A concise and efficient one-pot regio- and stereoselective synthesis of structurally diverse spirooxindoles was constructed by simply refluxing a mixture of different types of heterocyclic ketene aminals, isatins and ethyl trifluoroacetate using catalytic piperidine. The advantages of this method include high efficiency, mild reaction conditions and environmentally benign reagents. These spirooxindoles are promising candidates for drug discovery; consequently, a library of diverse spirooxindoles was rapidly constructed using the present protocol.

A efficient and concise one-pot procedure has been developed for the synthesis of highly functional morphan derivatives 3 based on diastereoselective double Michael addition reactions of various quinone monoketals 1 with a variety of heterocyclic ketene aminals (HKAs) 2 in the green solvent water at 60 °C. This protocol is especially suitable for efficient and rapid parallel syntheses of N-containing bridged heterocycles possessing pharmacological activities. As a result, a library of highly functional morphan derivatives was easily synthesized using this reported environmentally benign, mild, and catalyst-free one-pot reaction.

As a classical and well-established named reaction, the Nenitzescu reaction is of special value for the construction of biologically meaningful 5-hydroxyindole derivatives. However, to date, its sister, the anti-Nenitzescu reaction and the corresponding synthetic methodology for 3a-hydroxy-indol-6-one derivatives, has remained an unexplored area. We discovered herein an environmentally benign, mild, and catalyst-free reaction in ethanol for the site-selective construction of rarely fused [1,2-a]indolone derivatives (3) from quinones (1) and heterocyclic ketene aminals (HKAs) (2) via an unexpected anti-Nenitzescu strategy. This unconventional methodology suggests that it will be suitable for the site-selective synthesis of 3a-hydroxy-indol-6-one derivatives from a green perspective. On the other hand, the developed target compounds 3 have a promising future for the further synthesis of aromatic 6-hydroxyindoles or dehydroxylated indol-6-ones in situ. In order to systematically elucidate the mechanistic details and controlling factors of the two Nenitzescu reactions, density functional theory (DFT) calculations were also performed. According to the computational results, the origin of site-selectivity can be explained by the following reasons: all energy barriers for the anti-Nenitzescu reaction can be overcome at room temperature, yet the extremely high energy barrier of imine–enamine tautomerization for the Nenitzescu reaction indicates its failure under the same conditions. The reduced density gradient (RDG) analysis hinted that the greater thermodynamic stability of the Nenitzescu product 3h′ mainly depends on the release of the strong steric effect.