ORGANIC LETTERS
Highly Enantioselective and Organocatalytic r-Amination of 2-Oxindoles
2009 Vol. 11, No. 17 3874-3877
Liang Cheng,† Li Liu,*,† Dong Wang,† and Yong-Jun Chen*,† Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China, and Graduate School of Chinese Academy of Sciences, Beijing 100049, China
[email protected];
[email protected] Received June 21, 2009
ABSTRACT
An effective method for the asymmetric synthesis of 3-amino-2-oxindoles was developed. The tetrasubstituted chiral carbon center was generated by asymmetric amination of N-unprotected 2-oxindoles with azodicarboxylate catalyzed by commercial biscinchona alkaloids in good to excellent yields with high enantioselectivities.
As important substructures, chiral 3,3-disubstituted 2-oxindoles constitute a ubiquitous class of heterocycles found in numerous natural products, marketed drugs, and drug candidates.1 Among them, 3-amino-2-oxindole compounds bearing a chiral quaternary carbon center have been investigated extensively and recognized as core structures in a variety of biologically active compounds, which exhibit significant pharmaceutical properties (Figure 1),2 and challenging targets for medicinal chemistry and synthetic organic chemistry. A plethora of different procedures have been developed to accomplish the synthesis of tetrasubstituted 3-amino-2oxindoles, including cyclization of o-chlorinated anilines,3 †
Institute of Chemistry, Chinese Academy of Sciences. (1) Brown, R. T. In The Chemistry of Heterocyclic Compounds, Part 4. Indoles: The Monoterpenoid Indole Alkaloids; Saxton, J. E., Eds.; John Wiley and Sons: New York, 1983; Vol. 25. (2) (a) Ochi, M.; Kawasaki, Y.; Kataoka, H.; Uchio, Y. Biochem. Biophys. Res. Commun. 2001, 283, 1118. (b) Bernard, K.; Bogliolo, S.; Ehrenfeld, J. Br. J. Pharmacol. 2005, 144, 1037. (c) Chen, L.; Yang, S.; Zhang, J.; Zhang, Z. U. S. Patent 81810 A1, 2008. (3) (a) Marsden, S. P.; Watson, E. L.; Sraw, S. A. Org. Lett. 2008, 10, 2905. (b) Watson, E. L.; Marsden, S. P.; Raw, S. A. Tetrahedron Lett. 2009, 50, 3318. (c) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Ku¨ndig, E. P. Chem. Commun. 2008, 4040. 10.1021/ol901405r CCC: $40.75 Published on Web 08/05/2009
2009 American Chemical Society
Figure 1. Bioactive disubstituted 3-amino-2-oxindoles.
alkylation or addition of 2-oxindoles,4 and other miscellaneous sequences.5 However, these methods showed a lack of generality and gave variable yields, and most of them were hard to perform in a catalytic asymmetric manner.3c,4a,e (4) For selected examples, see: (a) Emura, T.; Esaki, T.; Tachibana, K.; Shimizu, M. J. Org. Chem. 2006, 71, 8559. (b) Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem. 2006, 71, 3159. (c) Magnus, P.; Turnbull, R. Org. Lett. 2006, 8, 3497. (d) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2005, 70, 3324. (e) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 4537. (5) For selected examples, see: (a) Bella, A. F.; Slawin, A. M. Z.; Walton, J. C. J. Org. Chem. 2004, 69, 5926. (b) O’Connor, S. J.; Liu, Z. Synlett 2003, 14, 2135.
Recently, the catalytic asymmetric nucleophilic addition reaction of 2-oxindole has attracted considerable attention.6,7 Since significant advances have been achieved in the metalcatalyzed or organocatalytic asymmetric R-amination of carbonyl compounds with azodicarboxylates,8 we envisioned that the enantioselective electrophilic amination of 2-oxindole with azodicarboxylates would be a direct method for the synthesis of 3-amino-2-oxindole alkaloid compounds. However, to the best of our knowledge, the use of oxindoles as simple R-aryl amides has never been reported. Herein we report the first enantioselective synthesis of the title compounds through the amination of various 2-oxindoles with azodicarboxylate catalyzed by commercial biscinchona alkaloids.9,10 This appealing methodology, using readily available N-unprotected 3-monosubstituted 2-oxindoles as starting materials,11 will undoubtedly provide effective method for the enantioselective synthesis of functionalized and complex 3,3′-disubstituted 3-amino-2-oxindole alkaloids. Initially, the enantioselective amination reaction of 2-oxindole 1a with 1.0 equiv of diethyl azodicarboxylate (DEAD, 2a) in dichloromethane in the presence of natural cinchona alkaloids 4a-d (10 mol %) (Figure 2) was carried out (Scheme 1).
Figure 2. Catalysts for screening.
Although 1a was smoothly converted to the adduct 3a in moderate yields (45-69%), unfortunately, very poor enantioselectivities of the product were obtained (Table 1, entries 1-4). Various biscinchona alkaloids were screened for this
Scheme 1
Org. Lett., Vol. 11, No. 17, 2009
Table 1. Catalyst Screening for Enantioselective R-Amination of 2-Oxindoles 1a with 2a entry
2
catalystb
products
yieldc (%)
ee of 3d (%)
1 2 3 4 5 6 7 8 9
2a 2a 2a 2a 2a 2a 2b 2c 2d
4a 4b 4c 4d 4e 4f 4e 4e 4e
3a 3a 3a 3a 3a 3a 3b 3c 3d
45 63 50 69 47 48 quant 85 58
7 5 1 7 33 -31 57 39
