JPH115769A - Production of tertiary amines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful for synthesizing medicines, agricultural chemicals and electronic materials by reacting a secondary amine compound with a specific chloride compound in the presence of a palladium catalyst and an alkali metal alkoxide. SOLUTION: This method for producing a tertiary amine comprises reacting a secondary amine of the formula: R<1> R<2> NH (R<1> , R<2> are each a monovalent group such as an alkyl, a cycloalkyl or an aryl; R<1> , R<2> may be bound to each other to form a ring together with the N atom) (preferably dihexylamine) with a chloride compound of the formula: R<3> Cl (R<3> is an aryl, a heteroaryl) in the presence of a palladium complex containing a tertiary phosphine as a ligand [e.g. dichloribos(tricyclohexylphosphine)palladium] as a catalyst essential for causing the reaction and in the presence of an alkali metal alkoxide (preferably sodium tert-butoxide) as a strong base in an inactive gas atmosphere, if necessary in a hydrocarbon or ether solvent at 80-200 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing tertiary amines by reacting a secondary amine with an aromatic chloride. The tertiary amines provided by the present invention are useful substances that can be used for the synthesis of pharmaceuticals, agricultural chemicals and electronic materials.

[0002]

2. Description of the Related Art It is known to react an aromatic chloride with a secondary amine to obtain a tertiary amine. However, the synthesis of a tertiary amine by this method is not easy. However, severe reaction conditions such as high temperature and the like were required, and it was not a satisfactory method yet.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel and efficient method for producing tertiary amines by reacting a secondary amine with an aromatic chloride. Things.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, the amination of aromatic chloride easily proceeds in the presence of a palladium catalyst and an alkali metal alkoxide. However, they have found a novel fact that a tertiary amine having an aromatic group bonded to a nitrogen atom can be obtained, and based on this, have completed the present invention.

That is, according to the present invention, in the presence of a palladium catalyst and an alkali metal alkoxide,
The following general formula (I) R ¹ R ² NH (I) (wherein R ¹ and R ² are the same or different from each other selected from an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group and an aralkyl group) R ¹ and R ² may be bonded to each other to form a ring together with a nitrogen atom), and are represented by the following general formula (II): R ³ Cl (II) (wherein, R ³ represents an aryl group or a heteroaryl group) characterized by being reacted with a chloride represented by the following general formula (III): R ¹ R ² NR ³ (III) (R Wherein ¹ , R ² and R ³ have the same meanings as described above).

[0006] The secondary amine used as one of the raw materials in the present invention is a compound represented by the aforementioned general formula (I). In the general formula (I), R ¹ and / or R ²
Is an alkyl group, the alkyl group has 1 to 1 carbon atoms.
2, preferably 1-4. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group. When R ¹ and / or R ² is a cycloalkyl group, the cycloalkyl group has 5 carbon atoms.
-12, preferably 5-8. Specific examples of the cycloalkyl group include a cyclohexyl group and a cyclooctyl group. When R ¹ and / or R ² is an aryl group, the aryl group has 6 to 14, preferably 6 to 10 carbon atoms. Specific examples of the aryl group include a phenyl group, a tolyl group, a naphthyl group, and an anisyl group. When R ¹ and / or R ² is a heteroaryl group, the number of ring-constituting atoms is 5 to 13, preferably 5 to 9. Further, the hetero atoms as ring constituent atoms include oxygen, sulfur, nitrogen and the like. Specific examples of the heteroaryl group include a thienyl group, a furyl group, and a pyrrolyl group. When R ¹ and / or R ² is an aralkyl group, the aralkyl group has 7 to 1 carbon atoms.
5, preferably 7 to 11. Specific examples of the aralkyl group include benzyl, phenethyl, naphthylmethyl and the like. R ¹ and R ² further represent an alkoxy group,
It may be substituted with a functional group such as a phenoxy group, a cyano group, a dialkylamino group, and a trimethylsilyl group. Among these secondary amines containing R ¹ and R ² which are preferably used in the reaction of the present invention, dihexylamine, morpholine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, N-methylaniline, N-methylaniline, -Methylnaphthylamine and the like.

On the other hand, the aromatic chloride used in the reaction of the present invention is a compound represented by the general formula (II). In the general formula (II), R ³ represents an aryl group or a heteroaryl group, and the aryl group or the heteroaryl group is an alkyl group, an aralkyl group,
Cycloalkyl group, may be substituted with a hydrocarbon group such as an aryl group, and these aryl group or heteroaryl group, and its substituent alkyl group, aralkyl group, cycloalkyl group, aryl group and the like The hydrocarbon group may be substituted with a functional group such as an alkoxy group, a cyano group, a dialkylamino group, and a silyl group. Specific examples include phenyl, naphthyl, thienyl, furyl, cyanophenyl, and tolyl groups.

In order for the reaction of the present invention to occur, the use of a palladium catalyst is essential.
No secondary amine is formed. As the palladium catalyst, those having various structures can be used. In general, the palladium catalyst is a palladium complex, preferably a so-called low-valent palladium complex having a valence of 0 to 2, especially a tertiary phosphine. The complex is preferably a dimer, specifically, dichlorobis (tricyclohexylphosphine) palladium,
Dibromo (triisopropylphosphine) palladium,
Dichlorobis (phenyldicyclohexylphosphine)
Palladium and the like are exemplified. Further, a method in which a complex not containing a tertiary phosphine as a ligand and a tertiary phosphine are mixed in a reaction system to generate a palladium complex having a tertiary phosphine as a ligand and used directly as a catalyst is also preferable. It is an aspect. Illustrative tertiary phosphines that exhibit advantageous performance in this method include diphenylcyclohexylphosphine, phenyldicyclohexylphosphine,
Tricyclohexylphosphine, triisopropylphosphine, ditert-butylphenylphosphine and the like. Complexes which do not contain tertiary phosphine as a ligand and which are used in combination with such a palladium complex having a tertiary phosphine as a ligand include palladium acetate, palladium chloride, and dichloro (1,5-cyclooctane). Diene) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (benzonitrile) palladium, dibromobis (benzonitrile) palladium, dichlorobis (acetonitrile) palladium, di-μ-chlorobis (π-allyl) D) palladium, dichlorobis (pyridine) palladium and the like. The ratio of palladium to phosphine ligand in the reaction system is 1: 0 to 1:20, preferably 1: 0 to 1: 4, in terms of the ratio of palladium atoms to phosphorus atoms.

The use amount of these palladium catalysts may be a so-called catalytic amount, which is 20 mol% or less, and generally 5 mol% or less, based on the secondary amine.

This reaction is carried out in the presence of a strong base. As a strong base, soda amide or the like can be used, but a lower alkoxide of an alkali metal having 1 to 6 carbon atoms in an alkoxy group is preferable, and
Particular preference is given to using t-butoxide. In general, an amount equal to or more than the molar amount of the secondary amine is used, but the reaction proceeds in an amount smaller than the molar amount according to the amount used. A preferable usage ratio of the strong base is 1 to 3 mol per 1 mol of the secondary amine.

The reaction does not need to use a solvent, but can be carried out in a solvent if necessary. As the solvent, a hydrocarbon-based or ether-based solvent is generally used. The reaction temperature depends on the structure of the aromatic chloride, but is generally preferably heated to 50 ° C. or higher, and is usually selected from the range of 80 to 200 ° C. The intermediate of this reaction is sensitive to oxygen, and the reaction is carried out using nitrogen, argon,
It is preferable to carry out in an atmosphere of an inert gas such as methane. Separation of the purified product from the reaction mixture is easily achieved by chromatography, distillation or recrystallization.

[0012]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the following examples.

Example 1 Chlorobenzene (0.5 mmol), N-methylpiperazine (0.5 mmol), sodium tert-butoxide (0.7 mmol), dichlorobis (tricyclohexylphosphine) palladium (0.01 mmol),
Then, a mixture of toluene (2 ml) was stirred at 120 ° C. for 12 hours under a nitrogen atmosphere. According to NMR measurement of the reaction solution, N-methyl-N′-phenylpiperazine was 64%.
% Yield.

Example 2 A reaction was carried out in exactly the same manner as in Example 1 except that the amount of chlorobenzene used was doubled. By NMR measurement of the reaction solution, N
It was found that -methyl-N'-phenylpiperazine was produced in a yield of 88%. The reaction solution was ether 10m
The mixture was diluted with 1 liter, washed with 5 ml of saturated saline, and dried over magnesium sulfate. After filtration, the ether was distilled off, and the residue was separated and purified by thin-layer chromatography (alumina, developed with a 4: 1 hexane / ether mixture) to recover 83% of N-methyl-N'-phenylpiperazine. Rate.

Examples 3 to 21 The same experiment as in Example 1 was conducted using various aromatic chlorides or secondary amines, and the results are shown in Table 1. In these examples, the amount of the secondary amine used was 0.5 mmol, and the amount of NaOt-Bu was 0.1 mmol.
7 mmol, the amount of palladium catalyst [dichlorobis (tricyclohexylphosphine) palladium] used is 0.0
1 mmol. Note that R ³ shown in Table 1 is chloride R ³
R ³ in Cl is shown. The yield indicates the yield based on the secondary amine, and the number in parentheses after the number indicating the yield indicates the isolation yield.

[0016]

[Table 1- (1)]

[0017]

[Table 1- (2)]

[0018]

According to the method of the present invention, tertiary amines useful as raw materials for pharmaceuticals, agricultural chemicals and electronic materials can be efficiently and safely produced from secondary amines and aromatic chlorides. Separation and purification are also easy. Therefore, the present invention has a great effect industrially.

Claims (1)

[Claims] In the presence of a palladium catalyst and an alkali metal alkoxide, a compound represented by the following general formula (I): R ¹ R ² NH (I) wherein R ¹ and R ² are an alkyl group, a cycloalkyl group, an aryl group R ¹ and R ² may be mutually bonded to form a ring together with a nitrogen atom. Reacting a secondary amine with a chloride represented by the following general formula (II) R ³ Cl (II) (wherein R ³ represents an aryl group or a heteroaryl group): A method for producing a tertiary amine represented by the general formula (III): R ¹ R ² NR ³ (III) (R ¹ , R ² and R ³ have the same meanings as described above).