Nickel Catalyst Alkylates Drug-Like Rings at Mild Temperatures

Chemists at Scripps Research, working with colleagues at Bristol Myers Squibb, have unveiled a nickel-catalysed method that can attach alkyl groups directly onto aromatic and heteroaromatic rings at temperatures no higher than 50 degrees Celsius, a temperature mild enough to preserve functional groups that would normally fall apart under the harsh conditions traditionally required for such transformations. The work, published in Nature Synthesis, addresses one of the most persistent bottlenecks in modern synthetic chemistry: how to forge carbon–carbon bonds between flat, drug-like ring systems and the three-dimensional alkyl fragments that medicinal chemists increasingly crave, without destroying the delicate molecular architecture already present in advanced intermediates.

The reaction relies on alkyl sulfonylhydrazides as the alkyl donors, a class of reagents that the team found can release alkyl radicals under remarkably gentle conditions. Conventional directed C–H alkylation protocols typically depend on alkyl halides or other electrophiles that demand elevated temperatures, strong bases, or aggressive activators to enter the catalytic cycle. By swapping in sulfonylhydrazide-derived donors, the researchers sidestepped that energetic barrier entirely. The hydrazide framework fragments to generate the carbon-centred radical directly, which is then captured within the nickel catalytic cycle, allowing the entire sequence to proceed below 50 degrees Celsius while remaining redox-neutral and operationally simple.

Directing groups sit at the heart of the strategy. The substrates carry an amide-type directing group that coordinates to nickel and positions the metal catalyst adjacent to the target C–H bond, enabling selective activation of the C(sp2)–H bond in arenes and heteroarenes. This chelation-assisted approach enforces site selectivity, so the alkylation occurs predictably at the position dictated by the directing group rather than at whichever reactive site happens to be most accessible. The team demonstrated the method on more than seventy examples, spanning simple benzamides through to heavily decorated heterocycles of the kind that populate the internal libraries of pharmaceutical companies.

The heterocycle compatibility is perhaps the feature that will resonate most strongly with practitioners of medicinal chemistry. Nitrogen-containing rings such as pyridines, pyrimidines, and related azines are ubiquitous in approved drugs, yet they are notoriously problematic substrates for metal-catalysed C–H functionalization because the ring nitrogen poisons many catalysts or redirects reactivity in unwanted ways. The Scripps team showed that the sulfonylhydrazide–nickel combination tolerates a wide range of these heteroaromatic systems, opening a practical route to alkylated heterocycles that previously required multi-step sequences or gave poor yields under existing protocols.

Beyond simple primary alkyl groups, the method accepts complex secondary alkyl donors, including fragments derived from elaborated building blocks, which dramatically expands its utility. Late-stage functionalization experiments demonstrated that the reaction can be performed on molecules already bristling with functional groups, appending an alkyl unit to a sophisticated scaffold without disturbing esters, ethers, halides, or other sensitive motifs. The researchers also applied the chemistry in the context of natural product synthesis, underscoring that the transformation is not merely a curiosity of model substrates but a genuinely useful tool for constructing molecules of real structural and biological complexity. The reaction was shown to be scalable, a further indication of its practical character.

Underpinning the synthetic scope is a mechanistic picture that the team assembled through a combination of experimental probes and computational analysis. Density functional theory calculations, alongside mechanistic experiments, point to an asynchronous, amine-assisted C–H activation pathway. Rather than proceeding through a single, synchronous transition state in which the C–H bond breaks in concert with metal–carbon bond formation, the activation appears to unfold in a stepwise, nonsynchronous fashion, with an amine component of the catalyst system assisting the deprotonation or proton-shuttling events that accompany metalation. This asynchronous character lowers the energetic cost of C–H cleavage, helping to explain why the reaction succeeds at such low temperatures where classical concerted metalation–deprotonation pathways would stall.

The choice of nickel as the catalyst metal is itself significant. Nickel has earned a reputation as the spirited workhorse of modern cross-coupling, prized for its abundance relative to palladium and its unusual willingness to engage radical intermediates. In this system, the sulfonylhydrazide-derived alkyl radicals are intercepted within the nickel manifold, and the mechanistic studies suggest that radical capture and C–H activation are choreographed within a single catalytic framework. The chemoselectivity observed across the substrate screen—where the reaction finds the directed C–H bond even in the presence of multiple potentially reactive sites—highlights how the interplay between the directing group, the nickel complex, and the gently generated radical donor produces a reaction that is both fast and discerning.

The broader context of this work is the long-running effort in the pharmaceutical industry to escape flatland. Decades of analyses of approved drugs and clinical candidates have shown that molecules richer in three-dimensional character, with more saturated carbon frameworks, tend to enjoy better clinical success rates, improved solubility, and more favourable promiscuity profiles. Yet most robust cross-coupling chemistry remains oriented toward joining flat fragments: aryl to aryl, aryl to vinyl. Methods that reliably weld sp2 ring systems to sp3 alkyl fragments remain comparatively scarce, and those that exist often require photoredox catalysts, electrochemical apparatus, elevated temperatures, or electrophilic alkyl halides that are themselves unstable or difficult to prepare. A thermal, redox-neutral, nickel-catalysed protocol that works below 50 degrees Celsius represents a meaningful addition to that limited toolbox.

The sulfonylhydrazide donor chemistry builds on recent demonstrations that these reagents can serve as a general redox-neutral platform for radical cross-coupling, but the present study extends that logic into the domain of directed C–H activation, where the substrate itself dictates where the new bond forms. The combination is powerful: the directing group provides the site selectivity, the nickel catalyst provides the bond-forming machinery, and the hydrazide reagent provides the alkyl fragment under the mildest possible activation conditions. Because the donors are straightforward to prepare from the corresponding hydrazines and carbonyl or sulfonyl precursors, practitioners can access a diverse panel of alkyl partners without exotic reagent synthesis.

For the synthetic community, the practical implications are immediate. A chemist seeking to methylate, ethylate, or append a branched alkyl group to a pyridine or benzamide scaffold can now contemplate a single-step operation conducted on a warm hotplate rather than a high-thermal or photochemical setup. The demonstrated scalability means medicinal chemistry campaigns can generate gram quantities of alkylated analogues for structure–activity studies, while the late-stage compatibility means proven lead compounds can be diversified without rebuilding them from scratch. As mechanistic understanding of amine-assisted, asynchronous C–H activation deepens, the design principles uncovered here are likely to inform the next generation of mild, selective, and sustainable C–H functionalization methods, bringing the long-promised efficiency of direct C–H chemistry closer to routine practice in laboratories focused on discovering the medicines of tomorrow.

Subject of Research: Mild nickel-catalysed directed C(sp2)–H alkylation of (hetero)arenes using alkyl sulfonylhydrazide radical donors

Article Title: Chemoselective Ni-catalysed directed C(sp2)–H alkylation at low temperature using alkyl sulfonylhydrazides

Article References: Wang, S., Cagan, D. A., Cao, Y., Vokits, B. P., Palkowitz, M. D., Kawamata, Y., Baran, P. S., & Engle, K. M. (2026). Chemoselective Ni-catalysed directed C(sp2)–H alkylation at low temperature using alkyl sulfonylhydrazides. Nature Synthesis. https://doi.org/10.1038/s44160-026-01158-6

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01158-6

Keywords: nickel catalysis, C–H activation, C–H alkylation, sulfonylhydrazides, radical cross-coupling, heterocycles, late-stage functionalization, medicinal chemistry, organometallic chemistry, directing groups, Nature Synthesis, asynchronous mechanism