A concise and convenient synthesis of 4-(trifluoromethylthio)aniline

Article abstract of DOI:10.14233/ajchem.2017.20138

4-(Trifluoromethylthio)aniline, a key agricultural intermediate, can be synthesized from 4-nitrobromobenzene. First 4-nitrothioanisole was obtained by the methylthiotriazine of 4-nitrobromobenzene with sodium salt of methyl mercaptan in the presence of phase-transfer catalyst in a 91.4 % yield; then 4-(trifuroromethylthio)nitrobenzene was produced through chlorination in a 83.7 % yield and fluorination in a 86.3 % yield; finally the hydrogenation in the presence of Pd/C can afford 4-(trifluoromethylthio)aniline with a 98 % yield.

Full text of DOI:10.14233/ajchem.2017.20138

Asian Journal of Chemistry; Vol. 29, No. 1 (2017), 91-93
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2017.20138
A Concise and Convenient Synthesis of 4-(Trifluoromethylthio)aniline
*
SHUNZE GONG, XINHONG CAI, HAO FU and DEFENG XU
School of Pharmaceutical and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, P.R. China
*
Corresponding author: Fax: +86 519 86334598; Tel: +86 519 86334597; E-mail: markxu@cczu.edu.cn
Received: 14 June 2016; Accepted: 6 September 2016; Published online: 29 October 2016;
AJC-18104
4
-(Trifluoromethylthio)aniline, a key agricultural intermediate, can be synthesized from 4-nitrobromobenzene. First 4-nitrothioanisole
was obtained by the methylthiotriazine of 4-nitrobromobenzene with sodium salt of methyl mercaptan in the presence of phase-transfer
catalyst in a 91.4 % yield; then 4-(trifuroromethylthio)nitrobenzene was produced through chlorination in a 83.7 % yield and fluorination
in a 86.3 % yield; finally the hydrogenation in the presence of Pd/C can afford 4-(trifluoromethylthio)aniline with a 98 % yield.
Keywords: Methylthiotriazine, Chlorination, Fluorination, Hydrogenation, Phase translation catalyst.
INTRODUCTION
EXPERIMENTAL
4
-(Trifluoromethylthio)aniline (7), a useful compound as
Reagents and solvents were obtained from commercial
suppliers and were used without further purification. Melting
points were determined on a XT34 binocular microscope
(Shanghai Tech Instrument Co., China) and were not corrected.
a production intermediate, such as pesticides, agricultural
chemicals and pharmaceutical industries [1-4]. It is a key
intermediate for the preparation of toltrazuril (1) and anilino-
triazoles (2). Toltrazuril is widely used in chickens, turkeys,
pigs and cattle for prevention and treatment of coccidiosis, by
administration via drinking water [5-7]. Anilinotriazoles a
novel potential insecticidal and acaricidal agent showed potent
bioactivities [8]. Several syntheses of 4-(trifluoromethylthio)-
aniline (7) had also been reported in the literature [2,9]. Most
of methods used were trifluoromethyl copper reagent for
trifluoromethylation and iron powder for reduction [2].A large
quantity of iron mud pollution was produced in the iron powder
reduction [10]. A clean and environmentally friendly hydro-
genation technique needs to be used. This paper reported a
convenient and efficient synthesis of 4-(trifluoromethylthio)-
aniline utilizing methylthiotriazine, chlorination, fluorination
and environment friendly hydrogenation reduction reaction
using Pd/C catalyst in good yield.
1
H NMR spectra were recorded on Mercury plus 400 (300
MHz) spectrometer, chemical shifts (δ) were reported in parts
per million relative to tetramethylsilane. Chemical shifts were
reported in parts per million relative to the solvent resonance
19
as the internal standard (CDCl
with internal standard (PhOCF
3
, δ = 7.16 ppm). F NMR assays
or PhF or PhCF ). Analytical
3
3
TLC and column chromatography were performed on silica
gel GF254 and silica gel H60, respectively. The following solvent
mixtures were used: cyclohexane/ethyl acetate (3:1), cyclo-
hexane/ethyl acetate (2:1), spots were visualized by short-wave
UV light and iodine vapour.
4-Nitrothioanisole (4): A mixture of 4-nitrobromoben-
zene (3) (60.6 g, 0.30 mol), 20 % methyl mercaptan sodium
salt in water (116 g, 0.33 mol), tetrabutyl ammonium bromide
(4.8 g, 0.015 mol) and acetone (250 mL) was stirred at room
temperature for 10 min. Then the resulting mixture was heated
to reflux and left for 5 h.After the reaction finished, the acetone
was removed in vacuo. The residue was then cooled to room
temperature, poured into ice-water (350 mL) and stirred for
0.5 h. The solid precipitate was filtered off, washed with cold
water and dry in vacuum. Recrystallized from ethanol to give
a bright yellow solid 4-nitrothioanisole (4) (Scheme-I) (46.4 g)
SCF
3
O
R
N
3
R
4
O
N
6 m
(R )
N
N
N
NH
R
1
N
R5
1
in 91.4 % yield, m.p.: 65-67 °C (lit. [12]; m.p.: 68-71 °C). H
R2
S
(
O
O
O)n
NMR (300 MHz, CDCl
(d, J = 9.1 Hz, 2H), 2.53 (s, 3H).
3
): δ = 8.11 (d, J = 9.1 Hz, 2H), 7.26
Toltrazuril (1)
Anilinotriazoles (2)

9
2 Gong et al.
Asian J. Chem.
4
-Nitrophenyl trichloromethylsulfide (5): A mixture of
RESULTS AND DISCUSSION
4
-nitrothioanisole (25.4 g, 0.15 mol), chloroform (250 mL)
and 2,2'-azo-bis-isobutyronitrile (0.65 g, 4.0 mmol) was stirred
at room temperature for 10 min. The resulting mixture was
heated to reflux. Then, chlorine gas was bubbled through the
resulting mixture during vigorous stirring for 3 h. After the
completion of the reaction, chlorine gas was stopped introducing.
Pass into nitrogen gas; extrude the excess chlorine gas and
hydrogen chlorine. The reaction solution was poured into 100
mL of ice water, The chloroform layer was separated, washed
twice with water and saturated brine and the organic phase
was washed with non-anhydrous sodium sulfate and evaporated
to dryness in chloroform to give the product of 4-nitrophenyl
Recently, we studied a novel oxadiazine insecticide SICO-
047 using a key intermediate 4-(trifluoromethylthio)aniline
(7), which showed that the efficient synthesis of 4-nitrophenyl
trifluoromethylsulfide (6) with hydrogen in the presence of
Pd/C catalyst can produce 4-(trifluoromethylthio) aniline in
very high yields. Meantime, the optimization of the synthetic
conditions for 4-nitrothioanisole (4), 4-nitrophenyl trichloro-
methylsulfide (5) and 4-nitrophenyl trifluoromethylsulfide (6)
were conducted.
There were several methods to prepare 4-nitrothioanisol.
It was reported to obtain 4-nitrothioanisol by the methylating
of thiophenolate [12,15], the nitration of 4-(methylthio)bromo-
benzene under copper MOFs as catalysts [16], or the methyl-
thiotriazine of 4-nitrobromobenzene [17]. A phase-transfer
catalyst can accelerate the reaction process. It was found that
the phase transfer catalyst tetrabutylammonium bromide can
improve the methylthiotriazine of 4-nitrobromobenzene. The
yield of methylthiotriazine was 91.4 %.
trichloromethylsulfide (5) (34.2 g) in 83.7 % yield, m.p.: 65-
1
6
7 °C (lit. [13] m.p.: 71-72 °C). H NMR (300 MHz, CDCl
3
,
ppm), δ = 8.33 (m, 2H), 7.99 (m, 2H).
-Nitrophenyl trifluoromethylsulfide (6): A mixture of
-nitrophenyl trichloromethylsulfide (40.9 g, 0.15 mol),
antimony trifluoride (30 g, 0.17 mol) and dichloromethane
275 mL) was stirred at room temperature for 10 min in a 500 mL
4
4
(
polytetrafluoroethylene reactor. Then the resulting mixture was
heated to 55-60 °C and stirred for 3 h.After the reaction finished,
the reaction solution was poured into 1000 mL ice-water, the
organic phase was separated and washed with saturated brine
two times and the organic phase was dried over anhydrous
sodium sulfate and the solvent was evaporated to give the crude
product of 4-nitrophenyl trifluoromethylsulfide. Recrystallized
from hot ethanol to give a brown crystals of 4-nitrophenyl
There were a few ways for halogenation such as free radical
halogenation, electrophilic halogenation and halogen addition
reaction. In this paper, it was used the chlorination with chlorine
gas in presence of 2,2'-azo-bis-iso-butyronitrile as catalyst and
fluorination with antimony trifluoride. The process is more
suitable for a large-scale preparation in 72.2 % yields.
The traditional reducing process usually adopts iron
powder reduction, which produces the serious pollution of iron
mud. The hydrogenation reduction technique is an environ-
ment friendly process in the chemical industry. The 4-nitro-
phenyl trichloromethylsulfide was treated with hydrogenation
reduction using Pd/C catalyst to give 4-(trifluoromethylthio)-
aniline in 98 % yields (Scheme-I).
trifluoromethylsulfide (6) (28.9 g) in 86.3 % yields, m.p.: 92-
1
9
2.5 °C (lit. [14]; m.p.: 94 °C). H NMR (300 MHz, CDCl
3
,
ppm), δ, 8.32 (dd, J = 8.38, J = 2.14, 2H). 7.89 (dd, J = 8.38,
1
9
J = 2.14, 2H). F NMR (220 MHz, CDCl
3
), δ = 41.4 (s, 3F,
SCF
3
).
4
-Aminophenyl trifluoromethylsulfide (7): To a solution
Conclusion
of 4-nitrophenyl trifluoromethylsulfide (6) (33.5 g, 0.15 mol)
in ethanol (400 mL) was added palladium on carbon (10 %
Pd/C, 3.5 g). The mixture was hydrogenated under 40 atmos-
pheric pressure at room temperature for 8 h. After completion
of the reaction, the reaction mixture was filtered through celite
and thoroughly washed with ethanol. The filtrate was evapo-
rated and the residue washed with water to give 28.4 g in a
8 % yield of 4-aminophenyl trifluoromethylsulfide (7) as
a brown liquid. b.p.: 110-112 °C/1.70 KPa (lit. [14]; b.p.:
13 °C/1.73 KPa). H NMR (300 MHz, CDCl
J = 8.30, 2H), 7.42 (dd, J = 8.30, J = 1.90, 2H); 3.84 (s, 2H,
The Pd/C catalyst is an environment friendly process for
the hydrogenation of 4-nitrophenyl trichloromethylsulfide. A
convenient and concise process for the synthesis of 4-(trifluoro-
methylthio)aniline has been proven to be practical, This synthesis
method presents a promising synthetic process for 4-(trifluoro-
methylthio)aniline because of the following advantages: (i)
high yield because of phase transfer catalytic availability in
methylthiotriazine, (ii) simplicity of process in chlorination,
fluorination and hydrogenation, (iii) recycling of solvent, (iv)
the experiment process reported in this paper can be easily
developed into large-scale preparation of 4-(trifluoromethylthio)-
aniline.
9
1
1
3
), δ = 7.62 (d,
19
13
NH
2
). F NMR (220 MHz, CDCl
NMR (75 MHz, CDCl
3
): δ: 44.5 (s, 3F, SCF ). C
3
3
): δ 149.1, 138.2, 126.7, 115.3, 111.3.
CH3
CCl3
CF3
CF
Br
3
S
S
S
S
a
1.4%
d
b
3.7%
c
9
8
86.3%
98.0%
NO2
NO2
NO2
NO2
NH
2
(3)
(4)
(
5)
(6)
(7)
a. CH SNa, (C H ) NBr, acetone
b. Cl , CHCl , AIBN c. SbF , ClCH CH Cl d. H , Pd/C, EtOH
3
4
9 4
2
3
3
2
2
2
Scheme-I

Vol. 29, No. 1 (2017)
A Concise and Convenient Synthesis of 4-(Trifluoromethylthio)aniline 93
8
.
Y. Watanabe, J. Mihara, D.Yamazaki, K. Shibuya, E. Shimojo andA. Emoto,
Insecticidal and Acaricidal Anilinotriazoles, Patent WO2006099957
(A1) (2006).
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