Simple, rapid, and clean condensation of sulfonamide and maleic anhydride derivatives: Synthesis of novel 1H- Pyrrole-2,5-diones under heterogeneous conditions

Article abstract of DOI:10.1080/10426507.2016.1193504

H₆P₂W₁₈O₆₂is used as an efficient catalyst for the synthesis of novel N-substituted sulfonyl maleimides (1H-Pyrrole-2,5-diones) via the condensation of sulfonamide and maleic anhydride derivatives. The Dawson heteropolyacid was used with a catalytic amount of 2?mmol% in acetonitrile at reflux. The reuse of H₆P₂W₁₈O₆₂as heterogeneous catalyst several times without decrease in their activity, short reaction times, easy isolation of desired products with good to excellent yields shows the advantages of this novel methodology.

Full text of DOI:10.1080/10426507.2016.1193504

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Simple, rapid and clean condensation of
sulfonamide and maleic anhydride derivatives:
Synthesis of novel 1H- Pyrrole-2,5-diones under
heterogeneous conditions
Chafika Bougheloum, Samia Guezane Lakoud, Robila Belghiche & Abdelrani
Messalhi
To cite this article: Chafika Bougheloum, Samia Guezane Lakoud, Robila Belghiche
&
Abdelrani Messalhi (2016): Simple, rapid and clean condensation of sulfonamide
and maleic anhydride derivatives: Synthesis of novel 1H- Pyrrole-2,5-diones under
heterogeneous conditions, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2016.1193504
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1193504
Accepted author version posted online: 31
May 2016.
Published online: 31 May 2016.
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Date: 22 June 2016, At: 21:41

ACCEPTED MANUSCRIPT
Simple, rapid and clean condensation of sulfonamide and maleic anhydride derivatives:
Synthesis of novel 1H- Pyrrole-2,5-diones under heterogeneous conditions
1
2
3
Chafika BOUGHELOUM , Samia GUEZANE LAKOUD , Robila BELGHICHE , Abdelrani
1
MESSALHI
1
Laboratoire des Systèmes et Matériaux Avancés, Badji Mokhtar Annaba-University, B.P 12,
2
3000 Annaba, Algeria.
2
Eco-compatible Asymmetric Catalysis Laboratory (LCAE), Badji Mokhtar Annaba-University,
B.P 12, 23000 Annaba, Algeria.
3
Laboratoire de Chimie des Matériaux Inorganiques, Badji Mokhtar Annaba-University, B.P
1
2, 23000 Annaba, Algeria.
Address correspondence to Chafika BOUGHELOUM, Sciences Faculty, Chemistry Department,
Badji Mokhtar-Annaba University, BP 12 El Hadjar, 23000, Algeria.
E-mail: c_bougheloum@yahoo.fr
Abstract- H P W O is used as an efficient catalyst for the synthesis of novel N-
6
2
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substituted sulfonyl maleimides (1H-Pyrrole-2,5-diones) via the condensation of
sulfonamide and maleic anhydride derivatives. The Dawson heteropolyacid was used
with a catalytic amount of 2 mmol % in acetonitrile at reflux. The reuse of H P W O as
6
2
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heterogeneous catalyst several times without decrease their activity, short reaction times,
1
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easy isolation of desired products with good to excellent yields shows the advantages of
this novel methodology.
Keywords: Sulfonamide, maleimides (1H- Pyrrole-2,5-diones), Dawson
heteropolyacid, heterogeneous conditions, catalyst reuse.
2
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INTRODUCTION
Cyclic imides, such as succinimide, maleimide and phthalimide are known as one of the
important nitrogen heterocyclic rings. These compounds possess structural features, which
[
1-4]
confer potential biological activity and pharmaceutical use
. Their molecules contain an imide
ring and the general structure –CO–N(R)–CO–, so they are hydrophobic and neutral, and can
[
5]
therefore cross biological membranes .
Maleimide derivatives, in particular, exhibit a wide range of biological activities such as
[
6]
[7, 8]
[9]
[10]
[11]
antibacterial
, antifungal
, analgesic
, antistress agents
, antiprotozoal
,
[
12]
[13]
antiangiogenic , cytotoxic, DNA binding and apoptotic inducing activity , and as selective
[14-18]
inhibitors
.
[19]
[20]
Also a number of natural products such as polycitrin , camphorataimides , rebeccamycine
[
21]
and staurosporine
which contain maleimide as a part in their framework have been reported.
[21]
[22]
These compounds exhibit angiogenesis inhibition
, protein kinase inhibition
and
[
23]
antiproliferative
activities (Fig 1, I-III).
[
24]
[25]
The introduction of the sulfonyl group with some rings such as oxazolidinone , phthalimide
[
26]
and benzothiazole
could be very interesting due to their high biological activity. Sulfonamide
[
27-30]
[31]
analogs posses a wide range of bioactivities including antibacterial
, anti-inflammatory
,
[
32]
[33]
[34]
anti-hyperglycemic , antihypertensive , antiviral and antitumor
activities (Fig 1, IV and
V).
Recently, a series of maleimide analogs bearing benzenesulfonamide were synthesized and
evaluated for anti-inflammatory activity using carrageenan induced rat paw edema model and
[
35]
COX-2 potency through in vitro cyclooxygenase assays (Fig 1, VI).
3
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In view of the high degree of bioactivity shown by maleimide and sulfonamide analogs, we have
focused on the design of novel structural entities that incorporate both of these structural and
functional moieties into a single molecular scaffold (Fig. 1, 3a-j and 4a-j)
Evaluation of the available methods for the synthesis of N-substituted cyclic imides indicates
that generally the amines are first reacted with the desired cyclic anhydride and the resulting
[
36]
amic acids are then cyclized to the corresponding imides using reagents such as Ac O/NaOAc,
2
[37]
[38]
Et N/Ac O,
dimethyl sulfate/Na CO /tetrabutylammonium bromide,
cyanuric
3
2
2
3
[39]
chloride/Et N,
3
[40]
[41-46]
[
Bmim]
among others.
[
37, 38]
However, some of these procedures lack generality and scalability
, use harsh reaction
conditions and hazardous , non-green reagents , involve tedious work-up and expensive
[39]
[42]
[
40]
reagents , give low yield and sometimes result in concomitant addition of HCl to the
[
45]
maleimide.
We now report our results to overcome these shortcomings and have examined the formation of
amic acids and their cyclization to the corresponding imides using an acidic solid as a catalyst in
a one-pot synthesis.
In last decade, there has been considerable interest in the use of solid acids as
heterogeneous catalysts in organic synthesis. Heterogeneous solid acids are more advantageous
than conventional homogeneous acid catalysts because they can be easily recovered from the
[
47]
reaction mixture by simple filtration and reused
.
Dawson heteropolyacid (HPA) is a common inorganic acid with mild acidity that is nonvolatile,
[
48-52]
noncorrosive, and utilized as a stable, highly efficient green catalyst in organic synthesis
.
4
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However, there are no reports of the use of Dawson heteropolyacid (HPA) as a catalyst for the
synthesis of maleimides.
Based on the previous studies on the use of heteropolyacids as catalysts, and in a continuation of
our endeavors for the development of simple and highly expedient methods for the synthesis of
[
53, 54]
novel molecules
, we examined herein the possibility of using Dawson type heteropolyacid
H P W O , as a catalyst for the synthesis of substituted N -sulfonyl-maleimide (3a–j and 4a-j)
6
2
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by the reaction of sulfonamides with maleic anhydride derivatives .
Results and discussion
The synthesis of N-substituted sulfonyl maleimide derivatives proceeded uneventfully
and is shown in Scheme 1. Briefly, chlorosulfonyl isocyanate was added dropwise to tert-butanol
kept in an ice bath and the resulting mixture was stirred with an appropriate primary or
[
55]
secondary amine in the presence of triethylamine , yielding compounds (1a–j). Removal of
[
56]
the Boc group transformed compounds (1a-j) into deprotected sulfonamides (2a-j)
.
Condensation of sulfonamides with maleic anhydride derivatives gave N-substituted-sulfonyl-
maleimides (3a–j and 4a-j).
The reaction of benzyl sulfonamide (2f) and maleic anhydride in the presence of
H P W O as catalyst was chosen as a model to optimize the reaction conditions (Scheme 2)
6
2
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and the results are listed in Tables 1, 2 and 3.
No product was detected in the absence of the catalyst. It was surprising to discover that 0.5
mmol% of H P W O could accelerate the reaction, but the reaction afforded the corresponding
6
2
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product in a low conversion. Further study showed that the use of 2 mmol% of H P W O was
6
2
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5
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sufficient to provide a satisfactory conversion in 60 min. An increase in the amount of catalyst
did not produce a better result (Table 1).
The reaction was carried out in different solvents such as CH Cl , CHCl , THF, toluene and
2
2
3
CH CN.
3
Preliminary experiments on model reaction in CH Cl , CHCl , and THF showed that the desired
2
2
3
N-benzylsulfonamide maleimide (3f) was actually formed but with lower conversions; when
toluene was used as solvent a good conversion was found and the best result was obtained when
the reaction was carried at reflux in acetonitile as solvent (Table 2).
The efficacy of Dawson heteropolyacid H P W O was compared against other catalysts such
6
2
18 62
as Montmorrillonite clay K10, H SO , Keggin heteropolyacids (H PW O , H PMo O ) and
2
4
3
12 40
3
12 40
Dawson heteropolyacids (H P W O , H P W Mo O ) on the reaction of benzylsulfonamide
6
2
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6
2
12
6
62
(2f) with maleic anhydride at refluxing acetonitrile (Table 3).
The results show that the reaction in the presence of H P W O and H P W Mo O (2 mmol
6
2
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6
2
12
6
62
%
) furnished the expected N-benzylsulfonyl maleimide (3f) in good to high conversions (85–
0%) in 60 min. The reactions in the presence of other catalysts required longer reaction time
60–90 min) and led to the product in lower conversions (20–50%). Notably, no product was
9
(
observed when the reaction was carried out in the absence of catalyst after 2 h. Therefore,
H P W O was chosen for further study.
6
2
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We also investigate the reusability of the catalyst. For this purpose after completion of the model
reaction in refluxing acetonitrile, the solvent was evaporated and dichloromethane (5 mL) was
added to the residue.
6
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The catalyst could be separated by a simple filtration, washed with dichloromethane and dried at
4
5 °C. The recovered H P W O catalyzed the same reaction without significant decrease in the
6 2 18 62
catalytic activity even after the five runs (Table S 1 Supplemental Materials).
To show the general applicability of the method, the reaction of various sulfonamides and maleic
anhydride derivatives (maleic and dichloromaleic anhydrides) in the presence of 2 mmol% of
H P W O at reflux in acetonitile was investigated and the results are summarized in Table 4.
6
2
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All the mentioned reactions delivered good product yields and accommodated a wide range of
sulfonamides bearing both primary and secondary amines derivatives.
EXPERIMENTAL
All the chemicals were commercially available and used as received.
[
57]
H P W O was prepared according to the literature. Melting points were determined
6
2
18 62
in open capillary tubes on Buchi B-540. Proton nuclear magnetic resonance was determined with
a 400 MHz Bruker spectrometer using CDCl and CD OD as solvent and TMS as an internal
3
3
standard. Chemical shifts are reported in δ units (ppm). All coupling constants J are reported in
Hertz. Multiplicity is indicated as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet)
and combination of these signals. The mass spectra were recorded on a DSQ Thermoelectron
apparatus (70 eV) by chemical ionization (gaseous ammonia) by direct introduction. Elemental
analysis was performed with a Perkin-Elmer 2400 C, H, N analyser and determined values were
within the acceptable limits of the calculated values. The Supplemental Materials contains
1
13
sample characterization data ( H, C NMR and MS) for products 3 and 4 (Figures S 1 – S 25
General procedure for the Synthesis of N-sulfonyl maleimides (3 a-j and 4a-j):
7
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Under nitrogen atmosphere, a mixture of sulfonamide 2a-h (1 mmol), maleic anhydride
derivatives (2 mmol) and H P W O catalyst (2 mmol %) in acetonitrile (2 mL), was stirred at
6
2
18 62
reflux. Reaction was monitored by TLC. After achieving the reaction, dichloromethane (2 x 10
mL) was added and the catalyst was filtered; water (10 ml) was then added. The organic layers
were combined and dried over anhydrous
sodium sulfate and removed under reduced pressure. The residue obtained was purified by flash
chromatography (Merck silica gel 60 H, CH Cl /MeOH, 9:1) to afford the corresponding
2
2
sulfonyl maleimide derivatives.
N-(propyl)-2,5-dioxopyrrole-1-sulfonamide (3a)
Yield: 81%, mp 142°C, R = 0.75 (CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 0.99 (t, 3H,
1
f
2
2
3
J=5.02Hz, CH ),1.65 (m, 2H, CH ), 2.67 (m, 2H, CH ), 5.31 (t, J=5.4Hz, 1H, NH), 6.96 (s, 2H,
3
2
2
1
3
+
CH= CH). C NMR (CDCl , δ ppm): 11.2, 22.2, 42.7, 136.2, 166.4 MS(ESI 70em/s):
3
+
+
5
8.12(25%), 219.13 ([M+1] , 15 %), 236([M+NH ] ,100%).
4
Elemental anal. (%), calculated for C H N SO : C, 38.53; H, 4.59; N, 12.84; found: C, 38.57;
7
10
2
4
H, 4.62; N, 12.79.
N-(Bromo-propyl)-2,5-dioxopyrrole-1-sulfonamide (3b)
1
Yield: 80%, mp 142°C, R = 0.72 (CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 2.10 (m, 2H,
f
2
2
3
CH ), 3.26 (m, 2H, CH ), 3.38 (m, 2H, CH ), 5.25 (t, 1H, J=5.4Hz, NH), 6.94 (s, 2H, CH= CH).
2
2
2
1
3
+
+
C NMR (CDCl , δ ppm): 30.7, 31.7, 38.4, 135.7, 166.4 MS(ESI 70em/s): 298.17 ([M+1] , 15
3
+
%
), 315.14([M+NH ] ,100%).
4
8
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Elemental anal. (%), calculated for C H N SO Br: C, 28.28; H, 3.03; N, 9.42; found: C, 28.36;
7
9
2
4
H, 3.01; N, 9.40.
N-(butyl)-2,5-dioxopyrrole-1-sulfonamide (3c)
Yield: 82%, mp 139°C, R = 0.76(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 0.91 (t, 3H,
1
f
2
2
3
J=5.02 Hz, CH ), 1.37 ( m, 2H, CH ), 1.54 (m, 2H, CH ), 3.11 (m, 2H, CH -N), 6.87 (s, 2H,
3
2
2
2
1
3
+
CH= CH). C NMR (CDCl , δ ppm): 13.5, 19.8, 30.9, 43.5, 136.6, 175.3. MS (ESI 70 eV m/z):
3
+
7
2.18 (30%), 136(15%), 250.07 ([M+NH ] , 100%). Elemental anal. (%), calculated for
4
C H N SO : C, 41.38; H, 5.17; N, 12.06; found: C, 41.42; H, 5.14; N, 12.08.
8
12
2
4
N-(tert-butyl)-2.5-dioxopyrrole-1-sulfonamide (3d)
Yield: 85%, mp 134°C, R = 0.76(CH Cl /MeOH, 9/1), H NMR(CDCl δppm): 1.42(s, 9H,
1
f
2
2
3,
13
+
3
(CH ); 6.78(s, 2H, CH= CH). CNMR(CDCl δppm): 29.6; 37.2, 135.9, 169.4. Ms(ESI 70
3 3,
+
eVm/s): 233.09 ([M+1] , 100%). Elemental anal. (%), calculated for C H N SO : C, 41.38; H,
8
12
2
4
5
.17; N, 12.06; found: C, 41.35; H, 5.24; N, 12.01.
N-(phenyl)-2,5-dioxopyrrole-sulfonamide (3e):
Yield: 80%, mp 140 °C, R = 0.72(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 6.86(m, 3H,
1
f
2
2
3
1
3
Ar-H), 6.97(s, 2H, CH= CH), 7.22(m, 2H, Ar-H). C NMR (CDCl , δ ppm): 117.9; 121.1,
3
+
+
+
1
29.5, 136.2, 139.6, 172.8. MS (ESI 70 eV m/z): 275.2 ([M+Na] , 87 %), 291.2 ([M+K] , 12
+
%
), 527.3([2M+Na] , 25%).
Elemental anal. (%), calculated for C H N SO : C, 47.62; H, 3.17; N, 11.11; found: C, 47.65; H,
1
0
8
2
4
3
.24; N, 11. 20.
9
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N-benzyl-2.5-dioxopyrrole-1-sulfonamide (3f):
1
Yield: 83%, mp 138 °C, R = 0.75(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 4.24(d,
f
2
2
3
J=4.02 Hz, 2H, CH -Ph), 5.51(t, 1H, J=5.6Hz, H-N); 6.94(d, 2H, J=12.2Hz, CH=CH), 7.34(m,
2
1
3
+
5
7
H, H-Ar). C NMR (CDCl , δ ppm): 39.0, 122.4, 123.2, 124.4, 133.2, 136.2, 164.8. MS (ESI
3
+
0 eV m/z): 91.96 (100%), 105.99 (64%), 267.06 ([M+1] , 40%).
Elemental anal. (%), calculated for C H N SO : C, 49.62; H, 3.76; N, 10.53; found: C, 49.68;
1
1
10
2
4
H, 3.70; N, 10.58.
N-(3-fluorophenyl)-2,5-dioxopyrrole-1-sulfonamide (3g):
1
Yield: 81%, mp 148°C, R = 0.73(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 6.94(m, 1H,
f
2
2
3
13
H-Ar), 6.90(s, 2H, CH= CH), 7.26(m, 1H, H-Ar), 7.46(m, 1H, H-Ar), 7.66(m, 1H, H-Ar). C
+
NMR (CDCl , δ ppm): 105.6, 110.1, 114.6, 130.7, 136.2, 139.4, 167.5. MS (ESI 70 eV m/z):
3
+
+
1
11.04 (10%), 190.06 (6 %), 271,19([M+1] , 15%), 288.13 ([M+NH ] , 100%). Elemental anal.
4
(
%), calculated for C H N SO F : C, 44.44; H, 2.59; N, 10.37; found: C, 44.49; H, 2.62; N,
10 7 2 4
1
0.32.
1
-(3,4-dihydroisoquinolin-2(1H)-yl) sulfonyl) 1H-pyrrole-2.5-dione (3h):
1
Yield: 84%, mp 130 °C, R = 0.76(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 2.97(t, 2H,
f
2
2
3
J=5.8Hz, CH -ph), 3.77(t, 2H, J=5.7Hz, CH N), 4.64(s, 2H, CH N), 6.76 (s, 2H, CH= CH),
2
2
2
1
3
7
1
1
5
.15(m, 4H, Ar-H). C NMR (CDCl , δ ppm): 28.4, 44.4, 47.2, 126.3, 126.7, 127.2, 129.8,
3
+
+
+
31.4, 133.5, 136.2, 167.2. MS (ESI 70 eV m/z): 315.1([M+Na] , 70%), 607.1 ([2M+Na] ,
00%). Elemental anal. (%), calculated for C H N SO : C, 53.42; H, 4.11; N, 9.59; found: C,
1
3
12
2
4
3.47; H, 4.08; N, 9.57.
10
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1
-((4-phenylpiperazine-1yl)sulfonyl)1H-pyrrole-2,5-dione (3i):
1
Yield: 83 %, mp 143 °C, R = 0.71(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 3.27(t, 4H,
f
2
2
3
J=6.3Hz, CH -N), 3.59(t, 4H, J=6.4Hz, CH -N), 6.83 (s, 2H, CH= CH), 6.93(m, 3H, Ar-H),
2
2
1
3
7
1
3
5
.27(m, 2H, Ar-H). C NMR (CDCl , δ ppm): 46.4, 49.1, 117.1, 121.1, 129.4, 135.3, 150.6,
3
+
+
+
+
67.8. MS (ESI 70 eV m/z): 322.2([M+H] , 24%), 344.1([M+Na] , 89%), 665.1 ([2M+Na] ,
3%). Elemental anal. (%), calculated for C H N SO : C, 52.33; H, 4.67; N, 13.08; found: C,
1
4
15
3
4
2.30; H, 4.74; N, 13.05.
1
-tosyl- 1H-pyrrole-2,5-dione (3j)
1
Yield: 84%, mp 142°C, R = 0.74 (CH Cl /MeOH, 9/1), H NMR (CD OD, δ ppm): 2.46 (s, 3H,
f
2
2
3
1
3
CH ), 6.33 (s, 2H, CH= CH), 7.41(dd, 2H, J=8.6Hz, Ar-H), 7.91(dd, 2H, J=8.5Hz, Ar-H). C
3
+
NMR (CD OD, δ ppm): 24.2, 127.4, 129.5, 135.9, 136.5, 141.3, 166.4 MS(ESI 70em/s): 252.12
3
+
+
(
[M+1] , 15 %), 269.14([M+NH ] ,100%).
4
Elemental anal. (%), calculated for C H NSO : C, 52.59; H, 3.58; N, 5.57; found: C, 52.56; H,
1
1
9
4
3
.55; N, 5.61.
N-(propyl) - 3,4- dichloro -2,5-dioxopyrrole-1-sulfonamide (4a)
1
Yield: 83%, mp 146°C, R = 0.68 (CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 0.98 (t, 3H,
f
2
2
3
1
3
J=5.02Hz, CH ),1.62 (m, 2H, CH ), 3.06 (m, 2H, CH ), 4.28 (t, 1H, J=5.4Hz, NH).. C NMR
3
2
2
+
+
(
CDCl , δ ppm): 11.3, 22.1, 42.7, 136.2, 166.4 MS(ESI 70em/s): 165.04(45%), 288.11 ([M+1] ,
3
+
1
2
0 %), 305.15.([M+NH ] , 5%). Elemental anal. (%), calculated for C H N SO Cl : C, 29.26; H,
4
7
8
2
4
2
.78; N, 9.75; found: C, 29.97; H, 2.90; N, 9.69.
11
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N-(Bromo-propyl) - 3,4- dichloro -2,5-dioxopyrrole-1-sulfonamide (4b)
1
Yield: 78%, mp 146°C, R = 0.68(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 2.06 (m, 2H,
f
2
2
3
CH ), 3.20 (m, 2H, CH ), 3.44 (m, 2H, CH ), 5.25 (t, 1H, J=5.4Hz, NH), 6.96 (s, 2H, CH= CH).
2
2
2
1
3
+
+
C NMR (CDCl , δ ppm): 30.9, 31.8, 38.8, 137.2, 166.5 MS(ESI 70em/s): 367.13 ([M+1] , 15
3
+
%
), 384.12([M+NH ] ,100%).
4
Elemental anal. (%), calculated for C H N SO BrCl : C, 22.95; H, 1.91; N, 7.65; found: C,
7
7
2
4
2
2
2.92; H, 1.96; N, 7.61.
N-(butyl)- 3,4- dichloro- 2,5-dioxopyrrole-1-sulfonamide (4c)
1
Yield: 84%, mp 147°C, R = 0.72(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 0.96 (t, 3H,
f
2
2
3
J=5.02 Hz, CH ), 1.39( m, 2H, CH ), 1.56 (m, 2H, CH ), 3.11 (m, 2H, CH -N), 4.51(s, 1H,
3
2
2
2
1
3
+
NH). C NMR (CDCl , δ ppm): 13.7, 20.6, 31.1, 41.8, 137.5, 167.2. MS (ESI 70 eV m/z):
3
+
7
2.18 (30%), 136(15%), 302.18 ([M+1] , 46%).
Elemental anal. (%), calculated for C H N SO Cl : C, 31.90; H, 3.32; N, 9.30; found: C, 31.82;
8
10
2
4
2
H, 3.24; N, 9.38.
N-(tert-butyl)- 3,4- dichloro-2.5-dioxopyrrole-1-sulfonamide (4d)
1
Yield: 83%, mp 139C, R = 0.71(CH Cl /MeOH, 9/1), H NMR(CDCl δ ppm): 1.42(s, 9H,
f
2
2
3,
1
3
+
+
3
1
3
(CH ). CNMR(CDCl δ ppm): 29.5; 37.4, 137.3, 166.5. Ms(ESI 70 eVm/s): 302.09 ([M+1] ,
3 3,
00%). Elemental anal. (%), calculated for C H N SO Cl : C, 31.90; H, 3.32; N, 9.30; found: C,
8
10
2
4
2
1.95; H, 3.34; N, 9.26.
N-(phenyl)- 3,4- dichloro-2,5-dioxopyrrole-sulfonamide (4e)
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1
Yield: 81%, mp 143 °C, R = 0.70(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 6.88(m, 3H,
f
2
2
3
1
3
Ar-H), 7.25(m, 2H, Ar-H). C NMR (CDCl , δ ppm): 117.8; 121.3, 129.4, 137.4, 139.4, 173.8.
3
+
+
+
+
MS (ESI 70 eV m/z): 322.2([M+H] , 24%), 344.1([M+Na] , 89%), 665.1 ([2M+Na] , 33%).
Elemental anal. (%), calculated for C H N SO Cl : C, 37.38; H, 1.87; N, 8.72; found: C, 37.42;
1
0
6
2
4
2
H, 1.90; N, 8.69.
N-benzyl-3,4- dichloro -2.5-dioxopyrrole-1-sulfonamide (4f)
1
Yield: 80%, mp 141 °C, R = 0.71(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 4.33(d, 2H,
f
2
2
3
1
3
J=4.02 Hz, CH -Ph), 6.15(t, 1H, J=5.7Hz, H-N); 7.34(m, 5H, H-Ar). C NMR (CDCl , δ ppm):
2
3
+
3
9.2, 122.2, 123.1, 124.5, 133.4, 137.5, 166.2. MS (ESI 70 eV m/z): 105.98 (8%), 353.18
+
(
[M+NH ] , 100%).
4
Elemental anal. (%), calculated for C H N SO Cl : C, 39.40; H, 2.40; N, 8.36; found: C, 39.43;
1
1
8
2
4
2
H, 2.38; N, 8.39.
N-(3-fluorophenyl)- 3,4- dichloro-2,5-dioxopyrrole-1-sulfonamide (4g)
1
Yield: 79%, mp 152°C, R = 0.70(CH Cl /MeOH, 9/1), H NMR (CD OD, δ ppm): 6.86(m, 1H,
f
2
2
3
1
3
H-Ar), 7.05(m, 2H, H-Ar), 7.36(m, 1H, H-Ar). C NMR (CDCl , δ ppm): 105.7, 110.3, 114.4,
3
+
+
1
30.9, 137.7, 139.6, 169.5. MS (ESI 70 eV m/z): 111.04 (10%), 340,10([M+1] , 15%), 357.12
+
(
[M+NH ] , 100%). Elemental anal. (%), calculated for C H N SO FCl : C, 35.40; H, 1.47; N,
4
10
5
2
4
2
8
.26; found: C, 35.44; H, 1.50; N, 8.22.
3
,4-Dichloro-1-(3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-1H-pyrrole-2.5-dione (4h)
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1
Yield: 85%, mp 135 °C, R = 0.73(CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 2.99(t, 2H,
f
2
2
3
1
3
J=5.8Hz, CH -ph), 3.75(t, 2H, J=5.7Hz, CH N), 4.63(s, 2H, CH N), 7.20(m, 4H, Ar-H). C
2
2
2
NMR (CDCl , δ ppm): 28.8, 44.5, 47.6, 126.2, 126.4, 126.9, 128.8, 131.8, 133.3, 137.6, 167.9.
3
+
+
MS (ESI 70 eV m/z): 362.10([M+1] , 70%).
Elemental anal. (%), calculated for C H N SO Cl : C, 43.21; H, 2.77; N, 7.75; found: C, 43.18;
1
3
10
2
4
2
H, 2.75; N, 7.78.
3
,4- Dichloro 1-((4-phenylpiperazine-1yl)sulfonyl)1H-pyrrole-2,5-dione (4i)
1
Yield: 81 %, mp 140 °C, R = 0.68 (CH Cl /MeOH, 9/1), H NMR (CD OD, δ ppm): 3.17(s, 8H,
f
2
2
3
CH -N), 6.68(t, 1H, J=6.4Hz, Ar-H), 6.92(d, 1H, J=6.5Hz, Ar-H), 7.18(t, 2H, J=6.5Hz, Ar-H).
2
1
3
+
C NMR (CDCl , δ ppm): 46.1, 49.3, 117.1, 121.1, 129.4, 136.9, 150.5, 167.7. MS (ESI 70 eV
3
+
m/z): 391.2([M+H] , 24%). Elemental anal. (%), calculated for C H N SO Cl : C, 43.06; H,
1
4
13
3
4
2
3
.33; N, 10.77; found: C, 43.10; H, 3.34; N, 10.74.
3
,4- Dichloro-1-tosyl- 1H-pyrrole-2,5-dione (4j)
1
Yield: 82%, mp 142°C, R = 0.68 (CH Cl /MeOH, 9/1), H NMR (CDCl , δ ppm): 2.46 (s, 3H,
f
2
2
3
1
3
CH ), 7.35(dd, J=8.6Hz, 2H, Ar-H), 7.85(dd, J=8.7Hz, 2H, Ar-H). C NMR (CDCl , δ ppm):
3
3
+
+
2
3
4.3, 127.2, 129.6, 136.4, 137.5, 141.3, 167.1 MS(ESI 70em/s): 343.2([M+Na] , 100%),
+
+
59.1([M+K] , 38%), 663.4 ([2M+Na] , 20%). Elemental anal. (%), calculated for
C H NSO Cl : C, 41.25; H, 2.18; N, 4.37; found: C, 41.30; H, 2.22; N, 4.31.
11
7
4
2
Conclusion
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In summary, we describe a convenient and efficient protocol for the synthesis of N-sulfonyl
maleimides (N-sulfonyl-1H- Pyrrole-2,5-dione ) derivatives via condensation of sulfonamides
with maleic anhydride derivatives using H P W O as a green recyclable and heterogeneous
6
2
18 62
catalyst. The simple experiment procedure combined with ease of recovery and reuses of this
catalyst make this procedure quite simple, more convenient and environmentally benign.
Supporting information
Full experimental detail for the first two steps and selected supplemental data of new compounds
(3a-j) and (4a-j) can be found via the ‘‘Supplemental Materials’’ section of this article’s Web
page.
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Table 1. Effect of catalytic amount of H P W O on the synthesis of 3f (scheme 2)
6
2
18 62
a
b
Entry
H P W O (mmol %) Time (min) Conversion (%)
6
2
18 62
1
2
3
4
0
120
90
00
35
66
78
0.5
1
90
1.5
60
5
2
60
90
6
2.5
60
91
7
8
3
5
60
60
91
91
The bold values indicate the best results
a
Reaction conditions: Benzyl sulfonamide 2f (2 mmol) and Maleic anhydride (2 mmol) at reflux
in the presence of the indicated amount of catalyst and CH CN as solvent.
3
b
1
The conversion was determined by H NMR analysis of the crude product.
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Table 2. Effect of solvent on the synthesis of 3f (scheme 2)
Entry
Solvent
CH Cl
CHCl3
Time (min)
120
Conversion (%)
1
2
55
60
2
2
120
3
4
5
THF
90
60
60
65
78
90
Toluene
CH CN
3
Reaction conditions: Benzyl sulfonamide 2f (2 mmol), Maleic anhydride (2 mmol),
H P W O (2% mmol), in CH CN as solvent at reflux
6
2
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3
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Table 3. Effect of different catalysts on the synthesis of 3f (scheme 2)
Entry
Catalyst (2 % mmol)
Time (min)
Conversion (%)
1
2
3
4
5
6
7
None
K10
120
90
90
60
60
60
60
00
20
30
50
38
90
85
H SO
2
4
H PW O
3
12 40
H P Mo O
3
12 40
H P W O
18 62
6
2
H P W Mo O
62
6
2
12
6
Reaction conditions: Benzyl sulfonamide 2f (2 mmol) and Maleic anhydride (2 mmol)
in CH CN as solvent at reflux using various catalysts.
3
23
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Table 4. H P W O catalyzed synthesis of N-sulfonyl 1H-Pyrrole-2,5-dione derivatives (3a-j)
6
2
18 62
and (4a-j) in acetonitrile under refluxing conditions
c
Entry
R
Product
3a/4a
Yield(%)
1
2
3
81/83
80/78
82/84
Br
NH
3
b/4b
3
c/4c
d/4d
3
85/83
83/80
4
5
3e/4e
6
7
3f/4f
83/80
81/79
3g/4g
8
3h/4h
84/85
83/81
3
i/4i
9
d
1
0
3j/4j
84/82
c
isolated Yield after 1 hour of reaction
commercial substrate
d
24
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Figure 1. Biological activities of some maleimide derivatives and sulfonamide scaffold.
25
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O
O
O
O
O
O
t-BuOH
CH Cl , 0°C
O
Et N, CH Cl , 0°C
O
3
2
2
S
C
S
R
S
Cl
N
O
Cl
N
O
N
N
O
amines
2
2
H
H
R'
1a-j
O
H O
2
R1
R2
110°C
O
O
R1
O
N S
O
R
O
O
R =R = H, Cl
1 2
N
O
S
R
R2
NH2
R'
H P W 0 , Reflux
N
6
2
18 62
O
R'
3
a-j R =R =H
1 2
2a-j
4a-j
R =R =Cl
1
2
R
NH
N
NH
NH
=
Br
NH
NH
d)
NH
R'
(a)
(b)
(c)
(
(e)
(f)
F
NH
N
N
H C
3
N
(
j)
(
g)
(h)
(i)
Scheme 1. Synthesis of N-sulfonyl 1-H Pyrrole-2,5-dione (3a-j and 4a-j) in the presence of
H P W O .
6
2
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Scheme 2. Model reaction
27
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