Advancing the Reactivity of Dimethylcyclopropane-1,1-dicarboxylates via Cross Metathesis

Abstract

Cross metathesis of the readily available dimethyl 2-vinylcycloropane-1,1-dicarboxylate with a variety of olefins gave divergent access to new donor–acceptor cyclopropanes bearing a π-donor alkenyl substituent. The synthetic utility of these cyclopropanes was shown by their participation in cycloaddition reactions with nitrones to yield the anticipated tetrahydro-1,2-oxazines. Hydrogenation yielded the alkyl-substituted adducts which would be more difficult to access via other means.

Key words

heterocycles - cycloaddition - cyclopropanes - metathesis - ruthenium

• References and Notes


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• 16 General Experimental Procedure for the Synthesis of Substituted Vinyl Cyclopropane 6a–k: Dimethyl 2-vinylcyclopropane-1,1-dicarboxylate (5; 1 equiv) and olefin (1.4–5.0 equiv) were dissolved in anhyd CH₂Cl₂. Grubbs 2^nd generation catalyst (G2; 0.01 equiv) was then added and a reflux condenser was attached. The reaction vessel was then purged with argon and the reaction was brought to reflux. Upon completion by TLC analysis the solvent was removed and the residue was purified by flash chromatography (EtOAc–hexanes) to yield the desired cyclopropanes 6a–k. Analytical Data for Selected Compounds: Dimethyl 2-(Hex-1-enyl)cyclopropane-1,1-dicarboxylate (6a): ¹H NMR (400 MHz, CDCl₃): δ = 5.71 (dt, J = 15.3, 7.0 Hz, 1 H), 5.35 (ddt, J = 15.2, 8.2, 1.2 Hz, 1 H), 3.72 (s, 6 H), 2.54 (q, J = 8.2 Hz, 1 H), 1.99 (q, J = 7.0 Hz, 2 H), 1.68 (dd, J = 7.4, 4.7 Hz, 1 H), 1.55 (dd, J = 9.4, 4.7 Hz, 1 H), 1.25–1.31 (m, 4 H), 0.86 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.2, 168.0, 135.6, 124.2, 52.6, 35.6, 32.1, 31.2, 27.5, 27.0, 22.0, 20.8, 13.9. IR (thin film): 3000, 2955, 2929, 2857, 1730, 1437, 1332, 1280, 1260, 1210, 1131 cm^–1. HRMS: m/z calcd for C₁₃H₂₀O₄: 240.1362; found: 240.1368 (6:1 trans to cis). Dimethyl 2-Styrylcyclopropane-1,1-dicarboxylate (6f): ¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.32 (m, 4 H), 7.20–7.26 (m, 1 H), 6.65 (d, J = 16.0 Hz, 1 H), 5.81 (dd, J = 16.0, 9.0 Hz, 1 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 2.76 (q, J = 8.2 Hz, 1 H), 1.85 (dd, J = 7.8, 5.1 Hz, 1 H), 1.70 (dd, J = 9.0, 5.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.9, 167.9, 136.7, 133.9, 128.6, 127.6, 126.1, 124.5, 52.8, 52.7, 36.0, 31.7, 21.3. IR (thin film): 3027, 2953, 2847, 1731, 1494, 1437, 1283, 1252, 1207, 1128, 964, 770, 744, 694 cm^–1. HRMS: m/z calcd for C₁₅H₁₆O₄: 260.1049; found: 260.1049 (only E-olefin observed by ¹H NMR). Dimethyl 2-(3-Oxobut-1-enyl)cyclopropane-1,1-dicarboxylate (6j): ¹H NMR (600 MHz, CDCl₃): δ = 6.23–6.30 (m, 2 H), 3.71 (s, 6 H), 2.56–2.65 (m, 1 H), 2.15 (s, 3 H), 1.78 (dd, J = 7.6, 5.3 Hz, 1 H), 1.72 (dd, J = 8.8, 4.7 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 197.0, 169.0, 167.2, 142.1, 133.3, 52.9, 52.8, 36.5, 29.8, 27.0, 21.5. IR (thin film): 3007, 2956, 2856, 1731, 1674, 1625, 1438, 1333, 1291, 1253, 1212, 1131, 983 cm^–1. HRMS: m/z calcd for C₁₁H₁₄O₅: 226.0841; found: 226.0831 (only E-olefin observed by ¹H NMR). General Experimental Procedure for the Synthesis of Tetrahydro-1,2-oxazines 9a–d: Yb(OTf)₃·xH₂O (5–20 mol %) was added to a solution of cyclopropane 6a, 6f, and 7a,b (1 equiv) and nitrone 8 (1.2 equiv) in CH₂Cl₂ or 1,2-dichloroethane. Reactions in CH₂Cl₂ were performed at r.t., while reactions in 1,2-dichloroethane were refluxed for 18 h. The reaction mixture was wet loaded and purified by flash chromatography (EtOAc–hexanes) to yield the desired tetrahydro-1,2-oxazine 9a–d. Analytical Data for Selected Compounds: Dimethyl 6-(Hex-1-enyl)-2-phenyl-3-p-tolylmorpholine-4,4-dicarboxylate (9a): ¹H NMR (600 MHz, CDCl₃): δ = 7.49–7.56 (m, 2 H), 7.14–7.21 (m, 3 H), 6.91–6.98 (m, 4 H), 5.88–5.97 (m, 1 H), 5.64–5.76 (m, 1 H), 5.62 (s, 1 H), 4.40–4.47 (m, 1 H), 3.88 (s, 3 H), 3.45 (s, 3 H), 2.44–2.61 (m, 2 H), 2.05–2.11 (m, 5 H), 1.33–1.49 (m, 4 H), 0.95 (t, J = 7.4 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 170.1, 168.4, 146.3, 135.2, 135.0, 130.8, 130.5, 129.0, 127.9, 127.8, 127.7, 116.0, 77.2, 65.9, 59.2, 53.3, 52.5, 32.2, 30.8, 22.3, 22.2, 20.5, 13.9. IR (thin film): 3028, 2954, 2927, 2859, 1742, 1509, 1453, 1434, 1235, 1177, 1149, 1082, 967, 821, 755, 702 cm^–1. HRMS: m/z calcd for C₂₇H₃₃NO₅: 451.2359; found: 451.2354. (6:1 trans to cis). General Experimental Procedure for Olefin Reduction to Tetrahydro-1,2-oxazines 9c–d: Vinyl tetrahydro-1,2-oxazines 9a and 9b (1 equiv) were dissolved in THF–H₂O (1:1). Tosylhydrazine (10 equiv) and NaOAc (13 equiv) were added and the reaction mixture was heated to reflux for 24 h. H₂O was added to the reaction and the aqueous layer was extracted with Et₂O (4 ×). The organic phases were combined and dried with MgSO₄, filtered, and the solvent was removed. The residue was purified by flash chromatography (EtOAc–hexanes) to yield the desired tetrahydro-1,2-oxazines (9c and 9d). Analytical Data for Selected Compounds: Dimethyl 6-Phenethyl-2-phenyl-3-p-tolylmorpholine-4,4-dicarboxylate (9d): ¹H NMR (600 MHz, CDCl₃): δ = 7.52–7.56 (m, 2 H), 7.30–7.34 (m, 2 H), 7.26–7.29 (m, 2 H), 7.17–7.24 (m, 4 H), 6.94–7.00 (m, 4 H), 5.67 (s, 1 H), 3.98–4.07 (m, 1 H), 3.85 (s, 3 H), 3.46 (s, 3 H), 2.96–3.04 (m, 1 H), 2.83–2.91 (m, 1 H), 2.46–2.52 (m, 2 H), 2.13–2.23 (m, 4 H), 1.97–2.06 (m, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 170.2, 168.5, 146.4, 141.6, 135.2, 130.7, 130.5, 129.1, 128.4, 128.0, 127.9, 126.0, 115.7, 76.5, 66.0, 59.2, 53.3, 52.5, 36.4, 31.9, 31.0, 20.6 (one carbon missing presumably due to overlap in the aromatic region). IR (thin film): 3027, 2951, 2924, 2857, 1741, 1509, 1453, 1434, 1236, 1166, 1090, 820, 753, 701 cm^–1. HRMS: m/z calcd for C₂₉H₃₁NO₅: 473.2202; found: 473.2191.