‘Green’ Synthesis of 2-Substituted 6-Hydroxy-[3H]-pyrimidin-4-ones and 4,6-Dichloropyrimidines: Improved Strategies and Mechanistic Study*

Andreas Opitz; Werner Sulger; Ewald Daltrozzo; Rainer Koch

doi:10.1071/CH14073

RESEARCH ARTICLE

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‘Green’ Synthesis of 2-Substituted 6-Hydroxy-[3H]-pyrimidin-4-ones and 4,6-Dichloropyrimidines: Improved Strategies and Mechanistic Study*

Andreas Opitz ^A ^C , Werner Sulger ^A , Ewald Daltrozzo ^A and Rainer Koch ^B

+ Author Affiliations

- Author Affiliations

^A Department of Chemistry, University of Konstanz, Universitätsstr. 10, D-78457 Konstanz, Germany.

^B Institut of Chemistry and Center for Interface Science, University Oldenburg, PO Box 2503, D-26111 Oldenburg, Germany.

^C Corresponding author. Email: andreasc.opitz@t-online.de

Australian Journal of Chemistry 68(5) 814-824 https://doi.org/10.1071/CH14073
Submitted: 14 February 2014 Accepted: 5 August 2014 Published: 13 November 2014

Abstract

An improved route to 2-substituted 6-hydroxy-[3H]-pyrimidin-4-ones 4 and to 2-substituted 4,6-dichloropyrimidines 5 is reported. Without using highly toxic reactants, compounds 4 can be prepared conveniently in a one pot synthesis on a one mol scale with average yields up to 80 %. 4,6-Dichloropyrimidines 5, which are usually prepared in small quantities, are synthesized with average yields of 80 %, using up to 80 g of starting material. The mechanism of the chlorination of 4 is investigated computationally for the first time. The results suggest that the chlorination with phosphoryl chloride occurs in an alternating phosphorylation–chlorination manner (pathway 1) which is preferred over a sequence which starts with two phosphorylations. The investigated 4,6-dichloropyrimidines described herein form strong complexes with dichlorophosphoric acid but weak complexes with hydrochloric acid (generated during workup). These latter complexes explain the necessity of using aqueous sodium carbonate during the working up. In order to prevent possible formation of pyrimidinium salts between intermediates or the final dichloropyrimidines and unreacted hydroxypyrimidone, the latter could be deactivated with a strong acid such as dichlorophosphoric acid, thus allowing chlorination but prohibiting salt formation. Because of its general applicability to all nitrogen heterocycle chlorinations with phosphoryl chloride, the proposed route to dichloropyrimidines without solvent or side products, using less toxic reactants, is of general synthetic interest.

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‘Green’ Synthesis of 2-Substituted 6-Hydroxy-[3H]-pyrimidin-4-ones and 4,6-Dichloropyrimidines: Improved Strategies and Mechanistic Study*

Abstract

References

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