JPWO2016027809A1 - Cross coupling method and method for producing organic compound using the cross coupling method - Google Patents

Abstract

An object of the present invention is to provide a cross-coupling reaction in which various compounds can be used as a substrate at low cost, and a method for producing a compound using the cross-coupling reaction. The said objective can be achieved by making a specific ester compound (especially aryl ester, heteroaryl ester, etc.) react with a specific boronic acid compound in the presence of a nickel compound.

Description

  The present invention relates to a cross-coupling method (specifically, a cross-coupling reaction between an ester compound and a boronic acid compound) and a method for producing an organic compound using the cross-coupling method.

  Conventionally, in synthesizing various compounds, a method (cross coupling reaction) in which two kinds of substrates as raw material compounds are reacted in the presence of an appropriate catalyst has been widely adopted. If this cross-coupling reaction is employed, a wide variety of organic compounds can be easily synthesized.

As such a cross-coupling reaction, for example,
(1) Deesterification type biaryl cross coupling in which a specific azole and a specific ester compound are reacted in the presence of a nickel catalyst (for example, Non-patent Document 1),
(2) C—H alkenylation reaction in which a specific azole and a specific ether compound are reacted in the presence of a nickel catalyst (for example, Non-patent Document 2),
(3) Decarbonylated biaryl cross-coupling using palladium catalyst (for example, Non-Patent Document 3)
Etc. are known.

J. Am. Chem. Soc. 2012, 134, 13573-13576 Angew. Chem. Int. Ed. 2013, 52, 10048-10051 Science 2006, 313, 662-664

  However, in the methods (1) to (2), it is necessary to use a specific azole as a substrate, and it cannot be applied to a cross-coupling reaction using another substrate. The method (3) is not suitable for practical use because it requires an expensive palladium catalyst and a stoichiometric amount of silver salt. As described above, the conventional cross-coupling method is limited in terms of substrate and cost.

  For this reason, an object of this invention is to provide the manufacturing method of the compound using the cross-coupling reaction which can use a various compound as a substrate cheaply, and this cross-coupling reaction.

  As a result of intensive studies to solve the above problems, the present inventors have used various compounds by using an inexpensive nickel compound as a catalyst and a specific ester compound and a specific boronic acid compound as a substrate. It has been found that a cross-coupling reaction that can be provided inexpensively is caused. Based on such knowledge, the present inventors have further studied and completed the present invention.

  That is, the present invention includes the following configurations.

  Item 1. General formula (1):

[Wherein, R ¹ represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted alkyl group. R ² represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted unsaturated hydrocarbon group. The carbon atom in R ¹ and the sp2 hybrid carbon atom in R ² are bonded. ]
A method for producing an organic compound represented by
A step of subjecting an ester compound and a boronic acid compound to a cross-coupling reaction in the presence of a nickel compound;
The ester compound has the general formula (2):

[Wherein, R ¹ is the same as defined above. R ³ represents an aryl group which may be substituted. ]
A compound represented by
The boronic acid compound has the general formula (3):

[Wherein R ² is the same as defined above. Further, the boron atom and the sp2 hybrid carbon atom in R ² are bonded. R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an alkyl group. R ⁴ and R ⁵ may be bonded to each other to form a ring together with adjacent —O—B—O—. ]
The manufacturing method which is a compound represented by these.

  Item 2. Item 2. The production method according to Item 1, wherein a ligand compound is further used in the cross-coupling reaction.

  Item 3. Item 3. The production method according to Item 2, wherein the ligand compound is a phosphine-based ligand compound.

  Item 4. Item 4. The production method according to any one of Items 1 to 3, wherein a base is further used in the cross-coupling reaction.

Item 5. A cross-coupling method in which an ester compound and a boronic acid compound are reacted in the presence of a nickel compound,
The ester compound has the general formula (2):

[Wherein, R ¹ represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted alkyl group. R ³ represents an aryl group which may be substituted. ]
A compound represented by
The boronic acid compound has the general formula (3):

[Wherein, R ² represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted unsaturated hydrocarbon group. The boron atom and the sp2 hybrid carbon atom in R ² are bonded. R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an alkyl group. R ⁴ and R ⁵ may be bonded to each other to form a ring together with adjacent —O—B—O—. ]
A method represented by the formula:

  Item 6. Item 6. The method according to Item 5, wherein a ligand compound is used.

  Item 7. Item 7. The method according to Item 6, wherein the ligand compound is a phosphine-based ligand compound.

  Item 8. Item 8. The method according to any one of Items 5 to 7, wherein a base is used.

  Item 9. The following general formula:

[Wherein TBS represents a t-butyldimethylsilyl group. ]
A compound represented by

  According to the present invention, a new type of cross-linkage that connects these two molecules by reacting an ester compound that is normally recognized not to undergo a cross-coupling reaction with a boronic acid compound in the presence of a nickel compound. Coupling reaction is possible (new reaction).

  The present invention is also an achievement accompanied by “discovery of new reactivity” which was completely unexpected that “the carbon-carbon bond of the ester compound is broken”. That is, the cross-coupling reaction of the present invention is a new reaction that provides a new option that an ester compound can be used for the cross-coupling reaction. In addition to the meaning of developing a new coupling partner called an ester compound, it has great synthetic chemistry. The cross-coupling reaction of the present invention also has an unprecedented feature that an ester compound can be used as it is in a cross-coupling reaction to lead to various compounds.

  Further, it is highly versatile in that it can be a trial of a cheaper and more stable (easy to handle) nickel compound in the air than a rare and expensive palladium compound.

  Furthermore, since a cheap ester compound and boronic acid compound can be used as a coupling partner without using a halogen compound such as an aromatic halogen compound, a cross-coupling reaction can be performed at a lower cost, and a by-product As a result, it is possible to perform a safe cross-coupling reaction that does not generate halogen waste, metal waste, or the like, which is a concern for environmental pollution.

  It is also possible to carry out the cross coupling reaction in a very high yield by appropriately selecting the substrate, ligand, reaction temperature and the like. In this case, since the selectivity is high, there is a high possibility that it will lead to an energy conservation law.

1. Method for producing arylcarbonyl compound and coupling method In the present invention, a specific organic compound is obtained by effectively coupling a specific ester compound and a specific boronic acid compound in the presence of a nickel compound. Can do.

  In the present invention, various organic compounds are obtained by using various nickel compounds (nickel complexes) and using various substrates as raw materials to proceed a coupling reaction between a specific ester compound and a specific boronic acid compound. It is also possible.

  In this coupling reaction, a specific aromatic compound can usually be obtained by reacting a specific ester compound with a specific boronic acid compound in the presence of a specific nickel compound (nickel complex; catalyst). Specifically, a specific organic compound can be obtained by reacting a specific ester compound and a specific boronic acid compound in a solvent in the presence of a specific nickel compound (nickel complex) and a base.

  The ester compound subjected to the reaction is not particularly limited, and for example, the general formula (2):

[Wherein, R ¹ represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted alkyl group. R ³ represents an aryl group which may be substituted. ]
An ester compound represented by

In the general formula (2), examples of the aryl group represented by R ¹ include a phenyl group, a naphthyl group, an anthracenyl group, and a biphenyl group.

Examples of the substituent that the aryl group represented by R ¹ may have include, for example, a halogen atom (such as a fluorine atom), an alkyl group (such as a C1-4 alkyl group such as a methyl group or an ethyl group), or a haloalkyl. Group (C1-4 haloalkyl group such as trifluoromethyl group), alkoxy group (C1-4 alkoxy group such as methoxy group), amino group (dialkylamino group such as diethylamino group), silyl group (t-butyldimethyl) And a group represented by —COOR (where R is an alkyl group such as a methyl group or an ethyl group). Moreover, you may have the above-mentioned aryl group which may be substituted by the above-mentioned substituent, the below-mentioned heteroaryl group which may be substituted by the above-mentioned substituent, etc. as a substituent. The number of this substituent is preferably 0-6, more preferably 0-3.

In the general formula (2), examples of the heteroaryl group represented by R ¹ include pyrrolyl group, pyridyl group, pyrrolidyl group, piperidyl group, imidazolyl group, pyrazolyl group, pyrazyl group, pyrimidyl group, pyridazyl group, piperazyl group, Triazinyl group, oxazolyl group, isoxazolyl group, morpholyl group, thiazolyl group, isothiazolyl group, furanyl group, thiophenyl group, indolyl group, quinolyl group, isoquinolyl group, benzoimidazolyl group, quinazolyl group, phthalazyl group, purinyl group, pteridyl group, benzofuranyl group , Coumaryl group, chromonyl group, benzothiophenyl group and the like.

Examples of the substituent that the heteroaryl group represented by R ¹ may have include, for example, a halogen atom (such as a fluorine atom), an alkyl group (such as a C1-4 alkyl group such as a methyl group or an ethyl group), Haloalkyl group (C1-4 haloalkyl group such as trifluoromethyl group), alkoxy group (C1-4 alkoxy group such as methoxy group), amino group (dialkylamino group such as diethylamino group), silyl group (t-butyl) A trialkylsilyl group such as a dimethylsilyl group), a group represented by -COOR (R is an alkyl group such as a methyl group or an ethyl group), and the like. Moreover, you may have said aryl group which may be substituted by the above-mentioned substituent, said heteroaryl group etc. which may be substituted by the above-mentioned substituent as a substituent. The number of this substituent is preferably 0-6, more preferably 0-3.

In the general formula (2), examples of the alkyl group represented by R ¹ include a chain or branched C 1-10 alkyl group, preferably a C 1-8 alkyl group. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group.

Examples of the substituent that the alkyl group represented by R ¹ may have include, for example, a halogen atom (fluorine atom and the like), an alkoxy group (C1-4 alkoxy group such as a methoxy group), and an amino group (diethylamino group). And a group represented by -silyl group (trialkylsilyl group such as t-butyldimethylsilyl group), -COOR (R is an alkyl group such as methyl group or ethyl group). In addition, the above-mentioned aryl group which may be substituted with the above-described substituent, the above-mentioned heteroaryl group which may be substituted with the above-described substituent, etc. (especially phenyl group, naphthyl group, etc.) It may be. The number of this substituent is preferably 0-6, more preferably 0-3.

As R ¹ , from the viewpoint of yield, a naphthyl group which may have the above substituent, a pyridyl group which may have the above substituent, a thiazolyl group which may have the above substituent, The quinolyl group which may have the above substituent, the chromonyl group which may have the above substituent, the benzothiophenyl group which may have the above substituent, or the above substituent A good alkyl group is preferred,

Etc. are more preferable.

In particular, in the present invention, even if R ¹ has another functional group having reactivity, such as an alkoxy group or an alkyl ester group, the aryl ester group is selectively removed, and the boronic acid described later A desired aromatic compound can be obtained by combining with an aryl group, heteroaryl group, unsaturated hydrocarbon group or the like of the compound.

In the general formula (2), as the aryl group represented by R ³ , those described above can be adopted. The same applies to the type and number of substituents. Of these, an unsubstituted aryl group is preferable, and a phenyl group is particularly preferable. In addition, when a compound (carboxylic acid compound, alkyl ester, etc.) in which R ³ is a hydrogen atom, an alkyl group or the like is employed as a substrate, the coupling reaction of the present invention hardly proceeds.

  As an ester compound as a substrate satisfying such conditions, for example,

[In the above formula, Piv represents a pivaloyl group. The same applies hereinafter. ]
Etc. can be used

Etc. are preferred.

  The boronic acid compound to be subjected to the reaction is not particularly limited, and for example, the general formula (3):

[Wherein R ² is the same as defined above. Further, the boron atom and the sp2 hybrid carbon atom in R ² are bonded. R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an alkyl group. R ⁴ and R ⁵ may be bonded to each other to form a ring together with adjacent —O—B—O—. ]
A boronic acid compound represented by

In the general formula (3), as the aryl group and heteroaryl group represented by R ² , those described above can be adopted. The same applies to the type and number of substituents.

In the general formula (3), the unsaturated hydrocarbon group represented by R ² is a group capable of bonding a boron atom and the sp2 hybrid carbon atom, and is preferably a 1-alkenyl group, specifically,

Etc.

From the viewpoint of yield, R ² is preferably a phenyl group which may have the above substituent, or a naphthyl group which may have the above substituent,

Etc. are more preferable.

In the general formula (3), the alkyl groups represented by R ⁴ and R ⁵ may be those described above. The same applies to the type and number of substituents.

In the general formula (3), when R ⁴ and R ⁵ are both alkyl groups, they may be bonded to each other to form a ring with adjacent —O—B—O—. In this case, the boronic acid compound is, for example,

[Wherein R ² is the same as defined above. ]
Etc.

Among these, from the viewpoint of yield, R ⁴ and R ⁵ are preferably both hydrogen atoms.

  As a boronic acid compound as a substrate satisfying such conditions, for example,

Etc. can be used

Etc. are preferred.

  Moreover, as a boronic acid compound, it is not limited only to said compound, For example,

A boroxine compound such as can also be used.

  The amount of the boronic acid compound used is not particularly limited, and from the viewpoint of yield, for example, usually about 0.1 to 10 mol is preferable and about 0.5 to 5 mol is more preferable with respect to 1 mol of the ester compound. 1 to 3 mol is more preferable.

  The nickel compound is not particularly limited, and a zero-valent Ni salt or a divalent Ni salt is preferable. These can be used individually by 1 type or in combination of 2 or more types. These complexes mean both those charged as reagents and those produced in the reaction. In the present invention, since a nickel compound can be used as a catalyst, the cost of the coupling reaction can be reduced and the handling is easy.

  The zero-valent Ni salt is not particularly limited, and examples thereof include bis (1,5-cyclooctadiene) nickel (0), bis (triphenylphosphine) nickel dicarbonyl, nickel carbonyl and the like.

  Examples of the divalent Ni salt include nickel acetate (II), nickel trifluoroacetate (II), nickel nitrate (II), nickel chloride (II), nickel bromide (II), nickel (II) acetyl. Acetonate, nickel (II) perchlorate, nickel (II) citrate, nickel (II) oxalate, nickel (II) cyclohexanebutyrate, nickel (II) benzoate, nickel (II) stearate, nickel stearate ( II), sulfamine nickel (II), nickel carbonate (II), nickel thiocyanate (II), nickel trifluoromethanesulfonate (II), bis (1,5-cyclooctadiene) nickel (II), bis (4- Diethylaminodithiobenzyl) nickel (II), nickel (II) cyanide, difluoride Kell (II), nickel boride (II), nickel borate (II), nickel hypophosphite (II), ammonium nickel sulfate (II), nickel hydroxide (II), cyclopentadienyl nickel (II), And hydrates thereof, and mixtures thereof.

  As the zero-valent Ni salt and the divalent Ni salt, a compound in which a ligand is coordinated may be used. For example, a nickel compound having a monodentate or bidentate dialkylphosphine or dicycloalkylphosphine skeleton (further a nickel compound having a bidentate dialkylphosphine or dicycloalkylphosphine skeleton, particularly a bidentate dicycloalkylphosphine skeleton Nickel compounds) can be preferably used.

  The nickel compound coordinated with such a ligand is preferably a nickel compound coordinated with a phosphine ligand in order to efficiently proceed with the coupling reaction.

[In the formula, Z ′ may or may not form a ring, and in the case of forming a ring, an aromatic hydrocarbon ring or a 5-membered or 6-membered heterocycle is Show. R ^{6 to} R ⁹ are the same or different and each represents an optionally substituted alkyl group or an optionally substituted cycloalkyl group. X < ¹ > -X < ² > is the same or different and shows a ligand. n1 and n2 are the same or different and represent an integer of 0 to 2. A solid line connecting the nickel atom and the two phosphorus atoms and the nickel atom with X ¹ and X ² is a coordination bond. ]
The nickel compound represented by these is preferable.

  In addition, although it is thought that a nickel atom and two phosphorus atoms generally form a coordination bond, in the general formula (4), it is indicated by a solid line for convenience.

  In the general formula (4), Z ′ may or may not form a ring.

  In the general formula (4), the aromatic hydrocarbon ring in the case where Z ′ forms a ring is not particularly limited, and examples thereof include a benzene ring, a naphthalene ring, and an anthracene ring.

  In the general formula (4), when Z ′ forms a ring, the heterocycle is not particularly limited as long as it is a 5-membered or 6-membered heterocycle, from the viewpoint of storage stability. A 5-membered or 6-membered heteroaromatic ring is preferable, and specific examples include a thiophene ring, a pyrrole ring, a furan ring, an imidazole ring, a pyrazole ring, an oxazole ring, a thiazole ring, a pyridine ring, and a pyrazine ring. A thiophene ring is particularly preferred.

  In the general formula (4), when Z ′ does not form a ring, nothing is present at the position of Z ′, and the general formula (4A):

[Wherein, R ^{6 to} R ⁹ , X ^{1 to} X ² , and n ^{1 to} n ² are the same as described above. A solid line connecting the nickel atom and the two phosphorus atoms and the nickel atom with X ¹ and X ² is a coordination bond. ]
The compound represented by these is meant.

In the general formula (4) and the general formula (4A), the alkyl groups represented by R ^{6 to} R ⁹ may be those described above. The same applies to the type and number of substituents.

In General Formula (4) and General Formula (4A), the cycloalkyl group represented by R ^{6 to} R ⁹ is not particularly limited, but is preferably a C 3-8 cycloalkyl group, and more preferably a C 4-6 cycloalkyl group. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like. From the viewpoint of the yield of the coupling reaction, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like. Etc. are preferable, and a cyclohexyl group is more preferable.

Examples of the substituent that the cycloalkyl group represented by R ^{6 to} R ⁹ may have include a halogen atom (fluorine atom, chlorine atom, bromine atom, etc.), an alkoxy group (C1- 4 alkoxy group), amino group (dialkylamino group such as diethylamino group), silyl group (trialkylsilyl group such as t-butyldimethylsilyl group), -COOR (R is an alkyl group such as methyl group or ethyl group) ) And the like. Moreover, you may have said aryl group which may be substituted by the above-mentioned substituent, said heteroaryl group etc. which may be substituted by the above-mentioned substituent as a substituent. The number of this substituent is preferably 0-6, more preferably 0-3.

In General Formula (4) and General Formula (4A), R ^{6 to} R ⁹ are the same or different and may be an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent. However, from the viewpoint of the yield of the coupling reaction, an optionally substituted cycloalkyl group is preferred, and an (unsubstituted) cycloalkyl group is more preferred. R ^{6 to} R ⁹ are particularly preferably a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like, and most preferably a cyclohexyl group.

In the general formula (4) and the general formula (4A), the ligand represented by X ^{1 to} X ² is not particularly limited as long as it is a ligand that can coordinate to a nickel atom. hydride; H ^-); halogen atom; a lower alkoxy group; the carbon monoxide (CO); boron ligand; phosphorus-based ligand; antimony ligand; arsenic ligand; sulfonic acid ligand Sulfate, perchlorate, nitrate, bis (trifuryl) imide, tris (trifuryl) methane, bis (trifuryl) methane, carboxylates, and the like.

In General Formula (4) and General Formula (4A), examples of the halogen atom as the ligand represented by X ^{1 to} X ² include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the general formula (4) and the general formula (4A), examples of the lower alkoxy group as the ligand represented by X ^{1 to} X ² include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group. A C1-3 alkoxy group etc. are mentioned.

In the general formula (4) and general formula (4A), examples of the boron-based ligand as the ligand represented by X ^{1 to} X ² include tetraphenylborate and tetrakis (bis (trifluoromethyl) phenyl). Examples include borate, tetrakis (pentafluorophenyl) borate, tetrafluoroborate, alkyl trifluoroborate, and aryl trifluoroborate.

In the general formula (4) and the general formula (4A), examples of the phosphorus ligand as the ligand represented by X ^{1 to} X ² include hexafluorophosphate.

In the general formula (4) and the general formula (4A), examples of the antimony-based ligand as the ligand represented by X ^{1 to} X ² include hexafluoroantimonate.

In the general formula (4) and general formula (4A), examples of the arsenic ligand as the ligand represented by X ^{1 to} X ² include hexafluoroarsenate.

In the general formula (4) and the general formula (4A), examples of the sulfonic acid-based ligand as the ligand represented by X ^{1 to} X ² include tosylate, mesylate, and triflate.

In the general formula (4) and the general formula (4A), examples of the carboxylates as the ligand represented by X ^{1 to} X ² include acetate.

  In General Formula (4) and General Formula (4A), n1 and n2 are integers of 0 to 2, and 0 or 1 is preferable from the viewpoint of yield.

  As the nickel compound represented by the general formula (4) satisfying such conditions,

[Solid lines connecting nickel atoms and two phosphorus atoms and nickel atoms and two COs are coordinate bonds. ]
Etc. can be used.

  As the nickel compound coordinated with these ligands, known or commercially available nickel compounds can be used. Moreover, when synthesize | combining the nickel complex (catalyst) which coordinated said ligand, you may synthesize | combine beforehand and may synthesize | combine in a system. That is, when the coupling reaction of the present invention is caused, a nickel compound coordinated with a ligand may be added, or a ligand compound and a nickel compound may be added.

  Said nickel compound may be used independently and may be used in combination of 2 or more type. Among them, the coupling reaction of the present invention can proceed with the coupling reaction of the present invention without using a nickel compound coordinated with the ligand, and since it is inexpensive, Non-coordinated nickel compounds are preferred, bis (1,5-cyclooctadiene) nickel (0), nickel (II) acetate, nickel (II) acetylacetonate, cyclopentadienyl nickel (II), and these More preferred are hydrates of these and mixtures thereof. Of these, nickel (II) acetate is preferred from the viewpoint of high reaction yield and stability to air. From the viewpoint of high reaction yield, bis (1,5-cyclooctadiene) nickel (0), nickel (II) acetate, nickel (II) acetylacetonate, and hydrates thereof, and these And the like, and bis (1,5-cyclooctadiene) nickel (0), nickel acetate (II), and the like are more preferable.

  The amount of the nickel compound used can be appropriately selected depending on the type of substrate (the number of reaction sites, etc.). For example, usually about 0.01 to 1 mol is preferable with respect to 1 mol of the ester compound as the substrate. , About 0.02 to 0.5 mol is more preferable, and about 0.03 to 0.3 mol is more preferable. When the nickel compound is synthesized in the system, it is preferable to adjust so that the amount of the nickel compound present in the system is within the above range.

  In the present invention, together with the nickel compound, a ligand compound capable of coordinating to a nickel atom can be used (added). Examples of the ligand compound include carboxylic acid-based, amide-based, phosphine-based, oxime-based, sulfonic acid-based, 1,3-diketone-based ligand compounds, Schiff base-based ligand compounds, and oxazoline-based coordination. Child compounds, diamine-based ligand compounds, carbon monoxide, carbene-based ligand compounds, and the like. The coordination atom in the ligand compound is a nitrogen atom, a phosphorus atom, an oxygen atom, a sulfur atom or the like. Carbon monoxide and carbene-based ligand compounds are ligand compounds having a carbon atom as a coordination atom. Among these ligand compounds, a ligand compound having a phosphorus atom as a coordination atom is preferable, and a phosphine-based ligand compound is more preferable in order to allow the coupling reaction to proceed efficiently. That is, when the nickel compound is not a compound in which a ligand having a phosphorus atom as a coordination atom (particularly a phosphine-based ligand) is coordinated, a phosphorus atom is coordinated as a ligand compound. It is preferable to separately use the ligand compound. These ligand compounds can be used alone or in combination of two or more. These ligand compounds include a monodentate ligand compound having only one coordinate atom and a multidentate ligand compound (such as a bidentate ligand compound) having two or more sites.

  Examples of the monodentate ligand compound include triphenylphosphine, trimethoxyphosphine, triethylphosphine, tri (i-propyl) phosphine, tri (t-butyl) phosphine, tri (n-butyl) phosphine, and tri (i-propoxy). Phosphine, tri (cyclopentyl) phosphine, tri (cyclohexyl) phosphine, tri (o-tolyl) phosphine, tri (p-tolyl) phosphine, trimesitylphosphine, triphenoxyphosphine, tri (2-furyl) phosphine, tri (p- Anisyl) phosphine, potassium bis (p-sulfonatephenyl) phenylphosphine, di (t-butyl) methylphosphine, methyldiphenylphosphine, dimethylphenylphosphine, n-propyldiphenylphosphine, di (n-propyl) Phenylphosphine, dicyclohexylphenylphosphine, (2-biphenyl) di-t-butylphosphine (JOHNPHOS), triethylamine, pyridine, N, N-dibenzyldinaphtho [2,1-d: 2′-f] [1,3 , 2] dioxaphosphepin-4-amine and the like.

  Examples of the bidentate ligand compound include 2,2′-bipyridine, 4,4 ′-(t-butyl) bipyridine, phenanthroline, 2,2′-bipyrimidyl, 1,4-diazabicyclo [2,2,2]. Octane, 2- (dimethylamino) ethanol, tetramethylethylenediamine, N, N-dimethylethylenediamine, N, N′-dimethylethylenediamine, 2-aminomethylpyridine, or (NE) -N- (pyridin-2-ylmethylidene) aniline 1,1′-bis (diphenylphosphino) ferrocene, 1,1′-bis (t-butyl) ferrocene, diphenylphosphinomethane, 1,2-bis (diphenylphosphino) ethane, 1,3-bis ( Diphenylphosphino) propane, 1,5-bis (diphenylphosphino) pentane, 1,2-bis (di N-fluorophenylphosphino) ethane, 1,2-bis (dicyclohexylphosphino) ethane, 1,3- (dicyclohexylphosphino) propane, 1,2-bis (di-t-butylphosphino) ethane, 1,3 -Bis (di-t-butylphosphino) propane, 1,2-bis (diphenylphosphino) benzene, 1,5-cyclooctadiene, BINAP, BIPHEMP, 1,2-bis (diphenylphosphino) propane (PROPHOS) ), 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane (DIOP), 3,4-bis (diphenylphosphino) -1-benzylpyrrolidine (DEGUPHOS) 1,2-bis [(2-methoxyphenyl) (phenyl) phosphino] ethane (D PAMP), 1,2-bis (substituted phosphorano) benzene (DuPHOS), 2,3-bis (diphenylphosphino) -5-norbornene (NORPHOS), N, N′-bis- (diphenylphosphino) -N, N′-bis (1-phenylethyl) ethylenediamine (PNNP), 2,4-bis- (diphenylphosphino) pentane (SKEWPHOS), 1- [1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethylamine (BPPFA) ), [(5,6), (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl] bisdiphenylphosphine (SEGPHOS), 2,3-bis (diphenylphosphino) butane (CHIRAPHOS), [2- (diphenylphosphino) ferrocenyl] ethyldicyclohexylphos Fin (JOSIPHOS), and mixtures thereof.

  The BINAP also includes derivatives of 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), and specific examples include 2,2′-bis (diphenylphosphino). -1,1'-binaphthyl, 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl, 2,2'-bis (di-p-tertiarybutylphenylphosphino) -1 , 1′-binaphthyl, 2,2′-bis (di-m-tolylphosphino) -1,1′-binaphthyl, 2,2′-bis (di-3,5-dimethylphenylphosphino) -1,1 ′ -Binaphthyl, 2,2'-bis (di-p-methoxyphenylphosphino) -1,1'-binaphthyl, 2,2'-bis (dicyclopentylphosphino) -1,1'-binaphthyl, 2,2 '-Bis (dicyclohexyl Phosphino) -1,1′-binaphthyl, 2-di (β-naphthyl) phosphino-2′-diphenylphosphino-1,1′-binaphthyl, 2-diphenylphosphino-2′-di (p-trifluoromethyl) Phenyl) phosphino-1,1′-binaphthyl and the like.

  The BIPHEMMP also includes derivatives of 2,2′-dimethyl-6,6′-bis (diphenylphosphino) -1,1′-biphenyl (BIPHEMP), and specific examples include 2,2 ′. -Dimethyl-6,6'-bis (diphenylphosphino) -1,1'-biphenyl, 2,2'-dimethyl-6,6'-bis (dicyclohexylphosphino) -1,1'-biphenyl, 2, 2'-dimethyl-4,4'-bis (dimethylamino) -6,6'-bis (diphenylphosphino) -1,1'-biphenyl, 2,2 ', 4,4'-tetramethyl-6 6'-bis (diphenylphosphino) -1,1'-biphenyl, 2,2'-dimethoxy-6,6'-bis (diphenylphosphino) -1,1'-biphenyl, 2,2 ', 3 3'-tetramethoxy 6,6′-bis (diphenylphosphino) -1,1′-biphenyl, 2,2 ′, 4,4′-tetramethyl-3,3′dimethoxy-6,6′-bis (diphenylphosphino)- 1,1′-biphenyl, 2,2′-dimethyl-6,6′-bis (di-p-tolylphosphino) -1,1′-biphenyl, 2,2′-dimethyl-6,6′-bis (di -P-tertiarybutylphenylphosphino) -1,1'-biphenyl, 2,2 ', 4,4'-tetramethyl-3,3'-dimethoxy-6,6'-bis (di-p- Methoxyphenylphosphino) -1,1′-biphenyl and the like.

  The ligand compound is preferably a monodentate ligand compound from the viewpoints of yield, cost, electron donating property, and the like, and is triphenylphosphine, tri (n-butyl) phosphine, tri (cyclohexyl) phosphine, tri (p- Tolyl) phosphine, tri (p-anisyl) phosphine, methyldiphenylphosphine, n-propyldiphenylphosphine, dicyclohexylphenylphosphine, (2-biphenyl) di-t-butylphosphine (JOHNPHOS), N, N-dibenzyldinaphtho [ 2,1-d: 2′-f] [1,3,2] dioxaphosphin-4-amine and the like are more preferable, and triphenylphosphine, tri (n-butyl) phosphine, tri (cyclohexyl) phosphine, Tri (p-tolyl) phosphine, tri (p-anisyl) phosphine, More preferred are rudiphenylphosphine, n-propyldiphenylphosphine, dicyclohexylphenylphosphine and the like, and tri (n-butyl) phosphine, tri (cyclohexyl) phosphine, tri (p-anisyl) phosphine, methyldiphenylphosphine, n-propyldiphenylphosphine, Particularly preferred is dicyclohexylphenylphosphine.

  When the above ligand compound is used (added), the amount used is preferably 0.01 to 50 mol, more preferably 0.1 to 20 mol, relative to 1 mol of the nickel compound, and 0.5 to 10 mol is more preferable, and 1 to 5 mol is particularly preferable.

  In the coupling reaction of the present invention, it is preferable to use a base in order to promote the reaction by reacting with boronic acid or to supplement the produced phenol.

  In the present invention, the coupling reaction can be further promoted by using a weak base as the base. For this reason, it is preferable to use a weak base in consideration of handleability.

  Examples of the base that can be used in the present invention include alkali metal phosphates such as potassium phosphate and sodium phosphate; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and rubidium carbonate; trimethylamine, triethylamine and the like. Examples include amines; metal diamides such as lithium diisopropylamide (LDA), lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide (particularly alkali metal amides); Grignard reagents and the like. Among these, from the viewpoint of yield, alkali metal phosphates, alkali metal carbonates and amines are preferable, potassium phosphate, sodium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, triethylamine and the like are more preferable. Sodium carbonate, triethylamine and the like are more preferable.

  The amount of the base used is usually preferably 0.2 to 20 mol, more preferably 0.5 to 10 mol, and even more preferably 1 to 5 mol with respect to 1 mol of the ester compound as the substrate.

  Examples of the solvent include chain ethers such as diethyl ether, dimethoxyethane, diisopropyl ether, and tert-butyl methyl ether; cyclic ethers such as dioxane; aromatic hydrocarbons such as toluene, benzene, and mesitylene; pentane, hexane, heptane, Examples include aliphatic hydrocarbons such as cyclohexane. These may be used alone or in combination of two or more. Among these, in the present invention, cyclic ethers, aromatic hydrocarbons and the like are preferable, dioxane, toluene and benzene are more preferable, and dioxane and toluene are particularly preferable.

  In the coupling reaction of the present invention, additives other than the above components may be appropriately used within the range not impairing the effects of the present invention. For example, the yield can be improved depending on the substrate by using an additive such as NaCl.

  The coupling reaction of the present invention is preferably carried out under anhydrous conditions and under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually about 0 to 200 ° C., preferably about 50 to 180 ° C. More preferably, it is about 100-160 degreeC. The reaction time is usually about 10 minutes to 72 hours, preferably about 1 to 48 hours.

  The coupling reaction of the present invention comprises a carbon-carbon bond of an ester compound (particularly, a bond between a carbon atom present in an aryl group or heteroaryl group of the ester compound and a carbon atom in the ester bond directly bonded thereto) Two molecules while breaking the carbon-boron bond of boronic acid compound (particularly, the bond between sp2 hybrid carbon atom in boronic acid compound's aryl group, heteroaryl group or hydrocarbon group and boron atom directly bonded to it) Is a new type of coupling reaction. In the present invention, even if the ester compound and boronic acid compound which are substrates have other functional groups (alkali ester group, alkoxy group) or the like, the above bond is selectively cleaved to perform a coupling reaction. Progresses. For this reason, since the coupling reaction can proceed efficiently without protecting other functional groups, the number of steps can be further reduced.

  After completion of the reaction, the target compound can be obtained through normal isolation and purification steps. Various useful organic compounds can be obtained by using the coupling reaction of the present invention.

  Of the compounds thus obtained,

[Wherein TBS is a t-butyldimethylsilyl group; the same shall apply hereinafter. ]
Etc. are novel compounds not described in any literature.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not restrict | limited at all by these Examples.

Unless otherwise specified, all the materials including the dry solvent were used as they were on the market. Nickel (II) acetate tetrahydrate (Ni (OAc) ₂ .4H ₂ O) and tri (n-butyl) phosphine (P (n-Bu) ₃ ) were purchased from Kanto Chemical Co., Inc. Na ₂ CO ₃ was purchased from Wako Pure Chemical Industries. Toluene was purified using Glass Contour as an organic solvent purifier. Phenylnicotinate, phenylisonicotinate, phenyl 2-phenylquinoline-4-carboxylate, phenylthiophene-2-carboxylate, phenylthiophene-3-carboxylate, phenyl 2-phenylthiazole-4-carboxylate, phenyl 2- Naphthoate, phenylfuran-2-carboxylate, phenylfuran-3-carboxylate, 4-oxo-4H-chromene-2-carboxylic acid, 5- (methoxycarbonyl) nicotinic acid, and 4-methylpiperazine-1-carbothioamide Was synthesized according to the method described in known literature (J. Am. Chem. Soc. 2012, 134, 13753, WO1998US24627, WO2006103038, J. Med. Chem. 2005, 48, 7520, etc.). Phenyl 3-methylbenzoate, phenyl 4-fluorobenzoate, phenyl 4-methylbenzoate, methylphenyl terephthalate, phenyl 2-methoxybenzoate, phenylquinoline-3-carboxylate, and phenyl 1-naphthoate are the corresponding carboxylic acids, phenols, Known documents using EDC / HCl / DMAP (Synth. Commun. 2006, 36, 275, Synlett. 2007, 6, 974, J. Org. Lett. 2008, 10, 1537, Org. Lett. 2012, 14, 3100 etc.), the HCl in their spectra was consistent with that reported in the literature. Unless otherwise noted, all reactions were performed in a dry glass vessel using a dry solvent under a nitrogen (N ₂ ) gas atmosphere using standard vacuum line techniques. All coupling reactions were heated in an 8-well reaction block (containing heater and magnetic stir bar) unless otherwise noted using a 20 mL glass container tube equipped with a J. Young® O-ring tap. I went there. All work-up and purification procedures were performed in air with reagent grade solvents.

Analytical thin layer chromatography (TLC) was performed using E. Merck silica gel 60 F ₂₅₄ precoated plates (0.25 mm). The developed chromatogram was analyzed with a UV lamp (254 nm). Flash column chromatography was performed using E. Merck silica gel 60 (230-400 mesh). Preparative thin layer chromatography (PTLC) was performed using a pre-prepared Wakogel B5-F silica-coated plate (0.75 mm). Gas chromatography (GC) was performed with a Shimadzu GC-2010 instrument equipped with an HP-5 column (30 m × 0.25 mm, Hewlett-Packard) using dodecane as an internal standard. GCMS analysis was performed on a Shimadzu GCMS-QP2010 equipped with an HP-5 column (30 m × 0.25 mm, Hewlett-Packard). High resolution mass spectra (HRMS) were obtained with a JMS-T100TD instrument (DART). Nuclear magnetic resonance (NMR) spectra were recorded on a JEOL JNM-ECA-400 spectrometer ( ¹ H 400 MHz, ¹³ C 100 MHz). ¹ H NMR chemical shifts were expressed in relative parts per million (ppm) of tetramethylsilane (δ0.00 ppm). ¹³ C NMR chemical shifts were expressed in relative parts per million (ppm) of CDCl ₃ (δ 77.0 ppm). Data include chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet doublet, t = triplet, q = quartet, m = multiplet, br = broad signal), binding constant (Hz), and integration Report in order.

Synthesis Example 1: Ester Compound [Synthesis Example 1-1]

[Wherein Ph is a phenyl group. Et is an ethyl group. DMAP is 4,4-dimethylaminopyridine. The same applies hereinafter. ]
Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 eq) and the mixture was stirred at reflux for 1 hour. The solution was concentrated under vacuum. Triethylamine (1.2 eq) was added to a solution of the residue in CH ₂ Cl ₂ (1.0 M). After cooling to 0 ° C., a small amount of phenol (1.0 eq) and 4,4-dimethylaminopyridine (DMAP) were added to the solution, and then the reaction mixture was allowed to warm to room temperature. The mixture was stirred for 1 hour and then passed through a short silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated under reduced pressure and the residue was purified by recrystallization or flash column chromatography to give the corresponding ester compound.

The spectral data of each compound was as follows.
Compound 1b (phenyl 6- (trifluoromethyl) nicotinate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.48 (s, 1H), 8.64 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz , 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.6, 151.7 (q, J = 35 Hz) , 151.4, 150.2, 139.3, 129.7, 128.1, 126.5, 121.4, 121.0 (q, J = 279 Hz), 120.3 (q, J = 3 Hz); HRMS (DART) m / z calcd for C ₁₃ H ₉ F ₃ NO ₂ [M + H] ⁺ : 268.0585, found: 268.0585.
Compound 1s (phenyl 5-fluoronicotinate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.22 (s, 1H), 8.72 (d, J = 2.8 Hz, 1H), 8.16-8.11 (m, 1H), 7.45 (t, J = 8.0 Hz, 2H) , 7.30 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 161.5 (d, J = 238 Hz), 150.3, 147.0 ( d, J = 4 Hz), 142.6, (d, J = 24 Hz), 129.6 (d, J = 3 Hz), 126.4, 124.0 (d, J = 20 Hz), 121.3; HRMS (DART) m / z calcd for C ₁₂ H ₉ FNO ₂ [M + H] ⁺ : 218.0617, found: 218.0620.

  [Synthesis Example 1-2]

[In the formula, EDC · HCl is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The same applies hereinafter. ]
In a round bottom flask, carboxylic acid (2.22 g, 15 mmol), phenol (1 eq), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC · HCl: 1.1 eq), N, N-dimethyl Aminopyridine (DMAP: 0.25 equivalent) and CH ₂ Cl ₂ (0.5M) were added. After stirring for several hours while monitoring the reaction on TLC, the reaction mixture was quenched with saturated NaHCO ₃ aq and extracted three times with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by recrystallization or flash column chromatography to obtain an ester compound.

The spectral data of each compound was as follows.
Compound 1i (phenylbenzo [b] thiophene-2-carboxylate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.25 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.4, 7.2 Hz, 1H), 7.47-7.40 (m, 3H), 7.31-7.23 (m, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 161.2, 150.6, 142.6, 138.6, 132.7, 131.9, 129.5, 127.3 , 126.1, 125.7, 125.1, 122.8, 121.6; HRMS (DART) m / z calcd for C ₁₅ H ₁₁ O ₂ S [M + H] ⁺ : 255.0480, found: 255.0477.
Compound 1k (3-methyl 5-phenylpyridine-3,5-dicarboxylate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.53 (d, J = 0.8 Hz, 1H), 9.44 (d, J = 2.0 Hz, 1H), 9.03 (dd, J = 2.0, 0.8 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 4.02 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 164.8, 163.0, 154.7, 154.6, 150.3, 138.5, 129.6, 126.4, 126.1, 126.0, 121.4, 52.8; HRMS (DART) m / z calcd for C ₁₄ H ₁₂ NO ₄ [M + H] ⁺ : 258.0766 , found: 258.0770.
Compound 11 (phenyl 2-methoxynicotinate):
₁ H NMR (CDCl ₃ , 400 MHz) δ 8.38 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.27 (t , J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.01 (dd, J = 7.6, 5.2 Hz, 1H), 4.08 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 163.4, 163.0, 151.6, 150.8, 141.8, 129.5, 126.0, 121.8, 116.5, 113.4, 54.3; HRMS (DART) m / z calcd for C ₁₃ H ₁₂ NO ₃ [M + H] ⁺ : 230.0817, found : 230.0819.
Compound 1q (phenyl 4-oxo-4H-chromene-2-carboxylate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.23 (d, J = 8.4 Hz, 1H), 7.78 (t, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.51-7.43 (m, 3H), 7.33 (t, J = 7.6 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J = 7.6 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 178.2, 159.1, 156.0, 151.6, 150.0, 134.9, 129.7, 126.7, 126.1, 125.8, 124.4, 121.1, 118.8, 115.7; HRMS (DART) m / z calcd for C ₁₆ H ₁₁ O ₄ [M + H] ⁺ : 267.0657, found: 267,0654.
Compound 1t (phenyloxazole-4-carboxylate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.45 (s, 1H), 8.02 (s, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.2, 151.6, 150.1, 145.1, 132.7, 129.5, 126.2, 121.5; HRMS (DART) m / z calcd for C ₁₀ H ₈ NO ₃ [M + H] ⁺ : 190.0504, found: 190.0505.
Compound 1ag (phenyl 6-chloronicotinate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.17 (d, J = 2.8 Hz, 1H), 8.39 (dd, J = 8.4, 2.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.0, 7.6 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 163.0, 156.3, 151.6, 150.3, 140.0, 129.6, 126.4, 124.6, 124.4, 121.4; HRMS (DART) m / z calcd for C ₁₂ H ₉ ClNO ₂ [M + H] ⁺ : 234.0322, found: 234.0318.

  [Synthesis Example 1-3]

[Wherein DMF is N, N-dimethylformamide. The same applies hereinafter. ]
To a solution of 2-chloro-5-phenoxypyridine (467 mg, 2 mmol) in DMF (4 mL), diethylamine (160.9 g, 2.2 mmol, 1.1 eq) and N, N-diisopropylethylamine (Hunig base: 510 μL g, 3 mmol, 1.5 eq) ) Was added. The mixture was stirred at room temperature for 3 days. The reaction was quenched with NH ₄ Claq and extracted four times with ethyl acetate (EtOAc). The combined organic layers were washed with brine and then dried over Na ₂ SO ₄ . After filtering the combined organic layers, the mixture was concentrated under reduced pressure. Purification by flash column chromatography (hexane / ethyl acetate = 15: 1 to 10: 1) gave the desired product as a white solid (198 mg, 37%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.96 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 9.2, 2.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 6.48 (d, J = 9.2 Hz, 1H), 3.59 (q, J = 7.2 Hz, 4H), 1.22 (t , J = 7.2 Hz, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 164.8, 159.5, 152.3, 151.0, 138.4, 129.3, 125.5, 121.8, 112.2, 104.4, 42.9, 12.8; HRMS (DART) m / z calcd for C ₁₆ H ₁₉ N ₂ O ₂ [M + H] ⁺ : 271.1447, found: 271.1451.

  [Synthesis Example 1-4]

To a solution of 3-methyl-2-thiophenecarboxylic acid (1 eq) in CH ₂ Cl ₂ (0.5 M) was added oxalyl chloride (1.5 eq) and a small amount of DMF. After stirring for 1.5 hours, phenol (1.5 equivalents) and a small amount of DMAP were added to the mixture. Then, at 0 ° C., triethylamine (Et ₃ N) (2 eq) was slowly added to the mixture. After stirring the solution overnight, the reaction mixture was quenched with saturated NaHCO ₃ aq and extracted 3 times with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexane / ethyl acetate = 20: 1) gave the desired product (phenyl 3-methylthiophene-2-carboxylate) as a brown oil (990 mg, 91%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.49 (d, J = 5.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.21 (d , J = 8.0 Hz, 2H), 6.99 (d, J = 5.2 Hz, 1H), 2.61 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 161.1, 150.5, 148.0, 131.9, 131.1, 129.4 , 125.9, 125.6, 121.8, 16.1; HRMS (DART) m / z calcd for C ₁₂ H ₁₁ O ₂ S [M + H] ⁺ : 219.0480, found: 219.0483.

  [Synthesis Example 1-5]

4-Methylpiperazine-1-carbothioamide (1.1 g, 6.7 mmol) was combined with ethyl 3-bromo-2-oxopropanoic acid (935 μL, 7.4 mmol, 1.1 eq) in ethanol (EtOH) (10 mL). Stir at 50 ° C. overnight. The mixture was cooled to room temperature and then concentrated under reduced pressure. NaHCO ₃ aq was added to the resulting solid and then extracted with diethyl ether (Et ₂ O). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give ethyl 2- (4-methylpiperazin-1-yl) thiazole-4-carboxylate (1.57 g, 91%) as an orange oil. Obtained.

The resulting oil (1.57 g, 6.1 mmol) was treated with a solution of NaOH (270 mg, 6.7 mmol, 1.1 eq) in EtOH / H ₂ O (10 mL / 5 mL) at room temperature. The mixture was stirred overnight and then concentrated to give sodium 2- (4-methylpiperazin-1-yl) thiazole-4-carboxylate as a yellow solid (1.53 g, quant).

To a solution of sodium carboxylate (1.53 g, 6.14 mmol) in CH ₂ Cl ₂ (20 mL) was added oxalyl chloride (791 μL, 9.2 mmol, 1.5 eq) and a small amount of DMF. After stirring for 1.5 hours, phenol (866 mg, 9.2 mmol, 1.5 eq) and a small amount of DMAP were added to the mixture. Then, at 0 ° C., triethylamine (Et ₃ N) (1.72 mL, 12 mmol, 2 eq) was slowly added to the mixture. After stirring the solution overnight, the reaction mixture was quenched with saturated NaHCO ₃ aq and extracted 3 times with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Then purified by flash column chromatography (CHCl ₃ / MeOH = 20: 1) and preparative HPLC (H ₂ O / MeCN), phenyl 2- (4-methylpiperazin-1-yl) thiazole-4-carboxylate Was obtained as a brown solid (1.38 g, 74%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.67 (s, 1H), 7.40 (dd, J = 8.0, 7.6 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H), 3.59 (t, J = 4.8 Hz, 4H), 2.53 (t, J = 4.8 Hz, 4H), 2.34 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 170.9, 159.9, 150.7, 143.0, 129.4, 125.8, 121.7, 118.2, 54.1, 48.3, 46.1; HRMS (DART) m / z calcd for C ₁₅ H ₁₈ N ₃ O ₂ S [M + H] ⁺ : 304.1120, found: 304.1125 .

  [Synthesis Example 1-6]

To a solution of phenol (470 mg, 5 mmol, 1 eq), DMAP (6 mg, 50 μmol, 1 mol%), and Et ₃ N (607 mg, 6 mmol, 1.2 eq) in CH ₂ Cl ₂ (5 mL) at 0 ° C., 3,5- Dimethylbenzoyl chloride (740 μL, 5 mmol, 1 eq) was added. The reaction mixture was stirred for 3 h before being quenched with saturated NaHCO ₃ aq and extracted 3 times with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (hexane / ethyl acetate = 50: 1) gave phenyl 3,5-dimethylbenzoate as a colorless liquid (1.13 g, quant).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.83 (s, 2H), 7.43 (t, J = 8.4 Hz, 2H), 7.30-7.24 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H) , 2.41 (s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.5, 152.9, 151.0, 138.3, 135.2, 129.5, 127.9, 125.8, 121.7, 21.2; HRMS (DART) m / z calcd for C ₁₅ H ₁₅ O ₂ [M + H] ⁺ : 227.1072, found: 227.1075.

  [Synthesis Example 1-7]

[Wherein Piv represents a pivaloyl group. The same applies hereinafter. ]
To a solution of 3-hydroxybenzoic acid (1.38g, 10mmol) and N, N-dimethylaminopyridine (DMAP: 12mg, 0.1mmol, 0.1mol%) in pyridine in pyridine (12mL) at 0 ° C, pivaloyl chloride (3.62g) , 30 mmol, 3 eq). The solution was warmed to room temperature and stirred for 1 hour. Carefully 30 mL of water was added to the mixture and stirred at room temperature overnight. This solution was extracted 3 times with CH ₂ Cl ₂ . The combined organic layers were washed 3 times with 2M H ₂ SO ₄ (20 mL). The organic layer was dried over Na ₂ SO ₄ and filtered. The solution was concentrated to give 3- (pivaloyloxy) benzoic acid as a white solid (2.15 g, 97%).

Put the obtained solid (2.15 g, 9.7 mmol, 1.0 equivalent) in a round bottom flask, and then add phenol (1.0 g, 10.7 mmol, 1 equivalent), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Salt (EDC · HCl: 2.0 g, 10.7 mmol, 1.1 eq), DMAP (237 mg, 1.9 mmol, 0.20 eq) and CH ₂ Cl ₂ (20 mL) were added. After stirring at room temperature for 3 hours, the reaction mixture was quenched with saturated NaHCO ₃ aq and extracted 3 times with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate = 20: 1) to give phenyl 3- (pivaloyloxy) benzoate as a white solid (2.56 g, 88%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.07 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz , 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 1.36 (s, 9H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 176.9, 164.3, 151.2, 150.8, 131.0, 129.54, 129.50, 127.4, 127.0, 126.0, 123.3, 121.6, 39.1, 27.1; HRMS (DART) m / z calcd for C ₁₈ H ₁₉ O ₄ [M + H] ⁺ : 299.1283, found: 299.1285.

Example 1

[In the formula, Ac is an acetyl group. n-Bu is an n-butyl group. The same applies hereinafter. ]
Put a magnetic stir bar in a 20 mL glass container equipped with a J. Young (registered trademark) O-ring tap, charge Ni (OAc) ₂ / 4H ₂ O (5.0 mg, 0.020 mmol, 5 mol%), and reduce the pressure. It dried with the heat gun below. Thereafter, the inside of the glass container was cooled to room temperature and then filled with nitrogen (N ₂ ) gas. The ester compound (1a) (0.40 mmol, 1.0 equivalent), boronic acid derivative (2a) (0.60 mmol, 1.5 equivalent), and Na ₂ CO ₃ (84.8 mg, 0.8 mmol, 2.0 equivalent) were placed in this container. The operation of evacuating the container and subsequently filling it with nitrogen (N ₂ ) gas was repeated three times. Thereafter, P (n-Bu) ₃ (19.0 μL, 0.08 mmol, 20 mol%) and anhydrous toluene (1.6 mL) were put into this container. The glass container was sealed with an O-ring tap and then heated at 150 ° C. for 24 hours with stirring in an 8-well reaction block. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated, and the residue was subjected to flash column chromatography (hexane / diethyl ether (Et ₂ O) = 2: 1) to give the desired product 3- (4-methoxyphenyl) pyridine (compound 3Aa) as a white solid. Obtained (69.7 mg, 95%). This example corresponds to entry 1 in Table 1 described later.
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.82 (dd, J = 2.4, 0.8 Hz, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 7.83 (dd, J = 8.0 Hz, 1H) , 7.53 (d, J = 9.2 Hz, 2H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.02 (d, J = 9.2 Hz, 2H), 3.87 (s, 3H); ¹³ C NMR ( CDCl ₃ , 100 MHz) δ 159.8, 148.1, 148.0, 136.3, 133.9, 130.3, 128.3, 123.6, 114.6, 55.5; HRMS (ESI) m / z calcd for C ₁₂ H ₁₂ NO [M + H] ⁺ : 186.0913, found: 186.0912.

Example 2
In Example 1, the coupling reaction was performed in the same manner except that the amount of the catalyst (Ni (OAc) ₂ .4H ₂ O) was 3 mol% and the reaction time was 48 hours. As a result, the yield was 73.4 mg, and the yield was 100%.

Example 3
As raw materials, various raw materials were used instead of the ester compound (1a) and boronic acid compound (2a) by the same method as in Example 1 (the purification method was appropriately changed if necessary), and the following table: The compounds shown in 1 and 2 were obtained. In entries 15, 45 and 46, the amount of Na ₂ CO ₃ was 1.2 equivalents. In entries 17 and 20, 1 equivalent of NaCl was used as the base.

The spectral data of each compound was as follows.
Compound 3Ba (3- (4-methyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.84 (d, J = 2.0 Hz, 1H), 8.56 (dd, J = 4.8, 1.6 Hz, 1H), 7.85 (dd, J = 8.0, 2.0 Hz, 1H) , 7.47 (d, J = 8.4 Hz, 2H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 2.41 (s, 3H); ¹³ C NMR ( CDCl ₃ , 100 MHz) δ 148.1, 138.0, 136.5, 134.9, 134.1, 129.7, 126.9, 123.5, 21.1; HRMS (ESI) m / z calcd for C ₁₂ H ₁₂ N [M + H] ⁺ : 170.0964, found: 170.0961.
Compound 3Ca (methyl-4- (pyridin-3-yl) benzoate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.89 (d, J = 1.6 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.92 (dd, J = 8.0, 2.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.40 (dd, J = 8.0, 4.8 Hz, 1H), 3.96 (s, 3H); ¹³ C NMR ( CDCl ₃ , 100 MHz) δ 166.6, 149.2, 148.3, 142.1, 135.4, 134.4, 130.3, 129.6, 127.0, 123.6, 52.1; HRMS (ESI) m / z calcd for C ₁₃ H ₁₁ NO ₂ [M + H] ⁺ : 214.0863, found: 214.0863.

Compound 3Da (3- (4-butylphenyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.84 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 7.87 (dd, J = 8.0, 4.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.35 (dd, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H), 1.64 (m, 2H), 1.38 (m, 2H), 0.95 (t, J = 7.8 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 148.24, 148.19, 143.0, 136.6, 135.1, 134.1, 129.2, 127.0, 123.5, 35.3, 33.6 , 22.4, 13.9; HRMS (ESI) m / z calcd for C ₁₅ H ₁₈ N [M + H] ⁺ : 212.1434, found: 212.1433.
Compound 3Ea (3- (3,4-dimethoxyphenyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.82 (d, J = 2.4 Hz, 1H), 8.56 (dd, J = 4.8, 2.0 Hz, 1H), 7.84 (dd, J = 8.0, 2.0 Hz, 1H) , 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.14 (dd, J = 8.4, 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 149.3, 149.1, 148.0, 147.9, 136.4, 133.9, 130.6, 123.4, 119.5, 111.6, 110.1, 55.9; HRMS (ESI) m / z calcd for C ₁₃ H ₁₄ NO ₂ [M + H] ⁺ : 216.1019, found: 216.1020.
Compound 3Fa (3-mesitylpyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 8.0, 1.6 Hz, 1H) , 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 6.97 (s, 2H), 2.34 (s, 3H), 2.00 (s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 150.3, 148.0 , 137.5, 136.9, 136.6, 136.2, 135.0, 128.3, 123.3, 21.0, 20.8; HRMS (ESI) m / z calcd for C ₁₄ H ₁₆ N [M + H] ⁺ : 198.1277, found: 198.1273.
Compound 3Ga (3-phenylpyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.86 (d, J = 2.4 Hz, 1H), 8.59 (dd, J = 5.2 Hz, 1H), 7.87 (dd, J = 8.0, 2.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 8.0, 2.4 Hz, 2H), 7.41 (dd, J = 8.0, 5.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H) ; ¹³ C NMR (CDCl ₃ , 100 MHz) δ 148.4, 148.3, 137.8, 136.6, 134.3, 129.0, 128.1, 127.1, 123.5; HRMS (ESI) m / z calcd for C ₁₁ H ₁₀ N [M + H] ⁺ : 156.0808, found: 156.0805.
Compound 3Ha (3- (4-((tert-butyldimethylsilyl) oxy) phenyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.81 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 4.8 Hz, 1H), 7.82 (dd, J = 8.0, 2.4 Hz, 1H), 7.46 (d, J = 6.8 Hz, 2H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 6.94 (d, J = 6.8 Hz, 2H), 1.01 (s, 9H), 0.24 (s, 6H) ; ¹³ C NMR (CDCl ₃ , 100 MHz) δ 156.0, 148.0, 147.8, 136.3, 133.8, 130.8, 128.1, 123.4, 120.7, 25.6, 18.2, -4.4; HRMS (DART) m / z calcd for C ₁₇ H ₂₄ NOSi [M + H] ⁺ : 286.1627, found: 286.1621.

Compound 3Ia (N, N-dimethyl-3- (pyridin-3-yl) aniline):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.85 (d, J = 2.4 Hz, 1H), 8.57 (dd, J = 4.8, 1.6 Hz, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H) , 7.36-7.31 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 2.8 Hz, 1H), 6.77 (dd, J = 8.4, 2.8 Hz, 1H), 3.00 ( s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 150.9, 148.4, 148.2, 138.7, 137.5, 134.4, 129.7, 123.3, 115.4, 112.1, 111.1, 40.5; HRMS (ESI) m / z calcd for C ₁₃ H ₁₅ N ₂ [M + H] ⁺ : 199.1230, found: 199.1227.
Compound 3Ja (3- (3-methoxyphenyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.85 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 7.86 (dd, J = 8.0, 2.4 Hz, 1H), 7.42-7.32 (m, 2H), 7.16 (d, J = 8.0, 2.4 Hz, 1H), 7.10 (s, 1H), 6.94 (d, J = 8.0, 2.4 Hz, 1H), 3.86 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 160.0, 148.6, 148.3, 139.2, 136.4, 134.3, 130.1, 123.4, 119.5, 113.3, 112.9, 55.3; HRMS (ESI) m / z calcd for C ₁₂ H ₁₂ ON [M + H] ⁺ : 186.0913, found: 186.0910.
Compound 3Ka (3- (4-fluorophenyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.81 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 7.82 (dd, J = 8.0, 2.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.20-7.11 (m, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.8 (d, J = 249 Hz), 148.4, 148.1 , 135.6, 134.1, 133.8 (d, J = 3 Hz), 128.7 (d, J = 8 Hz), 123.9, 116.0 (d, J = 21 Hz); HRMS (ESI) m / z calcd for C ₁₁ H ₉ FN [M + H] ⁺ : 174.0714, found: 174.0711.
Compound 3La (3- (naphthalen-2-yl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.99 (d, J = 2.4 Hz, 1H), 8.63 (d, J = 4.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 8.00 (dd , J = 8.0, 2.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.94-7.87 (m, 2H), 7.72 (dd, J = 8.8, 2.0 Hz, 1H), 7.58-7.49 ( m, 2H), 7.40 (dd, J = 8.0, 4.8 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 148.6, 148.5, 136.6, 135.2, 134.6, 133.6, 132.9, 128.9, 128.2, 127.7, 126.6, 126.4, 126.2, 125.0, 123.6; HRMS (ESI) m / z calcd for C ₁₅ H ₁₂ N [M + H] ⁺ : 206.0964, found: 206.0964.
Compound 3Ma (N, N-dimethyl-4- (pyridin-3-yl) aniline):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.82 (s, 1H), 8.48 (d, J = 4.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.49 (d.J = 8.8 Hz , 2H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 150.4, 147.7, 147.1, 136.6, 133.2, 127.7, 125.4, 123.4, 112.8, 40.4; HRMS (ESI) m / z calcd for C ₁₃ H ₁₅ N ₂ [M + H] ⁺ : 199.1230, found: 199.1228.

Compound 3Na (3- (4- (trifluoromethyl) phenyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.87 (s, 1H), 8.66 (d, J = 4.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.8 Hz , 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.41 (dd, J = 8.0, 4.0 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 149.3, 148.3, 141.3, 135.2, 134.4 , 130.2 (q, J = 32 Hz), 127.4, 126.0 (q, J = 4 Hz), 124.0 (q, J = 277 Hz), 123.6; HRMS (ESI) m / z calcd for C ₁₂ H ₉ F ₃ N [M + H] ⁺ : 224.0682, found: 224.0684.
Compound 3Oa (3- (thiophen-3-yl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.88 (s, 1H), 8.53 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 2.8, 1.2 Hz, 1H), 7.44 (dd, J = 5.2, 2.8 Hz, 1H), 7.39 (dd, J = 5.2, 1.2 Hz, 1H), 7.31 (dd, J = 8.0, 4.4 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 148.2, 147.6, 138.7, 133.4, 131.4, 126.9, 125.8, 123.6, 121.3; HRMS (ESI) m / z calcd for C ₉ H ₈ NS [M + H] ⁺ : 162.0372, found: 162.0369.
Compound 3Pa (3- (pyren-1-yl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.88 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.24-8.10 (m, 3H), 8.10-7.95 (m, 5H), 7.92 ( m, 2H), 7.46 (dd, J = 8.8, 4.8 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 151.0, 148.4, 137.6, 136.7, 133.4, 131.3, 131.0, 130.7, 128.5, 128.0, 127.8, 127.4, 127.2, 126.1, 125.4, 125.0, 124.8, 124.69, 124.66, 124.2, 123.2; HRMS (DART) m / z calcd for C ₂₁ H ₁₄ N [M + H] ⁺ : 280.1126, found: 280.1122.

Compound 3Qa ((E) -3- (Oct-1-en-1-yl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.56 (s, 1H), 8.42 (d, J = 4.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.0, 4.4 Hz, 1H), 6.40-6.25 (m, 2H), 2.23 (q, J = 8.0 Hz, 2H), 1.52-1.43 (m, 2H), 1.40-1.32 (m, 6H), 0.88 (q, J = 6.8 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 147.94, 147.86, 133.7, 133.5, 132.3, 126.2, 123.3, 33.1, 31.7, 29.1, 28.9, 22.6, 14.1; HRMS (ESI) m / z calcd for C ₁₃ H ₂₀ N [M + H] ⁺ : 190.1590, found: 190.1586.
Compound 3Ab (5- (4-methoxyphenyl) -2- (trifluoromethyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.90 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 9.0, 2H), 7.03 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 160.4, 148.0, 146.0 (J = 35 Hz), 139.0, 134.7, 128.6 , 128.4, 121.7 (J = 275 Hz), 120.3, 114.8, 55.3; HRMS (DART) m / z calcd for C ₁₃ H ₁₁ F ₃ NO [M + H] ⁺ : 254.0793, found: 254.0790.
Compound 3Ac (3- (4-methoxyphenyl) quinoline):
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.16 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.83 (d , J = 8.4 Hz, 1H), 7.68 (dd, J = 8.4, 7.8 Hz, 1H), 7.63 (d, J = 9.2 Hz, 2H), 7.54 (dd, J = 8.4, 7.8 Hz, 1H), 7.03 (d, J = 9.2 Hz, 2H), 3.85 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.7, 149.8, 146.9, 133.3, 132.3, 130.2, 129.1, 129.0, 128.4, 128.0, 127.8 , 126.8, 114.6, 55.3; HRMS (ESI) m / z calcd for C ₁₆ H ₁₄ NO [M + H] ⁺ : 236.1070, found: 236.1073.
Compound 3Qc ((E) -3- (Oct-1-en-1-yl) quinoline):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.97 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.63 (t, J = 8.8 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 6.54-6.40 (m, 2H), 2.27 (q, J = 8.0 Hz, 2H), 1.56-1.46 (m, 2H), 1.42-1.27 (m, 6H), 0.89 (q, J = 6.8 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 149.3, 147.1, 134.0, 131.4, 130.7, 129.1, 128.7, 128.1 , 127.6, 126.7, 126.5, 33.3, 31.7, 29.1, 28.9, 22.6, 14.1; HRMS (ESI) m / z calcd for C ₁₇ H ₂₂ N [M + H] ⁺ : 240.1747, found: 240.1752.
Compound 3Ad (4- (4-methoxyphenyl) -2-phenylquinoline):
¹ H NMR (CDCl ₃ , 600 MHz) δ 8.23 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 7.2 Hz, 2H), 7.94 (d, J = 8.4 Hz, 1H), 7.79 (s , 1H), 7.71 (td, J = 8.4, 1.2 Hz, 1H), 7.54-7.42 (m, 6H), 7.07 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H); ¹³ C NMR ( (CDCl ₃ , 150 MHz) δ 159.8, 156.9, 148.9, 148.8, 139.7, 130.8, 130.6, 130.1, 129.4, 129.2, 128.8, 127.5, 126.2, 125.9, 125.6, 119.3, 114.0, 55.4; HRMS (DART) m / z calcd for C ₂₂ H ₁₈ NO [M + H] ⁺ : 312.1388, found: 312.1389.
Compound 3Ae (4- (4-methoxyphenyl) pyridine):
¹ H NMR (CDCl ₃ , 600 MHz) δ 8.62 (d, J = 6.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 6.4 Hz, 2H), 7.00 (d , J = 8.4 Hz, 2H), 3.85 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 160.5, 150.1, 147.7, 130.3, 128.1, 121.0, 114.5, 55.3; HRMS (ESI) m / z calcd for C ₁₂ H ₁₂ NO [M + H] ⁺ : 186.0913, found: 186.0910.
Compound 3Af (2- (4-methoxyphenyl) furan):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.60 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 1.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.50 (d , J = 3.2 Hz, 1H), 6.43 (dd, J = 3.2, 1.6 Hz, 1H), 3.81 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.0, 154.0, 141.3, 125.2, 124.0 , 114.0, 111.5, 103.3, 55.3; HRMS (ESI) m / z calcd for C ₁₁ H ₁₁ O ₂ [M + H] ⁺ : 175.0754, found: 175.0752.
Compound 3Ag (3- (4-methoxyphenyl) thiophene):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.52 (d, J = 7.6 Hz, 2H), 7.38-7.30 (m, 3H), 6.92 (d, J = 7.6 Hz, 2H), 3.84 (s, 3H) ; ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.8, 142.0, 128.7, 127.5, 126.2, 126.0, 118.9, 114.1, 55.3; HRMS (DART) m / z calcd for C ₁₁ H ₁₀ OS [M + H] ⁺ : 252.1025, found: 252.1023.

Compound 3Ah (2- (4-methoxyphenyl) thiophene):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.53 (d, J = 8.4 Hz, 2H), 7.21-7.16 (m, 2H), 7.03 (d, J = 4.4 Hz, 1H), 6.89 (d, J = 8.1 Hz, 2H), 3.81 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.1, 144.3, 127.9, 127.23, 127.16, 123.8, 122.0, 114.2, 55.3; HRMS (ESI) m / z calcd for C ₁₁ H ₁₁ OS [M + H] ⁺ : 191.0525, found: 191.0522.
Compound 3Ai (2- (4-methoxyphenyl) benzo [b] thiophene):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.80 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 7.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.42 (s , 1H), 7.36-7.25 (m, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.8, 144.1, 140.9, 139.1 , 127.7, 124.4, 123.9, 123.2, 122.2, 118.2, 114.3, 55.4; HRMS (ESI) m / z calcd for C ₁₅ H ₁₃ OS [M + H] ⁺ : 241.0682, found: 241.0678.
Compound 3Aj (4- (4-methoxyphenyl) -2-phenylthiazole):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.03 (dd, J = 8.4, 2.0 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.47-7.38 (m, 3H), 7.31 (s, 1H), 6.96 (d, J = 7.2 Hz, 2H), 3.84 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 167.6, 159.6, 156.0, 133.8, 129.9, 128.9, 127.7, 127.5, 126.5 , 114.0, 110.9, 55.3; HRMS (DART) m / z calcd for C ₁₆ H ₁₄ NOS [M + H] ⁺ : 268.0796, found: 268.0795.
Compound 3Ak (methyl 5- (4-methoxyphenyl) nicotinate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.14 (s, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.0 Hz , 1H, 2H), 7.02 (d, J = 8.0 Hz, 2H), 3.98 (s, 3H), 3.86 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.8, 160.0, 151.3, 148.6 , 135.9, 134.5, 128.8, 128.2, 125.8, 114.6, 55.3, 52.4; HRMS (DART) m / z calcd for C ₁₄ H ₁₄ NO ₃ [M + H] ⁺ : 244.0794, found: 244.0791.
Compound 3Al (2-methoxy-3- (4-methoxyphenyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.12 (dd, J = 4.8, 1.2 Hz, 1H), 7.57 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H) , 6.99-6.92 (m, 3H), 3.97 (s, 3H), 3.83 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 160.8, 159.0, 145.1, 138.1, 130.2, 129.0, 124.3, 117.1 113.6, 55.2, 53.5; HRMS (ESI) m / z calcd for C ₁₃ H ₁₄ NO ₂ [M + H] ⁺ : 216.1019, found: 216.1020.
Compound 3Am (N, N-diethyl-5- (4-methoxyphenyl) pyridin-2-amine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.37 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H), 7.41 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 6.51 (d, J = 9.2 Hz, 1H), 3.82 (s, 3H), 3.52 (q, J = 7.2 Hz, 4H), 1.20 (t, J = 7.2 Hz , 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.4, 156.4, 145.9, 135.5, 131.4, 126.9, 123.6, 114.2, 105.3, 55.3, 42.5, 13.0; HRMS (DART) m / z calcd for C ₁₆ H ₂₁ N ₂ O [M + H] ⁺ : 257.1654, found: 257.1658.
Compound 3An (4′-methoxy-3-methyl-1,1′-biphenyl):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.51 (d, J = 9.2 Hz, 2H), 7.38-7.25 (m, 3H), 7.10 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 9.2 Hz, 2H), 3.80 (s, 3H), 2.39 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.0, 140.7, 138.2, 133.8, 128.6, 128.1, 127.5, 127.4, 123.8, 114.1 , 55.2, 21.5; HRMS (DART) m / z calcd for C ₁₄ H ₁₅ O [M + H] ⁺ : 199.1123, found: 199.1120.

Compound 3Ao (1- (4-methoxyphenyl) naphthalene):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.92 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.85-7.35 (m, 6H), 6.99 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.9, 139.9, 133.8, 133.1, 131.8, 131.1, 128.2, 127.3, 126.9, 126.0, 125.9, 125.7, 125.4, 113.7, 55.3; HRMS (DART) m / z calcd for C ₁₇ H ₁₅ O [M + H] ⁺ : 235.1123, found: 235.1122.
Compound 3Ap (2- (4-methoxyphenyl) -3-methylthiophene):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.37 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 5.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 2H), 6.88 (d , J = 5.6 Hz, 1H), 3.81 (s, 3H), 2.28 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.8, 137.6, 132.5, 130.9, 130.2, 127.1, 122.6, 113.9, 55.2, 14.8; HRMS (ESI) m / z calcd for C ₁₂ H ₁₃ OS [M + H] ⁺ : 205.0682, found: 205.0680.
Compound 3Aq (2- (4-methoxyphenyl) -4H-chromen-4-one):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.20 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 7.65 (dd, J = 8.8, 7.2 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.0, 7.2 Hz, 1H), 6.99 (d, J = 9.2 Hz, 2H), 6.71 (s, 1H), 3.86 (s, 3H) ; ¹³ C NMR (CDCl ₃ , 100 MHz) δ 178.2, 163.2, 162.3, 156.0, 133.4, 127.8, 125.5, 124.9, 123.8, 117.8, 114.3, 105.9, 55.4, 13.5; HRMS (DART) m / z calcd for C ₁₆ H ₁₄ O ₃ [M + H] ⁺ : 253.0865, found: 253.0861.
Compound 3Gq (2-phenyl-4H-chromen-4-one):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.22 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.68 (dd, J = 8.0, 7.6 Hz, 1H), 7.60 -7.46 (m, 4H), 7.40 (dd, J = 8.0, 7.6 Hz, 1H), 6.81 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 178.3, 163.2, 156.1, 133.7, 131.6, 131.5, 128.9, 126.2, 125.6, 125.1, 123.8, 118.0, 107.5; HRMS (ESI) m / z calcd for C ₁₅ H ₁₁ O [M + H] ⁺ : 223.0754, found: 223.0756.

Compound 3Ar (4′-methoxy-3,5-dimethyl-1,1′-biphenyl):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.49 (d.J = 9.2 Hz, 2H), 7.16 (s, 2H), 6.97-6.91 (m, 3H), 3.81 (s, 3H), 2.35 (s, 6H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.0, 140.8, 138.1, 133.9, 128.3, 128.1, 124.6, 114.0, 55.2, 21.4; HRMS (DART) m / z calcd for C ₁₅ H ₁₇ O (M + H] ⁺ : 213.1279, found: 213.1277.
Compound 3As (3-fluoro-5- (4-methoxyphenyl) pyridine):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.62 (s, 1H), 8.39 (s, 1H), 7.54-7.47 (m, 3H), 6.99 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 160.0, 159.6 (d, J = 260 Hz), 143.6 (d, J = 4 Hz), 137.7 (d, J = 4 Hz), 135.7 (d, J = 24 Hz), 128.5, 128.2, 120.2 (d, J = 19 Hz), 114.5, 55.2; HRMS (ESI) m / z calcd for C ₁₂ H ₁₁ FNO [M + H] ⁺ : 204.0819, found: 204.0820 .
Compound 3At (4- (4-methoxyphenyl) oxazole):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.91 (s, 1H), 7.86 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 6.95 (d. J = 8.4 Hz, 2H), 3.85 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.6, 151.2, 140.2, 132.6, 126.9, 123.4, 114.2, 55.3; HRMS (ESI) m / z calcd for C ₁₀ H ₁₀ NO ₂ [M + H] ⁺ : 176.0706, found: 176.0704.
Compound 3Au (3- (4-methoxyphenyl) furan):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.65 (d, J = 1.6 Hz, 1H), 7.44 (t, J = 1.6 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 6.91 (d , J = 8.8 Hz, 2H), 6.64 (d, J = 1.6 Hz, 1H), 3.81 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.7, 143.5, 137.6, 127.0, 126.0, 125.0 , 114.2, 108.8, 55.3; HRMS (ESI) m / z calcd for C ₁₁ H ₁₁ O ₂ [M + H] ⁺ : 175.0754, found: 175.0752.
Compound 3Av (4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazole):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.76 (d, J = 8.4 Hz, 2H), 6.90 (s, 1H), 3.82 (s, 3H), 3.56 (t, J = 5.2 Hz, 4H), 2.54 (t, J = 5.2 Hz, 4H), 2.35 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 170.9, 159.2, 151.6, 128.1, 127.3, 113.8, 99.6, 55.2, 54.5, 48.2, 46.2 HRMS (DART) m / z calcd for C ₁₅ H ₂₀ N ₃ OS [M + H] ⁺ : 290.1327, found: 290.1329.
Compound 3Cv (methyl 4- (2- (4-methylpiperazin-1-yl) thiazol-4-yl) benzoate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 6.91 (s, 1H), 3.92 (s, 3H), 3.59 (t, J = 5.2 Hz, 4H), 2.55 (t, J = 5.2 Hz, 4H), 2.36 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 171.0, 167.0, 150.8, 139.1, 129.9 , 128.8, 125.8, 103.7, 54.2, 52.0, 48.3, 46.2; HRMS (DART) m / z calcd for C ₁₆ H ₂₀ N ₃ O ₂ S [M + H] ⁺ : 318.1276, found: 318.1275.
Compound 3Aw (2- (4-methoxyphenyl) naphthalene):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.98 (s, 1H), 7.91-7.82 (m, 3H), 7.71 (dd, J = 8.4, 1.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.52-7.42 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.2, 138.1, 133.7, 133.6, 132.3, 128.4, 128.3, 128.0, 127.6, 126.2, 125.6, 125.4, 125.0, 114.3, 55.4; HRMS (DART) m / z calcd for C ₁₇ H ₁₅ O [M + H] ⁺ : 235.1123, found: 235.1120.
Compound 3Ax (2,4′-dimethoxy-1,1′-biphenyl):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.46 (d, J = 8.8 Hz, 2H), 7.32-7.25 (m, 2H), 7.00 (dd, J = 8.0, 7.2 Hz, 1H), 6.97-6.91 ( m, 3H), 3.82 (s, 3H), 3.79 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.6, 156.4, 130.8, 130.63, 130.55, 130.2, 128.1, 120.8, 113.4, 111.1, 55.5, 55.2; HRMS (DART) m / z calcd for C ₁₄ H ₁₅ O ₂ [M + H] ⁺ : 215.1072, found: 215.1076.
Compound 3Aab (4-methoxy-4′-methyl-1,1′-biphenyl):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.50 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.95 (d , J = 8.8 Hz, 2H), 3.84 (s, 3H), 2.38 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.9, 137.9, 136.3, 133.7, 129.4, 127.9, 126.6, 114.1, 55.3, 21.0; HRMS (DART) m / z calcd for C ₁₄ H ₁₅ O [M + H] ⁺ : 199.1123, found: 119.1121.
Compound 3Aac (4-fluoro-4′-methoxy-1,1′-biphenyl):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.51-7.43 (m, 4H), 7.12-7.06 (m, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.1 (d, J = 249 Hz), 159.1, 136.9 (d, J = 4 Hz), 132.8, 128.2 (d, J = 8 Hz), 128.0, 115.5 (d, J = 21 Hz), 114.2, 55.3; HRMS (DART) m / z calcd for C ₁₃ H ₁₂ FO [M + H] ⁺ : 203.0872, found: 203.0870.
Compound 3Aad (methyl 4′-methoxy- [1,1′-biphenyl] -4-carboxylate):
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.07 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 6.98 (d , J = 8.4 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 167.0, 159.8, 145.1, 132.3, 130.0, 128.3, 128.2, 126.4, 114.3, 55.3, 52.0; HRMS (DART) m / z calcd for C ₁₅ H ₁₅ O ₃ [M + H] ⁺ : 243.1021, found: 243.1019.
Compound 3Aae (4-methoxy-4 ′-(trifluoromethyl) -1,1′-biphenyl):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.67-7.62 (m, 4H), 7.53 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H) ; ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.8, 144.3, 132.1, 128.7 (q, J = 33 Hz), 128.3, 126.8, 125.7 (q, J = 4 Hz), 124.4 (q, J = 276 Hz ), 114.4, 55.3; HRMS (DART) m / z calcd for C ₁₄ H ₁₂ F ₃ O [M + H] ⁺ : 253.0840, found: 253.0838.
Compound 3Aaf (1-benzyl-4-methoxybenzene):
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.27 (dd, J = 7.6, 7.2 Hz, 2H), 7.21-7.15 (m, 3H), 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.92 (s, 2H), 3.78 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 157.9, 141.6, 133.2, 129.8, 128.8, 128.4, 126.0, 113.9, 55.2 , 41.0; HRMS (DART) m / z calcd for C ₁₄ H ₁₅ O [M + H] ⁺ : 199.1123, found: 199.1122.

  When the entry 40 was performed at 160 ° C., the yield was 47%, and when the entry 41 was performed at 160 ° C., the yield was 51%.

Comparative Example 1
The substrate is not an ester compound but a carboxylic acid

When the experiment was conducted in the same manner as in Example 1, the coupling reaction did not proceed.

Example 4
When using carboxylic acid as in Comparative Example 1, it was found that the coupling reaction can proceed according to entry 25 of Example 3 after esterification. Specifically, it is as follows.

[Wherein Tf is a trifluoromethylsulfonyl group. Me is a methyl group. The same applies hereinafter. ]
A 20 mL glass container with a J. Young® O-ring tap with a magnetic stir bar was dried with a heat gun under reduced pressure, cooled to room temperature, and charged with N ₂ gas. Here, thiophene-2-carboxylic acid (51.3 mg, 0.40 mmol), diphenyliodonium triflate (172.0 mg, 0.40 mmol, 1 equivalent), K ₂ CO ₃ (55.2 mg, 0.40 mmol, 1 equivalent), and then toluene (2.0 mL) was added. The vessel was sealed with an O-ring tap and heated at 130 ° C. for 2 hours in an 8-well reaction block with stirring. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure to remove toluene and obtain iodobenzene.

To the same tube containing the resulting crude product, Ni (OAc) ₂ (3.5 mg, 0.02 mmol, 5 mol%), p-methoxyphenylboronic acid (0.60 mmol, 91.9 g, 1.5 eq), and Na ₂ CO ₃ (84.8 mg, 0.8 mmol, 2.0 eq) was added. The container was evacuated and refilled with N ₂ gas three times. To this, P (n-Bu) ₃ (19.0 μL, 0.08 mmol, 20 mol%) and anhydrous toluene (1.6 mL) were added. The vessel was sealed with an O-ring tap and heated at 150 ° C. for 24 hours with stirring in an 8-well reaction block. The reaction mixture was cooled to room temperature and then passed through a short silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated and the residue was purified by column chromatography (hexane / ethyl acetate = 100: 1) to give 2- (4-methoxyphenyl) thiophene as a white solid (46.2 mg, 61% over 2 steps).

Example 5
After performing the coupling reaction of the present invention, it was possible to synthesize complex compounds by combining with other coupling reactions (for example, the method of Non-Patent Document 1). Specifically, it is as follows.

Add Ni (OAc) ₂ · 4H ₂ O (5.0 mg, 0.020 mmol, 5 mol%) to a 20 mL glass container with a J. Young® O-ring tap with a magnetic stir bar and under vacuum After drying with a heat gun, cooling to room temperature, it was filled with N ₂ gas. To this vessel was added phenylarene carboxylate (phenyl 3- (pivaloyloxy) benzoate) (0.40 mmol, 1.0 eq), arylboronic acid (p-methoxyphenylboronic acid) (0.60 mmol, 1.5 eq), and Na ₂ CO ₃ (84.8 mg, 0.8 mmol, 2.0 eq.) was added. The container was evacuated and then refilled with N ₂ gas three times. To this, P (n-Bu) ₃ (20 μL, 0.08 mmol, 20 mol%) and anhydrous toluene (1.6 mL) were added. The vessel was sealed with an O-ring tap and heated at 150 ° C. for 24 hours with stirring in an 8-well reaction block. After the reaction mixture was cooled to room temperature, the mixture was passed through a short silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated and the residue was subjected to flash column chromatography (hexane / ethyl acetate = 100: 1) and GPC to give the biaryl product as a colorless oil (84.2 mg, 74%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.41-7,37 (m, 2H), 7.22 (s, 1H), 7.01-6.98 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 1.39 (s, 9H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 177.2, 159.5, 151.6, 142.5, 132.9, 129.7, 128.3 , 124.0, 119.9, 119.7, 114.3, 55.4, 39.2, 27.3; HRMS (DART) m / z calcd for C ₁₈ H ₂₁ O ₃ [M + H] ⁺ : 285.1491, found: 285.1494.

[Wherein cod is 1,5-cyclooctadiene. dcypt

It is. The same applies hereinafter. ]
Cs ₂ CO ₃ (146.6 mg, 0.45 mmol, 1.5 eq) is placed in a 20 mL glass container equipped with a magnetic stir bar J. Young® O-ring tap, dried with a heat gun under reduced pressure, and cooled to room temperature And then filled with N ₂ gas. To this vessel was added phenylarene carboxylate (the biaryl product) (85.3 mg, 0.30 mmol, 1.0 equivalent) and 2,3-bis (dicyclohexylphosphine) thiophene (dcypt: 28.3 mg, 0.06 mmol, 20 mol%). And put in a glove box in an argon atmosphere. Bis (1,5-cyclooctadiene) nickel (0) (Ni (cod) ₂ : 8.3 mg, 0.03 mmol, 10 mol%) was added to the reaction vessel, and the reaction vessel was taken out from the glove box. Here, benzoxazole (47.6 mg, 0.40 mmol, 1.3 eq) and dry 1,4-dioxane (1.5 mL) was added while blowing N _2. The vessel was sealed with an O-ring tap and heated at 130 ° C. for 12 hours with stirring in an 8-well reaction block. The reaction mixture was cooled to room temperature and then passed through a short silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated and the residue was purified by flash column chromatography (hexane / ethyl acetate = 100: 1) to give the CH / CO coupling product as a white solid (76.8 g, 85%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.46 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.83-7.77 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H) , 7.65-7.53 (m, 4H), 7.40-7.33 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 163.0 , 159.5, 150.7, 142.1, 141.5, 132.5, 129.7, 129.3, 128.2, 127.5, 125.7, 125.1, 124.6, 120.0, 114.3, 110.6, 55.3; HRMS (DART) m / z calcd for C ₂₀ H ₁₆ NO ₂ [M + H] ⁺ : 302.1181, found: 302.1178.

Example 6

In a test tube with a screw cap containing a magnetic stir bar, telmisartan (772 mg, 1.5 mmol), phenol (155 mg, 1.65 mmol, 1.1 eq), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC · HCl: 316mg, 1.65mmol, 1.1 eq), N, N-dimethylaminopyridine (DMAP: 18.3mg, 0.15mmol, was added 0.1 eq) and CH ₂ Cl ₂ (3mL). The reaction mixture was stirred for 6 h before being quenched with saturated NaHCO ₃ aq and extracted 3 times with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate = 2: 1 to 1: 0 gradient) to give phenylcarboxylate as a white solid (850 mg, 96%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.03 (dd, J = 8.0, 1.6 Hz, 1H), 7.83-7.80 (m, 1H), 7.60 (td, J = 8.0, 1.6 Hz, 1H), 7.52- 7.44 (m, 3H), 7.40-7.35 (m, 3H), 7.34 (m, 3H), 7.21 (t, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.04 (t , J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H), 5.45 (s, 2H), 3.71 (s, 3H), 2.91 (t, J = 8.0 Hz, 2H), 2.79 (s , 3H), 1.91-1.81 (m, 2H), 1.03 (t, J = 8.0 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 166.6, 156.4, 154.7, 150.6, 143.2, 142.9, 142.3, 141.1, 136.7, 135.0, 131.9, 130.9, 130.4, 129.9, 129.5, 129.25, 129.20, 127.6, 125.9, 125.7, 124.0, 123.9, 122.4, 122.3, 121.1, 119.6, 109.5, 108.8, 46.9, 31.7, 29.8, 21.8, 16.9, 14.1; HRMS (DART) m / z calcd for C ₃₉ H ₃₅ N ₄ O ₂ [M + H] ⁺ : 591.2760, found: 591.2770.

Ni (OAc) ₂ · 4H ₂ O (3.5 mg, 0.0125 mmol, 5 mol%) is dried with a heat gun under reduced pressure in a 20 mL glass container with a J. Young (registered trademark) O-ring tap with a magnetic stir bar After cooling to room temperature, it was filled with N ₂ gas. To this vessel, phenylarene carboxylate (phenylcarboxylate obtained in the previous step) (145 mg, 0.25 mmol, 1.0 equivalent), p-methoxyphenylboronic acid (58.0 mg, 0.375 mmol, 1.5 equivalent), and Na ₂ CO ₃ (53 mg, 0.50 mmol, 2.0 eq) was added. The container was evacuated and refilled with N ₂ gas three times. To this, P (n-Bu) ₃ (12.5 μL, 0.05 mmol, 20 mol%) and anhydrous toluene (1.0 mL) were added. The vessel was sealed with an O-ring tap and heated at 150 ° C. for 24 hours with stirring in an 8-well reaction block. The reaction mixture was cooled to room temperature and then passed through Celite (registered trademark) with ethyl acetate (EtOAc). The filtrate is concentrated and the residue is purified by flash column chromatography (hexane / ethyl acetate = 1: 2-EtOAc gradient) and reverse phase HPLC (isolera; H ₂ O / MeCN) to give the coupled product as a white solid Obtained (111 mg, 78%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.84-7.81 (m, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.40-7.28 (m, 7H), 7.10 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 5.36 (s, 2H), 3.80 ( s, 3H), 3.72 (s, 3H), 2.87 (t, J = 7.6 Hz, 2H), 2.78 (s, 3H), 1.85-1.76 (m, 2H), 1.03 (t, J = 7.6 Hz, 3H ); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.3, 156.4, 154.7, 143.1, 142.9, 141.5, 140.1, 139.5, 136.7, 135.2, 133.9, 133.6, 130.8, 130.6, 130.4, 127.6, 125.8, 123.9, 123.7 , 122.4, 122.3, 119.5, 113.3, 109.5, 108.7, 55.1, 47.0, 31.8, 29.8, 21.7, 16.8, 14.0; HRMS (DART) m / z calcd for C ₃₉ H ₃₇ N ₄ O [M + H] ⁺ : 577.2967, found: 577.2969.

Example 7

Instead of Ni (OAc) ₂ · 4H ₂ O (5 mol%), the nickel compound shown in Table 5 was used in the amount shown in Table 5, and P (n-Bu) ₃ was used in 40 mol% instead of 20 mol%. ₂ Using Et ₃ N instead of CO ₃ , and using the same procedure as in Example 1 except that the reaction time was set to the time shown in Table 5 instead of 24 hours (the purification method was changed as necessary). Compound 3Aa was obtained. In entry 2, 20 mol% of 1,5-cyclooctadiene (cod) was further added. In Table 5, Ni (acac) ₂ is nickel (II) acetylacetonate, and Cp ₂ Ni is bis (cyclopentadienyl) nickel.

Example 8

Instead of Ni (OAc) ₂ · 4H ₂ O (5 mol%), Ni (cod) ₂ (10 mol%) is used, and the composition shown in Table 5 is used instead of P (n-Bu) ₃ (20 mol%). Using the same procedure as in Example 1 except that a ligand (40 mol%) was used, 1,4-dioxane was used instead of toluene, and the reaction time was 12 hours instead of 24 hours (purified as necessary) The method was changed as appropriate to give compound 3Aa. In entry 2, no base (Na ₂ CO ₃ ) was used. In entry 3, boroxin derivatives shown below as boron compounds:

It was used. In Table 6, PCy ₃ is a cyclohexyl group and n-Pr is an n-propyl group.

Claims (9)

General formula (1):

[Wherein, R ¹ represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted alkyl group. R ² represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted unsaturated hydrocarbon group. The carbon atom in R ¹ and the sp2 hybrid carbon atom in R ² are bonded. ]
A method for producing an organic compound represented by
A step of subjecting an ester compound and a boronic acid compound to a cross-coupling reaction in the presence of a nickel compound;
The ester compound has the general formula (2):

[Wherein, R ¹ is the same as defined above. R ³ represents an aryl group which may be substituted. ]
A compound represented by
The boronic acid compound has the general formula (3):

[Wherein R ² is the same as defined above. Further, the boron atom and the sp2 hybrid carbon atom in R ² are bonded. R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an alkyl group. R ⁴ and R ⁵ may be bonded to each other to form a ring together with adjacent —O—B—O—. ]
The manufacturing method which is a compound represented by these. The production method according to claim 1, wherein a ligand compound is further used in the cross coupling reaction. The manufacturing method according to claim 2, wherein the ligand compound is a phosphine-based ligand compound. The production method according to claim 1, wherein a base is further used in the cross-coupling reaction. A cross-coupling method in which an ester compound and a boronic acid compound are reacted in the presence of a nickel compound,
The ester compound has the general formula (2):

[Wherein, R ¹ represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted alkyl group. R ³ represents an aryl group which may be substituted. ]
A compound represented by
The boronic acid compound has the general formula (3):

[Wherein, R ² represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted unsaturated hydrocarbon group. The boron atom and the sp2 hybrid carbon atom in R ² are bonded. R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or an alkyl group. R ⁴ and R ⁵ may be bonded to each other to form a ring together with adjacent —O—B—O—. ]
A method represented by the formula: Furthermore, the method of Claim 5 using a ligand compound. The method according to claim 6, wherein the ligand compound is a phosphine-based ligand compound. Furthermore, the method in any one of Claims 5-7 using a base. The following general formula:

[Wherein TBS represents a t-butyldimethylsilyl group. ]
A compound represented by