Ni-Catalyzed β-Alkylation of Cyclopropanol-Derived Homoenolates

Abstract

Metal homoenolates are valuable synthetic intermediates which provide access to β-functionalized ketones. In this report, we disclose a Ni-catalyzed β-alkylation reaction of cyclopropanol-derived homoenolates using redox-active N-hydroxyphthalimide (NHPI) esters as the alkylating reagents. The reaction is compatible with 1°, 2°, and 3°NHPI esters. Mechanistic studies imply radical activation of the NHPI ester and 2e β-carbon elimination occurring on the cyclopropanol.

Synthesis of Cyclopentenones with Reverse Pauson–Khand Regiocontrol via Ni-Catalyzed C–C Activation of Cyclopropanone

“…Postulated mechanism for the Ni-catalyzed formal [3+2] cycloaddition of cyclopropanone and alkynes While this mechanism is consistent with analogous literature precedents, 9a,21 it is also known that Ni(II)-homoenolates can be generated from cyclopropanols in the presence of Zn(II) salts. 22 Thus, a mechanism akin to the one observed by Crimmins (see Scheme 1c), involving a carbometallation of the alkyne followed by Claisen-type condensation, must also be considered. Indeed, substrate 2a is also technically a cyclopropanol derivative, and its direct equilibration to a metal-homoenolate species is a reasonable consideration.…”

The Cyclopropane Ring as a Reporter of Radical Leaving-Group Reactivity for Ni-Catalyzed C(sp3)–O Arylation

“…The concentrate was triturated with hexanes to yield the product as a white solid (2.5 g, 15 mmol, 38%). Analytical data: 8…”

“…Namely, cyclopropyl electrophiles reveal two-electron versus one-electron reactivity via the product obtained in a substitution reaction (Figure 1). When cyclopropyl electrophiles are treated to two-electron substitution chemistry, the ringopened product is typically obtained; concerted substitutions result in an SN2' pathway (Figure 1a, top arrow), 8 while SN1 reactions occur via rapid ring-opening of the cyclopropyl cation 9 (Figure 1a, bottom arrow). 10,11 Alternatively, cyclopropyl radicals have a lifetime which allows them to be captured without rupture of the cyclopropane.…”

Nickel-catalyzed reductive coupling of homoenolates and their higher homologues with unactivated alkyl bromides

“…To the best of our knowledge, the use of inexpensive nickel catalysts for the generation and functionalization of β-, or γ-bound carboxylic acid derivatives remains underdeveloped, especially related to coupling of these intermediates with alkyl groups 38,39 . To circumvent the use of unactivated alkyl halides, Rousseaux and colleagues 40 developed an elegant alkylation of homoenolates derived from cyclopropanols that involves use of redox active esters (Fig. 1d).…”

“…1d). In this work, redox active esters undergo in situ decarboxylation to provide alkyl radicals, leading to alkylated homoenolates 40 . To the best of our knowledge, catalytic alkylations of any type of homoenolate, or their higher homologs, with unactivated alkyl halides remains a challenge.…”