# Syntheses of Chiral 2-Oxazolines from Isosorbide Epoxide Derivative

Mohammed Kadraoui, Stéphane Guillarme, Christine Saluzzo

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## To cite this version:

Mohammed Kadraoui, Stéphane Guillarme, Christine Saluzzo. Syntheses of Chiral 2-Oxazolines from Isosorbide Epoxide Derivative. Molbank, 2024, 2025, 10.3390/m1966_hal-05097552

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# Syntheses of Chiral 2-Oxazolines from Isosorbide Epoxide Derivative

Mohammed Kadraoui, Stéphane Guillarme and Christine Saluzzo

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MSO Institut des Molécules et Matériaux du Mans, Avenue O. Messiaen, 72085 LeMans, Cedex 9, France; mkadr19@yahoo.fr (M.K.); stephane.guillarme@univ-lemans.fr (S.G.)

* Correspondence: christine.saluzzo@univ-lemans.fr

**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.

**Keywords:** isosorbide; sustainable material; chiral aminoalcohol; chiral 2-oxazoline; oxirane; epoxide; imidate

## 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 [6–10] or be used as chiral auxiliaries [11,12]. In addition, they could be considered effective ligands in organometallic catalysis [13–15] 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 [20–22].

### 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,

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check for
updates

Academic Editor: Stefano D'Errico

Received: 14 January 2025

Revised: 3 February 2025

Accepted: 5 February 2025

Published: 8 February 2025

**Citation:** Kadraoui, M.; Guillarme, S.; Saluzzo, C. Syntheses of Chiral 2-Oxazolines from Isosorbide Epoxide Derivative. *Molbank* **2025**, *2025*, M1966. https://doi.org/10.3390/M1966

**Copyright:** © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
**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.

<figure><img src="image_6.png" /><figcaption>**Scheme 1.** Formation of aminoalcohol 5.</figcaption></figure>

## 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).

<figure><img src="image_7.png" /><figcaption>**Scheme 2.** Formation of oxazolines 6 and 7 from aminoalcohol 5.</figcaption></figure>

**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 $NH_4Cl$ (4 mL) and extracted with EtOAc (5 mL). After drying over $MgSO_4$ and the removal of the solvent, the residue was purified by chromatography ($Et_2O$) to produce compound 2 (206 mg, 0.7 mmol, 70%) as a white solid.

Rf 0.28 ($Et_2O$). mp 52.2-52.8 °C. [α]$_D^{20}$ = -39.5 (c 1.0, $CH_2Cl_2$). 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, $CDCl_3$) 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, $CDCl_3$) δ 24.5 ($CH_3$); 25.9 ($CH_3$), 69.7 (CH, C-2), 71.0 ($CH_2$, C-1), 72.6 ($CH_2$, C-6), 73.4 ($CH_2$, 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 $C_{16}H_{22}O_5$ 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 $K_2CO_3$ (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 $Et_2O$ (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/$Et_2O$ 80:20). mp 92-93 °C. [α]$_D^{20}$ = 1.9 (c 1.0, $CHCl_3$). IR (ATR) ν 2182, 2160, 2025, 1651, 1594, 1454, 1344, 1206, 1189, 1174, 1123, 1088, 1034, 784, 739, 690 cm⁻¹. ¹H NMR ($CDCl_3$, 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 ($CDCl_3$, 100 MHz) δ 21.6 ($CH_3$, C-9), 25.0 ($CH_3$), 26.0 ($CH_3$), 69.2 ($CH_2$, C-1), 72.9 ($C_2$, C-6), 73.5 ($CH_2$, 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 $C_{23}H_{28}O_7S$ 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 $CH_2Cl_2$ (175 mL) was added dropwise to a stirred solution of compound 2 (10.33 g, 35.1 mmol) in $Et_3N$ (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 $NaHCO_3$ then brine. After drying with $Na_2SO_4$, the solvent was removed to give rise to a solid residue, which was washed several times with $Et_2O$. The pure mesylate 3b (12.28 g, 33.0 mmol, 94%) was obtained as a white solid.

Rf 0.62 ($Et_2O$). mp 124-125 °C. [α]$_D^{20}$ = -33.0 (c 1.0, $CH_2Cl_2$). 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, H₃). 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, Cₐ), 128.0 (CH, Cₐ), 128.4 (CH, Cₐ), 137.7 (s, Cq.аром). 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, H₃), 12.0 (1H, brs, OH). ¹³C NMR (CDCl₃, 100 MHz) δ 24.9 (CH₃), 26.2 (CH₃), 59.7 (CH₃, C-2), 70.9 (CH₂, 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, Cₐ), 127.8 (C, Cₐ), 128.5 (CH, Cₐ), 138.0 (CH, Cₐ). 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 C$_9$H$_{18}$NO$_4$ 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 Et$_3$N (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 NaHCO$_3$, and then brine. After drying over MgSO$_4$ 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]$_D^{20}$ = -9.1 (c 0.95, CH$_2$Cl$_2$) IR (ATR) ν 2981, 2855, 1648, 1281, 1207, 1188, 1067, 734, 698 cm$^{-1}$. $^1$H NMR (CDCl$_3$, 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$_{ar}$). $^{13}$C NMR (CDCl$_3$, 100 MHz) δ 24.2 (CH$_3$), 25.6 (CH$_3$), 65.5 (CH, C-2), 69.3 (CH$_2$, C-1), 72.7 (CH$_2$, 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 C$_{16}$H$_{20}$NO$_4$ 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]$_D^{20}$ = +52.1 (c 0.3, CH$_2$Cl$_2$). 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$^{-1}$. $^1$H NMR (400 MHz, CDCl$_3$) 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). $^{13}$C NMR (100 MHz, CDCl$_3$) δ 24.3 (CH$_3$), 25.7 (CH$_3$), 64.4 (CH, C-2), 68.7 (CH$_2$, 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 C$_{16}$H$_{19}$NO$_5$ 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.

**Supplementary Materials:** Figures S1–S4: compound 2 NMR spectra; Figures S5–S8: compound 3a NMR spectra; Figure S9: compound 3a HRMS; Figures S10–S13: compound 3b NMR spectra; Figure S14: compound 3b HRMS; Figures S15–S18: compound 4 NMR spectra; Figure S19: compound 4 HRMS; Figures S20 and S21: compound 5 NMR spectra; Figure S22: compound 5 HRMS;
Figures S23–S25: compound **6** NMR spectra; Figure S26: compound **6** HRMS; Figures S27–S30: compound **7** NMR spectra; Figure S31: compound **7** HRMS.

**Author Contributions:** Conceptualization, C.S.; validation, S.G., M.K. and C.S.; investigation, M.K.; writing—original draft preparation, C.S.; writing—review and editing, S.G, M.K. and C.S.; visualization, C.S.; supervision, C.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** Data are contained within the article and Supplementary Materials.

**Acknowledgments:** The authors would like to thank the Ministère de la Recherche and the CNRS for their financial support. They also wish to extend thanks to Alexandre Benard for his contribution to the HRMS analysis.

**Conflicts of Interest:** The authors declare no conflicts of interest.

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