Microwave-assisted novel and efficient one-pot synthesis of fused steroidal and non-steroidal isothiazoles

Article abstract of DOI:10.1016/j.tetlet.2012.06.021

An efficient microwave promoted one-pot synthesis of steroidal and non-steroidal isothiazole derivatives from corresponding β-bromo-α, β-unsaturated aldehydes has been described using a sodium thiocyanate-urea system. The β-bromo-α,β-unsaturated aldehydes derivatives are efficiently synthesized from corresponding cyclic ketones using Vilsmeir formylation reaction. The synthetic protocol is also applied for the synthesis of antifungal brassilexin.

Full text of DOI:10.1016/j.tetlet.2012.06.021

Tetrahedron Letters 53 (2012) 4389–4392
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted novel and efficient one-pot synthesis of fused steroidal
and non-steroidal isothiazoles
⇑
Pranjal Bezbaruah, Junali Gogoi, Kommuri S. Rao, Pranjal Gogoi, Romesh C. Boruah
Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient microwave promoted one-pot synthesis of steroidal and non-steroidal isothiazole derivatives
Received 16 May 2012
Revised 4 June 2012
Accepted 6 June 2012
Available online 13 June 2012
from corresponding b-bromo-
a,b-unsaturated aldehydes has been described using a sodium thiocyanate-
urea system. The b-bromo- ,b-unsaturated aldehydes derivatives are efficiently synthesized from corre-
a
sponding cyclic ketones using Vilsmeir formylation reaction. The synthetic protocol is also applied for the
synthesis of antifungal brassilexin.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Microwave
Steroidal isothiazole
b-Bromo-a,b-unsaturated ketone
Brassilexin
Urea
Isothiazoles are important class of heterocyclic compounds
which have been incorporated into a wide range of biologically ac-
tive compounds, either as a substituent group or as a replacement
of another ring.1 Isothiazole derivatives are used as chiral auxiliaries
for asymmetric synthesis,2 electrophilic fluorination of enolates3
and has also been suggested for many industrial applications.4–6 In
addition, the isothiazole moiety constitutes the core structure of
many synthetic pharmaceuticals displaying broad spectrum of bio-
logical activities.7 A preliminary biological evaluation of some of
the isothiazole 1,1-dioxide and 4,5-dihydroisothiazole 1,1-dioxide
derivatives has shown promising pharmacological activities against
arterial smooth cell (SMC) proliferation.8 Additionally, derivatives of
isothiazoles are reported as potent inhibitors of VEGF receptors,9
histone acetyltransferase,10 and kinase,11 and also exhibit antiviral
activities12 and brain cholinergic channel activator properties.13
Some of the isothiazole bearing derivatives such as, Ziprasi-
done14 (1) (marketed as Geodon/Zeldox by Pfizer) and Perospi-
rone15 (2) (Lullan) are atypical antipsychotics approved for the
treatment of schizophrenia, mania and mixed states associated
with bipolar disorders. Similarly, naturally occurring Sinalexin (3)
and Brassilexin (6j) are among the most potent antifungal phytoal-
exins produced by economically important cruciferous plants
(Fig. 1).16
odologies are based on annulations of isothiazole moiety to non-ste-
roidal building blocks. On the other hand, the studies on steroidal
heterocycles emerge as an important area of research and enormous
efforts have been made for the synthesis of novel heterosteroids be-
cause of their inherent biological activities.18 To the best of our
knowledge, incorporation of an isothiazole moiety in the steroidal
core still received limited attentions. For example, Seldes et al.19
reported the synthesis of A-ring fused steroidal isothiazole from
5a
-cholestan-3-one via a tedious multi-step reaction. On the other
hand, Barton20 synthesized 3b-acetoxycholest-4-eno[6,5,4-c,d]
H
N
N
S
Cl
O
N
N
R
6j
R=H: Brassilexin (
)
N
N
R=OMe: Sinalexin (3)
1
Ziprasidone ( )
S
O
H
N
N
The importance of isothiazole pharmacophore in clinical drug
molecules has attracted organic chemists to look for new synthetic
strategies of their analogs.17 However, most of these syntheticmeth-
S
N
N
H
O
2
Perospirone ( )
⇑
Corresponding author. Tel.: +91 3762372948; fax: +91 3762370011.
E-mail address: rc_boruah@yahoo.co.in (R.C. Boruah).
Figure 1. Some important molecule having isothiazole molecular unit.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.021

4390
P. Bezbaruah et al. / Tetrahedron Letters 53 (2012) 4389–4392
O
Br
S
N
CHO
i
ii
H
H
H
AcO
AcO
AcO
4a
6a
5a
Scheme 1. Reagents and conditions: (i) PBr3/DMF/CHCl3, 72%; (ii) NaSCN/urea/DMF, MW 360 W, 10 bar 80%.
Table 1
isothiazole by thereaction of thiazyl chlorideand cholesteryl acetate
Synthesis of fused steroidal and non-steroidal Isothiazoles (6a–6j)
with very low yield (15%). The b-halo-a,b-unsaturated aldehyde
functional group is an interestingorganic synthon,21 however exam-
ple of its application in the field of steroids is scarce.22 In continua-
tion of our research interests on A- and D-ring fused
heterocycles,23 we report herein a one-pot synthesis of steroidal iso-
thiazoles from the reaction of easily accessible A- and D-ring ann-
Entry Substrate (5a–5j)
Products (6a–6j)
Yield
(%)
Br
Br
S
S
N
N
CHO
CHO
1
82
85
87
H
H
H
elated b-bromo-a,b-unsaturated aldehydes with a mixture of
AcO
AcO
sodium thiocyanate and urea as an environmentally benign source
6a
5a
of ammonia under microwave irradiation (MWI).24
In a typical experimental procedure, a mixture of 3b-acetoxy-17-
bromo-16-formyl-androst-5,17-diene (5a, 1 mmol), sodium thiocy-
anate (1.5 mmol), and urea (3 mmol) in DMF (1 ml) was exposed to
MWI in a Synthos 3000 (Anton Paar) microwave reactor for 3 min at
140 °C at 10 bar pressure and power at 80% (maximum output
360 W) to afford 3b-acetoxy-5,17-dieno-androst [16,17-d]isothiaz-
ole 6a in 82% yield (Scheme 1) (Table 1, entry 1). The product 6a was
characterized by comparison of physical and spectral data.25 When
the same reaction was carried out with chloroformyl steroid, for
example, 3b-acetoxy-17-chloro-16-formyl-androst-5,17-diene, we
obtained desired product 6a with lower yield (67%). The starting
material 5a was conveniently prepared from 3b-acetoxy-androst-
5-en-17-one (4a) using Vilsmeier reagent prepared freshly from a
mixture of phosphorous tribromide and N,N-dimethylformamide.
2
H
AcO
AcO
6b
5b
OAc
OAc
H
3
4
O
H
N
S
H
Br
6c
5c
H
H
H
H
H
86
79
O
H
H
N
S
H
H
Br
6d
5d
Similarly, steroidal A- and D-ring annelated b-bromo-a,b-unsatu-
rated aldehydes (5b–5g) were accomplished, respectively, from
the Vilsmeir reaction of commercially available estrone, testoster-
one, cholesterol, and stigmasterol.22c The reaction of 5b–5f with so-
dium thiocyanate and urea afforded corresponding isothiazoles (
6b–6f) in good yields (Table 1, entries 2–6).25 The synthesis of A-
and D-ring fused steroidal bis-isothiazole 6g was accomplished
from 4-androsten-3,17-dione by initial reduction to dihydroand-
rost-3,17-dione followed by Vilsmeier formylation reaction to
3,17-dibromo-2,16-diformyl-androst-2,16-diene (5g). The reaction
of 5g with sodium thiocyanate and urea in DMF under MWI afforded
the desired androst[2,3-d][16,17-d]bisisothiazole 6g in 75% yield
H
5
6
O
N
S
Br
O
O
O
5e
6e
H
H
H
81
O
H
N
S
H
Br
(Table 1, entry 7). Similarly, the non-steroidal b-bromo-a,b-unsatu-
5f
O
6f
rated aldehyde analogs, for example, 1-bromo-2-formyldihydro-
naphthalene (5h) reacted with sodium thiocyanate and urea
under microwave irradiation to afford 3,4-dihydronaphth[2,1-
d]isothiazole (6i) in 84% yield.
Br
S
N
H
CHO
7
8
75
84
O
N
S
H
H
In order to broaden the scope of our reaction, we planned to
synthesize antifungal brassilexin (6j)26 using our synthetic strat-
egy. A recent literature report revealed the synthesis of 6j from in-
dole-2-thione using Vilsmeier formylation and subsequent
oxidation, which in general led to undesired by-product 5H-thio-
pyrano[2,3-b:6,5-b0]diindole.27 In our strategy, we employed indo-
lin-2-one (4j) in place of indole-2-thione to afford corresponding
2-bromo-3-formylindole 5j28 using Vilsmeier reaction. The bassi-
lexin 6j was conveniently synthesized from 5j using our one-pot
synthesis protocol as the major isolable product (Scheme 2).
A plausible mechanism for the one-pot formation of 4,5-dihy-
dronaphtho[2,1-d]isothiazole 6h from 1-bromo-3,4-dihydronaph-
thalene-2-carbaldehyde 5h is proposed in Scheme 3. Under
microwave heating urea released ammonia29 and reacted with
aldehyde group to form intermediate A. The aldimine intermediate
Br
H
H
6g
5g
Br
N
S
CHO
6h
5h
Br
N
S
CHO
9
86
82
MeO
MeO
5i
6i
CHO
N
S
Br
10
N
H
N
6j
H
5j

P. Bezbaruah et al. / Tetrahedron Letters 53 (2012) 4389–4392
4391
Urea/NaSCN/DMF
CHO
MW, 360 W, 140o C,
PBr3/DMF/CHCl3
N
S
60-70 oC, 5h
70%
10 bar, 3 min
O
Br
N
H
82 %
N
H
N
H
4j
; 2g scale
5j
6j
)
Brassilexin (
Scheme 2. Microwave-assisted one-pot synthesis of Brassilexin (6j).
Urea
NC
Br
NH
Br
S
NH
MWI
NH3
CHO
- SCN
5h
A
B
NaSCN
MWI
NaSCN
Urea
-HCN
N
S
SCN
MWI
CHO
6h
7h
Scheme 3. Proposed mechanism for the synthesis of fused isothiazole.
A probably facilitated the nucleophilic addition of ‘SCN’ to form
intermediate B, which afforded the isothiazole 6h by nucleophilic
substitution at the S-atom. To support the mechanism, we inde-
pendently attempted to introduce the thiocyanate group under
identical condition via substitution reaction of compound 5h with
sodium thiocyanate in DMF in the absence of urea. The reaction did
not proceed at all and we failed to isolate the expected product 7h
under MWI as well as conventional heating of compound 5h. How-
ever, the addition of urea to the same reaction pot, smoothly
accomplished our desired product 4,5-dihydronaphtho[2,1-d]iso-
thiazole 6h with high yield, thus rendering support to our pro-
posed mechanism. The use of a mixture of sodium thiocyanate
and ammonium acetate (in place of urea) under identical condition
also led to product 6h, albeit in lower yield (48%).
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In conclusion, we have reported an efficient one-pot strategy for
the synthesis of steroidal and non-steroidal isothiazoles from corre-
sponding b-bromo-a,b-unsaturated aldehydes using a simple sys-
tem of sodium thiocyanate and urea. We could successfully
demonstrate the utility of urea as an environmentally benign and
safe source of ammonia as well as novel strategy for isothiazole syn-
thesis avoiding alternative use of toxic liquid ammonia. In addition,
the synthetic protocol is also conveniently employed for the im-
proved synthesis of brassilexin from 2-bromo-3-formylindole. The
advantages of the present procedure are relatively short reaction
time, easy work-up procedure, and high yield. Further work on the
synthetic potential toward sinalexin and its analogs is in progress.
Acknowledgments
We acknowledge the Department of Science & Technology (DST)
and CSIR, New Delhi for their financial support. One of us, P.B. thanks
UGC, New Delhi for the award Junior Research Fellowship. We are
grateful to the Director, CSIR-NEIST, Jorhat for his keen interests.
Supplementary data
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Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.021.

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155-57 °C; yield 85%, Rf = 0.3 (20% EtOAc in hexanes). 1H NMR (300 MHz,
CDCl3): d = 8.22 (s, 1H), 7.24–7.3 (m, 1H), 6.88–6.8 (m, 2H), 2.951.52 (m, 13H),
2.29 (s, 3H), 1.08 (s, 3H); 13C NMR (90 MHz, CDCl3): d = 178.4, 169.9, 152.2,
148.6, 143.2, 137.9, 137.5, 126.2, 121.7, 119.9, 61.8, 45.5, 44.1, 37.4, 35.5, 29.3,
27.3, 26.6, 26.1, 21.2, 19.3; IR (CHCl3): 3018, 2980, 2931, 2856, 1759, 1493,
;
1370, 1207, 1014, 755 cmꢀ1 MS (ESI): m/z 353 [M+]; Anal. Calcd for
C
21H23NO2S (353.48): C, 71.36; H, 6.56; N, 3.96%. Found: C, 71.35; H, 6.59; N,
3.99%.
Cholest-2,4,6-trieno-[2,1-d]isothiazole (6d): White solid, mp 106–10 °C; yield
86%, Rf = 0.4 (15% EtOAc in hexanes): 1H NMR (300 MHz, CDCl3): d = 8.18 (s,
1H), 6.28 (s, 1H), 6.08 (dd, J1 = 2.43 Hz, J2 = 9.8 Hz, 1H), 5.9 (d, J = 9.7 Hz, 1H),
2.95 (d, J = 15.6 Hz, 1H), 2.5 (d, J = 15.6 Hz, 1H), 2.2–0.86 (m, 32H), 0.74 (s, 3H);
13C NMR (90 MHz, CDCl3): d = 156.2, 156.1, 146.1, 135.9, 130.8, 127.4, 112.3,
56.0, 54.2, 50.7, 43.1, 39.7, 39.5, 38.2, 37.4, 36.1, 35.8, 33.9, 28.2, 28.0, 23.9,
23.8, 22.8, 22.6, 20.9, 18.7, 16.0, 11.8; IR (CHCl3): 2949, 2868, 1466, 1381, 771,
755 cmꢀ1; MS(ESI): m/z 423 [M+]; Anal. Calcd for C28H41NS (423.70): C, 79.37;
H, 9.75; N, 3.31%. Found: C, 79.35; H, 9.76; N, 3.31%.
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25. Spectral and analytical data of selected compounds:
Androst[2,3-d][16,17-d]bisisothiazole (6g): White solid, mp 217–20 °C; yield
86%, Rf = 0.4 (30% EtOAc in hexanes): 1H NMR (300 MHz, CDCl3): d = 8.19 (s,
1H), 8.18 (s, 1H), 2.9–1 (m, 18H), 1.1 (s, 3H), 0.82 (s, 3H); 13C NMR (90 MHz,
CDCl3): d = 178.4, 157.9, 157.2, 152.1, 143.3, 132.9, 62.4, 53.6, 45.2, 42.5, 36.9,
35.9, 35.5, 34.7, 31.2, 28.5, 27.8, 26.8, 20.8, 19.2, 11.6; IR (CHCl3): 2917, 2853,
1444, 1373, 752 cmꢀ1; MS(ESI): m/z 370.1 [M+]; Anal. Calcd for C21H26N2S2
(370.57): C, 68.06; H, 7.07; N, 7.56%. Found: C, 68.10; H, 7.01; N, 7.55%.
Indolo[3,2-d]isothiazole (Brassilexin 6j): Brown solid, mp 141–43 °C (literature
mp 140–42 °C)27 yield 70%, Rf = 0.2 (30% EtOAc in hexanes)]: 1H NMR
,
(300 MHz, CD3OD): d = 8.30 (s, 1H), 7.45 (dd, J1 = 1.9, J2 = 6.1 Hz, 1H), 7.10–
6.99 (m, 3H); 13C NMR (90 MHz, CD3OD): d = 176.0, 150.4, 138.0, 128.4, 122.7,
121.1, 114.4, 109.1, 107.2; IR (CHCl3): 3063, 3017, 2938, 2891, 1478, 1242, 949,
822, 759 cmꢀ1; MS(ESI): m/z 174 [M+]; Anal. Calcd for C9H6N2S (174.22): C,
62.05; H, 3.47; N, 16.08%. Found: C, 62.09; H, 3.44; N, 16.07%.
26. Pedras, M. S. C.; Okanga, F. I.; Zaharia, I. L.; Khan, A. Q. Phytochemistry 2000, 53,
161.
3b-Acetoxy-androst-5,17-dieno[16,17-d]isothiazole (6a): Yellow solid, mp 162–
65 °C; yield 82%, Rf = 0.3 (10% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3):
d = 8.12 (s, 1H), 5.36 (d, J = 5.0 Hz, 1H), 4.53 (m, 1H), 2.64–0.88 (m, 17H), 1.97
(s, 3H), 1.02 (s, 3H), 1.01 (s, 3H); 13C NMR (90 MHz, CDCl3): d = 178.4, 170.6,
152.1, 143.3, 140.0, 121.9, 73.7, 62.6, 49.9, 45.1, 38.1, 36.8, 35.5, 31.3, 30.9,
27.7, 26.8, 21.5, 20.6, 19.3, 19.1 (one peak is missing due to overlap); IR
(CHCl3): 2945, 2854, 1732, 1373, 1246, 1033, 756 cmꢀ1; MS(ESI): m/z 311.1
[M+ꢀCH3COOH]; Anal. Calcd for C22H29NO2S (371.54): C, 71.12; H, 7.87; N,
3.77%. Found: C, 71.13; H, 7.77; N, 3.69%.
27. Pedras, M. S.; Jha, M. J. Org. Chem. 2005, 70, 1828–1834.
28. The Vilsmeier reaction of 2-bromo-3-formylindole was carried out using
3 mequiv of phosphorous tribromide and dimethylformamide in 2 g scale with
70% yield.
29. (a) Barthakur, M. J.; Borthakur, M.; Devi, P.; Saikia, C. J.; Saikia, A.; Bora, U.;
Chetia, A.; Boruah, R. C. Synlett 2007, 223–226; (b) Borthakur, M.; Boruah, R. C.
Steroids 2008, 73, 637–641; (c) Borthakur, M.; Dutta, M.; Gogoi, S.; Boruah, R. C.
Synlett 2008, 3125–3128; (d) Borthakur, M.; Gogoi, S.; Gogoi, J.; Boruah, R. C.
Tetrahedron Lett. 2010, 51, 5160–5163.
3-Acetoxyestra-1,3,5(10),17-tetraeno[16,17-d]isothiazole (6b): White solid, mp