Copper catalyzed 1,3-dipolar cycloaddition reaction of azides with N-(2-trifluoroacetylaryl)propargylamines. A mild entry to novel 1,4-disubstituted-[1,2,3]-triazole derivatives

Article abstract of DOI:10.1016/j.jfluchem.2008.05.015

The synthesis of N-(2-trifluoroacetylaryl)propargylamines 10-14 and 17 is presented. The copper(I) catalyzed cycloaddition reaction of these propargylamines (dipolarophiles) with a series of azides (1,3-dipoles) 18-20, 21 and 24 was found to proceed smoothly in dimethylsulfoxide at room temperature, to furnish the corresponding 1,4-disubstituted-[1,2,3]triazole derivatives 26-36 in moderate to good yields.

Full text of DOI:10.1016/j.jfluchem.2008.05.015

Journal of Fluorine Chemistry 129 (2008) 788–798
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Copper catalyzed 1,3-dipolar cycloaddition reaction of azides with
N-(2-trifluoroacetylaryl)propargylamines
A mild entry to novel 1,4-disubstituted-[1,2,3]-triazole derivatives
a
a
a
a,
*
´
Jean-Florent Lamarque , Christophe Lamarque , Sandrine Lassara , Maurice Medebielle
,
a
b
b
b
´
´
Jerome Molette , Emilie David , Stephane Pellet-Rostaing , Marc Lemaire ,
Etsuji Okada c, Dai Shibata d, Guillaume Pilet e
a Universite´ de Lyon, Universite´ Claude Bernard Lyon 1 (UCBL), Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires (ICBMS),
ˆ
Laboratoire de Synthe`se de Biomole´cules (LSB), UMR 5246 CNRS-UCBL-INSA Lyon-CPE Lyon, Batiment Chevreul, 43 bd du 11 Novembre 1918,
69622 Villeurbanne Cedex, France
b Universite´ de Lyon, Universite´ Claude Bernard Lyon 1 (UCBL), Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires (ICBMS),
ˆ
Laboratoire de Catalyse et Synthe`se Organique (CASO), UMR 5246 CNRS-UCBL-INSA Lyon-CPE Lyon, Batiment 308 CPE Lyon, 43 bd du 11 Novembre 1918,
69616 Villeurbanne Cedex, France
c Department of Chemical Science and Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
d Graduate School of Science and Technology, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
e Universite´ de Lyon, Universite´ Claude Bernard Lyon 1 (UCBL), Laboratoire des Multimate´riaux et Interfaces (LMI), UMR CNRS 5615,
ˆ
Groupe de Cristallographie et Inge´nierie Mole´culaire, Batiment Raulin, 43 bd du 11 Novembre 1918, Villeurbanne, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of N-(2-trifluoroacetylaryl)propargylamines 10–14 and 17 is presented. The copper(I)
catalyzed cycloaddition reaction of these propargylamines (dipolarophiles) with a series of azides (1,3-
dipoles) 18–20, 21 and 24 was found to proceed smoothly in dimethylsulfoxide at room temperature, to
furnish the corresponding 1,4-disubstituted-[1,2,3]triazole derivatives 26–36 in moderate to good yields.
ß 2008 Elsevier B.V. All rights reserved.
Received 13 April 2008
Received in revised form 23 May 2008
Accepted 23 May 2008
Available online 7 July 2008
Keywords:
SNAr
Cycloaddition
Propargylamines
Azides
Triazole
1. Introduction
mixture of 1,4 and 1,5-disubstituted triazoles (3 and 4), often
difficult to separate. On the other hand the copper(I)-catalysis for
[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 1 and azides 2 (Scheme 1)
[2].
the regioselective cycloaddition of terminal alkynes and azides
originally developed by Sharpless and co-workers [3] and Meldal
and co-workers [4] (‘Click Chemistry’) has become the most useful,
However, this strategy exhibits several disadvantages such as
high temperature conditions with the potential for the decom-
position of labile compounds and poor regioselectivity affording a
* Corresponding author.
E-mail addresses: medebiel@univ-lyon1.fr (M. Me´debielle), pilet@univ-lyon1.fr
(G. Pilet).
Scheme 1.
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.05.015

J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
789
Scheme 2.
Scheme 3.
Scheme 4.
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 heterocycles 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 molecules. Among the
recent studies developed in our laboratories, we have launched a
program directed to the synthesis of novel trifluoromethylated
heterocycles using aromatic nucleophilic substitution reactions of
N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine [7], N,N-
dimethyl-2-trifluoroacetyl-4-halo-1-naphthyl-amines [8], N,N-
dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine
[9],
with
amines, thiols and alcohols and we have shown that the
corresponding exchanged products could be easily converted to
various fluorinated fused-heterocycles of potential biological
importance. Recently these aromatic nucleophilic substitution

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J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
Table 1
˚
F–H distances (A) inside 10
F16–H191
F25–H191
F17–H191
F24–H191
2.424 (6)
2.377 (5)
2.350 (6)
2.490 (6)
Table 2
Intra-hydrogen bonds inside 10
D–H–A
D–H–A
D–H bond
H–A
D–A
˚
˚
˚
angle (8)
length (A)
distance (A)
distance (A)
N4–H8–O22
148
124
156
1.11
1.06
1.06
1.62
2.14
2.43
2.63 (2)
2.87 (2)
3.43 (2)
C10–H121–O14
C7–H124–C2
D: donor; A: acceptor.
equivalent) in acetonitrile under refluxing conditions for 18 h. 8-
Amino quinoline derived substrate 14 was prepared as described
in Ref. [9] and was obtained in a quantitative yield; a temperature
of 0 8C in acetonitrile for 2 h was crucial to get such high yield. N,N-
dimethylamino precursors 5 and 9 were found to be the most
reactive substrates, while 7 being the less reactive in this series.
Benzo[b]thiophene is an important pharmacophore in medicinal
chemistry [14] and therefore it was of interest to prepare
derivative 17; this substrate was prepared in two steps from
the corresponding 15 (Scheme 4), which was in turn prepared in a
60% isolated yield from an original Heck reaction [16] developed
in our laboratories, between N,N-dimethyl-4-bromo-1-naphthy-
lamine [15] and benzo[b]thiophene-3-carbonitrile [16]. A mod-
erate 50% isolated yield of 17 was obtained using an excess of
propargylamine (3.0 equivalent) in refluxing acetonitrile for 7 h.
All the substrates 10–14 and 17 were obtained with a free NH
Fig. 1. Crystal structure of 10 with atomic labels. Hydrogen bonds and C–Fꢀ ꢀ ꢀH
interactions are also represented.
reactions were extended to 3-trifluoroacetyl-4-dimethylamino-
quinoline [10] and N,N-dimethyl-2-trifluoroacetyl-1-naphthyla-
mine [11]. Among the different nucleophiles used in these N–N
exchanged reactions, propargylamine was found to be a good
nucleophile giving access to novel N-(2-trifluoroacetylaryl)pro-
pargylamines. As part of a research program directed to the
synthesis of novel trifluoromethylated aromatics and heterocycles
using the peculiar reactivity of the propargylamine moiety [12], we
envisaged to use the N-(2-trifluoroacetylaryl)propargylamines in
the copper(I)-catalyzed 1,3-dipolar cycloaddition reactions with a
series of benzylic azides, carbohydrate and nucleoside-derived
azides that would give biologically relevant [1,2,3]-triazoles
(Scheme 2); specifically the nucleosides derivatives that could
be obtain are of significant importance because of the broad
biological activity of natural and non-natural nucleosides, includ-
ing some triazole nucleosides [13]. We wish to present herein our
recent results.
with
a noticeable deshielded peak of the amino proton
(
d
H > 9.0 ppm) in the proton NMR, due to hydrogen bonding
between NH and C=O. All compounds were obtained as solids after
evaporation of the solvent and recrystallization (12 and 14) or after
silica gel chromatography purification and recrystallization (10,
11, 13 and 17). The crystal structure of substrate 10 [17]1 has been
also confirmed by X-ray analysis (Fig. 1) and all the refined bond
lengths of this molecule are in good agreement with those
previously reported in the literature [18]. This structure shows
clearly two intra-molecular hydrogen bonds (O14ꢀ ꢀ ꢀH121 and
O22ꢀ ꢀ ꢀH8, Table 1) forcing both the position of C=O groups on a
particular orientation. It has to be noted that four intra-molecule
C–Fꢀ ꢀ ꢀH–C distances in the structure are significantly shorter than
the sum of the van der Waals radii of fluorine and hydrogen atoms
2. Results and discussion
2.1. Syntheses of the dipolarophiles
˚
(2.55 A) [19] showing the presence of Fꢀ ꢀ ꢀH weak bonds (F16, F17,
1,3-Dipolarophiles 10–14 and 17 were prepared in moderate
to quantitative yields (50–100%) through the N–N exchange
reaction of the corresponding N,N-dimethylamino precursors
with propargylamine (Schemes 3 and 4). Compound 10 was
prepared as described in Ref. [12] in a 82% isolated yield from the
N–N exchange reaction of N,N-dimethyl-2,4-bis(trifluoroacetyl)-
1-naphthylamine [7] with propargylamine (1.2 equivalent), in
anhydrous acetonitrile at room temperature. The substrate 11
was obtained in 68% isolated yield from N,N-dimethyl-2-
trifluoroacetyl-1-naphthylamine [11], but needed a large excess
of propargylamine (10 equivalent) in refluxing propionitrile for
16 h for a complete conversion. 4-Amino quinoline derived
substrate 12 was prepared as described in Ref. [10] and was
obtained in a 96% isolated yield in acetonitrile under refluxing
conditions for 4 h. The 4-bromo derivative 13 was prepared from
N,N-dimethyl-2-trifluoroacetyl-4-bromo-1-naphthylamine [8]
and needed as substrate 11, a large excess of the amine (10
F26 and F24 with H191, Table 2). These later block then the two CF3
groups in one configuration without any disorder on fluorine
atoms (in the opposite of what can be usually found in other
similar structures). In that sense, it is very important to investigate
the presence or not of Fꢀ ꢀ ꢀH bonds because of their influence on the
structure of the molecule and then on the reactivity of this later
and because little is known about hydrogen bonds containing
fluorine as one of the acting atoms [20].
The whole packing can be viewed like pseudo columns running
along the a-axis of the unit-cell (Fig. 2). Inside these columns
(Fig. 3), the packing is assumed by
P–P interactions between
phenyl rings of two consecutive 10 molecules (shortest distance
˚
between centres of two consecutive phenyl rings is 3.89 A). Then
1
CCDC 684268 reference contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
791
Fig. 2. Structural packing along a-axis of the unit-cell. For the clarity of the picture,
hydrogen atoms have been omitted.
substrate 10 molecules stack one on the other one to form infinite
columns. As no inter-molecule hydrogen bond has been found
during the refinement, the structural cohesion between columns is
assumed by van der Waals interactions.
2.2. Synthesis of the 1,3-dipoles
The benzylic azides 18–20 (Scheme 5) were conveniently
prepared (71–91%) from known literature procedures using
sodium azide (1.05 equivalent) and the corresponding benzylic
bromides in acetonitrile at room temperature for 90 h [21].
50-Azido-50-deoxy-20,30-O-isopropylidene uridine 21 was pre-
pared in three steps from commercially available uridine (Scheme
6). 20,30-O-Isopropylidene uridine 22 [22] and 50-deoxy-20,30-O-
isopropylidene-50-O-methanesuflonyle uridine 23 [23] were
obtained in respectively 88% and 63% isolated yields following
literature procedures. Uridine derivative 21 [24] was then obtained
in a 70% isolated yield through nucleophilic displacement of the –
OMs using sodium azide (3 equivalent) in anhydrous DMF at 70 8C
for 12 h. All the steps were completely stereoselective as evidenced
by 1D and 2D NMR analysis.
Fig. 3. Illustration of columns running along the a-axis of the unit-cell.
P–P
interactions between phenyl rings are represented as orange dash bonds. For clarity
of the picture, hydrogen atoms have been omitted.
Scheme 5.
2,3,5-Tri-O-benzoyl-
from commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-
b
-
D
-ribofuranosyl azide 24 was obtained
dimethylsulfoxide, afforded the desired [1,2,3]-triazole 26 in a 62–
64% isolated yields (Scheme 8).
b-D-
ribofuranose 25 in 95% isolated yield through the reaction of
trimethylsilyl azide (1.1 equivalent) in the presence of SnCl4
(5 mol%) according to [25] (Scheme 7). The reaction was
Although both conditions worked well with substrate 10, it was
then found that for other dipolarophiles, DMSO was a better
solvent in order to improve the yields due to a better solubility of
all reagents; in addition as already observed in the literature
catalytical amount of Cu(I) was enough to achieve complete
conversion. Under these mild conditions (room temperature for
24 h), [1,2,3]-triazoles 26–36 were obtained in good yields
(Schemes 9–11). Classical t-BuOH/H2O solvent combination [26]
could not be used with our substrates as side-reactions were
observed giving complex mixtures. In addition [1,2,3]-triazole 29
could not be obtained using 18 as 1,3-dipole despite many
attempts and different conditions [increasing amount of Cu(I),
increasing temperature] probably due to a competitive coordina-
completely stereoselective since only the
as already described in Ref. [25].
b-anomer was obtained
2.3. Coupling reactions
Substrate 10 and benzylic azide 18 were chosen as a model
partners in the copper(I) catalyzed 1,3-dipolar cycloaddition;
stoichiometric amount of CuI in the presence of i-Pr2NEt in
anhydrous THF as well as a stoichiometric combination of sodium
ascorbate/CuSO4ꢀ5H2O [26] [to pre-form the copper(I) species] in

792
J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
Scheme 6.
under mild conditions. However the 8-amino quinoline substrate
14 failed to react under various conditions. We are currently
extending this efficient approach to new substrates and more
complex azides, especially in nucleoside series, as well as studying
the ‘‘classical’’ thermal Huisgen 1,3-dipolar cycloaddition with the
substrates presented in this study; in addition deprotection of the
nucleosides is now actively pursued. We made significant progress
in this area and the results will be presented in our forthcoming
papers. Biological testings of all the triazole derivatives is currently
under way.
Scheme 7.
tion between the –NH of the propargylamine moiety and the
nitrogen of the quinoline.
As expected, the new triazoles were formed in a completely
regioselective manner, with no contamination by the 1,5-
regioisomer as highlighted from NOE experiments (Fig. 4): in
the case of 26 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 carbohydrate and nucleoside series the
reaction was found to be not only regioselective but also
stereoselective.
4. Experimental
4.1. General comments
Solvents were distilled before use. Reagents were obtained
commercially and used without further purification. Compounds
10 and 14 were already described in Refs. [12,9]. Benzo[b]thio-
phene-3-carbonitrile was prepared as described in Ref. [16].
Azides 18–20 were prepared as described in Ref. [21]. 21 and 22
were prepared as described in Ref. [18] and 23 as in Ref. [19]. 25
was prepared as described in Ref. [21]. 1H, 19F and 13C NMR were
recorded with a Bruker Avance 300 spectrometer (in CDCl3) at
300, 282 and 75 MHz, respectively. Chemical shifts are given in
3. Conclusions
In this study we demonstrated that N-(2-trifluoroacetylaryl)-
propargylamines 10–14 and 17 are good partners in copper(I)
catalyzed 1,3-dipolar cycloaddition with a series of azides. The
corresponding 1,4-disubstituted-[1,2,3]-triazole derivatives are
novel compounds and were obtained in moderate to good yields
ppm relative to residual peak of solvent (
C = 77.0 ppm for CDCl3) or CFCl3
19F). Coupling constants are
given in Hertz. Silica gel chromatography was performed on
dH = 7.26 ppm for CHCl3,
d
(
Scheme 8.

J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
793
Scheme 9.
Scheme 10.
Macherey–Nagel silica gel 60 M (0.04–0.063 mm). Solvents for
chromatography and work-up are: benzene (BE), dichloro-
methane (DCM), ethyl acetate (EA), n-hexane (Hx), methanol
(MET) and petroleum ether (PE). Mass spectra were recorded
using a FINIGAN MAT 95 [EI, CI (CH4 or NH3) and ESI]. Melting
points (uncorrected) were determined in capillary tubes on a
Buchi apparatus.
Structure of 10 has been solved by direct methods using the
SIR97 program [28] combined with Fourier difference syntheses
and refined against F using CRYSTALS program [29]. The hydrogen
atoms have been either found by Fourier difference and located
theoretically based on the conformation and environment of the
supporting atom. Then, the positions and the isotropic displace-
ment factors of these hydrogen atoms have been refined keeping
some restraints with the supporting atom. All the atomic
displacement parameters for non-hydrogen atoms have been
refined anisotropically.
4.2. X-ray characterization
4.2.1. Data collection
The data were processed using the KappaCCD analysis
programs [27]. The lattice constants were refined by least-squares
refinements. No absorption correction was applied to the data set
and the data collection has been performed at 293 K.
4.3. Synthesis of 15 and 16
In a 1 M solution of the benzo[b]thiophene-3-carbonitrile
(0.24 g, 1.51 mmol) in DMF were successively added DCH-18-C-
6 (1 eq, 0.562 g, 1.51 mmol), K2CO3 (3 eq, 0.626 g, 4.53 mmol) and
the 4-bromo-N,N-dimethylnaphthalen-1-amine (1.1 equiv). The
mixture was heated at 100 8C for 5 min and Pd(OAc)2 (5 mol%,
0.017 g, 0.076 mmol) was added. The resulting mixture was then
heated at 130 8C overnight. After cooling to room temperature, the
4.2.2. Structure solution and refinement
Complexes of 10 crystallizes in the monoclinic system.
According to the observed systematic extinctions, its structure
has been solved and refined in the P21/a space group.

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J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
Scheme 11.
4.3.2. 2-(4-(Dimethylamino)-3-(2,2,2-trifluoroacetyl)naphthalen-1-
yl)benzo[b]thiophene-3-carbonitrile, 16
To a stirred solution of 15 (0.328 g, 1.0 mmol) and pyridine
(1.2 mmol) in anhydrous dichloromethane (5 mL), was added
dropwise an anhydrous dichloromethane solution (10 mL) con-
taining trifluororoacetic anhydride (1.2 mmol) with cooling
(ꢁ10 8C). When the addition was finished (30 min), the reaction
mixture was slowly warmed-up to room temperature and stirred
at this temperature for 18 h. The solution was quenched with H2O
(20 mL) and extracted with dichloromethane (2ꢂ 20 mL). The
combined organic layers were washed with an aqueous solution of
1N HCl (2ꢂ 20 mL) and water (2ꢂ 20 mL) and dried over Na2SO4.
Evaporation of the solvent left a yellowish oil (0.416 g, 0.98 mmol,
98%) as crude product of enough purity (>95%) for the next step. 1H
Fig. 4.
mixture was filtered over celite which was rinsed with CH2Cl2. The
resulting organic layer was successively washed with water and
brine, dried over MgSO4, filtered and solvents were removed under
reduced pressure. The crude product was purified by flash
chromatography (DCM/PE = 5/5).
4.3.1. 2-(4-(Dimethylamino)naphthalen-1-yl)benzo[b]thiophene-3-
carbonitrile, 15
NMR (CDCl3):
1.5 Hz, Harom), 7.92–8.06 (2H, m, Harom), 7.76 (1H, s, Harom), 7.51–
7.67 (4H, m, Harom), 3.08 (6H, s, CH3). 19F NMR (CDCl3):
d 8.34–8.37 (1H, m, Harom), 8.04 (1H, dd, J = 12.2,
d
ꢁ72.53.
HRMS (EI): m/z calcd for
424.0892.
C23H15F3N2OS 424.0857; found:
4.4. General procedure for the synthesis of 10–14 and 17
To a solution of 5–9 and 16 in acetonitrile (8 mL/1 mmol)
were added propargylamine (1–10 equivalent) and the mixture
was stirred at 0 8C-reflux temperature for 2–18 h. The solvent
was evaporated to dryness to give the practically pure products
12 and 14. In the case of 10, 11, 13 and 17 the crude product
was purified by silica gel chromatography using Hx/BE (7/3) for
10, Hx/EA (24/1) for 11, Hx/EA (49/1) for 13 and PE/EA (98/2) for
17, as eluent. In the case of 11, propionitrile was used as a
solvent.
Yield: 60%, yellow solid, m.p.: 172–176 8C. 13C NMR (CDCl3):
d
45.0 (2CH3), 106.1 (C), 113.0 (CH), 114.7 (C), 122.3 (CH), 122.5 (CH),
122.6 (C), 125.0 (CH), 125.6 (CH), 125.7 (CH), 126.0 (CH), 126.1
(CH), 127.0 (CH), 128.6 (C), 129.5 (CH), 132.7 (C), 138.3 (C), 138.6
(C), 153.3 (C), 154.9 (C). 1H NMR (CDCl3):
d 8.35 (1H, d, J = 9.2 Hz),
8.02–8.07 (2H, m), 7.89 (1H, d, J = 7.9 Hz), 7.47–7.65 (5H, m), 7.14
(1H, d, J = 7.7 Hz), 3.00 (6H, s, CH3). HRMS (EI): m/z calcd for
21H16N2S 328.1034; found: 328.1048.
C

J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
795
4.4.1. 2,2,2-Trifluoro-1-(1-(propyl-2-ynylamino)naphthalen-2-
Yield: 50%, m.p.: 145 8C. 1H NMR (CDCl3):
d
10.09–10.12 (1H, br
yl)ethanone, 11
s, NH), 8.44 (1H, d, J = 8.2 Hz, Harom), 8.01 (1H, d, J = 6.9 Hz, Harom),
8.01 (1H, d, J = 7.7 Hz, Harom), 7.90 (2H, m, Harom), 7.59 (4H, m,
H
arom), 4.52 (2H, dd, J = 2.4, 2.2 Hz, CH2), 2.50 (1H, t, J = 2.1 Hz,
ꢃCH). 19F NMR (CDCl3):
d
ꢁ69.14. HRMS (ESI): m/z calcd for
C24H13F3N2OS 434.0701; found: 434.0713.
4.5. General procedure for the synthesis of 26–35
Yield: 68%, m.p.: 59–60 8C (Hx). 1H NMR (CDCl3):
(1H, br s, NH), 8.27–8.12 (1H, m, Harom), 7.75–7.28 (4H, m, Harom),
d 9.83–9.07
To a solution of dipolarophile 10–14 and 17 in dimethylsulfoxide
(1 mL/1 mmol), 0.1 mmol of CuSO4ꢀ5H2O followed by 0.2 mmol of
sodium ascorbate and 1.2 mmol of 1,3-dipole 18–21 and 24 were
added. 1 mL of additional dimethylsulfoxide was then added in
order to dissolve all materials. After 24 h of vigorous stirring, 2 mL of
asaturatedaqueoussolutionofammonium chloridewas thenadded
and the organic phase extracted with EA (3ꢂ 10 mL). The combined
organic phases were washed with brine (3ꢂ 10 mL), water (3ꢂ
10 mL), dried over Na2SO4, filtered and concentrated to yield a crude
product which was purified by silica gel chromatography.
7.07 (1H, d, J = 9.0 Hz, Harom), 4.32 (2H, dd, J = 6.0, 2.5 Hz, CH2), 2.37
(1H, t, J = 2.5 Hz, ꢃCH). 19F NMR (CDCl3):
d
ꢁ69.08. IR (KBr):
n
(cmꢁ1) 3321, 3052, 1621, 1584, 1532. HRMS (EI): m/z calcd for
C
15H10F3NO 277.0714; found: 277.0725.
4.4.2. 2,2,2-Trifluoro-1-(4-(prop-2-ynylamino)quinolin-3-
yl)ethanone, 12
4.5.1. 1-[4-[(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-amino]-3-(2,2,2-
trifluoro-acetyl)-naphthalen-1-yl]-2,2,2-trifluoro-ethanone, 26
Yield: 96%, m.p.: 167–168 8C (Hx/EA). 1H NMR (CDCl3):
d 10.93–
10.05 (1H, br s, NH), 8.97 (1H, q, JHF = 2.0 Hz, H-2), 8.37 (1H, d,
J = 8.0 Hz, Harom), 8.10–7.30 (3H, m, Harom), 4.63 (2H, dd, J = 6.0,
2.0 Hz, CH2), 2.55 (1H, t, J = 2.0 Hz, ꢃCH). 19F NMR (CDCl3):
d
ꢁ68.85. IR (KBr):
n
(cmꢁ1) 3183, 3068, 2103, 1635, 1575, 1530.
HRMS (EI): m/z calcd for C14H9F3N2O 278.0667; found: 278.0671.
4.4.3. 1-(4-Bromo-1-(prop-2-ynylamino)naphthalen-2-yl)-2,2,2-
trifluoroethanone, 13
Yield: 65%, silica gel chromatography (PE/EA = 8/2 ! 6/4),
yellow solid, m.p.: 123 8C. 1H NMR (CDCl3):
d 11.02 (1H, br s,
NH), 9.09 (1H, dd, J = 8.5, 0.8 Hz, Harom), 8.59 (1H, s, H-3), 8.35 (1H,
d, J = 8.3 Hz, Harom), 7.69 (2H, m, Harom), 7.57 (1H, s, Htriazole), 7.54
(1H, ddd, J = 8.5, 7.2, 1.1 Hz, Harom), 7.35 (1H, m, Harom), 7.25–7.29
(3H, m, Harom), 5.56 (2H, s, –CH2Ph), 5.19 (2H, d, J = 5.3 Hz, –
CH2NH). 19F NMR (CDCl3):
for C24H16F6N4O2 506.1177; found: 506.1182.
d
ꢁ69.12, ꢁ69.16. HRMS (ESI): m/z calcd
Yield: 62%, m.p.: 105–106 8C (Hx/EA). 1H NMR (CDCl3):
d 9.80–
4.5.2. 2,2,2-Trifluoro-1-(3-(2,2,2-trifluoro-acetyl)-4-{[1-(4-
trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-
naphtalen-1-yl)-ethanone, 27
9.27 (1H, br s, NH), 8.48–7.48 (5H, m, Harom), 4.40 (2H, dd, J = 6.0,
2.2 Hz, CH2), 2.44 (1H, t, J = 2.2 Hz, ꢃCH). 19F NMR (CDCl3):
d –
68.25. IR (KBr): n
(cmꢁ1) 3301, 3289, 3269, 2126, 1624, 1613, 1603,
1578, 1528. HRMS (EI): m/z calcd for C15H9BrF3NO 354.982; found:
354.984.
4.4.4. 2-(4-(Prop-2-ynylamino)-3-(2,2,2-trifluoroacetyl)naphthalen-
1-yl)benzo[b]thiophene-3-carbonitrile, 17
Yield: 63%, silica gel chromatography (PE/EA = 9/1), yellow
solid, m.p.: 125 8C. 1H NMR (CDCl3):
d 11.00 (1H, d, J = 4.8 Hz, NH),
9.08 (1H, dd, J = 8.5, 0.8 Hz, Harom), 8.59 (1H, s, Htriazole), 8.33 (1H, d,
J = 8.5 Hz, Harom), 7.79 (1H, m, Harom), 7.55 (2H, m, Harom), 7.36 (2H,

796
J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
d, J = 8.1 Hz, Harom), 6.89 (2H, d, J = 8.6 Hz, Harom), 5.63 (2H, s, –
CH2Ph), 5.21 (2H, d, J = 5.5 Hz, –CH2NH). 19F NMR (CDCl3):
Yield: 62%, silica gel chromatography (PE/EA = 8/2), greenish
solid, m.p.: 75–80 8C. 1H NMR (CDCl3):
10.89 (1H, d, J = 4.1 Hz,
NH), 8.95 (1H, s, Harom), 8.32 (1H, d, J = 8.6 Hz, Harom), 7.97 (1H, d,
J = 8.2 Hz, Harom), 7.78 (1H, t, J = 6.9 Hz, Harom), 7.54 (1H, s,
d
ꢁ69.29
d
(CF3), ꢁ69.13 (2ꢂ COCF3). HRMS (ESI): m/z calcd for C25H15F9N4O2
574.1051; found: 574.1064.
H
triazole), 7.40 (6H, m, Harom), 5.54 (2H, s, –CH2Ph), 5.02 (2H, d,
4.5.3. 2,2,2-Trifluoro-1-[4-{[1-(4-methoxy-benzyl)-1H-
[1,2,3]triazol-4-ylmethyl]-amino}-3-(2,2,2-trifluoro-acetyl)-
naphtalen-1-yl]-ethanone, 28
J = 5.8 Hz, –CH2NH). 19F NMR (CDCl3):
d
ꢁ68.84 (3F, d,
JHF = 2.28 Hz). HRMS (ESI): m/z calcd for C21H16F3N5O
411.1307; found: 411.1312.
4.5.6. 1-{1-[(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-amino]-4-
bromo-naphtalen-2-yl}-2,2,2-trifluoro-ethanone, 32
Yield: 65%, silica gel chromatography (PE/EA = 8/2), yellow
solid, m.p.: 135 8C. 1H NMR (CDCl3):
d 11.00 (1H, s, NH), 9.09 (1H, d,
J = 8.5 Hz, Harom), 8.60 (1H, d, J = 8.60 Hz, Harom), 8.32 (1H, d,
J = 8.5 Hz, Harom), 8.32 (1H, d, J = 8.5 Hz, Harom), 7.78 (2H, m, Harom),
7.50 (1H, m, Harom), 7.47 (1H, s, Htriazole), 7.22 (1H, d, J = 8.8 Hz,
H
arom), 6.89 (1H, d, J = 8.6 Hz, Harom), 5.47 (2H, s, –CH2Ph), 5.16 (2H,
Yield: 71%, silica gel chromatography (PE/EA = 7/3),
d, J = 5.5 Hz, –CH2NH), 3.79 (3H, s, CH3). 19F NMR (CDCl3):
d
ꢁ69.04,
yellow solid, m.p.: 75–80 8C. 1H NMR (CDCl3):
d 9.98 (1H, d,
ꢁ69.10. HRMS (ESI): m/z calcd for C25H18F6N4O3 536.1283; found:
J = 5.8 Hz, NH), 8.33 (1H, d, J = 8.4 Hz, Harom), 8.20 (2H, d,
J = 0.9 Hz, Harom), 7.91 (1H, s, Harom), 7.74 (1H, t, J = 7.2 Hz,
536.1278.
H
arom), 7.52 (2H, t, J = 6.0 Hz, Harom), 7.49 (1H, s, Htriazole), 7.36
(2H, d, J = 8.1 Hz, Harom), 7.23 (1H, d, J = 1.9 Hz, Harom), 5.54 (2H,
s, –CH2Ph), 5.02 (2H, d, J = 5.8 Hz, –CH2NH). 19F NMR (CDCl3):
4.5.4. 1-{1-[(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-amino]-
naphtalen-2-yl}-2,2,2-trifluoro-etha-none, 30
d
ꢁ69.27. HRMS (ESI): m/z calcd for C22H16BrF3N4O 488.046;
found: 488.052.
4.5.7. 2-[4-[(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-amino]-3-
(2,2,2-trifluoro-acetyl)-naphtalen-1-yl]-3-cyanobenzo[b]thiophene,
33
Yield: 64%, silica gel chromatography (PE/EA = 9/1), yellow
solid, m.p.: 103–105 8C. 1H NMR (CDCl3):
d
10.08 (1H, s, NH), 8.31
(1H, d, J = 8.6 Hz, Harom), 7.72 (2H, d, J = 9.0 Hz, Harom), 7.62 (1H, m,
H
H
arom), 7.49 (1H, s, Htriazole), 7.40 (2H, m, Harom), 7.25 (3H, m,
arom), 7.11 (2H, d, J = 9.0 Hz, Harom), 5.54 (2H, s, –CH2Ph), 5.08 (2H,
d, J = 5.5 Hz, –CH2NH). 19F NMR (CDCl3):
d –69.10 (3F, d,
JHF = 2.3 Hz). HRMS (ESI): m/z calcd for C22H17F3N4O 410.1354;
found: 410.1362.
4.5.5. 1-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-amino]-
quinolin-3-yl}-2,2,2-trifluoro-ethanone, 31
Yield: 90%, silica gel chromatography (PE/EA = 6/4 ! 4/6),
yellow solid, m.p.: 97 8C. 1H NMR (CDCl3):
d 10.47 (1H, t,
J = 5.6 Hz, NH), 8.43 (1H, d, J = 8.2 Hz,
Harom), 8.03 (1H, d,
J = 9.0 Hz, Harom), 7.72 (3H, m, Harom), 7.64 (4H, m, Harom), 7.55
(m, 3H, Haro), 7.36 (3H, m, Harom), 5.58 (2H, s, –CH2Ph), 5.17 (2H, d,
J = 5.6 Hz, –CH2NH). 19F NMR (CDCl3):
JHF = 2.29 Hz). HRMS (ESI): m/z calcd for C31H20F3N5OS
d
ꢁ68.91 (3F, d,
567.1341; found: 567.1351.

J.-F. Lamarque et al. / Journal of Fluorine Chemistry 129 (2008) 788–798
797
4.5.8. 50-Deoxy-20,30-O-isopropylidene-50-[4-{(2,4-bis-
trifluoroacetyl)naphtalen-1-yl)aminomethyl}-1,2,3-triazol-1-
yl]uridine, 34
Yield: 63%, silica gel chromatography (EP/EA = 8/2), yellow
solid, m.p.: 65 8C. 1H NMR (CDCl3):
11.05 (1H, s, NH), 9.13 (1H, d,
J = 7.7 Hz, Harom), 8.62 (1H, s, Harom), 8.31 (1H, d, J = 8.1 Hz, Harom),
d
7.95 (7H, m, Harom), 7.81 (1H, m, Harom), 7.57 (3H, m, Harom), 7.37
0
(7H, m, Harom), 6.47 (1H, d, J = 3.2 Hz, H1 ), 6.32 (1H, dd, J = 5.1,
0
0
3.2 Hz, H2 ), 6.14 (1H, t, J = 5.6 Hz, H3 ), 5.10 (2H, d, J = 5.3 Hz, –
CH2NH), 4.88 (2H, m, H5 ), 4.58 (1H, dd, J = 12.4, 4.5 Hz, H5 ). 19F
0
0
NMR (CDCl3):
d
ꢁ69.04 (2ꢂ COCF3). HRMS (ESI): m/z calcd for
C43H30F6N4O9 860.1917; found: 860.1923.
Acknowledgments
M.M would like to thank the CNRS for financial support as well
as fruitful discussions with Pierre Strazewski and Benoit Michel
(LSB). Denis Bouchu from the Centre de Spectroscopie de Masse of
Universite´ Lyon 1 is sincerely thanked for recording the mass
´
spectra. The Centre de Diffractometrie Henri Longchambon from
Yield:61%,silica gelchromatography(DCM/MET = 99/1), yellow-
the University of Lyon 1 is gratefully acknowledged for the X-ray
data collection. At Kobe University this research was supported in
part by the Ministry of Education, Culture, Sports, Science and
Technology, Grant-in-Aid for JSPS Fellows.
ish viscous oil. 1H NMR (CDCl3):
d 10.97 (1H, d, J = 5.1 Hz, NH), 10.28
(1H,s,NH, N-3), 8.57(1H,s,Harom), 8.34(1H,d,J = 8.3 Hz,Harom), 7.77
(1H, t, J = 7.0 Hz, Harom), 7.68 (1H, s, Htriazole), 7.54 (1H, t, J = 7.1 Hz,
arom), 7.14 (1H, d, J = 8.1 Hz, H-5), 5.65 (1H, dd, J = 8.1, 0.7 Hz, H-6),
H
0
5.43 (1H, d, J = 0.7 Hz, H1 ), 5.19 (2H, d, J = 5.3 Hz, –CH2NH), 5.16 (1H,
References
0
0
0
0
dd, J = 6.4, 1.1 Hz, H2 ,3 ), 4.94 (1H, dd, J = 6.4, 4.5 Hz, H2 ,3 ), 4.76 (2H,
0
0
dd, J = 14.1, 4.3 Hz, H5 ), 4.49 (1H, m, H4 ), 1.50 (3H, s, CH3), 1.30 (3H,
s, CH3). 19F NMR (CDCl3):
ꢁ69.02, ꢁ69.04. HRMS(ESI):m/z calcdfor
29H24F6N6O7 682.1611; found: 682.1622.
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7.63 (1H, s, Htriazole), 7.50 (1H, t, J = 7.3 Hz, Harom), 7.14 (1H, d,
0
J = 8.1 Hz, H-5), 5.72 (1H, dd, J = 7.9, 1.7 Hz, H-6), 5.45 (1H, s, H1 ),
0
0
5.10 (1H, dd, J = 6.4, 1.3 Hz, H2 ,3 ), 5.02 (2H, d, J = 6.1 Hz, –CH2NH), 4.
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92 (1H, dd, J = 6.4, 4.5 Hz, H2 ,3 ), 4.72 (2H, m, H5 ), 4.47 (1H, m, H4 ),
1.53 (3H, s, CH3), 1.33 (3H, s, CH3). 19F NMR (CDCl3):
ꢁ69.14. HRMS
(ESI): m/z calcd for C27H24BrF3N6O6 664.0893; found: 664.0891.
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´
3
˚
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