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-C1BP). In this synthesis 1-FBP was also produced. The overall yield was 16% for both 1-FBP and 3-FBP. After nitration of 6-C1BP 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-C1BP and 3-F-6-C1BP 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.