An effective method for the synthesis of 1,5-disubstituted 4-halo-1H-1,2,3-triazoles from magnesium acetylides

Article abstract of DOI:10.1007/s10593-018-2343-6

[Figure not available: see fulltext.] A simple one-pot two-stage method for the synthesis of disubstituted 4-chloro-, 4-bromo-, and 4-iodo-1,2,3-triazoles from terminal alkynes and organic azides is proposed.

Full text of DOI:10.1007/s10593-018-2343-6

DOI 10.1007/s10593-018-2343-6
Chemistry of Heterocyclic Compounds 2018, 54(7), 755–757
An effective method for the synthesis of 1,5-disubstituted
4-halo-1H-1,2,3-triazoles from magnesium acetylides
Iuliia V. Karsakova1, Alexander Yu. Smirnov2*, Mikhail S. Baranov2,3
1 Moscow M. V. Lomonosov State University,
1, Build. 3, Leninskie Gory, Moscow 119991, Russia; е-mail: julia.karsakova@yandex.ru
2 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences,
16/10 Miklukho-Maklaya St., Moscow 117997, Russia; е-mail: alexmsu@yandex.ru
3 Pirogov Russian National Research Medical University,
1 Ostrovityanova St., Moscow 117997, Russia; е-mail: baranovmikes@gmail.com
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(7), 755–757
Submitted January 24, 2018
Accepted July 4, 2018
A simple one-pot two-stage method for the synthesis of disubstituted 4-chloro-, 4-bromo-, and 4-iodo-1,2,3-triazoles from terminal
alkynes and organic azides is proposed.
Keywords: 4-halo-1,2,3-triazoles, organomagnesium compounds, 1,3-dipolar cycloaddition.
1,2,3-Triazoles are a well-studied class of heterocyclic
compounds. They find wide use to create dyes,1 polymers,2
energetic materials,3 as well as in organic synthesis and
homogeneous catalysis.4 1,2,3-Triazoles are most intensi-
vely studied in medicinal chemistry,5,6 as they exhibit
Our attempts to use this approach have shown that the
action of elemental iodine, chlorine, as well as N-chloro-
and N-iodosuccinimides, potassium iodide and chloride,
sodium hypochlorite, cyanuric chloride, sodium dichloro-
isocyanurate, and t-BuOCl on various triazolecarboxylic
acids does not lead to the production of target products.
As a result, we decided to use the reaction of non-
catalytic 1,3-dipolar cycloaddition of magnesium acetylides
to azides for the creation of 4-haloazoles, first described by
Akimova as a method for the synthesis of 1,5-disubstituted
triazoles.16,17 The mechanism of this reaction has not been
studied in detail, but it is assumed that at first a
nucleophilic attack of acetylide at the terminal nitrogen
atom of the azide group takes place (Scheme 1). The
resulting linear intermediate then closes to form 4-halo-
magnesium-1,2,3-triazoles, which give 1,5-disubstituted
derivatives during hydrolysis, as well as react with
electrophilic agents.17
Surprisingly, we found that this approach had not pre-
viously been utilized to synthesize 4-halotriazoles, and the
use of iodine, shown only in one example,18 turned out to
be ineffective. In our work, we investigated the possibility
of using other electrophiles and showed that the use of N-halo-
succinimides is the most effective (for 4-chloro derivatives,
perchloroethane with subsequent hydrolysis can also be used).
To carry out the reaction, the desired acetylene was
subjected to the action of methylmagnesium chloride, after
antitumor,7 antiparasitic,8 and antiviral9 activity.
A
powerful impetus in the development of the chemistry of
1,2,3-triazoles was the discovery of a highly effective
synthesis method, the 1,3-dipolar cycloaddition of terminal
alkynes to azides catalyzed by copper.10 However, this
approach makes it possible to obtain only 1,4-disubstituted
triazoles, while the creation of 1,4,5-trisubstituted
derivatives present a more difficult task.
Since one of the effective approaches to the
functionalization of heterocyclic compounds is employing
the cross-coupling reactions, the creation of various halo-
substituted triazoles becomes an important and urgent task.
Earlier, we already proposed an effective approach to the
synthesis of 5-halo derivatives11 which were successfully
used in the Suzuki–Miyaura reaction,12 but the issue of the
effective creation of various 4-halo-1,2,3-triazoles
remained open. It is known that 4-bromo derivatives can be
easily obtained by decarboxylation of triazolecarboxylic
acids in bromine water,13 however, more complex methods
of synthesis are often used to create 4-chloro- or
4-iodotriazoles,14,15 and analogous decarboxylation
methods are not described at all.
0009-3122/18/54(7)-0755©2018 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2018, 54(7), 755–757
Scheme 1
which the corresponding aryl azide was introduced into the
reaction mixture, followed by the corresponding
electrophile (Scheme 1). With this approach, no separation
of intermediate products is required, and the resulting
solutions of organomagnesium derivatives can be separated
and used to synthesize several different chloro-, bromo-,
and iodotriazoles 1–3. The method is demonstrated with 8
examples, all compounds were obtained with good yields.
It should be noted that the reaction requires strict
following of the temperature regime. Thus, the reaction of
acetylides with azides requires some heating, while the
addition of electrophiles requires cooling, since otherwise a
mixture of by-products will form leading to a decrease in
yield. It is interesting to note that similar reactions leading
to the formation of 1,5-disubstituted 1,2,3-1H-triazoles
have also been described for lithium derivatives,17 but an
attempt to carry out the proposed conversion using lithium
acetylides has led to a mixture of unidentifiable products.
To conclude, we have obtained a library of new halo-
substituted triazoles with various substituents. It was
shown that the nature and position of the substituents in the
aromatic azide practically do not influence the yield of the
reaction, while the replacement of aromatic acetylenes with
aliphatic, as well as bromine and chlorine with iodine,
leads to a decrease in the yield.
50°C and kept at this temperature for 1 h, then cooled to
room temperature, and the corresponding azide (11.0 mmol)
in anhydrous THF (5 ml) was added dropwise over 5 min.
The mixture was once more heated to 50°С and kept at this
temperature for 4 h. It was cooled to 0°С, and N-halo-
succinimide (20 mmol) was added in small portions with
vigorous stirring, then the mixture was kept at room
temperature for 12 h. Then distilled water (30 ml) was added,
the mixture stirred and extracted with ethyl acetate (3×50 ml).
The organic extracts were combined, washed with saturated
aqueous NaCl (2×35 ml), and dried over anhydrous Na2SO4.
The solvent was evaporated on the rotary evaporator, the
residue purified by column chromatography on silica gel
(eluent hexane–EtOAc, 5:1) and recrystallized from ethanol.
4-Chloro-1-phenyl-5-propyl-1H-1,2,3-triazole (1a).11
1
Yield 1.82 g (82%), white crystals, mp 80–82°С. H NMR
spectrum, δ, ppm (J, Hz): 0.86 (3H, t, 3J = 7.4,
CH2CH2CH3); 1.53 (2H, sex, 3J = 7.5, CH2CH2CH3); 2.64–
2.74 (2H, m, CH2CH2CH3); 7.39–7.47 (2H, m, H Ph); 7.52–
7.62 (3H, m, H Ph). 13C NMR spectrum, δ, ppm (J, Hz):
13.3 (CH2CH2CH3); 20.9 (CH2CH2CH3); 24.2 (CH2CH2CH3);
125.0; 129.4; 129.8; 133.6; 133.9; 136.1. Found, %:
С 59.53; Н 5.48; N 19.04. C11H12ClN3. Calculated, %:
С 59.60; Н 5.46; N 18.95.
4-Chloro-1,5-diphenyl-1H-1,2,3-triazole (1b).11 Yield
1
2.27 g (89%), white crystals, mp 102–105°С. H NMR
spectrum, δ, ppm: 7.22–7.29 (2H, m, H Ph); 7.29–7.34
(2H, m, H Ph); 7.35–7.47 (6H, m, H Ph). 13C NMR
spectrum, δ, ppm: 124.7; 124.9; 128.8; 129.4; 129.5
(2 signals); 129.7; 132.9; 134.3; 136.4. Found, %: С 65.81;
Н 3.88; N 16.45. C14H10ClN3. Calculated, %: С 65.76;
Н 3.94; N 16.43.
Experimental
1H and 13C NMR spectra were acquired on a Bruker
Avance III spectrometer (700 and 176 MHz, respectively)
in CDCl3, with TMS signal or the residual solvent signal
(7.27 ppm for Н and 77.2 ppm for 13С) used to assign
1
chemical shifts. Elemental analysis was performed on a
Thermo Flash-EA 200 Elemental Analyzer. Melting points
were determined on an SMP 30 apparatus and are
uncorrected. Reagents were supplied by Acros Organics
and were used without additional purification. Solvents
were freshly distilled before use. All operations with
moisture sensitive substances were performed using
Schlenk techniques under dry argon atmosphere.
5-tert-Butyl-4-chloro-1-phenyl-1H-1,2,3-triazole (1c).
1
Yield 1.32 g (56%), white crystals, mp 77–80°С. H NMR
spectrum, δ, ppm: 1.28 (9H, s, t-Bu); 7.34–7.38 (2H, m,
H Ph); 7.49–7.53 (2H, m, H Ph); 7.54–7.58 (1H, m, H Ph).
13C NMR spectrum, δ, ppm: 30.1 (C(CH3)3); 32.0
(C(CH3)3); 127.8; 129.0; 130.5; 132.7; 138.9; 140.4.
Found, %: С 61.22; Н 5.93; N 17.81. C12H14ClN3.
Calculated, %: С 61.15; Н 5.99; N 17.83.
The aryl azides were derived from monosubstituted
anilines by the diazotization reaction, followed by the
replacement of the diazo group by the azide.19,20
Synthesis of 4-halo-1H-1,2,3-triazoles 1a–c, 2a,b, 3a–c
(General method). The corresponding terminal alkyne
(10 mmol) was dissolved in anhydrous THF (30 ml); then
3 M methylmagnesium chloride solution in diethyl ether
(3 ml, 12 mmol) was added to the obtained solution
dropwise over 5 min. The obtained mixture was heated to
4-Bromo-1-(4-metoxyphenyl)-5-phenyl-1H-1,2,3-tri-
azole (2a). Yield 2.77 g (84%), white crystals, mp 112–
1
115°С. H NMR spectrum, δ, ppm (J, Hz): 3.83 (3H, s,
OCH3); 6.90 (2H, d, 3J = 9.0, H Ar); 7.23 (2H, d, 3J = 9.0,
3
4
H Ar); 7.29 (2H, dd, J = 8.0, J = 1.5, H Ph); 7.37–7.43
(3H, m, H Ph). 13C NMR spectrum, δ, ppm: 55.5 (OCH3);
114.4; 120.8; 125.4; 126.2; 128.7; 129.3; 129.5; 129.6;
135.3; 160.1. Found, %: С 54.80; Н 3.61; N 12.71.
C15H12BrN3O. Calculated, %: С 54.56; Н 3.66; N 12.73.
756

Chemistry of Heterocyclic Compounds 2018, 54(7), 755–757
4-Bromo-1-(2-metoxyphenyl)-5-phenyl-1H-1,2,3-tri-
of Sciences, supported by the Russian Ministry of Education
and Science (agreement identifier RFMEFI62117X0018).
azole (2b). Yield 2.90 g (88%), white crystals, mp 123–125°С.
1H NMR spectrum, δ, ppm (J, Hz): 3.46 (3H, s, OCH3);
4
6.90 (1H, d, 3J = 8.7, H Ar); 7.08 (1H, td, 3J = 7.6, J = 1.2,
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H Ar); 7.26–7.29 (2H, m, H Ar); 7.31–7.37 (3H, m, H Ar);
7.42–7.46 (2H, m, H Ar). 13C NMR spectrum, δ, ppm: 55.3
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128.5; 129.3; 131.7; 137.0; 153.3. Found, %: С 54.50;
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Н 3.66; N 12.73.
4-Iodo-1-phenyl-5-propyl-1H-1,2,3-triazole (3a).21
1
Yield 1.61 g (52%), white crystals, mp 133–136°С. H NMR
spectrum, δ, ppm (J, Hz): 0.85 (3H, t, 3J = 7.4,
CH2CH2CH3); 1.44–1.54 (2H, m, CH2CH2CH3); 2.64–2.72
(2H, m, CH2CH2CH3); 7.38–7.44 (2H, m, H Ph); 7.52–7.59
(3H, m, H Ph). 13C NMR spectrum, δ, ppm: 13.6
(CH2CH2CH3); 21.7 (CH2CH2CH3); 25.5 (CH2CH2CH3);
90.1 (CI); 125.4; 129.6; 130.0; 136.3; 140.2. Found, %:
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4-Iodo-1-(4-methoxyphenyl)-5-phenyl-1H-1,2,3-triazole
(3b). Yield 2.53 g (67%), white crystals, mp 120–124°С.
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6.87–6.90 (2H, m, H Ar); 7.19–7.22 (2H, m, H Ar); 7.27
(2H, dd, 3J = 8.0, 4J = 1.5, H Ar); 7.37–7.44 (3H, m, H Ar).
13C NMR spectrum, δ, ppm: 55.5 (CH3); 90.5 (CI); 114.4;
126.2; 126.3; 128.7; 129.3; 129.6; 129.8; 139.4; 160.2.
Found, %: С 47.80; Н 3.23; N 11.10. C15H12IN3O.
Calculated, %: С 47.77; Н 3.21; N 11.14.
4-Iodo-1-(2-methoxyphenyl)-5-phenyl-1H-1,2,3-triazole
(3с). Yield 2.30 g (61%), white crystals, mp 153–155°С.
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6.88 (1H, d, 3J = 8.7, H Ar); 7.05 (1H, td, 3J = 7.7, 4J = 1.1,
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3
4
H Ar); 7.26 (2H, dd, J = 8.1, J = 1.6, H Ar); 7.30–7.36
(3H, m, H Ar); 7.39–7.44 (2H, m, H Ar). 13C NMR
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125.2; 126.5; 128.1 (2 signals); 128.7; 129.1; 131.5; 140.8;
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1
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The study was carried out with the financial support of
the Russian Foundation for Basic Research in the
framework of the scientific project No. 18-33-00075 mole_a.
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