Open Access Short Note

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

Christine Saluzzo, Liliana Boiaryna, Stéphane Guillarme

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Christine Saluzzo, Liliana Boiaryna, Stéphane Guillarme. Open Access Short Note 5(S)-((3aR,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole. Mol-bank, 2024. hal-05097573

HAL Id: hal-05097573

https://univ-lemans.hal.science/hal-05097573v1

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Short Note

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

Liliana Boiaryna, Stéphane Guillarme and Christine Saluzzo * |

MSO, Institut des Molecules et Matériaux du Mans (IMMM), UMR CNRS 6283, Le Mans Université,
Avenue O. Messiaen, 72085 Le Mans, France; liliana.boiaryna@gmail.com (L.B.)

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

**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.

**Keywords:** chiral oxazoline; isosorbide; isohexide; sustainable material; epoxide; nitrile; carbohydrate; biomass

**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 [2–4] or as organocatalysts [5] to carry out
many chemical transformations efficiently.

More recently, they were used as monomers [6–8], 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 [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%.

<figure><img src="image_3.png" /><figcaption>**Scheme 1.** Synthesis of epoxide 1 according to the Ejjiyar et al. procedure [10,11].</figcaption></figure>

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**Citation:** Boiaryna, L.; Guillarme, S.; Saluzzo, C. 5(S)-((3aR,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole. *Molbank* **2024**, *M1843*. https://doi.org/10.3390/M1843

Academic Editor: Oleg A. Rakitin

Received: 28 May 2024

Revised: 21 June 2024

Accepted: 24 June 2024

Published: 28 June 2024

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**Copyright:** © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
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4.0/).
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 $BF_3·Et_2O$ 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 $CH_2-N$.

<figure><img src="image_6.png" /><figcaption>**Scheme 2.** Synthesis of oxazoline 2.</figcaption></figure>

### 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 $^{13}C$ NMR spectra were recorded on a Bruker Avance 400 spectrometer ($^1H$ 400 MHz and $^{13}C$ 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), $BF_3·Et_2O$ (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 $Na_2CO_3$ (200 mg) was added; then, after 3 h, a saturated aqueous solution of $NaHCO_3$ (10 mL) was added to the reaction mixture. After extraction with $CH_2Cl_2$ (2 × 5 mL), the combined organic phases were dried with $MgSO_4$ 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%).

$[\alpha]^{20}_D = -40.8$ (c 1.0, $CH_2Cl_2$); 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 ($CDCl_3$, 400 MHz) 1.33 (3H, s, $CH_3$), 1.51 (3H, s, $CH_3$), 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, HAr), 7.97 (1H, dd, *J* = 2.2 Hz, *J* = 1.7 Hz, HAr), 8.01 (1H, dd, *J* = 2.2 Hz, *J* = 1.7 Hz, HAr). ¹³C NMR (CDCl₃, 100 MHz) 24.8 (CH₃), 26.0 (CH₃), 57.4 (NCH₂, C4), 73.4 (OCH₂, 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, CAr), 128.29 (CH, CAr), 128.3 (CH, CAr), 131.4 (C, CAr), 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.

**Supplementary Materials:** Figure S1: Structure of 5(S)-((3aR,4R,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole (2). Figure S2: ¹H NMR spectrum of compound 2. Figure S3: H-H COSY spectrum of compound 2. Figure S4: ¹³C NMR spectrum of compound 2. Figure S5: HSQC spectrum of compound 2. Figure S6: HRMS spectrum of compound 2.

**Author Contributions:** Conceptualization, S.G. and C.S.; methodology, L.B., S.G. and C.S.; validation, L.B., S.G. and C.S.; investigation, L.B.; writing—original draft preparation, C.S.; writing—review and editing, L.B., S.G. 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 thank Alexandre Benard for his contribution to HRMS analysis.

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

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