Article Cite This: J. Org. Chem. 2019, 84, 7642−7651
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“On Water” Catalytic Aldol Reaction between Isatins and Acetophenones: Interfacial Hydrogen Bonding and Enamine Mechanism Jinsong Han,† Jin-Lei Zhang,† Wei-Qiang Zhang,† Ziwei Gao,† Li-Wen Xu,*,†,‡ and Yajun Jian*,†
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Key Laboratory of Applied Surface and Colloid Chemistry, MOE, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710062, P. R. China ‡ Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. China S Supporting Information *
ABSTRACT: “On water” catalytic aldol reaction catalyzed by polyetheramine (D230) has been developed for easy access to 3-substituted 3-hydroxyindolin-2-ones through the reaction between various substituted isatins and acetophenones/cyclic ketones in high yields under room temperature. Systematic mechanism investigation uncovers the secret for the on water catalytic aldol reaction: comparison of the heterogeneous and homogeneous reaction circumstances with yields of 95 and 20%, respectively, indicates the on-water reaction dominating; interfacial hydrogen bonding between isatin with H2O is tested based on the downfield shift of the C2 and C3’s 13C NMR signals when water was added to the CDCl3 solution of isatin; Lewis base polyetheramine D230 catalyzes the aldol reaction via the enamine mechanism verified by in situ NMR and ESI-MS analysis.
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INTRODUCTION Many chemists believe that solubility is a prerequisite for reactivity. Thus, even for organic reactions taking place in water-involved reaction media, many efforts have been made to make organic substrates more soluble, including transforming insoluble substrates, adding surfactants, and so on.1 Therefore, water solely as the reaction solvent is least considered in the organic synthesis community. However, the “on water” reaction, pioneered and conceptualized by Rideout and Breslow2 and Sharpless et al.,3 respectively, where the transition state occurs at the organic side of the water−organic interface, often showing better reactivity, has still attracted more attention.1c−e Based on experimental and computational studies, hydrogen bonding at water−organic interfaces is acknowledged as the main driving force for the on water reaction.4 However, from the practical point of view, there are scarce approaches to predict if one organic reaction is suitable to adopt on water conditions. Isatins, by reacting with a nucleophile or other reaction counterparts, could be transformed into various 3-hydroxy-2oxindoles and other related oxindole derivatives,5 prevalently present in a large number of natural products and biologically active compounds.6 Many of those transformations took place in pure water medium, primarily catalyzed by either amine-7 or amide-based8 organocatalysts, and were usually unclaimed as on water reactions, and the water usage was often aimed to © 2019 American Chemical Society
make the reaction greener, so many facts as far as on water reaction is concerned were not well illustrated during investigation, such as distinguishing in-water and on-water modes as well as the role H2O plays, not to mention that Brønsted acids7a,8 were always employed as cocatalysts to activate isatin. For those claimed to be on water catalytic reactions, although it has been widely thought that isatins can be activated by interfacial hydrogen bonding, no direct evidence was shown.9 We anticipate that once the interfacial hydrogen bond forms, the hydrogen atom from the water molecule serving as a hydrogen bond donor will make C2 and C3 in isatin more electrophilic, and such a chemical surrounding variation might be reflected by 13C NMR (Figure 1). Besides water activation on isatin via interfacial hydrogen bonding, a base such as tertiary amine DABCO9a,10 and Et3N11 is always needed to activate the nucleophilic counterpart to assure that the reaction completed in a shorter time unlike that under catalyst-free conditions9b,12 that can last 2 days. However, stronger Lewis basicity of tertiary bases compared with that of primary amines sometimes causes side reactions, such as condensation or rearrangement, so milder bases are still worth exploring.9b,13 As far as we know, no report has been Received: February 14, 2019 Published: May 22, 2019 7642
DOI: 10.1021/acs.joc.9b00441 J. Org. Chem. 2019, 84, 7642−7651
Article
The Journal of Organic Chemistry
detected when the catalyst was absent (entry 1). In general, catalysts having better water solubility helped the reaction proceed more efficiently, which is more obvious in a series of commercially available polyetheramine (entries 6−8). As the degree of polymerization decreased, the reaction yield elevated from 12 to 95% yield where upon the employment of D230 (n ≈2.5), the aldol adduct could be generated in 95% yield (entry 8). It seems that more hydrophilic polyetheramine guarantees better productivity, so D132, which bears just one propylene oxide group, was synthesized according to López-Calahorra’s procedure.14 However, D132 showed much worse catalytic activity in the model reaction and only led to a 25% product yield (entry 9). Taking the results in entries 6−9 together, D230 performed the best in those polyetheramine analogues, which may be attributed to two requirements for the optimal catalyst: one is to provide enough number of hydrogenbonding acceptor atoms (O and N atoms) to maintain the nucleophilic part at the periphery of the water−organic interface, and the other is to avoid a too long molecule to be dragged to the water−organic interface. The other exception was that ethylenediamine with pretty high water solubility showed poor catalytic efficiency (entry 2). Moreover, to test the practicality of optimized conditions, we conducted the aldol reaction on a gram scale as follows: water insoluble 1a and 2a and 10 mol % D230 were stirred in 25 mL of H2O. As shown in Figure 2, as the reaction
Figure 1. Proposed transition state for on water catalytic aldol reactions between isatins and acetophenones via the enamine mechanism.
disclosed yet with primary amines as the catalyst in an onwater mode for the aldol reaction between isatins and nucleophiles. Polyetheramine, an amine-terminated poly(oxypropylene), has several hydrogen-bonding acceptor atoms (O and N atoms), which might be helpful to drag the nucleophilic part to the periphery of the water−organic interface. Herein, we report our findings about the on water aldol reaction catalyzed by polyetheramine (D230, n ≈ 2.5) via the enamine mechanism in high efficiency.
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RESULTS AND DISCUSSION Our screening started with isatin 1a and acetophenone 2a in H2O at room temperature using various commercially available primary amines as catalysts, and the corresponding results are displayed in Table 1. The screening test suggested that the Lewis base catalyst was indispensable as no product was Table 1. Lewis Base Catalyst Screening for Aldol Reactiona
entry 1 2 3 4 5 6 7 8 9
catalyst none ethylenediamine 1-naphthylmethylamine chitosan polyethyene polyamine-275 D2000 D400 D230 D132d
catalyst solubility in H2Ob (mol·L−1)
yieldc (%)
N.A. 8.8
