Synthetic Methods
Synthesis of the THC-s is largely concerned with the preparation of the 5-(alkyl)-resorcinols required for the final and simple step (Reaction (i) on the chart) in which these 5-(alkyl)-resorcinols are condensed with another agent to form the various THC-s.
Methods I and II shown on the chart differ in the starting material used (1,3,5-trichlorobenzene or 3,5-dihydroxy-benzoic acid (a-resorcylic acid)). Method I is preferable for the variants THC-III through VIII; yields are higher, raw materials are cheaper, and the number of steps is less. THC itself, and THC-II can also be prepared by this route, but it is probably preferable to use instead the modified Method II for these materials, starting with gallic acid instead of a-resorcylic acid. See the section on Method II and Appendix One for details.
Intermediate Ketone: Synthetic Method I
The synthesis of the intermediate ketone and 5-(alkyl)-resorcinol required for THC-V is given here in detail. Preparation of THC or the other variants requires the simple substitution of a different nitrile for the 2-methylheptanonitrile used for THC-V. The preparation of 2-methylheptanonitrile and the others required is given in Appendix Eight.
(s). It is important that the methanolysis of 1,3,5-trichlorobenzene be carried out in the solvent diglyme (diethylene glycol dimethyl ether; also called dimethyl carbitol or Bis-2-(methoxyethyl)-ether). The amount of diglyme also is important and should not be reduced from that indicated.
Although it is commercially available, if desired 1,3,5-trichlorobenzene can be prepared by the method of Jackson (American Journal of chemistry, 9, page 352, 1887: American Journal of chemistry, 18, pages 666-7, 1896).
Example. A mixture of 294 grams (1.6 mole) 1,3,5-trichlorobenzene, 184 grams (3.4 moles) of sodium methoxide, and 450 grams (3.3 moles) diglyme is refluxed for 42 hours (temperature around 165 deg. C.). After cooling to room temperature the reaction mixture is filtered and most of the diglyme is distilled off at ordinary pressure (b.p. 162 deg. C.). Pure 1-chloro-3,5-dimethoxybenzene is then separated from small amounts of diglyme and incompletely methylated trichlorobenzene by fractionation under reduced pressure. In the report (Reference 407) a reduced pressure of 5 mm. was used and the product collected between 97.5 and 99 deg. C. Water-pump reduced pressure should be satisfactory for the fractionation and the calculated corresponding boiling range at about 25 mm. is 130-135 deg. C. Possibly the fractionation can also be carried out successfully at ordinary atmospheric pressure, in which case the range would be 242-244 deg. C. The material collected before the main product (8-10 deg. C. lower) is incompletely methylated and saved for inclusion with a later batch. Higher boiling material (tri-methylated) is easily separated as undistilled residue and discarded. (If the amount of sodium methoxide is increased to 190 gm., the yield drops from ca. 80% to ca. 65%, but the purity of product obtained in first distillation rises from 90% to 97%). With example proportions approximately 147 grams of 1-chloro-3,5-dimethoxybenzene are obtained, together with about 70 grams of the fore-run mixture to reuse. The literature fractionation was performed with a 12 inch glass-helices packed column. For further information on the techniques of fractionation a textbook on laboratory practice should be consulted. (Reference 407 and 409)
(t). This is a Grignard reaction and for general information references (185) and (186) should be consulted. Because of the particular nature of the present reactants the procedure given below is somewhat untypical and should be followed without alteration (except that the quantities used may be proportionately increased). It is probably not essential to use the protective nitrogen atmosphere, but it is recommended and will improve the yield. Nitrogen is inexpensively available from welder's suppliers, and it will be useful in other reactions as well.
Example. A 500 ml. round bottomed flask is fitted with stirrer, thermometer, reflux condenser with protective tube filled with anhydrous calcium chloride (the CaCl2 is held in place with cotton, and serves to exclude atmospheric moisture), and nitrogen inlet. The flask is filled with a slow stream of nitrogen and heated with a flame to ensure dryness. The slow stream of nitrogen is continued so as to prevent the entry of any air during the following operations.
In another flask a solution of 43.2 grams (0.25 mole) of 1-chloro-3,5-dimethoxybenzene in 54.1 grams (0.75 mole) pure (from a freshly opened bottle) tetrahydrofuran is made up. To the flame-dried flask there is added 7.3 grams (0.3 gram-atoms) of magnesium turnings, then only 15 ml. of the solution of 1-chloro-3,5-dimethoxybenzene with a crystal of iodine and 2-3 drops of ethyl bromide (only catalytic amounts). A vigorous reaction begins. Heating of the reaction mixture is begun and over the next half-hour the remainder of the 1-chloro-3,5-dimethoxybenzene is added from a dropping funnel. The reaction mixture is refluxed until the amount of undissolved magnesium is negligible (at least three hours).
After the Grignard reagent has been prepared as above and cooled to room temperature the dropping funnel is filled with a solution of 34 grams (0.27 mole) of 2-methylheptanonitrile in 30 ml. dry tetrahydrofuran. Corresponding weights for the other nitriles (Appendix Eight) are THC 19 grams; THC-II 21 grams; THC-III 28 grams; THC-IV 31 grams; THC-V 28 grams; THC-VI 31 grams; THC-VII 31 grams; THC-VIII 31 grams). From the funnel the solution is allowed to drip slowly over 30 minutes into the Grignard solution. The addition starting at room temperature (about 27 deg. C.) causes a rise in temperature to about 40 deg. C. by the end of the addition. The mixture is heated to 60 deg. C. and the temperature is held close to this point for another six hours. The nitrogen flow can then be stopped and the mixture worked up as below. (In (Reference 407) the mixture was allowed to stand before working up at room temperature over a weekend, but this is probably not required).
The reaction mixture is hydrolyzed by cautious addition of 160 grams 40% sulfuric acid, keeping the vigorous reaction under control and the temperature below 40 deg. C. by cooling during the hydrolysis with an ice bath. After stirring another 15 minutes, the solution is distilled at ordinary pressure to remove the tetrahydrofuran (boiling point about 65 deg. C.). When the solvent has been removed there is added 40 grams of 50% sulfuric acid solution and the mixture is heated for an hour at 95-100 deg. C. (Caution the sulfuric acid solutions should be made up by adding concentrated sulfuric acid to water, not vice-versa). After cooling, a 50 ml. portion of diethyl ether is added and the resulting two layers are separated. The aqueous portion is then extracted with three 75 ml. portions ether and the four ether solutions are combined. They are washed with three 100 ml. portions of water, dried with anhydrous magnesium sulphate, filtered, and the ether distilled off at ordinary pressure.
The residue of dark oil weighs about 70 grams, from which about 43 grams of nearly pure product are isolated by fractional distillation. The literature distillation was carried out at about 0.2 mm. and the following fractions were collected;
1 - Boiling Point: 0 to 90 deg. C.; weight not given.
2 - Boiling Point: 120 to 132 deg. C.; weight 1 gram.
3 - Boiling Point: 133 to 138 deg. C.; weight 43 grams.
4 - Boiling Point: 142 to 148 deg. C.; weight 1.5 grams.
>From the above it can be seen that the product is obtained very pure and that most of the material removed in the fractionation consists of low-boiling solvent.
Probably a product adequately pure for subsequent reaction can be obtained by simply removing the low-boiling fraction by distillation at water-pump reduced pressure, then the higher boiling crude residue (mixed fractions 2,3,4) can be used without distillation. This is probably preferable. The crude materials have been successfully used, but if it is desired to obtain the pure fraction at least water-pump reduced pressure should be used in the fractionation.
Caution: Throughout this book where feasible it has been suggested that crude products be used in subsequent reactions. As can be seen from the above, the crude oils obtained by evaporating solvent extracts of the reaction mixtures often contain a large proportion of residual solvent. It is thus essential even when crude mixtures are used that they be subjected to a purifying distillation at ordinary pressure, or preferably at water-pump reduced pressure (about 25 mm.), to ensure that all of the solvent has been removed. Neglect of this precaution will make it impossible to accurately measure the quantity of reactant being used in the subsequent procedure, since it will be a mixture of desired material with an unknown amount of solvent. When facilities permit it is usually best to isolate the desired product as a pure fraction, except when distillation also causes decomposition. In some reactions this matter will require some experimentation and necessary information is included here for particular cases.
In the present reaction the crude dark oil product can probably be fractionated successfully at water-pump reduced pressure (ca. 25 mm.) instead of the 0.2 mm. used in the literature. The approximate boiling ranges equivalent at the two pressures are as follows;
Calculated for 0.2 mm.
1) 0 - 90 deg. C.
2) 120 - 132 deg. C.
3) 133 - 138 deg. C.
4) 142 - 148 deg. C.
Calculated for 25 mm.
1) 0 - 180 deg. C.
2) 215 - 230 deg. C.
3) 230 - 240 deg. C.
4) 240 - 245 deg. C.
The corresponding calculated boiling range at 25 mm. for the other ketones intermediate for THC or the other variants will be found in the chart given in section (d) of Method II. It is a special advantage of the method I that these ketones are obtained in purer state than by the section (d) of Method II. However, other techniques of purification are given there and could be used here also. Note that the order in which the products and impurities are collected will alter with the different ketone boiling ranges.
THC Synthesis - Overview
Intermediate Ketone: Method II