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DOI: 10.1055/s-2002-35595
Synthesis of 3-Haloisoxazole Boronic Esters: Novel Heterocyclic Synthetic Intermediates Containing Independently Variable Functionality
Publikationsverlauf
Publikationsdatum:
20. November 2002 (online)
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
- 1
Thompson LA.Ellman JA. Chem. Rev. 1996, 96: 555 - For comprehensive reviews, see:
-
2a
Suzuki A. Pure Appl. Chem. 1994, 66: 213 -
2b
Miyaura N.Suzuki A. Chem. Rev. 1995, 95: 2457 -
3a
Antilla JC.Buchwald SL. Org. Lett. 2001, 3: 2077 -
3b
Evans DA.Katz JL.West TR. Tetrahedron Lett. 1998, 39: 2937 -
4a
Petasis NA.Zavialov IA. J. Am. Chem. Soc. 1997, 119: 445 -
4b
Ueda M.Miyaura N. J. Org. Chem. 2000, 65: 4450 -
4c
Takaya Y.Ogasawara M.Hayashi T.Sakai M.Miyaura N. J. Am. Chem. Soc. 1998, 120: 5579 -
5a
Davies MW.Johnson CN.Harrity JPA. Chem. Commun. 1999, 2107 -
5b
Davies MW.Johnson CN.Harrity JPA. J. Org. Chem. 2001, 66: 3525 -
5c
Davies MW.Wybrow RAJ.Johnson CN.Harrity JPA. Chem. Commun. 2001, 1558 -
6a
Farina F.Fraile MT.Martin MR.Martin MV.de Guerenu AM. Heterocycles 1995, 40: 285 -
6b
Hanson RN.Mohamed FA. J. Heterocycl. Chem. 1997, 34: 345 - 7
Chiarino D.Napoletano M.Sala A. Tetrahedron Lett. 1986, 27: 3181 - 10 For X-ray data of related isoxazole
boronic esters see:
Harrity JPA.Adams H.Davies MW.Wybrow RAJ.Johnson CN. Acta Cryst. 2002, C58: o168 - 12
Gagneux AR.Häfleger F.Geigy GR.Basle SA.Eugster CH.Good R. Tetrahedron Lett. 1965, 25: 2077 - 13 Preliminary investigations indicate
that 3-haloisoxazoles 4-10 are relatively unreactive towards Pd-catalysed
coupling reactions, nonetheless, there is substantial scope for
the optimisation of this process and these studies are ongoing in our
labs. In contrast, the introduction of amines by SNAr reactions
has been demonstrated:
Yevich JP.New JS.Smith DW.Lobeck WG.Catt JD.Minelli JL. J. Med. Chem. 1986, 29: 359 - 14
Bauer L.Nambury CNV.Bell CL. Tetrahedron 1967, 23: 4395
References
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.
9The X-ray data for isoxazole 3a has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 191718.
11Representative 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.