Methyl iodide → 1-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate

Participants

Reaction Conditions

Reaction Steps

A 250-mL round bottom flask equipped with an overhead mechanical stirrer, addition funnel, N2-inlet and temperature probe was charged with diisopropylamine (7.31 g, 71.5 mmol) and tetrahydrofuran (22 g) then chilled to less than −15° C. (internal temperature). Hexyllithium (2.25 M in hexane: 21.8 g, 68.5 mmol) was carefully charged to the addition funnel. The hexyllithium solution was added through the addition funnel over 45 minutes with a maximum internal temperature of −17° C. The reaction was mixed for 1 hour at an internal temperature of approximately −15° C. to 0° C. The flask was equipped with another addition funnel and the toluene solution obtained from Example 7 (15.01 g, 58.33 mmol) was added through the addition funnel, followed by 4 g of tetrahydrofuran. The total addition time was 1 hour 45 minutes with a maximum internal temperature of −15° C. The solution was stirred at about −20° C. for 30 minutes. The flask was equipped with an addition funnel, which was charged with methyl iodide (9.3 g, 64-64 mmol) and tetrahydrofuran (3 g); this solution was added to the reaction mixture over 30 minutes, maintaining the internal temperature at no more than −15° C. After 30 minutes, the reaction was quenched into a chilled (˜5° C.) 2M HCl solution (prepared from 31 mL, water and 8 g of concentrated HCl) while maintaining the temperature below 10° C. The reaction flask was rinsed with toluene (10 mL), which was added to the quench flask. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was rinsed with 17% NaCl solution (prepared by dissolving 2.5 g of NaCl in 15 g water). The tetrahydrofuran/toluene solution was used directly in the next step.

Provenance & Evidence