Borate esters: Simple catalysts for the sustainable synthesis of complex amides

Abstract

A commercially available borate ester catalyzes amide formation from carboxylic acids and amines with very high efficiency.

Protecting‐Group‐Free Amidation of Amino Acids using Lewis Acid Catalysts

“…Conveniently, 6aa is ap recursor to a marketed nootropic, Noopept, which can be accessed through af urther condensation employing our catalytic amidation conditions. [14] Glutamica cid also underwent successful cyclisation/ amidation with Ala-OtBu to give 6x in good yield. We were also ablet os ynthesize ab enzodiazepine derivative 8,w hich belongs to ac lass of anti-anxiolytic drugs,f rom 2-aminobenzophenonea nd l-Phei n5 2% yield, albeit under forcing conditions, which again led to an earf ull racemisation of the final product.…”

“…We have recently reported that the borate ester B(OCH 2 CF 3 ) 3 is an effective reagent for the direct synthesis of a-amino amides from unprotected amino acids and amines. [13,14] In this study,w eo utline the full scopeo fthed irect amidation of unprotected amino acidse mploying both stoichiometric and catalytic quantities of av ariety of boron Lewis acids as well as group(IV)m etal salts and "classical" coupling reagents.…”

“…Cp = 1,5-cyclopentadiene. Having recently developed am ethod for general amidation employing catalytic B(OCH 2 CF 3 ) 3 , [14] we wishedt oe xplore the applicability of this approach in the amidation of unprotected amino acids. In the optimisation of the general catalytic amidation reaction, we screened aw ide selection of organic solvents under Dean-Stark conditions and identified tert-amyl methyl ether (TAME) as as uitable alternative to CPME and PhMe, which crucially allows for azeotropic removal of water to be conducted at lower temperatures (86 8C).…”

“…In the optimisation of the general catalytic amidation reaction, we screened aw ide selection of organic solvents under Dean-Stark conditions and identified tert-amyl methyl ether (TAME) as as uitable alternative to CPME and PhMe, which crucially allows for azeotropic removal of water to be conducted at lower temperatures (86 8C). [14] Design of Experiments (DoE) reactiono ptimisation [18] was then conducted to understand the factorsp laying ar ole in the amidation of an unprotected amino acid,a nd to maximise the yield of product 3a and minimise the formation of diamide byproduct 4a,t he product of amidation of the amino acid with the desired amino amide product. The catalyst loading, amine loading and volumeo fs olvent used were investigateda sf actors (Scheme3).…”

Boron Ester‐Catalyzed Amidation of Carboxylic Acids with Amines: Mechanistic Rationale by Computational Study

“…developed an ovel amidation protocol that uses as imple, commercially availableb oron ester as the catalyst, safe solvents, and Dean-Stark apparatus (instead of additional drying reagents) to removet he water (Scheme 1). [14] The concentrations of substrates can reach 1 m.W ith this method, an unprecedented substrate scopeincludingfunctionalized heterocycles and even unprotecteda mino acids are compatible. Thek inetic study indicates that the amidation has positive dependences on the concentration of the borate ester catalyst( 0.8th order) and the carboxylic acids (0.5th order) but is independento fa mine concentration.…”