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Chem. Res. Toxicol. 1994, 7, 722-723
Communications Convenient Synthesis of 3=Methoxybenz[u] anthracene-7,la-dione Dhimant Desai, Jacek Krzeminski, and Shantu Amin* Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595 Received June 28, 1994@
The regioselective synthesis of 3-methoxybenz[alanthracene-7,12-dione by oxidative photocyclization is described. The synthesis involved preparation of 1-(l-bromo-2-naphthyl)-2-(3methoxypheny1)ethylene by Wittig reaction, followed by photocyclization for 4 h. This gave 7-bromo-3-methoxybenz[alanthracene.Extended photocyclization over 16 h under similar a n important intermediate in the conditions gave 3-methoxybenz[alanthracene-7,12-dione, synthesis of 7,12-dimethylbenz[alanthracene-3,4-diol 1,a-epoxide. 7,12-Dimethylbenz[alanthracene(DMBA)l is one of the most potent carcinogenic polycyclic aromatic hydrocarbons (PAH)' known and is widely used as a model compound in carcinogenesis studies with Laboratory animals (1). The synthesis of DMBA-3,4-diol-1,2-epoxide, an ultimate carcinogenic metabolite of DMBA, was reported by Lee and Harvey (11. The key intermediate in the synthesis, 3-methoxybenz[ulanthracene-7,12-dione (41, was prepared by condensation of the Grignard reagent of 6-methoxy-2-bromonaphthalenewith phthalic anhydride, followed by reduction, acetylation, cyclization, and oxidation. Earlier, Newman et al. also reported the synthesis of 4 by using a similar approach (2). In this paper, we report a simple synthesis of 4 (Scheme 1). The oxidative photocyclization of stilbenes and related arylethylenes is a valuable approach to the synthesis of a variety of PAH. Oxidative photocyclization of stilbene, substituted in the meta position, usually gives a 1:l mixture of 2-substituted and 4-substituted phenanthrenes. However, the elimination photocyclization of an o-methoxystilbene under controlled conditions, gives regioselective products (3).Mallory et al. have reported the regioselective synthesis of substituted phenanthrenes, using either oxidative or elimination photocyclization (3). When the starting material is a 2-styrylnaphthalene, oxidative photocyclization favors ring closure at the 1-position rather than the 3-position of the naphthalene ring. For example, 2-styrylnaphthalene undergoes oxidative photocyclization to give almost exclusively benzo[clphenanthrene with only a trace of benz[alanthracene (3). We have used this approach to synthesize 4-methoxybenzo[clphenanthrene, a key intermediate in the preparation of benzo[c]phenanthrene-3,4-dioll,2-epoxide (anti) (4); benz[a]anthracene derivatives were not formed. Similarly, when a 2-substituted phenanthrylstyrene was oxidatively photocyclized, it gave exclusively a benzo[c]Abstract published in Advance ACS Abstracts, September 15,1994. 'Abbreviations: DMBA, 7,12-dimethylbenz[alanthracene;PAH, polycyclic aromatic hydrocarbon. @
chrysene derivative.2 Mallory et al. have tried various conditions but remained unsuccessful in the isolation of benz[alanthracenes through eliminative photocyclization (3). In our approach to the synthesis of 4 (Scheme l ) , we thereby blocking have used l-bromo-2-styrylnaphthalene, the 1-positionof the naphthalene ring. Phosphonium salt 1 was prepared by reacting triphenylphosphine and l-bromo-2-(bromomethyl)naphthalene.Olefin 2 was prepared by Wittig reaction of phosphonium salt 1 and m-anisaldehyde. Photocyclization of olefin 2 for 4 h under standardized conditions by using a Pyrex filter gave 32% of 7-bromo-3-methoxybenz[alanthracene(3) and 26% of 4. The fragmentation products l-bromo-2naphthaldehyde and m-anisaldehyde were also observed. Photocyclization of olefin 2 for 16 h gave only 4 (44%) and fragmentation products. We could not isolate even a trace of 3. Probably, 3 was converted to 4 by peroxide formation, followed by elimination. We also did not see any traces of benzo[c]phenanthrene derivatives, which theoretically could have resulted from photodehalogenation of 2 and cyclization of the 1-position of the naphthalene ring. The effectiveness of blocking the ortho position was also observed by Olsen et al. in the preparation of 1-bromo-4-methylphenanthreneas well as l-bromo4-methoxychrysene (5). In another experiment, stilbene 2 was irradiated for 8 h in benzene solution under standard conditions by using iodine and air with a Vycorfiltered 450-W Hanovia medium-pressure mercury lamp. We identified less of the decomposition product; the major (4). product was 3-methoxybenz[alanthracene-7,12-dione Performing the photocyclization of olefin 2 for 8 h under nitrogen atmosphere in the absence of iodine by using a Vycor-filtered Hanovia lamp, we isolated only 2-5% of 7-bromo-3-methoxybenz[a]anthracene(3);the fragmentation products l-bromo-2-naphthaldehyde and m-anisalTroton NMR of 9-methoxybenzo[clch1ysene:(CDCls)6 4.10 (8,3H, OCH3),7.05 (d, lH, Hlo, Js,1o = 7.67 Hz), 7.60-7.80 (m, 3H, Hz, H3, and HI'), 7.90 (d, lH, H7, 57.8 = 8.84 Hz), 7.94 (d, 1H, H14, 513,14 = 9.19 Hz), 8.01 (dd, lH, Hi, 5 1 2 = 7.90 Hz,51,s = 1.23 Hz), 8.05 (d, lH, He, 56,6= 8.74 Hz), 8.45 (d, lH, Ha, 573 = 9.06 Hz),8.68 (d, lH, Hiz, 511,12 = 8.43 Hz), 8.84 (d, 2H, H4 and Hs), 9.05 (d, lH, H13, J13,14 = 9.24 Hz); mp 170-171 "C; MS m l z (relative intensity) 308 (M+, go), 293 (10).
0893-228d94/2707-0722$04.50/00 1994 American Chemical Society
Communications
Chem. Res. Toxicol., Vol. 7, No. 6,1994 723
Scheme 1. Synthesis of 3-Methoxybenz[a]anthracene~7,12-dione (4)a
b
10 9
1
Br
dehyde were observed as a major products. We did not observe traces of 4. 3-Methoxybenz[a]anthracene-7,12dione (4) can be converted to 7,12-DMBA-3,4-diol-1,2epoxide by the method of Lee and Harvey (1).
Experimental Section General. Melting points were determined with a ThomasHoover oil bath apparatus and are uncorrected. NMR spectra were obtained in CDC13 solution with Me4Si as a n internal standard using a Bruker AM 360 WB spectrometer (Billerica, MA). Mass spectra (MS) were determined with a Hewlett Packard Model 5988A instrument (Paramus, NJ). All starting materials were obtained from Aldrich Chemical Co. (Milwaukee, WI). l-Bromo-2-(bromomethyl)naphthalene was prepared in 80% yield by reacting 1-bromo-2-methylnaphthalene with N bromosuccinamide (6).
l-(l-Bromo-2-naphthyl)-2-(3-methoxyphenyl)ethylene (2). (1-Bromo-2-naphthylmethy1)triphenylphosphonium bromide (I) was prepared in 95%yield by heating 1-bromo-24bromomethyl)naphthalene and triphenylphosphine in refluxing benzene. Phosphonium salt l ( 1 5 g ,23.36 mmol), m-anisaldehyde (3.18 g , 23.36 mmol), and NaOCH3 (1.89 g , 35.04 mmol) in CH30H (200 mL) were allowed to react a t room temperature for 18 h. The reaction was quenched with dilute HC1 (lo%, 150 mL), the organic portion was extracted into CHzClz (3 x 150 mL), and after removal of CHzClz the residue was filtered through a silica gel column with elution by hexane. Upon concentration, the filtrate afforded a mixture of cis and trans olefin 2 as an oil (4.2 g , 53%): lH NMR 6 3.55 ( s , 2.16H, OCH3, from trans isomer), 3.90 (s, 0.84H, OCH3 from cis isomer), 6.60-8.50 (m, 12H); MS m l z (relative intensity) 340 (M + 1, 20). 7-Bromo-3-methoxybenz[a]anthracene (3)and 3-Methoxybenz[alanthracene-7,12-dione(4).A solution of 2 (1.6 g , 4.72 mmol) and iodine (5 mg) in dry benzene (1 L) was irradiated with a Pyrex-filtered Hanovia 450-W medium-pressure UV lamp, while dry air was bubbled through the solution. "he reaction was stopped after 4 h, the solvent was removed under reduced pressure, and the residue was purified by chromatography on a silica gel column with elution by petroleum ether/EtOAc (15:l) to yield 1-bromo-2-naphthaldehyde(0.1 g , 9%) and, with further elution, 3 (0.51 g , 32%) as a white solid:
2
Br
8
Br
31
mp 162-163 "C; lH NMR 6 3.99 (s,3H,OCH3), 7.28 (d, l H , Hq, = 2.69 Hz), 7.33 (dd, l H , Hz, Ji,z = 8.9 Hz, J i , 3 = 2.67 Hz), 7.56-7.67 (m, 2H, Hg and Hlo), 7.7 (d, l H , H5, J5,6= 9.51 Hz), 8.09 (d, l H , Ha or H11, J = 8.12 Hz), 8.40 (d, l H , &, J s ,=~ 9.48 Hz), 8.53 (d, l H , H8 or H11, J = 8.70 Hz), 8.73 (d, l H , HI, J1,z = 8.97 Hz), 9.07 (s, l H , Hlz); MS m l z (relative intensity) 336 and 338 (M+,100). Further elution with petroleum ether/EtOAc (10: 1)gave m-anisaldehyde (0.1 g , 17%),and 4 (0.34 g , 26%) as a yellowish orange solid: mp 159-160 "C [lit. (1)163-164 "CI; 'H NMR 6 3.96 (s, 3H, OCH3), 7.2 (d, l H , H4, 5 4 , = ~ 2.74 Hz), 7.4 (d, l H , Hz, J z ,=~9.65 Hz, &,4 = 2.78 Hz), 7.74-7.85 (m, 2H, Hg and Hlo), 8.08 (d, l H , H5, J5,6= 8.6 Hz), 8.23-8.32 (m, 2H, and H11), 8.34 (d, l H , H6, J5,6= 8.62 Hz), 9.64 (d, l H , HI, J1,z = 9.56 Hz); MS m l z (relative intensity) 289 (M 1, 90). Photocyclization of olefin 2 with a procedure similar to the one described above, except that it was extended over 16 h, yielded 4 (0.57 g, 44%).
J4,3
+
Acknowledgment. This study was supported by National Cancer Institute Contract N01-CP-21115. We thank Dr. Stephen Hecht for his critical comments and helpful suggestions. We thank Ilse Hoffmann for editorial assistance and Jyh-Ming Lin for providing NMR spectra.
References (1) Lee, H., and Harvey, R. G. (1988) Synthesis of the active diol epoxide metabolites of the potent carcinogenichydrocarbon 7,12dimethylbenz[alanthracene.J. Med. Chem. 31,154-159. (2) Newman, M. S., Khanna, J. M., Kanakarajan, K., and Kumar, S. (1978) Syntheses of 1-,2-, 3-, 4-, 6-, 9-, and lO-hydroxy-7,12dimethylbenz[alanthracene.J . Org. Chem. 43, 2553-2557. (3) Mallory, F. B., Rudolph, M. J., and Oh, S. M. (1989)Photochemistry of stilbenes. 8. Eliminative photocyclization of o-methoxystilbenes. J . Org. Chem. 54, 4619-4626. (4) Misra, B., and Amin, S. (1990)An improved synthesis of antibenzo[clphenanthrene-3,4-dioll,a-epoxide via I-methoxybenzo[clphenanthrene. J . Org. Chem. 56, 4478-4480. (5) Olsen, R. J., and Pruett, S. R. (1985)Photocyclization of o-halostilbenes. J . Org. Chem. 50, 5457-5460. (6) Smith, J. G., Dibble, P. W., and Sandborn, R. E. (1986) The preparation and reactions of naphtho[l,2-clfuran and naphtho[2,3-clfuran. J . Org. Chem. 51,3762-3768.
