Organic chemistry

Combinatorial chemistry

Reductive elimination

Electrophile

Stereochemistry

Catalysis

Nucleophile

Medicinal chemistry

Alkene

Chemistry

Alkyne

Coupling reaction

Accounts of Chemical Research

ConspectusRecently, alkene dicarbofunctionalization, i.e., the powerful organic synthesis method of alkene difunctionalization with two carbon sources, emerged as a formidable reaction with immense promise to synthesize complex molecules expeditiously from simple chemicals. This reaction is generally achieved with transition metals (TMs) through interception by carbon sources of an alkylmetal [β-H–C(sp3)–[M]] species, a key intermediate prone to undergo rapid β-H elimination. Related prior reports, since Paolo Chiusoli and Catellani's work in 1982 [ Tetrahedron Lett. 1982, 23, 4517], have used bicyclic and disubstituted terminal alkenes, wherein β-H elimination is avoided by geometric restriction or complete lack of β-H's. With reasoning that β-H–C(sp3)–[M] intermediates could be rendered amenable to interception with the use of first row late TMs and formation of coordination-assisted transient metallacycles, these two strategies were implemented to address the β-H elimination problem in alkene dicarbofunctionalization reactions.Because first row late TMs catalyze C(sp3)–C(sp3) coupling, Cu and Ni were anticipated to impart sufficient stability to β-H–C(sp3)–[M] intermediates, generated catalytically upon alkene carbometalation, for their subsequent interception by carbon electrophiles/nucleophiles in three-component reactions. Additionally, such an innate property could enable alkene difunctionalization with carbon coupling partners through entropically driven cyclization/coupling reactions. The cyclometalation concept to stabilize intractable β-H–C(sp3)–[M] intermediates was hypothesized when three-component reactions were performed. The idea of cyclometalation to curtail β-H elimination is founded upon Whitesides's [ J. Am. Chem. Soc. 1976, 98, 6521] observation that metallacycles undergo β-H elimination much slower than acyclic alkylmetals.In this Account, examples of alkene dicarbofunctionalization reactions demonstrate that Cu and Ni catalysts could enable cyclization/coupling of alkenylzinc reagents, alkyl halides, and aryl halides to afford complex carbo- and heterocycles. In addition, forming coordination-assisted transient nickellacycles enabled regioselective performance of three-component dicarbofunctionalization of various alkenyl compounds. In situ reaction of [M]-H with alkenes generated after β-H elimination induced an unprecedented metallacycle contraction process, in which six-membered metal-containing rings shrank to five-membered cycles, allowing creation of new carbon–carbon bonds at allylic (1,3) positions. Applications of these regioselective alkene dicarbofunctionalization reactions are discussed.

Transition Metal (Ni, Cu, Pd)-Catalyzed Alkene Dicarbofunctionalization Reactions