Maximilian D. Palkowitz

Diversity-oriented synthesis (DOS) has emerged as an efficient strategy for constructing diverse compound libraries, facilitating hit or lead identification in the drug discovery process. In parallel, developing diverse transformations at different sites is an appealing strategy to expand the diversity of appendages on scaffolds. Owing to the availability of C-H bonds at multiple sites of pharmacophores, diversity-oriented C-H activation reactions are an ideal approach to realize this goal. Given the pharmacophoric significance of the naphthalene scaffold in clinical drugs, diversity-oriented C-H functionalization reactions on this scaffold would be useful for drug discovery. Direct C-H activation at the challenging C6 and C7 positions has remained unexplored due to electronic similarity, remote distance from the directing group, and interference from geometrically identical positions (C7 vs C3, C6 vs C4). Herein, we report two types of templates designed to differentiate the C6 and C7 positions on the naphthalene scaffold. The success is attributed to manipulation of the distance parameter in the template and the utilization of an oligopeptide ligand. Notably, the utility of this diversity-oriented C-H activation is showcased through the divergent modification of naphthalene-containing complex molecules.

The hit-to-lead phase of drug discovery is frequently bottlenecked by the time-consuming, iterative synthesis of analogs, especially when incorporating small C(sp3)-rich fragments such as methyl, cyclopropyl, or oxetanyl groups—moieties known to improve drug solubility, bioactivity, and metabolic stability. Conventional approaches like Suzuki or Negishi couplings suffer from unstable reagents, high costs, and harsh reaction conditions, while many modern radical-based methods rely on exogenous redox agents or costly metal catalysts. To overcome these limitations, a toolbox of 15 sulfonyl hydrazide reagents is disclosed to facilitate redox-neutral, nickel- catalyzed radical cross-coupling of 14 distinct small fragments onto (hetero)arenes under mild conditions. These crystalline, bench-stable reagents are straightforward to synthesize from accessible precursors and require no additional oxidants, reductants, or precious metals, offering a modular and operationally simple platform. Demonstrated across a diverse set of over 60 (hetero)aryl halides, the method exhibits exceptional substrate scope and functional group tolerance, accommodating complex, medicinally relevant scaffolds. Comparative studies with existing techniques underscore its advantages, including a 51% yield for trideuteromethylation of a MET kinase inhibitor precursor (versus a precedented 14% via Kumada coupling) and a streamlined one-step cyclobutylation of an NLRP3 inhibitor intermediate at 41% yield (versus a known <5% over a four-step sequence). By accelerating analog synthesis for hit-to-lead optimization and enabling late-stage functionalization of drug-like molecules, this sulfonyl hydrazide toolbox is a useful resource for synthetic and medicinal chemistry, with significant potential to advance drug discovery and beyond.

Sulfonyl hydrazides are stable and usually crystalline substances that can be accessed in a variety of ways, including transiently from hydrazones, to achieve a net reductive arylation of carbonyl compounds. We show their utility as versatile radical precursors, as exemplified with seven C–C bond–forming, redox-neutral cross-couplings with activated olefins, alkyl halides, redox-active esters, aryl halides, alkenyl halides, alkynyl halides, and a trifluoromethylating reagent, to forge C(sp ³ )-C(sp ³ ), C(sp ³ )-C(sp ² ), and C(sp ³ )-C(sp) bonds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary because these functional groups serve the dual role of radical precursor and electron donor. The homogeneous, water-compatible reaction conditions are operationally simple and contribute to streamlining synthesis and mild late-stage functionalization.

Disclosed herein is the invention of a method for facile C–H alkylation of a range of (hetero)arenes under Ni-catalysis. This reaction takes place at 50 °C, is scalable, tolerates heterocyclic substrates, and can be applied to both primary and complex secondary alkyl donors. Success hinges on the use of sulfonylhydrazide-based alkyl donors that mildly generate alkyl radicals thereby obviating the need for alkyl halide precursors that require more harsh conditions to activate. The demonstrated substrate scope is broad (>70 examples), and the reaction was also applied to natural product synthesis. Mechanistic studies (both computational and experimental) suggest that an asynchronous, amine-assisted C–H activation pathway is operative which may have larger implications for the field.

A simple protocol for the Buchwald-Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse cereblon binding motifs is disclosed. The development of this C-N cross-coupling method was enabled by high-throughput combinatory screening of solvents, bases, temperatures, and ligands. Scope studies revealed generality across various heteroaryl and aryl halides with the reaction proceeding under mild conditions. In comparison, this method demonstrated strategic superiority over previously reported approaches, as evidenced by a significant decrease in step count from known syntheses in the patent literature.

Sulfonyl hydrazides are disclosed as versatile radical precursors as exemplified with seven new C–C bond forming, redox neutral cross-couplings with: (1) unsaturated olefins, (2) alkyl halides, (3) redox active esters, (4) aryl halides, (5) alkenyl halides, (6) alkynyl halides, and (7) a trifluoromethylating reagent to forge C(sp3)-C(sp3), C(sp3)-C(sp2), and C(sp3)-C(sp) bonds. Sulfonyl hydrazides are stable and usually crystalline substances that can be accessed in a variety of ways including transiently from hydrazones to achieve a net reductive arylation of carbonyl compounds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary as these functional groups serve the dual role of radical precursor and electron donor. The operational simplicity (homogeneous, water tolerant, dump-and-stir) and practicality of the method are demonstrated as well as applications to streamlining synthesis and mild late-stage functionalization.

Increasingly complex, three-dimensional leads for drug discovery are testing the limits of modern organic synthesis. In this context, the need for new methods to access gem-diarylated cyclobutanes, azetidines, and oxetanes is apparent. The present study outlines a modular, scalable, chemoselective approach to solve this problem using simple a-bromoacids and aryl halides as intuitive starting materials. As demonstrated herein, a sequential series of Ni-electrocatalytic cross-couplings can be enlisted to enable rapid access to such structures, many of which have never been accessible before, without recourse to time-consuming polar bond disconnections that are inherently limiting in terms of accessible chemical space. The scalability of this new reaction sequence is demonstrated, alongside direct applications to known patented structures. A simple user guide is also presented to accelerate adoption of this strategy in medicinal chemistry.

A simple protocol for the direct Buchwald-Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse Cereblon Binding Motifs is disclosed. This C-N cross-coupling method development was enabled by high throughput combinatory screening of key reaction parameters namely solvents, temperatures and ligands. Scope studies revealed generality across various heteroaryl and aryl halides, with the reaction proceeding under mild conditions. In comparison, this method demonstrated strategic superiority over previously reported approaches, as evidenced by a significant step count reduction from known syntheses in the patent literature.

Pd(COD)(DQ) (COD=1,5-cyclooctadiene, DQ=duroquinone) is a robust, air-stable, and well-defined 18-electron Pd(0)–olefin complex first synthesized by Sakai et al. in 1983. Herein, we describe an operationally convenient synthetic procedure to prepare this complex on decagram scale; we show that it undergoes facile ligand exchange with phosphines, N-heterocyclic carbenes, and other catalytically important ancillary ligands to give stable organometallic products; and we demonstrate its catalytic competence in numerous useful reactions in organic synthesis. We anticipate that the pronounced stability of Pd(COD)(DQ) and its favorable handling properties will allow it to find use as a convenient Pd(0) source in academic and industrial research labs.