JP6778588B2 - Method for forming catalyst, amide bond, and method for producing amide compound - Google Patents

Description

The present invention relates to a novel catalyst, a method for forming an amide bond using the catalyst, and a method for producing an amide compound using the same.

The amide bond is a basic structural unit of biopolymers such as proteins and synthetic polymers such as nylon, and is contained in 25% of synthetic pharmaceuticals. Therefore, the amide bond forming reaction is very useful industrially (see Non-Patent Document 1).

The amide bond forming reaction is usually carried out using a stoichiometric activator. Therefore, there is a problem that a large amount of waste is produced as a by-product while a desired amide is produced.
Therefore, in 2006, a working group consisting of multiple pharmaceutical companies belonging to the Green Chemistry Subcommittee of the American Chemical Society selected "Amide bond formation reaction with less waste" as the most desired reaction for development (Non-Patent Documents). 2).

Therefore, in recent years, a catalytic amide bond forming reaction has been studied and proposed (see Non-Patent Document 3).
For example, reactions using enzyme catalysts have been proposed. However, this reaction has the problem that the range of application of the substrate to the enzyme is limited.
For example, a reaction using a metal catalyst has been proposed. However, this reaction has a problem that it requires a high temperature of about 150 ° C.
For example, a reaction using boric acid, aromatic boronic acid, or aromatic boric acid as a catalyst has been proposed (see Non-Patent Document 4). However, in this method, about 10 mol% of the catalyst is used with respect to the substrate, and the yield is about 50% to 60%. In particular, there is a problem in that the applicable range of the substrate is limited, and specifically, it is not suitable for the reaction of a substrate having a sterically bulky group.

Therefore, at present, there is a demand for a catalyst that can be used for an amide bond forming reaction, does not require a reaction at a high temperature, and has a wide range of substrate application.

J. Med. Chem. , 2011, 54, 3451. Green Chem. , 2007, 5, 411. Chem. Soc. Rev. , 2014, 43, 2714. J. Org. Chem. , 2012, 77, 8386.

An object of the present invention is to solve the above-mentioned problems in the past and to achieve the following object. That is, the present invention provides a catalyst that can be used for an amide bond forming reaction, does not require a reaction at a high temperature, and has a wide range of substrate application, a method for forming an amide bond using the catalyst, and a method thereof. An object of the present invention is to provide a method for producing an amide compound using a catalyst.

The means for solving the above-mentioned problems are as follows. That is,
The catalyst of the present invention is represented by the following general formula (1).
However, in the general formula (1), R ^{1 to} R ¹⁶ independently represent either a hydrogen atom or a substituent.

The method for forming an amide bond of the present invention is characterized in that a carboxyl group of a carboxylic acid compound and an amino group of an amine compound are reacted in the presence of the catalyst of the present invention to form an amide bond.

The method for producing an amide compound of the present invention is characterized in that a carboxylic acid compound and an amine compound are reacted in the presence of the catalyst of the present invention to obtain an amide compound.

According to the present invention, a catalyst which can solve the above-mentioned problems in the past, can achieve the above-mentioned object, can be used for an amide bond forming reaction, does not require a reaction at a high temperature, and has a wide range of substrate application It is possible to provide, a method for forming an amide bond using the catalyst, and a method for producing an amide compound using the catalyst.

(catalyst)
The catalyst of the present invention is represented by the following general formula (1).
However, in the general formula (1), R ^{1 to} R ¹⁶ independently represent either a hydrogen atom or a substituent.

<Substituent>
The substituent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include an electron donating group and an electron attracting group.
As will be understood from Examples described later, the catalyst forms an amide bond even if R ^{1 to} R ¹⁶ have an electron donating group or an electron attracting group in the general formula (1). It functions as a catalyst in the reaction.

<< Electron donating group >>
Examples of the electron donating group include an alkyl group, a hydroxyl group, a mercapto group, an alkyloxy group, an acyloxy group, a sulfonyloxy group, an alkoxycarbonyloxy group, an aryloxycarbonyloxy group, an alkylthio group, an amino group, a mono or a di. Substituted amino groups and the like can be mentioned.

As the alkyl group, an alkyl group having 1 to 20 carbon atoms is preferable, an alkyl group having 1 to 12 carbon atoms is more preferable, and an alkyl group having 1 to 6 carbon atoms is particularly preferable.
Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, hexyl group, decyl group, dodecyl group, tetradecyl group and hexadecyl group. And so on.

As the alkyloxy group, an alkyloxy group having 1 to 20 carbon atoms is preferable, an alkyloxy group having 1 to 12 carbon atoms is more preferable, and an alkyloxy group having 1 to 6 carbon atoms is particularly preferable.
Examples of the alkyloxy group include a methoxy group, an ethoxy group, an isopropoxy group, a butoxy group, a t-butoxy group, a hexyloxy group, an octyloxy group, a decyloxy group, a dodecyloxy group, a tetradecyloxy group and an octadecyloxy group. And so on.

As the acyloxy group, an acyloxy group having 1 to 20 carbon atoms is preferable, an acyloxy group having 1 to 12 carbon atoms is more preferable, and an acyloxy group having 1 to 6 carbon atoms is particularly preferable.
Examples of the acyloxy group include a formyloxy group, an acetyloxy group, a propionyloxy group, a benzoyloxy group and the like.

Examples of the sulfonyloxy group include a benzenesulfonyloxy group and a p-toluenesulfonyloxy group.

As the alkoxycarbonyloxy group, an alkoxycarbonyloxy group having 2 to 21 carbon atoms is preferable, an alkoxycarbonyloxy group having 2 to 13 carbon atoms is more preferable, and an alkoxycarbonyloxy group having 2 to 7 carbon atoms is particularly preferable.

Examples of the aryloxycarbonyloxy group include a phenyloxycarbonyloxy group.

As the alkylthio group, an alkylthio group having 1 to 20 carbon atoms is preferable, an alkylthio group having 1 to 12 carbon atoms is more preferable, and an alkylthio group having 1 to 6 carbon atoms is particularly preferable.

Examples of the mono or di-substituted amino group include a mono or dialkylamino group, an acylamino group, a sulfonylamino group and the like.

<< Electron attracting group >>
Examples of the electron-withdrawing group include halogen atom, haloalkyl group, aryl group, carboxyl group, alkyloxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, acyl group, cyano group, nitro group, sulfo group and alkyl. Examples thereof include an oxysulfonyl group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

As the haloalkyl group, a haloalkyl group having 1 to 20 carbon atoms is preferable, a haloalkyl group having 1 to 12 carbon atoms is more preferable, and a haloalkyl group having 1 to 6 carbon atoms is particularly preferable.
Examples of the haloalkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group and the like.

Examples of the aryl group include a phenyl group, a tolyl group, a xsilyl group, a naphthyl group and the like.

As the alkyloxycarbonyl group, an alkyloxycarbonyl group having 1 to 20 carbon atoms is preferable, an alkyloxycarbonyl group having 1 to 12 carbon atoms is more preferable, and an alkyloxycarbonyl group having 1 to 6 carbon atoms is particularly preferable.
Examples of the alkyloxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a t-butoxycarbonyl group, a hexyloxycarbonyl group and the like.

As the aryloxycarbonyl group, an aryloxycarbonyl group having 6 to 20 carbon atoms is preferable.
Examples of the aryloxycarbonyl group include a phenyloxycarbonyl group and a naphthyloxycarbonyl group.

As the aralkyloxycarbonyl group, an aralkyloxycarbonyl group having 7 to 21 carbon atoms is preferable.
Examples of the aralkyloxycarbonyl group include a benzyloxycarbonyl group and the like.

As the acyl group, an acyl group having 1 to 20 carbon atoms is preferable, an acyl group having 1 to 12 carbon atoms is more preferable, and an acyl group having 1 to 6 carbon atoms is particularly preferable.
Examples of the acyl group include an aliphatic acyl group and an aromatic acyl group.
Examples of the acyl group include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a pivaloyl group, a hexanoyl group, a benzoyl group and a naphthoyl group.

As the alkyloxysulfonyl group, an alkyloxysulfonyl group having 1 to 20 carbon atoms is preferable, an alkyloxysulfonyl group having 1 to 12 carbon atoms is more preferable, and an alkyloxysulfonyl group having 1 to 6 carbon atoms is particularly preferable.
Examples of the alkyloxysulfonyl group include a methoxysulfonyl group and an ethoxysulfonyl group.

-R ¹² and R ^16-
Further, any of R ¹² and R ¹⁶ may be a group represented by the following general formula (2) as an electron-withdrawing group, or may be represented by the following general formula (3) as an electron-withdrawing group. It may be a group to be treated.
However, in the general formula (2), R ^{21 to} R ²⁷ each independently represent either a hydrogen atom or a substituent.
Examples of the substituent include the substituent exemplified in the description of the substituent in the general formula (1).
However, in the general formula (3), R ^{21 to} R ²⁷ and R ^{31 to} R ³⁵ each independently represent either a hydrogen atom or a substituent.
Examples of the substituent include the substituent exemplified in the description of the substituent in the general formula (1).

For example, R ^{21 to} R ²⁷ include the following groups.
R ²¹ is the same group as R ¹ .
R ²² is the same group as R ² .
R ²³ is the same group as R ³ .
R ²⁴ is the same group as R ⁴ .
R ²⁵ is the same group as R ⁵ .
R ²⁶ is the same group as R ⁶ .
R ²⁷ is the same group as R ⁷ .

Examples of the catalyst represented by the general formula (1) include a catalyst represented by the following general formula (1A), a catalyst represented by the following general formula (1B), and a catalyst represented by the following general formula (1C). Examples include catalysts. Of course, the catalyst of the present invention is not limited to the following general formula.
In the general formula (1A), ^{R 6} and ^{R 14} are respectively the same as the general formula (1) ^{R 6} and ^{R 14} in.
In the general formula (1B), ^{R 6} is the same as ^{R 6} in the general formula ^{(1), R 26} is the same as ^{R 26} in the general formula (2).
In the general formula (1C), ^{R 6} is the same as ^{R 6} in the general formula ^{(1), R 26} is the same as ^{R 26} in formula (3).

<Catalyst manufacturing method>
The method for producing the catalyst of the present invention is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include the methods exemplified in the following reaction schemes. More specific manufacturing methods are described in Examples below.

Although the compound obtained by the production method of the following scheme has an unstable B-Ph (phenyl) azaborin structure, there is no problem in using it as a catalyst.

(Method of forming an amide bond, method of producing an amide compound)
In the method for forming an amide bond of the present invention, the carboxyl group of the carboxylic acid compound and the amino group of the amine compound are reacted in the presence of the catalyst of the present invention to form an amide bond.
In the method for producing an amide compound of the present invention, a carboxylic acid compound and an amine compound are reacted in the presence of the catalyst of the present invention to obtain an amide compound.

<Carboxylic acid compound>
In the conventional amide bond forming reaction using a boron catalyst, a sterically bulky carboxylic acid compound cannot be used as a substrate.
On the other hand, unlike the conventional boron catalyst used in the amide bond forming reaction, the catalyst of the present invention can be used as a substrate for the amide bond forming reaction even if it is a sterically bulky carboxylic acid compound.
Therefore, in the method for forming the amide bond and the method for producing the amide compound, the carboxylic acid compound is not particularly limited as long as it is a compound having a carboxyl group, and can be appropriately selected depending on the intended purpose. ..

The carboxylic acid compound may be a monocarboxylic acid compound or a polyvalent carboxylic acid compound. The monocarboxylic acid compound is a compound having one carboxyl group in the molecule. The polyvalent carboxylic acid compound is a compound having two or more carboxyl groups in the molecule.
When the carboxylic acid compound is the polyvalent carboxylic acid compound, the amide bond forming reaction may be controlled by utilizing the difference in reactivity of each carboxyl group.

Examples of the carboxylic acid compound include compounds represented by the following general formula (A).
^Ra- COOH ... General formula (A)
However, the general formula (A), ^{R a} represents an organic group.

The molecular weight of the carboxylic acid compound is not particularly limited and may be appropriately selected depending on the intended purpose, but the molecular weight is preferably 1,000 or less, and more preferably 500 or less.

Specific examples of the carboxylic acid compound will be illustrated below. Of course, the carboxylic acid compound in the present invention is not limited to the following specific examples.

<Amine compound>
The amine compound is not particularly limited as long as it is a compound having an amino group, and can be appropriately selected depending on the intended purpose.

Examples of the amine compound include compounds represented by the following general formula (B).
R ^b −NR ^c H ・ ・ ・ General formula (B)
However, in the general formula (B), R ^b represents an organic group, R ^c represents a hydrogen atom or an organic group, and even if R ^b and R ^c are combined to form a ring structure. Good.

The molecular weight of the amine compound is not particularly limited and may be appropriately selected depending on the intended purpose, but the molecular weight is preferably 1,000 or less, and more preferably 500 or less.

The amine compound may be a monoamine compound or a multivalent amine compound. The amine compound is a compound having one amino group in the molecule. The polyvalent amine compound is a compound having two or more amino groups in the molecule.
When the amine compound is the polyvalent amine compound, the amide bond forming reaction may be controlled by utilizing the difference in reactivity of each amino group.

The amino group in the amine compound may be a primary amino group or a secondary amino group.

Specific examples of the amine compound will be illustrated below. Of course, the amine compound in the present invention is not limited to the following specific examples.

<Amide compound>
The amide compound is not particularly limited as long as it is a compound having an amide bond, and can be appropriately selected depending on the intended purpose. Examples thereof include compounds represented by the following general formula (C).
R ^a- CONR ^c- R ^b ... General formula (C)
However, in the general formula (A), ^Ra and R ^b independently represent an organic group, ^RC represents a hydrogen atom or an organic group, and R ^b and R ^c are combined. It may form a ring structure.

<Reaction conditions>
<< Amount of catalyst used >>
In the method for forming the amide bond and the method for producing the amide compound, the amount of the catalyst used is not particularly limited and may be appropriately selected depending on the intended purpose. However, the catalyst of the present invention is a conventional catalyst. The reaction can proceed with a smaller amount than the amount of the boron catalyst used. In that respect, the amount of the catalyst used is preferably 1 mol% to 10 mol%, more preferably 1 mol% to 8 mol%, particularly preferably 2 mol% to 7 mol%, based on the substrate (for example, the carboxylic acid compound). ..

<< Reaction temperature, reaction time >>
The reaction temperature in the method for forming the amide bond and the method for producing the amide compound is not particularly limited and may be appropriately selected depending on the intended purpose. However, the catalyst of the present invention has a high temperature (for example, 150 ° C.). ) Can proceed without the need for. In that respect, the reaction temperature is preferably 30 ° C. to 120 ° C., more preferably 40 ° C. to 100 ° C.
The reaction time is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include 1 hour to 48 hours.

<< Other conditions >>
The ratio of the amount of the carboxylic acid compound to the amount of the amine compound used is not particularly limited and may be appropriately selected depending on the intended purpose, but the equivalent ratio is preferable in terms of less waste.

The reaction in the method for forming the amide bond and the method for producing the amide compound is preferably carried out in the presence of an organic solvent. Examples of the organic solvent include benzene, toluene, xylene and the like.

The reaction in the method for forming the amide bond and the method for producing the amide compound is preferably carried out in an inert atmosphere. Examples of the inert atmosphere include a nitrogen atmosphere and an argon atmosphere.

Hereinafter, the present invention will be specifically described with reference to examples of the present invention, but the present invention is not limited to these examples.
In the following examples, "Ph" represents a phenyl group.

(Synthesis Example 1A)
<Synthesis of 2-bromo-6-phenylaniline>

2,6-Dibromoaniline (3.00 g, 11.9 mmol), phenylboronic acid (1.45 g, 11.9 mmol), sodium carbonate (7.60 g, 71.7 mmol), and tetrakis (triphenylphosphine) palladium ( 0) Ethanol (30 mL) and distilled water (30 mL) were added to a solution of (691 mg, 0.598 mmol) in toluene (120 mL) at room temperature, and the reaction solution was stirred under heating and reflux conditions under an argon atmosphere for 24 hours. Was cooled to room temperature. Distilled water (50 mL) was added and stirred, and the separated aqueous layer was extracted 3 times with n-hexane (50 mL). Then, all the organic layers were combined, saturated aqueous sodium chloride solution (50 mL) was added thereto, and the mixture was stirred and washed. Anhydrous sodium sulfate was added to the re-separated organic layer to dehydrate the organic layer, and the filtered filtrate was concentrated under reduced pressure. The concentrated solution thus obtained was purified by flash column chromatography (silica gel, n-hexane / chloroform) to obtain 2-bromo-6-phenylaniline as a white solid (1.66 g, 6.69 mmol, yield 56). %).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.48-7.33 (m, 6H), 7.05 (dd, J = 1.5, 7.6 Hz, 1H), 6.68 (dd, J = 1.5, 7.6 Hz, 1H) , J = 7.6, 7.8 Hz, 1H), 4.19 (s, 2H).

(Synthesis Example 1B)
<Synthesis of 2-Bromo-4-fluoro-6-phenylaniline>

2-Bromo in the same manner as in Synthesis Example 1A, except that 2,6-dibromoaniline (11.9 mmol) was changed to 2,6-dibromo-4-fluoroaniline (11.9 mmol) in Synthesis Example 1A. -4-Fluoro-6-phenylaniline was synthesized (yield 56%).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.51-7.44 (m, 2H), 7.44-7.34 (m, 3H), 7.20 (dd, J = 2.9, 7.9 Hz, 1H), 6.85 (dd, J = 2.9, 8.8 Hz, 1H), 4.02 (s, 2H).

(Synthesis Example 1C)
<Synthesis of 2-bromo-4-methyl-6-phenylaniline>

2-Bromo in the same manner as in Synthesis Example 1A, except that 2,6-dibromoaniline (11.9 mmol) was changed to 2,6-dibromo-4-methylaniline (11.9 mmol) in Synthesis Example 1A. -4-Methyl-6-phenylaniline was synthesized (yield 61%).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.47-7.34 (m, 4H), 7.39-7.34 (m, 1H), 7.27-7.26 (m, 1H) , 6.88 (d, J = 2.0 Hz, 1H), 3.87 (s, 2H), 2.26 (s, 3H).

(Synthesis Example 2A)
<Synthesis of 4-bromodibenzo [c, e] [1,2] azabolinin-6 (5H) -ol>

A solution of 2-bromo-6-phenylaniline (compound obtained in Synthesis Example 1A, 1.64 g, 6.61 mmol) in dichloromethane (83.0 mL) was cooled to 0 ° C. and stirred. Boron tribromide (1.0 M dichloromethane solution; 16.5 mL, 16.5 mmol) was slowly added dropwise, and then the reaction solution was stirred at room temperature for 24 hours. Then, distilled water (5 mL), saturated aqueous sodium hydrogen carbonate solution (30 mL), and diethyl ether (250 mL) were added at 0 ° C., and the mixture was stirred for 20 minutes, and the separated aqueous layer was extracted 3 times with diethyl ether (80 mL). .. Then, all the organic layers are combined, saturated aqueous sodium chloride solution (30 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtered filtrate is concentrated under reduced pressure. 4-Bromodibenzo [c, e] [1,2] azabolinin-6 (5H) -ol was obtained as a white solid (1.75 g, 6.39 mmol, 97% yield).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.43 (dd, J = 0.9, 8.3 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 8.09 (dd, J = 1.2, 7.5 Hz, 1H), 7.76-7.67 (m, 2H), 7.64 (s, 1H) , 7.49 (dd, J = 0.9, 7.4, 7.5 Hz, 1H), 7.02 (dd, J = 7.9, 8.0 Hz, 1H).

(Synthesis Example 2B)
<Synthesis of 4-bromo-2-fluorodibenzo [c, e] [1,2] azabolinin-6 (5H) -ol>

In Synthesis Example 2A, except that 2-bromo-6-phenylaniline (6.61 mmol) was changed to 2-bromo-4-fluoro-6-phenylaniline (compound obtained in Synthesis Example 1B, 6.61 mmol). Synthesized 4-bromo-2-fluorodibenzo [c, e] [1,2] azabolinin-6 (5H) -ol in the same manner as in Synthesis Example 2A (yield 100%).
^{1 1} H-NMR (400 MHz, d _6- DMSO) δ: 8.45 (dd, J = 0.9, 8.4 Hz, 1H), 8.33-8.25 (m, 2H), 8.10 (Dd, J = 1.3, 7.6 Hz, 1H), 7.75-7.67 (m, 2H), 7.61 (s, 1H), 7.53 (ddd, J = 0.9) , 7.3, 7.6 Hz, 1H).

(Synthesis Example 2C)
<Synthesis of 4-bromo-2-methyldibenzo [c, e] [1,2] azabolinin-6 (5H) -ol>

In Synthesis Example 2A, except that 2-bromo-6-phenylaniline (6.61 mmol) was changed to 2-bromo-4-methyl-6-phenylaniline (compound obtained in Synthesis Example 1C, 6.61 mmol). Synthesized 4-bromo-2-methyldibenzo [c, e] [1,2] azabolinin-6 (5H) -ol in the same manner as in Synthesis Example 2A (yield 98%).
^{1 1} H-NMR (400 MHz, d _6- DMSO) δ: 8.42 (dd, J = 0.8, 8.4 Hz, 1H), 8.21-8.19 (m, 2H), 8.07 (Dd, J = 1.6, 7.4 Hz, 1H), 7.69 (ddd, J = 1.6, 7.2, 8.4 Hz, 1H), 7.57-7.51 (m) , 2H), 7.47 (ddd, J = 0.8, 7.2, 7.4 Hz, 1H), 2.38 (s, 3H).

(Synthesis Example 3A)
<Synthesis of 2- (6-hydroxy-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boric acid 1,8-diaminonaphthalene protector>

4-Bromodibenzo [c, e] [1,2] azabolinin-6 (5H) -ol (compound obtained in Synthesis Example 2A, 1.55 g, 5.67 mmol), o-benzenediboronic acid pinacol ester 1 , 8-Diaminonaphthalene protectant (CAS: 950511-18-9, 2.10 g, 5.67 mmol), and tripotassium phosphate (3.61 g, 17.0 mmol) were added to the reaction vessel with bis (tri-tert). -Butylphosphine) Palladium (0) (528 mg, 1.03 mmol) was added in the glove box. After filling the reaction vessel with argon, dioxane (28 mL) and distilled water (2.8 mL) were added, and the mixture was stirred at 60 ° C. for 4 hours. After cooling the reaction solution to room temperature, distilled water and chloroform were added and stirred, and the separated aqueous layer was extracted with chloroform three times. Then, all the organic layers were combined, saturated aqueous sodium chloride solution was added thereto, and the mixture was stirred and washed. Anhydrous sodium sulfate was added to the re-separated organic layer to dehydrate the organic layer, and the filtered filtrate was concentrated under reduced pressure. The concentrated solution thus obtained is purified by flash column chromatography (silica gel, n-hexane / ethyl acetate), and the solid obtained after concentration under reduced pressure is dissolved in ethyl acetate at room temperature, and then n-hexane is added. The solid was precipitated with. This solid was collected by filtration and dried under reduced pressure to obtain (2- (6-hydroxy-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boric acid 1,8. A diaminonaphthalene protector was obtained as a gray solid (1.4 g, 3.2 mmol, 57% yield).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.42 (d, J = 8.4 Hz, 1H), 8.35 (dd, J = 1.4, 8.2 Hz, 1H), 8.09-7.99 (m, 2H), 7.86 (dd, J = 1.4, 7.4 Hz, 1H), 7.71-7.52 (m, 3H), 7.47- 7.38 (m, 2H), 7.34 (s, 2H), 7.32 (dd, J = 1.4, 7.4 Hz, 1H), 7.11 (dd, J = 7.4, 8.1 Hz, 1H), 6.7-6.87 (m, 3H), 6.78 (dd, J = 1.1, 8.2 Hz, 2H), 6.12 (dd, J = 1) .1, 7.3 Hz, 2H).

(Synthesis Example 3B)
<Synthesis of 2- (6-hydroxy-2-fluoro-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) borate 1,8-diaminonaphthalene protector>

In Synthesis Example 3A, 4-bromodibenzo [c, e] [1,2] azabolinin-6 (5H) -ol (5.67 mmol) was added to 4-bromo-2-fluorodibenzo [c, e] [1, 2] (2- (6-Hydroxy-2-fluoro-) in the same manner as in Synthesis Example 3A, except that it was changed to azabolinin-6 (5H) -ol (compound obtained in Synthesis Example 2B, 5.67 mmol). 5,6-Dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boronic acid 1,8-diaminonaphthalene protectant was obtained (yield 40%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.40 (d, J = 8.3 Hz, 1H), 8.15 (dd, J = 2.9, 11.2 Hz, 1H), 8.04 (dd, J = 1.5, 7.6 Hz, 1H), 7.81 (dd, J = 1.5, 7.3 Hz, 1H), 7.71-7.55 (m, 4H), 7.52 (s, 2H), 7.48-7.36 (m, 2H), 7.21 (dd, J = 2.8, 8.7 Hz, 1H), 6.93 (dd) , J = 7.4, 8.3 Hz, 2H), 6.87 (s, 1H), 6.79 (dd, J = 1.1, 8.3 Hz, 2H), 6.18 (dd, 1H) J = 1.1, 7.4 Hz, 2H).

(Synthesis Example 3C)
<Synthesis of 2- (6-hydroxy-2-methyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) borate 1,8-diaminonaphthalene protector>

In Synthesis Example 3A, 4-bromodibenzo [c, e] [1,2] azabolinin-6 (5H) -ol (5.67 mmol) was added to 4-bromo-2-methyldibenzo [c, e] [1, 2] (2- (6-Hydroxy-2-methyl-) in the same manner as in Synthesis Example 3A, except that it was changed to azabolinin-6 (5H) -ol (compound obtained in Synthesis Example 2C, 5.67 mmol). 5,6-Dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boronic acid 1,8-diaminonaphthalene protectant was obtained (yield 48%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.42 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.01 (dd, J = 1.4) , 7.5 Hz, 1H), 7.94-7.83 (m, 2H), 7.67-7.55 (m, 3H), 7.45-7.34 (m, 2H), 7. 30 (s, 2H), 7.18 (d, J = 1.9 Hz, 1H), 6.92 (dd, J = 7.4, 8.2 Hz, 2H), 6.79-6.76 (M, 3H), 6.11 (dd, J = 1.1, 7.4 Hz, 2H), 2.39 (s, 3H).

(Example 1)
<4-(2- (1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborazibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2 ] Azabolinin-6 (5H) -Ol synthesis>

(2- (6-Hydroxy-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) phenylboronic acid 1,8-diaminonaphthalene protector (obtained in Synthesis Example 3A) A 5N hydrochloric acid aqueous solution (0.41 mL) was added to a solution of the compound (150 mg, 0.343 mmol) in tetrahydrofuran (3.4 mL), and the reaction mixture was cooled to room temperature after stirring at 50 ° C. for 4 hours under an argon atmosphere. The reaction solution was slowly added dropwise to ice-cooled distilled water. The precipitated solid was washed 3 times with methanol and dried at room temperature to give 4- (2- (1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborazibenzo [fg, op] tetracene. -2-yl) phenyl) dibenzo [c, e] [1,2] azabolinin-6 (5H) -ol was obtained as a white solid (75 mg, 0.13 mmol, yield 76%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.40 (d, J = 8.0 Hz, 2H), 8.30-8.27 (m, 3H), 8.08 (dd, J) = 1.6, 7.4 Hz, 1H), 8.04 (dd, J = 1.4, 8.1 Hz, 1H), 7.93 (dd, J = 1.6, 7.5 Hz, 1H), 7.78 (dd, J = 1.6, 7.3 Hz, 2H), 7.64 (ddd, J = 1.6, 7.1, 8.5 Hz, 1H), 7.53 (Ddd, J = 1.6, 7.1, 8.4 Hz, 1H), 7.43-7.29 (m, 5H), 7.17 (dd, J = 1.4, 7.2 Hz) , 1H), 7.09 (dd, J = 1.4, 7.3 Hz, 1H), 7.04 (ddd, J = 0.8, 7.1, 7.3 Hz, 2H), 6. 81 (dd, J = 7.2, 8.1 Hz, 1H), 6.60 (s, 1H).

(Example 2)
<2-Floolo-4- (2- (9-fluoro-1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborazibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [ c, e] [1,2] Synthesis of azabolinin-6 (5H) -ol>

In Example 1, (2- (6-hydroxy-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boronic acid 1,8-diaminonaphthalene protectant (0. 343 mmol), (2- (6-hydroxy-2-fluoro-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boronic acid 1,8-diaminonaphthalene protectant 2-Floolo-4- (2- (9-fluoro-1,3-dioxa-3a- ¹ ) in the same manner as in Example 1 except that the compound was changed to (compound obtained in Synthesis Example 3B, 0.343 mmol). -Aza-2,3a, 14b-triborodibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2] azabolinin-6 (5H) -ol was obtained (yield). 70%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.25 (d, J = 8.5 Hz, 2H), 8.21-8.15 (m, 3H), 8.05 (dd, J) = 1.6, 7.4 Hz, 1H), 7.86 (dd, J = 1.6, 7.4 Hz, 1H), 7.76 (dd, J = 1.6, 7.4 Hz, 2H), 7.73-7.66 (m, 2H), 7.61 (ddd, J = 1.6, 7.4, 8.5 Hz, 1H), 7.51 (ddd, J = 1. 6, 7.4, 8.5 Hz, 2H), 7.45-7.32 (m, 3H), 7.09-7.05 (m, 3H), 6.90 (dd, J = 1. 6, 8.5 Hz, 1H), 6.50 (s, 1H).

(Example 3)
<2-Methyl-4- (2- (9-methyl-1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborodibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [ c, e] [1,2] Synthesis of azabolinin-6 (5H) -ol>

In Example 1, (2- (6-hydroxy-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boric acid 1,8-diaminonaphthalene protector (0. 343 mmol), (2- (6-hydroxy-2-methyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boronate 1,8-diaminonaphthalene protectant 2-Methyl-4- (2- (9-methyl-1,3-dioxa-3a- ¹ ) in the same manner as in Example 1 except that the compound was changed to (compound obtained in Synthesis Example 3C, 0.343 mmol). -Aza-2,3a, 14b-triborodibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2] azabolinin-6 (5H) -ol was obtained (yield). 68%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.25 (d, J = 8.4 Hz, 2H), 8.20 (s, 2H), 8.10 (d, J = 8.3) Hz, 1H), 8.03 (dd, J = 1.6, 7.4 Hz, 1H), 7.85 (dd, J = 1.6, 7.3 Hz, 1H), 7.78 (dd, J = 1.6, 7.3 Hz, 1H) , J = 1.6, 7.3 Hz, 2H), 7.64 (d, J = 1.8 Hz, 1H), 7.55 (ddd, J = 1.6, 7.4, 8.5 Hz, 1H), 7.49 (ddd, J = 1.6, 7.1, 8.4 Hz, 2H), 7.41-7.28 (m, 3H), 7.11-7.00 ( m, 3H), 6.88 (d, J = 1.8 Hz, 1H), 6.44 (s, 1H), 2.53 (s, 3H), 1.95 (s, 3H).

(Example 4)
<Synthesis of 2-Phenyl-1,3-Dioxa-3a ¹ -Aza-2,3a, 14b-Triborazibenzo [fg, op] tetracene>

(2- (6-Hydroxy-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) Phenylboronic acid 1,8-diaminonaphthalene protector (obtained in Synthesis Example 3A) A 5N aqueous hydrochloric acid solution (0.284 mL) was added to a solution of compound, 103 mg, 0.236 mmol) and phenylboronic acid (288 mg, 2.36 mmol) in tetrahydrofuran (2.40 mL), and 4 at 50 ° C. under an argon atmosphere. After stirring for hours, the reaction solution was cooled to room temperature. After adding a 2N aqueous hydrochloric acid solution (1.00 mL), the reaction solution was slowly added dropwise to ice-cooled distilled water. The precipitated solid was washed 3 times with methanol and dried at room temperature to whiten 2-phenyl-1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborazibenzo [fg, op] tetracene. Obtained as a solid (54.8 mg, 0.143 mmol, yield 61%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.55 (d, J = 7.9 Hz, 2H), 8.50 (d, J = 8.3 Hz, 2H), 8.32 ( dd, J = 1.5, 7.5 Hz, 2H), 7.78-7.74 (m, 4H), 7.55 (ddd, J = 0.9, 7.3, 7.5 Hz, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.30-7.24 (m, 2H), 7.22-7.18 (m, 1H).

(Example 5)
<Synthesis of 2- (4-fluorophenyl) -1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborodibenzo [fg, op] tetracene>

2- (4-Fluorophenyl) -1 in the same manner as in Example 4 except that phenylboronic acid (2.36 mmol) was changed to 4-fluorophenylboronic acid (2.36 mmol) in Example 4. , 3-Dioxa-3a ¹ -Aza-2,3a, 14b-Triborodibenzo [fg, op] tetracene was obtained (yield 70%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.54 (d, J = 8.0 Hz, 2H), 8.49 (d, J = 8.2 Hz, 2H), 8.31 ( d, J = 1.5, 7.4 Hz, 2H), 7.78-7.73 (m, 4H), 7.55 (dd, J = 7.2, 7.4 Hz, 2H), 7 .41 (t, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.5, 9.7 Hz, 2H).

(Example 6)
<Synthesis of 2- (4-methoxyphenyl) -1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborodibenzo [fg, op] tetracene>

2- (4-Methoxyphenyl) -1 in the same manner as in Example 4 except that phenylboronic acid (2.36 mmol) was changed to 4-methoxyphenylboronic acid (2.36 mmol) in Example 4. , 3-Dioxa-3a ¹ -Aza-2,3a, 14b-Triborodibenzo [fg, op] tetracene was obtained (yield 76%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.57 (d, J = 8.0 Hz, 2H), 8.52 (d, J = 8.3, 2H), 8.34 (dd) , J = 1.5, 7.4 Hz, 2H), 7.86-7.73 (m, 4H), 7.57 (dd, J = 7.3, 7.4 Hz, 2H), 7. 44 (t, J = 8.0 Hz, 1H), 6.94-6.88 (m, 2H), 3.75 (s, 3H).

(Example 7A)
<Synthesis of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide>
The catalyst obtained in Example 1 was used to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide.

2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 4- (2- (1,3-dioxa-3a)-(1,3-dioxa-3a) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. ¹ -Aza-2,3a, 14b-Triborazibenzo [fg, op] Tetracene-2-yl) Phenyl) Dibenzo [c, e] [1,2] Azabolinin-6 (5H) -ol (in Example 1) The obtained catalyst (2.4 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 12 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. The concentrated solution thus obtained was purified by preparative TLC (silica gel, n-hexane / ethyl acetate) to obtain N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide as a white solid (21). 0.0 mg, 77.5 μmol, yield 95%).

(Example 7B)
<Synthesis of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide>
The catalyst obtained in Example 2 was used to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide.

2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 2-fluoro-4- (2- (9-fluoro)) and 2-fluoro-4- (2- (9-fluoro)) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. -1,3-Dioxa-3a ¹ -Aza-2,3a, 14b-Triborazibenzo [fg, op] Tetracene-2-yl) Phenyl) Dibenzo [c, e] [1,2] Azabolinin-6 (5H) ) -All (catalyst obtained in Example 2, 2.5 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 4 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was 57%.

(Example 7C)
<Synthesis of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide>
The catalyst obtained in Example 3 was used to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide.

2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 2-methyl-4- (2- (9-methyl) 2-methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 2-methyl-4- (2- (9-methyl)) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. -1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborodibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2] azabolinin-6 (5H) ) -All (catalyst obtained in Example 3, 2.5 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 4 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was 85%.

(Example 7D)
<Synthesis of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide>
The catalyst obtained in Example 4 was used to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide.

2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 2-phenyl-1,3-dioxa-3a ^1- were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. Aza-2,3a, 14b-triborodibenzo [fg, op] tetracene (catalyst obtained in Example 4, 1.6 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 4 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was 40%.

(Example 7E)
<Synthesis of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide>
Using the catalyst obtained in Example 5, N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was synthesized.

2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 2- (4-fluorophenyl) -1,3- were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. Dioxa-3a ¹ -aza-2,3a, 14b-triborodibenzo [fg, op] tetracene (catalyst obtained in Example 5: 1.7 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. .. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 4 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was 9%.

(Example 7F)
<Synthesis of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide>
The catalyst obtained in Example 6 was used to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide.

2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 2- (4-methoxyphenyl) -1,3- were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. Dioxa-3a ¹ -aza-2,3a, 14b-triborodibenzo [fg, op] tetracene (catalyst obtained in Example 6 1.7 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. .. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 4 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was 33%.

(Comparative Example 1A)
An attempt was made to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide using 2,4,6-triphenylboroxin as a catalyst.
2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 2,4,6-triphenylboroxin (1.) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. 3 mg (4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 18 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, no formation of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was observed.

(Comparative Example 1B)
An attempt was made to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide using the molecule obtained in Synthesis Example 2A as a catalyst.
2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 4-bromodibenzo [c, e] [1, 2 ] Azabolinin-6 (5H) -ol (molecule obtained in Synthesis Example 2A, 1.1 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 12 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtered filtrate is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, no formation of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was observed.

(Comparative Example 1C)
An attempt was made to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide using the molecule obtained in Synthesis Example 2B as a catalyst.
2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 4-bromo-2-fluorodibenzo [c, e] were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. [1,2] Azabolinin-6 (5H) -ol (molecule obtained in Synthesis Example 2B, 1.8 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 12 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, no formation of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was observed.

(Example 8A)
<Synthesis of N- (4-fluorobenzyl) adamantane-1-carboxamide>
Using the catalyst obtained in Example 1, N- (4-fluorobenzyl) adamantane-1-carboxamide was synthesized.

Adamantane-1-carboxylic acid (14.7 mg, 81.6 μmol) and 4- (2- (1,3-dioxa-3a ¹ -aza) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and heated and dried under reduced pressure. -2,3a, 14b-Triborazibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2] azabolinin-6 (5H) -ol (obtained in Example 1) The catalyst (2.4 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring under heating and reflux conditions under an argon atmosphere for 14 hours. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-fluorobenzyl) adamantane-1-carboxamide was 90% or more.

(Example 8B)
<Synthesis of N- (4-fluorobenzyl) -3-methylthiophene-2-carboxamide>
Using the catalyst obtained in Example 1, N- (4-fluorobenzyl) -3-methylthiophene-2-carboxamide was synthesized.

3-Methylthiophen-2-carboxylic acid (11.6 mg, 81.6 μmol) and 4- (2- (1,3-dioxa-3a)) and 4- (2- (1,3-dioxa-3a)) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. ¹ -aza-2,3a, 14b-triborodibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2] azabolinin-6 (5H) -ol (in Example 1) The obtained catalyst (2.4 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 12 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-fluorobenzyl) -3-methylthiophene-2-carboxamide was 78%.

(Example 8C)
<Synthesis of (E) -N- (4-fluorobenzyl) -2-methylbutene-2-enamide>
Using the catalyst obtained in Example 1, (E) -N- (4-fluorobenzyl) -2-methylbutene-2-enamide was synthesized.

Tiglic acid (8.2 mg, 81.6 μmol) and 4- (2- (1,3-dioxa-3a ¹ -aza-2,3a) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. , 14b-Triborazibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2] azabolinin-6 (5H) -ol (catalyst obtained in Example 1), 2. 4 mg (4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 18 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of (E) -N- (4-fluorobenzyl) -2-methylbutene-2-enamid was 90% or more.

(Example 8D)
<Synthesis of N- (cyclopropylmethyl) -2,4,6-trimethylbenzamide>
Using the catalyst obtained in Example 1, N- (cyclopropylmethyl) -2,4,6-trimethylbenzamide was synthesized.

Molecular sieve 4A (67 mg) was added, and the mixture was heated and dried under reduced pressure in a reaction vessel containing 2,4,6-trimethylbenzoic acid (13.4 mg, 81.6 μmol) and 4- (2- (1,3-dioxa-3a). ¹ -aza-2,3a, 14b-triborodibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2] azabolinin-6 (5H) -ol (in Example 1) The obtained catalyst (2.4 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. Cyclopropylmethylamine (7.00 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 18 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (cyclopropylmethyl) -2,4,6-trimethylbenzamide was 83%.

(Example 8E)
<Synthesis of N- (2- (1H-indole-3-yl) ethyl) benzamide>
The catalyst obtained in Example 1 was used to synthesize N- (2- (1H-indole-3-yl) ethyl) benzamide.

Benzoic acid (10.0 mg, 81.6 μmol), tryptamine (13.1 mg, 81.6 μmol) and 4- (2- (1,3)) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and heated and dried under reduced pressure. -Dioxa-3a ¹ -Aza-2,3a, 14b-Triborazibenzo [fg, op] Tetracene-2-yl) Phenyl) Dibenzo [c, e] [1,2] Azabolinin-6 (5H) -ol ( The catalyst obtained in Example 1 (2.4 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. After stirring at 80 ° C. for 17 hours under an argon atmosphere, the reaction solution was cooled to room temperature. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (2- (1H-indole-3-yl) ethyl) benzamide was 77%.

(Example 8F)
<Synthesis of N- (4-methoxyphenyl) -2-methyl-2-phenylpropanamide>
Using the catalyst obtained in Example 1, N- (4-methoxyphenyl) -2-methyl-2-phenylpropanamide was synthesized.

2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 4-methoxyphenol (10.0 mg, 81.6 μmol) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. And 4- (2- (1,3-dioxa-3a ¹ -aza-2,3a, 14b-triborazibenzo [fg, op] tetracene-2-yl) phenyl) dibenzo [c, e] [1,2 ] Azabolinin-6 (5H) -ol (catalyst obtained in Example 1, 2.4 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. After stirring at 80 ° C. for 12 hours under an argon atmosphere, the reaction solution was cooled to room temperature. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-methoxyphenyl) -2-methyl-2-phenylpropanamide was 90% or more.

(Example 8G)
<Synthesis of N-benzylheptane amide>
The catalyst obtained in Example 1 was used to synthesize N-benzylheptane amide.

4- (2- (1,3-Dioxa-3a ¹ -aza-2,3a, 14b) triborodibenzo [fg, op] tetracene was placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and heated and dried under reduced pressure. -2-yl) Phenyl) Dibenzo [c, e] [1,2] Azabolinin-6 (5H) -ol (catalyst obtained in Example 1, 2.4 mg, 4.16 μmol) was added, and toluene (820 μL) was added. ) As a solution. Enanthic acid (11.6 μL, 81.6 μmol) and benzylamine (8.9 μL, 81.6 μmol) were added at room temperature, and the mixture was stirred at room temperature for 24 hours under an argon atmosphere. Then, distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N-benzylheptane amide was 90% or more.

(Example 9)
In addition to the above Examples 8A to 8G, an amide bond forming reaction for synthesizing the following amide from the following carboxylic acid and amine was carried out using the catalyst obtained in Example 1. The yield of amide is shown in Table 1.

(Synthesis Example 2D)
<Synthesis of 4-bromo-6-phenyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin>

Dichlorophenylboron (2.35 mL, 19.3 mmol) in a solution of 2-bromo-6-phenylaniline (compound obtained in Synthesis Example 1A, 1.60 g, 6.44 mmol) in o-dichlorobenzene (12.0 mL). And triethylamine (5.30 mL, 38.6 mmol) were added. The resulting solution was stirred under heating under reflux conditions for 16 hours. After cooling the solution to room temperature, distilled water and chloroform were added, and the separated aqueous layer was extracted 3 times with chloroform. Then, all the organic layers are combined, saturated aqueous sodium chloride solution is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the mixture, and the filtered filtrate is concentrated under reduced pressure to perform silica gel column chromatography. Purification by filtration gave 4-bromo-6-phenyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin as a white solid (1.49 g, 69% yield).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 8.51 (d, J = 8.2 Hz, 1H), 8.48-8.36 (m, 2H), 8.29 (dd, J = 1) .5, 7.6 Hz, 1H), 7.90-7.84 (m, 2H), 7.79 (ddd, J = 1.5, 7.1, 8.4 Hz, 1H), 7. 74 (dd, J = 1.2, 7.8 Hz, 1H), 7.61-7.48 (m, 4H), 7.18 (t, J = 8.0 Hz, 1H).

(Synthesis Example 3D)
<Synthesis of 2- (6-phenyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boric acid 1,8-diaminonaphthalene protector>

In Synthesis Example 3A, 4-bromodibenzo [c, e] [1,2] azabolinin-6 (5H) -ol and 4-bromo-6-phenyl-5,6-dihydrodibenzo [c, e] [1 , 2] In the same manner as in Synthesis Example 3A, except that it was changed to azabolinin (compound obtained in Synthesis Example 2D), (2- (6-phenyl-5,6-dihydrodibenzo [c, e] [1, 2] Azabolinin-4-yl) phenyl) Boronic acid 1,8-diaminonaphthalene protectant was obtained (yield 47%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.62-8.53 (m, 2H), 8.17 (dd, J = 1.5, 7.5 Hz, 1H), 7.85-7 .74 (m, 3H), 7.65-7.56 (m, 3H), 7.56-7.46 (m, 3H), 7.46-7.35 (m, 5H), 6.95 (Dd, J = 7.2, 8.3 Hz, 2H), 6.89 (dd, J = 1.1, 8.3 Hz, 2H), 5.50 (s, 2H).

(Synthesis Example 4A)
<Synthesis of (2- (6-phenyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boronic acid>

(2- (6-Phenyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) Phenylboronic acid 1,8-diaminonaphthalene protector (obtained in Synthesis Example 3D) A 5N aqueous hydrochloric acid solution (1.2 mL) was added to a solution of the compound (500 mg, 1.0 mmol) in tetrahydrofuran (10.0 mL), and the reaction mixture was cooled to room temperature after stirring at 50 ° C. for 3 hours under an argon atmosphere. A 2N aqueous hydrochloric acid solution (2.5 mL) and water (7.5 mL) were added to the reaction solution, and the separated aqueous layer was extracted 4 times with ethyl acetate. Then, all the organic layers are combined, a saturated aqueous sodium chloride solution is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. A reaction mixture (425 mg) containing 2- (6-phenyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boronic acid was obtained. The resulting reaction mixture was used in Example 10 below without purification.

(Example 10)
<(2- (6-Phenyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) -1,3-dioxa-3a ¹ -aza-2,3a, 14b -Synthesis of triborodibenzo [fg, op] tetracene>

In Example 4, phenylboronic acid (2.36 mmol) was replaced with (2- (6-phenyl-5,6-dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) boronic acid ( 2- (4-Fluorophenyl) -1,3-dioxa-3a1-aza-2,3a, in the same manner as in Example 4, except that the compound obtained in Synthesis Example 4A was changed to 0.68 mmol). 14b-Triborodibenzo [fg, op] tetracene was obtained (yield 95%).
¹ H-NMR (400 MHz, d _6- DMSO) δ: 8.39-8.37 (m, 3H), 8.22 (d, J = 8.3 Hz, 1H), 8.09-7.99 (M, 2H), 7.86 (dd, J = 1.5, 7.6 Hz, 2H), 7.72 (ddd, J = 1.5, 7.2, 8.4 Hz, 1H), 7.65 (dd, J = 1.5, 7.4 Hz, 2H), 7.54-7.22 (m, 13H), 7.15-7.09 (m, 1H), 6.99 ( ddd, J = 0.8, 7.4, 7.4 Hz, 2H), 6.84 (dd, J = 7.2, 8.3 Hz, 1H).

(Example 11)
<Synthesis of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide>
The catalyst obtained in Example 10 was used to synthesize N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide.

2-Methyl-2-phenylpropanoic acid (13.4 mg, 81.6 μmol) and 2- (2- (6-phenyl-5,6)) and 2- (2- (6-phenyl-5,6)) were placed in a reaction vessel to which molecular sieve 4A (67 mg) was added and dried under reduced pressure. -Dihydrodibenzo [c, e] [1,2] azabolinin-4-yl) phenyl) -1,3-dioxa-3a1-aza-2,3a, 14b-triborodibenzo [fg, op] tetracene (Example) The catalyst obtained in No. 10 (2.6 mg, 4.16 μmol) was added to prepare a toluene (820 μL) solution. 4-Fluorobenzylamine (9.28 μL, 81.6 μmol) was added at room temperature, and the reaction mixture was cooled to room temperature after stirring at 80 ° C. for 4 hours under an argon atmosphere. Distilled water (0.5 mL) was added and stirred, and the separated aqueous layer was extracted 4 times with ethyl acetate (1.5 mL). Then, all the organic layers are combined, saturated aqueous sodium chloride solution (1.5 mL) is added thereto, and the mixture is stirred and washed. Anhydrous sodium sulfate is added to the re-separated organic layer to dehydrate the organic layer, and the filtrate after filtration is concentrated under reduced pressure. did. When ¹ H-NMR of the reaction mixture was analyzed, the yield of N- (4-fluorobenzyl) -2-methyl-2-phenylpropanamide was 21%.

From the above results, it was confirmed that the catalyst of the present invention can be used in a reaction for synthesizing an amide compound from various carboxylic acid compounds and various amine compounds. In particular, the fact that the amide bond forming reaction can be carried out even when a sterically bulky carboxylic acid compound is used is an advantage of the catalyst of the present invention, which is not seen in the amide bond forming reaction using a conventional boron catalyst. This is one of the points.
Further, from the above results, in the catalyst represented by the general formula (1), whether the substituent of the benzene ring is an electron donating group or an electron attracting group, it is useful as a catalyst. It could be confirmed.
In Example 7E, the yield of the amide compound was 9%, but (1) the amide bond forming reaction could be carried out even when a sterically bulky carboxylic acid compound was used. (2) Considering that the reaction could be carried out at a low temperature (80 ° C.), it can be said that the reaction is superior to the conventional amide bond forming reaction.

The catalyst of the present invention can be suitably used for the amide bond forming reaction.

Aspects of the present invention are, for example, as follows.
<1> A catalyst characterized by being represented by the following general formula (1).
However, in the general formula (1), R ^{1 to} R ¹⁶ independently represent either a hydrogen atom or a substituent.
<2> The catalyst according to <1>, wherein the substituent is an electron donating group or an electron attracting group.
<3> The catalyst according to any one of <1> to <2>, which is represented by either the following general formula (1A) or the following general formula (1B).
However, in the general formula (1A), R ⁶ and R ¹⁴ independently represent any one of a hydrogen atom, an electron donating group, and an electron attracting group.
However, in the general formula (1B), R ⁶ and R ²⁶ represent any of a hydrogen atom, an electron donating group, and an electron attracting group.
<4> The catalyst according to any one of <1> to <2>, which is represented by the following general formula (1C).
However, in the general formula (1C), R ⁶ and R ²⁶ independently represent any one of a hydrogen atom, an electron donating group, and an electron attracting group.
<5> The carboxyl group of the carboxylic acid compound and the amino group of the amine compound are reacted in the presence of the catalyst according to any one of <1> to <4> to form an amide bond. This is a method for forming an amide bond.
<6> A method for producing an amide compound, which comprises reacting a carboxylic acid compound and an amine compound in the presence of the catalyst according to any one of <1> to <4> to obtain an amide compound. is there.

Claims (6)

A catalyst for an amide bond forming reaction, which is represented by the following general formula (1).
However, in the general formula (1), R ^{1 to} R ¹⁶ independently represent either a hydrogen atom or a substituent. The catalyst for an amide bond forming reaction according to claim 1, wherein the substituent is an electron donating group or an electron attracting group. The catalyst for an amide bond forming reaction according to any one of claims 1 to 2, which is represented by any of the following general formula (1A) and the following general formula (1B).
However, in the general formula (1A), R ⁶ and R ¹⁴ independently represent any one of a hydrogen atom, an electron donating group, and an electron attracting group.
However, in the general formula (1B), R ⁶ and R ²⁶ represent any of a hydrogen atom, an electron donating group, and an electron attracting group. The catalyst for the amide bond forming reaction according to any one of claims 1 to 2, which is represented by the following general formula (1C).
However, in the general formula (1C), R ⁶ and R ²⁶ independently represent any one of a hydrogen atom, an electron donating group, and an electron attracting group. A method for forming an amide bond, which comprises reacting a carboxyl group of a carboxylic acid compound with an amino group of an amine compound in the presence of the catalyst according to any one of claims 1 to 4 to form an amide bond. A method for producing an amide compound, which comprises reacting a carboxylic acid compound and an amine compound in the presence of the catalyst according to any one of claims 1 to 4 to obtain an amide compound.