Analogues of Anti-TB 2-Nitroimidazooxazines
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 3 643
2-Bromo-4-nitro-1H-imidazole (26). A suspension of 25 (18.36
g, 73.4 mmol) in MeOH (16.5 mL) and 5 N HCl (100 mL) was
stirred at 69 °C for 3 h, then cooled and stored at -20 °C for 3 h.
The solid was collected by filtration, washed with petroleum ether,
and dried at 50 °C under vacuum to give 26 (10.92 g, 77%) as a
cream solid: mp (MeOH/H2O) 238-240 °C (lit.34 mp 238-239
°C); 1H NMR [(CD3)2SO] δ 14.10 (br s, 1 H), 8.41 (s, 1 H).
Evaporation of the filtrate to dryness and chromatography of the
residue on silica gel, eluting with CH2Cl2, then 5% MeOH/CH2Cl2,
gave a further 2.55 g (18%) of 26.
calcd for C6H7N3O4 m/z (M+) 185.0437, found 185.0434. Anal.
(C6H7N3O4) H, N. C: calcd, 38.92; found, C, 39.38.
6-{[4-(Trifluoromethoxy)benzyl]oxy}-2-nitro-6,7-dihydro-5H-
imidazo[2,1-b][1,3]oxazine (1). NaH (21 mg of a 60% dispersion
in mineral oil, 0.52 mmol) was added at room temperature to a
solution of 31 (87.2 mg, 0.47 mmol) and 4-trifluoromethoxybenzyl
bromide (83 µL, 0.52 mmol) in dry DMF (3 mL), and the mixture
was stirred at room temperature for 24 h. After dilution with brine
and extraction with EtOAc, the organic solution was evaporated
and chromatographed on silica. Elution with EtOAc/petroleum ether
(1:1) gave foreruns, then elution with EtOAc gave the product,
which was triturated with Et2O (with addition of petroleum ether
when crystallization began) to give (racemic) 1 (0.11 g, 68%) as a
white powder: mp 121-123 °C (lit.15 for S-1, mp 149-150 °C);
1H NMR [(CD3)2SO] δ 8.02 (s, 1 H), 7.44 (d, J ) 8.7 Hz, 2 H),
7.34 (d, J ) 8.7 Hz, 2 H), 4.70 (d, J ) 12.2 Hz, 1 H), 4.69-4.63
(m, 1 H), 4.66 (d, J ) 12.2 Hz, 1 H), 4.47 (d, J ) 11.9 Hz, 1 H),
4.31-4.21 (m, 3 H). Anal. (C14H12F3N3O5) C, H, N.
6-{[4-(Benzyloxy)benzyl]oxy}-2-nitro-6,7-dihydro-5H-imid-
azo[2,1-b][1,3]oxazine (4). NaH (33 mg, 0.84 mmol) was added
in one portion to a solution of 31 (0.10 g, 0.56 mmol) and 4-ben-
zyloxybenzyl chloride (0.19 g, 0.84 mmol) in dry DMF (4 mL),
and the mixture was stirred at room temperature for 16 h. Water
was added. The mixture was extracted with EtOAc, and the extract
was washed well with brine, then evaporated to give an oil that
was chromatographed on silica. Elution with EtOAc/petroleum ether
(1:5) gave foreruns, and then elution with EtOAc gave 4 (56 mg,
30%), which crystallized from CH2Cl2/petroleum ether as pale-
yellow cubes: mp 158-160 °C; 1H NMR [(CD3)2SO] δ 8.00 (s, 1
H), 7.44-7.29 (m, 5 H), 7.24 (d, J ) 8.7 Hz, 2 H), 6.98 (d, J )
8.7 Hz, 2 H), 5.09 (s, 2 H), 4.64-4.60 (m, 1 H), 4.58 (d, J ) 11.5
Hz, 1 H), 4.53 (d, J ) 11.5 Hz, 1 H), 4.45 (d, J ) 11.9 Hz, 1 H),
4.22-4.16 (m, 3 H). Anal. (C20H19N3O5) C, H, N.
2-Bromo-1-[3-bromo-2-(tetrahydro-2H-pyran-2-yloxy)propyl]-
4-nitro-1H-imidazole (32) (Scheme 1). A mixture of 26 (3.32 g,
0.017 mol), 2-[2-bromo-1-(bromomethyl)ethoxy]tetrahydro-2H-
pyran22 (7.76 g, 0.024 mol), and K2CO3 (3.58 g, 0.024 mol) in dry
DMF (50 mL) was stirred at 80 °C for 18 h. After dilution with
brine, the mixture was extracted with EtOAc and the extract was
evaporated and chromatographed on silica. Elution with EtOAc/
petroleum ether (1:9) gave foreruns, and then elution with EtOAc/
petroleum ether (3:7) gave 32 (2.22 g, 31%) as a viscous oil, a mixture
of diastereomers: 1H NMR (CDCl3) δ 8.00, 7.90 (2s, 1 H), 4.70-3.30
(m, 8 H), 1.80-1.38 (m, 6 H); HRFABMS calcd for C11H14Br2N3O4
m/z (M - H+) 411.9508, found 411.9504.
2-Nitro-6-(tetrahydro-2H-pyran-2-yloxy)-6,7-dihydro-5H-imid-
azo[2,1-b][1,3]thiazine (33). n-Butyllithium (2.13 mL of a 2.5 M
solution in hexanes, 5.34 mmol) was added dropwise under N2 to
a stirred solution of triispropylsilanethiol (1.14 mL, 5.34 mmol) in
dry THF (50 mL) at 5 °C. After 5 min, the resulting solution was
added dropwise to a solution of 32 (2.22 g, 5.34 mmol) in dry
THF (50 mL) which had been cooled to -78 °C under N2. After 5
min, the cooling bath was removed and the solution was allowed to
warm to room temperature, when stirring was continued for 18 h. The
solution was diluted with water and extracted with EtOAc and the
extract was dried and evaporated to give an orange oil (2.97 g). This
was immediately dissolved in THF (60 mL). Tetra-n-butylammo-
nium fluoride (17.0 mL of a 1 M solution in THF, 0.017 mol) was
added, and the solution was stirred at room temperature for 1 h.
Brine was added, the mixture was extracted into EtOAc, and the
extract was washed with saturated aqueous NaHCO3 and evaporated
to give an oil, which was chromatographed on silica. Elution with
EtOAc/petroleum ether (1:1) gave foreruns, and then elution with
EtOAc/petroleum ether (3:1) gave an oily solid, which was triturated
with MeOH to give 33 (1.09 g, 71%) as a yellow solid, a mixture
of diastereomers: mp 129-131 °C; 1H NMR (CDCl3) δ 7.68, 7.67
(2s, 1 H), 4.85-4.80 (m, 1 H), 4.54-4.43 (m, 1 H), 4.27-4.05
(m, 2 H), 3.96-3.89 (m, 0.5 H), 3.80-3.73 (m, 0.5 H), 3.61-3.51
(m, 1H), 3.45-3.39 (m, 0.5 H), 3.36-3.30 (m, 0.5 H), 3.26 (d, J
) 4.9 Hz, 1 H), 1.83-1.40 (m, 6 H). Anal. (C11H15N3O4S·1/4H2O)
C, H, N.
1-(2-Bromo-4-nitro-1H-imidazol-1-yl)-3-{[tert-butyl(dimeth-
yl)silyl]oxy}-2-propanol (27). A mixture of 26 (2.00 g, 0.010 mol),
tert-butyl(dimethyl)(2-oxiranylmethoxy)silane (2.15 g, 0.011 mol,
1.1 equiv), and N,N-diisopropylethylamine (0.91 mL, 5.21 mmol,
0.50 equiv) in toluene (60 mL) was warmed at 70 °C for 18 h. The
solution was concentrated to dryness and the residue triturated with
petroleum ether to leave the crude product as an oily solid. This
material was adsorbed onto silica and chromatographed. Elution
with EtOAc/petroleum ether (1:3) gave foreruns, and then further
elution with EtOAc/petroleum ether (1:1) gave 27 (2.66 g, 67%):
mp (EtOAc/petroleum ether) 101 °C; 1H NMR [(CD3)2SO] δ 8.44
(s, 1 H), 5.31 (d, J ) 5.4 Hz, 1 H, exchanged with D2O), 4.18 (dd,
J ) 13.9, 3.4 Hz, 1 H), 3.96 (dd, J ) 13.9, 8.7 Hz, 1 H), 3.89-3.80
(m, 1 H), 3.64 (dd, J ) 10.5, 4.7 Hz, 1 H), 3.50 (dd, J ) 10.5, 6.7
Hz, 1 H), 0.88 (s, 9 H), 0.06 (s, 6 H); HRCIMS calcd for
C12H23BrN3O4Si m/z (M + H+) 382.0621, 380.0641; found
382.0619, 380.0637.
2-Bromo-1-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(tetrahydro-
2H-pyran-2-yloxy)propyl]-4-nitro-1H-imidazole (28). A solution
of 27 (2.65 g, 6.97 mmol), 3,4-dihydro-2H-pyran (6.50 mL, 0.07
mol, 10.0 equiv), and pyridinium p-toluenesulfonate (1.78 g, 1.0
equiv) in CH2Cl2 (50 mL) was stirred at room temperature for 16 h.
After being washed with water and saturated aqueous NaHCO3,
the solution was dried and concentrated to give 2820 (3.18 g, 98%)
as a yellow oil, a mixture of diastereomers. This material was not
characterized further and was used directly in the next step.
2-Nitro-6-(tetrahydro-2H-pyran-2-yloxy)-6,7-dihydro-5H-imid-
azo[2,1-b][1,3]oxazine (30). Tetra-n-butylammonium fluoride (19.3
mL of a 1 M solution in THF, 0.019 mol, 3.0 equiv) was added
under N2 to a solution of 28 (3.00 g, 6.45 mmol) in THF (60 mL),
and the solution was stirred at room temperature for 1 h. After
dilution with EtOAc, the solution was washed with brine, saturated
aqueous NaHCO3, and water. After the mixture was dried, the
extract was evaporated onto silica and chromatographed. Elution
with EtOAc/petroleum ether (1:4) gave silicon-containing residues,
and then further elution with EtOAc gave a mixture of 2920 and
3020 as a glassy solid (1.68 g). This product was dissolved in dry
DMF (15 mL), NaH (0.13 g, 5.41 mmol) was added, and the
mixture was stirred at room temperature for 3 h. Brine was added
and the mixture was extracted into EtOAc, washed well with brine,
and evaporated to give 3020 (0.95 g, 55%) as a viscous oil, a mixture
of diastereomers (lit.15 for S-30, mp 138-139 °C, and for R-30,
mp 145-146 °C); 1H NMR [(CD3)2SO] δ 8.06, 8.00 (2s, 1 H total,
diastereomers), 4.89, 4.84 (2m, 1 H total), 4.60-4.15 (m, 5 H),
3.79, 3.68, 3.47 (3m, 2 H total), 1.65-1.37 (m, 6 H).
2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol (31).
Methanesulfonic acid (5 drops) was added to a solution of 30 (0.95
g, 0.014 mol) in MeOH (60 mL), and the solution was stirred at
room temperature for 3 h and then concentrated to a small volume
under reduced pressure. The residue was treated with excess
saturated aqueous NaHCO3 solution and extracted into EtOAc
(6 times). The combined extracts were evaporated to give (racemic)
alcohol 31 (0.65 g, ∼100%) as a cream solid. A portion was
crystallized from EtOAc/petroleum ether to give an off-white
powder: mp 206-209 °C (lit.15 for S-31, mp 220 °C dec, and for
R-31, mp 208 °C dec); 1H NMR [(CD3)2SO] δ 8.05 (s, 1 H), 5.65
(br s, 1 H, exchanged with D2O), 4.41 (dd, J ) 11.3, 1.2 Hz, 1 H),
4.31 (ddd, J ) 11.3, 2.6, 2.6 Hz, 1 H), 4.29-4.24 (br, 1 H), 4.19
(dd, J ) 12.9, 3.3 Hz, 1 H), 3.96 (ddd, J ) 12.9, 2.6, 2.6 Hz, 1 H);
13C NMR δ 147.05, 142.02, 117.90, 70.64, 58.94, 49.12; HREIMS