Download PDF
Synlett 2008(6): 919-923  
DOI: 10.1055/s-2008-1042906
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Access to Isoxazoles from Alkenes

Jianping Xu, Ashton T. Hamme II*
Department of Chemistry, Jackson State University, Jackson, MS 39217-0510, USA
Fax: +1(601)9793674; e-Mail: ashton.t.hamme@jsums.edu;
Further Information

Publication History

Received 18 December 2007
Publication Date:
11 March 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

The direct regioselective synthesis of 3,5-disubstituted isoxazoles was achieved in one reaction vessel through a sequence of reactions involving the net bromination of an electron-deficient alkene, in situ generation of a nitrile oxide, 1,3-dipolar cycloaddition, and loss of HBr from an intermediate 5,5-disubstituted bromoisoxazoline. This one-pot process enables the synthesis of 3,5-disubstituted isoxazoles directly from electron-deficient alkenes thereby negating the isolation of the 1,1-disubstituted bromoalkene alkyne surrogate.

Key words

cycloadditions - heterocycles - tandem reactions - alkyne surrogate - dehydrohalogenation

    References and Notes

  • 1 Talley JJ. Brown DL. Carter JS. Graneto MJ. Koboldt CM. Masferrer JL. Perkins WE. Rogers RS. Shaffer AF. Zhang YY. Zweifel BS. Seibert K. J. Med. Chem.  2000,  43:  775 
    CrossrefGoogle Scholar
  • 2a Lee Y.-S. Kim BH. Bioorg. Med. Chem. Lett.  2002,  12:  1395 
    CrossrefGoogle Scholar
  • 2b Srivastava S. Bajpai LK. Batra S. Bhaduri AP. Maikhuri JP. Gupta G. Dhar JD. Bioorg. Med. Chem.  1999,  7:  2607 
    CrossrefGoogle Scholar
  • 3a Simoni D. Grisolia G. Giannini G. Roberti M. Rondanin R. Piccagli L. Baruchello R. Rossi M. Romagnoli R. Invidiata FP. Grimaudo S. Jung MK. Hamel E. Gebbia N. Crosta L. Abbadessa V. Di Cristina A. Dusonchet L. Meli M. Tolomeo M. J. Med. Chem.  2005,  48:  723 
    CrossrefPubMedGoogle Scholar
  • 3b Kaffy J. Pontikis R. Carrez D. Croisy A. Monneret C. Florent J.-C. Bioorg. Med. Chem.  2006,  14:  4067 
    CrossrefPubMedGoogle Scholar
  • 4a Pruitt JR. Pinto DJ. Estrella MJ. Bostrom LL. Knabb RM. Wong PC. Wright MR. Wexler RR. Bioorg. Med. Chem. Lett.  2000,  10:  685 
    CrossrefGoogle Scholar
  • 4b Nantermet PG. Barrow JC. Lundell GF. Pellicore JM. Rittle KE. Young M. Freidinger RM. Connolly TM. Condra C. Karczewski J. Bednar RA. Gaul SL. Gould RJ. Prendergast K. Selnick HG. Bioorg. Med. Chem. Lett.  2002,  12:  319 
    CrossrefGoogle Scholar
  • 4c Batra S. Srinivasan T. Rastogi SK. Kundu B. Patra A. Bhaduri AP. Dixit M. Bioorg. Med. Chem. Lett.  2002,  12:  1905 
    CrossrefGoogle Scholar
  • 4d Batra S. Roy AK. Patra A. Bhaduri AP. Surin WR. Raghavan SAV. Sharma P. Kapoor K. Dikshit M. Bioorg. Med. Chem.  2004,  12:  2059 
    CrossrefGoogle Scholar
  • 5 Jung HK. Doddareddy MR. Cha JH. Rhim H. Cho YS. Koh HY. Jung BY. Pae AN. Bioorg. Med. Chem.  2004,  12:  3965 
    CrossrefGoogle Scholar
  • 6a Sandanayaka VP. Youjun Y. Org. Lett.  2000,  2:  3087 
    CrossrefGoogle Scholar
  • 6b Croce PD. La Rosa C. Zecchi G. J. Chem. Soc., Perkin Trans. 1  1985,  2621 
    CrossrefGoogle Scholar
  • 6c Easton CJ. Heath GA. Hughes CMM. Lee CKY. Savage GP. Simpson GW. Tiekink ERT. Vuckovic GJ. Webster RD. J. Chem. Soc., Perkin Trans. 1  2001,  1168 
    CrossrefGoogle Scholar
  • 7 Dadiboyena S. Xu J. Hamme AT. Tetrahedron Lett.  2007,  48:  1295 
    CrossrefGoogle Scholar
  • 8 Hamme AT. Xu J. Wang J. Cook T. Ellis E. Heterocycles  2005,  65:  2885 
    CrossrefGoogle Scholar
  • 9a Houk KN. Sims J. Duke RE. Strozier RW. George JK. J. Am. Chem. Soc.  1973,  95:  7287 
    CrossrefGoogle Scholar
  • 9b Houk KN. Sims J. Watts CR. Luskus LJ. J. Am. Chem. Soc.  1973,  95:  7301 
    CrossrefGoogle Scholar
  • 9c Houk KN. Acc. Chem. Res.  1975,  8:  361 
    CrossrefGoogle Scholar
  • 9d Padwa A. 1,3-Dipolar Cycloaddition Chemistry   John Wiley and Sons; New York: 1984. 
    CrossrefGoogle Scholar
  • 10a Dunn GL. DiPasquo VJ. Hoover JRE. J. Org. Chem.  1968,  33:  1454 
    CrossrefGoogle Scholar
  • 10b Smith AB. Branca SJ. Pilla NN. Guaciaro MA. J. Org. Chem.  1982,  47:  1855 
    CrossrefGoogle Scholar
  • 10c Hanessian S. Mainetti E. Lecomte F. Org. Lett.  2006,  8:  4047 
    CrossrefGoogle Scholar
  • 11 Zamponi GW. Stotz SC. Staples RJ. Andro TM. Nelson JK. Hulubei V. Blumenfeld A. Natale NR. J. Med. Chem.  2003,  46:  87 
    Google Scholar
  • 12a Pathak R. Roy AK. Kanojiya S. Batra S. Tetrahedron Lett.  2005,  46:  5289 
    CrossrefGoogle Scholar
  • 12b Patra A. Batra S. Bhaduri AP. Khanna A. Chander R. Dikshit M. Bioorg. Med. Chem.  2003,  11:  2269 
    CrossrefGoogle Scholar
  • 13a Sandanayaka VP. Youjun Y. Org. Lett.  2000,  2:  3087 
    CrossrefGoogle Scholar
  • 13b Croce PD. La Rosa C. Zecchi G. J. Chem. Soc., Perkin Trans. 1  1985,  2621 
    CrossrefGoogle Scholar
  • 14a Miyaoka H. Kajiwara Y. Hara Y. Yamada Y. J. Org. Chem.  2001,  66:  1429 
    CrossrefGoogle Scholar
  • 14b Trost BM. Bridges AJ.
    J. Org. Chem.  1975,  40:  2014 
    CrossrefGoogle Scholar
15

General Experimental Procedure
After the alkene (0.5 mmol) was dissolved in CH2Cl2 (15 mL), bromine (0.55 mmol) was added dropwise. After all of the alkene was completely consumed, as confirmed by TLC on silica gel (hexanes-EtOAc, 4:1), the hydroximoyl chloride (0.5 mmol) was added, and Et3N (1.2 mmol) was added shortly thereafter. The reaction mixture was stirred at r.t. until the disappearance of the bromoalkene, as verified by TLC on silica gel (hexanes-EtOAc, 4:1). The reaction mixture was washed with H2O (3 × 10 mL), and the organic layer was dried over anhyd Na2SO4. The crude products were purified by flash column chromatography over silica gel using hexanes-EtOAc (4:1) as the eluent system. This procedure provides pure isoxazole products for entries 1-15 in 58-97% yield.
Spectroscopic data for Entry 9, Table 1
Colorless solid (74 mg, 73%), mp 84-87 °C. IR (CaF2, CCl4): ν = 1696 cm-1. 1H NMR: δ = 3.89 (s, 3 H), 7.00 (d, J = 8.9 Hz, 2 H), 7.25 (s, 1 H), 7.79 (d, J = 8.9 Hz, 2 H), 10.02 (s, 1 H). 13C NMR: δ = 55.4, 106.4, 114.2 (2 C), 119.9, 128.3 (2 C), 161.5, 162.7, 165.9, 178.5. HRMS (EI): m/z calcd for C11H9NO3 [M+ + 1]: 203.0582; found: 203.0628. All spectroscopic and HRMS data were obtained for previously unreported compounds.