Methanol → Methyl 4-(bromomethyl)benzoate

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Reaction Steps

Intermediate 1 was prepared as shown in Scheme 2. Esterification of 4-bromomethylbenzoic acid 4 (25 grams) was carried out in refluxing methanol (500 ml) in the presence of concentrated H2SO4 (5 ml) to yield methyl 4-bromomethylbenzoate 5. TLC (thin layer chromatography) monitoring of the reaction mixture showed formation, over time, of a side-product (about 15-20%), which according to 1H-NMR analysis, was identified as methyl 4-methoxymethylbenzoate. The mixture of methyl 4-bromomethylbenzoate 5 and the side-product (4.56 grams; 1 equiv) was reacted with commercially available 4-boc-aminopiperidine 6 (Aldrich™) (4.0 grams) in 100 ml of DCM or 100 ml of methanol in the presence-of potassium carbonate (4.14 grams; 1.5 equiv) at room temperature to yield compound 7. Reaction in methanol afforded compound 7, as identified by 1H NMR, in 72% yield compared to 57% obtained with DCM.

Provenance & Evidence