The difluoromethyl group (R-CFH) imparts desirable pharmacokinetic properties to drug molecules and is commonly targeted as a terminal functional group that is not amenable to further modification. Deprotonation of widely available Ar-CFH starting materials to expose nucleophilic Ar-CF synthons represents an unexplored, yet promising route to construct benzylic Ar-CF-R linkages. Here we show that the combination of a Brønsted superbase with a weak Lewis acid enables deprotonation of Ar-CFH groups and capture of reactive Ar-CF fragments. This route provides access to isolable and reactive Ar-CF synthons that react with a broad array of electrophiles at room temperature. The methodology is highly general in both electrophile and difluoromethyl (hetero)arene and can be applied directly to the synthesis of benzylic difluoromethylene (Ar-CF-R) linkages, which are useful lipophilic and metabolically resistant replacements for benzylic linkages in medicinal chemistry.
A fluoroform-derived borazine CF transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives, within minutes at 25 °C. Inorganic electrophiles spanning seven groups of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes, enabling C-H and C-X trifluoromethylation reactions. Mechanistic analysis supports a dissociative mechanism for CF transfer, and cation modification afforded a reagent with enhanced stability.
When subjected to arylboranes, anionic
trifluoromethyl and difluorobenzyl
palladium(II) complexes undergo fluoride abstraction followed by 1,1-migratory
insertion. The resulting intermediate fluoroalkyl species can be induced
to undergo a subsequent transmetalation and reductive elimination
from either an in situ formed fluoroboronate (FB(Ar3)−) or an exogenous boronic acid/ester (ArB(OR)2) and nucleophilic activator, representing a net defluorinative
arylation reaction. The latter method enabled a structurally diverse
substrate scope to be prepared from either an isolated palladium-CF3 complex, or from Pd(PPh3)4 and other
commercially available reagents.
Af luoroform-derived borazine CF 3 À transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives,w ithin minutes at 25 8 8C. Inorganic electrophiles spanning seven groups of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes,e nabling C À Ha nd C À X trifluoromethylation reactions.M echanistic analysis supports ad issociative mechanism for CF 3 À transfer,a nd cation modification afforded ar eagent with enhanced stability. À reagents. The countercation in 2 is K(18-crown-6) + .
Using nucleophilic, boron-based –CF2Ar reagents, we demonstrate three methods to form C–CF bonds: (1) nucleophilic aromatic substitution, (2) palladium catalyzed cross-coupling, and (3) nucleophilic substitution.
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