Substituted 1-(isoxazol-3-yl)methyl-1H-1,2,3-triazoles: Synthesis, palladium(II) complexes, and high-turnover catalysis in aqueous media

Article abstract of DOI:10.1016/j.tet.2018.05.016

New substituted 3-((1H-1,2,3-triazol-1-yl)methyl)-5-arylisoxazoles (aryl = Ph, p-Tol) and 2-(5-phenylisoxazol-3-yl)-5-(2-(1-((5-(p-tolyl)isoxazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-1,3,4-oxadiazole were synthesized by means of click-chemistry proce

Full text of DOI:10.1016/j.tet.2018.05.016

Accepted Manuscript
Substituted 1-(isoxazol-3-yl)methyl-1H-1,2,3-triazoles: Synthesis, palladium(II)
complexes, and high-turnover catalysis in aqueous media
Nikolay A. Bumagin, Alexey V. Kletskov, Sergey K. Petkevich, Irina A. Kolesnik,
Alexander S. Lyakhov, Ludmila S. Ivashkevich, Alexander V. Baranovsky, Peter V.
Kurman, Vladimir I. Potkin
PII:
S0040-4020(18)30531-3
10.1016/j.tet.2018.05.016
TET 29523
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 February 2018
Revised Date: 28 April 2018
Accepted Date: 4 May 2018
Please cite this article as: Bumagin NA, Kletskov AV, Petkevich SK, Kolesnik IA, Lyakhov AS,
Ivashkevich LS, Baranovsky AV, Kurman PV, Potkin VI, Substituted 1-(isoxazol-3-yl)methyl-1H-1,2,3-
triazoles: Synthesis, palladium(II) complexes, and high-turnover catalysis in aqueous media,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.016.
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Substituted 1-(isoxazol-3-yl)methyl-1H-1,2,3-
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Nikolay A. Bumagina, , Alexey V. Kletskovb, Sergey K. Petkevichb, Irina A. Kolesnikb, Alexander S.
Lyakhovc, Ludmila S. Ivashkevichc, Alexander V. Baranovskyd, Peter V. Kurmand and Vladimir I. Potkinb,

1
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Tetrahedron
journal homepage: www.elsevier.com
Substituted 1-(isoxazol-3-yl)methyl-1H-1,2,3-triazoles: synthesis, palladium(II)
complexes, and high-turnover catalysis in aqueous media
N.A. Bumagin,[a]* A.V. Kletskov,[b] S.K. Petkevich,[b] I.A. Kolesnik,[b] A.S. Lyakhov,[c] L.S.
Ivashkevich,[c] A.V. Baranovsky[d], P.V. Kurman[d] and V.I. Potkin[b]*
a M.V. Lomonosov Moscow State University, Chemical Department, Leninskie Gory, 1/3, Moscow 119991, Russian Federation
b Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova Str., 13, Minsk 220072, Belarus
c Research Institute for Physical Chemical Problems of Belarusian State University, Leningradskaya Str., 14, Minsk 220006, Belarus
d Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Academician V.F. Kuprevich Str., 5/2, Minsk, 222141, Belarus
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
New substituted 3-((1H-1,2,3-triazol-1-yl)methyl)-5-arylisoxazoles (aryl = Ph, p-Tol) and 2-(5-
phenylisoxazol-3-yl)-5-(2-(1-((5-(p-tolyl)isoxazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-
1,3,4-oxadiazole were synthesized by means of click-chemistry procedures. The obtained
compounds were used as ligands in preparation of palladium(II) complexes, and the latter
proved to be high-turnover-number catalysts for C–C cross-coupling reactions under Green
Chemistry conditions. One of the ligands was structurally characterized by single crystal X-ray
Available online
1
diffraction, and the structure of complexes was determined by H, 13C, 15N NMR spectroscopy
Keywords:
Ligand design
Palladium
and quantum-chemical modeling.
2018 Elsevier Ltd. All rights reserved.
Isoxazole
1,2,3-Triazole
Catalysis
Cross-coupling
1. Introduction
low Pd loading (0.0001–0.1 %) in neat water under air
atmosphere.3 It is reasonable to assume that the combination of
The isoxazole and 1,2,3-triazole chemistry arouse
considerable interest in recent years primarily due to the unique
diversity of their biological and pharmacological properties.
Isoxazole and 1,2,3-triazole heterocycles are structural
fragments of a large number of the bioactive molecules used in
medicine as anti-cancer, antiviral, antibacterial, anti-
inflammatory, anti-tubercular agents, etc.1 It has been found
over the last decades that both isoxazoles and triazoles can be
successfully used as ligands for the synthesis of palladium
complexes, demonstrating high catalytic activity in cross-
coupling reactions.2 The structure and functional surrounding of
the heterocycle in ligand molecule significantly affect its
complexation, as well as the stability and catalytic activity of
the complex.
the isoxazole and triazole heterocycles in the ligand structure
can increase the catalytic activity of palladium complexes.
Indeed, the triazole moiety contains effective coordination N-
centers and readily forms complexes with transition metals.2b
Moreover, the isoxazole and triazole rings differ in their
electronic structure and donating capability, which will allow
stabilizing both the Pd(0) and Pd(+2) species formed during the
catalytic cycle in cross-coupling reaction. Recently, we have
synthesized 5-(p-tolyl)isoxazol-3-(3-methyl-1Н-1,2,4-triazol-5-
yl)isoxazole ligand and its complex with PdCl2, and have
shown that catalytic activity of the latter is similar to that of the
aminoisoxazole complex in Suzuki-Miyaura reaction in
aqueous media under air but with Pd loading as low as 0.1 %.4
In continuation of our studies of catalysts for cross-coupling
reactions5 and development of methods for the 1,2-azole
synthesis,6 in the present work we report the synthesis of
During our previous investigations, we have synthesized the
air
and
moisture
stable
complex,
square-planar
containing
trans-
5-(p-
dichloropalladium(II)
a
isoxazole-1,2,3-triazole ligands with
a methylene bridge
tolyl)isoxazol-3-amine ligand, which proved to be a high-
turnover-number catalyst for Suzuki-Miyaura reaction with a
———
between the heterocycles. The basicity values of the 1,2,3- and
1,2,4-triazoles (pKB 1.17 and 2.19, respectively) differ by
Corresponding author. bna51@mail.ru (N.A. Bumagin).
Corresponding author. potkin@ifoch.bas-net.by (V.I. Potkin).

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2
Tetrahedron
almost an order of magnitude, which certainly affects the opportunities in palladium catalysis.2b In addition, the
stabilization of the complexes.7 Furthermore, the flexibility of
the nitrogen coordination of 1,2,3-triazoles provides additional
methylene bridge between the heterocyclic fragments gives the
ligand similarity to the well-studied 1-(2-picolyl)-1H-1,2,3-
Scheme 1. Preparation of 3-((1H-1,2,3-triazol-1-yl)methyl)-5-arylisoxazole derivatives 11–16.
triazole ligand, which forms stable complexes with transition
metals (Pd, Pt, Cu, etc.).8 With this background in mind, we
NaN3 on the 3-(chloromethyl)-5-arylisoxazoles 7,8. The
synthesis of azidomethylisoxazoles 9,10 was carried out in
prepared new substituted 3-((1H-1,2,3-triazol-1-yl)methyl)-5- DMF solution at 40 °C giving the products in quantitative yield.
arylisoxazoles 11–16 (Scheme 1) (aryl = Ph, p-Tol) and 2-(5-
phenylisoxazol-3-yl)-5-(2-(1-((5-(p-tolyl)isoxazol-3-yl)methyl)
-1H-1,2,3-triazol-4-yl)ethyl)-1,3,4-oxadiazole 20 (Scheme 2).
Starting 5-arylisoxazoles 7,8 were obtained via successive
transformation of available 5-arylisoxazole-3-carbaldehyde
oximes 1,2 into corresponding 5-arylisoxazole-3-carbaldehydes
3,4 and then 5-arylisoxazol-3-yl methanols 5,6.6b,11 The
obtained azidomethylisoxazoles 9,10 were introduced in the
reaction of 1,3-dipolar cycloaddition with different alkynes
(propargyl alcohol, 2-methylbut-3-yn-2-ol, phenylacetylene)
under classic conditions of the click-chemistry (CuSO4·5H2O,
sodium ascorbate, TBTA – tris[(1-benzyl-1H-1,2,3-triazol-4-
yl)methyl]amine, MeOH) and it resulted in isolation of
These ligands were reacted with Na2PdCl4 to give the
palladium(II) complexes L1PdCl2–L7PdCl2. Herein, we present
the detailed synthesis of the ligands and palladium(II)
complexes together with their characterization and catalytic
activity testing as new catalysts for C–C cross-coupling
reactions in neat water under ambient atmosphere. It is also
important to note that 3-((1H-1,2,3-triazol-1-yl)methyl)-5-
arylisoxazoles are of special interest for biological testing in
different domains, for example, as anti-cancer agents and
isosteres of 3-(aryl-1H-1,2,3-triazol-1-yl)benzisoxazole that
exhibit high anticancer activity in acute myeloid leukemia cell
lines.1b,9
corresponding
3-((1H-1,2,3-triazol-1-yl)methyl)-5-
arylisoxazoles 11-15 in high yields (91–99 %). Acylation of (1-
((5-phenylisoxazol-3-yl)methyl)-1H-1,2,3-triazol-4-
yl)methanol 11 with pivaloyl chloride, afforded (1-((5-
phenylisoxazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl
pivalate 16, which turned out to be useful for further NMR
studies of the Pd(II) complexes structure.
2. Results and Discussion
The 3-(azidomethyl)-5-(p-tolyl)isoxazole 10 was also
applied in the synthesis of the polycyclic derivative - 3-((1H-
1,2,3-triazol-1-yl)methyl)-5-arylisoxazole with several azole
heterocycles in one molecule 7. As alkyne co-reagent in the
click reaction with azidomethylisoxazole 10, 2-(but-3-yn-1-yl)-
5-(5-phenylisoxazol-3-yl)-1,3,4-oxadiazole 19 was used which
was synthesized from the previously described 3-(1Н-tetrazol-
5-yl)-5-phenylisoxazole 18.4 The tetrazole part of
isoxazolyltetrazole molecule 18 was transformed into butynyl-
1,3,4-oxadiazolic molecular fragment by selective recyclisation
of tetrazole heterocycle (Scheme 2).12 This was accomplished
2.1. Design and synthesis of ligands
Our synthetic strategy for the preparation of desired 3-((1H-
1,2,3-triazol-1-yl)methyl)-5-arylisoxazoles 11–16 and bis-
isoxazole-1,2,3-triazole-1,3,4-oxadiazole ligand 20 involved
the formation of the (1H-1,2,3-triazol-1-yl)methyl molecular
fragment in position 3 of the 5-arylisoxazoles by Cu(I)
catalyzed 1,3-dipolar cycloaddition (click reaction)10 of the
isoxazole azides with respective acetylene derivatives (Scheme
1). As azide components we chose 3-(azidomethyl)-5-
arylisoxazoles 9,10 which were synthesized by the action of

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3
Scheme 2. Preparation of bis-isoxazole-1,2,3-triazole-1,3,4-oxadiazole 20.
by treating isoxazolyltetrazole 18 with pent-4-ynoic acid in the
presence of DCC (N,N'-dicyclohexylcarbodiimide). The process
involved tetrazole acylation and elimination of nitrogen to form
2-butynyl-5-(5-phenylisoxazoyl)-1,3,4-oxadiazole 19 in 86 %
yield. The structures of synthesized isoxazolyl-1,2,3-triazoles 11-
16,
bis-isoxazolyl-1,2,3-triazole-1,3,4-oxadiazole
20,
azidomethylisoxazoles 9,10 and isoxazolyl-1,3,4-oxadiazole 19
1
were confirmed by IR, H and 13C NMR spectra as well as by
single crystal X-ray analysis of (1-((5-phenylisoxazol-3-
yl)methyl)-1H-1,2,3-triazol-4-yl)methanol 1. The obtained
isoxazole-1,2,3-triazoles 11–16 and bis-isoxazole-1,2,3-triazole-
1,3,4-oxadiazole 20 were used then as ligands (L1–L7) in the
synthesis of Pd(II) complexes L1PdCl2–L7PdCl2, aiming
evaluation of the latter catalytic activity in cross-coupling
reactions. They were synthesized by reaction of ligands with
Na2PdCl4 in methanol solutions. Addition of 0.025 M solution of
ligand (11–16, 20) in MeOH to a 0.1 M solution of sodium
tetrachloropalladate in methanol induced a quick disappearance
of a characteristic dark brown color of Na2PdCl4 and formation of
the complex precipitate. Complete consumption of the starting
ligands in the reaction mixture was observed within 5 min.
Figure 1. Molecular structure of 11, with the atom-numbering scheme
and displacement ellipsoids drawn at the 50 % probability level. The
hydrogen atoms are shown as spheres of arbitrary radii. Bond lengths in
heterorings: N1–N2
= 1.3345(16), N1–C5 = 1.3383(18), N2–N3 =
1.3138(17), N3–C4 = 1.3559(18), C4–C5 = 1.3639(19) Å; C7–N8 = 1.300(2),
C7–C11 = 1.405(2), N8–O9 = 1.4104(17), O9–C10 = 1.3512(18), C10–C11 =
1.342(2) Å.
Crystal data and structure refinement details for the compound
are gathered in Table 1. As follows from X-ray analysis of
compound 11, it crystallizes in the triclinic space group
P with
two formula units in the unit cell and one molecule in the
asymmetric unit (Figure 2).
The obtained palladium(II) complexes were identified by
elemental analysis and IR spectroscopy. According to elemental
analysis data, all complexes are of general formula LPdCl2.
Because the synthesized complexes were amorphous powders
with low solubility in organic solvents, we were not able to
perform their X-ray analysis and faced problems with registration
of NMR data and mass-spectra. Therefore, the structure
determination of complexes was based on the analysis of 2D
NMR (1H, 13C, 15N) and mass-spectra of the most soluble
complexes L1PdCl2 (L1 = (1-((5-phenylisoxazol-3-yl)methyl)-1H-
1,2,3-triazol-4-yl)methanol 11) and L6PdCl2 (L6 = (1-((5-
phenylisoxazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl
Table 1. Single crystal X-ray data and structure refinement details for 11.
Formula
Formula weight
Temperature [K]
Wavelength [Å]
Crystal system
Space group
a [Å]
C13H12N4O2
256.27
296(2)
0.71073
Triclinic
P
pivalate 16) as well as on the results of quantum-chemical
calculations of molecular geometry and vibrational frequencies
for L1PdCl2 followed by comparison of the calculated values of
frequencies with the experimental IR spectrum.
5.90940(10)
7.81760(10)
14.5953(3)
100.2381(9)
94.2600(11)
110.7872(11)
613.382(19)
b [Å]
2.2. Crystal structure of compound 11
c [Å]
α [°]
Single crystals of compound 11 suitable for X-ray analysis
were obtained by slow evaporation of acetone–chloroform (1:1
v/v) solution (Figure 1).
β [°]
γ [°]
V [Å3]

4
Tetrahedron
out a comparative study of two palladium(II) complexes and their
ACCEPTED MANUSCRIPT
Z
2
ligands by the correlation NMR spectroscopy methods in order to
dcalcd [g cm–3
]
1.388
estimate the most probable position of Pd and the ligand
coordination. As follows from a comparison of the H and 13C
1
µ [mm–1
]
0.098
NMR spectra of ligands L1, L6 and corresponding complexes
L1PdCl2 and L6PdCl2, the most significant changes in the
chemical shifts are observed for the triazole part of molecules (2–
3 ppm downfield in the 13C spectra and 0.2–0.3 ppm downfield in
Crystal size [mm]
Reflections collected
Independent reflections
Restraints
0.38 × 0.20 × 0.18
5770
1
the H spectra). Values of the chemical shifts of the isoxazole
5770 [R(int) = 0.0186]
residue signals change twice as less. This allowed us to assume
that the Pd is coordinated with the triazole molecular fragment.
Due to a low abundance of 15N, the chemical shifts of 15N nuclei
0
were determined by the use of the H-15N-HMBC method (see
1
Parameters
174
Figure 3).
Goodness-of-fit
R1 / wR2 [I > 2σ(I)]
R1 / wR2 [all data]
CCDC
1.020
H
H
H
H
H
H
H
H
0.0429 / 0.1063
0687 / 0.1213
1823325
240
N
242
N
Ph
Ph
OH
OPiv
N
N
364
N
N
N
N
355
361
O
O
372
372
11
16
H
H
H
H
H
H
H
H
244
N
246
N
Bond lengths and valence angles in heterocycles show usual
Ph
Ph
values. There are intermolecular hydrogen bonds in the crystal
structure of 11 (Table 2). Classic hydrogen bonds O19–
H19···N3a between the hydroxyl H and the 1,2,3-triazole ring N
atoms of neighboring molecules form centrosymmetric dimers,
linked together by non-classic hydrogen bonds C18-H18A···N2b
to give polymeric ribbons running along the a axis (Figure 2)
[symmetry codes (a) and (b) as in Table 2]. Only van der Waals
interactions take place between the ribbons.
N
N
354
OH
N
N
O
N
372
358
OPiv
O
N
373
Cl
228/248
Cl
235/253
Pd
Pd
Pd
Cl
Cl
Cl
Cl
Pd
N
Cl
H
Cl
N
N
H
N
N
O
N
O
N
Ph
N
Ph
OH
OPiv
H
H
H
H
H
H
L1PdCl2
L6PdCl2
Figure 3. 15N chemical shifts and the observed 15N-1H interactions in the
HMBC spectra of compounds 11, 16, L1PdCl2, L6PdCl2.
Table 2. Hydrogen bonds geometry (Å, deg) in the crystal structure of 11.
Such method allowed assigning three nitrogen nuclei of ligand
L1: N1 (cross-peaks with 5-H and CH2-group), N2 (cross-peak
with 5-H) of the triazole ring and N2’ of isoxazole ring (cross-
peaks with 4’-H and CH2-group). The signal of N3 atom of the
triazole ring was not found (expected cross-peak with HOCH2-
group13,14) despite the execution of several NMR experiments by
D–H···A
D–H
0.82
0.97
D···A
D–H···A)
170
O19-H19...N3a
C18-H18A...N2b
2.8308(16)
3.449(2)
164
Symmetry codes: (a) –x, 1–y, 1–z; (b) x+1, y, z.
1
varying of the H-15N coupling constant (1–8 Hz). This result
caused the exact coordination of Pd determination in the complex
less reliable. One of the reasons for the observed effect may be an
influence of the H-bonds OH···N3 of neighboring molecules, as it
was established by X-ray analysis (see Figure 2). To exclude the
effect of H-bonds, we acylated the OH group of ligand L1 with
pivaloyl chloride to prepare ester 16 (ligand L6) as was described
1
above. Indeed, in the H-15N-HMBC spectrum of pivalate 16 we
observed the signals of all four nitrogen atoms (N3 had a cross-
peak with the CH2OPiv group and resonated at 355 ppm).
Comparison of the spectra of the ligand L6 and the complex
L6PdCl2 unambiguously indicates the coordination of Pd with the
atom N3. While the signals of the rest complex nitrogens
resonated closely to those of ligand L6, the signal of N3 was
found almost 100 ppm upfield. The similar pattern of the 1H-15N-
HMBC spectrum was registered also for the complex L1PdCl2.
Such significant shielding influence on the nitrogen nuclei
coordinated with Pd was already shown for triazoles and other
16
nitrogen heterocycles.15, It should be noted that series of the
signals in H, 13C and 15N NMR spectra appear as couples with a
1
Figure 2. Fragment of hydrogen-bonded ribbon in the crystal structure of
11. Symmetry codes (a) and (b) as in Table 2.
close intensity. This may be due to the existence of complexes in
the form of bridge structures, with the possibility of rotation
around Pd–N3 bond and the formation of rotamer couples.
Another reason may be the existence of a complex as a mixture
of E,Z-isomers in the bridge fragment of the molecule. The ratio
of rotamers, as well as the ratio of isomers, should depend on the
2.3. NMR spectra of complexes L1PdCl2 and L6PdCl2
Along with X-ray analysis, NMR methods are powerful tools
for structure elucidation of organic complexes. We have carried

5
1
1
temperature. We recorded the H, 13C and H-15N-HMBC NMR
ACCEPTED MANUSCRIPT
spectra for the L6PdCl2 complex at 65 °C and found that the
signals ratio changed substantially and one of the rotamers (or
isomers) became predominant. It should be noted that after
cooling to room temperature, the signal ratio remains the same as
at 65 °C. This might indicate realization of the isomerization
process (Scheme 3). The correlation spectra give opportunity to
determinate proton/carbon signals of each rotamers (isomers) in
the triazole part of the complex molecules. Thus, the complexes
with the downfield N3 NMR signal (248 ppm - L1PdCl2 and 253
ppm - L6PdCl2) have downfield proton signals (5.33 and 5.78
ppm – CH2O, 8.50 and 8.73 ppm - Нtriazol for L1PdCl2 and
L6PdCl2 respectively). The resonances of the carbon nuclei
depend on the position of these nuclei in the molecule. For
example, the signals of CH2-group and Ctriazol carbons are upfield
(47.32, 57.69 and 145.12 ppm) whereas the CHtriazol signal is
observed in downfield (128.17 ppm) of the L6PdCl2 isomer with
253 ppm of the N3 NMR signal.
Figure 4. The optimized geometry of dimeric complex L1PdCl2.
Calculated vibrational frequencies appeared to be in good
agreement with experimental IR spectra of synthesized
compound L1PdCl2. Therefore, these data support the hypothesis
about a dimeric structure of the complex with coordination of
palladium atom by the triazole ring N3 atom. It should be noted
that we also modeled structural parameters for ligand L1 on the
same level of theory. The difference between calculated
geometrical parameters and parameters obtained through single
crystal X-Ray diffraction for substance 11 (L1) did not exceed
0.03Å for bond lengths and 3 degrees for angles. The only
significant difference that was observed is the conformational
position of isoxazole ring relatively to the triazole fragment.
Scheme 3. Principal scheme of dimeric complex isomerization.
2.4. Mass-spectometry of complexes L1PdCl2 and L6PdCl2
Table 3. Main experimental IR spectra bands and calculated vibrational frequencies
for complex L1PdCl2.
Our numerous attempts to perform a mass-spectrometric study
of the complexes were unsuccessful. The problem lays not only
in a low solubility of the complexes compounds, but it is
connected with their stability in the ESI-MS-experiment as well
as nature of the ligands. Nevertheless, we were able to observe
fragment ions of low intensity ([M - Cl-]+ for dimers) in the case
of the most soluble complexes [L1PdCl2]2 and [L6PdCl2]2 (Figure
1, SI). As shown in Figure 1 (SI), the fragment ions [M – Cl-]+ at
m/z 826-839 (830.942) for [L1PdCl2]2 and 994-1006 (998.988)
for [L6PdCl2]2 were detected. Moreover, peaks due to species
containing Pd were easily detected by the characteristic isotope
distribution of the metal [101.9Pd (1%), 103.9Pd (11.1%), 104.9Pd
(22.3%), 105.9Pd (27.3%), 107.9Pd (26.5%) and 109.9Pd (11.7%)].
Theoretical isotope patterns were calculated by MestReNova
program and used to help the assignment (file mass-spectra, SI).
Oscillation type (highest contribution)
Experimental
frequencies,
cm–1
Calculated
frequencies,
cm–1
δ(С-С)arom
492
494
δ(C-C, С-H)arom +δ(C-H)isox
688
686
δ(C-C, С-H)arom +δ(С-H)isox + δ(С-H)triaz
δ(С-H)isox + δ(С-H)triaz + δ(СH2)
δ(СH2) + δ(C-CH-C) isox + δ(O-H)
v(С-O)OH
764
765
797
786
950
952
1024
1050
1062
1095
1147
1250
1259
1340
1420
1455
1474
1504
1573
1591
1609
1027
1047
1054
1093
1146
1256
1272
1354
1444
1463
1475
1512
1561
1584
1603
v(C-O)OH + δ(N-N-N)triaz + δ(С-СH-N)triaz
δ(С-H)isox + v(С-O)isox + v(С-H)arom
δ(С-H)triaz + δ(N-NPd-C)triaz + v(C-C)triaz
δ(С-H)triaz + δ(N-N-CH)triaz + δ(СH2)
2.5. Quantum-chemical modeling of L1PdCl2 complex
Additionally, we compared experimental IR spectra of
synthesized complex L1PdCl2 with modeled vibrational spectra
for the complex of dimeric structure. Full geometry optimization
of the latter and its normal-mode vibrational frequencies
calculations were carried out at DFT level of theory, using
B3LYP117 functional in combination with Pople’s 6-31+G* basis
set18,19 for main-groups elements, and LANL2TZ(f) basis set with
corresponding effective core potential20 for palladium. All basis
sets were obtained through EMSL Basis Set Exchange Library.21
The applicability of this level of theory for modeling of some
1,2-azoles palladium complexes structures and their normal-
mode vibrational frequencies calculation was shown previously,6b
as well as the application of scale factors for analysis of obtained
frequencies.22 In the present work, we used a scale factor of
0.978. For calculations we used Firefly QC package.23 which is
partially based on the GAMESS (US)24 source code. The results
of the calculations were analyzed with the help of ChemCraft
package.25 Experimental frequencies for complex L1PdCl2 and
calculated vibrational frequencies are listed in Table 3, obtained
geometry for the dimeric complex is presented in Figure 3.
δ(С-H) arom + v(O-C)isox +v(С isox -Carom
v(NPd-N)triaz + δ(СH2) + δ(O-H)
δ(СH2)
)
δ(СH2) + v(СH-N)triaz
δ(С-H)arom + δ(С-H)isox + v(С-CH)isox
δ(С-H)arom + v(С-N)isox + v(С-CH)isox
v(С-N)isox + v(С-C)arom + δ(С-H)arom
δ(С-H)triaz + v(С-C)triaz
δ(С-H)arom + v(С-C)isox + v(С-С)arom
δ(С-H)arom + v(С-С)arom + v(С-C)isox

6
Tetrahedron
ACCEPTED MANUSCRIPT
2.6. Complexes in catalysis of cross-coupling reactions
100
1ꢀ103/4ꢀ103
16
17
18
19
L6PdCl2
20
15
<1
20
With synthesized water and air-stable complexes L1PdCl2 –
L7PdCl2 in hand, we further tested their catalytic activity in cross-
coupling reactions. Primarily, to test the activity of LPdCl2 for
the Suzuki-Miyaura reactions, the model reaction of 3-
bromobenzoic acid 21 with 4-methoxyphenylboronic acid 22 in
the presence of 0.1 mol % of LPdCl2 was studied under air
atmosphere (Scheme 4, Table 4). Water and aqueous methanol
were used as solvents and K2CO3 as a base for these reactions,
based on our previous results.3,5l
98
L6PdCl2
L7PdCl2
L7PdCl2
100
20
9.8ꢀ102/5.88ꢀ104
97
9.7ꢀ102/2.91ꢀ103
100
1ꢀ103/2ꢀ104
100
3
89
92
10
20
21
Na2PdCl4
Na2PdCl4
20
4 h
99
100
5
9.9ꢀ102/1.19ꢀ104
a Aryl halide (0.5 mmol), arylboronic acid (0.6 mmol), K2CO3 (1.25 mmol), 5
ml of solvent: H2O or H2O-MeOH (1:1).
b The experiments were performed in aqueous methanol solution at 20 and
75 °С or in water at 35 and 100 °С.
c 1H NMR yield with 1,1,2,2-tetrachloroethane (0.5 mmol) as internal
standard.
Scheme 4. Model Suzuki-Miyaura reaction: cross-coupling of 3-
bromobenzoic acid 21 with 4-methoxyphenylboronic acid 22 (0.1 mol % of
LPdCl2) yielding 4-methoxybiphenyl-3-carboxylic acid 23.
d Reaction with 3-iodobenzoic acid.
It should be noted that in the presence of the base, 3-
bromobenzoic acid was converted into the corresponding soluble
potassium benzoate and the reaction proceeded under
homogeneous conditions. We found that the reaction proceeded
smoothly at 20–35 °C in 10–15 min in a high yield without any
inert gas protection in the presence of tested complexes (Table 4,
entries 1, 3, 5, 10, 12, 14 and 16). At elevated temperatures (75–
100 °C), the reaction time did not exceed 1–4 min (entries 2, 4, 6,
11, 13, 15, 17 and 19). Much to our surprise, in all cases the
reaction proceeded without any apparent formation of Pd-black,
even after the complete conversion of the aryl halide. To
understand this phenomenon, we assumed that only a negligible
part of the original Pd(II) complex was reduced to the active
complex Pd(0) and participated in the catalytic cycle.
Consequently, if this assumption is correct, the reaction can be
carried out with a lower catalyst loading. Indeed, the amount of
catalyst can be reduced by an order of magnitude or more,
without appreciable decrease in activity. For example, in the
presence of 0.01–0.001 mol % of complex L2PdCl2, 3-
bromobenzoic acid reacted with 4-methoxyphenylboronic acid in
water at 100 °C in 4–5 min in quantitative yields with turnover
numbers (TON) up to 100,000 and turnover frequencies (TOF)
up to 1,200,000 h–1 (entries 7 and 8). In the case of aryl iodides,
the reaction was completed in less than 5 min with high yield in
the presence of 0.0001 mol % of catalyst (1 ppm level).
Remarkably high TON of 1,000,000 and TOF of 12,000,000 h–1
were achieved (entry 9). These results indicate that isoxazolyl-
1,2,3-triazole complexes L1PdCl2–L7PdCl2 are very effective and
high-turnover catalysts for Suzuki-Miyaura reaction in aqueous
media.
Table 4. Suzuki-Miyaura reaction of 3-bromobenzoic acid 21 with 4-
a
methoxyphenylboronic acid 22 in the presence of complexes LPdCl2 .
Yield,c %
TON/TOF, h-1
Entry
LPdCl2
Tb, °C
Time, min
99
1
2
3
4
5
6
L1PdCl2
L1PdCl2
L2PdCl2
L2PdCl2
L2PdCl2
L2PdCl2
20
15
9.9ꢀ102/3.96ꢀ103
100
1ꢀ103/3ꢀ104
100
20
2
100
1ꢀ103/4ꢀ103
15
2
100
1ꢀ103/3ꢀ104
75
100
1ꢀ103/6ꢀ103
35
10
2
100
1ꢀ103/3ꢀ104
100
L2PdCl2
100
7
100
100
100
4
5
5
1ꢀ104/1.5ꢀ105
0.01 mol %
L2PdCl2
100
1ꢀ105/1.2ꢀ106
8
0.001 mol %
L2PdCl2
100
1ꢀ106/1.2ꢀ107
9d
0.0001 mol %
98
10
11
12
13
14
L3PdCl2
L3PdCl2
L4PdCl2
L4PdCl2
L5PdCl2
20
15
2
9.8ꢀ102/3.92ꢀ103
On the other hand, the use of Na2PdCl4 as the catalyst in
aqueous methanol at room temperature afforded cross-coupling
product in 89 % yield in 10 min (Table 4, entry 20). However, at
this moment, the catalyst agglomerated completely into Pd-black.
After the formation of the Pd-black, the reaction almost stopped,
and within 4 h the yield increased to only 92 % (entry 20). At
elevated temperature, the cross-coupling product was formed
with a quantitative yield in 5 min (entry 21).
99
100
20
9.9ꢀ102/2.97ꢀ104
98
20
<1
15
9.8ꢀ102/2.94ꢀ103
100
1ꢀ103/6ꢀ104
100
35
100
1ꢀ103/4ꢀ103
The catalytic activity of LPdCl2 complexes was not limited to
Suzuki-Miyaura reactions. It can be readily extended to other
cross-coupling reactions such as Mizoroki-Heck26 and
Sonogashira27 reactions.
99
15
L5PdCl2
75
<1
9.9ꢀ102/5.94ꢀ104

7
We evaluated catalytic activity of some LPdCl2 complexes in
the Mizoroki–Heck reaction between m-iodobenzoic acid 24 and
acrylic acid 25 in the presence of K2CO3 under reflux in water to
give 3-carboxy-trans-cinnamic acid 26 (Scheme 5, Table 5).
cross-coupling products by separation of 2-MeTHF–water
ACCEPTED MANUSCRIPT
layers, then evaporation and full regeneration of 2-MeTHF. The
growing interest towards 2-MeTHF from both academia and
industries is also due to its abidance of Green Chemistry
principles.29
Table 6. Sonogashira reaction between methyl p-iodobenzoate 27 and prop-2-
a
yn-1-ol 28 in the presence of complexes LPdCl2
.
Yield,b %
TON/TOF, h-1
Entry
LPdCl2
Additives
PPh3
Time, min
97
1
2
3
L2PdCl2
L2PdCl2
L4PdCl2
15
10
15
9.7ꢀ102/3.88ꢀ103
Scheme 5. Model Mizoroki–Heck reaction: cross-coupling of m-
iodobenzoic acid 24 and acrylic acid 25.
–
23
PPh3
99
9.9ꢀ102/3.96ꢀ103
Table 5. Mizoroki–Heck reaction between m-iodobenzoic acid 24 and acrylic
a
acid 25 in the presence of complexes LPdCl2 .
PPh3
98
4
L6PdCl2
15
9.8ꢀ102/3.92ꢀ103
Yield,b%
TON/TOF, h-1
Entry
LPdCl2
Time, min
5
6
L6PdCl2
L7PdCl2
–
10
20
19
PPh3
96
L2PdCl2
L4PdCl2
L6PdCl2
L7PdCl2
30
30
30
40
99
1
2
3
4
9.9ꢀ102/1.98ꢀ103
a Aryl halide (0.5 mmol), prop-2-yn-1-ol (0.65 mmol), NEt3 (0.75 mmol),
1 mol % CuI, 5 mL of 2-MeTHF, 20 °С.
100
1ꢀ103/2ꢀ103
b 1H NMR yield with 1,1,2,2-tetrachloroethane (0.5 mmol) as internal
standard.
100
1ꢀ103/2ꢀ103
98
9.8ꢀ102/1.96ꢀ103
It is worthwhile noting that (PPh3)2PdCl2 afforded 29 in 82 % yield after a
prolonged reaction time (THF, 4 eq. of triethylamine, 1.5 mol % Pd-catalyst,
1.5 mol % CuI, 20 °C, overnight, argon).30
a Aryl halide (0.5 mmol), acrylic acid (0.6 mmol), K2CO3 (1.25 mmol), 5 mL
of H2O, 100 °С.
3. Conclusions
b 1H NMR yield with 1,1,2,2-tetrachloroethane (0.5 mmol) as internal
standard.
An efficient and convenient synthesis of new substituted 3-
((1H-1,2,3-triazol-1-yl)methyl)-5-arylisoxazoles (aryl = Ph, p-
Tol) and 2-(5-phenylisoxazol-3-yl)-5-(2-(1-((5-(p-tolyl)isoxazol-
3-yl)methyl)-1H-1,2,3-triazol-4-yl)eth-yl)-1,3,4-oxadiazole was
elaborated by means of click-chemistry procedures. The new
compounds served as ligands in preparation of water and air-
stable palladium(II) complexes. The obtained complexes
demonstrated high catalytic activity in the cross-coupling
reactions: 3-bromobenzoic acid with 4-methoxyphenylboronic
acid (Suzuki-Miyaura reaction), m-iodobenzoic acid with acrylic
acid (Mizoroki–Heck reaction) and methyl p-iodobenzoate with
propargyl alcohol (Sonogashira reaction). All reactions
proceeded in short time in water or environment friendly solvent
with quantitative yields of the target products. Currently, these
palladium complexes are being studied as precursors for the
development of effective homogeneous and reusable
heterogeneous catalysts for the synthesis of useful products in
environmentally safe conditions (Green Chemistry).
For all tested complexes, almost quantitative isolated yields of
26 were obtained in 30–40 min in air atmosphere. No by-
products were detected for any of the catalysts, and cinnamic acid
26 was isolated in pure form without the need of
chromatographic purification.
Finally, LPdCl2 complexes were assayed in the Sonogashira
reaction between methyl p-iodobenzoate 27 and prop-2-yn-1-ol
(propargyl alcohol) 28, to afford methyl 4-(3-hydroxyprop-1-yn-
1-yl)benzoate 29 (Scheme 6), under the conditions summarized
in Table 5 (2-methyltetrahydrofuran, 1.5 eq. of triethylamine as
base, 0.2 mol % LPdCl2 + 2PPh3, 1 mol % CuI, 20 °C, 15 min,
argon).
4. Experimental Section
Scheme 6. Model Sonogashira reaction: cross-coupling of p-iodobenzoate
27 and prop-2-yn-1-ol 28.
4.1. General Information
The IR spectra were recorded on a FTIR spectrometer
Protege-460 (Nicolet) in KBr pellets. 1H, 13C and 15N NMR
spectra were recorded on a Bruker Avance-500 spectrometer
operating at 500, 125, and 51 MHz for 1H, 13C and, 15N,
respectively. Chemical shifts are given on the δ scale (ppm) and
were determined relative to the residual solvent signal (δН 7.26
ppm, δС 77.2 ppm for CDCl3; δН 2.5 ppm, δС 40.1 -ppm for
DMSO-d6, δН 8.0 ppm, δС 162.5 ppm for DMF-d7). Nitrogen
chemical shift values for 15N NMR spectra were assigned relative
to the nitromethane used as an internal reference (δN 380.0 ppm).
Coupling constants (J) are given in Hertz. Assignments of proton
and carbon resonances were performed by standard 2D NMR
It is important to note that it was the use of an additional
phosphine ligand that provided a smooth reaction and a high
yield (Table 6, entries 1, 3, 4 and 6). In the absence of
triphenylphosphine, the reaction proceeded quickly but mainly
resulted in the formation of tar products of an unidentified
structure (entries 2 and 5). It is possible that without additives the
activity of the resulting palladium catalyst is so high that it
28
causes oligomerization of the acetylene compounds, both the
starting propargyl alcohol and the cross-coupling product. The
practical advantage of this protocol is the use of water-insoluble
2-MeTHF as a solvent, which provides convenient isolation of

8
Tetrahedron
techniques (1H,1H-COSY, HSQC, HMBC). Mass spectra were
214 (100) [M]+, 186 (15), 119 (97), 91 (79), 65 (31). Anal. Calcd
ACCEPTED MANUSCRIPT
recorded on an instrument Agilent 5975 inert MSD/6890N
Network GC System (EI ionisation at 70 eV), HP-5MS capillary
column 30 m × 0.25 mm, 5% PhMe Silicon stationary phase
(0.25 ꢁm), evaporator temperature 250 °С. Data are reported as
m/z (relative intensity in %). HPLC-MS studies were performed
using an Agilent 1200 liquid chromatograph with mass-selective
detector Agilent 6410 Triple Quad in Positive ESI mode.
Elemental analysis was performed on a Vario Micro cube CHNS-
analyser. The chlorine content was determined by classical
microanalysis according to the modified Pregl method.31 The
palladium content of complexes and residual palladium
contamination in target products was determined by atomic
absorption spectroscopy on a MGA-915 spectrometer. TLC was
performed on Merck Silica gel 60 F254 plates; the eluent was
hexane–Et2O, 2:1-1:3. Melting points were determined on
Boetius apparatus. All purchased chemicals were used as such.
for C11H10N4O: C 61.67; H 4.71; N 26.15. Found C 61.78; H
4.68; N 26.19.
4.5. General Procedure for the Synthesis of 3-((1H-1,2,3-
triazol-1-yl)methyl)-5-arylisoxazoles (11–15)
The mixture of 0.23 mmol CuSO4·5Н2О and 0.45 mmol
TBTA in 15 mL MeOH was stirred for 10 min at room
temperature and 0.91 mmol Na ascorbate was then added. After
stirring for 30 min, the solution of 4.5 mmol isoxazolylazide 9,10
and 4.6 mmol corresponding alkyne (propargyl alcohol, 2-
methylbut-3-yn-2-ol, phenyl acetylene) in 15 mL MeOH was
added. The reaction mixture was stirred for 4 h and diluted with
150 mL of brine. Precipitate was filtered off, washed with water
(3 x 20 mL), dried in vacuum and recrystallized from acetone –
CH2Cl2 (1 : 1).
4.6.
(1-((5-Phenylisoxazol-3-yl)methyl)-1H-1,2,3-triazol-4-
Single crystal X-ray diffraction data of 11 were collected on a
SMART Apex II diffractometer using graphite monochromated
Mo-Kα radiation (λ = 0.71073 Å) at a temperature of 296 K. The
structure was solved by direct methods (SIR201432) and refined
on F2 by the full-matrix least-squares technique
(SHELXL201633). The intensities were corrected for absorption.
For all compounds, non-hydrogen atoms were refined
anisotropically. The investigated crystal was a non-merohedral
twin, with a fractional contribution of 0.5079 (12) of the major
twin component. The hydrogen atoms were placed in calculated
positions and refined in a “riding” model, with Uiso(H) =
1.5Ueq(O) for the hydroxyl H atom and Uiso(H) = 1.2Ueq(C) for
remaining H atoms. Molecular graphics was performed with the
programs ORTEP-3 for Windows34 and PLATON.35
yl)methanol (11)
1
White solid (85 % yield); m.p. 156–157 °C. H NMR (500
MHz, DMF-d7): δ = 4.66 (d, J = 5.5 Hz, 2Н, СН2O), 5.25 (t, J =
5.5 Hz, 1Н, ОН), 5.87 (s, 2Н, CH2N), 7.05 (s, 1Нisox.), 7.49–7.57
(m, 3Нarom.), 7.86–7.92 (m, 2Нarom.), 8.19 (s, 1Нtriazol). 13C NMR
(125 MHz, DMF-d7): δ = 45.36 (СН2N), 55.18 (СН2O), 100.12
(СНisox.), 123.69 (СНtriazol), 126.17 (2СНarom.), 129.74 (2СНarom.),
131.10 (1СНarom.), 127.40, 149.54, 161.10, 170.85 (4Сquat.). 15N
NMR (50.7 MHz, DMF-d7): δ = 240 (N1), 361 (N2), 372 (Nisox.).
IR (KBr): ṽmax= 3286, 3139, 3126, 3085, 3058, 2992, 2930, 2883,
1614, 1594, 1576, 1553, 1505, 1468, 1454, 1427, 1372, 1303,
1232, 1137, 1065, 1049, 1039, 1022, 950, 913, 843, 787, 760,
742, 686, 676, 491 cm–1. HPLC-MS, m/z (I, %): 535 [2M + Na
]+ (19), 279 [M + Na]+ (18), 257 [M + H]+ (100). Anal. Calcd for
C13H12N4O2: C 60.93; H 4.72; N 21.86. Found C 61.08; H 4.62;
N 21.99.
4.2. General Procedure for the Synthesis of 3-(Azidomethyl)-
5-arylisoxazoles (9,10)
Sodium azide (11 mmol) was added to the corresponding 3-
(chloromethyl)-5-arylisoxazole 7,8 (10 mmol) in 20 mL
anhydrous DMF and the mixture was stirred for 4 h at 65–70 °С.
The reaction mixture was then poured into ice water saturated
with NaCl. The precipitate was filtered off, washed with water (3
x 20 mL) and dried over P2O5.
4.7. (1-((5-(p-Tolyl)isoxazol-3-yl)methyl)-1H-1,2,3-triazol-4-
yl)methanol (12)
1
White solid (97 % yield); m.p. 150–152 °C. H NMR (500
MHz, DMSO-d6): δ = 2.33 (s, 3Н, CH3), 4.56 (d, J = 5 Hz, 2Н,
СН2O), 5.29 (t, 1Н, J = 5 Hz, ОН,), 5.78 (s, 2Н, CH2N), 6.93 (s,
1 Нisox.), 7.31 (d, J = 8 Hz, 2Нarom.), 7.73 (d, J = 8 Hz, 2Нarom.),
8.14 (s, 1Нtriazol). 13C NMR (125 MHz, DMSO-d6): 21.57 (CH3),
45.24 (СН2N), 55.62 (СН2O), 99.74 (СНisox.), 124.01 (СНtriazol),
126.19 (2СНarom.), 130.40 (2СНarom.), 124.39, 141.21, 149.09,
160.80, 170.65 (5Сquat.). IR (KBr): ṽmax= 3289, 3147, 3132, 3123,
3059, 3037, 2992, 2958, 2921, 2853, 1619, 1598, 1568, 1515,
1470, 1436, 1376, 1368, 1319, 1226, 1132, 1116, 1063, 1049,
1038, 1017, 949, 842, 820, 810, 790, 737, 629, 503 cm–1. GC-MS
(EI), m/z (I, %): 270 (21) [M]+, 242 (24), 119 (100), 91 (59).
Anal. Calcd for C14H14N4O2: C 62.21; H 5.22; N 20.73. Found C
62.40; H 5.03; N 20.66.
4.3. 3-(Azidomethyl)-5-phenylisoxazole (9)
White solid (99 % yield); m.p. 45–46 °C. 1H NMR (500 MHz,
CDCl3): δ = 4.45 (s, 2H, CH2), 7.23–7.19 (m, 1H), 6.65 (s,
1Hisox.), 7.38–7.51 (m, 3Harom.), 7.70–7.82 (m, 2Harom.) ppm. 13C
NMR (125 MHz, CDCl3): δ = 45.82 (CH2), 98.59 (CHisox.),
125.93 (2CHarom.), 129.11 (2CHarom.), 130.58 (1CHarom.), 127.06,
159.88, 171.04 (3Cquat.) ppm. IR (KBr): ṽmax= 3129, 3068, 3008,
2950, 2852, 2133, 2098, 2077, 1612, 1592, 1573, 1499, 1459,
1428, 1253, 1209, 1048, 1021, 947, 908, 880, 810, 764, 690, 673,
649, 559, 493 cm–1. GC-MS (EI) m/z (I, %): 200 (76) [M]+, 172
(13), 105 (100), 77 (91), 51 (46). Anal. Calcd for C10H8N4O: C
59.99; H 4.03; N 27.99. Found C 60.12; H 4.09; N 27.87.
4.8. 2-(1-((5-(p-Tolyl)isoxazol-3-yl)methyl)-1H-1,2,3-triazol-
4-yl)propan-2-ol (13)
1
4.4. 3-(Azidomethyl)-5-(p-tolyl)isoxazole (10)
White solid (95 % yield); m.p. 152–153 °C. H NMR (500
MHz, DMSO-d6): δ = 1.47 (s, 6Н, 2CH3), 2.35 (s, 3Н, CH3), 5.13
(s, 1Н, ОН), 5.74 (s, 2Н, CH2), 6.95 (s, 1Нisox.), 7.33 (d, J = 8 Hz,
2Нarom.), 7.75 (d, J = 8 Hz, 2Нarom.), 8.00 (s, 1Нtriazol). 13C NMR
(125 MHz, DMSO-d6): δ = 21.56 (CH3), 31.22 (2CH3), 45.09
(СН2), 99.82 (СНisox.), 121.66 (СНtriazol), 126.17 (2СНarom.),
130.38 (2СНarom.), 67.62, 124.36, 141.19, 156.84, 160.71, 170.59
(6Сquat.). IR (KBr): ṽmax= 3355, 3129, 3075, 3038, 3001, 2970,
2930, 2874, 1619, 1600, 1568, 1515, 1469, 1441, 1368, 1355,
1301, 1218, 1181, 1135, 1116, 1062, 1047, 1019, 967, 949, 837,
825, 808, 779, 743, 722, 678, 502 cm–1. Anal. Calcd for
White solid (99 % yield); m.p. 37.5–38.5 °C. 1H NMR (500
MHz, CDCl3): δ = 2.38 (s, 3H, CH3), 4.43 (s, 2H, CH2), 6.49 (s,
1Hisox.), 7.24 (d, J = 7.4 Hz, 2Harom.), 7.65 (d, J = 7.4 Hz, 2Harom.
)
ppm. 13C NMR (125 MHz, CDCl3): δ = 21.49 (CH3), 45.80
(CH2), 97.95 (CHisox.), 125.82 (2CHarom.), 129.75 (2CHarom.),
124.34, 140.89, 159.78, 171.19 (4Cquat.) ppm. IR (KBr): ṽmax
=
3136, 3038, 3030, 3008, 2954, 2925, 2864, 2130, 2098, 2077,
1618, 1598, 1566, 1511, 1463, 1455, 1436, 1408, 1378, 1341,
1313, 1252, 1216, 1209, 1114, 1045, 1023, 949, 904, 883, 826,
806, 768, 716, 680, 661, 557, 506 cm-1. GC-MS (EI): m/z (I, %)

9
C16H18N4O2: C 64.41; H 6.08; N 18.78. Found C 64.75; H 6.20;
N 18.54.
CH3), 3.22 (t, J = 7.2 Hz, 2Н, CH2,), 3.38 (t, J = 7.2 Hz, 2Н,
ACCEPTED MANUSCRIPT
CH2,), 5.75 (s, 2Н, CH2N), 6.85 (s, 1Нisox.), 7.30 (d, J = 8 Hz,
2Нarom.), 7.55–7.61 (m, 3Нarom.), 7.71 (d, J = 8 Hz, 2Нarom.), 7.73
(s, 1Нisox.), 7.95–8.03 (m, 2Нarom.), 8.10 (s, 1Нtriazol). 13C NMR
(125 MHz, DMSO-d6): δ = 21.52 (CH3), 22.45 (СН2), 25.09
(СН2), 45.24 (СН2N), 99.58 (СНisox.), 100.05 (СНisox.), 123.75
(СНtriazol), 126.11 (2СНarom.), 126.52 (2СНаром.), 129.93
(2СНаром.), 130.33 (2СНаром.), 131.78 (1СНarom.), 124.31, 126.37,
141.13, 151.32, 157.21, 160.71, 167.81, 170.57, 171.73 (9Сquat.).
IR (KBr): ṽmax=3144, 3125, 3116, 3064, 3034, 2992, 2923, 2853,
1619, 1600, 1566, 1493, 1462, 1447, 1427, 1353, 1222, 1120,
1050, 995, 950, 816, 765, 688, 679, 498 cm–1. Anal. Calcd for
C26H21N7O3: C 65.13; H 4.41; N 20.45. Found C 65.27; H 4.75;
N 20.51.
4.9. 5-Phenyl-3-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)iso-
xazole (14)
1
White solid (98 % yield); m.p. 194–195 °C. H NMR (500
MHz, DMSO-d6): δ = 5.88 (s, 2Н, CH2), 7.07 (s, 1Нisox.), 7.34 (t,
J = 7.4 Hz, 1Нarom.), 7.45 (t, J = 7.7 Hz, 2Нarom.), 7.48–7.54 (m,
3Нarom.), 7.82–7.93 (m, 4Нarom.), 8.73 (s, 1Нtriazol). 13C NMR (125
MHz, DMSO-d6): δ = 45.61 (СН2), 100.38 (СНisox.), 122.65
(СНtriazol), 125.83 (2СНarom.), 126.26 (2СНarom.), 128.60
(1СНarom.), 129.50 (2СНarom.), 129.85 (2СНarom.), 131.27
(1СНarom.), 127.03, 131.10, 147.39, 160.76, 170.58 (5Сquat.). IR
(KBr): ṽmax= 3122, 3098, 3054, 2999, 2957, 2918, 2850, 1612,
1593, 1574, 1465, 1453, 1440, 1355, 1347, 1227, 1200, 1182,
1076, 1048, 1027, 1011, 973, 947, 912, 830, 786, 764, 749, 685,
507, 490 cm–1. HPLC-MS, m/z (I, %): 303 [M + H]+ (100). Anal.
Calcd for C18H14N4O: C 71.51; H 4.67; N 18.53. Found C 71.65;
H 4.64; N 18.39.
4.13. (1-((5-Phenylisoxazol-3-yl)methyl)-1H-1,2,3-triazol-4-
yl)methyl pivalate (16)
Anhydrous Et3N (0.10 g, 0.99 mmol) was added to a solution
of hydroxytriazol-isoxazole 11 (0.23 g, 0.90 mmol) and pivaloyl
chloride (0.11 g, 0.91 mmol) in 30 mL anhydrous
dichloromethane. The reaction mixture was stirred for 4 h at
reflux, diluted with water, acidified with HCl, organic layer
separated and dried over sodium sulfate. After removal of the
solvent in vacuo 0.30 g ester 16 was obtained which does not
need further purification. White solid (99 % yield); m.p. 117–119
°C. 1H NMR (500 MHz, DMF-d7): δ = 1.13 (s, 9Н, 3Ме), 5.21 (s,
2Н, CH2О), 5.92 (s, 2Н, CH2N), 7.05 (s, 1Нisox.), 7.50–7.56 (m,
3Нarom.), 7.86–7.91 (m, 2Нarom.), 8.38 (s, 1Нtriazol). 13C NMR (125
MHz, DMF-d7): δ = 26.96 (3CH3), 45.53 (СН2N), 57.99 (СН2O),
100.11 (СНisox.), 125.52 (СНtriazol), 126.17 (2СНarom.), 129.74
(2СНаром.), 131.12 (1СНаром.), 38.79, 127.38, 143.65, 160.91,
170.90, 177.84 (6Сquat.). 15N NMR (50.7 MHz, DMF-d7): δ = 242
(N1), 355 (N3), 364 (N2), 372 (Nisox.). IR (KBr): ṽmax= 3118, 3094,
3074, 2981, 2970, 2935, 2874, 1731, 1613, 1593, 1575, 1480,
1468, 1452, 1429, 1396, 1366, 1313, 1283, 1227, 1165, 1154,
1133, 1051, 1037, 1007, 964, 947, 916, 842, 821, 787, 764, 740,
689, 681, 500 cm–1. Anal. Calcd for C18H20N4O3: C 63.52; H
5.92; N 16.46. Found: C 63.75; H 5.88; N 16.35.
4.10.
3-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)-5-(p-
tolyl)isoxazole (15)
1
White solid (91 % yield); m.p. 178–179 °C. H NMR (500
MHz, DMSO-d6): δ = 2.33 (s, 3Н, CH3), 5.86 (s, J = 7.4 Hz, 2Н,
CH2), 6.99 (s,1Нisox.), 7.31 (d, J = 8.1 Hz, 2Нarom.), 7.34 (t, J = 7.4
Hz, 1Нarom.), 7.45 (t, J = 7.7 Hz, 2Нarom.), 7.75 (d, J = 8.1 Hz,
2Нarom.), 7.89 (d, J = 7.2 Hz, 2Нarom.), 8.73 (s, 1Нtriazol). 13C NMR
(125 MHz, DMSO-d6): δ = 21.56 (CH3), 45.62 (СН2), 99.71
(СНisox.), 122.64 (СНtriazol), 125.83 (2СНarom.), 126.20 (2СНarom.),
128.59 (1СНarom.), 129.49 (2СНarom.), 130.38 (2СНarom.), 124.38,
131.11, 141.21, 147.39, 160.68, 170.75 (6Сquat.). IR (KBr):
ṽmax=3108, 3088, 3047, 3032, 2991, 2946, 2917, 2856, 1619,
1597, 1517, 1463, 1440, 1431, 1350, 1223, 1200, 1184, 1117,
1079, 1047, 973, 948, 912, 839, 821, 783, 761, 752, 694, 517,
505 cm–1. Anal. Calcd for C19H16N4O: C 72.13; H 5.10; N 17.71.
Found: C 72.29; H 5.05; N 17.60.
4.11.
2-(But-3-yn-1-yl)-5-(5-phenylisoxazol-3-yl)-1,3,4-
oxadiazole (19)
4.14. General procedure for the synthesis of LPdCl2
complexes
DCC (0.97 g, 4.7 mmol) was added to a solution of pent-4-
inoic acid (0.94 g, 9.58 mmol) in 10 mL anhydrous toluene. The
reaction mixture was stirred for 30 min at room temperature,
General procedure for the synthesis of LPdCl2 complexes. 40
mL of 0.025 M solution (1 mmol) of the corresponding ligand
(L1-7) in MeOH was added dropwise under stirring to 10 mL of
0.1 M methanol solution of Na2PdCl4 (1 mmol), and the mixture
was stirred at room temperature. After 10 min, the precipitate
was filtered off, washed with water, methanol, and dried in air at
room temperature for one day.
precipitate
filtered
off,
and
3-(1H-tetrazol-5-yl)-5-
phenylisoxazole 18 (1g, 4.69 mmol) was added to the filtrate.
The obtained suspension was refluxed for 6 h, toluene was
removed, solid residue washed with chilled toluene, hexane and
dried on air to give 0.84 g compound 19 which used without
further purification. White solid (86% yield); m.p. 145–147 °C.
1H NMR (500 MHz, CDCl3): δ = 2.05 (t, 1Н, J = 2.5 Hz, ≡СН,),
2.80 (dt, J = 7.2 and 2.5 Hz, 2Н, СН2СН2С≡), 3.23 (t, 2Н, J = 7.2
Hz, СН2СН2С≡), 7.15 (s, 1Нisox.), 7.48–7.54 (m, 3Нarom.), 7.82–
7.87 (m, 2Нarom.). 13C NMR (125 MHz, CDCl3): δ = 16.27
(СН2СН2С≡), 25.21 (СН2СН2С≡), 70.29 (≡СН), 98.69 (СНisox.),
126.22 (2СНarom.), 129.39 (2СНarom.), 131.26 (1СНarom.), 81.06,
4.15. Complex L1PdCl2
Pale yellow solid (96 % yield); 1H NMR (500 MHz, DMF-d7):
δ (rotamer1 / rotamer2) = 5.29 / 5.33 (s, 2Н, СН2O), 5.75 (br.s,
1Н, ОН), 6.01 / 6.04 (s, 2Н, CH2N), 7.10 / 7.12 (s, 1Н, СНisox.),
7.49–7.66 (m, 3Нarom.), 7.80–7.95 (m, 2Нarom.), 8.47 / 8.50 (s, 1Н,
СНtriazol). 13C NMR (125 MHz, DMF-d7): δ = 47.15 / 47.25
126.40, 150.89, 157.77, 166.49, 172.10 (6Сquat.). IR (KBr): ṽmax
=
3257, 3142, 3068, 3051, 2923, 2853, 2118, 1617, 1607, 1565,
1494, 1470, 1459, 1445, 1428, 1327, 1227, 1119, 1048, 949, 938,
803, 767, 731, 692, 678 cm–1. Anal. Calcd for C15H11N3O2: C
67.92, H 4.18, N 15.84. Found C 67.84, H 4.09, N 15.94.
(СН2N), 57.01 / 57.15 (СН2O), 100.24 (СНisox.), 126.16
(2СНarom.), 126.33 (СНtriazol), 129.78 (2СНarom.), 131.22
(1СНarom.), 127.25, 151.26 / 151.86; 160.00 / 160.06; 171.10
(4Сquat.). 15N NMR (50.7 MHz, DMF-d7): δ = 228 / 248 (N3), 244
(N1), 354 (N2), 372 (Nisox.). IR (KBr): ṽmax =3417, 3111, 2988,
2943, 2871, 1610, 1591, 1573, 1607, 1455, 1420, 1340, 1243,
1147, 1093, 1062, 1024, 950, 797, 764, 688, 493 cm–1. HPLC-
MS, m/z: 830.942 (calcd for [M – Cl-]+ 830.905). Anal. Calcd for
C26H24Cl4N8O4Pd2: C 36.01; H 2.79; Cl 16.35; N 12.92; Pd
24.54. Found C 36.28; H 3.02; Cl 14.95; N 13.09; Pd 24.38.
4.12. 2-(5-Phenylisoxazol-3-yl)-5-(2-(1-((5(p-tolyl)isoxazol-3-
yl)methyl)-1Н-1,2,3-triazol-4-yl)ethyl)-1,3,4-oxadiazole (20)
The compound was prepared by the same procedure described
for 11–15, but reaction was carried out at 40 °C. Compound was
obtained (91 % yield) as white solid; m.p. 183–184 °C
1
(decomp.). H NMR (500 MHz, DMSO-d6): δ = 2.32 (s, 3Н,

10
Tetrahedron
ACCEPTED MANUSCRIPT
4.16. Complex L2PdCl2
HCl. The organic phase was separated, and the aqueous layer was
extracted with Et2O (2 x 5 mL). The combined organic layers
were washed with brine (5 mL), dried over Na2SO4, concentrated
in vacuo and the yield was determined by 1H NMR analysis with
1,1,2,2-tetrachloroethane (0.5 mmol) as internal standard (Tables
4). The pure product was obtained by a simple filtration of ether
solution through silica gel pad and evaporation of solvent.
Pale yellow solid (94% yield); ṽmax = 3429, 3132, 3097, 2949,
2922, 1612, 1595, 1476, 1454, 1407, 1161, 1020, 951, 820, 802
cm–1. Anal. Calcd for C14H14Cl2N4O2Pd: C 37.57; H 3.15; Cl
15.84; N 12.52; Pd 23.78. Found C 37.41; H 3.25; Cl 15.73; N
12.57; Pd 23.41.
4.17. Complex L3PdCl2
4.23. 4-Methoxybiphenyl-3-carboxylic Acid (23)
Pale yellow solid (91% yield); IR (KBr): ṽmax = 3435, 3118,
2976, 2917, 2870, 1614, 1597, 1474, 1369, 1184, 1175, 1124,
1078, 951, 816, 781 cm–1. Anal. Calcd for C16H18Cl2N4O2Pd: C
40.40; H 3.81; Cl 14.91; N 11.78; Pd 22.37. Found C 40.47; H
3.97; Cl 15.04; N 11.72; Pd 22.05.
White crystalline powder (98 % yield), m.p. 203-204°C (m.p.
202–203 °C36). 1H NMR (400 MHz, DMSO-d6): δ = 3.79 (s, 3H),
7.03 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 8.8
Hz, 2H), 7.82—7.90 (m, 2H), 8.12 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): δ = 55.2, 114.5, 126.8, 127.5, 127.9, 129.2, 130.6,
4.18. Complex L4PdCl2
131.4, 131.6, 140.2, 159.2, 167.3. IR (KBr): ṽ
= 3394, 3081,
max
2957, 2840, 1678, 1600, 1586, 1423, 1395, 1317, 1289, 1272,
1241, 1197, 1172, 1124, 1062, 1009, 931, 756 cm-1. Calcd for
C14H12O3: C 73.67; H 5.30. Found: C 73.69; H 5.37.
Pale beige solid (90% yield); IR (KBr): ṽmax = 3119, 3062,
3000, 2951, 1610, 1590, 1574, 1457, 1368, 1342, 1239, 1160,
1114, 1054, 951, 921, 818, 764, 691 cm–1. Anal. Calcd for
C18H14Cl2N4O2Pd: C 45.07; H 2.94; Cl 14.78; N 11.68; Pd 22.19.
Found C 45.17; H 3.16; Cl 14.83; N 11.63; Pd 22.08.
4.24. General procedure for the Mizoroki–Heck reaction
A 20 mL Schlenk tube with a magnetic stir bar was charged
with 3-iodobenzoic acid 24 (0.5 mmol), acrylic acid 25 (0.75
mmol), K2CO3 (1.5 mmol), 5 ml of water and 50 ꢁL of the
solution (1 10-2 M) of palladium complexes LPdCl2 in DMF
under air atmosphere. The reaction mixture was placed in a
preheated at 100 °C oil bath and stirred for the appropriate time
(Tables 5). After this time, the mixture was cooled, diluted with 5
mL of H2O, 5 mL of EtOAc and acidified by 1 M HCl. The
organic phase was separated, and the aqueous layer was extracted
with EtOAc (2 x 5 mL). The combined organic layers were
washed with brine (5 mL) and dried over Na2SO4. The yield was
4.19. Complex L5PdCl2
Pale beige solid (88 % yield); IR (KBr): ṽmax = 3431, 3131,
2920, 2855, 1615, 1598, 1565, 1515, 1488, 1467, 1459, 1441,
1369, 1339, 1331, 1315, 1239, 1206, 1184, 1158, 1111, 1058,
1019, 1004, 949, 822, 762, 744, 695, 503 cm–1. Anal. Calcd for
C19H16Cl2N4O2Pd: C 46.23; H 3.27; Cl 14.36; N 11.35; Pd 21.56.
Found C 46.15; H 3.36; Cl 14.48; N 11.39; Pd 21.41.
4.20. Complex L6PdCl2
1
1
Yellow solid (67 % yield); H NMR (500 MHz, DMF-d7): δ
determined by H NMR analysis with 1,1,2,2-tetrachloroethane
(rotamer1/rotamer2) = 1.24 / 1.25 (s, 9Н, 3CH3), 5.73 / 5.78 (s,
2Н, CH2О), 6.06 / 6.08 (s, 2Н, CH2N), 7.09 / 7.11 (s, 1Н,
СНisox.), 7.52–7.56 (m, 3Нarom.), 7.86–7.91 (m, 2Нarom.), 8.70 /
8.73 (s,1Нtriazol). 13С NMR (125 MHz, DMF-d7): δ (rotamer1 /
rotamer2) = 27.09 (3CH3), 47.32 / 47.41 (СН2N), 57.69 / 57.81
(СН2O), 100.22 / 100.25 (СНisox.), 126.16 (2СНarom.), 128.09 /
128.17 (СНtriazol), 129.79 (2СНarom.), 131.24 (1СНarom.), 38.98 /
39.01; 127.24; 145.12 / 145.72; 159.85 / 159.88; 171.12; 177.89
(6Сquat.). 15N NMR (50.7 MHz, DMF-d7): δ (rotamer1 / rotamer2)
= 235 / 253 (N3), 246 (N1), 358 (N2), 373 (Nisox.). IR (KBr): ṽmax
= 3442, 3153, 2971, 2933, 2871, 1731, 1611, 1592, 1575, 1457,
1398, 1280, 1147, 1101, 1049, 1035, 951, 803, 766, 690 cm–1.
HPLC-MS, m/z: 998.988 (calcd for [M – Cl-]+ 999.020). Anal.
Calcd for C36H40Cl4N8O6Pd2: C 41.76; H 3.89; Cl 13.70; N 10.82;
Pd 20.56. Found C 41.56; H 3.91; Cl 13.64; N 10.90; Pd 20.41.
(0.5 mmol) as internal standard (Tables 4). The pure product was
obtained by a simple filtration of solution through silica gel pad
and evaporation of solvent.
4.25. 3-[(E)-2-carboxyvinyl]benzoic acid (26)
White crystalline powder (97 % yield), m.p. 284–285 °C (m.p.
1
284–286 °C37). H NMR (400 MHz, DMSO-d6): δ = 6.58 (d, J =
16.0 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 16.0 Hz, 1H),
7.90-8.00 (m, 2H), 8.14 (s, 1H), 12.81 (br. s, 2H). 13C NMR (100
MHz, DMSO-d6): δ (ppm) = 120.5, 129.0, 129.3, 130.8, 131.6,
132.0, 134.7, 142.9, 166.9, 167.4. Calcd for C10H8O4: C 62.50; H
4.20; O 33.30. Found: C 62.46; H 4.27.
4.26. General procedure for the Sonogashira reaction
A 20 mL Schlenk tube with a magnetic stir bar was charged
with methyl p-iodobenzoate 27 (0.5 mmol), prop-2-yn-1-ol 28
(0.65 mmol), triethylamine (1.5 mmol), CuI (0.005 mmol), 4.9
ml of 2-methyltetrahydrofuran, 50 ꢁL of solution (4 10-2 M) of
PPh3 and 50 ꢁL of solution (2 10-2 M) of palladium complexes
LPdCl2 in 2-MeTHF under argon atmosphere. The reaction
mixture was stirred at room temperature for the appropriate time
(Tables 6). After this time, the mixture was added to a saturated
solution of brine (5 mL). The resulting water-organic phases
were separated and the organic phase was dried over Na2SO4.
4.21. Complex L7PdCl2
Pale brown solid (88% yield); IR (KBr): ṽmax = 3473,
3111,3066, 2947, 2858, 2922, 1614, 1589, 1566, 1464, 1444,
1431, 1400, 951, 766 cm–1. Anal. Calcd for C26H21Cl2N7O3Pd: C
47.55; H 3.22; Cl 10.79; N 14.93; Pd 16.20. Found C 47.44; H
3.31; Cl 10.64; N 14.87; Pd 16.01.
4.22. General procedure for the Suzuki-Miyaura reaction
1
A 20 mL Schlenk tube with a magnetic stir bar was charged
The yield was determined by H NMR analysis with 1,1,2,2-
with
3-bromobenzoic
acid
21
(0.5
mmol),
4-
tetrachloroethane (0.5 mmol) as internal standard (Tables 6). The
pure product was obtained by filtration of solution through silica
gel pad and evaporation of the solvent under reduced pressure.
Removal of solvent was carried out in a closed volume, which
allowed carrying out 90-95% regeneration of the solvent.
methoxyphenylboronic acid 22 (0.6 mmol), K2CO3 (1.25 mmol),
5 ml of solvent [H2O, H2O-MeOH (1:1)] and 50 ꢁL of solution
(1 10-2-1 10-5 M) of palladium complexes LPdCl2 in DMF under
air atmosphere. The reaction mixture was placed in a preheated
oil bath: at 100 °C for MeOH-H2O and at 35 °C or 100 °C for
H2O; and stirred for the appropriate time and under conditions
required (Tables 4). After this time, the mixture was cooled,
diluted with 5 mL of H2O, 5 mL of Et2O and acidified by 1 M

11
11. Potkin VI, Bumagin NA, Petkevich SK, Dikusar EA,
4.27. Methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate (29)
ACCEPTED MANUSCRIPT
Semenova EV, Kurman PV, Zolotar’ RM, Pashkevich SG,
Gurinovich TA, Kul’chitskii VA. Russ J Org Chem. 2015; 51:
1119–1130.
White crystalline powder (96 % yield), m.p. 83-84°C (m.p.
1
82–84 °C38). H NMR (400 MHz, CDCl3): δ = 2.00 (br.s, 1H),
12. Kun S, Nagy GZ, Tóth M, Czecze L, Van Nhien AN, Docsa T,
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3.90 (s, 3H), 4.50 (s, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.96 (d, J =
8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 51.5, 52.2, 84.9,
90.2, 127.2, 129.5, 129.7, 131.5, 166.5. IR (KBr): ṽ
= 3323,
max
1726, 1430, 1282, 1119, 1031 cm-1. Calcd for for C11H10O3: C,
69.46; H, 5.30; O 25.24. Found: C, 69.39; H, 5.40.
X-ray Crystal Data
CCDC 1823325 contains the supplementary crystallographic data
of compound 11 for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
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Acknowledgements
We thank the Russian Foundation for Basic Research (16-58-
00059-Bel_a) and the Belarusian Republican Foundation for
Fundamental Research (X16P-006) for financial support of this
work.
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