Synthesis of spiro[indoline-3,1′\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^\prime $$\end{document}-quinolizines] and spiro[indoline-3,4′\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^\prime $$\end{document}-pyrido[1,2-a]quinolines] via three-component reactions of azaarenes, acetylenedicarboxylate, and 3-methyleneoxindoles

The three-component reactions of substituted pyridines, dimethyl acetylenedicarboxylates, and 3-phenacylideneoxindoles afforded spiro[indoline-3,1′\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^\prime $$\end{document}-quinolizines] in high yields and with high diastereoselectivity. The Diels–Alder reactions of spiro[indoline-3,1′\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^\prime $$\end{document}-quinolizines] with maleic anhydride and N\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$N$$\end{document}-phenyl maleimides successfully resulted in polyfunctionalized isoquinolinuclidine derivatives. The similar three-component reactions with quinoline resulted in the novel spiro[indoline-3,4′\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^\prime $$\end{document}-pyrido[1,2-a]quinolines] in moderate to good yields.


Introduction
The spirooxindole core is a privileged heterocyclic ring system that is featured in a large number of bioactive naturally occurring alkaloids and medicinally relevant compounds [1][2][3][4][5]. Due to the exceptional high reactivity of the 3carbonyl group, 3-methylene and 3-phenacylideneoxindoles have attracted a lot of attention for synthetic reactions, especially multicomponent reactions [6][7][8] and catalytic asymmetric reactions [9][10][11] in the past few years. As a result, numerous elegant transformations have been developed for the diastereoselective and enantioselective construc-Electronic supplementary material The online version of this article (doi:10.1007/s11030-013-9459-5) contains supplementary material, which is available to authorized users. tion of versatile spirooxindole skeletons [12][13][14][15][16][17]. For the synthesis of these challenging heterocycles, the 1,4-dipolar cycloaddition of Huisgen 1,4-dipoles, which were generated from reactions of nitrogen heterocycles with electrondeficient alkynes, has proven to be a convenient and efficient synthetic methodology [18,19]. Nair et al. [20] first reported the three-component reaction of pyridine, dimethyl acetylenedicarboxylate (DMAD), and N -benzylisatins to give spiro[indololine-3,2 -pyrido [2,1-b] [1,3]oxazine]. Later, Yavari [21] and Nair [22] reported the similar reactions of quinoline and isoquinoline with DMAD and isatins for the preparation of complex spirooxindole derivatives. Shi and co-workers [23] found that the three-component reactions of pyridine, DMAD, and N -substituted isatylidene derivatives afforded spiro[indoline-3,2-quinolizine] in high yields and with good diastereoselectivities. Recently, we successfully developed an efficient synthetic protocol for dispirooxindole-fused heterocycles via the domino reaction of p-dimethylaminopyridine and DMAD with two molecules of 3-phenacylideneoxindoles [24]. In order to demonstrate the synthetic utility of this practical method, herein we wish to report the three-component reaction of azaarenes such as substituted pyridines and quinoline with DMAD and 3-phenacylideneoxindoles and 3ethoxycarbonylmethyleneoxindoles for the synthesis of spiro [indoline-3,1 -quinolizine] derivatives and their potential applications as effective dienes for Diels-Alder reactions.

Results and discussion
We initiated our studies by evaluating the reactivity of the Huisgen 1,4-dipoles generated from the reaction of alkylpyridines with DMAD. According to our previously established conditions for the reaction of 4-dimethylaminopyridine [24], the three-component reactions of 2-picoline with DMAD and 3-phenacylideneoxindoles in THF at room temperature proceeded very smoothly to give the expected 2 ,9adihydrospiro[indoline-3,1 -quinolizine] 1a-1b in moderate yields (Table 1, entries 1-2). Under similar conditions, the reactions with 3-picoline and 4-picoline gave the corresponding spiro products 1c-1h in high yields (Table 1, entries 3-8). When 4-methoxypyridine was utilized in the reactions, much higher yields of spiro compounds 1j-1o (Table 1, entries 9-15) were obtained. The structures of the prepared 2 ,9a -dihydrospiro[indoline-3,1 -quinolizin]-2-ones 1a-1n were fully characterized by 1 H NMR, 13 C NMR, HRMS, and IR. The 1 H NMR spectra of the spiro compounds 1a-1n usually show one set of signals for the characteristic groups in the molecule, which clearly indicated that only one diastereoisomer existed in each sample. The molecular structures of compounds 1f (Fig. 1), 1h (SPI, Fig. s1), and 1m (SPI, Fig. s2) were successfully confirmed by single-crystal X-ray diffraction. These three molecules (1f, 1h, 1m) have the same stereochemistry. In the newly formed tetrahydropyridyl ring, the two protons at 2-and 4-positions are in cis-orientation. The benzoyl and aryl groups of the oxindole moiety also exist in cis-position. It is reported that the benzoyl group and aryl group of oxindole moiety exist in cis-position in the starting 3-phenacylideneoxindoles [25,26] indicating that this configuration is expected to be retained in the reaction. Thus, we unambiguously ascertained that compounds 1a-1o are the cis-isomers proving that this three-component reaction undergoes with very high diastereoselectivity.
It should be pointed out that spiro compounds 1i-1o derived from the reactions with 4-methoxypyridine are not very stable in solution because of the presence of a reactive methyl vinyl ether moiety. The 4-methoxy group could be slowly transformed into the 4-carbonyl group during the purification process when dissolved in THF, DCM, ethyl acetate, and toluene (Scheme 1). The structures of the two spiro compounds 2a-2b were successfully characterized via spectroscopic methods, and the structure of spiro compound 2b was also confirmed by X-ray diffraction (SPI, Fig. s3).
To further demonstrate the substrate scope and the diastereoselectivity of this three-component reaction, quinoline was also utilized in the reaction. The three-component reaction of quinoline, DMAD, and 3-phenacylideneoxindoles in THF usually resulted in a complex mixture. After exploring different solvents, we were pleased to find that the reaction proceeded smoothly in DME to give the desired 3 ,4adihydrospiro[indoline-3,4 -pyrido[1,2-a]quinolines] 3a-3e in moderate yields after thin-layer chromatography (  [6][7][8][9][10]. The structures of spiro compounds 3a-3j were also confirmed using spectroscopic methods and compounds 3e and 3i were further confirmed by X-ray diffraction (Figs. 2, 3, respectively). A stereochemistry similar to that of 1a-1o was observed for the spiro compounds 3a-3j, in which the two protons at 2-and 4-positions existed in cis-orientation in the newly formed tetrahydropyridyl ring, and the benzoyl group and the aryl group of the oxindole moiety also existed in cis-position. These results also indicate that this three-component reaction is a high diastereoselective reaction.

Conclusion
In summary, an efficient protocol for the synthesis of functionalized spiro[indoline-3,1 -quinolizine] and spiro[indoline-3,4 -pyrido[1,2-a]quinoline] was successfully developed by three-component reactions of nitrogen heterocycles, DMADs, and 3-methyleneoxindoles. This MCR reaction can proceed smoothly under mild conditions to afford complex heterocycles in moderate to good yields and high diastereos- electivities. Furthermore, the prepared spiro[indoline-3,1quinolizines] can undergo Diels-Alder reactions with maleic anhydride and N -phenyl maleimides to give complex isoquinolinuclidine derivatives. The simplicity of the procedure, readily available substrates, and ease of handling render this protocol applicable for the synthesis of structurally diverse heterocyclic compounds.

Experimental section
General procedure for the three-component reaction of substituted pyridine, DMAD, and 3-phenacylideneoxindoles A mixture of substituted pyridine (1.2 mmol), DMAD (1.2 mmol, 0.170 g), and 3-phenacylideneoxindole (1.0 mmol) in 10.0 mL of tetrahydrofuran was stirred at room temperature for 6 h. Then, the solvent was removed by evaporation and the residue was subjected to thin-layer chromatography (15 × 25 cm SiO 2 plate) with a mixture of light petroleum and ethyl acetate (V/V = 2:1) as the developing reagent. The product was separated from silica gel by eluting with ethanol and is pure enough for spectroscopic analysis.     General procedure for the three-component reaction of quinoline, DMAD, and 3-methyleneoxindoles A mixture of quinoline (1.5 mmol), DMAD (1.5 mmol, 0.213 g), and 3-methyleneoxindole (1.0 mmol) in 10.0 mL of dimethoxyethane (DME) was stirred at room temperature for 6 h. Then, the solvent was removed by evaporation and the residue was quickly subjected to thin-layer chromatography (15 × 25 cm SiO 2 plate) with a mixture of light petroleum and ethyl acetate (V/V = 2:1) as the developing reagent.