Predicting success in Cu-catalyzed C-N coupling reactions using data science.

Data science is assuming a pivotal role in guiding reaction optimization and streamlining experimental workloads in the evolving landscape of synthetic chemistry. A discipline-wide goal is the development of workflows that integrate computational chemistry and data science tools with high-throughput experimentation as it provides experimentalists the ability to maximize success in expensive synthetic campaigns. Here, we report an end-to-end data-driven process to effectively predict how structural features of coupling partners and ligands affect Cu-catalyzed C-N coupling reactions. The established workflow underscores the limitations posed by substrates and ligands while also providing a systematic ligand prediction tool that uses probability to assess when a ligand will be successful. This platform is strategically designed to confront the intrinsic unpredictability frequently encountered in synthetic reaction deployment.

Iron-Catalyzed Vinylsilane Dimerization and Cross-Cycloadditions with 1,3-Dienes: Probing the Origins of Chemo- and Regioselectivity.

The selective, intermolecular, homodimerization and cross-cycloaddition of vinylsilanes with unbiased 1,3-dienes, catalyzed by a pyridine-2,6-diimine (PDI) iron complex is described. In the absence of a diene coupling partner, vinylsilane hydroalkenylation products were obtained chemoselectively with unusual head-to-head regioselectivity (up to >98% purity, 98:2 E/Z). In the presence of a 4- or 2-substituted diene coupling partner, under otherwise identical reaction conditions, formation of value-added [2+2]- and [4+2]-cycloadducts, respectively, was observed. The chemoselectivity profile was distinct from that observed for analogous α-olefin dimerization and cross-reactions with 1,3-dienes. Mechanistic studies conducted with well-defined, single-component precatalysts (MePDI)Fe(L2) (where MePDI = 2,6-(2,6-Me2-C6H3N═CMe)2C5H3N; L2 = butadiene or 2(N2)) provided insights into the kinetic and thermodynamic factors contributing to the substrate-controlled regioselectivity for both the homodimerization and cross cycloadditions. Diamagnetic iron diene and paramagnetic iron olefin complexes were identified as catalyst resting states, were characterized by in situ NMR and Mössbauer spectroscopic studies, and were corroborated with DFT calculations. Stoichiometric reactions and computational models provided evidence for a common mechanistic regime where competing steric and orbital-symmetry requirements dictate the regioselectivity of oxidative cyclization. Although distinct chemoselectivity profiles were observed in cross-cycloadditions with the vinylsilane congeners of α-olefins, these products arose from metallacycles with the same connectivity. The silyl substituents ultimately governed the relative rates of ß-H elimination and C-C reductive elimination to dictate final product formation.

High-Throughput Discovery and Evaluation of a General Catalytic Method for N-Arylation of Weakly Nucleophilic Sulfonamides.

Through targeted high-throughput experimentation (HTE), we have identified the Pd/AdBippyPhos catalyst system as an effective and general method to construct densely functionalized N,N-diaryl sulfonamide motifs relevant to medicinal chemistry. AdBippyPhos is particularly effective for the installation of heteroaromatic groups. Computational steric parametrization of the investigated ligands reveals the potential importance of remote steric demand, where a large cone angle combined with an accessible Pd center is correlated to successful catalysts for C-N coupling reactions.

Stable TEMPO and ABNO Catalyst Solutions for User-Friendly (bpy)Cu/Nitroxyl-Catalyzed Aerobic Alcohol Oxidation.

Two solutions, one consisting of bpy/TEMPO/NMI and the other bpy/ABNO/NMI (bpy =2,2'-bipyridyl; TEMPO = 2,2,6,6-tetramethylpiperidine N-oxyl, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl; NMI = N-methylimidazole), in acetonitrile are shown to have good long-term stability (≥1 year) under air at 5 °C. The solutions may be combined in appropriate quantities with commercially available [Cu(MeCN)4]OTf to provide a convenient catalyst system for the aerobic oxidation of primary and secondary alcohols.

Copper(I)/ABNO-catalyzed aerobic alcohol oxidation: alleviating steric and electronic constraints of Cu/TEMPO catalyst systems.

Cu/TEMPO catalyst systems promote efficient aerobic oxidation of sterically unhindered primary alcohols and electronically activated substrates, but they show reduced reactivity with aliphatic and secondary alcohols. Here, we report a catalyst system, consisting of ((MeO)bpy)Cu(I)(OTf) and ABNO ((MeO)bpy = 4,4'-dimethoxy-2,2'-bipyridine; ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl), that mediates aerobic oxidation of all classes of alcohols, including primary and secondary allylic, benzylic, and aliphatic alcohols with nearly equal efficiency. The catalyst exhibits broad functional group compatibility, and most reactions are complete within 1 h at room temperature using ambient air as the source of oxidant.

Copper(I)/TEMPO-catalyzed aerobic oxidation of primary alcohols to aldehydes with ambient air.

This protocol describes a practical laboratory-scale method for aerobic oxidation of primary alcohols to aldehydes, using a chemoselective Cu(I)/TEMPO (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxyl) catalyst system. The catalyst is prepared in situ from commercially available reagents, and the reactions are performed in a common organic solvent (acetonitrile) with ambient air as the oxidant. Three different reaction conditions and three procedures for the isolation and purification of the aldehyde product are presented. The oxidations of eight different alcohols, described here, include representative examples of each reaction condition and purification method. Reaction times vary from 20 min to 24 h, depending on the alcohol, whereas the purification methods each take about 2 h. The total time necessary for the complete protocol ranges from 3 to 26 h.

Catalyst-controlled regioselective Suzuki couplings at both positions of dihaloimidazoles, dihalooxazoles, and dihalothiazoles.

Various dihaloazoles can be monoarylated at a single C-X bond with high selectivity via Suzuki coupling. By changing the palladium catalyst employed, the selectivity can be switched for some dihaloazoles, allowing for Suzuki coupling at the other, traditionally less reactive C-X bond. These conditions are applicable to coupling of a wide variety of aryl-, heteroaryl-, cyclopropyl-, and vinylboronic acids with high selectivities and enable the rapid construction of diverse arrays of diarylazoles in a modular fashion.

Synthesis of a bulky bis(imino)pyridine compound: a methodology for systematic variation of steric bulk and energetic implications for metalation.

A new bis(imino)pyridine compound, 2,6-{(2,6-Me(2)-C(6)H(3))NC(t-Bu)}(2)C(5)H(3)N (), has been synthesized with t-butyl substituents on the imino carbon atoms. The stepwise synthetic method for assembly of this compound is novel. Compound and its synthetic precursor, mono(imino)pyridine , have been characterized using single-crystal X-ray diffraction. Metalation attempts of using iron(ii) chloride under forcing conditions does not yield the desired iron(ii) chloride complex; the use of refluxing acetic acid solvent provides a minimal amount of a paramagnetic species that has been characterized by NMR spectroscopy and magnetic susceptibility (NMR method). Computational methods have been used to evaluate the relative energies of three conformations of bis(imino)pyridine ligands with varying alkyl substitution at the imino carbon positions. The relative energies of these closed, open and open-planar conformations of reveal a thermodynamic argument for the difficulty in metalation of , as compared to related ligands with less steric hindrance at the imino carbon atoms.