Direct Amidation of Carboxylic
Acids Catalyzed by <i>ortho</i>-Iodo Arylboronic Acids: Catalyst Optimization, Scope, and Preliminary Mechanistic Study Supporting a Peculiar Halogen Acceleration Effect
The importance of amides as a component of biomolecules
and synthetic products motivates the development of catalytic, direct
amidation methods employing free carboxylic acids and amines that
circumvent the need for stoichiometric activation or coupling reagents. <i>ortho</i>-Iodophenylboronic acid <b>4a</b> has recently
been shown to catalyze direct amidation reactions at room temperature
in the presence of 4A molecular sieves as dehydrating agent. Herein,
the arene core of <i>ortho</i>-iodoarylboronic acid catalysts
has been optimized with regards to the electronic effects of ring
substitution. Contrary to the expectation, it was found that electron-donating
substituents are preferable, in particular, an alkoxy substituent
positioned para to the iodide. The optimal new catalyst, 5-methoxy-2-iodophenylboronic
acid (MIBA, <b>4f</b>), was demonstrated to be kinetically more
active than the parent des-methoxy catalyst <b>4a</b>, providing
higher yields of amide products in shorter reaction times under mild
conditions at ambient temperature. Catalyst <b>4f</b> is recyclable
and promotes the formation of amides from aliphatic carboxylic acids
and amines, and from heteroaromatic carboxylic acids and other functionalized
substrates containing moieties like a free phenol, indole and pyridine.
Mechanistic studies demonstrated the essential role of molecular sieves
in this complex amidation process. The effect of substrate stoichiometry,
concentration, and measurement of the catalyst order led to a possible
catalytic cycle based on the presumed formation of an acylborate intermediate.
The need for an electronically enriched <i>ortho</i>-iodo
substituent in catalyst <b>4f</b> supports a recent theoretical
study (Marcelli, T. <i>Angew. Chem. Int. Ed.</i> <b>2010</b>, <i>49</i>, 6840–6843) with a purported role for
the iodide as a hydrogen-bond acceptor in the orthoaminal transition
state