Tetrahedron Letters
Synthesis of 5-substituted 3-mercapto-1,2,4-triazoles via
Suzuki–Miyaura reaction
⇑
Sarmite Katkevica, Pavlo Salun, Aigars Jirgensons
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Bromo- and 3-iodo-N,S-dibenzyl-5-mercapto-1,2,4-triazoles were prepared and demonstrated as ver-
satile building blocks for Suzuki–Miyaura cross-coupling with aryl, heteroaryl, and vinyl boronic acid
derivatives. Deprotection of the resulting coupling products provided 5-substituted-3-mercapto-1,2,4-
triazoles in good overall yields. This represents a novel and convenient approach for the introduction
of a 3-mercapto-1,2,4-triazole substructure into target compounds.
Received 12 April 2013
Revised 1 June 2013
Accepted 14 June 2013
Available online 24 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
5-Mercapto-1,2,4-triazoles
Suzuki–Miyaura cross-coupling
Benzyl protection
Deprotection
Heterocyclic compounds incorporating the 3-mercapto-1,2,4-
triazole substructure exhibit a wide spectrum of biological activ-
ity.1–3 In addition, 3-mercapto-1,2,4-triazole has the ability to
coordinate metal ions.4–6 This property has been used to develop
non-hydroxamate Zn-dependent enzyme inhibitors based on
3-mercapto-1,2,4-triazoles.7 Despite the broad utilization potential
of 3-mercapto-1,2,4-triazoles, there are a limited number of meth-
ods available for their synthesis. The most common approach is an
intramolecular cyclization of acyl-thiosemicarbazides under basic
conditions.1–3,7–9 The intermediate acyl-thiosemicarbazides are
prepared by the addition of hydrazides to isothiocyanates or by
non-selective acylation of thiosemicarbazides. Thus, this approach
is limited to hydrazines and carboxylic acid derivatives as starting
materials. Another limitation is that substrates that tolerate rela-
tively harsh basic conditions are needed to achieve the cyclization.
Moreover, the substituent at position 5 of the resulting triazoles is
introduced via a multistep procedure that is not suitable for rapid
library generation.
SPG
SH
PGN
X
HN
R
R
B(OH)2
N
N
N
N
+
1
Scheme 1. Building block strategy for the synthesis of 5-substituted-3-mercapto-
1,2,4-triazoles.
SH
H
Bn NCS
3
H
H
N
NHBn
NH2
2 M NaOH
BnN
N
N
O
N
H
O
N
H
EtOH, 60 oC, 4 h
95%
S
THF, 60 oC, 24 h
85%
2
5
4
SBn
SBn
NaH, BnBr
a) NBS, CH2Cl2, r.t., 24 h
b) NIS, THF, 70 oC, 2 h
BnN
X
N
N
BnN
N
N
Our synthetic strategy for the synthesis of 5-substituted-3-mer-
capto-1,2,4-triazoles was based on the Suzuki–Miyaura cross-cou-
THF, r.t.
99%
pling of N,S-diprotected building block
1 with boronic acid
1a, X=Br
1b, X=I
a) 92%
b) 70%
6
derivatives followed by deprotection (Scheme 1). Benzyl groups
were chosen for N,S-protection as they are sufficiently stable to
avoid catalyst poisoning by generation of thiol in the reaction
mixture.10
Scheme 2. Synthesis of building blocks 1a,b.
Building blocks 1a,b were obtained in four steps starting from
commercially available formylhydrazine (2) and benzylisothiocya-
nate (3) according to the reported approach for the synthesis of
mercaptotriazoles (Scheme 2).11 Intermediate acyl thiosemicarba-
⇑
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0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.