Studies on the reactivity of 3-methyl-4-nitro-5-styrylisoxazoles with S-nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2011.05.007

We have investigated the reactivity of 3-methyl-4-nitro-5-styrylisoxazoles with S-nucleophiles. This study revealed that the title compounds were optimal Michael acceptors toward thiols. A procedure was also established to prepare isoxazole-containing sul

Full text of DOI:10.1016/j.tetlet.2011.05.007

Tetrahedron Letters 52 (2011) 3602–3604
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Studies on the reactivity of 3-methyl-4-nitro-5-styrylisoxazoles
with S-nucleophiles
⇑
Simone Bruschi, Maria Moccia, Mauro F. A. Adamo
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry, The Royal College of Surgeons in Ireland,
123 St. Stephen’s Green, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
We have investigated the reactivity of 3-methyl-4-nitro-5-styrylisoxazoles with S-nucleophiles. This
study revealed that the title compounds were optimal Michael acceptors toward thiols. A procedure
was also established to prepare isoxazole-containing sulfides in one-pot and without the use of chroma-
tography. Isoxazole-containing sulfides were converted into the corresponding sulfones in high yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 4 February 2011
Revised 7 April 2011
Accepted 3 May 2011
Available online 11 May 2011
Keywords:
Multicomponent synthesis
Polyfunctional scaffolds
4-Nitroisoxazoles
1. Introduction
electrophilic alkenes.21 Part of this study demonstrated that
3-methyl-4-nitro-5-isoxazoles 4 reacted efficiently with bisulfite
The conjugate addition of thiols to electron-deficient olefins
leading to the formation of C–S bonds is an important step in the
synthesis of organosulfur compounds,1 and in the synthesis of
many sulfur-containing bioactive compounds.2–4 Several thia Mi-
chael additions have been reported under the catalysis of zeolites,5
Hf(OTf)3,6 alumina,7 InBr3,8 InCl3,9 Bi(NO3)3,10 Bi(OTf)3,11 Nafion
SAC-13,12 Cu(BF4)2ÁxH2O,13 Zn(ClO4)2Á6H2O14 and boric acid.15 In
a different approach, Yadav described the use of an ionic liquid
as a solvent and promoter of the 1,4-conjugate additions of thiols
giving excellent isolated yields of isoxazole sulfonic acids. Based
on this information, it was anticipated that isoxazole 1, an alde-
hyde 2, and a thiol 3 would react in a sequential Knoevenagel–thia
Michael process in the presence of a suitable amine catalyst. In a
typical experiment styrylisoxazole 4b was reacted with a small
excess of thiol 3 (1.2 equiv) and a catalytic amount of piperidine
(Table 1, entry 2). Gratifyingly, under these conditions, full conver-
sion of 4b was achieved in 2 h and the desired compound 5b was
formed in high yield (Table 1, entry 2).
Encouraged by this result, we next investigated the nature of
the base required for this transformation (Table 1). This study
established that secondary and tertiary amines were efficient cat-
alysts with piperidine giving the best result. The desired adduct
5b was obtained in high yield even when piperidine was used at
5 mol % catalyst loading, (Table 1, entry 9).
to
a
,b-unsaturated ketones.16 As part of our ongoing efforts in
developing multicomponent syntheses of potentially bioactive
scaffolds, we envisaged a novel synthesis of isoxazole-thioethers
5 exploiting a nucleophilic addition of thiols to electrophilic al-
kenes 4. In turn, alkenes 4 could be obtained by condensation of
commercially available 3,5-dimethyl-4-nitroisoxazole (1) and aro-
matic aldehydes 2 (Scheme 1).
We recently reported some applications of 3,5-dimethyl-4-nit-
roisoxazole (1) in which spiroisoxazolines,17 3-arylpropionic
acids,18 indole propionic acids,19 or arylglutaric acids20 were ob-
tained in one-pot from commercially available materials. These
syntheses were based on the ability of compound 1 to undergo
sequential Knoevenagel–Michael tandem reactions, when reacted
with an aromatic aldehyde and a suitable Michael donor in the
presence of catalytic amounts of base. In addition, we have
established a mild protocol for the addition of sodium bisulfite to
NO2
NO2
NO2
N
N
N
O
O
O
1
4
S
Ph
Ar
O
Ar
HS
Ar
2a-l
5a-l
3
⇑
Corresponding author. Tel.: +353 1 4022208; fax: +353 1 4022168.
E-mail address: madamo@rcsi.ie (M.F.A. Adamo).
Scheme 1. A disconnection approach to compounds 5a–l.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.007

S. Bruschi et al. / Tetrahedron Letters 52 (2011) 3602–3604
3603
Table 1
the preparation of 5a–k directly from 1, aldehydes 2a–k, and 3.
Therefore, isoxazole 1 and 1 equiv of aromatic aldehyde 2a–k were
first reacted in refluxing CH3CN in the presence of 0.1 equiv of
piperidine for 4 h. Next, 1.2 equiv of 3 were added and the reaction
continued until intermediate 4a–k disappeared. These experi-
ments gave the expected compounds 5a–k in similar high yields
(Table 3).
Screening of the base in the thia Michael reaction of 4b and 3
NO2
NO2
SH
N
N
base
O
O
+
CH3CN
S
We also briefly explored the synthetic potential of compounds 5
by oxidising sulfide 5b to sulfone 6. Hence reaction of 5b and ex-
cess m-chloroperbenzoic acid gave silfone 6 in nearly quantitative
yield demonstrating the stability of the 4-nitroisoxazole core to
peracids (Scheme 2).
In conclusion, we have reported a new Michael-type reaction of
3-methyl-4-nitro-5-styrylisoxazoles which generated isoxazole-
containing sulfides. The method was complemented by a multi-
component one-pot synthesis which started from inexpensive
and commercially available materials. The products were obtained
in excellent yields and did not require chromatographic purifica-
tion. It was also shown that compound 5b could be converted into
sulfone 6 quantitatively.
Cl
Cl
4b
3
5b
Entry
Base
—
Piperidine
Pyrrolidine
Et3N
DBU
DMAP
Pyridine
Piperidine
piperidine
Time (h)
Yielda (%)
1
2
3
4
5
6
24
2
4
0.5
24
1.5
24
24
48
—
86
71
80
55
78
50
84
82
7
8b
9c
a
Isolated yield after crystallization. All reactions were carried out using 2 equiv
General procedure for the preparation of compounds 5a–k (Table
2): To a solution of styrylisoxazole 4 (200 mg, 1.0 equiv) in CH3CN
(4 mL) was added piperidine (0.1 equiv) followed by benzyl mer-
captan 3 (1.2 equiv). The mixture was stirred at room temperature
until the starting material disappeared. The solvent was removed
under vacuum and the crude residue was purified by crystalliza-
tion from MeOH.
General one-pot procedure for the preparation of compounds 5a–k
(Table 3): To a solution of 3,5-dimethyl-4-nitroisoxazole (1) (1 g,
7.04 mmol, 1.0 equiv) in CH3CN (10 mL) was added piperidine
(0.1 equiv) and an aromatic aldehyde (1.0 equiv). The reaction mix-
ture was refluxed for 4 h and then cooled to room temperature and
benzyl mercaptan 3 (1.2 equiv) was added. The mixture was stirred
at room temperature until compounds 4a–k were consumed. The
solvent was removed and the crude residue was purified by crys-
tallization from MeOH.
of thiol 3, 0.3 equiv of base and CH3CN as the solvent.
b
0.1 equiv of base used.
0.05 equiv of base used.
c
We found that the reaction of 4b and 3 was remarkably slower
in protic solvents such as MeOH and EtOH. This could be partially
explained by the poor solubility of compound 4b in these solvents.
Similarly, the reaction was slower when carried out in CH2Cl2 or
toluene. It was, therefore, concluded that CH3CN was the best reac-
tion medium.
Having determined an appropriate set of reaction conditions,
we next demonstrated the scope of this reaction preparing a small
family of adducts 5 (Table 2). Styryl isoxazoles 4 were reacted with
1.2 equiv of benzyl mercaptan (3) and 0.3 equiv of piperidine in
CH3CN to afford the desired adducts in good to excellent isolated
yields. Compounds 5 were obtained by crystallization from MeOH
without the intervention of chromatography.
5-(2-Benzylsulfanyl-2-phenyl-ethyl)-3-methyl-4-nitroisoxazole
(5a): White solid, (85%); mp 87–89 °C; Rf: 0.2 (PE/EtOAc, v/v
12:1); 1H NMR d: (400 MHz, CDCl3): 7.36–7.25 (8H, m),
Having determined that a basic catalyst was required for the
conversion of 4a–k into 5a–k, and considering that the generation
of 4a–k required similar basic conditions, we decided to attempt
Table 3
One-pot synthesis of compounds 5a–k
Table 2
NO2
Synthesis of thia Michael adducts 5
NO2
NO2
NO2
N
HS
SH
N
O
piperidine
CH3CN
N
N
O
piperidine (0.1 equiv.)
CH3CN
O
O
S
+
1
3
Ar
O
Ar
Ar
5a-m
S
5a-k
Ar
2a-k
4a-m
3
Entry
Substrate
Ar
Product
Yielda,b (%)
Entry
Product
Ar
Yield (%)a
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
p-ClC6H4
p-FC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
85
84
83
84
80
78
88
86
81
81
78
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
C6H5
p-ClC6H4
p-FC6H4
p-BrC6H4
p-H3COC6H4
p-H3CC6H4
p-O2NC6H4
2,4-Cl2C6H3
p-NCC6H4
70
65
63
81
64
69
80
68
63
65
68
p-BrC6H4
p-H3COC6H4
p-H3CC6H4
p-O2NC6H4
2,4-Cl2C6H3
p-NCC6H4
2,3-Cl2C6H3
3,5-Cl2C6H3
9
10
11
4j
4k
5j
5k
9
10
11
5j
5k
2,3-Cl2C6H3
3,5-Cl2C6H3
a
Isolated yield after crystallization.
Reactions carried out at room temperature using 1.2 equiv of thiol 3.
b
a
Isolated yield after crystallization.

3604
S. Bruschi et al. / Tetrahedron Letters 52 (2011) 3602–3604
NO2
Acknowledgments
NO
2
N
N
CH2Cl2
We thank the PTRLI cycle III and IRCSET for a grant to M.F.A.A.
and S.B., and FP7 Marie Curie for a grant to M.M. We also thank
SFI grant RFP2007 CHEF839 for generous support and highly valu-
able advice.
O
O
m-CPBA (3 equiv.)
r.t., 30 min
S
S
O
O
5b
6
97% yield
Cl
Scheme 2. Preparation of sulfone 6.
Cl
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.007.
7.20–7.18 (2H, m), 4.23 (1H, app t, J = 8.4 Hz), 3.70 (2H, d, J =
8.0 Hz), 3.61 (1H, d, J = 13.5 Hz), 3.50 (1H, d, J = 13.5 Hz), 2.50
(3H, s); 13C NMR d: (100 MHz, CDCl3): 171.7, 155.5, 140.0, 137.4,
129.0, 128.9, 128.6, 128.1, 127.7, 127.3, 46.2, 35.9, 34.5, 11.7; IR:
mmax (KBr)/cmÀ1: 3030, 2916, 1603, 1518, 1414, 1379, 1359, 827,
698; HRMS: Calcd for C19H18N2O3S ([M]+): 354.1038. Found:
354.1042.
References and notes
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isoxazole (5b): White solid (84%); mp 108–111 °C; 1H NMR d:
(400 MHz, CDCl3): 7.23–7.17 (7H, m), 7.10–7.08 (2H, m), 4.09
(1H, app t, J = 8.0 Hz), 3.57 (2H, dd, J = 8.0 Hz, J = 1.4 Hz), 3.52
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19H17ClN2O5S ([M]+): 420.0547, found 420.0529.