ClickEnam. 1. Synthesis of novel 1,4-disubsituted-[1,2,3]-triazole-derived β-aminovinyl trifluoromethylated ketones and their copper(II) complexes

Article abstract of DOI:10.1016/j.jfluchem.2011.05.011

The copper(I) catalyzed cycloaddition reaction of N-Boc propargyl amine (dipolarophile) 1 with benzyl azide (1,3-dipole) 2 was found to proceed smoothly in t-BuOH/H₂O at room temperature, to furnish the corresponding 1,4-disubstituted-[1,2,3]-triazole-derived N-Boc amine 3 in good yield. Deprotection of 3 with trifluoroacetic acid and addition of the trifluoroacetate salt 4 in the presence of triethylamine, with a series of methoxyvinyl(trifluoromethyl)ketones 10-14, gave the corresponding β-aminovinyl trifluoromethylated ketones 15-19 in moderate to good yields. Two copper(II) complexes, one monomer and one dimer with chlorine double bridge, 20 and 21, respectively, were also prepared and their crystal structure determined. β-Aminovinyl trifluoromethylated ketones 15-17 and complexes 20 and 21 have been screened as potential antifungal agents and the antimalarial activity of 15 and 16 were tested against two Plasmodium falciparum strains (3D7 and W2).

Full text of DOI:10.1016/j.jfluchem.2011.05.011

Journal of Fluorine Chemistry 132 (2011) 850–857
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
ClickEnam. 1. Synthesis of novel 1,4-disubsituted-[1,2,3]-triazole-derived
b
-aminovinyl trifluoromethylated ketones and their copper(II) complexes
a
a
a
a,
b
*
´
´
Nicolas Chopin , Sophie Decamps , Aude Gouger , Maurice Medebielle , Stephane Picot ,
Anne-Lise Bienvenu b, Guillaume Pilet c
a Universite´ de Lyon, Universite´ Claude Bernard Lyon 1 (UCBL), Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires (ICBMS), Synthe`se de Mole´cules d’Inte´reˆt
´
ˆ
Therapeutique (SMITH), UMR 5246 CNRS-UCBL-INSA Lyon, Batiment Curien, 43 bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
b
´
´
´
`
´
´ ˆ
Universite Claude Bernard Lyon 1 (UCBL), Malaria Research Unit (MRU), Institut de Chimie et Biochimie Moleculaires et Supramoleculaires (ICBMS), Synthese de Molecules d’Interet
The´rapeutique (SMITH), UMR 5246 CNRS-UCBL-INSA Lyon, Faculte´ de Me´decine, 8 avenue Rockefeller, 69373 Lyon, France
c Universite´ de Lyon, Universite´ Claude Bernard Lyon 1 (UCBL), Laboratoire des multiMate´riaux et Interfaces (LMI), UMR CNRS 5615, Groupe de Cristallographie et Inge´nierie
ˆ
Mole´culaire, Batiment Chevreul, 43 bd du 11 Novembre 1918, 69622 Villeurbanne cedex, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The copper(I) catalyzed cycloaddition reaction of N-Boc propargyl amine (dipolarophile) 1 with benzyl
azide (1,3-dipole) 2 was found to proceed smoothly in t-BuOH/H2O at room temperature, to furnish the
corresponding 1,4-disubstituted-[1,2,3]-triazole-derived N-Boc amine 3 in good yield. Deprotection of 3
with trifluoroacetic acid and addition of the trifluoroacetate salt 4 in the presence of triethylamine, with a
Received 1 April 2011
Received in revised form 10 May 2011
Accepted 13 May 2011
Available online 23 May 2011
series of methoxyvinyl(trifluoromethyl)ketones 10–14, gave the corresponding
b-aminovinyl trifluor-
omethylated ketones 15–19 in moderate to good yields. Two copper(II) complexes, one monomer and
one dimer with chlorine double bridge, 20 and 21, respectively, were also prepared and their crystal
structure determined. b-Aminovinyl trifluoromethylated ketones 15–17 and complexes 20 and 21 have
been screened as potential antifungal agents and the antimalarial activity of 15 and 16 were tested
against two Plasmodium falciparum strains (3D7 and W2).
Keywords:
Cycloaddition
Propargylamine
Azide
Triazole
ß 2011 Elsevier B.V. All rights reserved.
Enaminone
Copper
Antimalarial
Antifungal
Dedicated to Doctor Alain Tressaud
with recognition on the occasion
of his receipt of the 2011 ACS
Award for Creative Work
in Fluorine Chemistry.
1. Introduction
catalysis for the regioselective cycloaddition of terminal alkynes
and azides originally developed by Sharpless and co-workers [3]
[1,2,3]-Triazoles are an important class of five-membered
nitrogen heterocycles, found in various therapeutic agents [1]. The
well established approach utilized thus far for the synthesis of the
[1,2,3]-triazole ring system relies on the thermal 1,3-dipolar
Huisgen cycloaddition between alkynes A and azides B (Scheme 1)
[2].
However, this strategy exhibits some disadvantages such as
sometimes high temperature conditions with the potential for the
decomposition of labile compounds and poor regioselectivity
affording a mixture of 1,4 and 1,5-disubstituted triazoles (C and D),
often difficult to separate. On the other hand the copper(I)-
and Meldal and co-workers [4] (‘Click Chemistry’) has become the
most useful, mild and efficient process to produce exclusively the
1,4-disubstituted triazoles. Trifluoromethyl moiety can greatly
modify the physico-chemical features and thus the biological
properties of a molecule [5], and there is an increasing demand to
prepare such materials especially trifluoromethylated hetero-
cycles because of their high value and pronouncing biological
activity [6]. For some years we have been interested to develop
new synthetic approaches to prepare fluorinated organic mole-
cules. Among the recent studies developed in our laboratories, we
have launched a program directed to the synthesis and reactivity of
b
-aminovinyl chlorodifluoromethylated [7] and b-aminovinyl
trifluoromethylated ketones [8] and their potential use to prepare
novel acyclic and cyclic structures of potential biological impor-
tance, as well as novel ligands for the design of original metal
* Corresponding author.
E-mail address: maurice.medebielle@univ-lyon1.fr (M. Me´debielle).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.05.011

N. Chopin et al. / Journal of Fluorine Chemistry 132 (2011) 850–857
851
Scheme 3.
Scheme 1.
base (to neutralize the formed acid) and a reactant and di-tert-
butyl dicarbonate (Boc2O) in anhydrous dichloromethane (Scheme
3). The product was isolated in a very good yield and used without
further purification in the 1,3-dipolar cycloaddition. The 1,3-dipole
complexes [9]. As part of a research program directed to the
synthesis of novel trifluoromethylated aromatics and heterocycles
with therapeutic applications, we recently presented the cop-
per(I)-catalyzed 1,3-dipolar cycloaddition of N-(2-trifluoroacety-
(benzyl azide 2) is
a known compound [18] and is also
commercially available.
laryl)propargylamines with
a
series of benzylic azides,
carbohydrate and nucleoside-derived azides [10] that gave access
to biologically relevant [1,2,3]-triazoles [11]. In the continuation of
this study, we envisaged to use propargylamine in a copper(I)-
catalyzed 1,3-dipolar cycloaddition reaction with benzyl azide, to
prepare the corresponding [1,2,3]-triazole benzyl amine [12] that
2.2. 1,3-Dipolar cycloaddition
The copper(I) catalyzed 1,3-dipolar cycloaddition between
propargyl amine hydrochloride salt and benzyl azide 2, giving the
corresponding 1,4-disubstituted [1,2,3]-triazole as its hydrochlo-
ride salt, has been described [12]. Cu(0) nanosize activated powder
in H2O/t-BuOH solution has been used (no yield given) in the
presence of Et3NÁHCl salt (1.0 equiv.) [12a] as well as the reaction
of propargyl amine and 2 in the presence of a triazole catalyst or a
N-heterocyclic carbene (NHC) copper(I) complex [(SIMes)CuBr],
followed by subsequent protonation of the free –NH2 with
concentrated HCl [12b]. Since we were unable to repeat in a
reasonable yield the procedure presented in [12b], we preferred to
use N-Boc propargyl amine 1 in a more conventional procedure,
using sodium ascorbate/CuSO4Á5H2O [19] system in H2O/t-BuOH
solution (1/1). The 1,4-disubstituted-[1,2,3]-triazole-derived N-
Boc amine 3 [12a] was obtained as a solid in an excellent 95%
isolated yield (Scheme 4).
As expected, the triazole 3 was formed in a completely
regioselective manner, with no contamination by the 1,5-
regioisomer as highlighted from NOE experiments (Fig. 1):
irradiation of the resonance arising from Hb (triazole proton)
resulted in the observation of strong NOE in the resonance arising
from Hc and Ha. In addition according to the method presented by
Dondoni and Marra [20], the difference of the 13C chemical shift for
the carbon atoms of the triazole is always between 21.5 and
22.4 ppm which is a good indication of the observed regioselec-
tivity. The Boc protecting group in 3 was removed using excess
(10 equiv.) of trifluoroacetic acid in dichloromethane to produce in
could be efficiently used in coupling reactions with
omethylated enones, giving access to 1,4-disubsituted-[1,2,3]-
triazole-derived -aminovinyl trifluoromethylated ketones
b-trifluor-
b
(Scheme 2). Although the [1,2,3]-triazole skeleton is often claimed
and used as a potent amide replacement, [1,2,3]-triazole deriva-
tives have been also designed as new ligands in catalysis, receptors
for the recognition of metals and other applications [13]; our
hybrid triazole-derived b-aminovinyl trifluoromethylated ketones
offer also great potential to form stable metal complexes [9] and to
coordinate a number of biologically relevant metals. For such
reason, we were especially interested to screen our new triazole-
derived
b-aminovinyl trifluoromethylated ketones as potent
antimalarials and antifungals, since there is a growing interest
in designing metal complexes as potent anti-protozoal agents [14]
and potent antifungals [15]. We present herein our preliminary
results.
2. Results and discussion
2.1. Syntheses of the dipolarophile and 1,3-dipole
The N-Boc propargyl amine 1 [16,17] was prepared in a 80%
yield from a known literature procedure [16] with some slight
modifications, using propargyl amine (2.0 equiv.) which acts as a
Scheme 2.

852
N. Chopin et al. / Journal of Fluorine Chemistry 132 (2011) 850–857
Scheme 4.
a 93% isolated yield the corresponding trifluoroacetate salt 4 as an
oil. This salt can be stored for several months at room temperature
with no evidence of decomposition.
2.4. Synthesis of the
b-aminovinyl trifluoromethylated ketones
All the -aminovinyl trifluoromethylated ketones 15–19 were
b
prepared by reacting trifluoroacetate salt 4 in the presence of Et3N
(1.2 equiv.) in anhydrous acetonitrile for 1 h, followed by the
addition of the methoxyvinyl(trifluoromethyl)ketones 10–14.
The progress of the reaction was monitored by TLC and was
stopped after complete conversion of the methoxyvinyl(trifluor-
2.3. Synthesis of the methoxyvinyl(trifluoromethyl)ketones
Methoxyvinyl(trifluoromethyl)ketones 10 [21], 11–14 [22–24]
were prepared from ethyl vinyl ether 9 (for 10) [21] or from
corresponding dimethyl acetals 5–8 (acetal 8 is commercially
available) using trifluoroacetic anhydride in the presence of
pyridine in anhydrous dichloromethane (Scheme 5). Although
the methoxyvinyl(trifluoromethyl)ketones 11–13 (and their di-
methyl acetal precursors 5–7) are mentioned in several papers, we
were unable to find their full spectroscopic data.
omethyl)ketone (usually overnight). All the
fluoromethylated ketones 15–19 were obtained with a free NH
with noticeable deshielded peak of the amino proton
H > 9.0 ppm) in the proton NMR, due to hydrogen bonding
b-aminovinyl tri-
a
(
d
between NH and C55O. Compounds 15, 16, 18, 19 (solids) and 17
(oil) were obtained in moderate to good yields (44–87%) after
evaporation of the solvent and silica gel chromatography
purification (Scheme 6).
2.5. Synthesis of the copper(II) complexes
Two copper(II) complexes 20 and 21 were prepared in very
good yields (>80%) from the corresponding
b-aminovinyl tri-
fluoromethylated ketones 15 (L15, L for ligand) and 17 (L17, L for
ligand) by mixing a methanolic solution of CuCl2Á2H2O to a
dichloromethane solution of the corresponding ligands 15 and 17
and stirring the resulting solution at room temperature for 2 h.
Filtration, short filtration over silica gel and evaporation gave the
desired complexes as green powders. Slow evaporation of a MeOH/
CH2Cl2 solution of these complexes gave single crystals suitable for
X-ray determination.
Both 20 and 21 are copper(II)-based complexes: the first one is
mononuclear with the following refined formula [CuII(L15)Cl] (see
Fig. 1.
Scheme 5.

N. Chopin et al. / Journal of Fluorine Chemistry 132 (2011) 850–857
853
Scheme 6.
Fig. 2, 20) while the second one is a dimer with [CuII2(L17)2Cl2]Á
2.6. Biological evaluation
2(CH2Cl2) as refined formula and exhibits a double chlorine bridge
between the metallic centres (see Fig. 2, 21). Both are neutral and no
counter-ion crystallizes within the unit-cell. In case of 21,
dichloromethane co-crystallized solvent molecules have been also
found in the unit-cell.
b
-Aminovinyl trifluoromethylated ketones 15–17, and com-
plexes 20 and 21 were screened as potential antifungal agents.
They demonstrated to have MICs of >32 g/ml and were
considered to have no antifungal activity on C. albicans susceptible
reference strain. -Aminovinyl trifluoromethylated ketones 15
and 16 were also tested against P. falciparum 3D7 and W2 strains,
m
Copper cation in 20 is located in a N2O1Cl1 square plane
environment and is then surrounded by one L15H ligand and one
coordinated chlorine atom coming from the starting metal salt.
b
and results revealed weak in vitro activities (IC50 > 16
mM).
One nitrogen and one oxygen atoms belong to the
b-aminovinyl
trifluoromethylated ketone entity while the second nitrogen atom
is coming from the triazole moiety of the L15 ligand. All Cu–N
3. Conclusions
˚
˚
˚
(average: 1.966 A), Cu–O (1.907(2) A) and Cu–Cl (2.2228(9) A)
bond lengths are in good agreement with those previously
reported in the literature [25].
In this study we have presented the mild and efficient
preparation of some 1,4-disubstituted-[1,2,3]-triazole derived
b
-
aminovinyl trifluoromethylated ketones and the synthesis of two
copper(II) complexes. The copper(I)-catalyzed 1,3-dipolar cyclo-
addition methodology to prepare these new scaffolds is of
particular interest to prepare libraries of compounds for biological
screening, since variation of R1, R2, R3 (Scheme 2) as well as
substitutions on the triazole can be readily attained. Work under
these lines is under progress. Preliminary biological evaluation of
some compounds as antifungals and antimalarials was performed,
and preliminary data indicate that the structures are weakly active.
New derivatives will be prepared and will be screened again.
Complex 21 can be viewed as two mononuclear complexes
[CuL17Cl], isostructural of 20, connected together in a face-to-
face arrangement. Then, a double chlorine bridge is created
between the two complexes to form a dimmer. The copper(II)
ion is thus located in
a N2O1Cl2 square base pyramidal
environment. Within this dissymmetric Cl bridge, the top of
the pyramid of one metal centre (long Cu–Cl bond) is occupied
by the chlorine atom of the environment of the second metal
cation (chlorine atom located in the square base, short Cu–Cl
bond) of the dimer. In structure of 21, all Cu–N (average
˚
˚
˚
˚
ꢀ2.00 A), Cu–O (ꢀ1.93 A) and Cu–Cl (ꢀ2.27 A and ꢀ2.90 A for
the short and long bonds, respectively) bond lengths are in good
agreement with those previously reported in the literature
[9a,b]. The global packing of complexes 20 and 21 is character-
ized by a number of FÁ Á ÁF, FÁ Á ÁH and BrÁ Á ÁH weak bonds forming
then a dense 3D network.
4. Experimental
4.1. General comments
Solvents were distilled before use. Reagents were obtained
commercially and used without further purification. Compound 2
Fig. 2.

854
N. Chopin et al. / Journal of Fluorine Chemistry 132 (2011) 850–857
was prepared as described in Ref. [18]. Compound 10 was prepared
as described in Ref. [21]. Compound 14 was prepared as described
in Ref. [24]. 1H, 19F and 13C NMR were recorded with a Bruker
Avance 300 spectrometer (in CDCl3) at 300 MHz, 282 MHz and
75 MHz, respectively. Chemical shifts are given in ppm relative to
Concentration (MIC) values were determined visually after 24 h of
incubation as the lowest concentration of drug that caused a
significant diminution (ꢁ50% inhibition) of growth relative to that
of the growth control.
residual peak of solvent (dH = 7.26 ppm for CHCl3,
d
C = 77.0 ppm
4.3.1. In vitro drug sensitivity assay with cultured parasites
for CDCl3) or CFCl3
(
19F). Coupling constants are given in Hertz.
After they were taken out of liquid nitrogen, the cultured
parasites were grown for 10–12 days until a predominance of ring-
stage parasites of no less than 70% was reached. These parasites
were used for the drug sensitivity assays. Once the parasitemia
levels of the in vitro cultures reached an optimum density of 5–8%,
the infected red blood cells were centrifuged at 350 g for 5 min; the
supernatant was aspirated and the cells were suspended in RPMI
with and without phenol red (Invitrogen) supplemented with 0.5%
Albumax I (0.005 g/ml), HEPES (5.94 g/liter), and NaHCO3 (2.4 g/l).
An aliquot of the culture was diluted to reduce the parasitemia to
0.5%, and the hematocrit was adjusted to 2% with fresh RBCs. A
Silica gel chromatography was performed on Macherey-Nagel
Silica gel 60 M (0.04–0.063 mm). Solvents for chromatography and
work-up are: dichloromethane (DCM), ethyl acetate (AcOEt),
methanol (MeOH) and petroleum ether (EP). Mass spectra were
recorded using a FINIGAN MAT 95 [EI and ESI]. Melting points
(uncorrected) were determined in capillary tubes on a Bu¨chi
apparatus. High resolution mass spectra of the dimethyl acetals
were not recorded due their relative instability.
4.2. X-ray characterization
total of 180
mL/well of 0.5% parasitized RBCs at 2% hematocrit was
It was possible to determine by single-crystal X-ray diffraction
the structure of two original copper(II) complexes (20 and 21) and
to completely refine the structure of one (20). CCDC 819565 and
819566 contain the supplementary crystallographic data of
complex 20 and 21, respectively. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Diffraction data sets were collected on an Oxford Gemini
diffractometer equipped with a CCD camera using the related
softwares [25]. An absorption correction (analytical) based on the
crystal shape has been applied to all the data sets [26]. Structures
of 20 and 21 were solved by direct methods using the SIR97
program [27] combined to Fourier difference syntheses and refined
against F and using the CRYSTALS program [28]. In case of 20, all
atomic displacements for non-hydrogen atoms were refined using
an anisotropic model. Hydrogen atoms belonging to carbon atoms
have been placed theoretically and the others (belonging to oxygen
atoms) by Fourier Difference. All hydrogen atoms have been
refined using a riding method.
added, and the plates were incubated in a humidified modular
incubator chamber (Flow Laboratories) at 37 8C under a gas
mixture of 5% O2, 5% CO2, and 90% N2 for 72 h.
4.3.2. IC50 determination by the SYBR green I assay
Following incubation, the plates were frozen and stored at
À80 8C until the SYBR green I assay was performed. The plates were
thawed for 2 h at room temperature and each sample was mixed
by pipetting. Briefly, a total of 100
to a new 96-well plate, followed by the addition of 100
green I (Molecular Probes, Invitrogen, Carlsbad, CA) in lysis buffer
(0.2 L of SYBR green I/ml of lysis buffer, which consisted of Tris
m
L of the culture was transferred
m
L of SYBR
m
20 mM [pH 7.5], EDTA [5 mM], saponin [0.008%; wt/vol], and
Triton X-100 [0.08%; wt/vol]). The plates were covered and
incubated at room temperature for 1 h. The fluorescence intensity
was measured from below with a Berthold plate reader.
4.4. Synthesis of 1
In case of complex 21, crystal and data quality did not allow a
complete structural refinement. Blue plate crystals of 21 were very
thin (0.03 mm) and always twinned (at least two individuals)
giving bad refinement results when considering atoms with an
anisotropic model. It has never been possible to isolate a single
crystal. Results presented here in case of 21 are then a model where
atoms are refined using isotropic terms. Hydrogen atoms belong-
ing to carbon atoms have been placed theoretically and the others
(belonging to oxygen atoms) by Fourier Difference. All hydrogen
atoms have been refined using a riding method.
To an anhydrous dichloromethane solution (6.45 mL) contain-
ing propargylamine (12.9 mmol, 0.83 mL) was added 1.4 g
(6.45 mmol) of Boc2O. The solution was stirred under argon at
room temperature for 24 h and quenched with water (15 mL). The
resulting solution was extracted with dichloromethane
(2 Â 25 mL), the organic phases were combined and washed with
water (2 Â 30 mL), dried over Na2SO4 and filtered. Evaporation to
dryness under reduced pressure left the product which was pure
enough for the next step.
X-ray crystallographic data and refinement details for com-
plexes 20 and 21 are reported in Refs. [29] and [30], respectively.
4.4.1. tert-Butyl prop-2-ynyl carbamate [16,17]
4.3. Antifungal susceptibility testing
Molecules were tested in vitro for their antifungal activities
using the Clinical and Laboratory Standards Institute (CLSI)
reference method for antifungal susceptibility testing. Drugs were
diluted in DMSO as stock solutions and in RPMI 1640 medium as
test solutions in order to obtain a non-toxic concentration of DMSO
(final concentration of DMSO = 0.005%, demonstrated to be non-
toxic on yeasts). Fluconazole solution was provided by the hospital
pharmacy and diluted in RPMI 1640 medium. Candida albicans
reference susceptible strain (ATCC 90028) was used to perform
susceptibility testing. Personnel performing the tests were blinded
to the molecules tested. CLSI broth microdilution method was
performed as outlined in document M27-A3 [31], in microplate, by
using RPMI 1640 medium with 0.2% glucose, inocula of 0.5 Â 103 to
2.5 Â 103 cells/ml, and incubation at 35 8C. Minimal Inhibitory
Yield: 80%, yellowish oil. 1H NMR (CDCl3):
3.90 (2H, d, J = 3 Hz), 2.37 (1H, t, J = 2.1 Hz), 1.45 (9H, s). 13C NMR
(CDCl3): 155.2 (C55O), 80.12 (C), 80.06 (C), 71.20 (CH), 30.40
(CH2), 28.30 (3 Â CH3).
d 5.92 (1H, s, NH),
d
4.5. General procedure for the acetalization
To a solution of ketone (1 mmol), in anhydrous methanol
(10 mL), was added p-TsOH (1.4 mg, 0.008 mmol) and triethy-
lorthoformate (0.25 mL, 1.5 mmol). The mixture was stirred at
60 8C overnight under argon. After cooling down to room
temperature, solid Na2CO3 was added and the solution was

N. Chopin et al. / Journal of Fluorine Chemistry 132 (2011) 850–857
855
filtered before removing solvents under reduced pressure. The
dimethyl acetal is pure enough to be used for the next step.
(C), 177.5 (C, q, J = 33.3), 133.6 (C), 131.1 (CH), 128.7 (2CH), 127.9
(2CH), 116.7 (C, q, J = 290.0), 91.7 (CH), 57.2 (CH3). 19F NMR
+
(CDCl3):
d
À78.81. HRMS (ESI): m/z calcd for C11H10F3O2 [M+H]
4.5.1. (1,1-Dimethoxyethyl)benzene 5
231.06274; found: 231.06272.
4.6.2. (Z)-4-(4-Bromophenyl)-1,1,1-trifluoro-4-methoxybut-3-en-2-
one 121
Yield: 90%, orange oil. 1H NMR (CDCl3):
2.97 (6H, s, –OCH3), 1.34 (3H, s, –CH3). 13C NMR (CDCl3):
d
7.19 (5H, m, Harom),
142.9
d
(C), 128.1 (2CH), 127.5 (CH), 126.2 (2CH), 101.7 (C), 48.9 (2CH3),
26.1 (CH3).
Yield: 60%, yellow oil. 1H NMR (CDCl3):
arom), 7.15 (2H, d, J = 8.4, Harom), 5.63 (1H, s,55CH–CO), 3.69 (3H, s,
–OCH3). 13C NMR (CDCl3):
177.0 (C, q, J = 33.6), 176.7 (C), 132.4
(C), 131.0 (2CH), 130.4 (2CH), 125.5 (C), 91.9 (CH), 57.23 (CH3). 19
NMR (CDCl3):
d 7.31 (2H, d, J = 8.4,
H
4.5.2. 1-Bromo-4-(1,1-dimethoxyethyl)benzene 6
d
F
d
À78.96. HRMS (ESI): m/z calcd for C11H9BrF3O2
+
[M+H] 308.97325; found: 308.97324.
4.6.3. (Z)-1,1,1-Trifluoro-4-methoxy-4-(4-nitrophenyl)but-3-en-2-
one 13
Yield: 99%, yellow oil. 1H NMR (CDCl3):
arom), 7.22 (2H, d, J = 8.7, Harom), 3.00 (6H, s, –OCH3), 1.35 (3H, s, –
CH3). 13C NMR (CDCl3):
141.8 (C), 131.0 (2CH), 128.0 (2CH), 121.4
d 7.31 (2H, d, J = 8.7,
H
d
(C), 101.0 (C), 48.6 (2CH3), 25.7 (CH3).
4.5.3. 1-(1,1-Dimethoxyethyl)-4-nitrobenzene 7
Yield: 35%, yellow solid, m.p. 64 8C. 1H NMR (CDCl3):
d 8.15 (2H,
d, J = 9.0, Harom), 7.65 (2H, d, J = 9.0, Harom), 5.92 (1H, s, 55CH–CO),
3.96 (1H, s, –OCH3). HRMS (ESI): m/z calcd for C11H9F3NO4 [M+H] +
276.04782; found: 276.04784.
Yield: 77%, yellow solid, m.p. 54 8C. 1H NMR (CDCl3):
d 7.99 (2H,
4.7. Synthesis of 4
d, J = 8.7, Harom), 7.50 (2H, d, J = 8.7, Harom), 3.00 (6H, s, –OCH3), 1.35
(3H, s, –CH3). 13C NMR (CDCl3):
149.8 (C), 147.0 (C), 127.0 (2CH),
d
To a stirred solution of 3 (0.287 g, 1.0 mmol) in dichlor-
omethane (20 mL), was added dropwise trifluoroacetic acid
(0.73 mL, 10 mmol) with cooling (0 8C). The solution was
slowly ‘warmed up and stirred at room temperature for 24 h.
Solvents were carefully removed under reduced pressure and
the resulting oil was triturated with diethyl ether and
evaporation to dryness left a brownish oil (0.283 g, 93 mmol,
93%).
122.8 (2CH), 100.7 (C), 48.5 (2CH3), 25.2 (CH3).
4.6. General procedure for the synthesis of
methoxyvinyl(trifluoromethyl)ketones 11–13
To an ice-cold stirred mixture of dimethyl acetal (1 mmol),
pyridine (0.33 mL, 4 mmol), and anhydrous dichloromethane
(2 mL) was added dropwise trifluoroacetic anhydride (0.28 mL,
2 mmol). After the addition was complete, the solution was
warmed up to 45 8C and stirred overnight for 11 and 12 and 3 days
for 13. Then, ice-water was added (1.5 mL) and the mixture was
extracted with dichloromethane. Organic phase was washed with
2 N hydrochloric acid solution (1.5 mL), aqueous 10% sodium
carbonate (2 mL), and water (2 Â 2 mL), and was dried over
Na2SO4. After filtration the solvent was evaporated to dryness and
the crude product was purified by silica gel chromatography using
(EP/DCM = 1/1).
4.7.1. (1-Benzyl-1H-1,2,3-triazol-4-yl)methanaminium 2,2,2-
trifluoroacetate 4
1H NMR (D2O):
d
8.07 (1H, s, Htriazole), 7.24 (5H, m, Harom),
5.45 (2H, s, –CH2Ph), 4.30 (2H, s, –CH2NH). 13C NMR (D2O):
161.8 (C), 134.4 (2C), 128.9 (2CH), 128.6 (CH), 128.0 (2CH),
d
125.4 (C), 125.3 (CH), 54.0 (CH2), 34.1 (CH2). 19F NMR (D2O):
d
À75.85. HRMS (ESI): m/z calcd for C10H13N4 [M+H]+ 189.1135;
found: 189.1134.
4.8. General procedure for the synthesis of 15–19
4.6.1. (Z)-1,1,1-Trifluoro-4-methoxy-4-phenylbut-3-en-2-one 11
To a solution of 4 (302 mg, 1 mmol) in acetonitrile (2 mL) was
added triethylamine (0.14 mL, 1.2 mmol) and the mixture was
stirred at room temperature during 1 h. A solution of enone
(1 mmol) in acetonitrile (0.6 mL) was added dropwise and the
mixture was stirred overnight. Solvent was removed under
reduced pressure and the crude material was purified by silica
gel chromatography using EP/AcOEt (1/1) for 15, 18 and 19, (3/1)
for 16 and 17.
Yield: 65%, orange oil. 1H NMR (CDCl3):
7.26 (1H, s,55CH-CO), 3.97 (3H, s, –OCH3). 13C NMR (CDCl3):
d
7.50 (5H, m, Harom),
178.0
d

856
N. Chopin et al. / Journal of Fluorine Chemistry 132 (2011) 850–857
4.8.1. (Z)-4-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)-1,1,1-
4.8.4. (Z)-4-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)-1,1,1-
trifluorobut-3-en-2-one 15
trifluoro-4-(4-nitrophenyl)but-3-en-2-one 18
Yield: 80%, yellow solid, m.p. 108 8C. 1H NMR (CDCl3):
d 10.35
(1H, s br, –NH), 7.47 (1H, s, Htriazole), 7.30 (6H, m, Harom, –N–CH55),
5.46 (2H, s, –CH2Ph), 5.32 (1H, d, J = 6.9, =CH–CO), 4.54 (2H,
d 177.9 (C, q, J = 33.1),
157.8 (CH), 143.4 (C), 134.2 (C), 128.9 (2CH), 128.6 (CH),
Yield: 54%, pale yellow solid, m.p. 120 8C. 1H NMR (CDCl3):
11.20 (1H, s br, –NH), 8.31 (2H, d, J = 8.1, Harom), 7.71 (2H, d, J = 8.4,
d
d, J = 6.0, –CH2NH). 13C NMR (CDCl3):
H
arom), 7.43 (1H, s, Htriazole), 7.38 (3H, s, Harom), 7.28 (2H, s, Harom),
5.52 (2H, s, –CH2Ph), 5.44 (1H, s, 55CH–CO), 4.51 (2H, d, J = 6.3, –
CH2NH). 13C NMR (CDCl3):
177.2 (C, q, J = 33.5 Hz), 167.5 (C),
127.9 (2CH), 121.9 (CH), 116.9 (C, q, J = 287.0), 87.5 (CH), 54.02
d
(CH2), 44.06 (CH2). 19F NMR (CDCl3):
d
À77.88. HRMS (ESI):
148.9 (C), 143.3 (C), 139.2 (C), 134.1 (C), 129.1 (2CH), 129.0 (2CH),
128.9 (CH), 128.1 (2CH), 124.0 (2CH), 121.7 (CH), 116.5 (C, q,
m/z calcd for C14H14F3N4O [M+H]+ 311.1114; found:
311.1110.
J = 286.0 Hz), 90.7 (CH), 54.3 (CH2), 40.6 (CH2). 19F NMR (CDCl3):
d
À77.21. HRMS (ESI): m/z calcd for C20H16F3N5NaO3 [M+Na]+
4.8.2. (Z)-4-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)-1,1,1-
454.1103; found: 454.1090.
trifluoro-4-phenylbut-3-en-2-one 16
4.8.5. 1-(2-(((1-Benzyl-1H-1,2,3-triazol-4-
yl)methyl)amino)cyclohex-1-en-1-yl)-2,2,2-trifluoroethanone 19
Yield: 44%, brown solid, m.p. 109 8C. 1H NMR (CDCl3):
(1H, s, –NH), 7.44 (11H, m, Harom, Htriazole), 5.53 (2H, s, 55CH–CO),
5.49(2H,s, –CH2Ph), 4.60(2H,d,J = 6.3,–CH2NH).13CNMR(CDCl3):
d 11.33
Yield: 60%, brown solid, m.p. 74 8C. 1H NMR (CDCl3):
d 12.09 (1H,
s br, –NH), 7.41 (1H, s, Htriazole), 7.29–7.27 (3H, m, Harom), 7.20–7.17
(2H, m, Harom), 5.41 (2H, s, –CH2Ph), 4.52 (2H, d, J = 6.0, –CH2NH),
2.54–2.52 (2H, m, –CH2), 2.39–2.37 (2H, m, –CH2), 1.62–1.52 (4H,
d
175.8 (C, q, J = 32.6), 170.12 (C), 143.4 (C), 134.2 (C), 132.9 (C), 130.3
(CH), 128.7 (2CH), 128.5(2CH), 128.3 (CH), 127.6(2CH), 127.2 (2CH),
121.8 (CH), 117.2 (C, q, J = 286.0), 90.2 (CH), 53.7 (CH2), 40.4 (CH2).
m, 2CH2). 13C NMR (CDCl3):
d 174.8 (C, q, J = 31.0), 179.1 (C), 144.1
19F NMR (CDCl3):
d
À77.11. HRMS (ESI): m/z calcd for C20H18F3N4O
(C), 134.2 (C), 129.0 (2CH), 128.7 (CH), 127.9 (2CH), 121.7 (CH),
98.0 (C), 54.1 (CH2), 38.4 (CH2), 27.0 (CH2), 22.2 (2CH2), 21.0 (CH2),
[M+H]+ 387.1427; found: 387.1428.
–CF3 overlaped in the baseline. 19F NMR (CDCl3):
d
À72.32. HRMS
(ESI): m/z calcd for C18H19F3N4NaO [M+Na]+ 387.1409; found:
4.8.3. (Z)-4-(((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(4-
387.1403.
bromophenyl)-1,1,1-trifluorobut-3-en-2-one 17
4.9. General procedure for the synthesis of the Cu(II) complexes 20
and 21
A
methanolic solution (10 mL) of CuCl2Á2H2O (184 mg,
1.08 mmol), was added dropwise to a solution of enaminone in
dichloromethane (20 mL). The mixture was stirred at room
temperature for 2 h. After filtration, and short filtration over silica
gel, the complexes were obtained as green powders (>80%). Single
crystals suitable for X-ray characterization were obtained by slow
evaporation of a methanol/dichloromethane solution.
Yield: viscous colorless oil. 1H NMR (CDCl3):
d 11.24 (1H,
Acknowledgments
s br, –NH), 7.55 (2H, d, J = 8.4, Harom), 7.42 (1H, s, Htriazole), 7.34–
7.32(5H, m, Harom), 7.25–7.22 (2H, m, Harom), 5.47 (2H, s,
–CH2Ph), 5.40 (1H, s, 55CH–CO), 4.51 (2H, d, J = 6.3, –CH2NH).
´
ˆ
Part of this work was supported by the Region Rhone-Alpes
‘‘Cluster de Chimie’’ and the CNRS. N. Chopin is grateful to the
Region Rhone-Alpes for a PhD fellowship. The Centre de Spectro-
13C NMR (CDCl3):
d
176.5 (C, q, J = 33.1), 168.96 (C), 143.5 (C), 134.2
´
ˆ
(2C), 132.0 (2CH), 129.1 (2CH), 128.9 (2CH), 128.6 (CH), 127.9
me´trie de Masse (CCSM) of Universite´ Lyon 1 is sincerely thanked
´
(2CH), 125.0 (C), 121.7 (CH), 117.2 (C, q, J = 286.9), 90.4 (CH), 54.0
for recording the mass spectra. The Centre de Diffractometrie Henri
(CH2), 40.5 (CH2). 19F NMR (CDCl3):
d
À77.04. HRMS (ESI):
Longchambon from the University of Lyon is gratefully
acknowledged for the X-Ray data collection. We would like to
1
m/z calcd for C20H16BrF3N4NaO [M+Na]+ 487.0352; found:
487.0342.
thank C. Perez for the synthesis of 14.

N. Chopin et al. / Journal of Fluorine Chemistry 132 (2011) 850–857
857
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M = 408.3 g molÀ1, monoclinic, l(Mo) = 0.71069 A, a = 14.6915(4) A, b = 9.4734(3)
˚
˚
3
˚
˚
˚
A, c = 11.7399(4) A, b = 95.211(3)8, V = 1627.18(8) A , T = 293 K, space group P21/c
(no. 14), Z = 4, 8216 reflections measured, 2651 unique (Rint = 0.021), R(F,À3I/
s(I) > 3) = 0.0307, RW(F, I/s(I) > 3) = 0.0323, S = 1.11, Drmax = 0.26 eÀ
A
,
˚
[12] The hydrochloride salt of this amine is known:
Drmin = À0.27 eÀ
A
À3, 2800 reflections used to refine 217 parameters.
˚
´
(a) A. Maisonial, P. Serafin, M. Traikia, E. Debiton, V. Thery, D.J. Aitken, P. Lemoine,
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M = 12.96.4 g molÀ1, triclinic, l(Mo) = 0.71069 A, a = 17.737(2) A, b = 17.747(2)
˚
˚
3
˚
˚
˚
A,c = 18.305(1) A, a = 74.829(8)8, b = 89.967(7)8, g = 61.88(1)8, V = 4853.2(3) A ,
T = 110 K, space group PÀ1 (no. 2), Z = 4, 22,636 reflections measured, 22,636
unique (Rint = 0.084), R(F, I/s(I) > 3) = 0.1486, RW(F, I/s(I) > 3) = 0.1720, S = 1.11,
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Drmax = 2.625 eÀ
parameters.
À3, Drmin = À2.625 eÀ
A
À3, 8406 reflections used to refine 545
˚
˚
A
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