Synthesis of phenol and quinone metabolites of benzo[a]pyrene, a carcinogenic component of tobacco smoke implicated in lung cancer

Article abstract of DOI:10.1021/jo801864m

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants produced in the combustion of organic matter. PAHs are present in automobile exhaust and tobacco smoke, and they have recently been designated as human carcinogens. Current ev

Full text of DOI:10.1021/jo801864m

Synthesis of Phenol and Quinone Metabolites of Benzo[a]pyrene, a
Carcinogenic Component of Tobacco Smoke Implicated in Lung
Cancer
Daiwang Xu,† Trevor M. Penning,‡ Ian A. Blair,‡ and Ronald G. Harvey*,†
The Ben May Department for Cancer Research, The UniVersity of Chicago, Chicago, Illinois 60637, and
The Centers for Cancer Pharmacology and Excellence in EnVironmental Toxicology, UniVersity of
PennsylVania School of Medicine, Philadelphia, PennsylVania 19104
rharVey@ben-may.bsd.uchicago.edu
ReceiVed August 25, 2008
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants produced in the
combustion of organic matter. PAHs are present in automobile exhaust and tobacco smoke, and they
have recently been designated as human carcinogens. Current evidence indicates that PAHs are activated
enzymatically to mutagenic metabolites that interact with DNA. There is evidence for three pathways of
activation: the diol epoxide path, the radical-cation path, and the quinone path. The relative importance
of these paths for human lung cancer has not been established. We now report syntheses of the principal
phenol and quinone isomers of the prototype PAH carcinogen benzo[a]pyrene (BP) that are known or
are suspected to be formed as metabolites of BP in human bronchoalveolar cells. The methods of synthesis
were designed to be adaptable to the preparation of the 13C-labeled analogues of the BP metabolites.
These compounds are needed as standards for sensitive LC-MS/MS methods for analysis of BP
metabolites formed in lung cells. Efficient novel syntheses of the 1-, 3-, 6-, 9-, and 12-BP phenols and
the BP 1,6-, 3,6-, 6,12-, and 9,10-quinones are now reported. The syntheses of the BP phenols (except
6-HO-BP) involve the key steps of Pd-catalyzed Suzuki-Miyaura cross-coupling of a naphthalene boronate
ester with a substituted aryl bromide or triflate ester. The BP quinones were synthesized from the
corresponding BP phenols by direct oxidation with the hypervalent iodine reagents IBX or TBI. These
reagents exhibited different regiospecificities. IBX oxidation of the 7- and 9-BP phenols provided
the ortho-quinone isomers (BP 7,8- and 9,10-diones, respectively), whereas TBI oxidation of the 1-, 3-,
and 12-BP phenols furnished BP quinone isomers with carbonyl functions in separate rings (BP 1,6-,
3,6-, and 6,12-diones, respectively).
Introduction
implicated as causative agents for lung cancer,2,5-10 the principal
category of adult cancer death in the U.S. population.11
Polycyclic aromatic hydrocarbons (PAHs) are widespread
environmental pollutants that are produced in the combustion
of organic matter.1-3 PAHs are components of automobile and
diesel engine exhaust4 and tobacco smoke,5-7 and they are
For PAHs to exert their carcinogenic effects, metabolic
activation is required.3 Benzo-[a]pyrene (BP) is the prototype
PAH carcinogen that has been most intensively investigated.
Three activation pathways have been proposed. The most studied
path involves cytochrome P-450 (CYP)-mediated formation of
BP trans-7,8-dihydrodiol (BP 7,8-diol) and its oxidation to the
highly mutagenic BP trans-7,8-diol-anti-9,10-epoxide (anti-
BPDE).3,12 A second path entails aldo-keto reductase (AKR)-
* To whom correspondence should be addressed. Phone: 1-773-702-6998.
Fax: 1-773-702-6260. E-mail: rharvey@ben-may.bsd.uchicago.edu.
† The University of Chicago.
‡ University of Pennsylvania School of Medicine.
10.1021/jo801864m CCC: $40.75
Published on Web 12/09/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 597–604 597

Xu et al.
mediated oxidation of BP 7,8-diol to BP 7,8-catechol, which
enters into a redox cycle with O2 to form a quinone (BP 7,8-
dione) along with reactive oxygen species (ROS) that attack
DNA.13-16 The third path entails peroxidase-mediated oxidation
of BP to form a radical cation that reacts with DNA, leading to
the formation of depurinated adducts.17,18 The relative impor-
tance of these activation routes for human cancer has not been
established.
chromatography tandem mass spectrometric analytical method
to quantify the adducts formed with DNA by the metabolites
of BP was also reported.23
Enhancement of the scope and sensitivity of the LC-MS
analytical methodology requires13C-labeled analogues of BP and
its metabolites as authentic standards. In this connection, we
recently reported syntheses of 13C2-BP, 13C2-BP 7,8-diol, 13C2-
BP 7,8-dione, and 13C2-8-HO-BP.24 We now report improved
new syntheses of the principal phenol and quinone isomers of
BP formed in its metabolism in human bronchoalveolar H358
cells.21 The synthetic approaches were designed to be adaptable
to syntheses of the corresponding 13C-labeled analogues of these
BP metabolites with two or more 13C atoms in the PAH ring
system.
Results
The phenol and quinone isomers of BP chosen as synthetic
targets for this investigation include the 1-, 3-, 6-, 9-, and 12-
phenol isomers (1-HO-BP, 3-HO-BP, 6-HO-BP, 9-HO-BP, and
12-HO-BP) and the 1,6-, 3,6-, 6,12-, and 9,10-quinone isomers
(BP 1,6-dione, BP 3,6-dione, BP 6,12-dione, and BP 9,10-
dione). Although not all of these isomers have been identified
as metabolites of BP in H358 cells,21 the evidence suggests that
some phenol isomers may not have survived sufficiently long
enough to be detected due to the facility of their oxidation to
quinones or higher-oxidized products. For example, 6-HO-BP
was not found as a metabolite, yet BP 1,6-dione and BP 3,6-
dione were identified as the principal BP quinone metabolites.21
The fact that 6-HO-BP is a metabolic precursor of the BP 1,6-,
3,6-, and 6,12-diones20 suggests that 6-HO-BP is formed but
fails to persist due to its further oxidation to the BP 1,6-, 3,6-,
and 6,12-diones. Other unidentified BP phenol or quinone
isomers, for which standards were not available, may also have
been formed but escaped detection because they happen to
coelute on chromatography with an isomer for which a standard
was available. Satisfactory resolution of these questions requires
that the isomeric BP phenol and quinone metabolites that were
not available for the initial metabolism studies should be
synthesized to serve as additional analytical standards.
Numerous studies of the metabolism of BP by rodent liver
microsomesandothermodelcellsystemshavebeenconducted.3,19,20
However, most of these investigations were carried out without
an appreciation of all the participating pathways or sufficiently
sensitive analytical methods or standards to adequately char-
acterize all the metabolites formed. More recently, human
bronchoalveolar H358 cells were introduced as a model to study
the metabolic profile of BP in normal human lung epithelial
cells.21,22 Development of a stable isotope dilution, liquid
(1) International Agency for Research on Cancer. Polynuclear Aromatic
Compounds, Part 1, Chemical, EnVironmental and Experimental Data; Mono-
graphs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans;
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(2) Straif, K.; Baan, R.; Grosse, Y.; Secretan, B.; Ghissassi, F. E.; Cogliano,
V. Lancet Oncol. 2005, 6, 931–932.
(3) Reviews: (a) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry
and Carcinogenicity; Cambridge University Press: Cambridge, U.K., 1991. (b)
Gelboin, H. V. Physiol. ReV. 1980, 50, 1107–1166. (c) Conney, A. Cancer Res.
1982, 42, 4875–4917. (d) Singer, B.; Grunberger, D. Molecular Biology of
Mutagens and Carcinogens; Plenum Press: New York, 1982.
(4) Marr, L. C.; Kirchstetter, T. W.; Harley, R. A.; Miguel, A. H.; Hering,
S. V.; Hammond, S. K. EnViron. Sci. Technol. 1999, 33, 3091–3099.
(5) International Agency for Research on Cancer. Tobacco Smoke and
InVoluntary Smoking; Monographs on the Evaluation of the Carcinogenic Risk
of Chemicals to Humans; Lyon, France, 2004; 83.
Syntheses of all 12 BP phenol isomers by classical synthetic
methods have been described in the literature.25,26 However,
these syntheses involve relatively large numbers of steps, and
(6) Pfiefer, G. P.; Denissenko, M. F.; Olivier, M.; Tretyakova, N.; Hecht,
S.; Hainaut, P. Oncogene 2002, 21, 7435–7451.
(7) World Health Organization. Tobacco or Health: A Global Status Report;
Geneva, Switzerland, 1997; pp 10-48.
(20) (a) Marnett, L. J. In Polycyclic Hydrocarbons and Carcinogenesis;
Harvey, R. G., Ed.; ACS Symposium Series, Monograph 283; American
Chemical Society: Washington, D.C., 1985; Chapter 15, pp 307-326. (b)
Marnett, L. J.; Reed, G. A.; Johnson, J. T. Biochem. Biophys. Res. Commun.
1977, 79, 569–576. (c) Lorentzen, R. J.; Caspary, W. J.; Lesko, S. A.; Ts’o,
P. O. P. Biochemistry 1975, 14, 3970–3977. (d) Lesko, S. A.; Lorentzen, R. J.;
Caspary, W. J.; Ts’o, P. O. P. Biochemistry 1975, 14, 3978–3984.
(21) Jiang, H.; Gelhaus, S. L.; Mangal, D.; Harvey, R. G.; Blair, I. A.;
Penning, T. M. Chem. Res. Toxicol. 2007, 20, 1331–1341.
(8) Boffetta, P.; Jourenkova, N.; Gustavsson, P. Cancer, Causes Control 1997,
8, 444–472.
(9) Armstrong, B.; Hutchinson, E.; Unwin, J.; Fletcher, T. EnViron. Health
Perspect. 2004, 112, 970.
(10) Rubin, H. Carcinogenesis 2001, 22, 1903–1930.
(11) Ries, L.; Eisner, M. P.; Cosary, C. L. SEER Cancer Statistics ReView
1975-2006; National Cancer Institute, 2006, http//SEER.cancer.gov/esr.
(12) Jennette, K. W.; Jeffrey, A. M.; Blobstein, S. H.; Beland, F. A.; Harvey,
R. G.; Weinstein, I. B. Biochemistry 1977, 16, 932–938.
(22) Ruan, Q.; Gelhaus, S.; Penning, T. M.; Harvey, R. G.; Blair, I. A. Chem.
Res. Toxicol. 2007, 20, 424–431.
(13) Palackal, N. T.; Burczynski, M. E.; Harvey, R. G.; Penning, T. M.
Biochemistry 2001, 40, 10901–10910.
(14) Penning, T. M.; Onishi, S. T.; Onishi, T.; Harvey, R. G. Chem. Res.
Toxicol. 1996, 9, 84–92.
(15) Palackal, N. T.; Lee, S. H.; Harvey, R. G.; Blair, I. A.; Penning, T. M.
J. Biol. Chem. 2002, 277, 24799–24808.
(16) Park, J. H.; Mangal, D.; Tacka, K. A.; Quinn, A.; Harvey, R. G.; Blair,
I. A.; Penning, T. M. Proc. Natl. Acad. Sci. U.S.A. 2008, in press.
(17) Cavalieri, E. L.; Rogan, E. G. Xenobiotica 1995, 25, 677–688.
(18) Melendez-Colon, V. J.; Luch, A.; Seidel, A.; Baird, W. M. Carcino-
genesis 1999, 20, 1885–1891.
(23) Ruan, Q.; Kim, H. Y. H.; Jiang, H.; Penning, T. M.; Harvey, R. G.;
Blair, I. A. Rapid Commun. Mass Spectrom. 2006, 20, 1369–1380.
(24) Ran, C.; Xu, D.; Dai, Q.; Blair, I. A.; Penning, T.; Harvey, R. G.
Tetrahedron Lett. 2008, 49, 4531–4535.
(25) Review: ref 3a, Chapter 15, pp 361-382.
(26) (a) Yagi, H.; Holder, G. M.; Dansette, P. M.; Hernandez, O.; Yeh,
H. J. C.; LeMahieu, R. A.; Jerina, D. M. J. Org. Chem. 1976, 41, 977–985. (b)
Harvey, R. G.; Cho, H. J. Chem. Soc., Chem. Commun. 1975, 373–374. (c)
Cook, J. W.; Ludwiczak, R. S.; Schoental, R. J. Chem. Soc. 1950, 1112–1121.
(d) Fieser, L.; Hershberg, E. B. J. Am. Chem. Soc. 1939, 61, 1565–1574. (e)
Fieser, L.; Hershberg, E. B. J. Am. Chem. Soc. 1937, 59, 475–478. (f) Sims, P.
J. Chem. Soc. C 1968, 32–34. (g) Fu, P. P.; Harvey, R. G. Org. Prep. Proced.
Int. 1981, 13, 152–155.
(19) Penning, T. M.; Burczynski, M. E.; Hung, C. F.; McCoull, F. D.;
Palackal, N. T.; Tsuruda, L. S. Chem. Res. Toxicol. 1999, 12, 1–18.
598 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of Phenol and Quinone Metabolites
SCHEME 1
TABLE 1. Optimization of Conditions for the Synthesis of 3a
lacking a methoxy group, was acccompanied by secondary
rearrangement of the bay region methyl group of the product
to the adjacent ring position due to steric crowding. Rearrange-
ment was diminished by the use of TiCl4 as catalyst. TiCl4-
catalyzed cyclization of 5 furnished 3-methoxy-5-methylchry-
sene 6 as major product (74%). Conversion of the methyl group
of 6 to an aldehyde function was accomplished via bromination
with NBS to give 5-bromomethyl-3-methoxychrysene 7a, and
reaction of 7a with DMSO and NaHCO3 yielded 5-formyl-3-
methoxychrysene 7b. Although 7a was unstable, satisfactory
yields of 7b could be obtained by the direct use of 7a without
isolation. Wittig reaction of 7b with methoxymethylenetriph-
enylphosphine furnished 3-methoxy-5-(2-methoxyvinyl)chrysene
8 as a mixture of E- and Z-isomers. Acid-catalyzed cyclization
of 8 gave 3-methoxybenzo[a]pyrene (76% from 7b), and
demethylation by treatment with BBr3 provided 3-HO-BP.
Benzo[a]pyren-1-ol (1-HO-BP). Synthesis of 1-HO-BP was
carried out by a procedure analogous to that for the preparation
of 3-HO-BP (Scheme 2).29 The 2-boronate ester of 5-methox-
ynaphthalene (10) was prepared from 5-methoxy-2-naphthol 9a
via conversion to the triflate ester 9b, followed by reaction of
9b with 2 in the presence of Pd(dppf)Cl2 by the procedure for
the preparation of 3. Cross-coupling of 10 with 4 with Pd(PPh3)4
and Na2CO3 in DME gave 2-(5-methoxynaphthyl)phenylacetone
11 (77%). TiCl4-catalyzed cyclodehydration of 11 afforded
1-methoxy-5-methylchrysene 12 (68%), and reaction of 12 with
NBS gave 13a, which was converted to 5-formyl-1-methoxy-
chrysene 13b (74%) by reaction with DMSO and NaHCO3.28,30
entry
catalyst
solvent
time (h)
yield(%)
1
2
3
4
5
Pd(dppf)Cl2
Pd(pph3)4
Pd(dppf) Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
DMSO
DMSO
CH3CN
THF
2
3
5
3
40
35
40
70
82
dioxane
1.5
a Experimental: To a two-neck flask flushed with N2 were added Pd
catalyst (0.03 mmol), 2 (1.2 mmol), and a solution of 1b (1.0 mmol) in
a solvent (8 mL). The mixture was stirred at 80 °C for the time
indicated, the solvent was removed under vacuum, and the residue was
chromatographed on silica gel.
they were not designed to serve as the basis of methods for
efficient syntheses of the 13C-labeled analogues of the BP phenol
isomers.
Benzo[a]pyren-3-ol (3-HO-BP). 3-HO-BP was the principal
phenol isomer detected as a metabolite of BP in H358 cells.21
Synthesis of 3-HO-BP was accomplished via the reaction
sequence in Scheme 1. The key step entailed Pd-catalyzed
Suzuki-Miyaura cross-coupling of the 2-boronate ester of
7-methoxynaphthalene (3) with 2-bromophenylacetone 4. The
boronate ester 3 was prepared from 7-methoxy-2-naphthol 1a
via initial conversion to its triflate ester 1b by the procedure
reported.27 Reaction of 1b (1 mmol) with bis(neopentylglyco-
lato)diboron 2 (1.2 mmol) in the presence of Pd(dppf)Cl2 (0.03
mmol) as catalyst and KOAc as base took place in DMSO at
80 °C to afford the boronate ester 3 in moderate yield (40%).
A brief study of this reaction was undertaken with the aim of
improving the yield of 3 (Table 1). It was not significantly
enhanced by the use of Pd(PPh3)4 as catalyst, increasing reaction
time, or the use of CH3CN as solvent. On the other hand, the
yield of 3 was significantly improved and reaction time was
decreased with the use of THF or dioxane as solvent. The
optimum yield (82%) was obtained with dioxane as solvent.
Cross-coupling of 3 with 4 took place in the presence of
Pd(PPh3)4 and Na2CO3 in DME to furnish 2-(7-methoxynaph-
thyl)phenylacetone 5 as principal product (62%). It was recently
shown28 that acid-catalyzed cyclization of an analogue of 5,
Wittig reaction of 13b with methoxymethylenetriphenylphos-
phine yielded 1-methoxy-5-(2-methoxyvinyl)chrysene 14 (90%)
as a mixture of E- and Z-isomers. Acid-catalyzed cyclization
of 14 afforded 1-methoxybenzo[a]pyrene. Attempted demethy-
lation by treatment with BBr3 was unsuccessful, but conversion
of 1-MeO-BP to 1-HO-BP was accomplished by treatment with
HI/HOAc. The usefulness of HI/HOAc for demethylation of
aryl ethers was noted in an earlier study,32 but the scope of the
(29) Compound 10 was accompanied by minor amounts of one or more
isomeric products that were separable from 10 by recrystallization.
(30) Chen, H.; Luzy, J.-P.; Gresh, N.; Garbay, C. Eur. J. Org. Chem. 2006,
2329–2335.
(31) Harvey, R. G.; Lim, K.; Dai, Q. J. Org. Chem. 2004, 69, 1372–1373.
(32) Harvey, R. G.; Dai, Q.; Ran, C.; Penning, T. M. J. Org. Chem. 2004,
69, 2024–2032.
(27) Mewshaw, R. E.; Edsall, R. J., Jr.; Yang, C.; Manas, E. S.; Xu, Z. B.;
Henderson, R. A.; Keith, J. C., Jr.; Harris, H. A. J. Med. Chem. 2005, 48, 3953–
3979.
(28) Xu, D.; Duan, Y.; Blair, I. A.; Penning, T. M.; Harvey, R. H. Org. Lett.
2008, 10, 1059–1062.
J. Org. Chem. Vol. 74, No. 2, 2009 599

Xu et al.
SCHEME 2
SCHEME 3
Benzo[a]pyren-6-ol (6-HO-BP). The most convenient syn-
thetic precursors of 6-HO-BP and 13C2-6-HO-BP are BP and
13C2-BP themselves. An efficient synthesis of 13C2-BP was
recently reported.24 Direct synthesis of 6-HO-BP from BP was
accomplished via initial Vilsmeier-Haack reaction of BP with
POCl3 and DMF to furnish 8-formylbenzo[a]pyrene 23 (Scheme
5).33 Baeyer-Villager oxidation of 23 with m-chloroperbenzoic
acid provides 8-formyloxybenzo[a]pyrene 24. The formate ester
derivative was relatively stable, in contrast to 6-HO-BP that
exhibited a strong tendency to undergo oxidative decomposition
on exposure to air. The ease of autoxidation of 6-HO-BP accords
with the earlier findings of Lorentzen et al.,20c who showed the
principal products of autoxidation of 6-HO-BP to be the BP
1,6-, 3,6-, and 6,12-diones.
Synthesis of BP Quinones. Direct oxidation of BP with
chromium reagents, ceric ammonium nitrate, and other oxidants
has been shown by various investigators to furnish mixtures of
BP quinones that are difficult to separate.34 This problem was
reinvestigated by Cho and Harvey,35 who used careful chro-
matographic techniques to isolate and identify the pure BP 1,6-,
3,6-, and 6,12-dione isomers. They were obtained in yields of
40, 20, and 7%, respectively. However, this approach is
impractical for the synthesis of the individual pure 13C-labeled
BP 1,6-, 3,6-, and 6,12-diones.
method was not explored. It appears that HI/HOAc may be
superior to BBr3 as a reagent for demethylation of PAH methyl
ethers.
Benzo[a]pyren-9-ol (9-HO-BP). Synthesis of 9-HO-BP was
carried out by a procedure analogous to that reported for the
preparation of 7-benzo[a]pyren-7-ol (Scheme 3).31,32 2-Bro-
mobenzene-1,3-dialdehyde 15 was synthesized by the reported
method,31 and Suzuki-Miyaura coupling of 15 with the
boronate ester 3, catalyzed by Pd(PPh3)4, furnished the dialde-
hyde adduct 16. Double Wittig reaction of 16 with (methoxym-
ethylene)triphenylphosphine (CH3OCHdPPh3)24 provided the
di(methoxyvinyl) derivative (17) as a mixture of E- and
Z-isomers. Acid-catalyzed cyclization of 17 furnished 9-meth-
oxybenzo[a]pyrene, and demethylation with BBr3 gave 9-HO-
BP.
Benzo[a]pyren-12-ol (12-HO-BP). Synthesis of 12-HO-BP
is outlined in Scheme 4. The 2-boronate ester of 1-methylnaph-
thalene (19) was prepared from 1-methyl-2-naphthol 18a via
conversion to the triflate ester 18b, followed by reaction of 18b
with 2 in the presence of Pd(dppf)Cl2. Reaction of 19 with
2-bromobenzaldehyde in the presence of Pd(PPh3)4 and Na2CO3
in DME gave 2-(1-methylnaphthalen-2-yl)benzaldehyde 20
(74%), and reaction of 20 with methoxymethylenetriphenylphos-
phine furnished 21 as a mixture of E- and Z-isomers. Acid-
catalyzed cyclization of 21 afforded 12-methylbenz[a]anthracene
22a. This was converted to 12-HO-BP via bromination with
NBS to yield 22b, reaction of 22b with KCN to provide 22c,
hydrolysis of 22c with KOH in ethylene glycol to yield 22d,
and acid-catalyzed cyclization of 22d to furnish 12-HO-BP.26g
(33) Dai, Q.; Xu, D.; Lim, K.; Harvey, R. G. J. Org. Chem. 2007, 72, 4856–
4863.
(34) Review: ref 3a, Chapter 9, pp 201-204.
(35) Cho, H.; Harvey, R. G. J. Chem. Soc., Perkin Trans. 1 1976, 836–839.
600 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of Phenol and Quinone Metabolites
SCHEME 4
SCHEME 5
use for oxidation of PAH phenols with larger ring systems have
been reported. BTI holds promise as a reagent for regioselective
oxidation of PAH phenols to quinones with carbonyl functions
in separate rings, such as the BP 1,6- and 3,6-diones.
Discussion
Oxidative metabolism of BP and other PAHs in mammalian
cells is part of the normal process of enzymatic detoxification
of xenobiotic substances.3a,16,19 Metabolism of BP by P-450
microsomal enzymes affords initially arene oxides that may
either rearrange to phenols or undergo epoxide hydrolase-
catalyzed hydration to furnish trans-dihydrodiols, such as the
BP trans-7,8- or trans-9,10-dihydrodiols. These primary me-
tabolites are converted to glucuronides or other water-soluble
conjugates that are eventually excreted. However, some of the
primary metabolites are able to survive and undergo further
oxidative metabolism to quinones, diol epoxides, and other
potentially carcinogenic species.
A more promising synthetic route to the BP quinones of
interest is via oxidation of the individual BP phenol isomers.
In a prior study, we showed that oxidation of 8-HO-BP with
the hypervalent iodine reagent o-iodoxybenzoic acid (IBX)
provided convenient synthetic access to BP 7,8-dione.24,32 We
now report that oxidation of 9-HO-BP with IBX by a similar
procedure furnished BP 9,10-dione in good yield (82%).
This paper reports efficient syntheses of the principal phenol
and quinone isomers of BP that have been identified or are
suspected to be formed as metabolites of BP in normal human
bronchoalveolar cells.21 The BP phenols include the 1-, 3-, 6-,
9-, and 12-phenol isomers (1-HO-BP, 3-HO-BP, 6-HO-BP,
9-HO-BP, and 12-HO-BP). The BP quinone isomers are the
BP 1,6-, 3,6-, 6,12-, and 9,10-diones.
Attempts to oxidize 1-HO-BP or 3-HO-BP by IBX were not
successful, failing to provide either the unknown ortho-quinone
isomers (BP 1,2- or 2,3-dione) or the BP 1,6- or 3,6-quinone
isomers. Transformation of 1-HO-BP and 3-HO-BP to the
desired BP quinone isomers (BP 1,6-dione and BP 3,6-dione)
was accomplished by direct oxidation with another hypervalent
iodine reagent, [bis(trifluoroacetoxy)iodo]benzene (BTI). BP 1,6-
dione and BP 3,6-dione were obtained in yields of 82 and 85%,
respectively. Similarly, oxidation of 12-HO-BP by BTI provided
BP 6,12-dione. BTI was shown previously to oxidize substituted
1-naphthols to 1,4-naphthoquinones,36 but no examples of its
The syntheses of the BP phenols involve the key steps of
Pd-catalyzed Suzuki cross-coupling of a naphthalene boronate
ester derivative with an aryl bromide or a triflate ester. The BP
quinones were synthesized from the BP phenols by oxidation
with the hypervalent iodine reagents IBX and TBI. These
reagents exhibited different regiospecificities of oxidation.
Reaction of IBX with 7-HO- and 9-HO-BP yielded the ortho-
quinone isomers (BP 7,8- and 9,10-diones, respectively),
whereas reaction of TBI with 1-HO-, 3-HO-, and 12-HO-BP
furnished exclusively quinone isomers with carbonyl functions
in separate rings (BP 1,6-, 3,6-, and 6,12-diones, respectively).
The remarkable regioselectivities of these oxidations are
consistent with the mechanisms. Oxidations with IBX are
thought to proceed via initial reaction of the reagent with the
(36) Barret, R.; Daudon, M. Tetrahedron Lett. 1990, 31, 4871–4872.
(37) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus, T. R. R.
Org. Lett. 2002, 4, 285–288.
J. Org. Chem. Vol. 74, No. 2, 2009 601

Xu et al.
phenol to form an intermediate complex.37,38 This is followed
by intramolecular transfer of an oxygen atom from the IBX
component of the complex to the carbon atom adjacent to the
hydroxyl group of the phenolic component, leading to the
formation of an ortho-quinone product. Oxidations with BTI
also entail initial reaction of the reagent with the phenol to form
an intermediate complex.37 This reacts with water, generally at
a less sterically restricted para position, thereby generating a
para-catechol intermediate that undergoes further oxidation to
yield a quinone product. The BP 1-, 3-, and 12-phenols lack a
para position, so that the reactions of their intermediate
complexes with water take place at the most reactive alternative
site, the 6-position, to generate the BP 1,6-, 3,6-, and 6,12-
diones, respectively.39 These are the first examples of oxidation
of PAH phenols with TBI to afford PAH quinones with carbonyl
functions in separate rings.
The synthetic approaches to the BP phenol and quinone
metabolites outlined above were designed to be adaptable to
the preparation of 13C-labeled analogues of these compounds.
The isotopically labeled compounds are needed as substrates
and/or standards for metabolism and other studies in normal
human lung cells. Syntheses of the 13C-labeled analogues are
in progress. This work is virtually complete, and the findings
will be reported shortly.
3-Methoxy-5-methylchrysene (6). To a dry flask was added a
solution of 5 (460 mg, 1.6 mmol) in CH2Cl2 (15 mL) under argon.
Then a solution of TiCl4 (1.6 mL, 1 M in CH2Cl2) was added
dropwise at -78 °C. The resulting mixture was stirred for 3.5 h at
0 °C, and the reaction was monitored by TLC. The reaction was
quenched by pouring on crushed ice (15 g), extracted with EtOAc
(3 × 50 mL), and the combined organic layer was washed with
water and dried over Na2SO4. After evaporation of the solvent under
reduced pressure, the residue was purified by chromatography on
a silica gel column. Elution with hexane/EtOAc (10:1) afforded 6
and a small amount of an unidentified isomer. Crystallization from
EtOH gave pure 6 (321 mg, 74%): 1H NMR (500 MHz, CDCl3) δ
8.73 (d, J ) 8.5 Hz, 1 H), 8.64 (d, J ) 9.0 Hz, 1 H), 8.41 (d, J )
2.0 Hz, 1 H), 7.94-7.90 (m, 3 H), 7.83 (s, 1 H), 7.70-7.55 (m, 2
H), 7.32 (dd, J ) 8.5 and 2.0 Hz, 1 H), 4.04 (s, 3 H), 3.28 (s, 3 H);
13C NMR (125.8 MHz, CDCl3) δ 157.2, 133.0, 132.9, 131.7, 130.4,
130.2, 129.8, 129.7, 128.8, 128.4, 127.4, 127.2, 126.5, 126.0, 123.3,
119.5, 116.1, 109.4, 55.5, 27.7; MS (APCI) m/z ) 273 (100%).
3-Methoxy-5-formylchrysene (7b). To a dry flask containing a
solution of 6 (272 mg, 1 mmol) in CCl4 (10 mL) under argon were
added NBS (196 mg, 1.1 mmol) and benzoyl peroxide (6 mg), and
the mixture was heated at reflux for 3 h, and the reaction monitored
by TLC. Then the mixture was cooled to room temperature, and
the precipitate of 7a was filtered off and washed with CCl4 (2 mL).
To the resulting solution were added DMSO (2.8 mL) and NaHCO3
(168 mg, 2 mmol), and the mixture was heated at 80-90 °C for
3.0 h (the reaction was monitored by TLC). The mixture was diluted
with EtOAc (100 mL), washed with water (3 × 30 mL), and dried
over Na2SO4. After evaporation of the solvent under reduced
pressure, the residue was purified by chromatography on a silica
gel column. Elution with hexane/EtOAc (40:1) furnished 7b (170
mg, 60%): 1H NMR (500 MHz, CDCl3) δ 10.69 (s, 1 H), 8.73 (d,
J ) 9.5 Hz, 1 H), 8.56 (d, J ) 9.0 Hz, 1 H), 8.40 (s, 1 H), 8.11 (d,
J ) 7.5 Hz, 1 H), 8.01 (d, J ) 8.5 Hz, 1 H), 7.96 (d, J ) 8.5 Hz,
1 H), 7.82 (t, J ) 8.5 Hz, 1 H), 7.72 (t, J ) 7.5 Hz, 1 H), 7.46 (d,
J ) 2.0 Hz, 1 H), 7.35 (dd, J ) 9.0 and 2.0 Hz, 1 H), 4.00 (s, 3
H); 13C NMR (125.8 MHz, CDCl3) δ 193.2, 158.4, 133.8, 132.3,
130.6, 130.5, 130.4, 130.3, 130.2, 129.9, 129.2, 128.1, 128.0, 127.3,
126.0, 123.3, 118.8, 117.9, 109.2, 55.6; HRMS (M+) calcd for
C20H14O2 286.0994, found 286.0984.
The methods reported herein for synthesis of BP phenol
derivatives via Suzuki cross-coupling are potentially broad in
scope. They are expected to provide convenient synthetic access
to many other PAHs and their substituted derivatives.
Experimental Section
Caution. Benzo[a]pyrene (BP) has been designated a human
carcinogen by the World Health Organization.2 BP should be
handled with appropriate caution following the procedures recom-
mended in the publication: NIH Guidelines for the Laboratory Use
of Chemical Carcinogens. The phenol and quinone isomers of BP
have not been designated as carcinogenic hazards, but prudence
suggests that they also be handled with caution.
3-Methoxybenzo[r]pyrene. To a suspension of methoxymeth-
yltriphenylphosphonium chloride (222 mg, 0.65 mmol) in anhydrous
THF (1.0 mL) under argon at room temperature was added t-BuOK
(0.65 mL, 1 M in THF) dropwise. The resulting mixture was stirred
at room temperature for 1.5 h, and a solution of 7b (160 mg, 0.54
mmol) in THF (2 mL) was added. Stirring was continued for 1.5 h,
and the reaction was monitored by TLC. Diethyl ether (50 mL)
was added, and the precipitate was filtered off and washed with
Et2O (30 mL). Following removal of the solvent under pressure,
the residue was purified by quick chromatography on a silica gel
column. Elution with hexane/EtOAc (10:1) provided 8 (156 mg,
2-(7-Methoxynaphthyl)phenylacetone (5). To a solution of
2-bromophenylacetone 4 (0.852 g, 4.0 mmol) in DME (10 mL)
under argon was added Pd(PPh3)4 (46 mg, 0.40 mmol), and the
resulting solution was stirred for 20 min. Then the boronic ester 3
(1.30 g, 4.8 mmol) and EtOH (15 mL) were added. Stirring was
continued for 20 min, then NaCO3 (4 mL of a 2 M solution) was
added, and the solution was heated at reflux for 4 h, then cooled to
room temperature. The precipitate of was filtered off, washed with
EtOAc (50 mL), and the filtrate was evaporated to dryness. The
residue was dissolved in EtOAc (80 mL), washed with water (3 ×
15 mL), dried over Na2SO4, and evaporated to dryness. Chroma-
tography of the residue on a column of silica gel eluted with hexane/
EtOAc (20:1) afforded 5 (0.72 g, 62%): 1H NMR (500 MHz,
CDCl3) δ 7.85-7.78 (m, 2 H), 7.42 (s, 1 H), 7.45-7.30 (m, 3 H),
7.30-7.20 (m, 3 H), 7.17 (s, 1 H), 3.96 (s, 3 H), 3.77 (s, 2 H),
2.02 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 206.3, 157.8, 142.2,
139.1, 134.2, 132.1, 130.4, 130.0, 129.0, 127.6, 127.38, 127.35,
126.8, 126.5, 124.8, 118.8, 105.6, 55.0, 48.1, 29.4; HRMS (M+)
calcd for C20H18O2 (M+) 290.1307, found 290.1309.
1
92%) as an oil, shown by H NMR analysis to consist of a 1:1
mixture of E- and Z-isomers, that was used directly in the next
step.
To this solution of 8 (156 mg, 0.50 mmoL) in CH2Cl2 (5 mL)
was added CH3SO3H (50 µL) at 0 °C, and the mixture was stirred
at room temperature for 3 h as the reaction was monitored by TLC.
EtOAc (50 mL) was added, and the solution was washed with a
saturated NaHCO3 solution and dried over Na2SO4. After evapora-
tion of the solvent under reduced pressure, the residue was purified
by chromatography on a silica gel column. Elution with hexane/
1
(38) Nicolaou, K. C.; Montagon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem.
Soc. 2002, 124, 2245–2258.
Et2O (20:1) gave 3-methoxybenzo[R]pyrene (115 mg, 83%): H
NMR (500 MHz, CDCl3) δ 9.02 (d, J ) 8.5 Hz, 1 H), 8.90 (d, J
) 8.0 Hz, 1 H), 8.47 (s, 1 H), 8.34 (d, J ) 9.5 Hz, 1 H), 8.30-8.15
(m, 3 H), 8.00 (d, J ) 9.5 Hz, 1 H), 7.86-7.75 (m, 2 H), 7.65 (d,
J ) 8.0 Hz, 1 H), 4.21 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ
153.5, 131.6, 130.3, 128.8, 128.0, 127.9, 127.4, 127.0, 126.5, 126.3,
126.0, 125.9, 125.5, 123.9, 123.6, 123.1, 121.4, 119.9, 119.6, 109.9,
56.3; MS (APCI) m/z ) 283 (100%).
(39) Electrophilic reactions of BP are well known to take place preferentially
at the 6-position, in accordance with molecular orbital theoretical prediction (ref
3a). The presence of electron-donating groups, such as methoxy, in the 1-, 3-,
or 12-positions would likely increase the likelihood of substitution in the
6-position. A reviewer has pointed out that there are 36 possible BP quinone
structures and that the BP quinones formed as metabolites are among those with
the largest number of Kekule´ structures (six). Dias, J. J. Chem. Inf. Comput.
Sci. 1999, 30, 53–61.
602 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of Phenol and Quinone Metabolites
Benzo[r]pyren-3-ol (3-HO-BP). To a suspension of 3-methoxy-
benzo[R]pyrene (56 mg, 0.2 mmol) in HOAc (7 mL) was added
HI (7 mL of a 57% solution) under argon. The mixture was stirred
for 1.5 h at 140 °C, and the reaction was monitored by TLC. The
mixture was cooled to ambient temperature and poured onto crushed
ice (50 g). The solid precipitate was filtered off, washed with water,
and then dissolved in EtOAc. The solution was washed with brine
and dried over Na2SO4. Evaporation of the solvent under vacuum
gave a residue that was purified by chromatography on a silica gel
column. Elution with hexane/EtOAc (4:1) gave 3-HO-BP (40 mg,
75%): 1H NMR (500 MHz, acetone-d6) δ 9.53 (br s, 1H), 9.08 (d,
J ) 8.0 Hz, 1 H), 8.94 (d, J ) 9.0 Hz, 1 H), 8.49 (s, 1 H),
8.35-8.20 (m, 3 H), 8.19 (d, J ) 8.5 Hz, 1 H), 7.99 (d, J ) 9.5
Hz, 1 H), 7.85-7.70 (m, 2 H), 7.69 (d, J ) 8.0 Hz, 1 H); 13C
NMR (125.8 MHz, acetone-d6) δ 151.8, 131.7, 130.5, 128.6, 128.1,
127.8, 127.7, 126.73, 126.70, 126.3, 126.1, 125.6, 125.5, 123.9,
123.1, 123.0, 121.7, 119.3, 117.6, 115.0; MS (APCI) m/z ) 269
(70%), 283 (100%).
132.0, 130.6, 130.41, 130.40, 130.0, 129.9, 129.1, 127.2, 126.7,
126.3, 124.6, 123.3, 122.1, 120.9, 120.2, 105.6, 55.8; HRMS calcd
for C20H14O2 (M+) 286.0994, found 286.0999.
1-Methoxybenzo[r]pyrene (1-MeO-BP). The conversion of 13b
(162 mg, 0.566 mmol) to 1-MeO-BP was carried out by a procedure
analogous to that employed for the synthesis of 3-MeO-BP from
7b. 1-MeO-BP was obtained (117 mg, 73%): 1H NMR (500 MHz,
CDCl3) δ 9.05-8.95 (m, 2 H), 8.67 (d, J ) 9.5 Hz, 1 H), 8.38 (s,
1 H), 8.24 (dd, J ) 9.5 and 2.0 Hz, 1 H), 7.96 (d, J ) 8.5 Hz, 1
H), 7.83-7.75 (m, 3 H), 7.42-7.37 (m, 2 H), 4.17 (s, 3 H); 13C
NMR (125.8 MHz, CDCl3) δ 154.1, 131.6, 130.3, 128.7, 128.0,
127.8, 127.7, 126.4, 126.1, 125.6, 125.5, 125.23, 125.19, 124.0,
123.8, 123.1, 121.6, 121.4, 121.3, 106.5, 56.0; MS (APCI) m/z )
283 (100%).
Benzo[r]pyrene-1-ol (1-HO-BP). To a suspension of 1-MeO-
BP (74 mg, 0.262 mmol) in HOAc (9 mL) was added a HI solution
(57%, 9 mL) under argon. The mixture was stirred for 1.5 h at 140
°C, and the reaction was monitored by TLC. Then the mixture was
cooled to room temperature and poured onto crushed ice (50 g).
The resulting precipitate was filtered off and washed with water.
Then it was dissolved in EtOAc, washed with brine, and dried over
Na2SO4. After evaporation of the solvent under vacuum, the residue
was purified by chromatography on a silica gel column. Elution
2-(5-Methoxynaphthalen-2-yl)phenylacetone (11). To a solu-
tion of 2-bromophenylacetone 4 (1.214 g, 5.7 mmol) in DME (16
mL) under argon was added Pd(PPh3)4 (66 mg, 0.057 mmol). The
resulting solution was stirred for 20 min, then boronic ester 10 (1.85
g, 6.84 mmol) and EtOH (23 mL) were added. After 20 min, a
solution of Na2CO3 (2 M, 5.7 mL) was added, the mixture was
heated at reflux for 4 h, and the reaction was monitored by TLC.
The solution was cooled to room temperature, and the precipitate
was filtered off and washed with EtOAc (50 mL). The filtrate was
evaporated to dryness, and the residue was dissolved in EtOAc (100
mL), washed with water (3 × 20 mL), and dried over Na2SO4.
After evaporation of the solvent under reduced pressure, the residue
was purified by chromatography on a silica gel column eluted with
1
with hexane/EtOAc (4:1) provided 1-HO-BP (56 mg, 80%): H
NMR (500 MHz, DMSO-d6) δ 10.80 (br s, 1 H), 9.20-9.10 (m, 2
H), 8.60 (d, J ) 9.0 Hz, 1 H), 8.54 (s, 1 H), 8.32 (d, J ) 8.0 Hz,
1 H), 8.04 (d, J ) 8.0 Hz, 1 H), 7.92-7.75 (m, 4 H), 7.52 (d, J )
8.0 Hz, 1 H); 13C NMR (125.8 MHz, DMSO-d6) δ 153.1, 131.6,
130.4, 129.0, 128.4, 128.1, 127.5, 126.8, 126.6, 126.5, 126.2, 124.9,
124.0, 123.9, 123.8, 123.6, 122.4, 121.4, 120.5, 112.1; MS (APCI)
m/z ) 269 (70%), 283 (100%).
1
hexane/EtOAc (20:1) to afford 11 (1.27 g, 77%): H NMR (500
2-(7-Methoxynaphthalene-6-yl)benzene-1,3-dialdehyde (16).
2-Bromobenzene-1,3-dialdehyde 15 was synthesized by the reported
method.31 To a solution of 15 (104 mg, 0.49 mmol) in DME (1
mL) under argon was added Pd(PPh3)4 (6 mg, 0.005 mmol). The
resulting solution was stirred for 20 min, then boronic ester 3 (175
mg, 0.65 mmol) and EtOH (1.6 mL) were added. After 20 min, a
solution of Na2CO3 (2 M, 0.5 mL) was added, the mixture was
heated at reflux for 4 h, and the reaction was monitored by TLC.
Then it was cooled to room temperature, and the precipitate was
filtered off and washed with EtOAc (20 mL). The filtrate was
evaporated to dryness. The residue was dissolved in EtOAc (30
mL), washed with water (3 × 10 mL), and dried over Na2SO4.
After evaporation of the solvent under reduced pressure, the residue
was purified by chromatography on a silica gel column. Elution
MHz, CDCl3) δ 8.33 (d, J ) 8.5 Hz, 1 H), 7.70 (d, J ) 1.5 Hz, 1
H), 7.50-7.35 (m, 6 H), 7.32-7.28 (m, 1 H), 6.91-6.87 (m, 1 H),
4.06 (s, 3 H), 3.75 (s, 2 H), 2.01 (s, 3 H); 13C NMR (125.8 MHz,
CDCl3) δ 206.6, 155.5, 142.4, 139.4, 134.3, 132.3, 130.7, 130.4,
127.8, 127.4, 127.2, 126.7, 126.6, 124.5, 122.1, 120.3, 104.0, 55.6,
48.4, 29.7; HRMS calcd for C20H18O2 (M+) 290.1307, found
290.1309.
1-Methoxy-5-methylchrysene (12). To a dry flask was added a
solution of 11 (670 mg, 2.3 mmol) in CH2Cl2 (21 mL) under argon.
Then a solution of TiCl4 (2.3 mL, 1 M in CH2Cl2) was added
dropwise at -78 °C, and the resulting mixture was stirred for 3.5 h
at 0 °C. The reaction was monitored by TLC and then quenched
by pouring onto crushed ice (20 g). The mixture was extracted with
EtOAc (3 × 50 mL), and the combined extracts were washed with
water and dried over Na2SO4. After evaporation of the solvent under
reduced pressure, the residue was purified by chromatography on
a silica gel column. Elution with hexane/EtOAc (10:1) afforded
12 along with a minor unidentified compound. Recrystallization
1
with hexane/EtOAc (10:1) afforded 16 (124 mg, 88%): H NMR
(500 MHz, CDCl3) δ 9.85 (s, 2 H), 8.27 (d, J ) 8.0 Hz, 2 H), 7.91
(d, J ) 8.0 Hz, 1 H), 7.84 (d, J ) 8.0 Hz, 1 H), 7.74 (s, 1 H), 7.68
(t, J ) 8.0 Hz, 1 H), 7.34 (d, J ) 8.0 Hz, 1 H), 7.26 (d, J ) 8.0
Hz, 1 H), 7.17 (s, 1 H), 3.94 (s, 3 H); 13C NMR (125.8 MHz,
CDCl3) δ 190.9, 158.7, 148.2, 134.8, 133.8, 132.6, 130.2, 129.34,
129.31, 128.4, 128.3, 127.9, 125.8, 120.2, 105.7, 55.3; HRMS calcd
for C19H14O3 (M+) 290.0943, found 290.0948.
9-Methoxybenzo[r]pyrene. To a suspension of methoxymeth-
yltriphenylphosphonium chloride (324 mg, 0.95 mmol) in anhydrous
THF (1.5 mL) under argon at room temperature was added t-BuOK
(0.95 mL, 1 M in THF) dropwise. The resulting mixture was stirred
at room temperature for 1.5 h, and a solution of 15 (120 mg, 0.395
mmol) in THF (2 mL) was added. The resulting mixture was stirred
for 1.5 h, monitored by TLC, and quenched by dilution with Et2O
(50 mL). The precipitate was filtered off, washed with Et2O (30
mL), and the solvent was removed under pressure. The residue was
chromatographed on a silica gel column eluted with hexane/EtOAc
(10:1) to provide 17 as an oil (123 mg, 90%) that was used directly
in the next step.
1
from EtOH gave pure 12 (425 mg, 68%): H NMR (500 MHz,
CDCl3) δ 8.80-8.72 (m, 2 H), 8.56 (d, J ) 8.5 Hz, 1 H), 8.53 (d,
J ) 9.5 Hz, 1 H), 7.90 (dd, J ) 9.0 and 1.5 Hz, 1 H), 7.85 (s, 1
H), 7.70-7.55 (m, 3 H), 7.05 (d, J ) 7.5 Hz, 1 H), 4.11 (s, 3 H),
3.23 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 155.4, 133.2, 132.6,
131.6, 130.3, 130.0, 129.4, 129.1, 127.2, 126.3, 125.7, 125.1, 124.7,
123.1, 120.9, 120.7, 120.0, 104.6, 55.5, 27.8; MS (APCI) m/z )
273 (100%).
1-Methoxy-5-formylchrysene (13b). Bromination of 12 (272
mg, 1 mmol) with NBS (196 mg, 1.1 mmol) was carried out by
the procedure employed for the preparation of 7a. The product 13a
was reacted with DMSO (2.83 mL) and NaHCO3 (168 mg, 2 mmol)
according to the procedure employed for the synthesis of 7b.
Purification of the product by chromatography on silica gel gave
13b (213 mg, 74%): 1H NMR (500 MHz, CDCl3) δ 10.60 (s, 1 H),
8.72 (d, J ) 8.5 Hz, 1 H), 8.64 (d, J ) 9.0 Hz, 1 H), 8.52 (d, J )
9.5 Hz, 1 H), 8.41 (s, 1 H), 8.09 (d, J ) 8.0 Hz, 1 H), 7.78 (t, J )
7.5 Hz, 1 H), 7.75-7.50 (m, 3 H), 7.05 (d, J ) 7.5 Hz, 1 H), 4.09
(s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 193.2, 155.8, 133.7,
To a solution of 17 (123 mg, 0.36 mmoL) in CH2Cl2 (4.5 mL)
was added CH3SO3H (50 µL) at 0 °C. The mixture was stirred for
2.5 h at room temperature, and the reaction was monitored by TLC.
Reaction was quenched by dilution with EtOAc (50 mL), and the
J. Org. Chem. Vol. 74, No. 2, 2009 603

Xu et al.
solution was washed with a saturated NaHCO3 solution and dried
over Na2SO4. After evaporation of the solvent under reduced
pressure, the residue was purified by chromatography on a silica
gel column. Elution with hexane/Et2O (20:1) afforded 9-methoxy-
benzo[R]pyrene (71 mg, 70%): 1H NMR (500 MHz, CDCl3) δ 8.81
(d, J ) 9.0 Hz, 1 H), 8.35 (s, 1 H), 8.23-8.15 (m, 3 H), 8.12 (d,
J ) 9.0 Hz, 1 H), 8.05 (d, J ) 7.5 Hz, 1 H), 7.97 (t, J ) 7.5 Hz,
1 H), 7.91 (d, J ) 9.0 Hz, 1 H), 7.84 (d, J ) 9.0 Hz, 1 H), 7.43
(dd, J ) 9.0 and 2.0 Hz, 1 H), 4.10 (s, 3 H); 13C NMR (125.8
MHz, CDCl3) δ 158.0, 131.8, 131.5, 130.5, 129.4, 128.2, 127.9,
126.9, 126.73, 126.70, 126.1, 126.0, 125.5, 125.0, 124.6, 124.4,
124.1, 122.1, 118.5, 101.9, 55.5; MS (APCI) m/z ) 283 (100%).
Benzo[r]pyren-9-ol (9-HO-BP). To a solution of 9-MeO-BP
(64 mg, 0.226 mmol) in dry CH2Cl2 (15 mL) at -20 °C was added
dropwise a solution of BBr3 (1 M in CH2Cl2, 1.2 mL). The resulting
purple solution was stirred at -20 °C for 30 min and then at room
temperature overnight. The reaction mixture was then immersed
in dry ice, ice was added, and the organic solvent was removed at
room temperature under reduced pressure. The aqueous suspension
was extracted with EtOAc, and the combined extracts were washed
with brine, dried over Na2SO4, and evaporated to dryness. The
residue was chromatographed on a silica gel column eluted with
6-Formyloxybenzo[r]pyrene (24). 6-Formylbenzo[R]pyrene 23
was synthesized from BP by the procedure described previously.33
To a solution of 23 (219 mg, 0.782 mmol) in CH2Cl2 (60 mL) was
added m-chloroperbenzoic acid (403 mg, 2.35 mmol), and the
mixture was stirred at room temperature for 72 h. Sodium thiosulfate
(10 mL of a 10% aqueous solution) was added, stirring was
continued for 30 min, and the mixture was poured into an aqueous
Na2S2O3 solution (10 mL). The aqueous phase was extracted with
CH2Cl2 (50 mL) and combined with the organic layer, and the
combined organic phase was washed with 10% aqueous sodium
thiosulfate and brine, dried, and evaporated to dryness. The residue
was purified by chromatography on silica gel. Elution with hexane/
EtOAc (10:1) afforded pure 24 (93 mg, 40%): 1H NMR (500 MHz,
CDCl3) δ 9.07 (d, J ) 8.5 Hz, 1 H), 9.01 (d, J ) 9.0 Hz, 1 H),
8.78 (s, 1 H), 8.31 (d, J ) 8.5 Hz, 2 H), 8.26 (d, J ) 7.5 Hz, 1 H),
8.11 (d, J ) 7.5 Hz, 1 H), 8.10-7.90 (m, 3 H), 7.90-7.80 (m, 2
H); 13C NMR (125.8 MHz, CDCl3) δ 160.1, 139.4, 131.4, 130.9,
129.5, 128.6, 127.7, 127.0, 126.53, 126.49, 126.47, 126.4, 125.6,
125.0, 124.5, 123.7, 123.4, 121.93, 121.86, 121.2, 120.4; HRMS
calcd for C21H12O2 (M+) 296.0837, found 296.0817.
Benzo[a]pyren-9,10-dione (BP 9,10-dione). To a solution of
9-HO-BP (27 mg, 0.1 mmol) in DMSO (2 mL) was added IBX
(56 mg, 0.2 mmol). The mixture was stirred at room temperature
for 2 h. The purple precipitate was filtered off and purified by
chromatography on a column of silica gel. Elution with EtOAc/
CHCl3 (1:10) gave BP 9,10-dione (23 mg, 82%) as a purple solid:
1H NMR (500 MHz, CDCl3) δ 9.77 (d, J ) 9.5 Hz, 1 H), 8.40-8.25
(m, 4 H), 8.15-8.10 (m, 2 H), 8.02 (s, 1 H), 7.74 (d, J ) 10.0 Hz,
1 H), 6.60 (d, J ) 9.5 Hz, 1 H); 13C NMR (125.8 MHz, CDCl3) δ
181.9, 181.6, 147.6, 136.5, 134.8, 133.7, 133.6, 132.2, 131.4, 130.4,
128.5, 128.2, 128.0, 127.6, 127.5, 127.4, 125.6, 125.5, 123.7, 122.2;
MS (APCI) m/z ) 283 (100%).
1
10-25% EtOAc in hexane to give 9-HO-BP (44 mg, 72%): H
NMR (500 MHz, acetone-d6) δ 9.11 (br s, 1 H), 8.90 (d, J ) 9.0
Hz, 1 H), 8.50 (s, 1 H), 8.45 (d, J ) 2.0 Hz, 1 H), 8.29 (d, J ) 9.0
Hz, 1 H), 8.22 (t, J ) 7.5 Hz, 2 H), 8.08 (d, J ) 7.5 Hz, 1 H),
8.00-7.90 (m, 2 H), 7.87 (d, J ) 9.0 Hz, 1 H), 7.49 (dd, J ) 9.0
and 2.0 Hz, 1 H); 13C NMR (125.8 MHz, acetone-d6) δ 156.3, 131.9,
131.7, 130.8, 130.1, 128.3, 127.4, 126.9, 126.4, 126.3, 126.2, 125.8,
125.4, 125.0, 124.9, 124.3, 124.0, 122.3, 118.7, 105.1; MS (APCI)
m/z ) 269 (85%), 283 (100%).
1-Methyl-2-naphthyl trifluoromethanesulfonate (18b). To a
solution of 1-methylnaphthalen-2-ol (6.32 g, 40 mmol) and pyridine
(60 mmol) in CH2Cl2 (200 mL) was added Tf2O (50 mmol)
dropwise at 0 °C under argon. The mixture was stirred at room
temperature for 3 h, then the reaction was quenched by the addition
of water (50 mL). The organic layer was washed with water (3 ×
50 mL) and brine (50 mL) and dried over Na2SO4. After removal
of the solvent under reduced pressure, the residue was purified by
chromatography on a silica gel column eluted with hexane/EtOAc
(10:1) to afford 18b (10.67 g, 92%): 1H NMR (500 MHz, CDCl3)
δ 8.07 (d, J ) 8.5 Hz, 1 H), 7.90 (d, J ) 8.0 Hz, 1 H), 7.79 (d, J
) 8.0 Hz, 1 H), 7.70-7.55 (m, 2 H), 7.39 (d, J ) 9.0 Hz, 1 H),
2.73 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 145.4, 133.2, 132.4,
128.6, 128.4, 127.3, 126.7, 126.5, 124.6, 119.5, 118.7 (q, J ) 320.1
Hz), 12.2; 19F NMR (470.6 MHz, CDCl3) δ -73.7; HRMS calcd
for C12H9O3F3S (M+) 290.0225, found 290.0226.
Benzo[a]pyren-1,6-dione (BP 1,6-dione). To a solution of BTI
(63 mg, 0.147 mmol) in CH3CN/H2O (v/v ) 2/1, 1 mL) was added
1-HO-BP (18 mg, 0.067 mmol) in CH3CN/acetone/water (v/v/v )
5/2.5/2, 9.5 mL) dropwise under argon, and the mixture was stirred
at room temperature for 1.5 h. The orange solid was filtered off
and purified by chromatography on a silica gel column. Elution
with CHCl3/EtOAc (10:1) afforded BP-1,6 dione (15 mg, 78%) as
1
an orange solid: H NMR (500 MHz, CDCl3) δ 8.67 (d, J ) 7.5
Hz, 1 H), 8.64 (d, J ) 8.0 Hz, 1 H), 8.56 (d, J ) 8.0 Hz, 1 H),
8.47 (dd, J ) 8.0 and 1.5 Hz, 1 H), 8.34 (d, J ) 8.0 Hz, 1 H), 7.91
(d, J ) 7.5 Hz, 1 H), 7.80 (dt, J ) 8.0 and 1.5 Hz, 1 H), 7.74 (d,
J ) 10.0 Hz, 1 H), 7.64 (dt, J ) 7.5 and 0.5 Hz, 1 H), 6.78 (d, J
) 10.0 Hz, 1 H); 13C NMR (125.8 MHz, CDCl3) δ 185.3, 183.4,
141.2, 135.1, 134.1, 133.9, 133.6, 131.1, 130.91, 130.86, 130.5,
130.1, 129.9, 129.6, 129.2, 128.7, 127.7, 127.2, 123.99, 123.97;
MS (APCI) m/z ) 283 (100%).
Benzo[a]pyren-3,6-dione (BP 3,6-dione). Oxidation of 3-HO-
BP (30 mg, 0.112 mmol) with BTI (105 mg, 0.244 mmol) by the
procedure employed in the preceding example gave BP 3,6-dione
2-(1-Methyl-2-naphthyl)benzaldehyde (20). Synthesis of 20
was carried out by the procedure for the synthesis of 15. Reaction
of 19 (1.219 g, 4.8 mmol) with 2-bromobenzaldehyde (0.74 g, 4.0
1
1
(26 mg, 82%) as a red solid: H NMR (500 MHz, CDCl3) δ 8.84
mmol) provided 20 (0.728 g, 74%): H NMR (500 MHz, CDCl3)
(d, J ) 7.5 Hz, 1 H), 8.74 (d, J ) 7.5 Hz, 1 H), 8.47 (dd, J ) 8.0
and 1.0 Hz, 1 H), 8.39 (d, J ) 7.5 Hz, 1 H), 8.29 (d, J ) 8.0, 1 H),
7.85-7.70 (m, 3 H), 7.61 (t, J ) 7.5 Hz, 1 H), 6.73 (d, J ) 9.5
Hz, 1 H); 13C NMR (125.8 MHz, CDCl3) δ 185.3, 183.6, 141.8,
135.4, 134.1, 132.8, 132.1, 131.4, 131.0, 130.7, 129.7, 129.6, 129.4,
129.1, 129.0, 128.7, 127.98, 127.96, 124.0, 123.5; MS (APCI) m/z
) 283 (100%).
δ 9.86 (s, 1 H), 8.15 (d, J ) 7.5 Hz, 2 H), 7.96 (d, J ) 8.0 Hz, 1
H), 7.83 (d, J ) 8.0 Hz, 1 H), 7.75-7.55 (m, 4 H), 7.45-7.37 (m,
2 H), 2.53 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 192.0, 146.2,
134.3, 134.0, 133.5, 133.0, 132.4, 132.1, 131.0, 128.5, 127.9, 127.7,
126.9, 126.6, 126.0, 125.9, 124.3, 16.2; HRMS calcd for C18H14O
(M+) 246.1045, found 246.1064.
12-Methylbenz[a]anthracene (22a). Synthesis of 22a was
carried out by a procedure based on that employed for the synthesis
of 3-MeO-BP. Reaction of 20 (738 mg, 3.0 mmol) by this method
Acknowledgment. This investigation was supported by NIH
Grant Nos. P01 CA 92537, R01 CA 039504, R01 ES 015857,
and P30 ES 013508.
1
gave 22a (363 mg, 50%): H NMR (500 MHz, CDCl3) δ 8.65 (d,
J ) 9.0 Hz, 1 H), 8.39 (d, J ) 9.0 Hz, 1 H), 8.23 (s, 1 H), 8.08 (d,
J ) 8.0 Hz, 1 H), 7.89 (d, J ) 9.0 Hz, 1 H), 7.80-7.55 (m, 6 H),
3.43 (s, 3 H); 13C NMR (125.8 MHz, CDCl3) δ 133.8, 132.6,
131.52, 131.47, 131.4, 131.2, 129.8, 128.8, 128.4, 128.11, 128.06,
126.9, 126.5, 125.8, 125.4, 125.3, 125.2, 125.1, 20.9; MS (APCI)
m/z ) 243 (100%).
Supporting Information Available: 1H and 13C NMR
spectra of reported compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO801864M
604 J. Org. Chem. Vol. 74, No. 2, 2009