Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction

A convenient synthetic procedure for the construction of novel dispirooxindole motifs was successfully developed by base-promoted three-component reaction of ammonium acetate, isatins and in situ-generated 3-isatyl-1,4-dicarbonyl compounds. The piperidine-promoted three-component reaction of ammonium acetate, isatins and the in situ-generated dimedone adducts of 3-ethoxycarbonylmethyleneoxindoles afforded mutlifunctionalized dispiro[indoline-3,2'-quinoline-3',3''-indoline] derivatives in good yields and with high diastereoselectivity. On the other hand, a similar reaction of the dimedone adducts of 3-phenacylideneoxindoles afforded unique dispiro[indoline-3,2'-pyrrole-3',3''-indoline] derivatives with a cyclohexanedione substituent. A plausible reaction mechanism is proposed to explain the formation of the different spirooxindoles.


Results and Discussion
At first, 3-isatyl-1,4-dicarbonyl compound 1 was prepared by DBU-catalyzed Michael addition reaction of dimedone and ethyl 2-(2-oxoindolin-3-ylidene)acetate in toluene according to the published method [52]. Then, the reaction conditions of the three-component reaction of isatyl adduct 1a (0.20 mmol), isatin 2a (0.20 mmol) and ammonium acetate (0.5 mmol) were examined according to Zhang and co-workers reported reaction (reaction 1 in Scheme 1) [12]. In the presence of piperidine, the reaction in methanol at room temperature did not yield the product ( . When the loading of ammonium acetate was increased to 0.8 mmol and 1.0 mmol, the yield of 3a increased to 85% and 82% (Table 1, entries 10 and 11). Prolonging the reaction time did not increase the yield of product 3a (Table 1, entry 12). Therefore, the optimized reaction conditions found for this three-component reaction are the use of a mixture of methanol and toluene at 50 °C for seven hours in the presence of piperidine.
With the optimized reaction conditions in hand, the scope of the reaction was investigated by using various substrates. The results are summarized in Table 2. All reactions proceeded smoothly to give the desired dispiro compounds 3a-m in satisfactory yields. Various isatins with different substituents can be successfully used in the reaction. The substituents showed marginal effects on the yields. On the other hand, the dimedone adducts of alkyl 2-(2-oxoindolin-3-ylidene)acetate with various substituents were also successfully employed in the reaction to give the desired products. It can be seen that the dimedone adducts of alkyl 2-(2-oxoindolin-3-ylidene)acetate with 5-chloro and 5-fluoro substituent gave the spiro compounds 3a-k in satisfactory yields. However, the dimedone adducts of ethyl 2-(2-oxoindolin-3-ylidene)acetate itself and its derivatives with 5-methyl group gave the products 3l and 3m in moderate yields. The chemical structures of the obtained dispiro compounds 3a-m were fully characterized by IR, HRMS, 1 H and 13 C NMR spectroscopy. Because of the three chiral carbon atoms in the product, several diastereomers might be formed in the reaction. However, TLC monitoring and 1 H NMR spectra of the crude products clearly indicated that only one diastereoisomer was predominately produced in the reaction, while the other possible diastereomers were not detected. This result shows that this reaction has a high diastereoselectivity due to the large steric effect of two oxindole scaffolds and the thermodynamically controlling effect. The single crystal structure of compound 3a was determined by X-ray crystallographic diffraction ( Figure 1). From Figure 1 it can be seen that the two scaffolds of oxindole at neighboring positions are in trans-configuration. The ethoxycarbonyl group is also in trans-position to the carbonyl group in the neighboring oxindole scaffold. Therefore, it can be concluded that the obtained dispiro compounds 3a-m have this kind of relative configuration on the basis of 1 H NMR spectra and crystal structure determination. It should be pointed out that ammonium acetate was employed as nitrogen source in this three-component reaction. For investigating the scope of this reaction, aniline was also used in the reaction, but in this case no expected dispirooxindoles could be obtained. In order to investigate the scope of this reaction, similar dimedone adducts of 3-phenacylideneoxindoles were used in the three-component reaction. To our surprise, instead of the above mentioned dispiro[indoline-3,2'-quinoline-3',3''-indolines] 3a-m, the novel dispiro[indoline-3,2'-pyrrole-3',3''-indoline] derivatives 4a-i were obtained in high yields. The results are summarized in Table 3. The structural analysis showed that the carbonyl group of the dimedone does not take part in the further cyclization reaction, while the carbonyl group of the benzoyl group participated in the annulation reaction to give the pyrrolidyl ring. This result clearly indicated that the adducts of 3-phenacylideneoxindoles showed different reactivity to that of the adducts of 3-ethoxycarbonylmethyleneoxindoles. For confirming the chemical structures of dispirooxindoles 4a-i, the single crystal structure of compound 4a was determined by X-ray diffraction ( Figure 2). In Figure 2, the two oxindole scaffolds are in trans-position. The dimedone moiety is also in trans-position to the carbonyl group in the neighboring oxin- presence of piperidine, the three-component reaction proceeded smoothly at room temperature in twelve hours to give the expected dispiro[indoline-3,2'-pyrrole-3',3''-indoline] derivatives 4j-p in satisfactory yields. The 1,3-cyclohexanedione moiety does not take part in the further cyclization process. These results show that this reaction is largely general. The 1 H NMR spectra of the obtained compounds 4j-p clearly show similar chemical shifts of the characteristic groups as the spiro compounds 4a-i. Therefore, it can be concluded that the spiro compounds 4j-p have the same relative configuration as the spiro compounds 4a-i.
In order to explain the formation of different cyclic compounds, a plausible reaction mechanism was proposed in Scheme 2 on the basis of the present experiments and the previous works [51][52][53]. Firstly, 3-isatyl-1,4-dicarbonyl compound 1 was converted to a carbanion in the presence of base. In the meantime, the condensation of isatin 2 with ammonium acetate gave the

Conclusion
In summary, we have investigated the base-promoted multicomponent reaction of 3-methyleneoxindoles, dimedone, isatins and ammonium acetate. The reaction showed very interesting molecular diversity and diastereoselectivity. This reaction provided efficient synthetic protocols for the synthesis of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] derivatives. A plausible reaction mechanism was proposed to explain the selective formation of the different polycyclic compounds. This reaction has the advantages of using readily available materials, simple reaction conditions, satisfactory yields, high diastereoselectivity and atomic economy, which enable this reaction potential synthetic applications in heterocyclic chemistry and medicinal chemistry.

Experimental
General procedure for the preparation of compounds 3a-m To a round flask was added 3-isatyl-1,4-dicarbonyl compound 1 (0.20 mmol), isatin 2 (0.20 mmol), ammonium acetate (0.80 mmol), piperidine (0.30 mmol), toluene (2.0 mL) and methanol (2.0 mL). The mixture was heated at 50 °C for seven hours. After removing the solvent by rotatory evaporation at reduced pressure, the residue was subjected to column chromatography (silicon gel, 300-400 mesh) with petroleum ether and ethyl acetate (v/v = 1:1) to give the pure product for analysis. General procedure for the preparation of compounds 4a-p

Supporting Information File 1
Characterization data, 1 H NMR, 13 C NMR, and HRMS spectra of the compounds.

Funding
This work was financially supported by the National Natural Science Foundation of China (Nos. 21871227).