Chiral Bronsted acid-catalyzed inverse electron-demand aza Diels-Alder reaction

Article abstract of DOI:10.1021/ja064676r

Inverse electron-demand aza Diels-Alder reaction of aldimine with enol ethers proceeded under the influence of a phosphoric acid diester, derived from (R)-BINOL, to give tetrahydroquinoline derivatives with excellent enantioselectivity. Copyright

Full text of DOI:10.1021/ja064676r

Published on Web 09/20/2006
Chiral Brønsted Acid-Catalyzed Inverse Electron-Demand Aza Diels-Alder
Reaction
Takahiko Akiyama,* Hisashi Morita, and Kohei Fuchibe
Department of Chemistry, Faculty of Science, Gakushuin UniVersity, 1-5-1 Mejiro, Toshima-ku,
171-8588 Tokyo, Japan
Received July 12, 2006; E-mail: takahiko.akiyama@gakushuin.ac.jp
Table 1. Chiral Brønsted Acid-Catalyzed Aza Diels-Alder
Tetrahydroquinoline derivatives exhibit interesting biological
activity. For example, 2-aryl-2,3-dihydro-4-quinolone (1) exhibits
antitumor activity,1 and 2-aryl-1,2,3,4-tetrahydroquinoline (2) is a
core structure of the compounds possessing 5-lipoxygenase inhibi-
tory properties and potential therapeutic application in asthma.2
Development of novel methods for the preparation of a tetrahy-
droquinoline framework in scalemic form continues to be an
important goal of synthetic organic chemists.3
Reaction of Aldimines with Vinyl Ethersa
entry
Ar
R
yield (%)
cis/trans
ee(%)b
1c
Ph
Ph
Ph
Ph
Ph
Et
89
82
76
86
95
77
86
79
59
72
74
80
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
96:4
99:1
99:1
94
96
91
90
97
90
89
88
91
87
95
88
2c
n-Bu
Bn
4a
4b
Et
n-Bu
Et
Et
Et
Et
3d
4c
5d
6c
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-MeC6H4
2-ClC6H4
2-naphthyl
2-naphthyl
7c
8c
9d
10d
11d
12d
n-Bu
a The reaction time is 10-55 h by use of 10 mol % of (R)-3. b ee of the
cis isomer. c The reaction was carried out at -10 °C. d The reaction was
carried out at 0 °C.
The inverse electron-demand aza Diels-Alder reaction of
azabutadiene with an electron-rich alkene constitutes one of the
efficient methods for the preparation of the tetrahydroquinoline
derivatives.4 Although several enantioselective Diels-Alder reac-
tions of an electron-rich diene with an electron-deficient alkene
have been developed,5 a catalytic inverse electron-demand aza
Diels-Alder reaction of azabutadiene with an electron-rich alkene
has been scarcely studied. For example, Kobayashi et al. developed
a BINOL-based chiral lanthanide catalyst,6 while Sundararajan et
al. reported an aminodiol-based Ti(IV) catalyst for the aza Diels-
Alder reaction.7 However, the enantioselectivities are not always
high, and the development of more efficient chiral catalyst is
desired.
tives in good to high yields with excellent diastereoselectivity in
favor of the cis isomer, which exhibited high to excellent enantio-
selectivity (entries 1, 6, 8, 9, 10, 11). Not only ethyl ether, but also
butyl and benzyl ethers proved to be good substrates, and the
cycloadducts were obtained with excellent diastereo- and enantio-
selectivities (entries 2, 3, 7, 12). The absolute stereochemistry of
the cycloadduct (entry 6), which was obtained by the reaction of
an aldimine prepared from 4-bromobenzaldehyde and ethyl vinyl
ether, was unambiguously determined by X-ray analysis, and those
of other cycloadducts were surmised by analogy. The cycloaddition
reaction with cyclic vinyl ethers such as dihydrofuran (4a) and
dihydropyran (4b) also gave cycloadducts 5a and 5b, respectively,
in excellent enantioselectivities (entries 4, 5).12
Recently, chiral Brønsted acid catalysts have continued to
increase in popularity as green catalysts, which are free of metals.8,9
We have designed and synthesized chiral phosphoric acid, derived
from (R)-BINOL, and demonstrated its catalytic activity as chiral
Brønsted acid catalysts.10,11 As part of our continued effort on the
development of chiral Brønsted acid-catalyzed reactions, we wish
to report herein a chiral Brønsted acid-catalyzed enantioselective
aza Diels-Alder reaction of azabutadiene with electron-rich alkenes,
leading to tetrahydroquinolines with high enantioselectivity.
A phosphoric acid bearing 9-anthryl group on the 3,3′-position
(R)-3 turned out to be highly effective as a catalyst for the aza
Diels-Alder reaction of aldimine, derived from aromatic aldehyde
and o-hydroxyaniline, and ethyl vinyl ether in toluene at 0 °C. The
results are shown in Table 1. A range of aldimines derived from
aromatic aldehyde worked well to give tetrahydroquinoline deriva-
Next, the cycloadducts were transformed into the compounds
bearing a 2-aryl-2,3-dihydro-4-quinolone and 2-aryl-1,2,3,4-tetra-
9
13070
J. AM. CHEM. SOC. 2006, 128, 13070-13071
10.1021/ja064676r CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Preparation of Dihydro-4-quinolone Derivativesa
(2) Paris, D.; Cottin, M.; Demonchaux, P.; Augert, G.; Dupassieux, P.; Lenoir,
P.; Peck, M. J.; Jasserand, D. J. Med. Chem. 1995, 38, 669.
(3) For recent examples of the asymmetric synthesis, see (a) Wang, W.-B.;
Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003,
125, 10536. (b) Shintani, R.; Yamagami, T.; Kimura, T.; Hayashi, T. Org.
Lett. 2005, 7, 5317.
(4) For reviews, see (a) Waldmann, H. Synthesis 1994, 535. (b) Katritzky,
A. R.; Rachwal, S.; Rachwal, B. Tetradedron 1996, 52, 15031. (c)
Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558. (d) Johnson, J.
S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. (e) Buonora, P.; Olsen,
J.-C.; Oh, T. Tetrahedron 2001, 57, 6099. (f) Cycloaddition Reactions in
Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, Germany, 2002.
a Conditions: (a) triphosgene, Et3N, CH2Cl2, 8 h, 88%; (b) H2, Pd/C,
AcOH, 98%; (c) MnO2, CH2Cl2, 40 min, 56%.
(5) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed.
1998, 37, 979. (b) Kobayashi, S.; Ueno, M.; Saito, S.; Mizuki, Y.; Ishitani,
H.; Yamashita, Y. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5476. (c) Yao,
S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 1998, 37, 3121. (d) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A.
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G.; Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456.
hydroquinoline core structure. The 2-aryl-2,3-dihydro-4-quinolone
framework was synthesized starting from benzyl ether by use of
carbamate (Scheme 1). The 2-aryl-1,2,3,4-tetrahydroquinoline
derivative was obtained starting from ethyl ether (Scheme 2).
Scheme 2. Preparation of Tetrahydroquinoline Derivativesa
(6) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357.
(7) Sundararajan, G.; Prabagaran, N.; Varghese, B. Org. Lett. 2001, 3, 1973.
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Int. Ed. 2005, 44, 1758. (d) Pihko, P. M. Lett. Org. Chem. 2005, 2, 398.
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Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (g) Akiyama, T.;
Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999. (h) Connon, S. J.
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a Conditions: (a) triphosgene, Et3N, CH2Cl2, 4 h, 95%; (b) H2, Pd(OH)2,
AcOH, 39 h, 83%.
(9) For recent representative papers, see (a) Wenzel, A. G.; Jacobsen, E. N.
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Because the presence of the OH moiety on the N-aryl group is
essential for attaining high enantioselectivity,13 we surmised that
the present aza Diels-Alder reaction proceeds via a nine-membered
cyclic transition state, wherein phosphoryl oxygen forms a hydrogen
bond with the hydrogen of the imine OH moiety with the nucleo-
phile attacking the re-face of the imine preferentially (Figure 1).
Figure 1. Plausible transition state.
(10) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566. (b) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K.
Org. Lett. 2005, 7, 2583. (c) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe,
K. AdV. Synth. Catal. 2005, 347, 1523. (d) Akiyama, T.; Tamura, Y.;
Itoh, J.; Morita, H.; Fuchibe, K. Synlett 2006, 141. (e) Itoh, J.; Fuchibe,
K. Akiyama, T.; Angew. Chem., Int. Ed. 2006, 45, 4796.
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Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804. (c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
2005, 127, 9360. (d) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann,
T.; Bolte, M. Org. Lett. 2005, 7, 3781. (e) Rowland, G. B.; Zhang, H.;
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Chem. Soc. 2005, 127, 15696. (f) Hoffmann, S.; Seayad, A. M.; List, B.
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List, B. J. Am. Chem. Soc. 2006, 128, 1086. (h) Storer, R. I.; Carrera, D.
E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (i)
Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006,
45, 2254. (j) Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed.
2006, 45, 2617. (k) Rueping, M.; Antonchick, A. P.; Theissmann, T.
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H. J. Am. Chem. Soc. 2006, 128, 9626.
In summary, we have developed a chiral Brønsted acid-catalyzed
inverse electron-demand aza Diels-Alder reaction of aldimines with
electron-rich alkenes. Tetrahydroquinoline derivatives were obtained
with high to excellent enantioselectivity.
Acknowledgment. We thank Dr. Masato Nanjo (Gakushuin
University, Tokyo, Japan), Professor Youichi Ishii, and Dr. Yoshiaki
Tanabe (Chuo University, Tokyo, Japan) for the X-ray structural
determinations. This work was partially supported by a Grant-in
Aid for Scientific Research on Priority Areas “Advanced Molecular
Transformation of Carbon Resources” from the Ministry of Educa-
tion, Science, Sports, Culture, and Technology, Japan.
Supporting Information Available: Experimental procedure,
spectra data, and data of single-crystal X-ray analysis (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
(12) The absolute stereochemistries of 5a and 5b were also determined by the
analogy after X-ray analysis of a bromo analogue of 5a. For details, please
see Supporting Information.
(13) An aldimine, derived from p-methoxyaniline, did not give the correspond-
References
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JA064676R
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J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006 13071