SCHEME 1
Efficient and Green Telescoped Process to
2-Methoxy-3-methyl-[1,4]benzoquinone
Raquel Rodr´ıguez Gonza´lez, Cristian Gambarotti,†
Lucia Liguori, and Hans-Rene´ Bjørsvik*
Department of Chemistry, UniVersity of Bergen, Alle´gaten 41,
quinone with high selectivity and yield (86-92%). Other lengthy
protocols involving cerium diammonium hexanitrate10 as the
oxidant were also disclosed for the purpose of preparing [1,4]-
benzoquinone derivatives. There have also been some attempts
to develop green chemistry protocols for the synthesis of
benzoquinones. Notably, Orita and co-workers11 disclosed a
method using hydrogen peroxide and formic acid as the
oxidative system, but despite high conversion observed in most
of their examples, only low yields and selectivity were achieved.
N-5007 Bergen, Norway
ReceiVed October 28, 2005
Methods and Results
For a project in progress in our laboratory we needed access
to 2,4-dimethoxy-3-methyl-5-nitrophenol 2 as an intermediate
in the synthesis of carbazomycines G and H.12 During our initial
tests and adaptation of the reaction conditions for the nitration
of acetic acid 2,4-dimethoxy-3-methylphenyl ester 1, it was
found that significant quantities of the title compound 3 had
formed as well (Scheme 1).
We associated this finding with an incomplete protection of
the hydroxyl group of compound 1 that thus allowed a nitric
acid oxidation of the free hydroxyl group. This spurred us to
investigate the possibility of performing an oxidation of 2,4-
dimethoxy-3-methyl-phenol 4 to 2-methoxy-3-methyl-[1,4]ben-
zoquinone 3 by treatment with concentrated nitric acid. The
oxidation experiment was conducted under similar conditions
as for the nitration.13 The anticipated oxidation reaction
A telescoped process for the preparation of 2-methoxy-3-
methyl-[1,4]benzoquinone is disclosed. When this novel
process is compared to the prevailing method that utilizes
Na2Cr2O7 as the oxidant, the novel process represents a high
yielding (95%), green, and environmentally benign alterna-
tive with H2O2 and HNO3 as the oxidants and CH3COOH
as the reaction medium.
Introduction
Methoxy- and methyl-substituted [1,4]benzoquinone and
phenolic derivatives constitute important classes of building
blocks because such moieties are found in a wide range of
biologically active compounds. Thus, they are essential basic
building blocks for natural product synthesis.
(2) (a) Nakahara, S.; Kubo, A. Heterocycles 2004, 63, 1849-1854. (b)
Saito, N.; Tanaka, C.; Koizumi, Y.; Suwanborirux, K.; Amnuoypol, S.;
Pummangura, S.; Kubo, A. Tetrahedron 2004, 60, 3873-3881. (c) Saito,
N.; Tanaka, C.; Satomi, T.; Oyama, C.; Kubo, A. Chem. Pharm. Bull. 2004,
52, 282-286. (d) Plubrukarn, A.; Yuenyongsawad, S.; Thammasaroj, T.;
Jitsue, A. Pharm. Biol. 2003, 41, 439-442. (e) Saito, N.; Koizumi, Y.;
Tanaka, C.; Suwanborirux, K.; Amnuoypol, S.; Kubo, A. Heterocycles 2003,
61, 79-86. (f) Suwanborirux, K.; Amnuoypol, S.; Plubrukarn, A.; Pum-
mangura, S.; Kubo, A.; Tanaka, C.; Saito, N. J. Nat. Prod. 2003, 66, 1441-
1446. (g) Rashid, M. A.; Gustafson, K. R.; Boyd, M. R. J. Nat. Prod. 2001,
64, 1249-1250. (h) Kesteleyn, B.; De Kimpe, N. J. Org. Chem. 2000, 65,
635-639. (i) Parker, K. A.; Casteel, D. A. J. Org. Chem. 1988, 53, 2847-
2850.
An example of such a compound is 2-methoxy-3-methyl-
[1,4]benzoquinone, which is found as a molecular moiety in
several classes of natural products that exhibit a plethora of
biological activities. Examples of such compounds are the anti-
tumor antibiotic mitomycin,1 the antibiotic mimosamycin,2 the
marine diterpenoid elisabethin A,3,4 the allelochemical sorgo-
leone,5 the diterpenes colombiasin A6 and elisapterosin B,7 and
the small molecular mimetic of insulin demethylasterriquinone
B1.8 The synthetic processes toward such compounds require
normally several advanced and ingenious synthetic steps. How-
ever, the synthetic chemist often ignores the challenge related
to the synthesis of the basic starting compounds, which very
often thus results in synthetic paths involving environmentally
atrocious and noxious reagents. For example, CrVI salts (dichro-
mate) have for years been known to be carcinogenic; neverthe-
less, they are still utilized for oxidation purposes in organic
synthesis and are frequently employed in reaction protocols for
the preparation of [1,4]benzoquinone derivatives. The popularity
of the dichromate protocol for the preparation of benzoquinones
is probably a result of the high selectivity and yield that in
general is achieved. A protocol disclosed by Vliet9 more than
70 years ago gently provides [1,4]benzoquinone from hydro-
(3) Siddiqi, S. A.; Heckrodt, T. J. Z. Naturforsch., B: Chem. Sci. 2003,
58, 328-331.
(4) Zanoni, G.; Franzini, M. Angew. Chem., Int. Ed. 2004, 43, 4837-4841.
(5) Rimando, A. M.; Dayan, F. E.; Czarnota, M. A.; Weston, L. A.; Duke,
S. O. J. Nat. Prod. 1998, 61, 927-930.
(6) Nicolaou, K. C.; Vassilikogiannakis, G.; Magerlein, W.; Kranich,
R. Chem.sEur. J. 2001, 7, 5359-5371.
(7) (a) Waizumi, N.; Stankovic, A. R.; Rawal, V. H. J. Am. Chem. Soc.
2003, 125, 13022-13023. (b) Harrowven, D. C.; Pascoe, D. D.; Demurtas,
D.; Bourne, H. O. Angew. Chem., Int. Ed. 2005, 44, 1221-1222.
(8) (a) Pirrung, M. C.; Li, Z.; Park, K.; Zhu, J. J. Org. Chem. 2002, 67,
7919-7926. (b) Pirrung, M. C.; Liu, Y.; Deng, L.; Halstead, D. K.; Li, Z.;
May, J. F.; Wedel, M.; Austin, D. A.; Webster, N. J. G. J. Am. Chem. Soc.
2005, 127, 4609-4624.
(9) Vliet, E. B. Organic Syntheses; Wiley & Sons: New York, 1932;
Collect. Vol. 1, p 482.
(10) (a) Siddiqi, S.; Heckrodt, T. J. Z. Naturforsch., B: Chem. Sci. 2003,
58, 328-331. (b) Knolker, H.-J.; Frohner, W.; Reddy, K. R. Synthesis 2002,
557-564. (c) Orita, H.; Shimizu, M.; Hayakawa, T.; Takehira, K. Bull.
Chem. Soc. Jpn. 1989, 62, 1652-1657.
(11) Orita, H.; Shimizu, M.; Hayakawa, T.; Takehira, K. Bull. Chem.
Soc. Jpn. 1989, 62, 1652-1657.
† Current affiliation: Department of Chemistry, Milan Polytechnic, Milan, Italy.
(1) (a) Coleman, R. S.; Felpin, F.-X.; Chen, W. J. Org. Chem. 2004, 69,
7309-7316. (b) Macky, T. A.; Oelkers, C.; Rix, U.; Heredia, M. L.;
Kuenzel, E.; Wimberly, M.; Rohrer, B.; Crosson, C. E.; Rohr, J. J. Med.
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10.1021/jo0522512 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/19/2006
J. Org. Chem. 2006, 71, 1703-1706
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