A practical synthesis of 2-fluoro-4-bromobiphenyl

Full text of DOI:10.1080/00304940903328219

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Organic Preparations and Procedures
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A Practical Synthesis of 2-Fluoro-4-
bromobiphenyl
a
a
a
b
Ya-Yu Qiu , Haining Gu , Peng-Fei Zhang & Wei-Ming Xu
a
College of Material Chemistry and Chemical Engineering, Hangzhou
Normal University (Xiasha Campus), Hangzhou, 310036, P. R. China
b
Center of Analysis and Measurement, Zhejiang University, (Xixi
Campus), Hangzhou, P. R. China
Published online: 20 Nov 2009.
To cite this article: Ya-Yu Qiu , Haining Gu , Peng-Fei Zhang & Wei-Ming Xu (2009): A Practical
Synthesis of 2-Fluoro-4-bromobiphenyl, Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 41:6, 539-541
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Organic Preparations and Procedures International, 41:539–541, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903328219
A Practical Synthesis of 2-Fluoro-4-bromobiphenyl
1
1
2
2
Ya-Yu Qiu, Haining Gu, Peng-Fei Zhang, and Wei-Ming Xu
1College of Material Chemistry and Chemical Engineering, Hangzhou Normal
University (Xiasha Campus) Hangzhou 310036, P. R. China
2
Center of Analysis and Measurement, Zhejiang University (Xixi Campus),
Hangzhou, P. R. China
2
-Fluoro-4-bromobiphenyl (2) is the key intermediate for the manufacture of flurbiprofen,1,2
a non-steroidal anti-inflammatory and analgesic material. Though compound 2 is a useful
molecule, a review of the literature, including patents, indicated the absence of an easily-
3
performed synthesis. Lang et al. had developed a cross-coupling reaction of 2-fluoro-4-
bromoiodobenzene with phenylboronic acid to obtain 2-fluoro-4-bromobiphenyl in good
yield (87%). However, the high cost associated with the use (and removal) of palladium
and toxic phenylboronic acid have limited the more widespread use of such protocol in
large-scale production. Alternatively, diazotization of 2-fluoro-4-bromoaniline with sodium
4
5
nitrite and an organic or inorganic acid has commonly been used to generate the diazonium
salt for coupling with benzene. However, in spite of all precautions the formation of dark
decomposition products is unavoidable thus lowering the yield and making the product
difficult to isolate.
6
As part of our research program on the study of diazotizing systems, we have de-
veloped and now report a practical pilot-scale method for the preparation of 2-fluoro-4-
bromobiphenyl (Scheme 1) from methyl nitrite and 2-fluoro-4-bromoaniline, easily pre-
4
pared by bromination of 2-fluoroaniline according to the literature procedure. Methyl
nitrite is a toxic, volatile, heat-sensitive potentially explosive gas that is not commercially
available; its transport is prohibited in the U.S. and the European Union. Therefore its
6
generation previously described by us is reproduced in this article. Proper precautions and
a good hood should be used.
Scheme 1
Submitted June 4, 2009.
Address correspondence to Wei-Ming Xu, College of Material Chemistry and Chemical Engi-
neering, Hangzhou Normal University (Xiasha Campus), Hangzhou 310036, P. R. China. E-mail:
wmxu@zju.edu.cn
539

540
Qiu et al.
7
The above process is efficient, no acid is used during the diazotization, and the reaction
6
mixture is easy to work up because of the use of methyl nitrite. In this reaction, proper
control of temperature is important to maintain an adequate reaction rate and satisfactory
yield.
Experimental Section
Mps and bps are uncorrected. The purity of products was established on an Agilent
1
1
100 HPLC. H NMR spectra were recorded in CDCl3 on a Bruker 400 (400 MHz)
instrument with TMS as internal standard. Infrared spectrum was obtained as a KBr pel-
let on a Shimadzu IR-408 instrument. All chemicals were reagent grade and available
commercially. The elemental analysis was performed on a Flash EA1112 instrument.
Methyl Nitrite (prepared just prior to use)
In a 500 mL round-bottomed flask, fitted with a pressure equalizing addition funnel filled
with 125 mL 12M hydrochloric acid, and a gas tube in a well ventilated hood, was placed
8
6.3 g (1.25 mol) of sodium nitrite, 70 mL methanol and 125 mL water. The temperature
◦
was raised to 35 C and hydrochloric acid was added dropwise over 1.5 h. The colorless
methyl nitrite evolved was passed through a water trap to remove acid and then bubbled
through the reaction mixture below via the gas tube.
2-Fluoro-4-bromobiphenyl
In a 3 L round-bottomed flask, fitted with a mechanical stirrer, and a gas tube in a
well-ventilated hood, was placed 224.0 g (1.18 mol) of 2-fluoro-4-bromoaniline, 15.0
◦
g (0.15 mol) CuCl and 2 L benzene. The temperature was raised to 43 C and methyl nitrite
(
76.3 g, 1.25 mol, generated as described above) was added through the tube for about 1.5 h
◦
while the temperature was kept between 43–47 C by means of water bath. When the reaction
was complete, the temperature was raised to 50 C and the mixture was stirred for another
◦
20 min. to expel excess methyl nitrite. The mixture was then cooled to room temperature,
washed with 1500 mL water and dried over MgSO4. Benzene was then removed by distil-
◦
lation and recycled. The residue was evaporated under vacuum (105–107 C/0.5 mmHg) to
◦
afford 222.0 g (75%) of the product as a white solid, mp. 36–37 C (HPLC >98.5%).
1
13
H NMR (DMSO-d6): δ 7.31–7.55 (8 H, m). C NMR (DMSO-d6): δ 159.4 (J =
2
1
50.4 Hz), 134.7, 131.7 (J = 3.4 Hz), 128.8, 128.7, 128.5, 128.2 (J = 13.1 Hz), 128.0,
27.7, 127.6, 121.2 (J = 9.0 Hz), 119.7 (J = 26.2 Hz). An analytical sample was prepared by
◦
4
◦
recrystallization from benzene and methanol (v/v 5/95), mp. 36.5–37 C, lit. mp. 36–37 C.
Anal. Calcd for C12H8BrF: C, 57.40; H, 3.21. Found: C, 57.24; H, 3.13.
Acknowledgment
We thank the National Natural Science Foundation of China (Grant No. 20602029) and
the Science and Technology Foundation of Zhejiang Province (Grant No. 2007C11014) for
financial support.

Practical Synthesis of 2-Fluoro-4-bromobiphenyl
541
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