Intra- and intermolecular alkylation of N,O-acetals and TT-activated alcohols catalyzed by in situ generated acid

Hamon, Mélanie, Dickinson, Niall, Devineau, Alice, Bolien, David, Tranchant, Marie-José, Taillier, Catherine, Jabin, Ivan, Harrowven, David, Whitby, Richard, Ganesan, A. and Dalla, Vincent (2014) Intra- and intermolecular alkylation of N,O-acetals and TT-activated alcohols catalyzed by in situ generated acid. Journal of Organic Chemistry, 79 (5), 1900-1912. (doi:10.1021/jo4015886). (PMID:24533649)

Abstract

Intramolecular and intermolecular alkylations of carbocation precursors of limited ionization ability, principally N,O-acetals, without the use of an exogenous reagent have been developed. The reactions are carried out in 1,1,2,2-tetrachloroethane (TCE) and take advantage of the ability of this solvent to continuously release small amounts of HCl by thermolytic elimination. A study of the reaction led to several improved protocols such as (1) preheated TCE, (2) microwave-assisted reactions, and (3) flow or sealed-tube conditions, which allow significant reaction rate enhancements and made possible some challenging reactions such as the alpha-amidoalkylation of ketones. Studies using flow chemistry confirmed not only that very low concentrations of HCl generated from the solvent were responsible for the reactivity but also that TCE had additional beneficial properties in comparison to other chlorinated solvents such as dichloroethane. The method can easily be extended to the alkylation using proelectrophiles such as pi-activated alcohols, which are normally unreactive toward HCl catalysis. This work represents the first successful use of HCl, the simplest strong Bronsted acid, as an efficient alkylation catalyst.

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Contributors

Author: David Harrowven

Author: Richard Whitby

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