1676 J . Org. Chem., Vol. 67, No. 5, 2002
Kazuta et al.
m/z 379 ((M + H)+); HR-MS (FAB) calcd for C26H23N2O
379.1810, found 379.1780 ((M + H)+). Anal. Calcd for
(125 MHz, CD3OD) δ 10.70 (C-3), 11.66 (C-1), 16.85 (C-2), 40.93
(C-1′), 118.33 (C-5′′), 132.43 (C-4′′), 135.40 (C-2′′); LR-MS (FAB)
m/z 138 ((M + H)+); HR-MS (FAB) calcd for C7H12N3 138.1031,
found 138.0996 ((M + H)+). Anal. Calcd for C7H13Cl2N3‚H2O
C, 36.86; H, 6.63; N, 18.42. Found: C, 36.66; H, 6.82; N, 18.25.
C
26H22N2O: C, 82.51; H, 5.86; N, 7.40. Found: C, 82.43; H,
6.02; N, 7.22.
(1R,2S)-2-(Ben zyloxyim in o)m eth yl-1-(1-tr iph en ylm eth -
yl-1H-im id a zol-4-yl)cyclop r op a n e (23). A mixture of 22
(378 mg, 1.00 mmol), O-benzylhydroxylamine hydrochloride
(319 mg, 2.00 mmol), and molecular sieves 4A (300 mg) in THF
(5 mL) was stirred at room temperature for 12 h. The mixture
was filtered through Florisil, and the filtrate was evaporated.
The residue was purified by short column chromatography
(silica gel; AcOEt/hexane, 1:1) to give 23 as white crystals (E/Z
mixture; 425 mg, 88%). The E/Z mixture (242 mg, 0.5 mmol)
was separated further by column chromatography (silica gel;
AcOEt/hexane, 1:1) to give the (E)-isomer (118 mg) and the
(Z)-isomer (94 mg). Data for (E)-23: mp (hexane/AcOEt) 150-
(1R,2R)-2-(ter t-Bu tyld ip h en ylsilyloxy)m eth yl-1-(1-tr i-
p h en ylm eth yl-1H-im id a zol-4-yl)cyclop r op a n e (25). Com-
pound 25 was prepared from 8 (1.86 g, 5.50 mmol) as described
for 20. After purification by column chromatography (silica gel;
AcOEt/hexane, 1:1, and then MeOH/CHCl3,1:19), 25 was
obtained as a solid (1.90 g, 56%): mp (hexane/AcOEt) 145-
147 °C; [R]24 -38.3 (c 0.51, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 0.76 (1 H, m), 0.92 (1 H, m), 1.03 (9 H, s), 1.45 (1 H,
m), 1.65 (1 H, m), 3.69 (2 H, d, J ) 7.1 Hz), 6.50 (1 H, d, J )
0.9 Hz), 7.13-7.15 (6 H, m), 7.27 (1 H, s), 7.31-7.34 (13 H,
m), 7.36-7.39 (2 H, m), 7.65 (4 H, d, J ) 7.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 11.64, 14.36, 19.24, 22.76, 26.87, 66.19,
75.05, 116.90, 127.53, 127.90, 127.93, 129.46, 129.80, 134.00,
134.05, 135.61, 138.13, 142.48, 142,57; LR-MS (FAB) m/z 641
((M + Na)+); HR-MS (FAB) calcd for C42H42N2NaOSi 641.2964,
found 641.2977 ((M + Na)+). Anal. Calcd for C42H42N2OSi: C,
81.51; H, 6.84; N, 4.53. Found: C, 81.54; H, 6.92; N, 4.36.
151 °C; [R]24 +42.4 (c 1.60, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 1.28-1.36 (2 H, m), 1.94 (1 H, m), 2.33 (1 H, m),
5.02 (2 H, s), 6.60 (1 H, s), 7.09-7.12 (6 H, m), 7.16 (1 H, d, J
) 8.8 Hz), 7.26-7.34 (15 H, m); 13C NMR (125 MHz, CDCl3) δ
11.17, 16.77, 18.77, 75.20, 75.44, 119.41 (C-5”), 127.65, 127.97,
128.01, 128.11, 128.29, 129.72, 137.86, 138.21, 138.34, 142.40,
152.64; LR-MS (FAB) m/z 484 ((M + H)+); HR-MS (FAB) calcd
for C33H30N3O 484.2388, found 484.2387 ((M + H)+). Anal.
Calcd for C33H29N3O: C, 81.96; H, 6.04; N, 8.69. Found: C,
81.88; H, 6.02; N, 8.42. Data for (Z)-23: mp (hexane/AcOEt)
(1R,2R)-2-Hyd r oxym eth yl-1-(1-tr ip h en ylm eth yl-1H-im -
id a zol-4-yl)cyclop r op a n e (26). Compound 26 was prepared
from 25 (743 mg, 1.20 mmol) as described for 21. After
purification by column chromatography (silica gel; AcOEt/
hexane, 1:1, and then MeOH/CHCl3, 1:19), 26 was obtained
as white crystals (447 mg, 100%): mp (hexane/AcOEt) 146-
148-151 °C; [R]24 +98.5 (c 1.15, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 1.30-1.40 (2 H, m), 2.36 (1 H, m), 2.56 (1 H, m),
5.09 (2 H, s), 6.40 (1 H, d, J ) 8.8 Hz), 6.64 (1 H, d, J ) 0.8
Hz), 7.10-7.13 (6 H, m), 7.30-7.37 (15 H, m); 13C NMR (125
MHz, CDCl3) δ 12.01, 15.29, 17.33, 75.19, 75.63, 119.42, 127.58,
127.95, 128.00, 128.34, 128.43, 129.70, 137.42, 138.07, 138.35,
142.39, 152.26; LR-MS (FAB) m/z 484 ((M + H)+); HR-MS
(FAB) calcd for C33H30N3O 484.2388, found 484.2366 ((M +
H)+). Anal. Calcd for C33H29N3O: C, 81.96; H, 6.04; N, 8.69.
Found: C, 81.88; H, 6.01; N, 8.52.
147 °C; [R]24 -34.6 (c 1.13, MeOH); 1H NMR (500 MHz,
D
CDCl3: CD3OD, 10:1) δ 0.72 (1 H, m), 0.86 (1 H, m), 1.29 (1
H, m), 1.70 (1 H, m), 3.29 (1 H, dd, J ) 8.1, 11.4 Hz), 3.69 (1
H, dd, J ) 5.5, 11.4 Hz), 6.49 (1 H, d, J ) 0.7 Hz), 7.09-7.12
(6 H, m), 7.30 (1 H, d, J ) 1.1 Hz) 7.32-7.35 (9 H, m); 13C
NMR (125 MHz; CDCl3/CD3OD, 10:1) δ 10.35, 15.01, 23.32,
65.86, 75.29, 116.90, 127.95, 127.99, 129.61, 137.84, 141.95,
142,12; LR-MS (EI) m/z 380 (M+); HR-MS (EI) calcd for
(1S,2R)-2-Am in om eth yl-1-(1-tr ip h en ylm eth yl-1H-im i-
d a zol-4-yl)cyclop r op a n e (24). Red u ctive Am in a tion of 22.
A suspension of 22 (38 mg, 0.10 mmol), AcONH4 (77 mg, 1.0
mmol), and molecular sieves 3A (30 mg) in MeOH (3 mL) was
stirred at room temperature for 1 h, and then NaBH3CN (6.3
mg, 0.1 mmol) was added. The resulting mixture was stirred
at room temperature for 12 h, and then the solvent was
evaporated. The residue was partitioned between CHCl3 and
H2O, and the organic layer was washed with brine, dried (Na2-
SO4), and evaporated. The residue was purified by column
chromatography (silica gel; MeOH/CHCl3, 1:19 and then 1:4)
to give 24 as white crystals (13 mg, 32%).
Red u ction of 23. To a solution of 23 (242 mg, 0.50 mmol)
in THF (5 mL) was added LiAlH4 (1.0 M in THF, 1.5 mL), and
the mixture was stirred at room temperature for 1 h. After
the reaction was quenched with MeOH, the solvent was
evaporated, and the residue was partitioned between CHCl3
and H2O. The organic layer was washed with brine, dried (Na2-
SO4), and evaporated. The residue was purified by column
chromatography (silica gel; MeOH/CHCl3, 1:19 and then 1:4)
to give 24 as white crystals (187 mg, 98%): mp (EtOH/Et2O)
110-112 °C; [R]24D +45.97 (c 0.52, CHCl3); 1H NMR (500 MHz,
CD3OD) δ 0.68 (1 H, m), 1.04 (1 H, m), 1.29 (1 H, m), 2.06 (1
H, m), 2.65 (2 H, m), 6.70 (1 H, s), 7.03-7.05 (6 H, m), 7.28-
7.32 (10 H, m); 13C NMR (125 MHz, CD3OD) δ 10.49, 14.90,
16.02, 41.33, 76.99, 122.00, 129.31, 129.42, 130.79, 139.37,
139.57, 143.56; LR-MS (FAB) m/z 380 ((M + H)+); HR-MS
(FAB) calcd for C26H26N3 380.1889, found 380.2152 ((M + H)+).
Anal. Calcd for C26H25N3‚5H2O: C, 66.50; H, 7.51; N, 8.95.
Found: C, 66.58; H, 7.53; N, 8.88.
C
C
26H24N2O 380.1889, found 380.1883 (M+). Anal. Calcd for
26H24N2O‚H2O: C, 78.36; H, 6.58; N, 7.03. Found: C, 78.58;
H, 6.53; N, 7.04.
(1R,2R)-2-F or m yl-1-(1-tr ip h en ylm eth yl-1H-im id a zol-4-
yl)cyclop r op a n e (27). Compound 27 was prepared from 26
(190 mg, 0.50 mmol) as described for 22. After purification by
column chromatography (silica gel; AcOEt/hexane, 1:2), 27 was
obtained as white crystals (155 mg, 82%): mp (hexane/AcOEt)
162-163 °C; [R]24D -105.7 (c 1.15, MeOH); 1H NMR (500 MHz,
CDCl3) δ 1.59-1.66 (2 H, m), 2.30 (1 H, m), 2.50 (1 H, m),
6.67 (1 H, s), 7.11-7.15 (6 H, m), 7.31 (1 H, d, J ) 0.9 Hz),
7.32-7.34 (9 H, m), 9.27 (1 H, d, J ) 4.8 Hz); 13C NMR (125
MHz, CDCl3) δ 15.32, 20.74, 32.36, 75.26, 118.19, 128.02,
128.18, 129.68, 138.58, 138.76, 142.27, 200.09; LR-MS (FAB)
m/z 401 ((M + Na)+); HR-MS (FAB) calcd for C26H22N2NaO
401.1630, found 401.1634 ((M + Na)+). Anal. Calcd for
C
26H22N2O: C, 82.51; H, 5.86; N, 7.40. Found: C, 82.66; H,
6.04; N, 7.16.
(1R,2R)-2-(Ben zyloxyim in o)m eth yl-1-(1-tr iph en ylm eth -
yl-1H-im id a zol-4-yl)cyclop r op a n e (28). Compound 28 was
prepared from 27 (378 mg, 1.00 mmol) as described for 23.
After purification by short column chromatography (silica gel;
AcOEt/hexane, 1:1), the E/Z mixture of 28 was obtained as
white crystals (463 mg, 96%). The E/Z mixture (242 mg, 0.50
mmol) was separated further by column chromatography
(silica gel; AcOEt/hexane, 1:1) to give the (E)-isomer (129 mg)
and the (Z)-isomer (85 mg). Data for (E)-28: mp (hexane/
AcOEt) 162-163 °C; [R]24D -76.2 (c 1.20, CHCl3); 1H NMR (500
MHz, CDCl3) δ 1.15 (1 H, m), 1.39 (1 H, m), 1.97 (1 H, m),
2.05 (1 H, m), 5.02 (2 H, s), 6.59 (1 H, d, J ) 1.2 Hz), 7.10-
7.15 (7 H, m), 7.26-7.36 (15 H, m); 13C NMR (125 MHz, CDCl3)
δ 13.88, 18.13, 20.68, 75.13, 75.54, 117.43, 127.74, 127.95,
128.22, 128.32, 128.41, 129.72, 137.40, 138.39, 140.23, 142.40,
153.08; LR-MS (FAB) m/z 484 ((M + H)+); HR-MS (FAB) calcd
(1S,2R)-2-Am in om eth yl-1-(1H-im id a zol-4-yl)cyclop r o-
p a n e Dih yd r och lor id e (1). A solution of 24 (20 mg, 53 µmol),
HCl (4.0 M in AcOEt, 1.5 mL), and MeOH (0.5 mL) was heated
under reflux for 2 h. The solvent was evaporated, and then
the residue was treated with Et2O to give a white amorphous
C
33H30N3O 484.2388, found 484.2383 ((M + H)+). Anal. Calcd
solid of 1 as a dihydrochloride (110 mg, 95%): [R]24 -24.7 (c
for C33H29N3O: C, 81.96; H, 6.04; N, 8.69. Found: C, 81.66;
D
0.12, MeOH); 1H NMR (500 MHz, CD3OD) δ 0.98 (1 H, m,
H-3a), 1.34 (1 H, m, H-3b), 1.54 (1 H, m, H-2), 2.22-2.30 (2
H, m, H-1 and H-1′a), 3.05 (1 H, dd, H-1′b, J 1′b,2 ) 7.0, J 1′b,1′a
) 12.0 Hz), 7.31 (1 H, s, H-5′′), 8.75 (1 H, s, H-2′′); 13C NMR
H, 6.05; N, 8.63. Data for (Z)-28: mp (hexane/AcOEt) 159-
160 °C; [R]24 +80.3 (c 0.98, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 1.10 (1 H, m), 1.48 (1 H, m), 2.07 (1 H, m), 2.63 (1 H,
m), 5.09 (2 H, s), 6.11 (1 H, d, J ) 7.9 Hz), 6.61 (1 H, d, J )