“On water” direct catalytic vinylogous Henry (nitroaldol) reactions of isatins for the efficient synthesis of isoxazole substituted 3-hydroxyindolin-2-ones

Abstract

An efficient “on water”-promoted direct catalytic vinylogous Henry reaction is described, giving products in excellent yields and diastereoselectivities.

Effects of solvents on the DACBO-catalyzed vinylogous Henry reaction of isatin with 3,5-dimethyl-4-nitroisoxazole “on-water” and in solution from QM/MM MC simulations

“…However, the results are inconsistent with the experimental research, in which the reaction rate in water is faster than those in THF and methanol. 29 Whereaer, for the rate-determining step of Path A in water, microsolvent models with the introduction of one-, three-, and up to six-water clusters to the reaction centers were employed to simulate the local microhydration surrounding (the corresponding geometry structures of the reactants, transition states, and intermediates are given in Fig. S4 of the ESI †).…”

“…Therefore, effective methods for direct vinylogous Henry reactions have been discovered and explored in recent years. 29,30 In 2015, Zhang et al rst reported the vinylogous Henry reaction between isatin and 3,5-dialkyl-4-nitroisoxazole, leading to isoxazole-substituted 3-hydroxy-2-oxindole derivatives, medicinally important compounds, using water as the solvent for optimizing the reaction conditions at room temperature. 29 They found that organic base catalysts are more effective than inorganic bases and 1,4-diazabicyclo [2.2.2]octane (DABCO) is the optimal catalyst with a near quantitative yield (>99%) in 1.5 hours for the synthesis of the desired vinylogous product.…”

“…It was also found that water was the most suitable solvent with high yield (>99%) and the shortest reaction time (1.5 hours) compared to other organic solvents under "on-water" conditions. 29 However, the active catalysis mechanism and the internal causes of the remarkable rate enhancement for the reaction in water are still unclear. These require a detailed understanding at the molecular level.…”

“…To gain further insights into the effects of the solvents on the rate and geometries of transition states at the theoretical level, in this work, isatin 1a and 3,5-dimethyl-4-nitroisoxazole 2 are selected as the reactants and DABCO as the catalyst to investigate this vinylogous Henry reaction "on-water" and in the organic solvents THF and CH 3 OH (Scheme 1) by using a combination of multiscale computational levels. The computational results will be contrasted with the experimental study by Zhang et al 29 First, we adopt density functional theory (DFT) M06-2X/SMD/6-311+G(d,p)//B3LYP/SMD/6-31+G(d,p) methods to investigate the reaction mechanism and obtain the structures of the transition states and ground states in water. Three possible reaction pathways are considered.…”

Mechanistic insight on (E)‐methyl 3‐(2‐aminophenyl)acrylate cyclization reaction by multicatalysis of solvent and substrate

“…The utilization of “safer solvents” and “design for energy efficiency” can be considered two key principles of the 12 principles of green chemistry . Recent researches show that water is a promising medium for catalysis . Moreover, some reactions in aqueous media also achieve rate acceleration and higher yield as compared to the cases in organic solvents .…”