[CH3:1]N(C)CCNC.[Li]CCCC.[N:13]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CI>C1COCC1.CCCCCC>[CH3:1][C:23]1[CH:24]=[CH:25][CH:26]=[C:19]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:20]=1[CH:21]=[O:22]To a solution of N,N,N′-trimethylethylenediamine in dry THF (110 mL), cooled to −20° C., n-BuLi (27.3 mL of a 1.6 M solution in hexane, 43.68 mmol, 1.0 eq) was added dropwise. After 15 min, a solution of 2-piperidin-1-ylbenzaldehyde 3b (8.0 g, 42.27 mmol) in THF (20 mL) was added slowly while maintaining the temperature at −20° C. After an additional 15 min, additional n-BuLi (79.25 mL of a 1.6 M solution in hexane, 126.8 mmol, 3.0 eq) was slowly added. The reaction mixture was maintained at −20° C. for 90 h using a cryocool apparatus and then cooled to −78° C. for the addition of methyl iodide (15.8 mL, 253.8 mmol, 6.0 eq). The cooling bath was removed after the addition and the work-up was carried out once the reaction mixture was at RT. The mixture was poured into a cold solution of saturated NH4Cl and extracted 3X with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to afford a brown oil which was purified by flash chromatography using a mixture consisting of 5% EtOAc-95% hexane as eluent. The desired 2-methyl-6-piperidin-1-ylbenzaldehyde 3c was isolated as pale yellow oil (3.74 g, 43% yield).
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