Next Article in Journal
La3+’s Effect on the Surface (101) of Anatase for Methylene Blue Dye Removal, a DFT Study
Previous Article in Journal
Photonics of Trimethine Cyanine Dyes as Probes for Biomolecules
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 19
10.3390/molecules27196369
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

High-Pressure Metal-Free Catalyzed One-Pot Two-Component Synthetic Approach for New 5-Arylazopyrazolo[3,4-b]Pyridine Derivatives

by
AbdElAziz A. Nayl
1,*,
Hamada Mohamed Ibrahim
2,*,
Kamal M. Dawood
3,
Wael A. A. Arafa
1,
Ahmed I. Abd-Elhamid
4,
Ismail M. Ahmed
1,
Mohamed A. Abdelgawad
5,
Hazim M. Ali
1,
Ibrahim Hotan Alsohaimi
1,
Ashraf A. Aly
6,
Stefan Bräse
7,8,* and
Asmaa Kamal Mourad
2
1
Department of Chemistry, College of Science, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia
2
Chemistry Department, Faculty of Science, Fayoum University, Fayoum 63514, Faiyum, Egypt
3
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Giza, Egypt
4
Composites and Nanostructured Materials Research Department, Advanced Technology and New Materials Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg Al-Arab 21934, Alexandria, Egypt
5
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia
6
Chemistry Department, Faculty of Science, Organic Division, Minia University, El-Minia 61519, Menia, Egypt
7
Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76133 Karlsruhe, Germany
8
Institute of Biological and Chemical Systems—Functional Molecular Systems (IBCS-FMS), Director Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(19), 6369; https://doi.org/10.3390/molecules27196369
Submission received: 2 September 2022 / Revised: 15 September 2022 / Accepted: 20 September 2022 / Published: 27 September 2022
Browse Figures
Versions Notes

Abstract

:
An appropriate and efficient Q-tube-assisted ammonium acetate-mediated protocol for the assembly of the hitherto unreported 5-arylazopyrazolo[3,4-b]pyridines was demonstrated. This methodology comprises the cyclocondensation reaction of 5-amino-2-phenyl-4H-pyrazol-3-one with an assortment of arylhydrazonals in an NH4OAc/AcOH buffer solution operating a Q-tube reactor. This versatile protocol exhibited several outstanding merits: easy work-up, mild conditions, scalability, broad substrate scope, safety (the Q-tube kit is simply for pressing and sealing), and a high atom economy. Consequently, performing such reactions under elevated pressures and utilizing the Q-tube reactor seemed preferable for achieving the required products in comparison to the conventional conditions. Diverse spectroscopic methods and X-ray single-crystal techniques were applied to confirm the proposed structure of the targeted compounds.

1. Introduction

Heterocycles are pivotal in diversified domains as they are considered the essential motif in industrial, agricultural, and biological fields. Intriguingly, heterocyclic compounds are prevalent in more than 85% of the pharmacologically active substances, and over 60% of FDA-approved medications possess, in their structure, nitrogen-based heterocycles [1]. Considering that they are contained in numerous therapeutic medicines marketed as anxiolytics, including cartazolate, etazolate, and tracazolate, they have been recognized as potent pharmaceutically important compounds (Figure 1) [2]. Furthermore, pyrazolo[3,4-b]pyridines are the key components of the cardiovascular therapeutic drug BAY 41-2272 [3] and the Glycogen Synthase Kinase 3 (GSK-3) inhibitor that is effective in the treatment of Alzheimer’s disease [4,5]. They are generally utilized to treat pulmonary hypertension as sGC stimulators [6,7]. Interestingly, pyrazolo[3,4-b]pyridines have a substantial inhibitory impact on diverse enzymes, such as Cyclin-Dependent Kinase (CDK) [8], Anaplastic Lymphoma Kinase (ALK) [9], nucleotide pyrophosphatase, and human recombinant alkaline phosphatase [10,11,12]. It is noteworthy that the pyrazolo[3,4-b]pyridine motif is a versatile system with various advantages. Antiproliferative, antiviral, antimicrobial [13], anticancer [14], anti-inflammatory [15], anti-HIV [16], antioxidant [17], antiallergic, and antiherpetic [18] biological activities are just a few of these. Due to the diverse applications of the heterocycles that comprise the pyrazolo[3,4-b]pyridine moiety, developing new protocols for their synthesis is challenging for pharmaceutical and organic chemists. The first Q-tube-mediated, high-pressure strategy for the preparation of an unparalleled series of thiazolo[4,5-c]pyridazines was recently published by our group [19]. Consequently, as part of our continued endeavors to develop efficient, environmentally friendly, and expedient protocols, a metal-free catalyst, high-pressure-assisted strategy for synthesizing pyrazolo[3,4-b]pyridines was explored in the present study. High-pressure chemistry (HPC) has been an unconventional, promising, practical, and full-potential approach to organic synthesis since 1981 [20]. Specifically, the use of the Q-tube is regarded as a pioneer in HPC. Notably, the Q-tube-mediated approach has numerous substantial advantages, including high reaction rates, cleaner reaction profiles, smaller reaction volumes, and quantitative conversions. According to the Arrhenius equation, utilizing the Q-tube approach might exponentially enhance the reaction rate as the boiling point is elevated.
Furthermore, increasing the pressure inside the Q-tube improves the probability of reactant collision, which accelerates the reaction rate, resulting in the minimization of competitive reagent decompositions and a smoother reaction profile [20]. In addition, the Q-tube is a cost-effective alternative to the costly microwave (MW) technique; it permits the reactions to be performed at a temperature higher than the solvent’s boiling point, even for MW-transparent solvents [21]. AlMarzouq et al. reported an intriguing assessment of numerous traditional and alternative heating procedures in 2016. The Q-tube strategy was recommended as the technique of preference for the cleanest, shortest, and most effective preparation of the heterocyclic compounds under study [22]. In other respects, the coupling Q-tube-assisted approach with the one-pot multicomponent reactions (MCRs) strategy is considered to be one of the most advantageous protocols for achieving step efficiency and atom economy [19,23,24,25,26]. In this study, the coupling of the Q-tube-mediated protocol with the two-component reaction (MCR) strategy can be investigated to provide universal access to a series of unreported 5-arylazopyrazolo[3,4-b]pyridines with superior reaction profiles and higher rates and approximately quantitative yields.

2. Materials and Methods

2.1. General

The measured melting points were determined by employing a Griffin melting point device, and the results were given incorrectly. The FT-IR spectra (KBr) were obtained utilizing the Jasco FT-IR-6300 spectrometer. The NMR spectra (1H: 600 MHz and 13C: 150 MHz) were obtained utilizing the Bruker DPX 600 super-conducting spectrometer, where the TMS was used as an internal reference and DMSO-d6 or TFA-d as the solvent. The molecular weights of the synthesized compounds were recorded by employing both a high-resolution GC-MS (DFS) thermo-spectrometer [MS (EI) at 70.1 eV] and the magnetic sector mass analyzer [HRMS (EI)]. Thin layer chromatography (TLC) was used to monitor the progress of the reactions and to ensure product purity. All the reactions were carried out using a Q-tube gas purging kit (180 psi) from Q Labtech (Sigma-Aldrich, St. Louis, MO, USA), which included a catch bottle, PTFE-faced silicone septa, a borosilicate glass pressure tube (35.0 mL), a needle adapter, a Teflon sleeve, and a stainless steel adapter with a pressure gauge (300 psi). Microwave heating was carried out with a single-mode cavity Explorer Microwave synthesizer (CEM Corporation, Matthews, NC, USA), producing continuous irradiation and equipped with a simultaneous external air-cooling system. The Bruker X8 Prospector or Rigaku R-AXIS RAPID II diffractometer (Billerica, MA, USA) was used to record the X-ray crystallographic results. The arylhydrazonal derivatives (2) were synthesized by following up on the reported protocols [27].

2.2. General Protocol for the Synthesis of Compounds 3a–v

In the Q-tube reactor’s tube, a mixture of 5-amino-2-phenyl-4H-pyrazol-3-one (1) (5.0 mmol), arylhydrazonals 2 (5.0 mmol), glacial AcOH (10.0 mL), and AcONH4 (10.0 mmol) was introduced. The obtained mixture was then heated at 160 °C (oil bath) for 30 min, and the reaction progress was followed by employing TLC and GC/MS. After the reaction, the mixture was cooled to the ambient temperature. The obtained precipitate was filtered off, rinsed with EtOH (3 × 5.0 mL), and crystallized from the indicated solvent to yield pyrazolo[3,4-b]pyridin-3-ones 3a–v as pure products.
  • (E)-2,6-Diphenyl-5-(phenyldiazenyl)-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3a). Yellow crystals [EtOH/dioxane mixture (1:3)], yield: 1.90 g (98%), m.p. 255–256 °C; FT-IR 𝜈/cm−1: 3105 (N-H), 1656 (C=O), 1606 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.27–7.59 (m, 9H, Ar-H), 7.74–7.99 (m, 6H, Ar-H), 8.52 (s, 1H, C-H4), 12.34 ppm (brs, 1H, NH); 13C NMR (TFA-d, 100 MHz): δ 114.74, 12571, 126.29, 130.96, 131.47, 131.69, 132.27, 133.00, 133.23, 134.61, 135.32, 135.81, 136.00, 141.85, 146.39, 153.04, 159.07, 159.33 ppm; MS (EI) m/z (%): 392 (M+ + 1, 18.04), 391 (M+, 69.57), 390 (M+ − 1, 100); HRMS (EI) m/z: [M]+ calcd for C24H17N5O 391.1428, found 391.1428.
  • (E)-5-[(4-Chlorophenyl)diazenyl]-2,6-diphenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3b). Pale yellow crystals (dioxane), yield: 2.00 g (96%), m.p. 283–284 °C; FT-IR 𝜈/cm−1: 3106 (N-H), 1650 (C=O), 1620 (C=N); 1H NMR (TFA-d, 600 MHz): δ 8.19 (d, J = 8.4 Hz, 2H, Ar-H), 8.31–8.36 (m, 3H, Ar-H), 8.42–8.46 (m, 4H, Ar-H), 8.51–8.53 (m, 3H, Ar-H), 8.60 (d, J = 8.4 Hz, 2H, Ar-H), 10.18 ppm (s, 1H, C-H4), (exchanged proton with TFA, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 115.00, 126.97, 12765, 131.83, 132.07, 132.54, 132.92, 133.57, 133.80, 135.32, 136.28, 136.44, 142.90, 143.31, 147.49, 153.36, 159.33, 159.68 ppm; MS (EI) m/z (%): 427 (M+ + 2, 25.31), 426 (M+ + 1, 52.13), 425 (M+, 76.98), 424 (M+ − 1, 100); HRMS (EI) m/z: [M]+ calcd for C24H16ClN5O (M+) 425.1038, found 425.1038.
  • (E)-5-[(4-Methoxyphenyl)diazinyl]-2,6-diphenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3c). Yellow crystals [EtOH/dioxane mixture (1:2)], yield: 1.95 g (94%), m.p. 273–274 °C; FT-IR 𝜈/cm−1: 3116 (N-H), 1655 (C=O), 1602 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 3.82 (s, 3H, OCH3), 7.08 (d, J = 9.0 Hz, 2H, Ar-H), 7.27 (t, J = 7.2 Hz, 1H, Ar-H), 7.51 (t, J = 7.8 Hz, 2H, Ar-H), 7.54–7.56 (m, 3H, Ar-H), 7.71 (d, J = 7.8 Hz, 2H, Ar-H), 7.78 (d, J = 9.0 Hz, 2H, Ar-H), 7.98 (d, J = 7.2 Hz, 2H, Ar-H), 8.45 (s, 1H, C-H4), 12.30 ppm (brs, 1H, NH); 13C NMR (TFA-d, 100 MHz): δ 58.39 (OCH3), 113.77, 119.43, 126.38, 130.11, 130.75, 132.09, 132.41, 133.46, 133.56, 136.09, 136.46, 136.77, 137.03, 141.19, 146.86, 157.89, 160.54, 170.93 ppm; MS (EI) m/z (%): 422 (M+ + 1, 27.18), 421 (M+, 96.22), 420 (M+ − 1, 100); HRMS (EI) m/z: [M]+ calcd for C25H19N5O2 (M+) 421.1533, found 421.1533.
  • (E)-5-[(4-Nitrophenyl)diazinyl]-2,6-diphenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3d). Orange crystals [EtOH/DMF mixture (1:2)], yield: 2.05 g (95%), m.p. 299–300 °C; FT-IR 𝜈/cm−1: 3103 (N-H), 1659 (C=O), 1607 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.27 (t, J = 7.2 Hz, 1H, Ar-H), 7.51 (t, J = 7.8 Hz, 2H, Ar-H), 7.57–7.62 (m, 3H, Ar-H), 7.81 (d, J = 7.2 Hz, 2H, Ar-H), 7.87 (d, J = 8.4 Hz, 2H, Ar-H), 8.02 (d, J = 8.4 Hz, 2H, Ar-H), 8.37 (d, J = 7.8 Hz, 2H, Ar-H), 8.59 (s, 1H, C-H4), 12.33 ppm (brs, 1H, NH); 13C NMR (TFA-d, 100 MHz): δ 114.24, 126.56, 126.82, 127.42, 131.24, 131.71, 132.51, 133.28, 133.44, 134.96, 135.62, 136.17, 142.31, 147.04, 151.78, 157.88, 159.22, 159.79 ppm; MS (EI) m/z (%): 437 (M+ + 1, 28.19), 436 (M+, 92.89), 435 (M+ − 1, 100); HRMS (EI) m/z: [M]+ calcd for C24H16N6O3 (M+) 436.1278, found 436.1278.
  • (E)-5-[(4-Chlorophenyl)diazinyl]-6-(naphthalen-2-yl)-2-phenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3e). Pale orange crystals [EtOH/DMF mixture (1:3)], yield: 2.10 g (89%), m.p. 289–290 °C; FT-IR 𝜈/cm−1: 3111 (NH), 1653 (C=O), 1621 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.28 (t, J = 7.2 Hz, 1H, Ar-H), 7.53 (t, J = 7.8 Hz, 2H, Ar-H), 7.60–7.74 (m, 6H, Ar-H), 7.93–8.09 (m, 6H, Ar-H), 8.38 (s, 1H, Ar-H), 8.59 (s, 1H, C-H4), 12.57 ppm (brs, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 113.98, 126.49, 127.36, 128.32, 128.52, 130.40, 130.68, 131.57, 131.80, 132.25, 132.52, 132.65, 133.30, 134.59, 135.31, 135.81, 135.87, 138.06, 142.50, 142.56, 147.02, 152.71, 158.64, 159.05 ppm; MS (EI) m/z (%): 477 (M+ + 2, 34.11), 476 (M+ + 1, 52.35), 475 (M+, 100.00), 474 (M+ − 1, 71.98); HRMS (EI) m/z: [M]+ calcd for C28H18ClN5O (M+) 475.1194, found 475.1195.
  • (E)-6-(Naphthalen-2-yl)-2-phenyl-5-(p-tolyldiazenyl)-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3f). Orange crystals [EtOH/DMF mixture (1:2)], yield: 2.00 g (88%), m.p. 284–285 °C; FT-IR 𝜈/cm−1: 3116 (NH), 1656 (C=O), 1605 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 2.36 (s, 3H, CH3), 7.29 (t, J = 7.8 Hz, 1H, Ar-H), 7.34 (d, J = 7.8 Hz, 2H, Ar-H), 7.53 (t, J = 7.8 Hz, 2H, Ar-H), 7.61–7.68 (m, 4H, Ar-H), 7.95 (d, J = 7.8 Hz, 1H, Ar-H), 8.01–8.09 (m, 5H, Ar-H), 8.38 (s, 1H, Ar-H), 8.55 (s, 1H, C-H4), 12.42 ppm (brs, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 22.68 (CH3), 115.00, 125.88, 126.30, 128.20, 128.40, 130.36, 130.70, 131.63, 131.91, 132.57, 132.64, 133.06, 133.10, 133.41, 134.23, 135.26, 136.15, 138.16, 140.78, 146.82, 149.10, 150.03, 159.45, 159.57 ppm; MS (EI) m/z (%): 456 (M+ + 1, 29.67), 455 (M+, 100.00), 454 (M+ − 1, 72.86); HRMS (EI) m/z: [M]+ calcd for C29H21N5O (M+) 455.1741, found 455.1740.
  • (E)-6-(Naphthalen-2-yl)-5-[(4-nitrophenyl)diazinyl]-2-phenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3g). Deep orange crystals [EtOH/DMF mixture (1:3)], yield: 2.05 g (85%), m.p. above 300 °C; FT-IR 𝜈/cm−1: 3108 (NH), 1654 (C=O), 1622 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.27 (t, J = 7.8 Hz, 1H, Ar-H), 7.52 (t, J = 7.8 Hz, 2H, Ar-H), 7.60–7.69 (m, 4H, Ar-H), 7.88 (d, J = 7.8 Hz, 1H, Ar-H), 7.94–8.06 (m, 4H, Ar-H), 8.10 (d, J = 7.8 Hz, 2H, Ar-H), 8.36 (d, J = 8.4 Hz, 1H, Ar-H), 8.42 (s, 1H, Ar-H), 8.65 (s, 1H, C-H4), 11.99 ppm (brs, 1H, NH); 13C NMR (TFA-d, 100 MHz): δ 114.13, 126.98, 127.16, 127.28, 127.92, 128.81, 129.04, 129.83, 130.82, 131.10, 131.97, 132.25, 133.02, 135.09, 135.74, 136.20, 136.51, 138.47, 142.67, 147.85, 152.21, 158.34, 159.40, 160.19 ppm; MS (EI) m/z (%): 487 (M+ + 1, 29.98), 486 (M+, 100.00), 485 (M+ − 1, 66.18); HRMS (EI) m/z: [M]+ calcd for C28H18N6O3 (M+) 486.1435, found 486.1435.
  • (E)-5-[(4-Chlorophenyl)diazinyl]-6-(naphthalen-1-yl)-2-phenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3h). Orange crystals [EtOH/DMF mixture (1:3)], yield: 2.10 g (88%), m.p. 277–278 °C; FT-IR 𝜈/cm−1: 3117 (NH), 1659 (C=O), 1611 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.25–7.27 (m, 3H, Ar-H), 7.42 (d, J = 8.4 Hz, 2H, Ar-H), 7.47 (t, J = 7.2 Hz, 1H, Ar-H), 7.51 (t, J = 7.8 Hz, 2H, Ar-H), 7.68–7.74 (m, 3H, Ar-H), 8.06–8.08 (m, 3H, Ar-H), 8.16 (d, J = 7.8 Hz, 2H, Ar-H), 8.63 (s, 1H, C-H4), 12.52 ppm (brs, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 115.23, 125.98, 126.37, 126.73, 126.83, 128.73, 129.46, 130.67, 131.12, 131.52, 132.07, 132.30, 133.12, 133.46, 134.20, 135.00, 135.98, 136.00, 142.12, 143.86, 146.54, 152.40, 158.81, 159.28 ppm; MS (EI) m/z (%): 477 (M+ + 2, 28.97), 476 (M+ + 1, 52.00), 475 (M+, 94.87), 474 (M+ − 1, 100.00); HRMS (EI) m/z: [M]+ calcd for C28H18ClN5O (M+) 475.1194, found 475.1194.
  • (E)-6-(Naphthalen-1-yl)-5-[(4-nitrophenyl)diazinyl]-2-phenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3i). Orange crystals [EtOH/DMF mixture (1:3)], yield: 2.00 g (83%), m.p. 275–276 °C; FT-IR 𝜈/cm−1: 3112 (NH), 1660 (C=O), 1618 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.26 (t, J = 7.2 Hz, 1H, Ar-H), 7.38 (d, J = 9.0 Hz, 2H, Ar-H), 7.47–7.51 (m, 3H, Ar-H), 7.58 (t, J = 7.8 Hz, 1H, Ar-H), 7.69–7.74 (m, 2H, Ar-H), 7.77 (d, J = 7.8 Hz, 1H, Ar-H), 8.05 (d, J = 7.8 Hz, 2H, Ar-H), 8.08 (d, J = 7.8 Hz, 1H, Ar-H), 7.15–7.18 (m, 3H, Ar-H), 8.68 (s, 1H, C-H4), 12.28 ppm (brs, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 115.07, 126.54, 12671, 126.90, 127.16, 127.23, 129.10, 129.19, 129.81, 131.00, 131.52, 132.27, 132.53, 132.60, 133.46, 133.90, 134.28, 136.37, 143.54, 147.26, 151.63, 157.86, 159.31, 160.26 ppm; MS (EI) m/z (%): 487 (M+ + 1, 26.02), 486 (M+, 100.00), 485 (M+ − 1, 97.84); HRMS (EI) m/z: [M]+ calcd for C28H18N6O3 (M+) 486.1435, found 486.1435.
  • (E)-2-Phenyl-5-(phenyldiazenyl)-6-(thiophen-2-yl)-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3j). Pale yellow crystals [EtOH/dioxane mixture (1:2)], yield: 1.75 g (90%), m.p. 256–257 °C; FT-IR 𝜈/cm−1: 3112 (NH), 1656 (C=O), 1618 (C=N); 1H NMR (TFA-d, 600 MHz): δ 7.33 (t, J = 5.4 Hz, 1H, thiophene-H), 7.45–7.50 (m, 6H, Ar-H), 7.57 (d, J = 7.8 Hz, 2H, Ar-H), 7.92 (d, J = 7.8 Hz, 2H, Ar-H), 8.07 (d, J = 5.4 Hz, 1H, thiophene-H), 8.28 (d, J = 5.4 Hz, 1H, thiophene-H), 9.15 ppm (s, 1H, C-H4), (exchanged proton with TFA, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 111.76, 123.26, 124.85, 125.94, 126.48, 131.27, 131.71, 132.14, 132.75, 135.53, 135.90, 136.61, 139.61, 144.99, 146.45, 150.75, 153.13, 158.53 ppm; MS (EI) m/z (%): 398 (M+ + 1, 4.95), 397 (M+, 15.81), 396 (M+ − 1, 15.34); HRMS (EI) m/z: [M]+ calcd for C22H15N5OS (M+) 397.0992, found 397.0992.
  • (E)-5-[(4-Chlorophenyl)diazinyl]-2-phenyl-6-(thiophen-2-yl)-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3k). Yellow crystals (dioxane), yield: 2.00 g (92%), m.p. 265–266 °C; FT-IR 𝜈/cm−1: 3114 (NH), 1659 (C=O), 1622 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.23 (t, J = 4.8 Hz, 1H, thiophene-H), 7.27 (t, J = 7.8 Hz, 1H, Ar-H), 7.50 (t, J = 7.8 Hz, 2H, Ar-H), 7.64 (d, J = 8.4 Hz, 2H, Ar-H), 7.89–7.92 (m, 5H, Ar-H), 8.07 (d, J = 4.8 Hz, 1H, thiophene-H), 8.30 (s, 1H, C-H4), 12.32 ppm (brs, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 112.24, 126.49, 128.28, 131.74, 131.92, 132.48, 132.69, 133.19, 133.55, 136.44, 136.99, 140.84, 143.02, 144.52, 147.59, 150.99, 153.29, 159.19 ppm; MS (EI) m/z (%): 433 (M+ + 2, 7.14), 432 (M+ + 1, 9.97), 431 (M+, 18.21), 430 (M+ − 1, 14.06); HRMS (EI) m/z: [M]+ calcd for C22H14ClN5OS (M+) 431.0602, found 431.0601.
  • (E)-2-Phenyl-6-(thiophen-2-yl)-5-(p-tolyldiazenyl)-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3l). Yellow crystals (dioxane), yield: 2.05 g (88%), m.p. 263–264 °C; FT-IR 𝜈/cm−1: 3112 (NH), 1660 (C=O), 1618 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 2.44 (s, 3H, CH3), 7.28–7.31 (m, 2H, Ar-H), 7.47 (d, J = 7.8 Hz, 2H, Ar-H), 7.53 (t, J = 7.8 Hz, 2H, Ar-H), 7.91–7.94 (m, 4H, Ar-H), 7.96 (d, J = 4.8 Hz, 1H, thiophene-H), 8.15 (d, J = 4.8 Hz, 1H, thiophene-H), 8.39 (s, 1H, C-H4), 12.21 ppm (brs, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 22.40 (CH3), 111.96, 125.76, 126.63, 131.10, 131.41, 132.20, 132.69, 135.82, 136.66, 139.19, 145.17, 146.49, 148.78, 150.52, 150.78, 158.47 ppm; MS (EI) m/z (%): 412 (M+ + 1, 5.61), 411 (M+, 18.17), 410 (M+ − 1, 15.01); HRMS (EI) m/z: [M]+ calcd for C23H17N5OS (M+) 411.1148, found 411.1149.
  • (E)-5-[(2,4-Difluorophenyl)diazinyl]-2-phenyl-6-(thiophen-2-yl)-2,7-dihydro-3H-pyrazolo- [3,4-b]pyridin-3-one (3m). Orange crystals [EtOH/DMF mixture (1:2)], yield: 2.00 g (93%), m.p. 272–273 °C; FT-IR 𝜈/cm−1: 3110 (NH), 1650 (C=O), 1607 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.28–7.34 (m, 3H, Ar-H), 7.52 (t, J = 8.4 Hz, 2H, Ar-H), 7.62 (t, J = 8.4 Hz, 1H, Ar-H), 7.90–7.93 (m, 3H, Ar-H), 7.97 (d, J = 4.8 Hz, 1H, thiophene-H), 8.13 (d, J = 4.8 Hz, 1H, thiophene-H), 8.34 (s, 1H, C-H4), 12.45 ppm (brs, 1H, NH); 13C NMR (DMSO-d6, 150 MHz): δ (105.60, 105.77, 105.94) (t, 2JCF = 25.5 Hz), 109.60, (112.71, 112.86)] (dd, 2JCF = 22.5 Hz), 119.41, (120.15, 120.22) (d, 3JCF = 10.5 Hz), 121.14, 125.38, 128.27, 129.07, 132.60, 133.80, 137.01, 137.27, 139.30, 158.52, 159.03, 160.79, (163.28, 164.95 ppm) (d, 1JCF = 250.5 Hz); MS (EI) m/z (%): 434 (M+ + 1, 5.34), 433 (M+, 18.45), 432 (M+ − 1, 15.23); HRMS (EI) m/z: [M]+ calcd for C22H13F2N5OS (M+) 433.0803, found 433.0803.
  • (E)-6-(4-Chlorophenyl)-5-[(4-chlorophenyl)diazinyl]-2-phenyl-2,7-dihydro-3H-pyrazolo- [3,4-b]pyridin-3-one (3n). Yellow crystals (dioxane), yield: 2.25 g (99%), m.p. above 300 °C; FT-IR 𝜈/cm−1: 3114 (NH), 1651 (C=O), 1622 (C=N); 1H NMR (TFA-d, 600 MHz): δ 8.41 (d, J = 9.0 Hz, 2H, Ar-H), 8.53–8.57 (m, 3H, Ar-H), 8.62–8.66 (m, 4H, Ar-H), 8.74–8.77 (m, 4H, Ar-H), 10.42 ppm (s, 1H, C-H4), (exchanged proton with TFA, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 126.76, 127.47, 127.74, 129.78, 132.27, 132.35, 132.73, 133.54, 134.84, 135.10, 135.80, 142.65, 142.77, 143.87, 147.10, 152.85, 157.85, 159.04 ppm; MS (EI) m/z (%): 461 (M+ + 2, 66.28), 460 (M+ + 1, 92.93), 459 (M+, 100.00), 458 (M+ − 1, 98.02); HRMS (EI) m/z: [M]+ calcd for C24H15Cl2N5O (M+) 459.0648, found 459.0647.
  • (E)-5-[(3-Bromophenyl)diazenyl]-6-(4-chlorophenyl)-2-phenyl-2,7-dihydro-3H-pyrazolo- [3,4-b]pyridin-3-one (3o). Orange crystals (dioxane), yield: 2.40 g (97%), m.p. above 300 °C; FT-IR 𝜈/cm−1: 3111 (NH), 1650 (C=O), 1621 (C=N); 1H NMR (TFA-d, 600 MHz): δ 7.23 (t, J = 7.8 Hz, 1H, Ar-H), 7.42–7.48 (m, 4H, Ar-H), 7.53–7.57 (m, 4H, Ar-H), 7.66–7.70 (m, 3H, Ar-H), 7.74 (s, 1H, Ar-H), 9.28 ppm (s, 1H, C-H4), (exchanged proton with TFA, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 114.32, 125.57, 126.07, 126.26, 127.53, 129.37, 131.95, 132.36, 132.96, 133.08, 134.53, 134.74, 135.43, 138.11, 142.09, 143.59, 146.75, 155.01, 157.38, 158.89 ppm; MS (EI) m/z (%): 505 (M+ + 2, 89.91), 504 (M+ + 1, 100.00), 503 (M+, 61.42), 502 (M+ − 1, 55.03); HRMS (EI) m/z: [M]+ calcd for C24H15BrClN5O (M+) 503.0143, found 503.0144.
  • (E)-6-(4-Chlorophenyl)-5-[(2-nitrophenyl)diazinyl]-2-phenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3p). Orange crystals [EtOH/DMF mixture (1:3)], yield: 2.15 g (92%), m.p. 296–297 °C; FT-IR 𝜈/cm−1: 3106 (NH), 1662 (C=O), 1626 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.28 (t, J = 7.8 Hz, 1H, Ar-H), 7.50–7.52 (m, 3H, Ar-H), 7.61 (dd, J = 1.8, 8.4 Hz, 2H, Ar-H), 7.69 (t, J = 7.8 Hz, 1H, Ar-H), 7.79 (t, J = 7.8 Hz, 1H, Ar-H), 7.83 (d, J = 8.4 Hz, 2H, Ar-H), 7.99 (d, J = 8.4 Hz, 2H, Ar-H), 8.04 (d, J = 7.8 Hz, 1H, Ar-H), 8.37 (s, 1H, C-H4), 12.34 ppm (brs, 1H, NH); 13C NMR (DMSO-d6, 150 MHz): δ 118.12, 119.23, 122.20, 123.58, 124.93, 127.48, 128.51, 130.64, 132.28, 132.97, 133.77, 134.73, 137.23, 138.58, 140.62, 143.79, 146.80, 152.79, 158.36, 158.66 ppm; MS (EI) m/z (%): 472 (M+ + 2, 10.04), 471 (M+ + 1, 13.45), 470 (M+, 27.09), 469 (M+ − 1, 21.27); HRMS (EI) m/z: [M]+ calcd for C24H15ClN6O3 (M+) 470.0889, found 470.0887.
  • (E)-6-(4-Fluorophenyl)-2-phenyl-5-(p-tolyldiazenyl)-2,7-dihydro-3H-pyrazolo[3,4-b] pyridin-3-one (3q). Yellow crystals (dioxane), yield: 1.80 g (86%), m.p. above 300 °C; FT-IR 𝜈/cm−1: 3114 (NH), 1651 (C=O), 1622 (C=N); 1H NMR (TFA-d, 600 MHz): δ 2.43 (s, 3H, CH3), 7.35–7.40 (m, 4H, Ar-H), 7.57–8.62 (m, 3H, Ar-H), 7.69 (d, J = 8.4 Hz, 2H, Ar-H), 7.77 (d, J = 8.4 Hz, 2H, Ar-H), 7.90–7.92 (m, 2H, Ar-H), 9.46 (s, 1H, C-H4), (exchanged proton with TFA, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 22.29 (CH3), (118.91, 119.07) (d, 2JCF = 24.0 Hz), (125.34, 125.36) (d, 4JCF = 3.0 Hz), 126.87, 127.27, 128.26, 132.36, 132.42, (135.80, 135.87) (d, 3JCF = 10.5 Hz), 139.46, 140.78, 150.04, 150.28, 153.31, 153.45, 154.17, 155.53, 168.02, (168.18, 169.90 ppm) (d, 1JCF = 258.0 Hz); MS (EI) m/z (%): 424 (M+ + 1, 29.05), 423 (M+, 100.00), 422 (M+ − 1, 89.92); HRMS (EI) m/z: [M]+ calcd for C25H18FN5O (M+) 423.1490, found 423.1490.
  • (E)-6-(4-Fluorophenyl)-5-[(4-nitrophenyl)diazinyl]-2-phenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3r). Orange crystals [EtOH/DMF mixture (1:3)], yield: 2.05 g (91%), m.p. above 300 °C; FT-IR 𝜈/cm−1: 3112 (NH), 1662 (C=O), 1604 (C=N); 1H NMR (TFA-d, 600 MHz): δ 7.26 (t, J = 8.4 Hz, 2H, Ar-H), 7.45–7.49 (m, 3H, Ar-H), 7.56 (d, J = 7.8 Hz, 2H, Ar-H), 7.77–7.80 (m, 2H, Ar-H), 7.91 (d, J = 9.0 Hz, 2H, Ar-H), 8.29 (d, J = 9.0 Hz, 2H, Ar-H), 9.43 (s, 1H, C-H4), (exchanged proton with TFA, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 114.15, (118.86, 119.01) (d, 2JCF = 22.5 Hz), 126.35, 126.58, 127.16, 127.26, 132.32, 133.14, 134.83, 135.35, (135.81, 135.88) (d, 3JCF = 10.5 Hz), 142.02, 146.87, 151.65, 157.69, 158.36, 159.08, (167.97, 169.68 ppm) (d, 1JCF = 256.5 Hz); MS (EI) m/z (%): 455 (M+ + 1, 32.41), 454 (M+, 100.00), 422 (M+ − 1, 89.92); HRMS (EI) m/z: [M]+ calcd for C24H15FN6O3 (M+) 454.1184, found 454.1184.
  • (E)-5-[(3-Bromophenyl)diazinyl]-6-(4-fluorophenyl)-2-phenyl-2,7-dihydro-3H-pyrazolo- [3,4-b]pyridin-3-one (3s). Deep orange crystals [dioxane/DMF mixture (1:1)], yield: 2.10 g (87%), m.p. 285–286 °C; FT-IR 𝜈/cm−1: 3112 (NH), 1650 (C=O), 1622 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 7.26 (t, J = 7.2 Hz, 1H, Ar-H), 7.39 (t, J = 8.4 Hz, 2H, Ar-H), 7.48–7.51 (m, 3H, Ar-H), 7.66 (d, J = 7.2 Hz, 1H, Ar-H), 7.72 (d, J = 7.2 Hz, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.82–7.96 (m, 4H, Ar-H), 8.46 (s, 1H, C-H4), 12.75 ppm (brs, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 114.13, (118.70, 118.85) (d, 2JCF = 22.5 Hz), 125.40, 125.96, 126.25, 127.25, 132.20, 132.68, 133.03, 134.72, 135.03, (135.70, 135.76) (d, 3JCF = 9.0 Hz), 138.04, 142.25, 146.41, 152.56, 154.87, 157.45, 158.94, (167.85, 169.56 ppm) (d, 1JCF = 256.5 Hz); MS (EI) m/z (%): 489 (M+ + 2, 72.19), 488 (M+ + 1, 83.04), 487 (M+, 71.43), 486 (M+ − 1, 62.35); H HRMS (EI) m/z: [M]+ calcd for C24H15BrFN5O (M+) 487.0439, found 487.0438.
  • (E)-6-(4-Bromophenyl)-5-[(2,4-difluorophenyl)diazinyl]-2-phenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3t). Orange crystals (DMF), yield: 2.40 g (97%), m.p. above 300 °C; FT-IR 𝜈/cm−1: 3112 (NH), 1655 (C=O), 1610 (C=N); 1H NMR (TFA-d, 600 MHz): δ 6.92 (td, J = 9.0, 4.5 Hz, 1H, Ar-H), 7.01 (td, J = 9.0, 4.5 Hz, 1H, Ar-H), 7.57–7.67 (m, 4H, Ar-H), 7.69 (d, J = 7.2 Hz, 2H, Ar-H), 7.73 (d, J = 8.4, Hz, 2H, Ar-H), 8.84 (d, J = 8.4, Hz, 2H, Ar-H), 9.49 (s, 1H, C-H4), (exchanged proton with TFA, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ (107.36, 107.53, 107.69) (t, 2JCF = 25.5 Hz), 114.37, (114.50, 114.53) (d, 4JCF = 4.5 Hz), (122.15, 122.23) (d, 3JCF = 12.0 Hz), 126.34, 129.77, 131.56, 132.31, 133.14, 134.37, 134.91, 135.13, 135.18, (139.40, 139.43, 139.46) (t, 4JCF = 4.5 Hz), 142.87, 146.59, 157.32, 158.89, [(163.00, 163.09), (164.76, 164.85)] (dd, 1JCF = 13.5, 264.0 Hz), [(168.27, 168.35), (170.00, 170.08 ppm)] (dd, 1JCF = 12.0, 259.5 Hz); MS (EI) m/z (%): 507 (M+ + 2, 85.00), 506 (M+ + 1, 100.00), 505 (M+, 83.57), 504 (M+ − 1, 80.76); HRMS (EI) m/z: [M]+ calcd for C24H14BrF2N5O (M+) 505.0344, found 505.0351.
  • (E)-6-(4-Chlorophenyl)-5-[(2-fluoro-5-nitrophenyl)diazinyl]-2-phenyl-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3u). Orange crystals (DMF), yield: 2.25 g (94%), m.p. above 300 °C; FT-IR 𝜈/cm−1: 3117 (NH), 1656 (C=O), 1622 (C=N); 1H NMR (TFA-d, 600 MHz): δ 6.91–7.73 (m, 9H, Ar-H), 9.66–9.98 (m, 3H, Ar-H), 10.61 (s, 1H, C-H4), (exchanged proton with TFA, 1H, NH); 13C NMR (TFA-d, 150 MHz): δ 114.22, 117.38, (121.76, 121.92) (d, 2JCF = 24.0 Hz), 127.13, 130.02, (131.71, 131.79) (d, 3JCF = 12.0 Hz), 132.66, 133.01, 133.92, 135.12, 135.47, 136.35, 142.43, (142.89, 142.96) (d, 3JCF = 10.5 Hz), 144.31, 147.20, 147.89, 159.05, 159.35, (166.23, 168.04 ppm) (d, 1JCF = 271.5 Hz); MS (EI) m/z (%): 490 (M+ + 2, 36.42), 489 (M+ + 1, 57.98), 488 (M+, 100.00), 487 (M+ − 1, 89.83); HRMS (EI) m/z: [M]+ calcd for C24H14ClFN6O3 (M+) 488.0794, found 488.0796.
  • (E)-6-Methyl-2-phenyl-5-(phenyldiazenyl)-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3v). Pale yellow [EtOH/dioxane mixture (1:1)], yield: 1.35 g (83%), m.p. 283–284 °C; FT-IR 𝜈/cm−1: 3122 (NH), 1661 (C=O), 1620 (C=N); 1H NMR (DMSO-d6, 600 MHz): δ 2.89 (s, 3H, CH3), 7.18 (t, J = 7.8 Hz, 1H, Ar-H), 7.44 (t, J = 7.8 Hz, 2H, Ar-H), 7.49 (t, J = 7.8 Hz, 1H, Ar-H), 7.56 (t, J = 7.8 Hz, 2H, Ar-H), 7.84 (d, J = 7.8 Hz, 2H, Ar-H), 8.07 (d, J = 7.8 Hz, 2H, Ar-H), 8.42 (s, 1H, C-H4), 13.94 ppm (s, 1H, NH); 13C NMR (DMSO-d6, 150 MHz): δ 17.74 (CH3), 119.20, 122.75, 124.14, 124.89, 129.24, 129.77, 130.95, 135.71, 139.62, 152.71, 157.89, 160.03 ppm; MS (EI) m/z (%): 330 (M+ + 1, 23.91), 329 (M+, 100.00), 328 (M+ − 1, 8.23); HRMS (EI) m/z: [M]+ calcd for C19H15N5O (M+) 329.1271, found 329.1271.

3. Results and Discussion

Owing to the remarkable therapeutic usages of the pyrazolopyridines, it is worthwhile to assemble a unique family of arylazopyrazolo[3,4-b]pyridines (3a–v, Scheme 1, Figures S1–S44), utilizing a safer and greener approach. A series of arylhydrazonals 1a–v was constructed following the reported protocols [27]. The reaction involving 5-amino-2-phenyl-4H-pyrazol-3-one (1) and 3-oxo-2-arylhydrazonopropanal (2a) was chosen as a template reaction to evaluate and study the optimal reaction conditions (Scheme 1 and Table 1).
At the outset, it was observed that refluxing a mixture of 5-amino-2-phenyl-4H-pyrazol-3-one (1, 5.0 mmol) and arylhydrazonal (2a, 5.0 mmol) in various solvents, including polar aprotic solvents (dioxane and CH3CN) and polar protic solvents (ethanol and propanol), comprising AcONH4 or anhydrous AcONa (10.0 mmol) under normal pressure for 12 h, did not produce any new products (Table 1, entries 1–4). They were interesting; utilizing DMF as a reaction solvent produced a new product in a 14% yield within 6 h, while the reaction yield did not increase with the increasing of the reaction duration (Table 1, entry 6). Furthermore, refluxing the selected reactants in acetic acid for 3 h yielded a product of a 45% yield when AcONH4 was used as an additive and a 30% yield when anhydrous AcONa was employed (Table 1, entries 6 and 7). Consequently, AcONH4 will be employed as an additive in the subsequent experiments. According to the results of several analyses, the newly obtained products in the cases above (Table 1, entries 5–7) are matched and elucidated to be 2,6-diphenyl-5-(phenyldiazenyl)-2,7-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (3a) and not the open-chain derivative 4 (Scheme 2). Among these analyses, the high-resolution mass and mass spectrometric analyses (See SI) of 3a exhibited an exact mass of m/z 391.1428 and a mass of m/z 391, respectively, for the related molecular formula of C24H17N5O. The 1H NMR spectrum of 3a in DMSO-d6 revealed a multiplet at δ 7.27–7.99 ppm due to 15 aromatic protons, a singlet signal for pyridine C-H4 at δ 8.25 ppm, and an abroad singlet assigned for the NH proton at δ 12.34 ppm. Furthermore, as anticipated, the 13C NMR spectrum of 3a exhibited 18 signals with only one carbonyl signal.
The remarkable results motivated us to investigate the optimal parameters that impact the model reaction in a green and sustainable approach. Additionally, the investigation will be extended to demonstrate a comparative study between the microwave technique and the Q-tube methodology as an economical and affordable alternative to the costly MW. For comparison, we initially employed a MW (250 watts, 140 °C, 30 min) to perform the template reaction by mixing an equimolar amount (2.0 mmol) of compound 1 and 2a in the presence of ammonium acetate (4.0 mmol)/acetic acid (5.0 mL) buffer solution. After the usual working up, compound 3a was delivered in a 66% yield (Table 1, entry 8). Unfortunately, both the reaction rate and the obtained yield did not improve with the increasing of the reaction temperature and time. Interestingly, on employing the above-mentioned reaction utilizing the Q-tube pressure reactor (140 °C, 30 min), the targeted product 3a was obtained with an 85% yield (Table 1, entry 9). It is worthwhile observing that doubling the amount of the substrates yielded 3a with a comparatively similar efficiency and that prolonging the reaction interval would not enhance the reaction yield; therefore, employing the Q-tube provides a cleaner reaction profile and higher yields. Additionally, the Q-tube reactor was employed to perform such reactions safely under high pressure, avoiding the risk of unintentional explosions that could occur when a conventional sealed tube was utilized. After affirming the effectiveness and merits of the Q-tube and the AcOH/AcONH4 buffer in carrying out the desired reaction (Table 1, entry 9), the study was extended to investigate the impact of temperature on the reaction progress. The obtained results (Table 1, entries 10–12) indicated that the temperature considerably affects the reaction efficiency. For example, when the reaction was carried out at 150 °C, the target product was obtained at 92% (Table 1, entry 10); however, when the temperature was raised to 155, 160, and then 165 °C (Table 1, entries 11–13), compound 3a was obtained at 96%, 98%, and 98%, respectively, indicating that 160 °C is the optimized temperature for such a conversion (Table 1, entry 12).
Further investigations were carried out to study the potential, applicability, and limitations of the two NH4OAc-prompted successive condensation reactions (Figure 2) under the established optimal conditions (Table 1, entry 12). To achieve this target, a diversity of 3-oxo-arylhydrazonals 2a–v was prepared and introduced in order to evaluate their reactions with 5-amino-2-phenyl-4H-pyrazol-3-one (1) under the specified optimal conditions (Table 1, entry 12). In general, the electronic properties of the aryl motifs attached to 3-oxo-arylhydrazonals (2) had a minimal influence on reaction efficacy [28,29]. The reaction was exceptionally adaptable to both electron-releasing motifs as well as the electron-accepting motifs. Gratifyingly, the naphthyl 2e–i and thienyl 2j–m derivatives had similar, successful, and smooth pathways in the case of 5-amino-2-phenyl-4H-pyrazol-3-one (1), yielding the condensed products in excellent yields (Figure 2). After several attempts, a suitable crystal for the X-ray single-crystallographic investigations was isolated as 3v to confirm the initial results (Figure 3, Table 2). Moreover, the obtained single crystallographic data for the derivative 3v (Figure 3, Table 2) confirmed the proposed structure and verified the regioselectivity of the reaction, yielding only the (E)-isomer of the 5-arylazopyrazolo[3,4-b]pyridine derivatives.
Scheme 3 depicts a plausible mechanistic approach for synthesizing 5-arylazopyrazolo[3,4-b]pyridines 3a–v. In the presence of acetic acid, the carbonyl groups became more polarized, and thus, their reactivity towards nucleophiles was enhanced. Firstly, the nucleophile generated from compound 1 underwent nucleophilic attack to the protonated carbonyl carbon of derivative 2, to give the adduct A. Subsequently, the adduct (A) was easily converted to the non-isolable intermediary B by removing the good releasing group (OH2+). Secondly, the amino group underwent an intramolecular nucleophilic attack to the second protonated carbonyl carbon to obtain the intermediate C. Finally, the targeted products 3a–v were formed via the exclusion of another water molecule (Scheme 3).

4. Conclusions

In conclusion, the present study represented an effective, practical, and adequate protocol for designing an assortment of the unprecedented 5-arylazopyrazolo[3,4-b]pyridines via the reaction between 5-amino-2-phenyl-4H-pyrazol-3-one and a variety of arylhydrazonals in good to excellent yields. The applied methodology involves the utilization of the Q-tube reactor as a safe and efficacious technique to perform the targeted reactions successfully under high pressure. The protocol possesses a variety of remarkable merits, including an excellent atom economy, a broad range of reactants, the avoidance of the employment of toxic solvents, and safe, straightforward purification and work-up methods. The X-ray structure analysis confirmed regioselectivity and yielded only the (E)-isomer of 5-arylazopyrazolo[3,4-b]pyridines. Consequently, we anticipate that this protocol will deliver a possibility for the implementation of such heterocycles in developing and designing new pharmaceuticals.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27196369/s1. Figures S1–S44: Copies of NMR spectra for the reported compounds (PDF); the crystallographic data for compound 3v (PDF, CIF).

Author Contributions

Conceptualization, K.M.D., A.A.A. and S.B.; methodology, W.A.A.A., H.M.I., A.K.M., I.M.A. and A.I.A.-E.; software, M.A.A., I.H.A., I.M.A., H.M.A. and A.A.N.; validation, K.M.D., A.A.A., I.M.A., I.H.A., A.I.A.-E. and S.B.; formal analysis, H.M.I., I.H.A. and H.M.A.; investigation, H.M.I., W.A.A.A. and A.K.M.; writing—original draft preparation, H.M.I., W.A.A.A. and M.A.A.; writing—review and editing, W.A.A.A., A.A.A., A.A.N. and S.B.; project administration, A.A.N.; funding acquisition, A.A.N. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Deanship of Scientific Research at Jouf University under Grant No. (DSR2022-RG-0130).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data are contained within the article.

Acknowledgments

This work was funded by the Deanship of Scientific Research at Jouf University under grant No. (DSR2022-RG-0130). The authors acknowledge support from the KIT-Publication Fund of the Karlsruhe Institute of Technology. Stefan Bräse is grateful for support from the DFG-funded cluster program “3D Matter Made to Order” under Germany’s Excellence Strategy -2082/1-390761711. The authors acknowledge grants from the Science and Technology Commission of Shanghai Municipality (19440741300).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Heravi, M.M.; Zadsirjan, V. Prescribed drugs containing nitrogen heterocycles: An overview. RSC Adv. 2020, 10, 44247–44311. [Google Scholar] [CrossRef] [PubMed]
  2. Patel, J.; Malick, J.; Salama, A.; Goldberg, M. Pharmacology of pyrazolopyridines. Pharmacol. Biochem. Behav. 1985, 23, 675–680. [Google Scholar] [CrossRef]
  3. Boerrigter, G.; Burnett, J.C. Nitric Oxide-Independent Stimulation of Soluble Guanylate Cyclase with BAY 41-2272 in Cardiovascular Disease. Cardiovasc. Drug Rev. 2007, 25, 30–45. [Google Scholar] [CrossRef] [PubMed]
  4. Sanghvi, Y.S.; Larson, S.B.; Willis, R.C.; Robins, R.K.; Revankar, G.R. Synthesis and biological evaluation of certain C-4 substituted pyrazolo[3,4-b]pyridine nucleosides. J. Med. Chem. 1989, 32, 945–951. [Google Scholar] [CrossRef] [PubMed]
  5. Umar, T.; Shalini, S.; Raza, K.; Gusain, S.; Kumar, J.; Seth, P.; Tiwari, M.; Hoda, N. A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer’s disease. Eur. J. Med. Chem. 2019, 175, 2–19. [Google Scholar] [CrossRef] [PubMed]
  6. Li, L.; Zhang, W.; Lin, F.; Lu, X.; Chen, W.; Li, X.; Zhou, X.; Su, R.; Wang, L.; Zheng, Z.; et al. Synthesis and biological evaluation of pyrazolo[3,4-b]pyridine-3-yl pyrimidine derivatives as sGC stimulators for the treatment of pulmonary hypertension. Eur. J. Med. Chem. 2019, 173, 107–116. [Google Scholar] [CrossRef] [PubMed]
  7. Li, L.; Yin, M.; Hu, L.; Tian, X.; He, X.; Zhao, C.; Li, Y.; Li, Q.; Li, X. Novel Pyrazolo[3,4-b] Pyridine Derivative (HLQ2g) Attenuates Hypoxic Pulmonary Hypertension via Restoring cGKI Expression and BMP Signaling Pathway. Front. Pharmacol. 2021, 12, 691405. [Google Scholar] [CrossRef]
  8. Abdel-Rahman, A.; Shaban, A.; Nassar, I.; El-Kady, D.; Ismail, N.; Mahmoud, S.; Awad, H.; El-Sayed, W. Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity. Molecules 2021, 26, 3923. [Google Scholar] [CrossRef]
  9. Nam, Y.; Hwang, D.; Kim, N.; Seo, H.-S.; Selim, K.B.; Sim, T. Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors. J. Enzym. Inhib. Med. Chem. 2019, 34, 1426–1438. [Google Scholar] [CrossRef] [PubMed]
  10. Supe, L.; Afzal, S.; Mahmood, A.; Ejaz, S.A.; Hein, M.; Iaroshenko, V.O.; Villinger, A.; Lecka, J.; Sévigny, J.; Iqbal, J.; et al. Deazapurine Analogues Bearing a 1H-Pyrazolo[3,4-b]pyridin-3(2H)-one Core: Synthesis and Biological Activity. Eur. J. Org. Chem. 2018, 2018, 2629–2644. [Google Scholar] [CrossRef]
  11. El-Gohary, N.; Gabr, M.; Shaaban, M. Synthesis, molecular modeling and biological evaluation of new pyrazolo[3,4-b]pyridine analogs as potential antimicrobial, antiquorum-sensing and anticancer agents. Bioorganic Chem. 2019, 89, 102976. [Google Scholar] [CrossRef]
  12. Xing, Y.; Zuo, J.; Krogstad, P.; Jung, M.E. Synthesis and Structure–Activity Relationship (SAR) Studies of Novel Pyrazolopyridine Derivatives as Inhibitors of Enterovirus Replication. J. Med. Chem. 2018, 61, 1688–1703. [Google Scholar] [CrossRef]
  13. Hawas, S.S.; El-Gohary, N.S.; Gabr, M.T.; Shaaban, M.I.; El-Ashmawy, M.B. Synthesis, molecular docking, antimicrobial, antiquorum-sensing and antiproliferative activities of new series of pyrazolo[3,4-b]pyridine analogs. Synth. Commun. 2019, 49, 2466–2487. [Google Scholar] [CrossRef]
  14. Eissa, I.H.; El-Naggar, A.M.; El-Hashash, M.A. Design, synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents. Bioorgan. Chem. 2016, 67, 43–56. [Google Scholar] [CrossRef]
  15. Bilavendran, J.D.; Manikandan, A.; Thangarasu, P.; Sivakumar, K. Synthesis and discovery of pyrazolo-pyridine analogs as inflammation medications through pro- and anti-inflammatory cytokine and COX-2 inhibition assessments. Bioorgan. Chem. 2020, 94, 103484. [Google Scholar] [CrossRef] [PubMed]
  16. Fichez, J.; Soulie, C.; Le Corre, L.; Sayon, S.; Priet, S.; Alvarez, K.; Delelis, O.; Gizzi, P.; Prestat, G.; Gravier-Pelletier, C.; et al. Discovery, SAR study and ADME properties of methyl 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1H-pyrazole-5-carboxylate as an HIV-1 replication inhibitor. RSC Med. Chem. 2020, 11, 577–582. [Google Scholar] [CrossRef] [PubMed]
  17. Gouda, M.A. Synthesis and Antioxidant Evaluation of Some New Pyrazolopyridine Derivatives. Arch. der Pharm. 2011, 345, 155–162. [Google Scholar] [CrossRef]
  18. Gudmundsson, K.S.; Johns, B.A.; Wang, Z.; Turner, E.M.; Allen, S.H.; Freeman, G.A.; Boyd, F.L.; Sexton, C.J.; Selleseth, D.W.; Moniri, K.R.; et al. Synthesis of novel substituted 2-phenylpyrazolopyridines with potent activity against herpesviruses. Bioorgan. Med. Chem. 2005, 13, 5346–5361. [Google Scholar] [CrossRef] [PubMed]
  19. Ibrahim, H.M.; Behbehani, H. The first Q-Tube based high-pressure synthesis of anti-cancer active thiazolo[4,5-c]pyridazines via the [4 + 2] cyclocondensation of 3-oxo-2-arylhydrazonopropanals with 4-thiazolidinones. Sci. Rep. 2020, 10, 6492. [Google Scholar] [CrossRef] [PubMed]
  20. Nacca, F.G.; Merlino, O.; Mangiavacchi, F.; Krasowska, D.; Santi, C.; Sancineto, L. The Q-tube System, A Nonconventional Technology for Green Chemistry Practitioners. Curr. Green Chem. 2017, 4, 58–66. [Google Scholar] [CrossRef]
  21. Oliverio, M.; Costanzo, P.; Nardi, M.; Rivalta, I.; Procopio, A. Facile Ecofriendly Synthesis of Monastrol and Its Structural Isomers via Biginelli Reaction. ACS Sustain. Chem. Eng. 2014, 2, 1228–1233. [Google Scholar] [CrossRef]
  22. Almarzouq, D.S.; Zaky, O.S.; Alnajjar, A.A.; Sadek, K.U. Pressure as effective green technology for synthesis of polyfunctionally substituted heteroaromatics: Synthesis of a variety of pyrazolo[1,5-a]pyrimidines. Eur. J. Chem. 2016, 7, 347–351. [Google Scholar] [CrossRef]
  23. Costanzo, P.; Calandruccio, C.; Di Gioia, M.L.; Nardi, M.; Oliverio, M.; Procopio, A. First multicomponent reaction exploiting glycerol carbonate synthesis. J. Clean. Prod. 2018, 202, 504–509. [Google Scholar] [CrossRef]
  24. Alzaydi, K.M.; Abojabal, N.S.; Elnagdi, M.H. Multicomponent reactions in Q-Tubes™: One-pot synthesis of benzo[c]chromen-6-one and phenanthridin-6(5H)-one derivatives in a four-component reaction. Tetrahedron Lett. 2016, 57, 3596–3599. [Google Scholar] [CrossRef]
  25. Ibrahim, H.M.; Behbehani, H. TFA-catalyzed Q-Tube Reactor-Assisted Strategy for the Synthesis of Pyrido[1,2-b][1,2,4]triazine and Pyrido[1′,2′:2,3][1,2,4]triazino[5,6-b]indole Derivatives. ACS Omega 2021, 6, 16086–16099. [Google Scholar] [CrossRef]
  26. Ibrahim, H.M.; Behbehani, H. Palladium-Catalyzed Q-Tube-Assisted Protocol for Synthesizing Diaza-dibenzo[a,e]azulene and Diaza-benzo[a]fluorene Derivatives via O2 Acid-Promoted Cross-Dehydrogenative Coupling. J. Org. Chem. 2020, 85, 15368–15381. [Google Scholar] [CrossRef]
  27. Ibrahim, H.M.; Behbehani, H.; Mostafa, N.S. Scalable Sonochemical Synthetic Strategy for Pyrazolo[1,5-a]pyridine Derivatives: First Catalyst-Free Concerted [3 + 2] Cycloaddition of Alkyne and Alkene Derivatives to 2-Imino-1H-pyridin-1-amines. ACS Omega 2019, 4, 7182–7193. [Google Scholar] [CrossRef] [PubMed]
  28. Behbehani, H.; Dawood, K.M.; Aryan, F.A.; Ibrahim, H.M. Green Protocol for the Novel Synthesis of Thiochromeno[4,3-b]pyridine and Chromeno[4,3-b]pyridine Derivatives Utilizing a High-Pressure System. ACS Omega 2021, 6, 34065–34074. [Google Scholar] [CrossRef]
  29. Behbehani, H.; Aryan, F.A.; Dawood, K.M.; Ibrahim, H.M. High pressure assisted synthetic approach for novel 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline derivatives and their assessment as anticancer agents. Sci. Rep. 2020, 10, 21691. [Google Scholar] [CrossRef]
  30. Crystallographic Data for 3v (ref. CCDC 2188305) Can Be Obtained on Request from the Director, Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EW, UK. Available online: https://www.ccdc.cam.ac.uk/ (accessed on 1 September 2022).
Molecules 27 06369 g001 550
Figure 1. Structure of cartazolate, etazolate, and tracazolate.
Figure 1. Structure of cartazolate, etazolate, and tracazolate.
Molecules 27 06369 g001
Molecules 27 06369 sch001 550
Scheme 1. Synthesis of 5-arylazopyrazolo[3,4-b]pyridine derivatives 3a–v.
Scheme 1. Synthesis of 5-arylazopyrazolo[3,4-b]pyridine derivatives 3a–v.
Molecules 27 06369 sch001
Molecules 27 06369 sch002 550
Scheme 2. Reactions of 5-amino-2-phenyl-4H-pyrazol-3-one (1) with arylhydrazonal derivative 2a.
Scheme 2. Reactions of 5-amino-2-phenyl-4H-pyrazol-3-one (1) with arylhydrazonal derivative 2a.
Molecules 27 06369 sch002
Molecules 27 06369 g002 550
Figure 2. Cyclocondensation reactions between pyrazol-3-one 1 and arylhydrazonals 2 using Q-tube.
Figure 2. Cyclocondensation reactions between pyrazol-3-one 1 and arylhydrazonals 2 using Q-tube.
Molecules 27 06369 g002
Molecules 27 06369 g003 550
Figure 3. The X-ray crystallographic structure determined for 3v [30].
Figure 3. The X-ray crystallographic structure determined for 3v [30].
Molecules 27 06369 g003
Molecules 27 06369 sch003 550
Scheme 3. Plausible mechanistic route describes the formation of 5-arylazopyrazolo[3,4-b]pyridines 3a–v.
Scheme 3. Plausible mechanistic route describes the formation of 5-arylazopyrazolo[3,4-b]pyridines 3a–v.
Molecules 27 06369 sch003
Table
Table 1. Optimization of the reaction of pyrazol-3-one 1 with phenylhydrazonal (2a).
Table 1. Optimization of the reaction of pyrazol-3-one 1 with phenylhydrazonal (2a).
Molecules 27 06369 i001
EntrySolventAdditive (Equiv)Temp. (°C)TimeYield (%)
1 aEtOHNH4OAc or NaOAc12012 h0
2 aCH3CNNH4OAc or NaOAc12012 h0
3 a1,4-dioxaneNH4OAc or NaOAc14012 h0
4 apropanolNH4OAc or NaOAc13012 h0
5 aDMFNH4OAc or NaOAc1406h≈14
6 aAcOHNH4OAc1406 h45
7 aAcOHNaOAc1406 h30
8 bAcOHNH4OAc14030 min66
9 cAcOHNH4OAc14030 min85
10 cAcOHNH4OAc15030 min92
11 cAcOHNH4OAc15530 min96
12 cAcOHNH4OAc16030 min98
13 cAcOHNH4OAc16530 min98
a Reaction conditions: independent mixture of 5-amino-2-phenyl-4H-pyrazol-3-one (1) (5.0 mmol) and arylhydrazonal 2a (5.0 mmol) in AcOH (15.0 mL), comprising additive, was refluxed at the specified temp (°C) for the mentioned period. b Reaction conditions: independent mixture of 1 (2.0 mmol), arylhydrazonal 2a (2.0 mmol), and NH4OAc (4.0 mmol) in AcOH (5.0 mL) was heated using the microwave irradiation (140 °C, 250 W) for 30 min. c Reaction conditions: independent mixture of 1 (5.0 mmol), arylhydrazonal 2a (5.0 mmol), and NH4OAc (10.0 mmol) in AcOH (10.0 mL) was introduced into the Q-tube reactor and heated (oil bath) at the specified temp (°C) for 30 min.
Table
Table 2. Some selected bond lengths and angles for compound 3c.
Table 2. Some selected bond lengths and angles for compound 3c.
BondBond length (Å)BondBond Angle (o)
C5-C101.380 (9)C7-C8-C9119.5 (6)
C5-N51.444 (6)C6-C5-C10120.5 (5)
N4-C41.409 (6)C3-C4-C11121.0 (4)
N4-N51.258 (6)N5-N4-C4114.7 (5)
C3-C41.404 (8)N4-N5-C5112.3 (5)
N1-C111.353 (6)C11-N1-C13122.2 (4)
N2-N31.424 (6)C2-C3-C4118.7 (5)
C1-O11.238 (7)N3-N2-C14116.6 (4)
N3-C141.412 (6)O1-C1-C2131.9 (4)
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Nayl, A.A.; Ibrahim, H.M.; Dawood, K.M.; Arafa, W.A.A.; Abd-Elhamid, A.I.; Ahmed, I.M.; Abdelgawad, M.A.; Ali, H.M.; Alsohaimi, I.H.; Aly, A.A.; et al. High-Pressure Metal-Free Catalyzed One-Pot Two-Component Synthetic Approach for New 5-Arylazopyrazolo[3,4-b]Pyridine Derivatives. Molecules 2022, 27, 6369. https://doi.org/10.3390/molecules27196369

AMA Style

Nayl AA, Ibrahim HM, Dawood KM, Arafa WAA, Abd-Elhamid AI, Ahmed IM, Abdelgawad MA, Ali HM, Alsohaimi IH, Aly AA, et al. High-Pressure Metal-Free Catalyzed One-Pot Two-Component Synthetic Approach for New 5-Arylazopyrazolo[3,4-b]Pyridine Derivatives. Molecules. 2022; 27(19):6369. https://doi.org/10.3390/molecules27196369

Chicago/Turabian Style

Nayl, AbdElAziz A., Hamada Mohamed Ibrahim, Kamal M. Dawood, Wael A. A. Arafa, Ahmed I. Abd-Elhamid, Ismail M. Ahmed, Mohamed A. Abdelgawad, Hazim M. Ali, Ibrahim Hotan Alsohaimi, Ashraf A. Aly, and et al. 2022. "High-Pressure Metal-Free Catalyzed One-Pot Two-Component Synthetic Approach for New 5-Arylazopyrazolo[3,4-b]Pyridine Derivatives" Molecules 27, no. 19: 6369. https://doi.org/10.3390/molecules27196369

Article Metrics

Back to TopTop