Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1 H)-ones Using 4-(Iodomethyl)pyrimidines

Mateus Mittersteiner; Genilson S Pereira; Ludger A Wessjohann; Helio G Bonacorso; Marcos A P Martins; Nilo Zanatta

doi:10.1021/acsomega.2c01925

Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1 H)-ones Using 4-(Iodomethyl)pyrimidines

ACS Omega. 2022 May 24;7(22):18930-18939. doi: 10.1021/acsomega.2c01925. eCollection 2022 Jun 7.

Authors

Mateus Mittersteiner^{1

2}, Genilson S Pereira¹, Ludger A Wessjohann², Helio G Bonacorso¹, Marcos A P Martins¹, Nilo Zanatta¹

Affiliations

¹ Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil.
² Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany.

Abstract

This study reports two strategies for preparing O-alkyl derivatives of 6-substituted-4-(trifluoromethyl)pyrimidin-(1H)-ones: a linear protocol of alkylation, using a CCC-building block followed by [3 + 3]-type cyclocondensation with 2-methylisothiourea sulfate and a convergent protocol based on direct alkylation, using 4-(iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines. It was found that the cyclocondensation strategy is not feasible; thus, the direct chemoselective O-alkylation was performed, and 18 derivatives of the targeted pyrimidines were obtained in 70-98% yields. The structure of the products was unambiguously determined via single crystal X-ray analyses and two-dimensional nuclear magnetic resonance experiments.