dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate

Uses

Dimethyl Bicyclo[2.2.2]octane-1,4-dicarboxylate is used in preparation of cycloalkanecarboxamides and related compounds as modulators of the integrated stress pathway.

Synthesis

General procedure for the synthesis of dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate from dimethyl 1-(2-chloroethyl)cyclohexane-1,4-dicarboxylate: 2.5 M hexane solution of n-butyllithium (53.6 mL) was added slowly and dropwise to a solution of diisopropylamine (18.7 mL) in tetrahydrofuran (180 mL) cooled to -30 °C. The reaction mixture was stirred between -20°C and -30°C for 20 minutes and subsequently cooled to -78°C. The solution was slowly added to a tetrahydrofuran (440 mL) mixture of dimethyl dicyclo[2.2.2]octane-1,4-dicarboxylate (32 g) and hexamethylphosphorotriamine (90 mL), the product of Step A, that was cooled to -78°C over a period of 30 minutes, ensuring that the temperature of the mixture did not exceed -70°C. Stirring was continued at -78 °C for 25 minutes, followed by slow warming of the reaction mixture to room temperature over 110 hours. After being kept at room temperature for 11 h, the reaction was quenched with saturated aqueous ammonium chloride solution. Volatiles were removed by evaporation and the reaction mixture was diluted with cyclohexane and water. The aqueous phase was separated and extracted three times with cyclohexane. The combined organic phases were washed sequentially with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was recrystallized by cyclohexane to give dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (13.8 g, 50% yield). Mass spectral analysis showed [MH]+ = 227.

References

[1] Australian Journal of Chemistry, 1985, vol. 38, # 11, p. 1705 - 1718
[2] Patent: WO2006/128184, 2006, A2. Location in patent: Page/Page column 164-165
[3] Patent: WO2008/63671, 2008, A2. Location in patent: Page/Page column 177
[4] Synthetic Communications, 2007, vol. 37, # 8, p. 1267 - 1272
[5] Patent: US6649600, 2003, B1. Location in patent: Page/Page column 51-52