A facile and straightforward synthesis of 1,2,3-thiadiazoles from α-enolicdithioesters via nitrosation/reduction/diazotization/cyclization cascade in one-pot

Article abstract of DOI:10.1016/j.tetlet.2014.02.115

An operationally simple, economical, and straightforward synthesis of diverse 4,5-disubstituted 1,2,3-thiadiazoles from α-enolicdithioesters has been achieved via nitrosation/reduction/diazotization/cyclization sequence in one-pot through the formation of cascade 1-2 (N-S) and 3-4 (C-N) bonds. Importantly, this is the first straightforward entry to highly functionalized 1,2,3-thiadiazoles from dithioesters.

Full text of DOI:10.1016/j.tetlet.2014.02.115

Tetrahedron Letters 55 (2014) 2430–2433
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile and straightforward synthesis of 1,2,3-thiadiazoles
from a-enolicdithioesters via nitrosation/reduction/
diazotization/cyclization cascade in one-pot
Anugula Nagaraju a, B. Janaki Ramulu a, Gaurav Shukla a, Abhijeet Srivastava a, Girijesh Kumar Verma a,
Keshav Raghuvanshi b, Maya Shankar Singh a,
⇑
a Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
b Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstrasse 2, 37077 Göttingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
An operationally simple, economical, and straightforward synthesis of diverse 4,5-disubstituted 1,2,3-thi-
Received 28 January 2014
Revised 26 February 2014
Accepted 27 February 2014
Available online 6 March 2014
adiazoles from a-enolicdithioesters has been achieved via nitrosation/reduction/diazotization/cyclization
sequence in one-pot through the formation of cascade 1–2 (N–S) and 3–4 (C–N) bonds. Importantly, this
is the first straightforward entry to highly functionalized 1,2,3-thiadiazoles from dithioesters.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
a-Enolicdithioesters
Diazotization
Cascade annulation
1,2,3-Thiadiazoles
One-pot
The key goal in modern organic synthesis is to design and devel-
op new synthetic strategies by improving resource efficiency that
provides maximum structural diversity with economies of step,
atom, labor, and cost for the rapid generation of function-oriented
molecules. Cascade processes that incorporate multiple bond-
forming events carried out in one-pot have come into play, and
are of paramount interest in organic synthesis.1 The synthesis of
heterocycles has always been a key aspect, and increasingly at-
tracted the synthetic pursuit of chemists because they are a vital
part of new drug discovery and indispensable materials in the
implementation of any industrial evolution.2
Among the five-member N,S-heterocyclic frameworks, 1,2,3-
thiadiazoles3 are versatile privileged scaffolds present in many bio-
active natural products and pharmaceuticals4,5 exhibiting diverse
applications in medicine6 and agriculture.7 Furthermore, 1,2,3-thi-
adiazoles are not only useful intermediates to construct several
important bioactive compounds,8 but also utilized as key precur-
sors9a for the synthesis of dendrimers,9b,c tetrathiafulvalenes,9d,e
2-benzofuran thiolates,9f amides of 1-adamantylthioacetic acids,9g
and 1,1-dialkylindolium-2-thiolates.9h In addition, thiadiazole can
act as the bio-isosteric replacement of the thiazole moiety, so it
acts like third and fourth generation cephalosporins.
Among many strategies toward substituted 1,2,3-thiadiazoles,10
Hurd–Mori synthesis,10a Pechmann synthesis,10b,c and Wolff syn-
thesis10d are the most favorite and frequently utilized protocols.
Some applications of the Hurd–Mori reaction11 and the Wolff
synthesis12 are reported. Recently, Kumar et al.13 synthesized
1,2,3-thiadiazoles using ionic liquid-supported sulfonyl hydrazine.
However, the paucity of efficient one-pot synthetic method to ac-
cess 1,2,3-thiadiazoles, and significant limitations of the existing
methods such as poor availability of the starting materials, lack
of adequate derivatization, and harsh reaction conditions
prompted us to develop a more general and viable route with oper-
ational simplicity. Consequently, herein we report a simple, eco-
nomical, and straightforward method for the synthesis of diverse
1,2,3-thiadiazoles from
a-enolicdithioesters via nitrosation/reduc-
tion/diazotization/cyclization sequence in one-pot (Scheme 1).
a
-Enolicdithioesters are not commercially accessible and were
synthesized in good yields by the reported procedure.14a They
are valuable synthetic targets in organic synthesis due to their ver-
satile reactivity as well as powerful intermediates in the function-
alization of various heterocycles.14 Very recently, we reported the
synthesis of 4,5-disubstituted 1,2,3-thiadiazoles by treatment of
⇑
Corresponding author. Tel.: +91 542 6702502; fax: +91 542 2368127.
E-mail addresses: mssinghbhu@yahoo.co.in, mayashankarbhu@gmail.com (M.S.
Singh).
a-enolicdithioesters with tosyl azide in the presence of triethyl
http://dx.doi.org/10.1016/j.tetlet.2014.02.115
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. Nagaraju et al. / Tetrahedron Letters 55 (2014) 2430–2433
2431
Table 1
one-pot three steps
Synthesis of 1,2,3-thiadiazole derivatives 3a
SR2
O
NaNO2/AcOH
Zn/AcOH
OH
S
Product
R1
R2
Time (h)
Yieldb (%)
mp (°C)
R1
S
N
SR2
R1
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
Methyl
Methyl
Methyl
Methyl
Methyl
Allyl
Methallyl
Methallyl
Methallyl
Benzyl
4
3
4
6
4
4
5
4
6
5
5
6
61
78
65
48
60
65
68
73
53
60
70
55
109–11115
165–16715
99–10115
132–13415
172–17415
Liquid15
N
aq. NaNO2
1
4-MeC6H4
2-ClC6H4
4-CF3C6H4
2-Thienyl
C6H5
stir at 0 o
C
3
1
2
1
2
1a
1c
1e
1b
: R = C6H5, R =CH3; : R =4-MeC6H4, R =CH3
1
2
1
2
1d
: R =2-ClC6H4, R =CH3; : R =4-CF3C6H4, R =CH3
1
2
1
2
1f
: R =thienyl, R =CH3; : R =C6H5, R =allyl
C6H5
Liquid
77–79
87–89
1g: R1=C6H5, R2=methallyl; 1h: R1=4-MeC6H4, R2=methallyl
4-MeC6H4
2-Furyl
C6H5
4-MeC6H4
2-Furyl
1
2
1
2
1i
1j
: R =furyl, R =methallyl; : R =C6H5, R =benzyl
3j
3k
3l
134–13615
143–146
132–134
1k: R1=4-MeC6H4, R2=benzyl; 1l: R1=furyl, R2=benzyl
Benzyl
Benzyl
Scheme 1. Synthesis of 1,2,3-thiadiazoles 3.
a
Reaction conditions: a-Enolicdithioesters 1 (1 mmol), aq NaNO2 (3 equiv, 1 ml),
AcOH (1 ml), DCM (5 ml), MeOH (1 ml), Zn (3 equiv), and aq NaNO2 (1 equiv, 1 ml)
at 0 °C.
amine (TEA).15 The importance of 1,2,3-thiadiazole scaffolds in
medicinal and material-based applications prompted us to con-
struct this skeleton directly from dithioester in an atom- and
step-economical manner. We envisioned to introduce diazo func-
b
Yield of isolated products.
O
SR2
S
tional group at
a
-position of dithioester and further transform it
O
SR2
S
H
reduction
Zn/AcOH
nitrosation
[HNO2]
directly to 1,2,3-thiadiazole via Wolff cyclization. In this perspec-
tive, we hypothesized that first nitrosation would lead to the cor-
responding oxime, which upon reduction should give amine
followed by diazotization that could produce the diazo group. So,
in continuation of our ongoing research regarding the synthetic
OH
S
R1
R1
R1
SR2
NH2
N
A
HO
1
2
[HNO2]
SR2
diazotization
O
Wolff
O
SR2
H
utility of
a-enolicdithioesters for the synthesis of various heterocy-
cyclization
R1
S
clic systems,16,17 we report herein a simple, straightforward, and
R1
S
N
+
−
H
N
economical synthesis of 1,2,3-thiadiazoles from
ers (Scheme 1).18
a-enolicdithioest-
N
N
B
3
To optimize the reaction conditions for the synthesis of 1,2,3-
thiadiazoles, methyl-3-hydroxy-3-phenyl-prop-2-enedithioate 1a
was taken as model substrate. Initially, the solution of 1a (1 mmol)
in 5 ml of dichloromethane (DCM) was treated with aq NaNO2
(2 ml) followed by slow addition of zinc powder (1 equiv). The
reaction mixture was stirred at 0 °C for 3 h. The work-up of the
reaction provided 3a in 20% yield characterized as 4-benzoyl-5-
thiomethyl 1,2,3-thiadiazole with the help of satisfactory spectral
(IR, 1H & 13C NMR, mass) studies and comparison with the reported
one.15 Encouraged by the above result, the effects of various
parameters such as solvent, sodium nitrite loading, acetic acid,
and the amount of zinc were examined on the model substrate
1a. Screening of loading of NaNO2 and zinc showed 3 equiv of
NaNO2 (1 ml) and 3 equiv of zinc afforded the maximum yield of
the desired product in minimum time. Next, screening of various
solvents such as CHCl3, acetone, MeOH, and EtOH showed that
the reaction mixture is not fairly soluble at 0 °C; however DCM
was found to be the best among all. To get rid of the solubility
problem, 1 ml of methanol was added in DCM, which resolved
the solubility problem. Addition of methanol not only made the
reaction clean, but reduced the reaction time also. So, the best sol-
vent system was found to be a mixture of DCM and MeOH in 5:1
ratio. Thus, the best reaction conditions for the synthesis of 3a
was found to be 1a (1 mmol), 6 ml of DCM+MeOH (5:1), 1 ml of
AcOH, aqueous NaNO2 (3 equiv, 1 ml), and zinc powder (3 equiv)
at 0 °C.
Scheme 2. Tentative mechanism for the formation of 1,2,3-thiadiazoles 3.
suitable for this transformation giving the desired products in good
yields (Table 1, 3e, 3i, and 3l). Since the reaction is completed in a
three-step one-pot fashion, the final yield of the desired product
was considered to be good. In all the reactions the conversion of
dithioesters 1 are nearly 100%. The structures of all the synthesized
1,2,3-thiadiazoles 3 were confirmed by their spectral (IR, 1H & 13C
NMR and mass) studies and comparison with the reported ones.15
To rationalize the reaction outcome, based on our experimental
results, we propose a tentative mechanism as shown in Scheme 2.
First,
was subjected to Zn/AcOH reduction to give amine intermediate A.
Subsequent diazotization of intermediate A produces -diazo
a-enolicdithioester 1 upon nitrosation forms oxime 2, which
a
dithioester B, which undergoes Wolff-type cyclization that is a
nucleophilic attack of the thiocarbonyl sulfur to diazo group fol-
lowed by deprotonation to give the desired 1,2,3-thiadiazoles 3.
In summary we have developed a simple and straightforward
approach for the synthesis of 1,2,3-thiadiazoles from dithioesters
in one-pot under mild and rapid reaction conditions. The present
protocol not only serves as a step-economical alternative to
existing methods but also allows direct construction of 1,2,3-thi-
adiazoles via the formation of cascade C–N/N–N/N–S bonds.
Importantly, the presence of aroyl and alkylthio groups at 4- and
5-positions makes these molecules excellent entrants as precur-
sors for further synthetic renovations to meet the need for diverse
useful purposes.
With the optimized conditions in hand, we investigated the
scope and versatility of our newly developed protocol utilizing var-
ious dithioesters 1a–l (Table 1). Notably, the protocol tolerated
well a wide range of substituents such as aryl and hetaryl groups
at R1 and alkyl, allyl, methallyl, and benzyl substituents at R2 of
our precursor moiety 1. It was observed that dithioester bearing
electron-donating group at R1 (1b) reacted smoothly and afforded
the desired product in higher yield than those containing the elec-
tron-withdrawing group (1d). Even electron-rich heteroaromatic
groups such as 2-thienyl and 2-furyl at R1 (1e, 1i, and 1l) were also
Acknowledgments
We gratefully acknowledge the generous financial support from
the Science and Engineering Research Board (Grant No. SB/S1/OC-
30/2013) and the Council of Scientific and Industrial Research

2432
A. Nagaraju et al. / Tetrahedron Letters 55 (2014) 2430–2433
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to DAAD and George-August-Universität-Göttingen for financial
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17. Recent papers: (a) Verma, R. K.; Verma, G. K.; Shukla, G.; Nagaraju, A.; Singh, M.
S. ACS Comb. Sci. 2012, 14, 224; (b) Nandi, G. C.; Ila, H.; Junjappa, H.; Singh, M. S.
Eur. J. Org. Chem. 2012, 967; (c) Shukla, G.; Verma, G. K.; Nagaraju, A.; Verma, R.
K.; Raghuvanshi, K.; Singh, M. S. RSC Adv. 2013, 3, 13811; (d) Chowdhury, S.;
Chanda, T.; Koley, S.; Ramulu, B. J.; Jones, R. C. F.; Singh, M. S. Org. Lett. 2013, 15,
5386; (e) Koley, S.; Chowdhury, S.; Chanda, T.; Ramulu, B. J.; Singh, M. S.
Tetrahedron 2013, 69, 8013; (f) Samai, S.; Chanda, T.; Ila, H.; Singh, M. S. Eur. J.
Org. Chem. 2013, 4026; (g) Chowdhury, S.; Chanda, T.; Koley, S.; Ramulu, B. J.;
Raghuvanshi, K.; Singh, M. S. Tetrahedron 2014, 70, 914.
18. General procedure for the synthesis of 1,2,3-thiadiazoles 3: 1.0 mmol of
a-
enolicdithioester 1 was dissolved in 6 ml of DCM + MeOH (5:1) and set the
reaction on an ice-bath. Then 1 ml of glacial acetic acid was added followed by
drop-wise addition of aqueous NaNO2 (3 equiv, 1 ml). Reaction mixture was
stirred at 0 °C for 30–60 min. After complete conversion of dithioester to oxime
(monitored by TLC), zinc dust (3 equiv) was added in small portions over a
period of 30 min and stirring was continued till the complete consumption of
oxime. Finally, aqueous NaNO2 (1 equiv, 1 ml) was added and continued
stirring for further 30–40 min. Then reaction mixture was quenched with
K2CO3 followed by the addition of 20 ml of water. The mixture was extracted
with DCM (3 Â 20 ml), washed with brine, dried over anhydrous Na2SO4, and
concentrated. The residue thus obtained was purified by column
chromatography over silica gel using ethyl acetate/hexane (5: 95) as eluent
to give the pure product. Data of some selected compounds: 4-Benzoyl-5-
methylsulfanyl-1,2,3-thiadiazole (3a): White solid; mp 109–111 °C; 1H NMR
(300 MHz, CDCl3): d 8.36 (d, J = 7.2 Hz, 2H, ArH), 7.63–7.49 (m, 3H, ArH), 2.69
(s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 185.6, 170.3, 153.0, 136.9, 133.0,
130.5, 128.2, 21.7. IR (KBr, cmÀ1): 3064, 2906, 1621, 1559, 1543, 1424, 1381,
1207, 1056. HRMS (ESI+): calcd for C10H8N2OS2 [M+H]+ 237.0151, found
237.0156. 4-Benzoyl-5-(2-methylallylsulfanyl)-1,2,3-thiadiazole (3g): Yellow
viscous liquid; 1H NMR (300 MHz, CDCl3): d 8.35 (d, J = 7.2 Hz, 2H, ArH),
7.60–7.48 (m, 3H, ArH), 5.22 (s, 1H, @CH2), 5.12 (s, 1H, @CH2), 3.70 (s, 2H,
SCH2), 1.89 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 185.6, 167.2, 153.9, 137.4,
136.9, 133.0, 130.6, 128.2, 117.3, 45.4, 21.2. HRMS (ESI+): calcd for
C13H12N2OS2 [M+Na]+ 299.0283, found 299.0286. [5-(2-Methylallylsulfanyl)-4-
(4-methylbenzoyl]-1,2,3-thiadiazole (3h): White solid; mp 77–79 °C; 1H NMR
(300 MHz, CDCl3): d 8.29 (d, J = 8.1 Hz, 2H, ArH), 7.31 (d, J = 7.8 Hz, 2H, ArH),
5.22 (s, 1H, @CH), 5.12 (s, 1H, @CH), 3.70 (s, 2H, SCH2), 2.44 (s, 3H, ArCH3), 1.89
(s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 185.3, 166.9, 154.2, 144.1, 137.6,
134.4, 130.8, 129.0, 117.3, 45.5, 21.6, 21.2. IR (KBr, cmÀ1): 2927, 1603, 1412,
1388, 1273, 1226, 1176, 878, 757. HRMS (ESI+): calcd for C14H14N2OS2 [M+H]+
9. (a) Petrov, M. L.; Dehaen, W.; Abramov, M. A.; Abramova, I. P.; Androsov, D. A.
Russ. J. Org. Chem. 2002, 38, 1510; (b) Labbe, G.; Haelterman, B.; Dehaen, W.
Bull. Soc. Chim. Belg. 1996, 105, 419; (c) Al-Smadi, M. Asian J. Chem. 2007, 19,
1783; (d) Andreu, R.; Garin, J.; Orduna, J.; Saviron, M.; Cousseau, J.; Gorgues, A.;
Morisson, V.; Nozdryn, T.; Becher, J.; Clausen, R. P.; Bryce, M. R.; Skabara, P. J.;
Dehaen, W. Tetrahedron Lett. 1994, 35, 9243; (e) Clausen, R. P.; Becher, J.
Tetrahedron 1996, 52, 3171; (f) Abramov, M. A.; Dehaen, W.; D’hooge, B.;
291.0620,
found
291.0627.
4-(2-Furoyl)-5-(2-methylallylsulfanyl)-1,2,3-
thiadiazole (3i): White solid; mp 87–89 °C; 1H NMR (300 MHz, CDCl3): d 8.12
(d, J = 3.3 Hz, 1H, ArH), 7.77 (s, 1H, ArH), 6.64 (d, J = 1.8 Hz, 1H, ArH), 5.22 (s,
1H, @CH2), 5.12 (s, 1H, @CH2), 3.70 (s, 2H, SCH2), 1.89 (s, 3H, CH3). 13C NMR

A. Nagaraju et al. / Tetrahedron Letters 55 (2014) 2430–2433
2433
(75 MHz, CDCl3): d 172.0, 166.3, 151.1, 148.0, 137.5, 122.7, 117.3, 117.2, 112.5,
45.5, 21.2. IR (KBr, cmÀ1): 3126, 3107, 2913, 1627, 1465, 1429, 1278, 1028, 922,
859, 767. HRMS (ESI+): calcd for C11H10N2O2S2 [M+H]+ 267.0256, found
267.0261. 5-benzylsulfanyl-4-(4-methylbenzoyl)-1,2,3-thiadiazole (3k): White
solid; mp 143–146 °C. 1H NMR (300 MHz, CDCl3): d 8.28 (d, J = 7.8 Hz, 2H,
ArH), 7.43–7.28 (m, 7H, ArH), 4.24 (s, 2H, SCH2), 2.42 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3): d 185.1, 166.7, 153.6, 144.0, 134.3, 133.7, 130.8, 130.7, 129.0,
128.9, 128.4, 42.7, 21.6. IR (KBr, cmÀ1): 3073, 2914, 1619, 1599, 1412, 1389,
1274, 1181, 879, 709. HRMS (ESI+): calcd for C17H14N2OS2 [M+H]+ 327.0620,
found 327.0626. 5-Benzylsulfanyl-4-(2-furoyl)-1,2,3-thiadiazole (3l): White
solid; mp 132–134 °C. 1H NMR (300 MHz, CDCl3): d 8.12 (d, J = 3 Hz, 1H,
ArH), 7.77 (d, J = 6.6 Hz, 1H, ArH), 7.45–7.34 (m, 5H, ArH), 6.63 (s, 1H, ArH),
4.26 (s, 2H, SCH2). 13C NMR (75 MHz, CDCl3): d 172.0, 166.1, 152.0, 151.0,
148.1, 133.6, 129.1, 129.0, 128.5, 123.0, 112.5, 42.8. IR (KBr, cmÀ1): 3115, 2918,
1621, 1461, 1418, 1269, 1024, 855, 778. HRMS (ESI+): calcd for C14H10N2O2S2
[M+H]+ 303.0256, found 303.0265.