Ethyl 2,2,7,7-tetramethyl-6-oxooct-4-ynoate → 1,2,3,5-Tetrahydroindolizine

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Reaction Conditions

Reaction Steps

To a solution of 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(propan-2-yl)pyridinium bromide (1.55 g, 4.37 mmol) and ethyl 2,2,7,7-tetramethyl-6-oxooct-4-ynoate (1.04 g, 4.37 mmol) in DMF (8.0 mL) is added TEA (0.9 mL, 6.56 mmol). The mixture is heated at 70° C. for 24 h then cooled to 23° C. and partitioned between Et2O and water. The organics are washed with water, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 10% EtOAc in hexanes) gives dihydroindolizine (340 mg, 15%) that is dissolved in MeOH (10 mL) and treated with sodium borohydride (25 mg, 0.664 mmol). The mixture is stirred for 10 min then treated with water, extracted with EtOAc, dried with MgSO4, filtered, and concentrated in vacuo. The residue is dissolved in MeOH (4 mL) and 6M aqueous NaOH (4 mL) and heated at 70° C. for 1 h then cooled to 23° C. The mixture is acidified to pH=1 with concentrated aqueous HCl, then partitioned between CH2Cl2 and brine. The organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by reverse phase HPLC gives the title compound (44 mg, 14%).

Provenance & Evidence