Synthesis of 2-amino-substituted-1,3,4-thiadiazoles via 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated intramolecular C-S bond formation in thiosemicarbazones

Article abstract of DOI:10.1016/j.tetlet.2016.01.083

An effective oxidative intramolecular cyclization (C-S bond formation) of thiosemicarbazones using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) has been developed to afford a diverse array of 2-amino-substituted-1,3,4-thiadiazoles. The attractive featu

Full text of DOI:10.1016/j.tetlet.2016.01.083

Accepted Manuscript
Synthesis of 2-amino-substituted-1,3,4-thiadiazoles via 2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone (DDQ) mediated intramolecular C–S bond formation in
thiosemicarbazones
Sarangthem Joychandra Singh, Suresh Rajamanickam, Anupal Gogoi, Bhisma
K. Patel
PII:
S0040-4039(16)30082-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.083
TETL 47247
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 November 2015
21 January 2016
22 January 2016
Please cite this article as: Singh, S.J., Rajamanickam, S., Gogoi, A., Patel, B.K., Synthesis of 2-amino-
substituted-1,3,4-thiadiazoles via 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated intramolecular C–
S bond formation in thiosemicarbazones, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.01.083
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Graphical Abstract
Synthesis of 2-amino-substituted-1,3,4-thiadiazoles via Leave this area blank for abstract info.
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
mediated intramolecular CS bond formation in thiosemicarbazones
Sarangthem Joychandra Singh, Suresh Rajamanickam, Anupal Gogoi and Bhisma K. Patel*

1
Tetrahedron Letters
Synthesis of 2-amino-substituted-1,3,4-thiadiazoles via 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) mediated intramolecular CS bond formation in
thiosemicarbazones
Sarangthem Joychandra Singh, Suresh Rajamanickam, Anupal Gogoi and Bhisma K. Patel
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati – 781039, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An effective oxidative intramolecular cyclization (CS bond formation) of thiosemicarbazones
using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) has been developed to afford a diverse
array of 2-amino-substituted-1,3,4-thiadiazoles. The attractive features of this protocol are
operational simplicity, obviates the need of expensive transition-metal catalysts and broad
substrate scope.
Available online
Keywords:
1,3,4-Thiadiazoles
DDQ
Thiosemicarbazone
CS bond formation
Heterocycles
2015 Elsevier Ltd. All rights reserved.
Introduction
1,3,4-Thiadiazoles are important five membered N,S-
heterocycles with wide range of applications in medicine,1
agriculture2 and materials chemistry.3 In particular, 1,3,4-
thiadiazoles display a broad spectrum of biological activities
including anti-inflammatory,4a antimicrobial,4b anticonvulsant4c
and antihypertensive.4d The most familiar thiadiazole containing
drugs are acetazolamide (I), megazol (II), and cefazedone (III)
(Figure 1).1b
To date, various methods have been reported for the synthesis
of 1,3,4-thiadiazoles (Scheme 1): (i) dehydrative cyclization of
thiosemicarbazides with acidic reagents such as orthophosphoric
acid and sulfuric acid (route a, Scheme 1);5 (ii) reaction of acid
hydrazides and dithiocarbamates using triethylamine in water
(route b, Scheme 1);6 (iii) dehydrative cyclization of
thiosemicarbazide mediated by p-TsCl/TEA in N-methyl-2-
pyrrolidone (route c, Scheme 1);7 (iv) cyclization of
thiosemicarbazone using iron (III) salts (route d, Scheme 1)8 and
(v) condensation of thiosemicarbazide and corresponding
aldehyde followed by an iodine mediated oxidative cyclization
(route e, Scheme 1).9 Although, the above reported approaches
are useful for the synthesis of 1,3,4-thiadiazoles, there are still
disadvantages associated with these methodologies such as harsh
reaction conditions, longer reaction time, the use of relatively
harmful reagents and lacking of broad substrate scope. Therefore,
the development of simple and mild routes for the synthesis of
1,3,4-thiadiazole derivatives is highly appealing and would be of
great relevance to both synthetic and medicinal chemists.
Figure 1. Representative examples of 1,3,4-thiadiazole
containing drugs.
The development of transition metal catalyzed reactions using
CH bond functionalization/oxidation strategy is a challenging
and powerful strategy for preparing valuable sulfur containing
heterocycles.10 Various catalytic systems based on palladium,11
rhodium,12 ruthenium,13 copper14 and iron15 have been identified
as efficient catalysts for CS bond formation. Transition metal
free transformations are more preferred in pharmaceutical
industries over transition metal catalyzed reactions because the
later are not only expensive, but are associated with difficulties in
their removal from the desired products. To overcome these
limitations, metal free approaches for direct CS bond formation
through CH bond oxidation has drawn considerable interests.
Recently, many groups reported significant progress on CS
bond formation under metal free conditions with various oxidants
———
 Corresponding author. Tel.: +91-361-2582307; fax: +91-361-2690763; e-mail: patel@iitg.ernet.in

2
Tetrahedron
such as tert-butyl hydroperoxide (TBHP),16a tetra-n-
butylammonium fluoride (TBAF),16b di-tert-butyl peroxide
(DTBP)16c and iodine (I2).16d Despite the significant advance on
metal free oxidative CS bond formation, the synthesis of
biologically active heterocycles through oxidative cyclization
(CS bond formation) is rarely studied.9,17
Scheme 2. Selective formation of CO, CN and CS bonds via
imine CH bond functionalization.
Results and discussion
With this inspiration in mind, an initial reaction was attempted by
treating thiosemicarbazone (1a) with DDQ (1 equiv.) in CHCl3 at
room temperature. A product formation (53% yield) was
observed after 1 h and detailed spectroscopic analysis (1H NMR,
13C NMR, IR, HRMS) of the isolated product revealed its
structure to be N,5-diphenyl-1,3,4-thiadiazol-2-amine (2a). In
1
compound (2a) the NH proton signals in its H NMR was
observed at ~10.5 ppm and the C2 and C5 carbons of the
thiadiazole skeleton appear respectively at 164 and 156 ppm in
its 13C NMR. This observation is in sharp contrast to our recent
result on Cu catalyzed CN bond formation from
thiosemicarbazones.18b The isomeric product i.e 4,5-diphenyl-2,4-
dihydro-3H-1,2,4-triazole-3-thione (Scheme 2, equation II)
obtained from thiosemicarbazones18b showed NH proton signal
above 14 ppm in the same solvent (DMDO-d6) and C3 and C5
carbons signals in the 1,2,4-triazole skeleton around 168 and 150
ppm respectively. To investigate the optimal reaction conditions,
we began our studies using thiosemicarbazone (1a) as the model
substrate (Table 1). The precursor thiosemicarbazones (1a-1x)
are not commercially available, and were prepared according to
the reported methods.20
Scheme 1. Various methods for the synthesis of 2-amino-1,3,4-
thiadiazole.
Previously, we have achieved a direct access for the synthesis
of 2,5-disubstituted 1,3,4-oxadiazoles via the imine CH bond
functionalization
(CO
bond
formation)
of
N-
arylidenearoylhydrazides using a catalytic quantity of Cu(OTf)2
(Scheme 2 (i)).18a Very recently, we have demonstrated a Cu(II)
catalyzed
imine
CH
bond
functionalization
of
thiosemicarbazones where selective CN bond over CS bond
formations afforded 4,5-disubstituted 1,2,4-triazole-3-thiones
(Scheme 2 (ii)).18b However, the formation of 1,3,4-thiadiazole
(CS bond over CN) was observed only when any one of the
aryl rings in thiosemicarbazones is ortho-disubstituted. This is
probably due to the extreme steric factor imparted by ortho-
disubstituted substrates in any one of the aryl rings of
thiosemicarbazone. Due to the steric factor it adopts a syn-syn
conformation as opposed to syn-anti conformation and thereby
bringing the sulfur atom of thiocarbonyl to the proximity of
imine CH bond for oxidative cyclization (CS bond
Table 1. Optimization of reaction conditionsa,b
Entry
Oxidant
Solvent
Yield (%)
formation).18b
The
oxidative
cyclization
of
N-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
I2
DIB
CHCl3
CCl4
CH3CN
THF
1,4-dioxane
DMF
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
53
75
72
51
45
47
43
50
10
00
57
60
73
35
arylidenearoylhydrazide leading to 1,3,4-oxadiazoles via imine
CH bond oxidation have been achieved under a metal free
(using I2) condition by our group.18c On the other hand, DDQ has
been used for the CS bond formation during the synthesis of
cephalosporins from 3-thiocarbonylhydrazone.19a Further, DDQ
has been used for synthesis of thiadiazole from azomethene
derivatives or thiosemicarbazones.19b,c Taking cues from the
aforementioned reports we reasoned that a DDQ mediated
oxidative cyclization of thiosemicarbazone involving its imine
CH bond may provide either an aminothiadiazole (through CS
bond formation) or a triazole-3-thione (through CN bond
formation).
TEMPO
TBHP (in dec)
chloranil
DDQc
DDQd
aReaction conditions: (1a) (0.5 mmol), oxidant (0.5 mmol), and
solvent (2 mL) at room temperature for 1 h. bIsolated yield. c0.75
mmol of DDQ was used. d 0.25 mmol of DDQ was used.

3
varied from electron-neutral –H (1h) and electron-donating
Encouraged by this selective CS bond forming process,
further optimizations were carried out to attain an optimum yield
of the product. Various solvents such as CCl4 (75%), CH3CN
(72%), THF (51%), 1,4-dioxane (45%), DMF (47%) and toluene
(43%) (Table 1, entries 2-7) were screened, from which CCl4
(Table 1, entry 2) was found to be the most efficient medium.
Due to the toxicity and safety issues of chlorinated solvent CCl4
was avoided and CH3CN (Table 1, entry 3) was chosen as the
reaction medium, albeit in little lower yield than CCl4 (Table 1,
entry 2). A variety of other nonmetallic oxidants such as I2, DIB,
TEMPO, TBHP (in decane) and chloranil (Table 1, entries 8-12)
were examined, DDQ (Table 1, entry 3) was found to be the most
effective for this transformation. Higher percentage loading of
DDQ (1.5 equiv.) neither increased the yield nor reduced the
reaction time (Table 1, entry 13). However, a significant decrease
in the yield was observed by reducing the amount of DDQ (0.5
equiv.) (Table 1, entry 14). Thus, the optimized reaction
conditions for the oxidative intramolecular CS bond formation
of (1a) (0.5 mmol) was achieved using DDQ (0.5 mmol) in
CH3CN (2 mL) at room temperature for 1 h.
such as 4-CH3 (1i) and 3,4-diOCH3 (1j) and electron-
withdrawing substituents such as 4-Cl (1k) and 4-Br (1l) all
afforded their respective 1,3,4-thiadiazoles (2h) (78%), (2i)
(80%), (2j) (71%), (2k) (72%) and (2l) (62%) respectively.
Substitution on the aryl ring (Ar1) with electron-donating groups
such as 3,4-diCH3 (1m), 2-CH3 (1n), and 4-nBu (1o-1p) while the
other ring (Ar2) with 3,4-diCH3 (1m), electron neutral –H (1n-1o)
and 4-CH3 (1p) yielded their respective thiadiazoles (2m), (2n),
(2o) and (2p) in 65%, 48%, 57% and 56% yields respectively.
Similarly, the presence of
a
moderately electron
withdrawing substituent such as 4-Br (1q), on aryl ring (Ar1)
while the other aryl ring (Ar2) having no substituent -H (1q) or
substituents such as 4- CH3 (1r), 4-OCH3 (1s), 4-Cl (1t) and 3-Br
(1u) gave moderate to high yields of their corresponding products
(2q) (85%), (2r) (78%), (2s) (65%), (2t) (53%) and (2u) (51%)
(Scheme 3). The presence of 4-F (1v) on aryl ring (Ar1) and other
ring (Ar2) having an electron neutral -H gave product (2v) in
modest yield (67%) as compared to its corresponding substrate
(2q). Moreover, incorporation of an electron withdrawing
substituent at ortho position of both the aryl rings (Ar1 and Ar2)
as in (1w) considerably lowered the product (2w) yield to 53%.
As can been seen from Scheme 3 there is no correlation between
the effects of substituents on any of the aryl rings and their
product yields. Replacement of one of the aryl group (Ar1) with
an aliphatic group such as benzyl group (1x) provided the
corresponding 1,3,4-thiadiazole (2x) in lower yield (55%) as
compared to its corresponding diaryl substrate (2a).
Scheme 3. Substrate scope of 2-amino-substituted-1,3,4-
thiadiazoles.a,b
Based on literature reports,21 a plausible mechanism is
proposed as shown in Scheme 4. A single electron transfer (SET)
from the imine nitrogen to DDQ generates a nitrogen centered
radical cation (A) and a DDQ radical anion (B). The DDQ radical
anion (B) abstracts a hydrogen atom from the thioamidic
nitrogen, this is then followed by an intramolecular nucleophilic
attack of sulfur at the imine carbon to form a nitrogen centred
radical (C) and a DDQ radical (D). The DDQ radical (D) then
abstracts a proton from the intermediate (C) to form the desired
1,3,4-thiadiazole (2a) with the generation of DDQH2.
aReaction conditions: 1 (0.5 mmol), DDQ (0.5 mmol),
b
CH3CN (2 mL), rt, 1 h. Isolated yields.
Having achieved the optimal reaction conditions, we next
examined the scope and generality of this intramolecular CS
bond formation using various thiosemicarbazones (Scheme 3).
Initially, the effects of various substituents on the aryl ring (Ar2)
were screened. Various substituents such as 4-CH3 (1b), 4-tBu
(1c), 4-OCH3 (1d), 2-F (1e), 4-Cl (1f) and 3-Br (1g) on the aryl
ring (Ar2) of thiosemicarbazones were all reacted smoothly under
the optimized reaction condition affording their corresponding
1,3,4-thiadiazoles (2b), (2c), (2d), (2e), (2f) and (2g) respectively
in the yield ranging from 61% to 81% (Scheme 3). Subsequently,
the effects of various substituents on both the aryl rings (Ar1 and
Ar2) of thiosemicarbazones (Scheme 3) were examined. When
electron-donating substituents such as 4-CH3 is fixed on the aryl
ring (Ar1) and the substituents on the other aryl ring (Ar2) were
Scheme 4. Proposed mechanism for the formation of 2-amino-
1,3,4-thiadiazoles.
In summary, we have developed an effective oxidative
intramolecular CS bond formation to generate 2-amino-
substituted-1,3,4-thiadiazoles from thiosemicarbazones using
DDQ. This protocol represents an attractive route for a straight
forward access to a diverse range of 2-amino-substituted-1,3,4-
thiadiazole.We hope this clean procedure will be a valuable
addition to the synthesis of substituted thiadiazoles.

4
Tetrahedron
9.
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J. Org. Chem. 2015, 80, 1018–1024.
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B. K. P acknowledges the support of this research by the
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Research (CSIR) (02(0096)/12/EMR-II) and S.J.S to (DST)
(SB/FT/CS-006/2014). Thanks are due to Central Instruments
Facility (CIF) IIT Guwahati.
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Supplementary data associated with this article can be found
in
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.2015.xxxxxx.