JP5842252B2 - Method for producing pyrrole derivative - Google Patents

Description

  The present invention relates to a method for producing a pyrrole derivative.

Since the pyrrole derivative has a heterocyclic skeleton, it is not only important as an intermediate for pharmaceuticals and various chemical products, but it can also be used as a polymer with repeating units as a high-functional material such as a novel electronic material. It is a very important compound with the potential to develop.
The pyrroles used as the raw material can be given new physical properties by, for example, substituting one or more hydrogen atoms with various substituents, and have a desired function for the above purpose. In addition, it has been studied to design the structure of a pyrrole derivative.

For example, among pyrrole derivatives, alkyl pyrroles in which a hydrogen atom bonded to a carbon atom is substituted with an alkyl group can be easily obtained by chemical synthesis by alkylating pyrroles. Things are being considered.
However, in the conventional method, alkylation of pyrroles proceeds mainly at the 2-position of pyrroles (hereinafter abbreviated as α-position). This is because the α-position of pyrroles having high nucleophilicity preferentially reacts with an alkylating agent that is an electrophile. That is, as shown below, it is very difficult to perform alkylation at the 3-position (hereinafter abbreviated as β-position) of pyrroles having low nucleophilicity. So far, as a method for producing a pyrrole derivative having an alkyl group introduced at the β-position, for example, a method of alkylating pyrroles under acidic conditions in the presence of a cation exchange resin (see Non-Patent Document 1). However, the α-substituted product in which an alkyl group is introduced at the α-position is still the main product.

  Therefore, as a method for obtaining a β-substituted pyrrole derivative in which an alkyl group is introduced at the β-position, a bulky substituent is introduced into the nitrogen atom adjacent to the α-position of the pyrrole, and the alkylating agent is more sterically than the α-position. A method that makes it easy to react at the β-position with less obstacles, or a method that introduces an electron-attracting group at the 5-position of pyrroles to improve the nucleophilicity at the β-position and make it easier to react with an alkylating agent. (See Non-Patent Documents 2 and 3). In addition to these, a method of introducing an alkyl group at the β-position by using a metal complex of pyrroles (see Non-Patent Document 4) is also disclosed. In addition, in order to overcome the problem derived from the property that pyrroles have a high nucleophilicity at the α-position, a method of simultaneously performing the construction of the pyrrole skeleton and the introduction of an alkyl group at the β-position is also disclosed. ing. Furthermore, a method for directly introducing an alkyl group into the β-position of a pyrrole ring by reacting an alkyne or carbonyl compound, a pyrrole and a nucleophilic donor in the presence of a Lewis acid catalyst such as an indium compound (non-patent document) 5 and 6). In Non-Patent Document 5, when an alkyne, a pyrrole, and a nucleophilic donor are reacted in the presence of a Bronsted acid catalyst, an alkyl group cannot be directly introduced into the β-position of the pyrrole ring. It is disclosed.

I. Iove et. al. , Synthetic Communications, 18 (11), 1261-1266 (1988). J. et al. K. Groves et. al. , Canadian Journal of Chemistry, Vol. 49, 2427-2432 (1971) Hugh J. et al. Anderson et. al. , Synthesis, 353-364, April (1985). W. Dean Harman, Chemical Reviews, Vol. 97, no. 6,1953-1978 (1997) T. T. et al. Tsuchimoto et. al. , Organic Letters, Vol. 11, no. 10, 2129-2132 (2009) T. T. et al. Tsuchimoto et. al. , Chemistry A European Journal, Vol. 16, 8975-8979 (2010)

However, alkylation of pyrroles has the advantage that the process is simple. However, in many methods, the problem that the α-substituted product becomes the main product has not been solved in many methods. In contrast, in reactions using pyrroles having an electron withdrawing group at the 5-position and reactions using metal complexes of pyrroles, high β-position selectivity has been achieved in several reactions, Here, introduction of an electron withdrawing group or metal part and removal thereof are necessary, so that a multi-step synthesis process cannot be avoided, and there is a serious limitation in the alkyl group that can be introduced. It was. Moreover, the method of performing the construction of the pyrrole skeleton and the introduction of the alkyl group at the β-position has a problem that the process becomes complicated and is not practical. In addition, in the method of reacting an alkyne or carbonyl compound, pyrrole and a nucleophilic donor, a pyrrole derivative in which the β-position is alkylated can be synthesized in one step and with extremely high selectivity. Since Lewis acid catalysts are expensive and it is necessary to prepare these Lewis acid catalysts separately before the reaction, there is a problem in that the number of steps increases and labor is required.
Therefore, development of a simple and practical new method for producing a pyrrole derivative having a substituent such as an alkyl group at the β-position has been desired.

  This invention is made | formed in view of the said situation, and makes it a subject to provide the novel manufacturing method of the pyrrole derivative which has substituents, such as an alkyl group, in beta-position.

To solve the above problem,
In the present invention, a pyrrole represented by the following general formula (1), a carbonyl compound represented by the following general formula (2), and a nucleophilic donor are reacted in the presence of a fluorinated Bronsted acid. A method for producing a pyrrole derivative represented by the following general formula (3) is provided.

（式中、Ｒ^１は水素原子、脂肪族基、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及びＲ^３はそれぞれ独立に水素原子、あるいは置換基を有していてもよい脂肪族基、アリール基又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る。）

Wherein R ¹ is a hydrogen atom, aliphatic group, aryl group, arylalkyl group, alkylaryl group or trialkylsilyl group; R ² and R ³ each independently have a hydrogen atom or a substituent And may be an aliphatic group, 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 a nucleophilic species.)

In the method for producing a pyrrole 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 an arylalkyl group having 7 to 15 carbon atoms. Is preferred.
In the method for producing a pyrrole derivative of the present invention, R ² and R ³ are each independently a hydrogen atom, or an alkyl group, alkenyl group or aryl group having 20 or less carbon atoms, which may have a substituent, or It is preferably a heteroaryl group having 19 or less carbon atoms which may have a substituent.
In the method for producing a pyrrole 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 a pyrrole derivative of the present invention, the fluorine-containing Bronsted acid may have one or more selected from the group consisting of a fluoroalkyl group, a fluoroalkylene group, a fluoroaryl group, and a fluoroarylene group. preferable.

  According to the present invention, a novel method for producing a pyrrole derivative having a substituent such as an alkyl group at the β-position is provided.

The method for producing a pyrrole derivative of the present invention comprises a pyrrole represented by the following general formula (1) (hereinafter abbreviated as compound (1)) and a carbonyl compound represented by the following general formula (2) (hereinafter, A pyrrole derivative represented by the following general formula (3) (hereinafter referred to as compound (3)), which comprises reacting a compound (2) and a nucleophilic donor in the presence of a fluorinated Bronsted acid. 3)).
The present invention produces a pyrrole derivative by selectively introducing a substituted alkyl group (an alkyl group or the like) in which an alkyl group or one or more hydrogen atoms thereof is substituted with a substituent at the β-position of pyrroles. Is.

Wherein R ¹ is a hydrogen atom, aliphatic group, aryl group, arylalkyl group, alkylaryl group or trialkylsilyl group; R ² and R ³ each independently have a hydrogen atom or a substituent And may be an aliphatic group, 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 a nucleophilic species.)

<Compound (1)>
In the compound (1), R ¹ is a hydrogen atom, an aliphatic group, an aryl 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 in the aliphatic group for R ¹ has 3 or more carbon atoms, and may be either a monocyclic structure or a polycyclic structure, and more specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group. 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, it is preferable that the bond between the carbon atom bonded to the 1st-position nitrogen atom constituting the pyrrole ring skeleton and the carbon atom adjacent to the carbon atom is not an unsaturated bond. The unsaturated bond between carbon atoms is preferably separated 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.
Preferable examples of the arylalkyl group, phenylmethyl group (benzyl group), a phenyl ethyl group _{(Ph- (CH 2) 2 -} ), 3- phenyl -n- propyl (Ph- _{(CH 2)} 3 -) And 2-phenyl-isopropyl group (Ph- (CH ₃ ) ₂ C—). Here, “Ph” represents a phenyl group.

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 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 an arylalkyl group having 7 to 15 carbon atoms. It is more preferably an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an arylalkyl group having 7 to 12 carbon atoms.

  Particularly preferred examples of the compound (1) include N-methylpyrrole, N-tert-butylpyrrole, N-phenylpyrrole and N-benzylpyrrole.

  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 2-6 times mole amount normally of a compound (2), and 2-5 times mole amount. It is more preferable that the amount is 2.5 to 4.5 times the molar amount.

<Compound (2)>
In the compound (2), R ² and R ³ are each independently a hydrogen atom, or an aliphatic group, aryl group or heteroaryl group which may have a substituent. Then, ^{R 2} and ^{R 3} are bonded to each ^other, R 2, ^{R 3,} and may form a ring with the carbon atom ^{to which R 2} and ^{R 3} are attached.

Examples of the aliphatic group for R ² and R ³ are the same as the aliphatic groups for R ¹ . Of these, an alkyl group or an alkenyl group is preferable.

The alkyl group in the aliphatic group of R ² and R ³ may be linear, branched or cyclic, and preferably has 20 or less (1 to 20) carbon atoms.
The linear or branched alkyl group preferably has 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, and more specifically, a methyl group, an ethyl group, or n-propyl group. 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-dimethylpentyl Group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,3-dimethylpentyl group, 3-ethylpentyl group, 2,2,3-trimethylbuty Group, n- octyl group, an isooctyl group, a nonyl group, decyl group can be exemplified.
The cyclic alkyl group has 3 or more carbon atoms, and may be either a monocyclic structure or a polycyclic structure, preferably has 20 or less carbon atoms, more preferably 3 to 12 carbon atoms, 10 is particularly preferable, and more specifically, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, norbornyl group, isobornyl group, 1-adamantyl group. 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 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.

The alkenyl group in the aliphatic group of R ² and R ³ may be linear, branched or cyclic, and examples thereof are the same as the alkenyl in the aliphatic group of R ^1. It is preferable that it is a shape. Moreover, carbon number of this alkenyl group is 2 or more, it is preferable that it is 20 or less (2-20), it is more preferable that it is 2-12, and it is especially preferable that it is 2-8.
Alkenyl aliphatic group of R ² and R ^3, the carbon atom bonded to the carbon atom to which R ² and R ³ constitute a carbonyl group attached to the compound (2) is, with the adjacent carbon atoms It is preferable that no unsaturated bond is formed between them, and the smaller the number of unsaturated bonds, the better.

Examples of the aryl group in R ² and R ³ are the same as the aryl group in R ^1. The aryl group preferably has 20 or less carbon atoms, more preferably 12 or less, and a phenyl group. It is particularly preferred that

As the heteroaryl group for R ² and R ³ , among the aryl groups, one or more carbon atoms constituting the aromatic ring skeleton are substituted with a heteroatom, and the aromatic group, and the cyclic group 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 heteroatoms constituting the aromatic ring skeleton is not particularly limited, but is preferably 1 to 2.

The heteroaryl group in R ² and R ³ 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 19 or less carbon atoms.

When R ² and R ³ are bonded to each other to form a ring, the ring may be either a monocyclic structure or a polycyclic structure. Preferred examples of the ring having a polycyclic structure include an adamantyl group and a norbornyl group.
The number of carbon atoms in the ring (the total number of carbon atoms of R ² , R ³ , and carbon atoms to which R ² and R ³ 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 aliphatic group, aryl group and heteroaryl group in R ² and R ³ may have a substituent. Here, “the aliphatic group, aryl group, heteroaryl group has a substituent” means that one or more hydrogen atoms constituting the aliphatic group, aryl group, heteroaryl group are substituted with a group other than a hydrogen atom. Or one or more carbon atoms constituting an aliphatic group, aryl group, or heteroaryl group are substituted with a group other than carbon atoms. And both the hydrogen atom and the carbon atom may be substituted with a substituent.

Examples of the substituent that replaces the hydrogen atom in R ² and R ³ include an alkyl group, an aryl group, an alkyloxycarbonyl group, an alkylcarbonyloxy group, an alkoxy group, a hydroxyl group, a cyano group, and a halogen atom.
Examples of the alkyl group and aryl group as substituents for R ² and R ³ are the same as the alkyl group and aryl group for R ¹ .
Examples of the alkyloxycarbonyl group as a substituent in R ² and R ³ include a monovalent group in which the alkyl group in R ¹ is bonded to the carbon atom of the carbonyl group through an oxygen atom.
Examples of the alkylcarbonyloxy group as a substituent in R ² and R ³ include a monovalent group in which the alkyl group in R ¹ is bonded to the carbon atom of the carbonyloxy group.
Examples of the alkoxy group as a substituent in R ² and R ³ include a monovalent group in which the alkyl group in R ¹ is bonded to an oxygen atom.
Examples of the halogen atom as a substituent in R ² and R ³ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The number of substituents replacing the hydrogen atom is not particularly limited and can be arbitrarily adjusted according to the types of R ² and R ³ , 1 or 2 or more, and all the hydrogen atoms are substituted with substituents. It may be. However, it is usually preferably 1 to 4.
Further, the position of the hydrogen atom substituted with 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 ² and R ³ 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 ² and R ³ 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 substituting the carbon atom is not particularly limited, and can be arbitrarily adjusted according to the types of R ² and R ³ , 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 ² and R ³ are bonded (the carbon atom of the carbonyl group). .

When the aliphatic group, aryl group, and heteroaryl group in R ² and R ³ 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.

In at least one of R ² and R ³ , the compound (2) in which a carbon atom is substituted with a hetero atom includes a compound having a heterocyclic skeleton as in the compound (1). Useful compound (3) is obtained. For example, a compound (2) in which a plurality of carbon atoms are substituted with oxygen atoms and boron atoms, and a boron atom of an organic boron moiety represented by the following formula (2-1) is bonded to a carbon atom is carbon-carbon It is suitable as a raw material for Suzuki-Miyaura coupling, which is useful as a bond-forming reaction, and has very high industrial utility.

Among the above, R ² and R ³ may each independently have a hydrogen atom, or an alkyl group, an alkenyl group or an aryl group having 20 or less carbon atoms, which may have a substituent, or a substituent. It is preferably a good heteroaryl group having 19 or less carbon atoms.

<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-butyl dimethylsilane _{((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, alkylsilane is preferable as the silane compound.

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.
When a compound having a vinylaryl group is used as a nucleophilic species donor, the compound is added to the normal reaction site (carbon atom to which R ² and R ³ are bonded together) with respect to the intermediate during the reaction, and further pyrrole By reacting with the carbon atom at the 2-position of the ring, a new ring structure condensed with the pyrrole ring can be formed. In this case, X in the compound (3) becomes a cationic group. That is, in the present invention, the compound (3) may be a compound corresponding to an intermediate that itself can continuously react.

  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.

<Fluorine-containing Bronsted acid>
In the present invention, compound (1), compound (2) and nucleophilic donor are reacted in the presence of a fluorinated Bronsted acid. In the conventional method, it has been reported so far that if a Bronsted acid is used when an alkyl group or the like is introduced into the β-position of pyrroles, the desired reaction does not proceed as desired. On the other hand, in this invention, an alkyl group etc. can be selectively and smoothly introduce | transduced to (beta) position of a compound (1) by selecting the combination of a compound (2) and a fluorine-containing Bronsted acid. Moreover, the amount of fluorine-containing Bronsted acid used may be a catalytic amount. Furthermore, the fluorine-containing Bronsted acid is less expensive than a noble metal or a compound containing a noble metal, and it is not necessary to prepare it with a lot of trouble before the reaction.

In the present invention, the fluorine-containing Bronsted acid means a proton (H ⁺ ) donor having a fluorine atom, and by having a fluorine atom, a desired reaction (an alkyl group at the β-position of the compound (1), etc.) And a sufficient proton donating ability for carrying out the reaction.

  The fluorine-containing Bronsted acid is not particularly limited as long as it has a fluorine atom in its structure, that is, a fluorine-containing electron-withdrawing group (electron-withdrawing group having a fluorine atom). Those having one or more fluorine-containing electron withdrawing groups selected from the group consisting of a group, a fluoroalkylene group, a fluoroaryl group and a fluoroarylene group are preferred.

  The fluoroalkyl group and the fluoroalkylene group may be linear, branched or cyclic, but are preferably linear or branched. Further, the fluoroaryl group and the fluoroarylene group may be either a monocyclic structure or a polycyclic structure, but are preferably a monocyclic structure.

  The number of fluorine atoms that the fluoroalkyl group, fluoroalkylene group, fluoroaryl group, and fluoroarylene group have is not particularly limited, but the smaller the number of hydrogen atoms, the more preferable, and the absence of hydrogen atoms, that is, all the hydrogen atoms are fluorine. Those substituted with atoms (perfluoroalkyl group, perfluoroalkylene group, perfluoroaryl group and perfluoroarylene group) are particularly preferred.

The fluorine-containing Bronsted acid may have one fluorine-containing electron withdrawing group selected from the group consisting of a fluoroalkyl group, a fluoroalkylene group, a fluoroaryl group, and a fluoroarylene group, but has two or more. Is preferred. In the case of having two or more, these plural fluorine-containing electron withdrawing groups may all be the same, may all be different, or only a part may be the same. Further, the plurality of fluorine-containing electron withdrawing groups may be bonded to each other to form a ring.
The fluorine-containing Bronsted acid preferably has a fluoroalkyl group and / or a fluoroalkylene group as an essential fluorine-containing electron withdrawing group.

Among the above, the fluorine-containing Bronsted acid has one or more fluorine-containing electron withdrawing groups selected from the group consisting of a fluoroalkylsulfonyl group, a fluoroalkylenesulfonyl group, a fluoroarylsulfonyl group, and a fluoroarylenesulfonyl group. Those are more preferred. For example, a fluorine-containing Bronsted acid having a fluoroalkylsulfonyl group corresponds to the above-mentioned fluorine-containing Bronsted acid having a fluoroalkyl group.
In the fluorinated Bronsted acid, the fluoroalkylsulfonyl group, fluoroalkylenesulfonyl group, fluoroarylsulfonyl group and fluoroarylenesulfonyl group are preferably bonded directly to the atom to which the donated proton is bonded.

  In the fluorine-containing Bronsted acid, the atom to which the donated proton is bonded is divalent or more, preferably trivalent or more, more preferably a nitrogen atom or a carbon atom, and fluorine atom is contained in these atoms. Particularly preferred are those in which two or more electron-withdrawing groups are directly bonded.

  Preferred examples of the fluorine-containing Bronsted acid include those represented by the following formulas (41) to (46). In the fluorine-containing Bronsted acid represented by the following formulas (41) and (42), the atom to which the donated proton is bonded is a nitrogen atom, and a fluoroalkylsulfonyl group (nonafluorobutanesulfonyl group) is bonded to the nitrogen atom. , A trifluoromethanesulfonyl group). In addition, in the fluorine-containing Bronsted acid represented by the following formula (43), the atom to which the donated proton is bonded is a nitrogen atom, and a fluoroalkylenesulfonyl group (difluoromethylenesulfonyl group) is divalent to the nitrogen atom. And these groups are bonded to each other to form a ring. Further, in the fluorine-containing Bronsted acid represented by the following formula (44), the atom to which the donated proton is bonded is a carbon atom, and a fluoroalkylsulfonyl group (trifluoromethanesulfonyl group) is bonded to the carbon atom. One fluoroarylsulfonyl group (pentafluorophenyl group) is bonded to each other. In the fluorine-containing Bronsted acid represented by the following formulas (45) and (46), the atom to which the donated proton is bonded is an oxygen atom, and a fluoroalkylsulfonyl group (nonafluorobutane) is attached to the oxygen atom. A sulfonyl group or a trifluoromethanesulfonyl group).

The amount of the fluorine-containing Bronsted acid used may be appropriately adjusted according to the types of the compounds (1) and (2), but is usually 1 to 12 mol% based on the compound (2). Is more preferable, 1.5 to 10 mol% is more preferable, and 1.5 to 8 mol% is particularly preferable.
As described above, the fluorine-containing Bronsted acid may be used in a catalytic amount and in a very small amount. Moreover, many are marketed and can also prepare easily according to a well-known method. In addition, it is inexpensive because it contains no precious metal. Therefore, the present invention is extremely versatile. Furthermore, since it is not necessary to use a catalyst containing a metal, the present invention has a very low load on the environment.

  A fluorine-containing Bronsted acid 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 fluorine-containing Bronsted acid, other components are used within the range not impairing the effects of the present invention. You may let them. For example, when the reaction can be promoted by coexisting a small amount of water, water may be used in combination as other components.
Furthermore, for example, when using a compound unstable to water, such as a compound in which the boron atom of the organic boron moiety represented by the formula (2-1) is bonded to a carbon atom, as other components A dehydrating agent may be used in combination. 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 hinder the reaction in consideration of the types of the compound (1), the compound (2), the nucleophilic donor and the fluorinated Bronsted acid. 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) and hydrocarbon are 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.
An example of the hydrocarbon is toluene.
Of these, ether compounds, halogenated hydrocarbons, nitrile compounds, nitro compounds, and hydrocarbons are preferred as the reaction solvent.

  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.

  The amount of the reaction solvent used may be adjusted so that the concentration of the compound (2) is preferably 0.05 to 5 mol / L, more preferably 0.08 to 3 mol / L.

<Compound (3)>
In the present invention, for example, compound (1), compound (2), nucleophilic donor and fluorine-containing Bronsted acid are mixed and reacted in a reaction solvent in the presence of other components as necessary. Thus, compound (3) is obtained.
In compound (3), R ¹ is the same as R ¹ in compound (1). Further, in the compound (3), ^{R 2} and ^{R 3} are the same as ^{R 2} and ^{R 3} in the compound (2). In the compound (3), X is a monovalent group derived from a nucleophilic species donated from the nucleophilic species donor.

The reaction temperature may be appropriately adjusted and is not particularly limited, but is usually preferably 30 to 150 ° C, more preferably 40 to 130 ° C, and particularly preferably 50 to 120 ° C.
The reaction time may be appropriately adjusted according to other reaction conditions such as the reaction temperature, but is usually preferably 1 to 120 hours, more preferably 2 to 100 hours, and particularly preferably 3 to 80 hours.

Furthermore, in the present invention, the compound (1), the compound (2), and the fluorine-containing Bronsted acid 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.
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 fluorine-containing Bronsted acid, 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 present invention, as described above, an alkyl group or the like can be selectively and smoothly introduced into the β-position of the compound (1) by using the compound (2) and the fluorine-containing Bronsted acid in combination. Moreover, the amount of fluorine-containing Bronsted acid used is extremely small, many are commercially available, and are easy to prepare. In addition, it is inexpensive because it contains no precious metal. Further, the compound (2) which is a starting material for introducing an alkyl group or the like is a carbonyl compound, and these are highly versatile because they can be obtained in a very wide variety at low cost and easily. There are very few structural constraints on the compound (3) that can be introduced and produced. In addition, compound (3) can be produced with a short number of steps and without requiring complicated operations. Furthermore, since a catalyst containing a metal is unnecessary, the present invention has a very small load on the environment. Thus, the present invention provides a simple and practical new method for producing compound (3).

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 fluorine-containing Bronsted acid 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 Et: ethyl group t-Bu: tert-butyl group Bn: benzyl group HNTf _2: Formula (42) fluorine represented by the Bronsted acid HNNf _2: containing represented by the formula (41) Fluorine Bronsted acid HN (SO ₂ CF ₂ ) ₂ CF ₂ : Fluorine-containing Bronsted acid represented by the above formula (43) HOTf: Fluorine-containing Bronsted acid represented by the above formula (46) HONf: 45) Fluorine-containing Bronsted acid represented by 45) HCTf ₂ C ₆ F ₅ : Fluorine-containing Bronsted acid represented by the formula (44)

(Example 1)
As shown in Tables 1 and 2, a compound wherein ^{R 1} is a methyl group (1) (1.80 mmol), compound wherein ^{R 2} is a methyl group, ^{R 3} is a n- octyl group (2) (0.60 mmol) , Triethylsilane (0.90 mmol) and HNTf ₂ (3 mol%) were mixed in 1,4-dioxane (0.60 ml) and reacted at 85 ° C. for 5 hours. Next, 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 NMR data of the obtained compound (3101) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.87 (t, J = 7.2 Hz, 3 H), 1.17 (d, J = 6.9 Hz, 3 H), 1.20-1.35 (m, 12 H), 1.37- 1.47 (m, 1 H), 1.48-1.60 (m, 1 H), 2.60 (sext, J = 6.9 Hz, 1 H), 3.60 (s, 3 H), 5.99 (t, J = 2.3 Hz, 1 H ), 6.37 (t, J = 2.0 Hz, 1 H), 6.51 (t, J = 2.3 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.1, 22.2, 22.7, 27.7, 29.4, 29.7, 29.9, 31.8, 31.9, 36.0, 38.8, 106.6, 118.0, 121.2, 131.1.

(Example 2)
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 ) δ0.88 (t, J = 7.0 Hz, 3 H), 1.17 (d, J = 6.9 Hz, 3 H), 1.22-1.34 (m, 4 H), 1.37- 1.48 (m, 1 H), 1.49-1.59 (m, 1 H), 2.60 (sext, J = 6.9 Hz, 1 H), 3.60 (s, 3 H), 5.99 (t, J = 2.2 Hz, 1 H ), 6.37 (t, J = 2.0 Hz, 1 H), 6.50 (dd, J = 2.6, 2.3 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.1, 22.2, 22.9, 29.9, 31.8, 36.0, 38.5, 106.7, 118.0, 121.2, 131.1.

(Example 3)
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.
The NMR data of the obtained compound (3103) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ0.84 (t, J = 7.5 Hz, 6 H), 1.40-1.51 (m, 2 H), 1.51-1.65 (m, 2 H), 2.25 (tt, J = 8.1, 5.6 Hz, 1 H), 3.60 (s, 3 H), 5.93 (t, J = 2.2 Hz, 1 H), 6.35 (t, J = 1.9 Hz, 1 H), 6.51 (t, J = 2.4 Hz, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 12.1, 29.0, 36.0, 41.2, 106.9, 119.0, 121.1, 128.6.

Example 4
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 Table 2, it has been described one group only as R ² and R ^3, which indicates that R ² and R ³ are combined to form a ring with each other. The same applies to the following embodiments.
The NMR data of the obtained compound (3104) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ1.45-1.60 (m, 6 H), 1.60-1.67 (m, 2 H), 1.67-1.79 (m, 2 H), 1.93-2.02 (m, 2 H ), 2.60-2.69 (m, 1 H), 3.60 (s, 3 H), 5.99 (t, J = 2.0 Hz, 1 H), 6.38 (t, J = 2.0 Hz, 1 H), 6.50 (t, J = 2.6 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ26.5, 28.3, 36.0, 36.8, 38.6, 106.8, 117.6, 121.3, 132.5.

(Example 5)
As shown in Tables 1 and 2, compound (1) (2.40 mmol) in which R ¹ is a methyl group, compound (2) (0) in which R ² and R ³ are bonded to each other to form an adamantyl group .60 mmol) and HNTf ₂ (3 mol%) were mixed in 1,4-dioxane (0.6 ml) and reacted at 100 ° C. for 24 hours. Next, triethylsilane (0.90 mmol) was added, and the mixture was further reacted at 100 ° C. for 3 hours. Subsequently, the product was purified by silica gel column chromatography, and the target compound (3105) was taken out. In Table 2, “reaction time (h): 24 → 3” indicates that the reaction was performed at 100 ° C. for 24 hours before addition of triethylsilane and further at 100 ° C. for 3 hours after addition of triethylsilane. The same applies to the following embodiments.
The NMR data of the obtained compound (3105) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ1.51 (d, J = 12.6 Hz, 2 H), 1.75 (s, 3 H), 1.84-1.95 (m, 5 H), 1.99 (d, J = 12.6 Hz, 2 H), 2.15 (s, 2 H), 2.92 (s, 1 H), 3.63 (s, 3 H), 6.02 (t, J = 2.0 Hz, 1 H), 6.42 (dd, J = 3.2 , 2.0 Hz, 1 H), 6.54 (t, J = 2.6 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ28.15, 28.19, 32.15, 32.17, 36.1, 38.3, 39.0, 42.7, 107.1, 118.8, 121.0, 128.4.

(Example 6)
Compound (3106) 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 (3106) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ1.73 (qd, J = 12.5, 3.0 Hz, 2 H), 2.21 (dq, J = 13.8, 3.3 Hz, 2 H), 2.47 (tt, J = 11.8, 3.3 Hz, 1 H), 2.63-2.70 (m, 2 H), 2.79 (td, J = 12.9, 3.5 Hz, 2 H), 3.61 (s, 3 H), 6.00 (t, J = 2.3 Hz, 1 H), 6.38 (t, J = 2.0 Hz, 1 H), 6.52 (t, J = 2.6 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ29.1, 35.6, 36.0, 36.1, 106.4, 117.7, 121.5, 130.1.

(Example 7)
Compound (3107) 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 (3107) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ1.19 (d, J = 6.9 Hz, 3 H), 1.42-1.51 (m, 1 H), 1.55-1.62 (m, 1 H), 1.58 (d, J = 0.6 Hz, 3 H), 1.68 (d, J = 1.2 Hz, 3 H), 1.97 (q, J = 7.4 Hz, 2 H), 2.62 (sext, J = 7.0 Hz, 1 H), 3.60 (s , 3 H), 5.10-5.15 (m, 1 H), 5.99 (t, J = 2.3 Hz, 1 H), 6.37 (t, J = 1.7 Hz, 1 H), 6.51 (t, J = 2.6 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ17.7, 22.2, 25.7, 26.1, 31.4, 36.0, 38.7, 106.7, 118.1, 121.3, 125.0, 130.8, 131.1.

(Example 8)
Compound (3108) 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 (3108) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ1.20 (d, J = 6.8 Hz, 3 H), 1.44-1.74 (m, 4 H), 2.03 (s, 3 H), 2.64 (sext, J = 6.9 Hz, 1 H), 3.60 (s, 3 H), 4.04 (t, J = 6.6 Hz, 2 H), 5.97 (t, J = 2.1 Hz, 1 H), 6.37 (t, J = 1.8 Hz, 1 H), 6.51 (t, J = 2.5 Hz, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ21.0, 22.2, 26.7, 31.6, 34.8, 36.0, 64.9, 106.6, 118.1, 121.4, 130.1, 171.3.

Example 9
Compound (3109) 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. Here, a mixture of diastereomers (78/22, molar ratio) was obtained as the compound (3109).
The NMR data of the obtained compound (3109) are shown below.
Major isomers:
¹ H NMR (500 MHz) δ1.27 (d, J = 7.2 Hz, 3 H), 2.10-2.23 (m, 2 H), 2.88 (td, J = 9.5, 3.8 Hz, 1 H), 3.34 (qd , J = 7.1, 3.8 Hz, 1 H), 3.61 (s, 3 H), 4.10-4.20 (m, 2 H), 6.01 (t, J = 2.3 Hz, 1 H), 6.44 (t, J = 1.7 Hz, 1 H), 6.53 (t, J = 2.4 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ16.5, 24.3, 31.7, 36.1, 45.8, 66.7, 107.1, 118.8, 121.8, 126.5, 178.8.
Minor isomers:
¹ H MNR (500 MHz) δ1.34 (d, J = 7.2 Hz, 3 H), 2.05 (dq, J = 12.7, 8.5 Hz, 1 H), 2.12-2.20 (m, 1 H), 2.68 (td , J = 9.0, 4.5 Hz, 1 H), 3.42 (qd, J = 7.2, 4.3 Hz, 1 H), 3.59 (s, 3 H), 3.93 (td, J = 8.7, 4.4 Hz, 1 H), 4.09 (dt, J = 8.6, 8.0 Hz, 1 H), 6.00 (t, J = 2.3 Hz, 1 H), 6.43 (dd, J = 2.7 Hz, 1 H), 6.50 (t, J = 2.5 Hz, 1H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ19.7, 23.8, 31.7, 36.1, 46.5, 66.8, 107.5, 119.8, 121.5, 124.1, 179.4.

(Example 10)
Compound (3110) 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 (3110) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ1.19 (d, J = 6.9 Hz, 3 H), 1.36-1.61 (m, 4 H), 1.76 (quint, J = 7.0 Hz, 2 H), 2.62 ( sext, J = 6.8 Hz, 1 H), 3.51 (t, J = 6.9 Hz, 2 H), 3.60 (s, 3 H), 5.97 (t, J = 2.1 Hz, 1 H), 6.37 (t, J = 2.1 Hz, 1 H), 6.51 (t, J = 2.5 Hz, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 22.2, 25.0, 31.8, 32.9, 36.0, 37.9, 45.2, 106.6, 118.1, 121.4, 130.5.

(Example 11)
Compound (3111) was obtained in the same manner as in Example 5 except that the reaction was performed under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3111) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ1.56 (d, J = 7.3 Hz, 3 H), 3.58 (s, 3 H), 4.00 (q, J = 7.2 Hz, 1 H), 5.96 (t, J = 2.1 Hz, 1 H), 6.31 (t, J = 2.1 Hz, 1 H), 6.51 (t, J = 2.3 Hz, 1 H), 7.13-7.21 (m, 1 H), 7.23-7.33 (m , 4 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ22.8, 36.1, 38.0, 107.5, 118.9, 121.6, 125.7, 127.4, 128.2, 129.7, 147.9.

(Example 12)
Compound (3201) was obtained in the same manner as in Example 5 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 ) δ0.87 (t, J = 6.9 Hz, 3 H), 1.18-1.39 (m, 12 H), 1.23 (d, J = 6.9 Hz, 3 H), 1.44- 1.63 (m, 2 H), 2.68 (sext, J = 6.9 Hz, 1 H), 6.21 (t, J = 2.3 Hz, 1 H), 6.87 (s, 1 H), 7.02 (t, J = 2.6 Hz , 1 H), 7.19 (t, J = 6.9 Hz, 1 H), 7.34-7.43 (m, 4 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ14.1, 21.9, 22.7, 27.6, 29.4, 29.6, 29.9, 31.9, 38.5, 109.4, 115.3, 118.7, 119.9, 125.0, 129.4, 133.0, 140.9 (one signal is It was not possible to see clearly because it overlapped with other signals.)

(Example 13)
Compound (3301) 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 (3301) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.88 (s, 9 H), 1.50 (s, 9 H), 2.31 (s, 2 H), 5.93 (t, J = 2.0 Hz, 1 H), 6.55 (t, J = 2.0 Hz, 1 H), 6.70 (t, J = 2.6 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ29.4, 30.7, 31.1, 41.9, 54.2, 109.6, 116.3, 116.9, 120.7.

(Example 14)
Compound (3112) was obtained in the same manner as in Example 5 except that the reaction was carried out under the conditions shown in Tables 1 and 2.
The NMR data of the obtained compound (3112) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ1.61 (ddd, J = 13.1, 3.6, 2.7 Hz, 2 H), 1.70-1.77 (m, 3 H), 1.92 (ddd, J = 13.3, 3.6, 2.7 Hz, 2 H), 1.97-2.05 (m, 3 H), 2.41 (dd, J = 13.2, 2.3 Hz, 2 H), 2.46 (t, J = 2.9 Hz, 2 H), 3.64 (s, 3 H ), 6.10 (dd, J = 2.9, 1.7 Hz, 1 H), 6.55 (dd, J = 2.3, 1.7 Hz, 1 H), 6.57 (dd, J = 2.9, 2.3 Hz, 1 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ26.9, 31.5, 34.1, 34.9, 36.4, 37.63, 37.64, 42.9, 106.5, 119.6, 122.1, 123.0, 124.9.

(Example 15)
As shown in Tables 1 and 2, compound (1) (1.20 mmol) in which R ¹ is a benzyl group, compound (2) (0.30 mmol) in which R ² is a methyl group and R ³ is an n-hexyl group And HNTf ₂ (5 mol%) were mixed in 1,4-dioxane (2.4 ml) and reacted at 100 ° C. for 8 hours. Subsequently, 2-methylfuran (0.75 mmol) was added, and the mixture was further reacted at 70 ° C. for 15 hours. Subsequently, the product was purified by silica gel column chromatography, and the target compound (3401) was taken out. In Table 2, “reaction temperature (° C.): 100 → 70” and “reaction time (h): 8 → 15” are described as follows. It shows having made it react at 70 degreeC after furan addition for 15 hours.
The NMR data of the obtained compound (3401) are shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ0.85 (t, J = 6.9 Hz, 3 H), 1.07-1.30 (m, 8 H), 1.51 (s, 3 H), 1.77-1.86 (m, 1 H), 1.90-2.00 (m, 1 H), 2.24 (s, 3 H), 5.00 (s, 2 H), 5.80-5.83 (m, 1 H), 5.85 (d, J = 2.9 Hz, 1 H ), 6.06 (dd, J = 2.9, 1.7 Hz, 1 H), 6.45 (t, J = 2.0 Hz, 1 H), 6.55 (t, J = 2.6 Hz, 1 H), 7.08 (d, J = 6.9 Hz, 2 H), 7.22-7.35 (m, 3 H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ13.7, 14.1, 22.7, 24.6, 25.2, 29.9, 31.8, 39.1, 41.7, 53.3, 104.4, 105.3, 107.4, 118.0, 120.5, 126.9, 127.4, 128.6, 131.7, 138.5, 149.9, 161.1.

(Examples 16 to 25)
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 is 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 (5)

A pyrrole represented by the following general formula (1), a carbonyl compound represented by the following general formula (2), and a nucleophilic donor are reacted in the presence of a fluorinated Bronsted acid. The manufacturing method of the pyrrole derivative represented by following General formula (3).

Wherein R ¹ is a hydrogen atom, aliphatic group, aryl group, arylalkyl group, alkylaryl group or trialkylsilyl group; R ² and R ³ each independently have a hydrogen atom or a substituent And may be an aliphatic group, 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 a nucleophilic species.) 2. The pyrrole 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 an arylalkyl group having 7 to 15 carbon atoms. A method for producing a derivative. R ² and R ³ are each independently a hydrogen atom or an optionally substituted alkyl group, alkenyl group or aryl group having 20 or less carbon atoms, or an optionally substituted carbon number. The method for producing a pyrrole derivative according to claim 1, wherein the pyrrole derivative is 19 or less heteroaryl group.   The said X is a hydrogen atom, a cyano group, an aryl group, or heteroaryl group, The manufacturing method of the pyrrole derivative as described in any one of Claims 1-3 characterized by the above-mentioned.   The fluorine-containing Bronsted acid has at least one selected from the group consisting of a fluoroalkyl group, a fluoroalkylene group, a fluoroaryl group, and a fluoroarylene group. A method for producing a pyrrole derivative according to one item.