Download PDF
Synlett 2002(12): 2071-2073
DOI: 10.1055/s-2002-35595
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3-Haloisoxazole Boronic Esters: Novel Heterocyclic Synthetic Intermediates Containing Independently Variable Functionality

Jane E. Moorea, Katharine M. Goodenougha, Daniel Spinksb, Joseph P. A. Harrity*a
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
e-Mail: j.harrity@sheffield.ac.uk;
b Department of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse, Lanarkshire, ML1 5SH, UK
Further Information

Publication History

Received 3 October 2002
Publication Date:
20 November 2002 (online)

    Permissions and Reprints All articles of this category

Abstract

The regioselective cycloaddition reaction of nitrile oxides with alkynylboronates has been exploited in the preparation of 3-bromo- and 3-chloroisoxazolyl-4-boronates. The synthetic potential of these intermediates has been explored through a number of cross coupling reactions of the boronic ester unit and some representative reactions of the heteroaryl halide moiety.

Key words

regioselective - cycloadditions - Suzuki coupling - isoxazole

8

Representative experimental procedure for cyclo-addition reactions: 3-Bromo-5-butyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole 3b: A solution of 2-hexyn-1-yl-4,4,5,5-tetramethyl-[1,3,2]dioxa-boralane (0.90 g, 4.32 mmol), dibromoformaldoxime (0.877 g, 4.32 mmol) and KHCO3 (0.866 g, 8.65 mmol) in dimethoxyethane (5 mL) was stirred for 12 h at 50 ºC. The reaction mixture was cooled, the residual solid removed by vacuum filtration and the solvent removed in vacuo. Purification by flash chromatography eluting with hexane-EtOAc, (15:1) followed by kugelrohr distillation 110 °C/ 0.4 mmHg gave the title compound as a colourless oil (0.627g, 44% yield). 1H NMR (250 MHz, CDCl3): δ 0.91 (3 H, t, J = 7.0 Hz), 1.22-1.41 (2 H, m), 1.31 (12 H, s), 1.58-1.73 (2 H, m), 2.94 (2 H, t, J = 7.0 Hz). 13C NMR (62.9 MHz, CDCl3) δ 13.5, 22.0, 24.8, 26.8, 30.1, 83.8, 144.5, 183.6. FTIR (CHCl3/cm-1): 2978 (s), 2934 (s), 2874 (s), 1741 (m), 1589 (s). Anal. calcd for C13H21BNO3Br: C, 47.31; H, 6.41; N, 4.24; Br, 24.21. Found: C, 47.33; H, 6.58; N, 4.23; Br, 24.18. HRMS calcd for C13H22BNO3 79Br (MH+): 330.0871, Found: 330.0876. HRMS calcd for C13H22BNO3 81Br (MH+): 332.0851, Found: 332.0847.

9

The X-ray data for isoxazole 3a has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 191718.

11

Representative experimental procedure for Suzuki coupling reactions: 3-Bromo-5-butyl-4-(2-nitrophenyl)-isoxazole 7: A solution of boronic ester 3b (0.05 g, 0.15 mmol), PdCl2(dppf)·CH2Cl2 (0.012 g, 0.015 mmol), 1-iodo-2-nitrobenzene (0.075 g, 0.30 mmol) and K3PO4 (0.096 g, 0.45 mmol) in dioxane (1 mL) was stirred at 85 °C under N2 atmosphere for 16 h. The reaction was quenched with deionised water (10 mL), and allowed to cool to room temperature. The product was extracted into CH2Cl2 (3 × 10 mL) and the organic layer washed with saturated brine (10 mL), dried (MgSO4), filtered and the filtrate was concentrated in vacuo to give a brown solid. Purification by flash chromatography eluting with hexane-EtOAc (100:1) gave the title compound as yellow oil (0.043 g, 87% yield). 1H NMR (250 MHz, CDCl3): δ 0.77 (3 H, t, J = 7.0 Hz), 1.13-1.31 (2 H, m), 1.46-1.61 (2 H, m), 2.61 (2 H, t, J = 7.0 Hz), 7.28 (1 H, dd, J = 7.0 Hz, 7.5 Hz), 7.51-7.73 (2 H, m), 8.10 (1 H, dd, J = 8.0 Hz, 1.0 Hz). 13C NMR (62.9 MHz, CDCl3) δ 13.5, 22.1, 25.9, 29.1, 114.8, 123.3, 125.2, 130.2, 133.4, 141.6, 149.1, 171.4. FTIR (CHCl3/cm-1): 2960 (m), 1633 (m), 1601 (m), 1529 (m), 1441 (m). Anal. calcd for C13H13BrN2O3: C, 48.02; H, 4.03; N, 8.62; Br, 24.57. Found: C, 48.30; H, 4.12; N, 8.42; Br, 24.66. HRMS calcd for C13H14N2O3 79Br (MH+): 325.0188. Found: 325.0189. HRMS calcd for C13H14N2O3 81Br (MH+): 327.0168. Found: 327.0165.