JP2008530368A - Selective degradation of substituted benzylamides and substituted benzylamines. - Google Patents

Abstract

  A method for regioselective degradation of secondary amines or secondary amides is described.

Description

  The present invention relates to a method for regioselectively decomposing a secondary amine or secondary amide, in which case the primary amine can be obtained.

  Primary amines are important starting compounds or intermediates for industrial chemicals. A series of reactions are used to obtain the amine. Examples for this are Hoffman alkylation, reductive amination of carbonyl compounds, reduction of nitro compounds or Gabriel synthesis.

  Optically active forms of chiral amines are particularly important. This is because this chiral amine is used in a number of ways to produce pharmaceuticals or plant protection agents as intermediate products. Therefore, the production of optically active amines is particularly important.

From the description of E. Lee-Ruff, FJ Ablenos, Can. J. Chem., 1989, pp. 699-702, the selective oxidation of electron-rich aromatic compounds by the following reaction scheme is known. In this case, a charge transfer complex is formed between the electron-poor 2,3-dichloro-5,6-cyano-1,4-benzoquinone (DDQ) and the electron-rich substrate in the first reaction step. The resulting cationic species can be reacted with a nucleophile:

  From the description of R. Daniel Little, Kevin D. Moeller, The Electrochemical Society Interface, Winter 2002, pages 36-41, the electrochemical anodization of neutral compounds of the general formula (I) is known.

In this case, the reactive cation radical (II) is first formed as an intermediate, and this reactive cation radical (II) is further converted into the second cation intermediate (III) by elimination. Finally, the cation intermediate (III) is captured with a nucleophilic reagent such as methanol. Thus, the substituent Y in compound (I) is formally substituted by a nucleophilic group:

Examples of compounds that can be oxidized by the above method are N-acetyl of general formula (IV) which is converted to N-acetylated aminal of general formula (V) under anodization and subsequent capture with a nucleophilic reagent. Amide amide:

  Regioselective degradation of N-acetylated amides by electrochemical or wet chemical oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and subsequent, for example, nucleophilic reagents The production of amines by post-reaction with is not known.

  Thus, the subject of the present invention has been challenged to provide a process for the preparation of primary amines by electrochemical anodization, particularly starting from secondary amines or secondary amides. In this case, the process according to the invention should be formed in such a way that it proceeds under the maintenance of optical activity, in particular using optically active educates, and thus can give the product diastereomeric purity of the educates.

  The solution to this problem starts from a method of regioselectively decomposing secondary amines or secondary amides.

Furthermore, the method according to the invention, in a first embodiment, shows the following process steps:
(A ′) providing at least one second bisbenzylamine or second bisbenzylamide having at least one benzylic hydrogen atom in a solvent;
(B ′) electrochemically oxidizing a secondary amine or secondary amide in the presence of a conductive salt and reacting the electrolytic intermediate with a nucleophilic reagent to form an electrolytic product mixture;
(C ′) post-treating this electrogenerated mixture;
(D ′) hydrolyzing the post-treated electrolytic product mixture.

  Primary amines can be produced in an effective manner by the process according to the invention.

  In the first treatment step of the process according to the invention, at least one bisbenzylamine or bisbenzylamide having at least one benzylic hydrogen atom in a solvent is provided.

The amine or amide used in the process according to the invention is, for example, a bisbenzylamine of the general formula (VI) or a bisbenzylamide of the general formula (VII):

In the above formula, R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ are the same or different and are H or C ₁ -C ₅ alkyl, R ⁹ is H (VI) or R ⁹ is acyl (VII), in which the bisbenzylamine or bisbenzylamide has at least one benzylic hydrogen atom, so that at least R ⁷ or R ⁸ or R ¹⁰ or R ¹¹ is hydrogen.

  As secondary amine, in particular bisbenzylamine is used, in which the unsubstituted nitrogen function of bisbenzylamine is provided with a protecting group. In this case, the protecting group is in particular selected from the group consisting of acyl groups, sulfone groups, phosphoryl groups or silyl groups. When an acyl group is used as the protecting group, the bisbenzylamide of the general formula (VII) described above is used as the educt.

  Furthermore, it is further preferred that in particular at least one of the benzyl rings of bisbenzylamine or bisbenzylamide is substituted, in which case at least one substituted benzyl ring is substituted with an electron indentation substituent. Electroindentation substituents are understood when this substituent exerts a + I effect and / or a + M effect on the benzyl ring.

In this case, the electron indentation substituent is in particular selected from the group consisting of an alkoxy group, an alkyl group, a thioalkyl group or a halogen, in which case the alkyl group is in particular selected from the group of C ₁ -C ₅ alkyl.

  When an alkoxy group is used as an electron indentation substituent, this electron indentation substituent is selected from the group consisting of, in particular, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tertiary butoxy group. .

  The second benzyl group of bisbenzylamine or bisbenzylamide is not particularly substituted or substituted with an electron withdrawing group. Electron indentation substituents are understood when this substituent exerts a + I effect and / or a + M effect on the phenyl ring. Examples of suitable electron withdrawing substituents are selected from the group consisting of cyano groups, nitro groups, ester groups and halides, fluorine, chlorine, bromine and iodine.

  The classification of aromatic substituents into substituents having + I and −I effects and substituents having + M and −M effects is known per se to those skilled in the art. For full implementation, Beyer / Walter, “Lehrbuch der Organischen Chemie”, 1998, 23. Revised edition, pp. 515-518, the disclosure relating to the subject matter of this publication is incorporated herein by reference. included.

  In process step (a '), a secondary amine or secondary amide in a solvent is prepared. In particularly preferred embodiments, organic solvents, especially organic nucleophilic solvents, are important. In this case, it is preferred that the solvent is selected from the group consisting of protic polar solvents such as alcohols, aliphatic carboxylic acids such as acetic acid and water.

  When alcohol is used as solvent, for example methanol, ethanol, n-propanol or isopropanol, or butanol is important. Preference is given to methanol.

  Furthermore, in an embodiment of the present invention, a mixture of the above solvents may be used.

  In some cases, a normal cosolvent is added to the electrolytic solution. In this case, an inert solvent generally used in organic chemistry having a high oxidation potential is important. Illustrative examples include dimethyl carbonate, propylene carbonate, ethylene carbonate, tetrahydrofuran, dimethoxyethane, dichloromethane, trichloromethane, tetrachloromethane or acetonitrile.

  In process step (b '), the electrochemical oxidation of the secondary amine or secondary amide and the reaction of the nucleophilic reagent with the electrolytic intermediate are carried out, in this case an electrolytic product mixture is obtained.

  A conductive salt as a depolarizer is required for the electrochemical oxidation, and this conductive salt is added to the solution prepared in process step (a ').

The conductive salt contained in the electrolytic solution is generally an alkali metal ammonium salt, alkaline earth metal ammonium salt, tetra (C ₁ -C ₆ alkyl) ammonium salt, preferably tri (C ₁ -C ₆ alkyl). Methyl ammonium salt is important. Counter ions include sulfate, hydrogen sulfate, alkyl sulfate, aryl sulfate, halide, phosphate, carbonate, alkyl phosphate, alkyl carbonate, nitrate, alcoholate, tetrafluoroborate, hexafluorophosphate or peroxide. Chlorates fall under this category.

  Furthermore, the acid derived from the anion applies as a conductive salt.

  In addition, ionic liquids are also suitable as conductive salts. Suitable ionic liquids are described in "Ionic Ligands in Synthesis", edited by Peter Wasserscheid, Tom Welton, Verlag Wiley VCH, 2003, chapters 1 to 3 and German patent application 10 2004 011427. Are listed.

In particular, in the present case, strong mineral acids and sulfonic acids are suitable as conductive salts. Examples are H ₂ SO ₄ , H ₃ PO ₄ , methane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid. Within the scope of the present invention, the use of H ₂ SO ₄ is particularly preferred.

  The concentration of the conductive salt is generally 0.0001 to mol / l, in particular 0.001 to 1 mol / l, particularly preferably 0.001 to 0.1 mol / l, particularly preferably 0.005 to 0.00. 05 mol / l.

  The processing conditions for the electrochemical oxidation in relation to the temperature, electrolysis time, current strength and concentration of the secondary amine or secondary amide depend on the educt used, in particular the bisbenzylamine or bisbenzylamide and the solvent used. Dependent.

  The electrolysis is performed in a conventional electrolysis cell known to those skilled in the art. Suitable electrolysis cells are known to those skilled in the art. In particular, it is operated continuously in an undivided flow-through cell and discontinuously in a beaker cell with a reaction volume of less than 100 ml.

  Particularly suitable are bipolarly connected capillary gap cells or plate stack cells in which the electrodes are formed as plates and arranged parallel to the plates (Ullmann's Encyclopedia of Industrial Chemistry, 1999 electronic release, No. 1). 6th edition, VCH-Verlag Weinheim, Volume Electrochemistry, Chapter 3.5 special cell designs and Chapter 5, Organic Electrochemistry, Section 5.4.3.2 Cell Design).

The current density at which the method is carried out is generally 1-1000 mA / cm ² , in particular 10-100 mA / cm ² . The temperature is usually -20 to 60 ° C, particularly 10 to 60 ° C. In general, working at normal pressure. Higher pressures are advantageously used when working at higher temperatures, avoiding boiling of the starting compound or cosolvent.

Suitable anode materials are, for example, graphite, carbon, noble metals such as platinum, metal oxides such as ruthenium oxide or chromium oxide, mixed oxides of the type RuO _x TiO _x and diamond electrodes. Preference is given to a graphite electrode or a carbon electrode.

  Examples of the cathode material include iron, steel, special steel, nickel, noble metals such as platinum, graphite, carbon materials, and diamond electrodes. Preference is given to systems of graphite as anode and graphite as cathode, graphite as anode and nickel as cathode, special steel or steel, and systems of platinum as anode and platinum as cathode.

  Furthermore, electrochemical oxidation is carried out until the benzylamide used as educt is completely reacted or mostly reacted. The concept of “most” is, according to the present invention, a reactivity especially exceeding 90%. The progress of the reaction is followed by laboratory methods routinely used (eg gas chromatography or thin film chromatography). Usually, several times the theoretical charge of 2F / mol amide is required for a complete reaction.

  Furthermore, the concentration of the educt to be oxidized in the solution to be electrolyzed is in particular from 0.00001 to 5 mol / l, particularly preferably from 0.0001 to 3 mol / l, in particular from 0.001 to 2 mol / l.

  By the electrochemical oxidation provided in process step (b '), the nitrogen function of the secondary amine or secondary amide is oxidized, in this case forming a radical cation. In this case, the electrochemical oxidation takes place in particular on the side of the amine or amide where a stable radical is formed. This is the side of the secondary amine or secondary amide in which a benzyl ring with an electron indentation substituent is present. Regioselectivity is achieved especially in the case of substituents having alkoxy groups, thioalkyl groups or alkyls.

  In the treatment step (b ′), the reaction between the electrolytic intermediate and the nucleophilic reagent is also performed immediately after the electrochemical oxidation.

  The electrolytic product mixture is reacted with a nucleophilic reagent selected from the group consisting in particular of methanol, acetic acid and water.

  As the nucleophilic reagent, the solvent used in the treatment step (a ′) is used, and therefore the addition of other nucleophilic reagents can be omitted.

  The process according to the invention as described in the first embodiment is particularly suitable for the optical oxidation, ie the electrochemical oxidation of diastereomeric bisbenzylamines or bisbenzylamides. This is because electrochemical oxidation does not change the stereochemical purity of the resulting product. Within the scope of the present invention, “essentially unchanged” means that the optical purity of the product deviates from the optical purity of the educt at most 10%, particularly preferably at most 5%, in particular at most 3%. It is understood that it is.

  In process step (c '), the electrolytic product mixture is post-treated.

In this case, the electrolytic product mixture resulting from process step (b) is post-treated, in particular by the following process steps:
(C′1) solvent removed and selected from the group consisting of water, dichloromethane; chloroform; ethers such as diethyl ether, tert-butyl methyl ether; esters such as ethyl acetate; hydrocarbons such as toluene, xylene or cyclohexane Adding organic solvent and acid;
(C′2) The mixture resulting from process step (c′1) consists of dichloromethane; chloroform; ether such as diethyl ether, tertiary butyl methyl ether; ester such as ethyl acetate; hydrocarbon such as toluene, xylene or cyclohexane. Extracting with an organic solvent selected from the group;
(C′3) drying the resulting organic phase;
(C′4) The organic solvent is removed.

  In this case, all suitable acids can be used in process step (c′1). Suitable acids are known to those skilled in the art. Examples are hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid. Preference is given to using 10% hydrochloric acid.

  Drying of the organic phase in process step (c'3) is carried out, for example, on sodium carbonate or sodium sulfate. However, optionally all other desiccants may be used.

  In process step (c′4), the organic solvent is removed in particular by distillation.

  In the treatment step (d '), the post-processed electrolytic product mixture is hydrolyzed.

  In this case, the post-processed electrolytic product mixture is hydrolyzed, in particular with a sodium hydroxide solution or a mixture of potassium hydroxide solution and triethanolamine. In this case, preference is given to using 50% sodium hydroxide solution or potassium hydroxide solution. In this case, the content of 50% sodium hydroxide solution in the mixture is in particular 10-50% by weight, particularly preferably 20-40% by weight, in particular 25-35% by weight. The content of triethanolamine in the mixture is in particular from 10 to 50% by weight, particularly preferably from 20 to 40% by weight, in particular from 25 to 35% by weight. In the case of hydrolysis, a primary amine is formed.

  In a second embodiment, the present invention relates to a “wet chemical” process for regioselective degradation of secondary amines or secondary amides.

Furthermore, the method according to the invention of this second embodiment shows the following process steps:
(A ″) providing at least one second bisbenzylamine or second bisbenzylamide having at least one benzylic hydrogen atom in a solvent, wherein the solvent optionally comprises a nucleophilic reagent. Including;
(B ″) secondary amines or secondary amides can be oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), in which case an oxidation product mixture can be obtained;
(C ″) reacting the oxidation product mixture with a nucleophilic reagent.

  Process step (a ″) provides at least one secondary amine or secondary amide in a solvent, where the solvent optionally comprises a nucleophilic reagent.

  In connection with the educts to be used-secondary amines or secondary amides-the above implementations in relation to the process according to the invention described in the first embodiment are pointed out. However, it is preferred that at least one benzyl ring of the bisbenzylamine or bisbenzylamide specifically used as an educt has an alkoxy substituent. Particularly preferably in this case, the alkoxy substituent is selected from the group consisting of methoxy, ethoxy, propoxy, butoxy and tert-butoxy.

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

  Furthermore, it is preferred that the solvent is used in a mixture with nucleophilic reagents such as water, for example distilled water, alcohols such as methanol, ethanol, n-propanol, isopropanol or butanol. For example, a mixture 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 is suitable.

  Process step (b ″) comprises oxidation of a secondary amine or secondary amide with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), in this case an oxidation product mixture Can be obtained. The oxidation of the secondary amine or secondary amide provided in process step (b ″) is carried out in particular by the addition of DDQ to the educt to be oxidized, in which case this educt is optionally in the solvent. Is present in the presence of a nucleophilic reagent.

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

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

  Suitable nucleophilic reagents are for example water, alcohols such as methanol, ethanol or propanol.

  As already mentioned, the amine or amide to be oxidized in process step (a ″) can be prepared in a solvent and in a mixture with a nucleophilic reagent. Thereby, the oxidized amine or amide is directly captured by the nucleophilic reagent present after its oxidation in the processing step (b ″), so that further addition of the nucleophilic reagent can be omitted.

  The work-up of the product resulting from process step (c ″) is for example washed with saturated sodium carbonate solution and / or saturated sodium chloride solution, the resulting aqueous phase is extracted with an organic solvent, and the combined organic phases are treated with, for example, sulfuric acid. This can be done by drying over sodium and concentrating in a vacuum, for example.

  The process according to the invention described in the second embodiment also leads to regioselective degradation of secondary amines or secondary amides used as educts. That is, the regioselective oxidation described in the process according to the invention of the second embodiment for the electron-poor benzyl ring is carried out.

  Thereby, the process according to the invention as described in the second embodiment is likewise suitable in particular for the optical activity, ie the electrochemical oxidation of diastereomeric bisbenzylamines or bisbenzylamides. This is because the oxidation of DDQ does not essentially change the stereochemical purity of the resulting product. Within the scope of the present invention, “essentially unchanged” means that the optical purity of the product deviates from the optical purity of the educt at most 10%, particularly preferably at most 5%, in particular at most 2%. It is understood that it is.

  Further, the subject of the present invention is 2,3-dichloro-5,6-dicyano- for regioselectively oxidizing a secondary bisbenzylamine or secondary bisbenzylamide having at least one benzylic hydrogen atom. The use of 1,4-benzoquinone.

  The second bisbenzylamide used as an educt in the process according to the invention described in the first and second embodiments can be produced, for example, by reacting a second bisbenzylamine with acetic anhydride. it can.

In this case, the following processing steps can be mentioned in particular:
(1) acetic anhydride is added to the secondary amine or the secondary amine is added to the acetic anhydride, in this case the reaction mixture I is formed;
(2) The resulting reaction mixture is stirred in particular for 0.5 to 24 hours, particularly preferably for 1 to 15 hours, in particular for 1 to 2 hours, in this case yielding reaction mixture II;
(3) hydrolyzing the reaction mixture II resulting from process step (2) and extracting the resulting aqueous solution with an organic solvent, in which case an organic phase is formed;
(4) In some cases, acetic anhydride present in the organic phase is removed.

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

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

  Acetic anhydride present in the organic phase can be removed, for example, by addition of a base, in which case the base is present in particular in an aqueous solution. The base can be, for example, sodium carbonate.

In some cases, processing step (3) or optionally processing step (4) can be followed by further processing steps (5) and (6):
(5) While stirring the organic phase, an organic solvent selected from the group consisting of ethers or optionally halogenated hydrocarbons and a mixture of water, in particular for 0.1 to 24 hours, particularly preferably 0. Added for 5 to 4 hours, in particular 0.5 to 2 hours, and (6) separating the organic and aqueous phases, optionally shaking this aqueous phase several times with an organic solvent and combining the combined organic phases. And the organic solvent is removed.

  Further, the subject of the present invention is 2,3-dichloro-5,6-dicyano- for regioselectively oxidizing a secondary bisbenzylamine or secondary bisbenzylamide having at least one benzylic hydrogen atom. The use of 1,4-benzoquinone.

  The invention will be described in detail with reference to the following examples, but is not intended to represent limitations of the invention.

Example:
1. General method for preparing the secondary amide 5.5 ml of acetic anhydride is added dropwise at room temperature to 23.5 mmol of amine. Twenty minutes after complete addition, the temperature is raised to 90 ° C. with stirring for 30 minutes. This solution is taken up in 20 ml of cold water, 20 ml of ether are added and the resulting phases are separated. The combined extracts are dried over Na ₂ SO ₄ and concentrated in vacuo.

To remove unreacted acetic anhydride, 10 ml of a saturated aqueous solution of Na ₂ CO ₃ is added to the unpurified reaction product. Then 15 ml of ether and 10 ml of water are added, stirred for 30 minutes, and the resulting aqueous phase is extracted several times with ether (3-15 ml). The combined extracts are dried over Na ₂ SO ₄ and concentrated in vacuo.

  The purity of the diastereomers is determined by gas chromatography.

a) N- [1- (4-Methoxy-phenyl) -ethyl] -N- (1-phenyl-ethyl) -acetamide R, R-isomer: 92.7%, R, S-isomer: 7. 3%.

b) N- [1- (2-methoxy-phenyl) -ethyl] -N- (1-phenyl-ethyl) -acetamide R, R-isomer: 96.0%, R, S-isomer: 4. 0%.
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.6 (3H, m); 1.8 (3H, m); 2.4 (3H, s); 3.7 (3H, s); 4.2 (1H, q); 5.4 (1H, q); 6.4-7.4 (9H, aromatic).

c) N- [1-Phenyl-ethyl] -N- (1-o-tolyl-ethyl) -acetamide R, R-isomer: 87.0%, R, S-isomer: 13.0%.
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.4 to 1.6 (6H, m); 1.8 (3H, m); 2.4 (3H, s); 4.1 (1H, q); 4.2 (1H, q) 6.5-7.5 (9H, aromatic);

d) N- [1- (2,4-Dimethoxy-phenyl) -ethyl]-(1-phenyl-ethyl) -acetamide R, R-isomer: 96.6%, R, S-isomer: 3. 4%.
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.6 (3H, m); 1.8 (3H, m); 2.3 (3H, s); 3.6 (3H, s); 4.3 (1H, q); 5.3 (1H, q); 6.3-7.4 (8H, aromatic).

e) N- [1- (4-Chloro-phenyl) -ethyl]-(1-phenyl-ethyl) -acetamide _Rf value (silica gel): 0.44 (acetic ester: cyclohexane = 1: 1).

f) N- [1-Phenyl-ethyl] -N- (1-p-tolyl-ethyl) -acetamide S, S-isomer: 87.5%, S, R-isomer: 12.5%.
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.6 to 1.7 (6H, d); 1.9 (3H, s); 2.3 (3H, s); 4.8 (1H, br); 5.8 (1H, br) 6.8-7.5 (9H, aromatic).

g) N- [1- (4-Methoxy-phenyl) -ethyl] -N- (1-pyridin-3-yl-ethyl) -acetamide R, R-isomer: 88.0%, R, S-isomerism Body: 12.0%.

2. Electrochemical oxidation 8.4 mmol of the amide prepared in item 1 was dissolved in 47 g of methanol, 0.5 g (96%) of concentrated sulfuric acid was added to this solution, and two graphite electrodes (20 × 70 mm, immersed) Transfer into undivided beaker-type cells with a depth of 50 mm, mold: MKUS F04, manufacturer SGL Carbon, Meitingen, Deutschland) at intervals of 10 mm. The mixture is heated to 40 ° C. with stirring and electrolyzed at a current density of 34 mA / cm ² until most of the amide has reacted (1.0-4.5 hours, about 2 F / mol amide to about 16 F). equivalent to about 100% to 800% of theoretical current demand). Methanol is removed under reduced pressure and 25 ml of water, 50 ml of dichloromethane and 10 ml of 10% hydrochloric acid are added. The aqueous phase is extracted several times with dichloromethane (3.20 ml). The combined extracts are dried over Na ₂ SO ₄ and the solvent is removed. The crude yield of amide is 80%.

Add 12 mmol of triethanolamine and 2.5 mmol of 50% NaOH ₂ to 6.7 mmol of the amide mixture and stir at 120 ° C. for 3 hours. To this mixture is added 20 ml of ether and 15 ml of water. The aqueous phase is extracted with ether (3-15 ml). The combined extracts are dried over Na ₂ SO ₄ , the solvent is removed under reduced pressure and the residue is examined by GC and ¹ H-NMR.

a) N- [1- (4-Methoxy-phenyl) -ethyl] -N- (1-phenyl-ethyl) -acetamide (dr = 93.7)
N-1-phenylethylacetamide 77.5%,
p-methoxyacetophenone 10.9%,
1-methoxy-4- (1-methoxyethyl) -benzene,
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 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 (1H, q); 5.2 (1H, q); 5.7 (1H, br); 6.9-8.0 (13H, aromatic).
Optical purity:
R-1-phenyl-ethylamine 92%,
S-1-phenyl-ethylamine 8%.

b) N- [1- (2-methoxy-phenyl) -ethyl] -N- (1-phenyl-ethyl) -acetamide (dr = 87: 13)
N-1-phenylethylacetamide 100%
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.35 (3H, m); 2.0 (3H, s); 5.1 (1H, q); 5.8 (1H, br); 7.2 to 7.3 (5H, aromatic ).

c) N- [1-phenyl-ethyl] -N- (1-o-tolyl-ethyl) -acetamide (dr = 87: 13)
1-phenyl-ethylamine 65%, 1-p-tolyl-ethylamine 35%.
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.3 (6H, m); 1.6 (4H, br); 2.3 (3H, s); 4.2 (1H, q); 4.4 (1H, q); 7.1 -7.5 (9H, aromatic).
Optical purity:
R-1-phenyl-ethylamine 89.3%,
S-1-phenyl-ethylamine 10.7%.

d) N- [1- (2,4-dimethoxy-phenyl) -ethyl]-(1-phenyl-ethyl) -acetamido 1-phenyl-ethylamine 100%.

e) N- [1- (4-Chloro-phenyl) -ethyl]-(1-phenyl-ethyl) -acetamido 1-phenyl-ethylamine 74.8%,
1- (4-Chlorophenyl) -ethylamine 25.2%.
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.4-1.5 (6H, m); 1.6 (4H, br); 4.1 (2H, m); 7.2-7.4 (9H, aromatic).

f) N- [1-phenyl-ethyl] -N- (1-p-tolyl-ethyl) -acetamide (dr = 87.5: 12.5)
1-phenyl-ethylamine 90%,
1-p-Tolyl-ethylamine 10%.
¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.5 (3H, d); 2.0 (3H, s); 5.2 (1H, q); 5.7 (1H, br); 7.3-7.4 (5H, aromatic ).
Optical purity:
R-1-phenyl-ethylamine 89.3%,
S-1-phenyl-ethylamine 10.7%.

3. Oxidant DDQ
1.8 g (6 mmol) (dr = 82: 18) of N- [1- (4-methoxy-phenyl) -ethyl] -N- (1-phenyl-ethyl) -acetamide was added to 1,2-dichloroethane: water / 10 1: Dissolve in 20 ml (v / v). 2.1 g (9 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are added and the resulting mixture is heated under reflux for 7 hours. The mixture is washed with 20 ml of saturated Na ₂ CO ₃ solution and 15 ml of saturated NaCl solution. The combined aqueous phase is extracted several times with 1,2-dichloroethane (3 × 15 ml). The combined organic phases are dried over Na ₂ SO ₄ and concentrated in vacuo.

The residue consists of a mixture of N-1-phenylethylacetamide (37 GC area%) and 4-methoxyacetophenone (63 GC area%). The optical purity of N-1-phenylethylacetamide is as follows:
RN-1-phenylethylacetamide: 81.8%, S-N-1-phenylethylacetamide: 18.2%.

Claims (9)

In a method of regioselectively decomposing a secondary amine or secondary amide, the following processing steps:
(A ′) providing at least one second bisbenzylamine or second bisbenzylamide having at least one benzylic hydrogen atom in a solvent;
(B ′) electrochemically oxidizing a secondary amine or secondary amide in the presence of a conductive salt and reacting the electrolytic intermediate with a nucleophilic reagent to form an electrolytic product mixture;
(C ′) post-treating this electrogenerated mixture;
(D ′) A method for regioselectively decomposing a secondary amine or a secondary amide, which comprises hydrolyzing a post-treated electrolytic product mixture. In a method of regioselectively decomposing a secondary amine or secondary amide, the following process step: (a ″) at least one secondary bisbenzylamine having at least one benzylic hydrogen atom in the solvent or Providing 2-bisbenzylamide, wherein the solvent optionally comprises a nucleophilic reagent;
(B ″) secondary amines or secondary amides can be oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), in which case an oxidation product mixture can be obtained;
(C ″) A method of regioselectively decomposing a secondary amine or secondary amide, which comprises reacting the oxidation product mixture with a nucleophilic reagent.   The method according to claim 1 or 2, wherein at least one benzyl ring of bisbenzylamine or bisbenzylamide has an electron indentation substituent, which substituent exerts a + I effect and / or a + M effect on the benzyl ring. .   The process according to claim 1 or 3, wherein a nucleophilic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and butanol is used in the treatment step (a). The following conditions for electrochemical oxidation:
A temperature of -20 to 60 ° C;
A current density of 1-1000 mA / cm ² ;
The process according to any one of claims 1, 3 or 4, wherein the process is carried out at at least one concentration of the conductive salt from 0.0001 to 5 mol / l. The electrolytic solution is treated in step (c ′) as follows:
(C′1) removing the solvent and adding an organic solvent selected from the group consisting of water, dichloromethane, chloroform, ether, ester and hydrocarbon, and an acid;
(C′2) extracting the mixture resulting from process step (c′1) with an organic solvent selected from the group consisting of dichloromethane, chloroform, ether, ester and hydrocarbon;
(C′3) drying the resulting organic phase;
(C'4) The process according to any one of claims 1 or 3 to 5, wherein the post-treatment is performed by removing the organic solvent.   7. The process according to claim 1 or any one of claims 3 to 6, wherein the hydrolysis is carried out in process step (d ') with a sodium hydroxide solution or a mixture of potassium hydroxide solution and triethanolamine.   8. The stereochemical purity of the resulting product using diastereomeric secondary amines or secondary amides, in this case by oxidation, being essentially unchanged, according to any one of claims 1-7. Method.   Use of 2,3-dichloro-5,6-benzoquinone to regioselectively oxidize a secondary bisbenzylamine or secondary bisbenzylamide having at least one benzylic hydrogen atom.