Facile Reduction of β-Enamino Oxopyrrolidine Carboxylates Mediated by Heterogeneous Palladium Catalyst

Article abstract of DOI:10.1134/S1070428020060184

Abstract: The synthesis of diastereoisomers via diastereoselective hydrogenation ofunreactive endocyclic enamine system of ethyl 4-hydrazinyl- and4-(2-hydroxyethylamino)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylates using palladium-based catalyst wasdevelop

Full text of DOI:10.1134/S1070428020060184

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 6, pp. 1082–1088. © Pleiades Publishing, Ltd., 2020.
Facile Reduction of β-Enamino Oxopyrrolidine Carboxylates
Mediated by Heterogeneous Palladium Catalyst
F. N. A. Abdul Rashida, M. F. Mohammatb,*, F. E. Bouchammaa,
Z. Shaamerib, and A. S. Hamzahb
a Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam, 40450 Selangor, Malaysia
b Organic Synthesis Research Laboratory, Institute of Science, Universiti Teknologi MARA,
Bandar Puncak Alam, 42300 Selangor, Malaysia
*e-mail: mohdfazli@uitm.edu.my
Received December 16, 2019; revised March 21, 2020; accepted March 23, 2020
Abstract—The synthesis of diastereoisomers via diastereoselective hydrogenation of unreactive endocyclic
enamine system of ethyl 4-hydrazinyl- and 4-(2-hydroxyethylamino)-5-oxo-2,5-dihydro-1H-pyrrole-3-carbox-
ylates using palladium-based catalyst was developed. The steric and electronic properties of substituents,
especially of the C2 substituent, influenced both the yield and diastereoselectivity. Despite the reaction generated
three chiral centers, the reduced compounds had either cis–trans or all-trans configuration which was success-
fully determined by means of 1D and 2D NMR experiments.
Keywords: enamino ester, hydrogenation, palladium catalysis, chiral amine
DOI: 10.1134/S1070428020060184
Chiral amines represent an important functionality
for the synthesis of many bioactive molecules [1]. To
date, one of the most efficient synthetic protocols
toward chiral amines involves metal-catalyzed hydro-
genation of prochiral imines, enamines, and N-hetero-
aromatic compounds [2]. Common noble-metal cata-
lysts based on palladium, platinum, ruthenium,
rhodium, and iridium are known as effective reagents
for these chiral amine syntheses [3]. Among varieties
of heterocycle compounds, pyrrolidines are of great
pharmaceutical and medicinal interest as they are sub-
structures of a number of bioactive compounds [4].
Pyrrolidine derivatives are known to display consid-
erable medicinal properties such as antimicrobial,
analgesic, anti-inflammatory, and anticancer activities
[5]. In conjunction with our research endeavors on
synthesizing different classes of bioactive polyhydroxy
pyrrolidine alkaloids, we have successfully demon-
strated diastereoselective reduction of 5-substituted
2,3-dioxopyrrolidine esters using NaBH4/AcOH and
heterogeneous Pd-hydrogenation reactions [6]. It was
concurred that steric properties of the C5 substituent
have significant effect on both the yield and diastereo-
selectivity. Interestingly, a bulky C5-substituent
favored formation of more thermodynamically stable
trans-isomeric products in this metal-assisted hydro-
genation reaction. Consequently, as further extension
for synthetic exploration of similar pyrrolidine ester
systems, herein we report our attempts to reduce un-
saturated β-enamino esters and β-hydrazino (enamino)
esters of the pyrrolidone series. These protocols em-
ployed simple and diastereoselective heterogeneous
catalytic reaction using Pd/C, Pd(OH)2/C (Pearlman’s
catalyst) and PtO2 (Adam’s catalyst).
The starting materials, ethyl 2-R-4,5-dioxopyrroli-
dine-3-carboxylates 1 were prepared according to the
reported procedure [7, 8]. Nitrogen nucleophiles are
known to react with 2,3-dioxopyrrolidines at the
3-position to afford a variety of β-enamino esters via
a typical 1,2-nucleophilic addition reaction. It was
anticipated that the enol tautomer of 1 could be con-
verted to more stable keto form in a polar solvent such
as ethanol during the reaction. Thus, by refluxing in
ethanol with ammonium formate or hydrazine, com-
pounds 1 afforded N-unprotected enamines 2 and
hydrazine derivatives 3 in good to excellent yield (70–
91%; Scheme 1; Table 1, entry nos. 1–10) [9]. The
condensation of 1 with 2-aminoethanol in boiling
ethanol in the presence of formic acid gave hydroxy-
ethylamino derivatives 4 as different N-alkyl enamines
in a reasonable yield (60–92%; Table 1, entry nos. 11–
15) [10]. Apparently, compounds 2–4 exist predomi-
nantly in the enamine form due to resonance stabi-
1082

FACILE REDUCTION OF β-ENAMINO OXOPYRROLIDINE CARBOXYLATES
1083
Scheme 1.
O
O
HCOO– NH4
EtOH, reflux
HN
H2N
O
OEt
OEt
O
O
R2
R2
N
N
HO
OEt
R1
R1
2
O
R2
N
NH2
O
NH2
O
R1
NH2NH2·H2O
EtOH, reflux
HN
O
N
OEt
OEt
R2
O
R2
N
N
O
R1
R1
3
O
OEt
O
O
NH2(CH2)2OH
HCOOH, EtOH
reflux
HO
HO
O
R2
NH
N
OEt
OEt
4
N
3
R1
1
5
R2
O
R2
O
N
N
R1
R1
4
lization via intramolecular hydrogen bonding. Similar
imine–enamine tautomerism of β-enamino esters of the
pyrrolidinone series was reported previously [11].
the nucleophilicity of the endocyclic double bond of
the enamine was reduced due to its very high resonance
stability resulting from hydrogen bonding between the
amino group and ester functionality. It is also known
that the amino group has strong electron-donor prop-
erties and is capable of competing for coordination to
Pd metal, which could lead to poisoning of the catalyst
[12, 13]. For that reason, an acid was added to the
reaction system to prevent the catalyst from being
Initially, attempts towards hydrogenation of en-
amine 2 using 10% Pd/C in ethanol failed to give any
product, and only the starting material was recovered
(Scheme 2, i). Further attempts by prolonging the
reaction time, even under pressure (8 atm), also led to
negative results (Scheme 2, ii–v). It was reasoned that
Table 1. Yields of ompounds 2–4
Entry no.
Compound no.
R1
Me
Me
Me
Me
Me
R2
Yield,a %
77
1
2
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
H
Me
Et
76
3
80
4
4-MeOC6H4
83
5
4-NCC6H4
86
6
H
Me
H
78
7
H
74
Me
Me
Me
Me
Me
Me
Me
Me
8
Me
70
9
Et
91
10
11
12
13
14
15
4-MeOC6H4
85
H
92
Me
62
Et
67
4-MeOC6H4
4-MeC6H4
60
62
a
Isolated by column chromatography.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

ABDUL RASHID et al.
1084
Scheme 2.
O
O
H
HN
H2N
OEt
OEt
H2, Pd/C, i–v
O
R2
O
R2
N
N
R1
R1
2
i: EtOH, 1 atm, r.t., 12 h; ii: AcOH, 1 atm, r.t., 24 h; iii: EtOH, 8 atm, r.t., 12 h;
iv: AcOH, 8 atm, r.t., 12 h; v: EtOH, AcOH, 8 atm, r.t., 12 h.
Scheme 3.
NH2
O
NH2
O
NH2
O
HN
HN
OEt
HN
OEt
OEt H2, Pd/C, AcOH
1 atm, room temp.
4
3
2
4
3
2
+
5
5
1
N
R2
1
O
R2
O
R2
O
N
N
R1
R1
R1
5a–5e
all-cis
5c'–5e'
cis–trans
3a–3e
Et
Et
O
R2
O
O
O
R2
H
N
H
N
N
N
O
R1
O
R1
H2N
H2N
H
H
Pd
Pd
H
H
Less favored
Favored
poisoned via protonation of the amino group. Un-
fortunately, this attempt also failed to furnish the
desired reduction products despite similar synthetic ap-
proach was successfully demonstrated by Wang et al.
before [14].
was achieved by employing a heterogeneous Pd/C
catalytic system. It should be noted that all the reduc-
tion products of 3 and 4 have three chiral centers, so
that the formation of eight different diastereoisomers is
possible. However, regardless the absolute configura-
tion, only two diastereoisomers, all-cis and cis–trans
were present in the racemic mixture. Therefore, com-
plete diastereoselectivity (dr = 100:0) was observed for
compounds 3a and 3b which lack a substituent on C2.
If a substituent was present at the 2-position, the yield
Interestingly, further reduction study with more
electronegative substrates, β-enehydrazino esters 3a
and 3b, resulted in successful synthesis of hydrazinyl-
pyrrolidines 5a and 5b in good yield (88–89%;
Scheme 3, Table 2, entry nos. 1, 2) [15]. This reduction
Table 2. Reduction of dihydropyrrolecarboxylates 3a–3e to pyrrolidines 5a–5e
Yield, %
Entry no.
Compound no.
R1
R2
dra
all-cis
5a, 88
5b, 89
5c, 16
5d, 10
5e, 12
cis–trans
–
1
2
3
4
5
3a
3b
3c
3d
3e
H
H
100:0
100:0
41:59
30:70
32:68
Me
Me
Me
Me
H
–
Me
Et
5c′, 23
5d′, 23
5e′, 26
4-MeOC6H4
a
Diastereoisomer ratio was based on the isolated yield after column chromatography.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

FACILE REDUCTION OF β-ENAMINO OXOPYRROLIDINE CARBOXYLATES
1085
Scheme 4.
O
O
HO
HO
NH
NH
OEt
OEt
i–iii
R2
O
R2
O
N
N
R1
R1
6a–6e
4a–4e
Table 3. Hydrogenation of ethyl 4-(2-hydroxyethylamino)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylates 4a–4e
Entry no. Compound no.
R1
R2
Reaction conditions
Yield, %
1
2
3
4
5
6
7
4a
4a
4a
4b
4c
4d
4e
Me
Me
Me
Me
Me
Me
Me
H
i: H2, Pd/C, AcOH, 1 atm, room temp., 12 h
35
Traces
83
H
ii: H2, PtO2, AcOH, MeOH, 1 atm, room temp., 12 h
iii: H2, Pd(OH)2, AcOH, EtOH, 1 atm, room temp., 12 h
iii: H2, Pd(OH)2, AcOH, EtOH, 1 atm, room temp., 12 h
iii: H2, Pd(OH)2, AcOH, EtOH, 1 atm, room temp., 12 h
H
Me
Et
25
23
4-MeOC6H4 iii: H2, Pd(OH)2, AcOH, EtOH, 1 atm, room temp., 12 h
4-MeC6H4 iii: H2, Pd(OH)2, AcOH, EtOH, 1 atm, room temp., 12 h
34
33
and diastereoselectivity were lower (Table 2, entry
nos. 3–5), and mixtures of diastereoisomers 5c–5e
(all-cis) and 5c′–5e′ (cis–trans) were isolated in the
reduction of compounds 3c–3e. Both column chroma-
tography and 2D NMR spectroscopy revealed that the
major diastereoisomers had cis–trans configuration
(5c′–5e′), and the ratio cis–trans/all-cis increased in
parallel with the size of C2-substituent (Table 2). This
observation contradicted our previous results obtained
in the Pd-assisted enolic reduction which favored the
all-cis configuration [6].
but in a poor yield (35%; Table 3, entry no. 1). Never-
theless, replacement of the catalyst by Pd(OH)2/C
resulted in a superior yield (83%; Table 3, entry no. 3).
However, the use of PtO2 as catalyst led to the poorest
yield (Table 3, entry no. 2).
It should be noted that high diastereoselectivity was
observed with Pd(OH)2/C, as only all-cis isomers were
obtained. The all-cis configuration of the products was
1
confirmed by H NMR and 2D NMR experiments.
Proton correlations observed in the 2D NMR spectra
resembled those reported by us previously [15].
Likewise, the presence of a bulky substituent on C2
significantly reduced the yield. A different mechanism
was proposed for the reduction of 2-hydroxyethylamino
derivatives 4. Due to the presence of a terminal hy-
droxy group, the transition state has a structure differ-
ent from that shown in Scheme 3. Here, the concerted
syn addition becomes less significant, and all-cis dia-
stereoisomers are formed as the sole product (Table 3,
entry nos. 4–7). Thus, chelation effect of the terminal
hydroxy group significantly contributes to the observed
diastereoselectivity.
From the mechanistic viewpoint, it was proposed
that the hydrazine group would form a stable six-mem-
bered transition ring system via hydrogen bonding with
the ester carbonyl functionality and subsequently force
them away from the C2 substituent due to steric con-
gestion. Thus, the two hydrogen atoms are transferred
via the concerted syn addition from the opposite side of
the 2-H proton, leading to the cis–trans configuration
of the major product (Scheme 3). A similar observation
was also disclosed by Wang et al. during hydrogenation
of various aminopyrrolidinecarboxylates [14]. In addi-
tion, it was reasoned that bulkier substituent on C2
markedly contributes to lower yield by blocking off
hydrogen from the active site of the Pd-ene complex.
In conclusion, we have discovered a simple method
for the synthesis of chiral amines via palladium-cata-
lyzed syn-hydrogenation of ethyl 4-(2-hydroxyethyl-
amino)- and 4-hydrazinyl-5-oxo-2,5-dihydro-1H-pyr-
role-3-carboxylates with high diastereoselectivity.
However, hydrogenation of unprotected β-enamino
esters is still challenging, and further optimization of
this hydrogenation process is currently in progress in
our laboratory.
For further mechanistic study on the effect of steric
or electronic factors on the reduction process, 4-(2-hy-
droxyethylamino)pyrrolidinecarboxylate 4a containing
an alcohol functionality was subjected to similar Pd/C-
catalyzed heterogeneous reduction. Fortunately, this
reaction successfully gave compound 6a (Scheme 4)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

ABDUL RASHID et al.
1086
EXPERIMENTAL
4.28 m (3H, OCH2, 2-H). 13C NMR spectrum (CDCl3),
δC, ppm: 5.59, 14.60, 21.42, 27.32, 59.77, 59.88,
101.03, 147.11, 165.20. Found, %: C 56.57; H 7.48;
N 12.59. C10H16N2O3. Calculated, %: C 56.59; H 7.60;
N 13.20.
All reagents were supplied by Merck, Sigma–
Aldrich, and Acros Organics. The melting points were
measured using a Mettler Toledo FP62 automatic
melting point apparatus and are uncorrected. The IR
spectra (4000–400 cm–1) were recorded on a Varian
3100 Excalibur Series FT/IR spectrometer. The 1H and
13C NMR spectra were recorded on a Joel 400 spec-
trometer at 400 and 100 MHz, respectively. The prog-
ress of reactions was monitored by thin layer chroma-
tography (TLC) on silica gel 60 F254, and spots were
visualized with a UV lamp (λ 254 and 365 nm).
Ethyl 4-hydroxy-2-(4-methoxyphenyl)-1-methyl-
5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (2d).
Yield 83%, light yellow solid, mp 151–153°C. IR spec-
trum, ν, cm–1: 3409, 3310, 1678, 1643, 1238, 1093.
1H NMR spectrum (CDCl3), δ, ppm: 1.11 t (3H, J =
7.1 Hz, CH3), 2.76 s (3H, NCH3), 3.78 s (3H, OCH3),
4.01–4.09 m (2H, OCH2), 4.92 s (1H, 2-H), 6.83 d (2H,
J = 8.7 Hz, Harom), 7.06 d (2H, J = 8.7 Hz, Harom).
13C NMR spectrum (CDCl3), δC, ppm: 14.31, 27.59,
55.33, 59.71, 63.81, 104.25, 113.98, 128.51, 128.82,
146.08, 159.58, 164.93, 165.43. Found, %: C 61.17;
H 6.24; N 9.48. C15H17NO5. Calculated, %: C 62.06;
H 6.25; N 9.65.
Ethyl 3-amino-5-oxo-2,5-dihydro-1H-pyrrole-3-
carboxylates 2a–2e (general procedure). Ammonium
formate (21.60 mmol) was added to a solution of pyr-
rolidine 1a–1e (10.80 mmol) in ethanol (54 mL), and
the mixture was refluxed for 24 h. After completion
of the reaction, the mixture was concentrated under
reduced pressure, the residue was extracted with ethyl
acetate, the extract was dried over MgSO4 and evapo-
rated, and the residue was purified by chromatography
using ethyl acetate as eluent.
Ethyl 2-(4-cyanophenyl)-4-hydroxy-1-methyl-5-
oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (2e).
1
Yield 86%, light yellow solid. H NMR spectrum
(CD3OD), δ, ppm: 1.06 t (3H, J = 7.1, CH3), 2.74 s
(3H, NCH3), 4.05–3.97 m (2H, OCH2), 5.14 s (2H,
NH2), 5.47 s (1H, 2-H), 7.36 d (2H, J = 8.7 Hz, Harom),
7.69 d (2H, J = 8.7 Hz, Harom). 13C NMR spectrum
(CD3OD), δC, ppm: 13.27, 26.60, 59.40, 63.41, 101.97,
111.73, 118.15, 128.60, 132.24, 143.33, 146.95,
164.60, 165.95.
Ethyl 4-amino-1-methyl-5-oxo-2,5-dihydro-1H-
pyrrole-3-carboxylate (2a). Yield: 77%, white solid,
mp 153–155°C. IR spectrum, ν, cm–1: 3454, 3302,
1
1702, 1675, 1626, 1278, 1097. H NMR spectrum
(acetone-d6), δ, ppm: 1.24 t (3H, J = 7.1 Hz, CH3),
2.99 s (3H, NCH3), 3.89 s (2H, CH2), 4.17 q (2H, J =
7.2 Hz, OCH2). 13C NMR spectrum (acetone-d6), δC,
ppm: 14.02, 28.83, 48.82, 59.15, 103.66, 144.59,
164.45, 165.18. Found, %: C 52.66; H 6.61; N 16.35.
C8H12N2O3. Calculated, %: C 52.17; H 6.57; N 15.21.
Ethyl 4-hydrazinyl-5-oxo-2,5-dihydro-1H-pyrrole-
3-carboxylates 3a–3e were synthesized according to
the reported procedure [15].
Ethyl 4-(2-hydroxyethylamino)-5-oxo-2,5-dihy-
dro-1H-pyrrole-3-carboxylates 4a–4e (general pro-
cedure). 2-Aminoethanol (6.02 mmol) was added to
a solution of compound 1a–1e (5.02 mmol) and formic
acid (8.03 mmol) in ethanol (25 mL), and the mixture
was refluxed for 12 h. After completion of the reaction,
the solution was evaporated under reduced pressure,
the residue was extracted with ethyl acetate, and the
extract was washed with water, dried over MgSO4, and
evaporated. The crude product was purified by column
chromatography on silica gel (EtOAc–hexane, 1:1).
Ethyl 4-amino-1,2-dimethyl-5-oxo-2,5-dihydro-
1H-pyrrole-3-carboxylate (2b). Yield 76%, brown
solid, mp 92–94°C. IR spectrum, ν, cm–1: 3431, 3320,
1
1701, 1673, 1633, 1276, 1092. H NMR spectrum
(acetone-d6), δ, ppm: 1.26 t (3H, J = 7.1 Hz, CH3),
1.32 d (3H, J = 6.4 Hz, 2-CH3), 2.92 s (3H, NCH3),
4.03 q (1H, J = 6.4 Hz, 2-H), 4.12–4.26 m (2H, OCH2).
13C NMR spectrum (acetone-d6), δC, ppm: 14.04,
17.23, 26.22, 55.33, 59.05, 102.96, 146.79, 164.34,
164.83. Found, %: C 54.88; H 7.12; N 15.13.
C9H14N2O3. Calculated, %: C 54.53; H 7.12; N 14.13.
Ethyl 4-(2-hydroxyethylamino)-1-methyl-5-oxo-
2,5-dihydro-1H-pyrrole-3-carboxylate (4a). Yield
92%, yellowish solid, mp 72–74°C. IR spectrum, ν,
Ethyl 4-amino-2-ethyl-1-methyl-5-oxo-2,5-dihy-
dro-1H-pyrrole-3-carboxylate (2c). Yield 80%, light
yellow solid, mp 92–94°C. IR spectrum, ν, cm–1: 3438,
1
cm–1: 3346, 1662, 1623, 1215, 1096. H NMR spec-
1
trum (CDCl3), δ, ppm: 1.24 t (3H, J = 7.1 Hz, CH3),
3.00 s (3H, NCH3), 3.70 t (2H, J = 5.3 Hz, CH2), 3.90–
3.94 m (4H, 2-H, CH2), 4.15 q (2H, J = 7.2 Hz, OCH2).
13C NMR spectrum (CDCl3), δC, ppm: 14.55, 29.90,
3284, 1708, 1674, 1628, 1262, 1092. H NMR spec-
trum (CDCl3), δ, ppm: 0.50 t (3H, J = 7.3 Hz,
CH2CH3), 1.30 t (3H, J = 7.1 Hz, CH3), 1.83 m (1H,
CH2), 2.13 m (1H, CH2), 2.95 s (3H, NCH3), 4.17–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

FACILE REDUCTION OF β-ENAMINO OXOPYRROLIDINE CARBOXYLATES
1087
44.58, 49.60, 59.73, 63.20, 97.50, 147.36, 165.58,
166.27. Found, %: C 52.41; H 7.11; N 12.40.
C10H16N2O4. Calculated, %: C 52.62; H 7.07; N 12.27.
Mass spectrum (ESI): m/z 251.1 [M + Na]+.
C10H16N2NaO4. Calculated: M + Na 251.1.
3.74 t (2H, J = 5.3 Hz, CH2), 3.89–4.07 m (4H, OCH2,
CH2), 4.87 s (1H, 2-H), 6.98 d (2H, J = 7.8 Hz, Harom),
7.06 d (2H, J = 8.2 Hz, Harom). 13C NMR spectrum
(CDCl3), δC, ppm: 14.13, 21.20, 27.67, 44.67, 59.53,
63.03, 63.72, 103.46, 127.59, 129.18, 134.10, 137.88,
147.56, 165.45, 165.97. Found, %: C 63.07; H 6.79;
N 7.94. C17H22N2O4. Calculated, %: C 64.13; H 6.97;
N 8.80. Mass spectrum (ESI): m/z 341.1 [M + Na]+.
C17H22N2NaO4. Calculated: M + Na 341.1.
Ethyl 4-(2-hydroxyethylamino)-1,2-dimethyl-5-
oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (4b).
Yield 62%, dark brown oil. IR spectrum, ν, cm–1: 3201,
1
1670, 1622, 1217, 1051. H NMR spectrum (CDCl3),
δ, ppm: 1.24 t (3H, J = 7.1 Hz, CH3), 1.30 d (3H, J =
6.4 Hz, 2-CH3), 2.90 s (3H, NCH3), 3.68 t (2H, J =
5.3 Hz, CH2), 3.83–3.95 m (2H, CH2), 3.99 q (1H, J =
6.4 Hz, 2-H), 4.09–4.23 m (2H, OCH2). 13C NMR
spectrum (CDCl3), δC, ppm: 14.53, 18.01, 27.26, 44.45,
55.39, 59.63, 63.16, 103.84, 147.71, 165.31, 165.83.
Mass spectrum (ESI): m/z 265.1 [M + Na]+.
C11H18N2NaO4. Calculated: M + Na 265.1.
Ethyl 4-hydrazinyl-5-oxo-2,5-dihydro-1H-pyrrole-
3-carboxylates 5a–5e were synthesized according to
the procedure reported in [15].
Ethyl 4-(2-hydroxyethylamino)-5-oxopyrrolidine-
3-carboxylates 6a–6e (general procedure). A solution
of compound 4a–4e (2.19 mmol) in ethanol (15 mL)
containing glacial acetic acid (4.38 mmol) was
hydrogenated in the presence of 20 wt % of Pd(OH)2/C
(0.59 mmol) under a pressure of 1 atm at room
temperature for 12 h. The catalyst was removed by
filtration through Celite and rinsed with methanol. The
filtrate was evaporated under reduced pressure, and the
crude product was purified by column chromatography
on silica gel (EtOAc–hexane, 4:1).
Ethyl 2-ethyl-4-(2-hydroxyethylamino)-1-meth-
yl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (4c).
Yield 67%, yellow oil. IR spectrum, ν, cm–1: 3204,
1
1673, 1629, 1204, 1031. H NMR spectrum (CDCl3),
δ, ppm: 0.48 t (3H, J = 7.5 Hz, 2-CH2CH3), 1.25 t (3H,
J = 7.1 Hz, CH3), 1.79 m and 2.04–2.11 m (1H each,
2-CH2CH3), 2.88 s (3H, NCH3), 3.66–3.75 m (2H,
CH2), 3.82–3.89 m (1H, CH2), 3.97–4.04 m (1H, CH2),
4.10-4.22 m (3H, OCH2, 2-H). 13C NMR spectrum
(CDCl3), δC, ppm: 5.52, 14.50, 21.64, 27.30, 44.49,
59.27, 59.58, 63.07, 100.57, 148.57, 165.73, 166.03.
Mass spectrum (ESI): m/z 279.1 [M + Na]+.
C12H20N2NaO4. Calculated: M + Na]+ 279.1.
Ethyl 4-(2-hydroxyethylamino)-1-methyl-5-oxo-
pyrrolidine-3-carboxylate (6a). Yield 83%, light yel-
low oil. IR spectrum, ν, cm–1: 3377, 1646, 1558, 1222,
1069. 1H NMR spectrum (CDCl3), δ, ppm: 1.28 t (3H,
J = 7.1 Hz, CH3), 2.86–2.89 m (5H, NHCH2, NCH3),
3.00–3.09 m (1H, 3-H), 3.43–3.52 m (2H, CH2), 3.55–
3.67 m (2H, CH2OH), 3.73 d (1H, J = 10.1 Hz, 4-H),
3.75 s (1H, NH), 4.20 q.d (2H, J = 7.2, 1.5 Hz, OCH2),
4.93 br.s (1H, OH). 13C NMR spectrum (CDCl3), δC,
ppm: 14.25, 30.12, 45.76, 48.35, 50.05, 61.31, 61.69,
61.78, 172.24, 173.29. Mass spectrum (ESI): m/z 253.1
[M + Na]+. C10H18N2NaO4. Calculated: M + Na 253.1.
Ethyl 4-(2-hydroxyethylamino)-2-(4-methoxy-
phenyl)-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-
carboxylate (4d). Yield 60%, dark yellow solid,
mp 89–90°C. IR spectrum, ν, cm–1: 3478, 1692, 1621,
1242, 1031. 1H NMR spectrum (CDCl3), δ, ppm: 1.01 t
(3H, J = 7.1 Hz, CH3), 2.70 s (3H, NCH3), 3.74–
3.76 m (5H, OCH3, CH2), 3.90–4.10 m (4H, OCH2,
CH2), 4.87 s (1H, 2-H), 6.80 d (2H, J = 8.7 Hz, Harom),
7.03 d (2H, J = 8.7 Hz, Harom). 13C NMR spectrum
(CDCl3), δC, ppm: 14.19, 27.63, 44.60, 55.33, 59.53,
63.23, 63.40, 103.68, 113.87, 128.83, 129.02, 147.67,
159.46, 165.51, 165.94. Found, %: C 59.64; H 6.54;
N 7.74. C17H22N2O5. Calculated, %: C 61.07; H 6.63;
N 8.38. Mass spectrum (ESI): m/z 357.1 [M + Na]+.
C17H22N2NaO5. Calculated: M + Na 357.1.
Ethyl 4-(2-hydroxyethylamino)-1,2-dimethyl-5-
oxopyrrolidine-3-carboxylate (6b). Yield 25%, light
1
yellow oil. H NMR spectrum (CDCl3), δ, ppm: 1.29 t
(3H, J = 7.1 Hz, CH3), 1.35 d (3H, J = 5.9 Hz, 2-CH3),
2.52 d.d (1H, J = 9.4, 8.5 Hz, 3-H), 2.81 s (3H, NCH3),
2.83–2.88 m (2H, NHCH2), 3.54–3.66 m (3H, CH2OH,
2-H), 3.75 d (1H, J = 9.6 Hz, 4-H), 3.77 s (1H, NH),
4.22 q (2H, J = 7.2 Hz, OCH2). 13C NMR spectrum
(CDCl3), δC, ppm: 14.29, 19.32, 27.53, 50.10, 54.48,
54.81, 61.35, 61.63, 61.88, 172.20, 173.38. Mass spec-
trum (ESI): m/z 267.1 [M + Na]+. C11H20N2NaO4.
Calculated: M + Na 267.1.
Ethyl 4-(2-hydroxyethylamino)-1-methyl-2-(4-
methylphenyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-
carboxylate (4e). Yield: 62%, white solid, mp 123–
125°C. IR spectrum, ν, cm–1: 3362, 1668, 1617, 1203,
1087. 1H NMR spectrum (CDCl3), δ, ppm: 1.00 t (3H,
J = 7.1 Hz, CH3), 2.28 s (3H, CH3), 2.69 s (3H, NCH3),
Ethyl 2-ethyl-4-(2-hydroxyethylamino)-1-meth-
yl-5-oxopyrrolidine-3-carboxylate (6c). Yield 23%,
1
light yellow oil. H NMR spectrum (CD3OD), δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

ABDUL RASHID et al.
1088
0.99 t (3H, J = 7.2 Hz, 2-CH2CH3), 1.23 t (3H, J =
7.1 Hz, CH3), 1.35–1.43 m (1H, 2-CH2CH3), 1.94 s
(1H, NH), 1.97–2.03 m (1H, 2-CH2CH3), 2.79 s (3H,
NCH3), 2.84–2.90 m (2H, NHCH2), 3.52–3.68 m (4H,
CH2OH, 2-H, 3-H), 3.70 d (1H, J = 6.4 Hz, 4-H), 4.11–
4.25 m (2H, OCH2). 13C NMR spectrum (CD3OD), δC,
ppm: 8.69, 13.21, 21.71, 26.41, 47.66, 50.21, 59.60,
60.47, 60.58, 61.07, 172.23, 173.71. Mass spectrum
(ESI): m/z 281.1 [M + Na]+. C12H22N2NaO4. Calculat-
ed: M + Na 281.1.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
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(CD3OD), δ, ppm: 0.76 t (3H, J = 7.1 Hz, CH3), 2.70 s
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(2H, NHCH2, CH2OH), 3.78 s (3H, OCH3), 3.81–
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1
3364, 1671, 1569, 1225, 1095. H NMR spectrum
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(CD3OD), δ, ppm: 0.73 t (3H, J = 7.1 Hz, CH3), 2.34 s
(3H, CH3), 2.70 s (3H, NCH3), 3.45–3.53 m (2H,
NHCH2, CH2OH), 3.72–3.83 m (4H, OCH2, CH2OH,
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7.8 Hz, 4-H), 4.99 d (1H, J = 7.3 Hz, 2-H), 7.09 d (2H,
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ACKNOWLEDGMENTS
The authors thank Universiti Teknologi MARA and
Ministry of Higher Education for the support and members
of Organic Synthesis Research Laboratory, I.O.S., UiTM for
helpful discussions.
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FUNDING
https://doi.org/10.1021/jm000468c
This study was performed under financial support by the
Ministry of Higher Education of Malaysia [600-IRMI/FRGS
5/3 (398/2019)].
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and Hamzah, A.S., Org. Commun., 2019, vol. 12, p. 121.
https://doi.org/10.25135/acg.oc.62.19.07.1323
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020