Copper-catalyzed direct thiolation of benzoxazole with diaryl disulfides and aryl thiols

Article abstract of DOI:10.1016/j.tetlet.2009.02.214

The cross-coupling reaction of benzoxazole with aryl thiols using the CuI/2,2′-bipyridine complex as a catalyst in DMF at 80 °C under oxygen produced the corresponding aryl thioethers in moderate to good yields. The coupling reaction with diaryl disulfide

Full text of DOI:10.1016/j.tetlet.2009.02.214

Tetrahedron Letters 50 (2009) 2374–2376
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Copper-catalyzed direct thiolation of benzoxazole with diaryl disulfides
and aryl thiols
*
Shin-ichi Fukuzawa , Eiji Shimizu, Yuka Atsuumi, Masatake Haga, Kenichi Ogata
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
a r t i c l e i n f o
a b s t r a c t
The cross-coupling reaction of benzoxazole with aryl thiols using the CuI/2,20-bipyridine complex as a
catalyst in DMF at 80 °C under oxygen produced the corresponding aryl thioethers in moderate to good
yields. The coupling reaction with diaryl disulfide also occurred under similar oxidative conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 9 February 2009
Revised 26 February 2009
Accepted 27 February 2009
Available online 4 March 2009
Metal-catalyzed cross-coupling reactions have become a princi-
pal method of forming carbon–carbon and carbon–heteroatom
bonds. Among this class of reactions, a process that forms aromatic
thioethers from aryl halides and thiols has been of current interest
and intensively studied.1 This reaction provides unsymmetrical
aryl thioethers, which are not only valuable synthetic intermedi-
ates, but are also frequently found in biologically and pharmaceu-
tically active molecules. Palladium,2 nickel,3 copper,4 iron,5 and
cobalt6 complexes smoothly catalyzed the cross-coupling reactions
of aryl halides with thiols to provide aryl thioethers with a variety
of functional groups. Aryl triflates7 and boric acids8 are sometimes
used as good counterparts instead of aryl halides. An alternative
method for the access of aryl thioethers is the coupling reaction
of aryl halides with diaryl disulfides.9 Contrary to the intensive
studies on the coupling reaction with an aryl thiol, only a few
examples have been reported.
The direct arylation of the C–H bonds of heterocycles, that is,
the functionalization of aromatic heterocycles, is of current inter-
est because it represents a possible alternative approach to con-
ventional cross-coupling reactions with organometallic reagents
and would not require reactive functional groups such as halogens
or metal moieties.10 The analogous reaction forming the carbon–
sulfur bond without aryl halides should be desirable from the
viewpoint of atom economy and the waste treatment of hydrogen
halides. We have designed the direct thiolation of a heteroaromatic
compound with an aryl thiol and found that the copper/2,20-bipy-
dine complex catalyzed the reaction of benzoxazole with benzene
thiol under oxygen to give the 2-benzoxazole thioether in moder-
ated to good yields; some 2-azole thioethers are biologically active
compounds.11 To the best of our knowledge, this is the first direct
thiolation of heteroaromatic compounds. We now report the preli-
minary results of the direct thiolation with benzoxazole.
Due to the oxidative reaction conditions, aryl thiols could be
oxidized to the corresponding diaryl disulfides that should be an
actual counter part. We started with the coupling reaction of benz-
oxazole (1a) with diphenyl disulfide (2a) to assess the catalyst
activity and determine the optimum reaction conditions. The cou-
pling reactions were conducted with DMF as the solvent, Cs2CO3 as
the base and a copper salt/2,20-bipyridine as the catalyst (10 mol %)
under oxygen (1 atm).12 The products and yields are analyzed by
GC/MS. These results are shown in Table 1. The use of any Cu(I)
and Cu(II) salts to give the desired 2-(phenylthio)benzoxazole
(3aa) in moderate to good yields under oxygen without the forma-
tion of appreciable amounts of side products; CuI gave the highest
product yield (entry 2). The reaction was completed in 2 h at 80 °C
and part of the product was decomposed in an extended reaction
time (24 h) and/or at higher temperature (140 °C). The addition
of 2,20-bipyridine as the ligand was required for a satisfactory yield
(entry 3).13 The other bases, such as Na2CO3 and K2CO3, were not
effective as trace reaction products were produced. DMF was the
best choice of solvent; the yields of the products were 14% (MeCN),
7% (NMP), and 5% (DMSO). The reaction under oxygen was critical
for the reaction while the reaction under nitrogen (in the absence
of oxygen) produced a low yield (14%) of the product (entry 5).14
We then examined the scope with respect to the diaryl disul-
fides under the optimized conditions; CuI as the copper salt, DMF
as the solvent, at 80 °C for 2 h under oxygen. Typical results are
shown in Table 2. The diaryl disulfides 2b–c with an electron-
donating substituent, such as p-methoxy and p-methyl, afforded
the corresponding thioethers 3ab–3ac in moderate to good yields
(entries 2 and 3), and for the o-methyl substrate, the thioether
3ad was obtained in a low yield probably due to steric hindrance
(entry 4). The cross-coupling reaction with di(p-chlorophenyl)
disulfide (2e) occurred only at thio group to give the thioether
3ae in a moderate yield accompanied by the partial decomposition
of the disulfide (ca 5%) (entry 5). The coupling product at the chloro
position was hardly observed. The electron-deficient diaryl
* Corresponding author. Tel.: +81 3 3817 1916; fax: +81 3 3817 1895.
E-mail address: orgsynth@kc.chuo-u.ac.jp (S. Fukuzawa).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.214

S. Fukuzawa et al. / Tetrahedron Letters 50 (2009) 2374–2376
2375
Table 1
disulfide. The direct thiolation was examined using an aryl thiol in-
stead of diaryl disulfides. The reaction of 1a with aryl thiols was
carried out using a catalytic amount (10 mol %) of CuBr2 and 2,20-
bipyridine, and Cs2CO3 as a base in DMF in the presence of MS4A
at 80 °C for 2 h under oxygen. These results are summarized in Ta-
ble 3. The reaction of 1a with benzene thiol (4a) smoothly pro-
ceeded to give 3aa in good yield (72%) (entry 1), while in the
absence of MS4A, the product yield decreased to 42% (entry 2).
MS4A probably worked as a dehydrating agent; in this reaction,
water should be generated as a by-product. The thiols 4b–c with
an electron-donating substituent, such as p-methoxy and p-
methyl, afforded the corresponding thioether 3ab–ac in moderate
to good yields (entries 3 and 4). For the o-methylphenyl thiol 4d,
the thioether 3ad was obtained in a moderate yield (55%) although
the di(o-methylphenyl) disulfide 2d gave 3ad in a lower yield
(34%) (entry 5). For the p-chlorophenyl thiol 4e, the coupling prod-
uct was the only thioether 3ae without producing any C–C cou-
pling product as well as the disulfide 2e (entry 6). 2-Naphthalene
thiol 4h could react with 1a, but the yield of the product 3ah
was low (entry 7).
To discuss the reaction mechanism, we conducted the following
experiment. When we carried out the reaction of 1a with phenyl-
thiocopper (PhSCu) in the presence of 2,20-bipyridine (1 equiv to
PhSCu) and Cs2CO3 (2 equiv) in DMF at 80 °C for 2 h under oxygen
(1 atm), the corresponding thioether 3aa was obtained in 38%
yield. On the other hand, for the reaction under nitrogen (excluding
oxygen), no thioether was obtained. These results suggest that the
formation and oxidation of PhSCu should be involved in the reac-
tion. Based on this fact, we assumed the following catalytic cycle
illustrated in Scheme 1.15 The initial step of the reaction involves
the deprotonation of benzoxazole (Ar-H) at the C-2 position by
Cs2CO3 followed by cupration via transmetallation. In the next
step, the ArCu species reacted with diphenyl disulfide to afford
the thioether and PhSCu(I). PhSCu(I) is oxidized to the Cu(II) spe-
cies which reacts with Ar-H to produce the ArCuSPh intermediate.
The reductive elimination of the thioether from the Cu(II) complex
afforded the Cu(0) which is oxidized to CuX with oxygen and a hal-
ogen ion.16
The Cu-catalyzed direct thiolation of benzoxazole 1a with diphenyl disulfide 2aa
Cu/2,2'-bipy/
Ph
Cs2CO3/DMF
O2, 80 °C, 2 h
N
O
N
O
+
PhSSPh
S
1a
2a
3aa
Entry
Cu salts
Yield of 3aab (%)
1
2
—
CuI
CuI
CuI
0
81
22
0
3c
4d
5e
6
CuI
14
74
51
80
78
CuBr
CuCl
CuCN
CuBr2
7
8
9
a
1a (0.6 mmol), 2a (0.25 mmol), Cu salt (0.05 mmol), 2,20-bipyridine
(0.05 mmol), Cs2CO3 (1.0 mmol), DMF (3 mL); 80 °C, 2 h, 1 atm O2.
b
Determined by GC.
c
Without 2,20-bipyridine.
d
No base added.
Under N2.
e
disulfides, such as 2f (Ar = p-NO2C6H4) and 2g (Ar = 2-pyridyl),
hardly produced the corresponding thioethers (entries 6 and 7).
The reaction with the 5-substituted benzoxazole was examined,
and the results are also shown in Table 2 (entries 8 and 9). The
reaction of diphenyl disulfide 2a with the 5-methyl substituted
derivative 1b gave the corresponding thioether 3ba in a moderate
yield. For the reaction with the 5-chloro substituted derivatives 1c,
2-phenylthio 3ca and 2,5-dithioether were observed by GC/MS
analysis; 3ca could be isolated by preparative TLC in a 33% yield.
In this case, the reaction at the 5-chloro position should be in-
volved. The reaction with other azoles, such as oxazole, thiazole,
1-methyl-1H-imidazole, benzothiazole, and 1-methyl-1H-benzo-
imidazole, were examined, and only the benzothiazole gave the
corresponding 2-phenylthiobenzothiazole in 17% yield.
In conclusion, we have succeeded for the first time in the cop-
per-catalyzed direct thiolation of benzoxazole using diaryl disul-
fides or aryl thiols, and 2-benzoxazole thioethers were obtained
in moderate to good yields. The sulfide with an electron-donating
substituent afforded products in good yields, while the sulfides
with an electron-deficient group hardly gave the desired product.
As more varieties of substituted aryl thiols are commercially
available than diaryl disulfides, aryl thiols would be preferable as
thiolating agents, although the actual species would be a diaryl
Table 2
Scope of the thiolation of benzoxazoles with diaryl disulfidesa
CuI/2,2'-bipy/
Ar
Table 3
R
Direct thiolation of benzoxazole with aryl thiolsa
Cs2CO3/DMF
O2, 80 C, 2 h
N
O
R
N
O
+
ArSSAr
S
CuBr2/2,2'-bipy/
Ar
N
O
Cs2CO3/DMF
N
O
1a-c
2a-g
3aa-ag
+
ArSH
S
3ba-3ca
O2, MS4A
80 C, 2 h
1a
4a-e, 4h
3aa-ae, 3ah
Entry
R
Ar
Yieldb (%)
1
2
3
4
5
6
7
8
9
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = Me, 1b
R = Cl, 1c
Ph, 2a
3aa, 81
3ab, 71
3ac, 64
3ad, 34
3ae, 54c
3af, 0c
3ag, 0
3ba, 49
3ca, 33
Entry
Ar
Yieldb (%)
p-MeOC6H4, 2b
p-MeC6H4, 2c
o-MeC6H4, 2d
p-ClC6H4, 2e
p-NO2C6H4, 2f
2-pyridyl, 2g
Ph, 2a
1
2c
3
4
5
6
7
Ph, 4a
Ph, 4a
3aa, 72
3aa, 42
3ab, 51
3ac, 62
3ad, 55
3ae, 38
3ah, 18
p-MeOC6H4, 4b
p-MeC6H4, 4c
o-MeC6H4, 4d
p-ClC6H4, 4e
2-naphtyl, 4h
Ph, 2a
a
a
1a (0.6 mmol), ArSH (0.5 mmol), CuBr2 (0.05 mmol), 2,20-bipyridine
1a (0.6 mmol), 2a (0.25 mmol), CuI (0.05 mmol), 2,20-bipyridine (0.05 mmol),
(0.05 mmol), Cs2CO3 (1.0 mmol), MS4A (100 mg), DMF (3 mL); 80 °C, 2 h, 1 atm O2.
Cs2CO3 (1.0 mmol), DMF (3 mL); 80 °C, 2 h, 1 atm O2.
b
b
Isolated yield.
Isolated yield.
c
c
Without MS4A.
Mono sulfide was formed as a by-product.

2376
S. Fukuzawa et al. / Tetrahedron Letters 50 (2009) 2374–2376
9202–9211; (c) Hayakawa, M.; Kaizawa, H.; Kawaguchi, K.; Ishikawa, N.;
O2, X-
'Cu'
Ar-H, base
base·HX
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12. Typical experimental procedure: Under oxygen (balloon), 2a (55 mg, 0.25 mmol),
CuI (9.5 mg, 0.05 mmol), 2,20-bipyridine (7.8 mg, 0.05 mmol), and Cs2CO3
(326 mg, 1.0 mmol) were placed in a Schlenk tube containing a stirring bar, and
a DMF solution (3.0 mL) of 1a (71.5 mg, 0.6 mmol) was then added to the
Schlenk tube, and the resulting mixture was heated at 80 °C for 2 h. Twenty
milliliters of water were then added, and the mixture was then extracted with
ethyl acetate (10 mL ꢀ 3). The combined organic phases were washed with
brine, dried over MgSO4, and filtered. GC/MS analysis of the solution showed
the presence of 2-(phenylthio)benzoxazole (3aa) and yield was determined
using biphenyl as the internal standard. Evaporation of the solvent left a
residue, which was subjected to PTLC (silica gel, 8:1 hexane:ethyl acetate as
eluent) to give the pure 3aa.
CuX
ArSPh
Ar-Cu
PhSSPh
ArSPh
ArCuSPh
base·HX
Ar-H
PhSCu
O2, X-
PhSCuX
base
Scheme 1. Plausible catalytic cycle of the direct thiolation.
The scope and limitation of the substrate with respect to azoles
have also been demonstrated.
References and notes
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Compound 3aa: Colorless oil. 1H NMR (CDCl3, 300 MHz) d 7.21–7.30 (m, 2H),
7.40–7.47 (m, 4H), 7.59–7.62 (m, 1H), 7.69–7.72 (m, 2H); 13C NMR (CDCl3) d
110.0 (CH), 119.0 (CH), 124.2 (CH), 124.3 (CH), 127.1 (C) 129.6 (CH), 129.8
(CH), 134.4 (CH), 141.9 (C), 151.8 (C), 163.3 (C). ESI HRMS calcd for C13H9NOS
[M + H] 228.0483, found 228.0481. EI MS m/z = 227.
Compound 3ab: Colorless oil. 1H NMR (CDCl3, 300 MHz) d 3.84 (s, 3H), 6.98 (d,
2H, J = 8.6 Hz), 7.18–7.28 (m, 2H), 7.36–7.41 (m, 1H), 7.57–7.59 (m, 1H), 7.62
(d, 2H, J = 8.7 Hz); 13C NMR (CDCl3) d 55.4 (CH3), 109.9 (CH), 115.2 (CH), 117.0
(C), 118.9 (CH), 124.0 (CH), 124.2 (CH), 136.7 (CH), 142.0 (C), 151.8 (C), 161.1
(C), 164.4 (C). ESI HRMS calcd for C14H11NO2S [M + H] 258.0589, found
258.0585. EI MS m/z = 257.
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7.26 (m, 2H), 7.27 (d, 2H, J = 8.0 Hz), 7.39–7.42 (m, 1H), 7.59 (d, 2H, J = 8.0 Hz),
7.60 (m, 1H); 13C NMR (CDCl3) d 21.4 (CH3), 110.0 (CH), 119.0 (CH), 123.3 (C),
124.1 (CH), 124.3 (CH), 130.5 (CH), 134.7 (CH), 140.4 (C), 142.0 (C), 151.9 (C),
164.0 (C). ESI HRMS calcd for C14H11NOS [M + H] 242.0640, found 242.0672. EI
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Compound 3ad: Colorless oil. 1H NMR (CDCl3, 300 MHz) d 2.48 (s, 3H), 7.20–
7.41(m, 6H), 7.56–7.60 (m, 1H), 7.70 (d, 1H, J = 7.6 Hz); 13C NMR (CDCl3) d 20.9
(CH3), 110.0 (CH), 118.9 (CH), 124.0 (CH), 124.2 (CH), 126.2 (C), 127.0 (CH),
130.6 (CH), 131.1 (CH), 136.1 (CH), 142.0 (C), 142.5 (C), 151.8 (C), 163.2 (C). ESI
HRMS calcd for C14H11NOS [M + H] 242.0640, found 242.0642. EI MS m/z = 241.
Compound 3ae: Colorless oil. 1H NMR (CDCl3, 300 MHz) d 7.18–7.30 (m, 2H),
7.35–7.46 (m, 1H), 7.42 (d, 2H, J = 8.8 Hz), 7.56-7.60 (m, 1H), 7.63 (d, 2H,
J = 8.8 Hz); 13C NMR (CDCl3) d 110.0 (CH), 119.1 (CH), 124.4 (CH), 124.4 (CH),
125.5 (C), 129.9 (CH), 135.7 (CH), 136.4 (CH), 141.8 (C), 151.8 (C), 162.7 (C). ESI
HRMS calcd for C13H8NOSCl [M + H] 262.0093, found 262.0099. EI MS m/
z = 261, 263.
Compound 3ah: White solid. Mp = 79–81 °C. 1H NMR (CDCl3, 300 MHz) d 7.21–
7.26 (m, 2H), 7.38–7.41 (m, 1H), 7.52–7.61 (m, 3H), 7.69–7.72 (m, 1H), 7.84–
7.93 (m, 3H), 8.23 (s, 1H); 13C NMR (CDCl3) d 110.0 (CH), 119.1 (CH), 124.2 (C),
124.3 (CH), 124.4 (CH), 126.9 (CH), 127.5 (CH), 127.8 (CH), 128.0 (CH), 129.4
(CH), 130.7 (CH), 133.5 (C), 133.6 (C), 134.3 (CH), 142.0 (C), 151.9 (C), 163.3 (C).
ESI HRMS calcd for C17H11NOS [M + H] 278.0640, found 278.0492. EI MS m/
z = 277.
Compound 3ba: Colorless oil. 1H NMR (CDCl3, 300 MHz) d 2.42 (s, 3H), 7.05 (d,
J = 8.2 Hz, 1H), 7.26–7.99 (m, 1H), 7.39–7.47 (m, 4H), 7.67–7.71 (m, 2H); 13C
NMR (CDCl3) d 21.4 (CH3), 109.4 (CH), 119.1 (CH), 125.3 (CH), 127.3 (C), 129.6
(CH) , 129.7 (CH), 134.2 (CH), 134.2 (C), 142.1 (C), 150.1 (C), 163.0 (C). ESI
HRMS calcd for C14H11NOS [M + H] 242.0640, found 242.0612. EI MS m/z = 241.
Compound 3ca: White Solid. Mp = 73–75 °C. 1H NMR (CDCl3, 300 MHz) d 7.19–
7.20 (m, 1H), 7.22 (d, 1H, J = 8.2 Hz), 7.45–7.50 (m, 3H), 7.56–7.58 (m, 1H),
7.69–7.72 (m, 2H); 13C NMR (CDCl3) d 110.6 (CH), 119.0 (CH), 124.4 (CH), 126.5
(C), 129.7 (CH), 129.9 (C), 130.1 (CH), 134.6 (CH), 143.1 (C), 150.4 (C), 165.2 (C).
ESI HRMS calcd for C13H8NOSCl [M + H] 262.0093, found 262.0076. EI MS m/
z = 261, 263.
13. 1,10-Phenanthroline and TMEDA were not effective as ligands.
14. The reaction in air gave the unsatisfactory yield of the product.
15. Taniguchi, N. Synlett 2006, 1351–1354.
16. In the reaction using CuBr2 as a catalyst, Cu(II) can be reduced Cu(I) species by
thiol: thiol is oxidized to disulfide. Higashi, L. S.; Lundeen, M.; Hilti, E.; Seff, K.
Inorg. Chem. 1977, 16, 310–313.
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(c) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205.
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D.; Dutia, M.; Powell, D.; Floyd, B. M.; Torres, N.; Mallon, R.; Wojciechowicz, D.;
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