Fully Substituted Dihydropyrimidines, Pentasubstituted 2-Aryldihydropyrimidines Synthesized by Palladium-Catalyzed/Copper-Mediated Cross-Coupling Reaction

Abstract

Dihydropyrimidines (DPs) show a wide range of biological activities suitable for medicinal applications. Among DP derivatives, 2-aryl-DPs have been reported to display remarkable pharmacological properties. In this work, a method of synthesizing hitherto unavailable fully substituted pentasubstituted 2-aryl-DPs as tautomeric mixture is described using a Pd(PPh₃)₄-catalyzed/CuBr-mediated 2-arylation reaction. The reaction using aryltributylstannanes with various substituents such as MeO, Me, Ph, CF₃, CO₂Me, and NO₂ groups efficiently afforded the corresponding 2-aryl-DPs in high yields. Heteroaryltributylstannanes having 2-thienyl, 3-thienyl, or 2-pyridinyl groups were also suitable for the reaction. Regarding the substituents at the 4-, 5-, and 6-positions of DPs, the reactions of DPs bearing substituents such as Me, n-C₃H₇, n-C₅H₁₁, -(CH₂)₅-, phenyl, and fluorenylidene groups proceeded smoothly to give the desired products. The synthetic method was also applied to a 2-thioxo-DP to give the 2-aryl-DP. Therefore, the reaction will help expand DP-based molecular diversity, which may impact biological and pharmacological studies.

Key words

dihydropyrimidine - fully substituted 2-aryldihydropyrimidine - Pd-catalyzed/Cu-mediated reaction - Liebeskind–Srogl-type cross-coupling reaction - palladium catalyst - copper reagent - aryltributylstannanes - heteroaryltributylstannanes

Publication History

Received: 16 December 2022

Accepted after revision: 08 February 2023

Accepted Manuscript online:
08 February 2023

Article published online:
13 March 2023

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