Improved Gram-Scale Procedure for MIBA-Catalyzed Direct Amidation and Its Application to the Preparation of alpha and beta Peptides
Direct condensation between a carboxylic acid and amine must overcome the initial formation of a thermodynamically stable and unreactive carboxylate-ammonium salt, providing the amide product only at very high temperatures (over 160 o C) that are incompatible with many functionalized molecules. Currently, the most popular industrial methods of amide synthesis rely on activation of a carboxylic acid (using a coupling reagent such as a carbodiimide) and subsequent coupling of the activated
... with an amine. These methodologies suffer from inherent drawbacks such as low yields, racemization, degradation and difficult purification, thus making them expensive and wasteful. To address these challenges, numerous mild coupling reagents and methods have been developed that not only are high yielding, but that potentially help to prevent racemization of neighbouring stereogenic centres. The development of a mild and general direct amidation reaction is of great interest in organic synthesis and process chemistry. In the past decade, the use of boronic acids has emerged as a very useful and versatile tool for direct amidation at low temperatures. Driven by this goal, Hall and coworkers discovered the exceptional ability of orthoiodophenylboronic acid as a recoverable catalyst for direct amidations under mild and waste-free conditions at room temperature. A drawback of the initial optimal procedure is 126.96.36.199.2 Tridialkylboranes [BR 3 ], Trialkyloxyboranes [B(OR) 3 ] & Chlorodialkoxyboranes [ClB(OR') 2 ] 17 1.2.