Kinetic studies of 2-(2'-Haloethyl) and 2-ethenyl substituted quinazolinone alkylating agents. Acid-catalyzed dehydrohalogenation and alkylation involving a quinazolinone prototropic tautomer.
The mechanism of halide elimination from 2-haloethyl-5,8-dihydroxyquinazolin-4(3H)-ones was studied in aqueous buffer by means of a pH-rate profile, buffer dilution studies, isotopic labeling, and kinetic isotope effects. From the results of these studies, it is apparent that a quinazolinone tautomer, arising from a prototropic shift of the C(l') proton to the N(1) position, is formed in the rate determining step of elimination. Monobasic phosphate acts as a bifunctional catalyst for the tautomerism. The halide then eliminates from the tautomer to afford the alkene derivative. Conversely, hydroxyethyl mercaptide adds to the alkene to afford the tautomer. The significance of these studies lies in the discovery of a prototropic tautomer of quinazolinone, which is reversibly formed in aqueous buffer under mild conditions, and in the discovery of alkylation chemistry useful in the design of quinazolinone-based enzyme inhibitors.
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Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-1604.
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D000477:Alkylating Agents / Q000737:chemistry*; D000478:Alkylation; D006219:Halogens / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006873:Hydroquinones / Q000737:chemistry; D010710:Phosphates; D011799:Quinazolines / Q000737:chemistry*
D000477:Alkylating Agents; D006219:Halogens; D006873:Hydroquinones; D010710:Phosphates; D011799:Quinazolines