Facile access to 3,5-symmetrically disubstituted 1,2,4-thiadiazoles through phosphovanadomolybdic acid catalyzed aerobic oxidative dimerization of primary thioamides

Article abstract of DOI:10.1039/c4cc02313g

In the presence of Keggin-type phosphovanadomolybdic acids, e.g., H ₆PV₃Mo₉O₄₀, oxidative dimerization of various kinds of primary thioamides including aromatic, heterocyclic, and aliphatic ones efficiently proceeded to give the corresponding 3,5-disubstituted 1,2,4-thiadiazoles in excellent yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02313g

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Facile access to 3,5-symmetrically disubstituted
1,2,4-thiadiazoles through phosphovanadomolybdic
acid catalyzed aerobic oxidative dimerization of
primary thioamides†
Cite this: Chem. Commun., 2014,
50, 6748
Received 28th March 2014,
Accepted 7th May 2014
Kazuhisa Yajima, Kazuya Yamaguchi and Noritaka Mizuno*
DOI: 10.1039/c4cc02313g
www.rsc.org/chemcomm
In the presence of Keggin-type phosphovanadomolybdic acids, e.g., use of molecular oxygen for oxidative dimerization of primary thio-
H6PV3Mo9O40, oxidative dimerization of various kinds of primary amides, to date there has been only one report concerning the
thioamides including aromatic, heterocyclic, and aliphatic ones photocatalytic system using eosin Y (Table S1, ESI†),14 to the best of
efficiently proceeded to give the corresponding 3,5-disubstituted our knowledge.
1,2,4-thiadiazoles in excellent yields.
Here, we found that Keggin-type phosphovanadomolybdic
acids can act as efficient homogeneous catalysts for oxidative
1,2,4-Thiadiazoles are some of the most important heterocycles dimerization of primary thioamides using molecular oxygen as the
and have recently found their important utilization as pharmaco- sole oxidant without any additives and photoirradiation. In the
phores.1 The commercial antibiotic cefozopran (SCE-2787) contains presence of H6PV3Mo9O40, various kinds of structurally diverse
the 1,2,4-thiadiazole scaffold,2 and a number of 1,2,4-thiadiazole primary thioamides including aromatic, heterocyclic, and aliphatic
derivatives with unique biological activities, e.g., acetylcholinesterase ones could be converted into the corresponding 3,5-symmetrically
inhibitors, angiotensin II receptor antagonists, and G-protein disubstituted 1,2,4-thiadiazoles in excellent yields under mild reac-
coupled receptors, have been synthesized to date.3 In addition to tion conditions (30 1C, 1 atm O2) [eqn (1)].‡ Although phosphova-
their use as pharmacophores, thiadiazoles are potentially useful nadomolybdic acids have been reported to be catalytically active for
as pesticides and corrosion inhibitors.1,4
various oxidation reactions,15 their use for oxidative dimerization of
3,5-Unsymmetrically disubstituted 1,2,4-thiadiazoles have primary thioamides has never been reported so far.
generally been synthesized by intramolecular oxidative cyclization
of amidinothioureas and 1,3-dipolar cycloaddition of nitrile sulfides
to nitriles.1,5 Oxidative dimerization of primary thioamides is the
(1)
most frequently utilized reaction for synthesis of 3,5-symmetrically
disubstituted ones.6–14 Despite numerous efforts towards the
development of oxidative dimerization of primary thioamides,
Firstly, the oxidative dimerization of thiobenzamide (1a)
challenges still remain because almost all the previously reported to 3,5-diphenyl-1,2,4-thiadiazole (2a) was carried out using
oxidative dimerization systems employ metal and organic-based H6PV3Mo9O40 (5 mol%) at 30 1C under 1 atm of molecular
stoichiometric oxidants such as selenoxides,6 telluroxides,6,7 hyper- oxygen in various solvents. The reaction hardly proceeded in
valent iodines,8 pentylpyridinium tribromide,9 2,3-dichloro-5,6- the absence of H6PV3Mo9O40 in any solvents. The choice of the
dicyano-p-benzoquinone,10 N-bromosuccinimide,11 dimethyl solvents was very crucial, as shown in Table 1. Water and
sulfoxide,12 and tert-butylhydroperoxide13 (Table S1, ESI†). In chloroform were poor solvents (Table 1, entries 1 and 4) because
addition, some of these systems require large amounts of 1a and H6PV3Mo9O40 were almost insoluble in water and chloro-
additives (Table S1, ESI†). The choice of the oxidant determines form, respectively. Except for water and chloroform, the catalytic
the practicability and efficiency of systems, and molecular performance of H6PV3Mo9O40 was much dependent on the acceptor
oxygen is regarded as the greenest oxidant. With regard to the numbers of solvents used.16 The yields of 2a increased with an
increase in the acceptor numbers, and methanol (41.3) and ethanol
Department of Applied Chemistry, School of Engineering,
(37.1) with higher acceptor numbers were the most suitable solvents,
affording 2a in almost quantitative yields within 0.5 h (Table 1,
entries 2 and 3). Acetonitrile (18.9) and acetone (12.5) also gave
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp; Fax: +81-3-5841-7220;
Tel: +81-3-5841-7272
high yields of 2a (Table 1, entries 5 and 6). It is known that the
† Electronic supplementary information (ESI) available: Experimental details,
data of 2a–2h, Table S1, Fig. S1–S3, and Scheme S1. See DOI: 10.1039/c4cc02313g reduction potentials (oxidation abilities) of heteropolyanions
6748 | Chem. Commun., 2014, 50, 6748--6750
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Table 1 Oxidative dimerization of thiobenzamide (1a) to 3,5-diphenyl-
1,2,4-thiadiazole (2a) in various solventsa
just the stoichiometric amount of 2a with respect to vanadium
species employed (15 mol%) was produced (Table 2, entry 6),
indicating that molecular oxygen can act as the terminal
oxidant for the present oxidative dimerization.
Entry Solvent
Acceptor numberb Time (h) Yield of 2a (%)
1
2
3
4
5
6
7
Water
Methanol
Ethanol
Chloroform 23.1
Acetonitrile 18.9
Acetone
54.8
41.3
37.1
2
14
96
499
7
86
75
19
In the presence of vanadium-free heteropoly acids such as
H3PMo12O40, H4SiMo12O40, H3PW12O40, and H4SiW12O40, the
oxidative dimerization hardly proceeded (Table 2, entries 1,
7, 9, and 13). Although these results suggest that vanadium is an
indispensable component for the present oxidative dimerization,
simple vanadium compounds such as V2O5, NaVO3, and
VO(acac)2 (acac = acetylacetonato) hardly catalyzed the oxidative
dimerization (Table 2, entries 15–17). In addition, the oxidative
dimerization hardly proceeded in the presence of simple mixtures
of V2O5 + H3PMo12O40, NaVO3 + H3PMo12O40, and VO(acac)2 +
H3PMo12O40 (Table 2, entries 18–20). Therefore, the substitution
of vanadium into heteropoly acid frameworks is important to
obtain the high catalytic performance.18,19
The effects of heteroatoms as well as polyatoms were also
very significant. The phosphorous-centered H4PVMo11O40 gave
2a in a moderate yield, while the oxidative dimerization hardly
proceeded in the presence of the silicon-centered H5SiVMo11O40
(Table 2, entry 2 vs. entry 8). With regard to polyatoms, molybdenum
(H4PVMo11O40) was better than tungsten (H4PVW11O40) (Table 2,
entry 2 vs. entry 10). It is well known that the reduction
potentials of phosphometalates are generally higher than those
of silicometalates and that molybdates are much easily reduced
in comparison with tungstates.20
Under the optimized reaction conditions, we examined the
substrate scope for the present oxidative dimerization using
5 mol% H6PV3Mo9O40. Various kinds of primary thioamides
including aromatic, heterocyclic, and aliphatic ones could
be converted into the corresponding 3,5-disubstituted 1,2,4-
thiadiazoles in high yields (Fig. 1). Products could readily be
isolated by simple extraction using n-hexane.‡ The oxidative
dimerization of thiobenzamide derivatives, which contain
electron-donating as well as electron-withdrawing substituents on
the phenyl rings, efficiently proceeded to afford the corresponding
3,5-diarylsubstituted 1,2,4-thiadiazoles in high yields without
formation of nitriles and primary amides (Fig. 1, entries 1–5).
The 10 mmol-scale reaction of 1a was also effective and gave
a quantitative yield (HPLC) of 2a for 0.5 h. The amounts
of H6PV3Mo9O40 could be much reduced; even when using 0.4
mol% H6PV3Mo9O40, 2a was obtained in 93% yield for 5 h, which
corresponds to the turnover of 233 based on H6PV3Mo9O40
(Fig. 1, entry 2). In the case of 4-chlorothiobenzamide,
no dechlorination proceeded (Fig. 1, entry 4). Heterocyclic
thioamides such as furan-2-carbothioamide and thiophen-2-
carbothioamide gave the corresponding 3,5-disubstituted 1,2,4-
thiadiazoles in high yields (Fig. 1, entries 6 and 7). Notably,
less reactive aliphatic thioamides such as thioacetamide and
thiopropionamide could also be converted into the corresponding
3,5-dialkylsubstituted 1,2,4-thiadiazoles (Fig. 1, entries 8 and 9),
0.5
0.5
2
2
2
12.5
1,4-Dioxane 10.8
2
a
Reaction conditions: 1a (0.5 mmol), H6PV3Mo9O40 (5 mol%), solvent
(4 mL), O2 (1 atm), 30 1C. Yields were determined by HPLC using
naphthalene as an internal standard. In all cases, 2a was selectively
b
produced without formation of benzonitrile and benzamide. The
values of acceptor numbers of solvents were cited from ref. 16.
shift to more positive potentials with an increase in the acceptor
numbers of solvents.17 This shows that reduced heteropolyanions
are more stabilized by solvents with higher acceptor numbers.17
From the above results, we hereafter mainly use ethanol as the
solvent (not methanol, for safety reasons).
Next, the catalytic activities of various kinds of heteropoly
acids (5 mol%) were examined for the oxidative dimerization of
1a to 2a in ethanol. As summarized in Table 2, the desired
product 2a was significantly obtained only when the reaction
was performed using phosphovanadomolybdic acids, and the
catalytic activities increased with an increase in vanadium
contents (H4PVMo11O40 o H5PV2Mo10O40 o H6PV3Mo9O40)
(Table 2, entries 2–4). In these cases, 2a was selectively produced
without formation of benzonitrile and benzamide. Air could be
used for the oxidative dimerization while the reaction rate was
smaller than that in O2 (Table 2, entry 5). Under an Ar atmosphere,
Table 2 Oxidative dimerization of thiobenzamide (1a) to 3,5-diphenyl-
1,2,4-thiadiazole (2a) using various catalystsa
Entry
Catalyst
Atmosphere
Yield of 2a (%)
1
2
3
4
5
6
7
8
H3PMo12O40
H4PVMo11O40
H5PV2Mo10O40
H6PV3Mo9O40
H6PV3Mo9O40
H6PV3Mo9O40
H4SiMo12O40
H5SiVMo11O40
H3PW12O40
H4PVW11O40
H5PV2W10O40
H6PV3W9O40
H4SiW12O40
O2
O2
O2
O2
Air
Ar
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
3
24
63
85
35
15
4
7
2
3
5
8
2
3
2
2
2
2
2
9
10
11
12
13
14
15b
16b
17b
18c
19c
20c
H5SiVW11O40
V2O5
NaVO3
VO(acac)2
V2O5 + H3PMo12O40
NaVO3 + H3PMo12O40
VO(acac)2 + H3PMo12O40
2
a
Reaction conditions: 1a (0.5 mmol), heteropoly acid (5 mol%), ethanol while nitriles were formed as byproducts to some extent (10–18%)
(4 mL), O2 or Ar (1 atm), 30 1C, 10 min. Yields were determined by HPLC
in these cases.
using naphthalene as an internal standard. In all cases, 2a was selectively
b
The color of the reaction solution changed to dark green or dark
blue immediately at the beginning of the reaction (Fig. S1, ESI†),§
produced without formation of benzonitrile and benzamide. Vanadium
c
(15 mol%). Vanadium (15 mol%) + H3PMo12O40 (5 mol%).
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This work was supported in part by Grants-in-Aid for Scientific
Researches from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Notes and references
‡ Procedure for oxidative dimerization: 1 (0.5 mmol), H6PV3Mo9O40
(5 mol%), naphthalene (0.1 mmol, internal standard), and ethanol
(4 mL) were placed in a Pyrex-glass tube reactor with a magnetic stir
bar, and the reaction was carried out at 30 1C in 1 atm of O2. During the
reaction, the conversion of 1 and the yield of 2 (based on 1) were
periodically monitored by HPLC or GC analysis (Fig. S3, ESI†). As for
product isolation, naphthalene was not used. After complete conversion
of 1, n-hexane (25 mL) and water (25 mL) were added to the reaction
mixture, followed by extraction with n-hexane (25 mL Â 3) to afford 2.
§ The color of the ethanol solution of H6PV3Mo9O40 without 1 was
orange-yellow.
˜
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6750 | Chem. Commun., 2014, 50, 6748--6750
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