Synthesis of 3-Aryl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7- thiones as building blocks for potentially biologically active compounds

Article abstract of DOI:10.1080/10426500902849573

[1,2,3]Triazolo[4,5-d]pyrimidine-7-thiones as building blocks for potentially biologically active compounds were synthesized by the base-catalyzed cyclization of 2-cyanoethanethioamide with arylazides and further reaction of the cyclization products with

Full text of DOI:10.1080/10426500902849573

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of 3-Aryl-3,6-dihydro-7H-
[1,2,3]triazolo[4,5-d]pyrimidine-7-
thiones as Building Blocks for Potentially
Biologically Active Compounds
Nazariy T. Pokhodylo a , Vasyl S. Matiychuk a & Mykola D. Obushak a
a Department of Organic Chemistry, Ivan Franko National University
of Lviv, Lviv, Ukraine
Version of record first published: 24 Feb 2010.
To cite this article: Nazariy T. Pokhodylo , Vasyl S. Matiychuk & Mykola D. Obushak (2010): Synthesis
of 3-Aryl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7-thiones as Building Blocks for Potentially
Biologically Active Compounds, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:3,
578-581
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Phosphorus, Sulfur, and Silicon, 185:578–581, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902849573
SYNTHESIS OF 3-ARYL-3,6-DIHYDRO-7H-
[1,2,3]TRIAZOLO[4,5-d]PYRIMIDINE-7-THIONES AS
BUILDING BLOCKS FOR POTENTIALLY BIOLOGICALLY
ACTIVE COMPOUNDS
Nazariy T. Pokhodylo, Vasyl S. Matiychuk,
and Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv,
Lviv, Ukraine
[1,2,3]Triazolo[4,5-d]pyrimidine-7-thiones as building blocks for potentially bio-
logically active compounds were synthesized by the base-catalyzed cyclization of
2-cyanoethanethioamide with arylazides and further reaction of the cyclization products
with triethyl orthoformate.
Keywords Azides; heterocyclization; 1,2,3-triazole; [1,2,3]triazolo[4,5-d]pyrimidine
INTRODUCTION
1,2,3-Triazolo-pyrimidines are of increasing interest for biological applications.1–5
For example, triazolo[4,5-d]-pyrimidines (8-azaguanines) are inhibitors of the purine nu-
cleoside phosphorylase (PNPase), which is an important enzyme in the purine salvage
pathway. It catalyzes the phosphorolysis of guanosine, inosine, and the corresponding
2ꢀ-deoxyribose analogs to their purine bases in a reversible reaction.6 Some compounds
possess a high affinity and selectivity for the A1 and A2A adenosine receptors7–10 and the
ability to inhibit the benzodiazepine receptor.10 Adenosine is an endogenous nucleoside
that mediates a variety of important physiological effects by its specific receptors. All of
the adenosine receptor agonists synthesized thus far are structurally related to adenosine
itself. Moreover, triazolo[4,5-d]-pyrimidine nucleosides were evaluated for antiretroviral
activity as active agents in inhibiting reverse transcriptase.11 In addition, the antiprolifera-
tive potential of some 8-azapurine derivatives, reflecting their ability to activate p53 tumor
suppressor was described.12
With these facts in mind, we studied a synthetic route to triazolo[4,5-d]pyrimidines
containing a mercapto group. It is known that such a functional group is suitable for
modification by alkylation reactions and applicable for creation of substance libraries to be
tested for biological activity.
Received 22 January 2009; accepted 25 February 2009.
Address correspondence to Mykola D. Obushak, Department of Organic Chemistry, Ivan Franko National
University of Lviv, Kyryla i Mefodiya Str. 6, 79005 Lviv, Ukraine. E-mail: obushak@in.lviv.ua
578

1,2,3-TRIAZOLO-PYRIMIDINES AS BUILDING BLOCKS
579
RESULTS AND DISCUSSION
In pursuing our studies, we needed to synthesize 1,2,3-triazolo[4,5-d]pyrimidine
derivatives bearing a substituent suitable for modification. A well known synthetic route to
1,2,3-triazolo[4,5-d]pyrimidine is the reaction of azides with 2-cyanoacetamide. The next
step was the formation of the pyrimidine cycle by reaction with a bi-electrophilic reagent.
However, further modification of 1,2,3-triazolo[4,5-d]pyrimidines hardly occurs because
of the low nucleophilicity of oxygen. In some cases, oxygen was replaced by chlorine to
input new substituents.8
In the current work, we used 2-cyanoethanethioamide 2 for the base-catalyzed cy-
clization reaction with arylazides 1. By the reaction of the appropriate azides with 2 in the
presence of sodium methoxide in methanol at room temperature, 5-amino-1-aryl-1H-1,2,3-
triazole-4-carbothioamides 3a–c were formed in good yields. Furthermore, the appropriate
pure compounds 3 precipitated from the reaction medium. They may be used for other
reactions or analyzed without further purification. It is of note that the thiocarbamoyl group
is less electron-withdrawing in spite of the carbamoyl group, and may give poor yields of
aminotriazoles. However, in our case, the yields of compounds 3 are 74–87%, similar to the
results of 1,2,3-triazole-4-carboamide yields. Previously, 1,2,3-triazole-4-carbothioamide
3a was synthesized by a two-step reaction by L’abbe et al.13
Compounds 3a–c were heated with triethyl orthoformate to form the corresponding
1,2,3-triazolo[4,5-d]pyrimidines 4a–c.
The compound 4a easily reacted with 2-chloro-N-phenylacetamide 5 to yield 6. This
reaction showed one of the possible variations of 4a–c type structures (Scheme 1).
S
N3
N
R1
N
N
S
N
N
N
N
CH(OEt)3
MeONa
MeOH
N
1 a-c
+
R1
NH2
AcOH
TsOH
NH2
S
3 a-c
N
R1
NH2
4 a-c
O
2
O
H
N
Cl
N
KOH
EtOH
NHPh
N
N
S
5
N
N
6
R1 = H (a), 4-Me (b), 4-NO2 (c).
Scheme 1
The structure of the compounds was substantiated from microanalytical and spectral
1
data. Analytical, H NMR, and mass spectral data were in agreement with the proposed
structures.

580
N. T. POKHODYLO ET AL.
As a result, we have an optimized method for the synthesis of 1,2,3-triazolo[4,5-
d]pyrimidines suitable for modification on the base of cyclization reaction of 2-
cyanoethanethioamide with azides. This convenient synthesis provides access to
polynuclear heterocycles, which contain the basic ring structure found in molecules that
exhibit biological activity.
EXPERIMENTAL
All melting points are uncorrected. The 1H NMR spectra were recorded on a Mercury
400 MHz instrument using TMS as an internal reference and DMSO-d6 as a solvent. The
mass spectra were recorded on an Agilent 1100 chromatomass spectrometer at 70 eV. The
starting materials were commercially available and/or prepared in accordance to procedures
in the literature for 1a–c.14 Yields of products were not optimized.
Synthesis of 5-Amino-1-aryl-1H-1,2,3-triazole-4-carbothioamides (3a–c)
To the solution of sodium methoxide (540 mg, 10.0 mmol) in dry methanol (20 mL),
2-cyanoethanethioamide 2 (10.0 mmol) was added. To this solution, arylazide 1 (10.0 mmol)
in dry methanol (2 mL) was added dropwise, and a solid started to precipitate. The mixture
was stirred for 24 h. The resulting suspension was filtered, and the solid product was washed
with water and methanol to yield the corresponding 1,2,3-triazole-4-carbothioamides 3a–c.
5-Amino-1-phenyl-1H-1,2,3-triazole-4-carbothioamide (3a). This com-
pound was isolated as a white powder, mp 198–199◦C (ethanol) (Lit.13 193–195◦C) in
74% yield.
5-Amino-1-(4-methylphenyl)-1H-1,2,3-triazole-4-carbothioamide (3b).
This compound was isolated as a white powdered solid, mp 184–185◦C (ethanol) in 87%
yield. 1H NMR ppm: δ 2.46 (s, 3H, CH3), 7.23 (s, 2H, NH2), 7.40 (d, 2H, 3J 8.4, C6H4),
3
7.45 (d, 2H, J 8.4, C6H4), 8.99 (s, 2H, CSNH2). MS m/z: 233 (M+). Anal. requires for
C10H11N5S (233.29) calcd./found: C, 51.48/51.63; H, 4.75/4.82; N, 30.02/29.97.
5-Amino-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carbothioamide (3c). This
compound was isolated as a white powdered solid, mp 232–233◦C (ethanol) in 82% yield.
1H NMR ppm: δ 7.64 (s, 2H, NH2), 7.93 (d, 2H, 3J 8.4, C6H4), 8.43 (d, 2H, 3J 8.4, C6H4
H-2,6), 9.07 (s, 2H, CSNH2). MS m/z: 264 (M+). Anal. requires for C9H8N6O2S (264.26)
calcd./found: C, 40.90/40.80; H, 3.05/3.17; N, 31.80/31.94.
Synthesis of Compounds (4a–c)
The suspension of the appropriate compound 3 (50 mmol) in triethyl orthoformate
(25 mL), acetic acid (40 mL), and 0.2 g of TsOH were refluxed for 4 h at 95–100◦C. The
reaction medium was cooled to room temperature. The solid was filtered and recrystallized
from the mixture of EtOH–DMF. Physical and spectral properties of the compounds (4a–c)
are given below.
3-Phenyl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7-thione (4a).
This compound was isolated as a white powder, mp 188–189◦C (ethanol–DMF) (Lit.15
191◦C) in 84% yield.
3-(4-Methylphenyl)-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7-
thione (4b). This compound was isolated as a white powdered solid, mp 152–153◦C
(ethanol–DMF) in 81% yield. 1H NMR ppm: δ 2.44 (s, 3H, CH3), 7.17 (d, 2H, 3J 8.0, Ph

1,2,3-TRIAZOLO-PYRIMIDINES AS BUILDING BLOCKS
581
3
H-3,5), 7.80 (d, 2H, J 8.0, Ph H-2,6), 8.60 (s, 1H, pyrimidine), 11.22 (s, 1H, NH). MS
m/z: 243 (M+). Anal. requires for C11H9N5S (243.29) calcd./found: C, 54.30/54.14; H,
3.73/3.80; N, 28.79/28.62; S, 13.18/13.07.
3-(4-Nitrophenyl)-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidine-7-
thione (4c). This compound was isolated as a white powdered solid, mp 277–278◦C
(ethanol–DMF) in 89% yield. 1H NMR ppm: δ 7.55 (d, 2H, 3J 8.4, C6H4 H-3,5), 8.61 (d,
2H, 3J 8.4, C6H4 H-2,6), 8.64 (s, 1H, pyrimidine), 11.30 (s, 1H, NH). MS m/z: 274 (M+).
Anal. requires for C10H6N6O2S (274.26) calcd./found: C, 43.79/43.64; H, 2.21/2.18; N,
30.64/30.49; S, 11.69/11.52.
N-Phenyl-2-[(3-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)sulfanyl]
acetamide (6)
To a solution of potassium hydroxide (560 mg, 10.0 mmol) and compound 4a (2.3
g, 10.0 mmol)) in ethanol (30 mL), 2-chloro-N-phenylacetamide 2 (1.7 g, 10.0 mmol) was
added. The reaction medium was cooled to room temperature. The solid was filtered and
recrystallized from the mixture of EtOH–DMF. This compound was isolated as a white
1
powdered solid, mp 195–196◦C (ethanol–DMF) in 95% yield. H NMR ppm: δ 7.03 (t,
3
3
3
1H, J 7.8, Ph H-4), 7.27 (t, 2H, J 7.8, Ph H-3,5), 7.54 (t, 1H, J 7.8, Ph H-4), 7.58 (d,
2H, 3J 7.8, Ph H-2,6), 7.66 (t, 2H, 3J 7.8, Ph H-3,5), 8.18 (d, 2H, 3J 7.8, Ph H-2,6) 8.95 (s,
1H, pyrimidine), 10.34 (s, 1H, NH). MS m/z: 362 (M+). Anal. requires for C18H14N6OS
(362.41) calcd./found: C, 59.65/59.48; H, 3.89/4.04; N, 23.19/23.14; S, 8.85/8.71.
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