Synthesis of higher oxidized metabolites of dibenz[a,j]anthracene implicated in the mechanism of carcinogenesis

Article abstract of DOI:10.1021/jo980416j

Higher oxidized metabolites are implicated as active carcinogenic forms of polycyclic aromatic hydrocarbons which have two or more bay or fjord molecular regions, such as dibenz[a,j]anthracene. These include the bis(dihydrodiols) and phenolic dihydrodiols

Full text of DOI:10.1021/jo980416j

J . Org. Chem. 1998, 63, 8125-8132
8125
Syn th esis of High er Oxid ized Meta bolites of
Diben z[a , j]a n th r a cen e Im p lica ted in th e Mech a n ism of
Ca r cin ogen esis
J in-Tao Zhang, Wei Dai, and Ronald G. Harvey*
Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637
Received March 4, 1998
Higher oxidized metabolites are implicated as active carcinogenic forms of polycyclic aromatic
hydrocarbons which have two or more bay or fjord molecular regions, such as dibenz[a, j]anthracene.
These include the bis(dihydrodiols) and phenolic dihydrodiols which may potentially undergo further
metabolism to the corresponding diol epoxides. The latter react with DNA resulting in mutations
that lead to tumorigenesis. Prior characterization of these metabolites has been based largely on
HPLC and spectroscopic evidence. This paper reports efficient syntheses of the trans-trans-3,4,8,9-
dihydrodiol (1) and the 10- and 11-phenolic trans-3,4-dihydrodiols of dibenz[a, j]anthracene (3a ,b).
The synthetic route to 1 entails as the key steps asymmetric dihydroxylation of an appropriately
substituted stilbene precursor employing a Sharpless catalyst followed by intramolecular cyclode-
hydrobromination catalyzed by Pd(PPh3)2Cl2. The syntheses of 3a ,b proceed via sequences involving
a Wittig reaction of anisaldehyde with a phosphonium salt of 2-chloro-3-methylbenzyl bromide to
give a stilbene compound and then photocyclization, conversion of the product to a phosphonium
salt, a second Wittig reaction and photocyclization, reductive dechlorination, and conversion of the
resulting trimethoxydibenz[a, j]anthracenes to the phenolic dihydrodiols. A key feature of these
syntheses is the effective use of chloro substituents to block photocyclization in an undesired
direction. These methods are potentially applicable to the synthesis of analogous higher oxidized
metabolites of other polycyclic aromatic carcinogens.
The established mechanism of carcinogenesis of poly-
cyclic aromatic hydrocarbons (PAHs) entails activation
by P-450 microsomal enzymes to form reactive diol
epoxide metabolites1,2 that combine covalently with DNA.
These result in mutations that lead ultimately to tumor
induction.2,3 However, there is substantial evidence,
reviewed in the preceding paper, that more polar PAH
metabolites, such as bis(dihydrodiols), may also contrib-
ute to the carcinogenicity of dibenz[a, j]anthracene and
other PAHs that possess two or more sterically crowded
bay or fjord regions in the molecule. In most of these
cases the structural assignments of the higher oxidized
metabolites (bis(dihydrodiols), bis(diol) epoxides, and
phenolic dihydrodiol and diol epoxides have been based
largely on spectroscopic evidence due to their relative
inaccessibility through synthesis.
To obtain more definitive evidence concerning the
importance of this alternative mechanistic path relative
to the better established diol epoxide pathway for PAHs
with more than a single bay region, we undertook to
develop convenient synthetic approaches to the higher
oxidized metabolites of this class of PAHs. The synthetic
compounds are urgently required as authentic standards
for studies to confirm their formation metabolically as
well as to determine their mutagenic and carcinogenic
activities and their DNA binding properties in mam-
malian cells. The oxidized metabolites of dibenz[a, j]-
anthracene were selected as specific synthetic targets
because previous metabolism studies in primary cultures
of mouse keratinocytes revealed the formation of sub-
stantial number of metabolites more polar than the 3,4-
and 5,6-dihydrodiols of dibenz[a, j]anthracene.4 The ratio
of polar metabolites increased with time, and it was
proposed that they were mainly the 3,4,8,9- and 3,4,10,-
11-bis(dihydrodiols) (1 and 2)5 plus lesser amounts of
phenolic dihydrodiols, such as the 10- and 11-hydroxy-
3,4-dihydrodiols (3a ,b).
We now report the syntheses of the unsymmetrical
3,4,8,9-bis(dihydrodiol) 1 and the 10- and 11-phenolic
trans-3,4- dihydrodiols (3a ,b) of dibenz[a, j]anthracene.
The stereochemistry of the dihydrodiol functions in all
these compounds is trans, since it is well established that
metabolism of PAHs by mammalian enzymes furnishes
exclusively trans stereoisomers.2,3 The preceding paper
reported the syntheses of the terminal ring symmetrical
3,4,10,11-bis(dihydrodiol) of dibenz[a, j]anthracene (2)
along with several additional suspected more highly
oxidized metabolites of this hydrocarbon.5
(1) The active diol epoxide metabolites of carcinogenic PAHs contain
the epoxide ring in a sterically crowded bay or fjord region which favors
their resistance to epoxide hydrase and other detoxifying enzymes.2
(2) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and
Carcinogenesis; Cambridge University Press: Cambridge, England,
1991.
(3) Harvey, R. G.; Geacintov, N. E. Acc. Chem. Res. 1988, 21, 66.
Harvey, R. G. Polycyclic Hydrocarbons and Carcinogenesis; ACS
Symposium Series Monograph 283; American Chemical Society: Wash-
ington, DC, 1985. Dipple, A.; Moschel, R. C.; Bigger, C. A. H. In
Chemical Carcinogens, 2nd ed., Searle, C. E., Ed.; ACS Monograph
No. 182; American Chemical Society: Washington, DC, 1984; pp 63-
84. Conney, A. H. Cancer Res. 1982, 42, 4875.
Resu lts
Syn t h esis of tr a n s-3,4-tr a n s-8,9-Tet r a h yd r oxy-
3,4,8,9-t et r a h yd r od ib en z[a , j]a n t h r a cen e (1). Sev-
(4) Nair, R. V.; Nettikumara, A. N.; Cortez, C.; Harvey, R. G.;
DiGiovanni, J . Chem. Res. Toxicol. 1992, 5, 532.
(5) Harvey, R. G.; Dai, W.; Zhang, J .-T.; Cortez, C. J . Org. Chem.
1998, 63, 8118.
10.1021/jo980416j CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/22/1998

8126 J . Org. Chem., Vol. 63, No. 23, 1998
Zhang et al.
1
Sch em e 1
94% yield. The H NMR spectrum of 8a was fully con-
sistent with this assignment. Bromination of 8a with
N-bromosuccinimide in the presence of benzoyl peroxide
in refluxing CCl4 gave 2-bromomethyl-7,8-dimethoxy-
phenanthrene (8b) which in turn underwent reaction
with PPh3 to provide the corresponding phosphonium salt
8c.
The latter salt was the starting compound for the syn-
thesis of the key compounds 9 and 10 (Scheme 2). Wittig
reaction of 8c with 2-bromobenzaldehyde provided the
1
expected olefin (9) shown by its H NMR spectrum to be
a mixture of E- and Z-isomers. This mixture was con-
verted to the E-isomer by heating with a crystal of io-
dine for 1 day in refluxing heptane. Osmium tetraoxide-
catalyzed asymmetric dihydroxylation of 9 in the presence
of the catalyst (DHQD)2PHAL and methanesulfonamide
(the Sharpless AD-mix-â reagent6) by the procedure
employed previously for an analogous stilbene derivative8
afforded stereospecifically the cis-dihydroxylated product
(10a ). The dihydrodiol 10a was converted into its di-
acetate (10b) by stirring overnight with Ac2O in pyridine
in the presence of p-(N,N-dimethylamino)pyridine (DMAP).
Intramolecular cyclodehydrobromination of 10b catalyzed
by Pd(PPh3)2Cl2 in dimethylacetamide7,8 provided trans-
8,9-diacetoxy-8,9-dihydro-3,4-dimethoxydibenz[a, j]an-
thracene (11a ). Analysis of the 1H NMR spectrum of 11a
confirmed its structural assignment.
eral potential synthetic routes to the unsymmetrical
3,4,8,9-bis(dihydrodiol) of dibenz[a, j]anthracene (1) were
explored and abandoned prior to discovery of a satisfac-
tory synthetic method. The successful approach entailed
in the key steps asymmetric dihydroxylation of an
appropriately substituted stilbene precursor (9) in the
presence of a Sharpless catalyst6 followed by intramo-
lecular cyclodehydrobromination of the product catalyzed
by Pd(PPh3)2Cl2 (Scheme 2).7,8
It was envisioned that compound 11a might be con-
verted to the 3,4,8,9-bis(dihydrodiol) of dibenz[a, j]anthra-
cene (1) via demethylation and reduction with NaBH4/
O2.11,12 However, attempts to remove selectively the pro-
tective methyl groups of 11a with BBr3 or other reagents
failed due to competing secondary reactions, principally
elimination of acetic acid from the 8,9-positions. Conver-
sion of 11a to 1 was accomplished via an alternative
synthetic route involving deacetylation with NaOMe in
MeOH-THF to generate 3,4-dimethoxy-trans-8,9-dihy-
droxy-8,9-dihydrodibenz[a, j]anthracene (11b), oxidation
with DDQ in moist THF to the quinone (12a ), demeth-
ylation with BBr3 to the A-ring hydroquinone (12b), and
then reduction with NaBH4/O2 to the 3,4,8,9-bis(dihy-
drodiol) 1 in good overall yield.11-13 Reductions of the
hydroquinone and quinone functions both took place with
trans-stereospecificity in accord with previous findings
for reductions of this type.12-14 The NMR spectrum of
12b was consistent with its structural assignment.
However, 12b darkened in air, and in view of the well-
known sensitivity of PAH hydroquinones to autoxidation,
no attempts were made to characterize it further.
Syn th esis of tr a n s-3,4-Dih yd r oxy-3,4-d ih yd r o-10-
h yd r oxyd iben z[a , j]a n th r a cen e (3a ). The synthetic
route to the 10-phenol derivative of the dibenz[a, j]-
anthracene trans-3,4-dihydrodiol (3a ) involved two sepa-
rate photocyclization steps (Scheme 3). Wittig reaction
of o-anisaldehyde with the phosphonium salt derivative
5 of 2-chloro-3-methylbenzyl bromide gave the expected
The starting compound for this sequence was the
phenanthrene derivative 8c. It was itself synthesized via
a sequence based on Wittig reaction of 2,3-dimethoxy-
benzaldehyde (4) with the phosphonium salt derivative
of 2-chloro-3-methylbenzyl bromide (5) (Scheme 1). Phos-
phonium salt 5 was prepared from 2-chloro-m-xylene by
bromination with 1 equiv of NBS and a peroxide catalyst
to yield 2-chloro-3-methylbenzyl bromide followed by
reaction of the latter with triphenylphosphine. Wittig
reaction of 4 with 5 furnished the expected olefin (6)
1
shown by the complexity of its H NMR spectrum to be
a mixture of E- and Z-isomers in approximately 1:5 ratio.
The isomers were tentatively assigned on the basis of the
relatively larger coupling constant exhibited by the
olefinic protons of the minor E-isomer (δ 7.40, J ) 16
Hz) versus the major Z-isomer (δ 6.89, J ) 12 Hz).
Photocyclodehydrogenation of the resulting stilbene de-
rivative 6 took place smoothly in the presence of I2 and
epoxybutane9 without significant displacement of chlorine
to furnish 1-chloro-7,8-dimethoxy-2-methylphenanthrene
(7) as the principal product. The chloro substituent
served effectively to block the possible competing cycliza-
tion to its position. Subsequent removal of the chlorine
atom was achieved by reduction with LiAlH4 and NiCl2
by the method of Ashby and Lin.10 This reaction took
place smoothly at room temperature in anhydrous THF
to furnish 2,3-dimethoxy-7-methylphenanthrene (8a ) in
1
stilbene derivative (13) shown by its H NMR spectrum
(6) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768 and references cited
therein.
(7) (a) Deshpande, P. P.; Martin, O. R.; Tetrahedron Lett. 1990, 31,
6313. (b) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919. (c)
Bringmann, G.; Keller, P. A.; Ro¨lfing, K. Synlett 1994, 423.
(8) Tang, X.-Q.; Harvey, R. G. Tetrahedron Lett. 1995, 36, 6037.
(9) Epoxybutane serves to prevent competing reactions by scaveng-
ing the HI produced: Liu, L.; Yang, B.; Katz, T. J .; Poindexter, M. K.
J . Org. Chem. 1991, 56, 3769.
to be a mixture of E- and Z-isomers in approximately 1:5
(11) Dai, W.; Abu-Shqara, E.; Harvey, R. G. J . Org. Chem. 1995,
60, 4905. Platt, K.; Oesch, F. Synthesis 1982, 459.
(12) Reference 2, chapter 13, pp 306-329.
(13) In reductions of this type, O2 serves to oxidize hydroquinones
to quinones which undergo reduction with the hydride reagent to
dihydrodiols plus variable amounts of hydroquinones which are then
recycled.
(14) Harvey, R. G.; Goh, S. H.; Cortez, C. J . Am. Chem. Soc. 1975,
97, 3468.
(10) Ashby, E. C.; Lin, J . J . J . Org. Chem. 1978, 43, 1263.

Dibenz[a,j]anthracene Metabolites
J . Org. Chem., Vol. 63, No. 23, 1998 8127
Sch em e 2a
a
Asterisk indicates mixtures of bis(trans) isomers.
Sch em e 3
ratio. The isomeric assignments were tentatively based
on the larger coupling constant of the olefinic protons of
the minor E-isomer (δ 7.44, J ) 16 Hz) relative to that
of the major Z-isomer (δ 6.77, J ) 12 Hz). Separation of
the isomers was unnecessary, since interconversion of E-
and Z-isomers is known to take place readily during
photocyclization.15 Oxidative photoreaction of 13 in the
presence of I2 and epoxybutane9 gave 1-chloro-8-methoxy-
2-methylphenanthrene (14a ) as the major product. As
in the synthesis of 1, the chloro group effectively blocked
the alternate mode of cyclization.
trum of the former ressembled that of 7-chloro-3,4,11-
trimethoxydibenz[a, j]anthracene,5 exhibiting a charac-
teristic singlet at low field (δ 9.77) which is assigned to
1
the sterically crowded meso region H12 proton. The H
NMR spectrum of 17 ressembled that of the closely
related 1,2,9,10-tetramethoxybenzo[c]chrysene whose syn-
thesis was described in the preceding paper,5 exhibiting
characteristic low-field doublets at δ 8.98 and 8.82
assigned to the H12 and H13 protons, respectively, in the
sterically crowded fjord region of the benzo[c]chrysene
ring system.
The next stage in this synthesis entailed conversion
of the phenanthrene derivative 14a to the phosphonium
salt 14c. Bromination of 14a with NBS in the presence
of benzoyl peroxide gave 2-bromomethyl-1-chloro-8-meth-
oxyphenanthrene (14b) which in turn underwent reaction
with triphenylphosphine to furnish 14c. Wittig reaction
of 14c with 2,3-dimethoxybenzaldehyde (4) provided the
expected olefin (15). In this case, the Z-isomer was
strongly predominant, only traces of the E-isomer being
detectable. Photocyclization of 15 in the presence of I2
and epoxybutane took place with partial displacement
of the choro protecting group to furnish 7-chloro-3,4,10-
trimethoxydibenz[a, j]anthracene (16a ) (42% based on
conversion of 15) and 1,9,10-trimethoxybenzo[c]chrysene
Dechlorination of 16a by treatment with LiAlH4 and
NiCl2 took place smoothly at room temperature in
anhydrous THF to furnish 3,4,10-trimethoxydibenz[a, j]-
1
anthracene (16b). The H NMR spectrum of 16b exhib-
ited two singlets in the aromatic region at δ 8.25 and
9.79 assigned to the H7 and H14 meso region protons,
respectively, as well as other proton resonances consis-
tent with structural assignment as a dibenz[a, j]anthra-
cene derivative.
Conversion of trimethoxydibenz[a, j]anthracene (16b)
totrans-3,4-dihydroxy-3,4-dihydro-10-hydroxydibenz[a, j]-
anthracene (3a ) was accomplished via initial demethyl-
ation with BBr3 to 3,4,10-trihydroxydibenz[a, j]anthracene
(16c). In view of the air sensitivity of 16c, it was isolated
and characterized as its triacetate (16d ). Reduction of
16d with NaBH4 and O2 bubbling through the solution
took place smoothly with concurrent deacetylation to
1
(17) (35%) as the principal products. The H NMR spec-
(15) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30, 1.

8128 J . Org. Chem., Vol. 63, No. 23, 1998
Zhang et al.
Sch em e 4
provide the target phenolic trans-dihydrodiol 3a ste-
reospecifically.11
dibenz[a, j]anthracene (22c). In view of its air sensitivity,
22c was isolated and characterized as its triacetate (22d ).
Reduction of 22d with NaBH4 and O2 bubbling through
the solution took place smoothly and trans-stereospecifi-
cally12 with concurrent deacetylation to provide the target
phenolic dihydrodiol 3b.
Syn th esis of tr a n s-3,4-Dih yd r oxy-3,4-d ih yd r o-11-
h yd r oxyd iben z[a , j]a n th r a cen e (3b). Synthesis of the
11-phenol derivative of the trans-3,4-dihydrodiol of dibenz-
[a, j]anthracene (3b) was accomplished by a modification
of the route employed for the synthesis of the 10-phenol
derivative (3a ) (Scheme 4).
Discu ssion
Wittig reaction of 3-methoxybenzaldehyde with the
phosphonium salt 5 in the presence of NaOH and a
catalytic amount of 18-crown-6 afforded a stilbene de-
rivative (18) shown by its 1H NMR spectrum to be a
mixture of E- and Z-isomers in approximately 1:5 ratio.
Photocyclization of 18 under the conditions employed for
similar photoreactions took place with only minimal
displacement of chlorine to furnish the 1-chloro-7-meth-
oxy-2-methylphenanthrene isomer (19a ) arising from
cyclization to the position para to the methoxy group of
Although there is a substantial evidence that diol
epoxide metabolites are the principal active forms of most
carcinogenic alternant PAHs,2,3 recent studies on the
metabolic activation of PAHs with more than one bay or
fjord molecular region, such as dibenz[a, j]anthracene,
suggest that bis(dihydrodiols) and the corresponding
mono- or diepoxides, and possibly also phenolic dihydro-
diols and diol epoxides, may also play a role in carcino-
genicity.4,5 In this paper we report efficient syntheses
of the unsymmetrical bis-3,4,8,9-dihydrodiol (1) and the
10- and 11-phenolic trans-3,4-dihydrodiols dibenz[a, j]-
anthracene (3a ,b). The accompanying paper describes
syntheses of the symmetrical 3,4,10,11-bis(dihydrodiol)
(2) and several higher oxidized derivatives of dibenz[a, j]-
anthracene. The synthesis of these compounds completes
the preparation of all of the higher oxidized metabolites
of dibenz[a, j]anthracene suspected of playing a role in
the carcinogenicity of this PAH.
1
18. This structural assignment was supported by its H
NMR spectrum which exhibited a characteristic singlet
peak at δ 7.19 for the aromatic proton adjacent to the
methoxy group along with other appropriate resonances.
The alternative isomer, 1-chloro-5-methoxy-2-meth-
ylphenanthrene (20), anticipated to be formed by cycliza-
tion at the position ortho to the methoxy group of 18,
was not detected. Bromination of 19a with NBS and
benzoyl peroxide gave 2-bromomethyl-1-chloro-7-meth-
oxyphenanthrene (19b) which reacted with triphenylphos-
phine to furnish the phosphonium salt 19c.
Wittig reaction of 19c with 2,3-dimethoxybenzaldehyde
(4) provided the expected stilbene (21) mainly as the
Z-isomer. Photoreaction of 21 under the conditions
employed for previous examples afforded 7-chloro-3,4,-
11-trimethoxydibenz[a, j]anthracene (22a ) as the princi-
pal product. Dechlorination of 22a by treatment with
LiAlH4 and NiCl2 furnished 3,4,11-trimethoxydibenz[a, j]-
anthracene (22b). The 1H NMR spectrum of 22b was
consistent with structural assignment as a dibenz[a, j]-
anthracene derivative, exhibiting characteristic singlets
in the aromatic region at δ 8.30 and 9.78 for the H7 and
H14 meso region protons, respectively, and other charac-
teristic proton resonances.
Although the synthesis of 1 from precursors 4 and 5
requires 13 steps, good yields are obtained in all but one
step, and the overall yield of 1 is a respectable 17%. The
lowest yield step is palladium-catalyzed cyclization of 10b
which provides 11a in 60% yield. The alternative benzo-
[c]chrysene structure which could arise by reaction at the
alternative ring position is not formed. The assignment
1
of structure 11a was unequivocally supported by its H
NMR spectrum which exhibited characteristic singlets
in the aromatic region at δ 7.97 and 9.04 for the H7 and
H14 meso region protons. Other proton resonances were
also consistent with the dibenz[a, j]anthracene structure.
The preference for the formation of the dibenz[a, j]anthra-
cene ring system is likely to be, at least partially, a conse-
quence of greater steric hindrance in the more crowded
fjord region of the benzo[c]chrysene structure.15,16
The conversion of 3,4,11-trimethoxydibenz[a, j]anthra-
cene (22b) to trans-3,4-dihydroxy-3,4-dihydro-10-hydroxy-
dibenz[a, j]anthracene (3b) was accomplished via an
initial demethylation with BBr3 to 3,4,10-trihydroxy-
(16) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Wiley-VCH:
New York, 1997.

Dibenz[a,j]anthracene Metabolites
J . Org. Chem., Vol. 63, No. 23, 1998 8129
liquid, bp 78-80 °C/0.6 mmHg (lit.17 75-79 °C/0.2 mmHg):
1H NMR δ 7.28 (d, J ) 7.5 Hz, 1H), 7.20 (d, J ) 7.5 Hz, 1H),
7.14 (t, J ) 7.5, 7.0 Hz, 1H), 4.62 (s, 2H), 2.40 (s, 3H).
It is notable that the photochemical cyclizations of all
of the chloro-substituted compounds, except 15, exhibit
strong preference for reaction at the unsubstituted site
rather than the chloro-substituted position. The preced-
ing paper contains an additional example of the use of a
chloro substituent to direct cyclization to a desired site.5
The effectiveness of choro substituents for this purpose
is surprising in view of previous observations that
indicate that chloro substituents undergo relatively facile
displacement in these types of photocyclizations.15 This
difference may partially derive from differences in the
structures and electronic properties of the polycyclic
aromatic ring systems employed.
(2-Ch lor o-3-m eth ylben zyl)tr iph en ylph osph on iu m Br o-
m id e (5). A solution of 2-chloro-3-methylbenzyl bromide
(18.10 g, 82.5 mmol) and PPh3 (21.60 g, 82.5 mmol) in 200 mL
of toluene was heated at reflux for 6 h. The usual workup
afforded 5 (37.17 g, 94%) as a white solid, mp 250-252 °C
(recrystallized from CH2Cl2-EtOAc): 1H NMR δ 7.71-7.61
(m,15H), 7.39 (d, J ) 7.5 Hz, 1H), 7.16 (d, J ) 7.0 Hz, 1H),
7.03 (t, J ) 7.0, 7.5 Hz, 1H), 5.57 (d, J ) 13.5 Hz, 2H), 2.15 (s,
3H); MS (FAB) m/ e 481 (M+ + 1, 30); 401 (M+ - Br, 100)
(based on Br, 79, Cl, 35, and P, 31). Anal. Calcd for C26H23
-
BrClP: C, 64.82; H, 4.81; Br, 16.59; Cl, 7.36. Found: C, 64.91;
H, 4.85; Br, 16.51; Cl, 7.33.
As a consequence of the mode of synthesis, all the
dihydrodiol derivatives of dibenz[a, j]anthracene whose
syntheses are reported herein (1, 3a ,b) are racemic. It
is likely, on the basis of precedent,8 that the asymmetry
of the two chiral centers of 10b were preserved during
cyclization to 11. However, attempts to convert 11 di-
rectly to the 3,4,8,9-bis(dihydrodiol) (1) via demethylation
with BBr3 were not successful. Thus, it was necessary
to explore an alternative approach which unfortunately
led to loss of asymmetry. This method entails oxidation
to the quinone (12a ). It should be pointed out that the
use of racemic mixtures is not disadvantageous in pre-
liminary biological studies, since it is convenient to assay
the mixture of isomers for activity prior to attempting
their time-consuming separation. If significant biological
activity is found, the isomers may be resolved by methods
devised earlier for separation of other PAH dihydrodiol
isomers, such as resolution on a chiral column.12 They
can then be tested individually for activity.
1-Ch lor o-2-m et h yl-1′,2′-d im et h oxyst ilb en e (6). 1,2-
Dimethoxybenzaldehyde (2.68 g, 16.13 mmol), (2-chloro-3-
methylbenzyl)triphenylphosphonium bromide (8.08 g, 16.77
mmol), and a catalytic amount of 18-crown-6 were dissolved
in 350 mL of CH2Cl2, and 40 mL of 50% NaOH aqueous
solution was added. The reaction mixture was stirred for 5 h
until TLC indicated the absence of the starting aldehyde. The
usual workup and chromatography on a column of silica gel
eluted with hexane/EtOAc (98:2) afforded a mixture of Z- and
E-isomers of 6 (Z:E ) 5 from NMR; Z-isomer, δ 6.89, J ) 12
Hz; E-isomer, δ 7.40, J ) 16 Hz) as white solid, (4.42 g, 95%).
This mixture of olefins was used for photocyclization. Z-
isomer, mp 60-61 °C (EtOAc-hexane): 1H NMR δ 7.09 (d, J
) 7.3 Hz, 1H), 6.99 (d, J ) 6.9 Hz, 1H), 6.91 (d, J ) 7.6 Hz,
1H), 6.89 (d, J ) 12 Hz, 1H), 6.79 (d, J ) 12 Hz, 1H), 6.76-
6.75 (m, 2H), 6.58 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.41 (s,
3H). Anal. Calcd for C17H17ClO2: C, 70.71; H, 5.93; Cl, 12.28.
Found: C, 70.69; H, 5.90; Cl, 12.19.
1-Ch lor o-7,8-dim eth oxy-2-m eth yl-ph en an th r en e (7). Ar-
gon was bubbled through a stirred solution of 6 (1.0 g, 3.46
mmol) and I2 (1.30 g, 5.12 mmol) in 700 mL of Et2O-
cyclohexane (1:1) for 30 min before 10 mL of 1,2-epoxybutane
was added. The solution was irradiated by UV light generated
from Hanovia 400-W medium-pressure lamp with a Vycor
filter, and the argon flow was maintained throughout the
procedure. After 2 h, NMR analysis showed the absence of
the starting material. Solvent was evaporated and CH2Cl2 was
added. The organic layer was washed with an aqueous
solution of NaS2O3 and brine and dried over Na2SO4. Purifica-
tion of the crude product by chromatography on a silica gel
column eluted with hexanes-EtOAc (96:4) afforded 7 (0.90 g,
91%) as a white solid, mp 145.5-146.5 °C (EtOAc-hexane):
1H NMR δ 8.39 (d, J ) 8.0 Hz, 1H), 8.35 (d, J ) 8.5 Hz, 1H),
8.25 (d, J ) 9.5 Hz, 1H), 8.16 (d, J ) 9.5 Hz, 1H), 7.47 (t, J )
8.0 Hz, 1H), 7.36 (d, J ) 8.5 Hz, 1H), 4.05 (s, 6H), 2.64 (s,
3H). Anal. Calcd for C17H15ClO2: C, 71.21; H, 5.27; Cl, 12.36.
Found: C, 71.30; H, 5.29; Cl, 12.27.
2,3-Dim eth oxy-7-m eth ylph en an th r en e (8a). To a stirred
suspension of 7 (670 mg, 2.34 mmol) in 200 mL of freshly
distilled THF was added 1.50 g of NiCl2 (11.57 mmol). Stirring
was continued for 30 min and then 24 mL of a solution of
LiAlH4 in THF (1.0 M) was added dropwise and stirring was
continued for another 5 h at room temperature. Reaction was
quenched by addition of 0.2 mL of water. After being stirred
an additional 20 min, the solution was dried over MgSO4,
concentrated to a small volume, and chromatographed on a
column of silica gel eluted with hexane-CH2Cl2 (6:4) to yield
8a (556.8 mg, 94%) as a white solid, mp 106-108 °C (EtOAc-
hexane): 1H NMR δ 8.48 (d, J ) 8.4 Hz, 1H), 8.39 (d, J ) 8.7
Hz, 1H), 8.07 (d, J ) 9.9 Hz, 1H), 7.68 (d, J ) 9.9 Hz, 1H),
7.65 (s, 1H), 7.46 (d, J ) 8.4 Hz, 1H), 7.37 (d, J ) 8.4 Hz, 1H),
4.03 (s, 3H), 4.01 (s, 3H), 2.54 (s, 3H). Anal. Calcd for
The 3,4,8,9-bis(dihydrodiol) 1 and the 10- and 11-
phenolic derivatives of dibenz[a, j]anthracene (3a ,b) have
been submitted for metabolism, mutagenicity, and for
other biological studies to elucidate the possible role of
these higher oxidized metabolites in the mechanism of
carcinogenesis of dibenz[a, j]anthracene.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. m-Chloroperbenzoic acid (Ald-
rich) was purified by washing with pH 7.4 phosphate buffer
and drying under reduced pressure. THF was freshly distilled
from sodium benzophenone ketyl. 2,3-Dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) was purified by recrystallization from
benzene. N-Bromosuccinimide (NBS) was recrystallized from
water. The 1H NMR spectra were recorded on 300 or 500 MHz
spectrometers in CDCl3 with tetramethylsilane as internal
standard unless stated otherwise. Integration was consistent
with all the molecular structural assignments. The 13C NMR
spectra were recorded on a 125 MHz spectrometer in THF-d8.
Mass spectra (MS) and HRMS were performed by University
of Illinois at Urbana-Champaign School of Chemical Sciences.
TLC was carried out on silica gel sheets with fluorescence
indicator.
Ca u tion ! Dibenz[a, j]anthracene is a weak carcinogen in
animal assays. It and its dihydrodiol and diol epoxide me-
tabolites and their higher oxidized derivatives are potentially
hazardous and should be handled with care in accordance with
“NIH Guidlines for the Laboratory Use of Chemical Carcino-
gens”.
2-Ch lor o-3-m eth ylben zyl Br om ide. A solution of 2-chloro-
m-xylene (20.0 g, 142 mmol), NBS (25.6 g, 144 mmol), and
benzyol peroxide (0.58 g, 2.39 mmol) in 300 mL of CCl4 was
heated at reflux for 6 h. The reaction mixture was cooled to
room temperature, and filtered, and the CCl4 was removed
under reduced pressure. Distillation of the product gave
2-chloro-3-methylbenzyl bromide (24.6 g, 84%) as a colorless
C
17H16O2: C, 80.93; H, 6.39. Found: C, 80.95; H, 6.48.
2-(Br om om eth yl)-7,8-d im eth oxyp h en a n th r en e (8b). A
solution of 8a (2.40 g, 9.51 mmol), NBS (1.76 g, 9.89 mmol),
and benzoyl peroxide (41.2 mg, 0.17 mmol) in 300 mL of CCl4
(17) Bedard, T. C.; Corey, J . Y.; Lange, L. D.; Rah, N. P. J .
Organomet. Chem. 1991, 401, 261.

8130 J . Org. Chem., Vol. 63, No. 23, 1998
Zhang et al.
was heated at reflux for 2 days. Then the reaction mixture
was cooled to room temperature, filtered, and then evaporated
to dryness. Chromatography of the product on a silica gel
column eluted with hexanes-EtOAc (96:4) furnished 8b (2.23
g, 71%) as a white solid, mp 150-152 °C (EtOAc-hexane):
1H NMR δ 8.57 (d, J ) 8.5 Hz, 1H), 8.41 (d, J ) 10 Hz, 1H),
8.11 (d, J ) 8.5 Hz, 1H), 7.86 (s 1H), 7.71 (d, J ) 10 Hz, 1H),
7.66 (d, J ) 8.5 Hz, 1H), 7.39 (d, J ) 10 Hz, 1H), 4.71 (s, 2H),
4.03 (s, 3H), 4.02 (s, 3H). Anal. Calcd for C17H15BrO2: C,
61.65; H, 4.57; Br, 24.13. Found: C, 61.58; H, 4.59; Br, 24.21.
2-(7,8-Dim et h oxyp h en a n t h r yl)m et h ylt r ip h en ylp h os-
p h on iu m Br om id e (8c). A solution of 8b (220 mg, 0.664
mmol) and PPh3 (175 mg, 0.667 mmol) in 10 mL of toluene
was heated at reflux overnight. Conventional workup afforded
8c (379.3 mg, 96%) as white solid, mp 263-265 °C: 1H NMR
δ 8.30 (d, J ) 8.7 Hz, 1H), 8.26 (d, J ) 8.7 Hz, 1H), 8.00 (d, J
) 9.9 Hz, 1H), 7.82 (d, J ) 7.2 Hz, 1H), 7.78-7.45 (m, 16H),
7.39 (d, J ) 9.6 Hz, 1H), 7.33 (d, J ) 9.6 Hz, 1H), 5.68 (d, J )
15 Hz, 2H), 4.01 (s, 3H), 3.98 (s, 3H).
1H), 6.43 (d, J ) 5.0 Hz, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 2.10
(s, 3H), 2.04 (s, 3H). Anal. Calcd for C28H25BrO6: C, 62.58;
H, 4.69; Br, 14.87. Found: C, 62.59; H, 4.71; Br, 14.99.
tr a n s-8,9-Dia cetoxy-8,9-d ih yd r o-3,4-d im eth oxyd iben z-
[a , j]a n th r a cen e (11a ). A suspension of 10b (554 mg, 1.03
mmol), Pd(PPh3)2Cl2 (35 mg, 0.0499 mmol), and NaOAc (160.7
mg, 1.96 mmol) in 6.5 mL of N,N-dimethylacetamide was
heated for 1 day at 140 °C. After being cooled to room
temperature, the reaction mixture was diluted with EtOAc,
washed with water, and dried over Na2SO4. The solution was
concentrated and chromatographed on a silica gel column
eluted with hexanes-EtOAc (7:3) to provide 11a (282 mg, 60%)
as a white solid, mp 254-256 °C (triturated with EtOAc): 1H
NMR δ 9.04 (s, 1H), 8.54 (d, J ) 10 Hz, 1H), 8.16 (d, J ) 7.0
Hz, 1H), 8.12 (d, J ) 10 Hz, 1H), 7.97 (s, 1H), 7.75 (d, J ) 10
Hz, 1H), 7.57 (t, J ) 7.5, 8.5 Hz, 1H), 7.55 (d, J ) 7.5 Hz, 1H),
7.42 (d, J ) 9.5 Hz, 1H), 7.40 (t, J ) 8.0 Hz, 1H), 6.28 (d, J )
5.0 Hz, 1H), 6.16 (d, J ) 5.0 Hz, 1H), 4.06 (s, 3H), 4.03 (s,
3H), 2.03 (s, 3H), 1.98 (s, 3H). Anal. Calcd for C28H24O6: C,
73.67; H, 5.30. Found: C, 73.77; H, 5.27.
1-(2-Br om op h en yl)-2-[2-(7,8-d im eth oxyp h en a n th r yl)]-
eth en e (9). The phosphonium salt 8c (379.3 mg, 0.639 mmol),
2-bromobenzaldehyde (119 mg, 0.643 mmol), and a catalytic
amount of 18-crown-6 were dissolved in 15 mL of CH2Cl2, and
1.8 mL of a 50% aqueous solution of NaOH was added. The
reaction mixture was stirred overnight. The usual workup
followed by chromatography on a column of silica gel eluted
with hexane-CH2Cl2 (6:4) gave 9 (246.5 mg, 92%) as a mixture
of E- and Z-isomers which was converted to the E-isomer by
refluxing in heptane in the presence of a crystal of I2 for 1 day
(96% recovery). Z-isomer, white solid, mp 111-113 °C (CH2-
Cl2-hexane): 1H NMR δ 8.35 (d, J ) 9.5 Hz, 1H), 8.32 (d, J )
9.5 Hz, 1H), 8.04 (d, J ) 9.5 Hz, 1H), 7.66 (s, 1H), 7.63 (d, J
) 10 Hz, 1H), 7.58 (d, J ) 9.5 Hz, 1H), 7.37 (d, J ) 10 Hz,
1H), 7.33 (d, J ) 8.5 Hz, 1H), 7.24 (d, J ) 7.5 Hz, 1H), 7.12 (t,
J ) 7.5 Hz, 1H), 7.06 (t, J ) 7.5 Hz, 1H), 6.89 (d, J ) 12.0 Hz,
1H), 6.73 (d, J ) 12.0 Hz, 1H), 4.02 (s, 3H), 4.00 (s, 3H). Anal.
Calcd for C24H19BrO2: C, 68.74; H, 4.57; Br, 19.06. Found:
C, 68.69; H, 4.61; Br, 18.94. E-isomer, white solid, mp 157-
159 °C (EtOAc-hexane): 1H NMR: δ 8.59 (d, J ) 9.0 Hz, 1H),
8.42 (d, J ) 9.5 Hz, 1H), 8.11 (d, J ) 9.5 Hz, 1H), 7.95 (s, 1H),
7.89 (d, J ) 9.0 Hz, 1H), 7.76 (d, J ) 9.5, Hz, 1H), 7.74 (d, J
) 8.0 Hz, 1H), 7.65 (d, J ) 16.5 Hz, 1H), 7.62 (d, J ) 7.5 Hz,
1H), 7.40 (d, J ) 9.0 Hz, 1H), 7.35 (t, J ) 7.5 Hz, 1H), 7.25 (d,
J ) 16 Hz, 1H), 7.15 (t, J ) 7.5 Hz, 1H), 4.02 (s, 3H), 4.00 (s,
3H). Anal. Calcd for C24H19BrO2: C, 68.74; H, 4.57; Br, 19.06.
Found: C, 68.84; H, 4.63; Br, 19.12.
tr a n s-8,9-Dih yd r oxy-8,9-d ih ydr o-3,4-dim eth oxyd iben z-
[a , j]a n th r a cen e (11b). A solution of 11a (210 mg, 0.46
mmol) and MeONa (75 mg, 1.39 mmol) in MeOH (75 mL) and
THF (30 mL) was heated at reflux for 15 min. The usual
workup gave 11b (155 mg, 95%) as a yellow solid, mp 206-
208 °C: 1H NMR δ 8.90 (s, 1H), 8.50 (d, J ) 9.0 Hz, 1H), 8.09
(s, 1H), 8.07 (d, J ) 9.2 Hz, 1H), 8.04 (d, J ) 7.6 Hz, 1H), 7.75
(d, J ) 8.9 Hz, 1H), 7.73 (d, J ) 7.2 Hz, 1H), 7.50 (t, J ) 6.6,
7.7 Hz, 1H), 7.44 (t, J ) 7.4 Hz, 1H), 7.39 (d, J ) 9.0 Hz, 1H),
4.92 (d, J ) 10 Hz, 1H), 4.83 (d, J ) 10 Hz, 1H), 4.04 (s, 3H),
4.03 (s, 3H). Anal. Calcd for C24H20O4: C, 77.40; H, 5.41.
Found: C, 77.39; H, 5.47.
3,4-Dim eth oxyd iben z[a , j]a n th r a cen e-8,9-d ion e (12a ).
A solution of 11b (150 mg, 0.40 mmol) and DDQ (602 mg, 2.65
mmol) in 70 mL of wet THF (1% H2O) was stirred for 2 days
at room temperature. After removal of about 50% of the
solvent under vacuum, water was added. The orange solid
was collected and purified by column chromatography on
Florisil to yield 12a (136 mg, 92%), mp 289-291 °C: 1H NMR
δ 9.17 (s, 1H), 8.73 (s, 1H), 8.55 (d, J ) 9.1 Hz, 1H), 8.34 (d, J
) 8.1 Hz, 1H), 8.27 (dd, J ) 8.0, 1.6 Hz, 1H), 8.18 (d, J ) 9.2,
1H), 7.82 (t, J ) 7.2 Hz, 1H), 7.80 (d, J ) 9.0 Hz, 1H), 7.51 (t,
J ) 7.2, 8.0 Hz, 1H), 7.46 (d, J ) 9.2 Hz, 1H), 4.08 (s, 3H),
4.04 (s, 3H); MS m/e 368 (M+, 100). HRMS calcd for C24H16O4
368.1049, found 368.1050. Anal. Calcd for C24H16O2: C, 78.25;
H, 4.38. Found: C, 77.59; H, 4.40.
1-(2-Br om op h en yl)-1,2-d ih yd r oxy-2-(7,8-d im et h oxy-
p h en a n th r yl)eth a n e (10a ). A solution of 9 (1.4 g, 3.34
mmol), AD-mix-â (5.0 g), and CH3SO2NH2 (320 mg, 3.36 mmol)
in 65 mL of t-BuOH-H2O (1:1) was stirred for 24 h at room
temperature. Then Na2SO3 (5.57 g) and KOH (1.78 g) were
added, and the reaction mixture was stirred for another 3 h.
The solution was diluted with EtOAc, and the organic layer
was washed with water and dried over Na2SO4. The solution
was concentrated to a small volume and chromatographed on
a silica gel column eluted with EtOAc-hexane (2:8) to furnish
10a (1.41 g, 93%) as a white solid, mp 161-163 °C: 1H NMR
δ 8.51 (d, J ) 8.6 Hz, 1H), 8.38 (d, J ) 9.0 Hz, 1H), 8.07 (d, J
) 9.1 Hz, 1H), 7.84 (s, 1H), 7.68 (d, J ) 9.1 Hz, 1H), 7.66 (d,
J ) 8.5 Hz, 1H), 7.60 (d, J ) 8.5 Hz, 1H), 7.48 (d, J ) 8.0 Hz,
1H), 7.38 (t, J ) 7.5 Hz, 1H), 7.36 (d, J ) 9.1 Hz, 1H), 7.16 (t,
J ) 7.6 Hz, 1H), 5.35 (t, J ) 4.4 Hz, 1H), 5.10 (t, J ) 4.4 Hz,
1H), 4.03 (s, 3H), 4.01 (s, 3H). Anal. Calcd for C24H21BrO4:
C, 63.59; H, 4.67; Br, 17.63. Found: C, 63.66; H, 4.70; Br,
17.71.
1-(2-Br om op h e n yl)-1,2-d ia ce t oxy-2-(7,8-d im e t h oxy-
p h en a n th r yl)]eth a n e (10b). A solution of 10a (92.3 mg,
0.204 mmol) and DMAP (5 mg) in 160 µL of Ac2O and 3 mL of
pyridine was stirred overnight at room temperature. Con-
ventional workup gave 10b (108.6 mg, 94%) as a white solid,
mp 130-132 °C: 1H NMR δ 8.49 (d, J ) 8.5 Hz, 1H), 8.38 (d,
J ) 8.5 Hz, 1H), 8.09 (d, J ) 10 Hz, 1H), 7.78 (s, 1H), 7.68 (d,
J ) 8.5 Hz, 1H), 7.56 (d, J ) 7.5 Hz, 1H), 7.47 (d, J ) 7.5 Hz,
1H), 7.45 (d, J ) 8.5 Hz, 1H), 7.37 (d, J ) 9.5 Hz, 1H), 7.30 (t,
J ) 7.5 Hz, 1H), 7.13 (t, J ) 7.5 Hz, 1H), 6.61 (d, J ) 4.5 Hz,
tr a n s-3,4-tr a n s-8,9-Tetr a h yd r oxy-3,4,8,9-tetr a h yd r od i-
ben z[a , j]a n t h r a cen e (1). Compound 11b (120 mg, 0.326
mmol) was dissolved in 200 mL of CH2Cl2, and 6.4 mL of BBr3
in CH2Cl2 (1.0 M) was added dropwise at 0 °C. The solution
was stirred for 1.5 h at room temperature, and then reaction
was quenched by addition of 0.2 mL of water. The solvent
was removed under reduced pressure, and then EtOAc was
added and the organic layer was washed with water, dried
over Na2SO4, and evaporated to dryness, minimizing contact
with air. The 1H NMR spectrum of the air-sensitive residue
confirmed demethylation to be complete and was consistent
with assignment as 12b: 1H NMR (acetone-d6) δ 9.47 (s, 1H),
8.71 (d, J ) 8.0 Hz, 1H), 8.65 (s, 1H), 8.55 (d, J ) 8.8 Hz, 1H),
8.24 (d, J ) 9.1 Hz, 1H), 8.13 (d, J ) 7.9 Hz, 1H), 7.88 (d, J )
9.2 Hz, 1H), 7.85 (t, J ) 8.4 Hz, 1H), 7.56 (t, J ) 7.5 Hz, 1H),
7.40 (d, J ) 8.8 Hz, 1H).
A suspension of 12b and NaBH4 (680 mg,18.0 mmol) in 150
mL of EtOH was stirred at room temperature with O2 bubbling
through the solution for 24 h. Following removal of EtOH
under vacuum, water was added, and the aqueous suspension
was extracted with EtOAc-THF. The combined organic
extracts were washed with brine, dried over Na2SO4, and
evaporated to dryness. The crude 1 was purified by chro-
matograpy on Florisil to furnish pure 1 (85 mg,76%) as a white
solid, mp 225-227 °C: 1H NMR (DMSO-d6) δ 8.54 (d, J ) 7.7
Hz, 1H), 8.15 (dd, J ) 6.5, 7.3 Hz, 1 H), 8.02 (d, J ) 2.0 Hz,
1H), 7.82 (d, J ) 8.4 Hz, 1H), 7.71 (d, J ) 8.3 Hz, 1 H), 7.63
(d, J ) 7.2 Hz, 1H), 7.49-7.35 (m, 3H), 6.14 (d, J ) 10 Hz,
1H), 5.75 (dd, J ) 5.0, 5.0 Hz, exchangeable with D2O, 1H),

Dibenz[a,j]anthracene Metabolites
J . Org. Chem., Vol. 63, No. 23, 1998 8131
5.67 (dd, J ) 5.0, 5.15 Hz, exchangeable with D2O, 1H), 5.56
(dd, J ) 4.8, 4.85 Hz, exchangeable with D2O, 1H), 5.23 (dd, J
) 1.5, 5.1 Hz, exchangeable with D2O, 1H), 4.70-4.67 (br, 1H,
after addition of D2O changed to doublet, J ) 11.0 Hz), 4.56
(br, 1H, after addition of D2O changed to doublet, J ) 8.6 Hz),
4.49 (br, 1H, after addition of D2O changed to doublet, J )
9.50 Hz), 4.34-4.32 (br, 1H, after addition of D2O changed to
doublet, J ) 8.8 Hz); 13C NMR (THF-d8) δ 74.31, 74.40, 74.45,
74.54, 76.42, 76.46, 118.11, 122.66, 124.13, 124.54, 124.60,
125.24, 125.29, 126.11, 126.12, 127.84, 128.29, 128.59, 128.72,
132.56, 132.61, 133.82, 133.86, 133.91, 134.55, 134.57, 136.98,
139.86; MS m/e 346 (M+, 50), 328 (M+ - H2O, 100); HRMS
calcd for C22H18O4 346.1218, found 346.1214; UV (EtOH) λmax
(ꢀ) 207.3 (1.21 × 105), 252.3 (5.47 × 104), 276.2 (5.92 × 104),
334.6 (2.23 × 104) nm. HPLC on a reverse phase ZORBAX
ODS column (9.4 × 25 cm) eluted with a linear gradient of
50% aqueous MeOH to 100% MeOH (in 15 min) with a flow
rate of 4.0 mL/min showed the product to be a mixture of two
isomers with retention times 6.3 and 6.6 min, respectively.
Compound 1 was further characterized by conversion to its
tetraacetate with Ac2O and pyridine. 1-tetraacetate, mp 201-
204 °C (dec): 1H NMR δ 8.60 (s, 1H), 8.06 (d, J ) 7.7 Hz, 1H),
7.97 (d, J ) 2.8 Hz, 1 H), 7.81 (d, J ) 8.4 Hz, 1 H), 7.59 (d, J
) 10.2 Hz, 1 H), 7.51-7.54 (m, 2H), 7.48 (dd, J ) 8.4, 3.3 Hz,
1H), 7.40 (t, J ) 7.5 Hz, 1H), 6.29-6.32 (m, 2H), 6.24 (d, J )
4.9 Hz, 1H), 6.12 (dd, J ) 1.6, 4.8 Hz, 1H), 5.64 (m, 1H), 2.13
(s, 1.5 H), 2.12 (s, 1.5 H), , 2.060 (s, 1.5 H), 2.058 (s, 1.5 H),
2.00 (s, 1.5 H), 1.99 (s, 1.5 H), 1.964 (s, 1.5 H), 1.962 (s, 1.5
H); MS m/e 514 (M+, 11), 310 (100); HRMS calcd for C30H26O8
514.1628, found 514.1637.
1-Ch lor o-2-m eth yl-1′-m eth oxystilben e (13). Reaction of
o-anisaldehyde (4.05 g, 29.0 mmol) with 5 (14.60 g, 30.3 mmol)
by the procedure employed for preparation of 6 (16 h) gave
13. Purification by chromatography on a column of silica gel
eluted with hexanes-EtOAc (98:2) afforded a mixture of Z-
and E-isomers of 13 (Z/ E ) 5 by NMR; Z-isomer, δ 6.77, J )
12 Hz; E-isomer, δ 7.44, J ) 16 Hz) as a white solid (7.51 g,
98%). This mixture was used for photocyclization. Z-isomer,
mp 75.5-76.5 °C (EtOAc-hexane): 1H NMR δ 7.17 (t, J )
7.0, 8.5 Hz, 1H), 7.06 (d, J ) 7.0 Hz, 1H), 6.97-6.99 (m, 2H),
6.89 (d, J ) 7.5 Hz, 1H), 6.86 (d, J ) 8.5 Hz, 1H), 6.84 (d, J )
12 Hz, 1H), 6.77 (d, J ) 12 Hz, 1H), 6.68 (t, J ) 7.0, 7.5 Hz,
1H), 3.83 (s, 3H), 2.41 (s, 3H); MS m/e 258 (M+, 100) (based
on Cl, 35). Anal. Calcd for C16H15ClO: C, 74.27; H, 5.84; Cl,
13.70. Found: C, 74.37; H, 5.91; Cl, 13.57.
(d, J ) 8.5 Hz, 1H), 8.29 (d, J ) 9.5 Hz, 1H), 8.16 (d, J ) 8.5
Hz, 1H), 7.89 (d, J ) 9.5 Hz, 1H), 7.86 (d, J ) 8.5 Hz, 1H),
7.60-7.80 (m, 16H), 7.06 (d, J ) 8.5 Hz, 1H), 5.95 (d, J ) 13.5
Hz, 2H), 4.05 (s, 3H); MS (FAB) 517 (M+ - Br, 100, based on
Br, 79, Cl, 35, and P, 31). Anal. Calcd for C34H27BrClOP: C,
68.30; H, 4.55; Br, 13.36; Cl, 5.93. Found: C, 68.04; H, 4.53;
Br, 13.46; Cl, 5.97.
1-(1-Ch lor o-8-m eth oxy-2-p h en a n th r yl)-2-(2′,3′-d im eth -
oxyp h en yl)eth en e (15). Wittig reaction of 14c (0.80 g, 1.34
mmol) with 2,3-dimethoxybenzaldehyde (0.22 g, 1.32 mmol)
was carried out by the procedure employed for preparation of
9 and worked up in similar manner. Compound 15 (0.48 g,
90%) was obtained as a white solid consisting principally of
the Z-isomer with only traces of the E-isomer. Z-isomer, white
solid, mp 160-162 °C (EtOAc-hexane): 1H NMR δ 8.35 (d, J
) 9.5 Hz, 1H), 8.32 (d, J ) 8.0 Hz, 1H), 8.30 (d, J ) 9.5 Hz,
1H), 8.14 (d, J ) 8.5 Hz, 1H), 7.55 (t, J ) 8.0 Hz, 1H), 7.39 (d,
J ) 8.5 Hz, 1H), 7.03 (d, J ) 2.5 Hz, 2H), 7.01 (d, J ) 7.5 Hz,
1H), 6.77 (dd, J ) 1.5, 8.0 Hz, 1H), 6.71 (t, J ) 8.0 Hz, 1H),
6.59 (dd, J ) 1.5, 8.0 Hz, 1H), 4.05 (s, 3H), 3.92 (s, 3H), 3.87
(s, 3H); MS m/e 404 (M+, 15), 256 (100, based on Cl, 35). Anal.
Calcd for C25H21ClO3: C, 74.16; H, 5.23; Cl, 8.76. Found: C,
74.05; H, 5.28; Cl, 8.75.
7-Ch lor o-3,4,10-tr im eth oxydiben z[a , j]an th r acen e (16a).
Photocyclization of 15 (205 mg, 0.506 mmol) by the procedure
employed for preparation of 7 and 14a and flash chromatog-
raphy on a silica gel column eluted with hexane-CH2Cl2 (6:4)
gave initially 17 (56 mg, 30%) as a yellow solid, mp 154-155
1
°C: H NMR δ 8.98 (d, J ) 9.5 Hz, 1H), 8.82 (d, J ) 9.3 Hz,
1H), 8.76 (d, J ) 8.7 Hz, 1H), 8.41 (d, J ) 8.0 Hz, 1H), 8.39 (d,
J ) 9.2 Hz, 1H), 8.27 (d, J ) 8.9 Hz, 1H), 8.01 (d, J ) 8.6 Hz,
1H), 7.88 (d, J ) 8.9 Hz, 1H), 7.64 (t, J ) 8.1 Hz, 1H), 7.43 (d,
J ) 9.3 Hz, 1H), 7.06 (d, J ) 7.8 Hz, 1H), 4.10 (s, 3H), 4.09 (s,
3H), 4.08 (s, 3H). Anal. Calcd for C25H20O3: C, 81.50; H, 5.47.
Found: C, 81.24; H, 5.56. Further elution gave 16a (74 mg,
36%) as a yellow solid, mp 283-284 °C (CH2Cl2-hexane): 1H
NMR δ 9.77 (s, 1H), 8.60 (d, J ) 9.0 Hz, 1H), 8.46 (d, J ) 8.5
Hz, 1H), 8.33 (d, J ) 9.5 Hz, 1H), 8.32 (d, J ) 9.5 Hz, 1H),
8.25 (d, J ) 9.5 Hz, 1H), 8.13 (d, J ) 9.0 Hz, 1H), 7.58 (t, J )
8.0 Hz, 1H), 7.36 (d, J ) 9.0 Hz, 1H), 7.03 (d, J ) 8.0 Hz, 1H),
4.03 (s, 6H), 4.01 (s, 3H); MS m/e 402 (M+, 100, based on Cl,
35); HRMS Calcd for C25H19ClO3 402.1023, found 402.1023.
Anal. Calcd for C25H19ClO3: C, 74.52; H, 4.75; Cl, 8.80.
Found: C, 73.95; H, 4.80; Cl, 8.73.
3,4,10-Tr im eth oxydiben z[a , j]an th r acen e (16b). Dechlo-
rination of 16a (121 mg, 0.30 mmol) by the procedure employed
for preparation of 8a afforded 16b (96.5 mg, 92%) as a white
solid, mp 242-243 °C (EtOAC-hexane): 1H NMR δ 9.79 (s,
1H), 8.62 (d, J ) 8.5 Hz, 1H), 8.50 (d, J ) 8.0 Hz, 1H), 8.25 (s,
1H), 8.15 (d, J ) 9.0 Hz, 1H), 8.02 (d, J ) 9.0 Hz, 1H), 7.78
(m, 2H), 7.59 (t, J ) 8.0 Hz, 1H), 7.34 (d, J ) 8.5 Hz, 1H),
7.01 (d, J ) 8.0 Hz, 1H), 4.02 (s, 6H), 4.01 (s, 3H); MS m/e 368
(M+, 100). Anal. Calcd for C25H20O3: C, 81.50; H, 5.47.
Found: C, 81.39; H, 5.52.
3,4,10-Tr ih yd r oxyd ib en z[a , j]a n t h r a cen e (16c). De-
methylation of 16b (102 mg, 0.28 mmol) with BBr3 by the
procedure employed for the preparation of 12b provided 16c
(81 mg, 90%): 1H NMR (CD3COCD3): δ 10.02 (s, 1H), 8.66 (d,
J ) 8.1 Hz, 1H), 8.60 (d, J ) 8.7 Hz, 1H), 8.40 (s, 1H), 8.19 (d,
J ) 8.4 Hz, 1H), 8.16 (d, J ) 7.2 Hz, 1H), 7.86 (d, J ) 6.3 Hz,
1H), 7.84 (d, J ) 9.0 Hz, 1H), 7.53 (t, J ) 7.8, 8.1 Hz, 1H),
7.36 (d, J ) 8.7 Hz, 1H), 7.14 (d, J ) 7.5 Hz, 1H). In the view
of the air sensitivity of 16c, its exposure to air was kept to a
minimum, and it was isolated and characterized as its di-
acetate.
3,4,10-Tr ia cetoxyd iben z[a , j]a n th r a cen e (16d ). A solu-
tion of 16c (80.7 mg) in 0.5 mL of Ac2O and 2.0 mL of pyridine
was stirred overnight at room temperature. The usual workup
gave 16d (95.2 mg, 85%) as a white solid, mp 255-257 °C (CH2-
Cl2-hexane): 1H NMR δ 9.76 (s, 1H), 8.74 (d, J ) 8.5 Hz, 2H),
8.22 (s, 1H), 7.79 (m, 2H), 7.72 (d, J ) 9.0 Hz, 1H), 7.65 (m,
2H), 7.51 (d, J ) 9.0 Hz, 1H), 7.36 (d, J ) 7.5 Hz, 1H), 2.49 (s,
3H), 2.48 (s, 3H), 2.37 (s, 3H); MS m/e 452 (M+, 40), 326 (100).
Anal. Calcd for C28H20O6: C, 74.33; H, 4.46. Found, C, 74.21;
H, 4.46.
1-Ch lor o-2-m eth yl-8-m eth oxyph en an th r en e (14a). Pho-
tocyclization of 13 (1.03 g, 3.98 mmol) in the presence of I2
and 1,2-epoxybutane by the procedure employed for prepara-
tion of 7 (10 h) gave crude 14a . This was purified by
chromatography on a silica gel column eluted with hexanes-
EtOAc (96:4). Pure 14a (0.91 g, 92%) was obtained as a white
solid, mp 151-152 °C (EtOAc-hexane): 1H NMR δ 8.48 (d, J
) 8.5 Hz, 1H), 8.32 (d, J ) 9.5 Hz, 1H), 8.26 (d, J ) 9.5 Hz,
1H), 8.21 (d, J ) 8.0 Hz, 1H), 7.57 (t, J ) 8.0 Hz, 1H), 7.49 (d,
J ) 8.5 Hz, 1H), 7.01 (d, J ) 8.0 Hz, 1H), 4.07 (s, 3H), 2.66 (s,
3H); MS m/e 256 (M+, 100 based on Cl, 35). Anal. Calcd for
C
16H13ClO: C, 74.85; H, 5.10; Cl, 13.81. Found: C, 74.72; H,
5.17; Cl, 13.82.
2-Br om om eth yl-1-ch lor o-8-m eth oxyph en an th r en e (14b).
Bromination of 14a (1.10 g, 4.28 mmol) with NBS (0.76 g, 4.27
mmol) by the procedure employed for the preparation of 8b
(reaction time 16 h) gave 14b (1.23 g, 87%) as a yellow solid,
mp 161-163 °C (EtOAc-hexane): 1H NMR δ 8.57 (d, J ) 8.5
Hz, 1H), 8.36 (d, J ) 9.0 Hz, 1H), 8.26 (d, J ) 9.5 Hz, 1H),
8.21 (d, J ) 8.5 Hz, 1H), 7.66 (d, J ) 8.5 Hz, 1H), 7.60 (t, J )
8.0 Hz, 1H), 7.05 (d, J ) 7.5 Hz, 1H), 4.88 (s, 2H), 4.08 (s,
3H); MS m/e 336 (M+ + 2, 27); 255 (M+ - Br, 100, based on
Br, 79, and, Cl, 35). Anal. Calcd for C16H12BrClO, C, 57.26;
H, 3.60; Br, 23.81; Cl, 10.56. Found, C, 57.09; H, 3.56; Br,
23.93; Cl, 10.62.
2-(1-Ch lor o-8-m eth oxyp h en a n th r ylm eth yl)tr ip h en yl-
p h osp h on iu m Br om id e (14c). Reaction of 14b (0.76 g, 2.26
mmol) with PPh3 (0.60 g, 2.29 mmol) by the procedure
employed for preparation of 8c furnished 14c (1.35 g, 91%) as
a white solid, mp 289-290 °C (darkening): 1H NMR δ 8.48

8132 J . Org. Chem., Vol. 63, No. 23, 1998
Zhang et al.
tr a n s-3,4,-Dih yd r oxy-3,4-d ih yd r o-10-h yd r oxyd ib en z-
[a , j]a n th r a cen e (3a ). Reduction of 16d (42.0 mg, 0.093
mmol) with NaBH4/O2 in EtOH was carried out by the
procedure employed for the preparation of 1 (reaction time 3
days). Compound 3a (23.7 mg, 78%) was obtained as a yellow
solid, mp 270-272 °C: 1H NMR (CD3COCD3) δ 9.59 (s, 1H),
9.05 (s, 0.6 H, exchangeable with D2O), 8.58 (d, J ) 8.0 Hz,
1H), 8.45 (s, 1H), 8.11 (d, J ) 9.5 Hz, 1H), 8.04 (d, J ) 8.0 Hz,
1H), 7.92 (d, J ) 8.5 Hz, 1H), 7.80 (d, J ) 9.0 Hz, 1H), 7.69
(dd, J ) 2.5, 10.0 Hz, 1H), 7.49 (t, J ) 8.0 Hz, 1H), 7.12 (d, J
) 8.0 Hz, 1H), 6.29 (dd, J ) 2.5, 10.0 Hz, 1H), 4.92 (dd, J )
5.5, 12 Hz, 1H), 4.69 (d, J ) 5.5 Hz, 0.6 H, exchangeable with
D2O), 4.54 (dd, J ) 5.5, 12 Hz, 1H), 4.35 (d, J ) 5.5 Hz, 0.6 H,
exchangeable with D2O); 13C NMR (THF-d8) δ 74.48, 76.60,
112.04, 115.05, 117.71, 121.78, 122.78, 124.23, 125.97, 127.78,
127.82, 127.85, 128.60, 128.72, 128.96, 130.00, 131.32, 132.73,
133.23, 134.72, 136.73, 155.15; MS m/e 328 (M+, 35), 310 (M+
- H2O, 100); HRMS calcd for C22H16O3 328.1099, found
1H), 6.55 (d, J ) 8.0 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.84
(s, 3H); MS m/e 404 (M+, 100, based on Cl, 35). Anal. Calcd
for C25H21ClO3: C, 74.16; H, 5.23, Cl, 8.76. Found: C, 74.01;
H, 5.28; Cl, 8.68.
7-Ch lor o-3,4,11-tr im eth oxydiben z[a , j]an th r acen e (22a).
Photocyclization of 21 (172 mg, 0.43 mmol) by the procedure
employed for preparation of 14a and 19a (3 h) provided 22a
(77 mg, 45%) as a white solid, mp 250-252 °C (EtOAc-
hexane): 1H NMR δ 9.79 (s, 1H), 8.87 (d, J ) 9.5 Hz, 1H),
8.70 (d, J ) 9.0 Hz, 1H), 8.42 (d, J ) 9.5 Hz, 1H), 8.41 (d, J )
9.5 Hz, 1H), 8.19 (d, J ) 9.5 Hz, 1H), 7.79 (d, J ) 9.5 Hz, 1H),
7.44 (d, J ) 9.5 Hz, 1H), 7.38 (dd, J ) 2.6, 9.0 Hz, 1H), 7.31
(d, J ) 2.6 Hz, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 4.00 (s, 3H); MS
m/e 402 (M+, 100, based on Cl, 35); HRMS calcd for C25H19
-
ClO3 402.1023, found 402.1023.
3,4,11-Tr im eth oxyd iben z[a , j]a n th r a cen e (22b). Reduc-
tion of 22a (105 mg, 0.26 mmol) with NiCl2 (170 mg, 1.31
mmol) and 2.6 mL of LiAlH4 in THF (1.0 M) by the procedure
employed for reduction of 16a furnished 22b (86.8 mg, 90%)
as a white solid, mp 184-186 °C (EtOAC-hexane): 1H NMR
δ 9.78 (s, 1H), 8.88 (d, J ) 10 Hz, 1H), 8.70 (d, J ) 10 Hz,
1H), 8.30 (s, 1H), 8.08 (d, J ) 8.5 Hz, 1H), 7.85 (d, J ) 8.5 Hz,
2H), 7.66 (d, J ) 9.5 Hz, 1H), 7.41 (d, J ) 8.5 Hz, 1H), 7.36
(dd, J ) 2.5, 8.5 Hz, 1H), 7.30 (d, J ) 2.5 Hz, 1H), 4.07 (s,
3H), 4.05 (s, 3H), 4.00 (s, 3H); MS m/e 368 (M+, 100). Anal.
Calcd for C25H20O3: C, 81.50; H, 5.47. Found: C, 81.42; H, 5.51.
3,4,11-Tr ih yd r oxyd ib en z[a , j]a n t h r a cen e (22c). De-
methylation of 22b (76 mg, 0.21 mmol) with BBr3 by the
procedure employed for preparation of 12b gave 22c (58.5 mg,
87%) used directly in the next step: 1H NMR (CD3COCD3) δ
9.95 (s, 1H), 9.06 (d, J ) 9.0 Hz, 1H), 8.81 (s, 0.5 H,
exchangeable with D2O), 8.71 (br, 0.5 H, exchangeable with
D2O), 8.62 (d, J ) 8.5 Hz, 1H), 8.38 (s, 1H), 8.14 (d, J ) 9.0
Hz, 1H), 7.91 (br, 0.5 H, exchangeable with D2O), 7.87 (d, J )
9.5 Hz, 1H), 7.84 (d, J ) 9.5 Hz, 1H), 7.65 (d, J ) 8.5 Hz, 1H),
7.35 (d, J ) 9.0 Hz, 1H), 7.34 (d, J ) 2.5 Hz, 1H), 7.31 (dd, J
) 2.5, 9.0 Hz, 1H).
In the view of its air sensitivity, 22c was isolated and
characterized as its diacetate. Acetylation of 22c (58 mg) of
0.5 mL of Ac2O in 2.0 mL of pyridine overnight at room
temperature gave 22c diacetate (64 mg, 85%) as a white solid,
mp 267-269 °C: 1H NMR δ 9.90 (s, 1H), 8.99 (d, J ) 10 Hz,
1H), 8.90 (d, J ) 10 Hz, 1H), 8.37 (s, 1H), 7.93 (d, J ) 9.5 Hz,
1H), 7.89 (d, J ) 8.5 Hz, 1H), 7.76 (d, J ) 8.5 Hz, 1H), 7.71 (d,
J ) 10 Hz, 1H), 7.66 (d, J ) 2.5 Hz, 1H), 7.60 (d, J ) 9.0 Hz,
1H), 7.51 (dd, J ) 2.5, 10 Hz), 2.51 (s, 3H), 2.41 (s, 3H), 2.40
(s, 3H); MS, m/e 452 (M+, 34), 326 (100); HRMS calcd for
328.1100; UV (EtOH) λ
(ꢀ) 249 (5.25 × 104), 295 (4.35 ×
max
104), 320 (1.83 × 104) nm.
1-Ch lor o-2-m eth yl-2′-m eth oxystilben e (18). Reaction of
m-anisaldehyde (4.02 g, 29.5 mmol) with 5 (14.20 g, 29.5 mmol)
by the procedure employed for preparation of 6 (16 h) gave 18
as a mixture of Z- and E-isomers (Z/E ) 5 by NMR; Z-isomer,
δ 6.65, J ) 12 Hz; E-isomer, δ 7.57, J ) 16 Hz) as a colorless
oil (7.30 g, 96%). This mixture was used directly for photo-
cyclization. Z-isomer, colorless oil: 1H NMR δ 7.10 (d, J )
8.0 Hz, 1H), 7.08 (s, 1H), 7.06 (d, J ) 8.0 Hz, 1H), 6.96 (t, J )
7.5 Hz, 1H), 6.75 (d, J ) 7.5 Hz, 1H), 6.68-6.72 (m, 3H), 6.65
(d, J ) 12 Hz, 1H), 3.61 (s, 3H), 2.41 (s, 3H); MS m/e 258 (M+,
100 based on Cl, 35). Anal. Calcd for C16H15ClO: C, 74.27;
H, 5.84; Cl, 13.70. Found: C, 74.30; H, 5.83; Cl, 13.80.
1-Ch lor o-2-m eth yl-7-m eth oxyph en an th r en e (19a). Pho-
tocyclization of 18 (1.00 g, 3.46 mmol) by the procedure
employed for preparation of 14a (10 h) provided 19a (0.80 g,
81%) as a white solid, mp 170-171.5 °C (EtOAc-hexane): 1H
NMR δ 8.45 (d, J ) 9.0 Hz, 1H), 8.32 (d, J ) 8.0 Hz, 1H), 8.18
(d, J ) 9.0 Hz, 1H), 7.68 (d, J ) 9.0 Hz, 1H), 7.40 (d, J ) 8.0
Hz, 1H), 7.22, (d, J ) 9.0 Hz, 1H), 7.19 (s, 1H), 3.96 (s, 3H),
2.60 (s, 3H); MS m/e 256 (M+, 100) (based on Cl, 35). Anal.
Calcd for C16H13ClO: C, 74.85; H, 5.10; Cl, 13.81. Found: C,
74.72; H, 5.14; Cl, 13.76.
2-Br om om eth yl-1-ch lor o-7-m eth oxyph en an th r en e (19b).
Bromination of 19a (2.23 g, 8.69 mmol) with NBS (1.55 g, 8.7
mmol) by the procedure employed for preparation of 8b and
14b (16 h) provided 19b (2.34 g, 80%) as a yellow solid, mp
155-156 °C (EtOAc-hexane): 1H NMR δ 8.5 (d, J ) 9.0 Hz,
1H), 8.50 (d, J ) 8.6 Hz, 1H), 8.27 (d, J ) 9.3 Hz, 1H), 7.81 (d,
J ) 9.2 Hz, 1H), 7.66 (d, J ) 8.6 Hz, 1H), 7.32, (dd, J ) 2.7,
9.0 Hz, 1H), 7.28 (d, J ) 2.6 Hz, 1H) 4.86 (s, 2H), 3.98 (s, 3H);
MS m/e 336 (M+ + 2, 15), 255 (M+ - Br, 100, based on Br, 79,
and Cl, 35). Anal. Calcd for C16H12BrClO: C, 57.26; H, 3.60;
Br, 23.81; Cl, 10.56. Found: C, 57.22; H, 3.60; Br, 23.49; Cl,
10.42.
C
28H20O6 452.1260, found 452.1260.
tr a n s-3,4-Dih yd r oxy-3,4-d ih yd r o-11-h yd r oxyd ib en z-
[a , j]a n th r a cen e (3b). Reduction of 22d (55 mg, 0.167 mmol)
with NaBH4/O2 in EtOH by the procedure used for preparation
of 1 (3 days) afforded 3b (40 mg, 74%) as a yellow solid, mp
263-265 °C: 1H NMR (CD3COCD3) δ 9.49 (s, 1H), 8.96 (d, J
) 8.5 Hz, 1H), 8.81 (s, 0.5 H, exchangeable with D2O), 8.41 (s,
1H), 8.02 (d, J ) 8.5 Hz, 1H), 7.89 (d, J ) 9.5 Hz, 1H), 7.79 (d,
J ) 9.5 Hz, 1H), 7.70 (d, J ) 10 Hz, 1H), 7.57 (d, J ) 9.5 Hz,
1H), 7.32 (d, J ) 2.5 Hz, 1H), 7.26 (dd, J ) 2.5, 8.5 Hz, 1H),
6.29 (dd, J ) 2.5, 10 Hz, 1H), 4.94 (dd, J ) 6.0, 11 Hz, 1H),
4.69 (d, J ) 5.0 Hz, 0.6 H, exchangeable with D2O), 4.56 (d, J
) 10 Hz, 1H), 4.37 (d, J ) 10 Hz, 0.6H, exchangeable with
D2O); 13C NMR (THF-d8) δ 74.49, 76.64, 113.15, 116.05, 117.35,
122.85, 123.67, 124.67, 125.47, 127.57, 127.96, 128.13, 128.36,
128.72, 129.25, 130.38, 130.44, 132.03, 134.52, 134.81, 136.82,
158.04; MS m/e 328 (M+, 25), 310 (M+ - H2O, 100); HRMS
calcd for C22H16O3 328.1099, found 328.1100; UV (EtOH) λmax
(ꢀ) 240.0 (4.53 × 104), 246.9 (5.50 × 104), 293.8 (6.45 × 104),
306.2 (7.50 × 104) nm.
2-(1-Ch lor o-7-m eth oxyp h en a n th r ylm eth yl)tr ip h en yl-
p h osp h on iu m Br om id e (19c). Reaction of 19b (2.04 g, 6.08
mmol) with PPh3 (1.59 g, 6.06 mmol) by the procedure
employed for preparation of 8c furnished 19c (3.29 g, 91%) as
a white solid, mp 286-288 °C: 1H NMR δ 8.47 (d, J ) 8.5 Hz,
1H), 8.38 (d, J ) 8.5 Hz, 1H), 7.88 (d, J ) 10 Hz, 1H), 7.84 (d,
J ) 10 Hz, 1H), 7.57-7.81 (m, 17H), 7.31 (d, J ) 7.5 Hz, 1H),
5.90 (d, J ) 13.5 Hz, 2H), 3.97 (s, 3H); MS (FAB) 517 (M+
-
Br, 100, based on Br, 79, Cl, 35, and P, 31). Anal. Calcd for
34H27BrClOP: C, 68.30; H, 4.55; Br, 13.36; Cl, 5.93. Found:
C
C, 68.40; H, 4.61; Br, 13.28; Cl, 5.89.
1-(1-Ch lor o-7-m eth oxy-2-p h en a n th r yl)-2-(2′,3′-d im eth -
oxyp h en yl)eth en e (21). Wittig reaction of 19c (2.95 g, 4.93
mmol) with 2,3-dimethoxybenzaldehyde (0.82 g, 4.93 mmol)
by the procedure used for preparation of 9 gave 21 (1.83 g,
92%) as a white solid consisting mainly of the Z-isomer with
only traces of the E-isomer. Z-isomer, white solid, mp 161-
163 °C (EtOAc-hexane): 1H NMR δ 8.37 (d, J ) 9.5 Hz, 1H),
8.22 (d, J ) 9.0 Hz, 1H), 8.16 (d, J ) 8.5 Hz, 1H), 7.70 (d, J )
9.5 Hz, 1H), 7.32 (d, J ) 8.5 Hz, 1H), 7.19 (br, 2H), 6.95 (d, J
) 3.5 Hz, 2H), 6.71 (d, J ) 8.0 Hz, 1H), 6.65 (t, J ) 8.0 Hz,
Ack n ow led gm en t. This research was supported by
grants from the American Cancer Society (CN-22) and
the National Cancer Institute (CA 67937).
J O980416J