Organocatalytic Asymmetric Addition of Naphthols and Electron‐Rich Phenols to Isatin‐Derived Ketimines: Highly Enantioselective Construction of Tetrasubstituted Stereocenters

Abstract

A quinine-derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral 3-amino-2-oxindoles with a quaternary stereocenter in high yields (up to 99%) with excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.

The origin for highly enantioselective induction of 1-naphthol to isatin-derived N-Boc ketimines catalyzed by quinine thiourea catalyst: an experimental and computational study

“…The solvent phase calculated results also suggest that Re face attack predominates over Si face attack by 3.3 kcal mol À1 (Fig. 16 The recently reported results on the formation of enantiomeric excess with isatin derived N-Boc ketimine and 1-naphthol in presence of quinine thiourea organocatalyst also showed that Re face approach is preferred over the Si face approach using the X-ray crystal structure analysis. The Gibb's free energy calculated results for these transition states further conrmed the preference in Re face attack over Si face attack (Fig.…”

“…9). 16 Further, the efficiency of organocatalyst with N1-phenyl and N1-methyl isatin derived N-Boc ketimine has also been examined with DFT calculations. 9).…”

“…1 At the beginning of the 20th century, Mario Betti discovered the three-component reaction of 2-naphthol, aryl aldehydes and ammonia or amines for the synthesis of aminobenzylnaphthols, 2 known as the Betti reaction and the product as a Betti base. 16 7,8 Further, biologically active natural products and pharmaceuticals 9 like 3-amino-2-oxindoles can be obtained by aza Henry, 13 Strecker, 14 allylation and Friedel-Cras reactions [10][11][12]15 of isatin derived ketimines.…”

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

“…In 2015, Pedro et al . reported the first asymmetric Friedel–Crafts reaction of N -Boc-isatin imines 3 with naphthols performed in the presence of cinchona alkaloid-derived thiourea 40 [66]. As shown in Scheme 15, the reaction of 1-naphthols 42 promoted by 2 mol % of this bifunctional catalyst in toluene at room temperature led to the corresponding chiral 3-substituted 3-amino-2-oxindoles 43 in good to high yields (78–99%) and uniformly excellent enantioselectivities (94–99% ee) regardless of the electronic character of the aromatic rings of the isatin and 1-naphthol and the position of their substituent (R 1 and R 2 ).…”

Chiral Brønsted Acid‐Catalyzed Enantioselective α‐Amidoalkylation Reactions: A Joint Experimental and Predictive Study

“…of catalysti sp roposed to explain the stereochemical outcome of the reaction. [17] On the other hand, ac hiral phosphoric acidcatalyzed enantioselective a-alkylation of enamides with indolyl methanols [18] and 3-hydroxyoxindoles [19] has been reported, and its utility demonstrated in the total synthesis of (À)-folicanthine.…”