Christopher B. Kelly

Arylboronic esters are indispensable intermediates in synthesis. We report a direct deaminative borylation of anilines enabled by anomeric amide activation with copper catalysis. The transformation proceeds via in situ generation of aryl radicals from isodiazene intermediates, followed by interception with a Cu–Bpin species derived from bis(pinacolato)diboron. Key to the success of this process is the use of an N-fluorosulfonamide oxidant, which promotes copper catalyst turnover and generates an electrophilic radical competent for polarity-matched hydrogen-atom transfer with the isodiazene intermediate. The method operates under mild conditions, tolerates electron-neutral and electron-rich anilines, and is applicable to pharmaceutically relevant substrates. The resulting aryl boronates can be further elaborated through oxidation or Suzuki–Miyaura cross-coupling, enabling modular C–C bond formation from simple aniline precursors.

Metallocarbenes are powerful intermediates for constructing complex molecular architectures, yet their generation typically relies on hazardous diazo or ylide precursors. We report photocatalytic and electrochemical strategies for direct carbene formation from unmodified carbonyl compounds using a low-valent iron system. The reaction proceeds through net oxidative addition of Fe(I) into the carbonyl bond, followed by α-protonation and α-elimination to generate a reactive Fe–carbene intermediate. This platform enables cyclopropanation of diverse alkenes─including complex, drug-like, and amino-acid-derived substrates─under mild conditions, delivering highly functionalized, sp³-rich products. Mechanistic studies reveal direct carbonyl activation rather than free radical intermediacy, with a concerted–asynchronous olefin addition pathway. These findings establish a general strategy for carbonyl-to-carbene conversion, expanding the scope of base-metal catalysis and providing a blueprint for redefining carbonyl activation in synthetic chemistry.

The KRASG12C mutation is a critical therapeutic target in the management of solid tumors, owing to its role in oncogenic signaling. Recent advances in covalent inhibitors that target mutant KRAS cysteine-12 have demonstrated the potential to halt aberrant signaling associated with this historically “undruggable” target. Here, we report the identification of 6-cyanoquinazoline covalent irreversible KRASG12C inhibitors. Lead optimization used structure-based design to identify novel switch-II pocket-binding motifs and in silico models to forecast in vitro metabolic stability and permeability. Human dose was improved by maximizing the rate of covalent modification (kobs/[I]) of KRASG12C-GDP, along with optimizing ADME parameters, to identify potent, orally bioavailable lead molecule 13de which demonstrated significant antitumor efficacy in the NCI-H1373 human lung adenocarcinoma xenograft model. Studies evaluating KRASG12C-GDP covalent target engagement, pharmacokinetics, and tumor growth inhibition estimated the efficacious human dose of 13de to be 192 mg administered once daily (QD), using allometric scaling.

Herein, we report a new, highly selective copper-catalyzed synthesis of unsymmetrical N-aryl pyrazoles from 1,2,3-thiadiazine S-oxides (TDSOs) and diaryl iodonium electrophiles. The regiochemical outcome is determined by the choice of the copper catalyst and base, in contrast with typical substrate-controlled approaches. This "switchable" approach enables access to either pyrazole isomer from a given starting material, with high selectivity observed in each case. The scope of both protocols is broad and amenable to automation, thus facilitating the rapid generation of a medicinally relevant, diverse pyrazole library. Experimental and computational mechanistic studies reveal the origin of selectivity for each protocol and rationalize the role of base identity, base concentration, and copper ligation state in determining the regiochemical outcome. Overall, this approach addresses long-standing synthetic challenges in the preparation of unsymmetrical N-aryl pyrazoles and provides important mechanistic foundations for the development of further switchable pyrazole syntheses.

Couple-close as a synthetic paradigm has the potential to change the way that synthetic organic chemists approach cyclic scaffold construction. One class of cyclic molecules that has been increasingly sought after is semisaturated cyclic scaffolds, whose specific blend of Csp ² - and Csp ³ -hybridized components confers distinct properties to these species. However, existing methods to construct these scaffolds are limited, often relying on arene saturation or annulations that require lengthy de novo syntheses. Herein, we describe a unified and highly modular couple-close strategy for the synthesis of semisaturated scaffolds. This approach installs bifunctional linkers onto aromatic rings through a range of bond-forming reactions, and subsequent cyclization furnishes semisaturated bicyclic adducts. Key to this approach is a mechanistically distinct cobalt-catalyzed dehydrogenative radical cyclization that proceeds efficiently even on electronically unbiased arenes, enabling a broad substrate scope under mild reaction conditions.

Herein we report a new, highly selective copper-catalyzed synthesis of unsymmetrical N-aryl pyrazoles from 1,2,3-thiadiazine-S-oxides (TDSOs) and diaryl iodonium electrophiles. The regiochemical outcome is determined by the choice of copper catalyst and base, in contrast to typical substrate-controlled approaches. This “switchable” approach enables access to either pyrazole isomer from a given starting material with high selectivity observed in each case. The scope of both protocols is broad and is amenable to automation, thus facilitating rapid generation of a medicinally relevant, diverse pyrazole library. Experimental and computational mechanistic studies reveal the origin of selectivity for each protocol, and rationalize the role of base identity, base concentration and copper ligation state in determining the regiochemical outcome. Overall, this approach addresses long-standing synthetic challenges in the preparation of unsymmetrical N-aryl pyrazoles and provides important mechanistic foundations for the development of further switchable pyrazole syntheses.

Radical addition reactions have become an indispensable tool for constructing carbon-carbon bonds in organic chemistry. Given the significance of these processes, it is imperative that the underlying rules governing odd electron C-C bond forming processes be better understood. This study explores the fundamental case of methyl radical addition reaction (MRAR) to monosubstituted ethylene derivatives (H₂C_β═C_αHR, with R = H, CHO, and NMe₂) using Density Functional Theory at ZORA-(U)OLYP/TZ2P. We quantitatively analyzed the factors governing regioselectivity and substituent effects using the Activation Strain Model and Energy Decomposition Analysis. Regarding regioselectivity, radical addition@β is universally favored over addition@α due to reduction in the buildup of unfavorable Pauli repulsion (ΔE_Pauli) and maximization of orbital interactions (ΔE_oi) with the β-carbon. Substituents modulate reactivity through electronic effects: NMe₂ (a representative electron-donating group) and CHO (a representative electron-withdrawing group) lower activation barriers with respect to the unsubstituted reactions due to improved orbital interactions. Among the substituents, CHO lowers the activation barrier for radical addition more than NMe₂ due to a change in the orbital interaction mechanism. By linking qualitative theories like Frontier Molecular Orbital Theory with detailed computational insights, this work advances the mechanistic understanding of radical addition reactions and provides a physically sound and intuitive basis for understanding these key transformations.