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face of the 3-aminosubstituent), and an endo-selective manner,
suggesting a diastereoselective allenamide formation. The
obtained cycloadducts were hydrogenated and derivatized
into novel tricyclic heterocycles of interest as new core
structures for medicinal chemistry purposes. DFT calculations
of the Diels−Alder reaction of furan with allenamides 6 were in
accordance with the experimental outcome of the reaction. The
observed endo-approach is kinetically (17.64 vs 22.44, 25.90,
and 45.64 kcal/mol) as well as thermodynamically favored as
compared to the other possible approaches. A full exploration
of cyclic allenamides is under current investigation and will be
reported in due time.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectroscopic data (1H and 13C NMR spectra) for all new
compounds, LC−MS data of crude mixtures, and X-ray data
(CIF) for compounds 7a and 7a′. Additional computational
data regarding 6x and 6y. This material is available free of
(26) (a) Van Rompaey, K.; Van Den Eynde, I.; De Kimpe, N.;
Tourwe,
Van den Eynde, I.; De Wachter, R.; Kosson, P.; Misicka, A.; Lipkowski,
A.; Chung, N. N.; Schiller, P. W.; Tourwe, D. Tetrahedron 2006, 63,
1459. (c) Buysse, K.; Farard, J.; Nikolaou, A.; Vaucquelin, G.;
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D. Tetrahedron 2003, 59, 4421. (b) Pulka, K.; Feytens, D.;
́
AUTHOR INFORMATION
■
Corresponding Author
́
(27) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752.
Notes
(28) Kamber, M.; Just, G. Can. J. Chem. 1985, 63, 823.
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(30) Dubovyk, I.; Pichugin, D.; Yudin, A. K. Angew. Chem., Int. Ed.
2011, 50, 5924.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are indebted to the agency for Innovation by
Science and Technology (IWT) and Galapagos NV for
financial support. G.V. thanks Umicore for the generous gift
of M2 catalyst.
(31) Reaction conditions: reflux in CH2Cl2 [0.01 M], catalyst loading
of 0.1 mol %. For further discussion concerning the effects of tether
substituents in RCM, see: Gardiner, J.; Aitken, S. G.; McNabb, S. B.;
Zaman, S.; Abell, A. D. J. Organomet. Chem. 2006, 691, 5487.
(32) Reaction conditions: reflux in CH2Cl2 or PhMe [0.01 M],
catalyst loading of 0.05−0.5 mol %. This led to only starting material
and decomposition products. For examples of RCM reactions using
vinyl halides, see: (a) Matteis, V. D.; van Delft, F. L.; de Gelder, R.;
Tiebes, J.; Rutjes, F. P. J. T. Tetrahedron Lett. 2004, 45, 959. (b) Chao,
W.; Weinreb, S. M. Org. Lett. 2003, 5, 2505. (c) Kirkland, T. A.;
Grubbs, R. H. J. Org. Chem. 1997, 62, 10801. For one reference
reporting less than 15% yield using bromovinyl substrates, see: Paone,
D. V.; Shaw, A. W.; Nguyen, D. N.; Burgey, C. S.; Deng, J. Z.; Kane, S.
A.; Koblan, K. S.; Salvatore, C. A.; Mosser, S. D.; Johnston, V. K.;
Wong, B. K.; Miller-Stein, C. M.; Hershey, J. C.; Graham, S. L.; Vacca,
J. P.; Williams, T. M. J. Med. Chem. 2007, 50, 5564.
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