Journal of Medicinal Chemistry
Article
be >95% in each case. The purity of compound 7, as assessed by
N-Cyclopropyl-4,5-difluoro-2-nitroaniline (1). To a stirring
30 mL). The combined organic layers were washed with water, brine,
dried over MgSO , filtered, and concentrated in vacuo. The crude
4
product was purified by flash column chromatography (ethyl acetate/
solution of 2,4,5-trifluoronitrobenzene (5.0 g, 3.24 mL, 28.24 mmol,
dichloromethane 0 to 30%) on silica gel to afford the desired product
1
1.0 equiv) and triethylamine (8.57 g, 11.8 mL, 84.70 mmol, 3.0 equiv)
as a brown solid (324 mg) in 73% yield. H NMR (CDCl , 500
3
in tetrahydrofuran (25.7 mL) at room temperature, cyclopropylamine
MHz): δ 9.13 (d, J = 1.9 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.45 (t, J
= 2.1 Hz, 1H), 7.57 (dd, J = 10.2, 7.3 Hz, 1H), 7.41 (dd, J = 9.7, 7.0
Hz, 1H), 3.57 (tt, J = 6.9, 3.8 Hz, 1H), 1.29−1.21 (m, 2H), and
(
(
6.65 g, 8.07 mL, 118 mmol, 4.2 equiv) was added dropwise over 1 h
the solution became very thick during the addition). The resulting
1
3
yellow mixture was stirred at 60 °C for 2 h. After cooling to room
temperature, the reaction was quenched with water (20 mL) and
diluted with ethyl acetate (30 mL). The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate (2 × 30 mL).
The combined organic layers were washed with water, brine, dried
0.85−0.78 (m, 2H); C NMR (CDCl , 126 MHz): δ 151.8, 151.0,
3
149.6 (dd, J = 40.2, 15.2 Hz), 147.7, 147.7 (dd, J = 38.9, 17.6 Hz),
138.9, 138.0 (d, J = 24.0 Hz), 132.7 (d, J = 10.8 Hz), 128.0, 120.8,
1
9
107.7 (d, J = 19.7 Hz), 99.2 (d, J = 23.2 Hz), and 26.6, 9.2 (2C);
F
NMR (CDCl , 282 MHz): δ −139.41 (d, J = 20.5 Hz) and −142.23
3
+
over MgSO , filtered, and concentrated in vacuo. The crude product
(d, J = 20.5 Hz); and HRMS: 350.0109 (C H BrF N +H ) calcd,
4
15 10
2
3
was purified by flash column chromatography (ethyl acetate/petrol 0
350.0104.
to 10%) on a silica gel to afford the desired product as a yellow solid
2-Ethylhexyl 3-((3′,5′-Dimethoxy-5-methyl-[1,1′-biphenyl]-
1
(
690 mg) in 11% yield. H NMR (CDCl , 500 MHz): δ 8.09 (s, 1H),
2-yl)thio)propanoate (5). The compound was prepared as
3
20
8
.03 (dd, J = 10.7, 8.3 Hz, 1H), 7.09 (dd, J = 12.6, 6.9 Hz, 1H), 2.54
previously reported. In brief, heating of a mixture of 2-bromo-1-
iodo-4-methylbenzene (1 equiv), 2-ethylhexyl 3-mercaptopropanoate
(1 equiv), triethylamine (2 equiv), tris(dibenzylideneacetone)-
dipalladium(0) (1.5 mol %), and Xantphos (3 mol %) in toluene at
125 °C for 2 h and subsequent workup by filtration over Celite and
flash chromatography provided 2-ethylhexyl 3-((2-bromo-4-
methylphenyl)thio)propanoate as a colorless oil (96%). This
intermediate (1 equiv) was further reacted in a Suzuki cross-coupling
by refluxing it with (3,5-dimethoxy-phenyl)boronic acid (1.25 equiv),
potassium carbonate (4 equiv), and PEPPSI-IPr catalyst (3 mol %) in
a mixture of toluene and water for 2 h. Filtration over Celite, followed
by an aqueous workup and flash column chromatography afforded the
title compound as a colorless oil (95%).
(
(
tdd, J = 6.8, 3.4, 1.8 Hz, 1H), 0.99−0.92 (m, 2H), and 0.71−0.65
21
m, 2H). Consistent with literature data.
N-Cyclopropyl-4,5-difluorobenzene-1,2-diamine (2). Under
an inert atmosphere (argon), palladium on charcoal (10%; 34 mg,
0
4
.031 mmol, 0.01 equiv) was added to a solution of N-cyclopropyl-
,5-difluoro-2-nitroaniline (1; 683 mg, 3.18 mmol, 1.0 equiv) in
methanol (12.7 mL). Hydrogen gas was introduced via a balloon, and
the resulting mixture was stirred at room temperature for 16 h. The
reaction mixture was subsequently filtered through a pad of Celite
with ethyl acetate (20 mL) and concentrated in vacuo. The crude
product was purified by flash column chromatography (ethyl acetate/
petrol 0 to 50%) on a silica gel to afford the desired product as a
1
brown solid (540 mg) in 92% yield. H NMR (CDCl , 500 MHz): δ
1-Cyclopropyl-2-(5-((3′,5′-dimethoxy-5-methyl-[1,1′-bi-
phenyl]-2-yl)thio)pyridin-3-yl)-5,6-difluoro-1H-benzo[d]-
imidazole (6). To a flame-dried three-necked round-bottom flask
equipped with an argon inlet and condenser were added sequentially
tris(dibenzylideneacetone)dipalladium(0) (168 mg, 0.19 mmol, 0.2
equiv), bis(2-diphenylphosphinophenyl)ether (198 mg, 0.37 mmol,
0.4 equiv), 2-(5-bromopyridin-3-yl)-1-cyclopropyl-5,6-difluoro-1H-
benzo[d]imidazole (4; 322 mg, 0.92 mmol, 1 equiv), and toluene
(4.8 mL). The resulting mixture was stirred at room temperature for
10 min. A solution of 2-ethylhexyl 3-((3′,5′-dimethoxy-5-methyl-
[1,1′-biphenyl]-2-yl)thio)propanoate (5; 448 mg, 1.01 mmol, 1.1
equiv) in toluene (4.8 mL) was subsequently added, followed by the
addition of potassium tert-butoxide (144 mg, 1.28 mmol, 1.4 equiv).
The reaction mixture was degassed for 5 min using a balloon filled
with argon and a vent needle and then heated at 125 °C for 2 h. After
cooling to room temperature, the reaction mixture was concentrated
in vacuo. The crude product was purified by flash column
chromatography (ethyl acetate/petrol 10 to 60%) on silica gel to
3
6
.82 (dd, J = 12.5, 7.8 Hz, 1H), 6.51 (dd, J = 11.2, 7.6 Hz, 1H), 3.82
(
s, 1H), 3.16 (s, 2H), 2.38 (tt, J = 6.7, 3.6 Hz, 1H), 0.79−0.71 (m,
21
2
H), and 0.55−0.46 (m, 2H). Consistent with literature data.
1
-Cyclopropyl-5,6-difluoro-2-(5-fluoropyridin-3-yl)-1H-
benzo[d]imidazole (3). Oxone (326 mg, 1.06 mmol, 0.65 equiv)
was added to a solution of N-cyclopropyl-4,5-difluorobenzene-1,2-
diamine (2; 300 mg, 1.63 mmol, 1 equiv) and 5-fluoronicotinaldehyde
(
(
224 mg, 180 μL, 1.79 mmol, 1.1 equiv) in dimethylformamide/water
97%/3% v/v; 4.1 mL). The mixture was stirred at room temperature
for 1 h. The reaction was quenched with water (20 mL) and diluted
with ethyl acetate (20 mL), followed by the addition of solid K CO
2
3
until the aqueous layer reached pH = 9. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate (3 ×
3
0 mL). The combined organic layers were washed with water, brine,
dried over MgSO , filtered, and concentrated in vacuo. The crude
4
product was purified by flash column chromatography (ethyl acetate/
dichloromethane 0 to 50%) on silica gel to afford the desired product
1
as an orange solid (298 mg) in 64% yield. H NMR (CDCl , 500
afford the desired product as an orange solid (457 mg) in 94% yield.
3
1
MHz): δ 9.04 (t, J = 1.7 Hz, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.01 (ddd,
J = 9.1, 2.8, 1.7 Hz, 1H), 7.57 (dd, J = 10.3, 7.3 Hz, 1H), 7.41 (dd, J =
H NMR (CDCl , 500 MHz): δ 8.89 (d, J = 1.9 Hz, 1H), 8.38 (d, J =
3
2.1 Hz, 1H), 7.92 (t, J = 2.1 Hz, 1H), 7.52 (dd, J = 10.3, 7.3 Hz, 1H),
7.42−7.29 (m, 2H), 7.20 (d, J = 1.9 Hz, 1H), 7.17−7.11 (m, 1H),
6.45 (d, J = 2.2 Hz, 2H), 6.39 (t, J = 2.3 Hz, 1H), 3.72 (s, 6H), 3.39
(tt, J = 7.0, 3.8 Hz, 1H), 2.37 (s, 3H), 1.15−1.04 (m, 2H), and 0.92−
9
.7, 7.0 Hz, 1H), 3.58 (tt, J = 6.8, 3.8 Hz, 1H), 1.25 (dq, J = 6.9, 1.2
1
3
Hz, 2H), and 0.84−0.79 (m, 2H); C NMR (CDCl , 126 MHz): δ
1
3
59.1 (d, J = 258.2 Hz), 151.1, 150.2 (dd, J = 23.9, 15.4 Hz), 146.9
1
3
(
dd, J = 21.4, 15.4 Hz), 145.5 (d, J = 4.3 Hz), 139.2 (d, J = 23.1 Hz),
37.8 (d, J = 11.0 Hz), 132.6 (d, J = 10.8 Hz), 127.8 (d, J = 4.2 Hz),
0.80 (m, 2H); C NMR (CDCl , 126 MHz): δ 160.4, 151.9 (d, J =
3
1
1
2
−
2
3.3 Hz), 150.7, 149.4 (dd, J = 32.5, 15.3 Hz), 147.5 (dd, J = 30.0, 15.4
Hz), 147.0, 145.1, 142.5, 139.1, 137.7 (d, J = 10.6 Hz), 136.9, 135.1,
134.3, 132.5 (d, J = 10.7 Hz), 131.9, 129.5, 129.4, 127.7, 126.5, 107.6
23.2 (d, J = 20.0 Hz), 107.6 (d, J = 19.9 Hz), 99.2 (d, J = 23.1 Hz),
1
9
6.6, and 9.1 (2C); F NMR (CDCl , 282 MHz): δ −125.72,
3
139.48 (d, J = 20.6 Hz) and −142.30 (d, J = 20.6 Hz); and HRMS:
(2C), 107.5 (d, J = 19.8 Hz), 99.7, 99.0 (d, J = 23.1 Hz), 55.5 (2C),
+
19
90.0901 (C H F N +H ) calcd, 290.0900.
26.5, 21.2, and 9.0 (2C); F NMR (CDCl , 282 MHz): δ −140.01
15
10
3
3
3
2
-(5-Bromopyridin-3-yl)-1-cyclopropyl-5,6-difluoro-1H-
(d, J = 20.6 Hz) and −142.67 (d, J = 20.6 Hz); and HRMS: 530.1709
C H F N O S+H ) calcd, 530.1714.
+
benzo[d]imidazole (4). Oxone (252 mg, 0.82 mmol, 0.65 equiv)
was added to a solution of N-cyclopropyl-4,5-difluorobenzene-1,2-
diamine (2; 232 mg, 1.26 mmol, 1 equiv) and 5-bromonicotinalde-
hyde (258 mg, 1.39 mmol, 1.1 equiv) in dimethylformamide/water
(
3
0
25
2
3
2
5
-(5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-
pyridin-3-yl)-2,4-dimethoxy-8-methyl-5H-dibenzo[b,d]-
thiophen-5-ium Trifluoromethanesulfonate (7). To a solution
of 1-cyclopropyl-2-(5-((3′,5′-dimethoxy-5-methyl-[1,1′-biphenyl]-2-
yl)thio)pyridin-3-yl)-5,6-difluoro-1H-benzo[d]imidazole (6; 280 mg,
0.53 mmol, 1 equiv) and sodium trifluoromethanesulfonate (182 mg,
1.05 mmol, 2 equiv) in acetone (analytical reagent grade; 3.4 mL) at 0
(
97%/3% v/v; 3.1 mL). The mixture was stirred at room temperature
for 1 h. The reaction was quenched with water (20 mL) and diluted
with ethyl acetate (20 mL), followed by the addition of solid K CO
2
3
until the aqueous layer reached pH = 9. The organic layer was
separated and the aqueous layer was extracted with ethyl acetate (3 ×
°C, was added a freshly prepared solution of Ca(OCl) (a fresh bottle
2
9
326
J. Med. Chem. 2021, 64, 9321−9329