Direct amidation of non‐activated carboxylic acid and amine derivatives catalyzed by TiCp₂Cl₂

Abstract

This paper described a mild and efficient direct amidation of non‐activated carboxylic acid and amine derivatives catalyzed by TiCp2Cl2. Arylacetic acid derivatives reacted with different amines to afford the corresponding amides in good to excellent yield except of aniline. Aryl formic acids failed to react with aniline but smoothly reacted with aliphatic amines and benzylamine in moderate to good yield, fatty acids reacting with benzyl and aliphatic amines give amides in good to excellent yield. Chiral amino acids derivatives were transformed into amides without racemization in moderate yield. The possible mechanism of direct amidation catalyzed by TiCp2Cl2 was discussed. This catalytic method is very suitable for the amidation of low sterically hindered arylacetic acid, fatty acids with different low sterically hindered amines except aniline, as well as the amidation of aryl formic acid with benzyl and aliphatic amines.

Recent developments in catalytic amide bond formation

“…Huang and coworkers developed a variant of Adolfsson's hafnium catalyst, namely titanium (IV) bis(cyclopentadieneyl)bischloride. [85] It was found to be a competent catalyst, capable of amidating a variety of carboxylic acids including amino acids. However, it required the use of elevated temperature (70 C) and dehydrating agents.…”

“…Adolfsson [80] N 2 O 5 Toluene 40 50* None Shimizu [91] (NH 4 ) 2 Ce(NO 3 ) 6 Neat Microwave 2 None Markiewicz [92] NiCl 2 Toluene 110 10 None Huang [93] Ta(OMe) 5 Neat 40 10 None Yamamoto [94] TiCp 2 Cl 2 THF 70-80 10 4 Å M.S. Huang [85] TiO 2 Neat 100 36* None Cravotto [95] Zr [86] Zr-AzoBDC THF 70 2-10 4 Å M.S. Truong [96] ZrCl 4 THF 70 10 4 Å M.S.…”

A Simple and Cost-Effective FeCl3-Catalyzed Functionalization of Cellulose Nanofibrils: Toward Adhesive Nanocomposite Materials for Medical Implants

“…49,50 For the optimization of the catalytic direct amidation, benzylamine was used as the model molecule, a primary alkyl amine, which is frequently used as a nucleophile to validate new chemical conditions. 51 Initial experiments began with the screening of the reaction using FeCl 3 as the catalyst. Excitingly, as summarized in Table 1, the reaction employing 20 mol % of the catalyst in toluene at 110 °C (entry 2), resulted in the incorporation of benzylamine with a yield of 0.38 mmol benzylamine/g CNF.…”

“…Iron as catalyst has received attention because of its low cost, good reactivity, good stability under air, and nontoxicity . The reactions were carried out in toluene (PhMe) as solvent, which has been previously used for chemical modification of CNF. , For the optimization of the catalytic direct amidation, benzylamine was used as the model molecule, a primary alkyl amine, which is frequently used as a nucleophile to validate new chemical conditions …”

Methyltrimethoxysilane (MTM) as a Reagent for Direct Amidation of Carboxylic Acids

“…The direct amidation of carboxylic acids with amines is a topic of much ongoing interest, due to the importance of the amide bond in medicinal chemistry and in the pharmaceutical industry . State-of-the-art protocols include thermal amidations, boron-based catalysts and reagents, oxophilic transition metal catalysts, silicon-based reagents, and others . However, the search for a sustainable direct amidation reagent that is nontoxic, inexpensive, and widely available affording amide products in high yields with all acid–amine combinations and proceeds with an overall low process mass intensity (PMI) that avoids chromatography continues .…”