Chemoselective calcium-catalysed direct amidation of carboxylic esters

Abstract

carboxylic esters and primary amines undergo calciumcatalysed direct amide bond formation in excellent yields under homogeneous conditions in toluene. This green and mild reaction proceeds chemoselectively with esters, whereas related carboxylic acids and amides remain unreactive.Many highly useful transformations in organic chemistry are catalysed by transition metals, such as Ru, Rh, Ir, Os, Pt, Pd, Au, Cu, and Fe.1 Transition metal catalysis is no longer recognised as the most optimal method for generating organic compounds, mainly due to the increased toxicity, high cost and restricted accessibility of such catalysts. At present, however, basic transformations oen lack greener variations employing benign and cheap catalysts. Calcium, as one of the cheapest, most abundant and most non-toxic metals, is a particularly attractive candidate that could replace widely used transition metals.2 In the past decade, several calcium-catalysed reactions have been reported, most of them acting on alkenes, alcohols, or carbonylcontaining compounds. 3This work arises from our interest in developing novel catalytic amide bond formation reactions. Despite the ubiquitous presence of amides in nature, chemists' toolbox in making amides has remained more or less unchanged over the past decades. Synthetic methods still heavily rely on classical stoichiometric reactions between carboxylic acids and amines in the presence of diimide-based coupling reagents or transformations of acids into more reactive acyl chlorides, followed by reactions with amines.4 The reactions between carboxylic acids or carboxylic esters and amines lead to corresponding amides at elevated temperatures (>140 C) or under microwave conditions in the absence of any catalyst. 5 Catalytic variations of direct amide bond formations between commonly available carboxylic acids, esters or amides and amines have only recently been developed; these, however, generally require the presence of organocatalysts 6 or expensive and environmentally harmful transition metal catalysts.7 Herein, we report the development of chemoselective calcium-catalysed amide bond formation between unactivated carboxylic esters and primary amines.In order to develop a highly sustainable catalytic method for the formation of amides from readily available carboxylic esters and amines, we focused especially on the evaluation of cheap, non-toxic, and abundant metal salts as potential catalysts. Transition metals and rare earth metals have already been reported to catalyse direct amidation of esters into amides.8 We reasoned that simple alkali metals and alkaline earth metals might possess good catalytic properties for direct amidation of carboxylic esters. Alkali metal salts were observed to act as poor catalysts for the model reaction between methyl butyrate and benzylamine to yield N-benzyl butyramide in anhydrous toluene at 110 C in 4 hours; lithium, sodium, potassium, rubidium, and cesium salts afforded the amide in <40% conversions (Table 1). Alkaline earth metal salts have shown superior a...

Recent developments in catalytic amide bond formation

“…R = Alkyl in toluene with a variety of alkyl amines and could function at room temperature for select examples. [125] This method was capable of amidating protected amino acids and synthesizing the α-1 androgenic receptor antagonist alfuzosin. This work could serve as a cheap, green and atom economical option for the synthesis of simple peptide substrates if elaborated, especially if toluene could be replaced by a greener alternative such as p-cymene.…”

“…[132] F I G U R E 1 7 Tantalum catalyzed convergent peptide synthesis combining direct amidation of carboxylic acids with ester amidation. R 1,2,3,4,5 [125] La(OTf) 3 Toluene r.t.-70 2-5 Ethyl Ohshima [126] La[N(TMS) 2 ] 3 (μ-Cl)Li (THF) 3…”

Acetic acid as a catalyst for the N-acylation of amines using esters as the acyl source

“…6 Other more recent catalysts that couple esters and amines include BEMP, 7 K 3 PO 4 , 8 La(OTf) 3 , 9 NaOMe 10 and CaI 2 . 11 In addition to metal catalysts, non-metal compounds have also been found to catalyse amidation reactions successfully, with boronic acids and related compounds the most common examples.…”

Facile amidation of esters with aromatic amines promoted by lanthanide tris (amide) complexes

“…Moreover, this approach is superior to conventional methods with respect to that the sole byproduct is an alcohol. Some catalytic systems have been developed to promote this transformation, including inorganic bases (such as LiOH, K 3 PO 4 , NaOMe), organic catalysts (such as BEMP, 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD), DBU, 1,2,4‐triazole, NHCs,), enzyme, and metal complexes (such as Pd (IPr)(allyl)Cl, Ni (cod) 2 , La (OTf) 3 , Ru‐PNN, AlMe 3 , Zr complexes, Ln 2 Na 8 (OCH 2 CF 3 ) 14 (THF) 6, CaI 2 ). Nevertheless, further improvement is still required to expand the substrate scope and to realize the catalytic reaction under mild conditions.…”