An Exploration of Regioselectivity During Formation of Aminoboronates from Epoxides

Abstract

α-Aminoboronic acids and their derivatives are important synthetic targets. Our research interest has been focused on the synthesis and applications of MIDA (N-methyliminodiacetic acid) protected aminoboronates. Herein we report syntheses of regioisomeric β-borylated azidoalcohols. The geminal azidoboronate represents a rare example of an α-azidoalcohol and is produced through trapping of oxonium ions that develop during the rearrangement of α-boryl aldehydes. The vicinal azidoboronate can be obtained from α-bromoacetyl MIDA boronate and enables the preparation of aziridine MIDA boronate through the Staudinger reaction.

Key words

α-aminoboronic acids - azidoboronate - Staudinger reaction

Publication History

Received: 08 November 2023

Accepted after revision: 29 November 2023

Article published online:
11 January 2024

• References and Notes

• 1a Aziridines and Epoxides in Organic Synthesis. Yudin AK. Wiley-VCH; Weinheim: 2006
• 1b Sweeney B. Sci. Synth. 2009; 40: 643
• 2 Hili R, Yudin AK. J. Am. Chem. Soc. 2006; 128: 14772
• 3 Adams J, Behnke M, Chen S, Cruickshank AA, Dick LR, Grenier L, Klunder JM, Ma YT, Plamondon L, Stein RL. Bioorg. Med. Chem. Lett. 1998;  8: 333
• 4 He Z, Yudin AK. J. Am. Chem. Soc. 2011; 133: 13770
• 5 Li Y, Fan WX, Luo S, Trofimova A, Liu Y, Xue JH, Yang L, Li Q, Wang H, Yudin AK. J. Am. Chem. Soc. 2023; 145: 7548
• 6 He Z, Zajdlik A, Yudin AK. Acc. Chem. Res. 2014; 47: 1029
• 7 Staudinger H, Meyer J. Helv. Chim. Acta 1919; 2: 635

For the papers on the intermediacy of pinacol boronic ester aziridine, see:
• 8a Schmidt F, Keller F, Vedrenne E, Aggarwal VK. Angew. Chem. Int. Ed. 2009; 48: 1149
• 8b Fawcett A, Murtaza A, Gregson CH, Aggarwal VK. J. Am. Chem. Soc. 2019; 141: 4573
• 9a Kalisiak J, Sharpless KB, Fokin VV. Org. Lett. 2008; 10: 3171
• 9b Banert K, Berndt C, Firdous S, Hagedorn M, Joo YH, Rüffer T, Lang H. Angew. Chem. Int. Ed. 2010; 49: 10206
• 9c Banert K, Berndt C, Weigand K. Org. Lett. 2017; 19: 4900
• 10 Sun X, Li X, Song S, Zhu Y, Liang YF, Jiao N. J. Am. Chem. Soc. 2015; 137: 6059
• 11 Saito H, Nukada K, Kobayashi T, Morita K. J. Am. Chem. Soc. 1967; 89: 6605
• 12 Hernández-Toribio J, Hussain MM, Cheng K, Carroll PJ, Walsh PJ. Org. Lett. 2011; 13: 6094
• 13a Matteson DS, Sadhu KM. Organometallics 1984; 3: 614
• 13b Laplante C, Hall DG. Org. Lett. 2001; 3: 1487
• 14 Uno BE, Gillis EP, Burke MD. Tetrahedron 2009; 65: 3130
• 15a Lee CF, Tien C.-H, Adachi S, Yudin AK. Org. Synth. 2020; 97: 157
• 15b Adachi S, Liew SK, Lee CF, Lough A, He Z, Denis JD. S, Poda G, Yudin AK. Org. Lett. 2015; 17: 5594
• 16 Boryl 1,1-Azidoalcohol (7) To a flame-dried flask equipped with a magnetic stirring bar and a rubber septum was added oxiranyl MIDA boronate (4a, 0.3 mmol, 1.0 equiv., 83 mg) in 3 mL anhydrous DCM. The solution was cooled to –30 °C. TMSN₃ (0.6 mmol, 2.0 equiv., 0.079 mL) was added dropwise with stirring. After that, BF₃·Et₂O (0.3 mmol, 1.0 equiv., 0.037 mL) was added dropwise with stirring at –30 °C. The mixture was then stirred at –30 °C to 0 °C over 30 min. The reaction was quenched by saturated aqueous NaHCO₃. The organic layer was then separated using DCM for washing the flask; the aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude residue was purified using flash column chromatography on silica gel (hexanes/EtOAc, 1:1 → EtOAc → EtOAc/MeCN, 9:1) to afford pure products 5a (77% isolated yield, 63 mg) and 7 (10% isolated yield, 9 mg). The NMR spectra matched the reported spectra of 5a. ¹H NMR (600 MHz, CD₃CN): δ = 7.35–7.29 (m, 4 H), 7.28–7.23 (m, 1 H), 5.40 (d, J = 8.7 Hz, 1 H), 4.13–3.87 (m, 3 H), 3.49 (d, J = 17.2 Hz, 1 H), 2.94 (s, 3 H), 2.64 (d, J = 8.7 Hz, 1 H) ppm. ¹³C NMR (101 MHz, CD₃CN): δ = 168.8, 168.7, 140.2, 130.8, 129.4, 127.5, 81.4, 64.3, 63.8, 47.7 ppm. ¹¹B NMR (128 MHz, CD₃CN): δ = 11.5 ppm. As the carbon directly attached to the boron atom exhibited significant line broadening due to quadrupolar relaxation, its chemical shift was deduced from HMBC spectra and was 42.1 ppm.
• 17 Boryl 1,2-Azidoalcohol (2b) To a flask equipped with a magnetic stirring bar and a rubber septum was added α-bromoacetyl MIDA boronate (3b, 2.82 mmol, 1.0 equiv., 790 mg) in 5.6 mL DMSO (0.5 M) at room temperature under air. To a solution was added sodium azide (8.47 mmol, 3.0 equiv., 550 mg). The mixture was then heated to 60 °C, and the reaction was stirred at 60 °C for 18 h or as indicated by TLC. Upon completion, the reaction mixture was diluted with water and EtOAc and transferred to a separatory funnel. The organic layer was then separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated to dryness. The crude residue was purified using flash column chromatography on silica gel (EtOAc → EtOAc/MeCN, 9:1) to afford pure product 2b (42% isolated yield, 287 mg). ¹H NMR (400 MHz, CD₃CN): δ = 3.96 (dd, J = 16.8, 2.0 Hz, 2 H), 3.83 (dd, J = 16.8, 2.8 Hz, 2 H), 3.53–3.42 (m, 2 H), 3.33 (dd, J = 12.9, 10.0 Hz, 1 H), 3.04 (s, 3 H) ppm. ¹³C NMR (126 MHz, CD₃CN): δ = 169.5, 168.8, 63.1, 62.9, 56.2, 46.4 ppm. ¹¹B NMR (128 MHz, CD₃CN): δ = 10.3 ppm. HRMS (DART-AccuTOF 4G) [M + NH₄ ⁺]: m/z calcd for C₇H₁₅BN₅O₅: 260.1161; found: 260.1164.
• 18 Boryl Aziridine (1) To a flame-dried flask equipped with a magnetic stirring bar and a rubber septum was added 1,2-azidoalcohol 2b (0.48 mmol, 1.0 equiv., 116 mg) in 5 mL anhydrous MeCN at room temperature. Triphenylphosphine (0.96 mmol, 2.0 equiv., 251 mg) was then added to the solution. The mixture was allowed to stir at room temperature for 1 h. The mixture was then heated to 60 °C, and the reaction was stirred at 60 °C for 2 h or as indicated by TLC. Upon completion, the reaction mixture was concentrated in vacuo to dryness. Et₂O was added to a crude reaction and sonicated under air. Et₂O was decanted, and the washing was repeated 2 times. The white solid was then dried in vacuo to afford pure product 1 (88% isolated yield, 83 mg). ¹H NMR (400 MHz, CD₃CN): δ = 3.97–3.77 (m, 4 H), 3.03 (s, 3 H), 1.72 (d, J = 6.9 Hz, 1 H), 1.36 (d, J = 4.2 Hz, 1 H), 0.99 (dd, J = 6.9, 4.4 Hz, 1 H) ppm. ¹³C NMR (126 MHz, CD₃CN): δ = 168.9, 63.1, 62.7, 46.8, 22.5 ppm. ¹¹B NMR (128 MHz, CD₃CN): δ = 11.3 ppm. HRMS (ESI-MS) [M + H⁺]: m/z calcd for C₇H₁₂BN₂O₄: 198.0921; found: 198.0921.