JPH0244830B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for directly oxidizing a secondary amine to synthesize a nitrone. The nitrone obtained by the method of the present invention is an excellent 1,3-dipole and gives various olefin and 1,3-dipole adducts, which are important biologically active nitrogen-containing compounds. It is a precursor and is useful as an intermediate for various α-substituted amine compounds, amino acids, pyrrolidine alkaloids, piperazine alkaloids, etc., pharmaceuticals, agricultural chemicals, and fine chemicals. (Prior art) Conventionally, to synthesize nitrones, secondary hydroxylamine produced by thermal decomposition of N-oxide of tertiary amine is oxidized with a stoichiometric amount of an oxidizing agent such as mercury oxide, or Pd Synthesize it by oxidizing it with a catalyst, or
Alternatively, a method is known in which the primary hydroxylamine is condensed with an aldehyde. Since the production of the starting material hydroxylamine is difficult, a method based on direct oxidation of a secondary amine has been developed as an advantageous method. It was known that secondary amines can be directly oxidized to nitrones by enzymatic action, but separately, secondary amines can be oxidized with peroxides in the presence of metal matrix catalysts such as tungsten compounds, and secondary amines can be converted to nitrones. A method for obtaining nitrone in high yield through a one-step process was proposed by the present inventor in Japanese Patent Application Laid-open No. 164762/1983, and is well known. (Problems to be Solved by the Invention) As a result of continued intensive research into the catalytic oxidation reaction of the above-mentioned secondary amines, the present inventors have found that non-metallic selenium oxide exhibits an extremely effective catalytic action. We also found that these catalysts provide cleaner reactions than conventional methods and enable efficient reactions in organic catalysts, so that the separation of easily water-soluble nitrones can be effectively achieved. This has been confirmed and the present invention has been completed. That is, an object of the present invention is to provide a method for obtaining nitrones in high yield from secondary amines in a one-step process. Another object of the present invention is to provide an industrially advantageous method for producing nitrones from secondary amines by a clean reaction and for easily separating the products. Still other objects will become clear in the following description. (Means for Solving the Problems) The method of the present invention for achieving the above-mentioned object is based on the general formula, [In the above formula, R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or a monovalent substituted or unsubstituted saturated or unsaturated aliphatic, alicyclic, or heterocyclic group. or a residue of a hydrocarbon containing a different atom or an aromatic hydrocarbon, which may be optionally combined to form a ring] and a peroxide, particularly hydrogen peroxide, to react, general formula, [In the above formula, R ¹ , R ² and R ³ have the same meanings as above] It is characterized by producing a nitrone represented by the following. In the above formula, R ¹ , R ² and R ³ as defined above include: (a) a hydrogen atom; (b) an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, or aryl group having up to 20 carbon atoms; (c) up to three heteroatoms selected from oxygen, nitrogen, and sulfur. A monovalent residue of a 3- to 16-membered heterocyclic compound contained in the ring; (d) a substituent of the above (b) and (c) containing one or more of the following substituents; (i) a carbon number of 12 (ii) a monovalent residue of a 3- to 7-membered heterocyclic compound containing up to 3 heteroatoms selected from -O-, -N- and -S-; (iii) OH, C=O, CN, OR, CO ₂ R, NR ₂ ,
SO ₂ R, SiR ₃ or CONR ₂ groups [wherein R is a substituted or unsubstituted alkyl group having up to 10 carbons] (iv) a phenyl group, and (e) the above (b) to (d) are optional A saturated or unsaturated ring formed by bonding to. The catalyst used in the method of the present invention is selenium oxide, among which selenium dioxide SeO ₂ , selenite H ₂ SeO ₃ , and alkali metal salts of selenite such as K ₂ SeO ₃ have high activity. Particularly preferred, among which SeO ₂ is most suitable. It is sufficient that these catalysts are present in a catalytic amount in the reaction system. Further, an appropriate promoter may be used in combination. Hydrogen peroxide is the most effective peroxide applicable to the method of the present invention. Other peroxides such as t-butyl hydroperoxide and m-chloroperbenzoic acid can also be used, but the reaction tends to be dirty and the nitrone yield tends to decrease. Suitable reaction solvents are water-miscible organic solvents such as lower alcohols such as methanol and lower chain ketones such as acetone, which may be used alone or in combination. When water is used, the decomposition of hydrogen peroxide, which is an oxidizing agent, progresses slowly, but when benzene or ether is used, the decomposition of hydrogen peroxide becomes more intense, which is not preferable. There is no particular restriction on the reaction temperature, but it is usually about -50℃
The temperature may range from 100°C to approximately 100°C. Although it is desirable that the reaction be carried out in an inert gas atmosphere, it is not necessary. Furthermore, a nitrone receptor may be present in the reaction system, and in particular, a nitrone adduct can be efficiently obtained by coexisting an olefin. Examples of the present invention will be described below. Example 1 Synthesis of N-ethylideneethylamine N-oxide Diethylamine 0.183g, selenium dioxide 0.013g,
A mixture of 5.0 ml of methanol is stirred under ice cooling, and 0.860 g of 30% hydrogen peroxide solution is added dropwise under an argon atmosphere. After the addition, the mixture was stirred at room temperature for 3 hours. After distilling off methanol under reduced pressure, the resulting aqueous solution is extracted with dichloromethane and dried over anhydrous sodium sulfate.
The solvent is distilled off, and the residue is isolated and purified by column chromatography (alumina, eluent 9:1 chloroform-methanol). Yield 0.162g NMR spectrum δ ^CDCl3 _ppn 1.45 (t, J = 7.2Hz, 3H) 1.99 (d, J = 5.8Hz, 3H) 3.80 (q, J = 7.2Hz, 2H) 6.80 (q, J = 5.8Hz, 1H) Example 2 Synthesis of N-butylidenebutylamine N-oxide Using butylamine as a starting material, Example 1
In the same manner as above, the title compound having the following NMR spectrum was obtained in a yield of 80%. NMR spectrum δ ^CDCl3 _ppn 0.94 (t, J = 6.4Hz, 3H) 0.97 (t, J = 6.4Hz, 3H) 1.15−2.21 (m, 6H) 2.47 (dt, J = 6.0 and 6.5Hz, 2H) 3.73 ( t, J = 6.5Hz, 2H) 6.64 (t, J = 6.4Hz, 1H) Example 3 Synthesis of N-hexylidenehexylamine N-oxide Dihexylamine 0.460g, selenium dioxide
A mixture of 0.014g and methanol 5.0ml was stirred on ice,
Add 0.846 g of 30% hydrogen peroxide solution dropwise under an argon atmosphere. After the addition, the mixture was stirred at room temperature for 4 hours. After distilling off methanol under reduced pressure, the resulting aqueous solution is extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is isolated and purified by column chromatography (alumina, eluent: 9:1 hexane-ethyl acetate). Yield 0.421g NMR spectrum δ ^CDCl3 _ppn 0.89 (t, J=5.0Hz, 6H) 1.08−2.24 (m, 14H) 2.48 (dt, J=5.6 and 6.0Hz, 2H) 3.72 (t, J=6.8Hz, 2H ) 6.60 (t, J = 5.6Hz, 1H) Example 4 Synthesis of N-(1-methylethylidene)-1-methylethylamine N-oxide Diisopropylamine 0.258g, selenium dioxide
A mixture of 0.017g and methanol 5.0ml was stirred on ice,
Add 0.881 g of 30% hydrogen peroxide solution dropwise under an argon atmosphere. After dropping, stir at room temperature for 20 hours. After distilling off methanol under reduced pressure, the resulting aqueous solution is extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to column chromatography (alumina, eluent 9:1 chloroform-
Isolate and purify with methanol). Yield 0.194g NMR spectrum δ ^CDCl3 _ppn 1.37 (d, J = 6.6Hz, 6H) 2.14 (s, 6H) 4.47 (hept, J = 6.4Hz, 1H) Example 5 N-(2-methylpropylidene)- Synthesis of 2-methylpropylamine N-oxide Diisobutylamine 0.320g, selenium dioxide
A mixture of 0.015g and methanol 5.0ml was stirred on ice,
Add 0.877 g of 30% hydrogen peroxide solution dropwise under an argon atmosphere. After the addition, the mixture was stirred at room temperature for 5 hours. After distilling off methanol under reduced pressure, the resulting aqueous solution is extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is isolated and purified by column chromatography (alumina, eluent: ethyl acetate). Yield 0.279g NMR spectrum δ ^CDCl3 _ppn 0.93 (d, J=6.8Hz, 6H) 1.09 (d, J=6.8Hz, 6H) 2.44 (t-hept, J=7.1 and 6.8Hz, 1H) 3.12 (d- hept, J=7.0 and 6.8Hz, 1H) 3.57 (d, J=7.1Hz, 2H) 6.49 (d, J=7.0Hz, 1H) Example 6 N-[(E)-2-butenylidene]-tert- Synthesis of butylamine N-oxide N-tert-butyl-(E)-2-butenylamine
A mixture of 0.153g of selenium dioxide, 0.006g of selenium dioxide, and 2.5ml of methanol was stirred under ice cooling, and the concentration was reduced to 30% under an argon atmosphere.
Drop 0.410g of hydrogen peroxide solution. 24 hours at room temperature after dropping
Stir for an hour. After distilling off methanol under reduced pressure,
The resulting aqueous solution is extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is isolated and purified by column chromatography (alumina, eluent: 9:1 hexane-ethyl acetate). Yield 0.107g NMR spectrum δ ^CDCl3 _ppn 1.49 (s, 9H) 1.89 (dd, J=6.4 and 1.0Hz, 3H) 6.21 (dq, J=14.8 and 6.4Hz, 1H) 6.84 (ddd, J=14.8, 8.8 and 1.0Hz, 1H) 7.18 (d, J = 8.8Hz, 1H) Example 7 Even if N-tert-butyl-3-butenylamine was oxidized in the same manner as in Example 6, the same compound as above was obtained by 61
% yield. Example 8 Synthesis of N-butylidene-tert-butylamine N-oxide In the same manner as in Example 6 using N-tert-butyl-butylamine as a starting material, the title compound exhibiting the following NMR spectrum was obtained with a yield of 64%. . NMR spectrum δ ^CDCl3 _ppn 0.97 (t, J = 7.0Hz, 3H) 1.37-1.97 (m, 2H) 1.48 (s, 9H) 2.46 (dt, J = 5.6 and 6.5Hz, 1H) 6.76 (t, J = 5.6 Hz, 1H) Example 9 Synthesis of 2-hydroxyethylidene-tert-butylamine N-oxide Using 2-tert-butylaminoethanol as a starting material, 35% of the title compound showing the following NMR spectrum was prepared in the same manner as in Example 6. It was obtained in a yield of . NMR spectrum δ ^CDCl3 _ppn 1.50 (s, 9H) 3.83 (br s.1H) 4.38 (dJ=4.4Hz, 2H) 7.06 (tJ=4.4Hz, 1H) Example 10 Synthesis of 3,4-dihydroisoquinoline N-oxide 1,2,3,4-tetrahydroisoquinoline
A mixture of 0.345g of selenium dioxide, 0.013g of selenium dioxide, and 5.0ml of methanol was stirred under ice cooling, and the concentration was reduced to 30% under an argon atmosphere.
Drop 0.849g of hydrogen peroxide solution. 8 at room temperature after dropping.
Stir for an hour. After distilling off methanol under reduced pressure,
The resulting aqueous solution is extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is isolated and purified by column chromatography (silica gel, eluent 9:1 chloroform-methanol). NMR spectrum δ ^CDCl3 _ppn 3.14 (t, J=7.8Hz, 2H) 4.08 (t, J=7.8Hz, 2H) 6.92−7.42 (m, 4H) 7.69 (s, 1H) Example 11 6-benzyloxy-7- Synthesis of methoxy-3,4-dihydroisoquinoline 6-benzyloxy-7-methoxy-1,2,
A mixture of 0.339 g of 3,4-tetrahydroisoquinoline, 0.007 g of selenium dioxide, and 5.0 ml of methanol is stirred under ice cooling, and 0.437 g of 30% hydrogen peroxide solution is added dropwise under an argon atmosphere. After the addition, the mixture was stirred at room temperature for 7 hours. After distilling off methanol under reduced pressure, the resulting residue is extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is isolated and purified by column chromatography (alumina, eluent: 1:1 hexane-ethyl acetate). Yield 0.325g NMR spectrum δ ^CDCl3 _ppn 3.01 (t, J = 7.6Hz, 2H) 3.85 (s, 3H) 4.03 (t, J = 7.6Hz, 2H) 5.12 (s, 2H) 6.59 (s, 1H) 6.70 ( s, 1H) 7.32 (s, 5H) 7.59 (s, 1H) Example 12 Synthesis of 1-pyrroline N-oxide 0.184 g of pyrrolidine was added to a mixture of 0.014 g of selenium dioxide and 5.0 ml of acetone under cooling on an ice-water bath. Next, 0.857 g of 30% hydrogen peroxide solution is added dropwise under ice-cooling and stirring in an argon atmosphere. After dropping, stir at room temperature for 3 hours. After distilling off the acetone under reduced pressure, the resulting aqueous solution is extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is isolated and purified by column chromatography (alumina, eluent 9:1 chloroform-methanol). Yield 0.161g NMR spectrum δ ^CDCl3 _ppn 1.93−2.55 (m, 2H) 2.55−3.04 (m, 2H) 3.94 (tt, J=8.0 and 2.0Hz) 6.86 (t, J=2.0Hz, 1H) Example 13 2 ,3,4,5-tetrahydropyridine N-oxide A mixture of 0.012 g of selenium dioxide and 5.0 ml of acetone was cooled on an ice-water bath, 0.213 g of piperidine was added, and then 0.629 g of 30% hydrogen peroxide was added in an argon atmosphere. Add dropwise while stirring on ice. After the addition, the mixture was stirred at room temperature for 3 hours. After distilling off the acetone under reduced pressure, the resulting aqueous solution is extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is isolated and purified by column chromatography (alumina, eluent 9:1 chloroform-methanol). Yield 0.219g NMR spectrum δ ^CDCl3 _ppn 1.10−2.20 (m, 4H) 2.20−2.78 (m, 2H) 3.78 (t, J=5.0Hz, 2H) 7.14 (t, J=4.0Hz, 1H) Example 14 2 Synthesis of ,3,4,5,6,7-hexahydroazocine N-oxide 2,3,4,5,6,7-hexahydro-1H
Using -azonine as a starting material, the title compound exhibiting the following NMR spectrum was obtained in a yield of 34% in the same manner as in Example 13. NMR spectrum δ ^CDCl3 _ppn 1.08−2.19 (m, 8H) 2.19−2.80 (m, 2H) 3.73 (t, J=6.7Hz, 2H) 6.68 (t, J=5.8Hz, 1H) Example 15 2-Methyl- Synthesis of 3,4,5,6-tetrahydropyridine N-oxide A mixture of 0.014 g of selenium dioxide and 5.0 ml of acetone was cooled on an ice-water bath, and 0.247 g of 2-methylpiperidine was prepared.
Then, 0.619 g of 30% hydrogen peroxide solution is added dropwise under ice-cooling and stirring in an argon atmosphere. After dropping, at room temperature
Stir for 25 hours. After distilling off the acetone under reduced pressure, the resulting aqueous solution was extracted with dichloromethane,
Dry with anhydrous sodium sulfate. Distill the solvent,
The residue is isolated and purified by column chromatography (alumina, eluent 9:1 chloroform-methanol). Yield 0.222g NMR spectrum δ ^CDCl3 _ppn 0.98−2.26 (m, 4H) 2.11 (t, J=1.4Hz, 3H) 2.26−2.82 (m, 2H) 3.58−4.20 (m, 2H) Example 16 1-pyrroline- Synthesis of 2-carboxylate N-oxide Using methylprolinate as a starting material, Examples
The reaction was carried out under the same conditions as in 15, and the compound was isolated and purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound exhibiting the following NMR spectrum in a yield of 45%. NMR spectrum δ ^CDCl3 _ppn 1.87−2.47 (m, 2H) 3.04 (tt, J=8.0 and 2.0Hz, 2H) 3.83 (s, 3H) 4.16 (tt, J=8.0 and 2.0Hz, 2H) Example 17 2- Synthesis of cyano-3,4,5,6-tetrahydropyridine N-oxide Using 2-piperidinonitrile as a starting material, a reaction was carried out under the same conditions as in Example 15, and alumina column chromatography (eluent, The compound was isolated and purified using ethyl acetate), and the title compound exhibiting the following NMR spectrum was obtained with a yield of 60%. NMR spectrum δ ^CDCl3 _ppn 1.50-2.36 (m, 4H) 2.48-2.86 (m, 2H) 3.73-4.08 (m, 2H) Example 18 of 3-ethoxycarbonyl-2-methylpiperidino[1,2,-b]isoxazolidine Synthesis Selenium dioxide 0.013g, ethyl (E)-2-butenoate
0.210 g of piperidine was added to a mixture of 0.590 g and 5.0 ml of acetone while cooling on an ice-water bath, and then 0.629 g of 30% hydrogen peroxide was added dropwise under ice-cooling and stirring in an argon atmosphere. After the dropwise addition, the mixture was stirred at room temperature for 3 hours, the acetone was distilled off under reduced pressure, and the mixture was heated and stirred on an oil bath at 90°C for 2 hours. After cooling to room temperature, add saturated brine, extract with dichloromethane, and dry over anhydrous sodium sulfate. The solvent is distilled off, and the residue is isolated and purified by column chromatography (silica gel, eluent: 9:1 hexane-ethyl acetate). Yield 0.293g NMR spectrum δ ^CDCl3 _ppn 1.27 (t, J = 7.0Hz, 3H) 1.32 (d, J = 6.0Hz, 3H) 1.47−2.17 (m, 6H) 2.17−3.00 (m, 2H) 2.83 (dd, J=8.0 and 5.0Hz, 1H) 3.47 (dm, J=8.0Hz, 1H) 4.16 (q, J=7.0Hz, 2H) 4.48 (dq, J=5.0 and 6.0Hz, 1H) Above Examples 1 to 17 The following table summarizes the reactions carried out in which secondary amines were oxidized with hydrogen peroxide using selenium dioxide as a catalyst.

【table】

【table】

[Table] (Effects of the Invention) As is clear from the above description and as exemplified by the above examples, according to the method of the present invention, selenium oxide, which is a non-metallic compound, is used as a catalyst. Nitrones can be obtained in high yield from amines in a one-step process, and a clean reaction is achieved in organic solvents.
It is extremely easy to separate and purify water-soluble nitrone. In addition, when olefin is present in the reaction system, 1,
The present invention brings great benefits to industries such as pharmaceuticals, agrochemicals, and fine chemicals, since a 3-dipole adduct can be efficiently obtained in one step.

Claims (1)

[Claims] 1. In the presence of selenium oxide, the general formula, [In the above formula, R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or a monovalent substituted or unsubstituted saturated or unsaturated aliphatic, alicyclic, or heterocyclic group. or a residue of a hydrocarbon containing a different atom or an aromatic hydrocarbon, which may be optionally bonded to form a ring.] By reacting an amine represented by the following with hydrogen peroxide, the general formula: [In the above formula, R ¹ , R ² and R ³ have the same meanings as above]
A method for producing nitrone, characterized by producing nitrone represented by 2 R ¹ , R ² and R ³ in the above formula are (a) hydrogen atoms,
(b) Alkyl group, alkenyl group having up to 20 carbon atoms,
An alkynyl group, a cycloalkyl group, an aryl group, or (iii) a monovalent residue of a 3- to 16-membered heterocyclic compound containing up to three heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. The above (b) and (c) are aryl, alkenyl or alkynyl groups having up to 12 carbon atoms, or -O-, -N- and -S-
A monovalent residue of a 3- to 7-membered heterocyclic compound containing up to 3 heteroatoms selected from, or OH, C=
1 selected from O, CN, OR, CO ₂ R, NR ₂ , SO ₂ R, SiR ₃ or CONR ₂ groups (where R is a substituted or unsubstituted alkyl group having up to 10 carbons), or a phenyl group R 1 , R 2 and R 3 may contain one or more substituents, and R ¹ , R ² and R ³ are
Production of a nitrone according to claim 1, which may be optionally bonded to form a saturated or unsaturated ring which may contain a heteroatom selected from oxygen, nitrogen and sulfur. Law. 3. The method for producing nitrone according to claim 1 or 2, wherein the selenium oxide is selected from the group consisting of SeO ₂ , H ₂ SeO ₃ and alkali metal salts of selenite. 4. The method for producing a nitrone according to any one of the claims, wherein the reaction is performed using at least one water-miscible organic solvent selected from the group consisting of lower alcohols and lower chain ketones. 5. The method for producing nitrone according to claim 4, wherein the organic solvent is methanol or acetone. 6. The reaction is carried out in the presence of an olefin,
A method for producing nitrone according to any one of the preceding claims, wherein the nitrone produced is a 1,3-dipole adduct thereof.