Multicomponent reactions (MCRs) of arylmethyl bromides, arylamidines and elemental sulfur toward unsymmetric 3,5-diaryl 1,2,4-thiadiazoles

Article abstract of DOI:10.1016/j.tetlet.2017.05.061

A base-promoted three-component reaction between arylmethyl bromides, arylamidines and elemental sulfur was developed, leading to unsymmetric 3,5-diaryl-1,2,4-thiadiazoles in moderate to good yields with chemical diversity and complexity. This procedure shows broad substrates scope by employing elemental sulfur and commercially available starting materials under transition-metal free conditions.

Full text of DOI:10.1016/j.tetlet.2017.05.061

Accepted Manuscript
Multicomponent Reactions (MCRs) of Arylmethyl Bromides, Arylamidines and
Elemental Sulfur toward Unsymmetric 3,5-Diaryl 1,2,4-Thiadiazoles
Zhen Zhou, Miaochang Liu, Song Sun, En Yao, Suqin Liu, Zhiwen Wu, Jin-
Tao Yu, Yan Jiang, Jiang Cheng
PII:
S0040-4039(17)30641-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.061
TETL 48954
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 April 2017
15 May 2017
16 May 2017
Please cite this article as: Zhou, Z., Liu, M., Sun, S., Yao, E., Liu, S., Wu, Z., Yu, J-T., Jiang, Y., Cheng, J.,
Multicomponent Reactions (MCRs) of Arylmethyl Bromides, Arylamidines and Elemental Sulfur toward
Unsymmetric 3,5-Diaryl 1,2,4-Thiadiazoles, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.05.061
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Multicomponent Reactions (MCRs) of
Arylmethyl Bromides, Arylamidines and
Elemental Sulfur toward Unsymmetric 3,5-
Diaryl 1,2,4-Thiadiazoles
Zhen Zhou,† Miaochang Liu,‡ Song Sun,† En Yao,† Suqin Liu,† Zhiwen Wu,† Jin-Tao Yu,† Yan Jiang,† and Jiang
Cheng*,†

1
Tetrahedron Letters
journal homepage: www.els evier.com
Multicomponent Reactions (MCRs) of Arylmethyl Bromides, Arylamidines and
Elemental Sulfur toward Unsymmetric 3,5-Diaryl 1,2,4-Thiadiazoles
Zhen Zhou,† Miaochang Liu,‡ Song Sun,† En Yao,† Suqin Liu,† Zhiwen Wu,† Jin-Tao Yu,† Yan Jiang,† and
Jiang Cheng*,†1
†School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, and Institute for Natural and Synthetic Organic
Chemistry, Changzhou University, Changzhou 213164 P. R. China, P. R. China.
‡College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325000, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A base-promoted three-component reaction between arylmethyl bromides, arylamidines and
elemental sulfur was developed, leading to unsymmetric 3,5-diaryl-1,2,4-thiadiazoles in
moderate to good yields with chemical diversity and complexity. This procedure shows broad
substrates scope by employing elemental sulfur and commercially available starting materials
under transition-metal free conditions.
Received in revised form
Accepted
Available online
Keywords:
transition-metal free
elemental sulfur
multicomponent reactions
1,2,4-thiadiazoles
1,2,4-Thiadiazoles are important five-membered heterocycles
with broad biological and pharmaceutical activities.1,2 Among
which, the 3,5-diaryl- analogues serve as sphingosine 1-
phosphate receptor agonists,3 antifungal agents,4 and antibacterial
reagents.5 Compared with the intramolecular cyclization toward
such frameworks,6 the intermolecular pathway features the
simplicity for preparing starting materials as well as diversity of
the final products. For example, the oxidative dimerization of
either thioamides (Scheme 1, eq 1),7 or the annulation of aryl
nitriles with sulfur,8 SCl2,9 (NH4)2S10 and nitrile sulfide11
(Scheme 1, eq 2) allowed rapidly to construct symmetric 3,5-
diaryl-1,2,4-thiadiazole. Unfortunately, the cross-dimerization of
two kinds of thioamides resulted in the distribution of four 1,2,4-
thiadiazole with extremely low selectivity.
commercially available starting material under transition metal-
free conditions; 3) wide substrates scope.
Scheme 1. Synthetic Pathways toward 3,5-Diaryl-1,2,4-
Thiadiazoles
From both diversity and complexity points of view, either the
development of methodologies or the proper substrate design
toward unsymmetric 3,5-diaryl-1,2,4-thiadiazole kept highly
desired goal for organic chemists, yet challenging. And no
examples were reported till Deng developed the annulation
between amidines, elemental sulfur, and 2-methylquinolines (or
aromatic aldehydes) under transition-metal-free conditions
(Scheme 1, eq 3).12 As our continuous interest in the synthesis of
thiadiazole,13 herein, we wish to report a three-component
reaction between arylmethyl bromides, arylamidines and
elemental sulfur toward unsymmetric 3,5-diaryl-1,2,4-thiadiazole
(Scheme 1, eq 4). This procedure features: 1) high chemical
diversity and complexity of the products by multicomponent
reaction; 2) the employment of elemental sulfur14 and
Initially, we tested the reaction of (4-tolyl)methyl bromide
(1a), benzamidine hydrochloride (2a) and sublimed sulfur in
toluene at 140 oC under N2 in the presence of 4 equivalent of
K2CO3 as the model reaction. To our delight, 3,5-diaryl-1,2,4-
thiadiazole 3aa was isolated in 19% yield (Table 1, entry 1).
Replacing K2CO3 with NaOtBu increased the yield to 34% (Table
1, entry 2). A comparable 31% yield was obtained in the case of
KOtBu (Table 1, entry 3). The yield dramatically increased to
———
1* Corresponding author. E-mail:jiangcheng@cczu.edu.cn

2
Tetrahedron
66% by using LiOtBu (Table 1, entry 4). Under an air or O2
atmosphere, the reaction efficiency significantly decreased to
47% and 23%, respectively. So did the procedure under elevated
(59%, 150 oC) or lower (51%, 130 oC) reaction temperature
(Table 1, entry 4). The solvent tests demonstrated toluene was the
best (66%), though DMSO provided the product 3aa in an
acceptable 58% yield (Table 1, entries 5-9). The practicability of
this procedure was further increased since 3aa was isolated in a
comparable 62% yield in a 1 mmol scale reaction.
Table 1. Selected Results for Screening the Optimized Reaction
Conditionsa
entry base
solvent
toluene
toluene
toluene
toluene
DMAC
DMF
yieldb (%)
a Reaction conditions: arylmethyl bromide 1 (0.12 mmol), benzamidine
hydrochloride 2a (0.1 mmol), S8 (0.1 mmol), LiOtBu (0.4 mmol), toluene (2
mL), N2, 140oC, 12 h.
Notably, nBuBr worked to some extent under this procedure to
introduce the n-propyl to 5- position of 3-phenyl-1,3,4-
thiadiazole (3ja, 21%). However, replacing nBuBr with nBuI did
not have any positive effect on the reaction efficiency.
1
K2CO3
19
2
3
4
5
6
7
8
9
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
34
31
66,47c,23d,51e,59f
33
26
58
51
Figure 2. Scope of substituted benzamidine hydrochloride.a
DMSO
xylene
diglyme
13
a Reaction conditions: (4-tolyl)methyl bromide 1 (0.12 mmol), benzamidine
hydrochloride 2 (0.1 mmol), S8 (0.1 mmol), base (0.4 mmol), solvent (2.0
d
mL), N2, at 140 oC for 12 h, in a sealed Schlenk tube. b Isolated yield. c air.
O2. e 130 oC. f 150 oC. DMAC = dimethylacetamide; DMF = N,N-
dimethylformamide; DMSO = dimethyl sulfoxide.
After the establishment of the optimized reaction conditions,
the scope and limitation of arylmethyl bromides in the reaction
with benzamidine hydrochloride and sublimed sulfur were tested,
as shown in Fig. 1. As expected, this procedure was applicable
for arylmethyl bromides bearing both para-, meta- and ortho-
substitutents in the phenyl ring (3aa-ea and 3ga-ia), albeit with
low yield for ortho-substituted analogue (3ba, 35%). Some
functional groups, such as fluoro (3da, 50%), chloro (3ea, 69%),
trifluoromethyl (3ga, 57%), and cyano (3ha, 70%), survived
under this procedure, providing handles for further
a Reaction conditions: (4-tolyl)methyl bromide 1a (0.12 mmol), arylamidine
hydrochloride 2 (0.1 mmol), S8 (0.1 mmol), LiOtBu (0.4 mmol), toluene (2
mL), N2, 140oC, 12 h. b DMSO (2 mL).
transformation.
Figure 1. Scope of substituted benzyl bromidesa
Next, the scope of (4-tolyl)methyl bromide in the reaction with
arylamidine hydrochloride and sublimed sulfur was studied (Fig.
2). Once again, this procedure workedsmoothly, providing a
series of 3-aryl-5-(4-tolyl)-1,3,4-thiadiazoles in moderate yields
(3ab-ae, 56-67%). Notably, 3- and 4-pyridinyl were introduced
into 3- position of 5-(4-tolyl)-1,2,4-thiadiazoles (3af, 45%;
3ag,47%) by replacing toluene with DMSO as solvent.
Scheme 2. Mechanism Study
To get insights into the mechanism, the presumed intermediate
A was subjected to the procedure, and 3,5-diphenyl 1,2,4-
thiadiazole was isolated in a comparable 62% yield, which
indicated A may serve as intermediate during this tranformation.

3
Based on the experimental results, a proposed pathway of this
reaction is outlined in Scheme 3. In step 1, in the presence of
base, the reaction of arylmethyl bromide with arylamidine
produces intermediate A, which tautomerizes to B. Then, the
nucleophilic attack of elemental sulfur to nitrogen atom in amino
takes place leading to intermediate C.15 After the tautomerization
of C to D, the intermolecular nucleophilic attack of sulfur atom
to imino group provides cyclized intermediate E. Afterwards,
intermediate E transforms to intermediate F by the elimination of
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
References and notes
† Changzhou University
‡
Wenzhou University
-
S7 . Finally, the oxidation of intermediate F by sulfur furnishes
1
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of benzyl bromide produces aldehyde,16 which annulates with
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Scheme 3. Proposed Mechanism
path a: in the absence of DMSO
S8
Ar'
Ar'
Ar'
NH
N
N
HN
+
Ar'
Ar
Br
Ar
NH
Ar
NH2
Ar
NH
NH2
-S-S5-S-S
A
B
C
2
For selected recent examples, see: (a) Davison, E. K.; Sperry, J. Org.
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MedChemComm 2017, 8, 162. (c) Hoveyda, H. R.; Fraser, G. L.;
Dutheuil, G.; El Bousmaqui, M.; Korac, J.; Lenoir, F.; Lapin, Al.; Noel,
S. ACS Med. Chem. Lett. 2015, 6, 736. (d) Gurjar, A. S; Andrisano, V.;
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Sn2- + 4 H+
Sn
Ar'
NH
Ar'
Ar'
HN
Ar'
N
-S7
N
HN
N
Ar
S
Ar
NH
NH
Ar
Ar
-S-S5-S-S
S-S5-S-
S
S
F
E
D
path b: in the presence of DMSO
NH
S8
DMSO
Ar'
NH
Ar'
NH2
N
Ar'
NH
O
Ar
N
Ar
Ar
Br
S-S-S5-S-
Ar
H
Kornblum oxidation
A'
Ar'
Ar'
N
N
NH
3
Ren, F.; Deng, G.; Wang, H.; Luan, L.; Meng, Q.; Xu, Q.; Xu, H.; Xu,
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Ar
Ar
NH
S
S-S-S5-S-
S-S5-S-
E
B'
In conclusion, we have developed a base-promoted three-
component reaction between arylmethyl bromides, arylamidine
hydrochlorides and sublimed elemental sulfur leading to
unsymmetric 3,5-diaryl-1,2,4-thiadiazoles in moderate to good
yields with diversity and complexity. This procedure features
with broad substrates scope as well as the employment of
elemental sulfur and commercially available starting materials
under transition-metal free conditions.
4
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Acknowledgments
We thank the National Natural Science Foundation of China (nos.
21572025, 21372177, 21672028), “Innovation &
Entrepreneurship Talents” Introduction Plan of Jiangsu Province,
the Key University Science Research Project of Jiangsu Province
(15KJA150001), Jiangsu Key Laboratory of Advanced Catalytic
Materials &Technology (BM2012110) and Advanced Catalysis
and Green Manufacturing Collaborative Innovation Center for
financial supports. Sun thanks the National Natural Science
Foundation of China (no. 21602019) and Young Natural Science
Foundation of Jiangsu Province (BK20150263) for financial
support.
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5
1. high chemical diversity and complexity of the products
by multicomponent reaction
2. the employment of elemental sulfur and commercially
available starting material under transition metal-free
conditions
3. wide substrates scope