G. Pattison et al. / Tetrahedron 65 (2009) 8844–8850
8849
2
2
2
3
NHCH2CH2CH2CH3), 68.6 (s, C60), 81.7 (s, C20), 126.5 (dd, JCF 30.4,
(dd, JCF 31.4, JCF 6.9, C5), 144.0 (dd, 1JCF 257.2, JCF 10.2, C4), 147.3
2JCF 8.0, C5), 138.5 (dd, 1JCF 243.7, 3JCF 10.4, C4), 145.6 (dd, 1JCF 232.5,
3JCF 10.4, C6),155.3 (d, 2JCF 22.4, C3); dF (376 MHz, CDCl3) ꢁ100.0 (1F,
(dd, JCF 239.2, JCF 8.9, C6), 155.8 (d, JCF 22.6, C3); dF (376 MHz,
1
3
2
4
4
CDCl3) ꢁ97.7 (1F, d, JFF 20.4, F6), ꢁ141.1 (1F, d, JFF 20.4, F4); m/z
(ESþ) 324 (15%, [MþNaþMeCN]þ), 218 (68, [M–THPþMeCN]þ), 177
(79, [M–THPþH]þ).
d, JFF 22.4, F6), ꢁ150.5 (1F, d, JFF 22.4, F5); m/z (ESþ) 288 (11%,
3
3
[MþH]þ) 245 (45, [MꢁTHPþMeCN]þ), 204 (100, [MꢁTHPþH]þ).
4.5.3. 5,6-Difluoro-2-(tetrahydro-2H-pyran-2-yl)-4-morpholinopyr-
idazin-3(2H)-one 6b. 4,5,6-Trifluoro-2-(tetrahydro-2H-pyran-2-yl)-
pyridazin-3(2H)-one (0.10 g, 0.427 mmol), morpholine (0.038 ml,
0.427 mmol) and acetonitrile (5 ml), after filtration and evaporation,
the crude material was purified by flash column chromatography
(Hexane/ethyl acetate 4:1), gave 5,6-difluoro-2-(tetrahydro-2H-
pyran-2-yl)-4-morpholinopyridazin-3(2H)-one 6b (0.075 g, 58%) as
a white solid; mp 86–87 ꢀC (Found C, 51.6; H, 5.7; N, 13.6.
C13H17F2N3O3 requires C, 51.8; H, 5.7; N, 14.0%); nmax/cmꢁ1 1008,
1042, 1119, 1145, 1199, 1235, 1372, 1571, 1624, 1657, 2931 (br); dH
(700 MHz, CDCl3) 1.53 (1H, d, 2JHH 8.9), 1.60–1.69 (3H, m), 1.98–2.04
4.5.6. 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-4,5-dimorpholinopyr-
idazin-3(2H)-one 8a. 4,5,6-Trifluoro-2-(tetrahydro-2H-pyran-2-yl)-
pyridazin-3(2H)-one (100 mg, 0.427 mmol), morpholine (0.075 ml,
0.854 mmol) and acetonitrile (5 ml), after purification by mass di-
rected automated purification in DMSO/methanol (1:1) as eluant,
gave 6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-4,5-dimorpholinopyr-
idazin-3(2H)-one 8a (0.0703 g, 45%) as a white solid; mp 133–
134 ꢀC (Found [MH]þ 369.1931. C17H25FN4O4 requires [MH]þ
369.1933); nmax/cmꢁ1 1040, 1085, 1259, 1490, 1531, 1596, 1637, 2820
(br); dH (400 MHz, CDCl3) 1.52–1.60 (1H, m), 1.65 (3H, wt (peak
underneath), 2JHH 11.8), 1.99–2.06 (1H, m), 2.11–2.22 (1H, m), 3.12–
3
3
(1H, m), 2.09–2.16 (1H, m), 3.56 (4H, t, JHH 4.8, C200(H)), 3.68 (1H,
3.22 (4H, m, C200/C2%(H)), 3.40 (4H, t, JHH 4.5, C200/C2%(H)), 3.68
td, 2JHH 12.1, 3JHH 2.5, C60(H)), 3.78 (4H, t, 3JHH 4.8, C300(H)), 4.09 (1H,
(1H, dt, 2JHH 11.4, 3JHH 2.3, C60(H)), 3.75 (4H, t, 3JHH 4.8, C300/C3%(H)),
3.77 (4H, t, 3JHH 4.5, C300/C3%(H)), 4.08 (1H, ddd, 2JHH 11.4, 3JHH 2.0,
2
3
3
dd, JHH 12.1, JHH 4.2, C60(H)), 5.88 (1H, d, JHH 11.3, C20(H)); dC
(100 MHz, CDCl3) 23.0 (s, CH2), 25.0 (s, CH2), 28.6 (s, CH2), 49.8 (d,
4JCF 4.7, C200), 67.4 (d, 5JCF 1.4, C300), 69.0 (s, C60), 83.5 (s, C20), 134.3 (d,
2JCF 6.8, C5), 137.7 (dd, 1JCF 269.0, 2JCF 33.0, C4), 146.9 (dd, 1JCF 233.7,
2JCF 19.2, C6), 159.2 (d, 3JCF 9.6, C3); dF (376 MHz, CDCl3) ꢁ104.7 (1F,
3
3
4
2.0, C60(H)), 5.82 (1H, ddd, JHH 10.8, JHH 2.0, JHH 2.0, C20(H)); dC
(100 MHz, CDCl3) 22.8 (s, CH2), 24.8 (s, CH2), 28.3 (s, CH2), 49.9 (s,
C200), 50.0 (d, 4JCF 4.0, C2%), 67.0 (s, C300/C3%/C60), 67.4 (s, C300/C3%/
C60), 68.7 (s, C300/C3%/C60), 82.7 (s, C20), 129.8 (d, 2JCF 28.0, C5), 140.9
(d, 3JCF 11.2, C4), 152.3 (d, 1JCF 238.1, C6), 159.3 (s, C3); dF (376 MHz,
CDCl3) ꢁ91.4 (1F, s, F6); m/z (ESþ) 369 (33%, [MþH]þ), 285 (100,
[MþHꢁTHP]þ).
d, JFF 28.2, F6), ꢁ147.1 (1F, d, JFF 28.2, F5); m/z (ESþ) 365 (100%,
3
3
[MþNaþMeCN]þ).
4.5.4. 4-(4-Methoxyphenylamino)-5,6-difluoro-2-(tetrahydro-2H-
pyran-2-yl)pyridazin-3(2H)-one 6c. 4,5,6-Trifluoro-2-(tetrahydro-
2H-pyran-2-yl)pyridazin-3(2H)-one (100 mg, 0.427 mmol), p-ani-
sidine (0.1052 g, 0.854 mmol) and acetonitrile (5 ml), after mass
directed automated purification by flash column chromatography
using ethyl acetate/hexaned10–33% EtOAc as eluant, gave 4-(4-
methoxyphenylamino)-5,6-difluoro-2-(tetrahydro-2H-pyran-2-yl)-
pyridazin-3(2H)-one 6c (0.029 g, 20%) as a white solid; mp
162–164 ꢀC; (Found [MH]þ 338.1312. C16H17F2N3O3 requires [MH]þ
338.1311); nmax/cmꢁ1 1041, 1235, 1506, 1575, 1627, 1655, 2888 (br),
3204 (br); dH (400 MHz, CDCl3) 1.52–1.59 (1H, m), 1.64–1.79 (4H,
4.5.7. 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-4,5-diphenoxypyr-
idazin-3(2H)-one 8b. 4,5,6-Trifluoro-2-(tetrahydro-2H-pyran-2-yl)-
pyridazin-3(2H)-one (100 mg, 0.427 mmol), sodium phenoxide
(0.0991 g, 0.854 mmol) and acetonitrile (5 ml), after purification by
mass directed automated purification using DMSO/methanol (1:1)
as eluant and passage through a NH2 SPE column, gave 6-fluoro-2-
(tetrahydro-2H-pyran-2-yl)-4,5-diphenoxypyridazin-3(2H)-one 8b
(0.0891 g, 55%) as a colourless oil; (Found [MH]þ 383.1404.
C21H19FN2O4 requires [MH]þ 383.1407); dH (400 MHz, CDCl3) 1.57
2
3
(1H, dd, JHH 7.0, JHH 2.0), 1.68–1.78 (3H, m), 2.02–2.08 (1H, m),
2
3
3
m), 2.00–2.16 (2H, m), 3.72 (1H, ddd, JHH 11.4, JHH 11.5, JHH 2.5,
C60(H)), 3.80 (3H, s, CH3), 4.09 (1H, ddd, 2JHH 11.4, 3JHH 2.0, 3JHH 1.8,
C60(H)), 5.96 (1H, ddd, 3JHH 10.8, 3JHH 1.8, 4JHH 1.8, C20(H)), 6.86 (2H,
2.13–2.24 (1H, m), 3.72 (1H, td, 2JHH 11.5, 3JHH 2.5, C60(H)), 4.14 (1H,
2
3
3
3
ddd, JHH 11.5, JHH 2.5, JHH 1.8, C60(H)), 5.99 (1H, ddd, JHH 10.8,
3JHH 2.0, JHH 2.0, C20(H)), 6.81–6.85 (2H, dm, JHH 6.8, ArH), 6.88
(2H, dd, 3JHH 8.8, 4JHH 1.3, ArH), 7.02 (2H, dd, 3JHH 7.3, 7.3, ArH), 7.19–
7.28 (4H, m, ArH); dC (100 MHz, CDCl3) 22.7 (s, CH2), 24.8 (s, CH2),
28.4 (s, CH2), 68.8 (s, CH2), 82.9 (s, C20), 116.4 (s, ArC), 116.6 (s, ArC),
123.9 (s, ArC), 124.4 (s, ArC), 129.3 (s, ArH), 129.6 (s, ArC), 136.7 (d,
2JCF 31.2, C5), 142.8 (d, 3JCF 9.6, C4), 148.6 (d, 1JCF 240.5, C6), 155.4 (s,
ArC), 157.4 (s, ArC); dF (376 MHz, CDCl3) ꢁ97.2 (1F, s, F6); m/z (ESþ)
383 (45%, [MþH]þ), 340 (40, [MþMeCNꢁTHP]þ), 299 (100,
[MþHꢁTHP]þ).
4
3
3
3
4
d, JHH 8.9, C200(H)), 7.03 (2H, dd, JHH 8.9, JHH 2.3, ArH); dC
(100 MHz, CDCl3) 22.7 (s, CH2), 24.8 (s, CH2), 28.4 (s, CH2), 55.5 (s,
CH2), 68.7 (s, CH2), 83.0 (s, CH), 114.1 (s, ArCH), 123.8 (dd, 2JCF 30.4,
3JCF 8.0, C4), 124.5 (d, JCF 3.2), 130.3 (s, ArCH), 131.6 (s, ArC), 140.1
4
(dd, 1JCF 252.5, 2JCF 10.4, C5), 146.0 (dd, 1JCF 234.0, C6), 155.1 (d, 3JCF
3
21.6), 157.7 (s, ArC); dF (376 MHz, CDCl3) ꢁ97.4 (1F, d, JFF 20.1, F6),
ꢁ136.1 (1F, d, 3JFF 20.1, F5); m/z (ESþ) 338 (45%, [MþH]þ), 295 (60,
[MþMeCNꢁTHP]þ), 254 (100, [MþHꢁTHP]þ).
4.5.5. 5-Ethoxy-4,6-difluoro-2-(tetrahydro-2H-pyran-2-yl)pyr-
4.5.8. 4,5-Bis(allyloxy)-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)pyr-
idazin-3(2H)-one 8c. 4,5,6-Trifluoro-2-(tetrahydro-2H-pyran-2-yl)-
pyridazin-3(2H)-one (100 mg, 0.427 mmol), allyl alcohol (0.058 ml,
0.854 mmol), sodium hydride (0.034 g, 60% dispersion in mineral
oil, 0.854 mmol) and acetonitrile (5 ml), after purification by mass
directed automated purification using DMSO/methanol (1:1) as
eluant and passage through a NH2 SPE column, gave 4,5-bis(allyl-
oxy)-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
8c (0.046 g, 35%) as a colourless oil; (Found [MH]þ 311.1401.
C15H19FN2O4 requires [MH]þ 311.1407); nmax/cmꢁ1 1040, 1983, 1164,
1221, 1491, 1562, 1701, 2913 (br); dH (400 MHz, CDCl3) 1.51–1.60
(1H, m), 1.62–1.75 (3H, m), 1.98–2.18 (2H, m), 3.70 (1H, td, 2JHH 11.3,
3JHH 2.5, C60(H)), 4.10 (1H, ddd, 2JHH 11.3, 3JHH 2.3, 3JHH 2.0, C60(H)),
4.79–4.93 (4H, m, 2ꢂOCH2CH]CH2), 5.26–5.43 (4H, m,
2ꢂOCH2CH]CH2), 5.90–6.07 (3H, m, OCH2CH]CH2þC20(H)); dC
(100 MHz, CDCl3) 22.8 (s, CH2), 24.8 (s, CH2), 28.4 (s, CH2), 68.7 (s,
idazin-3(2H)-one
7d. 4,5,6-Trifluoro-2-(tetrahydro-2H-pyran-2-
yl)pyridazin-3(2H)-one (0.25 g, 1.07 mmol), sodium ethoxide
(0.073 g, 1.07 mmol) and ethanol (12.5 ml), after purification by
flash column chromatography using hexane/ethyl acetate 4:1 as
eluant, gave 5-ethoxy-4,6-difluoro-2-(tetrahydro-2H-pyran-2-yl)-
pyridazin-3(2H)-one 7d (0.19 g, 68%) as a white solid; mp 64–66 ꢀC
(Found C, 50.5; H, 5.6; N, 10.4. C11H14F2N2O3 requires C, 50.8; H, 5.4;
N, 10.8%); nmax/cmꢁ1 1007, 1031, 1080, 1166, 1185, 1379, 1442, 1586,
1660; dH (400 MHz, CDCl3) 1.38 (1H, td, 2JHH 7.1, 3JHH 3.2), 1.43 (3H,
td, 3JHH 7.0, 6JHF 0.8, OCH2CH3), 1.51–1.57 (1H, m), 1.60–1.74 (3H, m),
1.96–2.15 (2H, m), 3.71 (1H, td, 2JHH 11.6, 3JHH 2.6, C60(H)), 4.08 (1H,
2
3
3
5
dd, JHH 11.6, JHH 4.1, C60(H)), 4.51 (2H, qd, JHH 7.0, JHF 3.1,
OCH2CH3), 5.92 (1H, d, 2JHH 10.6, C20(H)); dC (100 MHz, CDCl3) 15.2
(d, 5JCF 2.3, OCH2CH3), 22.6 (s, CH2), 24.7 (s, CH2), 28.3 (s, CH2), 68.7
(s, C60), 70.0 (d, 4JCF 7.9, OCH2CH3), 82.3 (dd, 4JCF 1.5, 1.5, C20), 135.7