Direct amidation of unprotected amino acids using B(OCH₂CF₃)₃

Abstract

A commercially available borate ester, B(OCH2CF3)3, can be used to achieve protecting-group free direct amidation of α-amino acids with a range of amines in cyclopentyl methyl ether. The method can be applied to the synthesis of medicinally relevant compounds, and can be scaled up to obtain gram quantities of products.

Cyclopentyl Methyl Ether: An Elective Ecofriendly Ethereal Solvent in Classical and Modern Organic Chemistry

“…A slightly modified procedure has successfully been applied to the direct amidation of unprotected amino acids with a range of amines; the lack of significant self‐reaction of the amino acid is a notable feature of this procedure, and good yields are obtained for the majority of the common proteogenic α‐amino acids and for several unnatural amino acids. Additionally, two anticonvulsant amino amides can be synthesized in good yields with good enantiomeric ratios (Scheme ) …”

“…Additionally,t wo anticonvulsant amino amides can be synthesized in good yields with good enantiomeric ratios (Scheme 71). [119] Finally,i n-depthi nvestigationb yA lbericioa nd co-workers is worth mentioning to highlight the reactionc onditions under which CPME (or,e ven better,2 -MeTHF) can be employed as a green alternative in peptide synthesis. After screening aw ealth of reaction conditions, including different coupling reagents, additives,and resins, the authors conclude that the best results for both solvents can be obtained by using N,N'-diisopropylcarbodiimide as ac oupling reagentw ith ethyl 2-cyano-2-hydroxyimino acetate (OxymaPure) as an additiveo n, preferably,p olystyrene or polyethyleneglycol resins.…”

Mechanistic insights into boron-catalysed direct amidation reactions

“… 6 Although a direct thermally accessible reaction is possible, direct amidation is better facilitated at lower temperatures by using catalysts, 7 with boron-based systems being particularly effective. 8 Useful catalysts for direct amidation include boric acid, 9 borate esters 10 and boronic acids. 11 – 13 Borinic acids have also been claimed to promote direct amidation reactions under relatively mild conditions.…”

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

“…We have recently reported the use of B(OCH 2 CF 3 ) 3 as an effective reagent for the direct synthesis of α‐amino amides from unprotected amino acids and excess amine. In most cases, the pure amino amide could be obtained using a solid phase workup to remove amino acid and boron compounds, followed by evaporation of the volatile components . All 20 common proteogenic amino acids (Table , entries 1–20) as well as six unnatural amino acids (entries 21–26) were evaluated in the reaction.…”