Table of Contents
Organic Chemistry International
Volume 2014, Article ID 567053, 4 pages
http://dx.doi.org/10.1155/2014/567053
Research Article

Water Mediated Synthesis of N′-Arylmethylene-4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide Library

1Department of Industrial Chemistry, Shree M. & N. Virani Science College, Rajkot 360005, India
2Department of Chemistry, Saurashtra University, Rajkot 360005, India
3Department of Chemistry, Shree M. & N. Virani Science College, Rajkot 360005, India

Received 8 August 2014; Revised 21 September 2014; Accepted 21 September 2014; Published 15 October 2014

Academic Editor: Ashraf Aly Shehata

Copyright © 2014 Mahesh M. Savant et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A novel two-step synthesis of 4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide has been developed. The library of N′-arylmethylene-4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide was generated by coupling of hydrazide to various aromatic and heterocyclic aldehydes in water media at ambient temperature with great flexibility regarding reaction time and yield.

1. Introduction

Derivatives of indazole and other pyrazole-containing condensed systems are attracting attention because of their biological activity and the possibilities of further conversions. Anti-inflammatory, analgesic, antipyretic, and antirheumatic activity has been reported for pyrazole derivatives [13]. One of these derivatives, 2-(1-phenyl-pyrazole-4-yl)propionic acid I (Figure 1), has been shown to be clinically active in the treatment of rheumatic disorders. In addition, it has been reported that pyrazole corticoids III, IV (Figure 1) are more active than parent corticoids. One of these derivatives, 17α,21-dihydroxy-20-oxopregn-4-eno[3,2-c]-2′-(4-fluorophenyl) pyrazole II (Figure 1) [4], has been used clinically as a topical anti-inflammatory agent. However, literature reveals that 4,5,6,7-tetrahydro-2H-indazole derivatives exhibit dopaminergic [5], anti-inflammatory [6], herbicidal [7], and antitumor [8] activity and cannabinoid modulators [9], as HMG-COA reductase inhibitors [10]. Hydrazide analogues also possess other biological activities like anticonvulsant [11], antidepressant [12], anti-inflammatory [13], antimalarial [14], antimycobacterial [15], anticancer [16], and antimicrobial [1721] activities.

567053.fig.001
Figure 1

Our Continuous efforts for the synthesis of various novel heterocycles for biological interest using various catalyst and green approaches [2226] and the remarkable pharmaceutical importance of fused hydrazide and pyrazole derivatives, prompted us to design and synthesize a scaffold 4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide using water as a green solvent.

2. Materials and Methods

Melting points were determined on electrothermal apparatus using open capillaries and are uncorrected. Thin-layer chromatography was accomplished on 0.2 mm precoated plates of silica gel G60 F254 (Merck). Visualization was made with UV light (254 and 365 nm) or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer using DRS prob. 1H NMR spectra were recorded on a Bruker AVANCE II (400 MHz) spectrometer in DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010 mass spectrometer (Shimadzu). Elemental analysis was performed on a Carlo-Erba EA 1108 elemental analyzer. All reagents were purchased from Fluka, Sigma Aldrich, Merck, and Rankem and used without further purification.

2.1. Synthesis of Ethyl 2-Oxo-2-(2-oxocyclohexyl)acetate 2

To the stirred solution of sodium ethoxide (13.6 g, 0.2 mol), a mixture of cyclohexanone (1, 19.6 g, 0.2 mol) and diethyl oxalate (29.2 g, 0.2 mol) was added drop wise below 5–10°C. Vigorous stirring is required to prevent complete solidification of the reaction mixture. When the addition is complete, the ice bath is retained for an hour, and then the mixture is stirred at room temperature for about six hours. The reaction mixture is then decomposed by careful addition of cold 15% sulfuric acid solution. During this neutralization the temperature of the mixture is maintained at about 5–10°C by means of an ice-salt bath. The ethyl 2-ketocyclohexylglyoxalate 2 has been extracted using chloroform as colorless oil after evaporation of solvent in vaccuo. The product was sufficient pure for further reaction Yield-25.7 g (65%).

2.2. Synthesis of 4,5,6,7-Tetrahydro-2H-indazole-3-carbohydrazide 3

Ethyl 2-oxo-2-(2-oxocyclohexyl) acetate (2, 19.8 g, 0.1 mol) was stirred at 5–10°C and 25 mL of 80% hydrazine hydrate was added drop wise. After the complete addition reaction mixture was allowed at room temperature and refluxed for 2 to 3 h in water bath, the reaction mixture was allowed to cool at room temperature and the precipitate obtained was filtered, dried, and recrystallized from ethanol to give a pure 4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide 3 as a white crystal in 85% yield, Mp—128–130°C. Light yellow solid, IR (KBr): 3450, 3390, 2750, 1785, 1575, 1247, 982, 750. 1H NMR (DMSO), 12.31 (S, 1H, NH), 10.65 (S, 1H, NH), 3.15–2.75 (m, 4H, CH2), 2.20 (s, 2H, NH2), 1.82–1.73 (m, 4H, CH2), MS (m/z): 180 (M+), Anal. Calcd for C8H12N4O: C, 53.32, H, 6.71, N, 31.09. Found: C, 53.10, H, 6.90, N, 30.25.

2.3. Synthesis of N′-Arylmethylene-4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide 4a–t

A mixture of 4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide (3, 1.8 g, 1 mmol) and appropriate aromatic aldehyde (1.5 mmol) was taken in 20 mL of water. The reaction mixture was stirred for 30 min at room temperature. The obtained solid was filtered and washed with saturated aqueous sodium bicarbonate, water, 1 N aq HCl, and brine subsequently to remove the unreacted aldehyde. The crystallization of obtained crude product from ethanol gives a pure N′-arylmethylene-4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide 4a–t in good to excellent yield.

N′-Phenylmethylene-4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide 4a. White solid, IR (KBr): 3626, 3593, 2889, 2947, 2852, 1666, 1554, 1492, 1448, 1261, 709, 630 cm−1, 1H NMR (DMSO), 12.36 (S, 1H, NH), 10.78 (S, 1H, NH), 8.34 (s, 1H, =CH), 7.76–7.67 (m, 2H, Ar), 7.40–7.37 (m, 3H, Ar), 3.15–2.78 (m, 4H, CH2), 1.81–1.75 (m, 4H, CH2), MS (m/z): 268 (M+), Anal. Calcd for C15H16N4O: C, 67.15, H, 6.01, N, 20.88. Found: C, 67.10, H, 6.12, N, 20.84.

3. Results and Discussion

The desired 4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide 3 was obtained starting from cyclohexanone 1 and diethyl oxalate followed by subsequent treatment with hydrazine hydrate, Scheme 1. In the first step the anion of starting compound cyclohexanone was generated with the help of sodium ethoxide in ethanol at 0–5°C and reacted with diethyl oxalate which resulted into ethyl 2-oxo-2-(2-oxocyclohexyl)acetate 2 [21]. When compound 2 was reacted with hydrazine hydrate in solvent medium like methanol, ethanol, dioxane, and so forth, it gave ethyl 4,5,6,7-tetrahydro-2H-indazole-3-carboxylate, while without solvent in excess hydrazine hydrate on reflux afforded 4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide 3 in excellent yield (85%) as outlined in Scheme 1.

567053.sch.001
Scheme 1

The reaction of various hydrazides 3 with various aromatic aldehydes at room temperature in water media led to the formation of a series of new indazole derivatives 4a–t as demonstrated in Scheme 2. An excess of the aldehydes was used to achieve a high conversion. It is noteworthy that a maximum conversion of hydrazide 3 to 4a–t was achieved within 25–30 minutes by stirring at ambient temperature. Each coupling reaction was worked up by filtration and washing of solid with saturated aqueous sodium bicarbonate, water, 1 N aq HCl, and brine. Subsequent purification of each compound by crystallization in ethanol delivered pure N′-arylmethylene-4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide 4a–t with 85–95% yield.

567053.sch.002
Scheme 2

Concerning the functionalized indazoles 4a–t, we found no significant electronic effects caused by electron-withdrawing or electron-donating groups on the aryl ring of the hydrazone, though yields were variable. Also, the coupling of heterocyclic aldehydes to hydrazide works well without affecting reaction time and yield.

All the compounds were characterized by IR, mass, 1H NMR spectroscopy, and elemental analysis to confirm the compound identity, which is consistent with the proposed molecular structures. As per 1H NMR spectral study, the number of protons and their chemical shifts were found to support the proposed structures. Methylene protons of cyclohexane ring were observed between 1.7 to 2.9 δ ppm. Amide proton was observed at 10.7–11.0 δ ppm as a singlet, while cyclic NH proton of indazole ring was observed at very downfield with 12.34–12.85 δ ppm value as a singlet. The ethylenic proton was shown as a singlet around 8.3–8.8 δ ppm. Aromatic protons were observed between 6.8 to 7.8 δ ppm with characteristic splitting according to the substitution. In mass spectral study, molecular ion peak was observed in agreement with molecular weight of respective compound. As per IR spectral study, the presence of functional groups such as secondary amine, amide, and aromatic ring system was confirmed on the basis of its characteristic absorption range. The physicochemical data of synthesized compounds are presented in Table 1.

tab1
Table 1: Physicochemical properties of N′-arylmethylene-4,5,6,7-tetrahydro-2H-indazole-3-carbohydrazide derivatives 4a–t.

4. Conclusion

In summary, a new 4,5,6,7-tetrahydro-2H-indazole carbohydrazide has been developed and utilized for the synthesis of corresponding arylmethylene hydrazone in water media at ambient temperature. The methodology shows the great flexibility regarding reaction time, yield, and green solvent. In principle, the strategy should be applicable in the generation of hydrazone library.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

Authors are thankful for the facilities and grants given under UGC-SAP for Department of Research Support (DRS) and Department of Science and Technology (DST), New Delhi, also thankful for Fund for Improvement of Science and Technology (FIST) and Department of Chemistry, Saurashtra University, for providing laboratory facilities.

References

  1. “Orally administrable opioid formulations having extended duration of effect,” French Patent 2133 503, 1972.
  2. “Heterocyclic substituted pyrazole-4-acetic acids,” German Offen. 2141124, 1972.
  3. J. H. Fried, H. Mrozik, G. E. Arth et al., “16-Methylated steroids. IV. 6,16α-dimethyl-6-hydrocortisone and related compounds,” Journal of the American Chemical Society, vol. 85, no. 2, pp. 236–238, 1963. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Hannah, K. Kelly, A. A. Patchett, S. L. Steelman, and E. R. Morgan, “Substituted pyrazolo corticoids as topical antiinflammatory agents,” Journal of Medicinal Chemistry, vol. 18, no. 2, pp. 168–172, 1975. View at Publisher · View at Google Scholar · View at Scopus
  5. L. A. McQuaid, J. E. Latz, J. A. Clemens, R. W. Fuller, D. T. Wong, and N. R. Mason, “Substituted 5-amino-4,5,6,7-tetrahydroindazoles as partial ergoline structures with dopaminergic activity,” Journal of Medicinal Chemistry, vol. 32, no. 10, pp. 2388–2396, 1989. View at Publisher · View at Google Scholar · View at Scopus
  6. M. Suzanne, “Substituted Pyrazolyl Compounds For The Treatment Of Inflammation,” US Patent no. 7211597 B2, 2007.
  7. A. D. Wolf, “Tetrahydroindazole herbicides,” US Patent no. 4124373, 1978.
  8. P. Pevarello, “4,5,6,7-tetrahydroindazole derivatives as antitumor agents,” US 6716856 B1, 2004.
  9. B. Lagu, “Tetrahydro-indazole cannabinoid modulators,” WO 095353 A1, 2005.
  10. P. J. Conolly, “Tetrahydroindazole, tetrahydrocyclopentapyrazole, and hexahydrocycloheptapyrazole compounds and their use as hmg-coa reductase inhibitors,” US 5134155, 1992.
  11. J. V. Ragavendran, D. Sriram, S. K. Patel et al., “Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore,” European Journal of Medicinal Chemistry, vol. 42, no. 2, pp. 146–151, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. N. Ergenc and N. S. Gunay, “Synthesis and antidepressant evaluation of new 3-phenyl-5-sulfonamidoindole derivatives,” European Journal of Medicinal Chemistry, vol. 33, no. 2, pp. 143–148, 1998. View at Publisher · View at Google Scholar · View at Scopus
  13. A. R. Todeschini, A. L. P. de Miranda, K. C. M. da Silva, S. C. Parrini, and E. J. Barreiro, “Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2-pyridylarylhydrazone derivatives,” European Journal of Medicinal Chemistry, vol. 33, no. 3, pp. 189–199, 1998. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Gemma, G. Kukreja, C. Fattorusso et al., “Synthesis of N1-arylidene-N2-quinolyl- and N2-acrydinylhydrazones as potent antimalarial agents active against CQ-resistant P. falciparum strains,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 20, pp. 5384–5388, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. A. Bijev, “New heterocyclic hydrazones in the search for antitubercular agents: synthesis and in vitro evaluations,” Letters in Drug Design and Discovery, vol. 3, no. 7, pp. 506–512, 2006. View at Publisher · View at Google Scholar · View at Scopus
  16. B. N. Swamy, T. K. Suma, G. V. Rao, and G. C. Reddy, “Synthesis of isonicotinoylhydrazones from anacardic acid and their in vitro activity against Mycobacterium smegmatis,” European Journal of Medicinal Chemistry, vol. 42, no. 3, pp. 420–424, 2007. View at Publisher · View at Google Scholar
  17. A. Masunari and L. C. Tavares, “A new class of nifuroxazide analogues: synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus,” Bioorganic and Medicinal Chemistry, vol. 15, no. 12, pp. 4229–4236, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. C. Loncle, J. M. Brunel, N. Vidal, M. Dherbomez, and Y. Letourneux, “Synthesis and antifungal activity of cholesterol-hydrazone derivatives,” European Journal of Medicinal Chemistry, vol. 39, no. 12, pp. 1067–1071, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. S. G. Küçükgüzel, A. Mazi, F. Sahin, S. Öztürk, and J. Stables, “Synthesis and biological activities of diflunisal hydrazide-hydrazones,” European Journal of Medicinal Chemistry, vol. 38, no. 11-12, pp. 1005–1013, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. P. Vicini, F. Zani, P. Cozzini, and I. Doytchinova, “Hydrazones of 1,2-benzisothiazole hydrazides: Synthesis, antimicrobial activity and QSAR investigations,” European Journal of Medicinal Chemistry, vol. 37, no. 7, pp. 553–564, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. H. R. Snyder, L. A. Brooks, and S. H. Shapiro, “Pimelic acid,” Organic Synthesis, vol. 11, p. 42, 1931. View at Google Scholar
  22. M. M. Savant, A. M. Pansuriya, C. V. Bhuva et al., “Water mediated construction of trisubstituted pyrazoles/isoxazoles library using ketene dithioacetals,” Journal of Combinatorial Chemistry, vol. 12, no. 1, pp. 176–180, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. M. M. Savant, N. S. Gowda, A. M. Pansuriya et al., “A concise synthetic strategy to functionalized chromenones via [5+1] heteroannulation and facile C-N/C-S/C-O bond formation with various nucleophiles,” Tetrahedron Letters, vol. 52, no. 2, pp. 254–257, 2011. View at Publisher · View at Google Scholar · View at Scopus
  24. M. M. Savant, A. M. Pansuriya, C. V. Bhuva, N. P. Kapuriya, and Y. T. Naliapara, “Etidronic acid: a new and efficient catalyst for the synthesis of novel 5-nitro-3,4-dihydropyrimidin-2(1H)-ones,” Catalysis Letters, vol. 132, no. 1-2, pp. 281–284, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. M. M. Savant, C. V. Bhuva, A. M. Pansuriya et al., “Synthesis of some novel trifluoromethylated tetrahydropyrimidines using etidronic acid and evaluation for antimicrobial activity,” Der Pharmacia Lettre, vol. 1, no. 2, pp. 277–285, 2009. View at Google Scholar
  26. A. M. Pansuriya, M. M. Savant, C. V. Bhuva, J. Singh, and Y. T. Naliapara, “One-pot synthesis of 5-carboxanilide-dihydropyrimidinones using etidronic Acid,” Arkivoc, vol. 2009, no. 7, pp. 79–85, 2009. View at Publisher · View at Google Scholar · View at Scopus