Asymmetric Synthesis of α,α‐Disubstituted Allylic Amines through Palladium‐Catalyzed Allylic Substitution

Abstract

The first asymmetric synthesis of important α,α‐disubstituted N‐alkyl allyl amine scaffolds through allylic substitution is reported. This approach is based on palladium catalysis and features ample scope with respect to both the allylic precursor and amine reagent, and high asymmetric induction with enantiomeric ratios (e.r.) up to 98.5:1.5. The use of less‐reactive anilines is also feasible, providing enantioenriched α,α‐disubstituted N‐aryl allylic amines.

Catalytic Transformations of Functionalized Cyclic Organic Carbonates

“…TheP d-and Cu-catalyzed decarboxylative coupling of external nucleophiles and VCCs was examined by Kleij et al who reported the stereoselective synthesis of arange of allylic compounds through CÀN, CÀO, CÀS, CÀCand CÀBbond formation reactions. [27] As shown in Scheme 7, in the presence of as uitable palladium/copper precursor and ligand, the formation of as ix-membered palladacyclic or Cu-Bpin(VCC) intermediate sets up the subsequent nucleophilic attack to afford the substituted (Z)or (E)-configured allylic derivatives.Inthe case of aryl amine nucleophiles,e xtensive DFT calculations suggested that the pathway leading to the (E)-configured allylic amines proceeds through an epoxide intermediate requiring significantly high-er energy for the CO 2 extrusion step,a nd thus is disfavored under ambient conditions. [27a] This approach based on the use of VCC substrates as allylic surrogates offers ageneral entry for the synthesis of otherwise challenging tri/tetra substituted (Z)-allylic scaffolds.T he use of aliphatic amines in this system, however, predominantly gave carbamate products as discussed in section 2.…”

A Mechanistic Analysis of the Palladium‐Catalyzed Formation of Branched Allylic Amines Reveals the Origin of the Regio‐ and Enantioselectivity through a Unique Inner‐Sphere Pathway

“…Then, the amine attacks the zwitterionic Pd(allyl) intermediate at the internal carbon center of INT-A or INT-B guided by the alkoxy fragment in an outer-sphere mechanism through transition states TS-A or TS-B to afford branched-products (S)-3 or (R)-3,r espectively.T he phosphoramidite ligand L2 allows to kinetically differentiate between both outer-sphere attacks (Scheme 1d), and hence high enantiomeric excess in the allylic amine product is observed. [12] Despite the notable progress in the formation of elusive and sterically encumbered a,a-disubstituted allylic amines, [11][12][13] the origin of both the branched regioselectivity and high asymmetric induction exerted by ligand effects is not well-understood. Therefore,w ed ecided to investigate both computationally and experimentally the underlying mechanistic features that govern this unusual selectivity behavior in the Pd-mediated allylic amination.…”

Regio- and Enantioselective Iridium-Catalyzed Amination of Racemic Branched Alkyl-Substituted Allylic Acetates with Primary and Secondary Aromatic and Heteroaromatic Amines

“…These π-allyliridium C,O -benzoate catalyzed processes overcome a longstanding limitation associated with all known catalytic systems for asymmetric allylic amination - the ability to promote enantioselective aminations of racemic branched allylic acetates bearing n -alkyl groups with complete levels of regioselectivitity. 4 - 12,16 Another notable feature of these catalysts involves the ability to promote site-selective N -allylations of reactants that incorporate both primary and secondary aromatic amines. As demonstrated by mechanistic studies involving amination of the enantiomerically enriched deuterated allylic acetate 1h , an outer-sphere mechanism for C-N bond formation is operative.…”

“…15 These aminations proceed with complete branched regioselectivity, overcoming a significant limitation associated with Type I and II catalysts, which display incomplete regioselectivity for π-allyl precursors bearing linear alkyl groups. 16,17 With regard to the amine nucleophile, the Type III SEGPHOS-modified π-allyliridium complexes used in our initial study enforced high enantioselectivities in reactions of primary aliphatic amines (Figure 1). Here, we show that the corresponding tol-BINAP-modified iridium catalyst avail a significant expansion in scope, enabling highly enantioselective aminations of branched alkyl-substituted allylic acetates with electronically diverse primary and secondary aryl amines, including site-selective reactions of bis(amine) nucleophiles.…”