Cascade Cyclization Yields New Herbicides

Highly functionalized picolinic acids are plant growth regulators used as broadleaf herbicides to control weeds that crop up in grain fields and pastures. In an effort to develop more potent versions of the herbicides and with an eye toward lowering their environmental impact, a research team at Dow AgroSciences has developed a new synthetic approach to making picolinic acids (Org. Lett. 2015, DOI: 10.1021/acs.orglett.5b01176). Peter L. Johnson, Gregory T. Whiteker, Natalie C. Giampietro, and coworkers first scoped out how to make 4-amino-3-chloro-5-fluoropicolinates (shown) that have alkyl or aryl groups (R) at the 6-position of the pyridine ring. Chemists previously had tried fluorinating aminopicolinic acids followed by a standard cross-coupling step to add the alkyl or aryl group but with limited success. The Dow researchers decided to try a cascade cyclization reaction strategy instead. They generated N-protected fluoroalkyl alkynylimine intermediates, treated the intermediates with a primary amine, and after deprotection and chlorination steps reached their target. The cascade cyclization reaction has been patented by Dow, and the team has already used it to synthesize Rinskor Active, a low-application-rate herbicide that is pending regulatory approval for use on rice and other crops.