F-amphiphilic 1,2,3-triazoles by unexpected intramolecular cyclisation of vinyl azides

Article abstract of DOI:10.1002/ejoc.200700924

A series of fluoroalkylated 1,2,3-triazoles have been synthetised in significant yields through unexpected intramolecular cyclisations of vinyl azides bearing electron-withdrawing groups. The mechanism proposed in this study implies the participation of a catalytic amount of azide ions in the cyclisations of the vinyl azides to triazoles. The study includes the alkylation of these compounds with various alkylating agents and the evaluation of the surface activities of the ionic derivatives. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700924

FULL PAPER
DOI: 10.1002/ejoc.200700924
F-Amphiphilic 1,2,3-Triazoles by Unexpected Intramolecular Cyclisation of
Vinyl Azides
Estelle Mayot,[a] Pascal Lemière,[a] and Christine Gérardin-Charbonnier*[a]
Keywords: 1,2,3-Triazoles / Vinyl azides / Intramolecular cycloadditions / Fluorinated compounds
A series of fluoroalkylated 1,2,3-triazoles have been synthe-
tised in significant yields through unexpected intramolecular
cyclisations of vinyl azides bearing electron-withdrawing
groups. The mechanism proposed in this study implies the
participation of a catalytic amount of azide ions in the cycli-
sations of the vinyl azides to triazoles. The study includes the
alkylation of these compounds with various alkylating agents
and the evaluation of the surface activities of the ionic deriv-
atives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
covery of the advantages of the copper(I) catalyst reported
by Sharpless.[12] This concept has been developed in click
chemistry reactions in numerous studies.[13]
Alternative methods to improve the regioselectivity, such
as the use of push-pull alkenes containing leaving groups,
have also been developed.[14] Only a few methods involve
the synthesis of 1,2,3-triazoles through intramolecular
cyclisation.
We have recently reported the synthesis of a series of
highly fluoroalkylated amphiphilic 1,2,3-triazoles through
efficient and regioselective 1,3-dipolar cycloadditions be-
tween 2-(perfluoroalkyl)ethyl azides and acetylenic esters or
acids[15] (Scheme 1).
Introduction
Triazole derivatives have received significant attention as
biologically important heterocycles and have been reported
to display pharmacological, insecticidal, fungicidal and her-
bicidal activities.[1,2] They are interesting for a wide range
of applications covering a spectrum of therapeutic areas.
Indeed, many 1,2,3-triazoles have been found to be potent
antimicrobial,[3,4] analgesic,[5] anti-HIV and antiviral
agents,[6,7] as well as anti-betalactamase[8] drugs, while some
exhibit anticancer activity.[9] They also have numerous ap-
plications as agrochemicals, dyes, corrosion-retarding
agents or photostabilisers.[10]
For these reasons, methodologies for the preparation of
A large variety of well-defined pure perfluoroalkylated
1,2,3-triazoles have attracted much attention over the last amphiphiles have been synthesised during the last few years.
few years. They display properties and performances that generally
One of the most attractive ways to prepare these com- cannot be attained with standard surfactants, such as ther-
pounds involves thermal 1,3-dipolar cycloadditions of az- mal and chemical stability, high surface activity and sur-
ides with alkynes, as initially proposed by Huisgen.[11] The face-modification ability, as well as low critical-micelle con-
compounds are typically prepared by thermal cycloaddition centrations, and have been investigated as emulsion stabilis-
of azides and alkynes to yield mixtures of regioisomers. ers, vesicle-forming components, components of fluorinated
Interest in this reaction was much enhanced after the dis- emulsions for template preparation of mesoporous silica
Scheme 1. Fluoroalkylated amphiphilic 1,2,3-triazoles from azido compounds.
[a] Laboratoire de Chimie-Physique Organique et Colloïdale,
and, above all, as components of drug preparation and
Equipe “Synthèse et Assemblages de Composés Amphiphiles”
drug-delivery systems.[16] Continuing the synthesis of origi-
UMR 7565 SRSMC, Nancy Université – Université Henri Po-
incaré – Faculté des Sciences et Techniques
nal fluorocarbon amphiphilic compounds, we have there-
fore studied the reactivity of ramified fluorocarbon vinyl
azides.
54506 Nancy – Vandoeuvre
Fax: +33-3-83684322
E-mail: Christine.gerardin@lesoc.uhp-nancy.fr
2232
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2232–2239

F-Amphiphilic 1,2,3-Triazoles by Intramolecular Cyclisation of Vinyl Azides
Scheme 2. New conditions for efficient syntheses of azido compounds. a: CrO3, H2SO4, r.t., 2 h; b: 2  NaOH, THF, H2O, r.t., 2 h; c:
EtOH, H2SO4, toluene, 18 h, reflux; d: SOCl2, reflux, 15 h, then PhCH2OH or solketal or HNR1R, Et3N, THF, 0 °C; e: 10 equiv. NaN3,
acetone, reflux, 24 h.
Results and Discussion
Synthesis of Triazoles
In our efforts to develop polyfunctional amphiphilic tri-
Scheme 4. Intramolecular triazoles.
azoles, we have studied the reactivities of amide and ester
derivatives 3 (Scheme 2) of 3-azido-3-(perfluoroalkyl)pro-
These transformations have also been accomplished di-
penoic acids, the synthesis of which was described in a pre-
rectly by starting from the unsaturated esters 2 (Scheme 5).
The results depend on the experimental conditions (solvents
and temperature; Table 1).
vious paper.[17] We now propose a faster and more efficient
method for the preparation of this raw material. Indeed, the
replacement of the vinylic fluorine atom in 2 by azido
groups through addition/elimination is now accomplished
in acetone at reflux in the presence of a large excess of so-
dium azide in less than 3 h.
Table 1. Influence of the temperature and the nature of the solvent.
Solvent
Time Temperature
Product
Yield
Acetone
Formamide
Acetone/formamide 10 h
(1:1)
24 h
24 h
70 °C
70 °C
70 °C
3
3
5
100%
100%
60%
Under the new conditions the reactions lead to the prod-
ucts with yields higher than 90%. Only the (Z) isomers are
formed. The identification of this configuration was
1
achieved by detailed analyses and comparison of H and
Acetone/formamide 24 h
(9:1)
Acetone/water (9:1) 24 h
70 °C
50 °C
70 °C
5
90%
100%
100%
19F NMR literature data for similar products as described
previously.[17]
3 (12%), 5
(88%)
5
The reactivities of vinylic azides of this type were as-
sessed. Treatment with alkynes produced triazole rings
through 1,3-dipolar cycloadditions (Scheme 3).
Acetone/water (9:1) 24 h
The triazoles 5 were obtained quantitatively in acetone/
water mixtures (9:1) (Table 1). The total conversion needs a
temperature of 70 °C (reflux in acetone).
We also modified conditions to elucidate the mechanism
of this reaction. According to the literature, cyclisations of
vinyl azides to form triazoles are not characteristic.[18]
However, consistently with the proposals made in this study
and with other results, such cyclisations can be achieved
when electron-acceptor substituents are present at the car-
bon atoms of the double bonds in the vinyl azides.[19]
A first hypothesis to explain this reaction is to consider
the addition of the terminal nitrogen atom of the azide moi-
Scheme 3. 1,3-Dipolar cycloadditions with alkynes.
Despite many attempts to improve the yields of these re- ety on the double bond in the β-position relative to the
actions by varying different parameters, they would not ex- electron-withdrawing fluorinated group, together with a
ceed 60%.
second step relating to the weak basic character of sodium
On the other hand, if the vinyl azides are heated in the azide, leading to aromatic compounds by proton elimi-
presence of a mixture of acetone/polar solvent component nation (Scheme 6).
(water, formamide) with excess sodium azide, intramolecu-
However, when the sodium azide is replaced by a tertiary
lar cyclisation takes place to produce 1,2,3-triazoles 5 amine or by sodium iodide as soft base, the reaction does
(Scheme 4).
not take place. The role of the sodium azide is thus not
Scheme 5. Formation of azides 3 and/or triazoles 5.
Eur. J. Org. Chem. 2008, 2232–2239
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2233

E. Mayot, P. Lemière, C. Gérardin-Charbonnier
FULL PAPER
Scheme 6. First hypothesis for the mechanism of formation of triazole.
Scheme 7. Hypothesis for the mechanism of the triazole formation.
limited to that of a base. Therefore, it is very probable that Ester Hydrolysis
the mechanism corresponds to two successive additions of
azide before the cyclisation, as proposed by Timoshenko.
The second azide group acts as a leaving group (Scheme 7).
To modify the hydrophilic–lipophilic balance, it is neces-
sary to hydrolyse the ester moieties. The reactions are ef-
ficient under classical conditions and lead to the corre-
sponding acids (Scheme 9).
Reactivities of Triazole Compounds 5
Deprotonation of the triazole rings of compounds 5 is
indicated by different colours of the two forms (yellow in
acidic environments, red under basic conditions), confirmed
by UV/Vis spectroscopy (Scheme 8 and Figure 1).
Scheme 9. Ester saponification.
Determination of acidity constants by potentiometry and
by fitting the curves with PSEQUAD[20]gave two values
(4.5Ϯ0.5 and 5.89Ϯ0.05), attributed on the basis of IR
spectroscopy to the NH/N– and COOH/COO– functions,
respectively. Figure 2 shows IR spectra measured at dif-
ferent pH values. At pH = 7 an absorption corresponding
to a carboxylate function appears at 1565 cm–1, while at pH
= 5 another band is observed at 1730 cm–1, corresponding
to a carboxylic acid function. The acidity of the triazole is
comparable to that of other known triazoles with electron-
acceptor substituents.[19,21]
Figure 1. UV/Vis spectra of 5 at different pH values.
Scheme 8. Triazole deprotonation.
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Eur. J. Org. Chem. 2008, 2232–2239

F-Amphiphilic 1,2,3-Triazoles by Intramolecular Cyclisation of Vinyl Azides
Figure 3. N-2 isomer of the acid derivative of 7c.
Surface Activities of Salt Derivatives of Compounds 6
Self-association of surfactants is a well-known phenome-
non. Hydrophobic interactions are the driving forces that
induce the adsorption of the surfactant at the water/air
interface. Once this surface is saturated, the surfactant
molecules self-associate to minimise the free energy of the
whole system. The surfactant properties of the aqueous
solutions were evaluated by surface tension measurements
(γ) carried out by the Wilhelmy method.[23] Measurements
were made with basic solutions to limit the species to the
dianionic form. The solubility in sodium hydroxide solution
was sufficient to obtain a γ vs. logC (concentration) plot,
allowing the determination of the Critical Aggregative Con-
centration (CAC) and of the minimal surface tension
(γCAC). Typical curves of monodisperse surfactants were
obtained for the synthesised products (Figure 4, Table 3).
For concentrations superior to the CAC, γ remains practi-
cally constant and equal to the minimum value of γ attain-
able with a given amphiphilic compound. The good linearity
of the points below the CAC, and the constant values of
γ above it, as well as the sharp break in the curve, are a
confirmation of the purities of the compounds. At room
temperature, the two compounds lower the surface tension
of water to about 20 mNm–1, which corresponds to classi-
cal behaviour for fluorinated surfactants.
Figure 2. Changes in the IR spectrum of 6 (n = 7) with the pH in
aqueous solution.
Alkylation
Alkylation of the triazoles was achieved by an economi-
cally and environmentally friendly microwave procedure
(Scheme 10). In view of the pKa value (ca. 5.89, depending
on the nature of R1), triethylamine is sufficient to depro-
tonate the triazole ring. Alkylation results in two regioisom-
eric five-membered heterocycles, alkylated on nitrogen atom
N-2 or N-3 depending on the reaction conditions.[18,22]
The N-2 isomer is generally the major product, probably
due to steric hindrance. Product yields and ratios are sum-
marised in Table 2. In most cases, alkylation gave mixtures
of inseparable regioisomers.
Table 2. Alkylation of the triazole ring.
Series
R1
R2X
Solvent[a] Time Yield N-2/N-3
7a CH2CH3
7b CH2CH3
CH3I
C6H5CH2Br
C6H5CH2Br
A
A
B
A
A
A
20 min 68%
5 min 81%
30 min 87%
5 min 80%
180 min 70%
10 min 89%
50:50
65:35
70:30
60:40
75:25
75:25
7c
CH2Ph
7d CH2CH3 p-O2NC6H4CH2Br
7e CH2CH3 Me(OCH2CH2)3OTs
7f
CH2CH3
EtO2CCH2Br
[a] A = 1,4-dioxane; B = 1,4-dioxane/formamide.
The isomers were identified by H, 19F and 13C NMR
spectroscopy. The regioselectivity obtained in the case of
compound 7c was unambiguously confirmed by X-ray dif-
fraction of the acid form obtained after saponification,
showing the benzyl group at the N-2 position (Figure 3).
1
Figure 4. Surface activities of salt derivatives of 6.
Scheme 10. Triazole alkylation.
Eur. J. Org. Chem. 2008, 2232–2239
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2235

E. Mayot, P. Lemière, C. Gérardin-Charbonnier
FULL PAPER
Synthesis of Ethyl 3-Fluoro-3-(perfluoroalkyl)prop-2-enoate (2):
Ethanol (10 mL) and concentrated sulfuric acid (some drops) were
added to a solution of acid 1 (10 mmol) in toluene (75 mL). The
resulting mixture was heated under azeotropic reflux for 16 h. The
solvent was evaporated under reduced pressure, and the residue was
then taken up again with ethyl acetate. The organic phase was
washed with a saturated aqueous solution of NaCl, a solution of
NaHCO3 until it was neutral and once more with a saturated aque-
ous solution of NaCl. After drying with magnesium sulfate, the
solvent was evaporated under vacuum, and the ester 2 was obtained
as a yellow liquid. Yield: 90% (3.47 g for n = 5). 1H NMR
Table 3. Physicochemical properties of amphiphiles 6.
Product
n
γCAC [mNm–1] CAC [molL–1] σ [Å2/molecule]
a
b
7
9
18.4
17.2
3.8 10–2
308
93
6.1 10–5
The minimum area per surfactant head group at the mi-
cellar interface (σ, in Å2) was calculated from the slope of
the γ vs. logC curve below the CAC from the classical
Gibbs equation. The surface saturation (Γmax) can be used
as a measure of the maximum extent of adsorption of sur-
factant at the air/water interface and can be calculated from
the Gibbs adsorption equation for dilute systems:
3
(400 MHz, CDCl3): δ = 1.32 (t, JH,H = 7.1 Hz, 3 H, –CH3), 4.28
3
3
(q, JH,H = 7.1 Hz, 2 H, –CH2–), 5.98 (d, JH,F = 29.4 Hz, 1 H,
=CH–) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (–CH3), 62.0
(–CH2–), 106.8 (=CH–), 110–120 (C–F), 155.5 (CO) ppm. 19F
3
Γmax = –(1/2.303nRT)·(dγ/dlogC) (R = 8.314 JK–1 mol–1)
NMR (188 MHz, CDCl3): δ = –79 (t, JF,F = 9 Hz, 3 F, CF3–),
–108
(m,
1
F,
–CF=CH–),
–120
(m,
2
F,
From the surface excess values, it is possible to calculate
–CF2–CF=), –123 to –127 [m, (2n – 4) F, CF3–(CF2)n–2–CF2–CF=]
the minimum area per molecule in Å2 at the air/water inter-
ppm. IR: ν = 1740 (C=O), 1700 (C=C), 1100–1300 (C–F) cm–1.
˜
face from the following relation, where
R
=
Synthesis of 3-Fluoro-3-(perfluoroalkyl)prop-2-enoyl Chloride: Acid
1 (15 mmol) was dissolved in freshly distilled thionyl chloride
(8 mL), and the mixture was heated under reflux for 15 h. The total
conversion of the acid into the acyl chloride was checked by IR.
8.314 JK–1 mol–1, T = 298.15 K, with γ expressed in Nm–1,
NA is Avogadro’s number (6.022ϫ1023), and n is a constant
that depends on the number of species constituting the sur-
factant and which are adsorbed at the interface:
Synthesis of Amide and Ester Derivatives 2 with R =/ OEt: The
corresponding alcohol or amine (10 mmol) was dissolved in anhy-
drous THF (20 mL), and triethylamine (15 mmol) was added. The
mixture was then cooled to 0 °C. The acyl chloride was added drop-
wise, and the mixture was continuously stirred for 3 h. Afterwards,
HCl (0.1 , 20 mL) was added, and the product was extracted three
times with diethyl ether, and the combined organic phases were
washed with saturated aqueous NaHCO3 and dried with magne-
sium sulfate. The solvent was evaporated under vacuum, and after
purification by chromatography on silica (ether/hexane), the prod-
uct was obtained as a colourless liquid.
Amin = 1020/NA Γmax
For a univalent ionic surfactant the value n = 2 is generally
used. In the case of the dianionic compounds, we have con-
sidered the value n = 3. The surface area per polar head
group for these anionic surfactants is very important. The
planarity of the system and the repulsion between the two
negative charges could be a reasonable explanation for this
high mean area per molecule.
1
R = OCH2Ph: Yield 80% (3.58 g for n = 5). H NMR (200 MHz,
Conclusion
3
CDCl3): δ = 5.17 (s, 2 H, –CH2–), 5.95 (d, JH,F = 29.4 Hz, 1 H,
=CH–), 7.2 (m, 5 H, Ph) ppm. 13C NMR (50 MHz, CDCl3): δ =
67.4 (–CH2Ph), 106 (=CH–), 110 to 120 (Cfluor), 128.1, 128.5, 128.7,
134.9 (Ph), 161 (CO) ppm. 19F NMR (188 MHz, CDCl3): δ = –79
We propose an efficient synthesis of single-chain perfluo-
roalkylated 1,2,3-triazoles from vinyl azides by intramolecu-
lar cyclisation, or directly from fluoroalkenes with electron-
withdrawing substituents. The lowering of the surface ten-
sion of pure water by addition of small amounts of the am-
phiphile salt derivatives shows that they are surface-active
agents. The alkylation of the triazole ring is carried out un-
der simple conditions and could be extended to attach other
functional groups.
3
(t, JF,F = 9 Hz, 3 F, CF3–), –107.5 (m, 1 F, –CF=CH–), –120 (m,
2 F, –CF2–CF=), –123 to –127 [m, (2n – 4) F, CF3–(CF2)n–2–CF2–
CF=] ppm. IR: ν = 1738 (C=O), 1700 (C=C), 1100–1300 (C–F)
˜
cm–1.
Representative Amide Derivative with R = NEt2: Yield 3.32 g for n
1
3
= 5. H NMR (200 MHz, CDCl3): δ = 1.18 (t, JH,H = 7.1 Hz, 3
3
3
H, –CH3), 1.20 (t, JH,H = 7.1 Hz, 3 H, –CH3), 3.32 (q, JH,H
=
7.1 Hz, 2 H, –CH2–), 3.47 (q, 3JH,H = 7.1 Hz, 2 H, –CH2–), 6.21 (d,
3JH,F = 32.0 Hz, 1 H, =CH–) ppm. 13C NMR (50 MHz, CDCl3): δ
= 13.1, 14.5 (–CH3), 40.1, 43.1 (–CH2–), 109 (=CH–), 110 to 120
(C–F), 160 (CO) ppm. 19F NMR (188 MHz, CDCl3): δ = –79 (t,
3JF,F = 9 Hz, 3 F, CF3–), –106.8 (m, 1 F, –CF=CH–), –120 (m, 2
F, –CF2–CF=), –123 to –127 [m, (2n – 4) F, CF3–(CF2)n–2–CF2–
Experimental Section
General: All solvents were of reagent grade and used without fur-
ther purification. The progress of reactions was determined by IR
spectroscopy. NMR spectra were recorded with a Bruker AM 400
or AC 200 instrument. Chemical shifts (δ) are reported in ppm rela-
CF=] ppm. IR: ν = 1701 (C=C), 1641 (C=O), 1100–1300 (C–F)
˜
cm–1.
1
tive to TMS as internal standard for the H NMR spectra and to
CFCl3 for the 19F NMR spectra. Coupling constants (J) are given
in Hz. IR spectra were recorded with a Perkin–Elmer FTIR instru-
ment in ATR. Melting points were determined with a Tottoli appa-
ratus and are not corrected. Elemental analyses were performed
by CNRS Vernaison. Reactions were performed in a CEM 300 W
chemistry microwave oven. Starting material 1 was prepared from
the corresponding alcohol according a the published method.[24]
Synthesis of Alkyl 3-Azido-3-(perfluoroalkyl)prop-2-enoates or N-
Alkyl-3-azido-3-(perfluoroalkyl)prop-2-enamides (3): The ester de-
rivative 2 (15 mmol) or amide derivative 3 was dissolved in acetone
(80 mL), and sodium azide (10 equiv.) was then added. The mixture
was stirred at 50 °C for 3 h. Water (50 mL) was added, and the
product was extracted with diethyl ether. The organic phase was
washed with water and dried with sodium sulfate, and the solvent
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Eur. J. Org. Chem. 2008, 2232–2239

F-Amphiphilic 1,2,3-Triazoles by Intramolecular Cyclisation of Vinyl Azides
was evaporated under vacuum. The product was obtained as a yel-
low liquid. Yield: 90%.
(100 MHz, CDCl3): δ = 15 (–CH3), 63 (–CH2–), 110–120 (Cfluor),
138, 140 (Ctriazole), 160 (CO) ppm. 19F NMR (188 MHz, CDCl3):
δ = –79 (t, 3JF,F = 9 Hz, 3 F, CF3–), –105.4 [m, 2 F, –CF2–Ctriazole=],
Representative Ester Derivative with R = OEt: Yield 5.78 g for n =
–119 to –124 [m, (2n – 4) F, CF3–(CF2)n–2–CF –] ppm. IR: ν = 1704
˜
1
3
2
5. H NMR (400 MHz, CDCl3): δ = 1.34 (t, JH,H = 7.1 Hz, 3 H,
(C=O), 1100–1300 (C–F) cm–1. C12H6F15N3O2 (509.17): calcd. C
28.31, H 1.19, F 55.97, N 6.28; found C 27.76, H 1.21, F 51.15, N
7.89.
3
–CH3), 4.28 (q, JH,H = 7.1 Hz, 2 H, –CH2–), 6.14 (s, 1 H,
=CH–) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.6 (–CH3), 62.3
(–CH2–), 113.3 (=CH–), 110–120 (C–F), 140.9 (C–N3), 163.9 (CO)
ppm. 19F NMR (188 MHz, CDCl3): δ = –81.4 (t, JF,F = 9 Hz, 3
3
Treatment for R = OCH2Ph: On cooling to room temperature, the
solvent was evaporated under vacuum, and diethyl ether was then
added to precipitate the product, which was recovered by filtration.
A white solid was obtained. Yield: 85% (0.97 g for n = 7). 1H NMR
(400 MHz, CD3COCD3): δ = 2.94 (s, 1 H, NH), 5.35 (s, 2 H,
–CH2–), 7.3 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CD3COCD3):
δ = 67.1 (–CH2Ph), 110–120 (Cfluor), 129.1, 129.3, 129.5, 137.9 (Ph),
135.7, 136.9 (Ctriazole), 164.5 (CO) ppm. 19F NMR (188 MHz
F, CF3–), –115 [m, 2 F, –CF2–C(N3)=], –122.4 to –126.7 [m, (2n –
4) F, CF3–(CF2)n–2–CF –] ppm. IR: ν = 2164 (N ), 1720 (C=O),
˜
2
3
1100–1300 (C–F) cm–1.
Representative Amide Derivative with R = NEt2: Yield 6.36g for n
1
3
= 5. H NMR (400 MHz, CDCl3): δ = 1.18 (t, JH,H = 7.1 Hz, 3
3
3
H, –CH3), 1.21 (t, JH,H = 7.1 Hz, 3 H, –CH3), 3.33 (q, JH,H
=
3
7.1 Hz, 2 H, –CH2–), 3.47 (q, JH,H = 7.1 Hz, 2 H, –CH2–), 6.35
(s, 1 H, =CH–) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.2, 14.6
(–CH3), 40.5, 43.6 (–CH2–), 115 (=CH–), 110–120 (C–F), 141 (C–
N3), 164 (CO) ppm. 19F NMR (188 MHz, CDCl3): δ = –81.7 (t,
3JF,F = 9 Hz, 3 F, CF3–), –115 [m, 2 F, –CF2–C(N3)=], –122 to –127
3
CD3COCD3): δ = –79 (t, JF,F = 9 Hz, 3 F, CF3–), –101.6 (m, 2
F, –CF2–triazole), –119 to –124 [m, (2n – 4) F, CF3–(CF2)n–2– CF2–]
ppm. IR: ν = 1707 (C=O), 1100–1300 (C–F) cm–1. C H F N O
˜
17
8
15
3
2
(571.25): calcd. C 35.74, H 1.41, F 49.89, N 7.36; found C 34.68, H
1.20, F 47.14, N 7.11.
[m, (2n – 4) F, CF3–(CF2)n–2–CF –] ppm. IR: ν = 2150 (N ), 1647
˜
2
3
(C=O), 1100–1300 (C–F) cm–1.
Ester Saponification. Preparation of 5-(Perfluoroalkyl)-1H-1,2,3-tri-
azole-4-carboxylic Acids 6: NaOH (2 , 5 mL) was added to a solu-
tion of triazole 5 (2 mmol) in acetone (30 mL). The mixture is stirred
at room temperature for 8 h and then acidified with HCl (1 ) until
pH = 1. The product was extracted with diethyl ether, and the com-
bined organic phases were washed with water and dried with magne-
sium sulfate. The solvent was evaporated under vacuum, and the acid
triazole was obtained as a yellow transparent solid. Yield: 95%
(0.91 g for n = 7). 13C NMR (100 MHz, CD3COCD3): δ = 110–
120 (C–F), 138.2 and 160.3 (Ctriazole) ppm. 19F NMR (188 MHz,
Synthesis of Dimethyl 1-{1-[(Alkoxycarbonyl)methylene]perfluoro-
alkyl}-1H-1,2,3-triazole-4,5-dicarboxylates 4: The azide derivative
3 (5 mmol) and dimethyl acetylenedicarboxylate (1.3 equiv.) were
placed in a round-bottomed flask. The mixture was heated in an
oil bath at 75 °C for 24 h. The product was then purified by
chromatography on silica (ether/hexane). Yield: 55–60%.
Representative Ester Derivative with R = OEt: Yield 1.56g for n =
1
3
5. H NMR (400 MHz, CDCl3): δ = 1.15 (t, JH,H = 7.1 Hz, 3 H,
–CH3), 3.97 (s, 3 H, COOCH3), 4.01 (s, 3 H, COOCH3), 4.11 (q,
3JH,H = 7.1 Hz, 2 H, –CH2–), 6.93 (s, 1 H, =CH–) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.3 (–CH3), 53.6, 54.2 (–OCH3), 63.4
(–CH2–), 110–120 (C–F), 132.3, 133.5 (Ctriazole), 134 [–Ctriazole=],
140.4 (=CH–), 158.2, 160.6, 160.8 (CO) ppm. 19F NMR (188 MHz,
3
CD3COCD3): δ = –80.6 (t, JF,F = 9 Hz, 3 F, CF3–), –106.3 (m, 2
F, –CF2–triazole), –120 to –127 [m, (2n – 4) F, CF3–(CF2)n–2–CF2–]
ppm. IR: ν = 1703 (C=O), 1100–1300 (C–F) cm–1. C H F N O
˜
10
2
15
3
2
(481.12): calcd. C 24.96, H 1.41, F 59.23, 8.73; found C 24.92, H
0.58, F 56.66, N 8.73.
3
CDCl3): δ = –81.3 (t, JF,F = 9 Hz, 3 F, CF3–), –110 to –118 [m, 2
General Procedure for the Alkylation of Triazoles. Preparation of Ethyl
2- or 3-Alkyl-5-(perfluoroalkyl)-2H-1,2,3-triazole-4-carboxylates (7):
The triazole 5 (0.2 mmol) was dissolved in 1,4-dioxane (1 mL, and 4
drops formamide in the case of 8c), and triethylamine (1.1 equiv.)
and R2X [1.1 equiv., or 0.9 equiv. for Me(OCH2CH2)3-
OTs] were then added. The mixture was placed in a microwave tube,
sealed and then microwave-irradiated at 110 °C under pressure for
the time indicated in Table 3. After the system had cooled to room
temperature, diethyl ether was added, and the organic phase was
washed with a solution of HCl (1 ), and twice with a saturated
aqueous solution of NaCl. The organic phase was dried with sodium
sulfate, and the solvent was evaporated under vacuum to give the
triazole, which was purified by chromatography on silica (Et2O/hex-
ane).
F, –CF2–Ctriazole=], –122 to –127 [m, (2n – 4) F, CF3–(CF2)n–2–CF2–]
ppm. IR: ν = 1735 (C=O), 1100–1300 (C–F) cm–1.
˜
Representative Amide Derivative with R = NEt2: Yield 1.65g for n
1
3
= 5. H NMR (400 MHz, CDCl3): δ = 0.95 (t, JH,H = 7.1 Hz, 3
3
3
H, –CH3), 1.22 (t, JH,H = 7.1 Hz, 3 H, –CH3), 3.23 (q, JH,H
=
3
7.1 Hz, 2 H, –CH2–), 3.33 (q, JH,H = 7.1 Hz, 2 H, –CH2–), 3.96
(s, 3 H, COOCH3), 3.98 (s, 3 H, COOCH3), 7.25 (s, 1 H, =CH–)
ppm. 13C NMR (100 MHz, CDCl3): δ = 12.7, 14.2 (–CH3), 40.2,
43.1 (–CH2–), 53.2, 53.9 (–OCH3), 129.5 (–Ctriazole=), 134, 139.8
(Ctriazole), 135.5 (=CH–), 157.4, 160.2 (CO) ppm. 19F NMR
3
(188 MHz, CDCl3): δ = –81.3 (t, JF,F = 9 Hz, 3 F, CF3–), –110 to
–115 [m, 2 F, –CF2–Ctriazole=], –122 to –127 [m, (2n – 4) F, CF3–
(CF2)n–2–CF –] ppm. IR: ν = 1739, 1638 (C=O), 1100–1300 (C–F)
˜
2
cm–1.
R1 = Et, R2 = CH3: Colourless liquid. Yield: 68% (71.15 mg for n =
1
3
Synthesis of Alkyl 5-(Perfluoroalkyl)-3H-1,2,3-triazole-4-carboxyl-
ates 5: The azide derivative 3 (2 mmol) was dissolved in acetone
(9 mL) and water (1 mL), and sodium azide (10 equiv.) was then
added. The mixture was heated under reflux for 24 h.
7). H NMR (400 MHz, CDCl3): δ = 1.36 (t, JH,H = 7.1 Hz, 3 H,
–CH3), 4.31 [s, 3 H, –NCH3 (50%)], 4.33 [s, 3 H, –NCH3 (50%)],
4.41 (q, JH,H = 7.1 Hz, 2 H, –CH2–) ppm. 13C NMR (100 MHz,
3
CDCl3): δ = 13.7, 14 (–CH3), 38.6, 43.3 (NCH3), 62.6, 63.3 (–CH2–),
110–120 (C–F), 129.5, 137.5, 137.9, 139.5 (Ctriazole) 157.5, 159 (CO)
Treatment for R = OEt: On cooling to room temperature, ethyl
acetate (60 mL) was added, and the organic phase was washed
three times with a saturated aqueous solution of NaCl, and then
with a solution of HCl (0.1 ). The organic phase was then dried
with sodium sulfate, and the solvent was evaporated under vacuum
to give the triazole as a yellow solid. Yield: quantitative (1.01 g for
3
ppm. 19F NMR (188 MHz, CDCl3): δ = –81.4 (t, JF,F = 9 Hz, 3
F, CF3–), –107.5 [m, 2 F, –CF2–triazole (50%)], –107.7 [m, 2 F,
–CF2–triazole (50%)], –119 to –124 [m, (2n – 4) F, CF3–(CF2)n–2
–
CF –] ppm. IR: ν = 1741 (C=O), 1100–1300 (C–F) cm–1.
˜
2
R1 = Et, R2 = CH2Ph: Colourless liquid. Yield: 81% (97.22 mg for
1
3
1
3
n = 7). H NMR (400 MHz, CDCl3): δ = 1.39 (t, JH,H = 7.1 Hz,
n = 7). N-2: 65%. H NMR (400 MHz, CDCl3): δ = 1.39 (t, JH,H
3 H, –CH3), 4.45 (q, 3JH,H = 7.1 Hz, 2 H, –CH2–) ppm. 13C NMR = 7.1 Hz, 3 H, –CH3), 4.43 (q, JH,H = 7.1 Hz, 2 H, –CH2–), 5.70
3
Eur. J. Org. Chem. 2008, 2232–2239
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2237

E. Mayot, P. Lemière, C. Gérardin-Charbonnier
FULL PAPER
(s, 2 H, –CH2Ph), 7.37 (m, 5 H, Ph) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.2 (–CH3), 60.6 (–CH2Ph), 62.6 (–CH2–Me), 110–
120 (C–F), 130.7, 137.5, 139.6 (Ctriazole) 157.9, 159.1 (CO) ppm. 19
NMR (188 MHz, CDCl3): δ = –81.3 (t, JF,F = 9 Hz, 3 F, CF3–),
F
3
120 (C–F), 128.7, 129.4, 129.5, 133.5 (Ph), 138.2, 139.9 (Ctriazole), –107.5 [m, 2 F, –CF2–triazole (75%)], –107.8 [m, 2 F, –CF2–triazole
3
159.1 (CO) ppm. 19F NMR (188 MHz, CDCl3): δ = –81.3 (t, JF,F
(25%)], –121 to –127 [m, (2n – 4) F, CF3–(CF2)n–2–CF2–] ppm. IR:
= 9 Hz, 3 F, CF3–), –107.7 (m, 2 F, –CF2–triazole), –121 to –127
ν = 1742 (C=O), 1100–1300 (C–F) cm–1. C H F N O (655.36):
˜
19 20 15
3
2
[m, (2n – 4) F, CF3–(CF2)n–2–CF –] ppm. IR: ν = 1743 (C=O),
calcd. C 34.82, H 3.08, F 43.48, N 6.41; found C 34.15, H 2.96, F
46.07, N 6.33.
˜
2
1
1100–1300 (C–F) cm–1. N-3: 35%. H NMR (400 MHz, CDCl3): δ
3
3
= 1.31 (t, JH,H = 7.1 Hz, 3 H, –CH3), 4.36 (q, JH,H = 7.1 Hz, 2
H, –CH2–), 5.93 (s, 2 H, –CH2Ph), 7.3 (m, 5 H, Ph) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.7 (–CH3), 54.7 (–CH2Ph), 63.4
(–CH2–Me), 110–120 (C–F), 128.4, 129.2, 129.3, 134.4 (Ph), 129.4,
138.1 (Ctriazole), 157.7 (CO) ppm. 19F NMR (188 MHz, CDCl3): δ
= –81.3 (t, 3JF,F = 9 Hz, 3 F, CF3–), –107.6 (m, 2 F, –CF2–triazole),
Synthesis of Tosyl Triethylene Glycol Monomethyl Ether: Trieth-
ylene glycol monomethyl ether (20 mmol) and pyridine (12 mL) were
placed in a round-bottomed flask fitted with an addition funnel.
The mixture was cooled to 0 °C, and tosyl chloride (30 mmol), dis-
solved in pyridine (12 mL), was added dropwise. The ice bath was
removed, and the mixture was stirred at room temperature for 3 h.
Diethyl ether (60 mL) was then added, and the organic phase was
washed with a saturated aqueous solution of NaHCO3 followed
by a saturated aqueous solution of NaCl until neutralisation. The
organic phase was then dried with sodium sulfate, and the solvent
was evaporated under vacuum to give the tosyl triethylene glycol
monomethyl ether as a colourless liquid. Yield: 78% (4.98 g). 1H
NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3Ph), 3.32 (s, 3 H,
–OCH3), 3.4–3.7 (m, 8 H, CH2O), 4.11 (m, 2 H, SO3CH2–), 7.30
(d, 2 H, Haromat), 7.74 (d, 2 H, Haromat) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.0 (CH3Ph), 59.3 (–OCH3), 69 (SO3CH2), 68.9, 69.6,
70.8, 70.9, 71.0, 71.6, 72.2 (CH2O), 128.3, 130.2, 133.4, 145.2 (Ph)
–121 to –127 [m, (2n – 4) F, CF3–(CF2)n–2–CF –] ppm. IR: ν =
˜
2
1733 (C=O), 1100–1300 (C–F) cm–1.
R1 = CH2Ph, R2 = CH2Ph: Yield: 87% (115.25 mg for n = 5). N-
1
2: 70%. White solid. H NMR (400 MHz, CDCl3): δ = 5.39 (s, 2
H, O–CH2–), 5.67 (s, 2 H, N–CH2), 7.2 (m, 10 H, Ph) ppm. 13C
NMR (100 MHz, CDCl3): δ = 60.6 (N–CH2), 68.3 (O–CH2–), 110–
120 (Cfluor), 128.8, 129.0, 129.2, 129.4, 129.5, 133.4, 135.1 (Ph),
138.3, 139.6 (Ctriazole), 159.0 (CO) ppm. IR: ν = 1743 (C=O), 1100–
˜
1300 (C–F) cm–1. N-3: 30%. Colourless liquid. 1H NMR
(400 MHz, CDCl3): δ = 5.30 (s, 2 H, O–CH2–), 5.88 (s, 2 H, N–
CH2), 7.2 (m, 10 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ =
54.8 (N–CH2), 66.3 (O–CH2–), 110–120 (C–F), 128.4, 129.1, 129.2,
129.3, 129.4, 134.0, 134.2 (Ph), 129, 138.3 (Ctriazole), 157.6 (CO)
ppm. IR: ν = 1353 (SO ) cm–1.
˜
2
Saponification of the Ester Function of 7c: The procedure was the
same as that used for the saponification of the triazole 6.
ppm. IR: ν = 1732 (C=O), 1100–1300 (C-F) cm–1.
˜
R1 = Et, R2 = CH2C6H4NO2: Yield: 80% (103.20 mg for n = 5).
White solid. 1H NMR (400 MHz, CDCl3): δ = 1.4 (m, 3 H, –CH3),
4.4 (m, 2 H, –CH2–), 5.80 [s, 2 H, –CH2Ph (60%)], 6.03 [s, 2 H,
–CH2Ph (40%)], 7.5 (m, 2 H, Ph), 8.2 (m, 2 H, Ph) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.8, 14.2 (–CH3), 53.8, 59.4 (–CH2Ph),
62.9, 63.8 (–CH2–Me), 110–120 (C–F), 124.6, 124.7, 129.4, 129.7,
140.4, 141.0, 148.6, 148.8 (Ph), 130.3, 138.6, 140.0 (Ctriazole), 157.5,
N-2: Yield: 95% (1.08 g for n = 7). 1H NMR (400 MHz,
CD3COCD3): δ = 5.86 (s, 2 H, N–CH2), 7.4–7.5 (m, 5 H, Ph) ppm.
13C NMR (100 MHz, CD3COCD3): δ = 61 (N–CH2), 110–120 (C–
F), 129.6, 130.0, 130.2, 135.3 (Ph), 138.3 and 141 (Ctriazole), 160.2
3
(CO) ppm. 19F NMR (188 MHz, CD3COCD3): δ = –80.7 (t, JF,F
= 9 Hz, 3 F, CF3–), –106.2 (m, 2 F, –CF2–triazole), –120 to –126
[m, (2n – 4) F, CF3–(CF2)n–2–CF –] ppm. IR: ν = 1711 (C=O),
˜
2
3
158.8 (CO) ppm. 19F NMR (188 MHz, CDCl3): δ = –81.3 (t, JF,F
1100–1300 (C–F) cm–1. C17H8F15N3O2 (571.25): calcd. C 35.74, H
= 9 Hz, 3 F, CF3–), –107.6 (m, 2 F, –CF2–triazole), –121 to –127
1.41, F 49.89, N 7.36; found C 36.00, H 1.45, F 47.69, N 7.34.
[m, (2n – 4) F, CF3–(CF2)n–2–CF –] ppm. IR: ν = 1736 (C=O), 1520
˜
2
N-3: Yield: 95% (1.08 g for n = 7). 1H NMR (400 MHz,
CD3COCD3): δ = 6.03 (s, 2 H, N–CH2), 7.4–7.45 (m, 5 H, Ph)
ppm. 13C NMR (100 MHz, CD3COCD3): δ = 55 (N–CH2), 110–
120 (C–F), 129.2, 129.8, 136.3 (Ph), 131.3 and 138.3 (Ctriazole), 158
(NO2), 1100–1300 (C–F) cm–1. C24H14F15N3O2 (661.37): calcd. C
43.59, H 2.13, F 43.09, N 6.35; found C 43.87, H 2.26, F 41.92, N
6.35.
R1 = Et, R2 = CH2COOEt: Colourless liquid. Yield: 89%
(106.10 mg for n = 7). 1H NMR (400 MHz, CDCl3): δ = 1.27 (t,
3
(CO) ppm. 19F NMR (188 MHz, CD3COCD3): δ = –81.3 (t, JF,F
= 9 Hz, 3 F, CF3–), –106.3 (m, 2 F, –CF2–triazole), –120 to –126
3
3JH,H = 7.1 Hz, 3 H, –CH3), 1.34 (t, JH,H = 7.1 Hz, 3 H, –CH3),
[m, (2n – 4) F, CF3–(CF2)n–2–CF –] ppm. IR: ν = 1715 (C=O),
˜
2
3
3
1100–1300 (C–F) cm–1. C17H8F15N3O2 (571.25): calcd. C 35.74, H
4.26 (q, JH,H = 7.1 Hz, 2 H, –OCH2–), 4.41 (q, JH,H = 7.1 Hz, 2
H, –OCH2–), 5.33 [s, 2 H, NCH2– (75%)], 5.52 [s, 2 H, NCH2–
(25%)] ppm. 13C NMR (100 MHz, CDCl3): δ = 13.8, 14.16, 14.19,
14.23 (–CH3), 52.5, 57.0 (NCH2–), 62.8, 63.0, 63.1, 63.6 (OCH2–),
130.0 138.8, 140.4 (Ctriazole), 157.6, 158.8, 165.3, 165.9 (CO) ppm.
1.41, F 49.89, N 7.36; found C 36.29, H 1.44, F 47.96, N 7.29.
Acknowledgments
3
19F NMR (188 MHz, CDCl3): δ = –81.5 (t, JF,F = 9 Hz, 3 F,
We wish to thank the Institut Français du Pétrole and Salveco for
the acquisition of the microwave oven, Dupont de Nemours for
generous gifts of fluorinated materials, and Ludwig Rodehüser for
useful discussions.
CF3–), –107.8 [m, 2 F, –CF2–triazole (75%)], –108.1 [m, 2 F, –CF2–
triazole (25%)], –121 to –127 [m, (2n – 4) F, CF3–(CF2)n–2–CF2–]
ppm. IR: ν = 1711 (C=O), 1100–1300 (C–F) cm–1. C H F N O
˜
16 12 15
3
2
(595.27): calcd. C 32.28, H 2.03, N 7.06; found C 33.48, H 1.96, N
6.87.
R1 = Et, R2 = (CH2CH2O)3Me: Yield: 70% (91.94 mg for n = 7).
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Colourless liquid. H NMR (400 MHz, CDCl3): δ = 1.34 (t, JH,H
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2238
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: September 28, 2007
Published Online: March 17, 2008
Eur. J. Org. Chem. 2008, 2232–2239
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2239