Synthesis of dihydrodiol metabolites implicated in the mechanism of carcinogenesis of phenanthro[4,3-b][1]benzothiophene and phenanthro[3,4-b][1]benzothiophene, the polycyclic sulfur heterocycles with a "Fjord" structure.

Article abstract of DOI:10.1021/jo020493l

Dihydrodiols, which are potential proximate carcinogens of phenanthro[4,3-b][1]benzothiophene (3) and phenanthro[3,4-b][1]benzothiophene (4) and possess a "fjord" structure, were synthesized. The dihydrodiols synthesized were trans-3,4-dihydroxy-3,4-dihydrophenanthro[4,3-b][1]benzothiophene (5) and trans-3,4-dihydroxy-3,4-dihydrophenanthro[3,4-b][1]benzothiophene (6). The precursors to the dihydrodiols 5 and 6 were 3-methoxyphenanthro[4,3-b][1]benzothiophene (11) and 3-methoxyphenanthro[3,4-b][1]benzothiophene (16). Compound 11 was obtained via Suzuki cross-coupling reaction of easily accessible starting materials. However, this synthetic strategy utilizing Suzuki reaction for the preparation of 16 was comparatively less productive than that described previously due to time-consuming synthesis of the starting material(s), and extremely poor yield associated with cyclization of the epoxide 15 to 16. The methoxy derivatives 11 and 16 were converted to the corresponding dihydrodiols 5 and 6 by a sequence involving demethylation, oxidation, and reduction. The trans-stereochemistry of the dihydrodiols was established by (1)H NMR, which indicated a large coupling constant between vicinal carbinol protons. The UV spectra of the dihydrodiols 5 and 6 are presented.

Full text of DOI:10.1021/jo020493l

Syn th esis of Dih yd r od iol Meta bolites Im p lica ted in th e
Mech a n ism of Ca r cin ogen esis of
P h en a n th r o[4,3-b][1]ben zoth iop h en e a n d
P h en a n th r o[3,4-b][1]ben zoth iop h en e, th e P olycyclic Su lfu r
Heter ocycles w ith a “F jor d ” Str u ctu r e
Subodh Kumar*
Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of
New York College at Buffalo, 1300 Elmwood Avenue, Buffalo, New York 14222
kumars@buffalostate.edu
Received J uly 25, 2002
Dihydrodiols, which are potential proximate carcinogens of phenanthro[4,3-b][1]benzothiophene
(3) and phenanthro[3,4-b][1]benzothiophene (4) and possess a “fjord” structure, were synthesized.
The dihydrodiols synthesized were trans-3,4-dihydroxy-3,4-dihydrophenanthro[4,3-b][1]benzothiophene
(5) and trans-3,4-dihydroxy-3,4-dihydrophenanthro[3,4-b][1]benzothiophene (6). The precursors to
the dihydrodiols 5 and 6 were 3-methoxyphenanthro[4,3-b][1]benzothiophene (11) and 3-methoxy-
phenanthro[3,4-b][1]benzothiophene (16). Compound 11 was obtained via Suzuki cross-coupling
reaction of easily accessible starting materials. However, this synthetic strategy utilizing Suzuki
reaction for the preparation of 16 was comparatively less productive than that described previously
due to time-consuming synthesis of the starting material(s), and extremely poor yield associated
with cyclization of the epoxide 15 to 16. The methoxy derivatives 11 and 16 were converted to the
corresponding dihydrodiols 5 and 6 by a sequence involving demethylation, oxidation, and reduction.
1
The trans-stereochemistry of the dihydrodiols was established by H NMR, which indicated a large
coupling constant between vicinal carbinol protons. The UV spectra of the dihydrodiols 5 and 6
are presented.
In tr od u ction
generally more tumorigenic than those which contain a
bay region, suggesting that additional distortion in the
bay region enhances the carcinogenic potential of the
metabolite.1 Previously,8 I reported the synthesis of
trans-3,4-dihydroxy-3,4-dihydrophenanthro[3,2-b][1]ben-
zothiophene (2), a potentially carcinogenic metabolite of
phenanthro[3,2-b][1]benzothiophene (1), which contains
an isolated double bond in the bay region. To investigate
whether additional steric constraint in the bay region
enhances the carcinogenic potential of the dihydrodiol
metabolites of thia-PAHs, we have synthesized trans-
3,4-dihydroxy-3,4-dihydrophenanthro[4,3-b]benzothio-
phene (5) and trans-3,4-dihydroxy-3,4-dihydrophenan-
thro[3,4-b][1]benzothiophene (6), which are the poten-
tially carcinogenic metabolites of phenanthro[4,3-b][1]-
benzothiophene (3) and phenanthro[3,4-b][1]benzothio-
phene (4), respectively. 3, which contains a fjord region,
exhibits greater carcinogenic activity than that of its
carbon analogue, benzo[c]chrysene.5 However, 4, which
is expected to be more distorted in the bay region than 3
on the basis of the twist angle of their corresponding
It is known that polynuclear aromatic hydrocarbons
(PAHs) require metabolic activation to display their
carcinogenic potential and that the metabolites that have
expressed the greatest tumorigenicity are derived from
dihydrodiols, especially those in which the isolated double
bond is a part of a sterically hindered region (frequently
referred to as the bay region).1-3 Like PAHs, their sulfur
analogues (thia-PAHs) are also ubiquitous environmental
contaminants, and have been detected in a number of
environmental sources including the emission from brown-
coal-fired stoves, lubricating oils, coal tar derivatives,
exhaust from diesel engines, and cigarette smokes.4
Despite a number of thia-PAHs being known as carcino-
gens and mutagens,4-6 not much is known about their
mechanism of carcinogenic/mutagenic action, primarily
due to the unavailability of their potential metabolites
needed for such studies.
It has been demonstrated that the carcinogenic me-
tabolites of those PAHs which contain a fjord region7 are
(1) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and
Carcinogenesis; Cambridge University Press: Cambridge, U.K., 1991.
(2) J erina, D. M.; Chadha, A.; Cheh, A. M.; Schurdek, M. E.; Wood
A. W.; Sayer, J . M. Adv. Exp. Med. Biol. 1990, 283, 533.
(3) Dipple, A.; Moschel; R. C.; Bigger, C. A. H. In Chemical
Carcinogenesis; Searle, C. E., Ed.; American Chemical Society Mono-
graph 182; American Chemical Society: Washington, DC, 1984; p 41.
(4) J acob, J . In Sulfur Analogues of PAHs (Thiaarenes); Cambridge
University Press: Cambridge, U.K., 1990; see also references therein.
(5) Croisy, A.; Mispelter, J .; Lhoste, J . M.; Zajdela F.; J acqignon, P.
J . Heterocycl. Chem. 1984, 21, 353.
(6) Warshawsky, D. Environ. Carcinog. Ecotoxicol. Rev. 1992, C10,
1.
(7) The fjord region is defined as a bay region with additional steric
constraint as exemplified by the region enclosed between positions 1
and 13 of 3 and 4.
(8) Kumar, S. J . Chem. Soc., Perkin Trans. 1 2001, 1018.
10.1021/jo020493l CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/13/2002
8842
J . Org. Chem. 2002, 67, 8842-8846

Synthesis of Dihydrodiol Metabolites
SCHEME 1a
carbon analogues, benzo[c]phenanthrene and dibenzo[c,d]-
phenanthrene,9 has not been evaluated for its carcino-
genic activity.
a
Reagents: i, Pd(PPh3)4, CsF-DME; ii, Me3S+I-, KOH-MeCN;
iii, MeSO3H-CH2Cl2.
ity were, primarily, responsible for 10a existing as a
mixture of diastereomers.14 Acid-catalyzed cyclization of
10a with MeSO3H gave 3-methoxyphenanthro[4,3-b][1]-
benzothiophene (11) in 42% yield. The reaction was
carried out the same way as described before10 except
that the solution of epoxide 12a was added to the solution
of MeSO3H. A similar synthetic sequence starting from
the Suzuki coupling reaction of 7 and 8b (Scheme 1) was
also successfully applied to the synthesis of the parent
thia-PAH, 3, in overall 69% yield. Compound 3 has been
obtained previously by a photochemical method15 in trace
amounts, or by an Elbs reaction5 in an overall yield of
22%.
An approach similar to that outlined in Scheme 1 was
also investigated for developing a regiospecific synthesis
of 16 (Scheme 2), a key intermediate for the synthesis of
6. However, this approach was not productive compared
to that reported earlier by me8 due to multiple steps
involved in the synthesis of the key starting material
1-bromodibenzothiophene (12),16 and also due to ex-
tremely poor yield (∼3%) from the cyclization of the
epoxide 15 to 16. Due to scarcity of 15, no further attempt
was made to improve the yield of 16 from this route.
The conversion of 11 to 5 was achieved via an initial
demethylation of 11 with BBr3 to 3-hydroxyphenanthro-
[4,3-b][1]benzothiophene (17) (Scheme 3). The oxidation
of 17 with Fremy’s salt afforded the dione 18 as a bright
red solid in 75% yield. Reduction of 18 with NaBH4 while
O2 was bubbled through the solution took place smoothly
with trans-stereospecificity in accord with previous find-
ings for reductions of this type8,10 to afford 5 as one of
the target dihydrodiols. The presence of oxygen is abso-
lutely essential for the successful reduction of o-quinone
Resu lts a n d Discu ssion
The critical intermediates for preparation of dihydrodi-
ols 5 and 6 are the corresponding methoxy-substituted
thia-PAHs 11 and 14 (Schemes 3 and 4). Compound 11
was obtained previously8 as a major byproduct during
the synthesis of 2, while compound 14 was not previously
synthesized. Our approach to the synthesis of 14 was
based on our previous observation10 that a Suzuki cross-
coupling reaction11 of 2-bromo-5-methoxybenzaldehyde
(8b) with 2-(dihydroxyboryl)benzo[b]thiophene provides
easy access to the synthesis of analogous 2-methoxy-
naphtho[1,2-b][1]benzothiophene. The starting boronic
acid for the synthesis of 14 was 4-(dihydroxyboryl)di-
benzothiophene (7), which was prepared according to
the published procedure.12 Suzuki coupling reaction of 7
with 8a furnished the expected coupling product 9a in
91% yield (Scheme 1). Modification of the aldehyde
functionality of 9a with trimethylsulfonium iodide and
powdered KOH in acetonitrile13 produced ethylene ep-
1
oxide derivative 10a as a thick oil. The H NMR of 10a ,
which showed the lack of aldehydic proton signal and the
presence of four proton signals of equal integration
between 2.7 and 2.9 ppm for CH2 protons of the ethylene
epoxide functionality, indicated the formation of 10a as
a 1:1 mixture of diastereomers. The restricted rotation
of the aryl-aryl bond and the presence of a chiral center
at the benzylic carbon of the ethylene epoxide functional-
(9) Herndon, W. C. In Polynuclear Aromatic Compounds; Ebert, L.
W., Ed.; Advances in Chemistry Series 217; American Chemical
Society: Washington, DC, 1988; p 1.
(10) Kumar, S.; Kim, T. Y. J . Org. Chem. 2000, 65, 3883.
(11) Miyayura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(12) Goldfinger, M. B.; Crawford, K. B.; Swager, T. M.. J . Am. Chem.
Soc. 1997, 19, 4578.
(14) Kumar, S. J . Org. Chem. 1997, 62, 8535.
(15) Pratap, R.; Lee M. L.; Castle, R. N. J . Heterocycl. Chem. 1981,
19, 219.
(13) Borredon, E.; Delmas, M.; Gaset, A. Tetrahedron Lett. 1982,
23, 5283.
(16) Kudo H.; Castle, R. N. J . Heterocycl. Chem. 1985, 22, 215.
J . Org. Chem, Vol. 67, No. 25, 2002 8843

Kumar
SCHEME 2a
SCHEME 4a
a
Reagents: i, BBr3-CH2Cl2; ii, Fremy’s salt; iii, NaBH4-EtOH.
a
Reagents: i, Pd(PPh3)4, CsF-DME; ii, Me3S+I-, KOH-MeCN;
iii, MeSO3H-CH2Cl2.
SCHEME 3a
a
Reagents: i, BBr3-CH2Cl2; ii, Fremy’s salt; iii, NaBH4-EtOH.
to dihydrodiol because it reoxidizes the catechol, a major
byproduct of such a reaction, back to o-quinone.17 Con-
sequently, the end product of this reduction-oxidation
process in the presence of oxygen is pure dihydrodiol.
Synthesis of 6 was accomplished by a route similar to
that employed for the synthesis of 5. Thus, the demethy-
lation of 16 with BBr3 afforded the phenol 19, which was
oxidized with Fremy’s salt to produce the dione 18 as a
purple solid (Scheme 4). Reduction of the dione 20 with
NaBH4 in ethanol while O2 was bubbled through the
solution produced the remaining target dihydrodiol 6
with trans-stereospecificity. The UV spectra of dihydrodi-
ols 5 and 6 are shown in Figure 1.
Our preliminary studies have indicated that 6 was
nearly 8-fold more mutagenic than 3 in Salmonella
typhimurium strain TA100 at doses up to 10 nmol/plate.
In the same study, 6 showed mutagenic activity similar
to that of 3. A detailed study on the mutagenic activity
of these and other thia-PAH derivatives in various strains
F IGURE 1. UV spectra of dihydrodiols 5 (top) and 6 (bottom)
in absolute ethanol.
of S. typhimurium are currently under investigation, and
will be reported elsewhere.
Exp er im en ta l Section
All reagents and solvents (anhydrous or otherwise) were
used as received without further purification. Dry column
grade silica gel (63-200 µm) was used for column chromatog-
(17) Platt, K. L.; Oesch, F. J . Org. Chem. 1983, 48, 265.
8844 J . Org. Chem., Vol. 67, No. 25, 2002

Synthesis of Dihydrodiol Metabolites
raphy. The 1H and 13C NMR spectra were recorded on a 300
MHz multinuclear NMR spectrophotometer. Chemical shifts
are in parts per million relative to that for internal TMS for
1H NMR spectra and relative to solvent signals for 13C NMR
spectra. Electron impact (EI) mass spectra were obtained by
the mass spectral facility of the Department of Chemistry,
State University of New York at Buffalo. All the melting points
were uncorrected.
Caution! Phenanthro[b][1]benzothiophenes and their de-
rivatives are potential carcinogens and should be handled in
accordance with NIH guidelines for the Laboratory Use of
Chemical Carcinogens!
4-(2-F or m yl-4-m eth oxyp h en yl)d iben zoth iop h en e (9a ).
A mixture of 7 (3.0 g, 13.15 mmol),12 Pd(PPh3)4 (0.52 g, 0.42
mmol), 2-bromo-5-methoxybenzaldehyde (8a ; 2.63 g, 12.27
mmol),18 and anhydrous CsF (4.3 g, 28.25 mmol) in 100 mL of
anhydrous DME was stirred under reflux in an argon atmo-
sphere for 20 h. The mixture was cooled to rt, diluted with
water, and then extracted with ethyl acetate. The organic
phase was washed with water, 5% NaOH, and water succes-
sively. After the organic phase was dried over anhydrous
Na2SO4, the solvent was removed in vacuo to afford an oil,
which after chromatography over dry column grade silica gel
with 25% CH2Cl2 in hexane produced 3.55 g (91%) of colorless
oil, which solidified on standing. A small sample of the solid
was recrystallized from ethyl acetate-hexane to produce 9a
as light yellow crystals. Mp: 125-127 °C. 1H NMR (300 MHz,
CDCl3): δ 3.95 (s, 3 H), 7.28 (dd, 1 H, J ) 2.9, 8.5 Hz), 7.45-
7.62 (m, 5 H), 7.77-7.81 (m, 1 H), 8.18 - 8.23 (m, 2 H), 9.77
(s, 1 H). 13C NMR (CDCl3): δ 191.3 (CHO), 159.6, 140.7, 139.3,
136.8, 135.6, 135.4, 134.4, 132.3, 131.6, 128.4, 126.9, 124.6,
124.5, 122.6, 121.8, 121.6, 121.0, 110.0, 55.5 (OCH3). MS (EI):
m/z 318. Anal. Calcd for C20H14O2S: C, 75.47; H, 4.40. Found:
C, 75.31; H, 4.68.
4-(2-F or m ylp h en yl)d iben zoth iop h en e (9b). A mixture
of 7 (3.42 g, 15 mmol),12 Pd(PPh3)4 (0.6 g, 0.49 mmol),
2-bromobenzaldehyde (8b; 2.40 g, 13 mmol), and anhydrous
CsF (5.7 g, 37.45 mmol) in 75 mL of anhydrous DME was
stirred under reflux in an argon atmosphere for 20 h. The
crude product was isolated as described above for 9a and
chromatographed over dry column grade silica gel. The elution
of the column with 15% CH2Cl2 in hexane gave 3.15 g (84%)
of 9b as colorless crystals. Mp: 92-94 °C. 1H NMR (300 MHz,
CDCl3): δ 7.40 (dd, 1 H, J ) 1, 7.3 Hz), 7.45-7.55 (m, 2 H),
7.56-7.66 (m, 3 H), 7.70-7.83 (m, 2 H), 8.10-8.17 (m, 1 H),
8.19-8.28 (m, 2 H), 9.81 (s, 1 H). 13C NMR (300 MHz, CDCl3):
δ 191.4 (CHO), 143.8, 140.2, 139.3, 135.7, 135.3, 134.0, 133.4,
132.6, 130.3, 128.6, 128.1, 127.5, 126.9, 124.6, 124.6, 122.6,
121.8, 120.7. MS (EI): m/z 288. Anal. Calcd for C19H12OS: C,
78.89; H, 4.49. Found: C, 79.09; H, 4.38.
P h en a n th r o[4,3-b][1]ben zoth iop h en e (3). Compound 9b
(1.77 g, 6.14 mmol), trimethylsulfonium iodide (1.37, 6.72
mmol), and powdered KOH (1.03 g, 26.2 mmol) in acetonitrile
(60 mL) were heated with stirring at 65-70 °C for 16 h. The
1
workup of the reaction mixture produced 10b. H NMR (300
MHz, CDCl3): δ 2.72-2.81 (m, 1 H), 2.89-2.97 (m, 1 H), 3.67
(dd, 1 H, J ) 2.7, 4.1 Hz), 7.30-7.60 (m, 8 H), 7.72-7.83 (m,
1 H), 8.12-8.25 (m, 2 H). Treatment of the crude epoxide 10b
with CH3SO3H (15 mL) in CH2Cl2 (95 mL) as described for
the synthesis of 11 gave a semisolid. The chromatography of
the semisolid over dry column grade silica gel using 25%
CH2Cl2 in hexane as eluant afforded 1.45 g (82%) of 3 as
colorless crystals. Mp: 125-126 °C (lit.5 mp 127 °C). 1H NMR
(500 MHz, CDCl3): δ 7.51-7.60 (m, 2 H), 7.69-7.74 (m, 1 H),
7.85-8.08 (m, 6 H), 8.32-8.36 (m, 1 H), 8.45 (d, 1 H, J ) 8.24
Hz), 9.32 (d, 1 H, J ) 8.55 Hz).
1-(2-F or m yl-4-m eth oxyp h en yl)d iben zoth iop h en e (14).
A mixture of 1-bromodibenzothiophene (12)16 (1.5 g, 5.7 mmol),
Pd(PPh3)4 (0.22 g, 0.18 mmol), 2-(dihydroxyboryl)-5-methoxy-
benzaldehyde (13)8 (1.14 g, 6.3 mmol), and anhydrous CsF (2.1
g, 13.8 mmol) in 70 mL of anhydrous DME was stirred under
reflux in an argon atmosphere for 20 h. The usual workup of
the reaction mixture as described for 9a afforded an oil, which
after chromatography over dry column grade silica gel with
50% CH2Cl2 in hexane produced 1.7 g (87%) of colorless oil,
which solidified on standing in a freezer. A small sample of
the solid was recrystallized from CH2Cl2-hexane to produce
14 as light yellow crystals. Mp: 146-148 °C. 1H NMR (300
MHz, CDCl3): δ 3.99 (s, 3 H), 6.86 (d, 1 H, J ) 8.0 Hz), 7.08
(dt, 1 H, J ) 1 Hz, 7.2 Hz), 7.25-7.42 (m, 4 H), 7.50 (t, 1 H, J
) ∼ 7.5 Hz), 7.64 (d, 1 H, J ) 2.6 Hz), 7.84 (d, 1 H, J ) 8 Hz),
7.94 (dd, 1 H, J ) 1 Hz, 8.0 Hz), 9.67 (s, 1 H). 13C NMR (300
MHz, CDCl3): δ 191.7 (CHO), 159.8, 140.1, 139.8, 137.7, 135.1,
134.9, 134.0, 133.8, 132.1, 127.8, 126.6, 125.7, 124.3, 124.2,
122.8, 121.7, 122.1, 109.7, 55.7 (OCH3). MS (EI): m/z 318.
Anal. Calcd for C20H14O2S: C, 75.47; H, 4.40. Found: C, 75.31;
H, 4.68.
3-Met h oxyp h en a n t h r o[3,4-b][1]ben zot h iop h en e (16).
Compound 14 (0.9 g, 2.81 mmol) was treated with trimethyl-
sulfonium iodide (0.7 g, 3.43 mmol) and powdered KOH (0.3
g, 3.4 mmol) in acetonitrile (40 mL) as described for 10a to
produce sufficiently pure epoxide 15. 1H NMR (300 MHz,
CDCl3): δ 2.44 (dd, 0.5 H, J ) 2.6, 5.6 Hz), 2.50 (dd, 0.5 H, J
) 4.1, 5.6 Hz), 2.64 (dd, 0.5 H, J ) 2.6, 5.8 Hz), 2.83 (dd, 0.5
H, 4.1, 5.8 Hz), 3.45-3.53 (m, 1 H), 6.60-7.53 (m, 8 H), 7.77-
7.91 (m, 2 H). The treatment of the resulting 15 with
CH3SO3H (1.25 mL) in CH2Cl2 (15 mL) as described for the
synthesis of 11 gave a semisolid. The chromatography of the
semisolid over dry column grade silica gel using 25% CH2Cl2
in hexane followed by a preparative TLC using 5% ethyl
acetate-hexane as eluant afforded ∼0.03 g (3%) of 16 as light
yellow crystals. Mp: 129-130 °C (lit.8 mp 129-130 °C).
3-Meth oxyp h en a n th r o[4,3-b][1]ben zoth iop h en e (11). A
mixture of 9a (2.7 g, 8.44 mmol), trimethylsulfonium iodide
(1.88 g, 9.23 mmol), and powdered KOH (1.40 g, 35.7 mmol)
in acetonitrile (100 mL) containing a trace of water was stirred
under argon at 65-70 °C for 20 h. The mixture was cooled
and extracted with ethyl acetate. The organic phase was
washed with water, dried over anhydrous Na2SO4, and con-
centrated in vacuo to yield 2.75 g (100%) of sufficiently pure
4-(2-epoxyethyl-4-methoxyphenyl)dibenzothiophene (10a ) as a
1
colorless syrupy oil. H NMR (300 MHz, CDCl3): δ 2.70-2.77
(m, 1H), 2.90-2.94 (m, 1 H), 3.65 (dd, 1 H, J ) 2.7, 4.1 Hz),
3.87 (s, 3 H), 6.91 (d, 1 H, 2.6 Hz), 6.95 (dd, 1 H, J ) 0.9, 2.8
Hz), 7.23-7.41 (m, 2 H), 7.43-7.58 (m, 3 H), 7.76-7.82 (m, 1
H), 8.13-8.23 (m, 2 H).
A solution of the epoxide 10a (1.32 g, 4.33 mmol) in CH2Cl2
(25 mL) was added dropwise in 10 min to an ice-cooled solution
of CH3SO3H (12 mL) in anhydrous CH2Cl2 (75 mL) under
argon. The solution, which gradually turned dark, was stirred
at rt for 12 h. The mixture was diluted with ice-cold water,
and the CH2Cl2 solution was washed with water, 5% NaOH,
and water, successively. After being dried over anhydrous
Na2SO4, the organic solution was evaporated in vacuo to yield
a crude product, which was chromatographed over dry column
grade silica gel using 25% CH2Cl2 in hexane as eluant to
produce 0.55 g (42%) of 11 as a yellow crystalline solid. Mp:
116-118 °C. 1H NMR (300 MHz, CDCl3): δ 4.02 (s, 3 H), 7.41
(d, 1 H, J ) 2.8 Hz), 7.49 (dd, 1 H, J ) 2.8, 9.8 Hz), 7.51-7.61
(m, 2 H), 7.80 (d, 1 H, J ) 8.8 Hz), 7.92 (d, 1 H, J ) 8.8 Hz),
8.00 (d, 1 H, J ) 8.3 Hz), 8.01-8.06 (m, 1 H), 8.30-8.35 (m, 1
H), 8.38 (d, 1 H, J ) 8.3 Hz), 9.23 (d, 1 H, J ) 9.23 Hz). 13C
NMR (CDCl3): δ 157.6, 139.2, 135.1, 134.7, 134.6, 134.2, 131.2,
128.3, 127.7, 126.7, 126.5, 126.4, 126.3, 124.6, 124.2, 122.1,
121.4, 119.1, 116.9, 109.1, 55.4 (OCH3). MS (EI): m/z 314.
Anal. Calcd for C20H14OS: C, 80.24; H, 4.46. Found: C, 80.40;
H, 4.75.
3-H yd r oxyb e n zo[b]p h e n a n t h r o[4,3-b ][1]b e n zot h io-
p h en e (17). To a stirred solution of 11 (0.14 g, 0.44 mmol) in
anhydrous CH2Cl2 (35 mL) at 0-5 °C under argon was added
a 1 M solution of BBr3 (0.9 mL, 0.9 mmol) over a period of
(18) Fleming I.; Woolias, M. J . J . Chem. Soc., Perkin Trans. 1 1979,
829.
J . Org. Chem, Vol. 67, No. 25, 2002 8845

Kumar
2-3 min. After being stirred for 12 h at rt, the mixture was
hydrolyzed with ice-cold water. The organic layer was sepa-
rated, washed with water, dried over anhydrous Na2SO4, and
then evaporated to afford a solid. The solid was triturated with
hexane and filtered to yield 0.13 g (98%) of sufficiently pure
17 as a colorless crystalline solid. A small sample was further
purified by preparative TLC (20% ethyl acetate-hexane) to
produce 17 as a colorless crystalline solid. Mp: 174-176 °C.
1H NMR (300 MHz, CDCl3): δ 7.53 (dd, 1 H, J ) 2.8, 10.7
Hz), 7.55-7.68 (m, 3 H), 7.84 (d, 1 H, J ) 8.7 Hz), 8.00 (d, 1
H, J ) 8.9 Hz), 8.12 (d, 1 H, J ) 8.3 Hz), 8.12-8.23 (m, 1 H),
8.47-8.53 (m, 1 H), 8.55 (d, 1 H, J ) 8.3 Hz), 9.01 (s, 1 H,
exchangeable with D2O), 9.17 (d, 1 H, J ) 8.6 Hz). 13C NMR
(CDCl3): δ 155.4, 138.7, 134.7, 134.5, 134.1, 133.5, 130.5, 127.6,
127.1, 126.3, 126.2, 126.0, 124.3, 122.9, 122.5, 121.7, 121.0,
THF-EtOH): λmax (ꢀ) 199 (36200), 228 (34300), 242 (28500),
250 (26500), 272 (27200), 290 (14400), 312 (14200), 328
(10600), 340 (10800).
3-Hyd r oxyp h en a n t h r o[3,4-b][1]ben zot h iop h en e (19).
Compound 168 (0.5 g, 1.59 mmol) was dissolved in 60 mL of
CH2Cl2, and 3.2 mL (3.2 mmol) of BBr3 in CH2Cl2 (1 M) was
added dropwise at 0 °C under argon. The dark solution was
stirred for 18 h at rt. Conventional workup as described
for 8 afforded 0.47 g (100%) of 19 as a colorless solid. Mp:
1
170-172 °C (EtOAc-hexane). H NMR (300 MHz, CDCl3): δ
7.17 (dd, 1 H, J ) 9.0 and 2.6 Hz), 7.41 (d, 1 H, J ) 2.6 Hz),
7.41-7.57 (m, 2 H), 7.78 (d, 1 H, J ) 8.7 Hz), 7.88 (d, 1 H, J
) 8.7 Hz), 7.94 (d, 1 H, J ) 8.3 Hz), 8.04 (d, 1 H, J ) 8.3 Hz),
8.09 (dd, 1 H, J ) 7.8 and 0.7 Hz), 8.69 (d, 1 H, J ) 8.7 Hz),
8.86 (d, 1 H, J ) 9 Hz), 8.96 (s, 1 H). MS (EI): m/z 300 (M+,
118.4, 117.0, 111.9. MS (EI): m/z 300. Anal. Calcd for C20H12
-
100). Anal. Calcd for
Found: C, 78.6; H, 4.4.
C
20H12OS‚1/5H2O: C, 79.0; H, 4.1.
OS‚1/5H2O: C, 79.05; H, 4.10. Found: C, 78.80; H, 4.51.
P h en a n th r o[4,3-b][1]ben zoth iop h en e-3,4-d ion e (18). A
solution of 17 (0.13 g, 0.43 mmol) in 100 mL of CH2Cl2/benzene
(16:84) containing 5 drops of adogen-464 and 0.17 M KH2PO4
(30 mL) was stirred at rt while Fremy’s salt (0.35 g, 1.3 mmol)
was added in one portion with vigorous stirring. After the
solution was stirred for 15 h at rt, the organic layer was
separated, washed with water, and dried over anhydrous
Na2SO4. Evaporation of the solvent and the trituration of the
residue with 50% CH2Cl2/benzene gave 0.1 g (75%) of pure
dione 18 as a bright red crystalline solid. Mp: 224-226 °C.
1H NMR (300 MHz, CDCl3): δ 6.58 (d, 1 H, J ) 10.7 Hz), 7.55-
7.62 (m, 2 H), 7.84 (d, 1 H, J ) 8.6 Hz), 7.95-8.00 (m, 1 H),
8.03 (d, 1 H, J ) 8.4 Hz), 8.18 (d, 1 H, J ) 8.3 Hz), 8.22-8.27
(m, 1 H), 8.30 (d, 1 H, J ) 8.6 Hz), 9.03 (d, 1 H, J ) 10.7 Hz).
13C NMR (300 MHz, CDCl3): δ 180.4, 179.2, 142.4, 139.0,
137.8, 136.0, 134.8, 134.4, 132.5, 131.6, 131.1, 128.2, 127.5,
127.2, 126.9, 126.8, 125.3, 124.8, 123.2, 122.1, 121.8. HRMS
(EI): m/z calcd for C20H10O2S (M+) 314.0401, found 314.0378.
tr a n s-3,4-Dih ydr oxy-3,4-dih ydr oph en an th r o[4,3-b]ben -
zoth iop h en e (5). To a well-stirred suspension of quinone 18
(0.07 g, 0.23 mmol) in ethanol (50 mL) was added NaBH4 (0.2
g, 5.55 mmol). The mixture was stirred at rt while a stream
of oxygen was bubbled through the solution. After 48 h of
stirring, the resulting light yellow solution was concentrated
at rt in vacuo to 25 mL, diluted with water, and extracted with
ethyl acetate. The ethyl acetate solution was dried over
anhydrous Na2SO4 and evaporated under vacuum to yield a
solid, which was triturated with cold ether to give 0.04 g (56%)
of 5 as a light yellow solid. Mp: 179-182 °C. 1H NMR (300
MHz, acetone-d6 + D2O): δ 4.51-4.59 (m, 1 H), 4.88 (d, 1 H,
J ) 12 Hz), 6.42 (dd, 1 H, J ) 1.9, 10.3 Hz), 7.54-7.69 (m, 2
H), 7.80 (dd, 1 H, J ) 2.4, 10.3 Hz), 7.92-8.20 (m, 4 H), 8.39
(d, 1 H, J ) 8.6 Hz), 8.41-8.52 (m, 1 H). HRMS (EI): m/z
calcd for C20H14O2S (M+) 314.0714, found 314.0713. UV (5%
P h en an th r o[3,4-b][1]ben zoth ioph en e-3,4-dion e (20). Oxi-
dation of 19 (0.18 g, 0.6 mmol) with Fremy’s salt (0.49 g, 1.83
mmol) by the procedure employed for the preparation of 9
yielded, after trituraion with CH2Cl2-benzene, 0.16 g (87%)
1
of 20 as a purple crystalline solid. Mp: 235-237 °C. H NMR
(300 MHz, CDCl3): δ 6.44 (d, 1 H, J ) 10.4 Hz), 7.51-7.62
(m, 2 H), 7.86 (d, 1 H, J ) 8.6 Hz), 8.03-8.08 (m, 2 H), 8.10
(d, 1 H, J ) 8.6 Hz), 8.17 (d, 1 H, J ) 10.6 Hz), 8.15-8.22 (m,
1 H), 8.27 (d, 1 H, J ) 8.3 Hz). 13C NMR (300 MHz, CDCl3):
δ 181.1, 180.7, 145.2, 142.6, 140.0, 136.2, 136.1, 131.2, 130.7
(2 C), 129.2, 128.1, 127.2, 126.5, 126.0, 124.7 (2 C), 124.5, 124.0,
123.1. HRMS (EI): m/z calcd for C20H10O2S (M+) 314.0401,
found 314.0400.
tr a n s-3,4-Dih yd r oxy-3,4-d ih yd r op h en a n th r o[3,4-b][1]-
ben zoth iop h en e (6). Reduction of 20 (0.14 g, 0.45 mmol) with
NaBH4 (0.42 g, 11.66 mmol) in the presence of oxygen by the
usual procedure as described for 5 gave a crude product.
Trituration of the product with 1:1 ethyl acetate-hexane
afforded 0.04 g (30%) of pure 6. Mp: 177-179 °C. 1H NMR
(300 MHz, acetone-d6 + D2O): δ 4.76 (d, 1 H, J ) 10.5 Hz),
4.82 (d, 1 H, 10.5 Hz), 6.18 (d, 1 H, J ) 9.7 Hz), 6.84 (d, 1 H,
J ) 9.7 Hz), 7.47-7.56 (m, 2 H), 7.92-8.11 (m, 5 H), 8.35-
8.39 (m, 1 H). HRMS (EI): m/z calcd for C20H14O2S (M+)
318.0714, found 318.0683. UV (5% THF-EtOH): λmax (ꢀ) 194
(36500), 201 (71400), 212 (44700), 238 (52600, sh), 242 (27100),
260 (26500), 279 (25600), 290 (31300), 310 (10600), 337 (7300,
sh), 351 (5300, sh), 367 (3500).
Ack n ow led gm en t. This investigation was, in part,
supported by a grant (R826192-01-0) awarded to S.K.
by the United States Environmental Protection Agency,
Washington, DC.
J O020493L
8846 J . Org. Chem., Vol. 67, No. 25, 2002