Journal of Medicinal Chemistry
Article
Table 5. Experimental Details of the Optimized One-Pot Masuda−Suzuki Synthesis of the Alocasin A and Hyrtinadine A
Derivatives 4 by Using Methanol as a Cosolvent
entry
(7-aza)indole 2 [mg] ([mmol])
heteroaryl dihalide 3 [mg] ([mmol])
142 (0.50) of 5-bromo-2-iodopyrimidine (3e)
118 (0.50) of 2,6-dibromopyridine (3b)118 mg (0.50) of 2,6-
dibromopyridine (3b)
yield [mg] (%)
1
2
432 (1.00) of 5-chloro-3-iodo-1-tosyl-1H-indole (2c)
3-iodo-5-methoxy-1-tosyl-1H-indole (2a)
427 mg/1.00 mmol
177 (93) of 4j
142 (77) of 4l
3
4
5
3-iodo-5-fluoro-1-tosyl-1H-indole (2b)
432 (1.00) of 5-chloro-3-iodo-1-tosyl-1H-indole (2c)
398 (1.00) 3-iodo-1-tosyl-7-azaindol (2g)
118 (0.50) of 2,6-dibromopyridine (3b)
118 (0.50) of 2,6-dibromopyridine (3b)
118 (0.50) of 2,6-dibromopyridine (3b)
140 (81) of 4m
160 (84) of 4n
120 (90) of 4p
a
a
Even after repeated drying in vacuo at 80 °C for 42 h, dichloromethane in the crystal could not be completely removed.
2,5-Bis(5-bromo-1H-indole-3-yl)pyrazine (4d) (172 mg, 74%);
Mp, 287 °C. 1H NMR (300 MHz, DMSO-d6) δ 7.32 (dd, J = 8.6, 2.0
Hz, 2H), 7.46 (dd, J = 8.6, 0.6 Hz, 2H), 8.32 (d, J = 2.5 Hz, 2H), 8.67
(d, J = 1.9 Hz, 2H), 9.19 (s, 2H), 11.85 (s, 2H) (see Supporting
Information Figure S15). 13C NMR (126 MHz, DMSO-d6) δ 112.6,
113.2, 114.2, 124.0, 124.8, 127.2, 127.3, 136.0, 140.4, 146.6 (see
Supporting Information Figure S16). MS (ESI) m/z: calcd for
(C20H1279Br81BrN4 + H)+, 469.2; found, 469.3. Anal calcd for
C20H12Br2N4 (468.2): C, 51.31; H, 2.58; N, 11.97; found: C, 51.04;
H, 2.59; N, 11.78.
(7-Aza)indole (1.00 mmol) 2 and tetrakis(triphenylphosphane)-
palladium(0) (67 mg, 0.06 mmol) were placed in a dry screw-capped
vessel with a magnetic stir bar (for experimental details, see Table 5).
After three cycles of evacuating and refilling with dry argon, degassed
dry 1,4-dioxane (4.00 mL) was added. Then, dry triethylamine (1.40
mL, 10.0 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25
mL, 1.70 mmol) were successively added. Then, the reaction mixture
was stirred in a preheated oil bath at 80 °C for 4 h. The mixture was
cooled down to room temp. (water bath). Dry methanol (7.00 mL)
was added, and the mixture was stirred at room temp. for 10 min.
After the addition of heteroaryl dihalide 3 (0.50 mmol) and cesium
carbonate (823 mg, 2.50 mmol), the mixture was stirred in a
preheated oil bath at 60 °C for 18 h. After the Suzuki coupling was
completed, the mixture was cooled to room temp. (water bath).
Ground potassium hydroxide (140 mg, 2.50 mmol) was added, and
the reaction mixture was stirred at 100 °C for 4 h. Then, after cooling
to room temp. (water bath), the solvents were removed in vacuo, and
the residue was adsorbed onto Celite. After purification by
chromatography on silica gel (dichloromethane/methanol/aqueous
ammonia, 100:1:1), the desired compounds 4 were obtained (pure
according to 1H NMR). For further purification, trituration in
dichloromethane (3 × 10 mL) by ultrasonication was necessary.
3,3′-(Pyrimidine-2,5-diyl)bis(5-chloro-1H-indole) (4j), colorless
solid (177 mg, 93%); Mp, 266 °C. 1H NMR (DMSO-d6, 600
MHz): δ = 7.21 (d, J = 8.6 Hz, 2H), 7.52 (dd, J = 8.5 Hz, 4.2 Hz,
2H), 7.97 (s, 1H), 8.01 (s, 1H), 8.30 (s, 1H), 8.62 (s, 1 H), 9.13 (s,
2H), 11.80 (s, 1H), 11.86 (s, 1H) (see Supporting Information Figure
S21). 13C NMR (DMSO-d6, 150 MHz): δ = 109.8, 114.1, 115.0,
118.8, 121.5, 122.3, 122.4, 125.3, 126.4, 127.1, 130.6, 135.8, 136.0,
154.6, 160.8 (see Supporting Information Figure S22). HR-MS (ESI)
m/z: calcd for [C20H12Cl352N4 + H]+, 379.0519; found, 379.0514.
Anal calcd for C20H12Cl2N4 (379.2): C, 63.34; H, 3.19; N, 14.77;
found: C, 63.15; H, 3.02; N, 14.51.
2,5-Bis(5,6-dibromo-1H-indole-3-yl)pyrazine (4e) (122 mg, 39%);
1
Mp, >300 °C. H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 2H), 8.36
(d, J = 2.8 Hz, 2H), 8.86 (s, 2H), 9.21 (s, 2H), 11.92 (d, J = 2.4 Hz,
2H) (see Supporting Information Figure S17). 13C NMR (126 MHz,
DMSO-d6) δ 113.0, 115.4, 116.9, 117.5, 126.5, 127.04, 128.7, 137.5,
141.0, 146.9 (see Supporting Information Figure S18). MS (ESI) m/
z: calcd for (C20H1079Br281Br2N4 + H)+, 627.0; found, 627.1. Anal
calcd for C20H10Br4N4 (625.9): C, 38.38; H, 1.61; N, 8.95; found: C,
38.67; H, 1.66; N, 8.86.
2,5-Bis(6-bromo-1H-indole-3-yl)pyrazine (4f) (206 mg, 88%); Mp,
284 °C. 1H NMR (300 MHz, DMSO-d6) δ 7.29 (dd, J = 8.6, 1.8 Hz,
2H), 7.67 (d, J = 1.5 Hz, 2H), 8.28 (s, 2H), 8.40 (d, J = 8.6 Hz, 2H),
9.14 (s, 2H), 11.77 (s, 2H) (see Supporting Information Figure S19).
13C NMR (151 MHz, DMSO-d6) δ 113.2, 114.9, 115.1, 123.5, 123.6,
124.7, 127.0, 138.3, 140.6, 146.8 (see Supporting Information Figure
S20). MS (ESI) m/z: calcd for (C20H1279Br81BrN4 + H)+, 469.15;
found, 469.3. Anal calcd for C20H12Br2N4 (468.2): C, 51.31; H, 2.58;
N, 11.97; found: C, 50.97; H, 2.45; N, 11.65.
2,6-Bis(5-chloro-1H-indole-3-yl)pyridine (4n) (77 mg, 41%); Mp,
241 °C. 1H NMR (300 MHz, DMSO-d6) δ 7.19 (dd, J = 8.6, 2.1 Hz,
2H), 7.50 (dd, J = 8.6, 0.5 Hz, 2H), 7.64−7.59 (m, 2H), 7.76 (dd, J =
8.5, 7.1 Hz, 1H), 8.19 (d, J = 2.8 Hz, 2H), 8.56 (d, J = 2.1 Hz, 2H),
11.73 (d, J = 2.8 Hz, 2H) (see Supporting Information Figure S27).
13C NMR (75 MHz, DMSO-d6) δ 113.2, 115.7, 116.1, 120.7, 121.6,
124.7, 126.3, 127.2, 135.4, 136.7, 154.0 (see Supporting Information
Figure S28). MS (ESI) m/z: calcd for [C21H13Cl352N3 + H]+, 378.1;
found, 378.5. Anal calcd for C21H13Cl2N3 (378.3): C, 66.68; H, 3.46;
N, 11.11; found: C, 66.69; H, 3.17; N, 10.83.
2,6-Bis(5-chloro-1H-indole-3-yl)pyrazine (4r) (124 mg, 65%); Mp,
253 °C. 1H NMR (600 MHz, DMSO-d6) δ 7.21 (dd, J = 8.6, 2.2 Hz,
2H), 7.51 (d, J = 8.6 Hz, 2H), 8.34 (d, J = 2.8 Hz, 2H), 8.52 (d, J =
2.1 Hz, 2H), 9.19 (s, 2H), 11.85 (d, J = 2.7 Hz, 2H) (see Supporting
Information Figure S33). 13C NMR (151 MHz, DMSO-d6) δ 112.8,
113.9, 121.2, 122.4, 125.3, 126.8, 127.6, 135.9, 140.6, 146.8 (see
Supporting Information Figure S34). HR-MS (ESI) calcd for
(C20H12Cl352N4 + H)+ m/z, 379.0512. Found m/z, 379.0511. Anal
calcd for C20H12Cl2N4 (379.24): C, 63.34; H, 3.19; N, 14.77; found:
C, 63.15; H, 3.00; N, 14.66.
2,6-Bis(5-methoxy-1H-indol-3-yl)pyridine (4l), colorless solid (142
1
mg, 77%); Mp, 149 °C. H NMR (DMSO-d6, 300 MHz): δ 3.67 (s,
6H), 6.82 (dd, J = 8.8 Hz, 2.5 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.54
(d, J = 7.8 Hz, 2H), 7.72 (dd, J = 8.4 Hz, 1H), 8.05 (d, J = 2.8 Hz,
2H), 8.08 (d, J = 2.5 Hz, 2H), 11.36 (d, J = 2.9 Hz, 2H) (see
Supporting Information Figure S23). 13C NMR (acetone-d6,75
MHz): δ 55.8, 104.9, 113.0, 113.1, 116.6, 118.2, 126.4, 127, 133.6,
137.3, 155.8, 156.2 (see Supporting Information Figure S24). MS
(ESI) m/z: calcd for [C23H19N3O2 + H+]+, 370.4; found, 370.3. Anal
calcd for C23H19N3O2 (369.4): C, 74.78; H, 5.18; N, 11.37; found: C,
74.55; H, 5.34; N, 11.08.
2,6-Bis(5-fluoro-1H-indol-3-yl)pyridine (4m), colorless solid (140
mg, 81%); Mp, 227−229 °C. 1H NMR (DMSO-d6, 300 MHz): δ 7.04
(td, J = 9.1 Hz, 2.6 Hz, 2H), 7.43−7.53 (m, 2H), 7.57−7.64 (m, 2H),
7.75 (dd, J = 8.4 Hz, 7.1 Hz, 1H), 8.19 (d, J = 2.7 Hz, 2H), 8.24 (dd, J
= 10.8 Hz, 2.6 Hz, 2H), 11.60−11.73 (m, 2H) (see Supporting
Information Figure S25). 13C NMR (DMSO-d6, 75 MHz): δ 106.1
(d, J = 24.6 Hz), 109.8 (d, J = 26.1 Hz), 112.8 (d, J = 9.9 Hz), 115.9,
116.26 (d, J = 4.8 Hz), 125.6 (d, J = 10.8 Hz), 127.6, 133.7, 136.8,
154.2, 157.6 (d, J = 231.7 Hz) (see Supporting Information Figure
S26). MS (ESI) m/z: calcd for [C21H13F2N3 + H+]+, 346.3; found,
346.3. Anal calcd for C21H13F2N3 (345.4): C, 73.04; H, 3.79; N,
12.17; found: C, 73.06; H, 4.03; N, 11.94.
3,6-Bis(5-chloro-1H-indole-3-yl)pyridazine (4s) (0.143 mg, 75%);
Mp, 268 °C. 1H NMR (600 MHz, DMSO-d6) δ 7.24 (dd, J = 8.6, 2.1
Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 8.13 (s, 2H), 8.37 (d, J = 2.6 Hz,
2H), 8.67 (d, J = 2.1 Hz, 2H), 11.91−11.87 (m, 2H) (see Supporting
Information Figure S35). 13C NMR (151 MHz, DMSO-d6) δ 112.9,
113.8, 121.8, 122.5, 123.9, 125.4, 126.4, 128.8, 136.0, 154.5 (see
Supporting Information Figure S36). HR-MS (ESI) m/z: calcd for
[C20H12Cl352N4 + H]+, 379.0512; found, 379.0516. HPLC, 98.66%.
M
J. Med. Chem. XXXX, XXX, XXX−XXX