Identifying general reaction conditions by bandit optimization.

Reaction conditions that are generally applicable to a wide variety of substrates are highly desired, especially in the pharmaceutical and chemical industries. Although many approaches are available to evaluate the general applicability of developed conditions, a universal approach to efficiently discover these conditions during optimizations is rare. Here we report the design, implementation and application of reinforcement learning bandit optimization models to identify generally applicable conditions by efficient condition sampling and evaluation of experimental feedback.

Nickel/Photoredox-Catalyzed Amidation via Alkylsilicates and Isocyanates.

A nickel/photoredox, dual-catalyzed amidation reaction between alkylsilicate reagents and alkyl/aryl isocyanates is reported. In contrast to the previously reported reductive coupling process, this protocol is characterized by mild reaction conditions and the absence of a stoichiometric reductant. A mechanistic hypothesis involving a nickel-isocyanate adduct is proposed based on literature precedent and further validation by experimental results.

Enabling the Cross-Coupling of Tertiary Organoboron Nucleophiles through Radical-Mediated Alkyl Transfer.

The construction of quaternary centers is a common challenge in the synthesis of complex materials and natural products. Current cross-coupling strategies that can be generalized for setting these centers are sparse and, when known, are typically predicated on the use of reactive organometallic reagents. To address this shortcoming a new, photoredox-Ni dual catalytic strategy for the cross-coupling of tertiary organoboron reagents with aryl halides is reported.

Metal-free C-H alkylation of heteroarenes with alkyltrifluoroborates: a general protocol for 1°, 2° and 3° alkylation.

A photoredox-catalyzed C-H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts.

Preparation of visible-light-activated metal complexes and their use in photoredox/nickel dual catalysis.

Visible-light-activated photoredox catalysts provide synthetic chemists with the unprecedented capability to harness reactive radicals through discrete, single-electron transfer (SET) events. This protocol describes the synthesis of two transition metal complexes, [Ir{dF(CF)ppy}(bpy)]PF (1a) and [Ru(bpy)](PF) (2a), that are activated by visible light. These photoredox catalysts are SET agents that can be used to facilitate transformations ranging from proton-coupled electron-transfer-mediated cyclizations to C-C bond constructions, dehalogenations, and H-atom abstractions.

Single-Electron Transmetalation via Photoredox/Nickel Dual Catalysis: Unlocking a New Paradigm for sp(3)-sp(2) Cross-Coupling.

The important role of transition metal-catalyzed cross-coupling in expanding the frontiers of accessible chemical territory is unquestionable. Despite empowering chemists with Herculean capabilities in complex molecule construction, contemporary protocols are not without their Achilles' heel: Csp(3)-Csp(2)/sp(3) coupling. The underlying challenge in sp(3) cross-couplings is 2-fold: (i) methods employing conventional, bench-stable precursors are universally reliant on extreme reaction conditions because of the high activation barrier of transmetalation; (ii) circumvention of this barrier invariably relies on use of more reactive precursors, thereby sacrificing functional group tolerance, operational simplicity, and broad applicability.

Base-Free Photoredox/Nickel Dual-Catalytic Cross-Coupling of Ammonium Alkylsilicates.

Single-electron transmetalation is recognized as an enabling technology for the mild transfer of alkyl groups to transition metal catalysts in cross-coupling reactions. Hypercoordinate silicates represent a new and improved class of radical precursors because of their low oxidation potentials and the innocuous byproducts generated upon oxidation. Herein, we report the cross-coupling of secondary and primary ammonium alkylsilicates with (hetero)aryl bromides in good to excellent yields.

Single-Electron Transmetalation: Synthesis of 1,1-Diaryl-2,2,2-trifluoroethanes by Photoredox/Nickel Dual Catalytic Cross-Coupling.

Novel methods for the incorporation of fluorinated subunits into organic frameworks are important in pharmaceutical, agrochemical, and materials science applications. Herein, the first method for the cross-coupling of benzylic α-trifluoromethylated alkylboron reagents with (hetero)aryl bromides is achieved through application of a photoredox/nickel dual catalytic system. The harsh conditions and high temperatures required by conventional Suzuki-coupling protocols are avoided by exploitation of an odd-electron pathway that permits room temperature transmetalation of these recalcitrant reagents.

Photoredox Cross-Coupling: Ir/Ni Dual Catalysis for the Synthesis of Benzylic Ethers.

Single-electron transmetalation has emerged as an enabling paradigm for the cross-coupling of Csp(3) hybridized organotrifluoroborates. Cross-coupling of α-alkoxymethyltrifluoroborates with aryl and heteroaryl bromides has been demonstrated by employing dual catalysis with a combination of an iridium photoredox catalyst and a Ni cross-coupling catalyst. The resulting method enables the alkoxymethylation of diverse (hetero)arenes under mild, room-temperature conditions.

Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings.

The cross-coupling of sp(3)-hybridized organoboron reagents via photoredox/nickel dual catalysis represents a new paradigm of reactivity for engaging alkylmetallic reagents in transition-metal-catalyzed processes. Reported here is an investigation into the mechanistic details of this important transformation using density functional theory. Calculations bring to light a new reaction pathway involving an alkylnickel(I) complex generated by addition of an alkyl radical to Ni(0) that is likely to operate simultaneously with the previously proposed mechanism.

Single-electron transmetalation: an enabling technology for secondary alkylboron cross-coupling.

Single-electron-mediated alkyl transfer affords a novel mechanism for transmetalation, enabling cross-coupling under mild conditions. Here, general conditions are reported for cross-coupling of secondary alkyltrifluoroborates with an array of aryl bromides mediated by an Ir photoredox catalyst and a Ni cross-coupling catalyst.

Dual catalysis. Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis.

The routine application of C(sp3)-hybridized nucleophiles in cross-coupling reactions remains an unsolved challenge in organic chemistry. The sluggish transmetalation rates observed for the preferred organoboron reagents in such transformations are a consequence of the two-electron mechanism underlying the standard catalytic approach. We describe a mechanistically distinct single-electron transfer-based strategy for the activation of organoboron reagents toward transmetalation that exhibits complementary reactivity patterns.