Facile Preparation of Functionalized 1-Substituted Cycloalkenes via an Iodine Atom Transfer Radical Addition–Elimination Process

Abstract

An efficient and scalable two-step one-pot procedure for the preparation of cycloalkenes substituted with a functionalized alkyl side chain is reported. This method is based on a triethylborane-mediated iodine atom transfer radical addition (ATRA) of 1-iodoesters and related compounds to methylenecycloalkanes followed by treatment of the intermediate tertiary iodide with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to promote a selective endo elimination.

Key words

radical reaction - cycloalkenes - endo elimination - triethylborane - methylenecycloalkene

• References and Notes

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• 11 General Procedure for Iodine ATRA–Elimination Reaction A solution of Et₃B (0.5 mL, 1.0 M in EtOH, 0.5 mmol) was added over 2 h by syringe pump to a stirred mixture of the iodide 2, 4, or 5 (2.0 mmol) and olefin 1 (1 mmol) in EtOH–H₂O (1:1, 10 mL) in the dark and open to air. After complete addition, the brown mixture was allowed to stir for 1 h at r.t. DBU (457 mg, 3 mmol) was added at 0 °C, and the mixture was stirred at r.t. overnight. After addition of a sat. aq solution of NH₄Cl (50 mL), the mixture was extracted with Et₂O (20 and 10 mL), and the organic phases were washed with brine (10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated. The crude product was purified by column chromatography. Ethyl 3-{1,2,3,6-Tetrahydro-[1,1′-biphenyl]-4-yl}propanoate (3e) Colorless and clear oil; 76% yield; endo/exo = 94:6. ¹H NMR (300 MHz, CDCl₃): δ = 7.34–7.15 (m, 5 H), 5.54–5.48 (m, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 2.80–2.67 (m, 1 H), 2.47–2.40 (m, 2 H), 2.35–2.21 (m, 3 H), 2.20–1.91 (m, 4 H), 1.82–1.68 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 147.1, 136.1, 128.3 (2 C), 126.9, 126.8, 126.0, 121.2, 60.3, 40.1, 33.4, 32.9, 32.6, 30.0, 28.9, 14.3. IR (neat): 3043, 2915, 2087, 1731, 1602, 1493, 1160, 916. HRMS (ESI-TOF): m/z calcd for C₁₇H₂₃O₂ [M + H]⁺: 259.1693; found: 259.1691. 3-{1,2,3,6-Tetrahydro-[1,1′-biphenyl]-4-yl}propanenitrile (6e) Colorless and clear oil; 70% yield; endo/exo = 94:6. ¹H NMR (300 MHz, CDCl₃): δ = 7.32–7.26 (m, 2 H), 7.25–7.16 (m, 3 H), 5.67–5.61 (m, 1 H), 2.83–2.70 (m, 1 H), 2.51–2.47 (m, 2 H), 2.40–2.27 (m, 3 H), 2.26–2.10 (m, 2 H), 2.08–1.93 (m, 2 H), 1.85–1.71 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 146.6, 133.9, 128.4 (2 C), 126.9 (2 C), 126.1, 123.6, 119.6, 39.8, 33.3, 33.0, 29.8, 28.5, 16.1. IR (neat): 3025, 2919, 2836, 2248, 1602, 1494, 1436, 908, 729, 699. HRMS (ESI-TOF): m/z calcd for C₁₅H₁₈N [M + H]⁺: 212.1434; found: 212.1427. 4-[2-(Phenylsulfonyl)ethyl]-1,2,3,6-tetrahydro-1,1′-biphenyl (7e) Amorphous white solid; 68% yield; endo/exo >98:2; mp 80–82 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.01–7.88 (m, 2 H), 7.72–7.52 (m, 3 H), 7.32–7.26 (m, 2 H), 7.32–7.25 (m, 3 H), 5.53–5.46 (m, 1 H), 3.28–3.18 (m, 2 H), 2.72–2.58 (m, 1 H), 2.46–2.37 (m, 2 H), 2.28–2.16 (m, 1 H), 2.15–2.00 (m, 2 H), 1.99–1.85 (m, 2 H), 1.75–1.57 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 146.6, 139.3, 133.7, 133.4, 129.3, 128.4, 128.1, 126.8, 126.1, 123.2, 54.8, 39.7, 33.3, 30.3, 29.7, 28.8. IR (neat): 2939, 2892, 2831, 1495, 1446, 1305, 1283, 1147, 1139, 1121, 1088, 887. HRMS (ESI-TOF): m/z calcd for C₂₀H₂₃O₂S [M + H]⁺: 327.1413; found: 327.1404.
• 12 Scale-up Experiment for Ethyl 3-(Cyclohex-1-en-1-yl)propanoate (3a) A solution of Et₃B (30 mL, 1.0 M in EtOH, 30 mmol) was added over 2 h by syringe pump to a stirred solution of ethyl 2-iodoacetate (2, 25.68 g, 120 mmol) and methylenecyclohexane (1a, 5.77 g, 60 mmol) in EtOH–H₂O (3:1, 60 mL) in the dark and open to air. After complete addition, the brown mixture was allowed to stir for 2 h at r.t. DBU (27.40 g, 180 mmol) was added at <10 °C, and the mixture was stirred at r.t. overnight. After addition of a sat. aq solution of NH₄Cl (150 mL), the mixture was extracted with pentane (150 and 75 mL), and the organic phases were washed with H₂O (75 mL), dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography (Et₂O–pentane, 5:95) to provide 3a (8.06 g, 74%) as a colorless and clear oil. ¹H NMR (300 MHz, CDCl₃): δ = 5.45–5.37 (m, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 2.45–2.33 (m, 2 H), 2.25 (t, J = 7.7 Hz, 2 H), 2.02–1.87 (m, 4 H), 1.67–1.47 (m, 4 H), 1.25 (t, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 173.6, 136.1, 121.6, 60.2, 33.1, 33.0, 28.3, 25.2, 22.9, 22.4, 14.3. IR (neat): 2925, 1733, 1445, 1368, 1340, 1288, 1248, 1157, 1081, 1038, 919, 856, 838 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₁H₁₈O₂Na [M + Na]⁺: 205.1199; found: 205.1193.
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