A new strategy for the synthesis of novel spiro[indoline-3,2'- thiazolo[5,4-e ]pyrimido[1,2-a ]pyrimidine] derivatives

An environmentally benign, efficient and facile route is developed for the synthesis of novel spiro[indoline-3,2'-thiazolo[5,4-e ]pyrimido[1,2-a ]pyrimidine] derivatives. The benzylidene derivatives of spiro[indoline-thiazolidinones] 6 containing an α , β -unsaturated ketonic function [- CH=CH-CO-] have been used as a component of Michael addition with an equimolar amount of 2-aminopyrimidine 7 to give a series of novel spiroindole derivatives 9 in a single step using montmorillonite KSF as inorganic solid support with few drops of DMF. In comparison to conventional synthesis involving tedious multistep procedures, the present method indicates operational simplicity, shorter reaction time and higher yields which can prove this procedure as a useful alternative for the synthesis of novel spiro heterocycles.


Introduction
Heterocyclic scaffolds represent the central framework of many biologically active compounds.2] It is well known that the heterocyclic spiro-oxindole framework is an important structural motif in biologically relevant compounds as natural products and pharmaceuticals, 3 e.g., surugatoxin, horsfiline, spirotryprostatin A&B, elacomine, gelsemine, alstonisine and strychnofoline.
5] Spiro[indole-thiazolidinones] are known to possess various biological activities including antiinflammatory, 6 antimicrobial, 7 bacteriostatic, 8 anticonvulsant 9 and used as antifungal agents. 10In addition, the synthesis of pyridopyrimidine and their derivatives is of high interest in organic chemistry due to their potential biological and pharmacological activities such as antiviral, [11][12] antiinflammatory, 13 insecticidal, 14 antifolate, 15 tyrosine kinase inhibitor, 16 antimicrobial, 17 calcium channel antagonists, 18 antileishmanial, 19 diuretic and potassium-sparing. 20On the other hand thiazolo-pyrimidines are important class of compounds with wide range of biological activity. 21It has been observed that the incorporation of more than one bioactive heterocyclic moiety into a single framework may result into the production of novel heterocycles with enhanced bioactivity. 22Further, annulation of heterocyclic ring often improves biological properties such as potency, selectivity, toxicity and metabolic stability. 23eeping in view of diverse biological activities associated with spiroindoles, pyrimidopyrimidines and thiazolopyrimidines, it was thought to construct a novel system which may combine these bioactive rings together in a single molecular framework to see the additive effects towards their biological activities.Further, a literature survey reveals no report on the synthesis of title novel nucleus yet so far.As part of our ongoing program to develop efficient and robust methods for the preparation of biologically relevant compounds 24 from readily available building blocks, which are novel yet resemble known biologically active molecules by virtue of the presence of some critical structural features, we have developed a facile, efficient, one-pot method for the synthesis of novel spiro[indoline-3,2'-thiazolo [5,4-e]pyrimido[1,2a]pyrimidin]-2(1H)-one 9a-d by the reaction of 5'-benzylidene-3'-phenylspiro[indoline-3,2'thiazolidine]-2,4'(1H)-dione 6a-d with 2-aminopyrimidine 7 using montmorillonite KSF with few drops of DMF under microwave irradiation (scheme-1) and its comparison with synthesis under conventional conditions, which involves multistep tedious procedure requiring excessive use of solvent and extra labor for separation and purification of compounds as various steps.

Results and Discussion
The required biologically important scaffold spiro[indoline-thiazolidinones] 4 were prepared by the improved solvent free multicomponent condensation between substituted indole-2,3-diones 1, thioglycolic acid 2 and amines 3 using montmorillonite KSF as solid support.The required compound 4 was formed in reasonable purity (TLC) and could be used as such for next step without further purification.The reaction of 4 with benzaldehyde 5 yielded 5'-benzylidene-3'phenylspiro[indoline-3,2'-thiazolidine]-2,4'(1H)-dione 6 "in situ" in 4-5 min under same reaction conditions in one-pot.The spiro[indoline-thiazolidinones] system has been synthesized earlier conventionally by a two step procedure in 40-60% yield using isatin-3-imines as key intermediate, which were synthesized from substituted isatins and aromatic amines.The classical methods involving either the azeotropic removal of water 25 or reaction in presence of dehydrating agent 26 and use of large amount of volatile and toxic solvents at elevated temperature for several hours of heating were of some utility.Further, the products are generally purified by crystallization or column chromatography with further need of solvent.
The benzylidene derivatives 6 containing an α,β unsaturated ketonic functional group in their structure have been used as a component of Michael addition with 2-aminopyrimidine to afford novel spiro compound using montmorillonite KSF.However, the results obtained from spectral studies showed the formation of uncyclized Michael adduct 8a instead of expected spiro derivative 9 even after irradiating the reaction mixture for long duration of time (30 minutes).The desired spiro compound 9 was formed successfully within 4-5 minutes by adding few drops of DMF in the same reaction mixture (scheme-1).The reaction times and product yields for various substrates are summarized in Table 1.The ability of DMF is to act as energy transfer agent and homogenizer to increase the reaction temperature was also advocated by Loupy and co-workers. 27It did not lead to any side reaction and no detectable by-products were observed.Hence, the results showed that the combination of clay with DMF is most suitable reaction medium for present investigation involving the annulation of pyrimidine ring on 5'-benzylidene-3'-phenylspiro[indoline-3,2'thiazolidine]-2,4'(1H)-dione 6 in single step.Further, to check the possibility of formation of 8 or 9, the reaction of 6a with 2-aminopyrimidine was also carried out conventionally using fused sodium acetate in dioxane and in ethanol containing 4-5 drops of glacial acetic acid.The results showed the formation of

Experimental Section
General.Reagents and solvents were obtained from commercial sources and used without further purification.Melting points were determined on a Toshniwal apparatus.The elemental and spectral analyses of synthesized compounds have been carried out at the Central Drug Research Institute, Lucknow and Regional Sophisticated Instrumentation Centre, Chandigarh.The purity of compounds was checked on thin layers of silica gel in various non-aqueous solvent systems, for e.g.benzene: ethylacetate (9:1), benzene: dichloromethane (8:2).IR spectra (KBr) were recorded on a Magna FT IR-550 spectrophotometer and 1 H NMR and 13 C NMR spectra were recorded on Bruker DRX-300 using CDCl 3 at 300.15 and 75.46 respectively.TMS was used as internal reference.Mass spectrum of representative compound was recorded on Kratos 50 mass spectrometer at 70 eV.The microwave-assisted reactions were carried out in a commercial multimode MW oven equipped with inverter technology and also attached with a magnetic stirrer and reflux condenser, operating at 1000W generating 2450 MHz frequency.

Synthesis of 3'-phenylspiro[indoline-3,2'-thiazolidine]-2,4'(1H
)-diones 4.These compounds were synthesized in one-pot by multicomponent cyclocondensation reaction of indole-2,3-dione, amines and thioglycolic acid using montmorillonite KSF as solid support as previously reported by us. 28Since TLC studies showed 100% conversion with formation of single product hence it is used as such for further conversion without isolating them.For structural confirmations, some products are isolated by desorption with methanol and compared with authentic samples prepared by literature methods. 29