Ligand‐Controlled Regiodivergent Palladium‐Catalyzed Decarboxylative Allylation Reaction to Access α,α‐Difluoroketones

Abstract

α,α-Difluoroketones possess unique physicochemical properties that are useful for developing therapeutics and probes for chemical biology. In order to access the α-allyl-α,α-difluoroketone substructure, complementary Pd-catalyzed decarboxylative allylation reactions were developed to provide linear and branched α-allyl-α,α-difluoroketones. For these orthogonal processes, the regioselectivity was uniquely controlled by fluorination of the substrate and the structure of ligand.

Palladium‐Catalyzed Decarboxylative Asymmetric Allylic Alkylation: Development, Mechanistic Understanding and Recent Advances

“…More recently, Altman reported a regiodivergent decarboxylative allylation forming α,α‐difluoro ketones (Scheme A) . The regioselectivity of the reaction could be controlled by changing the ligand, using either the bulky t‐ BuBrettPhos ligand 72 to give linear products, or the more electron‐deficient PhXPhos ligand 73 to form branched products.…”

Palladium Catalysis Enables Benzylation of α,α‐Difluoroketone Enolates

“…Although recently reported reactions have coupled α,α-difluoroketone enolates with aryl [15] and allyl electrophiles, [16] never has a Pd-based catalytic system effectively promoted the benzylation reaction of α,α-difluoroketone enolates (Table 1A). In this reaction, a decarboxylative strategy would chemoselectively generate the appropriate α,α-difluoroenolate, and the critical C(α)–C(sp 3 ) bond would form by reductive elimination from a high-energy L n Pd(benzyl)(α, α-difluoroenolate) intermediate (Table 1B, A ).…”

Ligand-Controlled Regioselective Copper-Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)allenes

“…Propargyl electrophiles, including –Br, 7–9 –Cl, 8–11 –OMs, 12 –OTs, 10 –OAc, 13 and –O 2 CCF 2 X (X = F, Cl, Br), 8,14,15c react using either catalytic 11,15c or stoichiometric 7–10,12–14 “Cu–CF 3 ” to generate propargyl and/or allenyl products with minimal control of regiochemistry. Unsubstituted propargyl electrophiles provide trifluoromethylallene; 9,10,14 however, reactions of substituted substrates display distinct selectivities.…”

“…In our own work aimed at developing decarboxylative strategies for fluoroalkylation, 15 we reported a CuI/ N,N’ -dimethylethylenediamine catalyzed trifluoromethylation reaction of propargyl bromodifluoroacetates to generate propargyl trifluoromethanes preferentially. 15c For this reaction, a wide variety of N-, O- and P-based ligands provided propargyl products with modest regioselectivity (Figure 1A).…”

“…15c For this reaction, a wide variety of N-, O- and P-based ligands provided propargyl products with modest regioselectivity (Figure 1A). However, the use of 1,10-phenanthroline-based and 2,2’-bipyridine-based ligands reversed the regioselectivity of the transformation, and afforded trifluoromethylallene 3 with high regioselectivity (Figure 1B).…”