On the Nature of C(sp³)–C(sp²) Bond Formation in Nickel-Catalyzed Tertiary Radical Cross-Couplings: A Case Study of Ni/Photoredox Catalytic Cross-Coupling of Alkyl Radicals and Aryl Halides

Abstract

The merger of photoredox and nickel catalysis has enabled the construction of quaternary centers. However, the mechanism, role of the ligand, and effect of the spin state for this transformation and related Ni-catalyzed cross-couplings involving tertiary alkyl radicals in combination with bipyridine and diketonate ligands remain unknown. Several mechanisms have been proposed, all invoking a key Ni­(III) species prior to undergoing irreversible inner-sphere reductive elimination. In this work, we have used open-shell dispersion-corrected DFT calculations, quasi-classical dynamics calculations, and experiments to study in detail the mechanism of carbon–carbon bond formation in Ni bipyridine- and diketonate-based catalytic systems. These calculations revealed that access to high spin states (e.g., triplet spin state tetrahedral Ni­(II) species) is critical for effective radical cross-coupling of tertiary alkyl radicals. Further, these calculations revealed a disparate mechanism for the C–C bond formation. Specifically, contrary to the neutral Ni-bipyridyl system, diketonate ligands lead directly to the corresponding tertiary radical cross-coupling products via an outer-sphere reductive elimination step via triplet spin state from the Ni­(III) intermediates. Implications to related Ni-catalyzed radical cross-couplings and the design of new transformations are discussed.

Selective 1,2‐Aryl‐Aminoalkylation of Alkenes Enabled by Metallaphotoredox Catalysis

“…Both cyclic and acyclic a-silyl amines worked well to deliver the corresponding a-aryl substituted gamino acid esters in moderate to excellent yields.Especially, the substrates containing pharmaceutically relevant moieties such as piperidine,p yrrolidine,m orpholine and piperazine, which are among the most frequent N-heterocyclic functions employed in drugs,w ere incorporated smoothly with decent yields (4,(7)(8)(9)(10). Thereaction was not only limited to aliphatic a-silyl amines,b ut also be suitable for aromatic amines (13)(14). a-Silyl secondary amine with af ree NH group was not compatible (15), which made the reaction quite messy and only al ittle of radical precursor recovered (18 %f rom crude 1 HNMR spectrum).…”

“…Alternatively,t he Ni III Int D could also be formed by the recombination of radical B to Ni II Int F arising from the oxidative addition of Ar-X with Ni 0 (path b). [13] This process has two major challenges:1)compared with secondary or tertiary alkyl radicals,primary alkyl radicals are much less congested and thus,more reactive to participate the competitive two-component cross-coupling to delivery undesired byproduct 5; [14] 2) the thermodynamically favorable SET between alkyl radical [15] and the reduced state of PCC À (the oxidative potential for commonly used PCC À ranges from À0.8 to À2.2 V vs.SCE in CH 3 CN) [7a] facilitates undesired Giese-type hydroalkylation byproduct 6. [16] Besides,p rotodehalogenation of aryl halide under metallaphotoredox conditions is another obstacle, [9d] which could not be neglected.…”

Recent developments in enantioselective photocatalysis

“…This nickel catalytic cycle [Ni(0), Ni(I), Ni(III)] is different to that shown in Scheme 61 [Ni(0), Ni(I), Ni(II), Ni(III)], but both are plausible and it is difficult to determine which is in operation. Towards this, Molander and Gutierrez recently reported an interesting computational investigation that assessed the feasibility of different possible mechanisms for tertiary radicals in nickel/photoredox dual catalysis and concluded that multiple mechanisms are plausible, and which one is in operation is both substrate and ligand dependant [ 153 ].…”

Photochemical Methods for Peptide Macrocyclisation

“…This extremely powerful combination opens up unprecedented chemical transformations that are well‐suited to applications in complex settings on account of the mild reaction conditions [131, 137, 138] . Key to the success of this approach is the activation of transition‐metal complexes by a photocatalyst, either through redox modulation or energy transfer pathways, triggering mechanistic steps that would not be operative under transition‐metal catalysis alone [139–144] …”

“…[131,137,138] Key to the success of this approachi st he activation of transition-metal complexes by a photocatalyst, either through redox modulation or energy transfer pathways, triggering mechanistic steps that would not be operative under transition-metal catalysis alone. [139][140][141][142][143][144] The Sciammetta group disclosed am ethodology for the etherification of peptidic alcohols with aryl bromides by C(sp 2 )ÀOc ross-coupling under dual photoredoxa nd nickel catalysis. [145] In addition to intermolecular ether formation, the reaction conditions were also shown to be amenable to macrocyclisation of as eries of N-terminal bromobenzamides, via aryl etherification of C-terminal serine derivatives.…”