Synthesis of suspected carcinogenic metabolites of 7H-benzo[c]fluorene, a coal tar component implicated in causation of lung tumors.

Article abstract of DOI:10.1021/jo011149b

High incidences of lung tumors were observed in mice fed coal tar in their diet. The principal component of tar that gives rise to DNA-bound adducts in mouse lung was identified as 7H-benzo[c]fluorene (BcF). We now report the synthesis of suspected active

Full text of DOI:10.1021/jo011149b

The generally accepted mechanism of PAH carcino-
genesis entails activation by P-450 enzymes to diol
epoxide metabolites with an epoxide ring in a bay or fjord
molecular region. These intermediates react with DNA
to form mutagenic adducts.2,8 BcF (1) differs from the
known PAH carcinogens in that it has neither a bay nor
a fjord molecular region but possesses instead a pseudobay
region.
Syn th esis of Su sp ected Ca r cin ogen ic
Meta bolites of 7H-Ben zo[c]flu or en e, a Coa l
Ta r Com p on en t Im p lica ted in Ca u sa tion of
Lu n g Tu m or s
J i-Quan Wang,† Eric H. Weyand,‡ and
Ronald G. Harvey*,†
In connection with studies to identify metabolites of
BcF that bind to DNA in mouse lung, we undertook to
synthesize the probable active metabolites. We now
report the synthesis of the trans-3,4-dihydrodiol of BcF
(2) and the corresponding anti- and syn-diol epoxides (3
and 4) (the putative ultimate carcinogenic metabolites
that bind to DNA in vivo).
Ben May Institute for Cancer Research, University of
Chicago, Chicago, Illinois 60637, and Department of
Pharmaceutical Chemistry, Rutgers, The State University of
New J ersey, Piscataway, New J ersey 08854
rharvey@ben-may.bsd.uchicago.edu
Received December 17, 2001
Abstr a ct: High incidences of lung tumors were observed
in mice fed coal tar in their diet. The principal component
of tar that gives rise to DNA-bound adducts in mouse lung
was identified as 7H-benzo[c]fluorene (BcF). We now report
the synthesis of suspected active metabolites of BcF, specif-
ically the trans-3,4-dihydrodiol of BcF (2), its likely proxi-
mate carcinogenic metabolite, and the corresponding anti-
and syn-diol epoxides of BcF (3 and 4) in which the epoxide
ring resides in the pseudobay region. The diol epoxide
derivatives (3 and 4) are postulated to be ultimate carcino-
genic metabolites of BcF that bind to DNA in mouse lung.
Weyand and co-workers have recently demonstrated
a high incidence of lung tumors in female A/J mice fed
coal tar in their diet.1 Polycyclic aromatic hydrocarbons
(PAHs) have been shown by prior studies to be the major
carcinogenic components of coal tar.2-4 Three DNA-bound
adducts were detected in the lungs of mice treated with
coal tars.5 The predominant adduct was identified as a
derivative of 7H-benzo[c]fluorene (BcF).6 Subsequently,
BcF was shown to be a potent inducer of lung tumors in
mice fed BcF in their diet.7
The key intermediate in the proposed synthetic route
to the 3,4-dihydrodiol of BcF (2) is 3-hydroxy-7H-benzo-
[c]fluorene (10b). In principle, 10b is synthetically ac-
cessible via modification of the method for the synthesis
of BcF itself.9 This entails alkylation of the enamine of
cyclohexanone, pyrrolidino-1-cyclohexene (6), by 2-meth-
oxy-6-bromomethylnaphthalene (5c), followed by acid-
catalyzed cyclization, dehydrogenation, and demethyla-
tion (Scheme 1).
2-Methoxy-6-bromomethylnaphthalene (5c) was pre-
pared from 6-methoxy-2-naphthaldehyde (5a ) by reduc-
tion with NaBH4 in MeOH to 2-methoxy-6-hydroxy-
methylnaphthalene (5b),10 followed by reaction with
PBr3. Compound 5c exhibited a tendency to decompose
† University of Chicago.
‡ Rutgers, The State University of New J ersey.
(1) Weyand, E. H.; Chen, Y.-C.; Wu, Y.; Koganti, A.; Dunsford, H.
A.; Rodriguez, L. V. Chem. Res. Toxicol. 1995, 8, 949.
(2) (a) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry
and Carcinogenesis; Cambridge University Press: Cambridge, U.K.,
1991. (b) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Wiley-
VCH: New York, N.Y., 1997.
(3) International Agency for Research on Cancer. Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Humans.
Polynuclear Aromatic Compounds, Part 4, Bitumens, Coal Tar, and
Derived Products, Shale Oils, and Soots; IARC: Lyon, France, 1985;
Vol. 35.
(4) Kipling, M. D.; Cooke, M. In Chemical Carcinogens; Searle, C.
E., Ed.; ACS Monograph, No. 182; American Chemical Society:
Washington, D.C., 1984; Vol. 1, pp 165-174.
(5) (a) Weyand, E. H.; Wu, Y. Chem. Res. Toxicol. 1995, 8, 955. (b)
Culp, S. J .; Warbritton, A. R.; Smith, B. A.; Li, E. E.; Beland, F. A.
Carcinogenesis 2000, 21, 1433.
(7) Weyand, E. H.; Goldstein, E. S.; Reuhl, K.; Zhang, F.-J .; Harvey,
R. G. The Toxicologists 2002, 61, 909. Mice fed a diet containing 397
mmolBcF/kg had a 100% incidence of lung tumors (av 46 tumors/
mouse); whereas mice fed a similar diet containing benzo[a]pyrene
exhibited a 77% tumor incidence (av 1.4 tumors/mouse).
(8) Harvey, R. G.; Geacintov, N. E. Acc. Chem. Res. 1998, 21, 66.
Dipple, A.; Moschel, R. C.; Bigger, C. A. H. In Chemical Carcinogens,
2nd ed.; Searle, C. E., Ed.; ACS Monograph 182; American Chemical
Society: Washington, D.C., 1984; pp 63-84.
(6) (a) Koganti, A.; Singh, R.; Rozett, K.; Modi, N.; Goldstein, L. S.;
Roy, T. A.; Zhang, F.-J .; Harvey, R. G.; Weyand, E. H. Carcinogenesis
2000, 21, 1601. (b) The minor adducts were identified as derivatives
of benzo[a]pyrene and benzo[a]fluoranthene.5a
(9) Harvey, R. G.; Pataki, J .; Cortez, C.; Di Raddo, P.; Yang, C. X.
J . Org. Chem. 1991, 56, 1210.
(10) Eriguchi, A.; Takegoshi, T. Chem. Pharm. Bull. 1982, 30, 428.
10.1021/jo011149b CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/17/2002
6216
J . Org. Chem. 2002, 67, 6216-6219

SCHEME 1
SCHEME 2
Oxidation of 10b with Fremy’s salt [(SO3K)2NO] afforded
the quinone, BcF-3,4-dione (11). Products from competing
oxidation in the benzylic position of 10b were not
detected. Reduction of 11 with NaBH4 in ethanol with
O2 bubbling through the solution gave 2. Formation of
the trans isomer is consisent with the known stereospeci-
ficity of this reaction and in good agreement with the
proton NMR spectrum of 2.12,14
Epoxidation of 2 with m-chloroperbenzoic acid fur-
nished trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tet-
rahydro-BcF (3) stereospecifically and in good yield (94%).
This is consistent with prior findings that epoxidation of
PAH dihydrodiols free to adopt the diequatorial confor-
mation takes place trans-stereospecifically to give the
anti-diol epoxide isomers.12,13 The syn-diol epoxide isomer
(4) was prepared via reaction of 2 with NBS in moist
DMSO to yield the bromohydrin (12). Reaction of 12 with
potassium tert-butoxide in tert-butanol took place smoothly
to furnish the syn-diol epoxide, trans-3,4-dihydroxy-syn-
1,2-epoxy-1,2,3,4-tetrahydro-BcF (4), in good yield (87%).
The stereochemical assignments of 12 and 4 are in good
agreement with their proton NMR spectra and with those
for analogous compounds from similar reactions.12,13
The synthetic accessibility of the BcF derivatives
reported herein (2, 3, 4, 10b, 11)15 permits identification
of the active metabolites that bind to DNA in vivo and
determination of their biological properties. Preliminary
findings from DNA binding studies indicate that topical
administration of 2 to the skins of mice affords DNA
adducts in skin and lung.16 The lung adducts are chro-
matographically identical with those formed by admin-
istration of BcF. These results suggest that BcF is
metabolically activated to 2 that is further transformed
on chromatography, and best results were obtained by
its use directly without purification.
Reaction of 5c with enamine 6 (Scheme 1) by the
procedure used for synthesis of BcF9 gave the alkylated
cyclohexanone 7 in similar yield (72%). The proton NMR
spectrum of 7 was consistent with its assignment. Cy-
clodehydration of 7 in methanesulfonic acid furnished
7a,8,9,10,11,11a-hexahydro-3-methoxy-BcF (8) (33%) plus
a lesser amount (6%) of the primary product, 8,9,10,11-
tetrahydro-3-methoxy-BcF (9). Although it is likely that
8 is formed from acid-catalyzed disproportionation of 9,
significant amounts of BcF, the other expected product,
were not detected. Disproportionation was observed in
the synthesis of BcF,9 and it commonly occurs in cyclo-
dehydration reactions.11 Compound 8 was stable, but 9
exhibited a tendency to undergo autoxidation on stand-
ing. To minimize secondary processes, the reaction was
repeated with minimal reaction time. Dehydrogenation
of the crude product over a palladium-charcoal catalyst
furnished 3-methoxy-BcF (10a ) in good yield. Compound
10a was converted to the phenol (10b) by heating with
48% HBr in acetic acid.
(13) Harvey, R. G.; Cortez, C.; Sawyer, T. W.; DiGiovanni, J . J . Med.
Chem. 1988, 31, 1308. Lee, H.; Harvey, R. G. J . Org. Chem. 1986, 51,
3502. Harvey, R. G.; Lee, H.; Pataki, J . J . Org. Chem. 1986, 51, 1407.
Sukumaran, K. B.; Harvey, R. G. J . Org. Chem. 1980, 45, 4407.
(14) Oxygen recycles catechol byproducts by reoxidizing them back
to orthoquinones. These reductions occur stereoselectively to provide
trans-dihydrodiols: Harvey, R. G.; Cortez, C. Tetrahedron 1997, 53,
7101. Platt, K. L.; Oesch, F. J . Org. Chem. 1983, 48, 265.
(15) Synthesis of another probable metabolite, 7-hydroxy-BcF, was
reported: Harvey, R. G.; Yang, A. E.; Yang, C. X. J . Org. Chem. 1992,
57, 6313.
Synthesis of the 3,4-dihydrodiol of BcF (2) from 10b
was carried out by the standard sequence (Scheme 2).12,13
(11) Harvey, R. G.; Halonen, M. Can. J . Chem. 1967, 45, 2630. Cho,
H.; Harvey, R. G. J . Org. Chem. 1987, 52, 5668.
(12) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry
and Carcinogenesis; Cambridge University Press: Cambridge, U.K.,
1991; Chapter 13, pp 306-329.
(16) Parimoo, B.; Weyand, E. H.; Goldstein, L. S.; Wang, J .-Q.;
Harvey, R. G. Unpublished studies.
J . Org. Chem, Vol. 67, No. 17, 2002 6217

FAB HRMS calcd for C18H18O m/z 250.1358, found 250.1357.
Anal. Calcd for C18H18O: C, 86.36; H, 7.25. Found: C, 86.09; H,
7.27.
to a diol epoxide that binds to DNA. These findings may
be significant for lung cancer in human populations
because BcF is a widespread environmental pollutant
present in tobacco smoke, automobile exhaust, and other
sources.2,3
3-Meth oxyben zo[c]flu or en e (10a ). Dehydrogenation of a
mixture of 8 and 9 (130 mg, 0.5 mmol) in 10 mL of triglyme
over a 10% palladium-charcoal catalyst (100 mg) at 240 °C
(bath) followed by the usual workup gave the crude product.
Chromatography on a silica gel column eluted with hexane-
CH2Cl2 (6:1) furnished pure 10a (100 mg, 78%) as a white solid:
mp 101-102 °C; 1H NMR (CDCl3) δ 8.67 (d, 1, J ) 9.17 Hz),
8.34 (d, 1, J ) 7.87 Hz), 7.71 (d, 1, J ) 8.26 Hz), 7.60-7.65 (m,
2), 7.45-7.51 (m, 1), 7.26-7.37 (m, 3), 3.97 (s, 2, CH2), 3.95 (s,
3, CH3); 13C NMR (CDCl3) 156.64, 144.34, 142.70, 140.00, 136.12,
134.67, 126.78, 126.48, 125.67, 125.09, 124.91, 124.82, 123.72,
122.67, 118.73, 107.27, 55.20, 37.46; FAB MS m/z 246 (M+). Anal.
Calcd for C18H14O: C, 87.78; H, 5.73. Found: C, 87.84; H, 5.72.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. 2-Methoxy-6-hydroxymethylnaph-
thalene (5b) was synthesized from 6-methoxy-2-naphthaldehyde
(5a ) by reduction with NaBH4 in MeOH by the published
method.10 1-Pyrrolidino-1-cyclohexene (6), 6-methoxy-2-naph-
thaldehyde, Fremy’s reagent [(SO3K)2NO], and m-chloroperben-
zoic acid were purchased from a commerical source. 1,4-Dioxane,
triglyme, and THF were freshly distilled from sodium/benzophe-
none ketal. NBS was recrystallized from water. NMR spectra
were recorded on 400 or 500 MHz spectrometers in CDCl3 with
tetramethylsilane as internal standard unless stated otherwise.
Integration was consistent with all structural assignments. Mass
spectra (MS) and HRMS were performed by the University of
Illinois at Urbana-Champaign, School of Chemical Sciences. UV
spectra were measured with a Perkin-Elmer Lambda 6 spec-
trometer. Microanalyses were done by Atlantic Microlab, Inc.
All melting points are uncorrected.
3-Hyd r oxyben zo[c]flu or en e (10b). A mixture of 10a (1.38
g, 5.6 mmol) in 35 mL of HOAc and 45 mL of 48% hydrobromic
acid was heated at reflux for 2 h under argon. Conventional
workup and chromatography of the product on a silica gel
column eluted with CH2Cl2 gave 10b (1.21 g, 93%) as an off-
white solid: mp 178-179 °C; 1H NMR (CDCl3) δ 8.67 (d, 1, J )
8.87 Hz), 8.32 (d, 1, J ) 7.82 Hz), 7.60-7.67 (m, 3), 7.47 (t, 1, J
) 7.54 Hz), 7.33 (t, 1, J ) 7.43 Hz), 7.22-7.28 (m, 2), 4.95 (br s,
1, OH), 3.97 (s, 2, CH2); 13C NMR (CDCl3) 152.51, 144.36, 142.66,
137.53, 136.17, 134.74, 126.82, 126.14, 125.74, 125.52, 124.97,
124.87, 122.67, 117.89, 111.00, 37.53; FAB MS m/z 232 (M+).
Anal. Calcd for C17H12O: C, 87.90; H, 5.21. Found: C, 87.76; H,
5.23.
Ca u tion : Benzo[c]fluorene and its trans-3,4-dihydrodiol (2)
and diol epoxide metabolites (3, 4) are potentially hazardous and
should be handled with care in accordance with “NIH Guidelines
for the Laboratory Use of Chemical Carcinogens”.
Ben zo[c]flu or en e-3,4-d ion e (11). Oxidation of 10b (100 mg,
0.43 mmol) in acetone (20 mL) and 12 mL of 1.6 M aqueous KH2-
PO4 by Fremy’s salt (340 mg, 1.3 mmol) in 36 mL of water was
carried out overnight at room temperature under argon.2,13 The
usual workup followed by chromatography on silica gel eluted
with CH2Cl2 gave 11 (100 mg, 94%) as an orange solid: mp 175
2-Br om om eth yl-6-m eth oxyn a p h th a len e (5c). A solution
of PBr3 (4.3 mL, 45 mmol) in anhydrous ether (100 mL) was
added dropwise to a cold solution of 5b (7.27 g, 39 mmol) in
anhydrous ether (200 mL) at -30 to -40 °C under argon. The
solution was allowed to warm to room temperature in a period
of 2 h, then the reaction was neutralized by addition of 5%
aqueous NaHCO3 solution. The ether layer was washed with
water and dried over anhydrous MgSO4. Evaporation of the
solvent gave 5c as a white solid (9.09 g, 94%). Because of the
tendency of 5c to decompose, it was used directly in the next
step.
1
°C dec; H NMR (CDCl3) δ 8.39 (d, 1, J ) 10.48 Hz), 8.02 (d, 1,
J ) 7.69 Hz), 7.94-7.98 (m, 1), 7.52-7.59 (m, 2), 7.36-7.45 (m,
2), 6.45 (d, 1, J ) 10.49 Hz), 3.91 (s, 2, CH2); 13C NMR (CDCl3)
181.18, 179.21, 152.53, 144.31, 141.28, 140.44, 139.46, 131.43,
129.27, 129.13, 128.39, 127.59, 127.39, 126.86, 125.66, 123.79,
37.30. Anal. Calcd for C17H10O2: C, 82.91; H, 4.09. Found: C,
82.92; H, 4.14.
2-(2-Meth oxy-6-n a p h th ylm eth yl)cycloh exa n on e (7). Syn-
thesis of 7 was based on the method for the synthesis of BcF.9
Reaction of 5c (3.88 g, 15.5 mmol) with 6 followed by chroma-
tography of the crude product on a column of silica gel eluted
with hexane-EtOAc (9:1) gave 7 (3.02 g, 72%) as a white solid:
tr a n s-3,4-Dih yd r oxy-3,4-d ih yd r oben zo[c]flu or en e (2). To
a solution of 11 (70 mg, 0.28 mmol) in THF (40 mL) and ethanol
(150 mL) was added NaBH4 (1.0 g). The orange color disap-
peared, and the solution was stirred overnight with O2 bubbling
through it. The usual workup followed by chromatography on a
silica gel column eluted with EtOAc-hexane (1:1) gave 2 (50
1
mp 83-84 °C; H NMR (CDCl3) δ 7.64-7.67 (m, 2), 7.51 (s, 1),
7.25 (d, 1), 7.09-7.13 (m, 2), 3.89 (s, 3, CH3), 3.35 (dd, 1, one
benzylic CH2), 1.35-2.61 (m, 10, 1 benzylic and 9 aliphatic); 13
C
1
mg, 70%) as a white solid: mp 132-134 °C; H NMR (DMSO-
NMR (CDCl3) δ 212.60, 157.13, 135.40, 132.94, 128.88, 128.82,
127.20, 126.65, 118.66, 105.49, 55.20, 52.42, 42.11, 35.31, 33.32,
27.98, 24.97; FAB MS m/z 268 (M+). Anal. Calcd for C18H20O2:
C, 80.56; H, 7.51. Found: C, 80.69; H, 7.69.
d6) δ 8.02 (d, 1, J ) 7.70 Hz), 7.57 (d, 1, J ) 7.28 Hz), 7.49 (d,
1, J ) 7.62 Hz), 7.21-7.44 (m, 4), 6.11 (d, 1, J ) 10.01 Hz), 5.47
(d, 1, J ) 5.59 Hz, OH), 5.20 (d, 1, J ) 4.98 Hz, OH), 4.50-4.60
(m, 1, CH), 4.20-4.30 (m, 1, CH), 3.87 (s, 2, CH2); 13C NMR
(DMSO-d6) δ 143.93, 142.63, 141.10, 137.29, 135.75, 134.42,
127.36, 126.88, 126.30, 125.17, 123.95, 123.49, 123.01, 122.76,
73.81, 71.36, 36.03. Anal. Calcd for C17H14O2: C, 81.58; H, 5.64.
Found: C, 81.30; H, 5.77.
Cyclod eh yd r a tion of 7. Reaction of 7 (7.70 g, 26 mmol) in
CH2Cl2 (150 mL) and CH3SO3H (25 mL) was carried out by the
procedure for the preparation of BcF9 (16-h reaction). Chroma-
tography of the crude product on silica gel eluted with hexane-
CH2Cl2 (6:1) gave 7a,8,9,10,11,11a-hexahydro-3-methoxy-BcF (8)
(1.07 g, 33%) as a white solid: mp 70-71 °C: 1H NMR (CDCl3)
δ 7.75 (d, 1, J ) 8.83 Hz), 7.54 (d, 1, J ) 8.22 Hz), 7.36 (d, 1, J
) 8.23 Hz), 7.11-7.16 (m, 2), 3.90 (s, 3, CH3), 3.35-3.40 (m, 1,
benzylic CH), 3.03 (dd, 1, J ) 14.96 Hz, benzylic CH2), 2.80 (dd,
1, J ) 15.00 Hz, benzylic CH2), 2.61-2.71 (m, 1), 1.01-2.11 (m,
8); 13C NMR (CDCl3) 156.55, 145.70, 137.24, 133.67, 125.63,
125.17, 125.02, 124.40, 118.36, 106.49, 55.23, 42.67, 40.07, 35.13,
29.52, 27.24, 24.64, 21.86; FAB MS m/z 252 (M+). Anal. Calcd
for C18H20O: C, 85.67; H, 7.99. Found: C, 85.60; H, 7.97. Further
elution gave 8,9,10,11-tetrahydro-3-methoxy-BcF (9) (6.4%) as
a white solid: mp 76-77 °C; 1H NMR (CDCl3) δ 8.31 (d, 1, J )
9.23 Hz), 7.51 (s, 2), 7.18 (d, 1, J ) 2.68 Hz), 7.11 (d, 1, J ) 9.22
Hz), 3.92 (s, 3, CH3), 3.30 (s, 2, benzylic CH2), 2.99-3.02 (m, 2),
2.50-2.54 (m, 2), 1.79-1.94 (m, 4); 13C NMR (CDCl3) 156.19,
142.71, 141.18, 138.24, 136.94, 134.47, 125.50, 122.70, 122.67,
117.51, 106.80, 106.48, 55.10, 41.34, 26.78, 26.44, 23.31, 22.55;
tr a n s-3,4-Dih ydr oxy-a n ti-1,2-epoxy-1,2,3,4-tetr ah ydr oben -
zo[c]flu or en e (3). A solution of 3 (50 mg, 0.20 mmol) and
m-CPBA (350 mg) in anhydrous THF (40 mL) was stirred under
argon for 3 h. Then it was diluted with EtOAc and washed with
cold 10% NaOH solution (4 × 25 mL) and cold water (2 × 25
mL). The organic layer was dried over anhydrous Na2CO3, and
the solvent was removed under reduced pressure. All operations
were carried out rapidly and heating was avoided to minimize
hydrolysis and decomposition of the relatively sensitive diol
epoxide product. Trituration of the crude product with cold pure
1
EtOAc gave 3 (50 mg, 94%) as a white solid: mp 89 °C dec; H
NMR (DMSO-d6) δ 8.16 (d, 1, J ) 7.64 Hz), 7.61 (d, 1, J ) 7.09
Hz), 7.52-7.60 (m, 2), 7.32-7.42 (m, 2), 5.62 (d, 1, J ) 6.48 Hz,
OH), 5.56 (d, 1, J ) 4.92 Hz, OH), 4.92 (d, 1, J ) 4.45 Hz, CH),
4.35-4.43 (m, 1, CH), 3.91 (s, 2, CH2), 3.73-3.79 (m, 1, CH),
3.67 (d, 1, J ) 4.40 Hz, CH); 13C NMR (DMSO-d6) δ 144.18,
6218 J . Org. Chem., Vol. 67, No. 17, 2002

142.55, 140.44, 139.97, 139.92, 126.97, 126.77, 126.29, 125.48,
124.68, 124.00, 123.08, 71.16, 69.64, 55.93, 50.12, 36.15. Anal.
Calcd for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.38; H, 5.40.
2-â-Br om o-1r,3â,4r-tr ih yd r oxy-1,2,3,4-tetr a h yd r oben zo-
[c]flu or en e (12). A solution of 2 (50 mg, 0.20 mmol) and NBS
(200 mg, 1.12 mmol) in DMSO (10 mL) and water (0.3 mL) was
stirred at 30 °C for 6 h under argon. The usual workup followed
by chromatography on a silica gel column eluted with EtOAc-
hexane (2:1) afforded 12 (50 mg, 72%) as a, white solid: mp 149
°C dec; 1H NMR (DMSO-d6) δ 8.02 (d, 1, J ) 7.71 Hz), 7.50-
7.62 (m, 3), 7.28-7.43 (m, 2), 6.25 (d, 1, J ) 5.72 Hz, OH), 5.72
(d, 1, J ) 6.49 Hz, OH), 5.59 (d, 1, J ) 4.18 Hz, OH), 5.42-5.56
(m, 1, CH), 4.50-4.60 (m, 2, CH), 4.05-4.10 (m, 1, CH), 3.89 (s,
2, CH2); 13C NMR (DMSO-d6) δ 143.90, 142.84, 140.64, 139.75,
137.95, 128.44, 126.71, 126.35, 126.32, 124.84, 124.69, 124.08,
71.19, 70.19, 67.99, 61.22, 36.30. Anal. Calcd for C17H15BrO3:
C, 58.81; H, 4.35. Found: C, 58.59; H, 4.38.
temperature under argon for 25 min (reaction complete by TLC).
The solution was transferred to a separatory funnel, diluted with
cold EtOAc, and washed three times with cold water. The organic
layer was filtered and evaporated to dryness under reduced
pressure without heating. All operations were carried out rapidly
avoiding heating in order to minimize decomposition. Trituration
with cold pure EtOAc gave 4 (20 mg, 87%) as an off-white solid:
1
mp 177 °C dec; H NMR (DMSO-d6) δ 8.03 (d, 1, J ) 7.56 Hz),
7.57-7.67 (m, 2), 7.33-7.49 (m, 3), 5.70 (d, 1, J ) 4.85 Hz, OH),
5.35 (d, 1, J ) 6.40 Hz, OH), 4.53-4.59 (m, 1, CH), 4.49 (d, 1, J
) 4.24 Hz, CH), 3.95 (d, 1, J ) 22.0 Hz, CH2), 3.89 (d, 1, J )
22.0 Hz, CH2), 3.60-3.64 (m, 1, CH), 3.52-3.60 (m, 1, CH); 13
C
NMR (DMSO-d6) δ 143.95, 142.40, 140.72, 140.41, 138.98,
126.94, 126.90, 125.74, 125.41, 125.32, 125.11, 122.69, 71.33,
71.06, 58.78, 47.43, 36.20.
Ack n ow led gm en t. This research was supported by
a contract from the Electric Power Research Institute,
Palo Alto, CA.
tr a n s-3,4-Dih ydr oxy-syn -1,2-epoxy-1,2,3,4-tetr ah ydr oben -
zo[c]flu or en e (4). To a solution of 12 (30 mg, 0.086 mmol) in
anhydrous THF (10 mL) was added a solution of t-BuOK (15
mg) in t-BuOH (1 mL). The solution was stirred at room
J O011149B
J . Org. Chem, Vol. 67, No. 17, 2002 6219