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Catalyst-free synthesis of tetrahydrodipyrazolopyridines via an one-pot tandem and green pseudo-six-component reaction in water

Catalyst-free synthesis of tetrahydrodipyrazolopyridines via an one-pot tandem and green... OO .H 2 NH NH O 2 2 2 Catalyst-Free NH OAc H O N N N N Room Temperature N H H *Correspondence: fmirjalili@yazd.ac.ir Department of Chemistry, College of Science, Yazd University, Yazd, Iran © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Keihanfar and Mirjalili BMC Chemistry (2022) 16:9 Page 2 of 6 A common protocol for the synthesis of THDPP is the Introduction reaction of aldehydes, hydrazine hydrate, ethyl acetoac- Multicomponent reactions (MCRs) are selective, sim- etate, and ammonium acetate in a multi-component ple and effective as compared to the conventional mul - manner with the presence of a catalyst. Previously, pseu- tistep synthesis [1–4]. They have been utilized to reduce dopolymeric magnetic nanoparticles [13], KCC-1-NH - environmental pollution. Water, as a green solvent, is DPA [14], CuFe O @HNTs [15], acetic acid [16], and presumed to speed up some organic reactions through 2 4 carbonaceous material (CSO H) [17], Fe O /KCC1/IL/ hydrophobic effects [5]. Therefore, catalyst-free organic 3 3 4 HPWMNPs [24], Nano-CdZr (PO ) [25], Nano-Fe O @ reactions in water that yield resolvable products are 4 4 6 3 4 SiO –SO H [23], FeNi -ILs MNPs [21], Nano-CuCr O attractive for many organic chemists [6, 7]. THDPPs 2 3 3 2 4 [26], Nano-ovalbumin [20], M(II)/Schiff base@MWCNT- fuse the heterocyclic moieties of pyrazolopyridine with Fe O /SiO [27]. Meanwhile, a catalyst free protocol pharmaceutical activities, which exist in Etazolate, Carta- 3 4 2 using ammonium carbonate instead of ammonium ace- zolate and Tracazolate drugs [8] (Fig. 1). tate has been reported [16], Ammonium carbonate is a Meanwhile, Due to the existence of two biologically basic salt and can catalysis the synthesis of THDPP’s. In active moieties, namely pyrazole and 1,4-dihydropyridine here, we have used ammonium acetate as neutral salt pyrazole in the structure of THDPPs, these compounds for production of ammonia in water and absence of any have various pharmaceutical applications such as antial- catalyst. lergic, anti-herpetic and anxiolytic effects [9, 10], anti- In this study, THDPPs are synthesized with a green Leishmania activities [11] and HIF 1α-prolyl hydroxylase catalyst-free protocol implemented in a water medium at inhibition [12]. room temperature (Scheme 1). C H H 4 9 4 9 NH NH NH R EtO C EtO C 2 2 EtO C N N N N N N Water EtO Et Et + NH OAc + 2 NH NH + 4 2 2 2 N N Et R. T. O N N Tracazolate H H Etazolate Cartazolate H Scheme 1 Synthesis of THDPP’s in water Fig. 1 Pyrazolopyridine with pharmaceutical activity Table 1 Optimization of the reaction conditions for the synthesis of 4-(4-chlorophenyl)-3,5-dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4- b:4′,3′-e]pyridine a b Entry Solvent Conditions Time (min) Yield (%) 1 EtOH r.t 180 – 2 EtOH Reflux 120 23 3 H O Reflux 60 53 4 H O r.t 45 98 [This work] The molar ratio of hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol),4-chlorobenzaldehyde (1 mmol) and ammonium acetate (4 mmol) is equal to 2:2:1:4 Isolated yields Keihanfar and M irjalili BMC Chemistry (2022) 16:9 Page 3 of 6 Table 2 Synthesis of THDPP’s (5 ) in water in room temperature a–m Entry R Product Time Yield M.P Lit. M.P. (C) [Reference] (min) (%) (°C) 1 4-Cl 5a 45 98 244–246 254–256 [19] 2 4-NO 5b 60 96 274–276 278–283 [19] 3 3-NO 5c 50 98 268–270 282–284 [20] 4 4-OH 5d 80 96 266–268 267–268 [21] 5 4-Br 5e 75 96 222–224 221–224 [19] 6 2-Cl 5f 105 94 162–164 164–165 [22] 7 4-N(CH ) 5g 90 85 238–239 240–242 [19] 3 2 8 4-Me 5h 180 95 240–242 241–243 [20] 9 4-F 5i 75 97 255–257 258–260 [18] 10 4-OCH 5j 90 98 187–189 188–190 [20] 11 3-OMe-4-OH 5k 90 98 256–258 256–258 [20] 12 3,4-(OH) 5l 90 83 208–210 208–210 [20] 13 4-CHO 5 m 120 91 > 300° > 300° [23] Reaction conditions: hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol), 4-chloro benzaldehyde (1 mmol) and ammonium acetate (4 mmol), water (3 mL) at room temperature Technology (HP), Model: 5793, Ion source: Electron Experimental Impact (EI), 20-EV, 230 °C, and Quadrupole analyzer. Materials and methods General Chemistry A Bruker, Equinox 55 spectrometer was used to record General procedure for the synthesis of THDPP’s the Fourier transforms infrared (FT-IR) spectra. A Bruker Firstly, a solution of 2.0  mmol of hydrazine hydrate, (DRX-400 Avance) nuclear magnetic resonance (NMR) 2.0  mmol of ethyl acetoacetate and 3  mL of water was instrument was also used to record the NMR spectra. stirred in a 25-mL round-bottom flask at room temper - In addition, a Buchi B-540 B.V.CHI apparatus served to ature. Secondly, 1.0  mmol of aldehyde and 4.0  mmol of determine the melting points of the compounds. Mass ammonium acetate were added to it and stirred at room spectrometry spectra were recorded with a Agilent temperature. The reaction was monitored by thin-layer .H chromatography (TLC; n-hexane:EtOAc, 70:30). After NH NH O 2 2 2 EtO the completion of the reaction, the solution was diluted (3) with cold water, and the product was appeared as water Water (1) N N insoluble solid which isolated by simple filtration. R.T. N N H H NH OAc Results and discussion (4) (2) (5) Although, catalytic synthesis of THDPPs protocols have Time:240 min yield: 85% many advantages such as high yields of products and short reaction time. But the hard work-up and expensive Scheme 2 Synthesis of 4-(Z)-2,6-dimethylhepta-1,5-dien-1-yl)-3,5- catalysts are some of drawbacks of them. Therefore, we dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridine Keihanfar and Mirjalili BMC Chemistry (2022) 16:9 Page 4 of 6 Ar Knoevenagel condensation NH NH 2 2 O O O Ar H -H -H O O 2 2 NHNH -EtOH O H O H Ar Ar N N Ar H Cyclization N reaction N N -H N O N NH OAc N N N OHN H H F E Scheme 3 A proposed mechanism for synthesis of THDPP’s have decided to design a catalyst-free protocol for syn- A mechanism proposed for the catalyst-free syn- thesis of THDPPs. thesis of THDPPs is shown in Scheme  3. Ammonium In order to optimize the reaction conditions for the acetate was used as a source of nitrogen for the forma- preparation of THDPPs in the absence of a catalyst, some tion of 1,4-dihydropyridine ring in the THDPPs. Hydra- reactions were performed between ethylacetoacetate, zine is soluble and ethylacetoacetate is partially soluble ammonium acetate, 4-chlorobenzaldehyde and hydrazine (2.86 g/100 mL) in water. Initially, the reaction was begun hydrate in the presence of different solvents (Table  1). with the versatile condensation of ethyl acetoacetate with As the results indicated, tetrahydrodipyrazolopyridines hydrazine and then the elimination of ethanol to form could be synthesized in good-to-high yields and short pyrazolone A (B, tautomer of A) as a water insoluble reaction times. solid. The A (B) and aldehyde are hydrophobia materi - Hydrazine and ammonium acetate are soluble in water, als and react in a water cage to form the intermediate C ethyl acetoacetate is partially soluble and aldehyde is through the Knoevenagel condensation. Then, the sec - insoluble in water. In the first step, hydrazine hydrate and ond molecule of B was condensed with C via Michael ethyl acetoacetate react in water to produce a insoluble reaction to produce bipyrazolone D. Ammonia, which intermediate which react with aldehyde in water cage. was produced from ammonium acetate, condensed with Regarding the conditions for the synthesis of THDPPs, D to form imine E which produced product F through the optimization process was implemented with differ - intramolecular cyclization, tautomerization and water ent aldehydes, hydrazine hydrate, ethyl acetoacetate and removal. ammonium acetate (Table 2). In order to show the superiority of the THDPPs syn- Meanwhile, we have synthesis THDPP using citral as thesis process in the absence of catalysts, this process was aliphatic aldehyde (Scheme 2). compared to some others in terms of conditions, reaction time and yield. The results are listed in Table 3. Keihanfar and M irjalili BMC Chemistry (2022) 16:9 Page 5 of 6 Table 3 The comparison of catalyst-free protocol with other methods for synthesis of 5a Entry Catalyst Conditions Time (min)/yield (%) [Reference] 1 Fe O /KCC1/IL/HPWMNPs (0.0001 mg) H O/r.t 30/96 [24] 3 4 2 2 Nano-CdZr (PO ) (0.6 mol%) EtOH/reflux 43/88 [25] 4 4 6 3 Nano-Fe O @SiO -SO H (0.004 g) EtOH/MW 20/90 [23] 3 4 2 3 4 FeNi -ILs MNPs (0.002 g) EtOH/reflux 48/86 [21] 5 Nano-CuCr O (4 mol%) EtOH/25 °C 50/90 [26] 2 4 6 Nano-ovalbumin (0.05 g) H O/55 °C 45/93 [20] 7 M (II)/Schiff base@MWCNT-Fe O /SiO (0.02 g) –/r.t 90/85 [27] 3 4 2 8 Pseudopolymeric magnetic nanoparticles (10 mg) EtOH/r.t 10–180/45–92 [13] 9 KCC-1-NH -DPA (0.1 g) EtOH, reflux 30/95 [14] 10 CuFe O @HNTs (5 mg) EtOH, r.t 20/90–96 [15] 2 4 11 acetic acid AcOH/reflux 300/90 [16] 12 carbonaceous material (CSO H) (10 mg) H O/60 °C 360/86 [17] 3 2 13 Catalyst-free H O/r.t 45/98 [ This work] Isolated yields Abbreviations Conclusions THDPP’s: Tetrahydrodipyrazolopyridines; MCRs: Multi-component reactions; In this study, an environmentally friendly protocol is FT-IR: Fourier transform infrared; NMR: Nuclear magnetic resonance; TLC: Thin introduced for the synthesis of THDPPs in a neutral layer chromatography. aqueous medium without using any catalyst or organic solvent. In this green versatile protocol hydrophobia Supplementary Information intermediate and aldehyde had been reacted under high The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s13065- 022- 00802-4. pressure condition in water cage. In solubility of products in water caused having a simple work-up and purifica - Additional file 1: Spectroscopic data for the synthesized tion of them. The attractive advantages of the protocol tetrahydrodipyrazolo[3,4-b:4′,3′-e] pyridine derivatives. are excellent yields, mild reaction conditions, less pollu- tion, short time reaction, simple workup and high-purity Acknowledgements products. The Research Council of Yazd University gratefully acknowledged for the finan- cial support for this work. Keihanfar and Mirjalili BMC Chemistry (2022) 16:9 Page 6 of 6 Authors’ contributions synthesis of tetrahydrodipyrazolopyridine derivatives under mild reaction M.K. wrote the main manuscript and prepared figures. B.F.M edited the manu- conditions. Appl Organomet Chem. 2021;35(6):e6222. script and submit it as corresponding author. All authors read and approved 14. Azizi S, Shadjou N, Hasanzadeh M. KCC-1-NH -DPA: an efficient het - the final manuscript. erogeneous recyclable nanocomposite for the catalytic synthesis of tetrahydrodipyrazolopyridines as a well-known organic scaffold in various Funding bioactive derivatives. Nanocomposites. 2019;5(4):124–32. This study was financially supported by Yazd University. The funding bodies 15. Maleki A, Hajizadeh Z, Salehi P. Mesoporous halloysite nanotubes modi- played no role in the design of the study and collection, analysis, and interpre- fied by CuFe O spinel ferrite nanoparticles and study of its application as 2 4 tation of data and in writing the manuscript. a novel and efficient heterogeneous catalyst in the synthesis of pyrazo - lopyridine derivatives. Sci Rep. 2019;9(1):1–8. Availability of data and materials 16. Ghaedi A, Bardajee G, Mirshokrayi A, Mahdavi M, Shafiee A, Akbarzadeh T. All data generated or analyzed during this study are included in this published Facile, novel and efficient synthesis of new pyrazolo [3,4-b] pyridine prod- article. ucts from condensation of pyrazole-5-amine derivatives and activated carbonyl groups. RSC Adv. 2015;5(109):89652–8. 17. Chen Z, Shi Y, Shen Q, Xu H, Zhang F. Facile and efficient synthesis of Declarations pyrazoloisoquinoline and pyrazolopyridine derivatives using recover- able carbonaceous material as solid acid catalyst. Tetrahedron lett. Ethics approval and consent to participate 2015;56(33):4749–52. Not applicable. 18. Zhao K, Lei M, Ma L, Hu L. A facile protocol for the synthesis of 4-aryl-1, 4, 7, 8-tetrahydro-3, 5-dimethyldipyrazolo [3, 4-b: 4′, 3′-e] pyridine deriva- Consent for publication tives by a Hantzsch-type reaction. Monatsh Chem. 2011;142(11):1169–73. Not applicable. 19. Mirjalili BF, Jalili Bahabadi N, Bamoniri A. Triethanolamine–sodium acetate as a novel deep eutectic solvent for promotion of tetrahydrodipyra- Competing interests zolopyridines synthesis under microwave irradiation. J Iran Chem Soc. The authors declare no competing interests. 2021;18:1–7. 20. Salehi N, Mirjalili BF. Nano-ovalbumin: a green biocatalyst for biomimetic Received: 29 October 2021 Accepted: 22 February 2022 synthesis of tetrahydrodipyrazolo pyridines in water. Res Chem Intermed. 2018;44(11):7065–77. 21. Safaei-Ghomi J, Sadeghzadeh R, Shahbazi-Alavi H. A pseudo six-compo- nent process for the synthesis of tetrahydrodipyrazolo pyridines using an ionic liquid ilized on a FeNi nanocatalyst. RSC Adv. 2016;6(40):33676–85. References 22. Shabalala NG, Pagadala R, Jonnalagadda SB. Ultrasonic-accelerated rapid 1. Ahmadi T, Ziarani GM, Gholamzadeh P, Mollabagher H. Recent advances protocol for the improved synthesis of pyrazoles. Ultrason Sonochem. in asymmetric multicomponent reactions (AMCRs). 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Green Chem. 2012;14(8):2091–128. Synthesis and biological evaluation of 3, 6-diamino-1H-pyrazolo [3, 4-b] 5. Lubineau A, Augé J. Water as solvent in organic synthesis. In: Knochel P, pyridine derivatives as protein kinase inhibitors. Bioorg Med Chem Lett. editor. Modern solvents in organic synthesis. Topics in current chemistry, 2009;19(16):4566–9. vol. 206. Berlin: Springer; 1999. p. 1–39. 26. Shahbazi-Alavi H, Safaei-Ghomi J, Eshteghal F, Zahedi S, Nazemzadeh SH, 6. Katada M, Kitahara K, Iwasa S, Shibatomi K. Catalyst-free decar- Alemi-Tameh F, Tavazo M, Basharnavaz H, Lashkari MR. Nano-CuCr O : an 2 4 boxylative fluorination of tertiary β-keto carboxylic acids. Synlett. efficient catalyst for a one-pot synthesis of tetrahydrodipyrazolopyridine. 2018;29(18):2408–11. J Chem Res. 2016;40(6):361–3. 7. Tian Y, Liu Q, Liu Y, Zhao R, Li G, Xu F. Catalyst-free Mannich-type reactions 27. Lashanizadegan M, Nikoofar K, Aghaei A, Mehrikaram F, Mirzazadeh H. in water: expedient synthesis of naphthol-substituted isoindolinones. Immobilized Cu(II) and Co(II) Schiff base complexes on the surface of Tetrahedron Lett. 2018;59(15):1454–7. functionalized magnetized multiwalled carbon nanotubes: Novel cata- 8. Manjunatha UH, Vinayak S, Zambriski JA, Chao AT, Sy T, Noble CG, Bonamy lysts for oxidation and solvent-free pseudo six-component condensation GM, Kondreddi RR, Zou B, Gedeck P. A cryptosporidium PI (4) K inhibitor is reaction. Solid State Sci. 2019;95:105937. a drug candidate for cryptosporidiosis. Nature. 2017;546(7658):376–80. 9. Yu G, Mason H, Wu X, Wang J, Chong S, Beyer B, Henwood A, Pongrac Publisher’s Note R, Seliger L, He B. Substituted pyrazolopyridopyridazines as orally bioavail- Springer Nature remains neutral with regard to jurisdictional claims in pub- able potent and selective PDE5 inhibitors: potential agents for treatment lished maps and institutional affiliations. of erectile dysfunction. J Med Chem. 2003;46(4):457–60. 10. Liu C, Li Z, Zhao L, Shen L. One-step, facile synthesis of pyrazolopyridines and tetrahydropyrazolopyridines through disproportionation of initially formed pyrazolo Hantzsch dihydropyridine. ARKIVOC. 2009;2:258–68. 11. de Mello H, Echevarria A, Bernardino AM, Canto-Cavalheiro M, Leon LL. Antileishmanial pyrazolopyridine derivatives: synthesis and structure- activity relationship analysis. J Med Chem. 2004;47(22):5427–32. 12. Warshakoon NC, Wu S, Boyer A, Kawamoto R, Renock S, Xu K, Pokross M, Evdokimov AG, Zhou S, Winter C. Design and synthesis of a series of novel pyrazolopyridines as HIF 1-α prolyl hydroxylase inhibitors. Bioorg Med Chem Lett. 2006;16(21):5687–90. 13. Dashteh M, Yarie M, Zolfigol MA, Khazaei A, Makhdoomi S. Novel pseu- dopolymeric magnetic nanoparticles as a hydrogen bond catalyst for the http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Chemistry Springer Journals

Catalyst-free synthesis of tetrahydrodipyrazolopyridines via an one-pot tandem and green pseudo-six-component reaction in water

BMC Chemistry , Volume 16 (1) – Mar 4, 2022

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Abstract

OO .H 2 NH NH O 2 2 2 Catalyst-Free NH OAc H O N N N N Room Temperature N H H *Correspondence: fmirjalili@yazd.ac.ir Department of Chemistry, College of Science, Yazd University, Yazd, Iran © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Keihanfar and Mirjalili BMC Chemistry (2022) 16:9 Page 2 of 6 A common protocol for the synthesis of THDPP is the Introduction reaction of aldehydes, hydrazine hydrate, ethyl acetoac- Multicomponent reactions (MCRs) are selective, sim- etate, and ammonium acetate in a multi-component ple and effective as compared to the conventional mul - manner with the presence of a catalyst. Previously, pseu- tistep synthesis [1–4]. They have been utilized to reduce dopolymeric magnetic nanoparticles [13], KCC-1-NH - environmental pollution. Water, as a green solvent, is DPA [14], CuFe O @HNTs [15], acetic acid [16], and presumed to speed up some organic reactions through 2 4 carbonaceous material (CSO H) [17], Fe O /KCC1/IL/ hydrophobic effects [5]. Therefore, catalyst-free organic 3 3 4 HPWMNPs [24], Nano-CdZr (PO ) [25], Nano-Fe O @ reactions in water that yield resolvable products are 4 4 6 3 4 SiO –SO H [23], FeNi -ILs MNPs [21], Nano-CuCr O attractive for many organic chemists [6, 7]. THDPPs 2 3 3 2 4 [26], Nano-ovalbumin [20], M(II)/Schiff base@MWCNT- fuse the heterocyclic moieties of pyrazolopyridine with Fe O /SiO [27]. Meanwhile, a catalyst free protocol pharmaceutical activities, which exist in Etazolate, Carta- 3 4 2 using ammonium carbonate instead of ammonium ace- zolate and Tracazolate drugs [8] (Fig. 1). tate has been reported [16], Ammonium carbonate is a Meanwhile, Due to the existence of two biologically basic salt and can catalysis the synthesis of THDPP’s. In active moieties, namely pyrazole and 1,4-dihydropyridine here, we have used ammonium acetate as neutral salt pyrazole in the structure of THDPPs, these compounds for production of ammonia in water and absence of any have various pharmaceutical applications such as antial- catalyst. lergic, anti-herpetic and anxiolytic effects [9, 10], anti- In this study, THDPPs are synthesized with a green Leishmania activities [11] and HIF 1α-prolyl hydroxylase catalyst-free protocol implemented in a water medium at inhibition [12]. room temperature (Scheme 1). C H H 4 9 4 9 NH NH NH R EtO C EtO C 2 2 EtO C N N N N N N Water EtO Et Et + NH OAc + 2 NH NH + 4 2 2 2 N N Et R. T. O N N Tracazolate H H Etazolate Cartazolate H Scheme 1 Synthesis of THDPP’s in water Fig. 1 Pyrazolopyridine with pharmaceutical activity Table 1 Optimization of the reaction conditions for the synthesis of 4-(4-chlorophenyl)-3,5-dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4- b:4′,3′-e]pyridine a b Entry Solvent Conditions Time (min) Yield (%) 1 EtOH r.t 180 – 2 EtOH Reflux 120 23 3 H O Reflux 60 53 4 H O r.t 45 98 [This work] The molar ratio of hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol),4-chlorobenzaldehyde (1 mmol) and ammonium acetate (4 mmol) is equal to 2:2:1:4 Isolated yields Keihanfar and M irjalili BMC Chemistry (2022) 16:9 Page 3 of 6 Table 2 Synthesis of THDPP’s (5 ) in water in room temperature a–m Entry R Product Time Yield M.P Lit. M.P. (C) [Reference] (min) (%) (°C) 1 4-Cl 5a 45 98 244–246 254–256 [19] 2 4-NO 5b 60 96 274–276 278–283 [19] 3 3-NO 5c 50 98 268–270 282–284 [20] 4 4-OH 5d 80 96 266–268 267–268 [21] 5 4-Br 5e 75 96 222–224 221–224 [19] 6 2-Cl 5f 105 94 162–164 164–165 [22] 7 4-N(CH ) 5g 90 85 238–239 240–242 [19] 3 2 8 4-Me 5h 180 95 240–242 241–243 [20] 9 4-F 5i 75 97 255–257 258–260 [18] 10 4-OCH 5j 90 98 187–189 188–190 [20] 11 3-OMe-4-OH 5k 90 98 256–258 256–258 [20] 12 3,4-(OH) 5l 90 83 208–210 208–210 [20] 13 4-CHO 5 m 120 91 > 300° > 300° [23] Reaction conditions: hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol), 4-chloro benzaldehyde (1 mmol) and ammonium acetate (4 mmol), water (3 mL) at room temperature Technology (HP), Model: 5793, Ion source: Electron Experimental Impact (EI), 20-EV, 230 °C, and Quadrupole analyzer. Materials and methods General Chemistry A Bruker, Equinox 55 spectrometer was used to record General procedure for the synthesis of THDPP’s the Fourier transforms infrared (FT-IR) spectra. A Bruker Firstly, a solution of 2.0  mmol of hydrazine hydrate, (DRX-400 Avance) nuclear magnetic resonance (NMR) 2.0  mmol of ethyl acetoacetate and 3  mL of water was instrument was also used to record the NMR spectra. stirred in a 25-mL round-bottom flask at room temper - In addition, a Buchi B-540 B.V.CHI apparatus served to ature. Secondly, 1.0  mmol of aldehyde and 4.0  mmol of determine the melting points of the compounds. Mass ammonium acetate were added to it and stirred at room spectrometry spectra were recorded with a Agilent temperature. The reaction was monitored by thin-layer .H chromatography (TLC; n-hexane:EtOAc, 70:30). After NH NH O 2 2 2 EtO the completion of the reaction, the solution was diluted (3) with cold water, and the product was appeared as water Water (1) N N insoluble solid which isolated by simple filtration. R.T. N N H H NH OAc Results and discussion (4) (2) (5) Although, catalytic synthesis of THDPPs protocols have Time:240 min yield: 85% many advantages such as high yields of products and short reaction time. But the hard work-up and expensive Scheme 2 Synthesis of 4-(Z)-2,6-dimethylhepta-1,5-dien-1-yl)-3,5- catalysts are some of drawbacks of them. Therefore, we dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridine Keihanfar and Mirjalili BMC Chemistry (2022) 16:9 Page 4 of 6 Ar Knoevenagel condensation NH NH 2 2 O O O Ar H -H -H O O 2 2 NHNH -EtOH O H O H Ar Ar N N Ar H Cyclization N reaction N N -H N O N NH OAc N N N OHN H H F E Scheme 3 A proposed mechanism for synthesis of THDPP’s have decided to design a catalyst-free protocol for syn- A mechanism proposed for the catalyst-free syn- thesis of THDPPs. thesis of THDPPs is shown in Scheme  3. Ammonium In order to optimize the reaction conditions for the acetate was used as a source of nitrogen for the forma- preparation of THDPPs in the absence of a catalyst, some tion of 1,4-dihydropyridine ring in the THDPPs. Hydra- reactions were performed between ethylacetoacetate, zine is soluble and ethylacetoacetate is partially soluble ammonium acetate, 4-chlorobenzaldehyde and hydrazine (2.86 g/100 mL) in water. Initially, the reaction was begun hydrate in the presence of different solvents (Table  1). with the versatile condensation of ethyl acetoacetate with As the results indicated, tetrahydrodipyrazolopyridines hydrazine and then the elimination of ethanol to form could be synthesized in good-to-high yields and short pyrazolone A (B, tautomer of A) as a water insoluble reaction times. solid. The A (B) and aldehyde are hydrophobia materi - Hydrazine and ammonium acetate are soluble in water, als and react in a water cage to form the intermediate C ethyl acetoacetate is partially soluble and aldehyde is through the Knoevenagel condensation. Then, the sec - insoluble in water. In the first step, hydrazine hydrate and ond molecule of B was condensed with C via Michael ethyl acetoacetate react in water to produce a insoluble reaction to produce bipyrazolone D. Ammonia, which intermediate which react with aldehyde in water cage. was produced from ammonium acetate, condensed with Regarding the conditions for the synthesis of THDPPs, D to form imine E which produced product F through the optimization process was implemented with differ - intramolecular cyclization, tautomerization and water ent aldehydes, hydrazine hydrate, ethyl acetoacetate and removal. ammonium acetate (Table 2). In order to show the superiority of the THDPPs syn- Meanwhile, we have synthesis THDPP using citral as thesis process in the absence of catalysts, this process was aliphatic aldehyde (Scheme 2). compared to some others in terms of conditions, reaction time and yield. The results are listed in Table 3. Keihanfar and M irjalili BMC Chemistry (2022) 16:9 Page 5 of 6 Table 3 The comparison of catalyst-free protocol with other methods for synthesis of 5a Entry Catalyst Conditions Time (min)/yield (%) [Reference] 1 Fe O /KCC1/IL/HPWMNPs (0.0001 mg) H O/r.t 30/96 [24] 3 4 2 2 Nano-CdZr (PO ) (0.6 mol%) EtOH/reflux 43/88 [25] 4 4 6 3 Nano-Fe O @SiO -SO H (0.004 g) EtOH/MW 20/90 [23] 3 4 2 3 4 FeNi -ILs MNPs (0.002 g) EtOH/reflux 48/86 [21] 5 Nano-CuCr O (4 mol%) EtOH/25 °C 50/90 [26] 2 4 6 Nano-ovalbumin (0.05 g) H O/55 °C 45/93 [20] 7 M (II)/Schiff base@MWCNT-Fe O /SiO (0.02 g) –/r.t 90/85 [27] 3 4 2 8 Pseudopolymeric magnetic nanoparticles (10 mg) EtOH/r.t 10–180/45–92 [13] 9 KCC-1-NH -DPA (0.1 g) EtOH, reflux 30/95 [14] 10 CuFe O @HNTs (5 mg) EtOH, r.t 20/90–96 [15] 2 4 11 acetic acid AcOH/reflux 300/90 [16] 12 carbonaceous material (CSO H) (10 mg) H O/60 °C 360/86 [17] 3 2 13 Catalyst-free H O/r.t 45/98 [ This work] Isolated yields Abbreviations Conclusions THDPP’s: Tetrahydrodipyrazolopyridines; MCRs: Multi-component reactions; In this study, an environmentally friendly protocol is FT-IR: Fourier transform infrared; NMR: Nuclear magnetic resonance; TLC: Thin introduced for the synthesis of THDPPs in a neutral layer chromatography. aqueous medium without using any catalyst or organic solvent. In this green versatile protocol hydrophobia Supplementary Information intermediate and aldehyde had been reacted under high The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s13065- 022- 00802-4. pressure condition in water cage. In solubility of products in water caused having a simple work-up and purifica - Additional file 1: Spectroscopic data for the synthesized tion of them. The attractive advantages of the protocol tetrahydrodipyrazolo[3,4-b:4′,3′-e] pyridine derivatives. are excellent yields, mild reaction conditions, less pollu- tion, short time reaction, simple workup and high-purity Acknowledgements products. The Research Council of Yazd University gratefully acknowledged for the finan- cial support for this work. Keihanfar and Mirjalili BMC Chemistry (2022) 16:9 Page 6 of 6 Authors’ contributions synthesis of tetrahydrodipyrazolopyridine derivatives under mild reaction M.K. wrote the main manuscript and prepared figures. B.F.M edited the manu- conditions. Appl Organomet Chem. 2021;35(6):e6222. script and submit it as corresponding author. All authors read and approved 14. Azizi S, Shadjou N, Hasanzadeh M. KCC-1-NH -DPA: an efficient het - the final manuscript. erogeneous recyclable nanocomposite for the catalytic synthesis of tetrahydrodipyrazolopyridines as a well-known organic scaffold in various Funding bioactive derivatives. Nanocomposites. 2019;5(4):124–32. This study was financially supported by Yazd University. The funding bodies 15. Maleki A, Hajizadeh Z, Salehi P. Mesoporous halloysite nanotubes modi- played no role in the design of the study and collection, analysis, and interpre- fied by CuFe O spinel ferrite nanoparticles and study of its application as 2 4 tation of data and in writing the manuscript. a novel and efficient heterogeneous catalyst in the synthesis of pyrazo - lopyridine derivatives. Sci Rep. 2019;9(1):1–8. Availability of data and materials 16. 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Journal

BMC ChemistrySpringer Journals

Published: Mar 4, 2022

Keywords: Tetrahydrodipyrazolopyridines (THDPP’s); Multicomponent reaction; Environmentally friendly protocol; Catalyst-free reaction

References