THC Synthesis, Page 34
Appendix Three
A technique which has been used in recent years for the protection of hydroxy- groups takes advantage of the fact that benzylation gives a benzyloxy- ether, which can be split by catalytic hydrogenation using palladium catalysts, giving the original hydroxy- group. The advantage in the present case is that hydrogenation by palladium catalyst of the olefin obtained in reaction (f) will bring about simultaneous reduction of the side chain and splitting of the benzyl groups. In this way the 5-(alkyl)-resorcinols required for the THC variants THC-III through THC-VI can be obtained without the need of demethylation in step (h)

Although alternative methods such as transfer hydrogenation or hydrazine hydrate reduction with palladium catalyst can be expected to produce debenzylation as well as olefin side-chain reduction, it is suggested that these variations be avoided unless the laboratory is equipped to identify the products, or a paper is located in which the operation has been demonstrated to be successful. Catalytic hydrogenation as described in the main section or in Appendix Five should be used in the absence of this demonstration.

Example:
On a boiling water bath at 100 deg. C. there is heated for two hours (if the yield is not good this time may be lengthened) a mixture of 38 grams (0.25 mole) a-resorcylic acid (3,5-dihydroxy-benzoic acid), 97 grams (0.77 mole) benzyl chloride, potassium carbonate 127 grams (0.77 mole) and 500-750 ml. dimethyl-formamide. After cooling the product is isolated by diluting with water and filtering. This material is intermediate crude benzyl ester of 3,5-dibenzyloxy-benzoic acid. It should be freed of any unbenzylated acid or partially benzylated material by triturating at room temperature for 3 hours with a solution of 12 grams potassium hydroxide in 500 ml. of a 4:1 methanol-water mixture, filtered, washed well with methanol, and finally with water. After drying and recrystallizing from benzene-ligroin mixture. (The ester from gallic acid was purified in this way and still obtained in a yield of 80% of theory).

50 grams of the benzyl ester obtained as above are suspended in 400 ml. boiling methyl alcohol and over 1 hour there is added in portions 46 ml. of 20% potassium hydroxide solution. After 1 more hour on the boiling-water bath the solution is cooled and acidified with dilute hydrochloric acid. The desired 3,5-dibenzyloxy-benzoic acid is filtered out and washed with a little cold water. After drying it can probably be recrystallized from a mixture of petroleum ether and ethyl acetate. (benzene-ligroin has also been used for the gallic acid product).

To repeat, the above preparation has not actually been performed and may give poor results. If so the method described in (Reference 377) can probably be used. However the amount of labor involved is sufficient that unless the above procedure is satisfactory it is probably best to utilize the well tested method described in which the hydroxy- groups are protected by methylation (see main section) and the methyl- groups removed in the separate operation (h).


Appendix Two
Appendix Four