Conjugate‐Base‐Stabilized Brønsted Acids as Asymmetric Catalysts: Enantioselective Povarov Reactions with Secondary Aromatic Amines

Abstract

Triggered largely by the seminal studies of Akiyama et al. [1] and Uraguchi and Terada [2] nearly a decade ago, the field of asymmetric Brønsted acid catalysis has experienced rapid growth. [3] Chiral phosphoric acids in particular have enabled an ever increasing number of asymmetric transformations. [3] In a continuing trend, catalysts that surpass the acidity of phosphoric acids are being prepared for the purpose of activating moderately basic substrates through asymmetric ion-pairing catalysis. [3,4] Cooperative approaches in which a Brønsted acid acts in concert with either another Brønsted acid [5] or with a (thio)urea catalyst [6] have emerged and hold exceptional promise. [7] Intriguing applications of asymmetric cooperative Brønsted acid catalysis have been reported by Jacobsen and co-workers who have demonstrated that a combination of achiral Brønsted acids and chiral (thio)urea catalysts can enable a range of enantioselective transformations. [8] The main role of the (thio)urea catalyst is to act as a chiral anion receptor for the Brønsted acids conjugate base. [4,9,10] Herein we introduce a complementary concept for asymmetric Brønsted acid catalysis which merges certain features of previous approaches while perhaps offering some unique advantages.As illustrated in Figure 1, we envisioned a new type of chiral Brønsted acid in which the acidic site of the catalyst is connected by an appropriate linker to an anion receptor moiety such as a thiourea. [11][12][13] Upon substrate protonation, the conjugate base associates with the anion recognition site, [14] thus resulting in the formation of a substrate/catalyst ion pair of type I. Alternatively, the catalyst could facilitate the condensation of two different substrates to result in an ion pair of type II. While the anion may still interact with the substrate through hydrogen bonding in the type I ion pair, [15] hydrogen bonding between the ions should be reduced markedly in the type II ion pair, thus resulting in strict ion pairing. [4j] Importantly, both types of ion pairs feature a rigid anion which should facilitate an efficient transfer of chirality.While a range of acidic groups, XH, may be linked to an anion recognition site, we were particularly intrigued by the idea of using simple carboxylic acids. Although there are notable exceptions, in particular the prominent work of the Maruoka group, chiral carboxylic acids have not yet found widespread applications as asymmetric Brønsted acid catalysts. [16] This is likely because carboxylic acids are ultimately limited by their relatively weak acidities, thus restricting the number of substrates which can be activated. The propensity of carboxylate to engage in hydrogen bonding with a protonated substrate also reduces the potential level of substrate activation, as this interaction lowers the electrophilicity of the protonated species. Internal stabilization of the conjugate base (e.g., carboxylate) should circumvent both of these problems. Firstly, anion binding to the conjugate base is expected to lo...

Chiral Thioureas Promote Enantioselective Pictet–Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction

“…63,64 We hypothesize that the resulting complex exhibits increased acidity relative to free benzoic acid and thus contributes to substrate activation en route to product formation, as proposed in the catalytic cycle outlined in Scheme 2. Consistent with this analysis, added tetrabutylammonium benzoate (NBu 4 OBz), which forms a much stronger complex with thiourea 1a (Figure 2C), 34,49,51,52,65–80 inhibits the reaction. This inhibition is also of significance given that the secondary amine product of the Pictet–Spengler reaction is substantially more basic than the imine substrate, 81,82 thereby introducing the potential for formation of a similarly counterproductive ammonium benzoate complex during the course of the reaction (Scheme 2, step V).…”

Influence of the Substitution and Conformation of CH‐Bond‐Based Bis‐Triazole Acceptors in Anion‐Binding Catalysis

“…[8] On the contrary, in our bis-triazole family, BisTri3 (K acetone = 458 AE 45 m À1 ) shows a higher binding affinity to chloride than BisTri12 (K acetone = 152 AE 18 m À1 ). The relative chloride-binding affinity of BisTri3 and its triazole regioisomer BisTri12 was first examined.…”

“…H 2 O (30 mL) was added and the resulting mixture was extracted with Et 2 O (3 30 mL), dried over Na 2 SO 4 , and the solvent removed under reduced pressure. 1 mL mmol À1 ), and directly used in situ as 3,5-bis(trifluoromethyl)phenyl azide (8). Relative DG 298 -A C H T U N G T R E N N U N G (acetone) in kcal mol À1 .…”

“…1 8,135.9,132.5,132.2,131.8,130.9,130.4,128.7,128.4,49.9 ppm;19 F NMR (282 MHz,[D 8 ]THF): d = À62.12 ppm. 1 8,135.9,132.5,132.2,131.8,130.9,130.4,128.7,128.4,49.9 ppm;19 F NMR (282 MHz,[D 8 ]THF): d = À62.12 ppm.…”

“…[6] Seidel and co-workers utilized this anion-binding concept with carboxylates for the acylation reaction of amines using a simple acyl dimethylaminopyridinium salt as electrophile. [4,8] However, ureas and thioureas are almost exclusively applied as catalysts. [4,8] However, ureas and thioureas are almost exclusively applied as catalysts.…”