Mechanism of reaction of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) with nucleophiles and its crystal structure

Abstract

Hydrolysis of the title compound (1) occurs via reaction of the protonated species (16) with H₂O or HO^–. The high basicity of (1)[pK_a of (1H⁺) is 4.22], which is necessary for high reactivity, is shown by analogues with 2-aryloxy- or 2-alkoxy-substituents, but not by 2-cyano-compounds [Reissert compounds (11)] or by 3,4-dihydroquinolines (10). 1-Aryl- or 1-alkyl-oxycarbonyl-substituents have the largest effect on reactivity [e.g. the pK_a of (14H⁺) is 2.3 and its rate of reaction is increased 160-fold relative to (1H⁺)] suggesting that reaction of nucleophile initially occurs at this site. Both acetate and amine (trifluoroethylamine) buffers react with (1) by similar mechanisms involving reaction between (1H⁺) and either AcO^– or free amine; the reaction-rate–pH profiles are ‘bell-shaped.’ A new mechanism for the reaction of (1) as a reagent to promote peptide synthesis is suggested. Crystals of (1) are monoclinic, space group P2₁/n, with Z= 4 in a unit cell of dimensions a= 12.608(2), b= 7.644(1), c= 13.374(2)Å, β= 99.06(2)°. The structure was determined by direct methods from four-circle diffractometer data and refined to a final R value of 5.47% from 1 490 observed reflections.