Enantioselective synthesis of γ-aminobutyric acid derivatives by Ni(II)-catalyzed reaction of diethyl malonate with nitroalkenes

Article abstract of DOI:10.1134/S1070428013050047

A new synthetic approach to (3R)-4-amino-3-methylbutyric acid and [(4R)-2-oxo-4-phenylpyrrolidin-1-yl]acetamide [(R)-phenotropil] has been developed. Asymmetric center with a required configuration has been generated via enantioselective addition of dieth

Full text of DOI:10.1134/S1070428013050047

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 5, pp. 663−667. © Pleiades Publishing, Ltd., 2013.
Original English Text © A.N. Reznikov, E.V. Golovin, Yu.N. Klimochkin, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 5, pp. 682−686.
Dedicated to Full Member of the Russian Academy of Sciences
I.P. Beletskaya on occasion of her jubilee
Enantioselective Synthesis of γ-Aminobutyric
Acid Derivatives by Ni(II)-Catalyzed Reaction
of Diethyl Malonate with Nitroalkenes
A. N. Reznikov, E. V. Golovin, and Yu. N. Klimochkin
Samara State Technical University, ul. Molodogvardeiskaya 244, Samara, 443001 Russia
e-mail: orgphosphorus@yandex.ru
Received December 30, 2012
Abstract—Anew synthetic approach to (3R)-4-amino-3-methylbutyric acid and [(4R)-2-oxo-4-phenylpyrrolidin-
1-yl]acetamide [(R)-phenotropil] has been developed. Asymmetric center with a required configuration has been
generated via enantioselective addition of diethyl malonate to 1-nitropropene and β-nitrostyrene, catalyzed by
Ni(II) complexes with (R,R)- and (S,S)-N,N′-dibenzylcyclohexane-1,2-diamine.
DOI: 10.1134/S1070428013050047
γ-Aminobutyric acid (GABA) was found in the mam-
malian brain as early as 1950. It is the main inhibitory neu-
rotransmitter in the mammalian central nervous system.
GABA and its derivatives are used in the treatment of
nervous system disorders such as logopathy, memory im-
pairment, cerebral atherosclerosis, and mental deficiency
in children. GABAergic compounds can improve cerebral
circulation and its autoregulation, prevent peroxide lipid
oxidation, enhance the activity of antioxidant systems,
exhibit membrane protecting effect, improve glucose
utilization, and level energy deficiency [1]. Some GABA
derivatives show nootropic activity; they improve learn-
ing ability, mental activity, and memory. Therapeutic
effects of numerous GABAderivatives and analogs have
been studied up to now [2].
therefore, development of new enantioselective syntheses
of (R)-phenotropil is an important problem.
(3R)-4-Amino-3-methylbutanoic acid is a synthetic
precursor of dipeptidyl peptidase-IV (DPP-IV) inhibitors
that are promising for the treatment of type II diabetes
mellitus [5]; it may also be used as intermediate product in
the synthesis of a structural fragment of the antiasthmatic
drug Zeneca ZD 3523 [6].
The known methods for the synthesis of (R)-phenotro-
pil [4, 7] and (3R)-4-amino-3-methylbutanoic acid [8]
are based on chemoenzymatic separation of intermediate
compounds. An alternative synthetic route to (3R)-4-
amino-3-methylbutanoic acid implies radical cyclization
of (S)-N-allyl-2-bromo-N-(1-phenylethyl)acetamide or
S-(2-{allyl[(S)-1-phenylethyl]amino}-2-oxoethyl) O-
ethyl dithiocarbonate in the presence of an equimolar
amount of tributylstannane [9], which complicates the
overall synthesis procedure and is inadmissible from the
viewpoints of environmental safety and purity of phar-
maceutical substances.
Among new-generation nootropic drugs, a cyclic
GABA derivative, (2-oxo-4-phenylpyrrolidin-1-yl)acet-
amide (phenotropil, phenylpiracetam, carphedon), should
be noted. Numerous studies have shown that phenotropil
enhances cerebral metabolism and blood circulation,
stimulates redox reactions, increases the energy potential
via glucose utilization, and improves blood circulation in
ischemic brain regions [3]. The (R) isomer of phenotropil
was found to produce more profound muscle relaxant and
analgesic effects as compared to its (S) enantiomer [4];
A very promising synthetic approach to nonracemic
3-substituted GABAderivatives is based on enantioselec-
tive addition of 1,3-dicarbonyl compounds to nitroalkenes
in the presence of transition metal complexes [10]. The
addition of malonates to nitrostyrene derivatives can be
663

REZNIKOV et al.
664
catalyzed by chiral nickel [11], cobalt, and manganese
complexes [12] with various diamines.
methylbutanoic acid and (R)-phenotropil via enantiose-
lective addition of diethyl malonate to 1-nitropropene and
β-nitrostyrene in the presence of chiral nickel complexes
Ia and Ib.
In continuation of our previous studies, in the present
article we report on the synthesis of (3R)-4-amino-3-
Br
Br
NH
NH
NH
NH
NH
NH
NH
NH
Ni
Br
Ni
Br
(R,R)-Ia
(S,S)-Ib
The addition of diethyl malonate (III) to 1-nitropropene
(II) was catalyzed by 2 mol % of Ia. The reaction was
enantioselective, and (R)-nitro ester IV with an ee
value of more than 79% was obtained (Scheme 1). The
hydrogenation of IV over Raney nickel was accompanied
by pyrrolidine ring closure to give ester V which was
subjected to acid hydrolysis. After recrystallization from
ethanol, (3R)-4-amino-3-methylbutanoic acid (VI) with
ee 98% (according to the HPLC data) was isolated.
Phenylpyrrolidin-2-one (XII) was synthesized from ester
(XI) in a way similar to the synthesis of VIII (Scheme 3).
Thus the use of a low-cost and readily accessible
Ni(II) complex as catalyst in enantioselective Michael
addition as the key step ensures preparation of (3R)-4-
amino-3-methylbutanoic acid and (R)-phenotropil with
high enantiomeric excess.
EXPERIMENTAL
Alkaline hydrolysis of ester V, followed by decarbox-
ylation of acid VII, afforded (4R)-4-methylpyrrolidin-2-
one (VIII) (Scheme 2).
The 1H and 13C NMR spectra were recorded on a Jeol
JNM-ECX400 instrument at 399.78 and 100.53 MHz,
respectively, from solutions in CDCl3 using the residual
proton signal and carbon signal of the solvent as refer-
ence. The mass spectra were obtained on a Finnigan Trace
The addition of diethyl malonate (III) to β-nitrostyrene
(IX) in the presence of 0.2 mol % of complex Ib in toluene
gave (R)-nitro ester X with ee 92.3% (HPLC). (4R)-4-
Scheme 1.
COOEt
O
(1) HCl, H2O
(2) NaOH, MeOH
EtOOC
COOEt
NO2
,
H2 Ni-Ra
COOEt
COOEt
Iа
H2N
NO2
+
COOH
C
O
O
H
N
H
ee >98%
ee 79.7%
VI
II
IV
V
III
Scheme 2.
COOEt
O
COOH
(1) NaOH, H2O_i-PrOH
(2) HCl, H2O
PhMe, 110oC
_СO2
O
O
N
N
H
N
H
H
V
VIII
VII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 5 2013

ENANTIOSELECTIVE SYNTHESIS OF γ-AMINOBUTYRIC ACID DERIVATIVES
665
Scheme 3.
COOEt
EtOOC
COOEt
NO2
COOEt
COOEt
III
Ph
,
H2 Ni-Raney
Ib
NO2
+
O
Ph
Ph
N
H
ee 92.3%
IX
X
XI
Ph
Ph
Ph
(1) NaOH, H2O _THF
(2) HCl, H2O
(3) PhMe, 110oC
BrCH2COOEt
NH3
O
O
N
O
N
N
H
C(O)NH2
COOEt
ee 98.9%
ee 98.9%
XIV
XIII
XII
DCQ GC–MS system (SGE BPX-5 capillary column;
30 m × 0.32 mm; electron impact, 70 eV).
Hz). 13C NMR spectrum (CDCl3), δC, ppm: 14.05 (CH3),
15.53 (CH3), 32.01 (CHCH3), 54.17 [CH(COOEt)2],
61.88 and 61.92 (CH2O, mixture of rotamers), 78.58
(CH2NO2), 167.68 and 167.72 (C=O, mixture of rotam-
ers). Mass spectrum m/z (Irel, %): 186 (5) [M – CH3NO2]+,
168 (32), 140 (17), 113 (27), 80 (25), 69 (100). Found,
%: C 48.62; H 6.89; N 5.71. C10H17NO6. Calculated, %:
C 48.58; H 6.93; N 5.67.
Enantiomeric purity of the products was estimated by
HPLC on a Waters liquid chromatograph equipped with
a Waters 2487 UV detector and a Waters 2414 refractive
index detector; analysis conditions: IV: Chiralcel OD-3
column, eluent hexane–propan-2-ol (95 : 5), flow rate
1.0 ml/min; X, XII: Chiralcel AD, hexane–propan-2-ol
(95:5), 1.0 ml/min; XIV: LuxAmylose-2 (150×4.6 mm;
5 μm), hexane–ethanol (70:30), 2.0 ml/min. (3R)-4-
Amino-3-methylbutanoic acid (VI) was preliminary
derivatized by treatment with D-Marfey reagent; HPLC
conditions: YMC Pack Pro C18 (150×3.0 mm, 3 μm),
formate buffer (pH 3.0) in methanol (4:6)–methanol
(70:30), 0.6 ml/min. The elemental compositions were
determined on a EuroVector EA 3000 analyzer. The
optical rotatins were measured on a Rudolph Research
Analytical polarimeter.
Ethyl (4R)-4-methyl-2-oxopyrrolidine-3-carbox-
ylate (V). A high-pressure reactor was charged with
a solution of 173.0 g (0.700 mol) of ester IV in 350 ml
of propan-2-ol, 5 g of Raney nickel was added, and the
mixture was heated for 20 h at 50°C under a hydrogen
pressure of 10–15 atm. The solvent was distilled off under
reduced pressure, the residue was dissolved in 300 ml
of chloroform, the solution was filtered through a 3-cm
layer of silica gel (filter diameter 20 cm), the sorbent
was washed with 500 ml of chloroform, and the solvent
was distilled off under reduced pressure. Yield 111.6 g
(93%), [α]D20 = +39.45° (c = 0.0236 g ml–1, chloroform).
1H NMR spectrum (CDCl3), δ, ppm: 1.05 d (3H, CH3,
Chiral nickel complexes Ia and Ib were synthesized
according to the procedure reported in [10].
Diethyl 2-[(2R)-1-nitropropan-2-yl]propanedioate
(IV). Nickel complex Ia, 6.1 g (7.5 mmol, 1.02 mol %),
was added to a mixture of 63.8 g (0.733 mol) of 1-nitro-
propene (II) and 269.7 g (1.686 mol) of diethyl malonate
(III), and the mixture was kept for 48 h at 50°C. Ester IV
was isolated by vacuum distillation. Yield 173.0 g (96%),
bp 105–112°C (3.8×10–2 mm), ee = 79.7% (HLPC);
JHH = 6.8 Hz), 1.18 t (3H, CH3, JHH = 6.8 Hz), 2.74 m (1H,
CH), 2.85 m (2H, CH2), 3.44 t (1H, CH, JHH = 9.1 Hz),
4.12 q (2H, CH2O, JHH = 6.8 Hz). Mass spectrum, m/z (Irel,
%): 171 (75) [M]+, 126 (40), 125 (32), 98 (20), 97 (40),
87 (65), 69 (100), 57 (40). Found, %: C 56.20; H 7.69;
N 8.25. C8H13NO3. Calculated, %: C 56.13; H 7.65;
N 8.18. M 171.19.
20
retention time, min: (R)-IV 8.9, (S)-IV 10.5; [α]D
=
+12.12° (c = 0.025 g ml–1, chloroform). 1H NMR spec-
trum (CDCl3), δ, ppm: 1.10 d (3H, CH3, 3JHH = 6.8 Hz),
1.24 t (6H, CH3, 3JHH = 7.1 Hz), 2.99 m (1H, CHCH3),
3.44 d [1H, CH(COOEt)2, 3JHH = 6.6 Hz], 4.18 m (4H,
CH2O, mixture of rotamers), 4.42 d.d (1H, CH2NO2, JHH
= 7.9, 2.7 Hz), 4.60 d.d (1H, CH2NO2, JHH = 5.0, 12.7
(3R)-4-Amino-3-methylbutanoic acid (VI). A mix-
ture of 111.6 g (0.652 mol) of ester V, 107 ml of con-
centrated aqueous HCl, and 107 ml of water was heated
for 18 h at the boiling point. The mixture was cooled and
extracted with ethyl acetate (2× 100 ml) to remove neutral
impurities, and the aqueous phase was evaporated under
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REZNIKOV et al.
666
reduced pressure. The residue, amino acid hydrochloride,
88.9 g, was dissolved in 250 ml of methanol, a solution of
28.0 g (0.700 mol) of sodium hydroxide in 1 l of metha-
nol was added under stirring and cooling until pH 7, the
mixture was evaporated to a volume of 500 ml, 500 ml
of ethyl acetate was added, and the mixture was filtered
through a 3-cm layer of silica gel (filter diameter 20 cm).
The solvent was distilled off under reduced pressure, and
the residue was recrystallized from 700 ml of ethanol.
Yield 43.5 g (57%), mp 191–193°C, ee = 98% (HPLC),
[α]D25 = –8.36° (c = 0.052 g ml–1, water; published data
[8]: [α]D25 = –7.34° (c = 0.052 g ml–1, water); retention
time, min: (S)-VI 6.0, (R)-VI 7.8 min. 1H NMR spectrum
(CH2), 179.28 (C=O). Mass spectrum, m/z (Irel, %): 99
(100) [M]+, 69 (30), 56 (55). Found, %: C 60.61; H 9.09;
N 14.05. C5H9NO. Calculated, %: C 60.58; H 9.15;
N 14.13. M 99.13.
Diethyl 2-[(1R)-2-nitro-1-phenylethyl]propanedio-
ate (X). Complex Ib, 325 mg (0.402 mmol), was added
to a solution of 30.0 g (0.201 mol) of β-nitrostyrene (IX)
and 36.6 ml (38.7 g, 0.241 mmol) of diethyl malonate
in 68 ml of toluene, and the mixture was stirred for 6 h
at 50°C. The solvent was distilled off under reduced
pressure, and the residue was subjected to chromatog-
raphy on Kieselgel 60 using chloroform as eluent. Yield
30
48.1 g (77%), mp 45–46°C, ee = 92% (HPLC), [α]D
=
3
(CD3OD), δ, ppm: 1.02 d (3H, CH3, JHH = 6.9 Hz),
–6.62° (c = 0.015 g ml–1, CHCl3); published data [13]:
mp 43–45°C; retention time, min: (R)-X 18.5, (S)-X 43.1.
1H NMR spectrum (CDCl3), δ, ppm: 1.03 t (3H, CH3,
3JHH = 7.1 Hz), 1.24 t (3H, CH3, 3JHH = 7.1 Hz), 3.80 d
[1H, CH(COOEt)2, 3JHH = 9.2 Hz], 3.99 q (2H, CH2O,
3JHH = 7.1 Hz), 4.21 m (3H, CH2O, CHPh), 4.88 m (2H,
CH2NO2), 7.23–7.30 m (5H, Ph). 13C NMR spectrum
(CDCl3), δC, ppm: 13.79 (CH3), 14.02 (CH3), 43.06
(CHPh), 55.08 [CH(COOEt)2], 61.93 and 62.21 (CH2O),
78.68 (CH2NO2), 128.11 (Co), 128.41 (Cm), 128.99 (Cp),
136.36 (Ci), 166.90 and 167.53 (C=O). Mass spectrum,
m/z (Irel, %): 309 [M]+, 263 (12), 218 (12), 190 (13), 189
(100), 171 (58), 161 (56), 145 (30), 133 (22), 131 (20),
117 (28), 115 (70), 105 (15), 104 (55), 103 (34), 91 (26),
78 (15), 77 (20). Found, %: C 58.29; H 6.14; N 4.49.
C15H19NO6. Calculated, %: C 58.25; H 6.19; N 4.53.
M 309.31
2.15 m (1H, CH), 2.27 d (2H, CH2, 3JHH = 6.7 Hz), 2.86 d
(2H, CH2, 3JHH = 6.7 Hz), 4.96 br.s (3H, NH3 ). 13C NMR
+
spectrum (CD3OD), δC, ppm: 17.58 (CH3), 29.48 (CH),
43.69 (CH2), 45.37 (CH2), 179.17 (COO–). Found, %:
C 51.32; H 9.42; N 11.91. C5H11NO2. Calculated, %:
C 51.26; H 9.46; N 11.96.
(4R)-4-Methyl-2-oxopyrrolidine-3-carboxylic acid
(VII). A solution of 106 g (2.65 mol) of sodium hydrox-
ide in 212 ml of water was added to a solution of 39.0 g
(0.228 mol) of compound V in 106 ml of propan-2-ol,
and the mixture was stirred for 1.5 h at room temperature.
The precipitate of carboxylic acid sodium salt was filtered
off, washed with propan-2-ol (20 ml), and dried. The salt,
32.8 g, was dissolved in 25 ml of water, 25 ml of 35%
aqueous HCl was added on cooling, and the the precipitate
was filtered off, washed with 15 ml of water, and dried.
Yield 24.1 g (74%), mp 135–137°C (decomp.). 1H NMR
Ethyl (4R)-2-oxo-4-phenylpyrrolidine-3-carboxyl-
ate (XI). A high-pressure reactor was charged with 75 g
(0.242 mol) of nitro ester X in 200 ml of propan-2-ol, 5 g
of Raney nickel was added, and the mixture was heated at
50°C under a hydrogen pressure of 30 atm. The mixture
was filtered, the filtrate was evaporated under reduced
pressure, and the oily residue was crystallized from
spectrum (DMSO-d6), δ, ppm: 1.00 d (3H, CH3, JHH
=
6.8 Hz), 2.60 m (1H, CH), 2.73 t (1H, CH), 2.82 d (1H,
CH), 3.30 t (1H, CH), 7.78 br.s (1H, NH). 13C NMR spec-
trum (DMSO-d6), δC, ppm: 18.19 (CH3), 34.77 (CHCH3),
47.41 (CH2N), 56.25 (CHCOOH), 171.90 (C=O), 173.02
(COOH). Found, %: C 50.42; H 6.31; N 9.72. C6H9NO3.
Calculated, %: C 50.35; H 6.34; N 9.79.
petroleum ether–toluene. Yield 48.05 g (85%). 1H NMR
3
(4R)-4-Methylpyrrolidin-2-one (VIII). A solution
of 24.1 g (0.168 mol) of acid VII in 370 ml of toluene
was heated for 1.5 h under reflux, and the solvent was
removed under reduced pressure. Yield 16.2 g (97%).
1H NMR spectrum (CDCl3), δ, ppm: 0.91 d (3H, CH3,
3JHH = 6.8 Hz), 1.74 d.d (1H, 3JHH = 6.6, 2JHH 16.3 Hz),
2.26 d.d (1H, 3JHH = 8.7, 2JHH = 16.2 Hz), 2.31 m (1H),
2.75 d.d (1H, 3JHH = 6.0, 2JHH = 9.8 Hz), 3.31 d.d (1H,
3JHH = 7.8, 2JHH = 8.0 Hz). 13C NMR spectrum (CDCl3),
δC, ppm: 19.54 (CH3), 29.24 (CH), 38.60 (CH2), 49.81
spectrum (CDCl3), δ, ppm: 1.25 t (3H, CH3, JHH
=
7.1 Hz), 3.40 m (1H), 3.52 m (1H), 3.79 m (1H), 4.09 m
(1H), 4.22 q (2H, CH2, 3JHH = 7.1 Hz), 7.24–7.33 m (5H,
Ph), 7.44 br.s (1H, NH). 13C NMR spectrum (CDCl3),
δC, ppm: 14.23 (CH3), 44.51 (CH), 47.99 (CH2), 61.89
(CH), 127.10 (Co), 127.63 (Cm), 129.08 (Cp), 140.03 (Ci),
169.48 (C=O), 173.36 (C=O). Mass spectrum, m/z (Irel,
%): 233 [M]+, 187 (10), 160 (100), 130 (68), 115 (37),
103 (72), 91 (33), 77 (70). Found, %: C 67.02; H 6.42;
N 5.92. C13H15NO3. Calculated, %: C 66.94; H 6.48;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 5 2013

ENANTIOSELECTIVE SYNTHESIS OF γ-AMINOBUTYRIC ACID DERIVATIVES
667
N 6.00. M 233.26.
2.87 d.d (1H, 3-H, 3JHH = 8.4, 2JHH = 17.0 Hz), 3.54 m
(1H, 5-H), 3.64 m (1H, 4-H), 3.83 m (1H, 5-H), 4.11 d.d
(2H, NCH2CO, 3JHH = 16.3, 2JHH = 33.0 Hz), 4.20 q (2H,
CH2O, JHH = 7.1 Hz), 7.20–7.39 m (5H, Ph). Found,
%: C 68.08; H 6.87; N 5.62. C14H17NO3. Calculated, %:
C 68.00; H 6.93; N 5.66.
(4R)-4-Phenylpyrrolidin-2-one (XII). A solution of
40.5 g (0.174 mol) of esterXI in 380 ml ofTHF was cooled
to 0°C, 190 ml of 15% aqueous potassium hydroxide was
added, the mixture was stirred for 3 h, 500 ml of water
was added, and the mixture was extracted with diethyl
ether (2 × 200 ml) to remove neutral impurities. The
aqueous phase was acidified with concentrated aqueous
HCl until a colorless solid separated. The mixture was
cooled with an ice bath for complete precipitation, and the
precipitate was filtered off and dried in air. Yield of 2-oxo-
4-phenylpyrrolidine-3-carboxylic acid 25.5 g (71%). The
product, 25.5 g (0.124 mol), was heated for 6 h in 100 ml
of boiling toluene, the mixture was washed with a 30%
solution of Na2CO3 (2 × 100 ml) and with water, the
solvent was distilled off under reduced pressure, and the
residue was recrystallized from petroleum ether–toluene.
Yield 12.8 g (64%), mp 86–89°C, ee = 99% (HPLC),
3
2-[(4R)-2-Oxo-4-phenylpyrrolidin-1-yl]acet-
amide [(R)-phenotropil] (XIV) [4]. Gaseous ammonia
was bubbled over a period of 5 h through a solution of
0.25 g (1.01 mmol) of ester XIII in 30 ml of methanol
at room temperature. The solvent was distilled off
under reduced pressure, and the residue was purified by
flash chromatography on silica gel using chloroform–
methanol as eluent (gradient elution, 5–10% of
methanol). Yield 0.19 g (87%), mp 107–108°C, ee
20
= 99.8% (HPLC), [α]D = +8.5° (c = 3.0, MeOH);
retention time, min: (R)-XIV 12.9, (S)-XIV 16.2.
1H NMR spectrum (CDCl3), δ, ppm: 2.59 d.d (1H,
[α]D = –36° (c = 0.01 g ml–1, chloroform); retention
20
3
2
3-H, JHH = 8.4, JHH = 17.0 Hz), 2.81 d.d (1H, 3-H,
3JHH = 8.4, 2JHH = 17.0 Hz), 3.53 m (1H, 5-H), 3.63 m
(1H, 4-H), 3.85 m (1H, 5-H), 3.97 d.d (2H, NCH2CO,
3JHH = 16.3, 2JHH = 33.0 Hz); 6.24 br.s and 6.66 br.s (1H
each, NH2), 7.22–7.31 m (5H, Ph). 13C NMR spectrum
(CDCl3), δC, ppm: 37.48 (C3), 38.54 (C4), 46.25 (C5),
55.55 (NCH2CO), 126.89 (Cm), 127.27 (Cp), 129.01
(Co), 141.97 (Ci), 170.78 (C=O), 175.03 (CONH2).
Found, %: C 66.10; H 6.41; N 12.79. C12H14N2O2.
Calculated, %: C 66.04; H 6.47; N 12.84.
time, min: (R)-XII 6.2, (S)-XII 6.9. 1H NMR spectrum
(CDCl3), δ, ppm: 2.43 d.d (1H, 3-H, 3JHH = 6.8, 2JHH
=
16.8 Hz), 2.65 d.d (1H, 3-H, 3JHH = 8.8, 2JHH = 16.8 Hz),
3
2
3.36 d.d (1H, 5-H, JHH = 8.4, JHH = 8.8 Hz), 3.64 m
(1H, 4-H), 3.72 d.d (1H, 5-H, 3JHH = 8.4, 2JHH = 8.8 Hz),
7.20–7.27 m (5H, Ph). 13C NMR spectrum (CDCl3), δC,
ppm: 38.35 (C3), 40.11 (C4), 49.50 (C5), 126.52 (Co),
126.91 (Cm), 128.60 (Cp), 142.02 (Ci), 178.21 (C=O).
Mass spectrum, m/z (Irel, %): 161 [M]+, 104 (100), 78
(10). Found, %: C 74.56; H 6.81; N 8.61. C10H11NO.
Calculated, %: C 74.51; H 6.88; N 8.69. M 161.20.
ACKNOWLEDGMENTS
Ethyl [(4R)-2-oxo-4-phenylpyrrolidin-1-yl]acetate
(XIII) [4].Asolution of 345 mg (2.14 mmol) of compound
XII in 30 ml of 1,4-dioxane was added under argon to a
suspension of 93 mg (2.35 mmol) of 60% sodium hydride
in 1,4-dioxane. The mixture was stirred for 30 min at 80°C
and cooled to room temperature, 0.393 g (2.37 mmol)
of ethyl bromoacetate was added, and the mixture was
heated for 6 h under reflux. The solvent was removed
under reduced pressure, the residue was diluted with
50 ml of ethyl acetate, the solution was washed with 5%
aqueous HCl (2 × 10 ml) and brine (10 ml), the organic
phase was separated and dried over sodium sulfate, the
solvent was distilled off under reduced pressure, and
the residue was purified by flash chromatography on
silica gel using chloroform–methanol (95 : 5) as eluent.
This study was performed under financial support by
the Ministry of Education and Science of the Russian
Federation (state contract no. 11.519.11.2012).
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