Lewis acid catalyzed intramolecular direct ene reaction of indoles

Article abstract of DOI:10.1002/anie.201005296

How to fuse heterocycles: The direct enamine-imine isomerization of indoles and subsequent intramolecular imino-ene has been observed under Lewis acid catalysis. This unique reaction occurred for indoles that contain a tethered olefin functionality, and l

Full text of DOI:10.1002/anie.201005296

Angewandte
Chemie
DOI: 10.1002/anie.201005296
Indole Chemistry
Lewis Acid Catalyzed Intramolecular Direct Ene Reaction of Indoles**
Bo Han, You-Cai Xiao, Yuan Yao, and Ying-Chun Chen*
Synthetic modifications on indole skeletons have provoked
increasing interest because the related heterocyclic systems
are present in numerous alkaloid products, pharmaceuticals,
and agrochemicals.[1] Indole heterocycles, which basically
consist of a benzo[b]pyrrole framework, are considered
electron-rich compounds that exhibit substantial reactivity,
especially at the C3-position.[2] Not surprisingly, the majority
of studies in this field have been focused on the Friedel–Crafts
reaction of indoles with a range of electrophiles.[3] Indeed,
even C3-substituted indoles demonstrate high nucleophilic-
ity;[4] C3-selective reactions have been realized by means of
electrophilic compounds and subsequent tandem addition to
the newly formed imine group. This processes lead to the
construction of fused indolines having C3-quaternary stereo-
centers. In addition, C3-substituted indoles also show reac-
tivity at the C2-position,[5] and the most well-established
reaction is the Pictet–Spengler reaction.[6] On the other hand,
the heteroaromatic indolyl structure contains an enamine
functionality, which is likely to isomerize to an electrophilic
imine (or iminium) group through proton transfer under the
proper reaction conditions (such as by the activation of
Brønsted or Lewis acids).[7] As a consequence, a chemo-
selective, direct nucleophilic C2-functionalization pathway
could be developed for the synthesis of indoline compounds,
as proposed in Equation (1; Nu = nucleophile). Nevertheless,
such a synthetic approach has not yet been addressed.
quite successful in the direct asymmetric alkylation reaction
of 3-indolylmethanols[10] and g,g-disubstituted a,b-unsatu-
rated aldehydes. As shown in Scheme 1, under the catalysis of
Scheme 1. Organocatalytic asymmetric alkylation and subsequent dis-
covery of Lewis acid catalyzed intramolecular imino-ene reaction of
indole. TMS=trimethylsilyl.
Recently, our research group[8] has reported an a-regio-
and stereoselective Michael addition of g,g-disubstituted a,b-
unsaturated aldehydes to nitroolefins through dienamine
catalysis.[9] We further found that this activation mode was
a,a-diphenylprolinol O-TMS ether 1 (5 mol%) and AcOH
(10 mol%), the exclusive a-regioselective alkylation product
4a could be smoothly isolated in a diastereomerically pure
form from 3-indolylphenylmethanol 2a and 4-methyl-2-
pentenal 3a after reduction with NaBH4, and the reaction
also gave excellent enantioselectivity.[11] In an attempt to
conduct Friedel–Crafts annulation of 4a under the catalysis of
a Lewis acid such as AlCl3 (1.0 equiv), we discovered that an
unexpected and highly substituted cyclopentyl[b]indoline[12]
compound 5a could be cleanly obtained with complete
diastereocontrol within 30 minutes,[13,14] while the Friedel–
Crafts product A was not detected (Scheme 1).[15] We
recognized that an unprecedented and unique intramolecular
imino-ene reaction of the indole heterocycle had occurred—
probably through AlCl3-promoted enamine–imine isomer-
ization and a subsequent ene cyclization (Scheme 1; inter-
mediate B). The efficient participation of the inactivated
imine in the relatively less explored imino-ene-type reaction
was an unusual result.[16]
[*] Dr. B. Han, Y.-C. Xiao, Y. Yao, Prof. Dr. Y.-C. Chen
Key laboratory of Drug Targeting and Drug Delivery System
of the Education Ministry, Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (China)
Fax: (+86)288-550-2609
E-mail: ycchenhuaxi@yahoo.com.cn
Prof. Dr. Y.-C. Chen
To gain some insight into the reaction pathway, we
conducted isotopic labeling experiments. Compound 4a was
treated with NaH and subsequently quenched with D2O and
afforded deuterated product 4a’ (Scheme 2). Then, the AlCl3-
catalzyed imino-ene reaction of 4a’ was performed. Pleas-
ingly, significant deuteration (61%) was observed at the 3-
position of indoline 5a’; this result verified that enamine–
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041(China)
[**] We are grateful for financial support from the NSFC (20972101 and
21021001) and the National Basic Research Program of China
(973 Program; grant no. 2010CB833300).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005296.
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Communications
the ene reaction selectively occurred at the trisubstituted
alkene group (product 5i). Interestingly, the N-methyl indole
precursor could be smoothly converted into the imino-ene
product in a similar way, as shown in Scheme 3, product 5n.
Because a number of catalytic asymmetric reactions for
the synthesis of C3-functionalized chiral indole derivatives
have been well-established over the past years,[3] more
enantioenriched indole precursors that might be utilized in
the Lewis acid catalyzed imino-ene reaction could be
accessed. For example, the asymmetric C3-selective Friedel–
Crafts reaction of indole with benzylideneacetone was easily
conducted to give chiral intermediate 6,[17] which could be
transformed into alkene precursors through the traditional
Wittig reaction. To our delight, the imino-ene reaction of
alkene 7a with 1,1-disubstituted pattern proceeded smoothly
under AlCl3 catalysis, thus affording cyclohexyl[b]indoline
(8a), bearing an exo-methylene group, in outstanding diaste-
reoselectivity (Scheme 4). Although an E/Z mixture was
Scheme 2. Isotopic labeling experiments.
imine isomerization should occur through proton transfer in
the presence of AlCl3.[7]
Thus, we explored an array of 3-indolylmethanols 2 in the
reaction with g,g-disubstituted a,b-unsaturated aldehydes 3
under the catalysis of chiral secondary amine 1, which
successfully provided different types of olefinic indole
precursors 4, generally with excellent enantioselectivities
(see the Supporting Information).[11] Notably, the 3-indolyl-
methanols 2, bearing an alkyl substituent at the benzylic
position, could be smoothly utilized in this dienamine-
catalyzed alkylation procedure—the use of these substrates
has not been established under other catalytic conditions.[10]
As summarized in Scheme 3, all the indole substrates 4a–4m
were efficiently converted into the desired cyclopentyl[b]in-
doline products 5a–5m with retained configuration and in
moderate to high yields of the corresponding isolated
products, usually in less than half an hour. In general, the
tested reactions led to the formation of the single diastereo-
mer. It was noteworthy that an allylic group at the benzylic
position did not affect the expected annulation reaction, and
Scheme 4. Synthesis of enantioenriched cyclohexyl[b]indolines.
obtained for alkene 7b, it was pleasing to observe that the
E isomer could be preferably and chemoselectively converted
into the imino-ene product 8b in less than 10 minutes, and
with remarkable diastereocontrol. In contrast, the Z isomer
remained almost unchanged, while the transformation could
be continued to deliver Friedel–Crafts-type product 9 after a
longer reaction time, also with complete diastereoselectivity.
As shown in Scheme 5, the indoline 5a could be readily
and chemoselectively oxidized into indole derivative 10 under
mild conditions, even without affecting the primary alcohol
group. Thus, both fused indolines and indoles could be
efficiently accessed.
In conclusion, we have discovered a highly efficient,
direct, and diastereoselective intramolecular imino-ene reac-
tion of indoles bearing a tethered olefinic functionality. This
novel reaction proceeded through a key Lewis acid catalyzed
enamine–imine isomerization, which followed the Lewis acid
mediated ene cyclization. The olefinic indole precursors could
Scheme 3. Substrate scope in the synthesis of cyclopentyl[b]indolines
through intramolecular imino-ene reactions.
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[7] a) R. L. Hinman, E. R. Shull, J. Org. Chem. 1961, 26, 2339; b) C.-
B. Chen, X.-F. Wang, Y.- J. Cao, H.-G. Cheng, W.-J. Xiao, J. Org.
Chem. 2009, 74, 3532; c) D.-S. Wang, Q.-A. Chen, W. Li, C.-B.
Yu, Y.-G. Zhou, X. Zhang, J. Am. Chem. Soc. 2010, 132, 8909.
[8] B. Han, Y.-C. Xiao, Z.-Q. He, Y.-C. Chen, Org. Lett. 2009, 11,
4660.
[9] a) S. Bertelsen, M. Marigo, S. Brandes, P. Dinꢀr, K. A. Jørgen-
sen, J. Am. Chem. Soc. 2006, 128, 12973; b) R. M. de Figueiredo,
R. Frꢁhlich, M. Christmann, Angew. Chem. 2008, 120, 1472;
Angew. Chem. Int. Ed. 2008, 47, 1450; c) B. Han, Z.-Q. He, J.-L.
Li, R. Li, K. Jiang, T.-Y. Liu, Y.-C. Chen, Angew. Chem. 2009,
121, 5582; Angew. Chem. Int. Ed. 2009, 48, 5474; d) E. Marquꢀs-
Lꢂpez, R. P. Herrera, T. Marks, W. C. Jacobs, D. Kꢁnning, R. M.
de Figueiredo, M. Christmann, Org. Lett. 2009, 11, 4116; e) J.-L.
Li, T.-R. Kang, S.- L. Zhou, R. Li, L. Wu, Y.-C. Chen, Angew.
Chem. 2010, 122, 6562; Angew. Chem. Int. Ed. 2010, 49, 6418;
f) G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli, P.
Melchiorre, Proc. Natl. Acad. Sci. USA 2010, DOI: 10.1073/
pnas.1001150107.
[10] a) R. R. Shaikh, A. Mazzanti, M. Petrini, G. Bartoli, P. Mel-
chiorre, Angew. Chem. 2008, 120, 8835; Angew. Chem. Int. Ed.
2008, 47, 8707; b) P. G. Cozzi, F. Benfatti, L. Zoli, Angew. Chem.
2009, 121, 1339; Angew. Chem. Int. Ed. 2009, 48, 1313; c) Q.-X.
Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng, L.-Z. Gong,
Org. Lett. 2009, 11, 4620; d) F.-L. Sun, X.-J. Zheng, Q. Gu, Q.-L.
He, S.-L. You, Eur. J. Org. Chem. 2010, 47; e) F. Benfatti, E.
Benedetto, P. G. Cozzi, Chem. Asian J. 2010, 5, 2047.
[11] For more information, see the Supporting Information.
[12] a) B. Bajtos, M. Yu, H. Zhao, B. L. Pagenkopf, J. Am. Chem. Soc.
2007, 129, 9631; b) G. Zhang, X. Huang, G. Li, L. Zhang, J. Am.
Chem. Soc. 2008, 130, 1814; c) J. Barluenga, E. Tudela, A.
Ballesteros, M. Tomꢃs, J. Am. Chem. Soc. 2009, 131, 2096;
d) E. P. Balskus, C. T. Walsh, J. Am. Chem. Soc. 2009, 131, 14648;
e) Y. Lian, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132, 440;
f) R. R. Gataullin, Russ. J. Org. Chem. 2009, 45, 321.
[13] Sc(OTf)3 also could catalyze the imino-ene reaction (0.5 hours,
62% yield), but other Lewis acids tested (Yt(OTf)3, La(OTf)3,
Zn(OTf)2 and BF3· OEt2, etc.) exhibited no catalytic activity.
[14] The absolute structure of 5a was confirmed by X-ray crystallo-
graphic analysis after derivatization (S-10-camphorsulfonate).
CCDC 793950 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.
Scheme 5. Synthesis of fused indoles. PCC=pyridinium chlorochro-
mate.
be readily prepared by means of well-established asymmetric
catalytic procedures. A range of highly enantioenriched and
versatile cyclopentyl[b]indolines and cyclohexyl[b]indolines
has been prepared with remarkable efficiency. We hope that
the Lewis acid catalyzed enamine–imine isomerization of
indoles will be helpful for the development of a direct
nucleophilic C2-selective functionalization pathway for
indole chemistry. Studies aimed at further exploration of the
synthetic potential of this reaction are currently under way.
Received: August 25, 2010
Published online: November 16, 2010
Keywords: alkylation · dienamine catalysis · imino-ene reactions ·
.
indoles · Lewis acids
[1] For reviews, see: a) G. R. Humphrey, J. T. Kuethe, Chem. Rev.
2006, 106, 2875; b) M. Bandini, A. Eichholzer, Angew. Chem.
2009, 121, 9786; Angew. Chem. Int. Ed. 2009, 48, 9608; c) A. J.
Kochanowska-Karamyan, M. T. Hamann, Chem. Rev. 2010, 110,
4489.
[2] S. Lakhdar, M. Westermaier, F. Terrier, R. Goumont, T.
Boubaker, A. R. Ofial, H. Mayr, J. Org. Chem. 2006, 71, 9088.
[3] a) T. B. Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903;
b) S.-L. You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190.
[4] a) J. F. Austin, S.-G. Kim, C. J. Sinz, W.-J. Xiao, D. W. C.
MacMillan, Proc. Natl. Acad. Sci. USA 2004, 101, 5482; b) M.
Kimura, M. Futamata, R. Mukai, Y. Tamaru, J. Am. Chem. Soc.
2005, 127, 4592; c) B. M. Trost, J. Quancard, J. Am. Chem. Soc.
2006, 128, 6314; d) G. Zhang, V. J. Catalano, L. Zhang, J. Am.
Chem. Soc. 2007, 129, 11358; e) N. Kagawa, J. P. Malerich, V. H.
Rawal, Org. Lett. 2008, 10, 2381; f) Q.-F. Wu, H. He, W.-B. Liu,
S.-L. You, J. Am. Chem. Soc. 2010, 132, 11418.
[5] a) N. Srivastava, B. K. Banik, J. Org. Chem. 2003, 68, 2109; b) S.
Leitch, J. Addison-Jones, A. McCluskey, Tetrahedron Lett. 2005,
46, 2915; c) M. Bandini, A. Melloni, F. Piccinelli, R. Sinisi, S.
Tommasi, A. Umani-Ronchi, J. Am. Chem. Soc. 2006, 128, 1424.
[6] a) E. D. Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797; b) M. S.
Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558; c) J.
Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006, 128,
1086; d) I. T. Raheem, P. S. Thiara, E. A. Peterson, E. N.
Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404.
[15] a) H. Huang, R. Peters, Angew. Chem. 2009, 121, 612; Angew.
Chem. Int. Ed. 2009, 48, 604; b) E. M. Ferreira, B. M. Stoltz, J.
Am. Chem. Soc. 2003, 125, 9578.
[16] a) J.-M. Lin, K. Koch, F. W. Fowler, J. Org. Chem. 1986, 51, 167;
b) S. Yao, X. Fang, K. A. Jørgensen, Chem. Commun. 1998, 2547;
c) W. J. Drury III, D. Ferraris, C. Cox, B. Young, T. Lectka, J.
Am. Chem. Soc. 1998, 120, 11006; d) M. Yamanaka, A. Nishida,
M. Nakagawa, J. Org. Chem. 2003, 68, 3112.
[17] a) W. Chen, W. Du, L. Yue, R. Li, Y. Wu, L.-S. Ding, Y.-C. Chen,
Org. Biomol. Chem. 2007, 5, 816; b) G. Bartoli, M. Bosco, A.
Carlone, F. Pesciaioli, L. Sambri, P. Melchiorre, Org. Lett. 2007,
9, 1403.
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