Regio‐, Diastereo‐, and Enantioselective Organocatalytic Addition of 4‐Substituted Pyrazolones to Isatin‐Derived Nitroalkenes

Abstract

Hydroquinine 2,5‐diphenyl‐4,6‐pyrimidinediyl diether [(DHQ)2Pyr] catalyzed the regio‐, diastereo‐, and enantioselective addition of 4‐substituted pyrazolones to isatin‐derived nitroalkenes, providing a variety of chiral alkenylpyrazolone adducts containing a tetrasubstituted stereocenter bearing an oxindole moiety with excellent yields, regioselectivity, and diastereoselectivity, as well as a moderate enantioselectivity (up to 98 % yield, > 20:1 E/Z ratio dr and 78 % ee). The reaction harnesses a nitroalkene as an alkenylating agent through a Nucleophilic Vinylic Substitution (SNV) reaction.

Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis

“…In 2019, the Pedro group described an enantioselective Michael addition/elimination sequence to construct chiral alkenylpyrazolone derivatives (Scheme 12). 28 (DHQ) 2 Pyr C12 catalyzed the regioselective and stereoselective addition of 4-substituted pyrazolones 2a to isatin-derived nitroalkenes 54 followed by 1,2- cis -elimination based on the key intermediates 56 , affording a variety of alkenylpyrazolones 55 in good yields with excellent regioselectivities and diastereoselectivities. Although the enantioselectivity of this process was not perfect, this so-called nucleophilic vinylic substitution (SNV) reaction showed the ability of nitroalkenes to act as alkenylation reagents.…”

Organocatalytic Enantioselective Synthesis of Chiral Spiro‐indoline‐pyrazolones through a formal [4+1] Annulation Reaction of 4‐Bromopyrazolones and aza‐ortho‐Quinone Methides

“…[27] Therefore, the development of efficient strategies for the construction of spiro-indoline and spiro-pyrazolone derivatives in a selective way is highly valuable for medicinal chemistry and it is worth it for organic synthesis. Therefore, as a part of our ongoing interest in organocatalytic stereoselective synthesis of pyrazolones bearing a quaternary stereocenter [30][31][32] and chiral spirocyclic compounds [33,34] we became interested in the study of the synthesis of spirocyclic compounds bearing a pyrazolone and an indoline scaffolds (Scheme 1C).…”

Enantioselective Nucleophilic Vinylic Substitution (SNV) toward 3-Alkenyl-bisoxindoles Facilitated by C6′ Steric Bulk of Cinchona Alkaloid

“…Complementarily, enantioselective organocatalytic α-vinylation of aldehydes with vinyl trifluoroborate salts or vinyl iodonium triflates is also efficient. In comparison with these traditional cross-coupling reactions, the well-established nucleophilic vinylic substitution (S N V) , is an alternative synthetic methodology which found only limited developments in the enantioselective version (Scheme a) . The first example was reported by Jørgensen and co-workers who forged enantioenriched vinyl-substituted all-carbon quaternary stereocenters by reaction between β-ketoesters or β-cyanoesters and ( Z )-3-chloro-1-arylprop-2-en-1-ones (Scheme a: LG = Cl) under phase-transfer catalysis .…”