Switching reaction pathways of trifluoromethylated thiobenzanilides by choice of different oxidative systems

Article abstract of DOI:10.1016/j.jfluchem.2011.02.010

Trifluoromethylated thiobenzanilides are efficiently converted to 2-trifluoromethylbenzothiazoles via intramolecular oxidative cyclization under CAN/NaHCO₃ oxidation, while the dimerized products with "-S-S-" bond linkage are obtained when PIDA

Full text of DOI:10.1016/j.jfluchem.2011.02.010

Journal of Fluorine Chemistry 132 (2011) 306–309
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Switching reaction pathways of trifluoromethylated thiobenzanilides by
choice of different oxidative systems
Jiangtao Zhu a, Haibo Xie a, Shan Li a, Zixian Chen b, Yongming Wu a,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
b Department Chemistry, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Trifluoromethylated thiobenzanilides are efficiently converted to 2-trifluoromethylbenzothiazoles via
intramolecular oxidative cyclization under CAN/NaHCO3 oxidation, while the dimerized products with
‘‘–S–S–’’ bond linkage are obtained when PIDA is used as an oxidant.
Received 14 January 2011
Received in revised form 15 February 2011
Accepted 15 February 2011
Available online 22 February 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Trifluoromethyl
Benzothiazoles
Disulfides
CAN
PIDA
1. Introduction
sequence. As our ongoing research on fluorinated heterocycle
synthesis [12], we now report a facile synthesis of 2-trifluor-
2-Substituted benzothiazoles are of great interest nowadays
due to their potent pharmacological activities such as anti-tumor,
antimicrobial, antiviral, and antiparasitic [1]. Traditional methods
for their syntheses involve the condensation of o-aminothiophe-
nols with substituted carboxylic acids, aldehydes, nitriles, or
esters, but such methods suffer from difficulties in the preparation
of readily oxidizable o-aminothiophenol precursors [2]. Alterna-
tively, oxidative cyclization of thiobenzanilides has been the most
frequently used route to synthesize benzothiazoles with various
oxidants such as potassium ferricyanide(III) [3], cerium(IV)
ammonium nitrate (CAN) [4], hypervalent iodine reagents (DMP,
PIFA) [5], 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) [6],
and manganese(III) triacetate [7]. Recently, palladium or copper
catalyzed coupling reactions to construct benzothiazoles via C–S
bond formation from ortho-haloanilides have been developed [8].
To overcome the limited diversity of the ortho-halogen substituted
anilines, palladium-catalyzed cyclization of thiobenzanilides
leading to 2-substituted benzothiazoles (2-aryl by Doi and co-
workers [9], 2-amino by Joyce and Batey [10], 2-trifluoromethyl by
Wu and co-workers [11]) has been explored through an
intramolecular C–H bond functionalization/C–S bond formation
omethylbenzothiazoles from corresponding trifluoromethylated
thiobenzanilides using CAN as the oxidant, whereas the other
oxidant phenyliodine(III) diacetate (PIDA) results in disulfides by
intermolecular dimerization.
2. Results and discussion
During our investigation for the synthesis of 2-trifluoromethyl-
benzothiazoles by palladium-catalyzed cyclization of the
trifluoromethylated thiobenzanilides, we found that 2-trifluoro-
methylbenzothiazoles could be obtained in good yields using CAN as
oxidant. To identify an optimal oxidative reagent for this transfor-
mation, 2,2,2-trifluoro-N-p-tolylethanethioamide 1a, which was
chosen as a model substrate, was treated with several different
oxidants. As listed in Table 1, 2 equiv. of CAN was found essential for
the complete conversion of the substrate 1a and the desired product
2a was obtained in 93% yield. However, when 1a was treated with
1 equiv. of PIDA in CH2Cl2 for 5 min, disulfide 3a was unexpectedly
produced as the major product even with 2 equiv. of PIDA in CH3CN
at 80 8C. Utilization of FeCl3 gave 2a in lower yield, whereas other
oxidants such as DDQ, I2 were not capable of above conversion as the
starting material 1a was recovered after the reaction.
With the optimized reaction conditions in hand, we examined a
series of substituted trifluoromethylated thiobenzanilides 1 to
establish the scope and limitations of this process under different
* Corresponding author. Tel.: +86 21 54925190; fax: +86 21 64166128.
E-mail address: ymwu@sioc.ac.cn (Y. Wu).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.02.010

J. Zhu et al. / Journal of Fluorine Chemistry 132 (2011) 306–309
307
Table 1
Optimization of reaction conditionsa.
.
Entry
Oxidant (equiv.)
Solvent
Temp. (8C)
Time
Yield (%)b
1
2
3
4
5
6
7
CAN/2
CAN/1
CAN/2
PIDA/1
PIDA/2
DDQ/1.25
I2/2
CH3CN
CH3CN
CH3CN
CH2Cl2
CH3CN
CH3CN
CH2Cl2
80
80
r.t.
r.t.
80
80
r.t.
10 min
10 min
7 h
2a/93
2a/46
2a/78
3a/86
3a/80
1a
5 min
30 min
2 h
30 min
1a
a
Conditions: Reactions were carried out on a 0.5 mmol scale in solvent (5 mL).
b
Isolated yield.
Table 2
Table 3
Synthesis of 2-trifluoromethylbenzothiazolesa.
Synthesis of the dimerization product disulfidesa.
.
.
Entry
R (for 1)
Yield (%)b
Entry
R (for 1)
Yield (%)b
1
2
3
4
5
6
p-OMe
H
3b/89
3c/92
3d/78
3e/87
3f/62
3g/90
1
H
2b/73
2c/83
2d/76
2
p-F
p-I
3
p-Cl
p-Cl
c
4
p-Br
–
p-CF3
o,o-diMe
c
5
p-I
–
6
p-CF3
2e/65
2f/66
2g/35
2h/62
2i/86
2j/78
2k/81
2l/74
a
Reactions were carried out on a 1.0 mmol scale in CH2Cl2 (10 mL) with PIDA
7
p-COOEt
(1.1 mmol).
b
8
p-NO2
Isolated yield.
9
p-CN
10
11
12
13
2-Naphthyl
o-Me
H (CF2Cl instead of CF3)
H (CF2CF3 instead of CF3)
mation as the major products were identified as the corresponding
benzamides (Table 2, entries 4 and 5), while chloro and fluoro
substituents were intact and gave the desired benzothiazoles in
good yields (Table 2, entries 2 and 3). When trifluoromethyl group
was replaced by chlorodifluoromethyl or pentafluoroethyl group,
the corresponding benzothiazoles were formed in 81% and 74%
yield, respectively (Table 2, entries 12 and 13).
a
Reactions were carried out on a 0.8 mmol scale in CH3CN (8 mL) with CAN
(1.68 mmol), NaHCO3 (3.36 mmol).
b
Isolated yield.
c
The product was the corresponding benzamides.
oxidative systems. The substrates 1 were easily generated from the
reaction of 2,2,2-trifluoro-N-arylacetimidoyl chlorides with sodi-
um hydrosulfide hydrate in EtOH at room temperature which
could obviate using Lawesson’s reagent. As summarized in Table 2,
by using CAN, an array of benzothiazoles were formed in moderate
to good yields. Contrary to what we expected, some electron-
withdrawing groups (CF3, COOEt, NO2, and CN) were tolerated in
this reaction which was not observed in other similar oxidative
cyclization of thiobenzanilides (Table 2, entries 6–9). Unfortu-
nately, bromo and iodo substituents could hamper this transfor-
It is a common knowledge that molecules containing a disulfide
moiety play an important role in biochemistry. However, the
oxidative dimerization of thiobenzanilides was less reported than
the related thiols [13]. After investigating the CAN-oxidative
cyclization, we then turned our attention to dimerization of the
thiobenzanilides by PIDA. Some trifluoromethylated thiobenzani-
lides were treated with 1.1 equiv. of PIDA via this transformation to
obtain the corresponding disulfides 3. As indicated in Table 3, the
desired disulfides 3 were obtained in high yields even with iodo
substituent on the aryl ring (Table 3, entry 3). Disulfide 3f was not
Scheme 1.

308
J. Zhu et al. / Journal of Fluorine Chemistry 132 (2011) 306–309
separated as a pure compound through the silica chromatography
gel due to its instability of S–S bond (Table 3, entry 5). When the
disulfide product 3a was treated with 2 equiv. of CAN at 80 8C after
30 min, the main product characterized as the corresponding
benzamide 4a was obtained in 50% yield and 34% of 3a was
recovered (Scheme 1).
4.4. General procedure for the synthesis of dimerization products 3
using PIDA as an oxidant
A mixture of trifluoromethylated thiobenzanilides 1 (1.0 mmol)
and PIDA (354 mg, 1.1 mmol) in CH2Cl2 (10 mL) was stirred at
room temperature for 5 min. Then the reaction mixture was
concentrated under reduced pressure. The residue was then
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate to give the product 3.
3. Conclusion
In conclusion, we have developed a novel method for the
synthesis of 2-trifluoromethylbenzothialzoles via intramolecular
oxidative cyclization of thiobenzanilides under CAN/NaHCO3
oxidation. On the other hand, dimerization of thiobenzanilides
leads to the corresponding sulfides by using PIDA as the oxidant.
The application of the resultant disulfides becomes our next focus
now.
4.5. Spectroscopic data of dimerization products 3
4.5.1. Bis(N-p-methylphenyltrifluoroacetimidoyl) disulfide (3a)
1H NMR (300 MHz, CDCl3): 7.17 (d, J = 8.2 Hz, 4H), 6.77 (d,
J = 8.2 Hz, 4H), 2.35 (s, 6H); 19F NMR (282 MHz, CDCl3):
d
À64.67 (s,
6F); 13C NMR (75 MHz, CDCl3):
d 148.8 (q, J = 35.6 Hz), 142.9, 136.7,
129.8, 119.2, 117.8 (q, J = 281.6 Hz), 21.0.
MS (EI): m/z (%): 436 (3.97) [M+], 186 (100.00); HRMS
Calculated for C18H14N2F6S2: 436.0503, Found: 436.0504; IR
4. Experimental
(film): n .
2925, 1631, 1503, 1278, 1185, 1151, 950 cmÀ1
4.1. General
4.5.2. Bis(N-p-methoxyphenyltrifluoroacetimidoyl) disulfide (3b)
1H NMR (300 MHz, CDCl3): 6.90 (s, 8H), 3.81 (s, 6H); 19F NMR
1H NMR spectra were recorded on
spectrometer (300 MHz) with TMS as internal standard. 19F
NMR spectra were taken on Bruker AM-300 (282 MHz)
a
Bruker AM-300
(282 MHz, CDCl3):
d
À64.54 (s, 6F); 13C NMR (75 MHz, CDCl3):
d
158.6, 147.3 (q, J = 35.6 Hz), 138.1, 121.7, 118.0 (q, J = 281.2 Hz),
114.2, 55.3; MS (EI): m/z (%): 468 (6.44) [M+], 202 (100.00); HRMS
Calculated for C18H14N2O2F6S2: 468.0401, Found: 468.0403; IR
a
spectrometer using CFCl3 as external standard. 13C NMR spectra
were taken on a Bruker AM-400 (100 MHz) spectrometer. IR
spectra were obtained with a Nicolet AV-360 spectrophotome-
ter. All reagents were used as received from commercial sources.
Column chromatography over silica gel (mesh 300–400) and
petroleum ether/ethyl acetate combination was used as the
eluent. The characterization data of the benzothiazoles could be
found in Ref. [11].
(film):
n
2949, 2846, 1630, 1504, 1464, 1277, 1250, 1161, 1033,
.
952 cmÀ1
4.5.3. Bis(N-phenyltrifluoroacetimidoyl) disulfide (3c)
1H NMR (300 MHz, CDCl3): 7.42–7.35 (m, 4H), 7.27–7.20 (m, 2H),
6.85 (d, J = 7.4 Hz, 4H); 19F NMR (282 MHz, CDCl3):
d
À64.78 (s, 6F);
13C NMR (100 MHz, CDCl3):
d 149.5 (q, J = 35.9 Hz), 145.5, 129.3,
126.6, 118.9, 117.8(q, J = 281.2 Hz);MS(EI):m/z(%):408(3.22)[M+],
4.2. General procedure for the synthesis of 2-
172 (100.00); HRMS Calculated for C16H10N2F6S2: 408.0190, Found:
408.0192; IR (film):
trifluoromethylbenzothiazoles 2 under CAN/NaHCO3 system
n .
2929, 1645, 1277, 1150, 1137, 955 cmÀ1
A
mixture of trifluoromethylated thiobenzanilides
1
4.5.4. Bis(N-p-iodophenyltrifluoroacetimidoyl) disulfide (3d)
(0.8 mmol) and CAN (920 mg, 1.68 mmol) in CH3CN (8 mL)
was stirred at 80 8C for 30 min. Then water (10 mL) was added
and the mixture was extracted with ethyl acetate (15 mL Â 2).
The organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was then
purified by column chromatography on silica gel using
petroleum ether/CH2Cl2 as eluent to provide the desired
product 2.
1H NMR (300 MHz, CDCl3): 7.72 (d, J = 8.8 Hz, 4H), 6.61 (d,
J = 8.8 Hz, 4H); 19F NMR (282 MHz, CDCl3):
d
À65.01 (s, 6F); 13C
NMR (100 MHz, CDCl3): d 149.9 (q, J = 36.7 Hz), 144.9, 138.4, 120.7,
117.6 (q, J = 282.0 Hz), 91.2; MS (EI): m/z (%): 660 (1.60) [M+], 298
(100.00); HRMS Calculated for C18H8N2F6S2I2: 659.8123, Found:
659.8127; IR (film):
n .
1635, 1476, 1278, 1150, 955 cmÀ1
4.5.5. Bis(N-p-chlorophenyltrifluoroacetimidoyl) disulfide (3e)
1H NMR (300 MHz, CDCl3): 7.36 (d, J = 8.5 Hz, 4H), 6.80 (d,
4.3. Spectroscopic data of 2-trifluoromethylbenzothiazoles 2
4.3.1. 2,6-Bis(trifluoromethyl)benzo[d]thiazole (2e)
1H NMR (300 MHz, CDCl3):
J = 8.8 Hz, 1H); 19F NMR (282 MHz, CDCl3):
(s, 3F); 13C NMR (100 MHz, CDCl3):
159.0 (q, J = 41.1 Hz), 153.9,
J = 8.5 Hz, 4H); 19F NMR (282 MHz, CDCl3):
d
À64.99 (s, 6F); 13C
NMR (75 MHz, CDCl3):
d 150.0 (q, J = 36.0 Hz), 143.7, 132.4, 129.5,
120.3, 117.6 (q, J = 281.6 Hz); MS (EI): m/z (%): 476 (2.76) [M+], 206
d
8.34–8.29 (m, 2H), 7.86 (d,
À62.32 (s, 3F), À62.43
(100.00); HRMS Calculated for C16H8N2F6S2Cl2: 475.9410, Found:
2917, 1634, 1483, 1279, 1154, 955 cmÀ1
475.9408; IR (film): n .
d
d
135.1, 129.8 (q, J = 33.7 Hz), 125.6, 124.3 (q, J = 3.0 Hz), 123.6 (q,
J = 272.2 Hz), 119.9 (q, J = 3.6 Hz), 119.4 (q, J = 273.6 Hz); MS (EI):
m/z (%): 271 (100.00) [M+]; HRMS Calculated for C9H3NF6S:
271.9890, Found: 271.9888.
4.5.6. Bis(N-o,o-dimethylphenyltrifluoroacetimidoyl) disulfide (3g)
1H NMR (300 MHz, CDCl3): 7.05–7.02 (m, 6H), 2.03 (s, 12H); 19
F
NMR (282 MHz, CDCl3):
CDCl3):
d
À64.75 (s, 6F); 13C NMR (100 MHz,
d
150.8 (q, J = 35.9 Hz), 128.4, 125.6, 125.0, 117.5 (q,
J = 281.2 Hz), 17.1; MS (EI): m/z (%): 464 (3.26) [M+], 200 (100.00);
4.3.2. 4-Methyl-2-(trifluoromethyl)benzo[d]thiazole (2j)
HRMS Calculated for C20H18N2F6S2: 464.0816, Found: 464.0815; IR
(film):
1H NMR (300 MHz, CDCl3):
d
7.76 (d, J = 7.5 Hz, 1H), 7.44–7.35
(m, 2H), 2.78 (s, 3H); 19F NMR (282 MHz, CDCl3):
À61.33 (s, 3F);
13C NMR (100 MHz, CDCl3):
154.5 (q, J = 40.1 Hz), 151.8, 135.3,
n .
2924, 1639, 1467, 1280, 1209, 1151, 955 cmÀ1
d
Acknowledgement
d
134.9, 127.6, 127.5, 120.0 (q, J = 271.3 Hz) 119.3, 18.1; MS (EI): m/z
(%): 217 (100.00) [M+]; HRMS Calculated for C9H3NF3S: 217.0173,
Found: 217.0174.
The authors thank the National Natural Science Foundation of
China (NNSFC) (20772145) for financial support.

J. Zhu et al. / Journal of Fluorine Chemistry 132 (2011) 306–309
309
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