David N. Primer

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

A bright outlook for carbon coupling In contemporary organic chemistry, it is straightforward to forge bonds between unsaturated carbons (i.e., carbons already engaged in double bonds) using cross-coupling catalysis. The protocol runs into some trouble, however, if one or both starting carbon centers are saturated (purely single-bonded). Tellis et al. and Zuo et al. independently found that combining a second, light-activated catalyst with a nickel cross-coupling catalyst could achieve selective coupling of saturated and unsaturated reagents (see the Perspective by Lloyd-Jones and Ball). Their methods rely on single-electron transfer from the light-activated catalyst to the saturated carbon, thereby enhancing its reactivity more effectively than the twoelectron mechanisms prevailing in traditional protocols. Science, this issue p. 433, p. 437; see also p. 381 Combining two catalysts, one light-activated, facilitates bond formation between saturated and unsaturated carbons. [Also see Perspective by Lloyd-Jones and Ball] The routine application of Csp3-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. Application of an iridium photoredox catalyst in tandem with a nickel catalyst effects the cross-coupling of potassium alkoxyalkyl- and benzyltrifluoroborates with an array of aryl bromides under exceptionally mild conditions (visible light, ambient temperature, no strong base). The transformation has been extended to the asymmetric and stereoconvergent cross-coupling of a secondary benzyltrifluoroborate.

Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General Manifold for Stereoconvergence in Nickel-Catalyzed Cross-Couplings

The cross-coupling of sp3-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. Analysis of the enantioselective variant of the transformation reveals an unexpected manifold for stereoinduction involving dynamic kinetic resolution (DKR) of a Ni(III) intermediate wherein the stereodetermining step is reductive elimination. Furthermore, calculations suggest that the DKR-based stereoinduction manifold may be responsible for stereoselectivity observed in numerous other stereoconvergent Ni-catalyzed cross-couplings and reductive couplings.

Single-Electron Transmetalation via Photoredox/Nickel Dual Catalysis: Unlocking a New Paradigm for sp3–sp2 Cross-Coupling

Conspectus 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: Csp3–Csp2/sp3 coupling. The underlying challenge in sp3 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. Despite the ubiquity of this problem, the nature of the transmetalation step has remained unchanged from the seminal reports of Negishi, Suzuki, Kumada, and Stille, thus suggesting that the challenges in Csp3–Csp2/sp3 coupling result from inherent mechanistic constraints in the traditional cross-coupling paradigm. Rather than submitting to the limitations of this conventional approach, we envisioned that a process rooted in single-electron reactivity could furnish the same key metalated intermediate posited in two-electron transmetalation, while demonstrating entirely complementary reactivity patterns. Inspired by literature reports on the susceptibility of organoboron reagents toward photochemical, single-electron oxidative fragmentation, realization of a conceptually novel open shell transmetalation framework was achieved in the facile coupling of benzylic trifluoroborates with aryl halides via cooperative visible-light activated photoredox and Ni cross-coupling catalysis. Following this seminal study, we disclosed a suite of protocols for the cross-coupling of secondary alkyl, α-alkoxy, α-amino, and α-trifluoromethylbenzyltrifluoroborates. Furthermore, the selective cross-coupling of Csp3 organoboron moieties in the presence of Csp2 organoboron motifs was also demonstrated, highlighting the nuances of this approach to transmetalation. Computational modeling of the reaction mechanism uncovered useful details about the intermediates and transition-state structures involved in the nickel catalytic cycle. Most notably, a unique dynamic kinetic resolution process, characterized by radical homolysis/recombination equilibrium of a NiIII intermediate, was discovered. This process was ultimately found to be responsible for stereoselectivity in an enantioselective variant of these cross-couplings. Prompted by the intrinsic limitations of organotrifluoroborates, we sought other radical feedstocks and quickly identified alkylbis(catecholato)silicates as viable radical precursors for Ni/photoredox dual catalysis. These hypervalent silicate species have several notable benefits, including more favorable redox potentials that allow extension to primary alkyl systems incorporating unprotected amines as well as compatibility with less expensive Ru-based photocatalysts. Additionally, these reagents exhibit an amenability to alkenyl halide cross-coupling while simultaneously expanding the aryl halide scope. In the process of exploring these reagents, we serendipitously discovered a method to effect thioetherification of aryl halides via a H atom transfer mechanism. This latter discovery emphasizes that this robust cross-coupling paradigm is “blind” to the origins of the radical, opening opportunities for a wealth of new discoveries. Taken together, our studies in the area of photoredox/nickel dual catalysis have validated single-electron transmetalation as a powerful platform for enabling conventionally challenging Csp3–Csp2 cross-couplings. More broadly, these findings represent the power of rational design in catalysis and the strategic use of mechanistic knowledge and manipulation for the development of new synthetic methods.

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.

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. The base-free conditions have exceptional protic group tolerance on both partners, permitting the cross-coupling of unprotected primary and secondary amines.

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 Csp3 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.

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. This method represents the first direct and general route for the synthesis of unsymmetrical 1,1-diaryl-2,2,2-trifluoroethanes, thereby providing efficient access to a previously unexplored chemical space.

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. In addition to details on the cross-coupling scope and limitations, full screening efforts and mechanistic experiments are communicated.

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(CF3)2ppy}2(bpy)]PF6 (1a) and [Ru(bpy)3](PF6)2 (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. These photocatalysts have been used in the synthesis of medicinally relevant compounds for drug discovery, as well as the degradation of biological polymers to access fine chemicals. These catalysts are prepared from IrCl3 and RuCl3, respectively, in three chemical steps. These steps can be described as a series of two ligand modifications followed by an anion metathesis. Using the cost-effective, scalable procedures described here, the ruthenium-based photocatalyst 2a can be synthesized in a 78% overall yield (∼8.1 g), and the iridium-based photocatalyst 1a can be prepared in a 56% overall yield (∼4.4 g). The total time necessary for the complete protocols ranges from ∼2 d for 2a to 5–7 d for 1a. Procedures for applying each catalyst in representative photoredox/Ni cross-coupling to form Csp3–Csp2 bonds using the appropriate radical precursor—organotrifluoroborates with 1a and bis(catecholato)alkylsilicates with 2a—are described. In addition, more traditional photoredox-mediated transformations are included as diagnostic tests for catalytic activity.

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.