Synthesis of 1,2,4-thiadiazoles by oxidative dimerization of carbothioamides by using oxone

Article abstract of DOI:10.1002/ejoc.201402756

1,2,4-Thiadiazoles were efficiently synthesized in good yields through the oxidative dimerization of carbothioamides by using Oxone as a readily available, inexpensive, and environmentally safe oxidant. A similar reaction of phenylselenoamide led to the corresponding 1,2,4-phenylselenadiazole in high yield. Copyright

Full text of DOI:10.1002/ejoc.201402756

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402756
Synthesis of 1,2,4-Thiadiazoles by Oxidative Dimerization of Carbothioamides
by Using Oxone
Akira Yoshimura,*[a] Anthony D. Todora,[a] Brent J. Kastern,[a] Steven R. Koski,[a] and
Viktor V. Zhdankin*[a]
Dedicated to the memory of Professor Alan R. Katritzky
Keywords: Oxidation / Oxone / Sulfur / Selenium / Heterocycles
1,2,4-Thiadiazoles were efficiently synthesized in good
yields through the oxidative dimerization of carbothioamides
by using Oxone as a readily available, inexpensive, and envi-
ronmentally safe oxidant. A similar reaction of phenyl-
selenoamide led to the corresponding 1,2,4-phenylselenadi-
azole in high yield.
the corresponding carbonyl compounds in good yields was
reported.[8] However, to the best of our knowledge, the
Oxone-promoted dimerization of thioamides to 1,2,4-thia-
diazoles is still unknown.
Introduction
1,2,4-Thiadiazoles are important heterocycles with nu-
merous applications as pharmaceuticals, fungicides,
herbicides, bacteriocides, dyes, lubricant additives, and vul-
canization accelerators.[1] Particularly interesting are the
medicinal properties of 1,2,4-thiadiazoles that serve as im-
portant pharmacophores in inhibitors targeting the cysteine
residues of proteins.[2] The most common approach to the
synthesis of medicinally important 1,2,4-thiadiazoles in-
volves the oxidative dimerization of thioamides.[3] A par-
ticularly important class of oxidants for the synthesis of
1,2,4-thiadiazoles from thioamides is represented by or-
ganohypervalent iodine reagents,[4] for example, (diacetoxy-
iodo)benzene,[4d–4f] 2-iodoxybenzoic acid (IBX),[4g] and re-
cyclable hypervalent iodanes.[4e,4h] Other reagents, such as
polymer-supported diaryl selenoxide and telluroxide,[5a,5b]
tert-butyl hypochlorite (tBuOCl),[5c] N-bromosuccinimide
(NBS),[5d] and dimethyl sulfoxide derived electrophilic rea-
gents[5e] have also been utilized as oxidants in this dimeriza-
tion. However, these methods have only limited applica-
bility for the synthesis of thioamides because they involve
toxic reagents and harsh conditions and usually produce
nitriles and isothiocyanates as byproducts.[1,6] Oxone
(2KHSO5·KHSO4·K2SO4) is known as an inexpensive and
environmentally safe oxidant that is useful for numerous
oxidation reactions.[7a,7b] Previously, the reaction of thioam-
ides with Oxone under solvent-free conditions leading to
In this communication, we describe the dimerization of
thioamides and selenoamide by using Oxone as an inexpen-
sive and environmentally safe terminal oxidant. Oxone is
known to be a convenient oxidant, and it has been used
for many important reactions such as C–H oxidation,[9a–9c]
oxidative cleavage reactions,[9d,9e] and oxidative rearrange-
ment reactions.[9f–9h] Several research groups have also re-
ported the use of Oxone as a terminal oxidant for catalytic
reactions induced by organohypervalent iodine species gen-
erated in situ from iodoarenes as precatalysts.[10] Very re-
cently, our group also reported that Oxone is an excellent
terminal oxidant for the hypervalent iodine catalyzed Hof-
mann rearrangement[11a] and for the hypoiodite-mediated
catalytic oxidative cyclization of aldoximes and alkenes
leading to isoxazolines and isoxazoles.[11b,11c]
Results and Discussion
We investigated the dimerization reaction of thiobenz-
amide (1a, 1 equiv.) by using various solvents and different
terminal oxidants (Table 1). As the initial step, we at-
tempted to perform hypervalent iodine catalyzed oxidative
dimerization of thiobenzamide by analogy with the known
hypervalent iodine mediated cyclizations.[4,11] In the pres-
ence of PhI as a precatalyst (10 mol-%) and Oxone as a
terminal oxidant, the dimerization of 1a afforded desired
thiadiazole 2a in 97% yield (Table 1, entry 1). However, in
the absence of PhI under similar reaction conditions, de-
sired thiadiazole 2a was formed in a comparable 95% yield
(Table 1, entry 2), which led us to the conclusion that
[a] Department of Chemistry and Biochemistry, University of
Minnesota Duluth,
Duluth, MN 55812, USA
E-mail: ayoshimu@d.umn.edu; vzhdanki@d.umn.edu
http://www.d.umn.edu/~vzhdanki/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402756.
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A. Yoshimura, V. V. Zhdankin et al.
SHORT COMMUNICATION
Oxone alone could be used as an efficient oxidant in this Table 2. Oxidative dimerization of thioamides 1 with Oxone under
the optimized reaction conditions.[a]
reaction. Out of several solvents tested, dichloromethane
was found to be the best solvent for this reaction (Table 1,
entries 3–8). We also tested several other oxidants under
these conditions (Table 1, entries 9–14). The best yields of
thiadiazole 2a (95–100%) were obtained with Oxone,
NaIO4, and KBrO3, whereas NaIO3, tBuOOH, H2O2, and
K2S2O8 were inefficient oxidants in this reaction. We de-
cided to use Oxone in our following studies because NaIO4
and KBrO3 are potentially dangerous compounds owing to
their toxicity and their ability to form explosive mixtures
with organic materials. Decreasing the amount of Oxone
from 2.0 to 1.2 equiv. led to a reduced yield of the product
(Table 1, entry 15). The addition of water for better solubi-
lity of Oxone also resulted in a reduced yield (Table 1, en-
try 16).
Table 1. Optimization of the oxidative dimerization of thiobenz-
amide.[a]
Entry Solvent
Oxidant (equiv.)
Yield [%][b]
1[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CH2Cl2
CH2Cl2
MeCN
CHCl3
EtOAc
hexane
toluene
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/H2O (2:1)
Oxone (2)
Oxone (2)
Oxone (2)
Oxone (2)
Oxone (2)
Oxone (2)
Oxone (2)
Oxone (2)
KBrO3 (2)
NaIO3 (2)
NaIO4 (2)
tBuOOH (2)
H2O2 (2)
(97)
95 (95)
(64)
(82)
(76)
(62)
(73)
(1)
(100)
(5)
(100)
(0)
(6)
K2S2O8 (2)
Oxone (1.2)
Oxone (2)
(84)
(82)
(47)
[a] The oxidative dimerization of thiobenzamide (1a) was per-
formed at room temperature for 24 h (control by TLC) by using
the oxidant (1.2–2.0 equiv.). [b] Yield of isolated product; the yield
as determined by NMR spectroscopy is given in parentheses.
[c] PhI (10 mol-%) was added.
By using the optimized reaction conditions, we investi-
gated the conversion of various thioamides 1 to respective
1,2,4-thiadiazoles 2 (Table 2). In general, thiobenzamides
with either electron-donating or electron-withdrawing sub-
stituents afforded corresponding 1,2,4-thiadiazoles 2 in [a] The dimerization of thioamide 1 with Oxone (2 equiv.) was per-
formed in CH2Cl2 at room temperature for 24 h. [b] Yield of iso-
good yields (Table 2, entries 1–8). This reaction also gave
lated product. [c] Reaction was performed for 48 h. [d] Reaction
was performed for 72 h. [e] Reaction was performed for 72 h at
good yields for thiophene carbothiamide and naphthalene
carbothioamides (Table 2, entries 9–11). However, the reac-
40 °C.
tion of thiobenzamides with a bulky ortho and meta substit-
uents in the phenyl ring and the reaction of benzyl thioam-
ide required a longer time and heating to 40 °C (Table 2,
Compared to known methods for the oxidative dimeriza-
entries 4, 5, 8, and 12). Unfortunately, the reaction of ali- tion reaction of thiobenzamide by using various oxidizing
phatic thiocarboamides and dithiobenzamides did not af- reagents,[4,5] our method affords 1,2,4-benzothiadiazoles 2
ford the desired products.
in similar or better yields. Next, we tried to prepare 1,2,4-
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1,2,4-Thiadiazoles by Oxidative Dimerization of Carbothioamides
of the reaction, the mixture was filtered, the inorganic solids on
the filter were washed with CH2Cl2, and then the combined solu-
tion was evaporated in vacuo. The residue was separated by column
chromatography (hexane/ethyl acetate = 1:3 or 1:5) to afford ana-
lytically pure thiadiazole 2.
selenadiazole by replacing thiobenzamide with benzo-
selenoamide. Fortunately, our optimized reaction condi-
tions worked for the efficient preparation of 1,2,4-selenadi-
azole 4 by dimerization of benzoselenoamide 3 in quantita-
tive yield [Scheme 1, Equation (1)]. This reaction has also
been performed by using hypervalent iodine reagents[12a]
and other oxidants.[12b] As expected, the reaction of benz-
amide 5 under our conditions did not afford the correspond-
ing dimerization product, and reactant 5 was recovered
from the reaction mixture [Scheme 1, Equation (2)].
3,5-Diphenyl-1,2,4-thiadiazole (2a): Reaction of thiobenzamide 1a
(69 mg, 0.50 mmol) according to the general procedure afforded 2a
(57 mg, 95%) as a white microcrystalline solid. Colorless needles
(recrystallized from dichloromethane/hexane), m.p. 89.8–90.2 °C
(ref.[13] m.p. 89–90 °C). IR (KBr): ν = 3060, 3036, 1508, 1482, 1440,
˜
1
1423, 1331, 1274, 1248 cm–1. H NMR (500 MHz, [D6]acetone): δ
= 8.44–8.37 (m, 2 H), 8.19–8.11 (m, 2 H), 7.69–7.52 (m, 6 H) ppm.
13C NMR (125 MHz, [D6]acetone): δ = 189.3, 174.4, 133.8, 133.1,
131.4, 131.4, 130.4, 129.7, 129.0, 128.3 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental remarks, experimental details, and spec-
tra of the products.
Acknowledgments
Scheme 1. Dimerization reactions of benzoselenoamide and benz-
amide.
This work was supported by a research grant from the US National
Science Foundation (CHE-1262479).
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In conclusion, we developed an oxidative dimerization
reaction for the synthesis of 1,2,4-thiadiazoles by using
Oxone as a readily available, inexpensive, safe, and environ-
mentally benign oxidant under mild conditions. This conve-
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Experimental Section
General Procedure for the Synthesis of Thiadiazoles: Oxone
(1 mmol) was added to a solution of thioamide 1 (0.5 mmol) in
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Received: July 3, 2014
Published Online: July 23, 2014
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