Gold(III)-mediated aldol condensations provide efficient access to nitrogen heterocycles

Article abstract of DOI:10.1021/ol8005634

(Chemical Equation Presented) Quinolines, dihydroquinolines, and aza-xanthones can be synthesized efficiently and under mild reaction conditions by means of a reaction sequence employing Au(III)-catalyzed aldol reactions as the key step.

Full text of DOI:10.1021/ol8005634

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2159-2162
Gold(III)-Mediated Aldol Condensations
Provide Efficient Access to Nitrogen
Heterocycles
Herbert Waldmann,* Galla V. Karunakar, and Kamal Kumar*
Max-Planck-Institut fu¨r Molekulare Physiologie, Abteilung Chemische Biologie,
Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, and TU, Dortmund, Fachbereich 3,
Chemische Biologie, Otto-Hahn Strasse 6, 44227 Dortmund, Germany
kamal.kumar@mpi-dortmund.mpg.de; herbert.waldmann@mpi-dortmund.mpg.de
Received March 11, 2008
ABSTRACT
Quinolines, dihydroquinolines, and aza-xanthones can be synthesized efficiently and under mild reaction conditions by means of a reaction
sequence employing Au(III)-catalyzed aldol reactions as the key step.
Polycyclic N-heterocycles form the basic frameworks of
numerous natural product classes and hold a prominent role
in pharmaceutical and agrochemical research.1 In particular,
quinolines and their derivatives often are endowed with
biological activity including compounds with antitumor
activity,2 CysLT (LTD4) receptor antagonists3 and HIV-1
replication inhibitors.4 For quinoline synthesis, the Fried-
la¨nder annulation5 is widely used. It proceeds both in the
presence of Brønsted6 or Lewis acid catalysts7 and under
Zwaagstra, M. E.; Timmerman, H.; van de Stolpe, A. C.; de Kanter, F. J.;
Tamura, M.; Wada, Y.; Zhang, M.-Q. J. Med. Chem. 1998, 41, 1428–1438.
(c) Chambers, R. J.; Antognoli, G. W.; Cheng, J. B.; Kuperman, A. V.;
Liston, T. C.; Marfat, A.; Owens, B. S.; Pillar, J. S.; Shirley, J. T.; Watson,
J. W. Bioorg. Med. Chem. Lett. 1998, 8, 3577–3582.
(1) (a) ComprehensiVe Heterocyclic Chemistry; Katritzky, A., Rees,
C. W., Scriven, E. F. V., Eds.; Elsevier Science: Oxford, UK, 1996. (b)
Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic: New York, 1987;
Vol. 30, pp 251-377. (c) Lewis, J. R. Nat. Prod. Rep. 1994, 11, 329–332.
(d) Jeffs, P. W. In The Alkaloids; Rodrigo, R. G. A., Ed.; Academic: New
York, 1981; Vol. 19, pp 1-80.
(4) Zouhiri, F.; Desmaele, D.; d’Angelo, J.; Ourevitch, M.; Mouscadet,
J.-F.; Leh, H.; Le Bret, M. Tetrahedron Lett. 2001, 46, 8189–8192.
(5) (a) Cheng, C. C.; Yan, S. J. Org. React. 1982, 28, 37–201. (b)
Thummel, R. P. Synlett 1992, 1–12. (c) Rusanov, A. L.; Komarova, L. G.;
Prigozhina, M. P.; Likhatchev, D. Y. Russ. Chem. ReV. 2005, 74, 671–
683.
(2) Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989,
32, 393–401.
(6) (a) Na, J. E.; Lee, K. Y.; Park, D. Y.; Jae, J. N. Bull. Korean Chem.
Soc. 2005, 26, 323–326. (b) Yadav, J. S.; Rao, P. P.; Sreenu, D.; Rao, R. S.;
Kumar, V. N.; Nagaiah, K.; Prasad, A. R. Tetrahedron Lett. 2005, 46, 7249–
7253. (c) Jia, C.-S.; Zhang, Z.; Tu, S.-J.; Wang, G.-W. Org. Biomol. Chem.
2006, 4, 104–110.
(3) Selected references: (a) Sawyer, J. S.; Thrasher, K. J.; Bach, N. J.;
Stengel, P. W.; Cockerham, S. L.; Silbaugh, S. A.; Roman, C. R.; Froelich,
L. L.; Fleisch, J. H. Bioorg. Med. Chem. Lett. 1996, 6, 249–252. (b)
10.1021/ol8005634 CCC: $40.75
Published on Web 05/08/2008
2008 American Chemical Society

noncatalyzed thermal conditions (heating in the presence of
base or heating to temperatures up to 250 °C). In the course
of a program aimed at the development of new methodology
for the synthesis of heterocycle classes endowed with
biological activity8 we were inspired by a recent report on a
gold catalyzed quinoline synthesis9 to explore the versatility
of gold-catalysis10 for the synthesis of a collection of
N-heterocycles. Here, we report our preliminary results on
gold catalyzed condensation reactions leading to quinoline,
dihydroquinoline, and aza-xanthone frameworks.
catalytically active under a variety of conditions. Elevation
of the temperature resulted in an increased yield. However
the best results were obtained using AuCl3 and AgSbF6 in a
ratio of 1:3 in acetonitrile/methanol (4:1) at room tempera-
ture. After 8 h, the reaction was complete and yielded 3a in
91% yield (Table 1, entry 1). Both cyclic and acyclic
acetophenones displayed appreciable reactivity under these
reaction conditions yielding quinoline-fused polycycles with
preparatively very useful results (Table 1). For cyclic aryl
alkyl ketones, warming to 50 °C was required.
Table 1. Synthesis of Quinolines from Aryl Alkyl Ketones
Table 2. Synthesis of Azaxanthones from Aryl Alkyl Ketones
a AuCl3 (5 mol %), AgSbF6 (15 mol %), 2 (1.2 equiv), MeCN/MeOH
(4:1), rt, 8 h b isolated yields.
a AuCl3 (5 mol %), AgSbF6 (15 mol %), 2 (1.2 equiv), MeCN/MeOH
(4:1), rt, 8 h. b Isolated yields. c Reaction perforemd at 50 °C, 8 h.
These Au(III)-catalyzed condensations provide a wider
scope for the synthesis of N-heterocycles than previously
reported similar catalytic transformations which mostly
employed more reactive 1,3-dicarbonyl compounds,9 often
under harsher reaction conditions (e.g., NaAuCl4, 80-140
°C, 0.5 h to 4 d).11 In order to generate diverse N-heterocyclic
systems using gold-catalyzed condensation methodology, we
employed 2-amino-3-formylchromone (4) with acetophenone
In initial experiments, the Friedla¨nder-type condensation
of acetophenone (2a) in the reaction with 2-aminoacetophe-
none (1a) leading to quinoline 3a was investigated. While
AuCl3 did catalyze the reaction at room temperature leading
to the desired quinoline 3a in low yield, Au(I) was not
(7) (a) Wang, H.-M.; Kang, I.-J.; Chen, L.-C. Heterocycles 2003, 60,
1899–1905. (b) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5, 4257–
4259. (c) Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P.; Rao, R. S.; Nagaiah,
K. Synthesis 2004, 2381–2385. (d) Wu, J.; Zhang, L.; Diao, T.-N. Synlett
2005, 2653–2657.
(8) (a) Koch, M. A.; Schuffenhauer, A.; Scheck, M.; Wetzel, S.; Casaulta,
M.; Odermatt, A.; Ertl, P.; Waldmann, H. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 17272–17277. (b) Wetzel, S.; Schuffenhauer, A.; Roggo, S.;
Ertl, P.; Waldmann, H. Chimia 2007, 61, 355–360.
2160
Org. Lett., Vol. 10, No. 11, 2008

using reaction conditions described in Table 1. In the
reaction, the desired azaxanthone 5a was cleanly formed in
81% yield. By analogy, different cyclic aryl alkyl ketones
yielded fused azapolycycles in high yields at room temper-
ature (Table 2). Aza-xanthones are of substantial interest due
to their pronounced biological activity.12
Table 3. Synthesis of 1,5-Diketones from Aldehydes
Intriguingly and unexpectedly, the use of R-keto esters
(7, 2.2 equiv) instead of aryl alkyl ketones in the gold
catalyzed condensation with 2-aminoacetophenone (1.0
equiv) and also p-anisidine or aniline itself yielded dihyd-
roquinolines 8 (Scheme 1).13,14 Dihydroquinolines are of
significant interest to medicinal chemistry research,15 and
new synthetic routes to them are highly desired.
Scheme 1. Gold-Mediated Synthesis of Dihydroquinolines
These results underscore the synthetic versatility offered by
gold catalysis for the synthesis of such polycyclic heterocycles.
Thus, under the conditions described, a moderate variation in
the structure of the starting materials gives efficient access to a
substantially diverse collection of structurally different, biologi-
cally relevant N-heterocycle classes.
In order to develop a mechanistic rationale for the different
transformations described above we assumed that the con-
densation reactions involve gold-mediated formation of
enolates followed by an addition reaction.16 In order to probe
this notion, we investigated the model reaction of benzal-
dehyde with acetophenone in acetonitrile in the presence of
the gold and silver salts under the conditions described above.
Surprisingly the expected R-ꢀ-unsaturated ketone 12 (R
) Ar ) Ph) was obtained only as a minor product, and 1,5-
diketone 11a was isolated in 74% yield (Table 3, entry 1).
Subsequent experiments revealed that various aromatic
aldehydes yielded 1,5-diketones in high yields (Table 3,
entries 1-8). However aldehydes with electron-withdrawing
substituents (e.g., Cl, Br) and aliphatic aldehydes did not
give the analogous products. The reaction of cinnamaldehyde
a AuCl3 (5 mol %), AgSbF6 (15 mol %), 10 (2.2 equiv), MeCN, rt,
8-12 h b Isolated yields.
with acetophenone led to formation of a product mixture.
When phenylacetylene was employed instead of acetophe-
none, compound 11a was obtained in similar yield (70%).
Obviously under these reaction conditions phenylacetylene
is rapidly hydrated to yield acetophenone which then enters
the aldol reaction sequence. This possibility is further
supported by the fact that when Au(PPh3)Cl was used instead
of AuCl3 under strictly anhydrous conditions no reaction with
the alkyne was detected.
(9) (a) Arcadi, A.; Chiarini, M.; Giuseppe, S. Di; Marinelli, F. Synlett
2003, 203–206. (b) Arcadi, A.; Bianchi, G.; Giuseppe, S. D.; Marinelli, F.
Green Chem. 2003, 5, 64–67.
(10) Reviews: (a) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180–3211.
(b) Hoffmann-Ro¨ der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387.
(c) Sherry, B. D.; Toste, F. D. Chemtracts Org. Chem. 2005, 18, 14. (d)
Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200. (e) Nieto-
Oberhuber, C.; Lo´pez, S.; Jime’nez-Nu’nez, E.; Echavarren, A. M. Chem.
Eur. J. 2006, 12, 5916. (f) Widenhoefer, R.; Han, X. Eur. J. Org. Chem.
2006, 4555. (g) Hashmi, A. S. K.; Hutchings, G. Angew. Chem., Int. Ed.
2006, 45, 7896. (h) Fu¨rstner, A.; Davies, P. W.Angew. Chem., Int. Ed. 2007,
46, 3410–3449.
(11) Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.; Thomas, A. W.;
Verron, J.; Masciadri, R. Tetrahedron 2007, 63, 2811–2823.
(12) For reports on xanthone and related molecules, see: (a) Peres, V.;
Nagem, T. J.; Oliveira, F. F. Phytochemistry 2000, 55, 683–710. (b) Ciganek,
E.; Uyeda, R. T.; Cohen, M.; Smith, D. H. J. Med. Chem. 1981, 24, 336–
341. (c) Recanatini, M.; Bisi, A.; Cavalli, A.; Belluti, F.; Gobbi, S.; Rampa,
A.; Valenti, P.; Palzer, M.; Palusczak, A.; Hartmann, R. W. J. Med. Chem.
2001, 44, 672–680, and references therein.
Org. Lett., Vol. 10, No. 11, 2008
2161

We propose that the gold catalyst serves as Lewis acid in
both formation of ketone enolates and their addition reac-
tions. However, gold catalysis of these particular transforma-
tions under the conditions given significantly differs from
possible catalysis by other Lewis acids. Thus, the use of
ZnCl2, AlCl3 or BF3·OEt2 did not lead to formation of 1,5-
diketones.
By analogy to this mechanistic proposal, the formation of
quinolines detailed above (Scheme 2, A) possibly begins with
imine formation facilitated by the Lewis acidity of the gold
catalyst, followed by enamine addition (13) to the ketone.
Water elimination eventually leads to quinoline formation.
This mechanism is supported by a report of a successful
enamine intermediate isolation in a related gold-catalyzed
reaction.9
was treated under the same reaction conditions but without
acetophenone for 48 h, 12 was not formed. These findings
suggest that both products probably originate from 14.
Dihydroquinoline (8) formation most likely begins with
the generation of an imine from the aniline and the ketoester
(Scheme 2, C), followed by addition of the enolate to the
imine. Keto esters are more reactive substrates than ac-
etophenones and, therefore, should add to the R-imino ester
moiety (to give 16) which is a good electrophile17 in the
presence of a Lewis acid. An electron-rich benzene ring could
add to the keto ester group (to give 17), and water elimination
followed by proton shift would eventually form the dihyd-
roquinoline 8.
In conclusion, we have demonstrated the versatility of
gold-catalyzed aldol condensation reactions for the synthesis
of several different biologically relevant N-heterocycle
classes. Efficiency and ease of operation make these trans-
formations highly useful for the synthesis of compound
collections for chemical biology and medicinal chemistry
research.
Scheme 2
.
Proposed Mechanisms for the Gold-Catalyzed
Condensation Reactions
Acknowledgment. This work was supported by the
Ministry of Innovation, Science, Research and Technology
of North Rhine-Westphalia and Europa¨ische Union Euro-
paischer Fonds fu¨r Regionale Entwicklung.
Supporting Information Available: General experimental
procedures and data for selected compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL8005634
(13) For a recent gold catalyzed synthesis of diyhdroquinolines using
acetylenes, see: Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che, C.-M Org. Lett.
2007, 9, 2645–2648.
(14) For reports on the reaction of alkylpyruvates with anilines (yielding
products different from 8) see: (a) Chen, C.-Y.; Lieberman, D. R.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676–2677.
(b) Wu, Y.-C.; Liu, L.; Li, H.-J.; Wang, D.; Chen, Y.-J. J. Org. Chem.
2006, 71, 6592–6595. (c) Voronina, V.; Gein, E. V.; Khokhryakova, L. F.;
Tendryakova, N. P.; Vyaznikova, S. P.; Andreichikov, N. G.; Yu, S. Russ.
J. Gen. Chem. 1998, 68, 1267–1270. (d) Tapia, I.; Alcazar, V.; Grande,
M.; Moran, J. R. Tetrahedron 1988, 44, 5113–5116. (e) Eiter, K. Experientia
1955, 11, 189–191. For the reaction between anthranilic acid and pyruvic
acid, see: (f) Eiter, K.; Naegele, W.; Wendisch, D.; Haehner, B. Justus.
Liebigs. Ann. Chem. 1969, 724, 143–149.
(15) (a) Perry, N. B.; Blunt, J. W.; McCombs, J. D.; Munro, M. H. G.
J. Org. Chem. 1986, 51, 5476. (b) Johnson, J. V.; Rauckman, B. S.;
Baccanari, D. P.; Roth, B. J. Med. Chem. 1989, 32, 1942. (c) Carling, R. W.;
Leeson, P. D.; Moseley, A. M.; Baker, R.; Foster, A. C.; Grimwood, S.;
Kemp, J. A.; Marshall, G. R J. Med. Chem. 1992, 35, 1942. (d) Carling,
R. W.; Leeson, P. D.; Moseley, A. M.; Smith, J. D.; Saywell, K.;
Tricklebank, M. D.; Kemp, J. A.; Marshall, G. R.; Foster, A. C.; Grimwood,
S. Bioorg. Med. Chem. Lett. 1993, 3, 65. (e) Williamson, N. M.; March,
D. R.; Ward, A. D. Tetrahedron Lett. 1995, 36, 7721.
Similarly, the reaction of aldehydes with acetophenones
will involve intermediate 14 which is generated after enolate
addition to the aldehyde (Scheme 2, B). Attack of a further
enolate on 14 leads to 1,5-diketones 11. Water elimination
would yield the minor product 12. However, in a separate
reaction of 12 with acetophenone in the presence of the gold
catalyst, formation of 11 was not observed. Also, when 11
(16) For gold-catalyzed aldol reactions see: (a) Ito, Y.; Sawamura, M.;
Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405–6406. (b) Xu, L.-W.; Xia,
C.-G.; Li, L. J. Org. Chem. 2004, 69, 8482–8484.
(17) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36,
10–19.
2162
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