US3278606A - Method of providing 5-(1, 2-dimethylheptyl) resorcinols and intermediates therefor - Google Patents

Description

United States Patent 3,278,606 METHOD OF PROVIDING -(1,2-DIMETHYLHEP- TYL) RESORCINOLS AND INTERMEDIATES THEREFOR James L. Dever, Ambler, Pa., assignor to Monsanto Research Corporation, St. Louis, Mo., a corporation of Delaware No Drawing. Filed Aug. 7, 1962, Ser. No. 215,302 9 Claims. (Cl. 260-613) This invention relates to new methods of chemical synthesis, and more particularly, provides novel improvements in the synthesis of intermediates for and the preparation of S-alkylresorcinols.

The literature method of making 5-(1,2-dimethylheptyl)resorcinol is commercially unacceptable. The starting material is 3,5-dihydroxybenzoic acid, which is expensive. The synthesis from this acid proceeds through three steps to 3,5-dimethoxybenzamide. An aryl alkyl ketone is formed from this and the carbonyl carbon atom of the ketone is then alkylated to provide the branched chain at the point of conjunction of the alkyl and aryl groups, in accordance with the following sequence:

AlCONHg RMgX ArCOR .Ar-CHR where Ar is 3,5-dimethoxyphenyl one of R and R is CH and the other is CHO5H11 The step which makes the process particularly unacceptable lies in the formation of the ketone intermediate: reaction of the benzamide with the Grignard reagent is intolerably slow.

Extensive efforts have been expended on attempts to devise better syntheses. One approach which has been explored is a more direct route to the ketone from the acid. Thus, successively shorter routes includes, after the common step 00011 Ar-C O OH where Ar" HO C1130 RMgX (1) Ar-COOH ArCOCl ArCONHz ArCOR CdRa (2) Ar-OOOHArCOOl ArGOR then the carbonyl carbon atom can be alkylated effectively with the methylene Wittig reagent: x

ArC O CHC5H11 ArC-CHCrHu H2 CH (=phenyl) and the olefinic product can then be reduced smoothly to the desired alkyl compound. But if the ketone intermediate is to be the acet'ophenone so that the Wittig reagent required is the reaction product of a phosphine and 3,278,606 Patented Oct. 11, 1966 2-bromoheptane, the alkylation becomes a source of trouble. In synthesis of the Wittig reagent, at elevated temperatures this alkyl halide undergoes dehydrohalogenation instead of quaternizing the phosphine, and at low temperatures, the reaction is extremely slow.

Alternatives to the Wittig reagent for converting the acetophenone to 5-(heptenyl)resorcinol dimethyl ethers have also been explored without satisfactory results.

It is an object of this invention to provide an improved process for the production of 5-(1,2-dimethylheptyl)- resorcinols.

A particular object of this invention is to provide a commercially useful method of producing 5-(1,2-dimethylheptyl)resorcinols.

Another object is to provide an improved method for the synthesis of 3,5-dimethoxyphenyl 2-heptyl ketone.

Still another object is to provide an improved method for the synthesis of S-alkyl resorcinols, proceeding through 3,5-dimethoxyphenyl 2-heptyl ketones as intermediates.

Yet another object is to provide a novel method of preparing a dimethoxyphenyl compound useful in the synthesis of 3,5-dirnethoxyphenyl 2-heptyl ketone intermediates for the preparation of 5-(l-methylheptyl)resorcinols.

These and other objects will become evident from a consideration of the following specification and claims.

. It has now been found that dimethoxyphenyl chloride 7 is advantageously obtained by methanolyzing 1,3,5-trichlorobenzene with sodium methoxide in a fluidizing volume of a high-boiling, polar, unreactive solvent; and that 3,5-dimethoxyphenyl Z-heptyl ketones can be produced effectively and conveniently by a method comprising conducting the stated methanolysis, isolating the resulting 3,5 -dime-thoxyphenyl chloride :and contacting magnesium with a solution of said dimethoxyphenyl chloride in a reactive coordinating solvent to form the Grignard reagent;

' and contacting said Grignard reagent with a 2-methylheptanonitrile to provide the dimethoxyphenyl 2-heptyl ketone.

The resulting ketone may be converted by either of two methods to the S-alkyl resorcinols. These two alternative procedures maybe illustrated by the following equations, showing the conversion of dimethoxyphenyl 2-heptyl ketone to 5-(l,Z-dimethylheptyl)resorcinol:

- The method of the invention is applicable to the preparation of 5-(1,2-dimethylhepty1)resorcinols of the following formula RRR HO a Where each R is separately selected from the class consisting of H and CH including 5-(1,2-dimethylheptyl) resorcinol, 5-(1,2,3-trimethylheptyl)resorcinol and 5- (1,2,2-trimethylheptyl)resorcinol, proceeding respectively through the 3,5-dimethoxyphenyl 2-heptyl ketone, 3,5- dimethoxyphenyl 2-rnethylheptyl-2 ketone and the 3,5-dimethoxyphenyl 2,3-dimethylheptyl-2 ketone.

The stated process affords a method of arriving at the ketone which is the key intermediate in the 5-(1,2-di methylheptyl)resorcinol synthesis by a procedure which is unexpectedly and pronouncedly more advantageous than any known previous route and which, unlike the benzamide route of the literature, is susceptible of commercial application.

One of the important factors in the practice of the present invention lies in the use made of selected solvents. In the first step, a high-boiling, polar, nonreactive solvent is employed in the methanolysis of the halo benzene with sodium methoxide. Normally an alkali metal alkoxide is formed by combining the alkali metal with the corresponding alcohol, and the alcoholysis of a halide is conducted accordingly in the alcohol as solvent. Where high temperatures are found desirable to drive the reaction, the low-boiling alcoholic reaction mixture is placed under pressure. Another alternative which has been proposed for halobenzene alcoholysis is displacing the halogen atoms with groups which are bulkier than the methoxy group. With the higher-boiling, longerchain alkanols, alcoholysis yields are usually improved. But where these alkoxy groups are ultimately to be hydrolyzed off, as they are in producing the resorcinol products in the present process, using a larger etherifying radical is undesirably expensive; and in any case, even with the larger group, the yields reported of the diether obtained by alcoholysis of 1,3,5-trichlorobenzene have been inordinately low.

Simply heating the trichlorobenzene with sodium methoxide, in the absence of a solvent, at the temperatures herein employed, is not effective to produce the methanolysis, and heating with a high-boiling solvent such as diglyme is not in itself, it has been found, suflicient to produce practicable yields. But if a sufiicient quantity of the polar solvent is employed, amounting to about one mole per mole of the trichlorobenzene, then excellent yields of the dimethoxyphenyl chloride are produced.

By use of the stated conditions, the presently provided method for methanolyzing trichlorobenzene offers a direct and commercially practicable process for producing 3,5-dimethoxyphenyl chloride which is adapted for use in the synthesis of S-alkylresorcinols in accordance with this invention, or indeed, for use in other applications, as a chemical intermediate or the like.

Solvent is also a critical factor in the formation of Grignard reagent from the dimethoxyphenyl chloride. Techniques such as use of activators, entrainment and a solventless procedure usually effective in promoting otherwise sluggish reactions with magnesium have been found ineffective with this recalcitrant halide. Use of a reaction medium consisting essentially of a reactive coordinating solvent like tetrahydrofuran appears to be essential.

Still another critically important factor in the abovestated procedure is the use of the reaction of. the dimethoxyphenyl magnesium chloride with a nitrile to provide the ketone intermediate for the desired alkyl resorcinol.

A ketone can be reacted with 'a Grignard reagent to provide a carbinol which. can be dehydrated to the corresponding olefin. An alkenylresorcinol can-be hydrogenated to yield the desired alkyl resorcinol (as the dimethyl ether, which is then demethylated). In effect, this would be the counterpart of the known method of forming the 5-(1,2,-dimethylheptyl)resorcinol, wherein the dimethoxyphenyl 2-heptyl ketone formed from the benzamide is treated with methyl Grignard reagent to provide the dimethoxyphenyl isoheptyl methyl carbinol:

O OH AriiCHC5Hn CHaMgBr ArJ1CHC H a Ha a With the aryl Grignard reagent available, it would appear that this reaction could conveniently be adapted to production of the carbinol in one step, by a counterpart to this reaction, in which the dimethoxyphenyl magnesium chloride is reacted with 3-methyl- 2-octanone:

O OH ArMgOl -CHC H11 Ar+CHC/ H11 H3 C113 C11 OH:

This reaction has been tried, and it is found that the aliphatic ketone undergoes an aldol self-condensation. Consequently the yield of pure carbinol obtained through the stated procedure is uneconomically low and the reaction is wasteful of reactants. Furthermore, exploration of half a dozen proposed routes to this aliphatic ketone has proved each to be commercially unattractive, for reasons such as low yields, on the order of 30%, expensive reagents, and production of the ketone associated with products which are almost inseparable from it.

Thus, what might appear to be an unnecessarily devious route, proceeding through reaction of the aryl Grignard with a nitrile to form the ketone and then methylating the ketone, rather than proceeding directly from the aryl Grignard reagent and alkyl ketone to the aryl carbinol, is actually advantageous. The required Z-methylheptanonitrile reagents are available directly and in good yields by treatment of an alkyl halide with propionitrile or isobutyronitrile and their reaction with the Grignard reagent gives the desired ketone, not only in good yields but without either loss of reactants to byproducts or contamination of the desired product with inseparable contaminants.

-With the pure dimethoxyphenyl 2-heptyl ketone in hand, the remainder of the synthesis of the alkylresorcinol can be accomplished without difiiculty, as further described hereinafter.

Using the presently provided reaction conditions and particular route to the stated ketone thus gives a means of producing the required S-alkyl resorcinols which is unique in the purity of its products, and which is a significant improvement over the known benzamide method. The overall yield by the present method, referred to trichlorobenzene, is tripled as compared to proceeding from dihydroxybenzoi-c acid through the benzamide, and the cost is halved.

Referring now in more detail to the practice of the present invention, in conducting the method of the invention for providing 3,5-dimethoxyphenyl chloride, 1,3,5- trichlorobenzene will be contacted with about 2 moles of sodium methoxide per mole of the trichlorobenzene, in a reaction mixture comprising a fluidizing volume of a high-boiling, polar, nonreactive solvent. Useful solvents include, for example, the alkyl ethers of aliphatic polyols such as the dimethyl ether of ethylene glycol, the diethyl ether of ethylene glycol, the dimethyl ether of diethylene glycol, the diethyl ether of diethylene glycol, the dibutyl ether of ethylene glycol and the like, with the dimethyl ether of diethylene glycol (diglyme) being preferred. The volume of solvent employed has been found to affect the yield, and for good results, should be at least about one mole per mole of trichlorobenzene. The reaction mixture will be heated to cause reaction to occur. Temperatures of between about and 200 C. are generally preferable. The reflux temperature (at atmospheric pressure) of the reaction mixture containing diglyme, between and C., is generally most advantageous. Pressures may vary from subatmospheric to superatmospheric pressures, up to say about 5000 p.s.i.,

but usually can advantageously be ambient atmospheric pressure.

On completion of the reaction, the 3,5-dimethoxyphenyl chloride can be readily separated as essentially pure product from the remaining components of the reaction mixture by standard procedures such as distillation. While yields and conversions are high in the present process,

' where desired, after separation of the product, the reaction mixture can be recycled to produce further conversion.

' The 3,5-dimethoxyphenyl chloride is converted to the Grignard reagent in accordance with this invention by contacting it with magnesium in a reactive coordinating solvent such as tetrahydrofuran, preferably employing iodine and ethyl bromide as catalyst activators for the reaction. Advantageously, the dimethoxyphenyl chloride and the tetrahydrofuran will be combined and the combination added to the magnesium, in preparing the Grignard reagent. The proportion of the reactive tetrahydrofuran solvent to the aromatic halide should usually be between about 5 :1 and 1:1, preferably about 3:1. The amounts of the iodine and ethyl bromide accelerators of the reaction required are only catalytic; suitable minimum amounts can readily be ascertained for any given size operation by those skilled in the art.

During addition of the aryl halide solution to the magnesium, this reaction mixture will be heated. The temperature to be employed in this connection will be preferably between about 50 and 100 C., and most desirably the reflux temperature of the reaction mixture, between 75 and "90 C., will be employed. The heating may be continued until the amount of unreacted magnesium remaining as a separate phase in the reaction mixture has become substantially negligible.

After the formation of the Grignard reagent, the reaction mixture may itself be employed for further reaction, or the solvent may 'be displaced before proceeding to employ the reagent. In general, simple heating will drive oif the reactive solvent. The displaced solvent may be replaced by other ether solvents or diluents such as,

for example, diglyme, dibutyl ether, and the like.

To employ the 3,5-dimethoxyphenylmagnesium chloride in accordance with this invention to produce the aryl alkyl ketone intermediate in the preparation of a 5-(l,2- dimethylheptyl)-resorcin-ol, the Grignard reagent will be contacted with a Z-methylheptanonitrile. The Z-methyl alkane nitriles can be prepared conveniently, it has been found, from propionitrile or isobutyronitrile and the appropriate alkyl halide such as amyl chloride. The alkylation is effected in liquid ammonia with sodamide, using ferric nitrate nonahydra-te as a catalyst for the sodamide formation.

The Z-methylheptanonitrile may be added to the Grignard reagent of the aryl halide in the calculated stoichiometric quantity, and this is the most advantageous for economical use of the reactants. If desired, however, either of the reactants may be present in an excess amounting to, say, up to 50% or more excess. Usually the reaction will be conducted in the presence of solvents or diluents, which will conveniently be solvents as employed in the preparation of the Grignard reaction, such as tetrahydorfuran; but other solvents such as diglyme, or even low boiling solvents such as diethyl ether, may be employed if desired. In general, the reaction proceeds smoothly at relatively low temperatures, below about 100 C. Temperatures to be employed in this connection preferably will be on the order of between 50 and 75 C.

To isolate the ketonic product from the resulting reaction mixture, the reaction mixture will be hydrolyzed with an aqueous medium including an inorganic acid, such as 50% sulfuric or hydrochloric acids. Formation of the imine salt product upon initial addition of such acid to the reaction mixture will be followed byheating with additional acid, at for example, 75-125" 0., to effect the 'moved by distillation at ambient pressure.

hydrolysis. The ketone may be isolated from the resulting aqueous hydrolysis product by extraction with an organic solvent followed by distillation and the like. The 3,5-dimethoxyphenyl 2-heptyl ketone is isolated readily by distillation, substantially free of other components (after redi-stillation, greater than 96 area-percent purity according to vapor phase chromatographic (VPC) analysis).

The resulting ketone may be employed for the synthesis of 5-(1,2-dimethylheptyl)resorcinols by either of two procedures. One, as above discussed, comprises reaction with a methylene triphenylphosphine Wittig reagent, formed in situ by combination of methyltriphenylphosphonium bromide with butyl lithium in solution. The product is the terminal olefin, 5-(1-methylene-2-methylheptyl)-1,3-dimethoxybenzene.

Alternatively, the methylation of the carbonyl carbon atom of the ketone can be effected by treating the ketone with methyl Grignard reagent, such as methylmagnesium bromide. In general the conditions for conducting this Grignard reaction are substantially similar to those for conducting the aryl Grignard reaction described above: the ketone is added to the Grignard reagent in a solvent such as diethyl ether while the reaction is cooled to control the exotherm, and after addition is complete, the reaction mixture is further heated to effect maximum conversion if desired. On completion of the reaction, the reaction mixture is hydrolyzed with an aqueous medium, producing the aryl alkyl carbinol. The hydrolysis to the carbinol may be effected with water, with acidic reagents such as a 40 or 50% solution of sulfuric acid, with a neutral aqueous medium such as saturated ammonium chloride, and so forth. The resulting carbinol, a 2-(3,5-dimethoxyphenyl)octanol-2, is dehydrated by heating with a dehydrating reagent such as iodine, anhydrous oxalic acid, or the like, producing an olefin which is chiefly or exclusively the internal olefin, 5-(1,2-dimethyl-l-hep tenyl)-1,3-dimethoxybenzene.

Example 1 This example illustrates the methanolysis of symtrichlorobenzene.

A mixture of 294 parts (1.6 mole) 1,3,5-trichlorobenzene and 184 parts (3.4 moles) of sodium methoxide in about 450 parts (3.3 moles) diglyme (the dimethyl ether of diethylene glycol) is refluxed (164 C.) for fortytwo hours. After cooling to room temperature, the reaction mixture is tiltered and most of the solvent is re- Distillation of the residue isolates 1-chloro-3,5-dimethoxybenzene, in an overall yield of 70%.

Example 2 This example illustrates another preparation of the chlorodirnethoxybenzene.

A mixture of 454 parts (0.25 mole) of 1,3,5-trichlorobenzene and 297 parts (0.55 mole) of sodium methoxide is heated in 168 parts (0.125 mole) of diglyme, at re- The yield of the desired 1-chloro-3,5-dimethoxybenzene in this run, by VPC, is only 34%, and the product is admixed with a 29% yield of the incomplete conversion product, 3,5-dichloroanisole.

7 Example 3 Example 4 This example describes conversion of the chlorodimethoyxybenzene to the Grignard reagent.

Sixty parts of magnesium shavings (0.248 gram-atom) and a crystal of iodine are placed in a dried reaction flask under nitrogen. A solution of 428 parts (0.248 mole) of 1-chloro-3,S-dimethoxybenzene in 536 parts of tetrahydrofuran is placed in a container connected to the system containing the magnesium. A small amount of the chlorodimethoxybenzene solution is run in with the magnesium, and a few drops of ethyl bromide are added to initiate reaction. The iodine color discharges and exothermic reaction is initiated. The remaining tetrahydrofuran halide solution is gradually added over a period of about 1 hour, while the reaction mixture is heated, with the temperature of the mixture finally reaching 75 C. The combined reaction mixture is refluxed for an additional two hours, at the end of which time only a small amount of magnesium remains unreacted.

The Michlers ketone test for the presence of Grignard reagent is positive. Titration of the reaction product by hydrolysis With hydrochloric acid, followed by back titration with sodium hydroxide, indicates a Grignard reagent yield of 79%. Hydrolysis of the Grignard solution with hydrochloric acid produces m-dimethoxybenzene, identical with an authentic specimen.

Example 5 This example illustrates preparation of Z-methylheptanonitrile.

Anhydrous liquid ammonia is placed in a cooled reaction flask, ferric nitrate nonahydrate is added to the ammonia, and then small pieces of sodium are added to the ammonia and air bubbled through the resulting solution until reaction can be observed. More sodium is then added portionwise until a total of 115 parts (0.5 gram atoms) of sodium is in solution. To the ammonia solution, at its reflux temperature, 276 parts (0.5 mole) of propionitrile are added. The resulting solution is introduced dropwise to 533 parts (0.5 mole) of l-chloropentane. After the addition is complete, the ammonia is evaporated off, and diethyl ether followed by water is added to the residue. The aqueous layer is separated, extracted with ether, and the ethereal solutions are combined, washed and dried. After removal of solvent, distillation gives a 64% yield of 2-methylheptanonitrile.

Example 6 This example illustrates the reaction of the Grignard reagent with the nitrile to form the aryl alkyl ketone.

The Grignard reagent is prepared by adding 432 parts of 1-chloro-3,S-dimethoxybenzene in 540 parts of freshly distilled tetrahydrofuran to 73 parts of magnesium turnings, employing 1 part of ethyl bromide as initiator at the beginning of the addition. Addition of the tetrahydrofuran solution requires one half hour: after the addition is complete, the mixture is refluxed for three hours. The resulting solution of the Grignard reagent is cooled to room temperature and a solution of 340 parts (0.27 mole) of 2-methylheptanonitrile in tetrahydrofuran is added over a period of one half hour. At the end of the addition, the mixture is heated to 60 C. for six hours.

Hydrolysis of the reaction mixture is effected by addition of 1600 parts of a 40% sulfuric acid solution, the

temperature being maintained below 40 C. Solvent is removed by distillation, another 400 parts of 50% sulfuric acid solution is added, and the mixture is heated for one hour at 95-100 C. After cooling, ether is added, the

aqueous layer is separated and extracted with ether, and the ethereal solutions are combined, washed and dried. After filtration and removal of the ether, the residue is distilled. The fraction isolated in the boiling range of l33-138 C. at 0.2 mm. represents a 71% yield of product in 94 area-percent purity by VPC. Redistillation results in isolation of 2-(3,5-dimethoxybenzoyl)heptane, in greater than 96 area-percent purity.

Example 7 This example illustrates conversion of the 2-(3,5- dimethoxybenzoyl)heptane to the corresponding carbinol.

A solution of 218 parts (0.082) of 2-(3,5-dimethoxybenzoyl)heptane in ether is added dropwise, while the temperature is held at 15-20 C., to a 3 molar solution of methylmagnesium bromide in diethyl ether. The mixture is then refluxed for an hour, and hydrolyzed by pouring it into a solution of sulfuric acid in an ice-water mixture. Further sulfuric acid is added and the mixture stirred. The aqueous layer is extracted with ether and the ethereal solutions are combined, washed and dried. After filtration and removal of solvent, there remain 216 parts of pale yellow residue, which is better than area-percent 2-(3,5-dimethoxyphenyl)-3-methyloctanol-2.

Dehydration of the alcohol is accomplished by combining it with anhydrous oxalic acid and heating at 130140 C. Extraction of the reaction product with benzene isolates the resulting olefinic material, which can be separated by distillation in better than area-percent purity.

Reduction of the olefinic product of the preceding paragraph is accomplished by charging an autoclave with 25 parts of the 2-(3,5-dimethoxyphenyl)-3-methyloctenes- 1 and -2 and 2.5 parts of 65% nickel on kieselguhr catalyst in dry hexane. The autoclave is charged with hydrogen to a pressure of 1750 pounds per square inch gauge (p.s.i.g.) and the temperature is gradually increased to C. After three hours the pressure is increased to 1850 p.s.i.g. hydrogen and held there for another 2 and /2 hours. The reaction mixture is recovered, filtered, and solvent removed. The residue is identified by infrared and ultraviolet spectroscopy and VPC as 2- (3,5-dimethoxyphenyl)-3-methyloctane, 94.1 area-percent pure.

To convert the resulting dimethoxyphenyl compound to the resorcinol, a mixture of 20 parts (0.076 mole) of 2- (3,5-dimet'hoxyphenyl)-3-methyloctane With 38% hydrobromic acid and glacial acetic acid is stirred and refluxed for 6 hours, and then the reaction mixture is poured onto ice and water. Solid sodium bicarbonate is added to neutralize, the product is extracted with ether, and the ether extract is extracted with 10% aqueous sodium hydroxide. The basic aqueous solution is acidified with hydrochloric acid and extracted with ether. The resulting solution is evaporated and the residue distilled to provide 14 parts of 2-(3,5-dihydroxyphenyl)-3-methyloctane, better than 98 area-percent pure (VPC).

Example 8 This example illustrates the production of another 5- 1,2-dimet hy1heptyl resorcinol.

Using the procedure described earlier, propionitrile (82.6 parts, 1.5 mole) is alkylated with 220.1 parts (1.33 moles) of 2-bromohexane using a sodamide solution prepared from 34.5 parts (1.5 gram atom) of sodium in liquid ammonia. The product 2,3-dimethylheptanonitrile is recovered in 97.1 area percent purity, in an amount corresponding to 51% conversion.

3,5-dimethoxyphenylmagnesium chloride is prepared by combining 691 parts of 1-chloro-3,S-dimethoxybenzene in 86.5 parts anhydrous tetrahydrofuran with 9.5 parts of magnesium, employing a crystal of iodine and ethyl bromide as activators. The Grignard reagent is combined With 60 parts (0.43 mole) of the 2,3-dimethylheptano nitrile prepared as above described. The reaction prod- 9 uct is hydrolyzed and distilled, and 2-(3,5-dimethoxybenzoyl)-3-methylheptane is recovered in an amount corresponding to a 50% yield: 58.8 parts.

Wittig reagent is prepared by combining a solution of 642 parts (0.18 mole) of met hyltriphenylphosphonium bromide in dry benzene with 116 parts (in a 14% solution) 'butyllithium solution. The resulting mixture is then heated to 60 C. and cooled. A solution of 490 parts (0.176 mole) of 2-(3,5-dimethoxybenzoyl)-3-methylheptane in 40 ml of dry benzene is added, the temperature being kept below 40 C. Then the mixture is heated at reflux for two hours, cooled and filtered to remove triphenylphosphine oxide. After removal of the solvent, the octane is reduced by catalytic hydrogenation and the resulting saturated dimethoxy phenyl alkane is demethylated with hydrobromic acid and glacial aetic acid to provide 5-(1,2,3-trimethylheptyl) resorcinol.

Example 9 This example illustrates the preparation of still another 1,2-dimethylheptyl resorcinol.

Reaction of 103.7 parts (1.5 moles) of isobutyronitrile with 142.2 parts (1.33 moles) of n-amyl chloride, using a sodamide solution prepared from 34.5 parts (1.5 gram atoms) of sodium in liquid ammonia, results in isolation of 85.8 parts of 2,2-dimethylheptanonitrile, 97 area percent pure by VPC. 3,5-dimethylphenyl magnesium chloride is prepared by the above-described procedure, from the reaction of 69.1 parts (0. 4 mole) of 1-chloro-3,5-dimethoxybenzene in 86.5 parts of anhydrous tetrahydrofuran, with iodine and ethyl bromide activators. The resulting Grignard reagent is reacted with 59.9 parts (0.43 mole) of the 2,2-dimethylheptanonitrile prepared as just stated, and after hydrolysis, 2-(3,5-dimethoxybenzoyl)-2- methylheptane is isolated by distillation: B. 134-136 C./ 0.19 mm. Using the procedure described in the preceding example, the Wittig reagent is prepared by combining 89.3 parts (0.25 mole) of methyltriphenyl)phosphonium bromide and 16 parts (0.25 mole) of butyl lithium in benzene as solvent, with 61.1 parts (0.22 mole) of the 2-(3,5-dimethoxybenzoyl)-2-methylheptane in ibenzene. Catalytic hydrogenation yields 5-(1,2,2-trimethylheptyl)recorcinol.

The two resorcinols of the last two examples, like the 5-(1,2-dimethylheptyl)resorcinol, are extremely viscous liquids which are almost immobile at room temperature. The 5-(1,2,3-trimethylheptyl)resorcinol boils at 160 161 C./0.3 mm. The 5-(1,2,2-trimethylhepty1)resorcinol has a boiling point of 154-155 C./0.18 mm.

While the invention has been illustrated with reference to particular preferred embodiments thereof, it is to be appreciated that modifications and variations can be made without departing from the scope of the invention, which is limited only as stated in the appended claims.

What is claimed is:

1. The improvement in the method of providing 5- (1,2-dimethylheptyl)resorcinols which comprises methanolyzing 1,3,5-trichlorobenzene with sodium methoxide in a high-boiling polar solvent comprising a dialkyl ether of an alkylene glycol, in a ratio of about 2 moles of sodium methoxide per mole of the trichlorobenzene; adding the resulting 1-chloro-3,5 dimethoxybenzene as a solution in tetrahydrofuran to magnesium to provide the Grignard reagent; contacting said Grignard reagent with a Z-methylheptanonitrile and hydrolyzing to provide the 3,5-dimethoxyphenyl Z-heptyl ketone; reacting the 3,5-dimethoxyphenyl Z-heptyl ketone with methyl magnesium bromide to provide the 2-(3,5-dimethoxyphenyl)-3-methyl- 2-octano1; dehydrating the 2-(3,5-dimethoxyphenyl)-3- methyl-Z-octanol; hydrogenating the resulting 2-(3,5-dimethoxy-phenyl)-3-mthyl-2-octene; and demethylating the resulting 2 (3,5 dimethoxyphenyl) 3 methyloctane by treatment with hydrobromic acid in glacial acetic acid to produce the 5-(1,2-dimethylheptyl) resorcinol.

2. The method of claim 1 wherein said ketone is 3,5- dimethoxyphenyl 2-heptyl ketone.

3. The method of claim 1 wherein said ketone is 3,5- dimethoxyphenyl 3-methy1heptyl-2 ketone.

4. The method of claim 1 wherein said ketone is 3,5- dimethoxyphenyl Z-methylheptyl-Z ketone.

5. The method of providing the dimethyl ether of a chlororesorcinol which comprises contacting sodium methoxide with 1,3,5-trichlorobenzene, in about a 2 to 1 ratio, in a fluidizing volume of a high-boiling polar solvent comprising a dialkyl ether of an alkylene glycol.

6. The method of claim 5 wherein said solvent is the dimethyl ether of diethylene glycol.

7. The method of providing the Grignard reagent of 3,5-di-methoxyphenyl chloride which comprises methanolyzing sym-trichlorobenzene by contact with sodium methoxide, in about a 1 to 2 ratio, in a fluidizing volume of a high boiling polar solvent comprising a dialkyl ether of an alkylene glycol, and reacting the resulting 3,5-dimethoxyphenyl chloride with magnesium in tetrahydrofuran.

8. The method of providing 5-(1,2-dimethylheptyl)- resorcinols which comprises methanolizing 1,3,5-trichlorobenzene with sodium methoxide in a high boiling polar solvent comprising a dialkyl ether of an alkylene glycol, in a ratio of about two moles of sodium methoxide per mole of the trichlorobenzene; adding the resulting 1- c'hloro-3,S-dimethoxybenzene as a solution in tetrahydrofuran to magnesium to provide the Grignard reagent; contacting said Grignard reagent with a Z-methylheptanonitrile and hydrolyzing to provide the 3,5-dimethoxyphenyl 2-heptyl ketone; contacting the 3,5-dimethoxyphenyl 2- heptyl ketone with methylenetriphenylphosphine to provide the 2-(3,5-dimethoxyphenyl)-3-methy1-1-octene; hydrogenating the 2 3,5 dimethoxyphenyl) 3 methyll-octene; and demethylating the resulting 2-(3,5-dimethoxyphenyl) -3-methyloctane with hydrobromic acid in glacial acid to provide the 5-(1,2-di-methylhepty1) resorcinol.

9. The method of claim 8 wherein said ketone is 3,5- dimethoxyphenyl Z-methylheptyl-Z ketone.

Adams et al.: J. Am. Chem. Soc., vol. 70, pp. 664-8 (1948).

JOSEPH R. LIBERMAN, Primary Examiner.

LORRAINE A. WEINBERGER, Examiner.

D. D. HORWITZ, Assistant Examiner.

Claims (1)

1. THE IMPROVEMENT IN THE METHOD OF PROVIDING 5(1,2-DIMETHYLHETYL)RESORCINOLS WHICH COMPRISES METHANOLYZING 1,3,5-TRICHLOROBENZENE WITH SODIUM METHOXIDE IN A HIGH-BOILING POLAR SOLVENT COMPRISING A DIALKYL ETHER OF AN ALKYLENE GLYCOL, IN A RATIO OF ABOUT 2 MOLES OF SODIUM METHOXIDE PER MOLE OF THE TRICHLOROBENZENE; ADDING THE RESULTING 1-CHLORO-3,5-DIMETHOXYBENZENE AS A SOLUTION IN TETRAHYDROFURAN TO MAGNESIUM TO PROVIDE THE GRIGNARD REAGENT; CONTACTING SAID GRIGNARD REGENT WITH A 2-METHYLHEPTANONITRILE AND HYDROLYZING TO PROVIDE THE 3,5-DIMETHOXYPHENYL 2-HEPTYL KETONE; REACTING THE 3,5-DIOXYPHENYL 2-HEPTYL KETONE WITH METHYL MAGNESIUM BROMIDE TO PROVIDE THE 2-(3,5-DIMETHOXYPHENYL)-3-METHYL2-OCTANOL; DEHYDRATING THE 2-(3,5-DIMETHOXYPHENYL)-3METHYL-2-OXTANOL; HYDROGENATING THE RESULTING 2-(3,5METHOXYPHENYL)-3-METHYL-2-OCTENE; AND DEMETHYLATING THE RESULTING 2 - (3,5 - DIMETHOXYPHENYL) - 3 - METHYLOCTANE BY TREATMENT WITH HYDROBROMIC ACID IN GLACIAL ACETIC ACID TO PRODUCE THE 5-(1,2-DIMETHYLHEPTYL) RESORCINOL.