Efficient, highly diastereoselective MS 4 Å-promoted one-pot, three-component synthesis of 2,6-disubstituted-4-tosyloxytetrahydropyrans via Prins cyclization

A simple, efficient and highly diastereoselective one-pot three-component synthesis of functionalized 2,6-disubstituted-4-tosyloxytetrahydropyrans was performed. The synthesis features an optimized Prins cyclization in which an aromatic homoallylic alcohol, an aromatic/aliphatic aldehyde, and p-toluenesulfonic acid (catalyst and reagent) are reacted in the presence of molecular sieves (MS) 4 Å at reflux in dichloromethane to afford excellent yields (72–96%) within short reaction times (20–90 min). The MS 4 Å-promoted synthesis proved to be versatile enough to provide an array of symmetrical and unsymmetrical tetrahydropyran derivatives in economical manner. Furthermore, cleavage of the 4-tosyl group under mild conditions afforded 4-hydroxytetrahydropyran in excellent yields (95–96%).

p-Toluenesulfonic acid (PTSA) is reported as a versatile Brønsted acid catalyst in various organic transformations [32][33][34]. Previously, PTSA has been used as a catalyst in Prins cyclizations but the product yields were low even under extended reaction times [10].

Results and Discussion
The starting materials, aromatic homoallylic alcohols, were readily prepared by treatment of aromatic aldehydes with allylic Grignard reagents under a nitrogen atmosphere at −78 °C for 2 h [40]. Their structures were assigned by 1 H, 13 C NMR, IR, and GC-MS data and compared with reported values in the literature.
Initially, we carried out the reaction with homoallylic alcohols, aromatic aldehydes and PTSA at room temperature to afford 2,4,6-trisubstituted tetrahydropyrans. After 22 h stirring more side-products than the desired product were observed. This Scheme 1: Plausible side products mechanism. might be due to the formation of an oxo-carbenium intermediate, which further reacted in a [3,3]sigmatropic rearrangement to give another oxo-carbenium ion (Scheme 1).
To optimize the reaction yield, we varied the reaction conditions such as enhancing the catalytic loading (1.2 equiv to 1.4 equiv), varying solvents and temperature, rearranging the order of reagent addition and adding MS 4 Å as drying agent (Table 1). Under optimal reaction conditions we reacted a wide selection of aromatic homoallylic alcohols and aldehydes. The experimental results are summarized in Table 2. In all cases, the corresponding tetrahydropyrans were obtained in high diastereoselectivity and excellent yields without side products ( Table 2). A high degree of diastereoselectivity was determined from the 1 H NMR spectra without purification (crude product). We observed that substituents on the aromatic rings influenced the reaction rates and yields. For example, strong electrondonating groups such as methoxy or trimethoxy at homoallylic alcohols afforded the corresponding tetrahydropyrans in lower yields (72-75%) but in a faster rate ( Table 2, entries 7 and 9). Similarly, the presence of electron-withdrawing substituentssuch as chlorine or bromine atoms at homoallylic alcoholsgave the corresponding tetrahydropyrans in high yields (85-96%) but the reaction times were longer ( Table 2,    (Table 2, entries 2, 4, 6, 12-15). We further extended our method to aliphatic aldehydes (e.g., acetaldehyde) and hetero aromatic aldehydes (e.g., pyrrole aldehyde, furfural). Under optimal reaction conditions they reacted smoothly with homoallylic alcohols to afford the corresponding tetrahydropyran derivatives which show almost the same distereoselectivity and product yields (83-89%, Table 2, entries [16][17][18]. From a mechanistical point of view, these reactions are similar to the Prins cyclization [41]. First, the aldehyde got activated by PTSA protonation followed by a nucleophilic attack of the homoallylic alcohol and proton transfer to the hydroxy group. Then, a nucleophilic attack of PTSA resulted in α-tosyloxyether formation after losing a water molecule. In the α-tosyloxyether, the delocalization of lone-pair electrons on the oxygen atom led to the removal of the tosylate group and oxo-carbenium ion intermediate formation. Then, an intramolecular nucleophilic attack of the double bond in the oxo-carbenium ion led to cyclization and charge transfer complex formation with the tosylate group to afford the 2,6-disubstituted-4-tosyloxytetrahydropyran (Scheme 2).
All structures of the 2,6-disubstituted-4-tosyloxytetrahydropyrans were established by 1 H, 13 C NMR, IR, and GC-MS spectral data and elemental analysis. NOE studies of compound 3b ( All these findings confirm that the pyran ring takes a chair conformation, where the substituents at C 1 , C 3 and C 5 are present in equatorial position. The tosyl group at C 4 got easily deprotected at room temperature with Mg-MeOH (Scheme 3) [42] to afford 2,6-disubstited-4-hydroxytetrahydropyrans with retention of the stereochemistry in quantitative yield ( Table 3). The structures of 2,6-disubstituted-4-hydroxytetrahydropyrans were established by 1 H, 13 C NMR, IR, and GC-MS and elemental analysis and were compared with reported data [43].

Scheme 3:
Deprotection of the hydroxy group.

Conclusion
In conclusion, we have reported a simple and efficient one-pot three-component synthesis of highly diastereoselective and functionalized 2,6-disubstituted-4-tosyloxytetrahydropyrans via Prins cyclization. An aromatic homoallylic alcohol, an aromatic/aliphatic aldehyde, and p-toluenesulfonic acid (catalyst and reagent) are reacted in the presence of MS 4 Å in dichloromethane at reflux to afford 2,6-disubstituted-4-tosyloxytetrahydropyrans in excellent yields (72-96%) within short reaction times (20-90 min). The MS 4 Å promoted synthesis proved to be versatile enough to provide an array of symmetrical and unsymmetrical tetrahydropyran derivatives in an economical manner. Moreover, it was observed that MS 4 Å might have a vital part in controlling the reversibility of the [3,3]sigmatropic rearrangement. Furthermore, cleavage of the 4-tosyl group under mild conditions afforded 4-hydroxytetrahydropyrans in high diastereoselectivity and excellent yields (95-96%).

Supporting Information
Supporting Information File 1 Experimental details and characterization data of synthesized compounds, 1 H and 13 C NMR spectra.