Smiles Cascades toward Heterocyclic Scaffolds

Abstract

Two different Smiles rearrangements can be combined to afford a multicomponent formation of isoquinolinones and isoindolinones from nitro methyl salicylate. After a Ugi-Smiles four-component coupling, the base-triggered cyclization of the resulting adduct is followed by a ring contraction via a Truce-Smiles rearrangement.

The Truce–Smiles rearrangement and related reactions: a review

“…It could be argued that the ring contraction reactions observed as part of the tandem Ugi-SmilesTruce-Smiles reactions reported by El Kaim and colleagues are specially favoured by stable conformations accessible to the bicylic substrate, formed in situ, that are not easily accessed by typical acylic substrates. 47 Dudley and colleagues favour a hypothesis involving the intermediacy of an ionic benzyllithium species for their reported 1,2-aryl migration of 2-benzyloxypyridines, in keeping with the intramolecular S N Ar mechanism of the TruceSmiles rearrangement. However, they also concede that a radical mechanism, in keeping with the [1,2]-Wittig reaction, cannot be entirely ruled out.…”

“…Researchers have typically chosen to prepare an aryl ether substrate by Williamson ether synthesis 30,31,[44][45][46] or an aniline substrate, 47,48 with judicious choice of a base that can subsequently form the carbanion intermediate to instigate the TruceSmiles rearrangement. In one unusual example 43 (Scheme 7), a benzyne intermediate is used to form the sulfonamide bond linking the nucleophilic and electrophilic portions of the substrate 14 with concurrent production of the carbanion nucleophile.…”

“…Substrates featuring X = N may be anilides, 48,100 isolated as the less substituted amide or trapped by an electrophile, 52 or alternatively anilines, 47 isolated as the amine. One unusual example 101 of a substrate was a N-arylated pyrrole, 105, that yielded the N-unsubstituted pyrrole, 107, on rearrangement (Scheme 33).…”

Application of heterocyclic aldehydes as components in Ugi–Smiles couplings

“…Multicomponent coupling reactions (MCRs) have been combined with IMDA approaches to efficiently increase molecular complexity [14] and prepare complex molecular scaffolds for the synthesis of natural products [15–16]. While the Ugi–Smiles condensation has generally found success in cascade processes [17–19], the intolerance of heterocyclic aldehyde components has prevented use with common IMDA strategies.…”

Benzoxazinone synthesis via Passerini–Smiles couplings

“…6 Following our disclosure of Ugi-Smiles 7-9 and Passerini-Smiles 10 couplings (extensions of the Ugi and Passerini reactions replacing carboxylic acids by phenols), we mainly focused our efforts on synthetic applications of the more diverse Ugi-Smiles reaction. [11][12][13][14][15][16][17][18][19][20] The potential of the Passerini-Smiles coupling was neglected until we decided recently to re-examine the reaction. Our initial conditions for the Passerini-Smiles reaction suffered from a lack of reproducibility and a quite limited scope.…”