A facile synthesis of 3-(chloromethyl)-2-methyl-1,1'-biphenyl

Article abstract of DOI:10.14233/ajchem.2019.22322

3-(Chloromethyl)-2-methyl-1,1′-biphenyl is a key intermediate for the preparation of bifenthrin, an insecticide which belongs to pyrethroid. The traditional synthetic process of 3-(chloromethyl)-2-methyl-1,1′-biphenyl is complicated and involves high-toxic and high-risk reagents such as thionyl chloride, lithium aluminum hydride and methyl iodide, which causes significant environmental problems and safety issues. Herein, a facile and efficient synthesis process of 3-(chloromethyl)-2- methyl-1,1′-biphenyl was developed. The synthetic process is shortened from 6 steps to only 4 steps and avoids the use of high-toxic and high-risk reagents. Moreover, 3-(chloromethyl)-2-methyl-1,1′-biphenyl can be obtained by simple purification process in high yield (73.9 %). Compared with the traditional synthetic process, the synthetic process of 3-(chloromethyl)-2-methyl-1,1′-biphenyl reported here is more environmental friendly and efficient.

Full text of DOI:10.14233/ajchem.2019.22322

Asian Journal of Chemistry; Vol. 31, No. 12 (2019), 3009-3011
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22322
A Facile Synthesis of 3-(Chloromethyl)-2-methyl-1,1′-biphenyl
1
1
1,2,*
LELE ZHANG , SONGBO CHENG , HANG HU1,* and DEFENG XU
1School of Pharmaceutical and Life Sciences, Changzhou University, Changzhou 213164, P.R. China
2National & Local Joint Engineering Research Center for High-Efficiency Refining and High-Quality Utilization of Biomass, Changzhou University,
Changzhou 213164, P.R. China
*Corresponding authors: Fax: +86 519 86334598; Tel: +86 519 86334597; E-mail: hanghu@cczu.edu.cn; markxu@cczu.edu.cn
Received: 10 July 2019;
Accepted: 20 September 2019;
Published online: 16 November 2019;
AJC-19655
3-(Chloromethyl)-2-methyl-1,1′-biphenyl is a key intermediate for the preparation of bifenthrin, an insecticide which belongs to pyrethroid.
The traditional synthetic process of 3-(chloromethyl)-2-methyl-1,1′-biphenyl is complicated and involves high-toxic and high-risk reagents
such as thionyl chloride, lithium aluminum hydride and methyl iodide, which causes significant environmental problems and safety issues.
Herein, a facile and efficient synthesis process of 3-(chloromethyl)-2- methyl-1,1′-biphenyl was developed. The synthetic process is
shortened from 6 steps to only 4 steps and avoids the use of high-toxic and high-risk reagents. Moreover, 3-(chloromethyl)-2-methyl-1,1′-
biphenyl can be obtained by simple purification process in high yield (73.9 %). Compared with the traditional synthetic process, the synthetic
process of 3-(chloromethyl)-2-methyl-1,1′-biphenyl reported here is more environmental friendly and efficient.
Keywords: Bifenthrin, Intermediate, Biphenyl, Bromination, Amination
O
INTRODUCTION
Cl
O
3-(Chloromethyl)-2-methyl-1,1′-biphenyl is a key inter-
mediate for the preparation of bifenthrin (Fig. 1), a pyrethroid
F
F
F
insecticide used primarily against the red imported fire ant by
influencing its nervous system [1-3]. The traditional synthetic
process of 3-(chloromethyl)-2-methyl-1,1′-biphenyl consists
of six steps (Scheme-I) [4] viz. (a) (1,1′-biphenyl)-2-carboxylic
acid was chlorinated with thionyl chloride in the presence of
pyridine to produce (1,1′-biphenyl)-2-carbonyl chloride; (b)
(1,1′-biphenyl]-2-carbonyl chloride was reacted with N,N-
dimethylformamide to produce N,N-dimethyl-(1,1′-biphenyl)-
2-carboxamide; (c) N,N-dimethyl-(1,1′-biphenyl)-2-carbo-
xamide was reduced by lithium aluminum hydride to produce
N,N-dimethyl-(1,1′-biphenyl)-2-methanamine; (d) N,N-dimethyl-
(1,1′-biphenyl)-2-methanamine was reacted with methyl iodide
to obtain N,N,N-trimethyl-(1,1′-biphenyl)-2-methanaminium
iodide; (e) N,N,N-trimethyl-(1,1′-biphenyl)-2-methanaminium
iodide was converted to N,N-dimethyl-2-methyl-(1,1′-biphenyl)-
3-methanamine in the presence sodium amide and liquid NH3 by
Sommelet-Hauser rearrangement; and finally (f) N,N-dimethyl-
2-methyl-(1,1′-biphenyl)-3-methanamine was chlorinated with
ethyl chloroformate to get the target compound 3-(chloromethyl)-
1
Fig. 1. Structure of bifenthrin
2-methyl-1,1′-biphenyl. The whole synthetic process is compli-
cated, which makes it difficult to control the quality of the synthe-
sized product. The synthetic process involves high-toxic and
high-risk reagents such as thionyl chloride, lithium aluminum
hydride and methyl iodide, causing considerable environmental
and safety problems. For example, use of thionyl chloride in
the first step can produce highly corrosive hydrogen chloride,
the use of lithium aluminum hydride in the third step can produce
explosive gas hydrogen [5] and methyl iodide as a methylation
reagent may have carcinogenic toxicity and neurotoxicity [6].
To overcome the deficiencies of the traditional synthetic
process, a facile and clean synthetic process of 3-(chloromethyl)-
2-methyl-1,1′-biphenyl is developed by using 2-methyl-1,1′-
biphenyl as the starting material. The synthetic process is
shortened to four steps and avoids the use of high-toxic and
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3010 Zhang et al.
Asian J. Chem.
CH3
N
CH3
N
Cl
O
O
HO
O
H3C
O
SOCl2
H3C
LiAIH4
CH3
CH3
N
H3C
H3C
O
N
H3C
H3C
Cl
O
N
CH3I
NH3
CH3
Cl
Scheme-I: Traditional synthetic process of 3-(chloromethyl)-2-methyl-1,1'-biphenyl from [1,1'-biphenyl]-2-carboxylic acid
high-risk reagents. Moreover, 3-(chloromethyl)-2-methyl-1,1′-
biphenyl can be obtained by simple purification process in high
overall yield.
Synthesis of N,N-dimethyl-2-methyl-[1,1'-biphenyl]-3-
methanamine (5): Briefly, N,N,N-trimethyl-(1,1′-biphenyl)-
2-methanaminium bromide (23 g, 75 mmol) and sodium amide
(5.7 g, 146 mmol) were slowly added to liquid NH3 (80 mL)
under -50 ºC and the resulting mixture was stirred at -50 ºC
for 4 h. The excess of sodium amide was neutralized by the
addition of an aqueous solution of ammonium chloride.After-
wards, the reaction mixture was extracted with ethyl acetate
(250 mL × 2). The extracts were combined and washed with
brine, dried over anhydrous sodium sulfate and evaporated
under vacuum to get compound 5 as light grey oily liquid
(14.9 g, 87.8 %). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.35
(m, 8 H,ArH), 3.49 (s, 2H, CH2), 2.34 (s, 6H, CH3), 2.30 (s, 3H,
CH3).
Synthesis of 3-(chloromethyl)-2-methyl-1,1′-biphenyl
(6): Briefly, N,N-dimethyl-2-methyl-(1,1′-biphenyl]-3-methan-
amine (20.7 g, 91.7 mmol) was dissolved in cyclohexane (80
mL) and heated to 80 ºC. To the solution, ethyl chloroformate
(14.9 g, 137.8 mmol) was slowly added under stirring and the
resulting mixture was stirred at 80 ºC for 3 h. The reaction
mixture was cooled to room temperature and filtrated. The filtrate
was evaporated under vacuum to give compound 6 as white
solid (18.7 g, 94.2 %). m.p. 53.2-56.3 ºC. 1H NMR (300 MHz,
DMSO-d6): δ (ppm) 7.43 (m, 8 H, ArH), 4.96 (m, 2H, CH2),
2.25 (m, 3H, CH3).
EXPERIMENTAL
Reagents and solvents were obtained from commercial
suppliers and used without further purification. The melting
points were determined on a XT34 binocular microscope (Beijing
Tech Instrument Co., China) and are not corrected. 1H NMR
spectra were recorded on Mercuryplus 300 MHz spectrometer.
Chemical shifts (δ) were given in parts per million (ppm) relative
to tetramethylsilane. Thin-layer chromatography (TLC) and
column chromatography were performed on silica gel GF254
and silica gel H60, respectively. The purity of synthesized comp-
ounds was determined by high performance liquid chromato-
graphy (HPLC, 1260 Infinity, Agilent).
Synthesis of 2-(bromomethyl)-1,1′-biphenyl (3): Briefly,
2-methyl-1,1′-biphenyl (13.9 g, 83 mmol), N-bromosucci-
nimide (NBS,19.6 g, 110 mmol), and tert-butyl hydroperoxide
(TBHP, 1.8 g, 20 mmol) were dissolved in cyclohexane (80
mL). Then, above mixture was heated to 42 ºC and maintained
at 42-45 ºC for 2 h. The reaction mixture was cooled to room
temperature and the formed succinic imide was removed by
filtration. The filtrate was evaporated under vacuum to yield
compound 3 as light yellow oily liquid (18.7 g, 91.2 % in yield).
1H NMR (300 MHz, DMSO-d6): δ (ppm) 7.45 (m, 9 H, ArH),
4.87 (s, 2H, CH2).
RESULTS AND DISCUSSION
Synthesis of N,N,N-trimethyl-[1,1′-biphenyl]-2-meth-
anaminium bromide (4): Briefly, 2-(bromomethyl)-1,1′-biphenyl
(16.8 g, 67.9 mmol) and trimethylamine (4.42 g, 74.7 mmol)
were dissolved in ethyl acetate (60 mL) and the resulting
mixture was stirred at 32 ºC for 3 h. Then, the reaction mixture
was cooled to room temperature and evaporated under vacuum
to give compound 4 as white solid (21.5 g, 98.0 % in yield).
m.p. 221.5-223.7 ºC (lit. [7], m.p. 220-225 ºC). 1H NMR (300
MHz, D2O): δ (ppm) 7.35 (m, 9 H, ArH), 4.51 (br s, 2H, CH2),
2.65 (br s, 9H, CH3).
3-(Chloromethyl)-2-methyl-1,1′-biphenyl was synthesized
from 2-methyl-1,1′- biphenyl through four steps (Scheme-II):
(a) 2-methyl-1,1′-biphenyl was brominated with NBS in the
presence of TBHP to produce 2-(bromomethyl)-1,1′-biphenyl
[8,9]; (b) 2-(bromomethyl)-1,1′-biphenyl was reacted with
trimethylamine to produce N,N,N-trimethyl-(1,1′-biphenyl)-
2-methanaminium bromide; (c) N,N,N-trimethyl-(1,1′-
biphenyl)-2-methanaminium bromide was converted to N,N-
dimethyl-2-methyl-(1,1′-biphenyl)-3-methanamine in the
presence of sodium amide and liquid NH3 by Sommelet-Hauser

Vol. 31, No. 12 (2019)
A Facile Synthesis of 3-(Chloromethyl)-2-methyl-1,1′-biphenyl 3011
.Br
N
Br
a.
b.
91.2%
98.0%
4
3
2
Cl
N
d.
c.
94.2%
87.8%
6
5
(a) NBS, TBHP, C6H6 (b) N(CH3)3, ethyl acetate (c) NaNH2, NH3(l), NH4Cl (d) ClCOOC2H5, C6H6
Scheme-II: Synthetic scheme of 3-(chloromethyl)-2-methyl-1,1'-biphenyl from 2-methyl-1,1'-biphenyl
rearrangement; and finally (d) N,N-dimethyl-2-methyl-(1,1′-
amination with trimethylamine, Sommelet-Hauser rearrange-
ment and chlorination with ethyl chloroformate. Compared
with the traditional synthetic process of 3-(chloromethyl)-2-
methyl-1,1′-biphenyl, present synthetic process exhibits several
advantages, including simplicity in amination, simplicity in
product purification, high overall yield (73.9 %) and environ-
mental friendly. The synthetic process reported here represents
a promising synthetic method for 3-(chloromethyl)-2-methyl-
1,1′-biphenyl.
biphenyl)-3-methanamine was chlorinated with ethyl
chloroformate to get the target compound 3-(chloromethyl)-
2-methyl-1,1′-biphenyl.
Liquid bromine is the most commonly used bromination
reagent, which shows high reactivity in bromination reactions
[10]. However, liquid bromine is hyper-toxic and corrosive,
which may cause serious safety problems in industrial produ-
ction. Therefore, NBS was selected as the bromination reagent.
Although the reactivity of NBS is lower than liquid Br2 in
bromination, however, it is more environmental friendly and
safer, and by-products are recyclable. The synthesis of 2-(bromo-
methyl)- 1,1′-biphenyl (3) by bromination of 2-methyl-1,1′-
biphenyl (2) with NBS achieved the yield of 91.2 %. N,N,N-
trimethyl-(1,1′-biphenyl)-2-methanaminium bromide (4) was
synthesized by amination of 2-(bromomethyl)-1,1′-biphenyl
(3) with trimethylamine, a very common and cheap raw material,
which resulted in good yield of 98.0 %. After simple filtration
and evaporation, the synthesized intermediates 3, 4, 5 and target
compound 6 can be obtained with high purities (3: 85.6 %; 4:
99.6 %; 5: 96.4 %; 6: 89.9 %) as determined by HPLC. The
overall yield of the target compound 6 is 73.9 %.
ACKNOWLEDGEMENTS
This work was financially supported by grants from Leader
Talents of High-level Entrepreneurial and Innovative Talent
Team of Jiangsu Province (Grant No. 2017-37).
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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In the present work, a facile synthetic process for 3-(chloro-
methyl)-2-methyl-1,1′-biphenyl, a key intermediate for the
preparation of bifenthrin is developed. 3-(Chloromethyl)-2-
methyl-1,1′-biphenyl was synthesized from 2-methyl-1,1′-
biphenyl through four steps, including bromination with NBS,
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