KR20070103031A - Selective splitting of substituted bisbenzylamides and bisbenzylamines - Google Patents

Abstract

The invention relates to a method for the area-selective splitting of secondary amines or amides.

Description

Selective SPLITTING OF SUBSTITUTED BISBENZYLAMIDES AND BISBENZYLAMINES}

The present invention relates to a process for providing primary amines by regioselective cleavage of secondary amines or amides.

Primary amines are important starting compounds or intermediates for industrial chemistry. Multiple reactions can be used to produce amines. Examples include Hofmann alkylation, reductive amination of carbonyl compounds, reduction of nitro compounds, and Gabriel synthesis.

Chiral amines in optically active forms are particularly important because they can be used as intermediates in many processes for producing drugs or grain protectants. Therefore, there has been great interest, particularly in the preparation of optically active amines.

E. Lee-Ruff, F. J. Ablenos, Can. J. Chem., 1989, pages 699-702, discloses the selective oxidation of electron-rich aromatic compounds according to the following reaction scheme. Here, a charge transfer complex between the electron-poor 2,3-dichloro-5,6-cyano-1,4-benzoquinone (DDQ) and the electron-rich substrate is formed in the first reaction step Derived cationic species can be reacted with nucleophiles.

In R. Daniel Little, Kevin D. Moeller, The Electrochemical Society Interface, Winter 2002, pages 36-41, discloses the electrochemical anodic oxidation of non-charged compounds of general formula (1).

[Formula 1]

Here, the reactive cationic radical of formula (II) is first produced as an intermediate and is converted to the second cationic intermediate of formula (3) by further elimination reaction. The cationic intermediate of formula 3 is then reacted with a nucleophile, for example methanol. As a result, substituent Y is replaced by a nucleophilic radical in the compound of formula (1).

Examples of the compound which can be oxidized by the above-described method include N-acetylated general formula (4), which is converted into N-acetylated amineal compound of general formula (5) by anodic oxidation and subsequent reaction with nucleophile methanol. Amides include:

Regioselective of N-acetylated amides by electrochemical or wet chemical oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and subsequent further reactions with nucleophiles, for example It is not known to prepare amines by splitting.

It is therefore an object of the present invention to provide a process for preparing primary amines from secondary amines or amides, preferably by electrochemical anodic oxidation. The process of the present invention should preferably proceed while maintaining the optical activity when an optically active starting material is used so that the diastereomeric purity of the starting material can be retained in the product.

The attainment of this object begins with a regioselective cleavage process of secondary amines or amides.

The process of the invention thus comprises, in the first embodiment , the following process steps.

(a ') providing at least one secondary bisbenzylamine or bisbenzylamide to the solvent containing at least one benzyl hydrogen atom;

(b ') electrochemical oxidation of secondary amines or amides in the presence of an electrolyte salt, and providing an electrolysis product mixture through reaction of the electrolysis intermediate with the nucleophile;

(c ') finishing the electrolysis product mixture;

(d ') hydrolysis of the finished electrolysis product mixture.

By the process of the invention, primary amines can be produced in an efficient manner.

In a first process step of the process of the invention, at least one bisbenzylamine or bisbenzylamide containing at least one benzyl hydrogen atom in a solvent is provided.

The amines or amides used in the process of the invention are, for example, bisbenzylamines of the general formula (6) or bisbenzylamides of the general formula (7).

[Formula 7]

Wherein R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ are the same or different and each is H or C ₁ -C ₅ -alkyl, R ⁹ = H (Formula 6) or R ⁹ = Acyl (Formula 7), wherein bisbenzylamine or bisbenzylamide contains at least one benzyl hydrogen atom and therefore at least R ⁷ Or R ⁸ Or R ¹⁰ or R ¹¹ is hydrogen.

As secondary amines, preference is given to using bisbenzylamines having a protecting group on unsubstituted nitrogen functional groups of bisbenzylamine. The protecting group is preferably selected from the group consisting of acyl group, sulfone group, phosphoryl group and silyl group. If acyl groups are used as protecting groups, the bisbenzylamides of the general formula (7) mentioned above are used as starting materials.

It is also preferred that at least one of the benzyl rings of bisbenzylamine or bisbenzylamide is substituted, and more preferably one or more substituted benzyl rings are replaced by electron-pushing substituents. For the purposes of the present invention, an electron-pushing substituent is a substituent that has a + I effect and / or a + M effect on the benzyl ring.

The electron-pushing substituent is preferably selected from the group consisting of alkoxy groups, alkyl groups, thioalkyl groups and halogens, wherein the alkyl group is preferably selected from the group consisting of C ₁ -C ₅ -alkyl.

If an alkoxy group is used as the electron-pushing substituent, it is preferably selected from the group consisting of methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group and tert-butoxy group.

The second benzyl radical of bisbenzylamine or bisbenzylamide is preferably unsubstituted or substituted by an electron-pulling group. For the purposes of the present invention, electron-pooling substituents are substituents that exert an -I effect and / or an -M effect on the phenyl ring. Examples of suitable electron-pooling substituents are selected from the group consisting of cyano groups, nitro groups, ester groups, and halide fluorine, chlorine, bromine and iodine.

The classification of aromatic substituents into substituents with the + I and -I effects or the + M and -M effects is known per se to those skilled in the art. Further details can be found in Beyer / Walter, "Lehrbuch der Organischen Chemie", 1998, 23rd revised and updated edition, pages 515-518, the disclosure of which is added to the present invention by reference. .

In process step (a '), a secondary amine or amide is provided as solvent. In a particularly preferred embodiment, the solvent is an organic solvent, preferably an organic nucleophilic solvent. More preferably, the solvent is selected from the group consisting of protic polar solvents such as alcohols, aliphatic carboxylic acids (eg acetic acid) and water. If alcohol is used as the solvent, it is, for example, methanol, ethanol, n- or i- propanol or butanol. Preferably methanol.

In a further embodiment of the invention, mixtures of the abovementioned solvents can also be used.

Where appropriate, common cosolvents are added to the electrolytic solution. These are inert solvents with high oxidation potentials which are generally customary in organic chemistry. Examples that may be mentioned include dimethyl carbonate, propylene carbonate, ethylene carbonate, tetrahydrofuran, dimethoxyethane, dichloromethane, trichloromethane, tetrachloromethane and acetonitrile.

In process step (b '), the electrochemical oxidation of secondary amines or amides, and the reaction of the electrolysis intermediate with the nucleophile are carried out to give the electrolysis product mixture.

Electrolytic salts are required as depolarizers for electrochemical oxidation, which are added to the solution provided in process step (a ').

The electrolyte salts present in the electrolytic solution are generally alkali metal salts, alkaline earth metal salts, tetra (C ₁ -C ₆ -alkyl) ammonium salts, preferably tri (C ₁ -C ₆ -alkyl) methylammonium salts. Possible counterions are sulfates, hydrogensulfates, alkylsulfates, aryl sulfates, halides, phosphates, carbonates, alkylphosphates, alkylcarbonates, nitrates, alkoxides, tetrafluoroborates, hexafluorophosphates or perchlorates.

In addition, acids derived from the aforementioned anions are also possible as electrolyte salts.

Ionic liquids are also suitable as electrolyte salts. Suitable ionic liquids are described in "Ionic Liquids in Synthesis", edited by Peter Wasserscheid, Tom Welton, Verlag Wiley VCH, 2003, chapters 1 to 3, and DE-A-10 2004 011427.

In particular, strong inorganic acids and sulfonic acids are suitable as electrolyte salts for the purposes of the present invention. Examples thereof include H ₂ SO ₄ , H ₃ PO ₄ , methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid. For the purposes of the present invention, particular preference is given to using H ₂ SO ₄ .

The concentration of the electrolyte salt is generally 0.0001 to 5 mol / l, preferably 0.001 to 1 mol / l, particularly preferably 0.001 to 0.1 mol / l, very particularly preferably 0.005 to 0.05 mol / l.

The process conditions for the electrochemical oxidation, in terms of temperature, electrolysis time, current and concentration of secondary amines or amides, depend on the starting materials used, in particular bisbenzylamine or bisbenzylamide, and the solvents used.

Electrolysis is carried out in conventional electrolysis cells known to those skilled in the art. Suitable electrolysis cells are known to those skilled in the art. The electrolysis is preferably carried out continuously in an undivided flow cell, or in a batch manner in a glass beaker cell at a reaction volume of less than 100 ml.

Very particularly useful cells are bipolar capillary cells or plate stacked cells in which the electrodes are formed in plates and arranged in parallel with each other (Ullmann's Encyclopedia of Industrial Chemistry, 1999 electronic release, sixth edition, VCH-Verlag Weinheim, Volume Electrochemistry, chapter 3.5.special cell designs and chapter 5, Organic Electrochemistry, subchapter 5.4.3.2 Cell Design].

The current density at which the process is carried out is generally 1 to 1000 mA / cm ² , preferably 10 to 100 mA / cm ² . The temperature is usually from -20 to 60 ° C, preferably from 10 to 60 ° C. The process is usually carried out at atmospheric pressure. When the process is carried out at relatively high temperatures, higher pressures are preferably used to avoid boiling of the starting compounds or cosolvents.

Suitable anode materials include, for example, graphite; carbon; Precious metals such as platinum; Metal oxides such as ruthenium oxide or chromium oxide; Mixed oxides of the RuO _x TiO _x type; And diamond electrodes. Preferred are graphite or carbon electrodes.

Possible negative electrode materials include, for example, iron; River; Stainless steel; nickel; Precious metals such as platinum; black smoke; Carbon material; And diamond electrodes. Preferred are graphite as the anode and cathode, graphite as the anode and nickel, stainless steel or steel as the cathode, and platinum as the anode and cathode.

In addition, electrochemical oxidation is carried out until the benzylamide used as starting material is completely or mostly reacted. For the purposes of the present invention, the term "mostly reaction" means a conversion of preferably greater than 90%. The progress of the reaction is monitored by conventional laboratory methods such as gas chromatography or thin layer chromatography. In order to achieve complete conversion, amides, which in theory have a multiple of 2 F / mol of charge, may often be needed.

In addition, the concentration of starting material to be oxidized and electrolyzed in solution is preferably 0.00001 to 5 mol / l, particularly preferably 0.0001 to 3 mol / l, in particular 0.001 to 2 mol / l.

With electrochemical oxidation provided in process step (b '), the nitrogen functionality of the secondary amine or amide is oxidized and radical cations are formed. Electrochemical oxidation preferably takes place on the amine or amide side where more stable radicals are formed. This is the secondary amine or amide side with the benzyl ring containing the electron-pushing substituent. In particular, regioselectivity is achieved for substrates containing alkoxy groups, thioalkyl groups or alkyl groups.

In process step (b '), the reaction of the electrolysis intermediate with the nucleophile takes place immediately after the electrochemical oxidation.

Preferably, the electrolysis product mixture is reacted with a nucleophile selected from the group consisting of methanol, acetic acid and water.

The nucleophiles used are preferably the solvents used in process step (a ') so that no additional nucleophiles need to be added.

In the first embodiment the process of the invention is preferably suitable for the optical activity, ie electrochemical oxidation of the diastereomeric bisbenzylamine or bisbenzylamide, in which the stereochemical purity of the product obtained is subject to electrochemical oxidation. Because it does not change so much. For the purposes of the present invention, "not so changed" means that the optical purity of the product is 10% or less, particularly preferably 5% or less, especially 3% or less, from the optical purity of the starting material.

Finishing of the electrolysis product mixture is carried out in process step (c ').

Here, the electrolysis product mixture obtained from process step (b ') is preferably finished by the following process steps.

(c'1) removal of the solvent and dichloromethane with water; chloroform; Ethers such as diethyl ether, tert-butyl methyl ether; Esters such as ethyl acetate; Adding an acid with an organic solvent selected from the group consisting of hydrocarbons such as toluene, xylene or cyclohexane;

(c'2) dichloromethane; chloroform; Ethers such as diethyl ether, tert-butyl methyl ether; Esters such as ethyl acetate; Extracting the mixture obtained from process step (c'1) using an organic solvent selected from the group consisting of hydrocarbons such as toluene, xylene or cyclohexane;

(c'3) drying of the resulting organic phase,

(c'4) removing the organic solvent.

Any suitable acid can be used in process step (c'1). Suitable acids are known to those skilled in the art. Examples include hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Preferably, 10% concentration of hydrochloric acid is used.

Drying of the organic phase in process step (c'3) is carried out, for example, via sodium carbonate or sodium sulfate. As an alternative, it is also possible to use all further conventional desiccants.

In process step (c'4), the organic solvent is preferably removed by distillation.

In process step (d '), the finished electrolysis product mixture is hydrolyzed.

Hydrolysis of the finished electrolysis product mixture is preferably carried out using a sodium hydroxide solution or a mixture of potassium hydroxide solution and triethanolamine. Preference is given to using sodium hydroxide or potassium hydroxide solution at 50% concentration. Here, the content of the 50% concentration sodium hydroxide solution in the mixture is preferably 10 to 50% by weight, particularly preferably 20 to 40% by weight, in particular 25 to 35% by weight. The content of triethanolamine in the mixture is preferably 10 to 50% by weight, particularly preferably 20 to 40% by weight, in particular 25 to 35% by weight. Hydrolysis results in the formation of primary amines.

In a second embodiment , the present invention provides a "wet chemistry" process for the regioselective cleavage of secondary amines or amides.

Thus, in this second embodiment, the process of the invention comprises the following process steps.

(a ") providing one or more secondary bisbenzylamines or bisbenzylamides with one or more benzyl hydrogen atoms to a solvent, wherein the solvent optionally comprises a nucleophile;

(b ") providing an oxidation product mixture via oxidation of a secondary amine or amide with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ);

(c ") reaction of the oxidation product mixture with the nucleophile.

In process step (a "), at least one secondary amine or amide in the solvent is provided, wherein the solvent optionally comprises a nucleophile.

With regard to the starting materials to be used, ie secondary amines or amides, reference is made to those mentioned above with respect to the first embodiment of the process of the invention. Preferably, however, at least one benzyl ring of bisbenzylamine or bisbenzylamide which is preferably used as starting material contains an alkoxy substituent. Especially preferred are those wherein the alkoxy substituent is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

The solvent used in process step (a ") is preferably selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, tert-butyl methyl ether, acetonitrile, toluene and xylene.

Preferably, the solvent is used in a mixture with nucleophiles such as water (eg distilled water), alcohols (eg methanol, ethanol, n-propanol, i-propanol or butanol). Suitable mixtures are, for example, mixtures of 1,2-dichloroethane and water in a ratio of 100: 1 to 1: 1, particularly preferably 20: 1 to 5: 1, in particular 12: 1 to 8: 1.

Process step (b ") comprises the oxidation of a secondary amine or amide with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to provide an oxidation product mixture. Oxidation of the secondary amine or amide, provided in step (b "), is preferably carried out by adding DDQ to the starting material to be oxidized in the solvent described above, preferably in the presence of a nucleophile.

Preferably, the oxidation is carried out with stirring at a temperature of −10 to 150 ° C., particularly preferably 20 to 100 ° C., in particular 60 to 90 ° C. Under these preferred conditions the reaction time is preferably 0.2 to 24 hours, particularly preferably 1 to 12 hours, in particular 5 to 10 hours.

In process step (c "), the oxidation product mixture is reacted with a nucleophile. This is done by adding optionally dissolved nucleophiles to the oxidation product mixture.

Suitable nucleophiles include, for example, water; Alcohols such as methanol, ethanol or propanol.

As mentioned above, the amine or amide to be oxidized can be provided as a solvent which is a mixture with the nucleophile in process step (a "). As a result, the process step (b) can be avoided with the addition of further nucleophiles The amine or amide oxidized after oxidizing in "

The product obtained from process step (c ") is washed with, for example, saturated sodium carbonate solution and / or saturated sodium chloride solution, the resulting aqueous phase is extracted with an organic solvent, the combined organic phases are dried, for example with sodium sulfate, For example, it can finish by concentrating under reduced pressure.

In addition, a second embodiment of the process of the invention leads to regioselective cleavage of the secondary amine or amide used as starting material. Thus, in the second embodiment of the process of the invention the regioselective oxidation takes place on the more electron-rich benzyl ring.

Thus, a second embodiment of the process of the invention is also suitable for the electrochemical oxidation of optically active (ie diastereoisomer) bisbenzylamine or bisbenzylamide, wherein the stereochemical purity of the resulting product is determined by DDQ. This is because it is not changed very much by oxidation. For the purposes of the present invention, "not so changed" means that the optical purity of the product is not more than 10%, particularly preferably not more than 5%, especially not more than 2%, of the optical purity of the starting material.

The present invention also provides the use of 2,3-dichloro-5,6-benzoquinone for regioselective oxidation of secondary bisbenzylamine or bisbenzylamide containing one or more benzyl hydrogen atoms.

Secondary bisbenzylamides used as starting materials in the first and second embodiments thereof in the process of the present invention can be prepared, for example, by reacting secondary bisbenzylamine with acetic anhydride.

Herein, the following process steps can be mentioned in particular.

(1) obtaining reaction mixture I through the addition of acetic anhydride to the secondary amine, or the addition of the secondary amine to acetic anhydride;

(2) obtaining reaction mixture II through stirring of the reaction mixture I obtained, preferably for 0.5 to 24 hours, particularly preferably for 1 to 15 hours, in particular for 1 to 2 hours;

(3) obtaining an organic phase through hydrolysis of the reaction mixture II obtained from process step (2) and extraction with an organic solvent of the resulting aqueous solution;

(4) Where appropriate, removal of acetic anhydride present in the organic phase.

The addition of acetic anhydride to the secondary amine can preferably be carried out at a temperature of from 0 to 100 ° C, particularly preferably from 10 to 50 ° C, in particular from 20 to 30 ° C.

The reaction mixture I obtained is preferably stirred at a temperature of 0 to 150 ° C, particularly preferably 50 to 120 ° C, in particular 80 to 100 ° C.

Removal of acetic anhydride present in the organic phase can be effected, for example, by addition of a base, where the base is preferably present in an aqueous solution. The base may for example be sodium carbonate.

If appropriate, process step (3) or, if appropriate, following process step (4), the following process steps (5) and (6) may be followed.

(5) the organic phase with stirring, preferably for 0.1 to 24 hours, particularly preferably 0.5 to 4 hours, especially 0.5 to 2 hours, using a mixture of water and an organic solvent selected from the group consisting of ethers and optionally halogenated hydrocarbons Processing the, and

(6) separating the organic and aqueous phases and, if appropriate, shaking the aqueous phase with the organic solvent several times and drying the combined organic phases and removing the organic solvents.

The invention also provides the use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone for the regioselective oxidation of secondary bisbenzylamines or bisbenzylamides containing one or more benzyl hydrogen atoms. To provide.

Although the invention is illustrated in the following examples, the scope of the invention is not limited thereto.

1. General Procedure for the Preparation of Secondary Amides

5.5 ml of acetic anhydride were added dropwise to 23.5 mmol of amine at room temperature. 20 minutes after the addition was completed, the temperature was raised to 90 ° C. for 30 minutes with stirring. The solution was poured into 20 ml of cold water, mixed with 20 ml of ether and the resulting phases were separated. The combined extracts were dried over Na ₂ SO ₄ and concentrated under reduced pressure.

To remove unreacted acetic anhydride, 10 ml of saturated aqueous Na ₂ CO ₃ solution was added to the crude reaction product. The resulting mixture was then mixed with 15 ml of ether and 10 ml of water and stirred for 30 minutes to extract the aqueous phase obtained several times with ether (3.15 ml). The combined extracts were dried over Na ₂ SO ₄ and concentrated under reduced pressure.

Diastereomeric purity was determined by gas chromatography.

a) N- [1- (4-methoxyphenyl) ethyl] -N- (1-phenylethyl) acetamide

R, R isomer: 92.7% R, S isomer: 7.3%

b) N- [1- (2-methoxyphenyl) ethyl] -N- (1-phenylethyl) acetamide

R, R isomer: 96.0% R, S isomer: 4.0%

^{l H-NMR (400 MHz,} CDCl 3):

delta = 1.6 (3H, m); 1.8 (3H, m); 2.4 (3H, s); 3.7 (3H, s); 4.2 (1 H, q); 5.4 (1H, q); 6.4-7.4 (9H, aromatic).

c) N- [1-phenylethyl] -N- (1-o-tolylethyl) acetamide

R, R isomer: 87.0% R, S isomer: 13.0%

^{l H-NMR (400 MHz,} CDCl 3):

delta = 1.4-1.6 (6H, m); 1.8 (3H, m); 2.4 (3H, s); 4.1 (1H, q); 4.2 (1 H, q); 6.5-7.5 (9H, aromatic).

d) N- [1- (2,4-dimethoxyphenyl) ethyl] (1-phenylethyl) acetamide

R, R isomer: 96.6% R, S isomer: 3.4%

^{l H-NMR (400 MHz,} CDCl 3):

delta = 1.6 (3H, m); 1.8 (3H, m); 2.3 (3H, s); 3.6 (3H, s); 4.3 (1 H, q); 5.3 (1H, q); 6.3-7.4 (8H, aromatic).

e) N- [1- (4-chlorophenyl) ethyl] (1-phenylethyl) acetamide

R _f (silica gel): 0.44 (ethyl acetate: cyclohexane = 1: 1)

f) N- [1-phenylethyl] -N- (1-p-tolylethyl) acetamide

S, S isomer: 87.5% S, R isomer: 12.5%

¹ H-NMR (400 MHz, CDCl ₃ ):

delta = 1.6-1.7 (6H, d); 1.9 (3H, s); 2.3 (3H, s); 4.8 (1H, broad singlet); 5.8 (1H, broad singlet); 6.8-7.5 (9H, aromatic).

g) N- [1- (4-methoxyphenyl) ethyl] -N- (1-pyridin-3-yl-ethyl) acetamide

R, R isomer: 88.0% R, S isomer: 12.0%

2. Electrochemical Oxidation

8.4 mmol of the amide prepared in 1.) was dissolved in 47 g of methanol, mixed with 0.5 g of concentrated sulfuric acid (96%), two graphite electrodes (20 x 70 mm, impregnation depth: 50 mm, type: MKUS) F04, manufactured by SGL Carbon (Mytingen, Germany), was transferred to a finely divided glass beaker cell at 10 mm intervals. The mixture is heated to 40 ° C. with stirring, until most of the amides have reacted (corresponding to about 2 F / mol of amide to about 16 F / mol of amide, corresponding to about 100-800% of the theoretical charge required) 1.0 to 4.5 hours) was electrolyzed. Methanol was removed under reduced pressure and the residue was mixed with 25 ml of water, 50 ml of dichloromethane and 10 ml of hydrochloric acid (10% concentration). The aqueous phase was extracted several times with dichloromethane (3.20 ml). The combined extracts were dried over Na ₂ SO ₄ and the solvent was removed. The crude yield of amide was 80%.

12 mmol triethanolamine and 22.5 mmol NaOH (50% concentration) were added to the 6.7 mmol amide mixture and the resulting mixture was stirred at 120 ° C. for 3 hours. 20 ml of ether and 15 ml of water were added to the mixture. The aqueous phase was extracted with ether (3.15 ml). The combined extracts were dried over Na ₂ SO ₄ , the solvent was removed under reduced pressure and the residue was examined by GC and ¹ H-NMR.

a) N- [1- (4-methoxyphenyl) ethyl] -N- (1-phenylethyl) acetamide (dr = 93: 7)

77.5% N-1-phenylethylacetamide

10.9% p-methoxyacetophenone

11.6% 1-methoxy-4- (1-methoxyethyl) benzene

¹ H-NMR (400 MHz, CDCl ₃ ):

delta = 1.4 (3H, d); 1.5 (3H, d); 2.0 (3H, s); 2.6 (3H, s); 3.8 (3H, s); 3.9 (3H, s); 4.2 (1 H, q); 5.2 (1 H, q); 5.7 (1H, broad singlet); 6.9-8.0 (13H, aromatic).

Optical Purity:

92% of R-1-phenylethylamine

8% S-1-phenylethylamine

b) N- [1- (2-methoxyphenyl) ethyl] -N- (1-phenylethyl) acetamide (dr = 87:13)

100% N-1-phenylethylacetamide

¹ H-NMR (400 MHz, CDCl ₃ ):

delta = 1.35 (3H, m); 2.0 (3H, s); 5.1 (1H, q); 5.8 (1H, broad singlet); 7.2-7.3 (5H, aromatic).

c) N- [1-phenylethyl] -N- (1-o-tolylethyl) acetamide (dr: 87: 13)

65% 1-phenylethylamine

35% 1-p-tolylethylamine

¹ H-NMR (400 MHz, CDCl ₃ ):

delta = 1.3 (6H, m); 1.6 (4H, br); 2.3 (3H, s); 4.2 (1 H, q); 4.4 (1 H, q); 7.1-7.5 (9H, aromatic).

Optical Purity:

89.3% R-1-phenylethylamine

10.7% S-1-phenylethylamine

d) N- [1- (2,4-dimethoxyphenyl) ethyl] (1-phenylethyl) acetamide

100% 1-phenylethylamine

e) N- [1- (4-chlorophenyl) ethyl] (1-phenylethyl) acetamide

74.8% 1-phenylethylamine

25.2% 1- (4-chlorophenyl) ethylamine

¹ H-NMR (400 MHz, CDCl ₃ ):

delta = 1.4-1.5 (6H, m); 1.6 (4H, br); 4.1 (2H, m); 7.2-7.4 (9H, aromatic).

f) N- [1-phenylethyl] -N- (1-p-tolylethyl) acetamide (dr: 87.5: 12.5)

90% 1-phenylethylamine

10% 1-p-tolylethylamine

¹ H-NMR (400 MHz, CDCl ₃ ):

 delta = 1.5 (3H, d); 2.0 (3H, s); 5.2 (1 H, q); 5.7 (1H, broad singlet); 7.3-7.4 (5H, aromatic).

Optical Purity:

89.3% R-1-phenylethylamine

10.7% S-1-phenylethylamine

3. Oxidation by DDQ

1.8 g of N- (6 mmol) [1- (4- methoxyphenyl) ethyl] - N - (1- phenylethyl) acetamide (dr: 82:18) of a 20 ml 1,2- dichloroethane / Dissolved in water (10/1 (v / v)). 2.1 g (9 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added and the resulting mixture was refluxed for 7 hours. The mixture was washed with 20 ml of saturated Na ₂ CO ₃ solution and 15 ml of saturated NaCl solution. The combined aqueous phases were extracted several times with 1,2-dichloroethane (3.15 ml). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure.

The residue consisted of a mixture of N-1-phenylethylacetamide (37 GC-area%) and 4-methoxyacetophenone (63 GC-area%). The optical purity of N-1-phenylethylacetamide was as follows.

R-N-phenylethylacetamide: 81.8%

S-N-phenylethylacetamide: 18.2%

Claims (9)

(a ') providing at least one secondary bisbenzylamine or bisbenzylamide to the solvent containing at least one benzyl hydrogen atom; (b ') electrochemical oxidation of secondary amines or amides in the presence of an electrolyte salt, and providing an electrolysis product mixture through reaction of the electrolysis intermediate with the nucleophile; (c ') finishing the electrolysis product mixture; And (d ') hydrolysis step of the finished electrolysis product mixture A method of regioselective cleavage of secondary amines or amides comprising a. (a ") providing one or more secondary bisbenzylamines or bisbenzylamides with one or more benzyl hydrogen atoms to a solvent, wherein the solvent optionally comprises a nucleophile; (b ") providing an oxidation product mixture via oxidation of a secondary amine or amide with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); and (c ") reaction of the mixture of oxidation products with the nucleophile A method of regioselective cleavage of secondary amines or amides comprising a. The method of claim 1 or 2, wherein at least one benzyl ring of bisbenzylamine or bisbenzylamide is substituted by an electron-pushing substituent which has a + I effect and / or a + M effect on the benzyl ring. How it is. 4. Process according to claim 1 or 3, in process step (a) using a nucleophilic solvent selected from the group consisting of methanol, ethanol, n-propanol, i-propanol and butanol. The method according to any one of claims 1, 3 and 4, wherein the electrochemical oxidation A temperature of -20 to 60 ° C; Current density from 1 to 1000 mA / cm ² ; Electrolyte salt concentration of 0.0001 to 5 mol / l The method is carried out under at least one of the conditions. The process according to any one of claims 1 and 3 to 5, wherein in process step (c '), (c'1) the solvent is removed and water; Organic solvents selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons; And acid; (c'2) extracting the mixture obtained from process step (c'1) using an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons; (c'3) drying the resulting organic phase; (c'4) removing the organic solvent, How to finish the electrolytic solution. The process according to any one of claims 1 and 3 to 6, wherein the hydrolysis in process step (d ') is carried out by means of a sodium hydroxide solution or a mixture of potassium hydroxide solution and triethanolamine. 8. Process according to any one of the preceding claims, wherein the diastereomeric secondary amines or amides are used and the stereochemical purity of the resulting product is not so changed by oxidation. Use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone for regioselective oxidation of secondary bisbenzylamine or bisbenzylamide containing one or more benzyl hydrogen atoms.