Enormous effort has gone into the development of metal-catalyzed cross-coupling reactions with alkyl halides as electrophilic coupling partners. Whereas a wide array of primary alkyl halides can now be used effectively in cross-coupling reactions, the synthetic potential of secondary alkyl halides is just beginning to be revealed. This Minireview summarizes selected examples of the use of secondary alkyl halides as electrophiles in cross-coupling reactions. Emphasis is placed on the transition metals employed, the mechanistic pathways involved, and implications in terms of the stereochemical outcome of reactions.

Carbon-carbon bond formation is the basis for the biogenesis of nature's essential molecules. Consequently, it lies at the heart of the chemical sciences. Chiral catalysts have been developed for asymmetric C-C bond formation to yield single enantiomers from several organometallic reagents. Remarkably, for extremely reactive organolithium compounds, which are among the most broadly used reagents in chemical synthesis, a general catalytic methodology for enantioselective C-C formation has proven elusive, until now. Here, we report a copper-based chiral catalytic system that allows carbon-carbon bond formation via allylic alkylation with alkyllithium reagents, with extremely high enantioselectivities and able to tolerate several functional groups. We have found that both the solvent used and the structure of the active chiral catalyst are the most critical factors in achieving successful asymmetric catalysis with alkyllithium reagents. The active form of the chiral catalyst has been identified through spectroscopic studies as a diphosphine copper monoalkyl species.

Naphthol compounds bearing a pendant α,β‐unsaturated ester undergo a copper(I)‐catalyzed asymmetric conjugate addition/copper(II)‐mediated intramolecular oxidative coupling to afford benzofused spirocyclic cyclohexenones (see scheme). This one‐pot strategy results in two new carbon–carbon bonds and three contiguous stereocenters. The products contain a high degree of functionality and molecular complexity.

Sekundär, aber nicht zweitrangig: In den vergangenen fünf Jahren hat die Verwendung von sekundären Alkylhalogeniden in übergangsmetallkatalysierten Kreuzkupplungen erheblich zugenommen. Hier werden ausgewählte Beispiele für solche Prozesse unter Berücksichtigung von mechanistischen und stereochemischen Aspekten betrachtet.magnified imageEs wurde viel Kraft in die Entwicklung von metallkatalysierten Kreuzkupplungen mit Alkylhalogeniden als elektrophile Reaktionspartner investiert. Während schon heute zahlreiche primäre Alkylhalogenide wirksam in Kreuzkupplungen verwendet werden können, stehen Umsetzungen mit sekundären Alkylhalogeniden gerade erst am Anfang. Hier werden ausgewählte Kreuzkupplungen vorgestellt, in denen sekundäre Alkylhalogenide als Elektrophile wirken. Dabei wird den verwendeten Übergangsmetallen, den Reaktionsmechanismen und dem stereochemischen Verlauf besondere Beachtung geschenkt.

Cu-TolBINAP-catalyzed conjugate addition of Grignard reagents to 4-chloro-α,β-unsaturated esters, thioesters, and ketones leads to 4-chloro-3-alkyl-substituted thioesters and ketones in up to 84% yield and up to 96% ee upon protonation of the corresponding enolates at low temperature. Tandem conjugate addition-enolate trapping, however, yields trans-1-alkyl-2-substituted cyclopropanes in up to 92% yield and up to 98% ee. The versatility of this reaction is illustrated by the formation of key intermediates for the formal syntheses of cascarillic acid and grenadamide.

Inversion versus retention: A palladium‐catalyzed annulation with enantioenriched secondary alkyl iodides gives mechanistic insight into the stereochemistry of this CH bond functionalization reaction (see scheme) involving a proposed PdII/PdIV catalytic cycle.

A highly efficient method is reported for the asymmetric ring opening of oxabicyclic alkenes with organolithium reagents. Using a copper/chiral phosphoramidite complex together with a Lewis acid (BF(3)·OEt(2)), full selectivity for the anti isomer and excellent enantioselectivities were obtained for the ring opened products.

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