Ultrasound‐Assisted Highly Efficient Synthesis of C‐Terminus Amidated Amino Acids and Peptides

This work reports a fast, sustainable, straightforward, and metal‐free advanced method for C‐terminus and side‐chain amidation of amino acids and peptides, utilizing isocyanates in 1–10 min. The reaction is performed under ultrasound‐assisted conditions in the presence of N , N ‐diisopropylethylamine (DIPEA). The protocol demonstrates broad substrate compatibility (>70 examples), high efficiency, and excellent yields (up to 96%). This protocol's key strengths include ultrashort reaction time, high‐purity products, favorable green chemistry metrics, gram‐scale synthesis, and its applicability to postsynthetic modification of bioactive peptides, exemplified by RGDS ( 7d ) and endomorphin‐2 ( 7e ).