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POCl3 Chlorination of 4-Quinazolones

The reaction of quinazolones with POCl3 to form the corresponding chloroquinazolines occurs in two distinct stages, which can be separated through appropriate temperature control. An initial phosphorylation reaction occurs readily under basic conditions (R3N, aq pKa > 9) at t < 25 °C to give a variety of phosphorylated intermediates. Pseudodimer formation, arising from reaction between phosphorylated intermediates and unreacted quinazolone, is completely suppressed at these temperatures, provided the system remains basic throughout the POCl3addition. Clean turnover of phosphorylated quinazolones to the corresponding chloroquinazoline is then achieved by heating to 70−90 °C. (N)- and (O)-phosphorylated intermediates, involving multiple substitution at phosphorus, have been identified and their reactions monitored using a combination of 1H, 31P, and 19F NMR. Kinetic analysis of the reaction profiles suggest that the various intermediates react with both Cl− and Cl2P(O)O−, but product formation arises exclus...

Authors:   Euan A. Arnott; Lai C. Chan; Brian G. Cox; Brian Meyrick; Andy Phillips
Journal:   The Journal of Organic Chemistry
Year:   2011
DOI:   10.1021/jo102262k
Publication date:   04-Feb-2011
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