Synthesis of Mono- and Di-fluorinated benzimidazoles
3.78 (s, 6H), 4.14 (q, J=6.9 Hz, 1H), 4.42 (br, 1H),
4.58 (t, J=6.6 Hz, 2H), 6.64 (s, 2H), 6.70 (d, J=8.4 Hz,
2H), 7.12 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 7.35 (d, J=
10.8 Hz, 1H), 7.55 (s, 1H). HRMS calcd for
C27H28ClF2N4O4 (M+H)+ 545.1762, found 545.1768.
(S)-2-(1-(2-Cyclohexenylethyl)-5,7-difluoro-2-(3,4,
5-trimethoxyphenyl)-1H-benzo[d]imidazol-6-yla-
mino)propanamide (10d) White powder, yield 19%,
reaction was completed as detected by LC-MS, the
residue was filtered and washed with acetone thor-
oughly. The combined filtrate was evaporated in vacuo
to dryness. The residue was dissolved in a mixture of
2% HCl solution and DCM. The organic layer was
separated and then evaporated in vacuo to dryness, and
water was added to precipitate 12. The desired com-
pound was then collected by filtration and washed
thoroughly with water.
1
m.p. 89—90 ℃; H NMR (DMSO-d6, 300 MHz) δ:
1.28 (d, J=6.6 Hz, 3H), 1.33 (br, 4H), 1.62 (br, 2H),
1.74 (br, 2H), 2.28 (t, J=6.6 Hz, 2H), 3.73 (s, 3H), 3.83
(s, 6H), 4.08—4.13 (m, 1H), 4.38 (t, J=6.6 Hz, 2H),
4.65— 4.68 (m, 1H), 4.99 (s, 1H), 6.97 (s, 2H), 7.11 (s,
1H), 7.33 (d, J=11.4 Hz, 1H), 7.+53 (s, 1H). HRMS
calcd for C27H33F2N4O4 (M+H) 515.2464, found
515.2459.
N-Cyclopentyl-5-fluoro-2-nitroaniline
(12a)
1
Yellow oil, yield 74%; H NMR (DMSO-d6, 300 MHz)
δ: 1.43—1.75 (m, 6H), 2.01—2.08 (m, 2H), 3.96—4.06
(m, 1H), 6.50—6.56 (m, 1H), 6.88 (dd, J=12.3, 2.7 Hz,
1H), 8.08 (d, J=5.7 Hz, 1H), 8.15 (dd, J=9.6, 6.3 Hz,
1H). ESI-MS m/z: 225.1 (M+H)+.
5-Fluoro-2-nitro-N-(pyridin-2-ylmethyl)aniline
(12b/12e) Yellow powder, yield 86%; 1H NMR
(CDCl3, 300 MHz) δ: 4.64 (d, J =5.4 Hz, 2H),
6.37—6.43 (m, 1H), 6.50 (dd, J=11.4, 2.4 Hz, 1H),
7.29—7.34 (m, 2H), 7.72 (td, J=7.5, 1.2 Hz, 1H), 8.26
(dd, J=9.3, 6.0 Hz, 1H), 8.65 (d, J=4.5 Hz, 1H), 9.05
(br, 1H). ESI-MS m/z: 248.2 (M+H)+.
(S)-2-(1-Cyclopentyl-5,7-difluoro-2-(3,4,5-trime-
thoxyphenyl)-1H-benzo[d]imidazol-6-ylamino)pro-
panamide (10e) Yellow powder, yield 29%, m.p.
1
81—82 ℃; H NMR (DMSO-d6, 300 MHz) δ: 1.27 (d,
J=6.6 Hz, 3H), 1.65 (br, 2H), 1.89—2.07 (m, 6H), 3.74
(s, 3H), 3.84 (s, 6H), 4.08—4.13 (m, 1H), 4.66—4.69
(m, 1H), 4.83—4.86 (m, 1H), 6.89 (s, 2H), 7.10 (s, 1H),
7.35 (d, J=10.8 Hz, 1H), 7.54 (s, 1H). HRMS calcd for
C24H29F2N4O4 (M+H)+ 475.2151, found 475.2147.
(S)-2-(1-(1-Benzylpiperidin-4-yl)-5,7-difluoro-2-
(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazol-6-yl-
5-Fluoro-2-nitro-N-(2-(piperidin-1-yl)ethyl)ani-
1
line (12c/12f) Yellow powder, yield 88%; H NMR
(DMSO-d6, 300 MHz) δ: 1.39—1.41 (m, 2H),
1.49—1.52 (m, 4H), 2.38 (br, 4H), 2.56 (t, J=6.3 Hz,
2H), 3.31—3.37 (m, 2H), 6.48—6.55 (m, 1H), 6.82 (dd,
J=12.3, 2.4 Hz, 1H), 8.15 (dd, J=9.6,+6.0 Hz, 1H),
8.56 (br, 1H). ESI-MS m/z: 268.2 (M+H) .
amino)propanamide (10f)
Yellow powder, yield
1
19%, m.p. 91—93 ℃; H NMR (DMSO-d6, 300 MHz)
δ: 1.29 (d, J = 6.6 Hz, 3H), 1.88—2.01 (m, 4H),
2.28—2.32 (m, 2H), 2.91—2.95 (m, 2H), 3.48 (s, 2H),
3.75 (s, 3H), 3.82 (s, 6H), 4.08—4.11 (m, 1H), 4.34 (br,
1H), 4.70—4.73 (m, 1H), 6.89 (s, 2H), 7.11 (s, 1H),
7.24—7.37 (m, 6H), 7.55 (s, 1H). HRMS calcd for
C31H36F2N5O4 (M+H)+ 580.2730, found 580.2734.
(S)-2-(1-(Benzo[d][1,3]dioxol-5-ylmethyl)-5,7-di-
fluoro-2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imida-
N-(3,4-Dimethoxyphenethyl)-5-fluoro-2-nitroani-
1
line (12d/12g) Yellow powder, yield 82%; H NMR
(DMSO-d6, 300 MHz) δ: 2.97 (t, J=6.9 Hz, 2H),
3.45—3.51 (m, 2H), 3.87 (s, 3H), 3.90 (s, 3H), 6.36 (td,
J=9.6, 2.1 Hz, 1H), 6.47 (dd, J=11.4, 2.1 Hz, 1H),
6.78—6.87 (m, 3H), 8.17—8.22 (m, 2H). ESI-MS m/z:
321.1 (M+H)+.
General procedure for synthesis of 13
zol-6-ylamino)propanamide (10g)
Dark brown
powder, yield 28%, m.p. 180—181 ℃; 1H NMR
(DMSO-d6, 300 MHz) δ: 1.23 (d, J=6.6 Hz, 3H), 3.69
(s, 6H), 3.71 (s, 3H), 4.03—4.08 (m, 1H), 4.67 (d, J=
9.0 Hz, 1H), 5.45 (s, 2H), 5.97 (s, 2H), 6.44 (d, J=8.1
Hz, 1H), 6.61 (s, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.91 (s,
2H), 7.09 (s, 1H), 7.38 (d, J=11.1 Hz, 1H), 7.50 (s, 1H);
13C NMR (DMSO-d6, 100 MHz) δ: 19.83, 49.02, 53.83,
55.81, 60.11, 101.11, 101.34, 106.16, 106.42, 108.49,
118.62, 120.83, 121.45 (J=8.3 Hz), 124.41, 131.47,
135.63, 135.77, 137.53, 138.78, 139.93, 146.49, 147.67,
150.90 (d, J =239.0 Hz), 152.93, 153.+67, 175.22.
HRMS calcd for C27H27F2N4O6 (M+H) 541.1893,
found 541.1893.
It was the same to General procedure for synthesis
of intermediate 4. The desired compounds of 13 were
obtained after purified by silica gel column chromatog-
raphy eluting with DCM/MeOH (V∶V=20∶1) and
1
then characterized by H NMR, HRMS, and 13C NMR
for typical compounds.
1-Cyclopentyl-6-fluoro-2-(3,4,5-trimethoxyphenyl)-
1H-benzo[d]imidazole (13a) Dark brown powder,
yield 52%, m.p. 133—134 ℃; 1H NMR (DMSO-d6, 300
MHz) δ: 1.66—1.69 (m, 2H), 1.96—2.18 (m, 6H), 3.75
(s, 3H), 3.84 (s, 6H), 4.88—4.94 (m, 1H), 6.90 (s, 2H),
7.06—7.13 (m, 1H), 7.43 (dd, J=9.6, 2.4 Hz, 1H), 7.69
(dd, J=9.0, 5.1 Hz, 1H). HRMS calcd for C21H24FN2O3
(M+H)+ 371.1765, found 371.1771.
General procedure for synthesis of intermediate 12
6-Fluoro-1-(pyridin-2-ylmethyl)-2-(3,4,5-trime-
1.0 mmol of DFNB 11 was dissolved in 15 mL ace-
tone, followed by the addition of 1.0 equiv. of primary
amine and 5.0 equiv. of anhydrous K2CO3. The reaction
mixture was placed in a parallel synthesizer magneti-
cally stirried for 24 h at refluxing temperature. After
thoxyphenyl)-1H-benzo[d]imidazole (13b)
White
powder, yield 48%, m.p. 132—133 ℃; 1H NMR
(DMSO-d6, 300 MHz) δ: 3.67 (s, 6H), 3.70 (s, 3H), 5.62
(s, 2H), 7.05—7.12 (m, 3H), 7.29—7.40 (m, 3H), 7.70
(dd, J=8.7, 4.8 Hz, 1H), 7.81 (td, J=7.8, 1.8 Hz, 1H),
Chin. J. Chem. 2011, 29, 983— 990
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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