FULL PAPER DOI: 10.1002/ejoc.200900006 Stereoselective Synthesis of 2,6-Disubstituted-4-Aryltetrahydropyrans Using Sakurai–Hosomi–Prins–Friedel–Crafts Reaction Udagandla C. Reddy, [a] Somasekhar Bondalapati, [a] and Anil K. Saikia* [a] Keywords: Multicomponent reactions / Diastereoselectivity / Cyclization / Oxygen heterocycles The reaction of aldehydes with allyltrimethylsilane in arene solvents gives symmetrical 2,6-disubstituted-4-aryltetrahy- dropyrans in good yields. The reaction is highly stereoselec- tive. Introduction Multicomponent reactions are important in organic syn- thesis because of their ability to construct multiple bonds in a single step, which is crucial for pharmaceutically active and natural product synthesis. [1] The synthesis of the tetra- hydropyran unit is important because of its presence in many natural products. [2] The all-cis 2,6-disubstituted-4-ar- yltetrahydropyrans have olfactory properties [3] and shows nonredox 5-lipoxygenase inhibiting properties. [4] These tetrahydropyrans are prepared by hetero-Diels–Alder meth- ods, [5] manipulation of carbohydrates, [6] Prins cyclization, [7] and intramolecular Michael reactions. [8] Although the syn- thesis of 4-halo-, [9] 4-thio-, [10] 4-azido-, [11] 4-amino-, [12] and 4-hydroxytetrahydropyrans [7e,7f,9d,13] have been reported in the literature, the synthesis of 2,6-disubstituted-4-aryl- tetrahydropyrans is limited. [14,2h] We have shown in our previous investigation that 2,6- disubstituted-4-amidotetrahydropyrans can be synthesized in high yields with excellent stereoselectivity through BF 3 ·Et 2 O-mediated cyclization of aldehydes and allyltri- methylsilane in acetonitrile. In this protocol, a Sakurai– Hosomi–Prins–Ritter reaction sequence was used. [12e] We disclose here a stereoselective one-pot, three-compo- nent synthesis of 2,6-disubstituted-4-aryltetrahydropyrans from aldehydes, allyltrimethylsilane, and arenes by using a Sakurai–Hosomi–Prins–Friedel–Crafts reaction. Results and Discussion To start, benzaldehyde (1.0mmol) was treated with allyl- trimethylsilane (0.6 mmol) in benzene (5.0 mL) in the pres- [a] Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India Fax: +91-361-2690762 E-mail: asaikia@iitg.ernet.in Supporting information for this article is available on the WWW under http://www.eurjoc.org/ or from the author. Eur. J. Org. Chem. 2009, 1625–1629 © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1625 (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) ence of BF 3 ·Et 2 O (1.2 mmol) at 0 °C, and the reaction was warmed to room temperature. 2,4,6-Triphenyltetrahydro- pyran was obtained in 74% yield. To prove the general appli- cability of this reaction, a variety of alkyl and aryl alde- hydes were investigated as shown in Scheme 1. The results are summarized in Table 1. Scheme 1. Synthesis of symmetrical 2,6-disubstituted-4-aryltetra- hydropyran (R = alkyl, aryl). In all the cases studied, 4-aryltetrahydropyrans 1b–16b (Table 1) could be obtained in high purity without any side products. Both aliphatic and aromatic aldehydes gave good yields with high diastereoselectivity, as determined from the 1 H and 13 C NMR spectra of the crude products. The sub- stituents on the aromatic ring play an important role in this reaction: electron-withdrawing substituents and simple al- dehydes gave better yields than those obtained when elec- tron-donating groups were on the ring. Aliphatic aldehydes were found to be better substrates for this reaction. The substituents at the 2-, 4-, and 6-positions of the tetra- hydropyran ring are in a cis relationship and are equatorial. This is revealed from the coupling constants of the 2,6-H (J = 11.2 and 2.0 Hz) and the 4-H (J = 11.2 and 2.0 Hz) hydrogen atoms of compound 2b (Figure 1). This was also confirmed by an NOE experiment and single-crystal X-ray analysis. [15] To explore further utility of the method, other arenes were also studied as nucleophiles as shown in Table 2. Thus, the reaction of m-nitrobenzaldehyde (3a) in toluene gave product 17 as an inseparable mixture of two regioisomers with a ratio of 4.7:1 and 97% overall yield. o-Xylene gave