JPS5944304B2 - Method for producing α-ketoamides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing α-ketoamides.

More specifically, the general formula RIX (wherein R1 is an alkyl group,
an organic halogen compound represented by the general formula HNR2R3 (R2 and R3 each represent an alkyl group, an aryl group, an aralkyl group, or a cycloalkyl group); , R2 and R3 may be the same or different, and R', R3 and the nitrogen atom may form a cyclic structure). and carbon monoxide in the presence of a catalytic amount of a palladium compound that does not contain phosphines or arsines, with the general formula R1-Co-Co-NR
The present invention relates to an improved method for producing α-ketoamides represented by 2R3 (wherein R1, R2, and R3 are the same as above). α-ketoamides are a group of compounds that are themselves important as intermediates in the production of medicines and agrochemicals. Moreover, these are useful compounds in that α-keto acids, which can be easily obtained by hydrolyzing them, are particularly important raw materials for producing amino acids. Although various methods for producing these α-ketoamides have been proposed, a method using a carbonylation reaction of bromobenzene has recently been proposed as a method for producing phenylglyoxylamide. That is, by reacting bromobenzene with diethylamine and carbon monoxide in the presence of a palladium phosphine complex, N,N
-Diethyl phenylglyoxylamide is obtained (Proceedings of the 42nd Spring Annual Meeting of the Chemical Society of Japan, IC42, Tokyo, 19
82). However, in the method proposed here, when a palladium complex of triphenylphosphine, which is inexpensive and frequently used, is used as a catalyst, a large amount of N,N-diethylbenzamide is produced in addition to the target phenylglyoxylamide derivative. It has the disadvantage that it is produced as a by-product. In addition, when a palladium complex of alkyldiphenylphosphine is used as a catalyst, the by-product of N,N-diethylbenzamide is suppressed to some extent, but this type of phosphine is expensive, and in addition to recovering palladium, separation of this phosphine is required. Special and complicated operations are required for recovery. In this way, the method using the carbonyl reaction of organic halides has the advantage that the desired α-ketoamides can be obtained in a single reaction from an inexpensive starting material phase, but it does not have the technical level to be able to be carried out industrially advantageously. had not been reached. The present inventors, in order to overcome the above-mentioned problems regarding the method for producing α-ketoamides by carbonylation reaction of organic halides,
As a result of intensive research, it was surprisingly found that in addition to palladium phosphine complexes, palladium compounds that do not contain phosphines or arsines, such as simple palladium metal, palladium salts, or palladium oxides, can be organically synthesized in the presence of secondary amines. The inventors have discovered the novel and interesting fact that carbonylation of halides can catalyze a reaction for producing α-ketoamides with high selectivity, leading to the present invention.

That is, according to the present invention, an organic halogen compound represented by the general formula RlX (wherein R1 represents an alkyl group, an aryl group, an alkenyl group, or a heterocyclic group, and X represents a halogen atom) and an organic halogen compound represented by the general formula HNR2R3 (R2, R3 represents an alkyl group, an aryl group, an aralkyl group, or a cycloalkyl group, and both R2 and R3 may be the same or different, and R2 and R3 and a nitrogen atom form a cyclic structure. A general method characterized by reacting a secondary amine represented by Formula R1-CO-CO
An improved method for producing α-ketoamides represented by -NR2R3 (wherein Rl9R2 and R3 are the same as above) is provided.

The outstanding feature of the present invention is that α-ketoamides can be easily obtained with high selectivity even by using easily available palladium compounds without using expensive phosphines.
This was surprising considering the conventional wisdom that a palladium phosphine complex was essential as a catalyst for the synthesis of a-ketoamides by carbonyl reaction of halogen compounds.

Examples of catalysts in this case include palladium salts such as palladium chloride, palladium bromide, palladium acetate, palladium acetylacetonate, palladium black, palladium/C1 palladium/SiO2, palladium/BaSO, palladium/Al2O3, etc. Examples include palladium itself or metal palladium with a carrier, palladium complexes that do not contain phosphines, such as dichlorbis(benzonitrile)palladium, and dibenzylideneacetone palladium. The organic halogen compounds R1XO)R1 that can be used in the practice of the invention are alkyl, aryl, alkenyl or heterocyclic groups.

Moreover, various polar substituents other than those having active hydrogen such as -0H group, -COOH group, and -NH2 group may be bonded to R1. Examples of substituents in this case include dialkyl-rmino groups, carbamoyl groups, acyl groups, alkoxy groups, alkoxycarbonyl groups, halogen atoms,
Examples include sulfonyl group, sulfinyl group, sulfenyl group, cyano group, amyloxy group, silyl group, nitro group, -L poxy group, formyl group, and the like. The halogen atom X includes iodine and bromine. Examples of organic halogen compounds include halobenzene derivatives such as iodobenzene, iodoanisole, iodotoluene, and p-cyanobromobenzene, halogenated alkyl derivatives such as iodomethyl, iodoethyl, and ethyl α-bromoacetate, iodoethylene, Examples include haloolefins such as β-bromustyrene, and heterocyclic halides such as 2-bromopyridine and 2-iodothiophene. The type of amine R2R2NH used in the present invention is not particularly limited as long as it is a secondary amine, and can be freely selected depending on the purpose.

Examples of the organic group represented by R2R3 in this case include alkyl groups such as methyl, ethyl, propyl, and butyl; cycloalkyl groups such as cyclohexyl; aryl groups such as phenyl and tolyl; basis,
Examples include a benzyl group and those having substituents introduced into these organic groups. Furthermore, piperidine and pyrrolidine can also be suitably used as secondary amines. However, in the reaction of the present invention, a normal acid amide RlCONR2R3, in which only one molecule of carbon monoxide is bonded to one molecule of organic halide, is produced as a by-product, but the amount of this acid amide by-product is amine R2R3NH(7). Since it varies greatly depending on the structure of R2 and R3, the target α-kedamide R1-C-C-NR2R3 is hydrolyzed to form R1-
In the case of obtaining C-C-0H, the type of amine should be selected in consideration of the ease of hydrolysis and the amount of by-product acid amide. The reaction in the present invention proceeds in the absence of a solvent or in a solvent, and suitable solvents include hexane, benzene, ether, tetrahydrofuran, hexamethylphosphotriamide, dimethylformamide, acetonitrile, acetone, alcohols, carboxylic acids, etc. Any commonly used solvent can be used as long as it does not serve as an active proton source. The reaction of the present invention can be carried out under the same conditions as ordinary carbonylation reactions.

The partial pressure of carbon monoxide depends on the type of catalyst used, and in general, a higher partial pressure is advantageous because it increases the yield of the target product, but if the partial pressure becomes too high, it has the opposite effect. It reduces the reaction rate and causes equipment disadvantages. Therefore,
In the case of the present invention, the partial pressure of carbon monoxide is below normal pressure to 200
The pressure is preferably in the range of 1 to 50 atmospheres. The carbon monoxide used may be diluted with an inert gas such as nitrogen or methane. The molar ratio of the organic halide and the amine is usually selected from the range of 50:1 to 1:500, even if either is in excess, the reaction will not occur. Another advantageous embodiment of the present invention is a method in which an amine is used in large excess to serve as a solvent. The amount of the catalyst used is not particularly limited, and is generally 1/10 mol or less, especially 1/30-1 mol, per 1 mol of the organic halide.
/1000 mol. Although the reaction of the present invention may proceed at room temperature depending on the structure of the organic halide, it may be heated up to 300° C. to obtain a preferable reaction rate.

In the reaction of the present invention, if the temperature is too high, the amount of simple carboxylic acid amide by-products will increase and further decomposition of the product will occur, so the preferred reaction temperature is selected within the range of room temperature to 200°C. To separate and purify the target α-ketoamides from the reaction solution obtained by the reaction of the present invention, salts produced by the reaction solution are first removed by solid-liquid separation means such as centrifugation or filtration, or by washing with water. After that, it can be carried out by subjecting it to a usual purification treatment such as distillation.

In the method of the present invention, a wide variety of organic halides and amines can be used, and various α-ketoamides can be obtained in good yields.

In addition, the reaction operation is easy because it does not require complicated operations and does not use reactive bases such as organic thirium or Grignard reagents, and not only can the desired α-ketoamides be easily obtained, but also phosphine Since these compounds are not used as catalyst ligands, there is no need to separate and recover them. Next, the present invention will be explained in detail based on examples.

Example 1 Inner volume 27m10) Palladium chloride (1.88X
10-2mm01), iodobenzene (4.0mm01
), diethylamine (3.0 mO), 20 mO at room temperature.
After introducing atmospheric carbon monoxide, the reaction was carried out at 60° C. for 84 hours.

The reaction solution was subjected to glass chromatography (column: SE3).
N,N-diethyl-2-
It was found that phenylglyoxylamide was produced at a yield of 80.5% and N,N-diethylbenzamide was produced as a by-product at a yield of 9.6%. Comparative Example 1 PhPdI (PPh
3) The reaction was carried out in the same manner as in Example 1 except that 2 was used. As a result, the yield of N,N-diethyl-2-phenylglyoxylamide was only 47.5%, and the yield of N,N-diethyl-2-phenylglyoxylamide was only 47.5%. The amount of benzamide by-product was 48.2% yield.

Comparative Example 2 The reaction was carried out in the same manner as in Example 1, except that PdCl2 (PEtPh2) was used instead of palladium chloride as a catalyst, and the yield of N,N-diethyl-2-phenylglyoxylamide was 71.1. Only %, N
, N-diethylbenzamide by-product amount reached 25.0%.

Examples 2 to 12 Table 1 summarizes the results of reactions of various halides and amines in the same manner as in Example 1 by changing the catalyst.

Claims (1)

[Scope of Claims] 1 An organic halogen compound represented by the general formula R^1X (wherein R^1 represents an alkyl group, aryl group, alkenyl group, or heterocyclic group, and X represents a halogen atom);
General formula NHR^2R^3 (R^2 and R^3 each represent an alkyl group, an aryl group, an aralkyl group, or a cycloalkyl group, and both R^2 and R^3 may be the same or different. or R^2, R^3 and a nitrogen atom may form a cyclic structure) and carbon monoxide are combined with phosphines or arsine. general formula R^1-C, characterized in that the reaction is carried out in the presence of a catalytic amount of a palladium compound not containing
O-CO-NR^2R^3 (in the formula, R^1, R^2, R
^3 is the same as above). 2. The method according to claim 1, wherein the organic halide is an organic iodo compound.