One-Pot Directed Alkylation/Deprotection Strategy
1093.4, 1072.6, 1036.8, 1016.8, 997.8, 943.7, 928.7, 943.7, 928.7, 859.5, 833.4, 789.7, 748.6, 710.7, 697.6 cm–1. HRMS (ESI-TOF):
859.5, 833.4, 789.7, 748.6, 710.7, 697.6 cm–1. HRMS (ESI-TOF): calcd. for C17H28IN3O2Si [M + H]+ 462.1072; found 462.1074.
calcd. for C17H29N3O2Si [M + H]+ 336.2101; found 336.2107.
7-Iodo-4-isobutyl-6-(4-methoxybenzyl)-2-methyl-2,6-dihydro-1H-
pyrrolo[3,4-d]pyridazin-1-one (23): Yield 0.451 g, 64%. H NMR
1
4-Isobutyl-6-(4-methoxybenzyl)-2-methyl-2,6-dihydro-1H-pyrrolo-
(400 MHz, CDCl3): δ = 7.24 (s, 1 H), 7.08 (d, J = 8.8 Hz, 2 H),
[3,4-d]pyridazin-1-one (20): A dry 100 mL round-bottomed flask
6.89 (d, J = 8.8 Hz, 2 H), 5.26 (s, 2 H), 3.81 (s, 3 H), 3.70 (s, 3 H),
was put under argon and cooled to 0 °C. Anhydrous DMF
(50 mL), 9 (0.502 g, 2.44 mmol), K2CO3 (0.505 g, 3.65 mmol), p-
methoxybenzyl chloride (0.575 g, 3.65 mmol), and tetrabutylam-
monium iodide (0.089 g, 0.243 mmol) were added. The reaction
2.49 (d, J = 7.0 Hz, 2 H), 2.13–2.03 (septet, 1 H), 0.95 (d, J =
6.6 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.6, 157.6,
143.4, 128.8, 127.3, 121.8, 119.4, 118.7, 114.4, 55.3, 54.6, 42.2, 37.8,
27.8, 22.6 ppm. IR (neat): ν = 2954.7, 2867.8, 1638.3, 1616.5,
˜
mixture was allowed to warm to room temperature over 12 h, after
which time LCMS analysis indicated complete conversion. Satu-
rated aq. NH4Cl solution (10 mL) was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water (3ϫ 25 mL), and brine (25 mL), dried with Na2SO4, and
concentrated. The crude solid was purified using flash chromatog-
raphy (hexanes/ethyl acetate, 1:1) to give 20 (0.69 g, 87%) as a pale
brown solid. 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 2.0 Hz,
1 H), 7.14 (d, J = 8.7 Hz, 2 H), 6.99 (d, J = 2.0 Hz, 1 H), 6.89 (d,
J = 8.7 Hz, 2 H), 5.19 (s, 2 H), 3.82 (s, 3 H), 3.72 (s, 3 H), 2.54 (d,
J = 7.0 Hz, 2 H), 2.17–2.07 (septet, 1 H), 0.97 (d, J = 6.6 Hz, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 162.2, 159.8, 158.3, 143.9,
129.2, 127.6, 120.9, 119.4, 116.4, 115.2, 114.5, 55.4, 54.4, 42.4, 37.8,
1583.6, 1512.4, 1494.5, 1463.6, 1380.7, 1287.7, 1246.3, 1213.5,
1175.4, 1113.7, 1099.7, 1030.5, 997.6, 971.6, 881.8, 822.6, 759.5,
690.5 cm–1. HRMS (ESI-TOF): calcd. for C19H23IN3O2 [M + H]+
452.0833; found 452.0835.
General Procedure for the Alkylation of Compound 18: A dry
100 mL flask containing a stirrer bar was put under argon and
cooled to 0 °C. Anhydrous degassed DMF (10 mL) and NaH
(0.024 g, 0.585 mmol) were added, followed by a solution of 18
(0.200 g, 0.488 mmol) in degassed DMF (5 mL). The mixture was
stirred for 2 h. A solution of 2-chloro-4-bromomethyl pyridine (10;
0.037 g, 0.150 mmol) in degassed anhydrous DMF (5 mL) was then
added dropwise to the reaction mixture, and the resulting mixture
was stirred overnight during which time it was allowed to warm
room temperature. After this time, LCMS and TLC analysis indi-
cated full conversion. NH4Cl solution was added, and the mixture
was extracted with ethyl acetate. The organic extracts were washed
with water and brine, dried over Na2SO4, filtered, and concen-
trated. The resulting crude solid was then dissolved in a minimal
amount of THF to which was added HCl (4.0 m in dioxane, 2 mL).
After 2 h, the solvents were evaporated, and the crude material was
purified by preparative HPLC using a gradient combination of
(methanol/acetonitrile, 1:1) and (water with 1% TFA) to give the
pure product.
27.9, 22.7 ppm. IR (neat): ν = 2955.8, 1634.7, 1581.8, 1535.9,
˜
1515.8, 1464.8, 1347.8, 1306.9, 1285.9, 1243.7, 1209.8, 1178.8,
1151.8, 1075.8, 1041.7, 999.8, 971.9, 936.9, 831.7, 788.8, 755.8,
740.8, 695.8 cm–1. HRMS (ESI-TOF): calcd. for C19H23N3O2 [M
+ H]+ 326.1864; found 326.1869.
General Procedure for Iodination: The protected pyrrole compound
(1 equiv.), and I2 (2 equiv.) in anhydrous THF were added to a
clean dry flask containing a stirrer bar under argon. The mixture
was cooled to –78 °C, and LDA (0.5 m solution in THF; 3 equiv.)
was added dropwise over 10 min. The mixture kept at –78 °C for
4 h, and then it was warmed to room temperature over 15 h. MeOH
(10 mL) was added, and the mixture was stirred for 30 min. Satu-
rated aq. NH4Cl solution (30 mL) was added, and the mixture was
extracted with ethyl acetate. The combined organic layers were
washed with water (3 ϫ 25 mL), and brine (25 mL), dried with
Na2SO4, and concentrated. The crude solid was purified by flash
chromatography to give the desired iodinated product.
6-[(2-Chloropyridin-4-yl)methyl]-7-[(3-hydroxypropyl)thio]-4-iso-
butyl-2-methyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (35):
1
Pale brown oil (0.024 g, 70%). H NMR (400 MHz, CDCl3): δ =
8.32 (s, 1 H), 7.33 (obscured d, 1 H), 7.15 (s, 1 H), 5.52 (s, 2 H),
3.67 (s, 3 H), 3.54 (t, J = 6.1 Hz, 2 H), 2.93 (d, J = 7.2 Hz, 2 H),
2.60 (d, J = 7.3 Hz, 2 H), 2.20–2.09 (m, 1 H), 1.65–1.58 (m, 2 H),
0.96 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
157.7, 152.5, 150.3, 149.0, 143.6, 124.3, 121.8, 121.6, 119.9, 118.6,
117.0, 59.4, 49.8, 46.7, 41.9, 38.3, 35.3, 30.8, 29.7, 27.9, 22.7, 22.7,
7-Iodo-4-isobutyl-2-methyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-
1-one (21): In this case, the Boc protecting group was found to be
removed, giving compound 21 (0.627 g, 62 %). 1 H NMR
(400 MHz, CDCl3): δ = 10.76 (br. s, 1 H), 7.32 (s, 1 H), 3.74 (s, 3
H), 2.57 (d, J = 7.4 Hz, 2 H), 2.18–2.07 (septet, 1 H), 0.96 (d, J =
6.6 Hz, 6 H), 0.93 (obscured t, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.0, 144.9, 123.2, 121.2, 120.4, 70.2, 68.3, 43.7, 39.2,
14.1, 8.7 ppm. IR (neat): ν = 3422.9, 2955.8, 1726.8, 1630.7, 1594.7,
˜
1552.8, 1491.8, 1466.7, 1388.7, 1348.7, 1241.5, 1222.5, 1158.5,
1124.7, 1087.7, 1063.7, 1028.3, 876.8, 832.8, 767.7, 757.8, 716.7,
696.7 cm–1. HRMS (ESI-TOF): calcd. for C20H26N4O2ClS [M +
H]+ 421.1465; found 421.1454.
29.3, 24.1, 19.2, 0.0 ppm. IR (neat): ν = 2953.8, 1731.9, 1635.5,
˜
6-[(6-Chloropyridin-3-yl)methyl]-7-[(3-hydroxypropyl)thio]-4-iso-
1586.8, 1536.9, 1495.8, 1464.8, 1406.8, 1347.7, 1286.8, 1249.7,
1210.7, 1177.8, 1074.6, 1035.7, 1000.7, 973.8, 937.7, 915.8, 855.6,
833.3, 788.7, 758.6, 693.6, 663.7 cm–1. HRMS (ESI-TOF): calcd.
for C11H14IN3O [M + H]+ 332.0264; found 332.0260.
butyl-2-methyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (36):
1
Buff solid (0.016 g, 48%). H NMR (400 MHz, CDCl3): δ = 8.29
(d, J = 4.7 Hz, 1 H), 7.73 (s, 1 H), 7.12 (s, 1 H), 6.99 (d, J = 6.3 Hz,
1 H), 5.65 (s, 2 H), 3.94 (t, J = 6.1 Hz, 2 H), 3.74 (s, 3 H), 3.08
(obscured t, 2 H), 2.55 (d, J = 6.6 Hz, 2 H), 2.15–2.08 (m, 1 H),
7-Iodo-4-isobutyl-2-methyl-6-{[2-(trimethylsilyl)ethoxy]methyl}-2,6-
dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (22): Yield 0.728 g, 68%. 1.83–1.77 (m, 2 H), 0.96 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR
1H NMR (400 MHz, CDCl3): δ = 7.42 (s, 1 H), 5.47 (s, 2 H), 3.69
(100 MHz, CDCl3): δ = 157.8, 151.5, 148.4, 143.6, 137.4, 131.2,
(s, 3 H), 3.54 (br. t, 2 H), 2.53 (d, J = 7.0 Hz, 2 H), 2.16–2.06 124.7, 123.8, 121.5, 118.5, 116.7, 59.5, 48.2, 41.9, 38.2, 35.3, 30.9,
(septet, 1 H), 0.97 (d, J = 6.6 Hz, 6 H), 0.92 (br. t, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.8, 145.6, 122.6, 120.6, 118.1,
27.8, 22.6 ppm. IR (neat): ν = 3401.8, 3092.9, 2953.7, 2868.8,
˜
1724.9, 1632.4, 1586.6, 1564.7, 1537.8, 1490.6, 1460.5, 1383.6,
1346.5, 1333.5, 1285.7, 1245.7, 1206.6, 1164.7, 1133.7, 1101.5,
1060.6, 1022.5, 998.6, 968.7, 908.7, 851.7, 832.6, 801.7, 765.6,
116.3, 81.2, 68.4, 43.8, 39.3, 29.4, 24.1, 19.1, 0.0 ppm. IR (neat): ν
˜
= 3095.9, 2951.7, 2866.8, 1636.4, 1586.7, 1534.7, 1459.8, 1427.8,
1399.8, 1355.7, 1335.8, 1288.9, 1249.6, 1203.7, 1167.8, 1146.7, 691.5 cm–1. HRMS (ESI-TOF): calcd. for C20H26N4O2ClS [M +
1093.4, 1072.6, 1036.8, 1016.8, 997.8, 943.7, 928.7, 943.7, 928.7, H]+ 421.1465; found 421.1452.
Eur. J. Org. Chem. 2015, 1764–1770
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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