Conversion of the Ketones Obtained By Methods I or II
to the 5-(alkyl)-Resorcinols
The procedure is described in the following sections for THC-V. As indicated, the same methods are used for THC-III, THC-IV, and THC-VI. For THC itself, or THC-II, the ketone is instead directly reduced as described in Appendix One and Appendix Four.
(e). This is a Grignard reaction and for general information the references (Reference 199, 185 - page 365, and 186) should be read. Particularly when larger amounts are involved it is safer to use benzene and a tertiary amine in place of the highly inflammable diethyl ether. This technique is described in Appendix Six, and also below in Example 2.
The reaction is carried out in a 5 liter flask fitted with stirrer, thermometer, a reflux condenser with attached calcium chloride drying tube (to exclude atmospheric moisture), dropping funnel, and preferably a nitrogen inlet (use of protective nitrogen atmosphere is not essential, but will give a higher yield and is recommended). The flask is flushed with nitrogen, dried with a flame, and then a slow stream of nitrogen is continuously allowed to flow into the flask.
Example 1: Solvent Diethyl Ether. In the usual way (Reference 185) a Grignard solution of methyl magnesium bromide or iodide is prepared from 27 grams magnesium turnings (1.12 mole), 105 grams (1.12 mole) methyl bromide (or 158 grams methyl iodide can be used instead), and 600 ml. anhydrous diethyl ether. It is also possible to substitute equivalent amounts of commercial methyl magnesium bromide or iodide solutions.
To the cooled Grignard reagent is added over 1-2 hours dropwise from the funnel a solution of the appropriate ketone (1 mole) dissolved in 350 ml. of dry ether. The appropriate weights are;
THC-III; n-heptyl ketone, 267 grams.
THC-IV; n-octyl ketone, 281 grams.
THC-V; 1'-methyl-hexyl-ketone, 267 grams.
THC-VI; 1'-methyl-heptyl-ketone, 281 grams.
(THC-III and THC-V, THC-IV and THC-VI are isomeric and hence have the same weight)
During the addition an external ice bath must be used and the temperature of the solution kept below 15-20 deg. C. by slow addition. When the solution of ketone has been added the mixture is heated at reflux for one hour to complete the reaction, then cooled to room temperature.
The mixture is hydrolyzed by pouring carefully into a mixture of 1.2 liters ice-water and 2.4 liters of crushed ice to which has been added 120 grams concentrated sulfuric acid. The whole is stirred 10 minutes, then another 120 grams sulfuric acid added and stirring continued another half hour. The resulting two layers are separated and the aqueous portion extracted with three 800 ml. portions of ether. The four combined ether solutions are washed with water, then dried with anhydrous magnesium sulphate, filtered, and the ether distilled off at ordinary or water-pump reduced pressure, leaving about 256 grams of pale yellow; undistilled residue. This materia1 is 95% pure and suitable for the subsequent reaction (yield 93%). For case of THC-V the product distills at 134 deg. C./ 0.23 mm. and can be obtained 97% pure by a single distillation under reduced pressure. (References 128, 407 and 409)
Although it has not actually been carried out, the following modification (based on Reference 359) should give similar results and is safer.
Example 2: Solvent Benzene. Into a flask fitted as in the first example there is placed 33 grams (about 1.3 gram-atoms) magnesium, turnings with 75 ml. benzene and 112 grams (1.12 mole) triethylamine. The benzene used should be anhydrous; ordinary benzene can be dried by standing a few days in a bottle with a few pieces of sodium metal, then decanting the dry benzene.
To this there is added 70 ml. of a solution prepared from one liter benzene and 1.12 mole methyl bromide (105 grams) or methyl iodide (158 grams). The reaction is started by gently warming this mixture. Over the next two hours the remaining methyl halide solution is added in small portions (preferably dropwise by the dropping funnel) while the temperature is kept between 40 and 50 deg. C. (no higher). At the end of this time the solution of Grignard reagent is clear except for the excess magnesium turnings, which are removed after cooling the solution to room temperature. The Grignard solution in benzene is then cooled as required for the reaction as described in the first example.
To the Grignard reagent in benzene prepared as above the ketone solution (also in benzene, instead of diethyl ether) is added over 1-2 hours as described in the first example. Hydrolysis and extraction of the product with three 800 ml. portions of benzene is also carried out as in 1. (Note: to be certain that the product carbinol is extracted as efficiently by the benzene as by the ether originally used, it is advisable in the first experiment to follow the benzene extraction with an ether extraction of the aqueous portion. Evaporation of the ether will reveal if any product remained unextracted by the benzene. If there is a significant amount then the extractions in the future can be performed as in the first example with ether.
(note: in many of the reactions described here products are extracted from reaction mixtures by use of ether. It is usually possible (and preferable) to substitute the non-explosive methylene chloride for the ether. To be sure that the extraction is complete, the sane follow-up extraction with ether can be used as a test).
Reaction (f). The carbinols obtained as above by reacting the ketone with Grignard reagent have been dehydrated to olefins by a variety of methods. Adams obtained good yields in his early work by simply adding a few drops of 20% sulfuric acid to the carbinol in a distilling flask and distilling at water-pump reduced pressure. Water begins to be evolved at about 110-l30 deg. C., and after all the water has distilled out the receiver is changed and the pure olefin (produced by the removal of water from the carbinol) was distilled at the same pressure (Reference 128). Later on it was discovered that even better results were obtained by substituting a few pinches of p-toluene sulphonic acid for the sulfuric acid (Reference l87). Even with the earlier technique the yields of all intermediates for THC-III through THC-VI were in the range of 80-90%.
In the most recent work (Reference 407) the dehydrations have been carried out with oxalic acid or iodine. It appears that the use of iodine is superior to all the others, as it is used most frequently and gives an 85% yield of THC-V intermediate. (Anhydrous oxalic acid gave 65% yield of pure distilled material, See Appendix Nine).
Example. About 40 grams of the crude carbinol are added to 1.5 grams iodine crystals in a flask and heated at 99-103 deg. C. (conveniently attained in a water bath containing some dissolved calcium chloride) for 40 minutes. At the end of this time some condensation is visible around the mouth of the flask. The mixture is cooled and transferred to a separatory funnel where 50 ml. of benzene is added. The mixture is washed with two 25 ml. portions of 6% sodium thiosulfate solution, then with two 50 ml. portions of water. The benzene solution of product is then poured into a flask and heated with some decolorizing charcoal, filtered while hot, and the benzene distilled off. Distillation of the residue gives the following fractions;
1. 7.4 grams - b.p. to 88 deg. C./ 0.3 mm.
2. 2.6 grams - b.p. 94-115 deg. C./ 0.3 mm.
3. 19.8 grams - b.p. 113.5-115 deg. C./ 0.25 mm.
4. 6.4 grams - residue
Fraction 1 contains none of the desired product, fraction 2 contains about 25% of the product together with about 50% of byproduct 1-chloro-3,5-dimethoxybenzene (probably present as an impurity in the starting material), while fraction 3 contains 76% of the desired product and the residue (fraction 4) also contains a considerable amount.
>From the above information it is probably best simply to remove all materia1 boiling below 94-115 deg. C./ 0.3 mm. (the corresponding range at water-pump reduced pressure is 180-200 deg. C.; ordinary pressure might also be used, the range being 300-325 deg. C.), then using the remaining crude residue without distillation directly in the following reaction. (Note that the yield in this example is below the 85% claimed in (Reference 407). If it cannot be raised by trial, Adams' method with p-toluene sulphonic acid can be used, or oxalic acid (Appendix Nine).
Because of the possibility of rearrangement distillation of the olefins at ordinary pressure is best avoided, but if the undistilled material is unsatisfactory for the subsequent reaction they can be distilled at reduced pressure. The following shows the boiling points and pressures used Adams, while the calculated approximate boiling point at water-pump reduced pressure is also given.
THC-III: R-C(CH3)=CH(CH2)5 CH3 - b.p. 148 deg. C./ 1 mm.; 210-220 deg. C./ 25 mm.
THC-IV: R-C(CH3)=CH(CH2)6 CH3 - b.p. 175 deg. C./ 1.5 mm.; 235-245 deg. C./ 25 mm.
THC-V: R-C(CH3)=C(CH3)C5H11 - b.p. 132-134 deg. C./ 1 mm.; 195-210 deg. C./ 25 mm.
THC-VI: R-C(CH3)=C(CH3)C6H13 - b.p. 129 deg. C./ .08 mm., 235-245 deg. C./ 25 mm.
(R = 3,5-dimethoxy-phenyl)
Reaction (g) The olefins obtained in reaction (f) can be reduced in good yield and without special equipment other than a cylinder of hydrogen. If benzylation has been used instead of methylation to protect the hydroxy groups (Appendix Three), then the hydrogenation will simultaneously split these off and the product will be the 5-(alkyl)-resorcinols listed in section (h), thus eliminating the need for the demethylation described there.
Adams used Raney Nickel as catalyst in his work and this is satisfactory with the methoxy- protected. However, when simultaneous reduction and debenzylation are being performed palladium-on-charcoal should be used to ensure that after the benzy- groups have been removed the reduction does not proceed further in the nucleus. With this catalyst it will not matter if the hydrogenation is continued for a longer time than actually required. Anhydrous ethyl alcohol is usually used as solvent, however in some work ordinary 96% alcohol or glacial acetic acid have given good results. A discussion of catalytic hydrogenation and apparatus is in (Reference 185) and Organic Syntheses Col. Vol. I, p. 61. However such elaborate apparatus is not essential.
Information on removal of the benzyl groups can be found in (Reference 386), while further information on catalytic hydrogenation in general can be found in the above textbooks. While Adams used ordinary room temperature and 2-3 atmospheres hydrogen pressure the reduction can be carried out equally well at ordinary pressure, without special equipment. The hydrogen from a cylinder is simply bubbled into the solution. at atmospheric pressure more time would be needed but this can be off-set by use of additional catalyst. When palladium catalysts are used they can be preserved and used for several runs.
(Note: Although it is not to be expected in the present operation under certain circumstances catalytic reduction has given difficulty due to poisoning of the catalyst. This is the reason for proceeding through the dehydration of the carbinol then reducing the olefin, rather than by direct hydrogenolysis of the carbinol by catalytic hydrogenation. This difficulty can be overcome by removing the first batch of poisoned catalyst and replacing it with fresh. One or two repetitions of this will remove all of the poison and the hydrogenation can then be carried out successfully. For this purpose it will be most economical to use Raney Nickel. It is also suggested in (Reference 407) that this technique may make possible the direct hydrogenolysis of the carbinol obtained from (e), eliminating the intermediate olefin.
Example: A three-necked flask is fitted with efficient sealed stirrer, inlet tube for hydrogen leading to the bottom and terminating with a sintered glass gas distributor tube, and an outlet for overflow hydrogen connected by rubber tube to a safe vent. (The stirrer can be avoided if the vessel is tall, such as a graduated cylinder. The solvent, olefin, and catalyst are placed in the flask & hydrogen flow started directly from a cylinder at such a rate that only a small proportion escapes unabsorbed from the surface of the liquid. In some reactions the end of the reduction can be detected by lessened absorption. The time required must be determined by experiment so that records should be kept and the conditions standardized as much as possible. A 24 hour hydrogenation is suggested with commercial palladium-on-charcoal (0.5-1.0 mm. are used with 100-200 gram quantities) less with the catalysts of Appendix Five). With Raney Nickel 2 grams are used per 10 grams olefin.
When the reduction is completed it is simply necessary to filter out the catalyst and wash it on the filter with a small amount of fresh solvent and alcohol. The filtrate and washings are then distilled (usually under reduced water-pump pressure) to separate the glacial acetic acid or alcohol, together with toluene formed as by-product. If methylated olefins have been reduced the boiling points are given in this section; if benzylated olefins have been debenzylated simultaneously with the olefin-side chain reduction the boiling points of the products are listed in the next section (h).
The following listing shows the products obtained when methoxy-protected olefins are reduced by one of the above means; (a) is the name of the alkyl side chain, (b) the empirical formula of the product, (c) shows the structure of the side chain (R = 3,5-dimethoxy-phenyl), (d) the yield obtained by Adams.
Table One
THC: (a) n-amyl (b) C13 H20 O2 (c) R-CH2CH2CH2CH2CH2 (d) 65%
THC-II: (a) n-hexyl (b) C14 H22 O2 (c) R-CH2CH2CH2CH2CH2CH2 (d) 57%
THC-III: (a) 1'-methyl-octyl (b) C17 H28 O2 (c) R-CH(CH3)(CH2)6-CH3 (d) 73%
THC-IV: (a) 1'-methyl-nonyl (b) C18 H30 O2 (c) R-CH(CH3)(CH2)7-CH3 (d) 85%
THC-V (a) 1',2'-dimethyl-heptyl (b) C17 H28 O2 (c) R-CH(CH3)CH(CH3)-C5H11 (d) 79%
THC-VI: (a) 1',2'-dimethyl-octyl (b) C18 H30 O2 (c) R-CH(CH3)CH(CH3)-C6H13 (d) 86%
In Table Two there is given the boiling point under reduced pressure as given by Adams together with the boiling point (approximate) to be expected when the product is distilled at water-pump reduced pressure (ca. 25 mm.). The materials intermediate for THC and THC-II are obtained as described in Appendices One and Four.
Table Two
3,5-Dimethoxy-(alkyl)-benzenes
THC: 133-136 deg. C./ 6 mm. 160-170 deg. C./ 25 mm
THC-II: 141-142 deg. C./ 7 mm. 165-175 deg. C./ 25 mm
THC-III: 137 deg. C./ 0.5 mm. 210-220 deg. C./ 25 mm
THC-IV 160 deg. C./ 1 mm. 230-240 deg. C./ 25 mm
THC-V: 120 deg. C./ 0.5 mm. 200-210 deg. C./ 25 mm
THC-VI: 141-150 deg. C./ 0.05 mm. 270-280 deg. C./ 25 mm
(Reference 254, 126, 130, 129 and 187)
Although catalytic hydrogenation as described above gives good results it is not always convenient. Recently alternatives have become available. One method is transfer hydrogenation in which the gaseous hydrogen is replaced by a liquid reagent such as cyclohexene (see details in Appendix Eleven). Another method described in detail below is the use of hydrazine hydrate instead of hydrogen (Reference 201 and 388). In this case the reduction is probably best carried out in the absence of any catalyst. If benzyl-groups are to be split off as well, then it is performed after the reduction step by adding palladium catalyst and additional hydrazine (Reference 201 - page 65).
Ethyl or methyl alcohols are used for the hydrazine reduction and they need not be anhydrous. Hydrazine hydrate also may be 85% or even more dilute, but a molar excess of at least twice that theoretically required for each group to be reduced is needed.
Control of the pH of the reaction mixture is essential, as the reduction does not occur under acid conditions (below pH 7), while too much alkali depresses the reduction. The optimum pH is obtained by adding sufficient alkali to maintain the pH (measured frequently with an indicator paper) in the range pH 8.5 to 9.
The reduction also requires that oxygen be available. This condition can be met simply by stir ring efficiently in an open reaction flask or beaker. Alternatively hydrogen peroxide 30% solution can be added as oxidizing agent. This seems to be advisable whether or not the open flask is used; the need for stirring is reduced and at the same time the need for including a weak saturated organic acid (Reference 201) is eliminated. When hydrogen peroxide is used a greater excess of hydrazine hydrate than two moles is required and at least 4 moles is suggested. Use of potassium iodate together with 1-2 grams of decoic acid in place of hydrogen peroxide will eliminate the water introduced with the peroxide, but this also would complicate the isolation of product. When peroxide is used the alcohol, water, and product can probably be separated simply by distillation at water-pump reduced pressure. Relatively low temperatures are used, 50 deg. C. is convenient, with reaction times about 4-8 hours. Or the reaction can be carried out simply by allowing the reaction mixture to stand at room temperature for a week or two.
Debenzylations have not actually been carried out with the hydrazine reagent, but may be expected to be successful (Reference 201 - page 65). For this purpose it is probably best to complete the reduction as above, then to add palladium-on-charcoal catalyst and then additional hydrazine and peroxide. Twice the quantities are required for the debenzylation as for the reduction itself since there are two groups instead of one.
Both transfer hydrogenation (Reference 389) and hydrazine reduction (Reference 201 and 388) seem to be attractive alternatives to catalytic hydrogenation. If it is desired to use them these references should be consulted.
Another convenient technique is described in detail in Appendix Five. The use of the very active catalyst described there will speed the reaction and reduce the amount of hydrogen needed. References are also given for the insitu generation of hydrogen by sodium borohydride instead of external gaseous cylinder hydrogen.
Reaction (h). Demethylation of the 3,5-dimethoxy-(alkyl)-benzenes to give the 5-(alkyl)-resorcinols is carried out by refluxing with a mixture of glacial acetic acid and 48% hydrobromic acid.
Example. About 20 grams of the 3,5-dimethoxy-(alkyl)-benzene is added to 65 ml. of 48% hydrobromic acid and 200 ml. glacial acetic acid contained in a 3-necked 1 liter flask, fitted with condenser, stirrer, and thermometer. The mixture is stirred and refluxed for 6 hours, cooled to room temperature, then poured into a mixture of 300 grams crushed ice with 300 ml. water. Solid sodium bicarbonate is added cautiously to neutralize the strongly acid mixture. The neutral solution is then extracted with ether (extract I) and this extract is then itself extracted with 10% sodium hydroxide solution (extract II). This basic extract II is then acidified with hydrochloric acid and extracted with ether (extract III). All of these extractions should be made with at least two portions, which are then combined. by distilling off the ether from extract I there is recovered about 2.5 grams of the original dimethoxy- starting material, which is reused in a later demethylation operation. Extract III (made from acidified extract II) contains the desired product which is obtained as a very impure (about 50% inert liquid) brown-amber fluid by distilling off the ether. This material weighs about 27 grams and is fractionated to give about 14 grams of pure 5-(alkyl)-resorcinol. This material need not be very pure for the following reaction, however it is necessary to remove the inert liquid at least.
The following chart shows the boiling points (deg. C.) and pressures (mm. Hg) used by Adams in his distillation purification of the 5-(alkyl)-resorcinols. The intermediates for THC and THC-II are prepared as described in Appendix One or Appendix Four, the intermediates for THC-III through THC-VI may be obtained by demethylating the methoxy-protected materials as described in this section, or by simultaneous debenzylation and reduction of benzyloxy-protected groups as described in the previous section (g).
5-(Alkyl)-Resorcinols
THC: 163 deg. C./ 5 mm. 190-210 deg. C./ 25 mm.
THC-II: 192-195 deg. C./ 11 mm. 210-220 deg. C./ 25 mm.
THC-III: 160 deg. C./ 0.5 mm. 240-250 deg. C./ 25 mm.
THC-IV: 188 deg. C./ 1 mm. 260-270 deg. C./ 25 mm.
THC-V: 168 deg. C/ 1 mm. 245-255 deg. C./ 25 mm.
THC-VI: 150 deg. C./ 0.05 mm. 275-285 deg. C./ 25 mm.
(Note: It was found (Reference 407) that in the case of THC-VII it was necessary to subject the product to a second demethylation operation as it was not complete the first time).
Intermediate Ketone: Method II
Final Condensation Reaction