A new efficient route to the phenolic derivatives of chrysene and 5-methylchrysene, precursors to dihydrodiol and diol epoxide metabolites of chrysene and 5-methylchrysene, through Suzuki cross-coupling reaction

Abstract

A new, abbreviated synthesis of 5-methylchrysene (17), 2-hydroxychrysene (16), 8-hydroxy-5-methylchrysene (23), and 2-hydroxy-5-methylchrysene (24) is reported. The phenolic derivatives 16, 23, and 24 can easily be converted to carcinogenic dihydrodiol and diol epoxide metabolites of chrysene and 5-methylchrysene. The method entails the initial Suzuki cross-coupling reaction of naphthalene-2-boronic acid (1) and/or 6-methoxynaphthalene-2-boronic acid (2) with 2-bromo-5-methoxybenzaldehyde (3), methyl 2-bromophenylacetate (4), 2-bromophenylacetone (5), and/or 2-iodo-5-methoxyphenylacetone (6) to produce 2-(2-naphthyl)-5-methoxybenzaldehyde (7), methyl 2-(6-methoxy-2-naphthyl)phenylacetate (8), 2-(2-naphthyl)phenylacetone (9), 2-(2-naphthyl)-5-methoxyphenylacetone (10), and 2-(6-methoxy-2-naphthyl)phenylacetone (11) in 55–98% yields. 2-Methoxychrysene (15) was obtained with high regioselectivity by two different procedures. In the first procedure, the aldehyde function of 7 was elongated with trimethylsulfonium iodide under phase transfer conditions to generate the ethylene oxide 12 which after methanesulfonic acid treatment produced 15. The second procedure involved modification of ester 8 to its aldehyde analogue 14 which was subsequently treated with methanesulfonic acid to produce 15. Phenylacetone 10 was converted by methanesulfonic acid treatment into 8-methoxy-5-methylchrysene (18) with 90% regioselectivity. However, the similar cyclization of phenylacetones 9 and 11 to 5-methylchrysene (17) and 2-methoxy-5-methylchrysene (19) occurred with only 33–50% regioselectivity. The separation of 17 and 19 from their chromatographically similar 6-methylbenz[a]anthracene byproducts 20 and 22 was readily achieved by a chemical method. The methoxy derivatives of chrysene were finally demethylated with boron tribromide to the corresponding phenolic compounds in 90–98% yields.

References

1. P. G. Wislocki and A. Y. H. Lu, in Polycyclic Aromatic Hydrocarbon Carcinogenesis: Structure-Activity Relationships, eds. S. K. Yang and B. D. Silverman, CRC Press, Boca Raton, FL, 1988, vol. 1, p. 1 and other chapters.
2. R. E. Lehr, S. Kumar, W. Levin, A. W. Wood, R. L. Chang, A. H. Conney, H. Yagi, J. M. Sayer and D. M. Jerina, in Polycyclic Hydrocarbons and Carcinogenesis, ed. R. G. Harvey, ACS Symposium Monograph No. 283, American Chemical Society, Washington, DC, 1985, p. 63.
3. A. Dipple, in DNA Adducts. Identification and Biological Significance, eds. K. Hemminki, A. Dipple, D. E. G. Shuker, F. F. Kadlubar, D. Segerback and H. Bartsch, IARC Scientific Publication # 125, Lyon, France, 1994, p. 107.
4. J. DiGiovanni, L. Diamond, R. G. Harvey and T. J. Slaga, Carcinogenesis, 1983, 4, 403.
5. A. P. Grollman and S. Shibutani, in DNA Adducts. Identification and Biological Significance, eds. K. Hemminki, A. Dipple, D. E. G. Shuker, F. F. Kadlubar, D. Segerback and H. Bartsch, IARC Scientific Publication # 125, Lyon, France, 1994, p. 385.
6. A. K. Basu and J. M. Essigman, Chem. Res. Toxicol., 1988, 1, 1.
7. P. P. Fu and R. G. Harvey, J. Org. Chem., 1979, 44, 3778.
8. J. M. Karle, H. D. Mah, D. M. Jerina and H. Yagi, Tetrahedron Lett., 1977, 4021.
9. R. G. Harvey, J. Pataki and H. Lee, J. Org. Chem., 1986, 51, 1407.
10. S. Kumar, J. Org. Chem., 1997, 62, 8535.
11. N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
12. J. Pataki, P. D. Raddo and R. G. Harvey, J. Org. Chem., 1989, 54, 840.
13. A. S. Kiselyov, H. Lee and R. G. Harvey, J. Org. Chem., 1995, 61, 6123.
14. S. Amin, J. Camanzo, K. Huie and S. S. Hecht, J. Org. Chem., 1984, 49, 381.
15. L. J. Diorazio, D. A. Widdowson and J. M. Clough, Tetrahedron, 1992, 48, 8073.
16. V. Percec, P. Chu and M. Kawasumi, Macromolecules, 1994, 27, 4441.
17. I. Fleming and M. Woolias, J. Chem. Soc., Perkin Trans. 1, 1979, 829.
18. K. Binovic, S. Vrancea, O. Grandet, J. M. Lebourg and R. Porquet, Chim. Ther., 1968, 3, 313.
19. J. R. Carson, H. R. Almond, M. D. Brannan, R. J. Carmosin, S. F. Flaim, A. Gill, M. M. Gleason, S. L. Keely, D. W. Ludovici, P. M. Pitis, M. C. Rebarchak and F. J. Villani, J. Med. Chem., 1988, 31, 630.
20. S. W. Wright, D. L. Hageman and L. D. McClure, J. Org. Chem., 1994, 59, 6095.
21. M. S. Newman, J. Org. Chem., 1983, 48, 3249.
22. S. Amin, S. S. Hecht and D. Hoffman, J. Org. Chem., 1981, 46, 2394.
23. J. W. Cook and R. J. Schoental, J. Chem. Soc., 1945, 288.