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A Simple and Efficient Multicomponent Synthesis of Novel Pyrazole, N-aminopyridine and Pyrazolo[3,4-b]Pyridine Derivatives in Water

Submitted:

17 December 2023

Posted:

28 December 2023

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Abstract
The three-component reaction of enaminones, benzaldehyde and hydrazine-HCl or four-component reaction of enaminones, benzaldehyde, hydrazine–HCl and ethyl cyanoacetate in water in the presence of catalytic amount of ammonium acetate has been devised as a straightforward , sustainable approach for the synthesis of 1-H-pyrazole, N-aminopyridine and pyrazol[3,4-b]pyridine derivatives . The key benefits of this approach is simple experimental procedure associated with cost effective and environmentally friendly techniques.
Keywords: 
multicomponent reaction
;  
enaminones
;  
water
;  
pyrazoles
;  
Pyrazolo[3
;  
4-b]-Pyridine
;  
1
;  
2-Bis-arylidenehydrazine
Subject: 
Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

Nitrogen-containing heterocycles were recognized to possess diverse activities in fields related to biological and medicinal activities [1,2,3,4]. Among nitrogen-containing heterocycles pyrazole derivatives, play a crucial role in agrochemical and pharmacological research [5,6].
The most extensively utilized method for pyrazole synthesis was made through condensation reaction of hydrazine with α,β-unsaturated carbonyl scaffolds [7,8,9,10].
Other commonly utilized methods for pyrazole synthesis relied on 1,3-dipolar cycloaddition of toxic explosive diazo compounds onto triple bond systems [11], or the nucleophilic attack of hydrazines to isoxazoles, flavones or chromones [12], or tosyl hydrazine with substituted aldehydes [13,14,15]. It is worth mentioning that although hydrazine hydrate is applied as a major source of nitrogen, however a disadvantage associated with this protocol is the usual formation of 4,5-dihydro pyrazoles which needs further oxidation to the final pyrazole derivative. Examples of biologically active pyrazole-based moieties are illustrated below in Figure 1.
Pyrazolo[3,4-b]pyridine derivatives acquired significant attention in medicinal chemistry for their potent and privileged range of biological activities [16,17,18]. Several approaches have been reported for their synthesis. The reaction of 5-aminopyrazoles with 1,3-bis-electrophiles or unsaturated carbonyl compounds are among the widely used protocols [19,20,21,22,23,24,25]. However, these approaches usually afford dihydropyrazolo[3,4-b]pyridine derivatives. The synthesis of pyrazolo[3,4-b]pyridines has received little attention and few approaches addressed their direct synthesis [26,27,28,29]. Although these protocols have their specific advantages, they are limited by several factors such as low yields, multistep synthetic approaches, long reaction times, tedious work up either in conducting the reaction or isolation of products, as well as the use of hazardous catalysts and solvents.
Currently, multi-component reactions (MCRs) are recognized as important and reliable strategies in the rapid synthesis of complex molecules from readily available starting materials in a single step [30,31]. Therefore MCRs-based syntheses provide sustainable utility of chemical resources by reducing waste as well as minimizing the number of steps required for organic transformations [32].
Large quantities of solvents are essential for chemical reactions, extraction and purification processes [33]. Moreover, many organic solvents are toxic, hazardous, or environmentally harmful which pose risks to both the environment and human health [34]. In this regard the use of water as a green solvent with its low ESH (Environmental Safety and Health) impact, has led to intriguing developments of organic synthesis due to its environmental benignity, safety and low-cost nature [35,36,37,38,39,40].
As a part of our continuing work concerning the green synthesis of biologically relevant heterocycles, we report, herein a facile synthesis of novel polyfunctionally substituted pyrazoles and pyrazolo[3,4-b]pyridine derivatives via one-pot multi-component reaction of enaminones 1, benzaldehyde 2, and hydrazine hydrochloride 3 and ethyl cyanoacetate 5 in water in the presence of catalytic amount of ammonium acetate at reflux.

2. Results and Discussion

For optimizing the reaction conditions, the three-component reaction of equimolar amounts of enaminones 1a with benzaldehyde 2 and hydrazine hydrochloride 3 in water/ammonium acetate was selected as the model reaction for initial studies (Table 1).We are delighted to found that pyrazole 4a was obtained in good yield when the reaction mixture was heated under reflux for 1 hour. Several green solvents including glycerol and PEG [41,42,43,44,45,46] were examined and it was found that water provided the best yield.
The structure assigned for 4a was established based on analytical and spectral data. The mass The structure assigned for 4a was established based on analytical and spectral data. The mass spectrum of 4a showed a molecular ion peak m/z = 249 (M+ +1) (55%). The 1H NMR revealed signals at δ ppm 12.78 (1H, br s, D2O exchangeable, NH), 8.42 (1H, s, H-5), 8.10-8.01 (2H, m, phenyl-H), 7.91-7.51 (8H, m, phenyl-H).
Subsequently, the scope of such reaction with a variety of enaminones has been investigated. Thus, the reaction of 1b, c with 2 and 3 performing the same reaction conditions afforded the corresponding pyrazole derivatives 4b,c.
However, the reaction of 1d, with 2 and 3 afforded product 4d with molecular ion peak m/z = 158.06 (100%). Its 1H NMR revealed absorption bands at δ = 12.58 (1H br s, NH), 7.70-7.72 (2H, m, phenyl-H), 7.34-7.23 (3H, m, phenyl-H), 6.39 (1H, s, H-4), 2.21 (3H, s, CH3). Structure 4d was assigned for the reaction product which confirmed the non-involvement of benzaldehyde 2 in the reaction course presented in Table 1. Similarly, enaminones 4e,f reacted with 2 and 3 yielding the corresponding pyrazoles 4e,f in moderate yields (Scheme 1).
It is worth mentioning that – and to the best of our knowledge , it is the first reported synthesis of aryl/heteroaryl (3-phenyl-1H-pyrazol-4-yl)methanone 4a-c, while 3-aryl/heteroaryl-5-methyl-1H-pyrazoles 4d-e were synthesized via Heck reactions in a lengthy and expensive procedure [47].
To explore the generality of our procedure, we replicated our previous protocol with a four-component reaction of enaminones 1a-c, benzaldehyde 2, hydrazine hydrochloride 3 and ethyl cyanoacetate 5. Thus, equimolar amounts of 1a, 2, 3 and 5 were heated under reflux in water/ammonium acetate, a product of molecular formula C21H21N5O2 was obtained which was assigned the corresponding pyrazolo[3,4-b]pyridine 6a based on its analytical data, which showed a molecular ion peak m/z = 374 (M+ -1) (100%). The 1H NMR spectra revealed signals at δ 8.37 ( 1H, s, NH), 7.67 (2H, br s, NH2), 7.63-7.55 (5H, m, phenyl-H), 7.45-7.23 (5H, m, phenyl-H), 7.20 (2H, br s, NH2), 5.10 (1H, s, H-4), 4.01 (2H, q, J=7.2 Hz, CH2), 1.16 ( 3H, t, J = 7.2 Hz, CH3). The 13C NMR showed characteristic bands at δ= 193.86 (CO), 169.13 (C-6), 59.13 (CH2), 39.78 (C-4), 14.98 (CH3). Similarly, the reaction mixture of 1b, 2, 3 and 5 afforded the corresponding pyrazolo[3,4-b]pyridine derivatives 6b (Scheme 2).
On the other hand, the reaction mixture of 1c, 2, 3 and 5 afforded the corresponding 1,2-di-benzylidine)-hydrazine 7 as a result of the reaction of two molecules of benzaldehyde with one molecule of hydrazine HCl (Scheme 2).
Similar to the behavior of 1c toward 2, 3 and 5, the reaction mixture of 1d-f with 3, 5 and aryl aldehyde derivatives 8a,b, afforded the corresponding (1,2-di-arylidine)-hydrazines 9a-b (Scheme 3).
A reasonable mechanism to rationalize the formation of the reaction products 4a-c was depicted in (Scheme 4 and Scheme 5). where 1a-c reacted with hydrazine hydrochloride in water/ammonium acetate to yield the addition adduct 10 followed by attack of the amino group to the activated carbonyl group of benzaldehyde, afforded 11 which cyclizes to the corresponding dihydropyrazole 12, this is followed by aromatization via loss of dimethylamine in 13 to yield the final isolable products 4a-c.
Concerning for enaminones 1d-f, the formed sterically hindered 1:1 adduct 14 loses the dimethylamino function, affording 15, which will cyclizes to pyrazoles 4d-f via water molecule loss (Scheme 5).
Regarding the formation of 6a,b it is assumed that the condensation step of benzaldehyde and ethyl cyanoacetate afforded the in situ-formed benzylidene ethyl cyanoacetate 16, which reacted with enaminones 4a-b and hydrazine hydrochloride yielding N-aminopyridine derivative 17. The reaction of 17 with a second molecule of hydrazine hydrochloride yielded the final isolable products 6a-b (Scheme 6).

3. Materials and methods

3.1. General Information

Aldehydes, Ethyl cyanoacetate, N,N-Dimethylformamide dimethylacetal, N,N-dimethyl acetamide dimethyl acetal and Ketones were of commercial grade and purchased from Aldrich and Merck companies. IR spectra were measured on a PerkinElmer 317 grating IR spectrophotometer using KBr pellets. 1H NMR (500 MHz) and 13C NMR (500 MHz) spectra were recorded using JEOL E.C.A- spectrometer (δ ppm). Melting points were measured on an Electrothermal melting point apparatus and are uncorrected. Mass spectrometry was performed on a JEOL JMSAX 500 spectrometer. The appropriate precautions in handling moisture-sensitive compounds were considered. Solvents were dried by standard techniques. Elemental analyses were carried out at the Microanalysis Laboratory, National Research Center, Giza, Egypt; their values agreed favorably with the calculated ones.

3.2. Synthesis of Compounds

3.2.1. General procedure for compounds 1a-c and 1d-f

Compounds 1a-c were prepared as described previously [48]
Compounds 1d-f were prepared via adding dropwise N,N-dimethyl acetamide dimethyl acetal (1.33g,10 mmol) to a stirred solution of each of acetophenone, 2- acetyl thiophene, 2- acetyl furan (10 mmol) in CH2Cl2 (10 ml). The reaction mixture was stirred at ambient temperature (250C) for 24 hours. The solid product formed after removing solvent under reduced pressure was filtered and crystallized from cyclohexane.

3.2.2. 3-Hydroxy-1-phenylbut-2-en-1-one 1d

Yellowish crystals, yield 1.21 g (75 %), mp 86-88 oC. IR (cm-1): 1594cm-1 (CO) ; 1H NMR: (500 MHz, DMSO-d6 ) δ 16.30 (1H, br s, OH); 7.91-7.93 (2H, m, Ph-H); 7.49-7.93 (3H, m, Ph-H); 6.53 (1H, s, ethylene-H); 2.20 (3H, s, CH3). EIMS (m/z): 162 ( M+) for C10H10O2 (162).

3.2.3. 3-(Dimethylamino)-1-(thiophen-2-yl)but-2-en-1-one 1e

Brown crystals, yield 1.46 g (75 %); mp 101-103 oC; IR (cm-1): 1530 cm-1 (CO); 1H NMR: (500 MHz, DMSO-d6 ) δ 7.60-7.62 (2H, m, thienyl H-3,5); 7.06 (1H, t, J = 5.0 Hz, thienyl H-4); 5.61 (1H, s, ethylene-H); 3.01 (6H, s , NCH3); 2.51 ( 3H, s, CH3). EIMS: (m/z): 195 (M+) for C10H13NOS (195).

3.2.4. 3-(Dimethylamino)-1-(furan-2-yl)but-2-en-1-one 1f

Brown crystals, yield 1.30 g ( 73 %); mp 94-96 oC; IR (cm-1): 1538 cm-1 (CO); 1H NMR (500 MHz, DMSO-d6 ) δ 7.70 ( 1H, d, J = 5.0 Hz, furyl H-5); 6.94 (d, 1H, d, J = 5.0 Hz, furyl H-3); 6.51 (1H, t, J = 5.0 Hz, furyl H-4); 5.56 ( 1H, s, ethylene-H); 2.99 ( 6H, s , NCH3); 2.52 ( 3H, s, CH3). EIMS: (m/z): 180 (M+1). C10H13NO2 (179).

3.2.5. General procedure for the preparation of 4a-c and 4d-f

To a stirred suspension of enaminones 1a-f (10 mmol) and hydrazine hydrochloride 2 in water (10 ml), benzaldehyde 3 and ammonium acetate was refluxed under heating for 1 hr. The solid product formed after evaporation of solvent in vacuum, and trituration with ethanol was collected and crystalized from the proper solvent. In some cases, flash chromatography on silica gel using chloroform/n-hexane (3:1) as eluent was performed to afford analytically pure samples

3.2.6. Phenyl(3-phenyl-1H-pyrazol-4-yl)methanone 4a

Yellow crystals, yield 1.86 g (75 %) ; mp 160-162 oC. IR (cm-1): 3197 (NH) and 1658 cm-1 (CO); 1H-NMR ( 500 MHz, DMSO-d6 ) δ 12.78 (1H br s, NH,); 8.42 (1H, s, H-5) ; 8.10-8.01 ( 2H, m, phenyl-H) ; 7.91-7.51 ( 8H, m, phenyl-H). 13C-NMR ( 500 MHz, DMSO-d6 ) δ 188.40, 149.89, 147.14, 144.51, 139.45, 133.98, 133.86, 128.84, 128.58, 127.32, 126.94, 111.14. EIMS: (m/z): 249 (M+1) for C16H12N2O (248).

3.2.7. (3-phenyl-1H-pyrazol-4-yl)(thiophen-2-yl)methanone 4b

Brown crystals, yield 1.95g (77 %) ; mp 156-158 oC; IR (cm-1): 3432 br (NH) and 1654 cm-1 (CO); 1H-NMR: (500 MHz, DMSO-d6) δ 7-79-7.41 (7H, m, phenyl and thienyl-H); 8.09 (1H, J = 5 Hz, thienyl H-5); 8.36 (1H, s, H-5); 11.07 (1H, br s, NH). 13C-NMR ( 500 MHz, DMSO-d6 ) δ: 182.64, 149.79, 147.61, 146.53, 144.61, 134.53, 133.08, 132.56, 130.46, 129.35, 128.84, 127.44. EIMS: (m/z): 255 (M+1) for C14H10N2OS (254)

3.2.8. Furan-2-yl(3-phenyl-1H-pyrazol-4-yl)methanone 4c

Yellow crystals, yield 1.74g (73 %) ; mp 170-172 oC; IR (cm-1): 3428 br (NH) and 1650 cm-1 (CO); 1H NMR ( 500 MHz, DMSO-d6 ) δ 7.99-7.62 (7H, m, phenyl and furyl-H); 8.09 ( 1H, d, J = 5Hz, furyl H-5); 8.37 ( 1H, s, H-5); 12.47 ( 1H, br s, NH); 13C-NMR ( 500 MHz, DMSO-d6 ) δ: 176.99, 154.63, 150.00, 147.39, 146.69, 146.24, 134.51, 130.49, 129.38, 127.45, 115.16, 114.89, 112.71. EIMS m/z: 240 (M+2) for C14H10N2O2 (238).

3.2.9. 5-methyl-3-phenyl-1H-pyrazole 4d

Yellow crystals, yield 0.95 g ( 60 %) ; mp 124-126 oC. IR (cm-1): 3179 (NH); 1H NMR (500 MHz, DMSO-d6 ) δ 12.58 (1H, br s, NH, D2O exchangeable). 7.70-7.72 (2H, m, Ph-H); 7.23-7.34 (3H, m, Ph-H); 6.39 (1H, s, H-4); 2.21 (3H, s, CH3). 13C-NMR ( 500 MHz, DMSO-d6 ) δ: 129.13, 127.75, 125.49, 101.73, 100.0, 11.45. EIMS (m/z) 158 (M+) for C10H10N2 (158).

3.2.10. 5-methyl-3-(thiophen-2-yl)-1H-pyrazole 4e

Brown crystals, yield 1.08 g (66 %); mp 173-175 oC; IR (cm-1): 3120 br (NH); 1H NMR ( 500 MHz, DMSO-d6) δ 12.50 (1H, br s NH); 7.36 (1H, d, J = 5.0 Hz, thienyl H-5); 7.27 (1H, t, J = 5.0 Hz, thienyl H-3); 7.02 (1H, t, J = 5 Hz, thienyl H-4); 6.28 (1H, s, pyrazolyl-H); 2.20 (3H, s, CH3); 13C-NMR (500 MHz, DMSO-d6 ) δ: 139.74, 127.50, 124.24, 123.20, 120.4, 100.94, 54.55, 10.69. EIMS m/z : 164 (M+) for C8H8N2S : (164).

3.2.11. 3-(Furan-2-yl)-5-methyl-1H-pyrazole 4f

Brown crystals, yield 0.93 g (63 %); mp 162-164 oC; IR (cm-1): 3206 br (NH); 1H NMR (500 MHz, DMSO-d6) δ 12.46 ( 1H, br s, NH); 7.26-7.34 (2H, m, furyl 3,5- H); 7.01 (1H, t, J = 5.0 Hz, futyl H-4); 6.27 (1H, s, pyrazolyl-H); 2.21 (3H, s, CH3). 13C-NMR (500 MHz, DMSO-d6 ) δ: 11.01, 101.53, 123.73, 124.77, 128.03, 138.05, 140.03, 146.59. EIMS m/z: 148 (M+) for C8H8N2O: (148).

3.2.12. General procedure for the synthesis of 6a-b and 7

A stirred suspension of hydrazine hydrochloride 3 in water (20 ml) and ammonium acetate (1 g), was treated with each of the enaminone 1a-c (10 mmol), benzaldehyde 2 (10 mmol) and ethyl cyanoacetate 5 (10 mmol). The reaction mixture was heated at refluxed for 1 hr., allowed to cool to room temperature, and the formed precipitate was filtered of and crystallized from ethanol to afford analytically pure samples.

3.2.13. Ethyl 6,7-diamino-3,4-diphenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 6a

Yellow crystals, yield 1.68g (45 %); mp 160-162 oC; IR (cm-1): 3779, 3467 and 3334 (NH2) and (NH); and 1662 cm-1 (CO); 1H NMR (500 MHz, DMSO-d6) δ 8.37 (1H, s, NH). 7.67 (br s, 2H, NH2); 7.55-7.63 (m, 5H, phenyl-H); 7.23-7.45 (5H, m, phenyl-H); 7.20 (2H, br s, NH2); 5.10 (1H, s, H-4); 4.01 (2H, q, J = 7.2 Hz, CH2); 1.16 (3H, t, J = 7.2 Hz, CH3); 13C NMR: (500 MHZ, DMSO-d6) δ: 193.86 (CO), 169.13 (C-6), 152.29, 148.10, 146.75, 132.06, 129.33, 129.03, 128.59, 128.80, 127.70, 126.50, 120.51, 79.06, 59.13 (CH2), 39.78 (C-4), 14.98 (CH3). EIMS m/z: 374 (M+-1) for C21H21N5O2: (375)

3.2.14. Ethyl 6,7-diamino-4-phenyl-3-(thiophen-2-yl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 6b

Yellow crystals, yield 2.20g (58 %); mp 237-239 oC; IR (cm-1): 3467, 3402 and 2973 and (NH2 and NH) and 1662 cm-1 (CO); 1H NMR ( 500 MHz-DMSO-d6) δ 8.54 (1H, br s, NH); 7.90-8.04 (5H, m, thienyl-H and NH2); 7.40 (2H, br s, NH2); 7.07-7.19 (5H, m, phenyl-H); 5.03 (1H, s, H-4); 4.00 ( 2H, q, J = 7.2 Hz, CH2); 1.13 (3H, t, J = 7.2 Hz, CH3). 13C NMR: (500 MHZ, DMSO-d6) δ: 184.93, 169.08, 152.33, 147.78, 146.70, 143.81, 133.98, 133.69, 133.27, 129.23, 128.80, 128,56, 127.71, 100.0, 78.93, 59.10, 14.97 .EIMS m/z: 380 (M+-1) C19H19N5O2S: (381).

3.2.15. 1,2-Dibenzylidenehydrazine 7

Light brown crystals, yield 0.832g (40 %); mp 93-95 oC (lit. mp 92-93 oC) [49]; IR (cm-1): 1669 cm-1 (C=N); 1H NMR (500 MHz, DMSO-d6) δ 7.47-7.48 (6H, m, phenyl-H), 7.85-7.86 ( 4H, m, phenyl-H); 8.68 (s, 2H, Benzylidinimine-H). 13C NMR (500 MHZ, DMSO-d6) δ 162.01 (C=N); 134.35; 131.89; 129.45; 128.9 EIMS m/z: 208 (M+ ) for C14H12N2 .

3.2.16. General procedure for the preparation of 9a

To a mixture of hydrazine hydrochloride 3 and ammonium acetate (1 g), suspension in water (20 ml) was added the enaminone 1d-f (10 mmol), ethyl cyanoacetate 5 (10 mmol) and benzaldehyde derivatives 8a-b (10 mmol). The resulting mixture was refluxed for 1hr. and left to cool to room temperature. The precipitated product was collected by filtration and recrystallized from ethanol affording desired products 9a, b.

3.2.17. 1,2-bis(4-methoxybenzylidene)hydrazine 9a

Yellow crystals, yield 1.79 g ( 67 %) ; mp 174-176 oC. IR (cm-1): 1656 cm-1 (C=N); 1H NMR (500 MHz, DMSO-d6) δ 8.58 (2H, s, aldimine-H); 7.78 (4H, d, J = 7.5 Hz, phenyl H); 7.02 (4H, d, J = 7.5 Hz, phenyl H); 3.78 (6H, s, OCH3). 13C NMR (500 MHZ, DMSO-d6) δ 162.22 (CO-Me); 160.98 (C=N); 130.53; 127.08; 114.94; 55.92. EIMS m/z: 267 (M+-1 ) for C16H16N2O2: (268).

3.2.18. 1,2-bis-3-phenylallylidene)hydrazine 9b

Light brown crystals, yield 1.82 g (70 %) ; mp 173-175 oC. IR (cm-1): 1643 cm-1 (C=N); MS m/z (M+-1) = 259; 1H NMR ( 500 MHz, DMSO-d6) δ 8.35 (2H, d, J = 9.50 Hz, aldimine -H); 7.62 (2H, d, J = 7.15 Hz, ethylene-H); 7.39 (2H, t, J = 7.15 Hz, ethylene-H); 7.25-7.35 (4H, m, phenyl-H); 7.09-7.14 (6H, m, phenyl-H). EIMS m/z: 259 (M+-1 ) for C18H16N2: (260).

4. Conclusion

In summary a straightforward access to novel polyfunctionally substituted pyrazole and pyrazolo[3,4-b]pyridines were developed via three-component reaction of enaminones, benzaldehyde and hydrazine hydrochloride or four-component reaction of enaminones, benzaldehyde, hydrazine hydrochloride and ethyl cyanoacetate. The procedure reported herein is a simple, green and an efficient protocol. It is highly applicable and has the advantages of short reaction times and ease of execution either in conducting the reaction or isolation of products.

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org.

Author Contributions

Mervat Mohammed Abdelkhalik: Conceived and designed the experiments; Analyzed the Data, Wrote original and final draft. Abdulaziz Alnajjar: Writing-review & editing. Solwan Maher Ibrahim: Performed the experiments, Analyzed the Data. Mohammed Abdelmonem Raslan: Review & editing. Kamal Usef Sadek: Visualization, Methodology.

Funding

This research was done by the financial support of Public Authority for Applied Education and Training (Transform Grant TS-15-02) of Kuwait.

Acknowledgments

This work was supported by the Public Authority for Applied Education and Training of Kuwait.

References

  1. Musilek, K.; Dolezal, M.; Gunn-Moore, F.; Kuca, K. Design, evaluation and structure-Activity relationship studies of the AChE reactivators against organophosphorus pesticides. Med. Res. Rev. 2011, 31, 548–75. [Google Scholar] [CrossRef]
  2. Figueroa-Villar, J.D.; Petronilho, E.C.; Kuca, K.; Franca, T.C.C. Review about Structure and Evaluation of Reactivators of Acetylcholinesterase Inhibited with Neurotoxic Organophosphorus Compounds. Curr. Med. Chem. 2021, 28, 1422–42. [Google Scholar] [CrossRef] [PubMed]
  3. Demkowicz, S.; Rachon, J.; Daśko, M.; Kozak, W. Selected organophosphorus compounds with biological activity. Applications in medicine RSC Adv. 2016, 6, 7101–12. [Google Scholar] [CrossRef]
  4. Joly, D.; Bouit, P.A.; Hissler, M. Organophosphorus derivatives for electronic devices. J Mater Chem. C. 2016, 4, 3686–98. [Google Scholar] [CrossRef]
  5. Elguero, J., et al. (2002) Pyrazoles as Drugs: Facts and Fantasies. Targets in Heterocyclic Systems. 2002, 6, 52–98. ISBN 88-86208-19-7.
  6. Eicher, T.; Hauptman, S. The chemistry of Heterocycles Structure, Reactions, Synthesis and Application (Translated by Suschitzky H, Suschitzky J.). Georg Thieme: Stuttgart, 1995.
  7. Huang, Y.R.; Katzenellenbogen, J.A. Regioselective synthesis of 1,3,5-triaryl-4-alkylpyrazoles: novel ligands for the estrogen receptor. Org Lett. 2000, 2, 2833–6. [Google Scholar] [CrossRef]
  8. Katritzky, A.R.; Wang, M.; Zhang, S.; Voronkov, M.V; Steel, P.J. Regioselective Synthesis of Polysubstituted Pyrazoles and Isoxazoles. J. Org. Chem. 2001, 66, 6787–91. [Google Scholar] [CrossRef]
  9. Kim, J.; Song, H.; Park, S.B. Orthogonal Regioselective Synthesis of N-Alkyl-3-substituted Tetrahydroindazolones. Eur. J. Org. Chem. 2010, 20, 3815–22. [Google Scholar] [CrossRef]
  10. Chimichi, S.; Boccalini, M.; Matteucci, H. Regioselective synthesis of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones by the cyclization of 3-acyl-4-methoxy-1-methylquinolinones with hydrazines. Tetrahedron. 2008, 64, 9275–79. [Google Scholar] [CrossRef]
  11. Padwa, A. “1,3-Dipolar Cycloaddition Chemistry; John Wiley: Vol.1. New York: Ny; 1984.
  12. Elmaged, A.; Sammour, A. Notes- Action of Hydroxylamine, Hydrazine Hydrate, and Phenylhydrazine on 2-Acetoaceto-1-naphthol J. Org. Chem. 1960, 25, 1458–59. [Google Scholar] [CrossRef]
  13. Aggarwal, V.K.; Vicente, J.d.; Bonnert. R.V. A Novel One-Pot Method for the Preparation of Pyrazoles by 1,3-Dipolar Cycloadditions of Diazo Compounds Generated in Situ. J. Org. Chem. 2003, 68, 5381–83. [CrossRef]
  14. Lèvai, A.; Silva, A.M.S.; Cavaleiro, J.A.S.; Alkorta, I.; Elguero, J.; Jekö, J. Synthesis of Pyrazoles by Treatment of 3-Benzylchromones, 3-Benzylflavones and Their 4-Thio Analogues with Hydrazine. Eur. J. Org. Chem. 2006, 2006, 2825–32. [Google Scholar] [CrossRef]
  15. Sviridov, S.I.; Vasil'ev, A.A.; Shorshnev, S.V. Straightforward transformation of isoxazoles into pyrazoles: renewed and improved. Tetrahedron. 2007, 63, 12195–201. [Google Scholar] [CrossRef]
  16. Chavva, K.; Pillalamarri, S.; Banda, V.; Gautham, S.; Gaddamedi, J.; Yedla, P.; Kumar, C.G.; Banda, N. Synthesis and biological evaluation of novel alkyl amide functionalized trifluoromethyl substituted pyrazolo[3,4-b] pyridine derivatives as potential anticancer agents. Bioorg Med Chem Lett. 2013, 23, 5893–5. [Google Scholar] [CrossRef]
  17. Gunasekaran, P.; Perumal, S.; Menéndez, J.C.; Mancinelli, M.; Ranieri, S.; Mazzanti, A. Axial Chirality of 4-Arylpyrazolo[3,4-b]pyridines. Conformational Analysis and Absolute Configuration. J. Org. Chem. 2014, 79, 11039–50. [Google Scholar] [CrossRef]
  18. Zhao, B.; Li, Y.; Xu, P.; Dai, Y.; Luo, C.; Sun, Y.; Ai, J.; Geng, M.; Duan, W. Discovery of Substituted 1H-Pyrazolo[3,4-b] pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors. ACS Med. Chem. Lett. 2016, 7, 629–34. [Google Scholar] [CrossRef] [PubMed]
  19. Lavecchia, G.; Berteina-Raboin, S.; Guillaumet, G. Synthesis and Functionalization of 1H-Pyrazolo[3,4-b] pyridines Involving Copper and Palladium-Promoted Coupling Reactions. Tetrahedron Lett. 2004, 45, 2389–92. [Google Scholar] [CrossRef]
  20. El-Emary, T.I.; Chin, J. Synthesis of Newly Substituted Pyrazoles and Substituted Pyrazolo[3,4-b]Pyridines Based on 5-Amino-3-Methyl-1-Phenylpyrazole. Chem Soc. 2007, 54, 507–18. [Google Scholar] [CrossRef]
  21. Ghaedi, A.; Bradajee, G.R.; Mirshokrayi, A.; Mahdavi, M.; Shafiee, A.; Akbarzadeh, T. Facile, novel and efficient synthesis of new pyrazolo[3,4-b]pyridine products from condensation of pyrazole-5-amine derivatives and activated carbonyl groups. RSC Adv. 2015, 5, 89652–58. [Google Scholar] [CrossRef]
  22. Kendre, D.B.; Toche, R.B.; Jachak, M.N. Synthesis of pyrazolo[3,4-b]pyridines and attachment of amino acids and carbohydrate as linkers. J. Heterocycl. Chem. 2008, 45, 1281–86. [Google Scholar] [CrossRef]
  23. Chebanov, V.A.; Saraev, V.E.; Desenko, S.M.; Chernenko, V.N.; Knyazeva, I.V.; Groth, U.; Glasnov, T.N.; Kappe, C.O. Tuning of Chemo- and Regioselectivities in Multicomponent Condensations of 5-Aminopyrazoles, Dimedone, and Aldehydes. J. Org. Chem. 2008, 73, 5110–18. [Google Scholar] [CrossRef]
  24. Fu, R.G.; You, Q.D.; Yang, L.; Wu, W.T.; Jiang, C.; Xu, X.L. Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents. Bioorg. Med. Chem. 2010, 18, 8035–43. [Google Scholar] [CrossRef] [PubMed]
  25. Wang, S.L.; Liu, Y.P.; Xu, B.H.; Wang, X.H.; Jiang, B.; Tu, S.J. Microwave-assisted chemoselective reaction: a divergent synthesis of pyrazolopyridine derivatives with different substituted patterns. Tetrahedron. 2011, 67, 9417–25. [Google Scholar] [CrossRef]
  26. Hao, Y.; Xu, X.P.; Chen, T.; Zhao, L.L.; Ti, S.J. Multicomponent approaches to 8-carboxylnaphthyl-functionalized pyrazolo[3,4-b]pyridine derivatives. Org. Biomol. Chem. 2012, 10, 724–28. [Google Scholar] [CrossRef] [PubMed]
  27. Fan, L.; Yao, C.; Wei, X. FeCl3-catalyzed multicomponent synthesis of 8-alkoxycarbonylnaphthyl-functionalized pyrazolo[3,4-b]pyridines involving C-C bond cleavage. Monatsh Chem. 2016, 147, 1597–603. [Google Scholar] [CrossRef]
  28. Lee, S.; Park, S.B. An Efficient One-Step Synthesis of Heterobiaryl Pyrazolo[3,4-b]pyridines via Indole Ring Opening. Org Lett. 2009, 11, 5214–17. [Google Scholar] [CrossRef] [PubMed]
  29. Nagender, P.; Kumar, R.N.; Reddy, G.M.; Swaroop, D.K.; Poornachandra, Y.; Kumar, C.G.; Narsaiah, B. Synthesis of novel hydrazone and azole functionalized pyrazolo[3,4-b]pyridine derivatives as promising anticancer agents. Bioorg. Med. Chem. Lett. 2016, 26, 4427–32. [Google Scholar] [CrossRef] [PubMed]
  30. Nicolaou, K.C.; Edmonds, D.J.; Bulger, P.G. Cascade reactions in total synthesis. Angew Chem Int Ed Engl. 2006, 45, 7134–86. [Google Scholar] [CrossRef] [PubMed]
  31. Tietze, L.F.; Brasche, G.; Gericke, K.M. In: Domino Reaction in Organic Synthesis, Wieley-VCH, Weinheim; 2006.
  32. Murzin, D.Y.; Leino, R. Design. Sustainable chemical technology through catalytic multistep reactions. Chem. Eng. Res. 2008, 86, 1002–10. [Google Scholar] [CrossRef]
  33. Clark, J.H.; Farmer, T.J.; Hunt, A.J.; Sherwood, J. Opportunities for Bio-Based Solvents Created as Petrochemical and Fuel Products Transition towards Renewable Resources. Int J Mol Sci. 2015, 16, 17101–59. [Google Scholar] [CrossRef]
  34. Reichardt, C.; Welton, T. Solvents and solvent effects in Organic chemistry. 4th ed. Wiely-VCH Verlag Gmbll & Co. KGan: Weinheim Germany; 2011.
  35. Grieco, P.A. organic synthesis in water. Blackie A&P: London; 1998.
  36. Siskin, M.; Katritzky, A.R. Reactivity of Organic Compounds in Superheated Water:  General Background. Chem. Rev. 2001, 101, 825–36. [Google Scholar] [CrossRef]
  37. Poliakoff, M.; Fitzpatrick, J.M.; Farren, T.R.; Anastas, P.T. Green chemistry: science and politics of change. Science. 2002, 297, 807–10. [Google Scholar] [CrossRef] [PubMed]
  38. Ghanda, A.; Fokin, V.V. Organic synthesis “on water”. Chem. Rev. 2009, 109, 725–48. [Google Scholar]
  39. Minakata, S.; Komatsu, M. Organic Reactions on Silica in Water. Chem. Rev. 2009, 109, 711–24. [Google Scholar] [CrossRef] [PubMed]
  40. DeSimone, J.M. Practical Approaches to Green Solvents. Science. 2002, 297, 799–803. [Google Scholar] [CrossRef] [PubMed]
  41. Santosh, V.N.; Ajay, P.N.; Mohan, B.K.; Vijay, S.P.; Umesh, D.P.; Kamlesh, R.D.; Shamkant, L.P.; Sidhanath, V.B. One-Pot Four Component Synthesis of 4, 6-Disubstituted 3-Cyano-2- Pyridones in Polyethylene Glycol. Lett. in Org. Chem. 2010, 7, 406–10. [Google Scholar]
  42. Moustafa, M.S.; Mekheimer, R.A.; Al-Mousawi, S.M.; Abd-Elmonem, M.; El-Zorba, H.; Abdel Hameed, A.M.; Mohamed, T.M.; Sadek, K.U. Microwave-assisted efficient one-pot synthesis of N2-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines. Beilstein J. Org. Chem. 2020, 16, 1706–12. [Google Scholar] [CrossRef] [PubMed]
  43. Alnajjar, A.; Abdelkhalik, M.M.; Riad, H.M.; Sayed, S.M.; Sadek, K.U. Regioselectivity in the Reaction of 2-Aminobenzothiazoles and 2-Aminobenzimidazoles with Enaminonitriles and Enaminones: Synthesis of Functionally Substituted Pyrimido[2,1-b][1,3]benzothiazole and Pyrimido[1,2-a]benzimidazole Derivatives. J. Heterocycl. Chem. 2018, 55, 2760–65. [Google Scholar] [CrossRef]
  44. Sadek, K.U.; Al-Qalaf, F.; Abdelkhalik, M.M.; Elnagdi, M.H. Cerium (IV) ammonium nitrate as an efficient Lewis acid for the one-pot synthesis of 3, 4-dihydropyrimidin-2 (1H)-ones and their corresponding 2-(1H) thiones. J. Heterocycl. Chem. 2010, 47, 284–87. [Google Scholar] [CrossRef]
  45. Nazmy, M.H.; Mekheimer, R.A.; Shoman, M.E.; Abo-Elsebaa, M.; Abel-Elmonem, M.; Sadek, K.U. Densely functionalized cinnolines: Controlled microwave-assisted facile one-pot multi-component synthesis and in vitro anticancer activity via apoptosis induction. Bioorg. Chem. 2020, 101, 103932. [Google Scholar] [CrossRef]
  46. Mekheimer, R.A.; Allam, S.M.R.; Al-Sheikh, M.A.; Moustafa, M.S.; Almousawi, S.M.; Mostafa, Y.A.; Youssif, B.G.M.; Gomaa, H.A.M.; Hayallah, A.M.; Abdelaziz, M.; Sadek, K.U. Discovery of new pyrimido [5, 4-c] quinolines as potential antiproliferative agents with multitarget actions: Rapid synthesis, docking, and ADME studies. Bioorg. Chem. 2022, 121, 105693. [Google Scholar] [CrossRef]
  47. Stephan, M.; Panther, J.; Wilbert, F.; Ozog, P.; Müller, T.J.J. Heck Reactions of Acrolein or Enones and Aryl Bromides – Synthesis of 3-Aryl Propenals or Propenones and Consecutive Application in Multicomponent Pyrazole Syntheses. Eur. J. Org. Chem. 2020, 2086–92. [Google Scholar] [CrossRef]
  48. Al-Omran, F.; Al-Awadhi, N.; Abdel Khalik, M.M.; Kaul, K.; Abu EL-Khair, A.; Elnagdi, M.H. 1-Substituted 3-Dimethylaminoprop-2-en-1-ones as Building Blocks in Heterocyclic Synthesis: Routes to 6-Aryl- and 6-Heteroaryl-2H-pyran-2-ones and 6- and 4-Arylpyridin-2(1H)-ones. J Chem. Res. (S). 1997, 84–85. [Google Scholar] [CrossRef]
  49. Chemical Book (E,E)-bis(phenylmethylidene)hydrazine CAS No.588-68-1 Chemical Name: Benzaldehyde Azine.
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Figure 1. Pyrazole-based moieties marketed drugs.
Figure 1. Pyrazole-based moieties marketed drugs.
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Scheme 1. Multicomponent reaction of enaminones 1a-f with benzaldehyde 2 hydrazine hydrochloride and ammonium acetate in water.
Scheme 1. Multicomponent reaction of enaminones 1a-f with benzaldehyde 2 hydrazine hydrochloride and ammonium acetate in water.
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Scheme 2. Multicomponent reaction of enaminones 1a-c with benzaldehyde 2 hydrazine hydrochloride, ethyl cyanoacetate and ammonium acetate in water.
Scheme 2. Multicomponent reaction of enaminones 1a-c with benzaldehyde 2 hydrazine hydrochloride, ethyl cyanoacetate and ammonium acetate in water.
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Scheme 3. Synthesis of (1,2-di-arylidine)-hydrazines 9a-b.
Scheme 3. Synthesis of (1,2-di-arylidine)-hydrazines 9a-b.
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Scheme 4. Reasonable mechanism to rationalize for the synthesis of pyrazole derivatives 4a-c.
Scheme 4. Reasonable mechanism to rationalize for the synthesis of pyrazole derivatives 4a-c.
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Scheme 5. Proposed mechanism for the synthesis of pyrazole derivatives 4d-f.
Scheme 5. Proposed mechanism for the synthesis of pyrazole derivatives 4d-f.
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Scheme 6. Proposed mechanism for the synthesis of pyrazolo[3,4-b]pyridine derivatives 6a-b.
Scheme 6. Proposed mechanism for the synthesis of pyrazolo[3,4-b]pyridine derivatives 6a-b.
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Table 1. Description of synthesized pyrazole derivatives 4a-f.
Table 1. Description of synthesized pyrazole derivatives 4a-f.
Product R Ar Yield % m.p [oC]
4a H Phenyl 75 160-162
4b H 2-Thienyl 77 156-158
4c H 2-Furyl 73 170-172
4d Methyl Phenyl 60 124-126
4e Methyl 2-Thienyl 66 173-175
4f Methyl 2-Furyl 63 162-164
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