Eosin y catalyzed visible-light-driven aerobic oxidative cyclization of thioamides to 1,2,4-thiadiazoles

Article abstract of DOI:10.1055/s-0032-1318158

A new approach for an efficient metal-free synthesis of 1,2,4-thiadiazoles from primary thioamides using visible light and air in the presence of eosin Y as a photoredox catalyst is reported. The protocol involves an aerobic oxidative cyclization of thioamides via the formation of C-N and C-S bonds to afford excellent yields of the products in a simple one-pot operation under mild conditions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318158

LETTER
▌465
letter
Eosin Y Catalyzed Visible-Light-Driven Aerobic Oxidative Cyclization of
Thioamides to 1,2,4-Thiadiazoles
Visible-Light-Driven Synthesis of 1,2,4-Thiadiazoles
Vishnu P. Srivastava, Arvind K. Yadav, Lal Dhar S. Yadav*
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
Received: 06.12.2012; Accepted after revision: 14.01.2013
diazoles in very poor yield (8%).7 In continuation of our
work on heterocyclization reactions8 and intrigued by the
fact that organosulfur compounds form radicals easily and
have found wide applications in radical reactions, we pro-
Abstract: A new approach for an efficient metal-free synthesis of
1,2,4-thiadiazoles from primary thioamides using visible light and
air in the presence of eosin Y as a photoredox catalyst is reported.
The protocol involves an aerobic oxidative cyclization of thio-
amides via the formation of C–N and C–S bonds to afford excellent posed the present eosin Y catalyzed visible-light-mediat-
yields of the products in a simple one-pot operation under mild con-
ditions.
ed aerobic oxidative cyclodesulfurization of thioamides 1
to 1,2,4-thiadiazoles 2 as depicted in Scheme 1. We se-
Key words: visible light, eosin Y, photoredox, thioamides, cycliza-
tion, thiadiazoles
lected eosin Y as the photocatalyst for our present study
on the basis of earlier observations and properties of
organic dyes used as photoredox catalysts.5,9
During the last decade, visible-light photoredox catalysis
has emerged as a promising tool for organic synthesis.1
This is because of ready availability, ease of handling,
nontoxicity, sustainability, and potential applications of
visible light. However, owing to the inability of most or-
ganic molecules to absorb light in the visible region, gen-
erally photosensitizers or photocatalysts are required to
induce visible-light-driven reactions.2 Mostly, organome-
R
S
eosin Y, DMF
N
N
R
18 W CFL, r.t., air, 4–6 h
R
NH2
S
1
2
Br
Br
HO
Br
O
O
Br
2+
tallic complexes such as Ru(bpy)3 and Ir(ppy)2(dtb-
COOH
bpy)+ (where, bpy = 2,2′-bipyridine, ppy = 2-phenylpyri-
dine, dtb-bpy = 4,4′-di-tert-butyl-2,2′-bipyridine) have
been used as visible-light photoredox catalysts.1 Follow-
ing the seminal work of MacMillan et al.3 and Yoon et
al.,4 several powerful methods for a number of chemical
transformations in organic synthesis have been developed
employing these photoredox catalysts.1
eosin Y
Scheme 1 Synthesis of 1,2,4-thiadiazoles from primary thioamides
1,2,4-Thiadiazoles are an important class of biologically
and pharmaceutically important compounds.10–13 The an-
tibiotic cefozopram10 is a 1,2,4-thiadiazole drug, which is
currently in clinical use. Besides this, the 1,2,4-thiadia-
zole scaffold is a key structural unit in many synthetic
products with a broad range of biological activities as af-
fecting the cardiovascular system, suppressing inflamma-
tion, antibiotic action, central nervous system activity,
acetylcholinesterase inhibition, action on G-protein cou-
pled receptors, and glycogen synthase kinase 3b inhibi-
tion.11d Various 1,2,4-thiadiazoles exhibit thiol-trapping
properties and this has been reviewed.12 Another review
article has appeared on the synthesis and therapeutic ap-
plications of 1,2,4-thiadiazoles.13 Most of the methods
available for the synthesis of 1,2,4-thiadiazoles involve
oxidative cyclization of primary thioamides with a variety
of oxidizing agents such as hypervalent iodine,14
DMSO/HCl,15 and DMSO/2-chloro-1,3-dimethylimidaz-
olium chloride.16 IBX/TEAB,17 methansulfonic acid de-
rivative with benzenetellurinic acid,18 telluroxide or
selenoxide,19 methyl bromocyanoacetate, and20a DDQ.20b
However, the main disadvantages of these metal-based
methods are the high cost, potential toxicity, and low sus-
tainability of the ruthenium and iridium complexes. Re-
cently, metal-free organic dyes have been utilized as
visible-light photoredox catalysts,5 which are inexpen-
sive, easy to handle, and eco-friendly, and provide a supe-
rior alternative to transition-metal photocatalysts.
Importantly, these organocatalysts have great potential for
applications in visible-light-mediated useful organic
transformations
The literature records only a few reports on photocatalytic
reactions involving a sulfur radical; including the oxida-
tion of sulfides to sulfoxides,6a cyclization of thioamides
to 2-substituted benzothiazoles6b using Ru(bpy)3 as a
2+
catalyst, and rose bengal catalyzed photochemical oxida-
tion of thiobenzamides leading to 3,5-diphenyl-1,2,4-thia-
SYNLETT 2013, 24, 0465–0470
Advanced online publication: 06.02.2013
DOI: 10.1055/s-0032-1318158; Art ID: ST-2012-D1045-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Molecular oxygen is the best oxidizing agent because of
its easy availability, eco-friendliness, and sustainability,

466
V. P. Srivastava et al.
LETTER
but it has never been used as oxidant in the synthesis of 3 mol% did not improve the yield (Table 2, entries 1 and
1,2,4-thiadiazoles. Herein, we report an aerobic oxidative 7).
visible-light-initiated catalytic synthesis of 1,2,4-thiadia-
zoles. In a prototype reaction, benzothioamide (1a), in
Table 2 Optimization of Reaction Conditionsa
Ph
DMF solution and in the presence of 2 mol% eosin Y, was
S
exposed to air (but no air bubbling) and to the light of a
N
eosin Y (2 mol%)
NH2
household 18 W fluorescent lamp at room temperature.
Gratifyingly, the desired 1,2,4-thiadiazole 2a was ob-
tained in 91% yield (Table 1, entry 1). This result encour-
aged us to carry out a series of control experiments to
show that in the absence of any one of the reagents/reac-
tion parameters there was only trace or no product forma-
tion (Table 1, entries 2–5). The use of daylight in place of
fluorescent light was also less effective (Table 1, entries
6–8). These results indicate that the reaction conditions
(photocatalyst, visible light, and air) all are essential for
the reaction and support the photocatalytic model for the
reaction.
N
solvent, 18 W CFL, air, r.t., 4–6 h
Ph
S
1a
Entrya
Eosin Y
(mol%)
Solventc
Time
(h)
Yield
(%)b
1
2
3
4
5
6
7
8
2
2
2
2
2
2
3
1
DMF
4
6
8
7
7
8
4
6
91
87
76
57
55
51
91
67
DMSO
MeCN
MeOH
EtOH
THF
Table 1 Screening and Control Experimentsa
Ph
S
DMF
N
eosin Y (2 mol%)
NH2
N
DMF
DMF, 18 W CFL, air
Ph
S
a Reaction conditions: 1a (1.0 mmol), solvent (3 mL), 18 W CFL
(compact fluorescent lamp; Philips, 6500 K, 1010 lm, 85 mA) irradi-
ation under an air atmosphere at r.t.
1a
2a
Entry
Visible
light
Eosin
Y
Air
Time
(h)
Yield
(%)b
b Isolated yield of the product 2a.
1
2
3
4
5
6
7
8
+
–
+
+
–
+
+
+
+
–
+
4
6
6
6
8
8
8
8
91
With the optimized reaction conditions in hand, the func-
tional-group compatibility and scope of the present photo-
catalytic protocol were demonstrated across a range of
aromatic, heteroaromatic, and aliphatic primary thio-
amides (Table 3). The reaction is very mild and tolerates
many functional groups. All the primary thioamides 1 af-
forded the desired products 2 in good to high yields (72–
95%) regardless of differences in the electronic and steric
properties of the substrates 1. However, thioamides with
an electron-donating substituent on the aromatic ring ap-
pear to react faster and afford higher yields in comparison
to those bearing an electron-withdrawing substituent (Ta-
ble 3, entries 2 and 3 vs. entries 6–10).
+
n.r.c
n.r.
+
+
+
+
+
+
+
–
n.r.
N2
+
trace
13d
N2
N2
traced
n.r.d
a Reaction conditions: 1a (1.0 mmol), DMF (3 mL), 18 W CFL (com-
pact fluorescent lamp; Philips, 6500 K, 1010 lm, 85 mA) irradiation
under an air atmosphere at r.t.
b Isolated yield of the product 2a; n.r.= no reaction.
c The reaction was carried out in the dark.
On the basis of our observations and literature re-
ports,9,21,22 a plausible mechanism for the formation of
1,2,4-thiadiazoles 2 from thioamides 1 is proposed in
Scheme 2. The photoredox catalyst eosin Y (EY) is excit-
ed on absorption of visible light and its more stable triplet
d The reaction was carried out in daylight.
Next, we optimized the reaction conditions with respect to
solvents and catalyst loading. It was noted that the reac-
tion was not very sensitive to the reaction media because
in all solvents tested (DMF, DMSO, MeCN, MeOH,
EtOH, and THF) the yield was >50% (Table 2). The high-
est yield (91%) was in the case of DMF as solvent, and
this was used as solvent in subsequent studies. The opti-
mum catalyst loading was found to be 2 mol% (Table 2,
entry 1). On lowering the catalyst loading from 2 mol% to
1 mol%, there was a significant decrease in the yield;
while an increase in the catalyst loading from 2 mol% to
3
state EY* undergoes single electron transfer (SET).21
Both reductive and oxidative quenching are known for
3EY*.9 A SET from the thiolic form 1′ to 3EY* generates
the radical cation 3, which forms a sulfur radical 4 after
losing a proton. The cyclodesulfurization of 4 gives 5,
which forms the sulfur radical 6 following a similar path
through which 1′ forms 4. The sulfur radical 6 is oxidized
•–
with O2 , produced in the photoredox cycle of EY, to give
peroxysulfenate 7. An intramolecular nucleophilic attack
–
of the imino nitrogen of 7 on the carbon containing SO2
Synlett 2013, 24, 465–470
© Georg Thieme Verlag Stuttgart · New York

LETTER
Visible-Light-Driven Synthesis of 1,2,4-Thiadiazoles
467
N
R
N
R
S
N
S
S
SOO–
2–
– SO2
R
R
R
NH
S
N
R
NH
2
6
7
photoredox
cycle of
eosin Y
– 1e–
– H+
O2
eosin Y
visible light
N
R
eosin Y
visible light
S
O2
SH
(air)
R
NH
photocatalytic cycle
of eosin Y
5
eosin Y
eosin Y*
R
S
NH
SET
SH
NH
SH
NH
1'
S
S
– H+
R
R
R
NH
R
NH2
4
3
1
Photoredox catalytic cycle of eosin Y
hν
ISC
3EY*
1EY*
eosin Y
(EY)
EY
EY
reductant
oxidant
Scheme 2 Photoredox catalytic cycle of eosin Y for the oxidative cyclodesulfurization of thioamides to 1,2,4-thiadiazoles 2
as a good leaving group affords the desired product 2 with lyst. This protocol is a superior alternative to the existing
2– 22
the liberation of SO2
.
1,2,4-thiadizole syntheses with the advantages of high ef-
ficiency, sustainability, and eco-friendly reagents, that is,
visible light and air. Moreover, the reaction is performed
in a simple one-pot operation under mild conditions and
tolerates many functional groups.
In summary, we have developed an efficient metal-free
visible-light-initiated aerobic oxidative cyclization of pri-
mary thioamides to 1,2,4-thiadiazoles using molecular
oxygen as an oxidant and eosin Y as the photoredox cata-
Table 3 Visible-Light-Driven Aerobic Oxidative Conversion of Primary Thioamides into 1,2,4-Thiadiazoles23
R
S
eosin Y (2 mol%)
N
N
DMF, 18 W CFL, air, r.t.
R
R
NH2
S
2
1
Entry
1
Substrate 1
Product 2a
Time (h)
Yield (%)b
S
N
4
91
NH2
S
N
2a
MeO
OMe
S
N
NH2
2
3
4
4
95
S
N
N
MeO
2b
2c
S
N
NH2
93
S
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 465–470

468
V. P. Srivastava et al.
LETTER
Table 3 Visible-Light-Driven Aerobic Oxidative Conversion of Primary Thioamides into 1,2,4-Thiadiazoles23 (continued)
R
S
eosin Y (2 mol%)
N
N
DMF, 18 W CFL, air, r.t.
R
R
NH2
S
2
1
Entry
4
Substrate 1
Product 2a
Time (h)
Yield (%)b
F
F
S
N
6
86
NH2
S
N
F
2d
Cl
Cl
S
N
NH2
5
6
6
6
88
75
S
N
Cl
2e
O2N
NO2
S
N
NH2
S
N
O2N
2f
NO2
S
NH2
N
7
6
80
O2N
S
N
NO2
2g
NO2
S
N
NH2
8
9
6
6
72
90
S
N
O2N
NO2
2h
Cl
S
NH2
N
Cl
S
N
Cl
Cl
2i
Cl
S
Cl
N
NH2
10
6
74
Cl
S
N
Cl
Cl
S
2m
N
NH2
S
S
11
12
4
6
92
76
S
N
S
2n
S
N
N
N
NH2
S
N
N
2o
Synlett 2013, 24, 465–470
© Georg Thieme Verlag Stuttgart · New York

LETTER
Visible-Light-Driven Synthesis of 1,2,4-Thiadiazoles
469
Table 3 Visible-Light-Driven Aerobic Oxidative Conversion of Primary Thioamides into 1,2,4-Thiadiazoles23 (continued)
R
S
eosin Y (2 mol%)
N
N
DMF, 18 W CFL, air, r.t.
R
R
NH2
S
2
1
Entry
13
Substrate 1
Product 2a
Time (h)
5
Yield (%)b
87
N
S
S
N
NH2
2p
N
S
S
N
14
5
93
NH2
O2N
NO2
O2N
2q
a All the products are known compounds and were characterized by comparison of their mp and spectral data with those of reported in the
literature.20,24
b Isolated yield of product 2.
2012, 48, 3766. (f) Rai, A.; Yadav, L. D. S. Tetrahedron
Acknowledgment
2012, 68, 2459.
We sincerely thank the SAIF, Punjab University, Chandigarh, for
(9) (a) Lazarides, T.; McCormick, T.; Du, P.; Luo, G.; Lindley,
providing spectroscopic facilities. One of us (A.K.Y.) is grateful to
B.; Eisenberg, R. J. Am. Chem. Soc. 2009, 131, 9192.
the CSIR, New Delhi, for the award of a Junior Research Fellow-
(b) Encinas, M. V.; Rufs, A. M.; Bertolotti, S. G.; Previtali,
ship.
C. M. Polymer 2009, 50, 2762. (c) Lee, S. H.; Nam, D. H.;
Park, C. B. Adv. Synth. Catal. 2009, 351, 2589.
(10) Iizawa, Y.; Okonogi, K.; Hayashi, R.; Iwahi, T.; Yamazaki,
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Synlett 2013, 24, 465–470

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added eosin Y (2 mol%), and the mixture was irradiated with
a household 18 W CFL (Philips, 6500 K, 1010 lm, 85 mA)
with stirring under an air atmosphere (but no air bubbling) at
r.t. for 4–6 h. After completion of the reaction (monitored by
TLC), H2O (3 mL) was added, and the mixture was extracted
with EtOAc (3 × 5 mL). The combined organic phases were
dried over MgSO4, filtered, and evaporated under reduced
pressure. The resulting crude product was purified by silica
gel column chromatography using a gradient mixture of
hexane–EtOAc as eluent to afford an analytically pure
sample of 2. All the products are known compounds and
were characterized by the comparison of their melting points
and spectroscopic data with those reported in the
literature.20,24
(23) General Procedure for the Synthesis of 1,2,4-
Thiadiazoles 2
(24) El-Wassimy, M. T. M.; Jørgensen, K. A.; Lawesson, S.-O.
Tetrahedron 1983, 39, 1729.
To a solution of thioamide 1 (1.0 mmol) in DMF (3 mL) was
Synlett 2013, 24, 465–470
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