A synthetic route towards 3,4-disubstituted pyrrolidin-2-ones: via a Michael addition and reductive ring closing strategy

Article abstract of DOI:10.1039/c6nj04051a

Pyrrolidin-2-one derivatives were synthesized via DABCO mediated Michael addition of isoxazol-5(4H)-ones with nitroalkenes, followed by one pot reduction of the nitro group and ring cleavage with cyclization. 2-Pyrrolidinone scaffolds with a wide range of substituents were synthesized with good yield and diastereoselectivity by using this protocol.

Full text of DOI:10.1039/c6nj04051a

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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A Synthetic Route Towards 3, 4-disubstituted Pyrrolidin-2-ones via
Michael Addition and Reductive Ring Closing Strategy
Monali Dawangea, Nikita Parekha, Avinash Kumbhara, Wim Dehaenb and Radhika
Kusurkar*a
aDepartment of Chemistry, S P Pune University, Pune 411007, India
bMolecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan
200F, 3001 Leuven, Belgium
S
Pyrrolidin-2-one derivatives were synthesized via DABCO mediated Michael addition of
isoxazol-5(4H)-ones with nitroalkenes, followed by one pot reduction of nitro group and ring
cleavage with cyclization. 2-Pyrrolidinone scaffolds with a wide range of substitution were
synthesized with good yield and diastereoselectivity by using this protocol.
INTRODUCTION
Nitrogen containing heterocycles are the most common scaffolds present in bioactive
materials as well as pharmaceuticals.1 2-Pyrrolidinone, a class of 5-membered lactam has
always been attractive synthetic target due to its occurrence in biological as well as
pharmaceutical compounds. Some of the naturally occurring compounds containing 2-
pyrrolidinones are epolactaene (1) having anticancer activity2 and rigidiusculamide A (2)
exhibiting cytotoxicity3 against human tumor cell lines HeLa and MCF-7 (Figure 1).
A number of pharmaceutically active drugs include 2-pyrrolidinone core e.g. rolipram
(3) as antidepressant4 and levetiracetam (4) a member of Racetam class drugs, as an
antiepileptic drug5 (Figure 1). Owing to their importance, many methods have been reported6
for the synthesis of substituted 2-pyrrolidinones.
1

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Figure 1. Naturally occurring and synthetic drug molecules containing 2-pyrrolidinone unit
Isoxazol-5(4H)-ones have always been versatile substrates in synthetic organic
chemistry. A large number of reactions are reported in the literature on the reactivity of
isoxazol-5(4H)-ones such as Michael addition,7 aza-Michael addition,8 Pd-catalysed C-
alkylation,9 nucleophilic ring opening,10 Vilsmeier-Haack reaction,11 flash vacuum
pyrolysis,12 condensation reactions,13 and organocatalytic asymmetric fluorination.14
Nevertheless, only one report14b is available on the Michael addition of isoxazol-5(4H)-ones
with β-nitroalkenes. The Michael adduct can be further transformed to different scaffolds
however it is not much explored.
The Michael addition reaction is one of the important C-C bond forming reaction.
Michael addition of pyrazolones with nitroalkenes followed by reductive cyclization for the
synthesis of pyridine fused pyrazolones have been reported by us recently.15 Herein, we
describe the Michael addition of isoxazol-5(4H)-one derivatives with various β-nitroalkenes
and further reductive ring cleavage and cyclization to provide a wide range of substituted
pyrrolidin-2-one derivatives (Scheme 1).
Scheme 1. Retrosynthetic strategy towards pyrrolidin-2-one derivatives
2

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RESULTS AND DISCUSSION
In the beginning, the starting compound 3-phenylisoxazol-5(4H)-one (2a) was
prepared by reacting ethyl benzoylacetate with hydroxylamine hydrochloride in ethanol
according to literature procedure.16 We first carried out a model reaction with 3-
phenylisoxazol-5(4H)-one (2a) and transꢀβ-nitrostyrene (1a) using a catalytic amount of
acetic acid (20 mol%) in ethanol under reflux condition. The desired Michael adduct 3a was
isolated in 79% yield after 4 h (Table 1, entry 1). To standardize the reaction, various
conditions were tried as shown in Table 1. When 1 equiv. of triethyl amine was added instead
of acetic acid, the Michael adduct 3a was isolated in 75% yield after 5 h (Table 1, entry 2). A
lower yield (45%) was observed when DBU was used as a base in methylene chloride at
room temperature and reaction was incomplete even after 24 h (Table 1, entry 3). When
DABCO was used as a base in methylene chloride at room temperature, product 3a was
obtained in excellent yield (89%); moreover the reaction time was reduced to 30 min (Table
1, entry 4). Further, base loading was reduced to check the reaction progress, but it slowed
down the reaction rate and the reaction was incomplete even after 24 h (Table 1, entry 5, 6,
7). When 1 equiv. of DMAP was tried, the reaction was still incomplete and product 3a was
isolated in 59% yield after 24 h (Table 1, entry 8). While, reaction in pyridine was quite slow
as compared to other bases and furnished only 41% of 3a after 24 h (Table 1, entry 9). In the
absence of acid or base additive, no reaction was observed. Ultimately, the optimal reaction
condition was found to be the use isoxazolone, nitroalkene and DABCO in methylene
chloride in 1:1:1 molar ratio at room temperature.
3

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Table 1. Optimization of the Michael addition reactiona
entry
1
conditiona
AcOH, EtOH, reflux
Et3N, EtOH, reflux
DBU, DCM, rt
DABCO, DCM, rt
DABCO, DCM, rt
DABCO, DCM, rt
DABCO, DCM, rt
DMAP
equiv
time (h)
4
Yield (%)b
79
20 mol%
2
1
1
5
75
3
24
45 (incomplete)
89
4
1
0.5
12
5
0.1
0.2
0.5
1
55 (incomplete)
57 (incomplete)
63 (incomplete)
59 (incomplete)
41 (incomplete)
No reaction
6
24
7.
8.
9.
10.
24
24
Pyridene
1
24
DCM, rt
-
12
aReaction condition : 1a (1.24 mmol) and 2a (1.24 mmol) were stirred. bIsolated yield.
Under the optimized conditions (Table 1, entry 4), the substrate scope of substituted
nitroalkenes 1a-1k and isoxazolones 2a, 2b, 2c was examined and the results are summarized
in Table 2. The reaction was well tolerated with aromatic, heteroaromatic as well as aliphatic
nitroalkenes. It was observed that the rate of reaction was affected by the electronic as well as
steric effects. When 1d was used for the Michael addition (Table 2, entry 4), low yields were
obtained due to less reactivity of aliphatic nitroalkenes as compared to the aromatic ones.
Steric hindrance affected yields of the Michael addition reaction due to the bulky nature of R1
substituents in 1i and 1k (Table 2, entries 9 and 15) which resulted in reduced yield of the
4

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Table 2. DABCO-mediated Michael addition of nitroalkenes 1a-k and isoxazolones 2a, b, ca
Entry
1
Nitroalkene Isoxazolone
Time (h)
Product
3a
Yield (%)b
0.5
4
89
85
87
53
80
77
82
62
45
59
77
73
81
79
77
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2a
2
3b
3c
3
1
4
24
3
3d
3e
5
6
3
3f
7
4
1g
1h
1i
3g
8
4
3h
3i
9
24
12
3
10
11
12
13
14
15
1j
3j
1a
1b
1c
1a
1k
3k
3l
3
1
3m
3n
3o
0.5
24
5

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aReaction condition : 1 (1.24 mmol) and 2 (1.24 mmol) were stirred in presence of DABCO
(1.24 mmol) in dry DCM at rt. bIsolated yield.
Michael adducts. All other nitroalkenes furnished a good yield of the Michael adducts. To
check the substituent effect on phenyl ring (R3) on the Michael addition, isoxazolones 2c with
4-chloro substituent was reacted with 1a. But changing the substituent, did not affect the rate
of reaction. It was completed within 30 min and the Michael adduct 3n was formed in 79%
yield (Table 2, entry 14). Thus, it is clear that rate only depends on the nature of R1 and R2
substituents on the nitroalkene 1.
In case of Michael adducts 3i, 3k-m, 3o products were in only one tautomeric form as seen
1
from the H NMR spectra. This can be attributed to the steric effect17 of the substituents R1
and R3. Some of the Michael adducts showed the presence of mixture of tautomers. In those
1
cases, DABCO was added in the H NMR sample which suppressed one of the tautomers
from the mixture. The spectra of the Michael adducts were much simplified which showed
presence of only three aliphatic protons of the nitro alkyl chain similar to structure B or C
respectively (Figure 2). It has been well reported18 in literature that substituted isoxazolones
can exist in three different tautomeric forms as CH (A), NH (B), or OH (C) form (Figure 2).
The CH form is more prominent in CDCl3 while only NH form is present in DMSO. In the
presence of base, the OH form is noticeable in solution.
Figure 2. Possible tautomeric forms of isoxazol-5(4H)-one
From the analogy with the above report the Michael adducts except 3i, 3k-m, 3o might be
present in OH tautomeric form in DABCO. In case of adducts 3i, 3k-m, 3o only the OH
tautomer was seen in the 1H NMR spectra without addition of DABCO.
6

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Having the Michael adducts in hand we proceeded further for the reduction. It is well known
that Zn in acetic acid is used for the ring cleavage19 as well as to reduce the nitro group
effectively.20 By using one pot reductive cyclization strategy with Zn/AcOH, the nitro group
in the Michael adduct could be reduced to an amino and then in-situ cleavage of isoxazolone
ring and cyclization would afford the desired 2-pyrrolidone core. Thus, Michael adduct 3a
was subjected to reduction at room temperature using excess of Zn in acetic acid. Within an
hour, TLC analysis showed the consumption of the Michael adduct along with formation of a
new compound. Assuming that the reduction of the nitro group took place initially, the
reaction mixture was stirred for one hour at room temperature and further heated at 80 °C
without removing Zn for 12 h. It furnished a crude product which after usual workup was
1
found to be a mixture of two diastereomers in the ratio 99:1 from H NMR analysis. After
1
chromatographic purification a single diastereomer 4a was isolated in 55% yield. In the H
NMR spectra, the product showed one downfield multiplet in the aromatic region at around 8
δ in addition to the other signals of aromatic protons, one exchangeable singlet at 6.1 δ for
one proton, and four signals around 3.0 to 4.5 δ for alicyclic protons. The presence of
carbonyl group in structure 4a was supported by the signal at 195 δ in 13C NMR spectrum.
Finally, single crystal analysis confirmed the trans geometry of 4a for the product (Figure 3;
see
also
Supporting Information (SI) for more details).
Figure 3. ORTEP diagram of 4a
7

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The possible mechanism for the one pot reductive cleavage is as shown in scheme 2.
Scheme 2. Plausible reaction pathway for the formation of 4a
Further, the present protocol was applied to other Michael adducts as well. In all the cases
products 4b-n were obtained in satisfactory yield (Table 3). When Michael adduct 3e was
subjected to reductive cyclization, the crude reaction mass showed the presence of a mixture
1
of more than two diastereomers which was confirmed from the H NMR and was due to the
presence of three stereocenters in the product. The major isomer 4e was isolated using
chromatographic separation in good yield (62%). For the confirmation of the structure of 3-
acylpyrrolidin-2-ones, the crystal structure of 4l was investigated (Figure 4; see also
Supporting Information (SI) for more details) which showed the trans stereochemistry.
Figure 4. ORTEP diagram of 4l
8

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Table 3. Reductive ring cleavage followed by cyclization of Michael adducts 3a-na
entry
productc
yield
drb
entry
productc
yield
drb
Cl
O
O
Ph
1
55
>99:1
8
58
81:19
Ph
N
O
H
N
H
O
4a
OMe
4h
O
O
O
O
O
O
O
2
55
>99:1
9
41
>99:1
Ph
Ph
Ph
Ph
N
H
N
H
O
O
4b
4i
S
3
52
>99:1
10
44
>99:1
Ph
N
H
N
H
4j
O
O
4c
4
47
>99:1
11
56
>99:1
N
H
N
O
H
4d
4k
OMe
O
O
O
Ph
5
62
65:15:12:8
12
50
>99:1
N
H
N
O
H
4e
4l
COOMe
O
O
S
O
O
Ph
6
52
55
94:6
13
47
>99:1
N
N
H
H
4f
4m
O
O
O
Ph
O
O
7
83:17
14
51
>99:1
Ph
Cl
N
O
H
N
H
4g
4n
9

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aReaction condition: 3 (0.5 mmol) and Zn (5 mmol ) were stirred in AcOH for 1 h at rt then heated at
b
1
c
80 °C for 12 h. Ratios determined by H NMR analysis of reaction mixture. relative configurations
of other products were assigned on the basis of analogy with 4a and 4l.
When adduct 3o was subjected to the reaction, a complex mixture was obtained. After
removal of zinc from the reaction mixture, it was further refluxed for 48 h in AcOH. The
product was different than earlier products and was identified to be 2-phenyl-3H-
benzo[e]indole (5) from spectral and analytical data (Scheme 3).
Scheme 3. Novel observation during reduction of adduct 3o
Scheme
4
shows the possible mechanism for the formation of 5.
Scheme 4. Possible mechanism for the formation of 5
Reductive ring cleavage and cyclization resulted into the pyrrolidin-2-one (i), which
underwent acidic hydrolysis followed by decarboxylation at high temperature resulting into
the formation of cyclic imine (ii). Subsequent air oxidation furnished fully aromatised
compound 5. Cyclic imine formation through the amide hydrolysis and decarboxylation was
well matching with the previous reports.21 Thus, this reaction furnished a tricyclic benzo-
indole scaffold.
10

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CONCLUSION
A novel method for the synthesis of pyrrolidin-2-one derivatives through DABCO catalysed
Michael addition of isoxazol-5(4H)-ones and further Zn mediated one pot reductive ring
cleavage followed by cyclization was achieved during the present investigation. This protocol
provided a library of 2-pyrrolidinones with good yield and diastereoselectivity. Furthermore,
the strategy was employed for the synthesis of a benzoindole derivative in good yield. This
method opens possibility for the synthesis of a class highly substituted pyrrolidin-2-ones
which can have significant utility in organic synthesis.
EXPERIMENTAL SECTION
General Procedure for the Synthesis of Michael Adducts (3a-o)
Nitroalkene 1 (1.24 mmol), isoxazolone 2 (1.24 mmol), and DABCO (1.24 mmol) were
stirred in dry DCM (10 mL) under N2 at room temperature. The progress of the reaction was
monitored by TLC. When the reaction was complete, DCM was evaporated off. The crude
sample was purified by column chromatography on silica gel (with petroleum ether/EtOAc as
the eluent) to afford the corresponding Michael adduct 3.
Characterization of selected compounds
4ꢀ(2ꢀNitroꢀ1ꢀphenylethyl)ꢀ3ꢀphenylꢀ1,2ꢀoxazolꢀ5ꢀol (3a)
1H NMR (500 MHz, CDCl3 with DABCO) δ 7.41-7.36 (m, 7H), 7.31-7.28 (m, 2H), 7.23-
7.21(m, 1H), 5.49 (dd, J = 11.9, 10.4 Hz, 1H), 4.72 (dd, J = 12.1, 6.1 Hz, 1H), 4.49 (dd, J =
10.2, 6.1 Hz, 1H); 13C NMR (125 MHz, CDCl3 with DABCO) δ 176.6, 165.2, 141.3, 132.2,
1
131.5, 128.8, 128.5, 128.2, 127.9, 127.1, 82.6, 78.0, 39.6; H NMR (400 MHz, DMSO-d6) δ
7.50-7.48 (m, 3H), 7.42-7.38 (m, 4H), 7.32-7.28 (m, 2H), 7.24-7.20 (m, 1H), 6.52 (br s, 1H),
5.33 (dd, J = 12.8, 8.8 Hz, 1H), 5.11 (dd, J = 12.8, 7.3 Hz, 1H), 4.38 (t, J = 8.1 Hz, 1H); 13C
11

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NMR (100 MHz, DMSO-d6) δ 171.1, 162.4, 139.0, 131.3, 129.4, 129.0, 127.7, 127.5, 127.4,
126.9, 126.7, 76.3, 38.0; FT-IR (neat) 3064, 2934, 1732, 1556, 1377, 756, 698 cm-1; HRMS
(ESI) [M + H]+ found m/z 311.1022, calcd for C17H15N2O4 311.1026.
4ꢀ[2ꢀNitroꢀ1ꢀ(thiophenꢀ2ꢀyl)ethyl]ꢀ3ꢀphenylꢀ1,2ꢀoxazolꢀ5ꢀol (3c)
1H NMR (500 MHz, CDCl3 with DABCO) δ 7.46 (dd, J = 6.5, 2.9 Hz, 2H), 7.39-7.37 (m,
3H), 7.16 (dd, J = 5.0, 1.3 Hz, 1H), 6.94-6.92 (m, 2H), 5.41 (dd, J = 11.5, 9.5 Hz, 1H), 4.86-
4.77 (m, 2H); 13C NMR (125 MHz, CDCl3 with DABCO) δ 176.3, 164.9, 144.8, 131.4,
128.8, 128.4, 128, 127.1, 124.8, 124.5, 82.6, 77.8, 34.6; FT-IR (neat) 3066, 2923, 1711,
1553, 1426, 1376, 757, 699 cm-1; HRMS (ESI) [M + H]+ found m/z 317.0593, calcd for
C15H13N2O4S 317.0591.
4ꢀ(1ꢀNitropentanꢀ2ꢀyl)ꢀ3ꢀphenylꢀ1,2ꢀoxazolꢀ5ꢀol (3d)
1H NMR (500 MHz, CDCl3 with DABCO) δ 7.51-7.49 (m, 2H), 7.44-7.39 (m, 3H), 4.98 (dd,
J = 11.3, 9.8 Hz, 1H), 4.47 (dd, J = 11.4, 6.2 Hz, 1H), 3.31-3.25 (m, 1H), 1.69-1.63 (m, 1H),
13
1.40-1.36 (m, 1H), 1.30-1.25 (m, 1H), 1.14-1.12 (m, 1H), 0.75 (t, J = 7.3 Hz, 3H); C NMR
(125 MHz, CDCl3 with DABCO) δ 176.1, 165. 8, 132.2, 129.5, 128.7, 128.5, 128.4, 78.4,
33.6, 33.6, 20.4, 13.9; FT-IR (neat) 3065, 2961, 1697,1549, 1379, 758, 696 cm-1; HRMS
(ESI) [M + H]+ found m/z 277.1184, calcd for C14H17N2O4 277.1183.
4ꢀ(2ꢀNitroꢀ1,2,3,4ꢀtetrahydronaphthalenꢀ1ꢀyl)ꢀ3ꢀphenylꢀ1,2ꢀoxazolꢀ5ꢀol (3o)
mp 145-147 °C; 1H NMR (400 MHz, CDCl3 without DABCO) δ 7.59-7.5 (m, 5H), 7.19-7.12
(m, 3H), 6.98 (d, J = 7.4 Hz, 1H), 5.52 (td, J= 11.6, 3.5 Hz, 1H), 4.64 (d, J = 10.4 Hz, 1H),
3.16-3.09 (m, 1H), 3.03-2.99 (m, 1H), 2.58-2.55 (m, 1H), 2.40-2.30 (m, 1H). 13C NMR (100
MHz, CDCl3 without DABCO) δ 170.6, 165.5, 134.9, 133.4, 132.1, 129.7, 129.0, 127.8,
127.4, 127.1, 126.5, 102.1, 84.4, 38.7, 28.7, 28.0; FT-IR (neat) 3065, 2956, 1709, 1547,
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1374, 758, 698 cm-1; HRMS (ESI) [M + H]+ found m/z 337.1184, calcd for C19H17N2O4
337.1183.
General Procedure for Reductive Cyclization (4a-n and 5)
To a stirred solution of Michael adduct 3 (0.5 mmol) in acetic acid (10 mL) was added zinc
dust (5 mmol). The reaction mixture was stirred for 1 h at room temperature. After
disappearance of the starting material (monitored by TLC), the reaction mixture was
subjected for heating at 80 °C for 24 h and then filtered through celite. The reaction mixture
was evaporated under reduced pressure to remove acetic acid. The residue was quenched with
water, washed with saturated NaHCO3 solution and extracted with ethyl acetate, dried over
sodium sulfate and concentrated. Purification was done by column chromatography using
chloroform/ MeOH as the eluent.
Michael adduct 3o (178 mg, 0.5 mmol) was reacted with Zn (0.346 mg, 5 mmol) according to
the general procedure for reductive cyclization. After heating the reaction mass at 80 °C for
12 h, Zn was removed and the mixture was further refluxed in AcOH for 48 h in open air.
After usual work up; the mixture was purified by column chromatography to furnish solid
product 5.
Characterization of selected compounds
(3S,4S)ꢀ3ꢀBenzoylꢀ4ꢀphenylpyrrolidinꢀ2ꢀone (4a)
1
mp 156-158 °C; H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.58-7.55 (m, 1H), 7.48-
7.44 (m, 2H), 7.34-7.32 (m, 2H), 7.29-7.26 (m, 3H), 6.16 (br s, 1H), 4.53 (d, J = 7.0 Hz, 1H),
4.33 (dd, J = 15.0, 7.0 Hz, 1H), 3.96-3.89 (m, 1H), 3.53 (dd, J = 9.6, 6.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 195.1, 173.6, 141.4, 136.3, 133.6, 129.5, 129.1, 128.6, 127.5,127 57.5,
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47.7, 43.4; FT-IR (neat) 3240, 2927, 1701, 1674, 1494, 1270, 1054, 757,698 cm-1; HRMS
(ESI) [M + H]+ found m/z 266.1174, calcd for C17H16NO2 266.1176.
(3S,4R)ꢀ3ꢀBenzoylꢀ4ꢀ(thiophenꢀ2ꢀyl)pyrrolidinꢀ2ꢀone (4c)
1
mp 77-79 °C; H NMR (500 MHz, CDCl3) δ 8.06 (dd, J = 8.4, 1.2 Hz, 2H), 7.60-7.57 (m,
1H), 7.49-7.46 (m, 2H), 7.17 (dd, J = 4.8, 1.5 Hz, 1H), 6.93-6.9 (m, 2H), 6.62 (br s, 1H), 4.64
(dd, J = 15.3, 7.6 Hz, 1H), 4.54 (d, J = 7.9 Hz, 1H), 3.94-3.91 (m, 1H), 3.56 (dd, J = 9.6, 7.2
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 194.6, 172.4, 143.9, 136.3, 133.7, 129.5, 128.6,
127.1, 124.6 , 124.2, 58.4, 48.2, 39; FT-IR (neat) 3225, 2924, 1704, 1677, 1448, 1261, 1029,
750, 699 cm-1; HRMS (ESI) [M + H]+ found m/z 272.0741, calcd for C15H14NO2S 272.0740.
(3S,4R)ꢀ3ꢀBenzoylꢀ4ꢀpropylpyrrolidinꢀ2ꢀone (4d)
1
mp >193 °C (compound decomposes above); H NMR (500 MHz, CDCl3) δ 8.08-8.06 (m,
2H), 7.61-7.57 (m, 1H), 7.51-7.48 (m, 2H), 6.40 (br s, 1H), 4.12 (d, J = 7.02 Hz, 1H), 3.64 (t,
J = 8.24 Hz, 1H), 3.12-3.05 (m, 2H), 1.49 (q, J = 7.32 Hz, 2H), 1.29-1.24 (m, 2H), 0.88 (t, J
= 7.32 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 196.3, 174.0, 136.8, 133.6, 129.4, 128.7,
56.4, 46.6, 38.5, 36.5, 20.7, 14.1; FT-IR (neat) 3019, 2928, 1703, 1677, 1448, 1214, 1033,
748, 667 cm-1; HRMS (ESI) [M + Na]+ found m/z 254.1159, calcd for C14H17NNaO2
254.1151.
2ꢀPhenylꢀ3Hꢀbenzo[e]indole (5)22
mp 135-137 °C; 1H NMR (500 MHz, CDCl3) δ 8.67 (br s, 1H), 8.27 (d, J = 7.7 Hz, 1H), 7.90
(d, J = 8.1 Hz, 1H), 7.60-7.55 (m, 2H), 7.62-7.53 (m, 3H), 7.48-7.41 (m, 3H), 7.38-7.37 (m,
1H), 7.34-7.31 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 136, 133.2, 132.4, 129.3, 129.2,
128.6, 128, 127.3, 125.8, 124.8, 124.3, 123.5, 123.3, 122.9, 112.5, 99.3; FT-IR (neat) 3372,
3019, 2927, 1719, 1604, 1284, 1214, 1074, 754 cm-1; HRMS (ESI) [M + H]+ found m/z
244.1125, calcd for C18H14N 244.1121.
14

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ASSOCIATED CONTENT
Supporting Information
1
Copies of H and 13C NMR spectra of new compounds and X-ray crystallographic data for
compound 4a and 4l (CIF).
AUTHOR INFORMATION
Corresponding Author
∗E-mail: rsk@chem.unipune.ac.in
ACKNOWLEDGEMENTS
MD and NP are thankful to Council of Scientific and Industrial Research, New Delhi,
India, for financial assistance through fellowship and contingency. WD is thankful to
the KU Leuven and FWO-Vlaanderen for financial support.
15

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A Synthetic Route Towards 3, 4-disubstituted Pyrrolidin-2-ones via Michael Addition and
Reductive Ring Closing Strategy
Monali Dawange, Nikita Parekh, Avinash Kumbhar, Wim Dehaen and Radhika Kusurkar*
2-Pyrrolidinone scaffolds with a wide range of substitution were synthesized with good yield and
diastereoselectivity.