Reaction between isocyanides and nitrostyrenes in water: a novel and efficient synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides

Article abstract of DOI:10.1016/j.tetlet.2009.09.069

A novel synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides is described. Heating a mixture of an isocyanide and a nitrostyrene in water afforded the title compounds in excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.09.069

Tetrahedron Letters 50 (2009) 7246–7248
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Tetrahedron Letters
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Reaction between isocyanides and nitrostyrenes in water: a novel and
efficient synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides
a
a
a
b
Mehdi Adib a, , Mohammad Mahdavi , Samira Ansari , Farzad Malihi , Long-Guan Zhu ,
*
Hamid Reza Bijanzadeh c
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Chemistry Department, Zhejiang University, Hangzhou 310027, PR China
c Department of Chemistry, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides is described. Heating a mixture of
an isocyanide and a nitrostyrene in water afforded the title compounds in excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 April 2009
Revised 2 September 2009
Accepted 11 September 2009
Available online 13 October 2009
Keywords:
5-(Alkylamino)-4-aryl-3-
isoxazolecarboxamides
Isocyanides
Nitrostyrenes
Three-component reactions
Synthesis in water
Multi-component reactions (MCRs) have emerged as an effi-
cient and powerful tool in modern synthetic organic chemistry
due to their valued features. MCRs, leading to interesting heterocy-
clic scaffolds, are particularly useful for the construction of diverse
chemical libraries of ‘drug-like’ molecules. Isocyanide-based MCRs
are especially important in this area.1
Isoxazoles are five-membered aromatic ring systems containing
adjacent oxygen and nitrogen atoms, and have found diverse
medicinal, agricultural, and other industrial applications. Some
isoxazoles are used as organic electrolytes in non-aqueous batter-
ies, in photographic emulsions, and in fiber dyes.2,3
The most common synthetic approach for the construction of
the isoxazole ring system involves the cycloaddition of alkynes to
nitrile oxides.2,3
A number of synthetic routes have been reported for the prep-
aration of 5-aminoisoxazoles; these include condensation of esters
with nitrile anions and then cyclization of the resulting b-ketonitr-
iles with hydroxylamine,12 addition of nitrile anions to
a
-chloroox-
imes,13 condensation of
a
-bromo ketoximines with cyanide,14 and
rearrangement of 5-alkyl-4-cyanoisoxazoles on treatment with
LiAlH4.15
Isoxazoles containing a 3-carboxamide or 5-amino substituent
have been shown to possess antiepileptic,4 anticonvulsant (e.g.,
D2624, Fig. 1),5 antifungal,6 and insecticidal7 properties. Other
examples possess monoamine oxidase inhibitory activity and are
useful for the treatment of depression and cognitive disorders.8
3-Isoxazolecarboxamides have also been used for the treatment
of pain and/or fever.9 5-Aminoisoxazole 1 (Fig. 1) has been reported
as an antagonist of the human platelet thrombin receptor (PAR-
1),10 and other examples function as selective endothelin ETB
receptor antagonists.11
F
F
H3C
O
N
N
N
CH3
H
N
O
N
H3C
O
O
O
D2624
1
* Corresponding author. Tel./fax: +98 (21)66495291.
E-mail address: madib@khayam.ut.ac.ir (M. Adib).
Figure 1. Examples of biologically active 3-isoxazolecarboxamides and 5-aminois-
oxazoles.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.069

M. Adib et al. / Tetrahedron Letters 50 (2009) 7246–7248
7247
Table 1
The most common synthetic methods reported for the prepara-
Synthesis of 5-aminoisoxazole-3-carboxamides 4a–l
tion of 3-isoxazolecarboxamides involve amidation of the
corresponding carboxylic acids16 and cyclization of 2,4-dioxopen-
tanamides with hydroxylamine.9
4
Ar
R
Mpa (°C)
% Yieldb
a
b
c
d
e
f
g
h
i
C6H5
C6H5
Cyclohexyl
74–76
120–121
125
117
101–102
156
155–156
106
96–97
67
135
187–188
87
91
90
92
80
90
88
83
85
89
93
92
tBu
Water is a desirable solvent for chemical reactions because it is
safe, non-toxic, environmentally friendly, readily available, and
cheap compared to organic solvents.17 Although enzymatic pro-
cesses in Nature occur in aqueous environment by necessity, water
has been avoided as a solvent for common organic reactions due to
poor solubility of substrates and, in some cases, the instability of
organic reagents or reaction intermediates in aqueous solutions.
Since the pioneering studies on Diels–Alder reactions by Breslow,18
there has been increasing recognition that organic reactions can
proceed well in aqueous solution offering advantages over those
occurring in organic solvents, such as rate enhancement and insol-
ubility of the final products which facilitates their isolation.17
There are several reports in the literature concerning the reac-
tion of the activated methylene isocyanides and nitroalkenes. The
base-catalyzed reaction of nitroalkenes (or arenes) with iso-
cyanoacetate is known as the Barton–Zard pyrrole synthesis,19
which proceeds with elimination of nitrous acid in the final pyrrole
ring-formation step.
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-BrC6H4
2-Thienyl
2-Thienyl
3-CH3C6H4
4-FC6H4
Cyclohexyl
tBu
1,1,3,3-Tetramethylbutyl
tBu
Cyclohexyl
tBu
Cyclohexyl
Cyclohexyl
tBu
j
k
l
4-ClC6H4
Cyclohexyl
a
Recrystallized from n-hexane/EtOAc (1:1).
Isolated yield.
b
(d 156.85, 158.97, and 166.85; for N@C, ONC@C, and C@O, respec-
tively) were in agreement with the proposed structure.23 Single-
crystal X-ray analysis of one example, 4b, conclusively confirmed
the structures of these compounds. An ORTEP diagram of 4b is
shown in Figure 2.24
A mechanistic rationalization for this reaction is provided in
Scheme 2. On the basis of the chemistry of isocyanides,25–28 it is
reasonable to assume that the first step could involve Michael
addition of isocyanide 2 to the nitrostyrene 3 leading to the nitro-
nate intermediate 5, which may undergo cyclization via nucleo-
philic addition of the nitronate oxygen to the adjacent nitrilium
to form 4,5-dihydroisoxazolium N-oxide intermediate 6. A 1,3-H
In 2008, a new organocatalytic asymmetric formal [3+2] cyclo-
addition reaction of isocyanoesters to nitroolefins leading to the
corresponding dihydropyrroles was reported.20 Another reported
pyrrole synthesis involved cycloaddition of nitro-substituted ke-
tene S,S- and N,S-acetals with the activated methylene isocya-
nides.21 In both these cycloadditions the nitro group is retained
in the dihydropyrrole and pyrrole products.
Due to the pharmacological properties of isoxazoles containing
3-carboxamide or 5-amino substituent, the development of syn-
thetic methods, enabling easy access to these compounds, are
desirable. As part of our continuing efforts on the development
of new routes for the preparation of biologically active heterocyclic
compounds,22 herein, we describe a novel synthesis of functional-
ized isoxazoles using various nitrostyrenes and isocyanides. Thus, a
mixture of an isocyanide 2 and a nitrostyrene 3 was heated at 80 °C
in water to produce the corresponding 5-aminoisoxazole-3-car-
boxamide 4 in 80–93% yields (Scheme 1, Table 1).
All the reactions reached completion within 2.5 h. 1H NMR analy-
sis of the reaction products clearly indicated the formation of the cor-
responding 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides 4a–l in
good to excellent yields.23
The isolated products 4 were characterized on the basis of IR, 1H
and 13C NMR spectroscopy, mass spectrometry, and elemental
analysis. The mass spectrum of 4a displayed a molecular ion (M+)
peak at m/z 367, which is consistent with the 2:1 adduct of cyclo-
hexyl isocyanide and 1-nitro-2-phenylethylene. The 1H NMR spec-
trum of 4a exhibited characteristic signals with appropriate
chemical shifts and coupling constants for the 22 protons of the
two cyclohexyl rings (d 1.18–2.08 and 3.52–3.92) and the five
phenyl H atoms (d 7.27–7.42) along with two fairly sharp doublets
(d 4.59, J = 7.5 Hz and d 6.51, J = 7.9 Hz) for the amine and amide
NH protons. In the 13C NMR spectrum of 4a, the cyclohexyl and
phenyl carbon atoms resonated at appropriate chemical shifts. A
shielded carbon (d 93.44 for ONC@C) and three deshielded carbons
Figure 2. ORTEP representation of the molecular structure of 4b.
H
Ar
Ar
Ar
_
O
_
O
+
N
+
N
_
C
+
R
+
_
N
R
R
N
_
O
+
N
N
O
O
O
2
R
3
6
5
R
+
N
O
R
_
C
+
N
NR
H
Ar
Ar
Ar
R
Ar
N
Ar
_
+
N
water
80 OC, 2.5 h
H
2
+
N
R
R
R
2
+
C
_
O
O
_
O
R
N
N
4
N
N
N
N
N
O
O
O
NO2
H
H
H
O
H
9
7
2
4
3
8
Scheme 1.
Scheme 2.

7248
M. Adib et al. / Tetrahedron Letters 50 (2009) 7246–7248
2007, 63, 11135–11140; Adib, M.; Aali Koloogani, S.; Abbasi, A.; Bijanzadeh, H.
R. Synthesis 2007, 3056–3060; Adib, M.; Sheibani, E.; Abbasi, A.; Bijanzadeh, H.
R. Tetrahedron Lett. 2007, 48, 1179–1182; Adib, M.; Sheibani, E.; Mostofi, M.;
Ghanbary, K.; Bijanzadeh, H. R. Tetrahedron 2006, 62, 3435–3438; Adib, M.;
Mahdavi, M.; Mahmoodi, N.; Pirelahi, H.; Bijanzadeh, H. R. Synlett 2006, 1765–
1767.
shift may then result in isoxazolium N-oxide intermediate 7.
Nucleophilic addition of a second isocyanide to 7 would yield the
2:1 adduct 8, which can undergo cyclization to form bicyclic inter-
mediate 9. This bicyclic intermediate would then rearrange to
afford 5-(alkylamino)-4-aryl-3-isoxazolecarboxamide 4.
23. The procedure for the preparation of N3-cyclohexyl-5-(cyclohexylamino)-4-
phenyl-3-isoxazolecarboxamide (4a) is described as an example: A mixture of 1-
nitro-2-phenylethylene (0.149 g, 1 mmol) and cyclohexyl isocyanide (0.240 g,
2.2 mmol) in H2O (2 mL) was stirred at 80 °C for 2.5 h, and then the reaction
mixture was cooled to room temperature. The aqueous phase was extracted
with CH2Cl2 (2 Â 5 mL) and the combined organic layers were dried over
MgSO4. The solvent was evaporated and the residue was purified by column
chromatography using n-hexane/EtOAc (4:1) as an eluent. The solvent was
removed and the product was obtained as colorless crystals, mp 74–76 °C,
In conclusion, we have reported a convenient, simple, and effi-
cient synthesis of 5-(alkylamino)-4-aryl-3-isoxazolecarboxamides
of potential synthetic and pharmacological interest. The use of
water as a green medium, simple and readily available starting
materials, and good to excellent yields of the products are the main
advantages of this method. The simplicity of this method makes it
an interesting alternative to other isoxazole syntheses.29 To the
best of our knowledge, this is the first synthesis of 5-amino-3-iso-
xazolecarboxamides. In this reaction, the nitrogen and oxygen
atoms in the isoxazole ring are unusually derived from the nitro
group of the activated styrene. In the previously reported conden-
sation of methylene isocyanides and nitroolefins, the nitro group is
eliminated or appears in the obtained pyrrole product.
yield 0.32 g, 87%. IR (KBr) (m
max/cmÀ1): 3314 (NH), 1664 (C@O), 1614, 1553,
1510, 1479, 1450, 1371, 1348, 1313, 1245, 1231, 1207, 1144, 1114, 1086, 1010,
891, 837, 758, 698. EI-MS m/z (%): 367 (M+, 46), 319 (6), 242 (75), 187 (16), 160
(57), 133 (31), 117 (17), 83 (100), 55 (69). Anal. Calcd for C22H29N3O2 (367.49):
C, 71.9; H, 8.0; N, 11.4. Found: C, 71.8; H, 8.1; N, 11.2%. 1H NMR (300.1 MHz,
CDCl3): d 1.18–2.08 [20H, m, 2CH(CH2)5], 3.52–3.67 [1H, m, NCH(CH2)5], 3.80–
3.92 [1H, m, NCH(CH2)5], 4.59 (1H, d, J = 7.5 Hz, NH), 6.51 (1H, d, J = 7.9 Hz,
NHC@O), 7.27–7.32 (1H, m, CH), 7.38–7.42 (4H, m, 4CH). 13C NMR (75.5 MHz,
CDCl3): d 24.76, 24.79, 25.39, 25.47, 32.83 and 33.84 (6CH2), 48.18 and 52.41
(2NHCH), 93.44 (ONC@C), 127.10, 128.66 and 129.66 (3CH), 129.75 (C), 156.85
(N@C), 158.97 (ONC@C), 166.85 (C@O). N3-(tert-Butyl)-5-(tert-butylamino)-4-
phenyl-3-isoxazolecarboxamide (4b): Yield 0.29 g, 91%. Colorless crystals, mp
120–121 °C. 1H NMR (500.1 MHz, CDCl3): d 1.40 and 1.41 [18H, 2s, 2C(CH3)3],
4.64 (1H, s, NH), 6.45 (1H, br s, NHC@O), 7.30 (1H, tt, J = 1.4, 7.3 Hz, CH), 7.36
(2H, d, J = 7.7 Hz, 2CH), 7.41 (2H, dd, J = 7.3, 7.7 Hz, 2CH). 13C NMR (125.8 MHz,
Acknowledgment
This research was supported by the Research Council of the Uni-
versity of Tehran as research project (6102036/1/03).
CDCl3):
d 28.71 and 29.96 [2C(CH3)3], 51.59 and 53.28 [2C(CH3)3], 95.11
(ONC@C), 127.16, 128.76 and 129.55 (3CH), 129.92 (C), 156.50 (N@C), 158.98
(ONC@C), 167.43 (C@O). N3-Cyclohexyl-5-(cyclohexylamino)-4-(4-methylph-
enyl)-3-isoxazolecarboxamide (4c): Yield 0.34 g, 90%. Colorless crystals, mp
125 °C. 1H NMR (500.1 MHz, CDCl3): d 1.15–2.05 [20H, m, 2CH(CH2)5], 2.36
(3H, s, CH3), 3.54–3.63 [1H, m, NCH(CH2)5], 3.82–3.91 [1H, m, NCH(CH2)5], 4.51
(1H, d, J = 8.1 Hz, NH), 6.47 (1H, d, J = 7.9 Hz, NHC@O), 7.21 (2H, d, J = 8.1 Hz,
2CH), 7.28 (2H, d, J = 8.1 Hz, 2CH). 13C NMR (125.8 MHz, CDCl3): d 21.20 (CH3),
24.73, 24.77, 25.43, 25.51, 32.84 and 33.87 (6CH2), 48.17 and 52.43 (2NHCH),
93.53 (ONC@C), 126.68 (C), 129.37 and 129.61 (2CH), 136.87 (C), 156.53 (N@C),
159.03 (ONC@C), 166.87 (C@O). 4-(4-Bromophenyl)-N3-cyclohexyl-5-(cyclohex-
ylamino)-3-isoxazolecarboxamide (4g): Yield 0.39 g, 88%. Colorless crystals, mp
155–156 °C. 1H NMR (500.1 MHz, CDCl3): d 1.16–2.04 [20H, m, 2CH(CH2)5],
3.54–3.63 [1H, m, NCH(CH2)5], 3.81–3.90 [1H, m, NCH(CH2)5], 4.50 (1H, d,
J = 8.1 Hz, NH), 6.52 (1H, d, J = 7.8 Hz, NHC@O), 7.27 (2H, d, J = 8.3 Hz, 2CH),
7.51 (2H, d, J = 8.3 Hz, 2CH). 13C NMR (125.8 MHz, CDCl3): d 24.71, 24.80, 25.39,
25.49, 32.86 and 33.84 (6CH2), 48.29 and 52.48 (2NHCH), 92.58 (ONC@C),
121.13 and 128.81 (2C), 131.44 and 131.77 (2CH), 156.18 (N@C), 158.84
(ONC@C), 166.81 (C@O). N3-Cyclohexyl-5-(cyclohexylamino)-4-(2-thienyl)-3-
isoxazolecarboxamide (4i): Yield 0.31 g, 85%. Colorless crystals, mp 96–97 °C.
1H NMR (500.1 MHz, CDCl3): d 1.16–2.05 [20H, m, 2CH(CH2)5], 3.58–3.67 [1H,
m, NCH(CH2)5], 3.84–3.93 [1H, m, NCH(CH2)5], 4.82 (1H, d, J = 7.5 Hz, NH), 6.46
(1H, br s, NHC@O), 7.06 (1H, dd, J = 3.6, 5.2 Hz, CH), 7.19 (1H, d, J = 3.6 Hz, CH),
7.29 (1H, d, J = 5.2 Hz, CH). 13C NMR (125.8 MHz, CDCl3): d 24.64, 24.79, 25.41,
25.50, 32.83 and 33.73 (6CH2), 48.30 and 52.45 (2NHCH), 87.19 (ONC@C),
125.00, 127.37 and 127.47 (3CH), 130.50 (C), 156.37 (N@C), 158.74 (ONC@C),
167.05 (C@O). 4-(4-Chlorophenyl)-N3-cyclohexyl-5-(cyclohexylamino)-3-iso-
xazolecarboxamide (4l): Yield 0.37 g, 92%. Colorless crystals, mp 187–188 °C.
1H NMR (500.1 MHz, CDCl3): d 1.15–2.00 [20H, m, 2CH(CH2)5], 3.50–3.61 [1H,
m, NCH(CH2)5], 3.79–3.87 [1H, m, NCH(CH2)5], 4.56 (1H, d, J = 8.0 Hz, NH), 6.56
(1H, d, J = 8.0 Hz, NHC@O), 7.32 (2H, d, J = 8.9 Hz, 2CH), 7.33 (2H, d, J = 8.9 Hz,
2CH). 13C NMR (125.8 MHz, CDCl3): d 24.69, 24.77, 25.34, 25.45, 32.78 and
33.77 (6CH2), 48.25 and 52.44 (2NHCH), 92.47 (ONC@C), 128.26 (C), 128.74
and 131.08 (2CH), 132.92 (C), 156.17 (N@C), 158.83 (ONC@C), 166.81 (C@O).
24. Selected X-ray crystallographic data for compound 4b: C18H25N3O2, monoclinic,
space group = P21/n, a = 10.3226(12) Å, b = 15.1764(18) Å, c = 12.1519(14) Å,
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