Synthesis of substituted 1-trifluoromethyl and 1-perfluoroalkyl-3- (arylamino)prop-2-en-1-one: Advances in the mechanism of Combes 2-trifluoromethyl and 2-perfluoroalkyl quinolines synthesis

Article abstract of DOI:10.1016/j.tet.2013.12.073

We report a new synthesis and our study of the mechanism of formation of substituted 1-trifluoromethyl and 1-perfluoroalkyl-3-(phenylamino)prop-2-en-1- one starting from 3-(R-phenoxy)-3-perfluoroalkyl-prop-2-enals and arylamines. Reactivity study of the intermediates confirmed that 3-perfluoroalkyl-N, N′-diphenyl-1,5-diazapentadienes are the synthetic intermediates of the synthesis of 2-perfluoroalkylquinolines. The mechanism of the reaction of 1-trifluoromethyl and 1-perfluoroalkyl-3-(phenylamino)prop-2-en-1-one with POCl₃ was studied. To our knowledge this is the first detection and isolation of N,N′-diaryldiazapentadiene derivatives as intermediates in the Combes F-alkyl substituted quinoline synthesis starting from enaminoketones. Finally, we succeeded isolating and identifying unsymmetrically substituted 2-perfluorolakyldiazapentadiene.

Full text of DOI:10.1016/j.tet.2013.12.073

Tetrahedron 70 (2014) 1252e1266
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted 1-trifluoromethyl and 1-perfluoroalkyl-3-
(arylamino)prop-2-en-1-one: advances in the mechanism of
Combes 2-trifluoromethyl and 2-perfluoroalkyl quinolines synthesis
,
b
,
,
y
Salem El Kharrat a , Philippe Laurent y, Hubert Blancou c
*
a
ꢀ
ꢁ
ꢁ
Laboratoire de Synthese Bio-organique et Pharmaceutique, Faculte de Pharmacie, Universite Saint-Joseph, Rue de Damas, Beyrouth, Lebanon
Institut des Biomolecules Max Mousseron, UMR-CNRS 5247 Universite Montpellier 2 c.c.1706, Place E. Bataillon, 34095 Montpellier cedex 5, France
Institut des Biomolecules Max Mousseron, Universite Montpellier 2, Place E. Bataillon, 34095 Montpellier cedex 5, France
b
c
ꢁ
ꢁ
ꢁ
ꢁ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2013
Received in revised form 14 December 2013
Accepted 24 December 2013
Available online 8 January 2014
We report a new synthesis and our study of the mechanism of formation of substituted 1-trifluoromethyl
and 1-perfluoroalkyl-3-(phenylamino)prop-2-en-1-one starting from 3-(R-phenoxy)-3-perfluoroalkyl-
prop-2-enals and arylamines. Reactivity study of the intermediates confirmed that 3-perfluoroalkyl-
N,N0-diphenyl-1,5-diazapentadienes are the synthetic intermediates of the synthesis of 2-per-
fluoroalkylquinolines. The mechanism of the reaction of 1-trifluoromethyl and 1-perfluoroalkyl-3-
(phenylamino)prop-2-en-1-one with POCl3 was studied. To our knowledge this is the first detection and
isolation of N,N0-diaryldiazapentadiene derivatives as intermediates in the Combes F-alkyl substituted
quinoline synthesis starting from enaminoketones. Finally, we succeeded isolating and identifying un-
symmetrically substituted 2-perfluorolakyldiazapentadiene.
Keywords:
Enaminoketones
Pushepull ethylene
Trans-amination
Enamine
Ó 2014 Elsevier Ltd. All rights reserved.
diazapentadiene
Vinamidine
Malonic derivatives
2-Trifluoromethylquinolines
Combes reaction
1. Introduction
degradation.7 Consequently, synthetic methodology to incorporate
fluorine and fluorous synthons must be improved in order to pre-
Among the nitrogenous heterocycles, quinolines1e6 and their
derivatives represent an important class of organic molecules that
attract the interest of both synthetic and medicinal chemists due
to their broad spectrum of biological activities.1e3 Quinoline de-
rivatives have attracted considerable attention primarily due to
their presence in many compounds, which have been isolated from
natural substances and exhibit various biological activities.4,5 As
a heterocyclic moiety, quinolines also deserve special interest for
chelation of various metal cations, including lanthanide ions.6
In addition, it has been recognized that attachment of a tri-
fluoromethyl group into heterocycles can be used to modulate the
physical, chemical and biological properties.7,8 It is well documented
that the influence of the trifluoromethyl substituent onphysiological
activity is due mainly to the increased lipophilicity of the molecules,
causing greater cell permeability and resistance to enzyme
pare sophisticated fluoroorganic molecules on a practical scale.
One of the most satisfactory methods for introducing a CF3
group into heterocycles is via the trifluoromethylated building
block approach. The fluoroalkyl-containing enaminoketones 1
proved to be a useful building block for the syntheses of many se-
ries of heterocyclic compounds.9e15
Several approaches to perfluoroalkylated quinolines are
known, starting from enaminoketones 1 and typically providing
access to 2-perfluoroalkyl or 2-trifluoromethyl substituted
quinolines.16e18 Linderman and Kirollos17 reported the synthesis
of 2-CF3-substituted quinolines. In the same publication, another
intramolecular cyclization route was also described, which
allowed the synthesis of the 4-trifluoromethyl quinoline isomer. In
some cases, the reactions resulted in mixtures of 2- and
4-trifluoromethylquinolines. Thus, the cyclization of adducts of
acetylenic ketones (or 4-ethoxy-1,1,1-trifluoro-3-buten-2-one)
with aromatic amines in methanol gives
substituted trifluoromethyl-enones, which cyclize on treatment
with acids (POCl3, ZnCl2) giving rise to 2-trifluoromethyl or
a 3-arylamino-
* Corresponding author. E-mail addresses: salem.kharrat@usj.edu.lb, kharrat_
salem@yahoo.com (S. El Kharrat).
y
Fax: þ33 467631046.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.073

S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
1253
4-trifluoromethyl substituted quinolines in moderate yields
(Scheme 1).17 The ratio of the reaction products depends on the
acidic catalyst used and the structure of the starting enones.
Moreover, related conjugated systems such as pushepull poly-
enes have become important in the study of nonlinear optical
properties because these properties are enhanced by the large
Scheme 1. Synthesis of 2-trifluoromethyl and/or 4-trifluoromethyl quinolines. R0¼Me, OH, OMe, Hal; R¼H, alkyl, phenyl.
4-Trifluoromethylquinolines are the products of normal
cyclization of obtained by intramolecular electrophilic
changes in dipole moment and hence in charge distribution be-
tween the ground and excited states.25
1
aromatic substitution. While the mechanism of formation of
2-trifluoromethylquinolines was investigated by Gerus et al.,16 who
noted that in the case of the aniline derivative only the 2-
trifluoromethyl quinoline was obtained probably via retro-1,4 ad-
dition. However when R0¼alkyl or aryl, 4-trifluoromethylquinolines
are formed predominantly. The presence of electron-donating sub-
stituents in the meta-positions of the aromatic amine substantially
facilitates cyclization and increases the total yield.16
Furthermore, b-enaminones 1 have attracted much attention
due to the fact they are important synthons for the synthesis of
many biologically active compounds9b,26e31 such as dopamine
auto-receptor agonists,26 acetylcholinesterase inhibitors,27 and
anticonvulsants.28 They are also useful intermediates for the
preparation of several aminoacids,29 aminols,30 peptides and
alkaloids.9b
In the present work, we report our study of the mechanism of
formation of substituted 2-perfluoroalkylquinolines starting
from 3-perfluoroalkyl-3-aryloxypropenals 3 and 1-perfluoroalkyl-
3-(R1-phenylamino)prop-2-en-1-ones 4aeo.
In a first step, the synthesis and mechanism of formation of
1-trifluoromethyl and 1-perfluoroalkyl-3-(R1-phenylamino)prop-
2-en-1-ones 4aeo are described, then NMR investigations of the
reaction regioselectivity and tautomeric equilibrium in solution of
compounds 4 are detailed.
Schlosser et al.,18 who have investigated the synthesis of 2- and
4-trifluoromethyl quinolines and quinolinones, demonstrated that
4-anilino-1,1,1-trifluoro-3-buten-2-ones can be readily obtained
from 4-tert-butylamino-1,1,1-trifluorobut-3-en-2-one and aniline
by simple trans-amination. Upon heating in the presence of phos-
phoryl oxychloride, they undergo ring closure to afford 2-
trifluoromethyl quinolines rather than the expected 4-isomers in
50% average yield (Scheme 2).18a
Scheme 2. Synthesis of 2-trifluoromethylquinolines.18 RF¼CF3, C2F5, C3F7.
In subsequent experiments,18b these studies demonstrated that
some perfluoroalkyl-substituted 3-aminoenones, when heated in
the presence of phosphoryl chloride, cleaved hydrolytically, setting
free the substituted anilines and the 1,3-dicarbonyl compounds.
The authors postulated a non-proved recombination of these sub-
units through a vinylogous amidinium ion giving the unexpected
2-perfluoroalkylquinolines.18b
Furthermore, these 1,3-difunctional amino-derivatives 1 belong
to the malonic class of compounds very important in the prepa-
ration of metal chelates,13,19e24 thus, the development of a suitable
volatile precursor for chemical vapour deposition (CVD)19a or
atomic layer deposition (ALD)20a of thin metallic films is expected
to revolutionize the manufacturing of electronic devices.18
2. Results and discussion
2.1. Synthesis of substituted 1-trifluoromethyl and 1-
perfluoroalkyl-3-(phenylamino)prop-2-en-1-ones 4aeo
We
found
that
3-(R-phenoxy)-3-perfluoroalkyl-prop-2-
enals 3aee react easily with aniline under acidic conditions
and form 1-trifluoromethyl or 1-perfluoroalkyl-3-(R1-phenylamino)
prop-2-en-1-ones 4aeo, phenyl-(3-perfluoroalkyl-3-phenoxyprop-
2-enylidene)-amine 5, 2-perfluoroalkyl-N,N0-diaryl-1,5-diazapenta-
dienes 7 and 2-perfluoroalkylquinolines 6 (Scheme 3, Table 1).
The starting compounds, enals 3, can be easily prepared in a one
pot reaction of substituted sodium phenoxides with 1-iodo-1-
Scheme 3. Reaction of 3-trifluoromethyl and 3-perfluoroalkyl-3-aryloxypropenals 3 with arylamines under acidic conditions (R¼H, 4-OMe; R1¼H, 4-Me, 3-Me, 2-Me, 4-NO2, 4-Cl,
2-Cl, 4-CO2H, 3-CO2H, 4-CN; RF¼CF3, C3F7, C5F11).

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S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
electron-withdrawing substituents (R1¼4-Cl, 2-Cl, 4-NO2, 4-COOH,
3-COOH, 4-CN) (Table 2, entries 9e18).
Table 1
Reaction conditions and conversions observed for the reaction mixture at half time
and at the end of the reaction of 3-trifluoromethyl-3-(phenoxy)propenal 3b and
aniline
Conva [%]
2.2. Reaction mechanism
Product 4a
Time ½ (2 h)
Time (4 h)
The mechanism of formation of compounds 4aeo in acidic
conditions could be explained by a substitution of the carbonyl
group of 3aee and the formation of an N-arylimino enol-ether
derivative 5, which was isolated and identified. Then hydrolysis
and elimination of the phenoxy group with subsequent tautome-
rization gives with total regioselectivity the corresponding 1-
trifluoromethyl and 1-perfluoroalkyl-3-(R1-phenylamino)prop-2-
en-1-ones 4aeo (Scheme 4).16,35e37
In our case, under acidic condition, steric factors could favour an
1,2-addition of arylamines then an acid catalyzed hydrolysis of the
phenoxy group yielding compounds 4 in a total regiospecific
manner.
4a 5a 6a 7a 3b 4a 5a 6a 7a 3b
Procedure
45
50
d
d
d
55 95
30 85
d
d
d
d
d
A: 2% HCl/MeOH/65 ꢀC
Procedure
B: p-TsOH/toluene/111 ꢀC
5
10
5
15
d
Determined by 19F NMR spectroscopic analysis of the reaction mixtures; NMR
spectroscopic yields were based on consumed 3 and formed 4, 5, 6 and 7.
a
acetoxy-2-perfluoroalkylethane derivatives as we reported
earlier.32e34
The reaction of 3b (R¼H, RF¼CF3, Scheme 3) with aniline was
first tempted using p-toluenesulfonic acid in toluene as a solvent
under reflux. The desired product 4a was obtained in good
yield with a mixture of phenyl-(3-perfluoroalkyl-3-phenoxyprop-
2-enylidene)-amine 5a, 2-perfluoroalkylquinolines 6a and 2-
perfluoroalkyl-N,N0-diaryl-1,5-diazapentadienes 7a (Table 1).
However, we found that the reaction proceeds successfully
when toluene was replaced by 2% hydrochloric acid in methanol as
a solvent. Under these conditions, the expected compound 4a was
the only formed product and obtained in very good yield without
side reactions (Table 1).
2.3. Structure determination of enaminoketones 4aeo
Similarly, the reaction of arylamines with 3 under acidic con-
ditions (conditions A, Table 1), might give the 1,2- or/and the 1,4-
addition products. However, close NMR spectral analyses of 4aeo
revealed that this reaction led to the regiospecific formation of
single enaminoketone 4b tautomer (Scheme 5). Structural assign-
ments were accomplished without ambiguity using different 1H,
13C, 19F, 1He1H COSY and 1He13C HETCOR spectral signals.
NMR spectral analysis confirms the structure of the obtained
To further explore the structureereactivity of this reaction,
several starting arylamines were tested using conditions A as de-
scribed previously. The enaminones 4aeo were obtained in good to
excellent yield (Table 2).
enaminoketones 4b.
- The 1H NMR and 1He1H COSY spectra show a clear cross
peak between consequently three vicinal protons, which ex-
clude two possible regioisomers 4
g
and 4b0 (Scheme 5, see
Supplementary data).
Table 2
- Then the presence of a carbonyl function is confirmed by 13C
NMR spectroscopy (in all cases the C]O carbon signal are
observed around 175e180 ppm). As an experimental proof of
the presence of C]O group, we compared with our previous
results:32a,34a N,N0-diaryl-1,5-diazapentadiene compounds 7
(R¼CF3 or C5F11, R1¼H, p-Me, m-Me, o-Me, p-Cl, m-Cl, o-Cl, p-
NO2, o-OH, p-CN, m-COOH) and phenyl-(3-perfluoropenthyl-3-
Reaction conditions and conversions for the preparation of 1-trifluoromethyl and 1-
perfluoroalkyl-3-(R1-phenylamino)prop-2-en-1-ones 4aeo using procedure A
Entry Starting product
Enones Arylamines RF
Time (h) Conva [%]
3
R
4
R1
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3b
3b
3b
3e
3d
3b
3e
3b
3b
3b
3b
3e
3b
4-OMe
H
H
4-OMe
H
H
H
4a
4a
4b
4c
4c
4d
4e
4f
4g
4g
4h
4i
4j
4k
4l
4m
4n
4o
H
H
H
H
CF3a
CF3
C3F7
C5F11
C5F11
CF3
CF3
CF3
C5F11 24
C5F11 24
CF3
6
4
4
6
4
4
4
6
92
95
95
90
95
95
92
82
75
66
75
80
82
66
70
70
66
70
phenoxyprop-2-enylidene)-amine
5
(RF¼C5F11, R¼R1¼H)
(Scheme 3) their imine carbons showed 13C NMR shifts around
H
4-Me
3-Me
2-Me
4-NO2
4-NO2
4-NO2
4-Cl
4-Cl
2-Cl
4-CO2H
3-CO2H
4-CN
4-CN
153.2e154.5 and 152.9e154 ppm, respectively. Since there are
no observable imine carbon signals, the regioisomer 4g
0 is to be
H
H
rejected.
9
2
- Furthermore, the JCF coupling constant observed between
carbonyl carbon atoms C-1 and the fluorine atoms, which in all
cases appears as a quartet or triplet around 175e180 ppm
confirms the presence of a single stereochemically pure NH
10
11
12
13
14
15
16
17
18
4-OMe
H
H
H
H
H
H
H
H
24
C5F11 12
CF3
CF3
CF3
CF3
C5F11 24
CF3 24
12
24
48
48
tautomer 4b, excluding the presence of a tautomeric equilib-
rium for these derivatives5c (Scheme 5). This could be
explained by the low basicity of the carbonyl group compared
to imine function.
a
Determined by 19F NMR spectroscopic analysis of the reaction mixtures; NMR
spectroscopic yields were based on consumed 3 and formed 4.
According to the literature, most of the studied cases
corresponds to the stable 1
or N-unsubstituted enaminones
b
tautomers of N-monosubstituted
Slightly decreased yields were observed in the cases of aryl-
amines substituted with moderately electron-withdrawing groups
R1¼4-Cl, 2-Cl (Table 2, entries 12e14). In the case of strongly
electron-withdrawing substituents like R1¼4-NO2, 4-COOH, 3-
COOH, 4-CN moderate yields of 4g, h and 4leo were obtained
(Table 2, entries 9e11 and 15e18).
1
(R2NHeCH]CHeCOR1 or
NH2eCH]CHeCOR1), very few works deals with the iminoeenol
or OH tautomers (R2eN]CHeCHR1eOH), which were considered
to be unstable tautomers of enaminones 4b31 (Scheme 5). These
works showed that the NH tautomers 4
b are more stable than
the OH tautomers (by 2.93e3.54 kcal/mol) due to the higher
proton affinity of the nitrogen atom as compared to the oxygen
atom.31
Longer reaction times were required due to steric hindrance
(R1¼2-Me, 2-Cl) (Table 2, entries 8 and 14) or to the presence of

S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
1255
Scheme 4. Mechanism of formation of 1-trifluoromethyl and 1-perfluoroalkyl-3-(R1-phenylamino)prop-2-en-1-ones 4aeo in acidic conditions.
3. Reactivity study of 4aeo: mechanism of formation of 2-
trifluoromethyl and 2-perfluoroalkylquinolines 6
In order to study the mechanism of formation of 2-
trifluoromethyl and 2-perfluoroalkylquinolines 6, and to verify
that the synthesis of quinolines 6 proceeds through intermediates
of type 2-perfluoroalkyl-N,N0-diphenyl-1,5-diazapentadienes 7 or
1-perfluoroalkyl-3-(phenylamino)prop-2-en-1-one 4 and to reveal
the reaction route as a whole,32e34 we decided to study the intra-
molecular cyclization of 4aeo, which leads to the 2-
perfluoroalkylquinolines 6 (Scheme 6).
First we used different dehydrating reagents such as poly-
phosphoric acid (PPA) at 150 ꢀC or p-toluenesulfonic acid in toluene
under reflux. However, even when the reaction mixture
where refluxed or heated for long time, the formation of the
desired products 6 was not achieved, and complete degradation of
the starting compounds 4 was observed by TLC. However, when
4 was heated in phosphorus oxychloride (POCl3) at 100 ꢀC,
without any solvent, we obtained 2-trifluoromethyl or 2-
perfluoroalkylquinolines 6 as the only formed products, through
N,N0-diaryl-1,5-diazapentadienes 7 intermediates as detected by 19F
NMR spectroscopy of the reaction mixture (In DMSO-d6 CF3 signals
Scheme 5. Possible regioisomers and tautomers theoretically obtained from the
reaction of 3 with arylamines.
Scheme 6. Study and comparison of the reactivity of 1-perfluoroalkyl-3-(phenylamino)prop-2-en-1-ones 4aeo and symmetrically substituted 2-perfluoroalkyl-N,N0-di(R1-phenyl)-
1,5-diazapentadienes 7 towards the synthesis of 2-perfluoroalkylquinolines 6. *Published results32a,34b (R¼H, 4-OMe; R1¼H, 4-Me, 3-Me, 2-Me, 4-NO2, 4-Cl, 2-Cl, 4-CO2H, 3-CO2H,
4-CN; RF¼CF3, C3F7, C5F11).

1256
S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
of 7 around ꢁ65 to ꢁ66 ppm or CF2 signals at ꢁ109 ppm). Dia-
zapentadienes 7 were isolated and identified. Elimination of
hydrolysis of 7 occurs in the presence of trace of water to give
enaminoketones 4 as detected in the course of the reaction
(Scheme 6).
1
M equiv of arylamine by ring-closure cyclization of dia-
zapentadienes 7 regenerates the starting arylamine (Scheme 6).
In comparison, previously,32,34a,b we reported the synthesis and
reactivity of 2-trifluoromethyl and 2-perfluoroalkyl-N,N0-diphenyl-
1,5-diazapentadienes 7. We found that the formation of 7 starting
from 3 proceed via intermediates of type phenyl-(3-perfluoroalkyl-
3-(R1-phenoxy)-prop-2-enylidene)-amine 5, which by an aza-
Michael additioneelimination mechanism of substituted aryl-
amines affords the corresponding diazapentadienes 7 (Scheme
6).32a Then we investigated the structure and reactivity of
enamino-imine compounds 7 having a trifluoromethyl or a per-
fluoroalkyl group and we showed that the reactivity of these
pushepull systems strongly depends on the geometry of the con-
jugated unsaturated moiety.32,34a Thus the reactivity of pushepull
enamino-imines can be controlled to some extent by equilibrium
of stereoisomeric forms.36 Moreover, the remarkable polarization
of pushepull alkenes leads to special reactivity with
nucleophile or electrophile reagents.35a From this point of view we
investigate the stereochemistry and the mechanism of cyclization
of compounds 7.
Additionally, enaminones 4 gave in the presence of arylamine in
refluxing dichloromethane the corresponding symmetrically
substituted 2-perfluoroalkyl-N,N0-di(R1-phenyl)-1,5-diazapenta-
tnqh_0009;dienes 7. However, under acidic conditions the 1-
phenylimino-3-phenoxy-3-perfluoroalkyl-prop-2-ene derivatives
5 cleaved hydrolytically its phenyl-enol-ether function, liberating
1 M equiv of substituted phenol and setting free the N-aryl
enaminoketones 4 (Scheme 6).
3.1. Mechanism of the reaction of 4 with POCl3
Since no reaction of 4 in the presence of polyphosphoric acid
occurred it appears evident that protonation does not play a main
role in this reaction. It is known that POCl3 can substitute the ox-
ygen atom of a carbonyl compound (Vilsmeier reaction).38 Fur-
thermore since we could detect the presence of diazapentadiene 7
in this reaction we propose the following Scheme 7 to explain this
reaction.
Compounds 7 were found to cyclize in a total regiospecific
manner under acidic conditions (AcOH/1,2-dichloroethane/
reflux)34b or under basic conditions (arylamines/1,2-dichloroethane/
reflux) by an electrophilic aromatic cyclization mechanism or by a
pushepull cyclization mechanism, respectively, and gave the
corresponding 2-perfluoroalkylquinolines
6
in high yields
(Scheme 6).34b
We were the first to report the identification and isolation of
2-trifluoromethyl and 2-perfluoroalkyl-N,N0-diphenyl-1,5-diaza-
tnqh_0009;pentadienes 7 as reactional intermediates of the syn-
thesis of 2-trifluoromethyl and 2-perfluoroalkyl-quinolines starting
from perfluoroalkylated malonic derivative.33,34
Following our previous studies,32e34 in this work, we found,
after its isolation and identification in the reaction mixture that
phenyl-(3-perfluoroalkyl-3-(R1-phenoxy)-prop-2-enylidene)-
amine 5 could be the intermediate of the formation of enaminone 4
starting from 3.
Moreover, while monitoring the reaction of 5 with arylamines
by 19F NMR spectroscopy, we observed the formation of both dia-
zapentadienes 7 and enaminoketones 4 as intermediates. Both
compounds 7 and 4 were isolated and identified. The 19F NMR
signals of 4 appear during the reaction and after few hours
disappear completely to give 7 and new peak, which was assigned
to quinolines 6. At the end of the reaction only quinolines 6 where
detected and isolated and compared with authentic samples syn-
thesized in previous works.33,34b
Moreover, in the course of our studies of the reactivity and
stability of symmetrically substituted 2-perfluoroalkyl-N,N0-di(R1-
phenyl)-1,5-diazapentadienes 7, we found that in the presence of
highly electron-attracting substituents (such as R1¼4-NO2, 4-CO2H,
3-CO2H, 4-CN) or when an ortho-chloro substituent was present on
the phenyl group the corresponding diazapentadienes 7 were not
indefinitely stable at room temperature, after varying periods of
time (several days), they decompose and give 1-perfluoroalkyl-3-
(phenylamino)prop-2-en-1-ones 4g,h, and 4keo with elimination
of 1 M equiv of arylamine (Scheme 6). This regioselective hydrolysis
could be explained by the high electron-withdrawing effect of the
Scheme 7. Mechanism of the reaction of enaminoketones 4 with POCl3 giving quin-
olines 6.
POCl3 complexes two molecules of 4 in a double six-centre
heterobicyclic transition state having a trans-junction. The oxygen
atoms can exchange through the coordination of the phosphorus
atom leading to a molecule of 7 and a non-detectable ceto-enol,
which probably decomposes or reacts spontaneously with a mole-
cule of free arylamine to give 4 (Scheme 7).
To our knowledge until now this is the first detection and iso-
lation of N,N0-diaryl-diazapenatadiene derivatives
7 as in-
termediates in the Combes F-alkyl substituted quinolines synthesis
starting from enaminoketones. These results constitute a new ad-
vance in the comprehension of the quinoline synthesis using
malonic compounds.
3.2. Unsymmetrically substituted diazapentadienes
perfluoroalkyl chain, which could activate the
towards a nucleophilic attack of water, with elimination of the
corresponding arylamine.
These observations lead us to the conclusion that compounds 4
are formed from diazapentadienes 7 and these derivatives 7 are
effectively the intermediate of the synthesis of quinolines 6. Since
diazapentadienes 7 are probably more basic than compounds 5,
a
-imino function
We have carried out several experiments to check the reactivity
of compounds 5aeg towards arylamines (Scheme 8, Table 3). For
example, we first heated imino enol-ether compound 5c in
dichloromethane at 40 ꢀC, no trace of the expected dia-
zapentadienes or quinolines was found. In a second step, 5c was
subjected to reaction carried out in the presence of 1 equiv of 4-
methylaniline. After 1 h we were able to detect three sets of new

S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
1257
Scheme 8. Synthesis of quinolines 6aeh under basic conditions starting from 1-phenylimino-3-aryloxy-3-perfluoropentylprop-2-enes 5aeg (R¼H, 4-OMe; R1¼H, 4-Me, 3-Me,
2-Me, 4-NO2, 4-Cl, 2-Cl, 4-CO2H, 3-CO2H, 4-CN; RF¼CF3, C3F7, C5F11).
Table 3
Results and yields obtained of reaction for the preparation of 2-trifluoromethyl and 2-perfluoroalkyl-quinolines 6aeh and detection of their corresponding diazapentadiene
intermediates 7
5
Arylamines
MS analysisa
Time (h)
d
Convb [%]
Time (h)
24
R
R1
H
RF
R2
m/z (7)
R1-(6) (%)
R2-(6) (%)
5a
H
CF3
d
d
0
0
5a
H
H
CF3
4-Me
1.30
291, 319 and 305
291, 319 and 305
6
5b
5c
4-OMe
H
H
CF3
4-Me
4-Me
2.30
1.30
6
6
H
C5F11
7b 491, 7c 519
and 7d, 7e 505
5d
5a
5a
4-OMe
H
H
H
C5F11
4-Me
2-Me
4-NO2
2.30
491, 519 and 505
291, 319 and 305
291, 381 and 336
6
6
H
H
CF3
2
CF3
4
12
(continued on next page)

1258
S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
Table 3 (continued )
5
Arylamines
R2
MS analysisa
Time (h)
Convb [%]
Time (h)
R
R1
RF
m/z (7)
R1-(6) (%)
R2-(6) (%)
5e
5e
H
H
4-Me
CF3
2-Me
1.30
319
6
4-Me
CF3
4-NO2
2
319, 381 and 350
12
5f
H
H
4-Cl
C5F11
4-Me
4-Me
1.30
519, 559 and 539
519, 581 and 550
6
6
5g
4-NO2
C5F11
2
a
measured m/z : formation of these diazapentadienes was detected by mass spectrometry showing three different picks corresponding to the molecular mass [MþH]þ of 7.
Also all 19F NMR spectroscopic analyses were consistent with the formation of four different diazapentadienes showing in DMSO-d6 four CF3 signals around ꢁ65 to e 66 ppm
or four CF2 signals at ꢁ109 ppm and two enaminones as deduced from 19F NMR signals (in DMSO-d6: CF3 signal ꢁ75 to ꢁ76 ppm or CF2 signals between ꢁ119 and ꢁ120 ppm).
b
determined by 19F NMR spectroscopic analysis of the reaction mixtures; NMR spectroscopic yields were based on consumed 5 and formed 6a and 6b.
signals in the 19F NMR spectra of reaction mixtures. The first set of
three signals around ꢁ109.6 to ꢁ109.8 ppm corresponds to
four different symmetrically and unsymmetrically substituted
diazapentadienes 7bee, the second set showed two signals
around ꢁ120.3 to ꢁ120.4 assigned to two formed enaminoketones
4c and 4p and a signal at ꢁ114.3 attributed to the formed
substituted 2-perfluoroalkylquinolines 6c and 6d. All these
formed compounds were isolated and identified and compared to
authentic samples synthesized in previous publications33,34b
(Scheme 8) (see 19F NMR spectra in Supplementary data II).
We succeeded to isolate directly these dissymmetric
diazapentadienes as mixture of both regioisomers (2-perfluoro-
tnqh_0009;pentyl-N-phenyl,N0-(4-Methylphenyl)-1,5-
triplets near 153 ppm attributed to the C5F11eC]N imine function
(see Supplementary data).
Attempts to isolate the other unsymmetrically substituted dia-
zapentadienes 7 were unsuccessful. However, the formation of
these diazapentadienes was detected by mass spectrometry
showing three different picks corresponding to the molecular mass
of the formed intermediates (Table 3). Also all 19F NMR spectro-
scopic analyses of reaction mixtures were consistent with the for-
mation of four different diazapentadienes showing in DMSO-d6
four CF3 signals around ꢁ65 to ꢁ66 ppm or four CF2 signals at ꢁ109
to ꢁ110 ppm, and two enaminones as deduced from 19F NMR sig-
nals (in DMSO-d6: CF3 signal ꢁ75 to ꢁ77.5 ppm or CF2 signals be-
tween ꢁ119 and ꢁ121.8 ppm).
diazapentadiene 7d and 2-perfluoropentyl-N-(4-Methylphenyl),N0-
phenyl-1,5-diazapenta-tnqh_0009;diene 7e) (Scheme 9) and to
perform an NMR analyses quickly before degradation. The structure
of these conjugated pushepull derivatives 7d and 7e is supported
by 1H, 13C and 19F NMR spectra. The 1H NMR spectra of this vina-
midine compound showed the appearance of three set of signals at
5.5; 7.4 and 9.8 ppm characteristic of the propene bridge of these
conjugated pushepull compounds. The aromatic protons appear-
ing between 6.6 and 7.3 ppm integrate for nine protons corre-
sponding to the protons of the aromatic rings of an
unsymmetrically substituted diazapentadienes. The 13C spectra
also showed for the propene carbons of these diazapentadienes
characteristic signals around 90.8e91.6 and 140.6e141.7 ppm and
The detection of symmetrically substituted 2-perfluoroalkyl-
N,N0-di(R2-phenyl)-1,5-diazapentadiene and unsymmetrically
substituted
2-perfluoroalkyl-N-(R1-phenyl),N0-(R2-phenyl)-1,5-
diazapentadienes 7 suggests that in the presence of arylamine
(weak basic conditions) a trans-amination reaction occurred in
derivatives 5aeg and the expected cyclization products 6aeh are
obtained. The structure of the resulting quinolines was un-
equivocally assigned on the basis of a comparison of its physical
data with those obtained before.32a,34b The trans-amination
mechanism plays important roles in the biological area, specially
during the pyridoxal mediated amino acids catabolism.39
Results shown in Table 3 show that in the presence of electron-
donating substituent R2 on the aromatic ring of the entering aryl-
amine, R2-substituted quinolines 6 are obtained as major products.
However, an electron-attracting substitution on the entering R2-
arylamine (R2¼4-NO2) favours the trans-amination replacement of
the existing R1-aryl-imine function (R1¼H, 4-Me) and formation of
R1-substituted quinolines
6 is favoured (no 3-(aryloxy)-3-
perfluoroalkyl-prop-2-enals 3 was detected during this reaction)
(Scheme 8 and Table 3).
Scheme 9. Obtained dissymmetric pushepull diazapentadienes 7d and 7e.

S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
1259
These results reported here showed an interesting comparison
5.2. General procedure B
To mixture of 3-trifluoromethyl-3-phenoxypropenal 3b
of the chemical behaviour for the mechanism of cyclization
of these new enaminoketones and diazapentadienes, showing
selective route of ring closure including direct regiospecific cycli-
zation of 2-trifluoromethyl and 2-perfluoroalkyl-N,N0-diaryl-1,5-
diazapentadienes 7 as the intermediates of the synthesis of
2-trifluoromethyl and 2-perfluoroalkylquinolines 6.
a
(1 equiv) in toluene (10 mL/1 g of 3b) was added para-toluene-
sulfonic acid (1 equiv) portion wise and stirred until complete
dissolution. Then aniline (1 equiv) was added and the mixture was
stirred under reflux (Table 1) until complete consumption of the
starting material as judged by TLC and 19F NMR spectroscopy (4 h).
At the end of the reaction, the mixture was diluted, neutralized
with a solution of 1% NaHCO3 and washed with water. The organic
layer was dried over sodium sulfate and concentrated in vacuo. The
resulting oil was purified by column chromatography over silica gel
to afford compounds 4a and 6. In another procedure, we monitored
the evolution of the reaction by 19F NMR spectroscopy and at mid
reaction time (2 h) we stopped heating and we added a solution of
1% NaHCO3 into the mixture. Work up and washing as described
previously permitted the isolation of compounds 4a, 5a and 6a
and 7a.
4. Conclusion
In conclusion, we provided a new trifluoromethyl and per-
fluoroalkyl-containing 3-(phenylamino)-prop-2-en-1-ones 4aeo
in
a
one-step reaction starting from 3-perfluoroalkyl-3-
aryloxypropenals 3aee. These compounds have been used as pre-
cursors for the synthesis of a variety of substituted five- and six-
membered heterocycles.1,5e8 Using 1H, 13C NMR and 1He1H COSY
NMR spectroscopy we were able to confirm the obtained 4
b
regioisomer and to establish the structure of these unsaturated
pushepull derivatives 4aeo in solution (Scheme 5).
5.3. Reaction of 3-trifluoromethyl-3-phenoxypropenal (3b)
with aniline
Then we explored the reactivity of 4, we observed that enami-
nones 4aeo react in the presence of POCl3 and form regiospecifically
2-perfluoroalkylquinolines 6, through diazapentadienes 7 as reac-
tional intermediates. This confirms, our previous works according
to which the 3-perfluoroalkyl-N,N0-diaryl-1,5-diazapentadienes
Starting from 4.5 g (20.8 mmol) of 3b and 1.93 g (20.8 mmol) of
aniline, 2.2 g (10.2 mmol) of 4a was obtained as yellow liquid (yield:
50%), 0.31 g (1.06 mmol) of 5a was obtained as yellow liquid (yield:
5%), 0.4 g (2.03 mmol) of 6a was obtained as amorphous white solid
(yield: 10%) and 0.3 g (1.03 mmol) of 7a was obtained as yellow
amorphous solid (yield: 5%).
5
are the synthetic intermediates of the synthesis of 2-
perfluoroalkylquinolines 6. To our knowledge this is the first de-
tection and isolation of N,N0-diaryl-diazapentadiene derivatives 7 as
intermediates in the Combes F-alkyl substituted quinolines syn-
thesis starting from enaminoketones.
5.3.1. 1-Trifluoromethyl-3-(phenylamino)prop-2-en-1-one (4a). 1H
NMR (300 MHz, C6D6, ZZE 100%)
d
(ppm) 5.4 (d, 3JH2H3¼7.4 Hz, 1H,
3
3
5. Experimental section
H-2), 6.4 (m, 2H, PheH), 6.6 (dd, JH2H3¼7.4 Hz and JH3NH¼13 Hz,
1H, H-3), 6.8e7 (m, 3H, PheH), 11.7 (br s, 1H, NH); 13C NMR
5.1. General methods and spectroscopic measurements
(75.4 MHz, C6D6, ZZE 100%) d (ppm) 89.8 (s, ]CeC]O), 117.1, 117.8
(q, CF3, 1JCF¼289.2 Hz), 125.2, 129.6, 138.8, 149.1 (s, ]CeNH), 179.2
All reaction solvents were distilled before use. All synthetic re-
actions were performed in oven-dried glassware, and their prog-
ress was monitored by thin layer chromatography (TLC), using silica
gel plates, and by 19F NMR spectroscopy. Chromatographic column
(q, O]CeCF3, 2JCF¼33.7 Hz); 19F NMR (282.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ76.56 (s, 3F, CF3); MS FABþ m/z (%): 216 (MþHþ, 100), 215
(Mþ, 45), 146 (MþꢁCF3, 40). Anal. Calcd for C10H8F3NO: C, 55.82; H,
3.75; O, 7.44. Found: C, 55.89; H, 3.74; O, 7.44.
purifications were performed on silica gel (40e63 m
m). 1H, 13C, and
19F NMR spectra were recorded in CDCl3 or DMSO on 300 MHz and
400 MHz spectrometers. Chemical shifts are given in parts per
million (ppm); the internal standard reference was trimethylsilane
for 1H and 13C, and CFCl3 for 19F spectra. Abbreviations used in the
description of NMR spectra: s: singlet, d: doublet, t: triplet, q:
quadruplet, br s: broad signal, br d: broad doublet. The coupling
constant (J) is given in hertz (Hz). High-resolution mass spectra
were recorded in the FABþ mode, using NBA as matrix with
a Micromass Q-Tof Analyzer.
5.3.2. 1-Phenylimino-3-(phenoxy)-3-trifluoromethyl-prop-2-ene
3
(5a). 1H NMR (300.13 MHz, C6D6, EE)
d
(ppm) 6.3 (d, JHH¼9.1 Hz,
3
1 H), 6.8e7.5 (m, 10 H), 8.8 (d, JHH¼9 Hz, 1H); 13C NMR
(100.61 MHz, C6D6, EE)
d (ppm) 117.1, 117.5, 121, 121.2, 127.1, 127.4,
2
130.3, 131.4, 151.6 (q, C3eCF3, JCF¼28.9 Hz), 153.1, 153.5, 156.2 (q,
HC]N (EE), 4JC1F¼5.5 Hz); 19F NMR (282.4 MHz, C6D6, EE)
d (ppm)
66.5 (s, 3F, CF3); MS (m/z): 292 [MþH]þ; HRMS m/z [MþH]þ calcd
for
C16H13F3NO: 292.0949, found: 292.0955. Anal. Calcd for
C16H12F3NO: C, 65.98; H, 4.15; O, 5.49. Found: C, 65.99; H, 4.16; O,
5.51.
5.1.1. NMR measurements. The NMR spectra were run on
a 300 MHz NMR spectrometer, operating at 300.13 MHz for 1H
5.3.3. 2-Trifluoromethylquinoline (6a). 1H NMR (300 MHz,
observation, 75.46 MHz for 13C analyses and at 282.40 MHz for 19
F
CD3COCD3)
d
(ppm) 7.8 (m, 1H), 7.9 (m, 2H), 8.1 (d, J¼7.5 Hz, 1H), 8.2
acquisitions, in 5 mm sample tubes using 20e45 mg of the com-
pounds in deuterated solvents. The 1H, 13C and 19F NMR parameters
were acquired from the same sample.
(d, J¼8.6 Hz, 1H), 8.7 (d, J¼8.6 Hz, 1H); 13C NMR (75.4 MHz,
3
CD3COCD3)
d
(ppm) 117.6 (q, CH, JCF¼2.1 Hz), 122.6 (q, CF3,
1JCF¼273.8 Hz), 127.4, 130, 130.2, 134.1, 138.5, 141, 146.8 (q, CeCF3,
Due to E/Z isomerism about the pushepull system in 4aeo, two
sets of signals were observed for the resonance of these com-
pounds, in both the 1H and 13C NMR spectra. In each case, the
chemical shift differences were sufficient and signals were gener-
ally well dispersed and consequently, they were easily assigned.
The corresponding 1H and 13C NMR spectra were then assigned by
1He1H COSY and 1He13C HMQC experiments. However, when
having mixture of isomers in solutions of 4 the NMR signals of their
phenyl groups were in some cases strongly overlapped and could
not be differentiated.
2JCF¼34.1 Hz); 19F NMR (282.4 MHz, CD3COCD3)
d
(ppm) ꢁ67.7
(s, 3F, CF3); MS (m/z): 198 [MþH]þ; HRMS m/z [MþH]þ calcd for
C10H7F3N, 198.0531, found 198.0536. Anal. Calcd for C10H6F3N: C,
60.92; H, 3.07; N, 7.10. Found: C, 60.88; H, 3.12; N, 7.15.
5.3.4. 2-Trifluoromethyl-1-phenylamino-3-phenyliminopropene
(7a). 1H NMR (300 MHz, DMSO-d6, EEE)
d (ppm) 5.6 (d,
3JH2H3¼13.7 Hz, H2), 6.8 (d, J¼7.5 Hz, 2H), 7 (m, 3H), 7.15 (t, J¼7.4 Hz,
1H), 7.3 (t, J¼7.8 Hz, 2H), 7.4 (t, J¼7.7 Hz, 2H), 7.6 (t, J¼13 Hz, H3), 9.9
3
(d, JH3NH¼12.3 Hz, NH); 13C NMR (75.4 MHz, DMSO-d6, EEE)

1260
S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
d
(ppm) 90.8,115.1, 119.2, 120.5 (q, CF3, 1JCF¼279.2 Hz), 122.14, 123.5,
ZZE 100%) d (ppm) 91.4 (s, ]CeC]O), 117.4, 125.5, 129.8, 138.8, 149.1
4
2
129.3, 129.7, 140.7, 140.9 (q, C3H, JC3F¼2.9 Hz), 149.5, 153.3
(s, ]CeNH), 180.4 (t, O]CeCF2, JCF¼24.8 Hz); 19F NMR
(q, CeCF3, JC1F¼31.2 Hz); 19F NMR (282.4 MHz, DMSO-d6, EEE)
(235.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ81 (m, 3F), ꢁ120.3 (m, 2F),
2
d
(ppm) ꢁ65.8 (s, 3F); MS (m/z): 291 [MþH]þ; HRMS m/z [MþH]þ
ꢁ122.5 (m, 4F), ꢁ126.5 (m, 2F); MS FABþ m/z (%): 416 [MþH]þ; HRMS
m/z [MþH]þ calcd for C14H9F11NO 416.0508, found 416.0490. Anal.
Calcd for C14H8F11NO: C, 40.50; H, 1.94; O, 3.85. Found: C, 40.48; H,
1.95; O, 3.86.
calcd for C16H14F3N2: 291.1109, found: 291.1088. Anal. Calcd for
C
9.66.
16H13F3N2: C, 66.20; H, 4.51; N, 9.65. Found: C, 66.18; H, 4.50; N,
5.4. General procedure for the preparation of 1-trifluoromethyl
and 1-perfluoroalkyl-3-(R1-phenylamino)prop-2-en-1-ones
4aec (R1[H), 4def (R1[Me), 4iek (R1[Cl), and 4neo (R1[CN):
procedure A
5.4.4. 1-Trifluoromethyl-3-(4-methylphenylamino)prop-2-en-1-one
(4d). Same process as procedure A. Starting from 1 g (4.62 mmol)
of 3b and 0.49 g (4.62 mmol) of 4-methylaniline, 0.93 g (4 mmol) of
4d was obtained as yellow liquid (yield: 88%); 1H NMR (300 MHz,
C6D6, ZZE 100%)
d
(ppm) 2.2 (s, 3H), 5.4 (d, 3JH2H3¼7.3 Hz, 1H, H-2),
To a stirred solution of 3-perfluoroalkyl-3-aryloxypropenals 3
(1 equiv) in 2% hydrochloric methanolic solution (10 mL/1 g
of 1) was added 1 equiv of the corresponding arylamines. The
resulting mixture was stirred under reflux and the reaction moni-
tored by TLC and 19F NMR spectroscopy. The terminal CF3 or the CF2
signals of compound 3 faded upon evolution of the reaction and
new peaks appeared corresponding to the CF3 or CF2 signals of
product 4 (4e24 h). On completion of the reaction, the mixture was
diluted and extracted with diethyl ether (5ꢂ). The organic layers
were washed with water and dried with sodium sulfate then con-
centrated in vacuum. The resulting yellow oils were purified
by column chromatography on silica gel (EtOAc/petroleum
ether 15:100) to afford 4.
6.7 (dd, J¼7.3 Hz and 12.4 Hz, 1H, H-3), 6.9e7.3 (m, 4H, PheH), 11.9
(br s, 1H, NH); 13C NMR (75.4 MHz, C6D6, ZZE 100%)
d (ppm) 16.9,
1
91.6 (s, ]CeC]O), 117, 118.1 (q, CF3, JCF¼288.3 Hz), 125.3, 127.1,
127.3, 131.3, 137.3, 149.1 (s, ]CeNH), 180.1 (q, O]CeCF3,
2JCF¼24.9 Hz); 19F NMR (282.4 MHz, C6D6, ZZE 100%)
(ppm) ꢁ76.5
d
(s, 3F, CF3); MS FABþ m/z (%): 230 (MþHþ, 100), 229 (Mþ, 50), 160
(MþꢁCF3, 35); HRMS m/z [MþH]þ calcd for C11H11F3NO 230.0793,
found 230.0781. Anal. Calcd for C11H10F3NO: C, 57.64; H, 4.40; O,
6.98. Found: C, 57.66; H, 4.40; O, 6.96.
5.4.5. 1-Trifluoromethyl-3-(3-methylphenylamino)prop-2-en-1-one
(4e). Same process as procedure A. Starting from 1.1 g (5 mmol) of
3b and 0.54 g (5 mmol) of 3-methylaniline, 0.99 g (4.3 mmol) of 4e
was obtained as yellow liquid (yield: 85%); 1H NMR (300 MHz,
3
5.4.1. 1-Trifluoromethyl-3-(phenylamino)prop-2-en-1-one (4a). Same
process as procedure A. Starting from 1.2 g (5.55 mmol) of 3b and
0.51 g (5.55 mmol) of aniline, 1 g (5 mmol) of 4a was obtained as
yellow liquid (yield: 90%). Or starting from 1.1 g (4.47 mmol) of 3a
and 0.41 g (4.47 mmol) of aniline, 0.86 g (4 mmol) of 4a were ob-
tained as yellow liquid (yield: 90%); 1H NMR (300 MHz, C6D6, ZZE
C6D6, ZZE 100%)
d
(ppm) 2 (s, 3H), 5.6 (d, JH2H3¼7.3 Hz, 1H, H-2),
3
6.5 (d, J¼7.9 Hz, 1H, PheH), 6.8 (dd, JH2H3¼7.3 Hz and
3JH3NH¼13 Hz, 1H, H-3), 6.9e7.2 (m, 3H, PheH), 12.1 (br d,
3JH3NH¼11.6 Hz, 1H, NH); 13C NMR (75.4 MHz, C6D6, ZZE 100%)
d
(ppm) 16.9, 91.6 (s, ]CeC]O), 115.1, 117.8 (q, CF3, 1JCF¼289.4 Hz),
125.3, 127.2, 127.3, 131.3, 137.3, 149.1 (s, ]CeNH), 180.1 (q, O]
CeCF3, 2JCF¼24.9 Hz); 19F NMR (282.4 MHz, C6D6, ZZE 100%) ꢁ76.5
(s, 3F, CF3); MS FABþ m/z (%): 230 (MþHþ, 100), 229 (Mþ, 50), 160
(MþꢁCF3, 35); HRMS m/z [MþH]þ calcd for C11H11F3NO 230.0793,
found 230.0795. Anal. Calcd for C11H10F3NO: C, 57.64; H, 4.40; O,
6.98. Found: C, 57.68; H, 4.41; O, 6.94.
100%)
d
(ppm) 5.4 (d, 3JH2H3¼7.4 Hz, 1H, H-2), 6.4 (m, 2H, PheH), 6.6
(dd, 3JH2H3¼7.4 Hz and 3JH3NH¼13 Hz,1H, H-3), 6.8e7 (m, 3H, PheH),
11.7 (br s,1H, NH); 13C NMR (75.4 MHz, C6D6, ZZE 100%)
d (ppm) 89.8
(s, ]CeC]O), 117.1, 117.8 (q, CF3, 1JCF¼289.2 Hz), 125.2, 129.6, 138.8,
149.1 (s, ]CeNH), 179.2 (q, O]CeCF3, JCF¼33.7 Hz); 19F NMR
2
(282.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ76.56 (s, 3F, CF3); MS FABþ m/
z (%): 216 (MþHþ, 100), 215 (Mþ, 45), 146 (MþꢁCF3, 40). Anal. Calcd
for C10H8F3NO: C, 55.82; H, 3.75; O, 7.44. Found: C, 55.89; H, 3.74; O,
7.44.
5.4.6. 1-Trifluoromethyl-3-(2-methylphenylamino)prop-2-en-1-one
(4f). Same process as procedure A. Starting from 1.1 g (5 mmol) of
3b and 0.54 g (5 mmol) of 2-methylaniline, 0.9 g (3.93 mmol) of 4f
was obtained as yellow liquid (yield: 78%); 1H NMR (300 MHz,
5.4.2. 1-Perfluoropropyl-3-(phenylamino)prop-2-en-1-one (4b). Same
process as procedure A. Starting from 1 g (3.16 mmol) of 3c and 0.29 g
(3.16 mmol) of aniline, 0.89 g (2.8 mmol) of 4b was obtained as
C6D6, ZZE 100%)
d
(ppm) 2 (s, 3H), 5.8 (d, 3JH2H3¼7.2 Hz, 1H, H-2), 7.1
(t, J¼7.5 Hz,1H, PheH), 7.3 (m, 2H, PheH), 7.5 (d, J¼8 Hz, 1H, PheH),
3
8.2 (dd, JH2H3¼7.4 Hz and 3JH3NH¼12.3 Hz, 1H, H-3), 12.1 (br s, 1H,
yellow liquid (yield: 90%); 1H NMR (300 MHz, C6D6, ZZE 100%)
NH); 13C NMR (75.4 MHz, C6D6, ZZE 100%)
d (ppm) 16.7, 89.5 (s, ]
3
d
(ppm) 5.4 (d, JH2H3¼7.4 Hz, 1H, H-2), 6.3 (m, 2H, PheH), 6.7 (dd,
CeC]O), 115.5, 116.3 (q, CF3, 1JCF¼294.5 Hz), 125, 126.9, 127, 131.2,
3JH2H3¼7.4 Hz and 3JH3NH¼13 Hz, 1H, H-3), 6.9e7 (m, 3H, PheH), 11.9
137.4,151.5 (s, ]CeNH),177.9 (q, O]CeCF3, 2JCF¼33.9 Hz); 19F NMR
(br s,1H, NH); 13C NMR (75.4 MHz, C6D6, ZZE 100%)
d
(ppm) 89.7 (s, ]
(282.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ77.4 (s, 3F, CF3); MS FABþ m/z
CeC]O), 117.2, 117.6, 125.2, 130, 138.8, 149.5 (s, ]CeNH), 179.2 (t,
(%): 230 (MþHþ, 100), 229 (Mþ, 55), 160 (MþꢁCF3, 35); HRMS m/z
[MþH]þ calcd for C11H11F3NO 230.0793, found 230.0790. Anal.
Calcd for C11H10F3NO: C, 57.64; H, 4.40; O, 6.98. Found: C, 57.60; H,
4.40; O, 6.99.
2
O]CeCF2, JCF¼25.6 Hz); 19F NMR (282.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ80.4 (s, 3F), ꢁ119 (s, 2F), ꢁ126.7 (s, 2F); MS FABþ m/z (%):
316 [MþH]þ; HRMS m/z [MþH]þ calcd for C12H9F7NO 316.0572,
found 316.0568. Anal. Calcd for C12H8F7NO: C, 45.73; H, 2.56; O, 5.08.
Found: C, 45.70; H, 2.55; O, 5.10.
5.4.7. 1-Perfluoropentyl-3-(4-chlorophenylamino)prop-2-en-1-one
(4i). Same process as procedure A. Starting from 1.5 g (3.6 mmol) of
3e and 0.45 g (3.6 mmol) of 4-chloroaniline, 1.16 g (2.59 mmol) of 4i
was obtained as yellow liquid (yield: 72%); 1H NMR (300 MHz, C6D6,
5.4.3. 1-Perfluoropenthyl-3-(phenylamino)prop-2-en-1-one
(4c). Same process as procedure A. Starting from 1.5 g (3.36 mmol) of
3d and 0.31 g (3.36 mmol) of aniline, 1.25 g (3 mmol) of 4c was
obtained as yellow liquid (yield: 90%). Or starting from 1.5 g
(3.6 mmol) of 3e and 0.33 g (3.6 mmol) of aniline,1.34 g (3.2 mmol) of
ZZE 100%)
d
(ppm) 5.4 (d, 3JH2H3¼7.5 Hz, 1H, H-2), 6.4 (d, J¼8.2 Hz,
3
2H, PheH), 6.6 (dd, J¼7.5 Hz and JH3NH¼13.1 Hz, 1H, H-3), 7.4 (d,
J¼8.2 Hz, 2H, PheH), 11.5 (br d, JH3NH¼13 Hz, 1H, NH); 13C NMR
3
4c was obtained as yellow liquid (yield: 90%); 1H NMR (400 MHz,
(75.4 MHz, C6D6, ZZE 100%) d (ppm) 91.3 (s, ]CeC]O), 114.6,
3
C6D6, ZZE 100%)
d
(ppm) 5.7 (d, JH2H3¼7.1 Hz, 1H, H-2), 6.6 (d, 2H,
123.7, 131.6, 132.2, 148.7 (s, ]CeNH), 178.4 (t, O]CeCF2, 2JCF¼23.6
Hz); 19F NMR (282.4 MHz, C6D6, ZZE 100%) ꢁ80.6 (m, 3F), ꢁ120.1
(m, 2F), ꢁ122.2 (m, 2F), ꢁ122.3 (m, 2F), ꢁ126 (m, 2F); MS FABþ m/z
3
3
J¼8 Hz, PheH), 6.9 (dd, JH2H3¼7.4 Hz and JH3NH¼13 Hz, 1H, H-3),
7.1e7.2 (m, 3H, PheH),12.1 (br d,1H, NH); 13C NMR (100.6 MHz, C6D6,

S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
1261
(%): 450 (MþHþ, 55), 449 (Mþ, 100); HRMS m/z [MþH]þ calcd
Anal. Calcd for C11H7F3N2O: C, 55.01; H, 2.94; O, 6.66. Found: C,
55.10; H, 2.94; O, 6.65.
for
C14H8ClF11NO 450.0119, found 450.0122. Anal. Calcd for
C
14H7ClF11NO: C, 37.40; H, 1.57; O, 3.56. Found: C, 37.41; H, 1.57; O,
3.58.
5.5. General procedure for the preparation of 1-
perfluoroalkyl-3-(R1-phenylamino)prop-2-en-1-ones 4g,h
(R1[NO2), 4lem (R1[CO2H): procedure A
5.4.8. 1-Trifluoromethyl-3-(4-chlorophenylamino)prop-2-en-1-one
(4j). Same process as procedure A. Starting from 1 g (4.62 mmol) of
3b and 0.58 g (4.62 mmol) of 4-chloroaniline, 0.84 g (3.37 mmol) of
To a solution of 3-perfluoroalkyl-3-aryloxypropenals 3 (1 equiv)
in 2% HCl methanol (5 mL/1 g of 1) was added 1 equiv of the cor-
responding arylamines. The mixture was stirred under reflux until
disappearance of 19F NMR signals corresponding to the starting
product 3 (24e48 h). At the end of the reaction, the solution was left
at room temperature, a precipitate was formed. Then the reaction
mixture was cooled to 0 ꢀC and final pure derivatives 4 were isolated
as yellow needles by direct crystallization on removal of solvent.
4j was obtained as yellow liquid (yield: 73%); 1H NMR (300 MHz,
3
C6D6, ZZE 100%)
d
(ppm) 5.5 (d, JH2H3¼7.7 Hz, 1H, H-2), 6.4
(d, J¼¼8.8 Hz, 2H, PheH), 6.7 (dd, J¼7.7 Hz and 3JH3NH¼12.8 Hz, 1H,
H-3), 7.3 (d, J¼8.8 Hz, 2H, PheH), 11.6 (d, 3JH3NH¼12.8 Hz, 1H, NH);
13C NMR (75.4 MHz, C6D6, ZZE 100%)
d (ppm) 91.5 (s, ]CeC]O),
1
115.5, 117.6 (q, CF3, JCF¼292.6 Hz), 125.5, 127.2, 130.4, 135.2, 149
(s, ]CeNH), 178.6 (q, O]CeCF3, JCF¼33.4 Hz); 19F NMR
2
(282.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ77.5 (s, 3F); MS FABþ m/z (%):
250 (MþHþ, 80), 249 (Mþ, 100), 180 (MþꢁCF3, 40); HRMS m/z
[MþH]þ calcd for C10H8ClF3NO 250.0247, found 250.0250. Anal.
Calcd for C10H7ClF3NO: C, 48.12; H, 2.83; O, 6.41. Found: C, 48.13; H,
2.83; O, 6.45.
5.5.1. 1-Perfluoropentyl-3-(4-nitrophenylamino)prop-2-en-1-one
(4g). Same process as procedure A. Starting from 2.5 g (6 mmol) of
3e and 0.83 g (6 mmol) of 4-nitroaniline, 1.96 g (4.26 mmol) of 4g
was obtained as amorphous yellow solid (yield: 71%). Or starting
from 2 g (4.48 mmol) of 3d and 0.61 g (4.48 mmol) of 4-
nitroaniline, 1.34 g (2.91 mmol) of 4g was obtained as amorphous
yellow solid (yield: 65%); 1H NMR (300 MHz, C6D6, ZZE 100%)
5.4.9. 1-Trifluoromethyl-3-(2-chlorophenylamino)prop-2-en-1-one
(4k). Same process as procedure A. Starting from 1.2 g (5.55 mmol)
of 3b and 0.7 g (5.55 mmol) of 2-chloroaniline, 0.83 g (3.33 mmol)
d
(ppm) 5.5 (d, 3JH2H3¼7.5 Hz, 1H, H-2), 5.9 (d, 2H, J¼8.8 Hz, PheH),
of 4k was obtained as yellow liquid (yield: 60%); 1H NMR (300 MHz,
6.3 (dd, JH2H3¼7.8 Hz and JH3NH¼12.7 Hz, 1H, H-3), 7.8 (d, 2H,
3
3
3
3
C6D6, ZZE 100%)
d
(ppm) 5.4 (d, JH2H3¼7.5 Hz, 1H, H-2), 6.4 (d,
J¼8.8 Hz, PheH), 11.4 (d, JH3NH¼11.7 Hz, 1H, NH); 13C NMR
J¼8.2 Hz, 1H, PheH), 6.6 (m, 1H, H-3), 6.65 (m, 1H, PheH), 6.8
(75.4 MHz, C6D6, ZZE 100%) d (ppm) 91.5 (s, ]CeC]O), 114.7, 123.7,
2
(t, J¼8.4 Hz, 1H, PheH), 7 (d, J¼8.5 Hz, 1H, PheH), 12.1 (br d, 1H,
141.5, 142.8, 145.7 (s, ]CeNH), 179.9 (t, O]CeCF2, JCF¼24.6 Hz);
NH); 13C NMR (75.4 MHz, C6D6, ZZE 100%)
d
(ppm) 91.1 (s, ]CeC]
19F NMR (282.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ80.8 (m, 3F), ꢁ119.7
O), 115.4,117.6 (q, CF3, 1JCF¼289.76 Hz), 123.6,125.3,130.2,136, 147.6
(m, 2F), ꢁ122 (m, 2F), ꢁ122.1 (m, 2F), ꢁ126 (m, 2F); MS FABþ m/z
(%): 461 (MþHþ, 100), 460 (Mþ, 55), 391 (MþꢁCF3, 30); HRMS m/z
[MþH]þ calcd for C14H8F11N2O3 461.0359, found 461.0355. Anal.
Calcd for C14H7F11N2O3: C, 36.54; H, 1.53; O, 10.43. Found: C, 36.55;
H, 1.54; O, 10.46.
(s, ]CeNH), 179.6 (q, O]CeCF3, JCF¼34.7 Hz); 19F NMR
2
(282.4 MHz, C6D6, ZZE 100%)
d
ꢁ76.7 (s, 3F, CF3); MS FABþ m/z (%):
250 (MþHþ, 80), 249 (Mþ, 100), 180 (MþꢁCF3, 30); HRMS m/z
[MþH]þ calcd for C10H8ClF3NO 250.0247, found 250.0251. Anal.
Calcd for C10H7ClF3NO: C, 48.12; H, 2.83; O, 6.41. Found: C, 48.14; H,
2.80; O, 6.40.
5.5.2. 1-Trifluoromethyl-3-(4-nitrophenylamino)prop-2-en-1-one
(4h). Same process as 4g procedure A. Starting from 1.5
g
5.4.10. 1-Perfluoropentyl-3-(4-cyanophenylamino)prop-2-en-1-one
(4n). Same process as procedure A. Starting from 1.5 g (3.6 mmol)
of 3e and 0.42 g (3.6 mmol) of 4-cyanoaniline, 0.93 g (2.12 mmol) of
(6.94 mmol) of 3b and 0.95 g (6.94 mmol) of 4-nitroaniline, 1.26 g
(4.86 mmol) of 4h was obtained as yellow amorphous solid (yield:
70%); 1H NMR (400 MHz, C6D6, ZZE 100%)
d
(ppm) 5.4 (d, 3JH2H3¼7.7
4n was obtained as yellow liquid (yield: 59%); 1H NMR (300 MHz,
Hz, 1H, H-2), 5.9 (d, 2H, J¼9 Hz, PheH), 6.3 (dd, 3JH2H3¼7.7 Hz and
3
C6D6, ZZE 100%)
d
(ppm) 5.4 (d, JH2H3¼7.8 Hz, 1H, H-2), 6 (d, 2H,
3JH3NH¼12.8 Hz, 1H, H-3), 7.8 (d, 2H, J¼9 Hz, PheH), 11.2 (br d, 1H,
J¼9.1 Hz, PheH), 6.2 (dd, 3JH2H3¼7.8 Hz and 3JH3NH¼12.9 Hz, 1H, H-
NH); 13C NMR (100.6 MHz, C6D6, ZZE 100%)
d
(ppm) 91.6 (s, ]CeC]
3), 7.1 (d, 2H, J¼9.1 Hz, PheH), 11.4 (d, 3JH3NH¼12.9 Hz, 1H, NH); 13
C
O), 115.6, 118.2 (q, CF3, JCF¼290.6 Hz), 125.4, 127.3, 140.3, 141.3,
1
2
NMR (75.4 MHz, C6D6, ZZE 100%)
d
(ppm) 91.2 (s, ]CeC]O), 113.9,
145.5 (s, ]CeNH), 179.7 (q, O]CeCF3, JCF¼32.3 Hz); 19F NMR
116.1, 123.6, 141.7, 142.7, 145.5 (s, ]CeNH), 178.9 (t, O]CeCF2,
(235.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ77.4 (s, 3F); MS FABþ m/z (%):
2JCF¼25.1 Hz); 19F NMR (282.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ80.8
261 (MþHþ, 100), 260 (Mþ, 50), 191 (MþꢁCF3, 35); HRMS m/z
[MþH]þ calcd for C10H8F3N2O3 261.0487, found 261.0490. Anal.
Calcd for C10H7F3N2O3: C, 46.16; H, 2.71; O, 18.45. Found: C, 46.20;
H, 2.70; O, 18.46.
(m, 3F), ꢁ119.8 (m, 2F), ꢁ122.1 (m, 2F), ꢁ122.2 (m, 2F), ꢁ126 (m, 2F);
MS FABþ m/z (%): 441 (MþHþ, 100), 440 (Mþ, 50); HRMS m/z
[MþH]þ calcd for C15H8F11N2O 441.0461, found 441.0466. Anal.
Calcd for C15H7F11N2O: C, 40.93; H, 1.60; O, 3.63. Found: C, 40.95; H,
1.62; O, 3.58.
5.5.3. 1-Trifluoromethyl-3-(4-carboxylphenylamino)prop-2-en-1-
one (4l). Same process as 4g procedure A. Starting from 2.1 g
(9.72 mmol) of 3b and 1.33 g (9.72 mmol) of 4-carboxyaniline,1.51 g
(5.83 mmol) of 4l was obtained as yellow amorphous solid (yield:
5.4.11. 1-Trifluoromethyl-3-(4-cyanophenylamino)prop-2-en-1-one
(4o). Same process as procedure A. Starting from 1.4
g
(6.48 mmol) of 3b and 0.76 g (6.48 mmol) of 4-cyanoaniline, 1 g
60%); 1H NMR (400 MHz, CD3SOCD3, EEE/ZZE 80:20)
d
(ppm) (ZZE)
(4.16 mmol) of 4o was obtained as yellow liquid (yield: 66%); 1H
5.6 (d, JH2H3¼7.5 Hz, 1H, H-2), 7.5 (d, 2H, J¼8.5 Hz, PheH), 7.9 (d,
3
3
NMR (400 MHz, C6D6, ZZE 100%)
d
(ppm) 5.5 (d, JH2H3¼7.6 Hz,
2H, J¼8.5 Hz, PheH), 8.2 (bdd, 1H, H-3), 11.6 (d, 1H, 3JH3NH¼12.8 Hz,
3
3
1H, H-2), 6.1 (d, 2H, J¼9 Hz, PheH), 6.3 (dd, JH2H3¼7.6 Hz and
NH); (EEE) 5.9 (d, JH2H3¼12.4 Hz, 1H, H-2), 7.3 (d, 2H, J¼8.5 Hz,
3JH3NH¼13.1 Hz, 1H, H-3), 7.2 (d, 2H, J¼9 Hz, PheH), 11.3 (br d, 1H,
PheH), 7.9 (d, 2H, J¼8.5 Hz, PheH), 8.4 (t, 1H, J¼12.7 Hz, H-3), 11.2
NH); 13C NMR (100.6 MHz, C6D6, ZZE 100%)
d (ppm) 91.1 (s, ]
(d, 1H, 3JH3NH¼13.1 Hz, NH); 13C NMR (100.6 MHz, CD3SOCD3, EEE/
1
CeC]O), 115.6, 116, 118.2 (q, CF3, JCF¼291 Hz), 123.1, 127, 140.7,
ZZE 80:20) d (ppm) 90.4 (s, ]CeC]O, (ZZE)), 93.8 (s, ]CeC]O,
141.3, 145.5 (s, ]CeNH), 179.9 (q, O]CeCF3, JCF¼33.1 Hz); 19F
(EEE)), 113.2, 116.7, 117.6 (q, CF3, 1JCF¼291.6 Hz), 117.9, 125.3, 126.5,
127.6, 131.4, 131.6, 143, 143.6,149.9 (br d, ]CeNH, (EEE)), 151.7 (s, ]
CeNH, (ZZE)), 166.2 (s, CO2H), 167.2 (s, CO2H), 176.7 (q, O]CeCF3,
2
NMR (282.4 MHz, C6D6, ZZE 100%)
d
(ppm) ꢁ77.1 (s, 3F); MS FABþ
m/z (%): 241 (MþHþ, 100), 240 (Mþ, 50), 171 (MþꢁCF3, 50); HRMS
m/z [MþH]þ calcd for C11H8F3N2O 241.0589, found 241.0595.
2JCF¼29.6 Hz), 177.5 (q, O]CeCF3, JCF¼34.7 Hz); 19F NMR
2

1262
S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
(282.4 MHz, CD3SOCD3, EEE/ZZE 80:20)
d
(ppm) ꢁ76.1 (s, 3F, CF3
3JH1H2¼9 Hz, 1H), 3.8e7.4 (m, 9 H, PheH), 8.2 (d, 3JH1H2¼9 Hz, 1H);
(ZZE)), ꢁ76.2 (br s, 3F, CF3 (EEE)); IR (cmꢁ1, KBr) 3429 (CO2H); MS
FABþ m/z (%): 260 (MþHþ, 50), 259 (Mþ, 25), 242 (MþꢁH2O, 50),
190 (MþꢁCF3, 15); HRMS m/z [MþH]þ calcd for C11H9F3NO3
260.0535, found 260.0542. Anal. Calcd for C11H8F3NO3: C, 50.98; H,
3.11; O, 18.52. Found: C, 51.01; H, 3.10; O, 18.49.
13C NMR (75.4 MHz, CDCl3, ZE/EE 74:26)
d (ppm) 55.5, 112.5, 114.2,
116.5, 119.6, 120.7, 121.9, 129.8, 136.7, 137.6, 145.1, 146.9 (q, C3eCF3,
4
2JCF¼25.7 Hz), 148.1, 151.5, 153.4 (q, HC]N (EE), JC1F¼5.9 Hz); 19F
NMR (282.4 MHz, CDCl3, ZE/EE 74;26)
d
(ppm) ꢁ66.2 (s, CF3); MS
(m/z): 322 [MþH]þ; HRMS m/z [MþH]þ calcd for C17H15F3NO2
322.1055, found 322.1060. Anal. Calcd for C17H14F3NO2: C, 63.55; H,
4.39; O, 9.96. Found: C, 63.58; H, 4.40; O, 9.98.
5.5.4. 1-Trifluoromethyl-3-(3-carboxylphenylamino)prop-2-en-1-
one (4m). Same process as 4g procedure A. Starting from 2 g
(9.25 mmol) of 3b and 1.26 g (9.25 mmol) of 3-carboxyaniline,1.43 g
(5.55 mmol) of 4m was obtained as amorphous yellow solid (yield:
5.6.3. 1-Phenylimino-3-phenoxy-3-perfluoropentyl-prop-2-ene
5c. Starting from 1 g (2.4 mmol) of 3e and 0.223 g (2.4 mmol) of
aniline, 1.1 g (2.2 mmol) of 5c was obtained as yellow liquid (yield:
60%); 1H NMR (300 MHz, CD3SOCD3, EEE/ZZE 33:67)
d (ppm) (ZZE)
5.7 (d, 3JH2H3¼7.5 Hz,1H, H-2), 7.6 (t, J¼7.9 Hz,1H, PheH), 7.7 (m,1H,
PheH), 7.9 (dd, J¼7.6 and 2.5 Hz, 1H, PheH), 8 (d, J¼3.6 Hz, 1H,
PheH), 8.2 (dd, 3JH2H3¼7.5 Hz and 3JH3NH¼13.2 Hz, 1H, H-3), 11.8 (br
d,1H, 3JH3NH¼9.3 Hz, NH); (EEE) 6 (d, 3JH2H3¼12.4 Hz,1H, H-2), 7.6 (t,
J¼7.9 Hz,1H, PheH), 7.7 (m,1H, PheH), 7.9 (dd, J¼7.6 and 2.5 Hz,1H,
PheH), 8 (d, J¼3.6 Hz,1H, PheH), 8.5 (t,1H, J¼12.8 Hz, H-3),10.1 (br d,
1H, 3JH3NH¼12.5 Hz, NH); 13C NMR (100.6 MHz, CD3SOCD3, EEE/ZZE
94%); 1H NMR (300 MHz, CDCl3, ZE/EE 15:85)
d (ppm) (EE): 6.2 (d,
3JH1H2¼9 Hz, 1H), 7e7.5 (m, 10H), 8.5 (d, 3JH1H2¼9 Hz, 1H); (ZE): 6.9
3
3
(d, JH1H2¼8.9 Hz, 1H), 7e7.5 (m, 10H), 8.2 (d, JH1H2¼8.9 Hz, 1H);
13C NMR (75.4 MHz, CDCl3, ZE/EE 15:85)
d
(ppm) 115.1, 115.8, 120.8,
3
121, 123 (t, JC2F¼4.9 Hz, C2, (ZE)), 126.4, 126.7, 127.4, 129.2, 129.3,
2
130.1, 130.5, 146.8 (t, C3eCF3, JCF¼25.8 Hz), 150.7, 151.4, 152.2 (t,
2
C3eCF3, JCF¼27.3 Hz), 152.7, 153.2 (s, HC]N (ZE)), 154.6 (t, HC]N
33:67)
d
(ppm) 90.4 (s, ]CeC]O, (ZZE)), 94 (s, ]CeC]O, (EEE)),
(EE), 4JC1F¼5.9 Hz), 157.7; 19F NMR (282.4 MHz, CDCl3, ZE/EE 15:85)
1
112.2, 116.4, 117.9 (q, CF3, JCF¼289 Hz), 119.2, 120 (q, CF3,
1JCF¼274.6 Hz), 122.8, 122.9, 123.6, 126.1, 127.1, 133.1, 133.2, 140.5,
149.4 (br d, ]CeNH, (EEE)), 152.2 (s, ]CeNH, (ZZE)), 166.92 (s,
CO2H),167 (s, CO2H),179.4 (q, O]CeCF3, 2JCF¼33.5 Hz),179.5 (q, O]
d
(ppm) ꢁ80.8 (s, 3F), ꢁ111.7 (m, 2F, (EE), 85%), ꢁ114.9 (m, 2F, (ZE),
15%), ꢁ122.5 (m, 4F), ꢁ126.1 (s, 2F); MS (m/z): 492 [MþH]þ; HRMS
m/z [MþH]þ calcd for C20H13F11NO 492.0821, found 492.0822. Anal.
Calcd for C20H12F11NO: C, 48.89; H, 2.46; O, 3.26. Found: C, 48.90; H,
2.46; O, 3.28.
CeCF3, JCF¼33.4 Hz); 19F NMR (282.4 MHz, CD3SOCD3, EEE/
2
ZZE 33:67)
d
(ppm) ꢁ77.7 (s, 3F, CF3 (ZZE), 67%), ꢁ77.9 (br s, 3F, CF3
(EEE), 33%); IR (cmꢁ1, KBr) 3430 (CO2H); MS FABþ m/z (%): 260
(MþHþ, 50), 259 (Mþ, 20), 242 (MþꢁH2O, 50), 190 (MþꢁCF3, 20);
HRMS m/z [MþH]þ calcd for C11H9F3NO3 260.0535, found 260.0539.
Anal. Calcd for C11H8F3NO3: C, 50.98; H, 3.11; O, 18.52. Found: C,
50.99; H, 3.10; O, 18.56.
5.6.4. 1-Phenylimino-3-(4-methoxyphenoxy)-3-perfluoropentyl-
prop-2-ene 5d. Starting from 1.5 g (3.36 mmol) of 3d and 0.31 g
(3.36 mmol) of aniline, 1.66 g (3.19 mmol) of 5d was obtained as
yellow liquid (yield: 95%); 1H NMR (300 MHz, CDCl3, ZE/EE 75:25)
d
(ppm) (EE): 3.8 (s, 3H, OMe), 6.2 (d, 3JH1H2¼9.3 Hz,1H), 6.9e7.4 (m,
3
9H), 8.4 (d, JH1H2¼9.3 Hz, 1H); (ZE): 3.8 (s, 3H, OMe), 6.8 (d,
5.6. General procedure for the preparation of 1-(R1-phenyl-
imino)-3-(R-phenoxy)-3-perfluoroalkyl-prop-2-enes 5aeg
3JH1H2¼9 Hz, 1H), 6.9e7.4 (m, 9 H), 8.2 (d, JH1H2¼8.9 Hz, 1H); 13C
3
NMR (75.4 MHz, CDCl3, ZE/EE 75:25) d (ppm) 55.6, 55.68,114.5,115.3,
115.5, 116.9, 117.3, 117.8, 122 (t, 3JC2F¼5 Hz, C2, (ZE)), 122.9, 123, 126.1,
2
To a solution of 3-perfluoroalkyl-3-aryloxypropenals 3 (1 equiv)
in anhydrous dichloromethane (5 mL/1 g of 3) was added 1 equiv of
the corresponding substituted aniline. The mixture was stirred at
126.6, 127.1, 130.4, 131.5, 131.8, 146, 148.1 (t, C3eCF2, JCF¼25.5 Hz),
150.1,151.1,153 (t, C3eCF2, 2JCF¼25.8 Hz),154.6 (s, HC]N (ZE)),156 (t,
HC]N (EE), JC1F¼5.9 Hz), 157.5. 19F NMR (282.4 MHz, CDCl3, ZE/
4
ꢂ
room temperature for 2 h. Molecular sieve (3 A) was added when
EE 75:25)
d
(ppm) ꢁ80.7 (s, 3F), ꢁ111.8 (m, 2F, (EE), 25%), ꢁ114.7 (m,
arylamines having electron-withdrawing substituents (R1¼NO2, Cl)
were put in reaction with 3. At the end of the reaction, the reaction
mixture was concentrated in vacuo. Petroleum ether was added to
the resulting oil and the yellow mixture was cooled to 0 ꢀC and the
formed precipitate was immediately filtrated in a cooled Buchner
funnel to afford 5 as a yellow amorphous solids. Synthesis of de-
rivatives 5 could also be achieved as we reported in a previous
publication.32a
2F, (ZE), 75%), ꢁ122 (s, 2F), ꢁ122.5 (s, 2F), ꢁ126.1 (s, 2F); MS (m/z):
522 [MþH]þ; HRMS m/z [MþH]þ calcd for C21H15F11NO2 522.0927,
found 522.0935. Anal. Calcd for C21H14F11NO2: C, 48.38; H, 2.71; O,
6.14. Found: C, 48.41; H, 2.72; O, 6.10.
5.6.5. 1-(4-Methylphenylimino)-3-phenoxy-3-trifluoromethyl-prop-
2-ene 5e. Starting from 1.1 g (5.09 mmol) of 3b and 0.54 g
(5.09 mmol) of 4-methylaniline, 1.39 g (4.58 mmol) of 5e was ob-
tained as yellow liquid (yield: 90%); 1H NMR (300 MHz, CDCl3, ZE/
3
5.6.1. 1-Phenylimino-3-(phenoxy)-3-trifluoromethyl-prop-2-ene
(5a). Starting from 1.4 g (6.48 mmol) of 3b and 0.6 g (6.48 mmol) of
aniline,1.79 g (6.15 mmol) of 5a was obtained as yellow liquid (yield:
EE 62:38)
d
(ppm) (EE): 2.4 (s, 3H, Me), 6.2 (d, JH1H2¼9.3 Hz, 1H),
3
6.7e7.3 (m, 9 H), 8.3 (d, JH1H2¼9.3 Hz, 1H); (ZE): 2.45 (s, 3H, Me),
3
3
6.5 (d, JH1H2¼8.9 Hz, 1H), 6.7e7.3 (m, 9 H), 8.1 (d, JH1H2¼8.9 Hz,
95%); 1H NMR (300 MHz, C6D6, EE 100%)
d
(ppm) 6.3 (d, 3JHH¼9 Hz,
1H); 13C NMR (75.4 MHz, CDCl3, ZE/EE 62:38)
d
(ppm) 17.7, 17.8,
H2), 6.8e7.5 (m, 10H), 8.8 (d, 3JHH¼9 Hz, H1); 13C NMR (100.6 MHz,
114.4, 115.1, 115.4, 116.9, 117.2, 117.7, 122, 122.2, 126.1, 126.6, 126.7,
2
C6D6, EE 100%)
d
(ppm) 117.1, 117.5, 121.2, 121.3, 127.1, 127.5, 130.1,
126.9, 130.4, 130.5, 131.5, 132.6, 145.9, 147.3 (q, C3eCF3, JCF¼25.5
131.5, 151.8 (q, C3-CF3, 2JCF¼29 Hz), 153.2, 153.8, 156.1 (q, HC]N (EE),
Hz), 150.1, 151, 151.5, 153 (s, HC]N (ZE)), 154.6, 156 (q, HC]N (EE),
4JC1F¼5 Hz), 157.7; 19F NMR (282.4 MHz, CDCl3, ZE/EE 62:38)
4JC1F¼5.7 Hz); 19F NMR (282.4 MHz, C6D6, EE 100%)
d (ppm) 66.5 (s,
3F, CF3); MS (m/z): 292 [MþH]þ; HRMS m/z [MþH]þ calcd for
d
(ppm) ꢁ66.7 (m, 3F, (EE), 38%), ꢁ63.4 (m, 3F, (ZE), 62%); MS (m/z):
C16H13F3NO: 292.0949, found: 292.0952. Anal. Calcd for C16H12F3NO:
306 [MþH]þ; HRMS m/z [MþH]þ calcd for C17H15F3NO 306.1106,
found 306.1112. Anal. Calcd for C17H14F3NO: C, 66.88; H, 4.62; O,
5.24. Found: C, 66.90; H, 4.62; O, 5.22.
C, 65.98; H, 4.15; O, 5.49. Found: C, 65.98; H, 4.17; O, 5.54.
5.6.2. 1-Phenylimino-3-(4-methoxyphenoxy)-3-trifluoromethyl-
prop-2-ene (5b). Starting from 1.1 g (4.47 mmol) of 3a and 0.41 g
(4.47 mmol) of aniline, 1.36 g (4.24 mmol) of 5b was obtained as
5.6.6. 1-(4-Chlorophenylimino)-3-phenoxy-3-perfluoropentyl-prop-
2-ene 5f. Starting from 1.6 g (3.84 mmol) of 3e and 0.48 g
(3.84 mmol) of 4-chloroaniline, 1.67 g (3.19 mmol) of 5f was ob-
yellow liquid (yield: 95%); 1H NMR (300 MHz, CDCl3, ZE/EE: 74/26)
3
d
(ppm) (EE): 3.8 (s, 3H, OMe), (EE): 6.1 (d, JH1H2¼9.3 Hz, 1H),
tained as yellow liquid (yield: 83%); 1H NMR (300 MHz, C6D6, EE
3
3
6.8e7.4 (m, 9 H, PheH), 8.4 (d, JH1H2¼9.3 Hz, 1H); (ZE): 6.8 (d,
100%)
d
(ppm) 6.2 (d, JH1H2¼9 Hz, H2), 6.8e7.2 (m, 9 H), 8.8 (d,

S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
1263
3JH1H2¼9 Hz, H1); 13C NMR (75.4 MHz, C6D6, EE 100%)
d
(ppm) 117.1,
3H), 7.56 (d, J¼8.6 Hz, 1H), 7.8 (m, 2H), 8.2 (d, J¼8.6 Hz, 1H), 8.51 (d,
2
117.3, 121.7, 122, 127.2, 127.7, 130.7, 131.4, 151 (t, C3eCF2, JCF¼25.5
J¼8.5 Hz, 1H); 13C NMR (75.4 MHz, CD3COCD3)
d (ppm) 21.65, 117.63
4
3
Hz), 152.9, 153.6, 155 (t, HC]N (EE), JC1F¼5.7 Hz); 19F NMR
(q, CH, JCF¼2.2 Hz), 122.8 (q, CF3, 1JCF¼273.9 Hz), 127.6, 130, 130.2,
2
(282.4 MHz, C6D6, EE 100%)
d
(ppm) ꢁ80.7 (s, 3F), ꢁ111.4 (m, 2F,
134.2, 138.8, 140, 146.6, 147.4 (q, CeCF3, JCF¼34.7 Hz); 19F NMR
(EE)), ꢁ122.1 (s, 4F), ꢁ125.6 (s, 2F); MS (m/z): 526 [MþH]þ; HRMS
m/z [MþH]þ calcd for C20H12ClF11NO 526.0432, found 526.0440.
Anal. Calcd for C20H11ClF11NO: C, 45.69; H, 2.11; O, 3.04. Found: C,
45.75; H, 2.12; O, 3.08.
(282.4 MHz, CD3COCD3)
d
(ppm) ꢁ67.8 (s, 3F); MS (m/z): 212
[MþH]þ; HRMS m/z [MþH]þ calcd for C11H9F3N: 212.0687, found:
212.0607. Anal. Calcd for C11H8F3N: C, 62.56; H, 3.82; N, 6.63. Found:
C, 62.45; H, 3.76; N, 6.68.
5.6.7. 1-(4-Nitrophenylimino)-3-phenoxy-3-perfluoropenthyl-prop-
2-ene 5g. Starting from 1.5 g (3.6 mmol) of 3e and 0.49 g (3.6 mmol)
of 4-nitroaniline, 1.35 g (2.52 mmol) of 5g was obtained as yellow
amorphous solid (yield: 70%); 1H NMR (300 MHz, CDCl3, ZE/
5.7.3. Reaction of 5c with 4-methylaniline: synthesis of 2-
perfluoropentylquinoline (6c) and 2-perfluoropentyl-6-methylquinoline
(6d). Starting with 5c (1 g; 2.03 mmol) and 4-methylaniline
(0.217 g; 2.03 mmol) in 10 mL of dichloromethane under reflux
for 6 h, 0.1 g of 2-perfluoropentylquinoline 6c (15%) and 0.58 g of 2-
perfluoropentyl-6-methylquinoline 6d (85%) are obtained, total
yield 82%.
EE 70:30)
d
(ppm) (EE): 6.2 (d, 3JH1H2¼9.1 Hz, 1H), 6.9e7.3 (m, 9H),
8.5 (d, 3JH1H2¼9.1 Hz, 1H); (ZE): 6.8 (d, 3JH1H2¼9 Hz, 1H), 6.9e7.3 (m,
3
9H), 8.2 (d, JH1H2¼9 Hz, 1H); 13C NMR (75.4 MHz, CDCl3, ZE/
EE 70:30)
d (ppm) 112.2, 112.5, 114.5, 114.7, 115.6, 115.9, 117.2, 117.9,
120.1, 120.7, 121.5, 123.1, 123.3, 123.8, 130.1, 130.5, 136.7, 137.3, 146,
5.7.4. Reaction of 5d with 4-methylaniline: synthesis of 2-
perfluoropentylquinoline (6c) and 2-perfluoropentyl-6-methylquinoline
(6d). Starting with 5d (1 g; 1.91 mmol) and 4-methylaniline
(0.205 g; 1.91 mmol) in 10 mL of dichloromethane under reflux for
6 h, 91.4 mg of 2-perfluoropentylquinoline 6c (15%) and 0.53 g
2-perfluoropentyl-6-methylquinoline 6d (85%) are obtained, total
yield 80%.
146.4 (q, C3eCF3, 2JCF¼24.3 Hz),149,151.9,152.1,153,154.9 (s, HC]N
4
(ZE)), 156.2 (q, HC]N (EE), JC1F¼5.1 Hz); 19F NMR (282.4 MHz,
CDCl3, ZE/EE: 70/30)
d
(ppm) ꢁ80.7 (s, 3F), ꢁ111.6 (m, 2F, (EE), 30%),
ꢁ114.8 (m, 2F, (ZE), 70%), ꢁ122 (s, 2F), ꢁ122.4 (s, 2F), ꢁ126.1 (s, 2F);
MS (m/z): 537 [MþH]þ; HRMS m/z [MþH]þ calcd for C20H12F11N2O3
537.0672, found 537.0678. Anal. Calcd for C20H11F11N2O3: C, 44.79;
H, 2.07; O, 8.95. Found: C, 44.82; H, 2.07; O, 8.90.
5.7.4.1. 2-Perfluoropentylquinoline (6c). 1H NMR (300 MHz,
5.7. Reactivity study of 5aeg: general procedure for the
preparation of substituted 2-trifluoromethyl and 2-
perfluoroalkylquinolines 6aeh
CDCl3)
d
(ppm) 7.6 (t, JHH¼7.8 Hz, 1H), 7.65 (d, JHH¼8.5 Hz, 1H), 7.75
(t, JHH¼8.3 Hz, 1H), 7.8 (d, JHH¼8.3 Hz, 1H), 8.15 (d, JHH¼8.5 Hz, 1H),
8.25 (d, JHH¼8.5 Hz, 1H); 13C NMR (100.6 MHz, CDCl3)
d (ppm) 117.2
3
(t, CH, JCF¼3.8 Hz), 126.6, 127.6, 127.7, 129.3, 129.7, 136.6, 146.3,
In a typical procedure, a mixture of the imino-enol-ether de-
rivatives 5aeg (1 equiv) and substituted arylamines (1 equiv) in
dichloromethane (10 mL/1 g of 5) was refluxed at 40 ꢀC until dis-
appearance of 19F NMR signals corresponding to the starting
products 5 (6e24 h). The reaction mixture was concentrated under
reduced pressure to give brown oil. Chromatography on silica gel
column (eluent: petroleum ether/ethyl acetate 98:2) left two yel-
low oils, which were precipitated from methanol/water to give
pure samples of the corresponding substituted quinolines 6aeh as
amorphous white solids. Formation of the corresponding dia-
zapentadiene intermediates was detected by mass spectrometry
showing three different picks corresponding to the molecular mass
[MþH]þ of 7 after 2 h of heating.
146.7 (t, CeCF2, 2JCF¼25.2 Hz); 19F NMR (282.4 MHz, CDCl3)
d (ppm)
ꢁ81.3 (t, JFF¼7.8 Hz, 3F, CF3), ꢁ114.3 (t, JFF¼13.1 Hz, 2F, CF2), ꢁ122
(m, 2F, CF2), ꢁ122.8 (m, 2F, CF2), ꢁ126.5 (m, 2F, CF2). MS (m/z): 398
[MþH]þ; HRMS m/z [MþH]þ calcd for C14H7F11N 398.0403, found
398.0400. Anal. Calcd for C14H6F11N: C, 42.34; H, 1.52; N, 3.53.
Found: C, 42.36; H, 1.51; N, 3.50.
5.7.4.2. 2-Perfluoropentyl-6-methylquinoline
(6d). 1H
NMR
(300 MHz, CDCl3)
d
(ppm) 2.5 (s, 3H), 7.4 (d, J¼8.5 Hz, 1H), 7.7 (m,
2H), 8.1 (d, J¼8.6 Hz,1H), 8.5 (d, J¼8.6 Hz,1H); 13C NMR (100.6 MHz,
CDCl3)
d (ppm) 21.5, 117.5, 126.5, 130.5, 130.7, 135.2, 138.7,
139.8, 146.3, 147.7 (t, CeCF2, JCF¼26.1 Hz); 19F NMR (282.4 MHz,
2
CDCl3)
d
(ppm) ꢁ81.3 (m, 3F, CF3), ꢁ114.4 (m, 2F, CF2), ꢁ122 (m, 2F,
CF2), ꢁ122.5 (m, 2F, CF2), ꢁ126.5 (m, 2F, CF2). MS (m/z): 412
[MþH]þ; HRMS m/z [MþH]þ calcd for C15H9F11N 412.0559, found
412.0565. Anal. Calcd for C15H8F11N: C, 43.81; H, 1.96; N, 3.41.
Found: C, 43.84; H, 1.98; N, 3.40.
5.7.1. Reaction of 5a with 4-methylaniline: synthesis of 2-
trifluoromethylquinoline (6a) and 2-trifluoromethyl-6-methylquinoline
(6b). Starting with 5a (1 g; 3.43 mmol) and 4-methylaniline
(0.367 g; 3.43 mmol) in 10 mL of dichloromethane under reflux
for 6 h, 75.8 mg of 2-trifluoromethylquinoline 6a (14%) and 0.498 g
of 2-trifluoromethyl-6-methylquinoline 6b (86%) are obtained, to-
tal yield 80%.
5.7.5. Reaction of 5a with 2-methylaniline: synthesis of 2-
trifluoromethylquinoline (6a) and 2-trifluoromethyl-8-
methylquinoline (6e). Starting with 5a (1.1 g; 3.78 mmol) and 2-
methylaniline (0.404 g; 3.78 mmol) in 10 mL of dichloromethane
under reflux for 6 h, 0.189 g of 2-trifluoromethylquinoline 6a (30%)
and 0.47 g of 2-trifluoromethyl-8-methylquinoline 6e (70%) are
obtained, total yield 85%.
5.7.2. Reaction of 5b with 4-methylaniline: synthesis of 2-
trifluoromethylquinoline (6a) and 2-trifluoromethyl-6-methylquinoline
(6b). Starting with 5b (1.1 g; 3.42 mmol) and 4-methylaniline
(0.366 g; 3.42 mmol) in 10 mL of dichloromethane under reflux
for 6 h, 81 mg of 2-trifluoromethylquinoline 6a (15%) and 0.491 g of
2-trifluoromethyl-6-methylquinoline 6b (85%) are obtained, total
yield 80%.
5.7.5.1. 2-Trifluoromethylquinoline. 2-Trifluoromethylquinoline
see spectral description of (6a) and data also reported in our pre-
vious publication.34b
5.7.2.1. 2-Trifluoromethylquinoline. See spectral description of
(6a).
5.7.5.2. 2-Trifluoromethyl-8-methylquinoline (6e). 2-Trifluorome-
tnqh_0009;thyl-8-methylquinoline (6e) also reported in our pre-
vious publication.34b 1H NMR (300 MHz, CD3COCD3)
d (ppm) 2.8 (s,
5.7.2.2. 2-Trifluoromethyl-6-methylquinoline (6b). 2-Trifluorome-
tnqh_0009;thyl-6-methylquinoline (6b) also reported in our pre-
3H), 7.65 (m, 1H), 7.75 (d, J¼6.8 Hz, 1H), 7.92 (m, 2H), 8.61 (d,
J¼8.5 Hz, 1H); 13C NMR (75.4 MHz, CD3COCD3)
d (ppm) 17.6, 117.3 (q,
vious publication.34b 1H NMR (300 MHz, CD3COCD3)
d
(ppm) 2.52 (s,
CH, 3JCF¼2.1 Hz), 122.8 (q, CF3, 1JCF¼274.2 Hz),126.8, 129.5, 130, 131.8,

1264
S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
138.6, 139.8, 146.9, 147.1 (q, CeCF3, 2JCF¼29 Hz); 19F NMR (282.4 MHz,
reported in our previous publication.34b 1H NMR (300 MHz,
CD3COCD3)
d
(ppm) ꢁ67.8 (s, 3F). MS (m/z): 212 [MþH]þ; HRMS m/z
CD3COCD3)
d
(ppm) 7.4 (d, J¼9 Hz, 1H), 7.6 (d, J¼8.5 Hz, 1H), 7.7 (d,
[MþH]þ calcd for C11H9F3N: 212.0687, found: 212.0684. Anal. Calcd
for C11H8F3N: C, 62.56; H, 3.82; N, 6.63. Found: C, 62.45; H, 3.74; N,
6.61.
J¼9 Hz, 1H), 7.9 (s, 1H) 8.2 (d, J¼8.6 Hz, 1H); 13C NMR (75.4 MHz,
CD3COCD3)
d (ppm) 118.5, 122.5, 127, 132.7, 133.1, 134.1, 140.5,
145.5, 147.9 (t, CeCF2, JCF¼26 Hz); 19F NMR (282.4 MHz,
2
CD3COCD3)
d
(ppm) ꢁ81.5 (m, 3F, CF3), ꢁ114.2 (m, 2F, CF2), ꢁ122
5.7.6. Reaction of 5a with 4-nitroaniline: synthesis of 2-
trifluoromethylquinoline (6a) and 2-trifluoromethyl-6-nitroquinoline
(6f). Starting with 5a (1 g; 3.43 mmol) and 4-nitroaniline
(0.474 g; 3.43 mmol) in 10 mL of dichloromethane under reflux
for 12 h, 0.456 g of 2-trifluoromethylquinoline 6a (90%) and
62.37 mg of 2-trifluoromethyl-6-nitroquinoline 6f (10%) are ob-
tained, total yield 75%.
(m, 2F, CF2), ꢁ122.5 (m, 2F, CF2), ꢁ126 (m, 2F, CF2). MS (m/z): 432
[MþH]þ; HRMS m/z [MþH]þ calcd for C14H6ClF11N: 432.0013,
found: 432.0020. Anal. Calcd for C14H5ClF11N : C, 38.96; H, 1.17; N,
3.25. Found: C, 38.99; H, 1.17; N, 3.22.
5.7.10. Reaction of 5g with 4-methylaniline: synthesis of 2-
perfluoropentyl-6-methylquinoline (6d) and 2-perfluoropentyl-6-
nitroquinoline (6h). Starting with 5g (1.5 g; 2.79 mmol) and 4-
methylaniline (0.299 g; 2.79 mmol) in 15 mL of dichloromethane
under reflux for 6 h, 55.6 mg of 2-perfluoropentyl-6-nitroquinoline
6h (5%) and 0.983 g 2-perfluoropentyl-6-methylquinoline 6d (95%)
are obtained, total yield 90%.
5.7.6.1. 2-Trifluoromethylquinoline. see spectral description of
(6a) and data also reported in our previous publication.34b
5.7.6.2. 2-Trifluoromethyl-6-nitroquinoline (6f). 2-Trifluorome-
tnqh_0009;thyl-6-nitroquinoline (6f) also reported in our previous
publication.34b 1H NMR (300 MHz, CD3COCD3)
d
(ppm) 8.2 (d, J¼8.6
5.7.10.1. 2-Perfluoropentyl-6-methylquinoline. See spectral de-
scription of (6d).
Hz, 1H), 8.4 (d, J¼9.3 Hz, 1H), 8.6 (dd, J¼2.5 and 9.3 Hz, 1H), 9.1 (d,
J¼8.6 Hz, 1H) 9.19 (d, J¼2.5 Hz, 1H); 13C NMR (75.4 MHz, CD3COCD3)
d
(ppm) 119.5 (q, CH, 3JCF¼2.2 Hz), 122 (q, CF3, 1JCF¼275.4 Hz), 127.5,
5.7.10.2. 2-Perfluoropenthyl-6-nitroquinoline (6h). 2-Perfluoro-
tnqh_0009;penthyl-6-nitroquinoline (6h) also reported in our pre-
130.1, 132, 132.8, 134.5, 140.1, 145.2, 148 (q, CeCF3, JCF¼34 Hz); 19F
2
NMR (282.4 MHz, CD3COCD3)
d
(ppm) ꢁ68.5 (s, 3F). MS (m/z): 243
vious publication.34b 1H NMR (300 MHz, CD3COCD3)
d (ppm) 8.2 (d,
[MþH]þ; HRMS m/z [MþH]þ calcd for C10H6F3N2O2: 243.0381,
found: 243.0408. Anal. Calcd for C10H5F3N2O2: C, 49.60; H, 2.08; N,
11.57. Found: C, 49.74; H, 2.12; N, 11.69.
J¼8.5 Hz, 1H), 8.4 (d, J¼9 Hz, 1H), 8.6 (dd, J¼2.1 and 9 Hz, 1H), 9 (d,
J¼8.5 Hz, 1H) 9.1 (d, J¼2 Hz, 1H); 13C NMR (75.4 MHz, CD3COCD3)
d
(ppm) 120.1, 127.1, 130.1, 132.5, 132.8, 134.2, 141.5, 145.2, 148.5 (t,
CeCF2, 2JCF¼27.7 Hz); 19F NMR (282.4 MHz, CD3COCD3)
(ppm) ꢁ81
d
5.7.7. Reaction of 5e with 2-methylaniline: synthesis of 2-
trifluoromethyl-6-methylquinoline (6b) and 2-trifluoromethyl-8-
methylquinoline (6e). Starting with 5e (1.5 g; 4.91 mmol) and 2-
methylaniline (0.526 g; 4.91 mmol) in 15 mL of dichloromethane
under reflux for 6 h, 0.532 g of 2-trifluoromethyl-6-methylquinoline
6b (57%) and 0.4 g of 2-trifluoromethyl-8-methylquinoline 6e (43%)
are obtained, total yield 90%.
(m, 3F), ꢁ114 (m, 2F), ꢁ122.5 (m, 4F), ꢁ126.5 (m, 2F). MS (m/z): 443
[MþH]þ; HRMS m/z [MþH]þ calcd for C14H6F11N2O2: 443.0254,
found: 443.0264. Anal. Calcd for C14H5F11N2O2: C, 38.03; H, 1.14; N,
6.34. Found: C, 38.08; H, 1.15; N, 6.35.
5.8. Synthesis and isolation of unsymmetrically substituted:
2-perfluoropentyl-N-phenyl,N0-(4-methylphenyl)-1,5-
diazapentadiene (7d) and 2-perfluoropentyl-N-(4-
methylphenyl),N0-phenyl-1,5-diazapentadiene (7e) (Scheme 8,
Table 3).
5.7.7.1. 2-Trifluoromethyl-6-methylquinoline and 2-trifluorome-
tnqh_0009;thyl-8-methylquinoline. See spectral descriptions of 6b
and 6e and data also reported in our previous publication.34b
A mixture of 5.5 g (11.2 mmol) of 5c (1 equiv) and 1.19 g
(11.2 mmol) of 4-methylaniline (1 equiv) in 110 mL of dichloro-
methane (20 mL/1 g of 5) was refluxed at 40 ꢀC. The evolution of
the reaction was controlled by 19F NMR spectroscopy and by CCM.
After 1 h and a half, heating was stopped and the reaction mixture
was diluted with dichloromethane and washed 5ꢂ with water.
The organic layers were concentrated under reduced pressure to
give yellow oil. Excess of petroleum ether was added and the
yellow precipitate which had formed was filtered. 19F NMR anal-
ysis of this precipitate showed the presence of a mixture of three
different diazapentadienes. Chromatography on silica gel column
(eluent: petroleum ether/ethyl acetate 95:5) permitted to separate
three yellow amorphous solids corresponding to the correspond-
ing symmetrically and unsymmetrically substituted 7c, 7d, and 7e
and unsubstituted diazapentadienes 7b (22% of the formed
products). Then the organic filtrate was concentrated giving
a yellow liquid. Chromatography on silica gel column (eluent:
petroleum ether/ethyl acetate 90:10) gave two enaminoketones
4c and 4p as amorphous yellow solids (26% of the formed prod-
ucts) and the corresponding quinolines 6c and 6d as white
amorphous solids (22% of the formed products). Finally the
unreacted starting product 5c was recovered (1.15 g, 30% of the
reaction mixture).
5.7.8. Reactionof5ewith4-nitroaniline: synthesis of2-trifluoromethyl-
6-methylquinoline (6b) and 2-trifluoromethyl-6-nitroquinoline
(6f). Starting with 5e (1.6 g; 5.24 mmol) and 4-nitroaniline
(0.723 g; 5.24 mmol) in 15 mL of dichloromethane under reflux for
12 h, 0.967 g of 2-trifluoromethyl-6-methylquinoline 6b (95%) and
58.39 mg of 2-trifluoromethyl-6-nitroquinoline 6f (5%) are obtained,
total yield 92%.
5.7.8.1. 2-Trifluoromethyl-6-methylquinoline and 2-trifluorome-
tnqh_0009;thyl-6-nitroquinoline. See spectral descriptions of 6b and
6f and data also reported in our previous publication.34b
5.7.9. Reaction of 5f with 4-methylaniline: synthesis of 2-
perfluoropentyl-6-methylquinoline (6d) and 2- perfluoropentyl-6-
chloroquinoline (6g). Starting with 5f (1 g; 1.90 mmol) and 4-
nitroaniline (0.262 g; 1.90 mmol) in 10 mL of dichloromethane un-
der reflux for 6 h, 0.184 g of 2-perfluoropentyl-6-chloroquinoline 6g
(25%) and 0.528 g of 2-perfluoropentyl-6-methylquinoline 6d (75%)
are obtained, total yield 90%.
5.7.9.1. 2-Perfluoropentyl-6-methylquinoline. See spectral de-
scription of (6d).
5.7.9.2. 2-Perfluoropentyl-6-chloroquinoline (6g). 2-Perfluoro-
tnqh_0009;pentyl-6-chloroquinoline (6g) in acetone-d6 also
5.8.1. 2-Perfluoropentyl-N,N0-diphenyl-1,5-diazapentadiene (7b). 2-
Perfluoropentyl-N,N0-diphenyl-1,5-diazapentadiene (7b) was

S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
1265
also reported in our previous publication.32a Yellow solid, 0.15 g
[MþH]þ calcd for C11H11F3NO 430.0665, found 430.0670. Anal.
Calcd for C11H10F3NO: C, 41.97; H, 2.35; O, 3.73. Found: C, 41.99;
H, 2.38; O, 3.75.
(yield 4%); 1H NMR (300 MHz, DMSO-d6)
d (ppm) 5.5 (d,
3JH2H3¼13.7 Hz, H2), 6.8 (t, J¼8.7 Hz, 3H), 6.9 (t, J¼7.4 Hz, 1H), 7.1
(t, J¼7.4 Hz, 1H), 7.2 (t, J¼8.1 Hz, 2H), 7.4 (t, J¼7.8 Hz, 3H), 7.45
3
(m, 1H, H3), 9.9 (d, JH3NH¼12.4 Hz, NH); 13C NMR (75.4 MHz,
5.8.6. 2-Perfluoropentylquinoline. White solid, 0.124 g (yield 4%);
see spectral description of 6c.
DMSO-d6)
d (ppm) 91.4, 114.9, 118.4, 122.3, 123.6, 129.4, 129.5,
4
129.6, 140.5, 141.5 (t, C3H, JC3F¼5.5 Hz), 149.9, 153.5 (t, CeCF3,
2JC1F¼22.6 Hz); 19F NMR (282.4 MHz, DMSO-d6)
d
(ppm) ꢁ80.2 (s,
5.8.7. 2-Perfluoropentyl-6-methylquinoline. White solid, 0.58
(yield 18%); see spectral description of 6d.
g
3F), ꢁ109.6 (t, J¼11.2 Hz, 2F), ꢁ120.4 (s, 2F), ꢁ121 (s, 2F), ꢁ125.8
(s, 2F); MS (m/z): 491 [MþH]þ; HRMS m/z [MþH]þ calcd for
C
C
20H14F11N2 491.0981, found 491.0983. Anal. Calcd for
20H13F11N2: C, 48.99; H, 2.67; N, 5.71. Found: C, 48.97; H, 2.66;
5.9. Reaction of 4aeo with POCl3, general procedure for the
preparation of substituted 2-trifluoromethyl and 2-perfluoroal-
tnqh_0009;kylquinolines 6 and isolation of the corresponding
diazapentadiene intermediates 7
N, 5.73.
5.8.2. 2-Perfluoropentyl-N,N0-di-(4-methylphenyl)-1,5-
diazapentadiene (7c). Yellow solid, 0.56 g (yield 14%); 1H NMR
In a typical procedure, enaminones 4 were heated in excess of
POCl3 at 100 ꢀC for 12 h until complete consumption of the starting
material as judged by TLC and 19F NMR spectroscopy (see 19F NMR
spectra of the reaction mixture in Supplementary data). The
resulting brown dark mixture was stirred at room temperature
then cooled using an ice bath. Water was added slowly. To the
resulting mixture was added dichloromethane and then washed
three times with a solution of 2% sodium hydrogenocarbonate. The
organic layers were then dried over sodium sulfate and concen-
trated in vacuo. Chromatography on silica gel column (eluent: pe-
troleum ether/ethyl acetate: 98:2) left yellow oil, which was
crystallized from methanol/water to give pure samples of the cor-
responding substituted quinolines 6 (yield 65e80%).
(300 MHz, DMSO-d6)
d
(ppm) 2.2 (s, 3H), 2.3 (s, 3H), 5.5 (d, J¼13.6
Hz, 1H), 6.6 (d, J¼8.1 Hz, 2H), 6.8 (d, J¼8.2 Hz, 2H), 7 (d, J¼8.2 Hz,
2H), 7.2 (d, J¼8.1 Hz, 2H), 7.6 (t, J¼12.8 Hz, 1H), 9.8 (br d, J¼12.6 Hz,
1H); 13C NMR (75.4 MHz, DMSO-d6)
d (ppm) 20, 20.2, 90.6, 115.2,
118.9, 129.5, 129.7, 129.8, 131, 131.1, 132.5, 138.1, 142.8 (t, CH,
3JCF¼3 Hz), 147.7, 153.1 (t, CeCF2, JCF¼27.8 Hz); 19F NMR
2
(282.4 MHz, DMSO-d6)
d
(ppm) ꢁ80 (s, 3F), ꢁ109.8 (s, 2F), ꢁ120.5 (s,
2F), ꢁ121 (s, 2F), ꢁ125 (s, 2F); MS (m/z): 519 [MþH]þ; HRMS m/z
[MþH]þ calcd for C22H18F11N2: 519.1294, found: 519.1299. Anal.
Calcd for C22H17F11N2: C, 50.97; H, 3.31; N, 5.40. Found: C, 50.99; H,
3.30; N, 5.38.
5.8.3. 2-Perfluoropentyl-N-phenyl,N0-(4-methylphenyl)-1,5-
diazapentadiene (7d) and 2-perfluoropentyl-N-(4-methylphenyl),N0-
phenyl-1,5-diazapentadiene (7e). Yellow solid, 0.15 g (yield 4%); 1H
NMR (300 MHz, DMSO-d6)
(dt, J¼13.4 Hz and 4.4 Hz, 2H), 6.6e7.4 (m, 18 H), 7.5 (m, 2H), 9.8 (m,
2H); 13C NMR (75.4 MHz, DMSO-d6)
(ppm) 20.1, 20.12, 90.9, 91.5,
5.9.1. Isolation of diazapentadiene 7 intermediates. 10e20 min of
reaction at 100 ꢀC was sufficient to identify and isolate the dia-
zapentadiene intermediate 7 (as judged by TLC and 19F NMR
spectroscopy: see 19F NMR spectra of the reaction mixture in
Supplementary data). The brown mixture was stirred at room
temperature then cooled using an ice bath. Water was added
slowly. The resulting mixture was diluted with dichloromethane
and washed with a solution of 2% sodium hydrogenocarbonate. The
organic layers were then dried over sodium sulfate and concen-
trated in vacuo. Chromatography on silica gel column (eluent: pe-
troleum ether/ethyl acetate 98;2) left yellow solid of 7 (yield
40e62%).
d (ppm) 2.2 (3H, CH3), 2.3 (3H, CH3), 5.5
d
114.8, 118.4, 121.9, 122, 123, 123.4, 129.4, 129.5, 129.8, 129.9, 131.1,
3
131.2, 132.5, 132.6, 138.2, 140.6, 141 (t, CH, JCF¼1 Hz), 141.4, 141.7,
147.5, 147.6, 150, 150.2, 153.6 (t, CeCF2, JCF¼22 Hz); 19F NMR
2
(282.4 MHz, DMSO-d6)
d
(ppm) ꢁ80.5 (m, 3F), ꢁ80.8 (m, 3F),
ꢁ109.7 (m, 4F), ꢁ120.5 (m, 4F), ꢁ121.2 (m, 4F), ꢁ126 (m, 2F), ꢁ126.2
(m, 2F); MS (m/z): 505 [MþH]þ: HRMS m/z [MþH]þ calcd for
C
C
21H16F11N2: 505.1138, found: 505.1145. Anal. Calcd for
21H15F11N2: C, 50.01; H, 3.00; N, 5.55. Found: C, 50.04; H, 3.01; N,
Spectral data of the obtained 2-perfluoroalkyl and 2-
trifluoromethylquinolines or 2-perfluoroalkyl 6aeh and 2-
trifluoromethyl-N,N0-diaryl-1,5-diazapentadienes 7 are described
in sections before or in previous publications.32,34
5.57.
5.8.4. 1-Perfluoropenthyl-3-(phenylamino)prop-2-en-1-one
(4c). Yellow solid, 0.13 g (yield 4%); 1H NMR (400 MHz, C6D6), ZZE
3
100%:
d
(ppm) 5.7 (d, JH2H3¼7.1 Hz, 1H, H-2), 6.6 (d, 2H, J¼8 Hz,
3
3
Acknowledgements
PheH), 6.9 (dd, JH2H3¼7.4 Hz and JH3NH¼13 Hz, 1H, H-3), 7.1e7.2
(m, 3H, PheH), 12.1 (br d, 1H, NH); 13C NMR (100.6 MHz, C6D6)
We are particularly indebted to Professor Marianne Abi Fadel,
Dean of the Faculty of Pharmacy, Saint Joseph University, for her
help and her continued interest about this work. We acknowledge
the Saint Joseph University for its support. We also gratefully ac-
knowledge Montpellier 2 University for its generosity and its con-
tribution to the continued success of this work. We wish to thank
Doctors Marise Bejaud and Laurent Boiteau for assistance with the
NMR instrumentation and for interesting discussions. Finally, we
d
(ppm) 91.4 (s, ]CeC]O), 117.4, 125.5, 129.8, 138.8, 149.1 (s, ]
2
CeeNH), 180.4 (t, O]CeCF2, JCF¼24.8 Hz); 19F NMR (282.4 MHz,
C6D6)
d
(ppm) ꢁ81 (m, 3F), ꢁ120.3 (m, 2F, ZZE), ꢁ122.5 (m, 4F),
ꢁ126.5 (m, 2F); MS FABþ m/z (%): 416 [MþH]þ; HRMS m/z [MþH]þ
calcd for C14H9F11NO 416.0508, found 416.0490. Anal. Calcd for
C
3.86.
14H8F11NO: C, 40.50; H, 1.94; O, 3.85. Found: C, 40.48; H, 1.95; O,
ꢁ
express our gratitude to Professor Gerard Lefranc for all his help
5.8.5. 1-Perfluoropentyl-3-(4-methylphenylamino)prop-2-en-1-one
(4p). Yellow solid, 0.74 g (yield 22%); 1H NMR (400 MHz, C6D6),
and support making the collaboration between our laboratories
possible.
3
ZZE 100%:
d
(ppm) 2.1 (s, 3H), 5.6 (d, JH2H3¼7 Hz, 1H, H-2), 6.6
3
3
(dd, JH2H3¼7.1 Hz and JH3NH¼12.2 Hz, 1H, H-3), 6.8e7.3 (m, 4H,
PheH), 11.8 (br d, 1H, NH); 13C NMR (100.6 MHz, C6D6)
d
(ppm)
Supplementary data
16.6, 91.4 (s, ]CeC]O), 117.5, 125.5, 127.2, 128.1, 132.1, 138, 148.9
2
(s, ]CeNH), 180 (t, O]CeCF3, JCF¼24.1 Hz); 19F NMR
Copies of 1H, 13C, COSY 1He1H, HMQC 13Ce1H, 19F NMR and IR
spectra of 4aeo, 5aeg, 6aeh and 7. Copies of 19F NMR spectra of
reaction evolution of 4c with POCl3 and 5c with 4-methylaniline.
(282.4 MHz, C6D6)
d
(ppm) ꢁ81.2 (m, 3F), ꢁ120.4 (m, 2F), ꢁ122.5
(m, 4F), ꢁ126 (m, 2F); MS FABþ m/z: 430 [MþH]þ; HRMS m/z

1266
S. El Kharrat et al. / Tetrahedron 70 (2014) 1252e1266
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