This paper reports that 1,8-Diazabicyclo[5.4.0]undec-7-ene has the function of catalyzing the amination reaction of acylimidazole compounds. Especially for the traditionally inactive, electron-deficient aniline compounds, DBU has obvious advantages in terms of safety and dosage compared with catalysts commonly used in the past, such as 1-hydroxybenzotriazole (HOBt).
N,N’-Carbonyldiimidazole (CDI) is commonly used in the synthesis of amide compounds from carboxylic acids and amines. In a one-pot reaction, usually activated by CDI, the carboxylic acid and CDI (1) are first stirred until the activated intermediate acylimidazole compound (2) is formed, followed by the addition of the amine to give the product (Scheme 1). Only harmless by-products—carbon dioxide and imidazole are produced in this process, which is an effective method for synthesizing amide compounds, especially widely used in the pharmaceutical industry.
Acyl imidazole compounds are generally more stable and easier to handle than the corresponding acyl chloride compounds, but due to their lower activity, a catalyst is usually added to react with sterically hindered carboxylic acids, amines, or weakly nucleophilic amines. Increase the reaction rate. Among them, the most commonly used catalyst is 1-hydroxybenzotriazole (HOBt, 3), which has considerable stability for improving the reaction rate, but due to its large amount in the reaction, it is easy to decompose and even has the danger of explosion, and it is not easy to transport, thus limiting its application. In recent years, some new catalysts have been studied and used (Figure 1), such as 2-hydroxy-5-nitropyridine (NO2-HOPyr, 4) and imidazole hydrochloride (Im.HCl, 5), compared with HOBt, They have the advantages of less dosage, easy operation and stability.
Traditionally, 1,8-Diazabicyclo[5.4.0]undec-7-ene has been considered as a non-nucleophilic base, but it is more effective in Baylis-Hillman reactions than conventional catalysts such as 1,4-diazacyclo[2,2,2]octane (DABOC) and 4 -Dimethylaminopyridine (DMAP) exhibits stronger nucleophilicity, and can react carboxylic acid with dimethyl carbonate to generate methyl ester compounds. Furthermore, amidines are also used to catalyze the acylation of acetic anhydride with secondary phenethyl alcohol. Based on the above findings and the authors’ experience, they envisage the use of 1,8-Diazabicyclo[5.4.0]undec-7-ene in catalyzing amination reactions that are usually slower after CDI activation.
It can be seen from the table that in the presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene, the acylation reaction rate of traditionally inactive, electron-deficient aniline compounds can be greatly improved, and the yield of the reaction is also greatly improved. The possible mechanism of the reaction is:
In summary, 1,8-Diazabicyclo[5.4.0]undec-7-ene is a safe and efficient catalyst for the amination of acyl imidazoles. For aliphatic amines or anilines, its catalytic acceleration effect is comparable to other known catalysts, especially for electron-deficient aniline compounds. Better than NO2-HOPyr and Im﹒ HCl. Although the stronger basicity of 1,8-Diazabicyclo[5.4.0]undec-7-ene can affect some substrates, it can still serve as a useful complement to existing catalysts.