PROCESS FOR SELECTIVELY PRODUCING PARA-SUBSTITUTED DERIVATIVES OF PHENOLS

Abstract: A phenol compound is reacted with an organic halide selected from the group consisting of haloform, tetrahaloge­ nocarbon, and substituted or unsubstituted allyl halide in the presence of an alkali metal hydroxide using a modified or non-modified cyclodextrin as a catalyst to thereby introduce a substituent derived from said organic halide into a p-position of the phenol compound with an extremely high selectivity. The use of a p-substituted phenol compound gives a 4-dihalomethyl-2,5-cyclohexadienone derivative or 4-allyl-2,5-cyclohexadienone derivative, and the use of a p-unsubstituted phenol compound gives a 4-hydroxybenzoic acid derivative, 4-hydroxybenzaldehyde derivative or 4-­ allylphenol derivative.

Description: SPECIFICATION A PROCESS FOR INTRODUCING A SUBSTITUENT TO THE PARA-POSITION OF PHENOLS FIELD OF THE INVENTION The present invention relates to a process for introducing a substituent to the para-position of phenols. More particularly, the present invention is concerned with a process for introducing a substituent group derived from an organic halide to the para-position of a phenol compound, characterized by reacting a phenol compound with an organic halide selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide in the presence of an alkali metal hydroxide, using a cyclodextrin as a catalyst. DESCRIPTION OF THE PRIOR ART It is known that 2,5-cyclohexadienone derivatives having a dihalomethyl group at the 4-position, 2,5-cyclohexadienone derivatives having a substituted or unsubstituted allyl group at the 4-position, para-hydroxybenzoic acid derivatives, or para-hydroxybenzaldehyde derivatives are prepared by reacting a phenol with a haloform, a carbon tetrahalide or an allyl halide under alkaline conditions. The products thus obtained are extremely valuable compounds as pharmaceuticals, agricultual chemicals, or raw materials for polymers, various physiologically active substances such as agricultural chemicals and pharmaceuticals, and dyes. However, known reaction processes have serious disadvantages of extremely low selectivity and therefore poor yield. Accordingly, the known process cannot be used in practice. For example, para-hydroxybenzaldehyde which, nowadays, is of increasing importance as an anticarcinogen or a raw material for pharmacenticals, agricultural chemicals and dyes, has conventionally been synthesized by reacting phenol with chloroform in the presence of an alkali. In the reaction, however, parahydroxybenzaldehyde is obtained in a selectivity as low as about 30%, and a large amount of salicylaldehyde is formed as a by-product. Therefore, the production of parahydroxybenzaldehyde in accordance with this process requires not only a large amount of raw materials but also an operation for separation. 2,4-Dihydroxybenzaldehyde, nowadays, is also of increasing importance in view of its interesting behaviors such as cancer-controlling effect, plant root growth-promoting effect, antibacterial effect and photophosphorylation -oontrolling effect in chioroplast. For the production of 2,4-dihydroxybenzaldehyde, known is a process in which l,3-dihydroxybenzene is reacted with chloroform in the presence of an alkali. However, in this known process, a large amount of 2,4-dihydroxy3-formylbenzaldehyde is formed as a by-product, and 2,4dihydroxybenzaldehyde which is the intended product is obtained only in low yield and with low selectivity. Accordingly, for producing 2,4-dihydroxybenzaldehyde by this process, not only large amounts of raw materials but also an operation for separation is required. As to the production of para-hydroxybenzoic acid which, nowadays, is of increasing importance as a raw material for heat resistant polymers, agricultural chemicals and pharmaceuticals, known is the Kolbe-Schmitt reaction in which para-hydroxybenzoic acid is synthesized by treating phenol with potassium hydroxide and potassium carbonate, followed by heating together with carbon dioxide under elevated pressure. The reaction, however, has disadvantages that a costly pressure resistant apparatus is required because of high pressure applied during the reaction, and that much thermal energy is required for the evaporation of water in order to achieve an absolute anhydrous condition which is indispensable to the reaction. Also known is another process in which phenol is reacted with corbon tetrachloride in the presence of an alkali to prepare para-hydroxybenzoic acid. In the process, however, the selectivity for the formation of para-hydroxybenzoic acid is 57%, and the reaction gives a large amount of salicylic acid as a by-product. Therefore, the process also requires not only large amounts of raw materials but also an operation for separation. 2,5-Cyclohexadienone derivatives are highly reactive due to the conjugation of two C-C double bonds with a carbonyl group, and therefore are valuable as raw materials for the syntheses of physiologically active substances and other useful substances. Moreover, many of 2,5-cyclohexadienone derivatives themselves have physiological activities. Hitherto is known the Rezr-Tiexsn reaction in which a para-substituted phenol is reacted with a halo form and sodium hydroxide or potassium hydroxide to give a 4-dihalomethyl-2,5-cyclohexadienone derivative. The reaction, however, gives compounds having substituents introduced mainly to the ortho-position. Therefore, the conventional process gives 2,5-cyclohexadienone derivatives in an yield as low as 5 to 10%, and requires not only large amounts of raw materials, but also aNS b3id operation for separation. 2,5-Cyclohexadienone derivatives having an allyl group at the 4-position are also highly reactive due to the conjugation of two C-C double bonds and a carbonyl group. In addition, they have an allyl group at such a position that an intramolecular ring-forming reaction is readily caused to occur. Accordingly, the derivatives are valuable compounds as starting materials for preparing physiologically active substances and other useful substances. 2,5 Cyclohexadienone derivatives having an allyl group at the 4-position have conventionally been prepared in a process comprising two steps, namely, the first step in which a 1:1 mixture of sodium methoxide and a para-substituted phenol is reacted with an allyl halide in an aromatic solvent to produce a 2,4-cyclohexadienone derivative which is allyl-substituted at the 6-position, and the second step in which the product in the first step is then reacted in a methanol-hydrochloric acid mixture to allow the allyl group to transfer to the 6-position. The process has disadvantages that the 2,4-cyclohexadienone derivative which is a reaction product of the first step is difficult to separate and purify, and that the reactions involved in the process require large amounts of organic solvents. As described above, any of the conventional processes for introducing a substituent to the para-position-of phenols are unsatisfactory from a practical point of view because of extremely low selectivity or because of necessity of two reaction steps accompanied by other difficulties during the reaction. DISCLOSURE OF THE PRESENT INVENTION The present inventors have made extensive and intensive studies to develop a process in which a substituent is introduced to the 4-position of phenols with high selectivity to give intermediates for the production of various useful substances as mentioned above. As a result, it has been found that, when a phenol compound is reacted with an organic halide in the presence of cyclodextrin under an alkaline condition, a substituent group derived from said organic halide is introduced to the 4-position of the phenol compound with high selectivity, and therfore the intended product can be obtained in high yield. Based on such a novel finding, the present invention has been made. According to the present invention, there is provided a process for introducing a substituent to the para-position of phenols which comprises reacting a phenol compound represented by the formula (I) EMI5.1 wherein A, B, C, D and,E each independently stand for hydrogen,a.hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted allyl group, a substituted or unsubstituted alkoxyl group or a substituted or unsubstituted aryl group,-provided that A does not stand for a hydroxyl group and that when two or more of A, B, C, D and E each independently stand for a substituted or unsubstituted alkyl group or a substitutUo unsubstituted alkoxyl group, they have their re spective free terminal ends or at least one of them is bonded to another -group selected from said alkyl and alkoxyl groups to form a ring, with an organic halide selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide in the presence of an alkali metal hydroxide and a modified or unmodified cyclodextrin, thereby to introduce a substituent group derived from said organic halide to the para-position of the phenol compound. By the term "phenol compound" as used herein is meant phenol(hydroxybenzene) or its derivative which is defined by the above-mentioned formula (I). The substituted or unsubstituted alkyl group, the substituted or unsubstituted allyl group, the substituted or unsubstituted alkoxyl group and the substituted or unsubstituted aryl group each may preferably have carbon atoms of not more than 6 with respect to the substituents B, C, D and E, and each may preferably have carbon atoms of not more than 12 with respect to the substituent A. As the substituent to be introduced to the alkyl group, ally group, alkoxyl group and aryl group, -there can be mentioned an alkyl group, a halogen atom and others without specific restriction. Ibwseer, too large a group is undesired. The organic halide which is one of the reactants to be used in the process of the present invention is selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide. The substituted or unsubstituted allyl halide may preferably have carbon atoms of not more than 12. As such an allyl halide, the chloride and bromide are especially preferred. The organic halide may be used in an equimolar amount to the amount of phenol compound, but usually in an amount which is twice to 20 times the amount of the phenol compound,. because the organic halide tends to decompose in an aqueous medium used as a reaction solvent, about which aqueous medium a description will be given later. The alkali metal hydroxide to be used in the process of the present invention may preferably be sodium hydroxide or potassium hydroxide. The alkali metal hydroxide may be used in a stoichiometrical amount relative to the phenol ccnpound. Usually, however, 1 to 15 times the stoichiometrical amount of the alkali metal hydroxide may be used taking into consideration of a rate of reaction and the like. The reaction according to the process of the present invention is usually carried out in a reaction medium. As the reaction medium, there is employed an aqueous solvent, preferably water, because of the requirement that the reaction medium be capable of dissolving the alkali metal hydroxide therein. There may also be used, as the reaction medium , a mixture of water with a small amount of an organic solvent which is soluble in water and can be present stably under the reaction conditions. Examples of such an organic solvent include methanol, ethanol, acetone, dimethoxyethane and the like. The concentration of the alkali metal hydroxide in the reaction solvent may be in the range of 5 to 20 % by weight, preferably 10 to 15 % by weight. In the process according to the present invention, a better result in the reaction can be achieved by controlling the molar ratio of a modified or unmodified cyclodextrin (hereinafter often referred to simply as "cyclodextrin") to an organic halide selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide in the reaction system. To effect the reaction economically and advantageously, the molar ratio of the cyclodextrin to the organic halide may usually be 0.1 to 20, preferably 0.2 to 15, more preferably 0.5 to 10. When a large amount of the organic halide is present in the reaction system, a large amount of cyclodextrin is required to obtain a better result in the reaction. On the other hand, when the organic halide is dropwise added to a solution containing a phenol compound, an alkali hydroxide and cyclodextrin so that the molar ratio of the cyclodextrin to the organic halide is maintained in the range of from 0.1 to 20, preferably 0.2 to 15, more preferably 0.5 to 10, a better result in the reaction can be attained with a small amount of cyclodextrin, leading to economical advantages. The above-mentioned modified or unmodified cyclodextrin acts as a catalyst in the reaction of the process according to the present invention, and any of modified or modified i 72- and t-cyclodextrins may be used. Usually, satisfactory results can be obtained by the use of unmodified i - or }-cyclodextrin. However, a more improved yield and selectivity in the reaction are achieved by the use of a modified -, '- or -cyclodextrin of which the primary hydroxyl groups, for example, are all or partly substituted with a group which is stable under alkaline conditions, such as a N-methylformyl group. The above-mentioned modified cyclodextrin may be prepared according to the method described in J. Amer. Chem. Soc., 102, 762 (1980). The reaction temperature is not critical, and the reaction may be carried out at room temperature or higher temperature, preferably at a temperature of from 50 C to 800C. The reaction time is also not critical, and may be suitably determined according to the amounts of reactants, reaction temperature, manner of addition of reactants and the like. The reaction pressure is also not restricted, and the reaction is usually carried out at atmospheric pressure from a viewpoint of ease in operation. By the reaction of the phenol compound with the organic halide according to the process of the present invention, there is produced a para-substituted phenol derivative of the kind varied depending on the kinds of the phenol compound and the organic halide, as described later. From phenol compounds of the formula (I) in which A is a hydrogen atom, para-hydroxybenzaldehydes, para-hydroxybenzoic acids, or para-allyl phenols are obtained. From phenol compounds of the formula (I) in which A is other substituent than hydrogen, namely, a substituted or unsubstituted alkyl group, a substituted or unsubstituted allyl group, substituted or unsubstituted alkoxyl group or a substituted or unsubstituted aryl group, there are obtained 4dihalomethyl-2,5-cyclohexadienone derivatives or 4-allyl-2,5cyclohexadienone derivatives. Illustratively stated, when A in the formula (I) is hydrogen, there is obtained a parasubstituted phenol deviative represented by the formula (II) EMI10.1 wherein B, C, D and E are as defined above and Y stands for an aldehyde group, a substituted or unsubstituted allyl group or a carboxyl group, whereas when A in the formula (I) is a substituted or unsubstituted alkyl group, a substituted or unsubstituted allyl group, a substituted or unsubstituted alkoxyl group or a substituted or unsubstituted aryl group, there is obtained a para-substituted phenol derivative represented by the formula (III) EMI10.2 wherein A, B, C, D and E are as defined above, pro- vided that A does not--standfor hydrogen, and Z stands for a haloform-residue or a substituted or unsubstituted allyl group As described above, according to the process of the present invention, the introduction of a substituent to the paraposition of phenols can be attained with an extremely high selectivity to obtain the intended products which are valuable intermediates. PREFERRED EMBODIMENTS OF THE INVENTION The present invention will be illustrated in more detail with reference to the following Examples. Unless otherwise specified, reactions were carried out at atmospheric pressure in Examples and Comparative Examples as will be described hereinafter. Example 1 In 50 ml of an aqueous 10% sodium hydroxide solution were dissolved 1.0 g (10.6 mmol) of phenol (first class grade reagent, manufactured and sold by Koso Chemical Co., Ltd., Japan) and 2.2 g (2.1 mmol) of M-cyclodextrin (special grade reagent, manufactured and sold by Nakarai Chemical Ltd., Japan). The resulting solution was heated to 600C while agitating by means of a magnetic stirrer. Then, while dropwise adding 3 ml (37.4 mmol) of chloroform (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd. Japan) to the resulting solution, the reaction was allowed to proceed for 10 hours. Every 2 hours during the course of the reaction, part of the reaction mixture was taken, and subjected to the determination of chloroform contained therein by means of 701-type Gas Chromatograph manufactured by Ohkura Rikagaku Kenkyusho Co., Ltd., Japan (packing material, Porapak Q manufactured and sold by Gasukuro Kogyo Inc., Japan; column length, 2m; column temperature, 300C; carrier gas, helium). The analysis showed that the molar ratio of d-cyclodextrin to chloroform was 0.9 to 1.6. After completion of the reaction, the reaction mixture was acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 5 times. The ethyl ether layer was washed with water, and then evaporated to dryness, thereby to obtain 1.1 g of a solid. The solid thus obtained was treated with benzene to give 0.6 g of a benzene-insoluble matter and 0.5 g of a benzene-soluble matter. The infrared spectrum of the benzeneinsoluble matter was in agreement with that of para-hydroxybenzaldehyde (special grade reagent, manufactured by Tokyo Kasei Co., Ltd., Japan). On the other hand, the spectrum of the benzene-soluble matter was in agreement with that of phenol. Salicylaldehyde was observed neither in the benzene-soluble matter nor in the benzene-insoluble matter. The yield of the intended product was 46% and the selectivity was 92%. In this example,fi-cyclodextrin was used in an amount of 0.2 in terms of molar ratio with respect to the phenol. Comparative Example 1 In 50 ml of an aqueous 10% sodium hydroxide solution was dissolved 1.0 g (10.6 mmol) of phenol (first class grade reagent, manufactured and sold by Koso Chemical Co., Ltd., Japan). The resulting solution was heated to 600C while agitating by means of a magnetic stirrer. Then, while dropwise adding 3 ml (37.4 mmol) of chloroform (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) to the resulting solution, the reaction was allowed to proceed for 10 hours. After completion of the reaction, the reaction mixture was acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 5 times. The ethyl ether layer was washed with water, and then evaporated, thereby to obtain 1.0 g of an oily material. The oily material thus obtained was analyzed by means of 701-type Gas Chromatograph manufactured by Ohkura Rikagaku Kenkyusho Co., Ltd., Japan (packing material, Uniport HP manufactured and sold by Gasukuro Kogyo Inc., Japan; column length, 2 m; column temperature, 1400C; carrier gas, helium). The analysis showed that the oily material was a mixture of 0.2 g (1.6 mmol) of para-hydroxybenzaldehyde, 0.4 g (3.2 mmol) of salicylaldehyde and 0.4 g of phenol. Namely, the yield of the intended product was 15% and the selectivity was 25%. In this example, cyclodextrin was not used. Comparative Example 2 In 50 ml of an aqueous 10% sodium hydroxide solution were dissolved 1.0 g (10.6 mmol) of phenol (first class grade reagent, manufactured and sold by Koso Chemical Co., Ltd., Japan) and 2.2 g (2.1 mmol) of C-cyclodextrin (special grade reagent, manufactured and sold by Nakarai Chemical Ltd., Japan). To the resulting solution was added 3 ml (37.4 mmol) of chloroform (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan). Namely, the molar ratio of d-cyclodextrin to chloroform was 0.06 at the start of the reaction. The solution was heated at 600C for 10 hours while agitating by means of a magnetic stirrer. After completion of the reaction, the reaction mixture was acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 5 times. The ethyl ether layer was washed with water, and then evaporated, thereby to obtain 1.1 g of an oily material. The oily material thus obtained was analyzed by means of 701-type Gas Chromatograph manufactured by Ohkura Rikagaku Kenkyusho Co., Ltd., Japan (packing material, Uniport HP manufactured and sold by Gasukuro Kogyo Inc., Japan; column length, 2 m; column temperature, 1400C; carrier gas, helium). The analysis showed that the oily material was a mixture of 0.4 g (3.2 mmol) of para-hydroxybenzaldehyde, 0.3 g (2.4 mmol) of salicylaldehyde and 0.4 g of phenol. Namely, the yield of the intended product was 30% and the selectivity was 51%. In this example d-cyclodextrin was used in an amount of 0.2 in terms of molar ratio with respect to the phenol, which was the same as in Example 1. Example 2 Substantially the same procedures as in Example 1 were repeated except that 2.4 g (2.1 mmol) of p-cyclodextrin (special grade reagent, manufactured and sold by Nakarai Chemical Ltd., Japan) was used instead of 2.2 g of a-cyclodextrin. There was obtained 0.5 g (4.0 mmol) of para-hydroxybenzaldehyde, with 0.6 g of unreacted phenol recovered. Salicylaldehyde was not detected. Namely, the yield of the intended product was 39% and the selectivity was 98%. In this example,4 -cyclodextrin was used in an amount of 0.2 in terms of molar ratio with respect to the phenol. Comparative Example 3 Substantially the same procedures as in Comparative Example 2 were repeated except that 2.4 g (2.1 mmol) of p- cyclodextrin (special grade reagent, manufactured and sold by Nakarai Chemical Ltd., Japan) was used instead of 2.2 g of O(-cyclodextrin. Namely, the molar ratio of p-cyclodextrin to chloroform was 0.06 at the start of the reaction. There was obtained a mixture of 0.3 g (2.4 mmol) of para-hydroxybenzaldehyde, 0.2 g (1.6 mmol) of salicylaldehyde and 0.5 g of phenol. Namely, the yield of the intended product was 23% and the selectivity was 45%. In this example, p-cyclodextrin was used in an amount of 0.2 in terms of molar ratio with respect to the phenol, which was the same as in Example 2. Example 3 In 60 ml of an aqueous 10% sodium hydroxide solution were dissolved 1.0 g (9.1 mmol) of 1,3-dihydroxybenzene (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) and 8.0 g (7.0 mmol) of -cyclodextrin (special grade reagent, manufactured and sold by Nakarai Chemical lid., Japan). While gradually,dropwise adding 5 ml (62.3 mmol) of chloroform (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) to the resulting solution and agitating by means of a magnetic stirrer, the reaction was allowed to proceed at 600C for 4 hours. After completion of the reaction, the reaction mixture was acidified with hydrochloric acid and subjected to extractions each with 50 ml of ethyl ether 3 times. The ethyl ether layer was washed with water, and then dried, thereby to obtain 1.2 g of a product. The product thus obtained was analyzed by means of 701-type Gas Chromatograph manufactured by Ohkura Rikagaku Kenkyusho Co., Ltd., Japan (packing material, Tenax GC manufactured and sold by Gasukuro Kogyo Inc., Japan; column length, 2 m; column temperature,3000C; carrier gas, helium). The analysis showed that the product was entirely 2, 4-dihydroxybenzaldehyde, without any 2,4-dihydroxy-3formylbenzaldehyde detected. Namely, the yield of the intended product was 96% and the selectivity was 100%. Comparative Example 4 Each reagent used herein was of the same grade as in E =ple 3. In 60 ml of an aqueous 10% sodium hydroxide solution was dissolved 1 g (9.1 mmol) of 1,3-dihydroxybenzene. While gradually, dropwise adding 5 ml (62.3 mmol) of chloroform to the resulting solution and agitating by means of a magnetic stirrer, the reaction was allowed to proceed at 600C for 4 hours. After completion of the reaction, the reaction mixture was acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times. The ethyl ether layer was washed with water, and then dried, thereby to obtain 0.9 g of a product. The product thus obtained was analyzed by means of 701-type Gas Chromatograph manufactured by Ohkura Rikagaku Kenkyusho Co., Ltd., Japan. The analysis showed that the product was a mixture of 0.3 g of 2,4-dihydroxybenzaldehyde and 0.6 g of 2,4-dihydroxy-3-formylbenzaldehyde. Namely, the yield of the intended product was 24% and the selectivity was 38%. Example 4 In 20 ml of an aqueous 20% sodium hydroxide solution were dissolved 1.5 g of phenol (first class grade reagent, manufactured and sold by Koso Chemical Co., Ltd., Japan) and 1.5 g of 4-cyclodextrin (special grade reagent, manufactured and sold by Nakarai Chemical Ltd., Japan). To the resulting solution was added 3 ml of carbon tetrachloride (first class grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) and 0.1 g of copper powder (first class grade reagent, manufactured and sold by Voneyama Yakuhin Kogyo Co., Ltd., Japan). The resulting mixture was allowed to react at 800C for 10 hours under reflux by the use of a reflux condenser while agitating by means of a magnetic stirrer. After completion of the reaction, the solution was acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times. The ethyl ether layer was washed with water, and then dried, thereby to obtain 2.1 g of a product. The infrared spectrum of the product thus obtained was in agreement with that of para-hydroxybenzoic acid (special grade reagent, Tokyo Kasei Co., Ltd., Japan). Further, the product was treated with chloroform and, as a result, it was found that the product did not contain any chloroform-soluble matter any more. Since both phenol if any remaining unreacted and salicylaldehyde if any formed as a side reaction product are readily soluble, in chloroform, the yield of the intended product was 95 % and the selectivity was 100 %. Comparative Example S Each reagent used herein was of the same grade as in Example 4. In 20 ml of an aqueous 20% sodium hydroxide solution was dissolved 1.5 g of phenol. To the resulting solution, 3 ml of carbon tetrachloride and 0.1 g of copper powder were added. The resulting mixture was allowed to react at 800C for 10 hours under reflux by the use of a reflux condenser while agitating by means of a magnetic stirrer. After completion of the reaction, the reaction mixture was acidified with hydrochloric acid, and subjected to extractions each with 50 ml of ethyl ether 3 times, The ethyl ether layer was washed with water, and then dried, thereby to obtain 2.1 g of a product. The product thus obtained was treated with chloroform to give 1.2 g of a chloroform-insoluble matter and 0.9 g of a chloroformsoluble matter. The infrared spectrum of the chloroforminsoluble matter was in agreement with that of para-hydroxybenzoic acid. On the other hand, the infrared spectrum of the chloroform-soluble matter was in agreement with that of salicylic acid (special grade reagent, manufactured and sold by Koso Chemical Co., Ltd., Japan). Namely, the yield of the intended product was 55% and the selectivity was 57%. Example 5 In 50 ml of an aqueous 10 % sodium hydroxide solution were dissolved 1 g of p-cresol and 8 g of kWcyclodextrin. To the resulting solution, 5 ml of chloroform was gradually, dropwise added at 75 CC, and allowed to react for 10 hours. After completion of the reaction, the reaction mixture was subjected to extractions each with 50 ml of chloroform 5 times, and then the chloroform layer was dried, thereby to obtain 0.75 g of a product. The dH-NMR measurement showed that the product thus obtained was entirely 4-dichloromethyl-4-methyl-2,5-cyclohexadienon. Namely, the yield of the intended product was 43 % and the selectivity was 100 %. Comparative Example 6 In 50 ml of an aqueous 10 % sodium hydroxide solution was dissolved 1 g of p-cresol. To the resulting solution, 5 ml of chloroform was gradually, dropwise added at 750C, and allowed to react for 10 hours. After completion of the reaction, the reaction mixture was subjected to extractions each with 50 ml of chloroform 5 times. The chloroform layer was dried to obtain 0.29 g of a product. The product thus obtained was a mixture of 28 % of 4-dichloromethyl-4-methyl-2,5-cyclohexadienone, and 72 % of 2-formyl-4-methylphenol. Namely, the yield of the intended product was 5 % and the selectivity was 28 %. Example 6 Substantially the same procedures as in Example 5 were repeated except that 1 g of 4-phenylphenol was used instead of 1 g of p-cresol. There was obtained 0.89 g of a product. The 1H-NMR measurement showed that 95 % of the product was 4-dichloromethyl-4-phenyl-2, 5-cyclohexadienone and the balance was 2-formyl-4-phenylphenol. Namely, the yield of the intended product was 60 % and the selectivity was 95 %. Comparative Example 7 Substantially the same procedures as in comparative Example 6 were repeated except that 1 g of 4-phenylphenol was used instead of 1 g of p-cresol. There was obtained 0.50 g of a product. The product was a mixture of 12 % of 4-dichloromethyl-4-phenyl-2,5-cyclohexadienone and 88 % of 2-formyl-4phenylphenol. Namely, the yield of the intended product was 4 % and the selectivity was 12 %. Example 7 Substantially the same procedures as in Example 5 were repeated except that 1 g of 3,4,5-trimethylphenol was used instead of 1 g of p-cresol. There was obtained 0.90 g of a product. The product thus obtained was entirely 3,4,5 trimethyl-4-dichloromethyl-2,5-cyclohexadienone. Namely, the yield of the intended product was 56 % and the selectivity was 100 %. Comparative Example 8 Substantially the same procedures as in Comparative Example 6 were repeated except that 1 g of 3,4,5-trimethylphenol was used instead of 1 g of p-cresol. There was obtained 0.38 g of a product. The product thus obtained was a mixture of 5 % of 3,4,5-trimethyl-4-dichloromethyl-2,5-cyclohexadienone and 95 % of 3,4,5-trimethyl-2-formylphenol. Namely, the yield of the intended product was 1 % and the selectivity was 13 %. Example 8 Substantially the same procedures as in Example 5 were repeated except that 1 g of ar-2-tetrahydronaphthol was used instead of 1 g of p-cresol. There was obtained 0.56 g of 9-dichloromethyl-6-oxo-l, 2,3,4,6, 9-hexahydronaphthalene - Namely, the yield of the intended product was 36 % and the selectivity was 100 %. Comparative Example 9 Substantially the same procedures as in Comparative Example 6 were repeated except that 1 g of ar-2-tetrahydro- naphthol was used instead of 1 g of p-cresol. There was obtained 0.52 g of a product. The product thus obtained was a mixture of 19 % of 9-dichloromethyl-6-oxo-1,2,3,4,6,9-hexa- hydronaphthalene and 81 % of 1-formyl-ar- 2-tetrahydronaphtho 1. Namely, the yield of the intended product was 6 % and the selectivity was 19 %. Example 9 Substantially the same procedures as in Example 5 were repeated except that 1 g of 2,4,6-trimethylphenol was used instead of 1 g of p-cresol. There was obtained 0.75 g of 2,4,6-trimethyl-4-dichloromethyl-25-cyclohexadienonee Namely, the yield of the intended product was 47 % and the selectivity was 100 %. Example 10 Substantially the same procedures as in Example 6 were repeated except that 1 g of p-methoxyphenol was used instead of 1 g of p-cresol. There was obtained 0.31 g of a product. The product thus obtained was a mixture of 96 % of 4-dichloromethyl-4-methoxy-2,5-cyclohexadienone and 4 % of 2-formyl-4methoxyphenol. Namely, the yield of the intended product was 27 % and the selectivity was 96 %. Example 11 Substantially the same procedures as in Example 8 were repeated except that 8 g of o(-cyclodextrin was used instead of 8 g of -cyclodextrin. From 1 g of ar-2-tetrahydronaphthol, there was obtained 0.41 g of a product. The product contained 9-dichloromethyl-6-oxo-l ,2,3, 4,6, 9-hexahydronaphthalene in an amount of 93 %. Namely, the yield of the intended product was 24 % and the selectivity was 93 %. Example 12 Substantially the same procedures as in Example 5 were repeated except that an aqueous 10 % potassium hydroxide solution was used instead of an aqueous 10 % sodium hydroxide solution. From 1 g of p-cresol, there was obtained 0.52 g of 4-dichloromethyl-4-methyl-2,5-cyclohexadienone. Namely, the yield of the intended product was 29 % and the selectivity was 100 %. Example 13 In 50 ml of an aqueous I % sodium hydroxide solution were dissolved 0.20 g of 2,4,6-trimethyiphenol (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) and 7.5 g of i-cyclodextrin (special grade reagent, manufactured and sold by Nakarai Chemical Ltd., Japan). While dropwise adding 0.9 g of allyl bromide (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) to the resulting solution at room temperature, the reaction was allowed to proceed for 24 hours. After completion of the reaction, the reaction mixture was subjected to extractions each with 50 ml of ether 5 times. The ether layer was dried to obtain 0.18 g of a product. The 1H-NMR measurement showed that the product was a mixture of 53 % of 2,4,6-trimethyl-4-allyl-2,5-cyclo- hexadienone, 26 % of 2,4,6-trimethyl-6-allyl-2,4-cyclohexadienone and 21 % of 2,4,6-trimethylphenyl allyl ether. Namely, the yield of the intended product and the selectivity were 37 % and 53 %, respectively. Comparative Example 10 In 50 ml of an aqueous 1 % sodium hydroxide solution was dissolved 0.20 g of 2,4,6-trimethylphenol (special grade reagent, manufactured and sold by Tokyo Kasei Cho., Ltd., Japan). While dropwise adding 0.9 g of allyl bromide (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) to the resulting solution at room temperature, the reaction was allowed to proceed for 24 hours. After completion of the reaction, the reaction mixture was subjected to extractions each with 50 ml of ethyl ether 5 times. The ethyl ether layer was dried to obtain 0.19 g of a product. The 1H-NMR measurement showed that the product was a mixture of 25 % of 2,4,6-trimethyl-4-allyl2,5-cyclohexadienone, 50 % of 2,4,6-trimethyl-6-allyl-2,4cyclohexadienone and 25 % of 2,4,6-trimethylphenyl allyl ether. Namely, the yield of the intended product and the selectivity were 18 % and 25 %, respectively. Example 14 Substantially the same procedures as in Example 13 were repeated except that 7.5 g of 4-cyclodextrin (special grade reagent, manufactured and sold by Nakarai Chemical Ltd., Japan) was used instead of 7.5 g of o(-cyclodextrin. There was obtained 0.20 g of a product. The 1H-NMR measurement showed that the product was a mixture of 41 % of 2,4,6-trimethyl-4-allyl-2,5cyclohexadienone, 34 % of 2,4,6-trimethyl-6-allyl-2,4-cyclohexadienone and 28 % of 2,4,6-trimethylphenyl allyl ether. Namely, the yield of the intended product and selectivity were 32 % and 41 %, respectively. Example 15 In accordance with the method as described in J. Amer. Chem. Soc., 102 762 (1980), all of the primary hydroxyl groups of docyclodextrin were N-methylformylated. In 50 ml of an aqueous 1 % sodium hydroxide solution were dissolved 8 g of the above-obtained modified cyclodextrin and 0.20 g of 2,4,6trimethylphenol. While dropwise adding 0.9 g of allyl bromide (special grade reagent, manufactured and sold by Tokyo Kasei Co., Ltd., Japan) to the resulting solution at room temperature, the reaction was allowed to proceed for 24 hours. After completion of the reaction, the reaction mixture was subjected to extractions each with 50 ml of ethyl ether 5 times. The ethyl ether layer was dried to obtain 022 g of a product. The 1H-NMR measurement showed that the product was entirely 6-trimethyl-4-allyl-2, 5-cyclohexadienone. Namely, the yield of the product and selectivity were 85 % and 100 %, respectively. PROBADILITY-OF UTILIZATION IN INDUSTRY According to the process of the present invention, a variety of useful phenol derivatives having a substituent introduced to the para-position thereof are produced from phenols with high selectivity. Therefore, not only can be reduced the required amounts of phenols as raw materials but also the purification process can be extremely simplified, thus enabling the production process of the desired products to be economic.

Claims: What is claimed is: 1. A process for introducing a substituent to the paraposition of phenols which comprises reacting a phenol compound represented by the formula(I) EMI25.1 wherein A, B, C, D and E each independently stand for hydrogen,a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsub stituted allyl group, a substituted or unsubstituted alkoxyl group or a substituted or unsubstituted aryl group, provided that A does not stand for a hydroxyl group and that when two or more of A, B, C, D, and E each independently stand for a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxyl group, they have their re spective free terminal ends or at least one of them is bonded to another group selected from said alkyl and alkoxyl groups to form a ring, with an organic halide selected from the group consisting of a haloform, a carbon tetrahalide and a substituted or unsubstituted allyl halide in the presence of an alkali metal hydroxide and a modified or unmodified cyclodextrin, thereby to introduce a substituent group derived from said organic halide to the para-position of the phenol compound. 2. A process according to claim 1, wherein said substituted or unsubstituted alkyl, said substituted or unsubstituted allyl group, said substituted or unsubstituted alkoxyl group and said substituted or unsubstituted aryl group each have carbon atoms of not more than 6 with respect to B, C, D and E and each have carbon atoms of not more than 12 with respect to A. 3. A process according to claim 1 or 2, wherein said alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 4. A process according to any of claims 1 to 3, wherein said modified or unmodified cyclodextrin is employed in an amount of 0.1 to 20 in terms of molar ratio with respect to said organic halide. 5. A process according to claim 4, wherein the molar ratio of the modified or unmodified cyclodextrin to the organic halide is 0.2 to 15. 6. A process according to any of claims 1 to 5, wherein the reaction is effected in an aqueous medium. 7. A process according to any of claims 1 to 6, wherein A in the formula (I) is hydrogen to obtain a para-substituted phenol derivative represented by the formula (11) EMI27.1 wherein B, C, D and E are as defined above and Y stands for an aldehyde group, a substituted or unsubstituted allyl group or a carboxyl group, or A in the formula(I) is a substituted or unsubstituted alkyl group, a substituted or unsubstituted allyl group, a substituted or unsubstituted alkoxyl group or a substituted or unsubstituted aryl group to obtain a para-substituted phenol derivative represented by the formula(III) EMI27.2 wherein A, B, C, D and E are as defined above, provided that A does not stand for hydrogen, and Z stands for a halo form residue or a substituted or unsubstituted allyl group. What is claimed is: 1. A-process for introducing a substituent to the paraposition of phenols which comprises reacting a phenol compound represented by the formula (I) EMI28.1 wherein A, B, C, D and E each independently stand for hydrogen,a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsub stituted allyl group, a substituted or unsubstituted alkoxyl group or a substituted or unsubstituted aryl group, provided that A does not stand for a hydroxyl group and that when two or more of A, B, C, D, and E each independently stand for a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxyl group, they have their re spective free terminal ends or at least one of them is bonded to another group selected from said alkyl and alkoxyl groups to form a ring, with an organic halide selected from the group consisting of a halo form, a carbon tetrahalide and a substituted or unsubstituted allyl halide in the presence of an alkali metal hydroxide and a modified or unmodified cyclodextrin, thereby to introduce a substituent group derived from said organic halide to the para-position of the phenol compound. 2. A process according to claim 1, wherein said substituted or unsubstituted alkyl, said substituted or unsubstituted allyl group, said substituted or unsubstituted alkoxyl group and said substituted or unsubstituted aryl group each have carbon atoms of not more than 6 with respect to B, C, D and E and each have carbon atoms of not more than 12 with respect to A. 3. A process according to claim 1 or 2, wherein said alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 4. A process according to any of claims I to 3, wherein said modified or unmodified cyclodextrin is employed in an amount of 0.1 to 20 in terms of molar ratio with respect to said organic halide. 5. A process according to claim 4, wherein the molar ratio of the modified or unmodified cyclouextrin to to the organic halide is 0.2 to 15. 6. (new) A process according to claim 5, wherein the molar ratio of the modified or unmodified cyclodextrin to the organic halide is 0.5 to 10. 7. (new) A process according to any of claims 1 to 6, wherein the reaction between the phenol compound and the organic halide in the presence of an alkali metal hydroxide and a modified or unmodified cyclodextrin is effected by gradually adding the organic halide to a system comprising the phenol compound, the alkali metal hydroxide and the modified or unmodified cyclodextrin 8. (originally, claim 6) A process according to any of claims 1 to 7, wherein the reaction is effected in an aqueous medium. 9. (originally, claim 7) A process according to any of claims 1 to: 8, wherein A in the formula (I) is hydrogen to obtain a para-substituted phenol derivative represented by the formula (11) - EMI30.1 wherein B, C, D and E are as defined above and Y stands for an aldehyde group, a substituted or unsubstituted allyl group or a carboxyl group, or A in the formula (I) is a substituted or unsubstituted alkyl group, a substituted or unsubstituted allyl group, a substi- tuted or unsubstituted alkoxyl group or a substituted or un substituted aryl group to obtain a para-substituted phenol derivative represented by the fo=nula(11l) EMI31.1 wherein A, B, C, D and E are as defined above, provided that A does not stand for hydrogen, and Z stands for a haloforzn residue or a substituted or unsubstituted allyl group

Inventors: HIRAI, HIDEFUMI, KOMIYAMA, MAKOTO
Applicants: ASAHI KASEI KOGYO KABUSHIKI KAISHA
Application year: 1982
Main classification: C07C39
IPC codes: C07C51, C07C37, C07C45, C07C41, C07C43