Direct Aldehyde C–H Arylation and Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis

A mechanism that enables direct aldehyde C–H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis. This mild, operationally simple protocol transforms a wide variety of commercially available aldehydes, along with aryl or alkyl bromides, into the corresponding ketones in excellent yield. This C–H abstraction coupling technology has been successfully applied to the expedient synthesis of the medicinal agent haloperidol

Photoredox α‑Vinylation of α‑Amino Acids and <i>N</i>‑Aryl Amines

A new coupling protocol has been developed that allows the union of vinyl sulfones with photoredox-generated α-amino radicals to provide allylic amines of broad diversity. Direct C–H vinylations of <i>N</i>-aryl tertiary amines, as well as decarboxylative vinylations of <i>N</i>-Boc α-amino acids, proceed in high yield and with excellent olefin geometry control. The utility of this new allyl amine forming reaction has been demonstrated via the syntheses of several natural products and a number of established pharmacophores

Enantioselective Copper-Catalyzed Construction of Aryl Pyrroloindolines via an Arylation–Cyclization Cascade

An enantioselective arylation–cyclization cascade has been accomplished using a combination of diaryliodonium salts and asymmetric copper catalysis. These mild catalytic conditions provide a new strategy for the enantioselective construction of pyrroloindolines, an important alkaloid structural motif that is commonly found among biologically active natural products

Decarboxylative Arylation of α‑Amino Acids via Photoredox Catalysis: A One-Step Conversion of Biomass to Drug Pharmacophore

The direct decarboxylative arylation of α-amino acids has been achieved via visible light-mediated photoredox catalysis. This method offers rapid entry to prevalent benzylic amine architectures from an abundant biomass, specifically α-amino acid precursors. Significant substrate scope is observed with respect to both the amino acid and arene components

Enantioselective α-Vinylation of Aldehydes via the Synergistic Combination of Copper and Amine Catalysis

The enantioselective α-vinylation of aldehydes using vinyl iodonium triflate salts has been accomplished via the synergistic combination of copper and chiral amine catalysis. These mild catalytic conditions provide a direct route for the enantioselective construction of enolizable α-formyl vinylic stereocenters without racemization or olefin transposition. These high-value coupling adducts are readily converted into a variety of useful olefin synthons

Activation of C–H Bonds via the Merger of Photoredox and Organocatalysis: A Coupling of Benzylic Ethers with Schiff Bases

The photoredox-mediated coupling of benzylic ethers with Schiff bases has been accomplished. Direct benzylic C–H activation by a combination of a thiol catalyst with an iridium photocatalyst and subsequent radical–radical coupling with secondary aldimines affords a variety of β-amino ether products in good to excellent yields. Mechanistic studies suggest that a reductive quenching pathway of the photocatalyst is operable

Enantioselective α‑Alkenylation of Aldehydes with Boronic Acids via the Synergistic Combination of Copper(II) and Amine Catalysis

The enantioselective α-alkenylation of aldehydes has been accomplished using boronic acids via the synergistic combination of copper and chiral amine catalysis. The merger of two highly utilized and robust catalytic systems has allowed for the development of a mild and operationally trivial protocol for the direct formation of α-formyl olefins employing common building blocks for organic synthesis

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp³–sp² Cross-Coupling of Oxalates with Aryl Halides

Alkyl oxalates, prepared from their corresponding alcohols, are engaged for the first time as carbon radical fragments in metallaphotoredox catalysis. In this report, we demonstrate that alcohols, native organic functional groups, can be readily activated with simple oxalyl chloride to become radical precursors in a net redox-neutral C_sp³–C_sp² cross-coupling with a broad range of aryl halides. This alcohol-activation coupling is successfully applied to the functionalization of a naturally occurring steroid and the expedient synthesis of a medicinally relevant drug lead

Nine-Step Enantioselective Total Synthesis of (−)-Vincorine

A concise and highly enantioselective total synthesis of the akuammiline alkaloid (−)-vincorine has been accomplished. A key element of the synthesis is a stereoselective organocatalytic Diels–Alder, iminium cyclization cascade sequence, which serves to construct the tetracyclic alkaloid core architecture in one step from simple achiral precursors. The challenging seven-membered azepanyl ring system is installed by way of a single electron-mediated cyclization event initiated from an acyl telluride precursor. The total synthesis of (−)-vincorine is achieved in nine steps and 9% overall yield from commercially available starting materials

Fragment Couplings via CO₂ Extrusion–Recombination: Expansion of a Classic Bond-Forming Strategy via Metallaphotoredox

In this study we demonstrate that molecular fragments, which can be readily coupled via a simple, in situ ROCOR bond-forming reaction, can subsequently undergo metal insertion–decarboxylation–recombination to generate C_sp²–C_sp³ bonds when subjected to metalla­photo­redox catalysis. In this embodiment the conversion of a wide variety of mixed anhydrides (formed in situ from carboxylic acids and acyl chlorides) to fragment-coupled ketones is accomplished in good to high yield. A three-step synthesis of the medicinal agent edivoxetine is also described using this new decarboxylation–recombination protocol