Synthesis of the o-Quinones and Other Oxidized Metabolites of Polycyclic Aromatic Hydrocarbons Implicated in Carcinogenesis

Article abstract of DOI:10.1021/jo030348n

Efficient new syntheses of the o-quinone derivatives of benzo[a]pyrene (BPQ), 7,12-dimethylbenz-[a] anthracene (DMBAQ), and benz[a]anthracene (BAQ), implicated as active carcinogenic metabolites of the parent polycyclic aromatic hydrocarbons (PAHs), are reported. These PAH quinones also serve as starting compounds for the synthesis of the other active metabolites of these PAHs thought to be involved in their mechanism(s) of carcinogenesis. The latter include the corresponding o-catechols, trans-dihydrodiols, and the corresponding anti- and syn-diol epoxides.

Full text of DOI:10.1021/jo030348n

Syn th esis of th e o-Qu in on es a n d Oth er Oxid ized Meta bolites of
P olycyclic Ar om a tic Hyd r oca r bon s Im p lica ted in Ca r cin ogen esis
Ronald G. Harvey,*,† Qing Dai,† Chongzhao Ran,† and Trevor M. Penning‡
The Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637,
and Department of Pharmacology, School of Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania 19104
rharvey@ben-may.bsd.uchicago.edu
Received November 11, 2003
Efficient new syntheses of the o-quinone derivatives of benzo[a]pyrene (BPQ), 7,12-dimethylbenz-
[a]anthracene (DMBAQ), and benz[a]anthracene (BAQ), implicated as active carcinogenic metabo-
lites of the parent polycyclic aromatic hydrocarbons (PAHs), are reported. These PAH quinones
also serve as starting compounds for the synthesis of the other active metabolites of these PAHs
thought to be involved in their mechanism(s) of carcinogenesis. The latter include the corresponding
o-catechols, trans-dihydrodiols, and the corresponding anti- and syn-diol epoxides.
In tr od u ction
pyrene-7,8-dione (BPQ), generating reactive oxygen spe-
cies (ROS) that attack DNA.9,10 The o-quinones also react
with DNA to form both stable and depurinating ad-
ducts.11,12 A third mechanism has been proposed that
entails activation by CYP peroxidase to form PAH radical
cations that combine with DNA to yield unstable adducts
that are lost by depurination.13 The relative importance
of these pathways is unknown.
In connection with studies designed to clarify this
issue, we required methods for efficient synthesis of the
various activated PAH metabolites thought to be involved
(trans-dihydrodiols, anti- and syn-diol epoxides, catechols,
and o-quinones), as well as the adducts formed by reac-
tions of the active species (diol epoxides and quinones)
at deoxyguanosine (dG) and deoxyadenosine (dA) sites
in DNA. The PAHs chosen for study were the following:
benz[a]anthracene (BA), benzo[a]pyrene (BP), and 7,12-
dimethylbenz[a]anthracene (DMBA). They represent a
range of activity from weak or borderline (BA), to mod-
erately active (BP), to highly potent (DMBA).14 Athough
syntheses of oxidized metabolites of these PAHs have
been reported,2,15-19 the methods entail complex multistep
Polycyclic aromatic hydrocarbons (PAHs), some of
which are potent carcinogens, are widespread environ-
mental pollutants.1-4 They are formed in the incomplete
combustion of fossil fuels and other organic matter, and
significant levels are present in tobacco smoke, in many
common foods, and in automobile exhaust emissions.
Prior investigations have shown that PAHs, such as
benzo[a]pyrene (BP), are activated by CYP1A1 enzymes
to trans-dihydrodiol metabolites (e.g. BP-7,8-diol) that are
further transformed to anti- and syn-diol epoxides (Scheme
1).2,5 These metabolites react at deoxyguanosine and
deoxyadenosine sites at mutational hotspots in DNA to
generate stable adducts6,7 that lead to induction of
tumors. Recent evidence supports a second mechanistic
pathway that involves oxidation of the dihydrodiols by
aldo-keto reductase enzymes (AKRs) to generate cat-
echols, e.g. BP-catechol.8 These intermediates enter into
redox cycles with the related o-quinones, e.g. benzo[a]-
† University of Chicago.
‡ University of Pennsylvania.
(1) International Agency for Research on Cancer. Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Humans. In
Polynuclear Aromatic Compounds, Part 1, Chemical, Environmental
and Experimental Data; 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) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Wiley-VCH:
New York, 1997.
(9) Penning, T. M.; Onishi, S. T.; Onishi, T.; Harvey, R. G. Chem.
Res. Toxicol. 1996, 9, 84.
(10) Flowers, L.; Onishi, S. T.; Penning, T. M. Biochemistry 1997,
36, 8640.
(11) Shou, M.; Harvey, R. G.; Penning, T. M. Carcinogenesis 1993,
14, 475.
(12) McCoull, K. D.; Rindgen, D.; Blair, I. A.; Penning, T. M. Chem.
Res. Toxicol. 1999, 12, 237.
(13) Cavalieri, E. L.; Rogan, E. G. Xenobiotica 1995, 25, 677. The
importance of the radical-cation mechanism has been questioned:
Melendez-Colon, V.; Luch, A.; Seidel, A.; Baird, W. Carcinogenesis
1999, 20, 1885.
(14) Huggins, C. B.; Pataki, J .; Harvey, R. G. Proc. Natl. Acad. Sci.
1967, 58, 2253.
(15) Beland, F. A.; Harvey, R. G. J . Chem. Soc., Chem. Commun.
1976, 84.
(16) Yagi, H.; Thakker, D. R.; Hernandez, O.; Koreeda, M.; J erina,
D. M. J . Am. Chem. Soc. 1977, 99, 1604.
(5) Conney, A. H. Cancer Res. 1982, 42, 4875,
(6) Dipple, A. In DNA Adducts: Identification and Biological Sig-
nificance; Hemminki, K., Dipple, A., Segerba¨ck, D., Kadulbar, F. F.,
Shuker, D., Bartsch, H., Eds.; IARC Scientific Publication No. 125;
University Press: Lyon, France, 1994; pp 107-129.
(7) J effrey, A. M.; Weinstein, I. B.; J ennette, K.; Grzeskowiak, K.;
Nakanishi, K.; Harvey, R. G.; Autrup, H.; Harris, C. Nature (London)
1977, 269, 348. J ennette, K.; J effrey, A. M.; Blobstein, S. H.; Beland,
F. A.; Harvey, R. G.; Weinstein, I. B. Biochemistry 1977, 16, 932.
(8) Smithgall, T. E.; Harvey, R. G.; Penning, T. M. J . Biol. Chem.
1986, 261, 6184. Smithgall, T. E.; Harvey, R. G.; Penning, T. M. Cancer
Res. 1988, 48, 1227. Smithgall, T. E.; Harvey, R. G.; Penning, T. M. J .
Biol. Chem. 1988, 263, 1814.
(17) Harvey, R. G.; Sukumaran, K. Tetrahedron Lett. 1977, 2387.
(18) Lee, H.; Harvey, R. G.; Cortez, C.; Kiselyov, A. Bioorg. Med.
Chem. Lett. 1997, 7, 443.
(19) Lee, H.; Harvey, R. G. J . Org. Chem. 1986, 51, 3502.
10.1021/jo030348n CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/19/2004
2024
J . Org. Chem. 2004, 69, 2024-2032

New Syntheses of PAH o-Quinones
SCHEME 1
SCHEME 2
procedures that are mainly suitable for small-scale
preparations. Because a longer range objective of these
studies was to develop methods for synthesis of the
deoxyribonucleoside adducts of the PAH o-quinones, we
required larger amounts of the quinones than conve-
niently available by existing methods. Although synthe-
ses of the dG and dA adducts of anti- and syn-BPDE have
been described,20-27 syntheses of the related adducts of
BA and DMBA have not been reported, nor have syn-
theses of the stable dG and dA adducts of the o-quinone
metabolites of BP, BA, DMBA, or any other PAH quinone
larger than naphthoquinone.12,28
We now report efficient new syntheses of the o-quinone
metabolites of BP, BA, and DMBA. These syntheses are
simpler, entail fewer steps, are adaptable to preparative
scale synthesis, and afford substantially higher overall
yields than older methods.
Resu lts a n d Discu ssion
The o-quinones of BP, BA, and DMBA (BPQ, BAQ, and
DMBAQ) were chosen as the primary synthetic targets.
These quinones were needed for biological studies and
as potential synthetic precursors of the corresponding
o-quinone adducts of deoxyguanosine and deoxyadenos-
ine. The PAH o-quinones were also expected to serve as
starting compounds for the synthesis of other PAH me-
tabolites (trans-dihydrodiols, anti- and syn-diol epoxides,
and catechols) known to play a role in carcinogenesis.2,5-12
The o-quinones have the additional practical advantage
that they are relatively stable and easily purified.
(20) Lee, H.; Hinz, M.; Stezowski, J . J .; Harvey, R. G. Tetrahedron
Lett. 1990, 31, 6773.
(21) Lee, H.; Luna, E.; Hinz, M.; Stezowski, J . J .; Kiselyov, A. S.;
Harvey, R. G. J . Org. Chem. 1995, 60, 5604.
(22) Kiselyov, A.; Steinbrecker, T.; Harvey, R. G. J . Org. Chem. 1995,
60, 6129.
(23) Lakshman, M. K.; Sayer, J . M.; J erina, D. M. J . Am. Chem.
Soc. 1991, 113, 6589.
(24) Lakshman, M. K.; Sayer, J . M.; J erina, D. M. J . Org. Chem.
1992, 57, 3438.
(25) Lakshman, M. K.; Gunda, P. Org. Lett. 2003, 5, 39.
(26) Cooper, M. D.; Hodge, R. P.; Tamura, P. J .; Wilkinson, A. S.;
Harris, C. M.; Harris, T. M. Tetrahedron Lett. 2000, 41, 3555.
(27) Cosman, M.; Ibanez, V.; Geacintov, N. E.; Harvey, R. G.
Carcinogenesis 1990, 11, 1667.
(28) Gopishetty, S. R.; Harvey, R. G.; Lee, S.-H.; Blair, I. A.; Penning,
T. M. In Aldo-Keto Reductases and Toxicant Metabolism; Penning, T.
M., Petrash, J . M., Eds.; American Chemical Society Symp. Ser. No.
865; American Chemical Society: Washington, DC, 2003; Chapter 9.
J . Org. Chem, Vol. 69, No. 6, 2004 2025

Harvey et al.
SCHEME 3
Photocyclization of 4a was considerably faster with a
450-W UV lamp, and reaction was complete in ∼1 h. The
principal product was shown by TLC and NMR to be 5a
(60%) accompanied by a polymeric byproduct. An inher-
ent limitation of the photochemical method is the need
for dilute solutions to minimize polymerization and other
secondary reactions.33 As a consequence, photocyclization
is relatively impractical for preparative scale synthesis.
A more practical synthetic route to 5a was acid-
catalyzed cyclization of the bis-methoxyvinyl analogue
4b. Compound 4b was synthesized initially by Wittig
reaction of 3 with methoxymethyltriphenylphosphonium
chloride and PhLi.34 Although the yield of 4b (obtained
as a mixture of the E- and Z-isomers) was acceptable
(75%), the relative unavailability of PhLi from com-
mercial sources made it necessary to investigate alterna-
tive bases. t-BuLi was less satisfactory, affording 4b in
only 50% yield. More satisfactory was potassium tert-
butoxide,35 which provided 4b in 95% yield. Acid-
catalyzed cyclization of the mixture of isomers of 4b took
place smoothly to furnish 5a in excellent yield (95%).
Synthesis of 5a via acid-catalyzed reaction of 4b has
several advantages over the photochemical method that
include relative safety of operation, no special equipment
required, adaptability to preparative scale synthesis, as
well as higher yields. Demethylation of 5a with BBr3
furnished the free phenol, benzo[a]pyren-8-ol (5b), in
good overall yield. The physical and spectral properties
of 5a and 5b matched those of authentic samples.
Conversion of PAH â-phenols, such as 5b, to o-quinones
is usually accomplished by oxidation with Fremy’s salt
[(KSO3)2NO].2,36,37 However, this reagent requires aque-
ous conditions that are poorly compatible with the
relative insolubilities of PAH compounds in water. Oxi-
dations of PAH â-phenols with Fremy’s salt are notori-
ously erratic and difficult to reproduce. For this reason,
we investigated the use of o-iodoxybenzoic acid (IBX) as
a potential alternative reagent. IBX is a mild oxidant that
is soluble in organic solvents and is widely employed for
oxidation of alcohols.38 Oxidations with IBX, like those
with Fremy’s reagent, are thought to proceed principally
via a one-electron-transfer mechanism. Oxidation of 5b
with IBX took place smoothly in DMF to furnish BPQ as
the major product. Magdziak et al.39 recently reported
oxidation of several monocyclic phenols by IBX and
concluded that at least one electron-donating group was
Syn th esis of P AH o-Qu in on es. The synthetic route
to BPQ (Scheme 2) involves in the key step Suzuki
coupling of 6-methoxynaphthaleneboronic acid (1) with
2-bromobenzene-1,3-dialdehyde (2).29 The dialdehyde 2
was synthesized from 2-bromoxylene via bromination and
hydrolysis (Scheme 3). Initial experiments were con-
ducted in a photochemical apparatus in a reaction vessel
equipped with a condenser and a 450-W Hanovia UV
lamp in a quartz immersion well with internal cooling.
The principal products after 24 h were the mono- and
dibromo-substituted derivatives (6 and 7). An attempt
to increase the reaction rate by heating the solution to
reflux had to be aborted, because the reaction became
very vigorous and threatened to go out of control. A
simpler and less hazardous procedure was to conduct the
reaction in an ordinary Pyrex flask irradiated externally
by an 85-W UV lamp at reflux temperature. Under this
condition, reaction proceeded smoothly to furnish pure
1,3-bis(dibromomethyl)2-bromobenzene (8) (91%).30
Hydrolysis of 8 by the reported procedure31 with
NaOAc/CaCO3 as the base and tetrabutylammonium
bromide as a phase transfer agent afforded 2 in low yield.
Addition of toluene to aid solution of 1 failed to improve
the yield of 2. Efficient hydrolysis of 8 was accomplished
by the use of aqueous formic acid or AgNO3 in aqueous
CH3CN.31 Both methods were superior to the literature
procedure,30 requiring shorter reaction times and afford-
ing higher yields.
Coupling of 2 with 3 took place smoothly in the
presence of (Ph3P)4Pd and Na2CO3 (Scheme 2) to furnish
2-(2-methoxynaphthalene-6-yl)benzene-1,3-dialdehyde (3).
Double Wittig reaction of 3 with methylenetriphenylphos-
phine gave the divinyl compound 4a (R ) H). Oxidative
photocyclization of 4a (R ) H) in the presence of iodine
and 1,2-epoxybutane29 with a low wattage (85 W) UV
lamp was slow, affording 8-methoxybenzo[a]pyrene (5a )
in low yield, even at reflux temperature. However, the
relative slowness of the reaction made it feasible to
monitor the reaction by TLC and trap the primary
1
product. This was identified by its H NMR spectrum as
the chrysene derivative (9) formed by cyclization to the
1-position of the naphthalene ring. The benz[a]an-
thracene structure (10) expected to be formed by the
alternative mode of cyclization was ruled out by the
absence of the characteristic singlet peaks expected for
the 7,12-protons of this structure.
(32) Mataka, S.; Liu, G.-B.; Sawada, T.; Tori-I, A.; Tashiro, M. J .
Chem. Res. (S) 1995, 410.
(33) Mallory, F. B.; Mallory, C. W. Org. React. 1988, 30, 1-456.
(34) Zhang, J .-T.; Harvey, R. Tetrahedron 1999, 55, 625.
(35) Upadhya, T. T.; Garunath, S.; Sudalai, A. Tetrahedron: As-
symmetry 1999, 10, 2899.
(36) Sukumaran, K. B.; Harvey, R. G. J . Org. Chem. 1980, 45, 4407.
(37) Zimmer, H.; Lankin, D. C.; Horgan, S. W. Chem. Rev. 1971,
71, 229.
(38) Nicolaou, K. C.; Momtagnon, T.; Baran, P. S.; Zhong, Y.-L. J .
Am. Chem. Soc. 2002, 124, 2245.
(29) Zhang, F.-J .; Cortez, C.; Harvey, R. G. J . Org. Chem. 2000, 65,
3952.
(30) Mataka, S.; Liu, G.-B.; Sawada, T.; Kurisu, M.; Tashiro, M. Bull.
Chem. Soc. J pn. 1994, 67, 1113.
(39) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2001, 4, 284.
(31) Makosza, M.; Owczarczyk, Z. J . Org. Chem. 1989, 54, 5094.
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New Syntheses of PAH o-Quinones
SCHEME 4
SCHEME 5
) H) in good overall yield. The proton and carbon NMR
spectra and physical properties of 15b were in good
agreement with the values reported.19,36
Conversion of 15b to DMBAQ was accomplished by
oxidation with IBX in DMF by the procedure employed
for synthesis of BPQ. Reaction took place smoothly to
furnish DMBAQ as a deep purple crystalline solid. It is
notable that oxidation of the methyl groups of 15b did
not occur to significant extent under the conditions
employed, despite the fact that IBX has been employed
as a reagent for oxidation of benzylic methyl groups.38
The proton NMR spectrum and physical properties of
DMBAQ were in good agreement with its structural
assignment and with the values reported.19,36,40,45
Synthesis of BAQ was not feasible by direct application
of the method used for DMBAQ. Specifically, cyclization
of the methoxyvinyl intermediate analogous to 14 lacking
methyl groups in the naphthalene ring was expected to
take place preferentially in the unsubstituted 1-position
of the naphthalene ring, resulting in formation of a
chrysene derivative, rather than a benz[a]anthracene
derivative. To favor the desired mode of cyclization,
methoxy groups were employed to block the alternative
mode of cyclization. Although only a single blocking group
was required, it was convenient to employ the 1,4-di-
methoxynaphthalenederivative,i.e.2-bromo-1,4-dimethoxy-
naphthalene (16), as the starting compound.
Synthesis of BAQ was accomplished by Pd-catalyzed
coupling of 16 with 2-formyl-4-methoxyboronic acid (17)
(Scheme 6). Compound 16 was prepared by reductive
methylation of 2-bromonaphthalene-1,4-dione with NaBH4
and dimethyl sulfate. 2-Formyl-4-methoxyphenylboronic
acid (17) was synthesized from 2-bromo-4-methoxyben-
zaldehyde by the published method.42 Suzuki coupling
of 16 with 17 afforded 5-methoxy-2-(1,4-dimethoxynaph-
thalen-2-yl)benzaldehyde (18). Reaction of 18 with meth-
oxymethylenetriphenylphosphine provided the enol ether
19 (as a mixture of E- and Z-isomers). Acid-catalyzed
cyclization of the mixture with methanesulfonic acid
furnished 3,7,12-trimethoxybenz[a]anthracene (20).
required for oxidation to occur. However, oxidation of 5b
and other polycyclic phenols studied, all of which lack
electron-donating groups, with IBX took place readily.
Apparently, a polycyclic aromatic ring system is sufficient
to facilitate oxidation by this reagent.
Analogous synthesis of DMBAQ (Scheme 4) required
1,4-dimethyl-2-naphthalene boronic acid (11) and 2-bromo-
5-methoxybenzaldehyde (12) as starting compounds. The
boronic acid 11 was synthesized (Scheme 5) by Fe-
catalyzed bromination of 1,4-dimethylnaphthalene to
furnish 2-bromo-1,4-dimethylnaphthalene,40 followed by
consecutive reaction with n-BuLi and trimethylborate,
and hydrolysis of the resulting dimethylborate ester.41
The bromoaldehyde 12 was prepared from 3-methoxy-
benzaldehyde by the published method.42-44
Coupling of 11 with 12 took place smoothly in the
presence of (Ph3P)4Pd to furnish 5-methoxy-2-(1,4-dim-
ethylnaphthalen-2-yl)benzaldehyde (13) (Scheme 4). This
adduct was converted to the corresponding enol ether 14
by Wittig reaction with methoxymethylenetriphenylphos-
phine. Enol ether 14 was shown by NMR analysis to be
a mixture of E- and Z-isomers. Acid-catalyzed cyclization
of the mixture by treatment with methanesulfonic acid
furnished 3-methoxy-7,12-dimethylbenz[a]anthracene
(15a : R ) Me). Demethylation with BBr3 provided the
free phenol 7,12-dimethylbenz[a]anthracen-3-ol (15b: R
(40) Sharma, P. K. Synth. Commun. 1993, 23, 389.
(41) Washburn, R. M.; Levens, E.; Albright, C. F.; Billig, F. A.
Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 68.
(42) Harmata, M.; Kahraman, M. J . Org. Chem. 1999, 64, 4949.
(43) Le´o, P.-M.; Morin, C.; Philouze, C. Org. Lett. 2002, 4, 2711.
(44) Kumar, S. J . Chem. Soc., Perkin Trans. 1 1998, 3157.
(45) Newman, M. S.; Khanna, J . M.; Khanna, V. K.; Kanakarajan,
K. J . Org. Chem. 1979, 44, 4994.
J . Org. Chem, Vol. 69, No. 6, 2004 2027

Harvey et al.
SCHEME 6
SCHEME 7
SCHEME 8
Regioselective removal of the 7,12-methoxy groups of
20 without concurrent loss of the 3-methoxy group
presented a challenge. It was accomplished by reduction
of 20 with HI in acetic acid.46 The remarkable regiose-
lectivity of this reduction is likely due to the greater
reactivity of the meso region sites of benz[a]anthracene
in most reactions.46 Although reductive cleavage of the
3-methoxy group did not occur, demethylation of 20 took
place to yield the phenol 3-hydroxybenz[a]anthracene
(21) as the principal product. Oxidation of 21 with IBX
in DMF gave BAQ in good overall yield. The spectral and
physical properties of 21 and BAQ were in good agree-
ment with the values reported.2
SCHEME 9
Syn th esis of th e o-Ca tech ols a n d Oth er Oxid ized
P AH Meta bolites. The o-catechol derivatives of BP, BA,
and DMBA were synthesized by reduction of the corre-
sponding o-quinones with NaBH4 in DMA by the reported
procedure.47 Reduction of BPQ provided 7,8-dihydroxy-
benzo[a]pyrene (BP-catechol) isolated as its dibenzoate
or diacetate ester (22) (Scheme 7). BP-catechol, like most
other PAH catechols, undergoes facile autoxidation on
exposure to air to regenerate the quinone along with
other minor oxidized products. Formation of BPQ was
readily detectable by its intense purple color. In contrast
to the catechols, the diester derivatives of the catechols
are relatively stable solids that may be readily purified
and characterized. They may be reconverted to the cor-
responding catechols, as needed for experimental studies.
The facility of autoxidation of BP-catechol is consistent
with its observed rapid conversion to BPQ in vivo.8-12
Reduction of DMBAQ and BAQ with NaBH4 in DMF
(Scheme 7) gave the corresponding o-catechols, 3,4-
dihydroxy-7,12-dimethylbenz[a]anthracene (23a ) and 3,4-
dihydroxybenz[a]anthracene (24a ), respectively, isolated
as their more stable diacetate derivatives, 23b and 24b.
Reduction of PAH o-quinones with NaBH4 in the
presence of O2 was previously shown36 to provide the
corresponding trans-dihydrodiols. Reduction of BPQ with
NaBH4/O2 afforded smoothly trans-7,8-dihydro-7,8-dihy-
droxybenzo[a]pyrene (25) (Scheme 8). Analogous reduc-
tion of DMBAQ and BAQ furnished trans-3,4-dihydroxy-
3,4-dihydro-7,12-dimethylbenz[a]anthracene (26a ) and
trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene (26b),
respectively.
Com p a r ison of Met h od s of Syn t h esis of P AH
Qu in on es. The classic synthesis of BPQ4,48 entails a
seven-step sequence from pyrene based on the Haworth
method for fusing additional rings onto polycyclic aro-
matic ring systems (Scheme 9).2,4 Specifically, it involves
Friedel-Crafts reaction of pyrene with succinic anhy-
dride and AlCl3, reduction of the keto group of the keto-
acid product (obtained as a mixture of isomers), acid-cat-
alyzed cyclization to form 7-keto-7,8,9,10-tetrahydro-
benzo[a]pyrene (27),49 reduction to the alcohol with
(46) Konieczny, M.; Harvey, R. G. J . Org. Chem. 1979, 44, 4813.
(47) Cho, H.; Harvey, R. G. J . Chem. Soc., Perkin Trans. I 1976,
836.
(48) Reference 2, Chapter 15, pp 360-382.
2028 J . Org. Chem., Vol. 69, No. 6, 2004

New Syntheses of PAH o-Quinones
epoxide derivatives of benzo[a]pyrene, benz[a]anthracene, and
7,12-dimethyl benz[a]anthracene are potentially hazardous
and should be handled with care in accordance with “NIH
Guidelines for the Laboratory Use of Chemical Carcinogens”.
NaBH4, acid-catalyzed dehydration to 9,10-dihydrobenzo-
[a]pyrene, reaction with OsO4 to form the cis-7,8-tetrahy-
drodiol (28), and finally oxidation with DDQ.50,51
The new synthetic approach to BPQ (Scheme 2) in-
volves fewer steps, requires no tedious separations of
isomers or product mixtures, and affords a higher overall
yield than the older method. It involves in the key initial
step Suzuki coupling of 6-methoxynaphthaleneboronic
acid (1) with 2-bromobenzene-1,3-dialdehyde (2). The 1,3-
dialdehyde product (3) was readily transformed to the
1,3-dimethoxyvinyl derivative (4a : R ) OMe) by the
Wittig method. Although 4a was obtained as a mixture
of E- and Z-isomers, their separation was unnecessary
because of their facile interconversion in the subsequent
acid-catalyzed cyclization step to yield 5a .
A noteworthy feature of this synthesis is the use of the
hypervalent iodine(V) reagent IBX for oxidation of the
PAH â-phenols to PAH o-quinones. Oxidation of 5b by
IBX took place readily in DMF to provide BPQ in good
overall yield. The principal advantage of IBX over Fre-
my’s salt is that it allows oxidation of the relatively water
insoluble PAH compounds to be conducted in organic
solvents. On the basis of the relatively few examples
studied to date, it also appears that IBX is a milder, more
reliable oxidant than Fremy’s salt, and its use does not
result in excessive oxidation of the PAH substrates.
Extension of this synthetic approach to BAQ and
DMBAQ provided improved synthetic access to these
quinones, making them more accessible for biological
studies and as starting compounds for the synthesis of
their related oxidized metabolites and their adducts with
deoxyadenosine and deoxyguanosine. This synthetic
method is applicable, in principle, to the synthesis of
numerous other PAH quinones and their related oxidized
metabolites. The potential scope of the method is further
illustrated by its recent utilization as the basis of an
improved synthesis of benzo[a]pyrene.52
1,3-Bis(d ibr om om eth yl)-2-br om oben zen e (8). A solution
of 2-bromo-m-xylene (13.3 mL, 100 mmol), NBS (142.4 g, 800
mmol), and AIBN (100 mg) in benzene (1 L) under argon in a
250-mL round-bottom flask was heated at reflux and irradi-
ated with an external 85-W UV lamp. After 24 h, TLC showed
a mixture of the symmetrical di- and tetrabromo-substituted
derivatives, 7 (40%) and 8 (60%). After 48 h, TLC showed the
product composition to be 7 (20%) and 8 (80%). Additional
portions of NBS (71.2 g, 400 mmol) and AIBN (50 mg) were
added, and reaction was continued for another 24 h. At that
time, TLC showed the reaction to be essentially complete. The
reaction mixture was allowed to stand overnight and the
precipitate of succinimide and unreacted NBS was removed
by filtration and washed with benzene (3 × 100 mL) and 10%
aqueous sodium hydrogensulfite (500 mL). The organic layer
was separated, dried over NaSO4, and evaporated to dryness.
The residue was chromatographed on a silica gel column eluted
with 5% EtOAc to give crude 8, which was triturated with
hexane (2 × 50 mL) to remove trace amounts of 7. Pure 8 (45.6
g, 91%) was obtained as white platelets: mp 150-151 °C (lit.28
mp 148-149 °C); 1H NMR δ 8.03 (d, 2, J ) 7.9 Hz), 7.52 (t, 1,
J ) 8.0 Hz), 7.12 (s, 2), in good agreement with reported
values.30
2-Br om oben zen e-1,3-d ia ld eh yd e (2). Meth od 1: Hy-
d r olysis w ith AgNO3. To a solution of 8 (1.00 g, 2 mmol) in
acetonitrile (25 mL) was added a solution of AgNO3 (1.70 g,
10 mmol) and 10 mL of water, and the mixture was heated at
reflux under argon for 2 h. The solution was allowed to cool,
AgBr was filtered off and washed with CH2Cl2 (3 × 20 mL),
and the combined filtrate was washed with water (25 mL) and
dried over NaSO4. The solvent was evaporated and the residue
was purified by passage through a short column of silica gel
to yield 2 (396 mg, 93%) as a white solid: mp 135-136 °C
1
(lit.32 mp 132-134 °C); H NMR δ 10.45 (s, 2), 8.13 (d, 2, J )
7.5 Hz), 7.58 (t, 1, J ) 7.5 Hz) in agreement with reported
values.32
Meth od 2: Hyd r olysis in F or m ic Acid . A mixture of 8
(1.01 g, 2 mmol) and 88% formic acid (20 mL) was refluxed
under argon for 12 h. After cooling, the solution was concen-
trated under reduced pressure, poured into water (40 mL), and
extracted with CH2Cl2 (3 × 20 mL). The combined extracts
were dried and evaporated to dryness, and the residue was
purified by chromatography on a column of silica gel to yield
2 (405 mg, 94%): mp 135-136 °C; 1H NMR spectrum was
identical with an authentic sample.
2-(2-Me t h oxyn a p h t h a le n e -6-yl)b e n ze n e -1,3-d ia ld e -
h yd e (3). To a solution of 2 (18.5 g, 87 mmol) in DME (270
mL) under argon was added Pd(PPh3)4 (2.8 g. 2.4 mmol). The
resulting yellow solution was stirred for 20 min, then a solution
of 1 (18.9 g, 94 mmol) in ethanol (330 mL) was added. The
clear solution became cloudy. After 20 min, NaCO3 (210 mL
of a 2 M solution) was added, and the mixture was heated at
reflux overnight. Then the solution was cooled and concen-
trated under reduced pressure. CH2Cl2 (500 mL) was added,
and the organic phase was washed with water and brine, then
dried over NaSO4. The solvent was removed under reduced
pressure, and the residue was purified by chromatography on
a silica gel column. Elution with 10-20% EtOAc in hexane
provided 3 (23.1 g, 91%) as a white solid: mp 142-144 °C; 1H
NMR δ 9.82 (s, 2), 8.23 (dd, 2, J ) 8.0, 0.5 Hz), 7.85 (d, 1, J )
8.5 Hz), 7.75 (d, 1, J ) 9.0 Hz), 7.74 (s, 1), 7.63 (dd, 1, J ) 7.5,
2.5 Hz), 7.41 (dd, 1, J ) 8.5, 1.0 Hz), 7.23 (m, 2), 3.94 (s, 3);
13C NMR δ 191.0, 158.6, 148.2, 134.9, 134.3, 132.6, 132.5,
130.3, 129.5, 129.4, 128.5, 128.2, 128.1, 128.0, 127.2, 127.0,
126.3, 120.3, 105.6, 55.3. Anal. Calcd for C19H14O3: C, 78.61;
H, 4.86. Found: C, 78.45; H, 4.89.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. o-Iodoxybenzoic acid (IBX) was
prepared by the improved procedure of Frigerio et al.53 with
oxone in place of bromate for the oxidation of 2-iodobenzoic
acid. 6-Methoxynaphthaleneboronic acid (1) obtained from a
commercial source was shown by TLC to contain an impurity
that could be removed by trituration with CH2Cl2. Removal of
the contaminant after reaction of 1 was considerably more
difficult. 2-Bromo-5-methoxybenzaldehyde (12) was prepared
from 3-methoxybenzaldehyde by the published method.42-44
2-Formyl-4-methoxyphenylboronic acid (17) was prepared from
2-bromo-4-methoxybenzaldehyde by the literature procedure.42
Methoxymethyltriphenylphosphonium chloride was dried un-
der vacuum for 24 h prior to use. THF was freshly distilled
from sodium benzophenone ketal.
NMR spectra were recorded on a 400- or 500-MHz spec-
trometer in CDCl3 with tetramethylsilane as internal standard
unless stated otherwise. Integration was consistent with all
structural assignments. All melting points are uncorrected.
Ca u t ion : The o-quinone, o-catechol, dihydrodiol, and diol
(49) J ohnson, 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.
(50) Platt, K. L.; Oesch, F. Tetrahedron Lett. 1982, 23, 163.
(51) Compound 5 may also be prepared by oxidation of benzo[a]-
pyrene-8-ol with Fremy’s salt or phenylselenenic anhydride, ref 36.
(52) Harvey, R. G.; Lim, K.; Dai, Q. J . Org. Chem. In press.
(53) Frigerio, M.; Santagostino, M.; Sputore, S. J . Org. Chem. 1999,
64, 4537.
2-Meth oxy-6-(2,6-d ivin ylp h en yl)n a p h th a len e (4a ). To
a solution of methyltriphenylphosphonium bromide (34.0 g,
J . Org. Chem, Vol. 69, No. 6, 2004 2029

Harvey et al.
95 mmol) in 300 mL of dry THF was added dropwise 38.0 mL
of a 2.5 M solution of n-butyllithium in hexane at 0 °C under
argon. The solution became yellow then orange. It was stirred
for 30 min, then a solution of 3 (9,2 g, 32 mmol) in dry CH2Cl2
(80 mL) was added dropwise, and stirring was continued
overnight at room temperature. Water (2 mL) was added to
quench the reaction, and after 30 min the solution was filtered
and concentrated under reduced pressure. The residue was
chromatographed on a silica gel column eluted with 3-5%
EtOAc in hexane to yield 4a (8.2 g, 90%) as a white solid: mp
phy on a silica gel column. Elution with 8-10% ethyl acetate
in hexane afforded 4b as a mixture of E- and Z-isomers as an
oil (75%): 1H NMR δ 7.91 (m, 1), 7.70 (m, 2), 7.50 (m, 1), 7.09-
7.21 (m, 5), 6.78 (dd, 1, J ) 8.0, 7.5 Hz), 5.83 (dd, 1, J ) 7.5,
7.5 Hz), 5.37 (t, 1, J ) 12.5 Hz), 4.76 (dd, 1, J ) 7.5, 8.0 Hz),
3.87 (s, 3), 3.62 (d, 3), 3.27 (d, 3). Anal. Calcd for C23H22O3: C,
79.74; H, 6.40. Found: C, 79.65; H, 6.55.
Met h od 2: ter t-Bu t yllit h iu m . Similar reaction with
t-BuLi gave 4b (50%).
Met h od 3: t-Bu OK. To a solution of predried methoxy-
methyltriphenylphosphonium chloride (23.12 g, 69.1 mmol) in
200 mL of dry ether under argon was added dropwise a 1.0 M
solution of t-BuOK (69.1 mL, 69.1 mmol) in dry THF at room
temperature. The resulting red solution was stirred at room
temperature for 1 h, then a solution of 3 (8.0 g, 27.6 mmol) in
100 mL of THF was added dropwise. After being stirred
overnight, the solution was evaporated to dryness under
vacuum, and the crude product was purified by chromatogra-
phy on a silica gel column. Elution with 5-15% EtOAc in
hexane to gave a mixture of E- and Z-isomers of 4b (9.1 g,
95%) as an oil.
8-Meth oxyben zo[a ]p yr en e (5a ). To a solution of 4b (9.1
g) in CH2Cl2 (500 mL) was added MeSO3H (0.1 mL) under
argon at 0 °C, and the solution was stirred overnight. TLC
showed the reaction to be complete. A saturated solution of
NaHCO3 (100 mL) was added, and stirring was continued for
15 min. The organic phase was separated, washed with water
and brine, dried over NaSO4, and evaporated to dryness. The
residue was purified by chromatography on a column of silica
gel eluted with 7-10% EtOAc in hexane to provide 5a (6.2 g,
88%) as a yellow solid: mp 145-147 dec; 1H NMR δ 8.88 (t, 2,
J ) 10.0 Hz), 8.35 (s, 1), 8.25 (d, 1, J ) 9.0 Hz), 8.19 (d, 1, J
) 7.5 Hz), 8.06 (d, 1, J ) 7.0 Hz), 7.88-7.95 (m, 3), 7.55 (d, 1,
J ) 2.5 Hz), 7.45 (dd, 1, J ) 9.0, 2.5 Hz), 4.03 (s, 3); 13C NMR
δ 157.7, 132.6, 131.1, 130.8, 130.2, 127.8, 127.7, 127.5, 125.5,
125.4, 125.3, 124.8, 124.6, 123.6, 123.4, 122.4, 121.9, 118.6,
106.4, 55.4.
1
88-89 °C; H NMR δ 7.70 (d, 1, J ) 8.5 Hz), 7.65 (d, 1, J )
8.5 Hz), 7.52 (d, 2, J ) 8.0 Hz), 7.47 (d, 1, J ) 1.0 Hz), 7.28 (t,
1, J ) 8.0 Hz), 7.18 (dd, 1, J ) 8.5, 1.5 Hz), 7.11 (m, 2), 6.34
(dd, 2, J ) 17.5, 11.0 Hz), 5.55 (dd, 2, J ) 17.5, 1.5 Hz), 4.97
(dd, 2, J ) 11.0, 1.0 Hz), 3.87 (s, 3); 13C NMR 157.89, 139.55,
136.94, 135.88, 134.02, 133.55, 129.55, 129.21, 129.14, 128.59,
127.58, 126.49, 125.79, 124.72, 124.51, 124.26, 124.51, 119.18,
114.97, 114.54, 105.65, 55.36. Anal. Calcd for C21H18O: C,
88.08; H, 6.34. Found: C, 87.78; H, 6.35.
8-Meth oxyben zo[a ]p yr en e (5a ). Meth od 1: P h otocy-
cliza tion w ith a n 85-W UV La m p . Argon was bubbled
through a solution of 4a (300 mg, 1.06 mmol) and I2 (620 mg,
2.5 mmol) in 500 mL of benzene for 15 min. Epoxybutane (20
mL) was added, and the solution was irradiated by an external
85-W UV lamp. TLC indicated that no reaction took place over
a 3-h period. The irradiated solution was then heated at reflux.
After 1 day the product mixture was shown by TLC to consist
of equal amounts of unreacted 4a , a partially cyclized inter-
mediate, and 5a . After 2 additional days under these condi-
tions, TLC showed the principal products to be 5a plus
polymeric byproducts. The usual workup afforded the crude
product, which was purified by chromatography on a short
column of silica gel. Elution with 7-10% EtOAc in hexane gave
1
5a (149 mg, 50%) as a yellow solid whose H NMR spectrum
was identical with that of authentic 5a .
Meth od 2: P h otocycliza tion w ith a 450-W UV La m p .
The reaction was conducted in a quartz photoreactor with a
450-W Hanovia UV lamp in an inner well and external water
cooling. Argon was bubbled through a solution of 4a (260 mg,
0.91 mmol) and I2 (462 mg, 1.8 mmol) in 500 mL of benzene
for 15 min. 1,2-Epoxybutane (20 mL) was added, and the
mixture was irradiated. After 30 min, TLC showed that 4a
was largely consumed, and the products were the partially
cyclized intermediate 9 and 5a . After another 30 min, the
products were mainly 5a and polymeric byproducts. The usual
workup followed by chromatography on a short column of silica
gel eluted with 7-10% ethyl acetate in hexane gave 5a (149
Ben zo[a ]p yr en -8-ol (5b). To a solution of 5a (2.1 g, 7.45
mmol) in dry CH2Cl2 (500 mL) at -20 °C was added dropwise
a solution of BBr3 (1 M, 40 mL) in CH2Cl2. The resulting purple
solution was stirred at -20 °C for 30 min and then at room
temperature overnight. The reaction mixture was then im-
mersed in a 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 NaSO4,
and evaporated to dryness. The residue was chromatographed
on a silica gel column eluted with 10-25% EtOAc in hexane
to give 5b (1.7 g, 86.0%) as a yellow solid: mp 224-226 °C
1
mg, 60%) as a yellow solid whose H NMR spectrum matched
that of authentic 5a .
1
dec (lit.54 mp 228 °C); H NMR δ 8.93 (d, 1, J ) 9.0 Hz), 8.90
The partially cyclized intermediate was identified as the
chrysene derivative 9: mp 136-137 °C; 1H NMR δ 8.94 (d, 1,
J ) 9.0 Hz), 8.67 (d, 1, J ) 9.0 Hz), 8.62 (d, 1, J ) 9.0 Hz),
7.95 (d, 1, J ) 9.0 Hz), 7.90 (d, 1, J ) 7.5 Hz), 7.82 (d, 1, J )
9.0 Hz), 7.69 (d, 1, J ) 7.0 Hz), 7.56-7.61 (m, 2), 7.34 (dd, 1,
J ) 9.0, 3.0 Hz), 7.31 (d, 1, J ) 2.5 Hz), 5.87 (dd, 1, J ) 17.5,
1.5 Hz), 5.50 (dd, 1, J ) 11.0, 1.5 Hz), 3.99 (s, 3); 13C NMR δ
158.1, 141.7, 137.3, 133.0, 132.5, 129.7, 129.2, 128.6, 128.3,
127.8, 127.4, 127.1, 125.6, 124.9, 124.8, 124.7, 121.3, 117.8,
114.1, 107.1, 53.4. Anal. Calcd for C21H16O: C, 88.70; H, 5.67.
Found: C, 88.94; H, 5.62.
2-(2,6-Bis{2-m eth oxyvin yl}ph en yl)-6-m eth oxyn aph th a-
len e (4b). Meth od 1: P h en yllith iu m . To a solution of dry
methoxymethyltriphenylphosphonium chloride (10.0 g, 31
mmol) in anhydrous ether (300 mL) under argon at -78 °C
was added dropwise a 1.8 M solution of phenyllithium (16.7
mL, 31 mmol) in ether. The mixture was stirred at -78 °C for
0.5 h, allowed to warm to -15 °C for 0.5 h, and then cooled
back to -78 °C. The dialdehyde 3 (1.4 g, 4.8 mmol) was added
and stirring was continued for an additional hour. The solution
was allowed to warm to ambient temperature, and stirring
was continued overnight. Then the solvent was removed under
vacuum, and the crude product was purified by chromatogra-
(d, 1, J ) 9.0 Hz), 8.29 (s, 1), 8.22 (d, 1, J ) 9.0 Hz), 8.16 (d,
1, J ) 7.5 Hz), 8.02 (d, 1, J ) 7.0 Hz), 7.90 (d, 1, J ) 1.5 Hz),
7.89 (s, 1), 7.85 (m, 1), 7.51 (d, 1, J ) 2.5 Hz), 7.39 (dd, 1, J )
9.0, 2.5 Hz); the observed chemical shifts were in good
agreement with reported values;53 13C NMR δ 155.4, 133.2,
131.1, 130.7, 130.0, 127.5, 127.3, 127.2, 125.1, 125.0, 124.3,
122.9, 122.7, 121.8, 121.5, 118.0, 109.3.
Ben zo[a ]p yr en -7,8-d ion e (BP Q). To a solution of 5b (1.7
g, 6.3 mmol) in dry DMF (50 mL) at room temperature was
added IBX53 (1.8 g, 6.4 mmol) under argon. The resulting
purple solution was stirred for 1 h, 500 mL of EtOAc was
added, and the organic layer was washed with water (3 × 100
mL) and with brine. A purple precipitate in the organic phase
was removed by filtration and subsequently shown to be pure
BPQ. The filtrate was evaporated to dryness under reduced
pressure and the residue was purified by chromatography on
a silica gel column. Elution with EtOAc:hexane (1:2) gave BPQ
(combined wt ) 1.65 g, 92.2%) as a purple solid: mp 271-273
1
°C (lit.36 mp >260 °C); H NMR δ 8.86 (s, 1), 8.50 (d, 1, J )
(54) Yagi, H.; Holder, G. M.; Dansette, P. M.; Hernandez, O.; Yeh,
H. J . C.; LeMahieu, R. A.; J erina, D. M. J . Org. Chem. 1976, 41, 977.
2030 J . Org. Chem., Vol. 69, No. 6, 2004

New Syntheses of PAH o-Quinones
10.5 Hz), 8.38 (d, 1, J ) 10.5 Hz, 9.5 Hz), 8.10-8.27 (m, 6),
6.60 (d, 1, J ) 10.5 Hz); the observed chemical shifts were in
agreement with reported values except that a peak at δ 7.62
was not observed.36
7.07 (d, 1, J ) 3.5 Hz), 6.98 (d, 1, J ) 3.0 Hz), 6.94 (d, 1, J )
13.0 Hz), 6.80 (dd, 1, J ) 1.5, 2.0 Hz), 6.78 (dd, 1, J ) 1.5, 1.5
Hz), 5.94 (d, 1, J ) 7.5 Hz), 5.46 (d, 1, J ) 13.0 Hz), 4.85 (d,
1, J ) 7.5 Hz), 3.88 (s, 3), 3.87 (s, 3), 3.74 (s, 3), 3.39 (s, 3),
1
2.67 (s, 3), 2.38 (s, 3); the H NMR spectral data agreed with
2-Br om o-1,4-d im eth yln a p h a len e. To a solution of 1,4-
dimethylnaphthalene (4.68 g, 30.0 mmol) in CH2Cl2 (50 mL)
in an ice-water bath in subdued light was added iron powder
(200 mg, 3.6 mmol). To this suspension was added a solution
of bromine (4.77 g, 30.0 mmol) in CH2Cl2 (25 mL) dropwise
over 30 min. The resulting mixture was stirred for 2 h at 0
°C, then poured into a saturated NaCO3 solution, extracted
with CH2Cl2, and dried over NaSO4. Evaporation of the solvent
under reduced pressure afforded 7 (6.80 g, 96.5%) as a slightly
yellow semisolid that solidified on standing: mp 40-41 °C
the data previously reported.55
7,12-Dim eth yl-3-m eth oxyben z[a ]a n th r a cen e (15a ). To
a solution of 14 (0.64 g, 2.0 mmol) in CH2Cl2 (50 mL) was added
MeSO3H (0.48 g, 5.0 mmol) dropwise over 5 min. TLC showed
that reaction was complete within 10 min. The reaction
mixture was poured into a saturated solution of NaHCO3 (50
mL), extracted with CH2Cl2, dried over NaSO4, and purified
by passage through a Florisil column. Elution with hexanes-
CH2Cl2 (8:1) gave 15a (0.52 g, 91%): mp 131-132 °C (lit.19
mp 131-132 °C): 1H NMR δ 8.43 (d, 1, J ) 9.0 Hz), 8.34-
8.37 (m, 2), 8.06 (d, 1, J ) 10.0 Hz), 7.59-7.66 (m, 2), 7.54 (d,
1, J ) 10.0 Hz), 7.27 (d, 1, J ) 3.5 Hz), 7.19 (dd, 1, J ) 3.0,
9.0 Hz), 4.00 (s, 3), 3.34 (s, 3), 3.10 (s, 3).
7,12-Dim eth ylben z[a ]a n th r a cen e-3,4-d ion e (DMBAQ).
To a solution of 15a (140 mg, 0.5 mmol) in CH2Cl2 (20 mL)
under argon was added by syringe a solution of BBr3 (1.0 M
in CH2Cl2, 5 mL, 5 mmol). The resulting mixture was stirred
overnight at room temperature, quenched with water, ex-
tracted with CH2Cl2, washed with a NaCO3 solution and water,
dried over NaSO4, and evaporated to dryness to yield 7,12-
dimethylbenz[a]anthracen-3-ol (15b) as an oily solid used
directly in the next step.
To a solution of 15b in DMF (2 mL) was added IBX (130
mg, 0.5 mmol), and the resulting solution turned dark within
10 min. TLC indicated that reaction was complete. The
mixture was poured onto ice water (50 mL) and filtered. The
solid product was purified by chromatography on a Florisil
column. Elution with EtOAc-hexanes (1:8) gave DMBAQ as
a deep green solid (0.10 g, 71%): mp 156-157 °C (lit.19 mp
157-158 °C); 1H NMR (DMSO) δ 8.49 (d, 1, J ) 9.0 Hz), 8.36-
8.42 (m, 2), 8.29 (d, 1, J ) 10.5 Hz), 7.90 (d, 1, J ) 9.0 Hz),
7.70 (dd, 2, J ) 6.0, 7.0 Hz), 6.41 (d, 1, J ) 10.5 Hz), 3.19 (s,
3), 3.07 (s, 3).
1
(lit.40 mp 40-42 °C); H NMR δ 7.97-8.08 (m, 2), 7.55-7.57
(m, 2), 7.50 (s, 1), 2.79 (s, 3), 2.66 (s, 3).
1,4-Dim eth yl-2-n a p h th a len e Bor on ic Acid (11). P r o-
ced u r e A: To a solution of 2-bromo-1,4-dimethylnaphthalene
(2.35 g, 10 mmol) in anhydrous THF (20 mL) under argon at
-78 °C was added n-BuLi (1.6 M in hexane, 6.40 mL, 10.2
mmol) dropwise over 10 min. The resulting solution was stirred
at -78 °C for 1 h, then a solution of trimethyl borate (2.10 g,
20 mmol) in THF (20 mL) was added over 10 min. The solution
was stirred at -78 °C for 3 h, then warmed to room temper-
ature, and a solution of 10 M HCl was added. The solution
was extracted with ether, dried over NaSO4, and evaporated
to dryness to give crude 11, which was washed with CH2Cl2
to give 11 (0.94 g, 47.2%) as a white powder.
P r oced u r e B: To a solution of n-BuLi (1.6 M in hexane,
12.8 mL, 20.5 mmol) in anhydrous THF (20 mL) under argon
at -78 °C was added dropwise a solution of 2-bromo-1,4-
dimethylnaphthalene (2.35 g, 10 mmol) in THF (40 mL) over
2 h. The mixture was stirred at -78 °C for 30 min, then a
solution of trimethyl borate (2.10 g, 20.0 mmol) in THF (20
mL) was added over 10 min. The resulting solution was stirred
at -78 °C for 3 h and warmed to room temperature, and a
solution of 10 M HCl solution was added. The solution was
extracted with ether, dried over NaSO4, and evaporated to
dryness to give 11 (1.80 g, 90.0%) as a white powder: mp 198-
199 °C (lit.55 mp 310-312 °C); 1H NMR δ 8.08 (dd, 1, J ) 3.2,
4.75 Hz), 8.00 (dd, 1, J ) 3.1, 4.75 Hz), 7.56 (dd, 2, J ) 3.1,
8.0 Hz), 7.35 (s, 1), 2.74 (s, 3), 2.62 (s, 3).
1,4-Dim eth oxyn a p h th a len e. To a solution of 1,4-naph-
thoquinone (15.8 g, 100 mmol) in ethanol (100 mL) and water
(100 mL) was added NaBH4 (6.8 g, 200 mmol) in portions over
30 min. The resulting mixture was stirred for another 30 min,
then a solution of KOH (10 M, 40 mL) was added and the
resulting mixture was stirred for 30 min, then heated to reflux,
and dimethyl sulfate (50.4 g, 400 mmol) was added over 1 h.
The resulting mixture was stirred at reflux overnight, then it
was cooled to room temperature, extracted with EtOAc, and
purified by chromatography on a silica gel column to give 1,4-
dimethoxynaphthalene (17.8 g, 95%): mp 85-86 °C (lit.56 mp
5-Met h oxy-2-(1,4-d im et h yln a p h t h a len -2-yl)ben za ld e-
h yd e (13). To a solution of 11 (1.99 g, 10 mmol) and 12 (2.16
g, 10 mmol) in DME (20 mL) under argon was added Pd(PPh3)4
(300 mg, 0.2 mmol). The resulting mixture was stirred for 5
min, then ethanol (10 mL) and a 2.0 M sodium carbonate
solution (10 mL) were added, and the mixture was heated at
reflux overnight. Most of the solvent was removed by evapora-
tion under reduced pressure, and the solution was extracted
with EtOAc, dried over NaSO4, evaporated to dryness, and
purified by silica gel chromatography. Elution with EtOAc-
hexanes (1:30) gave 13 (2.63 g, 91%): mp 103-104 °C (lit.55
mp 104-105 °C); 1H NMR δ 9.73 (s, 1), 8.06-8.11 (m, 2), 7.58-
7.62 (m, 2), 7.54 (d, 2, J ) 2.66 Hz), 7.22-7.30 (m, 2), 7.18 (s,
1), 3.94 (s, 3), 2.69 (s, 3), 2.43 (s, 3); 13 H NMR δ 192.3, 159.1,
139.5, 134.9, 133.8, 132.7, 132.4, 132.3, 131.9, 130.7, 129.3,
126.3, 125.8, 124.9, 124.7, 121.4, 109.2, 55.6, 19.2, 16.2.
2-(4-Meth oxy-2-[2-m eth oxyvin yl]p h en yl)-1,4-d im eth yl-
n a p h th a len e (14). Reaction of methoxymethyltriphenylphos-
phonium chloride (1.88 g, 5.50 mmol) and phenyllithium (3.1
mL of a 1.8 M solution in hexanes, 5.50 mmol) with 13 (800
mg, 2.75 mmol) was carried out by the procedure employed
for the synthesis of 4b. The crude product was purified by
chromatography on a silica gel column. Elution with EtOAc-
hexanes (1:50) gave 14 (0.78 g, 88.9%) as an oil that solidified
1
86-87 °C); H NMR δ 8.20 (dd, 2, J ) 3.3, 6.5 Hz), 7.50 (dd,
2, J ) 3.3, 6.5 Hz), 6.69 (s, 2), 3.96 (s, 6).
2-Br om o-1,4-d im eth oxyn a p h th a len e (16). To a solution
of 1,4-dimethoxynaphthalene (17.8 g, 95 mmol) dissolved in
CCl4 (100 mL) in an ice bath at 0 °C was added a catalytic
amount of iron powder, followed by bromine (15.0 g, 95 mmol),
over 30 min. The resulting mixture was stirred for 3 h, then
the mixture was poured into a saturated NaCO3 solution,
extracted with CH2Cl2, and chromatographed on a silica gel
column. Elution with hexanes-EtOAc (20:1) gave 16 (22.4 g,
1
88%): mp 58-59 °C (lit.56 mp 56-58 °C); H NMR δ 8.20 (d,
1, J ) 0.5, 8.5 Hz), 8.05 (dd, 1, J ) 0.5, 8.5 Hz), 7.47-7.57 (m,
2), 6.87 (s, 1), 3.98 (s, 3), 3.95 (s, 3).
5-Meth oxy-2-(1,4-d im eth oxyn a p h th a len -2-yl)ben za ld e-
h yd e (18). To a solution of 16 (13.5 g, 50 mmol) in DME (100
mL) were added 2-formyl-4-methoxyphenyl boronic acid 17 (9.0
g, 50 mmol) and Pd(PPh3)4 (1.0 g), and the resulting mixture
was stirred for 10 min. EtOH (100 mL) and 50 mL of a 2.0 M
KOH solution were added, and the resulting mixture was
stirred at reflux overnight. The solution was cooled to room
temperature, solvents were removed under reduced pressure,
1
on standing: mp 102-104 °C; H NMR (E/Z ) 1) δ 8.09 (dd,
2, J ) 1.0, 7.5 Hz), 8.03 (dd, 2, J ) 1.0, 7.5 Hz), 7.81 (d, 1, J
) 3.0 Hz), 7.53-7.57 (m, 4), 7.13 (s, 2), 7.09 (d, 1, J ) 3.5 Hz),
(55) Sharma, A. K.; Amin, S.; Kumar, S. Poly. Arom. Compds.
2002, 22, 277.
(56) Karichiappan, K.; Wege, D. Aust. J . Chem. 2000, 53, 743.
J . Org. Chem, Vol. 69, No. 6, 2004 2031

Harvey et al.
and the residue was extracted with EtOAc, and purified by
chromatography on a silica gel column. Elution with hexanes-
CH2Cl2 (4:1) gave 18 (11.2 g, 70%): mp 160-161 °C; 1H NMR
δ 9.86 (s, 1), 8.29 (dd, 1, J ) 1.5, 8.5 Hz), 8.14 (dd, 1, J ) 1.5,
8.5 Hz), 7.54-7.62 (m, 2), 7.47 (d, 1, J ) 8.5 Hz), 7.28 (dd, 1,
J ) 3.0, 8.5 Hz), 6.73 (s, 1), 4.01 (s, 3), 3.95 (s, 3), 3.40 (s, 3);
13C NMR (CDCl3) δ 192.3, 159.3, 151.9, 146.9, 134.6, 132.2,
128.4, 127.1, 126.5, 126.1, 125.1, 122.3, 122.2, 121.2, 109.6,
106.1, 60.7, 55.7, 55.6. Anal. Calcd for C20H18O4: C, 74.52; H,
5.63. Found: C, 74.29; H, 5.55.
1,4-D im e t h o x y -2-(4-m e t h o x y -2-{2-m e t h o x y v in y l}-
p h en yl)n a p h th a len e (19). Reaction of 18 with methoxym-
ethylenetriphenylphosphine [generated in situ from meth-
oxymethyltriphenylphosphonium chloride (6.8 g, 20 mmol)]
and t-BuOK (1.0 M in THF, 20 mL, 20 mmol) by the procedure
employed for preparation of 4b afforded 19 (3.12 g, 89%) as
an oil consisting of a mixture of isomers (E/Z ) 1): 1H NMR
δ 8.28 (d, 2, J ) 8.0 Hz), 8.17 (d, 2, J ) 8.0 Hz), 7.87 (d, 1, J
) 2.5 Hz), 7.26-7.58 (m, 8), 7.04 (d, 1, J ) 2.5 Hz), 7.02 (d, 1,
J ) 12.5 Hz), 6.83-6.86 (m, 2), 6.64 (s, 1), 6.63 (s, 1), 6.06 (d,
1, J ) 7.5 Hz), 5.73 (d, 1, J ) 12.5 Hz), 5.13 (d, 1, J ) 7.5 Hz),
3.96 (s, 6), 3.90 (s, 6), 3.78 (s, 3), 3.53 (s, 6), 3.48 (s, 3).
Compound 19 was used directly in the next step.
the solid product was collected and purified by chromatography
on a Florsil column. Elution with hexanes-EtOAc (3:1) gave
BAQ (1.61 g, 83.0%): mp 212-213 °C (lit.55 mp 213-214 °C);
1H NMR δ 9.41 (s, 1), 8.81 (d, 1, J ) 10.5 Hz), 8.73 (s, 1), 8.29
(d, 1, J ) 8.5 Hz), 8.24 (d, 1, J ) 8.5 Hz), 8.17 (d, 1, J ) 8.5
Hz), 7.99 (d, 1, J ) 8.5 Hz), 7.66-7.70 (m, 2H), 6.66 (d, 1, J )
10.5 Hz).
7,8-Dia cetoxy ben zo[a ]p yr en e (22). To a solution of BPQ
(500 mg, 1.77 mmol) in DMF (10 mL) was added portionwise
NaBH4 (337 mg, 8.86 mmol). The color changed rapidly from
purple to deep red. After 0.5 h, Ac2O (1.0 mL, excess) and
Na2CO3 (1.0 g, excess) were added, and the mixture was stirred
overnight. The solvent was removed under vacuum, and the
residue was dissolved in EtOAc (100 mL), washed with water
and brine, and dried over sodium sulfate. After removal of
EtOAc under reduced pressure, the residue was chromato-
graphed. Elution with hexane-EtOAc (2:1) gave 22 (531 mg,
80%) as a yellow solid: mp 205-206 °C; 1H NMR δ 8.96 (d, 1
J ) 9.5 Hz), 8.94 (d, 1 J ) 10.1 Hz), 8.46 (s, 1), 8.32 (d, 1, J )
9.1 Hz), 8.23 (d, 1, J ) 7.7 Hz), 8.10 (d, 1, J ) 7.2 Hz), 7.99 (t,
1, J ) 7.5 Hz), 7.94 (d, 2, J ) 9.1 Hz), 7.66 (d, 1, J ) 9.2 Hz),
2.60 (s, 3), 2.42 (s, 3); 13C NMR δ 168.5, 168.3, 131.3, 131.2,
130.7, 128.6, 128.3, 128.0, 127.4, 126.9, 126.3, 125.9, 125.8,
125.3, 123.5, 122.0, 121.9, 121.1, 117.1, 20.8, 20.6. Anal. Calcd
for C24H16O4: C, 78.25; H, 4.38. Found C, 78.31; H, 4.36.
3,4-Dia cetoxy-7,12-d im eth ylben z[a ]a n th r a cen e (23b).
To a solution of DMBAQ (400 mg, 1.4 mmol) in DMF (5 mL)
was added portionwise NaBH4 (270 mg, 7 mmol). The color of
the reaction mixture was slightly yellow, and TLC indicated
that the reaction was complete. To the resulting mixture was
added pyridine (3.0 mL) followed by acetic anhydride (1.0 mL,
excess). The solution was stirred overnight, then poured onto
ice water (100 mL) and filtered, and the solid was collected
and purified by chromatography on a silica gel column to afford
23b (0.32 g, 61.5%): mp 188-190 °C (lit.36 mp 165 °C); 1H
NMR δ 8.36-8.40 (m, 3), 8.13 (d, 1, J ) 9.5 Hz), 7.64-7.70
(m, 2), 7.60 (d, 1, J ) 9.5 Hz), 7.41(d, 1, J ) 9.0 Hz), 3.35 (s,
3), 3.08 (s, 3), 2.52 (s, 3), 2.41 (s, 3); although the mp of 23b
3,7,12-Tr im eth oxyben z[a ]a n th r a cen e (20). To a solution
of 19 (3.0 g, 8.5 mmol) in CH2Cl2 (30 mL) was added a solution
of MeSO3H (1.92 g, 20 mmol) in CH2Cl2 (10 mL) dropwise over
10 min. TLC indicated reaction was complete in 10 min. The
mixture was poured into saturated NaCO3 solution, extracted
with CH2Cl2, dried over NaSO4, and evaporated to dryness to
give 20 (2.5 g, 92.0%) as a yellow brown solid, mp 164-165
°C, used directly in the next step: 1H NMR δ 9.50 (d, 1, J )
9.0 Hz), 8.34 (dd, 1, J ) 1.8, 7.5 Hz), 8.23 (d, 1, 8.0 Hz), 8.04
(d, 1, J ) 9.0 Hz), 7.46-7.53 (m, 3), 7.20 (dd, 1, J ) 2.5 Hz),
13
7.16 (s, 1, J ) 9.0 Hz), 4.01 (s, 3), 3.88 (s, 3), 3.85 (s, 3);
H
NMR δ 158.3, 150.0, 148.7, 134.4, 129.8, 127.4, 125.9, 125.6,
125.4, 123.7, 122.9, 122.3, 121.7, 120.9, 115.9, 110.0, 63.2, 60.7,
55.4. Anal. Calcd for C21H18O3: C, 79.22; H, 5.70. Found: C,
79.08; H, 5.77.
1
Ben z[a ]a n th r a cen -3-ol (21). To a solution of 20 (2.8 g, 8.8
mmol) in HOAc (70 mL) was added a 57% solution of HI (30
mL). The resulting solution was heated at reflux for 48 h,
cooled to room temperature, and poured into ice-water (500
mL). The solid product was collected to give 21 (1.92 g, 89%):
mp 207-208 °C (lit.57 mp 208-209 °C): 1H NMR δ 9.22 (s, 1),
8.82 (d, 1, J ) 9.0 Hz), 8.44 (s, 1), 8.17 (d, 1, J ) 8.0 Hz), 8.08
(d, 1, J ) 8.0 Hz), 7.83 (d, 1, J ) 9.0 Hz), 7.60 (d, 1, J ) 9.0
Hz), 7.52-7.58 (m, 2), 7.31 (d, 1, J ) 7.5 Hz), 7.27 (dd, 1, J )
4.5, 8.5 Hz).
Ben z[a ]a n th r a cen -3,4-d ion e (BAQ). To a solution of 21
(1.82 g, 7.5 mmol) in DMSO (5 mL) was added IBX (1.98 g,
7.5 mmol). The resulting mixture was stirred at room tem-
perature for 10 min and poured into ice-water (200 mL), and
was higher than the reported value, its H NMR spectrum was
in good agreement with that of the authentic compound.36
3,4-Dia cetoxyben z[a ]a n th r a cen e (24b). Reduction of
BAQ (200 mg, 0.8 mmol) with NaBH4 (0.27 g, 7 mmol) by the
procedure employed for the preparation of 23b afforded 24b
1
(150 mg, 57%): mp 212-214 °C; H NMR δ 9.02 (s, 1), 8.65
(d, 1, J ) 9.0 Hz), 8.28 (s, 1), 8.02 (d, 1, J ) 8.5 Hz), 7.96 (d,
1, J ) 8.5 Hz), 7.76 (d, 1, J ) 9.0 Hz), 7.55 (d, 1, J ) 9.0 Hz),
7.47 (dd, 2, J ) 3.5, 8.5 Hz), 7.44 (d, 1, J ) 8.5 Hz), 2.39 (s, 3),
2.28 (s, 3). Anal. Calcd for C22H16O4: C, 76.73; H, 4.68. Found
C, 76.61; H, 4.26.
Ack n ow led gm en t . This investigation was sup-
ported by grant PO1 CA-92537 from the National
Cancer Institute, DHHS.
(57) Harvey, R. G.; Cortez, C.; Sugiyama, T. J . Med. Chem. 1988,
31, 154.
J O030348N
2032 J . Org. Chem., Vol. 69, No. 6, 2004