5(S)-((3aR,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole

Abstract

5(S)-((3aR,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole was synthesized from isosorbide in a three-step sequence, with an overall yield of 46%. The first reaction step involves a single regioselective ring-opening reaction of isosorbide with Me₃SiI in the presence of acetone followed by an intramolecular nucleophilic substitution to transform the iodoalcohol into its corresponding epoxide. The last reaction allows the formation of the oxazoline ring directly from the epoxide with benzonitrile in the presence of BF₃·Et₂O.

1. Introduction

The 2-oxazolines, unsaturated five-membered heterocycles, have attracted considerable attention. Many compounds with this heterocycle present biological activities [1] and some of them are commercially available as drugs (e.g., rilmenidine for hypertension, deflacort, glucocorticoid, etc.).

In addition, concerning their chemical properties, the main application is devoted to catalysis as ligands for organometallic catalysis [2,3,4] or as organocatalysts [5] to carry out many chemical transformations efficiently.

More recently, they were used as monomers [6,7,8], and due to the potential applications of their corresponding polymers, this field of research is still continuing.

In this work, we report the synthesis of 5(S)-((3aR,4R,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole, a chiral 2-oxazolidine derived from isosorbide, a sustainable molecule, as starting material [9].

2. Results and Discussion

In 2001, Ejjiyar et al. efficiently transformed isosorbide into epoxide 1 (Scheme 1) [10]. The first reaction involves a single ring-opening reaction of isosorbide with Me₃SiCl–NaI (1:1 ratio) in the presence of acetone [11] to afford the corresponding iodoalcohol, which is subsequently treated with sodium hydride in tetrahydrofuran to form the desired epoxide 1 with an overall yield up to 80%.

Of all the procedures described in the literature for forming 2-oxazolines [12,13], their direct formation from an epoxide is made possible using a nitrile in the presence of a Lewis acid. Thus, according to the procedure of Stilling et al. [14], the reaction of epoxide 1 with benzonitrile and BF₃·Et₂O as Lewis acid led to the desired oxazoline in 58% yield after 3 h with traces of epoxide and degradation products (Scheme 2). We noticed that the longer the time, the lower the yield (i.e., 9% yield after 48 hours). The introduction of the nitrogen of the nitrile occurred on the less substituted carbon of the epoxide, as observed by Stilling and confirmed by the carbon chemical shift of 57.4 ppm for the CH₂-N.

3. Materials and Methods

The formation of epoxide 1 was carried out according to Ejjiyar et al.’s procedure [10,11]. We noticed that the yield of the iodoalcohol resulting from the ring-opening reaction of isosorbide with NaI/TMSCl in the presence of acetone (Scheme 1) depended mainly on the quality of the reagents; they must be anhydrous. TMSCl must be freshly distilled before use, acetone must be dried over 4 Å molecular sieves before distillation, and NaI must be dried overnight under vacuum using a heated desiccator. In addition, the reaction must be carried out under inert atmosphere and in the dark. Under these conditions, the crude iodoalcohol formed in 99% yield is sufficiently pure to be used without further purification. If these precautions are not taken into account, both crude yield and purity are lower.

Column chromatography was performed using a Kieselgel 60 (230–400 mesh-Merck, Darmstadt, Germany). The optical rotation was measured at the wavelength of the D line of sodium (589.3 nm) at 25 °C, a 1 dm path length cell using a JASCO P-2000 spectrometer (JASCO, Easton, MD, USA). Infrared spectrum was recorded on a Nicolet (AVATAR 370 DTGS) spectrometer (Thermo Fisher Scientific Inc., Bourgoin, France). ¹H and ¹³C NMR spectra were recorded on a Bruker Avance 400 spectrometer (¹H 400 MHz and ¹³C 100 MHz, respectively). Chemical shifts are given in ppm relative to TMS. Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), sept (septuplet), or br s (broadened singlet). The high-resolution time-of-flight mass spectrum (TOF-HRMS) was recorded on a Waters micromass^® GCT premier TM spectrometer (Waters Corporation, Milford, MA, USA). For the NMR assignment, the numbered structure (S1) and copies of NMR spectra (S2–S5) and HRMS of the compound 2 (S6) are available in the Supplementary Material.

5(S)-((3aR,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole (2)

At 0 °C, under argon, to a solution of epoxide 1 (500 mg, 2.7 mmol) in cyanobenzene (4 mL), BF₃·Et₂O (0.34 mL, 2.7 mmol) was added for 10 minutes; then, the reaction mixture was allowed to stir at room temperature for 3 h. Solid Na₂CO₃ (200 mg) was added; then, after 3 h, a saturated aqueous solution of NaHCO₃ (10 mL) was added to the reaction mixture. After extraction with CH₂Cl₂ (2 × 5 mL), the combined organic phases were dried with MgSO₄ then concentrated. Purification of the residue by flash chromatography (40:60 cyclohexane/ethyl acetate) gave the desired oxazoline 2 as a colorless liquid (0.452 g, 1.56 mmol, 58%).

[α]²⁰_D = −40.8 (c 1.0, CH₂Cl₂); IR (ATR): 2923, 2851, 2025, 1720, 1650, 1602, 1579, 1536, 1489, 1451, 1373, 1269, 1207, 1164, 1091, 1063, 1025, 985, 916, 858, 712, 696 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz) 1.33 (3H, s, CH₃), 1.51 (3H, s, CH₃), 3.58 (1 H, dd, J = 10.9 Hz, J = 3.4 Hz, H6′), 3.63 (1 H, dd, J = 8.6 Hz, 3.8 Hz, H4′), 3.82 (1H, dd, J = 15.1 Hz, J = 8.4 Hz, H4), 4.18 (1 H, d, J = 10.9 Hz, H6′), 4.30 (1 H, dd, J = 15.1 Hz, J = 9.9 Hz, H4), 4.74 (1 H, dd, J = 6.1 Hz, J = 3.8 Hz, H3′a), 4.82 (1H, dd, J = 6.1 Hz, J = 3.4 Hz, H6′a), 4.97 (1H, dd, J = 9.9 Hz, J = 8.6 Hz, H5), 7.35–7.50 (3H, m, H_Ar), 7.97 (1H, dd, J = 2.2 Hz, J = 1.7 Hz, H_Ar), 8.01 (1H, dd, J = 2.2 Hz, J = 1.7 Hz, H_Ar). ¹³C NMR (CDCl₃, 100 MHz) 24.8 (CH₃), 26.0 (CH₃), 57.4 (NCH₂, C4), 73.4 (OCH_2, C6′), 79.4 (CH, C5), 80.4 (CH, C6′a), 81.0 (CH, C3′a), 84.4 (CH, C4′), 112.8 (C, C2′), 127.6 (CH, C_Ar), 128.29 (CH, C_Ar), 128.3 (CH, C_Ar), 131.4 (C, C_Ar), 164.3 (C, C2). HRMS (DCI) m/z [M + H]⁺ 290,1398 (Cald for C₁₆H₂₀NO₄ 290,1392).

4. Conclusions

5(S)-((3aR,4R,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole was obtained using a three-reaction strategy with an overall yield of 46% from isosorbide.