Tin-Free, Radical-Mediated γ-Alkylations of α,β-Unsaturated Esters via O-tert-Alkyl Dienol Ethers

Abstract

Tin-free, radical-mediated γ-alkylation of α,β-unsaturated esters is accomplished by radical addition and β-fragmentation of O-tert-alkyl dienol ethers and subsequent iodine atom transfer process.

Key words

alkylation - carboxylic ester - fragmentation - radicals - tin-free

References and Notes

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• For other approaches, see:
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• For other radical-mediated alkylations, see:
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• For tin-free radical reactions, see:
• 9a Baguley PA. Walton JC. Angew. Chem. Int. Ed.  1998,  37:  3072 ; and references therein
• 9b Kim S. Song H.-J. Choi T.-L. Yoon J.-Y. Angew. Chem. Int. Ed.  2001,  40:  2524 
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13

Typical Experimental Procedure
A benzene solution (1 mL, 0.2 M in iodide) of iodomethyl phenyl sulfone (56 mg, 0.2 mmol), O-tert-alkyl dienol ether (9a, 93 mg, 0.3 mmol), and DLP (8 mg, 0.02 mmol) was degassed with nitrogen for 10 min and then the solution was stirred at 90 °C under nitrogen for 5 h. The solvent was evaporated under reduced pressure and the residue was diluted with THF (1 mL). Then, TBAF (240 µL, 0.24 mmol) and MeI (50 µL, 0.8 mmol) were added successively. The reaction mixture was allowed to stir at r.t. for 2 h. The reaction mixture was diluted with Et₂O, quenched with aq NH₄Cl and washed with H₂O and brine. The organic layer was dried over anhyd MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using EtOAc-n-hexane (1:10) as eluant to give 5-benzenesulfonylpent-2-enoic acid methyl ester (20a, 45 mg, 89%). ¹H NMR (400 MHz, CDCl₃): δ = 2.57-2.63 (m, 2 H), 3.16-3.20 (m, 2 H), 3.67 (s, 3 H), 5.79 (dt, J = 15.6, 1.3 Hz, 1 H), 6.78 (dt, J = 15.6, 6.8 Hz, 1 H), 7.53-7.57 (m, 2 H), 7.62-7.66 (m, 1 H), 7.86-7.89 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.3, 51.5, 54.2, 123.1, 128.0 (C2), 129.4 (C2), 133.9, 138.6, 143.3, 166.0. IR (KBr): 1728, 1659, 1447, 1323, 1204, 766, 748 cm^-1. HRMS: m/z calcd for C₁₂H₁₄O₄S [M⁺]: 254.0613; found: 254.0613.
Compound 20a (entry 2): MW (C₁₄H₁₈O₄S): 282.35. ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (t, J = 7.5 Hz, 3 H), 1.60-1.66 (m, 1 H), 1.84-1.87 (m, 1 H), 2.48-2.52 (m, 1 H), 2.68-2.72 (m, 1 H), 2.97-3.00 (m, 1 H), 3.67 (s, 3 H), 5.80 (dt, J = 15.6, 1.3 Hz, 1 H), 6.78 (dt, J = 15.6, 7.37 Hz, 1 H), 7.51-7.55 (m, 2 H), 7.60-7.64 (m, 1 H), 7.83-7.85 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.0, 20.7, 30.0, 51.5, 64.6, 123.8, 128.7 (C2), 129.2 (C2), 133.8, 137.6, 143.4, 166.0. IR (KBr): 1729, 1658, 1447, 1320, 1214, 731, 691 cm^-1. HRMS: m/z calcd for C₁₄H₁₈O₄S [M⁺]: 282.0926; found: 282.0929.
Compound 20a (entry 3): MW (C₁₀H₁₆O₄): 186.21. ¹H NMR (400 MHz, CDCl₃): δ = 1.21 (t, J = 7.1 Hz, 3 H), 2.39-2.43 (m, 2 H), 2.46-2.51 (m, 2 H), 3.67 (s, 3 H), 4.10 (q, J = 7.1 Hz, 2 H), 5.82 (dt, J = 15.7, 1.5 Hz, 1 H), 6.91 (dt, J = 15.7, 6.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 27.2, 32.4, 51.4, 60.5, 121.7, 146.9, 166.7, 172.1. IR (KBr): 1742, 1720, 1659, 1436, 1179, 1039, 859 cm^-1. HRMS: m/z calcd for C₉H₁₄O₄ [M⁺]: 186.0892; found: 186.0893.
Compound 20a (entry 4): MW (C₇H₉NO₂): 139.15. ¹H NMR (400 MHz, CDCl₃): δ = 2.47-2.55 (m, 4 H), 3.72 (s, 3 H), 5.93 (dt, J = 15.7, 1.54 Hz, 1 H), 6.89 (dt, J = 15.7, 6.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.1, 27.7, 51.6, 118.2, 123.6, 143.3, 166.1. IR (KBr): 1730, 1663, 1437, 1275, 1213, 1162, 766, 748 cm^-1. HRMS: m/z calcd for C₇H₉NO₂ [M⁺]: 139.0633; found: 139.0642.
Compound 20a (entry 5): MW (C₁₀H₁₆O₄: 200.23. ¹H NMR (400 MHz, CDCl₃): δ = 1.15 (d, J = 14.3 Hz, 3 H), 1.20 (t, J = 7.1 Hz, 3 H), 2.25-2.30 (m, 1 H), 2.50-2.57 (m, 2 H), 3.68 (s, 3 H), 4.09 (q, J = 7.1 Hz, 2 H), 5.82 (dt, J = 15.6, 1.1 Hz, 1 H), 6.84 (dt, J = 15.6, 6.9 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 25.5, 35.8, 38.4, 51.4, 60.4, 122.8, 145.8, 166.6, 175.2. IR (KBr): 1740, 1720, 1659, 1436, 1275, 1196, 1180 cm^-1. HRMS: m/z calcd for C₁₀H₁₆O₄ [M⁺]: 200.1049; found: 200.1041.
Compound 20a (entry 6): MW (C₁₄H₁₆O₃): 232.27. ¹H NMR (400 MHz, CDCl₃): δ = 1.21 (d, J = 7.0 Hz, 3 H), 2.30-2.36 (m, 1 H), 2.66-2.72 (m, 1 H), 3.54-3.59 (m, 1 H), 3.67 (s, 3 H), 5.84 (dt, J = 15.6, 1.5 Hz, 1 H), 6.91 (dt, J = 15.6, 6.9 Hz, 1 H), 7.43-7.46 (m, 2 H), 7.52-7.54 (m, 1 H), 7.90-7.92 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.5, 35.4, 39.8, 51.4, 122.8 (C2), 128.7 (C2), 133.1, 135.8, 146.3, 166.6, 202.4. IR (KBr): 1733, 1712, 1688, 1449, 1434, 971, 705 cm^-1. HRMS: m/z calcd for C₁₄H₁₆O₃ [M⁺]: 232.1099; found: 232.1086.
Compound 20a (entry 7): MW (C₁₂H₁₈O₆): 258.26. ¹H NMR (400 MHz, CDCl₃): δ = 1.23 (t, J = 7.1 Hz, 6 H), 2.73-2.77 (m, 2 H), 3.44 (t, J = 7.44 Hz, 1 H), 3.68 (s, 3 H), 4.18 (q, J = 7.1 Hz, 4 H), 5.87 (dt, J = 15.6, 1.5 Hz, 1 H), 6.86 (dt, J = 15.6, 7.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.0 (C2), 31.0, 50.6, 51.5, 61.7 (C2), 123.8, 144.0, 166.3, 168.2 (C2). IR (KBr): 1755, 1720, 1661, 1436, 1151, 1036, 774 cm^-1. HRMS: m/z calcd for C₁₂H₁₈O₆ [M⁺]: 258.1103; found: 258.1128.
Compound 20b (entry 1): MW (C₁₃H₁₆O₄S): 268.32. ¹H NMR (400 MHz, CDCl₃): δ = 1.19 (d, J = 8.9 Hz, 3 H), 2.90-2.96 (m, 1 H), 3.06 (dd, J = 14.1, 6.3 Hz, 1 H), 3.17 (dd, J = 14.1, 6.6 Hz, 1 H), 3.65 (s, 3 H), 5.72 (dd, J = 15.6, 1.0 Hz, 1 H), 6.71 (dd, J = 15.6, 7.6 Hz, 1 H), 7.50-7.55 (m, 2 H), 7.59-7.63 (m, 1 H), 7.84-7.90 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.5, 31.6, 51.5, 60.9, 120.9, 127.8 (C2), 129.2 (C2), 133.7, 139.4, 149.5, 166.3. IR (KBr): 1721, 1659, 1447, 1305, 1209, 766, 747 cm^-1. HRMS: m/z calcd for C₁₃H₁₆O₄S [M⁺]: 268.0769; found: 2268.0751.
Compound 20b (entry 2): MW (C₁₅H₂₀O₄S): 296.38. Ratio syn/anti = 1.67:1 (from ¹H NMR). ¹H NMR (400 MHz, CDCl₃): δ(anti) = 0.90 (t, J = 7.5 Hz, 3 H), 1.19 (d, J = 7.0 Hz, 3 H), 1.67-1.70 (m, 1 H), 1.84-1.88 (m, 1 H), 2.88-2.91 (m, 1 H), 3.05-3.12 (m, 1 H), 3.69 (s, 3 H), 5.77 (dd, J = 15.7, 1.4 Hz, 1 H), 6.99 (dd, J = 15.7, 7.0 Hz, 1 H), 7.51-7.55 (m, 2 H), 7.60-7.63 (m, 1 H), 7.84-7.87 (m, 2 H); δ(syn) = 0.85 (t, J = 7.5 Hz, 3 H), 1.21 (d, J = 7.0 Hz, 3 H), 1.67-1.70 (m, 1 H), 1.84-1.88 (m, 1 H), 2.95-2.99 (m, 1 H), 3.05-3.12 (m, 1 H), 3.68 (s, 3 H), 5.76 (dd, J = 15.7, 1.7 Hz, 1 H), 6.83 (dd, J = 15.7, 6.3 Hz, 1 H), 7.51-7.55 (m, 2 H), 7.60-7.63 (m, 1 H), 7.84-7.87 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.9, 13.0, 13.1, 13.4, 17.8, 18.9, 34.5, 34.8, 51.5, 51.6, 69.1, 70.5, 121.1, 121.9, 128.4 (C2), 128.6 (C2), 129.2 (C2), 129.3 (C2), 133.6, 133.7, 138.7, 138.9, 148.3, 150.5, 166.4, 166.5. IR (KBr): 1727, 1656, 1447, 1303, 1197, 765, 728 cm^-1. HRMS: m/z calcd for C₁₅H₂₀O₄S [M⁺]: 296.1082; found: 296.1089.
Compound 20b (entry 3): MW (C₁₀H₁₆O₄): 200.23. ¹H NMR (400 MHz, CDCl₃): δ = 1.07 (d, J = 6.7 Hz, 3 H), 1.20 (t, J = 7.1 Hz, 3 H), 2.27 (dd, J = 15.3 Hz, 7.2 Hz, 1 H), 2.36 (dd, J = 15.3, 7.1 Hz, 1 H), 2.77-2.84 (m, 1 H), 3.67 (s, 3 H), 4.08 (q, J = 7.1 Hz, 2 H), 5.79 (dd, J = 15.7, 1.2 Hz, 1 H), 6.86 (dd, J = 15.7, 7.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 18.9, 32.9, 40.3, 51.4, 60.4, 119.8, 152.0, 166.9, 171.5. IR (KBr): 1738, 1722, 1658, 1276, 1177, 765, 748 cm^-1. HRMS: m/z calcd for C₁₀H₁₆O₄ [M⁺]: 200.1049; found: 200.1048.
Compound 20b (entry 4): MW (C₈H₁₁NO₂): 153.17. ¹H NMR (400 MHz, CDCl₃): δ = 1.21 (d, J = 6.8 Hz, 3 H), 2.35-2.46 (m, 2 H), 2.68-2.75 (m, 1 H), 3.70 (s, 3 H), 5.87 (dd, J = 15.7, 1.2 Hz, 1 H), 6.82 (dd, J = 15.7, 7.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.6, 23.6, 33.1, 51.6, 117.5, 121.6, 148.7, 166.3. IR (KBr): 1728, 1659, 1436, 1277, 1197, 765, 749 cm^-1. HRMS: m/z calcd for C₈H₁₁NO₂ [M⁺]: 153.0790; found: 153.0781.
Compound 20b (entry 5): MW (C₁₁H₁₈O₄): 214.25. Ratio syn/anti = 1:1 (from ¹H NMR). ¹H NMR (400 MHz, CDCl₃): δ(syn) = 1.02 (d, J = 3.4 Hz, 3 H), 1.07 (t, J = 7.4 Hz, 3 H), 1.19 (t, J = 7.1 Hz, 3 H), 2.31-2.38 (m, 1 H), 2.55-2.65 (m, 1 H), 3.68 (s, 3 H), 4.06-4.14 (m, 2 H), 5.78 (dd, J = 15.7, 11.7 Hz, 1 H), 6.87 (dd, J = 15.7, 7.7 Hz, 1 H); δ(anti) = 1.03 (d, J = 3.2 Hz, 3 H), 1.07 (t, J = 7.4 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H), 2.41-2.48 (m, 1 H), 2.55-2.65 (m, 1 H), 3.69 (s, 3 H), 4.06-4.14 (m, 2 H), 5.79 (dd, J = 15.6, 10.8 Hz, 1 H), 6.77 (dd, J = 15.6, 8.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.4, 14.1, 14.2, 14.8, 15.5, 17.6, 38.9, 39.5, 43.9, 44.5, 51.4, 51.5, 60.3, 60.4, 120.6, 121.3, 150.9, 151.4, 166.8, 166.9, 174.8, 175.0. IR (KBr): 1735, 1723, 1658, 1435, 1277, 1243, 765, 748 cm^-1. HRMS: m/z calcd for C₁₁H₁₈O₄ [M⁺]: 214.1205; found: 214.1203.
Compound 20b (entry 6): MW (C₁₅H₁₈O₃): 246.30. Ratio syn/anti = 1.67:1 (from ¹H NMR). ¹H NMR (400 MHz, CDCl₃): δ(anti) = 1.03 (d, J = 6.8 Hz, 3 H), 1.15 (d, J = 6.9 Hz, 3 H), 2.76-2.84 (m, 1 H), 3.47-3.54 (m, 1 H), 3.66 (s, 3 H), 5.77-5.85 (m, 1 H), 6.94 (dd, J = 15.7, 7.4 Hz, 1 H), 7.42-7.47 (m, 2 H), 7.51-7.55 (m, 1 H), 7.87-7.93 (m, 2 H); δ(syn) = 1.02 (d, J = 6.6 Hz, 3 H), 1.11 (d, J = 6.9 Hz, 3 H), 2.76-2.84 (m, 1 H), 3.38-3.41 (m, 1 H), 5.77-5.85 (m, 1 H), 6.87 (dd, J = 15.6, 8.9 Hz, 1 H), 7.42-7.47 (m, 2 H), 7.51-7.55 (m, 1 H), 7.87-7.93 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.4, 14.9, 16.0, 18.4, 38.2, 39.4, 44.6, 45.2, 51.4, 51.5, 120.5 (C2), 121.3, 128.1 (C2), 128.7 (C2), 133.0, 133.1, 136.4, 136.8, 151.3, 151.9 (C2), 166.8, 166.9, 202.6, 203.2. IR (KBr): 1722, 1681, 1655, 1449, 1277, 765, 748 cm^-1. HRMS: m/z calcd for C₁₅H₁₈O₃ [M⁺]: 246.1256; found: 246.1255.
Compound 20b (entry 7): MW (C₁₃H₂₀O₆): 272.29. ¹H NMR (400 MHz, CDCl₃): δ = 1.12 (d, J = 6.8 Hz, 3 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 3.04-3.10 (m, 1 H), 3.30 (d, J = 8.5 Hz, 1 H), 3.68 (s, 3 H), 4.13 (t, J = 7.1 Hz, 2 H), 4.17 (t, J = 7.1 Hz, 2 H), 5.83 (dd, J = 15.6, 0.7 Hz, 1 H), 6.87 (dd, J = 15.6, 8.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 14.0, 17.3, 36.2, 51.4, 56.7, 61.4, 61.5, 121.4, 149.3, 166.6, 167.6, 167.7. IR (KBr): 1756, 1722, 1658, 1436, 1300, 1278, 1234, 988 cm^-1. HRMS: m/z calcd for C₁₃H₂₀O₆ [M⁺]: 272.1260; found: 272.1271.
Compound 23: MW (C₁₅H₁₈O₄S): 294.37. ¹H NMR (400 MHz, CDCl₃): δ = 1.36-1.44 (m, 1 H), 1.50-1.56 (m, 1 H), 1.68-1.74 (m, 1 H), 1.87-1.93 (m, 1 H), 2.10-2.17 (m, 1 H), 2.21-2.27 (m, 1 H), 2.85-2.89 (m, 1 H), 3.04 (dd, J = 14.1, 6.9 Hz, 1 H), 3.13 (dd, J = 14.1, 6.1 Hz, 1 H), 3.66 (s, 3 H), 6.74-6.75 (m, 1 H), 7.52-7.56 (m, 2 H), 7.60-7.64 (m, 1 H), 7.88-7.90 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.3, 23.8, 27.8, 31.1, 51.6, 60.4, 127.8, 129.3, 132.1, 133.7, 139.0, 139.7, 167.3. IR (KBr): 1715, 1447, 1276, 1255, 1151, 1086, 719 cm^-1. HRMS: m/z calcd for C₁₅H₁₈O₄S [M⁺]: 294.0926; found: 294.0936.
Compound 28: MW (C₁₈H₂₆O₆): 338.39. ¹H NMR (400 MHz, CDCl₃): δ = 0.84-0.95 (m, 1 H), 1.17-1.25 (m, 8 H), 1.49-1.59 (m, 1 H), 1.74-1.80 (m, 2 H), 2.62-2.73 (m, 2 H), 2.79-2.84 (m, 1 H), 3.28-3.36 (m, 2 H), 3.65 (s, 3 H), 4.07-4.22 (m, 4 H), 4.55-4.57 (m, 1 H), 4.90-4.91 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 14.0, 21.5, 23.2, 24.6, 37.8, 41.9, 44.4, 45.4, 51.5, 60.9, 61.4, 61.5, 107.4, 145.4, 169.5, 171.7, 174.9. IR (KBr): 1731, 1446, 1268, 1254, 1224, 1058, 1038, 1015 cm^-1. HRMS: m/z calcd for C₁₈H₂₆O₆ [M⁺]: 338.1729; found: 338.1750.