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.

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

References and Notes

1a Bishop AC. Ubersax JA. Petsch DT. Matheos DP. Gray NS. Blethrow J. Shimizu E. Tsien JZ. Schultz PG. Rose MD. Wood JL. Morgan DO. Shokat KM. Nature  2000,  407:  395 

1b Gray NS. Science  1998,  281:  533 

2 Cohen P. Nat. Rev. Drug Discovery  2002,  1:  309 

3 Bogoyevitch MA. Fairlie DP. Drug Discovery Today  2007,  12:  622 

4 Huwe A. Mazitschek R. Giannis A. Angew. Chem. Int. Ed.  2003,  42:  2122 

5a Wan Y. Hur W. Cho CY. Liu Y. Adrin FJ. Lozach O. Bach S. Mayer T. Fabbro D. Meijer L. Gray NS. Chem. Biol.  2004,  11:  247 

5b Sharma V. Lansdell TA. Jin G. Tepe JJ. J. Med. Chem.  2004,  47:  3700 

6 Meijer L. Thunnissen A.-MWH. White AW. Garnier M. Nikolic M. Tsai L.-H. Walter J. Cleverley KE. Salinas PC. Wu Y.-Z. Biernat J. Mandelkow E.-M. Kim S.-H. Pettit GR. Chem. Biol.  2000,  7:  51 

7 Mohammed R. Peng J. Kelly M. Hamann MT. J. Nat. Prod.  2006,  69:  1739 

8 Albizati KF. Faulkner DJ. J. Org. Chem.  1985,  50:  4163 

9a Kumar K. Michalik D. Castro IG. Tillack A. Zapf A. Arlt M. Heinrich T. Böttcher H. Beller M. Chem. Eur. J.  2004,  10:  746 

9b Michalik D. Kumar K. Zapf A. Tillack A. Arlt M. Heinrich T. Beller M. Tetrahedron Lett.  2004,  45:  2057 

9c Tewari A. Hein M. Zapf A. Beller M. Tetrahedron Lett.  2004,  45:  7703 

9d Khedkar V. Tillack A. Michalik M. Beller M. Tetrahedron  2005,  61:  7622 

9e Neumann H. Strübing D. Lalk M. Klaus S. Hübner S. Spannenberg A. Lindequist U. Beller M. Org. Biomol. Chem.  2006,  4:  1365 

For recent publications, see:

10a Gelalcha FG. Anilkumar G. Tse MK. Brückner A. Beller M. Chem. Eur. J.  2008,  14:  7687 

10b Bitterlich B. Schröder K. Tse MK. Beller M. Eur. J. Org. Chem.  2008,  4867 

10c Gelalcha FG. Bitterlich B. Anilkumar G. Tse MK. Beller M. Angew. Chem.  2007,  46:  7293 

10d Anilkumar G. Bitterlich B. Gelalcha FG. Tse MK. Beller M. Chem. Commun.  2007,  289 

10e Tse MK. Bhor S. Klawonn M. Anilkumar G. Jiao H. Döbler C. Spannenberg A. Mägerlein W. Hugl H. Beller M. Chem. Eur. J.  2006,  12:  1855 

10f Tse MK. Bhor S. Klawonn M. Anilkumar G. Jiao H. Spannenberg A. Döbler C. Mägerlein W. Hugl H. Beller M. Chem. Eur. J.  2006,  12:  1875 

10g Tse MK. Döbler C. Bhor S. Klawonn M. Mägerlein W. Hugl H. Beller M. Angew. Chem. Int. Ed.  2004,  43:  5255 

11a Mangu N. Kaiser HM. Kar A. Spannenberg A. Beller M. Tse MK. Tetrahedron  2008,  64:  7171 

11b Kaiser HM. Lo WF. Riahi AM. Spannenberg A. Beller M. Tse MK. Org. Lett.  2006,  8:  5761 

11c Kaiser HM. Zenz I. Lo WF. Spannenberg A. Schroder K. Jiao H. Gordes D. Beller M. Tse MK. J. Org. Chem.  2007,  72:  8847 

11d

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

12a Nakamura I. Yamamoto Y. Chem. Rev.  2004,  104:  2127 

12b Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 

13 Tessier PE. Nguyen N. Clay MD. Fallis AG. Org. Lett.  2005,  7:  767 

14 Stang PJ. Fisk TE. Synthesis  1979,  438 

15

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

16a Chacun-Lefèvre L. Joseph B. Mérour J.-Y. Tetrahedron  2000,  56:  4491 

16b Perron J. Joseph B. Mérour J.-Y. Tetrahedron  2003,  59:  6659 

16c Chacun-Lefèvre L. Joseph B. Mérour J.-Y. Synlett  2001,  848 ; Note: Although this reference reports a similar kind of approach, it suffers with the unprotected NH-CO-C-NH backbone, which is critical for kinase inhibition

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.

19 Sheldrick GM. Acta Crystallogr., Sect. A  2008,  64:  112