Download PDF
Synlett 2004(6): 1011-1014  
DOI: 10.1055/s-2004-822901
LETTER
© Georg Thieme Verlag Stuttgart · New York

Radical Cyclization of Epoxynitriles Mediated by Titanocene Chloride

A. Fernández-Mateos*, L. Mateos Burón , R. Rabanedo Clemente , Ana I. Ramos Silvo , R. Rubio González
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
e-Mail: afmateos@usal.es;
Further Information

Publication History

Received 16 December 2003
Publication Date:
01 April 2004 (online)

    Permissions and Reprints All articles of this category

Abstract

The reductive radical cyclization of β-, γ-, δ- and ε-epoxynitriles has been achieved using titanocene chloride. The reaction was regioselective and afforded cyclic β-hydroxyketones in good yield. The catalytic version of this radical cyclization is also reported.

Key words

radical cyclization - titanocene chloride - epoxynitrile - cyclobutanone - cycloheptanone

    References

  • 1a Curran DP. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Paquette LA. Pergamon; Oxford: 1991.  Chap. 4.2.5.
    CrossrefSearch in Google Scholar
  • 1b Giese B. Kopping B. Göbel T. Thoma G. Dickhaut J. Kulicke KJ. Trach F. In Organic Reactions   Vol. 48:  Paquette LA. Wiley; New York: 1996.  p.308 
    CrossrefSearch in Google Scholar
  • 1c Tsang R. Fraser-Reid B. J. Am. Chem. Soc.  1986,  108:  8102 
    CrossrefSearch in Google Scholar
  • 1d Chang SY. Jiaang WT. Cherng CD. Tang KH. Huang CH. Tsai YM. J. Org. Chem.  1997,  62:  9089 
    CrossrefSearch in Google Scholar
  • 1e Curran DP. Diederichsen U. Palovich M. J. Am. Chem. Soc.  1997,  119:  4797 
    CrossrefSearch in Google Scholar
  • 1f Kim S. Jon SY. Chem. Commun.  1996,  1335 
    Crossref
  • 1g Fernández-Mateos A. Martín de la Nava E. Pascual Coca G. Ramos Silvo A. Rubio González R. Org. Lett.  1999,  1:  607 
    CrossrefSearch in Google Scholar
  • 2a Beckwith ALJ. Hay BD. J. Am. Chem. Soc.  1989,  111:  230 
    CrossrefSearch in Google Scholar
  • 2b Beckwith ALJ. Hay BD. J. Am. Chem. Soc.  1989,  111:  2674 
    CrossrefSearch in Google Scholar
  • 2c Beckwith ALJ. Tetrahedron  1981,  37:  3073 
    CrossrefSearch in Google Scholar
  • 3 Bowman WR. Bridge CF. Brookes P. Tetrahedron Lett.  2000,  41:  8989 ; and references cited therein
    CrossrefSearch in Google Scholar
  • 4a Fallis AG. Brinza IM. Tetrahedron  1997,  53:  17543 
    Thieme ConnectSearch in Google Scholar
  • 4b Curran DP. Liu W. Synlett  1999,  117 
    Thieme Connect
  • 5a Corey EJ. Pyne SG. Tetrahedron Lett.  1983,  24:  28211 
    Search in Google Scholar
  • 5b Molander GA. Kenny C. J. Am. Chem. Soc.  1989,  111:  8236 
    Search in Google Scholar
  • 5c Shono T. Kise N. Fujimoto T. Tominaga N. Morita H. J. Org. Chem.  1992,  57:  7175 
    Search in Google Scholar
  • 6 Yamamoto Y. Matsumi D. Hattori R. Itoh K. J. Org. Chem.  1999,  64:  3224 
    CrossrefSearch in Google Scholar
  • 7 Zhou L. Hirao T. Tetrahedron  2001,  57:  6927 
    CrossrefSearch in Google Scholar
  • 8a RajanBabu TV. Nugent WA. J. Am. Chem. Soc.  1994,  116:  986 
    Search in Google Scholar
  • 8b Nugent WA. RajanBabu TV. J. Am. Chem. Soc.  1988,  110:  8561 
    Search in Google Scholar
  • 8c Gansäuer A. Pierobon M. Bluhm H. Angew. Chem. Int. Ed.  1998,  37:  101 
    Search in Google Scholar
  • 10a Gansäuer A. Bluhm H. Pierobon M. J. Am. Chem. Soc.  1998,  120:  12849 
    CrossrefPubMedSearch in Google Scholar
  • 10b Gansäuer A. Bluhm H. Chem. Rev.  2000,  100:  2771 
    CrossrefPubMedSearch in Google Scholar
  • 12 Geyde RN. Aura PC. Deck K. Can. J. Chem.  1971,  49:  1764 ; all compounds synthesized are racemic although, only one enantiomer is depicted.
    Search in Google Scholar
  • 13 The structure of epoxynitriles 6-10, in which the oxiranic oxygen and the side chain are cis, is based on spectroscopic data and comparison with the model compound I, whose structure was determined by X-ray crystallography (Figure 3): Mori K. Aki S. Kido M. Liebigs Ann. Chem.  1993,  83 
  • 14a

    The stereochemistry of the bicyclic hydroxyketone 7a was established by 1H NMR and 13C NMR spectra, H-C correlations and NOE experiments. The hydroxyketone 8a was reported by: Fernández-Mateos, A.; Pascual Coca, G.; Rubio González, R.; Tapia Hernández, C. J. Org. Chem. 1996, 61, 9097; the stereochemistry of hydroxyketone 9a was determined by 1H NMR and 13C NMR spectra.

  • 14b

    2-Methyl-1-nonen-3-ol ( 1a): IR (film): 3370, 1653 cm-1. 1H NMR (CDCl3): δ = 0.88 (3 H, t, J = 7.0 Hz), 1.20-1.60 (10 H, m), 1.72 (3 H, s), 4.05 (1 H, t, J = 6.5 Hz), 4.83 (1 H, s), 4.93 (1 H, s) ppm. 13C NMR (CDCl3): δ = 13.98, 17.41, 22.53, 25.49, 29.16, 31.74, 34.95, 75.97, 110.80, 147.67 ppm. MS (EI): m/z (%) = 156 (3) [M+], 113 (11), 99 (11), 94 (12), 86 (18), 71 (100), 55 (20). HRMS (IE): 156.1511 (M+, C10H20O), calcd 156.1514. 2-Hydroxymethyl-2-methyl-cyclobutanone ( 2a): IR (film): 3461, 1775 cm-1. 1H NMR (CDCl3): δ = 1.18 (3 H, s), 1.75 (1 H, m), 2.20 (1 H, m), 2.99 (2 H, m), 3.53 (1 H, d, J = 15.0 Hz), 3.69 (1 H, d, J = 15.0 Hz) ppm. 13C NMR (CDCl3): δ = 17.76, 21.25, 43.16, 65.75, 66.00, 215.21 ppm. MS (EI): m/z (%) = 96 (6) [M+ - 16], 85 (7), 69 (44), 57 (100). HRMS (IE): 114.0678 (M+, C6H10O2), calcd 114.0680.
    2-Hydroxymethyl-2-methyl-cyclopentanone ( 3a): IR (film): 3445, 1732 cm-1. 1H NMR (CDCl3): δ = 0.98 (3 H, s), 1.60-2.40 (6 H, m), 3.42 (1 H, d, J = 10.9 Hz), 3.58 (1 H, d, J = 10.9 Hz) ppm. 13C NMR (CDCl3): δ = 18.74, 19.20, 33.05, 38.29, 50.24, 66.91, 224.31 ppm. MS (EI): m/z = 128 (9) [M+], 110 (9), 97 (9), 82 (27), 69(89), 57 (100). HRMS (IE): 128.0836 (M+, C7H12O2), calcd 128.0837.
    2-Hydroxymethyl-2-methyl-cyclohexanone ( 4a): IR (film): 3443, 1703 cm-1. 1H NMR (CDCl3): δ = 1.11 (3 H, s), 1.50-2.00 (6 H, m), 2.24 (1 H, dt, J 1 = 4.2 Hz, J 2 = 14.0 Hz), 2.46 (1 H, ddd, J 1 = 6.0 Hz, J 2 = 12.5 Hz, J 3 = 14.2 Hz), 3.47 (2 H, dd, J 1 = 12.0 Hz, J 2 = 17.0 Hz) ppm. 13C NMR (CDCl3): δ = 20.12, 20.69, 27.19, 35.50, 38.89, 50.10, 68.85, 217.88 ppm. MS (EI): m/z (%) = 124 (27) [M+ - 18], 112 (36), 97 (18), 82 (100), 69 (50), 55 (97). HRMS (IE): 142.1001 (M+, C8H14O2), calcd 142.0994.
    2-Hydroxymethyl-2-methyl-cycloheptanone ( 5a): IR (film): 3447, 1694 cm-1. 1H NMR (CDCl3): δ = 1.14 (3 H, s), 1.40-1.80 (8 H, m), 2.43 (1 H, m), 2.63 (1 H, m), 3.37 (1 H, d, J = 11.0 Hz), 3.71 (1 H, d, J = 11.0 Hz) ppm. 13C NMR (CDCl3): δ = 21.20, 24.70, 26.21, 30.55, 34.96, 41.10, 51.98, 69.54, 219.68 ppm. MS (EI): m/z (%) = 156 (5) [M+], 138 (36), 126 (11), 109 (14), 95 (23), 81 (24), 69(79), 56 (100). HRMS (IE): 156.1154 (M+, C9H16O2), calcd 156.1150.
    7-Hydroxymethyl-7-heptenenitrile ( 5b) and 8-hydroxy-7-methyl-octanenitrile ( 5c): IR (film): 3432, 2926, 2861, 2247, 1715, 1653, 1464, 1427, 1375 cm-1. 1H NMR (CDCl3): δ 0.89 (3 H, d, J = 6.7 Hz), 1.00-2.10 (20 H, m), 2.34 (4 H, br s), 3.39 (1 H, dd, J 1 = 6.4 Hz, J 2 = 10.4 Hz), 3.46 (1 H, dd, J 1 = 6 Hz, J 2 = 10.4 Hz), 4.84 (1 H, s), 5.01 (1 H, s) ppm. 13C NMR (CDCl3): δ = 16.45, 17.01 (2 C), 25.13, 25.22, 26.05, 26.76, 28.26, 28.84, 32.47, 32.71, 35.52, 65.64, 68.00, 109.53, 119.67, 119.74, 148.42 ppm.
    (1 SR ,5 RS )-2,2-Dimethyl-5-hydroxy-6-methylen-cyclohexanecarbonitrile ( 6a): IR (film): 3435, 2241 cm-1. 1H NMR (CDCl3): δ = 1.00 (3 H, s), 1.17 (3 H, s), 1.40-1.80 (4 H, m), 3.48 (1 H, s), 4.40 (1 H, m), 5.23 (2 H, s) ppm. 13C NMR (CDCl3): δ = 21.78, 29.06, 29.56, 32.91, 35.58, 43.83, 70.30, 112.96, 118.58, 142.31 ppm. MS (EI): m/z (%) = 165 (2) [M+], 150 (98), 134 (10), 107 (11), 97 (12), 85 (16), 69 (100). HRMS (IE): 165.1152 (M+, C10H15NO), calcd 165.1154.
    (1 SR ,5 RS ,6 SR )-5-Hydroxy-2,2,6-trimethyl-bicyclo [4,2,0]octan-7-one ( 7a): Mp 91-94 °C. IR (film): 3482, 1769 cm-1. 1H NMR (CDCl3): δ = 0.92 (3 H, s), 1.00 (3 H, s), 1.18 (3 H, s), 1.22 (1 H, m), 1.62 (1 H, m), 1.78 (3 H, m), 2.68 (1 H, dd, J 1 = 9.0 Hz, J 2 = 16.4 Hz), 3.06 (1 H, dd, J 1 = 10.6 Hz, J 2 = 16.4 Hz), 3.83 (1 H, br s) ppm. 13C NMR (CDCl3): δ = 20.94, 26.70, 27.86, 28.93, 29.39, 29.49, 43.23, 47.71, 64.59, 69.99, 212.04 ppm. MS (EI): m/z (%) = 182 (2) [M+], 167 (15), 140 (8), 122 (69), 107(60), 84 (100), 69(31). HRMS (IE): 182.1302 (M+, C11H18O2), calcd 182.1307.
    (3a SR ,7 RS ,7a RS )-7-Hydroxy-4,4,7a-trimethyl-octahydro-inden-1-one ( 8b): IR (film): 3479, 1738 cm-1. 1H NMR (CDCl3): δ = 0.94 (3 H, s), 0.96 (3 H, s), 1.05 (3 H, s), 2.35 (2 H, m), 3.69 (1 H, dd, J 1 = 4.8 Hz, J 2 = 11.1 Hz) ppm. 13C NMR (CDCl3): δ = 10.32, 19.26, 21.49, 26.48, 31.39, 31.90, 39.22, 51.47, 52.27, 76.63, 222.89 ppm. MS (EI): m/z (%) = 196 (12) [M+], 181 (14), 140 (53), 123 (15), 97 (100), 81 (22), 69(15), 55 (24). HRMS (IE): 196.1460 (M+, C12H20O2), calcd 196.1463.
    (4a SR ,8 RS ,8a RS ) 8-Hydroxy-5,5,8a-trimethyl-octahydro-naphthalen-1-one ( 9a): IR (film): 3567, 1694 cm-1. 1H NMR (CDCl3): δ = 0.89 (3 H, s), 0.94 (3 H, s), 1.20 (3 H, s), 1.20-1.80 (7 H, m), 2.00-2.20 (2 H, m), 2.54 (2 H, m), 3.86 (1 H, m) ppm. 13C NMR (CDCl3): δ = 13.29, 20.67, 22.08, 25.25, 25.68, 32.70, 34.05, 37.71, 39.58, 52.12, 54.19, 73.40, 218.09 ppm. MS (EI): m/z (%) = 210 (7) [M+], 192 (20), 185 (5), 167 (5), 154 (16), 136 (11), 121 (8), 111 (100), 95 (11), 81 (16), 69 (20), 55 (52). HRMS (IE): 210.3124 (M+, C13H22O2), calcd 210.3126.
    (1 RS ,5 RS )-4-(5-Hydroxy-2,2,6-trimethyl-cyclohexyl)-butyronitrile ( 9b): IR (film): 3447, 2247 cm-1. 1H NMR (CDCl3): δ = 0.85 (3 H, s), 0.89 (3 H, s), 0.90 (3 H, d, J = 7.4 Hz), 1.10-1.60 (10 H, m), 2.35 (2 H, t, J = 6.2 Hz), 3.67 (1 H, m) ppm. 13C NMR (CDCl3): δ = 8.67, 17.44, 23.33, 24.28 (2 C), 26.04, 26.96, 31.45 (2 C), 33.12, 35.62, 47.49, 73.74, 119.55 ppm. MS (EI): m/z (%) = 209(23) [M+], 159 (17), 136 (17), 125 (18), 110 (24), 97 (31), 81(32), 69 (57), 55 (100). HRMS (IE): 209.1780 (M+, C13H23NO), calcd 209.1779.
    (1 RS ,5 RS ) 5-(5-Hydroxy-2,2,6-trimethyl-cyclohexyl)-pentanonitrile ( 10a): IR (film): 3432, 2247 cm-1. 1H NMR (CDCl3): δ = 0.81 (3 H, s), 0.83 (3 H, s), 0.85 (3 H, d, J = 7.4 Hz), 1.10-1.70 (11 H, m), 2.04 (1 H, m), 2.32 (2 H, t, J = 7.0 Hz), 3.63 (1 H, br s) ppm. MS (EI): m/z (%) = 205(45) [M+] 149 (95), 123 (47), 95 (36), 81 (100). HRMS (IE): 223.1931 (M+, C14H25NO), calcd 223.1936.

9

General Procedure. A mixture of Cp2TiCl2 (2.2 mmol) and Zn (3 mmol) in strictly deoxygenated THF (4 mL) was stirred at r.t. until the red solution turned green. In a separate flask, the epoxy nitrile (1 mmol) was dissolved in strictly deoxygenated THF (10 mL). The green Ti(III) solution was slowly added via cannula to the epoxide solution. After 30 min, an excess of sat. NaH2PO3 was added, and the mixture was stirred for 20 min. The product was extracted into Et2O and washed with sat. NaHCO3 and H2O. After removal of the solvent, the crude product was purified by flash chromatography.

11

Catalytic Radical Reaction. General Procedure. To a mixture of collidine hydrochloride (2.5 mmol), epoxy nitrile (1.0 mmol), and Zn (2.0 mmol) in THF (10 mL) was added titanocene dichloride (0.05 mmol), and the resulting mixture was stirred at r.t. After addition of Et2O, the mixture was washed with H2O, 2 N HCl, H2O, sat. aq NaHCO3, and H2O, and dried. After removal of the solvent, the crude product was purified by flash chromatography on silica gel.