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Direct ?- and ?-C(sp³ )-H Alkynylation of Free Carboxylic Acids*.

ABSTRACT: In this study we report the identification of a novel class of ligands for palladium-catalyzed C(sp³ )-H activation that enables the direct alkynylation of free carboxylic acid substrates. In contrast to previous synthetic methods, no introduction/removal of an exogenous directing group is required. A broad scope of acids including both ?-quaternary and challenging ?-non-quaternary can be used as substrates. Additionally, the alkynylation in the distal ?-position is reported. Finally, this study encompasses preliminary findings on an enantioselective variant of the title transformation as well as synthetic applications of the products obtained.

SUBMITTER: Ghiringhelli F

PROVIDER: S-EPMC7756274 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Direct β- and γ-C(sp<sup>3</sup> )-H Alkynylation of Free Carboxylic Acids*.

Ghiringhelli Francesca F Uttry Alexander A Ghosh Kiron Kumar KK van Gemmeren Manuel M

Angewandte Chemie (International ed. in English) 20201012 51

In this study we report the identification of a novel class of ligands for palladium-catalyzed C(sp<sup>3</sup> )-H activation that enables the direct alkynylation of free carboxylic acid substrates. In contrast to previous synthetic methods, no introduction/removal of an exogenous directing group is required. A broad scope of acids including both α-quaternary and challenging α-non-quaternary can be used as substrates. Additionally, the alkynylation in the distal γ-position is reported. Finally, ...[more]

PMID: 32898310

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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.

Dataset Information

Direct ?- and ?-C(sp3 )-H Alkynylation of Free Carboxylic Acids*.

Publications

Direct β- and γ-C(sp<sup>3</sup> )-H Alkynylation of Free Carboxylic Acids*.

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Direct ?- and ?-C(sp³ )-H Alkynylation of Free Carboxylic Acids*.