Functionalization of 2-Alkylidenetetrahydrofurans and 2-Alkylidene­pyrrolidines by Palladium(0)-Catalyzed Cross-Coupling Reactions

Abstract

2-Alkylidenetetrahydrofurans and 2-alkylidenepyrrol­idines were efficiently functionalized by bromination of the exo­cyclic double bond and subsequent palladium-catalyzed cross-coupling reactions.

bromination - cross-coupling - palladium - pyrrolidines - tetrahydrofurans

References

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2 Langer P. Armbrust H. Eckardt T. Magull J. Chem.-Eur. J.  2002,  8:  1443 ; and references cited therein

3 Langer P. Freifeld I. Chem. Commun.  2002,  2668 ; and references cited therein

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10

Typical Experimental Procedure for 3a: N-Bromo-succinimide (0.879 g, 4.9 mmol) was added to a CCl₄ solution (40 mL) of 2a (0.700 g, 3.8 mmol) at r.t. The reaction mixture was stirred under reflux for 3 h. The reaction mixture was allowed to cool to r.t. and Et₂O (20 mL) was added. The solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane-EtOAc, 100:1 to 1:1) to give 3a as a colorless solid (0.732 g, 73%). ¹H NMR (300 MHz, CDCl₃): δ = 1.51 (s, 9 H, Ot-Bu), 2.21 (quint, J = 7.2 Hz, 2 H, CH₂), 3.13 (t, J = 7.8 Hz, 2 H, CH₂), 4.37 (t, J = 7.2 Hz, 2 H, OCH₂). ¹³C NMR (150 MHz, CDCl₃): δ = 25.10 (CH₂), 28.46 (CH₃), 32.54 (CH₂), 72.83 (C-5), 81.65 (C), 85.80 (Br-C=C), 163.38 (O=C-O), 170.80 (O-C=C). IR (KBr): ν = 2975 (w, C-H), 1694 (s, C=C-O), 1613 (s, C=C-C=O), 1370 (m), 1295 (s), 1250 (w), 1243 (w), 1210 (m), 1170 (s), 1067 (s), 1039 (w), 1023 (w), 955 (w), 934 (w), 864 (w). MS (EI, 70 eV): m/z (%) = 263 (19)[M⁺], 206 (100), 190 (92), 162 (4) cm^-1. The exact molecular mass m/z = 262.0205 ± 2 mD [M⁺] for C₁₀H₁₅O₃Br was confirmed by HRMS (EI, 70 eV). Anal. Calcd for C₁₀H₁₅O₃Br (263.131): C, 45.65; H, 5.75. Found: C, 45.38; H, 6.03. All products gave satisfactory spectroscopic and analytical and/or high-resolution mass data.

11

Typical Experimental Procedure for 4a: Tetrakis(triphenylphosphine)palladium (0.20 g, 0.017 mmol) was added to a 1,4-dioxane solution (5 mL) of 3a (0.150 g, 0.57 mmol), K₃PO₄ (0.726 g, 3.42 mmol) and phenylboronic acid (0.209 g, 1.71 mmol) at r.t. The reaction mixture was stirred under reflux for 6 h. The solution was allowed to cool to r.t. and a sat. solution of NH₄Cl (20 mL) was added. The solution was extracted with Et₂O (4 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, n-hexane-EtOAc = 100:1 to 25:1) to give 4a as a slightly yellow solid (0.128 g, 87%). ¹H NMR (300 MHz, CDCl₃): δ = 1.44 (s, 9 H, Ot-Bu), 2.11 (quint, J = 7.2 Hz, 2 H, CH₂), 3.21 (t, J = 7.8 Hz, 2 H, CH₂), 4.17 (t, J = 6.9 Hz, 2 H, OCH₂), 7.20-7.34 (m, 5 H, Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 24.36 (CH₂), 28.46 (CH₃), 31.74 (CH₂), 71.92 (C-5), 79.83 (C), 106.37 (C=C-O), 126.35, 127.60, 130.60 (CH, Ph), 136.18 (C, Ph), 167.92 (O=C-O), 170.73 (O-C=O). IR (neat): ν = 3079 (w), 2974 (m), 2921 (w), 2907 (w, C-H), 1687 (s, C=C-O), 1608 (s, C=C-C=O), 1492 (m), 1474 (m), 1452 (m), 1420 (w), 1384 (m), 1368 (m), 1321 (m), 1301 (m), 1269 (m), 1251 (m), 1231 (m), 1157 (s), 1113 (m), 1063 (s), 1038 (s), 956 (m), 930 (m), 880 (w), 839 (m), 812 (m), 778 (m), 756 (m), 697 (m), 654 (w), 508 (w) cm^-1. MS (EI, 70 eV): m/z (%) = 260 (23) [M⁺], 203 (100), 186 (79), 169 (4), 157 (1). The exact molecular mass m/z = 260.1412 ± 2 mD [M⁺] for C₁₆H₂₀O₃ was confirmed by HRMS (EI, 70 eV).

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13 The 2,3¢-bifuranylidene subunit is present in the natural products charlic acid, charolic acid and terrestric acid: Arai H. Miyajima H. Mushiroda T. Yamamoto Y. Chem. Pharm. Bull.  1989,  12:  3229 

14 For the synthesis of 8, see: Lambert PH. Vaultier M. Carrié R. J. Org. Chem.  1985,  50:  5352