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L. Yu. Safina et al. / Tetrahedron Letters 50 (2009) 5245–5247
Based on this background, a study of the cyclization of the
F
F
+
Ph
+
Ph
+
Z
_2H+
Z
2,3,4,5-tetrafluoro- (1a), 2,4,5-trifluoro- (1b), 2,3,5-trifluoro- (1c),
4-X-3,5-difluoro- (X = H 1d, Br 1e, I 1f) anilides of cinnamic acid
to the corresponding fluorinated 4-phenyl-3,4-dihydroquinoline-
2-ones 2 and subsequent dehydrophenylation to quinolin-2-ones
3 is reported.
+
_
2H
2
+
OH
1a-f
+
OH
N
H
N
H
Y
Y
X
X
6
5
Cinnamanilides 1a–f were obtained in 70–82% yields by reac-
tion of cinnamoyl chloride with the corresponding polyfluoroani-
lines in aqueous acetone/K2CO3 according to the reported
procedure28 (see Supplementary data).
Scheme 3.
It seemed expedient to also study the direct conversion of ani-
lides 1a–f into quinolin-2-ones 3a–f in the presence of AlCl3. We
found that reaction of 1b–e with AlCl3 at 100–160 °C provided
compounds 3b–e in good yields (Scheme 2), although the reaction
of 1a with AlCl3 carried out at 120–125 °C and 155–160 °C led to
complex mixtures, containing only ꢀ40% and ꢀ60% of 3a,
respectively.
The successful synthesis of quinolinones 3a–e opens the oppor-
tunity to synthesize a large variety of their derivatives, particularly
products of their nucleophilic functionalization at both the carbocy-
clic and the heterocyclic moieties. As an example, reactions of com-
pounds 3a–e with POCl3 gave 2-chloroquinolines 4a–e in 61–73%
yields (Scheme 2) which are expected to serve as versatile starting
materials for preparing 2-functionalized polyfluoroquinolines.
In conclusion, we have developed an efficient synthesis of 4-phe-
nyl-3,4-dihydroquinolin-2-ones, quinolin-2-ones and 2-chloro-
quinolines with a polyfluorinated carbocyclic moiety based on
superacidic activation and electrophilic cyclization of the corre-
sponding polyfluorinated anilides of cinnamic acid.
The transformations of 1a–f into the target products 2a–f and
3a–f are shown in Scheme 2. Cyclization of 1a in CF3SO3H was
accomplished in 24 h at room temperature to give 5,6,7,8-tetra-
fluoro-4-phenyl-3,4-dihydroquinolin-2-one (2a) in 84% yield,
whereas 1b gave 5,6,8-trifluoro-4-phenyl-3,4-dihydroquinolin-2-
one (2b) in 70% yield in three days. Increasing the reaction time
did not improve the yields of 2a and 2b because of secondary reac-
tions. In contrast, compounds 1c–f were converted into the corre-
sponding phenyldihydroquinolin-2-ones 2c–f in good yields
(90À95%) in 24 h.
Following the originally suggested mechanism of cyclization for
nonfluorinated anilides 1,20 it can be assumed that compounds 1a–
f react through the intermediacy of superelectrophilic29 dications 5
formed by O,C-diprotonation according to Scheme 3.30
Substituents Z, X and Y could influence both the equilibrium
concentration of dications 5 and the energy of the cyclization tran-
sition state. The latter, to some extent, is structurally similar to
intermediates 6. The comparatively poor reactivity of 1a and 1b
compared with that of the other cinnamanilides can be explained
both by the lower concentration of the corresponding dications 5
owing to the ÀI effect of Z, X = F and by the decreased stability of
6 due to the sufficiently strong ÀI effect of the fluorine atoms meta
to the position attacked by the electrophile.
Acknowledgements
The Russian Foundation of Basic Research is acknowledged for
the financial support (Project 09-03-00248-a) and for access to
the STN International databases (Grant 00-03-40142) via the STN
Center in the Institute of Organic Chemistry, Siberian Branch of
the Russian Academy of Sciences.
In accord with known data for nonfluorinated 2,20 compounds
2a–f do not undergo elimination of benzene in triflic acid. In fact,
reaction 2?3 requires a stronger acid and harsher conditions, for
example, a large molar excess of AlCl3 at >100 °C.15–21 On the other
hand, dehydrophenylation of products 2a–f might suffer from sub-
stitution of fluorine by chlorine under the action of AlCl3 at
elevated temperature.11,17 Nevertheless, it turned out that dihy-
droquinolin-2-ones 2a and 2c,d reacted smoothly at 110–160 °C
to give quinolin-2-ones 3a and 3c,d, respectively, in 95–98% iso-
lated yields (Scheme 2). Reaction of 2f with AlCl3 (110–115 °C)
was complicated giving a 1:3 mixture of 3f and 3d resulting from
the partial hydrodeiodination of 2f and/or 3f. Taking this into
account, the reaction of the bromo compound 2e with AlCl3 was
carried out under milder conditions (95–100 °C) and this provided
a mixture of 3e and 3d in a 9:1 ratio.
Supplementary data
Supplementary data (complete experimental and spectroscopic
data) associated with this article can be found, in the online ver-
References and notes
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I Khimicheskij
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X
F
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CF3SO3H
Y
N
H
2a−f
O
F
Ph
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Z
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Y
N
H
O
AlCl3
for 2a,c-e
X
F
Z
1a−f
AlCl3
for 1a−e
POCl3
Z
Y
N
H
O
Y
N
Cl
X
X
4a−e
3a−e
11. Inglis, S. R.; Stojkoski, C.; Branson, K. M.; Cawthray, J. F.; Fritz, D.; Wiadrowski,
E.; Ryke, S. M.; Booker, G. W. J. Med. Chem. 2004, 47, 5405.
a X = Y = Z = F; b X = Z = F, Y = H; c X = Y = F, Z = H;
12. Antoine, M.; Barreau, M.; Disconclonclois, J. F.; Girard, P.; Piccaut, G. EP
379412; Chem. Abstr. 1991, 114, 143393p; EP 379414 Chem. Abstr. 1991, 114,
143394q; EP 431991; Chem. Abstr. 1992, 116, 6538s.
d X = Z = H, Y = F; e X = H, Y = F, Z = Br; f X = H, Y = F, Z = I
Scheme 2.