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New Journal of Chemistry
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heterocycle-aldehyde, could react with 1-(2-aminophenyl)ethan-1-
one 1a smoothly and the desired quinolones could be obtained
efficiently in good yields. Benzaldehydes with electron-donating
groups such as methyl and methoxyl, achieved better results than
those with electron-withdrawing groups (Scheme 2, 3ab-3ao), and
the functional groups at the para-position exhibited more
outstanding results than those at the meta-position, followed by
those at the ortho-position (Scheme 2, 3ab-3an). These results
demonstrated that the electronic effects and steric effect had
considerable influence on the formation of the target products.
Heterocycle-aldehyde 2p and 1-naphthaldehyde 2q were also
successfully converted to the desired product respectively (Scheme
2, 3ap-3aq). Unfortunately, an aliphatic aldehyde did not get desired
product (Scheme 2, 3ar). We then examined the substituent group
Conclusions
In conclusion, we have developed a noveDl OanI:d10e.1f0fi3c9ie/Cn7tNmJ0e1t2h9o3Dd
to synthesize substituted 2-Aryl-4-quinolones which are useful
intermediates for the preparation of biologically active
compounds. Simple operation with inexpensive reagents and
mild reaction conditions make this efficient protocol practical.
The avoidance of preparation of substrates and fewer synthetic
steps will arouse keen interest to chemistry and biology.
Notes and references
1
(a) A. F. Pozharskii, A. T. Soldatenkov and A. R. Katritzky, in:
Heterocycles and Health, in: Heterocycles in Life and Society,
John Wiley & Sons, Chichester, UK, 1997, p. 135–164; (b) O.
A. Attanasi, L. Bianchi, L. A. Campisi, L. D. Crescentini, G. Favi,
and F. Mantellini, Org. Lett., 2013, 15 (14), 3646; (c) S.
Mantenuto, C. Ciccolini, S. Lucarini, G. Piersanti, G. Favi, and
F. Mantellini, Org. Lett., 2017, 19 (3), 608; (d) G. N. Roviello,
G. Roviello, D. Musumeci, D. Capasso, S. D. Gaetano, M.
on
1-(2-aminophenyl)ethan-1-ones.
1b and
1-(2-amino-4-
1-(2-amino-4-
methylphenyl)ethan-1-one
fluorophenyl)ethan-1-one 1c transformed smoothly to give the
desired products (3ba, 3ca) in 58% and 52% yields, respectively
(Scheme 2, 3ba-3ca).
Costanzo and C. Pedone, RSC Adv., 2014, 4, 28691; (e) G. N.
Roviello, G. Roviello, D. Musumeci, E. M. Bucci and C.
Pedone, Amino Acids, 2012, 43, 1615.
2
(a) M. A. Beniddir, E. L. Borgne, B. I. Iorga, N. Loaec, O. Lozach,
L. Meijer, K. Awang and M. Litaudon, J. Nat. Prod., 2014, 77
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1117; (b) C. Mugnaini, S. Pasquini and F. Corelli, Curr. Med.
Chem., 2009, 16, 1746; (c) Y. Zhi, L. X. Gao, Y. Jin, C. L. Tang, J.
Y. Li, J. Li and Y. Q. Long, Bioorg. Med. Chem., 2014, 22, 3670;
(d) G. Manfroni, R. Cannalire, M. L. Barreca, N. Kaushik-Basu,
P. Leyssen, J. Winquist, N. Iraci, D. Manvar, J. Paeshuyse, R.
Guhamazumder, A. Basu, S. Sabatini, O. Tabarrini, U. H.
Scheme 3. Control Experiments.
Danielson, J. Neyts and V. Cecchetti, J. Med. Chem., 2014, 57
,
1952; (e) S. Cretton, S. Dorsaz, A. Azzollini, Q. Favre-Godal, L.
Marcourt, S. N. Ebrahimi, F. Voinesco, E. Michellod, D.
Sanglard, K. Gindro, J. L. Wolfender, M. Cuendet and P.
Christen, J. Nat. Prod., 2016, 79, 300; (f) H. Huse and M.
Whiteley, Chem. Rev., 2011, 111, 152.
To gain mechanistic insights into this transformation, some
control experiments were carried out (Scheme 3). Firstly, we
carried out a reaction of 1a and 2a in the presence of 3 equiv of
o
TEMPO and 2 equiv of KHCO3 at 80 C in DMSO, the desired
3
4
(a) P. Hradil, J. Hlavac, M. M. Soural, Hajduch, M. Kolar and R.
product 3aa was not gained, whereas the intermediate
harvested as major product (Scheme 3, a). Then the
intermediate was performed under standard conditions and
4 was
Vecerova, MiniRev. Med. Chem., 2009, 9, 696; (b) R. D. Larsen,
In Science of Synthesis, D. S. Black, Ed. Thieme: Stuttgart, 2005,
Vol. 15, p 551; (c) Y. Xia, Z. Y. Yang, P. Xia, K. F. Bastow, Y.
Tachibana, S. C. Kuo, E. Hamel, T. Hackl and K. H. Lee, J. Med.
Chem., 1998, 41, 1155; (d) S. X. Zhang, J. Feng, S. C. Kuo, A.
Brossi, E. Hamel, A. Tropsha and K. H. Lee, J. Med. Chem., 2000,
43, 167; (e) W. Hu, J. P. Lin, L. R. Song and Y. Q. Long, Org. Lett.,
2015, 17, 1268.
4
4
could convert to 3aa successfully (Scheme 3, b).
R. C. Read, I. Morrissey and J. E. Ambler, Respiratory Tract
Infections and Fluoroquinolones; Science Press: London, 2002,
pp 1-5.
5
6
C. P. Jones, K. W. Anderson and S. L. Buchwald, J. Org. Chem.,
2007, 72, 7968.
(a) G. Cheng, H. Hao, M. Dai, Z. Liu and Z. Yuan, Eur. J. Med.
Chem., 2013, 66, 555; (b) W. R. Baker, S. P. Cai, M. Dimitroff,
L. M. Fang, K. K. Huh, D. R. Ryckman, X. Shang, R. M. Shawar
and J. H. Therrien, J. Med. Chem., 2004, 47, 4693.
4-Quinolones have two tautomeric forms: either the hydroxy
tautomer as 4-hydroxyquinoline or the carbonyl tautomer as
4-quinolones, although these compounds exist favorably in
the keto form. For more information, see: (a) G. Pfister-
Guillouzo, C. Guimon, J. Frank, J. Ellison and A. R. Katritzky,
Justus Liebigs Ann. Chem., 1981, 366; (b) M. J. Mphahlele and
A. M. El-Nahas, J. Mol. Struct., 2004, 688, 129.
7
Scheme 4. Plausible mechanistic pathway.
Based on the above results and previous literatures,14 a plausible
mechanism is proposed for the formation of the 2-Aryl-4-quinolones
as shown in Scheme 4. Firstly, 1-(2-aminophenyl)ethan-1-one 1a
reacts with benzaldehyde 2a to provide intermediate 4. Then the
cyclization of 4 to get the intermediate A, which was further oxidized
to obtain the desired product 3aa.
8
(a) A. S. Wagman and M. P. Wentland, In Comprehensive
Medicinal Chemistry II, J. B. Taylor, D. J. Triggle, Eds. Elsevier:
Oxford, U. K., 2007; Vol.
7, p. 567. (b) M. G. Ferlin, G.
Chiarelotto, V. Gasparotto, L. D. Via, V. Pezzi, L. Barzon, G. Palu
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