An efficient approach for the synthesis of 6,7-dimethoxy-2-tetralone and 5,6-dimethoxy-1-tetralone

Transformation of 6-methoxy tetralin into 6,7-Dimethoxy-2-tetralone and 5,6-Dimethoxy-1-tetralone is described.


Introduction
6,7-Dimethoxy-2-tetralone 1 is a starting material for many dopaminergic compounds 1 .Its utility has been recorded in the synthesis of natural alkaloids 2 , cyclic amino acids 3 and as novel antagonists 4 of human TRPVI.5,6-Dimethoxy-1-tetralone 2 is a key intermediate in the synthesis of novel antidepresants 5 which are the α-2-antagonists and norepinephrine uptake inhibitors eg.ABT-200.It can also be a synthon for certain 2-substituted octobenzo(f) quinoline which are dopamine agonists 6 .An efficient, short step and high yielding approach of these tetralones will be of great utility for large scale synthesis of several bioactive compounds for their complete preclinical and clinical evaluations.Several , approaches have been developed for the synthesis of tetralone 7,8 1 and tetralone 9,10 2. In some of these methods we have observed (i) long reaction sequences affording low to moderate yield, (ii) difficult experimental procedures which require skilled experimentalists to reproduce the results, (iii).theuse of expensive reagents (rhodium, triphenylphosphonium chloride, ionic liquids etc) and (iv) the use of reagents (diazoketone,ethylene gas, βketosulfoxide etc) which are injurious for health.Analysing some of these draw backs and considering our interest on the synthesis of α and β-substituted tetralones 11 we believe that still a more efficient and facile synthesis can be developed for tetralones 1 and 2 which have proved to be potential intermediate for the synthesis of several bioactive compounds.We have sought a facile synthesis of the tetralones 1 and 2 by a single route instead of independent approach for each of these tetralones.To the best of our knowledge this is the first example of the synthesis of the tetralones 1 and 2 by a single route and the present paper documents our results.

Results and Discussion
The commercially available 6-methoxy-1,2,3,4-tetrahydronaphthalene 3 on aromatic bromination 12 with N-bromo succinimide provided a mixture of the bromo compounds 4 and 5 in a ratio 1.3:1 as evidenced by 1 H NMR spectroscopy.As their separation could not be effected by column chromatography their transformation to the tetralins 6 and 7 were effected by treatment of the mixture with CuI and dimethylformamide in a solution of sodium methoxide. 13The resuting material on chromatographic purification afforded tetralines 6 and 7 in an overall yield 31.1% and 30.7% respectively for the two steps.Their structures were confirmed by spectroscopic evidences (Scheme 1).

Scheme 1
As the oxidation is the only reaction which can provide the desired tetralones , suitable oxidizing reagents were sought to obtain the tetralones in satisfactory yield.A series of oxidizing reagents were tried to achieve the oxidation but among these KMnO 4 in acetonitrile 14 proved to be satisfactory.Oxidation of the tetralins 6 and 7 with this reagent afforded tetralones 8 and 2 in 44% and 39% respectively.The m.p. and the spectroscopic data perfectly matched with the data reported (see experimental).In one occasion the oxidation of the tetralin 6 was tried with chromium trioxide and acetic acid and the product obtained in major amount was identified as quinone 9 by spectroscopic analysis.
Heating the tetralone 8 with 2,4-pentanediol and p-toluenesulphonic acid in toluene 15 furnished the dihydronaphthalene 10 (Scheme 2) which on epoxidation with m-chloroperbenzoic acid in dichloromethane followed by hydrolysis of the resulting epoxide with dilute sulphuric acid furnished the tetralone 1 in 41% yield.

Conclusions
In conclusion a three step synthesis of tetralone 2 and a five step synthesis of tetralone 1 have been accomplished by a single route.The present approach for the synthesis of tetralone 1 and tetralone 2 is very practical, has the merit of relative brevity and offers advantages in ease of manipulation..The starting material is inexpensive and commercially available.Most of the intermediates were found to stable to permit its isolation even by repeated chromatographic purification..The present method can be utilized for the synthesis of tetralones 1 and 2 in quantities sufficient to accomplish their transformations to bioactive compounds in acceptable yield to investigate their broad biological and medicinal properties.

Experimental Section
General Procedures.Unless otherwise stated, IR spectra were taken on Nicolet FT and NMR spectra recorded on a Bruker AM-300 spectrometer were taken in CDCl TLC plates were coated with silica gel and the spots were located by exposing to UV light.Microanalyses were carried out in the Chemistry Deparment, IVIC, Caracas.