dihydroindoles with R,ꢀ-unsaturated aldehydes catalyzed by
diphenylprolinol ether, followed by a p-benzoquinone oxida-
tion.
Scheme 1. Strategy To Synthesize 2-Substituted Indoles
We initially investigated the reaction of the 4,7-dihydroin-
dole 1a with cinnamaldehyde 2a in the presence of the
readily available diphenylprolinol trimethylsilyl ether 3a (20
mol %) in toluene.10 The Friedel-Crafts alkylation pro-
ceeded smoothly to afford desired product 4a in 74% yield
and 70% ee (Table 1, entry 1). Encouraged by this, we
this reaction by utilizing chiral Lewis acid catalysts, provid-
ing easy access to enantioenriched 2-substituted indole
derivatives.7 More recently, an enantioselective Friedel-Crafts
alkylation8 of 4,7-dihydroindoles with imines and ꢀ,γ-
unsaturated R-keto esters activated by a chiral phosphoric
acid has been described by You et al.9 Interesting as the
optically pure 2-substituted indole derivatives are, their
catalytic asymmetric synthesis is still rather limited. For
instance, the use of R,ꢀ-unsaturated aldehydes as electrophilic
reagents has not been reported yet, although the aldehyde
group in the products would offer facile conversions to
versatile functionalities. In this paper, we present our results
on the functionalization of the indole nucleus at the 2-position
by a highly enantioselective Friedel-Crafts reaction of 4,7-
Table 1. Catalyst Screening and Reaction Optimizationa
entry catalyst solvent
additive
yieldb (%) eec (%)
(3) Selected examples: (a) Gathergood, N.; Zhuang, W.; Jørgensen, K. A.
J. Am. Chem. Soc. 2000, 122, 12517. (b) Austin, J. F.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 1172. (c) Zhou, J.; Tang, Y. J. Am. Chem.
Soc. 2002, 124, 9030. (d) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.;
Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780. (e) Yuan, Y.;
Wang, X.; Li, X.; Ding, K. J. Org. Chem. 2004, 69, 146. (f) Shirakawa, S.;
Berger, R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 2858. (g) Palomo,
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J. Org. Lett. 2006, 8, 2115. (k) Li, H.; Wang, Y.-Q.; Deng, L. Org. Lett.
2006, 8, 4063. (l) Zhao, J.-L.; Liu, L.; Sui, Y.; Liu, Y.-L.; Wang, D.; Chen,
Y.-J. Org. Lett. 2006, 8, 6127. (m) Zhou, W.; Xu, L.-W.; Li, L.; Yang, L.;
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Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y. C. Org. Biomol. Chem. 2007, 5, 816.
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Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J. Org. Lett. 2007, 9, 1847. (q) Yang, H.;
Hong, Y.-T.; Kim, S. Org. Lett. 2007, 9, 2281. (r) Blay, G.; Ferna´ndez, I.;
Pedro, J. R.; Vila, C. Org. Lett. 2007, 9, 2601. (s) Dong, H.-M.; Lu, H.-H.;
Lu, L.-Q.; Chen, C.-B.; Xiao, W.-J. AdV. Synth. Catal. 2007, 349, 1597. (t)
Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem.,
Int. Ed. 2008, 47, 593. (u) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem.,
Int. Ed. 2008, 47, 4016. (v) Tang, H.-Y.; Lu, A.-D.; Zhou, Z.-H.; Zhao,
G.-F.; He, L.-N.; Tang, C.-C. Eur. J. Org. Chem. 2008, 1406. (w) Hong,
L.; Wang, L.; Chen, C.; Zhang, B.; Wang, R. AdV. Synth. Catal. 2009,
351, 772.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3a
3b
3c
3d
3e
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
toluene none
toluene none
toluene none
toluene none
toluene none
toluene none
toluene PhCOOH
toluene Et3N
toluene 2,6-lutidine
toluene iPr2EtN
toluene Et3N-HCl
74
<10
<10
53
61
74
58
89
78
81
80
84
81
87
<10
78
73
70
n.d.d
n.d.d
31
43
83
56
88
69
87
71
89
THF
ether
MTBE
DMSO
Et3N
Et3N
Et3N
Et3N
91
96
n.d.d
81
CH2Cl2 Et3N
CH3CN Et3N
78
a Unless otherwise specified, the reaction was carried out with 1a (0.36
mmol) and 2a (0.30 mmol) in the presence of an organocatalyst 3 (0.06
mmol), additive (0.06 mmol), and solvent (1.0 mL) for 48 h. b Isolated
yield. c Determined by chiral HPLC on a Chiralpak OD-H column after
NaBH4 reduction. d Not determined.
(4) Selected successful examples: (a) Taylor, M. S.; Jacobsen, E. N.
J. Am. Chem. Soc. 2004, 126, 10558. (b) Seayad, J.; Seayad, A. M.; List,
B. J. Am. Chem. Soc. 2006, 128, 1086. (c) Raheem, I. T.; Thiara, P. S.;
Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (d)
Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438.
(5) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Scientific: London, 2000.
surveyed the organocatalysts11 3a-f for the reaction under
the same reaction conditions (Table 1, entries 1-6). The
results showed that 3f was an effective organocatalyst for
(6) (a) C¸ avdar, H.; Sarac¸ogˇlu, N. Tetrahedron 2005, 61, 2401. (b)
C¸ avdar, H.; Sarac¸ogˇlu, N. J. Org. Chem. 2006, 71, 7793.
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M. R. M.; Grondal, C.; Raabe, G. Nature (London) 2006, 441, 861. (e)
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(a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
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2178
Org. Lett., Vol. 11, No. 10, 2009