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

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.

regioselective - cycloadditions - Suzuki coupling - isoxazole

References

<A NAME="RD19402ST-1">1</A> Thompson LA. Ellman JA. Chem. Rev.  1996,  96:  555 

For comprehensive reviews, see:

<A NAME="RD19402ST-2A">2a</A> Suzuki A. Pure Appl. Chem.  1994,  66:  213 

<A NAME="RD19402ST-2B">2b</A> Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 

<A NAME="RD19402ST-3A">3a</A> Antilla JC. Buchwald SL. Org. Lett.  2001,  3:  2077 

<A NAME="RD19402ST-3B">3b</A> Evans DA. Katz JL. West TR. Tetrahedron Lett.  1998,  39:  2937 

<A NAME="RD19402ST-4A">4a</A> Petasis NA. Zavialov IA. J. Am. Chem. Soc.  1997,  119:  445 

<A NAME="RD19402ST-4B">4b</A> Ueda M. Miyaura N. J. Org. Chem.  2000,  65:  4450 

<A NAME="RD19402ST-4C">4c</A> Takaya Y. Ogasawara M. Hayashi T. Sakai M. Miyaura N. J. Am. Chem. Soc.  1998,  120:  5579 

<A NAME="RD19402ST-5A">5a</A> Davies MW. Johnson CN. Harrity JPA. Chem. Commun.  1999,  2107 

<A NAME="RD19402ST-5B">5b</A> Davies MW. Johnson CN. Harrity JPA. J. Org. Chem.  2001,  66:  3525 

<A NAME="RD19402ST-5C">5c</A> Davies MW. Wybrow RAJ. Johnson CN. Harrity JPA. Chem. Commun.  2001,  1558 

<A NAME="RD19402ST-6A">6a</A> Farina F. Fraile MT. Martin MR. Martin MV. de Guerenu AM. Heterocycles  1995,  40:  285 

<A NAME="RD19402ST-6B">6b</A> Hanson RN. Mohamed FA. J. Heterocycl. Chem.  1997,  34:  345 

<A NAME="RD19402ST-7">7</A> Chiarino D. Napoletano M. Sala A. Tetrahedron Lett.  1986,  27:  3181 

<A NAME="RD19402ST-8">8</A>

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.

<A NAME="RD19402ST-9">9</A>

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

<A NAME="RD19402ST-10">10</A> 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 

<A NAME="RD19402ST-11">11</A>

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.

<A NAME="RD19402ST-12">12</A> Gagneux AR. Häfleger F. Geigy GR. Basle SA. Eugster CH. Good R. Tetrahedron Lett.  1965,  25:  2077 

<A NAME="RD19402ST-13">13</A> 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 S_NAr reactions has been demonstrated: Yevich JP. New JS. Smith DW. Lobeck WG. Catt JD. Minelli JL. J. Med. Chem.  1986,  29:  359 

<A NAME="RD19402ST-14">14</A> Bauer L. Nambury CNV. Bell CL. Tetrahedron  1967,  23:  4395