Scope and Mechanism of a True Organocatalytic Beckmann Rearrangement with a Boronic Acid/Perfluoropinacol System under Ambient Conditions

Abstract

Catalytic activation of hydroxyl functionalities is of great interest for the production of pharmaceuticals and commodity chemicals. Here, 2-alkoxycarbonyl- and 2-phenoxycarbonyl-phenylboronic acid were identified as efficient catalysts for the direct and chemoselective activation of oxime N-OH bonds in the Beckmann rearrangement. This classical organic reaction provides a unique approach to prepare functionalized amide products that may be difficult to access using traditional amide coupling between carboxylic acids and amines. Using only 5 mol % of boronic acid catalyst and perfluoropinacol as an additive in a polar solvent mixture, the operationally simple protocol features mild conditions, a broad substrate scope, and a high functional group tolerance. A wide variety of diaryl, aryl-alkyl, heteroaryl-alkyl, and dialkyl oximes react under ambient conditions to afford high yields of amide products. Free alcohols, amides, carboxyesters, and many other functionalities are compatible with the reaction conditions. Investigations of the catalytic cycle revealed a novel boron-induced oxime transesterification providing an acyl oxime intermediate involved in a fully catalytic nonself-propagating Beckmann rearrangement mechanism. The acyl oxime intermediate was prepared independently and was subjected to the reaction conditions. It was found to be self-sufficient; it reacts rapidly, unimolecularly without the need for free oxime. A series of control experiments and O labeling studies support a true catalytic pathway involving an ionic transition structure with an active and essential role for the boronyl moiety in both steps of transesterification and rearrangement. According toB NMR spectroscopic studies, the additive perfluoropinacol provides a transient, electrophilic boronic ester that is thought to serve as an internal Lewis acid to activate the ortho-carboxyester and accelerate the initial, rate-limiting step of transesterification between the precatalyst and the oxime substrate.

Brønsted Acid and H‐Bond Activation in Boronic Acid Catalysis

“…Boronic acids have emerged as a promising class of catalysts that enable dehydrative nucleophilic substitution or rearrangements of alcohols, Beckmann rearrangement of oximes, and various reactions involving either carboxylic acids or epoxides under mild conditions. In depth studies into the catalytic mechanism have been performed in the case of carboxylic acids, whereas only preliminary mechanistic evidence exists for the reactions of alcohols and oximes . The arylboronic acid catalyst systems required for reactions involving alcohols and oximes ( B1 – B3 , Scheme ) are substantially more electrophilic than those used for the activation of carboxylic acids, the former requiring either multiple electron‐withdrawing groups, cationic boronic acids or complexation with highly electronically deactivated diols.…”

Visible Light‐Promoted Beckmann Rearrangements: Separating Sequential Photochemical and Thermal Phenomena in a Continuous Flow Reactor

“…Ortho ‐substituted acetophenone oximes ( 1e , 1h and 1l ) provided lower yields compared to their meta and para isomers, since the formation of a highly solvated intermediate is disfavored by the steric hindrance. Although these oximes ( 1e , 1h and 1l ) were isolated as mixture of E ‐ and Z ‐isomers (NMR spectra are collected in the Supporting Information), which in principle might lead to a mixture of the N ‐methyl and N ‐phenyl amide products, a single product ( N ‐phenyl) was obtained in all cases. This is most likely due to E/Z isomerization under the reaction condition…”

“…Apart from the well‐established methods mentioned above, many endeavors have been devoted to achieving Beckmann rearrangements under more benign and controllable conditions. These procedures include the use of boronic acid catalysts or radical pathways induced by (NH 4 ) 2 S 2 O 8 /DMSO . Several examples of photochemical Beckmann rearrangements were reported in the 1960s and 1970s using UV‐C irradiation .…”

SO2F2‐Activated Efficient Beckmann Rearrangement of Ketoximes for Accessing Amides and Lactams

“…Most notably, the self‐propagation mode of “organocatalytic” Beckmann rearrangements, as elegant studies, is activated by organic promoters, such as cyanuric chloride, chlorocyclopropenium, and dichloroimidazolidinediones . Intriguingly, a boronic acid were identified as an efficient catalyst for the activation of oximes . Other amusing variants, such as a facile radical (Scheme c) and visible‐light‐driven (Scheme d) Beckmann rearrangements,, also provides alternative strategies.…”