Next Article in Journal
4,4-Bis(hydroxymethyl)-2-phenyl-2-oxazoline
Previous Article in Journal
6-Bromo-N-(3-(difluoromethyl)phenyl)quinolin-4-amine
Open AccessShort Note

(7E)-3-(4-Methoxyphenyl)-7-[(4-methoxyphenyl)methylidene]-4,5,6,7-tetrahydro-3aH-indazole

1
Faculty of Pharmacy and Science, Universitas Muhammadiyah Prof. DR. HAMKA, Jakarta 13460, Indonesia
2
Faculty of Pharmacy, Universitas Indonesia, Depok, West Java 16424, Indonesia
3
Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
*
Author to whom correspondence should be addressed.
Molbank 2020, 2020(4), M1162; https://doi.org/10.3390/M1162
Received: 24 September 2020 / Revised: 15 October 2020 / Accepted: 19 October 2020 / Published: 21 October 2020
(This article belongs to the Section Organic Synthesis)

Abstract

Indazole derivatives are well known to have various pharmacological activities. We synthesized a novel derivative of indazole, namely (7E)-3-(4-methoxyphenyl)-7-[(4-methoxyphenyl)methylidene]-4,5,6,7-tetrahydro-3aH-indazole by condensation reaction between 3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indazole and 4-methoxy-benzaldehyde in good yield (61%).
Keywords: indazole derivatives; hexahydro-indazole; tetrahydro-indazole; p-methoxybenzaldehyde; condensation indazole derivatives; hexahydro-indazole; tetrahydro-indazole; p-methoxybenzaldehyde; condensation

1. Introduction

Indazole derivatives are well known to have various pharmacological activities such as antitumor, anti-inflammatory, antioxidant, antiplatelet, anti-HIV, antihypertensive, serotonin 5-HT3 receptor antagonist, and others. They are rarely obtained from nature, but most of them are synthetic compounds [1,2,3,4]. Due to the importance of the indazole ring in drug development, many chemists were motivated to take the initiative to develop different methods for this heterocycle synthesis. In the present time, there are more than 30 synthesis methods for indazole derivatives, most of them for 1H and 2H indazole derivatives [1,2,3]. Conversion of the benzene ring of 2H-indazol structure with cyclohexane ring afforded 3,3a,4,5,6,7-hexahydro-2H-indazoles. The general synthesis method for the compounds was by condensation of α,β-unsaturated carbonyl with hydrazine in ethanol as a solvent. These modified indazoles also showed various biological activities [3,5,6,7]. Attracting our interest in their anti-cancer activities, herein, we report the synthesis of a novel derivative of indazole, (7E)-3-(4-methoxyphenyl)-7-[(4-methoxyphenyl)methylidene]-4,5,6,7-tetrahydro-3aH-indazole.

2. Results and Discussion

The starting material, 3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (1), was prepared by the condensation of 2-benzylidenecyclohexanone and 4-methoxy-benzaldehyde according to the reported method [6]. The condensation reaction between 1 and 4-methoxy-benzaldehyde (2) in glacial acetic acid at 120 °C (reflux) for 3 h found compound 3, (7E)-3-(4-methoxyphenyl)-7-[(4-methoxyphenyl)methylidene]-4,5,6,7-tetrahydro-3aH-indazole (3) (Scheme 1).
The Fourier transform infrared (FTIR) indicated that the NH peak of the title compound (3) disappeared. In the 1H-NMR spectrum, protons of NH and HC-N at about 5.00 and 5.32 ppm were not observed either [7]. Meanwhile, six protons of the two methoxy groups in the two aromatic rings appeared as two peaks at 3.85 ppm (s, 3H) and 3.84 ppm (s, 3H). Protons of CH connecting the two C=N of indazole nucleus and ethylenic (CH=C) appeared as a triplet at 3.84–3.85 ppm (1H) and as singlet peak at 7.10 ppm (1H), respectively. While the eight protons of the two di-substituted phenyl rings at para position appeared as doublet peaks at 7.53 ppm (2H), 7.32 ppm (2H), and as a double doublet peak at 6.89 ppm (4H). The disappearance of CH2 protons adjacent to the C=N group (C7) indicated the substitution of phenylmethyledene moiety occurred at that position. The 13C-NMR spectrum showed the presence of two carbon of C=N (peaks at 158.9 and 157.8 ppm) and carbon of C=C (ethylenic) (peaks at 130.0 and 114.7 ppm) [8,9]. The spectroscopic data of the structure were supported by the high-resolution mass spectrum (HR-MS). The peak of the molecular ion was found at m/z 347.17514 ([M + H]+). Those values are fully in accordance with the structure of compound 3. The FTIR, NMR and HR-MS spectra can be seen in "Supplementary Materials."
The condensation reaction between the hexahydro-indazole 1 and aromatic aldehyde 2 occurred because the methylene group at position 7 of 1 has alpha hydrogen and adjacent to the azomethine (C=N) group having carbonyl properties [10]. The reaction conditions with glacial acetic acid as a solvent and reflux temperature caused dehydration to obtain α,β-unsaturated imine moiety accompanied by dehydrogenation of heterocycle: 3,3a,4,5,6,7-hexahydro-2H-indazole to be 4,5,6,7-tetrahydro-3aH-indazole. Probable dehydrogenation of the pyrazoline ring of 3,3a,4,5,6,7-hexahydro-2H-indazole was due to aerobic aromatization. The released H2O was then dehydrated by glacial acetic acid.
A similar product, its tautomeric enimine form, has already been prepared but with a different procedure. The compound was obtained by oxidation of (7E)-3-(4-methoxyphenyl)-7-[(4-methoxyphenyl)-methylidene]-3,3a,4,5,6,7-hexahydro-2H-indazole with a Fe(III)-based reagent in alkaline condition [11]. In the H-NMR spectrum, the main difference in the structure of the two compounds is clearly observed. In compound 3, the proton peak of 3a-H appears at 3.84–3.85 ppm and lacks proton NH at 9.91 ppm, while in the tautomer form, the NH proton appears at 9.91 ppm and lacks the proton peak at 3.85 ppm [11].

3. Materials and Methods

3.1. General

All chemicals (synthesis or analytical grade) used are purchased commercially. The TLC method was used to evaluate the purity of synthesized compounds. The melting point (uncorrected) was measured by the melting point device (Bibby Sterilin, Staffordshire, UK). Infrared (IR), proton/carbon nuclear magnetic resonance (1H/13C-NMR) spectra were recorded on an FTIR spectrophotometer (8400S, Shimadzu, Kyoto, Japan) and a JEOL spectrometer (JNM-ECZ500R/S1, Peabody, MA, USA), respectively. Meanwhile, the mass spectra (MS) were analyzed by LC-MS/MS (UNIFI-Waters, Milford, MA, USA) with ESI (+) mode.

3.2. Synthesis of (7E)-3-(4-Methoxyphenyl)-7-[(4-methoxyphenyl)methylidene]-4,5,6,7-tetrahydro-3aH-indazole (3)

The synthesis of the title compound (3) was performed according to synthesis method of styryl quinazolinones derivatives reported earlier [12,13]. A mixture of 3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (115 mg, 0.5 mmol) and 4-methoxy-benzaldehyde (68 mg, 0.5 mmol) was dissolved in glacial acetic acid (10 mL) and refluxed at 120 °C for 3 h until completion (TLC monitoring). Then, the mixture was poured onto crushed ice, filtered off and washed with cold water to obtain a solid product. Recrystallization from ethyl acetate afforded the pure compound (3) as a pale-yellow powder in 61% yield (106 mg) and mp 252–254 °C. FT-IR (KBr), υ (cm−1): 3053 (Ar-H), 2953 (C-H), 1605 and 1580 (C=N), 1512 and 1450 (C=C), 1250 and 1178 (Ar-O and C-O ether). 1H-NMR (500 MHz, CDCl3) δ, ppm: 7.53 (d, J = 8 Hz, 2H, H-Ar), 7.32 (d, J = 8 Hz, 2H, H-Ar), 7.10 (s, 1H, CH=), 6.89 (dd, J = 8 Hz, 4H, H-Ar), 3.84–3.85 (t, J = 2–4 Hz, 1H, 3a-H, little overlap with protons of OCH3), 3.84 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 2.77–2.79 (m, 4H, 4-H and 6-H), 1.86–1.88 (m, 2H, 5-H). 13C-NMR: (500 MHz, CDCl3) δ, ppm: 158.9 (1C), 157.9 (1C), 145.1 (1C), 144.4 (1C), 131.0 (2C), 130.0 (1C), 129.4 (1C), 128.6 (2C), 114.7 (1C), 114.2 (2C), 113.8 (2C), 55.5 (2C), 55.4 (1C), 27.1 (1C), 24.5 (1C), 22.0 (1C). ESI-MS+ (m/z): found 347.17514 [M + H]+; calc for neutral mass of C22H22N2O2 = 346.16813; Mass Error = −0.3 mDa.

Supplementary Materials

The following are available online, Figure S1: FTIR of 3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (1); Figure S2: FT-IR spectrum of compound 3; Figure S3: 1H-NMR spectrum of compound 3; Figure S4: 13C-NMR spectrum of compound 3; Figure S5: HR-MS spectrum of compound 3.

Author Contributions

H.H. (Hariyanti Hariyanti) conducted the experiment; H.H. (Hayun Hayun), A.Y., and K.K. supervised the experiment; H.H. (Hariyanti Hariyanti) and H.H. (Hayun Hayun) wrote and revised the manuscript. All authors agreed to the final version of this manuscript.

Funding

This research was funded by Doctoral Dissertation Research Grant, the Ministry of Research and Technology/National Research Agency, Republic of Indonesia, fiscal year 2020 (Grant No.: NKB-0373/UN2.RST/HKP.05.00/2020). The APC was supported by Universitas Indonesia.

Acknowledgments

Thanks the Ministry of Research and Technology/National Research Agency, Republic of Indonesia, for the funding support of this study, the Chemical Research Center of the Indonesian Institute of Sciences, Serpong, Indonesia, for recording NMR and HR-MS spectra; and Universitas Muhammadiyah DR. HAMKA, Jakarta, for the doctoral program (for Hariyanti).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zhang, S.G.; Liang, C.G.; Zhang, W.H. Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives. Molecules 2018, 23, 2783. [Google Scholar] [CrossRef] [PubMed]
  2. Gaikwad, D.D.; Warad, K.D.; Chapolikar, A.D.; Devkate, C.G.; Tayade, A.P.; Pawar, R.P.; Domb, A.J. Synthesis of indazole motifs and their medicinal importan ce: An overview. Eur. J. Med. Chem. 2015, 90, 707–731. [Google Scholar] [CrossRef] [PubMed]
  3. Shrivastava, A.; Chakraborty, A.K.; Upmanyu, N.; Singh, A. Recent Progress in Chemistry and Biology of Indazole and its Derivatives: A Brief Review. Austin. J. Anal. Pharm. Chem. 2016, 3, 1076. [Google Scholar]
  4. Thangadurai, A.; Minu, M.; Wakode, S.; Agrawal, S.; Narasimhan, B. Indazole: A medicinally important heterocyclic moiety. Med. Chem. Res. 2012, 21, 1509–1523. [Google Scholar] [CrossRef]
  5. Ismail, Z.H. The use of a-enone derivative in the preparation of some new heterocyclic compounds with expected biological and antitumor activities. Adv. Environ. Biol. 2013, 7, 1049–1057. [Google Scholar]
  6. Minu, M.; Thangadurai, A.; Wakode, S.R.; Agrawal, S.S.; Narasimhan, B. Synthesis, antimicrobial activity and QSAR studies of new 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazoles. Bioorg. Med. Chem. Let. 2009, 19, 2960–2964. [Google Scholar] [CrossRef] [PubMed]
  7. Bayomi, S.M.; El-Kashef, H.A.; El-Ashmawy, M.B.; Nasr, N.A.; El-Sherbeny, M.A.; Badria, A. Synthesis and biological evaluation of new curcumin derivatives as antioxidant and antitumor agents. Med. Chem. Res. 2013, 22, 1147–1162. [Google Scholar] [CrossRef]
  8. Silverstein, R.M.; Webster, F.X.; Kiemle, D.J. Spectrometric Identification of Organic Compounds, 7th ed.; John Wiley & Sons, Inc.: New York, NY, USA, 2005. [Google Scholar]
  9. MarvinSketch 20.8.0. Chemaxon Ltd. 1998–2020. Available online: http://www.chemaxon.com (accessed on 28 September 2020).
  10. Nájera, C.; Sansano, J.M.; Yus, M. 1,3-Dipolar Cycloadditions of azomethine imines. Org. Biomol. Chem. 2015, 13, 8596–8636. [Google Scholar] [CrossRef] [PubMed]
  11. Nuriev, V.N.; Vatsadze, I.A.; Sviridenkova, N.V.; Vatsadze, S.Z. Synthesis of 3,7-Disubstituted Hexahydro and Tetrahydro-2H-indazoles from Cross-Conjugated Dienones. Russ. J. Org. Chem. 2016, 52, 389–396. [Google Scholar] [CrossRef]
  12. Hudiyono, S.; Hanafi, M.; Yanuar, A. Synthesis and COX-2 Inhibitory Activity of 4-[(E)-2-(4-Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethenyl]benzene-1-sulfonamide and Its Analogs. Pharmaceuticals 2012, 5, 1282–1290. [Google Scholar] [PubMed]
  13. Sridhar, R.; Takei, H.; Syed, R.; Kobayashi, I.S.; Hui, L.B.; Kamal, A.; Tenen, D.G.; Kobayashi, S.S. Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα. Molecules 2018, 23, 1938. [Google Scholar] [CrossRef]
Scheme 1. Synthesis of the title compound.
Scheme 1. Synthesis of the title compound.
Molbank 2020 m1162 sch001
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Back to TopTop