A new synthesis of 3,4-disubstituted 1,2,5-thiadiazoles

Article abstract of DOI:10.1016/j.tetlet.2007.05.123

A simple and convenient reduction of 3,4-diamino derivatives of 2,5-thiadiazole-1-oxide to the corresponding 1,2,5-thiadiazoles has been accomplished using Ph₃P and CCl₄ in dichloromethane.

Full text of DOI:10.1016/j.tetlet.2007.05.123

Tetrahedron Letters 48 (2007) 5279–5282
A new synthesis of 3,4-disubstituted 1,2,5-thiadiazoles
*
Purakkattle Biju and Younong Yu
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA
Received 27 April 2007; revised 16 May 2007; accepted 21 May 2007
Available online 24 May 2007
Abstract—A simple and convenient reduction of 3,4-diamino derivatives of 2,5-thiadiazole-1-oxide to the corresponding 1,2,5-thia-
diazoles has been accomplished using Ph P and CCl in dichloromethane.
3 4
Ó 2007 Elsevier Ltd. All rights reserved.
3
,4-Disubstituted 2,5-thiadiazoles are important hetero-
O
S
HN
NH
aryl pharmacophores in drug discovery. For example,
the widely used b-adrenergic antagonist Timolol 1, a
drug for ocular hypertension, has a 3,4-disubstituted
1
antagonist 3, which were in early stage clinical develop-
ment, also possess the 1,2,5-thiadiazole motif. Owing to
the importance of this pharmacophore in drug discovery
programs in addition to our own efforts to discover a
S
HCl
Ò
N
N
N
N
1
O
MeOH
HN
R1 R2
NH
HN
NH
HN
R1
NH
R2
2
N S
,2,5-thiadiazole motif. Xanomeline 2 and an H-2
R R
1 2
3
2
4a
Scheme 1. Hydrolysis route.
4b
4
O
4
CXCR2 antagonist for anti-inflammatory conditions,
we became interested in the synthesis of 3,4-diamino
derivatives of 1,2,5-thiadiazole 4 from readily available
thiadiazole-1-oxide 4a. Herein we report a simple syn-
thesis of 3,4-diamino substituted 1,2,5-thiadiazoles from
the corresponding thiadiazole-1-oxides through a reduc-
tion procedure using triphenyl phosphine and carbon
tetrachloride.
treatment of readily available 3,4-diethoxy thiadiazole-
1-oxide 5 with various amines and alcohols, acid hydro-
lysis of the resulting sulfoxide 4a results in the formation
of diimine 4b. Subsequent treatment of diimine 4b with
N,N-thiobisphthalimide generates the desired thiadiaz-
ole 4. This Letter demonstrates a more concise approach
to avoid the acid catalyzed hydrolysis of sulfoxide and
S
S
N
N
N
N
S
S
N
N
NH2
NH
N
O
N
N
H
O
(
CH ) CH3
2 5
R1 NH
NH R2
N
N
O
OH
N
N
S
1
2
3
4
Previous reports3,5 suggest the inability to directly re-
duce thiadiazole 1-oxide to thiadiazole by conventional
methods. The reported synthesis of 3,4-disubstituted
reintroduction of sulfur, by use of a direct reduction
without ring cleavage.
1
,2,5-thiadiazole requires two steps from the corre-
The known 3,4-diethoxy 2,5-thiadiazole-1-oxide 5 was
4
a
sponding thiadiazole-1-oxide (Scheme 1). In general, fol-
lowing introduction of the 3- and 4-substituents by
treated with phenolic amine 6 to generate the corre-
sponding singly substituted compound 7. Sulfoxide 7
was again treated with the commercially available benz-
yl amine 8 and diisopropylethylamine in methanol to
afford the corresponding diamino-thiadiazole-1-oxide
Keywords: 2,5-Thiadiazole 1-oxide; 1,2,5-Thiadiazole; Triphenylphos-
9
. At this stage, we extensively studied the reduction
phine and carbon tetrachloride.
*
Corresponding author. Tel.: +1 908 740 3127; fax: +1 908 740
152; e-mail: purakkattle.biju@spcorp.com
of diamino thiadiazole-1-oxide 9 to the corresponding
thiadiazole 10 using standard reduction procedures.
7
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.123

5280
P. Biju, Y. Yu / Tetrahedron Letters 48 (2007) 5279–5282
After several unsuccessful attempts, reduction was final-
ly accomplished by treating a solution of monoxide 9 in
dichloromethane with triphenylphosphine, followed by
the drop-wise addition of carbon tetrachloride at
The following table shows the synthesis of a variety of
thiadiazoles from the corresponding thiadiazole oxides
using the Ph P/CCl reduction procedure. The mono-
3
4
oxide intermediates (9a to 9h) were prepared from the
4
a,b
0
°C. The resulting reaction mixture was slowly warmed
corresponding amines
and 3,4-diethoxy 2,5-thiadiaz-
to room temperature and then refluxed for 3 h. The
purification of the final thiadiazole was accomplished
by removal of the solvent under vacuum and subsequent
column chromatography or preparative thin layer chro-
matography using methanol and dichloromethane (1:20
ratio) to afford the desired thiadiazole 10 in 85% yield
ole-1-oxide 5 in excellent yield, using the same procedure
described for compound 9. The yields for the reduction
step vary from 72% to 82% in some cases.
In summary, we have accomplished a simple and mild
reduction of 2,5-thiadiazole-1-oxide to the correspond-
ing 1,2,5-thiadiazole using Ph P and CCl . A plausible
(
Scheme 2).
3
4
mechanism has been proposed and can be used for the
synthesis of substituted 1,2,5-thiadiazoles in one step
from the corresponding thiadiazole-1-oxide.
6
A plausible mechanism for the reaction includes the
formation of the intermediate 11, which then undergoes
an elimination of chloride ion and triphenylphosphine
oxide, resulting in the thiadiazole 4 (Scheme 3). Both
the X-ray crystal structure and ab initio theoretical cal-
culations have shown that thiadiazole sulfoxides are
1
Spectral data: Compound 7: H NMR (400 MHz,
DMSO-d ): 9.58 (1H, br s), 7.64 (1H, d, J = 8.0 Hz),
6
7.04 (1H, d, J = 7.6 Hz), 6.92 (1H, t, J = 8 Hz), 4.52
(2H, m), 2.89 (6H, s), 1.42 (3H, t, J = 7.0 Hz): LCMS
7
non-aromatic and have pyramidal sulfur. The driving
force for this reduction may be the formation of a more
stable, aromatic 1,2,5-thiadiazole.
+
(m/z): 325.2 (M+H) , 280.2, 234.1; HRMS calcd for
+
C H N O S (M+H) : 325.09705; found: 325.09662.
1
3
17
4
4
1
After successfully developing the reduction procedure, a
number of thiadiazoles (10a–h) were synthesized in good
yield as shown in Table 1. The reduction procedure is
quite compatible with functional groups including
amines, phenols, amides, esters, furans, and thiophenes.
Compound 9: H NMR (400 MHz, DMSO-d ): 9.72
6
(1H, br s), 8.77 (1H, s), 7.63 (1H, d, J = 7.6 Hz), 7.36–
7.40 (4H, m), 7.27 (1H, s), 7.01 (1H, d, J = 7.6 Hz),
6.91 (1H, t, J = 7.2 Hz), 4.77 (1H, s), 2.94 (6H, s),
1.84–1.97 (2H, m), 0.935 (3H, t, J = 6.8 Hz): LCMS
O
S
O
S
N
N
N
N
N
i
NH2
N
N
C H O
OC H
O
OH
OC H
2 5
2
5
2
5
H
O
OH
5
6
7
ii
NH2
8
O
S
N
N
S
N
N
N
iii
N
H
N
N
N
H
O
OH
H
N
O
OH
H
10
9
3 3 3
Scheme 2. Reagents and conditions: (i) diisopropylethylamine, CH OH, rt, 12 h, 90%; (ii) CH OH, diisopropylethylamine, rt, 12 h 80%; (iii) PPh
(
3 equiv), CCl , CH Cl , 0 °C–reflux, 3 h; 85%.
4
2
2
Ph P
3
CCl4
Ph PCl CCl3
Ph P CCl3 Cl
3
3
Ph P CCl3 Cl
3
Ph P
3
Ph P CCl2
3
Ph P Cl Cl
3
Ph P Cl Cl
Ph
3
PCl
2
3
Cl
Ph3+P
O
S
Cl
O
N
S
S
Ph
3
P
CCl
2
N
N
N
N
Ph PCl
3 2
N
Ph P
3
O
Ph P CCl3 Cl
3
R1 NH
NH R2
R1 NH
NH R2
R1 NH
NH R2
4
11
Scheme 3. Proposed mechanism for the reduction.

P. Biju, Y. Yu / Tetrahedron Letters 48 (2007) 5279–5282
Table 1. Examples of reduction of 2,5-thiadiazole-1-oxide to 1,2,5-thiadiazole
5281
O
S
S
N
N
N
N
Ph P (3.0 eqv.), CCl (excess)
3
4
R1
R2
R
1
R
2
N
H
N
H
CH Cl , 0
ºC - reflux, 3 h
N
N
2
2
H
H
Entry
2,5-Thiadiazole-1-oxide (9a–h)
Product (10a–h) 1,2,5-thiadiazole
Yield (%)
O
S
S
N
N
N
N
O
F
N
H
N
1
O
9a
10a
10b
81
78
F
N
H
OH
H
N
H
OH
O
O
S
S
N
N
N
N
O
N
2
O
9b
N
N
H
N
H
H
OH
N
H
OH
N
O
S
S
N
N
N
N
3
4
9c
9d
10c
10d
72
81
S
N
H
S
N
H
N
H
N
H
O
OH
O
OH
O
S
S
S
N
N
N
N
N
N
N
N
N
N
N
H
N
H
N
H
N
H
O
O
OH
OH
O
O
OH
OH
O
S
N
N
F
5
6
F
9e
9f
N
H
N
H
10e
10f
76
78
N
H
N
H
F
F
O
S
S
S
N
N
N
N
N
N
N
N
O
O
N
N
O
O
N
H
N
H
N
H
N
H
O
O
OH
OH
O
O
OH
OH
O
S
N
N
O
S
O
N
H
7
9g
N
H
10g
82
N
H
N
H
O
S
N
N
N
N
N
N
N
N
8
9h
10h
78
N
N
N
H
N
H
O
O
O
OH
O
OH
+
(
m/z) : 414.2 (M+H) , 351.2, 279.2, 233.1; HRMS calcd
4.74–4.84 (2H, m), 3.19 (6H, s), 2.06 (1H, m), 1.89
(1H, m), 0.95 (3H, t, J = 7.2 Hz): C NMR, (CDCl3):
+
13
for C H N O S (M+H) : 414.15998; found:
2
0
24
5
3
4
14.16200.
172.0, 149.1, 147.3, 143.4, 142.6, 130.2, 128.5, 128.5,
1
27.3, 126.8, 126.8, 120.9, 119.4, 118.6, 116.7, 60.2,
1
+
Compound 10: H NMR (400 MHz, CDCl ): 10.70 (1H,
38.5, 38.5, 29.9, 10.8; LCMS (m/z): 398.2 (M+H) ,
280.2, 235.1; HRMS calcd for C H N O S (M+H) :
398.16507; found: 398.16538.
3
+
s), 8.19 (1H, d, J = 7.6 Hz), 7.2–7.4 (5H, M), 7.16 (1H,
s), 6.96 (1H d, J = 7.2 Hz), 6.85 (1H, t, J = 8 Hz),
2
0
24
5
2

5282
P. Biju, Y. Yu / Tetrahedron Letters 48 (2007) 5279–5282
4. (a) Dwyer, M. P.; Yu, Y.; Chao, J.; Aki, C.; Chao, J.; Biju,
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We thank Dr. Arthur Taveras, Dr. Christopher Boyce,
Dr. Robert Aslanian, and Dr. John Piwinski from the
Schering-Plough Research Institute. We also thank the
NMR and Mass spectral groups of SPRI for the spectral
data.
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