A highly abbreviated synthesis of dibenzo[def,p]chrysene and its 12-methoxy derivative, a key precursor for the synthesis of the proximate and ultimate carcinogens of dibenzo[def,p]chrysene

Article abstract of DOI:10.1021/jo0303822

Dibenzo[def,p]chrysene (DBC) (1), is by far the most mutagenic and toxic polycyclic aromatic hydrocarbon identified. Its metabolic activation leads to trans-11,12-dihydroxy-11,12-dihydro-DBC (2), which is further metabolized to the ultimate metabolite, anti-trans-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydro-DBC (3), that binds to DNA causing mutations and ultimately tumor induction. We report a facile route for the syntheses of DBC (1) and its 12-methoxy derivative (12-methoxy-DBC) (13), a key intermediate for the synthesis of 2 and 3, using a Suzuki cross-coupling approach.

Full text of DOI:10.1021/jo0303822

8,9-dihydroxy-8,9-dihydro-DBC, trans-11,12-dihydroxy-
11,12-dihydro-DBC (2), and 7-hydroxy-DBC as its major
metabolites. Furthermore, Baird et al.8 have reported
that DBC activation in cultures of the human mammary
carcinoma cell line (MCF-7) led to fjord-region anti- and
syn-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydro-
DBC, which bind extensively to deoxyadenosine (dA) in
DNA.9 Both of these fjord region diol epoxides have been
shown to be far more potent than any of the previously
investigated diol epoxides in four His strains of Salmo-
nella typhimurium as well as in Chinese hamster V79
cells.10 In addition, the anti-trans-11,12-dihydroxy-13,14-
epoxy-11,12,13,14-tetrahydro-DBC (3) was found to be a
potent carcinogen in newborn mice11 and in the rat
mammary gland,12 besides being moderately carcinogenic
on mouse skin.13
A High ly Abbr evia ted Syn th esis of
Diben zo[d ef,p]ch r ysen e a n d Its 12-Meth oxy
Der iva tive, a Key P r ecu r sor for th e
Syn th esis of th e P r oxim a te a n d Ultim a te
Ca r cin ogen s of Diben zo[d ef,p]ch r ysen e
Arun K. Sharma,*,† Subodh Kumar,‡ and Shantu Amin†
Institute for Cancer Prevention, American Health
Foundation Cancer Center, 1 Dana Road, Valhalla,
New York 10595, and Environmental Toxicology and
Chemistry Laboratory, Great Lakes Center,
State University of New York College at Buffalo, 1300
Elmwood Avenue, Buffalo, New York 14222
asharma@ifcp.us
Received December 16, 2003
Abstr a ct: Dibenzo[def,p]chrysene (DBC) (1), is by far the
most mutagenic and toxic polycyclic aromatic hydrocarbon
identified. Its metabolic activation leads to trans-11,12-
dihydroxy-11,12-dihydro-DBC (2), which is further metabo-
lized to the ultimate metabolite, anti-trans-11,12-dihydroxy-
13,14-epoxy-11,12,13,14-tetrahydro-DBC (3), that binds to
DNA causing mutations and ultimately tumor induction. We
report a facile route for the syntheses of DBC (1) and its
12-methoxy derivative (12-methoxy-DBC) (13), a key inter-
mediate for the synthesis of 2 and 3, using a Suzuki cross-
coupling approach.
Previous syntheses of DBC (1)10,13,14 and its dihydrodiol
2 with a fjord region double bond10,13,15,16 have been
reported in the literature. However, the methods either
involve many steps or cannot be adapted to the large-
scale synthesis of 2 and 3 because of reaction limitations
in the synthesis of their key precursor, i.e., appropriately
substituted methoxy derivatives of DBC.10,13,15,16 As part
of our overall program to synthesize dA and deoxygua-
nosine (dG) adducts of DBC and corresponding phos-
phoramidites for the preparation of specifically adducted
oligomers, we have developed an abbreviated, high-yield
synthesis of DBC and its 12-methoxy derivative (Scheme
1), an intermediate for the synthesis of 2 and 3, involving
the Suzuki cross-coupling reaction. The palladium-
catalyzed cross-coupling reaction of aryl halides with
boronic acid is one the most versatile and widely used
procedures for selective construction of carbon-carbon
bonds.17 The method is easy, gives high yields, and can
Dibenzo[def,p]chrysene (DBC) (1) (commonly known as
dibenzo[a,l]pyrene), a peri-condensed hexacyclic polycy-
clic aromatic hydrocarbon (PAH), possesses a bay and a
fjord region and is the most carcinogenic PAH compound
known to date.1 It has been identified in cigarette smoke
condensate,2 coal combustion emissions,3 and in soil and
sediments.4 DBC is a potent tumorigen on mouse skin,
in mammary glands,5 and in lungs.6 Because of its
potency as a carcinogen, DBC has attracted the increas-
ing attention of chemists and biologists. A metabolism
study by Cavalieri and co-workers7 has identified trans-
† American Health Foundation Cancer Center.
‡ State University of New York College at Buffalo.
(1) (a) Cavalieri, E. L.; Higginbotham, S.; Rogan, E. G. Polycyclic
Aromat. Compd. 1994, 6, 177. (b) Cavalieri, E. L.; Rogan, E. G.;
Higginbotham, S.; Cremonesi, P.; Salmasi, S. J . Cancer Res. Clin.
Oncol. 1989, 115, 67.
(2) Snook, M. E.; Severson, R. F.; Arrendale, R. F.; Highman, H. C.;
Chortyk, O. T. Beitr. Tabakforsch. 1977, 9, 79.
(3) (a) Mumford, J . L.; Harris, D. B.; Williams, K. Environ. Sci.
Technol. 1987, 21, 308. (b) Mumford, J . L.; Xueming, L.; Fuding, H.;
Xu, B. L.; Chuang, J . C. Carcinogenesis 1995, 16, 3031. (c) DeRatt, W.
K.; Kooijman, S. A. L. M.; Gielen, J . W. J . Sci. Total Environ. 1989,
66, 95.
(4) Kozin, I. S.; Gooijer, C.; Velthorst, N. H. Anal. Chem. 1995, 67,
1623.
(5) (a) Cavalieri, E. L.; Higginbothom, S.; RamaKrishna, N. V. S.;
Devanesan, P. D.; Todorovic, R.; Rogan, E. G.; Salmasi, S. Carcino-
genesis 1991, 12, 1939. (b) Higginbothom, S.; RamaKrishna, N. V. S.;
J ohansson, S. L.; Rogan, E. G.; Cavalieri, E. L. Carcinogenesis 1993,
14, 875. (c) La Voie, E. J .; He, Z.-M.; Meegala, R. L.; Weyand, E. H.
Cancer Lett. 1993, 70, 7.
(6) Prahalad, A. K.; Ross, J . A.; Nelson, G. B.; Roop, B. C.; King, L.
C.; Nesnow, S.; Mass, M. J . Carcinogenesis 1997, 18, 1955.
(7) Devanesan, P. D.; Cremonesi, P.; Nunnally, J . E.; Rogan, E. G.;
Cavalieri, E. L. Chem. Res. Toxicol. 1990, 3, 580.
(8) Ralston, S. L.; Lau, H. H. S.; Seidel, A.; Luch, A.; Platt, K. L.;
Baird, W. M. Cancer Res. 1994, 54, 887.
(9) Ralston, S. L.; Seidel, A.; Luch, A.; Platt, K. L.; Baird, W. M.
Carcinogenesis 1995, 16, 2899.
(10) Luch, A.; Glatt, H.; Platt, K. L.; Oesch, F.; Seidel, A. Carcino-
genesis 1994, 15, 2507.
(11) Amin, S.; Desai, D.; Dai, W.; Harvey, R. G.; Hecht, S. S.
Carcinogenesis 1995, 16, 2813.
(12) Amin, S.; Krzeminski, J .; Rivenson, A.; Kurtzke, C.; Hecht, S.
S.; El-Bayoumy, K. Carcinogenesis 1995, 16, 1971.
(13) Gill, H. S.; Kole, P. L.; Wiley, J . C.; Li, K.-M.; Higginbotham,
S.; Rogan, E. G.; Cavalieri, E. L. Carcinogenesis 1994, 15, 2455.
(14) Vingiello, F. A.; Yanez, J .; Cambell, J . A. J . Org. Chem. 1971,
36, 2053.
(15) Krzeminski, J .; Lin, J .-M.; Amin, S.; Hecht, S. S. Chem. Res.
Toxicol. 1994, 7, 125.
(16) Zhang, J .-T.; Harvey, R. G. Tetrahedron 1999, 55, 625.
(17) For recent reviews, see: (a) Hassan, J .; Sevignon, M.; Gozzi,
C.; Schulz, E.; Lamaire, M. Chem. Rev. 2002, 102, 1359. (b) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (c) Suzuki, A.
J . Organomet. Chem. 1999, 576, 147. (d) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457. (e) Suzuki, A. Pure Appl. Chem. 1994, 66, 213.
10.1021/jo0303822 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/28/2004
J . Org. Chem. 2004, 69, 3979-3982
3979

SCHEME 1 a
a
Reagents and conditions. (i) Br2, CCl4. (ii) CsF, Pd(PPh3)4, DME, reflux. (iii) Ph-NH2, toluene, reflux. (iv) t-BuOK, DMF. (v) KOH,
DMF, 100 °C. (vi) DDQ, PhH, reflux, 30 min.
be adapted to large-scale synthesis. Therefore, it is used
not only in research laboratories but also on an industrial
scale.18 The Suzuki reaction has recently been applied
to the synthesis of PAH ring systems.19-23 In our labora-
tory, we have utilized this approach for the synthesis of
benzo[c]phenanthrene,19c benzo[g]chrysene,19c naphtho-
[1,2-a]pyrene,19c,20 naphtho[1,2-e]pyrene,19c,21 5-methyl-
chrysene,19a benzo[c]chrysene,23 7,12-dimethylbenz[a]an-
thracene,23 and their metabolites.20-23
The synthesis of DBC and the 12-methoxy-DBC is
outlined in Scheme 1. 5,6-Dihydro-4H-benz[de]anthracene
(4) was prepared from benzanthrone in 74% yield ac-
cording to the reported procedure.24 Bromination of 4
using Br2 in CCl4 led exclusively to the formation of the
7-bromo derivative 5. Palladium-catalyzed Suzuki cou-
pling reaction of 2-formylphenylboronic acid with 7-bromo-
5,6-dihydro-4H-benz[de]anthracene (5) gave the aldehyde
6. Intramolecular cyclization of 6 to 11 was investigated
by applying synthetic strategy analogous to the widely
used Siegrist reaction for the synthesis of stilbenes.25
Thus, the treatment of 6 with aniline in CH2Cl2 in the
presence of molecular sieves (4 Å) furnished the imine
8. An attempt to purify imine 8 by column chromatog-
raphy led to decomposition so that about 50% of it
reverted to aldehyde 6. However, the crude 8 was nearly
pure and was used as such for cyclization reaction.
Heating of the imine 8 in DMF in the presence of KOH
gave a mixture of 8,9-dihydro-DBC (11) (∼90%) and DBC
1
(1) (∼10%) as determined by H NMR. Mechanistically,
this transformation involves the formation of benzylic
anion by KOH, followed by the cyclization and base-
assisted elimination of aniline to give 11. The elimination
of aniline from intermediate 10 requires trans arrange-
ment of the anilino group and the vicinal hydrogen, and
such elimination of arylamines has been observed by us
earlier in the synthesis of substituted pyrimidinones.26
The formation of about 10% of DBC is attributed to
the KOH-assisted tandem aromatization. This percentage
could not be improved, even by heating the reaction for
24 h. Though this mixture was column-separable, for our
purpose, we treated it as such with DDQ in refluxing
benzene to afford DBC (1) in excellent yield. The struc-
ture was confirmed by 1H NMR, MS, and mp, all of which
were comparable to values reported in the literature.10,13
(18) Ennis, D.; McManus, J .; Wood-Kaczmar, W.; Richardson, J .;
Smith, G. E.; Carstairs, A. Org. Process Res. Dev. 1999, 3, 248.
(19) (a) Kumar, S. J . Chem. Soc., Perkin Trans. 1 1998, 3157. (b)
Zhang, F. J .; Cortez, C.; Harvey, R. G. J . Org. Chem. 2000, 65, 3952.
(c) Kumar, S. Synthesis 2001, 841. (d) Rice, J . E.; Cai, Z.-W. J . Org.
Chem. 1993, 58, 1415.
(20) Desai, D.; Sharma, A. K.; Lin, J .-M.; Krzeminski, J .; Pimental,
M.; El-Bayoumy, K.; Nesnow, S.; Amin, S. Chem. Res. Toxicol. 2002,
15, 964.
There are examples of aromatization of PAHs using
strong bases such as n-BuLi.27 The formation of about
10% of DBC on treatment of imine 8 with KOH indicated
that a stronger base might lead to complete formation of
DBC from the imine in one step. In view of this, we
(21) Desai, D.; Sharma, A. K.; Lin, J .-M.; El-Bayoumy, K.; Amin,
S.; Pimental, M.; Nesnow, S. Polycyclic Aromat. Compd. 2002, 22, 267.
(22) Kumar, S. J . Org. Chem. 1997, 62, 8535.
(23) Sharma, A. K.; Kumar, S.; Amin, S. Polycyclic Aromat. Compd.
2002, 22, 277.
(24) Ansell, L. L.; Rangarajan, T.; Burgess, W. M.; Eisenbraun, E.
J . Org. Prep. Proced. Int. 1976, 8, 133.
(26) (a) Dey, P. D.; Sharma, A. K.; Bharatam, P. V.; Mahajan, M.
P. Tetrahedron 1997, 53, 13829. (b) Dey, P. D.; Sharma, A. K.; Rai, S.
N.; Mahajan, M. P. Tetrahedron 1995, 51, 7459.
(25) Newman, M. S.; Dhawan, B.; Kumar, S. J . Org. Chem. 1976,
43, 524 and references therein.
(27) (a) Harvey, R. G.; Nazareno, L.; Cho, H. J . Am. Chem. Soc. 1973,
95, 2376. (b) Harvey, R. G.; Cho, H. J . Am. Chem. Soc. 1974, 96, 2434.
3980 J . Org. Chem., Vol. 69, No. 11, 2004

7.6 and 1.0 Hz), 7.41-7.46 (m, 2H), 7.57-7.65 (m, 3H), 7.76 (dt,
1H, J ) 7.6 and 1.3 Hz), 8.17 (dd, 1H, J ) 7.9 and 1.0 Hz), 8.64
(d, 1H, J ) 8.5 Hz), 8.74 (d, 1H, J ) 7.9 Hz), 9.61 (s, 1H). HRMS
calcd for C24H18O, 322.1352; found, 322.1357.
treated imine 8 with t-BuOK in DMF at room tempera-
ture. As expected, this gave DBC in 83% yield. While this
shortcut did not change the overall yield of the total
synthesis it definitely reduced one step.
7-(2-F or m yl-4-m eth oxy)p h en yl-5,6-d ih yd r o-4H-ben z[d e]-
a n th r a cen e (7). A mixture of 7-bromo-5,6-dihydro-4H-benz[de]-
anthracene (5) (2.67 g, 9.0 mmol), 2-formyl-(4-methoxyphenyl)-
boronic acid (1.78 g, 9.9 mmol), cesium fluoride (3.0 g, 19.8
mmol), and Pd(PPh3)4 (0.42 g, 19.8 mmol) in anhydrous DME
(70 mL) was refluxed for 24 h. A similar workup as described
for 6 gave the crude product, which was purified by silica gel
column chromatography (EtOAc/hexanes 3:97) as eluent to yield
7 (2.05 g, 65%) as a pale yellow crystalline solid. mp 213-214
To demonstrate the scope of this new method, we
applied the described reaction sequence to the synthesis
of 12-methoxy-DBC, the key intermediate for the syn-
thesis of trans-dihydrodiol 2 and anti-diol epoxide 3 of
DBC.13,15 The palladium-catalyzed Suzuki coupling reac-
tion of 2-formyl-4-methoxyphenylboronic acid28 with 5
gave the aldehyde 7 which, on treatment with aniline in
CH2Cl2 in the presence of 4 Å molecular sieves, afforded
the imine 9. Unlike imine 8, the methoxy-substituted
imine 9 was found to be stable to silica gel column
chromatography and thus was column purified without
any loss due to decomposition. It was then easily con-
verted to 12-methoxy-DBC (13) by treatment with t-
BuOK in DMF or by heating in DMF in the presence of
KOH, followed by treatment with DDQ in refluxing
benzene. The structure of 13 was assigned on the basis
of 1H NMR, MS, and mp, which were comparable to those
reported in the literature.13
In conclusion, the synthesis involving the Suzuki cross-
coupling reaction proved to be an excellent method for
preparing large quantities of DBC and its 12-methoxy
derivative in fewer steps with a high overall yield (∼33%)
from easily accessible reagents. The availability of a high-
yielding synthesis of 12-methoxy-DBC will allow us to
obtain 2 and 3 in practical quantities for the synthesis
of site-specific adducted oligonucleotides that will enable
the elucidation of molecular mechanisms by which DBC
induces its carcinogenic activity. The synthesis of these
site-specific adducted oligonucleotides has not yet been
attempted largely because of the lack of an efficient and
convenient method for the synthesis of 2 and 3.
1
°C. H NMR: δ 1.98 (m, 2H), 2.61-2.80 (m, 2H), 3.14 (t, 2H, J
) 6.2), 3.97 (s, 3H), 7.22-7.27 (m, 2H), 7.33 (dd, 1H, J ) 8.2
and 2.9 Hz), 7.41-7.46 (m, 2H), 7.56-7.62 (m, 2H), 7.55 (d, 1H,
J ) 2.9 Hz), 8.63 (d, 1H, J ) 8.2 Hz), 8.73 (d, 1H, J ) 8.2 Hz),
9.55 (s, 1H). HRMS calcd for C25H20O2, 352.1458; found, 352.1467.
N-[2-(5,6-Dih yd r o-4H-ben z[d e]a n th r a cen -7-yl)ben zylid e-
n e]a n ilin e (8). To a solution of aniline (0.23 g, 0.23 mL, 2.5
mmol) in CH2Cl2 (20 mL) at 0 °C were added the molecular
sieves (4 Å, 1.0 g), and a solution of 6 (0.80 g, 2.5 mmol) in
CH2Cl2 (10 mL) was introduced dropwise. The reaction mixture
was stirred for 4 h, filtered, and concentrated to give 0.95 g (96%)
of the imine 8, which was used as such for cyclization. It was
recrystallized from a mixture of ether and hexanes. mp 162-
163 °C. 1H NMR: δ 1.93-2.03 (m, 2H), 2.65-2.85 (m, 2H), 3.15
(t, 2H, J ) 6.2 Hz), 6.82-6.84 (m, 2H), 7.03-7.07 (m, 1H), 7.14-
7.18 (m, 2H), 7.29-7.31 (m, 2H), 7.41-7.46 (m, 2H), 7.57-7.64
(m, 4H), 8.02 (s, 1H), 8.51 (d, 1H, J ) 6.9 Hz), 8.64 (d, 1H, J )
8.2 Hz), 8.74 (d, 1H, J ) 8.2 Hz). HRMS calcd for C30H23N,
397.1825; found, 397.1835.
N-[2-(5,6-Dih yd r o-4H -b en z[d e]a n t h r a cen -7-yl)-5-m et h -
oxyben zylid en e]a n ilin e (9). To a solution of aniline (0.46 g,
0.45 mL, 5.0 mmol) in CH2Cl2 (40 mL) at 0 °C were added the
molecular sieves (4 Å, 2 g), and a solution of 7 (1.76 g, 5.0 mmol)
in CH2Cl2 (20 mL) was introduced dropwise. The reaction
mixture was stirred for 4 h, filtered, and concentrated to give a
nearly pure imine, which was purified by column chromatogra-
phy (EtOAc/hexanes 2:98) to give 2.0 g (94%) of the imine 9 as
1
a pale yellow solid. mp 145-146 °C. H NMR: δ 1.93-2.03 (m,
2H), 2.67-2.86 (m, 2H), 3.14 (t, 2H, J ) 6.2), 4.02 (s, 3H), 6.68-
6.71 (m, 2H), 7.03-7.07 (m, 1H), 7.14-7.20 (m, 4H), 7.34 (dd,
1H, J ) 8.2 and 1.0 Hz), 7.36 (dd, 1H, J ) 7.6 and 1.0 Hz), 7.42-
7.46 (m, 2H), 7.56-7.62 (m, 2H), 7.97 (s, 1H) 7.99 (d, 1H, J )
2.3 Hz), 8.63 (d, 1H, J ) 8.2 Hz), 8.73 (d, 1H, J ) 8.2 Hz). HRMS
calcd for C31H25NO, 427.1931; found, 427.1938.
Diben zo[d ef,p]ch r ysen e (1). Meth od 1. To a solution of 8
(0.60 g, 1.5 mmol) in DMF (6 mL) was added powdered KOH
(0.25 g, 4.5 mmol), and the reaction mixture was heated at 100
°C for 1 h. The reaction mixture was cooled, and water was
added, extracted with CH2Cl2, and dried over MgSO4. After
removal of solvent, the crude product obtained was purified by
silica gel column chromatography (EtOAc/hexane 2:98) to give
a mixture of DBC (1) and 11 in ∼ 1:9 ratio (as determined by
1H NMR). To a solution of this mixture in C6H6 was added DDQ
(1.02 g, 4.5 mmol), and the reaction was refluxed for 30 min.
The mixture was cooled, filtered, and concentrated. Purification
of the crude residue on silica gel column (EtOAc/hexanes 2:98)
gave 1 (0.40 g, 88%) as a pale yellow solid.
Meth od 2. To a solution of imine 8 (0.16 g, 0.4 mmol) in DMF
(4 mL) was added t-BuOK (0.13 g, 1.2 mmol), and the reaction
mixture was stirred at room temperature for 6 h. Water was
then added to the reaction mixture, and it was extracted with
EtOAc and dried over MgSO4. Removal of the solvent gave the
crude mixture, which was purified by silica gel column chroma-
tography (EtOAc/hexanes 2:98) to give 1 (0.1 g, 83%) as a pale
yellow solid. mp 161-162 °C (ref 10: mp 159-160 °C; ref 14:
162-163 °C). 1H NMR: δ 7.66-7.79 (m, 4H), 7.84 (d, 1H, J )
9.2 Hz), 7.95 (d, 1H, J ) 9.2 Hz), 7.99 (dd, 1H, J ) 7.8 and 7.6
Hz), 8.07 (d, 1H, J ) 7.6 Hz), 8.26-8.29 (m, 1H), 8.49 (s, 1H),
8.88-8.91 (m, 2H), 9.10 (d, 1H, J ) 7.8 Hz), 9.20-9.23 (m, 1H).
12-Meth oxyd iben zo[d ef,p]ch r ysen e (13). Meth od 1. To a
solution of 9 (0.85 g, 2.0 mmol) in DMF (9 mL) was added
Exp er im en ta l Section
7-Br om o-5,6-d ih yd r o-4H-ben z[d e]a n th r a cen e (5). A well-
stirred solution of 424 (4.36 g, 20 mmol) in CCl4 (40 mL) was
heated to gentle reflux, and to this was added bromine (3.83 g,
1.23 mL, 24 mmol) in CCl4 (20 mL) dropwise over a period of 1
h. The mixture was refluxed for an additional 2 h, cooled, and
poured into ice-cold water. It was then extracted with ethyl
acetate, dried (MgSO4), and concentrated in vacuo. The crude
product was purified by a silica gel column chromatography
(hexanes) to give 5 (5.1 g, 86%) as a white crystalline solid. mp
1
117-118 °C. H NMR: δ 2.11 (m, 2H), 3.12 (t, 2H, J ) 6.2 Hz),
3.33 (t, 2H, J ) 6.2), 7.40 (d, 1H, J ) 6.9 Hz), 7.57 (dd, 1H, J )
8.2 and 7.2 Hz), 7.60-7.70 (m, 2H), 8.45 (dd, 1H, J ) 9.5 and
2.0 Hz), 8.53 (d, 1H, J ) 8.5 Hz), 8.64 (dd, 1H, J ) 9.5 and 2.0
Hz). HRMS calcd for C17H13Br, 296.0195; found, 296.0197.
7-(2-F or m ylp h e n yl)-5,6-d ih yd r o-4H -b e n z[d e]a n t h r a -
cen e (6). A mixture of 7-Bromo-5,6-dihydro-4H-benz[de]an-
thracene (5) (1.48 g, 5.0 mmol), 2-formylphenyl boronic acid (0.82
g, 5.5 mmol), cesium fluoride (1.67 g, 11.0 mmol), and Pd(PPh3)4
(0.23 g, 0.20 mmol) in anhydrous DME (40 mL) was refluxed
for 24 h. The mixture was cooled to room temperature, and the
reaction was quenched with ice-cold H2O. The aqueous layer was
extracted with CH2Cl2 (3 × 30 mL), the combined organic layers
were washed with water and dried over anhydrous MgSO4.
Concentration in vacuo provided a residue that was purified by
silica gel column chromatography (EtOAc/hexanes 3:97) to give
6 (0.98 g, 61%) as a pale yellow crystalline solid. mp 206-208
1
°C. H NMR: δ 1.99 (m, 2H), 2.60-2.80 (m, 2H), 3.15 (t, 2H, J
) 6.2 Hz), 7.20 (dd, 1H, J ) 8.2 and 0.7 Hz), 7.36 (dd, 1H, J )
(28) Kumar, S. J . Chem. Soc., Perkin Trans. 1 2001, 1018.
J . Org. Chem, Vol. 69, No. 11, 2004 3981

powdered KOH (0.34 g, 6.0 mmol); the reaction mixture was
heated at 100 °C for 1 h. The crude product, obtained after
following a similar workup as mentioned above for 1/11, was
purified by silica gel column chromatography (EtOAc/hexanes
2:98) to give a mixture of 12 and 13 in ∼ 9:1 ratio (as determined
by 1H NMR). To a solution of this mixture in C6H6 was added
DDQ (1.36 g, 6.0 mmol), and this reaction was refluxed for 30
min. The mixture was then cooled, filtered, and concentrated.
Purification of the crude residue by silica gel column chroma-
tography (EtOAc/hexanes 2:98) gave 12-methoxy-DBC (13) (0.51
g, 84%) as a pale yellow solid.
Meth od 2. To a solution of 9 (0.94 g, 2.2 mmol) in DMF (15
mL) was added t-BuOK (0.74 g, 6.6 mmol), and the reaction
mixture was stirred at room temperature for 6 h. A similar
workup as mentioned above (Method 2 for 1) gave the crude
mixture, which was purified by silica gel column chromatography
(EtOAc/hexanes 2:98) to give 13 (0.60 g, 81%) as pale yellow
solid; mp 193-194 °C (ref 13: 192-193 °C). 1H NMR: δ 4.06 (s,
3H), 7.37 (dd, 1H, J ) 9.5 and 2.6 Hz), 7.53 (d, 1H, J ) 2.6 Hz),
7.69-7.78 (m, 2H), 7.85 (d, 1H, J ) 9.2 Hz), 7.94 (d, 1H, J ) 9.2
Hz), 7.98 (dd, 1H, J ) 8.0 and 7.6 Hz), 8.07 (d, 1H, J ) 7.6 Hz),
8.39 (s, 1H), 8.88-8.91 (m, 2H), 9.03 (d, 1H, J ) 8.0 Hz), 9.11
(d, 1H, J ) 9.5 Hz).
Ack n ow led gm en t. This study was supported by
NCI Contract NO2-CB-37025-48 and Cancer Center
Support Grant CA-17613. We thank Ms. Ilse Hoffmann
for editing the manuscript.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 1, 5, 6, 7, 8, 9, and 13. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0303822
3982 J . Org. Chem., Vol. 69, No. 11, 2004