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

Abstract

(1S,1′S)-2,2′-(Benzylazanediyl)bis(1-((3aR,4R,6aR)-2,2-dimethyltetrahydrofuro [3,4 d][1,3]dioxol-4-yl)ethan-1-ol), presenting a tertiary β-aminodiol moiety, was synthesized in 72% yield in a one-step reaction from an aminolysis of an isosorbide-derived oxirane with benzylamine. This β-aminodiol was fully characterized by ¹H and ¹³C NMR and HRMS analyses.

1. Introduction

Aminoalcohols represent an important class of compounds due to their versatility. Among them, diethanolamine and its derivatives have attracted much attention as they can be used as building blocks for heterocyclic compounds [1], amphiphiles [1,2] and polymers [1,3,4,5,6], and this moiety is found in compounds having biological activities [1,7,8]. They can be also employed as initiators in polymer syntheses [4,9,10,11,12,13,14] and as ligands for organometallic catalysis [15,16,17,18,19,20,21,22]. As a diethanolamine derivative, the title compound could be mainly used in the last two fields of application.

We report therein the synthesis of β-aminodiol structure through aminolysis of an epoxide [15,19,23,24,25].

2. Results and Discussion

In 2008, we showed that various primary amines were able to transform epoxide 1 [26] derived from isosorbide into the corresponding β-aminoalcohols [27,28]. The reaction occurred exclusively via the ring opening through the less hindered position leading to β-aminoalcohol in moderate to good yields. It is noteworthy that this reaction was performed with two equivalents of primary amines [27,28]. Herein, we present the bisalkylation of benzylamine by aminolysis of the epoxide 1 (Scheme 1).

Heating a solution of 1 equivalent of benzylamine with 3.3 equivalents of isosorbide-derived epoxide 1 in methanol afforded the β-aminodiol 2 in 72% yield as a single isomer along with the β-aminoalcohol 3 in 16% yield (Scheme 1). The ¹H NMR spectrum of compound 2 revealed that integrations of all protons were twice as high as the non-equivalent benzyl protons located at 3.65 and 3.92 ppm (Figure S1). Furthermore, the ¹³C NMR spectrum (Figure S2) presents at 56.7 and 59.8 ppm two chemical shifts corresponding to two CH₂N groups, the latter being the benzylic one (Figure S4). These observations confirm unequivocally that the β-aminodiol 2 presents a C-2 symmetry.

3. Materials and Methods

3.1. General

Commercially available compounds were used as received. Methanol was dried over 4 Å molecular sieves. The reaction was 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 along a 1 dm path length cell using a JASCO P-2000 spectrometer (JASCO, Easton, MD, USA). Thin-layer chromatography was performed with UV254 plates and revealed under UV light. All melting points were recorded on a ThermoFisher IA9300 apparatus and were uncorrected. ¹H and ¹³C NMR spectra were recorded in CDCl₃ on a Bruker Avance 400 spectrometer (¹H 400 MHz and ¹³C 100 MHz, respectively). 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; br s, broad signal. Proton and carbon assignments were established using COSY and HSQC experiments. High-resolution time-of-flight mass spectrum positive chemical ionization (TOF-HRMS (CI⁺)) was recorded on a Waters Micromass GCT Premier Device apparatus.

3.2. Synthesis and Characterization

Epoxide 1 was synthesized from isosorbide according to the literature procedure [26]. The NMR data of the β-aminoalcohols 3 are consistent with our previously published results [27,28].

For the NMR assignment, the copies of NMR spectra (Figures S1–S4) and HRMS (S5) of compound 2 are available in the Supplementary Materials. In a sealed tube, benzylamine (0.52 g, 4.89 mmol) and epoxide 1 (3.00 g, 16.14 mmol, 3.3 equiv.) in anhydrous methanol (16 mL) were heated at 60 °C. After 3 days, the reaction mixture was cooled to room temperature. After concentration, the residue was purified by chromatography (CH₂Cl₂/MeOH 98:2 then 95:5) to yield the β-aminodiol 2 (1.68 g, 3.51 mmol, 72%) as a white solid and the β-aminoalcohol 3 (226 mg, 0.77 mmol, 16%).

(1S,1′S)-2,2′-(Benzylazanediyl)bis(1-((3aR,4R,6aR)-2,2-dimethyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl)ethan-1-ol) (2),R_f 0.38 (UV, CH₂CI₂/MeOH 95/5). M.p. 107–108 °C. [α]²⁰_D−76.9 (c 1.0, CHCl₃). ¹H NMR (CDCl₃, 400 MHz) δ 1.29 (6H, s, CH₃), 1.46 (6H, s, CH₃), 2.73 (2H, dd, J = 13.1, 8.2 Hz, H-1a), 2.84 (2H, dd, J = 13.1, 3.8 Hz, H-1b), 3.29 (2H, dd, J = 6.7, 3.8 Hz, H-3), 3.40-3.55 (2H, br s, OH), 3.45 (2H, dd, J = 10.8, 3.8 Hz, H-6a), 3.65 (1H, d, J = 13.8 Hz, H-8a), 3.92 (1H, d, J = 13.8 Hz, H-8b), 4.04 (2H, d, J = 10.8 Hz, H-6b), 4.10 (2H, ddd, J = 8.2, 6.7, 3.8 Hz, H-2), 4.50 (2H, dd, J = 6.0, 3.8 Hz, H-4), 4.72 (2H, dd, J = 6.0, 3.8 Hz, H-5), 7.28–7.38 (5H, m, H_ar). ¹³C NMR (CDCl₃, 100 MHz) δ 24.7 (CH₃), 26.0 (CH₃), 56.7 (NCH₂, C-1), 59.8 (NCH₂, C-8), 68.4 (CH, C-2), 72.7 (CH₂, C-6), 80.7 (CH, C-4), 81.3 (CH, C-5), 83.7 (CH, C-3), 112.2 (C, C-7), 127.2 (CH, C_ar), 128.3 (CH, C_ar), 129.4 (CH, C_ar), 138.7 (C, C_ar). HRMS m/z [M+H]⁺ 480.2601 (Cald for C₂₅H₃₈NO₈ 480.2597).

4. Conclusions

(1S,1′S)-2,2′-(Benzylazanediyl)bis(1-((3aR,4R,6aR)-2,2-dimethyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl)ethan-1-ol) was obtained using an aminolysis of the isosorbide oxirane derivative 1 in 72% yield.