Sequential Metal-Free Thermal 1,3-Dipolar Cycloaddition of Unactivated Azomethine Ylides

Abstract

The thermal 1,3-dipolar cycloaddition of unactivated azomethine ylides derived from allylamine and aromatic or heteroaromatic aldehydes with maleimides and 1,1- and 1,2-bis(phenylsulfonyl)ethylene affords endo-2,5- trans cycloadducts in moderate to good yields. DFT calculations provide evidence that the diastereoselectivity observed depends on the isomerization between S- and W-ylides according to Curtin-Hammett's principle. DFT calculations also explain the different diastereomeric ratio observed for 2-pyridyl and 2-thienyl derivatives in which the isomerization is not possible due to the competitiveness between isomerization barrier and the rate-limiting step (ylide formation barrier). This methodology is applied to the diastereoselective synthesis of a tricyclic thrombin inhibitor.

The Crucial Role of S‐oxidation State on the Selectivity and Reaction Rate of the 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Homochiral Thiazolines

“…Although thermic activation is a known methodology for the 1,3-dipolar cycloaddition of azomethine ylides since several years ago [59][60][61] this methodology has been scarcely applied in the last years. [62][63][64] Surprisingly, the outcome of the reaction by thermic activation between thiazoline 1 b and α-imino ester 2 was better than expected. Thermic activation gave higher yields than metal activation in a highly diastereo-enantio-and regioselective way, giving solely the endo isomer from a 2,3-addition by the opposite face of the bulky tert-butyl group and syn to the oxygen attached to the sulfur atom starting from thiazoline 1 b (Table 2, entry 1).…”

Synthesis of Spiro{pyrrolidine‐3,1′‐pyrrolo[3,4‐c]pyrrole} Basic Framework by Multicomponent 1,3‐Dipolar Cycloaddition

“…It was clear that starting from preformed imine 6 a the reaction proceeded to give cycloadduct 4 upon heating at 120 °C, but the reaction was cleaner by mixing allylamine and benzaldehyde first and followed by the addition of maleimide. In this case, the formation of the imine 6 a occurred preferentially (Scheme 4a) [8] . This imine did not give the expected spirocyclic compound 5 a after reaction with 2 equiv.…”

“…More sophisticated structure 10 , with another condensed cycle, could be achieved from spirocycloadduct 5 l after ring‐closing metathesis reaction employing the Hoveyda‐Grubbs’ catalyst (1 mol%) in refluxing dichloromethane for 4 h. This catalyst was also employed by our group [8] in the synthesis of biologically active compounds [15] . The crude product was very clean and the purification (flash chromatography) gave almost quantitative yield (91 %) (Scheme 6).…”

“…[7] The ability to generate azomethine ylides using several routes open new perspectives to run efficiently this domino processes. During our study of MC-thermal 1,3-DC of unactivated azomethine ylides derived from allylamine 1 a and aromatic or heteroaromatic aldehydes 3 with maleimides 2, affording endo-2,5-trans-cycloadducts 4 (Scheme 1a), [8] we observed the generation of an unexpected major product (impurified with its corresponding adduct 5) when cinnamaldehyde was employed as aldehyde. This structure obeyed to the general pattern assigned for compound 5 (Scheme 1b).…”

Multilayer graphene functionalized through thermal 1,3-dipolar cycloadditions with imino esters: a versatile platform for supported ligands in catalysis

“…Concerning the stereoselectivity of the reaction, the relative configuration of C2 and C5 in the proline cycloadduct was not confirmed ( Table 2). The normal trend of this mechanism predicts a 2,5-cis arrangement as a consequence of the existence of the intermediate W-shape 1,3-dipole, [35] but in many other examples, performed at higher temperatures (e.g. 150-160 ºC), the presence of 2,5-trans arrangement was also favored.…”