InCl3-catalyzed allylic friedel-crafts reactions toward the stereocontrolled synthesis of 1,2,3,4-tetrahydroquinolines

Article abstract of DOI:10.1021/ol102023z

Allyl chlorides tethered to an N-aryl moiety readily undergo InCl ₃-catalyzed Friedel-Crafts reactions to furnish highly enantiomerically enriched 1,2,3,4-tetrahydroquinolines with good yields and excellent diastereoselectivity.

Full text of DOI:10.1021/ol102023z

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4884-4887
InCl3-Catalyzed Allylic Friedel-Crafts
Reactions toward the Stereocontrolled
Synthesis of 1,2,3,4-Tetrahydroquinolines
David S. Giera and Christoph Schneider*
Institut fu¨r Organische Chemie, UniVersita¨t Leipzig, Johannisallee 29,
04103 Leipzig, Germany
schneider@chemie.uni-leipzig.de
Received August 27, 2010
ABSTRACT
Allyl chlorides tethered to an N-aryl moiety readily undergo InCl3-catalyzed Friedel-Crafts reactions to furnish highly enantiomerically enriched
1,2,3,4-tetrahydroquinolines with good yields and excellent diastereoselectivity.
1,2,3,4-Tetrahydroquinolines are central subunits in a broad
range of natural products and medicinal agents which display
interesting biological and pharmacological properties.1 Ac-
cordingly, a wealth of synthetic methods has been developed
for the stereoselective synthesis of these heterocycles.2 Most
prominent among them are metal- and Brønsted acid-
catalyzed, enantioselective hydrogenations of quinolines3 as
well as enantioselective aza Diels-Alder reactions of aryl
imines and electron-rich alkenes (Povarov reaction)4 and
those of in situ generated aza-xylylenes and electron-rich
dienophiles.5 Other methods including ring expansion reac-
tions,6 asymmetric Reissert reactions,7 Heck-type cycliza-
tions,8 organocatalytic hydroarylations of enals,9 sequential
aza-Michael-Mannich reaction of ortho-amino benzalde-
hydes and enals,10 Pd-catalyzed hydroaminations of anilino
alkynes,11 intramolecular redox reactions,12 and the carbo-
(4) For the most recent enantioselective processes, see: (a) Akiyama,
T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070–13071.
(b) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem.
Soc. 2009, 131, 4598–4599. (c) Xie, M. M.; Chen, X.; Zhu, Y.; Gao, B.;
Lin, L.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2010, 49, 3799–3802.
(d) Xu, H.; Zuend, S. J.; Woll, M. G.; Te, Y.; Jacobsen, E. N. Science
2010, 327, 986–990.
(1) Selected examples: (a) Rauckman, B. S.; Tidwell, M. Y.; Johnson,
J. V.; Roth, B. J. Med. Chem. 1989, 32, 1927–1935. (b) Witherup, K. M.;
Ransom, R. W.; Graham, A. C.; Bernard, A. M.; Salvatore, M. J.; Lumma,
W. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga, S. L. J. Am. Chem.
Soc. 1995, 117, 6682–6685. (c) Jacquemond-Collet, I.; Benoit-Vical, F.;
Mustofa; Valentin, A.; Stanislas, E.; Mallie´, M.; Fouraste´, I. Planta Med.
2002, 68, 68–69.
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S. Heterocycles 1998, 46, 1103–1106. (b) Steinhagen, H.; Corey, E. J.
Angew. Chem., Int. Ed. 1999, 38, 1928–1931. (c) Steinhagen, H.; Corey,
E. J. Org. Lett. 1999, 1, 823–824. (d) Avemaria, F.; Vanderheiden, S.; Bra¨se,
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S. Eur. J. Org. Chem. 2006, 4916, 4923.
(2) Reviews :(a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031–15070. (b) Kouznetsov, V. V.; Mendez, L. Y. V.; Gomez,
C. M. M. Curr. Org. Chem. 2005, 9, 141–161. (c) Barluenga, J.; Rodriguez,
F.; Fananas, F. J. Chem. Asian J. 2009, 4, 1036–1048.
(3) (a) Review: Wang, D. W.; Zhou, Y. G.; Chen, Q. A.; Wang, D. S.
EnantioselectiVe Reduction of Nitrogen-Based Heteroaromatic Compounds
in Chiral Amine Synthesis: Methods, DeVelopments, and Applications;
Wiley-VCH: Weinheim, 2010; pp 299-340 and refs cited therein. Selected
recent reports: (b) Wang, W. B.; Lu, S. M.; Yang, P. Y.; Han, X. W.; Zhou,
Y. G. J. Am. Chem. Soc. 2003, 125, 10536–10537. (c) Wang, D. W.; Wang,
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2787. (d) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem.,
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10.1021/ol102023z  2010 American Chemical Society
Published on Web 09/29/2010

lithiation of unsaturated ortho-iodo anilines13 have been
developed additionally to access tetrahydroquinolines in
optically enriched form. Recently, Lautens and co-workers
reported a powerful palladium-catalyzed cyclization of allyl
acetates tethered to an N-aryl iodide giving rise to a variety
of 2,4-disubstituted tetrahydroquinolines in good yields and
perfect 2,4-trans-diastereoselectivity, albeit as racemic mix-
tures.14
through Dibal-H reduction and halogenation would form a
suitable allylic electrophile that was expected to undergo an
intramolecular, metal-catalyzed allylic alkylation reaction
with the electron-rich N-aryl group (Scheme 2).17
Scheme 2. Friedel-Crafts Reaction of Allyl Halides 3a and 4a
We report herein a straightforward and highly stereose-
lective approach for the synthesis of chiral, highly optically
enriched 2,4-disubstituted and 2,3,4-trisubstituted tetrahyd-
roquinolines through a metal-catalyzed, intramolecular
Friedel-Crafts-type reaction of allyl chlorides tethered to
an N-aryl moiety. Complementary to the Lautens process,
this new allylic alkylation reaction proceeds in a highly cis-
stereoselective fashion and does not require a halogen
substituent on the aryl ring.
We have recently developed the Brønsted acid-catalyzed,
highly enantioselective, vinylogous Mukaiyama-Mannich
reaction of vinylketene silyl-O,O-acetals 1 furnishing δ-amino-
R,ꢀ-unsaturated esters 2 with excellent enantioselectivity
(Scheme 1).15 With γ-substituted dienolates a second ste-
reogenic center was formed with good anti-diastereoselec-
tivity. As a first synthetic application of the Mannich products
obtained in this way, we recently reported a four-step
synthesis of the tobacco alkaloid S-anabasine in optically
highly enriched form.16
In addition to other Lewis acids commonly employed in
Friedel-Crafts reactions, InCl3 has specifically been intro-
duced as a catalyst for the intermolecular18 and intramo-
lecular19 reaction of arenes with allyl acetates and allyl
bromides, respectively. Accordingly, we prepared both allyl
bromide 3a and allyl chloride 4a starting from vinylogous
Mannich product 2a in good yields using standard methods
(see Supporting Information) and treated them with catalytic
amounts of InCl3 and powdered 4 Å molecular sieves in 1,2-
dichloroethane.
Friedel-Crafts cyclization of 3a was very rapid even at
ambient temperature and furnished tetrahydroquinoline 5a
in moderate yield (cis/trans > 25:1) along with some
unidentified byproducts (Scheme 2). In fact, 3a proved to
be so reactive that it partially cyclized during its preparation.
On the other hand, Friedel-Crafts reaction of allyl chloride
4a was a much cleaner process and delivered 5a in 82%
isolated yield as a single diastereomer (cis/trans > 25:1) with
95% ee after refluxing a solution of 4a for 18 h in
1,2-dichloroethane. We assume that the catalytic activity of
InCl3 in this reaction rests on its halophilic nature activating
the allyl system via chloride abstraction.20 Only trace
amounts of 5a were obtained in the absence of InCl3.
With optimal conditions for the cyclization in hand, a
series of vinylogous Mannich products 2b-n, which were
prepared in optically highly enriched form using our Brønsted
acid-catalyzed process, was converted into allyl chlorides
4b-n via the above-mentioned reduction-halogenation
sequence. Subsequently, they were cyclized with InCl3 as
catalyst (10 mol %) in the presence of 4 Å molecular sieves
to furnish 1,2,3,4-tetrahydroquinolines 5b-n in typically
good yields and up to >25:1 diastereoselectivity in favor of
Scheme 1
.
Chiral Brønsted Acid-Catalyzed Vinylogous
Mukaiyama-Mannich Reaction
In an effort to document further the synthesis potential of
the highly functionalized Mannich products, we speculated
that we could employ the N-aryl group not just as a nitrogen
protecting group but incorporate it into the target structure
through a Friedel-Crafts-type cyclization to form 1,2,3,4-
tetrahydroquinolines. Specifically, we envisaged that conver-
sion of the enoate moiety within 2 into an allylic halide
(10) (a) Li, H.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang, W.
Org. Lett. 2007, 9, 965–968. See also: (b) Fustero, S.; Moscardo, J.; Jiminez,
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(11) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2007, 72, 6577–
6579.
(17) Pd-catalyzed reactions of the corresponding allyl acetates did not
furnish the desired tetrahydroquinolines. For a related example with an
indole substrate, see: Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.;
Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424–1425.
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127, 72–73. See also: (b) Thansandote, P.; Raemy, M.; Rudolph, A.; Lautens,
M. Org. Lett. 2007, 9, 5255–5258.
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Synthesis 2003, 633, 655. (c) Frost, C. G.; Chauhan, K. K. J. Chem. Soc.,
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Org. Lett., Vol. 12, No. 21, 2010
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Table 1. Intramolecular InCl3-Catalyzed Friedel-Crafts Reactiona
a Reactions were performed with allyl chloride 4 (0.30 mmol, 1.00 equiv), InCl3 (0.03 mmol, 0.10 equiv), and 4 Å molecular sieves under reflux in
anhydrous 1,2-dichloroethane (2.0 mL). b Yields refer to chromatographically purified material. Enantiomeric excesses were determined by chiral HPLC and
1
were identical for vinylogous Mannich products 2 and tetrahydroquinolines 5 (see Supporting Information); diastereomeric ratios were determined by H
NMR spectroscopy or HPLC. c K2CO3 (3.0 equiv) was added. d 20 mol % of InCl3 was used. e 25 mol % of InCl3 was used.
the 2,4-cis-diastereomer (Table 1). The configurational
assignment was based upon the characteristic coupling
constants in the 1H NMR spectrum. The exceptionally high
diastereoselectivity in favor of the 2,4-cis-isomer is believed
to originate from the favorable pseudoequatorial positions
of the substituents in the transition state of the cyclization.
Whereas substrates with alkoxy-substituted N-aryl groups
reacted rather quickly, those with N-aryl groups lacking any
further electron donation or carrying electron-withdrawing
substituents required extended reaction times at elevated
temperatures and occasionally increased catalyst loadings
(entries 8 and 12). Also, the addition of 3 equiv of K2CO3
to the reaction mixture was beneficial in those cases to
neutralize the in situ generated HCl, which slowly led to
decomposition of the starting materials (entries 7-12).
Furthermore, the reaction could be successfully extended to
the preparation of the 2,3,4-trisubstituted tetrahydroquinoline
5n, which was obtained in 81% yield and 15:1 cis/trans-
diastereoselectivity (entry 13).
It is important to note that due to the modular-type three-
component vinylogous Mannich reaction a variety of tet-
rahydroquinolines with different substituents both in the
aromatic portion of the heterocycle as well as in the 2- and
3-positions are accessible in highly enantiomerically enriched
form. 2-Alkyl-, 2-aryl-, and 2-heteroaryl-substituted tetrahy-
droquinolines were all obtained in good yields and typically
excellent diastereoselectivity.
Moreover, the vinyl substituent intrinsically present in the
4-position of the heterocyclic skeleton offers some interesting
possibilities for modification (Scheme 3). Thus, cross me-
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Org. Lett., Vol. 12, No. 21, 2010

complished after conversion into N-acetyl tetrahydroquinoline
8 through a sequence comprising dihydroxylation,23 diol
cleavage, and reduction to provide tetrahydroquinoline
alcohol 9 in excellent overall yield.
Scheme 3. Elaboration of Tetrahydroquinolines 5a
In conclusion, we have developed a novel, flexible, and
highly stereoselective process for the synthesis of a broad
range of 1,2,3,4-tetrahydroquinolines through an InCl3-
catalyzed Friedel-Crafts reaction. Allyl chlorides with both
electron-rich and electron-poor N-aryl groups successfully
underwent the cyclization with high 2,4-cis-diastereoselec-
tivity, delivering products with diverse substitution patterns.
An additional key element of the strategy is the Brønsted
acid-catalyzed vinylogous Mannich reaction to provide the
substrates in highly optically enriched form.
Acknowledgment. We gratefully acknowledge the Deut-
sche Forschungsgemeinschaft for generous financial support
of this work (SPP 1179 “Organokatalyse”). We would like
to thank Susann Krake and Konrad Gebauer (University of
Leipzig) for preliminary experiments and Matthias Lang
(University of Leipzig) for providing vinylogous Mannich
product 2n.
tathesis employing the Hoveyda-Grubbs second-generation
catalyst21 furnished R ꢀ-unsaturated ester 6 in 74% yield
along with 11% of the readily separable Z-isomer. Further-
more, hydroboration22 followed by oxidative workup af-
forded tetrahydroquinoline alcohol 7 in 85% yield. Finally,
oxidative degradation of the vinyl group was readily ac-
Supporting Information Available: Detailed experimen-
tal procedures, characterization, and copies of spectra for
the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL102023Z
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