New and Efficient Synthesis of Amides from Acid Chlorides Using Diisobutyl(amino)aluminum

Abstract

Amides are valuable functional groups in biological, agrochemical, and pharmaceutical molecules. Several amides such as Weinreb amides, morpholine amides, and pyrrolidine amides are useful intermediates for the synthesis of aldehydes or ketones. Among them, morpholine amides are a cheap and good substitute for Weinreb amides. A large number of synthetic methods for making amides from various carboxylic acid derivatives have been reported. Among these, the aminolysis of acid chlorides in the presence of non-nucleophilic tertiary amines is generally considered to be the method of choice. Amides can also be synthesized using metals such as zinc, indium and samarium instead of tertiary amines from acid chlorides. Herein, we wish to report an alternative direct conversion of acid chlorides to secondary and tertiary amides (including morpholine amides), which proceeds under mild reaction conditions (0 °C) with an almost stoichiometric amount of amine and a short reaction time, and gives very good to excellent yields (Scheme 1). To demonstrate the feasibility of performing the desired reaction under a variety of conditions, we first carried out the synthesis of tertiary amides from benzoyl chloride. The corresponding morpholine amides could be obtained in 99% yield by reaction with benzoyl chloride under optimized reaction conditions in the presence of diisobutyl(morpholino)aluminum, which was easily prepared from morpholine and diisobutylaluminum hydride (DIBALH). The results are summarized in Table 1. We next synthesized various secondary and tertiary amides from other acid chlorides under the optimal conditions deduced from the previous experimental results. The results obtained for the reaction of benzoyl chloride with various primary and secondary amines are summarized in Table 2. As shown in Table 2, various noncyclic and cyclic primary amines underwent smooth conversion to the corresponding secondary amides in 90-99% yields (entries 1-5). Furthermore, the secondary amines also afforded the corresponding tertiary amides in 75-99% yields under similar reaction conditions (entries 6-10). From these results, we anticipated that the treatment of diisobutyl(morpholino)aluminum with representative acid chlorides would be effective for the direct synthesis of morpholine amides. Table 3 summarizes the results of the one-pot synthesis of morpholine amides from various acid chlorides. As expected, various aromatic acid chlorides with electronwithdrawing and electron-donating substituents underwent the conversion to the corresponding morpholine amides smoothly, in 89-99% yields (entries 1-7). A polyaromatic acid chloride such as naphthoyl chloride and a heterocyclic aromatic acid chloride such as furoyl chloride gave the corresponding morpholine amides in 92% and 91% yields, respectively, via the same methodology (entries 8 and 9). Furthermore, aliphatic acid chloride such as caproyl chloride smoothly afforded the corresponding morpholine amide in 96% under the same reaction conditions (entry 10). A proposed mechanism for this reaction is shown in Scheme 2 for the conversion of benzoyl chloride to the corresponding piperidine amide. Initially, the intermediate 2 is produced through the attack on the acid chloride by the secondary amino anion in diisobutyl(piperidino)aluminum 1 to give intermediate 3, with the release of an aluminum complex from intermediate 2. Finally, the hydrolysis of the Table 1. Optimization of reaction conditions for the synthesis of tertiary amides from acid chlorides