Squaramide‐Catalyzed Synthesis of Enantioenriched Spirocyclic Oxindoles via Ketimine Intermediates with Multiple Active Sites

Abstract

A new method for the construction of five-membered spirocyclic oxindoles is based on a Michael-Mannich cascade reaction of a ketimine intermediated catalyzed by a bifunctional quinine-derived squaramide. The desired products were obtained in excellent yields (up to 94%) and stereoselectivities (up to >20:1 d.r., >99% ee). A scaled-up variant also proceeded smoothly showing that the one-pot reaction might find application in the synthesis of bioactive-compound libraries.

Enantioselective Nitroso Aldol Intramolecular Transesterification Cyclization Domino Reaction for Highly Effective Construction of Chiral Spirooxindoles

“…Catalysts 4l and 4n with 3,5-(CF 3 ) 2 substituents on the phenyl ring, which may increase the acidity of the N-H proton of the thiourea group, afforded better enantioselectivities than those without substituents (Table 1, Entries 11 versus 12,and 13 versus 14). Cyclic substituents of tertiary amine catalysts 4h, 4l, and 4n afforded higher enantioselectivities relative to their counterparts 4g, 4i, and 4j (Table 1, Entries 8,12,and 14 versus 7,9,and 10). The size of the cyclic ring of the tertiary amine also had an obvious effect on the reaction time, yield, and enantioselectivity.…”

“…[5] In 2012, our group [6] and the Rios group [7] reported the same transformation in a satisfactory result in the presence of a bifunctional tertiary amine thiourea. [8] However, to the best of our knowledge, there are only two chiral examples that use nitrosobenzene to construct a spirooxindole scaffold with a quaternary carbon center at the C3 position: Lin [9] used nitrosobenzene to build the ketimine intermediate by means of a Michael-Mannich cascade reaction of a chiral bifunctional tertiary amine thiourea catalyst and water. [8] However, to the best of our knowledge, there are only two chiral examples that use nitrosobenzene to construct a spirooxindole scaffold with a quaternary carbon center at the C3 position: Lin [9] used nitrosobenzene to build the ketimine intermediate by means of a Michael-Mannich cascade reaction of a chiral bifunctional tertiary amine thiourea catalyst and water.…”

Recent Advances in Squaramide‐Catalyzed Asymmetric Mannich Reactions

“…In 2015, Lin group [73] reported the three‐component cascade Michael/Mannich reaction of acetylacetones 125 , nitrosobenzenes 126 and methyleneindolinones 127 catalyzed by 2 mol% squaramide catalyst C1 (Scheme 51). This provided a new method for constructing five‐membered spirocyclic oxindoles 128 bearing three continuous stereocenters in moderate to high yields (31–94%) with low to excellent diastereoselectivities (4:1–20:1 dr) and good to excellent enantioselectivities (74–>99% ee).…”

Facile and Efficient Synthesis of 3‐Pyrimidinyl Oxindoles by Phase‐Transfer‐Catalyzed Regioselective Nucleophilic Aromatic Substitution

“…Similar to pyrimidines, oxindoles and especially 3,3‐disubstituted oxindoles are found in a large number of natural products and synthetic analogues showing a broad range of biological activities . Development of efficient protocols for the synthesis of such compounds is crucial and consequently significant progress has been made in this field including construction of spirocyclic oxindoles, synthesis of 3,3‐diaryl oxindoles and enantioselective fluorination and trifluoromethylation, just to name a few …”