Asymmetric Cross‐Coupling of Non‐Activated Secondary Alkyl Halides

Abstract

asymmetric catalysis · cross-coupling · Negishi coupling · nickel · Suzuki-Miyaura couplingModern transition-metal-catalyzed cross-coupling reactions have altered organic synthesis enormously, [1] and the coupling of aryl and alkenyl electrophiles has become a routine transformation in natural product and fine-chemical synthesis. For a long time, equivalent reactions of alkyl electrophiles, especially those with non-activated b hydrogen atoms, remained elusive. The difficulties encountered in attempts to carry out such reactions have been ascribed to a slow oxidative-addition step and undesired side reactions, such as b-hydride elimination. Palladium complexes of electron-rich phosphines, in particular P(c-Hex) 3 and PtBu 2 Me, were eventually found to be competent catalysts for the Suzuki-Miyaura coupling and related reactions of primary alkyl halides under mild conditions. [2,3] Even more desirable and challenging is the coupling of secondary alkyl halides: challenging, as the increased steric demand and electron richness of these substrates leads to a reduced rate of oxidative addition; desirable, as a new stereogenic center is often formed. Whereas palladiumcatalyzed methods are limited to primary alkyl halide substrates, cheaper nickel complexes were found to be uniquely suited to the catalysis of the cross-coupling of secondary alkyl halides. [4,5] Bi-and tridentate nitrogen ligands (Scheme 1), many of which are commercially available, were found to be key to success of these nickel-catalyzed reactions. These chelate ligands favor the cis orientation of the coupling partners at the nickel center. Thus, the rate of reductive elimination is increased relative to that of undesired b-hydride elimination. Recently, Fu and co-workers developed a number of impressive highly enantioselective nickelcatalyzed Negishi, [6] Hiyama, [7] and Suzuki-Miyaura [8] crosscoupling reactions of secondary alkyl halides. The last of these methods is the only asymmetric cross-coupling described to date in which non-activated secondary alkyl halides can be used and thus paves the way for exciting future developments.In 2003, Zhou and Fu reported the high catalytic activity of nickel-pybox complexes formed in situ in the Negishi coupling of non-activated secondary alkyl bromides and iodides with organozinc reagents at ambient temperature. [2,9] Their study served as a starting point for the development of an impressive series of asymmetric Negishi coupling reactions of secondary alkyl halides.[6] Activated racemic alkyl halides, such as a-bromoamides,[6a] benzylic chlorides and bromides, [6b] and allylic chlorides, [6c] were coupled successfully as electrophiles with alkyl zinc reagents with high enantioselectivity (Schemes 2 and 3). The reactions were even carried out below ambient temperature. The reaction conditions were optimized carefully, and it was found that the optimal combination of a solvent, nickel precursor, and additive differed for each class of substrate.[6] Interestingly, in each of these studies, nickel-pybox comp...

Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

“…3B) (29). Preliminary mechanistic data indicated that the nickel-catalyzed cross-coupling methods described in the previous section proceed via the formation of a radical intermediate from the electrophile, which is ideal for an enantioconvergent process (Fig.…”

Nickel: The “Spirited Horse” of Transition Metal Catalysis

“…10 Different organometallic compounds were successfully employed in the Kumada-Corriu (magnesium), Suzuki-Miyaura (boron), Negishi (zinc), and Hiyama (silicon) reactions. 11,12,13,14 The selection of ligands made it possible to utilize a variety of reagents with very simple and cheap catalyst precursors. [10][11][12][13][14][15]16 Diverse reactivity and cost-efficiency provided a valuable driving force for the remarkable progress of nickel catalysts in this area, 17 with more challenges coming in the modern design of process equipment.…”

“…11,12,13,14 The selection of ligands made it possible to utilize a variety of reagents with very simple and cheap catalyst precursors. [10][11][12][13][14][15]16 Diverse reactivity and cost-efficiency provided a valuable driving force for the remarkable progress of nickel catalysts in this area, 17 with more challenges coming in the modern design of process equipment. 18,19 Further development of the field involved rapid progress in Ni-catalyzed C-X cross-coupling reactions 20,21,22 and the MizorokiHeck reaction.…”

Eco-Friendly Physical Activation Methods for Suzuki–Miyaura Reactions

“…The clear advantages such as, cheapness and earth abundance, of the first row transition metals compared to precious metals have moved the scientific community to study Ni catalyzed SMC [78]. A few papers have studied the effect that MW irradiation has on SMC in the absence of Pd [79,80].…”