WO2019208043A1 - Method for producing n-unprotected imine compound - Google Patents

Abstract

[Problem] To provide a method for simply producing various N-unprotected imine compounds inexpensively and safely. [Solution] This method for producing a N-unprotected imine compound comprises reacting a ketone compound and a nitrogen source compound in the presence of at least one catalyst selected from among: a catalyst containing a Lewis acidic metal salt such as triflate salts of Sc, Y, Sm, Eu, Gd, Er, Yb, Fe, In, Sn, and Bi; and a catalyst containing a fluorine-containing anion salt of tetraalkylammonium.

Description

Method for producing unprotected imine compound on nitrogen

The present invention relates to a method for producing (synthesizing) an unprotected imine compound on nitrogen.

Conventionally, synthesis of an imine compound from a ketone compound has been performed, but synthesis of an unprotected imine compound on nitrogen is considered to be relatively difficult. As a method for synthesizing such an unprotected imine compound on nitrogen, a method for synthesizing benzophenone imine in which benzophenone and ammonia are reacted in the presence of an iron salt or an iron complex has been proposed (for example, see Patent Document 1). .

The method described in Patent Document 1 requires a high temperature of reaction temperature of 100 ° C. or higher and an operation of blowing a large amount of ammonia gas that is highly toxic and difficult to handle, and is not easy to implement. Moreover, the reaction substrate is limited to benzophenone imine, and the substrate generality is poor.

In addition, a method using an organometallic reagent such as a Grignard reagent and a method using LiN (SiMe ₃ ) ₂ (see, for example, Non-Patent Document 1) have been proposed. There is a problem that the generality of the substrate is poor. Furthermore, a method using iminophosphorane (Ph ₃ P = NH) has also been proposed (for example, see Non-Patent Document 2). However, this method requires preparation of iminophosphorane separately, and a large amount of removal is difficult. Since a by-product (Ph ₃ P═O) is generated, it is difficult to apply to mass synthesis.

Japanese Patent Laid-Open No. 61-30563

An object of the present invention is to provide a method for easily and inexpensively producing various unprotected imine compounds on nitrogen.

The present inventors have eliminated various limitations in the conventional method for producing an unprotected imine compound on nitrogen, and can synthesize various unprotected imine compounds on nitrogen easily and inexpensively, As a result of intensive studies, it was found that this can be solved by using a specific catalyst, and the present invention has been completed.

That is, the present invention is as follows.

[1] In the presence of a catalyst containing a metal salt having Lewis acidity,
Following formula (1)

(R ¹ and R ² each represent an organic group, and may be linked to each other to form a ring);
Following formula (2)

[R ³ and R ⁴ each represent a hydrogen atom or an aliphatic group, and R ⁵ represents a hydrogen atom, an aliphatic group, or a group having the following structure bonded to each other:

(R ⁶ represents a hydrogen atom or an aliphatic group). And a nitrogen source compound (2) represented by
Following formula (3)

(R ¹ and R ² have the same meanings as those in the ketone compound (1) represented by the formula (1).) The nitrogen compound is characterized by producing the imine compound (3) or a salt thereof. A method for producing a protected imine compound.

[2] The metal salt having Lewis acidity is a triflate salt, nonaflate salt or trifluoromethanesulfonylimide salt of at least one metal selected from rare earth metals, Fe, In, Sn and Bi, or Sc (NO ₃ ) ₃ or characterized in that it is a BiBr ₃ [1] production method of nitrogen on unprotected imine compounds described.
[3] The method for producing an unprotected imine compound on nitrogen according to [2], wherein the rare earth metal is Sc, Y, Sm, Eu, Gd, Er, or Yb.
[4] The metal salt having Lewis acidity is Sc (OTf) ₃ , Y (OTf) ₃ , Sm (OTf) ₃ , Eu (OTf) ₃ , Gd (OTf) ₃ , Er (OTf) ₃ , Yb (OTf). ) ₃ , Fe (OTf) ₃ , In (OTf) ₃ , Sn (OTf) ₂ , Bi (OTf) ₃ , Sc (ONf) ₃ , and Sc (NTf ₂ ) ₃ The method for producing an unprotected imine compound on nitrogen as described in any one of [1] to [3].

[5] The process for producing an unprotected imine compound on nitrogen as described in any one of [1] to [4], wherein R ¹ and / or R ² contains an aromatic ring and / or an aliphatic group.
[6] The reaction of the ketone compound (1) and the nitrogen source compound (2) is performed in a solvent containing at least one selected from chlorobenzene, toluene, tetrahydrofuran, dioxane, fluorobenzene, dichloroethane, and acetonitrile. [1] A process for producing an unprotected imine compound on nitrogen as described in any one of [5].
[7] The unprotected imine on nitrogen according to any one of [1] to [5], wherein the reaction of the ketone compound (1) and the nitrogen source compound (2) is carried out substantially without using a solvent. A method for producing a compound.
[8] The reaction between the ketone compound (1) and the nitrogen source compound (2) in the presence of at least one reaction accelerator selected from water, alcohol and silanol [1] to [7] The manufacturing method of the unprotected imine compound on nitrogen in any one of these.

[9] In the presence of a catalyst comprising a fluorine-containing anion salt of tetraalkylammonium,
Following formula (1)

(R ¹ and R ² each represent an organic group, and may be linked to each other to form a ring);
Following formula (2)

[R ³ and R ⁴ each represent a hydrogen atom or an aliphatic group, and R ⁵ represents a hydrogen atom, an aliphatic group, or a group having the following structure bonded to each other:

(R ⁶ represents a hydrogen atom or an aliphatic group). And a nitrogen source compound (2) represented by
Following formula (3)

(R ¹ and R ² have the same meanings as those in the ketone compound (1) represented by the formula (1).) The nitrogen compound is characterized by producing the imine compound (3) or a salt thereof. A method for producing a protected imine compound.

[10] The method for producing an unprotected imine compound on nitrogen according to [9], wherein the alkyl moiety of the fluorine-containing anion salt of tetraalkylammonium has 1 to 6 carbon atoms.
[11] The unprotected imine compound on nitrogen according to [9] or [10], wherein the fluorine-containing anion salt of tetraalkylammonium is tetrabutylammonium fluoride or tetrabutylammonium dihydrogentrifluoride. Production method.
[12] The process for producing an unprotected imine compound on nitrogen as described in any one of [9] to [11], wherein R ¹ and / or R ² contains an aromatic ring and / or an aliphatic group.
[13] Chlorobenzene, toluene, tetrahydrofuran, dioxane, fluorobenzene, dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, hexamethylphosphoric triamide, N, N A reaction of a ketone compound (1) and a nitrogen source compound (2) in a solvent containing at least one selected from dimethylpropyleneurea and 1,3-dimethyl-2-imidazolidinone [9] A process for producing an unprotected imine compound on nitrogen as described in [12].
[14] The unprotected imine on nitrogen as described in any one of [9] to [12], wherein the reaction of the ketone compound (1) and the nitrogen source compound (2) is carried out substantially without using a solvent. A method for producing a compound.
[15] The reaction between the ketone compound (1) and the nitrogen source compound (2) is carried out in the presence of at least one reaction accelerator selected from water, alcohol and silanol [9] to [14] The manufacturing method of the unprotected imine compound on nitrogen in any one of these.

According to the present invention, various unprotected imine compounds on nitrogen can be easily and inexpensively produced.

The method for producing an unprotected imine compound on nitrogen according to the present invention comprises a ketone in the presence of at least one catalyst selected from a catalyst containing a metal salt having Lewis acidity and a catalyst containing a fluorine-containing anion salt of tetraalkylammonium. The imine compound (3) or a salt thereof is produced by reacting the compound (1) with the nitrogen source compound (2).

The production method of the present invention has a larger substrate selection range than conventional methods for producing unprotected imine compounds on nitrogen, and various inexpensive unprotected imine compounds on nitrogen can be obtained from commercially available compounds and catalysts that are readily available. It can be manufactured safely. Moreover, since it can implement under a normal pressure, a special reaction instrument and apparatus are not required and the unprotected imine compound on nitrogen can be obtained with a high yield on reaction conditions with easy implementation. In addition, the conventional method generally requires purification of an unprotected imine compound in order to remove a by-product that can inhibit the following reaction, whereas the present invention provides an unprotected imine compound on nitrogen in a high yield. In addition, since the reactivity of the co-product (hexamethyldisiloxane, etc.) is low and it is difficult to inhibit the next reaction, the imine compound can be used as it is in the next reaction without removing it from the reaction system (Example) 6, 7 and 16 (one-pot synthesis)).

[catalyst]
(Catalyst containing metal salt having Lewis acidity)
Examples of the metal salt having Lewis acid include a rare earth metal and a metal triflate, nonaflate, or trifluoromethanesulfonylimide salt selected from Fe, In, Sn, and Bi, Sc (NO ₃ ) ₃ , and BiBr _3. it can.

Among these, at least one metal triflate, nonaflate or trifluoromethanesulfonylimide salt selected from Sc, Y, Sm, Eu, Gd, Er, Yb, Fe, In, Sn and Bi, or Sc (NO ₃ ) ₃ or BiBr ₃ is preferred, and is a triflate, nonaflate or trifluoromethanesulfonylimide salt of at least one metal selected from Sc, Y, Sm, Eu, Gd, Er, Yb, Fe, In, Sn and Bi. Is more preferable, and a triflate salt of at least one metal selected from Sc, Y, Eu, Er, Yb, Fe, Sn, and Bi, or a nonaflate salt is more preferable, and at least one selected from Sc, Er, Sn, and Bi. Some metal triflate or nonaflate salts are particularly preferable.

Specifically, as the metal salt having Lewis acidity, Sc (OTf) ₃ , Y (OTf) ₃ , Sm (OTf) ₃ , Eu (OTf) ₃ , Gd (OTf) ₃ , Er (OTf) ₃ , Yb (OTf) ₃ , Fe (OTf) ₃ , In (OTf) ₃ , Sn (OTf) ₂ , Bi (OTf) ₃ , Sc (ONf) ₃ , Sc (NTf ₂ ) ₃ , Sc (NO ₃ ) ₃ , BiBr ₃ etc. can be mentioned.

When a metal salt having Lewis acidity is used in the production method of the present invention, the amount of the catalyst can be appropriately adjusted so that the reaction proceeds appropriately. For example, 0.001 per 1 mol of the ketone compound (1). About 0.3 mol, preferably about 0.002 to 0.2 mol, more preferably about 0.005 to 0.1 mol.

(Catalyst containing a fluorine-containing anion salt of tetraalkylammonium)
The alkyl part of the fluorine-containing anion salt of tetraalkylammonium preferably has 1 to 6 carbon atoms. Specific examples of the fluorine-containing anion salt of tetraalkylammonium include tetrabutylammonium fluoride (TBAF) and tetrabutylammonium dihydrogen trifluoride (TBAH ₂ F ₃ ). Tetrabutylammonium fluoride Is preferred. It may be an anhydride or a hydrate.

When a catalyst containing a fluorine-containing anion salt of tetraalkylammonium is used in the production method of the present invention, the amount of the catalyst can be appropriately adjusted so that the reaction proceeds appropriately, but relative to 1 mol of the ketone compound (1) For example, it is about 0.005 to 0.3 mol, preferably about 0.01 to 0.2 mol, and more preferably about 0.03 to 0.1 mol.

By using a catalyst containing a fluorine-containing anion salt of tetraalkylammonium, it is also possible to synthesize alkyl ketimine in high yield, which was difficult to synthesize in high yield using a catalyst containing a Lewis acid metal salt. can do.

[Ketone compound (1)]
The ketone compound (1) used in the production method of the present invention is a compound represented by the following formula (1).

R ¹ and R ² each represents an organic group and may be linked to each other to form a ring. Specifically, examples of R ¹ and R ² include an aromatic group including an aromatic ring, a heterocyclic group including a heterocyclic ring, and an aliphatic group. Examples of the aromatic ring of the aromatic group include benzene and naphthalene. Examples of the heterocyclic ring of the heterocyclic group include pyridine, pyrazine, quinoline and the like. The aliphatic group may be a linear, branched or cyclic aliphatic group, and may be saturated or unsaturated. In addition, the aliphatic group may be blocked with a heteroatom (a heteroatom may be present between the carbon linkages).

These aromatic groups, heterocyclic groups and aliphatic groups may have a substituent. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 4 carbon atoms which may be substituted with a halogen atom, a hydroxyl group and a halogen atom. it can. Moreover, the substituent shown below can be mentioned. R ⁷ to R ¹¹ each represents an aliphatic group, preferably an alkyl group having 1 to 4 carbon atoms.

Specifically, examples of the ketone compound (1) include the following.

Among the ketone compounds (1), a ketone compound having the following structure is extremely difficult to synthesize an imine compound by a conventional method using a Grignard reagent, etc., but according to the production method of the present invention, An imine compound can be obtained with a high yield.

[Nitrogen source compound (2)]
The nitrogen source compound (2) used in the production method of the present invention is a compound represented by the following formula (2).

R ³ and R ⁴ each represent a hydrogen atom or an aliphatic group. The aliphatic group may be a linear, branched or cyclic aliphatic group, and may be saturated or unsaturated. Among these, a saturated or unsaturated linear aliphatic group having 1 to 4 carbon atoms is preferable.
R ⁵ represents a hydrogen atom, an aliphatic group, or a substituent having the following structure bonded to each other. The aliphatic group is the same as R ³ and R ⁴ .

R ⁶ represents a hydrogen atom or an aliphatic group, and the aliphatic group is the same as R ³ and R ⁴ .

Specific examples of the nitrogen source compound (2) include the following.

The amount of the nitrogen source compound (2) used in the production method of the present invention is, for example, about 1.0 to 3.0 mol, preferably about 1.0 to 1.5 mol, relative to 1 mol of the ketone compound (1). . In the production method of the present invention, the nitrogen source compound may be used in the same amount or slightly more, and it is not necessary to use it excessively.

[Imine Compound (3)]
The imine compound (3) to be produced is a compound represented by the following formula (3).

R ¹ and R ² have the same meaning as described for the ketone compound (1).
The imine compound (3) may be in the form of a salt. The kind of salt is not particularly limited, and examples thereof include halides (fluorides, chlorides, bromides, iodides), sulfonates, and the like.

[solvent]
Solvents used in the production method of the present invention include chlorobenzene (preferably monochlorobenzene), toluene, tetrahydrofuran, dioxane (preferably 1,4-dioxane), fluorobenzene, dichloroethane, acetononitrile, alcohol, N, N-dimethyl. Formamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), N, N-dimethylpropylene urea (DMPU) ), 1,3-dimethyl-2-imidazolidinone (DMI) and the like, and these may be used as a mixture.

When using a catalyst containing a metal salt having Lewis acidity, chlorobenzene, toluene, tetrahydrofuran, fluorobenzene and acetononitrile are preferred.

When a fluorine-containing anion salt of tetraalkylammonium is used, chlorobenzene, toluene, tetrahydrofuran, fluorobenzene, N, N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, hexamethyl Phosphoric triamide, N, N-dimethylpropyleneurea and 1,3-dimethyl-2-imidazolidinone are preferred, N, N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N, N-dimethyl Polar solvents such as acetamide, hexamethylphosphoric triamide, N, N-dimethylpropyleneurea and 1,3-dimethyl-2-imidazolidinone are more preferred. For example, the reaction can be promoted by adding a polar solvent as an additional solvent to the nonpolar solvent.

[Reaction accelerator]
In the present invention, a reaction accelerator can be used. Examples of the reaction accelerator include water, alcohol, silanol and the like. Examples of the alcohol include methanol, ethanol, butanol and the like. Examples of silanols include trimethylsilanol.

The addition amount of the reaction accelerator is, for example, about 0.01 to 1.0 mol, preferably about 0.02 to 0.8 mol, preferably 0.05 to 0, per 1 mol of the ketone compound (1). More preferably, it is about 5 mol.

[Other conditions]
The temperature (reaction temperature) for reacting the ketone compound (1) and the nitrogen source compound (2) in the production method of the present invention is preferably about 0 to 150 ° C. When a metal salt having Lewis acidity is used, it is more preferably from room temperature (25 ° C.) to about 150 ° C., more preferably from about 50 to 100 ° C. When a catalyst containing a fluorine-containing anion salt of tetraalkylammonium is used, it is more preferably about 10 to 100 ° C, and further preferably about 15 to 70 ° C. The reaction in the production method of the present invention does not require an extremely low temperature or high temperature, and the production cost is low.

The reaction time depends on other conditions such as the reaction temperature, but is, for example, about 0.25 to 48 hours, preferably about 0.5 to 24 hours, and more preferably about 0.75 to 15 hours. Preferably, about 5 to 15 hours is more preferable.

The conditions of reaction temperature and reaction time can be determined optimally while confirming the yield. The yield is preferably 40 mol% or more, more preferably 60 mol% or more, further preferably 80 mol% or more, particularly preferably 90 mol% or more, and 95 mol% or more. Is most preferred.

In the production method of the present invention, the reaction of the ketone compound (1) and the nitrogen source compound (2) can be carried out substantially without using a solvent. Here, performing the reaction substantially without using a solvent means that the reaction is performed without using a general solvent amount of the solvent, for example, a reaction using a small amount of solvent that dissolves the catalyst. Is included in the reaction substantially using no solvent. Specifically, the amount of solvent in the reaction using substantially no solvent in the production method of the present invention is, for example, 0.1 mL or less with respect to 1 mmol of the ketone compound (1).

[Examination of catalyst (1)]
A stir bar was placed in a 4 mL vial, a catalyst (0.010 mmol, 5.0 mol%) was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, benzophenone (0.20 mmol) as the ketone compound (1), monochlorobenzene (0.20 mL, 1.0 M) as the solvent, bis (trimethylsilyl) as the nitrogen source compound (2) Amine (0.22 mmol, 1.1 eq) was added. After the mixture was stirred at 90 ° C. for 12 hours, the yield of the product was determined by ¹ H NMR measurement of the reaction crude product. The results are shown in Table 1.

As shown in Table 1, in the case of the catalyst (entry 1-15) used in the production method of the present invention, the yield exceeded 20% in all cases. Among these, Sc (OTf) ₃ , Y (OTf) ₃ , Sm (OTf) ₃ , Eu (OTf) ₃ , Gd (OTf) ₃ , Er (OTf) ₃ , Yb (OTf) ₃ , Fe (OTf) ₃ , In (OTf) ₃ , Sn (OTf) ₂ , Bi (OTf) ₃ , Sc (ONf) ₃ , and Sc (NTf ₂ ) ₃ were able to achieve a yield of 40% or more. For Gd (OTf) ₃ and Sc (NTf ₂ ) ₃ , the yield is 50% or more, and for Sm (OTf) ₃ , the yield is 60% or more. Y (OTf), Eu (OTf) ₃ , For Fe (OTf) ₃ and Yb (OTf) ₃ , the yield is 80% or more, and Sc (OTf) ₃ , Er (OTf) ₃ , Sn (OTf) ₂ , Bi (OTf) ₃ and Sc (ONf) For No. ₃ , the yield was 95% or more.
The above results indicate that TMSOTf (entry 17) is reported to be non-catalytic (entry 16) and to catalyze a similar reaction (T. Morimoto, M. Sekiya, Chem. Lett. 1985, 1371.). Was better than.

[Examination of catalyst (2)]
Regarding the Sc (OTf) ₃ , Er (OTf) ₃ , Yb (OTf) ₃ , Sn (OTf) ₂ and Bi (OTf) _{3 with} particularly good results, the ketone compound (1) and the nitrogen source compound (2) An experiment was conducted in the same manner as in the above "Examination of catalyst (1)" except that the mixture was stirred at 70 ° C for 1 hour. The results are shown in Table 2.

As shown in Table 2, Sc (OTf) ₃ achieves a yield of 80% or more despite being a low temperature and short time reaction condition of 70 ° C. for 1 hour, and is a particularly excellent catalyst. I understand.

[Examination of solvent]
A stir bar was placed in a 4 mL vial, scandium (III) trifluoromethanesulfonate (0.010 mmol, 5.0 mol%) as a catalyst was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, benzophenone (0.20 mmol) as ketone compound (1), solvent (0.20 mL, 1.0 M), bis (trimethylsilyl) amine (0. 22 mmol, 1.1 eq.) Was added. After the mixture was stirred at 70 ° C. for 1 hour, the yield of the product was determined by ¹ HNMR measurement of the reaction crude product. The results are shown in Table 3.

As shown in Table 3, monochlorobenzene, toluene, tetrahydrofuran, dioxane (1,4-dioxane), fluorobenzene, dichloroethane, and acetonitrile can be used as the solvent, and monochlorobenzene, toluene, tetrahydrofuran, fluorobenzene, and acetonitrile can be used. It turns out that it is especially excellent.

[Investigation of nitrogen source]
A stir bar was placed in a 4 mL vial, scandium (III) trifluoromethanesulfonate (0.010 mmol, 5.0 mol%) as a catalyst was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, benzophenone (0.20 mmol) as the ketone compound (1), monochlorobenzene (1.0 mL, 1.0 M) as the solvent, nitrogen source compound (2) (0.22 mmol, 1 0.1 equivalent) was added. After the mixture was stirred at 90 ° C. for 2 hours, the yield of the product was determined by ¹ H NMR measurement of the reaction crude product. The results are shown in Table 4.

As shown in Table 4, bis (trimethylsilyl) amine and 2,2,4,4,6,6-hexamethylcyclotrisilazane were particularly excellent as the nitrogen source compound with a yield of 95% or more. It turns out that it is a nitrogen source compound.

[Synthesis of various unprotected imine compounds on nitrogen]
(Basic reaction conditions)
A stir bar was placed in a 4 mL vial, scandium (III) trifluoromethanesulfonate (0.010 mmol, 5.0 mol%) as a catalyst was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, and the ketone compound (1) (0.20 mmol), monochlorobenzene (0.20 mL, 1.0 M) as a solvent, bis (trimethylsilyl) amine (0) as a nitrogen source compound (2) .22 mmol, 1.1 eq) was added. After the mixture was stirred at 90 ° C. for a predetermined time, disappearance of the raw materials was confirmed by ¹ H NMR measurement, and the unprotected imine compound on nitrogen was isolated by silica gel column chromatography. The above reaction conditions are called basic reaction conditions.

[Example 4-1-1]
(Synthesis of benzophenone imine)
The reaction was carried out for 2 hours using 0.20 mmol of benzophenone under the above basic reaction conditions. The obtained crude product was subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1 to obtain the desired benzophenone imine as a yellow oil (31.2 mg, 86% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.72 (br, 1H), 7.58 (br, 4H), 7.50-7.46 (m, 2H), 7.44-7.41 (m, 4H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 178.38, 139.35, 130.33, 128.45, 128.36.

[Example 4-1-2]
(Synthesis of benzophenone imine on large scale (10 mmol))
In accordance with the above basic reaction conditions, a 50 mL flask was charged with scandium trifluoromethanesulfonate (III) (12.3 mg, 0.025 mmol, 0.25 mol%), benzophenone (1.82 g, 10 mmol), monochlorobenzene (10 mL, 1.0 M). ), Bis (trimethylsilyl) amine (2.3 mL, 11 mmol, 1.1 equivalents) was added, and the mixture was stirred with heating at 90 ° C. for 24 hours. After the solvent was distilled off, the crude product was purified using silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1 to obtain the desired benzophenone imine as a yellow oil (1.79 g, 99% yield). rate).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.72 (br, 1H), 7.58 (br, 4H), 7.50-7.46 (m, 2H), 7.44-7.41 (m, 4H).

[Example 4-1-3]
(Synthesis of benzophenone imine on large scale (50 mmol))
In accordance with the above basic reaction conditions, in a 100 mL flask, scandim (III) trifluoromethanesulfonate (49.2 mg, 0.10 mmol, 0.20 mol%), benzophenone (9.11 g, 50 mmol), bis (trimethylsilyl) amine (11. 5 mL, 55 mmol, 1.1 equivalents) was added, and the mixture was stirred with heating at 90 ° C. for 24 hours. The reaction mixture was evaporated under reduced pressure at room temperature, and the crude product was distilled under reduced pressure to obtain the desired benzophenone imine as a yellow oil (7.66 g, 85% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.72 (br, 1H), 7.58 (br, 4H), 7.50-7.46 (m, 2H), 7.44-7.41 (m, 4H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 178.23, 140.25, 138.29, 130.29, 129.16, 128.28, 127.60.

[Example 4-2]
(Synthesis of 9-iminofluorene)
The reaction was performed for 2 hours using 0.20 mmol of 9-fluorenone under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1 to obtain the desired 9-iminofluorene as a yellow solid (34.7 mg, 97% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 10.27 (br, 1H), 7.91 (br, 2H), 7.62 (d, J = 7.5 Hz, 2H), 7.47 (td, J = 1.0, 7.5 Hz, 2H) , 7.34 (td, J = 1.0, 7.5 Hz, 2H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 173.17, 142.21, 134.67, 128.17, 122.25, 120.09.

[Example 4-3]
(Synthesis of 3-iminoindoline-2-one)
The reaction was carried out at room temperature for 10 hours using 0.20 mmol of isatin under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / dichloromethane / triethylamine = 3/1/1 to obtain the desired 3-iminoindolin-2-one as a yellow solid (26. 7 mg, 91% yield).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.35 * (s, 1H), 11.27 (s, 1H), 10.92 (br, 1H), 10.83 * (br, 1H), 7.73 * (d.J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.46 (td, J = 1.0, 7.5 Hz, 1H), 7.40 * (td, J = 1.0, 7.5 Hz, 1H), 7.08 (t , J = 7.5 Hz, 1H), 7.03 * (t, J = 7.5 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.86 * (d, J = 8.0 Hz, 1H).
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 165.01 *, 163.82 *, 163.54, 159.35, 146.47, 144.92 *, 143.39, 133.93 *, 123.59 *, 123.14, 122.59, 122.01 *, 120.45, 117.96 *, 111.33, 110.90 *.
[* designate the minor diastereomer]

[Example 4-4]
(Synthesis of 2- (imino (phenyl) methyl) phenol)
The reaction was performed for 2 hours using 0.20 mmol of 2-hydroxybenzophenone under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 4/1 to obtain the desired 2- (imino (phenyl) methyl) phenol as a yellow solid (27.8 mg, 70% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.33 (br, 1H), 7.53-7.47 (m, 3H), 7.42-7.40 (m, 2H), 7.36 (ddd, J = 1.5, 7.5, 8.5 Hz, 1H ), 7.20 (dd, J = 2.0, 8.0 Hz, 1H), 7.05 (dd, J = 1.0, 8.5 Hz, 1H), 6.74 (ddd, J = 1.0, 7.0, 8.0 Hz, 1H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 181.32, 163.57, 139.11, 133.46, 132.14, 129.91, 128.69, 127.21, 118.41, 118.31, 117.62.

[Example 4-5]
(Synthesis of bis (4-chlorophenyl) methanimine)
The reaction was performed for 2 hours using 0.20 mmol of 4,4′-dichlorobenzophenone under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography using a developing solvent of hexane / triethylamine = 9/1 to obtain the desired bis (4-chlorophenyl) methanimine as a white solid (47.6 mg, 95% yield). rate).

¹ H NMR (500 MHz, CDCl3) δ 9.76 (br, 1H), 7.58 (br, 4H), 7.41 (d, J = 8.0 Hz, 4H).
¹³ C NMR (125 MHz, CDCl3) δ 176.07, 137.23, 136.71, 129.67, 128.72.

[Example 4-6]
(Synthesis of di-p-tolylmethanimine)
The reaction was carried out using 0.20 mmol of 4,4′-dimethylbenzophenone under the above basic reaction conditions for 3 hours. The obtained reaction crude product was subjected to silica gel column chromatography using a developing solvent of hexane / triethylamine = 9/1 to obtain the desired di-p-tolylmethanimine as a colorless oil (39.7 mg, 95% yield). rate).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.56 (br, 1H), 7.47 (br, 4H), 7.22 (d, J = 8.0 Hz, 4H), 2.41 (s, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 178.12, 140.40, 136.71, 128.93, 128.43, 21.39.

[Example 4-7]
(Synthesis of bis (4-methoxyphenyl) methanimine)
The reaction was performed for 24 hours using 0.20 mmol of 4,4′-dichlorobenzophenone and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / dichloromethane / triethylamine = 8/1/1 to obtain the desired bis (4-methoxyphenyl) methanimine as a white solid (46. 8 mg, 97% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.31 (br, 1H), 7.53 (d, J = 6.5 Hz, 4H), 6.94-6.91 (m, 4H), 3.86 (s, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 177.05, 161.18. 132.14, 130.11, 113.52, 55.37.

[Example 4-8]
(Synthesis of (4-Bromophenyl) (phenyl) methanimine)
The reaction was performed for 2 hours using 0.20 mmol of 4-bromobenzophenone under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1 to obtain the desired (4-bromophenyl) (phenyl) methanimine as a yellow oil (50.2 mg, 96% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.74 (br, 1H), 7.56 (dd, J = 2.0, 6.5 Hz, 2H), 7.55-7.47 (m, 4H), 7.45-7.41 (m, 4H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 177.29, 139.01, 137.92, 131.52, 130.44, 130.18, 128.48, 128.12, 124.95.

[Example 4-9]
(Synthesis of bis (3- (trifluoromethyl) phenyl) methanimine)
The reaction was carried out for 48 hours using 0.20 mmol of 3,3′-bis (trifluoromethyl) benzophenone and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography using a developing solvent of hexane / triethylamine = 9/1 to obtain the desired bis (3- (trifluoromethyl) phenyl) methanimine as a colorless oil (56. 0 mg, 88% yield).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.26 (br, 1H), 8.00 (s, 1H), 7.93-7.90 (m, 2H), 7.83-7.82 (m, 2H), 7.76-7.68 (m , 3H).
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 172.61, 139.27, 139.02, 132.76, 131.72, 129.76, 129.73, 129.43 (q, J _CF = 32 Hz), 129.27 (q, J _CF = 32 Hz), 127.18 (q, J _CF = 3.5 Hz), 126.68 (q, J _CF = 3.5 Hz), 124.63 (q, J _CF = 3.8 Hz), 124.43 (q, J _CF = 3.8 Hz), 124.05 (q, J _CF = 271 Hz), 123.97 (q, J _CF = 271 Hz).
¹⁹ F NMR (470 MHz, DMSO-d ₆ ) δ-61.14 (s, 3F), -61.27 (s, 3F).

[Example 4-10]
(Synthesis of phenyl (pyridin-2-yl) methanimine)
The reaction was carried out for 12 hours using 0.20 mmol of 2-benzoylpyridine and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1 to obtain a desired mixture of phenyl (pyridin-2-yl) methanimine and ketone as a colorless oil (31 .6 mg, imine / ketone = 92/8, imine yield 81%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 11.05 (br, 1H), 8.75 (d, J = 4.0 Hz, 1H), 7.77 (dd, J = 7.5, 7.5 Hz, 1H), 7.66 (br, 2H) , 7.51-7.44 (m, 3H), 7.41-7.38 (m, 1H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 175.35, 155.35, 149.75, 137.88, 136.77, 130.24, 128.70, 128.34, 124.80.

[Example 4-11]
(Synthesis of 5H-dibenzo [a, d] [7] annulene-5-imine)
The reaction was performed for 12 hours using 0.20 mmol of dibenzosuberenone and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained reaction crude product is subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1 to obtain the desired 5H-dibenzo [a, d] [7] annulene-5-imine as a colorless oil. (40.1 mg, 98% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.72 (br, 1H), 7.70 (br, 2H), 7.48-7.44 (m, 4H), 7.40-7.38 (m, 2H), 6.93 (s, 2H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 178.49, 139.60, 133.16, 130.83, 129.42, 129.11, 129.03, 127.35.

[Example 4-12]
(Synthesis of 9H-xanthene-9-imine)
The reaction was carried out for 48 hours using 0.20 mmol of xanthone and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography using a developing solvent of hexane / dichloromethane / triethylamine = 8/1/1 to obtain the desired 9H-xanthene-9-imine as a white solid (38.5 mg). 99% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.49 (br, 1H), 8.17 (br, 2H), 7.58 (ddd, J = 1.5, 7.0, 8.5 Hz, 2H), 7.35 (dd, J = 1.0, 8.5 Hz, 2H), 7.31 (ddd, J = 1.0, 7.0, 8.0 Hz, 2H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 159.06, 152.84, 132.58, 124.56, 123.68, 119.73, 117.93.

[Example 4-13]
(Synthesis of 2- (4-((4-chlorophenyl) (imino) methyl) phenoxy) -2-methylpropionate)
The reaction was carried out for 24 hours using 0.20 mmol of fenofibrate and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained crude reaction product was subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1 to obtain the desired 2- (4-((4-chlorophenyl) (imino) methyl) phenoxy) -2-methyl. Isopropyl propionate was obtained as a yellow oil (67.2 mg, 93% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.46 (br, 4H), 7.39 (dd, J = 1.5, 6.5 Hz, 2H), 6.85-6.82 (m, 2H), 5.09 (septet, J = 6.0 Hz, 1H), 1.64 (s, 6H), 1.22 (d, J = 6.0 Hz, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 276.46, 173.33, 157.68, 137.94, 136.23, 129.58, 128.53, 117.77, 79.20, 69.18, 59.34, 25.34, 21.54, 8.49.

[Example 4-14]
(Synthesis of 2- (3- (imino (phenyl) methyl) phenyl) propionic acid)
The reaction was carried out for 24 hours using 0.20 mmol of ketoprofen and 2.0 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained reaction crude product is subjected to silica gel column chromatography with a developing solvent of dichloromethane / methanol = 9/1 to obtain the desired 2- (3- (imino (phenyl) methyl) phenyl) propionic acid as a yellow oil. (44.4 mg, 88% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.79-7.76 (m, 3H), 7.64 (d, J = 7.0 Hz, 1H), 7.59 (dd, J = 7.0, 7.0 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.47 (dd, J = 7.5, 7.5 Hz, 2H), 3.79 (q, J = 6.0 Hz, 1H), 1.53 (d, J = 6.0 Hz, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 198.86, 180.08, 141.36, 137.69, 137.29, 132.63, 131.84, 130.19, 129.18, 128.97, 128.42, 128.32, 45.99, 18.37.

[Example 4-15]
(Synthesis of 2,2-dimethyl-3,4-dihydronaphthalene-1 (2H) -imine)
The reaction was performed for 24 hours using 0.20 mmol of 2,2-dimethyl-3,4-dihydronaphthalen-1 (2H) -one under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / diethyl ether / triethylamine = 20/1/1 to obtain the desired 2,2-dimethyl-3,4-dihydronaphthalene-1 (2H). -The imine was obtained as a yellow oil (33.7 mg, 97% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.42 (br, 1H), 8.08 (br, 1H), 7.35 (td, J = 1.5, 7.5 Hz, 1H), 7.27 (tt, J = 0.5, 7.5 Hz, 1H), 7.17 (dd, J = 0.5, 7.5 Hz, 1H), 2.93 (t, J = 6.5 Hz, 2H), 1.85 (t, J = 6.5 Hz, 2H), 1.22 (s, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 181.16, 139.71, 132.50, 130.40, 128.76, 126.36, 126.11, 38.36, 36.42, 25.93, 25.73.

[Example 4-16]
(Synthesis of 1,7,7-trimethylbicyclo [2.2.1] heptane-2-imine)
The reaction was carried out for 24 hours using 0.20 mmol of DL-camphor and 1.5 equivalents of bis (trimethylsilyl) amine, 10 mol% of scandium (III) trifluoromethanesulfonate under the above basic reaction conditions. After confirming disappearance of the raw materials by ¹ HNMR measurement, hexane cooled to −50 ° C. was added to the reaction mixture, and added to a short pad silica gel column pre-equilibrated with hexane / triethylamine = 100/1. After washing the pad with chilled hexane, the resulting hexane layer was separated and the pad was eluted with dichloromethane cooled to -50 ° C. The solvent was distilled off from the obtained dichloromethane extract under reduced pressure to obtain the desired 1,7,7-trimethylbicyclo [2.2.1] heptane-2-imine as a pale yellow solid (15.3 mg, About 90% purity, about 45% yield).
The synthesis of 1,7,7-trimethylbicyclo [2.2.1] heptan-2-imine of this example requires at least 2-3 steps from a commercially available compound by a known method. However, this method can be synthesized in one step from commercially available compounds.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.47-2.42 (m, 1H), 1.97 (d, J = 17.5 Hz, 1H), 1.92 (t, J = 4.5 Hz, 1H), 1.91-1.83 (m, 1H), 1.69-1.63 (m, 1H), 1.38-1.25 (m, 2H), 0.94 (s, 3H), 0.93 (s, 3H), 0.80 (s, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ. 194.41, 54.86, 47.37, 43.74, 40.35, 32.06, 27.41, 19.64, 19.04, 10.44.

[Example 4-17]
(Synthesis of adamantane-2-imine)
The reaction was carried out for 48 hours using 1.0 mmol of adamantan-2-one and 3.0 equivalents of bis (trimethylsilyl) amine and 10 mol% of scandium (III) trifluoromethanesulfonate under the above basic reaction conditions. As a result of ¹ HNMR measurement of the crude product, the raw material and a single product were confirmed, and the yield of the product was 59%.

[Example 4-18]
(Synthesis of 2,2-dimethyl-1-phenylpropane-1-iminium chloride)
The reaction was performed for 6 hours using 1.0 mmol of tert-butyl phenyl ketone and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. After confirming disappearance of the raw material by ¹ HNMR measurement, the reaction mixture diluted with hexane was filtered through Celite. After the filtrate was concentrated under reduced pressure, the residue was dissolved in 1.0 mL of diethyl ether, 1.0 equivalent of hydrochloric acid (1M diethyl ether solution, 1.0 mL) was added, and the suspension was stirred for 1 hour. The suspension was filtered to give the desired 2,2-dimethyl-1-phenylpropane-1-iminium chloride as a white solid (143 mg, 72% yield,> 95% purity).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.75 (br, 2H), 7.67-7.63 (m, 1H), 7.59-7.58 (m, 4H), 1.35 (s, 9H).
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ. 199.86, 132.74, 132.11, 128.93, 127.59, 40.99, 27.93.

[Example 4-19-1]
(Synthesis of 2,2,2-trifluoro-1-phenylethanimine)
A stir bar was placed in a 4 mL vial, scandium (III) trifluoromethanesulfonate (0.020 mmol, 2.0 mol%) was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon and 2,2,2-trifluoroacetophenone (1.0 mmol), monochlorobenzene (1.0 mL, 1.0 M), bis (trimethylsilyl) amine (1.1 mmol, 1.1 mmol). Equivalent) was added. After the mixture was stirred at 90 ° C. for 24 hours, the yield was confirmed by ¹⁹ FNMR measurement, and conversion to 95% or more of 2,2,2-trifluoro-1-phenylethaneimine was confirmed.

[Example 4-19-2]
(Synthesis of 2,2,2-trifluoro-1-phenylethaneimine on a large scale (10 mmol))
According to the reaction conditions of Example 4-14-1 above, a 50 mL flask was charged with scandim (III) trifluoromethanesulfonate (49.2 mg, 0.10 mmol, 1.0 mol%), 2,2,2-trifluoroacetophenone ( 1.4 mL, 10 mmol), fluorobenzene (10 mL, 1.0 M), bis (trimethylsilyl) amine (2.3 mL, 11 mmol, 1.1 equivalents) were added, and the mixture was heated and stirred at 90 ° C. for 24 hours. After confirming the disappearance of the raw materials by ¹⁹ FNMR measurement, hexane cooled to −50 ° C. was added to the reaction mixture, and added to a short pad silica gel column pre-equilibrated with hexane / triethylamine = 100/1. After washing the pad with chilled hexane, the resulting hexane layer was separated and the pad was eluted with dichloromethane cooled to -50 ° C. The solvent was distilled off from the obtained dichloromethane extract under reduced pressure to obtain the desired 2,2,2-trifluoro-1-phenylethaneimine as a colorless oil (1.45 g, 84% yield). The diastereo ratio of the NH imine proton due to the E / Z isomer was determined to be 2.6: 1 by ¹⁹ FNMR.

¹ H NMR (500 MHz, CDCl ₃ ) δ 10.78 * (br, 1H), 10.69 (br, 1H), 7.99-7.97 (m, 2H + 2H *), 7.59-7.47 (3H + 3H *).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 166.76 * (q, J _CF = 33 Hz), 163.16 (q, J _CF = 31 Hz), 132.29 *, 123.32, 131.84 *, 130.93, 129.12 *, 128.70, 128.10 , 126.56 *, 120.27 * (q, J _CF = 278 Hz), 118.42 (q, J _CF = 280 Hz).
¹⁹ F NMR (470 MHz, CDCl ₃ ) δ-68.65 *, -69.56.
[* designate the minor diastereomer]

[Example 4-20]
(Synthesis of bis (4-fluorophenyl) methanimine)
The reaction was carried out for 2 hours using 0.20 mmol of 4,4′-difluorobenzophenone under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography using a developing solvent of hexane / triethylamine = 9/1 to obtain the desired bis (4-fluorophenyl) methanimine as a yellow oil (42.8 mg, 99% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.64 (br, 1H), 7.56 (br, 4H), 7.11 (t, J = 8.5 Hz, 4H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 176.07, 164.10 (d, J _CF = 250 Hz), 135.35, 130.43, 115.48 (d, J _CF = 22 Hz).
¹⁹ F NMR (360 MHz, CDCl ₃ ) δ -109.86 (br, 2F)

[Example 4-21]
(Synthesis of bis (4-bromophenyl) methanimine)
The reaction was carried out for 2 hours using 0.20 mmol of 4,4′-dibromobenzophenone under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography using a developing solvent of hexane / triethylamine = 9/1 to obtain the desired bis (4-bromophenyl) methanimine as a white solid (65.5 mg, 97% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.77 (br, 1H), 7.56 (d, J = 8.0 Hz, 4H), 7.43 (br, 4H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 176.21, 137.79, 131.70, 129.88, 125.12.

[Example 4-22]
(Synthesis of (4-nitrophenyl) (phenyl) methanimine)
The reaction was carried out for 2 hours using 0.20 mmol of 4-nitrobenzophenone under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / ethyl acetate / triethylamine = 8/1/1 to obtain the desired (4-nitrophenyl) (phenyl) methanimine as a yellow oil. (44.5 mg, 98% yield). The diastereo ratio of the NH imine proton by the E / Z isomer was determined to be 1.4: 1 by ¹ HNMR.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.12 (br, 1H), 10.93 (br, 1H *), 8.32-8.23 (m, 2H + 2H *), 7.86 (d, J = 8.5 Hz, 2H ), 7.67 (d, J = 8.5 Hz, 2H *), 7.63 (dd, J = 8.5, 1.5 Hz, 2H *), 7.56-7.44 (m, 5H + 3H *).
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 174.46, 174.18 *, 148.93, 148.37 *, 145.86 *, 145.06, 138.64, 138.02 *, 131.30 *, 130.71, 130.45, 129.49 *, 129.12, 128.94 *, 128.90 * , 128.06, 124.12 *, 123.94.
[* designate the minor diastereomer]

[Example 4-23]
(Synthesis of (4-((tert-butylcymethylsilyl) oxy) phenyl) (phenyl) methanimine)
The reaction was performed for 24 hours using 0.20 mmol of 4-((tert-butylcymethylsilyl) oxy) benzophenone and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1, and the target (4-((tert-butylcymethylsilyl) oxy) phenyl) (phenyl) methanimine was converted to yellow. As an oil (49.6 mg, 80% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.51 (br, 1H), 7.52 (br, 4H), 7.48-7.44 (m. 1H), 7.43-7.40 (m, 2H), 6.85 (dt, J = 9.5 , 2.5 Hz, 2H), 1.00 (s, 9H), 0.23 (s, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 177.92, 157.98, 139.92, 132.03, 130.23, 130.06, 128.30, 119.80, 115.44, 25.64, 18.24.

[Example 4-24]
(Synthesis of (4- (azidomethyl) phenyl) (phenyl) methanimine)
The reaction was carried out for 2 hours using 0.20 mmol of 4- (azidomethyl) benzophenone and 1.5 equivalents of bis (trimethylsilyl) amine under the above basic reaction conditions. The obtained reaction crude product is subjected to silica gel column chromatography with a developing solvent of hexane / dichloromethane / triethylamine = 8/1/1 to obtain the desired (4- (azidomethyl) phenyl) (phenyl) methanimine as a yellow oil. (39.8 mg, 84% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.76 (br, 1H), 7.62 (br, 4H), 7.50-7.47 (m, 1H), 7.43 (dd, J = 7.5, 7.5 Hz, 2H), 7.38 ( d, J = 8.0 Hz, 2H), 4.41 (s, 2H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 177.77, 139.22, 137.67, 130.38, 129.03, 128.42, 128.28, 128.04, 54.41.

[Example 4-25]
(Synthesis of 1,7,7-trimethylbicyclo [2.2.1] heptane-2-iminium chloride)
The reaction was carried out for 24 hours using 0.20 mmol of DL-camphor and 2.0 equivalents of bis (trimethylsilyl) amine, 10 mol% of scandium (III) trifluoromethanesulfonate under the above basic reaction conditions. After confirming disappearance of the raw materials by ¹ HNMR measurement, the reaction mixture was transferred to a 25 mL flask, 4.0 equivalents of methanol was added, and the mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, the residue was dissolved in 2.0 mL of diethyl ether, 5.0 equivalents of hydrochloric acid (1M diethyl ether solution, 1.0 mL) was added, and the suspension was stirred for 1 hour. The suspension was filtered to give the desired 1,7,7-trimethylbicyclo [2.2.1] heptane-2-iminium chloride as a white solid (25.4 mg, 68% yield).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.51 (br, 1H), 2.96-2.91 (m, 1H), 2.47 (d, J = 20 Hz, 1H), 2.12 (t, J = 4.5 Hz, 1H), 1.93-1.85 (m, 2H), 1.44-1.34 (m, 2H), 1.11 (s, 3H), 0.95 (s, 3H), 0.79 (s, 3H).
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ. 207.11, 57.51, 49.85, 43.32, 38.43, 31.84, 25.96, 19.63, 18.62, 10.19.

[Examination of reaction accelerator]
A stir bar was placed in a 4 mL vial, scandium (III) trifluoromethanesulfonate (0.010 mmol, 5.0 mol%) as a catalyst was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, benzophenone (0.20 mmol) as the ketone compound (1), monochlorobenzene (1.0 mL, 1.0 M) as the solvent, nitrogen source compound (2) (0.22 mmol, 1 0.1 equivalent), a reaction accelerator (0.010 mmol, 5.0 mol%) was added. Trimethylsilanol (TMSOH) and methanol (MeOH) were used as reaction accelerators. After the mixture was stirred at 50 ° C., the yield of the product was determined by ¹ H NMR measurement of the reaction crude product. The results are shown in Table 7.

As shown in Table 7, it can be seen that addition of trimethylsilanol or methanol promotes the reaction (improves yield).

[One-pot synthesis of glycine Schiff base via unprotected imine compound on nitrogen]
A stir bar was placed in a 4 mL vial, scandium (III) trifluoromethanesulfonate (0.010 mmol, 5.0 mol%) was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon and benzophenone (36.4 mg, 0.20 mmol), monochlorobenzene (0.20 mL, 1.0 M), bis (trimethylsilyl) amine (0.22 mmol, 1.1 eq) were added. . The mixture was stirred at 70 ° C. for 5 hours, and disappearance of raw materials was confirmed by ¹ HNMR measurement.

Thereafter, dichloromethane (0.80 mL, 0.25 M) and glycine t-butyl ester hydrochloride (33.5 mg, 0.20 mmol, 1.0 equivalent) were added. The mixture was stirred at room temperature for 24 hours, and the resulting reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / ethyl acetate = 10/1 to obtain the desired glycine Schiff base as a white solid (48 .3 mg, 82% yield (2 steps)).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.67-7.65 (m, 2H), 7.50-7.42 (m, 3H), 7.41-7.37 (m, 1H), 7.35-7.31 (m, 2H), 7.19-7.18 (m, 2H), 4.12 (s, 2H), 1.46 (s, 9H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 117.53, 169.90, 139.38, 136.18, 130.38, 128.76, 128.76, 128.63, 128.04, 127.74, 81.09, 56.31, 28.12.

[One-pot synthesis of isatin adducts via unprotected imine compounds on nitrogen]
A stir bar was placed in a 4 mL vial, scandium (III) trifluoromethanesulfonate (0.010 mmol, 5.0 mol%) was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon and isatin (29.4 mg, 0.20 mmol), monochlorobenzene (0.20 mL, 1.0 M), bis (trimethylsilyl) amine (0.22 mmol, 1.1 eq) were added. . The mixture was stirred at room temperature for 12 hours, and disappearance of the raw materials was confirmed by ¹ HNMR measurement, and then chlorobenzene (0.60 mL, 0.25 M) and β-keto acid (49.2 mg, 0.30 mmol, 1.5 eq) Was added. The mixture was stirred at room temperature for 9.5 hours, and the resulting reaction crude product was subjected to silica gel column chromatography with a developing solvent of dichloromethane / methanol / triethylamine = 100/5/1 to obtain the desired isatin adduct as a white solid. (46.6 mg, 87% yield (2 steps)).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.88 (d, J = 1.0 Hz, 2H), 7.56-7.53 (m, 2H), 7.42 (dd, J = 7.5, 8.0 Hz, 2H), 7.34 (d, J = 7.0 Hz, 1H), 7.24 (dd, J = 1.0, 8.0 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 3.89 (d, J = 18 Hz, 1H), 3.62 (d, J = 18 Hz, 1H), 1.90 (br, 2H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 196.30, 181.15, 140.92, 136.18, 133.48, 131.66, 129.24, 128.62, 128.02, 123.81, 122.73, 58.70, 46.79.

[Example 8-1]
[Synthesis of 2,2,2-trifluoro-1-phenylethaneimine using tetrabutylammonium fluoride (TBAF) as a catalyst (with solvent)]
A stir bar was placed in a 4 mL vial and 2,2,2-trifluoroacetophenone (1.0 mmol), chlorobenzene (1.0 mL, 1.0 M), bis (trimethylsilyl) amine (1.1 mmol, 1.1 eq) And tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 0.050 mL, 0.050 mmol, 5.0 mol%) were added. The mixture was stirred at 90 ° C. for 24 hours, and ¹⁹ FNMR measurement of the crude product was performed. As a result, the progress of the reaction of 95% or more was confirmed.

[Example 8-2]
[Synthesis of 2,2,2-trifluoro-1-phenylethanimine catalyzed by TBAF (substantially solvent-free)]
A stir bar was placed in a 4 mL vial and 2,2,2-trifluoroacetophenone (1.0 mmol), bis (trimethylsilyl) amine (1.1 mmol, 1.1 eq) and tetrabutylammonium fluoride (TBAF, 1. 0M in THF, 0.10 mL, 0.10 mmol, 10 mol%) was added. After stirring the mixture at 70 ° C. for 12 hours, ¹⁹ FNMR measurement of the crude product was performed, and it was confirmed that the reaction progressed by about 88%.

[Synthesis of benzophenone imine using TBAF as a catalyst (substantially solvent-free)]
A stir bar was placed in a 4 mL vial, benzophenone (1.0 mmol), bis (trimethylsilyl) amine (2.0 mmol, 2.0 eq), tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 0.10 mL, 0.10 mmol, 10 mol%) was added. The mixture was stirred at room temperature for 2 hours, and disappearance of the raw materials was confirmed by ¹ HNMR measurement. The obtained reaction crude product was subjected to silica gel column chromatography with a developing solvent of hexane / triethylamine = 9/1 to obtain the desired benzophenone. The imine was obtained as a yellow oil (162 mg, 90% yield).

[Examination of catalyst]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), tetrahydrofuran (0.1 mL) as the solvent, and bis (trimethylsilyl) amine (2. 0 mmol, 2.0 eq) and catalyst (0.10 mmol, 10 mol%) were added. As the catalyst, tetrabutylammonium fluoride (TBAF), tetrabutylammonium dihydrogen trifluoride (TBAH ₂ F ₃ ), and TBAF hydrate were used. The mixture was stirred at room temperature for 24 hours, and the yield was determined by ¹ HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 8.

As shown in Table 8, unprotected ketimine on nitrogen was produced by using a catalyst containing a fluorine-containing anion salt of tetraalkylammonium. Among these, TBAF was able to achieve a yield of 80% or more.

[Study of solvent (1)]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), solvent (0.1 mL), bis (trimethylsilyl) amine (2.0 mmol, nitrogen source compound (2)) 2.0 equivalents) and tetrabutylammonium fluoride hydrate (0.10 mmol, 10 mol%) was added as a catalyst. Tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and monochlorobenzene (PhCl) were used as the solvent. The mixture was stirred at room temperature for 24 hours, and the yield was determined by ¹ HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 9.

As shown in Table 9, when tetrahydrofuran, N, N-dimethylformamide, or monochlorobenzene was used as the solvent, the reaction proceeded well. It can be seen that N, N-dimethylformamide is particularly excellent.

[Study of solvent (2)]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine (2.0 mmol, 2.0 equivalents) as the nitrogen source compound (2), catalyst As a solution, tetrabutylammonium fluoride (0.10 mmol, 10 mol%) in THF and an additional solvent (0.1 to 2 equivalents) were added. Additional solvents include N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), N, N-dimethylpropyleneurea (DMPU) and 1,3-dimethyl-2-imidazolidinone (DMI) were used. The mixture was stirred at room temperature for 24 hours, and the yield was determined by ¹ HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 10.

As shown in Table 10, the yield of N, N-dimethylformamide (DMF) is improved by the addition of 10 mol% to 200 mol% (0.1 to 2 equivalents), and 100 mol% is particularly excellent. I understand. In addition to N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA) , N, N-dimethylpropyleneurea (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI) was also added to improve the yield. It can be seen that HMPU, DMPU, and DMI are excellent, and DMI is particularly excellent.

[Study of solvent (3)]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, benzophenone imine (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine (2.0 mmol, 2.0 equivalents) as the nitrogen source compound (2), and fluoride as the catalyst. Tetrabutylammonium (0.050 mmol, 5.0 mol%) in THF and additional solvent (1.0 eq) were added. Additional solvents include N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), N, N-dimethylpropylene Urea (DMPU) and 1,3-dimethyl-2-imidazolidinone (DMI) were used. After the mixture was stirred at room temperature for 2 hours, the yield of the product was determined by ¹ H NMR measurement of the reaction crude product. The results are shown in Table 11.

As shown in Table 11, N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), N, N -An improvement in yield was observed by adding dimethylpropyleneurea (DMPU) and 1,3-dimethyl-2-imidazolidinone (DMI). In particular, it can be seen that DMF and DMPU are excellent.

[Study of solvent (4)]
In the method of the examination of the solvent (3), while using a THF solution of tetrabutylammonium fluoride (0.025 mmol, 2.5 mol%) as a catalyst and using DMF with good results as an additional solvent, The amount added was varied. The results are shown in Table 12.

As shown in Table 12, it can be seen that the reaction proceeds sufficiently by using a relatively large amount of DMF even if the amount of the catalyst is reduced.
In the system using 13 equivalents (1.0 M) of DMF and bis (trimethylsilyl) amine (1.5 mmol, 1.5 equivalents) as the nitrogen source compound (2), TBAF was reduced to 1.0 mol%. However, the reaction proceeded (79-94% ( ¹ HNMR)).

[Examination of amount of nitrogen source compound (1)]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine as the nitrogen source compound (2), and tetrabutylammonium fluoride hydrate ( 0.10 mmol, 10 mol%) was added. The mixture was stirred at room temperature for 24 hours, and the yield was determined by ¹ HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 13.

As shown in Table 13, it can be seen that the nitrogen source compound is 3.0 to 1.1 equivalents, the reaction proceeds in a high yield, and the use of 1.5 equivalents is particularly excellent.

[Examination of amount of nitrogen source compound (2)]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, benzophenone imine (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine as the nitrogen source compound (2), tetrabutylammonium fluoride (0.025 mmol, 2. 5 mol%) was added. After the mixture was stirred at room temperature for 1 hour, the yield of the product was determined by ¹ H NMR measurement of the reaction crude product. The results are shown in Table 14.

As shown in Table 14, it can be seen that the nitrogen source compound is 2.0 to 1.1 equivalents, the reaction proceeds in a high yield, and the use of 1.5 equivalents is particularly excellent.

[Examination of reaction temperature]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine (2.0 mmol) as the nitrogen source compound (2), and tetrabutyl fluoride as the catalyst. Ammonium (0.010 mmol, 10 mol%) was added. The mixture was stirred at room temperature for 24 hours, and the yield was determined by ¹ HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 15.

As shown in Table 15, the reaction proceeded even at a low temperature of 0 ° C. In addition, the reaction proceeded particularly well at room temperature (25 ° C.).

[Synthesis of various alkyl ketimines catalyzed by TBAF]
(Basic reaction conditions)
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, the ketone compound (1) (1.0 mmol), bis (trimethylsilyl) amine (1.5 mmol, 1.5 equivalents) as the nitrogen source compound (2), and 1,3-dimethyl as the solvent -2-Imidazolidinone (1.0 mmol, 1.0 equivalent) and tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 0.10 mL, 0.10 mmol, 10 mol%) were added as a catalyst. The mixture was stirred at room temperature for 6 hours, and the yield was determined by ¹ HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The above reaction conditions are called basic reaction conditions.

[Example 14-1]
(Synthesis of cyclohexyl (phenyl) methanimine)
Stirring was performed for 6 hours using 1.0 mmol of cyclohexyl (phenyl) ketone under the above basic reaction conditions. ^{From 1} HNMR measurement, it was confirmed that the desired cyclohexyl (phenyl) methanimine was produced in a yield of> 99%.

[Example 14-2]
(Synthesis of cyclobutyl (phenyl) methanimine)
Stirring was performed for 6 hours using 1.0 mmol of cyclobutyl (phenyl) ketone under the above basic reaction conditions. ^{From 1} HNMR measurement, it was confirmed that the desired cyclobutyl (phenyl) methanimine was produced in a yield of> 99%.

[Example 14-3]
(Synthesis of cyclopropyl (phenyl) methanimine)
Stirring was carried out for 6 hours using 1.0 mmol of cyclopropyl (phenyl) ketone under the above basic reaction conditions. ^{From 1} HNMR measurement, it was confirmed that the desired cyclohexyl (phenyl) methanimine was produced in a yield of> 99%.

[Example 14-4]
(Synthesis of 2-methyl-1-phenylpropane-1-imine)
Stirring was carried out for 6 hours using 1.0 mmol of isobutyrophenone under the above basic reaction conditions. ^{From 1} HNMR measurement, it was confirmed that the desired 2-methyl-1-phenylpropane-1-imine was produced in a yield of 89%.

[Example 14-5]
(Synthesis of 1-phenylpropane-1-imine)
Stirring was performed for 24 hours using 1.0 mmol of propiophenone under the above basic reaction conditions. ^{From 1} HNMR measurement, it was confirmed that the target 1-phenylpropane-1-imine was produced in a yield of 87%, and 1% of unreacted propiophenone remained.

[Example 14-6]
(Synthesis of 1-phenylbutane-1-imine)
Stirring was carried out for 24 hours using 1.0 mmol of butyrophenone under the above basic reaction conditions. ^{From 1} HNMR measurement, it was confirmed that the target 1-phenylbutane-1-imine was produced in a yield of 90%, and 6% of unreacted butyrophenone remained.

[Example 14-7]
(Synthesis of 1-phenylpentane-1-imine)
Stirring was performed for 24 hours using 1.0 mmol of valerophenone under the above basic reaction conditions. ^{From 1} HNMR measurement, it was confirmed that the target 1-phenylpentane-1-imine was produced in a yield of 81%, and 10% of unreacted valerophenone remained.

[Example 14-8]
(Synthesis of dicyclopropylmethanimine)
Stirring was carried out for 24 hours using 1.0 mmol of dicyclopropyl ketone under the above basic reaction conditions. ^{From 1} HNMR measurement, it was confirmed that the target dicyclopropylmethanimine was produced in a yield of 60%, and 35% of unreacted dicyclopropylketone remained.

[Synthesis of benzophenone imine using TBAF as catalyst (with solvent)]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, ketone compound (1) (1.0 mmol), bis (trimethylsilyl) amine (1.5 mmol, 1.5 equivalents) as nitrogen source compound (2), N, N— Dimethylformamide (1.0 mL, 1.0 M) and tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 0.025 mL, 0.025 mmol, 2.5 mol%) were added as a catalyst. The mixture was stirred at room temperature for 1 hour, and disappearance of raw materials was confirmed by ¹ HNMR measurement. The reaction solution was transferred to a separatory funnel and H ₂ O (10 mL) was added. After extraction with diethyl ether, the organic layer was concentrated under reduced pressure and dried over sodium sulfate. After the solvent was distilled off, silica gel column chromatography was performed with a developing solvent of hexane / triethylamine = 9/1 to obtain the desired benzophenone imine as a yellow oil (173 mg, 96% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.72 (br, 1H), 7.58 (br, 4H), 7.49-7.46 (m, 2H), 7.44-7.40 (m, 4H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 178.36, 139.35, 130.30, 128.34, 128.34.

[One-pot synthesis of aminonitrile via unprotected imine compound on nitrogen]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol), bis (trimethylsilyl) amine (1.5 mmol, 1.5 eq), and tetrabutylammonium fluoride (TBAF, 1.0 M in) as the catalyst. THF, 0.10 mL, 0.10 mmol, 10 mol%) was added and the mixture was stirred at room temperature for 24 hours.

Thereafter, acetone cyanohydrin (3.0, mmol, 3.0 equivalents) was added and stirred at room temperature for 24 hours. After confirming the disappearance of the ketimine intermediate by ¹ HNMR measurement, the reaction crude product was subjected to silica column chromatography with a developing solvent of hexane / ethyl acetate = 6/1 to obtain the desired aminonitrile as a white solid (190 mg). , 89% yield (2 steps)).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.61-7.59 (m, 2H), 7.41-7.33 (m, 3H), 2.08 (br, 2H), 1.93-1.83 (m, 2H), 1.73-1.69 (m , 2H), 1.66-1.64 (m, 1H), 1.49-1.47 (m, 1H), 1.29-1.25 (m, 2H), 1.15-1.05 (m, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 139.40, 128.51, 128.45 (2C), 126.25 (2C), 122.83, 62.33, 48.82, 27.82, 27.37, 25.97 (2C), 25.80.

The reaction proceeded without any problem even when the cyano source was reduced to 1.5 equivalents. The reaction proceeded similarly when TMSCN was used as the cyano source.

[Examination of reaction accelerator (1)]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine (2.0 mmol, 2.0 equivalents) as the nitrogen source compound (2), reaction Accelerator (1.0 mmol, 1.0 eq) and tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 0.10 mL, 0.10 mmol, 10 mol%) as catalyst were added. As a reaction accelerator, trimethylsilanol (TMSOH), methanol (MeOH), and ethanol (EtOH) were used. The mixture was stirred at room temperature for 6 hours, and the yield was determined by ¹ HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 17.

As shown in Table 17, the reaction is accelerated (the yield is improved) by adding trimethylsilanol, methanol, and ethanol, and it can be seen that ethanol is particularly excellent. It can be seen that the yield is improved when the amount of ethanol is 10 to 50 mol%, and particularly 10 mol% is excellent. Moreover, it turns out that a yield improves by making the quantity of a nitrogen source into 1.5 equivalent. Further, it can be seen that the reaction proceeds almost quantitatively by extending the reaction time to 24 hours. It can be seen that trimethylsilanol gives better results when extended to 24 hours.

[Examination of reaction accelerator (2)]
A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine (2.0 mmol, 2.0 equivalents) as the nitrogen source compound (2), solvent As N, N-dimethylformamide (1.0 mmol), tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 0.10 mL, 0.10 mmol, 10 mol%) as a catalyst, and H ₂ O (0 .10 mmol, 10 mol%) was added. The mixture was stirred at room temperature for 6 hours, and the yield was determined by ¹ HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 18.

As shown in Table 18, it can be seen that the reaction is promoted (yield is improved) by adding 10 mol% of water.

The present invention is industrially useful because an unprotected imine compound on nitrogen can be produced.

Claims (11)

1. In the presence of at least one catalyst selected from a catalyst comprising a metal salt having Lewis acidity and a catalyst comprising a fluorine-containing anion salt of tetraalkylammonium.
   Following formula (1)
   

   

   (R ¹ and R ² each represent an organic group, and may be linked to each other to form a ring);
   Following formula (2)
   

   

   [R ³ and R ⁴ each represent a hydrogen atom or an aliphatic group, and R ⁵ represents a hydrogen atom, an aliphatic group, or a group having the following structure bonded to each other:
   

   

   (R ⁶ represents a hydrogen atom or an aliphatic group). And a nitrogen source compound (2) represented by
   Following formula (3)
   

   

   (R ¹ and R ² have the same meanings as those in the ketone compound (1) represented by the formula (1).) The nitrogen compound is characterized by producing the imine compound (3) or a salt thereof. A method for producing a protected imine compound.
2. The metal salt having Lewis acidity is a triflate salt, nonaflate salt or trifluoromethanesulfonylimide salt of at least one metal selected from rare earth metals, Fe, In, Sn and Bi, or Sc (NO ₃ ) ₃ or BiBr ₃ . The method for producing an unprotected imine compound on nitrogen according to claim 1.
3. The method for producing an unprotected imine compound on nitrogen according to claim 2, wherein the rare earth metal is Sc, Y, Sm, Eu, Gd, Er, or Yb.
4. Metal salts having Lewis acidity are Sc (OTf) ₃ , Y (OTf) ₃ , Sm (OTf) ₃ , Eu (OTf) ₃ , Gd (OTf) ₃ , Er (OTf) ₃ , Yb (OTf) ₃ , It is at least one selected from Fe (OTf) ₃ , In (OTf) ₃ , Sn (OTf) ₂ , Bi (OTf) ₃ , Sc (ONf) ₃ , and Sc (NTf ₂ ) ₃ The method for producing an unprotected imine compound on nitrogen according to any one of claims 1 to 3.
5. The method for producing an unprotected imine compound on nitrogen according to claim 1, wherein the alkyl part of the fluorine-containing anion salt of tetraalkylammonium has 1 to 6 carbon atoms.
6. The method for producing an unprotected imine compound on nitrogen according to claim 1 or 5, wherein the fluorine-containing anion salt of tetraalkylammonium is tetrabutylammonium fluoride or tetrabutylammonium dihydrogen trifluoride.
7. The method for producing an unprotected imine compound on nitrogen according to any one of claims 1 to 6, wherein R ¹ and / or R ² contains an aromatic ring and / or an aliphatic group.
8. In the presence of a catalyst containing a metal salt having Lewis acidity, a ketone compound (1) and a nitrogen source compound (2) in a solvent containing at least one selected from chlorobenzene, toluene, tetrahydrofuran, dioxane, fluorobenzene, dichloroethane and acetonitrile The method for producing an unprotected imine compound on nitrogen according to any one of claims 1 to 7, wherein
9. In the presence of a catalyst containing a fluorine-containing anion salt of tetraalkylammonium, chlorobenzene, toluene, tetrahydrofuran, dioxane, fluorobenzene, dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N, N- A ketone compound (1) and a nitrogen source compound in a solvent containing at least one selected from dimethylacetamide, hexamethylphosphoric triamide, N, N-dimethylpropyleneurea, and 1,3-dimethyl-2-imidazolidinone The process for producing an unprotected imine compound on nitrogen according to any one of claims 1 to 7, wherein the reaction (2) is carried out.
10. The method for producing an unprotected imine compound on nitrogen according to any one of claims 1 to 7, wherein the reaction of the ketone compound (1) and the nitrogen source compound (2) is carried out substantially without using a solvent.
11. 11. The reaction of the ketone compound (1) and the nitrogen source compound (2) in the presence of at least one reaction accelerator selected from water, alcohol and silanol. A method for producing an unprotected imine compound on nitrogen.