Appendix Two
Suter and Weston in their original work (Reference 126) attempted to use reaction (j) and an organo-cadmium reagent to convert the 3,5-dimethoxybenzoyl chloride from (b) directly to the 3,5-dimethoxy-phenyl-(n-alkyl)-ketones, but failed because they did not allow sufficient time for the formation of the organo-cadmium reagent (Reference 136).
In 1956 Huls (Reference 127) successfully used the organo-cadmium reagents to prepare 3,5-diacetoxy-phenyl-(n-alkyl)-ketones corresponding to those required for THC and THC-II. His modification was simply to allow sufficient time for formation of the reagent. There is no clear reason why the same reaction conditions could not be applied to the preparation of the 3,5-dimethoxy-phenyl-alkyl-ketones used here, however more recent papers (References 404 and 405) have utilized more special conditions (very low temperature and catalyst ferric chloride) specifically for the 3,5-dimethoxy-benzoyl chloride reaction (Reference 405). Example One describes a modification of the Huls procedure which should give satisfactory results. Example Two gives the conditions based on (References 404 and 405), which can be used if the first example for unexpected reasons is not satisfactory.
The articles on use of organo-cadmium reagents in (References 156 and 188) should be consulted before proceeding with the following.
Example One
A Grignard reagent is prepared in the usual way (Reference 185 and 186) from 1.15 mole (29 grams) magnesium and 1.25 mole (223 grams) 2-bromo-heptane in 575 ml. dry diethyl ether. To the ice-cold solution is added over 10-15 minutes 113 grams dry cadmium chloride in small portions. The solution is then stirred at boiling temperature (water-bath on electric hot plate) under a water-cooled reflux condenser for 20-50 minutes until the Gilman test shows that formation of the organo-cadmium reagent is complete
(This test is carried out by adding 1 ml. of the solution to an equal amount of a 1% solution of Michler's ketone (commercially available) in dry benzene. Next 1 ml. of water is carefully added while gently agitating the test tube and finally there is added several drops of a 2% solution of iodine in glacial acetic acid. If a greenish-blue color develops then the reaction is not yet completed and further reflux is required. When no color develops it shows that all of the Grignard reagent has reacted and the refluxing can be ended).
For reaction with the benzoyl chloride it is necessary to remove the ether in which the Grignard reagent was formed, and to replace it with benzene. This is accomplished by removing the reflux condenser and replacing it so that the distillate ether is collected in a suitable container. The distillation of the ether is conducted rapidly by heating on the boiling-water bath until distillation becomes slow and a nearly dry residue remains. 375 ml. benzene is then added and the distillation continued until 140 ml. of the benzene has been distilled out (this ensures dryness and complete removal of ether). Another 675 ml. benzene is then added and the stirred solution brought to the boiling point. External heating is then stopped and the 3,5-dimethoxy-benzoyl chloride (0.65 mole, 115 grams) dissolved in benzene (170 ml.) is added in portions over the next 5 minutes. (The reaction is exothermic and too rapid addition will cause it to go out of control). Heating is continued under reflux for one hour, after which the reaction mixture is cooled and acidified with dilute sulfuric acid. The product ketone is extracted with several portions of ether, the ether solution washed with sodium bicarbonate (dilute) solution, then with water. After drying with Drierite and filtering, the ether is distilled off on the boiling water-bath. If necessary the crude ketone can be purified as described in the main section.
While the above description is for the ketone intermediate for THC-V, variant intermediates are prepared similarly. The appropriate alkyl halides are listed in the main text, the amount used in the above reaction corresponding to 125% of the molecular weight of the particular halide. (References 136 and 156)
Example Two
115 Grams of 3,5-dimethoxy-benzoyl chloride are dissolved in a mixture of 450 ml. ethyl ether and 275 ml. toluene (both solvents must be anhydrous) and cooled to -60 deg. C. by means of a dry-ice acetone bath. (In the original paper a protective atmosphere of nitrogen was used, but this is probably not essential). This solution is then treated gradually with a solution of 20 grams anhydrous ferric chloride in a mixture of 120 ml. ether and 60 ml. toluene. By means of a dropping funnel there is then added drop-wise an etherial solution of the alkyl magnesium bromide (from 1.25 mole alkyl bromide as in the first example, using the Gilman test, but not removing any ether). The addition is made over several hours slowly enough to keep the temperature within a few degrees of -60 deg C. After further standing for half the time required for the addition the mixture is decomposed with ice and hydrochloric acid (dilute). The crude product is isolated by separating the organic layer from the aqueous layer, drying with anhydrous magnesium sulphate, filtering, and distilling off the solvent. Purification is carried out as described in main section (d).
Appendix One
Appendix Three