A Radical Clock for Reactions of Epoxy Derivatives Induced by Titanocene Chloride

Abstract

A new radical clock based on pinene derivatives has been designed to measure the radical cyclization rate onto cyano and carbonyl groups and the radical elimination rate of OR and CN. In this system, the known rate constant of cyclobutylcarbinyl radical cleavage is used as the internal clock. At room temperature, the cyclization rate constants for 4-exo and 5-exo processes onto nitrile and aldehyde carbonyl groups are in the order of 10⁷ to 10⁸ s^-¹. The radical elimination rate constants for CN, OH, OCHO, and OAc are in the order of 10⁵ to 10⁸ s^-¹.

epoxides - titanium(III) - radical clock - titanocene chloride - epoxynitriles - epoxyaldehydes - epoxyketones - epoxyesters

References and Notes

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<A NAME="RG29508ST-8">8</A>

Reaction of Epoxides with Cp ₂ TiCl A mixture of Cp₂TiCl₂ (3.3 mmol) and Zn (6.60 mmol) in strictly deoxygenated 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. NaH₂PO₄ was added, and the mixture was stirred for 20 min. The product was extracted into Et₂O, washed with sat. NaHCO₃ and brine, dried (Na₂SO₄), and filtered. After removal of the solvent, the crude product was purified by flash chromatography.
Compound 10: diastereomeric mixture (60:40). IR: 3408, 2923, 1462, 1053 cm^-¹. MS (EI): m/z (%) = 192 (14) [M⁺ - 18], 177 (7), 163 (3), 149 (12), 135 (17), 121 (16), 119 (25), 95 (31), 91 (82), 70 (65), 55 (100). HRMS (EI): m/z calcd for C₁₃H₂₂O₂Na [M⁺ + Na]: 233.1517; found: 233.1514. ^¹H NMR (400 MHz, CDCl₃): δ (major isomer) = 0.94 (3 H, s), 1.10 (3 H, d, J = 7.2 Hz), 1.22 (3 H, s), 1.60-2.60 (7 H, m), 3.47 (1 H, dd, J ₁ = 3.3 Hz, J ₂ = 8.5 Hz), 3.51 (1 H, d, J = 9.1 Hz), 3.95 (1 H, dd, J ₁ = 6.8 Hz, J ₂ = 8.5 Hz), 4.22 (1 H, d, J = 9.1 Hz), 4.53 (1 H, dd, J ₁ = 5.2 Hz, J ₂ = 9.3 Hz) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 16.17 (CH₃), 23.83 (CH₃), 27.77 (CH₃), 30.66 (CH₂), 38.15 (C), 39.31 (CH₂), 40.14 (CH), 41.77 (CH), 51.50 (CH), 55.05 (C), 64.65 (CH), 72.86 (CH₂), 75.30 (CH₂) ppm. ^¹H NMR (400 MHz, CDCl₃): δ (minor isomer) = 0.87 (3 H, d, J = 7.4 Hz), 0.88 (3 H, s), 1.21 (3 H, s), 1.60-2.90 (7 H, m), 3.31 (1 H, dd, J ₁ = 3.7 Hz, J ₂ = 8.4 Hz), 3.37 (1 H, d, J = 8.6 Hz), 3.77 (1 H, d, J = 8.6 Hz), 4.02 (1 H, dd, J ₁ = 7.4 Hz, J ₂ = 8.4 Hz), 4.28 (1 H, dd, J ₁ = 5.3 Hz, J ₂ = 9.3 Hz), ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 16.60 (CH₃), 23.91 (CH₃), 27.63 (CH₃), 30.51 (CH₂), 36.37 (CH), 38.15 (C), 38.68 (CH₂), 39.46 (CH), 40.92 (CH), 55.32 (C), 72.69 (CH), 72.76 (CH₂), 79.34 (CH₂) ppm.
Compound 11: IR: 3400, 1645 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.76 (3 H, s), 1.80-2.50 (5 H, m), 4.01 (1 H, m), 4.03 (2 H, s), 4.29 (1 H, s), 4.73 (1 H, s), 4.75 (1 H, s), 5.19 (1 H, d, J = 10.4 Hz), 5.27 (1 H, d, J = 15.6 Hz), 5.87 (1 H, br s), 5.89 (1 H, m) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 20.87 (CH₃), 30.86 (CH₂), 30.15 (CH), 35.57 (CH₂), 60.30 (CH), 71.38 (CH₂), 74.45 (CH₂), 109.03 (CH₂), 117.24 (CH₂), 129.49 (CH), 134.34 (CH), 134.94 (C), 149.01 (C) ppm. MS (EI): m/z (%) = 150 (22) [M⁺ - 58], 135 (20), 131 (13), 108 (69), 93 (68), 91 (100), 68 (79), 55 (98). HRMS (EI): m/z calcd for C₁₃H₂₀O₂Na [M⁺ + Na]: 231.1355; found: 231.1353; [α]_D ^²0 -49.2 (c 1.3, CHCl₃).
Compound 13a1: IR: 3451, 2928, 2899, 1761, 1252, 1042 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.96 (3 H, s), 1.13 (1 H, d, J = 10.2 Hz), 1.21 (3 H, s), 1.64 (2 H, m), 1.94 (1 H, m), 2.24 (1 H, t, J = 5.7 Hz), 2.33 (1 H, m), 2.56 (2 H, m), 2.70 (1 H, m), 3.03 (1 H, m), 4.59 (1 H, dd, J ₁ = 9.3 Hz, J ₂ = 4.9 Hz) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 18.56 (CH₂), 23.35 (CH₃), 27.07 (CH₃), 29.82 (CH₂), 38.35 (CH₂), 38.53 (C), 40.44 (CH), 41.63 (CH₂), 50.24 (CH), 62.53 (CH), 75.80 (C), 212.49 (C) ppm. MS (EI): m/z (%) = 179 (2) [M⁺ - 15], 161 (2), 134 (4), 133 (17), 119 (26), 105 (100), 91 (96), 77 (30), 67 (28), 55 (68). HRMS (EI): m/z calcd for C₁₂H₁₈O₂Na [M⁺ + Na]: 217.1199; found: 217.1206; [α]_D ^²0
-10.1 (c 1.4, CHCl₃).
Compound 13a2: IR: ν = 3451, 2928, 2894, 1765, 1217 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 0.87 (3 H, s), 1.20 (1 H, d, J = 10.1 Hz), 1.28 (3 H, s), 1.50-2.40 (6 H, m), 2.54 (1 H, m), 3.01 (2 H, t, J = 8.9 Hz), 4.38 (1 H, dd, J ₁ = 9.1 Hz, J ₂ = 3.7 Hz) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 22.65 (CH₃), 26.59 (CH₃), 27.16 (CH₂), 27.88 (CH₂), 39.16 (CH₂), 39.65 (C), 39.80 (CH), 42.98 (CH₂), 48.56 (CH), 53.40 (C), 70.61 (CH), 213.39 (C) ppm. MS (EI): m/z (%) = 179 (3) [M⁺ - 15], 151 (3), 134 (6), 133 (24), 119 (26), 105 (100), 91 (80), 77 (40), 67 (42), 55 (89). HRMS (EI): m/z calcd for C₁₂H₁₈O₂Na [M⁺ + Na]: 217.1199; found: 217.1195; [α]_D ^²0 +40.7. (c 1.9, CHCl₃).
Compound 14a: IR: ν = 3455, 2920, 2249, 1645, 1441, 1217, 1053 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.62 (1 H, dt, J ₁ = 4.0 Hz, J ₂ = 13.3 Hz), 1.73 (3 H, s), 1.90 (4 H, m), 2.10-2.60 (4 H, m), 4.09 (1 H, br s), 4.72 (1 H, s), 4.75 (1 H, s), 5.73 (1 H, m) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 16.71 (CH₂), 20.82 (CH₃), 30.47 (CH₂), 30.81 (CH₂), 35.04 (CH), 36.85 (CH₂), 66.90 (CH), 109.37 (CH₂), 119.73 (C), 128.03 (CH), 134.77 (C), 148.52 (C) ppm. MS (EI): m/z (%) = 173 (6) [M⁺ - 18], 158 (6), 131 (9), 117 (22), 105 (21), 91 (100), 77 (23), 65 (22), 51 (23); HRMS (EI): m/z calcd for C₁₂H₁₇NONa [M⁺ + Na]:214.1208; found: 214.1205.
Compound 16a1: IR: ν = 3439, 2929, 1455, 1260, 1052 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.90 (3 H, s), 1.21 (3 H, s), 1.66 (4 H, m), 1.90 (1 H, m), 1.98 (1 H, t, J = 5.8 Hz), 2.10-2.60 (4 H, m), 3.93 (1 H, t, J = 6.1 Hz), 4.68 (1 H, dd, J ₁ = 9.2 Hz, J ₂ = 5.4 Hz) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 22.62 (CH₂), 23.16 (CH₃), 27.49 (CH₃), 27.85 (CH₂), 29.90 (CH₂), 38.35 (CH₂, C), 40.76 (CH), 53.12 (CH, C), 62.02 (CH), 74.68 (CH) ppm. MS (EI): m/z (%) = 177 (3) [M⁺ - 19], 163 (3), 149 (13), 134 (14), 121 (3), 108 (35), 92 (72), 91 (100), 67 (23), 55 (23). HRMS (EI): m/z calcd for C₁₂H₂₀O₂Na [M⁺ + Na]: 219.1356; found: 219.1338. Mp 146-150 ˚C; [α]_D ^²0 -7.4 (c 0.6, CHCl₃).
Compound 16a2: IR: n = 3445, 2929, 1453, 1260, 1051 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.81 (3 H, s), 1.29 (3 H, s), 1.44 (2 H, m), 1.60-1.90 (4 H, m), 2.09 (1 H, m), 2.34 (2 H, m), 2.46 (1 H, m), 3.94 (1 H, d, J = 8.2 Hz), 4.69 (1 H, dd, J ₁ = 10.4 Hz, J ₂ = 10.4 Hz) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 23.04 (CH₃), 26.44 (CH₂), 27.00 (CH₃, CH₂), 27.71 (CH₂), 38.81 (CH₂), 39.50 (CH), 39.54 (C), 43.99 (CH), 55.52 (C), 69.39 (CH), 71.48 (CH) ppm. MS (EI):
m/z (%) = 163 (3) [M⁺ - 33], 163 (2), 149 (1), 134 (10), 121 (4), 117 (27), 92 (51), 91 (100), 70 (23), 55 (43). HRMS (EI): m/z calcd for C₁₂H₂₀O₂Na [M⁺ + Na]: 219.1356; found: 219.1344. Mp 166-168 ˚C; [α]_D ^²0 +33.5 (c 0.7, CHCl₃).
Compound 17c: IR: 3383, 2923, 2858, 1729, 1469, 1391, 1372 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.89 (3 H, d, J = 6.6 Hz), 0.91 (3 H, d, J = 6.6 Hz), 1.20-2.20 (12 H, m), 2.44 (2 H, t, J = 8.9 Hz), 4.05 (1 H, br s), 5.56 (1 H, m), 9.77 (1 H, s) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 19.45 (CH₃), 19.89 (CH₃), 21.78 (CH₂), 27.55 (CH₂), 28.99 (CH₂), 31.94 (CH), 33.99 (CH₂), 34.06 (CH), 35.48 (CH₂), 43.71 (CH₂), 67.13 (CH), 125.69 (CH), 137.92 (C), 202.57 (CH) ppm. MS (EI): m/z (%) = 206 (9) [M⁺ - 18], 188 (3), 163 (9), 153 (13), 145 (33), 121 (12), 117 (29), 93 (35), 91 (100), 67 (67), 55 (90). HRMS (EI): m/z calcd for C₁₄H₂₄O₂Na [M⁺ + Na]: 247.1674; found: 247.1681; [α]_D ^²0 -51.9 (c 2.1, CHCl₃).
Compound 20d: IR: 3407, 2927, 1729, 1457, 1247, 1040 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.73 (3 H, s), 1.50-2.40 (5 H, m), 2.07 (3 H, s), 4.20 (1 H, br s), 4.51 (1 H, d, J = 6.2 Hz), 4.72 (1 H, s), 4.73 (1 H, d, J = 6.2 Hz), 4.75 (1 H, s), 5.94 (1 H, br s) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 20.78 (CH₃), 20.94 (CH₃), 30.80 (CH₂), 34.99 (CH), 35.99 (CH₂), 64.78 (CH), 66.58 (CH₂), 109.27 (CH₂), 130.74 (CH), 133.76 (C), 148.61 (C), 171.11 (C) ppm. MS (EI): m/z (%) = 192 (2) [M⁺ - 18], 167 (1), 150 (25), 132 (20), 117 (96), 91 (100), 68 (50), 53 (70). HRMS (EI): m/z calcd for C₁₂H₁₈O₃Na [M⁺ + Na]: 233.1148; found: 233.1161; [α]_D ^²0
-108.5 (c 0.3, CHCl₃).

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