A Three-Component Approach to 3,5-Diaryl-1,2,4-thiadiazoles under Transition-Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.6b00806

A novel route is disclosed for the synthesis of 1,2,4-thiadiazoles starting from amidines, elemental sulfur, and 2-methylquinolines or aldehydes under transition-metal-free conditions. This three-component approach affords efficient and rapid access to 3,

Full text of DOI:10.1021/acs.orglett.6b00806

Letter
pubs.acs.org/OrgLett
A Three-Component Approach to 3,5-Diaryl-1,2,4-thiadiazoles under
Transition-Metal-Free Conditions
Hao Xie, Jinhui Cai, Zilong Wang, Huawen Huang,* and Guo-Jun Deng*
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China
S
* Supporting Information
ABSTRACT: A novel route is disclosed for the synthesis of
1,2,4-thiadiazoles starting from amidines, elemental sulfur, and
2-methylquinolines or aldehydes under transition-metal-free
conditions. This three-component approach affords efficient
and rapid access to 3,5-diaryl substituted 1,2,4-thiadiazoles
with good tolerance of a broad range of funcitional groups.
Mechanistic studies reveal a radical-involved pathway.
he thiadiazole is an important five-membered heterocyclic
motif containing two nitrogen atoms and a sulfur atom,
using readily available raw materials in one pot. Methylarenes
are cheap, commercially available, and easy to handle raw
materials and widely used as the carbon source to assemble
various heterocycles. In most cases, the methyl group attached
to the aryl ring was oxidized in situ to an aldehyde group and
used for further transformations. Therefore, it shows great
advantages are to be gained by directly using methylarenes or
aldehydes as the carbon as well as aryl source to construct
substituted thiadiazoles under mild reaction conditions. As our
continuing efforts on using readily available elemental sulfur to
construct functionalized heterocycles,9 herein, we disclose a
novel base-promoted route for the synthesis of 1,2,4-
thiadiazoles with different aryl substituents at positions 3 and
5 from amidines, elemental sulfur, and 2-methylquinolines or
aldehydes under transition-metal-free conditions (Scheme 1).
In this transformation, one substituent attached to 1,2,4-
thiadiazoles comes from the amidines and the other one comes
from 2-methylquinolines or aldehydes.
T
which constitutes the key structures of many natural products,
pharmaceutical drugs, and functional materials.1 In particular,
the 1,3,4-thiadiazoles which have a symmetrical core skeleton
display a wide range of biological activities such as
antituberculosis,2 antimicrobial,3 anti-inflammatory, and anti-
cancer activity.4 As an isomer of 1,3,4-thiadiazole, the 1,2,4-
thiadiazole motif which has an unsymmetrical five-membered
ring also showed a broad range of pharmacological activities,
including cardiovascular, anti-inflammatory, and antibiotic
activity.5 Among them, cefozopran,6 which contains a 3,5-
disubstituted 1,2,4-thiadiazole motif, is a commercial drug with
antibacterial activity. Despite their wide applications in
pharmacology and organic synthesis, few methods for the
synthesis of 3,5-disubstituted 1,2,4-thiadiazoles have been
developed in the literature partially due to the unsymmetrical
five-membered ring structure. The general methods for the
synthesis of 1,2,4-thiadiazoles with identical substituents at
positions 3 and 5 mainly rely on the oxidative dimerization
reaction of thioamides.7 A large number of oxidants such as
thionyl chloride,7a hydrogen peroxide,7b nitrous acid,7c
pyridinium salt-dimethyl sulfoxide (DMSO),7d HCl-DMSO,7e
bis(acyloxyiodo)arenes,7f polymer-supported iodobenzene diac-
etate,7g N,N′-dibromo phenytoin,7h and 2,4,6-trichloro-1,3,5-
triazine7i have been successfully employed for the conversion of
thioamides as well as thiobenzamide derivatives to the
corresponding 1,2,4-thiadiazoles. In recent years, few alternative
methodologies have been developed using different starting
materials such as aryl nitriles8a and 3,5-dichloro-1,2,4-
thiadiazole8b (via the Suzuki−Miyaura coupling reaction).
So far, most of the previously mentioned procedures require
strong oxidative reaction conditions or starting materials that
are not readily available. More importantly, these methods are
mainly suitable for preparation of 1,2,4-thiadiazoles with
identical substituents at positions 3 and 5. It is highly desirable
to develop an efficient method for the preparation of 1,2,4-
thiadiazoles with different substituents at positions 3 and 5
Our study was initiated by choosing 2-methylquinoline (1a),
benzamidine hydrochloride (2a), and elemental sulfur as the
model system for the optimization of reaction conditions,
which included base, solvent, temperature, and atmosphere
(Table 1). No desired product was observed when the mixture
in DMSO was stirred at 130 °C for 12 h in the absence of any
Scheme 1. New Strategy for the Synthesis of 3,5-Diaryl
Substituted 1,2,4-Thiadiazoles
Received: March 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00806
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Reaction of 1a with Various Amidines (2)
b
entry
base
solvent
DMSO
yield (%)
1
2
3
4
5
6
7
8
0
Cs2CO3
K2CO3
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
trace
trace
61
K2HPO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
52
93
22
1,4-dioxane
DMSO
DMSO
DMSO
33
c
9
63
d
10
31
e
11
93
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2 equiv), S (1.0
mmol, 5 equiv), base (3 equiv), and solvent (0.6 mL) under air at 130
b
c
d
°C. GC yield. Reaction temperature of 100 °C. S (0.8 mmol, 4
e
equiv). Under argon.
Scheme 3. Reaction of 2a with Various 2-Methylquinolines
(1)
additive (Table 1, entry 1). Subsequently, different bases were
screened (entries 2−6). While carbonates such as Cs2CO3 and
K2CO3 did not enable the desired transformation (entries 2−
3), KOH and K2HPO4 gave a moderate yield of 3-phenyl-5-
(quinolin-2-yl)-1,2,4-thiadiazole (3a) (entries 4−5). Then
K3PO4 was proven to be the most effective base, which
delivered 3a in 93% yield (entry 6). Different reaction mediums
(DMF and 1,4-dioxane) were investigated (entries 7 and 8).
The results suggested that only DMSO gave a good yield for
the reaction. No enhancement in yield was observed when the
reaction was carried out at a reduced temperature or decreasing
the amount of sulfur (entries 9 and 10). Notably, this reaction
could not be affected by the reaction atmosphere (entry 11).
With these optimized conditions in hand, we next
investigated the generality of the current procedure by first
testing various amidine hydrochlorides with 2-methylquinoline
(1a), and the results were summarized in Scheme 2. We were
quite pleased to observe no steric effect. For example, the
reactants with a methyl group at the para- and ortho-position of
benzamidine salts were all tolerated well, delivering the target
1,2,4-thiadiazoles 3b and 3c in 91% and 92% yields,
respectively. Furthermore, benzamidine hydrochlorides bearing
either a typical electron-donating free OH group or a strong
electron-withdrawing CF3 group on the benzene ring provided
good yields (3d and 3e). However, for chloro- substituted
benzamidines, decreased yields of the desired products (3f and
3g) were obtained, which could probably be attributed to the
coupling reactions of chloro-substituted benzamidines with
elemental sulfur. Notably, pyridyl amidines were well tolerated
in this reaction system, regardless of use of pyridyl-4-yl, pyridyl-
3-yl, or pyridyl-2-yl, providing 3h−3j in good yields. We then
were pleased to find that guanidine derivatives, or 1H-pyrazole-
1-carboximidamides, also worked well, giving 3-pyrazolyl-
thiadiazoles (3k and 3l) in good yields.
Cl− at the C7-position of quinolines led to the corresponding
products in lower yields (3p−q). The 2-methylquinoline with
methoxy at the C8-position was also tolerated well, giving the
corresponding 1,2,4-thiadiazole 3r in good yield (71%). The
substrate bearing a free amino group afforded an excellent yield
of the desired product, with the free amino group being well
reserved (3s, 85% yield). Other reactants with an alkyl amino
or a dialkyl amino were also competent, albeit affording
moderate yields of the target products (3t−w). These
observations highlight the great significance of the present
reaction system because the 4-aminoquinoline motif was widely
found in drug molecules and natural products.10b−e
For the attractive biological properties of functionalized
quinolines,10 various substituted 2-methylquinolines under the
optimized reaction conditions were then examined (Scheme 3).
While substituents at the C6-position of quinolines, such as
methyl, trifluoromethyl, and trifluoromethoxy, were all
compatible (3m−o), halogen substituents such as F− and
We speculate that the cyclization proceeds through an initial
step of in situ oxidation of methylarenes to aldehydes.
B
DOI: 10.1021/acs.orglett.6b00806
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Organic Letters
Letter
Therefore, a range of aromatic aldehydes were subjected to the
present system (Scheme 4). Aldehydes employed such as
obtained when using the two methylquinolines (Scheme 3, 3a
and 3m). This further demonstrates that the aldehyde-involved
procedure is not the predominant pathway when using
methylquinolines. Finally, the reaction of benzamidine hydro-
chloride with elemental sulfur in the absence of either
methylquinoline or aldehyde could not give the 3,5-diphenyl-
1,2,4-thiadiazole 5a in the present system (Scheme 5d).
On the basis of the experimental observations and reports, a
proposed mechanism is outlined in Scheme 6. In the presence
Scheme 4. Reaction of Aldehydes (4) with Amidines (2)
Scheme 6. Tentative Mechanism
benzaldehyde and picolinaldehyde afforded the desired
products in moderate yields (5a−c). Unfortunately, aliphatic
aldehydes such as n-octylaldehyde did not work in the present
system (5d). Then, the treatment of quinoline-2-carbaldehyde
gave the corresponding product 3a in a moderate yield (63%).
This observation indicated that, besides the in situ formation of
aldehyde followed by condensation to give a CN bond, the
reaction of methylquinolines would undergo an alternative
pathway to directly generate the C−N bond.
of elemental sulfur and a base, 2-methylquinoline (1a) could
generate radical intermediate A via the more active enamine.11
While the intermediate A would be oxidized into the
corresponding quinolyl aldehyde for further transformation,
more directly, it couples with 2a, followed by a single-electron
transfer with elemental sulfur to afford intermediate B.12 The
next steps would be the activation of elemental sulfur to form a
C−S bond by a nucleophilic attack of intermediate B on the S8
ring, generating intermediate C.13 Then, imine isomerization of
intermediate C produces intermediate D, which undergoes
intramolecular nucleophilic addition to give 4H-thiadiazole E.14
Finally, E was oxidized to 3a by 2 equiv of sulfur.
To understand the mechanism of the reaction, we performed
a number of radical trapping and control experiments (Scheme
5). First, the addition of 2,2,4,4-tetramethyl-1-piperidinyloxy
Scheme 5. Mechanistic Study
In summary, we have developed straightforward and efficient
access to 3,5-diarylsubstituted-1,2,4-thiadiazoles from amidines,
elemental sulfur, and methylarenes or benzaldehydes under
transition-metal-free conditions. The methyl group attached to
quinolines and aldehydes successfully served as the carbon
source, and elemental sulfur acted as the sulfur source to
selectively assemble the five-membered 1,2,4-thiadiazole
moiety. Functional groups such as halogen and trifluoromethyl
were well tolerated under the optimized reaction conditions.
This three-component approach affords a facile route for the
rapid synthesis of unsymmetrical 3,5-diaryl substituted 1,2,4-
thiadiazoles. The detailed mechanism and synthetic application
of this reaction are currently under investigation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00806.
(TEMPO), butylated hydroxytoluene (BHT), or ethene-1,1-
diyldibenzene (DBE) obviously inhibited the reaction under
the standard conditions (Scheme 5a), thereby suggesting the
involvement of a radical pathway. The starting material 1a was
not recovered when the reaction was carried out in the absence
of 2a (Scheme 5b), which indicates that the interaction of 1a
and sulfur may be the initial step. When a competitive reaction
between 1m and 1a′ with 2a was carried out within 4 h, the
corresponding products 3a and 3m were determined by GC in
a 1:3 ratio (Scheme 5c), while almost the same yields were
General experimental procedure and characterization
data of the products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hwhuang@xtu.edu.cn.
*E-mail: gjdeng@xtu.edu.cn.
C
DOI: 10.1021/acs.orglett.6b00806
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21372187, 21572194, and 21502160),
the Program for Innovative Research Cultivation Team in
University of Ministry of Education of China (1337304), and
the Hunan Provincial Innovative Foundation for Postgraduate
(CX2015B202).
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DOI: 10.1021/acs.orglett.6b00806
Org. Lett. XXXX, XXX, XXX−XXX