Efficient synthesis of diversely substituted pyrazolo[1,5-a]pyrimidine derivatives promoted by ultrasound irradiation in water and their antibacterial activities

Abstract

A green synthetic route leading to the discovery of a series of diversely substituted pyrazolo[1,5-a]pyrimidines, having CO2Et group embedded at position-2 has been unraveled in this article. A series of formylated active proton compounds that were chosen to react with a carboxylate substituted-3-aminopyrazole under ultrasonic irradiation in the presence of a mild acid as a catalyst and aqueous ethanol medium afforded the desired products. The molecular structures of all these synthesized compounds were established by their spectral and analytical data. A model molecule 3d, subjected to single-crystal X-ray crystallography analysis further confirms their molecular structure. The crystal crystallized to a monoclinic cell with P21/c space group, a = 7.468 (5) Å, b = 27.908 (17) Å, c = 7.232 (4) Å, β = 104.291 (7)o, V =1460.7(15) Å3, Z = 4, μ(MoKα) = 0.096 mm-1, Dcalc = 1.352 Mg/m3 16667 measured reflection (5.63 ≤ 2Θ ≤ 57.57°), 3720 unique (Rint = 0.0965, Rsigma = 0.0945) which were used in all calculations. The final R1 was 0.0750 (I > 2σ(I)) and wR2 was 0.2226 (all data). These compounds were further explored for their antibacterial potential, and a few of them have exhibited encouraging results.

Design, Synthesis, and Biological Evaluation of Aryl Pyrazolopyrimidines as Toll‐Like Receptor 7 Agonists

“…Ethyl 7-(pyridin-3-yl)pyrazolo [1,5-a]pyrimidine-3-carboxylate ( 7) 1 H NMR (700 MHz, DMSO-d6) δ 9.21 (d, J = 1.8 Hz, 1H, H-Py2), 8.92 (d, J = 4.6 Hz, 1H, H-5), 8.80 (dd, J = 5.0, 1.7 Hz, 1H, H-Py6), 8.67 (s, 1H, H-2), 8.51 (ddd, J = 8.3, 1.8, 1.7 Hz, 1H, H-Py4), 7.67 (dd, J = 8.3, 5.0 Hz, 1H, H-Py5), 7.59 (d, J = 4.6 Hz, 1H, H-6), 4.33 (q, J = 6.8 Hz, 2H, 3-COOCH 2 CH 3 ), and 1.33 (t, J = 6.8 Hz, 3H, 3-COOCH 2 CH 3 ); White powder, yield 58%; Calcd for C 14 H 13 N 4 O 2 (M + H) + : m/z 269.1039. Found: m/z 269.1025 (Das et al 2020). [1,5-a]pyrimidine-3-carbonitrile (8) 1 H NMR (700 MHz, DMSO-d6) δ 8.97 (d, J = 4.5 Hz, 1H, H-5), 8.89 (s, 1H, H-2), 8.87 (d, J = 5.8 Hz, 2H, H-Py2/Py6), 8.05 (d, J = 5.8 Hz, 2H, H-Py3/Py5), 7.70 (d, J = 4.5 Hz, 1H, H-6); 13 C NMR (175 MHz) δ 154.4 (C-5), 151.3 (C-7), 151.2 (C-9), 150.6 (C-Py2/Py6), 147.8 (C-2), 145.6 (C-Py4), 124.0 (C-Py3/Py5), 113.7 (3-CN), 111.7 (C-6), and 82.2 (C-3); White powder, yield 88%; Calcd for C 12 H 6 N 5 (M−H) + : m/z 222.0629.…”

Design, Synthesis, and Biological Evaluation of Aryl Pyrazolopyrimidines as Toll‐Like Receptor 7 Agonists

“…Ethyl 7-(pyridin-3-yl)pyrazolo [1,5-a]pyrimidine-3-carboxylate ( 7) 1 H NMR (700 MHz, DMSO-d6) δ 9.21 (d, J = 1.8 Hz, 1H, H-Py2), 8.92 (d, J = 4.6 Hz, 1H, H-5), 8.80 (dd, J = 5.0, 1.7 Hz, 1H, H-Py6), 8.67 (s, 1H, H-2), 8.51 (ddd, J = 8.3, 1.8, 1.7 Hz, 1H, H-Py4), 7.67 (dd, J = 8.3, 5.0 Hz, 1H, H-Py5), 7.59 (d, J = 4.6 Hz, 1H, H-6), 4.33 (q, J = 6.8 Hz, 2H, 3-COOCH 2 CH 3 ), and 1.33 (t, J = 6.8 Hz, 3H, 3-COOCH 2 CH 3 ); White powder, yield 58%; Calcd for C 14 H 13 N 4 O 2 (M + H) + : m/z 269.1039. Found: m/z 269.1025 (Das et al 2020). [1,5-a]pyrimidine-3-carbonitrile (8) 1 H NMR (700 MHz, DMSO-d6) δ 8.97 (d, J = 4.5 Hz, 1H, H-5), 8.89 (s, 1H, H-2), 8.87 (d, J = 5.8 Hz, 2H, H-Py2/Py6), 8.05 (d, J = 5.8 Hz, 2H, H-Py3/Py5), 7.70 (d, J = 4.5 Hz, 1H, H-6); 13 C NMR (175 MHz) δ 154.4 (C-5), 151.3 (C-7), 151.2 (C-9), 150.6 (C-Py2/Py6), 147.8 (C-2), 145.6 (C-Py4), 124.0 (C-Py3/Py5), 113.7 (3-CN), 111.7 (C-6), and 82.2 (C-3); White powder, yield 88%; Calcd for C 12 H 6 N 5 (M−H) + : m/z 222.0629.…”

A Green Synthetic Strategy for Pyrazolo[1,5-a]pyrimidin-7(4H)-one Derivatives by the Reaction of Aminopyrazoles and Symmetric/Non-symmetric Alkynes Assisted by KHSO4 in Aqueous Media

“…In the light of the importance of this class of compounds, our research group has also reported on the synthesis and biological properties of pyrazolo [1,5-a]pyrimidine derivatives [49][50][51] and molecular hybrids thereof [52][53][54]. In continuation with these studies, we herein present the synthesis of some novel pyrazolo[1,5-a]pyrimidine derivatives by the reaction of 5-aminopyrazoles with acetylenic esters assisted by KHSO 4 in aqueous media under the influence of ultrasound waves.…”

A new synthetic route for the preparation of 2,2′,5′‐trimethyl‐7‐oxo‐4,7‐dihydro‐[6,7′‐bipyrazolo[1,5‐a]pyrimidine]‐3,3′‐dicarbonitrile, structural elucidation, Hirshfeld surface analysis, energy framework, density functional theory and molecular docking investigations

“…Indeed, these heterocycles possess many active sites that make them favorable precursors for the synthesis of novel heterocyclic molecular systems capable of exhibiting a wide spectrum of activity. Moreover, they are used as antibacterial, [3,4] Tropomyosin receptor kinases (Trks), [5] anticancer, [6,7] anti-inflammatory, [8] and antitumor agents. [9] Recently, Das et al synthesized a series of substituted pyrazolo [1,5-a]pyrimidine derivatives via a green synthetic route, which show potential antibacterial activity.…”

“…[9] Recently, Das et al synthesized a series of substituted pyrazolo [1,5-a]pyrimidine derivatives via a green synthetic route, which show potential antibacterial activity. [3] Zhang et al reported the synthesis and inhibitory potency against Trk of a novel pyrazolo [1,5-a]pyrimidine. [5] The α-(benzoylamino)-β-substituted acrylic amides derivatives of pyrazolo [1,5-a]pyrimidine were tested in vitro for their antiproliferative activity, and they exhibited potent anticancer activity in HeLa and HepG 2 cell lines.…”

Design, Synthesis, and Biological Evaluation of Aryl Pyrazolopyrimidines as Toll‐Like Receptor 7 Agonists

“…Ethyl 7-(pyridin-3-yl)pyrazolo [1,5-a]pyrimidine-3-carboxylate ( 7) 1 H NMR (700 MHz, DMSO-d6) δ 9.21 (d, J = 1.8 Hz, 1H, H-Py2), 8.92 (d, J = 4.6 Hz, 1H, H-5), 8.80 (dd, J = 5.0, 1.7 Hz, 1H, H-Py6), 8.67 (s, 1H, H-2), 8.51 (ddd, J = 8.3, 1.8, 1.7 Hz, 1H, H-Py4), 7.67 (dd, J = 8.3, 5.0 Hz, 1H, H-Py5), 7.59 (d, J = 4.6 Hz, 1H, H-6), 4.33 (q, J = 6.8 Hz, 2H, 3-COOCH 2 CH 3 ), and 1.33 (t, J = 6.8 Hz, 3H, 3-COOCH 2 CH 3 ); White powder, yield 58%; Calcd for C 14 H 13 N 4 O 2 (M + H) + : m/z 269.1039. Found: m/z 269.1025 (Das et al 2020). [1,5-a]pyrimidine-3-carbonitrile (8) 1 H NMR (700 MHz, DMSO-d6) δ 8.97 (d, J = 4.5 Hz, 1H, H-5), 8.89 (s, 1H, H-2), 8.87 (d, J = 5.8 Hz, 2H, H-Py2/Py6), 8.05 (d, J = 5.8 Hz, 2H, H-Py3/Py5), 7.70 (d, J = 4.5 Hz, 1H, H-6); 13 C NMR (175 MHz) δ 154.4 (C-5), 151.3 (C-7), 151.2 (C-9), 150.6 (C-Py2/Py6), 147.8 (C-2), 145.6 (C-Py4), 124.0 (C-Py3/Py5), 113.7 (3-CN), 111.7 (C-6), and 82.2 (C-3); White powder, yield 88%; Calcd for C 12 H 6 N 5 (M−H) + : m/z 222.0629.…”

A Green Synthetic Strategy for Pyrazolo[1,5-a]pyrimidin-7(4H)-one Derivatives by the Reaction of Aminopyrazoles and Symmetric/Non-symmetric Alkynes Assisted by KHSO4 in Aqueous Media

“…In the light of the importance of this class of compounds, our research group has also reported on the synthesis and biological properties of pyrazolo [1,5-a]pyrimidine derivatives [49][50][51] and molecular hybrids thereof [52][53][54]. In continuation with these studies, we herein present the synthesis of some novel pyrazolo[1,5-a]pyrimidine derivatives by the reaction of 5-aminopyrazoles with acetylenic esters assisted by KHSO 4 in aqueous media under the influence of ultrasound waves.…”

A new synthetic route for the preparation of 2,2′,5′‐trimethyl‐7‐oxo‐4,7‐dihydro‐[6,7′‐bipyrazolo[1,5‐a]pyrimidine]‐3,3′‐dicarbonitrile, structural elucidation, Hirshfeld surface analysis, energy framework, density functional theory and molecular docking investigations

“…Indeed, these heterocycles possess many active sites that make them favorable precursors for the synthesis of novel heterocyclic molecular systems capable of exhibiting a wide spectrum of activity. Moreover, they are used as antibacterial, [3,4] Tropomyosin receptor kinases (Trks), [5] anticancer, [6,7] anti-inflammatory, [8] and antitumor agents. [9] Recently, Das et al synthesized a series of substituted pyrazolo [1,5-a]pyrimidine derivatives via a green synthetic route, which show potential antibacterial activity.…”

“…[9] Recently, Das et al synthesized a series of substituted pyrazolo [1,5-a]pyrimidine derivatives via a green synthetic route, which show potential antibacterial activity. [3] Zhang et al reported the synthesis and inhibitory potency against Trk of a novel pyrazolo [1,5-a]pyrimidine. [5] The α-(benzoylamino)-β-substituted acrylic amides derivatives of pyrazolo [1,5-a]pyrimidine were tested in vitro for their antiproliferative activity, and they exhibited potent anticancer activity in HeLa and HepG 2 cell lines.…”

Design, Synthesis, and Biological Evaluation of Aryl Pyrazolopyrimidines as Toll‐Like Receptor 7 Agonists

“…Ethyl 7-(pyridin-3-yl)pyrazolo [1,5-a]pyrimidine-3-carboxylate ( 7) 1 H NMR (700 MHz, DMSO-d6) δ 9.21 (d, J = 1.8 Hz, 1H, H-Py2), 8.92 (d, J = 4.6 Hz, 1H, H-5), 8.80 (dd, J = 5.0, 1.7 Hz, 1H, H-Py6), 8.67 (s, 1H, H-2), 8.51 (ddd, J = 8.3, 1.8, 1.7 Hz, 1H, H-Py4), 7.67 (dd, J = 8.3, 5.0 Hz, 1H, H-Py5), 7.59 (d, J = 4.6 Hz, 1H, H-6), 4.33 (q, J = 6.8 Hz, 2H, 3-COOCH 2 CH 3 ), and 1.33 (t, J = 6.8 Hz, 3H, 3-COOCH 2 CH 3 ); White powder, yield 58%; Calcd for C 14 H 13 N 4 O 2 (M + H) + : m/z 269.1039. Found: m/z 269.1025 (Das et al 2020). [1,5-a]pyrimidine-3-carbonitrile (8) 1 H NMR (700 MHz, DMSO-d6) δ 8.97 (d, J = 4.5 Hz, 1H, H-5), 8.89 (s, 1H, H-2), 8.87 (d, J = 5.8 Hz, 2H, H-Py2/Py6), 8.05 (d, J = 5.8 Hz, 2H, H-Py3/Py5), 7.70 (d, J = 4.5 Hz, 1H, H-6); 13 C NMR (175 MHz) δ 154.4 (C-5), 151.3 (C-7), 151.2 (C-9), 150.6 (C-Py2/Py6), 147.8 (C-2), 145.6 (C-Py4), 124.0 (C-Py3/Py5), 113.7 (3-CN), 111.7 (C-6), and 82.2 (C-3); White powder, yield 88%; Calcd for C 12 H 6 N 5 (M−H) + : m/z 222.0629.…”

A Green Synthetic Strategy for Pyrazolo[1,5-a]pyrimidin-7(4H)-one Derivatives by the Reaction of Aminopyrazoles and Symmetric/Non-symmetric Alkynes Assisted by KHSO4 in Aqueous Media

“…In the light of the importance of this class of compounds, our research group has also reported on the synthesis and biological properties of pyrazolo [1,5-a]pyrimidine derivatives [49][50][51] and molecular hybrids thereof [52][53][54]. In continuation with these studies, we herein present the synthesis of some novel pyrazolo[1,5-a]pyrimidine derivatives by the reaction of 5-aminopyrazoles with acetylenic esters assisted by KHSO 4 in aqueous media under the influence of ultrasound waves.…”

A new synthetic route for the preparation of 2,2′,5′‐trimethyl‐7‐oxo‐4,7‐dihydro‐[6,7′‐bipyrazolo[1,5‐a]pyrimidine]‐3,3′‐dicarbonitrile, structural elucidation, Hirshfeld surface analysis, energy framework, density functional theory and molecular docking investigations

“…Indeed, these heterocycles possess many active sites that make them favorable precursors for the synthesis of novel heterocyclic molecular systems capable of exhibiting a wide spectrum of activity. Moreover, they are used as antibacterial, [3,4] Tropomyosin receptor kinases (Trks), [5] anticancer, [6,7] anti-inflammatory, [8] and antitumor agents. [9] Recently, Das et al synthesized a series of substituted pyrazolo [1,5-a]pyrimidine derivatives via a green synthetic route, which show potential antibacterial activity.…”

“…[9] Recently, Das et al synthesized a series of substituted pyrazolo [1,5-a]pyrimidine derivatives via a green synthetic route, which show potential antibacterial activity. [3] Zhang et al reported the synthesis and inhibitory potency against Trk of a novel pyrazolo [1,5-a]pyrimidine. [5] The α-(benzoylamino)-β-substituted acrylic amides derivatives of pyrazolo [1,5-a]pyrimidine were tested in vitro for their antiproliferative activity, and they exhibited potent anticancer activity in HeLa and HepG 2 cell lines.…”