Synthesis of New Pyrazolo[1,5-α]quinazoline Derivatives

Abstract The reaction of various anthranilic acid derivatives or their esters with 4-oxotetrahydrothiophene-3-carbonitrile 2, 2-oxocyclopentanecarbonitrile (9, n = 1) or 2-oxocyclohexanecarbonitrile (9, n = 2) in ethanol under reflux conditions giving rise the formation of single products isolated in each case after simple filtration. The products were characterized as pyrazolo[1,5-a]quinazolin-5-ones 4 instead of the expected pyrazol-3-amines 3. These cascade condensation–intramolecular acylation processes generated in one-step reactions from simple starting materials novel heterocyclic scaffolds ready for further functionalization. The present synthetic protocol provides acceptable yields of new tetracyclic products in high purity. GRAPHICAL ABSTRACT


RESULTS AND DISCUSSION
The starting 2-hydrazino-benzoic acids or their esters 1 are commercially available; however, because of their relatively high price all of them were prepared in house from the corresponding anthranilic acid derivatives according to the procedures described in the literature. [7,8] These acids or their esters were reacted with 4oxotetrahydrothiophene-3-carbonitrile 2 in ethanol under reflux. After 3 h heating a single product was isolated (via 6, 7 and 8) in each case after simple filtration. These products were characterized as 6,7-dihydro-5H,9H-thieno[3 0 4 0 :3,4]pyrazolo[1,5-a] quinazolin-5-ones 4 instead of the expected thieno [3,4-c]pyrazol-3-amines 3 on the basis of their elemental analysis as well as infrared (IR), 1 H NMR, 13 C NMR, and mass spectral (MS) analysis. The IR spectrum of 4 revealed the presence of a carbonyl stretching vibration band around 1680 cm À1 , for the lactam carbonyl group, and in the NMR spectra a newly formed amide was visible instead of the amine. This lactam 4 was later reduced to the corresponding amine 5, which become the key compound for further diversification of this small compound library in our medicinal  chemistry program (Scheme 2, Table 1). Among the products 5a, 5c, and 5f were successfully prepared. In other cases, a complex mixture was observed during the reduction that lacked the desired products (5b, 5d, 5e, and 5g).
The formation of the pyrazole ring in the reaction of a keto-cyanide 1 and arylhydrazine 2 is well documented in the literature. However, the intramolecular acylation of the pyrazolamine 8 usually requires more activated acid derivatives such as chloride in the presence of base (Scheme 3).
In the same way, refluxing a solution of 2-oxocyclopentanecarbonitrile (9, n ¼ 1) or 2-oxocyclohexanecarbonitrile (9, n ¼ 2) in ethanol with arylhydrazines 1 afforded a series of novel tetracyclic pyrazolo[1,5-a]quinazoline 10 derivatives in a single step (Scheme 4, Table 2). Then the lactam 10 was reduced to the corresponding amine 11 under the same conditions described previously. Besides the successful reactions of 11a-c, 11e, and 11f (Table 2), the products 11d, 11 g, and 11 h were not observed, probably due to the decomposition of the proper lactams under the applied reaction conditions. In conclusion, we report a cascade condensation-intramolecular acylation process generated in the reaction of cyclic ketocyanides 2 and 2-hydrazino-benzoic acids or their esters 1 (R 1 ¼ CO 2 H or CO 2 Me accordingly) to afford novel heterocycles. The present synthetic protocol provides acceptable yields of new tetracyclic products in good purity. The bioactivity of the newly synthesized compounds will be published elsewhere.

EXPERIMENTAL Preparation of 2-Hydrazino-benzoic Acids
The corresponding anthranilic acid (1 mmol) was suspended in hydrochloric acid (6 M, 2.4 ml) and cooled to À5°C. Sodium nitrite (1.1 mmol) was dissolved in water (0.4 ml) and added dropwise. The reaction mixture was stirred for 1 h at À5°C and then SnCl 2 · 2H 2 O was added (0.451 g, 2 mmol dissolved in 0.6 ml of 6 M aqueous HCl). The product was precipitated, filtered, washed with water, and dried in vacuo. The product was used without any further purification (yield 64-100%).

SUPPLEMENTAL MATERIAL
Full experimental details, assignment, the 1 H and 13 C NMR spectra, IR spectra, and HRMS details for this article can be accessed on the publisher's website.