Synthesis of 1- and 3-fluorobenzo[a]pyrene

Fluoro-substituted aromatic hydrocarbons are useful probes for studying mechanistic details of oxygen transfer in metabolism catalyzed by cytochrome P450. Benzo[a]pyrene (BP) is a particularly suitable substrate for investigating this mechanism. Because 3-hydroxybenzo[a]-pyrene is one of the major metabolites of BP, preparation of 3-fluorobenzo[a]pyrene (3-FBP) was undertaken. Synthesis of 3-FBP was achieved in five steps starting from 6-chlorobenzo[a]pyrene (6-ClBP). In this synthesis 1-FBP was also produced. The overall yield was 16% for both 1-FBP and 3-FBP. After nitration of 6-ClBP at C-1 and C-3 with N2O4 and reduction by SnCl2 to the amino group, diazotization with NaNO2 in the presence of NaBF4 followed. The diazonium tetrafluoroborate salts were reacted with (CH3)2NH to produce the dimethyltriazonium tetrafluoroborate salts. By heating in toluene, a mixture of 1-F-6-ClBP and 3-F-6-ClBP was obtained. The two isomers were separated by normal-phase medium-pressure liquid chromatography. The chloro substituent was then selectively removed from both isomers by hydrogenolysis to yield 1-FBP and 3-FBP.