Access to azolopyrimidine-6,7-diamines as a valuable “building-blocks” to develop new fused heteroaromatic systems

Article abstract of DOI:10.1016/j.tet.2021.132172

A simple and convenient approach for the synthesis of new azolopyrimidine-6,7-diamines has been developed by the method of reductive cleavage of azo-group in series 6-[2-(4-methylphenyl)diazenyl]azolo[1,5-a]pyrimidine-7-amines, which was obtained by the interaction of aminoazoles with [2-(4-methylphenyl)hydrazinylidene]-3-oxo-propionitrile. The proposed approach allows to use a wide range of aminoazoles as a starting reagent and it also distinguishes itself by the simplicity of isolation and purification of products. The synthetic potential of presented diamines was demonstrated by the reaction of obtaining azolo[a]annulated pteridines.

Full text of DOI:10.1016/j.tet.2021.132172

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Access to azolopyrimidine-6,7-diamines as a valuable “building-
blocks” to develop new fused heteroaromatic systems
,
Denis A. Gazizov a *, Victor V. Fedotov b, Konstantin A. Chistyakov a, Evgeny B. Gorbunov a,
,
, b
Gennady L. Rusinov a b, Valery N. Charushin a
a Postovsky Institute of Organic Synthesis of Ural Branch of Russian Academy of Sciences, Sofia Kovalevskoy St. 22/20, Ekaterinburg, 620108, Russia
b Ural Federal University, Department of Organic and Biomolecular Chemistry, Mira St. 19, Ekaterinburg, 620002, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and convenient approach for the synthesis of new azolopyrimidine-6,7-diamines has been
developed by the method of reductive cleavage of azo-group in series 6-[2-(4-methylphenyl)diazenyl]
azolo[1,5-a]pyrimidine-7-amines, which was obtained by the interaction of aminoazoles with [2-(4-
Received 4 March 2021
Received in revised form
13 April 2021
Accepted 17 April 2021
Available online xxx
methylphenyl)hydrazinylidene]-3-oxo-propionitrile. The proposed approach allows to use
a wide
range of aminoazoles as a starting reagent and it also distinguishes itself by the simplicity of isolation and
purification of products. The synthetic potential of presented diamines was demonstrated by the reaction
of obtaining azolo[a]annulated pteridines.
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
universality as the “building-blocks” for the formation of the
polycyclic systems [13].
The chemistry of azoloannulated pyrimidines has lately been
developed rapidly [1], the interest to this system is caused by the
wide range of the possible usage of the structures containing the
present fragment. For example, various azolo[1,5-a]pyrimidines
exhibit antiviral [2], antiinflammatory [3], antibacterial [4], anti-
fungal [5], antiparasitic [6], and antitumour [7] activities. Besides
the biological application, [1,2,4]triazolo- and pyrazolo[1,5-a]py-
rimidine scaffolds are established as promising acceptor systems
for the construction of luminescent molecules [8], including those
with mechanochromic properties [9].
Polycyclic structures, containing the azolo[1,5-a]pyrimidine
fragment, also demonstrate the promising potential for the creation
of biologically active compounds [10]. However, approaches to their
preparation are presented in the literature by isolated examples of
the synthesis of azolopurines and azolopteridines [10a,11], which
emphasizes the urgency of developing a convenient and universal
method of obtaining these structures.
As a part of this approach, in our previous work, we developed
the method for the synthesis of the series of 2-R-triazolo[1,5-a]-
pyrimidine-6,7-diamines (Scheme 1, a) and demonstrated the
possibility of their cyclization to various triazolo-purines and
-pteridines [11d]. In spite of the efficiency of the proposed method
for some aminotriazoles, the nitration stage imposed significant
restrictions for the substituent in the azole ring and the azole
system as a whole.
Analyzing the literature we found two ways to obtain pyrazolo
[1,5-a]pyrimidine-6,7-diamines (Scheme 1, b).10b,11а While the first
approach turned out too labour-consuming, the second approach
excited our curiosity by the convenience amino-group introduc-
tion, using the ordinary stage of the reductive cleavage of the azo-
group in 6-(aryldiazenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-
amines, obtained
by the interaction of
3-oxo-2-(2-
arylhydrazinylidene)butanenitrile with 2-alkyl and -aryl
substituted 5-amino-1H-pyrazoles (Scheme 1, b (2)). In this case,
the azo-group acts as the nitro-group synthetic equivalent that
permits to avoid applying nitration, and using unstable compounds
such as nitroacetonitrile, nitroacetaldehyde, metazonic acid, and
their derivatives.
It is known that the annulation of the imidazole ring to the
diaminopyrimidines is one of the classic methods of the formation
of the purines [12], it is also important that the same diamines can
be used for the annulation of other rings; this fact confirms their
Inspired by this example, we continued our work and decided to
develop a common method of obtaining various azolo[1,5-a]py-
rimidine-6,7-diamines, that is based on using 1,3-bis-electrophile
* Corresponding author.
E-mail address: gazizov@ios.uran.ru (D.A. Gazizov).
https://doi.org/10.1016/j.tet.2021.132172
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: D.A. Gazizov, V.V. Fedotov, K.A. Chistyakov et al., Access to azolopyrimidine-6,7-diamines as a valuable “building-
blocks” to develop new fused heteroaromatic systems, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132172

D.A. Gazizov, V.V. Fedotov, K.A. Chistyakov et al.
Tetrahedron xxx (xxxx) xxx
Scheme 1. Literary approaches to azolopyrimidine-6,7-diamines.
which contains azo- and cyano-groups.
tetrazolopyrimidine 5i with a high yield.
Within the scope of the optimization of the conditions and
because of the precedent, shown earlier in literature, and also the
world tendency to the “green” processes, we attempted to obtain
the structures 5 in the solvent-free conditions. Despite all advan-
tages of the microwave activation [11a], the difficulty of the sub-
sequent laboratory scaling of the process made us choose
conventional heating.
2. Results and discussion
We have chosen 3-(morpholin-4-yl)acrylonitrile (1), which was
used by us before, as a readily available started reagent for
obtaining the aforementioned 1,3-bis-electrophile. Its interaction
with p-toluene diazonium chloride, by the methods presented in
the literature, led to the formation of the desired 2-[2-(4-
methylphenyl)-hydrazinylidene]-3-oxo-propionitrile (2) with the
yield of 56% and 2-[2-(4-methylphenyl)diazenyl]-2-[2-(4-
methylphenyl)-hydrazinylidene]-acetonitrile (3), as a by-product
(Scheme 2, condition (a)) [14].
As a model reaction, we carried out the interaction of equimolar
amounts of aminoazole 4с and hydrazine 2 under heating to the
Obviously, that the by-product 3 is formed as a result of the
Japp-Klingemann reaction (ESI, S73-74), which is promoted by
excess of the base [15]. To confirm it we carried out the reaction
without the base; it allowed us to obtain product 2 without the
formazan formation, but its yield formed only 29% (Scheme 2,
condition (b)). The reduction of the amount of the sodium acetate
allowed to obtain 2-[2-(4-methylphenyl)hydrazinyliden]-3-oxo-
propionitrile (2) with the yield of 82%. (Scheme 2, condition (c)).
The appropriate products of condensation 5 were obtained by
the reaction of hydrazinylidene 2 with a number of aminoazoles in
DMF at the temperature of 120ꢀС. In all cases, except the azole 4i,
the reaction in DMF proceeds smoothly, the products of cyclization
precipitate from the reaction mixture that makes their isolation
easy (Scheme 3). For aminotetrazole 4i the reaction with hydrazone
2
in acetic acid allows to obtain the appropriate
Scheme 2. Synthesis of 2-[2- (4-methylphenyl)-hydrazinylidene]-3-oxo-propionitrile.
Scheme 3.
2

D.A. Gazizov, V.V. Fedotov, K.A. Chistyakov et al.
Tetrahedron xxx (xxxx) xxx
temperature of 160ꢀС with the HPLC control. The heating of the
reaction mixture was carrying out continuously (without exposure)
under mechanical stirring and sampling upon reaching the neces-
sary temperature. It was found that about 2% of the product 5с was
formed after grinding the reaction mixture in a mortar; subsequent
stepwise heating ensured complete conversion of the starting
compounds, which made it possible to obtain a high-purity product
5c without purification (full data, ESI, S56-62).
By widening this approach to another aminoazoles, as the op-
timum conditions to carry out the reaction, we chose the temper-
ature of 160ꢀС and the exposure of an hour, because the carrying
out of the reaction by lower temperature, even with the longer
exposure, in some cases, didn't provide the full conversion of the
initial compounds.
The use of the optimum conditions allowed to obtain the
desired azolopyrimidines 5a-i with a high degree of purity
92e100% (HPLC data, ESI, S63-70), which makes it possible to use
them for synthesis without further purification. In the case of the
unsubstituted aminotriazole 4a by the reaction was formed the
mixture of two products, supposedly [1,5-a] and [4,3-a]regioizmers
in the 87/12 ratio (by HPLC and NMR data, ESI, S63, and S75). The
treatment of this mixture by the 1% aqueous-alcohol solution KOH
at room temperature during the night increases the part of the [1,5-
а]isomer, leading to the 98/2 ratio (by HPLC data, ESI, S63), that
allows us to make a conclusion about the proceeding of the Dim-
roth rearrangement. The [4,3-a] isomer formation is also fixed
when the reaction is carried out in DMF (by NMR data, ESI, S75), but
the subsequent heating leads exclusively to the [1,5-a] product, that
points to the possibility of the rearrangement proceeding without
the catalysis. We couldn't isolate [4,3-a] isomer in pure form
because of the bad solubility of the obtained isomers mixture and
the rearrangement proceeding at high temperatures, but in our
previous work we had demonstrated the tendency of the unsub-
stituted aminotriazole to form [4,3-a] isomer, that conforms to our
supposition [16].
The structure of the synthesized compounds was confirmed by
the data of the NMR spectra and the elemental analysis. The NMR
spectra for compounds 5b,f,g are presented in CDCl3/CF3COOD due
to limited solubility in other organic solvents; HRMS spectral data
are additionally presented. The azide-tetrazole tautomerism is
peculiar to the compound 5i, it is expressed by the presence of
three sets of the signals in the NMR 1H spectrum in DMSO‑d6. The
use of CDCl3 as a solvent allows to fix exceptionally azide form in
the NMR spectrum of this compound, that is confirmed by the data
of IR spectroscopy in CHCl3.
The next step of our work was the hydrogenolysis of the azo-
bond of compounds 5 in the presence of Pd/C in the atmosphere
of hydrogen at the pressure of 3e5 bar. The reaction proceeds in
mild conditions and with the high yield of the key diamines 6
(Scheme 4). It ought to mark that p-toluidine is educed as a single
by-product and after the insignificant purification can be used for
the second time for the obtaining of the hydrazone 2. In the case of
compound 6f, the 1H NMR spectrum contains no signals of the
protons of the amino groups, which probably occurs as a result of
the hydrogen-deuterium exchange process, and also the broad-
ening of the signal of the pyrimidine proton is observed. The peak
of the molecular ion is unambiguously recorded in the HRMS
spectrum. For further transformations, diamine 6f was used
without additional purification. Upon the reduction of the com-
pound 5i in EtOH, in addition to hydrogenolysis of the azo bond, the
tetrazole ring is destroyed, which leads to the formation of 1,2,4-
triaminopyrimidine 6i. We decided to appraise the influence of
the solvent on the azide-tetrazole equilibrium supposing that the
displacement of the equilibrium to the side of the tetrazole form
would assist in the conservation of the annulated tetrazole ring. So,
Scheme 4.
the band of the azido-group was fixed in the IR spectra, recorded in
the solutions of benzene, CHCl3, dioxane, DMF, EtOH, and in solid
form, in the region of 2133e2137 cmꢁ1 (ESI, S71). Nevertheless, in
the case of the DMF solution, its next exposure during a day at room
temperature leads to the disappearance of the absorption band of
the azido-group (ESI, S71). Despite this, the attempt of the reduc-
tion of the compound 5i in DMF with the beforehand exposure of
obtained solution also leads to triamine 6i.
To confirm the reproducibility and economic feasibility of the
developed protocol, as well as the possibility of using compounds 5
without preliminary purification, gram-scale synthesis of 2-(tri-
fluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6,7-diamine
(6c)
was carried out (Scheme 5).
In the capacity of the demonstration of the synthetic potential of
the obtained diamines and as a continuation of our previous work,
we carried out their reaction with glyoxal under acid catalysis to
obtain new azoloannulated pteridines 7 (Scheme 6). The molecular
structure of 7f was additionally established by XRD analysis (ESI,
S72).
3. Conclusion
Thus, we have developed a simple and convenient method of
azolo[1,5-a]pyrimidine-6,7-diamines synthesis. The proposed
synthetic strategy provides good yields of the target diamines
without the extra purification. Furthermore, high tolerance to the
starting aminoazoles and the possibility of the formed toluidine for
regeneration provides the practical significance and the economic
effectiveness of the process. The possibility of using the obtained
diamines was presented by the example of the reaction of obtaining
azolo[a]annulated pteridines.
3.1. Experimental data
3.1.1. General information
1H, 13С and 19F NMR spectra were acquired on a Bruker DRX-400
3

D.A. Gazizov, V.V. Fedotov, K.A. Chistyakov et al.
Tetrahedron xxx (xxxx) xxx
Scheme 5. Synthetic application of the obtained diamines.
and cooling. After 30 min exposure, the resulting p-toluenediazo-
nium salt solution was added to a cold (ꢁ10 ꢀC) solution of 3-
morpholinoacrylonitrile (1) in EtOH (150 mL) containing sodium
acetate trihydrate (0.08 mol, 10.88 g). The reaction mixture was
stirred for 1 h under cooling and for another 2 h at room temper-
ature. The solid product so formed was collected by filtration,
washed with EtOH and air-dried. Yellow solid (15.3 g, 82%), m. p.
(193-195 ꢀC). 1H NMR (500 MHz, DMSO‑d6)
d 12.70 (s, 1H), 9.49 (s,
1H), 7.46 (d, J ¼ 8.5 Hz, 2H), 7.25 (d, J ¼ 8.3 Hz, 2H), 2.31 (s, 3H). 13
C
NMR (126 MHz, DMSO‑d6)
d 186.5, 139.4, 135.1, 129.9, 116.5, 113.7,
110.3, 20.5. Anal. Calcd. For C10H9N3O: C, 64.16; H, 4.85; N, 22.45.
Found: С, 64.08; H, 4.85; N, 22.53.
3.1.3. [(4-Methylphenyl)diazenyl][2-(4-methylphenyl)
hydrazinylidene]acetonitrile (3)
1H NMR (400 MHz, DMSO‑d6)
d
12.46 (s, 1H), 7.74 (d, J ¼ 8.0 Hz,
4H), 7.28 (d, J ¼ 8.0 Hz, 4H), 2.42 (s, 6H). HRMS (þESI): Calcd. For
C
16H15N
5 m/z 278.1400 [MþH]þ, found m/z 278.1405 [Mþ H]þ.
3.2. General procedure for the synthesis of compounds 5a-i
3.2.1. Method I
A mixture of the corresponding aminoazole 4a-h (1 mmol or
1.2 mmol for 4i) and 2-[2-(4-methylphenyl)hydrazinylidene]-3-
oxopropanenitrile (2) (1 mmol, 187 mg) in DMF (5 mL) was stir-
red for 5 h at 140 ꢀC, then the mixture was cooled. The precipitate
that formed was collected by filtration, washed with a small
amount of EtOH, and air-dried.
Scheme 6.
instrument (400,101 and 376 MHz, respectively), a Bruker DRX-500
(500, 126 and 470 MHz, respectively) or a Bruker Avance NEO 600
instrument (600 and 151 MHz, respectively), equipped with a
Prodigy broadband gradient cryoprobe, using DMSO‑d6, CDCl3 or
CDCl3/CF3COOD (5/1) as solvent and TMS as internal standard. The
high-resolution mass spectrometry (HRMS) was performed using
Bruker Daltonik MaXis Impact HD quadrupole time-of-flight mass
spectrometer. Elemental analysis was performed on a PerkinElmer
PE 2400 elemental analyzer. Melting points were determined in
open capillaries on a Stuart SMP3 apparatus. The IR spectra were
recorded on “PerkinElmer Spectrum One FT-IR” by diffuse reflec-
tion accessory (DRA) or “Thermo Nicolet 6700 FT-IR” spectrometers
using the “Frustrated total internal reflection” (FTIR) method at
4000e400 cmꢁ1. HPLC experiments were carried out in a gradient
elution mode MeCN (20%)/H2O (80%), flow rate 0.8 m/min, Kro-
3.2.2. Method II
A mixture of the corresponding aminoazole 4a-h (1 mmol or
1.2 mmol for 4i) and 2-[2-(4-methylphenyl)hydrazinylidene]-3-
oxopropanenitrile (2) (1 mmol, 187 mg) was thoroughly ground
in a mortar or beaker. The resulting mixture was kept at 160 ꢀC
(140 ꢀC for 4i) in an oil bath with mechanical stirring for 1 h. After
cooling to room temperature, the crude product can be used
without further purification (except 5a,5f). To obtain analytically
pure samples, the crude product was washed with hot EtOH (5i
washed with water), the precipitate was filtered and air-dried.
masil 100-5C18 (250 ꢂ 4.6 mm, 5
mm), detection at 230/360 nm,
injection 5 L in DMF. All solvents and commercially available re-
3.3. 6-(4-Methylphenyl)diazenyl][1,2,4]triazolo[1,5-a]pyrimidine-
7-amine (5a)
m
actants/reagents were used as received. Noncommercial starting
materials were prepared as described below or according to liter-
ature procedures.
Method I. Orange solid (195 mg, 77%), m. p. (>300 ꢀC). Method
II. The crude product in 1/1 (v/v) H2OeEtOH mixture (5 mL) was
treated with a solution of KOH (112 mg) in Н2О (1 mL), stirred
overnight at 40 ꢀC, then cooled to room temperature, and
neutralized with 2 M HCl to pH ~7. EtOH was evaporated at reduced
pressure; the precipitate was filtered off and dried under reduced
pressure at 110 ꢀC over P2O5. Yellow solid (230 mg, 91%), m. p.
3.1.2. 2-[2-(4-Methylphenyl)hydrazinylidene]-3-oxopropanenitrile
(2)
A p-toluenediazonium salt (0.1 mol) solution was prepared by
adding sodium nitrite solution (0.13 mol in 100 mL H2O) to a chilled
(ꢁ5 ꢀC) solution of p-toluidine hydrochloride (0.1 mol (10.72 g) of
p-toluidine, 0.3 mol (27 mL) 11 M HCl in 125 mL H2O) with stirring
(>300 ꢀC). 1H NMR (500 MHz, DMSO‑d6)
8.99 (s, 1H), 8.60 (s, 1H), 7.93 (d, J ¼ 8.3 Hz, 2H), 7.37 (d, J ¼ 8.1 Hz,
d 9.64 (s, 1H), 9.32 (s, 1H),
4

D.A. Gazizov, V.V. Fedotov, K.A. Chistyakov et al.
Tetrahedron xxx (xxxx) xxx
2H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO‑d6)
d
155.8, 155.1, 152.2,
CF3COOD)
d
155.2,149.1,147.3,145.1,144.6,130.8,130.3,130.0,126.4,
150.1, 143.6, 140.6, 129.8, 122.2, 120.5, 21.0. Anal. Calcd. For
12H11N7: C, 56.91; H, 4.38; N, 38.71. Found: С, 57.07; H, 4.46; N,
38.95.
124.5, 122.9, 122.7, 114.7, 114.6, 21.0. Anal. Calcd. For C17H14N6: C,
67.54; H, 4.67; N, 27.80. Found: С, 67.36; H, 4.71; N, 27.56. HRMS
(þESI): Calcd. For C17H14N6 m/z 303.1353 [MþH]þ, found m/z
303.1358 [Mþ H]þ.
C
3.4. 6-[(4-Methylphenyl)diazenyl]-2-(methylsulfanyl)[1,2,4]triazolo
[1,5-a]pyrimidine-7-amine (5b)
3.9. Ethyl 7-amino-6-[(4-methylphenyl)diazenyl]pyrazolo[1,5-a]
pyrimidine-3-carboxylate (5g)
Method I. Yellow crystals (250 mg, 84%), m. p. (>300 ꢀC).
Method II. Light brown powder (245 mg, 82%), m. p. (>300 ꢀC). 1H
Method I. Yellow crystals (246 mg, 76%), m. p. (>300 ꢀC).
Method II. Light brown powder (297 mg, 92%), m. p. (>300 ꢀC). 1H
NMR (600 MHz, CDCl3/CF3COOD) d 9.22 (s, 1H), 8.50 (s, 1H), 7.73 (d,
NMR (600 MHz, CDCl3/CF3COOD)
d
9.16 (s, 1H), 7.79 (d, J ¼ 8.2 Hz,
2H), 7.35 (d, J ¼ 8.2 Hz, 2H), 2.73 (s, 3H), 2.47 (s, 3H). 13C NMR
(151 MHz, CDCl3/CF3COOD)
d
167.7, 151.3, 149.3, 147.8, 144.6, 142.8,
J ¼ 8.2 Hz, 2H), 7.25 (d, J ¼ 8.2 Hz, 2H), 4.44 (q, J ¼ 7.1 Hz, 2H), 2.40
130.3, 123.0, 121.5, 21.6, 13.7. Anal. Calcd. For C13H13N7S: C, 52.16; H,
4.38; N, 32.75. Found: С, 52.16; H, 4.21; N, 32.87. HRMS (þESI):
Calcd. For C13H14N7S m/z 300.1026 [MþH]þ, found m/z 300.1030
[Mþ H]þ.
(s, 3H), 1.40 (t, J ¼ 7.1 Hz, 1H). 13C NMR (151 MHz, CDCl3/CF3COOD)
d
161.0, 149.1, 148.1, 146.3, 145.2, 144.3, 138.8, 130.2, 122.8, 119.3,
101.9, 62.1, 21.5, 14.1. Anal. Calcd. For C16H16N6O2: C, 59.25; H, 4.97;
N, 25.91. Found: С, 59.10; H, 4.81; N, 25.77. HRMS (þESI): Calcd. For
C
16H16N6O2 m/z 325.1408 [MþH]þ, found m/z 325.1413 [Mþ H]þ.
3.5. 6-[(4-Methylphenyl)diazenyl]-2-(trifluoromethyl)[1,2,4]
triazolo[1,5-a]pyrimidine-7-amine (5c)
3.10. 7-Amino-6-[(4-methylphenyl)diazenyl]pyrazolo[1,5-a]
pyrimidine-3-carbonitrile (5h)
Method I. Bright yellow powder (205 mg, 64%), m. p. (>300 ꢀC).
Method II. Brown solid (293 mg, 91%), m. p. (>300 ꢀC). 1H NMR
Method I. Light brown powder (183 mg, 66%), m. p. (>300 ꢀC).
Method II. Light brown powder (230 mg, 83%), m. p. (>300 ꢀC). 1H
(500 MHz, DMSO‑d6)
d 9.78 (br s, 1H), 9.61 (br s, 1H), 9.07 (s, 1H),
7.96 (d, J ¼ 8.3 Hz, 2H), 7.37 (d, J ¼ 8.3 Hz, 2H), 2.40 (s, 3H). 13C NMR
NMR (400 MHz, DMSO‑d6)
8.79 (s, 1H), 7.94 (d, J ¼ 8.3 Hz, 2H), 7.37 (d, J ¼ 8.3 Hz, 2H), 2.40 (s,
3H). 13C NMR (101 MHz, DMSO‑d6)
150.4, 150.2, 149.8, 147.9, 143.9,
d 9.71 (s, 1H), 9.41 (s, 1H), 8.92 (s, 1H),
(101 MHz, DMSO‑d6)
d
155.5, 155.2 (q, J ¼ 38.6 Hz), 152.7, 150.0,
144.5, 141.1, 129.8, 122.5, 121.5, 119.6 (q, J ¼ 247.9 Hz), 21.0.19F NMR
d
(DMSO‑d6, 471 MHz):
d
97.93 (s). Anal. Calcd. For C13H10F3N7: C,
140.7, 129.7, 122.3, 120.7, 113.4, 81.1, 20.9. Anal. Calcd. For C14H11N7:
48.60; H, 3.14; N, 30.52. Found: С, 48.46; H, 3.15; N, 30.43.
C, 60.64; H, 4.00; N, 35.36. Found: С, 60.40; H, 3.91; N, 35.56.
3.6. 6-[(4-Methylphenyl)diazenyl]-2-(thiophen-2-yl)[1,2,4]triazolo
[1,5-a]pyrimidine-7-amine (5d)
3.11. 2-Azido-5-[(4-methylphenyl)diazenyl]pyrimidine-4-amine
(5i)
Method I. Orange crystals (224 mg, 67%), m. p. (>300 ꢀC).
Method II. Light brown powder (275 mg, 82%), m. p. (>300 ꢀC). 1H
Method I. Yellow powder (210 mg, 83%), m. p. (191-193 ꢀC).
Method II. Light brown powder (224 mg, 88%), m. p. (192-194 ꢀC).
NMR (400 MHz, DMSO‑d6)
d
9.64 (s, 1H), 9.23 (s, 1H), 8.97 (s, 1H),
1H NMR (400 MHz, CDCl3)
d 9.12 (s, 1H), 8.86 (s, 1H), 7.73 (d,
7.93 (d, J ¼ 8.3 Hz, 2H), 7.90 (d, J ¼ 3.6 Hz, 1H), 7.81 (d, J ¼ 5.0 Hz,
J ¼ 8.3 Hz, 2H), 7.31 (d, J ¼ 8.3 Hz, 2H), 5.87 (s, 1H), 2.44 (s, 3H). 13
C
1H), 7.37 (d, J ¼ 8.3 Hz, 2H), 7.27 (dd, J ¼ 3.6, 5.0 Hz,1H), 2.40 (s, 3H).
NMR (101 MHz, CDCl3) d 162.0,161.4,155.5,150.2,141.7,129.9,127.4,
13C NMR (101 MHz, DMSO‑d6)
d
160.8, 155.6, 152.8, 150.2, 143.2,
122.2, 21.5. Anal. Calcd. For C11H10N8: C, 51.96; H, 3.96; N, 44.07.
140.6, 133.2, 129.7, 129.4, 128.4, 128.3, 122.2,120.9, 20.9. Anal. Calcd.
For C16H13N7S: C, 57.30; H, 3.91; N, 29.23. Found: С, 57.02; H, 3.72;
N, 28.96.
Found: С, 51.67; H, 3.82; N, 44.01.
3.12. General procedure for the synthesis of compounds 6a-i
3.7. 2-(Furan-2-yl)-6-[(4-methylphenyl)diazenyl][1,2,4]triazolo
[1,5-a]pyrimidine-7-amine (5e)
A mixture of corresponding 6-[(4-methylphenyl)diazenyl]-azo-
lopyrimidine-7-amine 5a-i (1 mmol) and 10% (by weight) Pd/C
(5 wt %) in 10 mL DMF (for 5a,d,e,f,h,i) or EtOH (for 5b,c,g) was
hydrogenated in an autoclave at 50 ꢀC (100 ꢀC for 5f) and 3e5 bar
pressure of hydrogen for 5e10h. The resulting solution/suspension
was heated until the precipitate was completely dissolved, filtered
hot from Pd/C, the solvent was removed in vacuo, the precipitate
was washed off with Et2O (CHCl3 for 5f, 5i), filtered and air-dried.
Method I. Bright yellow solid (190 mg, 60%), m. p. (>300 ꢀC).
Method II. Light brown powder (249 mg, 78%), m. p. (>300 ꢀC). 1H
NMR (400 MHz, DMSO‑d6)
d 9.66 (s, 1H), 9.36 (s, 1H), 8.97 (s, 1H),
7.98 (dd, J ¼ 0.8, 1.8 Hz, 1H), 7.93 (d, J ¼ 8.3 Hz, 2H), 7.36 (d,
J ¼ 8.3 Hz, 2H), 7.26 (dd, J ¼ 0.8, 3.4 Hz, 1H), 6.75 (dd, J ¼ 1.8, 3.4 Hz,
1H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO‑d6)
d 157.4, 155.5, 152.7,
150.0, 145.7, 145.3, 143.4, 140.5, 129.7, 122.2, 120.8, 112.5, 112.2, 21.0.
Anal. Calcd. For C16H13N7O: C, 60.18; H, 4.10; N, 30.70. Found: С,
59.92; H, 3.99; N, 30.57.
3.13. [1,2,4]Triazolo[1,5-a]pyrimidine-6,7-diamine (6a)
Light brown solid (114 mg, 76%), m. p. (>300 ꢀC). 1H NMR
(400 MHz, DMSO‑d6) d 8.30 (s, 1H), 8.07 (s, 1H), 7.53 (s, 2H), 4.50 (s,
3.8. 3-[(4-Methylphenyl)diazenyl]pyrimido[1,2-a]benz[4,5]
imidazole-4-amine (5f)
2H). (lit., [17], m. p. >300 ꢀC [1],Н NMR (DMSO‑d6, 400 MHz):
d 4.50
(br s, 2H), 7.52 (br s, 2H), 8.08 (s, 1H), 8.30 (s, 1H)).
Method I. Orange powder (136 mg, 45%), m. p. (>300 ꢀC).
Method II. The crude product washed with a small amount of DMF,
then thoroughly washed with water and air-dried. Dark brown
powder (162 mg, 54%), m. p. (>300 ꢀC). 1H NMR (400 MHz, CDCl3/
3.14. 2-(Methylsulfanyl)[1,2,4]triazolo[1,5-a]pyrimidine-6,7-
diamine (6b)
Beige solid (174 mg, 89%), m. p. (245e247 ꢀC). 1H NMR
(500 MHz, DMSO‑d6) 7.93 (s, 1H), 7.53 (s, 2H), 4.52 (s, 2H), 2.62 (s,
3H). 13C NMR (126 MHz, DMSO‑d6)
164.6, 151.5, 140.2, 138.3, 116.1,
CF3COOD)
d
9.27 (s, 1H), 8.39 (d, J ¼ 8.6 Hz, 1H), 8.03e7.75 (m, 5H),
d
7.42 (d, J ¼ 8.1 Hz, 2H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3/
d
5

D.A. Gazizov, V.V. Fedotov, K.A. Chistyakov et al.
Tetrahedron xxx (xxxx) xxx
13.3. Anal. Calcd. For C6H8N6S: C, 36.72; H, 4.11; N, 42.83. Found: С,
36.60; H, 4.14; N, 42.69.
ESI-MS: 148 (5, [M þ Na]þ), 126 (100, [M þ H]þ)).
3.21. Procedure for the gram-scale synthesis of compound 6c
3.15. 2-(Trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine-6,7-
diamine (6c)
A mixture of the aminoazole 4c (10 mmol, 1.521 g) and 2-[2-(4-
methylphenyl)hydrazinylidene]-3-oxopropanenitrile (2) (10 mmol,
1.871 g) was thoroughly ground in a beaker. The resulting mixture
was kept at 160 ꢀC in an oil bath with mechanical stirring for 1 h.
After cooling to room temperature, Pd/C (5 wt %) (10% by weight,
321 mg) and EtOH (120 mL) was added to the reaction mixture, the
resulting mixture was transferred to an autoclave and hydroge-
nated at 50 ꢀC and 5 bar pressure of hydrogen for 10h. Isolation and
purification were performed similarly to the general procedure.
Brown solid (1.743 g, 80%), m. p. (226e228 ꢀC).
Brown solid (187 mg, 86%), m. p. (226e228 ꢀC). 1H NMR
(400 MHz, DMSO‑d6)
d 8.16 (s, 1H), 7.87 (s, 2H), 4.77 (s, 2H). (lit.,
[17], m. p. 226e228 ꢀC [1],Н NMR (DMSO‑d6, 500 MHz):
d 4.77 (br s,
2H), 7.84 (br s, 2H), 8.16 (s, 1H)).
2-(Thiophen-2-yl)[1,2,4]triazolo [1,5-a]pyrimidine-6,7-diamine
(6d).
Beige solid (210 mg, 91%), m. p. (284e286 ꢀC). 1H NMR
(500 MHz, DMSO‑d6)
8.02 (s, 1H), 7.76 (dd, J ¼ 0.9, 3.6 Hz, 1H), 7.70
(dd, J ¼ 0.9, 4.9 Hz, 1H), 7.53 (s, 2H), 7.21 (dd, J ¼ 3.6 Hz, 4.9 Hz, 1H),
4.55 (s, 2H). 13C NMR (126 MHz, DMSO‑d6)
159.1, 151.6, 141.3,
d
General procedure for the synthesis of compounds 7a-h.
A solution/suspension of the corresponding diamine 6a-h
(1 mmol) in EtOH (5 mL) was sequentially treated with HCl (36% w/
d
138.6, 134.4, 128.2, 128.0, 127.0, 116.3. Anal. Calcd. For C9H8N6S: C,
46.54; H, 3.47; N, 36.18. Found: С, 46.59; H, 3.74; N, 35.99.
w, 1 mmol, 86 mL) and glyoxal (40% w/w, 1 mmol, 115 mL). The
resulting mixture was kept at 50 ꢀC with stirring, the reaction
progress was monitored by TLC in the CH3Cl:CH3OH (9/1, v/v)
system for the disappearance of a spot of the starting diamine
(Rf ~ 0.1) and forming a spot of the product (Rf ~ 0.85). Then, the
reaction mixture was cooled, the formed precipitate was filtered
and air-dried.
3.16. 2-(Furan-2-yl)[1,2,4]triazolo[1,5-a]pyrimidine-6,7-diamine
(6e)
Beige solid (178 mg, 88%), m. p. (272e274 ꢀC). 1H NMR
(400 MHz, DMSO‑d6)
(s, 2H), 7.09 (dd, J ¼ 0.8 Hz, 3.4 Hz, 1H), 6.69 (dd, J ¼ 1.8, 3.4 Hz, 1H),
4.58 (s, 2H). 13C NMR (126 MHz, DMSO‑d6)
156.0, 151.4, 146.7,
d
8.04 (s, 1H), 7.88 (dd, J ¼ 0.8, 1.8 Hz, 1H), 7.61
Compounds 7
[11d].
а,c were obtained by the same method earlier
d
144.3, 141.4, 138.7, 116.3, 111.9, 110.7. Anal. Calcd. For C9H8N6O: C,
50.00; H, 3.73; N, 38.87. Found: С, 49.79; H, 3.91; N, 38.69.
3.22. 2-(Methylsulfanyl)[1,2,4]triazolo[1,5-a]pteridine (7b)
3.17. Pyrimido[1,2-a]benzo[4,5]imidazole-3,4-diamine (6f)
Bright yellow solid (181 mg, 83%), m. p. (226e228 ꢀC). 1H NMR
(400 MHz, DMSO‑d6)
d
9.61 (s, 1H), 9.20 (d, J ¼ 2.2 Hz, 1H), 9.17 (d,
Dark brown solid (129 mg, 65%), m. p. (>300 ꢀC). 1H NMR
J ¼ 2.2 Hz, 1H), 2.74 (s, 3H). 13C NMR (101 MHz, DMSO‑d6)
d 166.7,
(500 MHz, DMSO‑d6)
d
8.50 (d, J ¼ 8.3 Hz, 1H), 7.96 (br s, 1H), 7.60
159.5, 155.4, 149.8, 145.2, 141.4, 130.4, 13.5. Anal. Calcd. For
C8H6N6S: C, 44.03; H, 2.77; N, 38.51. Found: С, 43.84; H, 3.10; N,
38.52.
(d, J ¼ 8.2 Hz, 1H), 7.46e7.43 (m, 1H), 7.24e7.21 (m, 1H). 13C NMR
(101 MHz, DMSO‑d6)
d 148.0, 142.1, 126.2, 125.2, 118.7, 116.1, 115.1,
114.8. HRMS (þESI): Calcd. For C10H9N5 m/z 200.0931 [MþH]þ,
found m/z 200.0934 [Mþ H]þ.
3.23. 2-(Thiophen-2-yl)[1,2,4]triazolo[1,5-a]pteridine (7d)
3.18. Ethyl 6,7-diaminopyrazolo[1,5-a]pyrimidine-3-carboxylate
(6g)
Pale yellow solid (233 mg, 92%), m. p. (262e264 ꢀC). 1H NMR
(400 MHz, DMSO‑d6)
d
9.65 (s, 1H), 9.23 (d, J ¼ 2.2 Hz, 1H), 9.19 (d,
J ¼ 2.2 Hz, 1H), 7.96 (dd, J ¼ 1.2, 3.6 Hz, 1H), 7.84 (dd, J ¼ 1.2, 4.9 Hz,
White solid (190 mg, 86%), m. p. (229e231 ꢀC). 1H NMR
1H), 7.29 (dd, J ¼ 3.6, 4.9 Hz, 1H). 13C NMR (101 MHz, DMSO‑d6)
(500 MHz, DMSO‑d6)
d
8.36 (s, 1H), 8.06 (s, 1H), 7.53 (s, 2H), 4.61 (s,
d 160.9, 160.3, 155.8, 150.3, 145.9, 142.4, 133.3, 131.4, 130.1, 129.0,
2H), 4.22 (q, J ¼ 7.1 Hz, 2H), 1.28 (t, J ¼ 7.1 Hz, 3H). 13C NMR
128.9. Anal. Calcd. For C11H6N6S: C, 51.96; H, 2.38; N, 33.05. Found:
С, 51.74; H, 2.35; N, 33.03.
(126 MHz, DMSO‑d6)
d
162.4, 146.0, 143.1, 140.3, 138.5, 116.2, 98.2,
58.7, 14.6. Anal. Calcd. For C9H11N5O2: C, 48.86; H, 5.01; N, 31.66.
Found: С, 48.59; H, 5.28; N, 31.47.
3.24. 2-(Furan-2-yl)[1,2,4]triazolo[1,5-a]pteridine (7e)
3.19. 6,7-Diaminopyrazolo[1,5-a]pyrimidine-3-carbonitrile (6h)
Pale orange solid (196 mg, 92%), m. p. (273e275 ꢀC). 1H NMR
(400 MHz, DMSO‑d6)
d
9.66 (s, 1H), 9.24 (d, J ¼ 2.2 Hz, 1H), 9.20 (d,
Light brown solid (143 mg, 82%), m. p. (>300 ꢀC ꢀC). 1H NMR
J ¼ 2.2 Hz, 1H), 8.01 (dd, J ¼ 0.8, 1.7 Hz, 1H), 7.34 (dd, J ¼ 0.8, 3.4 Hz,
(500 MHz, DMSO‑d6)
d
8.51 (s, 1H), 8.05 (s, 1H), 7.76 (s, 2H), 4.72 (s,
146.4, 145.2, 140.0, 139.0, 117.0,
1H), 6.77 (dd, J ¼ 1.7, 3.4 Hz, 1H). 13C NMR (126 MHz, DMSO‑d6)
2H). 13C NMR (126 MHz, DMSO‑d6)
d
d 159.9, 157.2, 155.3, 149.8, 145.52, 145.47, 145.4, 142.1, 131.0, 112.4,
115.1, 76.4. Anal. Calcd. For C7H6N6: C, 48.27; H, 3.47; N, 48.25.
112.3. Anal. Calcd. For C11H6N6O: C, 55.46; H, 2.54; N, 35.28. Found:
Found: С, 48.04; H, 3.49; N, 47.99.
С, 55.54; H, 2.40; N, 35.14.
3.20. 2,4,5-Triaminopyrimidine (6i)
3.25. Benzo[4,5]imidazo[1,2-a]pteridine (7f)
Red-brown solid (89 mg, 71%). 1H NMR (500 MHz, DMSO‑d6)
Brown solid (150 mg, 68%), m. p. (208e210 ꢀC). 1H NMR
d
7.22 (s, 1H), 6.04 (s, 2H), 5.22 (s, 2H), 3.84 (br s, 2H). 13C NMR
(500 MHz, DMSO‑d6)
J ¼ 2.3 Hz, 1H), 8.81e8.79 (m, 1H), 8.03e8.00 (m, 1H), 7.64e7.58 (m,
2H). 13C NMR (101 MHz, DMSO‑d6)
159.8, 150.4, 148.3, 145.1, 143.6,
143.3, 130.9, 128.8, 125.9, 124.7, 120.7, 116.2. Anal. Calcd. For
12H7N5: C, 65.15; H, 3.19; N, 31.66. Found: С, 65.01; H, 3.08; N,
31.44.
d
d 9.47 (s, 1H), 9.15 (d, J ¼ 2.3 Hz, 1H), 9.04 (d,
(126 MHz, DMSO‑d6)
d
156.9, 155.8, 139.1, 118.3. HRMS (þESI):
Calcd. For C4H7N5 m/z 126.0774 [MþH]þ, found m/z 126.0773 [Mþ
H]þ. (lit., [18], 1H-NMR (600 MHz, (D6)DMSO): 7.23 (s, H-(C6)), 5.96
(br. s, NH2), 5.14 (br. s, NH2), 3.75 (br. s, NH2). 13C NMR (150 MHz,
(D6)DMSO): 157.12 (C(4)), 155.84 (C(2)), 140.12 (C(6)), 118.09 (C(5)).
d
C
6

D.A. Gazizov, V.V. Fedotov, K.A. Chistyakov et al.
Tetrahedron xxx (xxxx) xxx
99 (2020) 103833;
3.26. Ethyl pyrazolo[1,5-a]pteridine-3-carboxylate (7g)
(d) I.-P. Jung, N.-R. Ha, S.-C. Lee, S.-W. Ryoo, M.-Y. Yoon, Development of
potent chemical antituberculosis agents targeting Mycobacterium tubercu-
losis acetohydroxyacid synthase, Int. J. Antimicrob. Agents 48 (2016)
247e258;
Beige solid (190 mg, 78%), m. p. (216e218 ꢀC). 1H NMR
(400 MHz, DMSO‑d6)
J ¼ 2.2 Hz, 1H), 8.73 (s, 1H), 4.37 (q, J ¼ 7.1 Hz, 2H), 1.36 (t, J ¼ 7.1 Hz,
3H). 13C NMR (126 MHz, DMSO‑d6)
161.5, 156.7, 149.7, 146.5, 146.4,
d
9.49 (s, 1H), 9.19 (d, J ¼ 2.2 Hz, 1H), 9.17 (d,
(e) M. Hedidi, J. Maillard, W. Erb, F. Lassagne, Y.S. Halauko, O.A. Ivashkevich,
ꢀ
V.E. Matulis, T. Roisnel, V. Dorcet, M. Hamze, Z. Fajloun, B. Baratte, S. Ruchaud,
d
S. Bach, G. Bentabed-Ababsa, F. Mongin, Fused systems based on 2-
aminopyrimidines: synthesis combining deprotolithiation in-situ zincation
with N-arylation reactions and biological properties, Eur. J. Org Chem. 2017
(2017) 5903e5915;
145.5, 142.3, 130.9, 106.0, 60.1, 14.4. Anal. Calcd. For C11H9N5O2: C,
54.32; H, 3.73; N, 28.79. Found: С, 54.26; H, 3.64; N, 28.75.
(f) C.K. Skepper, R.J. Moreau, B.A. Appleton, B.M. Benton, J.E. Drumm, B.Y. Feng,
M. Geng, C. Hu, C. Li, A. Lingel, Y. Lu, M. Mamo, W. Mergo, M. Mostafavi,
C.M. Rath, M. Steffek, K.T. Takeoka, K. Uehara, L. Wang, J.-R. Wei, L. Xie, W. Xu,
Q. Zhang, J. De Vicente, Discovery and optimization of phosphopantetheine
adenylyltransferase inhibitors with gram-negative antibacterial activity,
J. Med. Chem. 61 (2018) 3325e3349.
3.27. Pyrazolo[1,5-a]pteridine-3-carbonitrile (7h)
Dark yellow solid (181 mg, 92%), m. p. (267e269 ꢀC). 1H NMR
(600 MHz, DMSO‑d6)
d
9.55 (s, 1H), 9.23 (d, J ¼ 2.2 Hz, 1H), 9.22 (d,
J ¼ 2.2 Hz, 1H), 8.94 (s, 1H). 13C NMR (151 MHz, DMSO‑d6)
d 158.2,
[5] (a) T. Wang, S. Yang, H. Li, A. Lu, Z. Wang, Y. Yao, Q. Wang, Discovery, struc-
tural optimization, and mode of action of essramycin alkaloid and its de-
rivatives as anti-tobacco mosaic virus and anti-phytopathogenic fungus
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150.4, 150.2, 147.5, 146.4, 143.0, 131.9, 113.3, 86.3. Anal. Calcd. For
C
11H9N5O2: C, 54.32; H, 3.73; N, 28.79. Found: С, 54.26; H, 3.64; N,
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Declaration of competing interest
ꢀ
[6] J.M. Salas, B. Caballero, G.M. Esteban-Parra, J.M. Mendez-Arriaga, Leishmani-
cidal and trypanocidal activity of metal complexes with 1,2,4-Triazolo[1,5-a]
pyrimidines: insights on their therapeutic potential against leishmaniasis and
chagas disease, Curr. Med. Chem. 24 (2017) 2796e2806.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[7] (a) J.D. Singleton, R. Dass, N.R. Neubert, R.M. Smith, Z. Webber, M.D.H. Hansen,
M.A. Peterson, Synthesis and biological evaluation of novel pyrazolo[1,5-a]
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Acknowledgements
(b) L. Wu, Y. Liu, Y. Li, Synthesis of spirooxindole-O-Naphthoquinone-Tetra-
zolo[1,5-a]Pyrimidine hybrids as potential anticancer agents, Molecules 23
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This work was supported by the Ministry of Education and
Science of the Russian Federation (Agreement No. 075-15-2020-
777). Analytical studies were carried out using equipment of the
Center for Joint Use “Spectroscopy and Analysis of Organic Com-
pounds” at the Postovsky Institute of Organic Synthesis of UB RAS.
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