Transition metal free K2CO3 mediated thioarylation, selenoarylation and arylation of 2-aminomaleimides at ambient temperature

Article abstract of DOI:10.1016/j.tet.2019.130486

Transition metal free thioarylation, selenoarylation and arylation of 2-aminomaleimide, using thiophenols, diaryl diselenides and arylhydrazine hydrochlorides respectively, has been reported in DMSO under aerobic condition in presence of K₂CO₃ at room temperature. The reaction occurs smoothly without prerequisite N-protection of 2-aminomaleimide. The synthesis of novel, polyfunctionalized maleimides has been achieved by the direct C–H activation of enamines. Thioarylation and selenoarylation are proposed to be proceeding via disulfides/diselenides and arylation has been proposed to be proceeding via aryl free radicals.

Full text of DOI:10.1016/j.tet.2019.130486

Accepted Manuscript
Transition metal free K CO mediated thioarylation, selenoarylation and arylation of
2
3
2-aminomaleimides at ambient temperature
Mohit Saroha, Gaurav Bartwal, Jitender M. Khurana
PII:
S0040-4020(19)30813-0
DOI:
https://doi.org/10.1016/j.tet.2019.130486
Article Number: 130486
Reference:
TET 130486
To appear in: Tetrahedron
Received Date: 15 May 2019
Revised Date: 23 July 2019
Accepted Date: 27 July 2019
Please cite this article as: Saroha M, Bartwal G, Khurana JM, Transition metal free K CO mediated
2
3
thioarylation, selenoarylation and arylation of 2-aminomaleimides at ambient temperature, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.130486.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Transition metal free K2CO3 mediated thioarylation, selenoarylation and
arylation of 2-aminomaleimides at ambient temperature
Mohit Saroha, Gaurav Bartwal and Jitender M. Khurana*
Department of Chemistry, University of Delhi, Delhi-110007, India
*Corresponding author. Tel.: +91 11 2766772; fax: +91 1 27667624
E-mail addresses: jmkhurana1@yahoo.co.in, jmkhurana@chemistry.du.ac.in
Abstract
Transition metal free thioarylation, selenoarylation and arylation of 2-aminomaleimide, using
thiophenols, diaryl diselenides and arylhydrazine hydrochlorides respectively, has been reported
in DMSO under aerobic condition in presence of K2CO3 at room temperature. The reaction
occurs smoothly without prerequisite N-protection of 2-aminomaleimide. The synthesis of novel,
polyfunctionalized maleimides has been achieved by the direct C−H activation of enamines.
Thioarylation and selenoarylation are proposed to be proceeding via disulfides/ diselenides and
arylation has been proposed to be proceeding via aryl free radicals.
Keywords: 2-aminomaleimide; thioarylation; selenoarylation; arylation; thiophenols;
arylhydrazine hydrochlorides; K2CO3/DMSO
Introduction
Maleimide is a very versatile motif in medicinal chemistry. Maleimide analogues, in conjunction
with other heterocycles, have shown significant biological applications as potent selective GSK-
3β inhibitors and neuroprotective agents (I),1 anticancer drug (carboplatin) (II),2 rhenium (I)
pyridine maleimide complex for biological labeling (III),3 PARP-1 [poly(ADP-
ribose)polymerase-1] inhibitors (IV),4 COX-2 inhibitors and anti-inflammatory agents (V)
(Figure 1).5 A variety of maleimide derivatives have also found applications as bioimaging
probes for thiols and also as fluorescent & colorimetric chemosensors.6
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Figure 1. Some biologically active maleimides.
Over last several decades, various synthetic methods have been developed for the formation of
complex molecules via CDC (Cross-Dehydrogenating Coupling) reaction between C–H and
thiolating/ sulfenylating reagents. Di erent thiolating/ sulfenylating reagents have been used in
these protocols such as arylthiols, arylsulfonyl hydrazides, arylsulfonyl chlorides, sodium
sulfinates, diaryldisulfides and 1-(substituted-phenylthio)-pyrrolidine-2,5-diones. These reactions
require the synthesis of sulfenylating reagents initially.7 Synthesis of arylsulfides via C–H
functionalization using arylthiols as sulfenylating agents under metal-free conditions has not
been explored significantly. Sulfenylation of compounds like indoles, naphthols, N,N-dimethyl
aniline, 4-hydroxy coumarins, pyrazolones, 6-aminouracil, acetophenone and oxadiazoles using
simple and eco-friendly reagents viz. I2/BSA,8a K2CO3/DMSO,8b I2/DMSO,8c N-
8f
chlorosuccinimide,8d I2/DMSO,8e Cs2CO3 and KClO3/ethylactate8g has been reported in
literature.
Transition metal catalyzed C-heteroatom bond formation, such as C-N, C-S and C-P bond
formation via alkene C-H activation, has been extensively used in recent years.9 With increasing
environmental concerns, the chemists are focussing on developing sustainable novel procedures.
In this direction, transition metal free arylations using phenylhydrazine in presence of base have
been reported.10 Molecular oxygen or aerial oxidation is a sustainable and mild oxidizing agent
which has found application in many of these synthetic transformations.11 To the best of our
knowledge, thiolation/ arylation of 2-amino maleimide has not been explored yet. In continuation
of our work aimed at development of metal free synthetic methodologies for synthesis of
bioactive molecules.12 we report herein metal free thioarylation, selenoarylation and arylation of
2-amino maleimide.
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RESULTS AND DISCUSSION
Thioarylation and selenoarylation of substituted 2-aminomaleimides
In this paper, we have reported a novel transition metal free K2CO3 mediated thioarylation,
selenoarylation and arylation of substituted 2-aminomaleimides by reaction with thiophenols,
diaryl bisselenides and phenyl hydrazines, respectively in DMSO under aerobic condition at
room temperature. The reactions of 1-methyl-3-(methylamino)-1H-pyrrole-2,5-dione (1a) and 4-
chlorothiophenol (2a) were attempted by changing solvents and bases to identify appropriate
conditions for the desired reaction.
Firstly, the reaction of 1-methyl-3-(methylamino)-1H-pyrrole-2,5-dione (1a) (1.0 mmol) and 4-
chlorothiophenol (2a) (2.0 mmol) was carried out in presence of K2CO3 (4.0 mmol) in
acetonitrile at room temperature (Table 1, entry 1). The reaction was incomplete even after 12 h
as monitored by TLC but showed the formation of a new product. The product was separated and
identified as 3-((4-chlorophenyl)thio)-1-methyl-4-(methylamino)-1H-pyrrole-2,5-dione (3a)
(78%) (Table 1, entry 1). The reaction was then carried out in DCM, MeOH, DMF, and DMSO
under otherwise identical conditions. The reactions in DCM and methanol were incomplete after
12 h and gave 72% and 55% of 3a, respectively, after separation (Table 1, entries 2-3). The
reactions carried out in DMF and DMSO were complete in 12 h and 6 h and yielded 82 % and
89% of 3a, respectively (Table 1, entry 4-5) (eq. 1). The reactions were attempted in presence of
other bases also such as NaOH, DBU and KOH under identical conditions. The reactions were
complete after 12 h and no significant improvement in yield was observed (Table 1, entry 6-8).
The reaction carried out using lower catalyst loading of K2CO3 (3 equiv.) in DMSO required
longer reaction time for completion (12 h) and also gave lower yield of the product (56%) (Table
o
1, entry 9). The reaction of K2CO3 (4 equiv.) attempted at higher temperature (60 C) also gave
an inferior yield of the product (81%) (Table 1, entry 10).
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Table 1: Optimization of reaction conditionsa
Entry
1.
Base (equiv.)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
NaOH (4)
DBU (4)
Solvent
CH3CN
DCM
Temperature
RT
Time (h)
12
Yield 3a (%)
78
72
55b
82
89
85
86
88
56
81
2.
RT
12
3.
MeOH
DMF
RT
12
4.
RT
12
5.
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
RT
6
6.
RT
12
7.
RT
12
8.
KOH (4)
RT
12
9.
K2CO3 (3)
RT
60 oC
12
10.
K2CO3 (4)
12
aReaction conditions: 1-Methyl-3-(methylamino)-1H-pyrrole-2,5-dione (1a) (1.0 mmol), 4-Chlorothiophenol (2a)
(2.0 mmol), solvent (2.0 mL) b Incomplete reaction
It can be inferred from Table 1 that the best yield of 3-thioarylated 2-amonomethylmaleimide
derivative (3a) was obtained when the reaction was carried out in presence of K2CO3 in DMSO
under aerobic condition at room temperature (Table 1, entry 5). Therefore, the generality of the
protocol was examined by attempting reactions of 2-aminomaleimides (1a) with different
thiophenols viz thiophenol, 4-methyl thiophenol, 2-naphthylthiol, 3-methoxythiophenol and 4-
bromothiophenol. All the reactions were complete in less than 8 h and gave the desired 3-
thioarylated-2-aminomaleimides (3b-3f) in high yields (Table 2). In addition, reactions of
benzyl, phenyl and 4-tolyl substituted 2-aminomaleimides were also attempted with thiophenols
under identical conditions. The reactions yielded corresponding thioarylated products 3g-3j in
80-84% yield. All the results are summarized in Table 2.
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Table 2: Thioarylation of substituted 2-aminomaleimidea
a Reaction conditions: Substituted 2-aminomaleimides (1) (1.0 mmol), thiophenols/ thionaphthol (2) (2.0 mmol),
K2CO3 (4 equiv.) and DMSO (2.0 mL)
The reaction of 2-mercaptoethanol was also attempted with 2-aminomaleimide (1a) under
identical condition but there was no reaction. Since we had observed that reactions of
thiophenols were proceeding via initial formation of disulphide, it was likely that 2-
marcaptoethanol does not undergo aerial oxidation rapidly unlike thiophenols. Therefore, the
reaction of 2-mercaptoethanol was repeated in presence of 2-3 crystals of iodine as it is known to
oxidize mercaptanes to disulphides. We observed that the reaction of 2-mercaptoethanol was
complete after 6 h and gave 1-(4-chlorophenyl)-3-((4-chlorophenyl)amino)-4-((2-hydroxyethyl)
thio)-1H-pyrrole-2,5-dione (3k) (Table 2) in 81 % yield.
The structure of compound 3b was confirmed by x-ray diffraction studies. The single crystal
required for x-ray diffraction studies was prepared by slow evaporation of Methanol. The crystal
data shows four molecule in a single crystal lattice (Figure 2).
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Figure 2: Crystal structure and unit cell packing of 1-methyl-3-(methylamino)-4-(phenylthio)-1H-
pyrrole-2,5-dione (3b)
After successful examination of above protocol for thiophenols, we attempted selenoarylation of
substituted 2-aminomaleimide (1a) with diphenyl bisselenide and di(4-tolyl) bisselenide in
DMSO in presence of 4 equiv. of K2CO3 at room temperature as it was easier to prepare
bisselenides than corresponding selenols. The reactions were complete in 4 h and 6 h and gave
the corresponding 3-selenoarylated 2-aminomaleimides (5a & 5b) in 83% and 84% yield,
respectively. The results are summarized in Table 3.
Table 3: Selenoarylation of 2-aminomaleimidea
aReaction conditions: Substituted 2-aminomaleimide (1) (1.0 mmol), diaryl bisselenids (4) (1.2 mmol), K2CO3 (4
equiv.) and DMSO (2.0 mL) at room temperature
The thioarylation and selenoarylation are proposed to be proceeding by nucleophilic attack of
substituted 2-aminomaleimide on disulfide/ diselenide linkage followed by loss of proton
(Scheme 1). The initial formation of disulfides was observed by TLC in all the reactions and was
confirmed by an independent reaction of substituted 2-aminomaleimide with 4-chlorophenyl
bissulphide (1.0 mmol) under identical conditions which gave the desired product. The
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thioarylation mechanism was further confirmed by reaction of 3-aryl-2-aminomaleimide and 4-
chlorothiophenol which did not give any product, as expected due to non-availability of proton
for abstraction, under identical condition.
Scheme 1: Mechanism for synthesis of 3-thioarylated-2-aminomaleimide
Arylation of substituted 2-aminomaleimides
After successful thioarylation and selenoarylation of 2-aminomaleimides, we decided to explore
arylation of 2-aminomaleimides as arylations of different substrates have been reported with
phenylhydrazine.11 Therefore, a reaction of substituted 2-aminomaleimide (1a) (1.0 mmol) was
attempted with phenylhydrazine hydrochloride (8a) (1.2 mmol) in DMSO under aerobic
condition in presence of K2CO3 (4 equiv.) at room temperature. The reaction was complete in 5 h
as monitored by TLC using ethyl acetate:petroleum ether (20:80, v/v) as eluent. After separation,
the product was identified as 1-methyl-3-(methylamino)-4-phenyl-1H-pyrrole-2,5-dione (9a)
(86%) by spectral analysis. Therefore, reactions of substituted 2-aminomaleimide (1a) were then
carried out with diversely substituted arylhydrazines (8b-8f) under identical reaction conditions.
All the reactions gave corresponding 3-arylated-2-aminomaleimides (9b-9f) in high yields. The
results are summarized in Table 4.
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Table 4: Scope of arylation of 2-aminomaleimidea
a Reaction conditions: Substituted 2-aminomaleimide (1a) (1 mmol), Arylhydrazine hydrochloride (8a-8f) (1.2
mmol), K2CO3 (4 equiv.) and DMSO (2.0 mL) at room temperature
The structure of compound 9a was confirmed by X-ray diffraction studies. The single crystal
required for x-ray diffraction studies was prepared by slow evaporation of methanol. The crystal
data shows four molecule in a single crystal lattice and the compound 9a also show hydrogen
bonding between C=O of maleimide and NH (Figure 3).
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Figure 3: Crystal structure and unit cell packing of 1-Methyl-3-(methylamino)-4-phenyl-1H-
pyrrole-2,5-dione (9a).
The arylation of 2-aminomaleimides have been proposed to be proceeding via aryl radicals
generated in situ from arylhydrazine.hydrochloride in presence of K2CO3 under atmospheric
conditions (Scheme 2).11 The aryl radical adds to 2-aminomaleimide to give intermediate B,
which on subsequent air oxidation gives 3-arylated-2-aminomaleimide 9.
Scheme 2: Proposed pathway of arylation of substituted 2-aminomaleimide
The involvement of free radicals has been confirmed by reaction of 2-aminomaleimide (1.0
mmol) and phenylhydrazine hydrochlodide (1.2 mmol) in presence of TEMPO (2.0 mmol) under
identical condition. We did not observe any reaction in presence of TEMPO.
Conclusion
In conclusion, we have reported a novel metal free methodology for thioarylation,
selenoarylation and arylation of substituted 2-aminomaleimides by K2CO3 mediated aerobic
oxidation in DMSO at room temperature. A variety of maleimide derivatives have been
synthesized in good yields using mild reaction conditions.
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EXPERIMENTAL
All the chemicals were commercial and purchased from Sigma-Aldrich or Merck and used as
received. Thin layer chromatography (GF-254) was used to monitor reaction progress. Melting
points were measured on Buchi M-560 melting point apparatus and are uncorrected. IR (neat)
spectra were recorded on a SHIMADZU FTIR spectrophotometer and the values are expressed
1
13
as ν max cm−1. The H NMR and C NMR spectra were recorded on Jeol JNM ECX-400P at
400 and 100 MHz respectively, using TMS as an internal standard. The chemical shift values are
recorded on δ scale and the coupling constants (J) are in Hz. Mass spectral data were recorded on
Agilent 6200 Q-TOf (ESI-HRMS) mass spectrometer.
General procedure for the thioarylation of 2-aminomaleimides (3a-3k)
A mixture of substituted 2-aminomaleimides (1) (1.0 mmol), thiophenol (2) (2.0 mmol) and
K2CO3 (4 equiv.) in 2 mL of DMSO was placed in a 50 mL round bottomed flask mounted over
a magnetic stirrer. The contents were stirred magnetically at room temperature and the progress
of the reaction was monitored by TLC (eluent: ethyl acetate:petroleum ether, 20:80, v/v). After
completion of the reaction (Table 2), the reaction was quenched by adding 20 mL of cold water.
The reaction mixture was extracted with DCM (3x10 mL) and the combined extract was dried
over anhyd. Na2SO4. The solvent was removed on a rotavapour and the crude product was
purified by flash column chromatography on silica gel (230-400 mesh) with petroleum
ether:ethyl acetate (95:5, v/v) as eluent to afford the pure products (3a-3j). The reaction of 2-
marcaptoethanol was carried out in presence of 2-3 crystals of iodine under otherwise identical
1
13
conditions and gave the product 3k. All the products were characterized by IR, H NMR, C
NMR and HRMS analysis.
General procedure for the selenoarylation of 2-aminomaleimides (5a-5b)
A mixture of substituted 2-aminomaleimides (1) (1.0 mmol), diarylselenides (4) (1.2 mmol) and
K2CO3 (4 equiv.) in 2 mL of DMSO was placed in a 50 mL round bottomed flask mounted over
a magnetic stirrer. The contents were stirred magnetically at room temperature and the progress
of the reaction was monitored by TLC (eluent: ethyl acetate:petroleum ether, 20:80, v/v). After
completion of the reaction (Table 3), reaction was quenched by addition of 20 mL of cold water.
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The reaction mixture was extracted with DCM (3x10 mL) and the combined extract was dried
over anhyd. Na2SO4. The solvent was removed on a rotavapour and the crude product was
purified by flash column chromatography on silica gel (230-400 mesh) with petroleum
ether:ethyl acetate (95:5, v/v) as eluent to afford the pure products (5). All the products were
characterized by IR, 1H NMR, 13C NMR and HRMS analysis.
General procedure for the arylation of 2-aminomaleimides (9a-9f)
A mixture of substituted 2-aminomaleimides (1) (1.0 mmol), arylhydrazine hydrochloride (8)
(1.2 mmol) and K2CO3 (4 equiv.) in 2 mL of DMSO was placed in a 50 mL round bottomed
flask mounted over a magnetic stirrer. The reactants were stirred magnetically at room
temperature and the progress of the reaction was monitored by TLC (eluent: ethyl
acetate:petroleum ether, 20:80, v/v). After completion of the reaction (Table 4), reaction was
quenched by adding 20 mL of cold water. The reaction mixture was extracted with DCM (3x10
mL) and the combined extract was dried over anhyd. Na2SO4. The solvent was removed on a
rotavapour and the crude product was purified by flash column chromatography on silica gel
(230-400 mesh) using petroleum ether:ethyl acetate (95:5, v/v) as eluent to afford the pure
1
products (9). All the products were characterized by IR, H NMR, 13C NMR and HRMS
analysis.
Spectral data
4-((4-Chlorophenyl)thio)-1-methyl-3-(methylamino)-1H-pyrrole-2,5-dione (3a)
1
Yellow solid; m.p.: 190-192 °C; IR (νmax cm−1)(Neat): 3294, 1703, 1445, 1382, 1084, 984; H
NMR (400 MHz, CDCl3): δ 7.23 (d, J = 8.7 Hz, 2H, ArH), 7.15 (d, J = 8.7 Hz, 2H, ArH), 5.93
(s, 1H, NH), 3.32 (d, J = 5.5 Hz, 3H, NHCH3), 3.06 (s, 3H, NCH3); 13C NMR (100 MHz,
CDCl3): δ 171.37, 165.83, 150.66, 138.38, 129.01, 126.19, 125.56, 30.41, 24.33; HRMS (ESI)
calcd. for C12H11ClN2O2S [M + H]+: 283.0308; Found: [M + H]+: 283.0303 and [M + H + 2]+:
285.0277.
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1-Methyl-3-(methylamino)-4-(phenylthio)-1H-pyrrole-2,5-dione (3b)
Yellow solid; m.p.: 161-163 °C; IR (νmax cm−1)(Neat): 3300, 1703, 1614, 1445, 1383, 988, 743;
1H NMR (400 MHz, CDCl3): δ 7.28-7.06 (m, 5H, ArH), 6.01 (s, 1H, NH), 3.29 (s, 3H, NHCH3),
3.04 (s, 3H, NCH3); 13C NMR (100 MHz, DMDO-d6): δ 171.56, 165.72, 152.60, 139.23, 130.18,
129.51, 127.34, 30.29, 24.54; HRMS (ESI) calcd. for C12H12N2O2S [M + H]+: 249.0698; Found:
[M + H]+: 249.0709.
1-Methyl-3-(methylamino)-4-(4-tolylthio)-1H-pyrrole-2,5-dione (3c)
1
Yellow solid; m.p.: 180-182 °C; IR (νmax cm−1)(Neat): 3238, 1736, 1649, 1240, 1008, 781; H-
NMR (400 MHz, CDCl3): δ 7.11 (d, J = 7.8 Hz, 2H, ArH), 7.04 (d, J = 8.2 Hz, 2H, ArH), 5.93
13
(s, 1H, NH), 3.30 (d, J = 5.5 Hz, 3H, NHCH3), 3.01 (s, 3H, NCH3), 2.26 (s, 3H, ArCH3); C
NMR (100 MHz, CDCl3): δ 171.33, 166.10, 150.30, 135.68, 129.82, 126.88, 30.50, 24.29, 20.88;
HRMS (ESI) calcd. for C13H14N2O2S [M + H]+: 263.0854; Found: [M + H]+: 263.0849.
1-Methyl-3-(methylamino)-4-(naphthalen-2-yl)thio)-1H-pyrrole-2,5-dione (3d)
1
Yellow solid; m.p.: 216-218 °C; IR (νmax cm−1)(Neat): 3321, 1697, 1620, 1437, 984, 678; H
NMR (400 MHz, CDCl3): δ 7.77-7.69 (m, 3H, ArH), 7.58 (s, 1H, ArH), 7.50-7.31 (m, 3H,
ArH), 5.98 (s, 1H, NH), 3.33 (d, J = 5.5 Hz, 3H, NHCH3), 3.08 (s, 3H, NCH3); 13C NMR (100
MHz, CDCl3): δ 171.51, 166.16, 150.90, 133.92, 131.75, 128.89, 127.85, 127.09, 126.73,
125.64, 124.88, 124.23, 30.62, 24.56; HRMS (ESI) calcd. for C16H14N2O2S [M + H]+: 299.0854;
Found: [M + H]+: 299.0872.
4-((3-Methoxyphenyl)thio)-1-methyl-3-(methylamino)-1H-pyrrole-2,5-dione (3e)
1
Yellow solid; m.p.: 141-143 °C; IR (νmax cm−1)(Neat): 3316, 1622. 1582, 1246, 1096, 750; H
NMR (400 MHz, CDCl3): δ 7.13 (t, J = 8.0 Hz, 1H, ArH), 6.77-6.68 (m, 2H, ArH), 6.63 (dd, J =
8.2, 2.3 Hz, 1H, ArH), 6.20 (bs, 1H, NH), 3.73 (s, 3H, OCH3), 3.25 (d, J = 5.6 Hz, 3H,
13
NHCH3), 3.01 (s, 3H, NCH3); C NMR (100 MHz, CDCl3): δ 171.60, 166.06, 160.15, 151.03,
140.17, 130.02, 118.46, 112.09, 110.86, 55.35, 30.54, 24.46; HRMS (ESI) calcd. for
C13H14N2O3S [M + H]+: 279.0803; Found: [M + H]+: 279.0803.
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4-((4-Bromophenyl)thio)-1-methyl-3-(methylamino)-1H-pyrrole-2,5-dione (3f)
1
Yellow solid; m.p.: 186-188 °C; IR (νmax cm−1)(Neat): 3296, 1701, 1612, 1383, 986; H NMR
(400 MHz, CDCl3): δ 7.37 (d, J = 8.7 Hz, 2H, ArH), 7.08 (d, J = 8.7 Hz, 2H, ArH), 5.98 (s, 1H,
13
NH), 3.31 (d, J = 5.5 Hz, 3H, NHCH3), 3.06 (s, 3H, NCH3); C NMR (100 MHz, CDCl3): δ
171.12, 165.81, 132.09, 127.93, 119.42, 30.50, 24.44; HRMS (ESI) calcd. for C12H11BrN2O2S
[M + H]+: 326.9803; Found: [M + H]+: 326.9809 and [M + H + 2]+: 328.9789.
1-Benzyl-3-(benzylamino)-4-(phenylthio)-1H-pyrrole-2,5-dione (3g)
1
Yellow solid; m.p.: 133-134 °C; IR (νmax cm−1)(Neat): 3316, 1707, 1622, 1431, 1074, 691; H
NMR (400 MHz, CDCl3): δ 7.40-7.11 (m, 15H, ArH), 6.06 (s, 1H, NH), 4.90 (d, J = 6.0 Hz, 2H,
13
NHCH2Ar), 4.70 (s, 2H, NCH2Ar); C NMR (100 MHz, CDCl3): δ 170.84, 165.81, 149.24,
136.34, 129.22, 129.07, 128.76, 128.66, 128.34, 127.96, 126.70, 125.92, 47.43, 42.25; HRMS
(ESI) calcd. for C24H20N2O2S [M + H]+: 401.1324; Found: [M + H]+: 401.1322.
1-Benzyl-3-(benzylamino)-4-((4-chlorophenyl)thio)-1H-pyrrole-2,5-dione (3h)
1
Yellow solid; m.p.: 125-126 °C; IR (νmax cm−1)(Neat): 3302, 1707, 1625,1059, 692; H NMR
(400 MHz, CDCl3): δ 7.39-7.23 (m, 8H, ArH), 7.22-7.11 (m, 4H, ArH), 7.06 (d, J = 8.2 Hz, 2H,
ArH), 6.25-6.07 (m, 1H, ArH), 4.92 (d, J = 6.0 Hz, 2H, NHCH2Ar), 4.69 (s, 2H, NCH2Ar); 13C
NMR (100 MHz, CDCl3): δ 170.71, 165.67, 149.30, 136.36, 136.25, 131.88, 129.27, 129.10,
128.79, 128.66, 128.35, 128.09, 128.00, 127.79, 47.40, 42.30; HRMS (ESI) calcd. for
C24H19ClN2O2S [M + H]+: 435.0934; Found: [M + H]+: 435.1021.
1-Phenyl-3-(phenylamino)-4-(phenylthio)-1H-pyrrole-2,5-dione (3i)
1
Yellow solid; m.p.: 130-132 °C; IR (νmax cm−1)(Neat): 3321, 1697, 1628, 1439, 1385, 1065; H
NMR (400 MHz, CDCl3): δ 7.57 (s, 1H, NH), 7.47 (m, 4H, ArH), 7.38-7.33 (m, 1H, ArH), 7.25-
7.16 (m, 3H, ArH), 7.10-7.02 (m, 5H, ArH), 6.94-6.90 (m, 2H, ArH); 13C NMR (100 MHz,
CDCl3): δ 169.75, 165.96, 143.05, 135.05, 135.01, 131.83, 129.14, 128.83, 128.42, 127.78,
126.39, 126.09, 125.77, 124.16, 92.32; HRMS (ESI) calcd. for C22H16N2O2S [M + H]+:
373.1011; Found: [M + H]+: 373.0981.
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3-(Phenylthio)-1-(4-tolyl)-4-(4-tolylamino)-1H-pyrrole-2,5-dione (3j)
1
Yellow solid; m.p.: 162-164 °C; IR (νmax cm−1)(Neat): 3030, 1705, 1618, 1491, 1389, 1088; H
NMR (400 MHz, CDCl3): δ 9.27 (s, 1H, NH), 7.44-7.37 (m, 3H, ArH), 7.26-7.18 (m, 2H, ArH),
7.17-7.02 (m, 4H, ArH), 7.00-6.92 (m, 2H, ArH), 6.79 (m, 1H, ArH), 2.26 (s, 3H, ArCH3), 2.24
(s, 3H, ArCH3); 13C NMR (100 MHz, CDCl3): δ 170.17, 166.13, 157.55, 143.98, 137.63, 136.68,
134.09, 132.64, 130.31, 129.44, 128.74, 127.51, 127.09, 125.74, 125.47, 123.48, 121.54, 121.10,
117.29, 20.02, 19.73; HRMS (ESI) calcd. for C24H21N2O2S [M + H]+: 401.1324; Found: [M +
H]+: 401.1327.
1-(4-chlorophenyl)-3-((4-chlorophenyl)amino)-4-((2-hydroxyethyl)thio)-1H-pyrrole-2,5-
dione (3k)
1
Yellow solid; m.p.: 125-126 °C; IR (νmax cm−1)(Neat): 3289, 1707, 1628, 1489, 1383, 826; H
NMR (400 MHz, CDCl3): δ 7.44 (s, 1H, NH), 7.39-7.28 (m, 6H, ArH), 7.21-7.15 (m, 2H, ArH),
3.56 (t, J = 5.5 Hz, 2H, CH2CH2OH), 2.63-2.57 (t, J = 5.4 Hz, 2H, SCH2CH2), 1.96 (s, 1H,
CH2OH); 13C NMR (100 MHz, CDCl3): δ 170.06, 165.26, 143.78, 134.05, 133.49, 132.40,
129.95, 129.27, 128.91, 126.68, 125.58, 60.57, 38.66; HRMS (ESI) calcd. for C18H14Cl2N2O3S
[M + H]+: 409.0180; Found: [M + H]+: 409.0193 and [M + H + 2]+: 411.0166.
1-Methyl-3-(methylamino)-4-(phenylseleno)-1H-pyrrole-2,5-dione (5a)
1
Yellow solid; m.p.: 141-142 °C; IR (νmax cm−1)(Neat): 3304, 1701, 1614, 1444, 984; H NMR
(400 MHz, CDCl3): δ 7.34 (d, J = 8.2 Hz, 2H, ArH), 7.27-7.13 (m, 3H, ArH), 5.87 (bs, 1H,
13
NH), 3.31 (d, J = 5.5 Hz, 3H, NHCH3), 3.04 (s, 3H, NCH3); C NMR (100 MHz, CDCl3): δ
171.79, 166.93, 150.91, 129.50, 129.43, 126.57, 30.65, 24.59; HRMS (ESI) calcd. for
C12H12N2O2Se [M + H]+: 297.0142; Found: [M + H]+: 297.0149.
1-Methyl-3-(methylamino)-4-(4-tolylseleno)-1H-pyrrole-2,5-dione (5b)
1
Yellow solid; m.p.: 152-154 °C; IR (νmax cm−1)(Neat): 3312, 1767, 1703, 1618, 983; H NMR
(400 MHz, CDCl3): δ 7.27 (d, J = 8.1 Hz, 2H, ArH), 7.03 (d, J = 8.0 Hz, 2H, ArH), 5.86 (s, 1H,
13
NH), 3.32 (d, J = 5.6 Hz, 3H, NHCH3), 3.02 (s, 3H, NCH3), 2.27 (s, 3H, ArCH3); C NMR
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(100 MHz, CDCl3): δ 171.84, 166.73, 150.37, 136.66, 130.21, 130.13, 30.70, 24.54, 21.09;
HRMS (ESI) calcd. for C13H14N2O2Se [M + H]+: 311.0299; Found: [M + H]+: 311.0306.
1-Methyl-3-(methylamino)-4-phenyl-1H-pyrrole-2,5-dione (9a)
1
Yellow solid; m.p.: 145-146 °C; IR (νmax cm−1)(Neat): 3352, 1697, 1634, 1445, 982, 654; H
NMR (400 MHz, CDCl3): δ 7.39-7.19 (m, 5H, ArH), 5.38 (s, 1H, NH), 2.99 (s, 3H, NCH3), 2.75
13
(d, J = 5.5 Hz, 3H, NHCH3); C NMR (100 MHz, CDCl3): δ 172.39, 167.87, 143.01, 130.46,
129.90, 127.79, 127.19, 99.41, 31.68, 23.79; HRMS (ESI) calcd. for C12H12N2O2 [M + H]+:
217.0977; Found: [M + H]+: 217.0982.
4-(4-Chlorophenyl)-1-methyl-3-(methylamino)-1H-pyrrole-2,5-dione (9b)
Yellow solid; m.p.: 144-146 °C; IR (νmax cm−1)(Neat): 3360, 1699, 1636, 1447, 1084, 980, 833;
1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 8.7 Hz, 2H, ArH), 7.25 (d, J = 8.2 Hz, 2H, ArH),
5.49 (s, 1H, NH), 3.02 (s, 3H, NCH3), 2.79 (d, J = 5.5 Hz, 3H, NHCH3); 13C NMR (100 MHz,
CDCl3): δ 172.34, 167.72, 143.37, 133.27, 131.82, 128.19, 98.17, 31.90, 23.98; HRMS (ESI)
calcd. for C12H11N2O2Cl [M + H]+: 251.0587; Found: [M + H]+: 251.0594 and [M + H + 2]+:
253.0568.
1-Methyl-3-(methylamino)-4-(4-tolyl)-1H-pyrrole-2,5-dione (9c)
1
Yellow solid; m.p.: 152-153 °C; IR (νmax cm−1)(Neat): 3364, 1697, 1633, 1447, 980, 750; H
NMR (400 MHz, CDCl3): δ 7.21 (m, 4H, ArH), 5.39 (d, J = 3.2 Hz, 1H, NHCH3), 3.05 (s, 3H,
NCH3), 2.81 (d, J = 5.5 Hz, 3H, NHCH3), 2.37 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCl3): δ
172.57, 168.01, 142.80, 137.01, 130.34, 128.55, 126.85, 99.54, 31.62, 23.78, 21.21; HRMS
(ESI) calcd. for C13H14N2O2 [M + H]+: 231.1134; Found: [M + H]+: 231.1823.
4-(4-Bromophenyl)-1-methyl-3-(methylamino)-1H-pyrrole-2,5-dione (9d)
Yellow solid; m.p.: 151-152 °C; IR (νmax cm−1)(Neat): 3362, 1695, 1636, 1449, 986, 831, 501;
1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.2 Hz, 2H, ArH), 7.23 (d, J = 8.2 Hz, 2H, ArH),
13
5.49 (s, 1H, NH), 3.06 (s, 3H NCH3), 2.84 (d, J = 5.5 Hz, 3H, NHCH3); C NMR (100 MHz,
CDCl3): δ 172.20, 167.70, 143.28, 132.12, 131.16, 129.00, 98.30, 121.48, 31.94, 24.01; HRMS
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(ESI) calcd. for C12H11N2O2Br [M + H]+: 295.0082; Found: [M + H]+: 295.0088 and [M + H +
2]+: 297.0069.
4-(4-Methoxyphenyl)-1-methyl-3-(methylamino)-1H-pyrrole-2,5-dione (9e)
1
Yellow solid; m.p.: 138-140 °C; IR (νmax cm−1)(Neat): 3360, 1703, 1656, 1451, 987; H NMR
(400 MHz, CDCl3): δ 7.23 (d, J = 8.7 Hz, 2H, ArH), 6.90 (d, J = 8.7 Hz, 2H, ArH), 5.30 (d, J =
3.7 Hz, 1H, NH), 3.81 (s, 3H, ArOCH3), 3.01 (s, 3H, NCH3), 2.79 (d, J = 5.5 Hz, 3H, NHCH3);
13C NMR (100 MHz, CDCl3): δ 172.88, 168.20, 158.97, 142.76, 131.76, 122.21, 113.51, 99.49,
55.36, 31.68, 23.91; HRMS (ESI) calcd. for C13H14N2O3 [M + H]+: 247.1083; Found: [M + H]+:
247.1080.
4-(1-Methyl-4-(methylamino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)benzonitrile (9f)
Yellow solid; m.p.: 184-186 °C; IR (νmax cm−1)(Neat): 3325, 2222, 1705, 1655, 1441, 982, 847;
1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.2 Hz, 2H, ArH), 7.43 (d, J = 8.2 Hz, 2H, ArH),
5.64 (s, 1H, NH), 3.04 (s, 3H, NCH3), 2.83 (d, J = 5.5 Hz, 3H, NHCH3); 13C NMR (100 MHz,
CDCl3): δ 171.62, 167.19, 144.05, 135.17, 131.69, 130.89, 118.85, 110.55, 97.60, 32.33, 24.16;
HRMS (ESI) calcd. for C13H11N3O2 [M + H]+: 242.0930; Found: [M + H]+: 242.0927.
Conflicts of interest
“There are no conflicts to declare”.
Acknowledgements
MS thanks CSIR, New Delhi, India for the grant of a SPM Fellowship. The authors also
acknowledge University of Delhi, Delhi, India for providing a Research grant and a DU-DST
Purse grant.
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Highlights
•
•
Transition metal free thioarylation, selenoarylation and arylation of 2-aminomaleimide
has been reported.
We develop a novel K2CO3/DMSO reagent for thioarylation, selenoarylation for different
substrates.
•
•
•
This methodology is provides general, green and efficient methods for thioarylation.
A novel method for synthesis of polyfunctionalized maleimides.
thioarylation, selenoarylation and arylation of 2-aminomaleimide has been reported at
room temperature in high yields.