Selective acylation of hydrazines

Abstract: This application relates to a process for selectively monoacylating hydrazines by reacting unsubstituted or monoalkylhydrazines with trichloromethyl aryl ketones.

Description: This invention relates to a process for preparing monoacylated hydrazines. More particularly, this invention relates to a process which comprises reacting a trichloromethyl aryl ketone with a monoalkylated hydrazine to obtain a monoacyl-monoalkylhydrazine. The monoacyl-monoalkylhydrazines are useful intermediates in the process of preparing 1-alkyl-1,2-diacylhydrazines which are known to have insecticidal activity against Coleoptera and Lepidoptera. Synthetic Communications, 17(14), 1741-1748 (1987) discusses the acylation of various nitrogen nucleophiles with 2,2,2-trichloro-1-(p-substituted phenyl)ethanones where two examples illustrate the acylation of unsubstituted hydrazine and of phenylhydrazine. Selectivity a problem when acylating hydrazines since hydrazine is a difunctional molecule. There are two types of selectivity problems. One is the selectivity to monoacylate hydrazine while preventing or minimizing diacylation. The other is control of the regioselectivity of acylation for monosubstituted hydrazines. The process of the present invention provides an efficient method of selectively monoacylating, and causing acylation on the unsubstituted nitrogen, of monoalkylated hydrazines. In the process of the present invention, the monoalkylated hydrazine is reacted with a trichloromethyl aryl ketone to obtain the desired monoacylated hydrazine derivative. Accordingly the present invention provides a process for preparing a monoacylated hydrazine of the formula which comprises reacting a hydrazine of the formula R-NHNH₂ or the corresponding hydrazine hydrate or hydrazine salt with a trichloromethyl aryl ketone of the formula wherein: R is (C₁-C₆)alkyl; and Aryl is (i) phenyl optionally substituted with one to three substituents which may be the same or different and which are selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl or halo(C₁-C₆)alkoxy; or (ii) naphthyl. (C₁-C₆)alkyl includes straight or branched alkyl groups, for example, methyl, ethyl, n -propyl, n -butyl, isopropyl, t -butyl, or neopentyl. (C₁-C₆)alkoxy includes, for example, methoxy. Halo means bromo, chloro, fluoro and iodo. Halo(C₁-C₆)alkyl includes, for example, trifluoromethyl. Halo(C₁-C₆)alkoxy includes, for example, trifluoromethoxy. In one preferred embodiment, R is t-butyl or methyl. In another preferred embodiment, Aryl is 4-((C₁-C₆)alkyl)phenyl, 2,3-di(C₁-C₆)alkylphenyl, 4-halophenyl, 2-(C₁-C₆)alkyl-3-(C₁-C₆)alkoxyphenyl, 2-(C₁-C₆)alkyl-3-halophenyl, 2,3-dihalophenyl, 2-halo-3-(C₁-C₆)alkylphenyl, 2,3-di(C₁-C₆)alkoxyphenyl, 2-halo-3-(C₁-C₆)alkoxyphenyl or 2,3,5-tri(C₁-C₆)alkylphenyl. More preferably, Aryl is 4-ethylphenyl, 4-chlorophenyl, 2,3-dimethylphenyl, 2-methyl-3-methoxyphenyl, 4-methylphenyl, 4- n -propylphenyl, 2-methyl-3-chlorophenyl, 2,3-dimethoxyphenyl, 2-methyl-3-bromophenyl, 2-methyl-3-fluorophenyl, 2,3-dichlorophenyl, 2-fluoro-3-chlorophenyl, 2,3-difluorophenyl, 4- iso propylphenyl, 2-chloro-3-methylphenyl, 2-bromo-3-methylphenyl, 2-chloro-3-methoxyphenyl, 2-ethyl-3-chlorophenyl, 2-fluoro-3-methylphenyl or 2,3-dimethyl-5- iso propylphenyl. The hydrazine used in the process can be a hydrate, the neat hydrazine such as methylhydrazine, or a hydrazine salt. For example, the hydrazine salt may be a hydrazine hydrohalide such as t -butylhydrazine hydrochloride. In the case where a hydrazine salt is used, an equivalent of base is added to the reaction to produce the free hydrazine. Examples of bases include potassium carbonate, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine, and sodium hydroxide. The preferred base is sodium hydroxide. The reaction process may be carried out in a variety of solvents such as methanol, ethanol, isopropanol, xylene, water, ethyl acetate, toluene and methylene chloride. Preferred solvents are aprotic solvents such as xylene, toluene and methylene chloride. The reaction process is carried out preferably at atmospheric pressure. The process may be carried out between about 10°C and about 100°C, preferably between about 20°C and about 50°C. The following Examples further illustrate the invention but are not intended to limit it in any way. EXAMPLES Example 1: 1-(4-Ethylbenzoyl)-2- t -butylhydrazine To a mixture of t -butylhydrazine hydrochloride (6.36 grams (g), 50 millimoles (mmol)) 5.3 g of water, 20 milliliters (ml) of methylene chloride and 4.0 g of 50% sodium hydroxide solution (50 mmol) under nitrogen there was added dropwise at room temperature over 12 minutes α,α,α-trichloro-4-ethylacetophenone (13.88 g, 95.2% purity, 52.5 mmol). The reaction mixture was stirred at room temperature for 5.75 hours, then 0.4 g of additional sodium hydroxide solution was added and the reaction mixture was stirred overnight. The reaction was quenched with water and the phases were separated. The methylene chloride phase was washed twice with water, dried over magnesium sulfate, filtered and evaporated in vacuo to yield 10.24 g (93% yield) of a pale yellow solid. This was found to contain 92.5% of 1-(4-ethyl)benzoyl-2- t -butylhydrazine, less than 0.3% of the isomer 1-(4-ethyl)benzoyl-1- t -butylhydrazine, and less than 0.3% of the 1,2-di-(4-ethyl)benzoyl-1- t -butylhydrazine. Example 2: 1-(4-Chlorobenzoyl)-2-methylhydrazine To a mixture of methylhydrazine (1.63 g, 34.6 mmol) and 55 ml of toluene under nitrogen, α,α,α,trichloro-4-chloroacetophenone (8.55 g, 97.9% purity, 34.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2.75 hours. The resulting slurry was filtered and the solids were washed with toluene and dried to yield 3.82 g (70% yield) of 1-(4-chlorobenzoyl)-2-methylhydrazine, mp 129.5-131°C (literature mp 132-133°C, Meyer, R. F., J. Heterocyclic Chem., 1965, 2, 305). Using essentially the reaction conditions described in Examples 1 and 2 the compounds listed in Table I were prepared. Where reaction conditions differed, they are noted in the Table. The products of the reactions listed in this Table were isolated either by filtering from the reaction solvent, or by extraction into acid, followed by neutralization and extraction of the product from the aqueous phase. The reported melting points are for the isolated material which had not been further purified by recrystallization. Ex. No. Aryl R Solvent Temp. Product Isolation Yield mp (°C) lit mp (°C) 3. Phenyl CH₃ Toluene RT Extraction 73 79.5-82 85-86 86-88 4. Phenyl C(CH₃)₃ Toluene 40°C Extraction 75 93.5-94.5 94-95 5. 4-Ethylphenyl CH₃ Toluene RT Extraction 81 65-71 6. 4-Ethylphenyl C(CH₃)₃ Toluene 40°C Filtration 76 By using essentially the reaction conditions described in Examples 1 and 2, Examples 8-25, listed in Table II, are prepared.

Claims: A process for preparing a monoacylated hydrazine of the formula which comprises reacting a hydrazine of the formula R-NHNH₂ or the corresponding hydrazine hydrate or hydrazine salt with a trichloromethyl aryl ketone of the formula wherein: R is (C₁-6₆)alkyl; and Aryl is (i) phenyl optionally substituted with one to three substituents which may be the same or different and which are selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl or halo(C₁-C₆)alkoxy, or (ii) naphthyl. A process as claimed in claim 1, wherein R is t -butyl or methyl. A process as claimed in claim 1 or 2, wherein Aryl is 4-(C₁-C₆)alkylphenyl, 2,3-di(C₁-C₆)alkylphenyl, 2-(C₁-C₆)alkyl-3-(C₁-C₆)alkoxyphenyl, 4-halophenyl, 2,3-dihalophenyl, 2-(C₁-C₆)alkyl-3-halophenyl, 2,3-di(C₁-C₆)alkoxyphenyl, 2-halo-3-(C₁-C₆)alkylphenyl, 2-halo-3-(C₁-C₆)alkoxyphenyl or 2,3,5-tri(C₁-C₆)alkylphenyl. A process as claimed in claim 3, wherein Aryl is 4-ethylphenyl, 4-methylphenyl, 4- n -propylphenyl, 4-isopropylphenyl, 2,3-dimethylphenyl, 2-methyl-3-methoxyphenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2-fluoro-3-chlorophenyl, 2-methyl-3-chlorophenyl, 2-methyl-3-bromophenyl, 2-methyl-3-fluorophenyl, 2-ethyl-3-chlorophenyl, 2,3-dimethoxyphenyl, 2-chloro-3-methylphenyl, 2-bromo-3-methylphenyl, 2-fluoro-3-methylphenyl, 2-chloro-3-methoxyphenyl or 2,3-dimethyl-5- iso propylphenyl. A process as claimed in any preceding claim, wherein said hydrazine is methyl hydrazine or a hydrazine hydrate. A process as claimed in any of claims 1 to 4, wherein the hydrazine is a hydrazine salt, and an equivalent of base, preferably potassium carbonate, sodium acetate, sodium methoxide, sodium ethoxide, sodium hydroxide or triethylamine, and more preferably sodium hydroxide, is added to the reaction mixture to produce free hydrazine. A process as claimed in claim 6, wherein said hydrazine salt is a hydrazine hydrohalide, preferably t -butylhydrazine hydrochloride. A process as claimed in any preceding claim, which is carried out in a solvent, preferably methanol, ethanol, isopropanol, water, xylene, toluene, methylene chloride or ethyl acetate, more preferably xylene, toluene or methylene chloride. A process as claimed in any preceding claim, which is carried out at a temperature between 10°C and 100°C, preferably between 20°C and 50°C.

Inventors: KELLY MARTHA JEAN, KELLY, MARTHA JEAN
Applicants: ROHM & HAAS, ROHM AND HAAS COMPANY
Application year: 1991
Main classification: C07C241
IPC codes: C07C241, C07C243