Transition-Metal-Free Indirect Friedl a¨ nder
Some of the aforementioned drawbacks have been overcome
by the use of the so-called indirect Friedl a¨ nder strategy, which
uses different 2-aminobenzylic alcohol derivatives 1 and ketones
†
Synthesis of Quinolines from Alcohols
2
, and it has been catalyzed by different transition-metal
Ricardo Mart ´ı nez, Diego J. Ram o´ n,* and Miguel Yus*
9
10
11
complexes derived from ruthenium, palladium, iridium,
rhodium, and copper. Even the ketone could be replaced
by the corresponding alcohol. However, this indirect method
gave final products contaminated with traces of transition metals,
which are not tolerated in some industrial applications.
1
2
13
Instituto de S ´ı ntesis Org a´ nica (ISO) and Departamento de
Qu ´ı mica Org a´ nica, Facultad de Ciencias, UniVersidad de
Alicante, Apdo. 99, E-03080-Alicante, Spain
1
4
djramon@ua.es; yus@ua.es
The Meerwein-Ponndorf-Verley reaction is typically con-
15
ducted using transition-metal catalysts. However, the reaction
can be performed in the absence of any type of catalysts, neither
base nor metal complexes, although the reaction must be
conducted under very high reaction conditions (temperatures
ReceiVed July 31, 2008
16
higher than 200 °C). On the other hand, the direct hydrogena-
tion of ketones can be performed in the presence of anionic
1
7
base catalysts such potassium tert-butoxide.
(3) See, for instance: (a) Ridley, R. G. Nature 2002, 415, 686–693. (b) Olliaro,
P. L.; Taylor, W. R. J. J. Exp. Biol. 2003, 206, 3753–3759. (c) Klingenstein, R.;
Melnyk, P.; Leliveld, S. R.; Ryckebusch, A.; Korth, C. J. Med. Chem. 2006, 49,
5
300–5308.
4) See, for instance: (a) Lal, B.; Bhise, N. B.; Gidwani, R. M.; Lakdawala,
The synthesis of polysubstituted quinolines can be easily and
greenly accomplished by the direct reaction between the
corresponding 2-aminobenzylic alcohol derivative and either
a ketone or alcohol in the presence of a base, without any
transition-metal catalyst.
(
A. D.; Joshi, K.; Parvardhan, S ARKIVOC 2005, ii, 77–97. (b) Chen, Y.-L.;
Zhao, Y.-L.; Lu, C.-M.; Tzeng, C.-C.; Wang, J.-P. Bioorg. Med. Chem. 2004,
1
2, 3607–3617.
(5) See, for instance: (a) Ishiwara, M.; Aoki, Y.; Takagaki, H.; Ui, M.;
Okajima, F J. Pharmacol. Exp. Ther. 2003, 307, 583–588. (b) Benedetti, P.;
Mannhold, R.; Cruciani, G.; Ottaviani, G. Bioorg. Med. Chem. 2004, 12, 3607–
3
617.
6) See, for instance: (a) Appelbaum, P. C.; Jacobs, M. R Curr. Opin.
(
Microbiol. 2005, 8, 510–517. (b) Narender, P.; Srinivas, U.; Ravinder, M.; Rao,
B. A.; Ramesh, C.; Harakishore, K.; Gangadasu, B.; Murthy, U. S. N.; Rao,
V. J. Bioorg. Med. Chem. 2006, 14, 4600–4609.
The presence of quinoline scaffolds in the frameworks of
various pharmacologically active compounds, as well as in
various natural products, has spurred the development of many
(
7) See, for instance: (a) Staalhandske, T.; Kalland, T. Immunopharmacology
986, 11, 87–92. (b) Thatcher, T. H.; Luzina, I.; Fishelevich, R.; Tomai, M. A.;
Miller, R. L.; Gaspari, A. A. J. InVest. Dermatol. 2006, 126, 821–831.
8) (a) Cheng, C. C.; Yan, S. J. Org. React. 1982, 28, 37–201. (b) Rusanov,
1
1
different methodologies for their synthesis. Among their
2
(
different applications, functionalized quinolines are widely used
3
4
A. L.; Komarova, L. G.; Prigozhina, M. P.; Likhatchev, D. Y. Russ. Chem. ReV.
as a result of their antimalarial, anti-inflamatory, antiasth-
2
005, 74, 671–683.
5
6
7
matic, antibacterial, and antihypersensitive activities.
(9) (a) Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Chem. Commun.
001, 2576–2577. (b) Cho, C. S.; Kim, B. T.; Choi, H.-J.; Kim, T.-J.; Shim,
2
Several different strategies for the preparation of substituted
quinolines are known, with the Friedl a¨ nder annulation being
S. C. Tetrahedron 2003, 59, 7997–8002. (c) Motokura, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Tetrahedron Lett. 2004, 45, 6029–6032. (d) Mart ´ı nez, R.; Brand,
G. J.; Ram o´ n, D. J.; Yus, M. Tetrahedron Lett. 2005, 46, 3683–3686. (e) Cho,
C. S.; Ren, W. X.; Shim, S. C. Bull. Korean Chem. Soc. 2005, 26, 2038–2040.
8
the most simple, straightforward, and widely used approach.
Nevertheless, most of the synthetic approaches reported so far
suffer from need of high temperatures or harsh reaction
conditions, low yields, use of hazardous and often expensive
catalysts, and problems associated with the storage of carbonyl
reagents. Moreover, the usual solvents employed result in very
tedious workup procedures.
(f) Mart ´ı nez, R.; Ram o´ n, D. J.; Yus, M. Tetrahedron 2006, 62, 8988–9001. (g)
Mart ´ı nez, R.; Ram o´ n, D. J.; Yus, M. Eur. J. Org. Chem. 2007, 159, 9–1605. (h)
Vander Mierde, H.; Ledoux, N.; Allaert, B.; Van Der Voort, P.; Drozdzak, R.;
De Vos, D.; Verpoort, F. New J. Chem. 2007, 31, 1572–1574. (i) Vander Mierde,
H.; Van Der Voort, P.; De Vos, D.; Verpoort, F. Eur. J. Org. Chem. 2008, 162,
5–1631.
(
10) (a) Cho, C. S.; Ren, W. X.; Shim, S. C. Bull. Korean Chem. Soc. 2005,
2
4
6, 1286–1288. (b) Cho, C. S.; Ren, W. X. J. Organomet. Chem. 2007, 629,
182–4186.
†
In memory of Prof. Dr. Albert I. Meyers.
(11) Taguchi, K.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2005, 46, 4539–
4542.
(
1) (a) For reviews on quinoline synthesis, see: Claret, P. A. In ComprehensiVe
Organic Chemistry; Barton, D.; Ollis, W. D., Eds.; Pergamon Press: Oxford,
(12) Cho, C. S.; Seok, H. J.; Shim, S. C. J. Heterocycl. Chem. 2005, 42,
1219–1222.
(13) Cho, C. S.; Ren, W. X.; Shim, S. C. Tetrahedron Lett. 2006, 47, 6781–
6785.
(14) Mart ´ı nez, R.; Ram o´ n, D. J.; Yus, M. Tetrahedron 2006, 62, 8982–8987.
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1
979; Vol. 4, pp 1479-1489. (b) Jones, G. In ComprehensiVe Heterocyclic
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89-549. (d) Larsen, R. D. In Science of Synthesis; Black, D. S., Ed.; Thieme:
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(16) Bagnell, L.; Strauss, C. R. Chem. Commun. 1999, 287–288.
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10.1021/jo801678n CCC: $40.75 2008 American Chemical Society
Published on Web 10/21/2008