Catalytic amide formation with α′-hydroxyenones as acylating reagents

Abstract

Abstractα′-Hydroxyenones undergo clean, catalytic amidations with amines promoted by the combination of an N-heterocyclic carbene and 1,2,4-triazole.The ubiquity of amide-containing organic compounds coupled with the generally expensive and wasteful methods for their formation have engendered intense, recent efforts in the identification and development of catalytic methods for amide-bond formation. 1 The most attractive approach, the direct catalytic coupling of carboxylic acids and amines, 2 can be achieved with certain boronic acids as catalysts under conditions involving high temperatures2a,b or the use of molecular sieves. 2c Elegant work with transition metal catalysts has made possible the formation of amides from amines and alcohols, with the formation of H 2 as the only stoichiometric byproduct. 3 Chemoselective, reagentless amide-formations, are an exciting area for the synthesis of peptides and biomolecules, 4 but the need for specialized starting materials limits the utility of these processes for the synthesis of simple amides. 5 In seeking to develop simple, waste-free methods for the synthesis of carboxylic acid derivatives, we have advanced the concept of redox esterifications and amidations. 6 These reactions, promoted by N-heterocyclic carbenes, 7 proceed via transient activated carboxylates catalytically generated by internal redox reactions of α-functionalized aldehydes including epoxyaldehydes, 8 α-haloaldehydes, 9 formyl cyclopropanes, 10 and α,β-unsaturated aldehydes. 11 Such esterifications proceed smoothly in high yield without stoichiometric amounts of reagents or byproducts. The amidations, however, are often complicated by competing imine formation and proceed only in the presence of a suitable additive such as imidazole or HOAt. 12 Thus, while feasible, this redox amidation requires further refinement to improve the yields, catalyst loadings, and scope to impact the need for simple amidation reactions. In this communication, we report such an advance in the form of catalytic amidations of α′-hydroxyenones in the presence of a triazolium precatalyst and 1,2,4-triazole as a co-catalyst.The use of α′-hydroxyenones as substrates for NHC-catalyzed reactions stems from our recent studies on their use as surrogates for α,β-unsaturated aldehydes. 13 These starting materials are attractive due to their facile, one-step preparation from widely available starting materials, 14 their stability towards long-term storage, and their tendancy to be crystalline products. In contrast, the corresponding α,β-unsaturated aldehydes often require multi-step syntheses employing expensive and wasteful reagents. 15 We also recognized that the use of α′- NIH Public Access Author ManuscriptChem Commun (Camb) We were pleased to see that esterifications from alcohols and the α′-hydroxyenones proceeded smoothly, but initial attempts to extend this to amidations gave rise to only small amounts of the desired products. Reasoning that the use of a suitable co-catalyst was essential for the success of the amidation...

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes

“…178,206 A wide variety of aromatic and heteroaromatic substituents are tolerated as reaction partners for annulation with vinylogous amides. The product 3,4-dihydropyridinones are isolated in good-to-excellent yields (59–99%).…”

6.11 N-Acylation Reactions of Amines

“…Bode and coworkers subsequently found that α-hydroxyenones could be used as masked N-acylating agents for both primary and secondary amines using an NHC and 1,2,4-triazole as a cocatalyst (Figure 62(c)). 383 Addition of NHC to an α-hydroxyenone promotes a retro-benzoin reaction that releases acetone, with the resulting Breslow intermediate then undergoing an imidazole-mediated redox amidation reaction. In 2012, Yamada and coworkers employed an NHC catalyst in conjunction with N-chlorosuccinimide (NCS) as an oxidant in the presence of HOBT to form secondary and tertiary amides from unfunctionalized aldehydes.…”

“…389 The potential of this approach has been demonstrated further by Barbas Carbene catalyst Figure 62 NHC-mediated protocols for the catalytic redox N-acylation of amines. [381][382][383][384][385] and TBHP in ethyl acetate to prepare NHS esters in situ, which could be intercepted by amines to afford their corresponding amides in good yield. 390 Other protocols that are proposed to proceed via free-radical intermediates using aldehyde donors have also been developed, including catalytic systems such as FeCl 3 /TBHP, 391 and the use of diacetoxyiodobenzene in the ionic liquid BMIMBF 4 .…”

Exploiting Acyl and Enol Azolium Intermediates via N‐Hetero‐ cyclic Carbene‐Catalyzed Reactions of α‐Reducible Aldehydes

“…Further work in this area by the Bode group has revealed that α‘ -hydroxy enones 88 obtained from aldehydes are also competent substrates with substoichiometric quantities of 1,2,4-triazole to provide saturated amide products 84 in 47-99 % yield (Scheme 21, b). [31] The reaction proceeds through a retro-benzoin reaction catalyzed by 55 and base to liberate acetone and give the Breslow intermediate 91 (Scheme 21, c). This then continues to the redox pathway to provide product.…”