Theoretical Studies of the Asymmetric Binary‐Acid‐Catalyzed tert‐Aminocyclization Reaction: Origins of the CH Activation and Stereoselectivity

Abstract

A mechanistic study of the tert-aminocyclization reaction was performed by using DFT calculations and labeling experiments. The results showed that the reaction proceeded through a rate-limiting-, stereospecific-, and suprafacial 1,5-H-transfer pathway, followed by a barrier-less C-C bond formation. The mode of stereocontrol for facial selection could be ruled out owing to the high activation energy of C-N bond rotation. The intrinsic feature of this Lewis acid activation was found to be the activation of the LUMO, as well as an intermediate-stabilization effect. The catalytically active species was believed to be a 1:1 complex of phosphoric acid and MgCl(2), which was stabilized by a H⋅⋅⋅Cl hydrogen bond. The chiral catalytic complex selectively recognizes and activates one of the two helical conformations of substrate A, required for 1,5-suprafacial H-transfer, which dictates the stereoselectivity of the forming products.

The Redox‐Neutral Approach to CH Functionalization

“…In this case, chiral phosphoric acid 71 is used as a ligand which enhances the electrophilicity of the magnesium center. A related theoretical study37 suggested that the stereoselectivity observed stems from the hydride transfer step, consistently with the proposals of Akiyama and Reinhoudt 35a. 6b…”

Asymmetric Tandem 1,5‐Hydride Shift/Ring Closure for the Synthesis of Chiral Spirooxindole Tetrahydroquinolines

“…(Table 1, entry 5), whereas the others were found to be ineffective Lewis acid mediators for the transformation. Other lanthanide metal salts could furnish the product in a range of yields and enantioselectivities, all of which were inferior to that obtained with scandium(III) triflate ( Table 1, entries [6][7][8][9]. The structure of the N,N'dioxide ligands had a large effect on the enantioselectivity.…”

“…Since Reinhoudt et al [2] provided an alternative method of cleavage of a C(sp 3 )ÀH bond through an intramolecular tandem 1,5-hydride shift/ring closure process in 1984, variants of this rearrangement have been reported. [3][4][5][6] One challenge associated with this chemistry has been to render it enantioselective under mild reaction conditions. Chiral organocatalysts (e.g., chiral phosphoric acid and iminium) and chiral Lewis acids (e.g., Mg II , Co II and Au I coordinating with chiral ligands) are general catalysts that are used for the asymmetric transitions.…”

“…Chiral organocatalysts (e.g., chiral phosphoric acid and iminium) and chiral Lewis acids (e.g., Mg II , Co II and Au I coordinating with chiral ligands) are general catalysts that are used for the asymmetric transitions. This concept has enabled the straightforward construction of tetrahydroquinoline,6a–c, f–h furan‐fused benzazepines,6d cyclic aminals,6e spiroethers,6i and others.…”

Lewis Acid Mediated Vinyl‐Transfer Reaction of Alkynes to N‐Alkylimines by Using the N‐Alkyl Residue as a Sacrificial Hydrogen Donor

“…Such a mechanism is also known for alkyllithium compounds that contain a β‐hydrogen atom, and hence act as hydride donors 15. Conceptually related [1,5]‐hydride‐transfer reactions, from carbon atoms α to the nitrogen atom to an electron acceptor, such as an activated vinyl group,9d,f,k,l iminium bond,9e imine,9c,h,i or aldehyde9j have been reported in the literature.…”