Copper-catalyzed thiolation annulations of 1,4-dihalides with sulfides leading to 2-trifluoromethyl benzothiophenes and benzothiazoles

Article abstract of DOI:10.1021/jo101675f

Copper-catalyzed double thiolation reaction of 1,4-dihalides with sulfides has been developed for selectively synthesizing 2-trifluoromethyl benzothiophenes and benzothiazoles. In the presence of CuI, a variety of 2-halo-1-(2-haloaryl)-3,3,3-trifluoropropylenes smoothly underwent the thiolation annulation with Na₂S to afford 2-trifluoromethyl benzothiophenes in moderate to good yields. Moreover, the conditions are compatible with N-(2-haloaryl)trifluoroacetimidoyl chlorides in the presence of NaHS and K₃PO₄, leading to 2-trifluoromethyl benzothiazoles.

Full text of DOI:10.1021/jo101675f

pubs.acs.org/joc
medicinal molecules, such as clinically used raloxifene,2
Copper-Catalyzed Thiolation Annulations
of 1,4-Dihalides with Sulfides Leading
to 2-Trifluoromethyl Benzothiophenes
and Benzothiazoles
zileuton,3 and zopolrestat.4 For this reason, many attractive
and efficient methods have been developed for synthesizing
benzothiophene and benzothiazole derivatives. In particu-
lar, the synthesis of trifluoromethyl-containing heterocycle
molecules is the subject of intense investigation because the
trifluoromethyl group has a significant effect on the biolog-
ical activity and often manifests changes in chemical and
physical properties.5-8 However, only a few effective ap-
proaches are available to synthesize trifluoromethyl-
containing benzothiophenes6 or benzothiazoles.7,8 Generally,
trifluoromethyl benzothiophenes are prepared through the
direct trifluoromethylation of the preexisting benzothio-
phene skelecton.6 However, these methods suffer from poor
regioselectivity and low yields. For trifluoromethyl benzo-
thiazoles, there are two synthetic transformations: one in-
volves the condensation of 2-aminothiophenols with trifluoro-
acetic acid or trifluoroacetic anhydride,7 and the other
transformation is palladium-catalyzed C-H bond function-
alization of trifluoromethylimidoyl chlorides with sodium
hydrosulfide hydrate.8
Chun-Lin Li,† Xing-Guo Zhang,*,†,‡ Ri-Yuan Tang,†
Ping Zhong,† and Jin-Heng Li*,†,‡
†College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou 325035, China, and
‡Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), Hunan Normal
University, Changsha 410081, China
jhli@hunnu.edu.cn; zxg@wzu.edu.cn
Received August 26, 2010
Recently, transition metal-catalyzed Ullmann reactions
for the formation of a carbon-sulfur bond have been exten-
sively studied.9 However, this Ullmann reaction strategy for
the one-pot formation of double carbon-sulfur bonds re-
mains as an unexplored area. As a continuing interest in the
synthesis of trifluoromethyl-containing heterocyclic com-
pounds,10 we report here a novel protocol for the synthesis
of 2-trifluoromethyl benzothiophenes and benzothiazoles by
Copper-catalyzed double thiolation reaction of 1,4-diha-
lides with sulfides has been developed for selectively
synthesizing 2-trifluoromethyl benzothiophenes and ben-
zothiazoles. In the presence of CuI, a variety of 2-halo-
1-(2-haloaryl)-3,3,3-trifluoropropylenes smoothly under-
went the thiolation annulation with Na2S to afford
2-trifluoromethyl benzothiophenes in moderate to good
yields. Moreover, the conditions are compatible with
N-(2-haloaryl)trifluoroacetimidoyl chlorides in the pre-
sence of NaHS and K3PO4, leading to 2-trifluoromethyl
benzothiazoles.
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DOI: 10.1021/jo101675f
r
Published on Web 09/17/2010
J. Org. Chem. 2010, 75, 7037–7040 7037
2010 American Chemical Society

Li et al.
JOCNote
SCHEME 1
TABLE 2. Thiolation Annulation Reactions of
2-Halo-1-(2-halophenyl)-3,3,3-trifluoropropylenes (1) with Na2Sa
TABLE 1. Screening Conditionsa
entry
[Cu]
CuI
CuBr
CuCl
Cu(OAc)2
Cu(OTf)2
CuI
CuI
CuI
base
solvent
ligand
T (°C) yield (%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
60
80
0
77
54
56
30
43
75
72
74
58
67
33
trace
trace
47
78
65
21
TMEDA
L-proline
bipyridine
10 CuI
NaOH DMF
Cs2CO3 DMF
K3PO4 DMF
toluene
11 CuI
12 CuI
13 CuI
14 CuI
15 CuI
16 CuI
17 CuI
18b CuI
THF
DMSO
DMF
DMF
DMF
aReaction conditions: 1 (0.2 mmol), Na2S 9H2O (2 equiv), [Cu] (10
mol %), ligand (20 mol %), and base (2 equiv) in solvent (3 mL) for 10 h.
3
bNaHS xH2O (2 equiv) instead of Na2S 9H2O.
3
3
copper-catalyzed thiolation annulations of 1,4-dihalides
with sodium sulfide or sodium hydrosulfide (Scheme 1).
We began our study with the reaction between 2-chloro-
1-(2-bromophenyl)-3,3,3-trifluoropropylene (1a) and Na2S
(2a) to explore the optimal reaction conditions (Table 1).
Initially, the effect of Cu catalysts, including CuI, CuBr,
CuCl, Cu(OAc)2, and Cu(OTf)2, was investigated, and CuI
displayed the highest efficiency (entries 1-6). While no de-
sired product 3 was observed from the reaction of substrate
1a with Na2S without Cu catalysts (entry 1), 77% yield of the
target product 3 was isolated in the presence of 10 mol % CuI
(entry 2). The other Cu catalysts, such as CuBr, CuCl, Cu-
(OAc)2, or Cu(OTf)2, were inferior to CuI; however, they can
catalyzed the reaction (entries 3-6). We found that the
previously reported effective ligands,9 including TMEDA,
L-proline, and bipyridine, have no influence on the reaction
in terms of yields (entries 7-9). According to the earlier
reports,9 bases could improve the Ullmann reactions by trap-
ping the halide atoms. However, the activity of substrate 1a was
lowered in the presence of bases (entries 10-12). Examination
of the effects of solvents and reaction temperatures showed that
the reaction proceeded optimally in DMF at 80 °C (entries
13-17). It is noteworthy that NaHS (2b) is less active for the
thiolation annulation reaction of substrate 1a (entry 18).
With the optimal reaction conditions determined, the 1,4-
dihalides scope for the thiolation annulation reaction was
aReaction conditions: 1 (0.2 mmol), Na2S 9H2O (2 equiv), and CuI
3
(10 mol %) in DMF (3 mL) at 80 °C for 10 h. bAt 120 °C for 10 h.
examined (Table 2). We initially investigated the reaction of
a variety of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)-
benzenes 1b-h with Na2S and CuI (entries 1-7). Several
functional groups, such as Me, MeO, methylendioxy, Cl,
NO2, and CF3 groups, on the aromatic ring were tolerated in
these reactions (entries 1-6). Me-substituted substrate 1b,
for instance, smoothly underwent the reaction with Na2S
and CuI in 76% yield (entry 1). Notably, product 7 was selec-
tively obtained by reacting with vinyl chloride in 62% yield
(entry 4). Substrates 1f and 1g, with an electron-withdrawing
group, were also suitable under optimal conditions (entries 5
and 6), whereas annulation of thiophene 1h with Na2S and
CuI afforded an interesting thieno[2,3-b]thiophene 10 in
64% yield (entry 7). As expected, iodide 1i displayed greater
activity, thereby leading to a good yield (entry 8). For less
active 1-chloro-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)ben-
zenes 1j and 1k, satisfactory yields were still achieved at higher
temperature (entries 9 and 10). We found that the trifluoro-
methyl group played an important role in this annulation
7038 J. Org. Chem. Vol. 75, No. 20, 2010

Li et al.
JOCNote
TABLE 3. Thiolation Reactions of N-(2-Haloaryl)trifluoroacetimidoyl
Chlorides (1) with NaSH and K3PO4
chlorides 1n-q were first examined in the presence of NaHS,
CuI, and K3PO4, and the conditions were compatible with
various functional groups, including Me, F, CF3, and NO2
groups, on the aryl ring (entries 5-8). For example, Me-
substituted substrate 1n gave the desired product 14 in 71%
yield (entry 5). Although the activities of the electron-
deficient substrates 1p and 1q were lower, moderate yields
were still obtained (entries 7 and 8). Two N-(2-bromophenyl)-
2,2,2-trifluoroacetimidoyl chlorides 1r and 1s were also suit-
able for the reaction with NaHS and K3PO4 (entries 9
and 10). Less active N-(2-chlorophenyl)-2,2,2-trifluoroace-
timidoyl chlorides 1t-v could undergo the annulation reac-
tion; however, the yields were not satisfactory (entries
11-13).
a
In summary, we have disclosed a practical protocol for
selectively synthesizing 2-trifluoromethyl benzothiophenes
and benzothiazoles by copper-catalyzed thiolation annula-
tion reactions of 1,4-dihalides with Na2S or NaHS. This
protocol allows the formation of two C-S bonds in a one-
pot reaction through the thiolation annulation of various
1,4-dihalides, including less active dichlorides, with CuI and
Na2S (or NaHS). Most importantly, these products with a
CF3 functional group may make this class of compounds
with some new biological activities as well as new chemical
and physical properties for further elaboration.
Experimental Section
Typical Experimental Procedure for the Synthesis of 2-Tri-
fluoromethyl Benzothiophenes in the Presence of Na2S. Substrate
1a-l (0.2 mmol), Na2S 9H2O (96.0 mg, 0.4 mmol), CuI (3.8 mg,
3
0.02 mmol), and DMF (3 mL) were added to a two-necked flask
in turn. Then the solution was stirred at 80 °C for 10 h until
complete consumption of starting material as monitored by
TLC and GC-MS analysis. After the reaction was finished, the
mixture was washed with brine, extracted with EtOAc, dried
over anhydrous Na2SO4, and evaporated under vacuum. The
residue was purified by flash column chromatography on
silica gel (EtOAc/petroleum ether) to afford the desired
product.
6-Methyl-2-(trifluoromethyl)benzo[b]thiophene (4): white so-
lid; mp 89.3-91.2 °C; 1H NMR (300 MHz, CDCl3) δ 7.73 (d,
J = 9.0 Hz, 1H),7.64 (d, J = 9.0 Hz, 1H), 7.26-7.23 (m, 1H),
2.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 140.5, 136.9,
aReaction conditions: 1 (0.2 mmol), CuI (10 mol %), NaSH xH2O
135.5, 130.0 (q, JC-F = 27.5 Hz, 1C), 127.1, 125.4 (q, JC-F
=
3
(2 equiv), and K3PO4 (2 equiv) in DMF (3 mL) at 80 °C for 10 h. bNa2S
3.8 Hz, 1C), 124.6, 122.6 (JC-F = 267.5 Hz, 1C), 122.3, 21.7;
19F NMR (282 MHz, CDCl3) δ -56.2 (s, 3F); LRMS (EI, 70
eV) m/z (%) 216 (Mþ, 77), 215 (40), 197 (6), 147 (100), 69 (12);
HRMS (EI) calcd for C10H7F3Sþ (Mþ) 216.0215, found
216.0219.
c
(2 equiv) without bases. Without bases. dK2CO3 (2 equiv) instead of
K3PO4. eAt 120 °C for 10 h.
reaction, and a low yield was isolated from substrate 1m
without the trifluoromethyl group (entry 11).
Typical Experimental Procedure for the Synthesis of 2-Tri-
fluoromethyl Benzothiazoles in the Presence of NaSH. Dihalides
Subsequently, Cu-catalyzed annulation reactions of nu-
merous 2,2,2-trifluoro-N-(2-haloaryl)acetimidoyl chlorides
1m-v were carried out (Table 3). However, a trace amount of
the desired product 13 was observed from the reaction of
2,2,2-trifluoro-N-(2-iodophenyl)acetimidoyl chloride (1m)
with Na2S under the optimal conditions (entry 1). After a
series of trials, we found that the treatment of substrate 1m
with NaHS (2a) could furnish product 13 in 62% yield
(entry 2). Interestingly, both K2CO3 and K3PO4 improved
the reaction, and the latter was more effective; the yield was
enhanced to 72% by using the K3PO4 base (entries 3 and 4).
Thus, a number of 2,2,2-trifluoro-N-(2-iodoaryl)acetimidoyl
1m-v (0.2 mmol), NaSH xH2O (24.4 mg, 0.4 mmol), K3PO4
3
3
3H2O (106.4 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), and DMF
(3 mL) were added to a two-necked flask in turn. Then the
solution was stirred at 80 °C for 10 h until complete consump-
tion of starting material as monitored by TLC and GC-MS
analysis. After the reaction was finished, the mixture was washed
with brine, extracted with EtOAc, dried over anhydrous
Na2SO4, and evaporated under vacuum. The residue was puri-
fied by flash column chromatography on silica gel (EtOAc/
petroleum ether) to afford the desired product.
2-(Trifluoromethyl)benzo[d]thiazole (13):6c. yellow oil; 1H
NMR (300 MHz, CDCl3) δ 8.17 (d, J = 7.9 Hz, 1H), 7.94 (d,
J = 7.9 Hz, 1H), 7.60-7.49 (m, 2H); 13C NMR (125 MHz,
J. Org. Chem. Vol. 75, No. 20, 2010 7039

Li et al.
JOCNote
CDCl3) δ 155.8 (q, JC-F = 40.0 Hz, 1C), 152.0, 134.9, 127.4,
127.3, 124.9, 121.9, 124.3 (q, JC-F =271.2 Hz, 1C); 19F NMR
(282 MHz, CDCl3) δ -61.5 (s, 3F); LRMS (EI, 70 eV) m/z (%)
203 (Mþ, 100), 153 (24), 108 (33), 69 (20).
Provincial Natural Science Foundation of China (No.
Y407116) for financial support.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products 3-11 and
13-18 and the typical procedure. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Natural Science Founda-
tion of China (Nos. 20872112 and 20972114) and Zhejiang
7040 J. Org. Chem. Vol. 75, No. 20, 2010