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
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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.
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The low yield is due to partial butanal aldol condensation prior to cyclization, leading
to a complex reaction mixture.
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All new compounds are fully characterized.
