JP2015172005A - Method of producing coupling compound by iron catalyst - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel method that makes it possible to produce a wide variety of coupling compounds with good environmental harmony without using organic halogen compounds, and in which large-scale synthesis can be conducted at a low cost.SOLUTION: According to the method, in the presence of iron catalysts, zinc compounds and oxidizing agents, organic boron compounds are reacted, so that desired coupling compounds can be produced without using organic halogen compounds.

Description

  The present invention relates to a method for producing a coupling compound. More specifically, the present invention relates to an organic halogen obtained by reacting an organic compound having an orientation group with an organic boron compound in the presence of an iron catalyst, a zinc compound and an oxidizing agent. The present invention relates to a method for producing a desired coupling compound without using a compound.

  The compound obtained by the coupling reaction is useful not only in the field of medicine and agricultural chemicals but also as an organic semiconductor material used in organic EL, organic solar cells, etc., or an intermediate thereof. As a representative example of the synthesis method of such a coupling compound, a Suzuki coupling reaction in which an organic halide and a boron compound are reacted is widely known as a highly versatile method. As a catalyst in the coupling reaction, noble metals such as palladium, nickel, and platinum are used in many processes. However, since they are expensive and have environmental harmony and resource problems, as an alternative catalyst in recent years, An iron catalyst that is abundant in the earth's crust and inexpensive and has low toxicity has attracted attention.

  As a Suzuki coupling reaction using an iron catalyst, it is reported that a cross coupling reaction between an aryl boronic acid ester and an alkyl halide proceeds by using a special iron diphosphine complex as a catalyst (non-patent document). Reference 1). However, organic halides such as alkyl halides not only have a problem in environmental harmony, but also have problems such as a problem of corrosion in the production process and an increase in production cost. Therefore, in recent years, research on a coupling reaction (so-called C—H activation reaction) in which a carbon-hydrogen bond is activated to directly introduce a functional group has been actively conducted. On the other hand, there is an example using a palladium catalyst as a method for producing a coupling compound that does not use an organic halogen compound (Non-patent Document 2). There are only reports (Non-Patent Documents 3 and 4, etc.).

Hatakeyama et al. Am. Chem. Soc. , 2010, 132, 10474-10676 Sun et al., Chemical. Commun. 2010, 46, 677-685 Wen et al., Org. Lett. 2010l, 12, 2694 Uchiyama et al., Chem. Lett. , 2011, 47, 11671

  Therefore, the present invention provides a novel method capable of producing a large variety of coupling compounds that can be synthesized in large quantities at low cost and has high environmental friendliness compared to conventional coupling methods. This is a problem.

  As a result of intensive studies to solve the above problems, the present inventors have used an organic compound having an orientation group and an organic boron compound using an inexpensive and low-toxic iron catalyst and without using an organic halide. It was found that a coupling reaction (C—H activation reaction) can be efficiently performed between the two, and the present invention has been completed.

That is, the present invention in one aspect,
(1) A compound of the following formula (1) in the presence of an iron catalyst, a zinc compound, and an oxidizing agent

Wherein X is a carbon atom or a nitrogen atom;
Y is ═O, ═S, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, Selected from the group consisting of optionally substituted aryloxy and esters;
R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted alkoxy, a substituted Represents optionally 1 or 2 identical or different substituents selected from the group consisting of aryloxy and ester, provided that at least one R ¹ is not a hydrogen atom;
R ² and R ³ are each a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylalkyl, or an optionally substituted Represents 1 to 2 identical or different substituents independently selected from the group consisting of good alkoxy, optionally substituted aryloxy, and ester;
Here, Y and R ¹ together with the X atom and N atom to which they are bonded may form a saturated or unsaturated ring structure that may contain a hetero atom,
R ² and R ³ together with the carbon atom to which they are attached may form a saturated or unsaturated ring structure that may contain heteroatoms;
Furthermore, Y and R ² together with the X atom and carbon atom to which they are bonded may form a saturated or unsaturated ring structure that may contain heteroatoms. )
And a boron compound salt of the following formula (2)

Wherein R ^A represents a substituent selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, and an optionally substituted aryl;
R ⁴ represents an optionally substituted alkyl having 1 to 10 carbon atoms;
Each R ⁵ independently represents the same or different, optionally substituted alkyl having 1 to 10 carbon atoms, wherein the two R ⁵ are combined with the oxygen atom to which they are bonded. To form a ring structure;
Z ⁺ is a lithium metal ion. )
And a coupling compound of the following formula (3):

(In the formula, X, Y, R ^{1 to} R ^3, and R ^A are as defined above.)
The present invention provides a method for producing a coupling compound, characterized in that

In a preferred embodiment, the present invention provides:
(2) In the compounds of the formulas (1) and (3), the X is a carbon atom; the Y is ═O; thereby, the site consisting of Y—X—N forms an amide, The production method according to 1);
(3) In the compounds of the formulas (1) and (3), the Y and the R ¹ together with the X atom and the N atom to which they are bonded are optionally substituted pyridyl or substituted The production method according to (1) above, which forms pyrazolyl which may be present;
(4) In the compounds of the formulas (1) and (3), R ² and R ³ together with the carbon atom to which they are bonded may each be substituted, phenyl, naphthyl, Any of (1) to (3) above, which forms a ring structure selected from the group consisting of thienyl, pyridyl, pyrazyl, quinolyl, pyrimidinyl, thiazolyl, oxazolyl, imidazolyl, indolyl, and cycloalkenyl having 3 to 10 carbon atoms Or the production method according to claim 1;
(5) In the compounds of formulas (1) and (3), R ² and R ³ together with the carbon atom to which they are bonded form an optionally substituted phenyl. The compounds of the formulas (1) and (3) are represented by the following formulas (4) and (5), respectively:

Wherein R ′ is a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylalkyl, a substituted Represents 1 to 4 identical or different substituents independently selected from the group consisting of optionally alkoxy, optionally substituted aryloxy, perfluoroalkyl, cyano, nitro, and ester; or When R ′ is present, the two R ′ together with the carbon atom to which they are attached may form a saturated or unsaturated ring structure that may contain heteroatoms. )
The production method according to (4) above, comprising:
(6) In the compounds of formulas (2) and (3), R ^A is optionally substituted phenyl, optionally substituted alkyl having 1 to 20 carbon atoms, or optionally substituted carbon. The production method according to (1) above, which is alkenyl having 1 to 20;
(7) In the compound of formula (2), R ⁴ is n-butyl, s-butyl, or t-butyl, the production method according to (1) above;
(8) The production method according to (1), wherein the iron catalyst is an iron salt or an iron complex composed of trivalent iron;
(9) The production method according to (8), wherein the iron complex is an iron (III) complex containing a phosphine compound or a nitrogen bidentate ligand as a ligand;
(10) The production method according to (9), wherein the phosphine compound is cis-1,2-bis (diphenylphosphino) ethylene;
(11) The production method according to (1), wherein the zinc compound is a divalent zinc halide;
(12) The method according to (11) above, wherein the divalent zinc halide is ZnBr ₂ or ZnCl ₂ ;
(13) The production method according to (1), wherein the oxidizing agent is a dihalogenated alkane;
(14) The production method according to the above (13), wherein the dihalogenated alkane is 1,2-dichloroisobutane; and (15) an alkyllithium compound is added to the organoboron compound, and the formula (2) is satisfied. The manufacturing method of any one of said (1)-(14) including the process of forming the salt containing a boronate ester anion is provided.

  In another aspect, the present invention provides a coupling compound obtained by the production method according to any one of (1) to (15) above.

  According to the present invention, a coupling reaction (C—H activation reaction) is efficiently performed using an inexpensive and low-toxic iron catalyst that is abundant in the earth's crust and without using an organic halide. Therefore, it is possible to produce a large variety of coupling compounds at low cost and with high environmental friendliness compared to conventional coupling reactions.

  Hereinafter, embodiments of the present invention will be described. The scope of the present invention is not limited to these descriptions, and other than the following examples, the scope of the present invention can be appropriately changed and implemented without departing from the spirit of the present invention.

1. Definitions In this specification, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

In the present specification, “alkyl” may be any of an aliphatic hydrocarbon group composed of linear, branched, cyclic, or a combination thereof. The number of carbon atoms of the alkyl group is not particularly limited, for example, 1-20 carbon atoms _{(C 1-20),} several 3 to 15 carbon atoms _{(C 3-15),} 5 to 10 carbon atoms _{(C 5 to 10} ). When the number of carbons is specified, it means “alkyl” having the number of carbons within the range. For example, C _1-8 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like are included. In the present specification, the alkyl group may have one or more arbitrary substituents. Examples of the substituent include, but are not limited to, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, and acyl. When the alkyl group has two or more substituents, they may be the same or different. The same applies to the alkyl part of other substituents containing an alkyl part (for example, an alkoxy group, an arylalkyl group, etc.).

  In the present specification, “alkenyl” refers to a linear or branched hydrocarbon group having at least one carbon-carbon double bond. For example, as non-limiting examples, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butanedienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl 4-pentenyl, 1,3-pentanedienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and 1,4-hexanedienyl). The double bond may be either cis or trans conformation.

  In the present specification, “alkynyl” refers to a linear or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, non-limiting examples include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.

  In the present specification, “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic ring system composed of the above alkyl. The cycloalkyl can be unsubstituted or substituted by one or more substituents, which can be the same or different, and non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl Non-limiting examples of polycyclic cycloalkyl include 1-decalinyl, 2-decalinyl, norbornyl, adamantyl and the like. In addition, the cycloalkyl may be a heterocycloalkyl containing one or more hetero atoms (for example, an oxygen atom, a nitrogen atom, or a sulfur atom) as ring-constituting atoms. Any —NH in the heterocycloalkyl ring may be protected, for example as a —N (Boc) group, —N (CBz) group and —N (Tos) group, a nitrogen atom in the ring or The sulfur atom may be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. For example, non-limiting examples of monocyclic heterocycloalkyl include diazapanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, lactam and Examples include lactones.

  As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic non-aromatic ring system containing at least one carbon-carbon double bond. The cycloalkenyl may be unsubstituted or substituted by one or more substituents, which may be the same or different, and non-limiting examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl And cyclohepta-1,3-dienyl, and non-limiting examples of polycyclic cycloalkenyl include norbornylenyl and the like. In addition, the cycloalkyl may be a heterocycloalkenyl which may be a heterocycloalkenyl containing one or more heteroatoms (for example, an oxygen atom, a nitrogen atom, or a sulfur atom) as a ring-constituting atom. Atoms may be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.

  In the present specification, “aryl” may be either a monocyclic or condensed polycyclic aromatic hydrocarbon group, and a hetero atom (for example, an oxygen atom, a nitrogen atom, or a sulfur atom) as a ring constituent atom Etc.) may be an aromatic heterocyclic ring. In this case, it may be referred to as “heteroaryl” or “heteroaromatic”. Whether aryl is a single ring or a fused ring, it can be attached at all possible positions. Non-limiting examples of monocyclic aryl include phenyl group (Ph), thienyl group (2- or 3-thienyl group), pyridyl group, furyl group, thiazolyl group, oxazolyl group, pyrazolyl group, 2-pyrazinyl Group, pyrimidinyl group, pyrrolyl group, imidazolyl group, pyridazinyl group, 3-isothiazolyl group, 3-isoxazolyl group, 1,2,4-oxadiazol-5-yl group or 1,2,4-oxadiazole-3 -An yl group etc. are mentioned. Non-limiting examples of fused polycyclic aryl include 1-naphthyl, 2-naphthyl, 1-indenyl, 2-indenyl, 2,3-dihydroinden-1-yl, 2,3 -Dihydroinden-2-yl group, 2-anthryl group, indazolyl group, quinolyl group, isoquinolyl group, 1,2-dihydroisoquinolyl group, 1,2,3,4-tetrahydroisoquinolyl group, indolyl group, Isoindolyl group, phthalazinyl group, quinoxalinyl group, benzofuranyl group, 2,3-dihydrobenzofuran-1-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzothiophen-1-yl group, 2 , 3-Dihydrobenzothiophen-2-yl group, benzothiazolyl group, benzimidazolyl group, fluorenyl group, thioxanthenyl group, etc. And the like. In the present specification, an aryl group may have one or more arbitrary substituents on the ring. Examples of the substituent include, but are not limited to, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, and acyl. When the aryl group has two or more substituents, they may be the same or different. The same applies to the aryl moiety of other substituents containing the aryl moiety (for example, an aryloxy group and an arylalkyl group).

  In the present specification, “arylalkyl” represents an alkyl substituted with the above aryl. The arylalkyl may have one or more arbitrary substituents. Examples of the substituent include, but are not limited to, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, and an acyl group. When the acyl group has two or more substituents, they may be the same or different. Non-limiting examples of arylalkyl include benzyl group, 2-thienylmethyl group, 3-thienylmethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-furylmethyl group, 3-furylmethyl group, 2-thiazolylmethyl group, 4-thiazolylmethyl group, 5-thiazolylmethyl group, 2-oxazolylmethyl group, 4-oxazolylmethyl group, 5-oxazolylmethyl group, 1-pyrazolylmethyl group 3-pyrazolylmethyl group, 4-pyrazolylmethyl group, 2-pyrazinylmethyl group, 2-pyrimidinylmethyl group, 4-pyrimidinylmethyl group, 5-pyrimidinylmethyl group, 1-pyrrolylmethyl group, 2-pyrrolylmethyl group, 3-pyrrolylmethyl group 1-imidazolylmethyl group, 2-imidazolylmethyl group, 4-imidazolylmethyl 3-pyridazinylmethyl group, 4-pyridazinylmethyl group, 3-isothiazolylmethyl group, 3-isoxazolylmethyl group, 1,2,4-oxadiazol-5-ylmethyl group Or a 1,2,4-oxadiazol-3-ylmethyl group etc. are mentioned.

  Similarly, in the present specification, “arylalkenyl” represents alkenyl substituted with aryl.

  In the present specification, the “alkoxy group” is a structure in which the alkyl group is bonded to an oxygen atom, and examples thereof include a saturated alkoxy group that is linear, branched, cyclic, or a combination thereof. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropoxy group, n-butoxy group, isobutoxy group, s-butoxy group, t-butoxy group, cyclobutoxy group, cyclopropylmethoxy group, n- Pentyloxy, cyclopentyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, n-hexyloxy, cyclohexyloxy, cyclopropylpropyloxy, cyclobutylethyloxy or cyclopentylmethyloxy are preferred Take as an example.

  In the present specification, the “aryloxy group” is a group to which the aryl group is bonded through an oxygen atom. Examples of the aryloxy group include phenoxy group, 2-thienyloxy group, 3-thienyloxy group, 2-pyridyloxy group, 3-pyridyloxy group, 4-pyridyloxy group, 2-furyloxy group, and 3-furyl. Oxy group, 2-thiazolyloxy group, 4-thiazolyloxy group, 5-thiazolyloxy group, 2-oxazolyloxy group, 4-oxazolyloxy group, 5-oxazolyloxy group, 1-pyrazolyloxy group, 3-pyrazolyloxy group Group, 4-pyrazolyloxy group, 2-pyrazinyloxy group, 2-pyrimidinyloxy group, 4-pyrimidinyloxy group, 5-pyrimidinyloxy group, 1-pyrrolyloxy group, 2-pyrrolyloxy group, 3-pyrrolyloxy group, 1-imidazolyloxy group 2-imidazolyloxy group, 4-imidazolyloxy group, -Pyridazinyloxy group, 4-pyridazinyloxy group, 3-isothiazolyloxy group, 3-isoxazolyloxy group, 1,2,4-oxadiazol-5-yloxy group, or Examples include a 1,2,4-oxadiazol-3-yloxy group.

  In the present specification, “alkylene” is a divalent group consisting of a linear or branched saturated hydrocarbon, such as methylene, 1-methylmethylene, 1,1-dimethylmethylene, ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1 -Methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1 -Diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethyl , Tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, 2,2-di-n-propyl Trimethylene and the like.

  In the present specification, “alkenylene” is a divalent group consisting of an unsaturated hydrocarbon having at least one linear or branched carbon-carbon double bond, such as ethenylene. 1-methylethenylene, 1-ethylethenylene, 1,2-dimethylethenylene, 1,2-diethylethenylene, 1-ethyl-2-methylethenylene, propenylene, 1-methyl-2-propenylene, 2-methyl -2-propenylene, 1,1-dimethyl-2-propenylene, 1,2-dimethyl-2-propenylene, 1-ethyl-2-propenylene, 2-ethyl-2-propenylene, 1,1-diethyl-2-propenylene 1,2-diethyl-2-propenylene, 1-butenylene, 2-butenylene, 1-methyl-2-butenylene, 2-methyl-2-butenylene, , 1-dimethyl-2-butenylene, 1,2-dimethyl-2-butenylene, and the like.

  In the present specification, “arylene” and “arylalkylene” mean a divalent group based on the above “aryl” and “arylalkyl”, respectively. Similarly, “oxyalkylene” and “aryleneoxy” mean a divalent group based on the above “alkoxy” and “aryloxy”, respectively.

In the present specification, “alkylamino” and “arylamino” mean an amino group in which a hydrogen atom of —NH ₂ group is substituted with 1 or 2 of the above alkyl or aryl. For example, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, benzylamino and the like can be mentioned. Similarly, “alkylthio” and “arylthio” mean a group in which the hydrogen atom of the —SH group is substituted with the above alkyl or aryl. For example, methylthio, ethylthio, benzylthio and the like can be mentioned.

  In the present specification, “acyl” may be either an aliphatic acyl group or an aromatic acyl group, or may be an aliphatic acyl group having an aromatic group as a substituent. Acyl groups may contain one or more heteroatoms. For example, as an acyl group, an alkylcarbonyl group (such as an acetyl group), an alkyloxycarbonyl group (such as an acetoxycarbonyl group), an arylcarbonyl group (such as a benzoyl group), an aryloxycarbonyl group (such as a phenyloxycarbonyl group), an aralkylcarbonyl group ( Benzylcarbonyl group), alkylthiocarbonyl group (such as methylthiocarbonyl group), alkylaminocarbonyl group (such as methylaminocarbonyl group), arylthiocarbonyl group (such as phenylthiocarbonyl group), or arylaminocarbonyl group (phenylaminocarbonyl group) And the like, but is not limited thereto. These acyl groups may have one or more arbitrary substituents. Examples of the substituent include, but are not limited to, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, and an acyl group. When the acyl group has two or more substituents, they may be the same or different.

  As used herein, “amide” includes both RNR′CO— (when R = alkyl, alkaminocarbonyl-) and RCONR′- (where R = alkyl, alkylcarbonylamino-).

  As used herein, “ester” includes both ROCO— (in the case of R = alkyl, alkoxycarbonyl-) and RCOO— (in the case of R = alkyl, alkylcarbonyloxy-).

  As used herein, the term “ring structure”, when formed by a combination of two substituents, means a heterocyclic or carbocyclic group, such group being saturated, unsaturated, or aromatic. Can be. Accordingly, it includes cycloalkyl, cycloalkenyl, aryl, and heteroaryl as defined above. Examples include cycloalkyl, phenyl, naphthyl, morpholinyl, piperidinyl, imidazolyl, pyrrolidinyl, pyridyl and the like. In the present specification, a substituent can form a ring structure with another substituent, and when such substituents are bonded to each other, those skilled in the art will recognize a specific substitution, such as bonding to hydrogen. Can be understood. Therefore, when it is described that specific substituents together form a ring structure, those skilled in the art can understand that the ring structure can be formed by an ordinary chemical reaction and can be easily generated. Both such ring structures and their process of formation are within the purview of those skilled in the art.

2. Coupling reaction (method for producing a coupling compound)
In the production method of the present invention, in the presence of an iron catalyst, a coupling reaction between a compound such as carboxamide having a nitrogen atom as an orientation group and an organoboron compound is performed to activate the CH bond of sp ² and select In particular, functional groups such as alkyl and aryl are directly introduced. In particular,
A compound of the following formula (1) in the presence of an iron catalyst, a zinc compound, and an oxidizing agent

And a boron compound salt of the following formula (2)

And a coupling compound of the following formula (3) in which R ^A is introduced into the carbon atom to which R ³ is bonded:

Is to be manufactured. The production method obtains the coupling compound of the above formula (3) in a very simple and high yield by using an abundant, inexpensive and low toxicity iron catalyst and without using an organic halide. It has the advantage that it can be used for a wide range of reaction substrates having various functional groups.

The compound of the above formula (1) is a compound into which an R ^A group is introduced by the production method of the present invention, and in the formula (1), X is a carbon atom or a nitrogen atom; Y is ═O, = S, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted Selected from the group consisting of aryloxy and esters. R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted alkoxy, a substituted It represents 1 to 2 identical or different substituents selected from the group consisting of aryloxy, which may be substituted, and ester, provided that at least one R ¹ is not a hydrogen atom.

Preferably, X and Y are a combination of a carbon atom and ═O, or a combination of a group containing a nitrogen atom and a carbon atom. For example, when X is a carbon atom and Y is ═O, a site consisting of Y—X—N forms an amide group, and R ¹ is as described above. Y and R ¹ can also form a saturated or unsaturated ring structure that may contain heteroatoms, together with the X and nitrogen atoms to which they are attached, for example, such The ring structure is preferably a heteroaryl, heterocycloalkyl or heterocycloalkenyl containing a nitrogen atom, particularly preferably an optionally substituted pyridyl or an optionally substituted pyrazolyl.

In the above formula (1), R ² and R ³ are each a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, or an optionally substituted aryl. It represents 1 to 2 identical or different substituents independently selected from the group consisting of alkyl, optionally substituted alkoxy, optionally substituted aryloxy, and ester. Here, R ² and R ³ can be combined with the carbon atom to which they are bonded to form a saturated or unsaturated ring structure that may contain a hetero atom. Preferably, such ring structures include phenyl, naphthyl, thienyl, pyridyl, pyrazyl, quinolyl, pyrimidinyl, thiazolyl, oxazolyl, imidazolyl, indolyl, and cycloalkenyl having 3 to 10 carbon atoms.

Also, in some cases, Y and R ² can be combined with the X and carbon atoms to which they are attached to form a saturated or unsaturated ring structure that may contain heteroatoms. For example, as described above, Y and R ¹ form pyridyl, R ² and R ³ form phenyl, and Y and R ² form a ring structure. A benzoquinoline ring can also be formed as shown.

In a preferred embodiment, when R ² and R ³ together with the carbon atom to which they are attached form phenyl, the compound of formula (1) has the structure of formula (4) below.

In the formula (4), R ′ represents a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylalkyl, a substituted Represents 1 to 4 identical or different substituents independently selected from the group consisting of optionally substituted alkoxy, optionally substituted aryloxy, perfluoroalkyl, cyano, nitro, and ester. Here, when two R ′ are present, the two R ′ together with the carbon atom to which they are bonded may be a saturated or unsaturated ring structure that may contain a hetero atom. Can also be formed. Similarly to R ² above, Y and R ′ together with the X atom and carbon atom to which they are bonded form a saturated or unsaturated ring structure that may contain heteroatoms. You can also

  The compound of the formula (2) is a boron compound salt that couples with the compound of the above formula (1), and is composed of a boronate ester anion and a lithium cation.

By the production method of the present invention, the R ^A group in the compound of the formula (2) is introduced into the CH bond in the compound of the formula (1) to obtain the coupling compound of the formula (3). It is preferable that the addition amount of the compound of Formula (2) is 2 molar equivalents or more with respect to the compound of Formula (1). More preferably, it is 3 molar equivalents or more, and still more preferably 4 molar equivalents or more.

In the formula (2), R ^A represents a substituent selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl. . Preferably, R ^A is an optionally substituted phenyl, an optionally substituted alkyl having 1 to 20 carbons, or an optionally substituted alkenyl having 1 to 20 carbons.

In Formula (2), R ⁴ represents an optionally substituted alkyl having 1 to 10 carbon atoms, and is preferably n-butyl, s-butyl, or t-butyl. Each R ⁵ independently represents the same or different, optionally substituted alkyl having 1 to 10 carbon atoms, wherein the two R ⁵ are combined with the oxygen atom to which they are bonded. To form a ring structure. Preferably, -B ^(OR _{5) 2} moiety has the following structure.

In the formula (2), Z ⁺ is a lithium metal ion.

A salt containing a boronate ester anion represented by the formula (2) can be obtained by adding an alkyl lithium compound to an organoboron compound. Therefore, the production method of the present invention can further include a step of forming such a compound of formula (2). In the production method of the present invention, when the R ^A group is introduced into the CH bond in the compound of the formula (1) to obtain the compound of the formula (3), the R ^A group is eliminated from the boron compound salt of the formula (2). R ⁴ —B (OR ⁵ ) ₂ is produced, and the compound of formula (2) can be obtained by reacting the boron compound again with an alkyl lithium compound as described above. Thus, the point that R ⁴ -B (OR ⁵ ) ₂ after the coupling reaction can be reused is also a feature of the production method of the present invention.

The compound of formula (3) is a product of the production method of the present invention, and as described above, is a compound in which an R ^A group is introduced into the CH bond of the compound of formula (1) by a coupling reaction. When R ² and R ³ together with the carbon atom to which they are attached form a phenyl and the compound of formula (1) has the structure of formula (4), the compound of formula (3) is And having a structure represented by the following formula (5).

Here, R ′ is as defined above. In formulas (3) and (5), only one (monosubstituted) is shown as the R ^A group to be introduced, but when there is a carbon atom located symmetrically with respect to the X atom. It will be readily apparent to those skilled in the art that further ^RA groups can be introduced at this position (disubstituted). Specific examples of the generated coupling compound of formula (3) will be described later.

  The iron catalyst used in the production method of the present invention is preferably an iron salt or iron complex composed of trivalent iron. Examples of the trivalent iron salt include iron (III) bromide, iron (III) chloride, iron (III) iodide, iron (III) fluoride, iron (III) oxalate, iron (III) acetate, and iron sulfate. (III), iron sulfide (III), iron nitrate (III), etc. are mentioned. The iron complex is preferably an iron (III) complex containing a phosphine compound or a nitrogen bidentate ligand as a ligand. The phosphine compound is preferably cis-1,2-bis (diphenylphosphino) ethylene (dppen), and the nitrogen bidentate ligand is a phenanthroline derivative or a dipyridyl derivative.

In the production method of the present invention, the boron compound salt of the above formula (2) is activated by the zinc compound. Such a zinc compound is preferably a divalent zinc halide, more preferably ZnBr ₂ or ZnCl ₂ . The zinc compound may be a diamine complex containing a divalent zinc halide. However, the use of the diamine complex is not essential for the progress of the coupling reaction in the production method of the present invention.

  The oxidant used in the production method of the present invention can be an oxidant that provides relatively mild oxidation, for example, preferably a dihalogenated alkane, more preferably 1,2-dichloroisobutane. . Moreover, dichloroethane can also be used as the oxidizing agent.

  The solvent used in the production method of the present invention is preferably an aprotic polar solvent. Non-limiting examples of aprotic polar solvents are tetrahydrofuran (THF), N, N′-dimethylpropyleneurea (DMPU), acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone. (NMP). Tetrahydrofuran is preferable.

  The reaction temperature in the production method of the present invention can be appropriately set by those skilled in the art, but is preferably 50 ° C. or higher, more preferably 70 ° C.

  In addition, the reaction conditions such as the reaction time in the production method are described in detail as representative examples in the examples described below, but are not necessarily limited thereto, and those skilled in the art can Each can be appropriately selected based on general knowledge in organic synthesis.

  In addition, regarding a method for synthesizing the compounds of the formulas (1) and (2) that are the above-mentioned raw materials used in the production method of the present invention, those skilled in the art will be based on general knowledge in organic synthesis. It can be fully understood.

3. Coupling compound (product)
The present invention also relates to a coupling compound represented by the formula (3) obtained as a product of the above production method. Specific examples of such a coupling compound include, but are not limited to, compounds having the following structure (hereinafter, “Q” represents quinolin-8-yl, and “p-Anisole”). "represents a _{(4-CH 3 OC 6 H} 4).).

  These compounds of the present invention may exist as salts. Examples of the salt include base addition salts, acid addition salts, amino acid salts and the like. Examples of the base addition salt include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, or organic amine salts such as triethylamine salt, piperidine salt, morpholine salt, and acid addition salt. Examples thereof include mineral acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as methanesulfonate, paratoluenesulfonate, citrate, and oxalate. Examples of amino acid salts include glycine salts.

  In addition, the compound of the present invention or a salt thereof may exist as a hydrate or a solvate, and any of these substances is included in the scope of the present invention. Although the kind of solvent which forms a solvate is not specifically limited, For example, solvents, such as ethanol, acetone, isopropanol, can be illustrated.

  Furthermore, the compounds of the present invention may have one or more asymmetric carbons, and stereoisomers such as optical isomers or diastereoisomers may exist, in which case the pure form of the stereoisomer Any mixture of stereoisomers, racemates and the like are included within the scope of the present invention.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these.

Unless otherwise specified, commercially available compounds (Tokyo Chemical Industry, Aldrich Inc., etc.) were purchased and used as they were. Anhydrous THF
What was purchased from Wako Pure Chemical Industries was refined with a solvent purifier (GlassContour) equipped with activated alumina and carrying a copper catalyst (Q-5) before use. Iron (III) acetylacetonate complex (Fe (acac) ₃ , purity 99.9% based on metal) and cis-1,2-bis (diphenylphosphino) ethylene (dppen) were obtained from Aldrich Inc. The one purchased from was used as it was. Allyl phenyl ether used as it was purchased from Tokyo Chemical Industry. ZnBr ₂ .TMEDA is described in Isobe et al., Chem. Lett. 1997, 679-682.

[Example 1]
Synthesis of 4-methyl-N- (quinolin-8-yl)-[1,1′-biphenyl] -2-carboxamide:
A. Synthesis of carboxamide compounds

  Tran et al. Am. Chem. Soc. 2012, 134, 18237-18240, as shown above, the carboxamide compound (3-methyl-N- (quinolin-8-yl) benzamide) of compound 1 is converted from an aroyl chloride compound and 8-aminoquinoline. Synthesized.

B. Synthesis of organoboron compounds

  At −78 ° C. under an argon atmosphere, a THF solution (10 ml, 2.0 mol / l, 20 mmol) of anhydrous 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane was added with an airtight syringe. The n-butyllithium hexane solution (12.5 ml, 1.6 mol / l, 20 mmol) was slowly added. The resulting mixture was stirred at −78 ° C. for 10 minutes, then heated to room temperature and stirred for 20 minutes to obtain a boronic acid lithium salt (Compound 2).

C. Arylation of carboxamide compounds (synthesis of 4-methyl-N- (quinolin-8-yl)-[1,1'-biphenyl] -2-carboxamide)

At room temperature under an argon atmosphere, Fe (acac) ₃ (0.5 mmol), dppen (0.5 mmol), ZnBr ₂ .TMEDA (1.0 mmol) and compound 1 (5.0 mmol) were dissolved in 10 ml of anhydrous THF to obtain a compound. Two boron compounds in THF were added using a cannula or an airtight syringe. The resulting orange mixture was stirred at room temperature for 10 minutes before 1,2-dichloroisobutane (DCIB: 1.15 ml, 10 mmol) was added. The resulting mixture was stirred at 70 ° C. for 24 hours (30-40 minutes after heating, the color of the mixture changed from red to black). After cooling to room temperature, an aqueous Rochelle salt solution (10 ml) was added and the organic phase was extracted with diethyl ether (30 ml × 3 times). The resulting organic phase was washed with brine, passed through a Florisil pad, dried over MgSO ₄ and concentrated under reduced pressure. The crude product mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) and white solid 4-methyl-N- (quinolin-8-yl)-[1,1′-biphenyl]. 2-Carboxamide was obtained (1.62 g, yield 96%).

Melting point: 153-154 ° C. (ethyl acetate / hexane)
¹ H NMR (500 MHz,) δ 9.75 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.53 − 8.45 (m, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.72 (s, 1H), 7.50 (ddd, J = 7.7, 4.4, 3.4 Hz, 3H), 7.43 (d, J = 8.2 Hz, 1H), 7.37 (s, 2H), 7.31 (ddd, J = 8.3, 4.2 , 0.9 Hz, 1H), 7.25 (t, J = 7.4 Hz, 2H), 7.13 (td, J = 7.7, 1.1 Hz, 1H), 2.46 (s, 3H).
¹³ C NMR (126 MHz,) δ 167.95, 147.62, 139.87, 138.29, 137.43, 137.30, 135.84, 134.48, 131.19, 130.53, 129.66, 128.90, 128.24, 127.58, 127.29, 127.14, 121.36, 121.27, 116.12, 20.96.
GC MS (EI) m / z (relative intensity): 338 (M ⁺ , 9), 195 (100), 165 (44), 152 (57), 144 (14), 116 (17), 89 (14) .
[Example 2]
The following compound 3 was used in place of the compound 1 of Example 1, and a coupling reaction with the boron compound of Compound 2 was carried out in the same manner as in Example 1 to introduce a phenyl group into the CH bond. The yield was 87%.

Using various compounds, a coupling reaction of the compound 2 with a boron compound was performed, and a phenyl group was introduced into the CH bond in these compounds in the same manner as in Example 1.

[Examples 3 to 13]
In place of the compound 1 of Example 1, various carboxamide compounds were used to carry out a coupling reaction with the boron compound of Compound 2 in the same manner as in Example 1 to introduce a phenyl group into the CH bond. The results are shown in Table 1 (in the table, “8-Q” represents quinolin-8-yl).

[Examples 14 to 17]
In place of compound 1 in Example 1, various compounds other than carboxamide were used to carry out a coupling reaction with the boron compound of Compound 2 in the same manner as in Example 1 to introduce a phenyl group into the CH bond. The results are shown in Table 2.

[Examples 18 to 38]
In the same manner as in Example 1, a coupling reaction was performed using various substituents for the introduction group ( ^RA group) of the boron compound of Compound 2 to introduce an ^RA group into the CH bond. The results are shown in Table 3 (in the table, “8-Q” represents quinolin-8-yl).

[Examples 39 to 42]
The compound 3 of Example 2 was subjected to a coupling reaction using various substituents for the boron compound introduction group ( ^RA group) of the compound 2 to introduce an ^RA group into the CH bond. The results are shown in Table 3 (in the table, “8-Q” represents quinolin-8-yl).

Verification of Synthesis Conditions Various synthesis conditions were compared for the synthesis scheme shown in Example 1 (Comparative Experiments 1 to 8).

(1) Comparison of zinc compounds As shown below, as a result of performing coupling reaction by changing various zinc compounds to be used, it was found that zinc halide is suitable. On the other hand, in the case of the magnesium (II) salt used for the activation of the boron compound in the reaction system using the conventional iron catalyst, it was found that the coupling reaction of the present case does not proceed.

(2) Comparison of iron catalysts Next, as shown below, as a result of examining the dependence of the iron catalyst to be used, it was found that it is preferable to use a trivalent iron catalyst. On the other hand, in the case of a divalent iron catalyst, it turned out that the coupling reaction of this case does not advance.

(3) Ligand Comparison As shown below, as a result of examining the dependence of the iron catalyst on the ligand, it was found that dppen is the most suitable as the ligand. It was also found that a preferable reaction proceeds even with a dipyridyl compound which is a nitrogen bidentate ligand such as phenanthroline.

(4) Comparison of oxidizing agents As shown below, as a result of conducting coupling reactions by changing various oxidizing agents to be used, it was found that DCIB is most suitable. It was also found that dichloroethane (DCE), which is generally used as a reaction solvent, was used as an oxidizing agent in this case, although the yield was slightly reduced.

(5) Comparison of reaction temperature As shown below, as a result of performing a coupling reaction by changing the reaction temperature, it was found that 70 ° C was preferable.

(6) Comparison of addition amount of boron compound As shown below, the addition amount of the boron compound with respect to the carboxamide compound was compared, and it was found that 4 equivalents were suitable.

(7) Comparison of organometallic compounds As shown below, as a result of comparing organometallic compounds for producing boronate ester anions, it was found that alkyllithium compounds are suitable. On the other hand, it was found that the reaction did not proceed with the MgBr compound.

(8) Comparison of boronic acid ester As shown below, when the structure of boronic acid ester is compared, boronic acid ester having -B (OR ⁵ ) ₂ site is preferred as in formula (2) in the present invention. I found out.

Claims (16)

A compound of the following formula (1) in the presence of an iron catalyst, a zinc compound, and an oxidizing agent

Wherein X is a carbon atom or a nitrogen atom;
Y is ═O, ═S, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, Selected from the group consisting of optionally substituted aryloxy and esters;
R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted alkoxy, a substituted Represents optionally 1 or 2 identical or different substituents selected from the group consisting of aryloxy and ester, provided that at least one R ¹ is not a hydrogen atom;
R ² and R ³ are each a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylalkyl, or an optionally substituted Represents 1 to 2 identical or different substituents independently selected from the group consisting of good alkoxy, optionally substituted aryloxy, and ester;
Here, Y and R ¹ together with the X atom and N atom to which they are bonded may form a saturated or unsaturated ring structure that may contain a hetero atom,
R ² and R ³ together with the carbon atom to which they are attached may form a saturated or unsaturated ring structure that may contain heteroatoms;
Furthermore, Y and R ² together with the X atom and carbon atom to which they are bonded may form a saturated or unsaturated ring structure that may contain heteroatoms. )
And a boron compound salt of the following formula (2)

Wherein R ^A represents a substituent selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl;
R ⁴ represents an optionally substituted alkyl having 1 to 10 carbon atoms;
Each R ⁵ independently represents the same or different, optionally substituted alkyl having 1 to 10 carbon atoms, wherein the two R ⁵ are combined with the oxygen atom to which they are bonded. To form a ring structure;
Z ⁺ is a lithium metal ion. )
And a coupling compound of the following formula (3):

(In the formula, X, Y, R ^{1 to} R ^3, and R ^A are as defined above.)
A process for producing a coupling compound, characterized in that 2. The compound of formulas (1) and (3), wherein X is a carbon atom; Y is ═O; thereby the site consisting of Y—X—N forms an amide. Manufacturing method. In the compounds of formulas (1) and (3), said Y and said R ¹ together with the X and N atoms to which they are attached may be optionally substituted pyridyl or substituted The process according to claim 1, wherein good pyrazolyl is formed. In the compounds of formulas (1) and (3), R ² and R ³ together with the carbon atom to which they are attached may each be substituted, phenyl, naphthyl, thienyl, pyridyl 5. A ring structure selected from the group consisting of: pyrazyl, quinolyl, pyrimidinyl, thiazolyl, oxazolyl, imidazolyl, indolyl, and cycloalkenyl having 3 to 10 carbon atoms. Production method. In the compounds of formulas (1) and (3), R ² and R ³ together with the carbon atom to which they are attached form an optionally substituted phenyl; The compounds of (1) and (3) are represented by the following formulas (4) and (5), respectively.

Wherein R ′ is a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted arylalkyl, a substituted Represents 1 to 4 identical or different substituents independently selected from the group consisting of optionally alkoxy, optionally substituted aryloxy, perfluoroalkyl, cyano, nitro, and ester; or When R ′ is present, the two R ′ together with the carbon atom to which they are attached may form a saturated or unsaturated ring structure that may contain heteroatoms. )
The manufacturing method of Claim 4 which has these. In the compounds of the formulas (2) and (3), R ^A is optionally substituted phenyl, optionally substituted alkyl having 1 to 20 carbon atoms, or optionally substituted carbon atoms 1 to 1. The production method according to claim 1, which is 20 alkenyl. The manufacturing method of Claim 1 whose R < ⁴ > is n-butyl, s-butyl, or t-butyl in the compound of Formula (2). The manufacturing method of Claim 1 whose said iron catalyst is an iron salt or iron complex which consists of trivalent iron. The production method according to claim 8, wherein the iron complex is an iron (III) complex containing a phosphine compound or a nitrogen bidentate ligand as a ligand. The production method according to claim 9, wherein the phosphine compound is cis-1,2-bis (diphenylphosphino) ethylene. The production method according to claim 1, wherein the zinc compound is a divalent zinc halide. The method according to claim 11, wherein the divalent zinc halide is ZnBr ₂ or ZnCl ₂ . The production method according to claim 1, wherein the oxidizing agent is a dihalogenated alkane. The production method according to claim 13, wherein the dihalogenated alkane is 1,2-dichloroisobutane. The manufacturing method of any one of Claims 1-14 including the process of adding the alkyl lithium compound to an organoboron compound, and forming the salt containing the boronate ester anion shown by Formula (2). The coupling compound obtained by the manufacturing method of any one of Claims 1-15.