Development of Efficient Synthetic Method for Tautomeric Dihydropyrimidines and Analysis of Their Functionality

Abstract

I here present the results of our studies on the synthesis and functional analysis of tautomeric dihydropyrimidines (DPs) and related compounds in two sections. In the first section, we describe our experimental and theoretical studies on the thermodynamics and properties of 2-substituted 1,4- and 1,6-dihydropyrimidine-5-carboxylates by 1H NMR measurements and density functional theory (DFT) calculations, respectively. The concentration ratios of tautomers a/b of DPs 1, 2, and 3 were determined under various conditions to determine the effects of temperature, solvent, and concentration on thermodynamics data. The obtained free energy differences (ΔG), enthalpy differences (ΔH), and entropy differences (ΔS) are discussed in terms of the molecular structures, dipole moments (DM), and electrostatic potential maps obtained by DFT calculations to clarify the nature of DPs 4-8. In the second section, an efficient synthetic method developed for 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-thiones 9 and 2-ones 10 is described. The novelties of the synthesis protocol are as follows: 1) the use of Lewis acid-mediated reaction, 2) good to high yields, and 3) its broad scope of applicability to aldehydes and ureas. Hitherto unavailable 6-unsubstituted 2-amino DP 11 and 2-aryl DP 12 were obtained from 9 by a substitution reaction with the amine and the Liebeskind-Srogl reaction, respectively. The compounds 9, 10, and related 6-methyl derivatives 19-21 were assessed for their antiproliferative effect on the human promyelocytic leukemia cell line HL-60. 4,4-Dipropyl derivative 20 showed relatively strong activity with an IC50 value of 341 nM.