COMMUNICATIONS
Enantioselective Synthesis of Azaflavanones
[6] For a review on asymmetric synthesis of azaflavanones
and related compounds, see: A. E. Nibbs, K. A.
Scheidt, Eur. J. Org. Chem. 2012, 449.
[7] a) R. Shintani, T. Yamagami, T. Kimura, T. Hayashi,
Org. Lett. 2005, 7, 5317; b) X. Zhang, J. Chen, F. Han,
L. Cun, J. Liao, Eur. J. Org. Chem. 2011, 1443.
[8] a) Z. Feng, Q. L. Xu, L. X. Dai, S. L. You, Heterocycles
2010, 80, 765; b) X. Liu, Y. Lu, Org. Lett. 2010, 12,
5592; c) X. Xiao, X. Liu, S. Dong, Y. Cai, L. Lin, X.
Feng, Chem. Eur. J. 2012, 18, 15922.
model, which was confirmed by comparison of the
specific optical rotation with the literature value of
the known enantiomer.[10a]
In summary, we have described a highly enantiose-
lective 6-endo aza-Michael addition of aminochalcone
derivatives, which leads to highly enantioenriched
azaflavanones. A variety of 2-aryl-, 2-vinyl and 2-
methylazaflavanones were prepared in good yields
(53–84%) and excellent enantioselectivities (97.6:2.4
to 99.3:0.7 er). Studies on the synthetic applications of
this reaction are underway and will be reported in
due course.
[9] M. Rueping, S. A. Moreth, M. Z. Bolte, Z. Natur-
forsch. B 2012, 67, 1021.
[10] For other catalytic enantioselective syntheses of azafla-
vanones, see: a) B.-L. Lei, C.-H. Ding, X.-F. Yang, X.-
L. Wan, X.-L. Hou, J. Am. Chem. Soc. 2009, 131,
18250; b) K. Kanagaraj, K. Pitchumani, J. Org. Chem.
2013, 78, 744; c) H. Zheng, Q. Liu, S. Wen, H. Yang, Y.
Luo, Tetrahedron: Asymmetry 2013, 24, 875.
[11] For recent reviews on asymmetric aza-Michael addi-
tion, see: a) M. Liu, M. P. Sibi, Tetrahedron 2002, 58,
7991; b) L.-W. Xu, C.-G. Xia, Eur. J. Org. Chem. 2005,
633; c) J. L. Vicario, D. Badꢂa, L. Carrillo, J. Etxebarria,
E. Reyes, N. Ruiz, Org. Prep. Proced. Int. 2005, 37,
513; d) J. L. Vicario, D. Bada, L. Carrillo, Synthesis
2007, 2065; e) P. R. Krishna, A. Sreeshailam, R. Srini-
vas, Tetrahedron 2009, 65, 9657; f) D. Enders, C. Wang,
J. X. Liebich, Chem. Eur. J. 2009, 15, 11058; g) S. Fus-
tero, M. Sꢃnchez-Rosellꢄ, C. del Pozo, Pure Appl.
Chem. 2010, 82, 669; h) A. Y. Rulev, Russ. Chem. Rev.
2011, 80, 197; i) J. Wang, P. F. Li, P. Y. Choy, A. S. C.
Chan, F. Y. Kwong, ChemCatChem 2012, 4, 917; j) Z.
Amara, J. Caron, D. Joseph, Nat. Prod. Rep. 2013, 30,
1211.
[12] For organocatalytic exo-type aza-Michael additions,
see: a) K. Takasu, S. Maiti, M. Ihara, Heterocycles
2003, 59, 51; b) S. Fustero, D. Jimꢅnez, J. Moscardꢄ, S.
Catalꢃn, C. del Pozo, Org. Lett. 2007, 9, 5283; c) E. C.
Carlson, L. K. Rathbone, H. Yang, N. D. Collett, R. G.
Carter, J. Org. Chem. 2008, 73, 5155; d) S. Fustero, J.
Moscardꢄ, D. Jimꢅnez, M. D. Pꢅrez-Carriꢄn, M.
Sꢃnchez-Rosellꢄ, C. del Pozo, Chem. Eur. J. 2008, 14,
9868; e) Q. Cai, C. Zheng, S.-L. You, Angew. Chem.
2010, 122, 8848; Angew. Chem. Int. Ed. 2010, 49, 8666;
f) Q. Gu, S.-L. You, Chem. Sci. 2011, 2, 1519; g) J.-D.
Liu, Y.-C. Chen, G.-B. Zhang, Z.-Q. Li, P. Chen, J.-Y.
Du, Y.-Q. Tu, C.-A. Fan, Adv. Synth. Catal. 2011, 353,
2721; h) S. Fustero, C. del Pozo, C. Mulet, R. Lazaro,
M. Sꢃnchez-Rosellꢄ, Chem. Eur. J. 2011, 17, 14267;
i) R. Miyaji, K. Asano, S. Matsubara, Org. Lett. 2013,
15, 3658.
Experimental Section
Representative Procedure for the Intramolecular
Aza-Michael Addition of Azaflavanones 5
To
a reaction vial, N-protected 2-aminochalcone 4a
(27.0 mg, 0.1 mmol), organocatalyst 3d (9.9 mg, 20 mol%),
PhCO2H (7.3 mg, 60 mol%) and toluene (1 mL) were se-
quentially added at room temperataure. The resultant solu-
tion was stirred at 908C for 2 d. After the reaction was com-
pleted (as indicated by TLC analysis), the crude reaction
mixture was subjected to flash chromatography on silica gel
with mixtures of hexanes and ethyl acetate as eluent to
afford the desired product 5a as a yellowish solid; yield:
22.6 mg (84%).
Acknowledgements
This work was supported by 863 program (2013AA092903),
National Natural Science Foundation of China (21102072
and 21272113) and Research Fund for the Doctoral Program
of Higher Education of China (20110091120008).
References
[1] B. E. Evans, K. E. Rittle, M. G. Bock, R. M. Dipardo,
R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F.
Veber, P. S. Anderson, R. S. L. Chang, V. J. Lotti, D. J.
Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P.
Springer, J. Hirshfield, J. Med. Chem. 1988, 31, 2235.
[2] a) Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Tachiba-
na, S.-C. Kuo, E. Hamel, T. Hackl, K.-H. Lee, J. Med.
Chem. 1998, 41, 1155; b) S.-X. Zhang, J. Feng, S.-C.
Kuo, A. Brossi, E. Hamel, A. Tropsha, K.-H. Lee, J.
Med. Chem. 2000, 43, 167.
[3] A. Patti, S. Pedotti, T. Grassi, A. Idolo, M. Guido, A.
De Donno, J. Organomet. Chem. 2012, 716, 216.
[4] S. Chandrasekhar, S. N. C. V. L. Pushpavalli, S. Chatla,
D. Mukhopadhyay, B. Ganganna, K. Vijeender, P. Sri-
hari, C. R. Reddy, M. J. Ramaiah, Bioorg. Med. Chem.
Lett. 2012, 22, 645.
[13] a) C. Zeng, H. Liu, M. Zhang, J. Guo, S. Jiang, S. Yu,
Synlett 2012, 23, 2251; b) H. Liu, C. Zeng, J. Guo, M.
Zhang, S. Yu, RSC Adv. 2013, 3, 1666.
[14] Y.-C. Chen, Synlett 2008, 1919.
[15] a) B. Vakulya, S. Varga, A. Csampai, T. Soos, Org. Lett.
2005, 7, 1967; b) J. Ye, D. J. Dixon, P. S. Hynes, Chem.
Commun. 2005, 4481; c) S. H. McCooey, S. J. Connon,
Angew. Chem. 2005, 117, 6525; Angew. Chem. Int. Ed.
2005, 44, 6367; d) B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen,
L.-S. Ding, Y. Wu, Synlett 2005, 4, 603.
[5] a) D. Ma, C. Xia, J. Jiang, J. Zhang, Org. Lett. 2001, 3,
2189; b) D. Ma, C. Xia, J. Jiang, J. Zhang, W. Tang, J.
Org. Chem. 2003, 68, 442.
[16] a) X.-J. Zhang, S.-P. Liu, J.-H. Lao, G.-J. Du, M. Yan,
A. S. C. Chan, Tetrahedron: Asymmetry 2009, 20, 1451;
Adv. Synth. Catal. 2014, 356, 982 – 986
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