Synthesis of Lactones and Lactams from Vinylcyclopropane by Palladium- Catalyzed Nucleophilic Allylation

Abstract

A palladium-catalyzed nucleophilic allylation of aldehydes with vinylcyclopropane in the presence of diethylzinc proceeded to provide homoallyl alcohols with anti stereoselectivity. Aldimines prepared from aldehyde and primary amines in situ underwent a similar nucleophilic allylation to give homoallylamines with syn stereoselectivity. The resulting homoallyl alcohols and homoallylamines could be converted by treatment with a tetranuclear zinc cluster into γ-vinyl-δ-valerolactones and γ-vinyl-δ-valerolactams, respectively.

Key words

palladium - vinylcyclopropane - nucleophilic allylation - aldehyde - aldimine

• References and Notes

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• 11 General Procedure for the Nucleophilic Allylation of Aldehyde with Vinylcyclopropane (Entry 1, Table 1): To a solution of Pd(acac)₂ (15.2 mg, 0.05 mmol), and Ph₃P (26.2 mg, 0.1 mmol) in anhyd THF (2 mL) were successively added vinylcyclopropane (221.0 mg, 1.2 mmol), benzaldehyde (106.1 mg, 1 mmol), and diethylzinc (2.4 mmol, 1.0 M hexane solution) via syringe under a nitrogen atmosphere. The mixture was stirred at r.t. for 48 h. The mixture was diluted with EtOAc (30 mL) and washed with 2 M HCl, and then brine. The extract was dried (MgSO₄) and concentrated in vacuo and the residual oil was subjected to column chromatography over silica gel (hexane–EtOAc, 2:1) to give 1a (210.5 mg, 72%; R_f 0.63; hexane–EtOAc, 2:1) and 2a (54.8 mg, 21%; R_f 0.5; hexane–EtOAc, 2:1). Dimethyl 2-[2-(Hydroxyphenylmethyl)but-3-en-1-yl]malonate (1a): IR (neat): 3524 (br), 3064 (m), 3030 (m), 1750 (s), 1732 (s), 1640 (m), 921 (m), 765 (m) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.80 (ddd, J = 14.3, 11.8, 5.0 Hz, 1 H), 1.94 (ddd, J = 14.3, 10.0, 3.7 Hz, 1 H), 2.11 (d, J = 2.5 Hz, 1 H), 2.38 (dddd, J = 11.8, 9.3, 7.1, 3.7 Hz, 1 H), 3.38 (dd, J = 10.0, 5.0 Hz, 1 H), 3.67 (s, 6 H), 4.50 (d, J = 7.1 Hz, 1 H), 5.13 (dd, J = 17.5, 1.7 Hz, 1 H), 5.26 (dd, J = 10.2, 1.7 Hz, 1 H), 5.63 (ddd, J = 17.5, 10.2, 9.3 Hz, 1 H), 7.27–7.34 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 29.7, 30.9, 49.6, 50.3, 52.4, 52.5, 120.0, 126.8, 127.9, 128.4, 137.2, 141.7, 169.4, 169.9. HRMS: m/z [M] calcd for C₁₆H₂₀O₅: 292.1311; found: 292.1311. Methyl Tetrahydro-2-oxo-6-phenyl-5-vinyl-2H-pyran-3-carboxylate (2a): obtained as a mixture of diastereomers in a 2:1 ratio. IR (neat): 3035 (w), 2954 (m), 1732 (s), 1643 (m), 1263 (m), 1070 (m), 1002 (m), 925 (m), 702 (s) cm^–1. ¹H NMR (400 MHz, CDCl₃: δ (major isomer) = 2.15 (ddd, J = 13.9, 9.8, 7.3 Hz, 1 H), 2.44 (ddd, J = 13.9, 11.3, 5.9 Hz, 1 H), 2.80–2.89 (m, 1 H), 3.80 (dd, J = 7.3, 5.9 Hz, 1 H), 3.83 (s, 3 H), 4.99 (d, J = 17.2 Hz, 1 H), 5.08 (d, J = 10.5 Hz, 1 H), 5.09 (d, J = 3.7 Hz, 1 H), 5.56 (ddd, J = 17.2, 10.5, 7.0 Hz, 1 H) 7.26–7.36 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ (2:1 mixture of diastereomers) = 28.2, 29.4, 41.7, 43.6, 45.8, 47.8, 52.9, 85.9, 86.5, 118.2, 118.3, 127.1, 127.3, 128.5, 128.8, 128.9, 134.9, 135.1, 137.3, 137.6, 166.2, 166.7, 169.4, 169.5. HRMS: m/z [M] calcd for C₁₅H₁₆O₄: 260.1049; found: 260.1047. Nucleophilic Allylation of Aldimine with Vinylcyclopropane (Entry 1, Table 2): A solution of benzaldehyde (106.1 mg, 1 mmol) and p-anisidine (129.3 mg, 1.05 mmol) in anhyd THF (1 mL) was refluxed for 30 min under nitrogen. The solvent was removed by distillation under atmospheric pressure of nitrogen (azeotropic removal of H₂O). The azeotropic distillation of THF (1 mL)/H₂O was repeated twice. A mixture of Pd(acac)₂ (15.2 mg, 0.05 mmol) and triphenylphoshine (26.2 mg, 0.1 mmol) in anhyd THF (2 mL) and vinylcyclopropane (221.0 mg, 1.2 mmol) dissolved in THF (1 mL) and diethylzinc (2.4 mmol, 1.0 M hexane solution) were successively added to the aldimine residue. The mixture was stirred at r.t. for 48 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with sat. NaHCO₃, and brine. The organic phase was dried (MgSO₄) and concentrated in vacuo to give a brown oil, which was subjected to column chromatography over silica gel (hexane–EtOAc, 70:30) to give 3a (167 mg, 42%; R_f 0.5; hexane–EtOAc, 2:1) and 4a (172 mg, 47%; R_f 0.27; hexane–EtOAc, 2:1). Dimethyl 2-[(p-Methoxyphenylamino)phenylmethylbut-3-en-1-yl]malonate (3a): obtained as a mixture of diastereomers in a 4:1 ratio. IR (neat): 3404 (m), 3001 (m), 2953 (m), 2833 (m), 1750 (s), 1732 (s), 1508 (s), 1435 (s), 1159 (br), 1038 (s), 925 (m), 704 (s) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ (major isomer) = 1.69 (ddd, J = 13.7, 11.3, 4.4 Hz, 1 H), 2.32 (ddd, J = 13.7, 10.5, 2.9 Hz, 1 H), 2.42–2.49 (m, 1 H), 3.37 (dd, J = 10.5, 4.4 Hz, 1 H), 3.67 (s, 6 H), 3.72 (s, 3 H), 4.30 (d, J = 5.1 Hz, 1 H), 5.09 (dd, J = 17.1, 1.5 Hz, 1 H), 5.17 (dd, J = 10.2, 1.5 Hz, 1 H), 5.46 (ddd, J = 17.1, 10.2, 9.8 Hz, 1 H), 6.45 (d, J = 8.9 Hz, 2 H), 6.65 (d, J = 8.9 Hz, 2 H), 7.18–7.31 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ (4:1 mixture of diastereomers) = 29.6, 30.4, 48.4, 49.1, 49.4, 49.5, 52.4, 52.5, 52.53, 55.56, 55.59, 51.0, 51.4, 114.6, 114.7, 114.74, 119.6, 127.8, 128.4, 128.6, 128.7, 128.8, 129.0, 132.8, 136.3, 137.2, 139.2, 140.5, 140.7, 141.1, 152.1, 152.3, 169.4, 169.6, 169.7, 169.8. HRMS: m/z [M] calcd for C₂₃H₂₇NO₅: 397.1889; found: 397.1899. Methyl 1-(p-Methoxyphenyl)-2-oxo-6-phenyl-5-vinylpiperidine-3-carboxylate (4a): obtained as a mixture of diastereomers in a 2:1 ratio. IR (neat): 2955 (m), 2839 (m), 1738 (s), 1693 (s), 1514 (s), 1250 (s), 1033 (m), 833 (m) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ (major isomer) = 2.09 (dt, J = 13.9, 7.0 Hz, 1 H), 2.40–2.47 (m, 1 H), 2.74–2.84 (m, 1 H), 3.70 (s, 3 H), 3.76–3.81 (m, 1 H), 3.84 (s, 3 H), 4.69 (d, J = 5.6 Hz, 1 H), 5.18 (dt, J = 17.3, 1.2 Hz, 1 H), 5.21 (dd, J = 10.5, 1.2 Hz, 1 H), 5.92 (ddd, J = 17.3, 10.5, 6.6 Hz, 1 H), 6.72 (d, J = 9.0 Hz, 2 H), 6.97 (d, J = 9.0 Hz, 2 H), 7.16–7.35 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃; 2:1 mixture of diastereomers): δ = 26.7, 29.1, 42.7, 45.3, 47.2, 49.5, 52.3, 52.5, 55.11, 55.14, 70.0, 70.5, 113.9, 114.1, 117.1, 117.2, 127.6, 127.7, 127.8, 127.9, 128.3, 128.35, 128.43, 128.7, 133.4, 134.3, 137.1, 137.3, 139.5, 140.1, 158.0, 158.1, 166.3, 167.1, 170.7, 171.8. HRMS: m/z [M] calcd for C₂₂H₂₃NO₄: 365.1627; found: 366.1663.