(C). Preparation and Use of (-)-2-Carbethoxy 5-Methylcyclohexane
Preparation of THC-C and variants in this series requires the use of optically active (-)-2-carbethoxy-5-methylcyclohexane. The THC-s obtained with this isomer are 11-15 times more powerful than are obtained with the (+)- isomer, so that the use of a racemic mixture is much less satisfactory.

Starting point for the synthesis is readily available 3-methyl-cyclohexanone, which is a mixture of (-)- and (+)- isomers. The desired (-)- isomer is separated by use of (l)-(alpha-phenylethyl) semioxamazide and the (+)- isomer discarded. When the (l)-(alpha-phenethyl)-semioxamazide is obtained commercially this route to active THC-s is particularly good however it can also be prepared without difficulty from commercial a-phenylethylamine (a-phenethylamine) as described below.

1. (1)-alpha-phenethylamine.
To a solution of 48 grams racemic (mixed d- and l- isomers) a-phenethylamine base (now usually called a-methylbenzylamine) in 600 ml. 96% ethyl alcohol there is added 59.6 grams ordinary tartaric acid. The solution is kept at 60 deg C. and stirred for 24 hours, then filtered while hot to collect the desired undissolved tartrate of (l)-a-phenethylamine. The liquid containing (d)- isomer is discarded. The solid can be purified by recrystallizing once from a minimum amount of hot water; yield 31 grams. The base (l)-a-phenethylamine is obtained by dissolving the salt (Mol. Wt. 271) in four parts water and adding excess 25% aqueous sodium hydroxide. The free base is extracted into several portions benzene and the benzene solution thoroughly dried with fresh sodium hydroxide pellets, filtered, and the product isolated by fractionation (b.p. 184-189 deg. C.). (References 371 and 372)

2. (1)-5-(alpha-phenethyl)-semioxamazide.
To 15 grams (0.12 mole) of (1)-a-phenethylamine in 150 ml. anhydrous ethyl alcohol at room temperature there is added slowly with stirring 38 ml. (0.25 mole) of pure diethyl oxalate. The reaction mixture is allowed to stand 24 hours, then filtered to remove a small amount of diamide. The solvent ethyl alcohol is then distilled off at ordinary pressure, then the excess diethyl oxalate is removed at water-pump reduced pressure. The residue, which solidifies, is purified by crystallization from anhydrous ethyl alcohol to give 23 grams (91% of theory) of product as glistening colorless needles.

3. Resolution of 3-methylcyclohexanone into (+) and (-)isomers.
To a solution of 25 grams (0.2 mole) of 3-methylcyclohexanone in 50 ml. benzene there is added 21 grams (0.1 mole) of (1)-5-(alpha-phenethyl)-semioxamazide and a crystal of iodine. The mixture is refluxed for a few minutes, or until a clear solution is obtained. The solution is concentrated and cooled, and the solid product so obtained is recrystallized five times from benzene. The colorless needles melt at 179-80 deg C. The yield of intermediate salt so obtained is about 27% of theory (4 grams). It is hydrolyzed by refluxing 8 grams in 20% sulfuric acid for a few minutes, cooling, then filtering out the precipitated hydrazine sulphate. The desired product is then extracted with several portions of ether, the combined ether extracts are dried with an anhydrous salt such as Drierite, filtered, and the ether distilled off. (Reference 370). (Note: For an alternative resolution procedure see Adams, J.A.C.S., 71, 519-26 (1949).)

4. (-)-2-carbethoxy-5-methyl-cyclohexanone.
A solution of sodium ethoxide is prepared by dissolving 5.95 grams sodium in 120 ml. anhydrous ethyl alcohol (or instead of sodium commercial sodium ethoxide(17 grams) can be added to 110 ml. dry ethanol). The reaction vessel should be protected against entry of atmospheric moisture by attaching a calcium chloride filled tube (the anhydrous calcium chloride is held in place by wads of cotton). The solution is cooled to 3-5 deg C. in an ice bath and with stirring or swirling 38 grams pure diethyl oxalate is added gradually in portions. The temperature is held at 3-5 deg C. during the addition and for another hour afterwards. After standing overnight at room temperature, the mixture is hydrolyzed by pouring it onto a mixture of 15 ml. concentrated sulfuric acid in crushed ice. The pale yellow oil is separated and the aqueous solution extracted with chloroform. The combined oil and extracts are washed with water plus a little sodium bicarbonate solution until neutral to congo red indicator paper, then dried with an anhydrous salt such as Drierite. The solution is then placed in a distilling flask and a small amount of powdered glass and a trace of iron powder are added. The pure product is then collected by distillation under water-pump reduced pressure (b.p. 126-130 deg C. at 17 mm. pressure; possibly experiment will show that reduced pressure is not essential). (Reference 363)

The condensation of (-)-2-carbethoxy-5-methylcyclohexane with olivetol has been catalyzed by sulfuric acid (References 367 and 368), but the use of phosphorus oxychloride gives yields of around 70% and has been preferred in recent work (Reference 219). The pyrones so obtained are treated with 12 molar equivalents of methyl magnesium iodide to convert them to the desired pyran (THC-C).

Unlike the other condensations the present method requires two steps (5 and 6) for reaction (i) of the chart. Reaction (5) has also been carried out using an extended period of reflux instead of prolonged standing at room temperature, but the yields are inferior (Reference129). With the conditions described yields in the range 60-80% should be expected. It is important to keep careful records of the reaction conditions and any variations in the treatment of each batch, as well as yields and amount of recovered 5-(alkyl)-resorcinol. This will make it possible to reproduce those conditions which give the best yields. The same applies to reaction (6), in which the following irregular yields have been obtained (THC-III 59%; THC-IV 66%; THC-V 80%; THC-VI 88%).

It is also suggested that some experiments with small quantities be undertaken to condense the (-)-2-carbethoxy-5-methylcyclohexanone with a 5-(alkyl)-resorcinol in the presence of boron trifluoride etherate instead of phosphorus oxychloride. The reaction conditions described under the Citral condensation can be used as starting point, using 1-10% of the catalyst. Although untested, this condensation can be expected to considerably improve the yields over those obtainable by the procedure of (5).

It has been found advantageous to use equimolar amounts in the condensation (5); some of the 5-(alkyl)-resorcinol remains unreacted but it can be almost completely recovered (Reference 187), probably by acidifying the aqueous portion of the reaction mixture and extracting the 5-(alkyl)-resorcinol with ether. In view of the effort required to prepare the resorcinol, this recovery should always be carried out.

5. Intermediate Pyrone
(l-hydroxy-3-(alkyl)-9-methyl-7,8,9,10-tetrahydro-6-dibenzopyron).
To a mixture of 183 grams (1 mole) of (-)-2-carbethoxy-5-methylcyclohexanone with 93 ml. (1 mole) phosphorus oxychloride in 1200 ml. of anhydrous benzene (ordinary benzene should be dried by standing a few days with several pieces of sodium in the bottle) there is added 1 mole to the appropriate 5-(alkyl)-resorcinol (weights are given in the introduction to this condensation section).

The mixture is heated to boiling for five minutes only, then it is allowed to stand for 21 hours at the room temperature, while protected against atmospheric moisture by an anhydrous calcium chloride filled tube (instead of calcium chloride these protective tubes can be filled with ordinary surgical cotton which has been dried in an oven). Two volumes of water are then added and the mixture shaken thoroughly to destroy the phosphorus oxychloride, then cooled. Most of the product crystallizes and is collected by filtering the benzene-water mixture. The benzene layer is separated from the aqueous layer in the filtrate, partially evaporated, and additional product filtered out. The benzene can be evaporated to dryness and the crude residue purified separately. (It is possible that recovery of unreacted 5-(alkyl)-resorcinol from the aqueous portion will be facilitated if the water used to destroy phosphorus oxychloride is replaced with aqueous sodium bicarbonate solution (Reference 383). For the recovery the separated aqueous layer is acidified, the 5-(alkyl)-resorcinol extracted with ether, and the ether distilled off on the water-bath.)

It is not clear whether it is necessary to purify this pyrone before reaction (6). Adams crystallized THC and THC-II from methanol; THC-III and THC-IV from ethanol-water; THC-V from (a) nitromethane, (b) ethanol-water; and THC-VI from ethanol-water (by adding water to faint turbidity at 50 deg. C., then refrigerating). Recent workers with THC-V (Reference 219) have preferred the use of cyclohexane for crystallizing, and the same solvent may be superior for purification of the other THC-s. Another method has been used recently (Reference 219) for preparing pure samples of the THC-V intermediate pyrone, in which about 5 grams in benzene are poured into an activated alumina chromatographic column (1 inch by 4 inches long; Reference 199). The partially purified materiel (the alumina absorbs some of the impurities) is then eluted with two 50 ml. portions of benzene, the first containing 5% and the second 10% of acetone. The acetone is evaporated and the residues triturated with petroleum ether to give tan solids. These were then combined and recrystallized using decolorizing charcoal from cyclohexane, giving off-white to tan powders in 39%-52% yield. It seems that some additional product could be recovered by washing the column a third time with 50% acetone-benzene, evaporating the solvents, then adding the residue for working up with a later batch or purifying it separately.

Whatever the yield obtained in the condensation reaction itself, the final yield obtained depends also on the amount lost during purification. For this reason it seems worth-while to attempt reaction (6) with the crude material and if unsatisfactory results are obtained to establish by experiment the minimum purity required. In these experiments it is important to bear in mind that the product from the second reaction (6) should be as pure as possible and it may well be that this objective can be obtained more easily by ensuring that the pyrone from (5) is as pure as possible for use in reaction (6), rather than by purification of the product from (6) itself. In their work using sulfuric acid as condensing agent an English group (Reference 361) found that (6) gave a cleaner product it the pyrone from (5) was first acetylated by refluxing with acetic anhydride in the presence of pyridine. The purest product can be expected if boron trifluoride etherate is used to prepare the pyrone.
6. Pyran Synthesis (THC-C and variants).
To a dry ether solution of 1.2 moles methyl magnesium iodide (prepared in the usual way from 29 grams magnesium, 170 grams methyl iodide, and 600 ml. anhydrous ethyl ether; see Reference 165 and 186 for general method and precautions) there is added 0.1 mole of the appropriate pyrone (prepared as in the previous section) dissolved in ??? ml. benzene. the weights of the appropriate pyrones are as follows;

THC-C 30 grams
THC-II 31 grams
THC-III 35 grams
THC-IV 37 grams
THC-V 35 grams
THC-VI 37 grams

(The 12 molar excess of methyl magnesium iodide is required in order to obtain a good yield based on the pyrone). After being refluxed for 12 hours the solution is poured into ice-cold ammonium chloride solution, the organic (ether-benzene) layer is separated, and the aqueous layer extracted with benzene once. The combined extract and organic layer are washed successively with water, dilute sodium carbonate solution, then with water. The solvent is then distilled off on a boiling water bath and the residue is suspended in ??? ml. of boiling petroleum ether (b.p. 60-100 deg C.). Three drops of 48% hydrobromic acid are added and the solution heated on the electric hot plate for 30 minutes, maintaining the volume by adding more petroleum ether as needed. After decanting from a small amount of insoluble material the products are converted directly to the desired acetate esters by refluxing with excess acetic anhydride and sodium acetate as described in the introduction to this condensation section. probably this can be carried out most conveniently in the present case by adding the acetic anhydride and sodium acetate directly to the petroleum ether solution of product, beginning the timing of 3 hour reflux when the volatile solvent has distilled off; otherwise the petroleum ether may first be boiled off using a boiling water bath. (Reference 220 and 219)

(Note: Adams has pointed out in one of his later papers that instead of 12 hours reflux, the above reaction is usually complete in 9 hours, and this will probably give the better yield. Also, instead of pouring into excess aluminum chloride solution, a slightly better yield can be expected by the dropwise addition of saturated solution. This method is detailed in (Reference 199), in the section of Grignard reactions.


Preparation and Use of (-)-Verbenol
Preparation and Use of (+)-p-2,8-menthadien-1-ol