Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

Abstract

Olefin double-bond functionalization has been established as an excellent strategy for the construction of elaborate molecules. In particular, the hydroalkylation of olefins represents a straightforward strategy for the synthesis of new C(sp3)–C(sp3) bonds, with concomitant formation of challenging quaternary carbon centers. In the last 20 years, numerous hydroalkylation methodologies have emerged that have explored the diverse reactivity patterns of the olefin double bond. This review presents examples of olefins acting as electrophilic partners when coordinated with electrophilic transition-metal complexes or, in more recent approaches, when used as precursors of nucleophilic radical species in metal hydride hydrogen atom transfer reactions. This unique reactivity, combined with the wide availability of olefins as starting materials and the success reported in the construction of all-carbon C(sp3) quaternary centers, makes hydroalkylation reactions an ideal platform for the synthesis of molecules with increased molecular complexity.

Efficient Radical‐Mediated Intermolecular α‐Alkylation Reactions of Carbonyl Compounds with Nonactivated Alkenes

“…In particular, reactions with nonactivated alkenes such as 1‐hexene do not proceed due to their very weak electrophilicity. Nevertheless, such nonactivated alkenes are important substrates in organic synthesis because the range of linear and branched alkenes with different alkyl chain lengths enables the introduction of carbon backbones into many useful molecules [3] . Furthermore, when alkenes bearing well‐functionalized alkyl chains are used, late‐stage alkylation processes are possible for convergent syntheses of complex molecules.…”

“…Nevertheless, such nonactivated alkenes are important substrates in organic synthesis because the range of linear and branched alkenes with different alkyl chain lengths enables the introduction of carbon backbones into many useful molecules. [3] Furthermore, when alkenes bearing well-functionalized alkyl chains are used, late-stage alkylation processes are possible for convergent syntheses of complex molecules. This is a highly useful and valuable method in synthetic organic chemistry.…”

Rhodium-Catalyzed Desymmetric Arylation of γ,γ-Disubsituted Cyclohexadienones: Asymmetric Synthesis of Chiral All-Carbon Quaternary Centers

“…The construction of enantio-enriched all-carbon quaternary stereogenic centers is considered particularly challenging in modern asymmetric synthesis . Recently, great attention has been paid to the stereocontrolled formation of all-carbon quaternary stereocenters through chemical catalysis, and a number of distinct catalytic enantioselective methodologies have been established .…”

“…Recently, great attention has been paid to the stereocontrolled formation of all-carbon quaternary stereocenters through chemical catalysis, and a number of distinct catalytic enantioselective methodologies have been established . Cyclohexane rings containing all-carbon quaternary stereogenic centers are important building blocks in a large number of pharmaceutical agents and natural compounds (Scheme a). , Intramolecular desymmetrization reactions of differently γ , γ -disubsituted cyclohexadienones have been developed for the synthesis of six-member rings with all-carbon quaternary stereocenters, whereas more challenging intermolecular variants have been developed with some organocatalysts (Scheme b). , To date, the transition metal-catalyzed intermolecular desymmetrization of prochiral cyclohexadienones has been rarely reported and has been focused on the desymmetric reduction of one olefinic group (Scheme c). , Recently, Nishiyama and coworkers disclosed a desymmetric reduction of γ , γ -disubstituted cyclohexadienone derivatives by Rh-catalyzed conjugated hydrosilylation, and Zhang reported a Ni-catalyzed desymmetric hydrogenation of cyclohexadienones . Meanwhile, Rh-catalyzed domino reactions for the intramolecular desymmetrization of alkene- and alkyne-tethered cyclohexadienones have been reported (Scheme d). , To our knowledge, there is no report on the intermolecular desymmetric arylation of cyclohexadienones.…”