Highly efficient synthesis of 1,2,4-thiadiazoles from thioamides utilizing tetra(n-butyl)ammonium peroxydisulfate

Article abstract of DOI:10.1080/00397911.2020.1751854

A new synthetic approach to 1,2,4-thiadiazoles using tetra(n-butyl)ammonium peroxydisulfate via oxidative dimerization of thioamides is described. This new oxidative protocol is simple, highly efficient, and allows the practical synthesis of 1,2,4-thiadiazoles from various primary thioamides in good to excellent yields.

Full text of DOI:10.1080/00397911.2020.1751854

Synthetic Communications
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Highly efficient synthesis of 1,2,4-thiadiazoles
from thioamides utilizing tetra(n-butyl)ammonium
peroxydisulfate
Kieseung Lee, Richard S. Lee & Yong Hae Kim
To cite this article: Kieseung Lee, Richard S. Lee & Yong Hae Kim (2020): Highly efficient
synthesis of 1,2,4-thiadiazoles from thioamides utilizing tetra(n-butyl)ammonium peroxydisulfate,
Synthetic Communications, DOI: 10.1080/00397911.2020.1751854
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1751854
Highly efficient synthesis of 1,2,4-thiadiazoles from
thioamides utilizing tetra(n-butyl)ammonium
peroxydisulfate
Kieseung Leea,b, Richard S. Leec, and Yong Hae Kimd
b
aDepartment of Applied Chemistry, Woosuk University, Chonbuk, Republic of Korea; Department of
c
Pharmaceutical Engineering, Woosuk University, Chonbuk, Republic of Korea; School of Pharmacy,
d
University of Southern California, Los Angeles, CA, USA; Department of Chemistry, Korea Advanced
Institute of Science & Technology, Daejon, Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 15 December 2019
A new synthetic approach to 1,2,4-thiadiazoles using tetra(n-buty-
l)ammonium peroxydisulfate via oxidative dimerization of thioamides
is described. This new oxidative protocol is simple, highly efficient,
and allows the practical synthesis of 1,2,4-thiadiazoles from various
primary thioamides in good to excellent yields.
KEYWORDS
Oxidative dimerization;
primary thioamide;
tetra(n-butyl)ammonium
peroxydisulfate;
GRAPHICAL ABSTRACT
124-thiadiazole
Introduction
1,2,4-Thiadiazole is an important class of five-membered heterocyclic compounds found
in many natural products, drugs, and bioactive synthetic molecules.[1] For example, the
commercial antibiotic, cefozopran, along with many biologically important synthetic
molecules, acetycholinesterase inhibitors and G-protein coupled receptors, possess 1,2,4-
thiadiazole moieties as pharmacophores in their structures.[2] In addition, 1,2,4-thiadia-
zoles are also utilized as thiol trapping agents, pesticides, and fungicides.[3]
Consequently, active research efforts have been devoted to the development of new
approaches to 1,2,4-thiadiazoles in recent years,[4] and the most common approach to
these compounds is the oxidative dimerization of primary thioamides using various
oxidizing reagents for example, CAN,[4a] Cu(OTf)2,[4b] Oxone,[4c] DDQ,[4d] IBX/
TEAB,[4e] and t-butyl nitrite.[4f] These methods, however, may have some limitations
CONTACT Kieseung Lee
kslee@woosuk.ac.kr
Department of Applied Chemistry, Woosuk University, 443 Samrye-
Ro, Samrye-Eup, Wanju-Kun, Chonbuk 55338, Republic of Korea.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
K. LEE ET AL.
O
O
O
S
N
R
R
(n-Bu)4N+-O S O O S O-+N(n-Bu)4
+-
+ 1/8S
+
1/2
+
NH2
2
(n-Bu)4N O S OH
8
R
N S
1
O
O
O
TBAP
2
Scheme 1. A new synthetic approach to 1,2,4-thiadiazoles from thioamides using TBAP.
such as strict reaction conditions, limited substrate scope, or use of toxic or less readily
available oxidants.
Tetra(n-butyl)ammonium peroxydisulfate (TBAP), easily prepared from tetrabutylam-
monium hydrogen sulfate and potassium persulfate (K2S2O8), have been used for useful
organic reactions conducted in organic solvents such as CH2Cl2, CH3CN, and other
organic solvents.[5]
In continuation of our efforts to develop useful organic reactions using TBAP in
organic solvents,[5,6] we herein wish to report a new synthesis of 1,2,4-thiadiazoles 1 via
oxidative dimerization of thioamides 2 using TBAP in good to excellent yields
(Scheme 1).
Results and discussion
Various types of primary thioamides were reacted with TBAP, and the representative
results are summarized in Table 1.
The optimization reaction was performed using thiobenzamide 1a as a model com-
pound which was reacted with TBAP (1.0 eq.) in CH2Cl2 at rt, and the reaction was
confirmed to be incomplete (entry 1). With a little excess of TBAP (1.2 eq.) at 40 ꢀC for
24 h, the reaction was completed to provide thiadiazole 1a in 81% yield (entry 2).
CH3CN and potassium persulfate were also attempted as a reaction medium and an
oxidant under the same conditions, however, the results were unsuccessful in terms of
isolated yields (entries 3 and 4). Thus, the procedure of entry 2 was adopted as the
standard protocol for the extensive study of this reaction. As shown in Table 1, the
reactions of TBAP with thiobenzamides bearing electron-donating or electron-
withdrawing groups on the aromatic rings generally proceeded smoothly regardless of
the positions on the aromatic rings (entries 5–14). No significant electronic effects were
observed, whereas minor steric effects appeared to be working in this reaction since thi-
obenzamides with a bulky substituent at p-position gave higher yields than those substi-
tuted at o- or m-positions. The desired thiadiazoles were obtained in good to excellent
yields ranging from 77 to 91% yield. This oxidative dimerization reaction was further
extended to other aromatic, heterocyclic, and aliphatic thioamides to determine the
scope of this reaction. Under standard conditions, thioamides with naphthyl, thio-
phenyl, and alkyl substituents (2l–n) were all similarly reactive toward TBAP to provide
the corresponding thiadiazoles (1l–n) in good yields (entry 15–17). Thioamide with
pyridine moiety, however, failed to give a successful result (Y ¼ 37%).
We also attempted the cross-dimerization reaction by using two different thiobenza-
mides (2a, 2i) to synthesize the corresponding unsymmetrical 1,2,4-thiadiazoles
(Scheme 2). Unfortunately, however, the self-dimerized symmetrical thiadiazoles (1a, 1i)
were obtained as major products in a combined yield of ca. 50%, whereas the

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SYNTHETIC COMMUNICATIONSV
3
Table 1. Highly efficient synthesis of 1,2,4-thiadiazoles utilizing TBAPa.
(Yields, %)b
44c
1o Thioamide
S
Entry
Time(h)
1,2,4-Thiadiazole
S
S
S
S
N
N
1a
1a
1a
24
1
2a
2a
NH2
S
N
81
2
NH2
S
24
N
N
67d
NH2
S
N
3
4
5
2
2a
2a
2b
N
NH2
S
3e
N
24
24
1a
1b
S N
N
NH2
80
Cl
Cl
N
Cl
S
S
S
S
S
Cl
1c
1d
82
84
6
7
2c
2d
24
24
Cl
Cl
NH2
NH2
N
N
N
S
N
Cl
Cl
Cl
NH2
N
1e
77
8
2e
2f
24
24
24
Me
S
Me
S
Me
N
9
1f
79
91
Me
Me
Me
NH2
N
S
S
N
1g
10
11
2g
NH2
NH
N
S
S N
MeO
MeO
OMe
1h
2 2h
85
81
N
20
24
20
20
S
S
N
S
F3C
O2N
F3C
O2N
CF3
NO
21i
12
13
14
2i
2j
NH2
NH2
NH
N
S
S
N
1j
88
90
N
S
N
F
F
F
22k
2l
1k
N
t-Bu
t-Bu
t-Bu
S
S
S
N
15
24
85
1l
NH2
N
N
S
S
16
17
2m
2n
22
24
1m
1n
81
82
N
NH2
NH2
S
S
N
S
S
N
a: Thioamide 2 (1.0 mmol), TBAP (1.2 eq), CH2Cl2 (10 mL), 40 ꢀC, 20-24 h, Ar; b: Isolated yields by flash column
chromatography on SiO2; c: 2a, TBAP (1.0 eq), rt, 24 h, Ar; d: 2a, TBAP (1.2 eq), CH3CN, 70 oC, 2 h, Ar; e: 2a, K2S2O8
(1.2 eq), 40 oC, 24 h, Ar, 2a was recovered in 93% yield.

4
K. LEE ET AL.
S
S
S
N
S N
1a (29%)
+
1i (21%)
TBAP
+
40 oC, 24 h
NH2
Ph
NH +
m-NO2Ph
2
m-NO2Ph
Ph
Ph
Ph(m-NO2)
1ia (20%)
N
N
2i
1ai (9%)
2a
Scheme 2. Attempted cross-dimerization reaction of 2a and 2i with TBAP.
N
O
Ph
Ph
TBAP
+
but
but
3a recovered
X
X
(1.2 eq)
Ph
NH2
N O
1,2,4-Oxadiazole
Ph
(Y = 92%)
3a
O
S
N
Me
Me
Ph
Ph
+
TBAP
(1.2 eq)
Me
N
H
Me
N
H
N S
Ph
4 (Y= 87%)
3b
1,2,4-thiadiazolidine
Scheme 3. Attempted reactions of phenyl amide 3a and thioacetanilide 3b with TBAP.
O
40 oC
(i)
H
N
TBAP
2 (n-Bu)4N+-O S O (I)
S
O
O
S
S
S
+-
R
(ii)
R
(n-Bu)4N O S OH
S
R
NH
R
N S
R
NH R
(II)
NH
R
O
NH
(I)
H
(III)
S
1l8 S8
SH
R
NH2
N
R
2
N
R
R
N S
O
N S
1
+-
(I)
H
(n-Bu)4N O S OH
(IV)
O
Scheme 4. Proposed reaction mechanism for TBAP-mediated dimerization of thioamides.
cross-dimerized unsymmetrical thiadiazoles (1ai, 1ia) were isolated as minor products
in 9%, 20% yields respectively.
Encouraged by the successful results obtained from the oxidative dimerization of thi-
oamides, we then investigated the reactions of phenyl amide 3a and thioacetanilide 3b
with TBAP to explore the possibility of preparing the corresponding cyclized products
(Scheme 3).
Thus, when phenyl amide 3a was reacted with TBAP under standard conditions, the
desired dimerization reaction did not take place and 3a was recovered in 92% yield.
Thioacetanilide 3b has shown different reactivity, and desulfurization took place as the
major reaction and acetanilide 4 was obtained in 87% yield.
A plausible reaction mechanism is proposed in Scheme 4. Upon heating at 40 ꢀC in
CH2Cl2, TBAP undergoes radical dissociation to form sulfate radical I which abstracts a
hydrogen atom from thioamide 2 to produce resonance-stabilized radical II. Dimerization
of radical II generates radical-adduct III, and subsequent nucleophilic attack of the imino
group on the thiocarbonyl group in intermediate III affords cyclized intermediate IV.

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SYNTHETIC COMMUNICATIONSV
5
Double hydrogen atom abstraction from intermediate IV by sulfate radicals and following
extrusion of elemental sulfur would furnish the final product, 1,2,4-thiadiazole 1.
In conclusion, an efficient and practical synthesis of 1,2,4-thiadiazoles from primary
thioamides using TBAP has been developed. Considering such advantages as utilization
of readily available and stable solid oxidant TBAP as a good source of sulfate radical,
simple and highly reproducible procedures, wide substrate scope, good to excellent
yields, this new synthetic protocol could be a method of choice in the synthesis of vari-
ous 1,2,4-thiadiazoles from primary thioamides. Currently, we are undertaking add-
itional research on reaction mechanisms and related studies, and those results will be
reported in due course.
General procedure for the synthesis of 1,2,4-thiadiazoles using TBAP
A solution of thioamide 2 (1.0 mmol) and TBAP (812.5 mg, 1.2 eq.) in 10 mL of dry
CH2Cl2 was heated at 40 ꢀC for the specified time under Ar. The reaction mixture was
concentrated in vacuo to provide a pale-brown oily residue, which was dissolved again
with a minimum amount (ca. 1.0 mL) of CH2Cl2. The resulting solution was loaded on
top of the column (SiO2), and flash chromatography was performed as usual using the
specified eluent to furnish pure 1,2,4-thiadiazole 1 as a solid.
3,5-Diphenyl-1,2,4-thiadiazole (1a): Yield: 81%; White solid; mp 89–90 ꢀC (lit.[4d]
89–90 ꢀC); Rf ¼ 0.41 (Hex/CH2Cl2, 3/2); IR (ATR) 3048, 2923, 2853, 1511, 1476, 1439,
1
1416, 1329, 988, 760, 705, 680 cmꢁ1; H NMR (CDCl3, 500 MHz) d 8.38–8.42 (m, 2H),
8.04–8.08 (m, 2H), 7.46–7.58 (m, 6H); 13C NMR (CDCl3, 125 MHz) d 188.1, 173.8,
132.9, 131.9, 130.7, 130.4, 129.3, 128.7, 128.3, 127.5; HRMS (APCI) calcd. for
C14H11N2S [M þ H]þ: 239.0643, found 239.0643.
Full experimental detail material can be found via the “Supplementary Content”
section of this article’s webpage.
Acknowledgments
The authors thank Woosuk University for supporting this work (2019).
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