Methods and Mechanisms for Cross-Electrophile Coupling of Csp² Halides with Alkyl Electrophiles

Abstract

ConspectusCross-electrophile coupling, the cross-coupling of two different electrophiles, avoids the need for preformed carbon nucleophiles, but development of general methods has lagged behind cross-coupling and C–H functionalization. A central reason for this slow development is the challenge of selectively coupling two substrates that are alike in reactivity. This Account describes the discovery of generally cross-selective reactions of aryl halides and acyl halides with alkyl halides, the mechanistic studies that illuminated the underlying principles of these reactions, and the use of these fundamental principles in the rational design of new cross-electrophile coupling reactions.Although the coupling of two different electrophiles under reducing conditions often leads primarily to symmetric dimers, the subtle differences in reactivity of aryl halides and alkyl halides with nickel catalysts allowed for generally cross-selective coupling reactions. These conditions could also be extended to the coupling of acyl halides with alkyl halides. These reactions are exceptionally functional group tolerant and can be assembled on the benchtop.A combination of stoichiometric and catalytic studies on the mechanism of these reactions revealed an unusual radical-chain mechanism and suggests that selectivity arises from (1) the preference of nickel(0) for oxidative addition to aryl halides and acyl halides over alkyl halides and (2) the greater propensity of alkyl halides to form free radicals. Bipyridine-ligated arylnickel intermediates react with alkyl radicals to efficiently form, after reductive elimination, new C–C bonds. Finally, the resulting nickel(I) species is proposed to regenerate an alkyl radical to carry the chain.Examples of new reactions designed using these principles include carbonylative coupling of aryl halides with alkyl halides to form ketones, arylation of epoxides to form β-aryl alcohols, and coupling of benzyl sulfonate esters with aryl halides to form diarylmethanes. Arylnickel(II) intermediates can insert carbon monoxide to form acylnickel(II) intermediates that react with alkyl halides to form ketones, demonstrating the connection between the mechanisms of reactions of aryl halides and acid chlorides with alkyl halides. The low reactivity of epoxides with nickel can be overcome by the use of either titanium or iodide cocatalysis to facilitate radical generation and this can also be extended to enantioselective arylation of meso-epoxides. The high reactivity of benzyl bromide with nickel, which leads to the formation of bibenzyl in attempted reactions with bromobenzene, can be overcome by using a benzyl mesylate along with cobalt phthalocyanine cocatalysis to convert the mesylate into an alkyl radical.

Nickel-Catalyzed Reductive Couplings

“…The last section of this chapter summarizes the coupling of C(sp 2 )-halides with other C(sp 2 )-and C(sp)-electrophiles. Due to the extensive reviews that have been published on reductive acylation (including CO 2 fixation), arylation of alkyl electrophiles [1][2][3][4][5][6], electrochemical coupling, as well as Co-catalyzed reductive coupling methods [3], only recent progress will be highlighted for these chemistries. [21].…”

“…In recent years, development of transition metal-catalyzed cross-coupling between two electrophiles has received considerable attention (for reviews, see [1][2][3][4][5][6]). These methods avoid the prepreparation of nucleophiles that are often converted from their more stable and accessible electrophile precursors, which may become critically useful when entries to certain nucleophiles are exceedingly difficult [7,8].…”

“…These methods avoid the prepreparation of nucleophiles that are often converted from their more stable and accessible electrophile precursors, which may become critically useful when entries to certain nucleophiles are exceedingly difficult [7,8]. In particular, reductive coupling of alkyl electrophiles with other electrophiles has advanced to be an important strategy for the construction of C-C(sp 3 ) bonds, wherein nickel, and in some cases cobalt, catalysts have proven to be exceptionally powerful (Scheme 1) (for reviews, see [1][2][3][4][5][6]). The electrophiles capable of coupling with alkyl halides and pseudo-halides include C(sp 3 )-(e.g., unactivated alkyl halides and allylic acetates) and C(sp 2 )-substrates (e.g., acyl and aryl/vinyl halides), as well as CO 2 and other carbonyl-type compounds.…”

“…Although insightful understanding of the reaction mechanisms still requires tremendous studies, it is now well accepted that alkyl halides participate in the Nicatalyzed reductive coupling reactions through a radical process [1][2][3][4][5][6]. The radical can diffuse to a bulk solution, and bind to an organonickel [e.g., C(sp 2 …”

Catalytic Cyclooligomerization of Enones with Three Methylene Equivalents

“…Thioethers are susceptible to ylide formation in the Simmons–Smith reaction but are left untouched under the catalytic cyclooligomerization conditions ( 8 ). 10 Likewise, aryl chlorides, which participate in nickel-catalyzed reductive cross-coupling reactions, 11 are not competitively activated. A substrate possessing two alkenes, one conjugated with a ketone and the other substituted only with alkyl groups, reacts exclusively at the electron-deficient alkene ( 19 ).…”