Facile and efficient synthesis of novel oxazine, oxazepine and phenoxazine of chromenones fused with 1,4-naphthoquinone

Article abstract of DOI:10.3987/COM-08-S(F)30

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.

Full text of DOI:10.3987/COM-08-S(F)30

HETEROCYCLES, Vol. 77, No. 1, 2009
611
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 611 - 615. © The Japan Institute of Heterocyclic Chemistry
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 – 226 007, India
E. mail: vishnutandon@yahoo.co.in
Dedicated to Professor Emeritus Keiichiro Fukumoto on occasion of his 75th
birthday.
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

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HETEROCYCLES, Vol. 77, No. 1, 2009
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.
O
O
O
O
O
O
NaN3
O
DMF/H2O
15 h, 120 oC
O
HO
N
H
Cl
O
O
(61%)
O
O
(72%)
10
5
2
O
O
O
DMSO, Na2CO3,
5 min. stirred, rt
O
O
O
O
O
O
N
H
O
O
(11%)
11
O
O
(11%)
6
O
O
O
1
13
14
HO
O
R
O
O
O
O
11
12
NaN3
O
O
O
2
10
9
O
DMF/H2O
8 h, 120 oC
6
Cl
a: R=CH3
b: R=H
3
Cl
Cl
N
H
7
4
5
8
3
O
O
R
O
(7a: 67%)
(7b: 60%)
R
7
DMSO, Na2CO3,
6 h stirred, rt
12
(12a: 72%)
(12b: 69%)
O
O
O
O
1
O
R
O
O
(8a: 12%)
(8b: 20%)
8
R
Me
Ph
O
HO
O
Me
Ph
O
O
O
4
O
O
O
DMSO, Na2CO3,
3h stirred, rt
O
Me
Ph
O
(61%)
9
Scheme 1
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-

HETEROCYCLES, Vol. 77, No. 1, 2009
613
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
o
5, 7a and 7b with sodium azide using DMF/H2O as solvent at 120 C 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
Table 1. Physical spectral and micro analytical data of 5-126,7
Entry
Mp
Spectra
1
5
>280 IR (KBr):1680,1632,1601 cm-1; H NMR (400 MHz, DMSO-d6): δ 7.40 (m, 2H), 7.71 (s,
1H), 7.95 (m, 2H), 8.07 (m, 2H), 8.14 (m, 2H); M+: 353; Anal. Calcd (C19H9ClO5): C,
64.70; H, 2.57. Found: C, 64.94; H, 2.68.
6
>280 IR (KBr): 1679, 1632, 1594 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 7.42 (m, 3H), 7.72 (m,
2H), 7.96 (m, 5H), 8.09 (d, 2H, J=6), 8.18 (d, 2H, J=6); M+: 479; Anal. Calcd (C28H14O8):
C, 70.30; H, 2.95. Found: C, 70.52; H, 3.10.
1
7a
7b
8a
215
207
220
IR (KBr): 2985, 1675,1591, 1539 cm-1; H NMR (400 MHz, DMSO-d6): δ 2.43 (s, 3H),
6.31 (s, 1H), 7.28 (d, 1H), 7.30 (d,1H, J=6) 7.40 (s, 1H, J=6), 7.96 (m, 2H), 8.01 (m, 2H);
M+: 367; Anal. Calcd (C20H11ClO5): C, 65.50; H, 3.02. Found: C, 65.36; H, 3.20
IR (KBr): 1657, 1586, 1542 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 6.17 (d, 1H, J=6), 6.75
(m, 2H), 7.50 (m, 2H) 7.90 (m, 2H), 8.01 (m, 2H); M+: 353; Anal. Calcd (C19H9ClO5): C,
64.70; H, 2.57. Found: C,64.88; H, 2.46.
IR (KBr): 2925, 1733,1655,1607 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 2.41 (s, 6H), 6.25
(s, 2H), 7.15 (m, 4H), 7.70 (m, 2H), 7.95 (m, 2H), 8.05 (d, 2H, J=6); 13CNMR (300 MHz,
DMSO-d6): 18.03, 18.19, 103.78, 103.33, 112.56, 113.09, 115.55, 126.47, 126.65, 126.99,
130.62, 131.56, 134.45, 134.63, 151.76, 152.37, 152.83, 153.11, 153.65, 153.86, 154.36,
156.19, 158.65, 159.04, 159.53, 159.75, 166.73, 176.90, 177.59, 178.05; M+: 508; Anal.
Calcd (C30H18O8): C, 71.15; H, 3.58. Found: C, 71.28; H, 3.70.
8b
9
214
187
118
IR (KBr): 1722, 1650, 1601 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 6.19 (m, 2H), 6.72 (m,
4H), 7.49 (m, 4H), 7.88 (m, 2H), 8.02 (m, 2H); M+: 479; Anal. Calcd (C28H14O8): C, 70.30;
H, 2.95. Found: C, 70.42; H, 3.14.
1
IR (KBr): 2928, 1627, 1591, 1543 cm-1; H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 6H),
6.89 (m, 4H), 7.28 (m, 1H),7.40 (m, 2H), 7.75 (m, 6H), 7.95 (m, 7H); M+: 659; Anal. Calcd
(C42H26O8): C, 76.59; H, 3.98. Found: C, 76.72; H, 4.18.
1
10
IR (KBr): 3447, 1652, 1605, 1543 cm-1; H NMR (400 MHz, DMSO-d6): δ 3.5 (bs, 1H),
13
7.25 (m, 2H), 7.60 (m, 2H), 7.90 (m, 2H), 8.05 (m, 2H); CNMR (300 MHz, DMSO-d6):
79.19,101.75, 115.49, 115.91, 116.71, 116.96, 119.49, 123.04, 124.54, 126.13, 130.29,
135.24, 135.24, 135.24, 135.67, 159.14, 161.26, 167.80, 168.67, 172.09; M+ (M++1): 332;
Anal. Calcd (C19H9NO5): C, 68.89; H, 2.74; N, 4.23. Found: C, 68.66; H, 2.82; N, 4.40.
1
11
>280 IR (KBr): 3444, 1767, 1635, 1621 cm-1; H NMR (400 MHz, DMSO-d6): δ 3.69 (bs, 1H),
5.82 (s, 1H), 6.87 (m, 1H), 7.09 (m, 1H), 7.26 (m, 1H), 7.53 (m, 2H), 7.90 (m, 2H); M+
(M++1): 332; Anal. Calcd (C19H9NO5): C, 68.89; H, 2.74; N, 4.23. Found: C, 68.68; H,
2.64; N, 4.32
1
12a
>280 IR (KBr): 3430, 1670, 1593, 1541 cm-1; H NMR (400 MHz, DMSO-d6): δ 2.50 (s, 3H,
CH3), 4.20 (bs, 1H, NH), 6.25 (s, 1H, C3-H), 6.70 (m, 2H, C5-H & C14-H), 7.63 (m, 2H, C8-
H & C11-H), 7.91 (m, 2H, C9-H & C10-H); M+ (M++1): 346; Anal. Calcd (C20H11NO5): C,
69.57; H,3.21; N, 4.06. Found: C, 69.70; H, 3.30; N, 4.14.
1
12b
>280 IR (KBr): 3433, 1668, 1592, 1535 cm-1; H NMR (400 MHz, DMSO-d6): δ 4.19 (bs, 1H,
NH), 6.18 (m, 1H, C3-H), 6.74 (m, 2H, C5-H & C14-H), 7.65 (m, 3H), 7.96 (m, 2H) M+
(M++1): 332; Anal. Calcd (C19H9NO5): C, 68.89; H, 2.74; N, 4.23. Found: C, 68.64; H,
2.82; N, 4.44.

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HETEROCYCLES, Vol. 77, No. 1, 2009
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.
REFERENCES AND NOTES
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Kolodziej, Planta Med., 1997, 63, 508.
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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

HETEROCYCLES, Vol. 77, No. 1, 2009
615
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 oC. 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%).
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