Heck Reactions of Quinoline-Derived Nonaflates

Abstract

An efficient synthesis of a series of quinolyl-substituted ketones or ketone precursors via the Heck reaction of 6- or 8-quinolyl nonaflates with an appropriate selection of olefins is ­presented. These ketones are useful building blocks for the dia­stereoselective construction of azapolycycles via SmI₂-induced ­intramolecular cyclization of (het)aryl-substituted ketones.

Heck coupling - Pd catalysis - nonaflate - samarium(II) iodide - quinoline

References and Notes

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10

Typical Procedure for the Heck Reaction of 7 and 21 Leading to 22. A high-pressure tube was loaded with NaHCO₃ (0.285 g, 3.40 mmol), triethylbenzylammonium chloride (0.389 g, 1.71 mmol), quinolin-8-yl 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonate (7, 0.362 g, 0.85 mmol), Pd(OAc)₂ (39 mg, 0.17 mmol) and DMF (3 mL). The suspension was stirred at r.t. under argon for 10 min, then a solution of rac-tert-butyl (3S,4R)-3-hydroxy-4-vinylpyrrolidine-1-carboxylate (21, 0.729 g, 3.42 mmol) in DMF (1 mL) was added, the vessel was sealed and heated to 90 °C for 48 h. The vessel was then cooled to r.t., distilled H₂O was added and the phases were separated. The product was extracted in CH₂Cl₂ (3 × 5 mL), the combined organic layers were washed with brine (2 × 5 mL), dried over MgSO₄ and the solvent was removed under reduced pressure to leave the crude product, which was purified by column chromatography on silica gel (eluent: hexane-EtOAc from 4:1 to 1:1) to afford tert-butyl 3-hydroxy-4-[(E)-2-quinolin-8-ylvinyl]pyrrolidine-1-carboxylate (22) as a colorless oil (0.259 g, 89% yield). Two distinct rotamers were visible from NMR analysis at r.t. ¹H NMR (500 MHz, CDCl₃): δ = 1.47 (s, 9 H, t-Bu), 3.01-3.07 (m, 1 H, 4-H), 3.30-3.36 (m, 2 H, 2-H, 5-H), 3.54 (br d, ^³ J = 16.2 Hz, 1 H, OH), 3.72-3.80 (m, 2 H, 2-H, 5-H), 4.24-4.26 (m, 1 H, 3-H), 6.23 (m_c, 1 H, 1′-H), 7.37 (m_c, 1 H, Ar-H), 7.45-7.48 (m, 1 H, Ar-H), 7.67-7.70 (m, 1 H, Ar-H), 7.73-7.77 (m, 2 H, 2′-H, Ar-H), 8.10 (d, ^³ J = 7.7 Hz, 1 H, Ar-H), 8.92 (m, 1 H, Ar-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 28.5 (q, t-Bu), 49.6, 49.8 (2 t, C-5), 50.3, 50.6 (2 d, C-4), 52.0, 52.2 (2 t, C-2), 70.4, 70.5 (2 d, C-3), 79.4 (s, t-Bu), 121.2 (d, C-Ar), 125.9 (s, C-Ar), 126.5 (d, C-2′), 127.4, 128.4 (2 d, C-Ar), 128.6 (s, C-Ar), 130.2, 135.4, 136.4 (3 d, C-Ar), 145.1 (s, C-Ar), 149.5 (d, C-1′), 154.6 (s, CO) ppm. IR (KBr): ν = 3380-3200 (OH), 3050-3005, 2970, 2940, 2880 (=CH, C-H), 1695 (C=O) cm^-1. MS (EI, 80 eV, 160 °C): m/z (%) = 340 (16) [M]⁺, 283 (8) [M - C₄H₉]⁺, 239 (8) [M - C₅H₉O₂]⁺, 154 (46) [M - C₈H₁₅O]⁺, 57 (100) [C₄H₉]⁺. HRMS (80 eV, 160 °C): m/z calcd for C₂₀H₂₄N₂O₃: 340.17868; found: 340.17944.

11

Formation of a stable dimeric complex would also be plausible.

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