Full text of DOI:10.1016/j.tet.2018.03.009

Accepted Manuscript
Isa‒NHC‒catalyzed intermolecular stetter reaction of aromatic aldehydes with
maleimides: An efficient access to 3‒aroylsuccinimides
Milind M. Ahire, Santosh B. Mhaske
PII:
S0040-4020(18)30252-7
10.1016/j.tet.2018.03.009
TET 29349
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 January 2018
Revised Date: 21 February 2018
Accepted Date: 5 March 2018
Please cite this article as: Ahire MM, Mhaske SB, Isa‒NHC‒catalyzed intermolecular stetter reaction of
aromatic aldehydes with maleimides: An efficient access to 3‒aroylsuccinimides, Tetrahedron (2018),
doi: 10.1016/j.tet.2018.03.009.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Isa‒NHC‒Catalyzed Intermolecular Stetter
Reaction of Aromatic Aldehydes with
Maleimides: An Efficient Access to 3‒
Aroylsuccinimides
Leave this area blank for abstract info.
a, b
Milind M. Ahire
a, b, *
Santosh B. Mhaske
a
b
Division of Organic Chemistry and Academy of Scientific and Innovative Research (AcSIR), CSIR-National
Chemical Laboratory, Pune 411008, India

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Isa‒NHC‒Catalyzed Intermolecular Stetter Reaction of Aromatic Aldehydes with
Maleimides: An Efficient Access to 3‒Aroylsuccinimides
a, b
a, b,
Milind M. Ahire , Santosh B. Mhaske
*
a
b
Division of Organic Chemistry and Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory, Pune 411008, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An intermolecular Stetter reaction of aromatic aldehydes with maleimides has been developed
using thiazolylidene salt derived Isa‒NHC as an efficient organocatalyst. The synthesized Stetter
products “3‒aroylsuccinimides” are important building blocks for the synthesis of natural
products and bioactive compounds. The reaction conditions are mild, and various substituents on
aromatic aldehyde and maleimide nitrogen were tolerated.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
N‒Heterocyclic carbene
Stetter reaction
Aromatic aldehyde
Maleimide
3
‒Aroylsuccinimides
1
. Introduction
Organocatalysis by N‒heterocyclic carbene (NHC) has
emerged as one of the important tools in organic synthesis over
1
the past two decades. The umpolung generated by NHC‒
catalysis has been reacted with several different electrophiles;
specifically, the acyl anion of aldehydes has been reacted with
electrophilic alkene substrates by 1,4‒conjugate addition to form
new C‒C bonds, thus providing scaffolds of biological
1,2
interests. This catalytic nucleophilic acylation of Michael
3
acceptors, known as the “Stetter” reaction, has been one of the
2,4
highly explored reactions in the area of NHC‒organocatalysis.
It provides an efficient access to unique 1,4‒dicarbonyl
compounds and related derivatives, such as ketophosphonates,
ketosulfones, nitroketones and ketonitriles. Finding new
2
14
Fig. 2. Traditional methods for the preparation of ketosuccinimides 1.
electrophilic partners for Stetter reaction and their application in
the synthesis of natural products and drugs has been the focus of
enduring research interest.
Maleimides 6and their derivatives are well-known
pharmacophores. Recently, we have reported an efficient
synthesis of succinimide derivatives by NHC‒catalyzed
intermolecular Stetter reaction of aromatic aldehydes with N‒
1,2,4,5
7
substituted itaconimides. In continuation of our interest in this
field, we planned to develop a general intermolecular Stetter
reaction of aldehydes with maleimide substrates to obtain
corresponding ketosuccinimides 1. Ketosuccinimides and their
congeners are important building blocks for the synthesis of
8-12
13
natural products
and bioactive compounds (Fig. 1), but the
traditional methods used for their preparation are harsh and in
14
general low yielding (Fig. 2).
In this context, the literature survey revealed that Rovis et al.
reported the NHC‒catalyzed intramolecular Stetter reaction of
the aliphatic aldehyde with maleimide to construct the
Fig. 1. Representative examples of natural products and bioactive
8
-13
compounds.

2
Tetrahedron
ACCEPTED MANUSCRIPT
Table 1
Optimization studies
1
5-17
Sr.
no.
1
2:3
(equiv)
1:1.0
1:1.0
1:1.0
1:1.0
1:1.0
1:1.0
1:1.0
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
NHC
Base
(equiv)
Solvent
(2 mL)
THF
Temp
Yield
Fig. 3. Prior studies on Stetter reaction with maleimides.
o
a
(equiv)
( C)
(%)
spirofuranone‒lactam core of antibiotic FD‒838 (Fig. 1 and 3
A (0.20)
A (0.20)
A (0.20)
A (0.20)
A (0.20)
A (0.20)
A (0.20)
A (0.20)
A (0.20)
A (0.20)
A (0.15)
A (0.10)
B (0.15)
C (0.15)
D (0.15)
E (0.15)
K CO (0.5)
rt
Trace
Trace
39
2
3
15
A). Recently, they have reported an elegant extension of this
strategy for the total synthesis of anticancer natural product (–)-
cephalimysin A (Fig. 1), wherein intramolecular Stetter reaction
of α‒substituted unsaturated aldehyde with maleimide has been
developed as key step (Fig. 3 A). Prior to these studies, there is
only one example known in the literature, wherein NHC‒
catalyzed [4+1] annulation of phthalaldehyde and N‒
phenylmaleimide furnished hydroxyl-indanone via a tandem
process involving intermolecular Stetter reaction, proton shift and
aldol reaction (Fig. 3 B). Nevertheless, to the best of our
knowledge, a general and efficient intermolecular Stetter reaction
of diverse aldehydes with varyingly substituted maleimides has
not been fully explored. The work presented herein deals with
this topic and demonstrates an efficient protocol to access novel
2
K CO (1.0)
THF
rt
2
3
3
K CO (0.5)
2
3
THF
50
4
NMP (0.3)
THF
rt-50
rt-50
rt-50
rt-50
50
NR
NR
NR
NR
71
5
K CO (0.5)
2
3
toluene
ACN
THF
16
6
2 3
K CO (0.5)
7
NaOAc (0.3)
K CO (0.3)
8
2
3
THF
9
K CO (0.3)
2
3
ACN
50
Trace
50
b
10
11
12
13
14
15
16
K CO (0.3)
2
3
dioxane
50
17
K CO (0.8)
2
3
THF
THF
THF
THF
THF
THF
50
90
K CO (0.8)
2
3
50
60
K CO (0.8)
2
3
rt-50
rt-50
rt-50
rt-50
21
K CO (0.8)
2
3
NR
NR
12
K CO (0.8)
2
3
3
‒aroylsuccinimides using intermolecular Stetter reaction.
2 3
K CO (0.8)
a
b
2
. Result and discussion
Isolated yield. NMP = N‒methyl piperazine. 1,4-Dioxane. NR = no
reaction.
The first reaction to achieve the desired Stetter reaction on
maleimide substrate was performed using p‒chlorobenzaldehyde
substituents (5‒7), alkyl chain with terminal substituent (8) or
secondary N‒alkyl substituent (9) did not have much effect on
the yield of the reaction. N‒Allyl maleimide smoothly provided
the product 10 in good yield. N‒Benzyl maleimide gave a low
yield of the product 11, but the corresponding benzylic carbon
substituted maleimide gave better yield to obtain the product 12.
N‒Phenyl maleimide was completely consumed under the
optimized reaction condition, but the Stetter product 13 was
obtained in very less yield along with many other unidentified
side products. Similarly, we observed that N‒ethoxycarbonyl
maleimide used to get consumed, but the Stetter product 14
18
in the presence of thiazolidene based Isa‒NHC catalyst A. Little
modifications in the reaction condition furnished the expected
product 4, though in low yield (Table 1, entries 1‒3). Further
optimization studies (Table 1, entries 4‒12), by variation in
solvents, bases, temperature and mole ratios, on the same
substrate using NHC‒catalyst A provided the best reaction
condition (Table 1, entry 11) to obtain Stetter product 4 in 90%
yield. We observed that heating the reaction mixture at a higher
o
temperature than 50 C or keeping it for more than two hours
drastically reduced the yield. To check the probability of further
optimization and to lower the catalyst loading, four other NHC‒
catalysts B-E were screened at room temperature as well as at 50
o
C (Table 1, entries 13‒16). None of them worked at room
temperature. The reaction using the catalyst B furnished the
compound 4 in low yield under the optimized reaction condition
(
Table 1, entry 13). However, the catalyst C and D did not show
the formation of the product 4 (Table 1, entries 14 and 15). The
NHC‒catalyst E showed some activity, and the expected product
was obtained in low yield (Table 1, entry 16). With the optimized
reaction condition (Table 1, entry 11) in hand, we began to
explore the scope and generality of the protocol.
The substrate scope of maleimide N‒substituents was studied
keeping the reactant p‒chlorobenaldehyde constant (Scheme 1).
We have mentioned earlier that the maleimide (3) having free‒
NH furnished the product 4 in excellent yield. The maleimides
with various N‒alkyl substituents also reacted well under the
developed protocol and the corresponding Stetter products
(Scheme 1, 5‒12) were obtained in good to excellent yields.
Thus, substrates with short to very long chain N‒alkyl
Scheme 1. Variation in the maleimide N‒substituents.

3
was not observed. In both the cases (13 and
A
14
C
),
C
it
E
is
P
u
T
n
E
cle
D
ar MA3.
N
C
U
on
SCR
clu
si
onIPT
whether the consumption of starting maleimides is due to high
reactivity or decomposition. In all the above-mentioned reactions,
the formation of the corresponding benzoin product was also
observed, however, that did not affect the yields due to its
reversibility.
In conclusion, we have developed an efficient process for the
synthesis of 3‒aroylsuccinimides by an intermolecular Stetter
reaction of aromatic aldehydes with maleimides. Isa‒NHC was
found to be the most efficient catalyst for this transformation.
The protocol is general, and the Stetter products were obtained in
good to excellent yields. Future work in our laboratory is focused
on the development of a suitable chiral NHC‒catalyst for an
intermolecular asymmetric Stetter reaction on substituted
maleimides.
4
. Experimental section
All reagents and solvents were used as received from
commercial sources unless and otherwise noted. THF was
distilled over benzophenone‒ketyl under an atmosphere of argon.
All experiments were carried out under an atmosphere of argon.
18,20
21
NHC precatalysts
and N‒substituted maleimides were
synthesized using the known literature procedures. Precoated
plates (silica gel 60 PF254, 0.25 or 0.5 mm) were utilized for
Thin Layer Chromatography (TLC). Column chromatographic
purifications were carried out on flash silica-gel (240‒400 mesh)
using petroleum ether and ethyl acetate as eluents. The 1H and
1
3C NMR spectra were recorded on Bruker AV 200/400/500
MHz, 50/100/125 MHz NMR spectrometer in CDCl , DMSO‒d
3
6
or Acetone‒d . Chemical shifts were reported as δ values from
6
a
Scheme 2. Variation in the aldehyde substrate
standard peaks. The multiplicities of signals are designated by the
following abbreviations: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet). Coupling constants (J) are reported in
hertz. Melting points were determined on a Buchi Melting Point
B-540 apparatus. High-resolution mass spectrometry (HRMS)
was performed on a TOF/Q‒TOF mass spectrometer.
We then turned our attention to explore the aldehyde substrate
scope on maleimide (3) (Scheme 2). Benzaldehyde furnished the
product 15 in good yield; however, p‒flurobenzaldehyde gave
compound 16 in moderate yield. Other substituents such as
methyl carboxylate-, methyl-, and methoxy- were tolerated to
obtain the corresponding 3-aroylsuccinimides in moderate to
good yields (17-19). β‒napthaldehyde also reacted smoothly to
provide a very good yield of the corresponding product 20. In the
case of 3‒pyridinecarboxaldehyde we observed the expected
product 21 on TLC and confirmed its formation by the analysis
4
.1 General method for the preparation of 3‒Aroylsuccinimides
All the reactions were performed on 50 mg scale of
(
aldehyde.)
A reaction mixture containing K CO3 (80 mol%), NHC
2
1
precatalyst A (15 mol%), maleimide 2 (1.5 equiv) and aldehyde 1
of a crude reaction mixture by H-NMR, but isolation of the
(
5
1.0 equiv) in THF (2 mL) under argon atmosphere was stirred at
0 C for 30 min. to 2 h. When the reaction was complete, the
product from the reaction mixture was not possible even after
several attempts using neutral, acidic or basic column conditions.
Cinnamaldehyde did not react under the developed condition;
hence neither the product 22 nor the product by homoenolate
addition was observed. Aliphatic aldehyde also remained
unreactive and the product 23 was not formed. Overall, the
developed protocol worked very well with the aromatic
aldehydes.
o
crude reaction mixture was allowed to attain room temperature,
followed by filtration of the reaction mixture through a bed of
celite. The residue was washed with ethyl acetate (5 mL x 3) and
the combined filtrate was evaporated under reduced pressure. The
crude reaction mixture was purified by column chromatography
on silica gel using solvent gradient of petroleum ether:ethyl
acetate to furnish the desired products 4-13, 15-21 in 10-90%
yield.
22
4
.2 3-(4-Chlorobenzoyl)pyrrolidine-2,5-dione (4).
Reaction time: 1 h; Rf: 0.5 (2:3 EtOAc: pet. ether); white
solid; 76 mg, 90% yield; Mp 165‒167 C; [keto : enol = 1 : 0.1].
Fig. 4. The protocol did not work with these substituted maleimides.
o
1
H NMR (500 MHz, Acetone‒d ) δ 12.49 (s, 0.07 x 1H), 10.38
We generalized the protocol by variation in maleimide N‒
substituent and aldehyde, but generalization of the protocol with
substituted maleimides (Fig. 4, 24‒27) was not possible under the
developed condition. We anticipated that the N‒protected
maleimide might prove to be a better substrate, hence N‒phenyl
6
(
=
s, 0.18 x 1H), 10.27 (s, 1H), 8.16 (d, J = 8.5 Hz, 2H), 7.85 (d, J
8.5 Hz, 0.21 x 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5
Hz, 0.25 x 2H), 5.22 (dd, J = 8.9 and 4.3 Hz, 1H), 3.64 (s, 0.22 x
2
8
1
H), 3.20 (dd, J = 18.0 and 4.0 Hz, 1H), 2.98 (dd, J = 18.0 and
13
.8 Hz, 1H). C NMR (125 MHz, Acetone‒d ) δ 193.5, 177.2,
3
‒methylmaleimide (28) was used. However, that also did not
6
74.5, 140.5, 135.5, 132.3, 130.1, 129.7, 51.1, 34.8, 33.5.
react under the developed protocol. Variation in NHC and use of
some additives might facilitate the reaction.
+
HRMS-ESI (m/z): calcd. for C H ClNO [M + Na] : 260.0085,
11
8
3
found: 260.0076.
The 3-aroylsuccinimides products obtained by our protocol
(
Scheme 1 and 2, 4‒13 and 15‒21) themselves are important
4
.3 3-(4-Chlorobenzoyl)-1-methylpyrrolidine-2,5-dione (5).
building blocks, but their utility also can be enhanced further by
converting them to the corresponding maleimides, diacids or
anhydrides using well-documented literature methods.
Reaction time: 2 h; Rf: 0.5 (3:7 EtOAc: pet. ether); white
6a,19
o
solid; 74 mg, 83% yield; Mp 111‒113 C; [keto : enol = 1 : 0.2].

41
Tetrahedron
MA29
H NMR (400 MHz, CDCl ) δ 12.11 (s, 0.21
A
x 1
C
H
C
), 7
E
.9
P
9
T
(d
E
, J
D
=
N
.0
U
, 2
S
8.
C
7,
R
28
I
.
P
6, 25.9, 25.8, 25.7, 25.0, 24.9. HRMS-ESI (m/z):
T
3
+
8
2
1
.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 0.44 x 2H), 7.44 (d, J = 8.7 Hz,
H), 7.38 (d, J = 8.7 Hz, 0.44 x 2H), 4.72 (dd, J = 8.7 and 4.1 Hz,
H), 3.44 (s, 0.44 x 2H), 3.35 (dd, J = 18.3 and 4.1 Hz, 1H), 3.02
calcd. for C H ClNO [M + H] : 320.1048, found: 320.1049.
17
18
3
4
.8 1-Allyl-3-(4-chlorobenzoyl)pyrrolidine-2,5-dione (10).
(
s, 0.66 x 3H), 2.93 (s, 3H), 2.78 (dd, J = 18.3 and 9.2 Hz, 1H).
Reaction time: 1 h; Rf: 0.5 (1:4 EtOAc: pet. ether); viscous
oil; 59 mg, 60% yield; [keto : enol = 1 : 0.18]. H NMR (400
1
3
1
C NMR (100 MHz, CDCl ) δ 191.0, 175.6, 173.9, 172.5, 141.0,
3
1
2
2
37.4, 133.7, 131.6, 131.2, 129.1, 129.0, 128.9, 48.6, 33.5, 31.4,
MHz, CDCl ) δ 12.12 (s, 0.17 x 1H), 8.01 (d, J = 8.8 Hz, 2H),
3
+
5.4, 24.5. HRMS-ESI (m/z): calcd. for C H ClNO [M + H] :
7.59 (d, J = 8.6 Hz, 0.42 x 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.38 (d,
J = 8.6 Hz, 0.46 x 2H), 5.84‒5.75 (m, 0.17 x 1H), 5.75‒5.63 (m,
12
10
3
52.0422, found: 252.0418.
1
8
H), 5.24‒5.17 (m, 0.40 x 2H), 5.17‒5.08 (m, 2H), 4.75 (dd, J =
.8 and 3.4 Hz, 1H), 4.15 (d, J = 5.9 Hz, 0.41 x 2H), 4.04 (d, J =
4
.4 1-Butyl-3-(4-chlorobenzoyl)pyrrolidine-2,5-dione (6).
Reaction time: 1 h; Rf: 0.5 (3:17 EtOAc: pet. ether); viscous
oil; 59 mg, 56% yield; [keto : enol = 1 : 0.19]. H NMR (400
5.9 Hz, 2H), 3.46 (s, 0.39 x 2H), 3.37 (dd, J = 18.1 and 3.9 Hz,
1H), 2.80 (dd, J = 18.1, 8.8 Hz, 1H). C NMR (100 MHz,
1
13
MHz, CDCl ) δ 12.18 (s, 0.18 x 1H), 8.00 (d, J = 8.8 Hz, 2H),
CDCl ) δ 191.1, 175.0, 172.0, 141.1, 133.7, 131.2, 130.1, 129.2,
3
3
7
.59 (d, J = 8.6 Hz, 0.40 x 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.38 (d,
J = 8.8 Hz, 0.5 x 2H), 4.70 (dd, J = 8.8 and 3.9 Hz, 1H), 3.53 (t, J
7.3 Hz, 0.44 x 2H), 3.47‒3.40 (m, 2H), 3.32 (dd, J = 18.1 and
129.1, 128.9, 118.6, 48.6, 41.4, 40.6, 33.5, 31.4. HRMS-ESI
+
(m/z): calcd. for C H ClNO [M + H] : 278.0578, found:
14
12
3
=
278.0572.
3
0
1
3
1
2
.9 Hz, 1H), 2.77 (dd, J = 18.1 and 8.8 Hz, 1H), 1.60‒1.52 (m,
.55 x 2H), 1.51‒1.42 (m, 2H), 1.31‒1.26 (m, 0.58 x 2H), 1.24‒
.18 (m, 2H), 0.88 (t, J = 7.3 Hz, 0.57 x 3H), 0.83 (t, J = 7.3 Hz,
4
.9 1-Benzyl-3-(4-chlorobenzoyl)pyrrolidine-2,5-dione (11).
Reaction time: 1.5 h; Rf: 0.5 (7:13 EtOAc: pet. ether);
13
1
H). C NMR (100 MHz, CDCl ) δ 191.2, 175.6, 172.5, 141.0,
viscous oil; 34 mg, 29% yield; [keto : enol = 1 : 0.17]. H NMR
(400 MHz, CDCl ) δ 12.11 (s, 0.20 x 1H), 7.98 (d, J = 8.5 Hz,
2H), 7.57 (d, J = 8.8 Hz, 0.46 x 2H), 7.43 (d, J = 8.5 Hz, 2H),
7.40‒7.33 (m, 0.98 x 4H), 7.31‒7.19 (m, 6H), 4.70 (dd, J = 8.8
and 3.9 Hz, 1H), 4.68 (s, 0.41 x 2H), 4.61 (d, J = 14.2 Hz, 1H),
3
33.8, 131.2, 129.1, 129.0, 128.8, 48.5, 39.2, 33.5, 31.4, 29.7,
3
9.5, 20.1, 19.9, 13.6, 13.5. HRMS-ESI (m/z): calcd. for
+
C H ClNO [M + H] : 294.0891, found: 294.0879.
15
16
3
4
.5 3-(4-Chlorobenzoyl)-1-dodecylpyrrolidine-2,5-dione (7).
4
.53 (d, J = 14.2 Hz, 1H), 3.44 (s, 0.46 x 2H), 3.37 (dd, J = 18.1
13
Reaction time: 45 min.; Rf: 0.5 (3:17 EtOAc: pet. ether);
and 3.4 Hz, 1H), 2.77 (dd, J = 18.1 and 8.8 Hz, 1H). C NMR
(100 MHz, CDCl ) δ 190.9, 175.2, 172.2, 141.0, 135.2, 133.7,
131.2, 129.1, 129.0, 128.9, 128.8, 128.7, 128.11, 128.05, 48.6,
o
white solid; 120 mg, 73% yield; Mp 65‒67 C; [keto : enol = 1 :
0
3
1
.22]. H NMR (400 MHz, CDCl ) δ 12.19 (s, 0.19 x 1H), 8.01
3
(
d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.8 Hz, 0.47 x 2H), 7.45 (d, J =
43.0, 33.6, 31.3. HRMS-ESI (m/z): calcd. for C H ClNO [M +
H] : 328.0735, found: 328.0732.
18
14
3
+
8
3
3
.7 Hz, 2H), 7.38 (d, J = 8.8 Hz, 0.5 x 2H), 4.70 (dd, J = 8.8 and
.9 Hz, 1H), 3.52 (t, J = 7.5 Hz, 0.46 x 2H), 3.43 (t, J = 7.3, 2H),
.40 (s, 0.55 x 2H), 3.33 (dd, J = 18.1 and 3.9 Hz, 1H), 2.77 (dd,
4
.10 3-(4-Chlorobenzoyl)-1-((S)-1-phenylethyl)pyrrolidine-2,5-
ione (12).
J = 18.1 and 9.1 Hz, 1H), 1.23‒1.14 (m, 28H), 0.81 (t, J = 6.7
Hz, 3H). C NMR (100 MHz, CDCl ) δ 191.2, 175.6, 172.5,
1
2
1
4
13
3
Reaction time: 45 min.; Rf: 0.5 (1:4 EtOAc: pet. ether);
o
41.0, 133.8, 131.2, 129.1, 129.0, 128.9, 48.5, 39.5, 31.9, 31.4,
9.68, 29.65, 29.5, 29.4, 29.4, 29.13, 29.05, 27.5, 26.7, 22.7,
white solid; 66 mg, 54% yield; Mp 111‒113 C; [keto : enol = 1 :
1
0.25]; d.r. (1:1). H NMR (400 MHz, CDCl ) δ 12.20 (s, 0.23 x
3
+
4.1. HRMS-ESI (m/z): calcd. for C H ClNO [M + H] :
1H), 7.97 (d, J = 3.7 Hz, 1H), 7.95 (d, J = 3.4 Hz, 2H), 7.55 (d, J
= 3.4 Hz, 0.5 x 2H), 7.46‒7.38 (m, 2H), 7.38‒7.29 (m, 3H),
27
40
3
62.2769, found: 462.2752.
7
1
.29‒7.16 (m, 4H), 5.43 (q, J = 7.3 Hz, 0.25 x 1H), 5.39‒5.26 (m,
H), 4.70‒4.58 (m, 1H), 3.39 (d, J = 2.0 Hz, 0.44 x 2H), 3.35‒
4
.6 3-(4-Chlorobenzoyl)-1-phenethylpyrrolidine-2,5-dione (8).
Reaction time: 45 min.; Rf: 0.5 (1:3 EtOAc: pet. ether);
3.26 (m, 1H), 2.79‒2.64 (m, 1H), 1.81 (d, J = 7.3 Hz, 0.74 x 3H),
1.74 (d, J = 7.3 Hz, 1.5 x 3H), 1.68 (d, J = 7.3 Hz, 1.5 x 3H). C
o
13
white solid; 72 mg, 59% yield; Mp 82‒84 C; [keto : enol = 1 :
1
0
.16]. H NMR (400 MHz, CDCl ) δ 12.13 (s, 0.15 x 1H), 7.98
NMR (100 MHz, CDCl ) δ 191.3, 191.1, 175.3, 175.2, 173.5,
3
3
(
8
7
d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.6 Hz, 0.33 x 2H), 7.44 (d, J =
.3 Hz, 2H), 7.37 (d, J = 8.6 Hz, 0.33 x 2H), 7.28‒7.09 (m, 4H),
.09 (d, J = 7.8 Hz, 2H), 4.65 (dd, J = 8.8 and 3.9 Hz, 1H), 3.76
172.2, 162.5, 141.0, 140.9, 139.0, 138.9, 137.3, 133.74, 133.71,
131.24, 131.19, 129.1, 129.0, 128.8, 128.5, 128.0, 127.9, 127.5,
127.3, 95.3, 51.0, 50.7, 50.1, 48.3, 33.5, 31.3, 16.7, 16.6, 16.2.
+
(
t, J = 7.3 Hz, 0.40 x 2H), 3.66 (t, J = 7.3 Hz, 2H), 3.39 (s, 0.32 x
H), 3.32 (dd, J = 18.1 and 3.9 Hz, 1H), 2.87 (t, J = 8.3 Hz, 0.38
x 2H), 2.79 (t, J = 8.3 Hz, 2H), 2.71 (dd, J = 18.1 and 9.5 Hz,
HRMS-ESI (m/z): calcd. for C H ClNO [M + H] : 342.0891,
19
16
3
2
found: 342.0880.
13
4.11 3-(4-Chlorobenzoyl)-1-phenylpyrrolidine-2,5-dione (13).
1
1
4
H). C NMR (100 MHz, CDCl ) δ 190.8, 175.2, 172.2, 141.0,
3
37.4, 133.7, 131.2, 129.1, 129.0, 128.9, 128.8, 128.6, 126.7,
Reaction time: 45 min.; Rf: 0.5 (1:4 EtOAc: pet. ether); oil;
1
8.5, 40.6, 33.4, 31.2. HRMS-ESI (m/z): calcd. for C H ClNO
M + H] : 342.0891, found: 342.0881.
10% yield; [keto : enol = 1 : 0.37]. H NMR (400 MHz, CDCl ) δ
19
16
3
3
+
[
12.27 (s, 0.33 x 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz,
1
H), 7.49‒7.30 (m, 9H), 7.22‒7.20 (m, 1H), 4.88 ( dd, J = 9.0
4
.7 3-(4-Chlorobenzoyl)-1-cyclohexylpyrrolidine-2,5-dione (9).
and 4.1 Hz, 1H), 3.63 (s, 0.74 x 2H), 3.53 (dd, J = 18.3 and 4.1
Hz, 1H), 2.97 (dd, J = 18.3 and 9.0 Hz, 1H). HRMS-ESI (m/z):
calcd. for C H ClNO [M + H] : 314.0578, found: 314.0575.
Reaction time: 45 min.; Rf: 0.5 (3:17 EtOAc: pet. ether);
o
+
white solid; 81 mg, 71% yield; Mp 99‒101 C; [keto : enol = 1 :
0
17
12
3
1
.20]. H NMR (200 MHz, CDCl ) δ 12.32 (s, 0.21 x 1H), 8.00
22
3
4
.12 3-Benzoylpyrrolidine-2,5-dione (15).
(d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.8 Hz, 0.48 x 2H), 7.44 (d, J =
8
4
1
1
.7 Hz, 2H), 7.37 (d, J = 8.8 Hz, 0.6 x 2H), 4.65 (dd, J = 9.0 and
.2 Hz, 1H), 4.01‒3.76 (m, 1H), 3.39 (s, 0.41 x 2H), 3.28 (dd, J =
8.1 and 4.2 Hz, 1H), 2.72 (dd, J = 18.1 and 9.0 Hz, 1H), 2.14‒
Reaction time: 30 min.; Rf: 0.5 (2:3 EtOAc: pet. ether);
o
white solid; 73 mg, 76% yield; Mp 135‒137 C; [keto : enol = 1
1
: 0.24]. H NMR (500 MHz, CDCl ) δ 12.04 (s, 0.21 x 1H), 8.15
3
13
.91 (m, 2H), 1.85‒1.55 (m, 5H), 1.31‒1.04 (m, 5H). C NMR
(s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2 Hz, 0.47 x 2H),
7.59 (t, J = 8.2 Hz, 1H), 7.48 (t, J = 7.9 Hz, 2H), 7.45‒7.39 (m,
(100 MHz, CDCl ) δ 191.4, 175.6, 172.6, 140.9, 133.8, 131.8,
3
1
31.2, 129.8, 129.1, 129.0, 128.8, 52.4, 51.6, 48.3, 33.5 31.2,

5
0
3
1
1
.67 x 3H), 4.83 (dd, J = 9.1 and 3.4 Hz, 1H), 3
A
.52
C
(
C
s, 0
E
.4
P
8
T
x
E
2H
D
), MA12
N
7.
U
4,
S RI
1
C
24
.3
,
PT50.1, 33.5. HRMS-ESI (m/z): calcd. for
+
.38 (dd, J = 18.3 and 3.4 Hz, 1H), 2.84 (dd, J = 18.3 and 9.1 Hz,
C H NO [M + H] : 254.0812, found: 254.0810.
5
1
11
3
13
H). C NMR (100 MHz, CDCl ) δ 191.9, 175.9, 172.8, 135.2,
3
4
.18 3-Nicotinoylpyrrolidine-2,5-dione (21).
34.4, 131.4, 129.8, 128.8, 128.7, 127.6, 49.8, 34.6, 32.7.
+
HRMS-ESI (m/z): calcd. for C H NO [M + H] : 204.0655,
found: 204.0654.
Reaction time: 1 h; Rf: 0.5 (EtOAc); 25% yield by NMR
using CH Br as an internal standard; Keto form. H NMR (500
2 2
11
9
3
1
MHz, Acetone‒d ) δ 10.04 (s, 1H), 9.00‒8.94 (m, 1H), 8.68‒8.63
6
4
.13 3-(4-Fluorobenzoyl)pyrrolidine-2,5-dione (16).
(m, 1H), 8.28‒8.22 (m, 1H), 8.15‒8.08 (m, 1H), 4.25‒4.18 (m,
Reaction time: 45 min.; Rf: 0.5 (2:3 EtOAc: pet. ether);
1H), 3.34 (dd, J = 18.7 and 8.8 Hz, 1H), 2.75 (dd, J = 8.78 and
4.2 Hz, 1H).
o
white solid; 79 mg, 53% yield; Mp 143‒145 C; [keto : enol = 1
1
:
8
0.04]. H NMR (400 MHz, CDCl ) δ 12.09 (s, 0.04 x 1H), 8.11‒
3
Acknowledgments
.06 (m, 2H), 8.03 (s, 1H), 7.19‒7.11 (m, 2H), 4.77 (dd, J = 8.8
and 4.2 Hz, 1H), 3.50 (s, 0.08 x 2H), 3.42 (dd, J = 18.3 and 4.2
Hz, 1H), 2.83 (dd, J = 18.3 and 8.8 Hz, 1H). C NMR (100
M.M.A. thanks, CSIR-New Delhi for the research fellowship.
S.B.M. gratefully acknowledges generous financial support from
DST-SERB, New Delhi.
13
MHz, CDCl ) δ 190.0, 175.2, 172.2, 173.7 (d, J = 257.4 Hz),
3
1
32.7 (d, J = 9.2 Hz), 131.7, 116.1 (d, J = 22.3 Hz), 49.8, 32.5.
+
HRMS-ESI (m/z): calcd. for C H FNO [M + H] : 222. 0561,
11
8
3
References
found: 222.0559.
1
.
(a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606.
4
.14 Methyl 4-(2,5-dioxopyrrolidine-3-carbonyl)benzoate (17).
(
(
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o
Dominguez de Maria, P.; Shanmuganathan, S. Curr. Org. Chem. 2011,
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solid; 62 mg, 78% yield; Mp 174‒176 C; [keto : enol = 1 : 0.16].
1
1
H NMR (500 MHz, Acetone‒d ) δ 12.48 (s, 0.1 x 1H), 10.44 (s,
6
Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314. (g)
Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew. Chem.,
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0
8
0
.16 x 1H), 10.29 (s, 1H), 8.26 (d, J = 8.2 Hz, 2H), 8.17 (d, J =
.2 Hz, 2H), 8.13 (d, J = 8.2 Hz, 0.47 x 2H), 7.95 (d, J = 8.2 Hz,
.32 x 2H), 5.29 (dd, J = 8.8 and 4.3 Hz, 1H), 3.94 (s, 3H), 3.92
(s, 0.52 x 3H), 3.67 (s, 0.32 x 2H), 3.22 (dd, J = 18.0 and 4.3 Hz,
13
1
H), 3.01 (dd, J = 18.0 and 8.8 Hz, 1H). C NMR (125 MHz,
Acetone‒d ) δ 194.4, 177.2, 174.4, 166.4, 140.1, 135.3, 130.6,
1
calcd. For C H NO [M + H] : 262.0710, found: 262.0710.
6
30.3, 128.6, 52.8, 52.6, 51.4, 34.8, 33.6. HRMS-ESI (m/z):
+
(n) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T.
13
11
5
Chem. Rev. 2015, 115, 9307. (o) Tang, W.; Du, D. Chem. Rec. 2016, 16,
1489. (p) Zhang, C.-H.; Hooper, J. F.; Lupton, D. W. ACS Catal. 2017, 7,
4
.15 3-(4-Methylbenzoyl)pyrrolidine-2,5-dione (18).
2
583.
Reaction time: 1 h; Rf: 0.5 (1:1 EtOAc: pet. ether); white
solid; 33 mg, 36% yield; Mp 159‒161 C; [keto : enol = 1 : 0.17].
2. (a) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632. (b) Read de
Alaniz, J.; Kerr, M. S.; Moore, J. L.; Rovis, T. J. Org. Chem. 2008, 73,
2033. (c) Rovis, T. Chem. Lett. 2008, 37, 2. (d) Read de Alaniz, J.;
Rovis, T. Synlett 2009, 2009, 1189. (e) Yetra, S. R.; Patra, A.; Biju, A. T.
Synthesis 2015, 47, 1357. (f) Hsu, D.-S.; Yeh , J.-Y.; Cheng, C.-Y. Org.
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P.; Nguyen, Q. N. N.; Paton, R. S.; Dixon, D. J. J. Am. Chem. Soc. 2017,
o
1
H NMR (400 MHz, CDCl ) δ 12.05 (s, 0.16 x 1H), 8.27 (s, 0.48
3
x 1H), 8.17 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 7.8 Hz,
.35 x 2H), 7.26 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 8.3 Hz, 0.35 x
H), 4.80 (dd, J = 9.3 and 4.4 Hz, 1H), 3.50 (s, 0.35 x 2H), 3.37
0
2
(
2
1
1
1
39, 17755.
dd, J = 18.1 and 3.9 Hz, 1H), 2.82 (dd, J = 18.6 and 9.3 Hz, 1H),
13
3. (a) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639. (b) Stetter, H.;
Kuhlmann, H. In Organic Reactions; Vol. 40; Paquette, L. A., Ed.; Wiley
.38 (s, 3H), 2.35 (s, 0.89 x 3H). C NMR (100 MHz, CDCl ) δ
3
91.3, 175.6, 172.7, 145.6, 132.7, 130.2, 129.9, 129.6, 129.5,
&
Sons: New York, 1991, 407.
29.2, 127.6, 49.6, 34.7, 32.7, 21.7. HRMS-ESI (m/z): calcd. for
4
.
(a) Enders, D.; Han, J.; Henseler, A. Chem. Commun. 2008, 3989. (b)
DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133, 10402. (c)
Fang, X.; Chen, X.; Lv, H.; Chi, Y. R. Angew. Chem., Int. Ed. 2011, 50,
+
C H NO [M + H] : 218.0812, found: 218.0810.
12
11
3
4
.16 3-(3-Methoxybenzoyl)pyrrolidine-2,5-dione (19).
1
1782. (d) Bhunia, A.; Yetra, S. R.; Bhojgude, S. S.; Biju, A. T. Org.
Lett. 2012, 14, 2830. (e) Jia, M.-Q.; Liu, C.; You, S.-L. J. Org. Chem.
012, 77, 10996. (f) Zhang, J.; Xing, C.; Tiwari, B.; Chi, Y. R. J. Am.
Reaction time: 2 h; Rf: 0.5 (1:1 EtOAc: pet. ether); white
2
o
solid; 57 mg, 66% yield; Mp 158‒160 C; [keto : enol = 1 : 0.07].
Chem. Soc. 2013, 135, 8113. (g) Patra, A.; Bhunia, A.; Biju, A. T. Org.
Lett. 2014, 16, 4798. (h) Rafinski, Z.; Kozakiewicz, A.; Rafinska, K.
ACS Catal. 2014, 4, 1404. (i) Lin, Q.; Li, Y.; Das, D. K.; Zhang, G.;
Zhao, Z.; Yang, S.; Fang, X. Chem. Commun. 2016, 52, 6459. (j) Takaki,
K.; Hino, M.; Ohno, A. ; Komeyama, K.; Yoshida, H.; Fukuoka, H.
Beilstein J. Org. Chem. 2017, 13, 1816. (k) Ragno, D.; Carmine, G.
D.; Brandolese, A.; Bortolini, O.; Giovannini, P. P.; Massi, A. ACS
Catal., 2017, 7, 6365.
1
H NMR (400 MHz, DMSO‒d ) δ 12.38 (s, 0.04 x 1H), 11.55 (s,
6
0
1
5
3
1
3
2
.08 x 1H), 11.46 (s, 1H), 7.67 (d, J = 7.3 Hz, 1H), 7.57‒7.54 (m,
H), 7.51 (t, J = 8.0 Hz, 1H), 7.29 (dd, J = 8.2 and 2.8 Hz, 1H),
.17 (dd, J = 8.2 and 5.0 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 0.2 x 3H),
13
.00‒2.86 (m, 2H). C NMR (100 MHz, DMSO‒d ) δ 194.6,
6
77.8, 175.1, 159.6, 137.1, 130.1, 122.3, 120.2, 114.2, 55.6, 50.2,
+
5
6
.
.
Li, Y.; Shi, F.-Q.; He, Q.-L.; You, S.-L. Org. Lett. 2009, 11, 3182.
(a) Mhaske, S. B.; Argade, N. P. Synthesis 2003, 2003, 863. (b) Baag, M.
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Devendar, B.; Aravindu, K.; Veerendhar, A. Chem.-Eur. J. 2010, 16,
3.5. HRMS-ESI (m/z): calcd. for C H NO [M + H] :
12
11
4
34.0761, found: 234.0758.
.17 3-(2-Naphthoyl)pyrrolidine-2,5-dione (20).
Reaction time: 1 h; Rf: 0.5 (1:1 EtOAc: pet. ether); white
4
2
031. (d) Garad, D. N.; Tanpure, S. D.; Mhaske, S. B. Beilstein J. Org.
Chem. 2015, 11, 1008. (e) Gruenenfelder, C. E.; Kisunzu, J. K.;
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Han, S. H.; Oh, Y.; Mishra, N. K.; Lee, S. H.; Oh, J. S.; Kim, I. S. Org.
Lett. 2016, 18, 2568.
o
1
solid; 64 g, 79% yield; Mp 176‒178 C; [keto : enol = 1 : 0.0]. H
NMR (400 MHz, DMSO‒d ) δ 11.45 (s, 1H), 8.76 (s, 1H), 8.11
6
(
d, J = 8.1 Hz, 1H), 8.04‒7.93 (m, 3H), 7.67 (t, J = 7.1 Hz, 1H),
7
.
Ahire, M. M.; Mhaske, S. B. ACS Omega 2017, 2, 6598.
7
2
1
.61 (t, J = 7.1 Hz, 1H), 5.30 (dd, J = 8.3 and 4.4 Hz, 1H), 3.05‒
8. Fredenhagen, A.; Tamura, S. Y.; Kenny, P. T. M.; Komura, H.; Naya, Y.;
13
.85 (m, 2H). C NMR (100 MHz, DMSO‒d ) δ 194.6, 178.0,
Nakanishi, K.; Nishiyama, K.; Sugiura, M.; Kita, H. J. Am. Chem. Soc.
6
1
987, 109, 4409.
75.3, 135.6, 133.1, 132.6, 132.2, 130.1, 129.5, 128.6, 127.9,

6
Tetrahedron
9
. Yamada, T.; Imai, E.; Nakatuji, K.; Numata, A.; Tanaka, R. Tetrahedron
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ACCEPTED MANUSCRIPT
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1
Click here to remove instruction text...
1
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