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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.

SUBMITTER: Yuan M

PROVIDER: S-EPMC7909746 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Iron-catalyzed cross-coupling reactions using alkynyl nucleophiles represent an attractive approach for the incorporation of alkynyl moieties into organic molecules. In the present study, a multitechnique approach combining inorganic spectroscopic methods, inorganic synthesis, and reaction studies is applied to iron-SciOPP catalyzed alkynyl-alkyl cross-couplings, providing the first detailed insight into the effects of variation from sp2- to sp-hybridized nucleophiles on iron speciation and reactivity. Reaction studies demonstrate that reaction of FeBr2(SciOPP) with 1 equiv (triisopropylsilyl)ethynylmagnesium bromide (TIPS-CC-MgBr) leads to a distribution of mono-, bis-, and tris-alkynylated iron(II)-SciOPP species due to rapid alkynyl ligand redistribution. While solvents such as THF promote these complex redistribution pathways, nonpolar solvents such as toluene enable increased stabilization of these iron species and further enabled assessment of their reactivity with electrophile. While the tris-alkynylated iron(II)-SciOPP species was found to be unreactive with the cycloheptyl bromide electrophile over the average turnover time of catalysis, the in situ formed neutral mono- and bis-alkynylated iron(II)-SciOPP complexes are consumed upon reaction with the electrophile with concomitant generation of cross-coupled product at catalytically relevant rates, indicating the ability of one or both of these species to react selectively with the electrophile. The nature of the reaction solvent and Grignard reagent addition rate were found to have broader implications in overall reaction selectivity, reaction rate, and accessibility of off-cycle iron(I)-SciOPP species. Additionally, the effects of steric substitution of the alkynyl Grignard reagent on catalytic performance were investigated. Fundamental insight into iron speciation and reactivity with alkynyl nucleophiles reported herein provides an essential foundation for the continued development of this important class of reactions.

Project description:In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research. However, the construction of a bond between two sp(3)-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions. In comparison to related procedures with sp(2)-hybridized species, the development of methods for sp(3)-sp(3) bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as ?-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp(3)-sp(3) bonds that utilize organometallic nucleophiles and alkyl electrophiles. In particular, the coupling of alkyl halides with pre-generated organozinc, Grignard and organoborane species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp(3)-sp(3) coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp(3)-sp(3) bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

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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.

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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.

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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.