Efficient Continuous-Flow Benzotriazole Activation and Coupling of Amino Acids

Abstract

Despite extensive research into peptide synthesis, coupling of amino acids with weakly nucleophilic heterocyclic amines remains a challenge. The need for microwave technology to promote this coupling interferes with the scalability of the process. By applying the microwave-to-flow paradigm, a library of (α-aminoacyl)amino-substituted heterocycles was continuously produced at near quantitative conversions and the reaction was scaled up successfully. Various N-Cbz-protected amino acids were activated using BtH/SOCl 2 under continuous-flow conditions with excellent yields. Their coupling with heterocyclic amines was accomplished in MeCN-NMP on a preparative scale. However, performing both steps in-line resulted in an inconvenient work-up. Therefore, a two-step approach was taken, isolating the intermediate Bt-activated amino acid via simple filtration. This allows for a solvent switch to DMSO for the coupling reaction which led to excellent conversions for a broad range of substrates.

Safe, Selective, and High‐Yielding Synthesis of Acryloyl Chloride in a Continuous‐Flow System

“…Katritzky et al. developed the benzotriazole method for the synthesis of N ‐acylbenzotriazoles as an alternative for acid chlorides, which can also be produced in flow . In this study, the scope of both the oxalyl chloride and the thionyl chloride methods was widened for other substrates.…”

A simple and versatile method to synthesize N-acyl-benzotriazoles

“…N-Protected a-aminoacyl-benzotriazoles were also used to efficiently access a-diazo-b-keto esters, phosphonates and sulfones via acylation of the corresponding diazomethyl anions [15], as well as to acylate oximes [16]. Recently, a two-step approach was proposed to efficiently produce a-aminoacyl-aminosubstituted heterocycles by applying the microwave-to-flow paradigm [17]. Interestingly, the benzotriazole ring cleavage of N-acyl-benzotriazole derivatives in the presence of Bu3SnH under free radical conditions resulted in the production of the corresponding N-phenylamides [18].…”

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

“…The coupling of carboxylic acids with amines in flow through a benzotriazole activation [19], or with immobilized reagents as for the synthesis of grossamide [20] is already known. However, we wanted to use m -(chlorosulfonyl)benzoyl chloride since this can be synthesized in one single step.…”