- Short communication
- Open Access
Synthesis of 2-cyclopropyl-3-(5-aryl-1H-pyrazol-3-yl)-1,8-naphthyridine
© Bucha et al; licensee Springer. 2014
Received: 21 August 2014
Accepted: 22 September 2014
Published: 21 December 2014
1,8-Naphthyridine derivatives have attracted considerable attention because the 1,8-naphthyridine skeleton is present in many compounds that have been isolated from natural substances, with various biological activities.
N,N-dimethoxy-N-methyl-1,8-naphthyridine-3-carboxamide (1) on reaction with Grignard reagent forms 2-methoxy-1,8-naphthyridine-3-carbaldehyde (2). Compound 2 on reaction with different aromatic aldehydes provided 1-(2-cyclopropyl-1,8-naphthyridin-3-yl)-3-arylprop-2-en-1-ones (3a-e) and these compounds on cyclisation with hydrazine hydrate 99% yielded 2-cyclopropyl-3-(5-aryl-1H-pyrazol-3-yl)-1,8-naphthyridines (4-a-e).
Synthesis of the target compounds involved the formation of 4a-e. It was accomplished using Grignard reaction, condensation reaction, and cyclisation reactions. All the synthesized compounds were readily soluble in DMSO. Spectral data of the synthesized compounds were in full agreement with the proposed structures.
In conclusion, we have developed a simple and an efficient Synthesis of 2-cyclopropyl-3-(5-aryl-1H-pyrazol-3-yl)-1,8-naphthyridine.
Among the wide variety of heterocycles that have been explored for developing pharmaceutically important molecules, such as chalcones, pyrazolines and amino pyrimidines have played an important role in medicinal chemistry. The presence of reactive α,β-unsaturated carbonyl function in chalcones is found to be responsible for their antibacterial and antifungal activity. Nitrogen containing heterocyclic compounds find extensive pharmaceutical applications and possess biologically activity. Many of the naphthyridines have shown bacterial, fungicidal and carcinogenic activity -. As a step in this direction and in continuation of our work on 1, 8-naphthyridines -, synthesis of the title compounds was carried out. The general synthetic procedures used in the preparation of these compounds involved the cyclisation of Schiff’s bases -.
A simple conventional method is followed to prepare all the title compounds.
Results and discussion
Compound (1), when reacted with Grignard reagent and gave 2-methoxy-1,8-naphthyridine-3-carbaldehyde (2) which was reacted with different aldehydes to form arylidene derivatives (3a-e), which on treatment with hydrazine hydrate afforded compound (4a-e).
Melting points were determined in open capillaries and are uncorrected. 1H NMR spectrum is taken on a Varian 500 MHz instrument with TMS as an internal standard. The chemical shifts are expressed δ ppm, and the solvent used is DMSO-d6. Mass spectrum is taken on Hewlett-Packard mass spectrometer operating at 70 eV. All the compounds are recrystalised from ethanol.
To a solution of 2-cyclopropyl-N-methoxy-N-methyl-1,8-naphthyridine-3-carboxamide (1) (1.01 mmol) in THF (10 mL), MeMgCl (3.03 mmol) was added drop wise at −30°C and stirred for about 2 h at −30°C. The resulting solution is quenched with a saturated NH4Cl solution (30 mL), filtered, extracted with EtOAc (3 × 30 mL) and dried over Na2SO4. The resulting crude compound was purified by a column chromatography by eluting 20% to 40% ethyl acetate in hexane to obtain the light yellow colour solid.
1H NMR (DMSO-d 6 , 500 MHz): δ 1.06-1.21 (m, 4H, 2CH2), 2.24 (s, 3H, CH3), 2.57 (m, 1H, CH), 7.57 (t, 1H, J = 12Hz CH), 8.31 (s, 1H, J = 12Hz CH), 8.42, (d, 1H, CH), 9.02 (d, 1H, J = 10Hz CH). Mass [M + 1] peak at m/z 213.
To a solution of 1-(2-cyclopropyl-1,8-naphthyridin-3-yl)ethanone (2) (0.53 mmol) in DMF, NaOH (0.79 mmol) and aldehyde (0.63 mmol) were added at 0°C and stirred for about 1 h. Then water was added and extracted with DCM (2 × 15 mL), dried over Na2SO4 and evaporated under reduced pressure. The resulting crude compound was purified by a column chromatography by eluting 20% to 40% ethyl acetate in hexane to obtain the light yellow colour solid.
1H NMR (DMSO-d 6 , 500 MHz): δ 1.12-1.28 (m, 4H, 2CH2), 2.61 (m, 1H, CH), 7.62 (m, 2H, J = 14Hz 2CH), 7.81 (dd, 2H, J = 18Hz 2CH), 8.23, (m, 3H, 3CH), 8.51-8.61 (m, 4H, J = 18Hz 4CH), 9.12 (s, 1H, CH). Mass [M + 1] peak at m/z 301.
Other compounds in the series were prepared similarly and their characterization data are recorded below.
1H NMR (DMSO-d 6 , 500 MHz): δ 1.14-1.29 (m, 4H, 2CH2), 2.52,(m, 1H, CH), 7.62 (m, 4H, 4CH), 7.71 (d, 2H, J = 12Hz 2CH), 8.23, (d, 1H, 1CH), 8.69 (s, 1H, 1CH), 9.22 (s, 1H, CH).Mass [M + 1] m/z 380.
1H NMR (DMSO-d 6 , 500 MHz): δ 1.16-1.27 (m, 4H, 2CH2), 2.48 (m, 1H, CH), 7.62 (m, 4H, 4CH), 7.69 (d, 2H, J = 12Hz 2CH), 8.33 (d, 1H, , J = 12Hz, 1CH), 8.71 (s, 1H, 1CH), 9.24 (s, 1H, CH). Mass [M + 1] peak at m/z 331.
1H NMR (DMSO-d 6 , 500 MHz): δ 1.19-1.28 (m, 4H, 2CH2), 2.53 (m, 1H, CH), 7.63 (m, 4H, 4CH), 7.72 (d, 2H, J = 14Hz 2CH), 8.42 (d, 1H, J = 14Hz, 1CH), 8.78 (s, 1H, 1CH), 9.28 (s, 1H, CH).Mass [M + 1] peak at m/z 315.
1H NMR (DMSO-d 6 , 500 MHz): δ 1.23-1.31 (m, 4H, 2CH2), 2.62 (m, 1H, CH), 7.73 (m, 4H, 4CH), 7.81 (d, 2H, J = 18Hz 2CH), 8.56 (d, 1H, J = 16Hz, 1CH), 8.64 (s, 1H, 1CH), 9.32 (s, 1H, CH).Mass [M + 1] peak at m/z 346.
2-cyclopropyl-3-(5-phenyl-1 H-pyrazol-3-yl)-1,8-naphthyridine (4a)
To a solution of 1-(2-cyclopropyl-1,8-naphthyridin-3-yl)-3-phenylprop-2-en-1-one (3a) (0.31 mmol) in ethanol (5 mL), hydrazine hydrate 99%(2 mL) was added. The resulting solution was refluxed for about 12 h. After completion of a starting material, the ethanol was evaporated completely under a reduced pressure then the title compound was recrystalised from diethyl ether to obtain the brown colour solid.
1H NMR (DMSO-d 6 , 500 MHz): δ 1.16(m, 2H, CH2), 1.22 (m, 2H, CH2), 2.21 (m, 1H, CH), 5.21(s, 1H, J = 12Hz CH), 5.41(s, 1H, J = 12Hz CH), 6.31 (m, 1H, J = 12Hz CH), 6.59, (m, 2H, 2CH), 7.19 (d, 1H, J = 10Hz CH), 7.69 (m, 4H, 4CH), 8.42 (m, 2H, 2CH), 9.11 (s, 1H, CH), 10.81 (s, 1H, NH). Mass [M + 1] peak at m/z 313.
Other compounds in the series were prepared similarly and their characterization data are recorded below.
3-(5-(4-bromophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-1,8-naphthyridine (4b)
1H NMR (DMSO-d 6 , 500 MHz): δ 1.21(m, 2H, CH2), 1.28 (m, 2H, CH2), 2.37 (m, 1H, CH), 6.21 (s, 1H, J = 12Hz CH), 7.32(s, 1H, CH), 7.41 (m, 4H, J = 12Hz 4CH), 8.19 (m, 2H, 2CH), 8.39 (d, 1H, CH), 10.69 (s, 1H, NH). Mass [M + 2] peak at m/z 392.
2-cyclopropyl-3-(5-(4-methoxyphenyl)-1 H-pyrazol-3-yl)-1,8-naphthyridine (4c)
1H NMR (DMSO-d 6 , 500 MHz): δ 1.24 (m, 2H, CH2), 1.29 (m, 2H, CH2), 2.28 (m, 1H, CH), 4.12 (s, 3H, CH3), 6.23 (s, 1H, CH), 7.35 (s, 1H, CH), 7.29 (m, 4H, J = 12Hz 4CH), 8.03, (m, 2H, 2CH), 8.42 (d, 1H, CH), 10.46 (s, 1H, NH). Mass [M + 1] peak at m/z 343.
2-cyclopropyl-3-(5-p-tolyl-1 H-pyrazol-3-yl)-1,8-naphthyridine (4d)
1H NMR (DMSO-d 6 , 500 MHz): δ 1.18 (m, 2H, CH2), 1.31 (m, 2H, CH2), 2.20 (m, 1H, CH), 2.39 (s, 3H, CH3), 6.28 (s, 1H, CH), 7.25 (s, 1H, CH), 7.39 (m, 4H, 4CH), 8.23, (m, 2H, 2CH), 8.44 (d, 1H, J = 12Hz, CH), 10.59 (s, 1H, NH). Mass [M + 1] peak at m/z 327.
2-cyclopropyl-3-(5-(4-nitrophenyl)-1 H-pyrazol-3-yl)-1,8-naphthyridine (4e)
1H NMR (DMSO-d 6 , 500 MHz): δ 1.18 (m, 2H, CH2), 1.31 (m, 2H, CH2), 2.20 (m, 1H, CH), 6.18 (s, 1H, CH), 7.15 (s, 1H, CH), 7.27 (m, 4H, 4CH), 8.12, (m, 2H, 2CH), 8.24 (d, 1H, J = 12Hz, CH), 11.19 (s, 1H, NH). Mass [M + 1] peak at m/z 358.
We have presented simple, cost effective, and practical method for preparation of some 1,8-naphthyridines. This methodology provides an efficient alternative to existing methods for the synthesis of 2-cyclopropyl-3-(5-aryl-1H-pyrazol-3-yl)-1,8-naphthyridine. Here in step-1, we observed the formation of Grignard product which on condensation of aldehydes Schiff's base is formed. Further reaction Schiff's base with hydrazine we obtained the pyrazoles.
- Nezval J, Halocka J: The enhancing effect on the antibacterial activity of nalidixix acid against Pseudomonas aeruginosa. Experientia 1967, 23: 1043. 10.1007/BF02136439View ArticleGoogle Scholar
- Egawa H, Miyamido A, Nishimra Y, Okada H, Uno H, Matsumato J: Pyridonecarboxylic acids as antibacterial agents. J Med Chem 1984, 27: 1543. 10.1021/jm00378a004View ArticleGoogle Scholar
- Suzuki N, Dohmori R: The chemistry of heterocyclic compounds: the naphthyridines. Chem Pharma Bull 1979, 27: 410. 10.1248/cpb.27.410View ArticleGoogle Scholar
- Shiva Shankar S, Laxminarayana E, Haripriya V, Thirumala Chary M: Synthesis of 5-(2-methoxy-1,8-naphthyridin-3-yl)-4-aryl-4H-1,2,4-triazole-3-thiols and 5-(2-methoxy-1,8-naphthyridin-3-yl)-n-aryl-1,3,4-thiadiazol-2-amines. Indian J Heterocycl Chem 2011, 21: 101.Google Scholar
- Narender A, Thirumala Chary M, Laxminarayana E, Haripriya V: Synthesis and antimicrobial activity of 2-cyclopropyl [1,8]naphthyridine-3- carboxylic acid (4-phenyl-2-thioxo-thiazol-3-yl)-amides, [1,3,5]triazine, [1,3,4]thiadiazole-2-thiol, [1,2,4]triazole-3-thiol and coumarine derivatives. Indian J Chem 2013, 52B: 440.Google Scholar
- Mallaiah B, Shiva Shankar S, Laxminarayana E, Thirumala Chary M: Synthesis of 2-(5-(2-methoxy-1,8-naphthyridin-3-yl)-1,3,4-oxadiazol/triazol-2-ylthio)-1-(4-alkylbenzofuran-2-yl)ethanones and 2-methoxy-3-(5-(4-alkylbenzofuran-2-yl)-7aH-thiazolo[2,3-b][1,3,4]oxadiazol/triazol-2-yl)-1,8-naphthyridines by conventional and eco-friendly methods and evaluation of their antibacterial activity. Indian J Heterocycl Chem 2013,22(2):333.Google Scholar
- Shiva Shankar E, Laxminarayana M, Thirumala C: Synthesis of 5-(2-methoxy-1,8-naphthyridin-3-yl)-1,3,4-oxadiazole-2(3H)-thione and 1-(2-methoxy-1,8-naphthyridin-3-acetyl)-4-arylthiosemicarbazides. Indian J Heterocycl Chem 2013,23(2):139.Google Scholar
- Vadim A, Soloshonok CC, Yamada T, Hisanori U, Ohfune Y, Hruby VJ: Michael addition reactions between chiral equivalents of a nucleophilic glycine and ( S )- or ( R )-3-[( E )-Enoyl]-4-phenyl-1,3-oxazolidin-2-ones as a general method for efficient preparation of β-substituted pyroglutamic acids: case of topographically controlled stereoselectivity. J Am Chem Soc 2005, 43: 127.Google Scholar
- Reddy KR, Kumar NS: Cellulose-supported copper(0) catalyst for Aza-Michael addition. Synlett 2006, 6: 224.Google Scholar
- Wu F, Li L, Hong R, Deng L: Construction of quaternary stereocenters via efficient and practical conjugate additions to α, β-unsaturated ketones with a chiral organic catalyst. Angew Chem Int 2006, 45: 947. 10.1002/anie.200502658View ArticleGoogle Scholar
- Bensa D, Constantieux T, Rodriguez J (2004) A new efficient and commercially available user-friendly and recyclable heterogeneous organocatalyst for the Michael addition of 1,3-dicarbonyl compounds. Synthesis 06:923Google Scholar
- Ooi T, Ohara D, Fukumoto K, Maruoka K: Importance of chiral phase-transfer catalysts with dual functions in obtaining high enantioselectivity in the Michael reaction of malonates and chalcone derivatives. Org Lett 2005, 7: 3195. 10.1021/ol050902aView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.