chiral Brønsted acids · enantioselectivity · heterocycles · hydroamination · organocatalysisThe coordination of substrates with Brønsted or Lewis acids results in an important increase of the reaction rate of numerous reactions involving unsaturated systems through the formation of more-electrophilic complexes or charged intermediates. The prochiral nature of these reaction intermediates and the need to access single enantiomers has driven the development of efficient chiral catalysts. While chiral Lewis acid catalyzed reactions are well developed, hydrogenbonding and chiral Brønsted acid catalysis are just emerging as new strategies to induce stereoselectivity through association or ion pairing.[1] Of note, pioneering work by Jacobsen and Sigman on organocatalysis using strong hydrogen-bond donors, such as chiral thioureas, and reports by Akiyama et al., and Terada and Uragichi on chiral phosphoric acid organocatalysts have led to intense research efforts; these strategies already show broad applicability in heteroatomcontaining p systems (Scheme 1). [2, 3a,b] In contrast, the asymmetric Brønsted acid catalysis of reactions that involve C = C bonds remains a very challenging problem, to which important synthetic applications are linked.[4a] In a recent publication, Toste et al. unveiled a new pathway for asymmetric Brønsted acid catalysis of reactions that involve dienes or allenes (Scheme 2) and achieved highly efficient intramolecular hydroamination and hydroarylation reactivity. [6] these activation manifolds occur with efficient transfer of stereochemical information. Conversely, chiral phosphoric acids possess both acidic and Lewis basic sites, thereby allowing for dual activation of the reagents and/or bidentate complexation. Hindered binol-derived phosphoric acids (binol = 2,2'-dihydroxy-1,1'-binaphthyl) and their derivatives have notably shown excellent results in the asymmetric catalysis of reactions involving prochiral imines. [3c, 7] In the work of Toste et al., binol-derived dithiophosphoric acids are used as chiral catalysts for the cyclization of nucleophiles onto activated allylic intermediates. The high yields and enantioselectivities obtained raised questions about the mechanism when compared to related reactions that rely on ion pairing.[8] Further investigations revealed that the dithiophosphoric acid added onto the diene substrate, and afforded intermediate I (Scheme 2). The transient positioning of the chiral conjugate base on the substrate likely results in the efficient transfer of chirality during its S N 2' displacement by an internal nucleophile. As such, stereoinduction in this system would be conceptually related to asymmetric enamine-or iminium-based organocatalysis, where the catalyst is transiently attached through covalent bonding and forms an activated substrate. This novel stereoinduction pathway was supported by the observation of intermediate A (Scheme 3) by TOF-MS and by reactions on strained substrates, which showed that both the addition and S N 2' displacement occur in...

Condensation of N-tert-butanesulfinamide (S)-1 with trifluoroacetaldehyde hydrate 2a afforded 2-methyl-N-(2,2,2-trifluoroethylidene)propane-2-sulfinamide 3. Without isolation and purification, imine 3 was added to various aryllithium reagents to give highly diastereomerically enriched adducts 5a-g. Acidic methanolysis of 5a-g provided the desired 1-aryl-2,2,2-trifluoroethylamine hydrochloride compounds 6a-g. [reaction: see text].

The tandem hydroamination/Meisenheimer rearrangement sequence was developed to address the issue of unfavorable reaction thermodynamics for intermolecular reactions of alkenes and to improve the scope of Cope-type hydroaminations. This tandem sequence allows intermolecular reactions of N-alkyl-N-methallylhydroxyl-amines to be energetically more favorable: the N-oxide intermediate formed via Cope-type hydroamination, which can revert to the starting materials via a Cope elimination, can form a more stable neutral product via a [2,3]-Meisenheimer rearrangement. This tandem sequence also leads to increased efficiency in intramolecular systems as illustrated by syntheses of two alkaloids (coniine and norreticuline) featuring difficult hydroamination key steps.

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Azomethine imines can be accessed upon heating appropriate alkynylhydrazide precursors. This simple thermal hydroamination approach allows the formation of five- and six-membered dipoles in modest to excellent yields. The structure of the acyl group is important to minimize side reactions and allow the isolation of the azomethine imines by column chromatography.