Synthesis of 3,3‐Disubstituted Oxindoles by Palladium‐Catalyzed Asymmetric Intramolecular α‐Arylation of Amides: Reaction Development and Mechanistic Studies

Abstract

Palladium complexes incorporating chiral N-heterocyclic carbene (NHC) ligands catalyze the asymmetric intramolecular α-arylation of amides producing 3,3-disubstituted oxindoles. Comprehensive DFT studies have been performed to gain insight into the mechanism of this transformation. Oxidative addition is shown to be rate-determining and reductive elimination to be enantioselectivity-determining. The synthesis of seven new NHC ligands is detailed and their performance is compared. One of them, L8, containing a tBu and a 1-naphthyl group at the stereogenic centre, proved superior and was very efficient in the asymmetric synthesis of fifteen new spiro-oxindoles and three azaspiro-oxindoles often in high yields (up to 99 %) and enantioselectivities (up to 97 % ee; ee=enantiomeric excess). Three palladacycle intermediates resulting from the oxidative addition of [Pd(NHC)] into the aryl halide bond were isolated and structurally characterized (X-ray). Using these intermediates as catalysts showed alkene additives to play an important role in increasing turnover number and frequency.

Nickel(0)‐Catalyzed Enantioselective Annulations of Alkynes and Arylenoates Enabled by a Chiral NHC Ligand: Efficient Access to Cyclopentenones

“…L5 was previously used only once in a single trial in asymmetric catalysis, resulting in a very poor selectivity for Pd-catalyzed oxindole formation. [15] This outcome is in stark contrast to the excellent results of the C 2 -symmetric carbene L2 for the same transformation as reported by Kündig. This striking performance discrepancy for two different reactions is clearly another testimony that one cannot conclude on the power of a chiral ligand for a specific transformation from a few established benchmark reactions.…”

Recent Developments in Inter- and Intramolecular Enolate Arylation

“…Kü ndig detailed the synthesis of seven new NHC ligands and compared their performance, 50 resulting in the selection of a ligand containing a tert-butyl and a 1-naphthyl group at the stereogenic center as the most efficient (Scheme 26). This contribution allowed the synthesis of fifteen new spirooxindoles and three azaspiro-oxindoles, often in high yields (up to 99%) and enantioselectivities (up to 97%).…”

Synthesis of [3.4]‐Spirooxindoles through Cascade Carbopalladation of Skipped Dienes

“…One of the factors influencing the biological activity of this type of compounds is the size of the ring that conforms the spirocyclic structure at the 3‐position of the oxindole moiety . In recent years, a plethora of synthetic methods giving rise to spirooxindoles with different substitution patterns has been reported in the literature . Thus it is possible to incorporate rings from 3 to 8 members at the 3‐position of the aforementioned nuclei.…”

“…The main methods reported in the literature include: a) 3,3‐dialkylation of the oxindole skeleton with 1,3‐dihalopropane (route a , Scheme ); b) the intramolecular cyclization of N ′‐phenylcyclobutanecarbohydrazide at high temperature (route b , Scheme ); and c) [2+2] cycloaddition reactions based on the use of activated 3‐methylene oxindole derivatives (route c , Scheme ) . Other approaches based on Pd‐catalyzed or mediated intramolecular C−H functionalization afford spirooxindoles where two carbons of the cyclobutyl ring belong to an aryl group (route d , Scheme ) . In addition, several strategies have been applied to the construction of the cyclobutyl ring present in the core of the welwitindolinone A isonitrile …”