WO2016190374A1

WO2016190374A1 - Poly-substituted aromatic compound and method for producing same

Info

Publication number: WO2016190374A1
Application number: PCT/JP2016/065516
Authority: WO
Inventors: 潤一郎山口; 健一郎伊丹; 鈴木　真
Original assignee: 国立大学法人名古屋大学
Priority date: 2015-05-25
Filing date: 2016-05-25
Publication date: 2016-12-01

Abstract

Provided is a poly-substituted aromatic compound represented by general formula (1), (In the formula, R¹ to R⁸ are an aryl group which may be substituted or a heteroaryl group which may be substituted. Five or more of R¹ to R⁸ are different groups.), or general formula (2), (In the formula, R⁹ to R¹⁶ are an aryl group which may be substituted or a heteroaryl group which may be substituted. R¹⁷ and R¹⁸ are a hydrogen atom, an aryl group which may be substituted, or a heteroaryl group which may be substituted. Five or more of R⁹ to R¹⁸ are different groups.)

Description

Polysubstituted aromatic compound and method for producing the same

The present invention relates to a polysubstituted aromatic compound and a method for producing the same. In particular, the present invention relates to a fully asymmetric polysubstituted aromatic compound and a method for producing the same.

Naphthalene and anthracene are organic molecules in which two or three benzene rings are condensed, and are used in fluorescent materials, organic electronics materials, etc. because of their various functions and high stability. Benzene, on the other hand, is a hexagonal organic molecule with the molecular formula C ₆ H ₆ , and has been said to be a symbol of organic chemistry because of its simplicity and beauty (tortoise shell). Benzene is also the most frequently used structural unit for medicines, agricultural chemicals, fragrances, dyes, plastics, liquid crystals, and electronic materials because of its versatile functions and high stability. For this reason, attempts have been made to impart various functions to naphthalene, anthracene and benzene.

In order to impart various functions to naphthalene and anthracene, it is required to replace the hydrogen atom bonded to the benzene ring of naphthalene and anthracene with various substituents. On the other hand, the key to imparting various functions to benzene is to replace the six hydrogen atoms bonded to the benzene ring with various substituents. The nature of the substituted aromatic compound varies greatly depending on what substituent is introduced and in what arrangement. For this reason, the development of techniques for introducing the desired substituents into naphthalene, anthracene and benzene has become one of the most important issues that support the development of chemistry. However, due to the exceptional structural diversity of polysubstituted naphthalene, polysubstituted anthracene and polysubstituted benzene, it was difficult to synthesize polysubstituted naphthalene, polysubstituted anthracene and polysubstituted benzene at will. This point has been regarded as an unsolved problem in chemistry for many years, such as the “multi-substituted benzene problem”.

The structural diversity of polysubstituted naphthalene, polysubstituted anthracene and polysubstituted benzene is remarkably large. For example, the structural diversity of poly-substituted benzene is represented by the formula N = (2n + 2n ² + 4n ³ + 3n ⁴ + n ⁶ ) / 12. (Burnside's theorem), its structural diversity stands out among organic molecules. Specifically, if a polysubstituted benzene can be synthesized at will, theoretically, more than 80,000 from a combination of 10 types of substituents and over 1.3 billion from a combination of 50 types of substituents Multi-substituted benzene can be produced. For this reason, if multi-substituted naphthalene, poly-substituted anthracene and poly-substituted benzene can be made separately, their versatility is very high and the impact is great.

However, due to the difficulty of the synthesis described above, substituted naphthalene and substituted anthracene into which many different substituents have been introduced have not been synthesized and isolated so far, and their physical properties remain unknown. On the other hand, the polysubstituted benzene is not only a hexa (hetero) arylbenzene in which all six hydrogen atoms of benzene are substituted with an aromatic substituent (aryl group or heteroaryl group), but can be a variety of optoelectronic functional materials, In recent years, it is a molecular group that has been attracting attention as a precursor of nanographene. However, because of the difficulty in the synthesis described above, the hexa (hetero) arylbenzenes that have been studied so far have only been highly symmetrical with one or two kinds of aryl groups (for example, Patent Document 1) ). In particular, fully asymmetric hexa (hetero) arylbenzenes substituted with six different aryl groups or heteroaryl groups have never been synthesized and isolated so far, and their physical properties remain unknown.

Under such circumstances, research and development of program synthesis methods for various polysubstituted organic molecules has been actively conducted. Programmed synthesis is a methodology that allows “creating all target molecular structures in a programmed manner at will” in an organic molecule to be synthesized. In such target setting, program synthesis of various polysubstituted organic molecules such as polysubstituted thiophene has been established (for example, Non-Patent Document 1). However, the program synthesis of polysubstituted naphthalene, polysubstituted anthracene, and polysubstituted benzene, which can be said to be the final goal, is extremely difficult, and even the clues have hardly been obtained.

JP 2008-050281 A

An object of the present invention is to provide a polysubstituted aromatic compound substituted with various aryl groups or heteroaryl groups.

As a result of intensive studies in view of the above problems, the present inventors obtained a tetra-substituted thiophene S-oxide compound by oxidizing a predetermined tetra-substituted thiophene compound for which program synthesis has already been established. It has been found that various polysubstituted aromatic compounds can be synthesized by reacting with an aromatic compound. In addition, by oxidizing a predetermined tetrasubstituted thiophene compound that has already been established for program synthesis to obtain a tetrasubstituted thiophene S-oxide compound, it is reacted with a compound having a predetermined triple bond to obtain various polysubstituted aromatic compounds. It has been found that group compounds can be synthesized and that all substituents can be different types of substituents. 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):

[Wherein R ¹ to R ⁸ represent an optionally substituted aryl group or an optionally substituted heteroaryl group. Five or more of R ¹ to R ⁸ are different groups. ]
Or general formula (2):

[Wherein, R ⁹ to R ^{16 each} represents an optionally substituted aryl group or an optionally substituted heteroaryl group. R ¹⁷ to R ^{18 each} represents a hydrogen atom, an optionally substituted aryl group or an optionally substituted heteroaryl group. 5 or more of R ⁹ to R ¹⁸ are different groups. ]
The polysubstituted aromatic compound represented by these.

Item 2. Item 4. The polysubstituted aromatic compound according to Item 1, wherein in the general formula (1), R ¹ to R ⁸ are all different groups.

Item 3. Item 2. The polysubstituted aromatic compound according to Item 1, wherein in the general formula (2), R ¹⁷ to R ¹⁸ are hydrogen atoms, and R ⁹ to R ¹⁶ are all different groups.

Item 4. In item 1, in the general formula (2), R ¹⁷ to R ¹⁸ are an optionally substituted aryl group or an optionally substituted heteroaryl group, and R ⁹ to R ¹⁸ are all different groups. The polysubstituted aromatic compound described.

Item 5. Item 5. The method for producing a polysubstituted aromatic compound according to any one of Items 1 to 4,
General formula (3):

[Wherein R ¹ to R ⁴ are the same as defined above. ]
A tetrasubstituted thiophene S-oxide compound represented by:
General formula (4):

[Wherein R ⁵ to R ⁸ are the same as defined above. One of R ¹⁹ and R ²⁰ is a carboxy group and the other is an amino group, or one is a silyl group and the other is a trifluoromethanesulfonate group. ]
Or a compound represented by the general formula (5):

[Wherein R ¹³ to R ¹⁸ are the same as defined above. One of R ²¹ and R ²² is a carboxy group and the other is an amino group, or one is a silyl group and the other is a trifluoromethanesulfonate group. ]
The manufacturing method provided with the process with which the compound represented by these is made to react.

Item 6. The compound represented by the general formula (4) is represented by the general formula (6):

[Wherein R ⁵ to R ⁸ are the same as defined above. ]
Obtained by reacting the compound represented by the formula with maleimide, and reacting the compound obtained in the previous step with the oxidizing agent and the first base, and further reacting with the second base. Item 6. The production method according to Item 5.

Item 7. The compound represented by the general formula (5) is represented by the general formula (7):

[Wherein R ¹³ to R ¹⁶ are the same as defined above. ]
And a compound of the general formula (8)

[Wherein R ¹⁷ to R ¹⁸ and R ²¹ to R ²² are the same as defined above. R ²³ is a silyl group. ]
Item 6. The production method according to Item 5, which is obtained by a method comprising a step of reacting a compound represented by formula (I) and a step of substituting a hydroxyl group of the compound obtained in the step with a trifluoromethanesulfonate group.

Item 8. General formula (31):

[Wherein R represents a nitrogen atom or a group represented by — (C—R ³⁶ ) ═. R ³¹ to R ³⁶ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. R ³⁵ and R ³⁶ may combine to form a ring. ]
A polysubstituted aromatic compound represented by:

Item 9. General formula (31A):

[Wherein, R ^31a to R ^36a are all different and each represents an ^optionally substituted aryl group or an optionally substituted heteroaryl group. ]
Item 9. The polysubstituted aromatic compound according to Item 8, represented by:

Item 10. General formula (31B):

[Wherein, R ^31b to R ^34b are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. A represents a ring. ]
Item 9. The polysubstituted aromatic compound according to Item 8, represented by:

Item 11. General formula (1C):

[Wherein, R ^31c to R ^35c are all different and each represents an ^optionally substituted aryl group or an optionally substituted heteroaryl group. ]
Item 9. The polysubstituted aromatic compound according to Item 8, represented by:

Item 12. Item 12. The polysubstituted aromatic compound according to any one of Items 8 to 11, wherein each of R ³¹ to R ³⁶ is different and represents an optionally substituted phenyl group or an optionally substituted monocyclic heteroaryl group.

Item 13. Item 13. A method for producing a polysubstituted aromatic compound according to any one of Items 8 to 12,
General formula (32):

[Wherein, R ³¹ to R ³⁴ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. ]
A tetrasubstituted thiophene S-oxide compound represented by:
General formula (33):
R≡C－R ³⁵ (33)
[Wherein R represents a nitrogen atom or a group represented by ≡ (C—R ³⁶ ). R ³⁵ and R ³⁶ are different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. R ³⁵ and R ³⁶ are different from any of R ³¹ to R ³⁴ . R ³⁵ and R ³⁶ may combine to form a ring. ]
The manufacturing method provided with the process with which the compound represented by these is made to react.

Item 14. The compound represented by the general formula (33) is
General formula (33A):
R ^36a -C≡C-R ^35a (33A)
[Wherein, R ^35a and R ^36a are different and each represents an ^optionally substituted aryl group or an optionally substituted heteroaryl group. R ^35a and R ^36a are different from any of R ³¹ to R ³⁴ . ]
A compound represented by
General formula (33B):

[Wherein A ′ represents a ring having a triple bond. ]
Or a compound represented by the general formula (33C):
N≡C－R ^35c
[Wherein, R ^35c represents an ^optionally substituted aryl group or an optionally substituted heteroaryl group. R ^35c is different from any of R ¹ to R ⁴ . ]
Item 14. The production method according to Item 13, which is a compound represented by:

Item 15. The tetrasubstituted thiophene S-oxide compound represented by the general formula (32) is represented by the general formula (34):

[Wherein, R ³¹ to R ³⁴ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. ]
Item 15. The method according to Item 13 or 14, which is obtained by oxidizing the tetrasubstituted thiophene compound represented by:

According to the present invention, it is possible to freely synthesize polysubstituted aromatic compounds substituted with various aryl groups or heteroaryl groups that have been impossible in the past. Such a polysubstituted aromatic compound of the present invention is expected to be applied to various uses such as fluorescent materials and organic electronics materials.

FIG. 2 is a drawing showing an X-ray crystal structure of the compound 30a obtained in Example 3-2 by thermal vibration ellipsoid drawing software (ORTEP) (the ellipse is 50% of atoms). For clarity, hydrogen atoms are omitted. It is a figure which shows the X-ray crystal structure of the compound 34b obtained in Example 5-1 by thermal vibration ellipsoid drawing software (ORTEP) (the ellipse is 50% of the atoms). For clarity, hydrogen atoms are omitted.

1. Multi-substituted aromatic compound (first embodiment)
The polysubstituted aromatic compound of the present invention according to the first aspect is represented by the general formula (1):

[Wherein R ¹ to R ⁸ represent an optionally substituted aryl group or an optionally substituted heteroaryl group. Five or more of R ¹ to R ⁸ are different groups. ]
And a polysubstituted aromatic compound (polysubstituted naphthalene compound) represented by formula (2):

[Wherein, R ⁹ to R ^{16 each} represents an optionally substituted aryl group or an optionally substituted heteroaryl group. R ¹⁷ to R ^{18 each} represents a hydrogen atom, an optionally substituted aryl group or an optionally substituted heteroaryl group. 5 or more of R ⁹ to R ¹⁸ are different groups. ]
Is a polysubstituted aromatic compound (polysubstituted anthracene compound).

In the general formula (1), R ¹ to R ⁸ are an aryl group or a heteroaryl group. Five or more of these R ¹ to R ⁸ are different groups, but according to the production method of the present invention described later, six or more of R ¹ to R ⁸ can be different groups, or R to seven or more of ¹ ~ R ⁸ may be different groups, it may be different based on all the R ¹ ~ R ^8.

In the general formula (2), R ⁹ to R ¹⁶ are an aryl group or a heteroaryl group. R ¹⁷ to R ¹⁸ are a hydrogen atom, an aryl group or a heteroaryl group. 5 or more of these R ⁹ to R ¹⁸ are different groups, but according to the production method of the present invention described later, when R ¹⁷ to R ¹⁸ are hydrogen atoms, 6 or more of R ⁹ to R ¹⁶ are used. it may be a different group, can either be different based on seven more of R ⁹ ~ R ^16, may be different based on all R ⁹ ~ R ^16. Further, when R ¹⁷ ~ R ¹⁸ is an aryl or heteroaryl group, it can either be different based on six or more of R ⁹ ~ R ^18, different groups of seven or more of R ⁹ ~ R ¹⁸ it may be a, it may be employed a different group of eight or more of R ⁹ ~ R ^18, may be employed a 9 or more different groups of ^{^{^{R 9 ~ R 18, R 9}}} ~ All of R ¹⁸ can be different groups.

That is, the polysubstituted aromatic compound of the present invention according to the first aspect includes the general formula (1A):

[Wherein, R ¹ to R ⁸ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. ]
A polysubstituted aromatic compound represented by the general formula (2A):

[Wherein, R ⁹ to R ¹⁶ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. ]
A polysubstituted aromatic compound represented by the general formula (2B):

[Wherein R ⁹ to R ¹⁸ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. ]
Any of the polysubstituted aromatic compounds represented by

In the general formulas (1) and (2), the aryl group represented by R ¹ to R ¹⁸ is not particularly limited and may be a monocyclic aryl group (phenyl group) or a polycyclic aryl group (fused ring aryl group, polycyclic ring). Non-condensed ring aryl group and the like may be used, and examples thereof include a phenyl group, a naphthyl group, an anthracenyl group, and a biphenyl group. Among these, from the viewpoints of ease of synthesis, yield, and the like, a monocyclic or condensed ring aryl group is preferable, and a phenyl group, a naphthyl group, and the like are more preferable.

The aryl group represented by R ¹ to R ¹⁸ may be substituted. The substituent that the aryl group represented by R ¹ to R ¹⁸ may have is not particularly limited, and examples thereof include a halogen atom (fluorine atom, chlorine atom, bromine atom, etc.), alkyl group (methyl group, ethyl group, C1-6 alkyl group such as t-butyl group), haloalkyl group (C1-6 haloalkyl group such as trifluoromethyl group), alkoxy group (C1-6 alkoxy group such as methoxy group), silyl group (t- Tri (C1-6 alkyl) silyl group such as butyldimethylsilyl group), acyl group (C2-7 acyl group such as acetyl group, propionyl group), alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group etc.) C1-6 alkoxy) carbonyl group and the like, and amino groups (di (C1-6 alkyl) amino groups such as diethylamino group) and the like. The number of these substituents is preferably 0-6, more preferably 0-3.

In general formulas (1) and (2), the heteroaryl group represented by R ¹ to R ¹⁸ is not particularly limited, and may be a monocyclic heteroaryl group or a polycyclic heteroaryl group (such as a condensed ring heteroaryl group). For example, pyrrolyl group, pyridyl group, pyrrolidyl group, piperidyl group, imidazolyl group, pyrazolyl group, pyrazyl group, pyrimidyl group, pyridazyl group, piperazyl group, triazinyl group, oxazolyl group, isoxazolyl group, morpholyl group, thiazolyl group, Examples include isothiazolyl group, furanyl group, thiophenyl group, indolyl group, quinolyl group, isoquinolyl group, benzoimidazolyl group, quinazolyl group, phthalazyl group, purinyl group, pteridyl group, benzofuranyl group, coumaryl group, chromonyl group, benzothiophenyl group, etc. . Among these, a monocyclic heteroaryl group is preferable from the viewpoint of ease of synthesis, yield, and the like.

The heteroaryl group represented by R ¹ to R ¹⁸ may be substituted. The substituent that the heteroaryl group represented by R ¹ to R ¹⁸ may have is not particularly limited, but examples thereof include a halogen atom (fluorine atom, chlorine atom, bromine atom, etc.), alkyl group (methyl group, ethyl group). C1-6 alkyl group such as t-butyl group), haloalkyl group (C1-6 haloalkyl group such as trifluoromethyl group), alkoxy group (C1-6 alkoxy group such as methoxy group), silyl group (t -Tri (C1-6 alkyl) silyl group such as butyldimethylsilyl group), acyl group (C2-7 acyl group such as acetyl group, propionyl group), alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, etc.) (C1-6 alkoxy) carbonyl group and the like), amino groups (di (C1-6 alkyl) amino groups such as diethylamino group) and the like. The number of these substituents is preferably 0-6, more preferably 0-3.

Examples of the polysubstituted aromatic compound of the present invention that satisfies the above conditions include:

[Wherein, Me represents a methyl group. t-Bu represents a t-butyl group. The same applies hereinafter. ]
Etc.

Note that the polysubstituted aromatic compound of the present invention according to the first embodiment is not limited to these. According to the production method of the present invention described later, a desired aryl group and heteroaryl group can be freely introduced into a desired location, and a huge number of polysubstituted aromatic compounds can be freely synthesized. Is possible.

2. Process for producing polysubstituted aromatic compound (first embodiment)
The method for producing a polysubstituted aromatic compound of the present invention according to the first aspect is a method for producing the polysubstituted aromatic compound of the present invention according to the first aspect described above, and is represented by the general formula (3):

[Wherein R ¹³ to R ¹⁸ are the same as defined above. One of R ²¹ and R ²² is a carboxy group and the other is an amino group, or one is a silyl group and the other is a trifluoromethanesulfonate group. ]
The step of reacting with the compound represented by (Step (1-IV))
Is provided.

(2-1) Step (1-I): Tetrasubstituted thiophene S-oxide compound and method for producing the same
The tetrasubstituted thiophene S-oxide compound has the general formula (9):

[Wherein R ¹ to R ⁴ are the same as defined above. ]
It can obtain by the process (process (1-I)) which oxidizes the tetrasubstituted thiophene compound shown by these. In the tetrasubstituted thiophene compound, R ¹ to R ⁴ can be all different groups, or can be all the same group depending on the type of R ⁵ to R ⁸ .

In the general formula (9), examples of the aryl group and heteroaryl group represented by R ¹ to R ⁴ include those described above, and the types and numbers of substituents that can be used can also be used. Such a tetra-substituted thiophene compound can be synthesized, for example, according to the synthesis method described in Non-Patent Document 1 or by slightly improving the synthesis method. Specifically, the following reaction formula 1:

[Wherein R ¹ to R ⁴ are the same as defined above. R ²⁴ represents an alkyl group. X ¹ represents a halogen atom. Y ¹ is the same or different and represents boronic acid or an ester group thereof. Tf represents a trifluoromethanesulfonyl group. ]
Can be synthesized according to

Examples of the alkyl group represented by R ²⁴ include C1-6 alkyl groups such as a methyl group, an ethyl group, and a t-butyl group, particularly a C1-4 alkyl group.

Examples of the halogen atom represented by X ¹ include a chlorine atom, a bromine atom, and an iodine atom.

Examples of the boronic acid represented by Y ¹ or an ester group thereof include, for example, the general formula (11):

[Wherein R ²⁵ are the same or different and each represents a hydrogen atom or an alkyl group. R ²⁵ may be bonded to each other to form a ring. ]
The group represented by these is preferable.

Examples of the alkyl group represented by R ²⁵ include a C1-6 alkyl group such as a methyl group, an ethyl group, and a t-butyl group, particularly a C1-4 alkyl group.

Examples of such boronic acid or ester groups thereof include:

[Wherein R ²⁶ to R ²⁷ are the same or different and each represents an alkyl group. ]
The group represented by these is mentioned.

Examples of the alkyl group represented by R ²⁶ to R ²⁷ include a C1-6 alkyl group such as a methyl group, an ethyl group, and a t-butyl group, particularly a C1-4 alkyl group.

Compound (10a) → Compound (10b)
The halogenating agent that can be used in this step is not particularly limited, and is chlorine (Cl ₂ ), bromine (Br ₂ ), iodine (I ₂ ), 1,2-dibromoethane, N-chlorosuccinimide, N-bromosuccinimide. (NBS), hydrogen bromide and the like. The amount of the halogenating agent to be used can be appropriately set depending on the kind of the halogenating agent to be used, but is usually preferably 0.2 to 5 mol, more preferably 0.5 to 2 mol, relative to 1 mol of the compound (10a). .

The amount of the compound represented by R ⁴ Y that can be used in this step is usually preferably 0.2 to 5 mol, more preferably 0.5 to 2 mol, per 1 mol of compound (10a).

Examples of the palladium compound that can be used in this step include palladium acetate (Pd (OCOCH ₃ ) ₂ ; Pd (OAc) ₂ ), tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ), trifluoro Palladium acetate (Pd (OCOCF ₃ ) ₂ ), Palladium chloride (PdCl ₂ ), Palladium bromide (PdBr ₂ ), Palladium iodide (PdI ₂ ), Pd (CH ₂ COCH ₂ COCH ₃ ) ₂ , K ₂ PdCl ₄ , K ₂ PdCl ₆ , K ₂ Pd (NO ₃ ) ₄ , tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ), bis (dibenzylideneacetone) palladium (0), dichloro (1,5 -Cyclooctadiene) palladium (II), 2,5-norbornadiene palladium dichloride, and the like. These palladium compounds may be solvates. These can be used alone or in combination of two or more. Among these, in this step, tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ) is preferable from the viewpoints of yield and ease of synthesis. The amount of the palladium compound used is usually preferably from 0.002 to 0.1 mol, more preferably from 0.005 to 0.05 mol, based on 1 mol of the compound (10a).

In this step, a ligand compound can be used as necessary. Examples of ligand compounds that can be used include triphenylphosphine, trimethoxyphosphine, triethylphosphine, triisopropylphosphine, tri (t-butyl) phosphine, tri (n-butyl) phosphine, triisopropoxyphosphine, and tricyclopentylphosphine. , Tricyclohexylphosphine, trimesitylphosphine, triphenoxyphosphine, di (t-butyl) methylphosphine, methyldiphenylphosphine, dimethylphenylphosphine, triethylamine, pyridine, 2,2'-bipyridyl, 4,4 '-(t-butyl ) Bipyridyl, 1,1'-bis (diphenylphosphino) ferrocene, 1,1'-bis (t-butyl) ferrocene, diphenylphosphinomethane, 1,2-bis (diphenylphosphino) ethane, 1,3- Bis (Gife Ruphosphino) propane, 1,5-bis (diphenylphosphino) pentane, 1,2-bis (dipentafluorophenylphosphino) ethane, 1,2-bis (dicyclohexylphosphino) ethane, 1,3- (dicyclohexylphos Fino) propane, 1,2-bis (di-t-butylphosphino) ethane, 1,3-bis (di-t-butylphosphino) propane, 1,2-bis (diphenylphosphino) benzene, 1, And 5-cyclooctadiene. These ligand compounds may be solvates. These can be used alone or in combination of two or more. Of these, tri (t-butyl) phosphine is preferable in this step from the viewpoint of yield and ease of synthesis. The amount of the ligand compound used is usually preferably 1 to 10 moles, more preferably 3 to 5 moles per mole of palladium compound.

In this step, a base can be used as necessary. Examples of the base that can be used in this step include metal alkoxides such as potassium t-butoxide, sodium t-butoxide and lithium t-butoxide; alkali metal phosphates such as lithium phosphate, sodium phosphate and potassium phosphate; water Metal hydroxides such as lithium oxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; amines such as triethylamine, diisopropylethylamine; Examples include piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine (TEMPO) and the like. These can be used alone or in combination of two or more. Among these, in this step, metal hydroxide is preferable and sodium hydroxide is more preferable from the viewpoint of yield and ease of synthesis. The amount of the base to be used is generally preferably 0.5-5 mol, more preferably 1-3 mol, per 1 mol of compound (10a).

This step can usually be carried out in a solvent. Examples of the solvent include chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, cyclopentyl methyl ether, and t-butyl methyl ether; cyclic ethers such as tetrahydrofuran (THF) and dioxane; pentane, hexane, heptane, Aliphatic hydrocarbons such as cyclohexane; Aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; Aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene; Aromatic halogens such as chlorobenzene and trifluorotoluene Hydrocarbons; alcohols such as methanol, ethanol, isopropyl alcohol and the like. These solvents can be used alone or in combination of two or more. In this step, from the viewpoint of yield and ease of synthesis, a cyclic ether is preferable, and tetrahydrofuran is more preferable.

This step is preferably performed under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually preferably about −50 to 150 ° C., more preferably about 0 to 100 ° C. The reaction time can be a time during which the reaction proceeds, and is usually preferably about 1 to 72 hours, and more preferably about 2 to 48 hours.

After completion of the reaction, the target compound (10b) can be obtained through ordinary isolation and purification steps as necessary.

Compound (10b) → Compound (10c)
The amount of the compound represented by R ² Y that can be used in this step is usually preferably 1 to 10 mol, more preferably 3 to 5 mol, per 1 mol of compound (10b).

It does not specifically limit as a palladium compound which can be used at this process, What was mentioned above is mentioned. In this step, palladium acetate (Pd (OCOCH ₃ ) ₂ ; Pd (OAc) ₂ ) is preferable from the viewpoints of yield and ease of synthesis. The amount of the palladium compound used is usually preferably from 0.02 to 0.5 mol, more preferably from 0.05 to 0.2 mol, per 1 mol of compound (10b).

In this step, a ligand compound can be used as necessary. The ligand compound that can be used is not particularly limited, and examples thereof include those described above. In this step, 2,2′-bipyridyl, 4,4 ′-(t-butyl) bipyridyl and the like are preferable and 2,2′-bipyridyl is more preferable from the viewpoint of yield and ease of synthesis. The amount of the ligand compound used is usually preferably 0.2 to 5 mol, more preferably 0.5 to 2 mol, relative to 1 mol of the palladium compound.

In this step, a base can be used as necessary. It does not specifically limit as a base which can be used at this process, What was mentioned above is mentioned. In this step, piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine (TEMPO) and the like are preferable from the viewpoint of yield and ease of synthesis, and 2,2,6,6-tetramethyl is preferable. Piperidine (TEMPO) is more preferred. The amount of base used is usually preferably 1 to 10 mol, more preferably 3 to 5 mol, per 1 mol of compound (10b).

This step can usually be carried out in a solvent. Examples of the solvent include chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, cyclopentyl methyl ether and t-butyl methyl ether; cyclic ethers such as tetrahydrofuran and dioxane; pentane, hexane, heptane and cyclohexane. Aliphatic hydrocarbons; Aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; Aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; Aromatic halogenated hydrocarbons such as chlorobenzene and trifluorotoluene Alcohols such as methanol, ethanol, isopropyl alcohol and the like. These solvents can be used alone or in combination of two or more. In this step, an aromatic halogenated hydrocarbon is preferred and trifluorotoluene is more preferred from the viewpoint of yield and ease of synthesis.

Although this step is preferably performed under an inert gas atmosphere (nitrogen gas, argon gas, etc.), it is not necessary to deaerate and it is not necessary to remove moisture, so that mass synthesis can be easily performed. it can. The reaction temperature is usually preferably about 0 to 150 ° C, more preferably about 50 to 100 ° C. The reaction time can be a time during which the reaction proceeds, and is usually preferably about 1 to 96 hours, more preferably about 2 to 72 hours.

After completion of the reaction, the target compound (10c) can be obtained through normal isolation and purification steps as necessary.

Compound (10c) → Compound (10d)
This step can be performed according to the method disclosed in Non-Patent Document 1. For example, R ¹ can be introduced into the compound (10c) using a compound represented by R ¹ X in the presence of a palladium compound such as palladium chloride (PdCl ₂ ). At this time, a ligand compound such as bipyridyl and a silver compound such as silver carbonate (Ag ₂ CO ₃ ) can be used as necessary.

Compound (10d) → Compound (10e)
This step can be performed according to the method disclosed in Non-Patent Document 1. For example, after dealkylating the compound (10d) using tribromoborane or the like, trifluoromethanesulfonylation can be performed using trifluoromethanesulfonic anhydride or the like. Trifluoromethanesulfonylation can also be performed in the presence of a base such as diisopropylethylamine as necessary.

Compound (10e) → Tetrasubstituted thiophene compound (9)
This step can be performed according to the method disclosed in Non-Patent Document 1. For example, the presence of tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃₎ ₄₎ a palladium compound, such as, by using a compound represented by R ³ Y, the R ³ for the compound (10e) Can be introduced. At this time, a base such as barium hydroxide may be used as necessary.

(2-2) Step (1-I): Oxidation of tetrasubstituted thiophene compound (9) Cyclization can be achieved by reacting tetrasubstituted thiophene compound (9) with compound (4) or compound (5) described below. The reaction does not proceed and the polysubstituted aromatic compound of the present invention cannot be obtained. In the present invention, in order to improve the reactivity of the tetrasubstituted thiophene compound (9), it is preferable to use the tetrasubstituted thiophene S-oxide compound (3) as a raw material.

In this step, the tetrasubstituted thiophene S-oxide compound (3) can be obtained by oxidizing the tetrasubstituted thiophene compound (9) (step 1-I).

In this step, the oxidizing agent used for the oxidation is not particularly limited. For example, chlorine; hydrogen peroxide; peracids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid (m-CPBA); Examples thereof include peroxides such as t-butyl peroxide; perhalogenates such as sodium metaperiodate. These can be used alone or in combination of two or more. Of these, in this step, peracid is preferable and m-chloroperbenzoic acid (m-CPBA) is more preferable from the viewpoint of yield and ease of synthesis. The amount of the oxidizing agent used is usually preferably 1 to 10 moles, more preferably 3 to 5 moles per mole of the tetrasubstituted thiophene compound (9).

In this step, it is preferable to use a boron trifluoride compound as an acid catalyst in addition to the oxidizing agent. Examples of the boron trifluoride compound that can be used include boron trifluoride diethyl ether complex (BF ₃ · OEt ₂ ), boron trifluoride tetrahydrofuran complex, and boron trifluoride methanol complex. These can be used alone or in combination of two or more. Among these, boron trifluoride diethyl ether complex (BF ₃ · OEt ₂ ) is preferable in this step from the viewpoint of yield and ease of synthesis. The amount of boron trifluoride compound used is usually preferably 2 to 30 moles, more preferably 5 to 20 moles per mole of tetrasubstituted thiophene compound (9).

This step can usually be carried out in a solvent. Examples of the solvent include chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, cyclopentyl methyl ether and t-butyl methyl ether; cyclic ethers such as tetrahydrofuran and dioxane; pentane, hexane, heptane and cyclohexane. Aliphatic hydrocarbons; Aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; Aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; Aromatic halogenated hydrocarbons such as chlorobenzene and trifluorotoluene Alcohols such as methanol, ethanol, isopropyl alcohol and the like. These solvents can be used alone or in combination of two or more. In this step, from the viewpoints of yield and ease of synthesis, aliphatic halogenated hydrocarbons are preferable, and dichloromethane is more preferable.

This step is preferably performed under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually preferably about −100 to 50 ° C., more preferably about −50 to 0 ° C. The reaction time can be a time during which the reaction proceeds, and is usually preferably about 1 to 24 hours, and more preferably about 2 to 12 hours.

After completion of the reaction, the target compound, tetrasubstituted thiophene S-oxide compound (3), can be obtained through ordinary isolation and purification steps as necessary.

(2-3) Steps (1-II) and (1-III): Compound (4) and Compound (5)
In the present invention, as a raw material to be reacted with the tetrasubstituted thiophene S-oxide compound (3), the above general formula (4):

[Wherein R ⁵ to R ⁸ are the same as defined above. One of R ¹⁹ and R ²⁰ is a carboxy group and the other is an amino group, or one is a silyl group and the other is a trifluoromethanesulfonate group. ]
The compound represented by these can be used.

In the general formula (4), one of R ¹⁹ and R ²⁰ is a carboxy group and the other is an amino group, or one is a silyl group (trimethylsilyl group, triethylsilyl group, etc.) and the other is a trifluoromethanesulfonate group.

The compound represented by the general formula (4) is, for example,

[Wherein, OTf represents a trifluoromethanesulfonate group. TMS represents a trimethylsilyl group. The same applies hereinafter. ]
Etc.

The compound represented by the general formula (4) is represented by the general formula (6):

[Wherein R ⁵ to R ⁸ are the same as defined above. ]
Obtained by reacting the compound represented by the formula with maleimide, and reacting the compound obtained in the previous step with the oxidizing agent and the first base, and further reacting with the second base. be able to.

As the compound represented by the general formula (6), a compound similar to the tetrasubstituted thiophene S-oxide compound represented by the general formula (3) can be employed.

In the present invention, first, the compound represented by the general formula (6) is reacted with maleimide.

The amount of maleimide used is usually preferably from 1 to 10 mol, more preferably from 2 to 5 mol, per 1 mol of compound (6).

This step can usually be carried out in a solvent. Examples of the solvent include chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, cyclopentyl methyl ether and t-butyl methyl ether; cyclic ethers such as tetrahydrofuran and dioxane; pentane, hexane, heptane and cyclohexane. Aliphatic hydrocarbons; Aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; Aromatic compounds such as benzene, toluene, xylene, mesitylene, chlorobenzene, nitrobenzene, trifluorotoluene; Methanol, ethanol, isopropyl alcohol And alcohol. These solvents can be used alone or in combination of two or more. In this step, an aromatic compound is preferable and nitrobenzene is more preferable from the viewpoints of yield and ease of synthesis.

This step is preferably performed under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually preferably about 100 to 300 ° C, more preferably about 150 to 250 ° C. The reaction time can be a time during which the reaction proceeds, and is usually preferably about 1 to 96 hours, more preferably about 2 to 72 hours.

After completion of the reaction, the general formula (11):

[Wherein R ⁵ to R ⁸ are the same as defined above. ]
Can be used in the next step.

In the next step, the compound represented by the general formula (11) is reacted with the oxidizing agent and the first base, and then further reacted with the second base, whereby the compound represented by the general formula (4) is obtained. Can be obtained.

Examples of the oxidizing agent used include chlorine; hydrogen peroxide; peracids such as peracetic acid, perbenzoic acid and m-chloroperbenzoic acid (m-CPBA); dimethyldioxirane, methyltrifluoromethyldioxirane, Examples thereof include peroxides such as t-butyl peroxide; perhalogenates such as sodium metaperiodate; hypochlorous acid such as sodium hypochlorite. These can be used alone or in combination of two or more. Among these, in this step, hypochlorite is preferable and sodium hypochlorite is more preferable from the viewpoint of yield and ease of synthesis. The amount of the oxidizing agent to be used is generally preferably 0.5 to 5 mol, more preferably 1 to 2 mol, relative to 1 mol of compound (11).

Examples of the first base used include metal alkoxides such as potassium t-butoxide, sodium t-butoxide and lithium t-butoxide; alkali metal phosphates such as lithium phosphate, sodium phosphate and potassium phosphate; water Metal hydroxides such as lithium oxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; amines such as triethylamine, diisopropylethylamine; Examples include piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine (TEMPO) and the like. These can be used alone or in combination of two or more. Among these, in this step, metal hydroxide is preferable and sodium hydroxide is more preferable from the viewpoint of yield and ease of synthesis. The amount of the first base used is usually preferably 2 to 20 mol, more preferably 3 to 10 mol, per 1 mol of compound (11).

Examples of the second base used include metal alkoxides such as potassium t-butoxide, sodium t-butoxide, and lithium t-butoxide; alkali metal phosphates such as lithium phosphate, sodium phosphate, and potassium phosphate; water Metal hydroxides such as lithium oxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; amines such as triethylamine, diisopropylethylamine; Examples include piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine (TEMPO) and the like. These can be used alone or in combination of two or more. Among these, in this step, metal hydroxide is preferable and potassium hydroxide is more preferable from the viewpoint of yield and ease of synthesis. The amount of the second base used is usually preferably 10 to 100 mol, more preferably 20 to 50 mol, per 1 mol of compound (11).

This step can usually be carried out in a solvent. Examples of the solvent include chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, cyclopentyl methyl ether and t-butyl methyl ether; cyclic ethers such as tetrahydrofuran and dioxane; pentane, hexane, heptane and cyclohexane. Aliphatic hydrocarbons; Aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; Aromatic compounds such as benzene, toluene, xylene, mesitylene, chlorobenzene, nitrobenzene, trifluorotoluene; Methanol, ethanol, isopropyl alcohol And alcohol. These solvents can be used alone or in combination of two or more. In this step, alcohol is preferable from the viewpoints of yield and ease of synthesis, and methanol, isopropyl alcohol, and the like are more preferable.

This step is preferably carried out under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually preferably carried out under heating, particularly under reflux. The reaction time can be a time during which the reaction proceeds, and is usually preferably about 1 to 48 hours, and more preferably about 2 to 24 hours.

After completion of the reaction, the compound represented by the above general formula (4) can be obtained through normal isolation and purification steps as necessary.

In the present invention, as a raw material to be reacted with the tetrasubstituted thiophene S-oxide compound (3), the above general formula (5):

[Wherein R ¹³ to R ¹⁸ are the same as defined above. One of R ²¹ and R ²² is a carboxy group and the other is an amino group, or one is a silyl group and the other is a trifluoromethanesulfonate group. ]
The compound represented by these can be used.

In the general formula (5), one of R ²¹ and R ²² is a carboxy group and the other is an amino group, or one is a silyl group (trimethylsilyl group, triethylsilyl group, etc.) and the other is a trifluoromethanesulfonate group.

The compound represented by the general formula (5) is, for example,

Etc. *

The compound represented by the general formula (5) is represented by the general formula (7):

[Wherein R ¹³ to R ¹⁶ are the same as defined above. ]
And a compound represented by the general formula (8):

[Wherein R ¹⁷ to R ¹⁸ and R ²¹ to R ²² are the same as defined above. R ²³ is a silyl group. ]
And a step of substituting a trifluoromethanesulfonate group for the hydroxyl group of the compound obtained in the above step.

As the compound represented by the general formula (7), a compound similar to the tetrasubstituted thiophene S-oxide compound represented by the general formula (3) can be employed.

In the general formula (8), examples of the silyl group represented by R ²³ include a trimethylsilyl group and a triethylsilyl group.

The amount of compound (8) used is usually preferably 1 to 10 mol, more preferably 2 to 5 mol, per 1 mol of compound (7). *

When reacting compound (7) and compound (8), if one of R ²¹ and R ²² is a silyl group and the other is a trifluoromethanesulfonate group, the reaction proceeds while deprotecting It is preferable to use a deprotecting agent in combination. Examples of the deprotecting agent include tetrabutylammonium fluoride. The amount of the deprotecting agent used is usually preferably 3 to 20 mol, more preferably 5 to 10 mol, relative to 1 mol of the compound (7).

This step can usually be carried out in a solvent. Examples of the solvent include chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, cyclopentyl methyl ether and t-butyl methyl ether; cyclic ethers such as tetrahydrofuran and dioxane; pentane, hexane, heptane and cyclohexane. Aliphatic hydrocarbons; Aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; Aromatic compounds such as benzene, toluene, xylene, mesitylene, chlorobenzene, nitrobenzene, trifluorotoluene; Methanol, ethanol, isopropyl alcohol And alcohol. These solvents can be used alone or in combination of two or more. In this step, from the viewpoint of yield and ease of synthesis, a cyclic ether is preferable, and tetrahydrofuran is more preferable.

This step is preferably performed under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually preferably −50 to 100 ° C., more preferably 0 to 50 ° C. The reaction time can be a time during which the reaction proceeds, and is usually preferably about 1 to 48 hours, more preferably about 2 to 36 hours.

After completion of the reaction, the general formula (12):

[Wherein R ¹³ to R ¹⁸ and R ²³ are the same as defined above. ]
Can be used in the next step.

Next, the hydroxyl group in the compound represented by the general formula (12) is substituted with a trifluoromethanesulfonate group. This step can be carried out by a method usually used for protecting a hydroxyl group with a trifluoromethanesulfonate group. Thereafter, the compound represented by the general formula (5) can be obtained through ordinary isolation and purification steps as necessary.

(2-4) Step (1-IV): Reaction of Compound (3) with Compound (4) or Compound (5) The tetrasubstituted thiophene S-oxide compound (3) described above exhibits reactivity as a diene. Have.

In addition, in the reaction system, the compound (4) has R ¹⁹ and R ²⁰ (carboxy group and amino group, or silyl group and trifluoromethanesulfonate group) removed, and the general formula (4 ′):

[Wherein R ⁵ to R ⁸ are the same as defined above. ]
And a condensation reaction with the tetrasubstituted thiophene S-oxide compound (3) can be obtained, and the polysubstituted aromatic compound of the present invention can be obtained.

Further, in the reaction system, the compound (5) has R ²¹ and R ²² (carboxy group and amino group, or silyl group and trifluoromethanesulfonate group) eliminated, and the compound represented by the general formula (5 ′):

[Wherein R ¹³ to R ¹⁸ are the same as defined above. ]
And a condensation reaction with the tetrasubstituted thiophene S-oxide compound (3) can be obtained, and the polysubstituted aromatic compound of the present invention can be obtained.

In this step, the amount of compound (4) or compound (5) used is usually preferably 0.1 to 2 mol, more preferably 0.2 to 1 mol, per 1 mol of tetrasubstituted thiophene S-oxide compound (3). .

This step can usually be carried out in a solvent. Examples of the solvent include chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, cyclopentyl methyl ether and t-butyl methyl ether; cyclic ethers such as tetrahydrofuran and dioxane; pentane, hexane, heptane and cyclohexane. Aliphatic hydrocarbons; Aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; Aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; Aromatic halogenated hydrocarbons such as chlorobenzene and trifluorotoluene Alcohols such as methanol, ethanol, isopropyl alcohol and the like. These solvents can be used alone or in combination of two or more. From the viewpoints of yield and ease of synthesis, cyclic ethers and aliphatic halogenated hydrocarbons are preferable, and tetrahydrofuran and dichloroethane are more preferable.

This step is preferably performed under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually preferably about −50 to 150 ° C., more preferably about 0 to 100 ° C. The reaction time can be a time during which the reaction proceeds, and is usually preferably about 0.5 to 48 hours, more preferably about 1 to 36 hours.

After completion of the reaction, the polysubstituted aromatic compound of the present invention can be obtained through ordinary isolation and purification steps as necessary.

In the present invention, the target polysubstituted aromatic compound of the present invention is obtained as a mixture of a plurality of isotopes, but can be easily isolated by ordinary isolation and purification means such as thin layer chromatography. Is possible.

3. Multi-substituted aromatic compound (second embodiment)
According to the second aspect of the present invention, it is possible to freely synthesize fully asymmetric hexa (hetero) arylbenzene, which has heretofore been impossible. In addition, according to the second aspect of the present invention, not only fully asymmetric hexa (hetero) arylbenzene, but also pyridine substituted with 5 types of aromatic substituents and 4 types of aromatic substituents. It is possible to synthesize a wide variety of polysubstituted aromatic compounds such as fused cyclic compounds. Such a polysubstituted aromatic compound of the present invention is expected to be applied to various uses such as medical and agricultural chemicals, fragrances, dyes, plastics, liquid crystals, and electronic materials.

The polysubstituted aromatic compound of the present invention according to the second aspect has the general formula (31):

[Wherein R represents a nitrogen atom or a group represented by — (C—R ³⁶ ) ═. R ³¹ to R ³⁶ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. R ³⁵ and R ³⁶ may combine to form a ring. ]
It is the polysubstituted aromatic compound represented by these.

In the general formula (31), R ³¹ to R ³⁶ are all different and each represents an aryl group or a heteroaryl group.

The aryl group represented by R ³¹ to R ³⁶ is not particularly limited, and may be a monocyclic aryl group (phenyl group) or a polycyclic aryl group (fused ring aryl group, polycyclic non-fused ring aryl group, etc.), For example, a phenyl group, a naphthyl group, an anthracenyl group, a biphenyl group, etc. are mentioned. Among these, from the viewpoints of ease of synthesis, yield, and the like, a monocyclic or condensed ring aryl group is preferable, and a phenyl group, a naphthyl group, and the like are more preferable.

The aryl group represented by R ³¹ to R ³⁶ may be substituted. Examples of the substituent that the aryl group represented by R ³¹ to R ³⁶ may have include, for example, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, etc.), an alkyl group (a C1-6 alkyl group such as a methyl group, an ethyl group, etc.) ), Haloalkyl group (C1-6 haloalkyl group such as trifluoromethyl group), alkoxy group (C1-6 alkoxy group such as methoxy group), silyl group (t-butyldimethylsilyl group and the like (C1-6 Alkyl) silyl group), acyl group (C2-7 acyl group such as acetyl group, propionyl group), alkoxycarbonyl group ((C1-6 alkoxy) carbonyl group such as methoxycarbonyl group, ethoxycarbonyl group), amino Group (di (C1-6 alkyl) amino group such as diethylamino group) and the like. The number of these substituents is preferably 0-6, more preferably 0-3.

The heteroaryl group represented by R ³¹ to R ³⁶ is not particularly limited and may be a monocyclic heteroaryl group or a polycyclic heteroaryl group (such as a condensed ring heteroaryl group). For example, a pyrrolyl group, a pyridyl group, Pyrrolidyl group, piperidyl group, imidazolyl group, pyrazolyl group, pyrazyl group, pyrimidyl group, pyridazyl group, piperazyl group, triazinyl group, oxazolyl group, isoxazolyl group, morpholyl group, thiazolyl group, isothiazolyl group, furanyl group, thiophenyl group, indolyl group Quinolyl group, isoquinolyl group, benzimidazolyl group, quinazolyl group, phthalazyl group, purinyl group, pteridyl group, benzofuranyl group, coumaryl group, chromonyl group, benzothiophenyl group and the like. Among these, a monocyclic heteroaryl group is preferable from the viewpoint of ease of synthesis, yield, and the like.

The heteroaryl group represented by R ³¹ to R ³⁶ may be substituted. Examples of the substituent that the heteroaryl group represented by R ³¹ to R ³⁶ may have include, for example, halogen atoms (fluorine atom, chlorine atom, bromine atom, etc.), alkyl groups (C1-6 alkyl such as methyl group, ethyl group, etc.) Group), a haloalkyl group (C1-6 haloalkyl group such as trifluoromethyl group), an alkoxy group (C1-6 alkoxy group such as methoxy group), a silyl group (t-butyldimethylsilyl group and the like (C1- 6alkyl) silyl group), acyl group (C2-7 acyl group such as acetyl group, propionyl group), alkoxycarbonyl group ((C1-6 alkoxy) carbonyl group such as methoxycarbonyl group, ethoxycarbonyl group), An amino group (di (C1-6 alkyl) amino group such as diethylamino group) and the like can be mentioned. The number of these substituents is preferably 0-6, more preferably 0-3.

In the general formula (31), R is a nitrogen atom or a group represented by — (C—R ³⁶ ) ═. R ³⁵ and R ³⁶ may be bonded to form a ring. That is, in the polysubstituted aromatic compound of the present invention, the benzene ring substituted with six different aryl groups or heteroaryl groups (fully asymmetric hexa (hetero) arylbenzene), and four different aryl groups or heteroaryl groups have one benzene ring. Any of the condensed ring aromatic compounds substituted with pyridine and pyridine substituted with five different aryl groups or heteroaryl groups are included.

That is, the polysubstituted aromatic compound of the present invention has the general formula (31A):

[Wherein, R ^31a to R ^36a are all different and each represents an ^optionally substituted aryl group or an optionally substituted heteroaryl group. ]
A compound represented by the general formula (31B):

[Wherein, R ^31b to R ^34b are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. A represents a ring. ]
A compound represented by the general formula (31C):

[Wherein, R ^31c to R ^35c are all different and each represents an ^optionally substituted aryl group or an optionally substituted heteroaryl group. ]
Any of the compounds represented by

In the general formula (31A), examples of the aryl group and heteroaryl group represented by R ^31a to R ^36a include those described above, and the types and numbers of substituents that may be included may be employed.

In the general formula (31B), examples of the aryl group and heteroaryl group represented by R ^31b to R ^34b include those described above, and the types and numbers of substituents that may be included may be employed.

In the general formula (31B), examples of the ring represented by A include:

Etc.

In the general formula (31C), examples of the aryl group and heteroaryl group represented by R ^31c to R ^35c include those described above, and the types and numbers of substituents that may be included may be employed.

For this reason, examples of the polysubstituted aromatic compound of the present invention include:

[Wherein TBS represents a t-butyldimethylsilyl group. The same applies hereinafter. ]
Etc.

Note that the polysubstituted aromatic compound of the present invention according to the second embodiment is not limited to these. According to the production method of the present invention to be described later, a desired aryl group and heteroaryl group can be freely introduced at a desired position, and by a combination of about 50 kinds of substituents usually used in organic chemistry. It is possible to freely synthesize a huge number of polysubstituted aromatic compounds of 1.3 billion or more.

4). Process for producing polysubstituted aromatic compound (second embodiment)
The method for producing a polysubstituted aromatic compound according to the second aspect of the present invention is a method for producing the polysubstituted aromatic compound according to the second aspect of the present invention, and is represented by the general formula (32):

[Wherein, R ³¹ to R ³⁴ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. ]
A tetrasubstituted thiophene S-oxide compound represented by:
General formula (33):
R≡C－R ³⁵ (33)
[Wherein R represents a nitrogen atom or a group represented by ≡ (C—R ³⁶ ). R ³⁵ and R ³⁶ are different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. R ³⁵ and R ³⁶ are different from any of R ³¹ to R ³⁴ . R ³⁵ and R ³⁶ may combine to form a ring. ]
The process with which the compound represented by (process (2-II)) is made to react is provided.

In the production method of the present invention, the tetrasubstituted thiophene S-oxide compound used as a raw material is represented by the general formula (34):

[Wherein, R ³¹ to R ³⁴ are all different and each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. ]
It can obtain by the process (process (2-I)) which oxidizes the tetrasubstituted thiophene compound represented by these.

(4-1) Tetra-substituted thiophene compound and method for producing the same In general formula (34), examples of the aryl group and heteroaryl group represented by R ³¹ to R ³⁴ include those described above. The number described above can be adopted as the number. Such a tetra-substituted thiophene compound can be synthesized, for example, according to the synthesis method described in Non-Patent Document 1 or by slightly improving the synthesis method. Specifically, reaction formula 2:

[Wherein R ³¹ to R ³⁴ are the same as defined above. R ³⁷ represents an alkyl group. X ² represents a halogen atom. Y ² is the same or different and represents boronic acid or an ester group thereof. Tf represents a trifluoromethanesulfonyl group. ]
Thus, a tetrasubstituted thiophene compound can be synthesized by the same method as in Reaction Scheme 1 above. Therefore, the above (2-1) can be adopted as a specific method and conditions.

(4-2) Step (1-I): Oxidation of tetrasubstituted thiophene compound (34) The cyclization reaction does not proceed even when the above tetrasubstituted thiophene compound (34) is reacted with compound (33) described below. Thus, the polysubstituted aromatic compound of the present invention according to the second embodiment cannot be obtained. In the present invention, in order to improve the reactivity of the tetrasubstituted thiophene compound (34), it is preferable to use the tetrasubstituted thiophene S-oxide compound (32) as a raw material.

In this step, the tetrasubstituted thiophene S-oxide compound (33) can be obtained by oxidizing the tetrasubstituted thiophene compound (34).

Oxidation can be carried out in the same manner as in the first aspect. Therefore, the above method (2-2) can be adopted for the oxidation method and conditions.

(4-3) Step (2-II): Reaction of Tetrasubstituted Thiophene S-Oxide Compound (32) with Compound (33) The tetrasubstituted thiophene S-oxide compound (32) described above exhibits reactivity as a diene. Therefore, the polysubstituted aromatic compound of the present invention according to the second aspect can be obtained by reacting with the compound (33).

In the general formula (33), examples of the aryl group and heteroaryl group represented by R ³⁵ to R ³⁶ include those described above, and the types and numbers of substituents that can be used may be used.

In the general formula (33), R is a nitrogen atom or a group represented by — (C—R ³⁶ ) ═. R ³⁵ and R ³⁶ may be bonded to form a ring. That is, the compound (33) has the general formula (33A):
R ^36a -C≡C-R ^35a (33A)
[Wherein, R ^35a and R ^36a are different and each represents an ^optionally substituted aryl group or an optionally substituted heteroaryl group. R ^35a and R ^36a are different from any of R ³¹ to R ³⁴ . ]
A compound represented by
General formula (33B):

[Wherein A ′ represents a ring having a triple bond. ]
And a compound represented by the general formula (33C):
N≡C－R ^35c
[Wherein, R ^35c represents an ^optionally substituted aryl group or an optionally substituted heteroaryl group. R ^35c is different from any of R ¹ to R ⁴ . ]
Any of the compounds represented by

In the general formula (33A), examples of the aryl group and heteroaryl group represented by R ^35a to R ^36a include those described above, and the types and numbers of substituents that may be included may be employed.

In the general formula (33B), as the ring represented by A ′, for example,

Etc.

In the general formula (33C), examples of the aryl group and heteroaryl group represented by R ^35c include those described above, and the types and numbers of substituents that may be included may be employed.

For this reason, examples of usable compounds (33) include:

Etc.

In this step, the amount of compound (33) used is usually preferably 0.5 to 5 moles, more preferably 1 to 3 moles per mole of tetrasubstituted thiophene S-oxide compound (32). Since compound (33C) is usually a liquid and functions as a reaction solvent, when compound (33C) is used, the amount used is excessive with respect to the tetrasubstituted thiophene S-oxide compound (32). It is preferable.

This step can usually be carried out in a solvent. Examples of the solvent include chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, cyclopentyl methyl ether and t-butyl methyl ether; cyclic ethers such as tetrahydrofuran and dioxane; pentane, hexane, heptane and cyclohexane. Aliphatic hydrocarbons; Aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; Aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; Aromatic halogenated hydrocarbons such as chlorobenzene and trifluorotoluene ; Alcohol such as methanol, ethanol, isopropyl alcohol and the like. These solvents can be used alone or in combination of two or more. From the viewpoints of yield and ease of synthesis, cyclic ethers and aromatic hydrocarbons are preferable, and tetrahydrofuran, xylene, and mesitylene are more preferable. Note that since the compound (33C) is usually a liquid, the reaction solvent need not be used when the compound (33C) is used.

In this way, the polysubstituted aromatic compound of the present invention can be obtained. *

When the compound (33A) is used as the compound (33), the general formula (31A):

[Wherein R ^31a to R ^36a are all different and are the same as defined above. ]
And a compound represented by the general formula (31A ′):

[Wherein R ^31a to R ^36a are all different and are the same as defined above. ]
It can obtain as a mixture with the compound represented by these. For this reason, the target compound can be isolated through normal isolation and purification steps.

However, depending on the combination of R ^31a to R ^36a , it may be difficult to isolate the compound (31A) and the compound (31A ′). In this case, the compound (31A) and the compound (31A ′) can be easily isolated by substituting R ^35a or R ^36a with a bulky substituent such as t-butyldimethylsilyloxy group by a conventional method. Is possible.

When the compound (33B) is used as the compound (33), the target compound can be obtained through normal isolation and purification steps as necessary. *

When compound (33C) is used as compound (33), general formula (31C):

[Wherein R ^31c to R ^35c are all different and are the same as defined above. ]
And a compound represented by the general formula (31C ′):

[Wherein R ^31c to R ^35c are all different and are the same as defined above. ]
It can obtain as a mixture with the compound represented by these. For this reason, the target compound can be isolated through normal isolation and purification steps.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Unless otherwise specified, all the materials including the dry solvent were used as they were on the market. Tetrakis (triphenylphosphine) palladium (0) was synthesized according to a previous report (J. Chem. Soc. 1186 (1957)). N-bromosuccinimide was newly recrystallized by a water coupling reaction. Boron trifluoride diethyl ether complex (BF ₃ · OEt ₂ ) was distilled with CaH ₂ before the oxidation reaction. Unless otherwise noted, all reactions were performed in a flame-dried glass container using a dry solvent under a nitrogen (N2) gas atmosphere using standard vacuum line techniques. All work-up and purification procedures were performed in air with reagent grade solvents.

Analytical thin layer chromatography (TLC) was performed using E. Merck silica gel 60 F ₂₅₄ precoated plates (0.25 mm). The developed chromatogram was analyzed with a UV lamp (254 nm). Flash column chromatography was performed using E. Merck silica gel 60 (230-400 mesh). Preparative recycle gel permeation chromatography (GPC) was performed using a JAI LC-9204 equipped with a JAIGEL-1H / JAIGEL-2H column with chloroform as the eluent. Preparative thin layer chromatography (PTLC) was performed using a Wakogel B5-F silica-coated plate (0.75 mm) prepared in advance. Gas chromatograph mass spectrometry (GC / MS) was performed on a Shimadzu GCMS-QP2010 equipped with an HP-5 column (30 m × 0.25 mm, Hewlett-Packard). High resolution mass spectra (HRMS) were obtained with a JMS-T100TD instrument (DART) and Thermo Fisher Scientific Exactive (APCI). Nuclear magnetic resonance (NMR) spectra were measured using a JEOL JNM-ECA-600 spectrometer ( ¹ H 600 MHz, ¹³ C 150 MHz), a JEOL JNM-ECA-400 spectrometer ( ¹ H 400 MHz, ¹³ C 100 MHz), and a cryogenic temperature. Recorded on a JEOL JNM-ECA-600II ( ¹ H 600 MHz, ¹³ C 150 MHz) equipped with a probe. ¹ H NMR chemical shifts were expressed as relative parts per million (ppm) of tetramethylsilane (δ0.00 ppm) or C ₂ D ₂ Cl ₄ (δ5.98 ppm). ¹³ C NMR chemical shifts were expressed in relative parts per million (ppm) of CDCl ₃ (δ 77.0 ppm) or C ₂ D ₂ Cl ₄ (δ 73.79 ppm). Data are reported in the order of chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet doublet, t = triplet, m = multiplet), binding constant (Hz), and integration.

[Synthesis Example 1: Synthesis of Compound (8)]
Synthesis Example 1-1: Synthesis of Compound 2

[Wherein, HMDS represents 1,1,1,3,3,3-hexamethyldisilazane. THF represents tetrahydrofuran. The same applies hereinafter. ]
A 50 mL two-necked flask was charged with a magnetic stir bar, flame dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask was added 2,5-dibromohydroquinone (compound 1; 2.68 g, 10 mmol, 1.0 equiv), 1,1,1,3,3,3-hexamethyldisilazane (HMDS; 8.38 mL, 40 mmol, 4.0 Eq), and THF (10 mL) were added under a stream of nitrogen. The reaction mixture was refluxed for 16 hours. Volatiles were removed under reduced pressure to give ((2,5-dibromo-1,4-phenylene) bis (oxy)) bis (trimethylsilane) (compound 2) as a white solid (4.12 g, quant) .
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.04 (s, 2H), 0.29 (s, 18H).

Synthesis Example 1-2: Synthesis of Compound 3

[Wherein TMSCl represents chlorotrimethylsilane. The same applies hereinafter. ]
A 100 mL two-necked flask was charged with a magnetic stir bar, flame-dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask, ((2,5-dibromo-1,4-phenylene) bis (oxy)) bis (trimethylsilane) obtained in Synthesis Example 1-1 (Compound 2; 2.06 g, 5 mmol, 1.0 equivalent), Sodium (460 mg, 20 mmol, 4.0 eq) and toluene (20 mL) were added under a nitrogen stream. After the mixture was refluxed for 1 hour, a solution of chlorotrimethylsilane (TMSCl; 1.4 mL, 11 mmol, 2.2 eq) in toluene (5 mL) was slowly added. The resulting mixture was refluxed for an additional 16 hours. After the reaction mixture was cooled to room temperature, the mixture was filtered through a glass filter (eluent: toluene, 50 mL). Volatiles were removed under reduced pressure to give (2,5-bis ((trimethylsilyl) oxy) -1,4-phenylene) bis (trimethylsilane) (compound 3) as a white solid (1.81 g, 91% ).
¹ H NMR (600 MHz, CDCl ₃ ): δ 6.76 (s, 2H), 0.29 (s, 18H), 0.24 (s, 18H).

Synthesis Example 1-3: Synthesis of Compound 4

A 100 mL two-necked flask was charged with a magnetic stir bar, flame-dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask, (2,5-bis ((trimethylsilyl) oxy) -1,4-phenylene) bis (trimethylsilane) obtained in Synthesis Example 1-2 (Compound 3; 1.20 g, 3 mmol, 1.0 equivalent), 6N HNO ₃ aqueous solution (3 mL) and dioxane (48 mL) were added under a nitrogen stream. After stirring at room temperature for 3 hours, water (30 mL) and CH ₂ Cl ₂ (50 mL) were added to the mixture. After extraction with CH ₂ Cl ₂ , the organic layer is dried over Na ₂ SO ₄ , volatiles are removed under reduced pressure, and 2,5-bis (trimethylsilyl) benzene-1,4-diol (compound 4) is removed. Obtained as a white solid (710 mg, 93%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.04 (s, 2H), 2.17 (s, 2H), 0.29 (s, 18H).

Synthesis Example 1-4: Synthesis of Compound 5

[In the formula, Tf ₂ O represents trifluoromethanesulfonic anhydride. The same applies hereinafter. ]
A magnetic stir bar was placed in a 25 mL screw cap tube, flame dried under vacuum, cooled to room temperature, and filled with nitrogen. To this tube, 2,5-bis (trimethylsilyl) benzene-1,4-diol (Compound 4; 254 mg, 1 mmol, 1.0 equivalent) obtained in Synthesis Example 1-3, trifluoromethanesulfonic anhydride (Tf ₂ O; 164 μL, 1 mmol, 1.0 equivalent) and pyridine (5 mL) were added under a stream of nitrogen. The resulting mixture was heated at 50 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, water (10 mL) and CH ₂ Cl ₂ (10 mL) were added to the mixture. After extraction with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography (hexane / ethyl acetate = 30: 1) and GPC to give 4-hydroxy-2,5-bis (trimethylsilyl) phenyl trifluoromethanesulfonate (compound 5) as a white solid. (226 mg, 59%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.23 (s, 1H), 6.75 (s, 1H), 4.92 (s, 1H), 0.35 (s, 9H), 0.31 (s, 9H).

[Synthesis Example 2: Synthesis of Compound (10b) and Compound (35b)]
Synthesis Example 2-1: Synthesis of Compound 21a

[Wherein, Me represents a methyl group. The same applies hereinafter. ]
A 500 mL three-necked flask was charged with a magnetic stir bar, flame-dried under vacuum, cooled to room temperature and filled with nitrogen. At 0 ° C., a solution of 3-methoxythiophene (3.0 mL, 30 mmol, 1.0 equiv) in THF (300 mL) and N-bromosuccinimide (NBS; 5.34 g, 30 mmol, 1.0 equiv) was added to the flask. . After the mixture was stirred at 0 ° C. for 1 hour, tris (dibenzylideneacetone) dipalladium (0) / chloroform adduct (Pd ₂ (dba) ₃ .CHCl ₃ ; 465.8 mg, 0.45 mmol, 1.5 mol%), tri- t-butylphosphonium tetrafluoroborate (P (t-Bu) ₃ · HBF ₄ ; 522.2 mg, 1.8 mmol, 6 mol%), 4-t-butylphenylboronic acid (31.5 mmol, 1.05 equivalents), and aqueous NaOH solution ( 3 M, 20 mL, 60 mmol, 2.0 eq) was added and the mixture was further stirred at 60 ° C. for 20 h. After evaporation of the solvent, water (500 mL) and CH ₂ Cl ₂ (200 mL) were added to the mixture. After extraction with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. Purification by flash column chromatography (hexane / ethyl acetate = 40: 1) and distillation by Kugelrohr gave Compound 21a as a colorless oil (7.4 g, quant).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 5.6 Hz, 1H), 6.92 ( d, J = 5.6 Hz, 1H), 3.90 (s, 3H), 1.33 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 153.3, 149.1, 130.5, 126.5, 125.3, 121.5, 120.1, 117.3, 58.5, 34.4, 31.2; HRMS (DART) m / z calcd for C ₁₅ H ₁₉ OS [MH] ⁺ : 247.11566, found 247.11528.

Synthesis Example 2-2: Synthesis of Compound 21b

Synthesis was carried out in the same manner as in Synthesis Example 2-1 except that m-tolylboronic acid was used as the aryl boronic acid compound to obtain compound 21b as a colorless oil (5.5 g, 90%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.57-7.50 (m, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 5.6 Hz, 1H), 3.91 (s, 3H), 2.38 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 153.5, 137.9, 133.2 , 128.3, 127.5, 127.1, 124.0, 121.9, 120.2, 117.4, 58.6, 21.5; HRMS (DART) m / z calcd for C ₁₂ H ₁₃ OS [MH] ⁺ : 205.06871, found 205.06863.

[Synthesis Example 3: Synthesis of Compound (10c) and Compound (35c)]
Synthesis Example 3-1: Synthesis of Compound 7

[Wherein, Me represents a methyl group. Pd (OAc) ₂ represents palladium acetate. 2,2'-bipy represents 2,2'-bipyridyl. TEMPO represents 2,2,6,6-tetramethylpiperidine 1-oxyl. The same applies hereinafter. ]
A 50 mL two-necked flask was charged with a magnetic stir bar, flame dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask, palladium acetate (Pd (OAc) ₂ ; 225.5 mg, 1.0 mmol, 10 mol%), 2,2'-bipyridyl (2,2'-bipy; 155.1 mg, 1.0 mmol, 10 mol%), p -Methylphenylboronic acid (5.47 g, 40 mmol, 4.0 eq), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO; 4.69 g, 30 mmol, 3.0 eq), obtained in Synthesis Example 2-2 3-methoxy-2- (m-tolyl) thiophene (Compound 21b; 2.04 g, 10 mmol, 1.0 equivalent) and α, α, α-trifluorotoluene (3.0 mL) were added under a nitrogen stream. The vessel was heated at 80 ° C. for 48 hours. The reaction mixture was filtered through silica gel (eluent: CHCl ₃ , 100 mL) and volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography (hexane / ethyl acetate = 50: 1) and gel permeation chromatography (GPC) to give 3-methoxy-2- (m-tolyl) -4- (p-tolyl) Thiophene (compound 7) was obtained as a yellow oil (2.26 g, 77%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.59-7.53 (m, 4H), 7.29 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.14 (s, 1H ), 7.11 (d, J = 7.2 Hz, 1H), 3.50 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H).

Synthesis Example 3-2: Synthesis of Compound 22ac

A 50 mL two-necked flask was charged with a magnetic stir bar, flame dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask, palladium acetate (Pd (OAc) ₂ ; 224.5 mg, 1.0 mmol, 10 mol%), 2,2'-bipyridyl (bipy: 156.8 mg, 1.0 mmol, 10 mol%), phenylboronic acid (40 mmol) , 4.0 equivalents), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO; 4.69 g, 30 mmol, 3.0 equivalents), compound 21a obtained in Synthesis Example 2-1 (10 mmol, 1.0 equivalents), And α, α, α-trifluorotoluene (3.3 mL) were added under a nitrogen atmosphere. The vessel was heated at 80 ° C. for 48 hours. The reaction mixture was filtered through silica gel (eluent: ethyl acetate, 100 mL) and volatiles were removed under reduced pressure. Purification by flash column chromatography (hexane / ethyl acetate = 20: 1) and gel permeation chromatography (GPC) gave compound 22ac as a white solid (2.43 g, 75% (β), β / α = 98. : 2).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.72-7.64 (m, 4H), 7.45-7.39 (m, 4H), 7.33 (t, J = 8.0 Hz, 1H), 7.16 (s, 1H), 3.51 (s, 3H), 1.36 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 151.3, 150.2, 136.7, 135.1, 130.2, 128.5, 128.2, 127.5, 127.2, 126.9, 125.6, 119.1, 60.7 , 34.6, 31.3; HRMS (DART) m / z calcd for C ₂₁ H ₂₃ OS [MH] ⁺ : 323.14696, found 323.14673.

Synthesis Example 3-3: Synthesis of Compound 22bc

Synthesis was performed in the same manner as in Synthesis Example 3-2 except that Compound 21b obtained in Synthesis Example 2-2 was used instead of Compound 21a obtained in Synthesis Example 2-1. Thus, Compound 22bc was obtained as a colorless oil (2.13 g, 76% (β), β / α = 91: 9).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.68-7.64 (m, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.36-7.27 (m , 2H), 7.18 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 3.50 (s, 3H), 2.40 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 151.5 , 138.3, 136.8, 135.0, 133.0, 128.6, 128.5, 128.3, 128.03, 127.97, 127.5, 127.3, 124.4, 119.4, 60.7, 21.5; HRMS (DART) m / z calcd for C ₁₈ H ₁₇ OS [MH] ⁺ : 281.10001, found 281.10046.

[Synthesis Example 4: Synthesis of Compound (10d) and Compound (35d)]
Synthesis Example 4-1: Synthesis of Compound 8

A J. Young O-ring tap was attached to a 100 mL glass container, a magnetic stirrer was placed, the frame was dried under vacuum, cooled to room temperature, and then filled with nitrogen. In this container, palladium chloride (PdCl ₂ ; 124 mg, 0.66 mmol, 10 mol%), 2,2'-bipyridyl (bipy; 110 mg, 0.66 mmol, 10 mol%), Ag ₂ CO ₃ (1.93 g, 6.6 mmol, 1.0 equivalent), compound 7 obtained in Synthesis Example 3-1 (1.95 g, 6.6 mmol, 1.0 equivalent), 1-chloro-4-iodobenzene (5.03 g, 19.9 mmol, 3.0 equivalent), and dry m- Xylene (33 mL) was added under a nitrogen atmosphere. The vessel was sealed with an O-ring tap and heated at 120 ° C. for 36 hours. After the reaction mixture was cooled to room temperature, the mixture was filtered through a short silica gel pad (ethyl acetate). The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (hexane / ethyl acetate = 50: 1) and gel permeation chromatography (GPC) to give 2- (4-chlorophenyl) -4- Methoxy-5- (m-tolyl) -3- (p-tolyl) thiophene (Compound 8) was obtained as a yellow solid (1.75 g, 66%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.62-7.58 (m, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.23-7.19 (m, 4H), 7.19-7.14 (m, 4H) , 7.12 (d, J = 7.2 Hz, 1H), 3.38 (s, 3H), 2.41 (s, 3H), 2.38 (s, 3H).

Synthesis Example 4-2: Synthesis of Compound 23acd

A J. Young O-ring tap was attached to a 100 mL glass container, a magnetic stirrer was placed, the frame was dried under vacuum, cooled to room temperature, and then filled with nitrogen. In this container, palladium chloride (PdCl ₂ ; 76.6 mg, 0.45 mmol, 10 mol%), 2,2'-bipyridyl (bipy: 70.2 mg, 0.45 mmol, 10 mol%), silver carbonate (Ag ₂ CO ₃ ; 1.24 g, 4.5 mmol, 1.0 equivalent), compound 22ac obtained in Synthesis Example 3-2 (4.5 mmol, 1.0 equivalent), 4-trifluoromethylphenyl iodide (13.5 mmol, 3.0 equivalent), and dry m-xylene (24 mL) was added under a nitrogen atmosphere. The vessel was sealed with an O-ring tap and heated at 120 ° C. for 48 hours. After the reaction mixture was cooled to room temperature, the mixture was filtered through a short silica gel pad (ethyl acetate). The filtrate was concentrated under vacuum and purified by gel permeation chromatography (GPC) to give compound 3acd as a white solid (1.77 g, 84%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.73 (d, J = 8.8 Hz, 2H), 7.49-7.42 (m, 4H), 7.40-7.30 (m, 7H), 3.39 (s, 3H), 1.36 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 152.1, 150.6, 138.1, 134.8, 134.2, 133.6, 130.0, 129.7, 129.0 (q, ² J _CF = 32.6 Hz), 128.7, 128.6, 128.0, 127.6, 125.7, 125.3 (q, ³ J _CF = 3.8 Hz), 124.1 (q, ¹ J _CF = 273 Hz), 60.6, 34.6, 31.3; HRMS (DART) m / z calcd for C ₂₈ H ₂₆ F ₃ OS [MH] ⁺ : 467.16564, found 467.16622.

Synthesis Example 4-3: Synthesis of Compound 23bce

Similar to Synthesis Example 4-2, except that Compound 22bc obtained in Synthesis Example 3-3 was used instead of Compound 22ac obtained in Synthesis Example 3-2, and 4-chloroiodobenzene was used as the aryl iodide. Synthesis gave compound 23bce as a white solid (1.69 g, 72%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.63-7.57 (m, 2H), 7.39-7.28 (m, 6H), 7.23-7.10 (m, 5H), 3.38 (s, 3H), 2.41 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 152.1, 138.3, 134.5, 134.3, 133.9, 133.3, 132.9, 132.6, 130.0, 129.9, 128.7, 128.6, 128.4, 128.1, 127.9, 127.4, 127.1, 124.4 HRMS (DART) m / z calcd for C ₂₄ H ₂₀ ClOS [MH] ⁺ : 391.09234, found 391.09257.

[Synthesis Example 5: Synthesis of Compound (10e) and Compound (35e)]
Synthesis Example 5-1: Synthesis of Compound 9

[Wherein, i-Pr2NEt represents N, N-diisopropylethylamine. DMAP represents N, N-dimethylaminopyridine. The same applies hereinafter. ]
A 100 mL two-necked flask was charged with a magnetic stir bar, flame-dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask, 2- (4-chlorophenyl) -4-methoxy-5- (m-tolyl) -3- (p-tolyl) thiophene obtained in Synthesis Example 4-1 (Compound 8; 1.76 g, 4.4 mmol, 1.0 equivalent), and dry CH ₂ Cl ₂ (44 mL) were added under a stream of nitrogen. The contents were cooled to −78 ° C. and boron tribromide (5.65 mL, 1 M in CH ₂ Cl ₂ , 6.5 mmol, 1.3 eq) was added slowly. The resulting mixture was stirred at −78 ° C. for 0.5 hour. After the reaction mixture was warmed to room temperature, the reaction was monitored by TLC. After quenching the reaction by adding saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO ₃ , water and CH ₂ Cl ₂ (20 mL) were added to the mixture. After the mixture was extracted with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was subjected to flash column chromatography (hexane / ethyl acetate = 50: 1 to 10: 1) to remove starting material. The filtrate was concentrated under vacuum and used in the next step without further purification.

A 100 mL two-necked flask was charged with a magnetic stir bar, flame-dried under vacuum, cooled to room temperature and filled with nitrogen. To the flask, the material obtained in the above step and dry CH ₂ Cl ₂ (22 mL) were added under a stream of nitrogen. The contents were cooled to 0 ° C., and N, N-diisopropylethylamine (i-Pr ₂ NEt; 1.14 mL, 6.52 mmol, 1.5 eq), N, N-dimethylaminopyridine (DMAP; 5.3 mg, 43.5 μmol) was added to the flask. , 1 mol%), and trifluoromethanesulfonic anhydride (Tf ₂ O; 1.07 mL, 6.52 mmol, 1.5 eq). The resulting mixture was stirred at 0 ° C. for 0.5 hour. The reaction mixture was warmed to room temperature and stirred for 12 hours, and then an aqueous NaHCO ₃ solution, water and CH ₂ Cl ₂ were added to the mixture. After the mixture was extracted with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was subjected to flash column chromatography (hexane / ethyl acetate = 50: 1) to give 5- (4-chlorophenyl) -2- (m-tolyl) -4- (p-tolyl) thiophen-3-yltrifluoro. Lomomethanesulfonate (Compound 9) was obtained as a white solid (1.02 g, 45%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.45 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.25-7.22 (m, 3H ), 7.20-7.14 (m, 6H), 2.42 (s, 3H), 2.38 (s, 3H).

Synthesis Example 5-2: Synthesis of Compound 24acd

A 50 mL Schlenk flask was charged with a magnetic stir bar, flame dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask, the compound 23acd (0.5 mmol, 1.0 equivalent) obtained in Synthesis Example 4-2 and dry CH ₂ Cl ₂ (5 mL) were added under a nitrogen stream. The contents were cooled to −78 ° C. and boron tribromide (650 μL, 1 M in CH ₂ Cl ₂ , 0.65 mmol, 1.3 eq) was added. The resulting mixture was stirred at −78 ° C. for 0.5 hour. After the reaction mixture was warmed to room temperature and TLC was monitored, water (20 mL) and CH ₂ Cl ₂ (20 mL) were added to the mixture. After extraction with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was filtered through a short silica gel pad (hexane / ethyl acetate = 1: 1). The filtrate was concentrated in vacuo and used directly in the next step without further purification.

A 20 mL Schlenk flask was charged with a magnetic stir bar, flame dried under vacuum, cooled to room temperature and filled with nitrogen. To the flask, the material obtained in the above step and dry CH ₂ Cl ₂ (2.5 mL) were added under a stream of nitrogen. The contents were cooled to 0 ° C., and N, N-diisopropylethylamine (i-Pr ₂ NEt; 130.6 μL, 0.75 mmol, 1.5 eq), N, N-dimethylaminopyridine (5.5 mg, 50 μmol, 10 mol) was cooled to 0 ° C. %), And trifluoromethanesulfonic anhydride (Tf ₂ O; 126.2 μL, 0.75 mmol, 1.5 equivalents). The resulting mixture was stirred at 0 ° C. for 0.5 hour. After the reaction mixture was warmed to room temperature and stirred for 12 hours, the mixture was filtered through a short silica gel pad (hexane / ethyl acetate = 1: 1). The filtrate was concentrated in vacuo and the crude product was purified by preparative thin layer chromatography (hexane / ethyl acetate = 10: 1) to give compound 24acd as a white solid (130.1 mg, 45%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.57 (dd, J = 8.4, 1.8 Hz, 2H), 7.52-7.49 (m, 4H), 7.41-7.38 (m, 3H), 7.34-7.29 (m, 4H), 1.37 (s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 152.6, 137.2, 136.9, 135.2, 133.9, 133.6, 131.8, 130.4, 129.9 (q, ² J _CF = 33.2 Hz), 128.9, 128.8, 128.6, 128.3, 127.0, 126.0, 125.6 (q, ³ J _CF = 2.9 Hz), 123.9 (q, ¹ J _CF = 274 Hz), 117.8 (q, ¹ J _CF = 323 Hz), 34.8, 31.2; HRMS (DART) m / z calcd for C ₂₈ H ₂₃ F ₆ O ₃ S ₂ [MH] ⁺ : 585.09928, found 585.10085.

Synthesis Example 5-3: Synthesis of Compound 24bce

Synthesis was performed in the same manner as in Synthesis Example 4-2, except that Compound 23bce obtained in Synthesis Example 4-3 was used instead of Compound 23acd obtained in Synthesis Example 4-2, and Compound 24bce was obtained as a white solid (136.8 mg, 54%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.48-7.34 (m, 6H), 7.31-7.21 (m, 5H), 7.15 (d, J = 8.8 Hz, 2H), 2.43 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 138.8, 137.2, 136.1, 134.2, 133.0, 132.8, 131.9, 131.7, 130.4, 130.01, 129.95, 129.8, 129.2, 128.94, 128.88, 128.7, 128.4, 125.7, 117.9 (q , J _CF = 323 Hz), 21.3; HRMS (DART) m / z calcd for C ₂₄ H ₁₇ ClF ₃ O ₃ S ₂ [MH] ⁺ : 509.02597, found 509.02611.

[Synthesis Example 6: Synthesis of tetrasubstituted thiophene compound (9) and tetrasubstituted thiophene compound (34)]
Synthesis Example 6-1: Synthesis of Compound 10

[Wherein Pd (PPh ₃ ) ₄ represents tetrakis (triphenylphosphine) palladium (0). The same applies hereinafter. ]
A 200 mL two-necked flask was charged with a magnetic stir bar, flame-dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask, tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ; 201 mg, 0.74 mmol, 10 mol%), Ba (OH) ₂ (594 mg, 3.48 mmol, 2.0 eq), ( 3,5-Dimethoxyphenyl) boronic acid (950 mg, 5.22 mmol, 3.0 equivalents), 5- (4-chlorophenyl) -2- (m-tolyl) -4- (p-tolyl) obtained in Synthesis Example 5-1. ) Thiophen-3-yl trifluoromethanesulfonate (Compound 9; 910 mg, 1.74 mmol, 1.0 eq), dry 1-butanol (70 mL), and H ₂ O (58 mL) were added under a stream of nitrogen. The flask was heated at 65 ° C. for 16 hours. After the reaction mixture was cooled to room temperature, the mixture was filtered through a short silica gel pad (ethyl acetate). The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (hexane / ethyl acetate = 20: 1) to give 2- (4-chlorophenyl) -4- (3,5-dimethoxyphenyl)- 5- (m-Tolyl) -3- (p-tolyl) thiophene (Compound 10) was obtained as a white solid (798 mg, 90%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.20-7.14 (m, 5H), 7.10 (t, J = 7.8 Hz, 1H), 7.05-7.01 (m, 2H), 6.96 (d, J = 8.4 Hz , 2H), 6.86 (d.J = 8.4 Hz, 2H), 6.25 (t, J = 2.4 Hz, 1H), 6.10 (d, J = 2.4 Hz, 2H), 3.49 (s, 3H), 2.28 (s , 3H), 2.27 (s, 3H).

Synthesis Example 6-2: Synthesis of tetrasubstituted thiophene compound 25acde

A magnetic stirring bar was placed in a 50 mL Schlenk tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. To this Schlenk tube, tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ; 10.4 mg, 9.0 μmol, 10 mol%), Ba (OH) ₂ (30.8 mg, 0.18 mmol, 2.0 equivalents), 4-chlorophenylboronic acid (0.270 mmol, 3.0 equivalents), compound 24acd (0.09 mmol, 1.0 equivalent) obtained in Synthesis Example 5-2, dry 1-butanol (3.6 mL), and H ₂ O (3.0 mL) were nitrogenated. Added under air flow. The Schlenk tube was heated at 65 ° C. for 16 hours. After the reaction mixture was cooled to room temperature, the mixture was filtered through a short silica gel pad (ethyl acetate). The filtrate was concentrated under vacuum and the crude product was purified by preparative thin layer chromatography (hexane / ethyl acetate = 10: 1) to give the tetrasubstituted thiophene compound 25acde as a white solid (34.9 mg, 71% ).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.45 (d, J = 8.0 Hz, 2H), 7.33-7.23 (m, 4H), 7.21-7.12 (m, 5H), 7.10 (d, J = 8.4 Hz , 2H), 6.95 (dd, J = 7.8, 2.0 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 1.30 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 150.8 , 140.4, 140.2, 137.9, 137.7, 136.4, 135.8, 134.7, 132.7, 132.1, 130.6, 130.5, 129.1, 128.9 (q, ² J _CF = 32.4 Hz), 128.7, 128.24, 128.18, 127.1, 125.5, 125.3 (q , ³ J _CF = 3.9 Hz), 124.1 (q, ¹ J _CF = 277 Hz), 34.6, 31.2; HRMS (DART) m / z calcd for C ₃₃ H ₂₇ ClF ₃ S [MH] ⁺ : 547.14741, found 547.14724 .

Synthesis Examples 6-3 to 6-5: Synthesis of tetrasubstituted thiophene compound 25acdf, tetrasubstituted thiophene compound 25bceg, tetrasubstituted thiophene compound 25bceh

The tetra-substituted thiophene compound 25acdf was obtained as a white solid (33.7 mg, 69%) in the same manner as in Synthesis Example 6-2 except that 4-methoxyphenylboronic acid was used instead of 4-chlorophenylboronic acid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.45 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.28-7.22 (m, 2H), 7.20-7.13 (m , 5H), 6.98-6.94 (m, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H), 1.29 (s, 9H) ; ¹³ C NMR (100 MHz, CDCl ₃ ): δ 158.3, 150.4, 140.8, 139.5, 139.0, 138.0, 136.2, 135.9, 131.9, 131.0, 130.7, 129.1, 128.8 (q, ² J _CF = 32.4 Hz), 128.6 , 128.1, 126.9, 125.3, 125.2 (q, ³ J _CF = 3.8 Hz), 124.1 (q, ¹ J _CF = 277 Hz), 113.3, 55.0, 34.5, 31.2; HRMS (DART) m / z calcd for C ₃₄ H ₃₀ F ₃ OS [MH] ⁺ : 543.19694, found 543.19636.

Synthesis except that compound 24cde obtained in Synthesis Example 5-3 was used in place of compound 24acd obtained in Synthesis Example 5-2, and 3,5-dimethoxyphenylboronic acid was used in place of 4-chlorophenylboronic acid Synthesis was carried out in the same manner as in Example 6-2 to obtain 25bceg of a tetrasubstituted thiophene compound as a white solid (42.3 mg, 95%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.21-7.08 (m, 9H), 7.06-6.96 (m, 4H), 6.42 (t, J = 2.4 Hz, 1H), 6.09 (s, 2H), 3.49 (s, 6H), 2.28 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 160.0, 139.7, 139.2, 139.1, 137.92, 137.89, 136.8, 136.3, 133.8, 133.1, 132.7, 130.6, 130.3 , 129.8, 128.5, 128.22, 128.17, 128.0, 126.8, 126.2, 108.8, 99.7, 55.1, 21.4; HRMS (DART) m / z calcd for C ₃₁ H ₂₆ ClO ₂ S [MH] ⁺ : 497.13420, found 497.13378.

Synthesis except that compound 24bce obtained in Synthesis Example 5-3 was used in place of compound 24acd obtained in Synthesis Example 5-2 and 4-n-butylphenylboronic acid was used in place of 4-chlorophenylboronic acid Synthesis was conducted in the same manner as in Example 6-2 to obtain the tetrasubstituted thiophene compound 25bceh as a white solid (42.9 mg, 97%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.20-6.98 (m, 11H), 6.98-6.89 (m, 4H), 6.84 (d, J = 8.0 Hz, 2H), 2.51 (t, J = 7.6 Hz , 2H), 2.22 (s, 3H), 1.53 (quin, J = 7.8 Hz, 2H), 1.27 (sext, J = 7.6 Hz, 2H), 0.89 (t, J = 7.6 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 141.2, 139.9, 139.6, 138.8, 137.8, 136.7, 136.3, 134.0, 133.5, 133.0, 132.9, 130.8, 130.5, 130.3, 129.8, 128.5, 128.1, 128.0, 127.9, 126.7, 126.2 , 35.2, 33.4, 22.1, 21.3, 14.0; HRMS (DART) m / z calcd for C ₃₃ H ₃₀ ClS [MH] ⁺ : 493.17567, found 493.17618.

[Synthesis Example 7: Synthesis of tetrasubstituted thiophene S-oxide compound (3) and tetrasubstituted thiophene S-oxide compound (32)]
Synthesis Example 7-1: Synthesis of Compound 11

[Wherein, m-CPBA represents m-chloroperbenzoic acid. BF ₃ · OEt ₂ represents a boron trifluoride diethyl ether complex. The same applies hereinafter. ]
A 50 mL two-necked flask was charged with a magnetic stir bar, flame dried under vacuum, cooled to room temperature and filled with nitrogen. To this flask, 2- (4-chlorophenyl) -4- (3,5-dimethoxyphenyl) -5- (m-tolyl) -3- (p-tolyl) thiophene (Compound 10) obtained in Synthesis Example 6-1 was added. 184.5 mg, 0.36 mmol, 1.0 eq), and dry CH ₂ Cl ₂ (1.5 mL) were added. After cooling to −20 ° C., boron trifluoride diethyl ether complex (BF ₃ · OEt ₂ ; 452 μL, 3.6 mmol, 10 equivalents) was added. After the mixture was stirred at −20 ° C. for 1 hour, a solution of m-chloroperbenzoic acid (m-CPBA; 0.36 mmol, 1.0 equiv) in CH ₂ Cl ₂ (720 μL) was slowly added (4 times per hour, totaling 4 times). 4.0 equivalents) was added and the resulting mixture was stirred at −20 ° C. for 1 hour. That is, the reaction time is 6 hours in total. Saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO ₃ were added to quench the reaction. The mixture was extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (CHCl ₃ ) to give 2- (4-chlorophenyl) -4- (3,5-dimethoxyphenyl) -5- (m-tolyl) -3- (p-tolyl) Thiophene 1-oxide (Compound 11) was obtained as a yellow solid (98.1 mg, 52%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.34-7.27 (m, 3H), 7.27-7.23 (m, 2H), 7.20-7.09 (m, 4H), 6.99 (d, J = 8.4 Hz, 2H) , 6.84 (d.J = 8.4 Hz, 2H), 6.25 (t, J = 2.4 Hz, 1H), 6.10 (d, J = 2.4 Hz, 2H), 3.49 (s, 3H), 2.28 (s, 3H) , 2.27 (s, 3H).

Synthesis Example 7-2: Synthesis of tetrasubstituted thiophene S-oxide compound 26acde

A magnetic stir bar was placed in a 20 mL Schlenk tube, flame dried under vacuum, cooled to room temperature, and then filled with nitrogen. To the Schlenk tube, the tetrasubstituted thiophene compound 25acde (0.1 mmol, 1.0 equivalent) obtained in Synthesis Example 6-2 and dry CH ₂ Cl ₂ (400 μL) were added. After cooling to −20 ° C., boron trifluoride diethyl ether complex (BF ₃ · OEt ₂ ; 120 μL, 1.0 mmol, 10 equivalents) was added. The mixture was stirred at −20 ° C. for 1 hour, then m-chloroperbenzoic acid (m-CPBA; 0.1 mmol, 1.0 equiv) in CH ₂ Cl ₂ (200 μL) was added slowly (4 times per hour) The resulting mixture was stirred at -20 ° C for 1 hour. Saturated aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO ₃ were added to quench the reaction. The mixture was extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (hexane / CHCl ₃ = 2: 3) to give the tetrasubstituted thiophene S-oxide compound 26acde as a yellow solid (22.0 mg, 39%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.36-7.24 (m, 5H), 7.23-7.17 (m , 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.95-6.87 (m, 4H), 1.30 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 152.5, 147.9, 144.1, 142.6, 138.7, 134.4, 134.1, 132.6, 131.6, 131.1, 130.3 (q, ² J _CF = 33.5 Hz), 129.9, 129.5, 129.3, 128.77, 128.70, 128.66, 126.9, 125.9, 125.6 (q, ³ J _CF = 3.9 Hz), 123.8 (q, ¹ J _CF = 270 Hz), 34.8, 31.1; HRMS (DART) m / z calcd for C ₃₃ H ₂₇ ClF ₃ OS [MH] ⁺ : 563.14232, found 563.14329.

Synthesis Examples 7-3 to 7-5: Synthesis of tetrasubstituted thiophene S-oxide compound 26acdf, tetrasubstituted thiophene S-oxide compound 26bceg, tetrasubstituted thiophene S-oxide compound 26bceh

Synthesis was performed in the same manner as in Synthesis Example 7-2 except that the tetrasubstituted thiophene compound 25acdf obtained in Synthesis Example 6-3 was used instead of the tetrasubstituted thiophene compound 25acde obtained in Synthesis Example 6-2. The oxide compound 26acdf was obtained as a yellow solid (30.0 mg, 54%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.34-7.30 (m, 4H), 7.25-7.16 (m , 3H), 6.94 (d, J = 6.8 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 6.68 (d, J = 9.2 Hz, 2H), 3.75 (s, 3H), 1.29 (s , 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 159.4, 152.0, 146.6, 143.7, 143.3, 139.9, 134.4, 133.0, 131.2, 130.1 (q, ² J _CF = 37.2 Hz), 129.9, 129.6, 129.3, 128.53, 128.46, 127.5, 125.7, 125.5 (q, ³ J _CF = 3.8 Hz), 125.2, 123.9 (q, ¹ J _CF = 276 Hz), 113.8, 55.1, 34.7, 31.1; HRMS (DART) m / z calcd for C ₃₄ H ₃₀ F ₃ O ₂ S [MH] ⁺ : 559.19186, found 559.19277.

Except that the tetrasubstituted thiophene compound 25bceg obtained in Synthesis Example 6-4 was used in place of the tetrasubstituted thiophene compound 25acde obtained in Synthesis Example 6-2, and the purification process was preparative thin layer chromatography (CHCl ₃ ). Was synthesized in the same manner as in Synthesis Example 7-2 to obtain 26bceg of a tetrasubstituted thiophene S-oxide compound as a yellow solid (22.4 mg, 44%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34-7.28 (m, 3H), 7.28-7.08 (m, 4H), 6.97 (d, J = 7.2 Hz, 2H), 6.28 (t, J = 2.4 Hz , 1H), 6.07-6.03 (m, 2H), 3.49 (s, 6H), 2.29 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 160.4, 146.7, 144.4, 141.7, 140.5, 138.3 , 134.75, 134.73, 133.3, 130.9, 130.2, 130.1, 129.7, 129.4, 129.1, 128.9, 128.5, 128.45, 128.41, 126.8, 107.7, 101.0, 55.2, 21.4; HRMS (DART) m / z calcd for C ₃₁ H ₂₆ ClO ₃ S [MH] ⁺ : 513.12912, found 513.12807.

Using the tetrasubstituted thiophene compound 25bceh obtained in Synthesis Example 6-5 instead of the tetrasubstituted thiophene compound 25acde obtained in Synthesis Example 6-2, purification treatment was performed by preparative thin layer chromatography (hexane / ethyl acetate = 5: The compound was synthesized in the same manner as in Synthesis Example 7-2 except that 1) was obtained to obtain a tetrasubstituted thiophene S-oxide compound 26bceh as a yellow solid (23.8 mg, 47%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.31 (d, J = 8.8 Hz, 2H), 7.27-7.06 (m, 9H), 6.97-6.89 (m, 4H), 6.81 (d, J = 8.0 Hz , 2H), 2.52 (t, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.52 (quin, J = 7.6 Hz, 2H), 1.26 (sext, J = 7.6 Hz, 2H), 0.89 (t , J = 7.6 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 146.2, 144.3, 143.1, 142.0, 141.0, 138.2, 134.7, 133.2, 130.9, 130.33, 130.27, 129.7, 129.6, 129.5, 129.2 , 128.9, 128.4, 128.30, 128.27, 126.9, 35.3, 33.2, 22.1, 21.4, 13.9; HRMS (APCI) m / z calcd for C ₃₃ H ₃₀ ClOS [MH] ⁺ : 509.1700, found 509.1688.

[Synthesis Example 8: Synthesis of Compound (11)]
Synthesis Example 8-1: Synthesis of Compound 13

[Wherein PhNO ₂ represents nitrobenzene. The same applies hereinafter. ]
A magnetic stir bar was placed in a 25 mL screw cap tube, flame dried under vacuum, cooled to room temperature, and filled with nitrogen. To this tube, 5- (4- (t-butyl) phenyl) -4- (4-methoxyphenyl) -3-phenyl-2- (4- (trifluoromethyl) phenyl) obtained in Synthesis Example 7-3 Thiophene 1-oxide (Compound 26acdf; 111.7 mg, 0.2 mmol, 1.0 eq), maleimide (59.5 mg, 0.6 mmol, 3.0 eq), and nitrobenzene (PhNO ₂ ; 1 mL) were added under a stream of nitrogen. The reaction mixture was stirred at room temperature for 1 hour and then heated at 210 ° C. for 48 hours. After the reaction mixture was cooled to room temperature, the mixture was filtered through a short silica gel pad (CHCl ₃ ) to remove nitrobenzene and filtered through a short silica gel pad (ethyl acetate) to drain compound 13. The filtrate was concentrated and the crude product was purified by flash column chromatography (hexane / ethyl acetate = 5: 1) to give 4- (4- (t-butyl) phenyl) -5- (4-methoxyphenyl)- 6-phenyl-7- (4- (trifluoromethyl) phenyl) isoindoline-1,3-dione (compound 13) was obtained as a white solid (103.3 mg, 85%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.57 (s, 1H), 7.44 (d, J = 7.8 Hz, 2H), 7.24-7.19 (m, 4H), 7.01 (d, J = 7.2 Hz, 2.4 Hz, 2H), 6.92-6.90 (m, 3H), 6.71-6.69 (m, 2H), 6.59 (dd, J = 6.6 Hz, 2.4 Hz, 2H), 6.41 (dd, J = 6.6 Hz, 2.4 Hz, 2H) 3.60 (s, 3H), 1.27 (s, 9H).

[Synthesis Example 9: Synthesis of Compound (4)]
Synthesis Example 9-1: Synthesis of Compound 14a and Compound 14b

[Wherein, i-PrOH represents isopropyl alcohol. The same applies hereinafter. ]
A magnetic stir bar was placed in a 25 mL screw cap tube, flame dried under vacuum, cooled to room temperature, and filled with nitrogen. To this tube, 4- (4- (t-butyl) phenyl) -5- (4-methoxyphenyl) -6-phenyl-7- (4- (trifluoromethyl) phenyl) obtained in Synthesis Example 8-1 Isoindoline-1,3-dione (compound 13; 59.9 mg, 0.1 mmol, 1.0 eq), aqueous NaOCl (ab. 6%, 200 μL, 1.5 eq), aqueous NaOH (3N, 170 μL, 5.0 eq), and methanol ( MeOH; 5.6 mL) was added under a stream of nitrogen. The resulting mixture was refluxed for 10 minutes. After the reaction mixture was cooled to room temperature, water (10 mL) and CH ₂ Cl ₂ (10 mL) were added to the mixture. The mixture was neutralized with 1M HCl and concentrated with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was used directly in the next step without purification.

A magnetic stir bar was placed in a 25 mL screw cap tube, flame dried under vacuum, cooled to room temperature, and filled with nitrogen. To the tube, the material obtained in the above step, KOH (200 mg, 3.6 mmol, 36 equivalents), and dry isopropyl alcohol (dry i-PrOH; 2.3 mL) were added under a nitrogen stream. The contents were refluxed for 16 hours. After cooling to room temperature, water (10 mL) and CH ₂ Cl ₂ (10 mL) were added to the mixture. The mixture was neutralized with 1M HCl and concentrated with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography (hexane / ethyl acetate = 1: 1 to 0: 1), and a mixture of compound 14a and compound 14b (14a / 14b = 2: 3 to 3: 2) as a white solid Obtained (54.2 mg, 91%).

[Synthesis Example 10: Synthesis of Compound (5)]
Synthesis Example 10-1: Synthesis of Compound 16a and Compound 16b

[Wherein TBAF is tetrabutylammonium fluoride; the same shall apply hereinafter. ]
A magnetic stir bar was placed in a 25 mL screw cap tube, flame dried under vacuum, cooled to room temperature, and filled with nitrogen. To this tube, 5- (4- (t-butyl) phenyl) -4- (4-methoxyphenyl) -3-phenyl-2- (4- (trifluoromethyl) phenyl) obtained in Synthesis Example 7-3 Thiophene 1-oxide (Compound 26acdf; 44.8 mg, 0.08 mmol, 1.0 equivalent), 4-hydroxy-2,5-bis (trimethylsilyl) phenyl trifluoromethanesulfonate obtained in Synthesis Example 1-4 (Compound 5; 94.0 mg, 0.24 mmol, 3.0 eq), and THF (400 μL) were added under a stream of nitrogen. Then, tetrabutylammonium fluoride (TBAF; 480 μL, 0.48 mmol, 6.0 eq, 1M in THF) was slowly added to the mixture. The reaction mixture was stirred at room temperature for 24 hours. After adding water (10 mL) and CH ₂ Cl ₂ (10 mL) to the mixture, the resulting mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was purified by preparative thin layer chromatography (hexane / ethyl acetate = 10: 1) and GPC, and a mixture of compound 16a and compound 16b (16a / 16b = 5: 4 to 4: 5) was obtained as a white solid. Obtained (45.3 mg, 84%).

Synthesis Example 10-2: Synthesis of Compound 17a and Compound 17b

A magnetic stir bar was placed in a 25 mL screw cap tube, flame dried under vacuum, cooled to room temperature, and filled with nitrogen. To this tube, a mixture of compound 16a and compound 16b obtained in Synthesis Example 10-1 (35.4 mg, 0.052 mmol, 1.0 equivalent) and CH ₂ Cl ₂ (500 μL) were added under a nitrogen stream. The contents were cooled to 0 ° C., and N, N-diisopropylethylamine (i-Pr ₂ NEt; 27.2 μL, 0.156 mmol, 3.0 eq), N, N-dimethylaminopyridine (DMAP; 1.3 mg, 10 μmol, 20 mol%) and trifluoromethanesulfonic anhydride (Tf ₂ O; 26.2 μL, 0.156 mmol, 3.0 eq) were added. The resulting mixture was stirred at 0 ° C. for 0.5 hour. The reaction mixture was warmed to room temperature and stirred for 12 hours, and then water (10 mL) and CH ₂ Cl ₂ (10 mL) were added to the mixture. After the mixture was extracted with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was purified by preparative thin layer chromatography (hexane / ethyl acetate = 10: 1) and GPC, and a mixture of compound 17a and compound 17b (17a / 17b = 5: 4 to 4: 5) was obtained as a white solid. Obtained (45.3 mg, 84%).

[Synthesis Example 11: Synthesis of Compound (33)]
Synthesis Example 11-1: Synthesis of Compound 27a

4-Ethynylacetophenone was synthesized according to the method reported in the previous report (Org. Lett. 15, 936 (2013)).

A magnetic stirring bar was placed in a 50 mL Schlenk tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. To this Schlenk tube, 4-ethynylacetophenone (288 mg, 2.0 mmol, 1.0 equivalent), 4-iodopyridine (410 mg, 2.0 mmol, 1.0 equivalent), bis (triphenylphosphine) palladium (II) dichloride (140 mg, 0.2 mmol, 20 mol%), copper (I) iodide (38 mg, 0.2 mmol, 20 mol%), triethylamine (836 μL, 6.0 mmol, 3.0 eq), and dry THF (10 mL) were added under a nitrogen stream. . After the mixture was stirred at room temperature for 3 hours, water (30 mL) and CH ₂ Cl ₂ (20 mL) were added. After extraction with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. Purification by flash column chromatography (hexane / ethyl acetate = 1: 1) and recrystallization (CHCl ₃ / hexane) gave compound 27a as orange crystals (196 mg, 44%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.64 (d, J = 5.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.41 ( d, J = 5.4 Hz, 1H), 2.63 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 197.1, 149.9, 136.9, 132.0, 130.7, 128.3, 126.8, 125.5, 92.7, 89.5, 26.6 HRMS (APCI) m / z calcd for C ₁₅ H ₁₂ NO [MH] ⁺ : 222.09134, found 222.09074.

Synthesis Example 11-2: Synthesis of Compound 27b

[In the formula, Ac represents an acetyl group. The same applies hereinafter. ]
A magnetic stirring bar was placed in a 50 mL Schlenk tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. To this Schlenk tube, 4-ethynylacetophenone (158.3 mg, 1.1 mmol, 1.1 eq), 2-iodonaphthalene (254.6 mg, 1.0 mmol, 1.0 eq), bis (triphenylphosphine) palladium (II) dichloride (35.1 mg, 0.05 mmol, 5 mol%), copper (I) iodide (9.5 mg, 0.05 mmol, 5 mol%), triethylamine (420 μL, 3.0 mmol, 3.0 eq), and dry THF (7 mL) were added under a nitrogen stream. . After the reaction mixture was stirred at room temperature for 9 hours, water (15 mL) and CH ₂ Cl ₂ (10 mL) were added to the mixture. After extraction with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. Purification by flash column chromatography (hexane / ethyl acetate = 10: 1) and recrystallization (CHCl ₃ / hexane) gave compound 7b as white crystals (196 mg, 73%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.08 (s, 1H), 7.95 (d, J = 6.6 Hz, 2H), 7.85-7.81 (m, 3H), 7.65 (d, J = 6.6 Hz, 2H ), 7.59 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.53-7.49 (m, 2H), 2.62 (s, 3H).

[Synthesis Example 12: Synthesis of Compound (33B)]
Synthesis Example 12-1: Synthesis of Compound 28

Compound 28 was synthesized according to the method reported in the previous report (Chem. Commun. 46, 931 (2010)).

[Example 1 (first aspect): Synthesis of compound (1)]
Example 1-1: Synthesis of Compound 15a and Compound 15b

A magnetic stirring bar was placed in a 7 mL screw cap tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. To this tube, a mixture of Compound 14a and Compound 14b obtained in Synthesis Example 4-1 (8.1 mg, 13.6 μmol, 1.0 equivalent), 2- (4-chlorophenyl) -4- (3 , 5-Dimethoxyphenyl) -5- (m-tolyl) -3- (p-tolyl) thiophene 1-oxide (Compound 11; 14.3 mg, 27.1 μmol, 2.0 eq) and dichloroethane (140 μL) under nitrogen flow Added. The temperature was raised to 80 ° C., and a solution of t-butylnitrile (2.4 μL, 20.4 μmol, 1.5 equivalents) in dichloroethane (140 μL) was slowly added to this tube for 1 hour. The resulting mixture was further heated at 80 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, water (5 mL) and CH ₂ Cl ₂ (5 mL) were added to the mixture. After the mixture was extracted with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was purified by preparative thin layer chromatography (hexane / ethyl acetate = 10: 1) to obtain a mixture of compound 15a and compound 15b (15a / 15b = 2: 1) as a white solid (3.0 mg, twenty two %)
1- (4- (t-butyl) phenyl) -5- (4-chlorophenyl) -7- (3,5-dimethoxyphenyl) -2- (4-methoxyphenyl) -3-phenyl-8- (m- Tolyl) -6- (p-tolyl) -4- (4- (trifluoromethyl) phenyl) naphthalene (compound 15a):
¹ H NMR (600 MHz, CDCl ₃ ): δ 6.94-6.25 (m, 30H), 5.89 (t, J = 2.4 Hz, 1H), 5.80 (s, 1H), 5.75 (s, 1H), 3.55 (s , 3H) 3.36 (s, 3H), 3.35 (s, 3H), 2.07 (s, 3H), 1.87 (s, 3H), 1.15 (s, 9H).

[Example 2 (first aspect): Synthesis of compound (2)]
Example 2-1: Synthesis of compound 18a and compound 18b

A magnetic stir bar was placed in a 25 mL screw cap tube, flame dried under vacuum, cooled to room temperature, and filled with nitrogen. To this tube, a mixture of compound 17a and compound 17b obtained in Synthesis Example 5-2 (11.8 mg, 0.015 mmol, 1.0 equivalent), 2- (4-chlorophenyl) -4- (3 , 5-Dimethoxyphenyl) -5- (m-tolyl) -3- (p-tolyl) thiophene 1-oxide (compound 11; 23.1 mg, 0.44 mmol, 3.0 eq) and THF (150 μL) under nitrogen flow Added. After cooling to 0 ° C., tetrabutylammonium fluoride (TBAF; 66 μL, 0.066 mmol, 4.5 eq, 1M in THF) was slowly added to the mixture. The reaction mixture was stirred at 0 ° C. for 3 hours. After adding water (10 mL) and CH ₂ Cl ₂ (10 mL) to the mixture, the resulting mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was purified by preparative thin layer chromatography (hexane / ethyl acetate = 20: 1) to isolate compound 18a (2.3 mg) and compound 18b (2.2 mg) as a yellow solid (29 %). The low polarity compound is Compound 18a and the high polarity compound is Compound 18b. The structure of compound 18a was determined by X-ray crystal structure analysis.
1- (4- (t-butyl) phenyl) -5- (4-chlorophenyl) -7- (3,5-dimethoxyphenyl) -2- (4-methoxyphenyl) -3-phenyl-8- (m- Tolyl) -6- (p-tolyl) -4- (4- (trifluoromethyl) phenyl) anthracene (compound 18a):
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.02 (s, 1H), 7.71 (s, 1H), 7.34-6.65 (m, 27H), 6.41-6.38 (m, 2H), 6.01-5.99 (m, 2H), 5.97 (t, J = 2.4 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 6H), 2.15 (s, 3H), 2.12 (s, 3H), 1.28 (s, 9H).
1- (4- (t-butyl) phenyl) -8- (4-chlorophenyl) -6- (3,5-dimethoxyphenyl) -2- (4-methoxyphenyl) -3-phenyl-5- (m- Tolyl) -7- (p-tolyl) -4- (4- (trifluoromethyl) phenyl) anthracene (compound 18b):
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.05 (s, 1H), 7.65 (s, 1H), 7.34-6.65 (m, 27H), 6.41-6.37 (m, 2H), 6.04-6.01 (m, 2H), 5.97 (t, J = 2.4 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 6H), 2.15 (s, 3H), 2.12 (s, 3H), 1.28 (s, 9H).

[Example 3 (second aspect): Synthesis of compound (31A)]
Example 3-1: Synthesis of polysubstituted aromatic compound 29a and polysubstituted aromatic compound 29b

[Wherein t-Bu represents a t-butyl group. The same applies hereinafter. ]
A magnetic stirring bar was placed in a 7 mL screw cap tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. To this screw cap tube, tetrasubstituted thiophene S-oxide compound 26acdf obtained in Synthesis Example 7-3 (25.5 mg, 0.045 mmol, 1.0 equivalent), compound 27a obtained in Synthesis Example 11-1 (19.9 mg, 0.090 mmol, 2.0 equivalents) and mesitylene (300 μL) were added under a stream of nitrogen. The screw cap tube was heated at 160 ° C. for 48 hours. After cooling the reaction mixture to room temperature, the mixture is concentrated in vacuo and the crude product is purified by preparative thin layer chromatography (hexane / ethyl acetate = 2: 1 and hexane / CHCl ₃ = 1: 2), A mixture of the polysubstituted aromatic compound 29a and the polysubstituted aromatic compound 29b was obtained as a white solid (10.5 mg, 32% (mixture), 29a / 29b = 5: 4). After recrystallization of the mixture of the polysubstituted aromatic compound 29a and the polysubstituted aromatic compound 29b was repeated 6 times, the polysubstituted aromatic compound 29a was obtained as a single isomer.
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.08 (dd, J = 4.2, 1.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.94-6.87 (m, 9H), 6.79-6.76 (m, 2H), 6.72 (d, J = 6.0 Hz, 1H), 6.69-6.66 (m, 4H), 6.41 (d, J = 8.4 Hz, 2H) , 3.61 (s, 3H), 2.44 (s, 3H), 1.13 (s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 197.6, 157.3, 148.9, 148.7, 148.3, 144.8, 143.8, 141.5, 141.2, 141.1, 139.6, 138.8, 138.2, 137.7, 136.2, 134.6, 132.2, 132.0, 131.4, 131.3, 131.1, 130.7, 127.7 (q, ² J _CF = 31.7 Hz), 127.2, 127.0, 126.2, 125.8, 124.0 ( q, ¹ J _CF = 270 Hz), 123.9, 123.8 (q, ³ J _CF = 2.85 Hz), 112.3, 55.0, 34.2, 31.1, 26.4; HRMS (APCI) m / z calcd for C ₄₉ H ₄₁ F ₃ NO ₂ [MH] ⁺ : 732.30839, found 732.30566.

Example 3-2: Synthesis of polysubstituted aromatic compound 30a and polysubstituted aromatic compound 30b

A magnetic stirring bar was placed in a 7 mL screw cap tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. A mixture (21.9 mg, 0.03 mmol, 1.0 equivalent) of the compound 29a and compound 29b obtained in Example 3-1 and methanol (1.2 mL) were added to the screw cap tube under a nitrogen stream. The contents were cooled to 0 ° C. and a solution of sodium borohydride in methanol (300 μL, 0.3 M, 0.09 mmol) was added slowly. After the mixture was stirred for 0.5 h, the reaction was quenched with aqueous NaHCO ₃ solution. The mixture was extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting mixture was used in the next step without further purification.

A magnetic stirring bar was placed in a 7 mL screw cap tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. To the screw cap tube, the material obtained in the above step and dry CH ₂ Cl ₂ (600 μL) were added under a nitrogen stream. The contents were cooled to 0 ° C. and 2,6-lutidine (17.5 μL, 0.15 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf: 34.5 μL, 0.15 mmol) were slowly added to the screw cap tube. . After the mixture was stirred for 0.5 h, the reaction was quenched with methanol (3 mL) and the mixture was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (hexane / ethyl acetate = 10: 1) to give polysubstituted aromatic compound 30a (9.0 mg) and polysubstituted aromatic compound 30b (8.8 mg) as a white solid. Obtained (70%). The more polar compound is the polysubstituted aromatic compound 30a, and the less polar compound is the polysubstituted aromatic compound 30b. The structure of the polysubstituted aromatic compound 30a was determined by X-ray crystal structure analysis. The X-ray crystal structure of the polysubstituted aromatic compound 30a is shown in FIG.
Polysubstituted aromatic compound 30a:
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.05 (d, J = 6.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 6.92-6.86 (m, 8H), 6.80-6.77 (m , 3H), 6.73-6.67 (m, 8H), 6.40 (d, J = 9.0 Hz, 2H), 4.58 (q, J = 6.0 Hz, 1H), 3.60 (s, 3H), 1.19 (d, J = 6.0 Hz, 3H), 1.13 (s, 9H), 0.80 (s, 9H), -0.12 (s, 3H), -0.25 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 157.2, 149.2, 148.7, 147.9, 144.9, 144.3, 141.1, 140.8, 140.5, 140.0, 139.5, 139.2, 137.9, 137.8, 136.5, 132.3, 132.2, 131.6, 131.5, 131.2, 130.9, 130.8, 130.7, 127.3 (q, ² J _CF = 33.0 Hz), 126.9, 126.5, 125.6, 124.2, 124.1 (q, ¹ J _CF = 271 Hz), 124.0, 123.8, 123.5, 112.2, 70.6, 55.0, 34.2, 31.2, 27.0, 25.8, 18.2, -4.79 , -5.16 ( ³ J _CF : not detected); HRMS (APCI) m / z calcd for C ₅₅ H ₅₇ F ₃ NO ₂ Si [MH] ⁺ : 848.41052 found 848.40628.
Polysubstituted aromatic compound 30b:
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.07 (d, J = 5.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.91- 6.76 (m, 9H), 6.73-6.64 (m, 8H), 6.40 (d, J = 8.4 Hz, 2H), 4.59 (q, J = 6.0 Hz, 1H), 3.61 (s, 3H), 1.17 (d , J = 6.0 Hz, 3H), 1.10 (s, 9H), 0.81 (s, 9H), -0.11 (s, 3H), -0.22 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 157.2, 149.0, 148.13, 148.08, 144.5, 144.0, 141.8, 141.1, 140.5, 140.3, 139.8, 138.11, 138.06, 137.1, 136.8, 132.4, 132.3, 131.5, 131.2, 130.84, 130.79, 127.8 (q, ² J _CF = 33.0 Hz), 127.0, 126.4, 125.6, 124.0 (q, ¹ J _CF = 270 Hz), 123.84 ( ³ J _CF : not detected), 123.78, 123.5, 123.4, 112.20, 112.17, 70.7, 55.0, 34.1, 31.1 , 27.1, 25.8, 18.2, -4.6 , -5.2; HRMS (APCI) m / z calcd for C 55 H 57 F 3 NO 2 Si [MH] +: 848.41052 found 848.40868.

Example 3-3: Synthesis of polysubstituted aromatic compound 31a and polysubstituted aromatic compound 31b

Instead of the tetrasubstituted thiophene S-oxide compound 6acdf obtained in Synthesis Example 7-3, the tetrasubstituted thiophene S-oxide compound 26acde (15.6 mg, 10.028 mmol) obtained in Synthesis Example 7-2 was used, and Synthesis Example 11- The compound 27b obtained in Synthesis Example 11-2 was used in place of the compound 27a obtained in 1, and the amount of mesitylene was 190 μL, and the purification treatment was performed by preparative thin layer chromatography (hexane / ethyl acetate = 3: 1). Except that, the synthesis was performed in the same manner as in Example 3-1, to obtain a polysubstituted aromatic compound 31a and a polysubstituted aromatic compound 31b as a mixture (6.8 mg, 31%).

[Example 4 (second aspect): Synthesis of compound (31B)]
Example 4-1: Synthesis of polysubstituted aromatic compound 32

A 20 mL Schlenk flask was charged with a magnetic stir bar, flame dried under vacuum, cooled to room temperature and filled with nitrogen. In this container, the tetrasubstituted thiophene S-oxide compound 26acdf obtained in Synthesis Example 7-3 (25.5 mg, 0.045 mmol, 1.0 equivalent), 2- (trimethylsilyl) phenyl trifluoromethanesulfonate (32.7 μL, 0.135 mmol, 3.0 equivalent) , And THF (450 μL) were added under a stream of nitrogen. The contents were cooled to 0 ° C., and a THF solution of tetrabutylammonium fluoride (200 μL, 1.0 M, 0.2 mmol) was added to the flask. The resulting mixture was warmed to room temperature and stirred for 1 hour, and then water (1 mL) was added to the mixture. After extraction with CH ₂ Cl ₂ , the organic layer was dried over Na ₂ SO ₄ and volatiles were removed under reduced pressure. The crude product was purified by preparative thin layer chromatography (hexane / CH ₂ Cl ₂ = 3: 2) to give the polysubstituted aromatic compound 32 as a white solid (22.5 mg, 85%).
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.72-7.70 (m, 1H), 7.52-7.48 (m, 2H), 7.42-7.38 (m, 2H), 7.33 (d, J = 7.8 Hz, 2H) , 7.26 (dd, J = 6.6, 2.4 Hz, 2H, overlapping with the peak of CHCl ₃ ), 7.10 (dd, J = 6.6, 1.8 Hz, 2H), 6.90-6.84 (m, 3H), 6.82-6.78 ( m, 2H), 6.70 (dd, J = 6.6, 2.4 Hz, 2H), 6.40 (dd, J = 6.9, 2.4 Hz, 2H), 3.60 (s, 3H), 1.30 (s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 157.1, 149.2, 143.8, 140.2, 139.4, 139.2, 138.5, 136.6, 136.3, 132.7, 132.3, 132.2, 131.6, 131.5, 131.2, 130.8, 128.5 (q, 2JCF = 33.2 Hz) , 127.3, 126.8, 126.3, 126.0, 125.9, 125.6, 124.5 (q, ³ J _CF = 2.9 Hz), 124.4, 124.3 (q, ¹ J _CF = 273 Hz), 112.1, 55.0, 34.4, 31.3; HRMS (APCI ) m / z calcd for C ₄₀ H ₃₄ F ₃ O [MH] ⁺ : 587.25563, found 587.25334.

Example 4-2: Synthesis of polysubstituted aromatic compound 33

A magnetic stirring bar was placed in a 7 mL screw cap tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. To this screw cap tube, tetrasubstituted thiophene S-oxide compound 26acdf obtained in Synthesis Example 7-3 (25.5 mg, 0.045 mmol, 1.0 equivalent), compound 28 obtained in Synthesis Example 12 (dibenzo [a, e] cyclooctyne ) (18.0 mg, 0.09 mmol, 2.0 equivalents) and m-xylene (450 μL) were added under a stream of nitrogen. The flask was heated at 100 ° C. for 16 hours. After cooling the reaction mixture to room temperature, the mixture is concentrated in vacuo and the crude product is purified by preparative thin layer chromatography (hexane / CHCl ₃ = 2: 1) to give the polysubstituted aromatic compound 33 as a white solid (14.1 mg, 44%).
¹ H NMR (600 MHz, C ₂ D ₂ Cl ₄ , 146 ° C): δ 7.14 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 7.01-6.75 (m, 15H ), 6.72-6.63 (m, 4H), 6.45 (d, J = 8.4 Hz, 2H), 3.62 (s, 3H), 3.35-3.23 (m, 2H), 3.03-2.94 (m, 2H), 1.17 ( s, 9H); ¹³ C NMR (150 MHz, C ₂ D ₂ Cl ₄ , 146 ° C): δ 157.4, 148.2, 144.6, 141.0, 140.9, 140.8, 140.7, 140.62, 140.59, 140.3, 140.2, 139.3, 139.0, 137.8, 137.2, 133.1, 132.3, 131.3, 130.9, 130.3, 130.2, 128.5, 128.3, 127.5 (q, ² J _CF = 31.7 Hz), 126.4, 126.3, 126.0, 125.2, 124.6, 124.5, 124.1 (q, ¹ J _CF = 274 Hz), 123.1, 123.0, 112.4, 55.1, 33.78, 33.75, 33.73, 30.9 ( ³ J _CF : not detected); HRMS (APCI) m / z calcd for C ₄₆ H ₃₄ F ₃ O [MC ₄ H ₈ ] ⁺ : 659.25563, found 659.25314.

[Example 5 (second aspect): Synthesis of compound (31C)]
Example 5-1: Synthesis of polysubstituted aromatic compound 34a and polysubstituted aromatic compound 34b

A magnetic stirring bar was placed in a 7 mL screw cap tube, flame-dried under vacuum, cooled to room temperature, and filled with nitrogen. To this screw cap tube, the tetra-substituted thiophene S-oxide compound 26acdf (0.03 mmol, 1.0 equivalent) obtained in Synthesis Example 7-3 and 3-cyanopyridine (300 μL, 3.0 mmol) were added under a nitrogen stream. The flask was heated at 160 ° C. for 24 hours. After the reaction mixture was cooled to room temperature, the mixture was purified by preparative thin layer chromatography to obtain polysubstituted aromatic compound 34a (1.6 mg) and polysubstituted aromatic compound 34b (1.6 mg) in a total yield of 17%. Obtained. The more polar compound is the polysubstituted aromatic compound 34a, and the less polar compound is the polysubstituted aromatic compound 34b. The structure of polysubstituted aromatic compound 34b was determined by X-ray crystal structure analysis. The X-ray crystal structure of the polysubstituted aromatic compound 34b is shown in FIG.
Polysubstituted aromatic compound 34a:
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.50 (d, J = 4.8 Hz, 1H), 7.50-7.45 (m, 3H), 7.41 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 7.8 Hz, 4.8 Hz, 1H), 7.08-7.01 (m, 3H), 6.98 (d, J = 7.8 Hz, 2H), 6.89-6.85 (m, 2H ), 6.78 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 9.0 Hz, 2H), 3.64 (s, 3H), 1.18 (s, 9H ); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 158.8, 157.9, 156.2, 155.1, 150.2, 149.1, 148.9, 144.4, 137.9, 135.4, 135.3, 134.6, 131.6, 131.2, 130.6, 130.5, 129.8, 129.1 ( q, ² J _CF = 31.7 Hz), 127.7, 126.6, 124.8, 124.4, 124.2 (q, ¹ J _CF = 271 Hz), 124.1, 122.0, 112.5, 55.0, 34.3, 31.2 ( ³ J _CF : not detected); HRMS (APCI) m / z calcd for C ₄₀ H ₃₄ F ₃ N ₂ O [MH] ⁺ : 615.26177 found 615.25989.
Polysubstituted aromatic compound 34b:
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.35 (d, J = 4.8 Hz, 1H), 7.63-7.58 (m, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.23-7.18 (m , 4H), 7.12-7.08 (m, 1H), 7.02 (d, J = 7.8 Hz, 2H), 6.98-6.93 (m, 3H), 6.79 (d, J = 9.0 Hz, 2H), 6.77-6.72 ( m, 2H), 6.56 (d, J = 9.0 Hz, 2H), 3.69 (s, 3H), 1.26 (s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 158.6, 158.0, 157.2, 155.0 , 150.5, 150.3, 148.5, 142.4, 137.65, 137.56, 135.9, 134.4, 132.7, 132.3, 131.3, 130.3, 129.8, 128.0 (q, ² J _CF = 31.7 Hz), 127.2, 126.5, 124.8, 124.6, 124.1 (q , ¹ J _CF = 270 Hz), 123.9 (q, ³ J _CF = 2.85 Hz), 122.2, 113.0, 55.0, 34.5, 31.2; HRMS (APCI) m / z calcd for C ₄₀ H ₃₄ F ₃ N ₂ O [ MH] ⁺ : 615.26177 found 615.26088.

Example 5-2: Synthesis of polysubstituted aromatic compound 35a and polysubstituted aromatic compound 35b

The amount of tetrasubstituted thiophene S-oxide compound 26acdf was 5.6 mg, 0.01 mmol, 4-methylbenzonitrile (145 mg, 1 mmol) was used instead of 2-cyanopyridine, and the heating temperature was 160 ° C to 230 ° C. Except that described above, synthesis was performed in the same manner as in Example 5-1, and a mixture of the polysubstituted aromatic compound 35a (0.5 mg) and the polysubstituted aromatic compound 35b (0.5 mg) was obtained with a total yield of 16%.

Example 5-3: Synthesis of polysubstituted aromatic compound 36a and polysubstituted aromatic compound 36b

Example 5 except that the amount of tetrasubstituted thiophene S-oxide compound 26acdf was 5.6 mg, 0.01 mmol, and 4- (trifluoromethyl) benzonitrile (171 mg, 1 mmol) was used instead of 2-cyanopyridine. Synthesis was carried out in the same manner as for -1, and a polysubstituted aromatic compound 36a and a polysubstituted aromatic compound 36b were obtained as a mixture (0.7 mg, 10% (mixture)).

Claims

General formula (1):

[Wherein R 1 to R 8 represent an optionally substituted aryl group or an optionally substituted heteroaryl group. Five or more of R 1 to R 8 are different groups. ]
Or general formula (2):

[Wherein, R 9 to R 16 each represents an optionally substituted aryl group or an optionally substituted heteroaryl group. R 17 to R 18 each represents a hydrogen atom, an optionally substituted aryl group or an optionally substituted heteroaryl group. 5 or more of R 9 to R 18 are different groups. ]
The polysubstituted aromatic compound represented by these.
The polysubstituted aromatic compound according to claim 1, wherein in the general formula (1), R 1 to R 8 are all different groups.
The polysubstituted aromatic compound according to claim 1, wherein, in the general formula (2), R 17 to R 18 are hydrogen atoms and R 9 to R 16 are all different groups.
The general formula (2), wherein R 17 to R 18 are an optionally substituted aryl group or an optionally substituted heteroaryl group, and R 9 to R 18 are all different groups. The polysubstituted aromatic compound described in 1.
A method for producing a polysubstituted aromatic compound according to any one of claims 1 to 4,
General formula (3):

[Wherein R 1 to R 4 are the same as defined above. ]
A tetrasubstituted thiophene S-oxide compound represented by:
General formula (4):

[Wherein R 5 to R 8 are the same as defined above. One of R 19 and R 20 is a carboxy group and the other is an amino group, or one is a silyl group and the other is a trifluoromethanesulfonate group. ]
Or a compound represented by the general formula (5):

[Wherein R 13 to R 18 are the same as defined above. One of R 21 and R 22 is a carboxy group and the other is an amino group, or one is a silyl group and the other is a trifluoromethanesulfonate group. ]
The manufacturing method provided with the process with which the compound represented by these is made to react.
The compound represented by the general formula (4) is represented by the general formula (6):

[Wherein R 5 to R 8 are the same as defined above. ]
Obtained by reacting the compound represented by the formula with maleimide, and reacting the compound obtained in the previous step with the oxidizing agent and the first base, and further reacting with the second base. The manufacturing method according to claim 5.
The compound represented by the general formula (5) is represented by the general formula (7):

[Wherein R 13 to R 16 are the same as defined above. ]
And a compound of the general formula (8)

[Wherein R 17 to R 18 and R 21 to R 22 are the same as defined above. R 23 is a silyl group. ]
The manufacturing method of Claim 5 obtained by the method of providing the process with which the compound represented by these are made to react and the process of substituting the hydroxyl group of the compound obtained at the said process by the trifluoromethanesulfonate group.