THC Synthesis, Page 35
Appendix Four
The original work of Suter and Weston (Reference 126) on the reduction of ketone intermediates for THC was done before the Wolff-Kishner reduction technique was perfected. Because they prepared the required hydrazone in a separate step they obtained a relatively low yield of alkyl benzene contaminated with about 30% of by-product azine. The following procedure raises the yield to 85-90% of theory, and is much simpler to carry out.
(k) Wolff-Kishner Reduction for THC & THC-II.
In the following example diethylene glycol is used. If desired ethylene glycol, triethylene glycol, or triethanolamine could be substituted.
Example:
To about 1.2 liters of diethylene glycol there is added 168 grams (3 moles) potassium hydroxide pellets and the loosely stoppered flask is swirled occasionally until the alkali has dissolved and the temperature returned to below 100 deg C. (the solution process is exothermic). To this alkali solution is added one mole of the ketone to be reduced (225 grams THC intermediate ketone-- n-butyl, or 239 grams THC-II intermediate- n-amyl) and about three moles 85-l00% hydrazine hydrate (100% hydrazine hydrate is probably preferable; 150 grams). The mixture is heated cautiously until the initial exothermic reaction is completed (about 110 deg. C.), then it is gently refluxed for one hour. The reflux condenser is then removed and replaced for downward distillation and from the reaction mixture there is distilled water (formed in the reaction) and excess hydrazine hydrate until the temperature of the liquid reaches 200-210 deg C. (if foaming is a problem it can be eliminated by agitation and addition of a commercial anti-foaming agent). At this point the condenser is again arranged for reflux end this is continued at 200-210 deg C. for another 3-5 hours. After cooling to room temperature sufficient water is added to dissolve the solids (an equal volume or up to two liters) and the product is extracted with ether or benzene (Suter and Weston used ether but benzene probably can be employed).
On distilling off the ether or benzene the product is obtained as residue, contaminated with some by-product azine. With the above technique the amount of azine may be negligible and the crude product may be suitable for further reaction without special purification. The pure products can be obtained by distilling the crude residue under reduced pressure (the THC intermediate boils at 133-136 deg C./ 6 mm.; probably water-pump reduced pressure can be used equally well), leaving the azine as a yellow solid residue in the distillation flask.
The azine by-product (if any) should be saved and can be converted to hydrazide for reduction in another operation. The conversion is carried out simply by refluxing in hydrazine hydrate (probably best in 100% hydrazine hydrate). A similar conversion is described for benzaldazine (Curtius; Berichte 35, page 3236, 1902). Anhydrous hydrazine has also been used, but it is much more dangerous to work with and should be avoided if the hydrate can be used (Smith, Open Chain Nitrogen Compounds, Vol. II, page 172, 1966: Staudlnger; Berichte 49, page 1897, 1916).
A discussion of the Wolff-Kishner reduction and possible variations of technique is found in the book by R.L. Augustine, Reduction, Marcel Dekker, Inc., N.Y. (1968).
The Clemmensen reduction has also been tried but failed in (Reference 126). Since this method has been recommended as a route to n-alkyl benzenes in later work (Fahim and Mustafa; J.C.S., p. 519, 1949) it may bear re-examination.
In his later work Adams (References129 and 130) preferred high pressure hydrogenation to the Wolff-Kishner method, but this requires special equipment and has no great advantage. However, two alternatives to high pressure reduction have been developed and have given good results with ketones such as employed here. The first technique was described by Rosenmund (Berichte 75B, pages 1850-59, 1942). In this method the ketone group is reduced to -OH under ordinary conditions by hydrogenation with palladium catalyst, then the reduction to alkyl-benzene is completed by raising the temperature and adding perchloric acid to activate the catalyst. In a similar procedure Kindler (Liebigs Annalen 564, pages 51-56, 1949) activates the catalyst before hand by washing several times with 15% sulfuric acid, then with water until free of acid, then with methanol, and finally heating the catalyst to 200 deg C. for 1 hour.
The ketone reduction method described in (References 417 and 375)(also in Reduction, pages 34 and 35) presents a particularly interesting possibility provided the conditions used will also hydrolyze acetyl- groups simultaneously. By applying this lithium aluminum hydride - aluminum chloride mixture reduction to the 3,5-diacetoxy- phenyl-(n-alkyl)-ketones one would then obtain directly the desired 3,5-dihydroxy-(n-alkyl)-benzene. Both of the required diacetoxy-(n-alkyl)-ketones required for THC and THC-II have been prepared by a convenient application of the organo-cadmium reagent by Huls (Reference 127; see 422).
Appendix Three
Appendix Five