2220
P.D. Patel et al. / European Journal of Medicinal Chemistry 45 (2010) 2214–2222
Quantum-filtered gradient COSY spectra were acquired with
a spectral width of 2400–2800 Hz using 8 K time-domain data
points in F2, 512 data points in F1, and one scan per increment.
Phase-sensitive 2D-NOESY spectra were acquired with spectral
widths similar to the COSY spectra, 2 K F2 data points, 128 F1 data
points, 4 scans per increment, and processed using a shifted-sine bell
in F2, modest resolution enhancement (see above) or a shifted-sine
bell and forward linear prediction in F1. Mass spectra were recorded
on a Hewlett-Packard GC-MS GCD system. The C, H, and N analyses
were performed by Atlantic Microlabs, Inc., (Norcross, GA) and the
observed values were within ꢁ0.4% of calculated values.
as a yellow solid in 44.8% yield. Rf ¼ 0.51 (95:5 EtOAc:MeOH); mp
170–175 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
) 8.93 (1H, d, J ¼ 2.1 Hz,
d
Bt-4), 8.38 (1H, dd, J ¼ 9.2, 2.1 Hz, Bt-6), 8.33 (1H, s, Tr-5), 7.99 (1H,
d, J ¼ 9.2 Hz, Bt-7), 7.84 (1H, s, Tr-3), 7.27 (1H, ddd, J ¼ 11.9, 9.1,
2.5 Hz, Ph-3), 6.96 (1H, app q, J ¼ 8.3, Ph-6), 6.78 (1H, td, J ¼ 8.5,
2.6 Hz, Ph-5), 6.53 (1H, s, OH), 5.40 (1H, d, J ¼ 14.8 Hz, CH2-Bt), 5.13
(1H, d, J ¼ 14.8 Hz, CH2-Bt), 4.91 (1H, d, J ¼ 14.5 Hz, CH2-Tr), 4.75
(1H, d, J ¼ 14.5 Hz, CH2-Tr); EI MS m/z 401 (Mþ), 224, 177, 141, 82.
Anal. (C17H13N7O3F2) C, H, N.
5.1.2.5. 2-(2,4-Difluorophenyl)-1-(6-nitro-1H-benzo[d][1,2,3]triazol-
1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3c0). This was obtained
as a yellow solid in 11.1% yield. Rf ¼ 0.64 (95:5 EtOAc:MeOH); mp
5.1.2. General procedure for the synthesis of derivatives of 1-(1H-
Benzo[d][1,2,3]triazol-1-yl)-2-(2, 4-difluorophenyl)-3-(1H-1,2,4-
triazol-1-yl)propan-2-ol (3a–3h; 3b0–3f0)
178–180 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
d) 8.86 (1H, d, J ¼ 1.9 Hz,
Bt-7), 8.32 (1H, s, Tr-5), 8.21 (1H, d, J ¼ 9.1 Hz, Bt-4), 8.16 (1H, dd,
J ¼ 9.1, 2.1 Hz, Bt-5), 7.82 (1H, s, Tr-3), 7.28 (1H, ddd, J ¼ 12.0, 9.2,
2.6 Hz, Ph-3), 6.92 (1H, app q, J ¼ 8.3 Hz, Ph-6), 6.75 (1H, td, J ¼ 8.5,
2.5 Hz, Ph-5), 6.58 (1H, s, OH), 5.47 (1H, d, J ¼ 14.8 Hz, CH2-Bt), 5.21
(1H, d, J ¼ 14.8 Hz, CH2-Bt), 4.94 (1H, d, J ¼ 14.5 Hz, CH2-Tr), 4.74
(1H, d, J ¼ 14.5 Hz, CH2-Tr); EI MS m/z 401 (Mþ), 224, 177, 141, 82.
Anal. (C17H13N7O3F2) C, H, N.
To a solution of (un)substituted benzotriazoles (2a–h, 1.0 mmol)
in DMF (2 mL) potassium carbonate (3 mmol) was added. A solu-
tion of oxirane 1 (1.5 mmol) in DMF (2 mL) was added drop wise
into the reaction mixture at 40 ꢂC, and then the reaction mixture
was stirred at 80 ꢂC for 4–5 h. The reaction mixture was cooled to
room temperature and was poured into chilled water (20 mL) and
extracted with ethyl acetate (3 ꢃ 20 mL). The combined organic
layer was washed with brine (10 mL), dried over anhydrous Na2SO4
and filtered. The filtrate was concentrated under reduced pressure
to get a mixture of isomers 3a–3h and 3b0–3f0. The isomers were
separated using flash silica gel column chromatography using
EtOAc/MeOH (95:5) as eluent.
5.1.2.6. 2-(2,4-Difluorophenyl)-1-(5-chloro-1H-benzo[d][1,2,3]-
triazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3d). This was
obtained as a white solid in 34.6% yield. Rf ¼ 0.55 (95:5 EtOAc:-
MeOH); mp 210–213 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
d) 8.32 (1H,
s, Tr-5), 8.09 (1H, d, J ¼ 1.4 Hz, Bt-4), 7.82 (1H, d, J ¼ 8.6 Hz, Bt-7),
7.78 (1H, s, Tr-3), 7.55 (1H, dd, J ¼ 8.9, 1.8 Hz, Bt-6), 7.27 (1H, ddd,
J ¼ 12.1, 9.1, 2.4 Hz, Ph-3), 6.98 (1H, app q, J ¼ 8.2 Hz, Ph-6), 6.80
(1H, td, J ¼ 8.3, 2.4 Hz, Ph-5), 6.46 (1H, s, OH), 5.30 (1H, d,
J ¼ 14.9 Hz, CH2-Bt), 5.03 (1H, d, J ¼ 14.8 Hz, CH2-Bt), 4.89 (1H, d,
J ¼ 14.4 Hz, CH2-Tr), 4.70 (1H, d, J ¼ 14.5 Hz, CH2-Tr); EI MS m/z 390
(Mþ), 224, 166, 141, 82. Anal. (C17H13N6O1F2Cl1) C, H, N.
5.1.2.1. 2-(2,4-Difluorophenyl)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-
(1H-1,2,4-triazol-1-yl)propan-2-ol (3a). This was obtained as
a white solid in 49.6% yield. Rf ¼ 0.51 (95:5 EtOAc:MeOH); mp 168–
171 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
d): 8.32 (1H, s, Tr-5), 7.95 (1H,
d, J ¼ 8.0 Hz, Bt-4), 7.81 (1H, s, Tr-3), 7.74 (1H, d, J ¼ 8.4 Hz, Bt-7),
7.49 (1H, t, J ¼ 7.2 Hz, Bt-5), 7.34 (1H, t, J ¼ 7.2 Hz, Bt-6), 7.25 (1H,
ddd, J ¼ 11.9, 9.3, 2.6 Hz, Ph-3), 7.01 (1H, app q, J ¼ 7.9 Hz, Ph-6),
6.76 (1H, td, J ¼ 8.7, 2.4 Hz, Ph-5), 6.41 (1H, s, OH), 5.25 (1H, d,
J ¼ 14.9 Hz, CH2-Bt), 5.04 (1H, d, J ¼ 15.0 Hz, CH2-Bt), 4.88 (1H, d,
J ¼ 14.4 Hz, CH2-Tr), 4.66 (1H, d, J ¼ 14.4 Hz, CH2-Tr); EI MS m/z 357
(M þ Hþ), 224, 141, 132, 82. Anal. (C17H14N6O1F2) C, H, N.
5.1.2.7. 2-(2,4-Difluorophenyl)-1-(6-chloro-1H-benzo[d][1,2,3]-
triazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3d0). This was
obtained as a white solid in 14.8% yield. Rf ¼ 0.64 (95:5 EtOAc:-
MeOH); mp 215–218 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
d) 8.32 (1H,
s, Tr-5), 7.91 (1H, d, J ¼ 1.5 Hz, Bt-7), 7.82 (1H, d, J ¼ 8.6 Hz, Bt-4),
7.78 (1H, s, Tr-3), 7.55 (1H, dd, J ¼ 8.8, 1.8 Hz, Bt-5), 7.27 (1H, ddd,
J ¼ 12.1, 9.1, 2.4 Hz, Ph-3), 6.98 (1H, app q, J ¼ 8.2 Hz, Ph-6), 6.80
(1H, td, J ¼ 8.3, 2.4 Hz, Ph-5), 6.48 (1H, s, OH), 5.34 (1H, d,
J ¼ 14.9 Hz, CH2-Bt), 5.09 (1H, d, J ¼ 14.8 Hz, CH2-Bt), 4.90 (1H, d,
J ¼ 14.5 Hz, CH2-Tr), 4.68 (1H, d, J ¼ 14.6 Hz, CH2-Tr); EI MS m/z 390
(Mþ), 224, 166, 141, 82. Anal. (C17H13N6O1F2Cl1) C, H, N.
5.1.2.2. 2-(2,4-Difluorophenyl)-1-(5,6-dimethyl-1H-benzo[d][1,2,3]-
triazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3b). This was
obtained as a white solid in 39.5% yield. Rf ¼ 0.55 (95:5 EtOAc:-
MeOH); mp 212–216 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
d) 8.31 (1H,
s, Tr-5), 7.80 (1H, s, Tr-3), 7.68 (1H, s, Bt-4), 7.48 (1H, s, Bt-7), 7.26
(1H, ddd, J ¼ 11.9, 9.3, 2.5 Hz, Ph-3), 7.00 (1H, app q, J ¼ 8.3 Hz, Ph-
6), 6.78 (1H, td, J ¼ 8.5, 2.4 Hz, Ph-5), 6.36 (1H, s, OH), 5.19 (1H, d,
J ¼ 14.7 Hz, CH2-Bt), 4.96 (1H, d, J ¼ 14.7 Hz, CH2-Bt), 4.90 (1H, d,
J ¼ 14.5 Hz, CH2-Tr), 4.65 (1H, d, J ¼ 14.5 Hz, CH2-Tr), 2.35 (3H, s,
CH3-Bt-6), 2.33 (3H, s, CH3-Bt-5); EI MS m/z 385 (M þ Hþ), 224, 161,
141, 82. Anal. (C19H18N6O1F2) C, H, N.
5.1.2.8. 2-(2,4-Difluorophenyl)-1-(5-methyl-1H-benzo[d][1,2,3]-
triazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3e). This was
obtained as a white solid in 43.6% yield. Rf ¼ 0.58 (95:5/EtOAc:-
MeOH); mp 198–200 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
d) 8.32 (1H,
s, Tr-5), 7.81 (1H, s, Tr-3), 7.71 (1H, d, J ¼ 9.0 Hz, Bt-7), 7.62 (1H, d,
J ¼ 8.9 Hz, Bt-6), 7.49 (1H, s, Bt-4), 7.26 (1H, ddd, J ¼ 12.0, 9.3, 2.6 Hz,
Ph-3), 7.01 (1H, app q, J ¼ 8.3 Hz, Ph-6), 6.78 (1H, td, J ¼ 8.4, 2.4 Hz,
Ph-5), 6.41 (1H, s, OH), 5.21 (1H, d, J ¼ 14.5 Hz, CH2-Bt), 4.99 (1H, d,
J ¼ 14.6 Hz, CH2-Bt), 4.90 (1H, d, J ¼ 14.7 Hz, CH2-Tr), 4.67 (1H, d,
J ¼ 14.6 Hz, CH2-Tr), 2.45 (3H, s, CH3-Bt-5); EI MS m/z 371 (M þ Hþ),
224, 147, 113, 82. Anal. (C18H16N6O1F2) C, H, N.
5.1.2.3. 2-(2,4-Difluorophenyl)-1-(5,6-dimethyl-2H-benzo[d][1,2,3]-
triazol-2-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3b0). This was
obtained as a white solid in 26.3% yield. Rf ¼ 0.68 (95:5 EtOAc:-
MeOH); mp 136–140 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
d) 8.28 (1H,
s, Tr-5), 7.75 (1H, s, Tr-3), 7.57 (2H, s, Bt-4/7), 7.20 (1H, ddd, J ¼ 12.1,
9.3, 2.6 Hz, Ph-3), 7.14 (1H, app q, J ¼ 8.3 Hz, Ph-6), 6.82 (1H, td,
J ¼ 8.5, 2.5 Hz, Ph-5), 6.40 (1H, s, OH), 5.19 (1H, d, J ¼ 13.8 Hz, CH2-
Bt), 5.05 (1H, d, J ¼ 13.8 Hz, CH2-Bt), 4.87 (1H, d, J ¼ 14.4 Hz, CH2-
Tr), 4.64 (1H, d, J ¼ 14.4 Hz, CH2-Tr), 2.32 (6H, s, CH3-Bt-5/6); EI MS
m/z 384 (Mþ), 224, 161, 141, 82. Anal. (C19H18N6O1 F2) C, H, N.
5.1.2.9. 2-(2,4-Difluorophenyl)-1-(6-methyl-1H-benzo[d][1,2,3]-
triazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3e0). This was
obtained as a white solid in 11.3% yield. Rf ¼ 0.66 (95:5 EtOAc:-
MeOH); mp 202–204 ꢂC; 1H-NMR (400 MHz, DMSO-d6,
d) 8.30 (1H,
s, Tr-5), 7.82 (1H, s, Tr-3), 7.75 (1H, d, J ¼ 9.0 Hz, Bt-4), 7.60 (1H, d,
J ¼ 8.9 Hz, Bt-5), 7.49 (1H, s, Bt-7), 7.26 (1H, ddd, J ¼ 12.0, 9.2, 2.6 Hz,
Ph-3), 7.00 (1H, app q, J ¼ 8.3 Hz, Ph-6), 6.79 (1H, td, J ¼ 8.4, 2.4 Hz,
5.1.2.4. 2-(2,4-Difluorophenyl)-1-(5-nitro-1H-benzo[d][1,2,3]triazol-
1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3c). This was obtained