Organic Process Research & Development 2010, 14, 1379–1384
A Switchable Oxidation Process Leading to Two Various Versatile Pharmaceutical
Intermediates
Giovanni Occhipinti, Lucia Liguori, Anna Tsoukala, and Hans-Rene´ Bjørsvik*
Department of Chemistry, UniVersity of Bergen, Alle´gaten 41, N-5007 Bergen, Norway
Abstract:
green processes for the preparation of such methyl- and
methoxy-substituted arenes suitable as building blocks for the
preparation of various antioxidants, pharmaceutical chemicals,
and compounds used in nutraceuticals. In this context, different
oxidation processes for the production of methyl- and methoxy-
substituted phenols and their corresponding hydroquinones and
benzoquinones have been of particular interest. Previous
disclosures from our group include a novel process for direct
hydroxylation of the aromatic ring of methyl- and methoxy-
substituted benzenes8 and a process for the preparation of
2-methoxy-3-methyl-[1,4]benzoquinone in a two-step, one-pot
telescoped oxidation process.9
A current research activity in our laboratory is dedicated to
the development of new total syntheses of coenzyme Q1010 and
the synthetic analogue idebenone,11 see Chart 1. In this context
we wanted to develop a new process for the preparation of 2,3-
dimethoxy-5-methylcyclohexa-2,5-diene-1,4-dione (coenzyme
Q0), 1,12 that functions as a key intermediate in the two
syntheses. For this purpose we assumed that our previously
developed process for 2-methoxy-3-methyl-[1,4]benzoquinone9
could be used for the preparation of coenzyme Q0, 1, whose
reaction conditions constitute a green and environmentally
benign alternative compared to formerly reported oxidation
methods whereof several make use of environmentally un-
friendly stoichiometric reagents.13-17
An efficient high-yielding and environmentally benign switchable
oxidation process that can selectively produce two different
versatile synthetic intermediates is disclosed. One of the two
intermediates, 2,3-dimethoxy-5-methylcyclohexa-2,5-diene-1,4-di-
one (coenzyme Q0), is obtained by means of a telescoped two-step
synthetic protocol that in the first step involves treatment of the
substrate (1,2,3-trimethoxy-5-methylbenzene) with hydrogen per-
oxide in acetic acid with p-toluene sulphonic acid present as a
Brønsted acid catalyst, succeeded by a telescoped second step that
entails treatment with fuming nitric acid to achieve the target
molecule in an excellent isolated yield (88%). If the substrate is
treated directly with nitric acid (65%) in glacial acetic acid two
different products can be obtained, namely acetic acid 3,4,5-
trimethoxybenzyl ester in a superb isolated yield (93%) or, under
slightly altered reaction conditions, 1,2,3-trimethoxy-5-(nitrom-
ethyl)benzene in a moderate to low yield (35%) and low selectivity.
The two pathways leading to the two different products in the
nitric acid oxidation protocol were investigated by means of DFT
calculations as an aid to elaborate a proposal for the reaction
mechanism.
Introduction
Methoxy- and methyl-substituted phenyl moieties constitute
integral parts of a vast number of natural products, biological
active compounds, and pharmaceutical chemicals within a
variety of therapeutic areas. A few examples include amoproxan
(antiarrhythmic),1 fedotozine (gastroprokinetic),2 hexobendine
(coronary vasodilator),3 pirozadil (antilipemic),4 trimebutine
(antispasmodic),5 trimethoprim (antibacterial),6 and trimetozine
(anxiolytic).7
(8) Bjørsvik, H.-R.; Occhipinti, G.; Gambarotti, C.; Cerasino, L.; Jensen,
V. R. J. Org. Chem. 2005, 70, 7290.
(9) Gonza´lez, R. R.; Gambarotti, C.; Liguori, L.; Bjørsvik, H.-R. J. Org.
Chem. 2006, 71, 1703.
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1979, 44, 868. (b) Naruta, Y. J. Org. Chem. 1980, 45, 4097. (c) Eto,
H.; Eguchi, C. Chem. Lett. 1988, 1597. (d) Lipshutz, B. H.; Mollard,
P. M.; Pfeiffer, S. S.; Chrisman, W. J. Am. Chem. Soc. 2002, 124,
14282. (e) Lipshutz, B. H.; Lower, A.; Berl, V.; Schein, K.; Wetterich,
F. Org. Lett. 2005, 7, 4095. (f) Yu, X. J.; Chen, F. E.; Dai, H. F.;
Chen, X. X.; Kuang, Y. Y.; Xie, B. HelV. Chim. Acta 2005, 88, 2575.
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1317.
A long-term project in our group is dedicated to the design,
development, investigation, and optimization of new efficient
* Author to whom correspondence may be sent. E-mail: hans.bjorsvik@
kj.uib.no. Telephone: +47 55 58 34 52. Fax: +47 55 58 94 90.
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10.1021/op100185x 2010 American Chemical Society
Published on Web 10/05/2010
Vol. 14, No. 6, 2010 / Organic Process Research & Development
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