An improved and regiospecific synthesis of trans-3,4-dihydrodiol metabolite of benzo[b]naphtho[2,1-d]thiophene

Full text of DOI:10.1021/jo991933k

J . Org. Chem. 2000, 65, 3883-3884
3883
(6). However, the synthesis of 8 was nonregiospecific and
required seven steps to produce it in <2.5% yield based
on the starting material 3-methylbenzo[b]thiophene. The
requirement of a fairly dilute solution during the photo-
cyclization of the stilbene derivative further limits the
efficiency of the synthesis of 6 and consequently of 8. The
present paper describes a short, regiospecific synthesis
of 8 from easily accessible reactants.
An Im p r oved a n d Regiosp ecific Syn th esis
of tr a n s-3,4-Dih yd r od iol Meta bolite of
Ben zo[b]n a p h th o[2,1-d ]th iop h en e
Subodh Kumar* and Tae-Young Kim1
Laboratory of Environmental Toxicology and Chemistry,
Great Lakes Center, and Department of Chemistry, State
University of New York College at Buffalo,
Buffalo, New York 14222
Received December 17, 1999
In tr od u ction
The thiachrysene, benzo[b]naphtho[2,1-d]thiophene
(BNT), a thiaster of chrysene, is an ubiquitous environ-
mental contaminant that has been detected in coal tar
and derivatives,2-4 crude oil,5,6 shale oil,7,8 fresh and used
engine oils,9,10 diesel exhaust,11,12 and in smoke conden-
sate of tobacco and related material.13 In a recent study,
BNT has been found in a concentration greater than
benzo[a]pyrene in the air samples of an aluminum
reduction plant.14 BNT has been shown to be metaboli-
cally activated to products mutagenic to Salmonella
typhimurium,15-17 and more tumorigenic than its carbon
analogue, chrysene.18 Recent studies have shown that,
like chrysene,19 BNT is also metabolized to benzo-ring
dihydrodiols20,21 together with the sulfoxide and the
sulfone.20-22 Among these metabolites, the sulfone and
trans-3,4-dihydroxy-3,4-dihydroBNT (8) are implicated in
the bioactivation of BNT.17,23 In an earlier study, Misra
and Amin17 reported the synthesis of 8 via 3-hydroxyBNT
Resu lts a n d Discu ssion
We have recently discovered the application of Suzuki
cross-coupling reaction of arylboronic acids with 2-bromo-
5-methoxybenzaldehyde (2) in the synthesis of the phe-
nolic derivatives of a number of PAHs,24-26 which are
suitable intermediates for the synthesis of carcinogenic
dihydrodiol and diol epoxide metabolites of PAHs. On the
basis of these studies, we visualized an analogous reac-
tion between benzo[b]thiophene-2-boronic acid (1) and
2-bromo-5-methoxybenzaldehyde (2) as a key step in for
the regiospecific synthesis of 6 (Scheme 1). Thus the
coupling reaction of 1 and 2 in refluxing dimethoxyethane
(DME) containing saturated sodium bicarbonate and a
catalytic amount of Pd(PPh3)4 produced 3 in 80-90%
yield. The reaction of aldehyde 3 with trimethylsulfonium
iodide and powdered potassium hydroxide in warm
acetonitrile (65 °C) produced nearly quantitative yield
of the relatively unstable ethylene oxide derivative 4. The
ethylene oxide formation under these conditions was
more rapid compared to the phase transfer conditions
reported for this kind of reaction.24 The acid-catalyzed
cyclization of the ethylene oxide 4 with boron trifluoride-
ether complex in anhydrous ether gave 3-methoxyBNT
(5) in 40-50% yield. 3-MethoxyBNT (5) has been pre-
pared previously in 5.6% yield by Elbs reaction of 3-(4-
methoxy-2-methylbenzoyl)benzo[b]thiophene.27 Demeth-
ylation of 5 with boron tribromide in methylene chloride
gave a nearly quantitative yield of 6. Oxidation of 6 with
Fremy’s salt produced exclusively BNT-3,4-dione (7)
which was finally reduced with sodium borohydride in
ethanol while bubbling oxygen through the solution
affording BNT trans-3,4-dihydrodiol (8). The 1H NMR
spectra of the dione 7 and the dihydrodiol 8 were
* To whom correspondence should be addressed. Phone: (716) 878-
5422. Fax: (716) 878-5400. E-mail: kumarsk@buffalostate.edu.
(1) Graduate Research Assistant in the Department of Chemistry
(1998-1999).
(2) Nishioka, M.; Bradshaw, J . S.; Lee, M. L.; Tominaga, Y.;
Tedjamulia, M.; Castle, R. N. Anal. Chem. 1985, 57, 309.
(3) Lucke, R. B.; Later, D. W.; Wright, C. W.; Chess, E. K.; Weimer,
W. C. Anal. Chem. 1985, 37, 633.
(4) Burchill, P.; Herod, A. A.; Pritchard, E. J . Chromatogr. 1982,
242, 51.
(5) Ho, T. Y.; Roger, M. A.; Drushel, H. V.; Koons, C. V. Am. Assoc.
Petr. Geol. Bull. 1975, 58, 2338.
(6) Grimmer, G.; J acob, J .; Naujack, K.-W. Fresenius Z. Anal. Chem.
1983, 314, 29.
(7) Kong, R. C.; Lee, M. L.; Tominaga, Y.; Pratap, R.; Thompson, R.
D.; Castle, R. N. Fuel 1984, 63, 702.
(8) Willey, C.; Iwao, M.; Castle, R. N.; Lee, M. L. Anal. Chem. 1981,
53, 400.
(9) Grimmer, G.; J acob, J . Naujack, K.-W. Fresenius Z. Anal. Chem.
1981, 306, 347.
(10) Grimmer, G.; J acob, J .; Naujack, K.-W.; Dettbarn, G. Fresenius
Z. Anal. Chem. 1981, 309, 13.
(11) Yu, L. M.; Hites, R. A. Anal. Chem. 1981, 53, 951.
(12) Tong, H. Y.; Karasek, F. W. Anal. Chem. 1984, 56, 2129.
(13) Bhide, S. V.; Murdia, U. S.; Nair, J . Cancer Lett. 1984, 24, 89.
(14) Becker, G.; Colmsjo, A.; Ostman, C. Environ. Sci. Technol. 1999,
33, 1321.
(15) Pelroy, R. A.; Stewart, D. L.; Tominaga, Y, Iwao, M.; Castle, R.
N.; Lee, M. L. Mutat. Res. 1984, 117, 31.
(16) McFall, T.; Boothe, G. M.; Lee, M. L.; Tominaga, Y.; Pratap,
R.; Tedjamulia, M.; Castle, R. N. Mutat. Res. 1984, 135, 97.
(17) Misra, B.; Amin, S. Chem. Res. Toxicol. 1990, 3, 93.
(18) Croisy, A.; Mispelter, J .; Lhoste, J . M.; Zajdela, F.; J acquignon
J . Heterocycl. Chem. 1984, 21, 353.
(19) Nordqvist, M.; Thakker, D. R.; Vyas, K. P.; Yagi, H.; Levin, W.;
Ryan, D. E.; Thomas, P. E.; Conney, A. H.; J erina, D. M. Mol.
Pharmacol. 1981, 18, 168.
(20) J acob, J .; Schmoldt, A.; Augustin, C.; Raab, G.; Grimmer, G.
Toxicology 1991, 67, 181.
(21) Murphy, S. E.; Amin, S.; Coletta, K.; Hoffmann, D. Chem. Res.
Toxicol. 1992, 5, 491.
(22) J acob, J .; Schmoldt, A.; Grimmer, G. Cancer Lett. 1986, 32, 107.
(23) J acob, J . Sulfur analogues of polycyclic aromatic hydrocarbons
(thiaarenes): Environmental occurrence, chemical and biological prop-
erties; Cambridge University Press: Cambridge, England, 1990.
(24) Kumar, S. J . Org. Chem. 1997, 62, 8535.
(25) Kumar, S. Tetrahedron Lett. 1996, 37, 6271.
(26) Kumar, S. J . Chem. Soc., Perkin Trans. 1 1998, 3157.
(27) Marie, C.; Buu-Hoi, N. P.; J acquignon J . Chem. Soc. (C) 1971,
431.
10.1021/jo991933k CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/24/2000

3884 J . Org. Chem., Vol. 65, No. 12, 2000
Notes
to afford a solid which was recrystallized from EtOAc-hexane
to yield 1.55 g (83%) of 3 as nearly colorless crystals, mp 125-
127 °C. 1H NMR (500 MHz, CDCl3) δ 3.91 (s, 3 H), 7.19 (dd, 1
H, J ) 8.5, 3.5 Hz), 7.26 (s, 1 H), 7.35-7.44 (m, 2 H), 7.52 (d, 1
H, J ) 3 Hz), 7.55 (d, 1 H, J ) 8.5 Hz), 7.81 (d, 1 H, J ) 7.6 Hz),
7.86 (d, 1 H, J ) 7.9 Hz), 10.22 (s, 1 H). 13C NMR (300 MHz,
CDCl3) δ 191.6 (CHO), 159.9, 140.5, 139.9, 138.8, 135.4, 132.7,
130.9, 125.9, 124.8, 124.7, 123.7, 122.1, 121.2, 110.3, 55.7 (OMe).
Anal. Calcd For C16H12O2S: C, 71.6; H, 4.5. Found: C, 71.2; H,
4.4.
Sch em e 1
3-Meth oxyben zo[b]n a p h th o[2,1-d ]th iop h en e (5). A mix-
ture of 3 (1.04 g, 3.88 mmol), trimethylsulfonium iodide (0.85 g,
4.16 mmol), and powdered KOH (0.64 g, 16 mmol) in acetonitrile
(50 mL) containing traces of water (0.1 mL) was stirred under
argon at 65-70 °C for 16 h. The mixture was cooled, and
extracted with EtOAc. The organic phase was washed with
water, dried over Na2SO4, and concentrated in vacuo to yield
1.06 g (97%) sufficiently pure, relatively unstable 2-(2-(2-(epoxy-
ethyl)-4-methoxyphenyl)benzo[b]thiophene (4) as a colorless
1
syrupy oil. H NMR (400 MHZ, CDCl3) of the major product: δ
2.82 (dd, 1 H, J A,B ) 5.9 Hz, J A,M ) 2.6 Hz), 3.18 (dd, 1 H, J B,M
) 4.4 Hz), 3.86 (s, 3 H), 4.13 (pseudo-t, 1 H), 6.88-7.88 (m, 8
H). The product was used as such in the next step without
further purification.
The cyclization of the epoxide 4 (1.06 g, 3.76 mmol) was
performed in a solution of anhydrous ether (65 mL) by dropwise
addition of BF3‚Et2O (3.9 mL, 31.7 mmol) at 0 °C under argon.
The solution was stirred for 15 h at room temperature. After
completion of the reaction (monitored by TLC), the excess of BF3‚
Et2O was decomposed by addition of cold water. The product
was extracted with CH2Cl2, and the combined organic extracts
were successively washed with 10% NaHCO3 and water and
dried over Na2SO4. After removal of the solvent, the residue was
chromatographed over dry column grade silica gel using hexane
as eluant to produce 0.48 g (48.5%) of 5 as colorless crystals,
consistent with their structures and nearly identical to
those reported earlier for these compounds.17
1
mp 166 °C (lit.27 mp 171 °C). H NMR (400 Mz, CDCl3): δ 3.98
In summary, the present study describes an efficient
application of the palladium-catalyzed cross-coupling
reaction of readily available reactants to the concise and
regiospecific synthesis of 3-methoxyBNT (5) and BNT
trans-3,4-dihydrodiol (8). The overall yield of 8 from
bromoaldehyde 2 was 27% which represent a significant
improvement over the previous method.17 In addition to
providing a practical and concise synthesis of 5 and 8,
the present method holds promise as a general route to
the synthesis of analogous phenolic and dihydrodiol
metabolites of substituted BNTs and other thia-PAHs.
(s, 3 H), 7.29 (dd, 1 H, J ) 2.4 Hz, 8.8 Hz), 7.31 (d, 1 H, J ) 2.4
Hz), 7.42-7.54 (m, 2 H), 7.79 (d, 1 H, J ) 8.8 Hz), 7.95 (d, 1 H,
J ) 7.3 Hz), 8.50 (d, 1 H, J ) 8.8 Hz), 8.15 (d, 1 H, J ) 8.4 Hz),
8.18 (d, 1 H, J ) 7.3 Hz).
3-Hyd r oxyben zo[b]n a p h th o[2,1-d ]th iop h en e (6). To a
stirred solution of 5 (0.96 g, 3.8 mmol) in anhydrous CH2Cl2 (25
mL) was added a 1 M solution of BBr3 (7.4 mL, 7.4 mmol) in
CH2Cl2 over a period of 2-3 min. After 12 h at room tempera-
ture, the mixture was hydrolyzed with ice-cold water, the organic
layer was washed with water and dried (Na2SO4), and the
solvent was removed to afford a solid. Trituration of the solid
with hexane produced 0.76 g (84%) of pure 6, mp 228-230 °C
(lit.17 mp 232-234 °C).
Ben zo[b]n a p h th o[2,1-d ]th iop h en e-3,4-d ion e (7). A solu-
tion of 6 (0.60 g, 2.49 mmol) in 200 mL of CH2Cl2/benzene (16:
84) containing 9 drops of adogen-464 and 0.17 M KH2PO4 (70
mL) was stirred at room temperature while Fremy’s salt (1.62
g, 6.06 mmol) was added in one portion with vigorous stirring.
After stirring for 2 h at room temperature, the organic layer
was separated, washed with water, and dried over Na2SO4.
Evaporation of the solvent and the recrystallization of dark
residue with CH2Cl2-hexane yielded 0.57 g (90.5%) of 7 as a
bright red crystalline solid, mp 177-181 °C (lit.17 mp 178-180
°C).
Tr a n s-3,4-d ih yd r oxy-3,4-dih yd r oben zo[b]n a p h th o[2,1-d ]-
th iop h en e (8). To a well stirred suspension of quinone 7 (0.32
g, 1.2 mmol) in 250 mL of ethanol was added NaBH4 (2.32 g,
81.2 mmol). The mixture was stirred at room temperature while
a stream of oxygen was bubbled through the solution. After 16
h of stirring, the resulting light yellow solution was concentrated
at room temperature under vacuum to one-third of its original
volume. The residue was diluted with water, extracted with
EtOAc, dried (Na2SO4), and concentrated. Trituration of the resi-
due with 10% EtOAc-hexane afforded 0.28 g (86%) of 8 as light
yellow solid, mp 205-207 °C. 1H NMR (400 MHz, acetone-d6)
spectrum of 8 was identical to that reported in the literature.17
Exp er im en ta l Section
Benzo[b]thiophene-2-boronic acid (1) was obtained commer-
cially (Lancaster synthesis). 2-Bromo-5-methoxybenzaldehyde
(2) was synthesized according to the published procedure.28 All
reagents and solvents (anhydrous or otherwise) were used as
received without further purification. Dry column grade silica
gel was purchased from E. Merck. NMR spectra were recorded
on 300, 400, or 500 MHZ NMR spectrometer in an appropriate
solvent with tetramethylsilane (TMS) as internal standard at
the NMR facility of the Chemistry Department, State University
of New York, Buffalo, NY. Chemical shifts were recorded in ppm
downfield from the internal standard. All the melting points
were uncorrected.
2-(Ben zo[b]th ien yl)-5-m eth oxyben za ld eh yd e (3). A mix-
ture of 2-bromo-5-methoxybenzaldehyde (2) (1.5 g, 7.0 mmol) and
Pd(PPh3)4 (0.27 g, 0.73 mmol) in dimethoxyethane (40 mL) was
stirred for 20 min in an argon atmosphere. To this mixture were
added saturated NaHCO3 (10 mL) and benzo[b]thiophene-2-
boronic acid (1) (1.36 g, 7.7 mmol), and the resulting mixture
was refluxed with stirring. The progress of the reaction was
monitored by TLC (5% EtOAc-hexane) for 1 h at which point
no more bromide 2 was detected. The reaction mixture was
cooled to rt, diluted with water (50 mL), and then extracted with
CH2Cl2. The organic solution was separated, washed with 5%
NaOH and water, and dried (Na2SO4). The solvent was removed
Ack n ow led gm en t. This study has been, in part,
supported by Grant R826192-01-0 from U. S. Environ-
mental Protection Agency, Washington, D.C., awarded
to S.K.
(28) Fleming, I.; Woolias, M. J . J . Chem. Soc., Perkin Trans. 1 1979,
829.
J O991933K