Palladium-Catalyzed Asymmetric Allylic Alkylation/α-Iminol Rearrangement: A Facile Access to 2-Spirocyclic-Indoline Derivatives

We report an unprecedented Pd-catalyzed asymmetric allylic alkylation of 1-(indol-2-yl) cyclobutanols followed by an alpha-iminol rearrangement. High yields with excellent chemo-, regio-, diastereo-, and enantioselectivities have been realized, affording a wide range of enantioenriched 2-spirocyclic-indolines bearing two contiguous stereocenters. The facial selectivity of the ensuing rearrangement is controlled by the subtle difference of the sub-stituents on the all-carbon quaternary stereogenic center formed in the allylic alkylation step. Non-activated racemic terminal allylic alcohols are utilized as efficient electrophiles via kinetic resolution pathways for the first time in Pd-catalyzed asymmetric allylic alkylation. The role of Et3B additive is pivotal to activating allylic alcohols toward the formation of pi-allylpalladium species and suppressing N/O allylic alkylation of indole with enhanced C3-nucleophilicity. Electrospray ionization high-resolution mass spectrometry (ESI-HRMS) experiments provided strong evidence for the existence of the key nucleophilic boron anionic species, which fully accounts for the essential role of the Et3B additive. The study of the mechanism indicates that the real catalytically active species is an electronic pi-cinnamyl-palladium complex coordinated by two phosphoramidite ligands, which is consistent with the observed nonlinear effect and control experiments and is further confirmed by X-ray structure analysis. [GRAPHICS] .

Automated summary

We report an unprecedented Pd-catalyzed asymmetric allylic alkylation, which can efficiently synthesize enantioenriched spirocyclic-indolines. The addition of Et3B is found to be crucial for activating allylic alcohols and suppressing N/O allylic alkylation.