A New and Concise Synthesis of 3-Hydroxybenzo[c]phenanthrene and 12-Hydroxybenzo[g]chrysene, Useful Intermediates for the Synthesis of Fjord-Region Diol Epoxides of Benzo[c]phenanthrene and Benzo[g]chrysene

Article abstract of DOI:10.1021/jo9712355

A new strategy which involves a palladium-catalyzed cross-coupling reaction has been developed for the rapid synthesis of 3-hydroxybenzo[c]phenanthrene (5) and 12-hydroxybenzo[g]chrysene (6). These phenolic compounds are the key intermediates for the synthesis of highly carcinogenic fjord-region diol epoxide metabolites 3 and 4 of benzo[c]phenanthrene (1) and benzo[g]chrysene (2). The cross-coupling reaction of 2-bromo-5-methoxybenzaldehyde (9) with naphthalene-1-boronic acid (7) and phenanthrene-9-boronic acid (8) produced 2-(1-naphthyl)-5-methoxybenzaldehyde (10) and 2-(9-phenanthryl)-5-methoxybenzaldehyde (11), respectively, in quantitative yields. After reaction of these aldehydes with trimethylsulfonium iodide under phase-transfer conditions or with the Wittig reagent obtained from (methoxymethyl)triphenylphosphonium bromide and phenyllithium to generate an oxiranyl or methoxyethene side chain, the acid-catalyzed cyclization with methanesulfonic acid (or boron trifluoride) produced 3-methoxybenzo[c]phenanthrene (16) and 12-methoxybenzo[g]chrysene (17) in 61-64percent yields. Finally, demethylation of these methoxy derivatives 16 and 17 with boron tribromide resulted in the formation of the hydroxy analogues 5 and 6, respectively. The availability of this short and high-yielding regiospecific method for the synthesis of phenols 5 and 6 should allow the preparative-scale synthesis of the fjord-region diol epoxides 3 and 4. These diol epoxides are required as starting compounds for the synthesis of site-specifically modified oligonucleotides which are critically needed to elucidate the mechanism of carcinogenesis at the molecular level.

Full text of DOI:10.1021/jo9712355

J . Org. Chem. 1997, 62, 8535-8539
8535
A New a n d Con cise Syn th esis of 3-Hyd r oxyben zo[c]p h en a n th r en e
a n d 12-Hyd r oxyben zo[g]ch r ysen e, Usefu l In ter m ed ia tes for th e
Syn th esis of F jor d -Region Diol Ep oxid es of Ben zo[c]p h en a n th r en e
a n d Ben zo[g]ch r ysen e
Subodh Kumar
Environmental Toxicology & Chemistry, Great Lakes Center for Environmental Research and Education,
State University of New York College at Buffalo, 1300 Elmwood Avenue, Buffalo, New York 14222
Received J uly 8, 1997X
A new strategy which involves a palladium-catalyzed cross-coupling reaction has been developed
for the rapid synthesis of 3-hydroxybenzo[c]phenanthrene (5) and 12-hydroxybenzo[g]chrysene (6).
These phenolic compounds are the key intermediates for the synthesis of highly carcinogenic fjord-
region diol epoxide metabolites 3 and 4 of benzo[c]phenanthrene (1) and benzo[g]chrysene (2). The
cross-coupling reaction of 2-bromo-5-methoxybenzaldehyde (9) with naphthalene-1-boronic acid (7)
and phenanthrene-9-boronic acid (8) produced 2-(1-naphthyl)-5-methoxybenzaldehyde (10) and 2-(9-
phenanthryl)-5-methoxybenzaldehyde (11), respectively, in quantitative yields. After reaction of
these aldehydes with trimethylsulfonium iodide under phase-transfer conditions or with the Wittig
reagent obtained from (methoxymethyl)triphenylphosphonium bromide and phenyllithium to
generate an oxiranyl or methoxyethene side chain, the acid-catalyzed cyclization with methane-
sulfonic acid (or boron trifluoride) produced 3-methoxybenzo[c]phenanthrene (16) and 12-meth-
oxybenzo[g]chrysene (17) in 61-64% yields. Finally, demethylation of these methoxy derivatives
16 and 17 with boron tribromide resulted in the formation of the hydroxy analogues 5 and 6,
respectively. The availability of this short and high-yielding regiospecific method for the synthesis
of phenols 5 and 6 should allow the preparative-scale synthesis of the fjord-region diol epoxides 3
and 4. These diol epoxides are required as starting compounds for the synthesis of site-specifically
modified oligonucleotides which are critically needed to elucidate the mechanism of carcinogenesis
at the molecular level.
Polycyclic aromatic hydrocarbons (PAHs) are wide-
spread environmental contaminants which are intro-
duced into our environment by the combustion of organic
matters.1 Some PAHs are potent carcinogens, and their
metabolism by cytochrome P-450 and epoxide hydrolase
to bay-region diol epoxides is considered to be involved
in the carcinogenic action of these chemicals.2-4 The
covalent binding of bay-region diol epoxide intermediates
to cellular DNA is believed to be involved in tumor-
induction. The additional steric constraint in the bay
region has been found to significantly enhance the
carcinogenic activity of the bay-region diol epoxide de-
rivatives.5,6 The fjord-region diol epoxides 3 and 4 of
benzo[c]phenanthrene (1) and benzo[g]chrysene (2), which
have additional crowding in the bay region, exhibit
significantly higher levels of carcinogenic activity.7-10
Furthermore, in contrast to bay-region diol epoxides
which react predominantly at the deoxyguanosine residue
of cellular DNA, fjord-region diol epoxides react exten-
sively with the deoxyadenosine residue of cellular
DNA.11-13 Since fjord-region diol epoxides 3 and 4
display high carcinogenic activity and a high level of
covalent binding to DNA with the deoxyadenosine resi-
dues, these metabolites are of particular interest for the
further elucidation of the mechanism of PAH-induced
carcinogenesis, especially, at the molecular level.
Recent advances14 have shown that the biochemical
event(s) that leads a diol epoxide-DNA adduct to induce
tumorigenic effects may be correlated with the preferred
conformation of the adduct in DNA template. Conse-
quently, site-specifically modified oligonucleotides have
emerged as useful probes for identifying the conforma-
tion-related mutational events that lead to tumorigen-
esis.15,16 Since the synthesis of site-specifically modified
oligonucleotides involves multistep synthesis and re-
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and
Carcinogenicity; Cambridge University Press: Cambridge, England,
1991.
(2) Lehr, R. E.; Kumar, S.; Levin, W.; Wood, A. W.; Chang, R. L.;
Conney, A. H.; Yagi, H.; Sayer, J . M. and J erina, D. M. Polycyclic
Aromatic Hydrocarbons and Carcinogenesis; Harvey, R. G., Ed.; ACS
Symposium Series 283, American Chemical Society: Washington, D.C.
1985; pp 63-84.
(3) Thakker, D. R.; Yagi, H.; Levin, W.; Wood, A. W.; Conney, A.
H.; J erina, D. M. Bioact. Foreign Compd. 1985, 7, 177.
(4) Harvey, R. G.; Geacintov, N. E. Acc. Chem. Res. 1988, 21, 66.
(5) Hecht, S. S.; El-Bayoumy, K.; Rivenson, A.; Amin, S. Cancer Res.
1994, 54, 21.
(6) Hecht, S. S.; Amin, S.; Huie, K.; Melikian, A. A.; Harvey, R. G.
Cancer Res. 1987, 47, 5310.
(7) Levin, W.; Wood, A. W.; Chang, R. L.; Ittah, Y.; Croisy-Delcey,
M.; Yagi, H.; J erina, D. M.; Conney, A. H. Cancer Res. 1980, 40, 3910.
(8) Glatt, H.; Piee, A.; Pauly, K.; Steinbrecher, T.; Schrode, R.; Oesch,
F.; Seidel, A. Cancer Res. 1991, 51, 1659.
(10) Amin, S.; Desai, D.; Dai, W.; Harvey, R. G.; Hecht, S. S.
Carcinogenesis 1995, 16, 2813.
(11) Dipple, A.; Pigott, M. A.; Agarwal, S. K.; Yagi, H.; Sayer, J . M.;
J erina, D. M. Nature (London) 1987, 327, 535.
(12) Agarwal, S. K.; Sayer, J . M.; Yeh, H. J .; Pannell, L. K.; Hilton,
B. D.; Yagi, H.; J erina, D. M. J . Am. Chem. Soc. 1987, 109, 2497.
(13) Szeliga, J .; Lee, H.; Harvey, R. G.; Page, J . E.; Ross, H. L.;
Routledge, M. N.; Hilton, B. D.; Dipple, A. Chem. Res. Toxicol. 1994,
7, 420.
(14) Geacintov, N. E.; Cosman, M.; Hingerty, B. E.; Amin, S.; Broyde,
S.; Patel, D. J . Chem. Res. Toxicol. 1997, 10, 111.
(15) Dipple, A. DNA Adducts: Identification and Biological Signifi-
cance; IARC Scientific Publication No. 125; Hemminki, K., Dipple, A.,
Shuker, D. E. G., Kadlubar, F. F., Segerback, D., Bartsch, H., Eds.;
International Agency for Research on Cancer: Lyon, France, 1994, pp
107-129.
(9) Amin, S.; Krzeminski, J .; Rivenson, A.; Kurtzke, C.; Hecht, S.
S.; El-Bayoumy, K. Carcinogenesis 1995, 16, 1971.
(16) Lakshman, M. K.; Sayer, J . M.; J erina, D. M. J . Am. Chem.
Soc. 1991, 113, 6589.
S0022-3263(97)01235-8 CCC: $14.00 © 1997 American Chemical Society

8536 J . Org. Chem., Vol. 62, No. 24, 1997
Kumar
Sch em e 1
quires fjord-region diol epoxides as key starting materi-
als, a practical and short synthesis of the fjord-region diol
epoxides of 1 and 2 is needed. A number of approaches
have been developed17-22 for the synthesis of 3 and 4
during recent years. The most convenient approach17-20
for the synthesis of 3 involves 3-hydroxy- (5) or 4-hy-
droxybenzo[c]phenanthrene (5a ), and for 4 it involves
either 12-hydroxy- (6), 11-hydroxy- (6a ), or 11,12-dihy-
droxybenzo[g]chrysene (6b). Although the yield of 6b or
its diacetate has not been reported,20 the other phenolic
compounds 5, 5a , 6, and 6a are best obtained in 4-6
steps with 16-31% yields from commercially or easily
accessible starting materials by two general methods.17-20
One of the general methods which can be adaptable to
the large scale synthesis of 5 is not only nonregiospecific
but also requires a relatively large number of steps,
thereby making the overall synthesis of 5 less efficient.17
The other general method, while requiring a smaller
number of steps for the synthesis of 5a ,18 6a ,19 or 6b,20
involves oxidative photocyclization, which works only
under high dilution conditions (10-3-10-4 molar in
benzene); consequently, this method is not suitable for
the synthesis of these phenolic compounds on a prepara-
tive scale. Furthermore, the formation of 5a and 6a
occurred in low yield (<50%), presumably due to a side
reaction involving the elimination of o-methoxy group
during photocyclization.23 In view of these synthetic
difficulties associated with the existing methods, a more
convenient and rapid approach is needed for the synthe-
sis of these phenols in desired amounts in a short amount
of time from readily accessible starting materials. I now
report such an efficient approach for the synthesis of
3-hydroxybenzo[c]phenanthrene (5) and 12-hydroxyben-
zo[g]chrysene (6). This synthetic approach, which in-
volves a palladium-catalyzed cross-coupling reaction
(Suzuki reaction24) of easily accessible reactants is, in
principle, adaptable to large scale synthesis of 5 and 6
in four convenient steps.
Resu lts a n d Discu ssion
The pioneering discovery of Suzuki reaction24 has set
a foundation for the synthetic development of PAHs and
their highly functionalized derivatives.25,26 However, the
application of this reaction to developing an efficient
route to the synthesis of carcinogenic PAH metabolites
has been explored only recently.27 In an earlier study,
Wright et al.28 demonstrated that the palladium-cata-
lyzed cross-coupling reaction of phenylboronic acid with
p-bromobenzaldehyde occurred in high yield in the pres-
ence of cesium fluoride under anhydrous conditions. On
the basis of this study, we envisaged analogous reaction
between arylboronic acids and 2-bromo-5-methoxybenz-
aldehyde as the key step in planning our strategy for the
synthesis of 3-hydroxybenzo[c]phenanthrene (5) and 12-
hydroxybenzo[g]chrysene (6) (see Scheme 1). The re-
quired boronic acids, naphthalene-1-boronic acid (7)29 and
phenanthrene-9-boronic acid (8),30 and 2-bromo-5-meth-
oxybenzaldehyde (9)31 were readily accessible according
to the literature procedures. Thus, the coupling reaction
of 7 or 8 with 9 in the presence of anhydrous CsF and a
(17) Pataki, J .; Raddo, P. D.; Harvey, R. G. J . Org. Chem. 1989, 54,
840, and references therein.
(18) Misra, B.; Amin, S. J . Org. Chem. 1990, 55, 4478.
(19) Krzeminski, J .; Lin, J .-M.; Amin, S.; Hecht, S. S. Chem. Res.
Toxicol. 1994, 7, 125.
(24) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(25) Snieckus, V. Chem. Rev. 1990, 90, 879.
(26) Chowdhury, S.; Zhao, B.; Snieckus, V. Polycyclic Aromat. Comd.
1994, 5, 27.
(20) Kiselyov, A. S.; Lee, H.; Harvey, R. G. J . Org. Chem. 1995, 60,
6123 and references therein.
(21) Bushman, D. R.; Grossman, S. J .; J erina, D. M.; Lehr, R. E. J .
Org. Chem. 1989, 54, 4, 3533.
(22) Sayer, J . M.; Yagi, H; Croisy-Delcey, M.; J erina, D. M. J . Am.
Chem. Soc. 1981, 103, 4970.
(23) Mallory, F. B.; Rudolph, M. J .; Oh, S. M. J . Org. Chem. 1989,
54, 4619.
(27) Kumar, S. Tetrahedron Lett. 1996, 37, 6271.
(28) Wright, S. W.; Hageman, D. L.; McClure, L. D. J . Org. Chem.
1994, 59, 6095.
(29) Washburn, R. M.; Levens, E.; Albright, C. F.; Billig, F. A.;
Cernak, E. S. Adv. Chem. Ser. 1959, 23, 102.
(30) Davidson, J . M.; French, C. M. J . Chem. Soc. 1960, 191.
(31) Fleming, I.; Woolias, M. J . Chem. Soc., Perkin Trans. 1 1979,
829.

Hydroxybenzo[c]phenanthrene and -chrysene Synthesis
J . Org. Chem., Vol. 62, No. 24, 1997 8537
Sch em e 2
mixture of diastereomers (1H NMR). The restricted
rotation between aryl-aryl bond and the presence of a
chiral center at the benzylic carbon of the ethylene oxide
functionality were responsible for producing 12 and 13
as a mixture of diastereomers. The acid-catalyzed cy-
clodehydration of 12 and 13 took place smoothly with
methanesulfonic acid in CH2Cl2 to provide 3-methoxy-
benzo[c]phenanthrene (16) and 12-methoxybenzo[g]chry-
sene (17) in 62% and 42% yields, respectively. When the
cyclodehydration reaction of 13 was effected with BF3‚Et2O
in Et2O, 17 was obtained in slightly higher yield (50%).
In the second approach, the aldehydes 10 and 11 were
treated with the Wittig reagent19 obtained from (meth-
oxymethyl)triphenylphosphonium bromide and phenyl-
lithium to produce the methoxyethene derivatives 14 and
15 in 54% and 83% yields, respectively, as a ∼1:1 mixture
of cis and trans isomers. The acid-catalyzed cyclization
of the cis/trans mixture of 14 and 15 with methane-
sulfonic acid in methylene chloride at 0 °C afforded the
corresponding 16 and 17 in 60% and 79% yields, respec-
tively. In none of the cases, the acid-catalyzed cyclization
occurred at the peri-position (C-8) of the epoxides 12 and
13 or methoxyethenes 14 and 15 to produce undesirable
seven-membered products. Comparison of the two ap-
proaches used for the two step synthesis of 16 and 17
from the corresponding aldehydes 10 and 11 indicated
that the first approach produced 16 in better yield. On
the other hand, 17 was produced in better yield following
the second approach. Finally, the methoxy PAHs 16 and
17 were demethylated (BBr3/CH2Cl2) to 3-hydroxyben-
zo[c]phenanthrene (5) and 12-hydroxybenzo[g]chrysene
(6) in 86-98% yields. The reaction sequence, phenol f
o-quinone f dihydrodiol f diol epoxide, is well estab-
lished in the literature17,20 for the conversion of the
phenols 5 and 6 to the corresponding fjord-region diol
epoxides 3 and 4, respectively.
catalytic amount of Pd(PPh3)4 produced 10 or 11 in nearly
quantitative yield (96-100%). The cross-coupling reac-
tion of relatively unhindered boronic acid with ortho-
substituted aryl halides has been reported to proceed in
moderate to high yields only if strong bases such as
aqueous NaOH or Ba(OH)2 are used.32-34 However, these
bases are not entirely compatible with the aldehyde group
present in 9. The present examples demonstrated that
the yield of the coupling product was very high even when
using relatively hindered boronic acid 7 or 8 in the
coupling reaction with ortho-substituted aryl halide in
the presence of CsF. Presumably, the high affinity of the
fluoride ion for boron, the considerable stability of the
product fluoborate ion, the relative weak basicity and
poor nucleophilicity of the fluoride ion, the weakness of
the palladium-fluoride bond, and the anhydrous condi-
tions all contribute to the high yield of the coupling
products.
In summary, the present study describes a highly
efficient application of the palladium-catalyzed cross-
coupling reaction of readily accessible reactants to the
concise synthesis of 3-hydroxybenzo[c]phenanthrene (5)
and 12-hydroxybenzo[g]chrysene (6). The overall yields
of these phenols 5 and 6 from bromo aldehyde 9 were 61
and 64%, respectively, which represent a significant
improvement over the previous methodologies. In addi-
tion to providing a practical and concise synthesis of 5
and 6, the method holds promise as a general synthetic
route to substituted benzo[c]phenanthrene and ben-
zo[g]chrysene, and their metabolites.
Exp er im en ta l Section
Naphthalene-1-boronic acid (7)29 and phenanthrene-9-bo-
ronic acid (8)30 were prepared as described in the literature.
2-Bromo-5-methoxybenzaldehyde (9)31 was synthesized by a
published procedure. All reagents and solvents (anhydrous
or otherwise) were used as received without additional puri-
fication. Dry column grade silica gel was purchased from E.
Merck. 1H NMR spectra were recorded on a 400 MHz NMR
spectrometer (Brucker) in d6-acetone with tetramethylsilane
(TMS) as internal standard at the NMR facility of Roswell
Park Cancer Institute, Buffalo, NY. Chemical shifts were
reported in ppm downfield from the internal standard. All
melting points were uncorrected.
Two approaches were investigated for converting 10
and 11 to the corresponding 3-methoxybenzo[c]phenan-
threne (16) and 12-methoxybenzo[g]chrysene (17) (Scheme
2). In one approach, the aldehydes 10 and 11 were
reacted under phase transfer reaction conditions with
trimethylsulfonium iodide to produce the corresponding
ethylene oxide derivatives 12 and 13, respectively, as a
(32) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(33) (a) Rocca, P.; Marsais, F; Godard, A.; Queguiner, G. Tetrahedron
Lett. 1993, 34, 2937. (b) Guillier, F.; Nivoliers, F.; Godard, A.; Marsais,
F.; Queguiner, G. Tetrahedron Lett. 1994, 35, 6489.
(34) Kelly, T. R.; Garcia, A.; Lang, F.; Walsh, J . J .; Bhaskar, K. V.;
Boyd, M. R.; Gotz, R.; Keller, P. A.; Walter, R.; Bringmann, G.
Tetrahedron Lett. 1994, 35, 7621.
2-(1-Na p h th yl)-5-m eth oxyben za ld eh yd e (10). A mix-
ture of naphthalene-1-boronic acid (7) (4.04 g, 0.023 mol),
2-bromo-5-methoxybenzaldehyde (9) (4.57 g, 0.02 mol), anhy-
drous CsF (7.23 g, 0.047 mol), and Pd(PPh3)4 (0.82 g, 0.0007
mol) in anhydrous DME (100 mL) was heated under reflux
for 18 h under argon. The reaction was monitored by TLC

8538 J . Org. Chem., Vol. 62, No. 24, 1997
Kumar
(15% EtOAc-hexane) until no more bromide was detected. The
reaction mixture was then cooled and extracted with a mixture
of EtOAc (200 mL) and water (200 mL). The EtOAc layer was
separated, dried (Na2SO4), and concentrated to yield a solid.
The crude product was recrystallized from CH2Cl2-hexane to
give 5.57 g (100% yield) of 10 as a light yellow crystalline solid,
mp 115-116 °C. 1H NMR (d6-acetone): δ 4.0 (s, 3 H), 7.37-
7.65 (m, 9 H), 8.05 (d, 1 H, J ) 9.7 Hz), 9.56 (s, 1 H). 13C
NMR (CDCl3): δ 191.4 (CHO), 159.4, 137.1, 135.6, 135.1,
133.4, 133.0, 132.9, 128.5, 128.4, 128.3, 126.6, 126.1, 125.8,
125.0, 121.4, 109.4, 55.6 (OMe). Anal. Calcd for C18H14O2: C,
82.4; H, 5.3. Found: C, 82.3; H, 5.4.
3-Meth oxyben zo[c]p h en a n th r en e (16). Meth od A. The
two-phase system containing aldehyde 10 (2.0 g, 7.6 mmol) in
50 mL of CH2Cl2 and 25 mL of 50% aqueous NaOH was treated
with trimethylsulfonium iodide (3.16 g, 15.5 mmol) and
tetrabutylammonium iodide (30 mg). The mixture was stirred
vigorously under reflux, and the progress of the reaction was
monitored by 1H NMR spectroscopy which showed that the
completion of the reaction required 96 h. After completion of
the reaction, the mixture was poured into ice-cold water, and
the product was isolated by extraction with CH2Cl2. The
organic phase was washed with water, dried over Na2SO4, and
filtered, and the solvent was removed by rotary evaporation
to afford 2.3 g (100%) of sufficiently pure 1-(2-(epoxyethyl)-4-
methoxyphenyl)naphthalene (12) as a light yellow syrupy oil.
1H NMR (d6-acetone): δ 2.64-2.72 (m, 2 H), 3.29-3.33 (m, 1
H), 3.90 (s, 3 H), 6.85-8.02 (m, 10 H).
with ice-cold water, and then extracted with Et2O. The Et2O
layer was washed thrice with cold water and dried over
anhydrous Na2SO4. Concentration of the solution gave a
semisolid which was recrystallized from hexane to give 0.20 g
(61%) of 16 as light yellow needles, mp 89-91 °C.
3-Hyd r oxyben zo[c]p h en a n th r en e (5). To a stirred solu-
tion of 16 (0.54 g, 2.0 mmol) in dry CH2Cl2 (25 mL) was added
a 1 M solution of BBr3 (4.2 mL, 4.2 mmol) in CH2Cl2 at 0 °C
under argon over a period of 2-3 min. After 12 h at rt, the
reaction mixture was hydrolyzed with ice-cold water, the
organic layer was washed with water and dried (Na2SO4), and
the solvent was removed to afford a solid. Trituration of the
solid with hexane gave 0.50 g (98%) of 5 as a crystalline solid,
mp 110-112 °C (lit.35 mp 107-110 °C). 1H NMR (d6-
acetone): δ 7.36 (dd, 1 H, H-2, J 1,2 ) 8.7, J 2,4 ) 3.0 Hz), 7.45
(d, 1 H, H-4, J 2,4 ) 3.0), 7.61-7.74 (m, 2 H, H-10, H-11), 7.81-
7.94 (m, 4 H, H-5, H-6, H-7, H-8), 8.08 (dd, 1 H, H-9, J 9,10
7.5 Hz, J 9,11 ) 1.3 Hz), 8.81 (s, 1 H, OH), 9.03 (d, 1 H, H-1, J 1,2
) 8.7 Hz), 9.10 (d, 1 H, H12, J 11,12 ) 8.7 Hz).
)
2-(9-P h en an th r yl)-5-m eth oxyben zaldeh yde (11). A mix-
ture of phenanthrene-9-boronic acid (8) (3.67 g, 0.0165 mmol),
9 (3.22 g, 0.015 mmol), anhydrous CsF (5.5 g, 0.036 mol), and
Pd(PPh3)4 (0.60 g, 0.0005 mol) in anhydrous DME (75 mL) was
heated under reflux for 18 h under argon. The reaction
mixture was worked up as described for 10 to produce a
semisolid. Trituration of the semisolid with Et2O-hexane
gave 4.67 g (100% yield) of sufficiently pure 11 as a crystalline
solid. A small sample of the crystalline solid was recrystallized
from CH2Cl2/hexane to produce 11 as light yellow granules,
mp 118.5-119 °C. 1H NMR (d6-acetone): δ 4.00 (s, 3 H), 7.39-
7.82 (m, 9 H), 8.02 (dd, 1 H, J ) 7.8 Hz, J ) 1.3 Hz), 8.89 (d,
1 H, J ) 7.8 Hz), 8.94 (d, 1 H, J ) 7.8), 9.7 (s, 1 H). 13C NMR
(CDCl3): δ 191.8 (CHO), 159.4, 137.0, 135.8, 133.7, 132.9,
132.2, 130.9, 130.2, 130.1, 129.4, 128.6, 127.1 (2 C), 127.0,
126.9, 126.8, 122.9, 122.5, 121.4, 109.5, 55.6 (OMe). Anal.
Calcd for C22H16O2: C, 84.6; H, 5.1. Found: C, 84.9; H, 5.2.
12-Meth oxyben zo[g]ch r ysen e (17). Meth od A. A bi-
phasic reaction mixture consisted of aldehyde 11 (1.5 g, 4.8
mmol) in 70 mL of CH2Cl2 and 20 mL of 50% NaOH was added
with trimethylsulfonium iodide (2.0 g, 9.8 mmol) and tetrabu-
tylammonium iodide (50 mg). The mixture was stirred vigor-
ously under reflux, and the reaction was monitored by 1H NMR
spectroscopy for the presence of an aldehyde peak at ∼9.7 ppm.
After 96 h of reflux, no aldehyde peak was present. The
product was isolated by extraction as described in the case of
12 to afford 1.6 g (100%) of sufficiently pure 9-(2-(epoxyethyl)-
4-methoxyphenyl)phenanthrene (13) as a light-yellow syrupy
oil. 1H NMR (d6-acetone): δ 2.62-2.87 (m, 2 H), 3.38-3.44
(m, 1 H), 3.90 (s, 3 H), 6.87-8.95 (m, 12 H).
To a stirred solution of the epoxide 12 (2.54 g) in anhydrous
CH2Cl2 (125 mL) under argon was added dropwise methane-
sulfonic acid (5 mL) in 2-3 min. The mixture was stirred at
rt for 4 h. The mixture was poured on to ice-cold 10% aqueous
NaOH and extracted with CH2Cl2. The organic phase was
washed with cold water, dried (Na2SO4), and concentrated
under vacuum to yield a dark oil. The oil was chromato-
graphed on dry column grade silica gel using 5% EtOAc-
hexane as eluant to provide 1.63 g (62% based on aldehyde
10) of pure 16 as a solid. A small sample of this solid was
recrystallized from hexane to yield shiny yellow flakes, mp 90-
91 °C (lit.35 mp 89-90 °C). 1H NMR (d6-acetone): δ 4.01 (s, 3
H, OCH3), 7.38 (dd, 1 H, H-2, J 1,2 ) 9.2, J 2,4 ) 3.4 Hz), 7.56 (d,
1 H, H-4, J 2,4 ) 3.4), 7.62-7.75 (m, 2 H, H-10, H-11), 7.86-
7.97 (m, 4 H, H-5, H-6, H-7, H-8), 8.09 (dd, 1 H, H-9, J 9,10
)
7.7 Hz, J 9,11 ) 1.4 Hz), 9.07 (d, 1 H, H-1, J 1,2 ) 9.2 Hz), 9.10
(d, 1 H, H12, J 11,12 ) 8.7 Hz). 13C NMR (CDCl3): δ 157.4, 135.0,
133.5, 130.0, 129.6, 129.4, 128.4, 127.8, 127.5, 127.4, 126.8,
126.7, 126.4, 125.9, 125.7, 125.0, 117.0, 107.8, 55.3 (OMe).
Anal. Calcd for C19H14O‚1/8C6H14: C, 88.1; H, 5.9. Found: C,
87.7; H, 5.5.
The cyclization of 13 (0.8 g, 2.45 mmol) was performed in a
solution of anhydrous Et2O (60 mL) by dropwise addition of
BF3‚Et2O (3 mL, 24.4 mmol) at 0 °C under argon. The solution
was stirred for an additional 8 h at rt. After completion of
the reaction (as monitored by TLC), the excess of BF3‚Et2O
was decomposed by addition of ice-cold water. The product
was extracted with ether (2 × 50 mL), and the combined
organic extracts were successively washed with 10% Na2CO3
(2 × 50 mL) and water (1 × 50 mL). After evaporation of the
solvent, the residue was chromatographed over dry column
grade silica gel using hexane as eluant to produce 0.38 g (50%)
of 17 as a crystalline solid. A small sample of the product was
recrystallized from hexane to give colorless needles of 17, mp
129-130 °C. 1H NMR (d6-acetone): δ 4.03 (s, 3 H, OCH3),
7.33 (dd, 1 H, H-13, J 11,13 ) 3.0 Hz, J 13,14 ) 9.2 Hz), 7.54 (d, 1
H, H-11, J 11,13 ) 3.0 Hz), 7.67-7.78 (m, 4 H, H-2, H-3, H-6,
H-7), 8.46 (d, 1 H, H-10, J 9,10 ) 9.2 Hz), 8.73 (d, 1 H, H-9, J 9,10
) 9.2 Hz), 8.76-8.90 (m, 5 H, H-1, H-4, H-5, H-8, H-14); 13C
NMR (CDCl3) δ 157.3, 134.9, 130.8, 129.9, 129.8, 129.4, 129.3,
129.2, 127.4, 127.1, 126.7, 126.6, 126.5, 126.4, 125.8, 125.0,
123.3, 123.2, 122.9, 121.1, 117.2, 106.9, 55.2 (OMe). Anal.
Calcd for C23H16O: C, 89.6; H, 5.2. Found: C, 89.6; H, 5.2.
Meth od B. The reaction of the Wittig reagent generated
from (methoxymethyl)triphenylphosphonium bromide (2.9 g,
8.45 mmol) and a 1.8 M solution of phenyllithium (5 mL, 9.0
mmol) in cyclohexane-ether (7:3) with the aldehyde 11 (0.9
g, 2.88 mmol) as described for 14 gave an oil. The purification
Meth od B. A 1.8 M solution of phenyllithium (5 mL, 9.0
mmol) in cyclohexane-ether (7:3) was added dropwise to a
solution of (methoxymethyl)triphenylphosphonium bromide
(2.9 g, 8.45 mmol) in dry Et2O (100 mL) at - 65 °C under
argon. The mixture was stirred at -65 °C for 0.5 h, then
warmed to -10 °C for 0.5 h, and then cooled again to -50 °C.
Solid aldehyde 10 (0.8 g, 3.05 mmol) was added portionwise
during 10 min, and the mixture was stirred at -50 °C for 1 h
and then at rt for 15 h. The mixture was treated with ice-
cold water, and the Et2O layer was separated. The aqueous
phase was extracted once with Et2O, and the combined organic
phases were washed with ice-cold water and dried (Na2SO4).
Removal of the solvent gave an oil which was further purified
by chromatography on dry column grade silica gel with elution
by hexane to remove nonpolar impurities and then by 3%
EtOAc-hexane. This gave 0.47 g (54%) of an oil containing a
mixture of nearly equal amounts of cis and trans isomers 14.
Partial H NMR (d6-acetone): for cis isomer, two doublets at
δ 4.65 and 6.11 (J ) 9.9 Hz); for trans isomer, two doublets at
δ 5.32 and 7.05 (J ) 15.4 Hz).
To a stirred solution of the isomeric mixture of 14 (0.37 g)
in 25 mL of anhydrous CH2Cl2 at 0 °C under argon was added
methanesulfonic acid (5 mL) in 5 min. The reaction mixture
was then stirred for an additional 1.75-2.5 h at 0 °C, diluted
1
(35) Newman, M. S.; Blum, J . J . Am. Chem. Soc. 1964, 86, 503.

Hydroxybenzo[c]phenanthrene and -chrysene Synthesis
J . Org. Chem., Vol. 62, No. 24, 1997 8539
of the oil by chromatography on dry column grade silica gel
with hexane followed by 3% EtOAc-hexane gave 0.80 g (82%)
of an oil containing a 1:1 mixture of cis and trans isomers of
1-[1-{2-(1-naphthyl)-5-methoxyphenyl}]-2-methoxyethene (15).
Partial H NMR (d6-acetone): for cis isomer, two doublets at
δ 4.73 and 6.00 (J ) 8.2 Hz); for trans isomer, two doublets at
δ 5.40 and 7.10 (J ) 13.0 Hz).
solid, mp 218-220 °C (lit.20 mp 220-221 °C). 1H NMR (d6-
acetone): δ 5.62 (s, 1 H, OH), 7.32 (dd, 1 H, H-13, J 11,13 ) 2.8
Hz, J 13,14 ) 8.5 Hz), 7.44 (d, 1 H, H-11, J 11,13 ) 2.8 Hz), 7.67-
7.82 (m, 4 H, H-2, H-3, H-6, H-7), 7.95 (d, 1 H, H-10, J 9,10
)
1
8.5 Hz), 8.70 (d, 1 H, H-9, J 9,10 ) 8.5 Hz), 8.75-8.92 (m, 5 H,
H-1, H-4, H-5, H-8, H-14).
Acid-catalyzed cyclization of the isomeric mixture of 15 (0.56
g) in 20 mL of anhydrous CH2Cl2 containing methanesulfonic
acid (5 mL) was conducted as described for 16 (method B) to
produce a semisolid which was triturated and recrystallized
from hexane to give 0.48 g (79%) of 17 as colorless needles,
mp 129-130 °C.
12-Hyd r oxyben zo[g]ch r ysen e (6). Demethylation of 17
(0.44 g, 1.4 mmol) in dry CH2Cl2 (25 mL) with a 1 M solution
of BBr3 (3.0 mL, 3.0 mmol) in methylene chloride was effected
under argon as described for 5. The isolated product was
triturated with hexane to give 0.36 g (86%) of 6 as a crystalline
Ack n ow led gm en t. The author acknowledges Dr.
Dinesh Sukumaran, State University of New York at
Buffalo, for recording 13C NMR spectra.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
10, 16, 11, and 17 (4 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O9712355