A practical synthesis of pyrene-4,5-dione

Full text of DOI:10.1021/jo970344g

J . Org. Chem. 1998, 63, 9995-9996
9995
Sch em e 1
A P r a ctica l Syn th esis of P yr en e-4,5-d ion e
Erick R. R. Young and Raymond L. Funk*
Department of Chemistry, The Pennsylvania State
University, University Park, Pennsylvania 16802
Received February 24, 1997
Pyrene-4,5-dione (3) has been used extensively to
prepare and study its corresponding K-region oxide.1
Arene oxides are the primary oxidative metabolites of
polycyclic aromatic hydrocarbons and consequently are
of significant biological interest.2 In addition, pyrene-
4,5-dione (3) participates in a variety of cyclization
reactions useful for the construction of other molecules
of interest.3 The o-quinone 3 is much less readily
available than related aromatic quinones because direct
oxidation of pyrene generally gives rise to a mixture of
products derived from competitive oxidation at other
sites, for example, C(1), C(6), and C(8).4 Thus, pyrene-
dione 3 is usually obtained through either oxidation of
pyrene with the costly and highly toxic reagent osmium
tetroxide3a,5 or oxidation of 4,5-dihydropyrene, which is
prepared by a problematic dissolving metal reduction.6
We have recently been investigating the photochemi-
cally promoted cycloaromatization reactions of o-dialky-
nylarenes and their DNA cleavage properties.7 We
developed an efficient protocol for synthesizing o-dialky-
nylarenes from aromatic o-quinones and therefore desired
large quantities of pyrenedione 3. Finding the afore-
mentioned methods unsatisfactory, we envisioned that
an intramolecular acyloin condensation8 of a phenan-
threne bay-region diester might provide a route more
amenable for the large-scale production of pyrenequinone
3.
acid.9 Not surprisingly, the attempted esterification of
the sterically congested diacid 1 using the standard
protocol of sulfuric acid in refluxing methanol resulted
in mixtures of starting material, monoester, and diester.
However, the sterically more accessible carboxylate ions
of 1 (vis-a`-vis the carbonyl carbons) could be generated
with sodium bicarbonate and alkylated with iodomethane
in DMF10 to produce the desired dimethyl 4,5-phenan-
threnedicarboxylate (2) in good yield (88%). Initial
attempts to effect the intramolecular acyloin condensa-
tion of diester 2 using standard dissolving metal condi-
tions in NH311 produced pyrenedione 3 contaminated with
suspected Birch reduction products. However, treatment
of diester 2 with excess sodium in refluxing THF provided
the desired pyrenequinone 3 after aerobic workup in
excellent yield (95%).
In summation, this route provides pyrenedione 3 in
multigram quantities from pyrene in three steps (76%
overall yield).
Exp er im en ta l Section
4,5-P h en a n th r en ed ica r boxylic Acid (1). To a solution of
pyrene (30.0 g, 148 mmol) in chlorobenzene (80.0 mL) were
added WO4 (1.53 g, 6.14 mmol), Aliquat 336 (2.40 mL, 5.84
mmol), and H3PO4 (10%, 1.40 mL). H2O2 (50%, 85 mL) was then
added via addition funnel at an appropriate rate to maintain
gentle reflux. Caution: extremely exothermic! The reaction was
heated to 80 °C for an additional 6 h, cooled to 0 °C, and filtered.
The mudlike filtrate was dissolved in 1.25 M NaOH (2.0 L),
decolorized with activated charcoal, and neutralized with glacial
acetic acid to provide a reddish brown precipitate (36.1 g, 91%):
mp 248-250 °C; IR (DMSO-d6) 3460, 3049, 2908, 2743, 1702,
Fortunately, pyrene can be regioselectively oxidized to
4,5-phenanthrenedicarboxylic acid (1, Scheme 1) in nearly
quantitative yields using hydrogen peroxide/tungstic
(1) (a) Dansett, P.; J erina, D. M. J . Am. Chem. Soc. 1974, 96, 1224.
(b) J eyaraman, R.; Murray, R. W. J . Am. Chem. Soc. 1984, 106, 2462.
(c) Morquardt, H.; Kuroki, T.; Huberman, E.; Selkirk, J . K.; Heidel-
berger, C.; Grover, P. L.; Sims, P. Cancer Res. 1972, 32, 716. (d) Shou,
M.; Yang, S. K. Drug Metab. Dispos. 1988, 16, 173. (e) Hetlich, R. H.;
Thornton-Manning, J . R.; Kinouchi, T.; Kataoka, K.; Ohnishi, Y. Mutat.
Res. 1991, 262, 232.
1255, 991 cm-1 1H NMR (200 MHz, DMSO-d6) δ 8.11 (d, J )
;
7.7 Hz, 2 H), 7.98 (d, J ) 7.3 Hz, 2 H), 7.91 (s, 2 H), 7.67 (t, J )
7.7 Hz, 2 H); 13C NMR (50 MHz, DMSO-d6) δ 170.4, 135.1, 134.2,
131.5, 128.2, 127.7, 126.7; exact mass calcd for
266.0579, found 266.0572.
C16H10O4
(2) Harvey, R. G. In Polycyclic Aromatic Hydrocarbons: Chemistry
and Carcinogenicity; Cambridge University Press: New York, 1991.
(3) With ortho-phenylenediamine: (a) Oberender, F. G.; Dixon, J .
A. J . Org. Chem. 1959, 24, 1226. With trimethyl phosphite: (b)
Ramirez, F.; Bhatia, S. B.; Patwardhan, A. V.; Chen, E. H.; Smith, C.
P. J . Org. Chem. 1968, 33, 20. (c) With sulfamide: Ege, G.; Beisiegel,
E. Synthesis 1974, 22. With alkenes: (d) Tintel, C.; Terheijden, J .;
Lughtenburg, J .; Cornelisse, J . Tetrahedron Lett. 1987, 28, 2060. With
1,3-diarylpropanones: (e) Pascal, R. A., J r.; McMillan, W. D.; Van
Engen, D.; Eason, R. G. J . Am. Chem. Soc. 1987, 109, 4660.
(4) (a) Dewar, M. J . S. J . Am. Chem. Soc. 1952, 74, 3357. (b) Cook,
J . W.; Schoental, R. J . Am. Chem. Soc. 1950, 72, 47. (c) Cho, H.; Harvey,
R. G. J . Chem. Soc., Perkin Trans. 1 1976, 836. (d) Fatiadi, A. J .
Synthesis 1974, 4, 257. (e) Ranganathan, S.; Ranganathan, D.; Ram-
achandran, P. V. Tetrahedron 1984, 40, 3145.
Dim eth yl 4,5-P h en an th r en edicar boxylate (2). To a slurry
of dicarboxylic acid 1 (16.52 g, 62.0 mmol) and NaHCO3 (27.0 g,
321 mmol) in DMF (330 mL) was added a solution of MeI (50.0
mL, 800 mmol) in DMF (100 mL). After 22 h of stirring at room
temperature, the reaction mixture was diluted with ethyl acetate
(1 L), washed with water (5 × 500 mL), dried (Na2SO4), and
concentrated. Column chromatography (4:1 hexanes/ethyl ac-
etate) provided a bright yellow solid (16.98 g, 88%): mp 159-
161 °C; IR (CDCl3) 3060, 2954, 1713, 831, 743 cm-1 1H NMR
;
(200 MHz, CDCl3) δ 8.04 (dd, J ) 7.7, 1.4 Hz, 2 H), 7.99 (dd, J
) 7.7, 1.4 Hz, 2 H), 7.75 (s, 2 H), 7.62 (t, J ) 7.7 Hz, 2 H), 3.80
(s, 6 H); 13C NMR (50 MHz, CDCl3) δ 169.6, 134.2, 132.7, 131.9,
128.8, 127.5, 126.4, 104.8, 52.1; exact mass calcd for C18H14O4
294.0892, found 294.0894. Anal. Calcd for C18H14O4: C, 73.44;
H, 4.79. Found: C, 73.41; H, 4.67.
(5) (a) Goh, S. H.; Harvey, R. G. J . Am. Chem. Soc. 1973, 95, 242.
(b) Moriarity, R. M.; Dansette, P.; J erina, P. M. Tetrahedron Lett. 1975,
30, 2557.
(6) (a) Harvey, R. G.; Rabideau, P. W. Tetrahedron Lett. 1970, 12,
3695. (b) Cho, H.; Harvey, R. G. Tetrahedron Lett. 1974, 16, 1491.
(7) Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.;
Cecil, T. L. J . Am. Chem. Soc. 1996, 118, 3291.
(8) For the preparation of a phenanthrenequinone using this ap-
proach, see: Wittig, G.; Zimmerman, H. Chem. Ber. 1953, 86, 629.
(9) Salto, Y.; Arale, S.; Sugita, Y.; Kurato, N. (Nippon Shokubai
Kagaku Kogyo Co. Ltd.) Eur. Pat. Appl. EP 103, 368.
(10) Bocchi, V.; Casnati, G.; Dossena, A.; Marchell, R. Synthesis
1979, 961.
(11) Finley, T. K. Chem. Rev. 1964, 64, 573.
10.1021/jo970344g CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

9996 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
P yr en e-4,5-d ion e (3). To a refluxing mixture of Na (3.80 g,
158 mmol) in THF (100 mL) was added diester 2 (12.0 g, 40.8
mmol) in THF (200 mL). The reaction progress was followed
by NMR aliquots, and additional Na (2.81 g, 116 mmol) was
added in small portions until the reaction was complete (3 h).
The dark red solution was then cooled to room temperature,
residual Na was carefully removed, the reaction mixture was
poured into ethyl acetate (500 mL) and water (200 mL), and the
resulting emulsion was left to stand overnight. The aqueous
layer was extracted with ethyl acetate (1 L), combined with the
organic layer, dried (Na2SO4), and concentrated. Column chro-
matography (4:1 hexanes/ethyl acetate) provided a bright orange
solid (9.0 g, 95%): mp 302-304 °C (lit.3a mp 304.5-306.4 °C);
1H NMR (200 MHz, CDCl3) δ 8.52 (dd, J ) 7.8, 1.3 Hz, 2 H),
8.20 (dd, J ) 7.8, 1.3 Hz, 2 H), 7.87 (s 2 H), 7.77 (t, J ) 7.8 Hz,
2 H); 13C NMR (50 MHz, DMSO-d6) δ 180.1, 135.4, 132.1, 131.0,
129.1, 128.4, 128.2, 127.6; MS (EI) m/z (relative intensity) 232
(40), 221 (24), 218 (11), 204 (94), 189 (16), 176 (55), 150 (11);
exact mass calcd for C16H18O2 232.0524, found 232.0513.
Ack n ow led gm en t. We appreciate the financial sup-
port provided by the National Institutes of Health
(GM28553).
J O970344G