2772 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
Sch em e 1
thylchrysene reported herein may be appropriately modi-
fied for the synthesis of analogous dihydro diol and diol
epoxide metabolites of other carcinogenic polycyclic hy-
drocarbons.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. m-Chloroperbenzoic acid (Aldrich)
was purified by washing with pH 7.4 phosphate buffer and
drying under reduced pressure. (2,3-Dimethoxybenzyl)tri-
phenylphosphonium bromide was prepared by heating an equimo-
lar solution of 2,3-dimethoxybenzyl bromide and PPh3 in a
minimum volume of benzene at reflux for 5 h. THF was freshly
1
distilled from LiAlH4. The H NMR spectra were recorded on a
QE-400 MHz spectrometer in CDCl3 with tetramethylsilane as
internal standard unless otherwise stated. Ca u tion : The
dihydro diol and diol epoxide derivatives of 5-methylchrysene are
implicated as active carcinogenic metabolites and should be
handled with caution in accord with “NIH Guidlines for the
Laboratory Use of Chemical Carcinogens.”.
3-Meth yl-1-n a p h th a ld eh yd e (3b). To a stirred solution of
1,3-dimethylnaphthalene (1.0 g, 6.4 mmol) in 50% AcOH (250
mL) at 80 °C was added dropwise a solution of ceric ammonium
nitrate (14.0 g, 25.5 mmol) in 50 mL of 50% AcOH. After being
stirred for 1 h at 80 °C, the mixture was cooled and extracted
with ether. The organic layer was washed with water and dried
over MgSO4. After evaporation of the solvent, the residue was
chromatographed on a silica gel column eluted with hexane to
afford 3b (440 mg, 41%) as a pale yellow oil: 1H NMR δ 2.55 (s,
3), 7.50-7.65 (m, 2), 7.45-7.75 (m, 3), 9.15 (d, 1, J ) 8.3 Hz),
10.3 (s, 1, CHO).13
(Z)- a n d (E)-1-[1-(3-Meth yln a p h th yl)]-2-(2,3-d im eth oxy-
p h en yl)eth ylen e (4a a n d 4b). To a solution of 3b (0.7 g, 4.1
mmol) and (2,3-dimethoxybenzyl)triphenylphosphonium bromide
(2.44 g, 4.9 mmol) in CH2Cl2 (35 mL) was added 3.5 mL of 50%
NaOH. The mixture was stirred at room temperature under
argon overnight, and then 100 mL of water was added. The
organic layer was separated, and the aqueous layer was ex-
tracted with CH2Cl2. The extracts were combined and washed
with water, dried (Na2SO4), and evaporated to dryness. The
residue was chromatographed on silica gel (hexane/EtOAc
99:1) to afford a mixture of the Z- and E-isomers 4a and 4b (1.19
g, 95%) as a colorless oil: 1H NMR δ 2.35 (s, 1.05, Z), 2.55 (s,
1.95, E), 3.84 (s, 1.05, Z), 3.88 (s, 1.95, E), 3.90 (s, 1.95, E), 3.92
(s, 1.05, Z), 6.43 (dd, 0.35, J ) 7.4, 1.3 Hz, Z), 6.57 (t, 0.35, J )
8.0 Hz, Z), 6.68 (dd, 0.35, J ) 7.4, 1.3 Hz, Z), 6.88 (dd, 0.65, J )
8.2, 1.3 Hz, E), 7.04-7.18 (m, 1.35, E + Z), 7.35 (dd, 0.65, J )
8.2, 1.3 Hz, E), 7.40-7.52 (m, 3.35, E + Z), 7.59 (br s, 0.65, E),
7.64 (d, 1, J ) 1.5 Hz, E), 7.74-7.80 (m, 1, E), 7.90 (d, 0.65, J )
16.0 Hz, E), 8.02 (br d, 0.35, J ) 8.0 Hz, Z), 8.14-8.18 (m, 0.65,
E). This mixture was used directly for photocyclization. After
this mixture was allowed to stand in the refrigerator for 2 weeks,
part of the oil solidified. The white solid was collected by
filtration and recrystallized from MeOH to give the E-isomer
thylchrysene (1).11a,15 The yield of 1 was independent of
whether the hydroquinone or its diacetate was employed.
Trans stereoselectivity is consistent with previous find-
ings for reductions of this type.15 The 300 MHz 1H NMR
spectrum and other physical properties of 1 were in good
agreement with those of an authentic sample, although
its melting point was somewhat higher (200-201 °C)
than reported earlier (188-189.5 °C).11 Transformation
of 1 to the corresponding anti-diol epoxide anti-2 was
carried out by treatment with m-chloroperbenzoic acid
in anhydrous THF using an improved procedure that
furnished pure anti-2 in higher yield than previously
reported.
This new synthetic route is considerably shorter than
prior syntheses, requiring only four steps for the synthe-
sis of 1 vs 10 steps by the most efficient of the older
methods.11 The overall yields of 1 and anti-2 from
3-methyl-1-naphthaldehyde are 70% and 59%, respec-
tively, which compare quite favorably with those reported
for older synthetic methods (0.9% and 0.7%, respectively).
3-Methyl-1-naphthaldehyde was obtained pure in 41%
yield from oxidation of 1,3-dimethylnaphthalene with
ceric ammonium nitrate in HOAc, although a crude yield
of 79% was claimed in the literature.13 This aldehyde is
reported to be obtained in 87% yield from photocatalytic
oxidation of 1,3-dimethylnaphthalene in the presence of
methyl viologen and FeCl2.16 In principle, the new
synthetic approach to the oxidized metabolites of 5-me-
1
as white needles: mp 89 °C; H NMR δ 2.55 (s, 3, Me), 3.88 (s,
3, MeO), 3.90 (s, 3, MeO), 6.88 (dd, 1, J ) 8.2, 1.3 Hz), 7.12 (t,
1, J ) 8.0 Hz), 7.35 (dd, 1, J ) 8.2, 1.3 Hz), 7.42-7.50 (m, 3),
7.59 (d, 1, J ) 3.0 Hz), 7.64 (d, 1, J ) 1.5 Hz), 7.76-7.80 (m, 1),
7.90 (d, 1, J ) 16.0 Hz), 8.14-8.18 (m, 1); MS (EI) m/z 304 [M]+,
289, 273. Anal. Calcd for C21H20O2: C, 82.86; H, 6.62. Found:
C, 82.96; H, 6.62.
1,2-Dim eth oxy-5-m eth ylch r ysen e (5a ). Argon was bubbled
through a solution of 4 (1.2 g, 3.95 mmol) and iodine (1 g, 3.95
mmol) in benzene (1.2 L) for 15 min, and then 1,2-epoxybutane
(10 mL) was added. The mixture was irradiated with a Hanovia
450 W medium-pressure mercury lamp through a Pyrex filter
for 2 h. TLC showed the reaction to be complete. The solvent
was concentrated under vacuum to 100 mL, and then the
solution was washed with 10% Na2S2O3 and water and dried
over MgSO4. The crude product was purified by flash chroma-
tography on a Florisil column eluted with hexane/CH2Cl2 (7:3)
to yield 5a (1.1 g, 92%) as a white solid: mp 160-161 °C
(hexane-CH2Cl2); 1H NMR δ 3.19 (s, 3, Me), 4.07 (s, 6, MeO),
7.38 (d, 1, J ) 7.5 Hz), 7.56-7.68 (m, 2), 7.82 (s, 1), 7.88 (dd, 1,
J ) 7.8, 1.5 Hz), 8.36 (dd, 1, J ) 9.3, 0.7 Hz), 8.70-8.78 (m, 3);
(15) The use of O2 for oxidation of catechols to quinones in reductions
of this type is well established: Reference 1a, Chapter 13, pp 306-
329 and references therein. Platt, K.; Oesch, F. Synthesis 1982, 459.
Lee, H.; Harvey, R. G. J . Org. Chem. 1986, 51, 3502. Harvey, R. G.
Synthesis 1986, 605. Dai, W.; Abu-Shqara, E.; Harvey, R. G. J . Org.
Chem. 1995, 60, 4905.
(16) Santamaria, J .; J roundi, R. Tetrahedron Lett. 1991, 32 4291.