Scalable Synthesis of p ‐Difluorobenzene, o ‐Difluorobenzene and 1, 2, 4‐Trifluorobenzene

ABSTRACT p ‐Difluorobenzene, o ‐difluorobenzene and 1, 2, 4‐trifluorobenzene are core raw materials for the synthesis of fluorinated pharmaceuticals, pesticides, dyes, and functional materials and there are numerous synthesis methods available. However, most of these methods have certain problems and shortcomings, such as the use of expensive raw materials, toxic and harmful reagents. To address these issues, we reported a scalable synthesis method of p ‐difluorobenzene ( 1 ), o ‐difluorobenzene ( 2 ) and 1, 2, 4‐trifluorobenzene ( 3 ), which involved two concise steps. In this process, the first step contains the reaction of p ‐fluoroaniline ( 7 ), o ‐fluoroaniline ( 8 ), and 2, 4‐difluoroaniline ( 9 ) with sodium nitrite to yield p ‐fluorodiazonium salt ( 4 ), o ‐fluorodiazonium salt ( 5 ), and 2, 4‐difluorodiazonium salt ( 6 ). The second step includes thermal decomposition fluorination to produce 1 , 2 , and 3 with good quality and an overall yield greater than 60%. The optimized process has been successfully demonstrated at large scale and can supply key raw materials for pharmaceutical and pesticide development.