JPH0129181B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a Michael adduct from an α,β-unsaturated carbonyl compound and an active methylene compound, and more specifically, a method for producing a Michael adduct from an α,β-unsaturated carbonyl compound and an active methylene compound by controlling the reaction temperature. This invention relates to a method for efficiently producing Michael adducts. Michael adducts are synthesized from α,β-unsaturated carbonyl compounds such as α-alkylcyclopentenone and crotonic acid esters and active methylene compounds such as malonic acid diesters.
It is an important substance as a synthetic intermediate for aromatic substances, physiologically active substances, etc. There have been many reports on the synthesis method of such Michael adducts. For example, in Tetrahedron Letters, Vol. 26, p. 1331, 2-dialkyl-3-acetyl-4-cyclopentenone and diethyl malonate A method has been described in which the reaction is carried out at room temperature in the presence of a sodium ethoxide catalyst, but the yield is low in both cases. Also, Journal of American Chemical Society No. 52
Volume 4598 describes a method of reacting crotonic acid ester and dimethyl malonate at about 40°C in the presence of a sodium ethoxide catalyst, and in this case, the desired product was obtained with a yield of 91.7%. However, the reaction takes a long time of 5 hours. As described above, according to the conventional methods, it is difficult to obtain the desired Michael adduct in a short reaction time and in a high yield, and an improvement thereof has been strongly desired. Therefore, the present inventors conducted intensive studies to improve this drawback of the conventional technology, and as a result, they focused on the fact that the Michael addition reaction between an α,β-unsaturated carbonyl compound and an active methylene compound is an equilibrium reaction, and discovered that The inventors have discovered that it is extremely effective to gradually lower the reaction temperature within the system, and have completed the present invention. Thus, according to the present invention, when producing a Michael adduct by reacting an α,β-unsaturated carbonyl compound and an active methylene compound in the presence of a basic catalyst, the temperature in the system is adjusted continuously or intermittently during the reaction. Provided is a method for producing a Michael adduct, which is characterized in that the reaction is continued while decreasing the temperature. The α,β-unsaturated carbonyl compound used in the present invention is not particularly limited as long as it is commonly used as a raw material for Michael adducts, and a specific example thereof is 2-methyl-2-cyclopene. tenone, 2-pentyl-2-cyclopentenone, 2-hexyl-2-cyclopentenone, 2-
Cyclic ketones such as heptyl-2-cyclopentenone, 2-alkyl-2-cyclohexenone, 2-pentenylmethylketone, 2-hexenylmethylketone, 2-heptenylmethylketone,
Examples include chain ketones such as methyl vinyl ketone, and carboxylic acid esters such as methyl acrylate, methyl methacrylate, and ethyl chromenate. These α,β-unsaturated carbonyl compounds can be easily obtained by conventionally known methods, for example, 2
-2-Alkyl-2-cyclopentenone can be easily synthesized by treating -alkylidenecyclopentanone in the presence of an acid catalyst. Examples of active methylene compounds include esters such as dimethyl malonate, diethyl malonate, ethyl 2-oxocyclopentanecarboxylate, 2-methylcyclopentanone, 2-methylcyclohexanone, 2-methyl-3-hydroxy-
Examples include ketones such as 2-cyclopentenone and nitriles such as malondinitrile. Although the present invention is not limited to these starting materials, among these, 2-alkyl-2-cyclopentenone is used as the α,β-unsaturated carbonyl compound, and carboxylic acid esters or ketones are used as the active methylene compound. Among them, particularly good results are obtained when malonic acid ester is used. The active methylene compound is used in a proportion of usually 0.1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the α,β-unsaturated carbonyl compound. On the other hand, the catalyst used in the present invention may be a basic catalyst commonly used in Michael addition reactions, and specific examples thereof include sodium methylate, sodium ethylate, potassium tert-butoxide, potassium hydroxide, sodium hydroxide, Examples include alkali catalysts and amine catalysts such as sodium hydride, sodium amide, and triethylamine. The ratio of the catalyst to the α,β-unsaturated carbonyl compound to be used is usually 0.005 to 1.0 mol, preferably 0.02 to 0.2 mol of the catalyst per 1 mol of the α,β-unsaturated carbonyl compound; The yield tends to decrease when the amount is below . Furthermore, if too much catalyst is used, the loss of unreacted raw materials increases during catalyst treatment after the reaction. The Michael addition reaction in the present invention is α,β-
The reaction is carried out by contacting an unsaturated carbonyl compound and an active methylene compound in the presence of a basic catalyst and an optionally inert diluent. It is necessary to maintain the temperature at the start of the reaction as high as possible within a range that allows the formation of by-products, and this temperature is usually 10 to 60°C, preferably 20 to 40°C. At this time, if the temperature is too high, by-products will increase, and on the other hand, if the temperature is too low, the reactivity will decrease. In the present invention, it is necessary to lower the temperature in the system continuously or intermittently during the course of the reaction after the reaction has started. Here, the term "in the middle of the reaction" refers to the stage when the reaction has reached an equilibrium state, that is, the stage when the reaction is close to equilibrium to the stage after some time has elapsed after reaching equilibrium. Note that the equilibrium conditions for each reaction can be easily confirmed through preliminary experiments. The temperature within the system at the end of the reaction is appropriately selected depending on the desired reactant, but is usually -30 to 20°C, preferably -15 to 5°C. Thus, according to the present invention, the desired Michael adduct can be obtained in a short time and in good yield. The present invention will be explained in more detail with reference to Examples below. Note that parts in Examples and Comparative Examples are based on weight. Comparative Example 1 2.0 parts of sodium methoxide was dissolved in 40 parts of methanol, 140 parts of dimethyl malonate was added at 20°C, and the solution was heated at a constant temperature (-10°C,
(40°C and 70°C). Furthermore, 98 parts of 2-pentylcyclopentenone was added at the same temperature with stirring, and the mixture was reacted for 5 hours. After the reaction was completed, 40 parts of 3% hydrochloric acid was added and stirred, and after neutralization, two layers were separated. The organic layer was distilled under reduced pressure to obtain a fraction of 135-140°C/0.5 mmΗg. Gas chromatography, infrared absorption spectrum, mass spectrum, and NMR spectroscopy confirmed that this fraction was dimethyl 2-n-pentyl-3-oxocyclopentylmalonate. The results are shown in Table 1.

[Table] Example 1 2.0 parts of sodium methoxide was dissolved in 40 parts of methanol, and after adding 140 parts of dimethyl malonate at 20°C, the mixture was heated to 40°C. then 98
of 2-pentylcyclopentenone was added with stirring, and the mixture was reacted for 1.5 hours. In this state, the reaction had almost reached an equilibrium state. Next, the reaction solution was continuously and gradually cooled to -10°C at a rate of 25°C per hour while stirring to continue the reaction. After the reaction is complete,
Dimethyl 2-n-pentyl-3-oxocyclopentylmalonate was prepared in the same manner as in Comparative Example 1.
172 parts (yield 94%) were obtained. The time from the start of the addition of pentylcyclopentenone to the end of the reaction was 3.5 hours. Example 2 140 parts of dimethyl malonate was added to a methanol solution of sodium methoxide prepared in the same manner as in Example 1, and then 98 parts of 2-pentylcyclopentenone was added with stirring at 40°C for 1.5 hours. A stirring reaction was performed. At this stage, the reaction had almost reached equilibrium. Next, the reaction solution was cooled to 20°C and the reaction was continued for 0.5 hours, then cooled to 5°C for 0.5 hours, then cooled to -5°C for 0.5 hours, and further cooled to -10°C and stirred for 0.5 hours. continued.
After the reaction, 2-
170 parts of dimethyl n-pentyl-3-oxocyclopentylmalonate (yield 93%) was obtained. The time from the start of the addition of pentylcyclopentenone to the end of the reaction was 4.5 hours. Example 3 2.0 parts of sodium methoxide were dissolved in 40 parts of methanol and 140 parts of dimethyl malonate were added at 20°C. The solution was then heated to 40°C and 65 parts of methyl crotonate was added with stirring. When the stirring reaction was carried out at the same temperature for 30 minutes after the addition, the reaction had almost reached equilibrium. Next, the reaction solution was continuously cooled to -5°C at a rate of 30°C per hour to continue the reaction. After the reaction, 144 parts of dimethyl 1-methyl-2-methoxycarbonylethylmalonate (yield
95%). The time from the start of addition of methyl crotonate to the end of the reaction was 2.25 hours.

Claims (1)

[Claims] 1. When producing a Michael adduct by reacting an α,β-unsaturated carbonyl compound and an active methylene compound in the presence of a basic catalyst, the temperature in the system is continuously or intermittently lowered during the reaction. ,
A method for producing a Michael adduct characterized by continuing the reaction.