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vacuo. The residue was dissolved in EtOH (4 mL), 1m HCl (4 mL)
was added and the reaction mixture was stirred for 3 days. The
mixture was quenched with a saturated NaHCO3 solution (7 mL)
and extracted with EtOAc. The organic layer was separated,
washed with brine, dried over MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(cyclohexane/EtOAc 95:5) to afford 3i as a pale-yellow gum
3,7-Diiodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole 2a
Following typical magnesiation procedure, metalation of 1b
(100 mg, 0.3 mmol) was completed within 1 h at À108C. A solution
of I2 (116 mg, 0.46 mmol) in dry THF (1 mL) was added and the re-
sulting mixture was stirred for 0.5 h at RT. The reaction mixture
was quenched with a saturated aqueous Na2S2O3, extracted with
EtOAc and dried over MgSO4. After filtration, the solvent was re-
moved in vacuo and the residue was purified by column chroma-
tography on silica gel (cyclohexane/EtOAc 12:1) to afford 2a as
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(83 mg, 59%). H NMR (400 MHz, CDCl3): d=11.24 (s, 1H), 8.28 (s,
1H), 7.84 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 4.43 (q, J=
7.1 Hz, 2H), 2.66 (s, 3H), 1.43 ppm (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=166.9, 142.4, 141.2, 129.6, 125.7, 121.4, 120.2,
112.7, 61.5, 16.0, 14.6 ppm; HRMS/ESI calcd for C11H13N2O2S:
237.0692 [M+H]+; found: 237.0693.
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a white solid (118 mg, 85%). M.p.=111–1138C; H NMR (400 MHz,
CDCl3): d=7.79 (d, J=7.0 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.85 (dd,
J=8.3, 7.0 Hz, 1H), 5.83 (dd, J=9.2, 2.9 Hz, 1H), 4.11–4.06 (m, 1H),
3.78–3.74 (m, 1H), 2.78–2.70 (m, 1H), 2.28–2.70 (m, 1H), 2.10–2.07
(m, 1H), 1.85–1.71 (m, 2H), 1.70–1.60 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=149.7, 137.1, 126.7, 124.3, 121.4, 88.4, 85.0,
77.0, 67.8, 29.4, 24.8, 22.2 ppm; HRMS/ESI calcd for C12H13I2N2O
[M+H]+ 454.9112; found: 454.9109.
3-(3-Chloro-1H-indazol-5-yl)-N,N-dimethylprop-2-yn-1-amine 3p:
3-Chloro-5-iodo-1H-indazole 2p (500 mg, 1.8 mmol, 1 equiv),
[PdCl2(PPh3)2] (63 mg, 0.09 mmol, 0.05 equiv), PPh3 (47 mg,
0.18 mmol, 0.1 equiv), CuI (34 mg, 0.18 mmol, 0.1 equiv), and trie-
thylamine (0.75 mL, 5 mmol, 3 equiv) were introduced in a nitro-
gen-flushed round bottom flask. The flask was evacuated and
backflushed with nitrogen. Acetonitrile (20 mL, degassed under ni-
trogen during 15 min) and 3-dimethylaminoprop-1-yne (0.3 mL,
2.7 mmol, 1.5 equiv) were then added and the resulting mixture
was stirred at 608C for 48 h. The solvent was evaporated and the
crude was purified by column chromatography on silica gel (CH2Cl2
to CH2Cl2/MeOH 95:5) to afford 3p as a brown solid (342 mg,
3-(2-Chlorobenzoyl)-6-iodo-1H-indazole 2l: Following typical
magnesiation procedure, the metalation of 1d (100 mg, 0.3 mmol)
was completed within 1 h at À108C. 2-Chlorobenzoyl chloride
(0.06 mL, 0.46 mmol) was added dropwise and the resulting mix-
ture was stirred for 1.5 h at RT. Then 1m HCl (1 mL) was added and
the reaction mixture was stirred overnight. THF was removed in
vacuo and the residue was partitioned between water and EtOAc.
The organic layer was separated, washed with a saturated NaHCO3
solution, dried over MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (cyclohex-
ane/EtOAc 8:1) to afford 2l as a white solid (73 mg, 64%). M.p.=
261–2638C; 1H NMR (400 MHz, DMSO): d=14.6 (m, 1H) 8.14 (s,
1H), 8.03 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.61 (d, J=
7.4 Hz, 1H), 7.60–7.53 (m, 2H), 7.51–7.45 ppm (m, 1H); 13C NMR
(100 MHz, DMSO): d=189.6, 142.7, 142.4, 138.9, 132.6, 131.6, 130.2,
129.8, 129.8, 127.0, 123.1, 121.2, 120.2, 93.5 ppm; HRMS/ESI calcd
for C14H9ClIN2O [M+H]+ 382.9443; found: 382.9439.
1
81%). M.p.=145–1478C. H NMR (400 MHz, CDCl3): d=7.76 (s, 1H),
7.44 (d, J=8.7 Hz, 1H), 7.40 (dd, J=8.7, 1.0 Hz, 1H), 3.59 (s, 2H),
2.49 ppm (s, 6H). Signal due to NH is missing. 13C NMR (100 MHz,
CDCl3): d=140.9, 134.9, 131.4, 123.5, 120.5, 116.2, 110.9, 85.9, 82.9,
48.6, 44.1 (2C) ppm; HRMS/ESI calcd for C12H13ClN3: 234.0792 [M+
H]+; found: 234.0794.
(E)-Methyl 3-(3-(methylsulfanyl)-1H-indazol-4-yl)acrylate 3s:
PPh3 (21 mg, 0.08 mmol, 0.1 equiv), [Pd(OAc)2] (9 mg, 0.04 mmol,
0.05 equiv) and triethylamine (0.11 mL, 0.8 mmol, 1 equiv) in diox-
ane (2 mL) were added in a nitrogen-flushed round bottom flask.
The mixture was stirred at room temperature for 10 min. A solution
of 2s (300 mg, 0.8 mmol, 1 equiv) in dioxane (9 mL) and methyl ac-
rylate (0.36 mL, 4 mmol, 5 equiv) was then added, and the reaction
mixture was stirred at 1008C for 27 h. H2O (10 mL) was added and
the mixture was extracted with EtOAc. The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The resi-
due was then solubilized in a mixture of EtOH (20 mL) and HCl
(37% in water, 3 mL).The resulting mixture was stirred at 258C for
18 h. After neutralization with a 2m NaOH solution, the solvent
was evaporated. The crude was then extracted with EtOAc. The or-
ganic layer was separated, washed with water, dried over MgSO4
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (cyclohexane/EtOAc 8:1 to 4:1) to
afford 3s as a yellow solid (141 mg, 71%). M.p.=156–1588C;
1H NMR (400 MHz, CDCl3): d=8.77 (d, J=15.8 Hz, 1H), 7.53 (dd, J=
7.4, 1.7 Hz, 1H), 7.42–7.35 (m, 2H), 6.52 (d, J=15.8 Hz, 1H), 3.86 (s,
3H), 2.65 ppm (s, 3H). Signal due to NH is missing. 13C NMR
(100 MHz, CDCl3): d=167.4, 142.4, 141.8, 141.5, 129.2, 127.6, 121.0,
120.2, 119.1, 111.9, 52.0, 16.6 ppm; HRMS/ESI calcd for C12H13N2O2S:
249.0692 [M+H]+; found: 249.0692.
4-Iodo-6,7,8,9-tetrahydro-11H-pyridazino[1,2-a]indazol-11-one
3d: A nitrogen-flushed 10 mL vial was charged with 2d (100 mg,
0.36 mmol, 1 equiv) in THF (10 mL). NaH (22 mg, 0.54 mmol,
1.5 equiv) was added slowly at 08C and the reaction mixture was
stirred for 1 h. 1,4-Dibromobutane (128 mL, 1.08 mmol, 3.0 equiv)
was added at 08C and the mixture was stirred for 2 h. THF was re-
moved in vacuo and the residue was heated at reflux in a mixture
of acetone/H2O (9:1) (4 mL) for 4 days. The solvent was removed in
vacuo and the residue was extracted with CH2Cl2. The organic layer
was collected, dried over MgSO4, filtered and concentrated. The
residue was purified by column chromatography on silica gel (cy-
clohexane/EtOAc 9:1 to 7:3) to afford 3d as a colourless oil (49 mg,
43%). 1H NMR (400 MHz, CDCl3): d=7.93 (dd, J=7.7, 1.1 Hz, 1H),
7.85 (dd, J=7.7, 1.1 Hz, 1H), 6.98 (t, J=7.7 Hz, 1H), 3.97 (m, 2H),
3.75 (m, 2H), 2.07–2.02 (m, 2H), 1.82–1.76 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3) d 159.6, 151.1, 142.8, 125.3, 124.1, 123.3, 77.3,
51.2, 40.8, 23.4, 22.9 ppm; HRMS/ESI calcd for C11H12IN2O [M+H]+
314.9989; found: 314.9988.
Ethyl 3-(methylsulfanyl)-1H-indazole-6-carboxylate 3i: In a nitro-
gen-flushed 10 mL vial was added 2i (207 mg, 0.56 mmol, 1 equiv)
in THF (2 mL). The solution was cooled to 08C and iPrMgCl·LiCl
(593 mL, 0.67 mmol, 1.2 equiv, 1.13m in THF) was added dropwise.
The mixture was stirred for 20 min at 08C. Ethyl choroformate
(124 mL, 0.73 mmol, 1.3 equiv) was slowly added. After stirring for
few minutes at 08C, the reaction mixture was allowed to warm to
258C and stirred for 1.5 h. The reaction mixture was quenched
with H2O, and extracted with EtOAc. The organic layer was separat-
ed, washed with brine, dried over MgSO4 and concentrated in
4-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-11H-pyridazino[1,2-a]in-
dazol-11-one 4d: Compound 3d (16 mg, 0.05 mmol, 1 equiv),
[Pd(OAc)2] (3 mg, 0.0025 mmol, 0.05 equiv), PPh3 (1 mg,
0.005 mmol, 0.10 equiv), Na2CO3 (21 mg, 0.2 mmol, 4.0 equiv) and
4-methoxyphenylboronic acid (11 mg, 0.075 mmol, 1.5 equiv) in
a 1:1 mixture of DME/H2O (6 mL) were added in a sealed tube,
evacuated and backfilled with nitrogen. The mixture was stirred for
22 h at 1008C, cooled to 258C, filtered through a pad of Celite,
Chem. Eur. J. 2016, 22, 4440 – 4446
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