Synthesis of Novel Annulated Hymenialdisine Analogues via Palladium-Catalyzed Cross-Coupling Reactions with Aryl Boronic Acids

Abstract

Palladium-catalyzed Suzuki cross-coupling reactions of an indole vinyl triflate provides an efficient pathway for the synthesis of a diverse class of novel hymenialdisine analogues.

Key words

hymenialdisine analogues - cross-coupling - silica gel - palladium - heterocycles

References and Notes

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  The use of these compounds as tools in activity-based profiling is currently ongoing

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15

Decomposition of compound 8 was observed on storage (˜5 d).

17

General procedure for the Suzuki coupling of 8 with aryl boronic acids 9a-k: To a stirring mixture of 8 (600 mg, 1.1 mmol) in toluene (3 mL) and absolute EtOH (3 mL) under an argon atmosphere, Pd(PPh₃)₄ (12.6 mg, 0.011 mmol), boronic acid (1.2 mmol) and 2 M aq Na₂CO₃ solution (0.55 mL) were added. The mixture was heated at 70 ˚C overnight (˜12-16 h), then the solvent was removed under reduced pressure and the mixture was extracted with CH₂Cl₂ (2 × 20 mL), the combined organic extracts were washed with brine (25 mL), dried over MgSO₄ and concentrated under reduced pressure to give the crude product, which was used for the deprotection step without further purification. The above crude product was dissolved in anhydrous CH₂Cl₂ (50 mL) and activated silica (2.46 g, 0.040-0.063 mm) was added. The solvent was removed under reduced pressure and the solid mixture was heated under argon at 100 ˚C for 1 h. Purification by column chromatography (silica gel 70-230 mesh, hexane-EtOAc, 6:4) yielded pure compounds 9a-k.

18

X-ray crystal data for 9d: Empirical formula: C₁₉H₁₆N₂O₂; M _r = 304.34; monoclinic; space group: P2₁/c; cell dimensions: a = 9.3756 (3), b = 6.5948 (2), c = 25.3990 (8) Å, β = 100.003 (2)˚; V = 1546.55 (8) Å^³; Z = 4; ρ _calcd = 1.307 g˙cm^-³; 22763 reflections measured, 3292 independent reflections, of which 2312 were observed [I >2σ(I)], final R indices [I >2σ(I)]: R ₁ = 0.0306, wR ₂ = 0.0686, R indices (all data): R ₁ = 0.0486, wR ₂ = 0.0715, 217 refined parameters. Data were collected on a STOE IPDS II diffractometer using graphite-monochromated MoKα radiation. The structure was solved by direct methods (SHELXS-97)^¹9 and refined by full-matrix least-squares techniques on F ^² (SHELXL-97).^¹9 XP (Bruker AXS) was used for graphical represen-tation. CCDC 748111 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallo-graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.