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

Abstract

Conspectus 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 in situ, 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 showcas...

Recent Developments in the Meyer‐Schuster Rearrangement

“…A remarkable example was reported by B. M. Trost's group in 2011. [39] They developed a cross-coupling reaction of a vanadium-mediated MSR with a Pd-catalyzed allylation process (Scheme 5). Extensive studies have been performed regarding the nature of the two catalysts, as well as the phosphine ligands, the solvents and the reaction conditions, in order to limit the competitive processes such as the classical MSR.…”

Meyer–Schuster-Type Rearrangement of Propargylic Alcohols into α-Selenoenals and -enones with Diselenides

“…However, studies using the in situ generated selenenium ions to attack propargylic alcohols of C–C triple bond (CC) are still very limited . The Meyer–Schuster rearrangement represents an atom-economical approach to the synthesis of α,β-unsaturated carbonyls from readily accessible propargylic alcohols . Most recently, Lüdtke and co-workers established a Meyer–Schuster-type rearrangement reaction of propargylthioalkynes with in situ generated PhSeI for the production of α-selanyl-α, β-unsaturated thioesters .…”

Direct Nucleophilic Substitution of Alcohols Using an Immobilized Oxovanadium Catalyst

“…The specific selectivity of VMPS4 for alcohol over acetate could be rationalized by the favorable covalent VÀ O bond formation between alcohol substrates and oxovanadium species of VMPS involved in the catalytic cycle. [20,[35][36][37] Chemoselectivity of the VMPS4-catalyzed substitution was further investigated using benzyl alcohol 1 b or thiol 6 (Scheme 1) as a substrate. Although the reaction required a higher temperature such as 80°C to proceed, it afforded thioether 3 ba in a moderate yield, along with a considerable amount of styrene and a trace amount of self-condensation product 4 b (eq.…”