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Stage #1: With N,N,N,N,-tetramethylethylenediamine; zinc(II) chloride In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuranInert atmosphere
To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) in THF (6 mL) were successively added BuLi(about 1.6 M hexanes solution, 3.0 mmol) and, 5 min later, ZnCl2·TMEDA7 (0.26 g, 1.0mmol). The mixture was stirred for 15 min at 0 °C before introduction of 2-chloropyrimidine(2, 0.11 g, 1.0 mmol). After 2 h at this temperature, a solution of I2 (0.76 g, 3.0 mmol) in THF(10 mL) was added. The mixture was stirred overnight before addition of an aqueoussaturated solution of Na2S2O3 (10 mL) and extraction with AcOEt (3 x 20 mL). The combinedorganic layers were dried over MgSO4, filtered and concentrated under reduced pressure.Purification was performed by chromatography on silica gel (eluent: heptane/AcOEt 95/5) toafford 4a in 18percent yield as a beige powder
Reference:
[1] Chemistry - A European Journal, 2009, vol. 15, # 6, p. 1468 - 1477
[2] Synlett, 2015, vol. 26, # 20, p. 2811 - 2816
The metalation of pyrimidine derivatives is a challenging problem due to the propensity of these heterocycles to add organometallic reagents.[8] The inventors found that the inverse addition of the pyrimidine derivatives 18-20 to a THF solution of 5b (1.05 equiv.) at -55°C for approx. 5 min. provides the corresponding magnesiated derivatives 21-23 in 83-90percent yields as indicated by iodolysis experiments leading to the iodinated pyrimidines 24-26 (scheme 3).
To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) in THF (6 mL) were successively added BuLi(about 1.6 M hexanes solution, 3.0 mmol) and, 5 min later, ZnCl2·TMEDA7 (0.26 g, 1.0mmol). The mixture was stirred for 15 min at 0 °C before introduction of 2-chloropyrimidine(2, 0.11 g, 1.0 mmol). After 2 h at this temperature, a solution of I2 (0.76 g, 3.0 mmol) in THF(10 mL) was added. The mixture was stirred overnight before addition of an aqueoussaturated solution of Na2S2O3 (10 mL) and extraction with AcOEt (3 x 20 mL). The combinedorganic layers were dried over MgSO4, filtered and concentrated under reduced pressure.Purification was performed by chromatography on silica gel (eluent: heptane/AcOEt 95/5) toafford 4a in 18percent yield as a beige powder
3-amino-1-(2-chloropyrimid-4-yl)indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane; In 1,4-dioxane; for 24.0h;Inert atmosphere; Reflux;
A solution of 3-aminoindazole (670.5 mg, 5.0 mmol) and 2-chloro-3-iodopyrimidine (1.202 g, 5 mmol)((Chem Eur J 15, 1468 (2009)), in dry dioxan (25 mL), containing CuI (47.5 mg, 0.25 mmol) trans-1,2-diaminocyclohexane (114 mg, 1.0 mmol) and K3PO4 (1.06 g, 5 mmol) is refluxed under N2 for 24 hrs. (Bioorg Med Chem Letters 22, 4358 (2012)) The mixture is cooled to 25 C and quenched with water (50 mL) and extracted with ethyl acetate (3 x 25 mL), washed with water (2 x 25 mL) and saturated brine (25 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and the residue is purified by column chromatography (Pet/EtOAc 10/1) to afford 3-amino-1-(2-chloropyrimidin-4-yl)-1H-indazole as a white solid.