The original synthesis of a CCR6 antagonist and subsequent enablement for kilogram manufacture is presented. Highlighted improvements made in the preparation for the scale-up campaign include (1) a re...

An organocatalyst containing boronic acid and phosphine oxide groups enables the coupling of carboxylic acids and amines at room temperature to achieve a sustainable route to the amide bonds present i...

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General procedures for the rhodium-catalyzed annulation of aryl/heteroaryl O-pivaloyl hydroxamic acids and norbornadiene have been developed. Employing norbornadiene as an acetylene equivalent enables...

A facile approach to obtaining densely functionalized cyclopropanes is described. The reaction proceeds under mild conditions via the directed nucleopalladation of nonconjugated alkenes with readily a...

Heteroatom insertions into chemically inert carbon–carbon single bonds are rare compared to their unsaturated analogues. Now, ligand-to-metal charge transfer offers a promising entry point for oxygen ...

New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicina...

The hydroxypicolinamide family of ligands has previously demonstrated utility in Cu-catalyzed C–N couplings and hydroxylation of heteroaryl halides. The application of these ligands has been extended ...

Single-atom skeletal editing has recently emerged as a powerful strategy for the direct diversification of the heterocyclic cores of various compounds. Yet, methods that enable monocycle-to-bicycle tr...

A decagram-scale preparation of the key intermediate (±)-2-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine is described. Key steps involve a double nucleophilic substitution of 3-bromocate...

Aryl alkyl sulfones are an important class of compounds in drug discovery; thus, new methods toward their synthesis are desirable. A general sulfur fluoride exchange (SuFEx) method to couple aryl sulf...

The well documented difficulties associated with direct (hetero)arylation of aza-aromatics (e.g., azines) at the α-position to nitrogen led to a collaborative project between the Willis group at Oxfor...

It is introduced in this report a unified toolbox comprising of 15 sulfonyl hydrazide reagents that enable the redox-neutral radical cross-coupling of 14 distinct C(sp3)-rich small fragments onto (he...

A linker fragment used in the preparation of an oncology candidate is efficiently synthesized via Cu-catalyzed C–N coupling. The original route required a Cu-catalyzed coupling, followed by an oxidati...

We present a metal-free strategy to access fluoroalkyl–olefin linkages from fluoroalkane precursors and vinyl-pinacol boronic ester (BPin) reagents. This reaction sequence is templated by the boron re...

A strategy utilizing gem-bis(boronates) as a stable and easily accessible surrogate for the analogous monoboronate and their efficient use in Suzuki–Miyaura cross-couplings to access the highly intere...

Hydroxylation of haloarenes is a fundamental transformation in synthetic organic chemistry. Hydroxypicolinamide ligands enable the efficient Cu-catalyzed hydroxylation of heteroaryl halides with a wide functional group tolerance. The Cu-MPBS system, originally designed for C–N coupling, enables the Cu-catalyzed hydroxylation of aryl bromides. A related derivative, Cu-HMPS, provides exceptional reactivity and purity for hydroxylation of aryl bromides, aryl iodides, and activated aryl chlorides. Ortho-activated substrates have shown exceptionally high reactivity and selectivity for Cu-catalyzed hydroxylation. More difficult aryl chlorides, substrates that require a higher activation temperature (120 °C), may be hydroxylated by the Cu-DMPS system that has superior intrinsic ligand stability. Reaction conditions may be tuned to target substrates through ligand, solvent, and base selection. Safe and robust processing conditions have been designed utilizing aqueous KOH, K2CO3, or K3PO4 in sulfolane or sulfolane and alcohol blends.

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The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional pola...

In the presence of a chiral palladium-based catalyst, 1,4-diboryl-2-alkenes undergo enantioselective cross-coupling that results in desymmetrization of the substrate structure. Depending on the reaction conditions and the choice of ligand, the reaction can occur with cis or trans selectivity, allowing the construction of an array of different substituted chiral carbocycles in an enantiomerically enriched fashion.

Metallaphotoredox chemistry has emerged as a powerful tool to access synthetically challenging motifs in a rapid and efficient manner. Generally, photoredox catalysis is recognized as a green technology, avoiding highly reactive chemicals and using ambient temperatures. Nevertheless, solvent choice is often overlooked with commonly used hazardous sulfoxides, ethers, and amides such as DMF or DMAc. Herein, we emphasize the importance of sustainable solvents in photoredox chemistry and their application to process chemistry. We present alternative conditions for two of the most utilized photocatalytic reactions in the pharmaceutical industry.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)–C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous liga...

A method to assemble (hetero)aryl sulfonamides via the reductive coupling of aryl sulfinates and nitroarenes is reported. Various reducing conditions with sodium bisulfite and with or without tin(II) ...

Cyclopropanes play an important role in drug discovery, and synthetic access to variedly substituted systems is an ongoing challenge for chemistry teams. A variety of scalable synthetic routes were de...