Synthesis of the K-Region Monofluoro- and Difluorobenzophenanthrenes

Article abstract of DOI:10.1021/jo00274a026

Polycyclic aromatic hydrocarbons are metabolically activated by cytochromes P-450 an epoxide hydrolase to ultimate mutagens and carcinogens.Substitution by fluorine at specific positions has been used to elucidate metabolic activation and detoxication pathways of polycyclic aromatic hydrocarbons.Substitution by fluorine at the K-region C-6 position of the weak carcinogen benzophenanthrene (1) causes a >4-fold increase in its tumorigenicity.Out of the six possible monofluorobenzophenanthrenes, only 5-fluorobenzophenanthrene (8a) has not been evaluated as a carcinogen, presumably because a convenient synthetic method for the 5-fluoro derivative has not been available.Hence, a new method has been developed for the synthesis of 8a from readily available starting materials.The method consists of selective bromination of benzophenanthrene (1) to 5-bromobenzophenanthrene (3), substitution of bromine by an amino group, and a modified Schiemann reaction of 5-aminobenzophenanthrene (6a) to yield 5-fluorobenzophenanthrene (8a).An improved method for the synthesis of 6-fluorobenzophenanthrene (19) has also been developed which consist of bromofluorination of β-naphthylstyrene, followed by selective dehydrobromination and photocyclization of the fluorostyrene to the 6-fluoro derivative 19.The above methods, with minor modifications, also provided synthetic routes for the preparation of the difluoro derivatives 5,7-, 5,8-, and 6,7-difluorobenzophenanthrenes.