1602
A. D. Sercel, V. G. Beylin, M. E. Marlatt, B. Leja, H. D. H. Showalter,
and A. Michel
Vol 43
1.3 L of absolute ethanol was treated with 68 mL (0.869 mol) of
(S)-epichlorohydrin (7b), and the resultant mixture was heated at
gentle reflux for 2 h. The hot solution was filtered through a
preheated pad of ethanol-moistened Celite, the pad was washed
with a little ethanol, and the filtrate (ca.1.8 L) was maintained at
-5 ºC for 2.5 d. The precipitate was collected, washed with 200
mL ethyl acetate:diethyl ether (1:1), and dried to give 49.6 g
(36%) of 8 as tan needles, mp 127-129 ºC, 91.9% chemically
4.2 Hz, 1H), 2.58 (dd, J = 4.5 Hz, 2.5 Hz, 1H); CIMS: m/z
(relative %) 170 (100, MH+), 114 (14).
Anal. Calcd. for C6H7N3O3: C, 42.61; H, 4.17; N, 24.84.
Found: C, 42.73; H, 4.09; N, 24.86.
(R)-2-Nitro-1-(2-oxiranylmethyl)-1H-imidazole was obtained
25
in a similar manner from (R)-8; mp 43-44 °C; [ꢀ]D +84.95°
[c1, methanol].
(R)-ꢁ-(1-Aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol
(1b).
pure by HPLC (system A1a).
The mother liquor was
concentrated to a solid residue that was suspended in 700 mL of
hot ethanol. The suspension was filtered hot, and then
concentrated to 400 ml. After cooling overnight, the solids were
collected as above to give 35.7 g (26%) of a second crop of 8,
mp 126-127 °C, 94.1% pure by HPLC. The mother liquor was
concentrated to a solid residue that was boiled in ethyl acetate.
The hot suspension was filtered through preheated moist Celite.
The filtrate was maintained at 25 ºC for 3 h, and then overnight
at 0-5 ºC. The resultant precipitate was collected as above to
provide 16.2 g (12%) of a third crop of 8, mp 122-126 ºC, 92.4%
pure by HPLC. An analytical sample was prepared by
dissolving a 9.9 g sample of second crop material in 195 mL of
boiling ethyl acetate. The solution was treated with charcoal,
filtered hot, and maintained at 25 ºC for 16 h, and then at 0-5 ºC
A
solution of 7.65 g (45 mmol) of (S)-2-nitro-1-(2-
oxiranylmethyl)-1H-imidazole (9) in 100 ml of 99:1 (v/v)
ethanol:triethylamine was treated with 3.9 g (90 mmol) of
aziridine. The solution was heated at reflux for 10 min, treated
with 2 mL of additional aziridine, and refluxed for another 20
min. The solution was concentrated to one-third volume and
placed in the refrigerator. The solids were collected, washed
with ice-cold ethanol:triethylamine (99:1), and dried at 40
°C/0.02 mm/2 h to give 7.74 g (81%) of 1b, mp 124-126 °C (lit.
[11] 119.5-121 ºC); Rf = 0.31 (dichloromethane : ethanol :
triethylamine, 85:14:0.5); 1b was 100% optically pure by HPLC
(system E4g); [ꢀ]D -26.9° [c0.95, chloroform] (lit. [11] -23.5°
[c1.15, chloroform]); The H NMR spectrum was identical to
that previously reported [11].
Anal. Calcd. for C8H12N4O3: C, 45.28; H, 5.70; N, 26.40.
Found: C, 45.46; H, 5.70; N, 26.27.
(S)-ꢁ-(1-Aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (1c)
was obtained in a similar manner from (R)-9; mp 123-125 °C
24
1
for 48 h. The resultant precipitate was processed as above to
25
give 7.45 g of 8, mp 128-129 ºC (lit. [11] 153-154 ºC); [ꢀ]D
-
1
+2.39° [c1, methanol]; H NMR (DMSO-d6): ꢀ 7.30 (s, 1H),
7.13 (s, 1H), 4.83 (dd, J = 13.6 Hz, 3.0 Hz, 1H), 4.66 (br s, 1H,
D2O exchangeable), 4.34 (dd, J = 13.6 Hz, 8.4 Hz, 1H), 4.24 –
4.12 (m, 1H), 3.66 – 3.50 (m, 2H); CIMS: m/z (relative %) 208
(40, 37Cl MH+), 206 (100, 35Cl MH+), 114 (24).
24
(lit. [11] 118.5-120 ºC); [ꢀ]D +26.6° [c0.90, chloroform] (lit.
[11] +21.4° [c0.98, chloroform]).
Anal. Calcd. for C6H8ClN3O3: C, 35.05; H, 3.92; N, 20.44;
Cl, 17.24. Found: C, 35.03; H, 3.87; N, 20.33; Cl, 17.09.
(R)-ꢀ-(Chloromethyl)-2-nitro-1H-imidazole-1-ethanol was
obtained in a similar manner from (R)-epichlorohydrin; mp 128-
(S)-3-[3-(2-Nitro-1H-imidazol-1-yl)-2-[(trimethylsilyl)oxy]prop-
yl]-2-oxazolidinone (10).
A vigorously stirring mixture of 40.3 mL (256 mmol) of 3-
trimethylsilyl-2-oxazolidinone (3b) and 274 mg (2.1 mmol) of
potassium trimethylsilanolate under a brisk stream of nitrogen
was heated to 95 °C. To the solution was added drop-wise a
25
129 °C; [ꢀ]D -2.57° [c1, methanol].
(S)-2-Nitro-1-(2-oxiranylmethyl)-1H-imidazole (9).
To a vigorously stirring ice-cold suspension of 100.5 g (489
mmol) of (S)-(ꢀ)-(chloromethyl)-2-nitro-1H-imidazole-1-
ethanol (8) in 1 L of dichloromethane was added slowly 1 L of
10% aqueous sodium hydroxide. The biphasic mixture was
stirred for 7.5 h at 0-5 ºC, and then diluted with 500 mL each of
chloroform and water. The phases were separated and the
aqueous phase was extracted 3 times with 200 mL portions of
chloroform. The combined organic phases were dried and
concentrated to leave 71.1 g of a yellow oil that crystallized
upon prolonged storage at 0-5 ºC. The crystals were collected
and dried at 0.05mm/25 ºC/8 h to give 69.1 g (84%) of 9, mp 42-
43 ºC, 98.4% chemically pure by HPLC (system B3d). An
analytical sample was prepared by passing a solution of 1.14 g
of 9 in 20 mL of ethyl acetate over a silica gel column, eluting
with 1:1 ethyl acetate:cyclohexane. Pure product fractions were
combined and concentrated to a solid that was dissolved in 5:2
hexanes:ethyl acetate. The solution was kept at -5 to 0 ºC for 6
h and the precipitate was collected, washed with diethyl ether,
and dried at 0.025 mm/25 ºC to give 681 mg of 9 as pale yellow
crystals, mp 43-44 ºC (lit. [11] 54-55 ºC); 99% chemically pure
solution of 36.15
g
(214 mmol) of (S)-2-nitro-1-(2-
oxiranylmethyl)-1H-imidazole (9) in 26 mL of tetrahydrofuran
followed by a 5 mL rinse. Addition took place over ca. 10 min
and at such a rate that the internal temperature never exceeded
105 °C. The flask was kept open during the entire addition of
epoxide and for 15 min afterwards. After heating at 95 °C for a
total of 1.5 h, 3.4 mL of additional 3b was added to the solution.
The mixture was heated for an additional 1.5 h and then
concentrated to leave an oil that was dissolved in 100 mL of 2:1
ethyl acetate:cyclohexane. The solution was purified by silica
gel chromatography, eluting with ca. 5 L of 2:1 ethyl
acetate:cyclohexane. Product fractions were combined and
concentrated to give 71.45 g of an oil that solidified on standing.
The solids were diluted with 200 mL of tert-butyl methyl ether,
and the suspension was refluxed for 45 min, cooled, and filtered.
The solids were collected, washed sparingly with tert-butyl
methyl ether and dried to leave 37.18 g (53%) of 10 as a light
yellow solid, mp 98-100 °C, 99% chemically pure (system C2c)
25
and 97% optically pure (system D4f) by HPLC; [ꢀ]D +15.4°
1
[c1, methanol]; H NMR (CDCl3): ꢀ 7.30 (d, J = 17 Hz, 1H),
25
and 100% optically pure (system D4e) by HPLC; [ꢀ]D -82.18º
7.15 (d, J = 22 Hz, 1H), 4.85 – 4.66 (m,1H), 4.52 – 4.40 (m,
2H), 4.35 – 4.20 (m, 2H), 3.94 – 3.66 (m, 2H), 3.58 – 3.28 (m,
2H), 0.20, 0.12, 0.05. 0.00 (s each, 9H); CIMS: m/z (relative %)
257 (25, MH+ - Me2SiCH2), 210 (100), 144 (59), 126 (63).
1
[c1, methanol]; H NMR (CDCl3): ꢀ 7.19 (d, J = 1 Hz, 1H),
7.18 (d, J = 1Hz, 1H), 5.07 (dd, J = 14.6 Hz, 2.4 Hz, 1H), 4.20
(dd, J = 14.6 Hz, 6.4 Hz, 1H), 3.47 – 3.38 (m, 1H), 2.94 (t, J =