Copper-Catalyzed, Chloroamide-Directed Benzylic C-H Difluoromethylation.

We report herein the first catalytic strategy to harness amidyl radicals derived from N-chloroamides for C-C bond formation, allowing for the discovery of the first catalytic benzylic C-H difluoromethylation. Under copper-catalyzed conditions, a wide variety of N-chlorocarboxamides and N-chlorocarbamates direct selective benzylic C-H difluoromethylation with a nucleophilic difluoromethyl source at room temperature. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage difluoromethylation of bioactive molecules. This copper-catalyzed, chloroamide-directed strategy has also been extended to benzylic C-H pentafluoroethylation and trifluoromethylation. Mechanistic studies on the difluoromethylation reactions support that the reactions involve the formation of benzylic radicals via intramolecular C-H activation, followed by the copper-mediated transfer of difluoromethyl groups to the benzylic radicals.

Csp3-Csp3 Bond-Forming Reductive Elimination from Well-Defined Copper(III) Complexes.

Carbon-carbon bond-forming reductive elimination from elusive organocopper(III) complexes has been considered the key step in many copper-catalyzed and organocuprate reactions. However, organocopper(III) complexes with well-defined structures that can undergo reductive elimination are extremely rare, especially for the formation of Csp3-Csp3 bonds. We report herein a general method for the synthesis of a series of [alkyl-CuIII-(CF3)3]- complexes, the structures of which have been unequivocally characterized by NMR spectroscopy, mass spectrometry, and X-ray crystal diffraction. At elevated temperature, these complexes undergo reductive elimination following first-order kinetics, forming alkyl-CF3 products with good yields (up to 91%). Both kinetic studies and DFT calculations indicate that the reductive elimination to form Csp3-CF3 bonds proceeds through a concerted transition state, with a Δ H⧧ = 20 kcal/mol barrier.

Copper-Catalyzed Decarboxylative Difluoromethylation.

We report herein a highly efficient Cu-catalyzed protocol for the conversion of aliphatic carboxylic acids to the corresponding difluoromethylated analogues. This robust, operationally simple and scalable protocol tolerates a variety of functional groups and can convert a diverse array of acid-containing complex molecules to the alkyl-CF2H products. Mechanistic studies support the involvement of alkyl radicals.

Copper-Mediated Trifluoromethylation of Benzylic Csp3 -H Bonds.

Trifluoromethyl-containing compounds play a significant role in medicinal chemistry, materials and fine chemistry. Although direct C-H trifluoromethylation has been achieved on Csp2 -H bonds, direct conversion of Csp3 -H bonds to Csp3 -CF3 remains challenging. We report herein an efficient protocol for the selective trifluoromethylation of benzylic C-H bonds. This process is mediated by a combination CuIII -CF3 species and persulfate salts. A wide range of methylarenes can be selectively trifluoromethylated at the benzylic positions. A combination of experimental and theoretical mechanistic studies suggests that the reaction involves a radical intermediate and a CuIII -CF3 species as the CF3 transfer reagent.

Approaches for Conjugating Tailor-Made Polymers to Proteins.

A series of methods are outlined for attaching functional polymers to proteins. Polymers with good control over structure, functionality, and composition can be created using reversible addition-fragmentation chain transfer (RAFT) polymerization. These polymers can be covalently linked to enzymes and proteins using either the "grafting-to" approach, where a preformed polymer is attached to the protein surface, or the "grafting-from" approach, where the polymer is grown from the protein surface. Methods for grafting-to, or attaching the RAFT chain transfer agent to the protein surface outlined include the commonly used carbodiimide/activated ester (EDC/NHS) coupling. Methods are also outlined to graft-from the surface of the protein using RAFT polymerization. Additionally, it is possible to site specifically introduce a reactive azide group to the protein surface using enzymatic ligation as a posttranslational modification. This reactive azide group can be conjugated to an alkyne-containing polymer using highly efficient click chemistry. These robust protocols can produce protein-polymer conjugates with various architectures and functionalities. Methods are also outlined for characterization of the resulting bioconjugates.