Turning mustard gas chemistry into green chemistry: a new tool for pharmaceutical synthesis

N,N -dialkyl ethylamine moiety can be found in numerous scaffolds of macromolecules, catalysts and especiallypharmaceuticals such as Tamoxifen, Raloxifene, Amiodarone, Phenyltoloxamine, Trifenagrel and Trimethobenzamide.Common synthetic procedures for its incorporation in a substrate rely on the use of a nitrogen mustard gas or onmultistep syntheses featuring chlorine hazardous/toxic chemistry. Herein are reported our latest results on the one-potsynthetic approach for the introduction of the N,N -dialkyl ethylamine moiety in different phenolic substrates via dialkylcarbonate chemistry. In a typical reaction, 2-dimethylaminoethanol was reacted with a nucleophile (a phenolic scaffold)and dialkyl carbonate (DAC), i.e., diethyl carbonate (DEC), in the presence of a base. In particular, DEC was used for thein-situ formation of ß-aminocarbonate (mustard carbonate) that in turn acts as an alkylating agent via nitrogen nitrogenanchimeric assistance. Different substrates were investigated including precursors of commercially available drugsgiving the related alkylated compound in good to quantitative yields. This one-pot alkylation approach is a striking example of chlorine-free direct substitution of an alcohol, indicated as oneof the key Green Chemistry research areas for pharmaceuticals manufacturers. Furthermore, an in vitro toxicity studyhas been conducted on ß-aminocarbonate and its alcohol precursor, giving an insight into the cytotoxicity values of thereagents for the synthetic procedure proposed.