Mechanistic Insight into the Photoredox-Nickel-HAT Triple Catalyzed Arylation and Alkylation of α-Amino C_sp3–H Bonds

Abstract

We report here a comprehensive computational analysis of the mechanisms of the photoredox-nickel-HAT (HAT: hydrogen atom transfer) catalyzed arylation and alkylation of αamino Csp3-H bonds developed by MacMillan and coworkers. Different alternatives for the three catalytic cycles were tested to identify unambiguously the operative reaction mechanism. Our analysis indicated that the IrIII photoredox catalyst, upon irradiation with visible light, can be either reduced or oxidized by the HAT and nickel catalysts, respectively, indicating that both reductive and oxidative quenching catalytic cycles can be operative, although the reductive cycle is favored. Our analysis of the HAT cycle indicated that activation of a -amino Csp3-H bond of the substrate is facile and selective relative to activation of a -amino Csp3-H bond. Finally, our analysis of the nickel cycle indicated that both arylation and alkylation of α-amino Csp3-H bonds occurs via the sequence of nickel oxidation states NiI-NiII-NiI-NiIII, and of elementary steps: radical addition-SET-oxidative addition-reductive elimination. transition metal catalysis can be a winning methodology to solve some of the challenges related to functionalization of Csp3-H bonds within C-C cross-coupling schemes.31-34 Recently, a strategy for the functionalization of α-amino Csp3-H bonds using photoredox catalysis, induced by visible-light in combination with a nickel and an organocatalyst, was reported by MacMillan and coworkers (Scheme 1).20, [35][36][37] In this protocol the organocatalyst acts as a hydrogen atom transfer, HAT, agent, generating an alkyl radical by selective activation of a α-amino Csp3-H bond. This merger has culminated in the ability to cross-couple alkyl radicals with metal-activated electrophiles, such as aryl and alkyl bromides, to forge new Csp3-Csp2 and Csp3-Csp3 bonds.Despite a large number of experimental papers in the field of photoredox-nickel dual catalysis, a comprehensive mechanistic picture of this chemistry is still missing. Focusing on theoretical studies, for C-N cross-coupling reaction it has been proposed that a Ni0 species, generated in situ, is the active coupling catalyst and the mechanism involves the modulation of the nickel oxidation state by SET from the photoredox catalyst, rather than by EnT.38 In contrast, for C-O cross-coupling it has been proposed that a NiI species is the active coupling catalyst.39 Different conclusions have been also proposed to explain formation of C-C bonds. In the case of the cross-coupling of aryl bromides with C-centered radicals derived from alkyltrifluoroborates it was proposed that a Ni0 species is the active coupling catalyst, with the Ni0-NiI-NiIII-NiI sequence of oxidation states.24 27, 40 Instead, for difunctionalization of alkynes to tri-substituted alkenes, an experimental and computational study indicated that NiI serves as the active catalyst.41 Scheme 1. Reactions and catalysts investigated in this work. The HAT catalyst Q is used for arylation reaction while Q' is used for alkylation reac...

Oxidative Addition of Aryl Halides to a Ni(I)-Bipyridine Complex

“…(C) The mechanism by which the C-Br bond undergoes activation (C1-C5). Possibilities include concerted oxidative additions (monometallic [38][39][40] or bimetallic 36,37 ), halogen atom abstraction, 34 single electron transfer 41 and nucleophilic aromatic substitution (SNAr). 42 Broadly, these describe whether C-Br bond activation is a 1-or 2-electron process, and the degree to which it is concerted or stepwise.…”

Photoredox Ni-Catalyzed Selective Coupling of Organic Halides and Oxalates to Esters via Alkoxycarbonyl Radical Intermediates

“…These results indicate that dtbbpy coordinated nickel complex is an active catalyst but Ni-II is not the intermediate in this alkoxycarbonyl radical cross coupling reaction. On the basis of the control experimental results as well as previous reprots, [111][112][113][114] the plausible catalytic cycle is proposed in Figure 5. .…”

The Morita–Baylis–Hillman reaction for non-electron-deficient olefins enabled by photoredox catalysis

“…[10][11][12][13][14][15][16][17][18] Since first being developed in 2015 by the Macmillan's group, 19 quinuclidine and derivatives as dual hydrogen atom transfer (HAT) catalysts in photoredox catalysis have enabled direct functionalization of substrates that are not readily oxidized by typical photocatalysts (Scheme 1B). [20][21][22][23][24][25][26][27][28] In a few cases, a quinuclidinium radical cation also works as an oxidant that reacts with nucleophilic radicals or transient-metal intermediate through single electron transfer Please do not adjust margins Please do not adjust margins (SET). 29,30 However, as an electrophilic species, the quinuclidinium radical cation adds to olefin has not yet been revealed.…”