Tunable Bifunctional Phosphine–Squaramide Promoted Morita–Baylis–Hillman Reaction of <i>N</i>‐Alkyl Isatins with Acrylates

Abstract

Abstract A series of highly tunable bifunctional phosphine‐squaramide H‐bond donor organocatalysts 6 has been synthesized from inexpensive and commercially available β ‐amino alcohols in moderate yields. Catalyst 6 f can efficiently promote the asymmetric Morita–Baylis–Hillman (MBH) reaction of N ‐alkyl isatins with acrylate esters providing the chiral 3‐substituted 3‐hydroxy‐2‐oxindoles in good yields and enantioselectivities (up to 93 % yield and 95 % ee ), in which the challenging substrate tert ‐butyl acrylate 9 d , provided the best ee value to date. Moreover, this methodology was applied successfully in the synthesis of chiral cyclic spiropyrrolizidineoxindole and γ ‐butyrolactone derivatives without enantioselectivity deterioration. The possible mechanism of this MBH reaction was also investigated by 31 P NMR, ESI‐MS and KIE studies. The KIE experiments show that the electrophilic addition of N ‐methyl isatin to the complex of acrylate ester and phophine‐squaramide is the rate‐determing step of the asymmetric MBH reaction. magnified image