JP3023197B2 - Method for producing indole - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a novel indole via a pi-allyl complex. Many compounds having an indole ring exist in the natural world as alkaloids, many of which have pharmacological effects, drugs, fragrances,
Widely used as cosmetics and the like. The present invention provides a novel production method for synthesizing these indole compounds themselves and for synthesizing indoles as raw materials for synthesis of alkaloids and the like.

[0002]

2. Description of the Related Art As a method for producing indoles, a Fischer method, a Bishler method, a Madelang method and the like are known. However, these production methods are production methods under severe conditions such as the presence of a strong acid or a strong alkali and long-time heating at a high temperature.Especially, an electron withdrawing group such as an alkoxycarbonyl group or a dialkylsulfamoyl group is used as a substituent. There were problems with the production of indoles.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a novel process for producing a desired indole compound in a high yield and a high purity under extremely mild reaction conditions without being affected by the type of the substituent. Provide a way.

[0004]

That is, the present invention provides a compound represented by the following general formula (1):

Embedded image (1) (wherein, R ¹ is selected from hydrogen, chlorine, bromine, iodine, an alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, a benzyloxy group and a dialkylaminosulfamoyl group. R ² represents one selected from hydrogen, an alkyl group having 1 to 4 carbon atoms, an aryl group, and a heteroaromatic ring)
An aminophenylethanol derivative and a compound of the general formula (2)

Embedded image (2) wherein R ³ represents an alkyl group, R ⁴ represents one selected from an allyl group, a methallyl group and a crotyl group, and a ruthenium catalyst or General formula (3) characterized by reacting in the presence of a palladium catalyst

Embedded image (3) a method for producing an indole represented by the formula (wherein R ¹ and R ² are the same as described above):

[0005] In addition, the general formula (1)

Embedded image (1) (wherein, R ¹ is selected from hydrogen, chlorine, bromine, iodine, an alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, a benzyloxy group and a dialkylaminosulfamoyl group. R ² represents one selected from hydrogen, an alkyl group having 1 to 4 carbon atoms, an aryl group, and a heteroaromatic ring)
An aminophenylethanol derivative and a compound of the general formula (4)

Embedded image (4) wherein R ⁵ represents one selected from an allyl group, a methallyl group and a crotyl group, and reacted with an allyl chloroformate represented by the general formula (5):

Embedded image (5) (wherein R ¹ and R ⁵ are the same as described above), which is heated and stirred in a solvent in the presence of a ruthenium catalyst or a palladium catalyst; 3)

Embedded image (3) (wherein R ¹ and R ² are the same as described above).

The compounds which can be produced by the present invention include hydrogen, chlorine, bromine, iodine, an alkoxy group having 1 to 4 carbon atoms, a carbon atom at one or more positions at positions 4, 5, 6, and 7 of the indole skeleton. Having a substituent selected from an alkoxycarbonyl group, a benzyloxy group and a dialkylaminosulfamoyl group of the formulas 2 to 4, hydrogen at the 2-position of the indole skeleton, an alkyl group having 1 to 4 carbon atoms, an aryl group and a heterocyclic ring; Indoles having one substituent selected from the formula aromatic rings. As the heterocyclic aromatic ring, for example,
Examples thereof include a furan ring, a pyridine ring, and a quinoline ring.

The compound as a starting material of the present invention is a compound having hydrogen, chlorine, bromine, iodine or an alkoxy group having 1 to 4 carbon atoms at one or more positions at positions 3, 4, 5, and 6 of a phenyl group. And a 2-aminophenethyl alcohol derivative having a substituent selected from an alkoxycarbonyl group having 1 to 4 carbon atoms, a benzyloxy group and a dialkylaminosulfamoyl group. The carbon at the α-position of phenethyl alcohol may be substituted with one selected from an alkyl group having 1 to 4 carbon atoms, an aryl group, and a heterocyclic aromatic ring.

[0008] In the method for producing a compound as a starting material of the present invention, an aldehyde compound is added to an o-nitrotoluene derivative to obtain an o-nitrophenethyl alcohol derivative. A phenethyl alcohol derivative can be produced.

The ruthenium catalyst which can be used in the present invention includes dihydridotetrakis (triphenylphosphine)
Ruthenium, dichlorotris (triphenylphosphine) ruthenium, ruthenium chloride and the like can be mentioned. Examples of the palladium catalyst that can be used in the present invention include palladium acetate, tetrakistriphenylphosphine palladium, palladium chloride, bis (dibenzylideneacetone) palladium, and the like. The amount of the catalyst used is in the range of 1/500 to 1/2 mol of the starting material, preferably in the range of 1/20 to 1/5 mol.

The allylic carbonate and allyl chloroformate used in the present invention can be obtained from known literatures (J. Tsuji et. Al., Tetrahedron Lett., 25 , 2791 (198)
It can be easily manufactured by the method described in 4)). The amount of the allyl carbonate and allyl chloroformate used is preferably an excess molar amount based on the starting materials.

Specific examples of the solvent which can be used in the method of the present invention include aliphatic nitriles such as acetonitrile, propionitrile and butyronitrile, and aromatic hydrocarbons such as benzene and toluene.

According to one embodiment of the present invention, a starting material, a catalyst, a solvent, and an allyl carbonate are placed in a pressure vessel, and the atmosphere in the system is replaced with an inert gas such as nitrogen or argon. The reaction is carried out in a temperature range of 100 ° C. for several hours to several tens hours. The end point of the reaction is checked by gas chromatography or the like. During the reaction, part of the catalyst is reduced to metallic palladium or metallic ruthenium, and precipitation is observed on the vessel wall. After filtering the reaction solution, the solvent is removed under reduced pressure, and the residue is purified by column chromatography or the like.
The target product of high purity can be easily obtained in high yield.

[0013]

The operation of the present invention will be described as follows. First, the allyl carbonate alkyl ester reacts with a palladium catalyst or a ruthenium catalyst to decarboxylate to form a pi-allyl complex. This complex undergoes an alcohol exchange reaction with an _o- aminophenethyl alcohol derivative to form an _o- aminophenethyl alcohol.
Generating a metal complex of Le derivative. Further, the complex is decomposed while spontaneously causing a dehydrogenation reaction, and at the same time, an oxidation reaction occurs to produce a carbonyl compound. Further, it is considered that the dehydration cyclization and transfer reaction proceed automatically, and finally an indole compound is formed.

Embedded image

Hereinafter, the present invention will be described more specifically with reference to examples.

EXAMPLE 1 1.97 g (1.7 m) of dihydridotetrakistriphenylphosphine ruthenium was placed in a pressure-resistant container purged with argon.
mol), dry toluene 120 ml, α-phenyl-2-
0.72 g of aminophenethyl alcohol (3.4 mmo
l) and 0.79 g (6.8 mmol) of methyl allyl carbonate
Was added and heated and stirred at 100 ° C. for 24 hours. After the completion of the reaction, insolubles were filtered, and toluene as a solvent was removed under reduced pressure. The residue was subjected to column chromatography (silica gel-
Benzene) to give 0.54 g (yield 82%) of 2-phenylindole white crystals. The melting point is 1
87-188 ° C.

Example 2 Under a nitrogen atmosphere, 2.13 g (0.01 mol) of 2-aminophenethyl alcohol was dissolved in 20 ml of dry ether containing 1.58 g (0.01 mol) of dry pyridine in a 200 ml three-necked flask. Cooled to ° C. While maintaining the same temperature, 20 ml of a dry ether solution containing 1.20 g (0.01 mol) of allyl chloroformate was added dropwise. After dropping,
After stirring at room temperature for 24 hours, the reaction solution was neutralized by adding dilute hydrochloric acid. After extraction with ether, the ether layer was washed with saturated saline and dried to remove the ether. The obtained residue was separated and purified by silica gel column chromatography (chloroform-methanol, 50: 1) to obtain 2.4 g of white crystals of allyl- (2-aminophenyl) -1-phenylethyl carbonate (81% yield). Obtained. The melting point was 121 to 122 ° C., and the results of infrared absorption spectrum, nuclear magnetic resonance analysis, mass spectrometry, and the like confirmed that there was no difference in the intended product. 1.97 g of dihydridotetrakistriphenylphosphine ruthenium in a pressure vessel replaced with argon
(1.7 mmol) and 1.00 g (3.4 mmol) of the above carbonate compound dissolved in 140 ml of dry benzene, and the mixture was heated and stirred at 100 ° C. for 24 hours. The treatment after the reaction was performed in the same manner as in Example 1 to obtain 0.43 g (yield: 66%) of the target white crystal of 2-phenylindole.

Example 3 Allyl-2- (2-amino-4-bromophenyl) -1
As a result of reacting in the same manner as in Example 2 using -phenylethyl carbonate as a starting material, white crystals of 6-bromo-2-phenylindole were obtained in a yield of 60%. The melting point is
182-183 ° C.

[0017] As Example 4 starting material, 2- (2-amino-4-dimethylamino-sulfamoylphenyl) -1-using phenylethanol <br/>, it was reacted in the same manner as in Example 1, 6 Light yellow crystals of-(dimethylaminosulfamoyl) 2-phenylindole were obtained in a yield of 62%. The melting point is 170-1
71 ° C.

Example 5 Using α-phenyl-2- aminophenethyl alcohol as a starting material, a palladium acetate catalyst and an acetonitrile solvent were used, and the other reaction conditions were the same as in Example 1. As a result, 2-phenylindole was obtained. Obtained in a yield of 23%.

[0019]

According to the present invention, an indole compound having an electron-withdrawing group such as an alkoxycarbonyl group or a dialkylsulfamoyl group as a substituent, which has been conventionally difficult to produce, can be synthesized under mild conditions with good yield. It has become possible.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 209/08 B01J 27/10 B01J 31/24 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (1) (1) (wherein, R ¹ is selected from hydrogen, chlorine, bromine, iodine, an alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, a benzyloxy group and a dialkylaminosulfamoyl group. R ² represents one selected from hydrogen, an alkyl group having 1 to 4 carbon atoms, an aryl group, and a heteroaromatic ring)
An aminophenylethanol derivative and a compound represented by the general formula (2): (2) wherein R ³ represents an alkyl group, R ⁴ represents one selected from an allyl group, a methallyl group and a crotyl group, and a ruthenium catalyst or General formula (3) characterized in that the reaction is carried out in the presence of a palladium catalyst. (3) A method for producing an indole represented by the formula (wherein R ¹ and R ² are the same as described above). 2. A compound of the general formula (1) (1) (wherein, R ¹ is selected from hydrogen, chlorine, bromine, iodine, an alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, a benzyloxy group and a dialkylaminosulfamoyl group. R ² represents one selected from hydrogen, an alkyl group having 1 to 4 carbon atoms, an aryl group, and a heteroaromatic ring)
An aminophenylethanol derivative and a compound represented by the general formula (4): (4) wherein R ⁵ represents one selected from an allyl group, a methallyl group and a crotyl group, and reacted with an allyl ester of chloroformate represented by the general formula (5): (5) (wherein R ¹ and R ⁵ are the same as described above), which is heated and stirred in a solvent in the presence of a ruthenium catalyst or a palladium catalyst; 3) (3) A method for producing an indole represented by the formula (wherein R ¹ and R ² are the same as described above).