WO2024135652A1

WO2024135652A1 - Reissert-henze reaction using phosphonic acid anhydride as activator

Info

Publication number: WO2024135652A1
Application number: PCT/JP2023/045419
Authority: WO
Inventors: 明日香山川; 晴也鈴木; 好廷野村; 泰啓平田; 祐介 ▲高▼平
Original assignee: Ａｇｃ株式会社
Priority date: 2022-12-22
Filing date: 2023-12-19
Publication date: 2024-06-27

Abstract

The present invention addresses the problem of providing an efficient method for producing a substituted aromatic heterocyclic compound. The present invention relates to a Reissert-Henze reaction that uses a phosphonic acid anhydride as an activator. The present invention makes it possible to provide a simple and practical method for producing a substituted aromatic heterocyclic compound which is useful as an intermediate for an agricultural chemical or a pharmaceutical.

Description

Reissert-Henze reaction using phosphonic anhydride as an activator

The present invention relates to a method for producing a substituted nitrogen-containing aromatic heterocyclic compound using the Reissert-Henze reaction with a phosphonic anhydride as an activator.

Substituted nitrogen-containing aromatic heterocyclic compounds, particularly those in which a substituent has been introduced into the carbon atom adjacent to the ring-constituting nitrogen atom of the nitrogen-containing aromatic heterocyclic compound (hereinafter sometimes referred to as the "2-position"), are useful as pharmaceuticals or agricultural chemicals, as synthetic intermediates thereof, and also in the field of materials chemistry.

　Methods of introducing a substituent into the 2-position of a nitrogen-containing aromatic heterocyclic compound include a method of converting the halo group at the 2-position of a 2-halopyridine into a substituent by a nucleophilic substitution reaction (Non-Patent Documents 1 and 2), a method using a coupling reaction using a metal catalyst (Non-Patent Document 3), a method using the Reissert reaction in which a cyanide source is nucleophilically added to the 2-position of a quinoline or isoquinoline in the presence of an acid halide (Non-Patent Document 4), and a method using the Reissert-Henze reaction in which a nucleophile is reacted with a nitrogen-containing aromatic heterocyclic N-oxide in the presence of an activator (Non-Patent Document 5). Among these, the Reissert-Henze reaction method allows the selection of the nucleophile, and many examples of reactions using carboxylic acid anhydrides, sulfonic acid anhydrides, or phosphonium salts such as (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Pybrop; registered trademark) as an activator have been reported (Non-Patent Document 5). In particular, the Reissert-Henze reaction, which uses Pybrop as an activator, has a wide range of applications and good yields, but there remain issues with its practical application in terms of cost and operability.

Phosphonic anhydrides have been reported to be used as condensing agents in peptide synthesis and the like (Non-Patent Document 6), but there have been no examples of their use as activating agents in the Reissert-Henze reaction.

The object of the present invention is to provide a practical method for producing 2-position substituted nitrogen-containing aromatic heterocyclic compounds that can be applied to a variety of substrates in an inexpensive and simple manner.

As a result of intensive research aimed at solving the above problems, the present inventors discovered that a substituted aromatic heterocyclic compound having a partial structure represented by the following formula (III) can be produced in a simple and inexpensive manner with few by-products and in good yield by reacting an N-oxide aromatic heterocyclic compound having a partial structure represented by the following formula (I) with a nucleophile represented by the following formula (II) in a solvent in the presence of a phosphonic acid anhydride, and thus completed the present invention.

That is, the present invention is as follows.
[1]
In a solvent, in the presence of a phosphonic acid anhydride, a compound of formula (I):

An N-oxide aromatic heterocyclic compound having a partial structure represented by formula (II):

(In the formula, Nu represents a nucleophilic group;
M represents a hydrogen atom, a tri-substituted silyl group, an alkali metal, or an alkaline earth metal halide.
The present invention comprises a step of reacting a nucleophilic agent represented by formula (III):

(In the formula, Nu has the same meaning as above.)
(hereinafter, also referred to as "the production method of the present invention" or "the reaction of the present invention").
[2]
Nu is a halogen atom, a cyano group, an azide group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted alkylsulfanyl group, an optionally substituted arylsulfanyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkylsulfonyl(aryl)amino group, an optionally substituted alkylsulfonyl(alkyl)amino group, an optionally substituted arylsulfonyl(alkyl)amino group, an optionally substituted arylsulfonyl(aryl)amino group, and a group represented by the following formula:

(wherein ^* indicates the bonding position with M;
R represents a hydrogen atom or a methyl group; and the two EWGs each independently represent a cyano group, a nitro group, a haloalkyl group, an optionally substituted alkyl-carbonyl group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl-carbonyl group, an optionally substituted aryloxy-carbonyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylsulfinyl group, an optionally substituted arylsulfinyl group, an optionally substituted dialkylphosphono group or an optionally substituted diarylphosphono group, or the two EWGs may, together with the carbon atom to which they are bonded, form an optionally substituted cyclic β-diketone, cyclic β-diester or cyclic β-ketoester.
However, when EWG is an optionally substituted alkyl-carbonyl group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl-carbonyl group or an optionally substituted aryloxy-carbonyl group, or when two EWGs, together with the carbon atoms to which they are bonded, form an optionally substituted cyclic β-diketone, cyclic β-diester or cyclic β-ketoester, they may be enol tautomers, and ^* may be on the oxygen atom derived from the carbonyl.)
The method according to the above-mentioned [1], wherein the nucleophilic group is selected from the group consisting of groups represented by the following formula (I):
[3]
Nu is an optionally substituted alkylsulfanyl group, an optionally substituted nitrogen-containing heterocyclic group, an optionally substituted monoarylamino group, an optionally substituted alkylsulfonyl(aryl)amino group, an optionally substituted arylsulfonyl(aryl)amino group, or a group represented by the following formula:

(wherein ^* indicates the bonding position with M;
R represents a hydrogen atom or a methyl group; and R' and R" each independently represent an optionally substituted alkyl group, alkoxy group, aryl group or aryloxy group, or R' and R" together with the carbon atom to which they are attached may form an optionally substituted 4- to 8-membered cycloalkane or saturated oxygen-containing heterocycle.
and M is a hydrogen atom.
[4]
The phosphonic anhydride is represented by formula (IV):

(In the formula, n+1 R ^1s each independently represent a C _1-6 alkyl group or a C _6-10 aryl group; and n represents an integer from 1 to 8.)
The method according to any one of the above [1] to [3], wherein the phosphonic acid anhydride is represented by the formula:
[5]
The phosphonic anhydride has the formula (V):

(In the formula, the three ^R2s each independently represent a _C1-6 alkyl group or a _C6-10 aryl group.)
The method according to any one of the above [1] to [3], wherein the phosphonic acid anhydride is represented by the formula:
[6]
The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA) or (IB):

[Wherein,
X ^1a represents CR ^1a or a nitrogen atom;
X ^1b represents CR ^1b or a nitrogen atom;
X ^1c represents CR ^1c or a nitrogen atom;
X ^1d represents CR ^1d or a nitrogen atom;
R ^1a , R ^1b , R ^1c and R ^1d each independently represent a hydrogen atom, a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group; or R ^1a and R ^1b , R ^1b and R ^1c , or R ^1c and R ^1d may, together with the carbon atom to which they are bonded, form a 6- to 10-membered aromatic ring optionally substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, and an optionally substituted aralkyl group;
X ^2a represents CR ^2a , a nitrogen atom, NR ^2a , a sulfur atom or an oxygen atom;
^X2b represents ^CR2b or a nitrogen atom;
X ^2c represents CR ^2c , a nitrogen atom, NR ^2c , a sulfur atom or an oxygen atom;
R ^2a , R ^2b and R ^2c each independently represent a hydrogen atom, a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R ^2a and R ^2b , or R ^2b and R ^2c may, together with the carbon atom to which they are bonded, form a 6- to 10-membered aromatic ring which may be substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, and an optionally substituted aralkyl group.]
The method according to any one of the above [1] to [5], wherein the compound is an N-oxide aromatic heterocyclic compound represented by the formula:
[7]
The method according to any one of the above [1] to [6], wherein the step is carried out in the presence of a base.
[8]
The method according to the above [7], wherein the base is an organic base.
[9]
The method according to the above [8], wherein the organic base is a tertiary amine.
[10]
The method according to any one of the above [1] to [9], wherein the solvent is an aprotic solvent.
[11]
The production method according to the above-mentioned [10], wherein the aprotic solvent is an aromatic hydrocarbon solvent selected from the group consisting of benzene, toluene and xylene; a halogenated hydrocarbon solvent selected from the group consisting of dichloromethane, chloroform and 1,2-dichloroethane; an aliphatic hydrocarbon solvent selected from the group consisting of n-hexane, n-heptane and cyclohexane; an ether solvent selected from the group consisting of tetrahydrofuran, dioxane, diethyl ether, glyme and diglyme; a nitrile solvent selected from the group consisting of acetonitrile, propionitrile, dimethylcyanamide and tert-butylnitrile; an amide solvent selected from the group consisting of N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide and dimethylimidazole; an ester solvent selected from the group consisting of ethyl acetate, propyl acetate and butyl acetate; or a mixed solvent of two or more thereof.
[12]
The method according to any one of the above-mentioned [1] to [11], further comprising a post-treatment step of adding water and an organic solvent which undergoes phase separation from water to the reaction mixture after the above-mentioned step, and subjecting the reaction mixture to a separation operation, thereby removing compounds derived from the phosphonic acid anhydride from the reaction mixture.

In accordance with the present invention, by subjecting N-oxide aromatic heterocyclic compound (I) to the Reissert-Henze reaction using an inexpensive and readily available phosphonic anhydride as an activator, it is possible to easily carry out post-treatment and purification, produce few by-products, and produce in good yield a 2-position substituted aromatic heterocyclic compound (III) that is useful as a synthetic intermediate for pharmaceuticals or agricultural chemicals and also in the field of materials chemistry. In addition, since the nucleophile (II) can be selected as needed, the present invention can provide a practical method for producing 2-position substituted aromatic heterocyclic compound (III) that has a wide range of applications and can be scaled up.

The definitions of the groups used in this specification are explained in detail below. Unless otherwise specified, the groups have the following definitions.

In this specification, compounds represented by a formula are referred to as "compound" followed by the formula number. For example, a compound represented by formula (1) is referred to as "compound (1)."

In this specification, a numerical range expressed as "~" or "-" means that the numbers before and after "~" or "-" are the lower and upper limits of the numerical range.

In this specification, when the element symbol "C" is followed by a numerical range indicated by numbers before and after "-" and is used to indicate the name of any group, it indicates any group having an integer number of carbon atoms, with the numbers before and after "-" being the lower or upper limit. For example, an alkyl group having 1 to 3 carbon atoms is sometimes indicated as a " _C1-3 alkyl group", which indicates each of _-CH3 _{, -C2H5} _, _-C3H7 _, etc. The same applies to other groups.

In this specification, "halogen atom" means a fluorine atom, chlorine atom, bromine atom, or iodine atom.

In the present specification, an "alkyl group" means a linear or branched saturated hydrocarbon group having one or more carbon atoms, and when there is no particular limitation on the carbon number range, is a _C1-20 alkyl group, and of these, a _C1-6 alkyl group is preferable.

In the present specification, a "C _1-20 alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms. Examples of the "C _1-20 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, stearyl (octadecyl), icosyl, and the like.

In the present specification, a " _C1-6 alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of the " _C1-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like, with a _C1-4 alkyl group being preferred.

In the present specification, a "C _1-4 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. Examples of the "C _1-4 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

In the present specification, a "haloalkyl group" means a group in which one or more hydrogen atoms in the above-mentioned "alkyl group" are substituted with a halogen atom, and when there is no particular limitation on the range of the carbon number, it is a _C1-20 haloalkyl group, and of these, a _C1-6 haloalkyl group is preferable.

In the present specification, the term " _C1-6 haloalkyl group" refers to a group in which one or more hydrogen atoms in the above " _C1-6 alkyl group" have been substituted with a halogen atom. Examples of the " _C1-6 haloalkyl group" include fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, trifluoromethyl, difluoromethyl, perfluoroethyl, perfluoropropyl, chloromethyl, 2-chloroethyl, bromomethyl, 2-bromoethyl, iodomethyl, 2-iodoethyl and the like. Of these, a _C1-6 fluoroalkyl group is preferable.

In the present specification, the term "C _1-6 fluoroalkyl group" refers to a group in which one or more hydrogen atoms in the above-mentioned "C _1-6 alkyl group" have been substituted with a fluorine atom. Examples of the "C _1-6 fluoroalkyl group" include fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, trifluoromethyl, difluoromethyl, perfluoroethyl, perfluoropropyl, and the like. Among these, C _1-4 fluoroalkyl groups (e.g., trifluoromethyl, pentafluoroethyl) are preferred.

In this specification, the term "perfluoroalkyl group" refers to an alkyl group in which all hydrogen atoms are replaced with fluorine atoms.

In the present specification, the term "cycloalkyl group" means a cyclic alkyl group, and unless there is any particular limitation on the range of the carbon number, it is preferably a C _3-8 cycloalkyl group.

In the present specification, "C _3-8 cycloalkyl group" means a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Of these, a C _3-6 cycloalkyl group is preferred.

In the present specification, an "alkenyl group" means a straight-chain or branched-chain unsaturated hydrocarbon group having at least one double bond, and, unless there is any particular limitation on the range of the number of carbon atoms, is preferably a _C2-20 alkenyl group, and of these, a _C2-6 alkenyl group is more preferable.

In the present specification, a " _C2-20 alkenyl group" means a straight-chain or branched unsaturated hydrocarbon group having 2 to 20 carbon atoms and having at least one double bond. Examples of the " _C2-20 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1-octenyl, 1-decenyl, 1-octadecenyl, 1-icosenyl and the like.

In the present specification, a " _C2-6 alkenyl group" refers to a straight-chain or branched-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and having at least one double bond. Examples of the " _C2-6 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl and the like.

In the present specification, an "alkynyl group" means a straight-chain or branched-chain unsaturated hydrocarbon group having at least one triple bond, and, unless there is any particular limitation on the range of the number of carbon atoms, is preferably a _C2-20 alkynyl group, and of these, a _C2-6 alkynyl group is more preferable.

In the present specification, a " _C2-20 alkynyl group" refers to a straight-chain or branched-chain unsaturated hydrocarbon group having 2 to 20 carbon atoms and having at least one triple bond. Examples of the " _C2-20 alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, 1-octynyl, 1-decynyl, 1-octadecynyl, 1-icosynyl and the like.

In the present specification, a "C _2-6 alkynyl group" refers to a straight-chain or branched-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and having at least one triple bond. Examples of the "C _2-6 alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl and the like.

In the present specification, the term "alkoxy group" refers to a group in which the above-mentioned alkyl group is bonded to an oxygen atom, and may be either linear or branched. The range of the carbon number is not particularly limited, but is preferably a _C1-6 alkoxy group.

In the present specification, "C _1-6 alkoxy group" means an alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like, with a C _1-4 alkoxy group being preferred.

In the present specification, the term "alkylsulfanyl group" refers to a group in which one alkyl group as described above is bonded to a sulfur atom, and may be either linear or branched. When there is no particular limitation on the range of the carbon number, it is a _C1-20 alkylsulfanyl group, and preferably a _C1-6 alkylsulfanyl group.

In the present specification, "C _1-6 alkylsulfanyl group" means an alkylsulfanyl group having 1 to 6 carbon atoms, and examples include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, hexylsulfanyl, etc. Among these, a C _1-4 alkylsulfanyl group is preferable.

In the present specification, the term "alkylsulfonyl group" refers to a group in which one alkyl group as described above is bonded to a sulfonyl (-S(=O) ₂ -) group, and may be either linear or branched. The carbon number range is not particularly limited, but a C _1-6 alkylsulfonyl group is preferred.

In the present specification, "C _1-6 alkylsulfonyl group" means an alkylsulfonyl group having 1 to 6 carbon atoms, and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl etc. Among these, a C _1-4 alkylsulfonyl group is preferable.

In the present specification, the "alkylsulfinyl group" means a group in which one alkyl group as described above is bonded to a sulfinyl (-S(=O)-) group, and may be either linear or branched. The range of the carbon number is not particularly limited, but a _C1-6 alkylsulfinyl group is preferred.

In the present specification, "C _1-6 alkylsulfinyl group" means an alkylsulfinyl group having 1 to 6 carbon atoms, and examples thereof include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl etc. Among these, a C _1-4 alkylsulfinyl group is preferable.

In the present specification, a "dialkylphosphono group" refers to a group in which two of the above-mentioned alkyl groups replace two hydrogen atoms of a phosphono group (-PO(OH) ₂ ). The range of the carbon number is not particularly limited, but a di-C _1-6 alkylphosphono group is preferred.

In the present specification, the "di-C _1-6 alkylphosphono group" means a dialkylphosphono group having 1 to 6 carbon atoms, and examples thereof include dimethylphosphono, diethylphosphono, dipropylphosphono, diisopropylphosphono, dibutylphosphono, diisobutylphosphono, disec-butylphosphono, ditert-butylphosphono, dipentylphosphono, dihexylphosphono, etc. Of these, a di-C _1-4 alkylphosphono group is preferable.

In the present specification, the term "monoalkylamino group" refers to a group in which one alkyl group as described above is bonded to an amino group. The range of the carbon number is not particularly limited, but a mono- _C1-6 alkylamino group is preferred.

In the present specification, examples of the "mono-C _1-6 alkylamino group" include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino and the like, and a mono-C _1-4 alkylamino group is preferable.

In the present specification, the term "dialkylamino group" refers to a group in which two of the above-mentioned alkyl groups are bonded to an amino group. The range of the carbon number is not particularly limited, but a di-C _1-6 alkylamino group is preferred.

In the present specification, examples of the "di-C _1-6 alkylamino group" include dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, disec-butylamino, ditert-butylamino, dipentylamino, dihexylamino and the like, and a di-C _1-4 alkylamino group is preferable.

In the present specification, the term "alkoxy-carbonyl group" means a group in which the above-mentioned alkoxy group is bonded to a carbonyl group, and while there are no particular limitations on the range of the carbon number, it is preferably a C _1-6 alkoxy-carbonyl group.

In the present specification, examples of the "C _1-6 alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like, and a C _1-4 alkoxy-carbonyl group is preferable.

In the present specification, the term "alkyl-carbonyl group" means a group in which the above-mentioned alkyl group is bonded to a carbonyl group, and although the range of the carbon number is not particularly limited, it is preferably a C _1-6 alkyl-carbonyl group.

In the present specification, examples of the "C _1-6 alkyl-carbonyl group" include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexylcarbonyl and the like, and a C _1-4 alkyl-carbonyl group is preferable.

In the present specification, the term "haloalkoxy group" means the above-mentioned alkoxy group in which one or more hydrogen atoms have been substituted with halogen, and while the carbon number range is not particularly limited, it is preferably a _C1-6 haloalkoxy group.

In the present specification, examples of the "C _1-6 haloalkoxy group" include bromomethoxy, 2-bromoethoxy, 3-bromopropoxy, 4-bromobutoxy, iodomethoxy, 2-iodoethoxy, 3-iodopropoxy, 4-iodobutoxy, fluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, tribromomethoxy, trichloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroethoxy, perfluoropropoxy, perfluoroisopropoxy, 1,1,2,2-tetrafluoroethoxy and 2-chloro-1,1,2-trifluoroethoxy.

In the present specification, an "aryl group" refers to a monocyclic or polycyclic (fused) hydrocarbon group having aromaticity, and examples thereof include _C6-14 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 1-anthryl, 2-anthryl, etc. Of these, a _C6-10 aryl group is preferred.

In the present specification, a "C _6-10 aryl group" means a hydrocarbon group having aromaticity and having 6 to 10 carbon atoms. Examples of the "C _6-10 aryl group" include phenyl, 1-naphthyl, and 2-naphthyl, with phenyl being preferred.

In the present specification, the term "aralkyl group" means a group in which the above-mentioned aryl group is bonded to the above-mentioned alkyl group, and among these, a C _7-16 aralkyl group is preferable.

In the present specification, the term " _C7-16 aralkyl group" refers to a " _C1-6 alkyl group" substituted with a " _C6-10 aryl group". Examples of the " _C7-16 aralkyl group" include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, (1-naphthyl)methyl, (2-naphthyl)methyl and the like, with benzyl being preferred.

In the present specification, the term "aryl-carbonyl group" means a group in which the above-mentioned aryl group is bonded to a carbonyl group, and although there are no particular limitations on the range of the carbon number, it is preferably a C _6-10 aryl-carbonyl group.

In the present specification, examples of the "C _6-10 aryl-carbonyl group" include phenylcarbonyl (benzoyl), 1-naphthylcarbonyl, 2-naphthylcarbonyl, and the like, and of these, benzoyl is preferable.

In the present specification, the term "aryloxy group" means a group in which the above-mentioned aryl group is bonded to an oxygen atom, and is preferably a C _6-10 aryloxy group.

In the present specification, examples of the "C _6-10 aryloxy group" include phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like, with phenyloxy being preferred.

In the present specification, the term "aryloxy-carbonyl group" means a group in which the aryloxy group is bonded to a carbonyl group, and although there are no particular limitations on the range of the number of carbon atoms, it is preferably a C _aryloxy -carbonyl group (e.g., phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), more preferably phenoxycarbonyl.

In the present specification, the term "arylsulfonyl group" means a group in which one aryl group as described above is bonded to a sulfonyl (-S(=O) ₂ -) group, and although there is no particular limitation on the carbon number range, it is preferably a C _6-10 arylsulfonyl group.

In this specification, examples of the "C _6-10 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.

In the present specification, an "arylsulfinyl group" means a group in which one aryl group as described above is bonded to a sulfinyl (-S(=O)-) group, and although there is no particular limitation on the carbon number range, it is preferably a _C6-10 arylsulfinyl group.

In the present specification, examples of the "C _6-10 arylsulfinyl group" include phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, and the like.

As used herein, a "diarylphosphono group" refers to a group in which two of the above-mentioned aryl groups replace two hydrogen atoms of a phosphono group (-PO(OH) ₂ ). There is no particular limitation on the range of the carbon number, but a di-C _6-10 arylphosphono group is preferred.

In the present specification, examples of the "di-C _6-10 arylphosphono group" include diphenylphosphono, di(1-naphthyl)phosphono, di(2-naphthyl)phosphono, etc. Of these, a diphenylphosphono group is preferable.

In the present specification, the term "monoarylamino group" means a group in which one of the above-mentioned aryl groups is bound to an amino group, and is preferably a mono-C _6-10 arylamino group.

In the present specification, examples of the "mono-C _6-10 arylamino group" include phenylamino, 1-naphthylamino, 2-naphthylamino and the like, with phenylamino being preferred.

In the present specification, the term "diarylamino group" means a group in which two of the above-mentioned aryl groups are bonded to an amino group, and is preferably a di-C _6-10 arylamino group.

In this specification, examples of the "di-C _6-10 arylamino group" include diphenylamino, di-1-naphthylamino, di-2-naphthylamino and the like, with diphenylamino being preferred.

In the present specification, the term "alkylsulfonyl(aryl)amino group" means a group in which one alkylsulfonyl group and one aryl group are bonded to an amino group, and is preferably a C _{alkylsulfonyl} (C _aryl )amino group.

In the present specification, examples of the "C _1-6 alkylsulfonyl(C _6-10 aryl)amino group" include methylsulfonyl(phenyl)amino, methylsulfonyl(1-naphthyl)amino, methylsulfonyl(2-naphthyl)amino, ethylsulfonyl(phenyl)amino, ethylsulfonyl(1-naphthyl)amino, ethylsulfonyl(2-naphthyl)amino, propylsulfonyl(phenyl)amino, propylsulfonyl(1-naphthyl)amino, propylsulfonyl(2-naphthyl)amino and the like.

In the present specification, the term "alkylsulfonyl(alkyl)amino group" means a group in which one alkylsulfonyl group and one alkyl group are bonded to an amino group, and is preferably a C _1-6 alkylsulfonyl(C _1-6 alkyl)amino group.

In the present specification, examples of the "C _1-6 alkylsulfonyl(C _1-6 alkyl)amino group" include methylsulfonyl(methyl)amino, methylsulfonyl(ethyl)amino, methylsulfonyl(propyl)amino, ethylsulfonyl(methyl)amino, ethylsulfonyl(ethyl)amino, ethylsulfonyl(propyl)amino, propylsulfonyl(methyl)amino, propylsulfonyl(ethyl)amino, propylsulfonyl(propyl)amino and the like.

In the present specification, the term "arylsulfonyl(alkyl)amino group" means a group in which one arylsulfonyl group and one alkyl group are bonded to an amino group, _{and is preferably a C arylsulfonyl(C 1-6} _alkyl )amino group.

In the present specification, examples of the " _C6-10 arylsulfonyl( _C1-6 alkyl)amino group" include phenylsulfonyl(methyl)amino, phenylsulfonyl(ethyl)amino, phenylsulfonyl(propyl)amino, 1-naphthylsulfonyl(methyl)amino, 1-naphthylsulfonyl(ethyl)amino, 1-naphthylsulfonyl(propyl)amino, 2-naphthylsulfonyl(methyl)amino, 2-naphthylsulfonyl(ethyl)amino, 2-naphthylsulfonyl(propyl)amino and the like.

In the present specification, the term "arylsulfonyl(aryl)amino group" means a group in which one arylsulfonyl group and one aryl group are bonded to an amino group, and is preferably a C _arylsulfonyl (C _aryl )amino group.

In the present specification, examples of the " _C6-10 arylsulfonyl ( _C6-10 aryl)amino group" include phenylsulfonyl(phenyl)amino, phenylsulfonyl(1-naphthyl)amino, phenylsulfonyl(2-naphthyl)amino, 1-naphthylsulfonyl(phenyl)amino, 1-naphthylsulfonyl(1-naphthyl)amino, 1-naphthylsulfonyl(2-naphthyl)amino, 2-naphthylsulfonyl(phenyl)amino, 2-naphthylsulfonyl(1-naphthyl)amino, 2-naphthylsulfonyl(2-naphthyl)amino and the like, with phenylsulfonyl(phenyl)amino being preferable.

In the present specification, a "tri-substituted silyl group" means a silyl group substituted by three identical or different substituents (for example, a C _1-6 alkyl group, a C _6-10 aryl group, etc.), and examples of the group include trialkylsilyl groups such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group (preferably a triC _1-6 alkylsilyl group, more preferably a triC _1-4 alkylsilyl group), a tert-butyldiphenylsilyl group, a triphenylsilyl group, and the like.

In this specification, "alkali metal" includes lithium, potassium, sodium, cesium, etc.

In this specification, "alkaline earth metal halide" means a group in which one halogen atom is bonded to a divalent alkaline earth metal (magnesium, calcium, barium, strontium), and preferably is a magnesium halide (e.g., magnesium chloride, magnesium bromide).

In this specification, "counter anion" includes halide ions, hydroxide ions, etc.

In this specification, the term "heterocyclic group" refers to a ring containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and may be aromatic or non-aromatic.
Examples of the "aromatic heterocyclic group" include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl,
5- or 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.;
Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.
Examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, pyrazolinyl, pyrazolidin ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as peridyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as zoimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

In this specification, the term "nitrogen-containing heterocyclic group" refers to the above-mentioned heterocyclic group that contains at least one nitrogen atom and may further contain a heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of the "nitrogen-containing heterocyclic group" include nitrogen-containing aromatic heterocyclic groups such as imidazolyl, pyrazolyl, benzimidazolyl, and 1H-indazolyl; and nitrogen-containing non-aromatic heterocyclic groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl. Among these, 5- or 6-membered nitrogen-containing aromatic heterocyclic groups or 3- to 8-membered nitrogen-containing non-aromatic heterocyclic groups are preferred, and 5-membered nitrogen-containing aromatic heterocyclic groups or 5- or 6-membered nitrogen-containing non-aromatic heterocyclic groups are more preferred.

In this specification, "4- to 8-membered saturated oxygen-containing heterocycle" means a 4- to 8-membered saturated non-aromatic heterocycle containing one or two oxygen atoms. Examples of "4- to 8-membered saturated oxygen-containing heterocycle" include oxetane, tetrahydrofuran, tetrahydropyran, 1,2-dioxolane, 1,3-dioxane, etc.

In this specification, examples of "nitrogen-containing bicyclo ring" include 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane, etc.

In this specification, the term "nitrogen-containing aromatic heterocyclic compound" refers to an aromatic heterocyclic compound that contains at least one nitrogen atom and may further contain a heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of "nitrogen-containing aromatic heterocyclic compounds" include pyridine, pyrazine, pyrimidine, imidazole, pyrazole, benzimidazole, 1H-indazole, quinoline, isoquinoline, etc.

In this specification, "unsaturated nitrogen-containing heterocycle" refers to a ring other than a nitrogen-containing aromatic heterocycle that contains at least one double bond and at least one nitrogen atom, and may further contain a heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of "unsaturated nitrogen-containing heterocycle" include octahydropyrimido[1,2-a]azepine, etc.

In this specification, "cyclic β-diketone" refers to an alicyclic 1,3-diketone compound. Examples of "cyclic β-diketone" include 1,3-cyclobutanedione, 1,3-cyclopentanedione, 1,3-cyclohexanedione, 1,3-cycloheptanedione, and 1,3-cyclooctanedione.

In this specification, "cyclic β-diesters" refer to alicyclic 1,3-diesters. Examples of "cyclic β-diesters" include 2,4-oxetanedione, 1,2-dioxolane-3,5-dione, and 1,3-dioxane-4,6-dione.

In this specification, "cyclic β-ketoester" refers to a compound that exhibits tautomerism with an alicyclic β-enol ester and exists as an equilibrium mixture of both isomers. Examples of "cyclic β-ketoester" include tetrahydro-2H-pyran-2,4-dione and oxepane-2,4-dione.

In this specification, the formula:

(wherein ^* indicates the bonding position with M;
R represents a hydrogen atom or a methyl group; and the two EWGs each independently represent an optionally substituted alkyl-carbonyl group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl-carbonyl group or an optionally substituted aryloxy-carbonyl group, or the two EWGs together with the carbon atom to which they are attached may form an optionally substituted cyclic β-diketone, cyclic β-diester or cyclic β-ketoester.
A group represented by the formula: may exist as its tautomer. In that case, it may exist as an individual tautomer or as a mixture of tautomers. For example, a group represented by the formula:

(The symbols in the formula have the same meanings as defined above.)
The structures shown in are as follows, unless otherwise noted:
(1)

(The symbols in the formula have the same meanings as defined above.)
A β-dicarbonyl compound represented by the formula:
(2)

(The symbols in the formula have the same meanings as defined above.)
or (3) a mixture containing these in any ratio.

In the present specification, the term "monovalent organic group" refers to a monovalent group essentially containing a carbon atom. Examples of the "monovalent organic group" include hydrocarbon groups such as a C _1-20 alkyl group, a C _2-20 alkenyl group, a C _2-20 alkynyl group, a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, a C _6-10 aryl group, and a C _7-16 aralkyl group; heterocyclic groups such as an aromatic heterocyclic group and a non-aromatic heterocyclic group; and the like. The "monovalent organic group" also includes groups having a substituent such as a C _1-6 alkyl group, an amino group, a mono-C _1-6 alkylamino group, and a di-C _1-6 alkylamino group.

In the present specification, the term "divalent organic group" refers to a divalent group essentially containing a carbon atom and having two bonds. Examples of the "divalent organic group" include a C _1-20 alkylidene group, a C _2-20 alkenylidene group, a C _3-20 alkynylidene group, a C _3-8 cycloalkylidene group, and a C _3-8 cycloalkenylidene group. The "divalent organic group" also includes a group having a substituent such as a C _1-6 alkyl group, an amino group, a mono-C _1-6 alkylamino group, or a di-C _1-6 alkylamino group.

"Optionally substituted" means unsubstituted or having 1 to 5 (preferably 1 to 3) substituents at substitutable positions, and each substituent may be the same or different.

Examples of the substituent of each group that is "optionally substituted" include (1) a halogen atom, (2) a hydroxy group, (3) a cyano group, (4) a nitro group, (5) an azido group, (6) a di-C _1-6 alkylamino group, (7) a C _1-6 alkyl group, (8) a C _1-6 haloalkyl group, (9) a C _1-6 alkoxy group, (10) a C _1-6 haloalkoxy group, (11) a C _3-8 cycloalkyl group, (12) a C _6-10 aryl group, (13) a C _7-16 aralkyl group, (14) a C _1-6 alkylsulfanyl group, (15) a mono- or di-C _1-6 alkylcarbamoyl group, (16) a C _1-6 alkylsulfonyl group, (17) a C _6-10 arylsulfonyl group, (18) a C _1-6 alkoxy-carbonyl group, (19) a C Examples of the alkyl group include a _6-10 aryloxy-carbonyl group, (20) a C _1-6 alkyl-carbonyl group, (21) a C _6-10 arylcarbonyl group, (22) a tri-substituted silyl group, and (23) a tri-substituted silyloxy group. Among these, a halogen atom, a C _1-6 alkyl, a C _1-6 haloalkyl, a C _{1-6 alkoxy, a C 1-6} _haloalkoxy , cyclopropyl, cyclopentyl, cyclohexyl, dimethylamino, methylsulfanyl, phenyl, benzyl, trimethylsilyl, triethylsilyl, and the like are preferable.

The production method of the present invention will be described below.
In the present invention, the 2-substituted aromatic heterocyclic compound (III) is produced by reacting the N-oxide aromatic heterocyclic compound (I) with the nucleophile (II) (Nu-M; represented as ^Nu- in the formula below) in the presence of a phosphonic anhydride (A) in a solvent. The reaction mechanism of the reaction of the present invention, for example, in the presence of a base, is presumed to be as follows.

Specific examples of N-oxide aromatic heterocyclic compounds (I) include the following N-oxide aromatic heterocyclic compounds (IA) and (IB).

[Wherein,
X ^1a represents CR ^1a or a nitrogen atom;
X ^1b represents CR ^1b or a nitrogen atom;
X ^1c represents CR ^1c or a nitrogen atom;
X ^1d represents CR ^1d or a nitrogen atom;
R ^1a , R ^1b , R ^1c and R ^1d each independently represent a hydrogen atom, a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group; or R ^1a and R ^1b , R ^1b and R ^1c , or R ^1c and R ^1d may, together with the carbon atom to which they are bonded, form a 6- to 10-membered aromatic ring optionally substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, and an optionally substituted aralkyl group;
X ^2a represents CR ^2a , a nitrogen atom, NR ^2a , a sulfur atom or an oxygen atom;
^X2b represents ^CR2b or a nitrogen atom;
X ^2c represents CR ^2c , a nitrogen atom, NR ^2c , a sulfur atom or an oxygen atom;
R ^2a , R ^2b and R ^2c each independently represent a hydrogen atom, a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R ^2a and R ^2b , or R ^2b and R ^2c may, together with the carbon atom to which they are bonded, form a 6- to 10-membered aromatic ring which may be substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, and an optionally substituted aralkyl group.]

Specific examples of N-oxide aromatic heterocyclic compounds (IA) include the following N-oxide aromatic heterocyclic compounds (IA-a) to (IA-e).

[Each symbol in the formula has the same meaning as defined above.]
Of these, (IA-a), (IA-b) and (IA-d) are preferred.
Specific examples of the N-oxide aromatic heterocyclic compound (IA) include the following compounds:

[Wherein,
R ^1aa , R ^1bb , R ^1cc and R ^1dd each independently represent a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, a sulfanyl group, a C _1-6 alkylsulfanyl group, an amino group, a mono-C _1-6 alkylamino group, a di-C _1-6 alkylamino group, a formyl group, a carboxy group, a C _1-6 alkoxy-carbonyl group, a C _6-10 aryl group or a C _7-16 aralkyl group;
m R ^1ee each independently represent a halogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, a sulfanyl group, a C _1-6 alkylsulfanyl group, an amino group, a mono-C _1-6 alkylamino group, a di-C _1-6 alkylamino group, a formyl group, a carboxy group, a C _1-6 alkoxy-carbonyl group, a C _6-10 aryl group, or a C _7-16 aralkyl group;
m represents an integer of 0 to 4.
R ^1aa , R ^1bb , R ^1cc and R ^1dd are preferably each independently a hydrogen atom, a cyano group or a C _1-6 alkyl group;
m R ^1ee are preferably each independently a C _1-6 alkoxy-carbonyl group;
m is preferably 0 or 1.

Specific examples of N-oxide aromatic heterocyclic compounds (IB) include the following N-oxide aromatic heterocyclic compounds (IB-a) to (IB-y).

[Each symbol in the formula has the same meaning as defined above.]
Of these, (IB-e), (IB-n) and (IB-p) are preferred.
Specific examples of suitable N-oxide aromatic heterocyclic compounds (IB) include the following compounds:

[In the formula, R ^2aa , R ^2bb and R ^2cc each independently represent a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, a sulfanyl group, a C _1-6 alkylsulfanyl group, an amino group, a mono-C _1-6 alkylamino group, a di-C _1-6 alkylamino group, a formyl group, a carboxy group, a C _1-6 alkoxy-carbonyl group, a C _6-10 aryl group or a C _7-16 aralkyl group;
m R ^2ee each independently represent a halogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, a sulfanyl group, a C _1-6 alkylsulfanyl group, an amino group, a mono-C _1-6 alkylamino group, a di-C _1-6 alkylamino group, a formyl group, a carboxy group, a C _1-6 alkoxy-carbonyl group, a C _6-10 aryl group, or a C _7-16 aralkyl group;
m represents an integer of 0 to 4.
R ^2aa , R ^2bb and R ^2cc are preferably each independently a hydrogen atom, a C _1-6 alkyl group or a C _7-16 aralkyl group;
m is preferably 0.

The N-oxide aromatic heterocyclic compound (I) may be a commercially available product or one produced by a method known per se.

The reaction of the present invention is carried out using a phosphonic anhydride as an activator. The phosphonic anhydride may be present from the start of the reaction or may be added after the other components (N-oxide aromatic heterocyclic compound (I), nucleophile (II) and base). From the viewpoints of reaction rate and suppression of side reactions, it is preferable to add the phosphonic anhydride last.

The phosphonic anhydride may be either cyclic or chain-like, and is not particularly limited. Commercially available products or products synthesized by known methods can be used. Suitable phosphonic anhydrides include, for example, those represented by the following formula (IV):

(In the formula, n+1 R ^1s each independently represent a C _1-6 alkyl group or a C _6-10 aryl group; and n represents an integer from 1 to 8.)
Among them, cyclic phosphonic acid anhydrides represented by the following formula (V):

(In the formula, the three ^R2s each independently represent a _C1-6 alkyl group or a _C6-10 aryl group.)
Phosphonic anhydrides represented by the formula (V) are preferred, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P: registered trademark) in which R ² in the above formula (V) is a propyl group is particularly preferred. Phosphonic anhydrides are inexpensively available, stable and easy to handle, and after the reaction, compounds derived from the phosphonic anhydride (reaction residues) can be removed simply by washing with water through a separation operation. Therefore, the production method of the present invention has the advantage that the post-treatment step can be carried out extremely easily, as compared with the Reissert-Henze reaction carried out using a conventionally known activator.

The amount of phosphonic anhydride used can be appropriately selected, but for example, it is usually 1 to 10 moles, preferably 1 to 3 moles, and more preferably 1 to 1.5 moles per mole of N-oxide aromatic heterocyclic compound (I).

The nucleophile used in the reaction of the present invention is not particularly limited, but may be, for example, the following formula (II):

(Wherein, Nu represents a nucleophilic group;
M represents a hydrogen atom, a tri-substituted silyl group, an alkali metal, or an alkaline earth metal halide.
Examples of nucleophiles include nucleophiles represented by the following formula (nucleophile (II)):
The Nu (nucleophilic group) is preferably a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a cyano group, an azide group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted alkylsulfanyl group, an optionally substituted arylsulfanyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkylsulfonyl(aryl)amino group, an optionally substituted alkylsulfonyl(alkyl)amino group, an optionally substituted arylsulfonyl(alkyl)amino group, an optionally substituted arylsulfonyl(aryl)amino group, and a group represented by the following formula:

(wherein ^* indicates the bonding position with M;
R represents a hydrogen atom or a methyl group; and the two EWGs each independently represent a cyano group, a nitro group, a haloalkyl group (preferably), an optionally substituted alkyl-carbonyl group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl-carbonyl group, an optionally substituted aryloxy-carbonyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylsulfinyl group, an optionally substituted arylsulfinyl group, an optionally substituted dialkylphosphono group or an optionally substituted diarylphosphono group, or the two EWGs may, together with the carbon atom to which they are bonded, form an optionally substituted cyclic β-diketone, cyclic β-diester or cyclic β-ketoester.
However, when EWG is an optionally substituted alkyl-carbonyl group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl-carbonyl group or an optionally substituted aryloxy-carbonyl group, or when two EWGs, together with the carbon atoms to which they are bonded, form an optionally substituted cyclic β-diketone, cyclic β-diester or cyclic β-ketoester, they may be enol tautomers, and ^* may be on the oxygen atom derived from the carbonyl.)
or a tautomeric group thereof,
More preferred are an optionally substituted alkylsulfanyl group; an optionally substituted nitrogen-containing heterocyclic group; an optionally substituted monoarylamino group; an optionally substituted alkylsulfonyl(aryl)amino group; an optionally substituted arylsulfonyl(aryl)amino group; and the following formula:

(wherein ^* indicates the bonding position with M;
R represents a hydrogen atom or a methyl group; and R' and R" each independently represent an alkyl group, an alkoxy group, an aryl group, or an aryloxy group, which may be substituted, or R' and R" together with the carbon atom to which they are attached may form an optionally substituted 4- to 8-membered cycloalkane or saturated oxygen-containing heterocycle.
It is a group selected from the group consisting of groups represented by the following formula:

M in the above formula (II) is preferably a hydrogen atom.

Particularly preferred nucleophiles (II) include, for example, C _1-20 alkylthiols such as 1-dodecanethiol, each of which may be substituted; 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic compounds such as piperidine, pyrrolidine, morpholine, etc.; 5-membered monocyclic nitrogen-containing aromatic heterocyclic compounds such as imidazole, pyrazole, etc.; monoarylamine compounds such as aniline, 4-trifluoromethylaniline, etc.; alkylsulfonyl(aryl)amines such as methanesulfonylaniline, trifluoromethanesulfonylaniline, etc.; arylsulfonyl(aryl)amines such as benzenesulfonylaniline, toluenesulfonylaniline, etc., and compounds represented by the following formula:

(In the formula, R represents a hydrogen atom or a methyl group; and R′ and R″ are as defined above.)
A β-dicarbonyl compound (or the corresponding keto-enol compound) represented by the formula:
The compound may be selected from the group consisting of:

As the nucleophile (II), a commercially available product or one produced by a method known per se can be used.

The amount of nucleophile (II) used can be appropriately selected, but for example, it is usually 1 to 10 moles, preferably 1 to 3 moles, and more preferably 1 to 1.5 moles per mole of N-oxide aromatic heterocyclic compound (I).

The reaction of the present invention is carried out in the presence of a base, if necessary.
When a compound having basicity is used as the nucleophile (II), the nucleophile (II) itself can also act as a base, and therefore the addition of an additional base is not necessarily required.

The reaction of the present invention is presumed to proceed according to the above reaction mechanism, so the presence of a base in the reaction system promotes the abstraction of protons in the reaction intermediate. This increases the reaction rate and reduces side reactions, improving the yield.

The base is not particularly limited as long as it is a base that can abstract a proton from the reaction intermediate, and examples thereof include Bronsted bases. The base may be one that is converted to a Bronsted base in the system.
The bases are broadly classified into organic bases and inorganic bases.
The organic base includes an amine compound, an ammonium compound, an imine compound, an iminium compound, a nitrogen-containing aromatic heterocyclic compound, and a salt of a nitrogen-containing aromatic heterocyclic compound.

The amine compound is, for example, a compound represented by the following formula (b1):

[Wherein,
R ³ , R ⁴ and R ⁵ each independently represent a monovalent organic group, or R ³ and R ⁴ together with the nitrogen atom to which they are bonded may form an optionally substituted nitrogen-containing heterocycle, or R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded may form a nitrogen-containing bicyclocycle.

The ammonium compound is, for example, a compound represented by the following formula (b2):

[Wherein,
R ³ , R ⁴ and R ⁵ each independently represent a monovalent organic group, or R ³ and R ⁴ together with the nitrogen atom to which they are bonded may form an optionally substituted nitrogen-containing heterocycle, or R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded may form a nitrogen-containing bicyclocycle;
^R6 represents a hydrogen atom or a monovalent organic group;
^- ^R7 represents a counter anion.

In the above formula (b1) and formula (b2), R ³ , R ⁴ and R ⁵ are preferably each independently a C _1-20 alkyl group (e.g., methyl, ethyl, isopropyl, stearyl), a C _1-6 alkyl-carbonyl group (e.g., acetyl), a C _6-10 aryl group (e.g., phenyl), or an aromatic heterocyclic group (e.g., pyridyl), or R ³ and R ⁴ together with the nitrogen atom to which they are bonded form a nitrogen-containing heterocycle (e.g., piperazine) which may be substituted with a C _1-6 alkyl group, or R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded form a nitrogen-containing bicyclo ring (e.g., 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane).
In the above formula (b2), R ⁶ is preferably a hydrogen atom or a C _1-6 alkyl group.
In the above formula (b2), ⁻ R ⁷ is preferably a halide ion (eg, a fluoride ion (F ⁻ )) or a hydroxide ion (OH ⁻ ).

Specific examples of suitable amine compounds include the following compounds:

Specific examples of suitable ammonium compounds include the following compounds:

The imine compound is, for example, a compound represented by the following formula (b3):

[Wherein,
^R8 represents a hydrogen atom or a monovalent organic group;
R ⁹ represents a divalent organic group, or R ⁸ and R ⁹ together with the nitrogen atom to which they are bonded may form an optionally substituted unsaturated nitrogen-containing heterocycle.

The iminium compound is, for example, a compound represented by the following formula (b4).

[Wherein,
R ⁸ and R ¹⁰ each independently represent a hydrogen atom or a monovalent organic group;
R ⁹ represents a divalent organic group, or R ⁸ and R ⁹ together with the nitrogen atom to which they are bonded may form an optionally substituted unsaturated nitrogen-containing heterocycle;
^- R ¹¹ represents a counter anion.

In the above formula (b3) and formula (b4), preferably, R ⁸ is a hydrogen atom, and R ⁹ is a C _1-6 alkylidene group (e.g., methylidene) optionally substituted with an amino group, or R ⁸ and R ⁹ together with the nitrogen atom to which they are bonded may form an unsaturated nitrogen-containing heterocycle (e.g., octahydropyrimido[1,2-a]azepine) optionally substituted with a C _1-6 alkyl group or a di-C _1-6 alkylamino group.
In the above formula (b4), R ¹⁰ is preferably a hydrogen atom.
In the above formula (b4), ⁻ R ¹¹ is preferably a halide ion (eg, a fluoride ion (F ⁻ )).

Specific examples of suitable imine compounds include the following compounds:

Specific examples of suitable iminium compounds include the following compounds:

The nitrogen-containing aromatic heterocyclic compound is, for example, the nitrogen-containing aromatic heterocyclic compound described above, such as pyridine, pyrazine, pyrimidine, imidazole, pyrazole, benzimidazole, 1H-indazole, quinoline, isoquinoline, etc.

Specific examples of suitable nitrogen-containing aromatic heterocyclic compounds include the following compounds:

The salt of the nitrogen-containing aromatic heterocyclic compound is, for example, a salt of the nitrogen-containing aromatic heterocyclic compound described above, such as a pyridinium salt, a pyrazinium salt, a pyrimidinium salt, an imidazolium salt, a pyrazolium salt, a benzimidazolium salt, a 1H-indazolium salt, a quinolinium salt, an isoquinolinium salt, etc.

Specific examples of suitable salts of the above nitrogen-containing aromatic heterocyclic compounds include the following compounds:

Among the above organic bases, amine compounds are preferred, tertiary amines are more preferred, and triethylamine or N,N-diisopropylethylamine is particularly preferred.

Specific examples of inorganic bases include metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, cesium tert-butoxide, potassium n-butoxide, sodium n-butoxide, and cesium n-butoxide; halide salts such as potassium fluoride, sodium fluoride, and cesium fluoride; hydroxide salts such as calcium hydroxide, aluminum hydroxide, potassium hydroxide, and sodium hydroxide; phosphates such as sodium monohydrogen phosphate and sodium dihydrogen phosphate; carbonates such as potassium carbonate; bicarbonates such as sodium bicarbonate; and acetates such as sodium acetate.

The base is appropriately selected depending on the type of N-oxide aromatic heterocyclic compound (I).
The amount of the base used varies depending on the type of base, but is usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the N-oxide aromatic heterocyclic compound (I).

The reaction of the present invention is carried out in an aprotic solvent selected from aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, halogenated hydrocarbon solvents, ether solvents, ester solvents, nitrile solvents, amide solvents, and mixtures of two or more of these solvents. By using such a solvent, the reaction substrate and the nucleophile can be dissolved well, and the 2-substituted aromatic heterocyclic compound (III) can be produced in good yield with few by-products.
Examples of aromatic hydrocarbon solvents include benzene, toluene, and xylene.
Aliphatic hydrocarbon solvents include n-hexane, n-heptane, cyclohexane, and the like.
Examples of halogenated hydrocarbon solvents include dichloromethane, chloroform, and 1,2-dichloroethane.
Examples of the ether solvent include tetrahydrofuran (THF), dioxane, diethyl ether, glyme, and diglyme.
Examples of the ester solvent include butyl acetate, propyl acetate, and butyl acetate.
Examples of the nitrile solvent include acetonitrile, propionitrile, dimethylcyanamide, and tert-butylnitrile.
Examples of the amide solvent include N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), and 1,3-dimethyl-2-imidazolidinone (DMI).
Among these, aromatic hydrocarbon solvents, ester solvents, halogenated hydrocarbon solvents, or mixed solvents thereof are preferred, and toluene, ethyl acetate, dichloromethane, or a mixed solvent of toluene and ethyl acetate is more preferred. In addition, the amount of impurities (e.g., water, etc.) that adversely affect the progress of the reaction in the solvent used is usually 10% or less, and it is preferable that the solvent is substantially free of impurities.

The reaction of the present invention can be carried out by mixing the N-oxide aromatic heterocyclic compound (I), the phosphonic anhydride, the nucleophile (II), and the base in a solvent, and the order of addition is not particularly limited. However, from the standpoint of reaction efficiency, yield, and reduction of by-products, it is preferable to add the phosphonic anhydride to a solution of the N-oxide aromatic heterocyclic compound (I), the nucleophile (II), and the base.

The reaction temperature depends on the type of N-oxide aromatic heterocyclic compound (I) and/or nucleophile (II), but is usually -100°C or higher, preferably -10°C to 300°C, and more preferably 15°C to 150°C.

The reaction time depends on the reaction temperature and the type of N-oxide aromatic heterocyclic compound (I) and/or nucleophile (II), but is usually 1 minute to 72 hours, preferably 1 hour to 48 hours.

After the reaction is completed, the desired 2-substituted aromatic heterocyclic compound (III) can be isolated and/or purified from the reaction mixture by a conventional separation method such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, or chromatography.

The manufacturing method of the present invention is characterized by the discovery for the first time that an inexpensive, stable, and easy-to-handle phosphonic anhydride can be used as an activator for the Reissert-Henze reaction. By using this activator, it is possible to synthesize substituted aromatic heterocyclic compounds (III) having various types of nucleophilic groups introduced at the 2-position with good yield. In addition, the phosphonic anhydride after the reaction can be easily removed simply by adding water and an organic solvent that phase separates from water to the reaction mixture after the reaction of the present invention and performing a simple post-treatment process of performing a liquid separation operation, which has the advantage of significantly improving the time and efficiency of the purification operation. Furthermore, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P: registered trademark), which is preferably used as the phosphonic acid anhydride in the production method of the present invention, is particularly inexpensive, easy to store, and is available commercially as a solution with an adjusted concentration, making it easy to handle. In addition, compared to other activators used as activators in the Reissert-Henze reaction, the range of applicable substrates and nucleophiles (functional groups that can be introduced) is wider, which is also an advantage of the production method of the present invention.

The 2-substituted aromatic heterocyclic compound (III) thus obtained is useful as a synthetic intermediate for pharmaceuticals or agricultural chemicals, and can lead to various pharmaceuticals or agricultural chemicals.

The present invention will be specifically explained below using examples, but the present invention is not limited to these examples.

Unless otherwise specified, the yields described in the following examples are isolated yields. % indicates mol/mol% for yields, and % by weight for other yields unless otherwise specified. Additionally, room temperature indicates a temperature of 15 to 30°C unless otherwise specified.

In the following reactions, hexafluoro-2,2-diphenylpropane or 1,4-bis(trifluoromethyl)benzene was used as an internal standard to monitor reaction progress or to calculate yields based on nuclear magnetic resonance spectroscopy (NMR), liquid chromatography (LC), and/or gas chromatography (GC) data.
Nuclear magnetic resonance spectroscopy (NMR) was measured using a Bruker Ascend (registered trademark) 400. ¹ H-NMR was measured at 400 MHz using tetramethylsilane as the standard. When a deuterated solvent was used as the measurement solvent, the name of the deuterated solvent is recorded.
The column chromatography apparatus used was Purif(R)-aios manufactured by Shoko Science Co., Ltd., and the silica gel column package used was Biotage(R) Sfar HCD.
In addition, the abbreviations used in the following examples have the following meanings.

s: singlet d: doublet t: triplet q: quartet m: multiplet dt: double triplet ddd: double doublet J: coupling constant ¹ H-NMR: proton nuclear magnetic resonance LC-MS: liquid chromatography mass spectrometry CH ₂ Cl ₂ : dichloromethane AcOEt: ethyl acetate CDCl ₃ : deuterated chloroform r.t.: room temperature T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide DIEA: N,N-diisopropylethylamine TEA: triethylamine

[Example 1]
Preparation of 2-(1H-imidazol-1-yl)quinoline (III-1)

A dichloromethane solution (1.0 M, 0.5 mL) of quinoline-N-oxide (I-1) was added to a dichloromethane (1.4 mL) solution of imidazole (II-1) (42 mg) and N,N-diisopropylethylamine (DIEA) (0.33 mL), and an ethyl acetate solution (1.7 M, 0.38 mL) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) was added, followed by stirring overnight at room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (III-1) (23 mg) as pale yellow crystals.
^1H -NMR (400MHz, _CDCl3 ) δ 8.50 (s, 1H), 8.29 (d, J = 8.8Hz, 1H), 8.04 (d, J = 8.5Hz, 1H), 7.84 (d, J = 8.1Hz, 2H), 7.80-7.69 (m, 1H), 7.63-7.45 (m, 2H), 7.25 (s, 1H).
LC-MS[M+1]=196.2

[Example 2]
Preparation of 2-(1H-pyrazol-1-yl)quinoline (III-2)

A solution of T3P in ethyl acetate (1.7 M, 0.38 mL) was added to a solution of quinoline-N-oxide (I-1) (68 mg), pyrazole (II-2) (45 mg), and N,N-diisopropylethylamine (DIEA) (0.33 mL) in toluene (1.9 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (III-2) (38 mg) as a white solid.
^1H -NMR (400MHz, _CDCl3 ) δ 8.81 (dd, J=2.6, 0.7Hz, 1H), 8.31-8.15 (m, 2H), 8.01 (dp, J=8.5, 0.7Hz, 1H), 7.87-7.77 (m, 2H), 7 .72 (ddd, J=8.5, 6.9, 1.5Hz, 1H), 7.51 (ddd, J=8.1, 6.9, 1.2Hz, 1H), 6.53 (dd, J=2.6, 1.7Hz, 1H).
LC-MS[M+1]=196.1

[Example 3]
Preparation of N-(4-(trifluoromethyl)phenyl)quinolin-2-amine (III-3)

The title compound (III-3) (22 mg) was obtained as a white solid from quinoline-N-oxide (I-1) (80 mg) and 4-aminobenzotrifluoride (II-3) (99 mg) by the same procedure as in Example 1.
^1H -NMR (400MHz, _CDCl3 ) δ 8.00 (d, J=8.8Hz, 1H), 7.84 (t, J=7.5Hz, 3H), 7.70-7.60 (m, 4H), 7.38-7.34 (m, 1H), 6.95 (d, J=8.8Hz, 1H), 6.83 (s, 1H).
LC-MS[M+1]=289.1

[Example 4]
Preparation of N-phenyl-N-(quinolin-2-yl)benzenesulfonamide (III-4)

The title compound (III-4) (15 mg) was obtained as an orange oil from quinoline-N-oxide (I-1) (0.50 mmol) and benzenesulfonanilide (II-4) (146 mg) by the same procedure as in Example 1.
^1H -NMR (400MHz, _CDCl3 ) δ 8.21-8.08 (m, 2H), 8.03-7.83 (m, 2H), 7.74-7.63 (m, 2H), 7.62-7.56 (m, 1H), 7.56-7.49 (m, 2H), 7.48-7.35 (m, 6H), 6.81 (d, J=8.8Hz, 1H).
LC-MS[M+1]=361.1

[Example 5]
Preparation of 4-(quinolin-2-yl)morpholine (III-5)

A solution of T3P in ethyl acetate (1.7 M, 0.60 mL) was added to a solution of quinoline-N-oxide (I-1) (98 mg), morpholine (II-5) (0.20 g), and triethylamine (TEA) (0.30 mL) in toluene (7.0 mL), and the mixture was stirred overnight at 100° C. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography to obtain the title compound (III-5) (81 mg) as a white solid.
^1H -NMR (400MHz, _CDCl3 ) δ 7.92 (d, J=9.1Hz, 1H), 7.72 (d, J=8.3Hz, 1H), 7.61 (d, J=7.9Hz, 1H), 7.55 (dt, J=10.6, 3.8Hz, 1 H), 7.25 (q, J=4.9Hz, 1H), 6.96 (d, J=9.1Hz, 1H), 3.86 (t, J=4.9Hz, 4H), 3.71 (t, J=4.8Hz, 4H).

[Example 6]
Preparation of ethyl 3-oxo-2-(quinolin-2-yl)butanoate (III-6)

A solution of T3P in ethyl acetate (1.7 M, 0.38 mL) was added to a solution of quinoline-N-oxide (I-1) (71 mg), ethyl acetoacetate (II-6) (0.19 mL), and N,N-diisopropylethylamine (DIEA) (0.33 mL) in ethyl acetate (1.9 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (III-6) (20 mg) as an orange solid.
^1H -NMR (400MHz, _CDCl3 ) δ 8.01-7.82 (m, 2H), 7.67-7.53 (m, 3H), 7.40-7.32 (m, 1H), 4.34 (q, J = 7.1Hz, 2H), 2.47 (s, 3H), 1.39 (t, J = 7.2Hz, 3H).
LC-MS[M+1]=258.1

[Example 7]
Preparation of 2-dodecylsulfanylquinoline (III-7)

The title compound (III-7) (50 mg) was obtained as a colorless oil from quinoline-N-oxide (I-1) (76 mg) and 1-dodecanethiol (II-7) (0.15 mL) by the same procedure as in Example 2.
^1H -NMR (400MHz, _CDCl3 ) δ 7.92 (d, J = 7.9Hz, 1H), 7.87 (d, J = 8.1Hz, 1H), 7.70 (dd, J = 8.1, 1.4Hz, 1H), 7.65-7.61 (m, 1H), 7.43-7.39 (m, 1H), 7.20 (d , J=8.6Hz, 1H), 3.33 (t, J=7.4Hz, 2H), 1.82-1.74 (m, 2H), 1.52-1.45 (m, 2H), 1.37-1.26 (m, 16H), 0.88 (t, J=6.9Hz, 3H).
LC-MS[M+1]=330.3

This application is based on Patent Application No. 2022-205515 filed in Japan on December 22, 2022, the contents of which are incorporated in their entirety into this specification. In addition, the entire contents of the documents cited in this specification are incorporated in this specification by reference.

Claims

In a solvent, in the presence of a phosphonic acid anhydride, a compound of formula (I):

and an N-oxide aromatic heterocyclic compound having a partial structure represented by formula (II):

(Wherein, Nu represents a nucleophilic group;
M represents a hydrogen atom, a tri-substituted silyl group, an alkali metal, or an alkaline earth metal halide.
The present invention comprises a step of reacting a nucleophilic agent represented by formula (III):

(In the formula, Nu has the same meaning as above.)
The present invention relates to a method for producing a 2-substituted aromatic heterocyclic compound having a partial structure represented by the following formula:
Nu is a halogen atom, a cyano group, an azide group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted alkylsulfanyl group, an optionally substituted arylsulfanyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkylsulfonyl(aryl)amino group, an optionally substituted alkylsulfonyl(alkyl)amino group, an optionally substituted arylsulfonyl(alkyl)amino group, an optionally substituted arylsulfonyl(aryl)amino group, and a group represented by the following formula:

(wherein * indicates the bonding position with M;
R represents a hydrogen atom or a methyl group; and the two EWGs each independently represent a cyano group, a nitro group, a haloalkyl group, an optionally substituted alkyl-carbonyl group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl-carbonyl group, an optionally substituted aryloxy-carbonyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylsulfinyl group, an optionally substituted arylsulfinyl group, an optionally substituted dialkylphosphono group or an optionally substituted diarylphosphono group, or the two EWGs may, together with the carbon atom to which they are attached, form an optionally substituted cyclic β-diketone, cyclic β-diester or cyclic β-ketoester.
However, when EWG is an optionally substituted alkyl-carbonyl group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl-carbonyl group or an optionally substituted aryloxy-carbonyl group, or when two EWGs, together with the carbon atoms to which they are bonded, form an optionally substituted cyclic β-diketone, cyclic β-diester or cyclic β-ketoester, they may be enol tautomers, and * may be on the oxygen atom derived from the carbonyl.)
The method according to claim 1, wherein the nucleophilic group is selected from the group consisting of groups represented by the following formula (I):
Nu is an optionally substituted alkylsulfanyl group, an optionally substituted nitrogen-containing heterocyclic group, an optionally substituted monoarylamino group, an optionally substituted alkylsulfonyl(aryl)amino group, an optionally substituted arylsulfonyl(aryl)amino group, or a group represented by the following formula:

(wherein * indicates the bonding position with M;
R represents a hydrogen atom or a methyl group; and R' and R" each independently represent an optionally substituted alkyl group, alkoxy group, aryl group or aryloxy group, or R' and R" together with the carbon atom to which they are attached may form an optionally substituted 4- to 8-membered cycloalkane or saturated oxygen-containing heterocycle.
and M is a hydrogen atom.
The phosphonic anhydride is represented by formula (IV):

(In the formula, n+1 R 1s each independently represent a C 1-6 alkyl group or a C 6-10 aryl group; and n represents an integer from 1 to 8.)
The method according to any one of claims 1 to 3, wherein the phosphonic acid anhydride is represented by the formula:
The phosphonic anhydride has the formula (V):

(In the formula, the three R2s each independently represent a C1-6 alkyl group or a C6-10 aryl group.)
The method according to any one of claims 1 to 3, wherein the phosphonic acid anhydride is represented by the formula:
The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA) or (IB):

[Wherein,
X 1a represents CR 1a or a nitrogen atom;
X 1b represents CR 1b or a nitrogen atom;
X 1c represents CR 1c or a nitrogen atom;
X 1d represents CR 1d or a nitrogen atom;
R 1a , R 1b , R 1c and R 1d each independently represent a hydrogen atom, a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group; or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d may, together with the carbon atom to which they are bonded, form a 6- to 10-membered aromatic ring optionally substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, and an optionally substituted aralkyl group;
X 2a represents CR 2a , a nitrogen atom, NR 2a , a sulfur atom or an oxygen atom;
X2b represents CR2b or a nitrogen atom;
X 2c represents CR 2c , a nitrogen atom, NR 2c , a sulfur atom or an oxygen atom;
R 2a , R 2b and R 2c each independently represent a hydrogen atom, a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R 2a and R 2b , or R 2b and R 2c may, together with the carbon atom to which they are bonded, form a 6- to 10-membered aromatic ring which may be substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a formyl group, a hydroxy group, a sulfanyl group, an amino group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted monoalkylamino group, an optionally substituted dialkylamino group, an optionally substituted monoarylamino group, an optionally substituted diarylamino group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryl group, and an optionally substituted aralkyl group.]
The method according to any one of claims 1 to 5, wherein the compound is an N-oxide aromatic heterocyclic compound represented by the formula:
The method according to any one of claims 1 to 6, characterized in that the process is carried out in the presence of a base.
The method according to claim 7, wherein the base is an organic base.
The method according to claim 8, wherein the organic base is a tertiary amine.
The method according to any one of claims 1 to 9, wherein the solvent is an aprotic solvent.
The method according to claim 10, wherein the aprotic solvent is an aromatic hydrocarbon solvent selected from the group consisting of benzene, toluene and xylene; a halogenated hydrocarbon solvent selected from the group consisting of dichloromethane, chloroform and 1,2-dichloroethane; an aliphatic hydrocarbon solvent selected from the group consisting of n-hexane, n-heptane and cyclohexane; an ether solvent selected from the group consisting of tetrahydrofuran, dioxane, diethyl ether, glyme and diglyme; a nitrile solvent selected from the group consisting of acetonitrile, propionitrile, dimethylcyanamide and tert-butylnitrile; an amide solvent selected from the group consisting of N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide and dimethylimidazole; an ester solvent selected from the group consisting of ethyl acetate, propyl acetate and butyl acetate; or a mixed solvent of two or more of these.
The method according to any one of claims 1 to 11 further comprises a post-treatment step of removing compounds derived from the phosphonic anhydride from the reaction mixture by adding water and an organic solvent that undergoes phase separation from water to the reaction mixture after the above step and subjecting the mixture to a separation operation.