An organocatalytic, δ-regioselective, and highly enantioselective nucleophilic substitution of cyclic Morita-Baylis-Hillman alcohols with indoles

Article abstract of DOI:10.1002/anie.201003131

The unexpected becomes possible: The first enantioselective, direct nucleophilic substitution of Morita-Baylis-Hillman alcohols has been developed through the use of iminium catalysis. Unexpected δ-substituted products were obtained with exclusive regiose

Full text of DOI:10.1002/anie.201003131

Communications
DOI: 10.1002/anie.201003131
Synthetic Methods
An Organocatalytic, d-Regioselective, and Highly Enantioselective
Nucleophilic Substitution of Cyclic Morita–Baylis–Hillman Alcohols
with Indoles**
Zhen Qiao, Zahid Shafiq, Li Liu,* Zheng-Bao Yu, Qi-Yu Zheng, Dong Wang, and Yong-
Jun Chen*
The direct substitution of alcohols with carbon and heter-
oatom nucleophiles without prederivatization is a significant
chemical transformation owing to its green, economical, and
environmentally benign properties where water is generated
as the only side product.[1] Recently, researchers in the area of
Scheme 1. The reaction of MBH alcohols with a nucleophile. EWG=
organocatalysis has made great progress in organic synthesis.
While multiform organocatalysts can be successfully used in
various addition reactions with carbonyl, imine, activated
alkene, and others compounds,[2] the enantioselective nucle-
ophilic substitution of alcohols catalyzed by organocatalysts is
rare.[3] Because positively charged intermediates would be
involved, it is a great challenge to exert enantioselective
control in the nucleophilic substitution of alcohols.[4,5]
Recently, the Morita–Baylis–Hillman (MBH) adducts
have attracted much attention in organic syntheses as
valuable synthons and starting materials owing to their easy
availability and versatile functionalities bearing allylic hy-
droxy and Michael acceptor units.[6] The reaction of MBH
alcohols with a nucleophile could proceed through either
conjugate addition,[7] or allylic substitution through dehydra-
tion to afford a- or g-substituted products (Scheme 1)[8]
Enantioselective reactions of MBH adducts with various O,
N, and C nucleophiles have been achieved to provide the
nucleophilic substitution products. These reactions have been
carried out through transition-metal catalysis with palla-
dium,[9] and organocatalysis with chiral phosphine[10a–b] and
tertiary amine compounds.[10c–h] However, none of these
asymmetric transformations directly uses MBH alcohols.
Furthermore, the hydroxy group is not a good leaving group
because free OH may participate in the asymmetric induc-
tion. Iminium activation is one of the most important methods
in organocatalysis.[11] Inspired by the efficient enantioselec-
electron-withdrawing group, Nu=nucleophile.
tive control of Michael acceptors by iminium activation, we
proposed that iminium activation might be used in the
nucleophilic substitution of MBH adducts derived from
enones. A suitable catalyst should also contain an acid
moiety to activate the hydroxy group of MBH alcohols.
Herein, we report the enantioselective reaction of cyclopent-
2-enone-derived MBH alcohols with indoles catalyzed by
chiral 9-amino-9-deoxyepiquinine in combination with an
acid. This approach yields an unexpected d-regioselective
product with good to excellent enantioselectivity.
Initially, the reaction of MBH alcohol 1a with indole 2a
was carried out in dichloromethane (Scheme 2). It was
reported that catalysts based on chiral primary amines could
Scheme 2. Nucleophilic substitution of MBH alcohol 1a with indole
2a through iminium catalysis.
[*] Z. Qiao, Dr. Z. Shafiq, Prof. L. Liu, Z.-B. Yu, Q.-Y. Zheng, D. Wang,
Y. J. Chen
Beijing National Laboratory for Molecular Science (BNLMS)
CAS Key Laboratory for Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
Fax: (+86)10-6255-4449
E-mail: lliu@iccas.ac.cn
be successfully used in iminium activation for a,b-unsaturated
ketones.[12] A chiral primary amine derived from cinchona
alkaloid was used. In the presence of 9-amino-9-deoxyepi-
quinine (C, 20 mol%; Scheme 3) in combination with tri-
fluoroacetic acid (TFA, 40 mol%) in CH2Cl2 at 308C, the
reaction provided g-allylic substitution product 3a in 18%
yield with 55% ee. To our surprise, besides g-product 3a the
d-allylic substitution product 4a was obtained in 50% yield
with promising enantioselectivity (66% ee; Table 1, entry 1).
In general, the nucleophilic substitution of allylic alcohol
affords the product with a or g regioselectivity (as shown in
yjchen@mail.iccas.ac.cn
[**] The research was financially supported by the National Natural
Science Foundation of China, Ministry of Science and Technology
(Nos. 2009ZX09501-006 and 2010CB833305) and the Chinese
Academy of Sciences.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003131.
7294
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7294 –7298

Angewandte
Chemie
yield of isolated d-product 4a could be raised up to 92% while
still maintaining a high enantioselecitivity (89% ee; Table 1,
entry 12).
An extensive screen of other chiral amine catalysts
showed that cinchonine-derived catalyst D gave a slightly
higher ee value of 90%, albeit with a lower yield of 4a
(Table 1, entry 7). Catalyst E, which has no double bond,
afforded 4a in low yield and with a low ee value (Table 1,
entry 8 versus 6). The opposite enantiomer of the d product
was provided with a very low ee value by employing
quinidine-derived primary amine catalyst F under the same
reaction conditions (Table 1, entry 9). It was found that the
TFA salt of (1R, 2R)-1,2-diphenylethane-1,2-diamine B was
not able to promote the reaction. Proline (A) did not catalyze
the reaction of 1a with 2a either. The acid additives had an
obvious effect on the reactivity of the catalyst and enantio-
selectivity of the nucleophilic substitution. TFA exhibited
specific reactivity for the reaction. If TSA was used as an acid
additive, the reaction provided only 18% of 4a with 63% ee
(Table 1, entry 11). In the absence of any Brønsted acid as a
co-catalyst, no product was observed and starting materials
were recovered.
Optimal results for d selectivity with high enantioselec-
tivity were eventually obtained in the solvent mixture
containing equal amounts of iPrOAc and THF in the presence
of 20 mol% of 9-amino-9-deoxyepiquinine (C) in combina-
tion with TFA (40 mol%), which allowed the reaction to
proceed smoothly within 5 days at 308C. Under the optimal
reaction conditions we investigated the scope of d products
with different combinations of indoles and a variety of cyclic
MBH alcohols. The results are summarized in Table 2. In each
case, the corresponding d products were obtained in good to
excellent yields as single regioisomers. In general, for indole
2a, variation in the MBH alcohols was well tolerated. For
para-substituted MBH alcohols (1b–1g; Table 2, entries 2–7),
regardless of having electron-donating or electron-withdraw-
ing groups, gave good to excellent ee values (83–93%) for
d products. For meta-substituted MBH alcohols (1h–1k;
Table 2, entries 8–11), high enantioselectivities (88–92% ee)
and moderate to good yields (71–86%) were obtained.
However, no reaction was observed with cyclohexenone-
derived MBH alcohols and indole 2a. The MBH alcohol with
an alkyl substituent instead of an aryl one did not afford the
product either, which indicated that the benzyl alcohol
structure was necessary for the reaction of MBH alcohols
with indoles. For indole derivatives, 5-bromoindole (2e), 5-
methoxylindole (2 f), 5-methylindole (2g), and 6-methylin-
dole (2h) gave high yields with good enantioselectivities
(Table 2, entries 15–18). Exceptionally, the reaction of 2-
methylindole (2b) with 1a provided a mixture of d and
g product (d/g = 65:35) with a high enantioselectivity of
d product 4b (93% ee; Table 2, entry 12). Whereas 2-phenyl-
indole (2d) still exhibited exclusive d regioselectivity with a
lower enantioselectivity (Table 2, entry 14). The poor regio-
selectivity of 2-methylindole (2b) could be ascribed to its high
nucleophilic character compared to simple indole.[13] N-
Methylindole (2c) was less reactive under the reaction
conditions. By increasing the reaction temperature to 408C,
2c afforded the d-product 4m in 70% yield with only 47% ee.
Scheme 3. Structures of the chiral amine catalysts.
Table 1: Selected screening studies of organocatalytic nucleophilic
substitution of cyclic MBH alcohol 1a with indole 2a.[a]
Entry
Catalyst[b]
Solvent
Yield of
ee of
4a [%][c]
4a [%][d]
1
2
3
4
5
6
7
8
C
C
C
C
C
C
D
E
CH2Cl2
Et2O
THF
EtOAc
50
59
28
70
77
45
35
35
35
70
18
92
66
52
85
49
64
89
90
80
-47
75
63
89
iPrOAc
iPrOAc/THF (1:1)
iPrOAc/THF (1:1)
iPrOAc/THF (1:1)
iPrOAc/THF (1:1)
iPrOAc/THF (1:1)
iPrOAc/THF (1:1)
iPrOAc/THF (1:1)
9
F
10[e]
11
12[g]
C
C[f]
C
[a] Reaction conditions: unless otherwise noted reactions were per-
formed with 0.2 mmol of 1a, 0.2 mmol of 2a, 0.04 mmol of catalyst C,
and 0.08 mmol of TFA in 2 mL of solvent at 308C for 3 days. [b] With TFA
as an acid additive. [c] Yield of isolated product. [d] Determined by HPLC
on a chiral stationary phase. [e] At 508C. [f] TSA was used as an acid
additive. [g] 0.4 mmol of 1a; the reaction was carried out over 5 days and
the yield is based on 2a. THF=tetrahydrofuran, TSA=p-toluenesulfonic
acid.
Scheme 1), while d selectivity is unusual and unexpected. The
reaction in Et2O provided 4a in 59% yield and 52% ee, but no
g product was detected (Table 1, entry 2). The examination of
solvent effects revealed that in THF the reaction afforded the
d-product 4a with good enantioselectivity (85% ee) but low
yield and no g product was observed (Table 1, entry 3);
whereas ethyl acetate significantly facilitated the reaction
and produced the d-product 4a in higher yield but with a
relatively lower ee value (Table 1, entry 4). In isopropyl
acetate, the reaction provided 4a in 77% yield and 64% ee
(Table 1, entry 5). Other solvents such as toluene, acetonitrile,
methanol, and N,N-dimethylformamide were also tested;
they were less effective for the reaction of 1a with 2a (see the
Supporting Information). Based on these experimental
results, a solvent mixture of iPrOAc/THF (1:1) was employed
as the reaction medium. The enantioselectivity of the d-
product 4a was increased up to 89% ee, but the yield still
remained low (compare Table 1, entrie 6 versus 3 and 5).
Although the yield could be increased to 70% by raising the
reaction temperature to 508C, unfortunately the ee value
decreased to 75% (Table 1, entry 10). To reach both high
yield and enantioselectivity, we changed the ratio of 1a/2a
from 1:1 to 2:1, and prolonged the reaction time to 5 days, the
Angew. Chem. Int. Ed. 2010, 49, 7294 –7298
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7295

Communications
Table 2: Reaction of MBH alcohols 1 with indoles 2 in the presence of
catalyst C and TFA.[a]
Figure 1. ORTEP plot of enantiomerically pure 4d drawn with ellip-
soids at 30% probability.
Entry
Alcohol
1
R
Indole
2
Prod.
4
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
H
p-F
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2 f
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
92
87
85
88
86
81
88
76
86
80
71
83[d]
70
85
87
90
68
72
89
91
85
93
83
90
84
90
88
92
90
93
47
57
79
86
83
80
activated by forming the iminium ion 5 with the chiral
primary amine catalyst C. A Brønsted acid such as TFA is
induced the formation of the iminium ion. The activated OH
group of the MBH alcohol undergoes a dehydration reaction
to form the intermediate 6 through hydrogen bonding assisted
by the protonated tertiary amine moiety in catalyst C. ESI-
MS analyses showed the existence of intermediates 5 (m/
z 494, without TFA) and 6 (m/z 476, without TFA) during the
reaction of MBH 1a with 20 mol% of catalyst C and co-
catalyst TFA (40 mol%) at 308C for 1 day, but in the absence
of indole 2a.[16] Then indole 2a attacks the butadiene unit of
intermediate 6 from the Re face to form (S)-d-product 4.
Although the reaction of cyclic MBH alcohols 1 with indoles 2
provided substitution products, the transformations could be
described as a conjugate-type addition when considering the
important unsaturated compound involved as reaction inter-
mediate.[3b,c] To the best of our knowledge, there are only a
few reports on the asymmetric reaction of cycloenones with
indoles, the enantioselectivities obtained here are the best
results so far.[17] Nevertheless, the mechanism of the reaction,
especially for d regioselectivity still needs more detail inves-
tigation.
p-Cl
p-Br
p-Me
p-OMe
p-Ph
m-OMe
m-F
m-Cl
m-Br
H
H
H
H
H
H
H
9
10
11
12
13[e]
14[e]
15
16
17
18
1j
1k
1a
1a
1a
1a
1a
1a
1a
2g
2h
[a] Reaction conditions: Unless otherwise noted reactions were per-
formed with 0.4 mmol of 1, 0.2 mmol of 2, 0.04 mmol of catalyst C, and
0.08 mmol of TFA in 2 mL of solvent at 308C. [b] Yield of isolated
product. [c] Determined by HPLC on a chiral stationary phase. [d] A
mixture of d and g products was obtained (d/g=65:35). [e] At 408C.
The remarkable decrease in ee value indicated that the NH
group in the indole framework should play a significant role in
enantiocontrol (compare Table 2, entry 1 versus
13).
The structure of the product 4d was con-
firmed by X-ray crystal structure analysis, which
demonstrated the d regioselectivity of the reac-
tion and deduced the absolute configuration of
the newly creating chiral centre of 4d to be S
(Figure 1).[14] Although the allylic-substituted g-
product 3 could rearrange to the a-substitution
product in the presence of an acid,[15] there was
no a product observed in the product mixture.
A control experiment showed that under the
reaction conditions, it was impossible for g-
product 3a to be directly converted into d-
product 4a. Meanwhile, our results indicated
À
that the Brønsted acid co-catalyst and the N H
group in the indole substrates were necessary
for high enantioselectivity in the nucleophilic
substitution of MBH alcohol catalyzed by the
chiral primary amine. Based on the above
experimental results, a plausible mechanism is
proposed in Scheme 4. MBH alcohol 1a was Scheme 4. Plausible mechanism for the enantioselective formation of d-product 4.
7296 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7294 –7298

Angewandte
Chemie
[5] Selected examples for the Friedel–Craft reactions of chiral
In conclusion, we have presented the first direct enantio-
selective nucleophilic substitution of cyclic Morita–Baylis–
Hillman alcohols with indoles under organocatalysis by using
a chiral primary amine as the catalyst in combination with a
Brønsted acid as the co-catalyst. Unexpected d products were
obtained with exclusive regioselectivity and high enantiose-
lectivity (up to 93% ee). The reaction can be considered a
new type of organocatalytic enantioselective nucleophilic
substitution through iminium-ion-assisted dehydration of
allylic alcohol and addition of a carbon nucleophile with an
unsaturated unit. Investigations of the mechanism and scope
of the present reaction with other nucleophiles are in
progress.
alcohols: a) D. Stadler, T. Bach, Angew. Chem. 2008, 120, 7668;
Angew. Chem. Int. Ed. 2008, 47, 7557; b) F. Mꢁhlthau, D. Stadler,
A. Goeppert, G. A. Olah, G. K. S. Prakash, T. Bach, J. Am.
Chem. Soc. 2006, 128, 9668.
[6] a) D. Basavaiah, A. J. Rao, T. Satyanarayana, Chem. Rev. 2003,
103, 811; b) D. Basavaiah, A. J. Rao, R. J. Reddy, Chem. Soc.
Rev. 2007, 36, 1581; c) G. Masson, C. Housseman, J. Zhu, Angew.
Chem. 2007, 119, 4698; Angew. Chem. Int. Ed. 2007, 46, 4614;
d) V. Singh, S. Batra, Tetrahedron 2008, 64, 4511.
[7] Selected examples for the conjugate addition of MBH alcohols:
a) L. A. Paquette, R. R. Rothhaar, M. Isaac, L. M. Rogers, R. D.
Rogers, J. Org. Chem. 1998, 63, 5463; b) W. Wang, M. Yu,
Tetrahedron Lett. 2004, 45, 7141; c) S. Nag, G. P. Yadav, P. R.
Maulik, S. Batra, Synthesis 2007, 911; d) R. Pathak, S. Batra,
Tetrahedron 2007, 63, 9448; e) S. Nag, R. Pathak, M. Kumar,
P. K. Shukla, S. Batra, Bioorg. Med. Chem. Lett. 2006, 16, 3824.
[8] Selected examples for a-allylic substitution of MBH alcohols:
a) K. Y. Lee, H. S. Lee, J. N. Kim, Bull. Korean Chem. Soc. 2008,
29. 1099; b) X. Zhang, W. Rao, S. P. W. H. Chan, Org. Biomol.
Chem. 2009, 7, 4186; c) C. Wu, L. Liu, D. Wang, Y. J. Chen,
Tetrahedron Lett. 2009, 50, 3786; selected examples for g-allylic
substitution of MBH alcohols: d) L. Navarre, S. Darses, J. P.
Genet, Chem. Commun. 2004, 1108; e) M. L. Kantam, K. B.
Shiva Kumar, B. Sreedhar, J. Org. Chem. 2008, 73, 320; f) L. R.
Reddy, B. Hu, M. Prashad, K. Prasad, Angew. Chem. 2009, 121,
178; Angew. Chem. Int. Ed. 2009, 48, 172.
Experimental Section
General Procedure: Catalyst C (13 mg, 0.04 mmol) was added to a
solution of Morita–Baylis–Hillman alcohol 1 (0.4 mmol) and indole 2
(0.2 mmol) in 2 mL of iPrOAc/THF (1:1), followed by stirring for
5 min. Then TFA (6 mL, 0.08 mmol) was added and the resulting
reaction mixture was heated at 308C till the reaction was complete (as
evident by TLC; reaction times are given in the Supporting
Information. The crude reaction mixture was then purified by
column chromatography on silica gel (eluent: petroleum ether/
EtOAc = 4:1) to afford the desired d-product 4.
[9] a) B. M. Trost, O. R. Thiel, H. C. Tsui, J. Am. Chem. Soc. 2002,
124, 11616; b) B. M. Trost, O. R. Thiel, H. C. Tsui, J. Am. Chem.
Soc. 2003, 125, 13155; c) B. M. Trost, M. R. Machacek, H. C.
Tsui, J. Am. Chem. Soc. 2005, 127, 7014; d) B. M. Trost, M. K.
Brennan, Org. Lett. 2007, 9, 3961; e) T. Nemoto, T. Fukuyama, E.
Yamamoto, S. Tamura, T. Fukuda, T. Matsumoto, Y. Akimoto, Y.
Hamada, Org. Lett. 2007, 9, 927; f) C. G. Chen, X. L. Hou, L. Pu,
Org. Lett. 2009, 11, 2073.
[10] a) C. W. Cho, M. J. Krische, Angew. Chem. 2004, 116, 6857;
Angew. Chem. Int. Ed. 2004, 43, 6689; b) Y. Q. Jiang, Y. L. Shi,
M. Shi, J. Am. Chem. Soc. 2008, 130, 7202; c) D. J. V. C.
van Steenis, T. Marcelli, M. Lutz, A. L. Spek, J. H. van Maar-
seveen, H. Hiemstra, Adv. Synth. Catal. 2007, 349, 281; d) H. L.
Cui, X. Feng, J. Peng, J. Lei, K. Jiang, Y. C. Chen, Angew. Chem.
2009, 121, 5847; Angew. Chem. Int. Ed. 2009, 48, 5737; e) H. L.
Cui, J. Peng, X. Feng, W. Du, K. Jiang, Y. C. Chen, Chem. Eur. J.
2009, 15, 1574; f) K. Jiang, J. Peng, H. L. Cui, Y. C. Chen, Chem.
Commun. 2009, 3955; g) J. N. Kim, H. J. Lee, J. H. Gong,
Tetrahedron Lett. 2002, 43, 9141; h) Y. S. Du, X. L. Han, X. Y.
Lu, Tetrahedron Lett. 2004, 45, 4967; i) P. V. Ramachandran, S.
Madhi, L. Bland-Berry, M. V. R. Reddy, M. J. OꢂDonnell, J. Am.
Chem. Soc. 2005, 127, 13450.
Received: May 24, 2010
Revised: July 9, 2010
Published online: August 26, 2010
Keywords: indoles · Morita–Baylis–Hillman alcohols ·
.
nucleophilic substitution · organocatalysis · d regioselectivity
[1] a) M. Bandini, M. Tragni, Org. Biomol. Chem. 2009, 7, 1501;
b) N. Ljungdahl, N. Kann, Angew. Chem. 2009, 121, 652; Angew.
Chem. Int. Ed. 2009, 48, 642; c) C.-J. Li; B. M. Trost, Proc. Natl.
Acad. Sci. USA 2008, 105, 13197; B. M. Trost, Proc. Natl. Acad.
Sci. USA 2008, 105, 13197; d) J. A. McCubbin, H. Hosseini, O. V.
Krokhin, J. Org. Chem. 2010, 75, 959.
[2] For selected reviews on organocatalysis, see: a) A. Berkessel, H.
Grꢀger, Asymmetric Organocatalysis: From Biomimetic Con-
cepts to Applications in Asymmetric Synthesis, Wiley-VCH,
Weinheim, 2004; b) B. List, Chem. Commun. 2006, 819; c) M. S.
Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550; Angew.
Chem. Int. Ed. 2006, 45, 1520; d) D. W. C. MacMillan, Nature
2008, 455, 304; e) S. Bertelsen, K. A. Jørgensen, Chem. Soc. Rev.
2009, 38, 2178.
[3] a) P. G. Cozzi, F. Benfatti, L. Zoli, Angew. Chem. 2009, 121,
1339; Angew. Chem. Int. Ed. 2009, 48, 1313; b) R. R. Shaikh, A.
Mazzanti, M. Petrini, G. Bartoli, P. Melchiorre, Angew. Chem.
2008, 120, 8835; Angew. Chem. Int. Ed. 2008, 47, 8707; c) Q. X.
Guo, Y. G. Peng, J. W. Zhang, L. Song, Z. Feng, L. Z. Gong, Org.
Lett. 2009, 11, 4620; d) D. Enders, A. A. Narine, F. Toulgoat, T.
Bisschops, Angew. Chem. 2008, 120, 5744; Angew. Chem. Int. Ed.
2008, 47, 5661.
[4] Selected examples for metal-catalyzed enantioselective substi-
tution of alcohols: a) M. Bandini, A. Eichholzer, Angew. Chem.
2009, 121, 9697; Angew. Chem. Int. Ed. 2009, 48, 9533; b) B. M.
Trost, J. Quancard, J. Am. Chem. Soc. 2006, 128, 6314; c) Y.
Yamashita, A. Gopalarathnam, J. F. Hartwig, J. Am. Chem. Soc.
2007, 129, 7508; d) H. Matsuzawa, Y. Miyake, Y. Nishibayashi,
Angew. Chem. 2007, 119, 6608; Angew. Chem. Int. Ed. 2007, 46,
6488.
[11] a) A. Erkkilꢃ, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107,
5416; b) P. Melchiorre, Angew. Chem. 2008, 120, 6232; Angew.
Chem. Int. Ed. 2008, 47, 6138.
[12] For a review on modified cinchona alkaloid, see: a) S. K. Tian, Y.
Chen, J. Hang, L. Tang, P. McDaid, L. Deng, Acc. Chem. Res.
2004, 37, 621; for selected asymmetric reactions catalyzed by
cinchona alkaloid C, see: b) J. W. Xie, W. Chen, R. Li, M. Zeng,
W. Du, L. Yue, Y. C. Chen, Y. Wu, J. Zhu, J. G. Deng, Angew.
Chem. 2007, 119, 393; Angew. Chem. Int. Ed. 2007, 46, 389;
c) J. W. Xie, L. Yue, W. Chen, W. Du, J. Zhu, J. G. Deng, Y.-C.
Chen, Org. Lett. 2007, 9, 413; d) W. Chen, W. Du, Y. Z. Duan, Y.
Wu, S. Y. Yang, Y. C. Chen, Angew. Chem. 2007, 119, 7811;
Angew. Chem. Int. Ed. 2007, 46, 7667; e) X. F. Li, L. F. C, Cun. X.
Lian, L. Zhong, Y. C. Chen, J. Liao, J. Zhu, J. G. Deng, Org.
Biomol. Chem. 2008, 6, 349; f) X. Wang, C. M. Reisinger, B. List,
J. Am. Chem. Soc. 2008, 130, 6070; g) C. M. Reisinger, X. Wang,
B. List, Angew. Chem. 2008, 120, 8232; Angew. Chem. Int. Ed.
2008, 47, 8112; h) X. Lu, Y. Liu, B. Sun, B. Cindric, L. Deng, J.
Angew. Chem. Int. Ed. 2010, 49, 7294 –7298
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7297

Communications
Am. Chem. Soc. 2008, 130, 8134; i) X. Lu, L. Deng, Angew.
Chem. 2008, 120, 7824; Angew. Chem. Int. Ed. 2008, 47, 7710;
j) R. P. Singh, K. Bartelson, Y. Wang, H. Su, X. J. Lu, L. Deng, J.
[16] See the Supporting Information. ESI-MS analyses for studies on
the mechanism of iminium catalysis, see: a) Z. J. Wu, S. W. Luo,
J. W. Xie, X. Y. Xu, D. M. Fang, G. L. Zhang, J. Am. Soc. Mass
Spectrom. 2007, 18, 2074; b) W. Schrader, P. P. Handayani, J.
Zhou, B. List, Angew. Chem. 2009, 121, 1491; Angew. Chem. Int.
Ed. 2009, 48, 1463.
[17] For the asymmetric Friedel–Crafts reaction of indoles with
cycloenones, see: a) G. Bartoli, M. Bosco, A. Carlone, F.
Pesciaioli, L. Sambri, P. Melchiorre, Org. Lett. 2007, 9, 1403;
b) W. Chen, W. Du, L. Yue, R. Li, Y. Wu, L.-S. Ding, Y. C. Chen,
Org. Biomol. Chem. 2007, 5, 816; c) H. Y. Tang, A. D. Lu, Z. H.
Zhou, G. F. Zhao, L. N. He, C. C. Tang, Eur. J. Org. Chem. 2008,
1406; for other selected examples for the addition of aromatic
compounds to cycloenones, see: d) K. Manabe, N. Aoyama, S.
Kobayasgi, Adv. Synth. Catal. 2001, 343, 174; e) H. Firouzabadi,
N. Iranpoor, A. A. Jafari, J. Mol. Catal. A 2006, 244, 168; f) W. D.
Li, X. W. Wang, Org. Lett. 2007, 9, 1211; g) M. A. Grundl, A.
Kaster, E. D. Beaulieu, D. Trauner, Org. Lett. 2006, 8, 5429.
Am. Chem. Soc. 2008, 130
, 2422; k) F. Pesciaioli, F. D.
Vincentiis, P. Galzerano, G. Bencivenni, G. Bartoli, A. Mazzanti,
P. Melchiorre, Angew. Chem. 2008, 120, 8831; Angew. Chem. Int.
Ed. 2008, 47, 8703; l) M. W. Paix¼o, N. Holub, C. Vila, M.
Nielsen, K. A. Jørgensen, Angew. Chem. 2009, 121, 7474; Angew.
Chem. Int. Ed. 2009, 48, 7338.
[13] a) S. Lakhdar, M. Westermaier, F. Terrier, R. Goumont, T.
Boubaker, A. R. Ofial, H. Mayr, J. Org. Chem. 2006, 71, 9088;
b) M. Westermaier, H. Mayr, Chem. Eur. J. 2008, 14, 1638.
[14] CCDC 775440 (4d) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[15] a) Z. Shafiq, Z. Qiao, L. Liu, Q.-Y. Zheng, D. Wang, Y. J. Chen,
Synlett 2009, 2965; b) Y. L. Liu, L. Liu, D. Wang, Y. J. Chen,
Tetrahedron 2009, 65, 3473; c) Z. Shafiq, L. Liu, Z. Liu, D. Wang,
Y. J. Chen, Org. Lett. 2007, 9, 2525.
7298 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7294 –7298