A three step one-pot regioselective synthesis of highly substituted pyrazolo[1,5-a]pyrimidines assisted by KHSO4 in aqueous media under ultrasound irradiation European Journal of Chemistry 11 (3) (2020) 179-186 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2020 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. http://dx.doi.org/10.5155/eurjchem.11.3.179-186.1977 European Journal of Chemistry View Journal Online View Article Online A three step one-pot regioselective synthesis of highly substituted pyrazolo[1,5-a]pyrimidines assisted by KHSO4 in aqueous media under ultrasound irradiation Shunan Kaping 1, Philippe Helissey 2 and Jai Narain Vishwakarma 1,* 1 Organic Research Laboratory, Department of Chemical Science, Assam Don Bosco University, Tapesia Gardens, Sonapur 782402, Assam, India shunankaping@yahoo.in (S.K.), jnvishwakarma@rediffmail.com (J.N.V.) 2 Laboratoire de Chimie Thérapeutique, UMR CNRS No. 8638, Université Paris Descartes, Faculte des Sciences Pharmaceutiqueset Biologiques, Paris, France philippe.helissey@parisdescartes.fr (P.H.) * Corresponding author at: Organic Research Laboratory, Department of Chemical Science, Assam Don Bosco University, Tapesia Gardens, Sonapur 782402, Assam, India. e-mail: jnvishwakarma@dbuniversity.ac.in (J.N. Vishwakarma). 10.5155/eurjchem.11.3.179-186.1977 Received: 29 February 2020 Received in revised form: 15 May 2020 Accepted: 12 June 2020 Published online: 30 September 2020 Printed: 30 September 2020 A simple and efficient synthesis of substituted pyrazolo[1,5-a]pyrimidine derivatives has been developed by the use of ultrasound. 5-Methyl-4-phenyl-1H-pyrazol-3-amine required for the synthesis of pyrazolo[1,5-a]pyrimidine derivatives has been easily obtained by the reaction of 3-(dimethylamino)-2-phenylacrylonitrile (formed from readily available 2- phenylacetonitrile) with hydrazine hydrate in refluxing ethanol. The 5-aminopyrazole was then reacted with various formylated active proton compounds in presence of KHSO4 in aqueous medium under ultrasound irradiation to give the desired products. The chemical structures of the newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and Mass spectral data. X-ray crystallographic study of a selected compound 6-(4-chlorophenyl)- 2-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-7-amine (7c) was performed to ascertain the regioselectivity of the reaction. Crystal data for compound 7c: Triclinic, space group P-1 (no. 2), a = 8.0198(3) Å, b = 14.0341(6) Å, c = 14.2099(6) Å, α = 87.672(2)°, β = 83.902(2)°, γ = 89.120(2)°, V = 1588.87(11) Å3, Z = 4, T = 293(2) K, μ(MoKα) = 0.248 mm-1, Dcalc = 1.400 g/cm3, 12918 reflections measured (4.012° ≤ 2Θ ≤ 49°), 5152 unique (Rint = 0.0411, Rsigma = 0.0429) which were used in all calculations. The final R1 was 0.0486 (I > 2σ(I)) and wR2 was 0.1320 (all data). Enaminones X-ray structure One pot procedure Pyrazolopyrimidine Ultrasound irradiation Pyrazolo[1,5-a]pyrimidines Cite this: Eur. J. Chem. 2020, 11(3), 179-186 Journal website: www.eurjchem.com 1. Introduction Ultrasound irradiation has found application in material science, life sciences, medicinal chemistry, cleaning, sonar, electronics, agriculture and oceanography, etc. [1]. Ultrasound technology has also gained significant attention in the field of organic synthesis [2], due to its general commercial availability as well as its various advantages like enhanced reaction rates, greater selectivity, shorter reaction time, precipitation of practically pure products, use of less hazardous solvents, high to excellent yields and minimization of waste products [3,4]. It offers an alternative and convenient pathway for reactions to be carried out efficiently [1]. Ultrasound irradiation works on the principle of cavitation. During the process of irradiation, sound waves pass through the reaction medium whereby the molecules of the medium are separated generating millions of microscopic bubbles. These bubbles grow in size and reach a state of maximum strain ultimately leading to its collapse. These rapid and violent implosions of millions of bubbles generate localised hot spots with transient temperatures of about 5000 °C and pressures of about 1000 atmospheres [2,5]. Such localized hot spots act as micro-reactor which enhances the chemical reaction more effectively [6]. The synthesis of pyrazolo[1,5-a]pyrimidine derivatives have gained significant interest due to their various biological [7-11] and pharmacological activities. Recently, pyrazolo[1,5- a]pyrimidines as translocator protein 18 kDa (TSPO) ligands [12] have been studied. Hassan and co-workers [13] reported the synthesis of 2-[(4-methoxyphenyl)amino]-5,7-dimethyl-N- phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide and 7-amino -N-(4-chlorophenyl)-6-cyano-5-(4-methoxyphenyl)-2-[(4-met- hoxyphenyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide which were found to exhibit growth inhibitory activity against Ehrlich Ascites Carcinoma (EAC) cells when compared with doxorubicin drug. Also, pyrazolo[1,5-a]pyrimidine nucleus is an interesting and versatile scaffold for the preparation of various drugs like zaleplon, indiplon and ocinaplon [14-16]. ABSTRACT RESEARCH ARTICLE KEYWORDS http://dx.doi.org/10.5155/eurjchem.11.3.179-186.1977 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.11.3.179-186.1977 mailto:shunankaping@yahoo.in mailto:jnvishwakarma@rediffmail.com mailto:philippe.helissey@parisdescartes.fr mailto:jnvishwakarma@dbuniversity.ac.in http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.11.3.179-186.1977&domain=pdf&date_stamp=2020-09-30 180 Kaping et al. / European Journal of Chemistry 11 (3) (2020) 179-186 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.179-186.1977 Scheme 1 Realising the importance of these molecules, we have recently reported [17-20] a general synthetic strategy and demonstrated the applicability for the synthesis of pyrazolo[1,5-a] pyrimidines. In view of the importance of these molecules we have extended our synthetic strategy for 5- methyl-4-phenyl pyrazolo[1,5-a]pyrimidine derivatives and the details are presented herein. 2. Experimental 2.1. Material and methods Melting points were recorded by open capillary method and are uncorrected. The IR spectra were recorded on a Perkin- Elmer 983 spectrometer (Perkin-Elmer). High resolution 1H NMR and 13C NMR (400 MHz and 600 MHz) were measured on a DRX-400 Varian spectrometer and Bruker spectrometer, respectively. CDCl3 and DMSO-d6 were used as the solvent. The chemical shifts (σ, ppm) and the coupling constants (Hz) are reported in the standard fashion with reference to tetramethylsilane (TMS) as internal reference. In the NMR spectral data, the abbreviations d, dd, bs, s, m, and t, stand for doublet, double-doublet, broad-singlet, singlet, multiplet, and triplet, respectively. The X-ray diffraction data was solved with Olex2 [21]. The structure was worked out with the olex2.solve [21] structure solution program using Charge Flipping and refined with the SHELXL [22] refinement package using Least Squares minimization. Molecular graphics and preparation of material for publication were obtained using Olex2 1.3-beta [23]. The electron spray mass spectra were recorded on a THERMO Finnigan LCQ Advantage max ion trap mass spectrometer. Ultrasound irradiation was carried out in an EQUITRON Digital Ultrasonic Cleaner-2.5 L, model 8425.025. 424 at 170 Watt and 50 Hz. Formylated active proton compounds were synthesized by our previously reported procedure [24,25]. 2.1.1. Synthesis 2.1.1.1. Synthesis of 2-methyl-3-phenyl-7-arylpyrazolo[1,5- a]pyrimidine (5a-e) A mixture of aminopyrazole (3) (Scheme 1) (1 mmol), enaminones (4) (1 mmol), and KHSO4 (2 mmol) was irradiated under the influence of ultrasound waves for 5-12 minutes in 5 mL of ethanol:water (1:1, v:v) mixture resulting in the formation of a precipitated product. After the completion of reaction monitored by thin layer chromatography (TLC) the precipitate was collected by filtration, washed repeatedly with water to ensure complete removal of acid and dried to give practically pure pyrazolopyrimidines (5) in 88-96 % yields. Further, purification was achieved by column chromatography using silica gel and 20 % EtOAc-Hexane (Scheme 2). 2-Methyl-3, 7-diphenylpyrazolo[1, 5-a]pyrimidine (5a): Color: Yellow solid. Yield: 96 %. M.p.: 142-143 °C [251 °C] [26]. FT-IR (KBr, ν, cm-1): 1605 (C=N), 1555 (C=C). 1H NMR (600 MHz, CDCl3, δ, ppm): 2.65 (s, 3H, CH3), 6.85 (d, 1H, C6-H, J = 4.2 Hz), 7.32-7.34 (m, 1H, Ar), 7.48-7.51 (t, 2H, Ar), 7.57-7.58 (m, 3H, Ar), 7.73-7.74 (m, 2H, Ar), 8.08-8.10 (m, 2H, Ar), 8.51 (d, 1H, C5- H, J = 4.2 Hz). 13C NMR (150 MHz, CDCl3, δ, ppm): 14.5, 107.3, 109.7, 126.5, 128.7, 128.9, 129.2, 129.5, 131.2, 131.4, 132.6, 146.3, 147.5, 149.1, 152.6. MS (EI, m/z (%)): 286 (MH)+. 2-Methyl-3-phenyl-7-(p-tolyl)pyrazolo[1, 5-a]pyrimidine (5b): Color: Yellow solid. Yield: 95 %. M.p.: 179-181°C [178-180 °C] [27]. FT-IR (KBr, ν, cm-1): 1600 (C=N), 1555 (C=C). MS (EI, m/z (%)): 300 (MH)+. 7-(4-Methoxyphenyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyri midine (5c): Color: Yellow solid. Yield: 88 %. M.p.: 176-177 °C. FT-IR (KBr, ν, cm-1): 1602 (C=N), 1553 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.63 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 6.85 (d, 1H, C6-H, J = 4 Hz), 7.07 (d, 2H, Ar, J = 8 Hz), 7.28-7.32 (t, 1H, Ar), 7.45-7.49 (t, 2H, ArOCH3), 7.71 (d, 2H, Ar, J = 8 Hz), 8.11 (d, 2H, ArOCH3, J = 8 Hz), 8.46 (d, 1H, C5-H, J = 4 Hz). 13C NMR (100 MHz, CDCl3, δ, ppm): 14.5, 106.5, 109.4, 114.2, 123.4, 126.4, 128.7, 129.1, 131.1, 132.7, 133.3, 146.0, 149.0, 152.4, 161.9. MS (EI, m/z (%)): 315 (M)+. 7-(4-Chlorophenyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimi dine (5d): Color: Yellow solid. Yield: 88 %. M.p.: 197-199°C [196-198 °C] [27]. MS (EI, m/z (%)): 320 (MH)+. 2-Methyl-7-(4-nitrophenyl)-3-phenylpyrazolo[1, 5-a]pyrimidine (5e): Color: Orange solid. Yield: 90 %. M.p.: 230-232 °C. FT-IR (KBr, ν, cm-1): 1613 (C=N), 1554 (N=N). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.62 (s, 3H, CH3), 6.89 (d, 1H C6-H, J = 4 Hz), 7.31-7.34 (t, 1H, Ar), 7.46-7.50 (t, 2H, Ar), 7.69 (d, 2H, Ar, J = 7.6 Hz), 8.27 (d, 2H, Ar-NO2, J = 8.8 Hz), 8.41 (d, 2H, ArNO2, J = 8.8 Hz), 8.55 (d, 1H, C5-H, J = 4 Hz). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 14.4, 107.8, 110.2, 124.0, 126.8, 128.8, 129.2, 130.6, 132.0, 137.3, 143.6, 146.7, 148.9, 149.1, 153.0. MS (EI, m/z (%)): 330 (M)+. 2.1.1.2. Synthesis of 2-methyl-3-phenyl-6-arylpyrazolo[1,5- a]pyrimidin-7-amine (7a-c) A mixture of aminopyrazole (3) (1 mmol) and enamino nitriles (6) (1 mmol) and KHSO4 (2 mmol) was irradiated under the influence of ultrasound waves for 8-21 minutes in 5 mL of ethanol:water (1:1, v:v) mixture to give a precipitated product. After the completion of reaction monitored by TLC the precipitate was collected by filtration, washed repeatedly with ethanol:water (1:1, v:v) to ensure complete removal of acid and dried to give practically pure pyrazolopyrimidines (7) in 75-84 % yields. Further, purification was achieved by column chromatography (silica gel, 20 % EtOAc-hexane) (Scheme 2). 2-Methyl-3, 6-diphenylpyrazolo[1, 5-a]pyrimidin-7-amine (7a): Color: Pale white solid. Yield: 75 %. M.p.: 219-220 °C [215- 216 °C] [28]. FT-IR (KBr, ν, cm-1): 3364 (N-H), 1599 (C=N), 1523 (N=N). 6-(4-Methoxyphenyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyri midin-7-amine (7b): Color: Pale white solid. Yield: 83 %. M.p.: 235-237 °C. FT-IR (KBr, ν, cm-1): 3362 (N-H), 1592 (C=N), 1525 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.62 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 6.04 (s, 2H, NH2), 7.03 (d, 2H, ArH, J = 8.6 Hz), 7.29-7.31 (m, 1H, ArH), 7.39 (d, 2H, ArH, J = 8.6 Hz), 7.45-7.49 (t, 2H, ArH), 7.71 (d, 2H, ArH, J = 7.4 Hz), 8.25 (s, 1H, C5-H). Kaping et al. / European Journal of Chemistry 11 (3) (2020) 179-186 181 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.179-186.1977 Scheme 2 13C NMR (100 MHz, CDCl3, δ, ppm): 14.3, 55.5, 102.1, 106.3, 108.1, 114.9, 115.1, 126.3, 128.7, 128.8, 129.7, 130.5, 144.8, 149.2, 152.4, 159.4. MS (EI, m/z (%)): 330 (M)+. 6-(4-Chlorophenyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimi din-7-amine (7c): Color: Off white solid. Yield: 84 %. M.p.: 248- 250 °C. FT-IR (KBr, ν, cm-1): 3344 (NH), 1601 (C=N), 1522 (C=C). 1H NMR (600 MHz, CDCl3, δ, ppm): 2.61 (s, 3H, CH3), 7.23- 7.25 (m, 1H, ArH), 7.42-7.44 (m, 2H, ArH), 7.49 (m, 4H, 2-ArH, 2-NH2), 7.72-7.74 (m, 2H, ArH), 7.85-7.86 (m, 2H, Ar), 8.11 (s, 1H, C5-H). 13C NMR (150 MHz, CDCl3, δ, ppm): 13.4, 100.2, 106.3, 124.5, 127.2, 127.3, 127.4, 128.1, 129.7, 131.8, 131.9, 143.6, 148.6, 148.8, 150.3. MS (EI, m/z (%)): 334 (M)+. 2.1.1.3. Synthesis of 2-methyl-3-phenyl-7-heteroaryl pyrazolo[1,5-a]pyrimidines (9a-d) A mixture of aminopyrazole (3) (1 mmol) and enaminone (8a or 8b) (1 mmol), in the presence of KHSO4 (2 mmol) was irradiated under the influence of ultrasound waves for 11-16 minutes in 5 mL of ethanol:water (1:1, v:v) mixture to give a precipitated product. After the completion of the reaction monitored by TLC, the precipitate thus formed was collected by filtration, washed repeatedly with ethanol:water (1:1, v:v) to ensure complete removal of acid and dried to give practically pure pyrazolopyrimidine (9) in 85-87 % yields. Further, purification was achieved by column chromatography (silica gel, 20 % EtOAc-hexane) (Scheme 3). In case of the reaction between compounds 3 and 8c under similar conditions, two regio-isomeric products 9c and 9d were isolated in 49 and 44 % yields, respectively. 2-Methyl-3-phenyl-7-(pyridin-4-yl)pyrazolo[1, 5-a]pyrimidine (9a): Color: Yellow solid. Yield: 87 %. M.p.: 204-206 °C. FT-IR (KBr, ν, cm-1): 1601 (C=N), 1553 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.66 (s, 3H, CH3), 6.89-6.92 (m, 1H, C6-H), 7.32- 7.36 (t, 1H, ArH), 7.48-7.51 (t, 2H, ArH), 7.72 (d, 2H, ArH, J = 8 Hz), 8.00 (bs, 2H, pyridine), 8.53-8.55 (m, 1H, C5-H), 8.86 (br, 2H, pyridine). 13C NMR (100 MHz, CDCl3, δ, ppm): 14.4, 107.5, 123.2, 126.8, 128.8, 129.1, 132.1, 138.7, 143.2, 147.3, 148.9, 150.6, 153.0, 152.9. MS (EI, m/z (%)): 287 (MH)+. 2-Methyl-3-phenyl-7-(pyridin-3-yl)pyrazolo[1, 5-a]pyrimidine (9b): Color: Yellow solid. Yield: 85 %. M.p.: 149-151 °C. FT-IR (KBr, ν, cm-1): 1608 (C=N), 1554 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.51 (s, 3H, CH3), 6.88 (d, 1H, C6-H, J = 4.4 Hz), 7.31-7.35 (t, 1H, Ar), 7.47-7.53 (m, 3H, 2H-Ar, 1H-pyridine), 7.72 (d, 2H, Ar, J = 8 Hz), 8.52-8.57 (m, 2H, pyridine) 8.78 (d, 1H, C5-H, J = 4.4 Hz), 9.2 (s, 1H, pyridine). 13C NMR (100 MHz, CDCl3, δ, ppm): 14.4, 107.2, 110.1, 123.4, 126.7, 127.6, 128.8, 129.1, 132.2, 137.0, 143.1, 147.3, 149.0, 149.8, 151.8, 152.8. MS (EI, m/z (%)): 287 (MH)+. 2-Methyl-3-phenyl-7-(pyridin-2-yl)pyrazolo[1, 5-a]pyrimidine (9c): Color: Yellow solid. Yield: 49 %. M.p.: 131-133 °C. FT-IR (KBr, ν, cm-1): 1604 (C=N), 1542 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.67 (s, 3H, CH3), 7.29-7.33 (t, 1H, Ar), 7.43-7.50 (m, 3H, 2H-Ar, 1H-pyridine), 7.61 (d, 1H, C6-H, J = 4.4 Hz), 7.73 (d, 2H, Ar, J = 6.8 Hz), 7.91-7.95 (m, 1H, pyridine), 8.59 (d, 1H, C5-H, J = 4.4 Hz), 8.80 (bs, 1H, pyridine), 9.09 (d, 1H, pyridine, J = 7.6 Hz). 13C NMR (100 MHz, CDCl3, δ, ppm): 14.5, 107.9, 125.9, 126.2, 126.6, 128.7, 129.2, 132.4, 136.8, 143.7, 148.7, 149.1, 150.1, 152.4. MS (EI, m/z (%)): 287 (MH)+. 2-Methyl-3-phenyl-5-(pyridin-2-yl)pyrazolo[1, 5-a]pyrimidine (9d): Color: Yellow solid. Yield: 44 %. M.p.: 152-154 °C. FT-IR (KBr, ν, cm-1): 1606 (C=N), 1552 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.66 (s, 3H, CH3), 7.30-7.35 (m, 2H, Pyridine), 7.48-7.52 (t, 2H, Ar), 7.79-7.84 (m, 3H, Ar), 7.98 (d, 1H, C7-H, J = 7.6 Hz), 8.52 (d, 1H, pyridine, J = 8 Hz), 8.63-8.68 (m, 2H, C6-1H, 1H-pyridine). 13C NMR (100 MHz, CDCl3, δ, ppm): 14.6, 105.2, 109.8, 121.9, 124.8, 126.4, 128.6, 128.9, 132.5, 134.6, 137.0, 145.0, 149.2, 153.1, 154.3, 155.1. MS (EI, m/z (%)): 287 (MH)+. 2.1.1.4. Synthesis of 6-acetyl/carboalkoxy-2,7-dimethyl-3- phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (12) In order to synthesize the target pyrazolo[1,5-a]pyrimidine (12), formylated active proton compounds of type 11 were required. This was synthesized by the irradiation of acyclic active proton compounds (10) (1 mmol) with DMF-DMA in microwave digester for 5 minutes. The reaction mixture (monitored by TLC) was evaporated to dryness under reduced pressure. To this, aminopyrazole (3) (1 mmol) as synthesized in Scheme 1 was added and dissolved in 5 mL of ethanol:water mixture (1:1, v:v). KHSO4 (2 mmol) was then added and subjected to ultrasound irradiation for 6-20 minutes to give a precipitated product. After the completion of reaction (monitored by TLC), the precipitate was collected by filtration, washed repeatedly with ethanol-water (1:1, v:v) and dried over anhydrous CaCl2 to give practically pure products (12) in 85-88 % yields. Further, purification was achieved by column chromatography (silica gel, 5 % EtOAc-hexane) (Scheme 4). 1-(2, 7-Dimethyl-3-phenylpyrazolo[1, 5-a]pyrimidin-6-yl) ethanone (12a): Color: Yellow solid. Yield: 88 %. M.p.: 105-107 °C. FT-IR (KBr, ν, cm-1): 1683 (CO), 1586 (C=N), 1524 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.66 (s, 3H, CH3), 2.67 (s, 3H, CH3), 3.16 (s, 3H, COCH3), 7.33-7.35 (m, 1H, Ar), 7.48-7.50 (m, 2H, Ar), 7.68-7.69 (m, 2H, Ar), 8.83 (s, 1H, C5-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 14.7, 15.3, 29.9, 111.0, 117.5, 127.0, 128.8, 129.1, 131.7, 145.3, 149.2, 150.3, 155.6, 196.6. MS (EI, m/z (%)): 266 (MH)+. 182 Kaping et al. / European Journal of Chemistry 11 (3) (2020) 179-186 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.179-186.1977 Scheme 3 Methyl 2, 7-dimethyl-3-phenylpyrazolo[1, 5-a]pyrimidine-6- carboxylate (12b): Color: Yellow solid. Yield: 85 %. M.p.: 110- 112 °C. FT-IR (KBr, ν, cm-1): 1725 (CO), 1602 (C=N), 1523 (C=C). 1H NMR (600 MHz, CDCl3, δ, ppm): 2.66 (s, 3H, CH3), 3.21 (s, 3H, CH3), 3.96 (s, 3H, OCH3), 7.32-7.34 (t, 1H, Ar), 7.47-7.49 (t, 2H, Ar), 7.68 (d, 2H, Ar, J = 8.4 Hz), 8.92 (s, 1H, C5-H). 13C NMR (150 MHz, CDCl3, δ, ppm): 14.6, 15.2, 52.5, 110.1, 111.1, 126.9, 128.8, 129.1, 131.7, 146.0, 149.9, 151.2, 155.1, 165.5. MS (EI, m/z (%)): 281 (M)+. Ethyl 2, 7-dimethyl-3-phenylpyrazolo[1, 5-a]pyrimidine-6- carboxylate (12c): Color: Yellow solid. Yield: 90 %. M.p.: 104- 106 °C. FT-IR (KBr, ν, cm-1): 1711 (CO), 1602 (C=N), 1531 (C=C). 1H NMR (600 MHz, CDCl3, δ, ppm): 1.42-1.44 (t, 3H, CH3), 2.66 (s, 3H, CH3), 3.21 (s, 3H, CH3) 4.41-4.44 (q, 2H, CH2), 7.32-7.34 (t, 1H, Ar), 7.47-7.49 (m, 2H, Ar), 7.68-7.69 (m, 2H, Ar), 8.94 (s, 1H, C5-H). 13C NMR (150 MHz, CDCl3, δ, ppm): 14.1, 14.3, 14.9, 61.3, 110.1, 110.8, 126.6, 128.5, 128.8, 131.5, 145.7, 149.7, 150.7, 154.7, 164.8. MS (EI, m/z (%)): 296 (MH)+. 3. Results and discussion 3.1. Chemistry For the synthesis of the target pyrazolo[1,5-a]pyrimidine we first required 3-aminopyrazole of type 3. This was synthe- sized as shown in Scheme 1 starting from easily accessible phenyl acetonitrile (1) which was acylated by its reaction with N,N-dimethylacetaldimethylacetamide (DMA-DMA). The inter- mediate (2) without further purification was reacted with hydrazine hydrate in refluxing ethanol [29]. After the completion of the reaction, monitored by TLC, the reaction mixture was evaporated and cooled. To this, water was added whereby brown solid was formed, which was collected by filtration and washed with water. Aminopyrazole (3) thus obtained was dried over anhydrous CaCl2 and was used for subsequent reaction without further purification. 3-Aminopyrazole (3) was then irradiated with an equi- molar quantity of enaminones (4) in the presence of KHSO4 (2 equivalents) in 5 mL of water-ethanol mixture (1:1, v:v) in an ultrasonic bath at 60 °C (Scheme 2). The progress of the reaction was monitored by thin layer chromatography. The products were obtained in 88-96 % yields in 5-12 minutes. The reaction mixture was allowed to cool to room temperature and the precipitate was collected by filtration, washed with ethanol- water (1:1, v:v) and finally dried over anhydrous CaCl2 to give practically pure product 5. Encouraged by this, the reaction of enaminonitriles 6 with aminopyrazole 3 (Scheme 2) was subsequently explored and the expected 7-aminopyrazolo pyrimidines 7 were obtained in 75-84 % overall yields in 8-21 minutes under similar conditions. The structures of the synthesised compounds were confirmed by their spectral data (IR, 1H NMR, 13C NMR and MS spectroscopy). Also X-ray crystallography for compound 7c as model was performed for ascertaining the structure. The 1H NMR spectra of compounds 5a-e, showed doublet for the C5-H and C6-H protons at around δ 8.51 and 6.85 ppm, respectively. The 1H NMR spectra of compound 7b-c, showed sharp singlet for C5-H protons at about δ 8.20 ppm, whereas, the -NH2 protons for compound 7b resonated as singlet at δ 6.04 ppm and that for compound 7c, the signal get mixed with the aromatic protons. Also, the reaction of aminopyrazole 3 with 3-(dimethyl amino)-1-(heteroaryl)prop-2-en-1-ones was investigated under similar conditions whereby the desired 2-methyl-3- phenyl-7-heteroaryl-pyrazolo[1,5-a]pyrimidine (9) was for- med (Scheme 3) in 12-16 minutes in 83-85 % yields. Surpri- singly, in case of the reaction of aminopyrazole 3 with compound 8c, regioisomeric products 9c and 9d were formed (Scheme 3). The regioisomeric products 9c and 9d showed Rf value at 0.2 and 0.4, respectively, and were therefore easily isolated by column chromatography using silica gel (60-120 mesh) and 20 % EtOAc-hexane as eluent. The products isolated were differentiated with the help of 1H NMR. A plausible mechanism for the formation of the products has been rationalized as follows: Assisted by KHSO4, the enaminone undergoes Aza-Michael addition-elimination reac- tion to give an adduct which subsequently undergoes cyclo- dehydration to yield the proposed pyrazolo[1,5-a]pyrimidines 9. The nucleophilic attack by aminopyrazole could follow two routes. Route 1 result in the formation compound 9c and route 2 gives compound 9d as shown in the following Scheme 5. The analysis and the identities of the compounds were established using 1H NMR. The C5-H, C6-H protons for compounds 9b, 9c appeared as doublets in the range δ 8.59- 8.78 and δ 6.88-7.61 ppm, respectively, with coupling constant of 4.4 Hz. For compound 9a, the C5-H, C6-H protons appeared as multiplet at δ 8.53-8.55 and δ 6.89-6.92 ppm, respectively. In case of regioisomeric product 9d clear distinction of the substitution at C-5 were made as observed in the coupling constant [30]. The C7-H proton showed doublet at δ 7.98 ppm with coupling constant 7.6 Hz [30] and the doublet of C6-H proton gets buried with the proton of the heteroaryl group. In order to further examine, the generality of this green methodology, we finally took up the reaction of aminopyrazole 3 with formylated active proton compounds 11 (Scheme 4) derived from 1,3-diketones in in situ. It was utterly pleasing to observe that the reactions went to completion giving the expected product 12 within 6-20 minutes in 88-90 % yields. The identities of these products and its distinction were established with the help of spectral analytic data. In the case of compounds 12b-c, the C5-H protons gave singlet at about δ 8.92 ppm and for compound 12a, it appeared as singlet at δ 8.83 ppm. The methyl protons at C-2, for all the synthesised compounds gave a sharp singlet at around δ 2.62 ppm. Kaping et al. / European Journal of Chemistry 11 (3) (2020) 179-186 183 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.179-186.1977 Scheme 4 Scheme 5 184 Kaping et al. / European Journal of Chemistry 11 (3) (2020) 179-186 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.179-186.1977 Table 1. Synthesis of pyrazolo[1,5-a]pyrimidine derivatives. Compounds Time (in minutes) Yield experimental/literature (%) M.p./Lit M.p. (ᵒC) 5a 5 96/76 142-143/251 [26] 5b 6 95/75 179-180/178-180 [27] 5c 6 88/Unreported 176-177 5d 12 88/67 197/196-198 [27] 5e 5 90/Unreported 230-232 7a 12 75/81 219-220/215‒216 [28] 7b 21 83/Unreported 235 7c 8 84/Unreported 248-250 9a 12 87/Unreported 204-206 9b 16 85/Unreported 149-151 9c 11 49/Unreported 131 9d 11 44/Unreported 152-154 12a 20 88/Unreported 265 12b 6 85/Unreported 110-112 12c 9 90/Unreported 104-106 Table 2. Crystal data and structure refinement for compound 7c. Empirical formula C19H15N4Cl Formula weight 334.80 Temperature (K) 293(2) Crystal system Triclinic Space group P-1 a (Å) 8.0198(3) b (Å) 14.0341(6) c (Å) 14.2099(6) α (°) 87.672(2) β (°) 83.902(2) γ (°) 89.120(2) Volume (Å3) 1588.87(11) Z 4 ρcalc (g/cm3) 1.400 μ (mm-1) 0.248 F(000) 696.0 Crystal size (mm3) 0.27 x 0.23 x 0.17 Radiation MoKα (λ = 0.71073) 2Θ range for data collection (°) 4.012 to 49 Index ranges -8 ≤ h ≤ 9, -16 ≤ k ≤ 16, -16 ≤ l ≤ 16 Reflections collected 12918 Independent reflections 5152 [Rint = 0.0411, Rsigma = 0.0429] Data/restraints/parameters 5152/0/449 Goodness-of-fit on F2 1.071 Final R indexes [I≥2σ (I)] R1 = 0.0486, wR2 = 0.1176 Final R indexes [all data] R1 = 0.0737, wR2 = 0.1320 Largest diff. peak/hole / (e Å-3) 0.30/-0.30 Figure 1. Molecular structure of compound 7c. Further, 13C NMR and mass spectroscopy were in support of the structure. A summary of the synthesized pyrazolo[1,5-a] pyrimidines is presented in Table 1. 3.2. X-ray crystallography The confirmation and regioselectivity of the structure was done with the help of X-ray crystal structure by taking compound 6-(4-chlorophenyl)-2-methyl-3-phenylpyrazolo[1, 5-a] pyrimidin-7-amine 7c (Figure 1) as a model. Single crystals of C19H15N4Cl practicable for X-ray data analysis were crystallized with methanol. A suitable crystal was selected and mounted on a CCD (Charge-Coupled Device) area detector diffractometer. The crystal was kept at 293(2) K during data collection. X-ray data for compound 7c was solved using Olex2. (Experimental section). Yellow crystals of compound 7c suitable for single X-ray diffraction measure- ments were grown by the slow crystallisation in methanol. The crystallographic data for the structure were deposited to the Cambridge Crystallographic Data Center (CCDC no. 967390). Kaping et al. / European Journal of Chemistry 11 (3) (2020) 179-186 185 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.179-186.1977 Table 3. Bond lengths for compound 7c. Atom Atom Length (Å) Atom Atom Length (Å) N8 C27 1.346(4) C13 C14 1.390(4) Cl1 C3 1.742(3) C13 C18 1.392(4) Cl2 C20 1.742(3) C5 C6 1.382(4) N2 C9 1.354(3) C5 C4 1.389(4) N2 N1 1.372(3) C12 C19 1.500(4) N2 C10 1.390(3) C20 C25 1.375(4) N6 C27 1.356(3) C20 C21 1.383(4) N6 N5 1.368(3) C23 C22 1.393(4) N6 C29 1.391(3) C23 C24 1.393(4) N3 C8 1.319(3) N5 C31 1.336(4) N3 C10 1.364(3) C30 C31 1.408(4) N7 C28 1.316(4) C30 C32 1.464(4) N7 C29 1.363(3) C6 C1 1.400(4) C7 C9 1.399(4) C2 C1 1.384(4) C7 C8 1.413(3) C32 C37 1.387(4) C7 C6 1.485(4) C32 C33 1.402(4) C29 C30 1.388(4) C14 C15 1.375(4) N4 C9 1.347(3) C33 C34 1.370(4) C26 C27 1.393(4) C24 C25 1.383(4) C26 C28 1.417(4) C22 C21 1.380(4) C26 C23 1.478(4) C31 C38 1.497(4) N1 C12 1.337(3) C18 C17 1.375(4) C10 C11 1.385(4) C15 C16 1.380(4) C11 C12 1.412(3) C36 C35 1.376(5) C11 C13 1.471(3) C36 C37 1.388(5) C3 C2 1.379(4) C34 C35 1.378(5) C3 C4 1.386(4) C16 C17 1.371(5) Table 4. Bond angles for compound 7c. Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) N8 C27 N6 115.6(3) C9 N2 N1 123.2(2) N8 C27 C26 127.9(3) N6 C27 C26 116.5(2) C9 N2 C10 124.3(2) N3 C8 C7 127.5(3) N1 N2 C10 112.4(2) N5 N6 C29 112.2(2) C27 N6 N5 124.1(2) C8 N3 C10 114.9(2) C27 N6 C29 23.7(2) C25 C24 C23 122.4(3) C34 C33 C32 121.1(3) C21 C22 C23 121.6(3) C28 N7 C29 114.8(2) C30 C29 N6 105.9(2) C9 C7 C6 122.6(2) C22 C21 C20 119.6(3) N7 C29 C30 133.0(2) C3 C4 C5 119.3(3) C8 C7 C6 120.8(2) C28 C26 C23 119.6(2) N7 C29 N6 21.1(2) C20 C25 C24 118.8(3) C27 C26 C28 16.5(3) C11 C10 N2 105.9(2) C27 C26 C23 23.8(2) C2 C3 C4 120.7(3) C12 N1 N2 103.69(19) C2 C3 Cl1 119.2(2) N3 C10 C11 133.5(2) C14 C13 C11 120.4(2) C10 C11 C12 105.0(2) C6 C5 C4 121.5(2) C12 C11 C13 127.8(2) N1 C12 C1 113.0(2) C4 C3 Cl1 120.1(3) C11 C12 C19 128.5(2) N7 C28 C26 127.4(2) N3 C10 N2 120.6(2) N4 C9 C7 128.0(3) C2 C1 C6 121.6(3) N1 C12 C1 113.0(2) C10 C11 C13 127.2(2) C25 C20 C21 120.7(3) N5 C31 C30 113.1(2) C31 N5 N6 104.0(2) C30 C31 C38 127.9(3) C29 C30 C32 126.3(2) C18 C13 C11 121.8(2) C5 C6 C7 121.7(2) N4 C9 N2 115.9(2) N5 C31 C30 113.1(2) N1 C12 C19 118.4(2) C14 C13 C18 117.8(2) C25 C20 Cl2 119.5(2) C17 C18 C13 120.9(3) C31 C30 C32 128.9(2) N2 C9 C7 116.1(2) C33 C32 C30 120.2(2) C14 C15 C16 120.3(3) C37 C32 C30 122.1(3) Compound 7c crystallizes in a triclinic cell (space group P- 1) with a = 8.0198 (3) Å, b = 14.0341 (6) Å, c = 14.2099 (6) Å, α = 87.672 (2)°, β = 83.902 (2)°, γ = 89.120 (2)°, V = 1588.87 (11) Å3 and Z = 4. The molecular graphic was performed using Olex2 1.3-beta (Figure 1). Crystal data, data collection and structure refinement details are listed in Table 2. The crystal structure consists of two independent molecules per asymmetric unit, the pyrazolo[1,5- a]pyrimidine nucleus arranged in an opposite manner. The interaction of H1 with the Cg ring C20--C25 stabilize the crystal packing. Also, the π-π interaction of the pyrazolo[1,5-a] pyrimidine ring between C10-C11-C12-N1-N2 and C31-C30- C29-N6-N5, C10-N3-C8-C7-C9-N2 and C29-N6-C27-C26-C28- N7 rings interactions could be the contributing factor to this arrangement and stacking [31]. In both molecules, the pyrazolo[1,5-a]pyrimidine rings are planar with torsional angles C30-C29-N6-C27 -178.56°, N5-N6-C29-N7 -178.91°, C31-C30-C29-N6 -0.04°. The bond length and angles are within the normal ranges [32]. The bond length C10-N3 and C29-N7 which is single bond does not differ very much from bond lengths of N1-C12, N3-C8 and N5-C31, N7-C28 which are double bonds. Similarly, C11-C12, C8-C7 and C30-C31, C28-C26 which are single bonds does not vary much with that of C11-C10, C7- C8 and C30-C29, C26-C27 which are formally double bonds. This pattern could be due to the delocalization of the ring system. Selected bond lengths and bond angles are given in Tables 3 and 4. The phenyl groups at C3 and C6 position in both the molecules are oriented to the plane of the pyrazolo[1,5- a]pyrimidine nucleus with torsion angles of C1-C6-C7-C9 and C18-C13-C11-C12 as 44.67° and 36.78°, respectively, and C24- C23-C26-C27 and C37-C32-C30-C31 as -41.63° and -41.05°, respectively. 186 Kaping et al. / European Journal of Chemistry 11 (3) (2020) 179-186 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.179-186.1977 4. Conclusion We have developed an efficient, facile and environmental friendly synthetic strategy for the synthesis of hitherto unknown pyrazolo[1,5-a]pyrimidine derivatives with formy- lated acetophenones and its equivalent in the presence of KHSO4 in aqueous medium in good to excellent yields. Use of KHSO4 led to mild reaction conditions with precipitation of practically pure products that could be easily isolated by filtration, ensuring complete removal of the acid by washing with EtOH:H2O (1:1, v:v). Acknowledgements Authors wish to thank Rev. Fr. Dr. Stephen Mavely, Vice Chancellor, Assam Don Bosco University for providing infrastructure for the execution of this work. Authors also wish to express their gratitude to Indian Institute of Technology (IIT), Guwahati, Tezpur University, Tezpur, Guwahati, Sophisticated Analytical Instrument Facility-North-Eastern Hill University (SAIF-NEHU), Shillong and Sophisticated Analytical Instrument Facility-Central Drug Research Institute (SAIF- CDRI) Lucknow, for providing spectral and analytical data. Our thanks are also due to the Department of Biotechnology, Government of India for a research grant. This manuscript is a part of the PhD thesis of Dr. Shunan Kaping, Assam Don Bosco University, India, 2016, www.shodhganga.inflibnet.ac.in Supporting information CCDC-967390 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered to. Sample availability: Samples of the compounds are available from the author. Funding Department of Biotechnology, Ministry of Science and Technology, Government of India, New Delhi-110 003, India ORCID Shunan Kaping http://orcid.org/0000-0001-7898-5039 Philippe Helissey http://orcid.org/0000-0003-4558-0961 Jai Narain Vishwakarma http://orcid.org/0000-0001-9068-4554 References [1]. Baluja, S.; Kachhadia, N.; Solanki, A. Open J. Org. Chem. 2013, 1, 1-5. [2]. Buriol, L.; Munchen, T. S.; Frizzo, C. P.; Marzari, M. R. B.; Zanatta, N. Bonacorso, H. G.; Martins, M. A. P. Ultrason. Sonochem. 2013, 20, 1139- 1143. [3]. Cravotto, G.; Cintas, P. Chem. Soc. Rev. 2006, 35, 180-196. [4]. Puri, S.; Kaur, B.; Parmar, A.; Kumar, H. Curr. Org. Chem. 2013, 17, 1790-1828. [5]. Bretanha, L. C.; Teixeira, V. E.; Ritter, M.; Siqueira, G. M.; Cunico, W.; Pereira, C. M. P.; Freitag, R. A. Ultrason. Sonochem. 2011, 18, 704-707. [6]. Mason, T. J.; Cobley, A. G.; Graves, J. E.; Morgan, D. Ultrason. Sonochem. 2011, 18, 226-230. [7]. Bruni, F.; Selleri, S.; Constanzo, A.; Guerrilli, G.; Casilli, M. L.; Giusti, L. J. Heterocycl. Chem. 1995, 32, 291-298. [8]. Maeba, I.; Nishiyama, Y.; Kanazawa, S.; Sato, A. Heterocycles 1995, 41, 507-513. [9]. Bellec, Ch.; Lhommet, G. J. Heterocycl. Chem. 1995, 32, 1793-1800. [10]. Howard, A. S. Comprehensive Heterocyclic Chemistry II, Vol. 8, Pergamon Press, Oxford, 249, 1995. [11]. Barret, D. Heterocycles 1997, 45, 1839-1855. [12]. Damont, A.; Medran-Navarrete, V.; Cacheux, F.; Kuhnast, B.; Pottier, G.; Bernards, N.; Marguet, F.; Puech, F.; Boisgard, R.; Dolle, F. J. Med. Chem. 2015, 58, 7449-7464. [13]. Hassan, A. S.; Hafez, T. S.; Osman, S. A. Sci. Pharm. 2015, 83, 27-39. [14]. George, C. F. P. Lancet 2001, 358, 1623-1626. [15]. Wegner, F.; Deuther-Conrad, W.; Scheunemann, M.; Brust, P.; Fischer, S.; Hiller, A.; Diekers, M.; Strecker, K.; Wohlfarth, K.; Allgaier, C.; Steinbach, J.; Hoepping, A. Eur. J. Pharmacol. 2008, 580, 1-2. [16]. Ahmetaj, S.; Velikanje, N.; Groselj, U.; Sterbal, I.; Prek, B.; Golobic, A.; Kocar, D.; Dahmann, G.; Stanovnik, B.; Svete, J. Mol. Divers. 2013, 17, 731-743. [17]. Kalita, U.; Kaping, S.; Nellanant, J.; Helissey, P.; Vishwakarma, J. N. Heteroletters 2014, 4, 137-145. [18]. Devi, A. S.; Kaping, S.; Vishwakarma, J. N. Mol. Divers. 2015, 19, 759- 771. [19]. Kaping, S.; Boiss, I.; Singha, L. I.; Helissey, P.; Vishwakarma, J. N. Mol. Divers. 2016, 20, 379-390. [20]. Kaping, S.; Kalita, U.; Sunn, M.; Singha, L. I.; Vishwakarma, J. N. Monatsch. Chem. 2016, 147, 1257-1276. [21]. Bourhis, L. J.; Dolomanov, O. V.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. Acta Cryst. A 2015, 71, 59-75. [22]. Sheldrick, G. M. Acta Cryst. C 2015, 71, 3-8. [23]. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K; Puschmann, H. J. Appl. Cryst. 2009, 42, 339-341. [24]. Chanda, K.; Dutta, M. C.; Karim, E.; Vishwakarma, J. N. J. Indian Chem. Soc. 2004, 81, 791-793. [25]. Chanda, K.; Dutta, M. C.; Vishwakarma, J. N. Ind. J. Chem. B 2004, 43, 2475-2477. [26]. Elnagdi, M. H.; Erian, A. W. Bull. Chem. Soc. 1990, 63, 1854-1856. [27]. Almazrao, S.; Elnagdi, M. H.; El-Din, A. M. S. J. Het. Chem. 2004, 41, 267- 272. [28]. Bellec, C.; Maitte, P. Can. J. Chem. 1981, 59, 2826-2832. [29]. Gopalsamy, A.; Ciszewski, G.; Shi, M.; Berger, D.; Hu, Y.; Lee, F.; Feldberg, L.; Frommer, E.; Kim, S.; Collins, K.; Wojciechowicz, D.; Mallon, R. Biorg, Med. Chem. Lett. 2009, 19, 6890-6892. [30]. Radl, S.; Blahovcova, M.; Tkadlecova, M.; Havlicek, J. Heterocycles 2010, 80, 1359-1379. [31]. Etse, K. S.; Dassonneville, B.; Zaragoza, G.; Demonceau, A. Tetrahedron Lett. 2017, 58, 789-793. [32]. Portilla, J.; Quiroga, J.; Cobo, J.; Low, J. N.; Glidewell, C. Acta. Cryst. C 2006, 62, 186-189. Copyright © 2020 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.shodhganga.inflibnet.ac.in/ https://www.ccdc.cam.ac.uk/structures/ mailto:data_request@ccdc.cam.ac.uk http://orcid.org/0000-0001-7898-5039 http://orcid.org/0000-0003-4558-0961 http://orcid.org/0000-0001-9068-4554 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. Material and methods 2.1.1. Synthesis 2.1.1.1. Synthesis of 2-methyl-3-phenyl-7-arylpyrazolo[1,5-a]pyrimidine (5a-e) 2.1.1.2. Synthesis of 2-methyl-3-phenyl-6-arylpyrazolo[1,5-a]pyrimidin-7-amine (7a-c) 2.1.1.3. Synthesis of 2-methyl-3-phenyl-7-heteroaryl pyrazolo[1,5-a]pyrimidines (9a-d) 2.1.1.4. Synthesis of 6-acetyl/carboalkoxy-2,7-dimethyl-3-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (12) 3. Results and discussion 3.1. Chemistry 3.2. X-ray crystallography 4. Conclusion Acknowledgements Supporting information Disclosure statement Funding ORCID PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: