Skip to main content Skip to main navigation menu Skip to site footer
International Journal Bioorganic and Medicinal Chemistry
International Journal of Bioorganic and Medicinal Chemistry
Articles
DOI: 10.55124/bmc.v1i1.112
Submitted: 2021-07-17
Published: 2021-07-17

Natural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology, Habsiguda, Hyderabad 500007, India.

International Journal Bioorganic and Medicinal Chemistry

ISSN 2769-3023

Revisit: The Synthesis of 3-amino pyrazoles promoted by p-toluenesulfonic acid as an efficient catalyst under solvent and solvent-free conditions

Authors

  • Suryakiran Navath Natural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology, Habsiguda, Hyderabad 500007, India.

Keywords

3-Amino pyrazoles, p-Toluenesulfonic acid, Solvent-free conditions

Abstract

An efficient and facile synthesis of 3-amino pyrazoles has been described. The reaction of b-keto nitriles with hydrazines using p-toluenesulfonic acid as an efficient catalyst under solvent and solvent-free conditions afford corresponding 3-amino pyrazoles in excellent yields

 

I ntroduction

Pyrazoles, in particular 3-amino pyrazoles are an important class of compounds in medicinal chemistry and it has been well documented to posses antihypertensive,1 antibacterial,2 anti-inflammatory muscle relaxant3,4 and inhibitors of cyclin dependent kinases (CDK) such as CDK2/cycling A-E.5 They are also potent and selective Aurora kinase inhibitors.6,7 In addition the 3-amino pyrazoles also have industrial appliance in inhibition of corrosion on metals such as Zn, Cu, Al and Brass.8

Despite their importance from a pharmacological, industrial and synthetic point of view, comparatively few methods for the preparation of 3-amino pyrazoles have been reported. These includes condensation of hydrazines with β-keto nitriles,9 β-formyl nitriles,4 β-methoxy vinyl nitriles,10 α-nitrilo ethyl acetate11 and solid phase synthesis of 5-substituted amino pyrazoles.12 Unfortunately many of these processes suffer from one or other limitations such as incompletion of starting materials, long reaction times, with unsatisfactory yields. Thus there is a need for the development of an alternate route to construct the 3-amino pyrazoles.

In recent years,p-toluenesulfonic acid is used as an efficient catalyst in various organic transformations,13 also it should be noted that p-toluenesulfonic acid is cheap, commercially available and comparatively non-toxic. The organic reactions assisted by microwaves,14 in particular have been gained special attention. One reason is that the use of microwave activation in organic synthesis can increase the purity of the resulting products, enhance the chemical yield and shorten the reaction times. And also organic reactions carried out in the absence of solvent, has been attracting attention of chemists due to ease of processing to the further step and eco-friendly in nature. In the case of synthesis of 3-amino pyrazoles, we thought that there is a scope for further innovation towards short reaction times and better yields. Here, we report an efficient and facile method for the synthesis of 3-amino pyrazoles catalyzed by p-toluenesulfonic acid under solvent and solvent-free conditions.

Scheme 1

Results and Discussion

Reaction of benzoyl acetonitrile i. e. -keto nitrile15 with 4-hydrazinobenzoic acid under reflux conditions in absolute ethanol for 8-10hr resulted in the formation of the corresponding 3-amino pyrazoles in <90% yield. However, we carried out the reaction in presence of catalytic amounts of p-toluenesulfonic acid (0.01 equiv.) and found reaction is completed in 45 min with nearly 100% conversion (Table 1, entry 7). This success has encouraged us to extend the generality of the reaction; various hydrazines with various -keto nitriles in presencep-toluenesulfonic acid proceeded efficiently and smoothly at refluxing temperature and the products are obtained in excellent yields. And the reaction conditions are very favorable, no by-products are observed (Table 1, Method A).

We further investigated the reaction conditions to improve the reaction conditions. It has been found that, -keto nitrile 1 (1 mmol) and hydrazine 2 (1 mmol) reacts very rapidly (<5min) to give 3-amino pyrazoles in the presence of p-toluenesulfonic acid under microwave irradiation in solvent-free conditions (Table 1, Method B). The experimental procedure for this reaction is remarkably simple and no solvents or inert atmosphere is required. Under above conditions, in many cases it is noticed that in the absence of p-toluenesulfonic acid, the reaction is incomplete and uncyclized product was isolated along with pyrazole.

Table 2: Synthesis of 3-Amino pyrazole catalyzed by p-toluenesulfonic acid under solvent and solvent free conditions.
Entry -Keto nitrile Hydrazine Product Method A Method B
Time (min) Yield (%) Time (min) Yield (%)
1 Pivoloyl acetonitrile Hydrazine hydrate 3a 45 98 3 99
2 α-Phenyl acetyl acetonitrile Hydrazine hydrate 3b 45 97 3 99
3 Benzoyl acetonitrile Hydrazine hydrate 3c 45 99 3 98
4 p-Chloro benzoyl acetonitrile Hydrazine hydrate 3d 45 98 3 98
5 p-methyl benzoyl acetonitrile Hydrazine hydrate 3e 45 97 3 98
6 Furoyl acetonitrile Hydrazine hydrate 3f 45 98 3 99
7 Benzoyl acetonitrile p-Hydrazino benzoic acid 3g 45 98 3 98
8 Benzoyl acetonitrile m-Hydrazino benzoic acid 3h 120 90 5 95
9 Benzoyl acetonitrile 3-Hydrazino thiophene 2-(ethyl carboxylate) 3i 45 99 3 98
10 Benzoyl acetonitrile α-Hydrazino ethyl acetate 3j 60 98 3 98
11 p-Chloro benzoyl acetonitrile p-Hydrazino benzoic acid 3k 45 98 3 98
12 p-Chloro benzoyl acetonitrile m-Hydrazino benzoic acid 3l 150 95 3 92
13 p-methyl benzoyl acetonitrile p-Hydrazino benzoic acid 3m 45 99 3 98
415 p-methyl benzoyl acetonitrilePivoloyl acetonitrile 3-Hydrazino thiophene 2-(ethyl carboxylatep-Nitro phenyl hydrazine 3n3o 45120 9995 34 9895
6 α-Phenyl acetyl acetonitrile p-Nitro phenyl hydrazine 3p 120 90 4 96
7 Benzoyl acetonitrile p-Nitro phenyl hydrazine 3q 120 90 4 97
18 p-Chloro benzoyl acetonitrile p-Nitro phenyl hydrazine 3r 120 96 4 98
19 p-methyl benzoyl acetonitrile p-Nitro phenyl hydrazine 3s 120 90 4 96
20 Furroyl acetonitrile p-Nitro phenyl hydrazine 3t 90 95 4 98

aIsolated yields after crystallization/column chromatography and all products gave satisfactory spectral (IR, 1HNMR and MASS) and analytical data

In summary, the present procedures for the synthesis of 3-amino pyrazole have been developed by condensation reaction of hydrazines with -keto nitriles catalyzed by p-toluenesulfonic acid under solvent and solvent free conditions. The advantage of present method is high efficient, reduced reaction time and inexpensive catalyst with high yields of products and simple experimental work-up procedure, which makes it, is a useful and important addition to the present existing methodologies.

Acknowledgements: The authors are thankful toDirector IICT for hisconstant encouragement and DOD New Delhi for providingfellowship.

Typical Experimental procedure (Method A, Conventional): A mixture of -keto nitile (10 mmol), hydrazine (10 mmol) and to this p-TSA (0.1mmol) was added and refluxed in absolute ethanol for appropriate time (Table 1, Method A). After completion of the reaction, as monitored by TLC, the solvent was evaporated under reduced pressure. The product was extracted into ethyl acetate (3 x 20 mL). The combined organic layer was washed with saturated sodium bicarbonate followed by brine solution, then dried over anhydrous sodium sulphate. The solvent was removed to afford crude product and purified by column chromatography.

Typical Experimental procedure (Method B, Microwave):A mixture of -keto nitile (10 mmol), hydrazine (10 mmol), p-TSA (0.1mmol) was suspended in water (1mL) in a reaction vessel, sealed without degassing and was subjected to microwave irradiation at 450Watt. at 1350C for appropriate time (Table 1, Method B). After completion of the reaction, as monitored by TLC, the reaction mass was cooled and product was extracted into ethyl acetate (3 x 20 mL). The combined organic layer was washed with saturated sodium bicarbonate followed by brine solution, then dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to afford crude product, it was purified by recrystallized from ethanol/column chromatography to give corresponding pure 3-amino pyrazoles.

3a:IR (KBr): 3418, 1618, 1509, 1009, 762, 707 cm-1;1H NMR (200 MHz, DMSO+CDCl3): δ 1.25 (s, 9H), 5.85 (s, 1H); EIMS: m/z139; Anal. Calcd. for C7H13N3: C, 60.431; H, 9.352; N, 30.215. Found: C, 60.399; H, 9.412, N, 30.186.

3b:IR (KBr): 3420, 1620, 1520, 750 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 2.26 (s, 3H), 4.75 (s, 2H br), 7.40 (s, 5H); EIMS: m/z 173; Anal. Calcd. for C10H11N3: C, 69.280; H, 6.350; N, 24.277. Found: C, 69.340; H, 6.401, N, 24.258.

3c:IR (KBr): 3415, 1618, 1124, 613 cm-1; 1H NMR (200 MHz, DMSO+CDCl3) δ 4.25 (s, 2H br.), 5.75 (s, 1H), 7.30 (m, 5H); EIMS: m/z 157; Anal. Calcd. for C9H9N3: C, 67.924; H, 5.660; N, 26.415. Found: C, 67.905; H, 5.698, N, 26.396.

3d:IR(neat): 3448, 1636 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 5.5 (s, 1H), 7.25 (d, 2H, J = 8.25Hz), 7.35 (d, 2H, J = 8.25Hz); EIMS: m/z 193, 195; Anal. Calcd. for C9H8ClN3: C, 55.958; H, 4.145; Cl, 18.393; N, 21.761. Found: C, 55.826; H, 4.164; Cl, 18.308; N, 21.700.

3e:IR (KBr): 3413, 1618, 1511, 1108, 613 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 2.50 (s, 3H), 5.95 (s, 1H), 7.45 (d, 2H, J = 8.20Hz), 7.75 (d, 2H, J = 8.20Hz); EIMS: m/z 173. Anal. Calcd. for C10H11N3: C, 69.364; H, 6.358; N, 24.277. Found: C, 69.340; H, 6.401; N, 24.258.

3f: IR (KBr): 3415, 1694, 1615, 1179, 616 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 5.68 (s, 1H), 6.41 (s, 1H), 6.59 (s, 1H), 7.4 (s, 1H); EIMS: m/z 149; Anal. Calcd. for C7H7N3O: C, 56.375; H, 4.697; N, 28.187; O, 10.738. Found: C, 56.369; H, 4.730; N, 28.173; O, 10.736.

3g:IR (KBr): 3414, 1616, 1091 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 6.60 (s, 1H), 7.40 (m, 5H), 7.8 (d, 2H, J = 8.50Hz), 8.40 (d, 2H, J = 8.50Hz); EIMS: m/z 279; Anal. Calcd. for C16H13N3O2: C, 68.817; H, 4.659; N, 15.053; O, 11,469. Found: C, 68.806; H, 4.691; N, 15.044; O, 11.456.

3h:IR (KBr): 3414, 1617, 1383, 618 cm-1; 1H NMR (200 MHz, DMSI+CDCl3): δ 5.9 (s, 1H), 7.15 (m, 5H), 7.35 (d, 1H, J = 8.15Hz), 7.60 (t, 1H, J = 3.15Hz), 7.85 (d, 1H, J = 8.25Hz), 7.9 (d, 1H, J = 8.15Hz), 8.30 (s, 1H); EIMS: m/z 279; Anal. Calcd. for C16H13N3O2: C, 68.817; H, 4.659; N, 15.053; O, 11.469. Found: C, 68.806; H, 4.691; N, 15.044; O, 11.456.

3i: IR (KBr): 3415, 1618, 1285, 761 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 1.25 (t, 3H), 3.90 (q, 2H), 6.25 (s, 1H), 7.40 (m, 5H), 7.7 (d, 2H, J = 8.25Hz), 8.05 (d, 2H, J = 8.25Hz); EIMS: m/z 313;

3j: IR (KBr): 3415, 1657, 1615, 1384, 1121, 758 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 1.25 (t, 3H), 4.25 (q, 2H), 4.925 (s, 2H), 5.85 (s, 1H), 7.5 (m, 5H); EIMS: m/z 245; Anal. Calcd. for C13H15N3O2: C, 63.673; H, 6.122; N, 17.142; O, 13.067. Found: C, 63.658; H, 6.164; N, 17.131; O, 13.045.

3k: IR (KBr): 3416, 1650, 1384, 1120, 758 cm-1; 1H NMR (200 MHz, DMSO+CDCl3) δ 6.02 (s, 1H), 7.15 (d, 2H, J = 8.15Hz), 7.35 (d, 2H, J = 8.23Hz), 7.60 (d, 2H, J = 8.15Hz), 8.10 (d, 2H, J = 8.23Hz); EIMS: m/z 303, 305; Anal. Calcd. for C16H12ClN3O2: C, 61.341; H, 3.833; Cl, 11.341; N, 13.415; O, 10.223. Found: C, 61.252; H, 3.855; Cl, 11.299; N, 13.393; O, 10.198.

3l: IR (KBr): 3415, 1650, 1090 cm-1; 1H NMR (200 MHz, DMSO+CDCl3) δ 6.8 (s, 1H), 7.4 (d, 2H, J = 8.15Hz), 7.6 (t, 1H, J = 3.00Hz), 7.8 (d, 3H, J = 8.25Hz), 8.1 (d, 1H, J = 8.25Hz), 8.3 (s, 1H, J = 8.15Hz), 9.93 (s, 1H); EIMS: m/z 303, 305; Anal. Calcd. for C16H12ClN3O2: C, 61.341; H, 3.833; Cl, 11.341; N, 13.415; O, 10.223. Found: C, 61.252; H, 3.855; Cl, 11.299; N, 13.393; O, 10.198.

3m:IR (KBr): 3415, 1617, 1384, 764, 619 cm-1;1H NMR (200MHz, DMSO+CDCl3) δ 2.37 (s, 3H), 3.75 (s, 2H broad), 7.1 (d, 2H, J = 8.22Hz), 7.4 (d, 2H, J = 8.15Hz), 7.7 (d, 2H, J = 8.15Hz), 8.0 (d, 2H, J = 8.22Hz); EIMS: m/z 291; Anal. Calcd. for C17H15N3O2: C, 69.624; H, 5.119; N, 14.334; O, 10.921. Found: C, 69.611; H, 5.154; N, 14.325; O, 10.908.

3n: IR (KBr): 3415, 1618, 1384, 1216, 1047, 816, 619, 476 cm-1; 1H NMR (200 MHz, DMSO+CDCl3) δ 1.25 (t, 3H), 2.50 (s, 3H), 3.90 (q, 2H), 6.25 (s, 1H), 7.1 (d, 2H, J = 8.25Hz), 7.6 (d, 2H, J = 8.25Hz), 7.7 (d, 2H, J = 8.15Hz),8.1 (d, 2H, J = 8.15Hz); EIMS: m/z 328; Anal. Calcd. for C17H17N3O2S: C, 62.385; H, 5.198; N, 12.84; O, 9.785; S, 9.785. Found: C, 62.365; H, 5.233; N, 12.834; O, 9.773; S, 9.793.

3o:1H NMR (200 MHz, DMSO+CDCl3): δ 1.26 (s, 9H), 5.95 (s, 1H), 7.60 (d, 2H, J = 8.80Hz), 8.50 (d, 2H, J = 8.80Hz); EIMS: m/z260.

3p: 1H NMR (200 MHz, DMSO+CDCl3): δ 2.26 (s, 3H), 7.40 (s, 5H), 7.62 (d, 2H, J = 8.60Hz), 8.56 (d, 2H, J = 8.60Hz); EIMS: m/z 294.

3q:1H NMR (200 MHz, DMSO+CDCl3) δ 5.75 (s, 1H), 7.30 (m, 5H), 7.66 (d, 2H, J = 8.30Hz), 8.46 (d, 2H, J = 8.30Hz); EIMS: m/z 280.

3r:1H NMR (200 MHz, DMSO+CDCl3): δ 5.5 (s, 1H), 7.26 (d, 2H, J = 8.25Hz), 7.36 (d, 2H, J = 8.25Hz), 7.68 (d, 2H, J = 8.20Hz), 8.49 (d, 2H, J = 8.20Hz); EIMS: m/z 314.

3s:1H NMR (200 MHz, DMSO+CDCl3): δ 2.50 (s, 3H), 6.05 (s, 1H), 7.55 (d, 2H, J = 8.26Hz), 7.76 (d, 2H, J = 8.55Hz), 7.80 (d, 2H, J = 8.26Hz), 8.49 (d, 2H, J = 8.55Hz); EIMS: m/z 294.

3t: IR (KBr): 3425, 1694, 1615, 1500, 1485, 1425, 1179, 616 cm-1; 1H NMR (200 MHz, DMSO+CDCl3): δ 5.75 (s, 1H), 6.46 (s, 1H), 6.65 (s, 1H), 7.4 (s, 1H), 7.66 (d, 2H, J = 8.30Hz), 8.46 (d, 2H, J = 8.30Hz); EIMS: m/z 270; Anal. Calcd. for C13H10N4O3: C, 57.77; H, 5.119; N, 20.74; O, 17.77. Found: C, 57.78; H, 3.73; N, 20.73; O, 17.76.

References:

  1. C. Almansa, L. A. Gomez, F. L Cavalcanti, A. F. de Arriba, J. Garcia-Rafanell, J. Form, J. Med. Chem., 1997,40, 547.
  2. G. Daidone, B. Maggio, S. Plescia, D. Raffa, C. Musiu, C. Milia, G. Perra, M. E. Marongiu, Eur. J. Med. Chem., 1998,33, 375; J. Finn, K. Mattia, M. Morytko, S. Ram, Y. Yang, X. Wu, E. Mak, P. Gallant, D. Keith, Bioorg. Med. Chem. Lett., 2003, 13, 2231.
  3. T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. R. Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M. Miyashiro, R. S. Rogers, D. S. Rogier, S. S. Yu, G. G. Anderson, E. G. Burton, J. N. Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert, A. W. Veenhuizen, Y. Y. Zhang, P. C. Isakson, J. Med. Chem., 1997,40,1347; S. Zhihua, J. Guan, F. P. Michael, M. Kathy, W. P. Michael, M. V. William, S. Monica, S. Michele, R. M. Dave, C. Dennis, Bioorg. Med. Chem. Lett., 2000, 10, 601.
  4. L. A. Elvin, E. C. John, C. G. Leon, J. L. John, E. R. Harry, J. Med. Chem., 1964,7, 259.
  5. P. Pevarello, M. G. Brasca, P. Orsini, G. Traquandi, A. Longo, M. Nesi, F. Orzi, C. Piutti, P. Sansonna, M. Varassi, A. Cameron, A. Vulpetti, F. Roletto, R. Alzani, M. Ciomei, C. Alanese, W. Pastori, A. Marsiglio, E. Pesenti, F. Fiorentini, R. Bischoff, C. Mercurio, J. Med. Chem.,2005, 48, 2944.
  6. D. Fancelli, D. Berta, S. Bindi, A. Cameron, P. Cappella, P. Carpinelli, C. Catana, B. Forte, P. Giordano, M. L. Giorgini, S. Mantegani, A. Marsiglio, M. Meroni, J. Moll, V. Pittala, F. Roletto, D. Severino, C. Soncini, P. Storici, R. Tonani, M. Varasi, A. Vulpetti, P. Vianello, J. Med. Chem., 2005, 48, 3080.
  7. W. Dymek, B. S. Janik, Z. Ryznerski. Acta.Polon.Pharma., 1966, 23, 207.
  8. A. G. Allah, M. M. Hefny, S. A. Salih, M. S. El-Basouny, Corrosion1989, 45, 574; A. G. Allah, M. W. Badawy, H. H. Reham, M. M. Abou-Romia, J. Appn. Electro Chem.,1989,19, 928; W. A. Badawy, M. M. Hefny, S. S. El-Egany, Corrosion,1990,46, 978; M. M. Abou-Romia, H. A. Abd El-Rahaman, H. A. M. El-Sayed, Bull.Electrochem.,1990, 6, 757.
  9. G.Jagath Reddy, D. Latha, K. Srinivasa Rao, Org. Prep. Proced., 2004, 36, 494; K. C. Joshi, V. N. Pathak, U. Garg, J. Het. Chem., 1979,16, 1141.
  10. U. Hanefeld, C. W. Rees, A. J. P. White, J. Chem. Soc., PerkinTrance-I,1996, 1545
  11. E. Vanotti, F. Fiorentini, M. Villa, J. Het. Chem., 1994, 31, 737.
  12. D. S. Dodd, R. L. Martinez, M. Kamau, Z. Ruam, K. V. Kirk, C. B. Cooper, M. A. Hermsmeier, S. C. Traeger, M. A. Poss, J. Comb. Chem., 2005, 7, 584. .
  13. A. R. Khospour, M. M. Kodhoaei, H. Monghannian, Synlett, 2005, 955; A. R. Khospour, K. Esmaeilpoor, A. Moradie, J. Iran. Chem. Soc., 2006, 3, 81; G. Shanmugam, M. Madhavi, P. Anil Kumar, M. Prabhakahr, N. Venu, S. Venkataraman, T. M. Vijayavitthal, G. Mahesh Reddy, Y. Ravindra Kumar, Chemlform, 2005, 36, 46.
  14. M. Larhed, A. Halberg, J. Org. Chem., 1996, 51, 9582; A. Lupy, TopicsinCurrentChem., 1999, 206, 153; D. Villemin, B. Labiad, A. Loupy, Synth.Commun.,1993, 23, 419; C. D. Wang, S. Xin-Zhong, R. J. Xie, Synth.Commun., 1997, 27, 2517;
  15. J. B. Dorsch, S. M. Mcelvain. J. Amer.Chem. Soc. 1932, 54, 2960; G. Wang, X. Liu, G. Zhao. Tetrahedron: Asymmetry 2005, 16, 1873.

Make a Submission

Make a Submission

Information

Current Issue

Browse

Published

2021-07-17

How to Cite

Navath, S. (2021). Revisit: The Synthesis of 3-amino pyrazoles promoted by p-toluenesulfonic acid as an efficient catalyst under solvent and solvent-free conditions. International Journal of Bioorganic and Medicinal Chemistry, 1(1), 20-24. https://doi.org/10.55124/bmc.v1i1.112

Issue

Vol. 1 No. 1 (2021): International Journal Bioorganic and Medicinal Chemistry

Section

Articles