Journal of Medicinal Chemistry
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concentrated. The residue was purified by flash chromatography (light
petroleum/ethyl acetate, 7:3) to give the title compound 5 as a brown
solid (96 mg, 38%) mp 214−215 °C (lit.,25 mp 195−198 °C) (found:
[M + H]+, 357.1071, C18H17N2O6 requires 357.1074); λmax
(methanol)/nm 240 (log ε 5.21), 434 (log ε 4.14); vmax (CHCl3)/
cm−1 3631, 3446, 3323, 3005, 2952, 1710, 1648 1579; δH (400 MHz;
CDCl3) 7.66 (1 H, d, J 8.1 Hz, ArH) 7.35 (1 H, d, J 8.1 Hz, ArH), 4.04
(3 H, s, CH3), 4.03 (3 H, s, CH3), 2.56 (3 H, s, CH3), 2.27 (3 H, s,
CH3); δC (100 MHz; CDCl3) 178.2 (C), 169.1 (C), 166.9 (C), 150.4
(C), 145.8 (C), 145.3 (C), 140.3 (C), 131.3 (C), 129.9 (CH), 128.8
(C), 128.5 (C), 125.5 (CH), 113.3 (C), 97.1 (C), 52.4 (CH3), 51.8
(CH3), 15.0 (CH3), 7.8 (CH3).
2-Amino-8-methyl-3H-phenoxazin-3-one 6. To a solution of
2-aminophenol (109 mg, 1.0 mmol) in acetone (10 mL) was added a
solution of NaIO3 (295 mg, 1.5 mmol) in water (26 mL), and the
mixture was stirred for 10 min at room temperature. Then a solution
4-methyl-2-aminophenol (184 mg, 1.5 mmol) in acetone (10 mL) was
added. The suspension was stirred for 20 h at room temperature, then
extracted with ethyl acetate (3 × 15 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated. The residue was
purified by flash chromatography (light petroleum/ethyl acetate 8:2)
to give the title compound 6 as a brown solid (79 mg, 35%), mp 222−
224 °C (Found: [M + H]+, 227.0820, C13H11N2O2 requires
227.0815); λmax (methanol)/nm 238 (log ε 4.96), 436 (log ε 4.20);
vmax (CHCl3)/cm−1 3631, 3515, 3393, 3011, 1710, 1600; δH (400
MHz; DMSO-d6) 7.72 (1 H, d, J 8.0 Hz, H-6), 7.40−7.50 (2H, m,
ArH), 6.79 (2 H, br, NH2), 6.37 (2 H, s, H-1, H-4), 2.09 (3 H, s,
CH3); δC (100 MHz; DMSO-d6) 180.1 (C), 149.3 (C), 148.7 (C),
147.8, (C), 142.4 (C), 134.2 (C), 129.2 (CH), 128.4 (CH), 125.7 (C),
116.4 (C), 103.9 (CH), 98.8 (C), 31.1 (CH3).
2-Amino-1,8-dimethyl-3H-phenoxazin-3-one 7. To a solution
of 3-methyl-2-aminophenol (123 mg, 1.0 mmol) in acetone (10 mL)
was added a solution of NaIO3 (295 mg, 1.5 mmol) in water (26 mL),
and the mixture was stirred for 10 min at room temperature. Then a
solution of 2-amino-4-methylphenol (184 mg, 1.5 mmol) in acetone
(10 mL) was added. The reaction mixture was stirred for 20 h at room
temperature, then extracted with ethyl acetate (3 × 15 mL), the
combined organic layers were dried (MgSO4), filtered, and
concentrated. The residue was purified by flash chromatography
(light petroleum/ethyl acetate 8:2) to give the title compound 7 as a
brown solid (96 mg, 40%), mp 226−227 °C (found: [M + Na]+,
263.0780, C14H12N2NaO2 requires 263.0765); λmax (methanol)/nm
242 (log ε 4.55), 435 (log ε 4.13); vmax (CHCl3)/cm−1 3515, 3391,
3011, 1710, 1594, 1577; δH (400 MHz; DMSO-d6) 7.60 (1 H, s, H-9),
7.41 (1 H, d, J 8.1 Hz, H-6), 7.30 (1 H, d, J 8.1 Hz, H-7), 6.42 (2 H,
br, NH2), 6,28 (1 H, s, H-4), 2.41 (3 H, s, CH3), 2.23 (3 H, s, CH3);
δC (100 MHz; DMSO-d6) 180.0 (C), 149.5 (C), 147.6 (C), 144.2 (C),
140.4 (C), 135.0 (C), 133.5 (CH), 130.4 (CH), 128.5 (C), 115.8
(CH), 105.7 (CH), 102.6 (C), 20.8 (CH3), 10.3 (CH3).
2-Amino-9-hydroxy-3H-phenoxazin-3-one 8. To a solution of
2-nitroresorcinol (310 mg, 2 mmol) in methanol (30 mL) was added
palladium on carbon (10% w/w, 31 mg) and the suspension was
stirred under an atmosphere of hydrogen for 2 h at room temperature.
The reaction mixture was filtered through a pad of Celite and
concentrated in vacuo to give 2-aminoresorcinol as dark-brown solid
(245 mg, 98%) mp 158−160 °C (lit.,34 mp 152.5 °C); (Found: [M +
Na]+, 148.0369, C6H7NNaO2 requires 148.0369); δH (400 MHz;
DMSO-d6) 8.82 (2 H, br, OH), 6.19−6.29 (3 H, m, ArH), 3.85 (2 H,
br, NH2); δC (100 MHz; DMSO-d6) 145.3 (C), 124.3 (C), 116.2
(CH), 107.0 (CH).
(methanol)/nm 272 (log ε 3.89), 430 (log ε 4.11); vmax (CHCl3)/
cm−1 3592, 3457, 3393, 3331, 3011, 1590; δH (400 MHz; DMSO-d6)
10.2 (1 H, br, OH), 7.29 (1 H, t, J 8.0 Hz, H-7), 6.92 (1 H, d, J 8.0 Hz,
H-8), 6.84 (1 H, d, J 8.0 Hz, H-6), 6.68 (2 H, br, NH2), 6.45 (1 H, s,
H-1), 6.34 (1 H, s, H-4); δC (100 MHz; DMSO-d6) 180.5 (C), 154.2
(C), 149.2 (C), 147.3 (C), 146.2 (C), 143.2 (C, 129.6 (C), 124.2
(CH), 111.3 (CH), 106.4 (CH), 103.7 (CH), 99.3 (CH).
N-(9-Hydroxy-3-oxo-3H-phenoxazin-2-yl)acetamide (Chan-
drananimycin A) 11. To a solution of 2-amino-9-hydroxy-3H-
phenoxazin-3-one (60 mg, 0.22 mmol) in dichloromethane (5 mL),
were added acetic anhydride (218 μL, 2.30 mmol) and 4-
dimethylaminopyridine (5.6 mg, 0.04 mmol), and the resulting
mixture was stirred 16 h at room temperature. Then the mixture
was poured into water (10 mL) and extracted with dichloromethane
(3 × 10 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
chromatography (light petroleum/ethyl acetate 8:2) to give the title
compound 11 as brown solid (23 mg, 39%), mp >300 °C (lit.,8 mp not
given) (found: [M + Na]+, 293.0535, C14H10N2NaO4 requires
293.0533); λmax (methanol)/nm 268 (log ε 3.94), 422 (log ε 4.32);
vmax (CHCl3)/cm−1 3469, 3355, 3011, 1701, 1648, 1503; δH (400
MHz; DMSO-d6) 10.6 (1 H, br NH), 9.67 (1 H, br, OH), 8.38 (1 H, s,
H-1), 7.45 (1 H, t, J 8.0 Hz, H-7), 6.96 (1 H, d, J 8.0 Hz, H-8), 6.89 (1
H, d, J 8.0 Hz, H-6), 6.45 (1 H, s, H-4), 2.24 (3H, s, Me); δC (100
MHz; DMSO-d6) 179.8 (C), 171.1 (C), 155.6 (C), 149.3 (C), 146.1
(C), 144.1 (C), 137.1 (C), 132.9 (CH), 124.4 (C), 114.3 (CH), 112.4
(CH), 106.7 (CH), 104.0 (CH), 25.2 (CH3).
2-Amino-8-[(tetrahydropyran-2-yloxy)methyl]-3H-phenoxa-
zin-3-one 9. Sodium borohydride (76 mg, 2 mmol) was added in
small portions to a solutions of 4-hydroxy-3-nitrobenzaldehyde (130
mg, 0.78 mmol) in methanol (2 mL) at 0 °C. The reaction was
maintained at 0 °C for 1 h and then diluted with chloroform (20 mL)
and poured into HCl (1 M; 10 mL). the organic layer was separated
and washed with water (10 mL). The organic extract was dried
(MgSO4), filtered, and concentrated to give 4-hydroxymethyl-2-
nitrophenol as a yellow solid (790 mg, 80%), mp 97−99 °C (lit.,35
mp 94−98 °C) (found: [M + Na]+, 192.0266, C7H7NNaO4 requires
192.0267); δH (400 MHz; CDCl3) 10.58 (1H, s, OH), 8.14 (1 H, s, H-
3), 7.63 (1 H, d, J 8.0 Hz, H-5), 7.19 (1 H, d, J 8.0 Hz, H-6), 4.72 (2
H, s, CH2); δC (100 MHz; CDCl3) 154.5 (C), 136.3 (CH), 133.2 (C),
123.0 (CH), 120.2 (C), 63.7 (CH2); one C unobserved.
To a solution of 4-hydroxymethyl-2-nitrophenol (500 mg, 3.0 mmol)
in dry dichloromethane (30 mL) under argon atmosphere were added
3,4-dihydro-2H-pyran (285 μL, 3.0 mmol) and pyridinium p-
toluenesulfonate (80 mg, 0.3 mmol). The resulting mixture was
stirred a room temperature for 16 h. Then the mixture was poured into
water (30 mL) and extracted with dichloromethane (3 × 20 mL), the
combined organic layers were dried (MgSO4), filtered, and
concentrated. The product was purified by flash chromatography
(light petroleum/ethyl acetate 8:2) to give 2-nitro-4-[(tetrahydropyr-
an-2-yloxy)methyl]phenol as a colorless oil (673 mg, 88%); (found:
[M + Na]+, 276.0833, C12H15NNaO5 requires 276.0842); δH (400
MHz; DMSO-d6) 10.94 (1 H, s, OH), 7.85 (1 H, s, H-3), 7.53 (1 H, d,
J 8.1 Hz, H-5), 7.13 (1 H, d, J 8.1 Hz, H-6), 4.62−4.69 (2 H, m, CH2),
4.43 (1 H, d, J 8.0 Hz, CH), 3.75−3.81 (1 H, m, CH2), 3.45−3.51 (1
H, m, CH2), 1.4−1.8 (6 H, m); δC (100 MHz; DMSO-d6) 151.9 (C),
136.8 (C), 135.2 (C), 130.1 (CH), 124.5 (CH), 119.5 (CH), 97.8
(CH), 67.2 (CH2), 61.8 (CH2), 30.6 (CH2), 25.4 (CH2), 19.5 (CH2).
To a solution of 2-nitro-4[(tetrahydropyran-2-yloxy)methyl]phenol
(600 mg, 2.3 mmol) in methanol (60 mL) was added palladium on
carbon (10% w/w, 80 mg), and the suspension was stirred under an
atmosphere of hydrogen for 2 h at room temperature. The reaction
mixture was filtered through a pad of Celite and concentrated in vacuo
to give 2-amino-4-[(tetrahydropyran-2-yloxy)methyl] phenol as dark-
brown oil (502 mg, 98%) used without further purification (found: [M
+ Na]+, 246.1091, C12H17NNaO3 requires 246.1101); δH (400 MHz;
DMSO-d6) 8.88 (1 H, s, OH), 6.58−6.60 (2 H, m, ArH), 6.36 (1 H, d,
J 6.0 Hz, H-5), 4.61 (1 H, m, CH), 4.50 (2 H, br, NH2), 4.45 (1 H, d, J
11.2 Hz, CHH), 4.20 (1 H, d, J 11.2 Hz, CHH), 3.75−3.81 (1 H, m,
CHH), 3.45−3.51 (1 H, m, CHH), 1.4−1.8 (6 H, m, CH2); δC (100
To a solution of 2-aminophenol (145 mg, 1.33 mmol) in acetone (10
mL) was added sodium iodate (262 mg, 1.3 mmol) in water (17 mL),
and the mixture was stirred for 10 min at room temperature. Then 2-
aminoresorcinol (200 mg, 1.6 mmol) in acetone (5 mL) was then
added. The resulting mixture was stirred for 20 h at room temperature,
extracted with ethyl acetate (3 × 10 mL), and the combined organic
layers were dried (MgSO4), filtered, and concentrated. The residue
was purified by flash chromatography (light petroleum/ethyl acetate
8:2) gave the title compound 8 as brown solid (75 mg, 25%), mp >300
°C (found: [M + H]+, 229.0607, C12H9N2O3 requires 229.0608); λmax
3314
dx.doi.org/10.1021/jm400049z | J. Med. Chem. 2013, 56, 3310−3317