Facile synthesis of substituted dihydro-1H-pyrazolo[3,4-d]thiazoles through enaminones of 4-thiazolidinones

Introduction

Heterocyclic compounds occupy a prominent place in medicinal chemistry as pharmaceutical and drug intermediates. Nearly 70% of all commercially available agrochemicals and pharmaceuticals are heterocyclic compounds. Pyrazole derivatives have been the focus of increasing attention owing to their numerous pharmacological applications and biological activities such as antimicrobial [1, 2], antiviral [3, 4], antitumor [5], and anti-inflammatory [6] properties. The pyrazole moiety is utilized within the core structure of various drugs such as diferanizole, celecoxib, and tepoxalin, among others. Most of these active compounds bear either one or more heterocyclic scaffolds or a benzannulated bicyclic core. There are only a few known active bicyclic scaffolds which are made up of two different heterocycles. Examples include imidazothiazole anthelmintics, such as levamisole and allopurinol, and a purine analog, xanthine oxidase (XO) inhibitor, used in the treatment of gout and hyperuricemia. Condensed pyrazoles are known for various biological activities, for example, pyrazolo[3,4-b]quinolines are potential antiviral [7] and antimalarial [8] agents, pyrazolo[4,3-c]quinolines are antiangiogenic [9] compounds, pyrazolo[3,4-c]pyrimidine are antitumor [10] agents, pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-ones are XO inhibitors [11], and pyrazolo[1,5-a]pyrimidines are cytotoxic agents [12].

In view of the above biological importance and in continuation of our studies on the synthesis and characterization of novel 4-thiazolidinone [13–15] and pyrazole derivatives, here we report facile synthesis of fused pyrazolo[3,4-d]thiazoles from enaminones of 4-thiazolidinones.

Results and discussion

A two-step synthesis of a pyrazolo[3,4-d]thiazole system from a thiazolidinone is described. The first step of the general approach involves the conversion of thiazolidinone 1 into its arylidene derivative 2 via Claisen condensation with an aldehyde. In the second step, condensation of 5-arylidenethiazolidinones [16, 17] with different hydrazine derivatives was attempted to furnish the desired tetrahydropyrazolo[3,4-d]thiazoles 3 (Scheme 1). Unfortunately, our several attempts by using acidic and basic reagents (acetic acid, sodium acetate, piperidine) and different solvents (methanol, trifluoroethanol, acetonitrile, tetrahydrofuran) did not bring about the desired ring closure reaction. The reaction of the arylidene derivative 2 with hydrazine hydrate produced compound 4 (Scheme 1), which was identified on the basis of its ¹H NMR and mass spectral data. ¹H NMR spectrum of 4 exhibits one multiplet of two protons and two triplets of two protons each at δ 1.93, 2.78, and 2.85, respectively, which are assigned to the tetrahydronaphthalene moiety. Mass spectrum of 4 exhibits an intense peak at m/z 289.2 for [M+H] (100%).

Scheme 1

The synthesis of hydrazono-thiazolidinone 1 bearing the tetrahydronaphthalene moiety has been reported in our previous communication [18] by using a conventional method as well as synthesis in ionic liquid. The reaction of thiazolidinone 1 with dimethylformamide-dimethylacetal furnished enaminone 5. It was found that in addition to the condensation of the active methylene function of thiazolidinone at position 5 with dimethylformamide-dimethylacetal, methylation of a cyclic amide function (CONH) also occurs during this reaction. Similar hydrazono-dihydropyrazolo[3,4-d]thiazoles have been obtained previously by condensation of an α-hydroxynitrile [19–21] and 5-α-amino-β-trichloroethanylidino-4-oxothiazole [22] with hydrazine derivatives. In this study, we attempted the synthesis of pyrazolo[3,4-d]thiazoles from thiazolidinone enaminone 5 and hydrazines using different basic reagents such as sodium acetate, pyridine, and piperidine. Unfortunately, ring closure was not achieved. Recently, Pelletier et al. [23] have reported the synthesis of tetrahydropyrazolo[3,4-d]thiazole by condensation of 5-benzylidene-4-thiazolidine-thione with hydrazines by enhancing the reactivity of thiazolidinone through thionation of the lactam function. Using a similar approach, we converted thiazolidin-4-one 1 into 4-thiazolidin-thione 6. This transformation was easily carried out with Lawesson’s reagent [24]. The reaction of enaminone 5 with Lawesson’s reagent in toluene furnished corresponding 4-thiazolidine-thiones 6. The reaction of thiazolidinone 1 with dimethylformamide-dimethylacetal and then conversion of enaminone 5 into the thione derivative 6 could also be achieved in a single step. Thiazolidinone 1 was first heated under reflux with Lawesson’s reagent in toluene and then the mixture was treated with dimethylformamide-dimethylacetal under continuing reflux conditions for an additional 60 min to give the same thione derivative 6. The reaction of 4-thiazolidin-thione 6 with hydrochloride salts of different hydrazines in ethanol furnished pyrazolo[3,4-d]thiazoles 7 (Scheme 2). The structures of the synthesized compounds were established by elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectral data. It should be noted that the products can exist in a number of geometrical isomers. In all cases, the TLC analysis indicated the presence of a single diastereomer but stereochemistry was not investigated.

Scheme 2

Reagents and conditions: (a) DMF-DMA, DMF, reflux; (b) R²NHNH₂·HCl, EtOH, stirring at 80°C; (c) Lawesson’s reagent, toluene, reflux; (d) Lawesson’s reagent, toluene, DMF-DMA. DMF-DMA, dimethylformamide-dimethylacetal.

Conclusion

A general synthesis of dihydro-1H-pyrazolo[3,4-d]thiazoles from 4-thiazolidinones was achieved in two simple steps. In the first step, 5-dimethylaminomethylene-3-methylthiazolidine-4-thiones were obtained by the reaction of thiazolidinones with Lawesson’s reagent and dimethylformamide-dimethylacetal. The ring construction of the second step was accomplished by treatment with hydrazine derivatives in acidic medium.

Experimental

All chemicals were obtained from Sigma and used without further purification. Melting points were determined in open capillaries and are uncorrected. Elemental analysis was done on a Euro EA 3000 elemental analyzer. Mass spectra were recorded on a Waters, Q-TOF Micromass, LC-MS instrument. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded in CDCl₃ on a Bruker Avance II 400 spectrometer using tetramethylsilane (TMS) as an internal standard. IR spectra were recorded on an Abb FTIR spectrometer. Thin layer chromatography (TLC) was performed on silica gel G-coated plates and using iodine vapor as a visualizing agent. Thiazolidin-4-ones 1a,b were obtained by cyclocondensation of thiosemicarbazone of 1-tetralone and chloroacetic acid, as reported previously [18].