1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів
Aim. To analyze and summarize the synthetic potential of 1,2,3-triazole-4(5)-amines as efficient building blocks in the synthesis of triazolo-annulated pyridine, azine and azepine systems.Results and discussion. Original literature sources revealing the synthetic potential of 4(5)-amino functionaliz...
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| Опубліковано в: | Журнал органічної та фармацевтичної хімії |
|---|---|
| Дата: | 2022 |
| Том: | 20 |
| Випуск: | 2 |
| Сторінки: | 27-51 |
| ISSN: | 2518-1548 |
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| Автори: | , , , |
| Формат: | Стаття |
| Мова: | Англійська |
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Репозитарії
Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874455185143627776 |
|---|---|
| author | Syrota, Natalia O. Kemskiy, Sergiy V. Saliyeva, Lesya M. Vovk, Mykhailo V. |
| author_facet | Syrota, Natalia O. Kemskiy, Sergiy V. Saliyeva, Lesya M. Vovk, Mykhailo V. |
| author_institution_txt_mv | [
{
"author": "Natalia O. Syrota",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Sergiy V. Kemskiy",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Lesya M. Saliyeva",
"institution": "Lesya Ukrainka Volyn National University",
"orcid": "0000-0002-1047-8652"
},
{
"author": "Mykhailo V. Vovk",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
}
] |
| author_orcid_str_mv | 0000-0002-1047-8652 |
| author_sort | Syrota, Natalia O. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 51 |
| container_issue | 2 |
| container_start_page | 27 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 20 |
| datestamp_date | 2026-08-24T13:21:16Z |
| description | Aim. To analyze and summarize the synthetic potential of 1,2,3-triazole-4(5)-amines as efficient building blocks in the synthesis of triazolo-annulated pyridine, azine and azepine systems.Results and discussion. Original literature sources revealing the synthetic potential of 4(5)-amino functionalized 1,2,3-triazoles as convenient and available building blocks for the preparation of triazolo-annulated pyridines, azines and azepines were analyzed and systematized. Condensation of 1,2,3-triazole-4(5)-amines with methylene active compounds was shown to be a powerful tool for the synthesis of versatile triazolo[4,5-b]pyridines. In turn, the cyclocondensation based on 5-amino-1,2,3-triazole-4-carboxylic acids and their structurally modified derivatives was proven to be a general way for obtaining a number of triazolo[4,5-d]pyrimidine systems. Few representatives of triazolo-annulated pyridazines, 1,3-oxazines and 1,3-thiazines were synthesized by the intramolecular cyclization of the corresponding 4-aryl(carboxy-, aminomethyl)-5-amino-1,2,3-triazoles. The cyclocondensation involving 4,5-diamino-, 4-carbofunctionalized 5-amino-1,2,3-triazoles and 4-amino-5-thiocarboxamido-1,2,3-triazoles was successful for the construction of di-, oxa- and thiazepino-annulated triazoles.Conclusions. The analysis, systematization and summary of the literature regarding the synthetic potential of 1,2,3-triazole-4(5)-amines conclusively demonstrate that these structures are easily available and convenient molecular blocks for the construction of triazolo-annulated pyridine, azine and azepine systems that are important for synthetic and biomedical research. |
| doi_str_mv | 10.24959/ophcj.22.258512 |
| first_indexed | 2025-07-17T13:01:25Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 27
Review Article
http://ophcj.nuph.edu.ua
UDC 547.791 + 547.82 + 547.853 + 547.782
N. O. Syrota1, S. V. Kemskiy1, L. M. Saliyeva2, M. V. Vovk1
1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5, Murmanska str., Kyiv, 02098, Ukraine
2 Lesya Ukrainka Volyn National University, 13, Voli Avenue, Lutsk, 43025, Ukraine
1,2,3-Triazole-4(5)-amines – Convenient Synthetic Blocks
for the Construction of Triazolo-Annulated Heterocycles
Abstract
Aim. To analyze and summarize the synthetic potential of 1,2,3-triazole-4(5)-amines as efficient building blocks in the syn-
thesis of triazolo-annulated pyridine, azine and azepine systems.
Results and discussion. Original literature sources revealing the synthetic potential of 4(5)-amino functionalized 1,2,3-triazoles
as convenient and available building blocks for the preparation of triazolo-annulated pyridines, azines and azepines were
analyzed and systematized. Condensation of 1,2,3-triazole-4(5)-amines with methylene active compounds was shown to be
a powerful tool for the synthesis of versatile triazolo[4,5-b]pyridines. In turn, the cyclocondensation based on 5-amino-1,2,3-
triazole-4-carboxylic acids and their structurally modified derivatives was proven to be a general way for obtaining a number
of triazolo[4,5-d]pyrimidine systems. Few representatives of triazolo-annulated pyridazines, 1,3-oxazines and 1,3-thiazines
were synthesized by the intramolecular cyclization of the corresponding 4-aryl(carboxy-, aminomethyl)-5-amino-1,2,3-triazoles.
The cyclocondensation involving 4,5-diamino-, 4-carbofunctionalized 5-amino-1,2,3-triazoles and 4-amino-5-thiocarboxami-
do-1,2,3-triazoles was successful for the construction of di-, oxa- and thiazepino-annulated triazoles.
Conclusions. The analysis, systematization and summary of the literature regarding the synthetic potential of 1,2,3-triazole-
4(5)-amines conclusively demonstrate that these structures are easily available and convenient molecular blocks for the con-
struction of triazolo-annulated pyridine, azine and azepine systems that are important for synthetic and biomedical research.
Keywords: 4(5)-amino-1,2,3-triazoles; triazolo[4,5-b]pyridines; triazolo[4,5-d]pyridines; triazoloannulated azepines;
cyclocondensation
Н. О. Сирота1, С. В. Кемський1, Л. М. Салієва2, М. В. Вовк1
1 Інститут органічної хімії Національної академії наук України, вул. Мурманська, 5, м. Київ, 02660, Україна
2 Волинський національний університет ім. Лесі Українки, просп. Волі, 13, м. Луцьк, 43025, Україна
1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих
гетероциклів
Анотація
Мета. Проаналізувати та узагальнити синтетичний потенціал 1,2,3-триазол-4(5)-амінів як ефективних білдинг-блоків
у синтезі триазолоанельованих піридинових, азинових та азепінових систем.
Результати та їх обговорення. Проаналізовано та систематизовано оригінальні літературні джерела, які розкрива-
ють синтетичні можливості 4(5)-амінофункціоналізованих 1,2,3-триазолів як зручних і доступних будівельних блоків
для одержання триазолоанельованих азинів та азепінів. Доведено, що конденсація 1,2,3-триазол-4(5)-амінів із метиленак-
тивними сполуками є потужним інструментом синтезу різноманітних триазоло[4,5-b]піридинів. Зі свого боку для
отримання низки триазоло[4,5-d]піримідинових систем досить загальними виявились циклоконденсації на основі
5-аміно-1,2,3-триазол-4-карбонових кислот та їхніх структурно модифікованих похідних. Нечисленних представників
триазолоанельованих піридазинів, 1,3-оксазинів та 1,3-тіазинів було синтезовано внутрішньомолекулярними циклі-
заціями відповідних 4-арил(карбокси-, амінометил)-5-аміно-1,2,3-триазолів. Для конструювання ді-, окса- та тіазепі-
ноанельованих триазолів вдалими виявились циклоконденсації за участю 4,5-діаміно-, 4-карбофункціоналізованих
5-аміно-1,2,3-триазолів та 4-аміно-5-тіокарбоксамідо-1,2,3-триазолів.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 28
Журнал органічної та фармацевтичної хімії 2022, 20 (2)
Висновки. Аналіз, систематизація та узагальнення літературних джерел, які стосуються синтетичного потенціалу
1,2,3-триазол-4(5)-амінів, переконливо засвідчують, що такого типу структури є доступними й зручними молекуляр-
ними блоками для конструювання важливих для синтетичних і біомедичних досліджень триазолоанельованих піри-
динових, азинових та азепінових систем.
Ключові слова: 4(5)-аміно-1,2,3-триазоли; триазоло[4,5-b]піридини; триазоло[4,5-d]піримідини; триазолоанельовані
азепіни; циклоконденсація
Citation: Syrota, N. O.; Kemskiy, S. V.; Saliyeva, L. M.; Vovk,, M. V. 1,2,3-Triazole-4(5)-amines – convenient synthetic blocks for the con-
struction of triazolo-annulated heterocycles. Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2), 27 – 51.
https://doi.org/10.24959/ophcj.22.258512
Received: 20 February 2022; Revised: 27 March 2022; Accepted: 03 April 2022
Copyright© 2022, N. O. Syrota, S. V. Kemskiy, L. M. Saliyeva, M. V. Vovk. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Funding: the work is a part of the departmental research at the Institute of Organic Chemistry on the topic “Functional design, synthesis
and directed modification of bioattractive condensed azole, azine and azepine compounds” (the State Registration No. 0120U104977;
the research period: 2021 – 2025). The work was supported by the National Academy of Sciences of Ukraine (grant No. 19/02 – 2021(3))
to groups of young scientists of the National Academy of Sciences of Ukraine (2021-2022).
Conflict of interests: the authors have no conflict of interests to declare.
■ Introduction
1,2,3-Triazole-4(5)-amines, including those ad-
ditionally modified with other functional substi-
tuents and heterocyclic rings, occupy their right-
ful place in the chemistry of azole compounds and
are of great interest to researchers due to their
pronounced synthetic capabilities. Particular in-
terest in heterocyclic systems annulated with a tri-
azole ring arose with the discovery of the drug
“Ticagrelor” I (Figure) indicated to prevent or re-
duce the risk of coronary thrombosis in patients
with the acute coronary syndrome and patients
undergoing the percutaneous coronary interven-
tion or coronary artery bypass grafting [1].
Inhibitors of the human carbonic anhydrase
isoenzyme type hCA IX II [2] and calcium/calmo-
dulin-regulated kinases PIM III [3], a potent an-
tagonist of the Dengue virus IV, were found in
a number of triazoloanelated pyridines [4].
A low molecular weight agonist of cannabi-
noid receptor 2 (CB2) V [5], inhibitors of replica-
tion of the Chikungunya virus (CHIKV) VI [6]
and a reversible inhibitor of lysine-specific dem-
ethylase 1 (LSD1) VII [7], compounds with the
antitumor activity against breast cancer cells
MCF-7, lungs A549 VIII [8] and lungs Н1650 ІХ
have been identified among the functionalized
triazolo[4,5-d]pyrimidines [9].
The bioscreening results of triazolo[4,5-b]-
[1,5]benzodiazepine X showed the antidopamin-
ergic and anticholinergic activity to bind [3H]spi-
perone and [3H]QNB receptors. The neuroleptic
potential of derivatives X was evaluated in terms
of their ability to induce hypothermia and cata-
lepsy in mice and to block conditioned avoidance
reactions in rats [10].
At the same time, despite the wide pharma-
ceutical profile of heteroannulated 1,2,3-triazole
systems, the original works related to the me-
thods of their synthesis based on functionalized
4(5)-aminotriazoles were not subjected to syste-
matic analysis. Thus, it seemed appropriate to
comprehensively summarize the published lite-
rature on the use of 1,2,3-triazole-4(5)-amines
for the preparation of triazoloannulated six- and
seven-member heterocyclic systems.
■ Results and discussion
1. The synthesis of triazolo[4,5-b]pyridines
5-Aminotriazoles 1 as heterocyclic analogs of
enamines were successfully used in the three-
component condensation with 5-chloroisatin (2)
and Meldrum’s acid (3) to obtain a series of spiro-
triazolopyridones 4 and 5 (Scheme 1) [4, 11, 12].
Thus, using (S)- and (R)-1-[1-(4-chlorophenyl)ethyl]-
1H-1,2,3-triazole-5-amines 1, diastereomeric mix-
tures of optically pure spiro-derivatives 4 and 5
were synthesized. Instead, the condensation of
1-(4-chlorobenzyl)- and 1-[(5-chloropyridin-2-yl)-
methyl]-1H-1,2,3-triazole-5-amines 1 led to the
formation of a mixture of enantiomers, of which
the preparative high-performance liquid chiral
chromatography yielded only (R)-diastereomer 4.
In the case of 1-[1-(4-chlorophenyl)ethyl(propyl)]-
1H-1,2,3-triazole-5-amines 1, racemate reaction
products were isolated.
4-Functionalized 5-amino-1,2,3-triazoles also
proved to be convenient building blocks for the
synthesis of substituted triazolo[4,5-b]pyridine
derivatives. Thus, the treatment of 5-amino-4-for-
myltriazoles 6 with an excess of acetone or ethyl
acetoacetate 7 in an aqueous solution of NaOH or
ISSN 2308-8303 (Print) / 2518-1548 (Online) 29
Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
N
N
N
N
N
HN
S
Me
F
F
OHHO
O
HO
I
N
N
N
N
NH2
CN
H2NO2S
NMe2
II
N
N
N
N
OCF3
N
H
NH
OMe
III
N
Cl
O
H
N
O
N
N
N
Me
Me
Me
Cl
IV
N
N
N
N
N
N
tBu
OH
N
N
N
N
V
N
NH
N
N
N
O
R2
R1
R1 = COMe, R2 = Me
R1 = OCHMe2, R2 = Et
VI
N
N
N
N
N
Bn
S
SBn
N
VII
N
H
NH
N
N
N
O
S
MeO
VIII
N
N
N
N
N
N
H
HN
H
N
S
H
N
S
Me
N
IX
N
N
N
N
H
N
N
R2
N
Me
R1 = Me, R2 = F, Cl, Br
R1 = Et, R2 = F, Cl
X
R1
Figure. The structures of the drug «Ticagrelor» I and bioactive triazoloannulated heterocycles II-X
Me
Cl
Me
ClCl
N
Cl
Me
CF3 Cl
Et
N
H
O
H
N
O
N
N
N
R
N
H
O
H
N
O
N
N
N
R
+
R =
4 5
D, 2-4 h
AcOH Cl Cl
N
N
N
NH2
R N
H
Cl
O
O
O O
Me Me
OO
+
1 2
3
Scheme 1. The synthesis of spirotriazolopyridones 4, 5
ISSN 2308-8303 (Print) / 2518-1548 (Online) 30
Журнал органічної та фармацевтичної хімії 2022, 20 (2)
in an alcoholic solution of sodium alkoxide yield-
ed di- and trisubstituted 1,2,3-triazolo[4,5-b]py-
ridine 8 (Scheme 2) [13]. In turn, their cyclocon-
densation with malononitrile (9) led to the for-
mation of 5-amino-1,2,3-triazolo[4,5-b]pyridine-
6-carbonitriles 10, and with ethyl malonate or
ethyl cyanoacetate 11 produced 3,6-disubstitut-
ed 1,2,3-triazolo[4,5-b]pyridine-5(4H)-ones 12.
The cyclization of 5-amino-4-[3-(dimethylami-
no)acryloyl]-2-methyl-1,2,3-triazole (14) obtained
from the corresponding N-{5-[3-(dimethylamino)-
acryloyl]-2-methyl-2H-1,2,3-triazol-4-yl}benzami-
de (13) proved to be effective for the preparation of
2-methyltriazolo[4,5-b]pyridin-7-one (15) (Sche-
me 3) [14].
The interaction of 4-acetyltriazole-2-phenyl-
5-amine (16) with malononitrile (9) in boiling DMF
led to the formation of 5-aminotriazolo[4,5-b]py-
ridine-6-carbonitrile (17), while the acetylation
with acetic anhydride yielded derivative 18 con-
densed with dimethylformamide dimethylacetal
(DMFDMA) to give cis-enaminone 19 (Scheme 4).
The latter underwent the cyclization upon the treat-
ment with phenyldiazonium chloride (20) under
basic conditions, followed by the deacylation, and
formed [1,2,3]triazolo[4,5-b]pyridin-7-one (21) [15].
The authors of [16] have developed an easy
variant of the synthesis of triazolo[4,5-b]pyri-
din-5-ones 24, which includes the interaction of
4-acyltriazole-5-amines 16 with carboxylic acids
or esters 22 under the microwave irradiation with
the formation of the corresponding acetamides 23;
the cyclization of the latter in boiling DMF yields
target products 24 (Scheme 5).
N
N
N
R
NH2
O
R
N
N
N
N Me
R1
8, 16-76 %
R1
R = Bn, Ph; R1 = H, CO2Et; R2 = CO2Et, CN
2 % NaOH aq.
or NaOMe, MeOH
or NaOEt, EtOH, rt
NaOMe, MeOH
or NaOEt, EtOH, rt
N
N
N
N
R
NH2
CN
10, 77-78 %
R2 CO2Et
12, 42-88 %
N
H
N
N
N
R
O
R2
NaOMe, MeOH
or NaOEt, EtOH, rt
6
7
9
11
NC CN
O
Me
Scheme 2. The cyclocondensation of 5-amino-4-formyltriazoles 6 with active methylene compounds
N
N
N
NH
Me
PhO
O
NMe2
NaOMe, MeOH
N
N
N
NH2
Me
O
NMe2
14, 83 %
N
N
N
Me
N
H
O
13 15, 60 %
�, 12 h
BuOH
�, 4 h
Scheme 3. The synthesis of 2-methyltriazolo[4,5-b]pyridin-7-one 15
ISSN 2308-8303 (Print) / 2518-1548 (Online) 31
Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
The condensation of 5-aminotriazole-4-car-
bonitrile 25 with ethyl cyanoacetate (11) led to
7-amino-5-oxotriazolo[4,5-b]pyridine-6-carboni-
trile 26, and with benzylidene derivatives 27 to
7-aminotriazolo[4,5-b]pyridine-6-carbonitriles
28 (Scheme 6) [2].
A convenient method for the synthesis of
7-aminotriazolo[4,5-b]pyridine-6-carboxylates 31
is based on the reaction of aminonitriles 29 with
acetoacetic ester (30) in the presence of a Lewis
acid (Scheme 7) [17].
The reaction of triazolylaminonitrile 32 with
nickel complexes of 1,3-dicarbonyl compounds 33
proved to be successful in the preparation of tri-
azoloannulated pyridines 34 (Scheme 8) [18].
The authors [19] proposed effective conditions
for the Friedlaender reaction of N-Boc-4-amino-
triazole-5-carbaldehydes 35 with acetylacetone (36)
or malononitrile (9) which resulted in the forma-
tion of target 6-acetyltriazolo[4,5-b]pyridines 37
and 5-aminotriazolo[4,5-b]pyridine-6-carbonitri-
les 38, respectively (Scheme 9).
It was found that heating of N-Boc-4-amino-
triazole-5-carbaldehydes 35 with malonic acid (39)
in acetic acid at 100 °C in the presence of cata-
lytic amounts of pyrrolidine led to the formation
of 5-oxo-4,5-dihydro-1Н-[1,2,3]triazolo[4,5-b]py-
ridine-6-carboxylic acids 40 previously undescri-
bed in 61 – 66 % yields (Method А) (Scheme 10).
However, the use of Meldrum’s acid (3), a syn-
thetic equivalent of malonic acid, in this process
under similar reaction conditions is much more
productive since it increases the yield of the tar-
get compounds to 91 – 94 % (Method B). The like-
ly transformation scheme in the case of malonic
acid is through intermediate products A and B,
while in the case of Meldrum’s acid it is through
C and D. Indeed, the efficiency of the latter is
due to the structure of intermediate D which, in
contrast to intermediate B, is characterized by
much higher selectivity of further transforma-
tion [20].
To obtain new heterocyclic analogs of carboan-
nulated triazolopyridines as promising bioactive
N
N
N
NH2
Me
O
Ph
NC CN
N
N
N
N
Ph
NH2
CN
Me
piperidine
DMF, , 3 h�
17, 57 %
N
N
N NH
Me
O
Ph
O Me
Ac2O,
AcOH, , 2h�
18, 79 %
DMFDMA
xylene, , 6h�
N
N
N
NH
O
Ph
O
Me
N
Me Me
Ph N N Cl
NaOAc,
EtOH, rt, 1h N
N
N
N
Ph
N
O HN
Ph
19, 65 % 21, 70 %
16
9
20
Scheme 4. Synthetic possibilities of 4-acetyltriazole-5-amine 16
N
N
N
R
O
NH2
Ph
N
N
N
R
O
NH
Ph
O
R1
R = Me, Ph
R1 = CN, CO2Et, MeCO, PhCO, 4-NO2-C6H4
R2 = H, Et
R1 COOR2
Ac2O, MW,
85-100 oC, 40-80 s
or zeolite, 150 oC, 1h
N
H
N
N
N
Ph
R
R1
O
NaOAc,
DMF, , 1h�
24, 76-85%16
22
23
Scheme 5. The method for the synthesis of trisubstituted triazolo[4,5-b]pyridin-5-ones 24
ISSN 2308-8303 (Print) / 2518-1548 (Online) 32
Журнал органічної та фармацевтичної хімії 2022, 20 (2)
compounds, aminoaldehydes 35 were tested in
the cyclocondensation with cycloalkanones 41 and
1,3-cyclohexanediones 43, which made it possible
to isolate carbocyclic derivatives 42 and hydro-
genated 1,2,3-triazolo[4,5-b]quinolines 44, respec-
tively (Scheme 11) [19].
Another method for the formation of the tri-
azolo[4,5-b]quinoline core reported by the authors
of the patent [21] was the use of the intramo-
lecular cyclization of 4-N-arylamino-substituted
1,2,3-triazole-5-carboxylic acids 45 by their heat-
ing in polyphosphoric acid (Scheme 12).
N
N
N
CN
NH2
NC COOEt
NC CN
Ar
EtOH, TEA
D, 5 h
210 oC, 10 min
26, 78 %
28, 70-89 %
N
H
N
N
N
NH2
CN
O
N
N
N
N
NH2
CN
Ar
H2NO2S
Ar = Ph, 2-Cl-C6H4, 4-Me2N-C6H4, 4-Cl-C6H4
25
11
27
H2NO2S
H2NO2S
Scheme 6. The synthesis of 7-aminotriazolo[4,5-b]pyridine-6-carbonitriles 26 and 28
N
N
N
R
CN
NH2
Me
O
OEt
O
N
N
N
N
NH2
CO2Et
Me
R
+
31, 45-62 %
R = Ph, 4-MeO-C6H4, 3,4,5- -MeO-Ctri 6H2
29 30
PhMe, , 4 h�
SnCl4
Scheme 7. The synthesis of 7-aminotriazolo[4,5-b]pyridine-6-carboxylates 31
N
N
N
Bn
CN
NH2
R1
O
O
R R1
O
O
R
Ni
R = Me, R1 = Me, OMe, OEt, OBn, O- But
R = Et, R1 = OEt
DCE, , 16 h�
+
34, 55-81 %
N
N
N
N
Bn
NH2 O
R1
R
32 33
Scheme 8. The reaction of 5-aminotriazole-4-carbonitrile 32 with nickel complexes
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Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
N
N
N
R
NHBoc
O
N
N
N
R
N
Me
Me
O
N
N
N
R
N NH2
CN
pyrrolidine
AcOH, , 2 h�
Me
O
Me
O
NC CN
35
37, 65-74 %
38, 84-92 %
pyrrolidine
AcOH, , 4 h�
36
9
R = Me, Ph(CH2)2, Ph, 2-MeO-C6H4
Scheme 9. The reaction of N-Boc-4-aminotriazole-5-carbaldehydes 35 with active methylene compounds
N
N
N
R
NHBoc
O
N
N
N
R
NHBoc
N
N
N
R
CO2H
CO2H
H
N O
O
OH
N
NN
R
NHBoc
O
O
O
O
Me
Me
35
A C
N
N
N
R
NH2
B
40
N
N
N
R
NH2
D
Method A Method B
HO2C CO2H
O
O
O
O
Me
Me
OH
OH
O
O
O
Me
Me
O
O
H
-isobutylene
-H2O -Me2CO
66-69 % 91-94 %
R = Me, Ph(CH2)2, Ph, 2-MeO-C6H4
O
AcOH, pyrrolidine,
100 oC, 4 h
AcOH, pyrrolidine,
100 oC, 4 h
3
39
H
-isobutylene
-CO2-CO2
Scheme 10. The synthesis of 5-oxo-4,5-dihydro-1Н-[1,2,3]triazolo[4,5-b]pyridine-6-carboxylic acids 40
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Журнал органічної та фармацевтичної хімії 2022, 20 (2)
2. The synthesis of triazolo[4,5-d]pyrimi-
dines
2.1. Reactions involving 5-amino-1,2,3-tri-
azole-4-carboxylates
An important field of application of amino-
functionalized 1,2,3-triazoles has become the de-
velopment of a method for the synthesis of tri-
azolo[4,5-d]pyrimidines, which can be considered
as isosteres of biologically promising purines.
Thus, the reaction of carboxylates 47 with tri-
ethyl orthoformate gave the corresponding 5-ethoxy-
methyleneamino-1,2,3-triazoles 48, which were
easily cyclized to 6-aminotriazolo[4,5-d]pyrimi-
din-7-ones 49 by the action of hydrazine hydra-
te (Scheme 13) [22]. Instead, the reaction of tri-
azoles 47 in the hydrazine solution after 3 h of
boiling led to 5-amino-1,2,3-triazole-4-carbohyd-
razides 50, which heterocyclization with triethyl
orthoformate proved to be effective for obtaining
(triazolo[4,5-d]pyrimidine-6-yl)formimidates 51.
In turn, the treatment of triazoles 47 with an ex-
cess of primary amine 52 in the presence of NH4Cl
at 200 °C led to aminoamides 53, which upon pro-
longed heating with triethyl orthoformate yielded
the target triazolo[4,5-d]pyrimidines 54.
The reaction of aminoester 55 with imidoyl
chloride 56 catalyzed by a Lewis acid under the
microwave irradiation resulted in the synthesis
of triaryl-substituted triazolo[4,5-d]pyrimidino-
ne 57 (Scheme 14) [23, 24].
The high-temperature cyclocondensation of
1-hetaryl-substituted 5-amino-1,2,3-triazole-4-
carboxylate 58 with urea or thiourea resulted
in the formation of triazolo[4,5-d]pyrimidine-
5,7(4H,6H)-dione and its 5-thio analog 59, respec-
tively (Scheme 15) [25].
The authors [26] developed a two-stage me-
thod for the synthesis of bis[1,2,3]triazolo[1,5-
a:4’,5’-e]pyrimidinones 62, the first stage of it
was azidation of amines 60 to the corresponding
5-azido-1,2,3-triazolocarboxylates 61, and the se-
cond stage was their cyclocondensation with ac-
tive methylene nitriles 9 leading to the target
products (Scheme 16).
A number of works [27 – 33] describe an approach
that is widely used to activate the triazole ami-
no group with reduced nucleophilicity. For this
purpose, 5-amino-1-aryl-1,2,3-triazole-4-carbox-
ylates 63 were converted by the action of Ph3Р
into the corresponding iminophosphoranes 64.
N
N
N
R
NHBoc
O
N
N
N
R
N
O
N
N
N
R
N
pirrolidine
AcOH, , 3 h�
O
O
O
35
42, 63-83 %
44, 61-78 %
n
n
R1
R1
R1
R1
41
43
R = Me, Ph, 2-MeO-C6H4
n = 1-3
R = Me, Ph, 2-MeO-C6H4
R1 = H, Me
Scheme 11. The synthesis of carbocyclic triazolopyridines 42 and 44
HN
N
N
CO2H
H
N
R
R = Ph, 4-Me-C6H4, 4-Cl-C6H4
100 oC, 2-6 h
H
N
N
H
N
N
O
R
45
PPA
46, 71-84 %
Scheme 12. The intramolecular cyclization of 4-N-arylamino-substituted 1,2,3-triazole-5-carboxylic acids 45
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Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
N
N
N
CO2Et
NH2
N
N
N N
N
O
N
N
N
COOEt
N
OEt
NH2
HC(OEt)3 H2NNH2
Ar = Ph, 2-Cl-C6H4,
4-Cl-C6H4, 2,4- -Cl-Cdi 6H3
47
48, 47-55 % 49, 61-69 %
130-135 oC, 5 h
Ar
Ar Ar
MeOH, rt, 30 min
H2NNH2
�, 3 h
N
N
N
NH2
50, 58-62 %
Ar
NHNH2
O
HC(OEt)3
130-135 oC, 18-20 h
N
N
N N
N
O
N
51, 54-57 %
Ar
OEt
OMe
OMe
H2N
52
NH4Cl
200-210 oC, 1.5 h
N
N
N
O
N
H
OMe
OMe
NH2
Ar
HC(OEt)3
135-140 oC, 48 h
53, 58-67 %
N
N
N
N
N
O
OMe
OMe
Ar
54, 64-73 %
Scheme 13. Preparation of 6-functionalized triazolo[4,5-d]pyrimidin-7-ones 49, 51, 54
N
N
N
CO2Et
NH2
N
N
N N
N
O
55 57, 73 %
Cl
N Cl
Br TiCl4, DCE
SO2Me
SO2Me
Br
Cl
56
+
1) MW, 170 oC, 1 h
2) oil bath, 115 oC, 48 h
Scheme 14. The microwave synthesis of triazolo[4,5-d]pyrimidin-7-one 57
N
N
NN
N N
N
CO2EtH2N
N
N
NN
N N
N
HN
NH
O
X
NH2H2N
X
X = O, S
170 oC, 2-3 h
58 59, 49-75 %
Me Me
Scheme 15. The cyclocondensation of aminoester 58 with (thіо)urea
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Журнал органічної та фармацевтичної хімії 2022, 20 (2)
The latter easily underwent aza-Wittig reaction
with aromatic isocyanates 65 to form triazolyl-
containing carbodiimides 66 which had found wide
application as effective precursors for the synthe-
sis of triazolo[4,5-d]pyrimidines (Scheme 17).
The authors of [27] showed that the interac-
tion of carbodiimides 66 with a number of alky-
lamines 67 in the presence of NaOEt led to the
selective formation of 5-alkylaminotriazolo[4,5-
d]pyrimidin-7-ones 68 (Scheme 18). At the same
time, the formation of regioisomeric 5-arylami-
noderivatives 69 was observed under the action
of ammonia or methylamine in the absence of
a base.
The reaction of triazolylcarbodiimides 66 with
hydrazine hydrate in alcohol at room tempera-
ture also led to 5-arylamino-6-aminotriazolo[4,5-
d]pyrimidin-7-ones 70 (Scheme 19) [29].
N
N
N
R
CO2Et
NH2
N
N
N
R
COOEt
N3
1) NaNO2, HCl, H2O, -30 oC
2) NaN3, H2O
N
N
N N
H
N
O
R
R = Bn, 4-MeO-C6H4
R1 = CN, Ph
60 61, 55-80 % 62, 20-28 %
N
N
R1
NaOEt, EtOH,
rt, 24 h
9
R1 CN
Scheme 16. The synthesis of bis[1,2,3]triazolo[1,5-a:4’,5’-e]pyrimidinone 62
N
N
N
Ar
CO2Et
N
PPh3
N
N
N
Ar
CO2Et
N
C
NAr1
Ar1NCO
63
65
N
N
N
Ar
CO2Et
NH2
Ar = Ph, 4-Cl-C6H4
Ar1 = Ph, 3-Cl-C6H4, 4-Me-C6H4, 4-Cl-C6H4
Ph3P, Et 3N,
MeCN, C2H6, rt, 3 h
64, 90 %
CH2Cl2, 0-5 oC
24-30 h
66
Scheme 17. The synthesis of triazolyl-containing carbodiimides 66
N
N
N
Ar
CO2Et
N
NHAr1
NHR
N
N
N N
N
O
Ar
NHR1
Ar1
EtOH, rt
67
69, 76-87 %
R = H, Me, Et, Pr, Pr, Bu, Bu, Bn, cyclohexyli t
R1 = Et, Pr, Pr, Bu, Bu, Bn, cyclohexyli t
R2 = H, Me
66
A
NaOEt,
EtOH, CH2Cl2, rt
N
N
N N
N
O
Ar
NHAr1
R2
68, 74-90 %
R
NH2
Scheme 18. Preparation of isomeric 5-alkylamino- and 5-arylaminotriazolo[4,5-d]pyrimidin-7-ones 68 and 69
EtOH, rt, 10 min
H2NNH2
70, 84-91 %
66
N
N
N N
N
O
Ar
NHAr1
NH2
Scheme 19. The synthesis of 5-arylamino-
6-aminotriazolo[4,5-d]pyrimidin-7-ones 70
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Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
To expand the boundaries of the reaction and
synthesize various 5-substituted triazolo[4,5-d]-
pyrimidin-7-ones 72, N,N-dialkylamines, secondary
amines and phenols 71 were used as nucleophi-
lic reagents for the formation of a pyrimidine ring
based on carbodiimides 66 (Scheme 20) [28, 30].
The reaction of carbodiimides 66 with thio-
phenols 73 at room temperature did not give the
expected cyclization products, whereas at 50 °C
it yielded 5-arylthiotriazolo[4,5-d]pyrimidin-7-
ones 74 [32, 33], among which compounds with
high herbicidal activity against rapeseed and
common flatweed were found (Scheme 21).
1,4-Bis[triazolo[4,5-d]pyrimidin-7(6H)-one]-
piperazines 76 were readily prepared by react-
ing carbodiimides 66 with substituted piperazi-
nes 75 (Scheme 22) [31].
2.2. The cyclization of 5-amino-1,2,3-tri-
azole-4-carboxamides
An effective approach to the synthesis of
3,5-disubstituted 1,2,3-triazolo[4,5-d]pyrimidin-
7-ones 78 is the cyclocondensation of 5-amino-
triazole-4-carboxamides 77 with benzaldehydes
[8, 34], acyl chlorides [5, 35 – 39] and esters of mono-
and dicarboxylic acids [6, 40 – 45] (Scheme 23).
The authors of [46] used the cyclocondensa-
tion of triazoloaminoamides 79 with amidines 80
to synthesize triazolo[4,5-d]pyrimidinones 81, as
well as the intramolecular cyclization of [(1-ami-
no-2,2,2-trichloroethylidene)amino]triazolocar-
boxamides 82 under basic conditions (Scheme 24).
To build a pyrimidine ring based on 5-amino-
4-triazolocarboxylic acid amides 83 and to form
3,6-disubstituted triazolo[4,5-d]pyrimidin-7-ones 84
NaOEt
EtOH, CH2Cl2
rt, 1-6 h
HY
72, 55-92 %
66
N
N
N N
N
O
Ar
Y
Ar1
71
Y = NEt2, NPr2, NBu2, N( Cn 5H11)2, N( Cn 6H13)2, N(CH2)5, N(CH2)4O, N( Bu)i 2, NMe(Ph), N( Pr)i 2,
OMe, OEt, OPr, OBu, O- Pr, OCHi 2CCH, OCH2CH=CH2, OPh, 4-Me-C6H4O, 4-MeO-C6H4O, 4-Cl-C6H4O
Ar = Ph, 4-Cl-C6H4
Ar1 = Ph, 4-Cl-C6H4, 3-Me-C6H4
Scheme 20. The synthesis of 5-substituted triazolo[4,5-d]pyrimidin-7-ones 72
N
N
N
Ar
CO2Et
N
NHAr1
SAr2
N
N
N N
N
O
Ar
SAr2
Ar1
Ar2SH
73
Ar2 = Ph, 2-Cl-C6H4, 4-Me-C6H4, 4-F-C6H4, 4-Cl-C6H4
66
K2CO3, MeCN, CH2Cl2
50 oC, 2-3 h
74, 83-96 %
K2CO3, CH2Cl2
rt, 2-3 h
Scheme 21. The synthesis of 5-arylthiotriazolo[4,5-d]pyrimidin-7-ones 74
1) CH2Cl2, rt, 2-3 h
2) NaOEt, EtOH, rt, 3-5 h
76, 74-87 %
66
N
N
N N
N
O
Ph
Ph
NHHN
R
N
N
NN
N
O
Ph
Ph
N
N
R
R = H, 2-Me, 2,5- -Me, 2,6- -Me, 2-Etdi di
75
Scheme 22. The synthesis of 1,4-bis[triazolo[4,5-d]pyrimidin-7(6H)-one]piperazines 76
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Журнал органічної та фармацевтичної хімії 2022, 20 (2)
orthoesters [8, 34, 47, 48], amides and formic
acid esters were used as one-carbon reagents
[41, 49 – 51], as well as Vilsmeier-Haack reagent
[50] (Scheme 25).
A similar scheme of a high-temperature con-
densation of 4-aminotriazole-5-carboxamide 85
with formamide was used to obtain 1-methyltri-
azolo[4,5-d]pyrimidin-7-one (86) (Scheme 26) [52].
N
N
N
R
NH2
NH2
O
R1 = Me, Et, Pr, Pr, Bu, Bn, CHi t 2CN, CF3, CO2Et, PhCH=CH, cyclopropyl, cyclobutyl,
R1CHO, EtOH, , 8 h�
or 1) R1COCl, pyridine, 80 oC, 2-5 h
2) 8 M NaOH, MeOH, 80 oC, 1 h or KHCO3, H2O, , 18 h�
or R1COOEt, NaOEt, EtOH, 90 oC, 1-24 h
N
NH
N
N
N
O
R
R1
78, 23-90 %
N
H
Ph
R2
77
F
MeOR = Pr, 2-Cl-Bn, 4-MeO-Bn, cyclopentyl, 3-( PrO)-Ci 6H4,
Ph, 2-EtO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Py,
Scheme 23. 5-Aminotriazole-4-carboxamides 77 in the synthesis of triazolo[4,5-d]pyrimidin-7-ones
N
N
N
NH2
O
NH2
R
N
N
N NH2
O
N
R = H, Me, Bn
R1 = H, Me, Ph
R2 = H, Me, CCl3, Ph
R1 NH2
NH
BuOH, , 8 h�
or C6H13OH, , 4 h�
or C8H19OH, , 4-48 h�
N
NH
N
N
N
O
R2
0.5 N KOH, BuOH,
-10 oC, 24 h
H2N CCl3
8179
80
82
R R
Scheme 24. Approaches to the construction of a triazolo[4,5-d]pyrimidine core based on triazoloaminoamides
N
N
N
R
NHR1
O
NH2
R = Bn, 4-MeOBn, Ph,
HC(OEt)3, 145 °C, 48 h
or HC(OEt)3, EtOH 100 °C, 8 h
or HCONH2, 180-200 °C
or DMF, POCl3, 40-80 oC, 0.5-4 h
or HCO2Et, NaOEt, EtOH, , 24 h�
N
N
N
N
N
R
O
R1
83 84, 30-94 %
O
F
TBDMSO
TBDMSO
F
MeO
R1 = H, Me, Bn, Ph, 2-MeO-C6H4
Scheme 25. The synthesis of 3,6-disubstituted triazolo[4,5-d]pyrimidin-7-ones 84
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Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
N
N
N
Me
NH2
NH2
O
NH
NN
N
N
Me O
86, 66 %
HCONH2
sealed tube,
180 oC, 3 5 h.
85
Scheme 26. The synthesis of 1-methyltriazolo[4,5-d]pyrimidin-7-one 86
HN
N
N
NH2
O
NH2
N
H
N
N NH2
O
NH N
N
N
N
N
H
NH
Ph
R-89, 7.7 %
S-89, 5.4 %
1) NaOEt, EtOH, , 10 min�
2) PhCO2Et, , 15 h�
88, 65 %
HMDS, (NH4)2SO4 cat.,
R S(+)- or (–)-1-phenylethylamine,
100 oC, 6 h, steel bomb
87
PhO
Me
Ph
Scheme 27. The synthesis of triazolo[4,5-d]pyrimidines 89
N
N
N
NHR
O
Bn
NH2
N
N
N
N
N
O
R
Me
Bn
R = H, Me, Bn, Ph
Ac2O, 160 oC, 4 h
91, 40-90 %90
Me
EtO
OEt
OEt
Scheme 28. The synthesis of 6-alkyl(aryl)substituted triazolo[4,5-d]pyrimidines 91
N
N
N
Bn
NH2
NHNH2
O
�, 22-92 h N
N
N
N
N
O
N
R
Bn
OEt
N
N
N
N
N
O
NH2
R
Bn
H2O, AcOH, , 26 h�
93, 61-62 %
R = H, Me
94, 38-69 %92
RC(OEt)3
Scheme 29. Preparation of 6-aminotriazolo[4,5-d]pyrimidine 94
5-Benzamidotriazole-4-carboxamide (88) ob-
tained from 5-amino-4-carbamoyl-1,2,3-triazole (87)
by the action of hexamethyldisilazane (HMDS),
catalytic amounts of (NH4)2SO4 and R- or S-1-phe-
nylethylamine was converted into 6-aminotriazo-
lo[4,5-d]pyrimidines 89 (Scheme 27) [53].
Heating of amides 90 with triethyl orthoace-
tate in the presence of acetic anhydride proved
to be successful to obtain 6-alkyl(aryl)substitu-
ted triazolo[4,5-d]pyrimidines 91 (Scheme 28) [50].
The cyclocondensation of 5-aminotriazol-
4-carbohydrazide 92 with an excess of triethyl
orthoformate or triethyl orthoacetate led to ethyl-
N-(triazolo[4,5-d]pyrimidin-6(7H)-yl)formimida-
tes 93 undergoing the hydrolysis under acidic
conditions to the corresponding 6-aminoderiva-
tives 94 (Scheme 29) [54].
The synthesis of triazolo[4,5-d]pyrimidine-
5,7(4H,6H)-diones 95 was successful by heating
triazolilaminoamides 77 with N,N’-carbonyldi-
imidazole (CDI) in DMF [6, 40, 47] or with di-
ethyl carbonate in ethanol [55 – 60] (Scheme 30).
The condensation of aminoamides 77 with car-
bon disulfide under alkaline conditions [8, 34, 40,
61 – 63] or co-melting with thiourea [64] led to
3-substituted 5-thioxotriazolo[4,5-d]pyrimidine-
7(4H)-ones 96 (Scheme 31).
The high-temperature reaction of 5-amino-
2-phenyltriazole-4-carboxamide (97) with dibutyl
phenylboronate (98) turned out to be a convenient
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method for the preparation of triazolo[4,5-d]-
[1,3,2]diazaborinin-7(4H)-one 99 (Scheme 32) [65].
2.3. The cyclocondensation of triazolilami-
nonitrites
Amidines or their salts 80 were used as 1,3-
binucleophilic reagents to complete the pyrimi-
dine ring to 5-aminotriazole-4-carbonitrile 100
in order to synthesize triazolo[4,5-d]pyrimidine-
7-amines 101 (Scheme 33) [66].
A similar reaction of 5-(methylamino)triazo-
le-4-carbonitrile 102 with acetimidate 80 produ-
ced 4-methyl-4H-[1,2,3]triazolo[4,5-d]pyrimidi-
ne-7-amine 103 (Scheme 34) [45].
A convenient method for the preparation of
triazolo[4,5-d]pyrimidine-7-amine 105 was heat-
ing aminonitrile 104 in an excess of diethylme-
thylamine (DEMA) followed by the treatment with
ammonia in MeOH (Scheme 35) [67].
The condensation of aminonitriles 106 with
phenylisothiocyanate led to 7-anilinotriazolo[4,5-
d]pyrimidine-5-thiones 107, while 106 with po-
tassium O-ethyldithiocarbonate or carbon disul-
fide followed by the treatment of the reaction mix-
ture with methyl iodide yielded 5,7-bis(methylthio)
derivatives 108 (Scheme 36). The intramolecular
cyclocondensation of 5-cyano-4-ethoxymethylene-
amino-1,2,3-triazoles 106 by 10 h reflux in NaHS
solution proved to be convenient for the synthe-
sis of triazolo[4,5-d]pyrimidine-7-thiones 109 [68].
The cyclization of 5-aminotriazole-4-carboni-
trile 25 with phenylisocyanate, isothiocyanates,
or thiourea at elevated temperatures was suc-
cessfully used to obtain triazolo[4,5-d]pyrimidin-
N
N
N
R
NH2
O
NH2
1) CDI, DMF, 90 °C, 18 h; 2) NH4F, MeOH, 60 °C, 7 h
or 1) (EtO2C)2CO, rt, 40 min; 2) 90 oC, 5 h
or 1) NaOEt, EtOH, , 40 min; 2) (EtO� 2C)2CO, , 4 h� 95, 39-83 %
N
H
NH
N
N
N
O
O
R
R = Bu, Pr, 3- PrO-Cn i i 6H4,
O
F
HO
HO O
77
Scheme 30. The synthesis of triazolo[4,5-d]pyrimidine-5,7(4H,6H)-diones 95
N
N
N
R
NH2
O
NH2
N
H
NH
N
N
N S
O
R
R = Me, Pr, 4-MeOBn,i
96, 64-86 %
N
Me
OMe
10 % NaOH, CS2, DMF, , 8 h�
or KOH, CS2, EtOH, H2O, , 48 h�
or CS2, BuOK,t THF, MW, 120 oC, 2 h
or (NH2)2CS, 175 oC
77
F
OMe
Scheme 31. The synthesis of 5-thioxotriazolo[4,5-d]pyrimidine-7(4H)-ones 96
NH2
NH2
N
N
N
Ph
O
NH
B
N
H
N
N
N
Ph
Ph
O
190 oC, 3 h
99, 23 %
Ph
B
BuO OBu
+
97 98
Scheme 32. The synthesis of triazolo[4,5-d][1,3,2]diazaborinin-7(4H)-one 99
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Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
5-ones 110 and triazolo[4,5-d]thiones 111, 112,
respectively (Scheme 37) [2].
Isomeric 4-aminotriazole-5-carbonitrile 113 was
subjected to the cyclization to triazolopyrimidine
systems 114-116 in the reaction with formamide,
phenylisothiocyanate, or carbon disulfide in an
alcoholic solution of KOH. Its interaction with
ethylenediamine formed imidazoyl-1,2,3-triazo-
le 117, which was converted to imidazo[1,2-c]-
[1,2,3]triazolo[4,5-e]pyrimidine 118 by the action
of triethyl orthoformate (Scheme 38) [69].
The authors of the work [70] successfully used
the condensation of 4-hetarylsubstituted triazole-
5-amines 120 (obtained from triazole-4-carbonit-
riles 119) with orthoesters to synthesize imidazo-
[1,2-c][1,2,3]triazolo[4,5-e]pyrimidines, pyrimido-
[1,2-c][1,2,3]triazolo[4,5-e]pyrimidines, triazolo-
[4’,5’:4,5]pyrimido[1,6-a][1,3]diazepines 121
(Scheme 39).
Hydrogenated analogs of imidazo[1,2-c][1,2,3]-
triazolo[4,5-e]pyrimidines 122 were obtained by
reacting imidazoyl-1,2,3-triazoles 120 with aro-
matic aldehydes (Scheme 39).
3. The synthesis of triazoloannulated
pyridazines, oxazines and thiazines
Despite the relative ease of fusion of the pyri-
dine and pyrimidine nuclei to the triazole ring,
obtaining polycyclic systems with other hetero-
nuclei proved to be a more difficult task. However,
the authors of [71] succeeded in synthesizing 3H-
[1,2,3]triazolo[4,5-c]cinoline 124 by the nitrosation
N
N
N CN
NH2
R = H, Me, Bn
R1 = H, Me, CCl3
R2 = H, Bu
NH
NH2R1
MeCO2H.
BuOH, 125 oC, 1-2 h
or nC6H13OH, 160 oC, 2-5 h
101, 20-90 %
N
N
N
N
N
NHR2
R1
NR2
NHR2R1
AcOH, BuOH, 120-160 oC, 2-4 h
or nAcOH, C8H19OH, 135 oC, 25 mmHg, 4 h
100
80
80
R R
Scheme 33. The synthesis of 5-substituted triazolo[4,5-d]pyrimidine-7-amines 101
N
H
N
N
CN
NHMe
N
N
N
N
N
NH2
Me
Me NH2
NH
nBuOH, , 125� oC, 1 h
+
103, 89 %102 80
Scheme 34. The synthesis of 4-methyl-4H-[1,2,3]triazolo[4,5-d]pyrimidine-7-amine 103
N
N
N
CN
NH2
O
OHOH
AcO 1) DEMA, 90 oC
2) NH3-MeOH, rt
104 105
N
N
N
O
OHOH
HO N
N
H2N
Scheme 35. The synthesis of triazolo[4,5-d]pyrimidine-7-amine 105
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Журнал органічної та фармацевтичної хімії 2022, 20 (2)
of the amino group of 1,4-diaryl-substituted
5-aminotriazole 123 followed by the intramolecu-
lar azo coupling (Scheme 40).
The cyclocondensation of 1-heteryl-substitu-
ted 5-aminotriazole-4-carboxylic acid 125 with
acetic anhydride proved to be effective for the
preparation of the triazolo[4,5-d][1,3]oxazine-
7-one derivative 126 (Scheme 41) [25].
The cyclization of sodium carbamodithioate
128 (synthesized from triazolodiamine 127) with
an excess of CS2 yielded triazolo[4,5-d][1,3]thiazi-
ne-5-thione 129 (Scheme 42) [72].
N
N
N CN
Y
R = H, Me, Bn
Y = NH2, N=CHOEt
N
H
N
N
N
N
N
NH
N
N
N
N
N
N
N
N
NHPh
S
S
SMe
SMe
1) 0.075 M or 0.2 M NaHS,
EtOH, , 10 h�
2) NaOH to pH = 10,
then 5 N H2SO4 to pH = 2
109, 83-97 %
1) EtOC(S)SK, DMF, , 2 h�
or CS2, Py, 115 oC, 2 h
2) NaOH, H2O, MeI, rt, 1 h
108, 88-96 %
PhNCS, Py, , 4 h�
107, 20-95 %
106
R
R
R
R
Scheme 36. Preparation of sulfur-containing triazolo[4,5-d]pyrimidines 107-109
N
N
N CN
NH2
Ar
Ar = 4-H2NO2S-C6H4
N
H
N
N
N
N S
Ar
N
H
N
N
N
N O
Ar
N
H
N
N
N
N S
Ar
NH2
Ph
NH
NH
R
R = Et,
S
O
OH
NN
N
112, 91 %
DMF, TEA, , 18 h�
110, 89 %
DMF, TEA, , 5 h�
or Py, , 10 h, then HCl, H� 2O
111, 89-90 %
25
PhNCO
RNCS
(NH2)2CS
180 oC, 15 min
Scheme 37. The synthesis of triazolo[4,5-d]pyrimidin-5-(thi)оnes 110-112
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Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
N
N
N CN
Y
R
R1
NH2
NH2
n
P2S5 cat., 70-80 oC
R = Bn, 4-Cl-Bn, 2,4- -Cl-Bn, 4-Cl-Cdi 6H4
Y = NH2, N=CHNMe2
R1 = H, Me, n = 1, 2, 3
R2 = H, Me;
R3 = H, 4-Cl-C6H4, 3-NO2-C6H4, 3,4,5- MeOtri- -C6H2
N
N
N
NH2
R
N
H
N
R1
n
120, 33-79 %
115-120 oC, 14-16 h N
NN
N
N
N
R
R2
R1
n
121, 24-77 %
PhH, , 8-10 h�
n = 1
N
H
NN
N
N
N
R
R3
122, 38-51 %
119
R2C(OEt)3
R3CHO
Scheme 39. The synthesis of tricyclic triazole-containing pyrimidines 121-122
N
N
N NH2
CN
Ar
N
H
N
N
N
N
NH
S
Ar
Ph
N
NN
N
N
Ar NH2
HCONH2
NH
H
NN
N
N
Ar S
S
CS2, 20 % KOH
H2N
NH2
CS2, , 3 h� N
N
N NH2
Ar
HN
N
CH(OEt)3
N
NN
N
N
NAr
Ar =
Ph
O
117, 77 % 118, 65 %
116, 65 %
115, 72 %
114, 71 %
AcOH, , 4 h�
113
�, 2 h
PhNCS
Py, , 4 h�
EtOH, , 5 h�
Scheme 38. The synthesis of bi- and tricyclic triazoloannulated pyrimidine systems
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Журнал органічної та фармацевтичної хімії 2022, 20 (2)
4. The synthesis of triazoloannulated di-,
oxa-, and thiazepines
In addition to the triazoloannulated azine
structures described above, aminotriazoles also
turned out to be important substrates for the syn-
thesis of triazolodi(oxa-, thi)azepine systems.
The condensation of 4,5-diaminotriazoles 130
with β-dicarbonyl compounds proved to be a con-
venient tool for constructing a triazolo[4,5-b][1,4]-
diazepine core with varying degrees of saturation
(Scheme 43) [73]. Thus, a series of 1,5,7-substi-
tuted 1,6-dihydrotriazolo[4,5-b][1,4]diazepines 133
was obtained by the reaction of triazoles 130 with
dibenzoylmethane, benzoylacetone and acetylace-
tone 131. In turn, the reaction with ethyl ace-
toacetate and ethyl butyroacetate 133 proceeded
through the step of forming enamino derivatives
134, which were cyclized under basic conditions
to 3,7-disubstituted triazolo[4,5-b][1,4]diazepin-
5-ones 135. In the case of benzoyl acetate 136,
the initially formed amides 137 were cyclized un-
der acidic conditions to 1,7-disubstituted triazo-
lodiazepin-5-ones 138. Finally, 1,6-disubstitu-
ted triazolo[4,5-b][1,4]diazepine-5,7-diones 140
were obtained by the cyclocondensation of tri-
azoles 130 with diethyl 2-methyl(2-phenyl)-
malonate 139.
For the synthesis of triazolo[4,5-b][1,5]benzo-
diazepines 144, aminonitriles 141 were subject-
ed to N-arylation with ortho-halogenonitroben-
zenes 142 to derivatives 143, their reduction and
subsequent cyclization were done by the action
of anhydrous SnСl2 in an alcoholic solution of НСl
(Scheme 44) [10, 74].
For the synthesis of optically active triazolo-
[4,5-d][1,3]diazepin-8-oles 148 and 149, N’-(4-for-
myltriazol-5-yl)-N,N-dimethylformimidates 145
were converted into trimethylsilylcyanohydrins
146, then the reduction of the nitrile group with
Raney nickel was accompanied by fusion of the
diazepine ring and the formation of triazolodi-
azepine 147 (Scheme 45). The deprotection of the
β-D-ribofuranosyl fragment and the subsequent
chromatographic separation of racemates 147 yields
target products with a high optical purity [75].
A convenient method for the synthesis of iso-
electronic analogs of isoazepinomycin, triazolo-
[4,5-e][1,4]diazepine derivatives, was developed
N
N
N
NH2
OMe
OMe
1) NaNO2, AcOH, rt, 15 min
2) , 5 min� N
N
N
N
N
OMe
OMe
ClCl
124, 35 %123
Scheme 40. The synthesis of 3H-[1,2,3]triazolo[4,5-c]cinoline 124
N
N
NN
N N
N
N
O
Ph
Me
O
N
N
NN
N N
N
H2N CO2H
Ph
Ac2O, , 4 h�
126, 68 %125
Scheme 41. The synthesis of triazolo[4,5-d][1,3]oxazine-7-one 126
N
H
S
N
N
N S
Bn
N
N
N
Bn
NH2
N
H
SNa
S
N
N
N
Bn
NH2
NH2
NaOEt, EtOH, 20 oC
129, 60 %
1) CS2, Py, TEA, 115 oC, 6 h
2) 1 N KOH
3) H+ to pH = 3.5
127 128
CS2
Scheme 42. The synthesis of triazolo[4,5-d][1,3]thiazine-5-thione 129
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Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
based on the intramolecular cyclization of N-func-
tionally substituted aminotriazolocarboxamides
150 (Scheme 46). It was found that the latter were
easily cyclized in formic acid at room tempera-
ture to 5-hydroxysubstituted triazolo[4,5-e][1,4]-
diazepines 151 in almost quantitative yields.
Under similar conditions, the action of S-nucleo-
philes 152 led to 5-sulfanylsubstituted triazolo-
diazepines 153. It was most likely that in this re-
action, the acid-catalyzed formation of the cyclic
iminium intermediate A took place, to which the
reagents containing the thiol group were then
added [76].
N-Boc-4-amino-1,2,3-triazole-5-carboxylic acids
154 are a new type of bifunctional reagents.
They were transformed into the corresponding
amides 155 by the action of ethyl glycinate hy-
drochloride in the presence of a 2-fold excess of
CDI (Scheme 47). Removal of the Boc-protec-
tion from their amino group by the action of an
N
N
N NH2
NH2
R
EtO
O
R3
O
N
N
N
H
N
NH2
R
R3
CO2Et
EtO
O
Ph
O
N
N
N N
N
HR
R3
O
N
N
N
H
N
N
R Ph
O
EtO
O
OEt
O
R4
N
N
N
H
N
N
HR O
O
R4
R = Bn, BnCH2
R1 = Me, Ph
R2 = Me, Bn
R3 = Me, Pr
R4 = H, Me, Ph
60 oC, 90 min
N
N
N
R
H
N
NH2
O
O
Ph
134, 65-84 %
NaOEt, EtOH,
�, 5 h
135, 72-90 %
90 oC, 8-24 h
EtOH, 12 M HCl (cat.)
137, 57-58 % 138, 47-51 %
NaOEt, EtOH, , 24 h�
140, 31-78 %
R1 R2
O O
N
N
N
N
N
R2
R1
R
132, 13-52 %
EtOH, 12 M HCl (cat.)
�, 5-10 h
130
131
133
136
139
�, 10 h
Scheme 43. 4,5-Diaminotriazoles 130 in the synthesis of triazolo[4,5-b][1,4]diazepines
N
N
N
CN
N
H
NO2
R = Me, Et
X = F, Cl, Br
R1 = H, 4-F, 4-Cl, 4-Br, 4-CF 3, 3,4- -Cldi
SnCl2, aq. EtOH
HCl conc., , 1 h�
N
N
N
N
H
N
H2N
144, 78-100 %
HCl.
N
N
N
CN
NH2
X
NO2
R1
NaH, THF, rt, 24 h
143, 22-91 %141
142
RR R
R1
R1
Scheme 44. The synthesis of triazolo[4,5-b][1,5]benzodiazepines 144
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Журнал органічної та фармацевтичної хімії 2022, 20 (2)
equivalent amount of hydrogen chloride in di-
oxane at room temperature and the subsequent
cyclocondensation by the action of NaOEt in the
ethanol solution were optimal conditions for ob-
taining target triazolo[4,5-e][1,4]diazepine-5,8-
diones 156 [77].
The authors of [78] used the reduction of amino
ketones 157 using NaВН4 to alcohols 158; they
proved to be convenient substrates for further
transformations (Scheme 48). In particular, tri-
azolooxazepinones 160 were obtained by the reac-
tion of amino alcohols 158 with bromoacetyl bro-
mide 159 followed by the cyclization under ba-
sic conditions. In turn, triazolothiazepinone 162
was synthesized by the cyclocondensation of ami-
noalcohol 158 with thioglycolic acid (161).
A selective S-alkylation of 4-(N-Boc-amino)-
1,2,3-triazole-5-carbothioamides 163 with ethyl
N
N
N O
N NMe2
R
N
N
N CN
N
R
NMe2
Me3SiO
Me3SiCN, BF3-OEt2
N2, Et2O
5 oC to rt, 20 h
146, 48 %
N
N
N
R
HO
N
NH
H
1) Parr apparatus, N2, dioxane,
Raney nickel, 3.1 MPa, 110 oC, 12 h
2) MeOH, 20 % AcOH, 0 oC, 3 h
N
N
N
R
H
N
NH
OH
N
N
N
R
HO
N
NH
H
+
1) NH3, MeOH, rt, 18 h
2) reverse phase silica gel column
S-149, 66 %R-148, 22 %
R =
145
147
OAc OAc
O
AcO
OH OH
O
HO
Scheme 45. The synthesis of triazolo[4,5-d][1,3]diazepin-8-oles 148-149 with optical purity
R = Bu, Bn, 4-MeO-Bn, 3-Cl-Bn, Ph, 4-Cl-Ci 6H4, 4-Me-C6H4,
4-MeO-C6H4, 4-NO2-C6H4, 2,4- -F-Cdi 6H3, 2,4- -Me-Cdi 6H3, 1-methylpyrazol-3-yl
R1 = CH2CO2H, CH2CO2Me, Ac, 4-Me-C6H4
N
N
N
N
H
NH
O
OHR
HCO2H
rt, 10-12 h
151, 81-96 %N
N
N
NH2
O
N
H
R
150
OMe
OMe
N
N
N
N
H
NH
O
SR1R
HCO2H
rt, 12 h
153, 92-95 %
N
N
N
N
NH
O
R
A
H
R1SH
152
Scheme 46. The synthesis of 5-hydroxy- та 5-sulfanylsubstituted triazolo[4,5-e][1,4]diazepines 151, 153
ISSN 2308-8303 (Print) / 2518-1548 (Online) 47
Journal of Organic and Pharmaceutical Chemistry 2022, 20 (2)
N
N
N
H
N
NH
R
O
O
1. HCl, dioxane, rt, 1 h
2. NaOEt, EtOH, , 6 h�
R = PhCH2CH2, Ph, 2-MeO-C6H4, 2-F3C-C6H4, 4-Me-C6H4
N
N
N
R
NHBoc
O
H
N CO2Et
155
156, 58 72 %-
N
N
N
R
NHBoc
CO2H
154
1. CDI, MeCN, 60 °C, 2 h
2. HCl H· 2NCH2CO2Et, MeCN, rt, 1 h
Scheme 47. The synthesis of triazolo[4,5-e][1,4]diazepine-5,8-diones 156
N
N
N
NH2
O
Cl
N
N
N
NH2
OH
Cl
1) NaBH4, MeOH,
rt, 20 min
2) 2N HCl, 5 min,
then NH4OH
158, 48-65 %
1) NaHCO3, H2O, PhMe,
rt, 20 min
2) NaH, PrOH, , 15 min�
Br
O
Br
N
N
N
O
H
N
O
Cl
N
N
N
S
H
N
O
Cl
Me
HS CO2H
160, 15-73 %
150-160 oC, 30 min
162, 65 %
157
159
161
Me Me
Me
Scheme 48. Preparation of triazolooxo- and triazolothiazepinones 160 and 162
N
N
N
NHBoc
H
N
S
R1
R
N
N
N
NHBoc
N
SR CO2Et
Br CO2Et
K2CO3, MeCN
40
163, 62-81 %
R1
R = Me, R1 = Et, Pr, Bu, cyclohexyli t
R = CH2CH2Ph, R1 = Et, But
R = Ph, R1 = Et, But
R = 2-MeO-C6H4, R1 = Et, Pri
N
N
N S
H
N
O
N
R
HCl, dioxane
rt, 5-6 h
R1
165, 87-92 %164
oC, h4-5
Scheme 49. The synthesis of [1,2,3]triazolo[4,5-e][1,4]thiazepin-5(6H)-ones 165
bromoacetate under mild conditions led to the
formation of 4-(N-Boc-amino)-5-thioimidates 164
(Scheme 49). The latter, when the protective Boc-
group was removed by the action of hydrogen
chloride in dioxane, underwent the intramolecu-
lar cyclocondensation with the formation of tar-
get [1,2,3]triazolo[4,5-e][1,4]thiazepin-5(6H)-ones
165 in high yields [79].
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Журнал органічної та фармацевтичної хімії 2022, 20 (2)
■ Conclusions
The analysis, systematization and generaliza-
tion of literature sources related to the synthetic po-
tential of 1,2,3-triazole-4(5)-amines convincingly
indicate that structures of this type are easily
accessible and convenient building blocks for the
construction of triazoloannulated pyridine, azine
and azepine systems that are important for syn-
thetic and biomedical research.
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Information about the authors:
Natalia O. Syrota, engineer of the Department of Chemistry of Functional Heterocyclic Systems, Institute of Organic Chemistry
of the National Academy of Sciences of Ukraine; https://orcid.org/0000-0001-8275-7514.
Sergiy V. Kemskiy, Ph.D. in Chemistry, researcher of the Department of Chemistry of Functional Heterocyclic Systems,
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; https://orcid.org/0000-0003-4313-0991.
Lesya M. Saliyeva (corresponding author), Ph.D. in Chemistry, Senior Lecturer of the Department of Organic Chemistry and Pharmacy,
Lesya Ukrainka Volyn National University; https://orcid.org/0000-0002-1047-8652; e-mail for correspondence: saliieva.lesia@vnu.edu.ua;
tel. +380 95 4886559.
Mykhailo V. Vovk, D.Sc. in Chemistry, Professor, Corresponding Member of the National Academy of Sciences of Ukraine, Director
of the Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; https://orcid.org/0000-0001-7739-670X.
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| id | oai:ojs.journals.uran.ua:article-258512 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-25T01:02:47Z |
| publishDate | 2022 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/aa/e860ea45a813a53b233961f061da9aaa.pdf |
| spelling | oai:ojs.journals.uran.ua:article-2585122026-08-24T13:21:16Z 1,2,3-Triazole-4(5)-amines – Convenient Synthetic Blocks for the Construction of Triazolo-Annulated Heterocycles 1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів Syrota, Natalia O. Kemskiy, Sergiy V. Saliyeva, Lesya M. Vovk, Mykhailo V. 4(5)-amino-1,2,3-triazoles triazolo[4,5-b]pyridines triazolo[4,5-d]pyridines triazoloannelated azepines cyclocondensation 4(5)-аміно-1,2,3-триазоли триазоло[4,5-b]піридини триазоло[4,5-d]піримідини триазолоанельовані азепіни циклоконденсація Aim. To analyze and summarize the synthetic potential of 1,2,3-triazole-4(5)-amines as efficient building blocks in the synthesis of triazolo-annulated pyridine, azine and azepine systems.Results and discussion. Original literature sources revealing the synthetic potential of 4(5)-amino functionalized 1,2,3-triazoles as convenient and available building blocks for the preparation of triazolo-annulated pyridines, azines and azepines were analyzed and systematized. Condensation of 1,2,3-triazole-4(5)-amines with methylene active compounds was shown to be a powerful tool for the synthesis of versatile triazolo[4,5-b]pyridines. In turn, the cyclocondensation based on 5-amino-1,2,3-triazole-4-carboxylic acids and their structurally modified derivatives was proven to be a general way for obtaining a number of triazolo[4,5-d]pyrimidine systems. Few representatives of triazolo-annulated pyridazines, 1,3-oxazines and 1,3-thiazines were synthesized by the intramolecular cyclization of the corresponding 4-aryl(carboxy-, aminomethyl)-5-amino-1,2,3-triazoles. The cyclocondensation involving 4,5-diamino-, 4-carbofunctionalized 5-amino-1,2,3-triazoles and 4-amino-5-thiocarboxamido-1,2,3-triazoles was successful for the construction of di-, oxa- and thiazepino-annulated triazoles.Conclusions. The analysis, systematization and summary of the literature regarding the synthetic potential of 1,2,3-triazole-4(5)-amines conclusively demonstrate that these structures are easily available and convenient molecular blocks for the construction of triazolo-annulated pyridine, azine and azepine systems that are important for synthetic and biomedical research. Мета. Проаналізувати та узагальнити синтетичний потенціал 1,2,3-триазол-4(5)-амінів як ефективних білдинг-блоків у синтезі триазолоанельованих піридинових, азинових та азепінових систем.Результати та їх обговорення. Проаналізовано та систематизовано оригінальні літературні джерела, які розкривають синтетичні можливості 4(5)-амінофункціоналізованих 1,2,3-триазолів як зручних і доступних будівельних блоків для одержання триазолоанельованих азинів та азепінів. Доведено, що конденсація 1,2,3-триазол-4(5)-амінів із метиленактивними сполуками є потужним інструментом синтезу різноманітних триазоло[4,5-b]піридинів. Зі свого боку для отримання низки триазоло[4,5-d]піримідинових систем досить загальними виявились циклоконденсації на основі 5-аміно-1,2,3-триазол-4-карбонових кислот та їхніх структурно модифікованих похідних. Нечисленних представників триазолоанельованих піридазинів, 1,3-оксазинів та 1,3-тіазинів було синтезовано внутрішньомолекулярними циклізаціями відповідних 4-арил(карбокси-, амінометил)-5-аміно-1,2,3-триазолів. Для конструювання ді-, окса- та тіазепіноанельованих триазолів вдалими виявились циклоконденсації за участю 4,5-діаміно-, 4-карбофункціоналізованих 5-аміно-1,2,3-триазолів та 4-аміно-5-тіокарбоксамідо-1,2,3-триазолів.Висновки. Аналіз, систематизація та узагальнення літературних джерел, які стосуються синтетичного потенціалу 1,2,3-триазол-4(5)-амінів, переконливо засвідчують, що такого типу структури є доступними й зручними молекулярними блоками для конструювання важливих для синтетичних і біомедичних досліджень триазолоанельованих піридинових, азинових та азепінових систем. National University of Pharmacy 2022-07-20 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/258512 10.24959/ophcj.22.258512 Journal of Organic and Pharmaceutical Chemistry; Vol. 20 No. 2 (2022); 27-51 Журнал органической и фармацевтической химии; Том 20 № 2 (2022); 27-51 Журнал органічної та фармацевтичної хімії; Том 20 № 2 (2022); 27-51 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/258512/258019 Copyright (c) 2022 Natalia O. Syrota, Sergiy V. Kemskiy, Lesya M. Saliyeva, Mykhailo V. Vovk http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | 4(5)-аміно-1,2,3-триазоли триазоло[4,5-b]піридини триазоло[4,5-d]піримідини триазолоанельовані азепіни циклоконденсація Syrota, Natalia O. Kemskiy, Sergiy V. Saliyeva, Lesya M. Vovk, Mykhailo V. 1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів |
| title | 1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів |
| title_alt | 1,2,3-Triazole-4(5)-amines – Convenient Synthetic Blocks for the Construction of Triazolo-Annulated Heterocycles |
| title_full | 1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів |
| title_fullStr | 1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів |
| title_full_unstemmed | 1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів |
| title_short | 1,2,3-Триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів |
| title_sort | 1,2,3-триазол-4(5)-аміни – зручні синтетичні блоки для конструювання триазолоанельованих гетероциклів |
| topic | 4(5)-аміно-1,2,3-триазоли триазоло[4,5-b]піридини триазоло[4,5-d]піримідини триазолоанельовані азепіни циклоконденсація |
| topic_facet | 4(5)-amino-1,2,3-triazoles triazolo[4,5-b]pyridines triazolo[4,5-d]pyridines triazoloannelated azepines cyclocondensation 4(5)-аміно-1,2,3-триазоли триазоло[4,5-b]піридини триазоло[4,5-d]піримідини триазолоанельовані азепіни циклоконденсація |
| url | https://ophcj.nuph.edu.ua/article/view/258512 |
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