Palladium-Catalyzed Aryldifluoromethylation of Aryl Halides with Aryldifluoromethyl Trimethylsilanes.

Diaryl difluoromethanes are valuable targets for medicinal chemistry because they are bioisosteres of diaryl ethers and can function as replacements for diaryl methane, ketone, and sulfone groups. However, methods to prepare diaryl difluoromethanes are scarce, especially methods starting from abundant aryl halides. We report the Pd-catalyzed aryldifluoromethylation of aryl halides with aryldifluoromethyl trimethylsilanes (TMSCF2 Ar). The reaction occurs when the catalyst contains a simple, but unusual, dialkylaryl phosphine ligand that promotes transmetallation of the silane. Computational studies show that reductive elimination following transmetallation occurs with a low barrier, despite the fluorine atoms on the α-carbon, due to coordination of the difluorobenzyl π-system to palladium. The co-development of a cobalt-catalyzed synthesis of the silanes broadened the scope of the process including several applications to the synthesis biologically relevant diaryl difluoromethanes.

Unusual Electronic Effects of Ancillary Ligands on the Perfluoroalkylation of Aryl Iodides and Bromides Mediated by Copper(I) Pentafluoroethyl Complexes of Substituted Bipyridines.

Several perfluoroalkylcopper compounds have been reported previously that serve as reagents or catalysts for the perfluoroalkylation of aryl halides. However, the relationships between the reactivity of such complexes and the electronic properties of the ancillary ligands are unknown, and such relationships are not well-known in general for copper complexes that mediate or catalyze cross coupling. We report the synthesis and characterization of a series of pentafluoroethylcopper(I) complexes ligated by bipyridine ligands possessing varied electronic properties. In contrast to the limited existing data on the reactivity of L2Cu(I)-X complexes bearing amine and pyridine-type ligands in Ullmann-type aminations with aryl halides, the reactions of aryl halides with pentafluoroethylcopper(I) complexes bearing systematically varied bipyridine ligands were faster for complexes bearing less electron-donating bipyridines than for complexes bearing more electron-donating bipyridines. Analysis of the rates of reaction and the relative populations of the neutral complexes [(R2bpy)CuC2F5] and ionic complexes [(R2bpy)2Cu][Cu(C2F5)2] formed by these reagents in solution suggests that this effect of electronics on the reaction rate results from an unusual trend of faster oxidative addition of aryl halides to [(R2bpy)CuC2F5] complexes containing less electron-donating R2bpy ligands than to those containing more electron-donating R2bpy ligands.

Lithium BINOL phosphate catalyzed desymmetrization of meso-epoxides with aromatic thiols.

A highly enantioselective method for desymmetrization of meso-epoxides using thiols is reported. This is the first example of epoxide activation achieved using metal BINOL phosphates. The reaction has a broad scope in terms of epoxide substrates and aromatic thiol nucleophiles. The resulting ß-hydroxyl sulfides are obtained in excellent yield and enantioselectivity.

Pd-catalyzed α-arylation of trimethylsilyl enolates of α,α-difluoroacetamides.

We report the arylation and heteroarylation of α,α-difluoro-α-(trimethylsilyl)acetamides with aryl and heteroaryl bromides catalyzed by an air- and moisture-stable palladacyclic complex containing P(t-Bu)2Cy as ligand. A broad range of electronically varied aryl and heteroaryl bromides underwent this transformation to afford α-aryl-α,α-difluoroacetamides in high yields. Due to the electrophilicity of the fluorinated amide, this palladium-catalyzed cross-coupling reaction provides a versatile platform to generate a range of α,α-difluoro carbonyl compounds, such as α-aryl-α,α-difluoroketones, -acetaldehydes, -acetates, and acetic acids, and difluoroalkyl derivatives, such as 2-aryl-2,2-difluoroethanols and -ethylamines, under mild conditions.

Copper-mediated perfluoroalkylation of heteroaryl bromides with (phen)CuRF.

The attachment of perfluoroalkyl groups onto organic compounds has been a major synthetic goal over the past several decades. Previously, our group reported phenanthroline-ligated perfluoroalkyl copper reagents, (phen)CuRF, which react with aryl iodides and aryl boronates to form the corresponding benzotrifluorides. Herein the perfluoroalkylation of a series of heteroaryl bromides with (phen)CuCF3 and (phen)CuCF2CF3 is reported. The mild reaction conditions allow the process to tolerate many common functional groups. Perfluoroethylation with (phen)CuCF2CF3 occurs in somewhat higher yields than trifluoromethylation with (phen)CuCF3, creating a method to generate fluoroalkyl heteroarenes that are less accessible from trifluoroacetic acid derivatives.

Chiral phosphoric acid-catalyzed addition of thiols to N-acyl imines: access to chiral N,S-acetals.

The first catalytic asymmetric method to prepare enantioenriched N,S-acetals using chiral BINOL phosphoric acids is reported. The reaction combines N-acyl imines with thiols to generate products in excellent yield and enantioselectivity. The addition reaction could also be achieved with an exceptional substrate to catalyst (S/C) molar ratio. Electron-rich and electron-deficient aromatic N-acyl imines, as well as a broad range of aliphatic and aromatic thiols, showed excellent reactivity.

Chiral magnesium BINOL phosphate-catalyzed phosphination of imines: access to enantioenriched α-amino phosphine oxides.

A new method to synthesize chiral α-amino phosphine oxides is reported. The reaction combines N-substituted imines and diphenylphosphine oxide and is catalyzed by a chiral magnesium phosphate salt. A wide variety of aliphatic and aromatic aldimines substituted by electron-neutral benzhydryl or dibenzocycloheptene groups were excellent substrates for the addition reaction. The dibenzocycloheptene protected imines afforded improved enantioselectivity in the resulting products. Substituted diphenylphosphine oxide nucleophiles also showed good reactivity.