Yanan Qiu, Haining Gu, Pengfei Zhang
Nov 20, 2009
Citations
0
Influential Citations
2
Citations
Quality indicators
Journal
Organic Preparations and Procedures International
Abstract
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 easilyperformed synthesis. Lang et al.3 had developed a cross-coupling reaction of 2-fluoro-4bromoiodobenzene 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 nitrite and an organic4 or inorganic acid5 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. As part of our research program on the study of diazotizing systems,6 we have developed and now report a practical pilot-scale method for the preparation of 2-fluoro-4bromobiphenyl (Scheme 1) from methyl nitrite and 2-fluoro-4-bromoaniline, easily prepared by bromination of 2-fluoroaniline according to the literature procedure.4 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 generation previously described by us6 is reproduced in this article. Proper precautions and a good hood should be used.