A facile and efficient ultrasound-assisted synthesis of novel dispiroheterocycles through 1,3-dipolar cycloaddition reactions

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Abstract

A facile and efficient one-pot three-component procedure for synthesis of novel dispirooxindolecyclo[pyrrolo[1,2-c]thiazole-6,5′-thiazolidine] derivatives without any catalysts under ultrasonic condition has been developed. Combining with the advantages of sonochemistry, such as mild reaction conditions, good yield and short reaction times, we have made a progress on construction of novel disiproheterocyclic compounds via the 1,3-dipolar cycloaddition of azomethine ylides. Several experiments were especially carried out for investigating the acceleration mechanism of ultrasound on the cycloaddition.

Highlights

► Ultrasonic-assisted synthesis of novel dispiroheterocyclic compounds. ► Ultrasonic irradiation was found to have beneficial effect on the synthesis. ► The effect of frequency and temperature of ultrasound irradiation on the reaction was studied. ► The role and acceleration mechanism of sonication in the present system was discussed. ► Mechanistic study of ultrasonic-assisted synthesis of novel dispiroheterocycle compounds.

Introduction

1,3-Dipolar cycloaddition reactions are efficient methods for the construction of heterocyclic units [1]. One of the most important classes for 1,3-dipolar cycloaddition involves azomethine ylide, which is a powerful method for the construction of biologically active five-membered heterocycles especially substituted pyrrolidine rings. The azomethine ylides were easily formed and readily trapped by dipolarophiles, such reaction can be taken placed either inter- or intra-molecularly [2], and the corresponding pyrrolidine derivatives were achieved. Particularly, 1,3-dipolar cycloaddition of azomethine ylide for synthesizing the compounds with spiro moiety were usually in a highly regio- and stereo-selectivity.

Molecules with the thiazolidine nucleus have shown a wide spectrum of bioactivities and drug activity [3]. In medicine, thiazolidine derivatives are well recognized for its anti-inflammatory and anti-hypertensive activities [4]; in pesticides, compounds with thiazolidine ring were treated as the research of novel pesticides for its low toxicity to human being and excellent biological activity, such as the goods of thifluzaminde, ethaboxam, benthiazole and clothianidim. The heterocyclic spiro-oxindole framework is an important structural motif in relevant compounds as natural products and also act as potent nonpeptide inhibitor of the p53-MDM2 interaction [5]. Spiropyrrolidine oxindole ring systems are found in a number of alkaloids such as horsifiline, spirotryprostatine A and B and elacomine [6]. Isatin derivatives are useful precursors in the synthesis of wide number of naturally occurring oxindole alkaloids [7].

Ultrasonic irradiation [8], as a powerful tool in modern chemistry for the organic reactions, has attracted more attention of chemists. The ultrasonic irradiation with its advantages of convenient operation, mild reaction conditions, short reaction time and high efficiency has become particularly popular in recent years, and numerous examples under this condition for constructing heterocycles with interesting properties have been reported in the literature [9].

To our knowledge, the synthesis of dispiroheterocyclic compounds by the 1,3-dipolar cycloaddition of azomethine ylides carried out under ultrasound condition were seldom reported [10]. As part of our interest in the synthesis of spiro compound via the 1,3-dipolar cycloadditions of azomethine ylides [11] and in order to expand the application of ultrasound in the synthesis of heterocyclic compound [12], herein, we report the facile synthesis of novel dispirooxindolecyclo[pyrrolo[1,2-c]thiazole-6,5′-thiazolidine] derivatives having both thiazolone and spirooxindole moieties via catalyst-free, one-pot, three-component 1,3-dipolar cycloaddition reaction of azomethine ylides promoted by ultrasound at room temperature (Scheme 1).

Section snippets

Solvent effect under classical refluxing and ultrasound irradiation

Azomethine ylides can be generated by several methods from easily available starting materials. Among them, the ‘decarboxylation route’ offers a general way for azomethine ylides prepared [13]. The in situ generated azomethine ylide is trapped by dipolarophiles and cycloadducts were produced. Here we have chosen isatin 1, thiazolidine-4-carboxylic acid 2 and 5-benzylidene-2-thioxothiazolidin-4-one 3a as a simple model substrate under both classical refluxing (Method A) and ultrasound

Conclusion

In conclusion, we have succeeded in developing the 1,3-dipolar cycloaddition of azomethine ylides under ultrasonic condition, and a series of novel regioselective dispirooxindolecyclo[pyrrolo[1,2-c]thiazole-6,5′-thiazolidine] derivatives were obtained. Because of the advantages of ultrasonic irradiation of mild reaction conditions, short reaction time and high efficiency, it is quite valuable to develop the 1,3-dipolar cycloaddition of azomethine ylides under this conditions.

Apparatus and analysis

All reagents were purchased from commercial sources and used without further purification. Melting points are uncorrected. IR spectra were recorded on a Varian F-1000 spectrometer in KBr with absorptions in cm−1. 1H NMR were determined on a Varian Invoa-300/400 MHz spectrometer in DMSO-d6 solution. J values are in Hz. Chemical shifts are expressed in ppm downfield from internal standard TMS. HRMS data were obtained using Bruker micrOTOF-Q instrument. Sonication was performed in a SY5200DH-T

Acknowledgements

We acknowledge the financial support from the Foundation of the Natural Science Foundation of China (No. 21072144), the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 10KJA150049), A project Funded by the Priority Academic Project Development of Jiangsu Higher Education Institutions and Key Laboratory of Organic Synthesis of Jiangsu Province (No. KJS0812). We are grateful to the Analytical and Testing Center of Soochow University

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