JPH0645594B2 - New method for producing 3-substituted indoles - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 3-substituted indoles utilizing a novel rearrangement reaction. More specifically, the present invention has the general formula (I) (In the formula, X represents hydrogen, an alkyl group, an alkoxy group, a hydroxy group or an aryl group, and R represents an alkyl group, a carboxyalkyl group or an alkoxycarbonylalkyl group), and the ortho-aminostyrene derivative is represented by iodine. General formula (II) characterized by reacting in the presence of silver or copper oxide or acetate (In the formula, X and R have the above-mentioned definitions) and a method for producing a 3-substituted indole.

The 3-substituted indoles obtained by the method of the present invention are a group of substances including a large number of chemical substances useful as a fragrance, a medicine or an intermediate thereof.

Conventional methods for synthesizing 3-substituted indoles are Fisher method utilizing rearrangement of phenylhydrazone, ω
-Bischular (B
The ishler method and the Madelung method are known. As a result of extensive studies on the method for producing the 3-substituted indole, the present inventor has completed a method for producing a 3-substituted indole utilizing a novel rearrangement reaction of which no similar technique is known.

An object of the present invention is to produce 3-substituted indoles from ortho-aminostyrene by utilizing a novel rearrangement reaction. From this, the possibility of application as a new synthetic method for various bioactive indoles is considered.

The starting compound of the method of the present invention has the general formula (I) Ortho-aminostyrene represented by Wherein X is hydrogen or an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and an amyl group, for example, a methoxy group, an ethoxy group, a propoxy group and a butoxy group. Represents an alkoxy group, a hydroxy group, and an aryl group such as a phenyl group, a tolyl group, a xylyl group, a biphenyl group and a naphthyl group. In the formula, R is an alkyl group such as a methyl group, an ethyl group, a butyl group, an isobutyl group, an amyl group and a heptyl group, a carboxyalkyl group such as a carboxymethyl group or a carboxyethyl group, or a methoxycarbonylmethyl group. , An alkoxycarbonylalkyl group such as a methoxycarbonylethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylethyl group, and the like.

The present invention uses silver or copper oxides or acetates, which may be used alone or in the form of a mixture. And, it is preferable to use these compounds in a 1.0 to 3.0 times molar amount, and optimally in a 1.5 times molar amount with respect to the starting compound of the general formula (I).

This method can be performed in a suitable solvent. As the solvent, hydrocarbons, halogenated hydrocarbons, alcohols,
Ethers and other known organic and inorganic solvents such as water are mentioned. However, it is preferable to use a water-containing organic solvent in this reaction.

The preferred water-containing solvent in the method of the present invention is 1,4-
Mention may be made of dioxane and tetrahydrofuran. The amount of water contained in the solvent is 1 to the total amount of the solvent.
30% is preferable.

The iodine used in the process of the present invention is 1.
It is preferably used in a molar amount of 0 to 2.0 times, and 0.8 to 1.0 for silver or copper oxide or acetate.
It is preferable to use it in a 0-fold molar amount.

A wide range of temperatures can be adopted as the reaction temperature in the method of the present invention. That is, the temperature in the range from the solidification temperature of the solvent used to the boiling temperature is possible. However, the reaction can usually proceed at room temperature.

Next, the present invention will be described in more detail with reference to Examples.

Example 1 3-Methylindole β-methyl-ortho-aminostyrene 0.20 g (1.
(52 mmol) was dissolved in a mixture of 5 ml of 1,4-dioxane and 1 ml of water, and 0.50 g of iodine was added while stirring at room temperature.
(1.97 mmol) and silver (I) oxide 0.47 g (2.0
(3 mmol) was added and reacted for 2 hours. The reaction solution was extracted with 20 ml of ether, and after removing insoluble matter, diluted sodium thiosulfate aqueous solution, water and saturated saline solution were added to each
It was washed once with each ml and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.46 g of a yellow oily substance.
This was purified by silica gel column chromatography (hexane) to give 0.10 g (0.76 mmol) of 3-
I got methylindole.

Example 2 0.3-g 3-ethylindole β-ethyl-ortho-aminostyrene (2.
(04 mmol) was dissolved in a mixture of 10 ml of 1,4-dioxane and 1 ml of water, and 0.77 iodine was stirred with stirring at room temperature.
g (3.03 mmol) and 0.75 g (3.
(06 mmol) was added and reacted for 5 hours. The reaction solution was extracted with 25 ml of ether, the insoluble matter was filtered off, and the diluted sodium thiosulfate aqueous solution, water and saturated saline solution were respectively added to 2 times each.
It was washed successively with 0 ml and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain 0.34 g of a red oily substance. This was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 0.12.
g (0.83 mol) of 3-ethylindole was obtained.

Example 3 0.53 g of 3-butylindole β-butyl-orthoaminostyrene (3.1
4 mmol) 10 ml of 1,4-dioxane and 0.5 ml of water
1.04 g of iodine at room temperature
(4.10 mmol) and silver (I) oxide 0.95 g (4.1
(0 mmol) was added and reacted for 3 hours. The reaction solution was extracted with 30 ml of ether, the insoluble matter was filtered off, and the diluted sodium thiosulfate aqueous solution, water and saturated saline solution were added to 20 times each.
It was washed successively with each ml and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.60 g of a brown oily substance.
This was separated and purified by silica gel column chromatography (hexane) to obtain 0.28 g (1.62 mmol) of 3-butylindole.

Example 4 3-isobutylindole 0.50 g of β-isobutyl-o-aminostyrene (2.
86 mmol), 1,4-dioxane 10 ml and water 0.1
0.87 g of iodine (3.
43 mmol) and 0.87 g (3.75 mmol) of silver (I) oxide were added and reacted for 24 hours. The reaction solution was extracted with 25 ml of ether, the insolubles were filtered off, washed successively with 20 ml each of dilute aqueous sodium thiosulfate solution, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.50 g of a red oily substance. This was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 3) to give 0.28 g (1.
(62 mmol) 3-isobutylindole was obtained.

Example 5 3-heptylindole β-heptyl-o-aminostyrene 0.10 g (0.4
6 mmol) was dissolved in a mixture of 5 ml of 1,4-dioxane and 1 ml of water, and 0.17 g of iodine was stirred at room temperature.
(0.67 mmol) and 0.16 g of silver (I) oxide (0.6
(8 mmol) was added and reacted for 3 hours. The reaction solution was extracted with 20 ml of ether, and the insoluble matter was filtered off.
It was washed successively with each ml and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.11 g of a brown oily substance.
This was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 0.051 g.
(0.24 mmol) of 3-heptylindole was obtained.

Example 6 3-heptylindole β-heptyl-o-aminostyrene 0.20 g (0.9
2 mmol) 9.5 ml of 1,4-dioxane and 0.5 of water.
Dissolve it in a mixture with ml, and stir at room temperature with iodine 0.2
5 g (0.98 mmol) and copper (II) oxide 0.17 g
(2.14 mmol) was added, and the mixture was reacted under heating and reflux for 2 hours. After cooling, the mixture was extracted with 25 ml of ether to remove insoluble matter, washed successively with 20 ml each of dilute aqueous sodium thiosulfate solution, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure,
0.29 g of a reddish brown oil was obtained. This was subjected to silica gel column chromatography (hexane: ethyl acetate = 5:
Separation and purification in 1) yielded 0.09 g (0.42 mmol) of 3-heptylindole.

Example 7 3-heptylindole β-heptyl-o-aminostyrene 0.10 g (0.4
6 mmol) was dissolved in a mixture of 5 ml of tetrahydrofuran and 0.5 ml of water, and 0.15 g of iodine was added with stirring at room temperature.
(0.59 mmol) and silver (I) oxide 0.21 g (0.9
1 mmol) was added and the reaction was carried out for 1 hour. The reaction solution was extracted with 15 ml of ether, and the insoluble matter was filtered off.
It was washed successively with each ml and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.11 g of a blackish brown oily substance. This was separated and purified by silica gel column chromatography (hexane-ethyl acetate = 5: 1) to give a 0.1.
04 g (0.18 mmol) of 3-heptylindole was obtained.

Example 8 3-heptylindole [beta] -heptyl-o-aminostyrene 0.20 g (0.9
(2 mmol) 1,4-dioxane (10 ml) and water (0.5 ml)
0.25g iodine dissolved in a mixture of
(0.98 mmol) and 0.53 g (3.17 mmol) of silver oxide were added and reacted for 6 hours. The reaction solution was extracted with 15 ml of ether and filtered to remove insoluble matter, and then 20 ml each of dilute aqueous sodium thiosulfate solution, water and saturated brine
Each of them was washed sequentially and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.26 g of a dark red oily substance. This was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give a 0.1.
08 g (0.37 mmol) of 3-heptylindole was obtained.

Example 9 3- (2-Carboxymethylethyl) indole 0.15 g (0.73 mmol) of β- (2-carboxymethylethyl) -o-aminostyrene was dissolved in 5 ml of 1,4-dioxane and 0.1 ml of water. It was dissolved in the mixture and, while stirring at room temperature, 0.22 g (0.87 mmol) of iodine and 0.22 g (0.95 mmol) of silver (I) oxide were added and reacted for 4 hours. The reaction solution was extracted with 30 ml of ether, the insoluble matter was filtered off, and the solution was washed successively with 20 ml each of dilute aqueous sodium thiosulfate solution, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to 0.1.
5 g of brown oil was obtained. This was separated and purified by silica gel column chromatography (benzene: ethyl acetate = 10: 2) to give 0.070 g (0.34 mmol) of 3-.
(2-Carboxymethylethyl) indole was obtained.

Claims (3)

[Claims] 1. A general formula (I) (In the formula, X represents hydrogen, an alkyl group, an alkoxy group, a hydroxy group or an aryl group, and R represents an alkyl group, a carboxyalkyl group or an alkoxycarbonylalkyl group), and the ortho-aminostyrene derivative is represented by iodine. General formula (II) characterized by reacting in the presence of silver or copper oxide or acetate A method for producing a 3-substituted indole represented by the formula (wherein X and R have the aforementioned definitions). 2. The method according to claim 1, wherein the reaction is carried out in a water-containing solvent. 3. A water-containing solvent which is a mixture of 1,4-dioxane or tetrahydrofuran and water.
The method described in the section.