HETEROCYCLES

Note | Special issue | Vol. 77, No. 1, 2009, pp. 611-615
Received, 21st June, 2008, Accepted, 15th August, 2008, Published online, 18th August, 2008.
DOI: 10.3987/COM-08-S(F)30

■ Facile and Efficient Synthesis of Novel Oxazine, Oxazepine and Phenoxazine of Chromenones Fused with 1,4-Naphthoquinone

Vishnu K. Tandon* and Hardesh K. Maurya

Department of Chemistry, University of Lucknow, Lucknow, U.P. 226007, India

Abstract

A series of novel mono ethers 5, 7, diethers 6, 8, 9, oxazine 10, oxazepine 11 and phenoxazines 12 of chromenones fused with 1,4-naphthoquinone have been synthesized.

The quinone group forms the basis of biological activity of number of clinical and experimental drugs that are associated with antitumor, antimalarial, antifungal and antibacterial studies.1 In addition chromenones have been reported to possess antimicrobial, anti-inflammatory and antitumor activity.2-4 The clinical significance of these two class of compounds has stimulated the synthesis of novel ring systems agents retaining the core quinone and chromenone moiety.
As part of our research program of the synthesis of biologically active quinones,1 we became interested in the synthesis of novel oxazine, oxazepine, phenoxazine and ether derivatives of chromenones fused with 1,4-naphthoquinone.
2,3-Dichloro-1,4-naphthoquinone 1 reacts readily with nucleophiles leading to substitution of one or both chlorine atoms.5 Based on the reactivity of 1, we have studied its reaction with chromenones 2-4 (one equivalents) in the presence of Na2CO3 using DMSO as solvent at room temperature.8 Quinone 1 was reacted with 4-hydroxy-2H-chromen-2-one 2 to give a mixture of the 2-chloro-3-(2-oxo-2H-chromen-4-yloxy)naphthalene-1,4-dione 5 and 2,3-bis(2-oxo-2H-chromen-4-yloxy)naphthalene-1,4-dione 6 in 72% and 11% yields respectively (Scheme 1) whereas reaction with 7-hydroxy-4-methyl-2H-chromen-2-one 3a and 7-hydroxy-2H-chromen-2-one 3b gave ethers, 2-chloro-3-(4-methyl-2-oxo-2H-chromen-7-yloxy)naphthalene-1,4-dione 7a and 2-chloro-3-(2-oxo-2H-chromen-7-yloxy)naphthalene-1,4-dione 7b in 67% and 60% yields respectively. In addition to formation of 7a and 7b, diethers, 2,3-bis(4-methyl-2-oxo-2H-chromen-7-yloxy)naphthalene-1,4-dione 8a and 2,3-bis(2-oxo-2H-chromen-7-yloxy)-naphthalene-1,4-dione 8b were obtained in 12% and 20% yields, respectively.
In separate experiments quinone 1 was reacted with two equivalents of chromenones 2, 3a and 3b at 100 oC resulting in the formation of diethers 6, 8a and 8b in 84%, 81% and 79% yield, respectively.

We then studied the reaction of quinone 1 with 7-hydroxy-2-metnyl-3-phenyl-4H-chromen-4-one 4 (one equivalents) at room temperature and 100 oC exclusively, monitoring TLC at regular interval, the reaction produced only disubstituted product, 2,3-bis(2-methyl-4-oxo-3-phenyl-4H-chromen-7-yloxy)naphthalene-1,4-dione 9 in 61% yield. It is believed9 that the chromenone 4 increased the reactivity of second substitution, therefore mono derivative was converted into disubstituted as soon as it formed.
In order to synthesize novel oxazine, oxazepine and phenoxazine, we studied the reaction of mono ethers7 5, 7a and 7b with sodium azide using DMF/H2O as solvent at 120 oC using methods as reported Kim et al.10 The reaction led to formation of chromeno[3,4-e]naphtho[2,3-b][1,4]oxazine-6,8,13(7H)-trione 10

and chromeno[5,4-ef]naphtha[2,3-b][1,4]oxazepine-2,8,13(7H)-trione (11) from mono ether 5, 4-methylbenzo[b]pyrano[2,3-i]naphthoxazine-2,7,12(6H)-trione (12a) and benzo[b]pyrano[2,3-i]-naphthoxazine-2,7,12(6H)-trione (12b) from mono ethers 7a and 7b in 61%, 11%, 72% and 69% yields respectively.
Compounds 5-12 synthesized were evaluated for their antibacterial activities against various strains of the bacteria, for example, Staphylococcus aureus, Streptococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli and antifungal activity against various strains of pathogenic fungi, for example, Candida albicans, Candida parapsilosis (ATCC 22019), Cryptococcus neoformans, Aspergillus fumigatus, Sporothrix schenckii and Trichophyton mentagraphytes and carried out according to the broth microdilution technique described by NCCLS1 of minimum inhibitory concentration(MIC) assay at 50 µg/mL or lower concentration. Compound 7a exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii at 25 µg/mL whereas compounds 7a also showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli.
In conclusion, we have synthesized novel oxazine, oxazepine, phenoxazines and ethers of different chromenones 2-4 fused with 1,4-naphtnoquinone 1. Further work to evaluate other biological effects is in progress.

ACKNOWLEDGEMENTS
H. K. M. acknowledged UGC, New Delhi, India for assessment of Senior Research Fellowship.

Dedicated to Professor Emeritus Keiichiro Fukumoto on occasion of his 75th birthday.

References

1. V. K. Tandon, H. K. Maurya, D. B. Yadav, A. Tripathi, M. Kumar, and P. K. Shukla, Bioorg. Med. Chem. Lett., 2006, 16, 5883 and references cited here. CrossRef
2. a) M. V. Kulkarni, B. G. Pujar, and V. D. Patil, Arch. Pharm., 1981, 314, 701; b) O. Kayser and H. Kolodziej, Planta Med., 1997, 63, 508. CrossRef
3. G. Manjunath, D. Manohar, V. Kulkarni, R. Shobha, and S. Y. Kattimani, Eur. J. Med. Chem., 2003, 38, 297. CrossRef
4. R. J. Griffin, G. Fontana, B. T. Golding, S. Guiard, I. R. Hardcastle, J. J. J. Leahy, N. Martin, C. Richardon, L. Rigoreau, M. Stockley, and G. C. M. Smith, J. Med. Chem., 2005, 48, 569. CrossRef
5. V. K. Tandon and H. K. Maurya, Heterocycles, 2008, 76, 1007. CrossRef
6. General procedure (5-9): To a solution of 2,3-dichloro-1,4-napthoquinone 1 (2 mmol) in DMSO (4 mL), chromenone 2-4 (2.2 mmol) was added followed by Sodium carbonate (2.2 mmol). The reaction mixture was stirred at rt as shown in Scheme 1. The reaction mixture was poured in crushed ice and extracted with EtOAc followed to wash with brine and dried in vacuo. The mixture of mono and diethers 5-9 was separated by column chromatography(SiO₂) using EtOAc in hexane (30-100%).
7. General Procedure (10-12): To a solution of mono ether 5, 7 (1 mmol) and NaN₃ (3 mmol) in DMF (3 mL) and H₂O (1 mL) was stirred at 120 °C. The reaction mixture was poured into crushed ice. The precipited solid was collected by filtration, washed with water, dried and purified by column chromatography (SiO₂) using EtOAc in hexane (20-80%).
8. J. M. M. del Corral, M. A. Castro, M. Gordaliza, M. L. Martin, A. M. Gamito, C. Cuevas, and A. S. Feliciano, Bioorg. Med. Chem., 2006, 14, 2816. CrossRef
9. T. Win and S. Bittner, Tetrahedron lett., 2005, 46,　3229. CrossRef
10. Y.-S. Kim, S.-Y. Park, H.-J. Lee, M.-E. Suh, D. Schollmeyer, and C.-O. Lee, Bioorg. Med. Chem., 2003, 11, 1709 CrossRef