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...

Urea‐Induced Acid Amplification: A New Approach for Metal‐Free Insertion Chemistry

“…Close consideration of our observations, taken along with the recent, inventive investigations of urea/Brønsted acid cocatalyst systems from the groups of both Jacobsen and Seidel, [4] led us to hypothesize that the mechanism may likely not involve urea activation of the diazo compound. Instead, a urea-catalyzed enhancement in the organic acid's acidity (B) is proposed to promote the stepwise insertion of aryldiazoacetates via an intermediate ion pair (C).…”

“…Instead, a urea-catalyzed enhancement in the organic acid's acidity (B) is proposed to promote the stepwise insertion of aryldiazoacetates via an intermediate ion pair (C). [5,6] Although many examples of urea/Brønsted acid cocatalysis in 1,2-additions have been described, [4,7] to the best of our knowledge, this concept has not been applied to catalytic substrate acidification for X-H insertions. [8] Herein, we report our initial success in the area of urea-induced heteroatom acid amplification as an innovative tactic for metal-free OÀH and SÀH insertion reactions.…”

“…Our success in developing reactions of urea-activated electrophilic diazo compounds prompted us to question the ability of urea catalysis to also control reactions of more basic diazo compounds, such as aryldiazoacetates (Scheme 1, 3). [4] At the onset of our studies, we anticipated that ureas would be unable to affect the outcome of reactions of aryldiazoacetates; it was not obvious to us how a urea could enhance their reactivity. Much to our surprise, urea catalysis proved to be an extraordinary tool for select OÀH and SÀH insertion reactions of aryldiazoacetates.…”

Catalytic Enantioselective Synthesis of Lactams through Formal [4+2] Cycloaddition of Imines with Homophthalic Anhydride

“…Imine and homophthalic anhydride 1 are thought to form the hydrogen-bonded ion pair 2 in equilibrium. [13][14][15] Our concept is based on the notion that ah ydrogen-bonding (HB) [16] catalyst, which itself remains neutral throughout the reaction, can confer enantioselectivity by simultaneously interacting with an anionic nucleophile and ac ationic electrophile.S pecifically,w e envisioned that the interaction of ac hiral thiourea catalyst with homophthalic anhydride 1 would result in increased substrate acidity via complex 4.T his in turn would lower the barrier for ion pair formation, thereby enabling the generation of chiral ion pair 5.Viewed from adifferent perspective, the presence of an anion receptor is expected to increase the equilibrium concentration of any ion pair intermediate. Theresulting intermediate 3 then engages in intramolecular aminolysis of the anhydride to form the lactam product.…”

Catalytic Enantioselective Synthesis of Lactams through Formal [4+2] Cycloaddition of Imines with Homophthalic Anhydride

“…[12] Since classic modes of substrate activation appeared unsuitable,w econceived of an ew anion binding/ion pairing approach in order to render this reaction catalytic enantioselective ( Figure 2). [13][14][15] Our concept is based on the notion that ah ydrogen-bonding (HB) [16] catalyst, which itself remains neutral throughout the reaction, can confer enantioselectivity by simultaneously interacting with an anionic nucleophile and ac ationic electrophile.S pecifically,w e envisioned that the interaction of ac hiral thiourea catalyst with homophthalic anhydride 1 would result in increased substrate acidity via complex 4.T his in turn would lower the barrier for ion pair formation, thereby enabling the generation of chiral ion pair 5.Viewed from adifferent perspective, the presence of an anion receptor is expected to increase the equilibrium concentration of any ion pair intermediate. Interaction of the iminium ion in 5 with as econdary hydrogen-bonding acceptor site on the catalyst would contribute to the creation of aw ell-defined ion pair that is set up for an enantioselective Mannich addition step.…”