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Synlett 2008(13): 1989-1992  
DOI: 10.1055/s-2008-1077966
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

1,3-Dipolar Cycloaddition of Difluoro(methylene)cyclopropanes with Nitrones: Efficient Synthesis of 3,3-Difluorinated Tetrahydropyridinols

Xiao-Chun Hang, Qing-Yun Chen, Ji-Chang Xiao*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. of China
Fax: +86(21)64166128; e-Mail: jchxiao@mail.sioc.ac.cn;
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Publication History

Received 19 April 2008
Publication Date:
15 July 2008 (online)

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Abstract

Difluoro-substituted spirocyclopropaneisoxazolidines were formed by 1,3-dipolar cycloaddition of difluoro(methylene)cyclopropanes (F2MCPs) with nitrones in high yields. The [3+2]-cycloaddition reactions exhibited good regioselectivity and high stereoselectivity. The cycloadducts could rearrange further to form highly substituted 3,3-difluorinated tetrahydropyridinols.

Key words

fluorine - difluoro(methylene)cyclopropanes - 3,3-di­fluorinated tetrahydropyridinols - ring rearrangement - 1,3-dipolar cycloaddition - nitrone

    References and Notes

  • For recent reviews, see:
  • 1a Goti A. Cordero FM. Brandi A. Top. Curr. Chem.  1996,  178:  1 
    Google Scholar
  • 1b Brandi A. Goti A. Chem. Rev.  1998,  98:  589 
    Google Scholar
  • 1c Brandi A. Cicchi S. Cordero FM. Goti A. Chem. Rev.  2003,  103:  1213 
    Google Scholar
  • 1d Nakamura I. Yamamoto Y. Adv. Synth. Catal.  2002,  344:  111 
    Google Scholar
  • 1e Rubin M. Rubina M. Gevorgyan V. Chem. Rev.  2007,  107:  3117 
    Google Scholar
  • 2a Brandi A. Guarna A. Goti A. De Sarlo F. Tetrahedron Lett.  1986,  27:  1727 
    Google Scholar
  • 2b Brandi A. Garro S. Guarna A. Goti A. Cordero F. De Sarlo F. J. Org. Chem.  1988,  53:  2430 
    Google Scholar
  • 2c Brandi A. Cordero FM. De Sarlo F. Goti A. Guarna A. Synlett  1993,  1 
    Google Scholar
  • 2d Brandi A. Durust Y. Cordero FM. De Sarlo F. J. Org. Chem.  1992,  57:  5666 
    Google Scholar
  • 2e Goti A. Anichini B. Brandi A. J. Org. Chem.  1996,  61:  1665 
    Google Scholar
  • 2f Ghosh AK. Bilcer G. Schiltz G. Synthesis  2001,  2203 
    Google Scholar
  • 2g List B. Castello C. Synlett  2001,  1687 
    Google Scholar
  • 3a Cordero FM. Brandi A. Querci C. Goti A. De Sarlo F. Guarna A. J. Org. Chem.  1990,  55:  1762 
    Google Scholar
  • 3b Cordero FM. Cicchi S. Goti A. Brandi A. Tetrahedron Lett.  1994,  35:  949 
    Google Scholar
  • 3c Cicchi S. Goti A. Brandi A. J. Org. Chem.  1995,  60:  4743 
    Google Scholar
  • For recent reviews, see:
  • 4a Buffat MGP. Tetrahedron  2004,  60:  1701 
    Google Scholar
  • 4b Felpin F.-X. Lebreton JM. Eur. J. Org. Chem.  2003,  3693 
    Google Scholar
  • 4c Weintraub PM. Sabol JS. Kane JM. Borcherding DR. Tetrahedron  2003,  59:  2953 
    Google Scholar
  • 5a Kirsch P. Modern Fluoroorganic Chemistry   Wiley-VCH; Weinheim: 2004. 
    Google Scholar
  • 5b Chambers RD. Fluorine in Organic Chemistry   Blackwell; Cambridge: 2004. 
    Google Scholar
  • 6a Arnone A. Bravo P. Donadelli A. Resnati G.
    J. Chem. Soc., Chem. Commun.  1993,  984 
    Google Scholar
  • 6b Reymond J.-L. Pinkerton AA. Vogel P. J. Org. Chem.  1991,  56:  2128 
    Google Scholar
  • 6c Kim D.-K. Kim G. Kim Y.-W. J. Chem. Soc., Perkin Trans. 1.  1996,  803 
    Google Scholar
  • 6d Kilonda A. Compernolle F. Hoornaert GJ. J. Org. Chem.  1995,  60:  5820 
    Google Scholar
  • 6e Arnone A. Bravo P. Donadelli A. Resnati G. Tetrahedron  1996,  52:  131 
    Google Scholar
  • 6f Harper S. Avolio S. Pacini B. Filippo MD. Altamura S. J. Med. Chem.  2005,  48:  4547 
    Google Scholar
  • 6g Fabio RD. Giovannini R. Bertani B. Borriello M. Bozzoli A. Bioorg. Med. Chem. Lett.  2006,  16:  1749 
    Google Scholar
  • 7a Wang R.-W. Qing F.-L. Org. Lett.  2005,  7:  2189 
    Google Scholar
  • 7b Wang R.-W. Qiu X.-L. Bols M. Ortega-Caballero F. Qing F.-L. J. Med. Chem.  2006,  49:  2989 
    Google Scholar
  • 8a Wang R. Ksebati MB. Corbett TH. Kern ER. Drach JC. Zemlicka J. J. Med. Chem.  2001,  44:  4019 
    Google Scholar
  • 8b Taguchi T. Okada M. J. Fluorine Chem.  2000,  105:  279 
    Google Scholar
  • 8c Dolbier WR. Burkholder CR. Chaves AL. Green A. J. Fluorine Chem.  1996,  77:  31 
    Google Scholar
  • 8d Dolbier WR. Seabury MJ. Tetrahedron  1987,  43:  2437 
    Google Scholar
  • 8e Dolbier WR. Seabury M. Daly D. J. Org. Chem.  1986,  51:  974 
    Google Scholar
  • 8f Dolbier WR. Sellers SF. Al-Sader BH. Fielder TH. J. Am. Chem. Soc.  1981,  103:  718 
    Google Scholar
  • 9a Cheng Z.-L. Xiao J.-C. Liu C. Chen Q.-Y. Eur. J. Org. Chem.  2006,  5581 
    Google Scholar
  • 9b Hang X.-C. Chen Q.-Y. Xiao J.-C. Eur. J. Org. Chem.  2008,  1101 
    Google Scholar
10

Preparation of 1,1-Difluoro-2,2,5-trimethyl-6-phenyl-7-tosyl-4-oxa-5-azaspiro[2.4]heptane (3a): Into a 5-mL sealed tube were added 1 (50 mg, 0.184 mmol), phenyl-N-methylnitrone (2a; 30 mg, 0.22 mmol) and PE (1.5 mL). The mixture was stirred at 50 ˚C for 12 h. After cooling to r.t., the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column (PE-EtOAc, 10:1) to yield 3a as a viscous oil (70 mg, 95%). ¹H NMR (300 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.53 (s, 3 H), 2.48 (s, 3 H), 2.55 (s, 3 H), 3.89 (d, J = 4.8 Hz, 1 H), 4.06 (d, J = 4.8 Hz, 1 H), 6.91-6.97 (m, 2 H), 7.15-7.25 (m, 3 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.72 (d, J = 8.2 Hz, 2 H). ¹9F NMR (282 MHz, CDCl3): δ = -144.9 (d, J = 151 Hz, 1 F), 158.2 (d, J = 151 Hz, 1 F). IR (film): 3066, 3035, 3008, 2969, 2933, 2878, 1597, 1496, 1479, 1457, 1436, 1325, 1305, 1249, 1209, 1188, 1149, 1125, 1087, 1078 cm-¹. MS (ESI): m/z = 430.0 [M + Na+]. Anal. Calcd for C21H23F2NO3S: C, 61.90; H, 5.69; N, 3.44. Found: C, 61.87; H, 5.80; N, 3.05.

11

The single-crystal X-ray structural data for 4a have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 684886.

12

Preparation of 3,3-Difluoro-1,2,2-trimethyl-6-phenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol (4a): Into a 5-mL sealed tube were added 1 (50 mg, 0.184 mmol), phenyl-N-methylnitrone (2a; 24 mg, 0.184 mmol) and PE (2.5 mL). The mixture was stirred at 100 ˚C for 8 h. After cooling to r.t., 3,3-difluoro-1,2,2-trimethyl-6-phenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol (4a) was precipitated. After removing the solvent by filtration, the residue was recrystallized in CHCl3 by slow evaporation. Yield: 52 mg, 70%. ¹H NMR (300 MHz, CDCl3): δ = 1.16 (s, 3 H), 1.30 (s, 3 H), 1.93 (s, 3 H), 2.32 (s, 3 H), 4.11 (d, J = 9.8 Hz, 1 H), 6.87-7.01 (m, 9 H), 10.6 (s, 1 H). ¹9F NMR (282 MHz, CDCl3): δ = -109.0 (dd, J = 9.7, 269 Hz, 1 F), -125.6 (d, J = 269 Hz, 1 F). ¹³C NMR (75 MHz, CDCl3): δ = 12.7, 20.2 (d, J FC = 4 Hz), 21.4, 32.1, 59.0 (dd, J FC = 15, 18 Hz), 62.7, 113.9 (m), 115.4 (t, J FC = 184 Hz), 126.3, 127.7, 127.9, 129.4, 130.3, 137.8, 138.3 (d, J FC = 2 Hz), 143.8, 152.3 (t, J FC = 19 Hz). IR (film): 3235, 2995, 2821, 1643, 1598, 1496, 1456, 1369, 1317, 1289, 1276, 1249, 1217, 1175, 1148, 1125, 1101, 1070, 1057, 1017, 994 cm-¹. MS (ESI): m/z = 408.1 [M + H+].