JPH0881432A - O-alkyl-n-(beta-nitroethyl)hydroxylamine derivative and its production - Google Patents

Abstract

PURPOSE: To readily and quantitatively obtain an O-alkyl-N-(β-nitroethyl) hydroxylamine derivative useful as a raw material, etc., for producing an intermediate for medicines and agrochemicals from industrially easily available raw material compounds by reacting specific nitroolefins with a specified amine derivative. CONSTITUTION: This method for producing a derivative of formula I [R1 and R2 are each H, a (substituted) 1-10C alkyl, a (substituted) phenyl or together may form a (bi)cycloalkyl; R3 is H or a lower alkyl; R4 is a lower alkyl or benzyl] [e.g. O-methyl-N-(β-nitroethyl)hydroxylamine] is to react (A) nitroolefins of formula II (e.g. nitroethylene) with (B) an O-alkylhydroxylamine of the formula R3 NHOR4 (preferably O-methylhydroxylamine) in a molar amount of, e.g. 1-2 times based on the component (A) at a temperature within the range of 0-50 deg.C.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel compound O-
It relates to an alkyl-N- (β-nitroethyl) hydroxylamine derivative and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, β-nitroenamine has been known as a specific compound having both the reactivity of both enamine and nitroolefin, and is known as a basic skeleton of agricultural insecticides. Since it can be induced to a heterocycle, it is a very important compound as an intermediate of medicines and agricultural chemicals, and its production method is also an α-nitrocarbonyl compound and an amine without a catalyst or in the presence of a titanium tetrachloride catalyst. Method of condensing under [J.Am.Chem.Soc., Vol.78, 3
405 (1956), Journal of Chemical Society of Japan 88 (1983)], Substitution reaction of amine with nitroolefins having a suitable leaving group (eg, halogen, alkoxyl group, alkylthio group, nitro group, amino group, etc.) at β-position. Method [Tetrahedro
n, Vol.37, 1453 (1981)], a method of condensing ethyl cyanoformate and nitromethane [Tetrahedron Letters, 2525
(1979)] and other methods are known.

However, in any of these methods, there are many problems in the reaction yield and the synthesis of the starting compounds,
It has been desired to develop a compound which can be easily produced by itself and can be easily converted into β-nitroenamine in good yield.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The present inventor has reached the present invention as a result of studies to develop a novel compound that can be easily produced and can be easily led to β-nitroenamine in good yield.

[0005]

That is, the present invention is based on the general formula (1) (In the formula, R ₁ and R ₂ are the same or different and each is a hydrogen atom,
A linear or branched alkyl group having 1 to 10 carbon atoms which may be optionally substituted with a halogen or a lower alkoxyl group, a phenyl group or a phenoxyl group, an optional halogen, a lower alkyl group, a lower alkoxyl group, a nitro group or It represents a phenyl group which may be substituted with a cyano group, and R ₁ and R ₂ may be taken together to form cycloalkyl or bicycloalkyl. R ₃ represents a hydrogen atom or a lower alkyl group, and R ₄ represents a lower alkyl group or a benzyl group. ) Is an O-alkyl-N- (β-nitroethyl) hydroxylamine derivative.

The O-alkyl-N- (β-nitroethyl) hydroxylamine derivative of the present invention has the above general formula (1).
In the respective substituents of the formula, the lower alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms, and the lower alkoxyl group is a linear or branched C 1 group. To 4 alkoxyl groups respectively, and specific examples of the substituents R ₁ and R ₂ are hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, chloromethyl, 2-chloropropyl, 2-bromopropyl,
2-chlorohexyl, phenylmethyl, 2-phenoxypropyl, methoxymethyl, 2-methoxypropyl, 3
-Ethoxybutyl, 4-methoxyhexyl, phenyl,
m-chlorophenyl, p-bromophenyl, p-tolyl, 2,4-xylyl, p-isopropylphenyl, m
-Methoxyphenyl, m-propoxyphenyl, m-nitrophenyl, m-cyanophenyl and the like are substituents R ₃
Specifically, hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and the like, and the substituent R ₄ is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl. , T-butyl, benzyl, etc. are each exemplified.

Specific examples of the O-alkyl-N- (β-nitroethyl) hydroxylamine derivative represented by the general formula (1) include O-methyl-N- (β-nitroethyl) hydroxylamine and O-. Methyl-N- (β
-Nitropropyl) hydroxylamine, O-ethyl-
N- (β-nitropropyl) hydroxylamine, O-
-T-butyl-N- (β-nitropropyl) hydroxylamine, O-benzyl-N- (β-nitropropyl)
Hydroxylamine, N, O-dimethyl-N- (β-nitropropyl) hydroxylamine, O-methyl-N-
(Α-Methyl-β-nitroethyl) hydroxylamine, O-methyl-N- (β-nitrobutyl) hydroxylamine, O-methyl-N- (α-methyl-β-nitropropyl) hydroxylamine, O-methyl-N -(Α
-(Nitromethyl) propyl] hydroxylamine, O
-Methyl-N- (β-nitropentyl) hydroxylamine, O-methyl-N- [α- (nitromethyl) butyl] hydroxylamine, O-methyl-N- (α-ethyl-β-nitropropyl) hydroxylamine, N-
(Α-Methyl-β-nitrobutyl) -O-methylhydroxylamine, O-methyl-N- [α- (nitromethyl) heptyl] hydroxylamine, O-methyl-N-
[Α- (Nitromethyl) octyl] hydroxylamine, O-methyl-N- [α- (nitromethyl) nonyl]
Hydroxylamine, O-methyl-N- [α- (nitromethyl) undecyl] hydroxylamine, N- (α-
Isopropyl-β-nitrobutyl) -O-methylhydroxylamine, O-methyl-N- [α- (nitromethyl) -β-phenylethyl] hydroxylamine, O-
Methyl-N- [1- (α-nitroethyl) -3-methoxybutyl] hydroxylamine, O-methyl-N- [1
-(Α-Nitroethyl) -3-phenoxybutyl] hydroxylamine, O-methyl-N- [1- (α-nitroethyl) -3-chlorobutyl] hydroxylamine, O
-Methyl-N- (β-nitro-α-phenylethyl) hydroxylamine, O-methyl-N- (β-nitro-α
-Phenylpropyl) hydroxylamine, O-methyl-N- (α, β-diphenyl-β-nitroethyl) hydroxylamine, O-methyl-N- [1- (3-chlorophenyl) -2-nitropropyl] hydroxylamine, O-methyl-N- [2-nitro-1- (p-tolyl) ethyl] hydroxylamine, O-methyl-N-
[1- (3-methoxyphenyl) -2-nitropropyl] hydroxylamine, O-methyl-N- [1-
(2,3-Dimethoxyphenyl) -2-nitropropyl] hydroxylamine, O-methyl-N- [1- (3
-Nitrophenyl) -2-nitroethyl] hydroxylamine, O-methyl-N- [1- (3-cyanophenyl) -2-nitropropyl] hydroxylamine, O-
Methyl-N- (2-nitrocyclohexyl) hydroxylamine, O-methyl-N- (2-methyl-6-nitrocyclohexyl) hydroxylamine, O-methyl-N
-(2-nitrocyclopentyl) hydroxylamine,
O-methyl-N- (3-nitronorbonan-2-yl)
Examples include hydroxylamine and the like.

The O-alkyl-N- (β-nitroethyl) hydroxylamine derivative has the general formula (2) (Wherein R ₁ and R ₂ have the same meanings as described above), and a nitroolefin represented by the general formula (3) (In the formula, R ₃ and R ₄ have the same meanings as described above.) The compound can be easily and quantitatively produced from an O-alkylhydroxylamine.

Here, the nitroolefins represented by the general formula (2) used as a raw material are, for example, a condensation reaction of an aldehyde and a nitroalkane or a deacetic acid reaction of β-nitroacetate [Org.Syn., Coll. Vol. .I, 413 (1941), J.
Org. Chem., Vol. 15, 8 (1950)] or dehydration reaction of β-nitroalcohol [J. Chem. Soc., 1471 (1947)] and the like. Examples of such nitroolefins include nitroethylene, (E) -1-nitropropene, 2-nitropropene, 2-nitro-1-butene, (E) -1-nitro-1-butene, (E) -2- Nitro-2-butene, 2-nitro-1-pentene, (E)
-1-Nitro-1-pentene, (E) -2-nitro-2
-Pentene, (E) -3-nitro-2-pentene,
(E) -1-nitro-1-octene, (E) -1-nitro-1-nonene, (E) -1-nitro-1-decene,
(E) -1-Nitro-1-dodecene, (E) -2-methyl-4-nitro-3-hexene, (E) -5-methoxy-2-nitro-2-hexene, (E) -5 Chloro-2
-Nitro-2-hexene, (E) -5-phenoxy-2
-Nitro-2-hexene, (E) -1-nitro-3-phenylpropene, (E) -β-nitrostyrene, (E)
-4-Methyl-β-nitrostyrene, (E) -3-nitro-β-nitrostyrene, (E) -1-phenyl-2-
Nitropropene, (E) -α-nitrostilbene,
(E) -1- (3-Methoxyphenyl) -2-nitropropene, (E) -1- (2,3-dimethoxyphenyl)
2-nitropropene, (E) -1- (3-chlorophenyl) -2-nitropropene, (E) -1- (3-nitrophenyl) -2-nitropropene, (E) -1- (3
-Cyanophenyl) -2-nitropropene, 1-nitrocyclohexene, 3-methyl-1-nitrocyclohexene, 1-nitrocyclopentene, 2-nitronorbornene and the like.

The other raw material, the general formula (3)
The O-alkylhydroxylamine represented by
For example, O-methylhydroxylamine, O-ethylhydroxylamine, Ot-butylhydroxylamine,
Examples thereof include O-benzylhydroxylamine and N, O-dimethylhydroxylamine, and among them, O-methylhydroxylamine is preferable.

In reacting such nitroolefins with O-alkylhydroxylamine, no other reaction reagent is required, and both raw material compounds may simply be mixed. At this time, the amount of O-alkylhydroxylamine used is usually 0.8 to
It is 3 times by mole, preferably 1 to 2 times by mole. The reaction solvent may not be particularly used, but there is no problem even if it is used.
When a solvent is used, the solvent is not particularly limited as long as it is inert to the reaction, but is generally an aprotic polar solvent such as N, N-dimethylformamide or dimethylsulfoxide, diethyl ether, ethylene glycol dimethyl ether, diethylene glycol. Dimethyl ether,
Ether solvents such as 1,4-dioxane and tetrahydrofuran, dichloromethane, 1,2-dichloroethane,
Halogen-based solvents such as chlorobenzene, aromatic hydrocarbon-based solvents such as benzene, toluene and xylene, and aliphatic hydrocarbon-based solvents such as hexane and heptane are used.
These may be used alone or in admixture of two or more.

The reaction temperature is usually in the range of -40 ° C to 100 ° C, preferably 0 ° C to 50 ° C. By such a reaction, the desired O-alkyl-N- (β-nitroethyl) hydroxylamine derivative represented by the general formula (1) is easily produced, and, for example, recrystallization, distillation, various chromatographies are carried out from the reaction mixture after completion of the reaction. It can be easily isolated and purified by a general operation such as.

O represented by the general formula (1) of the present invention
The -alkyl-N- (β-nitroethyl) hydroxylamine derivative has a base such as sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, alkali metal hydrides such as sodium hydride, sodium amides, alkali metal amides such as lithium diisopropylamide, sodium methoxide, sodium ethoxide, alkali metal such as potassium t-butoxide. By reacting an alkoxide, etc., the general formula (4) can be obtained in good yield. (Wherein R ₁ , R ₂ and R ₃ have the same meanings as described above), and β-nitroenamine can be obtained, and the β-nitroenamine is widely used as an intermediate for pharmaceuticals and agricultural chemicals. be able to.

[0014]

Industrial Applicability The O-alkyl-N- (β-nitroethyl) hydroxylamine derivative represented by the general formula (1) of the present invention can be easily prepared from a commercially available starting material compound.
It is possible to produce β-nitroenamine which is useful as an intermediate for pharmaceuticals and agricultural chemicals by a very easy method which can be quantitatively produced.

[0015]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited thereto.

Example 1 118 mg (2.5 mmol) of O-methylhydroxylamine was added to 174 mg (2 mmol) of 2-nitropropene.
Was added dropwise to a solution of N, N-dimethylformamide in 1 ml, and the mixture was stirred at 25 ° C. for 10 minutes. After that, water was added, and then methylene chloride extraction was performed. The obtained organic layer was thoroughly washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was isolated and purified by silica gel thin layer chromatography (developing solution: ethyl acetate / hexane = 1/5). did. O-methyl-N- (β-nitropropyl) hydroxylamine Yield 90% ¹ H NMR spectrum (CDCl ₃ , 270 MHz) δ1.55 (d, 3H, J = 6.93Hz), 3.18 (m, 1H), 3.40 ( m, 1H), 3.52
(s, 3H), 4.89 (m, 1H), 5.78 (br.s, 1H) Mass spectrum (EI-MS) m / z 134 (M +), 87, 72, 60, 56, 46, 41

Example 2 176 mg (3.75 mmol) of O-methylhydroxylamine was added to 303 mg of (E) -2-nitro-2-butene.
(3 mmol) and stirred at 25 ° C. for 10 minutes,
The product was subjected to silica gel thin layer chromatography (developing solution:
It was isolated and purified with ethyl acetate / hexane = 1/5). O-methyl-N- (α-methyl-β-nitropropyl)
Hydroxylamine (mixture of diastereomers)
Yield 95% (Diastereomer 1) ¹ H NMR spectrum (CDCl ₃ , 270MHz) δ1.07 (d, 3H, J = 6.27Hz), 1.54 (d, 3H, J = 6.27Hz), 3.44
(m, 1H), 3.53 (s, 3H), 4.86 (m, 1H), 5.62 (br.s, 1H) Mass spectrum (EI-MS) m / z 148 (M +), 102, 86, 74, 56, 42 (Diastereomer 2) ¹ H NMR spectrum (CDCl ₃ , 270 MHz) δ1.11 (d, 3H, J = 7.26Hz), 1.52 (d, 3H, J = 6.27Hz), 3.57
(m, 1H), 4.76 (m, 1H), 5.62 (br.s, 1H) Mass spectrum (EI-MS) m / z 148 (M +), 103, 101, 86, 74, 56, 42

Example 3 176 mg (3.75 mmol) of O-methylhydroxylamine was added to 471 m of (E) -1-nitro-1-octene.
g (3 mmol) in 1 ml of methylene chloride solution,
After stirring for 10 minutes at 25 ° C., the product was subjected to silica gel thin layer chromatography (developing solution: ethyl acetate / hexane =
1/10) and isolated and purified. O-methyl-N- [α- (nitromethyl) heptyl] hydroxylamine Yield 100% ¹ H NMR spectrum (CDCl ₃ , 270 MHz) δ 0.89 (m, 3H), 1.26-1.56 (m, 10H), 3.52 (m , 1H), 3.52
(s, 3H), 4.43 (dd, 1H, J = 4.29Hz, 12.54Hz), 4.58 (dd, 1H, J = 7.26Hz,
12.54Hz), 5.76 (br.s, 1H) ¹³ C NMR spectrum (CDCl ₃ , 270MHz) δ 14.25, 22.79, 26.13, 29.33, 29.47, 31.83, 59.30,
62.72, 76.87 Mass spectrum (EI-MS) m / z 204 (M +), 173, 160, 144, 126, 119, 100, 87,
73, 72, 55, 41

Example 4 176 mg (3.75 mmol) of O-methylhydroxylamine was added to 382 mg (3 mmol) of 1-nitrocyclohexene, and the mixture was stirred at 25 ° C. for 60 minutes, and then the product was subjected to silica gel thin layer chromatography (developing). Liquid: ethyl acetate / hexane = 1/5) for isolation and purification. O-methyl-N- (2-nitrocyclohexyl) hydroxylamine (mixture of diastereomers) Yield 100% (Diastereomer 1) ¹ H NMR spectrum (CDCl ₃ , 270 MHz) δ1.28-1.96 (m, 7H) , 2.28-2.39 (m, 1H), 3.32 (td, 1H, J =
4.29Hz, 10.56Hz), 3.46 (s, 3H), 4.56 (td, 1H, J = 4.29Hz, 1
0.56Hz), 5.71 (br.s, 1H) Mass spectrum (EI-MS) m / z 174 (M +), 127, 112, 99, 96, 86, 69, 54, 41 (diastereomer 2) ¹ HNMR spectrum (CDCl ₃ , 270 MHz) δ1.28-1.96 (m, 7H), 2.28-2.39 (m, 1H), 3.48 (s, 3H), 3.
53 (m, 1H), 4.77 (m, 1H), 5.71 (br.s, 1H) Mass spectrum (EI-MS) m / z 174 (M +), 128, 112, 96, 86, 69, 54, 41

Example 5 94 mg (2 mmol) of O-methylhydroxylamine
194 mg of (E) -3-nitro-β-nitrostyrene
(1 mmol) of N, N-dimethylformamide 1 ml
The solution was added dropwise to the solution and stirred at 25 ° C for 10 minutes. After that, water was added, and then methylene chloride extraction was performed. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was distilled off,
The product was subjected to silica gel thin layer chromatography (developing solution:
It was isolated and purified with ethyl acetate / hexane = 1/5). O-methyl-N- [1- (3-nitrophenyl) -2-
Nitroethyl] hydroxylamine yield 85
% ¹ H NMR spectrum (CDCl ₃ , 270 MHz) δ3.53 (s, 3H), 4.65 (m, 1H), 4.85-4.98 (m, 2H), 6.00 (b
rs, 1H) 7.59 (t, 1H, J = 7.92Hz), 7.72 (m, 1H), 8.21-8.29 (m, 1H) ¹³ C NMR spectrum (CDCl ₃ , 270MHz) δ61.92, 62.86, 76.68, 122.66, 123.94, 130.03, 13
3.82, 138.17, 148.52 Mass spectrum (FD-MS) m / z 241 (M +)

Reference Example 1 268 mg (2 mmol) of O-methyl-N- (β-nitropropyl) hydroxylamine obtained in the same manner as in Example 1 was dissolved in 2 ml of N, N-dimethylformamide,
A solution of 673 mg (6 mmol) of potassium t-butoxide in 3 ml of N, N-dimethylformamide was added at 25 ° C.
Was added dropwise over 5 minutes. After the dropwise addition was completed, the mixture was stirred at 25 ° C for 10 minutes, passed through a silica gel short column, and extracted with ethyl acetate. After evaporating the solvent, the product was isolated and purified by silica gel thin layer chromatography (developing solution: ethyl acetate / hexane = 1/1) to obtain 1-amino-2-nitropropene in a yield of 61%.

Reference Example 2 148 mg (1 mmol) of O-methyl-N- (α-methyl-β-nitropropyl) hydroxylamine (mixture of diastereomers) obtained in the same manner as in Example 2 was added to N,
Dissolved in 2 ml of N-dimethylformamide, potassium-
N, N containing 224 mg (2 mmol) of t-butoxide
-The solution was added dropwise to a 3 ml solution of dimethylformamide at 25 ° C over 5 minutes. After the dropwise addition was completed, the mixture was stirred at 25 ° C for 10 minutes, passed through a silica gel short column, and extracted with ethyl acetate. After distilling off the solvent, the product was subjected to silica gel thin layer chromatography (developing solution: ethyl acetate / hexane = 1/1).
Isolated and purified with (Z) -2-amino-3-nitro-2.
-Butene was obtained with a yield of 80%.

Reference Example 3 204 mg of O-methyl-N- [α- (nitromethyl) heptyl] hydroxylamine obtained in the same manner as in Example 3
(1 mmol) of N, N-dimethylformamide 2 ml
Was dissolved in 3 ml of N, N-dimethylformamide containing 336 mg (3 mmol) of potassium t-butoxide, and the mixture was added dropwise at 25 ° C. over 5 minutes. 25 after dropping
After stirring at 60 ° C for 60 minutes, the mixture was passed through a silica gel short column and extracted with ethyl acetate. After the solvent was distilled off, the product was isolated and purified by silica gel thin layer chromatography (developing solution: ethyl acetate / hexane = 1/1) to collect (Z) -2-amino-1-nitro-1-octene. It was obtained at a rate of 87%.

Reference Example 4 174 mg (1 mmol) of O-methyl-N- (2-nitrocyclohexyl) hydroxylamine (mixture of diastereomers) obtained in the same manner as in Example 4 was added to 2 ml of N, N-dimethylformamide. It melt | dissolved and it dripped at 25 degreeC over 5 minutes to the N, N- dimethylformamide 3 ml solution containing 224 mg (2 mmol) of potassium t-butoxide. After the dropping was completed, the mixture was stirred at 25 ° C. for 30 minutes, passed through a silica gel short column, and extracted with ethyl acetate. After the solvent was distilled off, the product was isolated and purified by silica gel thin layer chromatography (developing solution: ethyl acetate / hexane = 1/1) to obtain 1-amino-2-nitrocyclohexene with a yield of 91%.

Reference Example 5 O-methyl-N- [1- (3
241 mg (1 mmol) of -nitrophenyl) -2-nitroethyl] hydroxylamine was dissolved in 2 ml of N, N-dimethylformamide, and 25 ml of 3 ml of N, N-dimethylformamide containing 224 mg (2 mmol) of potassium t-butoxide was dissolved. The solution was added dropwise at 5 ° C over 5 minutes.
After the completion of dropping, the mixture was stirred at 25 ° C. for 30 minutes, saturated aqueous ammonium chloride solution was added, and methylene chloride extraction was performed. After drying the obtained organic layer with anhydrous magnesium sulfate,
The solvent was distilled off, and the product was isolated and purified by silica gel thin layer chromatography (developing solution: ethyl acetate / hexane = 1/1) to purify (Z) -3-nitro-α-amino-β-nitrostyrene. Was obtained with a yield of 88%.

Claims (4)

[Claims] 1. A general formula (1) (In the formula, R ₁ and R ₂ are the same or different and each is a hydrogen atom,
A linear or branched alkyl group having 1 to 10 carbon atoms which may be optionally substituted with a halogen or a lower alkoxyl group, a phenyl group or a phenoxyl group, an optional halogen, a lower alkyl group, a lower alkoxyl group, a nitro group or It represents a phenyl group which may be substituted with a cyano group, and R ₁ and R ₂ may be taken together to form cycloalkyl or bicycloalkyl. R ₃ represents a hydrogen atom or a lower alkyl group, and R ₄ represents a lower alkyl group or a benzyl group. ) O-alkyl-N- (β-nitroethyl) hydroxylamine derivative represented by 2. The O-alkyl-N- (β-nitroethyl) hydroxylamine derivative according to claim 1, wherein the substituent R ₃ is a hydrogen atom and R ₄ is a methyl group. 3. General formula (2) (In the formula, R ₁ and R ₂ are the same or different and each is a hydrogen atom,
A linear or branched alkyl group having 1 to 10 carbon atoms which may be optionally substituted with a halogen or a lower alkoxyl group, a phenyl group or a phenoxyl group, an optional halogen, a lower alkyl group, a lower alkoxyl group, a nitro group or It represents a phenyl group which may be substituted with a cyano group, and R ₁ and R ₂ may be taken together to form cycloalkyl or bicycloalkyl. ) Nitroolefins represented by
General formula (3) (In the formula, R ₃ represents a hydrogen atom or a lower alkyl group,
R ₄ represents a lower alkyl group or a benzyl group. ) O-alkylhydroxylamine represented by the formula (1) is reacted.
A method for producing a (β-nitroethyl) hydroxylamine derivative. 4. The method for producing an O-alkyl-N- (β-nitroethyl) hydroxylamine derivative according to claim 3, wherein the O-alkylhydroxylamine is O-methylhydroxylamine.