Reactivity of 1,2,3-triazoles towards sulfonyl chlorides. A novel approach to 1- and 2-sulfonyl-4-azolyl-1,2,3-triazoles

Article abstract of DOI:10.1016/j.tet.2015.06.088

Abstract The reactions of N-unsubstituted triazoles with sulfonyl chlorides afforded mixtures of regioisomeric 1- and 2-sulfonyl-1,2,3-triazoles. In some cases, pure regioisomers were obtained by crystallization of mixtures of isomers. 1,2,3-Triazoles bea

Full text of DOI:10.1016/j.tet.2015.06.088

Accepted Manuscript
Reactivity of 1,2,3-triazoles towards sulfonyl chlorides. A novel approach to 1- and 2-
sulfonyl-4-azolyl-1,2,3-triazoles
Tetyana V. Beryozkina, Ilya V. Efimov, Walter M.F. Fabian, Nikolai A. Beliaev, Pavel
A. Slepukhin, Maxim L. Isenov, Wim Dehaen, Gert Lubec, Oleg S. Eltsov, Zhijin Fan,
Joice Thomas, Vasiliy A. Bakulev
PII:
S0040-4020(15)00985-0
10.1016/j.tet.2015.06.088
TET 26924
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 May 2015
Revised Date: 11 June 2015
Accepted Date: 22 June 2015
Please cite this article as: Beryozkina TV, Efimov IV, Fabian WMF, Beliaev NA, Slepukhin PA, Isenov
ML, Dehaen W, Lubec G, Eltsov OS, Fan Z, Thomas J, Bakulev VA, Reactivity of 1,2,3-triazoles towards
sulfonyl chlorides. A novel approach to 1- and 2-sulfonyl-4-azolyl-1,2,3-triazoles, Tetrahedron (2015),
doi: 10.1016/j.tet.2015.06.088.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Reactivity of 1,2,3-triazoles towards sulfonyl chlorides.
A novel approach to 1- and 2-sulfonyl-4-azolyl-
1,2,3-triazoles
Leave this area blank for abstract info.
Tetyana V. Beryozkinaa*, Ilya V. Efimova, Walter M. F. Fabianb,
Nikolai A. Beliaeva, Pavel A. Slepukhina, Maxim L. Isenovc,
Wim Dehaend, Gert Lubece, Oleg S. Eltsova, Zhijin Fanf*,
Joice Thomasd and Vasiliy A. Bakuleva
a Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira st., 620002,
Yekaterinburg, Russia;
b Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria;
c I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Science, 20 S.
Kovalevskaya st., 620990, Yekaterinburg, Russia;
d Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven,
Belgium;
e Medical University of Vienna, Department of Pediatrics, 1090, 14 Lazarettgasse, Vienna, Austria;
f State Key Laboratory of Elemento-Organic Chemistry Nankai University, Collaborative Innovation Center of
Chemical Science and Engineering 300071, Tianjin, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Reactivity of 1,2,3-triazoles towards sulfonyl chlorides. A novel approach to 1- and 2-
sulfonyl-4-azolyl-1,2,3-triazoles
Tetyana V. Beryozkinaa*, Ilya V. Efimova, Walter M. F. Fabianb, Nikolai A. Beliaev a, Pavel A. Slepukhina,
Maxim L. Isenovc, Wim Dehaend, Gert Lubece, Oleg S. Eltsova, Zhijin Fanf*, Joice Thomasd and Vasiliy A.
Bakuleva
a Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira st., 620002, Yekaterinburg, Russia;
b Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria;
c I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Science, 20 S. Kovalevskaya st., 620990, Yekaterinburg, Russia;
d Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium;
e Medical University of Vienna, Department of Pediatrics, 1090, 14 Lazarettgasse, Vienna, Austria;
f State Key Laboratory of Elemento-Organic Chemistry Nankai University, Collaborative Innovation Center of Chemical Science and Engineering 300071,
Tianjin, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reactions of N-unsubstituted triazoles with sulfonyl chlorides afforded mixtures of
regioisomeric 1- and 2-sulfonyl-1,2,3-triazoles. In some cases, pure regioisomers were obtained
by crystallization of mixtures of isomers. 1,2,3-Triazoles bearing thiadiazole, isoxazole and
benzene rings react with mesyl chloride and tosyl chloride to form mainly 1-substituted 1,2,3-
triazoles. Conversely, reactions of triazoles 1a,b and oxadiazolyl triazole 1h with more bulky 1-
(2,4-dimethylphenyl)sulfonyl chloride affords mainly 2-substitued products. Oxadiazole 1b
furnishes an equal mixture of the regioisomeric products 3 and 4 as a result of the reaction with
mesyl and tosyl chlorides. Higher temperatures increase the ratio of isomers in favor of the 2-
substituted triazole. The ratio of isomers depends on both the nature of the azolyl ring and on the
size of the substituent in the sulfonyl chloride. Based on the results of experimental and
theoretical data, 1-substituted and 2-substituted 1,2,3-triazoles can be considered as the kinetic
and thermodynamic products.
Available online
Keywords:
1,2,3-Triazoles
Sulfonyl triazoles
Sulfonyl chlorides
Regioisomeric mixtures
2009 Elsevier Ltd. All rights reserved
1. Introduction
fused indoles, N-sulfonylamidines, cycloalkanes, enamines,
dienes, ketones, and sulfonamides.12-14
The discovery in 2002 by the Sharpless/Fokin and Meldal
groups of the CuAAC reaction opened the way to 1,2,3-triazole
derivatives of various structures available for testing their
material and biological properties.1,2 Further applications were
found in medicinal chemistry, biology, and analytical
chemistry.3 Due to the capacity for ring rearrangements and
transformations, 1,2,3-triazoles are widely used in organic
synthesis.4-11 1-Sulfonyl-1,2,3-triazoles were found to be
convenient chemical reagents to generate azavinyl carbenoids
that in turn can undergo reactions with compounds bearing
double and triple bonds and are capable of inserting into C–H,
N–H, O–H and C–C bonds.3,4 This approach is recognized by
many scientists as a powerful method to prepare, starting from
1-sulfonyl-1,2,3-triazoles, a huge variety of other heterocyclic
compounds and valuable organic compounds such as azoles, 1
The introduction of an azolyl fragment to 1,2,3-triazole
could increase both the stability of the intermediate azavinyl
carbenes and open the possibility for the reaction to proceed
even without catalyst.15 On the other hand, 4-azolyl-1,2,3-
triazoles evoke special interest in medicinal chemistry as close
structural analogs of 4-azolylpyrazoles that recently have been
discovered as novel types of anticancer compounds.16
The noncatalyzed17-19 and copper catalyzed20 1,3-dipolar
cycloaddition of alkynes to azides with sulfonyl azides were
often used for the synthesis of 1-sulfonyl substituted 1,2,3-
triazoles. However, this was never used for the synthesis of 1-
sulfonyl-4-azolyl-1,2,3-triazoles, most probably because the
azolyl acetylenes are poorly available chemicals.
Cycloaddition reactions of enamines and 1,3-dicarbonyl
compounds to azides present a promising approach to 1,4,5-
substituted-1,2,3-triazoles that however has been less studied
than the CuAAC method.13 Recently we have shown that
reactions of β-azolyl enamines with aryl and alkyl azides
———
*Corresponding author. E-mail adresses: tetber@mail.ru (T. V.
Beryozkina), fanzj@nankai.edu.cn (Z .J. Fan)

2
Tetrahedron
ACCEPTED MANUSCRIPT
represent a convenient, regioselective and general method to
decrease with increase of the molecular size of the sulfonyl
prepare 4-azolyl-1,2,3-triazoles in which these enamines are
the synthetic equivalents of azolyl alkynes.21 Unfortunately, we
did not manage to expand our approach to reactions of β-azolyl
enamines with sulfonyl azides for the synthesis of 1-sulfonyl-
4-azolyl-1,2,3-triazole. The formation of N-unsubstituted-4-
azolyl-1,2,3-triazoles took place in high yields instead of the
expected 1-sulfonyl-1,2,3-triazoles.21
chlorides in favor of 2-substitued-1,2,3-triazoles. The
replacement of the cyano group by an ester function (Table 1,
entries 11 and 13) also favors the formation of 2-sulfonyl
substituted 1,2,3-triazoles.
For comparison with the triazoles 1a-e, we have reacted
model 4-phenyl-1,2,3-triazole (1f) with 1.2 equivalent of tosyl
chloride (1b) and DIPEA in ethanol at room temperature. After
column chromatography, a 89% yield of a 7:3 mixture of the 1-
and 2-sulfonylated 4-phenyltriazoles 3o/4o was obtained. A
longer reaction time was observed in the case of 2,4-
dimethylbenzene-1-sulfonyl chloride (2c) and the expected
compound was isolated as a 3:2 mixture of 1- and 2-
sulfonylated 4-phenyltriazoles 3p/4p with an overall yield of
74%. Both experiments confirm the conclusion made on the
reactivity of 4-azolyl-1,2,3-triazoles in reaction with azides: a
more hindered sulfonyl chloride reagent favors the 2-
substituted isomer. On the other hand, the outcome of the
mesylation reaction of 4-phenyl-1,2,3-triazole was time
dependent as we could see if we studied the reaction by taking
1H NMR spectra at time intervals. Already after 10 minutes at
room temperature in either deuterated chloroform or methanol,
the conversion is around 70%, with a mixture of 1- and 2-
substituted regioisomers formed in about the same 7:3 ratio,
next to about 30% of the starting material. Unexpectedly,
longer reaction times lead to less conversion and at the same
time the ratio of the regioisomers changes in favor of the 2-
substituted compound. This can be explained by hydrolysis of
the sulfonylated products formed under the influence of traces
of water or other nucleophiles, which occurs faster for the 1-
substituted isomer. This phenomenon may be a reason for
different ratios of 1- and 2-sulfonylated triazoles found in the
literature.20, 31
We turned our attention to reactions of sulfonyl chlorides
with N-unsubstituted-1,2,3-triazoles. Though this reaction is
recognized as a traditional method to prepare 1-sulfonyl
triazoles14 the publications with data on reactivity of 1,2,3-
triazoles with sulfonyl chlorides are innumerous.22, 23, 24-30 The
parent 1,2,3-triazole, 4-phenyl- and 4-ethoxycarbonyl-1,2,3-
triazole are shown to react with tosyl chloride under basic
conditions to form mainly 1-tosyl-1,2,3-triazoles with a small
impurity of 2-substituted triazoles.22-24 Conversely, 4-nitro-
1,2,3-triazole reacts with 2,4,6-trimethylbenzene-1-sulfonyl
chloride to give a mixture of 1-substituted- and 2-substituted-
1,2,3-triazoles in almost equal quantity.25 To the best of our
knowledge, no systematic experimental or theoretical studies
were made to elucidate the factors governing the direction of
the reaction. Neither the effect of the structure of 1,2,3-
triazoles nor that of the nature of the sulfonyl chloride and the
reaction temperature on the ratio of isomers formed in the
reaction have been studied. It should be noted that reactions of
4-azolyl-N-unsubstituted 1,2,3-triazoles with sulfonyl chlorides
were not previously reported in the scientific or patent
literature. To prepare 1- and 2-sulfonyl substituted 1,2,3-
triazoles we have studied the reactions of 1,2,3-triazol-4-yl-
1,2,3-thiadiazoles 1a,b, 1,2,3-triazol-4-yl-1,2,4-oxadiazole
1c,d and 1,2,3-triazol-4-yl-isoxazole 1e with mesyl (2a), tosyl
(2b), 2,4-dimethyl- (2c) and 4-fluorobenzene-1-sulfonyl (2d)
chlorides.
To prepare pure 2-sulfonyl-1,2,3-triazole 4i we treated the
mixture of isomers 3i/4i with a solution of acetic acid in water
at 60 °C similar to the protocol published by Yamauchi et al.31
However, unsubstituted triazole 1c, instead of desired 4i, was
prepared in good yield due to hydrolysis in water/acid mixture.
Obviously, 1-sulfonyl-4-azol-yl-1,2,3-triazoles are very
sensitive to water.
2. Results and Discussion
N-Unsubstituted-1,2,3-triazoles 1a–e were obtained from
reactions of tosyl azide with enamines bearing in β-position
1,2,3-thiadiazole, 1,2,4-oxadiazole and isoxazole rings.21
We have found that reactions of NH-triazoles 1a–e with
sulfonyl chlorides 2a–d proceed smoothly at room temperature
in anhydrous ethanol in the presence of DIPEA
(diisopropylethylamine) to afford mixtures of 1- (3a–n) and 2-
sulfonyl-4-azolyl-1,2,3-triazoles (4a–n) of various ratios in
good yields (Table 1). The formation of 1,5-disubstituted
1,2,3-triazoles 5 was not registered by TLC and NMR spectra.
Unfortunately, the mixtures of regioisomers 3a–n and 4a–n
could not to be separated by column chromatography with
silica gel. However, crystallization of mixtures of products
3a/4a, and 3i/4i from ethyl acetate allowed us to prepare pure
1-sulfonyl substituted triazoles bearing in position 4 1,2,3-
thiadiazole ring 3a and isoxazole 3j of 90% purity (Table 1).
On the other hand, crystallization of mixtures 3c/4c and 3i/4i
(double crystallization) led to formation of pure 2-sulfonyl
substituted 1,2,3-thiadiazol-5-yl-1,2,3-triazole 4c and 1,2,4-
oxadiazol-5-yl-1,2,3-triazole 4i, respectively. In general, the
nature of the azole ring significantly affects the ratio of 3:4.
This ratio decreases in the following order 1,2,3-thiadiazole >
isoxazole > 1,2,4-oxadiazole (compare data for the reaction of
mesyl chloride (Table 1, entries 1, 4, 7, 10); for the reaction of
tosyl chloride (Table 1, entries 2, 5, 8, 11, 13)). Comparing
data of entries 1–6 for reactions of 1,2,3-thiadiazoles 3a–f,
entries 6–9 for oxadiazoles 3g–i with sulfonyl chlorides 2a–d
and entries 10–14 or reaction of isoxazoles 1d,e with sulfonyl
chlorides 2a–d allow us to conclude that the ratios of 3:4
The structures of compounds 3a–p and 4a–p were
confirmed by a combination of 1H and 13C NMR spectroscopy,
mass-spectrometry, and by X-ray analysis data for single
crystals of pure samples of triazoles 3a and 4c. NMR spectra
of all compounds exhibit signals that are similar to the signals
belonging to both the starting compounds, e.g. the hydrogen
and carbon atoms of azolyl triazoles 1 and sulfonyl chlorides 2.
Based on the spectra of the pure isomers, and their HSQC and
HMBC spectra, the singlet signals in low field at 8.81–9.39
1
and 8.39–8.90 ppm in H NMR spectra, and the signals in
regions 124.8–126.0, 135.0–136.0, 129.0–137.0 and 138.0–
140.0 ppm in 13C NMR spectra were assigned to protons of
C5–H and carbons of C–4 and C–5 of 1-sulfonyl- and 2-
sulfonyl-1,2,3-triazoles, respectively. The NMR spectra of
mixtures 3a–p and 4a–p demonstrate that all compounds
1
belong to the same structural type. Thus, the H NMR spectra
contain two singlets of C5–H protons at 9.35–9.39 and 8.74–
8.90 ppm (3,4a–f), 8.86–8.88 and 8.43–8.55 ppm (3,4g–i),
8.79–9.20 and 8.39–8.58 (3,4j–n), 8.32–8.34 and 8.06–8.07
(3,4o,p) and two singlets of methyl groups of substituents R in
sulfonyl fragments at 2.40–3.67 ppm in different intensity
ratio. 13C NMR spectra of mixtures 3,4a–p exhibit a set of
double signals. In the HMBC spectrum of compound 3a the
peak at 14.3 (CH2CH3) correlates with the peak at 4.59

3
(CH2CH3), the peak at 62.7 (CH2CH3) with the peak at 1.52
(CH2CH3), the peak at 135.9 (C4) with the peak at 9.36 (C5–
H), the peak at 160.9 (C=O) with the peak at 4.59 (CH2CH3).
The structures of prepared compounds 3 and 4 are further
supported by X-ray analysis (Fig.1 and Fig.2) for the crystals
of triazoles 3a and 4c. According to the X-ray data, compound
3a crystallizes in a centrosymmetric space group. All heavy
atoms of the azolyl-triazole fragment are in plane with only
0.02 Å deviation of the plane. The ester group is placed
approximately in the plane of the bis-heterocycle and the
ACCEPTED MANUSCRIPT
mesyl attached to N1 of the triazole ring. All bond lengths and
angles are in good agreement with the standard values. In the
molecular packing, a short contact between C(1) and C(4) with
d = 3.28 Å is observed. All atoms of the azolyl-triazolyl
fragment of compound 4c similarly to 3a are in the plane. In
contrast to 3a, the sulfonyl fragment is attached to N2 of the
triazole and has an approximately perpendicular orientation of
the R-sulfonyl moiety to the plane of the bis-heterocycle.
Table 1. Yields and ratios of regioisomers 3 and 4 in their mixtures prepared by reaction of 4-azolyl-1,2,3-triazoles with sulfonyl
chlorides
127-137 ppm
124.8-126 ppm
O
138-140 ppm
135 -136 ppm
EtOH
5
4
5
O
5
Az
Az
R
N
N
4
O O
S
Az
S
Az
N
NH
N N2
1 N N
S
R
O
O
N
N N 1
DIPEA
R
Cl
N
S
3
2
O
R
O
1a-f
2a-d
3a-p
4a-p
5
not registered
Entry
3, 4
Az
R
Ratio of 3:4a
90:10
Yield, %b
1
2
3
3a, 4a
3b, 4b
3c, 4c
Me
64
49c
93
100:0c
4-MeC6H4
75:25
2,4-(Me)2C6H3
33:67
0:100c
79:21
69:31
63:37
50:50
50:50
12:88
5:95c
90
50c
86
92
83
63
85
80
4
5
6
7
8
9
3d, 4d
3e, 4e
3f, 4f
Me
4-MeC6H4
4-FC6H4
3g, 4g
3h, 4h
3i, 4i
Me
4-MeC6H4
2,4-(Me)2C6H3
0:100d
70:30
90:10c
55:45
26d
58
10
11
3j, 4j
Me
40c
3k, 4k
4-MeC6H4
95
12
13
14
3l, 4l
3m, 4m
3n, 4n
2,4-(Me)2C6H3
4-MeC6H4
4-FC6H4
59:41
45:55
37:63
91
86
83
15
16
3o, 4o
3p, 4p
Ph
Ph
4-MeC6H4
70:30
60:40
89
74
2,4-(Me)2C6H3
a Determined by 1H NMR analysis; b Isolated yield; c After crystallization; d After double crystallization
To find optimal conditions for the syntheses of each isomer
formed in the reaction, we have studied the ratio of products 3i/4i
formed from azolyl triazole 1c and sulfonyl chloride 2c
depending on the nature of the solvent and temperature (Table 2).
We have not found any significant change in the ratio of isomers
for the reaction in different solvents. Conversely, the amount of
2-substited isomer 4i increases at higher temperatures. On the
other hand, the content of 1-substituted 1,2,3-triazoles increases
with lowering of the reaction temperature. In order to get some
insight into this different reactivity behavior density functional
theory calculations (M06-2X32-34) for the starting azoles 1a–e as
well as the regioisomeric products 3a, 4a, 5a; 3g, 4g, 5g; 3m,

4
Tetrahedron
ACCEPTED MANUSCRIPT
4m, and 5m have been performed. Since the reaction is base
catalyzed, the anions of the starting materials have been used in
Fig. 2. ORTEP of the compound 4c according XRD data
Table 3 (See Supplementary data) lists the Fukui index f–
describing the nucleophilicities of the relevant nitrogen atoms.
While in a charged-controlled reaction addition of the sulfonyl
chloride preferentially should occur at N1 or N3 (this latter attack
can be safely ruled out on thermodynamic grounds), in an orbital-
controlled reaction formation of 2-sulfonyl derivatives will be
preferred.
Fig.1. ORTEP of the compound 3a according XRD data
the calculations. Different conformations resulting from torsion
around C1–C2, C3–C4, and N1–S2 (3a, 3g, 3m), N2–S1 (4a, 4g,
4m) or N3–S2 (5a, 5g, 5m) were considered. Solvent effects
(EtOH) were taken into account by the SMD solvation model.35
In complete agreement with the X-ray data for 3a and 4c the
calculated lowest energy conformations of 3a and 4a are
characterized by an approximately planar arrangement of both
the heterocyclic rings and the ester group [τ(S1–C3–C4–C5)
~180°, τ(C3–C2–C1–O4) ~ 1°; for atom numbering, see Fig. 1)
and an approximately perpendicular orientation of the R-sulfonyl
moiety. Substitution at N3 is strongly disfavored since products
of type 5 are less stable than those of type 3 and 4 by ca. 6 kcal
mol–1. Generally, on thermodynamic grounds, substitution at N2,
i.e. formation of compounds of type 4, should preferentially
occur [∆∆G = -1.32 (4a), -1.95 (4g), and -0.34 kcal mol–1 (4m)].
As an alternative to product stability the reactivity of the
reactants also have been considered. Specifically, the charges q at
the possible reactive sites N1, N2, N3 obtained by several
population analyses (Mulliken,36 NPA,37 Hirshfeld,38 and ESP-
derived charges (CHelpG39)) were used as reactivity indices. The
results are presented in Table 1 in the Supplementary data.
Although both basis sets used as well as method of population
analysis affect the individual values generally the smallest
charges are found at N2 while those at N1 and N3 are similar and
significantly more negative. Recently, conceptual density
functional theory has become an important tool to assess the
reactivity of different molecules and/or different sites within one
molecule.40-42
3. Conclusions
4-Azolyl- and 4-phenyl-1,2,3-triazoles 3a-p/4a-p have been
shown to react with sulfonyl chlorides 2a-d at N1 and N2 of the
triazole ring to form mixtures of 1-sulfonyl- and 2-sulfonyl
substituted 4-azolyl(phenyl)-1,2,3-triazoles. No reaction at N3
could be observed. The ratio of isomeric products depends on the
nature of both the azole ring and the sulfonyl chlorides. 1,2,3-
Thiadiazole 1a and isoxazole 1d react with mesyl chloride (2a)
and tosyl chloride (2b) to form mainly 1-substituted 1,2,3-
triazoles. Conversely, reaction of 1a and oxadiazolyl triazole 1c
with more bulky 1-(2,4-dimethylphenyl)sulfonyl chloride (2c)
has been shown to give mainly 2-substituted product, most
probably because of more steric hindrance in compounds bearing
a 2,4-dimethylphenyl group than tosyl and mesyl moieties.
Density functional calculations indicate that, in agreement with
experimental observations, the third isomers 5 should not be
formed. Based on calculated product stabilities, 2-sulfonyl-4-
azolyl-1,2,3-triazoles are the preferred products. However, under
kinetic control, a delicate balance between nitrogen charges and
nucleophilicities either can lead to 1- and/or 2-sulfonyl
derivatives.
4. Experimental Section
4.1. General
Table 2. Effect of solvent and temperature on the ratio of
sulfonyltriazoles 3i and 4i
1H and 13C NMR spectra were recorded on Bruker Avance II
spectrometer in CDCl3 or DMSO-d6 (400 and 100 MHz,
respectively) using Me4Si as an internal standard. Mass
experiments were performed on Shimadzu GCMS-QP2010 Ultra
gas chromatograph operating at an ionization potential of 70 eV
(EI) or Thermo Finnigan LCQ Advantage apparatus (ESI).
Microanalyses were performed on PerkinElmer Series II
CHNS/O 2400 elemental analyzer. The melting point was
defined on Stuart SMP 3 apparatus.
Entry
Ratio 3i:4ia
13:87
14:86
8:92
Solvent
1,4-dioxane
CHCl3
CH3CN
Et2O
Temperature, °C
Yield, %
62
1
2
3
4
5
6
7
8
20
20
20
20
0
91
73
9:91
94
The progress of the reactions and the purity of the compounds
were monitored by TLC on TLC Silica gel 60 F245 Aluminum
sheets (Merck KGaA) in EtOAc-hexane (1:2) system.
33:67
12:88
9:91
EtOH
73
EtOH
20
40
60
79
EtOH
78
4.2. X-ray diffraction study
7:93
EtOH
70
4.2.1. X-ray diffraction study of 3a.
a Determined by 1H NMR analysis
Single crystals of 3a were obtained by recrystallization from
EtOAc. X-ray diffraction data for single crystals of 3a were

5
collected on an Xcalibur3 X-ray diffractometer equipped with a
CCD detector (λ-Mo-Kα, graphite monochromator, ω-scanning
technique). The structure was determined by the direct method
using the SHELXS97 program43 and refined by the SHELXL97
program using the least-squares method in the anisotropic form
Hz, OCH2CH3), 3.63 (3H, s, SO2CH3), 4.59 (2H, qv., J 8.0 Hz,
ACCEPTED MANUSCRIPT
J 16.0 Hz, OCH2CH3), 9.36 (s, 1H, C5–H); 13C NMR (100 MHz,
CDCl3): δ 14.4, 43.0, 63.0, 125.1, 136.1, 147.4, 150.7, 161.2;
Anal. Calcd for C8H9N5O4S2 (303.32): C, 31.68; H, 2.99; N,
23.09; S, 21.14. Found: C, 31.79; H, 2.82; N, 23.28; S, 21.19.
(isotropic for
H
atoms). Prismatic colorless crystal
4.4.1. Ethyl 5-(1-tosyl-1H-1,2,3-triazol-4-yl)-1,2,3-thiadiazole-4-
carboxylate (3b) and ethyl 5-(2-tosyl-2H-1,2,3-triazol-4-yl)-
1,2,3-thiadiazole-4-carboxylate (4b).
0.20x0.15x0.10 mm. Crystal system is monoclinic, a =
25.9490(11) Å,
b =
6.6154(3) Å,
c =
16.6949(6) Å,
β =120.056(4)°, V =2480.55(19) Å3, Completeness 99.9%., space
group C2/c, formula is C8H9N5O4S2 (for Z= 8), µ(Mo Kα) =
0.448, 5969 reflections measured, 3077 unique (Rint = 0.0249)
which were used in all calculations. The final wR2 was 0.1316
(all data) and R1 was 0.0385 (I>=2σ (I)), GooF = 1.009. Largest
diff. peak and hole 0.458 and -0.360 ēÅ-3.
Colourless crystals, yield 93%, 0.46 g, mp 152–159 °C; 3b/4b
ratio is 75:25; 1H NMR (400 MHz, CDCl3): δ 1.45–1.54 (3H, m,
OCH2CH3), 2.45 (4b), 2.47 (3b) (3H, 2s, SO2C6H4CH3), 4.52–
4.62 (2H, m, OCH2CH3), 7.38–7.43 (2H, m, Harom.), 8.01–8.07
(2H, m, Harom.), 8.74 (4b), 9.35 (3b) (1H, 2s, C5-H); 13C NMR
(100 MHz, DMSO-d6): δ 13.7, 14.0, 20.7, 21.2, 61.9, 62.1, 125.5,
126.0, 128.1, 128.6, 128.8, 130.9, 131.0, 134.0, 135.6, 136.7,
138.0, 139.4, 145.1, 146.5, 148.0, 151.9, 159.5, 160.3; MS m/z EI
(70 eV), (I, %): 379 (M+, 7), 155 (40), 152 (38), 91 (100); Anal.
Calcd for C14H13N5O4S2 (379.41): C, 44.32; H, 3.45; N, 18.46; S,
16.90. Found: C, 44.65; H, 3.69; N, 18.63; S, 16.71.
4.2.2. X-ray diffraction study of 4c.
Single crystals of 4c were obtained by crystallization from
EtOAc. A suitable crystal was selected and examined on a
Xcalibur, Eos diffractometer. The crystal was kept at 293(2) K
during data collection. Using Olex2,44 the structure was estimated
with the Superflip45 structure solution program using Charge
Flipping and refined with the ShelXL43 refinement package using
Least Squares minimisation. C15H15N5O4S2, M =393.44, triclinic,
a = 4.9502(4) Å, b = 12.0870(7) Å, c = 15.2704(9) Å, α =
104.228(5)°, β = 98.802(6)°, γ = 97.850(6)°, V = 860.63(10) Å3,
T = 293(2), space group P-1 (no. 2), Z = 2, µ(Mo Kα) = 0.343,
7744 reflections measured, 4662 unique (Rint = 0.0336) which
were used in all calculations. The final wR2 was 0.1270 (all data)
and R1 was 0.0592 (>2sigma(I)).
4.4.2. Ethyl 5-(1-(2,4-dimethylphenylsulfonyl)-1H-1,2,3-triazol-
4-yl)-1,2,3-thiadiazole-4-carboxylate (3c) and ethyl 5-(2-(2,4-
dimethylphenylsulfonyl)-2H-1,2,3-triazol-4-yl)-1,2,3-thiadiazole-
4-carboxylate (4c).
Colourless crystals, yield 90%, 0.41 g, mp 153–156 °C; 3c/4c
ratio is 33:67; 1H NMR (400 MHz, CDCl3): δ 1.46–1.56 (3H, m,
OCH2CH3), 2.41, 2.68 (3c) (3H, 2s, SO2C6H3(CH3)2), 2.40, 2.67
(4c) (3H, 2s, SO2C6H3(CH3)2), 4.53–4.62 (2H, m, OCH2CH3),
7.16–7.28 (2H, m, Harom.), 8.14–8.18 (1H, m, Harom.), 8.75 (4c),
9.36 (3c) (1H, 2s, C5–H); MS m/z EI (70 eV), (I, %): 393 (M+,
8), 169 (100), 152 (60), 105 (81); Anal. Calcd for C15H15N5O4S2
(393.44): C, 45.79; H, 3.84; N, 17.80; S, 16.30. Found: C, 46.03;
H, 3.62; N, 18.12; S, 16.38.
Deposition numbers for compounds 3a (CCDC 1400853) and
4c (CCDC 1400852) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
4c. Colourless crystals, yield 50%, 0.23 g, mp 176–178 °C
(from EtOAc); H NMR (400 MHz, CDCl3): δ 1.48 (3H, t, J 8.0
4.3. Quantum chemical calculations
1
Quantum chemical calculations were done with Gaussian09,46
Hz, OCH2CH3), 2.40 (3H, s, SO2C6H3CH3), 2.67 (3H, s,
SO2C6H3CH3), 4.55 (2H, qv., J 8.0 Hz, J 16.0 Hz, OCH2CH3),
7.16 (1H, s, Harom.), 7.24 (1H, d, J 8.0 Hz, Harom.), 8.15 (1H, d, J
8.0 Hz, Harom.), 8.75 (1H, s, C5–H); 13C NMR (100 MHz, DMSO-
d6): δ 14.0, 20.0, 20.5, 61.9, 125.1, 126.6, 127.3, 131.3, 134.0,
135.3, 137.9, 143.3, 146.5, 151.9, 160.3; 13C NMR (100 MHz,
CDCl3): δ 14.2, 20.7, 21.6, 62.8, 127.9, 130.5, 131.8, 134.1,
137.9, 138.9, 140.2, 147.6, 148.6, 149.5, 160.5; Anal. Calcd for
C15H15N5O4S2 (393.44): C, 45.79; H, 3.84; N, 17.80; S, 16.30.
Found: C, 45.91; H, 3.65; N, 17.60; S, 16.38.
GAMESS,47,48 and Jaguar.49
4.4. General synthetic procedure, exemplified by the
regioisomeric mixture of ethyl 5-(1-(methylsulfonyl)-1H-
1,2,3-triazol-4-yl)-1,2,3-thiadiazole-4-carboxylate (3a) and
ethyl 5-(2-(methylsulfonyl)-2H-1,2,3-triazol-4-yl)-1,2,3-
thiadiazole-4-carboxylate (4a).
A mixture of triazole 1a (0.575 g, 2.55 mmol), mesyl chloride
(2a) (0.35 g, 0.23 mL, 3.06 mmol) and DIPEA (0.39 g, 0.506
mL, 3.06 mmol) in anhydrous ethanol (4 mL) was stirred at room
temperature for 1 h. The formed precipitate was filtered off and
washed with anhydrous ethanol to give a mixture of isomeric 1-
and 2-sulfonyl-1,2,3-triazoles 3a and 4a in 90:10 ratio.
4.4.3. Methyl 5-(1-(methylsulfonyl)-1H-1,2,3-triazol-4-yl)-1,2,3-
thiadiazole-4-carboxylate (3d) and methyl 5-(2-(methylsulfonyl)-
2H-1,2,3-triazol-4-yl)-1,2,3-thiadiazole-4-carboxylate (4d).
Colourless crystals, yield 86%, 0.12 g, mp 176–177 °C; 3d/4d
ratio is 79:21; 1H NMR (400 MHz, CDCl3): δ 3.54 (4d), 3.64 (3d)
(3H, 2s, SO2CH3), 4.14 (3H, s, COOCH3), 8.90 (4d), 9.39 (3d)
(1H, 2s, C5-H); 13C NMR (100 MHz, CDCl3): δ 41.8, 42.9, 53.4,
53.5, 125.0, 129.4, 135.9, 138.3, 145.8, 146.9, 150.8, 154.0,
160.9, 161.4; MS m/z EI (70 eV), (I, %): 289 (M+, 8), 152 (66),
79 (100), 59 (97); Anal. Calcd for C7H7N5O4S2 (289.29): C,
29.06; H, 2.44; N, 24.21; S, 22.17. Found: C, 28.75; H, 2.29; N,
24.42; S, 22.41.
Crystallization of the mixture of triazoles 3a/4a gives pure 1-
sulfonyl substituted triazole 3a, the mixture of 3c/4c gives 2-
sulfonyl substituted triazole 4c, and the mixture of 3i/4i gives 2-
sulfonyl substituted triazole 4i (double recrystallization).
3a/4a. Colourless crystals, yield 64%, 0.49 g, mp 140–144 °C;
1H NMR (400 MHz, CDCl3): δ 1.52 (3H, t, J 8.0 Hz, OCH2CH3),
3.53 (4a), 3.63 (3a) (3H, 2s, SO2CH3), 4.59 (2H, qv., J 8.0 Hz, J
16.0 Hz, OCH2CH3), 8.87 (4a), 9.36 (3a) (1H, 2s, C5–H); MS
m/z EI (70 eV), (I, %): 303 (M+, 5), 152 (68), 79 (100), 69 (98);
Anal. Calcd for C8H9N5O4S2 (303.32): C, 31.68; H, 2.99; N,
23.09; S, 21.14. Found: C, 31.82; H, 3.22; N, 23.36; S, 21.46.
4.4.4. Methyl 5-(1-tosyl-1H-1,2,3-triazol-4-yl)-1,2,3-thiadiazole-
4-carboxylate (3e) and methyl 5-(2-tosyl-2H-1,2,3-triazol-4-yl)-
1,2,3-thiadiazole-4-carboxylate (4e).
3a. Colourless crystals, yield 49%, 0.30 g, mp 169–171 °C
(from EtOAc); H NMR (400 MHz, CDCl3): δ 1.52 (3H, t, J 8.0
1
Colourless crystals, yield 92%, 0.16 g, mp 134–137 °C; 3e/4e
ratio is 69:31; 1H NMR (400 MHz, CDCl3): δ 2.45 (4e), 2.47 (3e)

6
Tetrahedron
ACCEPTED MANUSCRIPT
(3H, 2s, SO2C6H4CH3), 4.08 (4e), 4.13 (3e) (3H, 2s, COOCH3),
125.5, 126.0, 126.1, 127.5, 127.6, 127.9, 128.1, 128.9, 129.0,
7.38–7.44 (2H, m, Harom.), 8.02–8.08 (2H, m, Harom.), 8.76 (4e),
9.36 (3e) (1H, 2s, C5–H); 13C NMR (100 MHz, CDCl3): δ 21.9,
22.0, 53.3, 53.4, 124.9, 125.9, 129.0, 129.2, 130.5, 130.7, 132.0,
132.3, 135.7, 138.3, 139.2, 146.7, 147.7, 148.1, 149.6, 151.2,
160.9, 161.4; MS m/z EI (70 eV), (I, %): 365 (M+, 7), 155 (30),
91 (100), 65 (30); Anal. Calcd for C13H11N5O4S2 (365.39): C,
42.73; H, 3.03; N, 19.17; S, 17.55. Found: C, 43.03; H, 2.86; N,
18.95; S, 17.66.
130.4, 131.6, 131.7, 131.9, 133.8, 134.1, 134.4, 137.1, 137.5,
140.2, 140.3, 147.8, 148.3, 167.4, 167.6, 169.0, 169.2; MS m/z EI
(70 eV), (I, %): 381 (M+, 10), 169 (13), 105 (100), 77 (40); Anal.
Calcd for C18H15N5O3S (381.41): C, 56.68; H, 3.96; N, 18.36; S,
8.41. Found: C, 56.91; H, 4.21; N, 18.23; S, 8.59.
4i: Colourless crystals, yield 26%, 0.23 g, mp 176–178 °C
(from EtOAc, double recrystallization); H NMR (400 MHz,
CDCl3):
1
δ 2.40 (3H, s, SO2C6H3(CH3)2), 2.69, (3H, s,
4.4.5. Methyl 5-(1-(4-fluorophenylsulfonyl)-1H-1,2,3-triazol-4-
yl)-1,2,3-thiadiazole-4-carboxylate (3f) and methyl 5-(2-(4-
fluorophenylsulfonyl)-2H-1,2,3-triazol-4-yl)-1,2,3-thiadiazole-4-
carboxylate (4f).
SO2C6H3(CH3)2), 7.17 (1H, s, Harom.), 7.26 (1H, d, J 8.0 Hz,
Harom.), 7.49–7.55 (3H, m, Harom.), 8.15 (2H, d, J 8.0 Hz, Harom.),
8.20 (1H, d, J 8.0 Hz, Harom.), 8.43 (1H, s, C5–H); 13C NMR (100
MHz, CDCl3): δ 20.6, 21.6, 126.0, 127.6, 127.9, 128.9, 130.5,
131.6, 131.9, 134.1, 137.1, 137.5, 140.4, 147.7, 167.5, 169.2;
Anal. Calcd for C18H15N5O3S (381.41): C, 56.68; H, 3.96; N,
18.36; S, 8.41. Found: C, 56.59; H, 3.87; N, 18.30; S, 8.47.
Colourless crystals, yield 83%, 0.081 g, mp 129–132 °C; 3f/4f
ratio is 63:37; 1H NMR (400 MHz, CDCl3): δ 4.07 (4f), 4.12 (3f)
(3H, 2s, COOCH3), 7.29–7.35 (2H, m, Harom.), 8.15–8.23 (2H, m,
Harom.), 8.77 (4f), 9.36 (3f) (1H, 2s, C5–H); 13C NMR (100 MHz,
CDCl3): 53.3, 53.4, 117.5, 117.7, 125.0, 131.0, 131.3, 132.2,
132.3, 135.8, 146.4, 148.4, 149.3, 150.9, 160.8, 161.4, 167.2,
167.3; MS m/z EI (70 eV), (I, %): 369 (M+, 10), 277 (20), 159
(57), 95 (100); Anal. Calcd for C12H8FN5O4S2 (369.35): C, 39.02;
H, 2.18; N, 18.96; S, 17.36. Found: C, 39.14; H, 2.24; N, 18.90;
S, 17.58.
4.4.9. 5-(1-(Methylsulfonyl)-1H-1,2,3-triazol-4-yl)-3-
phenylisoxazole-4-carbonitrile (3j) and 5-(2-(methylsulfonyl)-
2H-1,2,3-triazol-4-yl)-3-phenylisoxazole-4-carbonitrile (4j).
Colourless crystals, yield 40%, 0.16 g, mp 150–153 °C (from
EtOAc); 3j/4j ratio is 90:10; 1H NMR (400 MHz, CDCl3): δ 3.63
(4j), 3.69 (3j) (3H, 2s, SO2CH3), 7.54–7.62 (3H, m, Harom.), 8.01–
8.04 (2H, m, Harom.), 8.53 (4j), 8.81 (3j) (1H, 2s, C5-H); 13C
NMR (100 MHz, CDCl3): 41.8, 42.9, 110.8, 111.1, 123.7, 125.4,
125.6, 127.5, 129.4, 129.5, 131.8, 131.9, 133.8, 134.2, 134.9,
136.2, 137.6, 146.3, 161.8, 162.0, 166.3, 166.6; MS m/z EI (70
eV), (I, %): 315 (M+, 8), 236 (32), 169 (20), 79 (Ms, 100); Anal.
Calcd for C13H9N5O3S (315.31): C, 49.52; H, 2.88; N, 22.21; S,
10.17. Found: C, 49.19; H, 3.17; N, 22.45; S, 9.98.
4.4.6. 5-(1-(Methylsulfonyl)-1H-1,2,3-triazol-4-yl)-3-phenyl-
1,2,4-oxadiazole (3g) and 5-(2-(methylsulfonyl)-2H-1,2,3-triazol-
4-yl)-3-phenyl-1,2,4-oxadiazole (4g).
Colourless crystals, yield 63%, 0.40 g, mp 122–127 °C; 3g/4g
ratio is 50:50; 1H NMR (400 MHz, CDCl3): δ 3.60 (4g), 3.67 (3g)
(3H, 2s, SO2CH3), 7.50–7.59 (3H, m, Harom.), 8.17–8.20 (2H, m,
Harom.), 8.55 (4g), 8.86 (3g), (1H, 2s, C5–H); 13C NMR (100
MHz, CDCl3): δ 41.9, 42.9, 125.4, 125.9, 126.0, 127.7, 128.9,
129.0, 129.1, 131.5, 131.7, 131.8, 137.7, 137.9, 147.6, 149.3,
167.1, 167.2, 169.2, 169.3; MS m/z EI (70 eV), (I, %): 291 (M+,
10), 212 (21), 145 (47), 79 (Ms, 100); Anal. Calcd for
C11H9N5O3S (291.29): C, 45.36; H, 3.11; N, 24.04; S, 11.01.
Found: C, 45.13; H, 3.25; N, 24.11; S, 11.09.
4.4.10. 3-Phenyl-5-(1-tosyl-1H-1,2,3-triazol-4-yl)isoxazole-4-
carbonitrile (3k) and 3-phenyl-5-(2-tosyl-2H-1,2,3-triazol-4-
yl)isoxazole-4-carbonitrile (4k).
Colourless crystals, yield 95%, 0.25 g, mp 198-201 °C; 3k/4k
1
ratio is 55/45; H NMR (400 MHz, CDCl3): δ 2.46 (4k), 2.49
(3k) (3H, 2s, SO2C6H4CH3), 7.41–7.46 (2H, m, Harom.), 7.52–7.60
(3H, m, Harom.), 7.98–8.01 (2H, m, Harom.), 8.07–8.12 (2H, m,
Harom.), 8.40 (4k), 8.79 (3k) (1H, 2s, C5–H); 13C NMR (100 Mz,
CDCl3): δ 21.9, 22.0, 110.7, 111.1, 123.6, 125.5, 127.5, 125.7,
129.2, 129.3, 129.4, 129.5, 130.6, 130.8, 131.7, 131.8, 134.0,
136.1, 137.4, 147.9, 148.5, 161.7, 161.8, 166.3, 166.6; MS m/z EI
(70 eV), (I, %): 391 (M+, 9), 139 (100), 91 (93), 77 (29); Anal.
Calcd for C19H13N5O3S (391.40): C, 58.30; H, 3.35; N, 17.89; S,
8.19; Found: C, 58.59; H, 3.08; N, 17.76; S, 8.37.
4.4.7. 3-Phenyl-5-(1-tosyl-1H-1,2,3-triazol-4-yl)-1,2,4-
oxadiazole (3h) and 3-phenyl-5-(2-tosyl-2H-1,2,3-triazol-4-yl)-
1,2,4-oxadiazole (4h).
Colourless crystals, yield 85%, 0.29 g, mp 177–180 °C; 3h/4h
1
ratio is 50:50; H NMR (400 MHz, CDCl3): δ 2.45 (4g), 2.48
(3h) (3H, 2s, SO2C6H5CH3), 7.40–7.45 (2H, m, Harom.), 7.48–7.56
(3H, m, Harom.), 8.06–8.10 (2H, m, Harom.), 8.14–8.17 (2H, m,
Harom.), 8.43 (4h), 8.86 (3h) (1H, 2s, C5–H); 13C NMR (100
MHz, CDCl3): δ 21.8, 21.9, 125.4, 126.0, 126.1, 127.5, 127.6,
128.9, 129.0, 129.1, 129.3, 130.5, 130.8, 131.6, 131.7, 132.0,
132.1, 133.9, 137.5, 137.9, 147.8, 148.4, 167.4, 167.6, 169.0,
169.2; MS m/z EI (70 eV), (I, %): 367 (M+, 9), 155 (40), 145
(33), 91 (100); Anal. Calcd for C17H13N5O3S (367.38): C, 55.58;
H, 3.57; N, 19.06; S, 8.73. Found: C, 55.39; H, 3.89; N, 18.96; S,
8.64.
4.4.11. 5-(1-(2,4-Dimethylphenylsulfonyl)-1H-1,2,3-triazol-4-
yl)-3-phenylisoxazole-4-carbonitrile
(3l)
and
5-(2-(2,4-
dimethylphenylsulfonyl)-2H-1,2,3-triazol-4-yl)-3-
phenylisoxazole-4-carbonitrile (4l).
Colourless crystals, yield 91%, 0.124 g, mp 142–145 °C; 3l/4l
ratio is 59:41; 1H NMR (400 MHz, CDCl3): δ 2.40 (4l), 2.43 (3l)
(3H, 2s, SO2C6H3(CH3)2), 2.70 (3l), 2.75 (4l) (3H, 2s,
SO2C6H3(CH3)2), 7.19–7.29 (2H, m, Harom.), 7.53–7.60 (3H, m,
Harom.), 7.97–8.02 (2H, m, Harom.), 8.15–8.20 (1H, m, Harom.), 8.39
(4l), 8.81 (3l) (1H, 2s, C5–H); 13C NMR (100 Mz, CDCl3): δ
20.8, 20.9, 21.6, 21.7, 110.7, 111.1, 123.2, 123.6, 125.5, 125.7,
127.5, 127.9, 128.2, 129.3, 129.4, 130.3, 131.6, 131.7, 131.9,
133.9, 134.2, 134.4, 135.8, 137.1, 140.4, 140.7, 147.9, 148.4,
161.7, 161.8, 166.3, 166.7; MS m/z EI (70 eV), (I, %): 405 (M+,
11), 169 (30), 105 (100), 77 (66); Anal. Calcd for C20H15N5O3S
(405.43): C, 59.25; H, 3.73; N, 17.27; S, 7.91; Found: C, 59.55;
H, 3.45; N, 17.35; S, 8.17.
4.4.8. 5-(1-(2,4-Dimethylphenylsulfonyl)-1H-1,2,3-triazol-4-yl)-
3-phenyl-1,2,4-oxadiazole (3i) and 5-(2-(2,4-
dimethylphenylsulfonyl)-2H-1,2,3-triazol-4-yl)-3-phenyl-1,2,4-
oxadiazole (4i).
Colourless crystals, yield 80%, 0.71 g, mp 150–153 °C; 3i/4i
ratio is 12:88; 1H NMR (400 MHz, CDCl3): δ 2.40 (4i), 2.43 (3i)
(3H, 2s, SO2C6H3(CH3)2), 2.68 (3i), 2.69 (4i) (3H, 2s,
SO2C6H3(CH3)2), 7.17–7.29 (2H, m, Harom.), 7.49–7.56 (3H, m,
Harom.), 8.14–8.22 (3H, m, Harom.), 8.43 (4i), 8.88 (3i) (1H, 2s,
C5–H); 13C NMR (100 MHz, CDCl3): δ 20.6, 20.7, 21.6, 21.7,

7
4.4.12. Methyl 3-phenyl-5-(1-tosyl-1H-1,2,3-triazol-4-
yl)isoxazole-4-carboxylate (3m) and methyl 3-phenyl-5-(2-tosyl-
2H-1,2,3-triazol-4-yl)isoxazole-4-carboxylate (4m).
Professor Fan Zhijin thanks The International Science &
ACCEPTED MANUSCRIPT
Technology Cooperation Program of China (2014DFR41030)
and the National Natural Science Foundation of China
(21372132) for financial support; TVB thanks The Ministry of
Education and Science of the Russian Federation (State task
4.1626.2014/K), VAB thanks RFBR (14-03-01033), W.D. thanks
the KU Leuven and FWO-Vlaanderen.
Colourless crystals, yield 86%, 0.18 g, mp 95–99 °C; 3m/4m
1
ratio is 45:55; H NMR (400 MHz, CDCl3): δ 2.48 (4m), 2.50
(3m) (3H, 2s, SO2C6H4CH3), 3.80 (3H, s, CO2CH3), 7.41–7.55
(5H, m, Harom.), 7.62–7.66 (2H, m, Harom.), 8.08–8.11 (2H, m,
H
arom.), 8.57 (4m), 9.19 (3m) (1H, 2s, C5–H); 13C NMR (100
References
MHz, CDCl3): δ 21.8, 21.9, 52.2, 52.3, 109.1, 110.8, 125.9,
127.5, 127.9, 128.2, 128.3, 129.0, 129.1, 129.2, 130.1, 130.2,
130.5, 130.7, 132.2, 132.4, 134.2, 135.1, 138.4, 139.0, 147.6,
148.1, 161.6, 162.0, 162.6, 162.7, 162.8, 163.6; MS m/z EI (70
eV), (I, %): 424 (M+, 6), 155 (40), 143 (29), 91 (100); Anal.
Calcd for C20H16N4O5S (424.43): C, 56.60; H, 3.80; N, 13.20; S,
7.55. Found: C, 56.85; H, 4.07; N, 13.09; S, 7.63.
1. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057.
2. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, B. K.
Angew. Chem. Int. Ed. 2002, 41, 2596.
3. Mignani, S.; Zhou, Y.; Lecourt, T.; Micouin, L. Top Heterocycl.
Chem. 2012, 28, 185.
4. Bakulev, V.; Dehaen, W.; Beryozkina, T. Top Heterocycl. Chem.
2015, 40, 1.
4.4.13. Methyl 5-(1-(4-fluorophenylsulfonyl)-1H-1,2,3-triazol-4-
yl)-3-phenylisoxazole-4-carboxylate (3n) and methyl 5-(2-(4-
fluorophenylsulfonyl)-2H-1,2,3-triazol-4-yl)-3-phenylisoxazole-
4-carboxylate (4n).
5. Shafran, E. A.; Bakulev, V. A.; Rozin, Y. A.; Shafran, Y. M.
Chem. Heterocycl. Compd. 2008, 44, 1040.
6. Krivopalov, V. P.; Shkurko, O. R. Russ. Chem. Rev. 2005, 74,
339.
7. Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S.; Alexeev, S. G.
Khim. Geterotsikl. Soedin. 1984, 9, 1266.
8. Rozin, Y. A.; Leban, J.; Dehaen, W.; Nenajdenko, V. G.;
Muzalevskiy, V. M.; Eltsov, O. S.; Bakulev, V. A. Tetrahedron
2012, 68, 614.
Colourless crystals, yield 83%, 0.074 g, mp 135–137 °C;
3n/4n ratio is 37:63; H NMR (400 MHz, CDCl3): δ 3.76 (4n),
1
3.77 (4n) (3H, 2s, CO2CH3), 7.26–7.35 (2H, m, Harom.), 7.45–7.53
(3H, m, Harom.), 7.59–7.63 (2H, m, Harom.), 8.21–8.26 (2H, m,
Harom.), 8.58 (4n), 9.20 (3n) (1H, 2s, C5–H); 13C NMR (100
MHz, CDCl3): δ 52.2, 52.3, 109.8, 111.0, 117.6, 117.7, 126.0,
128.4, 129.2, 131.2, 131.4, 132.2, 132.3, 134.5, 135.3, 138.7,
139.3, 161.5, 162.0, 162.5, 162.6, 162.8, 163.4, 166.9, 167.3; MS
m/z EI (70 eV), (I, %): 428 (M+, 35), 143 (87), 95 (100), 77 (50);
Anal. Calcd for C19H13FN4O5S (428.39): C, 53.27; H, 3.06; N,
13.08; S, 7.48. Found: C, 53.48; H, 3.17; N, 13.11; S, 7.33.
9. Lebedev, A. T.; Bakulev, V. A.; Hayes, R. N.; Bowie, J. H. Rapid
Commun. Mass-spectrom. 1991, 5, 234.
10. Bakulev, V. A.; Tarasov, E. V.; Morzherin, Y. Y.; Luyten, I.;
Toppet, S.; Dehaen, W. Tetrahedron 1998, 54, 8501.
11. Bakulev, V. A.; Lebedev, A. T.; Dankova, E. F.; Mokrushin, V.
S.; Petrosyan, V. S. Tetrahedron 1989, 45, 7329.
12. Chattopadhyay, B.; Gevorgyan, V. Angew. Chem. Int. Ed. 2012,
51, 862.
13. Gulevich, A. V.; Gevorgyan, V. Angew. Chem. Int. Ed. 2013, 52,
1371.
14. Davies, H. M. L.; Alford, J. S. Chem. Soc. Rev. 2014, 34, 5151.
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16. Leban, J.; Tasler, S.; Saeb, W.; Chevrier C., WO 2012/101263,
2012.
17. Meza-Aviña, M. E.; Patel, M. K.; Lee, C. B.; Dietz, T. J.; Croatt,
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37, 1797.
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Sharpless, K. B.; Chang, S. Angew. Chem. Int. Ed. 2007, 46, 1730.
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U.; Leban, J.; Zhi-Jin, F.; Eltsov, O.; Slepukhin, P.; Ezhikova, M.;
Dehaen, W. Eur. J. Org. Chem. 2014, 17, 3684.
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V. V. J. Am. Chem. Soc. 2008, 130, 14972.
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8210.
27. Potapova, I. A.; Purygin, P. P.; Lipatov, I. S.; Belousova, Z. P.;
Yakimova, N. A.; Tezikov, Yu. V.; Selezneva, E. S. Pharm.
Chem. J. 2001, 35, 588.
28. Belousova, Z. P.; Lipatov, I. S.; Potapova, I. A.; Tezikov, Yu. V.;
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Chem. J., 2009, 46, 297.
4.4.14. 4-Phenyl-1-tosyl-1H-1,2,3-triazole (3o) and 4-phenyl-2-
tosyl-2H-1,2,3-triazole (4o).
Colourless crystals, yield 89%, 0.09 g, mp 110–112 °C; 3o/4o
ratio is 70:30; 1H NMR (400 MHz, CDCl3): δ 2.41 (4o), 2.44 (3o)
(3H, 2s, SO2C6H4CH3), 7.32–7.45 (5H, m, Harom.), 7.81–7.83 (2H,
m, Harom.), 7.98–8.03 (2H, m, Harom.), 8.07 (4o), 8.32 (3o) (1H, 2s,
C5–H); 13C NMR (100 Mz, CDCl3): δ 21.6, 21.7, 118.8, 126.5,
125.9, 128.0, 128.5, 128.4, 128.7, 129.7, 128.9, 129.8, 129.0,
130.0, 130.3, 132.8, 132.9, 135.6, 146.5, 147.1, 151.3; MS
(ESI+): m/z: 322 [M+Na]+. Anal. Calcd for C15H13N3O2S
(299.35): C, 60.18; H, 4.38; N, 14.04; S, 10.71. Found: C, 60.49;
H, 4.58; N, 13.99; S, 10.89.
4.4.15. 1-(2,4-Dimethylphenylsulfonyl)-4-phenyl-1H-1,2,3-
triazole (3p) and 1-(2,4-dimethylphenylsulfonyl)-4-phenyl-1H-
1,2,3-triazole (4p).
Colourless crystals, yield 74%, 0.08 g, mp 120–123 °C; 3p/4p
ratio is 60:40; 1H NMR (400 MHz, CDCl3): δ ): δ 2.37 (4p), 2.38
(3p) (3H, 2s, SO2C6H4CH3), δ 2.61 (3p), 2.67 (4p) (3H, 2s,
SO2C6H4CH3), 7.11–7.26 (2H, m, Harom.), 7.42–7.44 (2H, m,
Harom.), 7.80–7.84 (2H, m, Harom.), 8.11–8.15 (2H, m, Harom.), 8.06
(4p), 8.34 (3p) (1H, 2s, C5–H); 13C NMR (100 Mz, CDCl3): δ
20.2, 20.7, 21.5, 21.6, 126.2, 126.8, 127.7, 127.9, 128.5, 129.1,
130.0, 130.2, 131.3, 131.4, 131.6, 133.4, 133.9, 134.2, 135.2,
138.2, 139.9, 144.6, 146.8, 151.1 ; MS (ESI+): m/z: 336
[M+Na]+. Anal. Calcd for C16H15N3O2S (313.37): C, 61.32; H,
4.82; N, 13.41; S, 10.23; Found: C, 61.57: H, 5.02; N, 13.20; S,
10.30.
29. Meshcheryakov, V. I.; Shainyan, B. A.; Tolstikova, L. L.;
Albanov, A. I. Russ. J. Org. Chem. 2003, 39, 1517.
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2009, 113, 6378.
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8
Tetrahedron
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Supplementary Material
Supplementary data associated with this article can be found
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Supplementary Data
Reactivity of 1,2,3-triazoles towards sulfonyl chlorides. A novel approach to 1- and 2-
sulfonyl-4-azolyl-1,2,3-triazoles
Tetyana V. Beryozkinaa*, Ilya V. Efimova, Walter M. F. Fabianb, Nikolai A. Beliaeva, Pavel
A. Slepukhina, Maxim L. Isenovc, Wim Dehaend, Gert Lubece, Oleg S. Eltsova, Zhijin Fanf*,
Joice Thomasd and Vasiliy A. Bakuleva
a Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira st.,
620002, Yekaterinburg, Russia;
b Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz,
Austria;
c I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Science,
20 S. Kovalevskaya st., 620990, Yekaterinburg, Russia;
d Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F,
3001 Leuven, Belgium
e Medical University of Vienna, Department of Pediatrics, 1090, 14 Lazarettgasse, Vienna,
Austria
f State Key Laboratory of Elemento-Organic Chemistry Nankai University, Collaborative
Innovation Center of Chemical Science and Engineering 300071, Tianjin, China
E-mail: tetber@mail.ru; fanzj@nankai.edu.cn
Table of contens
Density functional calculations
NMR spectra
2
5
Hydrolysis of 2-sulfonyl-1,2,3-triazole 3i/4i
14

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1. Density functional calculations
Table 3 Atomic charges q obtained by various population analyses [M06-2X/6-31G(d,p)] and
Fukui index f–.
qa
Mulliken
-0.374
f–
NPA
Hirshfeld
-0.226
CHelpG
-0.379
N1
N2
N3
N1
N2
N3
N1
N2
N3
-0.367
(-0.374)
-0.118
(-0.129)
-0.328
(-0.334)
-0.369
(-0.373)
-0.137
(-0.147)
-0.309
(-0.312)
-0.362
0.071
1a
1c
1d
(-0.257)
-0.144
(-0.227)
-0.151
(-0.395)
-0.217
0.199
0.011
0.060
0.244
0.005
0.070
0.203
0.008
(-0.013)
-0.400
(-0.156)
-0.183
(-0.236)
-0.319
(-0.242)
-0.375
(-0.178)
-0.232
(-0.321)
-0.435
(-0.254)
-0.155
(-0.232)
-0.162
(-0.457)
-0.154
(-0.022)
-0.407
(-0.166)
-0.206
(-0.159)
-0.434
(-0.372)
-0.369
(-0.204)
-0.224
(-0.456)
-0.391
(-0.248)
-0.141
(-0.224)
-0.151
(-0.412)
-0.209
-0.124
-0.304
(0.040)
-0.408
(-0.154)
-0.186
(-0.223)
-0.311
(-0.359)
(-0.181)
(-0.308)

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N1
N2
N3
-0.371
-0.361
-0.125
-0.299
-0.223
-0.412
0.066
0.206
0.007
1e
(-0.248)
-0.143
(-0.223)
-0.152
(-0.427)
-0.155
(-0.017)
-0.394
(-0.155)
-0.197
(-0.163)
-0.411
(-0.357)
(-0.196)
(-0.428)
avalues in parentheses refer to M06-2x/6-311+G(2df,2p) results.
Table 4. Relative Gibbs free energies (kcal mol–1) in the gas phase and EtOH solution of reactant
conformations and product regioisomers/conformationsa
Compd
∆G
τ1
τ2
τ3
Gas phase
EtOH
1a–
0.00
0.00
-3.52
-4.06
0.00
-0.15
0.00
0.02
2.81
0.64
0.00
1.73
2.09
4.39
23.5
180.0
180.0
0.0
-131.0
-1.63
-2.20
0.00
-0.62
0.00
-0.25
6.16
2.45
0.00
5.09
4.46
6.24
-180.0
0.0
1b–
1c–
3a
-180.0
0.4
-179.8
54.3
-154.8
176.0
-1.0
123.7
126.1
124.5
-171.4
178.9
51.6
-150.9
-132.9
-134.4
-126.8
-107.9
44.2
36.0
4a
33.0

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3.78
3.84
3.57
-0.47
7.06
7.99
7.32
4.99
7.89
0.81
0.00
0.01
-1.34
-0.85
-1.15
5.42
5.20
5.69
0.48
0.63
0.00
0.19
-0.60
0.56
1.09
2.42
-1.32
5.12
6.22
5.08
4.82
7.74
0.20
0.00
-0.70
-1.95
-0.89
-0.74
5.91
5.96
5.98
0.00
0.20
0.82
1.16
0.54
-145.2
-144.0
54.5
168.9
170.7
17.3
-87.3
57.2
89.6
170.2
54.1
1.7
75.4
-171.4
-174.5
6.3
-54.6
-60.7
-54.2
61.4
5a
-80.4
52.0
60.9
2.4
-127.0
0.2
-20.0
-20.4
125.8
125.9
94.2
3g
4g
-179.7
0.6
1.0
111.4
90.5
-179.1
-178.7
27.5
128.0
106.0
-18.4
97.2
5g
-152.1
-133.9
-0.7
-127.2
126.7
-125.1
125.0
145.5
3m
1.7
-179.3
178.2
7.5
4m

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-0.49
5.86
5.47
6.00
5.13
-0.34
6.29
6.55
6.02
7.51
-180.0
-132.9
-145.4
132.8
47.1
88.6
96.5
5m
-22.6
-97.1
71.1
a anionic forms of reactants (N-deprotonated triazole ring). For products, within each series 3a –
5a, 3g – 5g, and 3m – 5m Gibbs free energies are given relative to the lowest energy
conformation of 3a, 3g, 3m, respectively. Torsional angles τ1, τ2, and τ3 describe the orientations
of the two heterocyclic rings [τ1 = τ(S1–C3–C4–C5) in compounds of series a, oxygen instead of
S1 for compounds 1b, 1c, and products of series g and m], the ester moiety [τ2 = τ(C3–C2–C1–
O4)], and the substituent of the sulfonyl group [τ3 = τ(X–Y–S2–C6) with X=C5, Y=N1 for 3,
X=N1, Y=N2 for 4; and X=N2, Y=N3 for 5]. For atom numbering see Fig. 1
2. NMR spectra

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2017
Berezkina TB-329
8E+08
7E+08
6E+08
6E+08
6E+08
5E+08
4E+08
4E+08
4E+08
3E+08
2E+08
2E+08
2E+08
1E+08
5E+07
0
-5E+07
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
f1 (мд)
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0

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3. Hydrolysis of 2-sulfonyl-1,2,3-triazole 3i/4i
A mixture of compounds 3i/4i (0.12 g, 0.3 mmol) was dissolved in HOAc (5 mL) and H2O (0.5
mL). The reaction mixture was stirred at 60 °C for 4 h, and then concentrated under reduced
pressure. The crude product was purified by flash column chromatography (EtOAc/hexane 1/3)
to yield 1c as colorless solid (0.04g, 60%). Mp 210-213°C. The spectral data were as described
in the literature.21