Studies defining the scope of the reaction and understanding the factors controlling the unusual regioselectivity observed in the Pd/{BINAP(S)}-catalyzed allylic amination reaction are presented. Most of the unsymmetrically substituted allylic substrates tested show regioselectivity that is the reverse of that which would normally be expected in Pd-catalyzed systems. Several cationic η3-allylic complexes containing a Pd{BINAP(S)} fragment have been synthesized in an attempt to correlate this behavior with structural features of the ligand and the solution structure of the allylpalladium complex. Notably, allylic amines with an α-quaternary carbon center may be prepared with high regioselectivity with this system. Spin-saturation transfer studies (SST) were performed on two (κ2-P,S)Pd-π-allyl complexes in order to determine relative rates for Pd-η3−η1−η3-allyl interconversions and the hemilabile behavior of the BINAP(S) ligand.

The reactivity of a series of symmetrical chiral Brønsted acids (polar ionic hydrogen bond donors) follows the counterintuitive trend wherein the more Brønsted basic member is a more effective catalyst for the aza-Henry (nitro-Mannich) reaction. This new design element leads to a substantially more reactive catalyst for the aza-Henry reaction, and one that can promote the addition of a secondary nitroalkane. Additionally, when achiral Brønsted acid (TfOH) is used in slight excess to the neutral, chiral BisAMidine ligand, diastereoselection can be optimized to levels generally greater than 15:1 while enantioselection remains unchanged at generally >90% ee.The development of small molecule catalysts that manage the key aspects of an asymmetric reaction has been tremendously successful, bringing stereochemically sophisticated organic compounds into hand in as little as a single operation from bench-stable reactants. 1 There are now numerous cases of small molecules that catalyze the reaction of two (or more) reactants in a highly diastereo-and enantioselective process, and these findings have illustrated that catalyst structural and functional complexity is not a prerequisite for high levels of stereoselection. 2 Despite this proliferation of examples, contributors often remain focused on a fraction of available catalyst motifs. 3 This is perhaps less intentional than it is necessary, as in multifunctional catalysis, it remains difficult to manipulate reactivity independently of other stereocontrol factors; 4 the bond distances and angles that determine stereocontrol also impact overall reactivity. 5 We report here the finding that multifunctional catalysts 2 provide the opportunity to increase overall reactivity through manipulation of their Brønsted basicity 6 without detriment to stereocontrol. The behavior is suggestive of a semiorthogonal hierarchy among reactivity, diastereocontrol, and enantiocontrol that can be used to extend the scope of the enantioselective aza-Henry reaction, 7,8,9 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript beyond nitroethane. In essence, the orthogonality (or priority) described in this study for an ostensibly symmetrical catalyst achieves the same goal as modularity in unsymmetrical ligand design.Chiral Bis(AMidine) Brønsted acids (e.g. 1a·HOTf (2)) are among the organocatalysts that have expanded the range of nonracemic vic-diamines available in two steps from nitroalkanes. With few exceptions, the enantioselective aza-Henry reaction remains generally limited to activated or unhindered nitroalkane pronucleophiles, and warm reaction temperatures at relatively long reaction times. Based on the knowledge that Brønsted acidity is central to stereocontrol, 4 we prepared a range of electron deficient ligands, but these failed to improve either reactivity or stereocontrol. Instead, improvement of reaction rate and stereoselection was achieved through the preparation of ligands with increased Brønsted basicity. Using the addition of nitroethane to imine...

The enantioselective allylic amination of acyclic allylic carbonates catalyzed by a palladium/(S)-BINAP(S) system was investigated. Amination of several substrates proceeded with high ee. Crotyl carbonates show an unusually high regioselectivity for the branched isomer. The use of (S)-TolBINAP(S) and (S)-3,5-xylyl-BINAP(S) as ligands was found to increase the enantioselectivity of the aminations. A P,S binding mode of the BINAP(S) ligand was found in an X-ray crystallographic study. [reaction: see text]

Highly diastereo- and enantioselective additions of alpha-nitrophosphonates to imines catalyzed by a chiral Brønsted acid are described.

Effective kinetic resolutions of acyclic allylic acetates and benzoates have been obtained using a palladium/(S)-BINAP(S) catalyst system. Unusually large preferences for the formation of branched alkylation products from 3-but-2-enyl and crotyl substrates have been observed. [reaction: see text]

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The preparation of an enantiomerically enriched beta-diketimine composed of isoquinoline and 2-aminonaphthalene (IAN amine) is described, thereby offering new opportunities in the synthesis of nonracemic beta-diketimine- and pyridine-based chiral catalysts.