HFIP-promoted Lewis acid-free one-pot synthesis of pyran derivatives under mild conditions

A one-pot, three-component reaction of aromatic aldehyde, malononitrile, dimedone or ethyl acetoacetate was developed in which the reaction medium and promoter was 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). The conditions were optimized (0.30 mL HFIP, around 2.85 mmol, 55 °C) and the model tetrahydrobenzo[ b ]pyran 4a was obtained in 92% isolated yield after only 5 min. Application of the protocol to the examined aromatic aldehydes afforded tetrahydrobenzo[ b ]pyran derivatives 4a–f in 85–95% yields within 90–110 min, while replacement of dimedone with ethyl acetoacetate afforded 2-amino-3-cyano-4H-pyran derivatives 6a–d in 83–94% yields within 90–200 min. HFIP is described here primarily as a reaction medium and promoter, not as a conventional catalyst, because it is used in a stoichiometrically significant amount and no catalytic turnover has been demonstrated. The protocol avoids an added Lewis acid and provides short reaction times and simple product isolation. The green-chemistry assessment is therefore presented cautiously: the high atom economy and short reaction time are advantageous, whereas the fluorinated nature of HFIP, solvent burden, recovery energy, and potential environmental and safety concerns must also be considered.