General Ambient Temperature Benzylic Metalations Using Mixed-Metal Li/K-TMP Amide

Abstract

Highly regioselective benzylic metalations in hydrocarbon solvent have been achieved at rt and 0 °C using a mixed-metal Li/K-TMP amide comprised of KOtBu, BuLi, and 2,2,6,6,-tetramethylpiperidine (TMP(H)). Mixing of KOtBu, BuLi, and TMP(H) in heptane gave a solution of the base mixture which when used in deuterium labeling experiments confirmed the requirement of the three reagent components for both reactivity and selectivity. The reaction protocol is operationally straightforward and found to be applicable to a broad range of substrates. Upon generation of the metalated products, they are reacted in heptane at ambient temperature in a variety of synthetically useful ways. Illustrated examples include generation of the benzyltrimethylsilanes and α,α-bis(trimethylsilyl)toluenes reagents, which are bench-stable surrogates of benzyl anions and α-silyl carbanions utilized for nucleophilic addition and Peterson olefination reactions. Direct C-C couplings mediated by 1,2-dibromoethane provided entries into bibenzyls and [2.2]metacyclophanes. Comparison of reaction outcomes with the same reactions carried out in THF at -78 °C showed no negative effects for conducting the reactions under these milder more user-friendly conditions.

Catalytic Direct‐Type Addition Reactions of Alkylarenes with Imines and Alkenes

“…[13] Here,w er eport the development of Brønsted base catalyzed addition reactions of nonactivated alkylarenes,i ncluding regio-and stereocontrolled reactions. [16] In these systems,s trongly basic metal dialkylamides forms as product bases. [16] In these systems,s trongly basic metal dialkylamides forms as product bases.…”

“…[14] Catalytic addition reactions of toluene to N-alkylimines were designed and conducted in the presence of ac atalytic amount of KO t Bu and lithium 2,2,6,6-tetramethylpiperidide (LiTMP), [15] as ystem that has sufficiently strong basicity to deprotonate the benzylic hydrogen atom smoothly even at À78 8 8C, as investigated by OShea et al (LiNK system). [16] In these systems,s trongly basic metal dialkylamides forms as product bases. [17] When N-tert-butylimine 1a was used as an electrophile,t he desired reaction proceeded smoothly with 20 mol %ofthe base species (Table 1, entry 1).…”

Synthesis of Nitrile‐Bearing Quaternary Centers by an Equilibrium‐Driven Transnitrilation and Anion‐Relay Strategy

“…For the synthesis of 10 c and 10 d , TMPH (2,2,6,6‐tetramethylpiperidine) was used as an additive to generate a potassium/lithium amide. This helps to avoid the formation of side‐products resulting from directed ortho metalation by the OMe group . Complete selectivity for deprotonation of the methyl group was observed and the corresponding secondary benzylic nitriles were synthesized in excellent yields.…”

Synthesis of Nitrile‐Bearing Quaternary Centers by an Equilibrium‐Driven Transnitrilation and Anion‐Relay Strategy

“…Twostrategies for the generation of benzylithium reagents were investigated:c arbolithiation of styrene (Scheme 5a) [17] and selective deprotonation of toluene derivatives (Scheme 5b). [18] Using the carbolithiation protocol, three new CÀCb onds can be formed in ao ne-pot process to generate functionalized a-arylnitriles from styrene and 2b as the electrophilic CN source.Asaproof of concept, products 8a-8c were prepared in 69-80 %u sing n-BuLi, s-BuLi, and t-BuLi as nucleophiles.Asolvent switch to THF was required here too to initiate fragmentation of the lithium imine intermediate.…”