JP2005239595A - Method for removing phenolic hydroxy group - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for removing a phenolic hydroxy group, which has a high yield, hardly affects parts except a phenolic hydroxy group, has a wide application range and relatively readily secures safety. <P>SOLUTION: The method for removing a phenolic hydroxy group comprises an esterification process for converting a phenolic hydroxy group-containing compound into a trifluoromethanesulfonic acid ester by trifluoromethanesulfonic acid anhydride and then a reduction process for reacting the trifluoromethanesulfonic acid ester obtained by the esterification process with magnesium in the presence of Pd/C catalyst to replace a trifluoromethanesulfonic acid group with hydrogen. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for removing a phenolic hydroxyl group in which a hydroxyl group in a phenol compound is substituted with hydrogen.

  The phenolic hydroxyl group is often expressed as a partial structure of a substance closely related to a living body, such as pharmaceuticals such as morphine, polyphenols contained in plants, and essential oil components such as catechin. In addition, substances having a phenolic hydroxyl group such as bisphenol A and alkylphenol may show endocrine disrupting action as so-called environmental hormones.

  In order to investigate the role of hydroxyl groups in substances having phenolic hydroxyl groups that are closely related to these organisms, it is necessary to compare these phenolic hydroxyl group substances with substances from which hydroxyl groups have been removed. Necessary. In addition, in order to decompose and detoxify environmental hormones, it is important to establish a method for removing phenolic hydroxyl groups by replacing hydroxyl groups in phenolic compounds with hydrogen.

  Conventionally, as a method for removing a phenolic hydroxyl group, a method in which a phenol compound is directly substituted with a strong reducing agent such as lithium aluminum hydride is known (for example, see Non-Patent Document 1).

Severin, T .; et al. Synthesis, 1973, 796

  However, this method has a low yield, and since a strong reducing agent is used, a portion other than the phenolic hydroxyl group may be reduced and cannot be used for general purposes.

  As a method for removing the phenolic hydroxyl group in a better yield than the above method, the phenolic hydroxyl group is converted into a substituent which is easily removed such as tetrazolyl ether (Non-patent Document 2) or isourea (Non-patent Document 3), and then a palladium catalyst There is also known a method of removing by catalytic reduction using.

Hussey, B.J; et al. Tetrahedron, 1982, 38, 3775

Musliner, W.J .; et al. J. Am. Chem. Soc. 1966, 88, 4271

  According to these methods, the phenolic hydroxyl group can be removed with a relatively high yield. However, it is difficult to introduce a leaving group such as tetrazolyl ether or isourea, and there is a problem that the substrate is not versatile.

  Also known are a method of reductively removing phenolic hydroxyl groups after converting them to triflate (Non-patent Document 4) and a method of reductively removing them after converting to tosylate (Non-patent Document 5). .

Vowinkel, E .; et al. Chem. Ber. 1974, 107, 1213

Sebok, P .; et al. J. Org. Chem. 1994, 59, 6318

  However, in these methods, applicable phenolic compounds are limited and cannot be used for general purposes. In addition, it is necessary to use a highly toxic phosphine ligand, which is a problem in ensuring safety.

  The present invention has been made in view of the above-described conventional circumstances, has a high yield, is difficult to affect parts other than phenolic hydroxyl groups, has a wide range of applications, and is relatively easy to ensure safety. Providing a method for removing a phenolic hydroxyl group is a problem to be solved.

  The inventors have already discovered that the phenolic hydroxyl group can be removed by catalytic reduction in a hydrogen atmosphere in the presence of a platinum group element and diethylamine after converting the phenolic hydroxyl group to a sulfonate ester. (See Non-Patent Document 6)

Abstracts of the 123rd Annual Meeting of the Pharmaceutical Society of Japan 2, 91 (2003)

  As a result of further earnest studies, the inventors have found that the above problem can be solved by using magnesium instead of hydrogen gas as a reducing agent, and the present invention has been completed.

  That is, the method for removing a phenolic hydroxyl group of the present invention comprises an esterification step in which a compound having a phenolic hydroxyl group is a sulfonic acid ester, and the sulfonic acid ester is reacted with magnesium in the presence of a platinum group element to form a sulfonic acid group. A reduction step of substituting hydrogen with hydrogen.

  In the method for removing a phenolic hydroxyl group of the present invention, both the esterification step and the reduction step proceed in a high yield. In addition, the reduction process is a relatively mild condition and does not easily affect parts other than the phenolic hydroxyl group, so that the range of applicable substrates is wide. Furthermore, the chemicals used are also relatively toxic and easy to ensure safety. Further, since magnesium is used instead of hydrogen gas, a hydrogen cylinder, a regulator, a flow meter and the like for introducing hydrogen gas are not required, and the handling risk is reduced.

  According to the test results of the inventors, the reduction process is completely inhibited by the addition of tetracyanoquinodimethane (TCNQ), which is a one-electron scavenger, and therefore the chemical reaction in the reduction process is one-electron transfer. It is thought that it progresses by the mechanism that goes through. That is, the white metal element is coordinated to the benzene ring of the sulfonate ester phenol to form a π-Pd complex. As a result, one-electron transfer occurs from magnesium in the benzene ring that has become electron deficient, and an anion radical is formed. Then, it is presumed that the sulfonate anion is eliminated, hydrogen is extracted from the solvent via the phenyl radical, and hydrogenation is completed.

  Alcohol can be used as the reaction solvent in the reduction step. According to the test results of the inventors, the reduction process proceeds rapidly by using alcohol as the reaction solvent. This action is particularly effective when the alcohol is methanol. This is probably because alcohol is the source of hydrogen for the phenyl radical.

  The sulfonic acid ester synthesized in the esterification step is preferably an alkyl sulfonic acid ester. According to the test results of the inventors, when the sulfonic acid ester is an alkyl sulfonic acid ester, the reaction in the reduction step easily proceeds. This is presumed to be because the alkyl group of the alkyl sulfonate ester does not affect the one-electron transfer from magnesium to the benzene ring. In particular, if the sulfonic acid ester is a fluorine-substituted alkyl sulfonic acid ester in which the hydrogen of the alkyl group is fluorine-substituted, such as perfluoroalkane sulfonic acid ester, the elimination of the sulfonic acid group in the reduction step is facilitated. Is preferred.

  Further, the platinum group element used in the reduction step can be palladium. According to the test results of the inventors, when the platinum group element is palladium, the reaction in the reduction process easily proceeds.

  Furthermore, the platinum group element may be used as it is, such as palladium black or platinum black, but may be supported on a carrier such as carbon, silica, or alumina. By carrying it on the carrier, the platinum group element is finely dispersed and the function as a catalyst is enhanced. In addition, recovery of the catalyst after the reaction is facilitated. The inventors have confirmed that if carbon is used as a support, the reaction in the reduction process proceeds very easily.

  Examples 1 to 6 embodying the present invention will be described below.

<Esterification process>
In Examples 1 to 6, as shown in the following formula, various phenol compounds were used as starting materials in the esterification step and esterified with trifluoromethanesulfonic anhydride.

  Specifically, 5 mmol of the phenol derivative shown in Table 1 is first dissolved in 10 ml of toluene, 10 ml of 30% aqueous potassium phosphate solution is added, and 6 mmol of anhydrous trifluoromethanesulfonic acid is added dropwise under ice cooling. After completion of dropping, the temperature is returned to room temperature and stirred for 30 minutes. After confirming the disappearance of the raw materials by thin layer chromatography, the toluene layer was separated, washed sequentially with 10 ml of water and 10 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the corresponding trifluoromethane. A sulfonic acid ester was obtained.

<Reduction process>
Next, as a reduction process, as shown in the following formula, the trifluoromethanesulfonic acid ester obtained by the esterification process was reacted in the presence of a Pd / C catalyst and magnesium.

  That is, 0.5 mmol of trifluoromethanesulfonic acid ester obtained in the esterification step, 0.6 mmol of magnesium metal, 10 mass% of Pd / C on which 10 mass% of Pd is supported with respect to the carbon support (20,569 manufactured by Aldrich) -9) is added to 2 ml of methanol and stirred at room temperature for 24 hours while introducing argon gas. Thereafter, the reaction solution was filtered through a 0.45 μm membrane filter, the solvent was distilled off under reduced pressure, and the residue was extracted by adding 10 ml of ether and 10 ml of water, and after separating the ether layer, 10 ml of water and 10 ml of saturated brine were used. After sequentially washing and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a product in which trifluoromethanesulfonic acid groups were converted to hydrogen. The product yields are shown in Table 2.

  As can be seen from Table 2, in all examples, the phenolic hydroxyl group was replaced with hydrogen by the reduction step. Particularly in Examples 1 to 3, the yield was 88% or more, which was a very high yield. In Example 1, three methoxy groups, which are electron emission groups, are bonded, and it is considered that hydrogen substitution is extremely difficult by the conventional method. Further, as can be seen from Example 6, only the sulfonic acid group is selectively reduced without reducing the naphthalene skeleton in the reduction step. From the above results, it was found that the methods of Examples were extremely versatile as a method for removing phenolic hydroxyl groups. In addition, the isolation yield in Examples 4 to 6 is low because the boiling point of the product is low, and thus the product was also distilled off when the solvent was distilled off under reduced pressure. Was expensive.

  According to the present invention, a compound in which a hydroxyl group in a phenol compound is substituted with hydrogen can be obtained.

Claims (9)

An esterification step in which a compound having a phenolic hydroxyl group is a sulfonic acid ester;
A reduction step of reacting the sulfonic acid ester with magnesium in the presence of a platinum group element to replace the sulfonic acid group with hydrogen, and a method for removing a phenolic hydroxyl group.   The method for removing a phenolic hydroxyl group according to claim 1, wherein the reaction solvent in the reduction step is an alcohol.   The method for removing a phenolic hydroxyl group according to claim 2, wherein the alcohol is methanol.   The method for removing a phenolic hydroxyl group according to any one of claims 1 to 3, wherein the sulfonic acid ester is an alkyl sulfonic acid ester.   The method for removing a phenolic hydroxyl group according to claim 4, wherein the sulfonic acid ester is a fluorine-substituted alkylsulfonic acid ester in which hydrogen of an alkyl group is fluorine-substituted.   6. The method for removing a phenolic hydroxyl group according to claim 5, wherein the sulfonic acid ester is a perfluoroalkanesulfonic acid ester.   The method for removing a phenolic hydroxyl group according to any one of claims 1 to 6, wherein the platinum group element is palladium.   The method for removing a phenolic hydroxyl group according to any one of claims 1 to 7, wherein the platinum group element is supported on a carrier.   The method for removing a phenolic hydroxyl group according to claim 8, wherein the carrier is carbon.