Synthesis and X-ray analysis of 2-aryl-4-chloropyrrolidine-2-carbonitrile derivatives

Article abstract of DOI:10.1134/S1070428015060068

Abstract A procedure has been developed for the synthesis of ethyl 1-benzoyl-4-chloro-2-phenylpyrrolidine- 2-carboxylate and 4-chloro-5-oxo-1,2-diphenyl-, 1-benzoyl-2-(2-benzyloxy-5-chlorophenyl)-4-chloro-, and 1-benzoyl-2-(4-benzyloxyphenyl)-4-chloropyrr

Full text of DOI:10.1134/S1070428015060068

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 6, pp. 853–859. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © S.P. Gasparyan, M.V. Alexanyan, G.K. Harutyunyan, A.H. Martirosyan, R.A. Tamazyan, A.G. Ayvazyan, H.A. Panosyan, 2015,
published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 6, pp. 870–876.
Synthesis and X-Ray Analysis
of 2-Aryl-4-chloropyrrolidine-2-carbonitrile Derivatives
S. P. Gasparyana, M. V. Alexanyana, G. K. Harutyunyana, A. H. Martirosyana, R. A. Tamazyanb,
A. G. Ayvazyanb, and H. A. Panosyanb
Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia:
a Mndzhoyan Institute of Fine Organic Chemistry
b Molecular Structure Research Center
e-mail: g_sahak@yahoo.com
Received October 15, 2014
Abstract—A procedure has been developed for the synthesis of ethyl 1-benzoyl-4-chloro-2-phenylpyrrolidine-
2-carboxylate and 4-chloro-5-oxo-1,2-diphenyl-, 1-benzoyl-2-(2-benzyloxy-5-chlorophenyl)-4-chloro-, and
1-benzoyl-2-(4-benzyloxyphenyl)-4-chloropyrrolidine-2-carbonitriles in high yields via intramolecular cycliza-
tion of the corresponding 2,3-dichloropropionamides under conditions of phase-transfer catalysis.
DOI: 10.1134/S1070428015060068
Proline and other cyclic α-amino acids are impor-
tant components of many biologically active natural
substances [1, 2]. In recent years functionally substi-
tuted proline derivatives have been used as starting
compounds in the synthesis of new medications [3–5].
Chiral 2-substituted prolines are used not only in
syntheses of new compounds but also as ligands in
coordination chemistry [6–8]. Studies of chemical and
biological properties of substituted prolines are limited
due to the lack of accessible methods for their prepara-
tion. The known procedures are laborious and rather
sensitive to reaction conditions, and the yields are gen-
erally low [9–13].
We previously proposed a procedure for the syn-
thesis of ethyl 4-chloro-5-oxo-1,2-diphenylpyrrolidine-
2-carboxylate under phase-transfer catalysis [14, 15].
In the present work we used this procedure for the
preparation of 4-chloro-5-oxo-1,2-diphenylpyrrolidine-
2-carbonitrile 3 (Scheme 1). For this purpose, 2-ani-
lino-2-phenylacetonitrile (1) [16] was acylated with
2,3-dichloropropanoyl chloride, and the subsequent
intramolecular cyclization of amide 2 under conditions
of phase-transfer catalysis afforded compound 3. The
phase-transfer catalyst was benzyl(triethyl)ammonium
chloride (BTEAC).
The other three chloro-substituted pyrrolidine ana-
logs were synthesized in a different way. The alkyla-
tion of ethyl 2-bromo-2-phenylacetate with allylamine
gave ethyl 2-(allylamino)-2-phenylacetate (4) which
was acylated with benzoyl chloride in the presence of
triethylamine and subjected to chlorination and intra-
molecular cyclization under phase-transfer conditions.
We thus synthesized amide 6 (Scheme 2). The reac-
tions of 2- and 4-benzyloxybenzaldehydes with sodium
cyanide and allylamine in acid medium afforded the
corresponding 2-(allylamino)-2-phenylacetonitriles 7
and 10; their acylation with benzoyl chloride, followed
by chlorination and cyclization led to the formation of
4-chloro-substituted 1-benzoylpyrrolidine-2-carbo-
nitriles 9 and 12 (Scheme 2).
Scheme 1.
Cl
O
O
Ph
Ph
Ph
NEt3
K2CO3, BTEAC
+
Cl
Cl
Cl
N
CN
CN
N
O
PhNH
CN
Cl
Cl
Ph
Ph
1
2
3
853

GASPARYAN et al.
854
Scheme 2.
R3
R4
R2
R3
R4
R2
R3
R4
R2
(1) Cl2, pyridine
(2) K2CO3, BTEAC
PhC(O)Cl, Et3N
R1
R1
R1
N
Bz
HN
N
Bz
CH2
CH2
Cl
6, 9, 12
4, 7, 10
5, 8, 11
4–6, R1 = COOEt, R2 = R3 = R4 = H; 7, 8, R1 = CN, R2 = PhCH2O, R3 = R4 = H; 9, R1 = CN, R2 = PhCH2O, R3 = H, R4 = Cl;
10–12, R1 = CN, R2 = R3 = H, R4 = PhCH2O.
Unlike compounds 5 and 11, the chlorination of 8
(Fig. 4) were determined by X-ray analysis. The
principal crystallographic parameters of 3 and 12 are
given in table. Their molecules each possess two
asymmetric carbon atoms (C1 and C4 in the pyrrolidine
ring); therefore, the formation of four diastereoiso-
mers, (2R,4R), (2R,4S), (2S,4R), and (2S,4S), is pos-
sible. According to the X-ray diffraction data, all four
possible stereoisomers were detected only for ethyl
1-benzoyl-4-chloro-2-phenylpyrrolidine-2-carboxylate
(6) [17]. It crystallized in the P21 non-centrosymmetric
space group, and its unit cell contained two symmetry-
independent molecules. Nevertheless, all four isomers
of 6 were present in crystal, and the (2R,4R)/(2R,4S)/
(2S,4R)/(2S,4S) ratio was ~7:3:5:5. As a result, the
structure is not ordered, and the two symmetry-
independent molecules are represented by the pairs of
diastereoisomers (2R,4R)/(2R,4S) and (2S,4R)/(2S,4S)
(Fig. 5).
was accompanied by introduction of a chlorine atom
into the 5-position of the benzene ring. The benzene
ring in 8 and 11 is activated to electrophilic substitu-
tion due to the presence of an electron-donor ortho/
para orienting benzyloxy group; however, the chlori-
nation in the ortho position with respect to the benzyl-
oxy group is hindered for steric reasons; therefore,
the chlorine atom enters only the benzene ring in 8,
where the para position with respect to the benzyloxy
group is free.
The proposed procedure for the synthesis of com-
pounds 3, 6, 9, and 12 is less laborious than known
methods for the preparation of substituted prolines, it
affords high yields, and can be used to obtain other
proline derivatives.
The molecular and crystal structures of compounds
3 (Fig. 1), 6 (Fig. 2) [17], 9 (Fig. 3) [18], and 12
C18
C19
ClB
C17
C20
C4B C5B
C12
C3B
C13
C14
C22
C23
C21
C16
C14
C13
N9
C21
N2
C15
C8
C5
C11
C6
C16
C15
N2
C1
C1
C17
C18
C19
C12
C10
C11
O10
O7
C8
C20
O24
C3
C4
Cl7
O6
C9
Fig. 1. Structure of the molecule of 4-chloro-5-oxo-1,2-di-
phenylpyrrolidine-2-carbonitrile (3) according to the X-ray
diffraction data (arbitrary atom numbering); non-hydrogen
atoms are shown as thermal vibration ellipsoids with a prob-
ability of 50%. Hereinafter, hydrogen atoms are not shown
for clarity.
Fig. 2. Structure of the molecule of ethyl 1-benzoyl-4-
chloro-2-phenylpyrrolidine-2-carboxylate (6) according to
the X-ray diffraction data (arbitrary atom numbering); non-
hydrogen atoms are shown as thermal vibration ellipsoids
with a probability of 50%. Only one stereoisomer is shown.
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SYNTHESIS AND X-RAY ANALYSIS OF 2-ARYL-4-CHLOROPYRROLIDINE-...
855
C26
C13
C14
C25
C24
C12
C11
C27
C28
O23
C22
C15
C3
N21
Cl30
C10
C29
C5
C20
N2
C8
C26
C25
C3
O9
C17
C1
C27
C23
O22
C18
C4
C4
C24
N2
C6
C19
C20
C16
C18
C7
C16
C15
C14
C11
Cl31
C17
C1
C6
Cl
C29 C28
C5
O12
C13
C8
C21
C9
N7
C19
C10
Fig. 3. Structure of the molecule of 1-benzoyl-2-(2-benzyl-
oxy-5-chlorophenyl)-4-chloropyrrolidine-2-carbonitrile (9)
according to the X-ray diffraction data (arbitrary atom
numbering); non-hydrogen atoms are shown as thermal
vibration ellipsoids with a probability of 50%.
Fig. 4. Structure of the molecule of 1-benzoyl-2-(4-benzyl-
oxyphenyl)-4-chloropyrrolidine-2-carbonitrile (12) accord-
ing to the X-ray diffraction data (arbitrary atom numbering);
non-hydrogen atoms are shown as thermal vibration ellip-
soids with a probability of 50%.
Unlike ester 6, nitriles 3, 9, and 12 were equimolar
mixtures of only two stereoisomers, (2R,4S) and
(2S,4R) (Figs. 6–8). They crystallized in centrosym-
metric space groups P-1, P21/n, and C2/c, respectively.
Presumably, the presence of a cyano group in mole-
cules 3, 9, and 12 is responsible for the lack of the
corresponding (2R,4R) and (2S,4S) stereoisomers.
The pyrrolidine ring in molecules 6, 3, 9, and 12
adopts an envelope conformation, i.e., four atoms in
the ring lie in one plane. This plane in 6, 9, and 12
includes the C1, N2, C3, and C5 atoms; the maximum
deviation from the mean-square plane does not exceed
0.0120(4) Å, while the C4 atom deviates from that
plane by 0.3738(3)–0.5374(4) Å. The corresponding
plane in molecule 3 is formed by the C1, N2, C3, and C4
atoms [the maximum deviation is 0.0083(2) Å], and
the C5 atom deviates from the plane by 0.374(3) Å.
The observed difference in the conformations of the
pyrrolidine ring in molecules 6, 9, and 12, on the one
hand, and 3, on the other, is likely to be determined by
different hybridizations of the C3 atom (sp3 in 6, 9, and
12 and sp2 in 3).
DMSO proton signal (δ 2.50 ppm). The progress of
reactions and the purity of products were monitored by
TLC on Silufol UV-254 plates using the following
solvent systems: acetone–nonane, 1:1 (A), 1:2 (C),
2:1 (F), 3:2 (G); acetone–hexane, 2:1 (B), 1:1 (D),
1:2 (E); development with iodine vapor.
The X-ray diffraction data for compounds 3 and 12
were obtained at room temperature on an Enraf–
(a)
C4B
C4A
C1
(b)
C4A′
C4B′
EXPERIMENTAL
C1
The IR spectra were recorded from thin films on
1
a Nicolet Avatar 330 FT-IR spectrometer. The H and
13C NMR spectra were measured from solutions in
DMSO-d6–CCl4 (1:3) at 303 K on a Varian Mercury-
300VX instrument operating at 300.078 and
75.46 MHz, respectively. Signals were assigned using
DEPT and HMQC double-resonance techniques. The
chemical shifts were determined relative to the residual
Fig. 5. (a) (2R,4R)/(2R,4S) and (b) (2S,4R)/(2S,4S) Dia-
stereoisomer pairs of ethyl 1-benzoyl-4-chloro-2-phenylpyr-
rolidine-2-carboxylate (6). The C1′ and C4′ atoms correspond
to C26 and C29 in [17].
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GASPARYAN et al.
(b)
856
(a)
Nonius CAD-4 automated diffractometer (MoKα radia-
tion, graphite monochromator, θ/2θ scanning). A cor-
rection for absorption was applied by the psi scan
technique [19]. The structures were solved by the
direct method. The coordinates of atoms were deter-
mined from the Fourier difference syntheses. The
structures were refined by the full-matrix least-squares
procedure in anisotropic approximation for non-hydro-
gen atoms and isotropic approximation for hydrogen
atoms. All calculations were performed using
SHELXTL software [20]. The crystallographic data
were deposited to the Cambridge Crystallographic
Data Centre. The data for compounds 6 and 9 were
reported in [17, 18], and the data for 3 and 12 are
given in table.
C1
C1
C4
C4
Fig. 6. (a) (2R,4S) and (b) (2S,4R) Diastereoisomers of
4-chloro-5-oxo-1,2-diphenylpyrrolidine-2-carbonitrile (3)
symmetry-related (in crystal) through an inversion center.
(a)
(b)
2,3-Dichloro-N-[cyano(phenyl)methyl]-N-phenyl-
propanamide (2). A mixture of 2 g (10 mmol) of
2-anilino-2-phenylacetonitrile (1) [16] and 1.05 g
(10 mmol) of triethylamine in 30 mL of acetone was
cooled to 0–5°C, 1.6 g (10 mmol) of 2,3-dichloropro-
panoyl chloride was added, and the mixture was stirred
for 30 min at room temperature. The solvent was
distilled off, the residue was treated with 50 mL of
diethyl ether, and the extract was washed with dilute
aqueous HCl and water, dried over Na2SO4, and evap-
orated. Yield 2.5 g (77%), mp 94–95°C (from EtOH),
C1
C1
C4
C4
Fig. 7. (a) (2R,4S) and (b) (2S,4R) Diastereoisomers of
1-benzoyl-2-(2-benzyloxy-5-chlorophenyl)-4-chloropyrroli-
dine-2-carbonitrile (9) symmetry-related (in crystal) through
1
an inversion center.
Rf 0.61 (A). H NMR spectrum, δ, ppm: 3.67 d.d (1H,
CHCl, J = 8.3, 3.2 Hz), 4.09 d.d (1H, J = 9.1, 3.2 Hz)
and 4.14 d.d (1H, J = 9.1, 8.3 Hz) (CH2Cl), 6.54 br.s
(1H, NCH), 7.25–7.47 m (10H, Harom). Found, %:
C 61.40; H 4.51; Cl 21.50; N 8.70. C17H14Cl2N2O.
Calculated, %: C 61.28; H 4.23; Cl 21.28; N 8.4.
(a)
4-Chloro-5-oxo-1,2-diphenylpyrrolidine-2-carbo-
nitrile (3). A mixture of 3.33 g (10 mmol) of com-
pound 2, 2.76 g (20 mmol) of anhydrous potassium
carbonate, and 0.12 g (5 mmol) of benzyl(triethyl)-
ammonium chloride (BTEAC) in 20 mL of acetonitrile
was stirred for 4 h at 45–50°C. The mixture was
filtered, the filtrate was evaporated, the residue was
dissolved in chloroform, and the solution was washed
with water, dried over CaCl2, and evaporated. Yield
1.9 g (58%), mp 169–171°C (from i-PrOH), Rf 0.47
(B). IR spectrum, ν, cm–1: 2228 (C≡N), 1719 (C=O).
1H NMR spectrum, δ, ppm: 3.10 d.d (1H, J = 14.9,
2.5 Hz) and 3.28 d.d (1H, J = 14.9, 7.4 Hz) (CH2),
4.90 d.d (1H, CHCl, J = 7.4, 2.5 Hz), 7.17–7.41 m
(8H, Harom), 7.58–7.63 m (2H, Harom). 13C NMR spec-
trum, δC, ppm: 45.4 (PhCH2), 51.9 (C4), 63.8 (C2),
118.0 (CN), 125.6 (2C, CH), 126.0 (2C, CH), 127.0
(CH), 128.3 (2C, CH), 128.5 (2C, CH), 128.9 (CH),
134.9, 135.0, 168.6 (C5). Found, %: C 68.55; H 4.49;
C4
C1
(b)
C4
C1
Fig. 8. (a) (2R,4S) and (b) (2S,4R) Diastereoisomers of
1-benzoyl-2-(4-benzyloxyphenyl)-4-chloropyrrolidine-2-
carbonitrile (12) symmetry-related (in crystal) through an in-
version center.
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SYNTHESIS AND X-RAY ANALYSIS OF 2-ARYL-4-CHLOROPYRROLIDINE-...
857
Principal crystallographic parameters of 2-aryl-4-chloropyrrolidine-2-carbonitriles 3 and 12a
Parameter
CCDC entry no.
3
12
1019216
1019218
Formula
Molecular weight
Space group
a, b, c, Å
β, deg
C17H13ClN2O
C25H21ClN2O2
296.74
P21/n
416.89
C2/c
8.774(2), 17.491(4), 9.350(2)
34.487(7), 6.166(1), 23.843(5)
90.34(3)
1434.9(5)
123.14(3)
4245(2)
V, Å3
Z
d
T
4
8
calc, g/cm3
min/Tmax, μ(MoKα), mm–1
1.374
0.889/0.913, 0.266
1.305
0.637/0.857, 0.204
F(000)
616
1744
Crystal dimensions, mm
0.30×0.35×0.40
0.32×0.35×0.40
θmin/θmax, deg
2.3, 30.0
1.4, 30.0
Scan range
–12 = h = 12, 0 = k = 24, –13 = l = 13
–48 = h = 40, 0 = k = 8, 0 = l = 33
Total reflection number
Number of reflections with I > 2σ(I)]
Number of independent reflections
Number of variables
8309
3026
4161
0202
8258
3218
6186
0355
R, wR2, S
Weight scheme
0.0629, 0.2120, 1.05
0.0602, 0.1471, 1.00
W = 1/[σ2(Fo2) + (0.1214P)2 + 0.4422P]b W = 1/[σ2(Fo2) + (0.0546P)2 + 1.4026P]b
a
Monoclinic crystals, λ 0.71073 Å, 293 K.
P = (Fo2+2Fc2)/3.
b
Cl 12.10; N 9.20. C17H13ClN2O. Calculated, %:
C 68.81; H 4.42; Cl 11.95; N 9.44.
wise to a mixture of 2.19 g (10 mmol) of ester 4 and
1.05 g (10 mmol) of triethylamine in 10 mL of diethyl
ether, cooled to 0–5°C. The mixture was stirred for
30 min at room temperature and for 2 h at 25–30°C,
cooled, and treated with 50 mL of diethyl ether. The
extract was washed with water, dried over Na2SO4, and
evaporated. Yield 2.8 g (93%), viscous liquid, Rf 0.54
(C). IR spectrum, ν, cm–1: 1712 (C=O), 1680 (C=O).
1H NMR spectrum, δ, ppm: 1.28 t (3H, CH3, J =
7.1 Hz), 3.75 d.d and 3.89 d.d (1H each, NCH2, J =
16.9, 5.5 Hz), 4.20 d.q and 4.23 d.q (1H each, OCH2,
J = 10.7, 7.1 Hz), 4.86 d.q (1H, J = 16.9, 1.5 Hz) and
4.89 d.q (1H, J = 10.3, 1.5 Hz) (=CH2), 5.47 d.d.t (1H,
=CH, J = 16.9, 10.3, 5.5 Hz), 5.54 s (1H, NCH), 7.39–
7.53 m (8H, Harom), 7.94–7.98 m (2H, Harom). Found,
%: C 74.43; H 6.68; N 4.19. C20H21NO3. Calculated,
%: C 74.28; H 6.55; N 4.33.
Ethyl 2-allylamino-2-phenylacetate (4). Allyl-
amine, 0.6 g (10 mmol), was added dropwise at 10–
15°C to a mixture of 2.43 g (10 mmol) of ethyl
2-bromo-2-phenylacetate and 1.38 g (10 mmol) of
potassium carbonate in 10 mL of chloroform. The
mixture was stirred for 30 min at room temperature
and for 2 h at 35–40°C, cooled, and filtered, and the
filtrate was washed with water, dried over CaCl2, and
evaporated. Yield 2.1 g (98%), viscous liquid; oxalate:
mp 124–128°C (decomp.), Rf 0.65 (A). 1H NMR spec-
trum, δ, ppm: 1.21 t (3H, CH3, J = 7.1 Hz), 3.16 d.t
(2H, NCH2, J = 6.0, 1.5 Hz), 4.08 d.q and 4.16 d.q (1H
each, OCH2, J = 10.7, 7.1 Hz), 4.39 s (1H, NCH),
5.10 d.q (1H, J = 10.4, 1.5 Hz) and 5.15 d.q (1H, J =
16.9, 1.5 Hz) (=CH2), 5.84 d.d.t (1H, =CH, J = 16.9,
10.4, 6.0 Hz), 7.00 br.s (3H, NH, COOH), 7.23–7.38 m
(5H, Harom). Found, %: C 58.55; H 6.27; N 4.34.
C13H17NO2·(COOH)2. Calculated, %: C 58.25; H 6.19;
N 4.53.
Ethyl 1-benzoyl-4-chloro-2-phenylpyrrolidine-2-
carboxylate (6). A mixture of 3.23 g (10 mmol) of
ester 5, 0.9 g (10 mmol) of pyridine, and 10 mL of
1,2-dichloroethane was cooled to 0–5°C and saturated
with gaseous chlorine until a gain in weight of 0.71 g
(10 mmol Cl2) was attained, and the mixture was left
Ethyl 2-(N-allylbenzamido)-2-phenylacetate (5).
Benzoyl chloride, 1.3 g (10 mmol), was added drop-
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GASPARYAN et al.
858
overnight at room temperature. The mixture was dilut-
ed with 30 mL of 1,2-dichloroethane, washed with
water, dried over CaCl2, and evaporated. Dry potas-
sium carbonate, 2.76 g (20 mmol), BTEAC, 0.12 g
(5 mmol), and acetonitrile, 20 mL, were added to the
residue, and the mixture was stirred for 4 h at 45–
50°C. The mixture was cooled and filtered, the filtrate
was evaporated, the residue was dissolved in chloro-
form, and the solution was washed with water, dried
over CaCl2, and evaporated. Yield 2.35 g (66%),
mp 157–159°C (from EtOH), Rf 0.45 (D). IR spec-
7.44–7.48 m (3H, C6H5). Found, %: C 65.04; H 5.23;
N 7.88. C18H18N2O·(COOH)2. Calculated, %: C 65.21;
H 5.47; N 7.60.
N-Allyl-N-[(2-benzyloxyphenyl)(cyano)methyl]-
benzamide (8) was synthesized as described above for
compound 5 from 2.78 g (10 mmol) of nitrile 7. Yield
2.4 g (63%), mp 109–110°C (from EtOH), Rf 0.45 (D).
IR spectrum, ν, cm–1: 2242 (C≡N), 1656 (C=O).
1H NMR spectrum, δ, ppm: 3.64 d.d.t (1H, J = 16.4,
6.1, 1.3 Hz) and 3.92 d.d.t (1H, J = 16.4, 5.7, 1.3 Hz)
(NCH2), 4.87 d.q (1H, J = 17.0, 1.3 Hz) and 5.01 d.q
(1H, J = 10.4, 1.3 Hz) (=CH2), 5.15 s (2H, OCH2),
5.60 d.d.t (1H, =CH, J = 17.0, 10.4, 5.7 Hz), 6.64 br.s
(1H, NCH), 7.03 t.d (1H, J = 7.5, 0.8 Hz), 7.09 d (1H,
J = 8.3 Hz), 7.22 m (2H), 7.31–7.44 m (9H, Harom) and
7.64 d.d (1H, Harom, J = 7.6, 1.6 Hz). Found, %:
C 78.23; H 5.95; N 7.67. C25H22N2O2. Calculated, %:
C 78.51; H 5.80; N 7.32.
1-Benzoyl-2-(2-benzyloxy-5-chlorophenyl)-4-
chloropyrrolidine-2-carbonitrile (9) was synthesized
as described above for compound 6 from 3.82 g
(10 mmol) of nitrile 8. Yield 0.9 g (20%), mp 197–
198°C (from EtOH), Rf 0.48 (E). IR spectrum, ν, cm–1:
2242 (C≡N), 1637 (C=O). 1H NMR spectrum, δ, ppm:
2.99 br.d (1H, J = 15.0 Hz) and 3.12 br.d.d (1H, J =
15.0, 4.6 Hz) (CH2), 3.52 br.d (1H, J = 12.0 Hz) and
3.80 br.d.d (1H, J = 12.0, 4.0 Hz) (NCH2), 4.60 br.d.d
(1H, CHCl, J = 4.6, 4.0 Hz), 5.19 d and 5.24 d (1H
each, OCH2, J = 10.8 Hz), 7.20–7.60 m (13H, Harom).
13C NMR spectrum, δC, ppm: 47.4 (CH2), 55.7 (CH),
58.9 (CH2), 60.1 (C2), 70.6 (OCH2), 114.3 (CH), 117.1
(CN), 124.6, 125.9, 126.8 (CH), 127.6 (CH), 127.7
(CH), 128.1 (CH), 128.2 (CH), 128.4 (CH), 129.1
(CH), 130.0 (CH), 134.6, 135.4, 153.2, 166.7 (CO).
Found, %: C 66.39; H 4.81; Cl 15.44; N 6.03.
C25H20Cl2N2O2. Calculated, %: C 66.53; H 4.47;
Cl 15.71; N 6.21.
2-(Allylamino)-2-(4-benzyloxyphenyl)acetoni-
trile (10) was synthesized as described above for
compound 7 from 2.12 g (10 mmol) of 4-(benzyloxy-
phenyl)benzaldehyde and was used in the next step
without isolation and purification.
N-Allyl-N-[(4-benzyloxyphenyl)(cyano)methyl]-
benzamide (11). A solution of 1.05 g (10 mmol) of
triethylamine in 10 mL of diethyl ether was added to
nitrile 10, the mixture was cooled to 0–5°C, 1.3 g
(10 mmol) of benzoyl chloride was added dropwise,
and the mixture was stirred for 30 min at room tem-
perature and for 2 h at 25–30°C. The mixture was
cooled and treated with 50 mL of diethyl ether, and the
extract was washed with water, dried over Na2SO4, and
1
trum, ν, cm–1: 1735 (C=O), 1628 (C=O). H NMR
spectrum (mixture of two stereoisomers at a ratio of
3:2), δ, ppm: 1.29 t (1.8H) and 1.32 t (1.2H) (CH3, J =
7.1 Hz), 2.41 d.d (0.6H, J = 13.4, 9.2 Hz), 2.76–2.88 m
(0.8H) and 3.21 d.d (0.6H, CH2, J = 13.4, 6.5 Hz),
3.70–3.79 m (0.8H) and 3.88 d.d (0.6H) (NCH2, J =
10.9, 8.2 Hz), 4.09–4.32 m (3.4H, OCH2, NCH2,
CHCl), 4.62 m (0.6H, CHCl), 7.23–7.65 m (10H,
H
arom). 13C NMR spectrum, δC, ppm: 13.6 and 13.7
(CH3), 49.3 and 49.5 (NCH2), 51.2 and 51.6 (CH),
56.8 and 57.7 (CH2), 60.7 and 60.8 (OCH2), 70.5 and
70.7 (C2), 126.0, 126.3, 126.5, 126.7, 126.8, 127.0,
127.1, 127.9, 129.4 and 130.1 (CH, Ph), 135.1 and
135.8 (Ci), 137.7 and 138.9 (Ci), 168.4 and 169.1
(CO), 169.9 (CO). Found, %: C 67.40; H 5.15;
Cl 10.2; N 4.0. C20H20ClNO3. Calculated, %: C 67.13;
H 5.63; Cl 9.91; N 3.91.
2-(Allylamino)-2-(2-benzyloxyphenyl)acetoni-
trile (7). A solution of 0.49 g (10 mmol) of sodium
cyanide in 5 mL of water was added under stirring at
room temperature to a solution of 2.12 g (10 mmol) of
2-(benzyloxy)benzaldehyde in 10 mL of ethanol. The
mixture was stirred for 10 min, 0.6 g (10 mmol) of
acetic acid was added, the mixture was stirred for
10 min, and a solution of 1.4 g (10 mmol) of allyl-
amine in 10 mL of ethanol was added at 25–30°C. The
mixture was stirred for 2 h at that temperature, treated
with 10 mL of water and extracted with 1,2-dichloro-
ethane. The extract was washed with water, dried over
CaCl2, and evaporated. Nitrile 7 was isolated as a vis-
cous liquid, 2.4 g (88%), which was characterized as
oxalate, mp 112–118°C (decomp.), Rf 0.42 (E).
1H NMR spectrum, δ, ppm: 3.28 d.d.t (1H, J = 14.0,
6.3, 1.5 Hz) and 3.39 d.d.t (1H, J = 14.0, 5.5, 1.5 Hz)
(NCH2), 4.93 s (1H, NCH), 5.07 d.d.t (1H, =CH2, J =
10.2, 1.7, 1.5 Hz), 5.18 s (2H, OCH2), 5.22 d.d.t (1H,
=CH2, J = 17.1, 1.7, 1.5 Hz), 5.81 d.d.d.d (1H, =CH,
J = 17.1, 10.2, 6.3, 5.5 Hz), 6.98 t.d (1H, 5-H, J = 7.5,
1.0 Hz), 7.03 d.d (1H, 3-H, J = 8.2, 1.0 Hz) and 7.27–
7.33 m (2H, 4-H, 6-H, C6H4), 7.34–7.38 m (2H) and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

SYNTHESIS AND X-RAY ANALYSIS OF 2-ARYL-4-CHLOROPYRROLIDINE-...
859
2. Nakatani, S., Yamamoto, Y., Hayashi, M., Komi-
yama, K., and Ishibashi, M., Chem. Pharm. Bull., 2004,
vol. 52, p. 368.
evaporated. Yield 2.7 g (70%), mp 95–97°C (from
EtOH), Rf 0.66 (F). IR spectrum, ν, cm–1: 2238 (C≡N),
1653 (C=O), 1633 (C=O). 1H NMR spectrum, δ, ppm:
3.73 d.d.t (1H, J = 16.5, 6.2, 1.4 Hz) and 3.99 d.d.t
(1H, J = 16.5, 5.6, 1.4 Hz) (NCH2), 4.95 d.q (1H, J =
17.0, 1.4 Hz) and 5.05 d.q (1H, J = 10.3, 1.4 Hz)
(=CH2), 5.11 s (2H, OCH2), 5.65 d.d.d.d (1H, =CH, J =
17.0, 10.3, 6.2, 5.6 Hz), 6.51 br.s (1H, NCH), 6.97–
7.08 m (2H, Harom), 7.25–7.50 m (12H, Harom). Found,
%: C 78.34; H 5.63; N 7.09. C25H22N2O2. Calculated,
%: C 78.51; H 5.80; N 7.32.
3. Shibata, T., Iino, K., and Sugimura, Y., Heterocycles,
1986, vol. 24, p. 1331.
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Heterocycles, 1997, vol. 46, p. 53.
1-Benzoyl-2-(4-benzyloxyphenyl)-4-chloropyrro-
lidine-2-carbonitrile (12). A mixture of 3.82 g
(10 mmol) of nitrile 11, 0.9 g (10 mmol) of pyridine,
and 10 mL of 1,2-dichloroethane was cooled to 0–5°C
and saturated with gaseous chlorine until a gain in
weight of 0.71 g (10 mmol of Cl2) was attained. The
mixture was left overnight at room temperature, 30 mL
of 1,2-dichloroethane was added, and the mixture was
washed with water, dried over CaCl2, and evaporated.
The residue was mixed with 2.76 g (20 mmol) of
anhydrous potassium carbonate, 0.12 g (5 mmol)
of BTEAC, and 20 mL of acetonitrile, and the mixture
was stirred for 4 h at 45–50°C. The mixture was
cooled and filtered, the filtrate was evaporated, the
residue was dissolved in chloroform, and the solution
was washed with water, dried over CaCl2, and evapo-
rated. Yield 1.7 g (41%), mp 110–112°C (from EtOH),
Rf 0.51 (G). IR spectrum, ν, cm–1: 2238 (C≡N), 1640
7. Sato, T., Kawasaki, S., Oda, N., Yagi, S., El
Bialy, S.A.A., Uenishi, J., Yamauchi, M., and Ikeda, M.,
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8. Tamura, O., Yanagimachi, T., Kobayashi, T., and
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10. Maeda, K., Miller, R.A., Szumigala, R.H., Jr.,
Shafiee, A., Karady, S., and Armstrong, J.D., Tetra-
hedron Lett., 2005, vol. 46, p. 1545.
11. Fan, R., Wen, F., Qin, L., Pu, D., and Wang, B., Tetra-
hedron Lett., 2007, vol. 48, p. 7444.
12. Ha, D., Yun, K., Park, H., Choung, W., and Kwon, Y.,
Tetrahedron Lett., 1995, vol. 36, p. 8445.
13. Amjad, M. and Knight, D.W., Tetrahedron Lett., 2006,
vol. 47, p. 2825.
14. Martirosyan, A.O., Gasparyan, S.P., Oganesyan, V.E.,
Mndzhoyan, Sh.L., Alexanyan, M.V., Nikishchen-
ko, M.N., and Babayan, G.Sh., Chem. Heterocycl.
Compd., 2000, vol. 36, p. 416.
15. Martirosyan, A.O., Hovhannesyan, V.E., Gaspa-
ryan, S.P., Karapetyan, H.A., Panosyan, G.A., and
Martirosyan, V.O., Chem. Heterocycl. Compd., 2004,
vol. 40, p. 1007.
16. Gasparyan, S.P., Aleksanyan, M.V., Arutyunyan, G.K.,
Oganesyan, V.E., Martirosyan, V.V., Paronikyan, R.V.,
Stepanyan, G.M., and Martirosyan, A.O., Pharm.
Chem. J., 2012, vol. 46, no. 6, p. 331.
17. Tamazyan, R., Ayvazyan, A., Martirosyan, A., Marti-
rosyan, V., and Schinazi, R., Acta Crystallogr., Sect. E,
2007, vol. 63, p. o3967.
1
(C=O). H NMR spectrum, δ, ppm: 2.83 br.d.d (1H,
J = 14.7, 4.7 Hz) and 3.03 d.t (1H, J = 14.7, 1.9 Hz)
(CH2), 3.82 br.d (1H, J = 12.0 Hz) and 4.56 d.d (1H,
J = 12.0, 4.3 Hz) (NCH2), 4.73–4.78 m (1H, CHCl),
5.10 s (2H, OCH2), 6.96–7.03 m (2H, Harom), 7.25–
7.51 m (10H, Harom), 7.56–7.68 m (2H, Harom).
13C NMR spectrum, δC, ppm: 51.4 (CH2), 55.4 (CH),
59.4 (NCH2), 60.8 (C2), 69.2 (OCH2), 114.6 (2C, CH),
118.0 (CN), 125.6 (2C, CH), 126.9 (2C, CH), 127.0
(2C, CH), 127.2 (CH), 127.8 (2C, CH), 127.9 (2C,
CH), 130.1 (CH), 130.7, 134.8, 136.4, 158.0 (CO).
Found, %: C 72.34; H 5.27; Cl 8.69; N 6.44.
C25H21ClN2O2. Calculated, %: C 72.02; H 5.08;
Cl 8.50; N 6.72.
18. Tamazyan, R., Matevosyan, L., Martirosyan, A., Gaspa-
ryan, S., and Schinazi, R., Acta Crystallogr., Sect. E,
2007, vol. 63, p. o4069.
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