Communication
DOI: 10.1002/bkcs.11969
BULLETIN OF THE
K. Lee et al.
KOREAN CHEMICAL SOCIETY
Expedient Synthesis of 1,2,4-Thiadiazoles from Primary Thioamides
Using Calcium Hypochlorite in Dichlomethane
Kieseung Lee, Joanne S. Lee, and Seok-Ki Lee§
†,*
‡
†Department of Applied Chemistry & Department of Pharmaceutical Engineering, Woosuk University,
‡
School of Pharmacy, University of the Pacific, Stockton, California, 90123, USA
§
Department of Applied Chemistry, Woosuk University, Chonbuk 55338, South Korea
Received December 12, 2019, Accepted January 12, 2020
Keywords: 1,2,4-thiadiazole, Primary thioamide, Calcium hypochlorite, Oxidative dimerization
Recently, 1,2,4-thiadiazoles have drawn a considerable
research interest from synthetic and medicinal chemists
since many natural and synthetic compounds incorporating
these structural units have shown a wide range of biological
the standard conditions, and various thioamides were
reacted with Ca(OCl) and the results are summarized in
2
Table 1.
As shown in Table 1, the reactions of thiobenzamides
1
activities. For example, 1,2,4-thiadiazoles are found as the
with Ca(OCl) generally proceeded smoothly in all cases
2
2a
core structural units in such molecules as cefozopran,
commercial antibiotic, acetycholinestrase inhibitors.
a
regardless of the nature (EWG or EDG) and the positions
of substituents on the aromatic rings (Entries 4–12). No sig-
nificant electronic effect of the substituent on the aromatic
ring was observed, whereas minor steric effect appeared to
be working since thioamides bearing substituent at
o-position gave lower yields than those bearing substituent
at at p-position. In general, the desired thiadiazoles 1 were
obtained in good to excellent yields ranging from 78% to
88%. Delighted with the successful results, we then
attempted reaction of thioamides with naphthyl, benzyl,
and thiophene. Thioamide 2k was reacted smoothly to give
the desired thiadiazole 1k in 79% yield, whereas thioamide
2b
Therefore, various new synthetic approaches to 1,2,4-
thiadiazole derivatives have been explored in the last
decade. Among them, the oxidative dimerization of thio-
amides using a variety of oxidizing reagents, e.g.,
IBX/TEAB, CAN, Cu(OTf) , t-BuOCl, oxone, t-butyl
2
3
nitrite, is the most typical approach to these compounds.
Many synthetic methods, however, have limitations such as
strict reaction conditions, use of expensive oxidants, and
the formation of toxic byproducts. Therefore, it is highly
desired to develop simple and eco-friendly synthetic routes
for 1,2,4-thiadiazoles using inexpensive oxidants under
mild conditions.
2
l required more oxidant and a longer reaction time to com-
plete the reaction. In the case of thioamide 2m, a less
Calcium hypochlorite (Ca(OCl) ), a stable solid alterna-
2
amount of Ca(OCl) was used to obtain 1m in 67% yield.
2
tive to NaOCl, has been used as a useful oxidant in organic
A plausible reaction mechanism is proposed in Scheme 2.
4
reactions. We herein wish to report an expedient synthesis
Hypochlorite anion, dissociated from Ca(OCl) , converts
2
3d
of thiadiazoles 1 from primary thioamides 2 using
thioamide 2 into S-chloro thioimine I. This intermediate
I is then nucleophilic attacked by another thioamide
Ca(OCl) in CH Cl under mild conditions (Scheme 1).
2
2
2
To obtain the basic information regarding the optimal
reaction conditions, thiobenzamide 2a was tested as a
model compound. When 2a was reacted with Ca(OCl)2
2
through amino group to form II, which is then proton-
–
abstracted by OH to furnish III. Intramolecular
(
65% purity, 1.0 equiv) in CH Cl at rt. for 24 h, the reac-
2 2
(
i) Ca(OCl)2
Ca2+ + 2 ClO-
H2N
tion was incomplete (Entry 1). With an excess of Ca(OCl)2
1.7 equiv), 2a was completely converted to thiadiazole 1a
HO-
H
(
(ii)
-
-
H
-
ClO HO Cl
R
N
+
R HO H O
S
N
NH
S
2
S
S
S
2
S
in 83% yield (Entry 2). CH CN was also attempted as a
reaction solvent, however, the result was poor (Entry 3).
Thus, the reaction conditions of Entry 2 were adopted as
R
R
3
S
Cl-
R
NH2
R
NH
R
N
H
II
2
H
I
III
ClO-
S
N
H
S
N
ClOHClO-
HS-
S
N
Ar
Ar
R
R
R
R
2
+
Ca(OCl)2
+
CaCl2 + 2 H O + 1/8 S
2
8
N
N
IV
SH
Ar
NH
2
N S
1
1
ClOH + HS-
-
(iii)
2
H O + Cl + 1/8 S8
2
Scheme 1. A novel approach to thiadiazoles 1 from primary thio-
amides 2 utilizing Ca(OCl)
2
Scheme 2. Plausible reaction mechanism for Ca(OCl) -mediated
synthesis of thiadiazoles 1 from primary thioamides 2.
2
.
Bull. Korean Chem. Soc. 2020, Vol. 41, 110–111
© 2020 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
110
Lee, Joanne S.
