Synthesis of secondary and tertiary amides without coupling agents from amines and potassium acyltrifluoroborates (KATs)

Abstract

Although highly effective for most amide syntheses, the activation of carboxylic acids requires the use of problematic coupling reagents and is often poorly suited for challenging cases such as N-methyl amino acids. As an alternative to both secondary and tertiary amides, we report their convenient synthesis by the rapid oxidation of trifluoroborate iminiums (TIMs). TIMs are easily prepared by acid-promoted condensation of potassium acyltrifluoroborates (KATs) and amines and are cleanly and rapidly oxidized to amides with hydrogen peroxide. The overall transformation can be conducted either as a one-pot procedure or via isolation of the TIM. The unique nature of the neutral, zwitterionic TIMs makes possible the preparation of tertiary amides via an iminium species that would not be accessible from other carbonyl derivatives and can be conducted in the presence of unprotected functional groups including acids, alcohols and thioethers. In preliminary studies, this approach was applied to the late-stage modifications of long peptides and the iterative synthesis of short, N-methylated peptides without the need for coupling agents.

Fig. 1. Amide-forming reaction with potassium acyltrifluoroborates (KATs) and amines via trifluoroborate iminiums (TIMs). (a) Traditional amide coupling methods using coupling reagents. (b) Formation of TIMs and oxidative conversion to amides.

Scheme 1. Substrate scope for the amide formation from trifluoroborate iminiums (TIMs). The yields are isolated yields. ^a Reaction time of 2 h.

Scheme 2. Substrate scope for the one-pot amide formation from potassium acyltrifluoroborates (KATs) and scale-up experiment. The yields are isolated yields. ^a Yield for the reaction at 3.0 mmol scale instead of 0.2 mmol scale.

Scheme 3. Preliminary studies toward solid-phase peptide synthesis (SPPS) using KAT amino acids as monomers. (a) Schematic representation of the application of KATs in SPPS. (b) Model synthesis of a peptide on solid support via TIMs. Conversion was determined by Fmoc loading test and HPLC analysis after cleavage from the resin.

Scheme 4. Application of the trifluoroborate iminium (TIM) formation and subsequent oxidation for the modification of different peptides. (a) Modification of a GLP-1 analogue with different KATs. (b) Modification of a peptide containing methionine. (c) Modification of a proline residue in a peptide.

Scheme 5. Possible mechanisms for the oxidative amide formation from trifluoroborate iminiums (TIMs).