Catalytically Generated Vanadium Enolates Formed via Interruption of the Meyer-Schuster Rearrangement as Useful Reactive Intermediates.

Enolate chemistry is one of the most fundamental strategies for the formation of carbon-carbon and carbon-heteroatom bonds. Classically, this has been accomplished through the use of stoichiometric quantities of strong base and cryogenic reaction temperatures. However, these techniques present issues related to enolate regioselectivity and functional group tolerance. While more modern methods utilizing stoichiometric activating agents have overcome some of these limitations, these processes add additional steps and suffer from poor atom economy. While certain classes of highly acidic nucleophiles have enabled the development of elegant and general catalytic solutions to address all of these limitations, functionalizing less acidic nucleophiles remains difficult.To overcome these challenges, we developed an alternative general approach for the formation and subsequent functionalization of metal enolates that leverages catalytic amounts of Lewis acid and entirely avoids the need for exogenous base or stoichiometric additives. To do so, we re-engineered the classical Meyer-Schuster rearrangement, which normally converts propargylic alcohols into α,β-unsaturated carbonyl compounds. By careful control of reaction conditions and by selection of an appropriate vanadium-oxo catalyst, the transient metal enolates formed via the 1,3-transposition of propargylic or allenylic alcohols can be guided away from simple protonation reaction pathways and toward more synthetically productive carbon-carbon, carbon-halogen, and carbon-nitrogen bond-forming processes.By utilizing readily available propargylic and allenylic alcohols as our starting materials and relying on a catalytic 1,3-transposition to generate metal enolates , all issues related to the regioselectivity of enolate formation are resolved. Likewise, utilization of a simple isomerization for enolate formation results in a highly efficient process that can be 100% atom economical. The mild reaction conditions employed also allow for remarkable chemoselectivity. Functional groups not typically conducive to enolate chemistry, such as alkynyl ketones, methyl ketones, free alcohols, and primary alkyl halides, are all well tolerated. Finally, by varying the substitution patterns of the alcohol starting materials, enolates of ketones, esters, and even amides are all accessible.Utilizing this strategy starting from propargylic alcohols, we have developed functionalization reactions that produce highly substituted and geometrically defined α-functionalized α,β-unsaturated carbonyl compounds. Such processes include aldol, Mannich, and electrophilic halogenation reactions, as well as dual catalytic reactions wherein catalytically generated vanadium enolates are trapped with catalytically generated palladium π-allyl electrophiles. In the case of allenylic alcohols, we have developed complementary aldol, Mannich, halogenation, and dual catalytic processes to generate α'-functionalized α,β-unsaturated carbonyl products.The results described in this work showcase the power and generality of our alternative approach to enolate chemistry. Additionally, we point out unaddressed challenges in the field and invite other groups to help innovate in these areas.