4-Methoxypyridine → 1-Piperidinecarboxaldehyde
Reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C[Si](C[Li])(C)C>>[CH:9]([N:4]1[CH2:3][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:10].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:1]=[O:2]Participants
Procedure
A reaction scheme according to embodiments of the present invention is illustrated in FIG. 1. As illustrated in FIG. 1, methoxypyridine is deprotonated using the alkylmetal reagent (trimethylsilylmethyl)lithium. According to embodiments of the present invention, 4-methoxypyridine may be reacted with (trimethylsilylmethyl)lithium then N-formylpiperidine to produce 4-methoxy-3-pyridinecarboxaldehyde (MPC). The reaction is carried out at a temperature of about −20° C. or less in the presence of tetrahydrofuran (THF). HCONR2 is also added to the reaction mixture, wherein R is an alkyl group, for example, dimethylformamide or 1-formylpiperidine. The resulting 4-methoxy-3-pyridinecarboxaldehyde is crystallized directly from the reaction mixture with yields between about 60 percent to about 100 percent MPC, depending on temperature used. For example, in the reaction scheme of FIG. 1, a 60 percent yield was achieved at −10° C. and a 100 percent yield was achieved at −30° C. Yields may be higher at temperatures below about −20° C. but are still acceptable at higher temperatures, for example at about −12° C. or higher. The presence of directed ortho metallating groups gives typical selectivity for deprotonation on the aromatic rings. Likewise, lateral lithiation, where side chains on the aromatic ring are metallated, is possible with these bases.
Workup
- customA reaction scheme
Sources & evidence
- ORD record
- ord-0cbe65615f0e468e8aeed79ace53cb3c
- Source dataset
- uspto-grants-2009_12
- Patent number
- US07638635B2
Reaction notes
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