Efficient one-pot catalyst-free synthesis of novel coumarin- spiro[indoline-3,4'-pyran] conjugates via three-component domino reaction in aqueous medium

ABSTRACT A simple, efficient, eco-friendly and catalyst-free procedure was developed for the construction of novel coumarin-spiro[indoline-3,4'-pyran] conjugates via three-component reactions of various synthetic beta-ketoesters with isatins and malononitrile in aqueous medium. In addition to operational simplicity and absence of tedious separation procedures, being catalyst–free is the prominent advantage of this method. GRAPHICAL ABSTRACT

One of the desirable goals in organic synthesis is the assembly of simple and readily available precursor molecules into chemically complex products. Multicomponent reactions (MCRs), in which three or more starting materials are brought together in an efficiently convergent way to construct molecular structure and complexity, have been enthralling considerable attention over the past decades (25)(26)(27)(28)(29).
As far as we know coumarins have already been used as starting materials in MCRs (30)(31)(32), and it is noteworthy that coumarins fused with other heterocyclic scaffolds have arresting properties. Studies have revealed that numerous biologically important properties of the coumarins fused with other heterocycles are dependent upon structural features of other heterocycles (33). Chemical modification of other heterocycles offers a way to alter the functional groups, sizes, and stereochemistry of the coumarin derivatives, and many structure-activity relationships have been built up by such synthetic alterations (34)(35)(36). Due to the distinctive biological and pharmacological properties of the coumarin, pyran and spiro-oxindole scaffolds, the research on developing synthetic methods to enable facile access to heterocyclic compounds of this sort is being interesting. To the best of our knowledge, however, no protocol access to fluorescent coumarin-spiro[indoline-3,4'-pyran] conjugates has been reported yet. Accordingly, the aim of this work is to set up a protocol for achieving a novel collection of coumarin-spiro[indoline-3,4'-pyran] conjugates from synthetic coumarin beta-ketoester derivatives in efficient way.
The coumarin beta-ketoesters 3 were confirmed by analysis of 1 H NMR. With the coumarin beta-ketoesters in hand, to seek out the best synthesis condition for the titled compounds 6 we chose coumarin beta-ketoester 3ca (0.4 mmol), 4-Bromoisatin 4b (0.4 mmol) and malononitrile 5 (0.4 mmol) as model substrates. Ethanol is coincidently a better solvent from an environmental perspective, however, studies indicate that ethanolwater mixtures are more environmentally favorable compared to pure alcohol (38,39). Using aqueous medium as a solvent in organic reaction is not only inexpensive and environmentally benign, but also offers advantages over those occurring in organic solvents (40,41).Thus, the model reaction was performed without any catalysts in a mixture of ethanol-water (EtOH/H 2 O = 1:1) at 75°C, we were pleased to see that excellent yield of product was afforded after 9 h (Table 1, entry 1). With this fascinating result of the model reaction, we examined other catalysts to shorten the reaction time as well as increase the yield further.
Therefore, various catalysts such as L-proline, CTAB, DABCO, TEBA, BHDC were tested in the same condition of the model reaction. However, using these catalysts neither increased the yield of product nor shortened the reaction time significantly. The results were    Table 1. Among them, 30 mol % amount of L-proline and 20 mol % amount of BHDC showed the highest yield (Table 1, entries 7 and 8).Afterwards, when the amount of BHDC was increased to 30 mol %, except the slight decreasing of yield, not any improvement was observed. Having optimized the reaction parameters, we generalized the applicability of this method for synthesis of a series of coumarin-spiro[indoline-3,4'-pyran] conjugates starting from various substituted coumarin βketoesters and isatins( Table 2). The work-up procedure of the reaction is very convenient, after completion the reaction(monitored by TLC), the product was isolated from the reaction mixture simply by filtration and pure target compounds were obtained in considerably high yields after further recrystallization.
The coumarin-spiro[indoline-3,4'-pyran] conjugates 6 structural assignments have been made on the basis of IR, 1 H NMR, 13 C NMR and mass spectra. The 1 H NMR spectra of compounds 6 reveal typical singlet at δ7.27-7.52 for two protons of amino hydrogens (N-CH 2 ) which confirms the formation of pyran ring. In addition, a singlet of NH which originated from the isatin moiety appears in the region of δ10.48-11.29 could also be identified easily.
We suggest Scheme 2 as a working mechanism. In the first step, isatin 4 undergoes Knoevenagel condensation with malononitrile 5 to give intermediate product A, which acts as a Michael acceptor. The carbanion of coumarin β-ketoester is generated by the abstraction of a proton from the active methylene group, which is stabilized by resonance. Then it attacks at the Knoevenagel adduct intermediate A in Michael addition manner to produce an acyclic intermediate B which might undergo intramolecular cyclization followed by tautomerization to form the desired coumarin-spiro[indoline-3,4'-pyran] conjugate.

Conclusion
In conclusion, we have developed a completely ecofriendly, efficient, facile, one-pot, three-component, catalyst-free protocol for the synthesis of fluorescent coumarin-spiro[indoline-3,4'-pyran] conjugates in aqueous ethanol. No chromatography, no toxic organic solvents, and good to excellent product yields are some of the obvious achievements of this protocol.

General information
Reagents and solvents were from Aladdin, Acros or Energy Chemical. Melting points were determined in capillary tubes using Buchi B-540 digital melting point apparatus; they are uncorrected. The progress of the reaction was monitored by TLC using analytical-grade silica gel plates (GF254). All target compounds were characterized from their 1 H NMR, 13 C NMR, IR, and MS spectra. 1 H NMR (400 MHz) and 13 C NMR (100 MHz) were run on a Bruker Inova-400 instrument using DMSO-d 6 as solvent. Chemical shifts are given in ppm relative to TMS as an internal standard, and J values are given in Hz. IR spectra were recorded on a Bruker Vertex70 spectrophotometer using samples as KBr pellets. HRMS data were obtained using Thermo Scientific LTQ Orbitrap XL spectrometer.