US EPA

2140869 

Journal Article 

Synthesis of 8-fluorobenzo(a)pyrene and 9-fluoro-7,12-dimethylbenzo(a)anthracene and 10-fluoro-7,12-dimethylbenzo(a)anthracene 

Newman, MS; Kannan, R 

1979 

Yes 

Journal of Organic Chemistry
ISSN: 0022-3263
EISSN: 1520-6904 

AMER CHEMICAL SOC 

WASHINGTON 

HEEP/80/07526 

44 

19 

3388-3390 

English 

10.1021/jo01333a024 

WOS:A1979HL51600024 

HEEP COPYRIGHT: BIOL ABS. 5-Fluoro-3-(2-naphthyl)phthalide (9) and 5-fluoro-3-(1-naphthyl)phthalide (16) were synthesized by condensation of 2-(4-fluoro-2-lithiophenyl)-4,4-dimethyl-2-oxazoline with 2- and 1-naphthaladehyde, respectively, followed by hydrolysis and cyclization. Reduction of 9 to 4-fluoro-2-(2-naphthylmethyl)benzoic acid (10) in 94% yield followed by reaction of 10 with methyllithium afforded the corresponding methyl ketone (not isolated) which on heating with PPA gave 9-fluoro-12-methylbenz(a)anthracene (12) in 51% yield from 10. Oxidation of 16 yielded 83% of 4-fluoro-2-(1-naphthoyl)benzoic acid (17) which on reaction with methyllithium afforded 78% of 5-fluoro-3-methyl-3-(1-naphthyl)phthalide (18). Condensation of 8 with 1-acetonaphthone yielded 41% of 18. Reduction of 18 afforded an almost quantitative yield of 4-fluoro-2-(1-naphthylethyl)benzoic acid (19) which on cyclization by treatment with acetic anhydride, using catalytic ZnCl2, gave an acetate (not isolated) which was reduced by alkaline Zn dust treatment to 10-fluoro-12-methylbenz(a)anthracene (20) in 84% overall yield from 19. By bromination with NBS, 12 and 20 were converted in 86-88% yields into 12-(bromomethyl)-9-fluorobenz(a)-anthracene (13) and 12-(bromomethyl)-10-fluorobenz(a)anthracene (21), respectively. Treatment of 13 and 21 with KCN in a phase-transfer medium gave in 75% yields 12-(cyanomethyl)-9-fluorobenz(a)anthracene (14) and 12-(cyanomethyl)-10-fluorobenz(a)anthracene (22) which were reduced to the corresponding aldehydes (not isolated) and then cyclized with PPA to 8-fluorobenzo(a)pyrene (4) (55% overall from 14) and 9-fluorobenzo(a)pyrene (5) (42% overall from 22). Cyclization of 10 with acetic anhydride and ZnCl2 afforded crude 12-acetoxy-9-fluorobenz(a)anthracene which was oxidized to 9-fluoro-7,12-benz(a)anthraquinone (24) in 92% overall yield. Reaction of 24 with methyllithium afforded 7,12-dihydro-7,12-dihydroxy-7,12-dimethyl-9-flurobenz(a)anthracene (25) in 77% yield. This was converted into 9-fluoro-7,12-dimethylbenz(a)anthracene (27) in 81% yield by treatment with HCl followed by reduction with HCl-SnCl2. Treatment of 19 with methyllithium gave 85% of 4-fluoro-2-(1-naphthylethyl)acetophenone (28) which on heating with PPA yielded 99% of 10-fluoro-7,12-dimethylbenz(a)anthracene (29). (These fluoro derivatives should be useful in determining which metabolites of the parent compounds are responsible for their carcinogenicity.)