JP2013184917A - Method for manufacturing indole - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method for manufacturing indole derivatives.SOLUTION: A method for manufacturing an indole derivative expressed by formula (3) includes reacting an indole expressed by formula (1), a carbonyl compound expressed by (2) and a nucleophilic donor. In the formulas, Ris a hydrogen atom, an aliphatic group, an aryl group, a heteroaryl group, an arylalkyl group, an alkylaryl group, or a trialkylsilyl group; Ris an aliphatic group, an aryl group, a heteroaryl group, an arylalkyl group, an alkylaryl group or a trialkylsilyl group; Ris a monovalent group except a hydrogen atom; Rand Rmay each independently be a hydrogen atom, or an alkyl group optionally having a substituent, an aryl group or a heteroaryl group which may be bonded to each other to form a ring; X is a monovalent group derived from nucleophilic species; l is 0 or 1; m is an integer of 0-4; and when m is 2-4, a plurality of R's are mutually the same as or different from each other.

Description

  The present invention relates to a method for producing an indole derivative.

Since indole derivatives have a heterocyclic skeleton, they are important as intermediates for pharmaceuticals, various chemical products, highly functional materials and the like, and are very important compounds.
The indole used as the raw material can be given new physical properties by, for example, substituting one or more hydrogen atoms with various substituents, and has a desired function for the purpose as described above. Thus, designing the structure of indole derivatives obtained from indoles has been studied.

Of the indole derivatives, for alkyl indoles in which a hydrogen atom bonded to a carbon atom is substituted with an alkyl group, various methods for alkylating mainly the 3-position of indoles have been studied.
For example, Non-Patent Document 1 discloses a method for alkylating the 3-position of indoles by reacting the indoles with an alkene while heating by irradiating microwaves in the presence of a gold catalyst.
Non-Patent Document 2 discloses a method of alkylating the 3-position of indoles by reacting the indoles with an alkene at a high pressure of 50 psi in the presence of a platinum chloride catalyst.
Further, in Non-Patent Documents 3 and 4, there is a method of alkylating the 3-position of indoles by reacting a carbonyl compound, indoles and hydrosilane using a Brönsted acid in a stoichiometric amount or more. It is disclosed.
Non-Patent Document 5 discloses a method of alkylating the 3-position or 2-position of indoles by reacting an alkyne, an indole and a nucleophilic donor in the presence of an indium catalyst. Yes.

Ming-Zhong Wang et. al. Chem. Eur. J. et al. , 14, 8353-8364 (2008) Zhibin Zhang et. al. Chem. Commun. 3717-3719 (2006). Anu Mahadevan et. al. , Tetrahedron Lett. , 44, 4589-4591 (2003) John R. Rizzo et. al. , Tetrahedron Lett. , 49, 6749-6751 (2008) Teruhisa Tsuchimoto et. al. Org. Lett. , 13, 912-915 (2011)

However, the method described in Non-Patent Document 1 has a problem in that a special apparatus is required to irradiate microwaves. In addition, the reaction temperature is high, and by reacting under such severe conditions, a large amount of by-products such as a part of the alkyl group undergoes a transfer reaction or reacts at a site other than the target of the alkene. Therefore, there is a problem that the yield of the desired target product is lowered. Furthermore, in order to obtain the target product with a relatively good yield, the alkene that can be used has a limited structure such as a structure having an aromatic skeleton other than the terminal, and the usable raw materials are limited. There was a problem that it was.
In addition, the method described in Non-Patent Document 2 has a problem that a special apparatus is required because the reaction is performed under high pressure. Also, the reaction temperature is high, and by reacting under such severe conditions, a large amount of by-products such as a part of the alkyl group undergoes a transfer reaction, resulting in a decrease in the yield of the desired target product. There was a problem of doing.
Further, in the methods described in Non-Patent Documents 3 and 4, since it is necessary to use Bronsted acid in a stoichiometric amount or more with respect to the carbonyl compound, it is necessary to use a large amount of base for the post-treatment of the reaction solution. Furthermore, depending on the combination of raw materials, there is a problem that the yield of a desired target product is low and usable raw materials may be limited.
In addition, the method described in Non-Patent Document 5 is excellent in that various alkylated indole derivatives can be obtained in a yield of 70% or more, but by using alkyne as a source of alkyl groups. For example, there is a problem that there exists an alkyl group of a type that cannot be introduced onto the indole ring skeleton, such as a cyclic alkyl group or a primary alkyl group.
Therefore, there is no need for special equipment, there are few restrictions on the raw materials used, simple post-treatment, and various alkyl groups can be introduced onto the indole ring skeleton. Development was desired.

  This invention is made | formed in view of the said situation, and makes it a subject to provide the novel manufacturing method of an indole derivative.

To solve the above problem,
The present invention is characterized by reacting an indole represented by the following general formula (1), a carbonyl compound represented by the following general formula (2), and a nucleophilic donor, represented by the following general formula ( A method for producing an indole derivative represented by 3) is provided.

（式中、Ｒ^１は水素原子、脂肪族基、アリール基、ヘテロアリール基、アリールアルキル基、アルキルアリール基又はトリアルキルシリル基であり；Ｒ^２は脂肪族基、アリール基、ヘテロアリール基、アリールアルキル基、アルキルアリール基又はトリアルキルシリル基であり；Ｒ^３は水素原子以外の一価の基であり；Ｒ^４及びＲ^５はそれぞれ独立に水素原子、又は置換基を有していてもよいアルキル基、アリール基若しくはヘテロアリール基であり、相互に結合して環を形成していてもよく；Ｘは求核種由来の一価の基であり；ｌは０又は１であり；ｍは０〜４の整数であり、ｍが２〜４である場合には、複数のＲ^３は互いに同一でも異なっていてもよい。）

Wherein R ¹ is a hydrogen atom, aliphatic group, aryl group, heteroaryl group, arylalkyl group, alkylaryl group or trialkylsilyl group; R ² is an aliphatic group, aryl group, heteroaryl group, An arylalkyl group, an alkylaryl group or a trialkylsilyl group; R ³ is a monovalent group other than a hydrogen atom; and R ⁴ and R ⁵ each independently have a hydrogen atom or a substituent. A good alkyl group, aryl group or heteroaryl group, which may be bonded to each other to form a ring; X is a monovalent group derived from a nucleophilic species; l is 0 or 1; When it is an integer of 0 to 4 and m is 2 to 4, a plurality of R ³ may be the same as or different from each other.)

In the method for producing an indole derivative of the present invention, R ¹ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heteroaryl group having 3 to 11 carbon atoms. Is preferred.
In the method for producing an indole derivative of the present invention, R ² is preferably an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heteroaryl group having 3 to 11 carbon atoms.
In the method for producing an indole derivative of the present invention, R ⁴ and R ⁵ are each independently a hydrogen atom or an optionally substituted alkyl group having 1 to 10 carbon atoms or 6 to 12 carbon atoms. It is preferably an aryl group or a heteroaryl group having 3 to 11 carbon atoms.
In the method for producing an indole derivative of the present invention, X is preferably a hydrogen atom, a cyano group, an aryl group, or a heteroaryl group.
In the method for producing an indole derivative of the present invention, it is further preferable to carry out the reaction using a Lewis acid catalyst.
In the method for producing an indole derivative of the present invention, the Lewis acid catalyst is preferably a metal sulfonate or a metal sulfonimide.

  According to the present invention, a novel method for producing an indole derivative is provided.

The method for producing an indole derivative of the present invention comprises an indole represented by the following general formula (1) (hereinafter abbreviated as “compound (1)”) and a carbonyl compound represented by the following general formula (2) ( The indole derivative represented by the following general formula (3) (hereinafter abbreviated as “compound (3)”) is characterized by reacting a nucleophilic donor with the compound (hereinafter abbreviated as “compound (2)”). )) Manufacturing method.
The present invention provides a substituted alkyl group in which an alkyl group or one or more hydrogen atoms thereof are substituted with a substituent at the 2-position or 3-position of an indole (hereinafter sometimes abbreviated as “alkyl group etc.”). By selectively introducing it, an indole derivative is produced.

（式中、Ｒ^１は水素原子、脂肪族基、アリール基、ヘテロアリール基、アリールアルキル基、アルキルアリール基又はトリアルキルシリル基であり；Ｒ^２は脂肪族基、アリール基、ヘテロアリール基、アリールアルキル基、アルキルアリール基又はトリアルキルシリル基であり；Ｒ^３は水素原子以外の一価の基であり；Ｒ^４及びＲ^５はそれぞれ独立に水素原子、又は置換基を有していてもよいアルキル基、アリール基若しくはヘテロアリール基であり、相互に結合して環を形成していてもよく；Ｘは求核種由来の一価の基であり；ｌは０又は１であり；ｍは０〜４の整数であり、ｍが２〜４である場合には、複数のＲ^３は互いに同一でも異なっていてもよい。）

Wherein R ¹ is a hydrogen atom, aliphatic group, aryl group, heteroaryl group, arylalkyl group, alkylaryl group or trialkylsilyl group; R ² is an aliphatic group, aryl group, heteroaryl group, An arylalkyl group, an alkylaryl group or a trialkylsilyl group; R ³ is a monovalent group other than a hydrogen atom; and R ⁴ and R ⁵ each independently have a hydrogen atom or a substituent. A good alkyl group, aryl group or heteroaryl group, which may be bonded to each other to form a ring; X is a monovalent group derived from a nucleophilic species; l is 0 or 1; When it is an integer of 0 to 4 and m is 2 to 4, a plurality of R ³ may be the same as or different from each other.)

<Compound (1)>
In the compound (1), R ¹ is a hydrogen atom, an aliphatic group, an aryl group, a heteroaryl group, an arylalkyl group, an alkylaryl group or a trialkylsilyl group.
The aliphatic group for R ¹ may be either a saturated aliphatic group or an unsaturated aliphatic group. Further, the aliphatic group in R ¹ may be any of linear, branched and cyclic (aliphatic cyclic group), and is preferably linear or branched. The aliphatic group for ^{R 1} preferably has a carbon number 1 to 30, and more preferably 1 to 20.

The linear or branched saturated aliphatic group (alkyl group) in the aliphatic group for R ¹ is preferably an alkyl group having 1 to 10 carbon atoms, specifically, a methyl group, an ethyl group, n- Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 2,2-dimethyl Pentyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,3-dimethylpentyl group, 3-ethylpentyl group, 2,2,3-trimethylbutyl Examples include a til group, an n-octyl group, an isooctyl group, a nonyl group, and a decyl group. Of these, an alkyl group having 1 to 6 carbon atoms is more preferable.

The cyclic alkyl group (cycloalkyl group) in the aliphatic group of R ¹ has 3 or more carbon atoms, and may be either a monocyclic structure or a polycyclic structure. More specifically, a cyclopropyl group, a cyclobutyl group And cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, norbornyl group, isobornyl group, 1-adamantyl group, 2-adamantyl group and tricyclodecyl group.
The cyclic alkyl group preferably has 3 to 10 carbon atoms, and more preferably 5 to 10 carbon atoms.

The alkyl group is a mixture of a linear and / or branched chain structure such as a cyclopentylmethyl group, 1-cyclopentylethyl group, cyclohexylmethyl group, and 1-cyclohexylethyl group, and a cyclic structure. It may be what you did. Here, examples of the chain structure and the cyclic structure include the alkyl group or a group obtained by removing one or more hydrogen atoms from the alkyl group.
Such an alkyl group in which a chain structure and a cyclic structure are mixed preferably has 4 to 10 carbon atoms.

As the unsaturated aliphatic group in the aliphatic group for R ^{1, in} the alkyl group, one or more single bonds (C—C) between carbon atoms are double bonds (C═C) or triple bonds (C≡ The thing substituted by C) can be illustrated, The number and position of these unsaturated bonds (double bond and triple bond) are not specifically limited, You may have both a double bond and a triple bond.

In the unsaturated aliphatic group represented by R ¹ , the bond between the carbon atom bonded to the 1-position nitrogen atom constituting the indole ring skeleton and the carbon atom adjacent to the carbon atom is not an unsaturated bond. It is preferable that the unsaturated bond between carbon atoms is away from the carbon atom bonded to the nitrogen atom, and the smaller the number of unsaturated bonds, the better.

The unsaturated aliphatic group in the aliphatic group for R ¹ is preferably a linear, branched or cyclic alkenyl group, or a linear, branched or cyclic alkynyl group.

The aryl group in R ¹ may be either a monocyclic structure or a polycyclic structure, but is preferably a monocyclic structure. The aryl group preferably has 6 to 12 carbon atoms, and more preferably a phenyl group.

Examples of the arylalkyl group in R ¹ include a monovalent group in which the aryl group is bonded to an alkylene group, and the alkylene group is a group obtained by removing one hydrogen atom from the alkyl group in the aliphatic group of R ^1. Can be illustrated. The arylalkyl group preferably has 7 to 15 carbon atoms.

The alkylaryl group for R ^1, one hydrogen atom of the aryl group can be exemplified monovalent group substituted with an alkyl group, as the alkyl group, the same alkyl group in the aliphatic group R ¹ The thing can be illustrated. The alkylaryl group preferably has 7 to 15 carbon atoms.

The heteroaryl groups in R ^1, of the aryl group in R ^1, one or more of the carbon atoms constituting the aromatic ring backbone is replaced with a heteroatom, and group having aromaticity, and the annular Examples of the unsaturated aliphatic group include a group in which one or more carbon atoms constituting the ring skeleton are substituted with a heteroatom and have aromaticity. Here, examples of the hetero atom include an oxygen atom, a sulfur atom, and a nitrogen atom. The number of carbon atoms substituted with a heteroatom is not particularly limited, but is preferably 1 to 2.
The heteroaryl group in R ¹ preferably has 3 to 11 carbon atoms.

The alkyl groups in the trialkylsilyl group in R ^1, may be exemplified the same as the alkyl group in the aliphatic group R ^1, to all be the same, all or different, only two have the same There may be.
The trialkylsilyl group in R ¹ is preferably a trimethylsilyl group, a triethylsilyl group or a triisopropylsilyl group.

Among the above, R ¹ is preferably a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heteroaryl group having 3 to 11 carbon atoms. More preferably, it is a 1-6 alkyl group, and it is especially preferable that they are a hydrogen atom or a C1-C3 alkyl group.

In the compound (1), R ² is an aliphatic group, aryl group, heteroaryl group, arylalkyl group, alkylaryl group or trialkylsilyl group, and is the same as R ¹ except that it does not become a hydrogen atom. It is.

When R ² is an unsaturated aliphatic group, the unsaturated aliphatic group is bonded to a carbon atom that is a bonding site to the indole ring skeleton, that is, a carbon atom at the 2nd or 3rd position constituting the indole ring skeleton. The bond between the carbon atom and the carbon atom adjacent to the carbon atom is preferably not an unsaturated bond, and the unsaturated bond between the carbon atoms is bonded to the carbon atom at the 2nd or 3rd position. The number of unsaturated bonds is preferably as small as possible.

R ² is preferably an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heteroaryl group having 3 to 11 carbon atoms, and is an alkyl group having 1 to 6 carbon atoms or a phenyl group. More preferably, it is particularly preferably an alkyl group having 1 to 3 carbon atoms or a phenyl group.

In the compound (1), R ³ is a monovalent group other than a hydrogen atom.
The monovalent group in R ³ may be a single atom or a group composed of a plurality of atoms.
Examples of the monovalent group of R ³ include the same aliphatic groups, aryl groups, heteroaryl groups, arylalkyl groups, alkylaryl groups, and trialkylsilyl groups as those of R ¹ and R ² . In addition to these, alkoxy groups, alkenyloxy groups, aryloxy groups, arylalkyloxy groups, alkylaryloxy groups, hydroxyl groups, and halogen atoms can be exemplified.

The alkoxy group in R ³ may be any of linear, branched or cyclic, and examples thereof include a group in which the linear, branched or cyclic alkyl group in R ¹ and R ² is bonded to an oxygen atom. . Of these, an alkoxy group having 1 to 6 carbon atoms is particularly preferable.
Similarly, the alkenyloxy group in R ³ may be any of linear, branched and cyclic, and a group in which the linear, branched or cyclic alkenyl group in R ¹ and R ² is bonded to an oxygen atom. Can be illustrated.
Examples of the aryloxy group, arylalkyloxy group, and alkylaryloxy group in R ³ include groups in which the aryl group, arylalkyl group, and alkylaryl group in R ¹ and R ² are each bonded to an oxygen atom.
Examples of the halogen atom in R ³ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The monovalent group illustrated here may have a substituent. Here, having a substituent means that one or more carbon atoms constituting the monovalent group are substituted with a group other than a carbon atom, or one or more hydrogen atoms constituting the monovalent group. It means that the atom is substituted with a group other than a hydrogen atom. And both the hydrogen atom and the carbon atom may be substituted with a substituent. Here, the number of substituents is not particularly limited, and when there are a plurality of substituents, all of these substituents may be the same, or all may be different, or only some may be the same.
Examples of the substituent for substituting the carbon atom include heteroatoms such as oxygen atom, nitrogen atom, sulfur atom and boron atom.
As a substituent which substitutes a hydrogen atom, a C1-C3 alkyl group or an alkoxy group can be illustrated as a preferable thing.

In the compound (1), l is 0 or 1.
When l is 1, R ² is bonded to the 2nd or 3rd carbon atom constituting the indole ring skeleton.

In the compound (1), m is an integer of 0 to 4, preferably 0 to 2, and more preferably 0 or 1.
when m is 2 to 4, a plurality of R ³ may be the same or different from each other. That is, all R ³ may be the same, only some R ³ may be different from each other, or all R ³ may be different from each other.
When m is 1 to 4, R ³ is bonded to any carbon atom at positions 4 to 7 constituting the indole ring skeleton. The bonding position is not particularly limited. For example, when m is 1, R ³ is preferably bonded to the 5-position carbon atom constituting the indole ring skeleton.

Particularly preferable compounds (1) include, for example, those in which l is 0, or those in which l is 1 and R ² is bonded to the carbon atom at the 2-position constituting the indole ring skeleton. Examples are those represented by formulas (1101) to (1112) and (1201) to (1212).

  In particular, the compound (1) represented by the formulas (1110) to (1112) and (1210) to (1212) has an organic boron moiety and is useful as a carbon-carbon bond forming reaction (Suzuki-Miyaura coupling ( It is suitable as a raw material for Suzuki-Miyaura coupling) and is extremely useful in industry.

  Although the usage-amount of a compound (1) should just adjust suitably according to the kind etc. of a compound (2), it is preferable that it is preferable normally 1-5 times mole amount of a compound (2), 1-4 times A molar amount is more preferable, and a molar amount of 1 to 3.5 times is particularly preferable.

<Compound (2)>
In the compound (2), R ⁴ and R ⁵ are each independently a hydrogen atom or an optionally substituted alkyl group, aryl group or heteroaryl group, which are bonded to each other to form R ⁴ , R ⁵ and a carbon atom to which R ⁴ and R ⁵ are respectively bonded may form a ring.

The alkyl group in R ⁴ and R ⁵ may be linear, branched or cyclic, and preferably has 1 to 10 carbon atoms.
Examples of the linear or branched alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, and n-pentyl group. , Isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 2,2-dimethylpentyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,3-dimethylpentyl group, 3 Examples include -ethylpentyl group, 2,2,3-trimethylbutyl group, n-octyl group, isooctyl group, nonyl group, and decyl group.
The cyclic alkyl group has 3 or more carbon atoms, and may be either a monocyclic structure or a polycyclic structure, and preferably has 3 to 10 carbon atoms, and more specifically, a cyclopropyl group or cyclobutyl group. Group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, norbornyl group, isobornyl group, 1-adamantyl group, 2-adamantyl group and tricyclodecyl group.
The alkyl group is a mixture of a linear and / or branched chain structure such as a cyclopentylmethyl group, 1-cyclopentylethyl group, cyclohexylmethyl group, and 1-cyclohexylethyl group, and a cyclic structure. It may be what you did. Here, examples of the chain structure and the cyclic structure include the alkyl group in R ⁴ and R ⁵ or a group in which one or more hydrogen atoms are removed from the alkyl group.
Such an alkyl group in which a chain structure and a cyclic structure are mixed preferably has 4 to 10 carbon atoms.

The aryl group in R ⁴ and R ⁵ may be either a monocyclic structure or a polycyclic structure, but preferably has 6 to 12 carbon atoms, preferably a monocyclic structure, a phenyl group, 4-methyl A phenyl group, a 3-methylphenyl group, and a 2-methylphenyl group are particularly preferable.

The heteroaryl group for R ⁴ and R ^5, one of the aryl group for R ⁴ and R ^5, one or more of the carbon atoms constituting the aromatic ring structure is substituted with a hetero atom, and having aromatic character Examples of the group and the cyclic unsaturated aliphatic group in the compound (1) include a group in which one or more carbon atoms constituting the ring skeleton are substituted with a heteroatom and have aromaticity. Here, examples of the hetero atom include an oxygen atom, a sulfur atom, and a nitrogen atom. The number of carbon atoms substituted with a heteroatom is not particularly limited, but is preferably 1 to 2.

The heteroaryl group in R ⁴ and R ⁵ preferably has a total number of carbon atoms and hetero atoms constituting the aromatic ring skeleton of 6 to 12. The heteroaryl group preferably has 3 to 11 carbon atoms.
Preferred examples of the heteroaryl group for R ⁴ and R ⁵ include a 2-thienyl group and a 3-thienyl group.

When R ⁴ and R ⁵ are bonded to each other to form a ring, the ring may be either a monocyclic structure or a polycyclic structure.
The number of carbon atoms in the ring (the total number of carbon atoms of R ^4, the number of carbon atoms of R ⁵ , and the number of carbon atoms to which R ⁴ and R ⁵ are bonded together (ie, “1”)) is 4 to 15 It is preferable that it is, and it is more preferable that it is 5-12.

The alkyl group, aryl group or heteroaryl group in R ⁴ and R ⁵ may have a substituent. Here, “the alkyl group, aryl group, heteroaryl group has a substituent” means that one or more hydrogen atoms constituting the alkyl group, aryl group, heteroaryl group are substituted with a group other than a hydrogen atom. Or one or more carbon atoms constituting an alkyl group, an aryl group, or a heteroaryl group is substituted with a group other than a carbon atom. And both the hydrogen atom and the carbon atom may be substituted with a substituent.

Examples of the substituent that substitutes a hydrogen atom in R ⁴ and R ⁵ include an alkyl group, an aryl group, an alkylcarbonyloxy group, a trialkylsilyloxy group, a phthalimidoyl group, a hydroxyl group, a cyano group, and a halogen atom.
Examples of the alkyl group and aryl group as substituents for R ⁴ and R ⁵ are the same as the alkyl group and aryl group for R ¹ and R ² .
Examples of the alkylcarbonyloxy group as a substituent in R ⁴ and R ⁵ include a monovalent group in which the alkyl group in R ¹ and R ² is bonded to the carbonyloxy group.
Examples of the trialkylsilyloxy group as a substituent in R ⁴ and R ⁵ include a monovalent group in which the trialkylsilyl group in R ¹ and R ² is bonded to an oxygen atom, and a trimethylsilyloxy group is preferable. A triethylsilyloxy group or a triisopropylsilyloxy group can be exemplified.
Examples of the halogen atom as a substituent in R ⁴ and R ⁵ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The number of substituents substituting for hydrogen atoms is not particularly limited, and can be arbitrarily adjusted according to the types of R ⁴ and R ⁵ , and may be 1 or 2 or more, and all hydrogen atoms may be substituted with substituents. It may be. However, it is usually preferably 1 to 4.
Further, the position of the hydrogen atom substituted by the substituent is not particularly limited, but usually the carbon atom to which the hydrogen atom is bonded is the carbon atom to which R ⁴ and R ⁵ are bonded (the carbon of the carbonyl group). The more distant from the atom), the better.

Examples of the substituent for substituting the carbon atom in R ⁴ and R ⁵ include a carbonyl group (—C (═O) —), a carbonyloxy group (—C (═O) —O—), an amide group (—NH—C). (= O)-) and heteroatoms can be exemplified. Examples of the hetero atom include an oxygen atom, a nitrogen atom, a sulfur atom, a boron atom, and a silicon atom. Of these substituents, the asymmetrical substituents such as a carbonyloxy group and an amide group are not limited in the direction of substitution and may be any. For example, in the case of a carbonyloxy group, a carbon atom of the carbonyl group (or an oxygen atom bonded to the carbonyl group) may be bonded to any of two groups (atoms) adjacent at the substitution position.

The number of substituents for substituting the carbon atom is not particularly limited and can be arbitrarily adjusted according to the types of R ⁴ and R ⁵ , and may be 1 or 2 or more. However, it is usually preferably 1 to 4.
Further, the position of the carbon atom substituted with the substituent is not particularly limited, but usually it is preferably not a carbon atom adjacent to the carbon atom to which R ⁴ and R ⁵ are bonded (the carbon atom of the carbonyl group). .

When the alkyl group, aryl group, and heteroaryl group in R ⁴ and R ⁵ have a substituent, the carbon number of these groups is preferably in the above numerical range including the substituent.
Moreover, when there are a plurality of substituents, these substituents may all be the same, may be all different, or only part of them may be the same.

R ⁴ and R ⁵ are each independently a hydrogen atom, or an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heteroaryl having 3 to 11 carbon atoms. It is preferably a group.

<Nucleophilic donor>
The nucleophilic species donor is a donor that provides a nucleophilic species in the reaction system, and the nucleophilic species undergoes a nucleophilic addition reaction with respect to the intermediate during the reaction, whereby the compound (3) is generated. X in the compound (3) is a monovalent group derived from a nucleophilic species.
As the nucleophilic donor, any known nucleophilic donor can be used as long as it can donate such a nucleophilic species. Preferable examples include a hydride donor, a cyano ion donor, an alkenylstannane, a compound having an allyl group (2-propenyl group), a compound having a vinyl group (ethenyl group), an aryl compound or a heteroaryl compound. Can be illustrated. For example, hydride (H ⁻ ) is donated as a nucleophilic species from a hydride donor, and X in compound (3) is a hydrogen atom. Similarly, X in compound (3) is a compound having a cyano group when the nucleophilic donor is a cyano ion donor, an alkenyl group or an allyl group (2-propenyl group) when it is an alkenylstannane. Is an allyl group, a vinyl group in the case of a compound having a vinyl group (ethenyl group), an aryl group in the case of an aryl compound, and a heteroaryl group in the case of a heteroaryl compound.

The hydride donor may be any known hydride donor as long as it can donate hydride (H ⁻ ). Preferable examples include silane compounds and stannane compounds.

Examples of the silane compound in the hydride donor include alkyl silane, alkoxy silane, aryl silane, and alkyl aryl silane.
Examples of the alkyl silane include diethyl silane ((CH ₃ CH ₂ ) ₂ SiH ₂ ), dimethyl ethyl silane (CH ₃ CH ₂ (CH ₃ ) ₂ SiH), and dimethyl isopropyl silane ((CH ₃ ) ₂ CH (CH ₃ ) _2. SiH), tert-butyldimethyl silane _{((CH 3) 3 C (} CH 3) 2 SiH), diethyl isopropyl silane _{((CH 3) 2 CH (} CH 3 CH 2) 2 SiH), cyclohexyl dimethylsilane _(C 6 H ₁₁ (CH ₃ ) ₂ SiH), tri (n-propyl) silane ((CH ₃ CH ₂ CH ₂ ) ₃ SiH), triethylsilane ((CH ₃ CH ₂ ) ₃ SiH), triisopropylsilane (((CH ₃ ) ₂ CH) ₃ SiH), tris (trimethylsilyl) silane (((CH ₃ ) ₃ Si) ₃ S iH) can be exemplified.
Examples of the alkoxysilane include trimethoxysilane ((CH ₃ O) ₃ SiH) and triethoxysilane ((CH ₃ CH ₂ O) ₃ SiH).
Examples of the aryl silane include phenyl silane (C ₆ H ₅ SiH ₃ ), diphenyl silane ((C ₆ H ₅ ) ₂ SiH ₂ ), and triphenyl silane ((C ₆ H ₅ ) ₃ SiH).
Examples of the alkylarylsilane include phenylmethylsilane (C ₆ H ₅ (CH ₃ ) SiH ₂ ), phenyldimethylsilane (C ₆ H ₅ (CH ₃ ) ₂ SiH), and diphenylmethylsilane ((C ₆ H ₅ ) ₂ CH. ₃ SiH).
Among these, as a silane compound, alkylsilane, arylsilane, and alkylarylsilane are preferable.

Examples of the stannane compound in the hydride donor include alkylstannane and arylstannane.
Examples of the alkyl stannane include trialkyl stannanes such as tri (n-butyl) stannane ((CH ₃ CH ₂ CH ₂ CH ₂ ) ₃ SnH).
Examples of the aryl stannane include triaryl stannanes such as triphenyl stannane ((C ₆ H ₅ ) ₃ SnH).

The cyano ion donor may be any known one as long as it can donate a cyano ion (CN ⁻ ). Preferable examples include alkylcyanosilane, and more specifically, trimethylcyanosilane ((CH ₃ ) ₃ SiCN), triethylcyanosilane ((CH ₃ CH ₂ ) ₃ SiCN), triisopropyl An example is cyanosilane (((CH ₃ ) ₂ CH) ₃ SiCN).

Examples of the compound having an allyl group, an allyl tributyltin _{((CH 3 CH 2 CH 2} CH 2) 3 SnCH 2 CH = CH 2), Arirutori and allyl trimethyltin _{((CH 3) 3 SnCH 2} CH = CH 2) Examples thereof include alkyl tin; tetraallyl tin (Sn (CH ₂ CH═CH ₂ ) ₄ ).

As the compound having a vinyl group, a compound having a vinylaryl group in which a vinyl group is bonded to a carbon atom constituting the aromatic ring skeleton of the aryl group is preferable, and 4-vinylanisole (CH ₂ ═CH—Ph—OCH ₃ ) is preferable. Can be illustrated.

  The aryl compound and heteroaryl compound as the nucleophilic species donor may be either a monocyclic structure or a polycyclic structure, but is preferably a monocyclic structure. Benzene can be exemplified as a preferred aryl compound, and furan (1-oxa-2,4-cyclopentadiene) and thiophene (thiacyclopentadiene) can be exemplified as a preferred heteroaryl compound. In addition, those in which one or more hydrogen atoms of these unsubstituted aryl compounds and heteroaryl compounds having no substituent such as benzene, furan, thiophene and the like are substituted with groups other than hydrogen atoms (substituents) Preferred as a compound or heteroaryl compound. In this case, the substituent is preferably an alkyl group or an alkoxy group.

The alkyl group as the substituent for the unsubstituted aryl compound and heteroaryl compound is preferably linear or branched, and more preferably linear. And it is preferable that carbon number is 1-3, and it is more preferable that it is a methyl group.
Examples of the alkoxy group as the substituent for the unsubstituted aryl compound and heteroaryl compound include a monovalent group in which the alkyl group is bonded to an oxygen atom.
Although the number of the said substituents changes with kinds of these aryl compounds and heteroaryl compounds, for example in the case of furan and thiophene, it is 1-3, and it is preferable that it is 1. Moreover, when there are a plurality of substituents, these substituents may all be the same, may be all different, or only part of them may be the same.
The bonding position of the substituent may be other than the reaction site at the nucleophilic reaction of these aryl compounds and heteroaryl compounds, and varies depending on the type of these compounds. For example, in the case of furan and thiophene, 2 Is preferred.

  Preferred examples of the furan having a substituent include 2-methylfuran and 2-methoxyfuran, and preferred examples of the thiophene having a substituent include 2-methylthiophene and 2-methoxythiophene.

  As the alkenyl stannane, tetraalkenyl stannane such as tetravinyl stannane is particularly preferable.

Among these, as the nucleophilic species donor, a hydride donor, a cyano ion donor, an aryl compound or a heteroaryl compound is preferable, and a silane compound, an alkylcyanosilane, an aryl compound or a heteroaryl compound is more preferable.
That is, X is preferably a hydrogen atom, a cyano group, an aryl group, or a heteroaryl group.

  The amount of the nucleophilic species donor to be used may be appropriately adjusted according to the types of the compounds (1) and (2), but usually it is preferably 1 to 6 times the molar amount of the compound (2). It is more preferably 1 to 5 times the molar amount, and particularly preferably 1 to 4 times the molar amount.

  It is preferable to use one kind of nucleophilic species donor alone, but two or more kinds may be used in combination as long as the nucleophilic species to be donated is the same. When two or more kinds are used in combination, the combination and ratio may be appropriately selected according to the purpose.

<Lewis acid catalyst>
In the present invention, in addition to the compound (1), the compound (2) and the nucleophilic donor, it is preferable to carry out the reaction using a Lewis acid catalyst. By using the compound (2) in combination with a Lewis acid catalyst, a particularly excellent effect is obtained that the compound (3) can be obtained more quickly and in a high yield. The combination of the compound (2) and Bronsted acid cannot provide such an effect of the present invention.

  The Lewis acid catalyst may be a known one, among which metal sulfonate or metal sulfonimide is preferable.

Examples of the metal sulfonate include a compound represented by the following general formula (41) (hereinafter abbreviated as M (OTf) _n ) and a compound represented by the following general formula (42) (hereinafter abbreviated as M (ONf) _n ). Can be exemplified.
An example of the metal sulfonimide is a compound represented by the following general formula (43) (hereinafter abbreviated as M (NTf ₂ ) _n ). These are all known compounds.

（式中、Ｍは金属原子であり；ｎは１以上の整数である。）

(In the formula, M is a metal atom; n is an integer of 1 or more.)

In the formula, M is a metal atom, and preferred examples include indium (In), zinc (Zn), copper (Cu), silver (Ag), gold (Au), bismuth (Bi), zirconium (Zr), Examples include scandium (Sc), mercury (Hg), gallium (Ga), iron (Fe), and hafnium (Hf).
n is an integer of 1 or more, and is determined by the type of M.

In the present invention, examples of preferable metal sulfonates include those in which M is indium (In), and particularly preferable examples include In (OTf) ₃ and In (ONf) ₃ .
Then, as the preferred metals sulfonimide, M can be exemplified those in which indium _{(In), In (NTf 2} ) 3 can be exemplified as particularly preferable.

  The amount of the Lewis acid catalyst used may be appropriately adjusted depending on the types of the compounds (1) and (2), but is usually preferably 2 to 45 mol% based on the compound (2). 3 to 40 mol% is more preferable, and 3 to 35 mol% is particularly preferable.

  A Lewis acid catalyst may be used individually by 1 type, and may use 2 or more types together. When two or more kinds are used in combination, the combination and ratio may be appropriately selected according to the purpose.

<Other reaction conditions>

In the present invention, in addition to the compound (1), the compound (2), the nucleophilic donor and the Lewis acid catalyst, other components may be used and reacted within the range not impairing the effects of the present invention. Also good.
For example, when using a compound unstable to water like the compound (1) represented by the formulas (1110) to (1112) and (1210) to (1212), a dehydrating agent is used in combination. May be. As the dehydrating agent, known ones such as anhydrous magnesium sulfate can be used, and the amount used can be arbitrarily adjusted.

In the present invention, the reaction solvent can be appropriately selected from those that do not interfere with the reaction in consideration of the types of the compound (1), the compound (2), and the hydride donor. Among them, ether compounds (compounds having an ether bond), halogenated hydrocarbons (hydrocarbons having a halogen atom as a substituent), nitrile compounds (compounds having a cyano group), nitro compounds (compounds having a nitro group), ester compounds (Compound having an ester bond) is preferred.
Examples of the ether compound include linear or cyclic ether compounds such as 1,4-dioxane, tetrahydrofuran (THF), diethyl ether, dibutyl ether, 1,2-dimethoxyethane, and 1,2-diethoxyethane.
Examples of the halogenated hydrocarbon include aliphatic or aromatic halogenated hydrocarbons such as 1,2-dichloroethane and chlorobenzene.
An example of the nitrile compound is propionitrile.
An example of the nitro compound is nitromethane.
An example of the ester compound is ethyl acetate.
Of these, ether compounds, halogenated hydrocarbons, and ester compounds are preferred as the reaction solvent.

  The amount of the reaction solvent used may be adjusted so that the concentration of the compound (2) is preferably 0.1 to 5 mol / L, more preferably 0.2 to 3 mol / L.

  A reaction solvent may be used individually by 1 type, and may use 2 or more types together as a mixed solvent. When two or more kinds are used in combination, the combination and ratio may be appropriately selected according to the purpose.

  In the present invention, an excellent effect is exhibited particularly by using a combination of the above Lewis acid catalyst and a solvent. Moreover, the amount of Lewis acid catalyst used may be extremely small. In the indole alkylation and the like, a stoichiometric amount of Bronsted acid is usually used. However, in the present invention, a novel reaction capable of alkylation is realized by selecting the above Lewis acid catalyst. ing.

<Compound (3)>
In the present invention, for example, the compound (1), the compound (2) and a nucleophilic donor, more preferably a Lewis acid catalyst, are mixed in a reaction solvent in the presence of other components as necessary, and reacted. Thereby, a compound (3) is obtained.
In the compound ^{(3), R 1, R} 2, R 3, l and m are the same as ^{R 1, R 2, R 3} , l and m in the compound (1). Further, in the compound (3), ^{R 4} and ^{R 5} are the same as ^{R 4} and ^{R 5} in the compound (2). In the compound (3), X is a monovalent group derived from a nucleophilic species donated from the nucleophilic species donor.

In the compound (1), when l is 0, the compound (2) can react with both the 2-position and 3-position carbon atoms constituting the indole ring skeleton of the compound (1). Reacts highly selectively with the carbon atom at the 3-position. That is, as compound (3), when l is 0, the group represented by the general formula “—C (R ⁴ ) (R ⁵ ) X” is the carbon at the 2-position constituting the indole ring skeleton. There can be both those bonded to the atom and those bonded to the carbon atom at the 3-position, but those bonded to the carbon atom at the 3-position are usually obtained with high selectivity.
On the other hand, in the compound (1), when l is 1 and R ² is bonded to the 2-position carbon atom constituting the indole ring skeleton, the compound (2) is an indole ring of the compound (1). The compound (3) in which a group represented by the general formula “—C (R ⁴ ) (R ⁵ ) X” is bonded to the carbon atom at the 3-position reacts with the carbon atom at the 3-position constituting the skeleton. .
Similarly, in the compound (1), when l is 1 and R ² is bonded to the 3-position carbon atom constituting the indole ring skeleton, the compound (2) is an indole of the compound (1). The compound (3) in which a group represented by the general formula “—C (R ⁴ ) (R ⁵ ) X” is bonded to the carbon atom at the 2-position reacts with the carbon atom at the 2-position constituting the ring skeleton. It is done.

The reaction temperature may be appropriately adjusted and is not particularly limited, but is usually preferably 10 to 120 ° C and more preferably 20 to 110.
The reaction time may be appropriately adjusted according to other reaction conditions such as the reaction temperature, but usually 0.5 to 130 hours are preferable, and 5 to 100 hours are more preferable.

Furthermore, in the present invention, the compound (1) and the compound (2), more preferably a Lewis acid catalyst, are mixed in a reaction solvent in the presence of other components as necessary to carry out the first stage reaction. Then, the compound (3) may be obtained in a higher yield by applying a two-stage reaction in which the nucleophilic donor is added to the same reaction vessel and the second-stage reaction is performed. . In this case, in the first stage reaction, the compound (1) and the compound (2) react to produce an intermediate, which may be relatively stable. The intermediate may be taken out and subjected to the necessary treatment before the second stage reaction.
Whether or not the two-stage reaction is applied may be appropriately selected according to the combination of raw materials used.

The temperature during the first stage reaction and the second stage reaction may be the same as described above. And reaction temperature may be changed by the 1st step and the 2nd step, and you may make it react, changing reaction temperature in any of the 1st step and the 2nd step. In general, it is preferable that the reaction temperature at the second stage is lower than the reaction temperature at the first stage in terms of suppressing the formation of by-products.
Moreover, it is preferable to adjust reaction time so that it may become the same as the above with the sum total of the 1st step and the 2nd step.
The raw materials such as compound (1), compound (2), nucleophilic donor and Lewis acid catalyst, and the amount of reaction solvent used may be the same as described above.

  In the present invention, the compound (3) may be taken out by a known method after the completion of the reaction, if necessary, after-treatment. That is, as needed, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration are performed alone or in combination of two or more to concentrate, crystallize, reprecipitate, column chromatography. The compound (3) may be taken out by, for example. In addition, the extracted product may be further subjected to crystallization, reprecipitation, column chromatography, extraction, stirring and washing of the crystals with a solvent, etc., if necessary, or one or more times in combination of two or more. It may be purified by performing.

Depending on the type of compound (3), R ¹ can also be converted by conducting a separate reaction. This reaction is generally known as a reaction for converting a protecting group of a nitrogen atom constituting a heterocyclic ring, and a known method can be appropriately selected. For example, the reaction for converting R ¹ which is a group other than a hydrogen atom to a hydrogen atom is a deprotection reaction, for example, the reaction for converting R ¹ from a benzyl group (—Bn) to a hydrogen atom (debenzylation reaction). Is mentioned.

For example, in the present invention, when the compound (1) in which R ¹ is a hydrogen atom is used and the yield of the compound (3) is not improved for some reason, R ¹ is a group other than a hydrogen atom. After obtaining the corresponding compound (3) using the compound, the compound (3) is subjected to a deprotection reaction, and R ¹ is converted to a hydrogen atom, whereby the desired product can be obtained.

In the conventional alkylation reaction of indoles, even if an alkyl group or the like can be introduced at the 3-position or the 2-position, a special apparatus is necessary because microwave irradiation or pressurization is required. The yield of the target product was low, and the raw materials that could be used were sometimes limited. In addition, a method using Bronsted acid as a catalyst is also known, but these catalysts must be used in stoichiometric amounts, and a post-treatment step for treating an excess of Bronsted acid is essential. It was difficult to improve the yield.
In contrast, in the present invention, a special apparatus is not required, a wide range of raw materials can be used, the process is simple, and the target product can be produced under mild reaction conditions. In other words, various objects can be easily obtained. Further, the target product can be obtained with high selectivity, for example, it reacts very highly selectively at the carbon atom at the 3rd or 2nd position. Furthermore, since the amount of the catalyst used can be extremely reduced, the post-treatment load after the reaction is small and the environmental load is also small.

Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the present invention is not limited to the following examples. In addition, the usage-amount (mol%) of the Lewis' acid catalyst shown below is the quantity on the basis of a compound (2) all. “Mmol” represents 10 ⁻³ mol. Furthermore, each abbreviation shows the following.
Ph: phenyl group n-Hex: n-hexyl group n-Bu: n-butyl group 4-HO-Ph: 4- hydroxyphenyl _4-CF 3 -Ph: 4- trifluoromethylphenyl group n-Non: n - nonyl group t-Bu: tert-butyl group 3-Thi: 3- thienyl in _{(NTf 2) 3:} in the general formula (43), M is indium (in), a Lewis acid catalyst n is 3 .

Example 1
As shown in Tables 1 and 2, R ¹ and R ² are hydrogen atoms and m is 0 (1) (0.6 mmol), R ⁴ is an n-hexyl group, and R ⁵ is a methyl group. Compound (2) (0.4 mmol), diphenylmethylsilane (0.6 mmol) and In (NTf ₂ ) ₃ (10 mol%) were mixed in 1,4-dioxane (0.4 ml), and the mixture was stirred at 50 ° C. for 24 hours. After the reaction, the product was purified by silica gel column chromatography, and the target compound (3101) was taken out. In Table 2, “Yield (%)” indicates the isolated yield (%) of the target product based on the compound (2). The same applies to Examples 2 to 16 and 18 described later.
The NMR data of the obtained compound (3101) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.86 (t, J = 7.2 Hz, 3 H), 1.12-1.42 (m, 8 H), 1.34 (d, J = 6.9 Hz, 3 H), 1.55- 1.67 (m, 1 H), 1.71-1.86 (m, 1 H), 3.02 (sext, J = 6.9 Hz, 1 H), 6.95 (dd, J = 2.3, 0.6 Hz, 1 H), 7.09 (ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 7.17 (ddd, J = 8.3, 7.2, 1.2 Hz, 1 H), 7.35 (dd, J = 8.0, 1.2 Hz, 1 H), 7.65 (dd, J = 8.0, 1.2 Hz, 1 H), 7.87 (bs, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.1, 21.4, 22.7, 27.7, 29.5, 30.8, 31.9, 37.7, 111.1, 118.9, 119.4, 119.8, 121.7, 122.9, 126.9, 136.5.

(Example 2)
Compound (3201) was obtained in the same manner as in Example 1 except that the reaction was performed under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3201) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.86 (t, J = 6.9 Hz, 3 H), 1.19-1.39 (m, 8 H), 1.33 (d, J = 6.9 Hz, 3 H), 1.55- 1.64 (m, 1 H), 1.71-1.82 (m, 1 H), 3.01 (sext, J = 7.0 Hz, 1 H), 3.74 (s, 3 H), 6.79 (s, 1 H), 7.08 (ddd , J = 8.0, 6.9, 1.2 Hz, 1 H), 7.20 (ddd, J = 8.3, 7.2, 1.2 Hz, 1 H), 7.28 (dt, J = 8.1, 1.2 Hz, 1 H), 7.63 (dt, J = 8.1, 1.2 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.1, 21.6, 22.7, 27.8, 29.5, 30.8, 31.9, 32.6, 37.9, 109.1, 118.3, 119.5, 121.3, 121.4, 124.7, 127.3, 137.1.

(Example 3)
Compound (3102) was obtained in the same manner as in Example 1 except that the reaction was performed under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3102) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.83 (t, J = 6.9 Hz, 3 H), 1.06-1.33 (m, 8 H), 1.38 (d, J = 7.5 Hz, 3 H), 1.62- 1.76 (m, 1 H), 1.77-1.90 (m, 1 H), 2.36 (s, 3 H), 2.87-2.97 (m, 1 H), 7.02 (ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 7.07 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.25 (dt, J = 8.0, 1.1 Hz, 1 H), 7.62 (dd, J = 8.0, 1.2 Hz, 1 H), 7.62 (bs, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 12.2, 14.1, 21.3, 22.7, 28.3, 29.4, 31.3, 31.9, 37.1, 110.2, 116.7, 118.6, 119.5, 120.5, 127.5, 129.9, 135.4.

Example 4
Compound (3202) was obtained in the same manner as in Example 1 except that the reaction was performed under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3202) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.83 (t, J = 6.9 Hz, 3 H), 1.05-1.30 (m, 8 H), 1.38 (d, J = 7.5 Hz, 3 H), 1.65- 1.75 (m, 1 H), 1.77-1.88 (m, 1 H), 2.34 (s, 3 H), 2.89-2.99 (m, 1 H), 3.63 (s, 3 H), 7.01 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.12 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.23 (dd, J = 8.0, 1.2 Hz, 1 H), 7.64 (dd, J = 8.0 , 1.2 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ10.5, 14.1, 21.6, 22.7, 28.4, 29.40, 29.43, 31.7, 31.9, 37.2, 108.5, 115.9, 118.1, 119.5, 120.0, 126.4, 131.8, 136.8.

(Example 5)
Compound (3103) was obtained in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2. In the compound (1), m is 1 and R ³ is bonded to the 5-position carbon atom of the indole ring.
The NMR data of the obtained compound (3103) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.86 (t, J = 7.2 Hz, 3 H), 1.15-1.37 (m, 8 H), 1.31 (d, J = 6.9 Hz, 3 H), 1.52- 1.66 (m, 1 H), 1.67-1.79 (m, 1 H), 2.96 (sext, J = 6.9 Hz, 1 H), 6.95 (d, J = 2.3 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 1 H), 7.23-7.29 (m, 1 H), 7.75 (d, J = 1.7 Hz, 1 H), 7.92 (bs, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.1, 21.4, 22.7, 27.6, 29.5, 30.7, 31.9, 37.6, 112.3, 112.5, 121.1, 122.0, 122.7, 124.6, 128.7, 135.1.

(Example 6)
Compound (3104) was obtained in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2. In the compound (1), m is 1 and R ³ is bonded to the 5-position carbon atom of the indole ring.
The NMR data of the obtained compound (3104) are shown below.
¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ0.84 (t, J = 6.9 Hz, 3 H), 1.09-1.33 (m, 8 H), 1.35 (d, J = 6.9 Hz, 3H), 164 -1.72 (m, 1 H), 1.77-1.86 (m, 1 H), 2.34 (s, 3 H), 2.86-2.95 (m, 1 H), 3.81 (s, 3 H), 6.69 (dd, J = 8.6, 2.3 Hz, 1 H), 7.04 (dt, J = 2.3, 0.6 Hz, 1 H), 7.14 (d, J = 8.6 Hz, 1 H), 7.65 (bs, 1H).
¹³ C NMR (125 MHz, CD ₂ Cl ₂ ) δ12.4, 14.2, 21.4, 23.1, 28.7, 29.9, 31.6, 32.4, 37.2, 56.2, 102.5, 110.0, 116.6, 128.4, 131.1, 131.7, 153.7.

(Example 7)
Compound (3203) was obtained in the same manner as in Example 1 except that the reaction was performed under the conditions shown in Tables 1 and 2. In the compound (1), m is 1 and R ³ is bonded to the 5-position carbon atom of the indole ring.
The NMR data of the obtained compound (3203) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.86 (t, J = 6.9 Hz, 3 H), 1.19-1.37 (m, 8 H), 1.31 (d, J = 6.9 Hz, 3 H), 1.37 ( s, 12 H), 1.54-1.64 (m, 1 H), 1.71-1.80 (m, 1 H), 3.08 (sext, J = 6.9 Hz, 1 H), 3.74 (s, 3 H), 6.78 (s , 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.65 (dd, J = 8.0, 1.2 Hz, 1 H), 8.13 (d, J = 1.2 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.1, 22.0, 22.7, 24.88, 24.90, 27.6, 29.5, 30.4, 31.9, 32.6, 37.8, 83.3, 108.5, 122.5, 124.5, 127.06, 127.11, 127.6, 139.0.

(Example 8)
A compound (3204 was obtained in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3204) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ1.38 (t, J = 6.9 Hz, 6 H), 3.07 (sept, J = 6.9 Hz, 1 H), 3.51 (s, 3 H), 7.12 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.23 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.31-7.38 (m, 3 H), 7.40-7.49 (m, 3 H), 7.80 (dd, J = 8.0, 6.9 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ23.4, 26.3, 30.6, 109.5, 118.7, 119.3, 120.5, 121.3, 126.0, 128.0, 128.2, 130.9, 132.6, 136.5, 137.4.

Example 9
As shown in Tables 1 and 2, R ¹ and R ² are methyl groups and m is 0 (1) (1.2 mmol), R ⁴ and R ⁵ are both n-butyl groups (2 ) (0.4 mmol) and In (NTf ₂ ) ₃ (10 mol%) were mixed in 1,4-dioxane (0.4 ml) and reacted at 85 ° C. for 20 hours. Next, diphenylmethylsilane (0.6 mmol) was added, and the mixture was further reacted at 50 ° C. for 48 hours. Subsequently, the product was purified by silica gel column chromatography, and the target compound (3205) was taken out. In Table 2, the descriptions “reaction temperature (° C.): 85 → 50” and “reaction time (h): 20 → 48” are 20 hours at 85 ° C. before addition of diphenylmethylsilane and further addition of diphenylmethylsilane. It shows that it was made to react 48 hours later at 50 degreeC. The same applies to the following embodiments.
The NMR data of the obtained compound (3205) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.83 (t, J = 8.9 Hz, 6 H), 1.14-1.37 (m, 8 H), 1.69 (dt, J = 9.9, 8.8 Hz, 4 H), 2.80 (quint, J = 3.9 Hz, 1 H), 3.74 (s, 3 H), 6.77 (s, 1 H), 7.06 (ddd, J = 10.0, 8.6, 1.2 Hz, 1 H), 7.19 (ddd, J = 10.2, 8.8, 1.2 Hz, 1 H), 7.28 (dd, J = 8.6, 1.2 Hz, 1 H), 7.62 (dd, J = 8.6, 1.2 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.1, 22.9, 30.0, 32.6, 36.0, 36.8, 119.4, 119.7, 121.1, 125.6, 127.7, 137.1.

(Example 10)
Compound (3206) was obtained in the same manner as in Example 9 except that the reaction was carried out under the conditions shown in Tables 1 and 2. In Table 1, it has been described one group only as R ⁴ and R ^5, which shows that R ⁴ and R ⁵ are combined to form a ring with each other.
The NMR data of the obtained compound (3206) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ1.56-1.89 (m, 12 H), 1.96-2.04 (m, 2 H), 3.13 (tt, J = 9.5, 3.5 Hz, 1 H), 3.73 (s , 3 H), 6.81 (s, 1 H), 7.08 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H), 7.20 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.27 (dd , J = 8.1, 1.2 Hz, 1 H), 7.61 (dd, J = 8.0, 1.2 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ25.8, 26.3, 27.4, 32.6, 33.0, 35.0, 109.1, 118.3, 119.4, 121.3, 122.9, 124.6, 127.0, 137.0.

(Example 11)
Compound (3207) was obtained in the same manner as in Example 1 except that the reaction was performed under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3207) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ1.69 (d, J = 6.9 Hz, 3 H), 3.74 (s, 3 H), 4.30 (q, J = 7.1 Hz, 1 H), 4.60 (bs, 1 H), 6.72 (dt, J = 9.2, 2.3 Hz, 2 H), 6.81 (s, 1 H), 6.99 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.13-7.20 (m, 3 H), 7.27 (dd, J = 8.0, 1.2 Hz, 1 H), 7.36 (dd, J = 8.0, 1.2 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ22.6, 32.6, 36.0, 109.1, 115.1, 118.6, 119.8, 120.2, 121.5, 125.9, 127.2, 128.5, 137.3, 139.3, 153.5 (two signals are the other signals Could not be confirmed clearly.)

(Example 12)
Compound (3208) was obtained in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3208) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.88 (t, J = 6.9 Hz, 3 H), 1.20-1.42 (m, 14 H), 1.69 (quint, J = 7.5 Hz, 2 H), 2.73 ( t, J = 7.4 Hz, 2 H), 3.74 (s, 3 H), 6.82 (s, 1 H), 7.09 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.20 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.24 (dd, J = 7.5, 1.2 Hz, 1 H), 7.59 (dd, J = 6.9, 1.2 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.1, 22.7, 25.1, 29.4, 29.6, 29.7, 30.5, 31.9, 32.5, 109.0, 115.7, 118.7, 119.1, 121.3, 125.9, 128.0, 137.0.

(Example 13)
Compound (3105) was obtained in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3105) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.96 (s, 9 H), 2.36 (s, 3 H), 2.57 (s, 2 H), 7.05 (dt, J = 7.5, 1.2 Hz, 1 H) , 7.08 (dt, J = 7.3, 1.2 Hz, 1 H), 7.25 (dd, J = 6.9, 1.2 Hz, 1 H), 7.50 (dd, J = 7.4, 1.2 Hz, 1 H), 7.74 (bs, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ12.6, 30.0, 34.1, 38.0, 109.9, 110.3, 118.9, 119.3, 120.6, 130.1, 132.2, 135.1.

(Example 14)
Compound (3209) was obtained in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3209) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ 2.36 (s, 3 H), 3.66 (s, 3 H), 4.06 (s, 2 H), 6.85 (dd, J = 2.9, 1.7 Hz, 1 H) , 6.93 (dd, J = 4.9, 1.7 Hz, 1 H), 7.03 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.14 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H), 7.18 (dd, J = 5.2, 2.9 Hz, 1 H), 7.25 (dd, J = 8.0, 1.2 Hz, 1 H), 7.43 (dd, J = 8.0, 1.2 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ10.3, 25.2, 29.5, 108.5, 109.5, 118.1, 118.8, 120.2, 120.5, 125.2, 127.7, 128.2, 133.2, 136.5, 142.5.

(Example 15)
Compound (3210) was obtained in the same manner as in Example 9 except that the reaction was performed under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3210) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ0.84 (t, J = 6.9 Hz, 3 H), 1.19-1.41 (m, 7 H), 1.42-1.53 (m, 1 H), 1.82 (s, 3 H), 1.93-2.02 (m, 1 H), 2.11-2.20 (m, 1 H), 3.77 (s, 3 H), 7.06 (s, 1 H), 7.14 (ddd, J = 8.3, 6.9, 1.4 Hz, 1 H), 7.26 (ddd, J = 8.3, 7.0, 1.0 Hz, 1 H), 7.33 (dt, J = 8.3, 0.9 Hz, 1 H), 7.74 (dt, J = 8.3, 0.9 Hz, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ14.0, 22.6, 25.6, 26.5, 29.2, 31.6, 32.8, 36.9, 40.3, 109.8, 114.4, 119.4, 119.9, 122.0, 124.1, 124.7, 126.3, 137.8.

(Example 16)
Compound (3106) was obtained in the same manner as in Example 9 except that the reaction was carried out under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3106) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ2.23 (s, 3 H), 3.83 (s, 3 H), 5.99 (d, J = 4.1 Hz, 1 H), 6.33 (d, J = 4.2 Hz, 1 H), 6.73 (d, J = 2.8 Hz, 1 H), 6.96 (ddd, J = 8.0, 7.1, 0.9 Hz, 1 H), 7.12 (dd, J = 8.2, 0.9 Hz, 1 H), 7.16 (ddd, J = 8.3, 6.9, 1.4 Hz, 1 H), 7.36 (dt, J = 8.3, 0.9 Hz, 1 H), 7.45 (dt, J = 8.2, 0.9 Hz, 2 H), 7.53 (dt, J = 8.2, 0.9 Hz, 2 H), 7.98 (bs, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ30.2, 46.2, 60.0, 102.4, 111.3, 119.4, 121.6, 122.0, 122.7, 123.3, 124.26, 124.31 (q, J = 270.7 Hz), 124.9 (q, J = 3.6 Hz), 125.7, 128.1, 128.5 (q, J = 32.2 Hz), 137.0, 138.7, 151.9, 165.3.

(Example 17)
Compound (3211) was obtained in the same manner as in Example 1 except that the reaction was performed under the conditions shown in Tables 1 and 2. As compound (2), formaldehyde was reacted, but paraformaldehyde was used as a raw material. It was confirmed by NMR that the compound (3211) was obtained. Further, the yield of the compound (3211) obtained from NMR data based on the compound (2) was 36% (*).

(Example 18)
Compound (3101) was obtained in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2 (reaction temperature was changed to 45 ° C instead of 50 ° C).
The NMR data of the compound (3101) obtained were the same as in Example 1.

(Examples 19 to 28)
Compound (3101) was obtained in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 3 and 4. The NMR data of the obtained compound (3101) were the same as in Example 1 in all cases. In Table 4, “Yield (%)” indicates the yield (%) of the target product based on the compound (2), and Examples 19 to 25 and 27 to 28 are obtained from gas chromatography data. Example 26 was obtained from NMR data.

  The present invention can be used for the manufacture of pharmaceuticals, various chemical products, highly functional materials and the like.

Claims (7)

The indole represented by the following general formula (1), the carbonyl compound represented by the following general formula (2), and a nucleophilic donor are reacted, represented by the following general formula (3) For producing an indole derivative.

Wherein R ¹ is a hydrogen atom, aliphatic group, aryl group, heteroaryl group, arylalkyl group, alkylaryl group or trialkylsilyl group; R ² is an aliphatic group, aryl group, heteroaryl group, An arylalkyl group, an alkylaryl group or a trialkylsilyl group; R ³ is a monovalent group other than a hydrogen atom; and R ⁴ and R ⁵ each independently have a hydrogen atom or a substituent. A good alkyl group, aryl group or heteroaryl group, which may be bonded to each other to form a ring; X is a monovalent group derived from a nucleophilic species; l is 0 or 1; When it is an integer of 0 to 4 and m is 2 to 4, a plurality of R ³ may be the same as or different from each other.) 2. The indole according to claim 1, wherein R ¹ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heteroaryl group having 3 to 11 carbon atoms. A method for producing a derivative. The indole derivative according to claim 1 or 2, wherein R ² is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heteroaryl group having 3 to 11 carbon atoms. Manufacturing method. R ⁴ and R ⁵ are each independently a hydrogen atom or an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heterogeneity having 3 to 11 carbon atoms. It is an aryl group, The manufacturing method of the indole derivative as described in any one of Claims 1-3 characterized by the above-mentioned.   The said X is a hydrogen atom, a cyano group, an aryl group, or heteroaryl group, The manufacturing method of the indole derivative as described in any one of Claims 1-4 characterized by the above-mentioned.   Furthermore, it reacts using a Lewis' acid catalyst, The manufacturing method of the indole derivative as described in any one of Claims 1-5 characterized by the above-mentioned.   The method for producing an indole derivative according to claim 6, wherein the Lewis acid catalyst is a metal sulfonate or a metal sulfonimide.