Metallaphotoredox-catalysed sp3–sp3 cross-coupling of carboxylic acids with alkyl halides

Abstract

Over the last half-century, transition metal-mediated cross-coupling reactions have changed the way in which complex organic molecules are synthesized. Indeed, the predictable and chemoselective nature of these transformations has led to their widespread adoption across a vast array of chemical research areas1. However, the construction of sp3–sp3 bonds, a fundamental unit of organic chemistry, remains an important yet elusive objective for cross-coupling reaction engineering2. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3–sp3 bond formation via transition metal catalysis has been historically hampered by deleterious side-reactions, such as β-hydride elimination with Pd-catalysis, and the reluctance of alkyl halides to undergo oxidative addition3,4. To address this issue, a number of research groups have demonstrated the feasibility of nickel-catalyzed cross-coupling processes to form sp3–sp3 bonds that utilize organometallic nucleophiles and alkyl electrophiles5–7. In particular, the coupling of alkyl halides with pregenerated organozinc8–10, Grignard11,12, and organoborane13 species has been used to furnish diverse molecular structures. However, the poor step and atom economies along with the operational difficulties associated with making, carrying, and using these sensitive coupling partners has hindered their widespread adoption. The prospect of establishing a generically useful sp3–sp3 coupling technology that employs bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be a valuable addition to fields of research that rely on organic molecule construction. Here, we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3–sp3 bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. The outlined protocol is suitable for a wide array of primary and secondary carboxylic acids and does not require the presence of radical stabilizing groups. The merit of this coupling strategy is illustrated by the expedient synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

Visible‐Light Photocatalysis as an Enabling Tool for the Functionalization of Unactivated C(sp3)‐Substrates

“…Very recently, this reaction manifold was further extended to the C(sp 3 )-C(sp 3 ) coupling of carboxylic acids with alkyl halides (Scheme 7C). [38] Notably, seven examples with unactivated radical precursors were presented, including an application to the synthesis of the antiplatet drug tirofiban.…”

A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and Esters

“…In conclusion, we have developed anew set of photoredox reaction conditions taking advantage of the Lewis acidity of boronic esters and boroxines (from boronic acids) to generate primary,s econdary,a nd tertiary alkyl or aryl radicals.T hese intermediates were engaged in redox-neutral C À Cc ouplings with electron-deficient olefins,f orming ar ange of new C(sp 3 )ÀC(sp 3 )a nd C(sp 2 )ÀC(sp 3 )c ross-coupled products. Over 50 structurally and functionally diverse products were …”

“…[12] Based on this knowledge,w eh ypothesized that the use of ac atalytic amount of an organic Lewis base would be av iable option for the photoredox activation of boronic acids and esters. [13] Herein, we describe adual catalytic method to effectively form alkyl and aryl radicals from aw ide array of boronic esters and acids by direct photoredox single-electron oxidation under mild and safe conditions,without the requirement for stoichiometric activators or oxidants.T hese reactive species were further engaged in intermolecular C À Cb ondforming processes to deliver desirable C(sp 3 )ÀC(sp 3 )a nd C(sp 2 )ÀC(sp 3 )bonds in ar edox-neutral fashion. Thea ddition of electron-rich carbon-centered radicals onto electron-deficient olefins,a lso known as Giese-type addition, [14] is an interesting method to form C À Cb onds in ar edox-neutral fashion and can also be used to assess the presence of the postulated radical intermediates.…”

“…[4] Ar ange of reductive or oxidative carbon radical precursors are now available to generate carbon radicals in the context of ap hotocatalytic cycle. [5] Oxidative carbon radical precursors are often anionic species suffering from poor solubility in common organic solvents.F or example,e xtensively studied organoborates [6] possess an electron-rich B(sp 3 )m oiety that can be subjected to singleelectron oxidation, leading to an eutral carbon radical after CÀBbond cleavage (Scheme 1A).…”

“…[1] They are particularly attractive in the context of C À Cb ond-forming reactions, [2] overcoming problems often associated with two-electron processes. [3] By enabling visible-light-promoted single electron transfer, photoredox catalysis has become am ethod of choice for the single-electron reduction or oxidation of organic substrates and allows to generate open-shell intermediates in amild and selective fashion. [4] Ar ange of reductive or oxidative carbon radical precursors are now available to generate carbon radicals in the context of ap hotocatalytic cycle.…”