Substituted 4-(1H-1,2,3-triazol-1-yl)-tetrafluorobenzoates: Selective synthesis and structure

Article abstract of DOI:10.1016/j.jfluchem.2016.05.005

Regioselective, simple and fast synthesis of a series of [2 + 3]-cycloaddition products, 2-11, 4-(4-RC₂HN₃)C₆F₄CO₂Et (2: R = Ph; 3: R = CMe₂OH; 4: R = CH₂OH; 5: R = CO₂Et; 6: R = n-C₅H₁₁; 7: R = CH₂O-o-C₆H₄CHO; 8: R = CH₂O-p-C₆H₄NHBoc; 9: R = CH₂O-p-C₆H₄CH₂OH; 10: R = CH₂O₂CC₆F₅; 11: R = p-C₆H₄Bu-t), in reaction between ethyl 4-azido-2,3,5,6-tetrafluorobenzoate, 1, and a number of substituted alkynes was elaborated under conditions of copper-catalyzed click chemistry reaction. The optimized conditions include application of CuBr and Et₃N in dichloromethane. The structure of compounds 2-11 was investigated in solution by 1D and 2D NMR and IR spectroscopy. The molecular structure of 2 in solid state was established by X-ray analysis.

Full text of DOI:10.1016/j.jfluchem.2016.05.005

Accepted Manuscript
Title: Substituted
4-(1H-1,2,3-triazol-1-yl)-tetrafluorobenzoates: Selective
synthesis and structure
Author: Nikolai N. Solodukhin Nataliya E. Borisova Andrei
V. Churakov Kirill V. Zaitsev
PII:
S0022-1139(16)30107-5
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.05.005
FLUOR 8775
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
16-3-2016
4-5-2016
8-5-2016
Please cite this article as: Nikolai N.Solodukhin, Nataliya E.Borisova,
Andrei V.Churakov, Kirill V.Zaitsev, Substituted 4-(1H-1,2,3-triazol-1-yl)-
tetrafluorobenzoates: Selective synthesis and structure, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.05.005
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Substituted 4-(1H-1,2,3-triazol-1-yl)-tetrafluorobenzoates:
selective synthesis and structure
Nikolai N. Solodukhina, Nataliya E. Borisovaa, Andrei V. Churakovb,c, Kirill V. Zaitseva, *
aDepartment of Chemistry, M.V. Lomonosov Moscow State University, Leninskye Gory 1, 3,
Moscow 119991, Russia
bN.S. Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of
Sciences, Leninsky pr., 31, Moscow, Russia
cDepartment of Chemistry, Tomsk State University, Lenina prosp. 36, Tomsk 634050, Russia
 Corresponding author. Tel.: +7-495-939-3887; fax: +7-495-939-0067; e-mail:
zaitsev@org.chem.msu.ru
1

Graphical abstract
A number of 1,4-substituted triazolyltetrafluorobenzoates containing both electron donor or
electron acceptor substituents was obtained under conditions of copper catalyzed alkyne – azide
cycloaddition. The method is tolerant to various groups.
Highlights
 -convenient method for the synthesis of 1,4-substituted triazolyl tetrafluorobenzoates
 -CuBr (5 mol %), Et3N in CH2Cl2 are optimal for CuAAC
 -electron donor and electron acceptor substituents in triazolyl cycle are present
 -molecular structure of 4-Ph(C2HN3)-4-C6F4CO2Et was investigated
 -new NMR procedure for establishment of C-4 substituted 1-aryl-triazoles is elaborated
2

Abstract
Regioselective, simple and fast synthesis of a series of [2+3]-cycloaddition products, 2-11, 4-
(4-RC2HN3)C6F4CO2Et (2: R= Ph; 3: R= CMe2OH; 4: R= CH2OH; 5: R= CO2Et; 6: R= n-
C5H11; 7: R= CH2O-o-C6H4CHO; 8: R= CH2O-p-C6H4NHBoc; 9: R= CH2O-p-C6H4CH2OH;
10: R= CH2O2CC6F5; 11: R= p-C6H4Bu-t), in reaction between ethyl 4-azido-2,3,5,6-
tetrafluorobenzoate, 1, and a number of substituted alkynes was elaborated under conditions of
copper-catalyzed click chemistry reaction. The optimized conditions include application of
CuBr and Et3N in dichloromethane. The structure of compounds 2-11 was investigated in
solution by 1D and 2D NMR and IR spectroscopy. The molecular structure of 2 in solid state
was established by X-ray analysis.
Keywords: Azide; Click-chemistry; 1,2,3-Triazole; Perfluorobenzoic acid; X-ray diffraction
analysis
1. Introduction
Fluorine containing benzoic acids and benzoates are sharply differed on their properties
from related hydrogen analogs and so nowadays found wide application for construction of
new materials [1], as ligands for various metals [2], precursors for liquid crystals and
luminescent materials [3], biologically active compounds [4]. Furthermore, metal
perfluorobenzoates may be regarded as catalysts of different processes in organic synthesis [5].
Reaction of 1,3-dipolar cycloaddition between azides and alkynes, widely known as click
chemistry reaction, is applied for synthesis of different triazoles under green chemistry
conditions [6]. Substituted triazoles possess potential biological activity and may be used for
medicaments elaboration against tuberculosis [7], HIV [8], and also as antiepileptic [9],
anticancer [10] and antimicrobial agents [11]. The 4-aryl-1H-1,2,3-triazoles were discovered to
be a unique template for the inhibition of the metalloprotease MetAP2 [12]. Furthermore, these
derivatives find application as proton transfer agents [13], precursors for construction of
3

polymer [14] or liquid crystals [15]. So a simple and efficient way of synthesis of such
compounds should be developed.
It should be noted that synthesis of differently substituted triazoles containing
perfluorophenyl group has been elaborated only partly. Thus substituted aryl azides with
electron withdrawing group reacts in cycloaddition reactions very easily [16]. There are only
several works concerning related compounds [17] and there are no well-performed [18] works
concerning copper-catalyzed azide - alkyne cycloaddition (CuAAC) and especially
corresponding benzoic acids. The aim of this work is a development of a method of synthesis
of a wide range of substituted triazoles containing tetrafluorobenzoate fragment.
2. Results and Discussion
In this work the synthesis of initial compounds, ethyl pentafluorobenzoate and ethyl 4-
azidopentafluorobenzoate (1), is described. The well known synthetic procedures (carboxylic
acid esterification, nucleophilic substitution in C6F5 ring) [19] were used for the synthesis of
the target compounds. At the same time we worked out new approach to synthesize C6F5CO2Et
using Grignard reagent [20] what allows to obtain esters in moderate yields (Scheme 1). The
last method should be used for the synthesis of substituted perfluoroarene carboxylic acids. It
was established that reverse slow addition (addition of Grignard reagent to the ethyl
chloroformate at low temperature) is crucial for the successful synthesis. Even despite this the
significant amount (up to 30 %) of undesired by-product, (C6F5)2C=O [21], may be isolated
from the reaction mixture. Besides, ethyl pentafluorobenzoate may be prepared using common
method from free acid using SOCl2 (Scheme 1).
Compound 1 was synthesized by the selective nucleophilic aromatic substitution of a para-
fluorine atom in ethyl pentafluorobenzoate with azide ion using known way [22]. It should be
noted that two ethyl esters obtained in this work, C6F5CO2Et and p-N3C6F5CO2Et (1), are new
compounds.
The most general methodology suitable for the synthesis of 1,2,3-triazoles is the Huisgen
1,3-dipolar cycloaddition, i.e. the reaction between alkyl or aryl azides and terminal acetylenes
[23]. If the cycloaddition is thermally induced, approximately equimolar mixture of the 1,4-
and 1,5-regioisomers of triazole is usually obtained [24]. Various attempts to control the
regioselectivity without much success were reported until the discovery of the copper(I)-
catalyzed reaction, which exclusively yields the 1,4-disubstituted 1H-1,2,3-triazoles [25].
4

In this article a wide series of substituted triazoles was obtained containing electron donating
and electron withdrawing substituents. At the first stage the known conditions for related non-
fluorinated aryl azides [26] were used. The conditions of copper-catalyzed azide-alkyne
cycloaddition (CuAAC) reaction have been used in this case. There were catalytic quantity of
CuI (up to 20 molar %), sodium ascorbate (up to 40 %) and DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene) as a base (up to 1 eq.) were applied (Scheme 2, Table 1). It
should be noted that absence or decreasing the quantity of DBU or sodium ascorbate results in
decreasing the yield of target product and appearance of significant amount of side products,
for example, the products of homocoupling ([PhCC]2 in the case of 2) which may be isolated
after column chromatography with preparative yield (up to 18 %). The related situation is
observed at decreasing the quantity of sodium ascorbate. It should be noted that increase the
temperature results in partial azide reduction [27]. But anyway in this case the target
compounds were isolated only in moderate yields (36 - 42 %).
So the work concerning the searching for better conditions has been done using model
interaction of p-N3C6F4CO2Et with PhC≡CH (Table 1). It should be noted that typical
conditions of CuAAC reaction with CuSO4*5H2O [25] gave unsatisfactory results. Changing
the copper source and applying trivial base we established that using CuBr, Et3N in
dichloromethane instead of CuI, DBU in DMF allows to obtain the target compounds in higher
yields (up to 84 %, see Table 1). Furthermore, in the last case the isolation procedure is simpler
including only filtration. In the absence of the base the reaction is very slow (see Table 1). Thus
the found conditions should be used in CuAAC reactions with perfluorobenzoates.
Based on the results obtained the proposed mechanism is described in Scheme 3. In the first
stage of the catalytic cycle the base added deprotonate alkyne molecule in the presence of CuBr
resulting to acetylide A. Then the triazole B is formed in the course of [3+2]-cycloadditon
between activated ion A and the azide. At the next stage under protonation the target product
and catalytically active copper particle are formed.
Compounds 2-11 are white or yellowish powders soluble in common organic solvents
(CHCl3, Et2O, EtOAc, toluene), sparingly soluble in polar organic (EtOH, MeOH) and
insoluble in nonpolar solvents (hexane). The composition of compounds 2-11 was established
based on elemental analysis data, and structure was studied in gas phase by mass-spectrometry,
5

13
19
and in solution by multinuclear (1H, C, F) 1D NMR and IR spectroscopy (see Supporting
information, Figs. S1-S44).
According to mass-spectroscopy (electron ionization) the intensity of the molecular ion for
2-11 is low (up to 7 %). There are two main fragmentation ways including typical for esters
(sequential elimination of [OEt]+ and then CO) and also elimination of N2. All compounds have
common ions with m/z 176 ([C6F4CO]+) and 148 ([C6F4]+). Also ions 274
([OCH2(C2HN2)C6F4CO + H]+), 246 ([OCH2(C2HN2)C6F4 + H]+), 220 ([C6F4CO2Et - H]+) and
202 ([C6F3CO2Et]+) as typical may be found in several compounds, what corresponds to the
structure of 2-11.
In IR spectra (nujol) all compounds have common intensive band approximately at 1726-
1736 cm-1 corresponding to C=O vibration (for further details see Experimental part).
For compounds 2-11 the signals of protons of CO2CH2CH3 fragment (near 4.48 and 1.40
ppm, respectively) in the 1H NMR spectra are almost the similar. On contrary, the signals of C-
5 proton are significantly differed depending on the electron effects of the group R (Table 2).
There is an upfield shift for compounds with electron donating groups (δ= 7.62 ppm for 6,
R= n-C5H11) in comparison with compounds with electron withdrawing groups (δ= 8.43 ppm
19
for 5, R= CO2Et). The F NMR spectra of derivatives 2-11 are very similar and there are two
13
multiplets near -137.0 and -145.0 ppm. The C NMR spectra are similar for compounds 2-11
but the values of signals of C-5 and C-4 carbon atoms of triazole ring significantly differ
(Δ[δ(C-4) - δ(C-5)], Table 2) what reflects strong effect of electronic properties of substituents
on the chemical shifts, especially in the case of compounds 5 and 10. Furthermore, it is
necessary to stress out the downfield shift of the signals of C-5 carbon in comparison with
common ranges known for 1,4-substituted triazoles from the literature (118 - 130 vs. 106 - 127
ppm) [28] due to the presence of C6F4-ring. The 1,4-substitution in 2-11 is correlate with
13
known data concerning comparison these C NMR data and positive differences in chemical
shifts between C-4 and C-5 carbons (Table 2) [29].
It should be noted that, for example, in the case of phenylacetylene, reaction mixture
contains the signals only of one product, namely 2, without presence of possible C5-
regioisomer.
Anyway application of routine NMR techniques for determination of substitution of
triazoles (C-4 or C-5-substituted) is not evident. This problem has been solved for related 1-
benzyl-1,2,3-1H-triazoles by special NMR techniques (usually NOE [25b], heteronuclear
6

correlations [28b]), but using the same methods for 1-aryl-1,2,3-1H-triazoles, especially 1-
perfluorophenyl-1,2,3-1H-triazoles as in this work, is insufficient. To overcome these
difficulties new NMR way was elaborated. For example, under protonation [25f] by
trifluoroacetic acid added in equimolar quantity to the solution of 6 in CDCl3 it is possible to
observe NOE according to Scheme 4 (see Supporting Information, Figure S45).
Furthermore, this type of substitution is approved by single crystal X-ray analysis.
Molecular structure of compound 2 in the solid state was investigated by X-ray analysis (Figs.
1, 2, Table S1, Supporting Information). It should be noted that before this work there are no
known structures of substituted fluorine containing triazoles investigated by X-ray analysis.
Furthermore, there are only several structures of the related para substituted benzoic acids
containing triazolic cycle known nowadays [30].
It should be noted that in the solid state the molecule conformation is skewed, so that
carbonyl group and all three cycles, Ph-, p-C6F4- and triazolic ring, are not coplanar (torsion
angle C(3)-C(4)-C(7)-O(2) is -47.98o; C(17)-N(1)-C(1)-C(2) is -41.92o; C(16)-C(11)-C(18)-
C(17) is -14.81o).
In a crystal an intermolecular hydrogen bonding of C-H...O type between carbonyl oxygen
atom and proton of triazole cycle from another molecule is observed. This contact results in
ribbon-like packing in a crystal (Fig. 2).
In general such hydrogen bond may be regarded as a weak bonding with
electrostatic/dispersion forces nature [31]. It should be noted that this type of hydrogen bonds is
typical for proteins [32].
Compounds 2-11 are significantly stable and may be easily hydrolyzed to potassium salts
under action of KOH yielding corresponding carboxylates, for example 2a (Scheme 5,
Supporting Information, Figs. S46-48).
In general typical alkaline hydrolysis gave in high yield potassium salt which is suitable for
metal complex formation.
3. Conclusions
In this work a number of 4-(1,2,3-triazol-1-yl)tetrafluorobenzoates containing electron
donating or electron withdrawing substituents was obtained in moderate and good yields under
conditions of CuAAC. The ideal conditions include application of CuBr as a catalyst and
7

triethylamine as a base. Only one regioisomer (C-4) is obtained in this reaction. This approach
is highly tolerant to various substrates and reagents. The application of this methodology to the
synthesis of fluorine benzoates opens new perspectives to organic and coordination chemistry.
New NMR technique including in situ protonation of the triazolyl ring and subsequent NOE
was successfully applied for unequivocal establishment of C-4 substitution in 4-(1,2,3-triazol-
1-yl)-aryl derivatives.
4. Experimental part
4.1 General methods and remarks
All reactions were conducted in a dry argon atmosphere using standard Schlenk techniques.
1H (400.130 MHz), 13C (100.613 MHz) and 19F (376.498 MHz) spectra were recorded on
Bruker 400 or Agilent 400MR spectrometers at 298 K. Chemical shifts are given in ppm
13
relative to internal reference, Me4Si (1H and C NMR spectra), or external reference, CFCl3
(19F spectra). Elemental analyses were carried out by the Microanalytical Laboratory of the
Chemistry Department of the Moscow State University using Heraeus Vario Elementar
instrument. Mass spectra (EI-MS, 70 eV) were recorded on a quadropoule mass spectrometer
FINNIGAN MAT INCOS 50 with direct insertion; all assignments were made with reference to
the most abundant isotopes. IR spectra were recorded using Nicolet iS5 Fourier Transform IR
spectrometer, with resolution 4 cm-1, 32 scans. The samples were prepared as a mulls in Nujol
(high-boiling petroleum oil). Mulls were prepared by thoroughly grinding 2-5 mg of a solid in a
smooth agate mortar. Grinding continued after the addition of 1 or 2 drops of the mulling oil.
The mull was examined as a thin film between flat ZnSe plates. The hydrocarbon bands not
interfered with the spectra.
The solvents were dried using common procedures. DMF, ethanol, MeCN, CH2Cl2 and
CDCl3 were refluxed and distilled over CaH2 under argon atmosphere. K2CO3 was dried before
using.
Sodium ascorbate, copper(I) iodide, copper(I) bromide, pentafluorobenzoic acid, SOCl2,
EtOC(O)Cl, PhC≡CH, HOCMe2C≡CH, HOCH2C≡CH, HC≡CCO2Et, n-C5H11C≡CH, t-Bu-p-
C6H4C≡CH, BrCH2C≡CH (80 % in toluene), p-HOC6H4NHBoc, p-HOC6H4CH2OH were
commercially available (“Sigma-Aldrich”) compounds. Copper salts were used without
additional purification. Usually liquid alkynes were distilled before synthesis.
8

HC≡CCH2-o-OC6H4CHO [33] was obtained using known procedure.
4.2. Syntheses
4.2.1. Ethyl pentafluorobenzoate, C6F5CO2Et. Method 1. At 0oC SOCl2 (45.00 ml, 380.00
mmol) was added dropwise to the solution of pentafluorobenzoic acid (20.00 g, 94.31 mmol) in
EtOH (130 ml). Reaction mixture was warmed to room temperature and refluxed for 12 h. All
volatile materials were removed under reduced pressure, the residue was dissolved in ethyl
acetate, washed with water and saturated solution of aq. NaHCO3, water, and dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure. C6F5CO2Et was isolated
o
as a colorless liquid. Yield 19.93 g (88%), b.p. 112-113 oC (20 mm Hg). Method 2. At -78 C
the solution of C6F5MgBr in ether (prepared from C6F5Br (15.60 g, 65.00 mmol), Mg (1.50 g,
62.50 mmol) in ether (200 ml) [20]) was added dropwise to the solution of EtOC(O)Cl (7.30 g,
67.00 mmol) in ether (80 ml). The reaction mixture was warmed to the room temperature,
stirred for 6 h, treated at 0oC with 10% aq. HCl, extracted with ether (3 x 20 ml), dried over
1
anhydrous MgSO4. The pure substance was obtained after distillation. Yield 6.65 g (44 %). H
3
3
NMR (400.130 MHz, CDCl3): δ= 4.43 (q, JH,H= 7.2 Hz, 2H, OCH2), 1.38 (t, JH,H= 7.2 Hz,
3H, CH3) ppm. 13C NMR (100.613 MHz, CDCl3): δ= 14.0 (CH3), 62.9 (OCH2), 108.6-109.5 m,
136.2-136.4 m, 138.8-139.1 m, 143.7-144.1 m, 146.5-146.7 m (aromatic carbons), 159.0 (C=O)
ppm. 19F NMR (376.498 MHz, CDCl3): δ= -138.77 to –139.88 (m, 2F), -150.37 (tt, 3JF,F= 20.7
4
Hz, JF,F= 4.6 Hz, 1F), -161.77 to -161.93 (m, 2F) ppm. IR (nujol): ν= 2990 (m), 1742 (s)
(C=O), 1510 (s), 1235 (s) cm-1. Elemental analysis calc. for C9H5F5O2: C 45.02, H 2.10. Found:
C 45.14, H 2.17.
4.2.2. Ethyl 4-azido-2,3,5,6-tetrafluorobenzoate, p-N3C6F4CO2Et (1). Sodium azide (0.80 g,
12.30 mmol) was added to the mixture of C6F5CO2Et (2.80 g, 11.70 mmol), acetone (20 ml)
and water (10 ml). The reaction mixture was refluxed for 8 h under stirring, cooled to room
temperature, partially evaporated, extracted with ether (3 x 20 ml), dried over anhydrous
MgSO4. All volatile materials were removed in vacuum giving the target product as yellowish
1
3
solid (3.00 g, 93 %). H NMR (400.130 MHz, CDCl3): δ= 4.40 (q, JH,H= 7.2 Hz, 2H, OCH2),
3
13
1.37 (t, JH,H= 7.2 Hz, 3H, CH3) ppm. C NMR (100.613 MHz, CDCl3): δ= 14.0 (CH3), 62.6
(OCH2), 107.9-108.2 m, 122.9-123.2 m, 139.1-139.3 m, 141.5-141.8 m, 143.8-144.0 m, 146.3-
19
146.6 m (aromatic carbons), 159.2 (C=O) ppm. F NMR (376.498 MHz, CDCl3): δ= -139.13
to –139.22 (m, 2F), -151.17 to -151.25 (m, 2F) ppm. IR (nujol): ν= 2990 (m), 2048 (m) (N3),
1738 (s) (C=O), 1504 (s), 1235 (s) cm-1. Elemental analysis calc. for C9H5F4N3O2: C 41.08, H
1.92, N 15.97. Found: C 41.24, H 1.98, N 15.73.
9

4.2.3. tert-Butyl-[4-(prop-2-yn-1-yloxy)phenyl]carbamate, HC≡CCH2-p-OC6H4NHBoc. The
mixture of p-HOC6H4NHBoc (2.00 g, 9.65 mmol, 1.0 eq.), K2CO3 (2.00 g, 14.47 mmol, 1.5
eq.) and DMF (30 mL) was stirred at room temperature for 30 min. Then solution of
HC≡CCH2Br (80 % solution in toluene, 1.7 mL, 14.47 mmol, 1.5 eq.) was added dropwise.
After 7 h (TLC control, ethyl acetate/petroleum ether= 1:2, Rf = 0.5) the mixture was filtered,
diluted with aq. saturated solution of NH4Cl (40 mL). Ethyl acetate (50 mL) was added, and
then organic phase was thoroughly washed with aq. saturated solution of NaCl (5x 20 mL),
dried over Mg SO4 and evaporated. The residue was recrystallized from ethanol giving the
o
target compound as a white substance (1.86 g. 78 %), m.p. 78-79 C. 1H NMR (400.130 MHz,
CDCl3): δ= 7.28-7.25 (br m, 2H, aromatic protons), 6.93-6.88 (m, 2H, aromatic protons), 6.42
4
4
(br s, 1H, NH), 4.63 (d, JH,H= 2.4 Hz, 2H, OCH2), 2.49 (t, JH,H= 2.4 Hz, 1H, ≡CH), 1.49 (s,
13
9H, C(CH3)3) ppm. C NMR (100.613 MHz, CDCl3): δ= 153.5, 153.1, 132.3, 120.4, 115.4
(C=O, aromatic carbons), 89.2 (CMe3), 78.6 (≡C), 75.4 (≡CH), 56.2 (OCH2), 28.3 (CMe3) ppm.
Elemental analysis calc. for C14H17NO3 (Mw 247.2897): C 68.00, H 6.93, N 5.66. Found: C
68.12, H 7.08, N 5.54.
4.2.4. [4-(Prop-2-yn-1-yloxy)phenyl]methanol, HC≡CCH2-p-OC6H4CH2OH. The mixture of
p-HOC6H4CH2OH (2.50 g, 20.14 mmol, 1.0 eq.), K2CO3 (4.17 g, 30.21 mmol, 1.5 eq.) and
MeCN (30 mL) was stirred at room temperature for 30 min. Then solution of HC≡CCH2Br (80
% solution in toluene, 2.0 mL, 22.15 mmol, 1.1 eq.) was added dropwise. Reaction mixture was
stirred at 50 oC for 40 h (TLC control, ethyl acetate/petroleum ether= 1:1, Rf = 0.5) the mixture
was filtered and evaporated. The residue was treated with hexane and stored at -20 oC resulting
o
1
in orange crystals (2.91 g. 89 %), m.p. 29-30 C. H NMR (400.130 MHz, CDCl3): δ= 7.30,
6.96 (2d, 3JH,H= 7.8 Hz, each 2H, aromatic protons), 4.71 (d, 4JH,H= 2.4 Hz, 2H, OCH2C≡), 4.59
2
(s, 2H, HOCH2), 2.64 (br s, 1H, OH), 2.42 (t, JH,H= 2.4 Hz, 1H, ≡CH) ppm. 13C NMR
(100.613 MHz, CDCl3): δ= 156.9, 133.9, 128.4, 114.8 (aromatic carbons), 78.4 (≡C), 75.5
(≡CH), 64.6 (CH2OH), 55.7 (OCH2C≡) ppm. Elemental analysis calc. for C10H10O2 (Mw
162.1852): C 74.06, H 6.21. Found: C 74.24, H 6.33.
4.2.5. Prop-2-yn-1-yl pentafluorobenzoate, C6F5C(O)OCH2C≡CH. A) Synthesis of
pentafluorobenzoyl chloride, C6F5CO2Cl. Solid C6F5CO2H (5.00 g, 23.58 mmol) was added
portionwise to SOCl2 (20 mL, 274.19 mmol) at room temperature and then was refluxed for 3
h. All volatile materials were removed under reduced pressure resulting to yellowish low
melting glassy solid, C6F5CO2Cl (5.42 g, >99 %). The substance was pure and used without
19
further purification. F NMR (376.498 MHz, CDCl3): δ= -135.64 to –135.68 (m, 1F), -137.38
10

to -137.48 (m, 1F), -143.33 to -144.94 (m, 1F), -158.84 to -159.05 (m, 2F) ppm. B) Synthesis of
C6F5C(O)OCH2C≡CH. At 0oC the solution of HOCH2C≡CH (1.65 mL, 28.20 mmol), Et3N
(3.45 mL, 24.76 mmol) in CH2Cl2 (10 mL) was added dropwise to the solution of C6F5CO2Cl
(5.42 g, 23.51 mmol) in CH2Cl2 (30 mL). Reaction mixture was warmed to room temperature
and stirred overnight. Then water (30 mL) was added, organic phase was separated, aq. phase
was extracted with CH2Cl2 (2x 20 mL). Combined organic phases were washed with water
(2x20 mL), dried (MgSO4) and evaporated under reduced pressure. After recrystallization from
methanol C6F5C(O)OCH2C≡CH (3.77 g, 64 %) was isolated as a white low melting substance,
1
4
m.p. 36oC. H NMR (400.130 MHz, CDCl3): δ= 4.95 (d, JH,H= 2.4 Hz, 2H, OCH2), 2.56 (t,
13
4JH,H= 2.4 Hz, 1H, ≡CH) ppm. C NMR (100.613 MHz, CDCl3): δ= 158.3 (C=O), 146.96-
146.79 m, 144.33-144.20 m, 142.54-141.94 m, 139.16-138.83 m, 136.51-136.30 m, 107.38-
107.16 m (aromatic carbons), 77.8 (≡C), 76.1 (≡CH) ppm. One aromatic carbon did not found.
19F NMR (376.498 MHz, CDCl3): δ= -137.45 to –137.57 (m, 2F), -147.58 to -147.71 (m, 1F), -
160.13 to -160.29 (m, 2F) ppm. Elemental analysis calc. for C10H3F5O2 (Mw 250.1216): C
48.02, H 1.21. Found: C 48.37, H 1.41.
4.2.6. General procedure for the synthesis of the click chemistry products
Procedure A. Under argon atmosphere at 0oC DBU (0.30 mL, 2.00 mmol, 1.0 eq.) was
added dropwise to a mixture of sodium ascorbate (0.16 g, 0.80 mmol, 0.4 eq.), p-N3C6F4CO2Et
(0.53 g, 2.00 mmol, 1.0 eq.), copper (I) iodide (0.08 g, 0.40 mmol, 0.2 eq.) and corresponding
acetylene (3.00 mmol, 1.5 eq.) in DMF (20 mL). Reaction mixture was slowly warmed to room
temperature and stirred (TLC control, ethyl acetate/petroleum ether = 1:1, usually 2-4 h). Water
was added, extraction with CH2Cl2 (3x15 mL) is performed, combined organic phases were
thoroughly washed with water (3x15 mL), dried over anhydrous MgSO4 and refluxed with
charcoal. After filtration volatile materials were removed under reduced pressure and the
residue was recrystallized.
Procedure B. Triethylamine (1.00 mL, 7.17 mmol, 3.6 eq.) was added to the solution of p-
N3C6F4CO2Et (0.53 g, 2.00 mmol, 1.0 eq.), copper (I) bromide (0.0144 g, 0.10 mmol, 5 mol %)
and corresponding acetylene (2.10 mmol, 1.05 eq.) in dry CH2Cl2 (10 mL). Then (TLC control,
ethyl acetate/petroleum ether = 1:3, usually 4-6 h) reaction mixture was filtered, evaporated and
recrystallized from ethanol.
4.2.6.1. Synthesis of ethyl 2,3,5,6-tetrafluoro-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoate, 4-
Ph(C2HN3)-p-C6F4CO2Et (2). White powder after recrystallization from ethanol/petroleum
11

ether mixture (1:1), m.p. 186 oC. Procedure A: yield: 0.30 g (40 %). Procedure B: yield: 0.62 g
1
(84 %). H NMR (400.130 MHz, CDCl3): δ= 8.12 (s, 1H, CH), 7.92-7.88 (m, 2H, aromatic
protons), 7.48-7.42 (m, 2H, aromatic protons), 7.40-7.35 (m, 1H, aromatic protons), 4.49 (q,
3
3
13
2H, JH,H =7.1 Hz, OCH2), 1.42 (t, 3H, JH,H =7.1 Hz, CH3) ppm. C NMR (100.613 MHz,
CDCl3): δ= 158.5 (C=O), 148.4 (br s, CN), 146.2-146.1 m, 143.6-143.5 m, 142.6-142.4 m,
140.1-139.9 m, 119.0-118.8 m, 113.96 (t, 2J13C,19F= 16.1 Hz) (C6F4), 129.1, 128.9, 128.8, 125.9
(aromatic carbons), 121.8 (br s, CHN), 63.3 (OCH2), 13.0 (CH3) ppm. 19F NMR (376.498
MHz, CDCl3): δ= -137.09 to –137.21 (m, 2F), -145.04 to -145.12 (m, 2F) ppm. IR (nujol): ν=
2985 (w), 1736 (s) (C=O), 1477 (s), 1282 (m), 988 (m) cm-1. EIMS, 70 eV, m/z (rel. int.): 365
(1) [M]+, 337 (100) [M - N2]+, 309 (58) [M - N2 – C2H4]+, 292 (11) [M – CO2Et]+, 264 (19) [M
– CO2Et – N2]+, 176 (11) [C6F4CO]+, 148 (15) [C6F4]+, 116 (88) [PhC2HN]+, 89 (56), 63 (14),
29 (28). Anal. Calcd for С17H11F4N3O2 (Mw 365.2818): С, 55.90; H, 3.04; N, 11.50 %. Found:
C, 55.97; H, 3.12; N, 11.17 %.
4.2.6.2. Synthesis of ethyl 2,3,5,6-tetrafluoro-4[4-(1-hydroxy-1-methylethyl)-1H-1,2,3-
triazol-1-yl]benzoate, 4-HOCMe2(C2HN3)-p-C6F4CO2Et (3). White powder after
o
recrystallization from ethyl acetate/hexane, m.p. 113-114 C. Procedure A: yield: 0.29 g (42
%). Procedure B: yield: 0.46 g (67 %). 1H NMR (400.130 MHz, CDCl3): δ= 7.82 (s, 1H, CH),
3
3
4.47 (q, 2H, JH,H =7.1 Hz, OCH2), 2.69 (br s, 1H, OH), 1.70 (s, 6H, 2CH3), 1.41 (t, 3H, JH,H
13
=7.1 Hz, CH3) ppm. C NMR (100.613 MHz, CDCl3): δ= 158.5 (C=O), 156.2 (CN), 146.2-
146.1 m, 143.7-143.5 m, 142.8-142.6 m, 140.2-140.0 m, 119.2-118.8 m, 114.2-113.9 m (C6F4),
19
121.6 (CHN), 68.7 (COH), 63.3 (OCH2), 30.4 (2CH3), 14.0 (CH3) ppm. F NMR (376.498
MHz, CDCl3): δ= -137.25 to –137.37 (m, 2F), -145.15 to -145.25 (m, 2F) ppm. IR (nujol): ν=
3380 (s) (OH), 2980 (m), 1732 (s) (C=O), 1477 (s), 1282 (m), 1236 (m) cm-1. EIMS, 70 eV,
m/z (rel. int.): 347 (1) [M]+, 330 (1) [M - OH]+, 319 (2) [M - N2]+, 303 (100) [M – N2 - OH]+,
274 (40) [M – CO2Et]+, 261 (7) [M - N2 – Me2CO + H]+, 248 (8) [HCNC6F4CO2Et]+, 228 (11)
[Me2C3HNC6F4]+, 202 (9) [C6F3CO2Et]+, 176 (9) [C6F4CO]+, 148 (15) [C6F4]+, 84 (8), 59 (22),
29 (18). Anal. Calcd for С14H13F4N3O3 (Mw 347.2649): С, 48.42; H, 3.77; N, 12.10 %. Found:
C, 47.99; H, 3.76; N, 12.22 %.
4.2.6.3. Synthesis of ethyl 2,3,5,6-tetrafluoro-4[4-(hydroxymethyl)-1H-1,2,3-triazol-1-
yl]benzoate, 4-HOCH2(C2HN3)-p-C6F4CO2Et (4). Yellowish crystals after recrystallization
o
from i-propanol, m.p. 75-76 C. Procedure A: yield: 0.23 g (36 %). Procedure B: yield: 0.47 g
1
(74 %). H NMR (400.130 MHz, CDCl3): δ= 7.94 (s, 1H, CH), 4.89 (s, 2H,CH2OH), 4.47 (q,
2H, 3JH,H =7.1 Hz, OCH2), 3.38 (br s, 1H, OH), 1.40 (t, 3H, 3JH,H =7.1 Hz, CH3) ppm. 13C NMR
12

(100.613 MHz, CDCl3): δ= 158.5 (C=O), 151.3 (CN), 146.2-146.1 m, 143.6-143.5 m, 142.8-
142.5 m, 140.2-139.9 m, 124.4-124.1 m, 114.4-114.0 m (C6F4), 118.8 (CHN), 63.3 (OCH2),
19
56.1 (CH2OH), 14.0 (CH3) ppm. F NMR (376.498 MHz, CDCl3): δ= -137.25 to –137.37 (m,
2F), -145.15 to -145.25 (m, 2F) ppm. IR (nujol): ν= 3378 (s) (OH), 2982 (m), 1736 (s) (C=O),
1475 (s), 1277 (m), 977 (m) cm-1. EIMS, 70 eV, m/z (rel. int.): 319 (2) [M]+, 302 (1) [M -
OH]+, 288 (50) [M – CH2O]+, 274 (94) [M – OEt]+, 261 (50) [M – CH2O – N2 + H]+, 246 (68)
[M – CO2Et]+, 220 (38) [C6F4CO2Et - H]+, 202 (25) [C6F3CO2Et]+, 176 (36) [C6F4CO]+, 163
(19) [C6F4N]+, 148 (59) [C6F4]+, 29 (100). Anal. Calcd for С12H9F4N3O3 (Mw 319.2118): С,
45.15; H, 2.84; N, 13.16 %. Found: C, 44.89; H, 2.74; N, 12.82 %.
4.2.6.4. Synthesis of ethyl 1-[4-(ethoxycarbonyl)-2,3,5,6-tetrafluorophenyl]-1H-1,2,3-
triazol-4-carboxylate, 4-EtO2C(C2HN3)-p-C6F4CO2Et (5). White powder after recrystallization
from ethanol/hexane, m.p. 107-108 oC. Procedure A: yield: 0.30 g (42 %). Procedure B: yield:
1
0.61 g (86 %). H NMR (400.130 MHz, CDCl3): δ= 8.43 (s, 1H, CH), 4.52-4.45 (m, 4H,
13
2OCH2), 1.45-1.40 (m, 6H, 2CH3) ppm. C NMR (100.613 MHz, CDCl3): δ= 159.8, 158.3
(2C=O), 146.3-146.1 m, 143.6-143.5 m, 142.8-142.6 m, 140.2-140.0 m, 118.2-118.1 m, 115.1
19
m (C6F4), 140.8 (CN), 129.8 (CHN), 63.5, 61.9 (2OCH2), 14.3, 14.0 (2CH3) ppm. F NMR
(376.498 MHz, CDCl3): δ= -136.61 to –136.73 (m, 2F), -144.77 to -144.89 (m, 2F) ppm. IR
(nujol): ν= 2988 (m), 1736 (s) (C=O), 1732 (s) (C=O), 1472 (s), 1244 (m) cm-1. EIMS, 70 eV,
m/z (rel. int.): 361 (1) [M]+, 316 (12) [M - OEt]+, 288 (50) [M – CO2Et]+, 243 (64) [M – CO2Et
- OEt]+, 220 (38) [C6F4CO2Et - H]+, 215 (100) [M – 2CO2Et]+, 202 (14) [C6F3CO2Et]+, 176
(18) [C6F4CO]+, 148 (48) [C6F4]+, 29 (76). Anal. Calcd for С14H11F4N3O3 (Mw 361.2485): С,
46.55; H, 3.07; N, 11.63 %. Found: C, 46.32; H, 2.94; N, 11.36 %.
4.2.6.5. Synthesis of ethyl 2,3,5,6-tetrafluoro-4-(4-pentyl-1H-1,2,3-triazol-1-yl)benzoate, 4-
(n-C5H11)(C2HN3)-p-C6F4CO2Et (6). White powder after recrystallization from ethanol/hexane,
o
1
m.p. 53 C. Procedure A: yield: 0.26 g (36 %). Procedure B: yield: 0.56 g (78 %). H NMR
(400.130 MHz, CDCl3): δ= 7.62 (s, 1H, CH), 4.48 (q, 3JH,H = 7.1 Hz, 2H, OCH2), 2.82 (t, 3JH,H
= 7.7 Hz, 2H, CH2), 1.78-1.71 (m, 2H, CH2), 1.42 (t, 3JH,H = 7.1 Hz, 3H, OCH2CH3), 1.38-1.32
13
(m, 4H, 2CH2), 0.92-0.86 (m, 3H, CH3) ppm. C NMR (100.613 MHz, CDCl3): δ= 158.6
(C=O), 149.1 (CN), 146.3-146.1 m, 143.7-143.5 m, 142.8-142.4 m, 140.3-139.9 m, 113.9-
113.8 m, 107.4 m (C6F4), 122.7 (CHN), 63.3 (OCH2), 31.4, 28.8, 25.4, 22.4 (4CH2), 14.0, 13.9
19
(2CH3) ppm. F NMR (376.498 MHz, CDCl3): δ= -137.49 to –137.60 (m, 2F), -145.40 to -
145.50 (m, 2F) ppm. IR (nujol): ν= 3071 (w), 2927 (m), 1738 (s) (C=O), 1480 (s), 1313 (s),
991 (s) cm-1. EIMS, 70 eV, m/z (rel. int.): 359 (1) [M]+, 330 (3) [M – C2H4]+, 314 (18) [M -
13

OEt]+, 286 (19) [M – CO2Et]+, 273 (75) [M – 3C2H4]+, 258 (19) [M – CO2Et – C2H4]+, 246 (90)
[M – 4C2H4]+, 229 (23) [M – CO2Et – 2C2H4]+, 220 (23) [C6F4CO2Et - H]+, 202 (49)
[C6F3CO2Et]+, 176 (56) [C6F4CO]+, 148 (46) [C6F4]+, 41 (100), 29 (58). Anal. Calcd for
С16H17F4N3O2 (Mw 359.3187): С, 53.48; H, 4.77; N, 11.69 %. Found: C, 53.54; H, 5.26; N,
11.87 %.
4.2.6.6. Synthesis of ethyl 2,3,5,6-tetrafluoro-4-(4-[(2-formylphenoxy)methyl]-1H-1,2,3-
triazol-1-yl)benzoate, 4-(OHC-o-C6H4OCH2)(C2HN3)-p-C6F4CO2Et (7). Light yellow powder
o
1
after recrystallization from ethanol, m.p. 126 C. Yield: 0.63 g (74 %). H NMR (400.130
MHz, CDCl3): δ= 10.47 (s, 1H, CHO), 8.27 (s, 1H, CH), 7.81 (d, 3JH,H = 7.6 Hz, 1H, aromatic
3
protons), 7.59-7.55, 7.20-.7.17 (2m, each 1H, aromatic protons), 7.07 (t, JH,H = 7.6 Hz, 1H,
3
aromatic protons), 5.43 (br s, 2H, OCH2Ar), 4.47 (q, JH,H = 7.1 Hz, 2H, OCH2CH3), 1.40 (t,
3JH,H = 7.1 Hz, 3H, OCH2CH3) ppm. 13C NMR (100.613 MHz, CDCl3): δ= 189.2 (CHO), 160.0
(aromatic carbon), 158.4 (CO2Et), 154.3 (CN), 146.2-146.0 m, 144.1-143.5 m, 142.7-142.5 m,
140.1-139.9 m, 119.4-119.1 m, 114.5-114.2 m (C6F4), 135.9, 129.0 (aromatic carbons), 125.2
(br, CHN), 121.6, 112.87 (aromatic carbons), 63.3 (OCH2CH3), 62.0 (OCH2Ar), 14.0 (CH3)
19
ppm. One aromatic carbon signal was not found due to overlap with other signals. F NMR
(376.498 MHz, CDCl3): δ= -136.95 to –137.03 (m, 2F), -144.96 to -145.05 (m, 2F) ppm. IR
(nujol): ν= 3146 (w), 2969 (m), 1730 (s) (C=O), 1684 (s) (HC=O), 1597 (m), 1489 (s), 1289
(m), 1234 (m), 985 (s) cm-1. EIMS, 70 eV, m/z (rel. int.): 423 (6) [M]+, 394 (5) [M - CHO]+,
366 (9) [M – CHO – C2H4]+, 274 (100) [M – OEt – C6H4CHO + H]+, 246 (65) [M – CO2Et –
C6H4CHO + H]+, 228 (28) [M – CO2Et – OC6H4CHO - H]+, 202 (63) [C6F3CO2Et]+, 176 (40)
[C6F4CO]+, 148 (47) [C6F4]+, 122 (79) [OC6H4CHO + H]+, 93 (17) [OC6H4 + H]+, 29 (88).
Anal. Calcd for С19H13F4N3O4 (Mw 423.3178): С, 53.91; H, 3.10; N, 9.93 %. Found: C, 54.23;
H, 3.18; N, 9.76 %.
4.2.6.7. Synthesis of ethyl 4-(4-[(4-N-Boc-aminophenoxy)methyl]-1H-1,2,3-triazol-1-yl)-
2,3,5,6-tetrafluorobenzoate, 4-(BocNH-p-C6H4OCH2)(C2HN3)-p-C6F4CO2Et (8). Yellowish
powder after recrystallization from ethanol, m.p. 168 oC. Procedure B. Yield: 0.84 g (85 %). 1H
NMR (400.130 MHz, CDCl3): δ= 8.12 (br s, 1H, CH), 7.28, 6.93 (2d, 3JH,H = 8.3 Hz, each 2H,
3
aromatic protons), 6.43 (br s, 1H, NH), 5.27 (br s, 2H, OCH2Ar), 4.48 (q, JH,H = 7.1 Hz, 2H,
3
13
OCH2CH3), 1.49 (s, 9H, OCMe3), 1.42 (t, JH,H = 7.1 Hz, 3H, OCH2CH3) ppm. C NMR
(100.613 MHz, CDCl3): δ= 158.4 (CO2Et), 153.8 (CN), 153.0 (NCO), 146.2-146.0 m, 143.6-
2
143.4 m, 142.7-142.5 m, 140.1-139.9 m, 119.1-118.8 m, 114.1 (t, J13C,19F= 16.8 Hz) (C6F4),
132.3, 120.4, 115.2 (aromatic carbons), 125.7 (br, CHN), 80.2 (OCMe3), 63.3 (OCH2CH3),
14

62.0 (OCH2Ar), 28.2 (OCMe3), 13.9 (CH3) ppm. One aromatic carbon signal was not found.
19F NMR (376.498 MHz, CDCl3): δ= -137.09 to –137.18 (m, 2F), -144.96 to -145.05 (m, 2F)
ppm. IR (nujol): ν= 3370 (w), 2987 (w), 1736 (s) (C=O), 1692 (NC=O) (s), 1523 (s), 1496 (s),
1295 (m), 1227 (s), 1165 (m), 995 (s) cm-1. EIMS, 70 eV, m/z (rel. int.): 510 (2) [M]+, 454 (4)
[M – N2 – C2H4]+, 381 (2) [M – OEt – CO2 – Me3C + H]+, 274 (15) [M – OEt – BocNHC6H4 +
H]+, 246 (13) [M – CO2Et – BocNHC6H4 + H]+, 220 (7) [C6F4CO2Et - H]+, 202 (25)
[C6F3CO2Et]+, 176 (11) [C6F4CO]+, 148 (100) [C6F4]+, 109 (29) [OC6H4NH2]+, 57 (84), 29
(24). Anal. Calcd for С23H22F4N4O5 (Mw 510.4382): С, 54.12; H, 4.34; N, 10.98 %. Found: C,
54.36; H, 4.16; N, 11.23 %.
4.2.6.8. Synthesis of ethyl 2,3,5,6-tetrafluoro-4-(4-{[4-(hydroxymethyl)phenoxy]methyl}-1H-
1,2,3-triazol-1-yl)benzoate, 4-(HOCH2-p-C6H4OCH2)(C2HN3)-p-C6F4CO2Et (9). Yellow
powder after recrystallization from ethanol, m.p. 109 oC. Procedure B. Yield: 0.74 g (87 %). 1H
NMR (400.130 MHz, CDCl3): δ= 8.06 (br s, 1H, CH), 7.30, 6.99 (2d, 3JH,H = 8.1 Hz, each 2H,
3
aromatic protons), 5.30 (br s, 2H, OCH2Ar), 4.66 (br s, 2H, CH2OH), 4.49 (q, JH,H = 7.1 Hz,
3
13
2H, OCH2CH3), 1.80 (br s, 1H, OH), 1.42 (t, JH,H = 7.1 Hz, 3H, OCH2CH3) ppm. C NMR
(100.613 MHz, CDCl3): δ= 158.5 (CO2Et), 157.5 (CN), 153.6 (aromatic carbon), 146.2-146.0
m, 143.7-143.5 m, 142.7-142.5 m, 140.1-139.9 m, 119.2-118.9 m, 114.3 (t, 2J13C,19F= 16.6 Hz)
(C6F4), 134.2, 128.2, 114.8 (aromatic carbons), 130.2 (br, CHN), 64.8 (CH2OH), 63.4
(OCH2CH3), 61.6 (OCH2Ar), 14.0 (CH3) ppm. 19F NMR (376.498 MHz, CDCl3): δ= -137.05 to
–137.13 (m, 2F), -145.01 to -145.10 (m, 2F) ppm. IR (nujol): ν= 3298 (w), 3107 (w), 2919 (w),
1730 (s) (C=O), 1495 (s), 1294 (m), 1236 (s), 1022 (m), 990 (s) cm-1. EIMS, 70 eV, m/z (rel.
int.): 425 (7) [M]+, 366 (11) [M – CHO – C2H4 + H]+, 274 (35) [M – OEt – HOCH2C6H4 + H]+,
246 (35) [M – CO2Et – HOCH2C6H4 + H]+, 228 (6) [CH(C2N3H)C6F4 - H]+, 220 (10)
[C6F4CO2Et - H]+, 202 (36) [C6F3CO2Et]+, 176 (21) [C6F4CO]+, 148 (25) [C6F4]+, 124 (100)
[HOCH2C6H4OH]+, 106 (26) [C6H4CHO]+, 77 (20), 29 (60). Anal. Calcd for С19H15F4N3O4
(Mw 425.3337): С, 53.65; H, 3.55; N, 9.88 %. Found: C, 53.32; H, 3.46; N, 9.64 %.
4.2.6.9. Synthesis of {1-[4-(ethoxycarbonyl)-2,3,5,6-tetrafluorophenyl]-1H-1,2,3-triazol-4-
yl}methyl pentafluorobenzoate, 4-(C6F5C(O)OCH2)(C2HN3)-p-C6F4CO2Et (10). Light brown
o
powder after recrystallization from ethanol, m.p. 83 C. Procedure B. Yield: 0.78 g (76 %). 1H
3
NMR (400.130 MHz, CDCl3): δ= 8.15 (br s, 1H, CH), 5.63 (br s, 2H, OCH2), 4.48 (q, JH,H
=
7.1 Hz, 2H, OCH2CH3), 1.41 (t, 3JH,H = 7.1 Hz, 3H, OCH2CH3) ppm. 13C NMR (100.613 MHz,
CDCl3): δ= 158.9 (CO2Et), 158.6 (CO2CH2), 144.8 (CN), 146.3-146.0 m, 143.7-143.4 m,
142.7-142.5 m, 140.2-139.9 m, 118.9-118.6 m, 114.5 (t, 2J13C,19F= 16.8 Hz) (C6F4), 147.0-146.8
15

m, 144.4-144.2 m, 139.1-138.7 m, 136.6-136.2 m, 107.5-107.1 m (C6F5), 127.3-126.7 m
(CHN), 63.4 (OCH2CH3), 59.0 (OCH2), 14.0 (CH3) ppm. 19F NMR (376.498 MHz, CDCl3): δ=
-137.01 to –137.10 (m, 2F), -145.13 to -145.22 (m, 2F) (C6F4), -137.47 to –137.55 (m, 2F), -
147.33 to –147.44 (m, 1F), -159.98 to –160.12 (m, 2F) ppm. IR (nujol): ν= 3135 (w), 2991 (w),
1735 (s) (C=O), 1493 (s), 1303 (m), 1219 (s), 993 (s) cm-1. EIMS, 70 eV, m/z (rel. int.): 468 (1)
[M – OEt]+, 274 (26) [M – OEt –C6F5CO + H]+, 246 (21) [M – CO2Et – C6F5CO + H]+, 228 (4)
[CH(C2N3H)C6F4 - H]+, 220 (4) [C6F4CO2Et - H]+, 202 (11) [C6F3CO2Et]+, 195 (100)
[C6F5CO]+, 176 (11) [C6F4CO]+, 167 (22) [C6F5]+, 148 (65) [C6F4]+, 55 (26), 29 (23). Anal.
Calcd for С19H8F9N3O4 (Mw 513.2701): С, 44.46; H, 1.57; N, 8.19 %. Found: C, 44.08; H,
1.32; N, 8.53 %.
4.2.6.10. Synthesis of ethyl 4[4[(4-tert-butylphenyl)-1H-1,2,3-triazol-4-yl]-2,3,5,6-
tetrafluorobenzoate, 4-(p-(t-Bu)C6H4)(C2HN3)-p-C6F4CO2Et (11). Yellowish powder after
o
1
recrystallization from ethanol, m.p. 91 C. Procedure B. Yield: 0.66 g (78 %). H NMR
3
(400.130 MHz, CDCl3): δ= 8.09 (s, 1H, CH), 7.83, 7.49 (2d, JH,H= 8.2 Hz, each 2H, aromatic
protons), 4.49 (q, 3JH,H = 7.1 Hz, 2H, OCH2CH3), 1.41 (t, 3JH,H = 7.1 Hz, 3H, OCH2CH3), 1.35
13
(s, 9H, t-Bu) ppm. C NMR (100.613 MHz, CDCl3): δ= 158.6 (CO2Et), 152.2, 125.9, 125.8,
126.3 (aromatic carbons), 148.3 (CN), 146.3-146.1 m, 143.8-143.6 m, 142.7-142.5 m, 140.2-
2
139.9 m, 119.0-118.9 m, 114.0 (t, J13C,19F= 16.6 Hz) (C6F4), 121.1 (CHN), 63.3 (OCH2CH3),
37.7 (CMe3), 31.2 (CMe3), 14.0 (CH3) ppm. 19F NMR (376.498 MHz, CDCl3): δ= -137.21 to –
137.34 (m, 2F), -145.04 to -145.16 (m, 2F) ppm. IR (nujol): ν= 3155 (w), 2964 (w), 2871 (w),
1726 (s) (C=O), 1489 (s), 1313 (m), 1233 (m), 1025 (m), 988 (s) cm-1. EIMS, 70 eV, m/z (rel.
int.): 421 (1) [M]+, 393 (46) [M - N2]+, 376 (100) [M - OEt]+, 348 (23) [M – CO2Et]+, 320 (9)
[M - N2 – CO2Et]+, 176 (10) [C6F4CO]+, 148 (7) [C6F4]+, 115 (28) [PhC2N]+, 91 (25), 29 (49).
Anal. Calcd for С21H19F4N3O2 (Mw 421.3881): С, 59.86; H, 4.54; N, 9.97 %. Found: C, 60.12;
H, 4.42; N, 9.83 %.
4.2.7. Synthesis of potassium 2,3,5,6-tetrafluoro-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoate,
4-Ph(C2HN3)-p-C6F4CO2K (2a). Solution of KOH (0.05 g, 0.89 mmol) in dry EtOH (20 mL)
was added dropwise to the solution of compound 2 (0.34 g, 0.92 mmol) in dry EtOH (20 mL).
Reaction mixture was refluxed for 4 h, concentrated in twice, filtered off and washed with
1
toluene. Compound 2a was isolated as a white powder. Yield: 0.28 g (84 %). H NMR
(400.130 MHz, D2O): δ= 8.48 (s, 1H, CH), 7.74-7.67 (m, 2H, aromatic protons), 7.45-7.38 (m,
13
2H, aromatic protons), 7.36-7.32 (m, 1H, aromatic protons) ppm. C NMR (100.613 MHz,
D2O): δ= 161.9 (C=O), 151.4 (CPh), 149.4 m, 147.5 m, 144.2 m, 141.4 m, 115.5 m, 109.3 m
16

(C6F4), 129.0, 128.3, 125.6 (aromatic carbons), 124.0 (CHN) ppm. One carbon signal was not
19
found. F NMR (376.498 MHz, D2O): δ= -142.27 to –142.40 (m, 2F), -147.02 to -147.10 (m,
2F) ppm. IR (nujol): ν= 2955 (s), 2865 (s), 1568 (m), 1407 (s) cm-1. Anal. Calcd for
С15H6F4KN3O2 (Mw 375.3190): С, 48.00; H, 1.61; N, 11.20 %. Found: C, 48.27; H, 1.71; N,
11.07 %.
4.3. X-ray diffraction studies
Intensity data for 2 were measured on a Bruker SMART APEX II diffractometer (graphite
monochromatized MoK radiation, = 0.71073 Å) using -scan mode. The structure was
solved by direct methods and refined by full matrix least-squares on F2 with anisotropic
thermal parameters for all non-hydrogen atoms [34]. All H atoms were found from difference
Fourier synthesis and refined isotropically. Details of X-ray experiment are given in Table S1
(Supporting Information).
Crystallographic data have been deposited at the Cambridge Crystallographic Data Center as
supplementary publication (CCDC-1448752) containing the supplementary crystallographic
data.
The
data
can
be
obtained
free
of
charge
via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk.
Acknowledgments
The authors are grateful to the RFBR (project 13-03-12453) for partial financial support.
This work was supported in part by M.V. Lomonosov Moscow State University Program of
Development. X-ray diffraction studies were performed at the Centre of Shared Equipment of
IGIC RAS.
Supplementary Material
Supplementary data associated with this article (NMR spectra for compounds obtained,
crystalloraphic data) can be found in the online version.
17

References and notes
[1] W. Tong, Y. Zhang, Q. Zhang, X. Luan, F. Lv, L. Liu, Q. An, Adv. Funct. Mater. 25 (2015)
7029-7037.
[2] a) G. Schmid, J. H. Wemken, A. Maltenberger, C. Diez, A. Jaeger, T. Dobbertin, O.
Hietsoi, C. Dubceac, M. A. Petrukhina, Adv. Mater. 26 (2014) 878-885;
b) L.-J. Han, Y.-J. Kong, N. Sheng, X.-L. Jiang, J. Fluorine Chem. 166 (2014) 122-126.
[3] X. He, P. Zhang, J.-B. Lin, H. V. Huynh, S. E. Navarro Muñoz, C.-C. Ling, T.
Baumgartner, Org. Lett. 15 (2013) 5322-5325.
[4] a) H. Amii, K. Uneyama, Chem. Rev. 109 (2009) 2119-2183;
b) M. L. Tang, A. D. Reichardt, N. Miyaki, R. M. Stoltenberg, Z. Bao, J. Am. Chem. Soc. 130
(2008) 6064-6065;
c) A. Gangjee, H. D. Jain, J. Phan, X. Guo, S. F. Queener, R. L. Kisliuk, Bioorg. Med. Chem.
18 (2010) 953-961.
[5] a) J. Tang, L. M. Wang, D. Mao, W. B. Wang, L. Zhang, S. Y. Wu, Y. S. Xie, Tetrahedron
67 (2011) 8465-8469;
b) D. Mao, J. Tang, W. Wang, S. Wu, X. Liu, J. Yu, L. Wang, J. Org. Chem. 78 (2013) 12848-
12854.
[6] a) J. E. Moses, A. D. Moorhouse, Chem. Soc. Rev. 36 (2007) 1249-1262;
b) K. Kempe, A. Krieg, C. R. Becer, U. S. Schubert, Chem. Soc. Rev. 41 (2012) 176-191.
[7] a) M. S. Costa, N. Boechat, É. A. Rangel, F. d. C. da Silva, A. M. T. de Souza, C. R.
Rodrigues, H. C. Castro, I. N. Junior, M. C. S. Lourenço, S. M. S. V. Wardell, V. F.
Ferreira, Bioorg. Med. Chem. 14 (2006) 8644-8653;
b) A. K. Jordão, P. C. Sathler, V. F. Ferreira, V. R. Campos, M. C. B. V. de Souza, H. C.
Castro, A. Lannes, A. Lourenco, C. R. Rodrigues, M. L. Bello, M. C. S. Lourenco, G. S.
L. Carvalho, M. C. B. Almeida, A. C. Cunha, Bioorg. Med. Chem. 19 (2011) 5605-5611;
c) T. Yempala, J. P. Sridevi, P. Yogeeswari, D. Sriram, S. Kantevari, Eur. J. Med. Chem. 71
(2014) 160-167.
[8] a) R. Alvarez, S. Velazquez, A. San-Felix, S. Aquaro, E. D. Clercq, C.-F. Perno, A.
Karlsson, J. Balzarini, M. J. Camarasa, J. Med. Chem. 37 (1994) 4185-4194;
b) F. d. C. da Silva, M. C. B. V. de Souza, I. I. P. Frugulhetti, H. C. Castro, S. L. d. O.
Souza, T. M. L. de Souza, D. Q. Rodrigues, A. M. T. Souza, P. A. Abreu, F. Passamani, C.
R. Rodrigues, V. F. Ferreira, Eur. J. Med. Chem. 44 (2009) 373-383.
18

[9] J. L. Kelley, C. S. Koble, R. G. Davis, E. W. McLean, F. E. Soroko, B. R. Cooper, J. Med.
Chem. 38 (1995) 4131-4134.
[10] a) H. Elamari, R. Slimi, G. G. Chabot, L. Quentin, D. Scherman, C. Girard, Eur. J. Med.
Chem.60 (2013) 360-364;
b) K. Lal, C. P. Kaushik, K. Kumar, A. Kumar, A. K. Qazi, A. Hamid, S. Jaglan, Med.
Chem. Res. 23 (2014) 4761-4770.
[11] B. S. Holla, M. Mahalinga, M. S. Karthikeyan, B. Poojary, P. M. Akberali, N. S. Kumari,
Eur. J. Med. Chem. 40 (2005) 1173-1178.
[12] L. S. Kallander, Q. Lu, W. Chen, T. Tomaszek, G. Yang, D. Tew, T. D. Meek, G. A.
Hofmann, C. K. Schulz-Pritchard, W. W. Smith, C. A. Janson, M. D. Ryan, G.-F. Zhang,
K. O. Johanson, R. B. Kirkpatrick, T. F. Ho, P. W. Fisher, M. R. Mattern, R. K. Johnson,
M. J. Hansbury, J. D. Winkler, K. W. Ward, D. F. Veber, S. K. Thompson, J. Med. Chem.
48 (2005) 5644-5647.
[13] C. Nagamani, C. Versek, M. Thorn, M. T. Tuominen, S. Thayumanavan, J. Polym. Sci.,
Part A: Polym. Chem. 48 (2010) 1851-1858.
[14] a) V. Haridas, K. Lal, Y. K. Sharma, Tetrahedron Lett. 48 (2007) 4719-4722;
b) Z. A. Li, G. Yu, P. Hu, C. Ye, Y. Liu, J. Qin, Z. Li, Macromolecules 42 (2009) 1589-
1596.
[15] a) H. Gallardo, F. Ely, A. J. Bortoluzzi, G. Conte, Liq. Cryst. 32 (2005) 667-671;
b) S. Balamurugan, G.-Y. Yeap, W. A. K. Mahmood, Liq. Cryst. 41 (2014) 776-783.
[16] S. Xie, S. A. Lopez, O. Ramström, M. Yan, K. N. Houk, J. Am. Chem. Soc. 137 (2015)
2958-2966.
[17] a) R. E. Banks, A. Prakash, J. Chem. Soc., Perkin Trans. 1 (1974) 1365-1371;
b) J. Wu, D. Fu, S. Cao, J. Fluorine Chem. 168 (2014) 230-235;
c) C. Liu, H. Wang, X. Xing, Y. Xu, J.-A. Ma, B. Zhang, Tetrahedron Lett. 54 (2013)
4649-4652;
d) L. Qin, C. Sheridan, J. Gao, Org. Lett. 14 (2012) 528-531;
e) L. Cao, C. Liu, X. Tang, X. Yin, B. Zhang, Tetrahedron Lett. 55 (2014) 5033-5037.
[18] H. Chen, B.-B. Ni, F. Gao, Y. Ma, Green Chem. 14 (2012) 2703-2705.
[19] a) C. Pérez Medina, C. López, R. M. Claramunt, J. Elguero, Eur. J. Org. Chem. (2010)
890-899;
b) J. Kim, D. Hong, S. Jeong, B. Kong, S. M. Kang, Y.-G. Kim, I. S. Choi, Chem. –Asian
J. 6 (2011) 363-366.
19

[20] K. V. Zaitsev, A. A. Kapranov, A. V. Churakov, O. K. Poleshchuk, Y. F. Oprunenko, B.
N. Tarasevich, G. S. Zaitseva, S. S. Karlov, Organometallics 32 (2013) 6500-6510.
[21] M. M. Kremlev, W. Tyrra, D. Naumann, Y. L. Yagupolskii, J. Fluorine Chem. 126 (2005)
1327-1331.
[22] a) J. M. Birchall, R. N. Haszeldine, M. E. Jones, J. Chem. Soc. C: Org. (1971) 1343-1348;
b) J. F. W. Keana, S. X. Cai, J. Org. Chem. 55 (1990) 3640-3647;
c) K. A. H. Chehade, H. P. Spielmann, J. Org. Chem. 65 (2000) 4949-4953.
[23] a) R. Menegatti, A. C. Cunha, V. t. F. Ferreira, E. F. R. Perreira, A. El-Nabawi, A. T.
Eldefrawi, E. X. Albuquerque, G. Neves, S. M. K. Rates, C. A. M. Fraga, E. J. Barreiro,
Bioorg. Med. Chem. 11 (2003) 4807-4813;
b) K. Dabak, Ö. Sezer, A. Akar, O. Anaç, Eur. J. Med. Chem. 38 (2003) 215-218.
[24] a) R. Huisgen, Angew. Chem., Int. Ed. Engl. 2 (1963) 633-645;
b) M. Damodiran, D. Muralidharan, P. T. Perumal, Bioorg. Med. Chem. Lett. 19 (2009)
3611-3614.
[25] a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem., Int. Ed. 40 (2001) 2004-2021;
b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem., Int. Ed. 41
(2002) 2596-2599;
c) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 67 (2002) 3057-3064;
d) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharpless, V. V.
Fokin, J. Am. Chem. Soc. 127 (2005) 210-216;
e) S. Bräse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem., Int. Ed. 44 (2005) 5188-
5240;
f) B. Schulze, U. S. Schubert, Chem. Soc. Rev. 43 (2014) 2522-2571.
[26] M. Xu, C. Kuang, Z. Wang, Q. Yang, Y. Jiang, Synthesis (2011) 223-228.
[27] Y. Xia, W. Li, F. Qu, Z. Fan, X. Liu, C. Berro, E. Rauzy, L. Peng, Org. Biomol. Chem. 5
(2007) 1695-1701.
[28] a) X. Creary, A. Anderson, C. Brophy, F. Crowell, Z. Funk, J. Org. Chem. 77 (2012)
8756-8761;
b) M. Corredor, J. Bujons, A. Messeguer, I. Alfonso, Org. Biomol. Chem. 11 (2013) 7318-
7325.
[29] A. Marra, A. Vecchi, C. Chiappe, B. Melai, A. Dondoni, J. Org. Chem. 73 (2008) 2458-
2461.
[30] a) D. H. A. Ishak, H. A. Tajuddin, Z. Abdullah, S. N. Abd Halim, E. R. T. Tiekink, Acta
Crystallogr., Sect. E 67 (2011) o1658;
20

b) B. Sureshbabu, R. Venkatachalam, S. Sankararaman, CrystEngComm 16 (2014) 6098-
6106.
[31] a) T. Steiner, Angew. Chem., Int. Ed. 41 (2002) 48-76;
b) G. R. Desiraju, Acc. Chem. Res. 35 (2002) 565-573.
[32] S. Scheiner, Phys. Chem. Chem. Phys. 13 (2011) 13860-13872.
[33] R. Rohlmann, C.-G. Daniliuc, O. G. Mancheno, Chem. Commun. 49 (2013) 11665-11667.
[34] G. M. Sheldrick, Acta Crystallogr., Sect. A 64 (2008) 112-122.
21

Fig. 1. Molecular structure of compound 2. Displacement ellipsoids are shown at 50 %
probability level. Selected bond lengths (Å) and angles (deg): N(1)-C(17) 1.3531(18), N(1)-
N(2) 1.3677(16), N(1)-C(1) 1.4176(17), N(2)-N(3) 1.2994(17), N(3)-C(18) 1.3708(18), F-Cav
1.3389(15); N(3)-N(2)-N(1) 106.43(11).
22

Fig. 2. Packing of molecules of 2 in a crystal. Hydrogen bonding in 2. Displacement ellipsoids
are shown at 50 % probability level. Selected bond lengths (Å) and angles (deg): C(17)-H(17)
0.946(16), H(17)...O(2) 2.383(17), C(17)...O(2) 3.2711(18); C(17)-H(17)...O(2) 156.1(13).
23

Scheme 1. Synthesis of C6F5CO2Et and 4-N3C4F4CO2Et (1).
24

Scheme 2. Synthesis of compounds 2-6.
25

Scheme 3. Proposed mechanism for CuAAC in the case of 4-azidotetrafluorobenzoates.
26

Scheme 4. NOE in protonated triazole 6.
27

Scheme 5. Alkaline hydrolysis of compound 2. Synthesis of potassium salt 2a.
28

Table 1. Conditions for CuAAC in the case of ethyl 4-azido-tetraflurobenoate.
Copper system
Base
DBU
Et3N
-
Conversion/timea (yield, %)
CuI, sodium ascorbate, DMF
CuI, sodium ascorbate, DMF
CuI, sodium ascorbate, DMF
CuI, DMF
>98/2 (40)
>98/4 (44)
traces/40
26/40
DBU
Et3N
CuI, DMF
30/40
CuSO4*5H2O,
sodium
ascorbate, -
12/40
H2O:t-BuOH
CuBr, CH2Cl2
CuBr, CH2Cl2
-
traces/40
Et3N
>98/4 (84)
aAccording to 19F NMR, isolated yield in parentheses
29