INTRODUCTION:

1,8-Naphthyridine derivatives acquired a special place in the heterocyclic field because of their diversified activities. The main driving force towards the synthesis of naphthyridine is the search for compounds of therapeutic importance^1,2.1,8-Naphthyridine derivatives represent one of the most active classes of compound possessing a wide spectrum of biological activities such as antifungal³, antitumor⁴, antimalarial⁵ anti-inflammatory⁶ and antihypertensive⁷.

The study on naphthyridines has been of considerable interest to organic and medicinal chemistry. The synthetic research on naphthyridines derived antibacterias and antimalarial experienced a renaissance during the seventies of this century. Now-a-days a rapid chemical synthesis on various fused naphthyridines using quinoline derivatives as a convenient starting material^8,9as they display characteristic properties in pharmacological and chemotherapeutic field. A simple way to the synthesis of naphthyridine is treatment of amino pyridine with a,b-unsaturated ketones or aldehydes. A large number of derivatives of the naphthyridines and related systems are synthesized for chemotherapeutic and pharmacological evaluation.

In continuing our interest in the synthesis of heterocyclic compounds^10-12 in this article we wish to report a one-pot synthesis of of novel [1,8]naphthyridine derivatives 2a-g by condensation of 2-chloro-3-formylquinolines (1a-g) with 1-naphthylamine under basic condition.

MATERIAL AND METHODS:

Melting points (mp) were determined using Boetieus micro heating table and are uncorrected. IR (KBr, cm^-1) spectra were obtained on Shimadzu-8201 spectrophotometer. ¹H-NMR spectra were recorded on Bruker AMX-400 (400 MHz) spectrometer using TMS as an internal reference (Chemical shifts in δ, ppm). Elemental analyses were performed on Perkin Elmer CHN-analyzer. Mass spectra were recorded on Shimadzu GCMS-QP5050A (70 eV) mass spectrometer.

General Procedure for Synthesis of benzo[g]naphtho[b][1,8]naphthyridines: (2a-g)

The mixture of 2-chloro-3-formyl quinolines (0.005 mol), 1-naphthylamine (0.0075 mol), few drops of triethylamine and dry benzene (20 mL) were taken in a 100 mL round bottomed flask and was refluxed for 6-12 hr. After completion of the reaction, benzene was evaporated and the resulted yellow colour precipitate was poured into ice. The precipitate was neutralized with dilute HCl, filtered and dried. The resulting yellow solids purified by column chromatography [petroleum ether: ethylacetate; 98:2 as effluent] afford the pure product.

Benzo[g]naphtho[b][1,8]naphthyridine 2a: IR (KBr, cm^-1): 1612, 1571 (C=N); ¹H NMR (DMSO-d₆) d: 7.16-8.42 (m, 10H, Ar-H), 9.10 (s, 1H, C₈-H), 9.22 (s, 1H, C₇-H); Ms (m/z): 280; Anal. Calc. (C₂₀H₁₂N₂): C, 85.71, H, 4.32, N, 10.00; Found: 85.69, H, 4.31, N, 9.98.

10-Methylbenzo[g]naphtho[b][1,8]naphthyridine 2b: IR (KBr, cm^-1): 1612, 1570 (C=N); ¹H NMR (DMSO-d₆) d: 2.58 (s, 3H, C₁₀-CH₃), 7.16-8.96 (m, 9H, Ar-H), 9.11 (s, 1H, C₈-H), 9.26 (s, 1H, C₇-H); Ms (m/z): 294; Anal. Calc. (C₂₁H₁₄N₂): C, 85.71, H, 4.80, N, 9.52; Found: C, 85.70, H, 4.78, N, 9.50.

12-Methylbenzo[g]naphtho[b][1,8]naphthyridine 2c: IR (KBr, cm^-1): 1613, 1575 (C=N); ¹H NMR (DMSO-d₆) d: 2.55 (s, 3H, C₁₂-CH₃), 7.20-8.45 (m, 9H, Ar-H), 9.08 (s, 1H, C₈-H), 9.20 (s, 1H, C₇-H); Ms (m/z): 294; Anal. Calc. (C₂₁H₁₄N₂): C, 85.71, H, 4.80, N, 9.52; Found; C, 85.71, H, 4.77, N, 9.51.

10-Methoxybenzo[g]naphtho[b][1,8]naphthyridine 2d: IR (KBr, cm^-1): 1614, 1570 (C=N); ¹H NMR (DMSO-d₆) d: 3.96 (s, 3H, C₁₀-OCH₃), 7.30-8.65 (m, 7H, Ar-H), 8.96 (s, 1H, C₉-H), 8.99 (d, 1H, C₆-H), 9.15 (s, 1H, C₈-H), 9.24 (s, 1H, C₇-H); Ms (m/z): 310; Anal. Calc. (C₂₁H₁₄N₂O): C, 81.29, H, 4.55, N, 9.03; Found: C, 81.26, H, 4.53, N, 9.01.

12-Methoxybenzo[g]naphtho[b][1,8]naphthyridine 2e: IR (KBr, cm^-1): 1612, 1570 (C=N); ¹H NMR (DMSO-d₆) d: 3.90 (s, 3H, C₁₂-OCH₃), 7.36-8.65 (m, 7H, Ar-H), 8.90 (d, 1H, C₉-H), 8.99 (d, 1H, C₆-H), 9.05 (s, 1H, C₈-H), 9.11 (s, 1H, C₇-H); Ms (m/z): 310; Anal. Calc. (C₂₁H₁₄N₂O): C, 81.29, H, 4.55, N, 9.03; Found: C, 81.28, H, 4.52, N, 9.02.

10-Chlorobenzo[g]naphtho[b][1,8]naphthyridine 2f: IR (KBr, cm^-1): 1612, 1568 (C=N); ¹H NMR (DMSO-d₆) d: 7.30-8.72 (m, 9H, Ar-H), 9.07 (s, 1H, C₈-H), 9.21 (s, 1H, C₇-H); Ms (m/z): 314; Anal. Calc. (C₂₀H₁₁N₂Cl): C, 76.43, H, 3.53, N, 8.91; Found: C, 76.40, H, 3.53, N, 8.89.

10-Bromobenzo[g]naphtho[b][1,8]naphthyridine 2g: IR (KBr, cm^-1):1610, 1567 (C=N); ¹H NMR (DMSO-d₆) d: 7.10-8.64 (m, 9H, Ar-H), 9.08 (s, 1H, C₈-H), 9.29 (s, 1H, C₇-H); Ms (m/z): 359; Anal. Calc. (C₂₀H₁₁N₂Br): C, 66.87, H, 3.08, N, 7.80; Found: C, 66.87, H, 3.09, N, 7.77.

RESULTS AND DISCUSSION:

We commenced our synthesis thermally by effecting the condensation of the 2-chloro-3-formylquinolines (1a) with 1-naphthylamine. Accordingly, a mixture of 2-chloro-3-formylquinoline, 1-naphthylamine, few drops of triethylamine and dry benzene (20 mL) was refluxed for 6 hr. After completion of the reaction (monitored by TLC), benzene was removed by distillation and cooled. The reaction mixture was poured into crushed ice and neutralized with dilute hydrochloric acid, which gave a yellow product 2a in 80% yield (mp-194°C).

The IR spectrum exhibited the absence of carbonyl peak at 1680 cm^-1 which indicated the loss of aldehyde group due to condensation and showed the presence of two absorption bands at 1612, 1571 cm^-1 for two C=N groups. The ¹H NMR spectrum revealed two sharp singlets at d 9.22 and d 9.10 for C₇- and C₈-protons respectively. All other aromatic protons are appearing unresolved multiplet at in the region d 7.16-8.42. The mass spectrum indicated the molecular ion peak at m/z 280 and other fragment ion peaks at m/z 251, 227, 185, 154, 140 and 127. All the above spectral data 2a confirmed as benzo[g]naphtho[b][1,8]naphthyridine (Scheme 1).

The 1,8-naphthyridine derivatives with substitutions in the quioline ring with 6-methyl, 8-methyl, 6-methoxy, 8-methoxy, 6-chloro and 6-bromo to furnish a series of products 2a-g (Scheme-1). The Structure of all the synthesised compound were established on the basis of their spectral (IR, ¹H NMR, and Mass spectrum) and elemental analysis data. The melting point, time required for preparation and yield percentage of all the products have been summarised in Table 1.

Table 1. Physical data of 1,8-naphthyridines ( 2a-g)

Compound	Reaction Time (hr)	Yield (%)	mp °C
2a	6	80	192-194
2b	8	82	172-174
2c	12	80	210-212
2d	10	76	194-196
2e	12	70	190-192
2f	12	66	204-206
2g	12	72	242-244

CONCLUSIONS:

In conclusion, we have demonstrated the synthesis of novel of benzo[g]-naphtho[b][1,8]naphthyridines in a single step from quinoline derivatives. Though many methods have been reported for the synthesis of 1,8-naphthyridine derivatives, our methodology involves highly efficient one pot synthesis of the same. Here, first time we are reporting the synthesis of naphtho[b][1,8]naphthyrindes from quinoline derivatives.

ACKNOWLEDGEMENTS:

The author VN is grateful to Director of Collegiate Education, Govt. of Tamilnadu, India, for financial support. Authors thank NMR Research centre, Indian Institute of Science, Bangalore, INDIA for providing ¹H NMR spectral data.

REFERENCES:

1. Egawa H, Miyamota T, Minamida A, Nishimura, Y, Okada H and Uno H. Motosumota,Pyridonecarboxylic acids as antibacterial agents. Synthesis and antibacterial activity of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its analogs. J Med Chem. 1984; 27: 1543-1548.

2. Cooper CS, Klock PL, Chu DTW, Hardy DJ, Swanson RN and Plattner JJ, Preparation and in vitro and in vivo evaluation of quinolones with selective activity against Gram-positive organisms. J Med Chem. 1992; 35: 1392-1398.

3. Fathy NM, Aly AS, Abd.-El. Mohi F and Abdel-Megeid F.M.E. Egypt J Chem. 1987; 29: 609.

4. Buu Hoi NP, Jacquignon IP, Thany DC and Bartnik T. J Chem Soc. Perkin Trans-I. 1972; 263.

5. Balin GB and Tan WL. Potential Antimalarials. I: 1,8-Naphthyridines. Aust J Chem. 1984; 37:1065-1073.

6. Kuroda T, Suzuki F, Tamura T, Ohmori K and Hoise H. A novel synthesis and potent anti-inflammatory activity of 4-hydroxy-2(1H)-oxo-1-phenyl-1,8-naphthyridine-3-carboxamides. J Med Chem. 1992; 35: 1130-1136.

7. Ferrarini M, Clendio M, Calderone U and Lovella G. Synthesis of 1,8-naphthyridine derivatives: Potential antihypertensive agents-Part VII. Eur J Med Chem. 1998; 33: 383-397.

8. Kidwai M and Kohli S. Indian J Chem. 2000; 40B: 248.

9. Sampth Kumar N, Venkatesh Kumar N and Rajendran SP. A Simple Synthesis of Dibenzo[b,g][1,8]naphthyridines. Synth Commun. 2004; 34: 2019-2024.

10. Nadaraj V, Thamarai Selvi S and Mohan S. Microwave-induced synthesis and anti-microbial activities of 7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one derivatives. Eur J Med Chem 2009; 44: 976-980.

11. Nadaraj V and Thamarai Selvi S. Microwave-assisted solvent-free synthesis of 4-methyl-2-hydroxy and 2-methyl-4-hydroxyquinolines. Indian J Chem. 2007; 46B: 1203-1207.

12. Nadaraj V, Kalaivani S and Thamarai Selvi S. One-pot multicomponent synthesis of some novel acridines. Indian J Chem. 2007; 46B: 1703-1706.