Synthesis of 5-substituted 3-mercapto-1,2,4-triazoles via Suzuki-Miyaura reaction

Article abstract of DOI:10.1016/j.tetlet.2013.06.067

3-Bromo- and 3-iodo-N,S-dibenzyl-5-mercapto-1,2,4-triazoles were prepared and demonstrated as versatile 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.

Full text of DOI:10.1016/j.tetlet.2013.06.067

Tetrahedron Letters 54 (2013) 4524–4525
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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-
⇑
Corresponding author. Tel.: +371 67 01 48 40; fax: +371 67 54 14 08.
E-mail address: aigars@osi.lv (A. Jirgensons).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.067

S. Katkevica et al. / Tetrahedron Letters 54 (2013) 4524–4525
4525
SH
SBn
SBn
RB(OH)2 or RBPin
HN
R
AlCl3
BnN
R
BnN
X
N
N
7a-r
N
N
N
N
K2CO3,
toluene, 80 oC, 4 h
cat. Pd(PPh3)4
THF, H2O, 80 oC, 48 h
1a,b
8a-p
9a-m
Scheme 3. Suzuki–Miyaura coupling of protected mercaptotriazole building blocks 1a,b and deprotection of the coupling products 8a–m.
of both the N- and S-benzyl protecting groups in coupling products
8a–m to give mercaptotriazoles 9a–m in good to high yields. With
compounds 8f–h, concomitant cleavage of the methyl groups took
place providing hydroxyphenyl substituted triazoles 9f–h (Table 1,
entries 10–13). The deprotection conditions with AlCl3 were also
used for 5-(phenylvinyl)-mercaptotriazole 8n, however this led
to the formation of a mixture consisting of several unidentified
decomposition products. Deprotection of other 5-vinyl-mercapto-
triazole derivatives 8o and 8p were not attempted under these
conditions.
In summary, we have demonstrated the synthesis of 5-substi-
tuted mercaptotriazoles via Suzuki–Miyaura reaction of specifi-
cally designed building blocks 1a,b followed by deprotection.
Building blocks 1a,b might be useful in other types of coupling
reactions to give modified triazoles.
Table 1
Suzuki–Miyaura cross-coupling of building block 1 with boronic acid derivatives 7
leading to intermediates 8 and deprotection to give mercaptotriazoles 9
Entry Building
Boronic acid derivative, 7
8, Yielda (%) 9, Yielda (%)
block 1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a
1b
1b
1a
1b
1a
1b
1a
1b
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
C6H5B(OH)2, 7a
C6H5B(OH)2, 7a
8a, 99
8a, 70
8b, 89
8c, 86
8c, 71
8d, 77
8d, 72
8e, 91
8e, 79
8f, 74
8f, 85
8g, 81
8h, 89
8i, 77
8j, 80
8k, 43
8l, 60
8m, 43
8n, 51
9a, 90
4-(Me)C6H4B(OH)2, 7b
4-(t-Bu)C6H4B(OH)2, 7c
4-(t-Bu)C6H4B(OH)2, 7c
3,5-(di-Me)C6H3B(OH)2, 7d
3,5-(di-Me)C6H3B(OH)2, 7d
4-(F)C6H4B(OH)2, 7e
4-(F)C6H4B(OH)2, 7e
2-(MeO)C6H4B(OH)2, 7f
2-(MeO)C6H4B(OH)2, 7f
3-(MeO)C6H4B(OH)2, 7g
4-(MeO)C6H4B(OH)2, 7h
2-(H2N)C6H4BPin, 7i
3-(HO)C6H4B(OH)2, 7j
3-PyBPin, 7k
3-Quinolinyl-BPin, 7l
4-(CN)C6H4B(OH)2, 7m
trans-C6H5CH@CHB(OH)2,
7n
CH2@CHBF3K, 7o
Cyclohexen-1-ylB(OH)2, 7p
i-PrCH2B(OH)2, 7q
9b, 85
9c, 95
9d, 94
9e, 96
9f, 95b
9g, 91b
9h, 93b
9i, 86
9j, 91
9k, 72
9l, 80
9m, 95
—
Acknowledgment
Financial support from ESF grant No. 2009/ 0203/1DP/1.1.1.2.0/
09/APIA/VIAA/023 is acknowledged.
Supplementary data
20
21
22
23
1b
1b
1b
1b
8o, 79
8p, 60
8q,—
—
—
—
—
Supplementary data (experimental procedures for the synthesis
of compounds 1–9 and characterization data) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.06.067.
B2Pin2, 7r
8r,—
a
Isolated yields.
Cleavage of the Me group occurred.
b
References and notes
1. Shaker, R. M. Arkivoc 2006, ix, 59–112.
zide 4 was subjected to base-promoted cyclization to give triazole
5. Benzylation of compound 5 provided N,S-diprotected mercapto-
triazole 6, which was halogenated at position 5 with NBS or NIS
yielding triazole derivatives 1a and 1b, respectively.
2. Zhou, C.-H.; Wang, Y. Curr. Med. Chem. 2012, 19, 239–280.
3. Faridoon; Hussein, W. M.; Vella, P.; Islam, N. U.; Ollis, D. L.; Schenk, G.;
McGeary, R. P. Bioorg. Med. Chem. Lett. 2012, 22, 380–386.
4. Zhang, R.-B.; Li, Z.-J.; Cheng, J.-K.; Qin, Y.-Y.; Zhang, J.; Yao, Y.-G. Cryst. Growth
Des. 2008, 8, 2562–2573.
Mercapto triazole building blocks 1a,b were subjected to Suzu-
ki–Miyaura cross-coupling with Pd(PPh3)4 as the catalyst and
K2CO3 as the base in degassed THF/H2O (Scheme 3).12–14 The cou-
pling reactions with a range of boronic acid derivatives 7 are sum-
marized in Table 1. Both aromatic and vinyl boronic acids or their
pinacol esters 7a–p could be used as coupling partners to give 5-
substituted N,S-protected mercaptotriazoles 8a–p. Aliphatic
boronic acid 7q and pinacolate diborane 7r were also used to cou-
ple with building blocks 1a,b. However, despite the wide range of
catalytic systems investigated, no or very low conversion into the
desired products and/or dehalogenated N,S-dibenzyl-mercapto-
triazole was obtained as the major product.
Deprotection of triazole derivative 8a was investigated under
various conditions. No conversion was achieved with: (a) SmI2 in
THF at rt; (b) Mg and Zn, HCOOꢀNHþ4 in MeOH or THF at 80 °C. Mix-
tures of products were obtained with (a) KOtBu, O2 in DMSO at rt;
(b) Na in liquid NH3 at ꢀ78 °C; (c) BBr3 in CH2Cl2. Finally, we were
pleased to find that deprotection could be achieved successfully
using AlCl3 in toluene at 80 °C.15 These conditions led to cleavage
5. Wang, Y.-L.; Zhang, N.; Liu, Q.-Y.; Shan, Z.-M.; Cao, R.; Wang, M.-S.; Luo, J.-J.;
Yang, E.-L. Cryst. Growth Des. 2010, 11, 130–138.
6. Sanina, N. A.; Rakova, O. A.; Aldoshin, S. M.; Shilov, G. V.; Shulga, Y. M.; Kulikov,
A. V.; Ovanesyan, N. S. Mendeleev Commun. 2004, 14, 7–8.
7. Gilmore, J. L.; King, B. W.; Asakawa, N.; Harrison, K.; Tebben, A.; Sheppeck, J. E.,
II; Liu, R.-Q.; Covington, M.; Duan, J. J.-W. Bioorg. Med. Chem. Lett. 2007, 17,
4678–4682.
8. Guda, D. R.; Wang, T.; Cho, H. M.; Lee, M. E. Tetrahedron Lett. 2012, 53, 5238–
5242.
9. Yavari, I.; Shirgahi-Talari, F.; Hossaini, Z.; Sabbaghan, M.; Seyfi, S. Mol. Divers.
2012, 22, 380–386.
10. Bromo-S-(4-methoxybenzyl)-5-mercapto-1,2,4-triazole was also prepared and
tested in the Suzuki–Miyaura reaction, however, no coupling product was
obtained.
11. Kruse, L. I.; Kaiser, C.; DeWolf, W. E.; Finkelstein, J. A.; Frazee, J. S.; Hilbert, E. L.;
Ross, S. T.; Flaim, K. E.; Sawyer, J. L. J. Med. Chem. 1990, 33, 781–789.
12. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
13. Hartnett, J. C.; Barnett, S. F.; Bilodeau, M. T.; Defeo-Jones, D.; Hartman, G. D.;
Huber, H. E.; Jones, R. E.; Kral, A. M.; Robinson, R. G.; Wu, Z. Bioorg. Med. Chem.
Lett. 2008, 18, 2194–2197.
14. Szommer, T.; Lukács, A.; Kovács, J.; Szabó, M. J.; Hoffmann, M. G.; Schmitt, M.
H.; Gerencsér, J. Mol. Divers. 2012, 16, 81–90.
15. Fleš, D.; Markovac-Prpic, A.; Tomašic, V. J. Am. Chem. Soc. 1958, 80, 4654–4657.