A convenient method for the synthesis of 3,5,7-trimethoxy-2-phenyl-4-quinolones

Article abstract of DOI:10.1016/S0040-4039(00)01226-0

The synthesis of 2-aryl-3,5,7-trimethoxy-4-quinolones was accomplished in three steps starting from 3,5-dimethoxyaniline and an aroyl chloride. These structures might be used as potential flavonol analogs. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01226-0

Tetrahedron Letters 41 (2000) 7037±7039
A convenient method for the synthesis of 3,5,7-trimethoxy-
2-phenyl-4-quinolones
Chantal Beney, Mohamed Hadjeri, Anne-Marie Mariotte and Ahcene Boumendjel*
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Laboratoire de Pharmacognosie, Departement de Pharmacochimie Moleculaire (UMR-CNRS 5063),
UFR de Pharmacie de Grenoble, 38706 La Tronche, France
Received 15 June 2000; accepted 18 July 2000
Abstract
The synthesis of 2-aryl-3,5,7-trimethoxy-4-quinolones was accomplished in three steps starting from 3,5-
dimethoxyaniline and an aroyl chloride. These structures might be used as potential ¯avonol analogs.
# 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 3-methoxyphenylquinolones; synthesis.
Since the discovery that ¯avonoids possess good inhibitory activity toward protein tyrosine
kinases,1,2 the synthesis and SAR studies on ¯avonoids have been the goal of many research
groups.3 Among the ¯avonoid analogs studied, 2-phenyl-4-quinolones were found to be particularly
interesting (Fig. 1).4 They are structurally similar to ¯avonoids, and they also have an available
nitrogen for further extension and for branching di€erent substituents. In ¯avonoids, 3,5,7-tri-
hydroxyl groups are often required for good activity and this was correlated with their ability to
mimic the adenine moiety of ATP. This analogy was recently demonstrated by the high-resolution
X-ray structure of cyclin-dependent protein kinase 2 co-crystallized with an 8-substituted ¯avone
(L868276).5 The recent co-crystallization of quercetin (5,7,30,40-tetrahydroxy¯avonol) with
tyrosine kinase Hck con®rmed the role of 3-, 5- and 7-hydroxy groups for mimicking the adenine
moiety of nucleotides.6
Figure 1. X=O: ¯avonol; X=N: 3-hydroxy-2-phenyl-4-quinolone
* Corresponding author. Tel: +33-4-76518688; fax: +33-4-76637165; e-mail: ahcene.boumendjel@ujf-grenoble.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01226-0

7038
If the synthesis of ¯avonols can now be accomplished through convenient methods,7 to the best
of our knowledge, there is no available synthesis of quinolones having 3,5,7-hydroxyl groups. The
search for an approach to 3,5,7-trihydroxy-4-quinolones as potential analogs of quercetin was
undertaken in the framework of a project related to the synthesis of biologically active ¯avonol
analogs.
2-Phenyl-4-quinolones can be synthesized by several pathways.8 The most convenient method
is the one using ortho-aminoacetophenones as starting building blocks prepared by nitration of
the corresponding acetophenone, followed by hydrogenation in the presence of active carbon.4c
However, the introduction of an oxygen atom at position 3 requires an oxidation of the
assembled quinolones, which might be incompatible with the presence of oxidant-sensitive
substituents. In our method, the oxygen atom at position 3 was introduced early in the synthesis
via a Friedel±Crafts reaction, as shown in Scheme 1.
Scheme 1.
Reaction of 3,5-dimethoxyaniline with a benzoyl chloride derivative in the presence of Et3N
gave quantitatively the 3,5-dimethoxyphenyl-N-phenylamide 1. Friedel±Crafts acylation with
methoxyacetyl chloride in 1,2-dichloroethane and in the presence of stannic chloride (SnCl4) gave
the corresponding N-phenylamido methoxyacetophenone 2 in 26±42% yield. It should be
mentioned that anhydrous 1,2-dichloroethane and high dilution (30 ml solvent/mmol of 1) are
very important for the success of this step. Cyclization of 2 in the presence of t-BuOK in t-butanol
at 80ꢀC gave quinolones 3 in 53±80% yield (Table 1).
Table 1
Preparation of 2-aryl-3,5,7-trimethoxy-4-quinolones 3

7039
In conclusion, a three-step synthesis of 3,5,7-trimethoxy-2-phenyl-4-quinolones is reported
starting from commercially available materials. These quinolones 3 can be used as analogs of
methoxylated ¯avones, they can be demethylated to give hydroxylated ¯avones and, more
interestingly, N-substituted quinolones can be easily prepared, since the hydroxyls are fully
protected.
(4,6-Dimethoxy-2-benzamido)methoxyacetophenone 2. To an ice-cooled solution of N-(3,5-
dimethoxyphenylbenzamide 1 (prepared from 3,5-dimethoxyaniline and a benzoyl chloride) in
anhydrous 1,2-dichloroethane (30 ml/mmol) under N2 was slowly added SnCl4 (2 equiv.). Freshly
distilled methoxyacetyl chloride (1 equiv.) was added dropwise as a solution in 1 ml of 1,2-
dichloroethane and the reaction was allowed to warm to room temperature and stirred for 4 h.
After this time, the solution was poured onto ice and the product was extracted with AcOEt (three
times). The organic layers were washed with water, dried and evaporated. Compound 2 (more
polar than 1) was isolated by silica gel column chromatography, eluting with cyclohexane:ethyl
acetate (9:1).
3,5,7-Trimethoxy-2-phenyl-4-quinolones 3. To a solution of 2 in distilled t-butanol (2 ml/mmol)
was added t-BuOK (5 equiv.) and the mixture was heated at 80ꢀC under N2 for 24 h. The mixture
was cooled to room temperature, poured onto an aqueous NH4Cl saturated solution and
extracted with AcOEt. The organic layers were washed with water, brine, dried and concentrated.
The mixture was puri®ed by silica gel ¯ash chromatography, eluting with cyclohexane:ethyl
acetate (8:2), to a€ord quinolones 3.
References
1. Harborne, J. R. The Flavonoids: Advances in Research Since 1986; Chapman & Hall: London, 1994.
2. (a) Hagiwara, M.; Inoue, S.; Tanaka, T.; Nunoki, K.; Ito, M.; Hidaka, H. Biochem. Pharmacol. 1988, 37, 2987±
2993. (b) Geahlen, R. L.; Koonchanok, N. M.; McLaughlin, J. L.; Pratt, D. E. J. Nat. Prod. 1989, 52, 982±986.
3. (a) Levitzki, A.; Gazit, A. Science 1995, 267, 1782±1788. (b) Cushman, M.; Zhu, H.; Geahlen, R. L.; Kraker, A. J.
J. Med. Chem. 1994, 37, 3353±3362. (c) Cunningham, B. D.; Threadgill, M. D.; Groundwater, P. W.; Dale, I. L.;
Hickman, J. A. Anticancer Drug. Des. 1992, 7, 365±384.
4. (a) Kuo, S. C.; Juang, J. P.; Lin, Y. T.; Wu, T. S.; Lednicer, D.; Paul, K. D.; Lin, C. M.; Hamel, E.; Lee, K. H.
J. Med. Chem. 1993, 36, 1146±1156. (b) Li, L.; Wang, H. K.; Kuo, S. C.; Wu, T. S.; Mauger, A.; Lin, C. M.;
Hamel, E.; Lee, K. H. J. Med. Chem. 1994, 37, 3400±3407. (c) Li, L.; Kang, H.; Kuo, S. C.; Wu, T. S.; Lednicer,
D.; Lin, C. M.; Hamel, E.; Lee, K. H. J. Med. Chem. 1994, 37, 1126±1135.
5. De Azevedo, W. F.; Mueller-Dieckmann, H. J.; Schulze-Gahnem, U.; Worland, P. J.; Saysville, E.; Kim, S. H.
Proc. Natl. Acad. Sci. USA 1996, 93, 2735±2740.
6. Sicheri, F.; Moare®, I.; Kuriyan, J. Nature 1997, 385, 602±609.
7. Fougerousse, A.; Gonzalez, E.; Brouillard, R. J. Org. Chem. 2000, 65, 583±586.
8. (a) Desai, K.; Desai, C. M. Indian J. Chem. 1967, 5, 170±176. (b) Fuson, R. C.; Burness, D. M. J. Chem. Soc. 1946,
68, 1270±1275. (c) Chen, B. C.; Huang, X.; Wang, J. Synthesis 1987, 482±483. (d) Chong, R. J.; Siddiqui, M. A.;
Snieckus, V. Tetrahedron Lett. 1982, 27, 5325±5328.