An Umpolung Route to Amides from α‐Aminonitriles under Metal‐Free Conditions

Abstract

A metal-free, base-mediated decyanation of α-aminonitriles has been developed to synthesize secondary and tertiary amides using O 2 or air as an amide oxygen source. Radical scavenging studies disclosed that the cleavage of CÀ CN bond may proceed via an anionic pathway. The practicality of the work was also demonstrated through an in situ generated α-aminonitriles from corresponding aldehydes and amines to afford amides. The important features of this work include broad functional group compatibility, 41% to 89% product yields, gramscale synthesis of 2°and 3°amides, broad substrate scope, and an umpolung strategy.

Recent Advances in Carbon‐Nitrogen/Carbon‐Oxygen Bond Formation Under Transition‐Metal‐Free Conditions

“…For selected chiral α‐amino‐N‐aryl amides, no racemization/epimerization was observed with the complete conservation of configuration. In the same year, the Senadi group reported another amide synthesis approach based on the UmAS strategy via DBU/Et 3 N‐mediated decyanation of α‐aminonitriles ( 132 ) using O 2 or air as the amide oxygen source (Scheme 24b) [74b] . Both secondary and tertiary amides ( 134 ) bearing diverse functional groups were obtained in moderate to good yields.…”

Deoxygenative Hydroboration of Aromatic Nitro Compounds Catalyzed by Tetra(diisopropylamido) Rare-Earth Metal–Lithium Bimetallic Complexes

“…1 N-(4-Bromophenyl)enzamide (2d). 19 (1:1 v/v, PE/EA) white solid, 96 mg, yield 70%. 1 N-(4-(Trifluoromethyl)henyl)enzamide (2e).…”

“…1 N-(4-Tolyl)enzamide (2l). 19 (1:1 v/v, PE/EA) white solid, 56 mg, yield 53%. 1 H NMR (400 MHz, CDCl3): δ 7.85 (dd, J = 11.0, 9.7 Hz, 3H, ArH, NH), 7.53 (dd, J = 7.8, 3.1 Hz, 3H, ArH), 7.47 (t, J = 7.5 Hz, 2H, ArH), 7.17 (d, J = 8.3 Hz, 2H, ArH), 2.34 (s, 3H, ArCH 3 ) ppm.…”

FeCl3-Catalyzed Decyanative [4 + 2] Annulation of α-Aminonitriles with Alkynes: Access to 2,4-Diaryl Quinolines in Batch and Continuous-Flow Processes

“…9a On the other hand, α-aminonitrile, a versatile bifunctional intermediate with the ideal combination of amine and nitrile functionality, is a potential toolbox for synthesizing an array of pharmacologically relevant compounds. 11 The concept of reversal in polarity, also called umpolung strategy, brings about the carbanion by deprotonation of α-H of aminonitrile under basic conditions, and Lewis (Bronsted) acids promoted the loss of the cyanide anion to afford masked iminium equivalents which are known for a variety of synthetic transformations with appropriate coupling partners. 11 Our ongoing interest in exploiting α-aminonitriles prompted us further to study their multifaceted application in synthesizing aza-heterocycles.…”

“…11 The concept of reversal in polarity, also called umpolung strategy, brings about the carbanion by deprotonation of α-H of aminonitrile under basic conditions, and Lewis (Bronsted) acids promoted the loss of the cyanide anion to afford masked iminium equivalents which are known for a variety of synthetic transformations with appropriate coupling partners. 11 Our ongoing interest in exploiting α-aminonitriles prompted us further to study their multifaceted application in synthesizing aza-heterocycles. In our previous work, we developed a basemediated synthesis of amides from α-aminonitriles via an umpolung methodology, 11a and in this work, replacing the base with FeCl 3 as a Lewis acid resulted in the in situ generation of iminium ions followed by trapping with aryl acetylenes which produced 2,4-diaryl quinolines via decyanative [4 + 2] annulation in batch and continuous-flow processes (Scheme 1e).…”