Mild, Metal‐Free and Protection‐Free Transamidation of N‐Acyl‐2‐piperidones to Amino Acids, Amino Alcohols and Aliphatic Amines and Esterification of N‐Acyl‐2‐piperidones

• Published in: European journal of organic chemistry 2019-06, Vol.2019 (22), p.3677-3686
• Main Authors: Subramani, Muthuraman, Rajendran, Saravana Kumar
• Format: Article
• Language: English
• Subjects: Alcohols; Aliphatic amines; Alkaloids; Amide alkaloid; Amide bond twist; Amides; Amines; Amino acids; Aromatic compounds; Biological materials; Carboxylic acids; Conjugation; Dopamine; Esterification; Glycine; High temperature; Hydroxyl groups; Imides; Natural products; Pharmaceuticals; Piperidones; Piperlongumine; Selectivity; Single crystals; Substrates; Synthesis; Transamidation
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201900517

Amides are indispensable building blocks of biological systems, pharmaceuticals, and materials. We report a highly selective method for the synthesis of amides via transamidation process. Transamidation of N‐acyl‐2‐piperidones with a broad range of amines is demonstrated under exceedingly mild and metal‐free reaction condition that relies on the amide bond twist to weaken the amidic resonance. Transamidation proceeds under the neat condition at room temperature, in short reaction times (30–90 min) with good yields. Considerable variation is tolerated with both amine and imide substrates. Of note, amines bearing carboxylic acids (glycine and serine) and hydroxyl groups (dopamine, tyramine, etc.) are well tolerated which are otherwise problematic under the metal‐catalyzed protocol. Our current method is applicable for transamidation of both alkyl and aryl‐N‐acyl‐2‐piperidones. The practical value of the method is highlighted by the synthesis of four natural product amide alkaloids in high yields under mild reaction conditions. In the absence of nucleophilic amines, N‐acyl‐2‐piperidones undergoes esterification with EtOH at elevated temperature. Single crystal X‐ray analysis of an N‐acyl‐2‐piperidone shows amide bond twist, τ = –20.39° and pyramidalization, χN = –11.73°. This weakens the amidic conjugation and might be the factor controlling the reactivity and selectivity of these imides. We envision that the N‐acyl‐2‐piperidone scaffold would be useful in the synthesis of pharmaceuticals and materials. A highly selective mild and metal‐free protocol for transamidation of N‐acyl piperidones to unprotected amino acids, amino alcohols and other aliphatic amines at short reaction times (30–45 min), with no additional base and at neat condition. Esterification of N‐acyl piperidones with aliphatic alcohols at 85 °C. Amide bond twist, τ = –20.39° and pyramidalization, χN = –11.73°.