JP6367121B2 - Coupling method and method for producing aromatic group-substituted heterocyclic compound using the coupling method - Google Patents

Description

  The present invention relates to a coupling method and a method for producing an aromatic group-substituted heterocyclic compound using the coupling method.

  A series of compounds called biaryls, in which aromatic molecules and aromatic molecules are bonded, are frequently used in the fields of medical pesticides and organic electronics materials. For this reason, the development of a method for efficiently constructing a biaryl compound group has become one of the most important issues in the chemical field.

  The “classical” cross-coupling method, in which Prof. Akira Suzuki and Prof. Eiichi Negishi received the Nobel Prize in Chemistry in 2010, for example, has the following formula:

[Wherein Z is an oxygen atom or a sulfur atom; Ar ″ is an aromatic hydrocarbon group, an alicyclic hydrocarbon group or a heterocyclic group.]
It is the most reliable method for producing biaryl, and has been improved by many chemists so far.

However, in order for the coupling reaction to proceed,
(1) Since it is necessary to use an aromatic metal compound prepared from an aromatic compound in several steps as a coupling partner, the process is complicated.
(2) Since it is necessary to use a halogen compound as the other coupling partner, halogen waste is generated.
(3) It is necessary to use rare and expensive palladium as a catalyst.
The current situation is that there are still many issues to be solved.

  On the other hand, the catalytic reaction developed by Prof. Akira Suzuki, Prof. Eiichi Negishi, and Prof. Richard Heck described above has the following formula:

[Wherein, X is a halogen atom; R ′ is a substituent. ]
It is possible to connect using a palladium catalyst. Aromatic-alkene bonded molecules obtained by this reaction are used in various applications such as organic dyes, medical pesticides, bioactive molecules, and organic electronics materials.

Conventionally, halogen atoms have been used as markers for aromatic molecules, and hydrogen atoms have been used as markers for alkene molecules. In recent years, new coupling reactions have been developed in which these markers and catalysts have been changed.
(1) As an aromatic compound, it is necessary to use a halogen compound or a metal compound as a coupling partner, so that a halogen waste or a metal waste that has an adverse effect on the environment is generated.
(2) It is necessary to use rare and expensive palladium or rhodium as a catalyst.
The current situation is that there are still many issues to be solved.

  Currently, the development of a “new next-generation coupling reaction” that makes the above-mentioned elements greener and environmentally friendly is in intense competition all over the world including the present inventors.

  A compound group in which an aromatic molecule and an aromatic molecule are combined, a compound group in which an aromatic molecule and an alkene molecule are combined, etc. can be easily synthesized, and no rare and expensive palladium is produced without generating halogen waste. An object is to provide a simple method (coupling method) which does not need to be used.

As a result of intensive studies in view of the above problems, the present inventors have developed a new type of coupling reaction using a nickel catalyst, and brought a big breakthrough in this field. Specifically, using a nickel compound,
Formula (A):
Ar-H
[In the formula, Ar is an optionally substituted monovalent heterocyclic group. ]
A compound (A) represented by:
General formula (B1):
R ^a OCO-Ar ′
[In the formula, Ar ′ is an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, and an optionally substituted monovalent alicyclic group. A hydrocarbon group or an optionally substituted monovalent heterocyclic group; R ^a is a substituent; ]
A compound (B1) represented by:
General formula (B2):

[In the formula, Ar ″ represents a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, or an optionally substituted monovalent hydrocarbon group. An alicyclic hydrocarbon group or an optionally substituted monovalent heterocyclic group (except when two Ar ″ are both hydrogen atoms); R ^b is a substituent other than an alkyl group; . ]
Compound (B2) represented by the general formula (B3):

[Wherein Ar ″ is the same as above; R ^c is a substituent.]
Compound (B3) represented by
The reaction of deesterifying coupling of aromatic compounds (mainly azoles) and aromatic esters, and the coupling reaction of aromatic compounds and alkene molecules, can be carried out easily with aromatic molecules. It has been found that a compound group in which an aromatic molecule or an alkene molecule is bonded can be synthesized. In this case, a nickel compound is used as a catalyst, but 1,2-bisdicyclohexylphosphinoethane (dtype), 1,2-bisdicyclopentylphosphinoethane, or the like is preferably used as a ligand.

  The present invention has been completed as a result of further research based on such knowledge. That is, the present invention includes the following configurations.

Item 1. General formula (1):
Ar-Ar '
[Wherein Ar and Ar ′ are the same or different and Ar is a monovalent heterocyclic group which may be substituted; Ar ′ is a hydrocarbon group having 1 to 20 carbon atoms which may be substituted; A monovalent aromatic hydrocarbon group which may be substituted, a monovalent alicyclic hydrocarbon group which may be substituted or a monovalent heterocyclic group which may be substituted. ]
Or general formula (2):

[Wherein Ar and two Ar ″ are the same or different, Ar is the same as above; Ar ″ is a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, and may be substituted] A good monovalent aromatic hydrocarbon group, a monovalent alicyclic hydrocarbon group which may be substituted, or a monovalent heterocyclic group which may be substituted (wherein two Ar ″ are both Except for hydrogen atoms)]
A process for producing a compound represented by
Formula (A):
Ar-H
[Wherein Ar is the same as defined above. ]
A compound (A) represented by:
General formula (B1):
R ^a OCO-Ar ′
[Wherein Ar ′ is the same as defined above; R ^a is a substituent. ]
A compound (B1) represented by:
General formula (B2):

[Wherein Ar ″ is the same as above; R ^b is a substituent other than an alkyl group.]
Compound (B2) represented by the general formula (B3):

[Wherein Ar ″ is the same as above; R ^c is a substituent.]
Compound (B3) represented by
And
A manufacturing method provided with the reaction process made to react in presence of a nickel compound.

  Item 2. Ar represents the general formula (a):

[In the formula, Y ^a is ¹² C or ¹³ C; Z ^a is an oxygen atom or a sulfur atom; R ¹ and R ² are the same or different, and each is a hydrogen atom or an optionally substituted carbon atom having 1 to 20 carbon atoms. A hydrogen group, an optionally substituted alkoxy group having 1 to 20 carbon atoms, an optionally substituted alkoxy group having 2 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, a substituted group A monovalent heterocyclic group which may be substituted, an amino group which may be substituted; R ¹ and R ² may be bonded to each other to form an aromatic ring together with the adjacent —C═C—. ]
Item 2. The production method according to Item 1, which is a group represented by:

Item 3. Ar ′ is a monovalent aromatic hydrocarbon group which may be substituted, or a monovalent heterocyclic group which may be substituted (however, when Z ^a is a sulfur atom, a heterocyclic group) Item 3. The method according to Item 1 or 2, wherein

Item 4. Ar ″ is a hydrogen atom, an optionally substituted monovalent aromatic hydrocarbon group, or an optionally substituted monovalent heterocyclic group (provided that when Z ^a is a sulfur atom, a hydrogen atom Or a heterocyclic group), and the production method according to any one of Items 1 to 3, except that when two Ar ″ are both hydrogen atoms.

Item 5. R ^a in the general formula (B1) is an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, and an optionally substituted monovalent group. Item 5. The production method according to any one of Items 1 to 4, which is an alicyclic hydrocarbon group, a monovalent heterocyclic group that may be substituted, or an amino group that may be substituted.

Item 6. R ^b in the general formula (B2) is R ^b1 CO— (R ^b1 is a substituent), a monovalent aromatic hydrocarbon group that may be substituted, or a monovalent alicyclic group that may be substituted. Item 6. The production method according to any one of Items 1 to 5, which is a hydrocarbon group, a monovalent heterocyclic group which may be substituted, or an amino group which may be substituted.

Item 7. R ^c in the general formula (B3) is an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, and an optionally substituted monovalent group. Item 7. The production method according to any one of Items 1 to 6, which is an alicyclic hydrocarbon group, an optionally substituted monovalent heterocyclic group, or an optionally substituted amino group.

  Item 8. The manufacturing method in any one of claim | item 1 -7 whose usage-amount of the said nickel compound is 0.01-1 mol with respect to 1 mol of compounds (A).

  Item 9. Furthermore, the manufacturing method in any one of claim | item 1 -8 which uses a ligand in the said reaction process.

  Item 10. The ligand is represented by the general formula (C1):

[Wherein, four R ^{3 s} are the same or different and may be a monovalent aromatic hydrocarbon group which may be substituted or a monovalent alicyclic hydrocarbon group which may be substituted; An integer of ˜20; provided that when one or more of R ³ is an aromatic hydrocarbon group, n is an integer of 3-20. ]
A compound (C1) represented by:
General formula (C2):

[In the formula, three R ^{4 s} are the same or different and are each a linear hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, or optionally substituted. Monovalent alicyclic hydrocarbon group; except when all R ⁴ are phenyl groups. ]
Compound (C2) represented by the general formula (C3):

[Wherein, two R ^{5 s} are the same or different and each represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted alkoxy group having 1 to 20 carbon atoms. ]
A compound represented by formula (C3)
The manufacturing method of claim | item 9 which is these.

  Item 11. Item 11. The method according to Item 9 or 10, wherein the amount of the ligand used is 0.5 to 5 mol with respect to 1 mol of the nickel compound.

  Item 12. Furthermore, the manufacturing method in any one of claim | item 1 -11 which uses a base in the said reaction process.

  Item 13. Item 13. The production method according to Item 12, wherein the base is an alkali metal or alkaline earth metal phosphate, carbonate or carboxylate, or an amine.

  Item 14. Furthermore, the manufacturing method in any one of claim | item 1 -13 which uses a solvent in the said reaction process.

  Item 15. The solvent is aromatic hydrocarbons, esters, cyclic ethers, halogenated hydrocarbons, ketones, amides, nitriles, alcohols having 3 to 20 carbon atoms, dimethyl sulfoxide, or N-methylpyrrolidone. Item 15. The manufacturing method according to Item 14.

  Item 16. Item 16. The production method according to any one of Items 1 to 15, wherein a reaction temperature in the reaction step is 80 to 200 ° C.

  Item 17. Item 18. The production method according to any one of Items 1 to 16, wherein the reaction time in the reaction step is 1 to 50 hours.

Item 18. Formula (A):
Ar-H
[In the formula, Ar is an optionally substituted monovalent heterocyclic group. ]
A compound (A) represented by:
General formula (B1):
R ^a OCO-Ar ′
[In the formula, Ar ′ is an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, and an optionally substituted monovalent alicyclic group. A hydrocarbon group or an optionally substituted monovalent heterocyclic group; R ^a is a substituent; ]
A compound (B1) represented by:
General formula (B2):

[Wherein Ar ″ is the same as above; R ^b is a substituent other than an alkyl group.]
Compound (B2) represented by the general formula (B3):

[Wherein Ar ″ is the same as above; R ^c is a substituent.]
Compound (B3) represented by
And
A coupling method comprising reacting in the presence of a nickel compound.

Item 19. Obtained by the production method according to any one of Items 1 to 17,
The following formula:

A compound represented by

  According to the present invention, a new type of coupling reaction that connects two molecules while breaking a carbon-hydrogen bond (CH bond) of an aromatic compound that is usually extremely stable and a carbon-carbon bond of an aromatic ester. Is possible (new reaction). In addition, a coupling reaction between an alkene molecule and an aromatic compound that has not been active until now is also possible (new reaction).

  In addition, the aromatic compound itself (compound (A)) can be used as a coupling partner (achievement of C—H coupling). For this reason, it is not necessary to prepare an aromatic metal compound as a coupling partner of a conventional cross coupling from an aromatic compound, the number of overall steps is drastically reduced, and an aromatic molecule and an aromatic can be more easily A group of compounds bonded to molecules can be synthesized easily.

  Furthermore, aromatic esters (compound (B1)) and alkene molecules (compounds (B2) and (B3)) can be used as the other coupling partner in place of aromatic halides (conventional type). Since a coupling reaction is possible without using a metal, a coupling reaction that does not generate halogen waste or metal waste, which may cause environmental pollution, can be achieved.

  In addition, instead of a rare and expensive palladium catalyst or rhodium catalyst (conventional type), a nickel complex that is inexpensive and stable in air can be used as a catalyst.

  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 is broken” when the compound (B1) is used. In addition, when using the compounds (B2) and (B3), it is also an achievement accompanied by the discovery of a completely unexpected new reaction that causes a coupling reaction between an alkene molecule and an aromatic compound that has not been active until now. . For this reason, it has great significance not only for the development of new coupling partners such as esters and alkenes, but also for synthetic chemistry. In the case of using the compound (B1), the synthesis of the heteroaromatic compound can be efficiently performed in the presence of an ester in many cases. The reaction according to the present invention also has an unprecedented feature that the ester can be directly used for a coupling reaction to be led to a biaryl compound.

It is drawing which shows the structure of a Ni (dcype) (CO) ₂ catalyst by the thermal vibration ellipsoid drawing software (ORTEP) (the ellipse is 50% atomic existence). For clarity, hydrogen atoms are omitted.

1. Production method and coupling method The production method (coupling method) of the present invention comprises:
Formula (A):
Ar-H
[In the formula, Ar is an optionally substituted monovalent heterocyclic group. ]
A compound (A) represented by:
General formula (B1):
R ^a OCO-Ar ′
[In the formula, Ar ′ is an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, and an optionally substituted monovalent alicyclic group. A hydrocarbon group or an optionally substituted monovalent heterocyclic group; R ^a is a substituent; ]
A compound (B1) represented by:
General formula (B2):

[Wherein Ar ″ is the same as above; R ^b is a substituent other than an alkyl group.]
Compound (B2) represented by the general formula (B3):

[Wherein Ar ″ is the same as above; R ^c is a substituent.]
Compound (B3) represented by
And
By reacting in the presence of nickel compounds,
General formula (1):
Ar-Ar '
[Wherein Ar and Ar ′ are the same or different and are the same as described above. ]
Or general formula (2):

[Wherein Ar and two Ar ″ are the same or different, Ar is the same as above; Ar ″ is a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, and may be substituted] A good monovalent aromatic hydrocarbon group, a monovalent alicyclic hydrocarbon group which may be substituted, or a monovalent heterocyclic group which may be substituted (wherein two Ar ″ are both Except for hydrogen atoms)]
Is a method for obtaining a compound represented by the formula:

[1-1] Compound (A)
In the present invention, the compound (A) used as a coupling partner is represented by the general formula (A):
Ar-H
[Wherein Ar is the same as defined above. ]
It is a compound shown by these. This compound (A) can also use a commercially available aromatic compound as it is.

  In the general formula (A), Ar is a monovalent heterocyclic group which may be substituted. In consideration of reactivity, the general formula (a):

[In the formula, Y ^a is ¹² C or ¹³ C; Z ^a is an oxygen atom or a sulfur atom; R ¹ and R ² are the same or different, and each is a hydrogen atom or an optionally substituted carbon atom having 1 to 20 carbon atoms. A hydrogen group, an optionally substituted alkoxy group having 1 to 20 carbon atoms, an optionally substituted alkoxy group having 2 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, a substituted group A monovalent heterocyclic group which may be substituted; R ¹ and R ² may be bonded to each other to form an aromatic ring together with the adjacent —C═C—. ]
Is preferred.

In the general formula (a), Y ^a is ¹² C or ¹³ C. Usually, it is ¹² C, but even in the case of ¹³ C, the coupling reaction can proceed by cutting the C—H bond between adjacent hydrogen atoms.

Z ^a is an oxygen atom or a sulfur atom. That is, the ring general formula (a) has may be a thiazole ring may be a oxazole ring, from the viewpoint of reactivity (yield), it is preferable that Z ^a is an oxygen atom. That is, the ring that the general formula (a) has is preferably an oxazole ring.

R ¹ and R ² are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted alkoxy group having 1 to 20 carbon atoms, and a substituted group. An alkoxycarbonyl group having 2 to 20 carbon atoms, a monovalent aromatic hydrocarbon group which may be substituted, a monovalent heterocyclic group which may be substituted, or an amino group which may be substituted. is there.

  The “C1-C20 hydrocarbon group” is a saturated linear or branched aliphatic hydrocarbon group or alicycle having 1 to 20 (preferably 1 to 12, more preferably 1 to 6) carbon atoms. Preferred are hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methyl. Propyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, n-heptyl group, n-octyl group, n-nonyl group, Examples thereof include alkyl groups such as n-decyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.

  The substituent in the case where “the hydrocarbon group having 1 to 20 carbon atoms” is substituted is not particularly limited, but halogen such as fluorine atom, chlorine atom, bromine atom; alkoxycarbonyl group having 2 to 20 carbon atoms (for example, A methoxycarbonyl group, an ethoxycarbonyl group, an isopropylcarbonyl group, etc.); an acyl group having 2 to 20 carbon atoms (for example, an acetyl group, a propionyl group, etc.) and a cyano group. The number of substituents when substituted with a substituent is not particularly limited, and can be, for example, about 1 to 3.

  The “C1-C20 alkoxy group” is preferably a saturated linear or branched alkoxy group having 1 to 20 carbon atoms (preferably 1 to 12, more preferably 1 to 6), such as a methoxy group. Ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentoxy group, isopentoxy group, neopentoxy group, 1-methylpropoxy group, n-hetoxy group, isohetoxy group, Examples include 1,1-dimethylbutoxy group, 2,2-dimethylbutoxy group, 3,3-dimethylbutoxy group, n-heptoxy group, n-octoxy group, n-nonoxy group, n-decoxy group and the like.

  The substituent in the case where the “C1-C20 alkoxy group” is substituted is not particularly limited, but is a halogen such as a fluorine atom, a chlorine atom or a bromine atom; an alkoxycarbonyl group having 2 to 20 carbon atoms (for example, methoxy A carbonyl group, an ethoxycarbonyl group, an isopropylcarbonyl group, etc.); a C2-C20 acyl group (for example, an acetyl group, a propionyl group, etc.), a cyano group, etc. are mentioned. The number of substituents when substituted with a substituent is not particularly limited, and can be, for example, about 1 to 3.

  The “C2-C20 alkoxycarbonyl group” is preferably a saturated straight-chain or branched alkoxycarbonyl group having 2 to 20 carbon atoms (preferably 2 to 12 and more preferably 2 to 6). Methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isoporopoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, n-pentoxycarbonyl group, isopentoxycarbonyl group, Neopentoxycarbonyl group, 1-methylpropoxycarbonyl group, n-hetoxycarbonyl group, isohetoxycarbonyl group, 1,1-dimethylbutoxycarbonyl group, 2,2-dimethylbutoxycarbonyl group, 3,3-dimethylbutoxycarbonyl Group, n-heptoxycarbonyl group n- octoxy group, n- nonoxynol carbonyl group, n- Deco alkoxycarbonyl group, and the like.

  The substituent in the case where the “C2-C20 alkoxycarbonyl group” is substituted is not particularly limited, but is a halogen such as a fluorine atom, a chlorine atom or a bromine atom; an acyl group having 2 to 20 carbon atoms (for example, acetyl) Group, propionyl group, etc.), cyano group and the like. The number of substituents when substituted with a substituent is not particularly limited, and can be, for example, about 1 to 3.

  The “monovalent aromatic hydrocarbon group” is a monovalent group having an aromatic hydrocarbon ring, and one hydrogen atom bonded to one carbon atom constituting the aromatic hydrocarbon ring is eliminated. It is a group to be made. In addition, the derivative group (monovalent derivative group) substituted by the functional group may be sufficient as the hydrogen atom couple | bonded with carbon which comprises this aromatic-hydrocarbon ring.

  Examples of the aromatic hydrocarbon ring include not only a benzene ring but also a ring obtained by condensing a plurality of benzene rings (benzene condensed ring), a ring obtained by condensing a benzene ring and another aromatic hydrocarbon ring, etc. A ring obtained by condensing a plurality of benzene rings and a ring obtained by condensing a benzene ring with another ring may be collectively referred to as “condensed hydrocarbon ring”). Examples of the condensed hydrocarbon ring include a pentalene ring, an indene ring, a naphthalene ring, a dihydronaphthalene ring, an anthracene ring, a tetracene ring, a pentacene ring, a pyrene ring, a perylene ring, a triphenylene ring, an azulene ring, a heptalene ring, a biphenylene ring, Examples include indacene ring, acenaphthylene ring, fluorene ring, phenalene ring, phenanthrene ring and the like.

  The substituent in the case where the “monovalent aromatic hydrocarbon group” is substituted (in the case of a monovalent derivative group) is not particularly limited, but halogen such as fluorine atom, chlorine atom, bromine atom, etc .; -20 hydrocarbon group (for example, methyl group, ethyl group, n-propyl group, etc.), C1-C20 alkoxy group (for example, methoxy group, ethoxy group, n-propoxy group, etc.), C2-C2 20 alkoxycarbonyl groups (for example, methoxycarbonyl group, ethoxycarbonyl group, isopropylcarbonyl group, etc.); C2-C20 acyl groups (for example, acetyl group, propionyl group, etc.), cyano groups and the like. The number of substituents when substituted with a substituent is not particularly limited, and can be, for example, about 1 to 3.

  The “monovalent heterocyclic group” is a monovalent group having a heterocyclic ring, and is a group formed by removing one hydrogen atom bonded to one carbon atom constituting this heterocyclic ring. The hydrogen atom bonded to the carbon constituting the heterocyclic ring may be a derivative group (monovalent complex derivative group) substituted with a functional group.

  Examples of the heterocycle include a heterocycle having at least one atom selected from a nitrogen atom, an oxygen atom, a boron atom, a phosphorus atom, a silicon atom and a sulfur atom (specifically, a heteroaromatic ring or a heteroaliphatic ring). Ring, especially heteroaromatic ring). Specific examples of the heterocyclic ring include a furan ring, a thiophene ring, a pyrrole ring, a silole ring, a borol ring, a phosphole ring, an oxazole ring, a dioxol ring, a thiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, and a pyrazine ring. A ring etc. are mentioned. In addition, a hetero-condensed ring such as these or a benzene ring, the above condensed hydrocarbon ring or the like (thienothiophene ring, quinoline ring, benzodioxole ring, etc.) can also be used.

  The substituent in the case where the “monovalent heterocyclic group” is substituted is not particularly limited, but halogen such as fluorine atom, chlorine atom, bromine atom; alkoxycarbonyl group having 2 to 20 carbon atoms (for example, methoxycarbonyl) Groups, ethoxycarbonyl groups, isopropylcarbonyl groups, etc.); acyl groups having 2 to 20 carbon atoms (for example, acetyl groups, propionyl groups, etc.), cyano groups and the like. But it can be adopted. The number of substituents when substituted with a substituent is not particularly limited, and can be, for example, about 1 to 3.

  The substituent in the case where the “amino group” is substituted is not particularly limited, but is a halogen such as a fluorine atom, a chlorine atom or a bromine atom; a hydrocarbon group having 1 to 20 carbon atoms (for example, a methyl group, an ethyl group, n -Propyl group, etc.), C1-C20 alkoxy groups (for example, methoxy group, ethoxy group, n-propoxy group, etc.), C2-C20 alkoxycarbonyl groups (for example, methoxycarbonyl group, ethoxycarbonyl group, Isopropylcarbonyl group etc.); C2-C20 acyl group (for example, acetyl group, propionyl group etc.), cyano group, etc. are mentioned. The number of substituents when substituted with a substituent is not particularly limited, and can be, for example, about 1 to 3.

R ¹ and R ² may be bonded to each other to form an aromatic ring with adjacent —C═C—. The aromatic ring at this time includes the above-described aromatic hydrocarbon ring and heteroaromatic ring, and may be a monovalent derivative group having the above-described substituent.

  Specifically, Ar satisfying such conditions is:

Etc.

Etc. are preferred.

  Moreover, as such a compound (A), specifically,

Etc.

Etc. are preferred.

[1-2] Compound (B)
In the present invention, the compound (B) used as the other coupling partner is:
General formula (B1):
R ^a OCO-Ar ′
[Wherein Ar ′ is the same as defined above; R ^a is a substituent. ]
A compound (B1) represented by:
General formula (B2):

[Wherein Ar ″ is the same as above; R ^b is a substituent other than an alkyl group.]
Compound (B2) represented by the general formula (B3):

[Wherein Ar ″ is the same as above; R ^c is a substituent.]
Compound (B3) represented by
It is.

(1-2-1) Compound (B1)
Compound (B1) may be a commercially available aromatic ester or the like, or may be produced from a commercially available aromatic carboxylic acid.

  In General Formula (B1), Ar ′ represents an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, and an optionally substituted monovalent aromatic group. An alicyclic hydrocarbon group or a monovalent heterocyclic group which may be substituted.

  Substituent when “C 1-20 hydrocarbon group”, “C 1-20 hydrocarbon group” is substituted, “monovalent aromatic hydrocarbon group”, “monovalent aromatic” The substituent when the “hydrocarbon group” is substituted, the substituent when the “monovalent heterocyclic group”, and the “monovalent heterocyclic group” are substituted are as described above. The same thing.

  The “monovalent alicyclic hydrocarbon group” is a monovalent group having a cycloalkane, and is a group formed by removing one hydrogen atom bonded to one carbon atom constituting this cycloalkane. is there. In addition, the hydrogen atom couple | bonded with carbon which comprises this cycloalkane may be the derivative group (monovalent alicyclic derivative group) substituted by the functional group.

  The cycloalkane is not limited as long as it has 3 to 20 carbon atoms, and examples thereof include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.

  The substituent in the case where the “monovalent alicyclic hydrocarbon group” is substituted is not particularly limited, but is a halogen such as a fluorine atom, a chlorine atom or a bromine atom; an alkoxycarbonyl group having 2 to 20 carbon atoms (for example, A methoxycarbonyl group, an ethoxycarbonyl group, an isopropylcarbonyl group, etc.); an acyl group having 2 to 20 carbon atoms (for example, an acetyl group, a propionyl group, etc.) and a cyano group. The number of substituents when substituted with a substituent is not particularly limited, and can be, for example, about 1 to 3.

Of these, Ar ′ is preferably an optionally substituted hydrocarbon group having 1 to 20 carbon atoms or an optionally substituted monovalent heterocyclic group in consideration of reactivity (however, When Z ^a is a sulfur atom, a heterocyclic group is preferred.

  In particular,

Etc.

Etc. are preferred.

  As Ar ′, in addition to the above,

Etc. can also be adopted.

In General Formula (B1), R ^a is a substituent. In consideration of reactivity, the C1-C20 hydrocarbon group which may be substituted, the monovalent aromatic hydrocarbon group which may be substituted, the monovalent alicyclic which may be substituted A hydrocarbon group, a monovalent heterocyclic group which may be substituted, or an amino group which may be substituted is preferable, a hydrocarbon group having 1 to 20 carbon atoms which may be substituted, or a substituted group The monovalent aromatic hydrogen-sensitive group which may be sufficient is more preferable.

  Substituent when “C 1-20 hydrocarbon group”, “C 1-20 hydrocarbon group” is substituted, “monovalent aromatic hydrocarbon group”, “monovalent aromatic” A substituent when the “hydrocarbon group” is substituted, a “monovalent alicyclic hydrocarbon group”, a substituent when the “monovalent alicyclic hydrocarbon group” is substituted, The substituent when the “heterocyclic group”, “monovalent heterocyclic group” is substituted, and the substituent when the “amino group” is substituted are the same as described above. is there.

Specific examples of such ^Ra include phenyl, o-tolyl, m-tolyl, p-tolyl, 3,5-xylyl, 2,4-xylyl, 3,4,5. -Trimethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 3,5-dimethoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, 4-formylphenyl group, 4- (methoxycarbonyl) ) Phenyl group, 4-acetamidophenyl group and the like.

  Specifically, as the compound (B1) satisfying such conditions,

Etc.

(1-2-2) Compound (B2)
Compound (B2) may be a commercially available product or may be generated from a commercially available product.

  In General Formula (B2), Ar ″ is a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, or optionally substituted. A monovalent alicyclic hydrocarbon group or a monovalent heterocyclic group which may be substituted (except when two Ar ″ are both hydrogen atoms), which may be substituted C1-C20 hydrocarbon group, monovalent aromatic hydrocarbon group which may be substituted, monovalent alicyclic hydrocarbon group which may be substituted or monovalent which may be substituted The heterocyclic group is the same as described above. Preferred specific examples are also the same.

In the general formula (B2), R ^b is a substituent other than an alkyl group. In consideration of reactivity, R ^b1 CO— (R ^b1 is a substituent), a monovalent aromatic hydrocarbon group that may be substituted, a monovalent alicyclic hydrocarbon group that may be substituted, A monovalent heterocyclic group which may be substituted or an amino group which may be substituted is preferable.

  “Monovalent aromatic hydrocarbon group”, a substituent when “monovalent aromatic hydrocarbon group” is substituted, “monovalent alicyclic hydrocarbon group”, “monovalent alicyclic” Substituent when "hydrocarbon group" is substituted, substituent when "monovalent heterocyclic group", "monovalent heterocyclic group" is substituted, and "amino group" are substituted In this case, the substituents are the same as those described above.

In R ^b1 CO—, R ^b1 is a substituent, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, or optionally substituted. A preferable monovalent alicyclic hydrocarbon group, a monovalent heterocyclic group which may be substituted, or an amino group which may be substituted is preferable.

  Substituent when “C 1-20 hydrocarbon group”, “C 1-20 hydrocarbon group” is substituted, “monovalent aromatic hydrocarbon group”, “monovalent aromatic” A substituent when the “hydrocarbon group” is substituted, a “monovalent alicyclic hydrocarbon group”, a substituent when the “monovalent alicyclic hydrocarbon group” is substituted, The substituent when the “heterocyclic group”, “monovalent heterocyclic group” is substituted, and the substituent when the “amino group” is substituted are the same as described above. is there.

Specific examples of such R ^b include t-BuCO (t-Bu is a tert-butyl group), N (CH ₃ ) ₂ CO, and the like.

  As the compound (B2) satisfying such conditions, specifically,

Etc.

(1-2-3) Compound (B3)
Compound (B3) may be a commercially available product or may be generated from a commercially available product.

  In general formula (B3), Ar ″ represents a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, or optionally substituted. A monovalent alicyclic hydrocarbon group or a monovalent heterocyclic group which may be substituted (except when two Ar ″ are both hydrogen atoms), which may be substituted C1-C20 hydrocarbon group, monovalent aromatic hydrocarbon group which may be substituted, monovalent alicyclic hydrocarbon group which may be substituted or monovalent which may be substituted The heterocyclic group is the same as described above. Preferred specific examples are also the same.

In General Formula (B3), R ^c is a substituent. In consideration of reactivity, the C1-C20 hydrocarbon group which may be substituted, the monovalent aromatic hydrocarbon group which may be substituted, the monovalent alicyclic which may be substituted A hydrocarbon group, a monovalent heterocyclic group which may be substituted, or an amino group which may be substituted is preferable, a hydrocarbon group having 1 to 20 carbon atoms which may be substituted, or a substituted group The monovalent aromatic hydrogen-sensitive group which may be sufficient is more preferable.

  Substituent when “C 1-20 hydrocarbon group”, “C 1-20 hydrocarbon group” is substituted, “monovalent aromatic hydrocarbon group”, “monovalent aromatic” A substituent when the “hydrocarbon group” is substituted, a “monovalent alicyclic hydrocarbon group”, a substituent when the “monovalent alicyclic hydrocarbon group” is substituted, The substituent when the “heterocyclic group”, “monovalent heterocyclic group” is substituted, and the substituent when the “amino group” is substituted are the same as described above. is there.

Specific examples of such R ^c include phenyl, o-tolyl, m-tolyl, p-tolyl, 3,5-xylyl, 2,4-xylyl, 3,4,5. -Trimethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 3,5-dimethoxyphenyl group, 4-fluorophenyl group, 4-trifluoromethylphenyl group, 4-formylphenyl group, 4- (methoxycarbonyl) ) Phenyl group, 4-acetamidophenyl group and the like.

  As the compound (B3) satisfying such conditions, specifically,

Etc.

[1-3] Nickel Compound The nickel compound is not particularly limited and various compounds can be used, but a zero-valent Ni salt or a divalent Ni salt is preferable. These can be used alone or in combination of two or more. These complexes mean both those charged as reagents and those produced in the reaction.

The zero-valent Ni salt is not particularly limited, but bis (1,5-cyclooctadiene) nickel (0) (Ni (cod) ₂ ), bis (triphenylphosphine) nickel dicarbonyl (Ni (CO ) ₂ (PPh ₃ ) ₂ ), 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 described later is coordinated in advance may be used.

Among these, considering reactivity (yield), stability, and the like, a zero-valent Ni salt is preferable, and Ni (cod) ₂ , Ni (CO) ₂ (PPh ₃ ) _{2, and the} like are preferable. When a divalent Ni salt is employed, it is preferable to use zinc, diisobutylaluminum hydride, or the like as the reducing agent.

  The amount of the nickel compound used is usually 0.01 to 1 mol, preferably 0.05 to 0.7 mol of the nickel compound added as a reagent with respect to 1 mol of the compound (A) as a raw material. More preferably, it is 0.07-0.5 mol.

[1-4] Ligand In the production method of the present invention, a ligand capable of coordinating to nickel (nickel atom) can be used together with the nickel compound. As this ligand, considering reactivity (yield) and the like,
General formula (C1):

[Wherein, four R ^{3 s} are the same or different and may be a monovalent aromatic hydrocarbon group which may be substituted or a monovalent alicyclic hydrocarbon group which may be substituted; An integer of ˜20; provided that when one or more of R ³ is an aromatic hydrocarbon group, n is an integer of 3-20. ]
A compound (C1) represented by:
General formula (C2):

[In the formula, three R ^{4 s} are the same or different and are each a linear hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, or optionally substituted. Monovalent alicyclic hydrocarbon group; except when all R ⁴ are phenyl groups. ]
Compound (C2) represented by the general formula (C3):

[Wherein, two R ^{5 s} are the same or different and each represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted alkoxy group having 1 to 20 carbon atoms. ]
A compound represented by formula (C3)
Is preferred.

In the general formula (C1), four R ^{3 s} are the same or different and each may be substituted monovalent aromatic hydrocarbon group or optionally substituted monovalent alicyclic hydrocarbon group It is.

  “Monovalent aromatic hydrocarbon group”, substituent when “monovalent aromatic hydrocarbon group” is substituted, “monovalent alicyclic hydrocarbon group”, and “monovalent alicyclic ring” The substituent in the case where “formula hydrocarbon group” is substituted is the same as described above. In particular, an optionally substituted alicyclic hydrocarbon group is preferable, and an optionally substituted cyclohexyl group and cyclopentyl group are more preferable.

Moreover, 2-20 are preferable, as for n, 2-12 are more preferable, and 2-6 are more preferable. However, when one or more of R ³ is an aromatic hydrocarbon group, n is preferably from 3 to 20, more preferably from 3 to 12, and even more preferably from 3 to 6.

  Specific examples of the compound (C1) satisfying the general formula (C1) include 1,2-bisdicyclohexylphosphinoethane (dtype), 1,2-bisdicyclopentylphosphinoethane, 1,4- Bis (dicyclohexylphosphino) butane, 1,4-bis (dicyclopentylphosphino) butane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,5-bis (Diphenylphosphino) pentane, 1,6-bis (diphenylphosphino) hexane and the like can be mentioned.

In the general formula (C2), three R ^{4 s} are the same or different and each may be substituted monovalent aromatic hydrocarbon group or optionally substituted monovalent alicyclic hydrocarbon group It is.

  “Monovalent aromatic hydrocarbon group”, substituent when “monovalent aromatic hydrocarbon group” is substituted, “monovalent alicyclic hydrocarbon group”, and “monovalent alicyclic ring” The substituent in the case where “formula hydrocarbon group” is substituted is the same as described above.

Specific examples of the compound (C2) that satisfies the general formula (C2) include tricyclohexylphosphine (PCy ₃ ), trimethylphosphine (PMe ₃ ), and tris (2,4,6-trimethoxyphenyl) phosphine. , Tris (2,6-dimethoxyphenyl) phosphine, and the like.

In the general formula (C3), two R ^{5 s} are the same or different and each is an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted alkoxy group having 1 to 20 carbon atoms. is there.

  Substituent in the case where “C 1-20 alkyl group”, “C 1-20 alkyl group” is substituted, “C 1-20 alkoxy group”, and “C 1-20 carbon group” The substituent in the case where “alkoxy group” is substituted is the same as described above.

  Specific examples of the compound (C3) that satisfies the general formula (C3) include 4,4'-dimethoxy-2,2'-bipyridine and the like.

Among these, examples of the ligand include 1,2-bisdicyclohexylphosphinoethane (dtype), 1,2-bisdicyclopentylphosphinoethane, tricyclohexylphosphine (PCy ₃ ), trimethylphosphine (PMe ₃ ), and the like. 1,2-bisdicyclohexylphosphinoethane (dtype), 1,2-bisdicyclopentylphosphinoethane and the like are more preferable.

  When using the said ligand, 0.5-5 mol is preferable normally with respect to 1 mol of said nickel compounds, and 1-3 mol is more preferable.

[1-5] Base In the above reaction step, a base may be used as necessary. This base is used as a scavenger for the acid to be generated or to promote the nickelation reaction of the compound (A) (Ar—H).

  Examples of the base include alkali metal or alkaline earth metal phosphates (sodium phosphate, potassium phosphate, etc.), alkali metal or alkaline earth metal carbonates (sodium bicarbonate, potassium bicarbonate, lithium carbonate, carbonate) Sodium, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal acetates (sodium acetate, potassium acetate, calcium acetate, etc.), amines (triethylamine, trimethylamine, diazabicycloundecene), and the like. Of these, potassium phosphate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, diethylamine, diazabicycloundecene and the like are preferable, and potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, diethylamine and the like are preferable. More preferred are potassium phosphate, potassium carbonate, cesium carbonate and the like.

  The amount of the base used is usually preferably 0.01 to 10 mol, more preferably 0.1 to 5.0 mol, and more preferably 0.5 to 3.0 mol per 1 mol of the compound (A) as a raw material. Mole is more preferred.

[1-6] Solvent The above reaction step is usually performed in the presence of a reaction solvent. Examples of the reaction solvent include aromatic hydrocarbons such as toluene, xylene, and benzene; esters such as methyl acetate, ethyl acetate, and butyl acetate; cyclic ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diisopropyl ether; Halogenated hydrocarbons such as methyl chloride, chloroform, dichloromethane, dichloroethane and dibromoethane; Ketones such as acetone and methyl ethyl ketone; Amides such as dimethylformamide and dimethylacetamide; Nitriles such as acetonitrile; Isopropyl alcohol and tert-butyl alcohol C2-20 alcohols such as dimethyl sulfoxide, N-methylpyrrolidone and the like. These may be used alone or in combination of two or more. Among these, in the present invention, toluene, xylene (m-xylene and the like), dioxane (1,4-dioxane and the like), tert-butyl alcohol, dimethylacetamide, acetonitrile, dimethyl sulfoxide and the like are preferable, and toluene, xylene (m- Xylene), dioxane (1,4-dioxane, etc.), dimethylacetamide, acetonitrile, dimethyl sulfoxide, etc. are more preferred, and dioxane (1,4-dioxane, etc.) is more preferred.

[1-7] Other conditions The reaction temperature in the reaction step is usually selected from the range of 0 ° C. or higher and lower than the boiling temperature of the reaction solvent. -200 degreeC is preferable and 130-170 degreeC is more preferable.

  The reaction pressure is not particularly limited and may be about normal pressure.

  The reaction atmosphere is not particularly limited, but is preferably an inert gas atmosphere, and is preferably an argon gas atmosphere, a nitrogen gas atmosphere, or the like. An air atmosphere can also be used.

  After the reaction step, a purification step can be provided as necessary. In this purification step, it can be subjected to general post-treatment such as solvent (solvent) removal, washing, chromatographic separation and the like.

  As described above, a compound group in which an aromatic molecule and an aromatic molecule are bonded can be easily synthesized by a novel coupling reaction.

  Of the compounds obtained by the production method of the present invention,

Is a novel compound not described in any literature.

2. Usefulness Using the production method of the present invention, various useful compounds can be synthesized. For example, by using the production method of the present invention, it is also possible to synthesize a natural product muskolide A having an antibacterial action in a short step, as shown in Examples described later.

  Further, synthesis of siphonazole B which is a biologically active molecule, hoboxazole A which is a complex natural organic compound, an organic phosphorescent complex, an organic dye, and the like is also expected.

3. Reaction mechanism Although the reaction mechanism is not necessarily clear, taking the case of synthesizing the compound represented by the general formula (1) as an example, it is considered that Ni0 / NiII redox catalytic reaction is performed as follows.

Specifically, when bis (triphenylphosphine) nickel dicarbonyl (Ni (CO) ₂ (PPh ₃ ) ₂ ) is used as the nickel compound and 1,2-bisdicyclohexylphosphinoethane (dtype) is used as the ligand. Take for example
(I) CO is extruded from the nickel complex to produce an active catalyst (ii) Oxidative addition of Ni0 to the CO bond of compound (B) (iii) CO transfer to nickel as the central metal (iv) Nickelization of C—H bond of compound (A) (v) Reductive elimination to form a compound represented by general formula (1) as a coupling product (the nickel catalyst to be eliminated can be reused)
It is considered that the compound represented by the general formula (1) can be obtained by the reaction route of

  In addition, when synthesizing the compound represented by the general formula (2), it is considered that the reaction mechanism is similar.

  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 restricted, all materials, including dry solvents, were used as purchased without purification. Bis (1,5-cyclooctadiene) nickel (0) (Ni (cod) ₂ ) and K ₃ PO ₄ were obtained from Wako Chemical Co., Ltd. 1,2-bisdicyclohexylphosphinoethane (dtype) was obtained from Sigma-Aldrich. 1,4-Dioxane was distilled over calcium or sodium metal and benzophenone before the coupling reaction. 5-phenyloxazole, 5- (p-anisyl) oxazole, 5-phenylthiazole, 2-phenylthiazole-4-carboxylic acid, 5- (benzo [d] [1,3] dioxol-5-yl) oxazole, and 3,4-Dihydronaphthalen-2-yl N, N-dimethylcarbamate is described in the literature (Besselievre, F., et al. J. Org. Chem. 2008, 73, 3278, Parisien, M., et al. Org. Chem. 2005, 70, 7578, Chen, H., et al. Chem. Biol. 2001, 8, 899., Yamamoto, T., et al. Chem. Eur. J. 2011, 17, 10113., And Olofson, RA et al., Tetrahedron Lett. 1980, 21, 819.). Unless otherwise noted, all reactions were performed using a dry solvent in an argon or nitrogen atmosphere in a glass vessel flame dried using standard vacuum line techniques. All C—H bond arylation reactions or alkenyl reactions are equipped with a J. Young O-ring tap, heated in an 8-well reaction block (heater + magnetic stirrer), and unless otherwise noted, in a 20 mL glass container Done in a tube. All workup and purification procedures were performed using reagent grade solvents in air.

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 on a Shimadzu GC-2010 instrument equipped with an HP-5 column (30 m × 0.25 mm, Hewlett-Packard) using decane as an internal standard. GCMS analysis was performed on a Shimadzu GCMS-QP2010 equipped with an HP-5 column (30 meters x 0.25 mm, Hewlett-Packard). High resolution mass spectra (HRMS) were obtained from a JMS-T100TD instrument (DART). The optical rotation was measured using chloroform and a JASCO P-1010-GT digital polarimeter as a solvent. Nuclear magnetic resonance (NMR) spectra were recorded with a JEOL JNM-ECA-600 spectrometer ( ¹ H 600 MHz, ¹³ C 150 MHz) and a JEOL JNM-ECA-400 spectrometer ( ¹ H 400 MHz, ¹³ C 100 MHz) . ¹ H NMR chemical shifts were expressed as relative parts per million (ppm) of tetramethylsilane (δ0.00 ppm), residual peak of benzene (δ7.16 ppm) or DMSO (δ2.50 ppm). ¹³ C NMR chemical shifts are expressed in relative parts per million (ppm) of CDCl ₃ (δ77.0 ppm), C ₆ D ₆ (δ128.06 ppm) or DMSO-D ₆ (δ39.52 ppm). did. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet doublet, t = triplet, q = quartet, m = multiplet, br = broad signal), association constant (Hz), integration.

Synthesis of Compound (A) [Synthesis Example 1-1: Synthesis of [2-13C] benzoxazole (a1)]

A mixture of triethyl orthoformate (formyl- ^13C , purity 99%, 500 mg, 3.4 mmol, 1.0 equiv), 2-aminophenol (742 mg, 6.8 mmol, 2.0 equiv) was refluxed in toluene (1.2 mL) for 2 hours. did. The mixture was cooled to room temperature, then concentrated, and the residue was purified by flash column chromatography (hexane / ethyl acetate (EtOAc) = 10: 1) to give [2- ¹³ C] benzoxazole (a1) as a colorless oil. Obtained (295.0 mg, 72%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.11 (d, 1JCH = 232.4 Hz, 1H), 7.81-7.78 (m, 1H), 7.61-7.58 (m, 1H), 7.43-7.35 (m, 2H) ; ¹³ C NMR (100 MHz, CDCl ₃ ): δ 152.6, 150.1 (JCC = 3.8 Hz), 140.2 (JCC = 2.9 Hz), 125.7, 124.7, 120.8 (JCC = 6.7 Hz), 111.1 (JCC = 3.8 Hz) HRMS (DART) m / z calcd for C ₆ ¹³ CH ₆ NO [MH] ⁺ : 121.04829, found 121.04836.

  [Synthesis Example 1-2: Synthesis of 5-methylbenzoxazole (a2)]

To a solution of 4-methyl-2-aminophenol (3.46 g, 28 mmol) and molecular sieves 3 in toluene (20 mL) was added triethylorthoformate (7.0 mL, 42 mmol, 1.5 eq) and the mixture was concentrated at 100 ° C. Heated in a late oil bath. After cooling to room temperature, saturated aqueous NH ₄ Cl was added. After extraction three times with ethyl acetate (EtOAc) and drying over Na ₂ SO ₄ , the filtrate was evaporated under reduced pressure. The obtained crude product was purified by flash column chromatography using silica gel (hexane / ethyl acetate (EtOAc) = 20: 1) to give 5-methylbenzoxazole (a2) as a white solid (2.71 g, 73%).

[Synthesis Examples 1-3 to 1-4]
Using the various raw materials instead of 4-methyl-2-aminophenol as the raw materials, the compounds shown in the following Table 1 were obtained as white solids by the same method as in Synthesis Example 1-2.

The spectral data of each compound was as follows.
Compound (a3): 5-methoxybenzoxazole
¹ H NMR (400 MHz) δ 8.06 (s, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.27 (s, 1H), 6.99 (dd, J = 9.2, 2.7Hz, 1H), 3.90 ( s, 3H).
Compound (a4): 5-tert-butylbenzoxazole
¹ H NMR (400 MHz) δ 8.07 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.52-7.47 (m, 2H), 1.39 (s, 9H).

Synthesis of Compound (B1) [Synthesis Example 2-1: Synthesis of phenyl nicotinate (b1a)]

[Ph is a phenyl group; Et is an ethyl group. ]
Thionyl chloride (9 mL) was added to nicotinic acid (1.23 g, 10 mmol, 1.0 equiv), the mixture was stirred at reflux for 1 h, and the solution was concentrated in vacuo. To a THF solution (10 mL) of the residue was added triethylamine (1.7 mL, 12 mmol, 1.2 eq). After cooling the mixture to 0 ° C., phenol (941 mg, 10 mmol, 1.0 eq) and 4,4-dimethylaminopyridine (DMAP) pieces were added and the reaction mixture was warmed to room temperature. After stirring for 1 hour, the resulting mixture was filtered through a silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated under reduced pressure and purified by recrystallization using hexane to obtain the residue as a white solid (1.91 g, yield 96%). As a result, it was confirmed that phenyl nicotinate (b1a) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.41 (d, J = 1.2 Hz, 1H), 8.86 (dd, J = 5.0, 1.8 Hz, 1H), 8.47-8.44 (m, 1H), 7.49-7.43 (m, 3H), 7.30 (t, J = 7.8 Hz, 1H), 7.26-7.22 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 164.0, 154.2, 151.6, 150.7, 137.7, 129.8 126.4, 125.8, 123.6, 121.7.

[Synthesis Examples 2-2 to 2-11]
The compounds shown in Table 2 below were obtained as white solids by the same method as in Synthesis Example 2-1, using various raw materials instead of nicotinic acid.

The spectral data of each compound was as follows.
Compound (b1b): phenyl thiophene-2-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.98 (dd, J = 4.0, 1.2 Hz, 1H), 7.66 (dd, J = 5.2, 1.2 Hz, 1H), 7.45-7.39 (m, 2H), 7.29 -7.21 (m, 3H), 7.17 (dd, J = 5.2, 4.2 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 160.7, 150.7, 134.8, 133.6, 133.1, 129.6, 128.2, 126.1, 121.8.
Compound (b1c): phenyl thiophene-3-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.31 (dd, J = 2.8, 1.2 Hz, 1H), 7.67 (dd, J = 5.0, 1.4 Hz, 1H), 7.44-7.40 (m, 2H), 7.38 (dd, J = 5.0, 3.0 Hz, 1H), 7.29-7.25 (m, 1H), 7.21-7.19 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 161.2, 150.8, 134.2, 133.1 , 129.6, 128.4, 126.5, 126.0, 121.8.
Compound (b1d): furan-2-carboxylic acid phenyl
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.68 (m, 1H), 7.45-7.38 (m, 3H), 7.29-7.21 (m, 3H), 6.60 (dd, J = 3.4, 1.8 Hz, 1H) ; ¹³ C NMR (100 MHz, CDCl ₃ ): δ 157.1, 150.3, 147.3, 144.2, 129.7, 126.2, 121.7, 119.6, 112.3.
Compound (b1e): furan-3-carboxylic acid phenyl
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (dd, J = 1.4, 0.6 Hz, 1H), 7.50 (t, J = 1.6 Hz, 1H), 7.44-7.39 (m, 2H), 7.28-7.24 (m, 1H), 7.19-7.16 (m, 2H), 6.87 (dd, J = 2.0, 0.8 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 161.6, 150.6, 148.8, 144.2, 129.6 , 126.1, 121.8, 119.0, 110.2; HRMS (DART) m / z calcd for C ₁₁ H ₉ O ₃ [MH] ⁺ : 189.05517, found 189.05517.
Compound (b1f): phenyl isonicotinate
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.87 (d, J = 6.0 Hz, 2H), 8.01 (d, J = 6.4 Hz, 2H), 7.46 (t, J = 8.2 Hz, 2H), 7.33- 7.22 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 163.9, 151.0, 150.6, 137.0, 129.8, 126.5, 123.4, 121.5; HRMS (DART) m / z calcd for C ₁₂ H ₁₀ NO ₂ [MH] ⁺ : 200.07115, found 200.07108.
Compound (b1g): phenyl picolinate
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.86-8.84 (m, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.92 (td, J = 8.0, 2.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.48-7.41 (m, 2H), 7.31-7.25 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 164.0, 151.0, 150.3, 147.7, 137.4, 129.7, 127.5, 126.3, 126.0, 121.8; HRMS (DART) m / z calcd for C ₁₂ H ₁₀ NO ₂ [MH] ⁺ : 200.07115, found 200.07113.
Compound (b1h): Pyrazine-2-carboxylate phenyl
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.48 (s, 1H), 8.85 (d, J = 1.2 Hz, 1H), 8.82 (d, J = 1.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.39-7.21 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 162.7, 150.6, 148.3, 146.9, 144.8, 143.1, 129.8, 126.6, 121.6; HRMS (DART) m / z calcd for C ₁₁ H ₉ N ₂ O ₂ [MH] ⁺ : 201.06640, found 201.06621.
Compound (b1i): 2-phenylquinoline-4-carboxylic acid phenyl
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.86 (d, J = 8.8 Hz, 1H), 8.65 (s, 1H), 8.29-8.24 (m, 3H), 7.80 (dd, J = 8.4, 6.8 Hz , 1H), 7.65 (dd, J = 8.6, 7.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.50 (t, J = 7.6 Hz, 3H), 7.36-7.32 (m, 3H) ; ¹³ C NMR (100 MHz, CDCl3): δ 164.9, 156.9, 150.7, 149.5, 138.8, 134.8, 130.6, 130.2, 130.0, 129.9, 129.1, 128.3, 127.6, 126.6, 125.4, 124.2, 121.8, 121.0; HRMS ( DART) m / z calcd for C ₂₂ H ₁₆ NO ₂ [MH] ⁺ : 326.11810, found 326.11815.
Compound (b1j): 2-phenylthiazole-4-carboxylic acid phenyl
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 8.06-8.03 (m, 2H), 7.48-7.41 (m, 5H), 7.30-7.25 (m, 3H); ¹³ C NMR ( 100 MHz, CDCl ₃ ): δ 169.3, 159.9, 150.7, 147.2, 132.8, 131.0, 129.6, 129.2, 128.8, 127.1, 126.2, 121.8; HRMS (DART) m / z calcd for C ₁₆ H ₁₂ NO ₂ S (MH ] ⁺ : 282.05887, found 282.05868.
Compound (b1k): phenyl naphthalene-2-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.81 (d, J = 0.8 Hz, 1H), 8.21 (dd, J = 8.8, 1.6 Hz, 1H), 8.02 (dd, J = 8.0, 0.8 Hz, 1H ), 7.98-7.91 (m, 2H), 7.67-7.56 (m, 2H), 7.50-7.44 (m, 2H), 7.33-7.27 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 165.5, 151.2, 136.0, 132.7, 132.1, 129.7, 129.6, 128.8, 128.5, 128.0, 127.0, 126.9, 126.1, 125.6, 121.9.

Synthesis of Compound (B2) [Synthesis Example 2-12: Synthesis of Styryl Pivalic Acid (b2a)]

Triethylamine (Et ₃ N) (3.6 mL, 25 mmol, 1.7 eq) and pivaloyl chloride (2.4 g, 20 mmol, 1.3 eq) were added to a solution of phenylacetaldehyde (1.81 g, 15 mmol) in dichloroethane (30 mL). . The mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH ₄ Cl and then extracted 3 times with CH ₂ Cl ₂ and the organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel (hexane / ethyl acetate (EtOAc) = 20: 1) to obtain styryl pivalic acid (b2a) of E and Z mixture as a yellow oil (3.04 g , Quant, E / Z = 1: 1).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.84 (d, J = 13.0 Hz, 1H, (E)), 7.59 (dd, J = 8.7, 1.3 Hz, 2H, (Z)) 7.34-7.26 (m, 9H, (E and Z)), 6.41 (d, J = 13.0 Hz, 1H), 5.71 (d, J = 7.3 Hz, 1H, (Z)), 1.34 (s, 9H, (Z)), 1.29 ( s, 9H, (E)).

  [Synthesis Example 2-13: Synthesis of styryl dicarbamate (b2b)]

To a solution of phenylacetaldehyde (1.81 g, 15 mmol) in dichloroethane (30 mL), triethylamine (Et ₃ N) (3.6 mL, 25 mmol, 1.7 eq), N, N-dimethylaminopyridine (DMAP: 457 mg, 3.7 mmol) 25 mol%) and N, N-dimethylcarbamoyl chloride (2.14 g, 20 mmol, 1.3 eq) were added. The mixture was stirred at 80 ° C. overnight. The reaction was quenched with saturated aqueous NH ₄ Cl and then extracted 3 times with CH ₂ Cl ₂ and the organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel (hexane / ethyl acetate (EtOAc) = 5: 1) to obtain styryldimethylcarbamate (b2b) of E and Z mixture as a yellow oil (2.86 g). , Quant, E / Z = 1: 3).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.78 (d, J = 13.1 Hz, 1H (E)), 7.53 (d, J = 7.8 Hz, 6H (Z)), 7.34-7.15 (m, 17H, (E and Z)), 6.30 (d, J = 13.1 Hz, 1H, (E)), 5.61 (d, J = 7.3 Hz, 3H, (Z)), 3.07 (s, 9H, (Z)), 2.99 ( s, 12H, (E and Z)), 2.97 (s, 3H); 13C NMR (CDCl ₃ , 100 MHz) δ 153.6, 153.4, 137.9, 135.5, 134.7, 134.5, 128.63, 128.56, 128.3, 126.8, 126.7, 125.9, 112.8, 109.6, 36.7, 36.6, 36.2, 35.9; HRMS calcd for C ₁₁ H ₁₄ NO ₂ [M + H] ⁺ : 192.1025, found: 192.1024.

  [Synthesis Example 2-14: Synthesis of (E) styryl pivalic acid (b2a)]

[Wherein LiTMP is lithium tetramethylpiperidide; Piv is COt-Bu (t-Bu is a tert-butyl group). ]
2,2,6,6-Tetramethylpiperidine (678 mg, 4.8 mmol, 2.2 eq) in THF (6.0 mL) at 0 ° C. in n-butyllithium in hexane (1.6 M, 4.8 mmol, 2.2 eq) Was added. The mixture was slowly transferred via cannula at −90 ° C. to a solution of CH ₂ Br ₂ (383 mg, 2.2 mmol, 1.1 eq) in THF (6 mL). After stirring for 5 minutes, a THF solution (4.0 mL) of ethyl benzoate (300 mg, 2.0 mmol) was added dropwise, and 5 minutes later, a hexane solution of n-butyllithium (10.0 mmol, 5.0 equivalents) was added dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. Then 1,3-cyclohexadiene (1.60 g, 20.0 mmol, 10 eq) was added and the reaction mixture was refluxed for 60 minutes. To the reaction mixture was added pivaloyl chloride (3.62 g, 30 mmol, 15 eq) at 0 ° C. After stirring at room temperature for 5 minutes or longer, saturated aqueous NaHCO ₃ solution was added. The mixture was extracted 3 times with ether. The organic phase was washed with brine and dried over MgSO ₄ . The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give (E) styrylpivalic acid (b2a) as a colorless oil (52 mg, 13%, E / Z ≧ 20/1).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.84 (d, J = 13.0 Hz, 1H), 7.34-7.26 (m, 4H), 7.25-7.21 (m, 1H), 6.41 (d, J = 13.0 Hz, 1H), 1.29 (s, 9H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 175.6, 136.7, 134.3, 128.7, 127.3, 126.2, 115.0, 38.8, 27.0; HRMS calcd for C ₁₃ H ₁₇ O ₂ [M + H] ⁺ : 205.1229, found: 205.1230.

  By the same method as above, for example,

Etc. can also be synthesized.

Synthesis of Compound (B3) [Synthesis Example 2-15: Synthesis of phenyl cinnamate (b3a)]

[Wherein Ph is a phenyl group; EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; DMAP is N, N-dimethylaminopyridine. ]
Cinnamic acid (2.22 g, 15 mmol) was placed in a 100 mL round bottom flask and phenol (1.55 g, 16.5 mmol, 1.1 eq), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC · HCl: 3.16 g, 16.5 mmol , 1.1 eq), N, N-dimethylaminopyridine (DMAP: 458 mg, 565 mmol , was added 0.25 eq) and _{CH 2 Cl 2 (30 mL)} . After stirring for 9 hours, the reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted three times with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by recrystallization from hexanes to give phenyl cinnamate (b3a) as a white solid (2.47 g, 73%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.88 (d, J = 16.2 Hz, 1H), 7.63-7.56 (m, 2H), 7.45-7.38 (m, 5H), 7.25 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 2H), 6.64 (d, J = 16.2 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.3, 150.7, 146.5, 134.1, 130.6, 129.4, 128.9, 128.2, 125.7, 121.6, 117.2; HRMS calcd for C ₁₅ H ₁₃ O ₂ [M + H] ⁺ : 225.0916, found: 225.0915.

[Synthesis Examples 2-16 to 2-19]
The compounds shown in Table 3 below were obtained in the same manner as in Synthesis Example 2-15 using various raw materials instead of cinnamic acid as raw materials.

The spectral data of each compound was as follows.
Compound (b3b): (E) Phenyl 3- (4-methoxyphenyl) acrylate
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.83 (d, J = 16.2 Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.40 (t, J = 8.5, 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 16.2 Hz, 1H), 3.85 (s , 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.7, 161.7, 150.9, 146.2, 130.0, 129.4, 126.9, 125.6,
121.7, 114.6, 114.4, 55.4; HRMS calcd for C ₁₆ H ₁₅ O ₃ [M + H] ⁺ : 255.1021, found: 255.1022.
Compound (b3c): (E) Phenyl 3- (o-tolyl) acrylate
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.16 (d, J = 16.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 8.4 Hz, 2H), 7.34-7.22 (m, 4H), 7.18 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 16.0 Hz, 1H), 2.47 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.4, 150.8, 144.2, 137.9, 133.1, 130.9, 130.4, 129.4, 126.6, 126.4, 125.7, 121.6, 118.3, 19.8; HRMS calcd for C ₁₆ H ₁₅ O ₂ [M + H] ⁺ : 239.1072, found: 239.1071.
Compound (b3d): (E) Phenylbut-2-enoate
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.38 (t, J = 8.0 Hz, 2H), 7.26-7.14 (m, 2H), 7.11 (d, J = 8.2 Hz, 2H), 6.05 (dd, J = 15.8, 0.7 Hz, 1H), 1.97 (dd, J = 6.9, 0.7 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 164.8, 150.7, 146.9, 129.3, 125.6, 122.0, 121.6, 18.2; HRMS calcd for C ₁₀ H ₁₁ O ₂ [M + H] ⁺ : 163.0759, found: 163.0758.
Compound (b3e): (E) Phenylpent-2-enoate
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.43-7.35 (m, 2H), 7.27-7.18 (m, 2H), 7.12 (d, J = 8.2 Hz, 2H), 6.02 (dt, J = 15.8, 1.8 Hz, 1H), 2.38-2.26 (m, 2H), 1.13 (t, J = 7.3 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.1, 153.0, 150.8, 129.4, 125.6, 121.6, 119.7 , 25.5, 12.1; HRMS calcd for C ₁₁ H ₁₃ O ₂ [M + H] ⁺ : 177.0916, found: 177.0913.

  [Synthesis Example 2-20: Synthesis of phenyl (E) 3- (thiophen-2-yl) acrylate (b3f)]

[Wherein Ph is a phenyl group; EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; DMAP is N, N-dimethylaminopyridine. ]
Add thiophene-2-carbaldehyde (561 mg, 5.0 mmol), CH ₂ Cl ₂ (20 mL), and Wittig reagent (1.92 g, 5.5 mmol, 1.1 eq) to a 100 mL round bottom flask with a magnetic stir bar. It was. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated in vacuo to give the corresponding ethyl ester. This ester was used without further purification.

To a 100 mL round bottom flask containing the ethyl ester thus obtained, THF (12 mL), water (4 mL), LiOH · H ₂ O (629.4 mg, 15 mmol, 3.0 eq) were added. . After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. At 0 ° C., the pH of the residue was adjusted to 2 by addition of 1 M HCl. The reaction mixture was extracted 3 times with CH ₂ Cl ₂ and the organic layer was dried over Na ₂ SO ₄ and then filtered. After concentrating the filtrate, the corresponding carboxylic acid was obtained. This product was used without further purification.

To a 100 mL round bottom flask containing the carboxylic acid thus obtained (635 mg, 4.1 mmol), phenol (427 mg, 4.5 mmol, 1.1 eq), 1- (3-dimethylaminopropyl) -3 -Add ethyl carbodiimide hydrochloride (EDC · HCl: 869 mg, 4.5 mmol, 1.1 eq), N, N-dimethylaminopyridine (DMAP: 126 mg, 1.0 mmol, 0.25 eq), and CH ₂ Cl ₂ (10 mL) It was. After stirring at room temperature for 9 hours, the reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (3 × 30 mL). The organic layer was dried over Na ₂ SO ₄ and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (hexane / ethyl acetate (EtOAc) = 5: 1) to give phenyl (E) 3- (thiophen-2-yl) acrylate (b3f). Obtained as a viscous colorless oil (830.6 mg, 72% over 3 steps).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.97 (d, J = 15.8 Hz, 1H), 7.43 (d, J = 5.5 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.33 (d , J = 3.6 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H), 7.09 (dd, J = 5.5, 3.6 Hz, 2H), 6.43 (d , J = 15.8 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.2, 150.7, 139.3, 138.9, 131.6, 129.4, 129.1, 128.2, 125.7, 121.6, 115.9; HRMS calcd for C ₁₃ H ₁₁ O ₂ S [M + H] ⁺ : 231.0480, found: 231.0477.

[Synthesis Examples 2-21 to 2-22]
All the compounds shown in Table 4 below were obtained as a white solid by the same method as in Synthesis Example 2-20 using various raw materials instead of thiophene-2-carbaldehyde as the raw materials.

The spectral data of each compound was as follows.
Compound (b3g): (E) Phenyl 3- (3,4-dimethoxyphenyl) acrylate
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.82 (d, J = 16.0 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.20-7.14 (m, 3H), 7.11 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 16.0 Hz, 1H), 3.931 (s, 3H), 3.928 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.6, 151.4, 150.8, 149.2, 146.4, 129.4, 127.1, 125.6, 123.0, 121.6, 114.8, 111.0, 109.6, 55.9, 55.8; HRMS calcd for C ₁₇ H ₁₇ O ₄ [M + H] ⁺ : 285.1127, found: 285.1127.
Compound (b3h): (E) Phenyl 3- (furan-3-yl) acrylate
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.77 (d, J = 16.0 Hz, 1H), 7.71 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.40 (t, J = 8.7, 7.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 1.0 Hz, 1H), 6.35 (d, J = 16.0 Hz , 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 165.3, 150.7, 145.0, 144.6, 136.5, 129.4, 125.7, 122.5, 121.6, 117.0, 107.4; HRMS calcd for C ₁₃ H ₁₁ O ₃ [M + H ] ⁺ : 215.0708, found: 215.0710.

  [Synthesis Example 2-23: Synthesis of phenyl 3,3-diphenyl acrylate (b3i)]

[Where nBuLi is n-butyllithium. ]
A 100 mL round bottom flask with a magnetic stir bar was dried and acetonitrile (615.8 mg, 15 mmol, 3.0 eq) and THF (10 mL) were added. The vessel was cooled to −78 ° C. and 1.6 M n-butyllithium (nBuLi) in hexane (9.38 mL, 15 mmol, 3.0 eq) was added slowly. After stirring for 1 hour, a THF solution (10 mL) of benzophenone (911 mg, 5.0 mmol) was added at −78 ° C., and then warmed to room temperature. After stirring for 90 minutes, the reaction mixture was quenched with saturated aqueous NH ₄ Cl. The aqueous phase was extracted 3 times with ethyl acetate (EtOAc) and the organic layer was washed with brine and dried over MgSO ₄ . After concentrating the filtrate, white solid SI-1 was obtained (1.11 g). This solid was used without further purification.

Pyridine (0.48 mL, 6.0 mmol, 1.2 eq) was added to the methylene chloride solution (10 mL) of SI-1 thus obtained, and the reaction mixture was cooled to 0 ° C. SOCl ₂ (0.40 mL, 5.5 mmol, 1.1 eq) was added dropwise to the reaction mixture over 10 minutes and stirred at room temperature for 3 hours. After the reaction was complete, ice-cold water (3 mL) and CH ₂ Cl ₂ (10 mL) were added. The organic layer was washed with dilute HCl, water, and saturated NaHCO ₃ . The organic layer was separated and dried over Na ₂ SO ₄ . After concentrating the filtrate, the desired product SI-2 was obtained as a liquid. This liquid was used without further purification.

To the resulting SI-2 in THF / H ₂ O (15 mL / 5 mL) was added KOH (2.80 g, 10 eq) and the vessel was heated to 90 ° C. After stirring for 2 days, THF was removed under reduced pressure and 1 M HCl was added at 0 ° C. to adjust the pH of the residue to 2. The reaction mixture was extracted 3 times with CH ₂ Cl ₂ and the organic layer was washed with saturated brine and dried over Na ₂ SO ₄ . The filtrate was concentrated to give the corresponding carboxylic acid SI-3 (787 mg). This product was used without further purification.

To a 100 mL round bottom flask containing the carboxylic acid SI-3 (787 mg, 3.5 mmol) thus obtained, phenol (363.2 mg, 3.86 mmol, 1.1 eq), 1- (3-dimethylaminopropyl) was added. ) -3-Ethylcarbodiimide hydrochloride (EDC · HCl: 740 mg, 3.86 mmol, 1.1 eq), N, N-dimethylaminopyridine (DMAP: 107 mg, 0.88 mmol, 0.25 eq), and CH ₂ Cl ₂ (10 mL) was added. After stirring for 12 hours, the reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted three times with CH ₂ Cl ₂ . The organic layer was washed with brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the residue was purified by recrystallization from hexanes to give phenyl 3,3-diphenyl acrylate (b3i) as a white solid (838.7 mg, 56% over 4 steps).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.43-7.35 (m, 8H), 7.34-7.27 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 7.3 Hz, 2H), 6.58 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 164.3, 158.7, 150.6, 140.6, 138.6, 129.8, 129.2, 128.5, 128.4, 128.0, 125.5, 121.5, 116.3; HRMS calcd for C ₂₁ H ₁₇ O ₂ [M + H] ⁺ : 301.1229, found: 301.1221.

Synthesis of nickel compound [Synthesis Example 3-1: Synthesis of Ni (dcype) (CO) ₂ catalyst]
In a glove box under an argon atmosphere, Ni (CO) ₂ (PPh ₃ ) ₂ (Ph is a phenyl group; 1.92 g, 3.0 mmol, 1.0 equivalent) and 1,2-bisdicyclohexylphosphinoethane (dcype; 1.39 g, 3.3 mmol, 1.1 eq) was added to the reaction vessel. The container was removed from the glove box and THF (9 mL) was added. The mixture was stirred at 40 ° C. for 2 hours. After cooling the mixture to room temperature, the mixture is concentrated and the residue is purified by recrystallization with THF and hexane, Ni (dcype) (CO) ₂ catalyst:

Was obtained as a white solid (1.55 g, 96%).
¹ H NMR (400 MHz, C ₆ D ₆ ): δ 1.95 (br, 2H), 1.92 (br, 2H), 1.72-1.59 (m, 20H), 1.36-1.13 (m, 24H); ¹³ C NMR ( 100 MHz, C ₆ D ₆ ): δ 205.0, 35.8 (t, JPC = 8.2 Hz), 29.3, 28.5, 27.6, 27.53, 27.47, 27.41, 26.7, 23.2 (t, JPC = 19.7 Hz); ³¹ P NMR ( 160 MHz, C ₆ D ₆ ): δ 64.0; IR (KBr): 1979, 1922, 1912 cm ^-1 ; anal calcd for C ₂₈ H ₅₀ O ₂ P ₂ Ni: C 62.35, H 9.34, found C 62.47, H 8.97.

[Synthesis Example 3-2: Synthesis of Ni Catalyst]
1,2-bisdicyclopentylphosphinoethane diborane (532 mg, 1.35 mmol) and morpholine (8.0 mL) were added to the reaction vessel in a glove box under an argon atmosphere. Thereafter, the mixture was stirred at 120 ° C. for 2 hours to obtain 1,2-bisdicyclopentylphosphinoethane (Cp-Taxy).

Next, Ni (CO) ₂ (PPh ₃ ) ₂ (Ph is a phenyl group; 591 mg, 1.23 mmol, 1.0 equivalent) was added to the reaction vessel (1.1 equivalents). The container was removed from the glove box and THF (20 mL) was added. The mixture was stirred at room temperature for 4 hours. The mixture is concentrated and the residue is purified by reprecipitation with cold acetone to give the desired Ni catalyst:

Was obtained as a white solid (334.2 mg, 56%).

  [Example 1-1: Synthesis of 2- (thiophen-2-yl) benzoxazole]

[Ni (cod) ₂ is bis (1,5-cyclooctadiene) nickel (0); dtype is 1,2-bisdicyclohexylphosphinoethane. ]
Put a K ₃ PO ₄ (170.0 mg, 0.80 mmol, 2.0 eq) into a 20 mL glass stirrer with a J. Young O ring tap, dry with a heat gun under reduced pressure, cool to room temperature, ₂ was filled. To this container, phenyl (b1b) thiophene-2-carboxylate (0.60 mmol, 1.5 equivalents) obtained in Synthesis Example 2-2 was added and placed in a glove box under an argon atmosphere. In this reaction vessel, bis (1,5-cyclooctadiene) nickel (0) (Ni (cod) ₂ ) (11.2 mg, 0.04 mmol, 10 mol%) and 1,2-bisdicyclohexylphosphinoethane (dtype) (33.8 mg, 0.08 mmol, 20 mol%) was added. The container was taken out from the glove Books, it was added benzoxazole (0.40 mmol) and dry 1,4-dioxane (1.5 mL) while blowing N _2. The vessel was sealed with an O-ring tap and heated with stirring at 150 ° C. for 24 hours in an 8-well reaction block. After the reaction mixture was cooled to room temperature, the mixture was filtered through a silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated and the residue was subjected to preparative thin layer chromatography (hexane / ethyl acetate (EtOAc) = 10: 1) to give the decarbonylated coupling product 2- (thiophen-2-yl) benzoxazole. Was obtained as a white solid (77.3 mg, 96%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.89 (dd, J = 3.8, 1.4 Hz, 1H), 7.76-7.70 (m, 1H), 7.56-7.50 (m, 2H), 7.36-7.29 (m, 2H), 7.16 (dd, J = 5.0, 3.8 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 159.1, 150.5, 142.1, 130.3, 130.0, 129.7, 128.3, 125.2, 124.8, 119.9, 110.5 HRMS (DART) m / z calcd for C ₁₁ H ₈ NOS [MH] ⁺ : 202.03266, found 202.03279.

  When the reaction time was changed to 12 hours, the yield was 76%.

Even when the nickel catalyst was changed to Ni (dcype) (CO) ₂ catalyst obtained in Synthesis Example 13 instead of Ni (cod) ₂ , it was obtained in a yield of 96%.

Furthermore, when the nickel catalyst was changed to NiCl ₂ instead of Ni (cod) ₂ and zinc (Zn) (0.80 mmol, 2.0 equivalents) was further used, the yield was 75%.

[Examples 1-2 to 1-10]
All the compounds shown in Table 5 below were obtained as a white solid by the same method as in Example 1-1 using various raw materials instead of phenyl thiophene-2-carboxylate (b1b) as a raw material.

  As for Example 1-2, when the Ni catalyst having a cyclopentyl group obtained in Synthesis Example 3-2 was used instead of dcype, the yield was further improved.

  For Example 1-3, the yield was 73% when the reaction time was changed to 12 hours.

For Examples 1-5, when various ligands were used instead of dcype, dcype had the highest yield, and tricyclohexylphosphine (PCy ₃ ) and trimethylphosphine (PMe ₃ ) had the next highest yield. It was rate. Also, tris (2,4,6-trimethoxyphenyl) phosphine, tris (2,6-dimethoxyphenyl) phosphine, 4,4′-dimethoxy-2,2′-bipyridine, 1,4-bis (dicyclohexylphosphino) ) Butane, 1,3-bis (diphenylphosphino) propane (dppp), 1,4-bis (diphenylphosphino) butane (dppb), 1,5-bis (diphenylphosphino) pentane (dpppn), 1, When 6-bis (diphenylphosphino) hexane (dpphe) was used, the reaction proceeded although the yield was low.

For Examples 1-5, the _base was using various ligands in place of _{K 3 PO 4, K 3 PO} 4 is most _{yield, Cs 2 CO 3, K 2} CO 3, Na ₂ CO ₃ and triethylamine (NEt ₃ ) were next in high yield, followed by Li ₂ CO ₃ , potassium acetate (KOAc) and diazabicycloundecene.

  For Example 1-5, when various solvents were used instead of 1,4-dioxane as the solvent, 1,4-dioxane had the highest yield, and toluene, m-xylene, dimethylacetamide, acetonitrile And dimethyl sulfoxide were next in high yield, and tert-butyl alcohol was next in high yield. When N-methylpyrrolidone was used, the reaction proceeded although the yield was low.

For Example 1-5, the content (and content ratio) of the Ni (cod) ₂ catalyst and the dcype ligand was variously changed.
Ni (cod) ₂ catalyst: 40 mol% dcype ligand: 80 mol% (1: 2)
Is the highest yield,
Ni (cod) ₂ catalyst: 20 mol% dcype ligand: 40 mol% (1: 2)
Is the next highest yield,
Ni (cod) ₂ catalyst: 10 mol% dcype ligand: 20 mol% (1: 2)
Is the next highest yield,
Ni (cod) ₂ catalyst: 10 mol% dcype ligand: 10 mol% (1: 1)
Ni (cod) ₂ catalyst: 10 mol% dcype ligand: 30 mol% (1: 3)
Was the next highest yield.

  About Example 1-5, when reaction temperature was variously changed, it was a high yield in order of 150 degreeC, 180 degreeC, and 120 degreeC.

  In Example 1-5, the yield was 70% without changing the reaction time to 24 hours.

The spectral data of each compound was as follows.
Compound (1b): 2- (thiophen-3-yl) benzoxazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (dd, J = 2.6, 1.0 Hz, 1H), 7.79 (dd, J = 5.0, 1.0 Hz, 1H), 7.77-7.71 (m, 1H), 7.58 -7.50 (m, 1H), 7.48-7.42 (m, 1H), 7.38-7.32 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 159.8, 150.4, 142.0, 129.4, 128.2, 127.1, 126.7, 125.1, 124.7, 120.0, 110.6; HRMS (DART) m / z calcd for C ₁₁ H ₈ NOS [MH] ⁺ : 202.03266, found 202.03249.
Compound (1c): 2- (furan-2-yl) benzoxazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82-7.73 (m, 1H), 7.72-7.65 (m, 1H), 7.62-7.55 (m, 1H), 7.43-7.34 (m, 2H), 7.28 ( d, J = 3.6 Hz, 1H), 6.62 (dd, J = 3.6, 2.0 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 155.4, 150.2, 145.8, 142.7, 141.7, 125.4, 124.9, 120.2, 114.4, 112.4, 110.7; HRMS (DART) m / z calcd for C ₁₁ H ₈ NO ₂ [MH] ⁺ : 186.05550, found 186.05563.
Compound (1d): 2- (furan-3-yl) benzoxazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.22 (d, J = 0.8 Hz, 1H), 7.74-7.68 (m, 1H), 7.56-7.48 (m, 2H), 7.35-7.28 (m, 2H) , 7.03 (d, J = 1.6 Hz, 1H); ¹³ C NMR (100 MHz, CDCl3): δ 158.4, 150.3, 144.5, 144.4, 141.9, 125.0, 124.6, 119.8, 115.5, 110.5, 109.0; HRMS (DART) m / z calcd for C ₁₁ H ₈ NO ₂ [MH] ⁺ : 186.05550, found 186.05544.
Compound (1e): 2- (pyridin-3-yl) benzoxazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.45 (d, J = 1.6 Hz, 1H), 8.74 (dd, J = 5.0, 1.4 Hz 1H), 8.51-8.45 (m, 1H), 7.83-7.72 ( m, 1H), 7.61-7.55 (m, 1H), 7.47 (dd, J = 8.2, 5.0 Hz, 1H), 7.40-7.34 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 160.8 , 152.2, 150.9, 148.9, 141.9, 134.8, 125.8, 125.0, 123.8, 123.6, 120.4, 110.9; HRMS (DART) m / z calcd for C ₁₂ H ₉ N ₂ O [MH] ⁺ : 197.07149, found 197.07148.
Compound (1f): 2- (pyridin-4-yl) benzoxazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.81 (dd, J = 4.4, 1.6 Hz, 2H), 8.06 (dd, J = 4.6, 1.8 Hz, 2H), 7.87-7.78 (m, 1H), 7.65 -7.58 (m, 1H), 7.48-7.38 (m, 2H); ¹³ C NMR (100 MHz, CDCl3): δ 160.6, 150.9, 150.8, 141.8, 134.3, 126.4, 125.2, 121.0, 120.7, 111.0; HRMS ( DART) m / z calcd for C ₁₂ H ₉ N ₂ O [MH] ⁺ : 197.07149, found 197.07132.
Compound (1 g): 2- (pyridin-2-yl) benzoxazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.82 (d, J = 4.4 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.95-7.80 (m, 2H), 7.67 (d, J = 7.2 Hz, 1H), 7.60-7.35 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 161.5, 151.1, 150.4, 146.2, 141.9, 137.2, 126.1, 125.6, 125.0, 123.5, 120.7, 111.3; HRMS (DART) m / z calcd for C ₁₂ H ₉ N ₂ O [MH] ⁺ : 197.07149, found 197.07148.
Compound (1h): 2- (pyrazin-2-yl) benzoxazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.58 (d, J = 1.2 Hz, 1H), 8.82-8.68 (m, 2H), 7.86 (dd, J = 6.6, 2.2 Hz, 1H), 7.68 (dd , J = 7.0, 1.8 Hz, 1H), 7.48-7.38 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 159.4, 151.0, 146.2, 144.71, 144.65, 142.0, 141.6, 126.7, 125.3, 121.0, 111.3; HRMS (DART) m / z calcd for C ₁₁ H ₈ N ₃ O [MH] ⁺ : 198.06674, found 198.06687.
Compound (1i): 2- (2-phenylquinolin-4-yl) benzoxazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.44 (d, J = 8.8 Hz, 1H), 8.73 (s, 1H), 8.28 (t, J = 7.2 Hz, 1H), 7.94-7.92 (m, 1H ), 7.82 (t, J = 7.2 Hz, 1H), 7.74-7.70 (m, 2H), 7.58 (t, J = 7.6 Hz, 2H), 7.53-7.44 (m, 3H); ¹³ C NMR (100 MHz , CDCl3): δ 161.0, 156.9, 150.4, 149.5, 142.2, 139.1, 131.9, 130.6, 130.2, 129.9, 129.1, 128.1, 127.7, 126.5, 126.3, 125.2, 123.7, 121.0, 119.6, 111.0; HRMS (DART) m / z calcd for C ₂₂ H ₁₅ N ₂ O [MH] ⁺ : 323.11844, found 323.11834.

Compound (1j): 2- (2-Phenylthiazol-4-yl) benzoxazole ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.22-8.21 (m, 1H), 8.11-8.09 (m, 2H), 7.84 -7.82 (m, 1H), 7.64-7.62 (m, 1H), 7.48-7.47 (m, 3H), 7.40-7.37 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.0, 158.4 , 150.6, 144.5, 141.9, 132.8, 130.9, 129.1, 127.2, 125.7, 125.0, 122.3, 120.6, 111.0; HRMS (DART) m / z calcd for C ₁₆ H ₁₁ N ₂ OS [MH] ⁺ : 279.05921, found 279.05907 .

[Examples 1-11 to 1-13]
All the compounds shown in Table 6 below were obtained as white solids in the same manner as in Example 1-5 using various raw materials instead of benzoxazole.

The spectral data of each compound was as follows.

Compound (1k): 5-phenyl-2- (pyridin-3-yl) oxazole ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.35 (d, J = 1.2 Hz, 1H), 8.70 (dd, J = 5.0 , 1.4 Hz, 1H), 8.40-8.32 (m, 1H), 7.78-7.70 (m, 2H), 7.51-7.35 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 158.9, 152.2, 151.1, 147.7, 133.5, 129.2, 129.0, 127.7, 124.5, 123.8, 123.8, 123.7; HRMS (DART) m / z calcd for C ₁₄ H ₁₁ N ₂ O [MH] ⁺ : 223.08715, found 223.08715.
Compound (1l): 5-phenyl-2- (pyridin-3-yl) thiazole
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.18 (d, J = 1.6 Hz, 1H), 8.66-8.62 (m, 1H), 8.25-8.19 (m, 1H), 8.05 (s, 1H), 7.61 -7.56 (m, 2H), 7.44-7.31 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 163.5, 150.7, 147.6, 140.3, 139.5, 133.3, 130.9, 129.7, 129.2, 128.7, 126.8 , 123.8; HRMS (DART) m / z calcd for C ₁₄ H ₁₁ N ₂ S [MH] ⁺ : 239.06429, found 239.06437.
Compound (1m): 3- (2- [2- ¹³ C] benzoxazolyl) pyridine
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.49 (t, J = 1.8 Hz, 1H), 8.78 (dd, J = 4.8, 0.8 Hz, 1H), 8.55-8.49 (m, 1H), 7.88-7.84 (m, 1H), 7.65-7.59 (m, 1H), 7.48 (dd, J = 8.2, 5.0 Hz, 1H), 7.44-7.37 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 160.7, 152.1, 150.8 (JCC = 3.8 Hz), 148.9 (JCC = 2.8 Hz), 141.9 (JCC = 1.9 Hz), 134.8, 125.8, 125.0, 123.7 (JCC = 4.8 Hz), 123.4 (JCC = 52.2 Hz), 120.4 (JCC = 7.7 Hz), 110.8 (JCC = 3.9 Hz); HRMS (DART) m / z calcd for C ₁₁ ¹³ CH ₉ N ₂ O [MH] ⁺ : 198.07484, found 198.07500.

[Example 1-14]
Similar to the above example,

[R is a substituent; Ni (cod) ₂ is bis (1,5-cyclooctadiene) nickel (0); dtype is 1,2-bisdicyclohexylphosphinoethane. ]
The reaction was performed.

As a result, the yield is
R = phenyl group: 82%
R = o-tolyl group: 76%
R = m-tolyl group: 76%
R = p-tolyl group: 68%
R = 3,5-xylyl group: 46%
R = 2,4-xylyl group: 25%
R = 3,4,5-trimethylphenyl group: 57%
R = 2-methoxyphenyl group: 81%
R = 3-methoxyphenyl group: 91%
R = 3,5-dimethoxyphenyl group: 86%
R = 4-fluorophenyl group: 96%
R = 4-trifluoromethylphenyl group: 35%
R = 4-formylphenyl group: 6%
R = 4- (methoxycarbonyl) phenyl group: 39%
R = 4-acetamidophenyl group: 41%
Met.

[Example 1-15: Synthesis of Muscolide A]
<First step: Phenyl ester 8>

Round-bottomed flask 100 mL, the above reaction formula of methyl ester 11 (2.17 g, 7.0 mmol) were charged, there THF (20 mL), and _{LiOH · H 2 O (590.0 mg} , 2.0 equiv) was added. After stirring at room temperature for 1 hour, THF was removed in vacuo. At 0 ° C., the pH of the residue was adjusted to 2 by adding 1M HCl. The reaction mixture was then extracted in CH ₂ Cl ₂ (3 × 30 mL) and the organic layer was dried over Na ₂ SO ₄ and filtered. After concentrating the mixture, oxazole carboxylic acid 12 was obtained. This product was used without purification.

To a 100 mL round bottom flask containing oxazole carboxylic acid 12, phenol (0.724 g, 1.1 eq), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC · HCl: 1.48 g, 1.1 eq) , N, N- dimethylaminopyridine (DMAP: 0.214 g, 0.25 eq) and CH ₂ Cl was added ₂ (60 mL). After stirring for 9 hours, the reaction mixture was quenched with saturated aqueous NaHCO ₃ solution. And extracted with CH ₂ Cl ₂ (3 × 30 mL). The organic layer was dried over Na ₂ SO ₄ and filtered. After evaporating the solvent under reduced pressure, the residue was purified by flash column chromatography (hexane / ethyl acetate (EtOAc) = 3: 1 to 2: 1) and phenyl ester 8 (2.18 g, 84 steps total, 84 steps). %) As a colorless viscous oil.
¹ H NMR (600 MHz, DMSO-d ⁶ , 373 K): δ 7.46 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 2H), 4.88 (dd, J = 7.6, 3.5 Hz, 1H), 3.52-3.41 (m, 2H), 2.64 (s, 3H), 2.37-2.26 (m, 1H), 2.10-1.97 (m, 2H) , 1.96-1.88 (m, 1H), 1.35 (s, 9H); ¹³ C NMR (150 MHz, DMSO-d ⁶ , 373 K): δ 162.6, 159.5, 156.3, 152.8, 149.8, 128.9, 126.0, 125.3, 121.1, 78.6, 53.7, 45.8, 30.9, 27.5, 22.8, 11.3; HRMS (DART) m / z calcd for C ₂₀ H ₂₅ N ₂ O ₅ [MH] ⁺ : 373.17635, found 373.17613. [Α] _D ²⁰ =- 62 (c = 1.0, CHCl ₃ ).

  <Second Step: Methyl 5-methyloxazolecarboxylate 7>

DBU (1,8-diazabicyclo [5.4.0] -7-ene, 4.24 g, 1.1 eq) was added to 25 mL of a THF solution of methyl 2-isocyanoacetic acid (2.41 g, 25 mmol). The reaction mixture was cooled to 0 ° C. and a solution of acetic anhydride (2.81 g, 1.1 eq) was added slowly. The temperature was raised to room temperature, and the reaction mixture was stirred. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated in vacuo. To this vessel was further added 30 ml of ethyl acetate (EtOAc) and 20 ml of water. The aqueous layer was extracted with ethyl acetate (EtOAc; 20 mL × 3), and the organic layer was treated with Na ₂ SO ₄ and then filtered. After evaporating the solvent under reduced pressure, the crude residue was purified by flash column chromatography (hexane / ethyl acetate (EtOAc) = 2: 1) to give the desired product 7 as a white solid (3.20 g, yield). 93%).

  <Third step: Methyl ester 9>

A 20 mL glass container equipped with a J. Young O ring tap with a magnetic stir bar was cooled to room temperature, dried with a heat gun under reduced pressure, and filled with nitrogen. To this vessel was added a CH ₂ Cl ₂ solution of phenyl ester 8 (111.7 mg, 0.30 mmol) obtained in the first step. After concentration in vacuo, oxazole 7 obtained in the second step (63.5 mg, 1.5 equivalents) was added and placed in a glove box under an argon atmosphere. In a glove box, Ni (cod) ₂ (16.5 mg, 0.06 mmol, 20 mol%), 1,2-bis (dicyclohexylphosphino) ethane (dcype; 50.7 mg, 0.12 mmol, 40 mol%), and K ₃ PO ₄ (127.3 mg, 2.0 eq) was added. The container was taken out from the glove box, and 1,4-dioxane (1.2 mL) was added under a nitrogen stream. The vessel was sealed with an O-ring tap and then heated at 165 ° C. for 2 hours in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, the mixture was filtered through a silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated, and the residue was subjected to preparative thin layer chromatography (hexane / ethyl acetate (EtOAc) = 3: 2) to give methyl ester 9 as a coupling product as a colorless viscous oil (45.7 mg). , 39%).
¹ H NMR (600 MHz, DMSO-d ⁶ , 373 K): δ 4.86 (dd, J = 7.2, 3.0 Hz, 1H), 3.85 (s, 3H), 3.53-3.40 (m, 2H), 2.64 (s , 3H), 2.61 (s, 3H), 2.35-2.26 (m, 1H), 2.08-1.97 (m, 2H), 1.96-1.88 (m, 1H), 1.32 (s, 9H); ¹³ C NMR (150 (MHz, DMSO-d ⁶ , 373 K): δ 163.3, 161.4, 155.0, 153.0, 152.7, 149.2, 127.3, 123.5, 78.5, 53.7, 50.8, 45.8, 30.9, 27.5, 22.8, 11.0, 10.5; HRMS (DART) m / z calcd for C ₁₉ H ₂₅ N ₃ O ₆ [MH] ⁺ : 392.18216, found 392.18213. [α] _D ²¹ = -53 (c = 1.1, CHCl ₃ ).

<4th step: Muscolide A>
Muscolide A was synthesized from methyl ester 9 according to the synthesis method developed by Wipf (Wipf, P .; Venkatraman, SJ Org. Chem. 1996, 61, 6517-6522). Muscolide A was obtained as a colorless viscous oil. Rf = 0.42 (hexane / EtOAc = 1: 1).
¹ H NMR (600 MHz, d ⁶ -DMSO, 373 K): δ 5.43 (t, J = 6.9 Hz, 1H), 4.89-4.84 (m, 1H), 4.78 (d, J = 6.9 Hz, 2H), 3.45 (m, 2H), 2.63 (s, 3H), 2.61 (s, 3H), 2.35-2.26 (m, 1H), 2.08-1.96 (m, 2H), 1.95-1.88 (m, 1H), 1.77 ( s, 3H), 1.75 (s, 3H), 1.32 (s, 9H); ¹³ C NMR (150 MHz, d ⁶ -DMSO, 373 K): δ 162.3, 160.9, 155.0, 153.0, 152.7, 149.2, 138.0, 127.5, 123.6, 118.2, 78.5, 60.5, 53.7, 45.8, 31.0, 27.5, 24.7, 22.8, 17.3, 11.1, 10.6; ¹ H NMR (600 MHz, CDCl ₃ , 333 K): δ 5.46 (t, J = 7.6 Hz, 1H), 5.00-4.86 (br, 1H), 4.82 (d, J = 6.9 Hz, 2H), 3.66-3.41 (br, 2H), 2.662 (s, 3H), 2.657 (s, 3H), 2.36 -2.19 (br, 1H), 2.18-2.01 (m, 2H), 1.96-1.88 (m, 1H), 1.77 (s, 3H), 1.76 (s, 3H), 1.33 (s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ , 333 K): δ 164.0, 162.3, 155.5, 154.2, 150.0, 138.9, 128.8, 124.8, 118.8, 80.0, 61.8, 54.8, 46.6, 32.4, 28.3, 25.6, 23.9, 19.0, 17.1, 12.1, 11.7; HRMS (DART) m / z calcd for C ₂₃ H ₃₁ N ₃ O ₆ [MH] ⁺ : 446.22911, found 446.22896. [Α] _D ²¹ = -49 (c = 0.95, CHCl ₃ ).

  [Examples 2-1 to 2-13]

[Wherein, R COt-Bu (t-Bu is tert- butyl group), or CON _{(CH 3) 2.} ]
Coupling reactions were performed using various raw materials (various compounds (A) and (B2)). The common conditions are described below.

Put a magnetic stir bar and K ₃ PO ₄ (169.7 mg, 0.80 mmol, 2.0 eq) in a 20 mL glass container equipped with a J. Young O ring tap, dry with a heat gun under reduced pressure, cool to room temperature, and then add nitrogen. Filled with gas. The compound (B2) shown in Tables 7 and 8 (0.60 mmol, 1.5 equivalent in terms of the amount of E form) was added to this container and introduced into a glove box under an argon atmosphere. In the reaction vessel, bis (1,5-cyclooctadiene) nickel (0) (Ni (cod) ₂ ) (11.2 mg, 0.04 mmol, 10 mol%), 1,2-bis (dicyclohexylphosphino) ethane (dcype) (33.8 mg, 0.08 mmol, 20 mol%) was added. The container was taken out of the glove box, and compound (A) (0.40 mmol) and 1,4-dioxane (1.5 mL) shown in Tables 7 and 8 were added under a N ₂ stream. The container was sealed with an O-ring tap and then heated and stirred at 130 to 135 ° C. for 36 hours in an 8-well reaction block. After the reaction mixture was cooled to room temperature, the mixture was filtered through a silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (PTLC) to obtain the desired product (CH / CO coupling product) shown in Table 7.

  The results are shown in Tables 7 and 8.

The spectral data of each compound was as follows.
Compound (2a): (E) 2- (2-phenylethenyl) -benzoxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.81 (d, J = 16.5 Hz, 1H), 7.75-7.69 (m, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.56-7.50 (m, 1H), 7.46-7.38 (m, 3H ), 7.36-7.31 (m, 2H), 7.09 (d, J = 16.5 Hz, 1H); 13C NMR (CDCl 3, 100 MHz) δ 162.8, 150.4, 142.2, 139.5 , 135.1, 129.8, 129.0, 127.6, 125.2, 124.5, 119.9, 114.0, 110.3; HRMS calcd for C ₁₅ H ₁₂ NO [M + H] ⁺ : 222.0919, found: 222.0917.
Compound (2b): (E) 5-methyl-2-styrylbenzoxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.77 (d, J = 16.7 Hz, 1H), 7.60 (d, J = 6.9 Hz, 2H), 7.50 (s, 1H), 7.46-7.35 (m, 4H) , 7.15 (dd, J = 8.5, 1.6 Hz, 1H), 7.07 (d, J
= 16.7 Hz, 1H), 2.48 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.8, 148.6, 142.3, 139.0, 135.1, 134.3, 129.6, 128.9, 127.4, 126.3, 119.7, 114.0, 109.6 , 21.4; HRMS calcd for C ₁₆ H ₁₄ NO [M + H] ⁺ : 236.1075, found: 236.1075.
Compound (2c): (E) 5-methoxy-2- (2-phenylethenyl) benzoxazole (yellow solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.76 (d, J = 16.5 Hz), 7.59 (d, J = 8.4 Hz, 2H), 7.43-7.39 (m, 4H), 7.19 (d, J = 2.5 Hz , 1H), 7.05 (d, J = 16.5 Hz, 1H), 6.93 (dd, J = 8.9, 2.5 Hz, 1H), 3.86 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ163.6 , 157.3, 145.0, 143.0, 139.1, 135.2, 129.7, 128.9, 127.5, 114.0, 113.8, 110.4, 102.7, 55.9; HRMS calcd for C ₁₆ H ₁₄ NO ₂ [M + H] ⁺ : 252.1025, found: 252.1024.
Compound (2d): (E) 5- (tert-butyl) -2- (2-phenylethenyl) benzoxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.77 (d, J = 16.5 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 6.8 Hz, 2H), 7.46-7.39 (m, 5H), 7.07 (d, J = 16.5 Hz, 1H), 1.39 (s, 9H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.9, 148.4, 148.0, 142.1, 138.9, 135.2, 129.6, 128.9, 127.4, 122.9, 116.3, 114.1, 109.4, 34.8, 31.7; HRMS calcd for C ₁₉ H ₂₀ NO [M + H] ⁺ : 278.1545, found: 278.1541.
Compound (2e): (E) 5-methyl-2-styryloxazole-4-carboxylate (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.53 (d, J = 16.7 Hz, 1H), 7.51 (d, J = 6.9 Hz, 2H), 7.41-7.34 (m, 3H), 6.89 (d, J = 16.7 Hz, 1H), 3.93 (s, 3H), 2.68 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.7, 159.3, 156.0, 137.0, 135.1, 129.4, 128.9, 128.4, 127.2, 113.0 , 51.9, 12.0; HRMS calcd for C ₁₄ H ₁₄ NO ₃ [M + H] ⁺ : 244.0974, found: 244.0970.
Compound (2f): 2- (3,4-dihydronaphthalen-2-yl) benzoxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.38 (s, 1H), 7.23-7.13 (m, 4H), 3.93 (s, 3H), 2.93-2.91 (m, 2H), 2.89-2.82 (m, 2H ), 2.68 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.7, 160.0, 156.1, 135.8, 129.6, 128.5, 127.5, 126.6, 51.8, 27.2, 22.7,
12.0; HRMS calcd for C ₁₆ H ₁₆ NO ₃ [M + H] ⁺ : 270.1130, found: 270.1133.
Compound (2g): 2- (3,4-dihydronaphthalen-2-yl) -5-methyloxazole-4-carboxylate (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.38 (s, 1H), 7.23-7.13 (m, 4H), 3.93 (s, 3H), 2.93-2.91 (m, 2H), 2.89-2.82 (m, 2H ), 2.68 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.7, 160.0, 156.1, 135.8, 129.6, 128.5, 127.5, 126.6, 51.8, 27.2, 22.7, 12.0; HRMS calcd for C ₁₆ H ₁₆ NO ₃ [M + H] ⁺ : 270.1130, found: 270.1133.

  In Example 2-1, synthesis was carried out in the same manner except that the base shown in Table 9 was used and the reaction temperature was 130 ° C. and the reaction time was 12 hours. The following results were obtained. .

  [Examples 2-14 to 2-31]

[Wherein Ph is a phenyl group. ]
The coupling reaction was performed using various raw materials (various compounds (A) and (B3)). The common conditions are described below.

Put a magnetic stir bar and K ₃ PO ₄ (170.0 mg, 0.80 mmol, 2.0 eq) in a 20 mL glass container equipped with a J. Young O ring tap, dry with a heat gun under reduced pressure, cool to room temperature, and then add nitrogen. Filled with gas. The compound (B3) shown in Tables 10 to 11 (0.60 mmol, 1.5 equivalent in terms of the amount of E form) was added to this container and introduced into a glove box under an argon atmosphere. In the reaction vessel, bis (1,5-cyclooctadiene) nickel (0) (Ni (cod) ₂ ) (11.2 mg, 0.04 mmol, 10 mol%), 1,2-bis (dicyclohexylphosphino) ethane (dcype) (33.8 mg, 0.08 mmol, 20 mol%) was added. The container was taken out of the glove box, and the compound (A) (0.40 mmol) shown in Tables 10 to 11 and 1,4-dioxane (1.5 mL) were added under a N ₂ stream. The container was sealed with an O-ring tap and then heated and stirred at 150 ° C. for 24 hours in an 8-well reaction block. After the reaction mixture was cooled to room temperature, the mixture was filtered through a silica gel pad with ethyl acetate (EtOAc). The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (PTLC) to obtain the desired product (CH coupling product) shown in Table 9.

  The results are shown in Tables 10-11.

The spectral data of each compound was as follows.
Compound (2h): (E) 5-phenyl-2- (2-phenylethenyl) oxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.71 (d, J = 7.3 Hz, 2H), 7.61-7.54 (m, 3H), 7.46-7.32 (m, 7H), 7.00 (d, J = 16.5 Hz, ¹³ C NMR (CDCl ₃ , 100 MHz) δ 161.1, 150.9, 135.8, 135.6, 129.1, 128.91, 128.87, 128.4, 127.9, 127.2, 124.2, 123.7, 113.9; HRMS calcd for C ₁₇ H ₁₄ NO (M + H] ⁺ : 248.1075, found: 248.1074.
Compound (2i): (E) 5- (4-methoxyphenyl) -2- (2-phenylethenyl) oxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.64 (d, J = 8.9 Hz, 2H), 7.60-7.48 (m, 3H), 7.40 (t, J = 7.8 Hz, 2H), 7.37-7.32 (m, 1H), 7.29 (s, 1H), 6.99 (d, J = 15.8 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz ) δ 160.5, 159.8, 151.0, 135.7, 135.2, 129.0, 128.9, 127.1, 125.8, 122.2, 120.8, 114.4, 114.0, 55.4; HRMS calcd for C ₁₈ H ₁₆ NO ₂ [M + H] ⁺ : 278.1181, found: 278.1185.
Compound (2j): (E) 5- (1,3-benzodioxol-5-yl) -2- (2-phenylethenyl) oxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.56-7.51 (m, 3H), 7.39 (t, J = 7.9 Hz, 2H), 7.34-7.31 (m, 1H), 7.27 (s, 1H), 7.21 ( dd, J = 8.0, 1.6 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 6.97 (d, J = 16.7 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.00 ( s, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 160.6, 150.8, 148.2, 147.9, 135.6, 135.5, 129.1, 128.9, 127.1, 122.6, 122.1, 118.4, 113.9, 108.9, 104.8, 101.4; HRMS calcd
for C ₁₈ H ₁₄ NO ₃ [M + H] ⁺ : 292.0974, found: 292.0972.
Compound (2k): (E) 2- [2- (4-methoxyphenyl) ethenyl] benzoxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.75 (d, J = 16.5 Hz, 1H), 7.71-7.68 (m, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.52-7.50 (m, 1H), 7.34-7.30 (m, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 16.5 Hz, 1H), 3.84 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 163.2, 161.0, 150.4, 142.3, 139.1, 129.1, 127.9, 124.9, 124.4, 119.6, 114.4, 111.5, 110.2, 55.4; HRMS calcd for C ₁₆ H ₁₄ NO ₂ [M + H] ⁺ : 252.1025, found: 252.1023.
Compound (2l): (E) 2- [2- (3,4-dimethoxyphenyl) ethenyl] benzoxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.69 (d, J = 16.5 Hz, 1H), 7.70-7.65 (m, 2H), 7.51-7.46 (m, 2H), 7.33-7.25 (m, 2H), 7.13 (dd, J = 8.4, 2.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 16.5 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.9, 150.5, 150.2, 149.1, 142.1, 139.1, 128.0, 124.8, 124.2, 121.7, 119.5, 111.5, 111.0 , 110.0, 109.0, 55.8, 55.7; HRMS calcd for C ₁₇ H ₁₆ NO ₃ [M + H] +: 282.1130, found: 282.1131.
Compound (2m): (E) 2- [2- (2-methylphenyl) ethenyl] benzoxazole (brown solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.05 (d, J = 16.2 Hz, 1H), 7.76-7.70 (m, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.57-7.50 (m, 1H), 7.37-7.20 (m, 5H), 7.00 (d, J = 16.2 Hz, 1H), 2.51 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.9, 150.4, 142.2, 137.1, 137.0, 134.0, 130.8, 129.5, 126.4, 125.8, 125.2, 124.5, 119.8, 114.9, 110.3, 19.9; HRMS calcd for C ₁₆ H ₁₄ NO [M + H] ⁺ : 236.1075, found: 236.1070.
Compound (2n): (E) 2- [2- (2-thienyl) ethenyl] benzoxazole (yellow solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.89 (d, J = 16.2 Hz, 1H), 7.71-7.69 (m, 1H), 7.52-7.50 (m, 1H), 7.38 (d, J = 5.0 Hz, 1H), 7.35-7.23 (m, 2H), 7.28 (d, J = 3.6 Hz, 1H), 7.08 (dd, J = 5.0, 3.6 Hz, 1H), 6.87 (d, J = 16.2 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.5, 150.4, 142.2, 140.5, 132.0, 129.6, 128.1, 127.7, 125.1, 124.5, 119.8, 112.9, 110.2; HRMS calcd for C ₁₃ H ₁₀ NOS [M + H] ⁺ : 228.0483, found: 228.0484.
Compound (2o): (E) 2- [2- (3-furyl) ethenyl] benzoxazole (yellow solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.71-7.64 (m, 3H), 7.52-7.48 (m, 1H), 7.47 (s, 1H), 7.34-7.30 (m, 2H), 6.78 (d, J = 16.2 Hz, 1H), 6.69 (d, J = 1.8 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.7, 150.3, 144.4, 143.6, 142.1, 129.4, 125.0, 124.4, 123.3, 119.8, 113.7, 110.2, 107.2; HRMS calcd for C ₁₃ H ₁₀ NO ₂ [M + H] ⁺ : 212.0712, found: 212.0712.
Compound (2p): (E) 2- (2,2-diphenyl) ethenylbenzoxazole (white solid)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.64 (d, J = 7.3 Hz, 1H), 7.42-7.16 (m, 13H), 7.04 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.3, 152.4, 150.1, 141.7, 141.3, 139.0 129.9, 129.2, 128.4, 128.3, 128.2, 128.0, 125.0, 124.3, 119.8, 113.1, 110.3; HRMS calcd for C ₂₁ H ₁₆ NO [M + H] ⁺ : 298.1232, found: 298.1231.
Compound (2q): (E) 2- (prop-1-en-1-yl) benzoxazole (colorless oil)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.70-7.64 (m, 1H), 7.50-7.44 (m, 1H), 7.32-7.27 (m, 2H), 7.04 (dq, J = 16.0, 7.1 Hz, 1H ), 6.46 (dq, J = 16.0, 1.8 Hz, 1H), 2.01 (dq, J = 7.1, 1.8 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.4, 150.2, 141.9, 139.1, 124.8 , 124.2, 119.7, 118.2, 110.2, 18.7; HRMS calcd for C ₁₀ H ₁₀ NO [M + H] ⁺ : 160.0762, found: 160.0764.
Compound (2r): (E) 2- (but-1-en-1-yl) benzoxazole (colorless oil)
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.70-7.64 (m, 1H), 7.50-7.45 (m, 1H), 7.32-7.27 (m, 2H), 7.09 (dt, J = 16.3, 6.9 Hz, 1H ), 6.44 (dt, J = 16.3, 1.6 Hz, 1H), 2.41-2.31 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 162.7, 150.2, 145.5, 141.9, 124.8, 124.3, 119.7, 115.9, 110.2, 26.0, 12.5; HRMS calcd for C ₁₁ H ₁₂ NO [M + H] ⁺ : 174.0919, found: 174.0917.

  In Example 2-14, synthesis was carried out in the same manner except that the ligands shown in Table 12 were used. The following results were obtained.

  In Example 2-14, when the synthesis was performed in the same manner except that the ligand obtained in Synthesis Example 3-2 was used, a higher yield than that in the case of dtype was obtained.

[Example 2-32: Synthesis of intermediate of siphonazole B]
<First Step: Synthesis of 4-[(benzyloxy) methyl] -5-methyloxazole>

[Wherein Me is a methyl group; DBU is 1,8-diazabicyclo [5.4.0] -7-ene; THF is tetrahydrofuran; DIBAL-H is diisobutylaluminum hydride; PMB is a p-methoxybenzyl group. . ]
A magnetic stir bar was placed in a 50 mL round bottom flask and methyl isocyanoacetate (2.82 g, 28.4 mmol) and THF (30 mL) were added. To this reaction mixture was added 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU: 4.74 mL, 31.3 mmol, 1.1 eq). The reaction mixture was cooled to 0 ° C. with an ice-salt mixture and then acetic anhydride (2.96 mL, 31.2 mmol, 1.1 eq) was added. After stirring at room temperature for 19 hours, the reaction mixture was quenched with water, extracted six times with ethyl acetate (EtOAc), and the organic layer was washed with saturated brine and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (hexane / ethyl acetate (EtOAc) = 2: 1-1: 1) to give 5-methyloxazole-4-carboxylate ( 1E) was obtained as a white solid (3.54 g, 88%).

Containing a magnetic stir bar in a two-neck round-bottom flask 100 mL, 5-methyloxazole-4-carboxylate (1E: 1.41 g, 10 mmol ), and was was added CH ₂ Cl ₂ (20 mL). The reaction mixture was cooled to 0 ° C. with an ice-salt mixture and then 0.97 M diisobutylaluminum hydride (DIBAL-H) in hexane (24 mL, 23.3 mmol, 2.3 eq) was added slowly. After stirring for 30 minutes, the reaction mixture was quenched with methanol and Na ₂ SO ₄ .10H ₂ O (19 g, 60 mmol, 6.0 eq) and extracted with ethyl acetate (EtOAc). The mixture was stirred for 30 minutes, then filtered and washed with ethyl acetate (EtOAc). The filtrate was concentrated to give (5-methyloxazol-4-yl) methanol (979 mg, 87%). This product was used without further purification.

A round bottom flask was charged with tetrahydrofuran (THF) (5 mL) and NaH in 60% mineral oil dispersion (164 mg, 4.1 mmol, 1.5 eq), and further obtained (5-methyloxazol-4-yl) methanol. (309.6 mg, 2.73 mmol) was added. After stirring for 1 hour, p-methoxybenzyl chloride (513.0 mg, 3.3 mmol, 1.2 eq) and NaI strips were added. After stirring for 6 hours, the mixture was quenched with saturated aqueous NaHCO _{3 and} extracted three times with diethyl ether (Et ₂ O). The organic layer was washed with saturated brine and dried over MgSO ₄ . After concentrating the filtrate, the residue was purified by flash column chromatography using silica gel (hexane / ethyl acetate (EtOAc) = 4: 1-3: 1) to give 4-[(benzyloxy) methyl] -5- Methyl oxazole (1J) was obtained as a yellow liquid (469 mg, 73%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.73 (s, 1H), 7.28 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.53 (s, 2H), 4.40 (s, 2H), 3.81, (s, 3H), 2.31 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 159.2, 149.1, 146.8, 131.4, 130.1, 129.5, 113.8, 72.0, 63.0, 55.3, 10.1; HRMS calcd for C ₁₃ H ₁₆ NO ₃ [M + H] ⁺ : 234.1130, found: 234.1126.

  <Second Step: (E) Synthesis of 3,4-dimethoxystyryldimethylcarbamate>

[Wherein, Me is a methyl group; Ph is a phenyl group; THF is tetrahydrofuran; Et is an ethyl group; DMAP is N, N-dimethylaminopyridine] ]
To a THF solution (90 mL) of (methoxymethyl) triphenylphosphonium chloride (15.4 g, 45 mmol, 1.5 eq) was added a 60% mineral oil dispersion of NaH (1.80 g, 45 mmol, 1.5 eq). After stirring this solution for 30 minutes, 3,4-dimethoxybenzaldehyde (4.98 g, 30 mmol) was added and refluxed. The reaction was quenched by adding H ₂ O while monitoring the progress of the reaction by TLC. It was then extracted 5 times with diethyl ether (Et ₂ O) and the organic phase was dried over MgSO ₄ and filtered. After the filtrate was concentrated, ethyl ether (Et ₂ O) was added to the resulting crude product. Then, after removing triphenylphosphine oxide by filtration, the obtained solution was concentrated. The residue was purified by flash column chromatography using silica gel (hexane / ethyl acetate (EtOAc) = 5: 1) to give enol ether (SI-4) (4.89 g, 84%).

1M HCl (80 mL) was added to a tetrahydrofuran (THF) solution (160 mL) of SI-4 (4.89 g, 25 mmol) thus obtained, and the mixture was refluxed for 3 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution. After removing tetrahydrofuran (THF) under reduced pressure, the reaction mixture was extracted three times with diethyl ether (Et ₂ O). The organic layer was washed with saturated brine and dried over MgSO ₄ . After filtration, the solution was concentrated under reduced pressure to give aldehyde (SI-5) as a yellow oil (4.58 g). This oil was used without further purification.

To the dichloroethane solution (50 mL) of SI-5 (4.58 g, 25 mmol) thus obtained, triethylamine (Et ₃ N) (4.6 mL, 32.5 mmol, 1.3 eq), N, N-dimethylaminopyridine was added. (DMAP: catalytic amount) and N, N-dimethylcarbamoyl chloride (3.0 mL, 32.5 mmol, 1.3 eq) were added and the mixture was refluxed overnight. The mixture was quenched with saturated aqueous NH ₄ Cl and then extracted 3 times with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was subjected to flash column chromatography using silica gel to give enol carbamate (2C) as a white solid (4.47 g, 71% over 2 steps, E / Z = 4: 25). (E) Isomers were isolated by flash column chromatography.
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.69 (d, J = 13.0 Hz, 1H), 6.90-6.78 (m, 3H), 6.27 (d, J = 13.0 Hz, 1H), 3.91 (s, 3H) , 3.87 (s, 3H), 3.02 (s, 3H), 2.99 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 153.8, 149.1, 148.3, 136.7, 127.6, 119.1, 112.8, 111.3, 108.3 , 55.9, 55.8, 36.6, 36.0; HRMS calcd for C ₁₃ H ₁₈ NO ₄ [M + H] ⁺ : 252.1236, found: 252.1233.

  <Third step: nickel-catalyzed C—H / C—O coupling reaction between 5-methyloxazole-4-carboxylate (1E) and enol carbamate (2C)>

Wherein Me is a methyl group; Ni (cod) ₂ is bis (1,5-cyclooctadiene) nickel (0); dtype is 1,2-bisdicyclohexylphosphinoethane. ]
A 20 mL tube equipped with a J. Young O-ring tap was charged with a magnetic stir bar and K ₃ PO ₄ (84.9 mg, 0.40 mmol, 2.0 eq) and dried with a heat gun under reduced pressure. After cooling to room temperature and filling with nitrogen gas, add enol carbamate (2C) (75.4 mg, 0.30 mmol, 1.5 eq) and 5-methyloxazole-4-carboxylate (1E) (28.2 mg, 0.20 mmol) did. This tube was placed in a glove box in an argon atmosphere. In the glove box, bis (1,5-cyclooctadiene) nickel (0) (Ni (cod) ₂ ) (5.5 mg, 0.02 mmol, 10 mol%) and 1,2-bisdicyclohexylphosphinoethane (dcype ) (16.6 mg, 0.04 mmol, 20 mol%) was added and the container was removed from the glove box. 1,4-Dioxane (0.8 mL) was added thereto under a nitrogen stream, and sealed with a J. Young O ring tap. The reaction mixture was heated in a 135 ° C. oil bath for 24 hours and then cooled to room temperature. The reaction mixture was filtered through a silica gel pad with ethyl acetate (EtOAc) and concentrated. The residue was subjected to PTLC (hexane / ethyl acetate (EtOAc) = 1: 1) to give (E) 2- (3,4-dimethoxystyryl) -5-methyloxazole-4-carboxylate (5EC) as a yellow solid. (42.8 mg, 72%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.47 (d, J = 16.7 Hz, 1H), 7.08 (dd, J = 8.2, 1.3 Hz, 1H), 7.04 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 16.7 Hz, 1H), 4.00-3.85 (m, 9H), 2.67 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ162.8, 159.6, 155.8, 150.4, 149.2, 136.8, 128.3, 128.2, 121.2, 111.1, 111.0, 109.0, 55.9, 55.8, 51.9, 12.0; HRMS calcd for C ₁₆ H ₁₈ NO ₅ [M + H] ⁺ : 304.1185, found: 304.1187.

  <Fourth step: nickel-catalyzed C—H coupling reaction of 4-[(benzyloxy) methyl] -5-methyloxazole (1J) and (E) phenyl 3- (3,4-dimethoxyphenyl) acrylate (b3g)>

[Wherein PMB is p-methoxybenzyl group; Me is methyl group; Ni (cod) ₂ is bis (1,5-cyclooctadiene) nickel (0); dtype is 1,2-bisdicyclohexylphosphinoethane is there. ]
A 20 mL tube equipped with a J. Young O-ring tap was charged with a magnetic stir bar and K ₃ PO ₄ (170.0 mg, 0.80 mmol, 2.0 eq) and dried with a heat gun under reduced pressure. After cooling to room temperature and filling with nitrogen gas, (E) phenyl 3- (3,4-dimethoxyphenyl) acrylate (b3g) (170.6 mg, 0.60 mmol, 1.5 equivalents) was added. This tube was placed in a glove box in an argon atmosphere. In the glove box, bis (1,5-cyclooctadiene) nickel (0) (Ni (cod) ₂ ) (11.2 mg, 0.04 mmol, 10 mol%) and 1,2-bisdicyclohexylphosphinoethane (dcype ) (33.4 mg, 0.08 mmol, 20 mol%) was added and the container was removed from the glove box. 4-[(Benzyloxy) methyl] -5-methyloxazole (1J) (93.2 mg, 0.40 mmol) and 1,4-dioxane (1.5 mL) were added thereto under a nitrogen stream, and the J. Young O-ring was added. Sealed with a tap. The reaction mixture was heated in a 170 ° C. oil bath for 24 hours and then cooled to room temperature. The reaction mixture was filtered through a silica gel pad with ethyl acetate (EtOAc) and concentrated. The residue was subjected to PTLC (hexane / ethyl acetate (EtOAc) = 2: 1) and (E) 2- (3,4-dimethoxystyryl) -4-(((4-methoxybenzyl) oxy) methyl)- 5-Methyloxazole (SI-6) was obtained as a yellow viscous oil (74.8 mg, 47%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.37 (d, J = 16.5 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 7.05 (s , 1H), 6.91-6.84 (m, 3H), 6.75 (d, J = 16.5 Hz, 1H), 4.55 (s, 2H), 4.39 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 2.33 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ159.8, 159.2, 149.9, 149.1, 146.0, 134.8, 133.1, 130.0, 129.5, 128.7, 120.9 , 113.7, 112.0, 111.1, 108.8, 72.0, 63.2, 55.9, 55.7, 55.2, 10.3; HRMS calcd for C ₂₃ H ₂₆ NO ₅ [M + H] ⁺ : 396.1811, found: 396.1814.

  <Step 5: Synthesis of (E) 2- (3,4-dimethoxystyryl) -5-methyloxazole-4-carbaldehyde (5Jd)>

[Wherein PMB is a p-methoxybenzyl group; Me is a methyl group; DDQ is dichlorodicyanobenzoquinone. ]
Into the reaction tube was added a magnetic stir bar and (E) 2- (3,4-dimethoxystyryl) -4-(((4-methoxybenzyl) oxy) methyl) -5-methyloxazole (SI-6) (22.9 mg, 0.058 mmol) and dichlorodicyanobenzoquinone (DDQ) (52.6 mg, 0.23 mmol, 4.0 eq), CH ₂ Cl ₂ (0.5 mL), and H ₂ O (0.05 mL) were further added. The mixture was stirred for 2 hours while monitoring by TLC. After completion of the reaction, saturated aqueous NaHCO ₃ solution was added and extracted 3 times with CH ₂ Cl ₂ . The organic layer was washed with brine, dried over MgSO ₄ and filtered. The residue was concentrated under reduced pressure and purified by PTLC (hexane / ethyl acetate (EtOAc) = 3: 1) and (E) 2- (3,4-dimethoxyphenyl) -5-methyloxazole-4-carbaldehyde. (5Jd) was obtained as a white solid (6.5 mg, 41%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 9.98 (s, 1H), 7.49 (d, J = 16.5 Hz, 1H), 7.11 (dd, J = 8.2, 2.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 16.5 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 2.68 (s, 3H) ; ¹³ C NMR (CDCl ₃ , 100 MHz) δ 185.4, 160.5, 155.9, 150.6, 149.3, 137.5, 135.9, 128.1, 121.5, 111.2, 110.7, 109.0, 56.0, 55.9, 11.8; HRMS calcd for C ₁₅ H ₁₆ NO ₄ [M + H] ⁺ : 274.1079, found: 274.1079.

  Using (E) 2- (3,4-dimethoxystyryl) -5-methyloxazole-4-carboxylate (5EC) obtained in the third step, a known method (J. Linder, CJ Moody, Chem. Commun. 2007, 1508. and J. Linder, AJ Blake, CJ Moody, Org. Biomol. Chem. 2008, 6, 3908.), the bioactive molecule siphonazole B:

Can be synthesized.

  Similarly, using (E) 2- (3,4-dimethoxystyryl) -5-methyloxazole-4-carbaldehyde (5Jd) obtained in the fifth step, a known method (J. Zhang, MA Ciufolini, Org. Lett. 2009, 11, 2389.), it is also possible to synthesize the bioactive molecule siphonazole B.

  In addition, (E) 2- (3,4-dimethoxystyryl) -5-methyloxazole-4-carboxylate (5EC) and (E) 2- (3,4-dimethoxystyryl) -5-methyloxazole-4- Carbaldehyde (5Jd) is a known compound, but in the conventional method, 7 steps are required for synthesis, the number of positives can be reduced, and siphonazole B can be synthesized efficiently.

  In addition, by applying the method of the present invention,

Etc. can also be expected.

As described above, the coupling reaction was able to proceed under various conditions. The examples given above are only examples of successful coupling reactions,
As the compound (A), 5- (benzo [d] [1,3] dioxol-5-yl) oxazole, 5- (4-methoxyphenyl) oxazole, 5-methylbenzo [d] oxazole, 5-tertbutylbenzo [d ] (E) -phenyl cinnamate, (E) -2-methyl cinnamate phenyl, (E) -4-methoxy as compound (B) such as oxazole and methyl-6-methylbenzo [d] oxazole-5-carboxylate Phenyl cinnamate, phenyl (E) -4-trifluoromethylcinnamate, (E) -phenyl-3- (thiophen-2-yl) acrylate, (E) -phenyl-3- (thiophen-3-yl) ) Acrylate, (2E, 4E) -phenyl-5-phenylpenta-2,4-dienoate, (E) -phenyl-3- (3,4-dimethoxy) Even when phenyl) acrylate, naphthalen-2-ylcarbamate, naphthalen-2-ylpivalate, or the like was used, the coupling reaction could proceed in the same manner (the reaction proceeded even if the reaction time was increased to 48 hours). In addition, the reaction proceeded even if the amount of catalyst was changed).

[Test Example 1: X-ray crystal structure of Ni (dcype) (CO) ₂ catalyst]
The Ni (dcype) (CO) ₂ catalyst crystal obtained in Synthesis Example 13 is immersed in mineral oil, placed on glass fiber, and a goniometer CCD single crystal automatic X-ray structure analyzer “Saturn” (product) Name). Graphite monochromatic light Mo Kα radiation (λ = 0.71070 mm) was used. The results are shown in Table 13 and FIG.

Claims (12)

General formula (1):
Ar-Ar '
[Wherein Ar and Ar ′ are the same or different, and Ar represents the general formula (a):

[In the formula, Y ^a is ¹² C or ¹³ C; Z ^a is an oxygen atom or a sulfur atom; R ¹ and R ² are the same or different, and each is a hydrogen atom or an optionally substituted carbon atom having 1 to 20 carbon atoms. A hydrogen group, an optionally substituted alkoxy group having 1 to 20 carbon atoms, an optionally substituted alkoxy group having 2 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, a substituted group A monovalent heterocyclic group which may be substituted, an amino group which may be substituted; R ¹ and R ² may be bonded to each other to form an aromatic ring together with the adjacent —C═C—. ]
Ar ′ represents an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, or an optionally substituted monovalent aromatic group It is a heterocyclic group. ]
A process for producing a compound represented by
Formula (A):
Ar-H
[Wherein Ar is the same as defined above. ]
A compound (A) represented by:
General formula (B1):
R ^a OCO-Ar ′
[Wherein, Ar ′ is the same as defined above; R ^a is an optionally substituted phenyl group; ]
A compound represented by formula (B1 )
And
Nickel compound and general formula (C1):

[Wherein, four R ^{3 s} are the same or different and may be a monovalent aromatic hydrocarbon group which may be substituted or a monovalent alicyclic hydrocarbon group which may be substituted; An integer of ˜20; provided that when one or more of R ³ is an aromatic hydrocarbon group, n is an integer of 3-20. ]
A compound (C1) represented by:
General formula (C2):

[In the formula, three R ^{4 s} are the same or different and are each a linear hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted monovalent aromatic hydrocarbon group, or optionally substituted. Monovalent alicyclic hydrocarbon group; except when all R ⁴ are phenyl groups. ]
Compound (C2) represented by the general formula (C3):

[Wherein, two R ^{5 s} are the same or different and each represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted alkoxy group having 1 to 20 carbon atoms. ]
In Bei El reaction step of reacting in the presence of a ligand comprising a compound (C3) represented method. Ar ′ is a monovalent aromatic hydrocarbon group which may be substituted, or a monovalent heterocyclic group which may be substituted (however, when Z ^a is a sulfur atom, a heterocyclic group) The manufacturing method according to claim 1, wherein General formula (2):

[Wherein Ar and two Ar ″ are the same or different and Ar is the same as above; Ar ″ comprises a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, a phenyl group, a dihydronaphthyl group or a heteroaromatic ring] Monovalent heterocyclic group (except when two Ar ″ are both hydrogen atoms)]
A process for producing a compound represented by
Formula (A):
Ar-H
[Wherein Ar is the same as defined above. ]
A compound (A) represented by:
General formula (B2):

[Wherein Ar ″ is the same as above; R ^b Is R ^b1 CO- (R ^b1 Is an alkyl group which may be substituted, or an amino group which may be substituted. ]
Or a compound (B2) represented by
General formula (B3):

[Wherein Ar ″ is the same as above; R ^c Is an optionally substituted phenyl group. ]
Compound (B3) represented by
And
Nickel compound and general formula (C1):

[Wherein four R ³ Are the same or different and may be a monovalent aromatic hydrocarbon group which may be substituted, or a monovalent alicyclic hydrocarbon group which may be substituted; n is an integer of 2 to 20; ³ When one or more of is an aromatic hydrocarbon group, n is an integer of 3-20. ]
A compound (C1) represented by:
General formula (C2):

[Wherein three R ⁴ Are the same or different and are each a linear hydrocarbon group having 1 to 20 carbon atoms, a monovalent aromatic hydrocarbon group which may be substituted, or a monovalent alicyclic hydrocarbon group which may be substituted But all R ⁴ Except when is a phenyl group. ]
Or a compound (C2) represented by
General formula (C3):

[Wherein two R ⁵ Are the same or different and each is an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted alkoxy group having 1 to 20 carbon atoms. ]
The reaction process made to react in presence with the ligand which consists of a compound (C3) shown by these
A manufacturing method comprising: The manufacturing method in any one of Claims 1-3 whose usage-amount of the said nickel compound is 0.01-1 mol with respect to 1 mol of compounds (A). The manufacturing method in any one of Claims 1-4 whose usage-amount of a ligand is 0.5-5 mol with respect to 1 mol of nickel compounds. Furthermore, the manufacturing method in any one of Claims 1-5 which uses a base in the said reaction process. The production method according to claim 6 , wherein the base is an alkali metal or alkaline earth metal phosphate, carbonate or carboxylate, or an amine. Further, in the reaction step, a solvent is used, the production method according to any one of claims 1-7. The solvent is aromatic hydrocarbons, esters, cyclic ethers, halogenated hydrocarbons, ketones, amides, nitriles, alcohols having 3 to 20 carbon atoms, dimethyl sulfoxide, or N-methylpyrrolidone. The manufacturing method of Claim 8 which exists. The reaction temperature in the reaction step is the 80 to 200 ° C., The process according to any one of claims 1-9. The manufacturing method in any one of Claims 1-10 whose reaction time in the said reaction process is 1 to 50 hours. The following formula:

A compound represented by

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