ChemMedChem
10.1002/cmdc.201900576
FULL PAPER
1
H), 7.43 (dd, J=7.9, 1.4, 1H), 7.21 (d, J=8.2, 1H), 7.08 (d, J=3.1, 1H), 6.57
carbonate (0.52 g, 2.0 mmol, 2.0 eq) and methyl 4-(bromomethyl)-3-
methoxybenzoate (19, 0.52 g, 2.0 mmol, 1.0 eq) were dissolved in DMF
(abs., 20 mL). The mixture was stirred under reflux for 12 h. After cooling
to room temperature, aqueous hydrochloric acid (5%, 30 mL) was added,
phases were separated, and the aqueous layer was extracted with EtOAc
(
d, J=7.9, 1H), 6.43 – 6.38 (m, 1.6, 2H), 6.27 (d, J=3.2, 1H), 5.23 (s, 2H),
4
1
1
.73 (s, 2H), 3.96 (s, 3H), 3.83 (s, 3H). 13C NMR (126 MHz, DMSO) δ =
65.98, 156.24, 144.23, 137.47, 131.92, 129.81, 127.07, 126.10, 121.55,
20.74, 119.80, 110.59, 109.94, 101.08, 93.35, 55.71, 52.22, 44.08.
(
ESI+): m/z 311.53 ([M+H]+).
4
(3x30 mL). The combined organic layers were dried over MgSO , and the
solvents were evaporated in vacuum. The crude product was purified by
column chromatography using toluene/acetone (10:1) as mobile phase. 68
was obtained as a yellow solid (0.45 g, 66%). H NMR (500 MHz, DMSO)
δ = 8.57 (d, J=2.1, 1H), 7.95 (s, 1H), 7.90 (d, J=8.9, 1H), 7.81 (d, J=9.0,
Methyl 4-((6-(4-(tert-butyl)benzamido)-1H-indol-1-yl)methyl)benzoate
64): 4-tert-Butylbenzoic acid (31, 0.24 g, 1.4 mmol, 1.2 eq) was dissolved
in CHCl (abs., 20 mL). EDC·HCl (0.26 g, 1.4 mmol, 1.2 eq), 4-DMAP (0.20
1
(
3
1
3
1
1
H), 7.53 – 7.50 (m, 2H), 7.31 (d, J=7.8, 1H), 5.63 (s, 2H), 3.90 (s, 3H),
.83 (s, 3H). 13C NMR (126 MHz, DMSO) δ = 165.79, 157.01, 149.32,
48.62, 143.13, 137.87, 131.07, 129.46, 129.28, 121.63, 119.30, 118.53,
11.20, 111.14, 55.78, 52.34, 44.01. MS (ESI+): m/z 342.14 ([M+H]+).
g, 1.7 mmol, 1.5 eq) and methyl 4-((6-amino-1H-indol-1-
yl)methyl)benzoate (61, 0.32 g, 1.1 mmol, 1.0 eq) were added. The
reaction mixture was stirred at 50 °C for 12 h. Aqueous hydrochloric acid
(
10%, 10 mL) was then added, phases were separated, and the aqueous
layer was extracted with EtOAc (3x10 mL). The combined organic layers
were dried over MgSO , and the solvents were evaporated in vacuum.
4
Methyl
4-((6-amino-1H-benzimidazol-1-yl)methyl)-3-
Further purification was performed by column chromatography using
methoxybenzoate (69): Methyl 3-methoxy-4-((6-nitro-1H-benzmidazol-1-
yl)methyl)benzoate (68, 0.68 g, 2.0 mmol, 1.0 eq) was dissolved in MeOH
(20 mL) and Pd(C) (loading 10% w/w, 0.21 g, 0.20 mmol, 0.10 eq) was
toluene/acetone (10:1) as mobile phase to obtain 64 as pale purple solid
1
(
0.47 g, 97%). H NMR (500 MHz, DMSO) δ = 10.09 (s, 1H), 7.96 (s, 1H),
7
.93 – 7.83 (m, 4H), 7.52 (d, J=8.3, 3H), 7.48 (d, J=3.1, 1H), 7.34 (dd,
J=8.5, 1.7, 1H), 7.24 (d, J=8.4, 2H), 6.50 – 6.47 (m, 1H), 5.49 (s, 2H), 3.81
s, 3H), 1.31 (s, 9H). 13C NMR (126 MHz, DMSO) δ = 165.96, 165.19,
added. The suspension was stirred at room temperature under H
atmosphere for 6 h. The mixture was then filtered through celite, the filtrate
2
(
was dried over MgSO
4
, and the solvent was evaporated in vacuum to
1
154.12, 143.88, 135.64, 133.87, 132.54, 129.54, 129.28, 128.63, 127.42,
126.84, 125.09, 124.85, 120.30, 113.95, 101.75, 101.27, 52.12, 48.80,
3
4.67, 30.96. MS (ESI+): m/z 463.19 ([M+Na]+).
obtain the title compound as pale purple solid (0.50 g, 80%). H NMR (500
MHz, DMSO) δ = 7.55 – 7.46 (m, 2H), 7.34 – 7.26 (m, 1H), 7.12 – 7.03 (m,
1H), 6.91 (d, J=7.9, 1H), 6.51 (dd, J=8.5, 2.0, 1H), 6.45 (d, J=1.9, 1H), 5.31
(
s, 2H), 3.94 (s, 3H), 3.83 (s, 3H). 13C NMR (126 MHz, DMSO) δ = 165.98,
156.68, 145.18, 141.89, 135.48, 135.05, 130.43, 130.31, 128.10, 121.64,
119.63, 111.39, 110.93, 93.40, 55.82, 52.34, 42.71. MS (ESI+): m/z
3
11.94 ([M+H]+).
Methyl 3-((6-(4-(tert-butyl)benzamido)-1H-indol-1-yl)methyl)benzoate
65): 4-tert-Butylbenzoic acid (31, 0.34 g, 1.9 mmol, 1.2 eq) was dissolved
in CHCl (abs., 20 mL). EDC·HCl (0.36 g, 1.9 mmol, 1.2 eq), 4-DMAP
0.29 g, 2.4 mmol, 1.5 eq) and methyl 3-((6-amino-1H-indol-1-
(
3
(
yl)methyl)benzoate (62, 0.45 g, 1.6 mmol, 1.0 eq) were added. The
reaction mixture was stirred at 50 °C for 12 h. Aqueous hydrochloric acid
Methyl
4-((6-(4-(tert-butyl)benzamido)-1H-benzoimidazol-1-
(70): Methyl 4-((6-amino-1H-
yl)methyl)-3-methoxybenzoate
(
10%, 20 mL) was then added, phases were separated, and the aqueous
layer was extracted with EtOAc (3x20 mL). The combined organic layers
were dried over MgSO , and the solvents were evaporated in vacuum.
benzoimidazol-1-yl)methyl)-3-methoxybenzoate (69, 0.50 g, 1.6 mmol, 1.0
eq) and 4-tert-butylbenzoyl chloride (29, 0.41 g, 2.1 mmol, 1.3 eq) were
dissolved in THF (abs., 50 mL), DMF (abs., 10 mL) and pyridine (0.39 mL,
4.8 mmol, 3.0 eq). The mixture was stirred at room temperature for 12 h.
After acidification with aqueous hydrochloric acid (2 N, 30 mL), the mixture
was extracted with EtOAc (3x30 mL). The combined organic layers were
4
Further purification was performed by column chromatography using
toluene/acetone (10:1) as mobile phase. 65 was obtained as a yellow solid
1
(0.41 g, 59%). H NMR (500 MHz, DMSO) δ = 10.10 (s, 1H), 7.98 (s, 1H),
7
7
5
1
1
1
.88 – 7.82 (m, 3H), 7.75 (s, 1H), 7.54 – 7.46 (m, 3H), 7.41 (d, J=7.8, 1H),
.34 (dd, J=8.5, 1.7, 1H), 7.27 – 7.23 (m, 2H), 6.49 (dd, J=3.1, 0.6, 1H),
.48 (s, 2H), 3.81 (s, 3H), 1.31 (s, 9H). 13C NMR (126 MHz, DMSO) δ =
66.02, 165.19, 154.12, 139.21, 137.36, 135.59, 133.84, 132.55, 131.51,
29.96, 128.92, 128.22, 127.41, 127.20, 125.33, 125.09, 120.30, 113.95,
01.75, 101.25, 52.20, 48.63, 34.66, 30.96. MS (ESI+): m/z 463.19
4
dried over MgSO , and the solvents were evaporated in vacuum. Further
purification was performed by column chromatography using
EtOAc/hexane (1:5) as mobile phase to obtain 70 as a yellow solid (0.41
1
g, 55%). H NMR (500 MHz, DMSO) δ = 7.92 – 7.88 (m, 7H), 7.56 – 7.53
(m, 4H), 5.68 (s, 2H), 3.94 (s, 3H), 3.83 (s, 3H), 1.31 (s, 9H). 13C NMR
(126 MHz, DMSO) δ = 167.26, 167.00, 158.15, 156.06, 145.36, 137.41,
132.37, 132.32, 132.23, 131.10, 128.33, 127.48, 126.28, 122.49, 120.12,
(
[M+Na]+).
1
(
17.02, 112.09, 56.65, 53.34, 49.60, 35.19, 31.82. MS (ESI+): m/z 472.16
[M+H]+).
Methyl
4-((6-(4-(tert-butyl)benzamido)-1H-indol-1-yl)methyl)-3-
methoxybenzoate (66): 4-tert-Butylbenzoic acid (31, 50 mg, 0.28 mmol,
1
.2 eq) was dissolved in CHCl
3
(abs., 10 mL). EDC·HCl (54 mg, 0.28 mmol,
Methyl 3-methoxy-4-((5-nitro-1H-indol-1-yl)methyl)benzoate (71): 5-
Nitro-1H-indole (17, 0.16 g, 1.0 mmol, 1.0 eq), potassium carbonate (0.25
g, 2.0 mmol, 2.0 eq) and methyl 4-(bromomethyl)-3-methoxybenzoate (19,
0.26 g, 1.0 mmol, 1.0 eq) were dissolved in DMF (abs., 20 mL). The
mixture was stirred under reflux for 12 h. After cooling to room temperature,
aqueous hydrochloric acid (5%, 30 mL) was added, phases were
separated, and the aqueous layer was extracted with EtOAc (3x30 mL).
1.2 eq), 4-DMAP (43 mg, 0.35 mmol, 1.5 eq) and methyl 4-((6-amino-1H-
indol-1-yl)methyl)-3-methoxybenzoate (63, 70 mg, 0.23 mmol, 1.0 eq)
were added. The reaction mixture was stirred at 50 °C for 12 h. Aqueous
hydrochloric acid (10%, 10 mL) was then added, phases were separated,
and the product was extracted with EtOAc (3x10 mL). The combined
4
organic layers were dried over MgSO , the solvents were evaporated in
vacuum. Further purification was performed by column chromatography
4
The combined organic layers were dried over MgSO , and the solvents
using EtOAc/hexane (1:3) as mobile phase to yield 66 as a yellow solid
were evaporated in vacuum. The crude product was purified by column
1
(42 mg, 42%). H NMR (500 MHz, DMSO) δ = 10.09 (s, 1H), 7.96 (s, 1H),
chromatography using toluene/acetone (10:1) as mobile phase. 71 was
1
7
.86 (d, J=8.4, 2H), 7.54 – 7.51 (m, 3H), 7.46 – 7.41 (m, 3H), 7.35 (dd,
J=8.5, 1.4, 1H), 6.65 (d, J=7.9, 1H), 6.48 (d, J=2.9, 1H), 5.38 (s, 2H), 3.98
s, 3H), 3.82 (s, 3H), 1.31 (s, 9H). 13C NMR (126 MHz, DMSO) δ = 165.96,
obtained as a yellow solid (0.16 g, 47%). H NMR (500 MHz, DMSO) δ =
8.50 (d, J=1.9, 1H), 7.91 (dd, J=8.8, 2.1, 1H), 7.89 (d, J=3.1, 1H), 7.76 (d,
J=8.8, 1H), 7.53 (d, J=1.4, 1H), 7.48 (dd, J=7.8, 1.5, 1H), 6.96 (d, J=7.9,
1H), 6.72 (dd, J=3.1, 0.7, 1H), 5.60 (s, 2H), 3.94 (s, 3H), 3.83 (s, 3H). 13C
NMR (126 MHz, DMSO) δ = 165.85, 156.59, 142.15, 135.97, 134.43,
133.10, 130.75, 130.51, 128.29, 121.69, 120.86, 114.37, 111.00, 107.27,
102.47, 55.74, 52.28, 44.69. MS (ESI+): m/z 363.08 ([M+Na]+).
(
1
1
1
65.19, 156.34, 154.13, 135.78, 133.90, 132.56, 131.56, 130.05, 129.41,
29.21, 127.43, 127.29, 125.39, 125.10, 124.70, 120.29, 113.79, 110.71,
01.58, 101.20, 55.76, 52.25, 44.29, 34.68, 30.98. MS (ESI+): m/z 493.24
(
[M+Na]+).
Methyl 3-methoxy-4-((6-nitro-1H-benzimidazol-1-yl)methyl)benzoate
68): 6-Nitro-1H-benzimidazole (67, 0.33 g, 2.0 mmol, 1.0 eq), potassium
Methyl 4-((5-amino-1H-indol-1-yl)methyl)-3-methoxybenzoate (72):
Methyl 3-methoxy-4-((5-nitro-1H-indol-1-yl)methyl)benzoate (71, 0.16 g,
(
1
3
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