5748 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 23
recrystallized from Hex/EtOAc (0.198 g, 26%): mp 110-112
Chien et al.
Hz), 5.82 (dd, 1 H, J ) 2.0 & 5.8 Hz), 4.84-4.73 (m, 3 H), 2.07
(s, 3 H, CH3); 13C & DEPT135 NMR (CDCl3, 125 MHz) δ 169.8,
164.5, 164.0, 151.6, 151.3, 134.8, 134.1, 131.3 (2 × CH), 129.4,
124.4 (CH), 124.1 (CH), 117.3, 114.5, 90.3 (CH), 79.8 (CH), 77.6
(CH), 77.3 (CH), 62.5 (CH2), 20.8 (CH3).
1
°C (Hex/EtOAc); H NMR (DMSO-d6, 360 MHz) δ 5.64 (d, 1
H, J ) 6.7 Hz, 1′-H), 5.63 (d, 1 H, J ) 6.2 Hz, 2′-OH), 5.30 (d,
1 H, J ) 5.2 Hz, 3′-OH), 4.90 (t, 1 H, J ) 5.7 Hz, 5′-OH), 4.51
(dd, 1 H, J ) 6.2 & 12.5 Hz), 4.02 (dt, 1 H, J ) 3.6 & 5.4 Hz),
3.84 (dt, 1 H, J ) 3.6 & 5.5 Hz), 3.59 (dd, 1 H, J ) 5.5 & 11.7
Hz, 5′-H), 3.52 (dd, 1 H, J ) 5.8 & 11.7 Hz, 5′-H). Anal. (C8H9-
Cl3N2O4) C, H, N.
2-Bromo-4,5-dichloro-1-(â-D-ribofuranosyl)imidazole
(7b). A mixture of 5b (0.39 g, 0.82 mmol) and methanolic
ammonia (40 mL) was stirred at room temperature for 12 h.
The excess MeOH and NH3 were removed under reduced
pressure. The resulting residue was purified by column chro-
matography (CHCl3/MeOH ) 95:5) followed by crystallization
from Hex/EtOAc to give 7b (0.17 g, 60%): mp 135-138 °C
(Hex/EtOAc); 1H NMR (DMSO-d6, 360 MHz) δ 5.64 (d, 1 H, J
) 6.7 Hz, 1′-H), 5.61 (d, 1 H, J ) 6.1 Hz, OH), 5.28 (d, 1 H, J
) 5.1 Hz, OH), 4.89 (t, 1 H, J ) 5.6 Hz, 5′-OH), 4.51 (dd, 1 H,
J ) 6.2 & 12.4 Hz), 4.01 (dd, 1 H, J ) 4.8 & 9.8 Hz), 3.82 (dd,
1 H, J ) 5.6 & 9.3 Hz), 3.62-3.49 (m, 2 H, 5′-H). Anal. (C8H9-
BrCl2N2O4) C, H, N.
2,4,5-Tribromo-1-(â-D-ribofuranosyl)imidazole (7c).
Method A. Compound 7c (0.293 g, 0.67 mmol, 61%) was
obtained from the deprotection of 5c (0.62 g, 1.10 mmol) with
Na2CO3 (0.35 g, 3.30 mmol, 3 equiv) in EtOH/H2O [50 mL, 9:1
(v/v)] as described for 7a and then purified by column
chromatography (CHCl3/MeOH ) 9:1): mp 162-165 °C (dec)
(Hex/EtOAc).
Method B. Compound 7c (1.54 g, 3.53 mmol, 76%) was
obtained from the deprotection of 6c (3.48 g, 4.64 mmol) with
28% NH4OH/MeOH/acetone [100 mL, 2:2:1 (v/v/v)] as de-
scribed for 7b, and then purified by column chromatography
[CHCl3/MeOH ) 95:5, Rf ) 0.3 (CHCl3/MeOH ) 9:1)]. An
analytical sample of 7c was obtained by recrystallization from
CH3CN: mp 165-167 °C (CH3CN).
2,4,5-Tribromo-1-[2-O-acetyl-3,5-di-O-(4-nitrobenzoyl)-
1-â-D-xylofuranosyl]imidazole (9c). Compound 9c (foam,
2.44 g, 3.14 mmol, 53%) was prepared from 2,4,5-tribromoimi-
dazole18 (3c, 2.00 g, 6.55 mmol, 1.1 equiv) using BSA (1.92
mL, 1.58 g, 7.75 mmol, 1.3 equiv), CH3CN (60 mL), and then
8 (3.17 g, 5.96 mmol) and TMSOTf (1.61 mL, 1.86 g, 8.34 mmol,
1.4 equiv) by the method described for 5a and purified by
column chromatography [Hex/EtOAc ) 6:4-5:5, Rf ) 0.40
(Hex/EtOAc ) 6:4)]. An analytical sample was obtained by
recrystallization from Hex/EtOAc: mp 111-114 °C (dec) (Hex/
EtOAc); 1H NMR (CDCl3, 500 MHz) δ 8.36 (d, 2 H, J ) 8.9
Hz, Ph), 8.30 (d, 2 H, J ) 8.9 Hz, Ph), 8.23 (d, 2 H, J ) 8.9 Hz,
Ph), 8.19 (d, 2 H, J ) 8.9 Hz, Ph), 6.01 (d, 1 H, J ) 6.1 Hz,
1′-H), 5.90 (dd, 1 H, J ) 2.3 & 5.5 Hz, 3′-H), 5.86 (dd, 1 H, J
) 2.3 & 6.1 Hz, 2′-H), 4.86-4.82 (m, 1 H, 4′-H), 4.81-4.77 (m,
2 H, 5′-H), 2.20 (s, 3 H, CH3); 13C & DEPT135 NMR (CDCl3,
125 MHz) δ 169.8, 164.5, 164.0, 151.5, 151.3, 134.8, 134.1,
131.3 (2 × CH), 124.4 (CH), 124.1 (CH), 120.4, 119.0, 104.1,
90.4 (CH), 79.9 (CH), 77.8 (CH), 77.2 (CH), 62.5 (CH2), 20.8
(CH3). Anal. (C24H17Br3N4O11·1/2EtOAc) C, H, N.
2,4,5-Trichloro-1-(â-D-xylofuranosyl)imidazole (10a).
Compound 10a (0.488 g, 1.61 mmol, 71%) was obtained from
the deprotection of 9a (1.45 g, 2.27 mmol) with methanolic
ammonia (23 mL) as described for 7b and then purified by
column chromatography [CHCl3/MeOH ) 95:5-93:7, Rf ) 0.33
(CHCl3/MeOH ) 9:1)]. An analytical sample of 10a was
obtained by recrystallization from EtOAc/MeOH: mp 187-
190 °C (dec) (EtOAc/MeOH); 1H NMR (DMSO-d6, 500 MHz) δ
5.87 (d, 1 H, J ) 5.4 Hz, OH), 5.53 (d, 1 H, J ) 6.4 Hz, 1′-H),
5.39 (d, 1 H, J ) 4.7 Hz, OH), 4.56 (t, 1 H, J ) 5.7 Hz, OH),
4.45 (dd, 1 H, J ) 5.4 & 10.7 Hz), 4.17 (dd, 1 H, J ) 4.6 &
10.7 Hz), 4.11 (dt, 1 H, J ) 4.3 & 6.7 Hz), 3.73-3.68 (m, 1 H,
5′-H), 3.66-3.61 (m, 1 H, 5′-H); 13C & DEPT135 NMR (DMSO-
d6, 500 MHz) δ 130.5, 125.8, 114.5, 91.3 (CH), 82.4 (CH), 79.6
(CH), 76.1 (CH), 60.9 (CH2). Anal. (C8H9Cl3N2O4) C, H, N.
Compound 7c: 1H NMR (DMSO-d6, 300 MHz) δ 5.71 (d, 1
H, J ) 4.7 Hz, 1′-H), 5.53 (d, 1 H, J ) 5.9 Hz, OH), 5.26 (d, 1
H, J ) 5.3 Hz, OH), 4.78 (t, 1 H, J ) 5.6 Hz, OH), 4.52 (dd, 1
H, J ) 5.0 & 10.2 Hz), 4.11 (dd, 1 H, J ) 4.8 & 9.5 Hz), 3.89
(dd, 1 H, J ) 4.9 & 9.7 Hz), 3.37-3.50 (m, 2 H, 5′-H); 13C NMR
(DMSO-d6, 75 MHz) δ 129.9, 120.0, 101.0, 92.4, 86.8, 74.0, 71.3,
62.7; MS (CI, CH4) m/z 133 (100), 226 (30), 306 (45), 408 (15),
435 (5) (M+ + 1); HRMS calcd for C8H10Br3N2O4 (M + 1)
434.8191, found 434.8176. Anal. (C8H9Br3N2O4) C, H, N.
2,4,5-Trichloro-1-[2-O-acetyl-3,5-di-O-(4-nitrobenzoyl)-
1-â-D-xylofuranosyl]imidazole (9a). Compound 9a (oil, 1.46
g, 2.27 mmol, 61%) was prepared from 2,4,5-trichloroimida-
zole18 (3a, 0.634 g, 3.70 mmol) using BSA (1.19 mL, 0.978 g,
4.81 mmol, 1.3 equiv), CH3CN (40 mL), and then 1,2-di-O-
acetyl-3,5-di-O-(4-nitrobenzoyl)-1-â-D-xylofuranose21 (8, 1.97 g,
3.70 mmol, 1.0 equiv) and TMSOTf (1.07 mL, 1.23 g, 5.55
mmol, 1.5 equiv) by the method described for 5a and purified
by column chromatography [Hex/EtOAc ) 7:3-5:5, Rf ) 0.37
(Hex/EtOAc ) 65:35)]: 1H NMR (CDCl3, 500 MHz) δ 8.37 (d,
2 H, J ) 8.8 Hz, Ph), 8.30 (d, 2 H, J ) 8.8 Hz, Ph), 8.22 (d, 2
H, J ) 8.9 Hz, Ph), 8.19 (d, 2 H, J ) 8.9 Hz, Ph), 5.91 (d, 1 H,
J ) 5.6 Hz, 1′-H), 5.88 (dd, 1 H, J ) 3.4 & 6.3 Hz), 5.81 (dd,
1 H, J ) 1.9 & 5.6 Hz), 4.83-4.72 (m, 3 H), 2.21 (s, 3 H, CH3);
13C & DEPT135 NMR (CDCl3, 125 MHz) δ 169.8, 164.5, 163.9,
151.6, 151.3, 134.8, 134.0, 131.3 (2 × CH), 130.1, 127.8, 124.4
(CH), 124.1 (CH), 113.9, 89.3 (CH), 79.8 (CH), 77.8 (CH), 77.4
(CH), 62.5 (CH2), 20.8 (CH3).
2-Bromo-4,5-dichloro-1-[2-O-acetyl-3,5-di-O-(4-nitroben-
zoyl)-1-â-D-xylofuranosyl]imidazole (9b). Compound 9b
(oil, 4.81 g, 6.99 mmol, 89%) was prepared from 2-bromo-4,5-
dichloroimidazole18 (3b, 1.70 g, 7.89 mmol) using BSA (2.55
mL, 2.09 g, 10.25 mmol, 1.3 equiv), CH3CN (100 mL), and then
8 (5.45 g, 10.25 mmol, 1.3 equiv) and TMSOTf (2.44 mL, 2.81
g, 12.62 mmol, 1.6 equiv) by the method described for 5a and
purified by column chromatography [Hex/EtOAc ) 7:3-5:5,
Rf ) 0.23 (Hex/EtOAc ) 7:3)]: 1H NMR (CDCl3, 500 MHz) δ
8.37 (d, 2 H, J ) 8.8 Hz, Ph), 8.31 (d, 2 H, J ) 8.8 Hz, Ph),
8.22 (d, 2 H, J ) 8.7 Hz, Ph), 8.19 (d, 2 H, J ) 8.7 Hz, Ph),
5.95 (d, 1 H, J ) 5.8 Hz, 1′-H), 5.89 (dd, 1 H, J ) 1.8 & 5.0
2-Bromo-4,5-dichloro-1-(â-d-xylofuranosyl)imidazole
(10b). Compound 10b (0.49 g, 1.41 mmol, 63%) was obtained
from the deprotection of 9b (1.53 g, 2.22 mmol) with metha-
nolic ammonia (30 mL) as described for 7b, and then purified
by column chromatography (CHCl3/MeOH ) 95:5-93:7, Rf )
0.20 (CHCl3/MeOH ) 93:7)). An analytical sample of 10b was
obtained by recrystallization from MeOH. mp 185-187 °C (dec)
1
(MeOH). H NMR (DMSO-d6, 500 MHz) δ 5.86 (d, 1 H, J )
5.6 Hz, OH), 5.53 (d, 1 H, J ) 6.7 Hz, 1′-H), 5.39 (d, 1 H, J )
4.8 Hz, OH), 4.55 (t, 1 H, J ) 5.6 Hz, 5′-OH), 4.48 (dd, 1 H, J
) 5.6 Hz, 11.0 Hz), 4.18 (dt, 1 H, J ) 4.7 & 6.4 Hz), 4.11 (dt,
1 H, J ) 4.1 & 6.9 Hz), 3.73-3.68 (m, 1 H, 5′-H), 3.66-3.62
(m, 1 H, 5′-H); 13C & DEPT135 NMR (DMSO-d6, 75 MHz) δ
127.3, 119.0, 114.8, 92.1 (CH), 82.2 (CH), 79.5 (CH), 76.2 (CH),
61.0 (CH2). Anal. (C8H9BrCl2N2O4) C, H, N.
2,4,5-Tribromo-1-(â-D-xylofuranosyl)imidazole (10c).
Compound 10c (0.794 g, 1.82 mmol, 58%) was obtained from
the deprotection of 9c (2.44 g, 3.14 mmol) with methanolic
ammonia (31 mL) as described for 7b and then purified by
column chromatography [CHCl3/MeOH ) 93:7-9:1, Rf ) 0.19
(CHCl3/MeOH ) 9:1)]. An analytical sample of 10c was
obtained by recrystallization from MeOH: mp 186-188 °C
(dec) (MeOH); 1H NMR (DMSO-d6, 500 MHz) δ 5.84 (d, 1 H, J
) 5.6 Hz, OH), 5.55 (d, 1 H, J ) 7.0 Hz, 1′-H), 5.41 (d, 1 H, J
) 4.7 Hz, OH), 4.56-4.52 (m, 2 H, OH & CH), 4.20 (dd, 1 H,
J ) 4.7 & 11.2 Hz), 4.12 (dt, 1 H, J ) 4.5 & 6.8 Hz), 3.74-3.69
(m, 2 H, 5′-H); 13C & DEPT135 NMR (DMSO-d6, 125 MHz) δ
120.5, 119.1, 105.5, 92.1 (CH), 82.0 (CH), 79.6 (CH), 76.2 (CH),
61.1 (CH2); MS (EI, 70 eV) m/z 302 (37), 304 (100), 306 (97),
308 (35), 434 (5) (M+), 436 (25) (M + 2), 438 (24) (M + 4), 440
(4) (M + 6); HRMS calcd for C8H9Br3N2O4 (M+): 433.8112,
found 433.8114. Anal. (C8H9Br3N2O4) C, H, N.
2-Bromo-4,5-dichloro-1-(2,3,5-tri-O-benzyl-r-D-arabino-
furanosyl)imidazole (12b-r) and 2-Bromo-4,5-dichloro-