A general and straightforward method for the synthesis of 2-trifluoromethylbenzothiazoles

Article abstract of DOI:10.1021/ol1006899

An efficient one-pot method for the synthesis of 2- trifluoromethylbenzothiazoles by the treatment of trifluoromethylimidoyl chlorides with sodium hydrosulfide hydrate using PdCl₂ as the sole catalyst in DMSO is described. The reaction proceeds via thiolation/C-H bond functionalization/C-S bond formation in moderate to high yields with good functional group tolerance.

Full text of DOI:10.1021/ol1006899

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2434-2436
A General and Straightforward Method
for the Synthesis of
2-Trifluoromethylbenzothiazoles
Jiangtao Zhu,† Zixian Chen,†,‡ Haibo Xie,† Shan Li,† and Yongming Wu*,†
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China, and
Department of Chemistry, Huazhong UniVersity of Science and Technology, Wuhan,
Hubei 430074, China
ymwu@mail.sioc.ac.cn
Received March 24, 2010
ABSTRACT
An efficient one-pot method for the synthesis of 2-trifluoromethylbenzothiazoles by the treatment of trifluoromethylimidoyl chlorides with
sodium hydrosulfide hydrate using PdCl2 as the sole catalyst in DMSO is described. The reaction proceeds via thiolation/C-H bond
functionalization/C-S bond formation in moderate to high yields with good functional group tolerance.
Benzothiazoles are a important class of heterocyclic com-
pounds due to their wide range of biological properties such
Scheme 1. Methods for Synthesis of Benzothiazoles
as antimicrobial,1 antitumor,2 antiviral,3 and antiparasitic.4
Synthesis of this privileged structure in medicinal chemistry
† Chinese Academy of Sciences.
‡ Huazhong University of Science and Technology.
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¨
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ˇ
has recently attracted much attention.5 To date, these
molecules are commonly prepared by the following methods
(Scheme 1): (a) condensation of o-aminothiophenols with
substituted carboxylic acids, aldehydes, nitriles, or esters;6
(b) oxidative cyclization of thiobenzamides with various
oxidants, including potassium ferricyanide(III),7 ammonium
cerium(IV) nitrate (CAN),8 hypervalent iodine reagents
(DMP, PIFA),9 and 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ);10 (c) palladium- or copper-catalyzed cy-
clization of o-halothio-benzamides;11 and (d) palladium-
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10.1021/ol1006899  2010 American Chemical Society
Published on Web 04/19/2010

catalyzed cyclization of thiobenzamides through a C-H
functionalization/C-S bond formation reaction.12 These
approaches suffer from some limitations such as the limited
diversity of the starting materials (routes a and c), multistep
synthesis especially utilizing the Lawesson’s reagent (routes
b, c, and d), the harsh reaction conditions (route a), and the
lack of regioselectivity and functional group tolerance (route
b). Although two elegant studies have been reported for the
preparation of 2-substituted benzothiazoles via route d, the
C-S bond formation via transition metal-catalyzed C-H
bond functionalization is still limited.13
trifluoromethylimidoyl chlorides with sodium hydrosulfide
hydrate by PdCl2 as the sole catalyst in DMSO via the
intermediate trifluoromethylthiobenzamides.
2,2,2-Trifluoro-N-phenylethanethioamide (2a), as the model
substrate, was treated with several different oxidants and
palladium sources to obtain the optimal reaction conditions,
which was readily prepared in excellent yield from the
reaction of 2,2,2-trifluoro-N-phenylacetimidoyl chloride (1a)
with sodium hydrosulfide hydrate in EtOH at room temper-
ature. As listed in Table 1, the product 2-trifluoromethyl-
It is well-known that regioselective replacement of hy-
drogen on an aromatic or heterocyclic system by a fluorine
atom or a fluoroalkyl group may have a profound influence
on the biological and physical properties of such a mol-
ecule.14 As part of our ongoing project to investigate new
synthetic methods for fluorine-containing heterocycles,15 we
attempted to develop a mild and efficient process for the
preparation of 2-trifluoromethylbenzothiazoles.16 Inspired by
the recent development of C-H bond functionalization17 and
the chemistry of trifluoromethylimidoyl halides as useful
building blocks in synthetic organofluorine chemistry,18
herein we wish to report a novel cascade synthesis of
2-trifluoromethylbenzothiazoles based on the reaction of the
Table 1. Optimization of Reaction Conditions
oxidant
(2 equiv)
temp
(degdC) yield (%)d
entry
catalyst (mol %)
1a
FeCl3
DDQ
PhI(OAc)2 rt or 80
rt
rt
3a/40
2a
4a/90
5a
3a/74
3a/73
3a/65
3a/16
3a/64
3a/43
3b/83
3b/82
2a
3a
4b
Cu(OTf)2 (20)
PdCl2 (10)
PdCl2(PPh3)2 (10)
PdCl2(CH3CN)2 (10)
Pd (OAc)2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (5)
140
110
110
110
110
110
110
110
110
5b
6b
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7b
8b
9b
Cu(OAc)2
DDQ
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10b
11c
12c
a The reactions were carried out on a 0.4 mmol scale in CH2Cl2. b The
reactions were carried out on a 0.4 mmol scale in DMSO for 3 h.
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sodium hydrosulfide hydrate in DMSO at 50 °C for half an hour, followed
by addition of PdCl2 and elevated temperature to 110 °C; the mixture was
stirred for 3 h. d Isolated yields.
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ometric ferric chloride was used as the oxidant (entry 1).
Unfortunately, only the starting material 2a was recovered
when DDQ was employed (entry 2). Utilizing phenyliodi-
ne(III) diacetate (PIDA) as the oxidant, disulfide 4a was
detected as the main product (entry 3), while acetylamide
5a was formed when Cu(OTf)2 was used as the catalyst
(entry 4). After treatment of 2a under air atmosphere with
10 mol % PdCl2 in DMSO at 110 °C for 3 h, the desired
product 3a was obtained in 74% yield (entry 5). Other
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Org. Lett., Vol. 12, No. 10, 2010
2435

palladium salts were found to have comparable activity
except for Pd(OAc)2 (entries 6-8). Addition of oxidants
(Cu(OAc)2 or DDQ) to the system did not improve the yield
of the desired product 3a (entries 9 and 10). After screening
the different solvents and temperature, the results showed
that the solvent DMSO was crucial for this transformation
and lower temperature gave no satisfactory results.
Table 2. Synthesis of Various 2-Trifluoromethylbenzothiazolesa
Encouraged by the results of the above experiments, we
became interested in developing a tandem reaction to
construct 2-trifluoromethylbenzothiazoles using imidoyl chlo-
rides 1 as the starting substrates directly, which could
eliminate the separation process of thiobenzamides 2. Then
2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride 1b
was selected to confirm this hypothesis. However, none of
the desired product 3b was obtained when the mixture of
1b, sodium hydrosulfide hydrate, and 10 mol % PdCl2 in
DMSO was stirred at 110 °C for 3 h. Interestingly, we were
pleased to find that treating 1b with sodium hydrosulfide
hydrate at 50 °C for half an hour, followed by addition of
10 mol % PdCl2 then elevating temperature to 110 °C for
3 h gave 3b in 83% yield (entry 11). Decreasing the loading
of PdCl2 to 5 mol % under the same operation also gave a
82% yield (entry 12).
The optimized reaction conditions were also evaluated for
a range of substituted precursors 1 in the presence of 5 mol
% PdCl2. As summarized in Table 2, a range of 2-trifluo-
romethylbenzothiazoles bearing electron-donating or electron-
withdrawing groups were formed in moderate to high yields.
A number of functional groups were tolerated in this reaction,
such as the carbonyl group (entries 9 and 11), the cyano
group (entry 10), the trifluoromethyl group (entry 22), and
halogens (entries 5-8 and 13-15). Meta-substituted sub-
strates could react regioselectively to afford 5-substituted
products 3s-v exclusively (entries 19-22), and this is in
accordance with the results reported in many C-H bond
functionalization reactions. o-Halogen-substituted compounds
led to the products in good yields (entries 13-15) except
o-iodide, which afforded the dehalogenated cyclized product
3a in 63% yield (entry 16). Substrates bearing electron-
withdrawing groups were dramatically affected by water, a
better yield of 3 was obtained by using the corresponding
thiobenzamides 2 as the substrates (entries 8-12), while
addition of drying agents such as molecular sieves and
MgSO4 failed to improve the overall yield. When the
trifluoromethyl groups were replaced by pentafluoroethyl or
chlorodifluoromethyl groups, the corresponding benzothia-
zoles were generated in 52% and 16% yield, respectively
(entries 23 and 24).
entry
substrate
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
R
product
yield (%)c
1
2
3
4
5
6
7
8
H
3a
3b
3c
3d
3e
3f
72
82
71
66
69
77
67
p-OMe
p-Me
p-NMe2
p-F
p-Cl
p-Br
p-I
p-COOEt 3i
p-CN 3j
p-COCH3 3k
p-NO2
o-F
o-Cl
o-Br
o-I
3g
3h
43 (83)b
51 70)b
(60)b
(57)b
(55)b
65
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3l
3m
3n
3o
3a
3q
65
60
62
o-OMe
naphthyl 3r
74 (78)d
69
m-OMe
m-Me
m-Cl
m-CF3
H
3s (R ) 5-OMe)
3t (R ) 5-Me)
3u (R ) 5-Cl)
3v (R) 5-CF3)
3w
78
74
66
(61)b
(52)b
(16)b
1w (CF2CF3)
1x (CF2Cl)
H
3x
a Imidoyl chloride 1 (1.0 mmol), sodium hydrosulfide hydrate (1.0
mmol), PdCl2 (0.05 mmol), DMSO (3 mL). b Thiobenzamide 2 (1.0 mmol),
PdCl2 (0.05 mmol), DMSO (3 mL). c Yields of isolated products under
condition a and yields in parentheses under condition b. d The second step
was carried out at 140 °C.
trifluoroimidoyl chlorides and sodium hydrosulfide. This one-
pot protocol showed good functional group tolerance and
utilized PdCl2 as the sole catalyst without needing any other
additives or oxidants.
Acknowledgment. Support of our work by the National
Science Foundation of China (No. 20772145) is gratefully
acknowledged.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, we have developed a novel and straightfor-
ward method for the synthesis of 2-trifluoromethylbenzothia-
zoles via Pd-catalyzed C-H bond functionalization from
OL1006899
2436
Org. Lett., Vol. 12, No. 10, 2010