Synthesis of 3-methylthio-1-phenyl-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-4-one derivatives via tandem aza-Wittig reaction

Article abstract of DOI:10.1080/00397911.2019.1711414

An efficient and convenient procedure for the synthesis of 3-methylthio-1-phenyl-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-4-one derivatives (4a–m) via tandem aza-Wittig and annulation reactions with iminophosphoranes 1, aryl isocyanate, and substitu

Full text of DOI:10.1080/00397911.2019.1711414

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of 3-methylthio-1-phenyl-pyrazolo[3,4-d]
[1,2,4]triazolo[1,5-a]pyrimidin-4-one derivatives via
tandem aza-Wittig reaction
Jin Luo, Qiongwen Kang, Wenfei Huang, Jiajun Zhu & Tao Wang
To cite this article: Jin Luo, Qiongwen Kang, Wenfei Huang, Jiajun Zhu & Tao Wang (2020):
Synthesis of 3-methylthio-1-phenyl-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-4-one derivatives
via tandem aza-Wittig reaction, Synthetic Communications, DOI: 10.1080/00397911.2019.1711414
To link to this article: https://doi.org/10.1080/00397911.2019.1711414
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1711414
Synthesis of 3-methylthio-1-phenyl-pyrazolo[3,4-d]
[1,2,4]triazolo[1,5-a]pyrimidin-4-one derivatives via tandem
aza-Wittig reaction
Jin Luoa, Qiongwen Kangb, Wenfei Huangb, Jiajun Zhub, and Tao Wangb
b
aAnalytical and Testing Center, Jiangxi Normal University, Nanchang, China; Jiangxi Province Key
Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, China
ABSTRACT
ARTICLE HISTORY
Received 12 August 2019
An efficient and convenient procedure for the synthesis of 3-methyl-
thio-1-phenyl-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-4-one deriv-
atives (4a–m) via tandem aza-Wittig and annulation reactions with
iminophosphoranes 1, aryl isocyanate, and substituted 2-phenoxyace-
tohydrazide is described. This protocol provides a simple and facile
approach to synthesize pyrazolo[3,4-d][1,2,4] triazolo[1,5-a]pyrimidine
derivatives under mild conditions.
KEYWORDS
Mild conditions;
pyrazolo[3,4-d][1,2,4]tria-
zolo[1,5-a]pyrimidin-4-one
derivatives; synthesis;
tandem aza-Wittig and
annulation reactions
GRAPHICAL ABSTRACT
Introduction
Pyrazolotriazolopyrimidine derivatives have attracted considerable attention owing to
their diverse pharmacological activities such as antimicrobial,[1] anti-inflammatory,[2]
antifungal,[3] antitumor,[4] anti-acetylcholinesterase,[5] potential xanthine oxidase inhibi-
tory,[6] and adenosine receptor antagonist activities.[7–10] In recent years, the studies on
synthesis and pharmacological activities of these derivatives have become a hot topic.
Among the pyrazolotriazolopyrimidine derivatives, numerous synthetic studies are
focused on the construction and modification of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyr-
imidines,[11,12] and pyrazolo[4,3-e][1,2,4]triazolo[4,3-c] pyrimidines.[13,14] However,
there are few reports on the synthesis of pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine
derivatives. Orlov and colleagues developed a new procedure toward pyrazolo[3,4-d]
CONTACT Jin Luo
330022, China; Tao Wang
jinluo@jxnu.edu.cn
Analytical and Testing Center, Jiangxi Normal University, Nanchang,
Jiangxi Province Key Laboratory of Chemical Biology, College of
wangtao@jxnu.edu.cn
Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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J. LUO ET AL.
Scheme 1. The previous work for synthesis of pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine
derivatives.
[1,2,4]triazolo[1,5-a]pyrimidine compound via the cyclocondensation of 6-acetyl-4,7-
dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine with hydrazine (Scheme
1a).[15] Gothi used a one-pot, microwave-assisted, catalyst-free, Biginelli-like cyclocon-
densation reaction to synthesize a series of pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimi-
dines (Scheme 1b).[16] Wang and coworkers reported a novel approach for synthesis of
3-alkylthio-8-aryl-1-phenyl-2H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-4-ones via
the reaction of 5-amino-6-arylamino-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one with tri-
ethyl orthoformate at refluxing in the presence of p-TsOH (Scheme 1c).[3] Considering
its high importance, it is of great interest in synthetic methodology and pharmaceutical
chemistry for the synthesis of pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine derivatives
under mild reaction.
The aza-Wittig reactions of iminophosphoranes are simple, efficient and inexpensive
methods for synthesizing N-heterocyclics.[3,17–20] Up to now, many fused N-heterocycles
such as pyrazolopyrimidine,[21] triazolopyrimidine,[18] pyridopyrimidine,[22] and
imidazolopyrimidine[23] derivatives have been prepared by the aza-Wittig reactions
of functionalized iminophosphoranes. Herein, it is envisioned that the tandem
aza-Wittig and annulation reactions could be used to provide pyrazolo[3,4-d][1,2,4]tria-
zolo[1,5-a]pyrimidine compounds 4 from iminophosphoranes 1, aryl isocyanate, and
various 2-phenoxyacetohydrazide.

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SYNTHETIC COMMUNICATIONSV
3
Scheme 2. The synthetic route of the compound 4.
Results and discussion
The title compounds 4 were successfully prepared by the synthetic procedures demon-
strated in Scheme 2. Iminophosphorane 1, obtained according to Luo’s method[21]
,
reacted with aryl isocyanate to furnish carbodiimides 2 in dry dichloromethane.
Carbodiimides 2 can be easily converted to intermediate 3 when various 2-phenoxyace-
tohydrazide were employed as substrates. By treating with a catalytic amount of sodium
ethoxide, the intermediate 3 readily underwent an intramolecular cyclization to give rise
to the pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine compounds 4 at room tempera-
ture (Table 1).
The structures of the products 4 were identified by 1H NMR, 13C NMR, and
HRMS. For example, the 1H NMR spectra of 3-methylthio-7-[(4-chlorophenoxy)
methyl]-1,8-diphenyl-1,8-dihydro-4H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-4-
one (4c) showed that two single peaks at d 2.5 and 5.3 were assigned to the SCH3 and
Ph–OCH2, respectively. Its 13C NMR revealed that the carbon of the SCH3 and
Ph–OCH2 appeared at d 13.1 and 61.3. The high-resolution mass spectra of 4c exhibited
the expected molecular at m/z: 515.1051 [M þ H]þ. Furthermore, the structure of 4c
was confirmed by X-ray crystallography analysis (Fig. 1).
Conclusions
In conclusion, we reported tandem aza-Wittig and annulation reactions of iminophos-
phoranes, aryl isocyanate, and various 2-phenoxyacetohydrazide for the synthesis of pyr-
azolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidines 4. This study represented an effective and
promising approach to prepare various substituted pyrazolo[3,4-d][1,2,4]triazolo[1,5-
a]pyrimidine derivatives.

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J. LUO ET AL.
Table 1. The structures and yields of compounds 4a–4m.
OCH3
Cl
N
O
O
N
O
N
O
O
O
N
N
N
N
S
N
N
S
S
N
N
N
N
N
N
N
N
N
4a, 80% yield
4c
, 76% yield
4b, 69% yield
Cl
F
CF3
N
O
O
N
N
O
O
O
O
N
Cl
N
N
N
N
N
S
S
S
N
N
N
N
N
N
N
O
N
N
4d, 74% yield
4f
, 77% yield
4e, 78% yield
N
O
N
N
O
O
O
O
N
N
N
N
N
N
S
S
S
N
N
N
N
N
N
N
N
N
Cl
4i, 76% yield
Cl
4g, 68% yield
4h, 74% yield
N
O
N
O
O
O
N
O
O
N
N
N
N
N
N
S
S
Cl
S
N
N
N
N
N
Cl
N
N
N
N
Cl
NO2
4l, 81% yield
Cl
4k, 72% yield
4j, 73% yield
N
O
O
N
N
S
N
N
N
CF3
4m, 74% yield

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5
Figure 1. ORTEP diagram of 4c.
Experimental
Melting points were recorded on an electrothermal melting-point apparatus. Bruker 400
spectrometer with DMSO-d6 as the solvent at 400 MHz (1H), 376 MHz (19F), and
1
100 MHz (13C) was used to record H, 19F and 13C NMR. High resolution mass spectra
(HRMS) were performed with a micro-TOF II Instrument. The X-ray single-crystal dif-
fraction was carried out by a SuperNova E G8910B Instrument. All commercial reagents
were AR grade. All solvents were dried and distilled before used. Substituted 2-phenox-
yacetohydrazide was synthesized according to the literature.[24]
General procedure for the synthesis of 3-(methylthio)-7-[(4-substituted
phenoxy)methyl]-8-(4-substituted phenyl)-1-phenyl-1,8-dihydro-4H-pyrazolo[3,4-
d][1,2,4]triazolo[1,5-a]pyrimidin-4-one 4
To a solution of iminophosphorane 1 (2 mmol) in dry dichloromethane (25 mL), aryl
isocyanate (2 mmol) was quickly added under nitrogen at room temperature. After 6 h,
substituted 2-phenoxyacetohydrazide (2 mmol) was added to the solution, which was
stirred for additional 2 h. Then, the solvent was removed under vacuum, and anhydrous
ethanol (25 mL) and cat. sodium ethoxide were added to the mixture. After stirring for
8 h at room temperature, the precipitate was collected by filtration and recrystallized
from dimethyl sulfoxide to give pure 3-(methylthio)-7-[(4-substituted phenoxy)methyl]-
8-(4-substituted
phenyl)-1-phenyl-1,8-dihydro-4H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-
1
a]pyrimidin-4-one 4. The supplemental materials contains sample H and 13C NMR for

6
J. LUO ET AL.
products 4, together with full characterization data 4b-4m and X-ray crystallography
analysis information for 4c.
3-Methylthio-7-phenoxymethyl-1,8-diphenyl-1,8-dihydro-4H-pyrazolo[3,4-d][1,2,4]tri-
azolo[1,5-a]pyrimidin-4-one (4a)
1
White solid; Yield: 80%; m p 224-226 ꢁC; H NMR (400 MHz, DMSO-d6): d 7.95
ꢀ
(d, J ¼ 8.0 Hz, 2 H), 7.78 (d, J ¼ 7.1 Hz, 2 H), 7.63 (dd, J ¼ 15.8, 8.0 Hz, 3 H), 7.38
(t, J ¼ 7.8 Hz, 2 H), 7.25 (dt, J ¼ 20.7, 7.6 Hz, 3 H), 6.98 (t, J ¼ 7.3 Hz, 1 H), 6.92
(d, J ¼ 8.1 Hz, 2 H), 5.32 (s, 2 H), 2.61 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): d 157.6,
153.6, 151.1, 150.5, 149.3, 146.4, 138.9, 131.9, 130.5, 130.1, 130.0, 129.4, 127.7, 126.4,
122.4, 120.6, 115.4, 101.2, 60.9, 13.1; HRMS (ESI) calcd for C26H20N6O2Sþ: 481.1447
[M þ H]þ, found: 481.1441.
Funding
We would like to thank the National Natural Science Foundation of China [No. 21562026,
21762025] for financial support.
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