Synthesis of 6‑Aryl-5-fluoropicolinate Herbicides via Halex Reaction of Tetrachloropicolinonitrile

The development of a new synthesis of 6-aryl-5-fluoropicolinate herbicides is described. This general route employs the halogen exchange (halex) reaction of tetrachloropicolinonitrile to give a mixture of chlorofluoropicolinonitriles. It was found that the isomeric purity of the trifluorochloropicolinonitrile fraction increased, with eventual conversion to tetrafluoropicolinonitrile. The desired product of this reaction, 3-chloro-4,5,6-trifluoropicolinonitrile, reacted with NH3 regioselectively at the 4-position. Introduction of the aryl substituent was accomplished by initial conversion of the 6-fluoro substituent to 6-bromo using HBr in acetic acid followed by Pd-catalyzed Suzuki–Miyaura cross-coupling. The moderate regioselectivity of the halex reaction of tetrachloropicolinonitrile was studied computationally using a modified G3MP2B3* ab initio method. These computations were in agreement with the observed regioselectivity of the reaction. Recycle of the main byproduct, tetrafluoropicolinonitrile, was shown to be possible by two routes. The reverse halex reaction of tetrafluoropicolinonitrile using LiCl in DMSO gave a mixture of chlorofluoro products. In addition, scrambling of halogens between tetrafluoropicolinonitrile and tetrachloropicolinonitrile using catalytic n-Bu4PCl gave a mixture of chlorofluoropicolinonitriles that could be resubjected to halex conditions to give additional 4,5,6-trifluoro-3-chloropicolinonitrile.