Synthesis of Purine Analogues: Photocatalyst-Free Visible-Light-Enhanced Annulation Approach to Pyrazolo[1,5- A[[1,3,5]triazine-2,4-diamines

Article abstract of DOI:10.1021/acs.joc.1c00783

A new photocatalyst-free visible-light-enhanced strategy for the synthesis of pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines via the formation of electron donor-acceptor (EDA) complexes is reported. The in situ generated pyrazolthiourea intermediates from 1H-pyrazol-3-amines and isothiocyanates undergo formal [4 + 2] annulation with 1,1,3,3-tetramethylguanidines (TMG) to deliver the corresponding products involved in three C-N bond formations in a one-pot protocol. The formation of EDA complex from pyrazolthiourea and TMG is confirmed by UV-vis spectroscopy and 1H NMR experiments. Moreover, this mild reaction proceeds in the absence of any external transition metals, oxidants, bases, and ligands. This efficient methodology for the synthesis of purine analogues pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines provides potential synthetic applications in the field of drug research and development.

Full text of DOI:10.1021/acs.joc.1c00783

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Article
Synthesis of Purine Analogues: Photocatalyst-Free Visible-Light-
Enhanced Annulation Approach to Pyrazolo[1,5‑a][1,3,5]triazine-
2,4-diamines
Wei Guo,*,† Zhen Xie,† Liuhuan Cai, Gongping Liu, Ling Deng, Weijie Mei, Xiaoying Zou,
Yumei Zhong, Xiaoya Zhuo, Lvyin Zheng,* and Xiaolin Fan*
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ABSTRACT: A new photocatalyst-free visible-light-enhanced
strategy for the synthesis of pyrazolo[1,5-a][1,3,5]triazine-2,4-
diamines via the formation of electron donor−acceptor (EDA)
complexes is reported. The in situ generated pyrazolthiourea
intermediates from 1H-pyrazol-3-amines and isothiocyanates
undergo formal [4 + 2] annulation with 1,1,3,3-tetramethylguani-
dines (TMG) to deliver the corresponding products involved in
three C−N bond formations in a one-pot protocol. The formation
of EDA complex from pyrazolthiourea and TMG is confirmed by
1
UV−vis spectroscopy and H NMR experiments. Moreover, this
mild reaction proceeds in the absence of any external transition
metals, oxidants, bases, and ligands. This efficient methodology for the synthesis of purine analogues pyrazolo[1,5-a][1,3,5]triazine-
2,4-diamines provides potential synthetic applications in the field of drug research and development.
reaction under microwave irradiation or high reaction temper-
ature conditions.10−12 Dolzhenko et al. explored a multi-
component reaction (MCR) of aminopyrazole-4-carboxylates
with trimethyl orthoformate and cyanamide for constructing
pyrazolo[1,5-a][1,3,5]triazines under microwave irradiation
(Scheme 1, a).13 In 2013, Insuasty’s group discovered an
efficient two-step strategy for the synthesis of 2-amino-
substituted pyrazolo[1,5-a][1,3,5]triazines from 5-amino-3-
hetaryl-1H-pyrazoles, isothiocyanates, and amines (Scheme 1,
b).14 In this case, the amination/cyclization process is promoted
by the couple HgCl2/TFA and DMF as solvent. Chu et al. and
Kaiser et al. further reported a multistep synthesis of
pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine derivatives as potent
protein kinase CK2 inhibitors and antibiotics (Scheme 1, c).15
Although the above contributions we discuss here are useful for
the construction of pyrazolo[1,5-a][1,3,5]triazines,16,17 these
reactions proceed under the conditions of high reaction
temperature, microwave irradiation, and multistep reactions.
Some starting materials and reagents are unstable, moisture-
sensitive, unavailable, and even highly toxic. To solve those
INTRODUCTION
■
Pyrazolo[1,5-a][1,3,5]triazines and their derivatives incorporat-
ing two privileged N-heterocycles are one of the most prevalent
purine analogues and/or bioisosteres with diverse biological
activities in drug discovery.1 Typically, BOF-4272 (I) can be
used as an antihyperuricaemic agent to inhibit xanthine oxidase
activity in the biosynthesis of uric acid (Figure 1).2 Compound
II is a selective corticotropin-releasing factor receptor-1 (CRF1)
antagonist and may be a potential anxiolytic or antidepressant
drug.3 Compound III represents a new and selective
phosphodiesterase type-4 inhibitor.4 Furthermore, many
specifically pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines and
their derivatives exhibit a broad spectrum of pharmacological
properties.5 For example, compound IV shows micromolar
antiproliferative activity,6 compound V is a threonine tyrosine
kinase (TTK) inhibitor,7 and compound VI can inhibit cyclic-
dependent kinase (CDK) activities and induce cell death for
various human tumor cell lines.8
Considering the diverse biological and pharmacological
activities of pyrazolo[1,5-a][1,3,5]triazines, the exploration of
various synthetic approaches attracts particular attention in the
field of organic and medicinal chemistry.8,9 Significant
representative methodologies have been reported in previous
works. For example, reaction of 5-amino-1H-pyrazoles with
sodium cyanocarbonimidodithioate salt, O,S-diethyl heteroar-
ylimidothiocarbonates, S,S-dimethyl 4-methylbenzoylimidodi-
thiocarbonates, or N-acyl imidates can provide pyrazolo[1,5-
a][1,3,5]triazine-4-thiol derivatives through a condensation
Received: April 3, 2021
Published: June 7, 2021
https://doi.org/10.1021/acs.joc.1c00783
© 2021 American Chemical Society
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Figure 1. Important drug molecules containing pyrazolo[1,5-a][1,3,5]triazines, pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines, and their derivatives.
Scheme 1. Multicomponent Synthesis of Pyrazolo[1,5-a][1,3,5]triazines, Pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines, and Their
Derivatives
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a
Table 1. Screening of Reaction Conditions
b
entry
photocatalyst (1 mol %)
solvent (1 mL)
base (2 equiv)
T (°C)
4a, yield (%)
1
2
3
4
5
6
7
8
Ru(bpy)3Cl2
eosin B
eosin Y
fac-Ir(ppy)3
Rose Bengal
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH2Cl2
CH3COOC2H5
DMF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
60
60
60
60
60
60
27
20
22
21
15
26
20
16
35
24
12
33
38
42
64
40
38
53
38
38
46
84
22
37
76
15
47
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
DMSO
H2O
CH3CN
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
CH3CN/DMF (1:1)
c
d
d
NaOH
d
K2CO3
NaHCO3
DABCO
DBU
d
d
d
d
TMEDA
d
de
,
df
,
dg
,
dh
,
di
,
a
Reaction conditions: Unless otherwise stated, the reaction of 1H-pyrazol-3-amine 1a (12.5 mg, 0.15 mmol) and isothiocyanatobenzene 2a (13.5
mg, 0.10 mmol) was carried out in CH3CH2OH (1 mL) at 25 °C for 2 h under air, and then 1,1,3,3-tetramethylguanidine 3 (11.5 mg, 0.10 mmol)
and photocatalyst (1 mol %) were introduced to the reaction. The reaction further proceeded under 10 W blue LED (470 nm) irradiation at 25 °C
b
c
d
e
f
g
for 12 h. Isolated yields based on 2a. 3 (23 mg, 0.20 mmol, 2 equiv). 3 (34.5 mg, 0.30 mmol, 3 equiv). In the dark at 60 °C. Under N2. Under
h
i
O2. Under Ar through three freeze−pump−thaw cycles. Gram-scale experiment based on 2a (675 mg, 5 mmol).
disadvantages, it is necessary to explore a green and efficient
pathway to access pyrazolo[1,5-a][1,3,5]triazines from available
materials under mild reaction conditions.
intermediates with TMG was characterized by UV and 1H NMR
experiments. Raw materials used in this reaction are
economically available and air-compatible and tolerate various
functional groups. Furthermore, no additional additives are
required, such as catalysts, metals, bases, ligands and oxidants.
In previous reports, visible-light-catalyzed/promoted reac-
tions have emerged as powerful synthetic platforms to prepare
diverse useful organic products, which exhibit high efficiency
and environmental friendliness.18 Our group also successfully
developed a series of visible-light-catalyzed/promoted coupling
annulations to furnish various N-heterocyclic compounds from
simple substrates.19 Based on the our previous reports in the
field of photochemical transformations enabled by electron
donor−acceptor (EDA) complexes,20 we further described an
efficient photocatalyst-free visible-light-enhanced annulation
strategy for the synthesis of pyrazolo[1,5-a][1,3,5]triazine-2,4-
diamines via the formation of EDA complexes under mild
reaction conditions (Scheme 1, d). The in situ generated
pyrazolthiourea intermediates from 1H-pyrazol-3-amines and
isothiocyanates undergo formal [4 + 2] annulations with 1,1,3,3-
tetramethylguanidines (TMG) to deliver the corresponding
products involving in three C−N bond formations. The
formation of EDA complexes derived from pyrazolthiourea
RESULTS AND DISCUSSION
■
We first screened the optimal conditions using 1H-pyrazol-3-
amine 1a, isothiocyanatobenzene 2a, and 1,1,3,3-tetramethyl-
guanidine 3 as starting materials through a two-step one pot
reaction process. The reaction of 3-aminopyrazole 1a (0.15
mmol) and isothiocyanatobenzene 2a (0.10 mmol) was first
carried out in CH3CH2OH (1 mL) at 25 °C for 2 h under air,
and then 1,1,3,3-tetramethylguanidine 3 (0.10 mmol) and
Ru(bpy)3Cl2 (1 mol %) were introduced into the reaction
system. The reaction further proceeded under the irradiation of
a 10 W blue LED (470 nm) at 25 °C for 12 h. Gratifyingly, the
desired product 4a was obtained in 27% yield (Table 1, entry 1).
The structure of 4a was characterized by X-ray crystal diffraction
measurement (CCDC 2034391) (see Figure S2). However,
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a
Table 2. Scope of 1H-Pyrazol-3-amines
a
Isolated yield based on 2a.
investigating other photocatalysts did not afford a higher yield of
4a (Table 1, entries 2−5). Subsequently, the reaction was
performed in the absence of any external photocatalysts,
affording the product 4a in 26% yield (Table 1, entry 6).
Next, different reaction solvents such as CH2Cl2,
CH3COOC2H5, DMF, DMSO, H2O, and CH3CN were tested
for the transformations, respectively (Table 1, entries 7−12).
The above results showed that the yield of 4a improved to 35%
using DMF as solvent (Table 1, entry 9). Furthermore, a
combination of CH3CN and DMF (v/v = 1:1) as a solvent
system gave the compound 4a in 38% yield (Table 1, entry 13).
Increasing the amount of 3 from 0.10 to 0.30 mmol improved
the yield of 4a to 64% (Table 1, entries 14 and 15). However,
utilization of NaOH, K2CO3, NaHCO3, DABCO, DBU, and
TMEDA as the base additives decreased the yield (Table 1,
entries 16−21). Gratifyingly, we conducted the second-step
reaction at 60 °C without the addition of any photocatalysts and
bases, and the isolated yield of 4a reached up to 84% (Table 1,
entry 22). However, when the reaction was performed in the
dark, the yield of 4a reduced obviously, showing that light is
crucial to promote this reaction (Table 1, entry 23). We also
carried out the reaction under N2 and O2 atmosphere,
respectively. The results suggested that O2 in air might facilitate
the transformation (Table 1, entries 24 and 25). When the
reaction was performed under argon atmosphere through three
freeze−pump−thaw cycles, 4a was obtained in 15% yield (Table
1, entry 26). For this reaction, light and reaction temperature
could influence the yield of 4a. After screening of light sources,
reaction time, and temperature (see Tables S1−S3), the optimal
reaction conditions in entry 22 were selected as the standard
conditions for subsequent investigations. Finally, a gram-scale
experiment was performed on 5 mmol scale based on 2a under
the standard conditions, affording the compound 4a in 47%
yield, which shows the potential synthetic application of this
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Scheme 2. Synthesis of 5
a
Table 3. Scope of Isothiocyanate Substrates
a
Isolated yield based on 2.
methodology in organic synthesis and medicinal chemistry
(Table 1, entry 27, see the Experimental Section).
substrate 4,5-dimethyl-1H-pyrazol-3-amine also afforded the
desired product (4g) in 62% yield. Moreover, a serial of phenyl
group substituted 1H-pyrazol-3-amine substrates were capable
of providing the corresponding products (4h−4l) in 41−67%
yields. It was satisfying that when some 1H-indazol-3-amine
derivatives were employed in the reaction the desired fused ring
[1,3,5]triazino[1,2-b]indazole-2,4-diamine products (4m−4p),
which might be applied in the field of drug screening, were
obtained in moderate yields. Furthermore, 2H-tetrazol-5-amine
Encouraged by the above experimental results, we first probed
the 1H-pyrazol-3-amines substrate scope under the optimal
reaction conditions (Table 2). A variety of 1H-pyrazol-3-amines
containing electron-donating (−CH3, −C2H5, and −C(CH3)3)
or electron-withdrawing groups (−Br and −CN) were tolerated
in this transformation, delivering the corresponding products
(4b−4f) with moderate to good yields. The disubstituted
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Scheme 3. Control Experiments
Figure 2. UV/vis absorption spectra of EDA complexes. (a) 1a, 2a, 3, and the mixture of (1a + 2a) and (1a+2a+3) in CH3CN from 380 to 500 nm,
respectively ([1a] = [2a] = [3] = 0.05 M). (b) 7, 3, and the mixture of (7 + 3) in CH3CN from 380 to 500 nm, respectively ([7] = [3] = 0.05 M).
was proven to be suitable for delivering the energetic and
potential biologically active molecular 5 in 61% yield (Scheme
2).
Furthermore, a series of mechanistic experiments were carried
out to clarify the possible reaction mechanism (Scheme 3). First,
compound 1a was reacted with 2a in CH3CN/DMF at 25 °C for
2 h to produce the compound 7 in 91% yield. The structure of
compound 7 was confirmed by X-ray diffraction measurement
(CCDC 2034814) (see Figure S3) (Scheme 3, a). Subsequently,
the transformation of compound 7 with compound 3 gave the
desired product 4a in 92% yield, indicating that compound 7 is a
plausible intermediate for the reaction (Scheme 3, b). However,
the above reaction was suppressed by the addition of radical
scavenger 2,2,6,6-teramethylpiperidinyl-1-oxy (TEMPO), and
the yield of 4a was reduced from 92% to 17%, which meant that
radical process should be involved in this transformation
(Scheme 3, c). Furthermore, the quantum yield (Φ) of 19.2
was obtained from the reaction of 7 and 3 (λ = 436 nm) using
potassium trioxalatoferrate(III) trihydrate as a standard
chemical actinometer,21a,b which might suggest that the
transformation proceeded through radical combination or
radical chain mechanism (see the Supporting Information).21c−e
In previous work, the in situ generated electron donor−
acceptor (EDA) complexes have been investigated in various
visible-light-promoted organic synthesis reactions.22 In these
cases, the photochemical transformations proceeded without
the requirement of any photocatalysts under mild conditions.
Then the substrate scope of the photocatalyzed annulation
was turned to various substituted isothiocyanate compounds. As
shown in Table 3, an array of isothiocyanatobenzene substrates
bearing electron-deficient (−F, −Cl, −Br, −CF3, and −CN) and
electron-rich groups (−OCH3 and −C2H5) at the para-position
delivered the cyclization products (6a−6g) in 51−72% yields.
The meta- and ortho- substituted isothiocyanatobenzenes also
afforded the desired products (6h−6m) in good yields (64−
82%). The influence of steric and electronic effects seems
negligible. Furthermore, disubstituted (3,4-di-Cl, 2,4-di-F, 2,4-
di-OCH3, and 3,5-di-CF3) and trisubstituted (2,4,6-tri-CH3 and
3,4,5-tri-OCH3) substrates also proceeded smoothly to produce
the corresponding compounds (6n−6s) in 60−70% yields.
Meanwhile, 2-isothiocyanatonaphthalene could be converted
into the desired product (6t) in 63% yield. To our delight,
(isothiocyanatomethyl)benzene and benzoyl isothiocyanate
were suitable partners and furnished 6u and 6v in 58% and
60% yields, respectively. In addition, alkyl-substituted iso-
thiocyanates also afforded the corresponding compounds (6w−
6y) in moderate yields (52−55%).
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Figure 3. 1H NMR titration experiments between 7 and 3.
Scheme 4. Possible Reaction Mechanism for the Visible-Light-Enhanced Annulations
Notably, assembling a colorless electron-donating compound
with a colorless electron-accepting partner can form a colored
complex, which means the generation of a new absorption band
and/or charge transfer band.23 The new absorption phenom-
enon can be detected by UV/visible absorption spectrum.
Remarkably, in our experiments, when compound 1a was mixed
with 2a and 3 in CH3CN, the mixture solution displayed an
obvious yellow color change from the three colorless starting
materials (Figure 2, a). Similarly, the mixture of colorless
compound 7 and 3 also exhibited a visibly color change (Figure
2, b). Furthermore, the optical absorption spectrum of the above
samples showed a significant bathochromic shift in the visible
spectral region, thus demonstrating the formation of an EDA
complex.21 The absorption of the mixture of compound 7 and 3
falls into the range of blue LED wavelength, which indicates that
the irradiation of visible light is necessary to this transformation.
Additionally, a Job’s plot was recorded to assess the
stoichiometry of the EDA complexes from compound 7 and 3
in CH3CN (see Figure S6). We found that the ratio of 7/3 was
much closer to 1:1 in the maximal absorbance, which might be
determined that charge transfer occurred between 7 and 3
during the formation of EDA complex under visible light
1
irradiation. The H NMR titration experiments were further
carried out to study the interaction between compound 7 and 3
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infrared spectrometer using KBr pellets. 1H and 13C NMR spectra were
measured on a 400 MHz NMR spectrometer with CDCl3 or DMSO-d6
as solutions. Gas chromatography−mass spectrometry (GC−MS) was
carried out using electron ionization. High-resolution mass spectrom-
etry (HRMS) data were recorded on a high-resolution mass
spectrometer (LCMS-ITTOF). The crystal data were collected on a
diffractometer Rigaku Oxford diffraction supernova dual source, Cu at
Zero equipped with an AtlasS2 CCD using Cu Kα radiation (1.54178
Å) by a scan mode. The reaction proceeded on the photoreaction
instrument (WP-TEC-1020L, WATTCAS, China) with a heating
mantle and a condenser system. The distance from the light source to
the irradiation vessel is 5 mm. The thin-layer chromatography (TLC)
and column chromatography were prepared on commercially available
100−400 mesh silica gel.
General Procedure for the Synthesis of Pyrazolo[1,5-
a][1,3,5]triazine-2,4-diamines. 3-Aminopyrazoles (0.15 mmol),
isothiocyanatobenzenes (0.10 mmol), and CH3CN/DMF (v/v = 1/
1, 1 mL) were introduced into a quartz reaction tube. The mixture was
stirred at 25 °C for 2 h under air, then 1,1,3,3-tetramethylguanidine 3
(0.30 mmol) was added to the reaction system. The reaction further
proceeded under the irradiation of a 10 W blue LEDs (470 nm) at 60
°C for 12 h. After completing the reaction (monitored by TLC), the
reaction solvent was concentrated under reduced pressure. The
obtained crude residue was purified by chromatography on a silica
gel using petroleum ether/ethyl acetate (v/v = 5/1) as eluent to afford
the desired product.
(Figure 3). The peaks of compound 7 in the δ 7.60−6.50 ppm
range move toward high field with the increasing amount of 3,
indicating that compound 3 can be used as electron donor to
provide compound 7 with higher electron density (Figure 3, a).
Meanwhile, for compound 3, the electron acceptor 7 can
withdraw more electrons from 3, thus resulting in the increase of
chemical shift in the δ 2.90−2.55 ppm range (Figure 3, b).
On the basis of the above experimental results and previous
reports,24 a possible mechanism is outlined in Scheme 4. First,
the in situ generated compound 7 from compound 1a and 2a is
combined with 3a to produce the EDA complex 8 or 9 (path a).
The binding-constant value (KEDA = 19.91 M−1) was tested by
Benesi−Hildebrand analysis (see Figure S7).25 Then irradiation
of EDA complex 9 provides the excited complex 9*, which
further undergoes the photoinduced single electron transfer
(SET) process to deliver the tight radical-ion-pair (solvent cage
molecule) intermediate radical anion 10 and imine nitrogen-
centered radical 11.21b,c,24a In addition, the O2 in air is
considered to be beneficial for the SET process in this aerobic
oxidative EDA reaction.24,26 Subsequently, radical combination
reaction of intermediate 10 and 11 provides the intermediate 12,
accompanied with the release of H2S.21,24 Intermediate 12 is not
stable, which is further converted into the desired product 4a
and compound 13 through an intramolecular annulation
process. In this case, compound 13 was detected by GC−MS
through the addition of TsCl (see Figure S8). Furthermore, the
generated H2S was also confirmed by Pb(OAc)2 test papers (see
Figure S9). A radical-chain mechanism could be involved in this
transformation according to the quantum yield test. Irradiation
of radical intermediate 10 could generate intermediate anion 14.
Then imine radical 11 is trapped by intermediate 14 to produce
intermediate 15. Next, the elimination of a H2S from
intermediate 15 delivers intermediate 12. The yield of 4a was
also affected by the reaction temperature. (Table 1, entry 23). In
the dark at 60 °C (path b), compound 7 is converted into
compound 16 by isomerization, which might further react with
3a to form intermediate 12 via an SN (nucleophilic substitution)
type reaction.24c However, this reaction is easily affected by
electronic or steric factors. Therefore, photoexcited process is
important in promoting the three-component annulation.
For the gram-scale synthesis of 4a, the mixture of 1H-pyrazol-3-
amine 1a (0.622 g, 7.5 mmol), isothiocyanatobenzene 2a (0.675 g, 5
mmol), and CH3CN/DMF (v/v = 1/1, 4 mL) was stirred at 25 °C for 2
h under air, then 1,1,3,3-tetramethylguanidine 3 (1.725 g, 15 mmol)
was added to the reaction system. The reaction was performed under
the irradiation of a 10 W blue LED (470 nm) at 60 °C for 12 h. The
mixture was concentrated and purified by flash column chromatog-
raphy on silica gel using petroleum ether/ethyl acetate (v/v = 5/1) as
eluent to provide the desired compound 4a (0.596 g, 2.35 mmol, yield
of 47%).
N4,N4-Dimethyl-N2-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4-dia-
mine (4a). Eluent: petroleum ether/ethyl acetate (v/v = 5/1). Pink
solid: 84% yield (21.4 mg, 0.08 mmol); mp 162−163 °C; IR (KBr,
cm−1) 3309, 3040, 2924, 2847, 1629, 1594, 1485, 1359, 1239, 1098,
915, 840, 798, 692, 509; 1H NMR (400 MHz, CDCl3, ppm) δ 7.80 (d, J
= 2.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.03 (t,
J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.00 (d, J = 2.0 Hz, 1H), 3.58 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 155.0, 153.2, 150.5, 144.9,
CONCLUSIONS
■
In conclusion, we have demonstrated a visible-light-enhanced
annulation of 1H-pyrazol-3-amines and isothiocyanates with
1,1,3,3-tetramethylguanidines (TMG) to give pyrazolo[1,5-
a][1,3,5]triazine-2,4-diamines through the generation of EDA
complexes. The reaction proceeds involving formation of three
C−N bonds in one pot. Mechanistic exploration showed that
the in situ formed EDA complex is the important photoactive
species for the photochemical reaction. This procedure has the
advantage of being photocatalyst-/metal-/base-/oxidant-/li-
gand-free and having broad scope and mild reaction conditions,
despite the fact that the scale-up protocol might be improved.
Moreover, these synthetic purine analogues have potential
applications in medicinal chemistry in future work.
139.6, 128.8, 122.4, 119.5, 91.5, 40.4; MS (EI, 70 eV) m/z 254, 214,
144, 132, 92; HRMS (ESI) calcd C13H15N6 [M + H]+ m/z 255.1353,
found m/z 255.1362.
N4,N4,7-Trimethyl-N2-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4-di-
amine (4b). Eluent: petroleum ether/ethyl acetate (v/v = 5/1). Pink
solid: 81% yield (21.7 mg, 0.08 mmol); mp 132−134 °C; IR (KBr,
cm−1) 3233, 2920, 2824, 1595, 1484, 1353, 1253, 1098, 1005, 902, 762,
1
EXPERIMENTAL SECTION
696; H NMR (400 MHz, CDCl3, ppm) δ 7.60 (d, J = 8.0 Hz, 2H),
■
7.31−7.28 (t, J = 8.0 Hz, 2H), 7.19 (s, 1H), 7.02−6.98 (t, J = 8.0 Hz,
1H), 5.79 (s, 1H), 3.54 (s, 6H), 2.34 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 154.9, 154.8, 153.7, 150.2, 139.7, 128.8, 122.3,
119.4, 91.6, 40.2, 14.7; MS (EI, 70 eV) m/z 268, 253, 212, 199, 92;
HRMS (ESI) calcd C14H17N6 [M + H]+ m/z 269.1509, found m/z
269.1503.
General Information. The starting materials, reagents and solvents
were purchased from Beijing InnoChem Science & Technology Co.,
Ltd. (China). All purchased products were used without further
purification.
Melting points were investigated using a digital melting point
apparatus and are uncorrected. IR spectra data were collected on an
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Article
N4,N4,7,8-Tetramethyl-N2-phenylpyrazolo[1,5-a][1,3,5]triazine-
2,4-diamine (4g). Eluent: petroleum ether/ethyl acetate (v/v = 5/1).
Pink solid: 62% yield (17.5 mg, 0.06 mmol); mp 193−195 °C; IR (KBr,
cm−1) 3256, 2921, 1590, 1494, 1353, 1257, 1136, 1055, 898, 745, 691,
599; 1H NMR (400 MHz, CDCl3, ppm) δ 7.66 (d, J = 8.0 HZ, 2H),
7.30 (t, J = 8.0 HZ, 2H), 6.99 (t, J = 8.0 HZ, 2H), 3.54 (s, 6H), 2.30 (s, 3
H), 2.08 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 154.2,
154.2, 150.2, 150.2, 140.0, 128.8, 121.9, 118.9, 98.5, 40.1, 12.8, 6.8; MS
(EI, 70 eV) m/z 282, 228,214, 161, 118; HRMS (ESI) calcd C15H19N6
[M + H]+ m/z 283.1666, found m/z 283.1661.
7-Ethyl-N4,N4-dimethyl-N2-phenylpyrazolo[1,5-a][1,3,5]triazine-
2,4-diamine (4c). Eluent: petroleum ether/ethyl acetate (v/v = 5/1).
Pink solid: 70% yield (19.6 mg, 0.07 mmol); mp 112−114 °C; IR (KBr,
1
cm−1) 3240, 3044, 3969, 2605, 1254, 1171, 1007, 954, 764, 693; H
NMR (400 MHz, CDCl3, ppm) δ 7.61 (d, J = 4.0 Hz, 2H), 7.29 (t, J =
8.0 Hz, 2H), 7.22 (s, 1H), 7.00 (t, J = 8.0 Hz, 1H), 5.83 (s, 1H), 3.55 (s,
6H), 2.70 (q, J = 8.0 Hz, 2H), 1.29 (t, J = 8.0 H, 3H); 13C{1H} NMR
(100 MHz, CDCl3, ppm) δ 160.5, 154.9, 153.6, 150.3, 139.8, 128.8,
122.2, 119.4, 90.1, 40.2, 22.4, 13.2; MS (EI, 70 eV) m/z 282, 241, 228,
174, 132; HRMS (ESI) calcd C15H19N6 [M + H]+ m/z 283.1666, found
m/z 283.1661.
N4,N4-Dimethyl-N2,7-diphenylpyrazolo[1,5-a][1,3,5]triazine-2,4-
diamine (4h). Eluent: petroleum ether/ethyl acetate (v/v = 5/1).
Yellow solid: 67% yield (22 mg, 0.07 mmol); mp 170−172 °C; IR (KBr,
cm−1) 3235, 3133, 3032, 1598, 1479, 1354, 1294, 1104, 943, 830, 759,
695; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.29 (s, 1H), 7.96 (d, J =
8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 8.0 Hz, 2H), 7.41 (t, J
= 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H), 6.95 (t, J = 8.0 Hz, 1H), 6.51 (s,
1H), 3.59 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 155.6,
155.0, 154.0, 150.2, 139.6, 133.0, 128.9, 128.8, 128.6, 126.4, 122.4,
119.5, 88.7, 40.5; MS (EI, 70 eV) m/z 330, 278, 253, 200, 132; HRMS
(ESI) calcd C19H18N6Na [M + Na]+ m/z 353.1485, found m/z
353.1479.
7-tert-Butyl-N4,N4-dimethyl-N2-phenylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (4d). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Brown solid: 71% yield (22 mg, 0.07 mmol); mp 180−182 °C;
IR (KBr, cm−1) 3268, 3142, 2956, 1661, 1530, 1353, 1298, 1134, 1095,
978, 811, 776, 671; 1H NMR (400 MHz, CDCl3, ppm) δ 7.61 (d, J = 8.0
Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H), 7.23 (s, 1H), 6.99 (t, J = 8.0 Hz, 1H),
5.88 (s, 1H), 3.56 (s, 6H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 167.3, 154.8, 153.3, 150.3, 139.8, 128.8, 122.1, 119.4,
88.4, 40.3, 32.8, 30.1; MS (EI, 70 eV) m/z 310, 295, 253, 225, 185;
HRMS (ESI) calcd C17H23N6 [M + H]+ m/z 311.1979, found m/z
311.1973.
N4,N4-Dimethyl-N2-phenyl-7-(m-tolyl)pyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (4i). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). White solid: 52% yield (17.9 mg, 0.05 mmol); mp 185−187 °C;
IR (KBr, cm−1) 3238, 3064, 2921, 2850, 1599, 1447, 1382, 1255, 1107,
1062, 962, 882, 763, 686; 1H NMR (400 MHz, CDCl3, ppm) δ 7.70 (d,
J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 3H), 7.19
(d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.31 (s, 1H),
3.62 (s, 6H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ
155.8, 154.9, 153.9, 150.3, 139.6, 138.2, 132.9, 129.7, 128.8, 128.5,
127.0, 123.6, 122.4, 119.5, 88.8, 40.5, 21.5; MS (EI, 70 eV) m/z 344,
291, 276, 253, 211; HRMS (ESI) calcd C20H21N6 [M + H]+ m/z
345.1822, found m/z 345.1839.
4-(Dimethylamino)-2-(phenylamino)pyrazolo[1,5-a][1,3,5]-
triazine-8-carbonitrile (4e). Eluent: petroleum ether/ethyl acetate (v/
v = 5/1). White solid: 52% yield (14.5 mg, 0.05 mmol); mp 151−153
°C; IR (KBr, cm−1) 3328, 3299, 2922, 2219, 1619, 1556, 1468, 1412,
1325, 1246, 1193, 1057, 900, 760, 692 ; 1H NMR (400 MHz, CDCl3,
ppm) δ 8.11 (s, 1H), 7.87 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.35 (t, J =
8.0 Hz, 2H), 7.14 (t, J = 8.0 Hz, 1H), 3.19 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 158.6, 154.2, 146.6, 145.7, 136.0, 129.2, 125.2,
120.7, 113.9, 37.7, 37.2; MS (EI, 70 eV) m/z 279, 253, 214, 173, 118;
HRMS (ESI) calcd C14H14N7 [M + H]+ m/z 280.1311, found m/z
280.1314.
7-(3-Bromophenyl)-N4,N4-dimethyl-N2-phenylpyrazolo[1,5-a]-
[1,3,5]triazine-2,4-diamine (4j). Eluent: petroleum ether/ethyl acetate
(v/v = 5/1). Yellow solid: 41% yield (17 mg, 0.04 mmol); mp 161−163
°C; IR (KBr, cm−1) 3280, 2923, 2852, 1623, 1561, 1470, 1346, 1243,
1072, 952, 899, 743, 683; 1H NMR (400 MHz, CDCl3, ppm) δ 8.05 (s,
1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0
Hz, 1H), 7.35−7.27 (m, 3H), 7.04 (t, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.29
(s, 1H), 3.63 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 155.0,
154.3, 154.1, 150.3, 139.5, 135.1, 131.7, 130.1, 129.3, 128.9, 125.1,
122.8, 122.6, 119.6, 88.9, 40.5; MS (EI, 70 eV) m/z 408, 329, 278, 212,
173; HRMS (ESI) calcd C19H18N6Br [M + H]+ m/z 409.0771, found
m/z 409.0791.
8-Bromo-N4,N4-dimethyl-N2-phenylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (4f). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). White solid: 57% yield (18.9 mg, 0.06 mmol); mp 180−182 °C;
IR (KBr, cm−1) 3260, 3105, 2931, 1603, 1493, 1363, 1248, 1116, 1045,
961, 870, 754, 615; 1H NMR (400 MHz, CDCl3, ppm) δ 7.76 (s, 1H),
7.63 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.10 (s, 1H), 7.04 (t, J
= 8.0 Hz, 1H), 3.56 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ
155.4, 154.5, 150.2, 149.9, 144.5, 139.3, 128.9, 122.7, 119.4, 40.6; MS
(EI, 70 eV) m/z 332, 294, 196, 132, 118; HRMS (ESI) calcd
C13H14BrN6 [M + H]+ m/z 333.0458, found m/z 333.0453.
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Article
7-(4-Fluorophenyl)-N4,N4-dimethyl-N2-phenylpyrazolo[1,5-a]-
[1,3,5]triazine-2,4-diamine (4k). Eluent: petroleum ether/ethyl
acetate (v/v = 5/1). White solid: 63% yield (22 mg, 0.06 mmol); mp
196−198 °C, IR (KBr, cm−1) 3237, 3140, 2923, 2853, 1611, 1524,
1480, 1350, 1223, 1155, 1096, 943, 845, 772, 669, 580;1H NMR (400
MHz, CDCl3, ppm) δ 7.88 (t, J = 4.0 Hz, 2H), 7.63 (t, J = 8.0 Hz, 2H),
7.33 (t, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 3H), 7.05 (J = 8.0 Hz, 1H),
6.28 (s, 1H), 3.63 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ
164.6, 162.1, 154.7 (d, J = 4 Hz), 153.8, 150.2, 139.4, 129.1 (d, J = 3
Hz), 128.9, 128.2 (d, J = 8 Hz), 122.6, 119.6, 115.6 (d, J = 22 Hz), 88.5,
40.5; MS (EI, 70 eV) m/z 348, 329, 291, 252, 214; HRMS (ESI) calcd
C19H18N6F [M + H]+ m/z 349.1577, found m/z 349.1575.
8-Fluoro-N4,N4-dimethyl-N2-phenyl[1,3,5]triazino[1,2-b]-
indazole-2,4-diamine (4o). Eluent: petroleum ether/ethyl acetate (v/
v = 5/1). Brown solid: 43% yield (13.7 mg, 0.04 mmol); mp 154−156
°C; IR (KBr, cm−1) 3369, 3268, 3143, 2923, 2850, 1618, 1564, 1495,
1349, 1204, 1159, 1052, 962, 833, 756; 1H NMR (400 MHz, DMSO-d6,
ppm) δ 9.73 (s, 1H), 7.84 (t, J = 8.0 Hz, 3H), 7.31 (t, J = 8.0 Hz, 2H),
7.14 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.76 (t, J = 8.0 Hz,
1H), 3.60 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 164.9 (d,
J = 256 Hz), 154.5, 151.7 (d, J = 14 Hz), 150.4, 149.2, 139.1, 128.9,
123.9 (d, J = 12 Hz), 122.9, 119.5, 110.3 (d. J = 28 Hz), 107.0, 99.2 (d, J
= 24 Hz), 40.6; MS (EI, 70 eV) m/z 322, 278, 252, 223, 189; HRMS
(ESI) calcd C17H16N6F [M + H]+ m/z 323.1420, found m/z 323.1417.
7-(4-Chlorophenyl)-N4,N4-dimethyl-N2-phenylpyrazolo[1,5-a]-
[1,3,5]triazine-2,4-diamine (4l). Eluent: petroleum ether/ethyl acetate
(v/v = 5/1). White solid: 60% yield (21.8 mg, 0.06 mmol); mp 169−
171 °C; IR (KBr, cm−1) 3265, 3136, 2924, 2854, 1599, 1484, 1350,
8-Chloro-N4,N4-dimethyl-N2-phenyl-[1,3,5]triazino[1,2-b]-
indazole-2,4-diamine (4p). Eluent: petroleum ether/ethyl acetate (v/
v = 5/1). Yellow solid: 36% yield (12 mg, 0.04 mmol); mp 171−173
°C; IR (KBr, cm−1) 3277, 2923, 2851, 1741, 1609, 1565, 1446, 1347,
1
1248, 1107, 1011, 943, 833, 765, 695; H NMR (400 MHz, CDCl3,
1
ppm) δ 7.83 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0
Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 7.04 (t, J = 8.0 Hz, 2H), 6.29 (s, 1H),
3.63 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 154.9, 154.5,
154.0, 150.2, 139.4, 134.8, 131.4, 128.9, 128.8, 127.6, 122.6, 119.6, 88.7,
40.5; MS (EI, 70 eV) m/z 364, 302, 253, 132, 92; HRMS (ESI) calcd
C19H18N6Cl [M + H]+ m/z 365.1276, found m/z 365.1294.
1233, 1152, 1042, 949, 844, 752, 694, 507; H NMR (400 MHz,
CDCl3, ppm) δ 7.80 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.43
(s, 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.11 (s, 1H), 7.00 (t, J = 8.0 Hz, 1H)
6.81 (d, J = 8.0 Hz, 1H), 3.60 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 154.5, 151.3, 150.5, 149.2, 139.1, 136.7, 129.0, 123.1,
122.9, 120.1, 119.5, 115.0, 108.2, 40.7; MS (EI, 70 eV) m/z 338, 296,
268, 239, 205; HRMS (ESI) calcd C17H16N6Cl [M + H]+ m/z
339.1125, found m/z 339.1124.
N4,N4-Dimethyl-N2-phenyl-[1,3,5]triazino[1,2-b]indazole-2,4-dia-
mine (4m). Eluent: petroleum ether/ethyl acetate (v/v = 5/1). Brown
solid: 56% of yield (17 mg, 0.06 mmol); mp 172−174 °C, IR (KBr,
cm−1) 3253, 3159, 3041, 2924, 2842, 1684, 1597, 1496, 1338, 1248,
1157, 1029, 901, 747, 692; 1H NMR (400 MHz, CDCl3, ppm) δ 8. 08
(d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7. 68 (d, J = 8.0 Hz, 2H),
7.51 (d, J = 12.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz,
2H), 7. 04 (t, J = 8.0 Hz, 1H), 6. 94 (t, J = 8.0 Hz, 1H), 3.65 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 154.8, 151.3, 150.8, 148.2,
N7,N7-Dimethyl-N5-phenyltetrazolo[1,5-a][1,3,5]triazine-5,7-dia-
mine (5). Eluent: petroleum ether/ethyl acetate (v/v = 5/1). White
solid: 61% yield (15.6 mg, 0.06 mmol); mp 179−181 °C; IR (KBr,
cm−1) 3331, 2925, 2223, 2134, 1584, 1497, 1349, 1261, 1062, 967, 799,
685; 1H NMR (400 MHz, CDCl3, ppm) δ 7.59 (d, J = 8.0 Hz, 2H), 7.33
(t, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 7.04(d, J = 4.0 Hz, 1H),
3.20−3.18 (d, J = 8.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3,
ppm) δ 165.8, 163.4, 141.3, 128.3, 123.6, 113.2, 36.4; MS (EI, 70 eV):
m/z = 256, 243, 204, 179, 164; HRMS (ESI) calcd C11H13N8 [M + H]+
m/z 257.1258, found m/z 257.1262.
139.5, 132.1, 129.5, 122.6, 121.8, 120.6, 118.2, 116.0, 111.1, 40.7; MS
(EI, 70 eV) m/z 304, 265, 250, 208, 132; HRMS (ESI) calcd C17H17N6
[M + H]+ m/z 305.1509, found m/z 305.1503.
10-Fluoro-N4,N4-dimethyl-N2-phenyl-[1,3,5]triazino[1,2-b]-
indazole-2,4-diamine (4n). Eluent: petroleum ether/ethyl acetate (v/
v = 5/1). Brown solid: 46% of yield (15 mg, 0.05 mmol); mp 192−194
°C; IR (KBr, cm−1) 3404, 3145, 3089, 2922, 2851, 1614, 1547, 1498,
N2-(4-Fluorophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6a). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Pink solid: 72% yield (19.6 mg, 0.07 mmol); mp 161−163 °C;
IR (KBr, cm−1) 3266, 3114, 3052, 2999, 1613, 1569, 1499, 1340, 1209,
1158, 1097, 915, 834, 755, 687, 531, 1H NMR (400 MHz, CDCl3, ppm)
δ 7.79 (d, J = 4.0 Hz, 1H), 7.56−7.53 (m, 2H), 7.17 (s, 1H), 7.00 (t, J =
8.0 Hz, 2H), 5.96 (d, J = 2.0 Hz, 1H), 3.56 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 158.5 (d, J = 240 Hz), 155.0, 153.2, 150.5, 144.9,
135.6, 121.4 (d, J = 7 Hz), 115.3 (d, J = 22 Hz), 91.5, 40.4; MS (EI, 70
eV): m/z = 272, 228, 203,190, 136; HRMS (ESI) calcd C13H14FN6 [M
+ H]+ m/z 273.1259, found m/z 273.1251.
1
1351, 1218, 1153, 1064, 02, 867, 786, 691; H NMR (400 MHz,
DMSO-d6, ppm) δ 9.78 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.37−7.28 (m,
4H), 6.99 (t, J = 8.0 Hz, 1H), 6.60 (t, J = 8.0 Hz, 1H), 3.63 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 159.1, 156.6, 154.3, 152.8
(d, J = 5 Hz), 150.3, 139.0, 131.0 (d, J = 9 Hz), 128.8, 123.0, 119.5,
112.0 (d, J = 5 Hz), 102.2 (d, J = 18 Hz), 99.4, 40.8; MS (EI, 70 eV) m/z
322, 303, 265, 214, 92; HRMS (ESI) calcd C17H15N6FNa [M + Na]+
m/z 345.1234, found m/z 345.1246.
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N2-(4-Methoxyphenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6f). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Brown solid: 71% yield (20.1 mg, 0.07 mmol); mp 141−143
°C; IR (KBr, cm−1) 3240, 3092, 2923, 1628, 1574, 1491, 1366, 1246,
1173, 1041, 913, 809, 739, 624; 1H NMR (400 MHz, CDCl3, ppm) δ
7.76 (s, 1H), 7.48 (J = 8.0 Hz, 2H), 7.32 (s, 1H), 6.86 (d, J = 8.0 Hz,
2H), 5.93 (d, J = 3.0 Hz, 1H), 3.78 (s, 3H), 3.53 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3, ppm) δ 155.4, 155.4, 153.4, 150.4, 144.8, 132.7,
121.9, 114.0, 91.2, 55.5, 40.3; MS (EI, 70 eV): m/z = 284, 240, 199,
188, 122; HRMS (ESI) calcd C14H17N6O [M + H]+ m/z 285.1458,
found m/z 285.1453.
N2-(4-Chlorophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6b). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Pink solid: 52% yield (15 mg, 0.05 mmol); mp 213-215 °C; IR
(KBr, cm−1) 3234, 3103, 2979, 2853, 1603, 1569, 1490, 1365, 1247,
1090, 913, 834, 762, 680; 1H NMR (400 MHz, CDCl3, ppm) δ 7.80 (s,
1H), 7.57 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H),
6.01 (d, J = 4.0 Hz, 1H), 3.58 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 154.7, 153.5, 150.6, 145.0, 138.2, 128.8, 127.3, 120.7,
91.8, 40.4; MS (EI, 70 eV): m/z = 288, 259, 244, 219, 178; HRMS
(ESI) calcd C13H14ClN6 [M + H]+ m/z 289.0963, found m/z 289.0958.
N2-(4-Ethylphenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]triazine-
2,4-diamine (6g). Eluent: petroleum ether/ethyl acetate (v/v = 5/1).
Red solid: 64% yield (18.1 mg, 0.06 mmol); mp 113−115 °C; IR (KBr,
cm−1) 3251, 3127, 2959, 2864, 1621, 1597, 1489, 1366, 1252, 1177,
N2-(4-Bromophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6c). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Pink solid: 56% yield (18.6 mg, 0.06 mmol); mp 165−167 °C;
IR (KBr, cm−1) 3273, 3021, 2931, 1627, 1584, 1489, 1362, 1241, 1096,
919, 866, 756, 671, 474; 1H NMR (400 MHz, CDCl3, ppm) δ 8.03 (s,
1H), 7.79 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.14 (d, J = 8.0
Hz, 2H), 6.02 (d, J = 2.0 Hz,, 1H), 3.60 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 154.5, 152.7, 150.4, 145.0, 141.0, 130.0, 125.1,
122.5, 122.2, 117.7, 91.8, 40.5; MS (EI, 70 eV): m/z = 332, 281, 265,
207, 184; HRMS (ESI) calcd C13H14BrN6 [M + H]+ m/z 333.0458,
found m/z 333.0453.
1
1097, 915, 810, 759, 625, 487; H NMR (400 MHz, CDCl3, ppm) δ
7.79 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz,
2H), 6.99 (s, 1H), 5.98 (d, J = 4.0 Hz, 1H), 3.56 (s, 6H), 2.62 (q, J = 4.0
Hz, 2H), 1.23 (t, J = 4.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3,
ppm) δ 155.0, 153.3, 150.5, 144.9, 138.6, 137.1, 128.2, 119.8, 91.4, 40.4,
28.3, 15.8; MS (EI, 70 eV): m/z = 282, 238, 213, 197, 172; HRMS
(ESI) calcd C15H19N6 [M + H]+ m/z 283.1666, found m/z 283.1662.
N2-(3-Chlorophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6h). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Pink solid: 75% yield (21.6 mg, 0.08 mmol); mp 167−169 °C;
IR (KBr, cm−1) 3263, 3147, 3049, 2895, 1642, 1552, 1417, 1364, 1266,
1100, 967, 854, 764, 688; 1H NMR (400 MHz, CDCl3, ppm) δ 7.88 (t, J
= 4.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.19 (t,
J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 3.0 Hz 1H), 3.59
(s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 154.6, 152.9, 150.5,
145.0, 140.9, 134.4, 129.7, 122.1, 119.3, 117.2, 91.8, 40.5; MS (EI, 70
eV): m/z = 288, 259, 178, 126, 71; HRMS (ESI) calcd C13H14ClN6 [M
+ H]+ m/z 289.0963, found m/z 289.0958.
N4,N4-Dimethyl-N2-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]-
[1,3,5]triazine-2,4-diamine (6d). Eluent: petroleum ether/ethyl
acetate (v/v = 5/1). Brown solid: 51% yield (16.6 mg, 0.05 mmol);
mp 123−125 °C; IR (KBr, cm−1) 3462, 3349, 3201, 3102, 2932, 2813,
1673, 1595, 1468, 1374, 1279, 1167, 1095, 914, 837, 769, 641,523; 1H
NMR (400 MHz, DMSO-d6, ppm) δ 9.70 (s, 1H), 7.99 (d, J = 8.0 Hz,
2H), 7.91 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 6.04 (s, 1H), 3.53 (s, 6H);
13C{1H} NMR (100 MHz, DMSO-d6, ppm) δ 154.7, 152.9, 150.7,
146.0, 144.7, 126.1 (d, J = 4 Hz), 125.2 (d, J = 268 Hz), 121.6 (d, J = 31
Hz), 118.9, 91.8, 40.4; MS (EI, 70 eV): m/z = 322, 278, 253, 212, 186;
HRMS (ESI) calcd C14H14F3N6 [M + H]+ m/z 323.1227, found m/z
323.1222.
N2-(3-Bromophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6i). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Pink solid: 78% yield (26 mg, 0.08 mmol); mp 168−170 °C; IR
(KBr, cm−1) 3270, 3130, 2921, 1627, 1590, 1489, 1362, 1242, 1097,
919, 891, 756, 681; 1H NMR (400 MHz, CDCl3, ppm) δ 8.03 (s, 1H),
7.8 (d, J = 4.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.14−7.11
(m, 2H), 6.01 (d, J = 3.0 Hz, 1H), 3.59 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 154.5, 152.9, 150.5, 145.0, 141.0, 130.0, 125.1,
122.6, 122.2, 117.7, 91.9, 40.5; MS (EI, 70 eV): m/z = 332, 290, 224,
184, 155; HRMS (ESI) calcd C13H14BrN6 [M + H]+ m/z 333.0458,
found m/z 333.0453.
4-((4-(Dimethylamino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-
benzonitrile (6e). Eluent: petroleum ether/ethyl acetate (v/v = 5/1).
Brown solid: 54% of yield (15 mg, 0.05 mmol); mp 211−212 °C; IR
(KBr, cm−1) 3314, 3177, 2923, 2216, 1591, 1406, 1371, 1257, 1177,
1
1097, 915, 818, 760, 679, 545; H NMR (400 MHz, CDCl3, ppm) δ
7.84 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz,
2H), 7.21 (s, 1H), 6.08 (d, J = 3.0 Hz, 1H), 3.61 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3, ppm) δ 154.1, 152.5, 150.4, 145.1, 143.9, 133.1,
118.6, 104.6, 92.4, 40.6; MS (EI, 70 eV): m/z = 279, 227, 162, 157, 102;
HRMS (ESI) calcd C14H14N7 [M + H]+ m/z 280.1305, found m/z
280.1301.
N2-(3-Methoxyphenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6j). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Brown solid: 81% yield (23 mg, 0.08 mmol); mp 152−153 °C;
IR (KBr, cm−1) 3279, 3153, 3097, 2959, 1627, 1572, 1494, 1364, 1280,
1197, 1047, 905, 863, 756, 682; 1H NMR (400 MHz, CDCl3, ppm) δ
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7.80 (d, J = 4.0 Hz, 1H), 7.42 (t, J = 4.0 Hz, 1H), 7.20 (t, J = 8.0 Hz,
1H), 7.13 (s, 1H), 7.09 (dd, J = 4.0 Hz, 1H), 6.58 (dd, J = 4.0 Hz, 1H),
6.00 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.58 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 160.2, 154.7, 152.9, 150.5, 144.9, 140.8, 129.5,
111.9, 107.9, 105.5, 91.6, 55.3, 40.5; MS (EI, 70 eV): m/z = 284, 269,
240, 215, 185; HRMS (ESI) calcd C14H17N6O [M + H]+ m/z
285.1458, found m/z 285.1452.
ppm) δ 9.61 (s, 1H), 8.22 (d, J = 4.0 Hz, 1H), 7.92 (d, J = 4.0 Hz, 1H),
7.69 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.04 (d, J = 4.0 Hz,
1H), 3.53 (s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6, ppm) δ 155.3,
153.3, 150.3, 146.0, 141.3, 131.3, 129.5, 122.8, 120.1, 119.2, 93.6, 40.5;
MS (EI, 70 eV): m/z = 322, 315, 311, 307, 299, 287; HRMS (ESI) calcd
C13H13Cl2N6 [M + H]+ m/z 323.0573, found m/z 323.0570.
N2-(2,4-Difluorophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6o). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Pink solid: 66% yield (19 mg, 0.07 mmol); mp 147−149 °C; IR
(KBr, cm−1) 3233, 3114, 3085, 2974, 1625, 1579, 1492, 1364, 1255,
N2-(2-Chlorophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6k). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Orange solid: 82% yield (23.6 mg, 0.08 mmol); mp 157−158
°C; IR (KBr, cm−1) 3263, 3147, 3049, 2895, 1642, 1552, 1417, 1364,
1266, 1100, 967, 854, 764, 688; 1H NMR (400 MHz, CDCl3, ppm) δ
8.58 (dd, J = 8.0 Hz, 1H), 7.80 (d, J = 3.0 Hz, 1H), 7.35 (dd, J = 8.0 Hz,
1H), 7.29 (t, J = 8.0 Hz, 1H), 7.26−7.24 (m, 1H), 6.93 (t, J = 8.0 Hz,
1H), 6.04 (d, J = 4.0 Hz, 1H), 3.57 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 154.5, 153.0, 150.4, 144.9, 136.3, 129.1, 127.3, 122.5,
122.3, 120.6, 92.1, 40.4; MS (EI, 70 eV): m/z = 288, 231, 187, 126, 71;
HRMS (ESI) calcd C13H14ClN6 [M + H]+ m/z 289.0963, found m/z
289.0959.
1
1196, 1094, 963, 842, 763, 698, 595; H NMR (400 MHz, CDCl3,
ppm) δ 8.45−8.38 (m, 1H), 7.80 (s, 1H), 6.90−6.88 (m, 2H), 6.87−
6.83 (m, 1H), 6.02 (d, J = 2.0 Hz, 1H), 3.57 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3, ppm) δ 157.5 (q, J = 242 Hz), 154.6, 152.9, 152.5
(q, J = 233 Hz), 150.5, 144.9, 124.3 (d, J = 11 Hz), 122.1 (d, J = 11 Hz),
110.7 (d, J = 22 Hz), 103.4 (d, J = 24 Hz), 91.5, 40.4; MS (EI, 70 eV):
m/z = 290, 271, 228, 221, 203; HRMS (ESI) calcd C13H13F2N6 [M +
H] + m/z 291.1164, found m/z 291.1158.
N2-(2,4-Dimethoxyphenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6p). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Black solid: 70% yield (22 mg, 0.07 mmol); mp 171−173 °C;
IR (KBr, cm−1) 3435, 3229, 3108, 2922, 1734, 1630, 1535, 1342, 1277,
N2-(2-Bromophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6l). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Brown solid: 81% of yield (27 mg, 0.08 mmol); mp 150−152
°C; IR (KBr, cm−1) 3397, 3112, 2920, 1903, 1792, 1650, 1537, 1456,
1319, 1162, 1014, 915, 794, 686, 581;1H NMR (400 MHz, CDCl3,
ppm) δ 8.55 (d, J = 8.0 Hz, 1H), δ 7.81 (d, J = 4.0 Hz, 1H), 7.52 (d, J =
8.0 Hz, 1H), 7.33−7.28 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.04 (d, J =
2.0 Hz, 1H), 3.58 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ
154.5, 153.0, 150.5, 145.0, 137.4, 132.3, 128.0, 123.1, 121.0, 113.2, 92.2,
40.4; MS (EI, 70 eV): m/z = 332, 277, 224, 187, 126; HRMS (ESI)
calcd C13H14BrN6 [M + H]+ m/z 333.0458, found m/z 333.0453.
1
1155, 1096, 911, 824, 763, 625, 579; H NMR (400 MHz, CDCl3,
ppm) δ 8.33−8.31 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.21 (s,
1H), 6.53−6.50 (m, 2H), 5.98 (d, J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.80 (s,
3H), 3.57 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 155.3,
154.9, 153.3, 150.4, 149.4, 144.8, 122.7, 120.1, 103.7, 98.7, 91.3, 55.7,
55.6, 40.4; MS (EI, 70 eV): m/z = 314, 283, 268, 229, 207; HRMS
(ESI) calcd C15H19N6O2 [M + H]+ m/z 315.1564, found m/z
315.1559.
N2-(3,5-Bis(trifluoromethyl)phenyl)-N4,N4-dimethylpyrazolo[1,5-
a][1,3,5]triazine-2,4-diamine (6q). Eluent: petroleum ether/ethyl
acetate (v/v = 5/1). Pink solid: 67% yield (26.1 mg, 0.07 mmol); mp
188−190 °C; IR (KBr, cm−1) 3283, 3133, 3048, 2937, 1637, 1502,
1424, 1383, 1289, 1171, 1229, 952, 877, 758, 682, 599; 1H NMR (400
MHz, CDCl3, ppm) δ 8.16 (s, 3H), 7.85 (d, J = 2.0 Hz, 1H), 7.47 (s,
1H), 6.02 (d, J = 2.0 Hz, 1H), 3.63 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 154.5, 152.4, 150.5, 145.2, 141.3, 132.1 (q, J = 43 Hz),
123.5 (d, J = 271 Hz), 118.8, 115.0, 92.0, 40.7; MS (EI, 70 eV): m/z =
390, 371, 321, 294, 213; HRMS (ESI) calcd C15H13F6N6 [M + H]+ m/z
391.1100, found m/z 391.1093.
N4,N4-Dimethyl-N2-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]-
[1,3,5]triazine-2,4-diamine (6m). Eluent: petroleum ether/ethyl
acetate (v/v = 5/1). White solid: 64% yield (20.6 mg, 0.06 mmol);
mp 200−202 °C; IR (KBr, cm−1) 3276, 3147, 3091, 2934, 1625, 1599,
1491, 1328, 1294, 1109, 1068, 971, 841, 758, 624; 1H NMR (400 MHz,
CDCl3, ppm) δ 8.42 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.59
(d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H),
7.08 (s, 1H), 6.03 (d, J = 2.0 Hz, 1H), 3.57 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 155.4, 152.9, 150.5, 145.4, 136.4, 132.4, 126.0 (q,
J = 5 Hz), 123.6, 123.0, 122.4, 119.3, 93.8, 39.3; MS (EI, 70 eV): m/z =
322, 278, 253, 210, 187; HRMS (ESI) calcd C14H14F3N6 [M + H]+ m/z
323.1227, found m/z 323.1222.
N2-Mesityl-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]triazine-2,4-dia-
mine (6r). Eluent: petroleum ether/ethyl acetate (v/v = 5/1). Pink
solid: 60% yield (17.8 mg, 0.06 mmol); mp 151−153 °C; IR (KBr,
cm−1) 3226, 3102, 2952, 2347, 1769, 1601, 1518, 1487, 1392, 1251,
1152, 1097, 936, 847, 760, 622, 564; H NMR (400 MHz, CDCl3,
ppm) δ 7.70 (d, J = 2.0 Hz, 1H), 6.90 (s, 2H), 5.78 (s, 1H), 3.44 (s, 6H),
N2-(3,4-Dichlorophenyl)-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6n). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). White solid: 62% yield (20 mg, 0.06 mmol); mp 218−220 °C;
IR (KBr, cm−1) 3267, 3136, 3060, 2931, 1627, 1583, 1487, 1362, 1241,
1156, 1097, 928, 866, 759, 656, 540; 1H NMR (400 MHz, DMSO-d6,
1
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2.28 (s, 3H), 2.23 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ
156.8, 154.0, 150.6, 144.7, 136.0, 133.2, 128.7, 93.2, 40.1, 21.0, 18.6;
MS (EI, 70 eV): m/z = 296, 281,252, 226, 184; HRMS (ESI) calcd
C16H21N6 [M + H]+ m/z 297.1822, found m/z 297.1818.
N2,N4,N4-Trimethylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
(6w). Eluent: petroleum ether/ethyl acetate (v/v = 5/1). Orange solid:
55% yield (10.6 mg, 0.06 mmol); mp 179−181 °C; IR (KBr, cm−1)
3267, 3130, 2994, 2824, 1813, 1729, 1670, 1565, 1451, 1297, 1167,
1092, 981, 905, 798, 680; 1H NMR (400 MHz, CDCl3, ppm) δ 7.73 (d,
J = 1.6 Hz, 1H), 5.90 (s, 1H), 5.13 (s, 1H), 3.50 (s, 6H), 2.98 (d, J = 4.0
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 158.2, 153.9,
150.3, 144.6, 88.0, 40.1, 28.3; MS (EI, 70 eV): m/z = 192, 163, 123, 82,
57; HRMS (ESI) calcd C8H13N6 [M + H]+ m/z 193.1196, found m/z
193.1194.
N4,N4-Dimethyl-N2-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]-
[1,3,5]triazine-2,4-diamine (6s). Eluent: petroleum ether/ethyl
acetate (v/v = 5/2). White solid: 66% yield (22.7 mg, 0.07 mmol);
mp 172−173 °C; IR (KBr, cm−1) 3285, 3100, 2935, 1614, 1494, 1363,
1
1233, 1127, 1041, 926, 822, 755, 627; H NMR (400 MHz, CDCl3,
ppm) δ 7.80 (d, J = 2.0 Hz, 1H), 7.15 (s, 1H), 6.92 (s, 2H), 5.98 (d, J =
2.0 Hz, 1H), 3.86 (s, 6H), 3.82 (s, 3H), 3.59 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3, ppm) δ 154.9, 153.2, 153.1, 150.5, 144.9, 135.7,
133.5, 97.4, 91.6, 61.0, 56.1, 40.4; MS (EI, 70 eV): m/z = 344, 329, 312,
283, 271; HRMS (ESI) calcd C16H21N6O3 [M + H]+ m/z 345.1670,
found m/z 345.1662.
N2-Butyl-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]triazine-2,4-dia-
mine (6x). Eluent: petroleum ether/ethyl acetate (v/v = 5/1). Pink
solid: 52% yield (12.2 mg, 0.05 mmol); mp 98−100 °C, IR (KBr, cm−1)
3262, 3121, 3013, 2925, 2867, 1650, 1503, 1407, 1339, 1240, 1145,
1
1091, 904, 886, 760, 681, 623; H NMR (400 MHz, CDCl3, ppm) δ
7.73 (d, J = 2.0 Hz, 1H) 5.89 (s, 1H), 4.84 (s, 1H), 3.51 (s, 6H), 3.40 (q,
J = 4.0 Hz, 2H), 1.62−1.55 (m, 2H), 1.46−1.37 (m, 2H), 0.95 (t, J = 8.0
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 157.6, 153.9,
150.4, 144.6, 60.4, 41.2, 40.1, 31.9, 20.1, 13.9; MS (EI, 70 eV): m/z =
234, 205, 192, 163, 135; HRMS (ESI) calcd C11H19N6 [M + H]+ m/z
235.1666, found m/z 235.1662.
N4,N4-Dimethyl-N2-(naphthalen-2-yl)pyrazolo[1,5-a][1,3,5]-
triazine-2,4-diamine (6t). Eluent: petroleum ether/ethyl acetate (v/v
= 5/1). Pink solid: 63% yield (19.1 mg, 0.06 mmol); mp 170−172 °C;
IR (KBr, cm−1) 3218, 3102, 3057, 2924, 1631, 1587, 1490, 1345, 1294,
1102, 1022, 913, 818, 785, 690; 1H NMR (400 MHz, CDCl3, ppm) δ
8.08 (d, J = 8.0 Hz, 1H), 8.02 (t, J = 4.0 Hz, 1H), 7.86−7.84 (m, 1H),
7.77 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.51−7.45 (m, 3H),
7.38 (s, 1H), 5.93 (d, J = 2.0 Hz, 1H), 3.49 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 156.1, 153.4, 150.5, 144.9, 134.4, 134.3, 128.6,
127.6, 125.9, 125.8, 125.8, 124.3, 121.4, 119.8, 91.5, 40.3; MS (EI, 70
eV): m/z = 304, 278, 262, 206, 142; HRMS (ESI) calcd C17H17N6 [M +
H]+ m/z 305.1509, found m/z 305.1502.
N2-Cyclohexyl-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]triazine-2,4-
diamine (6y). Eluent: petroleum ether/ethyl acetate (v/v = 5/1).
Orange solid: 53% of yield (13.8 mg, 0.05 mmol); mp 131−133 °C; IR
(KBr, cm−1) 3259, 3116, 2923, 2850, 1626, 1499, 1339, 1235, 1150,
1
1091, 969, 883, 762, 623, 584; H NMR (400 MHz, CDCl3, ppm) δ
7.72 (d, J = 2.0 Hz, 1H), 5.86 (s, 1H), 4.83 (s, 1H), 3.82 (s, 1H), 3.50 (s,
6H), 2.07−2.02 (m, 2H), 1.75−1.72 (m, 2H), 1.64−1.61 (m, 1H),
1.45−1.36 (m, 2H), 1.25−1.19 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 156.8, 154.0, 150.5, 144.6, 91.7, 50.1, 40.1, 33.4, 25.7,
24.9; MS (EI, 70 eV): m/z = 260, 231, 203, 178, 135, 109; HRMS (ESI)
calcd C13H21N6 [M + H]+ m/z 261.1822, found m/z 261.1815.
N2-Benzyl-N4,N4-dimethylpyrazolo[1,5-a][1,3,5]triazine-2,4-dia-
mine (6u). Eluent: petroleum ether/ethyl acetate (v/v = 5/1). Pink
solid: 58% yield (15.5 mg, 0.06 mmol); mp 151−153 °C; IR (KBr,
cm−1) 3235, 3114, 2999, 1611, 1504, 1403, 1340, 1237, 1127, 1088,
962, 802, 759, 698, 508, 490; 1H NMR (400 MHz, CDCl3, ppm) δ 7.74
(s, 1H), 7.36−7.31 (m, 5H), 5.88 (s, 1H), 5.33 (s, 1H), 4.62 (d, J = 4.8
Hz, 2H), 3.49 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ
157.5, 152.4, 150.5, 143.7, 139.4, 128.6, 127.6, 127.2, 90.8, 47.4, 41.3;
MS (EI, 70 eV): m/z = 268, 224, 197, 163, 134; HRMS (ESI) calcd
C14H17N6 [M + H]+ m/z 269.1509, found m/z 269.1502.
1-Phenyl-3-(1H-pyrazol-3-yl)thiourea (7).27 Eluent: petroleum
ether/ethyl acetate (v/v = 1/1). White solid: 91% of yield (19.8 mg,
0.11 mmol); mp 174−176 °C; IR (KBr, cm−1) 3346, 3187, 3064, 2923,
1726, 1580, 1462, 1361, 1270, 1187, 1057, 995, 898, 758, 689, 506; 1H
NMR (400 MHz, DMSO-d6, ppm) δ 12.68 (s, 1H), 11.79 (s, 1H),
10.75 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 8 Hz, 2H), 7.37 (t, J = 8 Hz,
2H), 7.19 (t, J = 8 Hz, 1H), 6.08 (s, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6, ppm) δ 176.8, 149.9, 139.5, 130.1, 129.0, 125.7, 124.6, 94.8;
HRMS (ESI) calcd C10H10N4SNa [M + Na]+ m/z 241.0518, found m/z
241.0537.
N-(4-(Dimethylamino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)-
benzamide (6v). Eluent: petroleum ether/ethyl acetate (v/v = 5/1).
Yellow solid: 60% of yield (16.9 mg, 0.06 mmol); mp 152−154 °C; IR
(KBr, cm−1) 3111, 3071, 2989, 1064, 1580, 1474, 1353, 1277, 1125,
ASSOCIATED CONTENT
■
1
1096, 939, 827, 725, 690, 559; H NMR (400 MHz, CDCl3, ppm) δ
sı
* Supporting Information
8.71 (s, 1H), 7.90−7.85 (m, 3H), 7.52 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0
Hz, 2H), 6.20 (d, J = 1.2 Hz, 1H), 3.59 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 165.4, 152.5, 152.2, 150.5, 145.1, 134.6, 132.2,
128.7, 127.5, 94.1, 40.4; MS (EI, 70 eV): m/z = 282, 253, 239, 203, 185,
172; HRMS (ESI) calcd C14H15N6O [M + H]+ m/z 283.1302, found
m/z 283.1300.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00783.
Optimization of the reaction conditions for 4a, Job’s plot,
X-ray crcstallography data (4a and 7), GC−MS for the
8377
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J. Org. Chem. 2021, 86, 8365−8380

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
detected intermediate, copies of H and 13C{1H}NMR
Jiangxi Province (2019), the Jiangxi Provincial Natural Science
Foundation (20202ACBL206022, 20171BAB203010), the
Science Foundation of Jiangxi Provincial Department of
Education (GJJ201429), and the Graduate Innovation Research
Project of Gannan Normal University (YCX19A004).
spectra of all synthesized products (PDF)
Accession Codes
CCDC 2034391 and 2034814 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
Wei Guo − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China; orcid.org/0000-0002-4456-
3927; Email: guoweigw@126.com; Fax: (+86) 0797-
8393536
Lvyin Zheng − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China; Email: zhenglvyin@126.com
Xiaolin Fan − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China; Email: fanxl2008@gnnu.edu.cn
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Authors
Zhen Xie − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China
Liuhuan Cai − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China
Gongping Liu − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China
Ling Deng − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China
Weijie Mei − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China
Xiaoying Zou − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China
Yumei Zhong − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China
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Xiaoya Zhuo − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00783
Author Contributions
†W.G. and Z.X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21867001, 21662002, and 21602031), the Academic &
Technical Leadership Development Program of Jiangxi Province
(20194BCJ22014), the Double-Thousand Talents Plan of
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