POCl_3 Chlorination of 4-Quinazolones

摘要

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 (R_3N, aq pK_a > 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 exclusively from reaction of (O)-phosphorylated intermediates with Cl?. (O)- and (N)-phosphorylated intermediates equilibrate rapidly on the time scale of the reaction. A minimum of 1 molar equiv of POCl_3 is required for efficient conversion of the intermediates to product.