Synthetic Applications and Mechanistic Studies of the Hydroxide-Mediated Cleavage of Carbon–Carbon Bonds in Ketones

Abstract

The hydroxide-mediated cleavage of ketones into alkanes and carboxylic acids has been reinvestigated and the substrate scope extended to benzyl carbonyl compounds. The transformation is performed with a 0.05 M ketone solution in refluxing xylene in the presence of 10 equiv of potassium hydroxide. The reaction constitutes a straightforward protocol for the synthesis of certain phenyl-substituted carboxylic acids from 2-phenylcycloalkanones. The mechanism was investigated by kinetic experiments which indicated a first order reaction in hydroxide and a full negative charge in the rate-determining step. The studies were complemented by a theoretical investigation where two possible pathways were characterized by DFT/M06-2X. The calculations showed that the scission takes place by nucleophilic attack of hydroxide on the ketone followed by fragmentation of the resulting oxyanion into the carboxylic acid and a benzyl anion.

Enantioconvergent Palladium‐Catalyzed Alkylation of Tertiary Allylic C−H Bonds

“…In contrast, much lower diastereoselectivity, but higher enantioselectivity, was observed when the aryl substituent was located away from the allylic carbon (10)(11)(12). A variety of functional groups were also tolerated (13)(14)(15)(16)(17)(18)(19) to quickly enlarge the pool of α-alkene substrates amenable to this enantioconvergent allylic CÀ H alkylation reaction. Notably, a carbonyl group adjacent to the allylic CÀ H bond could also participate in the reaction, generating α-quaternary carbonyl compounds (20)(21)(22)(23) with high levels of stereo-and regioselectivity, albeit with a diminished enantioselectivity for an aliphatic ketone substrate (24).…”

“…[18] Notably, the allylation products obtained from this enantioconvergent allylic CÀ H alkylation actually provide densely functionalized platform molecules for the synthesis of important building blocks bearing an all-carbon quaternary stereogenic center that are otherwise difficult to access (Scheme 5c). For instance, the treatment of 18 with LiAlH 4 , followed by a base-mediated retro-Claisen reaction, [19] afforded benzothiazole 58 in 95 % yield via two steps. Following a one-pot After removal of the triphenylmethyl protecting group with p-toluenesulfonic acid, oxidation of the resulting primary alcohol with Dess-Martin periodinane (DMP) afforded aldehyde 61 in 90 % yield in two steps.…”

Enantioconvergent Palladium‐Catalyzed Alkylation of Tertiary Allylic C−H Bonds

“…[18] Notably, the allylation products obtained from this enantioconvergent allylic CÀ H alkylation actually provide densely functionalized platform molecules for the synthesis of important building blocks bearing an all-carbon quaternary stereogenic center that are otherwise difficult to access (Scheme 5c). For instance, the treatment of 18 with LiAlH 4 , followed by a base-mediated retro-Claisen reaction, [19] afforded benzothiazole 58 in 95 % yield via two steps. Following a one-pot sequence consisting of N-methylation of benzothiazole with MeOTf, reduction of benzothiazolium with NaBH 4 and hydrolysis of benzothiazoline with AgNO 3 , 58 was converted to chiral aldehyde 59 in 95 % yield.…”

tert-Butoxide-Mediated Protodeformylative Decarbonylation of α-Quaternary Homobenzaldehydes

“…7 Recently, Madsen and co-workers studied the mechanism of Haller-Bauer-type decarbonylations of enolizable aldehydes (Scheme 1B) as well as non-enolizable aldehyde substrates like 2,6-dichlorobenzaldehyde (not shown). 8 Similar conditions are known to be capable of deformylating certain non-enolizable aldehydes like triphenylacetaldehyde 9 despite benzaldehydes being especially sensitive to hydroxide-mediated Cannizzaro-type disproportionation into the alcohol and carboxylic acid. 10 Other methods for formal protodeformylation of aldehydes have also been described.…”