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

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Australian Journal of Chemistry. 2015, 68(5), pp. 814-824. ISSN 0004-9425. eISSN 1445-0038. Available under: doi: 10.1071/CH14073
Zusammenfassung

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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ISO 690OPITZ, Andreas, Werner SULGER, Ewald DALTROZZO, Rainer KOCH, 2015. ‘Green’ Synthesis of 2-Substituted 6-Hydroxy-[3H]-pyrimidin-4-ones and 4,6-Dichloropyrimidines : Improved Strategies and Mechanistic Study. In: Australian Journal of Chemistry. 2015, 68(5), pp. 814-824. ISSN 0004-9425. eISSN 1445-0038. Available under: doi: 10.1071/CH14073
BibTex
@article{Opitz2015Green-31759,
  year={2015},
  doi={10.1071/CH14073},
  title={‘Green’ Synthesis of 2-Substituted 6-Hydroxy-[3H]-pyrimidin-4-ones and 4,6-Dichloropyrimidines : Improved Strategies and Mechanistic Study},
  number={5},
  volume={68},
  issn={0004-9425},
  journal={Australian Journal of Chemistry},
  pages={814--824},
  author={Opitz, Andreas and Sulger, Werner and Daltrozzo, Ewald and Koch, Rainer}
}
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    <dcterms:abstract xml:lang="eng">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.</dcterms:abstract>
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