Syntheses of Chiral 2-Oxazolines from Isosorbide Epoxide Derivative

Abstract

Two chiral monooxazolines were synthesized from a secondary amino alcohol, as a key intermediate, isolated in four steps from an isosorbide-derived epoxide. The 2-oxazolines were then obtained through a reaction between this aminoalcohol and an imidate. The new compounds were fully characterized by FTIR, ¹H and ¹³C NMR, and HRMS analyses.

1. Introduction

Since their first synthesis at the end of the nineteenth century [1], 2-oxazolines have played an important role in many areas of chemistry. They can be used as protecting groups for carboxylic acids [2,3], as auxiliaries for direct ortho-metallation [4], or as monomers for poly(2-oxazolines) (Pox) [5]. Furthermore, chiral oxazolines may present interesting biological activities [6,7,8,9,10] or be used as chiral auxiliaries [11,12]. In addition, they could be considered effective ligands in organometallic catalysis [13,14,15] or organocatalysts [16] to achieve a wide range of chemical transformations.

We report herein the formation of 2-substituted chiral oxazolines from commercially available isosorbide, a sustainable material produced by Roquette [17].

2. Results and Discussion

Among the methods available in the literature to prepare 2-oxazolines [18,19], most of them use an aminoalcohol as a key intermediate. For the formation of the oxazoline ring, we opted for a direct way involving a reaction of an aminoalcohol with imidates [20,21,22].

2.1. Formation of the Aminoalcohol

In order to prepare the key intermediate aminoalcohol 5 from isosorbide (Scheme 1), the latter was first converted into epoxide 1 according to our previous work [23]. A ring-opening reaction of epoxide 1 was then carried out using sodium benzyloxide formed in situ, leading to alcohol 2 in a 70% yield. The tosylation and mesylation of the resulting alcohol were then performed. It was noticeable that under classical conditions, the formation of tosylate 3a was tough, and only a low conversion rate was observed after 20 h. In 2007, Kazemi et al. [24] reported tosylation by mechanochemistry, employing a mixture of potassium hydroxide and potassium carbonate as the base. Under these conditions, the transformation was successful, and tosylate 3a was isolated in a 68% yield. On the contrary, mesylation under standard conditions yielded 94% of the expected compound, 3b. Subsequent nucleophilic substitution with sodium azide was first performed in DMF in the presence of 18-crown-6 ether (18C6). After 48 h, azide 4 was, respectively, isolated in a 24% and 22% yield from tosylate 3a and mesylate 3b. However, under the same conditions, mesylate 3b required an extended reaction time of five days to achieve a yield of 40%, whereas the same yield was observed using DMSO as a solvent in only 48 h (Scheme 1). It should be noted that the two isomers of the elimination product were also detected in the ¹H NMR spectrum of the crude product (6.29 ppm for the Z isomer (J_cis = 6.3 Hz) and 6.73 ppm for the E isomer (J_trans = 12.8 Hz)). The presence of these two alkenes complicated the purification process, which was performed by chromatography, as their Rf values were very close to that of azide 4. Aminoalcohol 5 was finally obtained in a 97% yield through a hydrogenation/hydrogenolysis procedure involving azide 4 in the presence of Pd/C.

2.2. Synthesis of Oxazolines

The formation of oxazolines 6 and 7 was achieved in 47% and 19% yields, respectively, using ethyl benzimidate hydrochloride and ethyl 2-hydroxybenzimidate hydrochloride (Scheme 2). The latter, which is not commercially available, was synthesized in an 85% yield through the reaction of 2-hydroxybenzonitrile with a saturated solution of HCl gas in ethanol according to Black and Wade [25].

It should be noted that ethyl 2-hydroxybenzimidate hydrochloride was not very soluble in 1,2-dichloroethane. The latter was replaced by chlorobenzene for the preparation of oxazoline 7, according to the procedure of Brunner and Berghofer [22]. Furthermore, the low yield of oxazoline 7 was mainly due to the formation of degradation products, the difficulty we encountered when carrying out column chromatography to reveal the compound, and the lack of reactivity of the imidate, as a hydrogen bond could be formed between the OH of the phenolic moiety and the OEt of the imidate function.

The structures of these oxazolines were well established by 2D NMR experiments. For example, for compound 7, the CHN of the oxazoline ring, showing a chemical shift at 64.4 ppm, is correlated with only one hydrogen atom (HSQC Figure S31). The latter is correlated to two signals at 4.47 and 4.59 ppm, belonging to an AB system (COSY/HSQC Figures S30 and S31). These protons are linked to the carbon atom located at 68.7 ppm (i.e., CH₂O of the oxazoline ring). The presence of a quaternary carbon atom at 166.4 ppm is characteristic of O–C=N. In addition, the presence of hydrogen bonding due to the presence of the OH of the phenolic substituent is in agreement with the signal’s shift to lower-fields (i.e., 12.00 ppm) (¹H NMR, Figure S28).

3. Materials and Methods

3.1. General

Commercially available compounds were used as received. Dichloromethane, diethyl ether, and THF were dried over an activated alumina column in DRY STATION Glass Technology (Geneva, Switzerland) GTS 100 glassware. All reactions were monitored by TLC. 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, with a 1 dm path length cell using a JASCO P-2000 spectrometer (JASCO, Easton, MD, USA). The infrared spectrum was recorded on a Nicolet (AVATAR 370 DTGS) spectrometer (Thermo Fisher Scientific Inc., Bourgoin, France). Thin-layer chromatography was performed with UV254 plates and revealed under UV light, and then it was performed with phosphomolybdic acid, vanillin, or p-anisaldehyde stains. All melting points were recorded on ThermoFisher IA9300 apparatus and were uncorrected. The NMR spectra were acquired with a Bruker AVANCE 400 spectrometer (Bruker, Billerica, MA, USA) operating at 400 and 100 MHz for ¹H and ¹³C nuclei, respectively, and were recorded in CDCl₃. Chemical shifts and coupling constants were presented in parts per million relative to Me₄Si and Hertz, respectively. Abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and brs, broad signal. Proton and carbon assignments were established using COSY and HSQC experiments. Infrared spectra were recorded on an FT Agilent technologies spectrophotometer (Agilent, Santa Clara, CA, USA) from neat compounds using an ATR (Attenuated Total Reflection) module. High-resolution, time-of-flight mass positive chemical ionization spectra (TOF-HRMS-CI) were recorded on Waters Micromass GCT Premier Device apparatus.

3.2. Synthesis and Characterization

Epoxide 1 was synthesized from isosorbide according to a procedure outlined in [23]. Ethyl 2-hydroxybenzimidate hydrochloride was prepared according to Black and Wade’s procedure [25].

(S)-2-(Benzyloxy)-1-((3aR,4R,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethan-1-ol (2)

At reflux, benzyl alcohol (0.3 mL, 3 mmol, 3 equiv.) was added to a solution of a 60% oil dispersion of NaH (120 mg, 3 mmol, 3 equiv.) in THF (5 mL). After 1 h, epoxide 1 (0.186 g, 1 mmol) was added. After 22 h, the red reaction mixture was quenched with a saturated aqueous solution of NH₄Cl (4 mL) and extracted with EtOAc (5 mL). After drying over MgSO₄ and the removal of the solvent, the residue was purified by chromatography (Et₂O) to produce compound 2 (206 mg, 0.7 mmol, 70%) as a white solid.

Rf 0.28 (Et₂O). mp 52.2–52.8 °C. [α] _D ²⁰ = –39.5 (c 1.0, CH₂Cl₂). IR (ATR) ν 3422, 2978, 2854, 2030, 1603, 1498, 1477, 1455, 1432, 1369, 1315, 1292, 1205, 1143, 1100, 1004, 927, 853, 818, 739, 696, 602 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 1.28 (3H, s, Me), 1.47 (3H, s, Me), 3.21 (1H, brs, OH), 3.46 (1H, dd, J = 10.9, 3.7 Hz, H-6a), 3.52 (1H, dd, J = 6.2, 3.7 Hz, H-3), 3.67 (1H, dd, J = 9.8, 3.7 Hz, H-1a), 3.70 (1H, dd, J = 9.8, 3.7 Hz, H-1b), 4.50 (1H, d, J = 10.9 Hz, H-6b), 4.18 (1H, ddd, J = 6.2, 3.7, 3.7 Hz, H-2), 4.50 (1H, dd, J = 6.1, 3.7 Hz, H-4), 4.54 (1H, d, J = 12.2 Hz, H-8a), 4.60 (1H, d, J = 12.2 Hz, H-8b), 4.74 (1H, dd, J = 6.1, 3.7 Hz, H-5), 7.25–7.35 (5H, m, H_ar). ¹³C NMR (100 MHz, CDCl₃) δ 24.5 (CH₃); 25.9 (CH₃), 69.7 (CH, C-2), 71.0 (CH₂, C-1), 72.6 (CH₂, C-6), 73.4 (CH₂, C-8), 80.7 (CH, C-4), 81.3 (CH, C-5), 82.2 (CH, C-3), 112.2 (C, C-7), 127.6 (CH, C_ar), 127.7 (CH, C_ar) 128.3 (CH, C_ar), 138.1 (C, C_ar). Anal. C 65.23, H 7.73%, calcd for C₁₆H₂₂O₅ C 65.29, H 7.53%.

(S)-2-(Benzyloxy)-1-((3aR,4S,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl 4-methylbenzenesulfonate (3a)

To a mixture of alcohol 2, KOH (2 g, 35.6 mmol, 10 equiv.), and K₂CO₃ (2 g, 14.5 mmol), ground vigorously in a mortar, tosyl chloride (2 g, 10.7 mmol, 3 equiv.) was added. The whole mixture was ground vigorously for 1 h. A few drops of t-BuOH were then added to accelerate the disappearance of tosyl chloride. The tosylate formed was extracted with Et₂O (5 mL) and filtered. After the removal of the solvent, tosylate 3a was obtained as a white solid (1.10 g, 2.45 mmol, 68%), pure enough to be used without further purification.

Rf 0.21 (petroleum ether/Et₂O 80:20). mp 92–93 °C. [α]_D²⁰ = 1.9 (c 1.0, CHCl₃). IR (ATR) ν 2182, 2160, 2025, 1651, 1594, 1454, 1344, 1206, 1189, 1174, 1123, 1088, 1034, 784, 739, 690 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz) δ 1.24 (3H, s, Me), 1.36 (3H, s, Me), 2.41 (3H, s, H-9), 3.37 (1H, dd, J = 10.8, 3.8 Hz, H-6a), 3.75 (1H, dd, J = 8.6, 3.5 Hz, H-3), 3.84 (1H, dd, J = 11.9, 2.3 Hz, H-1a), 3.86 (1H, dd, J = 11.9, 3.6 Hz, H-1b), 3.89 (1H, d, J = 10.8 Hz, H-6b), 4.44 (1H, d, J = 11.9 Hz, H-8a), 4.56 (d, 1H, J = 11.9 Hz, H-8b), 4.57 (1H, dd, J = 6.1, 3.5 Hz, H-4), 4.70 (1H, dd, J = 6.1, 3.8 Hz, H-5), 4.92 (1H, ddd, J = 8.6, 3.6, 2.3 Hz, H-2), 7.24–7.35 (7H, m, H_ar), 7.81 (2H, d, J = 8.3 Hz, H_ar). ¹³C NMR (CDCl₃, 100 MHz) δ 21.6 (CH₃, C-9), 25.0 (CH₃,), 26.0 (CH₃), 69.2 (CH₂, C-1), 72.9 (C₂, C-6), 73.5 (CH₂, C-8), 80.1 (CH, C-4), 80.4 (CH, C-3), 81.1 (CH, C-5), 81.2 (CH, C-2), 112.4 (C, C-7), 127.7 (CH, C_ar), 128.2 (CH, C_ar), 128.3 (CH, C_ar), 129.3 (CH, C_ar), 134.2 (C, C_ar), 137.8 (C, C_ar), 144.3 (C, C_ar). HRMS (CI) m/z 448.1556 [M+H]⁺ (Calcd for C₂₃H₂₈O₇S 448.1556).

(S)-2-(Benzyloxy)-1-((3aR,4S,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl methanesulfonate (3b)

Under nitrogen, at 0 °C, mesyl chloride (8.7 mL, 112.3 mmol, 3.2 equiv.) in anhydrous CH₂Cl₂ (175 mL) was added dropwise to a stirred solution of compound 2 (10.33 g, 35.1 mmol) in Et₃N (19.5 mL, 140.4 mmol, 4 equiv.). After 5 h at r.t., the reaction mixture was filtered to remove the solid. The filtrate was washed with a saturated aqueous solution of NaHCO₃ then brine. After drying with Na₂SO₄, the solvent was removed to give rise to a solid residue, which was washed several times with Et₂O. The pure mesylate 3b (12.28 g, 33.0 mmol, 94%) was obtained as a white solid.

Rf 0.62 (Et₂O). mp 124–125 °C. [α]_D²⁰ = −33.0 (c 1.0, CH₂Cl₂). IR (ATR) ν 2870, 1504, 1379, 1364, 1342, 1222, 1204, 1173, 1125, 1106, 1087, 1056, 1032, 797, 742, 723, 696 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz) δ 1.27 (3H, s, Me), 1.46 (3H, s, Me), 3.07 (3H, s, H-9), 3.47 (dd, 1H, J = 10.8, 3.7 Hz, H-6a), 3.78 (1H, dd, J = 8.6, 3.5 Hz, H-3), 3.86 (1H, dd, J = 11.7, 2.3 Hz, H-1a), 3.96 (1H, dd, J = 11.7, 3.9 Hz, H-1b), 4.04 (1H, d, J = 10.8 Hz, H-6b), 4.53 (1H, d, J = 11.9 Hz, H-8a), 4.59 (1H, dd, J = 6.1, 3.5 Hz, H-4), 4.67 (1H, d, J = 11.9 Hz, H-8b), 4.76 (1H, dd, J = 6.1, 3.7 Hz, H-5), 4.96 (1H, ddd, J = 8.6, 3.9, 2.3 Hz, H-2); 7.26- 7.35 (5H, m, H_ar). ¹³C NMR (CDCl₃, 100 MHz) δ 24.7 (CH₃), 26.1 (CH₃), 38.5 (CH₃, C-9), 69.7 (CH₂, C-1), 72.9 (CH₂, C-6), 73.6 (CH₂, C-8), 80.0 (CH, C-3), 80.7 (CH, C-4), 81.3 (CH, C-5), 81.8 (CH, C-2), 112.2 (C, C-7), 127.8 (CH, C_ar), 128.0 (CH, C_ar), 128.4 (CH, C_ar), 137.7 (s, Cq.arom). HRMS (CI) m/z 373.1321 [M+H]⁺ (Calcd for C₁₇H₂₅O₇S 373.1321).

(3aS,4R,6aR)-4-((R)-1-Azido-2-(benzyloxy)ethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole (4)

From tosylate 3a

Sodium azide (2.85 g, 43.8 mmol. 15 equiv.) and 18-crown-6 ether (18C6) (3.10 g, 11.68 mmol, 4 equiv.) were added to a solution of tosylate 3a (1.3 g, 2.9 mmol) in DMF (15 mL). After 48 h of stirring at 120 °C, the reaction mixture was cooled at r.t., and then 60 mL of water and Et₂O were added. After decantation, the aqueous phase was extracted with Et₂O (3 × 40 mL). The combined organic phases were dried over MgSO₄. After the removal of the solvent, the residue was purified by chromatography (cyclohexane then cyclohexane/EtOAc 50:50) to produce azide 4 (226.7 mg, 0.7 mmol, 24%) as a pale yellow liquid.

From mesylate 3b

Sodium azide (1.22 g, 18.80 mmol. 10 equiv.) was added to a solution of mesylate 3b (0.70 g, 1.88 mmol) in DMSO (11 mL). After 48 h of stirring at 140 °C, the reaction mixture was cooled at r.t., and then 60 mL of water and Et₂O were added. After decantation, the aqueous phase was extracted with Et₂O (3 × 40 mL). The combined organic phases were dried over MgSO₄. After the removal of the solvent, the residue was purified by chromatography (cyclohexane then cyclohexane/EtOAc 50:50) to produce azide 4 (240 mg, 0.752 mmol, 40%) as a pale yellow liquid.

Rf 0.49 (petroleum ether/Et₂O 50:50). [α]_D²⁰ = −66.4 (c 0.5, CH₂Cl₂). IR (ATR) ν 3439, 3089, 2987, 2860, 2099, 1702, 1625, 1454, 1381, 1310, 1272, 1167, 1109, 1028, 987, 906, 862, 738, 699. ¹H NMR (CDCl₃, 400 MHz) δ 1.35 (3H, s, Me), 1.48 (3H, s, Me), 3.39 (1H, dd, J = 9.6, 3.1 Hz, H-3), 3.46 (1H, dd, J = 10.7, 3.2 Hz, H-6a), 3.67 (1H, dd, J = 10.2, 6.9 Hz, H-1a), 3.86–3.92 (2H, m, H-2, H-1b), 3.99 (1H, d, J = 10.7 Hz, H-6b), 4.60 (2H, s, H-10), 4.73 (1H, dd, J = 6.1, 3.1 Hz, H-4), 4.78 (1H, dd, J = 6.1, 3.2 Hz, H-5), 7.25–7.37 (5H, m, H_ar), 12.0 (1H, brs, OH). ¹³C NMR (CDCl₃, 100 MHz) δ 24.9 (CH₃), 26.2 (CH₃), 59.7 (CH₃, C-2), 70.9 (CH_2, C-1), 73.3 (CH₂, C-6), 73.6 (CH₂, C-10), 80.5 (CH, C-3), 80.6 (CH, C-4), 80.8 (CH, C-5), 112.5 (C, C-7), 127.7 (CH, C_ar), 127.8 (C, C_ar), 128.5 (CH, C_ar), 138.0 (CH, C_ar). HRMS (CI) m/z 319.1532 (Calcd for C₁₆H₂₁N₃O₄ 319.1532).

(R)-2-Amino-2-((3aS,4R,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethan-1-ol (5)

In a stainless autoclave, at 50 °C, azide 4 (2.96 g, 9.27 mmol) and 20% Pd/C (1.78, 8.14 mmol) in EtOH (45 mL) were stirred under hydrogen (50 bar). After 48 h, the mixture was cooled at r.t. and filtered, and then the solvent removed to give rise to aminoalcohol 5 as a yellow pasty solid (2.82 g, 97%), pure enough to be used without further purification.

Rf 0.17 (CH₂Cl₂/CH₃OH 90:10). [α]_D²⁰ = −40.0 (c 1.0, CH₂Cl₂). IR (ATR) ν 3303, 3000, 2855, 2931, 2979, 1586, 1206, 1164, 1080, 1058 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz) δ 1.31 (3H, s, Me), 1.48 (3H, s, Me), 2.87 (1H, dd, J = 12.4, 8.6 Hz, H-1a), 3.16 (1H, d, J = 12.4 Hz, H-1b), 3.49 (1H, dd, J = 6.4, 3.5 Hz, H-3), 3.52 (1H, dd, J = 10.8, 3.7 Hz, H-6a), 4.06 (1H, d, J = 10.8 Hz, H-6b), 4.05–4.12 (1H, dd, J = 8.6, 6.4 Hz, H-2), 4.25–4.42 (3H, brs, NH₂, OH), 4.72 (1H, dd, J = 6.1, 3.5 Hz, H-4), 4.79 (1H, dd, J = 6.1, 3.7 Hz, H-5). ¹³C NMR (CDCl₃, 100 MHz) δ 24.6 (Me), 26.0 (Me), 45.5 (CH₂, C-1), 69.5 (CH, C-2), 72.3 (CH₂, C-6), 80.5 (CH, C-5), 81.4 (CH, C-4), 83.1 (CH, C-3), 112.3 (s, C-7). HRMS (CI) m/z 204.1236 [M+H]⁺ (Calcd for C₉H₁₈NO₄ 204.1236).

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

A solution of aminoalcohol 5 (650 mg, 3.20 mmol), ethyl benzimidate hydrochloride (500 mg, 3.2 mmol), and Et₃N (0.43 mL, 3.20 mmol) in anhydrous 1,2-dichloroethane (5 mL) was refluxed over 7 days. After the removal of triethylamine hydrochloride by filtration, the filtrate was washed with water, an aqueous solution of NaHCO₃, and then brine. After drying over MgSO₄ and the removal of the solvent, the residue was purified by column chromatography (cyclohexane/EtOAc 80:20 →60:40). Oxazoline 6 (435 mg, 1.5 mmol, 47%) was obtained as a viscous orange oil.

Rf 0.32 (cyclohexane/EtOAc 40:60). [α]_D²⁰ = −9.1 (c 0.95, CH₂Cl₂) IR (ATR) ν 2981, 2855, 1648, 1281, 1207, 1188, 1067, 734, 698 cm⁻¹. ¹H NMR (CDCl₃, 400 MHz) δ 1.34 (3H, s, Me), 1.51 (3H, s, Me), 3.52 (1H, dd, J = 10.7, 3.2 Hz, H-6a), 3.72 (1H, dd, J = 4.7, 3.1 Hz, H-3), 4.06 (1H, d, J = 10.7 Hz, H-6b), 4.49 (1H, dd, J = 9.9, 8.4 Hz, H-1a), 4.58 (1H, dd, J = 8.4, 8.0 Hz, H-1b), 4.65 (1H, ddd, J = 9.9, 8.0, 4.7 Hz, H-2), 4.76 (1H, dd, J = 6.2, 3.1 Hz, H-4), 4.78 (1H, dd, J = 6.2, 3.2 Hz, H-5), 7.35–7.40 (2H, m, H_ar), 7.43–7.47 (1H, m, H_ar), 7.96–7.98 (2H, m, H_ar). ¹³C NMR (CDCl₃, 100 MHz) δ 24.2 (CH₃), 25.6 (CH₃), 65.5 (CH, C-2), 69.3 (CH₂, C-1), 72.7 (CH₂, C-6), 80.4 and 80.8 (CH, C-4, C-5), 83.5 (CH, C-3), 112.1 (C, C-7), 127.5 (C, C_ar), 128.1 (CH, C_ar), 128.4 (CH, C_ar), 131.3 (CH, C_ar), 164.8 (C, C-8). HRMS (CI) m/z 290.1392 [M+H]⁺ (Calcd for C₁₆H₂₀NO₄ 290.1392).

2-((R)-4-((3aS,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4,5-dihydrooxazol-2-yl)phenol (7)

A solution of aminoalcohol 5 (230 mg, 1.13 mmol) and ethyl 2-hydroxy benzimidate hydrochloride (228 mg, 1.13 mmol) in anhydrous chlorobenzene was refluxed over 7 days. After the removal of the solvent, the residue was purified by column chromatography (cyclohexane/EtOAc 60:40). Oxazoline 7 (67.5 mg, 0.22 mmol, 19%) was obtained as a white powder.

Rf 0.18 (cyclohexane/EtOAc 60:40). mp 104.9–105.3 °C. [α]_D²⁰ = +52.1 (c 0.3, CH₂Cl₂). IR (ATR) ν 3175, 2942, 2840 (C-H), 1637, 1600, 1490 (C=C), 1420, 1367, 1309, 1255, 1217, 1069, 1059, 956, 915, 853, 960 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 1.34 (s, 3H, Me), 1.51 (3H, s, Me), 3.53 (1H, dd, J = 10.9, 3.7 Hz, H-6a), 3.72 (1H, dd, J = 4.6, 3.5 Hz, H-3), 4.06 (1H, d, J = 10.9 Hz, H-6b), 4.47 (1H, dd, J = 9.9, 8.6 Hz, H-1a), 4.59 (1H, dd, J = 8.6, 7.9 Hz, H-1b), 4.70 (1H, ddd, J = 9.9, 7.9, 4.6 Hz, H-2), 4.74 (1H, dd, J = 6.1, 3.5 Hz, H-4), 4.79 (1H, dd, J = 6.1, 3.7 Hz, H-5), 6.86 (1H, ddd, J = 7.9, 7.2, 1.2 Hz, H_ar), 6.99 (1 H, dd, J = 8.2, 1.2 Hz, H_ar), 7.36 (1H, ddd, J = 8.2, 7.2, 1.6 Hz, H_ar), 7.65 (1H, dd, J = 7.9, 1.6 Hz, H_ar), 12.00 (1H, brs, OH). ¹³C NMR (100 MHz, CDCl₃) δ 24.3 (CH₃), 25.7 (CH₃), 64.4 (CH, C-2), 68.7 (CH₂, C-1), 73.0 (CH, C-6), 80.5 (CH, C-4), 80.9 (CH, C-5), 83.4 (CH, C-3), 110.7 (C, C_ar), 112.3 (C, C-7), 116.7 (CH, C_ar), 118 (CH, C_ar), 128.2 (CH, C_ar), 133.5 (CH, C_ar), 159.9 (C, C_ar), 166.4 (C, C-8). HRMS (CI) m/z 305.1264 (Calcd for C₁₆H₁₉NO₅ 305.1263).

4. Conclusions

Monooxazolines 6 and 7 were obtained from an isosorbide epoxide 1 derivative using a five-reaction strategy with an overall yield of 12% and 5%, respectively. The key steps of this process were the formation of azide 4 from tosylate 3a or mesylate 3b and the reaction between amino alcohol 5 and an imidate.