Amide Activation by Tf₂O: Reduction of Amides to Amines by NaBH₄ under Mild Conditions

Abstract

An expeditious and practical method for the reduction of amides to amines is reported. The method is consisted of activation of amides with Tf₂O followed by reduction with sodium borohydride in THF at room temperature. Various amides/lactams gave the corresponding amines in good to excellent yields, even with hindered amides and secondary amides. This method also presents other advantages such as TBDPS-group tolerance, short reaction time, simple workup and purification procedure.

Key words

reduction - amides - amines - amide activation - triflic anhydride

References and Notes

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14

All new compounds gave satisfactory analytical and spectral data. General Procedure for the Preparation of Amines from Amides
To a solution of an amide (1.0 mmol) in anhyd CH₂Cl₂ (10 mL) was added Tf₂O (1.1 mmol) in an ice bath. After stirring for 30 min, NaBH₄ (1.3 mmol) was added in one portion, and THF (5 mL) was added dropwise. After stirring for 60 min at r.t., the reaction was quenched with H₂O (5 mL). The solution was brought to pH 10.5-11.0 by addition of a sat. aq Na₂CO₃ solution at 0 ˚C. The cooled aqueous solution was extracted with Et₂O (5 × 15 mL). The combined organic layers were washed with brine (5 mL), dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the corresponding amine (yields 69-93%). All new compound gave satisfactory spectral and analytical data (see Supporting Information).