Lewis acid-catalyzed, copper(II)-mediated synthesis of heteroaryl thioethers under base-free conditions

Article abstract of DOI:10.1021/jo202624s

A Lewis acid (Ag^I, Ni^II, or Fe^II) catalyzed, Cu^II-mediated thiolation reaction between heteroarenes and thiols was achieved with good yield under base-free conditions. DMSO could serve as an effective methylthiolation reagent for the synthesis of heterocyclic methyl thioethers.

Full text of DOI:10.1021/jo202624s

Note
pubs.acs.org/joc
Lewis Acid-Catalyzed, Copper(II)-Mediated Synthesis of Heteroaryl
Thioethers under Base-Free Conditions
Chao Dai,†,‡ Zhaoqing Xu,*,† Fei Huang,† Zhengkun Yu,*,† and Yan-Feng Gao*,‡
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
‡Department of Bioengineering, Zhengzhou University, Zhengzhou 450001, China
S
* Supporting Information
ABSTRACT: A Lewis acid (AgI, NiII, or FeII) catalyzed, CuII-mediated
thiolation reaction between heteroarenes and thiols was achieved with
good yield under base-free conditions. DMSO could serve as an effective
methylthiolation reagent for the synthesis of heterocyclic methyl
thioethers.
DMSO could serve as a simple, cheap, and easy-to-handle
methylthiolation reagent and directly reacted with heteroarenes
to give the corresponding heteroaryl methyl thioethers with
good yields, which is a significant practical advantage.
eteroaromatic compounds and their derivatives are
known to exhibit interesting biological activities,1
H
especially for heteroaryl sulfide structural motifs, which are
found in many pharmaceutically active compounds and
advanced materials.2 Over the last decades, the activation of
C−H bonds has emerged as an active field in organometallic
catalysis, which allows superior step- and atom-economic
transformations. Direct activation of heteroarene C−H bonds
and coupling with a functional group represents the most
straightforward way to functionalize heteroaryls. Recently,
numerous methods have been reported for direct construction
of heteroarene C−C, C−N, C−O, and C−halogen bonds by
transition-metal-catalyzed C−H activations.3 However, the
synthesis of heteroaryl thioethers by direct thiolation of
heteroarene C−H bonds with thiols still remains a challenge.
In 2009, Daugulis reported a base-mediated direct thiolation of
heterocycles by using disulfide as the thiolation reagent, but the
products were limited to phenyl thioethers.4a Since the reaction
proceeded under basic conditions with high temperature, when
dialkyl disulfides were used as substrates, the thiolation product
would further sulfenylate and dealkylate to give the thionone as
the final product.4a Fukuzawa and co-workers first reported the
synthesis of heterocyclic thioethers by CuI-catalyzed C−H/S−
H cross-coupling, and the substrates were also limited to phenyl
thiols.4b Very recently, Huang and Liu described a CuI and base
mediated direct thiolation of thiazoles and imidazoles in the
presence of stoichiometric 2,2′-bipyridine as ligand.4c However,
the method was not effective for azole and its derivatives. In our
study, we found that a proper Lewis acid could activate
heteroarenes and coupling with thiols in the presence of a
suitable mediator/oxidant. Several Lewis acids were effective to
catalyze this reaction. Among them, AgI (AgNO3, AgO2CCF3,
and AgF), NiII (NiCl2 and NiF2), AuCl, AuCl3, CuF2,
Zn(OTf)2, and FeF2 showed high reactivities and gave the
thiolation products in good yields. Moreover, the reaction
proceeded under neutral conditions that tolerate a broad range
of substrates and functional groups. Remarkably, in our system,
We initially investigated the reaction of benzothiazole (1a)
and n-butyl thiol (2a) in DMF at 120 °C under an argon
atmosphere. To our delight, 48% of the desired product was
obtained by using Ag2CO3 (0.2 equiv) as the catalyst and
Cu(OAc)2 (2 equiv) as the mediator/oxidant (Table 1, entry
1). After a brief screening of different Ag salts, AgNO3,
AgO2CCF3, and AgF showed high reactivities (entries 2−5).
The reaction did not proceed in the absence of either Ag
catalyst or Cu(OAc)2 (entries 6 and 7). The use of a catalytic
amount of Cu(OAc)2 (0.2 equiv) and O2 as co-oxidant sharply
decreased the yield (entry 8). This result clearly revealed that a
stoichiometric amount of Cu(OAc)2 is necessary and Cu-
(OAc)2 may assume the role of not only the oxidant but also
the metal mediator. Variation of oxidants such as BQ (1,4-
benzoquinone), K2S2O8, PhI(OAc)2, and TEMPO was
ineffective (entries 9−12). Lowering the reaction temperature
led to a poor yield (entry 13). Other Lewis acids were also
employed in the reactions to compare their catalytic activities.
NiCl2, NiF2, AuCl, AuCl3, FeF2, CuF2, and Zn(OTf)2 exhibited
good catalytic activities (entries 14−20), whereas FeCl3, CuI,
Sc(OTf)3, BF3·Et2O, and AlCl3 only gave moderate to low
yields (entries 21−25).
We first investigated the substrate scope with respect to
heteroarenes by using n-butyl thiol as coupling partner and
AgO2CCF3 as the catalyst under optimal conditions. As shown
in Table 2, uniformly good yields and high selectivities were
achieved with a variety of heteroarenes (3a−u). Benzothiazoles,
thiazoles, benzoxazoles, azoles, benzimidazole, imidazole,
oxadiazole, as well as their analogues, all provided good yields
Received: December 26, 2011
Published: April 17, 2012
© 2012 American Chemical Society
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Note
a
Table 1. Optimizing Reaction Conditions
Table 2. Thiolation with a Variety of Heteroarenes and
a,b
Thiols
b
entry
cat.
oxidant
yield (%)
1
2
3
4
5
Ag2CO3
AgOAc
AgNO3
AgO2CCF3
AgF
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
48
60
95
>99 (91)
97
c
6
trace
N.D.
15
d
7
e
AgO2CCF3
AgO2CCF3
AgO2CCF3
AgO2CCF3
AgO2CCF3
AgO2CCF3
AgO2CCF3
NiCl2
8
Cu(OAc)2 + O2
BQ
9
N.D.
trace
N.D.
N.D.
32
10
11
12
K2S2O8
PhI(OAc)2
TEMPO
f
13
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
14
15
16
17
18
19
20
21
22
23
24
25
98
NiF2
80
AuCl
79
AuCl3
88
FeF2
79
CuF2
78
Zn(OTf)2
FeCl3
92
65
Cul
69
Sc(OTf)3
AlCl3
50
10
BF3·Et2O
14
a
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (0.04 mmol),
b
oxidant (0.4 mmol), 2 mL of DMF, 120 °C, except as noted. GC
c
yield with isolated yield in parentheses. Without AgO2CCF3.
d
e
f
Without Cu(OAc)2. 0.2 equiv of Cu(OAc)2 was used. Run at 100
°C.
regardless of the electronic property of the substituent. It is
worth mentioning that with these neutral conditions, sensitive
functional groups such as −NO2, −NH2, −CF3, −CO2CH3,
and −OH were all compatible (3c−e,g,j). We then chose NiCl2
and FeF2 as the model catalysts to compare their catalytic
relativities with AgO2CCF3 for other heteroarene substrates
(3d,j,l,s). FeF2 showed competitive reactivity, whereas NiCl2
gave only moderate results. In some cases, compared with
AgO2CCF3 catalyst, FeF2 exhibited better catalytic activities
(3d and 3j). The scope with respect to thiols was also
investigated. To our delight, the thiols with aryl, benzyl,
heteroaryl, and cyclohexyl groups were also suitable and
exhibited good reactivities (3v−y).
a
Conditions: 1 (0.2 mmol), 2 (0.4 mmol), AgO2CCF3 (0.04 mmol),
b
Cu(OAc)2 (0.4 mmol), 2 mL DMF, 120 °C, except as noted. Isolated
yields. NiCl2 (0.04 mmol) was used. FeF2 (0.04 mmol) was used.
c
d
Heterocyclic methyl thioether structural motifs play
important roles in biological and pharmaceutical areas.5 Very
few examples have been reported for transition-metal-catalyzed
C−H functionalization to synthesize heterocyclic methyl
thioethers. Furthermore, there is no report about cross-
coupling of heteroarene C−H bonds and methanethiol to
prepare heteroaryl methyl thioethers. The boiling point of
CH3SH is around 7 °C, which may cause a technical problem
for its handling and measurement at room temperature. Hence,
the development of a simple and facile method for heteroarene
methylthiolation remains a highly desired goal for chemists. In
2006, Yu reported a CuII-catalyzed methyl thioetherification of
2-phenylpyridine C−H bond with MeSSMe.6a Qing and co-
workers disclosed a CuF2-mediated methylthiolation of 2-
phenylpyridine by using DMSO as the methylthiolation
reagent.6b Very recently, Yamaguchi reported a Rh-catalyzed
synthesis of benzothiazole and benzoxazole methyl thioether
using α-(methylthio)isobutyrophenone as methylthiolation
reagent. The reaction required a large excess (5 equiv) of
heterocycles, and the yields were moderate.6c To our
knowledge, no general and facile method has been reported
for the synthesis of thiazole/azole/imidazole methyl thioethers
by direct C−H methylthiolation. We envisioned that DMSO
could serve as an effective methylthiolation reagent in our
system. Indeed, by using AgF as catalyst and Cu(OAc)2 as
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Note
mediator/oxidant, the reactions went smoothly and gave the
Scheme 2. Kinetic Isotope Effect (KIE) Study
desired products with good yields (Table 3, 4a−f). Thiazoles,
a,b
Table 3. Methylthiolation of Heteroarenes with DMSO
elimination. The KIE experiments suggested that the rate-
determining step could be the reductive elimination or
disproportion step (Figure 1). However, at the present stage,
a
Conditions: 1 (0.2 mmol), AgF (0.04 mmol), Cu(OAc)2 (0.4 mmol),
b
c
1 mL of DMSO, 140 °C, except as noted. Isolated yields. NiCl2
(0.04 mmol) was used. FeF2 (0.04 mmol) was used.
d
azoles, imidazole, and oxadiazole with sensitive functional
groups (4d), as well as different electronic property
substituents, were all tolerable. Other Lewis acid catalysts
such as NiCl2 and FeF2 were also employed in the reactions
(4a,b,d,e). The product yields were significantly lower than
when AgF was used. Only in the case of 4e did NiCl2 give
better results. In the reaction, CuII might serve for trapping the
methylmercaptan formed in situ from the thermal decom-
position of DMSO.7
To obtain some mechanistic insights, the following experi-
ments were performed. In CuBr2-catalyzed azole C−H/S−H
cross-coupling, Fukuzawa proved that thiols were first oxidized
to form disulfides, which then served as the thiolation
reagents.4b However, under our standard conditions, dibutyl
disulfide led to no formation of thiolation product, indicating
that the disulfides were not involved in the reaction (Scheme
1).
Figure 1. Plausible mechanism.
the pathway of nucleophilic addition to heteroarene CN by
thiols in the presence of a suitable mediator/oxidant (Cu, Ag, et
al.) and subsequent oxidative rearomatization to give
heteroaromatic thioether cannot be ruled out.4c,14−16
In conclusion, we have developed a new Lewis acid−CuII
catalyst system for the synthesis of heteroaryl thioethers by
direct C−H thiolation of heteroarenes. The base-free
conditions tolerate a broad range of substrates and functional
groups. Moreover, in our system, DMSO could serve as a
methylthiolation reagent, which is a significant practical
advantage.
Scheme 1. Disulfide as Thiolation Reagent
EXPERIMENTAL SECTION
■
General Methods. The solvents were dried and distilled prior to
1
use by the literature methods. H and 13C{1H} NMR spectra were
recorded on a 400 and 100 MHz FT-NMR spectrometer, and all
chemical shift values refer to δTMS = 0.00 ppm or CDCl3 (δ(1H), 7.26
ppm; δ(13C), 77.16 ppm). The HRMS analysis was obtained on a GC-
TOF mass spectrometer. All chemical reagents were purchased from
commercial sources and used as received unless otherwise indicated.
Literature procedures were used to synthesize 5-chlorobenzothia-
zole,17 6-methylbenzothiazole,18 5-tert-butylbenzoxazole,17 5-phenyl-
oxazole,19 5-(4-methoxyphenyl)oxazole,19 5-(naphthalene-2-yl)-
oxazole,19 3-(trifluoromethyl)phenyloxazole,19 5-(4-chlorophenyl)-
oxazole,19 5-phenylthiazole,20 5-(4-methoxyphenyl)thiazole,20 5-p-
tolylthiazole,20 5-(3-(trifluoromethyl)phenyl)thiazole,20 and 1-benzyl-
benzimidazole,21 respectively.
Typical Procedure for the Synthesis of 3 and 4. For the
synthesis of 3a,21 under an argon atmosphere, a 15-mL Schlenk tube
was charged with Cu(OAc)2 (73 mg, 0.4 mmol), AgO2CCF3 (10 mg,
0.04 mmol), benzothiazole 1a (27 mg, 0.2 mmol), BuSH (42 μL, 0.4
mmol), and DMF (2 mL). The resultant mixture was stirred at 120 °C
for 12 h. After the reaction was completed by TLC monitoring, the
mixture was cooled to ambient temperature, poured into 20 mL of
brine, and extracted with ethyl acetate (3 × 20 mL). The combined
organic phase was dried over anhydrous Na2SO4 and filtered, and all of
the volatiles were removed under reduced pressure. The resulting
The intermolecular kinetic isotope effect (KIE) was also
investigated by using 2-deuteriobenzothiazole. At an early stage
in the reaction, a KIE of 1.1 was observed, suggesting that C−H
bond cleavage at the C2 position(s) of the heteroarene
substrates is not involved in the rate-determining step (Scheme
2).8
It is known that Lewis acid bonding to azole could increase
the azole C2 C−H bond acidity,9 which could facilitate a
carboxylated-assisted concerted metalation−deprotonation
under base free conditions.10 On the basis of the above
considerations and experimental results, the reaction could
consist of (1) thiols reacting with Cu(OAc)2 to form a
RSCuOAc species A,11 (2) a Lewis acid promoted carboxy-
lated-assisted concerted metalation−deprotonation to give the
CarCuSR intermediate B,9,12 (3) , disproportion of CuII into
CuI and CuIII in view of the necessity of a stoichiometric
amount of Cu(OAc)2,8,13 and (4) productive reductive
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Note
residue was purified by flash silica gel column chromatography (eluent:
petroleum ether (30−60 °C)/EtOAc, v/v = 50/1) to afford the
desired products 3a as a yellow oil (41 mg, 91%). For the synthesis of
4, the synthetic reactions were carried out at 140 °C for 15 h under an
argon atmosphere and used DMSO as the methylthiolation reagent:
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8 Hz, 1 H), 7.82 (d, J = 8
Hz, 1 H), 7.5−7.45 (t, J = 8 Hz, 1 H), 7.4−7.35 (t, J = 8 Hz, 1 H),
3.45−3.4 (t, J = 8 Hz, 2 H), 1.9−1.8 (m, 2 H), 1.65−1.55 (m, 2 H),
1.04 (t, J = 7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 167.4, 153.4,
135.1, 126.0. 124.1, 121.5, 120.9, 33.4, 31.3, 21.9, 13.6.
8.57 (s, 1 H), 8.15 (d, J = 9 Hz, 1 H), 7.93 (d, J = 9 Hz, 1 H), 4.02 (s,
3 H), 3.44 (t, J = 8 Hz, 2 H), 1.9−1.85 (m, 2 H), 1.6−1.55 (m, 2 H),
1.05 (t, J = 7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 166.7, 156.7,
142.2, 140.5, 127.5, 122.9, 120.9, 52.3, 33.3, 31.1, 21.9, 13.5; HRMS
calcd for C12H15NO2S 237.0823, found 237.0824.
2-Butylsulfanyl-5-methyl-benzoxazole (3n): 39 mg, 89% yield;
yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1 H), 7.44 (d, J = 8
Hz, 1 H), 7.25 (d, J = 8 Hz, 1 H), 3.29 (t, J = 7 Hz, 2 H), 2.43 (s, 3 H),
1.83 (t, J = 7 Hz, 2 H), 1.6−1.55 (m, 2 H), 1.03 (t, J = 7 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 163.8, 151.5, 141.3, 129.2, 124.8, 123.4,
107.1, 31.9, 31.5, 21.7, 16.3, 13.5; HRMS calcd for C12H15NOS
221.0874, found 221.0891.
2-(Butylthio)-7-methylbenzothiazole (3b): 40 mg, 84% yield;
yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.35−7.3 (m, 1 H), 7.2−7.1
(m, 2 H), 7.25 (d, J = 8 Hz, 1 H), 3.39 (t, J = 8 Hz, 2 H), 2.64 (s, 3
H), 1.88 (t, J = 8 Hz, 2 H), 1.65−1.55 (m, 2 H), 1.02 (t, J = 7 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ 163.8, 160.6, 138.1, 137.6, 129.8.
128.4, 126.4, 34.3, 31.4, 21.9, 21.2, 13.6; HRMS calcd for C12H15NS2
237.0646, found 237.0644.
5-tert-Butyl-2-butylsulfanylbenzoxazole (3o): 41 mg, 78%
1
yield; yellow solid; mp 53−55 °C; H NMR (400 MHz, CDCl3) δ
7.66 (s, 1 H), 7.45−7.3 (m, 2 H), 3.38 (t, J = 7 Hz, 2 H), 1.90−1.8 (m,
2 H), 1.6−1.55 (m, 2 H), 1.43 (s, 9 H), 1.04 (t, J = 7 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 147.7, 142.0, 121.2, 115.0, 108.9, 38.9,
34.9, 32.0, 31.7 (3 C), 21.8, 13.5; HRMS calcd for C15H21NOS
263.1344, found 263.1361.
2-Butylsulfanyl-6-nitrobenzothiazole (3c):22 40 mg, 70% yield;
white solid; mp 61−63 °C; 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1
H), 8.36 (d, J = 9 Hz, 1 H), 7.96 (d, J = 9.0 Hz, 1 H), 3.48 (t, J = 7 Hz,
2 H), 1.9−1.8 (m, 2 H), 1.55−1.65 (m, 2 H), 1.06 (t, J = 7 Hz, 3 H).
2-Butylsulfanyl-benzothiazol-6-ylamine (3d):23 34 mg, 70%
2-Butylsulfanyl-5-(3-trifluoromethylphenyl)oxazole (3p): 42
1
mg, 70% yield; white solid; mp 46−48 °C; H NMR (400 MHz,
CDCl3) δ 7.87 (s, 1 H), 7.8−7.75 (m, 1 H), 7.6−7.55 (m, 1 H), 7.44
(s, 1 H), 3.29 (t, J = 7 Hz, 2 H), 1.95−1.80 (m, 2 H), 1.55 (m, 2 H),
1.02 (t, J = 7 Hz, 3 H); 13C NMR (100 MHz, CDCl3, C−F coupling
not assigned) δ 151.2, 131.3, 129.4, 128.5, 126.7, 124.6, 124.5, 124.2,
120.4, 120.4, 32.3, 31.4, 21.8, 13.5; HRMS calcd for C14H14NOSF3
301.0748, found 301.0735.
1
yield; yellow solid; mp 39−41 °C; H NMR (400 MHz, CDCl3) δ
7.72 (d, J = 9 Hz, 1 H), 7.09 (s, 1 H), 6.83 (d, J = 8 Hz, 1 H), 3.35 (t, J
= 7 Hz, 2 H), 1.91−1.79 (m, 2 H), 1.6−1.5 (m, 2 H), 1.02 (t, J = 7 Hz,
3 H).
2-Butylsulfanylbenzothiazole-6-carboxylic acid methyl
1
ester (3e): 37 mg, 65% yield; white solid, mp 69−71 °C; H NMR
2-Butylsulfanyl-5-phenyloxazole (3q):28 32 mg, 68% yield;
(400 MHz, CDCl3) δ 8.52 (s, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 7.92 (d,
J = 8 Hz, 1 H), 4.00 (s, 3 H), 3.44 (t, J = 7 Hz, 2 H), 1.9−1.85 (m, 2
H), 1.6−1.55 (m, 2 H), 1.04 (t, J = 7 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 171.8, 166.6, 156.3, 135.4, 127.4, 125.8, 122.9, 120.9, 52.2,
33.3, 31.1, 21.9, 13.5; HRMS calcd for C13H15NO2S2 281.0544, found
281.0531.
1
yellow oil; H NMR (400 MHz, CDCl3) δ 7.65−7.6 (m, 2 H), 7.5−
7.45 (m, 2 H), 7.4−7.35 (m, 1 H), 7.36 (s, 1 H), 3.28 (t, J = 7.3 Hz, 2
H), 1.9−1.8 (m, 2 H), 1.6−1.5 (m, 2 H), 1.03 (t, J = 8 Hz, 3 H).
2-Butylsulfanyl-5-naphthalen-2-yl-oxazole (3r): 40 mg, 70%
yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1 H), 7.95−
7.85 (m, 3 H), 7.72 (d, J = 8 Hz, 1 H), 7.6−7.5 (m, 2 H), 7.48 (s, 1
H), 3.33 (t, J = 7 Hz, 2 H), 1.9−1.8 (m, 2 H), 1.6−1.55 (m, 2 H),
1.05−1.0 (t, J = 7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 133.4,
132.9, 128.7, 128.2, 127.8, 126.7, 126.4, 125.1, 123.6, 122.4, 121.7,
32.4, 31.5, 21.8, 13.6; HRMS calcd for C17H17NOS 283.1031, found
283.1026.
2-Butylsulfanyl-5-phenylthiazole (3f):24 39 mg, 79% yield;
yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1 H), 7.6−7.55 (m,
2 H), 7.5−7.35 (m, 3 H), 7.38 (t, J = 7 Hz, 1 H), 3.30 (t, J = 7 Hz, 2
H), 1.85−1.8 (m, 2 H), 1.6−1.55 (m, 2 H), 1.1−0.95 (m, 3 H).
2-Butylsulfanyl-5-(4-trifluoromethylphenyl)thiazole (3g): 42
1
mg, 67% yield; yellow solid; mp 38−40 °C; H NMR (400 MHz,
2-Butylsulfanyl-5-phenyl[1,3,4]oxadiazole (3s):29 46 mg, 98%
CDCl3) δ 7.94 (s, 1 H), 7.7−7.6 (m, 4 H), 3.32 (t, J = 7 Hz, 2 H),
1.85−1.8 (m, 2 H), 1.6−1.5 (m, 2 H), 1.03 (t, J = 7 Hz, 3 H); 13C
NMR (100 MHz, CDCl3, C−F coupling not assigned) δ 161.6, 151.2,
131.3, 129.4, 128.6, 126.7, 124.4, 124.5, 124.3, 120.5, 120.4, 32.3, 31.5,
21.9, 13.5; HRMS calcd for C14H14F3NS2 317.0520, found 317.0538.
2-Butylsulfanyl-5-(4-methoxyphenyl)thiazole (3h): 36 mg,
1
yield; yellow oil; H NMR (400 MHz, CDCl3) δ 8.05 (d, 2 H), 7.6−
7.55 (m, 3 H), 3.38 (t, J = 7 Hz, 2 H), 1.95−1.85 (m, 2 H), 1.6−1.5
(m, 2 H), 1.02 (t, J = 8 Hz, 3 H).
2-Butylsulfanyl-1-methylimidazole (3t):30 26 mg, 76% yield;
yellow solid; mp 89−91 °C; 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1
H), 6.98 (s, 1 H), 3.69 (s, 3 H), 3.13 (t, J = 7 Hz, 2 H), 1.75−1.7 (m, 2
H), 1.55−1.45 (m, 2 H), 0.98 (t, J = 7 Hz, 3 H).
1
65% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 7.58 (d, J =
7.6 Hz, 2 H), 7.24 (s, 1 H), 7.00 (d, J = 8 Hz, 2 H), 3.90 (s, 3 H), 3.27
(t, J = 7 Hz, 2 H), 1.9−1.8 (m, 2 H), 1.6−1.5 (m, 2 H), 1.1−0.95 (m,
3 H); 13C NMR (100 MHz, CDCl3) δ 159.6, 159.2, 138.9, 125.3,
121.6, 120.7, 114.3, 55.3. 32.3, 31.6, 21.8, 13.6; HRMS calcd for
C14H17NOS2 279.0752, found 279.0759.
1-Benzyl-2-butylsulfanylbenzoimidazole (3u): 45 mg, 75%
1
yield; yellow oil; H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8 Hz, 1
H), 7.4−7.2 (m, 8 H), 5.38 (s, 2 H), 3.49 (t, J = 7 Hz, 2 H), 1.85−1.8
(m, 2 H), 1.6−1.5 (m, 2 H), 1.02 (t, J = 7 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 152.6, 143.6, 136.2, 135.7, 128.8 (2 C), 127.9, 126.9
(2 C), 122.0, 121.9, 118.3, 109.1, 47.5, 32.5, 31.3, 21.9, 13.6; HRMS
calcd for C18H20N2S 296.1347, found 296.1366.
2-Butylsulfanyl-4,5-dimethylthiazole (3i):25 26 mg, 64% yield;
yellow oil; 1H NMR (400 MHz, CDCl3) δ 3.16 (t, J = 7 Hz, 2 H), 2.36
(s, 3 H), 2.34 (s, 3 H), 1.76 (t, J = 8 Hz, 2 H), 1.6−1.45 (m, 2 H), 0.99
(t, J = 7 Hz, 3 H).
2-(Pyridin-2-ylthio)benzothiazole (3v):31 36 mg, 73% yield;
1
2-(2-Butylsulfanyl-4-methylthiazol-5-yl)ethanol (3j):26 27 mg,
yellow oil; H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8 Hz, 2 H),
1
8.03 (d, J = 8 Hz, 2 H), 7.65−7.45 (m, 4 H).
57% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 3.88 (s, 2 H),
2-Benzylsulfanylbenzothiazole (3w):32 32 mg, 61% yield;
3.20 (t, J = 7 Hz, 2 H), 3.01 (t, J = 6 Hz, 2 H), 2.39 (s, 3 H), 1.85−
1
yellow oil; H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8 Hz, 1 H),
1.75 (m, 2 H), 1.55−1.5 (m, 2 H), 1.01 (t, J = 7 Hz, 3 H).
2-Butylsulfanylthiazole (3k):24 27 mg, 77% yield; yellow oil; H
1
7.83 (d, J = 8 Hz, 1 H), 7.55−7.3 (m, 7 H), 4.69 (s, 2 H).
2-Phenylsulfanyl-benzothiazole (3x):4c 37 mg, 76% yield;
NMR (400 MHz, CDCl3) δ 7.73 (s, 1 H), 7.27 (s, 1 H), 3.28 (t, J = 7
Hz, 2 H), 1.85−1.8 (m J = 7 Hz, 2 H), 1.54 (dd, J = 15, 7 Hz, 2 H),
1.01 (t, J = 7 Hz, 3 H).
1
yellow oil; H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8 Hz, 1 H),
7.82 (d, J = 7 Hz, 2 H), 7.73 (d, J = 8 Hz, 1 H), 7.65−7.45 (m, 4 H),
2-Butylsulfanylbenzoxazole (3l):27 35 mg, 84% yield; yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 1 H), 7.50 (d, J = 8
Hz, 1 H), 7.35−7.25 (m, 3 H), 3.39 (t, J = 8 Hz, 2 H), 1.95−1.85 (m,
2 H), 1.6−1.55 (m, 2 H), 1.04 (t, J = 7 Hz, 3 H).
7.35 (d, J = 8 Hz, 1 H).
2-Cyclohexylsulfanylbenzothiazole (3y):33 35 mg, 69% yield;
yellow solid; mp 46−48 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J
= 8 Hz, 1 H), 7.82 (d, J = 8 Hz, 1 H), 7.5−7.45 (t, J = 4 Hz, 1 H),
7.4−7.35 (m, 1 H), 2.27 (d, J = 10 Hz, 2 H), 1.9−1.85 (m, 2 H), 1.7−
1.3 (m, 7 H).
2-Butylsulfanyl-5-methoxybenzoxazole (3m): 38 mg, 80%
1
yield; white solid; mp 34−36 °C; H NMR (400 MHz, CDCl3) δ
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Note
2-(Methylthio)benzothiazole (4a):34 30 mg, 73% yield; yellow
oil; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8 Hz, 1 H), 7.84 (d, J
= 8 Hz, 1 H), 7.49 (t, J = 8 Hz, 1 H), 7.37 (d, J = 8 Hz, 1 H), 2.88 (s, 3
H); 13C NMR (100 MHz, CDCl3) δ 168.2, 153.4, 135.2, 126.1, 124.1,
121.4, 120.9, 15.9.
(5) (a) Laufer, S. A.; Striegel, H.-G.; Wagner, G. K. J. Med. Chem.
2002, 45, 4695. (b) Gallardo-Godoy, A.; Fierro, A.; McLean, T. H.;
Castillo, M.; Cassels, B. K.; Reyes-Parada, M.; Nichols, D. E. J. Med.
Chem. 2005, 48, 2407.
(6) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790. (b) Chu, L.; Yue, X.; Qing, F.-L. Org. Lett. 2011,
13, 1644. (c) Arisawa, M.; Toriyama, F.; Yamaguchi, M. Tetrahedron
Lett. 2011, 52, 2344.
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221. (b) Luo, F.; Pan, C.; Li, L.; Chen, Fan.; Cheng, J. Chem. Commun.
2011, 47, 5304.
(8) For an example of Cu-mediated azole C−H dehydrogenative
cross-coupling, in which C−H bond cleavage was not involved in the
rate-determining step, see: Kitahara, M.; Umeda, N.; Hirano, K.;
Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 133, 2160.
(9) (a) Gorelsky, S. I. Organometallics 2012, 31, 794. (b) Huang, J.;
Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D.; Faul,
M. M. J. Am. Chem. Soc. 2010, 132, 3674.
2-Methylsulfanyl-5-phenylthiazole (4b):35 30 mg, 73% yield;
1
yellow oil; H NMR (400 MHz, CDCl3) δ 7.7−7.65 (m, 2 H), 7.5−
7.45 (m, 2 H), 7.4−7.35 (m, 1 H), 7.37 (s, 1 H), 2.78 (s, 3 H).
2-Methylsulfanyl-5-phenyl[1,3,4]oxadiazole (4c):29 27 mg,
71% yield; yellow solid; mp 32−34 °C; 1H NMR (400 MHz,
CDCl3) δ 8.1−8.05 (m, 2 H), 7.6−7.5 (m, 3 H), 2.86 (s, 3 H).
2-(5-Methyl-2-methylsulfanylthiazol-4-yl)ethanol (4d):36 30
mg, 80% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ 3.87 (t, J =
6 Hz, 2 H), 3.01 (t, J = 6 Hz, 2 H), 2.70 (s, 3 H), 2.39 (s, 3 H).
2-Methylsulfanyl-5-phenyloxazole (4e):37 23 mg, 60% yield;
yellow solid; mp 57−59 °C; 1H NMR (400 MHz, CDCl3) δ 7.6−7.55
(m, 2 H), 7.5−7.4 (m, 3 H), 7.38 (s, 1 H), 2.81 (s, 3 H).
1-Benzyl-2-methylbenzoimidazole (4f):38 41 mg, 81% yield;
yellow solid; mp 77−79 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J
= 8 Hz, 1 H), 7.4−7.2 (m, 8 H), 5.37 (s, 2 H), 2.89 (s, 3 H).
Disulfide as Thiolation Reagent (Scheme 1). Under an argon
atmosphere, a 15-mL Schlenk tube was charged with Cu(OAc)2 (73
mg, 0.4 mmol), AgO2CCF3 (10 mg, 0.04 mmol), benzothiazole 1a (27
mg, 0.2 mmol), BuSSBu (76 μL, 0.4 mmol), and DMF (2 mL). The
resultant mixture was stirred at 120 °C for 12 h. After completion, the
mixture was cooled to room temperature and subject to GC analysis
by using n-dodecane as the internal standard.
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deprotonation of azole: Kondo, Y.; Komine, T.; Sakamoto, T. Org.
Lett. 2000, 2, 3111.
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Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010,
132, 12068 and references cited therein..
Kinetic Isotope Effect Study (Scheme 2). Two sets of reaction
were carried out in a parallel manner under the optimized conditions
(Table 1, entry 4) using 1a and its deuterated derivatives[D]-1a. The
GC yields from the reactions were carefully checked by the signal
integration of the desired product 3a by using n-dodecane as the
internal standard. The kH/kD (0.21/0.19 = 1.1) value was calculated
according to the yields of 3a at the point of 1 h.
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2011, 30, 93.
(16) In the course of reaction, acetic acid is presumably generated. A
control experiment was carried out using 1 equiv of HOAc as the
catalyst and 2 equiv of Cu(OAc)2 as the oxidant. Only a trace amount
of desired product was obtained. The mechanism of Brønsted acids
catalysis was ruled out.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.
org.”
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xuzq@dicp.ac.cn, zkyu@dicp.ac.cn, gaoyf@zzu.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank DICP, NSFC (21102141), and 973
(2009CB825300) for support of this research.
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