Iodine → N-[4-(1-Ethyl-propyl)-6-methyl-pyridazin-3-yl]-2,2-dimethyl-propionamide

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Reaction Steps

Activated magnesium powder (19.2 g, 0.792 moles) is added to a dry 3 L flask fitted with a condensor and a drop funnel. The entire apparatus is heated with a gun dry under vacuum and allowed to cool. Enough ether is added to cover the magnesium. 3-Bromopentane (100 g, 0.662 mmol) is added to the addition funnel in 175 ml of diethyl ether. A ⅓ of the bromopentane solution is added to the magnesium and the reaction mixture is stirred under nitrogen until bubbling occurs. Then, the rest is dripped in at such a rate that the bubbling continues gently. The reaction is stirred for 30 minutes after bubbling ceases. Next, 2,2-dimethyl-N-(6-methyl-pyridazine-3-yl)-propionamide (21.3 g, 0.110 mmol) dissolved in 225 ml of dry THF is added dropwise. The reaction mixture is stirred for 1 hour. Saturated sodium tartrate (1 L) is carefully added, and the reaction is stirred for 30 minutes. The reaction mixture is transferred to a larger flask, 2 L of ethyl acetate is added, and the reaction is stirred 1 hour more. The layers are separate and the aqueous layer is extracted several times with ethyl acetate. The organic extracts are combined, and the solvents are evaporated. The residue is taken up in 600 mL of dichloromethane, and iodine (28 g, 0.110 mol) is added. The reaction is stirred for 2 hours. The organic layer is washed once with aqueous solution of sodium sulfite and then with water. The organic layer is dried over sodium sulfate, filtered, and evaporated to red oil. The crude product is purified via silica gel chromatography using a hexanes:ethyl acetate gradient. The product fractions are combined and evaporated. The residue is triturated in ethyl acetate and a light tan solid is filtered to obtain 12.0 g (45.6 mmol, 41%) of the title compound. 1H-NMR (DMSO-d6), δ 9.88 (s, 1H); 7.59 (s, 1H); 2.60 (s, 3H); 2.39-2.42 (m, 1H); 1.21-1.37 (m, 2H); 1.38-1.43 (m, 2H); 1.23 (s, 9H); 0.71 (t, J=7.49 Hz, 6H) ppm. MS/ES+=264.

Provenance & Evidence