Three-component synthesis of dialkyl 2-(cyclohexyliminomethylene)-3- arylsulfonylamino succinate

Article abstract of DOI:10.3184/174751911X12964930076881

The reactive 1:1 intermediate produced in the reaction between cyclohexyl isocyanide and dialkyl acetylenedicarboxylates was trapped by arylsulfonamides to yield highly functionalised stable ketenimines under mild reaction conditions in fairly good yields

Full text of DOI:10.3184/174751911X12964930076881

9
8
RESEARCH PAPER
FEBRUARY, 98–100
JOURNAL OF CHEMICAL RESEARCH 2011
Three-component synthesis of dialkyl
2
-(cyclohexyliminomethylene)-3-arylsulfonylamino succinate
a
b
b
Hossein Anaraki-Ardakani *, Mohammad Hossein Mosslemin , Hesamaddin Sadoughi and
c
Nima Makvandi
a
Department of Chemistry, Islamic Azad University, Mahshahr Branch, PO Box 63519, Mahshahr, Iran
b
Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
c
College of Natural Resources, Islamic Azad University, Bandar Abbas, Iran
The reactive 1:1 intermediate produced in the reaction between cyclohexyl isocyanide and dialkyl acetylenedicarbox-
ylates was trapped by arylsulfonamides to yield highly functionalised stable ketenimines under mild reaction
conditions in fairly good yields.
Keywords: multicomponent reactions, ketenimines, sulfonamides, zwitterion
Multicomponent reactions (MCRs) provide a powerful tool
towards the one-pot synthesis of diverse and complex com-
pounds on the one hand and small and ‘drug-like’ heterocycles
on the other hand. MCRs that involve isocyanides are by far
the most versatile reactions in terms of scaffolds and number
of accessible compounds. A number of advantages make
MCRs very popular in the community of combinatorial chem-
ists: superior atom economy, simple procedures, the one-pot
character, and the high and ever-increasing number of acces-
sible backbones. Sulfonamide-containing compounds have a
high potential as pharmaceutical and agricultural agents due
to their diverse biological profiles. The ability to serve as
amide surrogates, with unique physical properties, have made
them ideal functional groups for the development of novel
building blocks for the preparation of a large variety of
cyclic compounds via inter- or intramolecular cycloaddition
reactions.
2
0,21
Although the trapping of the 1:1 intermediate formed
between dialkyl acetylenedicarboxylate and isocyanides with
2
2–25
OH, NH, and CH acids has been widely studied,
trapping
of the initially formed 1:1 intermediate with arylsulfonamides
has not been reported. In the course of our works on the
26–29
reaction between isocyanides and acetylenic esters,
we
now report a simple one-pot three-component reaction between
dialkyl acetylenedicarboxylates, cyclohexyl isocyanide, and
arylsulfonamide leading to dialkyl 2-cyclohexyliminometh-
ylene-3-arylsulfonylamino succinate derivatives.
1–3
peptidomimetics. In addition, sulfonamides have served
as key functional groups in the development of novel nonpep-
Results and discussion
4
,5
The reaction of cyclohexyl isocyanide 1 with dialkyl
acetylenedicarboxylate 2 in the presence arylsulfonamides
3 proceeds with a smooth 1:1:1 addition reaction in dich-
loromethane at ambient temperature, to produce dialkyl 2-
cyclohexyliminomethylene-3-arylsulfonylamino succinates 4
in 80–89% yields (Scheme 1).
tidal HIV protease inhibitors, matrix metalloproteinase
6
,7
8,9
inhibitors, 0thrombin inhibitors, and fibrinogen receptor
1
antagonists.
On the other hand, ketenimines are important reactive inter-
mediates that occur as transient compounds in many thermal
1
1–13
and photochemical reactions.
est in their addition reactions, such as cycloaddition,
There has been intense inter-
14,15
The structures of compounds 4a–f were deduced from their
12,16,17
18,19
1
13
nucleophilic,
and electrophilic,
addition. Ketenimines
mass spectra, elemental analyses, IR, and high-field H and C
NMR spectra.
have been extensively used in organic synthesis as versatile
Scheme 1
*
Correspondent. E-mail:hosseinanaraki@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2011 99
The mass spectrum of compound 4a displayed the molecu-
lar-ion peak at m/z = 450. The IR spectrum of 4a exhibited the
To a magnetically stirred solution of cyclohexyl isocyanide
1 mmol) and aryl sulfonamide (1 mmol) in CH Cl (10 ml) was added
(
2
2
–
1
a solution of dialkyl acetylenedicarboxylate (1 mmol) in CH Cl2
absorption band for the ketenimine moiety at 2065 cm , for
2
−1
(5 ml) dropwise at room temperature. over 10 min. The mixture was
then allowed to stir for 24 h. The solvent was removed under reduced
pressure, and the residue was separated by column chromatography
silica gel, hexane–EtOAc, 5:1) to afford the pure title compounds.
Diethyl 2-cyclohexyliminomethylene-3-(4-methyl-benzenesulfonyl-
the ester carbonyl groups at 1737 and 1685 cm and for the
–
1
NH group at 3345 cm .
1
The H NMR spectrum of compound 4a exhibited a multi-
(
plet readily recognized as arising from two methyl group
protons (δ = 1.18), and the signals related to methylene groups
of the cyclohexyl moiety were observed as multiplets at 1.26–
amino) succinate (4a ): Yellow oil; yield 0.40 g (89%); IR (KBr)
−
1
(νmax, cm ): 3345 (NH), 2065 (N=C=C), 1737, 1685 (C=O, ester). MS
+
1
1
.96 ppm. A single signal was observed at 2.41 ppm which
(m/z, %): 450 (M , 7). H NMR (500.1 MHz, CDCl
m, 2OCH CH ), 1.26–1.96 (10 H, m, 5 CH of cyclohexyl), 2.41 (3 H,
s, CH ), 3.80 (1 H, m, CH of cyclohexyl), 4.04–4.12 (4 H, m,
3
): δ = 1.18 (6 H,
arises from tolyl methyl protons. Two multiplets were observed
for the methylene protons of the ethyl groups and the methine
proton of the cyclohexyl group at 4.08 and 3.80 ppm respec-
tively. The methine and NH protons couple to each other and
two doublets were observed for them at 4.65 and 5.78 ppm,
2
3
2
3
3
3
2
OCH CH ), 4.65(1 H, d, J = 8 Hz, CH), 5.78 (1 H, d, J = 8 Hz,
2 3 HH HH
3 3
NH), 7.28 (2 H, d, J = 6.8 Hz, arom), 7.74 (2 H, d, J = 6.8 Hz,
HH
HH
13
arom) ppm. C NMR (125.7MHz, CDCl ): δ = 13.93 (OCH CH ),
3
2
3
1
4.28 (OCH CH ), 21.50 (CH ), 25.15, 23.79, 33.28 and 33.35 (5 CH
2
3
3
2
1
respectively. When the H NMR spectrum was recorded after
of cyclohexyl), 53.78 (CH of cyclohexyl), 60.33 (OCH CH ), 60.76
2
3
addition of some D O to the CDCl solution of 4a the doublet
2
3
(OCH CH ), 62.25 (CH), 62.47(N=C=C), 127.15, 129.45, 137.61,
2 3
relating to the NH proton disappeared and the doublet relating
to the methine proton was converted to a singlet. The protons
of the aryl group exhibited characteristic signals in the
aromatic region of the spectrum.
143.27 (C arom), 166.12 (N=C=C), 168.12 (CO Et), 169.77 (CO Et)
2 2
ppm. Anal. Calcd for C H N O S: C, 58.65; H, 6.71; N, 6.22. Found:
22
30
2
6
58.71; H, 6.59; N, 6.29%.
Diethyl -2-cyclohexyliminomethylene-3-(4-nitro-benzenesulfonyl-
13
amino) succinate (4b): Yellow oil; yield 0.40 g (85%); IR (KBr)
The C NMR spectrum of compound 4a showed 19 distinct
−
1
2
(νmax, cm ): 3230 (NH), 2050 (N=C=C), 1750, 1663 (C=O, ester).
resonances in agreement with the proposed structure. The sp
-
+ 1
MS (m/z, %): 481 (M , 9). H NMR (500.1 MHz, CDCl ): δ = 1.19
3
hybridised carbon atom of the ketenimine residue appears at
δ = 62.47 ppm, as a result of strong electron delocalisation.
Partial assignments of these resonances are given in the
Experimental section.
(
(
(
6 H, m, 2OCH CH ), 1.25–1.96 (10 H, m, 5 CH of cyclohexyl), 3.71
2
3
2
1 H, m, CH of cyclohexyl), 4.01–4.13 (4 H, m, 2OCH CH ), 4.70
2
3
3
3
1 H, d, J = 7.6 Hz, CH), 6.06 (1 H, d, J = 7.7 Hz, NH), 8.05 (2H,
HH
HH
3
3
13
d, J = 6.8 Hz, arom), 8.31 (2 H, d, J = 6.8 Hz, arom) ppm.
C
HH
HH
Although we have not established the mechanism of the
reaction between isocyanides and acetylenic esters in the
presence of the arylsulfonamide in an experimental manner, a
possible explanation is proposed in (Scheme 2).
NMR (125.7MHz, CDCl ): δ = 14.37 (OCH CH ), 14.50 (OCH CH ),
3 2 3 2 3
23.08, 24.05, 25.52, 32.31 and 33.68 (5 CH
(CH of cyclohexyl), 60.98 (OCH CH ), 61.15 (OCH
CH), 62.92 (N=C=C), 124.42, 128.83, 147.15, 150.32 (C arom),
of cyclohexyl), 54.55
2
CH ), 61.99
2
3
2
3
(
1
65.09 (N=C=C), 168.80 (CO Et), 169.42 (CO Et) ppm. Anal. Calcd
2
2
On the basis of the well-established chemistry of isocya-
30–35
for C21H N O S: C, 52.38; H, 5.65; N, 8.73. Found: 52.31; H, 5.65;
27 3 8
nides,
it is reasonable to assume that the functionalised
N, 8.65%.
ketenimine 4 apparently results from initial addition of the
cyclohexyl isocyanide 1 to the acetylenic ester 2 and subse-
quent protonation of the 1:1 adduct 5 by arylsulfonamide 3.
Then, the positively charged ion 6 is attacked by anion 7 to
give the product 4.
Dimethyl 2-cyclohexyliminomethylene-3-(4-nitro-benzenesulfonyl-
amino) succinate (4c): Yellow oil; yield 0.37 g (82%); IR (KBr)
−1
(
νmax, cm ): 3415 (NH), 2075 (N=C=C), 1742, 1717 (C=O, ester). MS
+
1
(m/z, %): 453 (M , 11). H NMR (500.1 MHz, CDCl ): δ = 1.26–2.01
3
(10 H, m, 5 CH of cyclohexyl), 3.59 (3 H, s, OCH ), 3.69 (3 H, s,
2
3
OCH ), 3.83 (1 H, m, CH of cyclohexyl), 4.74 (1 H, br, CH), 6.01
3
3
3
(
8
2
1 H, br, NH), 8.05 (2H, d, J = 8.5 Hz, arom), 8.34 (2 H, d, J
.5 Hz, arom) ppm. C NMR (125.7MHz, CDCl ): 23.84, 25.05,
9.69, 32.58 and 33.38 (5 CH of cyclohexyl), 51.72 (OCH ), 53.33
=
HH
HH
Conclusion
13
3
In conclusion, the reaction between isocyanides and dialkyl
acetylenedicarboxylates in the presence of aryl sulfonamide
provides a simple one-pot entry into the synthesis of dialkyl
2
3
(
OCH ), 54.09 (CH of cyclohexyl), 60.89 (CH), 61.12 (N=C=C),
3
124.04, 128.40, 146.57 and 149.97 (C arom), 164.34 (N=C=C),
168.92 (CO Me), 169.55 (CO Me) ppm.Anal. Calcd for C H N O S.:
2
-cyclohexyliminomethylene-3-arylsulfonylamino succinate
2
2
19 23
3
8
derivatives of potential synthetic and pharmaceutical interest.
The advantages of the suggested method are simple reaction
conditions, good yields and using starting materials without
any activation or modification.
C, 50.32; H, 5.11; N, 9.27. Found: 50.45; H, 5.01; N, 9.32%.
Dimethyl 2-cyclohexyliminomethylene-3-(4-methyl-benzenesulfonyl-
amino) succinate (4d): Yellow oil; yield 0.33 g (80%); IR (KBr)
−
1
(
νmax, cm ): 3205 (NH), 2075 (N=C=C), 1754, 1661 (C=O, ester).
+ 1
MS (m/z, %): 422 (M , 9). H NMR (500.1 MHz, CDCl ): δ = 1.17–
3
1
.90 (10 H, m, 5 CH of cyclohexyl), 2.41(3 H, s, CH ), 3.55 (3 H, s,
2
3
Experimental
OCH ), 3.71 (3 H, s, OCH ), 3.80 (1 H, m, CH of cyclohexyl), 4.70
3
3
3
3
Elemental analyses were performed using a Heraeus CHN-O-Rapid
analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430
mass spectrometer operating at an ionization potential of 70 eV.
(1 H, d, J = 8.9 Hz, CH), 5.77 (1 H, d, J = 8.9 Hz, NH), 7.29
HH HH
3 3
(2H, d, J = 8.2 Hz, arom), 7.74 (2 H, d, J = 8.2 Hz, arom) ppm.
HH
HH
13
C NMR (125.7MHz, CDCl ): 24.99, 25.04, 25.87, 32.99 and 33.07
3
1
IR spectra were recorded on a Shimadzu IR-470 spectrometer. H and
(5 CH of cyclohexyl), 21.49 (CH ), 49.14 (CH of cyclohexyl), 53.39
(OCH ), 53.98 (OCH ), 61.29 (CH), 62.39 (N=C=C), 127.69, 130.02,
3 3
2
3
13
C NMR spectra were recorded on Bruker DRX-500 Avance
spectrometer at solution in CDCl using TMS as internal standard.
137.57 and 143.95 (C arom), 164.71 (N=C=C), 169.71 (CO Me),
3
2
The chemicals used in this work were purchased from Fluka (Buchs,
Switzerland) and were used without further purification.
170.34 (CO Me) ppm. Anal. Calcd for C H N O S: C, 56.86;
H, 6.20; N, 6.63. Found: 56.78; H, 6.29; N, 6.71 %.
2
20 26
2
6
Scheme 2

1
00 JOURNAL OF CHEMICAL RESEARCH 2011
Dimethyl 2-benzenesulfonylamino-3-cyclohexyliminomethylene suc-
cinate (4e): Yellow oil; yield 0.33 g (80%); IR (KBr) (νmax, cm ):
7
8
T. Tamura, F. Watanabe, T. Nakatani, K. Yasui, M. Fuji, T. Komurasaki, H.
Tsuzuki, R. Maekawa, T. Yoshioka, K. Kawada, K. Sugita and M. Ohtani,
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Anderson, R.J. Gould, R.J. Lynch, C-T. Chang, J.J. Cook, J.J. Lynch, M.A.
Holahan, G.R. Sitko and M.T. Stranieri, Bioorg. Med. Chem. Lett., 1997, 7,
1531.
−1
3
4
5
345 (NH), 2070 (N=C=C), 1736, 1685 (C=O, ester). MS (m/z, %):
+
1
08 (M , 9). H NMR (500.1 MHz, CDCl ): δ = 1.14–1.89 (10 H, m,
3
CH of cyclohexyl), 3.49 (3 H, s, OCH ), 3.68 (3 H, s, OCH ), 3.80
2
3
3
9
0
3
(
1 H, m, CH of cyclohexyl), 4.70 (1 H, d, J = 9 Hz, CH), 5.91 (1 H,
HH
3 13
1
d, JHH = 9 Hz, NH), 7.48–7.89 (5H, m, arom) ppm. C NMR
125.7MHz, CDCl ): 24.57, 24.62, 25.42, 29.66 and 32.53 (5 CH of
(
3
2
cyclohexyl), 48.74 (CH of cyclohexyl), 52.91 (OCH ), 53.55 (OCH ),
3
3
6
(
0.27(CH), 62.14 (N=C=C), 127.15, 128.87, 132.64 and 140.37
11 M.W. Barkers, The chemistry of ketenes, allenes and related compounds,
Part 2, Wiley, New York, 1980.
T.T. Tidwell, Acct. Chem. Res., 1990, 23, 273.
Y. Chiang, A.S. Grant, H-X. Guo, A.J. Kresge and S.W. Paine, J. Org.
Chem., 1997, 62, 5363.
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Hanrath, Angew. Chem. Int. Ed., 1998, 37, 1562.
M. Alajarin, A.Vidal, F. Tovar and M.C.R. Arellano, Tetrahedron
Asymmetry, 2004, 15, 489.
C arom), 164.49 (N=C=C), 169.01 (CO Me), 169.89 (CO Me) ppm.
2
2
1
1
2
3
Anal. Calcd for C H N O S: C, 55.87; H, 5.92; N, 6.86. Found:
19
24
2
6
5
5.79; H, 5.99; N, 6.79%.
Diethyl 2-benzenesulfonylamino-3-cyclohexylimin)methylene suc-
1
1
4
5
−1
cinate (4f): Yellow oil; yield 0.37 g (85%); IR (KBr) (νmax, cm ): 3345
(
(
NH), 2065 (N=C=C), 1733, 1675 (C=O, ester). MS (m/z, %): 436
+ 1
M , 6). H NMR (500.1 MHz, CDCl ): δ = 1.18(6 H, m, 2OCH CH ),
3 2 3
1
.25–1.92 (10 H, m, 5 CH of cyclohexyl), 3.78 (1 H, m, CH of cyclo-
16 G.G.H. Qiao, J. Andraos and C. Wentrup, J. Am. Chem. Soc., 1996, 118,
5634.
17 K. Sung and T.T. Tidwell, J. Am. Chem. Soc., 1998, 120, 3043.
18 C. Fromont and S. Masson, Tetrahedron, 1999, 55, 5405.
2
3
hexyl), 4.03–4.29 (4 H, m, 2OCH CH ), 4.64 (1 H, d, J = 8.6 Hz,
2
3
HH
3
CH), 6.06 (1 H, d, J = 9 Hz, NH), 7.40–7.88 (5H, m, arom) ppm.
HH
13
C NMR (125.7MHz, CDCl ): δ = 14.17 (OCH CH ), 14.52
3
2
3
1
9
N. Pietri, T. Chiavassa, A. Allouche and J.P. Aycard, J. Phys. Chem. A.,
(
OCH CH ), 23.09, 24.99, 25.04, 30.09 and 33.68 (5 CH of cyclo-
2
3
2
1
997, 101, 1093.
hexyl), 49.11 (CH of cyclohexyl), 60.77 (OCH CH ), 61.16
2
3
2
2
0
1
M. Alajarín, A. Vidal and F. Tovar, Targets Heterocycl. Syst., 2000, 4, 293.
S. Patai, The chemistry of ketenes allenes and related compounds. Wiley,
New York, 1980.
(
OCH CH ), 62.58 (CH), 62.84 (N=C=C), 127.64, 129.31, 133.06,
2 3
and140.75 (C arom), 164.98 (N=C=C), 168.94 (CO Et), 169.82
2
(
CO Et) ppm.
22 A. Alisadeh, S. Rostamnia and L. G. Zhu, Tetrahedron, 2006, 62, 5641.
23 I. Yavari, M. Anary-Abbasinejad, A. Alisadeh and Z.A. Hossaini,
Tetrahedron, 2003, 59, 1289.
2
Anal. Calcd for C H N O S: C, 57.78; H, 6.47; N, 6.42. Found:
21
28
2
6
5
7.82; H, 6.57; N, 6.35%.
2
4
I. Yavari, A. Alisadeh, M. Anary-Abbasinejad and H.R. Bijanzadeh,
Tetrahedron, 2003, 59, 6083.
M. Anary-Abbasinejad, H. Anaraki-Ardakani and F. Ghanea, Monatsh.
Chem., 2009, 140, 397.
Received 25 November 2010; accepted 21 December 2010
Paper 1000446 doi: 10.3184/174751911X12964930076881
Published online: 10 February 2011
2
5
26 M. Anary-Abbasinejad, M.H. Moslemine and H. Anaraki-Ardakani, J.
Fluor. Chem., 2009, 130, 368.
2
7
M.H. Mosslemin, M. Anary-Abbasinejad and H. Anaraki-Ardakani,
Synlett, 2009, 16, 2676.
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