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

Abstract

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 NH 3 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-Bu 4 PCl gave a mixture of chlorofluoropicolinonitriles that could be resubjected to halex conditions to give additional 4,5,6-trifluoro-3-chloropicolinonitrile.

Catalyst-Free Hydrodefluorination of Perfluoroarenes with NaBH4

“…The preservation of the chlorine substituents at the meta positions, which is characteristic of nucleophilic displacements, contrasts with the trend of electron-transfer radical anion fragmentation hydrodehalogenations . Moreover, we observed that HDF can be completely blocked at a position by substitution with a heavier halogen, which is possible via the retrohalex reaction. ,, 4-Cl-tetra-F-nitrobenzene, in which the site of preferential fluoride fragmentation (4-F) has been replaced with 4-Cl, undergoes smooth double HDF with no evidence of chlorine cleavage to yield 20b , indicating that chlorine substitution will effectively block the innate regiochemical preference of the ring.…”

“…26 Moreover, we observed that HDF can be completely blocked at a position by substitution with a heavier halogen, which is possible via the retrohalex reaction. 26,43,44 4-Cl-tetra-F-nitrobenzene, in which the site of preferential fluoride fragmentation (4-F) has been replaced with 4-Cl, undergoes smooth double HDF with no evidence of chlorine cleavage to yield 20b, indicating that chlorine substitution will effectively block the innate regiochemical preference of the ring.…”

Design and Synthesis of “Chloropicolinate Amides and Urea Derivatives” as Novel Inhibitors for Mycobacterium tuberculosis

“…However, five compounds, 16 (6.96 μM), 19 (6.98 μM), 28 (7.00 μM), 22 (7.86 μM), and 10 (7.90 μM), showed good MIC values that are prominently exhibiting in vitro potency close to isoniazid and higher than ethambutol. Among the other compounds, 13,14,17,18,20,21,24,29,30,31, and 32 are also promising candidates based on their MIC values reported in Table 2 for the inhibitors of Mtb.…”

“… 16 , 17 Recently, highly potent 6-arylpicolinate herbicides, including 5 DAS-534, Arylex active, and Rinskor active, have been developed. 18 In fact, Rinskor and Arylex were commercially launched and exhibited very good control of broadleaf weeds. In the above herbicides, 16 − 18 the chloropicolinate amide heterocyclic moiety plays a crucial role in reducing weeds without affecting the immune system of the plants for maximum crop production.…”

Development of SNAr Nucleophilic Fluorination: A Fruitful Academia-Industry Collaboration

“…Instead the synthesis of 1-F requires substantial rerouting, which introduces several extra inefficient steps to the sequence. In particular, the fluorine is installed via an early stage nucleophilic aromatic (S N Ar) fluorination reaction that is low yielding (<20%) and produces multiple isomers and side products …”