Imidazole- and Benzimidazole-Based Inhibitors of the Kinase IspE
40 mL). The combined organic phases were washed with water (3ϫ
100 mL) and brine (100 mL), dried with MgSO4, filtered, and con-
centrated. CC (SiO2; pentane/EtOAc, 5:1 Ǟ 2:1) gave (Ϯ)-27
IR (ATR): ν = 3307 (w), 2932 (m), 2856 (w), 2123 (w), 1504 (w),
˜
1450 (w), 1385 (m), 1378 (w), 1271 (m), 1165 (s), 1120 (s), 1100 (s),
1018 (w), 971 (w), 891 (w), 869 (w), 838 (w), 806 (w), 698 (m) cm–1.
(440 mg, 85 %) as an off-white solid. Rf = 0.44 (SiO2; pentane/ HRMS (ESI): calcd. for C15H20F3N2O+ [M + H]+ 301.1522, found
EtOAc, 7:3), m.p. 76–78 °C. 1H NMR (300 MHz, CDCl3): δ =
1.26–1.43 (m, 3 H, 4Ј-Hax and 3Ј,5Ј-Hax), 1.59–1.76 (m, 3 H, 2Ј,6Ј-
Hax and 4Ј-Heq), 1.85–1.93 (m, 4 H, 3Ј,5Ј-Heq and 2Ј,6Ј-Heq), 2.92
(s, 6 H, NMe2), 3.14 (tt, J = 11.5, 3.3 Hz, 1 H, 1Ј-H), 3.51 (d, J =
301.1528 (100%).
(؎)-5-{3-[2-Cyclohexyl-4-(2,2,2-trifluoro-1-methoxyethyl)-1H-imid-
azol-1-yl]prop-1-yn-1-yl}-1-(tetrahydrothien-2-yl)cytosine [(؎)-17]:
Alkyne (Ϯ)-29 (56 mg, 0.19 mmol) was treated with 5-iodocytosine
(Ϯ)-16 (60 mg, 0.19 mmol), Et3N (78 μL, 0.56 mmol),
[PdCl2(PPh3)2] (13 mg, 0.02 mmol), and CuI (7 mg, 0.04 mmol) in
DMF (4.6 mL) according to General Procedure B. The suspension
was stirred at 25 °C for 7 h. CC (SiO2–NH2; CH2Cl2 ǞCH2Cl2/
EtOH, 95:5) gave (Ϯ)-17 (43 mg, 47%) as a light-yellow solid. Rf
= 0.34 (SiO2; CH2Cl2/MeOH, 94:6), m.p. 117–120 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.25–1.44 (m, 3 H, 4ЈЈЈ-Hax and 3ЈЈЈ,5ЈЈЈ-
Hax), 1.63–1.94 (m, 8 H, 4ЈЈЈ-Heq, 3ЈЈЈ,5ЈЈЈ-Heq, 2ЈЈЈ,6ЈЈЈ-H2, and 4Ј-
Ha), 2.05–2.20 (m, 2 H, 3Ј-Ha and 4Ј-Hb), 2.29–2.41 (m, 1 H, 3Ј-
Hb), 2.68 (tt, J = 11.5, 3.3 Hz, 1 H, 1ЈЈЈ-H), 2.92–3.01 (m, 1 H, 5Ј-
Ha), 3.17–3.26 (m, 1 H, 5Ј-Hb), 3.50 (s, 3 H, OMe), 4.66 [q, 3J(H,F)
= 6.8 Hz, 1 H, HC–CF3], 4.91 (s, 2 H, NCH2), 5.74–5.85 (br. s, 1 H,
NH), 6.30 (dd, J = 6.1, 3.5 Hz, 1 H, 2Ј-H), 7.10 (s, 1 H, 5ЈЈ-H),
7.71–7.88 (br. s, 1 H, NH), 8.23 (s, 1 H, 6-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.62, 26.27 (2 C), 28.23, 31.74, 31.78,
33.42, 35.94, 36.20, 38.86, 58.51, 66.16, 77.05 [q, 2J(C,F) =
31.9 Hz], 77.25, 88.64, 89.31, 117.68 [br. q, 4J(C,F) = 1.2 Hz],
124.05 [q, 1J(C,F) = 282.0 Hz], 133.11 [br. q, 3J(C,F) = 1.4 Hz],
146.39, 151.96, 154.39, 164.04 ppm. 19F NMR (376 MHz, CDCl3):
3
0.6 Hz, 3 H, OMe), 5.31 [qd, J(H,F) = 6.2, J = 0.6 Hz, 1 H, HC–
CF3], 7.18 (br. s, 1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 25.68, 26.39 (2 C), 32.58, 32.64, 37.62 (2 C), 38.02, 58.58, 72.84
[q, 2J(C,F) = 32.1 Hz], 123.84 [q, 1J(C,F) = 283.2 Hz], 125.55 (br.),
130.34 [q, 4J(C,F) = 2.3 Hz], 157.35 ppm. 19F NMR (376 MHz,
CDCl ): δ = –74.31 [d, 3J(H,F) = 6.4 Hz] ppm. IR (ATR): ν = 3152
˜
3
(w), 2931 (w), 2859 (w), 1570 (w), 1497 (w), 1475 (w), 1461 (w),
1417 (w), 1389 (m), 1364 (m), 1347 (m), 1262 (m), 1239 (w), 1208
(w), 1159 (s), 1128 (s), 1113 (m), 1099 (m), 1084 (s), 1015 (w), 969
(m), 856 (m), 844 (m), 767 (m), 726 (s), 705 (s), 640 (w) cm–1
.
HRMS (EI): calcd. for C14H22F3N3O3S+ [M]+ 369.1328, found
369.1330 (16 %); calcd. for C12H16F3N2O+ [M – Me2NSO2]+
+
261.1209, found 261.1215 (100 %); calcd. for C11H12F3N2
[M – Me2NSO2 – MeOH]+ 229.0947, found 229.0947 (73 %);
194.0669 (45%); 108.0111 (60%). C14H22N3O3F3S (369.4) calcd.
C 45.52, H 6.00, N 11.38; found C 45.81, H 6.00, N 11.26.
(؎)-2-Cyclohexyl-4-(2,2,2-trifluoro-1-methoxyethyl)-1H-imidazole
[(؎)-28]: A suspension of (Ϯ)-27 (300 mg, 0.81 mmol) in 5% aq.
HCl (10 mL) was stirred at 25 °C for 7 h. The mixture was cooled
to 0 °C, neutralized with sat. aq. NaHCO3, and extracted with
CH2Cl2 (3ϫ 20 mL). The combined organic phases were washed
with brine (30 mL), dried with MgSO4, filtered, and concentrated.
CC (SiO2; pentane/EtOAc, 2:1Ǟ1:1) gave (Ϯ)-28 (191 mg, 90%)
δ = –76.12 [t, 3J(H,F) = 7.4 Hz] ppm. IR (ATR): ν = 3326 (w),
˜
3178 (w), 2931 (m), 2854 (w), 2235 (w), 1639 (s), 1496 (s), 1448
(m), 1402 (m), 1328 (w), 1297 (w), 1271 (m), 1228 (w), 1162 (s),
1120 (s), 1097 (s), 1017 (w), 969 (w), 884 (w), 838 (w), 806 (w), 779
(m), 697 (w) cm–1. HRMS (MALDI; 3-HPA): calcd. for
C23H28F3KN5O2S+ [M + K]+ 534.1547, found 534.1555 (8%);
calcd. for C23H28F3N5NaO2S+ [M + Na]+ 518.1808, found
518.1816 (12%), calcd. for C23H29F3N5O2S+ [M + H]+ 496.1989,
1
as a white crystalline solid, m.p. 154–155 °C. H NMR (400 MHz,
CDCl3): δ = 1.23 (qt, J = 12.2, 3.3 Hz, 1 H, 4Ј-Hax), 1.36 (qt, J =
12.2, 3.2 Hz, 2 H, 3Ј,5Ј-Hax), 1.48 (qd, J = 12.2, 2.8 Hz, 2 H, 2Ј,6Ј-
H
ax), 1.69–1.74 (m, 1 H, 4Ј-Heq), 1.79–1.84 (m, 2 H, 3Ј,5Ј-Heq),
+
2.02–2.06 (m, 2 H, 2Ј,6Ј-Heq), 2.74 (tt, J = 11.7, 3.5 Hz, 1 H, 1Ј-
found 496.1993 (100%); calcd. for C19H23F3N5O2 [M – C4H6S +
3
H]+ 410.1798, found 410.1799 (48%).
H), 3.44 (s, 3 H, OMe), 4.63 [q, J(H,F) = 6.7 Hz, 1 H, HC–CF3],
7.03 (s, 1 H, 5-H), 9.40–9.86 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.76, 25.94 (2 C), 31.94 (2 C), 37.80,
58.15, 114.26 (br.), 153.32 (br.) ppm, the signals of C(4) and CF3
are not visible. 19F NMR (376 MHz, CDCl3): δ = –76.27 [d,
2-Cyclohexyl-1H-benzimidazol-4-ol (36): A solution of 2-amino-3-
nitrophenol (35; 1.10 g, 7.13 mmol) and cyclohexanecarbaldehyde
(13; 0.86 mL, 7.13 mmol) in EtOH (28 mL) was treated with aq.
Na2S2O4 (1 m, 21.4 mL, 21.4 mmol) at 25 °C and heated to 70 °C
for 5 h. The mixture was cooled to 25 °C, treated dropwise with
aq. NH3 (1 m, 14.3 mL), and cooled to 0 °C. The resulting precipi-
tate was filtered off, washed with H2O, and dried in a desiccator
over CaCl2 to give 36 (1.24 g, 80%) as a white solid, m.p. 225–
227 °C. 1H NMR [300 MHz, (CD3)2SO]: δ = 1.22–1.43 (m, 3 H, 4Ј-
Hax and 3Ј,5Ј-Hax), 1.55–1.72 (m, 3 H, 2Ј,6Ј-Hax and 4Ј-Heq), 1.77–
1.81 (m, 2 H, 3Ј,5Ј-Hax), 1.96–2.00 (m, 2 H, 2Ј,6Ј-Heq), 2.80 (tt, J
= 11.5, 3.6 Hz, 1 H, 1Ј-H), 6.45–6.52 (m, 1 H, 5-H), 6.84–6.94 (m,
2 H, 6-H and 7-H), 9.52 (br. s, 1 H, NH), 11.93 (br. s, 1 H,
OH) ppm. 13C NMR [100 MHz, (CD3)2SO]: δ = 25.59, 25.63 (2 C),
31.36 (2 C), 37.78, 106.13, 121.74, 157.38 ppm, four aromatic sig-
3J(H,F) = 4.8 Hz] ppm. IR (ATR): ν = 2930 (m), 2856 (w), 1577
˜
(w), 1531 (w), 1451 (w), 1371 (w), 1270 (m), 1240 (m), 1167 (s),
1120 (s), 1104 (s), 1015 (w), 971 (m), 879 (w), 806 (w), 707 (m) cm–1.
HRMS (ESI): calcd. for C12H18F3N2O+ [M + H]+ 263.1366, found
263.1376 (100%).
(؎)-2-Cyclohexyl-1-(prop-2-yn-1-yl)-4-(2,2,2-trifluoro-1-methoxy-
ethyl)-1H-imidazole [(؎)-29]: Imidazole (Ϯ)-28 (170 mg,
0.65 mmol) was treated with Cs2CO3 (232 mg, 0.71 mmol) and pro-
pargyl bromide (56 μL, 0.65 mmol) in DMF (5 mL) according to
General Procedure A. The suspension was stirred at 25 °C for 8 h.
CC (SiO2; pentane/EtOAc, 4:1Ǟ1:1) gave (Ϯ)-29 (94 mg, 48%) as
a colorless oil. Rf = 0.34 (SiO2; pentane/EtOAc, 4:1). 1H NMR
(300 MHz, CDCl3): δ = 1.31–1.44 (m, 3 H, 4Ј-Hax and 3Ј,5Ј-Hax),
1.60–1.75 (m, 3 H, 2Ј,6Ј-Hax and 4Ј-Heq), 1.84–1.93 (m, 4 H, 3Ј,5Ј-
Heq and 2Ј,6Ј-Heq), 2.46 (t, J = 2.6 Hz, 1 H, HCϵC), 2.64 (tt, J =
11.7, 3.4 Hz, 1 H, 1Ј-H), 3.47 (d, J = 0.5 Hz, 3 H, OMe), 4.65 [br.
q, 3J(H,F) = 6.8 Hz, 1 H, HC–CF3], 4.65 (d, J = 2.6 Hz, 2 H,
NCH2), 7.08 (s, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
25.81, 26.44 (2 C), 31.74, 31.76, 35.55 and 35.98 (1 C), 58.34, 74.50,
74.56, 76.17, 76.65 [q, 2J(C,F) ≈ 34.6 Hz], 117.66, 123.79 [q, 1J(C,F)
nals are not visible. IR (ATR): ν = 3211 (w), 3062 (w), 3030 (w),
˜
2925 (m), 2851 (w), 2373 (w), 1896 (w), 1731 (w), 1625 (w), 1597
(m), 1519 (w), 1430 (m), 1381 (m), 1300 (m), 1239 (m), 1194 (m),
1154 (m), 1128 (m), 1064 (s), 1044 (s), 887 (m), 850 (w), 788 (s),
732 (s), 713 (m), 665 (w), 606 (w) cm–1. HRMS (ESI): calcd. for
C13H17N2O+ [M + H]+ 217.1335, found 217.1330 (100%).
2-Cyclohexyl-4-isopropoxy-1H-benzimidazole (37): A solution of
alcohol 36 (700 mg, 3.24 mmol), PPh3 (1.02 g, 3.89 mmol), and
= 280.7 Hz], 132.48 [br. q, 4J(C,F) ≈ 1.7 Hz], 151.66 ppm. 19F iPrOH (0.30 mL, 3.89 mmol) in THF (30.8 mL) was treated with
3
NMR (376 MHz, CDCl3): δ = –76.25 [d, J(H,F) = 6.5 Hz] ppm. DIAD (94% in toluene, 0.82 mL, 3.89 mmol) at 25 °C. The mixture
Eur. J. Org. Chem. 2013, 1068–1079
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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