Regioselective Alcoholysis and Hydrochlorination Reactions of Spiro‐Epoxy Oxindoles at the Spiro‐Centre: Synthesis of 3,3‐Disubstituted Oxindoles and Application for Anticancer Agents

Abstract

An efficient and highly regioselective BiIII catalyzed alcoholysis and Hydrochlorination reaction of spiro‐epoxy oxindole is demonstrated with alcohols and chlorine for easy access to 3,3‐disubstituted oxindoles. This protocol furnished alkyloxy and chlorinated products at the C3 spiro center of the epoxy ring in high yields up to 98 % with excellent regioselectivity > 99 %. The synthetic protocol was further exploited for the synthesis of the anti‐cancer active molecule, 1‐benzyl‐3‐(hydroxymethyl)‐3‐(phenylamino)indolin‐2‐one.

Cycloaddition of CO2 with an Epoxide-Bearing Oxindole Scaffold by a Metal–Organic Framework-Based Heterogeneous Catalyst under Ambient Conditions

“…Spiro-epoxy oxindole derivatives ( S1–S8 ) were synthesized according to a previous report. , Trimethylsulfoxonium iodide (1.0 mmol) and CsCO 3 (2.0 mmol) were dissolved in dry CH 3 CN at 50 °C for 1 h under a N 2 atmosphere. The N-substituted isatin derivative (1.0 mmol) was dissolved in dry CH 3 CN (5 mL) and added dropwise over a 10 min period to the solution described above.…”

“…The conventional CO 2 –epoxide cycloaddition reaction mainly focused on aromatic/aliphatic epoxide substrates, and heterocyclic epoxides have been infrequently explored. − Spirocyclic compounds with a privileged heterocyclic oxindole motif are widely available in natural alkaloids and recognized as pharmacologically interesting compounds . For example, oxindole-fused tetrahydropyrane or chroman scaffolds designated as oxaspirooxindole are notable for their pharmaceutical activities. − Spirocyclic alkaloids spirotryprostatins, horsfiline and gelsemine, with an oxindole scaffold have attracted a significant amount of interest of medicinal chemists because of the presence of the spirotryprostatins in bioactive natural products. − Due to their biological activity and physical properties, oxindole or spiro-oxindole core structures represent an interesting synthetic challenge. − The strategy for CO 2 –oxindole epoxide cycloaddition by developing a suitable catalyst is an innovative way to access spirocyclic oxindoles. So far, the only synthetic procedure for spirocyclic oxindole carbonate by CO 2 –epoxide cycloaddition is reported on the basis of a deep eutectic solvent .…”

Enzymatic Kinetic Resolution of Bulky Spiro-Epoxyoxindoles via Halohydrin Dehalogenase-Catalyzed Enantio- and Regioselective Azidolysis

“…Kinetic resolution of racemic spiro-epoxyoxindoles via enantio- and regiospecific ring-opening enables the straightforward formation of 3-substituted 3-hydroxy­oxindoles with remaining unresolved spiro-epoxyoxindoles in chiral forms. Although many efficient strategies have been developed for highly regioselective ring-opening of spiro-epoxyoxindoles to a diverse variety of 3-substituted 3-hydroxy­oxindoles, enantioselectivity control in these processes remains challenging. ,,− Several efforts have been devoted by Wang’s group to realize ring-opening of spiro-epoxyoxindoles in high enantio- and regioselectivity with indole or 1-naphthols (Figure a). , Very recently, Hajra’s group has also achieved catalytic kinetic resolution of spiro-epoxyoxindoles via Co­(III)­salen-catalyzed asymmetric C3-indolylation reactions (Figure b). , These elegant works feature broad substrate scope and mild conditions, which is a milestone for the asymmetric ring-opening of spiro-epoxyoxindoles and provides both chiral spiro-epoxyoxindoles and 3-substituted 3-hydroxy­oxindoles. However, these methods suffer from the use of expensive catalysts, hazardous solvents and long reaction time.…”

Influence of Hydrogen Bond Donating Sites in UiO‐66 Metal‐Organic Framework for Highly Regioselective Methanolysis of Epoxides

“…Epoxides are one of the most important intermediates in organic synthesis that can undergo nucleophilic ring‐opening reactions by various nucleophiles including alcohols to produce compounds like β‐alcoxyalcohols, 1,2‐diols and other compounds having pharmaceutical and agrochemical importance . Thus, methanol is one of the frequently used nucleophiles for the ring‐opening of epoxides due to its high reactivity and importance of the resulting product .…”