One-Pot Synthesis of 5-Amino-1,2,3-triazole Derivatives via Dipolar Azide?Nitrile Cycloaddition and Dimroth Rearrangement under Solvent-Free Conditions

Article abstract of DOI:10.1002/ejoc.202001620

An efficient one-pot methodology for the preparation of 5-amino-1,2,3-triazole derivatives based on the combination of dipolar azide?nitrile cycloaddition with Dimroth rearrangement under solvent-free conditions has been developed.

Full text of DOI:10.1002/ejoc.202001620

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doi.org/10.1002/ejoc.202001620
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One-Pot Synthesis of 5-Amino-1,2,3-triazole Derivatives via
Dipolar AzideÀ Nitrile Cycloaddition and Dimroth
Rearrangement under Solvent-Free Conditions
Pavel S. Gribanov,*[a] Edita M. Atoian,[a] Anna N. Philippova,[a] Maxim A. Topchiy,[b]
Andrey F. Asachenko,[b] and Sergey N. Osipov[a, c]
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An efficient one-pot methodology for the preparation of 5-
amino-1,2,3-triazole derivatives based on the combination of
dipolar azideÀ nitrile cycloaddition with Dimroth rearrangement
under solvent-free conditions has been developed.
Introduction
Due to their unique physicochemical properties, 1,2,3-triazole-
containing compounds have been the subject of intensive
research over the past two decades. This important class of
heterocycles has found many applications in various fields: as
precursors in organic synthesis,[1] ligands in homogeneous
catalysis,[2] components of optoelectronic devices,[3] polymeric
materials,[4] and building blocks in agricultural chemicals.[5]
Despite the fact that 1,2,3-triazoles have not yet been found
in any natural source,[6] this class of molecules is often used in
the design of biologically active molecules[7] and is actively
investigated in medicinal chemistry along with 1,2,4-triazoles[8]
in the development of a number of new potential drugs.[9]
Biologically active 1,2,3-triazoles primarily include 1,4-disub-
stituted 5-amino 1,2,3-triazoles[10] and 5-alkyl(aryl)amino deriva-
tives of 1,2,3-triazole.[11] The presence of an amino group at
position 5 is often responsible for the manifestation of the
maximum biological activity.[6,12] Thus, derivatives of 5-amino-
1,2,3-triazoles are used in the treatment of pulmonary
fibrosis,[13] kidney diseases,[14] and a number of other patholo-
gies (Figure 1).[12c,15]
Figure 1. 5-Amino 1,2,3-triazoles and their derivatives used in medicinal
chemistry.
tionalized triazoles. In this regard, the set of existing methods
for the preparation of these compounds is still essentially
limited to rare examples.
The main synthetic route to them is dipolar [3+2]-cyclo-
addition reaction (DCR) between arylazides and monosubsti-
tuted acetonitriles, conducted in a sodium alkoxide/alcohol
medium,[20] or with a catalytic amount of tert-amines or
carbonate salts in DMSO/H2O mixture,[10] or by generating
lithium carbanion by the addition of BuLi to alkyl nitriles in THF
(Figure 2).[6]
Also, a method for the preparation of aminotriazoles by
one-pot cycloaddition/Raney-Ni reduction of 1-alkynyltriazenes
with aryl and alkylazides has recently been described.[21]
Subsequent thermal isomerization of 5-amino-1,2,3-triazoles
by Dimroth reaction has been also demonstrated on a few
examples in solution.[10,20a,b] It was found that the reaction
occurs irreversibly only under basic conditions, the absence of
base leads to equilibrium between starting and final
products.[20b]
Given the extreme importance of 5-amino-1,2,3-triazoles
and their derivatives in medicinal chemistry, an important issue
is the development of robust and highly efficient, and atom-
economical methods for their synthesis, which would allow
excluding the use of chemical reagents that cause the
formation of hazardous wastes and to get the target products
via a shorter way with maximum efficiency and selectivity.[22]
Taking into account modern environmental problems,
avoiding the use of toxic organic solvents, which account for
The presence of an active amino group at position 5 of
1,2,3-triazole core makes the main approaches based on Cu(I)-,
ruthenium- or iridium- catalyzed azideÀ alkyne cycloaddition,[16]
organocatalytic azideÀ carbonyl cycloadditon,[17] reactions of N-
tosylhydrazones with anilines[18] and other syntheses of fully
substituted 1,2,3-triazoles[19] inapplicable to this type of func-
[a] Dr. P. S. Gribanov, E. M. Atoian, A. N. Philippova, Prof. S. N. Osipov
A. N. Nesmeyanov Institute of Organoelement compounds
Russian Academy of Sciences
Vavilov str. 28, 119991 Moscow, Russian Federation
E-mail: gribanovps@mail.ru
https://istina.msu.ru/profile/gribanovps/
[b] Dr. M. A. Topchiy, Prof. A. F. Asachenko
A. V. Topchiev Institute of Petrochemical Synthesis
Russian Academy of Sciences
Leninsky Prospect 29, Moscow, 119991, Russian Federation
[c] Prof. S. N. Osipov
Peoples’ Friendship University of Russia (RUDN University)
Miklukho-Maklaya Str. 6, 117198 Moscow, Russian Federation
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001620
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primary test with cesium carbonate, which was previously
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5
identified to be the most effective base in a similar reaction in
solution,[10] resulted in an unsatisfactory result. The target 1,4-
diphenyl-1H-1,2,3-triazol-5-amine (3a) was isolated just in 6%
yield (Table 1, entry 1).
Replacing Cs2CO3 with K2CO3 or Na2CO3 (Table 1, entries 2
and 3), or with organic bases such as DBU or DABCO (Table 1,
entries 4 and 5) did not significantly increase the yield. Switch-
ing to NaOH and KOH (entries 6 and 7) improved the yields to
moderate. Finally, potassium tert-butoxide was found to be the
most effective base for this reaction (entry 10) to afford the
target 5-amino-triazole 3a in 70% yield.
In order to determine the scope of the dipolar azideÀ nitrile
cycloaddition under optimized solvent-free conditions, we
performed a series of reactions between different aryl/alkyl
azides and monosubstituted acetonitriles to access a variety of
1,4-disubstituted 5-amino-1,2,3-triazoles (Table 2).
As a result, the target 1,4-disubstituted 5-amino-1,2,3-
triazoles 3 were obtained in high to almost quantitative yields
with the only exceptions for bisaminotriazoles 3z (35%) and
3aa (30%) due to extremely low solubility of the reaction
partners and the products in the reaction media. The method
allows one to efficiently obtain the corresponding 5-amino-
triazoles from various alkyl and aryl azides bearing donor (3a–j),
acceptor (3k, 3n–s) or sterically hindered (3e, 3i, 3j, 3l, 3m)
substituents and both aryl and hetaryl acetonitriles without the
use of any solvents.
After the cycloaddition step, the presence of an amino
group at position 5 of the 1,2,3-triazole product polarizes the
NÀ N bond in the triazole ring, which enables the Dimroth
rearrangement[33] (the triazole opens, the atoms rotate around
the CÀ C bond followed by ring closure, thus exo- and
endocyclic nitrogen atoms of the 1,2,3-triazole ring are
swapped) (Scheme 1).
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Figure 2. Synthetic approaches to 5-Amino 1,2,3-triazoles and their deriva-
tives.
about 80% of chemical industry waste, is one of the most
important tasks in organic chemistry.[23] In this regard, a number
of industries started introducing methods of “green” chemistry,
such as the application of more effective catalysts, reduction of
the volume of traditional organic solvents, using ecologically-
safe ones instead, or, ideally, complete avoidance of the
solvents in the reaction media.[24] Currently, the development of
solvent-free methodologies is a rapidly developing field of
synthetic organic chemistry. Highly efficient protocols for
Suzuki-Miyaura,[25] Buchwald-Hartwig,[26] and Stille,[27] cross-cou-
pling of aryl lithium compounds,[28] borylation reactions,[29] and
“click” reactions,[30] amide synthesis,[31] and hydrohydrazination
of acetylenes[32] are reported to date.
Here we wish to disclose an efficient method for the
preparation of different 5-amino-1,2,3-triazole derivatives using
a one-pot two-step strategy based on the combination of
dipolar cycloaddition reaction (DCR) of azides and monosub-
stituted acetonitriles with Dimroth rearrangement under sol-
vent-free conditions. We have consistently investigated the
azideÀ nitrile DCR, Dimroth, and one-pot DCR/Dimroth reactions
under the above-mentioned conditions in the presence of
catalytic amounts of cheap bases without the usage of an inert
atmosphere. To the best of our knowledge, the combination of
solvent-free azideÀ nitrile cycloaddition with Dimroth rearrange-
ment in a one-pot manner has never been reported before.
Despite the fact that this approach was used to prepare
some heterocyclic compounds including fused heterocycles,[34]
there are only several sporadic examples in the literature that
involve prolonged heating of an aminotriazole in dry
[10]
pyridine[16b,b] or toluene at 180 C. Therefore, the search for
°
less laborious methods that would significantly simplify the
synthetic availability of biologically relevant N-aryl-substituted
aminotriazoles is of current interest.[12b,35]
Table 1. Optimization of the reaction conditions.[a]
Results and Discussion
As a model reaction, we chose the [3+2]-cycloaddition of 2-
phenylacetonitrile (1a) with phenylazide (2a) to optimize the
conditions in the absence of any solvents. The corresponding
base was added in portions to a mixture of the starting
compounds homogenously mixed at room temperature. After
24 h, the reaction mixture was dissolved in ethyl acetate/H2O
mixture, the aqueous mixture was extracted with ethyl acetate,
and the product was purified by flash chromatography. A
Entry
Base
Yield [%]
Entry
Base
Yield [%]
1
2
3
4
5
Cs2CO3
K2CO3
Na2CO3
DBU
6
0
0
25
0
6
7
8
9
KOH
NaOH
t-BuOLi
t-BuONa
t-BuOK
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29
59
70
DABCO
10
[a] Reaction conditions: 2-Phenylacetonitrile 1a (1 mmol), phenyl azide 2a
°
(1.1 mmol), base (10 mol%), neat, 25 C, 24 h, 700 RPM. Isolated yield.
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Table 2. Solvent-free DCR of azides and acetonitriles.[a]
Table 3. Dimroth rearrangement of 5-amino-1,2,3-triazoles (route A) and
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one-pot two-step DCR/Dimroth reaction (route B) under solvent-free
conditions.[a]
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[a] Conditions: acetonitrile 1a–c (1 mmol), aryl (alkyl) azide 2 (1.1 mmol), t-
°
BuOK (10 mol%), neat, 25 C, 24 h. [b] aryl azide (1 mmol), 2-Phenylace-
tonitrile (3 mmol). [c] acetonitrile 1a or 1c (2 mmol), alkyl azide (1 mmol), t-
BuOK (20 mol%).
[a] Conditions: 1) Route A: 5-Amino-1,2,3-triazole 3 (1 mmol), t-BuOK
°
(10 mol%), neat, 150–180 C (depending on melting point of 5-amino-
1,2,3-triazole), 6 h. 2) Route B (yields in parenthesis): DCR step: acetonitrile
°
1a–c (1 mmol), aryl azide 2 (1.1 mmol), t-BuOK (10 mol%), neat, 25 C, 24 h.
°
Dimroth step: t-BuOK (10 mol%), neat, 150–180 C, 6 h.
heterocycles,[36] we investigated the feasibility fof the one-pot
preparation of 5-amino-1,2,3-triazoles 4 (Table 3, route B).
Thus, after completion of cycloaddition step (TLC control) a
new portion of t-BuOK was added to the same flask and the
resulting mixture was heated for 6 h to afford desired Dimroth
products 4 (route B).
The new one-pot protocol demonstrates a broad substrate
scope, good tolerance towards functional groups (CN, NO2, Br),
and higher overall yields of N-aryl-substituted aminotriazoles
compared to the two-step protocol.
Scheme 1. Proposed mechanism for one-pot two-step DCR/Dimroth reac-
tion.
Thus, the heating of a mixture of the previously obtained
1,4-diphenyl-5-amino-1,2,3-triazole 3a and 10 mol% of pow- Conclusion
dered potassium tert-butoxide under aerobic and solvent-free
°
conditions at 180 C for 6 h allowed to obtain the product of
Dimroth rearrangement 4a in 94% yield (Table 3, route A).
Based on this result, we investigated the reactivity of the other
In conclusion, we developed a robust, highly efficient, and
environmentally benign methodology for the preparation of 5-
amino-1,2,3-triazole derivatives based on the combination of
dipolar azideÀ nitrile cycloaddition with Dimroth rearrangement
under solvent-free conditions. The elaborated protocol has
various advantageous features, such as broad substrate scope,
operational simplicity, and step economy. The reactions can be
easily performed under relatively mild aerobic conditions to
afford a variety of biologically relevant aminotriazoles with
excellent regioselectivity and good to excellent yields. To our
N-aryl-substituted 5-amino-triazoles
3 in Dimroth reaction
under found conditions (route A). As a result, the target N-aryl-
substituted aminotriazoles 4 containing substituents of different
steric and electronic nature were obtained in excellent yields.
Given modern trends in the development of new ecologi-
cally benign methodologies for the synthesis of diversified
organic
compounds
including
biologically
relevant
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vacuo. Purification by chromatography using petroleum ether/ethyl
acetate as eluent afforded pure product.
knowledge, this work is the first solvent-free methodology for
the preparation of 5-amino-1,2,3-triazoles.
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N,4-diphenyl-1H-1,2,3-triazol-5-amine (4a). Following Route
A
(221 mg, 94% yield) and Route B (223 mg, 94% yield), 4a was
obtained as a white solid, m.p. 163–165 C. 1H NMR (400 MHz,
°
Experimental Section
DMSO-d6 +NaOH/D2O) δ 7.73 (d, J=7.7 Hz, 2H), 7.20 (t, J=7.6 Hz,
2H), 7.08–6.95 (m, 3H), 6.61–6.48 (m, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6 +NaOH/D2O) δ 148.3, 140.9, 135.1, 134.9, 129.2, 128.6,
125.4, 125.3, 116.9, 113.8. IR (υ/cmÀ 1): 689 (VS), 747 (VS), 765 (S),
875 (W), 994 (M), 1022 (M), 1118 (M), 1175 (S), 1246 (M), 1297 (M),
1442 (S), 1498 (S), 1533 (S), 1602 (S), 2911 (M), 2934 (M), 3031 (M),
3050 (M), 3146 (M), 3217 (M), 3277 (S). HRMS (ESI) calc. for C14H13N4
[M+H]+: 237.1135, found: 237.1139; calc. for C14H12N4Na [M+Na]+:
259.0954, found: 259.0959.
General information
All reagents were purchased from commercial sources and were
used as received. Analytical TLC was performed with Merck silica
gel 60 F 254 plates; visualization was accomplished with UV light or
iodine vapors. Chromatography was carried out using Merck silica
gel (Kieselgel 60, 0.063–0.200 mm) and petroleum ether/ethyl
acetate as an eluent. The NMR spectra were obtained with Bruker
AV-400 (400 MHz 1H, 101 MHz 13C, 376 MHz 19F) and AV-600
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4-phenyl-N-p-tolyl-1H-1,2,3-triazol-5-amine (4b). Following Route
A (211 mg, 84% yield) and Route B (159 mg, 64% yield), 4b was
1
(600 MHz H, 151 MHz 13C) spectrometers using TMS and CCl3F as
1
references for H and 19F NMR spectra respectively. High-resolution
obtained as a white solid, m.p. 147–149 C. 1H NMR (400 MHz,
°
mass spectra (HRMS) were measured using AB Sciex TripleTOF 5600
+ equipped with TurboV electrospray ionization (ESI) source.
Melting points were determined on a melting point apparatus and
are uncorrected.
DMSO-d6 +NaOH/D2O) δ 7.78 (d, J=7.6 Hz, 2H), 7.37 (t, J=6.6 Hz,
2H), 7.30–7.22 (m, 1H), 6.92 (d, J=7.2 Hz, 2H), 6.79 (d, J=6.4 Hz,
2H), 2.16 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6 +NaOH/D2O) δ
143.2, 142.8, 135.0, 131.2, 129.4, 128.7, 127.2, 126.7, 126.1, 114.6,
20.3. IR (υ/cmÀ 1): 689 (VS), 762 (VS), 807 (VS), 971 (VS), 994 (S), 1022
(S), 1048 (S), 1072 (S), 1183 (S), 1198 (S), 1243 (S), 1289 (S), 1311 (S),
1399 (S), 1439 (VS), 1505 (S), 1535 (VS), 1617 (S), 2916 (S), 3021 (M),
3133 (M), 3356 (M). HRMS (ESI) calc. for C15H15N4 [M+H]+: 251.1291;
found: 251.1288.
General procedure for solvent-free preparation of 1,4-disubsti-
tuted-5-amino-1,2,3-triazoles 3via dipolar azideÀ nitrile cyclo-
addition (DCR). A screw-cap vial equipped with a magnetic stir bar
was charged with 1 mmol of arylacetonitrile and 1.1 equiv. of
corresponding azide. The reaction vial was placed into a water bath
(room temperature) and 10 mol% of powdered potassium tert-
butoxide was added portionwise. The reaction mixture was allowed
to stir (750 RPM) for 24 h at room temperature. After 24 h, the
reaction mixture was dissolved in EtOAc/H2O mixture (1:1, 10 mL),
the organic phase was separated, and the aqueous mixture was
extracted with ethyl acetate (3×5 mL). The organic extract was
evaporated to dryness in vacuo. Purification by chromatography
using petroleum ether/ethyl acetate as eluent yielded an analyti-
cally pure product.
4-phenyl-N-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-5-amine
(4c). Following Route A (282 mg, 93% yield) and Route B (302 mg,
1
°
99% yield), 4c was obtained as a white solid, m.p. 128–129 C. H
NMR (400 MHz, Benzene-d6) δ 11.75 (s, 1H), 7.68 (d, J=7.4 Hz, 2H),
7.29 (s, 1H), 7.15 (d, J=8.2 Hz, 2H), 7.07 (t, J=7.4 Hz, 1H), 6.98 (d,
J=7.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.88 (t, J=7.8 Hz, 1H), 5.60 (s,
1H). 13C{1H} NMR (101 MHz, Benzene-d6) δ 144.2, 143.4, 131.7 (q, J=
32.0 Hz), 129.9, 129.4, 128.8, 127.4, 126.4, 123.7, 118.9, 117.0 (q, J=
3.9 Hz), 112.8 (q, J=3.9 Hz). 19F NMR (376 MHz, DMSO-d6) δ À 61.29.
IR (υ/cmÀ 1): 698 (VS), 777 (VS), 873 (S), 916 (S), 984 (S), 1072 (S),
1099 (S), 1126 (VS), 1166 (VS), 1336 (VS), 1447 (S), 1458 (S), 1490 (S),
1557 (S), 1571 (S), 1620 (S), 2925 (M), 3085 (M), 3168 (M), 3412 (M).
HRMS (ESI) calc. for C15H12F3N4 [M+H]+: 305.1008, found: 305.1011.
General procedure for solvent-free Dimroth rearrangement of
3into 4 (Route A). A screw-cap vial equipped with a magnetic stir
bar was charged with 1 mmol of 1,4-disubstituted-5-amino-1,2,3-
triazole and 10 mol% of powdered potassium tert-butoxide was
°
replaced into a preheated oil bath (150–180 C, depending on
4-(pyridin-2-yl)-N-o-tolyl-1H-1,2,3-triazol-5-amine (4d). Following
Route A (219 mg, 87% yield) and Route B (158 mg, 63% yield), 4d
appropriate 5-amino-1,2,3-triazole melting temperature) and al-
lowed to stir (750 RPM) for 6 h at this temperature. After 6 h the
reaction mixture was cooled, dissolved in EtOAc/H2O mixture (1:1,
10 mL), the organic phase was separated, and the aqueous mixture
was extracted with ethyl acetate (3×5 mL). The organic extract was
evaporated to dryness in vacuo. Purification by chromatography
using petroleum ether/ethyl acetate as eluent gave the analytically
pure product.
1
°
was obtained as a white solid, m.p. 174–175 C. H NMR (400 MHz,
Benzene-d6) δ 9.99 (s, 1H), 9.84 (s, 1H), 8.85–8.75 (m, 1H), 8.10 (d,
J=4.9 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.05 (t,
J=7.9 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 6.51 (t, J=6.1 Hz, 1H), 2.36 (s,
3H). 13C{1H} NMR (101 MHz, Benzene-d6) δ 148.1, 136.6, 130.5, 127.6,
121.5, 120.5, 120.1, 116.2, 18.3. IR (υ/cmÀ 1): 746 (VS), 787 (VS), 981
(S), 994 (S), 1049 (S), 1066 (S), 1097 (S), 1153 (S), 1261 (S), 1280 (S),
1302 (S), 1316 (S), 1344 (S), 1416 (S), 1450 (S), 1464 (S), 1480 (S),
1518 (S), 1553 (VS), 1576 (VS), 1596 (VS), 2911 (M), 3055 (M), 3121
(M), 3183 (M), 3256 (M). HRMS (ESI) calc. for C14H14N5 [M+H]+:
252.1243; found: 252.1244.
General procedure for one-pot solvent-free azideÀ nitrile DCR/
Dimroth rearrangement (Route B). A screw-cap vial equipped with
a magnetic stir bar was charged with 1 mmol of arylacetonitrile and
1.1 equiv. of the corresponding azide. The reaction vial was placed
into a water bath (room temperature) and 10 mol% of powdered
potassium tert-butoxide was added portionwise. The reaction
mixture was allowed to stir (750 RPM) for 24 h at room temper-
ature. After 24 h new powdered potassium tert-butoxide portion
(10 mol%) was added and the reaction vial was replaced into a
N-phenyl-4-(pyridin-2-yl)-1H-1,2,3-triazol-5-amine (4e). Following
Route A (192 mg, 81% yield) and Route B (178 mg, 75% yield), 4e
1
°
was obtained as a white solid, m.p. 168–170 C. H NMR (400 MHz,
Benzene-d6) δ 10.09 (s, 1H), 9.89 (s, 1H), 8.21 (d, J=5.5 Hz, 1H), 8.01
(d, J=8.1 Hz, 1H), 7.83 (d, J=7.9 Hz, 2H), 7.29 (t, J=7.8 Hz, 2H), 7.05
(t, J=7.8 Hz, 1H), 6.90 (t, J=7.6 Hz, 1H), 6.57–6.47 (m, 1H). 13C{1H}
NMR (151 MHz, Benzene-d6) δ 152.6, 148.2, 142.3, 136.6, 131.1,
129.5, 128.3, 121.6, 120.7, 120.2, 117.2. IR (υ/cmÀ 1): 695 (VS), 746
(VS), 788 (VS), 981 (VS), 1152 (S), 1280 (S), 1443 (S), 1499 (S), 1517
(S), 1554 (VS), 1576 (VS), 1601 (VS), 2918 (M), 3050 (M), 3118 (M),
°
preheated oil bath (150–180 C, depending on appropriate 5-
amino-1,2,3-triazole melting temperature) and allowed to stir for
6 h at this temperature. After 6 h the reaction mixture was cooled,
dissolved in EtOAc/H2O mixture (1:1, 10 mL), the organic phase was
separated, and the aqueous mixture was extracted with ethyl
acetate (3×5 mL). The organic extract was evaporated to dryness in
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3183 (M). HRMS (ESI) calc. for C13H12N5 [M+H]+: 238.1087; found:
238.1087.
4-(2-bromophenyl)-N-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-
5-amine (4k). Following Route A (374 mg, 98% yield) and Route B
(234 mg, 61% yield), 4k was obtained as a white solid, m.p. 146–
1
2
3
4
5
6
7
8
9
4-(pyridin-2-yl)-N-p-tolyl-1H-1,2,3-triazol-5-amine (4f). Following
Route A (180 mg, 72% yield) and Route B (166 mg, 57% yield), 4f
148 C. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.72 (d, J=
°
8.0 Hz, 1H), 7.59 (s, 1H), 7.47 (dd, J=13.6, 5.9 Hz, 3H), 7.35 (t, J=
7.1 Hz, 2H), 7.00 (d, J=7.6 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 144.6, 143.8, 133.4, 132.8, 132.4, 131.8, 130.3, 129.7, 129.5 (q, J=
30.8 Hz), 127.6, 124.5 (q, J=272.1 Hz), 123.7, 118.5, 114.4 (q, J=
3.8 Hz), 110.6 (q, J=3.7 Hz). 19F NMR (376 MHz, DMSO-d6) δ À 61.30.
IR (υ/cmÀ 1): 699 (VS), 754 (VS), 872 (VS), 992 (VS), 1019 (VS), 1069
(VS), 1125 (VS), 1166 (VS), 1337 (VS), 1475 (S), 1541 (S), 1571 (S),
1604 (S), 2914 (M), 3120 (M), 3256 (M). HRMS (ESI) calc. for
C15H11F3BrN4 [M+H]+: 383.0113, 385.0093, found: 383.0118,
385.0099.
1
°
was obtained as a white solid, m.p. 191–193 C. H NMR (400 MHz,
Benzene-d6) δ 10.06 (s, 1H), 9.86 (s, 1H), 8.22 (d, J=5.0 Hz, 1H), 8.03
(d, J=8.1 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.2 Hz, 3H),
7.04 (t, J=7.8 Hz, 1H), 6.54–6.47 (m, 1H), 2.17 (s, 3H). 13C{1H} NMR
(151 MHz, Benzene-d6) δ 148.2, 140.0, 136.5, 130.0, 129.7, 128.4,
121.5, 120.2, 117.3, 20.8. IR (υ/cmÀ 1): 785 (VS), 822 (VS), 981 (VS),
994 (VS), 1276 (S), 1341 (S), 1517 (VS), 1554 (S), 1573 (S), 1599 (VS),
2914 (M), 3120 (M), 3185 (M), 3271 (M), 3368 (M). HRMS (ESI) calc.
for C14H14N5 [M+H]+: 252.1244; found: 252.1245.
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4-(pyridin-2-yl)-N-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-5-
amine (4g). Following Route A (257 mg, 84% yield) and Route B
(190 mg, 62% yield), 4g was obtained as a white solid, m.p. 150–
N-(3,5-bis(trifluoromethyl)phenyl)-4-(2-bromophenyl)-1H-1,2,3-
triazol-5-amine (4l). Following Route A (439 mg, 97% yield) and
Route B (284 mg, 63% yield), 4l was obtained as a white solid, m.p.
1
°
152 C. H NMR (400 MHz, Benzene-d6) δ 9.95 (s, 1H), 9.72 (s, 1H),
1
°
135–136 C. H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.97 (s, 2H),
8.30 (s, 1H), 8.16–8.11 (m, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.59 (d, J=
7.6 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.02 (td, J=8.0, 1.7 Hz, 2H), 6.50
(ddd, J=7.5, 5.0, 1.2 Hz, 1H). 13C{1H} NMR (101 MHz, Benzene-d6) δ
155.9, 148.2, 148.0, 136.8, 129.8, 121.8, 120.2, 119.9, 116.9 (q, J=
3.6 Hz), 113.4 (q, J=3.5 Hz). 19F NMR (376 MHz, DMSO-d6) δ À 61.17.
IR (υ/cmÀ 1): 786 (VS), 865 (VS), 920 (VS), 981 (VS), 1068 (VS), 1120
(VS), 1164 (VS), 1236 (S), 1338 (VS), 1460 (S), 1559 (VS), 1586 (VS),
1606 (VS), 2942 (M), 3057 (M), 3121 (M), 3182 (M). HRMS (ESI) calc.
for C14H11F3N5 [M+H]+: 306.0967; found: 306.0970.
7.77 (d, J=8.0 Hz, 1H), 7.49 (d, J=3.6 Hz, 2H), 7.42 (ddd, J=8.9, 5.4,
3.5 Hz, 1H), 7.35 (s, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 145.3,
143.4, 133.3, 132.9, 132.5, 131.4, 131.0, 130.8 (q, J=32.2 Hz), 130.5,
123.8, 123.6 (q, J=272.9 Hz), 114.4, 110.5. 19F NMR (376 MHz,
DMSO-d6) δ À 61.25. IR (υ/cmÀ 1): 681 (VS), 699 (VS), 737 (S), 760 (S),
871 (S), 956 (S), 1019 (S), 1073 (S), 1122 (VS), 1168 (VS), 1281 (VS),
1388 (VS), 1435 (S), 1471 (S), 1543 (S), 1588 (S), 1627 (S), 3272 (M),
3446 (M). HRMS (ESI) calc. for C16H10F6BrN4 [M+H]+: 450.9987,
452.9967, found: 450.9988, 452.9968.
N-(2-bromophenyl)-4-phenyl-1H-1,2,3-triazol-5-amine (4h). Fol-
lowing Route A (257 mg, 84% yield) and Route B (190 mg, 62%
N-(4-nitrophenyl)-4-phenyl-1H-1,2,3-triazol-5-amine (4m). Follow-
ing Route A (267 mg, 95% yield) and Route B (261 mg, 93% yield),
1
°
yield), 4g was obtained as a grey solid, m.p. 123–125 C. H NMR
4m was obtained as a yellow solid, m.p. 145–147 C. 1H NMR
°
(400 MHz, Benzene-d6) δ 7.89 (d, J=8.3 Hz, 1H), 7.83 (d, J=7.6 Hz,
2H), 7.30 (d, J=7.9 Hz, 1H), 7.14 (s, 1H), 7.05 (t, J=7.2 Hz, 1H), 6.97
(t, J=7.7 Hz, 1H), 6.78 (s, 1H), 6.43 (t, J=7.6 Hz, 1H). 13C{1H} NMR
(101 MHz, Benzene-d6) δ 144.1, 140.5, 136.9, 132.6, 130.4, 129.3,
128.8, 128.6, 127.2, 121.3, 116.4, 111.1. IR (υ/cmÀ 1): 697 (VS), 735
(VS), 765 (VS), 985 (VS), 1021 (VS), 1050 (S), 1316 (VS), 1445 (VS),
1469 (S), 1558 (VS), 1597 (VS), 2917 (M), 3060 (M), 3163 (M), 3410
(M). HRMS (ESI) calc. for C14H12BrN4 [M+H]+: 315.0240, 317.0219,
found: 315.0244, 317.0224.
(400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.07 (d, J=8.7 Hz, 2H), 7.75 (d,
J=8.2 Hz, 2H), 7.44 (t, J=7.6 Hz, 2H), 7.35 (t, J=7.4 Hz, 1H), 6.98 (d,
J=8.9 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 151.9, 140.5,
138.2, 136.0, 129.6, 128.9, 128.1, 126.3, 126.0, 113.4. IR (υ/cmÀ 1): 749
(VS), 764 (VS), 842 (VS), 987 (VS), 1112 (VS), 1188 (VS), 1303 (VS),
1326 (VS), 1442 (S), 1505 (S), 1546 (S), 1576 (S), 1602 (VS), 2914 (M),
3153 (M), 3396 (M). HRMS (ESI) calc. for C14H12N5O2 [M+H]+:
282.0986; found: 282.0997.
4-(4-phenyl-1H-1,2,3-triazol-5-ylamino)benzonitrile (4n). Follow-
ing Route A (196 mg, 75% yield) and Route B (179 mg, 68% yield),
4-(2-bromophenyl)-N-phenyl-1H-1,2,3-triazol-5-amine (4i). Fol-
lowing Route A (224 mg, 71% yield) and Route B (220 mg, 70%
1
°
4n was obtained as a light-brown solid, m.p. 144–146 C. H NMR
yield), 4i was obtained as a grey solid, m.p. 124–125 C. 1H NMR
°
(400 MHz, DMSO-d6 +NaOH/D2O) δ 7.69 (d, J=7.7 Hz, 2H), 7.34 (d,
J=8.5 Hz, 2H), 7.22 (t, J=7.7 Hz, 2H), 7.05 (t, J=7.9 Hz, 1H), 6.63 (d,
J=8.5 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6 +NaOH/D2O) δ
152.7, 139.7, 134.8, 134.8, 133.5, 128.5, 125.3, 121.5, 113.7, 96.6,
95.5. IR (υ/cmÀ 1): 696 (M), 766 (M), 830 (M), 986 (M), 1021 (W), 1047
(W), 1174 (M), 1249 (M), 1324 (M), 1443 (M), 1511 (S), 1543 (S), 1596
(VS), 1606 (VS), 2216 (S), 2911 (M), 3065 (M), 3160 (M), 3396 (M).
HRMS (ESI) calc. for C15H12N5 [M+H]+: 262.1087, found: 262.1093.
(400 MHz, Benzene-d6) δ 7.34 (dd, J=8.1, 1.2 Hz, 1H), 7.25 (dd, J=
7.6, 1.7 Hz, 1H), 7.22–7.18 (m, 2H), 7.13 (d, J=8.6 Hz, 1H), 6.86 (td,
J=7.6, 1.2 Hz, 1H), 6.81 (tt, J=7.2, 1.2 Hz, 1H), 6.67 (td, J=7.8,
1.7 Hz, 1H), 5.69 (s, 1H). 13C{1H} NMR (101 MHz, Benzene-d6) δ 146.1,
142.5, 133.5, 132.8, 131.8, 130.5, 129.3, 123.9, 120.8, 116.5. IR (υ/
cmÀ 1): 695 (VS), 735 (VS), 766 (VS), 916 (M), 982 (S), 1025 (S), 1070
(M), 1160 (M), 1217 (M), 1283 (S), 1317 (M), 1372 (S), 1425 (S), 1455
(S), 1515 (VS), 1573 (S), 1599 (VS), 1624 (VS), 2851 (W), 2924 (W),
3061 (M), 3187 (M), 3317 (S), 3425 (M). HRMS (ESI) calc. for
C14H12BrN4 [M+H]+: 315.0240, 317.0219, found: 315.0241, 317.0222.
N-(3,5-bis(trifluoromethyl)phenyl)-4-phenyl-1H-1,2,3-triazol-5-
amine (4j). Following Route A (338 mg, 91% yield) and Route B
(355 mg, 87% yield), 4j was obtained as a grey solid, m.p. 154–
Acknowledgements
This work was financially supported by the Russian Science
Foundation (grant RSF No 20-73-00291). NMR studies and spectral
characterization were performed with financial support from the
Ministry of Science and Higher Education of the Russian
Federation using the equipment of the Center for Molecular
Composition Studies of INEOS RAS. Part of this work was carried
out by M.A. Topchiy and A.F. Asachenko as a part of the State
Program of A. V. Topchiev Institute of Petrochemical Synthesis of
the Russian Academy of Sciences (TIPS RAS). The publication was
1
°
156 C. H NMR (400 MHz, Benzene-d6) δ 11.18 (s, 1H), 7.58 (d, J=
7.4 Hz, 2H), 7.35 (d, J=13.1 Hz, 3H), 7.20 (d, J=7.3 Hz, 2H), 7.10 (t,
J=7.4 Hz, 1H), 5.58 (s, 1H). 13C{1H} NMR (101 MHz, Benzene-d6) δ
143.8, 143.5, 142.6, 132.6 (q, J=33.0 Hz), 129.9, 129.5, 129.1, 127.5,
125.4, 122.7, 120.0, 115.7, 115.7, 113.5 (p, J=3.9 Hz). 19F NMR
(376 MHz, DMSO-d6) δ À 61.85. IR (υ/cmÀ 1): 766 (S), 870 (S), 956 (S),
997 (S), 1026 (S), 1052 (S), 1129 (VS), 1176 (VS), 1276 (VS), 1387 (VS),
1471 (S), 1499 (S), 1595 (S), 1624 (S), 2858 (M), 2919 (M), 3309 (M).
HRMS (ESI) calc. for C16H11F6N4 [M+H]+: 373.0882, found: 373.0889.
Eur. J. Org. Chem. 2021, 1378–1384
www.eurjoc.org
1382
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202001620
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: Cyclization · Heterocycles · Synthetic methods ·
Triazoles
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