Unusual Reversal of Enantioselectivity in the Proline-Mediated α-Amination of Aldehydes Induced by Tertiary Amine Additives

Abstract

The renaissance in organocatalysis that was sparked by the List, Lerner, and Barbas 1 study of the proline-mediated aldol reaction has led to reports of a wide variety of electrophile/ nucleophile reactions catalyzed by a range of primary and secondary amines. 2 In addition to its efficiency in the archetypal aldol reaction, proline has also been shown to be effective in other enantioselective transformations thought to proceed via an enamine mechanism, including Mannich reactions, enamine addition to azo and nitroso groups, and conjugate addition to a number of different Michael acceptors.Additives such as water, acids, and bases have been shown to influence either or both reactivity and enantioselectivity in transformations catalyzed by amine-based catalysts. 3 Our recent studies suggest that the rate of proline enamine formation is enhanced in the presence of protic additives, without affecting product enantioselectivity, in the aminoxylation and -amination of propionaldehyde (Scheme 1). 3g We report here that addition of organic bases in the -amination of aliphatic aldehydes results in an intriguing reversal of product enantioselectivity as well as changes in the kinetic profile. The mechanistic implications of these findings are discussed in the context of contending models for the enantiodifferentiating step in enamine catalysis. Figure 1 compares reaction rate as a function of fraction conversion in the -amination of propionaldehyde with DEAD (Scheme 1) using fully solubilized proline 4 as catalyst both in the absence and presence of catalytic amounts of the organic base DBU. The kinetic profile is altered from the sigmoidal shape characteristic of this reaction to reveal initially positive order kinetics followed by a zero order regime. Strikingly, the presence of DBU induces a reversal of product enantioselectivity from 85% (R) to 46% (S). A similar reversal of enantioselectivity was observed with other tertiary amines, correlating roughly with pK a as shown in Figure 2. Interestingly, phosphazene bases of even higher pK a gave product ee values similar to DBU (P 1 -t Bu, 58% ee; P 2 -t Bu, 56% ee; BEMP, 57% ee). The strongest (and bulkiest) base tested, P 4 -t Bu, gave none of the reaction product 3a. Table 1 shows that this reversal of enantioselectivity holds for a range of aliphatic aldehydes (compare entries 7-12 to 1-6). The reaction product was stable to racemization when [DBU] did not exceed [4], although racemization is observed when DBU is mixed with the product in the absence of proline. 4 Product enantioselectivity in the presence of DBU was highest when the DBU: proline [4] ratio was ca. 0.9:1, while lower DBU concentrations gave the same trend but a less pronounced reversal of enantioselectivity. Addition of bases in enamine catalysis has not been been extensively studied, 3a,3h and to our knowledge an inversion of ee in the presence of base such as we observe here has not been reported previously. 5 The most significant conceptual role proposed for base additives comes from the work ...

Kinetischer Nachweis der Bildung von Oxazolidinonen im stereogenen Schritt prolinkatalysierter Reaktionen

“…Zusammen mit den Ergebnissen der Gruppen von Blackmond und Armstrong [4] stützen diese Daten die Annahme, dass im stereogenen Schritt von prolinkatalysierten Reaktionen die Bildung von Oxazolidinonen möglich ist, [3] vor allem wenn starke Basen zugegen sind. Unsere Ergebnisse tangieren nicht die Deutung der Stereoselektivitäten einer Vielzahl prolinkatalysierter Reaktionen durch ÜZ-A, wenn das effektive Nucleophil eine Enamincarbonsäure [1e, 20] und nicht ein Enamincarboxylat-Ion ist.…”

“…[4] Diese Umkehr wurde durch einen Wechsel von ÜZ-A zu ÜZ-C bei Anwesenheit tertiärer Amine erklärt, wobei der Angriff des Elektrophils am s-trans-Isomer des Enamincarboxylats I-2 erfolgt. Die Funktion der Carboxylatgruppe konnte jedoch nicht geklärt werden; sie soll entweder als sterisch abschirmende Gruppe wirken oder in Übereinstim-mung mit Seebach, Eschenmoser et al am Additionsschritt beteiligt sein.…”

“…Die Funktion der Carboxylatgruppe konnte jedoch nicht geklärt werden; sie soll entweder als sterisch abschirmende Gruppe wirken oder in Übereinstim-mung mit Seebach, Eschenmoser et al am Additionsschritt beteiligt sein. [4] Anchimere Unterstützung (Nachbargruppenbeteiligung) wurde bei einer Vielzahl von Reaktionen, z. B. bei solvolytischen Substitutionsreaktionen sowie elektrophilen Additionen und Eliminierungen, aus stereochemischen und kinetischen Untersuchungen abgeleitet.…”

Kinetic Evidence for the Formation of Oxazolidinones in the Stereogenic Step of Proline‐Catalyzed Reactions

“…In order to account for the observed stereoselectivities, it was assumed that TS-B (Scheme 1), which yields the more stable oxazolidinone, is favored over the stereoelectronically preferred TS-C. [3] Support for the involvement of the enamine carboxylate I-2 has recently been provided by Blackmond, Armstrong et al, who reported that the enantioselectivity of prolinecatalyzed reactions of aliphatic aldehydes with azodicarboxylates is reversed in the presence of tertiary amines. [4] This reversal was explained by a change from TS-A to TS-C in the presence of amines, where the attack of the electrophile occurs at the s-trans isomer of the enamine carboxylate. The role of the carboxylate group could not be clarified, however, and it was suggested that CO 2 À either acts as a steric blocking group, or in accordance with Seebach, Eschenmoser et al, participates in the addition step.…”

“…The role of the carboxylate group could not be clarified, however, and it was suggested that CO 2 À either acts as a steric blocking group, or in accordance with Seebach, Eschenmoser et al, participates in the addition step. [4] Traditionally, anchimeric assistance (neighboring-group participation) has been derived from stereochemical as well as kinetic investigations in a variety of reactions, e.g., solvolytic displacement reactions, electrophilic additions, and eliminations. [5] Owing to the conformational flexibility of the intermediate enamines stereochemical investigations did not provide unequivocal evidence for or against the formation of oxazolidinones in the stereogenic step.…”