DiMethyl bicyclo[2.2.1]heptane-1,4-carboxylate

2435-36-1

107-04-0

15448-76-7

The general procedure for the synthesis of methyl bicyclo[2.2.1]heptane-1,4-dicarboxylate from methyl cyclopentane-1,3-dicarboxylate and 1-bromo-2-chloroethane was as follows: n-butyllithium (2.5 M hexane solution, 419.0 mL, 1048 mmol) was slowly added dropwise to a solution containing diisopropylamine (152 mL, 1090 mmol) at -78 °C (dry ice/acetone bath). 1090 mmol) in a solution of anhydrous THF (1000 mL), and the reaction system was maintained in an N2 atmosphere. Subsequently, the reaction mixture was stirred at 0 °C for 0.5 h and then cooled to -78 °C again. DMPU (404 mL, 3350 mmol) was added through the addition funnel. Next, a solution of anhydrous THF (300 mL) of methyl cyclopentane-1,3-dicarboxylate (78.0 g, 419 mmol) was slowly added through the addition funnel. The reaction mixture was slowly warmed to 0 °C and stirred for 30 min, after which it was cooled again to -78 °C and a solution of anhydrous THF (200 mL) of 1-bromo-2-chloroethane (59.0 mL, 712 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred at room temperature for 12 hours. Upon completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution (400 mL). The reaction mixture was diluted with ethyl acetate (500 mL), the organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The organic extracts were combined, washed with brine (2 × 300 mL), dried over anhydrous MgSO4, filtered and concentrated to dryness. The residue was filtered through a silica gel pad and washed with ethyl acetate (2000 mL). The filtrate was concentrated to dryness and the residue was purified by fast column chromatography (petroleum ether/ethyl acetate, 30:1 to 20:1, gradient elution) to afford methyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (48.5 g, 54% yield) as a white solid.1H NMR (400 MHz, CDCl3): δ 3.69 (s, 6H), 2.08- 1.99 (m, 4H), 1.91 (s, 2H), 1.73-1.63 (m, 4H).