Appendix Six
Several reactions in the present synthesis of THC-s require the preparation of Grignard reagents. These preparations have the disadvantage that they require the use of ether as solvent. Ether is not only expensive but it is dangerous to work with, particularly in large amounts, due to the high inflammability and explosive quality of the vapor.
It is strongly recommended that the alternative technique described by Ashby (Reference 399) by which benzene can be used as solvent be used. The modification is very simple, essentially consisting only of the inclusion of a tertiary amine (in equimolar amount with the alkyl halide).
The procedure is described here for the preparation of the intermediate 3,5-dimethoxy-pheny(l'-methyl-hexyl)-ketone corresponding to the operation using ether described in section (d). By substituting the appropriate alkyl halide for the 2-chloroheptane the 3,5-dimethoxy-phenyl-(alkyl)-ketones intermediate for the other variants can be prepared.
Example: 1.25 mole of the alkyl halide to be used (168 grams of 2-chloro-heptane) is dissolved in one liter of dry benzene (if the commercial material is not anhydrous it should be allowed to stand a few days with several pieces of sodium in the bottle). About 30 ml. of this solution is added to another large flask containing a mixture of 1.25 moles triethylamine (126 grams) and 75 ml. benzene with 1.5 moles magnesium turnings (37 grams; a larger amount is used here than in (d), the excess simply being filtered out after the solution is prepared). The reaction is started by gently warming this mixture (the reaction may sometimes be difficult to start; if it is, the addition of a crystal of iodine is usually sufficient, or if this fails, two drops of methyl iodide can be used) and during the next three hour period the remainder of the alkyl halide-benzene solution is added slowly, keeping the temperature of the reaction mixture at 40-50 deg. C. At the end of this time a clear solution containing some excess magnesium should be obtained. The magnesium is removed by filtration through glasswool and the solution of Grignard reagent reacted with 3,5-dimethoxy-benzamide as described in section (d).
(Note the above reaction is not typical in that this Grignard reagent when prepared in ether is nearly insoluble and as a result requires the long reaction time with the benzamide, as described in (d). It may be that the reagent formed in benzene as above will on the contrary be soluble. If it is, the reaction time can be reduced to a few hours from the 50 hours. If the material is also not soluble in the benzene then probably the long reaction time will be required here as well. With a solid product rather than a clear solution it will be difficult to remove the excess magnesium and it may be best to reduce the excess to the theoretical amount (1.25 moles). If it is soluble then the two-step reactions (c)(d) become nearly as convenient as the method described in Appendix Two).
The method can be used as well in the other Grignard reactions (except (t)) described here. It can also probably be used in the example one described in Appendix Two: in this case it will not be necessary to remove ether and substitute benzene.
Appendix Five
Appendix Seven