A Convenient New Synthesis of Benzo[a]pyrene
SCHEME 1
Ronald G. Harvey,* Keunpoong Lim, and Qing Dai The Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois 60637
[email protected] Received October 10, 2003
Abstract: A convenient new synthesis of the ubiquitous environmental carcinogen benzo[a]pyrene (BaP) is described. In the key step, the method entails Suzuki coupling of naphthalene 2-boronic acid with 2-bromobenzene-1,3-dialdehyde and requires only three steps. It is considerably shorter and simpler than the older methods and provides BaP in higher overall yield.
Benzo[a]pyrene (BaP) is a widespread environmental pollutant and a relatively potent carcinogen.1-3 BaP is produced, along with other polycyclic aromatic hydrocarbons (PAHs), in the combustion of fossil fuels and other organic matter, and recent investigations have implicated it as a causative agent for lung cancer in cigarette smokers.4 BaP is also commonly employed as a standard in investigations of the environmental occurrence and mechanisms of carcinogenicity of PAHs. Despite the importance of BaP as an environmental carcinogen, it is not readily accessible through synthesis.2,5 The most common synthetic route to BaP entails a conventional Haworth multistep sequence6 involving Friedel-Crafts reaction of pyrene with succinic anhydride, reduction of the carbonyl group of the keto-acid product, acid-catalyzed cyclization, reduction of the keto group of the cyclized product with NaBH4, acid-catalyzed dehydration of the resulting alcohol, and palladiumcatalyzed dehydrogenation, or some variation of this sequence. We now report a new synthesis of BaP that entails fewer steps, is readily adaptable to large-scale preparation, and provides a higher overall yield than previous methods.
mobenzene-1,3-dialdehyde (2) in the key step.7 The dialdehyde 2 was prepared by an improved modification of the method of Mataka et al.8,9 via bromination of 2-bromo-m-xylene with NBS to yield 1,3-bis(dibromomethyl)-2-bromobenzene followed by hydrolysis. Reaction of 1 with 2 in the presence of a (Ph3P)4Pd catalyst and Na2CO3 furnished the coupled adduct 2-(naphthalene-2yl)benzene-1,3-dialdehyde (3). Double Wittig reaction of 3 with methoxymethylenetriphenylphosphine (generated in situ from reaction of methoxymethyltriphenylphosphonium chloride with t-BuOK) provided the diolefinic product (4) as a mixture of the (E)- and (Z)-isomers (1:1 by NMR analysis). Cyclization of 4 catalyzed by methanesulfonic acid took place smoothly to yield pure BaP in good overall yield. The stepwise nature of the double cyclization of 4 is indicated by isolation of the primary intermediate product and its identification as a chrysene derivative (5) arising from initial reaction at the 1-position of the naphthalene ring of 4. Compound 5 was distinguished
Results and Discussion The new synthesis of BaP (Scheme 1) entails Suzuki coupling of naphthalene 2-boronic acid (1) with 2-bro(1) Polynuclear Aromatic Compounds, Part 1, Chemical, Environmental and Experimental Data; International Agency for Research on Cancer. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans.; IARC: Lyon, France, 1983; Vol. 32. (2) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and Carcinogenicity; Cambridge University Press: Cambridge, UK, 1991. (3) Dipple, A.; Moschel, R. C.; Bigger, C. A. H. In Chemical Carcinogenesis; American Chemical Society: Washington, DC, 1985. (4) Denissenko, M. F.; Pao, A.; Tang, M.; Pfeifer, G. P. Science 1996, 274, 430. Pfeifer, G. P.; Denissenko, M. F. Environ. Mol. Carcin. 1998, 31, 197. Denissenko, M. F.; Chen, J. X.; Tang, M.; Pfeifer, G. P. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 3893. Chen, J. X.; Zheng, Y.; West, M.; Tang, M. Cancer Res. 1998, 58, 2170. (5) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Wiley-VCH: New York, 1997. (6) Johnson, W. S. Org. React. 1944, 2, 114. Schlude, H. Chem. Ber. 1971, 104, 3995. Cook, J. W.; Hewett, C. L. J. Chem. Soc. 1933, 398.
by NMR analysis from the benz[a]anthracene derivative (6) expected to be formed by electrophilic attack at the 3-position of the naphthalene ring of 4. The proton NMR spectrum of 5 was fully consistent with its structural assignment as a chrysene derivative, and the absence of the characteristic singlet peaks for the 7,12-protons of (7) Method employed is based on the procedure reported: Zhang, F.-J.; Cortez, C.; Harvey, R. G. J. Org. Chem. 2000, 65, 3952. The use of Suzuki coupling for the synthesis of PAH compounds has also been described by: Kumar, S. J. Chem. Soc., Perkin Trans. 1 1998, 3157. (8) Mataka, S.; Liu, G. B.; Sawada, T.; Kurisa, M.; Tashiro, M. Bull. Chem. Soc. Jpn. 1994, 67, 1113. Mataka, S.; Liu, G.-B.; Sawada, T.; Tori-I, A.; Tashiro, M., J. Chem. Res., Synop. 1995, 410. (9) An improved procedure for the synthesis of 2 is described in: Harvey, R. G.; Dai, Q.; Ran, C.; Penning, T. M. J. Org. Chem., in press. 10.1021/jo030313n CCC: $27.50 © 2004 American Chemical Society
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Published on Web 01/22/2004
the alternative benz[a]anthracene structure 6 confirmed this assignment. This novel synthesis of BaP, in addition to being significantly shorter and more convenient than older methods, is also readily adaptable to the synthesis of various substituted derivatives of BaP. The most important of these are the oxidized derivatives of BaP implicated as its active carcinogenic metabolites.2 Modification of this synthetic approach for the synthesis of benzo[a]pyren-8-ol, benzo[a]pyren-7,8-dione, and trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene will be reported separately.9 Experimental Section Materials and Methods. Naphthalene 2-boronic acid (1) and 2-bromo-m-xylene were purchased from commercial sources. 2-Bromobenzene-1,3-dialdehyde (2) was prepared from 2-bromom-xylene by bromination with NBS and hydrolysis of the 1,3bis(dibromomethyl)-2-bromobenzene product by a modification of the literature method.8,9 Methoxymethyltriphenylphosphonium chloride was dried under vacuum for 24 h prior to use. THF was freshly distilled from sodium benzophenone ketal. NMR spectra were recorded on a 400 MHz spectrometer in CDCl3 with tetramethylsilane as an internal standard. Integration was consistent with all structural assignments. Caution: Benzo[a]pyrene is a carcinogen and should be handled with care in accord with “NIH Guidelines for the Laboratory Use of Chemical Carcinogens.” 2-(Naphthalene-2-yl)benzene-1,3-dialdehyde (3). To a solution of 2 (10.7 g, 50 mmol) in DME (200 mL) under argon was added Pd(PPh3)4 (1.2 g, 1.0 mmol). The resulting yellow solution was stirred for 20 min, and a solution of 1 (9.26 g, 54 mmol) in ethanol (300 mL) was added. The clear solution turned cloudy. After 20 min, NaCO3 (210 mL of a 2 M solution) was added, and the mixture was heated at reflux overnight. The solution was cooled to room temperature; most of the solvent was removed under reduced pressure, and CH2Cl2 (500 mL) was added. The organic phase was washed with water and brine and dried over MgSO4. The solution was evaporated to dryness, and the residue was purified by chromatography on a silica gel column eluted with 10-20% EtOAc in hexane to yield 3 (9.15 g,
70%) as a greenish oil: 1H NMR δ 9.84 (s, 2), 8.29 (d, 2, J ) 7.7 Hz), 8.00 (d, 1, J ) 8.4 Hz), 7.97 (m, 1), 7.89 (m, 1), 7.85 (s, 1), 7.70 (t, 1, J ) 7.7 Hz), 7.62 (m, 2), 7.50 (dd, 1, J ) 8.3, 1.8 Hz); 13C NMR δ 190.9, 148.1, 134.9, 133.0, 132.6, 132.5, 130.6, 129.8, 128.5, 128.4, 128.1, 128.0, 127.9, 127.5, 127.3. Anal. Calcd for C18H12O2: C, 83.06; H, 4.65; O, 12.29. Found: C, 82.91; H, 4.63; O, 12.51. 2-(2,6-Bis[2-methoxyvinyl]phenyl)naphthalene (4). To a suspension of methoxymethyltriphenylphosphonium chloride (3.79 g, 11 mmol) in anhydrous ethyl ether (20 mL) and THF (20 mL) under an argon atmosphere at -78 °C was added (tBuOK) (1 M in dry THF, 11 mL, 11 mmol) dropwise over 5 min. The resulting red solution was stirred at -78 °C for 30 min., then stirred for an additional 30 min. at ∼ 0 °C. The temperature was lowered again to -78 °C, and a solution of 3 (1.15 g, 4.4 mmol) in dry THF (20 mL) was added. The resulting solution was stirred overnight at room temperature. The reaction was quenched by addition of water, and the product was extracted with EtOAc, dried over MgSO4, and evaporated to dryness. Purification of the residue by chromatography on a silica gel column eluted with 15% EtOAc in hexane gave 4 essentially quantitatively as an oil shown by NMR analysis to consist of a 1:1 mixture of (E)- and (Z)-isomers. The product was used directly in the next step. Benzo[a]pyrene (BaP). To a solution of 4 (1.18 g, 3.7 mmol) in CH2Cl2 (20 mL) at 0 °C was added 2-3 drops of CH3SO3H, and the color became dark blue. The mixture was stirred overnight. Sodium carbonate (3 g) and MgSO4 (3 g) were added, and the mixture was stirred for 1 h. After removal of the solid by filtration, the solvent was evaporated under reduced pressure and the product was purified by chromatography on a silica gel column. Elution with hexane gave pure BaP (540 mg, 57%), mp 178 °C (lit.2,5 179-80 °C); the 1H NMR matched that of an authentic sample of BaP.10
Acknowledgment. This investigation was supported by a grant (PO1 CA-92537) from the National Cancer Institute, DHHS. JO030313N (10) Karcher, W.; Fordham, R.; DuBois, J.; Goude, P. Spectral Atlas of Polycyclic Aromatic Compounds; D. Reidel: Dordrecht, Netherlands, 1985; Vol. 2.
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