Rapid synthesis of quinoline-4-carboxylic acid derivatives from arylimines and 2-substituted acrylates or acrylamides under indium(III) chloride and microwave activations. Scope and limitations of the reaction

Article abstract of DOI:10.1039/b509400c

Rapid synthesis of quinoline-4-carboxylic acid derivatives has been achieved by reaction of 2-methoxy acrylates or acrylamides with N-arylbenzaldimines in acetonitrile under InCl₃ catalysis and microwave irradiation. Isolated yields up to 57% within 3 min have been obtained. The Lewis acid and the microwave activation appeared as crucial parameters for the reaction. The role of indium chloride and ytterbium triflate was specified using ¹³C NMR data and model theoretical studies. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b509400c

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A R T I C L E
Rapid synthesis of quinoline-4-carboxylic acid derivatives from
arylimines and 2-substituted acrylates or acrylamides under
indium(III) chloride and microwave activations. Scope and
limitations of the reaction
Dorothe´e Duvelleroy,a Ce´cile Perrio,*b Olivier Pariselc and Marie-Claire Lasne*a
a Laboratoire de Chimie Mole´culaire et Thioorganique, UMR 6507 CNRS-ENSICAEN,
Universite´ de Caen-Basse Normandie, 6 Boulevard du Mare´chal Juin, 14050 Caen Cedex,
France. E-mail: marie-claire.lasne@ensicaen.fr; Fax: 33 2 31 45 28 77; Tel: 33 2 31 45 28 92
b Groupe de De´veloppements Me´thodologiques en Tomographie par Emission de Positons, UMR
CEA, FRE CNRS 2698, Universite´ de Caen-Basse Normandie, Centre Cyceron, 15 boulevard
Henri Becquerel, 14070 Caen Cedex, France
c Laboratoire de Chimie The´orique, UMR 7616 CNRS-UPMC, Universite´ Pierre et Marie
Curie, 4 place Jussieu, F. 75252 Paris Cedex 05, France
Received 5th July 2005, Accepted 1st August 2005
First published as an Advance Article on the web 9th September 2005
Rapid synthesis of quinoline-4-carboxylic acid derivatives has been achieved by reaction of 2-methoxy acrylates or
acrylamides with N-arylbenzaldimines in acetonitrile under InCl3 catalysis and microwave irradiation. Isolated yields
up to 57% within 3 min have been obtained. The Lewis acid and the microwave activation appeared as crucial
parameters for the reaction. The role of indium chloride and ytterbium triflate was specified using 13C NMR data and
model theoretical studies.
common method to prepare quinolines (Skraup reaction).16 This
approach has been successfully applied to quinolines substituted
Introduction
Quinoline derivatives are entities often synthesised because
on the heterocycle moiety using a,b-unsaturated ketones under
of their occurrence in natural products and their widespread
indium trichloride catalysis and under microwave activation.17
biological activities (i.e. inhibitor of neurokinin receptors,1
Quinoline derivatives have also been formed under basic condi-
of Na+/H+ exchange,2 of caspase,3 and phosphodiesterase
tions when 2-aminobenzaldehydes are condensed with ketones
enzyme4), their potential as chemotherapeutic agents (malaria,5
(Friedlander reaction).14,16,18 However, this approach, and the
cancer,6 disorders of central nervous system,7 antimicrobial
previous ones, are limited to the synthesis of 4-alkyl-substituted
agents8) or as imaging agents.9 Recently, we showed that
quinolines.
the introduction of a fluorine atom in the 8-position of the
The introduction of a carboxylic acid function in the 4-
quinoline ring did not alter the affinity towards NK-3 receptors
position of the heterocycle has only been achieved by the
(Fig. 1) compared to Talnetant, a selective and potent NK-3
Pfitzinger or by the Doebner reactions. The former (Pftizinger)
antagonist.10 In our continuing interest for the development
is based on the condensation of isatic acids with a-methylene
of NK-3 receptor radioligands,11 for medical imaging using
carbonyl compounds.14,16,19 The poor availability of isatins,
positron emission tomography (PET), we needed to develop a
the lengthy reaction times and the reaction conditions have
rapid synthesis of fluoroquinoline-4-carboxylic acid derivatives
restricted this route to the synthesis of base-stable quinolinecar-
in order to have in hand a method for the introduction of
boxylic acids. The Doebner reaction, a three-component reac-
tion between benzaldehyde, pyruvic acid and an aniline, allows
the preparation of various 2-phenyl-4-quinolinecarboxylic acids
an 18F isotope (t1/2 110 min) from easily available radiolabeled
precursors.12
including those bearing a fluorine atom in the 5-, 6-,20 7-
or 8-position.14,21,22 However, attempts to prepare the 6-fluoro
derivative with the claimed yields failed in our hands.
The aza-Diels–Alder reaction between an N-arylimine and
vinyl ethers,23–25 or cyclopentadiene26 catalyzed by a Lewis
acid (the Povarov reaction)27 was studied. According to the
reaction conditions alkyltetrahydroquinolines or alkylquino-
lines were obtained. This methodology was also applied to the
preparation of 2-trifluoromethylquinolines via their tetrahydro
intermediates.28
It seemed to us that the Povarov reaction could be a
good alternative to the previously described methods for the
rapid preparation of fluoro-substituted quinolinecarboxylic acid
derivatives. Indeed, N-(fluorophenyl)benzaldimines or to N-aryl
fluorobenzaldimines labeled with fluorine-18 could be easily
synthesised from [2-] 29 or [4-18F]fluoroaniline,30 [4-18F] or [2-
18F]fluorobenzaldehydes.31 We anticipated that the reaction of
N-arylimines 1 with an acrylate bearing a leaving group at
C2 (2–7) could rapidly afford quinoline-4-carboxylic derivatives
Fig. 1 NK-3 receptors.
Several methods have been described for the synthesis of
substituted quinolines. They are usually based on the reaction of
primary aromatic amines with b-diketones (Combes reaction),13
with b-keto esters14 followed by a ring closure of the intermedi-
ate, under heating (Conrad–Limpach) or acid-catalysis (Knorr
synthesis).15 Reaction of anilines with acrolein (from glycerol
and sulfuric acid) in the presence of an oxidizing agent is another
3 7 9 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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8–10 (Scheme 1) via an in situ sequence: cycloaddition, elimina-
tion and aromatization (Scheme 2).26 Such a procedure, in which
the corresponding intermediate tetrahydroquinolines are not
isolated, would avoid the time-consuming oxidizing step.25–27,38
Here, we present the scope and limitations of the reaction of
imines 1 and dienophiles 2,32 3–5, 6,33 and 7,34 presented in
Scheme 1, with an attempt to understand the reactivity of the
different partners.
Results and discussion
Acrylates bearing a leaving group at C2 were chosen as
dienophiles and the reaction of imine 1a and acrylate 2 was stud-
ied as a model for the preparation of ethyl quinolinecarboxylic
esters 8a1 (Scheme 2).
In our first attempts, imine 1a was allowed to react with
an excess (2.5 equiv.) of acrylate 2 either without, or in the
presence of ytterbium triflate (0.1–0.4 equiv.).24 Whatever the
temperature and heating mode (room temperature, reflux of
acetonitrile or microwave activation), no reaction was observed
(i.e., Table 1, entries 1, 2). Different Lewis acids were then
tested. The starting material was completely recovered when
using BiCl3,35 whereas decomposition was the major reaction
with ZnCl2,36 SnCl4,37 InF3, In(OtBu)3, Sc(OTf)3,23,38,39 the esters
8a1 and 8a2 (not separable) being obtained in yields around 10%
(relative ratio: 75 : 25). The formation of this mixture of esters
is not surprising due to the ability of Lewis acids to promote
transesterifications.40 The best results (yield: 57%, Table 1,
17
entry 4) were obtained when InCl3 was used in conjunction
with microwave irradiation. InBr3 or InI3 were less efficient
(Table 1, entries 5, 6) and the use of a mixture of indium and
chlorotrimethylsilane41 did not improve the yields (Table 1, entry
9). As expected, the tetrahydroquinoline intermediate X was
never detected in the 1H NMR spectra of the crude products. In
order to optimize the yields, different solvents (DMF,42 CH3CN,
EtOH, toluene,43 H2O/CH3CN 23) or solid supports (SiO2,17
Al2O3,44 montmorillonite 45) were tested. Some of the results are
shown in Table 2. Acetonitrile gave the best results (Table 2, entry
1). DMF and toluene (Table 2, entries 2, 4) gave no reaction.
Yields of less than 40% were obtained when the reaction was
performed on silica gel impregnated with indium(III) chloride
and with microwave irradiation (Table 2, entries 8, 9), a method
which was previously shown to be efficient for the preparation of
4-alkylquinolines from anilines and a,b-unsaturated ketones.17
Ionic liquids, which have been found to catalyze the three-
component coupling reaction of aldehydes, amines and cyclic
enol ethers at room temperature,47 were also tested under
microwave irradiation. No reaction was observed when the
reaction was performed in 1,3-di-n-butylimidazolium bromide
or tetrafluoroborate, [bbim]Br or [bbim]BF4. However traces
Scheme 1 Reaction of imines 1 with 2-substituted acrylic acid deriva-
tives 2–7.
1
of the expected esters 8a were detected in the crude H NMR
spectrum when indium(III) chloride was added to the ionic
liquid (Table 2, entry 7). Using montmorillonite KSF at room
temperature according to a described procedure,48 or indium(III)
chloride (0.2 equiv.) supported on alumina49 under microwave
activation (150 W, 10 min) did not allow the reaction of imine 1
with acrylate 2 to proceed.
Fig. 2 presents the yields of quinolinecarboxylic esters 8a1
and 8a2 as a function of (a) the amount of indium trichloride,
(b) the microwave power, and (c) the reaction time. All the data
show that the reaction is sensitive to all of these parameters. The
highest yields can be reached when using 0.5 equiv. of indium
Scheme 2 Postulated intermediates in the reaction of imine 1a with
acrylate 2.
Table 1 Lewis acid screen for the reaction of imine 1a with 2-methoxy acrylate 2 a
Entry
Lewis acid
Loading/equiv.b
Activationc
90 ◦
Time
Yield (%)d
1
2
3
Yb(OTf)3
Yb(OTf)3
InCl3
0.4
0.4
0.5
C
24 h
3 min
24 h
0e
Trace
41
150 W
90 ◦
C
4
5
6
7
8
9
10
InCl3
InBr3
InI3
In(OTf)3
In(OtBu)3
In–TMSCl
Sc(OTf)3
0.5
0.5
0.5
0.5
0.5
0.5 : 10
0.2
150 W
150 W
150 W
150 W
150 W
150 W
150 W
3 min
3 min
3 min
3 min
3 min
3 min
3 min
57
30
36
18
0
24
12
a Solvent: acetonitrile; reaction carried out with 0.1 mmol of imine 1a, 0.25 mmol of 2. b Lewis acid equivalent for one equivalent of imine. c Classical
heating or microwave irradiation. d Isolated yields of esters 8a1 and 8a2. e The starting material was quantitatively recovered.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4
3 7 9 5

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Table 2 Solvent and solid support screen for the reaction of imine 1a with acrylate 2 a
Entry
InCl3/equiv.
Reaction mediumb
Time/min
Yield (%)c
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.2
0.2
CH3CN
DMF
EtOH
Toluene
3
3
3
3
3
3
3
4
10
57
0
18
0
H2O–CH3CN (v : v, 1 : 1)
0
CH3CN–perfluoro(methylcyclohexane) (v : v, 1 : 1)46
39
<5
33
38
[bbim][BF4] d
SiO2
SiO2
a Reaction carried out with imine 1a (0.1 mmol), 2 (0.25 mmol), and InCl3. b Microwave activation, 150 W, solvent (2 mL) or solid support (200 mg).
c Isolated yields. d [bbim][BF4]: 1,3-di-n-butylimidazolium tetrafluoroborate.
(Fig. 2b). When going from 150 to 200 W the yields dropped
from 57 to 35%.
To account for these results, the stability of the dienophile
under the reaction conditions was studied. When acrylate 2 or
imine 1a was separately submitted to the reaction conditions
[acetonitrile, InCl3 (0.5 equiv.), 150 W microwave activation,
3 min], complete polymerization of acrylate 2 was observed
whereas more than 80% of imine 1a were recovered. Under these
conditions, the quinolines 8a1 and 8a2 were stable.
Other acrylates were then tested. Substitution of the methoxy
group of acrylate 2 for a triflyl or a bromo substituent
dramatically decreased the yields of the quinoline carboxylates
(Table 3, entries 1–3). The transformation of 2-methoxy acrylate
into amide 3 and the reaction of the latter with imine 1a gave the
expected amide 9 in moderate yields (Table 3, entry 4). The use
of one equivalent of Lewis acid (Table 3, comparison of entries
4–7) was necessary for reaching 57%. Under these conditions
and starting from acrylamide 4, the quinoline 10 was formed in
47% yield (Table 3, entry 8). No reaction was observed with the
N-phenyl amide 5 whatever the amount of InCl3 (0.5 or 1 equiv.)
used (data not shown).
Acrylate 2 being formed by thermal elimination of methanol
from the acetal 12 of ethyl pyruvate 13,32 reaction of this acetal
12 with imine 1a was attempted under microwave activation
(3 min, 150 W) and in the presence of indium trichloride (0.5
equiv.). The expected quinolines 8a1 and 8a2 were formed in
17% yield. Under the same conditions, ethyl pyruvate 13 and
imine 1a yielded the quinolinecarboxylic esters 8a in 27% yield.
Finally, attempts to carry out the reaction in a one-pot procedure
[aniline, benzaldehyde, acrylate 2, InCl3 (0.5 equiv.), 150 W,
3 min] did not afford the expected esters 8a but gave tars.
The scope and limitations of the reaction were studied. The
results are presented in Table 4. The cycloaddition appears to
be dependent on the substituent on both aromatic rings. On the
aldehyde end of the imine, an electron withdrawing group in
the ortho- or meta-position impeded the cycloaddition (Table 4,
entries 3, 5) whereas a halogen in these positions allowed the
formation of quinolines 8b, 8d, 9b, 10b and 10n in 35–53% yields
(Table 4, entries 2, 4, 15, 17 and 20). No such effect resulted
from substitution in the para-position (Table 4, entries 7–10, 18).
Fig. 2 Reaction of imine 1a with acrylate 2. Yields as a function of
(a) amount of InCl3, (b) power of microwave irradiation, (c) reaction
time.
trichloride, and a 150 W microwave power for 3 min. Lowering
or increasing the amount of indium rapidly decreased the yields
(Fig. 2a). The reaction time appeared very important: the yields
dropped to 30% if the time was increased to 3.5 and 5 min
(Fig. 2c). A similar trend was observed with the microwave power
Table 3 Reaction of imine 1a with different dienophiles
Entry
X
Y
Dienophilea
InCl3/equiv.
Yield (%)b
1
2
3
4
5
6
7
8
OMe
OTf
Br
OMe
OMe
OMe
OMe
OMe
OEt
OEt
2
6
7
3
3
3
3
4
0.5
0.5
0.5
0.5
0.8
1.0
1.5
1.0
57
20
4
36
45
57
34
47
OMe
NHiPr
NHiPr
NHiPr
NHiPr
NH–(S)–CH(Ph)Et
a Reaction conditions: 2.5 equiv. vs. imine, microwave 150 W, 3 min. b Isolated.
3 7 9 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4

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Table 4 Synthesis of quinolinecarboxylic esters and amides 8–10 a
Entry Product
Y
Z1
Z2
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
8a
ORc
H
H
H
H
H
H
H
H
H
H
6-F
6-Cl
6-Br
H
H
H
H
H
H
57
40
0
45
0
8b
ORc
2ꢀ-F
8c
ORc
2ꢀ-CF3
3ꢀ-Br
3ꢀ-NO2
8d
ORc
8e
ORc
8f
ORc
3ꢀ,4ꢀ-(OMe)2 31
8g
ORc
4ꢀ-Br
4ꢀ-CN
4ꢀ-NO2
4ꢀ-F
H
20
32
23
27
24
25
52
57
43
47
35
48
49
53
53
8h
ORc
8i
8j
ORc
ORc
Fig. 3 Structures and numbering considered in the 13C NMR and
computational modelling. The dihedral angles Hi reported in Table 6
are defined according to: H1 = (10, 9, 1, 2), H2 = (1, 2, 1ꢀ, 2ꢀ) and H3 =
(10, 9, 1ꢀ, 2ꢀ) for imines 1 and H1 = (1, 2, 3, 4) for compounds 16 and 17.
8k
8l
8m
9a
9b
10a
10b
10j
10k
10n
10o
ORc
ORc
H
H
ORc
NHiPr
NHiPr
NHCH(Ph)Et
NHCH(Ph)Et
NHCH(Ph)Et
H
2ꢀ-F
H
intensity of the signals being 45% of their initial value at a
0.2 equiv. loading of Lewis acid. The signals of carbons C2
(substituted ethylenic carbon) and C3 (carbonyl) disappeared
as soon as 0.05 equiv. of Yb(OTf)3 was added. The same
experiments were carried out using InCl3. Such a strong effect of
the Lewis acid was not observed: carbons C2 and C3 disappeared
from the spectrum only at loadings higher than 0.2 equiv. The
chemical shifts of the other carbons were not modified and their
intensity was around 80% of their initial value at 0.2 equiv.
and 60% at 0.5 equiv. of Lewis acid. Complexation of enol
ether 14 was then studied. Addition of 0.05 equiv. of Yb(OTf)3
has no effect on the 13C NMR chemical shifts. However, at 0.1
and 0.2 equiv. Lewis acid loadings, important modifications of
the 13C NMR spectra between 10 and 70 ppm were observed
as well as the disappearance of the C1 and C2 signals. At
0.5 equiv. of Yb(OTf)3, all the carbons of enol ether 14 have
disappeared. With InCl3, the 13C NMR spectrum of enol ether
14 was modified as soon as 0.05 equiv. of the Lewis acid was
added, and higher amounts of the indium salt led to a complete
removal of the signals. Finally, the spectra of imine 1a in the
presence of Lewis acid at different loadings were recorded. The
results are presented in Table 5. Here again, a different behavior
of Yb(OTf)3 and InCl3 was observed. Comparison of the data
shows that Yb(OTf)3 is a stronger chelating agent than InCl3.
For example, the 13C chemical shift of C2 (imine carbon) is
deshielded by 3.4 ppm and carbon C4ꢀ by 3.7 ppm with a 0.5
equiv. loading of Yb(OTf)3 (Table 5, entry 5). In the presence
of InCl3 the same carbons are shifted by 0.4 and 0.5 ppm
respectively (Table 5, entry 10). At 0.2 equiv., the intensity of
the remaining signals was around 30% of their initial value.
The comparison of entries 11–14 with entries 5 and 10
(Table 5) shows that the 13C chemical shifts of the mixture imine
1a, Lewis acid and dienophile are strongly modified. With the
acrylate 2, the major effect is observed with Yb(OTf)3, whereas
with enol ether 14 the largest modifications were observed with
InCl3. The strong chelation of both partners in the reaction of
imine 1a and acrylate 2 in the presence of Yb(OTf)3 or in the
reaction of imine 1a and enol ether 14 catalyzed by InCl3 explain
why the expected adduct was not obtained in our reactions
(Table 1, entries 1 and 2, and Scheme 3) whereas Makioka et al.,24
Kobasyashi et al.23 and Reddy et al.53 observed the cycloaddition
of enol ethers.
2ꢀ-F
4ꢀ-F
H
NHCH(Ph)Et 6-F
NHCH(Ph)Et
NHCH(Ph)Et 8-F
H
3ꢀ-F
H
a Reaction conditions: imine 1a (0.1 mmol), 2 (0.25 mmol), and InCl3
(0.5 equiv. for 2, 1 equiv. for 3 and 4), 150 W, acetonitrile (2 mL), 3 min.
b Isolated yield. c Mixture of ethyl and methyl esters in a 75 : 25 ratio.
When the aniline component was substituted with a halogen
on the para-position, the best yields were observed with less
electron withdrawing atoms (Br compared to Cl and F, Table 4,
entries 11–13). Finally, comparisons of the yields obtained in
the formation of fluoroquinoline carboxylic esters and amides
showed that higher yields were obtained with amides wherever
the halogen was located (Table 4, entries 2, 10, 11, 15, 17–21).
All these data significantly differ from previous observations,50
where high yields were obtained for the Brønsted acid-catalyzed
reaction of electron-deficient imines with vinyl ethers such as
dihydropyran as the dienophile.
For comparison, we studied the reaction of imine 1a with
vinyl ethyl ether 14 and with 2-methoxypropene 15 (Scheme 3)
under the conditions determined above (InCl3, 0.5 equiv., 150
W, 3 min). Vinyl ethyl ether 14 gave no reaction whereas 2-
methoxypropene 15 yielded the expected quinoline in 28% yield.
These results contrast with those reported by Makioka et al.24
for the preparation of 11b (yield: 75%) using ytterbium triflate in
acetonitrile at room temperature, or with those from Kobayashi
et al.23 who, under similar conditions (ytterbium triflate in
acetonitrile, at room temperature, 20 h), described the formation
of the tetrahydro derivative of quinoline 11a (yield: 69%).
Theoretical modelling
Scheme 3
Computational procedure
In an attempt to understand how binding of the compounds
1a, 2 and 14 to ytterbium(III) and indium(III) might be occurring,
13C NMR experiments51,52 were performed with varying catalyst
loadings. Addition of increasing amounts (0.02, 0.05, 0.1, 0.2
equiv.) of Yb(OTf)3 to acrylate 2 did not modify the chemical
shifts of carbons C1, C7, C8, C9 (numbering in Fig. 3), the
In order to get another point of view liable to clarify the role of
Lewis acids, some computations have been performed on model
systems. Semiquantitative conclusions can be drawn using the
well-known semiempirical AM1 method,54 the results of which
can then be used within the framework of Fukui’s theory,55
which, in its simplest formulation, requires the determination
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4
3 7 9 7

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Table 5 Differences between the 13C NMR chemical shift values of imine 1a at various loadings of Lewis acid in d3-acetonitrilea
Dd
Dd
Dd
Dd
Dd
Dd
Dd
Dd
Dd
Entry
Lewis acid
Loading/equiv.
C2
C9
C1ꢀ
C4ꢀ
C2ꢀ
C7
C3ꢀ
C6
C10
Imine 1a + Lewis acidb
1
2
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
InCl3
0.02
0.05
0.1
0.2
0.5
0.02
0.05
0.1
0.2
0.5
0.1
−0.2
c
c
c
−0.1
−0.6
0.1
0.4
0.4
1.7
3.7
0.1
0.2
0.1
0.1
0.5
0.0
0.1
0.2
0.4
1.7
0.0
0.0
0.0
0.0
0.1
0.0
0.0
0.2
0.7
0.9
0.0
0.0
0.0
0.0
0.2
0.1
0.2
0.3
0.5
0.9
0.0
0.1
0.1
0.1
0.3
0.1
0.0
0.0
0.0
0.1
0.2
0.0
0.0
0.0
0.0
0.0
c
0.3
0.2
1.6
3.4
0.1
0.1
0.0
0.1
0.4
0.3
0.2
1.3
2.7
0.0
0.0
0.0
0.0
0.3
3
4
5
−0.4
c
c
6
7
−0.1
−0.1
−0.2
−0.1
−0.1
−0.1
−0.2
−0.6
InCl3
8
9
InCl3
InCl3
−0.2
c
10
InCl3
Imine 1a + acrylate 2 + Lewis acidb
c
c
c
c
c
c
c
c
c
11
12
Yb(OTf)3
InCl3
0.5
0.5
d
d
d
d
1.4
−0.6
0.1
0.6
−0.1
Imine 1a + ether 14 + Lewis acidb
d
c
d
c
d
c
d
c
d
c
13
14
Yb(OTf)3
InCl3
0.5
0.5
−0.0
−0.2
−0.1
−0.1
c
c
c
c
a Dd = d{[reagent(s) + Lewis acid] − d[reagent(s)]}. b Ratio imine–acrylate 2 or enol ether 14–Lewis acid = 1 : 2.5 : 0.5. c The signal of the carbon
disappears when adding Lewis acid. d The different signals cannot be assigned.
of HOMO/LUMO gaps between the reagents (frontier molec-
ular orbital approximation56): the smaller this gap, the more
favourable the associated reaction. In the present case, whether
the normal or inverse electron demand is involved may depend
on whether or not the process is concerted. The ground principle
of such an analysis must, however, always be kept in mind: it
states that the reaction must be under orbital control, which is far
from certain when dealing with aza-Diels–Alder cycloadditions
or with substituents combined in such a way that subtle capto-
dative effects appear, as might here be the case for dienophiles
such as 2, for example.57
The above-mentioned dihedral angles have been collected
with the p HOMO/LUMO energy values in Table 6. The
HOMO/LUMO gaps, DE, are shown in Table 7 for a selected
set of reactions, normal or inverse Diels–Alder:
Normal Electron Demand (NED):
DENED = | HOdiene − LUdienophile
|
Inverse Electron Demand (IED):
DEIED = | HOdienophile − LUdiene
|
The 26 reactions summarised in Table 7 have been selected
so that both reagents are not positively charged simultaneously
(an unfavourable Coulomb repulsion might occur in that case),
and also ensure that these reagents do not bind to AlCl3
simultaneously. However, Table 6 reports any quantity required
to investigate the full set of reactions being susceptible to arising
from the sets of non-substituted reagents.
A series of AM1 calculations has thus been performed58
on the compounds presented in Fig. 3, or on some of their
substituted analogues. The geometries of these species have
been fully optimized at the AM1 level of calculation, and the
nature of the stationary structures found, namely transition
states or not, has been characterized by the mean of a vibrational
analysis performed within the harmonic approximation: only
minimum energy structures are reported here, and, when several
stable conformers were found, only that of lowest energy
was considered. We then qualitatively investigated the role of
catalysts using two very simple models of Lewis acids: H+ and
AlCl3.59 Using H+ and AlCl3 as models precludes accounting
precisely for the possible p interactions occurring between the
Analysis and discussion
In the absence of any catalyst, 16 (methoxyethylene as a model
of ethoxyethylene) and 17 (methyl methoxyacrylate as a model
of acrylate 2) behave differently with respect to 1a. As seen
from Table 7 (entries 1 and 5), 16 undergoes an IED reaction,
whereas 17 favours the NED reaction. For the reaction between
1a and 17 there is, however, only a small difference between
the DENED and DEIED gaps (less than 0.6 eV, to be compared
with the 1.45 eV found for the reaction with 16). Consequently,
substitution effects on 1a might easily make the reaction become
of IED nature. Substitutions of the phenyl group with electron
withdrawing groups (NO2 and CF3 on 1a: cf. Table 7, entries 2–4
and 6–8) decrease the energy of both the HOMO and LUMO
of diene 1a, which results in reversing the electronic demand
when opposed to 17: the corresponding reactions become IED
reactions. Of course, when the substituted analogues of diene
1a are opposed to 16, the corresponding reactions remain of
IED type. The fact that, for the 1a + 17 reaction, only a very
small difference between DENED and DEIED is observed appears
especially interesting as theoretical calculations have shown that
the closer these gaps, the less control and the less reactivity.65
This might help to explain why no reaction of the imine 1a and
acrylate 2 was observed in the absence of catalyst and without
microwave activation.
catalyst and the chelated species. However, it is clear for both
60,61
InCl3 and Yb(OTf)3 – analogues to BF3
and it seems established for Yb(OTf)3
or to B(OR)3,62
63,64
– that coordination
to the catalyst involves the r skeleton, namely the in-plane
lone pair of nitrogen (N) of imine 1a, and the lone pair(s)
of oxygens O3, O4 (in-plane lone pairs), O5 and O6 in 16
and 17.
As our calculations have evidenced that strong deformations
of the skeletons might occur when chelating one reagent to the
model catalysts, we also report the value of some critical dihedral
angles Hi, the definitions of which are given in Fig. 3. Such
variations in the geometries, and, consequently, the sometimes
significant distortion with respect to (quasi-) planarity in the
vicinity of the relevant p bond(s), made it sometimes difficult
to unambiguously identify the p HOMOs and LUMOs: in such
cases, the orbital(s) having the proper symmetry with respect
to the double bond local plane, and also having the most
evident localization on the p bond(s) concerned, has (have) been
retained.
3 7 9 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4

View Article Online
Table 6 HOMO and LUMO energy levels (eV), and dihedral angles Hi for the model reagents, with or without catalyst
Entry
Reagent
HO
LU
H1
H2
H3
No catalyst
1
2
3
4
5
6
1a (diene)
−8.90
−9.30
−9.38
−9.17
−9.41
−9.99
−0.50
−1.21
−1.50
−0.87
+1.46
+0.06
35
31
30
32
180
180
7
0
0
−23
−142
−152
−152
−171
—
1a–NO2 (3ꢀ)
1a–NO2 (4ꢀ)
1a–CF3 (2ꢀ)
16 (dienophile)
17 (dienophile)
—
—
—
H+ as a catalyst
7
8
9
10
11
1a–H+ (N3)
16–H+ (O3)
17–H+ (O4)
17–H+ (O5)
17–H+ (O6)
−13.09
−16.27
−14.53
−16.22
−14.57
−5.51
−4.57
−6.15
−5.09
−5.49
33
116
177
177
171
3
—
—
—
—
−147
—
—
—
—
AlCl3 as a catalyst
12
13
14
15
16
17
18
19
1a–AlCl3 (N3)
−10.10
−11.15
−11.31
−11.70
−10.40
−10.56
−10.63
−10.34
−1.63
−0.14
−1.65
−0.96
−0.92
−2.09
−2.20
−1.88
62
115
173
168
170
−60
−60
−57
−36
—
—
—
—
40
50
46
−164
—
—
—
—
168
176
174
16–AlCl3 (O3)
17–AlCl3 (O4)
17–AlCl3 (O5)
17–AlCl3 (O6)
1e–AlCl3 (N3)
1i–AlCl3 (N3)
1c–AlCl3 (N3)
Table 7 HOMO/LUMO gaps (DENED and DEIED in eV) for selected
(more than 10 eV). Such variations are unlikely to be reversed
by substitution effects. It is thus clear that using the protonated
diene 1a–H+ always will lead to IED reactions when reacting
with 16 (the same result as without a catalyst) and also with
17 (the opposite result to that obtained without a catalyst). In
contrast, if the O-protonated 16 and 17 species are considered,
the reactions with 1a turn out to become of NED type.
Very similar conclusions can be drawn if using a more realistic
Lewis catalyst such as AlCl3 (Table 7, entries 15–26). It is worth
noting, however, that the numerical decreases of the HOMOs
and the LUMOs are by far less pronounced than when using
H+: the differences between the DENED and DEIED gaps remain at
about only 2–4 eV. Consequently, substitution effects on either
the chelated diene or the chelated dienophile might be able to
reverse the type of the reaction. We point out that, because of
the steric hindrance induced by AlCl3, the structure of 1a–AlCl3
is strongly distorted when compared to that of 1a and 1a–H+.
Complexing structure 1a when substituted by electroattractive
groups reinforces the conclusions found when no catalyst is used
(Table 7, entries 2–4 and 6–8): in these cases, an IED reaction
is still expected to occur with both 16 and 17 (Table 7, entries
21–26). The corresponding IED gaps suggest that the reaction
will be more efficient if catalyzed.
reactions involving model reagents, with or without catalysis
Entry
Reaction
DENED
DEIED
No catalyst
1
2
3
4
5
6
7
8
1a + 16
10.36
10.76
10.84
10.63
8.96
9.36
9.44
8.91
8.20
7.91
8.54
9.49
8.78
8.49
9.12
1a–NO2 (3ꢀ) + 16
1a–NO2 (4ꢀ) + 16
1a–CF3 (2ꢀ) + 16
1a + 17
1a–NO2 (3ꢀ) + 17
1a–NO2 (4ꢀ) + 17
1a–CF3 (2ꢀ) + 17
10.05
H+ as a catalyst
9
10
11
12
13
14
1a–H+ (N3) + 16
14.55
13.15
4.33
2.75
3.81
3.41
3.90
4.48
15.77
14.03
15.72
14.07
1a–H+ (N3) + 17
1a + 16–H+ (O3)
1a + 17–H+ (O4)
1a + 17–H+ (O5)
1a + 17–H+ (O6)
AlCl3 as a catalyst
15
16
17
18
19
20
21
22
23
24
25
26
1a–AlCl3 (N3) + 16
11.56
10.16
8.76
7.25
7.94
7.78
8.36
10.65
10.81
11.20
9.90
7.32
7.21
7.53
7.90
7.79
8.11
1a–AlCl3 (N3) + 17
1a + 16–AlCl3 (O3)
1a + 17–AlCl3 (O4)
1a + 17–AlCl3 (O5)
1a + 17–AlCl3 (O6)
1e–AlCl3 (N3) + 16
1i–AlCl3 (N3) + 16
1c–AlCl3 (N3) + 16
1e–AlCl3 (N3) + 17
1i–AlCl3 (N3) + 17
1c–AlCl3 (N3) + 17
If we consider AlCl3 as a model of Yb(OTf)3 or of InCl3, a
preferential complexation of imine 1a with respect to the acrylate
should favor an IED Diels–Alder reaction (Table 7, entry 16).
The 13C NMR data which show a stronger complexation of imine
1a than that of acrylate 2 in the presence of InCl3, and of imine
1a vs. enol ether 14 in the presence of Yb(OTf)3 are in good
agreement with this hypothesis. However, further investigations
are necessary to clarify the exact molecular mechanism of these
reactions.
7.98
12.02
12.09
11.80
10.62
10.69
10.40
If we now consider the role of a proton H+, the simplest
model of Lewis acid, we first observe (Table 6, entries 7–11)
a huge decrease of the HOMO and LUMO energies of the
protonated reagents when compared to those of their neutral
precursors. Moreover, significant geometrical distortions with
respect to the unprotonated species appear, which implies large
modifications in the conjugation effects within the reagents, and
thus variations in the HOMO/LUMO energy values. In all cases
(Table 7, entries 9–14), and in contrast with the previous results, a
large difference now appears between the DENED and DEIED gaps
Conclusion
Substituted quinoline 4-carboxylic esters or amides have been
synthesised in a one-pot procedure from N-arylimines and 2-
methoxyacrylic acid derivatives. The choice of the catalyst and
the microwave activation were crucial in obtaining satisfactory
yields and in determining the reactivity of the partners in the
formal aza-Diels–Alder reaction.
The described procedure, allowing the introduction of a
functional group in the 4-position of the heterocyclic ring,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4
3 7 9 9

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complements well the previously described synthesis of quino-
line derivatives. The conditions (3 min, excess of acrylic deriva-
tive versus the fluoro imine) could be easily adapted to the
synthesis of fluorine-18 ligands for medical imaging.
acid 5% (3 × 25 mL), then with aqueous NaHCO3 50% (3 ×
25 mL) and with water (1 × 25 mL). After drying over MgSO4,
filtration then evaporation of the solvent, the residue was diluted
with dichloromethane (25 mL). (S)-Phenylpropylamine (4.7 mL,
1.3 equiv.) and triethylamine (4.2 mL, 1.2 equiv.) were added to
the solution. The mixture was stirred under reflux for 4 h. After
cooling to room temperature, it was poured into aqueous citric
acid 5% (25 mL). The organic layer was successively washed with
aqueous citric acid 5% (2 × 25 mL), with saturated aqueous
NaHCO3 (1 × 25 mL), with brine (1 × 25 mL) and with
water (1 × 25 mL). It was then dried over MgSO4, filtered
and concentrated. The crude product was purified by column
chromatography over silica gel (pentane–ethyl acetate 80 : 20)
to yield the title compound 4 (4.9 g, 90%) as a white solid, mp
88 ◦C. [a]D20 = −143 (c 1 in MeOH). IR mmax/cm−1 (KBr): 3053,
2985, 1421, 1265, 896, 743. 1H NMR: dH 7.35–7.23 (5H, m), 6.80
(1H, s, NH), 5.37 (1H, d, J 1.5), 4.92 (1H, q, J 7.4), 4.42 (1H, d,
J 1.5), 3.64 (3H, s, OMe), 1.89–1.85 (2H, m), 0.91 (3H, t, J 7.4).
13C NMR: dC 161.9, 154.4, 142.3, 129.0, 127.7, 127.1, 90.2, 55.9,
Experimental
1H NMR, 13C NMR (62.9 MHz, with decoupling H broad
1
band) and 19F NMR (235 MHz) spectra were recorded on a
Bruker DPX 250 MHz instrument, with chloroform (CDCl3)
as the solvent and TMS (1H, 13C) or freon (19F) as the
internal standard. Data appear in the following order: chemical
shift in ppm, multiplicity (s: singlet, d: doublet, t: triplet, q:
quadruplet, sept: septuplet, m: multiplet), coupling constant
J in Hz. GC–MS analyses were recorded on Varian 3800
(GC) and Saturn 2000 (MS) instruments; CP-SIL 8CB (Low
BLEED/MS) column (30 m × 0.32 mm), with 5% phenyl 95%
dimethoxypolysiloxane as the stationary phase, was used for the
analysis. High resolution mass spectra (HRMS) were recorded
using a QTOF Micro spectrometer (Waters). Infrared spectra
(IR) were recorded on a Perkin-Elmer spectrometer 16 PC-
FT-IR. The conditions of analysis are specified in each case.
The melting points were obtained from a Kofler bench. Thin-
layer chromatography (TLC) was performed on silica gel 60F254
plates and visualized by UV irradiation. A Synthewave 402
Prolabo was used for the microwave irradiations. The reactions
were carried out in an open glass tube (id: 1.5 cm). Optical
rotation, measured with a Perkin Elmer 241 polarimeter, are
given in 10−1 deg cm2 g−1. Microanalyses were carried out with
a ThermoQuest CHNS-O apparatus. Tetrahydrofuran (THF)
was dried and distilled from sodium benzophenone ketyl under
nitrogen prior to use. Acetonitrile (CH3CN) was dried over CaH2
and distilled. Dimethylformamide (DMF) was dried over CaH2
and distilled under vacuum prior to use (0.02 bar). Ytterbium
triflate was dried at 200 ◦C for 48 h under reduced pressure
(0.02 bar). All the reagents commercially available were used
without further purification. Imines 1 were prepared by reaction
of the appropriate aniline and aldehyde. Spectroscopic and
analytical data of imines 1 are in agreement with the literature:
(1a, 1g, 1h),66 1b,67 1c,68 (1d, 1l),69 1e,70 1f,71 1j,72 1k,73 1m,74
1n,75 1o.72 Ethyl-2-methoxypropenoate 2 76 was prepared from
the methoxyacetal of ethyl pyruvate 13.32
•
55.1, 29.5, 11.1. MS (EI, GC–MS) m/z 219 (M+ , 55%), 204 (46),
190 (100, M − CH2CH3), 176 (36), 159 (21), 131 (37), 106 (44),
91 (65). CHN requires for C13H17NO2: C, 71.2; H, 7.8; N, 6.4%.
Found: C, 71.5; H, 8.2; N, 6.4%. HRMS calc.: 219.1259, found:
219.1266.
N-Phenyl-2-methoxypropenamide (5)
Using the same method as described above, the amide 5 was
obtained from 2-methoxypropenoic acid (1 g, 9.8 mmol) and
aniline (1.52 mL, 11.7 mmol) as a white solid (300 mg, 17%),
mp 78 ◦C. IR mmax/cm−1 (KBr): 3053, 2986, 1695, 1600, 1530,
1
1443, 1265, 1047, 895, 738. H NMR: dH 8.38 (1H, br s, NH),
7.60 (2H, d, J 7.7), 7.35 (2H, t, J 7.7), 7.12 (1H, t, J 7.7), 5.51
(1H, d, J 2.5), 4.56 (1H, d, J 2.5), 3.74 (3H, s, OMe). 13C NMR:
dC 159.8, 153.7, 137.2, 128.8, 124.3, 119.7, 90.5, 55.6. MS (EI,
GC–MS) m/z 177 (M•+, 100%), 162 (25), 146 (55), 134 (32), 57
(47). HRMS (C10H12NO2) calc.: 178.0868, found: 178.0858.
General procedure for the preparation of
2-arylquinoline-4-carboxylates
Ethyl-79 and methyl-2-phenylquinoline-4-carboxylate80 (8a1,
8a2). N-(Benzyliden)aniline 1a (0.4 mmol) and ethyl 2-
methoxypropenoate 2 (130 mg, 1 mmol) were added to indium
trichloride (44 mg, 0.2 mmol) in acetonitrile (2 mL). The mixture
was irradiated in a microwave oven at 150 W for 3 min. The
temperature of the reaction was recorded as a function of time
(Fig. 4).
N-(Isopropyl)-2-methoxypropenamide (3)77
Isopropylamine (429 mg, 7.8 mmol) was added to a solution of
ethyl-2-methoxypropenoate 2 (500 mg, 3.9 mmol) in methanol
(10 mL). The solution was heated under reflux for two days. The
solvent was evaporated under vacuum and the crude product
extracted with dichloromethane. The organic layers were washed
with aqueous HCl 5% (10 mL) then with brine (10 mL). After
drying over MgSO4, filtration and evaporation of the solvent,
the crude product was purified by chromatography over silica gel
(pentane–ethyl acetate 60 : 40) to yield the pure title compound
3 (167 mg, 30%) as a white solid, mp 52 ◦C. IR mmax/cm−1 (KBr):
3500, 3000, 1746, 1628, 1518, 1380, 1170. 1H NMR: dH 6.64 (1H,
br s), 5.37 (1H, d, J 2.1), 4.41 (1H, d, J 2.1), 4.14 (1H, sept, J
6.7), 3.65 (3H, s), 1.23 (6H, d, J 6.7). 13C NMR: dC 161.7, 154.6,
•
90.1, 55.8, 42.3, 23.0. MS (EI, GC–MS) m/z 144 (M+ , 85%), 128
(100), 110 (49), 100 (49), 57 (82). CHN requires for C7H13NO2:
C, 58.7; H, 9.2; N, 9.8%. Found: C, 58.8; H, 9.4; N, 9.6%.
(S)-N-(1-Phenylpropyl)-2-methoxypropenamide (4)
2-Methoxypropenoic acid 78 (3.2 g, 32 mmol), N-hydroxy-
succinimide (4.3 g, 1.2 equiv.) and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI·HCl, 7.4 g, 1.2 equiv.)
and anhydrous DMF (50 mL) were stirred under nitrogen at
−5 ◦C for 1 h then at room temperature for 12 h. The solvent was
evaporated and the residue was extracted with dichloromethane
(25 mL). The organic layers were washed with aqueous citric
Fig. 4 Temperature (◦C) as a function of time (min) inside the
microwave oven (irradiation power: 150 W).
After cooling to room temperature, the residue was poured
into water (20 mL) and extracted with dichloromethane (20 mL).
3 8 0 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4

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The organic layers were combined, washed with brine, dried
over MgSO4 and the solvent evaporated under vacuum. The
residue was purified by column chromatography over silica gel
(pentane–ethyl acetate 95 : 5) to yield a mixture of the two esters
8a1 and 8a2 (63 mg, 57%). Attempts to separate these two esters
were unsuccessful, but because of the product distribution (3 : 1
ratio) the NMR could nevertheless be resolved. 8a1: 1H NMR:
dH 8.66 (1H, d, J 8.5, H arom), 8.30 (s, H3), 8.16–8.11 (3H,
m), 7.69–7.60 (1H, m), 7.57–7.40 (4H, m), 4.45 (2H, q, J 7,
OCH2CH3), 1.39 (3H, t, J 7, OCH2CH3). MS (EI, GC–MS)
Ethyl- and methyl-2-(4ꢀ-bromophenyl)-quinoline-4-carboxylate
(8g1, 8g2). Using the general procedure, imine 1g (0.4 mmol)
afforded a mixture of esters 8g1 and 8g2 (27 mg, 20%). Attempts
to separate these two esters were unsuccessful, but because of the
product distribution (3 : 1 ratio) the NMR could nevertheless
be resolved. 8g1: 1H NMR: dH 8.92 (1H, d, J 8.3), 8.35 (1H, d,
J 6.4), 8.20 (1H, d, J 8.3), 8.08 (2H, d, J 7.6), 7.78 (1H, t, J
1.1), 7.69–7.63 (3H, m), 7.43 (1H, d, J 8.3), 4.55 (2H, q, J 7.1,
OCH2CH3), 1.51 (3H, t, J 7.1, OCH2CH3). MS (EI, GC–MS)
•
•
m/z (tR = 18.8 min) 357 (M+ , C18H1481BrNO2, 99%), 355 (M+ ,
C18H1479BrNO2, 99%), 285 (89), 284 (100), 204 (28), 203 (28).
HRMS (C18H1579BrNO2) calc.: 356.0286, found: 356.0274. 8g2:
1H NMR: dH 8.92 (1H, d, J 8.3), 8.35 (1H, d, J 6.4), 8.20 (1H,
d, J 8.3), 8.08 (2H, d, J 7.6), 7.78 (1H, t, J 1.1), 7.69–7.63 (3H,
m), 7.43 (1H, d, J 8.3), 4.08 (3H, s, OCH3). MS (EI, GC–MS)
•
m/z (tR = 23.3 min) 277 (M+ , 100%), 206 (46, M − OCH2CH3).
1
8a2: H NMR: dH 8.66 (1H, d, J 8.5, H arom), 8.33 (s, H3),
8.16–8.11 (3H, m), 7.69–7.60 (1H, m), 7.57–7.40 (4H, m), 3.99
•
(3H, s, OCH3). MS (EI, GC–MS) m/z (tR = 22.6 min) 263 (M+ ,
100%), 206 (46, M − OCH3).
•
•
m/z (tR = 18.1 min) 343 (M+ , C17H1281BrNO2, 97%), 341 (M+ ,
C17H1279BrNO2, 98%), 286 (13), 285 (98), 284 (37), 283 (100), 203
(30). HRMS (C17H1379BrNO2) calc.: 342.0130, found: 342.0114.
Ethyl-81 and methyl-2-(2ꢀ-fluorophenyl)-quinoline-4-carboxy-
late (8b1, 8b2). Using the general procedure, imine 1b
(0.4 mmol) afforded a mixture of esters 8b1 and 8b2 (42 mg,
40%). Attempts to separate these two esters were unsuccessful,
but because of the product distribution (3 : 1 ratio) the NMR
Ethyl- and methyl-2-(4ꢀ-cyanophenyl)-quinoline-4-carboxylate
(8h1, 8h2). Using the general procedure, imine 1h (0.4 mmol)
afforded a mixture of esters 8h1 and 8h2 (27 mg, 20%). Attempts
to separate these two esters were unsuccessful, but because of the
product distribution (3 : 1 ratio) the NMR could nevertheless be
resolved. 8h1: 1H NMR: dH 8.75 (1H, d, J 9.5), 8.39–8.32 (3H, m),
8.23 (1H, d, J 7.8), 7.85–7.82 (3H, m), 7.68–7.64 (1H, m), 4.56
(2H, q, J 7.1, OCH2CH3), 1.44 (3H, t, J 7.1, OCH2CH3). MS
1
could nevertheless be resolved. 8b1: H NMR: dH 8.77 (1H, d,
J 8.0), 8.41–8.39 (1H, m), 8.23 (1H, d, J 8.3), 8.12 (1H, td, J 6.1
J 1.6), 7.79 (1H, td, J 7.2, J 1.2), 7.69–7.65 (1H, m), 7.50–7.44
(1H, m), 7.32 (1H, td, J 7.2, J 1.2), 7.22–7.18 (1H, m), 4.54
(2H, q, J 7.1, OCH2CH3), 1.48 (3H, t, J 7.1, OCH2CH3). 19F
NMR: dF −116.9. MS (EI, GC–MS) m/z (tR = 17 min) 295
•
•
(EI, GC–MS) m/z 302 (M+ , 100%). 288 (M+ , 100%), 231 (33)
•
(100%, M+ ), 223 (56). HRMS (C18H15FNO2) calc.: 296.1087,
found: 296.1082. 8b2: 1H NMR: dH 8.77 (1H, d, J 8.0), 8.41–8.39
(1H, m), 8.23 (1H, d, J 8.3), 8.12 (1H, td, J 6.1 J 1.6), 7.79 (1H,
td, J 7.2, J 1.2), 7.69–7.65 (1H, m), 7.50–7.44 (1H, m), 7.32 (1H,
td, J 7.2, J 1.2), 7.22–7.18 (1H, m), 4.05 (3H, s, OCH3). 19F
NMR: dF −116.9. MS (EI, GC–MS) m/z (tR = 16.3 min) 281
230 (53). HRMS (C19H15N2O2) calc.: 303.1134, found: 303.1129.
1
8h2: H NMR: dH 8.75 (1H, d, J 9.5), 8.39–8.32 (3H, m), 8.23
(1H, d, J 7.8), 7.85–7.82 (3H, m), 7.68–7.64 (1H, m), 3.99 (3H, s,
•
OCH3). MS (EI, GC–MS) m/z 288 (M+ , 100%), 231 (33), 230
(53). HRMS (C18H12N2O2) calc.: 288.0899, found: 288.0886.
•
(M+ , 100%), 223 (36). HRMS (C17H13FNO2) calc.: 282.0919,
Ethyl- and methyl-2-(4ꢀ-nitrophenyl)-quinoline-4-carboxylate
(8i1, 8i2). Using the general procedure, imine 1i (0.4 mmol)
afforded a mixture of esters 8i1 and 8i2 (29 mg, 23%). Attempts
to separate these two esters were unsuccessful, but because of the
product distribution (3 : 1 ratio) the NMR could nevertheless
be resolved. 8i1: 1H NMR: dH 8.77 (1H, d, J 8), 8.44–8.38 (5H,
m), 8.24 (1H, d, J 8), 7.82 (1H, t, J 0.8), 7.69 (1H, t, J 0.8), 4.56
(2H, q, J 8, OCH2CH3), 1.52 (3H, t, J 8, OCH2CH3). MS (EI,
found: 282.0924.
Ethyl- and methyl 2-(3ꢀ-bromophenyl)-quinoline-4-carboxylate
(8d1, 8d2). Using the general procedure, imine 1d (0.4 mmol)
afforded a mixture of esters 8d1 and 8d2 (64 mg, 45%). Attempts
to separate these two esters were unsuccessful but because of the
product distribution (3: 1 ratio), the NMR could nevertheless
1
be resolved. 8d1: H NMR: dH 8.74 (1H, d, J 8.5), 8.39–8.32
•
GC–MS) m/z (tR = 23.1 min) 322 (M+ , 100%), 251 (70), 250
(2H, m), 8.21 (1H, d, J 8.4), 8.11 (1H, d, J 7.5), 7.79 (1H,
t, J 7.8), 7.66–7.58 (2H, m), 7.39 (1H, t, J 7.8), 4.55 (2H, q,
J 7.1, OCH2CH3), 1.51 (3H, t, J 7.1, OCH2CH3). MS (EI,
(23). HRMS (C18H14N2O4) calc.: 323.1032, found: 323.1038. 8i2:
1H NMR: dH 8.77 (1H, d, J 8), 8.44–8.38 (5H, m), 8.24 (1H, d, J
8), 7.82 (1H, t, J 0.8), 7.69 (1H, t, J 0.8), 4.10 (3H, s, OCH3). MS
•
GC–MS) m/z (tR = 18.7 min), 357 (M+ , C18H1481BrNO2, 69%),
•
(EI, GC–MS) m/z (tR = 21.5 min) 308 (M+ , 100%), 251 (66),
•
355 (M+ , C18H1479BrNO2, 69%), 285 (100), 283 (97), 203 (25).
250 (42). HRMS (C17H12N2O4) calc.: 309.0875, found: 309.0886.
HRMS (C18H1579BrNO2) calc.: 356.0286, found: 356.0288. 8d2:
1H NMR: dH 8.74 (1H, d, J 8.5), 8.39–8.32 (2H, m), 8.21 (1H,
d, J 8.4), 8.11 (1H, d, J 7.5), 7.79 (1H, t, J 7.8), 7.66–7.58
(2H, m), 7.39 (1H, t, J 7.8), 4.07 (3H, s, OCH3). MS (EI, GC–
Ethyl- and methyl-2-(4ꢀ-fluorophenyl)-quinoline-4-carboxylate
(8j1, 8j2). Using the general procedure, imine 1j (0.4 mmol)
afforded a mixture of esters 8j1 and 8j2 (32 mg, 27%). Attempts
to separate these two esters were unsuccessful, but because of the
product distribution (3 : 1 ratio) the NMR could nevertheless
•
MS) m/z (tR = 18.5 min) 343 (M+ , C17H1281BrNO2, 72%), 341
•
(M+ , C17H1279BrNO2, 68%), 285 (98), 283 (100), 203 (40). HRMS
(C17H1379BrNO2) calc.: 342.0130, found: 342.0130.
1
be resolved. 8j1: H NMR: dH 8.75 (1H, dd, J 4.0 J 1.2), 8.36
(1H, s), 8.25–8.21 (3H, m), 7.79 (1H, td, J 6.4, J 1.2), 7.65 (1H,
td, J 7.2, J 1.6), 7.25 (2H, t, J 6.4), 4.57 (q, J 7.2, OCH2CH3),
1.53 (t, J 7.2, OCH2CH3). 19F NMR: dF −112.1. MS (EI, GC–
Ethyl-82 and methyl-2-(3ꢀ,4ꢀ-dimethoxyphenyl)-quinoline-4-
carboxylate82 (8f1, 8f2). Using the general procedure, imine 1f
(0.4 mmol) afforded a mixture of esters 8f1 and 8f2 (40 mg,
31%). Attempts to separate these two esters were unsuccessful,
but because of the product distribution (3 : 1 ratio) the NMR
•
MS) m/z (tR = 16.7 min) 295 (M+ , 100%), 223 (38). HRMS
1
(C18H14FNO2) calc.: 296.1087, found: 296.1086. 8j2: H NMR:
dH 8.75 (1H, dd, J 4.0 J 1.2), 8.38 (1H, s), 8.25–8.21 (3H, m),
7.79 (1H, td, J 6.4, J 1.2), 7.65 (1H, td, J 7.2, J 1.6), 7.25 (2H,
t, J 6.4), 4.10 (3H, s, OCH3). 19F NMR: dF −112.1. MS (EI,
1
could nevertheless be resolved. 8f1: H NMR: dH 8.69 (1H, dt,
J 8.5, J 1.6), 8.34 (1H, s), 8.20 (1H, dd, J 7.5, J 0.9), 7.9 (1H,
d, J 1.7), 7.90 (1H, s), 7.62–7.56 (1H, m), 7.00 (1H, dd, J 7.5,
J 0.9), 4.56 (2H, q, J 7.1, OCH2CH3), 4.05 (3H, s, OCH3), 3.96
(3H, s, OCH3), 1.53 (3H, t, J 7.1, OCH2CH3). MS (EI, GC–MS)
•
GC–MS) m/z (tR = 16.1 min) 281 (M+ ,100%), 223 (20). HRMS
(C17H12FNO2) calc.: 282.0930, found: 282.0935.
•
1
m/z (tR = 21.3 min) 337 (100%, M+ ), 309 (18). 8f2: H NMR:
dH 8.69 (1H, d, J 8.5), 8.36 (1H, s), 8.20 (1H, dd, J 7.5, J 0.9),
7.91 (1H, s), 7.78–7.68 (1H, m), 7.62–7.56 (1H, m), 7.00 (1H,
dd, J 7.5, J 0.9), 4.07 (3H, s, COOCH3), 4.05 (3H, s, OCH3),
3.96 (3H, s, OCH3). MS (EI, GC–MS) m/z (tR = 20.1 min) 323
Ethyl- and methyl-6-fluoro-2-phenylquinoline-4-carboxylate
(8k1, 8k2). Using the general procedure, imine 1k (0.4 mmol)
afforded a mixture of esters 8k1 and 8k2 (28 mg, 24%). Attempts
to separate these two esters were unsuccessful, but because of the
product distribution (3 : 1 ratio) the NMR could nevertheless
be resolved. 8k1: 1H NMR dH 8.39 (2H, m), 8.17–8.09 (3H, m),
•
(M+ , 100%), 308 (16), 293 (20), 278 (34), 265 (12).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4
3 8 0 1

View Article Online
1
7.50–7.41 (4H, m), 4.51 (2H, q, J 7.1, OCH2CH3), 1.43 (3H, t,
1546, 1265, 741. H NMR: dH 8.12 (2H, dd, J 5.4, J 1.2), 8.00
(1H, dt, J 7.8, J 1.8), 7.80 (1H, d, J 2.3), 7.66 (1H, dt, J 7, J 1.2),
7.51 (1H, dt, J 8.1, J 0.9), 7.37–7.31 (1H, m), 7.25–7.07 (2H, m),
6.10 (1H, s), 4.04 (1H, sept, J 6.6), 1.23 (3H, d, J 6.6). 13C NMR:
dC 167.1, 161.7, 161.1 (d, 1J 249), 149.1, 143.0, 131.8 (d, 4JCF 2.5),
•
J 7.1, OCH2CH3). MS (EI, GC–MS) m/z 295 (M+ , 100%), 223
(56). HRMS (C18H15FNO2) calc.: 296.1087, found: 296.1078.
1
8k2: H NMR: dH 8.39 (2H, m), 8.17–8.09 (3H, m), 7.50–7.41
•
(4H, m), 3.99 (3H, s, OCH3). MS (EI, GC–MS) m/z 281 (M+ ,
3
100%), 224 (32), 223 (21). HRMS (C17H13FNO2) calc.: 282.0930,
found: 282.0918.
131.5 (d, JCF 8.1), 130.5, 127.9, 127.7, 127.5, 125.4, 125.1 (d,
4JCF 3.7), 123.9, 120.1, 119.9, 116.6 (d, 2JCF 22.6), 42.7, 23.1. 19
F
•
NMR: dF −117.3 (m). MS (EI, GC–MS) m/z 308 (M+ , 93%),
293 (56), 250 (100), 222 (67), 202 (12). HRMS (C19H18FN2O)
calc.: 309.1403, found: 309.1396.
Ethyl- and methyl-6-chloro-2-phenylquinoline-4-carboxylate83
(8l1, 8l2). Using the general procedure, imine 1l (0.4 mmol)
afforded a mixture of esters 8l1 and 8l2 (31 mg, 25%). Attempts
to separate these two esters were unsuccessful, but because of the
product distribution (3 : 1 ratio) the NMR could nevertheless be
resolved. 8l1: 1H NMR: dH 8.83 (1H, s), 8.43 (1H, d, J 4.2), 8.20–
8.12 (3H, m), 7.71–7.68 (1H, m), 7.55–7.32 (3H, m), 4.54 (2H, q,
J 7.1, OCH2CH3), 1.50 (3H, t, J 7.1, OCH2CH3). MS (EI, GC–
(S)-N -(1-Phenylpropyl)-2-phenylquinoline-4-carboxamide
(10a)1. White solid (67 mg, 47%), mp 158 ◦C (lit.1: 140–141 ◦C)
[a]D20 = −24.2 (c 0.5, MeOH, lit.1 [a]D20 = −26.7). H NMR: dH
1
8.03–8.00 (2H, m), 7.99 (1H, dd, J 7.6, J 0.8), 7.69 (1H, s), 7.63
(1H, dt, J 5.5, J 1.5), 7.46–7.31 (10H, m), 6.80 (d, 1H, J 8.4),
5.16 (1H, q, J 8.1), 0.98 (3H, t, J 8.1). 13C NMR: dC 167.4,
157.0, 148.9, 143.4, 141.9, 139.2, 130.4, 130.1, 129.1, 128.1,
127.9, 127.6, 127.2, 126.9, 125.3, 123.7, 116.6, 56.1, 29.5, 11.6.
•
MS) m/z (tR = 25.1 min) 311 (M+ , 100%), 297 (10), 239 (81),
241 (29), 240 (21), 204 (17), 203 (20). HRMS (C18H14ClNO2)
calc.: 312.0791, found: 312.0791. 8l2: 1H NMR: dH 8.83 (1H, s),
8.43 (1H, d, J 4.2), 8.20–8.11 (3H, m), 7.71–7.68 (1H, m), 7.55–
7.32 (3H, m), 4.07 (3H, s, OCH3). MS (EI, GC–MS) m/z (tR =
(S)-N-(1-Phenylpropyl)-2-(2ꢀ -fluorophenyl)-quinoline-4-car-
boxamide (10b). White solid (53 mg, 35%), mp 160 ◦C. [a]D20
=
•
24.1 min) 297 (M+ , 100%), 241 (26), 240 (23), 239 (82), 204 (15).
−46 (c 1, MeOH). IR mmax/cm−1 (KBr): 3260, 2964, 1705, 1641,
1555, 1467, 1260. 1H NMR: dH 8.16–8.07 (3H, m), 7.88 (1H, s),
7.72 (1H, t, J 2.1), 7.52 (1H, d, J 1), 7.36–7.14 (7H, m), 6.49
(1H, d, J 8.3), 5.16 (1H, q, J 7.5), 2.01–1.90 (2H, m), 0.85 (3H,
HRMS (C17H13ClNO2) calc.: 298.0635, found: 298.0654.
Ethyl-84 and methyl-6-bromo-2-phenylquinoline-4-carboxy-
late84 (8m1, 8m2). Using the general procedure, imine 1m
(0.4 mmol) afforded a mixture of esters 8m1 and 8m2 (78 mg,
52%). Attempts to separate these two esters were unsuccessful,
but because of the product distribution (3 : 1 ratio) the NMR
could nevertheless be resolved. 8m1: 1H NMR: dH 9.00 (1H, d, J
2.1, H5), 8.43 (1H, s, H3 arom), 8.21–8.17 (2H, m), 8.06 (1H, s),
7.85 (1H, d, J 1.2, H8 arom), 7.58–7.49 (2H, m), 7.35–7.21 (2H,
m), 4.55 (2H, q, J 7.1, OCH2CH3), 1.51 (3H, t, J 7.1, OCH2CH3).
t, J 7.5). 13C NMR: dC 165.4, 159.3 (d, JCF 249), 152.1, 147.3,
1
3
140.9, 140.1, 129.9 (d, JCF 8.1), 129.7, 128.7, 128.6, 127.4,
4
127.2, 126.2, 125.2, 123.6, 123.3 (d, JCF 3.7), 122.1, 118.1
(d, JCF 8.1), 114.8 (d, JCF 22.6), 54.1, 27.7, 9.1. 19F NMR:
3
2
•
dF −105.6 (m). MS (EI, GC–MS) m/z 384 (M+ , 12%), 355
(16, M − CH2CH3), 270 (33), 255 (23), 250 (48), 222 [35, M −
CONHCH(PhCH2CH3)], 99 (100). HRMS (C25H21FN2O) calc.:
384.1638, found: 384.1620.
•
MS (EI, GC–MS) m/z (tR = 27.1 min) 357 (M+ , C18H1481BrNO2,
•
100%), 355 (M+ , C18H1479BrNO2, 99%), 285 (81), 284 (77), 203
(S)-N-(1-Phenylpropyl)-2-(4ꢀ -fluorophenyl)-quinoline-4-car-
(28). HRMS (C18H1579BrNO2) calc.: 356.0286, found: 356.0283.
8m2: 1H NMR: dH 9.00 (1H, d, J 2.1, H5), 8.45 (1H, s, H3 arom),
8.21–8.17 (2H, m), 8.09 (1H, s), 7.81 (1H, d, J 1.2, H8 arom),
7.58–7.49 (2H, m), 7.35–7.21 (2H, m), 4.07 (3H, s, OCH3). MS
boxamide (10j). White solid (74 mg, 48%), mp 160 ◦C. [a]D20
=
−27 (c 1, MeOH). IR mmax/cm−1 (KBr): 3053, 2986, 1701, 1670,
1421, 1264, 738. 1H NMR: dH 8.00–7.94 (3H, m), 7.61 (1H, s),
7.38–7.24 (6H, m), 7.13 (2H, t, J 8.6), 6.76 (1H, d, J 8.3), 5.15
(1H, q, J 7.6), 2.00–1.89 (2H, m), 0.98 (3H, t, J 7.6). 13C NMR:
•
(EI, GC–MS) m/z (tR = 26.0 min) 343 (M+ , C17H1281BrNO2,
•
96%), 341 (M+ , C17H1279BrNO2, 68%), 285 (99), 284 (87), 203
1
dC 167.3, 164.3 (d, JCF 249), 155.8, 148.8, 143.3, 141.9, 135.2
(d, JCF 3.1), 130.5, 130.3, 129.7 (d, JCF 8.2), 129.2, 129.1,
(40). HRMS (C17H1379BrNO2) calc.: 342.0130, found: 342.0123.
4
3
2
128.1, 127.6, 127.2, 125.2, 123.5, 116.3, 116.2 (d, JCF 21.4),
56.2, 29.8, 11.8. 19F NMR: dF −112.1 (m). MS (EI, GC–MS)
General procedure for the preparation of
2-arylquinoline-4-carboxamides
•
m/z 384 (M+ , 25%), 363 (31), 355 (31, M − CH2CH3), 250
(100), 222 [69, M − CONHCH(PhCH2CH3)], 190 (64). HRMS
A solution of imine 1a (72 mg, 0.4 mmol) and amide 3 (219 mg,
1 mmol) or 4 (159 mg, 1 mmol) was added to indium chloride
(88 mg, 0.4 mmol) in acetonitrile (2 mL) in a reaction tube. The
solution was heated in a microwave oven (150 W) for 3 min. The
mixture was cooled to room temperature, poured into water
(20 mL) and extracted with dichloromethane (20 mL). The
organic layers were combined, washed with brine, dried over
MgSO4 and evaporated under vacuum. The crude product was
purified by column chromatography over silica gel (pentane–
ethyl acetate 95 : 5 to 80 : 20) to yield the expected quinoline
4-carboxamide.
(C25H21FN2O) calc.: 384.1638, found: 384.1652.
(S)-N -(1-Phenylpropyl)-6-fluoro-2-phenylquinoline-4-car-
boxamide (10k). White solid (75 mg, 49%), mp 160 ◦C. [a]D20
=
−24.8 (c 1, MeOH). IR mmax/cm−1 (KBr): 3258, 2964, 1705,
1
1641, 1555, 1467, 1260. H NMR: dH 8.03–7.97 (3H, m), 7.70
(1H, s), 7.62–7.50 (1H, dd, J 6.9, J 2.8), 7.50–7.26 (9H, m),
6.57 (1H, d, J 8.4), 5.19 (1H, q, J 7.5), 2.06–1.97 (2H, m), 1.01
(3H, t, J 7.5). 13C NMR: dC 166.5, 160.1 (d, JCF 249), 156.0,
1
3
145.8, 142.2, 141.4, 138.5, 132.4 (d, JCF 9.4), 129.8, 128.9,
2
128.8, 128.6, 128.0, 127.8, 127.3, 126.8, 126.6, 120.4 (d, JCF
25.8), 116.8, 108.8 (d, 2JCF 23.4), 55.8, 24.4, 10.9. 19F NMR: dF
•
−111.5 (m). m/z (EI, GC–MS) 384 (M+ , 12%), 355 (16, M −
N-Isopropyl-2-phenylquinoline-4-carboxamide (9a). Yellow
solid (66 mg, 57%), mp 148–150 ◦C. IR mmax/cm−1 (KBr): 3270,
2990, 2950, 1634, 1595, 1570, 785. 1H NMR: dH 8.22–8.15
(4H, m), 7.88 (1H, s), 7.76 (1H, t, J 6.0), 7.58–7.50 (4H, m),
5.91 (1H, br s), 4.46 (1H, sept, J 6.7), 1.36 (6H, d, J 6.7).
13C NMR: dC 171.1, 166.8, 154.2, 148.7, 143.9, 138.9, 130.1,
129.7, 128.9, 127.9, 124.9, 123.4, 116.4, 41.9, 22.4. MS (EI)
CH2CH3), 333 (14), 288 (15), 270 (33), 250 (48), 222 [31, M −
CONHCH(PhCH2CH3)], 99 (100). HRMS (C25H22FN2O) calc.:
385.1716, found: 385.1705.
(S)-N-(1-Phenylpropyl)-2-(3ꢀ -fluorophenyl)-quinoline-4-car-
boxamide (10n). White solid (81 mg, 53%), mp 160 ◦C. [a]D20
=
•
−27.6 (c 1 in MeOH). IR mmax/cm−1 (KBr): 3260, 3060, 1705,
m/z 290 (M+ , 100%), 275 (M − CH3, 48%), 247 (11), 232
1
1641, 1467, 1353, 1260. H NMR: dH 8.05 (1H, d, J 8.4), 7.95
[65, M − NHCH(CH3)2], 204 [33, M − CONHCH(CH3)2], 176
(1H, d, J 7.8), 7.82–7.77 (2H, m), 7.70–7.66 (2H, m), 7.46–7.15
(8H, m), 6.68 (1H, d, J 7.7), 5.19 (1H, q, J 7.7), 2.13–2.04 (2H,
m), 1.02 (3H, t, J 7.7). 13C NMR: dC 164.4, 160.5 (d, 1JCF 246),
(12). HRMS (C19H19N2O) calc.: 291.1497, found: 291.1487.
N-Isopropyl-2-(2ꢀ-fluorophenyl)-quinoline-4-carboxamide (9b).
Yellow oil (53 mg, 43%). IR mmax/cm−1 (NaCl): 3058, 1634, 1610,
3
153.0, 152.9, 146.3, 141.0, 139.3, 138.9, 128.1 (d, JCF 10.7),
3 8 0 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 9 4 – 3 8 0 4

View Article Online
127.9, 126.7, 126.4, 125.6, 125.4, 124.6, 122.7, 121.3, 120.8 (d,
20 H. A. Aboul-Enein and S. A. Ibrahim, J. Fluorine Chem., 1992, 59,
233–237.
2
2
4JCF 3.1), 114.4 (d, JCF 21.4), 113.8, 112.2 (d, JCF 22.7), 53.4,
27.0, 8.8. 19F NMR: dF −115.3 (m). MS (EI, GC–MS) m/z 384
21 O. Doebner and W. V. Miller, Berichte, 1883, 16, 24–64.
22 A. Gopalsamy and P. V. Pallai, Tetrahedron Lett., 1997, 38, 907–910;
R. E. Lutz, P. S. Bailey, M. T. Clark, J. F. Codington, A. J. Deinet,
J. A. Freek, G. H. Harnest, N. H. Leake, T. A. Martin, R. J. Rowlett,
J. M. Salsbury, N. H. Shearer, J. D. Smith and J. W. Wilson, J. Am.
Chem. Soc., 1946, 68, 1813–1861; M. M. Rapport, A. E. Senear,
J. F. Mead and J. B. Koepfli, J. Am. Chem. Soc., 1946, 68, 2697–
2703.
•
(M+ , 20%), 363 (56), 355 (27, M − CH2CH3), 250 (81), 222
[54, M − CONHCH(PhCH2CH3)], 190 (51), 134 (100). HRMS
(C25H21FN2O) calc.: 384.1712, found: 384.1702.
(S)-N-(1-Phenylpropyl)-8-fluoro-2-phenylquinoline-4-carbox-
◦
amide (10o). White solid (80 mg, 53%), mp 160 C. [a]D20
=
23 S. Kobayashi, H. Ishitani and S. Nagayama, Synthesis, 1995, 1195–
−9.4 (c 1, MeOH). IR mmax/cm−1 (KBr): 3260, 2964, 1705, 1641,
1555, 1467, 1260. 1H NMR: dH 8.04–8.00 (3H, m), 7.74 (1H, s),
7.73–7.72 (1H, m), 7.45–7.22 (10H, m), 6.68 (1H, d, J 7.5), 5.18
(1H, q, J 7.5), 2.02–1.93 (2H, m), 1.00 (3H, t, J 7.5). 13C NMR:
1202.
24 Y. Makioka, T. Shindo, Y. Taniguchi, K. Takaki and Y. Fujiwara,
Synthesis, 1995, 801–804.
25 Y. Ma, C. Qian, M. Xie and J. Sun, J. Org. Chem., 1999, 64, 6462–
6467.
26 G. Babu and P. T. Perumal, Tetrahedron Lett., 1997, 38, 5025–5026;
G. Babu and P. T. Perumal, Tetrahedron, 1999, 55, 4793–4802; G.
Babu and P. T. Perumal, Tetrahedron, 1998, 54, 1627–1638; G. Babu
and P. T. Perumal, Tetrahedron Lett., 1998, 39, 3225–3228.
27 L. S. Povarov, Russ. Chem. Rev., 1967, 36, 656–670.
28 B. Crousse, J.-P. Be´gue´ and D. Bonnet-Delpon, J. Org. Chem., 2000,
65, 5009–5013 and refs. cited therein.
1
dC 166.9, 158.5 (d, JCF 257), 157.1, 143.3, 141.8, 139.1, 138.6,
3
130.4, 129.3, 129.0 (d, JCF 6.9), 128.4, 128.1, 127.9, 127.3,
127.2, 126.9, 125.3, 121.0 (d, 4JCF 5), 117.4, 114.5 (d, 2JCF 18.9),
53.6, 29.5, 11.4. 19F NMR: dF −124.3 (m). MS (EI, GC–MS)
•
m/z 384 (M+ , 17%,), 355 (23, M − CH2CH3), 250 (67), 233
(32), 222 [35, M − CONHCH(PhCH2CH3)], 204 (76), 72 (100).
HRMS (C25H21FN2O) calc. 384.1638, found: 384.1656.
29 H. F. Van Brocklin, J. P. O’Neil, D. L. Hom and A. R. Gibbs,
J. Labelled Compd. Radiopharm., 2001, 44, S880.
30 M. Attina, F. Cacace and A. P. Wolf, J. Chem. Soc., Chem. Commun.,
1983, 108–109; M. Collins, M.-C. Lasne and L. Barre´, J. Chem. Soc.,
Perkin Trans. 1, 1992, 3185–3188 and refs. cited therein.
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Acknowledgements
We gratefully acknowledge financial support from the CNRS
(Centre National de la Recherche Scientifique), the ‘Re´gion
Basse-Normandie’ (grant to D. D., 2002–2005) and the Euro-
pean Union (FEDER funding).
33 M.-J. Tranchant, V. Dalla, I. Jabin and B. Decroix, Tetrahedron, 2002,
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