LETTER
A New Green Approach to the Friedländer Synthesis of Quinolines
205
Table 1 Gold Catalysed Synthesis of Quinolines 3a,b (continued)
Entry
Compound 1
Compound 2
Product 3 Yield (%)
Previously reported results
1
1
O
2a
Ph
HCl, 100–200 °C,18 2 h (Yield: 47%)
N
1i
3
k (73%)d,e
a
b
c
d
e
Yields refer to single runs, are given for pure isolated product and are based on 2.
Unless otherwise stated reactions were carried out using the following molar ratios: 1:2:NaAuCl = 1.5:1:0.025, at r.t. in EtOH.
The hydrochloride salts of o-aminobenzophenone and o-aminoacetophenone were used.
Reactions were carried out at 60 °C.
4
The catalyst used was KAuCl (Strem Chemicals).
4
In the reaction of the aryl-alkyl dicarbonyl 1c with 2a we ‘green’ approach to the Friedländer synthesis of quinol-
observed the regioselective formation of quinoline 3c de- ines that requires neither harsh conditions nor the use of
rived by the amination of the aliphatic carbonyl group hazardous acids or bases.
(
Table 1, entry 3). Surprisingly, when the 1,1,1-tri-
fluoacetylacetone 1e was allowed to react with 2a under
the usual reaction conditions a regioselective condensa-
Acknowledgement
tion reaction at the acetyl group led to β-enaminone 4 as The authors gratefully acknowledge the Ministero dell’Università e
1
9
della Ricerca Scientifica (MURST) for financial support.
the main reaction product (65% yield) (Scheme 3). The
sequential condensation/annulation reaction to form 3g
was accomplished by heating the reaction mixture at
References
6
0 °C for 12 hours (Scheme 3). Very likely, the strong
electron-withdrawing trifluoroacetyl group hinders the
annulation step.
(
1) Doubè, D.; Blouin, M.; Brideau, C.; Chan, C.; Desmarais, S.;
Ethier, D.; Falgueyret, J. P.; Friesen, R. W.; Girard, M.;
Girard, Y.; Guay, J.; Tagari, P.; Young, R. N. Bioorg. Med.
Chem. Lett. 1998, 8, 1255.
R
(2) Kalluraya, B.; Sreevinasa, S. Farmaco 1998, 53, 399.
R
(
3) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.;
O
R''
O
EtOH
Zilberstein, A. J. Med. Chem. 1994, 37, 2129.
R'' +
X
X
R'
(4) (a) Huma, H. Z. S.; Halder, R.; Kaltra, S. S.; Das, J.; Iqbal,
J. Tetrahedron Lett. 2002, 43, 6485. (b) Kim, J. N.; Chung,
Y. M.; Im, Y. J. Tetrahedron Lett. 2002, 43, 6209.
NH2
Au (III)
N
R'
1
2
3
R = Ph, Me
X = H, Cl
(
c) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Moreno-Manãs,
M.; Vallribera, A. Tetrahedron Lett. 2002, 43, 5537.
d) Legros, J.-Y.; Primault, G.; Fiaud, J.-C. Tetrahedron
001, 43, 2507. (e) Coffey, D. S.; May, S. A.; Ratz, A. M. In
(
2
Scheme 2
Progress in Heterocyclic Chemistry, Vol. 13; Gribble, G.
W.; Gilchrist, T. L., Eds.; Pergamon: London, 2001, 243;
and references therein.
Ph
(
5) Cheng, C.-C.; Yan, S.-J. In Organic Reactions, Vol. 28; J.
Wiley: New York, 1982, 37; and references therein.
EtOH
r.t.
O
O
(6) (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Catalysis
Today 2002, 72, 19. (b) Dyker, G. Angew. Chem. Int. Ed.
H
CF
3
N
2
000, 39, 4237.
NaAuCl
4
4
(65%)
Ph
1e + 2a
(7) (a) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Adv.
Synth. Catal. 2001, 343, 443. (b) Arcadi, A.; Di Giuseppe,
S.; Marinelli, F.; Rossi, E. Tetrahedron: Asymmetry 2001,
12, 2715.
O
EtOH
CF
3
(
8) Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F. Green
Chemistry, in press.
60 °C
N
(
9) (a) Rossi, E.; Abbiati, A.; Arcadi, A.; Marinelli, F.
Tetrahedron Lett. 2001, 42, 3705. (b) Arcadi, A.; Marinelli,
F.; Rossi, E. Tetrahedron 1999, 55, 13233.
3g (50%)
Scheme 3
(
10) ZnCl has been previously reported as catalyst in the
2
Friedländer synthesis of quinolines: Walser, A.; Flynn, T.;
Fryer, R. I. J. Heterocycl. Chem. 1975, 12, 737.
It is clear from our results that the gold catalysed reaction
of o-amino substituted aromatic carbonyls with ketones
containing active methylene groups appears to provide an
efficient new tool for the synthesis of quinolines under
mild conditions. In conclusion, we have developed a
(11) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002,
4, 1319.
12) A typical procedure for quinoline 3 is as follows: to a
solution of 2-amino-5-chlorobenzophenone 2c (0.2 g, 0.86
mmol) and 2,4-pentanedione 1b (0.13 g, 1.29 mmol) in
(
Synlett 2003, No. 2, 203–206 ISSN 0936-5214 © Thieme Stuttgart · New York