Tetrahydropyranylation of 1-phenylethanol using ionic liquids; THP ethers

Luis Alexandre Almeida Fernandes Cobra Branco (luis_c_branco@yahoo.com),
A contribution from the Afonso C.A.M. Group, FCT- Universidade Nova de Lisboa, Portugal

Chemicals Used
3,4-Dihydro-2H-pyran (Aldrich); 1-phenylethanol (Aldrich); Dichlorometane (distilled over calcium hydride powder); catalysts: triphenylphosphine hydrobromide (TPP.HBr), pyridinium p- toluenesulphonate (PPTS); ionic liquid: 1-n-butyl-3-methylimidazolium [bmim][PF₆].

Procedure
A solution of 3,4-dihydro-2H-pyran (310 ml; 3.28 mmol) was added to a stirred mixture of 1-phenylethanol (200 ml; 1.64 mmol) and the catalyst [10 mol % triphenylphosphine hydrobromide (TPP.HBr), 65 mg or pyridinium p- toluenesulphonate (PPTS), 50 mg] in 2 ml of ionic liquid (1-n-butyl-3-methylimidazolium [bmim][PF₆]), under an argon atmosphere. The resulting mixture was further stirred for 1 h at room temperature. The reaction medium was extracted with diethyl ether (5 x 5 ml) and the resulting solution was evaporated in vacuo. Purification by flash chromatography using hexane/ diethyl ether 9:1 gave 1-phenylethanol tetrahydropyranyl ether as a yellow oil (263 mg, 78%).

Author's Comments
This reaction has been carried out lab in more than 50 times. According comparative study between three catalysts: triphenylphosphine hydrobromide (TPP.HBr), pyridinium p-toluenesulphonate (PPTS) and p-toluenesulphonic acid (TsOH) in the common organic solvent dichloromethane (DCM) and in the ionic liquid [bmim][PF₆], we concluded that in the case of the ionic liquid [bmim][PF₆] the milder catalysts PPTS and TPP.HBr gave higher yields and cleaner reaction mixtures than the catalyst TsOH. In the absence of catalyst no reaction was observed in both solvents during the first 3 h. The catalysts used are soluble in ionic liquid and the product can be removed from the ionic reaction mixture by successive extractions with diethyl ether. We found that the catalyst TsOH promotes the tetrahydropyranylation of alcohols under reversible conditions, while for the milder catalysts PPTS and TPP.HBr the transformation occurs under a non-reversible process. The ionic liquid [bmim][PF₆] is a convenient medium for this transformation using the catalysts PPTS and TPP.HBr. We prepared in moderate to high yields (62% - 96%) others tetrahydropyranes from several representative alcohols such as benzyl alcohol, (-)-menthol, cholesterol, geraniol and 1-adamantanol. This reaction media can also be successfully recycled on at least 22 occasions without an appreciable loss of activity.

Data
1H nmr (400 MHz, CDCl3) 7.32-7.46 (5Harom, m), 4.90 (2H, m), 4.43 (1H, br s), 3.38-4.05 (2H, m), 1.45-1.95 (8H, m).

Lead Reference
Branco, Luis C.; Afonso, Carlos A. M.; Tetrahedron; 57; 2001; 4405-4410.

Other References
Hoyer, S.; Laszlo, P.; Synthesis; 1986; 655-657.

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