Bicyclopentylation of Alcohols with Thianthrenium Reagents.

Herein we present the first method for the synthesis of bicyclo[1.1.1]pentyl (BCP) alkyl ethers from alcohols. The reaction uses BCP-thianthrenium reagents and is catalyzed by a dual copper/photoredox catalyst system. Unlike known alkylations of tertiary alcohols via carbocation intermediates, our Cu-mediated radical process circumvents the labile BCP carbocations. The approach demonstrates a broad tolerance for functional groups when applied to primary, secondary, and even tertiary alcohols. In addition, we highlight the utility of this method in late-stage functionalizations of both natural products and pharmaceuticals as well as in the rapid construction of BCP analogs of known pharmaceuticals that would otherwise be difficult to access.

Bifunctional sulfilimines enable synthesis of multiple N-heterocycles from alkenes.

Intramolecular cyclization of nitrogen-containing molecules onto pendant alkenes is an efficient strategy for the construction of N-heterocycles, which are of paramount importance in, for example, pharmaceuticals and materials. Similar intermolecular cyclization reactions, however, are scarcer for nitrogen building blocks, including N-centred radicals, and divergent and modular versions are not established. Here we report the use of sulfilimines as bifunctional N-radical precursors for cyclization reactions with alkenes to produce N-unprotected heterocycles in a single step through photoredox catalysis. Structurally diverse sulfilimines can be synthesized in a single step, and subsequently engage with alkenes to afford synthetically valuable five-, six- and seven-membered heterocycles. The broad and diverse scope is achievable by a radical-polar crossover annulation enabled by the bifunctional character of the reagents, which distinguishes itself from all other N-centred-radical-based reactions. The modular synthesis of the sulfilimines allows for larger structural diversity of N-heterocycle products than is currently achievable with other single cyclization methods.

ß-Lactam Synthesis via Copper-Catalyzed Directed Aminoalkylation of Unactivated Alkenes with Cyclobutanone O-Benzoyloximes.

A new protocol for amide-directed Cu-catalyzed aminoalkylation of unactivated alkenes using cyclobutanone oxime esters as alkyl radical donors is developed. Both primary and secondary alkyl groups can be selectively installed at the C4 position of terminal or cis-internal 3-alkenamides in moderate to good yield. This reaction offers a useful method for the diastereoselective synthesis of ß-lactams bearing 4-cyanoalkyl ß-substituents. The use of a weakly coordinating counteranion as the Cu catalyst is critical for the formation of ß-lactam products.

Enantioselective Alkylamination of Unactivated Alkenes under Copper Catalysis.

An enantioselective addition reaction of various alkyl groups to unactivated internal alkenes under Cu catalysis has been developed. The reaction uses amide-linked aminoquinoline as the directing group, 4-alkyl Hantzsch esters as the donor of alkyl radicals, and rarely used biaryl diphosphine oxide as a chiral ligand. ß-lactams featuring two contiguous stereocenters at Cß and the ß substituent can be obtained in good yield with excellent enantioselectivity. Mechanistic studies indicate that a nucleophilic addition of the alkyl radical to CuII-coordinated alkene is the enantio-determining step.

Palladium-Catalyzed Amide-Directed Enantioselective Hydrocarbofunctionalization of Unactivated Alkenes Using a Chiral Monodentate Oxazoline Ligand.

A Pd-catalyzed amide-directed enantioselective hydrocarbofunctionalization of unactivated alkenes with C-H nucleophiles has been developed using a chiral monodentate oxazoline (MOXin) ligand. Various indoles react at C3 position with aminoquinoline-coupled 3-alkenamides to give γ addition products in good to excellent yield and enantioselectivity. This study represents an important advance of the development of chiral monodentate oxazoline ligands, which have been underexplored for asymmetric catalysis.