Effective method for the synthesis of azolo[1,5-a]pyrimidin-7-amines

Article abstract of DOI:10.1007/s10593-019-02498-2

[Figure not available: see fulltext.] Condensation of aminoazoles with (2E)-(3-morpholin-4-yl)acrylonitrile and 3,3-diethoxypropionitrile was used to synthesize a series of azolo[1,5-a]pyrimidin-7-amines. It was established that the reactions with certain aminotriazoles gave mixtures of regioisomers: azolo[1,5-а]pyrimidin-7-amines and azolo[4,3-а]pyrimidin-5-amines.

Full text of DOI:10.1007/s10593-019-02498-2

DOI 10.1007/s10593-019-02498-2
Chemistry of Heterocyclic Compounds 2019, 55(6), 573–577
SHORT COMMUNICATIONS
Effective method for the synthesis
of azolo[1,5-a]pyrimidin-7-amines
Denis A. Gazizov1*, Victor V. Fedotov2,
Evgeny B. Gorbunov1, Evgeny N. Ulomskiy1,2, Oleg S. Yeltsov2,
Gennady L. Rusinov1,2, Vladimir L. Rusinov1,2
1 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi / 20 Akademicheskaya St., Yekaterinburg 620990, Russia; е-mail: dengaz94@mail.ru
2 Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia; е-mail: victor0493@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(6), 573–577
Submitted April 19, 2019
Accepted May 29, 2019
Condensation of aminoazoles with (2E)-(3-morpholin-4-yl)acrylonitrile and 3,3-diethoxypropionitrile was used to synthesize a series of
azolo[1,5-a]pyrimidin-7-amines. It was established that the reactions with certain aminotriazoles gave mixtures of regioisomers: azolo-
[1,5-а]pyrimidin-7-amines and azolo[4,3-а]pyrimidin-5-amines.
Keywords: azolo[1,5-a]pyrimidin-7-amines, 3,3-diethoxypropionitrile, (2E)-(3-morpholin-4-yl)acrylonitrile, Dimroth rearrangement,
heterocyclization.
The class of azolo[1,5-a]pyrimidines contains compounds
that are known as antiviral, antibacterial, antiparasitic, and
antitumor agents.1,2 The broad range of biological activity
among such compounds can be explained by their
structural analogy to natural purine bases involved in the
control of key biological processes, as well as their ability
to form chelates with metal ions.3–5 The synthetic methods
most commonly used for the construction of azolopyrimi-
dine systems typically include heterocyclization reactions
starting from the appropriate aminoazoles or functionalized
pyrimidine derivatives. In the first case, the synthesis of
pyrimidines according to [3+3] process relied on addition
reactions between 3-aminoazoles and 1,3-dicarbonyl
systems or their structural analogs.2,6 Another route for the
preparation of azolo[1,5-a]pyrimidines starting from
pyrimidine derivatives is more versatile, but is complicated
by the limited availability of these derivatives. Such
approach, as a rule, employed heterocyclization reactions
between 2-hydrazinopyrimidines or diaminopyrimidines
and carbonyl compounds,7–11 as well as oxidative
cyclization of (pyrimidin-2-yl)amidines.12,13 However, the
synthesis of 7-amino-substituted azolopyrimidines has been
described in the literature only twice – as preparation of
unsubstituted [1,2,4]triazolo[1,5-а]pyrimidin-7-amine and
2-methyl[1,2,4]triazolo[1,5-а]pyrimidin-7-amine by reactions
of the respective aminotriazole with 3-(piperidino)-
acrylonitrile or 3-(dimethylamino)acrylonitrile.14–16 Many
derivatives of [1,2,4]triazolo[1,5-а]pyrimidin-7-amines
have been characterized with respect to various useful
biological properties.1 The synthesis of such amino
derivatives most often involves a chlorodeoxygenation step
that proceeds with mediocre yields, followed by ipso-
substitution of halogen.17 Thus, it is important to continue
the search for new and convenient synthetic approaches to
this class of compounds.
In the current work, we propose an alternative to the
previously reported syntheses of azolo[1,5-а]pyrimidin-
7-amines from aminoazoles 1a–h and (2E)-(3-morpholin-
4-yl)acrylonitrile (2), which can be obtained by a three-
component condensation reaction of cyanoacetic acid with
morpholine and triethylorthoformate18 or from the
commercially available 3,3-diethoxypropionitrile.
It was established that refluxing solutions containing
azoles 1a–h with (2E)-(3-morpholin-4-yl)acrylonitrile (2)
0009-3122/19/55(6)-0573©2019 Springer Science+Business Media, LLC
573

Chemistry of Heterocyclic Compounds 2019, 55(6), 573–577
Scheme 3
provided the target compounds – azolo[1,5-а]pyrimidin-
7-amines 3a–h (Scheme 1). In such solvents as MeCN,
DMF, and AcOH, products 3a–h were obtained in 30–40%
yields. However, using a mixture of Py and AcOH in
equimolar ratio allowed to increase the yields of these
products to 60–75%.
Scheme 1
Method I
O
N
NH2
CN
N NH
2
In order to select optimal conditions for the synthesis,
N
Y
N
X
the reaction of acetal 4 with aminoazoles 1a–h was studied
in various solvents. It was established that the reaction in
AcOH was accompanied by acetylation of the starting
aminoazoles 1a–h, substantially degrading the target
product yields. The system of Py and AcOH was also
unsuitable. Better results were obtained by performing the
synthesis in DMF, EtOH, and dioxane, with similar yields
of the products.
NH2
1a h
X
Py, AcOH
Y
, 5 h
N
3a h
–
–
3 a X = CH, Y = N (75%), b X = CSMe, Y = N (60%),
c X = CCF3, Y = N (63%), d X = Y = N (72%),
e X = CH, Y = CCO2Et (67%), f X = C(2-thienyl), Y = N (69%),
g X = C(2-Fur),Y = N (65%), h X = CMe, Y = N (62%)
Another synthetic approach, based on the interaction of
3-aminoazoles 1a–h with 3,3-diethoxypropionitrile (4)
(Scheme 2), proceeded nonselectively with compounds
1a,b,h – the reaction in three examples was accompanied
by the formation of isomeric azolo[4,3-a]pyrimidines 5.
The structure of the synthesized compounds was
confirmed by NMR and IR spectra, as well as the results of
elemental analysis. IR spectra of compounds 3a–h
contained the characteristic absorption bands of primary
1
amino group in the region of 3210–3430 cm–1. H NMR
Scheme 2
spectra of all compounds featured a broadened singlet at
7.84–8.51 ppm, with its integral value corresponding to
two protons, which was assigned to the amino group, as
well as two doublets of pyrimidine protons H-5 and Н-6 in
the ranges of 8.17–8.98 ppm and 6.30–6.58 ppm,
respectively, and other signals that were assigned to the
azole part of the molecule.
The structure of the regioisomeric products and the
occurrence of Dimroth rearrangement were proved by
1
1
using two-dimensional H–13C HSQC and H–13С HMBC
NMR experiments for compounds 3а and 5а that were
isolated as individual samples (Fig. 1). The following
In the case of aminoazoles 1a,h, the regioisomeric
products 5a,h were predominant in the reaction mixture
(their content was 95 and 60%, respectively), while in the
case of compound 1b the fraction of isomer 5b was around
5% (the product ratio was determined from 1Н NMR
spectra). However, the subsequent treatment of mixtures
containing compounds 3a + 5а and 3h + 5h with 2% KOH
solution in water and treatment of a mixture of compounds
3b + 5b with 1% KOH solution in aqueous alcohol solution
was accompanied by Dimroth rearrangement of the less
stable isomers 5a,b,h into products 3a,b,h with good
yields. The proposed mechanism of this rearrangement
process is given in Scheme 3.
As described in the literature, azaindolizines have a
general tendency to undergo Dimroth rearrangement,
involving the migration of two heteroatoms in the ring
system, which occurs either under basic or acidic
conditions.19,20 The initial step of the base-catalyzed
reaction includes a nucleophilic attack by hydroxide ion at
position 5, followed by opening of the pyrimidine ring,
tautomerization of the formed intermediate, and its
recyclization.
signals were clearly identified in H–13С НSQС spectrum
1
of [1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3a): the С-2
carbon atom (154.4 ppm), which showed a cross peak with
the only singlet of H-2 proton (8.44 ppm), the С-6 carbon
atom (90.8 ppm), which was shifted upfield due to the
electron-donating effect of the amino group, and the C-5
carbon atom (153.5 ppm), which was identified by method
1
of exclusion. On the basis of H–13С HMBC spectrum it
was possible to identify the signal of the С-7 atom
(149.3 ppm), which gave cross peaks with the signals of
H-5 (8.26 ppm) and H-6 (6.30 ppm) protons, as well as the
signal of bridgehead С-3а atom was recognized by its cross
peak with the signals of triazole proton Н-2 (8.44 ppm) and
pyrimidine proton Н-5 (8.26 ppm), in agreement with the
structure presented in Figure 1.
1H–13С НSQС spectrum of [1,2,4]triazolo[4,3-a]-
pyrimidin-5-amine (5a), by analogy to the spectrum of com-
pound 3а, allowed to unequivocally assign the signals of
С-3 carbon atom (131.5 ppm), C-6 carbon atom (88.1 ppm),
and С-7 carbon atom (155.1 ppm). The signals of
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Chemistry of Heterocyclic Compounds 2019, 55(6), 573–577
[1,2,4]Triazolo[1,5-a]pyrimidin-7-amine (3а). Yield
1.01 g (75%, method I), beige powder, mp 276–279°C
(MeCN). Method II. The obtained suspension was
neutralized with Et3N, the precipitate was filtered off,
washed with EtOH, CHCl3, and air-dried. The dry product
was dissolved in Н2О (20 ml) and treated by adding a
solution of KOH (0.561 g) in Н2О (10 ml), then stirred
overnight at room temperature. The obtained suspension
was neutralized with AcOH to pH ~7 and evaporated to
dryness at reduced pressure, the dry residue was triturated
with EtOH, filtered, and washed with EtOH. Yield 0.96 g
(71%, method II), white powder, mp 276–278°C.
IR spectrum, ν, cm–1: 3244, 3298 (NH2). 1H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 6.30 (1H, d, J = 5.5,
H-6); 8.14 (2H, br. s, NH2); 8.26 (1H, d, J = 5.5, H-5); 8.43
(1H, s, H-2). 13C NMR spectrum (101 MHz), δ, ppm 90.8
(C-6); 149.3 (C-7); 153.5 (C-5); 154.4 (C-2); 155.9 (C-3a).
Found, %: С 44.29; H 3.88; N 52.10. C5H5N5. Calculated,
%: С 44.44; H 3.73; N 51.83.
Figure 1. The key interactions in 1H–13C HSQC and 1H–13С HMBC
spectra of compounds 3а, 5a (δ, ppm).
pyrimidine protons H-6 (6.03 ppm) and H-7 (8.19 ppm)
showed cross peaks with the signal of С-5 carbon atom
(147.9 ppm), enabling unequivocal determination of its
position. The signal of the only triazole ring proton H-3
(9.24 ppm) in this case did not show a cross peak with the
signal of the bridgehead carbon atom С-8а (155.1 ppm),
the position of which, in turn, was established from the
spin-spin coupling to the Н-7 proton (8.19 ppm). At the
same time, a cross peak was observed between the signal of
H-3 proton (9.24 ppm) and the С-5 carbon atom
(147.9 ppm), which was in agreement with the structure
presented in Figure 1.
[1,2,4]Triazolo[4,3-a]pyrimidin-5-amine (5а). The
suspension of compound 3а obtained according to method
II was neutralized with Et3N, the precipitate was filtered
off, washed with EtOH, CHCl3, and air-dried. The product
was adsorbed on silica gel (0.04–0.063 mm), isomer 3а
was eluted (СHCl3–MeOH, 5:1), then product 5а was
eluted with MeOH. Yield 0.97 g (72%), beige powder,
Thus, we have developed a convenient and simple
method for the synthesis of azolo[1,5-a]pyrimidin-7-amines
by using (2E)-(3-morpholin-4-yl)acrylonitrile and 3,3-di-
ethoxypropionitrile.
1
mp 287–289°C. H NMR spectrum (600 MHz), δ, ppm
Experimental
(J, Hz): 6.03 (1H, d, J = 5.1, H-6); 8.18 (2H, br. s, NH2);
8.20 (1H, d, J = 5.1, H-7); 9.24 (1H, s, H-3). 13C NMR
spectrum (151 MHz), δ, ppm 88.1 (C-6); 131.5 (C-3);
148.0 (C-5); 155.1 (C-7); 155.1 (C-8a). Found, %: С 44.36;
H 3.56; N 52.08. C5H5N5. Calculated, %: С 44.44; H 3.73;
N 51.83.
IR spectra were recorded on
a Bruker Alpha
spectrometer equipped with a ZnSe ATR accessory. One-
1
dimensional H and 13С NMR spectra, as well as two-
1
1
dimensional H–13C HSQC and H–13С HMBC experiments
were acquired on a Bruker DRX-400 instrument (400 and
101 MHz, respectively) or a Bruker Avance NEO 600
instrument (600 and 151 MHz, respectively), equipped with
a Prodigy broadband gradient cryoprobe, using DMSO-d6
as solvent and TMS as internal standard. Elemental
analysis was performed on a PerkinElmer PE 2400
elemental analyzer. Melting points were determined in open
capillaries on a Stuart SMP3 apparatus. Column chromato-
graphy was performed with Silica gel 60 (40–63 μm).
Preparation of compounds 3а–h (General method).
Method I. A mixture of Py (4.4 ml) and AcOH (3.0 ml)
was stirred and treated by the addition of 5-aminoazole
1a–h (0.01 mol) and (2E)-(3-morpholin-4-yl)-acrylonitrile
(2) (1.38 g, 0.01 mol). The obtained mixture was refluxed
at 150°C for 5 h. After refluxing, the mixture was cooled.
The precipitate that formed was filtered off, washed with a
small amount of EtOH, and dried.
2-(Methylsulfanyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
(3b). Yield 1.08 g (60%, method I), beige powder, mp 230–
233°C (MeCN). Method II. The precipitate was filtered off
and air-dried. The dry precipitate was dissolved in 1:1
H2O–EtOH mixture (50 ml) and treated with a solution of
KOH (1.122 g) in Н2О (10 ml), stirred overnight at 40°C,
then cooled to room temperature, and neutralized with
AcOH to pH ~7. EtOH was evaporated at reduced pressure,
the precipitate was filtered off and dried under reduced
pressure at 110°C over P2O5. Yield 1.56 g (86%, method
II), white powder, mp 231–233°C. IR spectrum, ν, cm–1:
1
3274, 3308 (NH2). H NMR spectrum (400 MHz), δ, ppm
(J, Hz): 2.64 (3H, s, СН3); 6.24 (1H, d, J = 5.7, H-6); 8.05
(2H, br. s, NH2); 8.17 (1H, d, J = 5.7, H-5). 13C NMR
spectrum (101 MHz), δ, ppm 13.3 (CH3); 91.1 (C-6); 148.2
(C-7); 152.9 (C-5); 156.4 (C-3a); 165.6 (C-2). Found, %:
С 39.96; H 3.93; N 38.68; S 17.54. C6H7N5S. Calculated,
%: С 39.77; H 3.89; N 38.65; S 17.69.
2-(Trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-
7-amine (3c). Yield 1.28 g (63%, method I), white powder,
mp 233–235°C (i-PrOH). Method II. The obtained solution
was neutralized with Et3N, then the reaction mixture was
evaporated at reduced pressure, the dry residue was
triturated with CHCl3, the precipitate was filtered off. The
obtained product was crystallized from i-PrOH. Yield 1.31 g
(65%, method II), white powder, mp 233–235°C. IR spect-
Method II. A solution (or suspension) of the appropriate
aminoazole 1a–h (0.01 mol) in solvent (15 ml) (EtOH in
the case of compound 3a, dioxane in the case of
compounds 3b–h) was stirred at 50°C and treated by
adding 3,3-diethoxypropionitrile (4) (1.5 ml, 0.01 mol),
then 36% HCl solution (0.86 ml, 0.01 mol). The reaction
mixture was refluxed for 2.5–3 h, the suspension (or
solution) was cooled to room temperature, and the target
product was isolated by the method indicated for each
particular compound.
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Chemistry of Heterocyclic Compounds 2019, 55(6), 573–577
rum ν, cm–1: 1180 (CF), 3312, 3331 (NH2). 1H NMR
reduced pressure at 110°C over P2O5. Yield 1.37 g (68%,
method II), light-beige powder, mp 276–278°C. IR spect-
rum ν, cm–1: 3368, 3426 (NH2). 1H NMR spectrum
(600 MHz), δ, ppm (J, Hz): 6.33 (1H, d, J = 5.5, H-6); 6.66
(1H, dd, J = 3.5, J = 1.8, H-4'); 7.17 (1H, d, J = 3.5, H-3');
7.89 (1H, d, J = 1.8, H-5'); 8.25 (2H, br. s, NH2); 8.26 (1H,
d, J = 5.5, H-5). 13C NMR spectrum (151 MHz), δ, ppm 91.5
(C-6); 111.9 (C-3'); 112.1 (C-4'); 144.9 (C-5'); 146.3
(C-2'); 149.3 (C-7); 153.7 (C-5); 156.4 (C-2); 156.5 (C-3a).
Found, %: С 53.75; H 3.58; N 34.75. C9H7N5O. Calculated,
%: С 53.73; H 3.51; N 34.81.
2-Methyl[1,2,4]triazolo[1,5-а]pyrimidin-7-amine (3h).
Yield 0.92 g (62%, method I), beige powder, mp 208–210°C
(MeCN). Method II. The precipitate was filtered off and
air-dried. The dry residue was dissolved in H2O (20 ml)
and treated with a solution of KOH (1.122 g) in H2O
(10 ml), then maintained overnight at room temperature.
The obtained solution was neutralized with AcOH to pH ~7
and cooled on ice bath. The cold suspension was filtered,
the precipitate was dried under reduced pressure at 110°C
over P2O5. Yield 0.90 g (60%, method II), beige powder,
mp 209–211°С. IR spectrum, ν, cm–1: 3210, 3342 (NH2).
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 2.42 (3H, s,
СН3); 6.23 (1H, d, J = 5.5, H-6); 8.05 (2H, br. s, NH2);
8.17 (1H, d, J = 5.5, H-5). 13C NMR spectrum (151 MHz),
δ, ppm 14.8 (CH3); 90.6 (C-6); 148.7 (C-7); 153.0 (C-5);
156.4 (C-3a); 163.5 (C-2). Found, %: С 48.37; H 4.70;
N 46.88. C6H7N5. Calculated, %: С 48.32; H 4.73; N 46.95.
spectrum (600 MHz), δ, ppm (J, Hz): 6.45 (1H, d, J = 5.7,
H-6); 8.37 (1H, d, J = 5.7, H-5); 8.51 (2H, br. s, NH2).
13C NMR spectrum (151 MHz), δ, ppm (J, Hz): 92.8 (C-6);
119.6 (q, JCF = 271.0, CF3); 150.3 (C-7); 154.4 (q,
JCF = 38.0, C-2); 155.1 (C-5); 156.2 (C-3a). Found, %:
С 35.26; H 1.81; N 34.28. C6H4F3N5. Calculated, %:
С 35.48; H 1.98; N 34.48.
Tetrazolo[1,5-a]pyrimidin-7-amine (3d). Yield 0.98 g
(72%, method I), beige powder, mp 270–275°C (DMF).
Method II. The precipitate was filtered off and air-dried.
The dry residue was dissolved in H2O (15 ml); the solution
was stirred and adjusted with aqueous ammonia to pH ~8,
the precipitate was filtered off, and dried in a vacuum
desiccator over P2О5. Yield 0.91 g (67%, method II), pale-
yellow powder, mp 274–276°C. IR spectrum, ν, cm–1:
1
3274, 3296 (NH2). H NMR spectrum (600 MHz), δ, ppm
(J, Hz): 6.58 (1H, d, J = 7.5, H-6); 7.84 (2H, br. s, NH2);
8.98 (1H, d, J = 7.5, H-5). 13C NMR spectrum (151 MHz),
δ, ppm 104.4 (C-6); 132.9 (C-5); 155.5 (C-3a); 162.3
(C-7). Found, %: С 35.16; H 2.92; N 61.92. C4H4N6.
Calculated, %: С 35.30; H 2.96; N 61.74.
Ethyl 7-aminopyrazolo[1,5-a]pyrimidine-3-carboxy-
late (3e). Yield 1.38 g (67%, method I), white powder,
mp 164–167°C (i-PrOH). Method II. Isolation and
purification were performed analogously to the procedure
for compound 3с. Yield 1.82 g (88%, method II), white
powder, mp 165–167°C. IR spectrum, ν, cm–1: 1666
1
(C=O), 3320, 3430 (NH2). H NMR spectrum (400 MHz),
Supplementary information file containing 1Н, 13С NMR
δ, ppm (J, Hz): 1.28 (3H, t, J = 7.1, СН3); 4.25 (2H, q,
J = 7.1, CH2); 6.31 (1H, d, J = 5.4, H-6); 8.08 (2H, br. s,
NH2); 8.25 (1H, d, J = 5.4, H-5); 8.47 (1H, s, H-2).
13C NMR spectrum (101 MHz), δ, ppm 14.5 (CH2CH3);
59.0 (CH2CH3); 90.8 (C-6); 99.8 (C-3); 146.3 (C-2); 148.5
(C-3a); 148.7 (C-7); 151.9 (C-5); 162.2 (СООCH2). Found,
%: С 52.41; Н 4.88; N 27.16. C9H10N4O2. Calculated, %:
С 52.42; Н 4.89; N 27.17.
1
1
and H–13C HSQC, H–13С HMBC spectra of compounds
3a–h, 5a is available at the journal website at http://
link.springer.com/journal/10593.
The results were obtained within the framework of State
Assignment of the Ministry of Education and Science of the
Russian Federation (No. 4.6351.2017/8.9).
2-(Thiophen-2-yl)[1,2,4]triazolo[1,5-а]pyrimidin-
7-amine (3f). Yield 1.49 g (69%, method I), beige powder,
mp >300°C (МеCN). Method II. The precipitate was
filtered off and air-dried. The dry residue was dissolved in
EtOH (40 ml) and treated by adding Et3N to pH 8–9, the
precipitate was filtered off, washed with CHCl3, and air-
dried. Yield 1.80 g (83%, method II), white powder,
mp >300°C. IR spectrum ν, cm–1: 3288, 3427 (NH2).
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 6.31 (1H, d,
J = 5.5, H-6); 7.22 (1H, dd, J = 5.0, J = 3.6, H-4'); 7.72
(1H, d, J = 5.0, H-3'); 7.83 (1H, d, J = 3.6, H-5'); 8.17 (2H,
br. s, NH2); 8.25 (1H, d, J = 5.5, H-5). 13C NMR spectrum
(151 MHz), δ, ppm 91.4 (C-6); 127.9 (C-3'); 128.2 (C-4');
128.9 (C-5'); 133.8 (C-2'); 149.0 (C-7); 153.6 (C-5); 156.5
(C-3a); 159.5 (C-2). Found, %: С 49.62; H 3.17; N 32.24.
C9H7N5S. Calculated, %: С 49.76; H 3.25; N 32.24.
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