Stereoselective Radical Cascade Cyclizations of Unsaturated Epoxynitriles: Quadruple Radical Cyclization Terminated by a 4-exo Process onto Nitrile

Abstract

Radical cascade cyclizations of unsaturated epoxy­nitriles induced by titanocene chloride proceed in good yields and with excellent diastereoselectivities. From three to seven stereocenters were created by the reaction and a single isomeric product was obtained from most of the substrates examined. The relative configuration of the products is consistent with cyclization occurring via a chair-like transition state. The termination of the radical cascade reaction by 4-exo, 5-exo or 6-exo cyclization onto nitrile is remarkable.

radical cyclization - titanocene chloride - epoxynitriles - cascade reactions

References and Notes

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8a

Reaction of Epoxides with Cp ₂ TiCl: A mixture of Cp₂TiCl₂ (3.3 mmol) and Zn (6.60 mmol) in strictly deoxy-genated THF (4 mL) was stirred at r.t. until the red solution turned green. In a separate flask, the epoxy compound (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 brine, dried (Na₂SO₄), and filtered. After removal of the solvent, the crude product was purified by flash chromatography.

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11

Crystallographic data for the structures 2a(dinitrobenzoate), 5a, and 8a(dinitrobenzoate) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 646905, CCDC 646904, CCDC 646903, respectively. These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.

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20

Data for 1a: IR: ν = 3466, 2245 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.84 (3 H, s), 0.88 (3 H, s), 1.13 (3 H, s), 1.53 (1 H, m), 1.70 (2 H, t, J = 7.2 Hz), 2.10 (1 H, m), 2.21 (2 H, br s), 3.87 (1 H, dd, J ₁ = 6.4 Hz, J ₂ = 8.2 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 17.4 (CH₃), 22.0 (CH₃), 22.3 (CH₃), 27.0 (CH₂), 29.9 (CH₂), 34.4 (CH₂), 44.2 (C), 46.2 (C), 80.6 (CH), 119.2 (C) ppm. MS (EI): m/z (%) = 167 (4) [M⁺], 150 (6), 139 (7), 126 (60), 108 (56), 96 (25), 86 (98), 71 (100). ESI-HRMS: m/z calcd for C₁₀H₁₇NO: 167.1310; found: 167.1315 [M⁺].
Data for 1b: IR: ν = 3475, 2249 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (3 H, s), 0.89 (3 H, s), 1.08 (3 H, s), 1.57 (2 H, m), 1.87 (1 H, m), 2.16 (1 H, m), 2.27 (1 H, d, J = 16.7 Hz), 2.68 (1 H, d, J = 16.7 Hz), 3.92 (1 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.8 (CH₃), 22.2 (CH₃), 22.7 (CH₃), 26.6 (CH₂), 30.1 (CH₂), 34.6 (CH₂), 44.0 (C), 46.5 (C), 80.8 (CH), 119.4 (C) ppm. MS (EI): m/z (%) = 167 (3) [M⁺], 126 (60), 108 (54), 86 (96), 71 (100). ESI-HRMS: m/z calcd for C₁₀H₁₇NO: 167.1310; found: 167.1319 [M⁺].

21

Data for 2a: colourless oil. IR: ν = 3491, 1765 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.98 (3 H, s), 1.06 (3 H, s), 1.25 (3 H, s), 1.28 (1 H, m), 1.65-1.90 (4 H, m), 2.14 (1 H, td, J ₁ = 4.2 Hz, J ₂ = 13.9 Hz), 2.71 (1 H, dd, J ₁ = 8.8 Hz, J ₂ = 16.3 Hz), 3.64 (2 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.9 (CH₃), 21.5 (CH₂), 24.2 (CH₃), 24.4 (CH₂), 28.9 (CH₃), 32.82 (C), 41.0 (CH), 47.0 (CH₂), 58.1 (C), 74.3 (CH), 212.0 (C) ppm. MS (EI): m/z (%) = 182 (2) [M⁺], 167 (3), 139 (10), 122 (38), 107 (17), 96 (100), 81 (28), 69 (19). ESI-HRMS: m/z calcd for C₁₁H₁₈O₂: 182.1307; found: 182.1311 [M⁺].
Data for 2b: viscous oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.03 (6 H, s), 1.22 (3 H, s), 1.40-2.00 (5 H, m), 2.70 (1 H, dd, J ₁ = 8.8 Hz, J ₂ = 16.4 Hz), 3.14 (1 H, dd, J ₁ = 10.4 Hz, J ₂ = 16.4 Hz), 3.67 (1 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.6 (CH₃), 21.3 (CH₃), 25.1 (CH₃), 26.8 (CH₂), 29.2 (CH₂), 34.4 (C), 44.6 (CH₂), 45.0 (CH), 58.9 (C), 74.4 (CH), 209.9 (C) ppm. MS (EI): m/z (%) = 182 (2) [M⁺], 165 (3), 139 (11), 122 (40), 107 (20), 96 (100), 81 (30), 71 (18). ESI-HRMS: m/z calcd for C₁₁H₁₈O₂: 182.1307; found: 182.1301 [M⁺].

22

Data for 3a: viscous oil: IR: ν = 3457, 1734 cm^-1. H NMR (400 MHz, CDCl₃): δ = 0.93 (3 H, s), 1.00 (3 H, s), 1.04 (3 H, s), 1.33 (1 H, m), 1.60-1.90 (5 H, m), 2.14 (1 H, dt, J ₁ = 8.9 Hz, J ₂ = 19.3 Hz), 2.47 (1 H, dd, J ₁ = 8.8 Hz, J ₂ = 19.3 Hz), 3.30 (1 H, dd, J ₁ = 4.5 Hz, J ₂ = 11.3 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.7 (2 CH₃), 18.4 (CH₂), 27.3 (CH₃), 27.8 (CH₂), 30.2 (CH₂), 36.0 (CH₂), 38.9 (C), 47.8 (C), 53.1 (CH), 79.2 (CH), 219.9 (C) ppm. MS (EI): m/z (%) = 196 (92) [M⁺], 178 (19), 134 (67), 96 (100), 81 (54), 69 (79). ESI-HRMS: m/z calcd for C₁₂H₂₀O₂: 196.1463; found: 196.1453 [M⁺].

23

Data for 4a: colourless oil. IR: ν = 3447, 1699 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (3 H, s), 1.02 (3 H, s), 1.12 (1 H, m), 1.15 (3 H, s), 1.50-2.15 (9 H, m), 2.20 (1 H, m), 2.56 (1 H, dt, J ₁ = 7.0 Hz, J ₂ = 13.9 Hz), 3.20 (1 H, dd, J ₁ = 4.4 Hz, J ₂ = 11.2 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.7 (CH₃), 18.5 (CH₃), 20.7 (CH₂), 26.2 (CH₂), 26.9 (CH₂), 27.9 (CH₃), 31.2 (CH₂), 37.4 (CH₂), 39.7 (C), 48.6 (C), 52.5 (CH), 78.1 (CH), 215.1 (C) ppm. MS (EI): m/z (%) = 210 (35), 192 (24), 177 (11), 121 (55), 107 (30), 95 (41), 82 (82), 69 (100). ESI-HRMS: m/z calcd for C₁₃H₂₂O₂: 210.1620; found: 210.1628 [M⁺].

24

Data for 5a: white solid; mp137-139 °C. IR: ν = 3449, 1763 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (3 H, s), 0.93 (3 H, s), 0.99 (3 H, s), 1.05 (1 H, m), 1.20 (3 H, s), 1.38 (2 H, m), 1.40-1.80 (5 H, m), 1.93 (2 H, m), 2.98 (2 H, m), 3.27 (1 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.1 (CH₃), 17.2 (CH₂), 17.9 (CH₃), 23.6 (CH₃), 24.8 (CH₂), 37.3 (CH₂), 27.8 (CH₃), 33.6 (C), 39.1 (C), 41.9 (CH₂), 44.0 (CH₂), 47.0 (2CH), 61.2 (C) 79.1 (CH), 214.0 (C) ppm. MS (EI): m/z (%) = 208 (11) [M⁺ - 42], 190 (51), 175 (100), 147 (49), 120 (53), 105 (50), 95 (44), 81 (48), 69 (50), 55 (70). ESI-HRMS: m/z calcd for C₁₆H₃₄N₂O₂: 268.2271; found: 268.2253 [M⁺ + NH₄].

25

Data for 6a: colourless oil. IR: ν = 3461, 1728 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.81 (3 H, s), 0.95 (3 H, s), 0.98 (3 H, s), 0.99 (3 H, s), 1.00-1.30 (3 H, m), 1.40-1.80 (9 H, m), 2.07 (1 H, td, J ₁ = 8.9 Hz, J ₂ = 19.2 Hz), 2.42 (1 H, dd, J ₁ = 8.8 Hz, J ₂ = 16.3 Hz), 3.22 (2 H, dd, J ₁ = 5.2 Hz, J ₂ = 10.8 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.1 (CH₃), 16.4 (CH₃), 16.8 (CH₃), 18.0 (CH₂), 18.3 (CH₂), 26.8 (CH₂), 28.1 (CH₃), 33.2 (CH₂), 35.6 (CH₂), 37.3 (CH₂), 38.8 (C), 48.1 (C), 53.3 (C) 55.9 (CH), 58.2 (CH), 78.2 (CH), 220.7 (C) ppm. MS (EI): m/z (%) = 264 (25) [M⁺], 231 (10), 213 (23), 203 (12), 187 (27), 175 (19), 152 (12), 135 (27), 121 (21), 107 (29), 95 (26), 81 (30), 67 (100), 55 (80). ESI-HRMS: m/z calcd for C₁₇H₂₈ONa: 287.1981; found: 287.1977 [M⁺ + Na].

26

Data for 7a: colourless oil. IR: ν = 3455, 1701 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.79 (3 H, s), 0.94 (3 H, s), 0.98 (3 H, s), 1.14 (3 H, s), 1.25 (2 H, m), 1.20-1.80 (12 H, m), 2.00-2.20 (2 H, m), 2.31 (1 H, t, J = 7.2 Hz), 2.54 (1 H, td, J ₁ = 13.9 Hz, J ₂ = 6.9 Hz), 3.18 (1 H, dd, J ₁ = 5.2 Hz, J ₂ = 11.2 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.3 (CH₃), 16.4 (CH₃), 17.6 (CH₂), 19.7 (CH₃), 19.9 (CH₂), 26.1 (CH₂), 27.1 (CH₂), 29.9 (CH₃), 34.5 (CH₂), 37.5 (CH₂), 38.2 (C), 38.3 (CH₂), 38.8 (C), 49.0 (C), 54.9 (CH), 57.7 (CH), 78.5 (CH), 215.7 (C) ppm. MS (EI): m/z (%) = 278 (11) [M⁺], 263 (8), 245 (5), 227 (6), 207 (30), 189 (27), 175 (6), 161 (7), 135 (27), 121 (39), 107 (29), 95 (36), 81 (41), 67 (69), 55 (100). ESI-HRMS: m/z calcd for C₁₈H₃₀O₂Na: 301.2138; found: 301.2139 [M⁺ + Na].

27

Data for 8a: colourless oil: IR: ν = 3345, 1767 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.79 (3 H, s), 0.92 (3 H, s), 0.94 (3 H, s), 0.80-1.00 (2 H, m), 0.99 (3 H, s), 1.19 (3 H, s), 1.10-1.90 (13 H, m), 2.99 (2 H, m), 3.22 (1 H, dd, J ₁ = 4.6 Hz, J ₂ = 11.2 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.5 (CH₃), 15.7 (CH₃), 16.5 (CH₂), 18.4 (CH₂), 19.1 (CH₃), 22.9 (CH₃), 24.5 (CH₂), 27.1 (CH₂), 28.0 (CH₃), 33.9 (C), 37.5 (C), 38.1 (CH₂), 38.8 (C), 44.1 (CH₂), 45.9 (CH₂), 47.4 (CH), 51.9 (CH), 55.1 (CH), 61.3 (C), 78.8 (CH), 214.6 (C) ppm. MS (EI): m/z (%) = 281 (2) [M⁺ - 37], 244 (2), 207 (4), 189 (2), 174 (2), 161 (3), 136 (11), 121 (9), 107 (8), 95 (15), 81 (56), 69 (100), 55 (19). HRMS (ESI): m/z calcd for C₂₁H₃₄O₂Na: 341.2451; found: 341.2463 [M⁺ + Na].