Radical Cyclization of Epoxynitriles Mediated by Titanocene Chloride

A. Fernández-Mateos; L. Mateos Burón; R. Rabanedo Clemente; Ana I. Ramos Silvo; R. Rubio González

doi:10.1055/s-2004-822901

LETTER

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;

Abstract

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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

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References

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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.

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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.

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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.

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.