JPH0350746B2 - - Google Patents

Description

[Detailed description of the invention]

(Field of Application) The present invention relates to a method for producing N-substituted amides.
Specifically, the present invention provides a method for producing an N-substituted amide in which a specific N-halomethylamide and a specific aromatic ring compound are reacted in the coexistence of an acid catalyst and a basic compound. (Prior art and problems to be solved by the invention) Conventionally, as a method for producing an amide compound, a specific aromatic ring compound and an N-halomethylamide compound are reacted using an aluminum chloride catalyst to produce an N-substituted amide. is known (Chemistry and industry).
(1982 issue, p. 808). However, the above method cannot be applied when a heterocyclic aromatic ring compound is used as a raw material, and from an industrial perspective, it cannot necessarily be said to be a satisfactory method in terms of yield, operation, etc. (Means for Solving the Problems) The present inventors have been conducting research on the production of aromatic ring compounds, particularly amide compounds having a heterocycle, for many years. As a result, when producing the above-mentioned compound by reacting N-halomethylamide with an aromatic ring compound, it is possible to obtain the desired product in good yield by carrying out the reaction in the presence of an acid catalyst and a basic compound. They discovered what they could do and completed the present invention. That is, the present invention provides (a) general formula (), (However, R ¹ is a substituted or unsubstituted hydrocarbon group,
R ² and R ³ are the same or different hydrogen atoms or alkyl groups, R ⁴ is a hydrogen atom or a substituted or unsubstituted alkyl group, and X is a halogen atom. ) N-halomethylamide represented by the general formula (), Ar-H...() (However, Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. ) is reacted with the aromatic ring compound represented by the general formula (), (However, R ¹ , R ² , R ³ , R ⁴ and Ar are the same as above.) In the method for producing the N-substituted amide shown by, an acid catalyst and a basic compound are added to the reaction system. This is a method for producing an N-substituted amide, characterized in that the reaction is carried out in the coexistence of N-substituted amide. The greatest feature of the present invention is that an acid catalyst and a basic compound are allowed to coexist in the reaction between the N-halomethylamide represented by the general formula () and the aromatic ring compound represented by the general formula (). It is something to do. The acid catalyst used in the present invention is not particularly limited, and known acid catalysts can be suitably employed. Generally, Lewis acids, Bronsted acids, etc. can be used. In particular, Lewis acids are most suitable because they have good interaction with the basic compounds described below. More specific examples of those preferably used as the acid catalyst include copper, silver,
Gold, beryllium, magnesium, zinc, cadmium, mercury, boron, aluminum, gallium, indium, thallium, silicon, germanium, tin, lead, thorium, zirconium, panadium,
Metal halides such as chromium, molybdenum, tungsten, manganese, iron, nickel, and platinum are preferred, and halides of iron and zinc are expected to have the best effects. Further, as the halide, chlorine, bromine, iodine and fluorine can be used without particular limitation, but chlorine and bromine are most suitable from the viewpoint of handling. The basic compound used in the present invention is not particularly limited, and may be appropriately selected from known compounds as needed. Since the reaction of the present invention generally produces hydrogen halide as a by-product, it is preferable to use a reaction mixture that has the ability to capture the hydrogen halide produced as a by-product. Particularly suitable are basic compounds such as tertiary amine compounds and carbonates. For example, as a tertiary amine compound, the general formula

[Formula] (where R ^A , R ^B and R ^C are the same or different types of hydrocarbon groups. Those represented by the formula can be used without particular limitation.
In the above general formula, the hydrocarbon groups represented by R ^A , R ^B and R ^C are not particularly limited, but due to their easy availability, methyl group, ethyl group, isopropyl group, allyl group, butyl group, cyclohexyl group, etc. A hydrocarbon group having 1 to 10 carbon atoms, such as a phenyl group or a naphthyl group, is suitable. The carbonate is not particularly limited and any known carbonate may be used, but carbonates of alkaline earth and alkali metals are generally preferably used because of their ease of availability. Most of the target products of the present invention, ie, the N-substituted amides represented by the above general formula (), are new compounds. For example, among the compounds represented by the above general formula (), general formula (A) (However _, R is a hydrogen atom or an _alkyl group; Heterocyclic aromatic ring compound shown and general formula (B) (However, R ⁵ to ^{R 7} and R ¹⁰ to R ¹² are the same or different hydrogen atoms, alkyl groups, and alkoxy groups, and R ⁸ ,
R ⁹ and R ¹³ are the same or different hydrogen atoms or alkyl groups, and X is a halogen atom. N-substituted halomethylamides of hydrocarbon aromatic ring compounds represented by ) are known. Therefore, the above general formula (A) and
The compounds represented by the general formula () other than (B) are new compounds. These new compounds have particularly excellent herbicidal activity and are generally used as herbicides. Among the compounds represented by the above general formula (), the structural formula of the new compound has an infrared absorption spectrum,
It can be confirmed by instrumental analysis such as 1H-nuclear magnetic resonance spectrum, ^13C -nuclear magnetic resonance spectrum, mass spectrometry, and elemental analysis. These compounds also have specific physical constants such as melting point, boiling point, and refractive index. Furthermore, the compound represented by the above general formula () is usually a colorless, pale yellow, or pale brown solid or viscous substance, although it varies somewhat depending on its purity. As mentioned above, a combination of the N-halomethylamide of the general formula () and the aromatic ring compound of the general formula (), which is a raw material corresponding to a new compound among the N-substituted amides represented by the general formula (). is new. However, as is clear from the structures of the general formulas (), (), and (), the reaction in the present invention is based on the structure of the N-halomethylamide represented by the general formula (). "X" shown by and Ar shown by general formula ()
-H reacts with "H" to produce hydrogen halide, so hydrogen halide is produced as a by-product.
Moreover, as long as the above-mentioned skeleton has a remaining function, these raw material compounds can be selected and used as required. Examples of raw materials that can generally be suitably used are as follows. N-halomethylamide, which is a raw material used in the present invention, has the general formula (), that is, (However, R ¹ is a substituted or unsubstituted hydrocarbon group, R ²
and R ³ are the same or different hydrogen atoms or alkyl groups, R ⁴ is a hydrogen atom or a substituted or unsubstituted alkyl group, and X is a halogen atom. ) is N-halomethylamide. In the above general formula (), the hydrocarbon group represented by R ¹ is not particularly limited and any number of carbon atoms can be used as required.
Hydrocarbon groups having 1 to 10 carbon atoms such as isopropyl group, allyl group, butyl group, cyclohexyl group, phenyl group, and naphthyl group are preferred. Further, the hydrocarbon group may be substituted with a substituent, and the type of the substituent is not limited at all, and any type of substituent can be used as required. However, due to the ease of obtaining raw materials, the substituents are generally lower alkyl groups having 1 to 5 carbon atoms such as methyl group, ethyl group, isopropyl group, butyl group; methoxy group, ethoxy group, propoxy group,
Lower alkoxy groups with 1 to 5 carbon atoms such as butoxy; lower alkoxycarbonyl groups with 1 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl; methylthio, ethylthio, propylthio , a lower alkylthio group having 1 to 5 carbon atoms such as butylthio group; a lower alkylcarbonyl group having 1 to 5 carbon atoms such as an acetyl group, propionyl group, butanyl group; cyano group; nitro group; halogen atom (chlorine, bromine, iodine , fluorine, any of which can be used, but chlorine and bromine are preferred from the viewpoint of easy availability of raw materials). (If two or more types are used, they may be the same or different types.) The following substituents are preferably used. Also, the general formula ()
Among them, the alkyl groups represented by R ² , R ³ and R ⁴ are not limited at all, but lower alkyl groups having 1 to 5 carbon atoms such as methyl group, ethyl group, isopropyl group and butyl group is preferred. The alkyl group of R ⁴ may be substituted with a substituent, and the type of the substituent is not limited at all and ^any one can be used as required. Similar substituents can be used. Further, as the halogen atom represented by X, chlorine, bromine, iodine, and fluorine atoms can be used without any restriction, but chlorine and bromine atoms are preferably used because of the ease of obtaining raw materials. . Other raw material compounds used in the present invention are aromatic ring compounds represented by the general formula (), that is, Ar--H. The aromatic ring compounds can be broadly classified into heterocyclic aromatic ring compounds and hydrocarbon aromatic ring compounds. In the present invention, these unsubstituted or substituted aromatic ring compounds can be used without particular limitation, but in general, five-membered heterocyclic aromatic ring compounds and six-membered hydrocarbon aromatic ring compounds are most preferred. It is. Further, as the above-mentioned heterocyclic aromatic ring compound, the following compounds are generally suitably used.

【formula】

【formula】

[Formula] (However, A is an oxygen atom, a sulfur atom, or N-R(R
is a hydrogen atom or an alkyl group having 5 or less carbon atoms)
It is. ) In the aromatic ring compound used in the present invention, the hydrogen atom bonded to the aromatic ring may be substituted with another atom or group. These substituted atoms or groups are not particularly limited, but generally halogen atoms such as chlorine, bromine, iodine, and fluorine, alkyl groups, nitro groups, amino groups, etc. are preferred, and the following substituents are also often preferred. used. ^-OR5 , ^-SR5 ,

【formula】

[Formula]-B-COOR ⁶ ,

[Formula] -B-CN, -NHCOR ⁵ (However, R ⁵ is an alkyl group; R ⁶ is a hydrogen atom, an alkyl group, a monovalent metal ion, a divalent metal ion, or an ammonium salt; B is

[expression] or

[Formula] (However, R ⁸ is a hydrogen atom or an alkyl group, and l
is 0 or a positive integer less than or equal to 10), and R ⁷
is a hydrogen atom or an alkyl group. Furthermore, as the alkyl group of these substituents, a linear or branched lower alkyl group having 1 to 5 carbon atoms is generally preferably used. Since the compound represented by the general formula () as a raw material is active against water, the compound in the reaction system, that is, the compound represented by the general formula () and () above, and the solvent used as necessary. , an acid catalyst, a basic compound, etc. are all used in a dry state, and it is preferable to maintain the gas phase of the reaction system in a dry state. The molar ratio of the compounds represented by the general formulas () and () may be appropriately determined and used as required, but it is common to use equimolar amounts. The molar ratio of the acid catalyst to the compound represented by the general formula () is not limited, but is generally preferably in the range of 0.01 to 5. Furthermore, the molar ratio of the basic compound to the acid catalyst is not particularly limited, but is between 0.1 and 100.
The range is preferably 0.5 to 50, more preferably 0.5 to 50. In the reaction in the present invention, it is generally preferable to use an organic solvent. As the solvent,
Examples include carbon disulfide, methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, diethyl ether, nitromethane, benzene, toluene, and nitrobenzene. The order of adding the raw materials, acid catalyst, basic compound, and solvent in the reaction is not particularly limited, but generally the solvent is charged into a reactor, the acid catalyst is added, and then the basic compound is added while stirring. After stirring for a predetermined time, it is preferable to add the compound represented by the general formula () dissolved in the solvent with stirring, and finally add the compound represented by the general formula () dissolved in the solvent while stirring. Of course, it is also possible to continuously add the above-mentioned components to the reaction system and to continuously take out the generated reactants from the reaction system. The temperature in the reaction can be selected from a wide range, generally -20°C to 150°C, preferably 0°C to
It is sufficient to choose from the range of 120℃. The reaction time varies depending on the raw materials, acid catalyst, reaction temperature, and type of solvent, but is usually 5 minutes to 10 days, preferably 20 days.
It is sufficient to choose from a range of minutes to 50 hours. Further, the reaction system is preferably stirred during the reaction. The method for isolating and purifying the target product, ie, the compound represented by the general formula () from the reaction system, is not particularly limited, and any known method can be employed. For example, the reaction solution is ice-cooled and poured into ice water with stirring. After stirring for 10 minutes, separate the aqueous and organic layers, and shake the organic layer with a 5% aqueous sodium hydrogen carbonate solution. The separated aqueous layer is acidified with dilute hydrochloric acid and extracted with ether. After sequentially washing the ether layer with water, 5% sodium bicarbonate and water, and drying with a desiccant such as Glauber's salt or calcium chloride,
The ether is distilled off, and the residue is isolated and purified by column chromatography. It is also possible to use purification by recrystallization instead of column chromatography, or to use both in combination. In some cases, purification means such as vacuum distillation may also be used. Among the compounds represented by the general formula () used as raw materials, a plurality of compounds represented by the general formula () may be produced depending on the type, number, and substitution position of the substituents. These can be isolated and purified by the above-mentioned purification methods such as column chromatography and fractional recrystallization. (Effect of the invention) According to the present invention, N represented by the general formula ()
N-substituted-methylamide can be produced in good yield from -halomethylamide and the aromatic ring compound represented by the general formula (). In particular, it can be said that the advantage of being able to obtain a methylamide in which a heterocyclic ring is bonded in high yield even for a heterocyclic aromatic ring compound is extremely large. (Example) Examples of the present invention will be shown below, but the present invention is not limited thereto. The structures of the products in the following Examples and Comparative Examples were determined in the same manner as in Example 1. Example 1 12.67 g of zinc chloride was suspended in 30 ml of methylene chloride, and a solution of 9.11 g of triethylamine dissolved in 30 ml of methylene chloride was added dropwise while stirring under ice-water cooling. After continuing to stir for 2 hours under ice-water cooling, the mixture was returned to room temperature and a solution of 3.43 g of 3-methoxythiophene dissolved in 10 ml of methylene chloride was added dropwise. Then N-
A solution of 7.38 g of chloromethyl-chloroaceto-2,6-dimethylanilide dissolved in 20 ml of methylene chloride was added dropwise with stirring. The mixture was then heated under reflux for 5 hours while stirring. The mixture was then cooled to room temperature and poured into 50 ml of ice water with stirring. After stirring for 10 minutes, the layers were separated, and the organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution, water, 1N hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate solution, and water. After drying the organic layer with sodium sulfate, low-boiling substances were distilled off and the resulting residue was vacuum distilled to obtain the desired product with a boiling point of 182℃/0.2mmHg.
Obtained 7.54 g as a white solid. The isolated product is shown in the following formula [2-
It was confirmed that it was (N-chloroacetyl-2',6'-dimethylanilino)methyl-3-methoxythiophene. The IR chart was as shown in Figure 1 of the attached drawings. Absorption based on aromatic ring carbon-hydrogen bonds at 3130 cm ^-1 and 3080 cm ^-1 , absorption based on aliphatic carbon-hydrogen bonds between 3000 and 2850 cm ^-1 , and strong absorption based on carbon-oxygen bonds in amide groups at 1660 cm ^-1 Absorption was observed. Figure 2 of the attached drawings shows a ¹ H-NMR chart. At 7.4 to 7.0 ppm, the proton of the benzene ring and the proton at the 4th position of the thiophene ring appear as a multiple of 4 protons, and at 6.70 ppm, the proton at the 5th position of the thiophene ring appears as a doublet (spin coupling constant 6 Hz), and 1 proton appears at 4.87 ppm. Two singlets of methylene protons connecting the nitrogen atom and the thiophene ring appear at , two singlets of chloroacetyl group protons appear at 3.67ppm, three singlets of methoxy group protons appear at 3.48ppm, Six methyl group protons appeared as a singlet at 2.04 ppm. As a result of the mass vector measurement, the following peaks were observed. m/e 323, 324 and 325 (molecular ion peak, corresponding to M) m/e 288 (corresponding to M-Cl). Elemental analysis values are carbon 59.51wt%, hydrogen 5.59wt%,
Nitrogen 4.25wt%, chlorine 10.81wt%, sulfur 9.82wt%
and the theoretical value of C ₁₆ H ₁₈ NO ₂ ClS (molecular weight 323.84) is 59.34 wt% carbon, 5.60 wt% hydrogen, and nitrogen.
4.33wt%, chlorine 10.95wt%, and sulfur 9.90wt%, all within the analytical error range. Comparative Example 1 The reaction and post-treatment were carried out in the same manner as in Example 1, except that the use of the methylene chloride solution of triethylamine in Example 1 was omitted. As a result, 0.51 g of the same product as that obtained in Example 1 was obtained. Comparative Example 2 The same procedure as Comparative Example 1 was carried out except that aluminum trichloride was used instead of zinc chloride. As a result, the reaction product became tar-like, and Example 1
It was not possible to obtain a product identical to that obtained in . Comparative Example 3 The same procedure as in Example 1 was carried out except that aluminum trichloride was used instead of zinc chloride. As a result, the reaction product became tar-like, and the same product as that obtained in Example 1 could not be obtained. Example 2 The reaction and post-treatment were carried out in the same manner as in Example 1, except that chloroform was used instead of methylene chloride as the solvent in Example 1, and the same product as that obtained in Example 1 was obtained in 6.53 I got g. Example 3 The reaction and post-treatment were carried out in the same manner as in Example 1 except that the amount of zinc chloride used in Example 1 was changed to 4.50 g and the amount of triethylamine used was changed to 3.04 g. 5.66 g of product identical to that obtained in step 1 was obtained. Example 4 The reaction and post-treatment were carried out in the same manner as in Example 1, except that 16.65 g of tributylamine was used instead of triethylamine in Example 1, and 7.36 g of the same product as that obtained in Example 1 was obtained. Ta. Example 5 Instead of triethylamine in Example 1,
The reaction and post-treatment were carried out in the same manner as in Example 1, except that 20.0 g of sodium carbonate was used, and 2.31 g of the same product as that obtained in Example 1 was obtained. Example 6 Instead of triethylamine in Example 1,
The reaction and post-treatment were carried out in the same manner as in Example 1, except that 25.0 g of potassium carbonate was used, and 2.28 g of the same product as that obtained in Example 1 was obtained. Example 7 The reaction and post-treatment were carried out in the same manner as in Example 1, except that 5.49 g of ferric chloride was used instead of zinc chloride in Example 1, and the amount of triethylamine used was changed to 3.03 g. 2.95 g of product identical to that obtained in Example 1 was obtained. Example 8 Zinc bromide was used instead of zinc chloride in Example 1.
The reaction and post-treatment were carried out in the same manner as in Example 1, except that 20.94 g was used, and 7.51 g of the same product as that obtained in Example 1 was obtained. Example 9 The reaction and post-treatment were carried out in the same manner as in Example 1, except that 10.00 g of ferric bromide was used instead of zinc chloride in Example 1, and the amount of triethylamine used was changed to 3.03 g. 2.81 g of product identical to that obtained in Example 1 was obtained. Example 10 Instead of triethylamine in Example 1,
The reaction and post-treatment were carried out in the same manner as in Example 1, except that 19.0 g of calcium carbonate was used, and 19.5 g of the same product as that obtained in Example 1 was obtained. Example 11 When 4.27 g of thiophene-3-acetic acid was used in place of 3-methoxythiophene in Example 1 and the reaction and post-treatment were carried out in the same manner as in Example 1, 5 as shown in the following formula () was obtained. -(N-chloroacetyl-
2',6'-diethylanilino)methyl-3-thiopheneacetic acid and 2-(N-
Chloroacetyl-2',6'-diethylanilino)methyl-3-thiopheneacetic acid was isolated. The elemental analysis value of compound () is carbon 60.15wt%,
Hydrogen 5.78wt%, nitrogen 3.53wt%, chlorine 9.21wt%, and the elemental analysis values of the compound () are carbon 59.95wt%,
Hydrogen was 5.71wt%, nitrogen was 3.45wt%, and chlorine was 9.50wt%. Both coincided with the theoretical values of C ₁₉ H ₂₂ NO ₈ ClS of 60.07 wt% carbon, 5.84 wt% hydrogen, 3.69 wt% nitrogen, and 9.33 wt% chlorine within the analytical error range. In the mass spectra, the molecular ion peak for both was 379, which matched the theoretical molecular weight of C ₁₉ H ₂₂ NO ₈ ClS. The 1H-NMR spectrum of compound () is 7.5
At ~6.6 ppm, the proton of the aromatic ring appears as a multiplet of 5 protons, at 4.85 ppm the methylene proton that connects the nitrogen atom and the thiophene ring appears as a singlet of 2 protons, and at 3.67 ppm the methylene proton of the chloroacetyl group appears. appears as a singlet for two protons, the methylene proton of the acetate group appears as a singlet for two protons at 3.52 ppm, and the methylene proton of the ethyl group appears as a quartet at 2.31 ppm (spin coupling constant 7).
Hz), and 4 protons appeared at 1.06 ppm, and a methyl proton of the ethyl group appeared as a triplet (spin coupling constant 8 Hz), corresponding to 6 protons. In the proton-NMR spectrum of compound (),
At 7.5 to 6.6 ppm, the protons of the aromatic ring appear as a multiple of 5 protons, at 4.95 ppm the methylene proton that connects nitrogen and the thiophene ring appears as a singlet of 2 protons, and at 3.67 ppm the methylene proton of the chloroacetyl group appears. appears as a singlet for two protons, the methylene proton of the acetate group appears as a singlet for two protons at 3.29 ppm, and the methylene proton of the ethyl group appears as a quartet at 2.31 ppm (spin coupling constant 7).
Hz), and 4 protons appeared at 1.06 ppm, and a methyl proton of the ethyl group appeared as a triplet (spin coupling constant 8 Hz), and 6 protons. Compounds () and () both have their respective ^1H
-The chemical shift, splitting pattern, spin coupling constant, and relative intensity ratio of each peak in the NMR spectrum support the above structural formula. Example 12 Various amidomethylated aromatic ring compounds represented by the general formula () were synthesized by carrying out reactions in the same manner as described in Example 1. The structure of the product is shown in Table 1. The structures of R ¹ , R ² , R ³ , R ⁴ and Ar shown in Table 1 refer to those shown below. That is, R ¹ ;

【formula】 Ar;

[Formula] (However, R ⁹ is -B- COOR ⁶ , and in the case of classification () in Table 1, B is

[Formula], when Table 1 middle classification () is B

[Formula]) R ⁴ ;

【formula】 In addition, in Table 1, the values in the column for bonding position of Ar are

Substitution of the functional group represented by [Formula] with Ar It shows the location where it is located.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] Example 13 A reaction was carried out in the same manner as described in Example 12,
Various amidomethylated aromatic ring compounds shown in Table 2 were synthesized. However, the aromatic ring compounds shown in Table 2 are the same as in Example 12, except that Ar in Example 12 is replaced by a hydrocarbon aromatic ring compound shown below. Ar;

【formula】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】 [Brief explanation of drawings]

Figure 1 of the accompanying drawings is an IR chart of the product obtained in Example 1, and Figure 2 is a 1H-NMR chart.

Claims (1)

[Claims] 1 (a) General formula, [Formula] (wherein R ¹ is a substituted or unsubstituted hydrocarbon group,
R ² and R ³ are the same or different hydrogen atoms or alkyl groups, R ⁴ is a hydrogen atom or a substituted or unsubstituted alkyl group, and X is a halogen atom. ) N-halomethylamide represented by (b) and an aromatic ring compound represented by the general formula Ar-H (wherein Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group) , in a method for producing an N-substituted amide represented by the general formula, [Formula] (wherein R ¹ , R ² , R ³ , R ⁴ and Ar are the same as above). A method for producing an N-substituted amide, characterized in that the reaction is carried out in the presence of an acid catalyst and a basic compound in the reaction system.