Synthesis of Pyrazole Compounds by Using Sonication Method

Introduction

Pyrazole and its derivative compounds have importance in medicinal chemistry, plays important role in agrochemicals¹, building blocks for pharmaceutical such as Zometapine,² Celebrex,³ Viagra,⁴ Cyenopyrafen,⁵ Tebufenpyrad⁶ and Fenpyroximate,⁷, are well-known compounds bearing a pyrazole unit. Majority of the pyrazole containing compounds show significant biological activities such as cholesterol-lowering,⁸ antimicrobial,⁹ anti-inflammatory,¹⁰ hypoglycemic,¹¹ antihypertensive,¹² analgesic,¹³ antidepressant,¹⁴ anticancer¹⁵, antiviral,¹⁶ antibacterial,¹⁷ antiobesity,¹⁸ appetite and suppressant,¹⁹ activities.

A literature survey reveals that several reported methods for the synthesis of Pyrazole unit generally synthesized i.e  using the  3 component coupling reaction of aldehydes, 1,3-dicarbonyls, and diazo compounds, as well as tosyl hydrazones,  rhodium-catalyzed addition-cyclization of hydrazines with alkynes²¹ cyclic enol triflates and an elaborated set of diazoacetates²² hydrazones and β-protonation / nucleophilic addition/aromatization sequence^.23A copper-mediated cyclization, trifluoromethylation, and detosylation.²⁴ Potassium 1,1,3,3-tetranitropropane treated readily with various (hetero)arylamines.²⁵ other methods with metals, Lewis acids, or bases were also reported.²⁶⁻³⁰  But, those techniques have their benefit whilst a number of these are the problem by the limitation of long time response, individual situations and lower yields. for this reason, the improvement of a brand new technique for the synthesis of Pyrazole derivatives might be fairly applicable.

 From the last three decades, ultrasound utility has been utilized in natural product synthesis ³¹ Which has an overwhelming interest because it gives chemists tremendously simple and less expensive techniques for chemical activation.³² similarly, this method is also recognized to accelerate the rate of a chemical response, and at the same time increases the reaction yield.³³ Transition metal-free synthesis of quinolino [2′, 3′: 3, 4] pyrazolo [5, 1-b] quinazolin-8 (6 H)-ones via cascade dehydrogenation and intramolecular N-arylation.³⁴ Evaluation of Medicinal Effects of Isoxazole Ring Isosteres on Zonisamide for Autism Treatment by Binding to Potassium Voltage-Gated Channel Subfamily D Member 2 (Kv 4.2).³⁵ Morpholine and Thiomorpholine: A Privileged Scaffold Possessing Diverse Bioactivity Profile. ³⁶recently, there are developing pursuits in this non-conventional method because it promotes shorter response time.

within the route of our research in ultrasound synthesis of heterocyclic compounds, our laboratory result confirmed that pyrazole derivatives could be readily prepared from the beginning materials of carboxylic acid derivatives beneath ultrasound probe irradiation in neat circumstance as mentioned in this paper (Scheme 1)

Scheme 1 Click here to View scheme

Table 1: synthesis of substituted pyrazole (3a-j ).

Table 1: synthesis of substituted pyrazole (3a-j ). Click here to View table

Methodology

General Procedure for the synthesis of pyrazole derivativein our research, we developed novel, simple, efficient, and rapid method for synthesis of pyrazole derivative by using  carboxylic acid as starting material. First the carboxylic acid is converted into ester using methanol and con. sulphuric acid reflux under nitrogen atmosphere for 16hr.In the second step acetonitrile in toluene mixed with a solution of NaH under nitrogen atmosphere and stirred for 30 minutes was added methyl ester and reflux reaction mixture for 17 h to give oxonitrile. In the third step the oxonitrile.in acetic acid and hydrazine hydrate undergo cyclization reaction to got final products pyrazole in sonication for 1-2 h. In this method, we used different halogen aromatic substituted carboxylic acid, nicotinic acid, and acetic acid but we observed the percentage of final products.

To study the generality of this method type of examples had been illustrated for the synthesis pyrazole and outcomes are summarized . The reaction is well matched for various substituents inclusive of CH₃, I, NO₂, CN, and F. This approach is also powerful for the heteroaromatic carboxylic acid which shapes their corresponding pyrazole derivatives in 55-67% of yields. The formation of the desired product becomes confirmed by using ¹H NMR, ¹³C NMR and IR.

Experimental

Melting points had been determined in an open capillary tube and are uncorrected. IR spectra have been recorded in KBr on a Perkin-Elmer spectrometer. ¹H-NMR and ¹³Cspectra have been recorded on a Gemini 400 MHz tool in DMSO as solvent and TMS as an inner fashionable. The purity of products was checked by thin-layer chromatography (TLC) on silica gel.

Synthesis of ester 1(a-J)

To a stirred solution of substituted acid (1.0 eq.) in methanol (10 mL,) turned into delivered con.H₂SO₄ (cat.) at 0-5 °C below N₂ environment. The resultant became heated at reflux temperature for 16 h. the reaction turned into monitored through TLC (mobile phase: – 20 % ethyl acetate: hexane). Upon entire conversion reaction aggregate became distilled out, obtained crude was poured into ice water, extracted with ethyl acetate (3 x 25 mL), blended natural layer changed into washed with sat. bicarbonate answer, dried over Na₂SO₄, distilled out organic layer underneath reduced pressure to get methyl ester intermediate(Yield:68-81 %)

Synthesis of 3-oxonitril 2(a-J)

In a smooth and dry a 100 mL round bottom flask were taken acetonitrile (5.0 eq.) in Toluene (10 ml), cool to 0-5 °C, in that solution NaH (55 %, 2.5 eq.) became introduced lot wise below N₂ atmosphere and stirred for 30 minutes, then an answer of substituted methyl ester intermediate in toluene (5.0 mL) . reaction combination becomes heated at reflux temperature for 17 h. response become monitored via TLC ( 30 % ethyl acetate: hexane). Upon entire conversion reaction mixture was poured into ice water slowly, extracted with ethyl acetate (3 x 25 ml),  layer changed into dried over Na₂SO₄, distilled out organic layer under reduced vacuum to get 3-oxonitrile intermediate (Yield: 80-93 %)

Synthesis of 3-oxonitrile 3(a-J)

To a stirred  of 3-oxonitrile (1.0eq.) in acetic acid (5mL), hydrazine hydrate (2.0 eq.) . reaction combination becomes sonicated for 1-2 h. the reaction became monitored with the aid of TLC (cellular section: – 50 % ethyl acetate: hexane). Upon complete conversion  become poured into water, basify the use of 20 % NaOH solution, extracted with ethyl acetate (3 x 30 ml), mixed natural layer became dried over Na₂SO₄, distilled out organic layer beneath reduced pressure. obtained crude turned into purified with the aid of column chromatography the usage of ethyl acetate: hexane as an eluent to get  substituted three-amino pyrazole intermediate (Yield:  55-67%)

The Formation of all preferred Products has been Purified through the usage of column chromatography & confirmed by ¹H &¹³ C NMR.

3-(5-fluoro-2-methyl-3-nitrophenyl)-1H-pyrazol-5-amine (4a)

FT-IR (cm⁻¹): 3350, 3245,3100, 2950,1477,1292. ¹H-NMR (400 MHz; DMSO): δ: 2.33 (s, 3H CH₃), 4.32 (brs, 2H, NH₂), 6.15(s, CH), 7.68 (d, 1H, J=2.4Hz Ar-H), 7.46 (d, 1H, J=2.4Hz, Ar-H), 7.86 (s, NH) ¹³C-NMR 96.03,112.53, 121.08, 126.99, 133.18, 143.08, 147.01, 151.61,158.20,160.68.

3-(pyridin-3-yl)-1H-pyrazol-5-amine (4b)

FT-IR (cm⁻¹): 3352, 3238, 3098, ¹H-NMR (400 MHz; DMSO): δ: 4.39(brs, 2H, NH₂), 5.76 (s, CH), 7.81- 8.81 (m – 4H Ar-H), 11.54 (s, NH) ¹³C-NMR δ:  88.99,111.21, 122.12, 142.12, 146.01, 152.21,152.21,158.42.

3-(5-amino-1H-pyrazol-3-yl)benzonitrile  (4c)

FT-IR (cm⁻¹): 3342, 3222, 3101, 2242. ¹H-NMR (400 MHz; DMSO): δ: 4.51 (brs, 2H, NH₂), 5.74(s, CH), 7.39-7.92 (m, 4H, Ar-H), 11.85 (s, NH) ¹³C-NMR  δ:  88.72, 112.30, 118.87, 128.40, 129.44, 129.62, 130.47.135.56,158.20,160.68.

3-(4-fluorophenyl)-1H-pyrazol-5-amine (4d)

FT-IR (cm⁻¹): 3344, 3232, 2991, ¹H-NMR (400 MHz; DMSO): δ: 4.21 (brs, 2H, NH₂), 5.67(s, CH), 7.56 (d, 2H, Ar-H), 6.98 (d, 2H Ar-H )  11.06 (s, NH) ¹³C-NMR  δ:  87.52, 115.63, 127.04, 146.09, 152.53, 160.74, 163.17.

3-(5-bromo-2-iodophenyl)-1H-pyrazol-5-amine (4e)

FT-IR (cm⁻¹): 3342, 3233, 3104, ¹H-NMR (400 MHz; DMSO): δ: 4.31 (brs, 2H, NH₂), 5.75 (s, CH), 7.76- 7.05 (m, 3H, Ar-H), 10.85 (s, NH), ¹³C-NMR  δ:  91.00, 122.03, 132.07, 132.97, 140.03, 145.45, 147.88,150.89,168.99.

3-methyl-1H-pyrazol-5-amine (4f)

FT-IR (cm⁻¹): 3341, 3221, 3104, 2982 ¹H-NMR (400 MHz; DMSO): δ:2.17 (s, 3H, CH₃),  5.39 (brs, 2H, NH₂), 7.26 (s, CH), 10.85 (s, NH), ¹³C-NMR  δ: 18.00, 96.03, 132.07,  141.11, 148.45.

3-(3-fluorophenyl)-1H-pyrazol-5-amine (4g)

FT-IR (cm⁻¹): 3344, 3228, 3098, 2989  ¹H-NMR (400 MHz; DMSO): δ: 4.21 (brs, 2H, NH₂), 5.71 (s, CH), 6.83- 7.37 (m, 4H, Ar-H), 7.78 (s, NH), ¹³C-NMR  δ:  96.00, 123.12, 131.11, 133.41, 141.01, 14551, 147.52, 151.09,161.54.

3-phenyl-1H-pyrazol-5-amine (4h)

FT-IR (cm⁻¹): 3351, 3239, 3150, 2997  ¹H-NMR (400 MHz; DMSO): δ: 4.24 (brs, 2H, NH₂), 5.75 (s, CH), 7.15- 7.60 (m, 5H, Ar-H), 7.78 (s, NH), ¹³C-NMR  δ:  97.01, 121.16, 133.15, 134.61, 142.11, 146. 25, 148.62.

3-(4-iodophenyl)-1H-pyrazol-5-amine (4i)

FT-IR (cm⁻¹): 3341, 3251, 3101, 2957  ¹H-NMR (400 MHz; DMSO): δ: 4.14 (brs, 2H, NH₂), 5.72 (s, CH), 7.17 (d, 2H, Ar-H),  7.23 (d, 2H, Ar-H),  7.91 (s, NH), ¹³C-NMR  δ:  94.06, 110.89, 121.11, 129.09, 134.46, 142.12, 144..25, 147.52, 151.09,161.54.

3-(4-bromophenyl)-1H-pyrazol-5-amine (4j)

FT-IR (cm⁻¹): 3332, 3221, 3056, 2925  ¹H-NMR (400 MHz; DMSO): δ: 4.21 (brs, 2H, NH₂), 5.72(s, CH), 7.20 (d, 2H, Ar-H),  7.35 (d, 2H, Ar-H),  8.21 (s, NH), ¹³C-NMR  δ:  96.11, 111.80, 122.10, 138.49, 146.62, 151.09,161.91.

Conclusion

We defined a successful approach such as an efficient and handy inexperienced synthesis, for pyrazole derivatives using a sonication technique. The approach offers several advantages increasing the  yield of products, the usage of the inexpensive starting fabric, and an easy experimental workup technique that makes it a beneficial process for the synthesis of pyrazole derivatives.

Acknowledgments

 We’re grateful to the Dept. of Chemistry of MSP Mandal’s Shri Shivaji college Parbhani major Dr. B. U Jadhav for imparting the laboratory facility. Also thanks to my college Principal Dr. Omprakash Jadhav sir for Supporting & enhancing me for doing research.

Conflict of Interest

There is no conflict of Interest.

Funding Source

There is no funding source.

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