ChemMedChem
10.1002/cmdc.202000092
FULL PAPER
2
3 6
CH ): δ 169.4, 142.5, 141.1,
).13C-NMR (101 MHz, acetone-d
1
18.7, 110.0, 52.0, 46.7, 18.2, 16.1, 10.2. HRMS: m/z calculated
CH
138.3, 136.3, 134.9, 132.3, 132.1, 131.4, 130.5, 130.4, 129.5,
+
for C26
H25NO
2
[M+Na] : 406.1778, found: 406.1774.
1
28.2, 126.8, 123.8, 121.2, 114.3, 112.5, 111.9, 52.1, 46.9, 18.0,
+
Methyl 4'-((3-bromo-9H-carbazol-9-yl)methyl)-[1,1'-biphenyl]-
16.0, 10.3. HRMS: m/z calculated for C26
H
24BrNO
2
[M+H] :
2
2
3
-carboxylate (5a): From 3-bromo-9H-carbazole 4 (0.50 g,
.0 mmol) in anhydrous THF (6 ml) with 60% NaH (1.2 g,
462.1063, found: 462.1152.
.0 mmol) and methyl 4'-(bromomethyl)-[1,1'-biphenyl]-2-
General procedures for saponification of the methyl esters:
1
carboxylate (0.68 g, 2.2 mmol). Colorless solid, yield: 44%. H-
NMR (400 MHz, DMSO-d
4
6
): δ 8.45 (d, 1H, J = 2.0 Hz, H4’’), 8.25
Method A: THF (50 ml/mmol) was applied to dissolve the
respective methyl ester. 14% LiOH (5 ml/mmol) was added and it
was heated at 60 °C for 140 h. The reaction mixture was diluted
with water to double the volume and acidified to a pH of 5 with 1 N
HCl. Then, it was extracted with EA (3×), the organic layers were
3
(
d, 1H, J = 7.7 Hz, H5’’), 7.73-7.64 (m, 3H, H3, H1’’, H8’’), 7.61-
7
.53 (m, 2H, H5, H2’’), 7.53-7.40 (m, 2H, H4, H7’’), 7.35 (dd, 1H,
3
4
J = 7.8 Hz, J = 1.3 Hz, H6), 7.29-7.21 (m, 1H, H6’’), 7.21-7.17
(
m, 4H, H2’, H3’, H5’, H6’), 5.73 (s, 2H, NCH
2
), 3.53 (s, 3H,
CO CH ): δ 168.3, 140.8, 140.6,
2
3
). 13C-NMR (101 MHz, DMSO-d
6
2 4
combined, washed with brine, and dried over anhydrous Na SO .
1
1
1
39.5, 138.9, 136.6, 131.5, 130.7, 130.5, 129.3, 128.4, 128.2,
27.4, 126.7, 126.6, 124.2, 123.0, 121.3, 121.0, 119.5, 111.7,
After filtration, the solvent was removed under reduced pressure
and the resulting crude product was purified by flash column
chromatography with stepwise gradient elution (PE/EA, 9:1 to
7:3).
11.2, 109.9, 51.8, 45.4. HRMS: m/z calculated for C27
H
20BrNO
2
+
[
M+Na] : 492.0570, found: 492.0624.
Methyl
4'-((5-bromo-2-propyl-1H-benzo[d]imidazol-1-
Method B: The respective methyl ester was dissolved in MeOH
(50 ml/mmol), 3 N NaOH (1 ml/mmol) was added and the solution
was heated at 65 °C for 72 h. After adding water, 6 N HCl was
used to reach a pH of 1. It was extracted with DCM (3×), the
organic layers were combined, washed with brine, and dried over
yl)methyl)-[1,1'-biphenyl]-2-carboxylate (5b) and methyl 4'-
(6-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-
biphenyl]-2-carboxylate (6-Br-CO CH ): From 12 (0.50 g,
.1 mmol) in anhydrous DMF (2 ml) with NaH (0.06 g, 2.5 mmol)
(
2
3
2
and
methyl
4'-(bromomethyl)-[1,1'-biphenyl]-2-carboxylate
2 4
anhydrous Na SO . After filtration, the solvent was removed
(
5
0.70 g, 2.3 mmol).
b: Colorless solid, yield: 17%. H-NMR (400 MHz, acetone-d
under reduced pressure and the resulting crude product was
purified by flash column chromatography with stepwise gradient
elution (PE/EA, 9:1 to 7:3).
1
6
):
δ 7.83-7.72 (m, 2H, H3, H4’’), 7.62-7.54 (m, 1H, H5), 7.50-7.43
(
m, 1H, H4), 7.43-7.35 (m, 2H, H6’’, H7’’), 7.35-7.24 (m, 3H, H6,
3
H2’, H6’), 7.17 (d, 2H, J = 8.5 Hz, H3’, H5’), 5.57 (s, 2H, NCH
3
1
1
2
),
Method C: KOH (2 eq) was dissolved in EG (0.5-1.5 ml/mmol)
and added to the respective methyl ester (1 eq). After adding a
few drops of water, the mixture was heated at 160 °C for 14 h.
Water was added to double the volume and the reaction mixture
was acidified to a pH of 3 with 6 N HCl. It was extracted with EA
(3×), the organic layers were combined, washed with brine, and
3
.57 (s, 3H, CO
.79 (m, 2H, CH
2
CH
CH
C-NMR (101 MHz, acetone-d
3
), 2.89 (t, 2H, J = 7.4 Hz, CH
2
CH
2
CH
3
), 1.93-
CH ).
3
2
2
CH
3
), 1.00 (t, 3H, J = 7.4 Hz, CH
2
CH
2
3
3
6
): δ 157.73, 142.31, 141.60,
1
36.71, 132.21, 132.15, 131.39, 130.43, 129.68, 128.25, 127.17,
125.36, 122.37, 114.83, 112.44, 52.07, 47.20, 21.36, 14.19.
+
HRMS: m/z calculated for C25
H23BrN
2
O
2
[M+H] : 463.1016, found:
2 4
dried over anhydrous Na SO . Then it was filtered, the solvent
4
63.1054.
was removed under reduced pressure and the resulting crude
product was purified by chromatography with stepwise gradient
elution (DCM/MeOH, 95:5 to 9:1).
6-Br-CO CH
2
3
: Colorless solid, yield: 13%. 1H-NMR (400 MHz,
): δ 7.77 (dd, 1H, J = 7.7 Hz, 4J = 1.4 Hz, H3), 7.65
3
acetone-d
6
4
(
dd, 1H, J = 1.9 Hz, H7’’), 7.62-7.56 (m, 1H, H5), 7.54 (d, 1H,
J = 8.5 Hz, H4’’), 7.50-7.44 (m, 1H, H4), 7.41 (dd, 1H,
J = 7.6 Hz, J = 1.3 Hz, H5’’), 7.35-7.26 (m, 3H, H6, H2’, H6’),
3
Method D: The respective methyl ester was dissolved in EtOH
and THF (each 1.9 ml/mmol). 2 N KOH (4 ml/mmol) was added
and the mixture was heated at 70 °C for 18 h. After adding water,
6 N HCl was used to reach a pH of 2. The formed precipitate was
sucked off, washed with cold water, and dried in vacuo. The crude
product was purified by recrystallization from MeOH.
3
4
3
7.18 (d, 2H, J = 8.5 Hz, H3’, H5’), 5.59 (s, 2H, NCH
2
), 3.57 (s,
), 1.94-1.80
CH CH
). 13C-
3
3H, CO
2
CH
3
), 2.89 (t, 2H, J = 7.6 Hz, CH
CH
2
CH
2
CH
3
3
(
m, 2H, CH
2
2
CH
3
), 1.01 (t, 3H, J = 7.4 Hz, CH
2
2
3
NMR (101 MHz, acetone-d
6
): δ 169.4, 157.3, 143.2, 142.4, 141.6,
38.0, 136.8, 132.3, 132.2, 131.4, 130.4, 129.7, 128.3, 127.2,
25.4, 121.3, 115.3, 113.8, 52.1, 47.1, 21.4, 14.2.
1
1
4'-((9H-Carbazol-9-yl)methyl)-[1,1'-biphenyl]-2-carboxylic
acid (3a): Method A: from 2a (0.10 g, 0.3 mmol) in THF (15 ml)
with 14% LiOH (1.3 ml). Colorless oil, yield: 46%. 1H-NMR
Methyl 4'-((5-bromo-3-ethyl-2-methyl-1H-indol-1-yl)methyl)-
1,1'-biphenyl]-2-carboxylate (5c): From 18 (0.09 g, 0.4 mmol)
3
[
(400 MHz, acetone-d
6
): δ 8.19 (d, 2H, J = 7.8 Hz, H4’’, H5’’), 7.81
3
4
3
in anhydrous DMF (1 ml) with 60% NaH (0.02 g, 0.8 mmol) and
methyl 4'-(bromomethyl)-[1,1'-biphenyl]-2-carboxylate (0.13 g,
(dd, 1H, J = 7.7 Hz, J = 1.5 Hz, H3), 7.62 (d, 2H, J = 8.2 Hz,
H1’’, H8’’), 7.57-7.50 (m, 1H, H5), 7.50-7.40 (m, 3H, H4, H2’’,
H7’’), 7.33 (dd, 1H, J = 7.6 Hz, J = 1.3 Hz, H6), 7.30-7.20 (m,
6H, H2’, H3’, H5’, H6’, H3’’, H6’’), 5.71 (s, 2H, NCH
). 13C-NMR
(151 MHz, CD OD): δ 142.4, 142.1, 141.9, 138.0, 131.6, 131.5,
.4 mmol). Light brown solid, yield 12%. 1H-NMR (400 MHz,
3
4
0
3
4
acetone-d
6
): δ 7.75 (dd, 1H, J = 8.1 Hz, J = 1.3 Hz, H3), 7.67 (d,
2
4
1
H, J = 1.9 Hz, H4’’), 7.62-7.53 (m, 1H, H5), 7.50-7.42 (m, 1H,
3
H4), 7.39 (dd, 1H, J = 8.0 Hz, 4J = 1.3 Hz, H6), 7.33 (d, 1H,
3
130.1, 129.9, 128.1, 127.4, 126.9, 124.3, 121.1, 120.2, 110.2,
3
3
+
J = 8.6 Hz, H7’’), 7.24 (d, 2H, J = 8.3 Hz, H2’, H6’), 7.16 (dd, 1H,
46.9. HRMS: m/z calculated for C26
H19NO
2
[M+Na] : 400.1308,
3
4
3
J = 8.6 Hz, J = 2.0 Hz, H6’’), 7.04 (d, 2H, J = 8.3 Hz, H3’, H5’),
found: 400.1300.
5
.47 (s, 2H, NCH
2
), 3.57 (s, 3H, CO
), 2.37 (s, 3H, CH
2
CH
3
), 2.76 (q, 2H,
3
3
J = 7.5 Hz, CH
2
CH
3
3
), 1.20 (t, 3H, J = 7.5 Hz,
9
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