A Simple Stereoselective Access to α-Trifluoromethylated Piperidines

Abstract

An intramolecular Mannich-type reaction, involving ­either an α-trifluoromethyl-1,3-aminoketal or a fluoral synthetic equivalent, was employed to prepare diastereoselectively α-tri­fluoromethylpiperidines. This simple strategy allows a facile access to a wide range of new α-trifluoromethyl saturated N-heterocyclic compounds.

Key words

piperidines - fluorine - intramolecular Mannich reaction - diastereoselectivity

References

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• 10a

  Ref. 7

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16

Typical procedure for the intramolecular Mannich-type reaction using amine 3 (route B): To a stirred solution of amine 3 (1 mmol) in dichloromethane (10 mL) was added MgSO₄ (ca. 1 g) followed by a solution of aldehyde (1.2 mmol) in dichloromethane (5 mL) and then a catalytic amount of p-TsOH. The resulting solution was heated at reflux until the amine had disappeared (TLC) (1-3 h).The solution was then cooled to r.t. and transferred via a cannula to a solution of anhyd p-TsOH (2 mmol) in toluene (40 mL). The resulting mixture was heated at 70 °C for 3-4 h. After being cooled to r.t., a saturated aqueous solution of NaHCO₃ (10 mL) was added and the keto-protected piperidone extracted with ethyl acetate (4 × 30 mL). The combined organic extracts were dried, filtered, and concentrated. The residue was purified by column chromatography using ethyl acetate-cyclohexane as eluent.

17

The low yield is due to partial butanal aldol condensation prior to cyclization, leading to a complex reaction mixture.

18

All new compounds are fully characterized.