C O M M U N I C A T I O N S
Table 2. Cinchona Alkaloid-Catalyzed Friedel-Crafts Reactions of
3-indolyl methanamines 3, which should facilitate the asymmetric
synthesis of biologically interesting indole compounds. Its unique
applicability to alkyl imines, in particular, should open new possibil-
ities in the total synthesis of indole alkaloids and their analogues.
Acknowledgment. We are grateful for the generous financial
support from National Institutes of Health (GM-61591).
Supporting Information Available: Experimental procedures and
characterization of the products; X-ray analysis data for (-)-(S)-3Af.
This material is available free of charge via the Internet at http://
pubs.acs.org.
a
Indoles with Aryl Imines
References
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1) (a) Atta-ur-Rahman; Basha, A. Indole Alkaloids; Harwood Academic:
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2) For recent reviews of catalytic asymmetric Friedel-Crafts reactions, see:
(
a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
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3) For select examples of catalytic asymmetric Michael additions of indoles
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D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942.
a
Unless noted, reactions were carried out with 0.3 mmol of 2, 0.6 mmol
(
c) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J.
of 1 in 0.15 mL of EtOAc with 10 mol % of 7, and the results in parentheses
were obtained with 6 to give the opposite enantiomer; see Supporting
Information. Isolated yield. Determined by HPLC analysis. The absolute
Am. Chem. Soc. 2005, 127, 4154.
(
4) For Michael additions of indoles catalyzed by chiral organic catalysts,
b
c
d
see: (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
configuration was determined to be S; see Supporting Information.
1
24, 1172. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D.
e
Reaction at 70 °C.
W. C. J. Am. Chem. Soc. 2005, 127, 15051. (c) Austin, J. F.; Kim, S.-G.;
Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5482. (d) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A.
Angew. Chem., Int. Ed. 2005, 44, 6576.
Table 3. Enantioselective Friedel-Crafts Reactions of Indoles
with Alkyl Iminesa
(
5) For catalytic asymmetric additions of indoles to ethyl 3,3,3-trifluoropy-
ruvate, see: (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 2001, 66, 1009. (b) T o¨ r o¨ k, B.; Abid , M.; London,
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Angew. Chem., Int. Ed. 2005, 44, 3086.
(
6) For catalytic asymmetric Pictet-Spengler reactions, see: (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.
entry
2
T/
°
C
time/h
yield/%b
ee/%c
1
2
3
4
2i
2j
2k
2l
2m
50
50
50
50
48(48)
48(48)
12(12)
12(12)
10(10)
86(88)
85(84)
85(85)
53(55)
65(65)
94(92d)
94(94 )
95(96)
96(97)
96(96)
(7) (a) Jia, Y.; Xie, J.; Duan, H.; Wang, L.; Zhou, Q. Org. Lett. 2006, 8,
1621. (b) Johannsen, M. Chem. Commun. 1999, 2233.
(
8) (a) Esquivias, J.; Arrayas, R. M.; Carretero, J. C. Angew. Chem., Int. Ed.
2006, 45, 629. (b) Mi, X.-L.; Luo, S.-Z.; He, J.-Q.; Cheng, J.-P.
Tetrahedron Lett. 2004, 45, 4567. (c) Hao, J.; Taktak, S.; Aikawa, K.;
Yusa, Y.; Hatano, M.; Mikami, K. Synlett 2001, 1443.
e
5
-25
a
Unless noted, reactions were carried out with 2 (0.3 mmol) and 1A
(
9) For asymmetric C-C bond formations with 6′-OH cinchona alkaloids as
acid-base bifunctional catalysts, see: (a) Li, H.; Wang, Y.; Tang, L.;
Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (b) Li, H.; Wang, Y.; Tang,
L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem.,
Int. Ed. 2005, 44, 105. (c) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am.
Chem. Soc. 2005, 127, 8948. (d) Wu, F.; Li, H.; Hong, R.; Deng, L. Angew.
Chem., Int. Ed. 2006, 44, 947. (e) Li, H.; Wang, B.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 732. (f) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 3928.
(
0.6 mmol) in EtOAc (0.15 mL), and the results in parentheses were obtained
with 6 to give the opposite enantiomer; see Supporting Information; Iso-
lated yield. Determined by HPLC analysis. The absolute configuration
was determined to be R; see Supporting Information. Reaction in toluene.
b
c
d
e
Scheme 2. Conversion of N-Ts to N-Cbz 3-Indolyl Methanamine 8
(
10) For a pioneering study of 6′-OH cinchona alkaloid as a nucleophilic acid
bifunctional catalyst for asymmetric C-C bond formations, see: Iwabuchi,
Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999,
121, 10219.
(
11) For asymmetric C-C bond forming reactions with 9-thiourea cinchona
alkaloids as acid-base bifunctional catalysts, see: (a) Li, B.; Jiang, L.;
Liu, M.; Chen, Y.; Ding, L.; Wu, Y. Synlett 2005, 4, 603. (b) Vakulya,
B.; Varga, S.; Cs a´ mpai, A.; So o´ s, T. Org. Lett. 2005, 7, 1967. (c) Mccooey,
S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (d) Ye, J.;
Dixon, D. J.; Hynes, P. Chem. Commun. 2005, 35, 4481. (e) Tillman, A.
L.; Ye, J.; Dixon, D. J. Chem. Commun., 2006, 1191. (f) Song, J.; Wang,
Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
imines 2. Aryl imines of various electronic properties (2a-h) could
be readily converted into the desired adducts in 89-97% ee and
83-99% yield. The ability of catalysts 6 and 7 to afford high
enantioselectivity at elevated temperature allows the reaction of
even relatively electron-deficient indole 1C with an electron-rich
aryl imine 2d to proceed in useful enantioselectivity (entry 15, Table
(
12) For synthetic and mechanistic studies of cinchona alkaloids as a highly
efficient chiral general base catalyst, see: Hang, J.; Tian, S.-K.; Tang,
L.; Deng, L. J. Am. Chem. Soc. 2001, 123, 12696.
(13) For the first demonstration of a chiral thiourea as an efficient chiral organic
2). Most significantly, excellent enantioselectivity could be achieved
catalyst, see: (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998,
1
20, 4901. (b) For a mechanistic elucidation of chiral thioureas as highly
with various N-Ts alkyl imines, including those bearing no
R-substituent (2i-m, Table 3). Finally, the removal of the N-Ts in
efficient hydrogen-bond donors, see: Vachal, P.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 10012.
(14) For a review of chiral hydrogen-bonding catalysis, see: Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
3
could be readily accomplished in excellent yield without compro-
17
mising the integrity of the stereocenter (Scheme 2).
(
15) For a chiral organic acid-catalyzed aza-F-C reaction with 2-methoxy
In summary, we have developed the first highly enantioselective
Friedel-Crafts reaction of indoles with imines using a chiral organic
catalyst. With unprecedented scope for both indoles and imines
and utilizing practical chiral catalysts, this reaction provides a direct
and broadly useful catalytic enantioselective approach toward
furan, see: Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
2004, 126, 11804.
(
16) The reaction with the N-Boc imine afforded racemic product.
(17) Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987,
109, 6493.
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