Efficient, environment friendly and regioselective synthetic strategy for 2/3-substituted-8,8-dimethyl-8,9-dihydropyrazolo[1,5-a]quinazolin-6(7H)-ones and their structure elucidation European Journal of Chemistry 13 (1) (2022) 41-48 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2022 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.13.1.41-48.2168 European Journal of Chemistry View Journal Online View Article Online Efficient, environment friendly and regioselective synthetic strategy for 2/3-substituted-8,8-dimethyl-8,9-dihydropyrazolo[1,5-a]quinazolin-6(7H)-ones and their structure elucidation Susma Das , Labet Bankynmaw Marpna and Jai Narain Vishwakarma * Department of Chemical Science, Assam Don Bosco University, Tapesia Gardens, Kamarkuchi, Sonapur, 782402, Assam, India * Corresponding author at: Department of Chemical Science, Assam Don Bosco University, Tapesia Gardens, Kamarkuchi, Sonapur, 782402, Assam, India. e-mail: jnvishwakarma@dbuniversity.ac.in (J.N. Vishwakarma). 10.5155/eurjchem.13.1.41-48.2168 Received: 31 July 2021 Received in revised form: 21 September 2021 Accepted: 07 October 2021 Published online: 31 March 2022 Printed: 31 March 2022 An efficient and regioselective synthetic reaction friendly to the environment has been described to synthesize various derivatives of pyrazolo[1,5-a]quinozolinone. Condensation of aminopyrazole (4a-m) with formylated dimedone (3) in the presence of KHSO4, under ultrasonic irradiation furnished 2/3-substituted 8,8-dimethyl-8,9-dihydropyrazolo[1,5- a]quinazolin-6(7H)-one (6a-m). This is a clean reaction, giving excellent yields with short reaction time. The structures were elucidated with the help of spectral and analytical data. X-ray crystallographic studies of a model compound 6a ascertained its structural configuration, crystal data for C12H12BrN3O (M =294.152 g/mol): Triclinic, space group P-1 (no. 2), a = 5.872(4) Å, b = 10.870(8) Å, c = 19.523(15) Å, α = 90.013(10)°, β = 90.009(11)°, γ = 93.838(11)°, V = 1243.3(16) Å3, Z = 4, T = 296.15 K, μ(Mo Kα) = 3.293 mm-1, Dcalc = 1.571 g/cm3, 37271 reflections measured (4.18° ≤ 2Θ ≤ 52.7°), 5073 unique (Rint = 0.2404, Rsigma = 0.2366) which were used in all calculations. The final R1 was 0.0596 (I≥2σ(I)) and wR2 was 0.1759 (all data). Regioselective Aminopyrazole X-ray crystallography Ultrasound irradiation Pyrazolo[1,5-a]pyrimidine Pyrazolo[1,5-a]quinozolinone Cite this: Eur. J. Chem. 2022, 13(1), 41-48 Journal website: www.eurjchem.com 1. Introduction In view of the biological properties of pyrazolo[1,5-a]pyri- midine derivatives, we have recently published the synthesis and biological properties of a variety of molecules of this class for example 3, 7-diarylpyrazolo[1,5-a]pyrimidines (A) [1], 3, 6- diarylpyrazolo[1, 5-a]pyrimidin-7-amines (B) [1], 7-aryl-3-(4- chlorophenyl)-N-phenylpyrazolo[1, 5-a]pyrimidin-2-amines (C) [2], 6/7-substituted N-phenylpyrazolo[1,5-a]pyrimidine-3- carboxamides (D) [3], 6,7-substituted 2-(4-methoxyphenyl) pyrazolo[1,5-a]pyrimidines (E) [4], 6/7-substituted N-(1,5- dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazol-4-yl)pyra- zolo[1, 5-a]pyrimidine-3-carboxamides (F) [5], ethyl 7-(p- halide / nitro / aryl)pyrazolo[1, 5-a]pyrimidine-3-carboxylates (G) [6], ethyl 7-(naphthalen-2-yl)pyrazolo[1,5-a]pyrimidine-3- carboxylates (H) [6], 2-methyl-3,6-diphenylpyrazolo[1,5-a] pyrimidin-7-amines (I) [7], etc. (Figure 1). Recently, synthesis and studies of pyrazoloquinazoline derivatives are becoming popular among researchers, as they are reported to exhibit a wide spectrum of bioactivities such as antibacterial [8], anticancer [9], antioxidant [10], anti-inflam- matory [11], anti-diabetic [12], antiviral [13] and therapeutic applications in neurodegenerative disorders [14], adenosine receptor antagonist [15], GABAA subtype receptor [16], etc. In continuation with these studies and in view of the importance of pyrazoloquinozolines, we herein report the synthesis and X- ray crystallographic studies of pyrazolo[1,5-a]quinozolin- 6(7H)-one derivatives. 2. Experimental 2.1. Instrumentation The melting points of each of the synthesized compounds 6a-m were recorded by the open capillary method and are uncorrected. The 1H NMR and 13C NMR spectra were recorded using DELTA JNM-ESC 400 MHz using (Me)4Si as the internal standard in chloroform-d. Chemical shift (δ ppm) and coupling constants (Hz) are reported in the standard manner. The abbreviations s, d, dd, t, and m stand for singlet, doublet, double- doublet, triplet, and multiplet, respectively. Chemical shift (δ, ppm) and coupling constants (Hz) are reported in a standard fashion. The electrospray mass spectrum was recorded on a Thermo Finnigan LCQ Advantage max ion trap mass spectro- meter. The FT-IR spectra were recorded using Perkin Elmer Spectrum Two spectrometer. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.13.1.41-48.2168 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.13.1.41-48.2168 mailto:jnvishwakarma@dbuniversity.ac.in http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.13.1.41-48.2168&domain=pdf&date_stamp=2022-03-31 42 Das et al. / European Journal of Chemistry 13 (1) (2022) 41-48 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.41-48.2168 N NN N NN NH2 N NNHN Cl N NN O HN A B C D N NN MeO E NH2 N NN O HN NH2 NN O Me Me F N N N O O N N N O O Et H N N N NH2 Me I Cl G Me Et Cl Figure 1. Some of our reported pyrazolo[1,5-a]pyrimidine derivatives. The X-ray diffraction data were collected at 293 K with MoKα radiation (λ = 0.71073 Å) using a Bruker APEX-II CCD (Charge Coupled Device) [17] diffractometer which is equipped with a graphite monochromator. The structures were refined by using Olex2-1.3 [18,19] via full-matrix least-squares based on F-square. All non-H-atoms were refined in anisotropic approximation, and H-atoms were located at calculated positions. US irradiation was carried out in an Equitron Digital Ultrasonic cleaner 2.5 L, model number 8425.025.424 at 170 Watts and 50 Hz. 3-Aminopyrazoles (4a-d) and (4f-j) were obtained from commercial sources and compounds 4e and 4k- m were prepared by a reported procedure [4]. 2.2. Synthesis of substituted 8,9-dihydropyrazolo[1,5- a]quinazolin-6(7H)-ones (6a-m) To a solution of 2-((dimethylamino)methylene)-5,5-dimet hylcyclohexane-1,3-dione (3) (0.5 mmol) (prepared by a reported procedure [6]) and 3-aminopyrazole (4) (0.5 mmol) in 1.5 mL of ethanol in a round bottom flask, a solution of KHSO4 (1 mmol) in 1.5 mL of water was added and the resulting mixture was irradiated in an ultrasound cleaner bath main- tained at 60 °C for 5-12 minutes monitoring the progress of the reaction by thin layer chromatography. At the end of the reaction, the flask was cooled to room temperature and the precipitate formed was collected by filtration, washed repeatedly with water ensuring complete removal of the acid, and finally dried to give practically pure compound 6 in 70-95% overall yields. Analytically pure products were obtained by column chromatography (silica gel, 10% ethyl acetate:hexane). The characterization data of the unreported compounds are presented below and the known compounds were compared with the reported data. 3-Bromo-8, 8-dimethyl-8, 9-dihydropyrazolo[1, 5-a]quinazo lin-6(7H)-one (6a): Color: Light brown solid. Yield: 86%. M.p.: 130-131 °C. FT-IR (KBr, ν, cm-1): 1682 (C=O), 1606 (C=N), 1531 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.19 (s, 6H, 2(CH3)), 2.56 (s, 2H, C7-H), 3.30 (s, 2H, C9-H), 8.22 (s, 1H, C2-H), 8.99 (s, 1H, C5-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 28.6 (2C, CH3), 32.9 (1C, C8), 36.9 (1C, C9), 50.9 (1C, C7), 87.2 (1C, C3), 113.9 (1C, C5-C-C6), 146.0 (1C, C2), 147.5 (1C, C3-C-N), 148.0 (1C, C5), 152.9 (1C, N-C-C9), 194.5 (1C, C=O). MS (ESI, m/z): 295.2 (MH+). 8, 8-Dimethyl-2-phenyl-8, 9-dihydropyrazolo[1, 5-a]quinazo lin-6(7H)-one (6b): Color: White solid. Yield: 70%. M.p.: 241- 242 °C (244-245 °C [20]). MS (ESI, m/z): 292.0 (MH+). 8, 8-Dimethyl-8, 9-dihydropyrazolo[1, 5-a]quinazolin-6(7H)- one (6c): Color: Pale yellow solid. Yield: 85 %. M.p.: 140-141 °C (142 °C [21]). FT-IR (KBr, ν, cm-1): 1680 (C=O), 1608 (C=N), 1532 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.19 (s, 6H, 2(CH3)), 2.55 (s, 2H, C7-H), 3.33 (s, 2H, C9-H), 6.75 (s, 1H, C3-H), 8.22 (s, 1H, C2-H), 8.94 (s, 1H, C5-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 28.7 (2C, CH3), 32.9 (1C, C8), 37.3 (1C, C9), 51.0 (1C, C7), 99.2 (1C, C3), 113.4 (1C, C5-C-C6), 147.1 (1C, C2), 147.6 (1C, C3- C-N), 149.4 (1C, C5), 152.4 (1C, C9-C-N), 194.8 (1C, C=O). MS (ESI, m/z): 216.0 (MH +). 2-(Tert-butyl)-8, 8-dimethyl-8, 9-dihydropyrazolo[1, 5-a]qui nazolin-6(7H)-one (6d): Color: Light brown solid. Yield: 84 %. M.p.: 203-204 °C. FT-IR (KBr, ν, cm-1): 1690 (C=O), 1607 (C=N), 1533 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.20 (s, 6H, 2(CH3)), 1.39 (s, 9H, C(CH3)3), 2.53 (s, 2H, C7-H), 3.35 (s, 2H, C9- H), 6.61 (s, 1H, C3-H), 8.88 (s, 1H, C5-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 28.7 (2C, CH3), 30.3 (3C, C(CH3)), 32.8 (1C, C(CH3)), 33.3 (1C, C8), 37.3 (1C, C9), 51.1 (1C, C7), 95.7 (1C, C3), 112.7 (1C, C5-C-C6), 146.6 (1C, C3-C-N), 149.7 (1C, C2), 152.2 (1C, C5), 171.0 (1C, C9-C-N), 195.0 (1C, C=O). MS (ESI, m/z): 272.3 (MH +). 2, 8, 8-Trimethyl-3-phenyl-8, 9-dihydropyrazolo[1, 5-a]quina zolin-6(7H)-one (6e): Color: Brown solid. Yield: 95 %. M.p.: 196- 197 °C (195-197 °C [4,20,22,23]). 8, 8-Dimethyl-6-oxo-6, 7, 8,9-tetrahydropyrazolo[1,5-a]quina zoline-3-carbonitrile (6f): Color: Pale yellow solid. Yield: 93 %. M.p.: 165-166 °C (162-163 °C [24]). 8,8-Dimethyl-8,9-dihydropyrazolo[1,5-a]quinazoline-2,6(1H, 7H)-dione (6g): Color: Cream colored solid. Yield: 82 %. M.p.: 202-203 °C. FT-IR (KBr, ν, cm-1): 1686 (C=O), 1614 (C=N), 1540 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 0.95 (s, 6H, 2(CH3)), 2.29 (s, 2H, C7-H), 2.98 (s, 2H, C9-H), 5.84 (s, 1H, C3-H), 8.57 (s, 1H, C5-H), 10.77 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, δ, ppm): 28.5 (2C, CH3), 32.5 (1C, C8), 37.2 (1C, C9), 39.9 (1C, C7), 84.2 (1C, C3), 111.9 (1C, C5-C-C6), 146.7 (1C, C9-C-N), 149.9 (1C, C3-C-N), 151.1 (1C, C5), 168.7 (1C, NH-C=O), 194.4 (1C, C=O)., Das et al. / European Journal of Chemistry 13 (1) (2022) 41-48 43 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.41-48.2168 Scheme 1. Optimization of the reaction conditions. Table 1. Results of the optimization of the reaction. Entry Mode Temperature (°C) Solvent Reaction time (min) Yield (%) 1 Silent Room temperature Water 300 28 2 Silent Room temperature Water-ethanol (1:1, v:v) 270 32 3 Silent 60 Water 300 32 4 Silent 60 Water-ethanol (1:1, v:v) 270 35 5 Sonication Room temperature Water 36 57 6 Sonication Room temperature Water-ethanol (1:1, v:v) 30 62 7 Sonication 60 Water 5 78 8 Sonication 60 Water-ethanol (1:1, v:v) 5 86 2-(4-Methoxyphenyl)-8, 8-dimethyl-8,9-dihydropyrazolo[1,5- a]quinazolin-6(7H)-one (6h): Color: Pale yellow solid. Yield: 86 %. M.p.: 210-212 °C (214 °C [4]). 2, 8, 8-Trimethyl-8, 9-dihydropyrazolo[1, 5-a]quinazolin-6 (7H)-one (6i): Color: Pale yellow solid. Yield: 81 %. M.p.: 132- 133 °C (134-135 °C [25]). 3-Bromo-8, 8-dimethyl-2-phenyl-8,9-dihydropyrazolo[1, 5-a] quinazolin-6(7H)-one (6j): Color: Brown solid. Yield: 86 %. M.p.: 81-83 °C. FT-IR (KBr, ν, cm-1): 1672 (C=O), 1602 (C-N), 1514 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.23 (s, 6H, 2(CH3)), 2.39 (s, 2H, C7-H), 2.46(s, 2H, C9-H), 7.40-7.45 (m, 3H, ArH), 7.67-7.74 (m, 2H, ArH), 9.04 (s, 1H, C5-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 28.4 (2C, CH3), 28.7 (1C, C8), 31.0 (1C, C9), 51.4 (1C, C7), 94.2 (1C, C3), 120.4 (1C, C5-C-C6), 126.9 (2C, C2’, C6’), 128.5 (1C, C4’), 128.7 (2C, C3’,C5’), 135.1 (1C, C1’), 136.3 (1C, C3- C-N), 144.5 (1C, C2), 156.6 (1C, C5), 172.4 (1C, C9-C-N), 191.8 (1C, C=O). 8, 8-Dimethyl-3-(naphthalen-2-yl)-8, 9-dihydropyrazolo[1, 5- a]quinazolin-6(7H)-one (6k): Color: Light brown solid. Yield: 84 %. M.p.: 212-214 °C. FT-IR (KBr, ν, cm-1): 1683 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.15 (s, 6H, 2(CH3)), 2.84 (s, 2H, C7- H), 2.90 (s, 2H, C9-H), 7.42-7.46 (m, 2H, ArH), 7.79-7.81 (m, 3H, ArH), 8.10-8.13 (m, 1H, ArH), 8.44 (s, 1H, ArH), 8.62 (s, 1H, C2- H), 9.01 (s, 1H, C5-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 28.6 (2C, CH3), 32.7 (1C, C8), 37.2 (1C, C9), 50.8 (1C, C7), 112.7 (1C, C3), 113.6 (1C, C5-C-C6), 124.8 (1C, C10’), 127.7 (2C, C6’, C7’), 128.2 (1C, C2’, C3’), 128.4 (2C, C5’, C8’), 128.6 (1C, C3-C-N), 132.4 (1C, C2), 145.7 (1C, C1’), 146.9 (1C, C4’), 152.6 (1C, C5), 162.6 (1C, C9-C-N), 194.7 (1C, C=O). MS (ESI, m/z): 342.2 (MH +). 3-Benzoyl-8, 8-dimethyl-8, 9-dihydropyrazolo[1, 5-a]quinazo lin-6(7H)-one (6l): Color: Light yellow solid. Yield: 83 %. M.p.: 113-115 °C. FT-IR (KBr, ν, cm-1): 1738 (C=O), 1679 (C-N), 1608 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.23 (s, 6H, 2(CH3)), 2.16 (s, 2H, C7-H), 2.58 (s, 2H, C9-H), 6.98-7.01 (m, 3H, ArH), 7.75-7.78 (m, 2H, ArH), 7.93 (s, 1H, C2-H), 8.94 (s, 1H, C5-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 26.4 (2C, CH3), 36.5 (1C, C8), 42.0 (1C, C9), 46.6 (1C, C7), 114.6 (1C, C3), 120.4 (1C, C5-C-C6), 128.1 (1C, C3’), 128.2 (1C, C5’), 132.5 (1C, C2’, C6’), 132.6 (1C, C4’), 140.6 (1C, C1‘), 150.1 (2C, C2, C3-C-N), 161.2 (1C, C5), 176.6 (1C, C9-C-N), 198.5 (2C, C=O). 3-(4-Methoxybenzoyl)-8, 8-dimethyl-8, 9-dihydropyrazolo[1, 5-a]quinazolin-6(7H)-one (6m): Color: Light yellow solid. Yield: 71 %. M.p.: 133-134 °C. FT-IR (KBr, ν, cm-1): 1672 (C=O), 1616 (C=O), 1518 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.23 (s, 6H, 2(CH3)), 2.16 (s, 2H, C7-H), 2.58 (s, 2H, C9-H), 3.86 (s, 3H, OCH3), 6.99 (d, 2H, J = 9.2 Hz, ArH), 7.25 (s, 1H, C2-H), 7.76 (d, 2H, J = 9.2 Hz, ArH), 7.93 (s, 1H, C5-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 26.4 (2C, CH3), 31.0 (1C, C8), 36.5 (1C, C9), 42.0 (1C, C7), 46.6 (1C, OCH3), 89.2 (1C, C3), 114.6 (2C, C3’, C5’), 114.7 (1C, C5- C-C6), 120.3 (1C, C1’), 128.2 (2C, C2’, C6’), 132.5 (1C, C2), 140.6 (1C, C3-C-N), 150.1 (1C, C5), 161.1 (1C, C4’-C-OCH3), 176.6 (1C, C9-C- N), 207.6 (2C, C=O). MS (ESI, m/z): 350.0 (MH +). 3. Results and discussion 3.1. Chemistry In this paper, we have reported the synthesis of various pyrazolo[1,5-a]quinazolin-6(7H)-one derivatives by reacting enaminone derived from dimedone with 2/3-substituted 3- amino-1H-pyrazole by an eco-friendly and simple protocol. To standardize the synthetic protocol, dimedone 1 (0.5 mmol) was formylated by reacting with dimethylformamide-dimethyl- acetal (DMF-DMA) to produce enaminone 3 according to a reported protocol [6]. To crude enaminone 3 was added 4- bromo-3-amino-1H-pyrazole (0.5 mmol) 4a and the resulting mixture was taken in selected solvents. Subsequently, KHSO4 5 (1 mmol) in the selected solvent was added and the resulting mixture was subjected to reaction under various conditions of solvent, temperature, and silent/ultrasonication conditions (Scheme 1, Table 1). At the end of each reaction (as monitored by TLC) the precipitated product was collected by filtration with repeated washing with cold water to remove traces of acid present, and then dried. For its analytical studies, the product was purified further via column chromatography (silica gel, 10% ethyl acetate:hexane). The structure of the product was assigned to be 3-bromo-8,8-dimethyl-8,9-dihydropyrazolo[1,5- a]quinazolin-6(7H)-one (6a). The data presented in Table 1 clearly shows that the most suitable condition (yield 86 %) for the reaction was ultrasonication at 60 °C in a solvent system of water-ethanol (1:1). Hence, this condition was further adopted to generalize the synthetic strategy. For further reactions, we selected thirteen aminopyrazoles of which compounds 4a-j of which were commercially available and compounds 4k-m were synthesized by our reported proce- dure [4]. Enaminone 3 derived from dimedone was prepared using our previous reported method [6]. Thus, enaminone 3 was synthesized by reacting dimedone with DMF-DMA under microwave irradiation. Enaminone 3 was then reacted with an equimolar amount of animopyrazole 4 in the presence of 2 equivalents of KHSO4 in a water-ethanol mixture (1:1) under ultrasonication when a solid product precipitated in good to excellent yield (70-95%). The product thus formed was practically pure. However, for analytical studies, the products were purified by column chromatography. 44 Das et al. / European Journal of Chemistry 13 (1) (2022) 41-48 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.41-48.2168 Scheme 2. Synthesis of 2,3-substituted 8,8-dimethyl-8,9-dihydropyrazolo[1,5-a]quinazolin-6(7H)-one derivatives. The structures of the products 6a-m were well established to be 2/3-substituted 8,8-dimethyl-8, 9-dihydropyrazolo[1, 5- a]quinazolin-6(7H)-one with the help of analytical and spectral data such as 1H NMR, 13C NMR, FT-IR, and mass spectrometry and also by comparison with reported data of the known products. Thus, following this strategy, we have successfully synthesized thirteen molecules (Scheme 2). In the 1H NMR spectra, singlets were found resonating for six protons (two methyl groups) at δ 1.19 ppm for compounds 6a and 6c, at δ 1.20 ppm for compound 6d, at δ 0.95 ppm for compound 6g, at δ 1.23 ppm for compounds 6j, 6l-m and at δ 1.15 ppm for compound 6k. The two CH2 protons at C7 and C9 at two distinct singlets at δ 2.57 and 3.31 ppm for compound 6a, at δ 2.55 and 3.33 ppm for compound 6c, while at δ 2.53 and 3.35 ppm for compound 6d, at δ 2.29 and 2.98 ppm for compound 6g, at δ 2.34 and 2.46 ppm for compound 6j, at δ 2.84 and 2.91 ppm for compound 6k, in δ 2.16 and 2.58 ppm for compounds 6l and 6m. In the NMR spectra of compound 6a, the C2-H and C5-H protons resonated as singlets at δ 8.21 and 8.99 ppm, respectively. In compound 6c, C3-H, C2-H and C5-H appeared as clear singlet at δ 6.75, 8.22 and 8.95 ppm, respec- tively. Furthermore, in compound 6d, the C3-H and C5-H protons gave singlets at δ 6.61 and 8.88 ppm, respectively, and the nine protons of the substituent C(CH3)3 gave a singlet at δ 1.40 ppm. The NMR spectra of compound 6g exhibited singlets for C3-H and C5-H of pyrazolo[1,5-a]quinozoline ring at δ 5.84 and 8.57 ppm, respectively, and at δ 10.77 ppm for NH proton. In compound 6j, C5-H was found to resonate at δ 9.04 ppm as a singlet. In compound 6k, C5-H and C2-H were resonating as singlets at δ 8.62 and 9.01 ppm, respectively, whereas, the seven protons of naphthyl group appeared as multiplet in the range δ 7.43-7.46 ppm for two protons, as multiplet in the range δ 7.79-7.89 ppm for three protons, as singlets at δ 8.45 and 8.13 ppm for one proton each. In compound 6l, C2-H and C5-H resonated as singlets at δ 7.93 and 8.94 ppm respectively, whereas the phenyl group protons gave signals at expected chemical shifts. The spectral data for compound 6m exhibited singlets for C2-H and C5-H at δ 7.25 and 7.93 ppm, respectively, and the three protons of OCH3resonatedas singlet at δ 3.86 ppm, whereas the protons of the phenyl group gave two doublets at δ 6.99 and 7.76 ppm with coupling constant J = 9.2 Hz. The 13C spectra of the new derivatives of 8,8-dimethyl-8,9- dihydroxypyrazolo[1,5-a]quinozolin-6-(7H)-one showed sig- nals at expected chemical shifts. In the FT-IR spectra of the products, neither signals for NH2 group (3400-3600 cm-1) nor for carbonyl of enaminones (1600-1750 cm-1) were observed, thus conforming participation of the two groups leading to cyclization. The mass spectra of the molecules were also in support of the proposed structures. A plausible mechanism for the formation of target molecules is rationalized as follows (Scheme 3). Thus, assisted by KHSO4, Aza-Michael addition elimination occurs resulting in the formation of an adduct which further, in the presence of KHSO4, undergoes cyclodehydration to yield the target molecule 6. Das et al. / European Journal of Chemistry 13 (1) (2022) 41-48 45 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.41-48.2168 O OMe Me N Me Me S O O O OK H + O OMe Me N Me Me H + N N H2N X Y H O OMe Me NMe2 HN H NHN Y X S O OO OK O OMe Me S O O O OK H + O O Me Me N H NN Y X H H N H NN X Y H OMe Me NN HO N HH Y X S O OO OK S O O O OK+ + O MeMe N NN Y X + N N NH2X Y H + OMe Me N Me Me NHHO N N H OMe Me NN N N H H Me Me S O OO OK S O OH2O OK ++ O Me Me N N N Route 1Route 2 X Y Route 1Route 2 X Y X Y Not formed 6 Scheme 3. A representative plausible mechanism for the formation of pyrazolo[1,5-a]quinozoline. 3.2. Crystallographic details of molecule 6a To ascertain the structural configuration of the synthesized compounds, a model molecule 6a was selected and its detailed single-crystal X-ray was studied. Pale yellow crystals of compound 6a were obtained by slow recrystallization from a mixture of dichloromethane and hexane (9:1). The X-ray diffraction data of the crystal 6a was collected at 296.2 K with MoKα radiation using a Bruker APEX-II CCD diffractometer equipped with a graphite monochromator. Compound 6a crystallized in a triclinic crystal system with space group P-1. It was also found that the molecule exists as a dimer (Figure 2). The summary of various refinement factors and parameters is tabulated in Table 3. The three fused rings in pyrazolo[1,5- a]quinozolione were found to be in the same plane, which could be easily understood from its geometrical parameters, such as the length of the bond, the angles of the bond and the angles of torsion of some selected atoms obtained from the crystal structure mentioned in Tables 4 and 5 (Figure 3). The C-C bond lengths in the three fused rings of pyrazolo[1,5-a]quinozolinone ranged from 1.311 to 1.536 Å, while the torsion angles between C13-C24-N5-C15, C21-C22-C23-N6, C21-C22-C15-N5, C16-C15-C22-C21, N4-N5-C15-C22, N3-C11-C10-C3, C4- C3-C10-C9, N3-C12-N2-N1, N2-C3-C4-C5 were obtained at 176.96°, 46 Das et al. / European Journal of Chemistry 13 (1) (2022) 41-48 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.41-48.2168 Table 3. Crystal data and structure refinement for compound 6a. Empirical formula C12H12BrN3O Formula weight 294.152 Temperature (K) 296.15 Crystal system Triclinic Space group P-1 a, (Å) 5.872(4) b, (Å) 10.870(8) c, (Å) 19.523(15) α (°) 90.013(10) β (°) 90.009(11) γ (°) 93.838(11) Volume (Å3) 1243.3(16) Z 4 ρcalc (g/cm3) 1.571 μ (mm-1) 3.293 F(000) 591.4 Radiation Mo Kα (λ = 0.71073) 2Θ range for data collection (°) 4.18 to 52.7 Index ranges -7 ≤ h ≤ 7, -14 ≤ k ≤ 14, -26 ≤ l ≤ 26 Reflections collected 37271 Independent reflections 5073 [Rint = 0.2404, Rsigma = 0.2366] Data/restraints/parameters 5073/0/312 Goodness-of-fit on F2 1.023 Final R indexes [I≥2σ (I)] R1 = 0.0596, wR2 = 0.1160 Final R indexes [all data] R1 = 0.2104, wR2 = 0.1759 Largest diff. peak/hole (e.Å-3) 1.32/-0.96 CCDC No 2064851 Figure 2. Molecular structure of compound 6a. Figure 3. Packing of compound 6a. 178.48°, 179.69°, -1.66°, 179.63°, 2.30°, 2.65°, -179.04-157.48°, respectively. The single bond lengths between C13-C14, C24-N5, C24-N6, C22-C23, N5-C15, or C1-C2, C12-N2, N1-N2, N3-C12, C3-N2, C11- C10, N2-C3 are mostly equal to those of double bonds between C13-C24, C14-N4, N6-C23, C22-C15 or C1-C12, C2-N1, N3-C11, C10-C3 which could be explained due to the 10π electron delocalization. However, the bond lengths between C16-C17, C17- C20, C20-C21, C21-C22, C22-C15 or C21-C20, C22-C21, C17-C20, C17-C16, C15-C16 are equivalent to C-C single bonds. Das et al. / European Journal of Chemistry 13 (1) (2022) 41-48 47 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.41-48.2168 Table 4. Bond lengths for compound 6a. Atom Atom Length (Å) Atom Atom Length (Å) Atom Atom Length (Å) Br1 C13 1.875(7) Br2 C1 1.859(7) C1 C12 1.356(9) O2 C21 1.229(8) O1 C9 1.235(8) C3 C4 1.482(8) N4 N5 1.367(7) N1 N2 1.376(7) C3 C10 1.359(8) N4 C14 1.342(8) N1 C2 1.329(8) C4 C5 1.532(8) N5 C15 1.354(7) N2 C3 1.371(7) C5 C6 1.543(8) N5 C24 1.396(8) N2 C12 1.383(8) C5 C7 1.529(9) N6 C23 1.311(8) N3 C11 1.306(8) C5 C8 1.510(8) N6 C24 1.357(8) N3 C12 1.356(8) C8 C9 1.482(9) C13 C14 1.374(10) C1 C2 1.393(10) C9 C10 1.498(9) C13 C24 1.372(10) C20 C21 1.513(9) C10 C11 1.416(9) C15 C16 1.489(8) C21 C22 1.470(9) C17 C19 1.539(9) C15 C22 1.376(8) C22 C23 1.432(9) C17 C20 1.526(8) C16 C17 1.526(8) C17 C18 1.539(8) Table 5. Bond angles for compound 6a. Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) C14 N4 N5 102.4(6) C2 N1 N2 102.7(6) C10 C3 N2 114.3(6) C15 N5 N4 124.7(6) C3 N2 N1 124.5(6) C10 C3 C4 125.8(6) C24 N5 N4 112.9(6) C12 N2 N1 111.9(6) C5 C4 C3 112.0(6) C24 N5 C15 122.4(7) C12 N2 C3 123.5(6) C6 C5 C4 109.4(5) C24 N6 C23 115.3(6) C12 N3 C11 115.3(7) C7 C5 C4 109.9(5) C14 C13 Br1 128.7(7) C2 C1 Br2 127.8(6) C7 C5 C6 108.3(6) C24 C13 Br1 124.8(7) C12 C1 Br2 126.8(7) C8 C5 C4 109.1(6) C24 C13 C14 106.3(7) C12 C1 C2 105.2(7) C8 C5 C6 109.2(5) C13 C14 N4 113.7(7) C1 C2 N1 113.8(7) C8 C5 C7 110.8(6) C16 C15 N5 119.6(6) C4 C3 N2 119.8(6) C9 C8 C5 114.7(6) C22 C15 N5 116.1(6) C21 C20 C17 113.0(5) C8 C9 O1 123.0(7) C22 C15 C16 124.3(6) C20 C21 O2 121.4(7) C10 C9 O1 120.1(7) C17 C16 C15 112.4(6) C22 C21 O2 121.9(7) C10 C9 C8 116.9(7) C18 C17 C16 110.3(5) C22 C21 C20 116.7(7) C9 C10 C3 118.1(7) C19 C17 C16 109.8(5) C21 C22 C15 119.6(6) C11 C10 C3 120.3(6) C19 C17 C18 109.2(6) C23 C22 C15 119.0(6) C11 C10 C9 121.6(7) C20 C17 C16 109.0(5) C23 C22 C21 121.4(7) C10 C11 N3 124.9(7) C20 C17 C18 109.5(5) C22 C23 N6 124.8(7) N3 C12 N2 121.6(7) C20 C17 C19 109.2(5) N6 C24 N5 122.4(7) C1 C12 N2 106.4(7) C13 C24 N5 104.6(7) C13 C24 N6 132.9(8) C1 C12 N3 132.0(8) 4. Conclusions In this article, we have reported a facile, regioselective, environment-friendly, effective, and high-yielding synthetic protocol for substituted pyrazolo[1,5-a]quinozolinone deriva- tives by the reaction of formylated dimedone with various subs- tituted 3-amino-1H-pyrazoles. The structural configurations of all of the novel molecules were done with the help of their structural and analytical data. The formations of the reported molecules were established by comparison with the data reported in the literature. X-ray crystallographic study of compound 6a was done to establish the structure of the molecules. The biopotential of all these molecules is yet to be explored. Acknowledgments The authors thank Rev. Fr. Dr. Stephen Mavely, Vice-Chancellor, and Rev. Fr. Joseph Nellanant, Pro Vice-Chancellor, Assam Don Bosco University, for providing infrastructure for the execution of this work. We also wish to express our gratitude to the Sophisticated Analytical Instrumentation Centre (SAIC), Tezpur University, Tezpur, for providing spectral and analytical data and X-ray analysis for our molecules. We are also grateful to the Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, New Delhi, and Indian Council of Agricultural Research (ICAR)- Barapani, Shillong for research grants. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. CRediT authorship contribution statement Conceptualization: Jai Narain Vishwakarma; Methodology: Susma Das; Software: Susma Das; Validation: Jai Narain Vishwakarma; Formal Analysis: Susma Das; Investigation: Susma Das; Resources: Jai Narain Vishwakarma; Data Curation: Labet Bankynmaw Marpna; Writing - Original Draft: Susma Das; Writing - Review and Editing: Labet Bankynmaw Marpna; Visualization: Jai Narain Vishwakarma; Funding acquisition: Jai Narain Vishwakarma; Supervision: Jai Narain Vishwakarma; Project Administration: Jai Narain Vishwakarma. ORCID and Email Susma Das susmadas91@gmail.com https://orcid.org/0000-0002-2391-8792 Labet Bankynmaw Marpna bankynmaw95@gmail.com https://orcid.org/0000-0002-2067-4315 Jai Narain Vishwakarma jnvishwakarma@rediffmail.com https://orcid.org/0000-0001-9068-4554 References [1]. Devi, A. S.; Kaping, S.; Vishwakarma, J. N. A Facile Environment- Friendly One-Pot Two-Step Regioselective Synthetic Strategy for 3,7- Diarylpyrazolo[1,5-a]Pyrimidines Related to Zaleplon and 3,6- Diarylpyrazolo[1,5-a]Pyrimidine-7-Amines Assisted by KHSO4 in Aqueous Media. Mol. Divers. 2015, 19 (4), 759–771. [2]. Kalita, U.; Kaping, S.; Nellanant, J.; Helissey, P.; Vishwakarma, J. N. A facile ultrasound-assisted regioselective synthetic strategy for pyrazolo(1,5-a]pyrimidines mediated by KHSO4 in aqueous media. Heterocyclic Lett. 2014, 4 (1), 137–145. [3]. Kaping, S.; Boiss, I.; Singha, L. I.; Helissey, P.; Vishwakarma, J. N. A Facile, Regioselective Synthesis of Novel 3-(N-Phenylcarboxamide) Pyrazolo[1,5-a]Pyrimidine Analogs in the Presence of KHSO4 in Aqueous Media Assisted by Ultrasound and Their Antibacterial Activities. Mol. Divers. 2016, 20 (2), 379–390. [4]. Kaping, S.; Kalita, U.; Sunn, M.; Singha, L. I.; Vishwakarma, J. N. A Facile, Regioselective Synthesis of Pyrazolo[1, 5-a]Pyrimidine Analogs in the Presence of KHSO4 in Aqueous Media Assisted by Ultrasound and Their Anti-Inflammatory and Anti-Cancer Activities. Monatsh. Chem. 2016, 147 (7), 1257–1276. mailto:susmadas91@gmail.com https://orcid.org/0000-0002-2391-8792 mailto:bankynmaw95@gmail.com https://orcid.org/0000-0002-2067-4315 mailto:jnvishwakarma@rediffmail.com https://orcid.org/0000-0001-9068-4554 48 Das et al. / European Journal of Chemistry 13 (1) (2022) 41-48 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.41-48.2168 [5]. Kaping, S.; Sunn, M.; Singha, L. I.; Vishwakarma, J. N. Ultrasound Assisted Synthesis of Pyrazolo[1,5-a]Pyrimidine-Antipyrine Hybrids and Their Anti-Inflammatory and Anti-Cancer Activities. Eur. J. Chem. 2020, 11 (1), 68–79. [6]. Das, S.; Khanikar, S.; Kaping, S.; Roy, J. D.; Sen, A.; Helissey, P.; Vishwakarma, J. N. Efficient Synthesis of Diversely Substituted Pyrazolo[1,5-a]Pyrimidine Derivatives Promoted by Ultrasound Irradiation in Water and Their Antibacterial Activities. Eur. J. Chem. 2020, 11 (4), 304–313. [7]. Kaping, S.; Helissey, P.; Vishwakarma, J. N. A Three Step One-Pot Regioselective Synthesis of Highly Substituted Pyrazolo[1,5-a] Pyrimidines Assisted by KHSO4 in Aqueous Media under Ultrasound Irradiation. Eur. J. Chem. 2020, 11 (3), 179–186. [8]. Hassanzadeh, F.; Jafari, E.; Hakimelahi, G. H.; Khajouei, M. I.; Jalali, M.; Khodarahmi, G. A. Antibacterial, antifungal and cytotoxic evaluation of some new quinazolinone derivatives. Res. Pharm. Sci. 2012, 7 (2), 87– 94. [9]. Shekarrao, K.; Kaishap, P. P.; Saddanapu, V.; Addlagatta, A.; Gogoi, S.; Boruah, R. C. Microwave-Assisted Palladium Mediated Efficient Synthesis of Pyrazolo[3,4-b]Pyridines, Pyrazolo[3,4-b]Quinolines, Pyrazolo[1,5-a]Pyrimidines and Pyrazolo[1,5-a]Quinazolines. RSC Adv. 2014, 4 (46), 24001–24006. [10]. Metwally, N. H.; Mohamed, M. S. Pyrazoloquinazoline Derivatives: Synthesis, Reactions, and Biological Applications. Synth. Commun. 2018, 48 (7), 721–746. [11]. Garg, M.; Chauhan, M.; Singh, P. K.; Alex, J. M.; Kumar, R. Pyrazolo quinazolines: Synthetic Strategies and Bioactivities. Eur. J. Med. Chem. 2015, 97, 444–461. [12]. Zhao, H.; Hu, X.; Zhang, Y.; Tang, C.; Feng, B. Progress in Synthesis and Bioactivity Evaluation of Pyrazoloquinazolines. Lett. Drug Des. Discov. 2020, 17 (2), 104–113. [13]. Storer, R.; Ashton, C. J.; Baxter, A. D.; Hann, M. M.; Marr, C. L. P.; Mason, A. M.; Mo, C.-L.; Myers, P. L.; Noble, S. A.; Penn, C. R.; Weir, N. G.; Woods, J. M.; Coe, P. L. The Synthesis and Antiviral Activity of 4-Fluoro-1-β-D- Ribofuranosyl-1H-Pyrazole-3-Carboxamide. Nucleosides Nucleotides 1999, 18 (2), 203–216. [14]. Steckiewicz, K. P.; Barcińska, E.; Woźniak, M. Nerve Growth Factor as an Important Possible Component of Novel Therapy for Cancer, Diabetes and Cardiovascular Diseases. Cell. Mol. Biol. (Noisy-le-grand) 2018, 64 (9), 16–23. [15]. Catarzi, D.; Colotta, V.; Varano, F.; Poli, D.; Squarcialupi, L.; Filacchioni, G.; Varani, K.; Vincenzi, F.; Borea, P. A.; Dal Ben, D.; Lambertucci, C.; Cristalli, G. Pyrazolo[1,5-c]Quinazoline Derivatives and Their Simplified Analogues as Adenosine Receptor Antagonists: Synthesis, Structure-Affinity Relationships and Molecular Modeling Studies. Bioorg. Med. Chem. 2013, 21 (1), 283–294. [16]. Guerrini, G.; Ciciani, G.; Ciattini, S.; Crocetti, L.; Daniele, S.; Martini, C.; Melani, F.; Vergelli, C.; Giovannoni, M. P. Pyrazolo[1,5-a]Quinazoline Scaffold as 5-Deaza Analogue of Pyrazolo[5,1-c][1,2,4]Benzotriazine System: Synthesis of New Derivatives, Biological Activity on GABAA Receptor Subtype and Molecular Dynamic Study. J. Enzyme Inhib. Med. Chem. 2016, 31 (2), 195–204. [17]. Bruker (2008). SAINT, SMART, APEXII. Bruker AXS Inc., Madison, Wisconsin, USA. [18]. Sheldrick, G. M. SHELXT - Integrated Space-Group and Crystal- Structure Determination. Acta Crystallogr. A Found. Adv. 2015, 71 (Pt 1), 3–8. [19]. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Crystallogr. 2009, 42 (2), 339–341. [20]. Sadek, K. U.; Mekheimer, R. A.; Mohamed, T. M.; Moustafa, M. S.; Elnagdi, M. H. Regioselectivity in the Multicomponent Reaction of 5- Aminopyrazoles, Cyclic 1,3-Diketones and Dimethylformamide Dimethylacetal under Controlled Microwave Heating. Beilstein J. Org. Chem. 2012, 8, 18–24. [21]. Al-Mousawi, S.; John, E.; Abdelkhalik, M. M.; Elnagdi, M. H. Enaminones as Building Blocks in Heterocyclic Syntheses: A New Approach to Polyfunctionally Substituted Cyclohexenoazines. J. Heterocycl. Chem. 2003, 40 (4), 689–695. [22]. Petrov, A. A.; Kasatochkin, A. N.; Emelina, E. E.; Nelyubina, Y. V.; Antipin, M. Y. α-Amino Azoles in the Synthesis of Heterocycles: VI. Synthesis and Structure of Cycloalkane-Annulated Pyrazolo[1,5-a] Pyrimidines. Russ. J. Org. Chem. 2009, 45 (9), 1390–1401. [23]. Kryl’skii, D. V.; Shikhaliev, K. S.; Chuvashlev, A. S. Three-Component Condensations with 5-Amino-4-Phenylpyrazole. Russ. J. Org. Chem. 2010, 46 (3), 410–416. [24]. Ghotekar, B. K.; Jachak, M. N.; Toche, R. B. New One-Step Synthesis of Pyrazolo[1,5-a]Pyrimidine and Pyrazolo[1,5-a]Quinazoline Deriva- tives via Multicomponent Reactions. J. Heterocycl. Chem. 2009, 46 (4), 708–713. [25]. Low, J. N.; Cobo, J.; Mera, J.; Quiroga, J.; Glidewell, C. Molecular Conformation and Supramolecular Aggregation in Two Fused Pyrazoles: Pi-Stacked R(2)(2)(6) Dimers in 2,8,8-Trimethyl-6,7,8,9- Tetrahydropyrazolo[2,3-a]Quinazolin-6-One, and Sheets of Alterna- ting R(2(2)12) and R(6)(6)(48) Rings in 3-Tert-Butyl-4’,4’-Dimethyl- 1-Phenyl-4,5,6,7-Tetrahydro-1H-Pyrazolo[3,4-b]Pyridine-5-Spiro-1’- Cyclohexane-2’,6’-Dione. Acta Crystallogr. C 2004, 60 (Pt 4), o265-9. Copyright © 2022 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. Synthesis of substituted 8,9-dihydropyrazolo[1,5-a]quinazolin-6(7H)-ones (6a-m) 3. Results and discussion 3.1. Chemistry 3.2. Crystallographic details of molecule 6a 4. Conclusions Acknowledgments Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: