Site‐Specific Alkene Hydromethylation via Protonolysis of Titanacyclobutanes

Abstract

Methyl groups are ubiquitous in biologically active molecules. Thus, new tactics to introduce this alkyl fragment into polyfunctional structures are of significant interest. With this goal in mind, a direct method for the Markovnikov hydromethylation of alkenes is reported. This method exploits the degenerate metathesis reaction between the titanium methylidene unveiled from Cp2Ti(μ‐Cl)(μ‐CH2)AlMe2 (Tebbe's reagent) and unactivated alkenes. Protonolysis of the resulting titanacyclobutanes in situ effects hydromethylation in a chemo‐, regio‐, and site‐selective manner. The broad utility of this method is demonstrated across a series of mono‐ and di‐substituted alkenes containing pendant alcohols, ethers, amides, carbamates, and basic amines.

Multicomponent Direct Assembly of N-Heterospirocycles Facilitated by Visible-Light-Driven Photocatalysis

“…The crude residue was then purified by flash chromatography to yield the desired heterocyclic olefin. The literature data for compounds 2aa ( 37 ) and 2ac ( 37 ) matched the data obtained using this procedure.…”

Copper Hydride-Catalyzed Enantioselective Olefin Hydromethylation

“…More recently, Shenvi disclosed a hydroalkylation protocol utilizing Ni/Mn dual catalysis, in which MeI and CD 3 I were utilized to afford the corresponding methylated products, and Nocera has reported on the use of photochemically generated Me-radical from acetic acid . Finally, Frederich delineated the use of a superstoichiometric quantity of Tebbe’s reagent . Despite the emergence of several formal hydromethylation strategies, controlling the absolute stereochemistry at the newly formed C–Me bond remains a largely elusive goal (Figure B). − The most relevant asymmetric variant is limited to Lu and Fu’s elegant Co-catalyzed hydromethylation of fluoroalkenes (Figure C) …”

“…Finally, Frederich delineated the use of a superstoichiometric quantity of Tebbe’s reagent . Despite the emergence of several formal hydromethylation strategies, controlling the absolute stereochemistry at the newly formed C–Me bond remains a largely elusive goal (Figure B). − The most relevant asymmetric variant is limited to Lu and Fu’s elegant Co-catalyzed hydromethylation of fluoroalkenes (Figure C) …”

Transition Metal–(μ-Cl)–Aluminum Bonding in α-Olefin and Diene Chemistry

“…A degenerate metathesis reaction between titanium methylidene unveiled from Ti01 and unactivated alkenes, followed by acid hydrolysis, was recently proposed by Frederich et al [ 62 ] as a direct method for the Markovnikov hydromethylation of alkenes ( Scheme 4 ). The reaction is site-specific; the reactivity of olefins decreases in the order α-olefins > methylenealkanes > trisubstituted alkenes.…”

“… ( a ) General reaction scheme; ( b ) relative stability of titanacyclobutane intermediates; ( c ) scope and limitations of the titanium-mediated hydromethylation of alkenes [ 62 ]. …”