N
Synthesis
S. E. Pearson et al.
Paper
1
H NMR (500 MHz, DMSO-d ): δ = 10.80 (br s, 1 H), 9.54 (s, 1 H), 7.42
6-Fluoro-1-(7-hydroxy-1H-indol-3-yl)-7-methoxy-N,N-dimethyli-
soquinoline-2(1H)-sulfonamide (51)
6
(d, J = 7.8 Hz, 1 H), 7.27–7.33 (m, 2 H), 7.24 (dd, J = 7.8, 1.7 Hz, 1 H),
6
1
3
.80 (t, J = 7.8 Hz, 1 H), 6.69 (dd, J = 7.4, 1.3 Hz, 1 H), 6.65 (d, J = 2.4 Hz,
H), 6.46–6.51 (m, 2 H), 6.24 (d, J = 7.4 Hz, 1 H), 2.98 (s, 3 H), 2.92 (s,
H), 2.55 (s, 6 H).
Synthesised by a method analogous to that used for 37, starting from
dimethylsulfamoyl chloride (34; 0.079 mL, 0.73 mmol), 6-fluoro-7-
methoxyisoquinoline (17; 100 mg, 0.56 mmol), DIPEA (0.128 mL, 0.73
mmol) and 1H-indol-7-yl acetate (33; 99 mg, 0.56 mmol). The 3-com-
ponent coupling took place in 40% yield, after concentrating the mix-
ture and stirring at 50 °C for 8 h. The deprotection was carried out in
55% yield to afford the title compound 51 (52 mg) as a white solid; mp
13
C NMR (126 MHz, DMSO-d ): δ = 170.3, 144.0, 136.3, 133.0, 130.2,
6
1
1
27.3, 127.1, 126.8, 126.7, 126.3, 124.2, 123.6, 120.1, 116.1, 111.1,
10.6, 106.1, 54.7, 39.2, 38.2, 35.5.
MS (ES–): m/z = 439 [M – H]–.
178–179 °C.
1
H NMR (500 MHz, DMSO-d ): δ = 10.75 (d, J = 1.9 Hz, 1 H), 9.50 (s, 1
7
2
-Ethyl-1-(7-hydroxy-1H-indol-3-yl)-N,N-dimethylisoquinoline-
(1H)-sulfonamide (49)
6
H), 7.35 (d, J = 7.9 Hz, 1 H), 7.27 (d, J = 8.5 Hz, 1 H), 7.18 (d, J = 11.9 Hz,
1
H), 6.46 (s, 1 H), 6.15 (d, J = 7.4 Hz, 1 H), 3.79 (s, 3 H), 2.56 (s, 6 H).
H), 6.80 (t, J = 7.9 Hz, 1 H), 6.53 (d, J = 2.4 Hz, 1 H), 6.48–6.52 (m, 2
Synthesised by a method analogous to that used for 37, starting from
dimethylsulfamoyl chloride (34; 0.105 mL, 0.98 mmol), 7-ethyliso-
quinoline (21; 140 mg, 0.89 mmol), DIPEA (0.171 mL, 0.98 mmol) and
13
C NMR (126 MHz, DMSO-d ): δ = 152.1 (J = 242.7 Hz), 146.9 (J = 11.1
6
Hz), 143.9, 128.7 (J = 2.9 Hz), 127.5, 126.9, 125.0, 124.5, 123.7 (J = 7.8
Hz), 120.1, 115.7, 112.7, 112.5, 112.4, 111.2, 106.0, 56.6, 54.4, 38.2.
MS (ES–): m/z = 416 [M – H]–.
1
H-indol-7-yl acetate (33; 156 mg, 0.89 mmol). The 3-component
coupling took place in 31% yield, after concentrating the mixture and
stirring at 50 °C for 1 h. The deprotection was carried out in 89% yield
to afford the title compound 49 (116 mg) as a beige foam.
1
H NMR (500 MHz, DMSO-d ): δ = 10.72 (br s, 1 H), 9.49 (s, 1 H), 7.30
5-(7-Hydroxy-1H-indol-3-yl)-N,N-dimethyl-[1,3]dioxolo[4,5-g]iso-
quinoline-6(5H)-sulfonamide (52)
6
(d, J = 8.1 Hz, 1 H), 7.14–7.19 (m, 2 H), 7.12 (dd, J = 7.8, 1.6 Hz, 1 H),
6
1
.78 (t, J = 7.8 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 6.53 (dd, J = 7.4, 1.3 Hz,
H), 6.48 (dd, J = 7.50, 0.6 Hz, 1 H), 6.38 (s, 1 H), 6.18 (d, J = 7.4 Hz, 1
Synthesised by a method analogous to that used for 37, starting from
dimethylsulfamoyl chloride (34; 0.099 mL, 0.92 mmol), 6,7-methy-
lenedioxyisoquinoline (19; 145 mg, 0.92 mmol), DIPEA (0.160 mL,
0.92 mmol) and 1H-indol-7-yl acetate (33; 161 mg, 0.92 mmol). The
3-component coupling took place in 31% yield, after concentrating
the mixture and stirring at 50 °C for 2 h. The deprotection was carried
out in 93% yield to afford the title compound 52 (101 mg) as a colour-
less oil.
H), 2.53 (s, 6 H), 2.52 (q, J = 7.6 Hz, 2 H), 1.14 (t, J = 7.6 Hz, 3 H).
13
C NMR (126 MHz, DMSO-d ): δ = 143.9, 143.7, 132.4, 127.9, 127.5,
6
1
1
27.4, 126.8, 126.1, 125.4, 125.1, 124.2, 120.0, 116.3, 111.6, 111.1,
06.0, 55.0, 38.2, 28.4, 15.9.
MS (ES–): m/z = 396 [M – H]–.
HRMS: m/z [M – H]– calcd for C21H23N O S: 396.1382; found:
3
3
1
H NMR (400 MHz, CDCl ): δ = 8.19 (s, 1 H), 7.54 (d, J = 8.1 Hz, 1 H),
3
396.1370.
6
.94 (dd, J = 8.1, 7.5 Hz, 1 H), 6.67 (s, 2 H), 6.62 (s, 1 H), 6.55 (d, J = 7.5
Hz, 1 H), 6.46 (dd, J = 7.3, 1.1 Hz, 1 H), 6.39 (s, 1 H), 5.99 (d, J = 7.3 Hz,
H), 5.96 (d, J = 1.3 Hz, 1 H), 5.93 (d, J = 1.3 Hz, 1 H), 2.63 (s, 6 H).
MS (ES–): m/z = 412 [M – H]–.
6
2
-Ethyl-1-(7-hydroxy-1H-indol-3-yl)-N,N-dimethylisoquinoline-
(1H)-sulfonamide (50)
1
Synthesised by a method analogous to that used for 37, starting from
dimethylsulfamoyl chloride (34; 0.063 mL, 0.58 mmol), 6-ethyliso-
quinoline (22; 83 mg, 0.53 mmol), DIPEA (0.102 mL, 0.58 mmol) and
1-(7-Hydroxy-1H-indol-3-yl)-6,7-dimethoxy-N,N-dimethyliso-
quinoline-2(1H)-sulfonamide (53)
1
H-indol-7-yl acetate (33; 93 mg, 0.53 mmol). The 3-component cou-
pling took place in 38% yield, after concentrating the mixture and
stirring at 50 °C for 5 h. After deprotection, purification was carried
out first by flash silica gel chromatography, eluting with 5 to 70%
EtOAc in heptane, then by flash reverse-phase chromatography [elu-
ent: gradient 35 to 60% MeCN in H O (containing 1% NH OH as modi-
Synthesised by a method analogous to that used for 47, starting from
dimethylsulfamoyl chloride (34; 0.072 mL, 0.67 mmol), 6,7-dime-
thoxyisoquinoline (24; 115 mg, 0.61 mmol), DIPEA (0.116 mL, 0.67
mmol) and 1H-indol-7-yl acetate (33; 106 mg, 0.61 mmol). For the 3-
component coupling, the mixture was concentrated and heated to
50 °C for 5 h. Additional 34 (0.036 mL, 0.33 mmol) and DIPEA (0.058
mL, 0.33 mmol) were added and heating continued for a further 3 h at
50 °C, giving the acetyl ester intermediate in 38% isolated yield. After
deprotection, purification was carried out by flash reverse-phase
2
4
fier)]. The title compound 50 (58 mg) was obtained in 83% yield as a
cream-coloured solid; mp 144–148 °C.
1
H NMR (500 MHz, DMSO-d ): δ = 10.71 (br s, 1 H), 9.49 (s, 1 H), 7.31
6
(d, J = 8.0 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 1 H), 7.08–7.11 (m, 2 H), 6.76–
chromatography [eluent: gradient 30 to 60% MeCN in H O (containing
2
6
6
.81 (m, 1 H), 6.60 (dd, J = 7.4, 1.3 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H),
.47–6.50 (m, 1 H), 6.39 (s, 1 H), 6.17 (d, J = 7.4 Hz, 1 H), 2.60 (q, J = 7.6
1
% NH OH as modifier)]. The title compound 53 (76 mg) was obtained
4
in 84% yield as a cream-coloured solid; mp 187–190 °C.
1H NMR (500 MHz, DMSO-d
): δ = 10.70 (d, J = 2.1 Hz, 1 H), 9.48 (s, 1
H), 7.35 (d, J = 8.0 Hz, 1 H), 7.02 (s, 1 H), 6.92 (s, 1 H), 6.79 (t, J = 7.9 Hz,
Hz, 2 H), 2.54 (s, 6 H), 1.19 (t, J = 7.6 Hz, 3 H).
13
6
C NMR (126 MHz, DMSO-d ): δ = 143.9, 143.5, 130.1, 129.8, 127.4,
6
1
1
27.3, 126.8, 126.7, 126.2, 124.4, 124.1, 120.0, 116.6, 111.5, 111.2,
06.0, 54.8, 38.2, 28.3, 15.9.
1
6
H), 6.45–6.51 (m, 2 H), 6.42 (dd, J = 7.3, 1.2 Hz, 1 H), 6.38 (s, 1 H),
.17 (d, J = 7.3 Hz, 1 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 2.56 (s, 6 H).
HRMS: m/z [M – H]– calcd for C21H23N O S: 396.1382; found:
3
3
13
C NMR (126 MHz, DMSO-d ): δ = 148.8, 148.5, 143.9, 127.6, 126.9,
6
396.1370.
1
1
24.8, 124.5, 124.0, 123.3, 119.9, 116.1, 112.5, 111.3, 110.7, 108.8,
06.0, 56.1, 56.0, 54.5, 38.3.
MS (ES–): m/z = 428 [M – H]–.
HRMS: m/z [M – H]– calcd for C21H23N O S: 428.1280; found:
3
5
428.1264.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–S