, 193.96 ppm; IR:
for methyl group and n = 1.2 for other hydrogen atoms).
2
Full-matrix least-squares refinement against
F
in
m = 3448 (NH , asym), 3404 (NH , sym), 3313 (NH-
2
2
anisotropic approximation. Final atomic coordinates,
geometrical parameters and crystallographic data have
been deposited with the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (fax:
?44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk) de-
position number CCDC 912324. These data can be
obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/products/
csd/request/.
-
pyrroline), 1635 (C=O) cm ; MS (CI): m/z = 285.2 ([M–
1
?
Cl] ).
2
-(3-Amino-1-oxo-4-azaspiro[4.4]non-2-en-2-yl)-1-
ethyl-3-methyl-3H-benzo[d]imidazol-1-ium chloride
3e, C H ClN O)
(
1
8
23
4
1
Yield 61 %; m.p.: [300 °C; H NMR: d = 1.40 (t,
J = 7.2 Hz, 3H, NCH CH ), 1.87 (m, 6H, cyclopentane),
2
3
1
2
.97 (m, 2H, cyclopentane), 3.86 (s, 3H, NCH ), 4.39 (m,
3
H, NCH CH ), 7.59 (m, 2H, H-5 and H-6), 7.93 (m, 4H,
2
3
H-4 and H-7, NH ), 9.10 (br. s, 1H, NH-pyrroline) ppm;
2
Quantum-chemical calculations
1
3
C NMR: d = 14.02, 24.98, 32.29, 36.66, 41.10, 72.96,
4.76, 112.53, 112.78, 125.37, 125.45, 130.67, 132.15,
7
1
3
Molecular structure of cation 9c and its deprotonated tau-
tomers was optimized using M06-2X functional [20] with
6-311G(d,p) basis set. Atomic charges were calculated
within Natural Bonding Orbitals theory [21]. All calcula-
tions were performed using Gaussian09 program [22].
46.48, 165.27, 193.35 ppm; IR: m = 3410 (NH , asym),
2
-
1
;
232 (NH , sym), 3132 (NH-pyrroline), 1678 (C=O) cm
2
?
MS (CI): m/z = 311.2 ([M–Cl] ).
-(3-Amino-1-oxo-4-azaspiro[4.5]dec-2-en-2-yl)-1-
ethyl-3-methyl-3H-benzo[d]imidazol-1-ium chloride
3f, C H ClN O)
2
Acknowledgments Alexey Dobrydnev acknowledges Patricia Do-
brydneva for a fellowship and technical support.
(
1
9
25
4
1
Yield 65 %; m.p.: 289 °C; H NMR: d = 1.34 (m, 1H,
cyclohexane), 1.40 (t, J = 7.2 Hz, 3H, NCH CH ), 1.53
2
3
(
m, 2H, cyclohexane), 1.64 (m, 4H, cyclohexane), 1.79 (m,
H, cyclohexane), 3.83 (s, 3H, NCH ), 4.37 (m, 2H,
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2
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4
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6
3
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1
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˚
a = 8.2305(12) A, b = 9.9710(15) A, c = 13.6382(17) A,
˚
˚
1
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123