The investigation of the stereoelectronic influence of N-aryl substituted NHC ligands on Ni(0) is reported. The structural analysis of a family of [(NHC)­Ni­(styrene)2] complexes are correlated to known literature parameters (TEP and %V Bur). The analysis involved NMR spectroscopic techniques and X-ray crystallography analysis of the isolated [(NHC)­Ni­(styrene)2] complexes. The synthesis and characterization of this user-friendly and easy accessible Ni(0) precatalysts can be realized in a two-step synthesis starting from deprotonation of the imidazolium salt followed by direct coordination onto nickel in the presence of excess styrene.

This manuscript describes a mild, functional group tolerant, and metal-free C−H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. This demonstrates a significant expansion of the accessible chemical space of azole-2-amides, compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C−H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates. A diverse azole substrate scope designed via machine-learning-guided analysis demonstrates the broad utility of the sequence. Density functional theory calculations provide detailed insights into the role of silyl triflates in the reaction mechanism. Transferrable applications of the protocol are successfully established: (i) A low pressure (CO 2 balloon) option for synthesizing azole-2-carboxylic acids without the need for high-pressure equipment; (ii) the use of 13 CO 2 for the synthesis of labeled compounds; (iii) isocyanates as alternative electrophiles for direct C−H amidation; (iv) and the use of the developed chemistry in a 24 × 12 parallel synthesis workflow with a 90% library success rate. Fundamentally, the reported protocol expands the use of heterocycle C− H functionalization from late-stage functionalization applications toward its use in library synthesis. It provides general access to densely functionalized azole-2-carboxylic acid building blocks and demonstrates their one-pot diversification.

A mechanistic investigation into the origins of the regio- and chemoselectivities observed in iron/pyridine dialdimine (PDAI)-catalyzed intermolecular [2+2+2] cycloaddition reactions of terminal alkynes and cyanamides to yield substituted 2-amino-pyridines is reported. The combination of experimental and computational studies disclosed herein reveals the role of the hemilabile PDAI ligand as an important factor controlling the resultant product’s observed regio- and chemoselectivity.

This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide couplings in one pot. This sequence accesses a large variety of azole-2-amides, demonstrating the significant expansion of the accessible chemical space, as compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C-H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates. A diverse azole substrate scope designed via ma-chine learning-guided analysis demonstrates the broad utility of the sequence. DFT calculations provide insights into the role of silyl triflates in the reaction mechanism. Transferrable applications of the protocol are successfully established: (i) A low pressure (CO2 balloon) option for synthesizing azole-2-carboxylic acids without the need for high-pressure equipment; (ii) the use of 13CO2 for the synthesis of labeled compounds; and (iii) isocyanates as alternative electrophiles for direct C-H amidation. Fundamentally, the reported protocol expands the use of heterocycle C-H functionalization from late-stage functionalization applications towards its use in library synthesis. It provides general access to densely functionalized azole-2-carboxylic acid building blocks and demonstrates their one-pot use in diversifying amide couplings.

This manuscript reports the development of a mild, highly functional group tolerant and metal-free C-H aminoalkylation of azoles via a three-component coupling approach. This method enables the C-H functionalization of...