METHOD FOR THE PRODUCTION OF ALKYL AND ALKOXYALKYL SUBSTITUTED BENZENE COMPOUNDS

Abstract: Alkyl and alkoxyalkyl substituted benzenes having the formula in which R is C₁-C₅ alkyl, C₁-C₄ alkoxy, methylenedioxy or hydrogen and R′ is C₂-C₂₀ alkyl or C₂-C₂₀ alkoxyalkyl are prepared from corresponding benzyl halides by a three-step process of cyanation, alkylation, and decyana­ tion.

Description: METHOD FOR THE PRODUCTION OF ALKYL AND ALKOXYALEYL SUBSTITUIED BENZENE COMPOUNDS Background and Prior Art This application relates to a new method for production of alkyl and alkoxyalkyl substituted benzene compounds, and more parti- cularly of di-substituted benzene compounds having an alkyl or alkoxy alkyl substituent on one position in the ring, and another substituent at a second position on the ring. More particularly, this application relates to processes for producing compounds having the formula EMI1.1 in which R is C15 alkyl, C15 alkoxy, methylenedioxy or hydrogen, and R is C2-C20 alkyl or C2-C20 alkoxyalkyl. More preferably, R is Cl-C5 alkyl and R' is C10-C15 alkoxyalkyl. Most preferably, the compounds have the formula EMI1.2 in which R is as defined above, and is located at the para position on the phenyl ring, R2 and R3 are independently methyl or ethyl, and R4 is an alkyl group having from 1 to 4 'carbon atoms. Compounds of this type are sometimes referred to as arylterpenoid compounds and have been found useful for regulating and controlling the growth, and parti- cularly the maturation, of insects. In U.S. Patent 4,002,769, there is described a series of such compounds and a method for their preparation. The method described therein requires five steps, namely: a) reaction of a substituted benzyl alcohol with hydrogen chloride to produce the corresponding substituted benzyl chloride: b) reaction of the benzyl chloride with triphenylphosphine in the presence of acetonitrile to produce a benzyl triphenylphosphonium chloride; c) reaction of the chloride with an olefinically unsaturated aldehyde in the presence of ethanol and sodium ethoxide to produce a phenyl substituted diene; d) the combination of alkoxy mercuration and demercuration of this diene using mercuric acetate, an alcohol and a mixture of sodium hydroxide and sodium borohydride, to produce an alkoxyolefinically substituted phenyl compound; and finally, e) hydrogenation of the olefinic bond with, for example, a platinum catalyst, producing an alkoxy substituted phenyl compound (i.e., an arylterpenoid compound). The process involves a lengthy sequence of steps and expensive reagents such as triphenylphosphine and sodiun borohydride, and produces a multitude of by-products, all which must be removed and disposed of. Summary of the Invention According to the present invention, there is provided a three-step process for production of substituted benzene compounds, and more particularly disubstituted benzene compounds having the formula EMI2.1 in which R is C1-C5 alkyl, C1-C4 alkoxy, methylenedioxy or hydrogen and R' is C2-C20 alkyl or C2-C20 alkoxyalkyl, comprisng the steps of a) reacting a benzyl halide having the formula EMI2.2 in which X is chlorine, bromine or iodine, with an alkali metal cyanide to produce the corresponding benzyl cyanide; ; b) reacting the benzyl cyanide produced in step (a) with a canpound having the formula R1Y in which R1 is Cl-Cl9 alkyl or Cl-Clg alkoxyallyl and Y is chlorine or bromine, in the presence of an alkali metal hydroxide, water and a phase transfer catalyst, to produce a compound having the formula EMI3.1 c) reacting the product of step (b) with an alkali metal and a compound having the formula R50H in which R5 is an alkyl group having from 1 to 5 carbon atans. More particularly, this invention relates to a process for production of compounds having the formula EMI3.2 in which R is C1-C5 alkyl, C1-C4 alkoxy, methylenedioxy or hydrogen, R2 and R3 are independently methyl or ethyl and R4 is C14 alkyl, comprising the steps of a) reacting a compound having the formula EMI3.3 in which X is chlorine, bromine or iodine, with an alkali metal cyanide, producing the corresponding benzyl cyanide; ; b) reacting the benzyl cyanide produced in step (a) with a compound having the formula EMI3.4 in which Y is chlorine or bromine, in the presence of an alkali metal hydroxide, water and a phase transfer catalyst, to produce a compound having the formula EMI4.1 c) reacting the product of step (b) with an alkali metal and a compound having the formula R5OH in which R5 is an alkyl group having fran 1 to 5 carbon atoms. Detailed Description of the Invention As used in this Application, the term "alkyl" includes both straight and branched-chain moieties of this type, in which the total number of carbon atoms is as indicated. The term "alkoxyalkyl" refers to two alkyl groups, which may independently be straight or branchedchain, Joined by an oxygen atan, in which the total number of carbon atoms is as indicated. In the first step of the three-step process to which this invention relates, a benzyl halide having the formula EMI4.2 is reacted with an alkali metal cyanide such as sodium or potassium cyanide, and preferably sodium cyanide, to displace the halide moiety by the cyano group. This reaction is preferably conducted in the presence of an organic solvent such as benzene, toluene or xylene, a phase transfer catalyst and sufficient water to dissolve the cyanide. Alternatively, the reaction can be carried out in reflexing aqueous lower alkanol such as methanol, a propanol, or preferably ethanol, in which case a phase transfer catalyst is not necessary. By-product alkali metal chloride is readily removed by washing the reaction 'product with water. In the conduct of this first reaction, there may be produced some quantity of the benzyl alcohol corresponding to the benzyl halide used as a starting material, by reaction of the latter with water or OH- ion. The removal of ethanol and such benzyl alcohol, if produced, is highly recomnended because the presence of an alcohol is known to inhibit a phase-transfer catalyzed alkylation of aryl acetonitriles, as performed in the second step of this process. Removal of the alcohols is performed by appropriate extraction and/or distillation before proceeding to the second step. Benzyl halides in which R is hydrogen are generally available fran commercial sources. Ring-substituted benzyl halides (R is alkyl, alkoxy or methylenedioxy), if not commercially available, can be prepared, for instance, by reaction of the appropriate substituted benzene with formaldehyde and hydrogen chloride, using a zinc chloride catalyst. The second reaction, the alkylation of the benzyl cyanide, is carried out in the presence of excess alkali metal hydroxide, preferably sodium hydroxide, water, and a phase transfer catalyst as described below. The use of the phase transfer catalyst strongly favors monoalkylation of the benzyl cyanide over dialkylation, which is undesirable. In addition, it is not necessary to utilize a solvent for the organic phase, and stronger, expensive, air- or water-sensitive bases are not required. The preferred alkylating agents of this second step are comparatively long-chain alkoxyalkyl halides of the formula EMI5.1 in which Y is chlorine or bromine, R2 and R3 are independently methyl or ethyl and R4 is an alkyl group having from 1 to 4 carbon atoms. A preferred member of this group is 7-methoxycitronellyl chloride (Y is chlorine, R2, R3 and R4 are each methyl). This com- pound may be prepared, for instance, by reaction of methoxycitronellol with phosgene and dimethylformamide. In general, this reaction is conducted at temperatures of from about OOC. to about 1000C., preferably from about 20 C. to about 80 C., for a period generally ranging from about 1 to about 10 hours, preferably from about 1 to about 7 hours. The alkali metal hydroxide is preferably used in a 50 percent aqueous solution. The third step, namely the decyanation of the second stage product, is carried out in the presence of an organic solvent such as benzene, ethylbenzene, xylenes, trimethylberizenes (e.g., mesitylene) or, preferably toluene, under reflux, using excesses of an alkali metal, preferably sodium, and a lower alkanol. Preferred alkanols are ethanol, isopropanol and 2-methyl-2-butanol. As by-products there are produced, for each mole of the desired product, one mole of alkali metal cyanide and one mole of the corresponding alkoxide. Small amounts of a by-product amine (resulting from reduction of the cyano group instead of reductive cleavage) may be formed. Such by-products can be readily removed by washing the product with aqueous solutions of strong acids. Ihe phase transfer catalyst used in the first step may be selected from a nunber of substances which have been found satisfactory for phase transfer catalysis. In general, these compounds fall into four classes: quaternary oniun salts, long-chain primary amines, high molecular weight secondary amines, and crown ethers. In the second step, quaternary onion, preferably ammonium salts, are preferred. The quaternary oniun salts utilized in this invention are disclosed in a nunber of publications, including U.S. Patent 3,992,432. Such salts generally have the formula (R5RM7R8M )e- in which R5, R6, R7, and R8 are independently alkyl or alkenyl, M is nitrogen, phosphorus or arsenic and Z is a monovalent anion. The alkyl groups of such salts may be straight-chain or branched-chain groups and perferably contain fran 1 to 25 carbon atoms each. The alkenyl groups of this class of compounds preferably contain from 2 to 25 carbon atoms each. If one or more of the groups EG;-A8 are alkyl, then the total number of carbon atoms contained in all four groups is preferably from 10 to 70, most preferably from 15 to 70. If all four groups R5:R8 are of the alkenyl type, the total number of carbon atoms contained in these groups is preferably from 10 to 40. Ihe alkyl moieties of the group Rs-Rg can be a mixture of alkyl groups, derived from mixtures of long-chain fatty alkyl amines or similar compounds. For M, the most preferred is nitrogen; that is, the compounds are quaternary amnonium salts. Z may be any suitable monovalent anion and is preferably a halide, hydroxyl, bisulfate, perchlorate, or nitrate ion. Most preferably, Z is a halide ion, particularly chloride. Some ammonium salts of this type, in addition to those disclosed in the above-mentioned U.S. patent, are ccmmercially available from Henkel Corporation, Minneapolis, Minnesota, under the registered trademark Aliquat. A preferred member of this class of catalysts is the compound methyltricaprylyl ammonium chloride, sold as Aliquate 336. The term "caprylyl" indicates that this component comprises mixtures of alkyl groups having from 8-10, predcminantly 8, carbon atoms. The higher molecular weight amines suitable for use in these processes include both primary and secondary alkyl amines. The primary amines have the formula R9NH2 in which ç is a tertiary alkyl group having from about 18 to about 22 carbon atoms, or a mixture of such groups. The secondary amines have the formula RlORllNH in which R10 and R11 are branched alkyl groups. These secondary amines have a molecular weight generally between about 350 and about 400. The groups R10 and R11 may be the same or different alkyl and mixtures of various secondary amines of such molecular weight may be similarly utilized. On example of a suitable type of primary aliphatic amine is the product "Primene JM-T', a mixture of tertiary alkyl primary amines comprised primarily of such compounds having between 18 and 22 carbon atoms, available from Rohn and Haas Company, Piiladelthia, Pennsylvania. Its molecular weight may vary reran about 259 to about 325. Some suitable secondary aliphatic amines are those sold by tbfti and Haas Company under the designations "Amberlite" LA-1 and LA-2. These substances have molecular weights of 351 to 393 and 353 to 395 respectively and contain highly branched alkyl groups attached to the nitrogen atom. The crown ethers which are useable in this process are described in the literature, for example in Tetrahedron Letters, No. 18 (1972), pages 1793-1796. They are macrocyclic polyethers and are commonly named by reference to the total number of atoms forming the macrocyclic ring together with the nunber of oxygen atoms in that ring. Thus, the macrocyclic polyether whose formal chemical name is 1, 4, 7,10,13,16-hexaoxacyclooctadecane 'is designated as 18-crown-6. EXAMPLE By way of example, the following is a description of the production of the compound 2-methoxy-2,6-dimethyl-9-p-(isopropylphenyl)- nonane (R is p-isopropyl; R2, R3, R4 are all methyl). Reaction (a) Cyanation In a flask were placed 64.5 grams (g) (1.25 mole) 95 sodium cyanide and 56 milliliters (ml) water. The mixture was warmed at 4000. for five minutes to dissolve most of the sodium cyanide. Then, through a dropping funnel, there was added, over a pericd of 27 minutes, with the temperature maintained constant, a solution of 169 g (1.00 mole) p-isopropylbenzyl chloride in 127 g (157 ml) ethanol. Ihe mixture was heated to reflux temperature (about 81 C.), then maintained at this temperature for about three hours. The supernatant red liquid was decanted away and the solids were washed with methylene chloride, which was canbined with the red liquid. The solids (primarily sodium chloride) were then discarded as waste. The liquid was stripped under vacuum at about 6000., then taken up in 150 ml methylene chloride and 150 ml carbon tetrachloride respectively and washed with 20 ml water. The aqueous phase was discarded as waste. The organic phase was washed with 100 ml of 2.5 percent aqueous sodium chloride, then dried over magnesium sulfate, filtered and stripped under vacuum at 500C. to leave 162.0 g of a red liquid , identified as p-isopropylbenzyl cyanide by infrared (ir) and nuclear magnetic resonance (rmr) spectroscopy and mass spectrometry (ms). This product was distilled under vacuum at j5-790C. to separate unreacted ethanol and any by-product p-isopropylbenzyl alcohol. Reaction (b): Alkylation In a flask was placed 27 ml 50% aqueous sodium hydroxide, 3.0 g mesitylene (internal standard for gas chranatographic analysis), 0.6 g methyltricaprylyl ammonium chloride (Aliquate 336) and 17.7 g (0.111 mole) p-isopropylbenzyl cyanide (prepared in the previous step). The temperature was established at 22.50C. There was then added, over a period of 10 minutes, with stirring, 20.7 g (0.100 mole) 7-methoxycitronellyl chloride. The mixture was maintained at about 250C, for about three and one-half hours. Then the temperature was raised to 48-520C., and the mixture maintained at this temperature for eight and one-half hours. The temperature was then raised to 700C. and held for three hours. At the end of this time, the temperature decreased to about 61-64 C. and the mixture was maintained at this temperature for twits and one-half additional hours. The reaction mixture was then cooled to -40C. in a carbon dioxide-isopropanol bath and 100 ml water was added with cooling to keep the temperature below 100C. There was then added, with stirring, 100 ml toluene. Phase separation of the mixture readily occurred. The aqueous phase was extracted with an additional 50 ml toluene and the organic phase washed respectively with 100 ml water, 100 ml 2N hydrochloric acid and a second portion of 100 ml water. The organic liquid, which had a dark brown color, was retained, and vacuum stripped of solvent to leave 34.1 g of an oil, 2-nethOxy-2,6-dimethyl-8-cyano-9(p-isopropylphenyl)nonane, identified by ir, rmr, and ms. Reaction (c): Decyanation In a flask, blanketed with nitrogen, there was placed 17.5 g (0.76 mole) metallic sodiun and 75 ml anhydrous toluene. The mixture was heated to reflux and stirred until the sodiun was finely divided. Then there was added dropwise, at a rate sufficient to maintain the mix under vigorous reflux, with stirring, 18.2 g (0.050 mole) of the product of reaction (b) and 22.8 g (29 ml) of absolute isopropanol. When this addition was complete, a second portion of 29 ml of isopropanol was added at the same rate. The mixture was then cooled and 100 ml of 95% ethanol was then added until all the sodium had disappeared. The reaction mixture was a pale, yellow liquid' with a mass of white crystals. The liquid was decanted. The crystals were rinsed twice with toluene and the toluene solutions combined with the organic liquid. This liquid was then stripped of solvent under vacuum at 500C., then taken up in 200 ml toluene and washed with 100 ml water. The aqueous phase was further washed with 50 ml toluene. The confined organic phase was again washed with 50 ml of water, then with tw: por- tions, each 50 ml, LIN hydrochloric acid, and again water, followed by washing with 50 ml saturated sodiun bicarbonate and again water. The organic phase was then stripped under vacuum at 600C. leaving 15.6 g of a clear, yellow-brown mobile oil, quantitatively analyzed by gas chromatography as containing 83.3 weight percent of the desired product. This corresponds to a yield of 81% based on methoxycitronellyl chloride. The structure of the product was confirned by ir, rmr, and ms. Example II This example illustrates the conduct of reaction (a), namely the cyanation step, using a phase transfer catalyst. In a flask was placed 42.2 g (0.052 mole) p-isopropylbenzyl chloride, 4.2 g mesitylene and 0.7 g (0.0013 mole) methyltricaprylyl amnoniun chloride. Ihe ingredients were well mixed, then 18.4 g (0.375 mole) sodiun cyanide was added and the mixture cooled to 000. There was then added 2.5 g water. The temperature rose rapidly and then leveled at 70C. The mixture was then cooled to OOC. and the temperature maintained at about that value for about two hours. Ihe cooling bath was removed, the temperature was allowed to rise to 250C. and the mixture maintained at that temperature for one and onehalf hours. The temperature was then raised to 500C. and the mixture maintained for one hour, then raised to 750C., and the mixture maintained at that temperature for six additional hours. The reaction mixture was washed with methylene chloride and water, then dried over magnesiun sulfate. Solvent was stripped under vacuum at 40 C. leaving 42.4 g of p-isopropylphenylacetonitrile, a red liquid. The structure was confirmed by nnr and ir analysis.

Claims: CLAIMS 1. A process for the production of a compound having the formula EMI12.1 in which R is C1-C5 alkyl, C1-C4 alkoxy, methylenedioxy or hydrogen and R' is C2-C20 alkyl or C2-C20 alkoxyalkyl, comprising: a) reacting a benzyl halide having the formula EMI12.2 in which X is chlorine, bromine or iodine, with an alkali metal cyanide to produce the corresponding benzyl cyanide; b) reacting the benzyl cyanide produced in step (a) with a compound having the formula R1Y in which R1 is C1-C19 alkyl or C1-C19 alkoxyalkyl and Y is chlorine or bromine in the presence of an alkali metal hydroxide, water and a phase transfer catalyst to produce a compound having the formula EMI12.3 c) reacting the compound produced in step (b) with an alkali metal and a compound having the formula R5OH in which R5 is an alkyl group having from 1 to 5 carbon atoms. 2. A according to Claim 1 in which R1 is EMI12.4 R2 and R3 are independently methyl or ethyl and PW is C1-C4 alkyl. 3. A process according to Claim 2 in which R is p-isoprotyl and R2, R3 and R4 are each methyl. 4. A process according to Claim 1 in which step (a) is conduced in the presence of water, an organic solvent and a phase transfer catalyst. 5. A process according to Claim 4 in which the phase transfer catalyst employed in step (a) is a quaternary onium salt having the formula (R5R6R7El81!I)+Z- in which Rs, R6, R7, and R8 are independently C1-C25 alkyl or C2-C25 alkenyl, M is nitrogen, phosphorus or arsenic and Z is a monovalent anion. 6. A process according to Claim 1 in which step (a) is conducted in the presence of an aqueous solution of a lower alkanol. 7. A process according to Claim 1 in which the phase transfer catalyst employed in step (b) is a quaternary onium salt having the formula (R5R6R7R8M) Z in which Rs, R6, R7 and R8 are independently Cl-C25 alkyl, or C2-C25 alkenyl, M is nitrogen, phosphorus or arsenic and Z is a monovalent anion. 8. A process according to Claim 1 further comprising removing from the product of reaction (a) any alcoholic component which may be present before conducting reaction (b). 9. A process according to Claim 1 in which the alkali metal cyanide is sodium cyanide. 10. A process according to Claim 1 in which the alkali metal of step (c) is sodium.

Inventors: ROBBINS, JEFFREY DEAN
Applicants: STAUFFER CHEMICAL COMPANY
Application year: 1981
Main classification: C07C43
IPC codes: C07B61, B01J31, C07C41, C07C15, C07C43, C07C67, C07C1