An environmentally benign approach for the synthesis of bifunctional sulfonamide-amide compounds via isocyanide-based multicomponent reactions

Article abstract of DOI:10.1039/c0gc00442a

Three-component reaction of the zwitterion generated from dialkyl acetylenedicarboxylate and an alkyl or aryl isocyanide with an alkyl or aryl sulfonamide is described. The reaction afforded the corresponding special type of ketenimine sulfonamide derivatives in water without using any activation and modification. The products could be easily hydrolyzed to the corresponding sulfonamide-butanamide derivatives at 80 °C in good yields without using a catalyst. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00442a

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COMMUNICATION
An environmentally benign approach for the synthesis of bifunctional
sulfonamide-amide compounds via isocyanide-based multicomponent
reactions†
Ahmad Shaabani,*a Afshin Sarvary,a Sabrieh Ghasemi,a Ali Hossein Rezayan,a Rahim Ghadaria and
Seik Weng Ngb
Received 14th August 2010, Accepted 5th January 2011
DOI: 10.1039/c0gc00442a
Three-component reaction of the zwitterion generated from
dialkyl acetylenedicarboxylate and an alkyl or aryl iso-
cyanide with an alkyl or aryl sulfonamide is described. The
reaction afforded the corresponding special type of keten-
imine sulfonamide derivatives in water without using any
activation and modification. The products could be easily
hydrolyzed to the corresponding sulfonamide-butanamide
derivatives at 80 ◦C in good yields without using a catalyst.
Fig.
compounds.
1
Some biologically active bifunctional sulfonamide-amide
The amide and sulfonamide bonds are the most important
linkages in organic chemistry and constitute the key func-
tional group in peptides, polymers, many natural products and
pharmaceuticals.1 Compounds that contain both sulfonamide
and amide functional groups are an important category of
pharmaceutical compounds with a broad spectrum of biological
activities. Some of these compounds exhibit various types of
biological properties such as histone deacetylase,2 Hepatitis C
virus,3 HIV-protease,4 and b-secretase (BACE1) inhibitors.5 Bi-
ologically important examples include the inhibitors of the avb3
integrin (A),6 glycine transporter 1(GlyT1) (B),7 matriptase (C)8
and as a cholecystokinin type 2 receptor (CCK2R) (D)9 (Fig. 1).
Bifunctional sulfonamide-amide containing compounds have
been synthesized via multistep approaches in the presence of
expensive catalysts under sensitive conditions.9–11
Multicomponent reactions (MCRs), due to their productivity,
simple procedures, convergence, and facile execution, are one of
the best tools in combinatorial chemistry. Therefore, the design
of novel MCRs, especially isocyanide-based multicomponent
reactions (IMCRs) have attracted great attention from many
research groups working in areas such as drug discovery, organic
synthesis and materials science.12
It has been shown that alkyl or aryl isocyanide add to
dialkyl acetylenedicarboxylate to generate zwitterionic species,
which serve as intermediates in many different reactions.13
Recently, these highly reactive zwitterionic intermediates have
been captured by suitable NH acid such as 2,2,2-trifluoro-N-
aryl-acetamides,14 ethyl carbazones,15 and benzoyl hydrazone16
substrates. To the best of our knowledge, the use of an alkyl
or aryl sulfonamide for trapping zwitterionic intermediates
derived from dialkyl acetylenedicarboxylate and an alkyl or aryl
isocyanide in water has not been explored until now.
In view of our current interest on IMCRs, involving zwitteri-
onic species17 and potential use of sulfonamides18 and amides,19
herein we describe an environmentally benign approach to
the synthesis of ketenimine sulfonamide derivatives 4 and
bifunctional sulfonamide-amide compounds 7 via the reaction
of an isocyanide 1 with a dialkyl acetylenedicarboxylate 2 and a
sulfonamide 3 in high yields without using any catalyst in water
(Scheme 1).
aDepartment of Chemistry, Shahid Beheshti University, G. C. P. O. Box,
19396-4716, Tehran, Iran. E-mail: a-shaabani@cc.sbu.ac.ir
Scheme 1 Synthesis of ketenimine sulfonamide derivatives 4.
bDepartment of Chemistry, University of Malaya, 50603, Kuala Lumpur,
Malaysia
† Electronic supplementary information (ESI) available: Detailed exper-
imental procedures, including spectroscopic data for all the compounds
with1H NMR,13C NMR, IR and mass spectra. CCDC reference
numbers 776454 and 776455. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c0gc00442a
As indicated in Scheme 1, isocyanides 1 with dialkyl
acetylenedicarboxylates 2 and sulfonamides 3 undergo a smooth
1 : 1 : 1 addition reaction to produce selectively stable ketenimine
sulfonamides 4 in H2O at room temperature.
582 | Green Chem., 2011, 13, 582–585
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The structures of the products were deduced from their IR,
mass, 1H NMR, and 13C NMR spectra. The 1H NMR spectrum
of 4h consisted of a singlet for the C(CH3)3 (d = 1.15 ppm), a
multiplet for two methyl groups of OCH2CH3 (d = 1.17–1.20
ppm), three singlets for –C(CH3)2– (d = 1.47 ppm), –CH2– (d =
1.66 ppm) and CH3 (d = 2.41 ppm), a multiplet for two CH2
groups of OCH2CH3 (d = 4.01–4.13 ppm), two doublets for
NH–CH (d = 3.62 ppm, 3JHH = 8.2 Hz) and NH–CH (d = 5.82
ppm, 3JHH = 8.2 Hz), two doublets for the aromatic protons (d =
3
3
7.26 ppm, JHH = 8.3 Hz) and (d = 7.75 ppm, JHH = 8.3 Hz).
The 1H decoupled 13C NMR spectrum of 4h showed 20 distinct
resonances, partial assignment of these resonances is given in
the experimental section. The mass spectra of these compounds
displayed molecular ion peaks at the appropriate m/z values.
Finally, the structure of the product 4h was confirmed
unambiguously by single-crystal X-ray analysis (Fig. 2).
Fig. 3 Ketenimine sulfonamide derivatives.
adduct by the NH-acids. Then, the positively charged ion 6
might be attacked by the anion of the sulfonamides and lead to
the ketenimine sulfonamides 4a–m (Scheme 2).
Fig. 2 ORTEP diagram of 4h.
In order to obtain the best solvent, the model reaction has
been investigated in water and various organic solvents (Table
1). As Table 1 shows, water is the best solvent respect to reaction
yield (Table 1, entry 3).
Scheme 2 Proposed mechanism pathway.
We explored the use of various alkyl or aryl isocyanides
with alkyl or aryl sulfonamides in H2O at room temperature,
which lead to the formation of the corresponding ketenimine
sulfonamides derivatives in high yields.
The reaction proceeds under mild conditions and is compat-
ible with a wide range of functional groups. Owing to the great
diversity of the substitution patterns, this reaction may be used
in the production of combinatorial libraries (Fig. 3).
Although the mechanism of this reaction has not been estab-
lished experimentally, the formation of these compounds can
be rationalized by initial Michael-type addition of isocyanides
to acetylenic systems13 and subsequent protonation of the 1 : 1
We investigated the possibility of sulfonamide-butanamide
derivatives synthesis 7 without isolation of products 4 under
a one-pot strategy. As mentioned, Nasiri and Yosefdad have
reported hydrolysis of ketenimines in the THF–H2O system
previously.20,21
In a pilot experiment, a three-component condensation reac-
tion of cyclohexyl isocyanide, dimethyl acetylenedicarboxylate
and 4-toluenesulfonamide was stirred in water for 3 h at room
temperature. Then without isolation of product 4b, the reaction
mixture was heated in water for 12 h at 80 ◦C. After completion
of the reaction (the progress of the reaction was monitored by
TLC), the product was filtrated and afforded 7b with 75% yield
(Scheme 3). On the other hand, isolated ketenimines 4 could be
easily hydrolyzed to the corresponding sulfonamide-butanamide
derivatives 7 in water at 80 ◦C without using any catalyst
(Fig. 4).
Table 1 Effect of solvent on the reaction yielda
Entry
Solvent
Yield (%)
1
2
3
4
5
CH2Cl2
EtOEt
H2O
PhCH3
CH3CN
67
61
78b
30
60
a 1,1,3,3-Tetramethyl-butyl isocyanide (1.0 mmol), diethyl acetylenedi-
carboxylate (1.0 mmol), 4-methylbenzenesulfonamide (1.0 mmol), at
room temperature, 6 h. b 3 h for solvent H2O.
Scheme 3 One-pot synthesis of sulfonamide-butanamide derivatives
7a–g.
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temperature. The mixture was stirred for 3 h in H2O or 6 h in
CH2Cl2. The solvent was removed under vacuum and the residue
was crystallized from n-hexane/dichloromethane (2 : 1) and the
product 4h was obtained. White crystals (0.37 g, 78%). mp 84–
86 ◦C. IR (KBr) (nmax/cm-1: 3229, 2993, 2947, 2056, 1751, 1675.
MS, m/z (%): 481 (M++1, 1), 369 (2), 351(3), 323 (10), 247
1
(10), 213 (100), 155 (20), 107 (10), 91 (80), 57 (70). H NMR
(300 MHz, CDCl3): dH (ppm) 1.15 (9H, s, C(CH3)3), 1.15–1.20
(6H, m, 2OCH2CH3), 1.47 (6H, s, C(CH3)2), 1.63 (2H, s, CH2),
2.41 (3H, s, CH3), 4.01–4.14 (4H, m, 2OCH2CH3), 4.62 (1H, d,
3JHH = 8.3 Hz, CHNH), 5.82 (1H, d, 3JHH = 8.3 Hz, CHNH), 7.26
(2H, d, 3JHH = 8.4 Hz, arom), 7.74 (2H, d, 3JHH = 8.4 Hz, arom).
13C NMR (75 MHz, CDCl3): dC (ppm) 14.0, 14.3, 21.5, 31.1,
31.3, 31.4, 31.7, 53.7, 54.7, 60.3, 62.2, 63.5, 65.5, 127.2, 129.4,
137.5, 143.2, 165.1, 168.5, 169.5. Anal. Calcd for C24H36N2O6S:
C, 59.98; H, 7.55; N, 5.83. Found: C, 59.73; H, 7.41; N, 5.88.
Fig. 4 Structures of sulfonamide-butanamide derivatives synthesized
via the one-pot reaction.
It is important to note that compound 7 has two stereogenic
Typical procedure for the preparation of product 7g
centers and therefore, two pairs of diastereoisomers expected.
1
The H NMR and 13C NMR spectra of the crude products
To a magnetically stirred solution of methanesulfonamide
(0.09 g, 1.0 mmol) and dimethyl acetylenedicarboxylate (0.14 g,
1.0 mmol) in H2O (10 mL) was added, 1,1,3,3-tetramethyl-butyl
isocyanide (0.14 g, 1.0 mmol) at room temperature. The mixture
was stirred for 3 h in H2O at room temperature and then kept
12 h at 80 ◦C. After completion of the reaction, as indicated by
TLC (ethyl acetate : n-hexane, 1 : 1), the precipitate product was
washed with ethyl acetate : n-hexane, (1 : 3) and the product 7g
was obtained as a white crystals (0.31 g, 80%). mp 126–129 ◦C.
showed only one of two possible diastereomers (RS or SR) was
present in the reaction mixture. These structures were confirmed
by single-crystal X-ray analysis (Fig. 5).
IR (KBr) (nmax/cm-1: 3358, 3178, 2957, 2916, 1735, 1654. H
1
NMR (300 MHz, DMSO-d6): dH (ppm) 0.92 (9H, s, C(CH3)3),
1.27 (6H, s, C(CH3)2), 1.56 (1H, AB-q, 2JHH = 14.5 Hz, CHAHB),
2
1.77 (1H, AB-q, JHH = 14.5 Hz, CHAHB), 2.91 (S-CH3), 3.60
(3H, s, OCH3), 3.63 (3H, s, OCH3), 3.84 (1H, d, 3JHH = 8.2 Hz,
3
CH), 4.50 (1H, dd, JHH = 9.5 and 8.2 Hz, CHNH), 7.47 (1H,
d, JHH = 9.5 Hz, CH–NH), 7.74 (1H, s, CONH). 13C NMR
3
Fig. 5 ORTEP diagram of 7c.
(75 MHz, DMSO-d6): dC (ppm) 29.2, 29.4, 31.5, 31.6, 42.1, 50.6,
52.5, 52.8, 54.6, 55.0, 55.4, 164.6, 168.6, 171.0. Anal. Calcd for
C16H30N2O7S: C, 48.71; H, 7.67; N, 7.10. Found: C, 48.65; H,
7.74; N, 7.11.
In conclusion, the environmentally benign synthesis of
carbon-nitrogen bonds continues to be an important and
challenging field of chemical research. We have developed a new
and efficient approach to the synthesis of libraries of biologically
bifunctional sulfonamide-amide containing compounds from
various isocyanides and dialkyl acetylenedicarboxylates in the
presence of alkyl or aryl sulfonamides in water and absence
of any catalyst. By controlling the reaction temperature or
using an organic solvent such as CH2Cl2, the reaction selectively
produced ketenimines. The reaction has been shown to display
relatively good functional group tolerance, high yield, and
product isolation is very straightforward. We hope that this
approach may be of value to others seeking novel synthetic
fragments with unique properties for medicinal chemistry.
Acknowledgements
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
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To a magnetically stirred solution of 4-methylbenzenesulfona-
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