Methylation of 1,8-dihydroxy-9,10-anthraquinone with and without use of solvent-free technique

Article abstract of DOI:10.1016/j.tetlet.2003.10.057

A convenient and environmentally friendly solvent-free procedure has been developed for dimethylation of 1,8-dihydroxy-9,10-anthraquinone with excellent yield. A highly selective monomethylation of 1,8-dihydroxy-9,10-anthraquinone in refluxing tetraglyme makes monomethylated peri-dihydroxy-9,10-anthraquinones easily available. Alternatively, irradiation in a domestic microwave oven has been employed for the solvent-free monomethylation of 1,8-dihydroxy-9,10-anthraquinone.

Full text of DOI:10.1016/j.tetlet.2003.10.057

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9125–9126
Methylation of 1,8-dihydroxy-9,10-anthraquinone with and
without use of solvent-free techniqueꢀ
Grigoriy A. Sereda* and David G. Akhvlediani
University of South Dakota, Department of Chemistry, 414 E. Clark Street, Vermillion, SD 57069, USA
Received 23 July 2003; accepted 8 October 2003
Abstract—A convenient and environmentally friendly solvent-free procedure has been developed for dimethylation of 1,8-dihy-
droxy-9,10-anthraquinone with excellent yield. A highly selective monomethylation of 1,8-dihydroxy-9,10-anthraquinone in
refluxing tetraglyme makes monomethylated peri-dihydroxy-9,10-anthraquinones easily available. Alternatively, irradiation in a
domestic microwave oven has been employed for the solvent-free monomethylation of 1,8-dihydroxy-9,10-anthraquinone.
© 2003 Elsevier Ltd. All rights reserved.
In the course of our current research we encountered a
necessity to synthesize 1,8-dimethoxy-9,10-anthraquin-
one (2) in large quantities. The known procedure of
dimethylation1 of 1,8-dihydroxy-9,10-anthraquinone (1)
employs carcinogenic dimethylsulfate, dangerous
sodium hydride, flammable tetrahydrofuran, takes 2–4
days for completion and provides a moderate yield of
57%.
The methylation system used (methyl tosylate with
sodium carbonate) is known and was applied before to
the methylation of 1,4-dihydroxy-9,10-anthraquinone
and required continuous refluxing (20 h) in toxic 1,2-
dichlorobenzene followed by concentration in vacuum
and chromatographic separation.3
Refluxing of the same reactants taken at the same ratio,
in tetraglyme for 2 h led to highly selective monomethy-
lation of the starting 1 (Scheme 1) and produced 1-
hydroxy-8-methoxy-9,10-anthraquinone (3)4 in excellent
yield (93%). The use of a high boiling solvent is essen-
tial for the reaction. Our attempt to methylate 1 by
refluxing with methyl tosylate and sodium carbonate in
acetone failed and only the starting material 1 was
isolated.
The suggested procedure is a fast, convenient and envi-
ronmentally friendly method for the complete methyla-
tion of 1 by heating of a ground mixture of 1, methyl
tosylate and sodium carbonate taken in a molar ratio of
1:2.8:1.6 at 320°C in a 6¦ test tube open to air for 5 min
(Scheme 1). This procedure represents solvent-free reac-
tions that have received a great deal of attention due to
their simplicity and usefulness in novel green chemistry
technologies2
Use of a microwave-assisted solvent-free technique for
monomethylation of 1 also proved to be quite selective.
Although the solvent-free procedure provided a lesser
yield of monomethylation (61% versus 93%), it required
less time (20 min versus 2 h) and did not require any
solvents.
The procedure does not require chromatographic sepa-
ration and provided a nearly quantitative yield (95%) of
2.
Although both 1,8-dimethoxy-9,10-anthraquinone 2
and 1-hydroxy-8-methoxy-9,10-anthraquinone 3 are
known,1,4 we obtained an additional proof of the struc-
ture of 2 by the single crystal X-ray analysis and a
proof for the structure of 3 by a separate experiment of
its methylation to 2.
Scheme 1.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.10.057
* Corresponding author.
Interestingly, monomethylation of 1 in tetraglyme
proved to be very selective. The methylating system
taken in a two-fold excess produced exclusively the
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.057

9126
G. A. Sereda, D. G. Akh6lediani / Tetrahedron Letters 44 (2003) 9125–9126
monomethylated product 3. The selectivity might be
attributed to a decreased stability of the intermediate
anion on the second step of methylation due to the strong
repulsion between the phenoxide, methoxy- and carbonyl
oxygen of the species.
compounds 2 and 3, X-ray diffraction data for the
compound 2.
Acknowledgements
The developed solvent-free procedure of dimethylation
provides an easy access to peri-dimethoxyan-
thraquinones, starting compounds for synthesis of model
bicyclic systems for studies of electron transfer.1 We have
shown that the solid state procedure can be safely scaled
up to at least 50 g of the starting reaction mixture without
any indication of self heating or going the reaction out
ofcontrol. Ofspecialinterestarederivativesof1-hydroxy-
8-methoxy-9,10-anthraquinone (3) that are capable of
intercalating into DNA5 and can be easily accessed via
our selective protocol of monomethylation. So far,
synthesis of this class compounds was carried out by
complete methylation followed by partial hydrolysis.4
We thank the Department of Chemistry of the Univer-
sity of South Dakota for financial support of this work
(NSF Photodynamics grant c0082978) and the NSF-
REU-grant c0138951 for the summer support of
David Akhvlediani. Also we are thankful to Dr.
Andrew Sykes for X-ray analysis of 1,8-dimethoxy-
9,10-anthraquinone (2).
References
1. Quast, H.; Fuchsbauer, H.-L. Chem. Ber. 1986, 119, 1016–
1038.
2. Tamaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
3. Criswell, T. R.; Klanderman, B. H. J. Org. Chem. 1974,
39, 770–774.
4. Klemm, K.; Gehrke, G. 1-Methoxy-5 (or 8) hydroxyan-
thraquinones, German Patent No 1178441, 1964.
5. Koyama, M.; Takahashi, K.; Chou, T. C.; Darzynkiewicz,
Z.; Kapuscinski, J.; Kelly, T. R.; Watanabe, K. A. J. Med.
Chem. 1989, 32, 1594–1599.
Besides the synthetic value of the suggested solvent free
protocols, they are carried out within a standard labora-
tory period and therefore can be used for educational
purposes to introduce students to environmentally safe
‘green chemistry’ techniques for organic synthesis.
Supplementary material
Experimental procedures and 1H NMR spectra for