Contrasting Reactions of Ketones and Thioketones with Alkyllithiums: A Coordinated Experimental and Computational Investigation

Abstract

The reaction of ketones with organolithium reagents generally proceeds by addition of the organometallic to the electrophilic carbon of the C═O group to give the lithium salt of a tertiary alcohol. The seemingly analogous reaction of thioketones with organolithiums is a fundamentally different process: such reactions typically afford a variety of products, and addition of the organolithium to carbon of the C═S group to give a thiol is a relatively unimportant component. Reactions of the stable thioketone, adamantantanethione (1), with several alkyllithiums (MeLi, n-BuLi and t-BuLi) in a variety of solvents have been studied in the first comprehensive investigation of the reactions of organolithiums with a representative alkyl-substituted thione. Reactions of 1 with n-BuLi or t-BuLi afforded 2-adamantanethiol (2) as the major product. In an effort to explain the marked difference in behavior of ketones and thioketones in reactions with organolithiums, transition states for both the addition and reduction reactions have been located at the B3LYP/6-311+G* level using acetone and thioacetone as model substrates. The transition states for the addition of dimeric MeLi to the C═O and C═S carbons of acetone and thioacetone were significantly different as a result of the small bond angles preferred by divalent sulfur, and this accounts for the much slower addition to a C═S carbon vis-à-vis a C═O group. Transition states for reduction of acetone and thioacetone by EtLi were similar, but the greater exothermicity of the reduction of the thioketone results in an earlier transition state and lower activation energy for this process than that for the reduction of a ketone. The possible role of radical-mediated processes in this chemistry is also discussed.

Computational Perspectives on Organolithiums

“…While for ketones, the main product results from addition to the carbonyl carbon, thioketones tend to undergo addition to sulfur or reduction of the C-S double bond [125]. In their study, TSs for addition to thioketones were found to require a higher activation barrier than the corresponding TSs for ketone addition, in fine agreement with their observations.…”

Chemistry of Ketene N,S-Acetals: An Overview

“…This reaction presents an alternative approach for the synthesis of 2,3-dicarbonylpyrrole derivatives. , In contrast with the construction of 88 , in the synthesis of 95 with N -methylprop-2-yn-1-amine as the amine component, the thiophilic nucleophilic reaction ,− for formation of thiiranium intermediate 98 , (also see Scheme ) should be critical for the formation of 95 via 1,2-acyl migration (Scheme ). …”

Taming Metal/Fluorine Carbenoids

“…Hydrolysis gave the corresponding thioethers 6 (see the Supporting Information). Such a 1,2‐addition of organolithium reagents to thiocarbonyl compounds—with inverse selectivity compared to carbonyl compounds—has only recently been noticed . However, the high selectivity of the reactions with thio‐ 1 and thio‐ 2 is remarkable.…”

“…Such a1 ,2-addition of organolithium reagents to thiocarbonyl compounds-with inverse selectivity comparedt oc arbonyl compounds-has only recently been noticed. [33] However,t he high selectivity of the reactions with thio-1 and thio-2 is remarkable. This reverse 1,2-addition is also in line with the formation of the cyclization products 3 and 4,i nw hich the carbenoid itself selectively adds to the C=Sbond.…”