Nitrogen → 5-(3-Methoxyphenyl)-8,9-dimethyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]methyl-2-oxa-8-azabicyclo[3.3.1]nonane

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

Into a dry 1 L flask containing a solution of 1,5-dimethyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine 7 (24 g, 0.11 mol) in dry THF (600 mL) cooled in a salted ice bath was added 1.4 M s-BuLi in cyclohexane (85 mL, 119 mmol) drop wise under a N2 atmosphere over a period of 0.5 h. The dark red solution was further stirred at reduced temperature for an additional 15 min whereupon the mixture was cannula transferred into a second dry 2 L flask containing tetrahydro-2-(oxiranylethoxy)-2H-pyran (13) (20 g, 0.11 mol) in anhydrous Et2O (150 mL) cooled to −10° C. Upon complete addition of the metalated enamine to the epoxide, the resulting mixture was stirred for additional 30 min at −5° C. The reaction was quenched with a solution of 13 g of NaOH and 42 g of NaCl in 350 mL H2O at such a rate so as to maintain the solution temperature below 0° C. and the mixture subsequently poured into 500 mL H2O. The layers were separated, and the aqueous layer extracted with Et2O/EtOAc (1:1, 3×200 mL). The combined organic layers were dried over anhydrous K2CO3, concentrated, and purified via flash column chromatography on silica gel (50% EtOAc/hexanes to 100% EtOAc gradient) to afford 5-(3-methoxyphenyl)-8,9-dimethyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]methyl-2-oxa-8-azabicyclo[3.3.1]nonane (14) as a mixture of diastereomers (30 g, 70%): LCMS (ESI): m/z 390.5 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.22-7.28 [m, 1H], 6.71-6.97 [m, 3H], 4.59 [br m, 1H], 4.48 [br m, 1H], 4.19 [br m, 1H], 3.81-3.87 [m, 2H], 3.80 [s, 3H], 3.52 [br m, 2H], 2.62-2.64 [m, 3H], 2.37 [s, 3H], 2.45 [m, 1H], 1.51-1.82 [m, 2H], 0.69 [d, J=6 Hz, 3H].

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