Transition metal-free direct C-H bond thiolation of 1,3,4-oxadiazoles and related heteroarenes

Article abstract of DOI:10.1039/c2cc36711d

A convenient transition metal-free procedure for the direct thiolation of 1,3,4-oxadiazole C-H bonds using diaryl disulfides has been developed. Other substrates including indole, benzothiazole, N-phenylbenzimidazole, and caffeine were also thiolated in this manner, providing the corresponding products in good to excellent yields. This journal is

Full text of DOI:10.1039/c2cc36711d

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Transition metal-free direct C–H bond thiolation of 1,3,4-oxadiazoles
and related heteroarenesw
Liang-Hua Zou, Jens Reball, Jakob Mottweiler and Carsten Bolm*
Received 14th September 2012, Accepted 4th October 2012
DOI: 10.1039/c2cc36711d
A convenient transition metal-free procedure for the direct
thiolation of 1,3,4-oxadiazole C–H bonds using diaryl disulfides
has been developed. Other substrates including indole, benzothiazole,
N-phenylbenzimidazole, and caffeine were also thiolated in this
manner, providing the corresponding products in good to excellent
yields.
including indole, benzothiazole, N-phenylbenzimidazole, and
caffeine were converted to the corresponding thioethers.
The initial screening and optimization of the reaction conditions
was conducted with 2-phenyl-1,3,4-oxadiazole (1a) and di-p-tolyl
disulfide (2a) as substrates (Table 1). Assuming that a metal
catalyst was needed, the first reaction was performed in the
presence of CuI (20 mol%). Using 1a and 2a in a 1 : 2.5 ratio
(on a 0.5 mmol scale), Cs2CO3 (2 equiv.) as base and toluene as
solvent, product 3aa was obtained in 47% yield after 18 h at
130 1C under argon (Table 1, entry 1). To our surprise, however,
an increase in yield (54%) was observed in the absence of the
copper salt (entry 2). With 5 equivalents of disulfide 2a the yield of
3aa was 77% (entry 3), and with 7 equivalents of 2a this value
remained the same (entry 4). Noteworthily, the excess of di-p-tolyl
disulfide (2a) could be recovered quantitatively upon work-up.
Next, various solvents were screened for their influence on
the reaction behaviour (entries 5–8). The reaction in acetonitrile
gave a lower yield of 3aa. No product was observed when
DMSO and DMF were used. 1,4-Dioxane proved to be the best
solvent, providing 3aa in 87% yield (entry 8). Further studies
The formation of C–S bonds represents a key step in the
synthesis of a broad range of biologically active molecules and
functional materials.1 In the past decade, the cross-coupling of
aryl halides with thiols has become one of the dominant methods
for the construction of C–S bonds. Complexes and salts of
palladium,2 nickel,3 copper,4 cobalt,5 iron,6 and indium7 have
been identified as efficient catalysts for these types of reactions.
As an alternative to aryl halides, aryl triflates8 and boronic acids9
can be used as reaction partners in such transformations. The
formation of C–S bonds has also been realised by coupling
aryl halides with diaryl disulfides.10 Although these traditional
coupling reactions are effective in constructing various C–S
bonds either metal–ligand combinations and/or prefunctionalised
reaction partners are required, which significantly restricts
potential applications of these methods.
Table 1 Thiolation of 2-phenyl-1,3,4-oxadiazole (1a) with di-p-tolyl
disulfide (2a)a
Recently, major advances have been achieved in C–H bond
functionalisation of 1,3,4-oxadiazoles.11 These are relevant
heterocycles because of their interesting properties in medicinal
chemistry12 and material sciences.13 The 1,3,4-oxadiazole core is an
important pharmacophoric substructure, and various derivatives
show substantial bioactivities.14 Although a few methods for the
synthesis of heterocyclic thioethers containing 1,3,4-oxadiazole
units and derivatives thereof are known,4j,15 most of them require
pre-functionalised 1,3,4-oxadiazoles and/or metal catalysts. Hence,
the development of a transition metal-free protocol for C–S bond
formations of non-activated 1,3,4-oxadiazoles appears desirable
and synthetically attractive.16 Here, we report progress along those
lines and describe a method for direct thiolation of 1,3,4-oxadiazole
C–H bonds using diaryl disulfides. Analogously, other heteroarenes
Entry
Base
Solvent
Temp. (1C)
Yield (%)
1b
2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NEt3
t-BuOLi
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
Toluene
Toluene
Toluene
130
130
130
130
130
130
130
130
130
130
130
110
130
130
47
54
77
77
30
0
0
87
0
3c
4d
5
CH3CN
DMSO
DMF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
6
7
8
9
10
11e,f
12e
13g
14h
0
85
83
58
86
a
Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), base (1 mmol),
b
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany.
E-mail: carsten.bolm@oc.rwth-aachen.de; Fax: +49 241-8092391
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data as well as NMR spectra. See DOI:
10.1039/c2cc36711d
solvent (2 mL), 130 1C, argon atmosphere, 18 h. Addition of
20 mol% of CuI. Use of 5 equiv. of 2a. Use of 7 equiv. of 2a.
c
d
e
f
g
h
24 h. Use of 1.3 equiv. of Cs2CO3. Performed in air. The purity
of Cs2CO3 was 99.994%.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11307–11309 11307

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Table 2 Thiolation of 1,3,4-oxadiazoles and related heteroarenes
with di-p-tolyl disulfide (2a)a
to high yields of the corresponding thiolated products were
obtained. A straightforward correlation between the stereo-
electronic properties of the substrate and the reaction efficiency
could not be deduced. It appeared, however, as if 2-aryl-1,3,4-
oxadiazoles with electron-donating substituents on the arene
gave higher yields than those with electron-withdrawing groups.
For example, while tolyl-substituted products 3ba and 3ca were
obtained in 85% and 80% yield, respectively, trifluoromethyl
derivative 3ha was isolated in only 36% yield (Table 2, entries 1
and 2 versus entry 7). In the latter case, the yield could be
improved to 72% by performing the reaction at a slightly lower
temperature (110 1C) for an extended reaction time (24 h).
While this modification of the reaction conditions was beneficial
for the preparation of product 3da (entry 3; 60% versus 73%)
too, it proved to be disadvantageous in the synthesis of 3ga.
There, the original conditions were better (entry 6: 75% versus
65%). The 1,3,4-oxadiazole series was completed by the pre-
paration of 2-(3-pyridyl)-substituted product 3ia, which was
obtained in 65% yield indicating that such a heteroaryl group in
the 2 position of the substrate was tolerated well (entry 8).
To extend the substrate scope, related heterocycles were
applied and reacted with di-p-tolyl disulfide (2a) to produce
the corresponding heteroaryl thioethers (Table 2, entries
9–13). To our delight, indole and its 5-methylated derivative
gave 3-thiolated products 3ja and 3ka in very high yields (91%
and 93%, respectively; entries 9 and 10). Those results com-
pare well to the known metal-catalysed procedure for the
synthesis of 3-sulfenyl indoles.18 The reaction of benzothiazole
with 2a was slow, affording 3la in only 55% yield after 10 days.
Changing the base from Cs2CO3 to t-BuOLi, however,
shortened the reaction time to 32 h and increased the yield
to 86% (entry 11). Similarly, with t-BuOLi as base, N-phenyl-
benzimidazole and caffeine were directly thiolated to afford
the corresponding products 3ma and 3na in 71% and 55%
yields, respectively (entries 12 and 13).
Entry Product, yield
Entry Product, yield
1
8
2
3
9
10
4
5
11
12
6
13
Next, the diaryl disulfide component was varied and 2-phenyl-
1,3,4-oxadiazole (1a) and indole (1j) served as coupling partners
(Table 3). Accordingly, thiolation of 1a with diphenyl-, 4,40-
dimethoxydiphenyl-, 4,40-difluorodiphenyl-, 4,40-dichlorodi-
phenyl- and 2,20-dinaphthyl-substituted disulfides (2b–2f) provided
3ab–3af in yields ranging from 58% to 81%. Indole (1j)
reacted with diaryl disulfides 2b and 2e to give the corre-
sponding products (3jb and 3je) in 91% and 96% yield,
respectively.19 Subsequent screenings showed that dibenzyl
disulfide and bis(4-nitrophenyl) disulfide did not react with
1a under the given reaction conditions.
7
a
Reaction conditions: heteroarene (0.5 mmol), 2a (1.25 mmol), Cs2CO3
(1 mmol), 1,4-dioxane (2 mL), 130 1C, argon atmosphere, 18 h.
b
c
d
Performed at 110 1C for 24 h. Reaction time of 10 days. Use of
3 equiv. of t-BuOLi as base instead of Cs2CO3; reaction time of 32 h.
showed that the use of other bases such as triethylamine and
t-BuOLi was ineffective (entries 9 and 10). Using less base or
performing the reaction at lower temperature decreased the
yield of 3aa slightly, and after 24 h, the product was obtained
in 85% and 83% yields, respectively (entries 11 and 12). In air
instead of argon, the yield of 3aa dropped to 58% (entry 13). To
exclude a possible catalytic effect of a trace metal contamination,17
a control experiment was performed using Cs2CO3 with a purity
of 99.994% and freshly distilled 1,4-dioxane. The yield of 86%
(entry 14) made it unlikely that a trace metal was involved in these
reactions.
With respect to the reaction mechanism we assume that a
deprotonation of the heterocycle occurs providing an anion,
which reacts with the diaryl disulfide by nucleophilic attack,
resulting in C–S bond formation.20,21
In conclusion, we developed a facile procedure for the
synthesis of heterocyclic thioethers under transition metal-free
conditions. Various 2-aryl-1,3,4-oxadiazoles were thiolated at
C5 in good to high yields using diaryl disulfides as the aryl
sulfide source. Also aryl thiols could be applied, albeit the
product yields were only moderate.19 Finally, the method
proved applicable to other heterocycles providing thioethers
from indole, benzothiazole, N-phenylbenzimidazole, and caffeine
in good yields.
In Table 2 the screening results with respect to the substrate
scope are shown. Various 2-aryl substituted 1,3,4-oxadiazoles
and related heterocycles were reacted with disulfide 2a under
the previously optimized reaction conditions. In general, good
c
11308 Chem. Commun., 2012, 48, 11307–11309
This journal is The Royal Society of Chemistry 2012

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Table 3 Scope of diaryl disulfide coupling partnersa
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a
For the reaction conditions, see Table 1, entry 8.
This study was supported by the Fonds der Chemischen
Industrie. L.-H.Z. and J.M. thank the Chinese Scholarship
Council (CSC) and the NRW Graduate School BrenaRo,
respectively, for predoctoral stipends.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11307–11309 11309