John C. Tellis

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.

Photochemical Nickel-Catalyzed C–H Arylation: Synthetic Scope and Mechanistic Investigations

An iridium photocatalyst and visible light facilitate a room temperature, nickel-catalyzed coupling of (hetero)aryl bromides with activated α-heterosubstituted or benzylic C(sp3)–H bonds. Mechanistic investigations on this unprecedented transformation have uncovered the possibility of an unexpected mechanism hypothesized to involve a Ni–Br homolysis event from an excited-state nickel complex. The resultant bromine radical is thought to abstract weak C(sp3)–H bonds to generate reactive alkyl radicals that can be engaged in Ni-catalyzed arylation. Evidence suggests that the iridium photocatalyst facilitates nickel excitation and bromine radical generation via triplet–triplet energy transfer.

Protecting group-free, selective cross-coupling of alkyltrifluoroborates with borylated aryl bromides via photoredox/nickel dual catalysis

Significance Efficient assembly of small-molecule scaffolds is among the most fundamental goals of organic synthesis. Iterative synthesis, wherein predefined building blocks are unified in an “assembly line” fashion using only a small number of reaction types, is an attractive means for achieving this ideal. These methods are particularly well-suited for applications in drug discovery, agrochemistry, and materials science, where rapid generation of structural diversity is a central objective. A strategy is described in which two reactive sites are differentiated by their preferred mode of reactivity (single vs. two electron). This unique platform allows discrimination between the two sites without artificial blocking of reactivity, streamlining the iterative process by removing the need for deprotection or interconversion of functional groups. Orthogonal reactivity modes offer substantial opportunities for rapid construction of complex small molecules. However, most strategies for imparting orthogonality to cross-coupling reactions rely on differential protection of reactive sites, greatly reducing both atom and step economies. Reported here is a strategy for orthogonal cross-coupling wherein a mechanistically distinct activation mode for transmetalation of sp3-hybridized organoboron reagents enables C-C bond formation in the presence of various protected and unprotected sp2-hybridized organoborons. This manifold has the potential for broad application, because orthogonality is inherent to the activation mode itself. The diversification potential of this platform is shown in the rapid elaboration of a trifunctional lynchpin through various transition metal-catalyzed processes without nonproductive deprotection or functional group manipulation steps.

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.

1,4-Dihydropyridines as Alkyl Radical Precursors: Introducing the Aldehyde Feedstock to Nickel/Photoredox Dual Catalysis

A Ni/photoredox dual catalytic cross-coupling is disclosed in which a diverse range of (hetero)aryl bromides are used as electrophiles, with 1,4-dihydropyridines serving as precursors to Csp3-centered alkyl radical coupling partners. The reported method is characterized by its extremely mild reaction conditions, enabling access to underexplored cores.

Organocatalytic, Diastereo- and Enantioselective Synthesis of Nonsymmetric cis-Stilbene Diamines: A Platform for the Preparation of Single-Enantiomer cis-Imidazolines for Protein–Protein Inhibition

The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein–protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate–catalyst matching. This method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein–protein interactions.

Single-Electron Transmetalation: Protecting-Group-Independent Synthesis of Secondary Benzylic Alcohol Derivatives via Photoredox/Nickel Dual Catalysis

Protecting-group-independent cross-coupling of α-alkoxyalkyl- and α-acyloxyalkyltrifluoroborates with aryl and heteroaryl bromides is achieved through application of photoredox/nickel dual catalysis. Reactions occur under exceptionally mild conditions, with outstanding functional group compatibility and excellent observed tolerance of heteroarenes. This method offers expedient access to protected secondary benzylic alcohol motifs bearing benzyl, pivaloyl, and N,N-diisopropylcarbamoyl protecting groups.