Simple access toward 3-halo- and 3-nitro-pyrazolo[1,5-a] pyrimidines through a one-pot sequence

Article abstract of DOI:10.1039/c7ra04336h

Herein, a regioselective, time-efficient and one-pot route for the synthesis of diversely substituted 3-halo- and 3-nitropyrazolo[1,5-a]pyrimidines in good to excellent yields through a microwave-assisted process is provided. The reaction features a sequential cyclocondensation reaction of β-enaminones with NH-5-aminopyrazoles, followed by a regioselective electrophilic substitution with easily available electrophilic reagents. This methodology is distinguished by its short reaction times, high-yield, operational simplicity, broad substrate scope and pot-economy. Furthermore, these 3-functionalized heterocycles have been successfully used in the synthesis of 3-alkynyl and 3-aminopyrazolo[1,5-a]pyrimidines in yields up to 92%.

Full text of DOI:10.1039/c7ra04336h

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Simple access toward 3-halo- and 3-nitro-pyrazolo
[1,5-a]pyrimidines through a one-pot sequence†
Cite this: RSC Adv., 2017, 7, 28483
*
Juan-Carlos Castillo, Hernan-Alejandro Rosero and Jaime Portilla
´
Herein, a regioselective, time-efficient and one-pot route for the synthesis of diversely substituted 3-halo-
and 3-nitropyrazolo[1,5-a]pyrimidines in good to excellent yields through a microwave-assisted process is
provided. The reaction features a sequential cyclocondensation reaction of b-enaminones with NH-5-
aminopyrazoles, followed by a regioselective electrophilic substitution with easily available electrophilic
reagents. This methodology is distinguished by its short reaction times, high-yield, operational simplicity,
broad substrate scope and pot-economy. Furthermore, these 3-functionalized heterocycles have been
successfully used in the synthesis of 3-alkynyl and 3-aminopyrazolo[1,5-a]pyrimidines in yields up to 92%.
Received 18th April 2017
Accepted 22nd May 2017
DOI: 10.1039/c7ra04336h
rsc.li/rsc-advances
diodes (OLEDs)10 and semiconductors materials.11 These
promising biological and photophysical properties have
Introduction
prompted the development of various methods for the synthesis
of functionalized pyrazolo[1,5-a]pyrimidines.12–16 The vast
majority of these methods mostly involve the interaction
between NH-5-aminopyrazoles with 1,3-bis-electrophilic
reagents (e.g., b-dicarbonyl compounds,12 b-enaminones,13 b-
haloenones,14 b-ketonitriles,15 among others16). Although such
methodologies are generally reliable, many of them involved
harsh reaction conditions, prolonged reaction times and
tedious work-up, require use of additives, and oen proceed
with moderate yields. Particularly, ultrasound- and microwave-
assisted reactions using b-enaminones as precursor have been
successfully implemented (shorter reaction times and good
yields). However, these methods suffer some limitations,
including the use of potassium bisulphate as additive or Mg–Al
hydrotalcite as solid base catalyst (Scheme 1a).17 Despite the
success of different methods to obtain the interesting pyrazolo
[1,5-a]pyrimidine core, we are surprised that its construction
Among the broad range of privileged structures, fused-
pyrimidines represents one of the most prominent classes of
heterocyclic scaffolds for novel synthetic drug discovery.1
Particularly, some synthetic purine analogues containing pyr-
azolo[1,5-a]pyrimidine nucleus have received augmented
interest in recent years due to their broad range of applications
in medicinal chemistry and drug design.2 For instance, the
anxiolytic agent ocinaplon,3 and the hypnotic drugs indiplon,4
lorediplon,5 and zaleplon,6 among others potential drugs7 have
this structural motif of pyrazolo[1,5-a]pyrimidine (Fig. 1). Too,
some 3-halopyrazolo[1,5-a]pyrimidines have been reported as
a nonbenzodiazepinoid class of antianxiety agents.8
Besides medicinal applications, pyrazolo[1,5-a]pyrimidines
and structural analogues have been found in the dyestuff
industry (also used as uorophores),9 organic light emitting
Fig. 1 Examples of biologically active pyrazolo[1,5-a]pyrimidines.
Bioorganic Compounds Research Group, Department of Chemistry, Universidad de los
´
Andes, Carrera 1 No. 18A-10, Bogota 111711, Colombia. E-mail: jportill@uniandes.
edu.co
† Electronic supplementary information (ESI) available: Experimental,
characterization data, X-ray structures of 4q, 5g, and NMR spectra. CCDC
1542479 and 1542481. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c7ra04336h
Scheme
conditions.
1
Synthesis of pyrazolo[1,5-a]pyrimidines under mild
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and subsequent functionalization in a single pot has remained
largely unexplored. The introduced functional groups in this
heterocyclic core are susceptible to undergoing successive post-
functionalization reactions, which is important in drug
discovery among other applications. For example, halogenation
reactions have been conveniently explored (Scheme 1a)18 by
obtaining suitable substrates for coupling reactions, however,
the incorporation of others functional groups such as nitro or
sulphonyl is less frequent. From the viewpoint of economy and
environmental sustainability, developing operationally simple,
high-yielding, and additive-free method for preparing 3-func-
tionalized pyrazolo[1,5-a]pyrimidines in a one-pot manner is
highly desirable.
Scheme 2 Solvent-free microwave-assisted synthesis of b-enami-
nones. Reaction conditions: methyl ketone 1 (8.0 mmol) and N,N-
dimethylformamide-dimethylacetal (12.0 mmol); see ESI† for details.
a 8.0 mmol of ethyl acetoacetate used.
Recently, we reported a microwave-assisted synthesis of 6-
aryldiazenylpyrazolo[1,5-a]pyrimidin-7-amines from a-arylhy-
drazinylidene-b-ketonitriles, and their use in the preparation of
substituted pyrazolo[5,1-b]purines.15b Inspired by these results,
and our continuing interest in the synthesis of biologically
active N-heterocycles using green chemistry tools,19 we envi-
sioned that microwave-assisted reactions of b-enaminones with
NH-5-aminopyrazoles might generate the pyrazolo[1,5-a]
pyrimidine core, which could be halogenated and nitrated at
the C-3 position of the heterocycle. As a result, leading to the
formation of 3-halo and 3-nitropyrazolo[1,5-a]pyrimidines
through a catalyst- and additive-free one-pot approach (Scheme
1b). It is important to note that the cyclocondensation-
electrophilic substitution sequence between b-enaminones,
NH-5-aminopyrazoles and easily available electrophilic reagents
would open a practical and eco-compatible synthetic approach
to properly functionalized pyrazolo[1,5-a]pyrimidines through
the formation of three new bonds in a single reaction vessel and
the release of water as the unique byproduct. In this sense, the
microwave-assisted one-pot synthesis has proved to be an
extremely powerful tool because several synthetic trans-
formations and bond-forming steps can be carried out in
a single pot. Thereby, minimal chemical waste, time saving, and
operational simplicity are achieve.20
methylketones 1b–f, providing the b-enaminones 2b–f in nearly
quantitative yields without further purication (Scheme 2).
Subsequently, our exploratory study toward the synthesis of
pyrazolo[1,5-a]pyrimidine core began with the model reaction
between the phenylpropenone (2a) and 5-amino-3-methyl-1H-
pyrazole (3a) (Table 1). We carried out the optimization by
varying the temperature, the solvent and testing the effect of
conventional heating versus microwave irradiation. Heating to
reux of an equimolar mixture of 2a and 3a in ethanol or
toluene for 12 h did not lead to the pyrazolo[1,5-a]pyrimidine 4a
(Table 1, entries 1 and 2, respectively). When we performed the
reaction in DMF at higher temperature, provided compound 4a
in poor yield (Table 1, entry 3). The structure of 4a was
conrmed by 1H NMR, 13C NMR and mass spectroscopy. These
preliminary results, showed that higher temperatures favor the
Table 1 Optimization of the reaction parameters for the synthesis of
pyrazolo[1,5-a]pyrimidinea
Results and discussion
Considering the aforementioned aspects and prior to test the Entry
feasibility of the one-pot approach towards properly function-
Solvent
T (ꢀC)
Time t
Yieldb (%)
1
EtOH
PhMe
DMF
EtOH
PhMe
DMF
—
—
—
—
Reuxc
Reuxc
150c
12 h
12 h
12 h
3 min
3 min
3 min
1 min
2 min
2 min
30 min
—
—
15
10
alized pyrazolo[1,5-a]pyrimidines, we started our investigation
2
by examining a strategy to efficiently prepared b-enaminones
under microwave irradiation. Although there are diverse
protocols to obtain these 1,3-bis-electrophiles,21 the develop-
ment of convenient, high-yielding and sustainable methods are
still highly desirable due to their synthetic importance. As a test
reaction, we submitted a 1 : 1.5 mixture of acetophenone (1a)
and N,N-dimethylformamide-dimethylacetal under microwave
irradiation at 160 ꢀC for 15 min in a sealed tube under solvent-
free conditions. We were pleased to nd that the desired b-
enaminone 2a could be obtained with high purity and almost
quantitative yield aer simple evaporation of residues in the
reaction (Scheme 2). Stimulated by this result, we examined the
scope of this eco-compatible reaction with a variety of
3
4
5
6
7
8
9
10
150d
180d
180d
180e
78
80
91
95
180e
180e
Quantitativeg
51
180f
a
Reaction conditions: b-enaminone 2a (0.50 mmol) and NH-5-
aminopyrazole 3a (0.50 mmol).
b
c
Isolated yield.
Conventional
d
heating. Run in 10 mL sealed tubes at a power of 300 W in
anhydrous solvent (2.0 mL). e Run in 10 mL sealed tubes at a power of
f
300 W in the absence of solvent. Conventional heating with a sand
bath without solvent (fusion procedure). Yield is given for the crude
g
product.
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formation of the pyrazolo[1,5-a]pyrimidine 4a. To further regioselectively afforded pyrazolo[1,5-a]pyrimidines 4a–p in 85–
improve the reaction yield, we examined the inuence of 97% yields, without tedious purication (Scheme 3). Almost no
microwave irradiation on this reaction in different solvents loss of efficiency was observed for the substrates tested, which
such as ethanol, toluene, and DMF, and among these, ethanol indicated the low electronic inuence of the substituents on the
gave the worst yield of compound 4a (10%) (Table 1, entries 4– reactivity. This methodology also provided an interesting
6). In the reaction with ethanol as solvent, was not possible to synthetic access to the valuable product 4q which could be used
increase the temperature above 150 ꢀC due to system over- to synthesize pyrazolo[1,5-a]pyrimidine-based dendritic archi-
pressure. In a modied protocol, we performed the solvent-free tectures with potential applications in pharmaceutical and
reaction of 2a and 3a at 180 C for 1–2 min under microwave medicinal chemistry, as well as in materials science.22 The
ꢀ
irradiation to afford the desired product 4a in high to nearly structure of the tris-pyrazolo[1,5-a]pyrimidine 4q was solved by
quantitative yield, aer simple collection with mixtures of single-crystal X-ray diffraction analysis.23 Additionally, b-enam-
ethanol–water (Table 1, entries 7 and 8, respectively). Indeed, inone 2f exhibit two different types of carbonyl groups, which
the reaction proceed in quantitative yield (Table 1, entry 9) aer reacted chemo- and regioselectively with 3-methyl-1H-pyrazol-5-
high vacuum removal of all volatiles of the reaction mixture. amine (3a) under optimized conditions, to give ethyl 2,7-dime-
This result was evidenced by 1H NMR analysis of the crude thylpyrazolo[1,5-a]pyrimidine-6-carboxylate (4r) in 89% isolated
product (ESI,† page S22). Therefore, we corroborated the feasi- yield. Also, aminopyrazol 3f substituted with an electron-
bility of our hypothesis to carry out reliable functionalization withdrawing group (R: 4-NO2Ph) reacted efficiently with b-
reactions in the same reactor without further isolation of the enaminone 2c (Ar: 4-MeOPh) under optimized conditions,
pyrazolo[1,5-a]pyrimidine. In order to determine the specic giving the corresponding pyrazolo[1,5-a]pyrimidine 4s in 87%
microwave effect on accelerating the reaction vs. conventional isolated yield (Scheme 3). Notably, this synthetic methodology
heating, a pre-heated sand bath was used as a source of heat in to obtain pyrazolo[1,5-a]pyrimidines 4a–s was distinguished by
comparative experiments (Table 1, entries 8 vs. 10). The low its broad substrate scope, operational simplicity, no additives,
yield obtained with conventional heating at the same temper- no solvent, no excess of substrate is used, short reaction times,
ature for 30 min, indicated that the effect of microwave irradi- high-yielding without chromatographic purication, and eco-
ation is not purely thermal.
compatibility in terms of energy and waste.
With the optimized reaction conditions in hand (Table 1,
Halogenated pyrazolo[1,5-a]pyrimidines belong to a class of
entry 8), we then examined the scope of the reaction with important building blocks and versatile synthons, which could
a variety of b-enaminones 2a–f and NH-5-aminopyrazoles (3a– be converted into more complex molecules by cross-coupling
e). The results are summarized in Scheme 3. In general, the reactions.25 Nevertheless, existing methods to synthesize 3-hal-
solvent-free microwave-assisted reaction of b-enaminones 2a–f opyrazolo[1,5-a]pyrimidines are scarcely reported. Most of these
with a wide range of NH-5-aminopyrazoles (3a–e) bearing both involve the cyclocondensation reaction between 1,3-bis-
electron-donating and electron-withdrawing substituents electrophilic reagents and 5-amino-4-halopyrazoles25a or by
multistep sequences that proceed with the preformation of
pyrazolo[1,5-a]pyrimidines and subsequent halogenation reac-
tion with diverse halogen sources such as N-hal-
osuccinimides,18,24 iodine monochloride,25b bromine25c and 1-
chlorobenzotriazole.25d The drawbacks of these strategies
include: long reaction times, large volume of hazardous
solvents, as well as difficult protocols. Therefore, and
continuing with the implementation of greener and economic
strategies, the development of an efficient and practical one-pot
approach to halogenated pyrazolo[1,5-a]pyrimidines that allows
use of readily available starting materials, short reaction times,
and easier workup is highly desirable. Consequently, and
according to the noteworthy results obtained in our former
synthetic method (Scheme 3), we planned to study a consecutive
approach toward 3-halopyrazolo[1,5-a]pyrimidine 5 in a single
reaction vessel, starting from an equimolar mixture of b-
enaminone 2 and NH-5-aminopyrazole (3), and nishing with
the addition of 1 equiv. of N-iodosuccinimide (NIS). Usually,
halogenation reactions have been carried out successfully in
chlorinated solvents, thus we decided to use 1,2-dichloroethane
(EDC) instead of dichloromethane (DCM) to evaluate the effect
Scheme 3 Microwave-assisted synthesis of b-enaminones and pyr-
of temperature. In addition, the rst step reaction was per-
azolo[1,5-a]pyrimidines. Reaction conditions: b-enaminone 2 (0.50
formed using conditions analogous to those previously opti-
mized (Table 1, entry 8), while the second step was optimized as
indicated below (Table 2).
mmol) and NH-5-aminopyrazole 3 (0.50 mmol) at 180 ꢀC for 2 min
a
under solvent-free conditions. 1.50 mmol of 3-(tert-butyl)-1H-pyr-
azol-5-amine used. b 0.50 mmol of b-enaminoester used.
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Table 2 Optimization of the reaction parameters for the one-pot
synthesis of 3-iodopyrazolo[1,5-a]pyrimidine 5fa
Entry
T (ꢀC)
Time t
Yieldb (%)
1
2
3
4
5
6
7
8
80c
5 min
5 min
5 min
5 min
2 min
20 min
20 min
10 min
96
94
95
62
70
73
94
76
60c
40c
30c
40c
Reuxd
25e
25e
a
Reaction conditions: b-enaminone 2a (0.25 mmol) and NH-5-
aminopyrazole 3a (0.25 mmol) at 180 ꢀC under microwave irradiation
for 2 min; aer cooling by airow addition of NIS (0.25 mmol) and
b
c
EDC (2.0 mL). Isolated yield. Run in 10 mL sealed tubes under
d
microwave irradiation. Run in a 10 mL round-bottom ask with 2.0
e
mL of EDC under reux (not one-pot procedure). Run in 10 mL
sealed tubes at 25 ꢀC.
Scheme 4 Synthesis of 3-halopyrazolo[1,5-a]pyrimidines. Reaction
conditions: b-enaminone 2 (0.50 mmol) and NH-5-aminopyrazole 3
(0.50 mmol) at 180 ꢀC under microwave irradiation for 2 min; after
cooling by airflow addition of N-halosuccinimide (0.50 mmol) and
EDC (2.0 mL) at 25 ꢀC for 20 min. a From 4q, 1.50 mmol of NBS used.
This approach is termed one-pot when the last reaction
occurred in the same microwave tube. In this sense, we carried
out the optimization by varying the temperature and testing the
effect of microwave irradiation in contrast to conventional
heating. The reaction of the crude product 4a with 1 equiv. of
NIS in 2.0 mL of EDC using temperatures between 30–80 ꢀC for
2–5 minutes under microwave irradiation afforded the desired
product 5f in good to nearly quantitative yield (Table 2, entries
1–5). However, the reaction at reux was not completely satis-
factory due to loss of precursor mass during the transfer process
from the microwave tube to the round-bottom ask (Table 2,
entry 6). Pleasingly, this one-pot synthesis could be performed
at room temperature without microwave heating, affording the
3-iodoheterocycle 5f in good to excellent yields and short reac-
tion times (Table 2, entries 7 and 8, respectively). These results
evidenced the high electron density of carbon atom at position 3
of the pyrazolo[1,5-a]pyrimidine ring (see 13C NMR spectra of
compounds 4a–s in the ESI†). In consequence, the optimum
conditions for the regioselective 3-iodination of the pyrazolo
[1,5-a]pyrimidine 4a were achieved using a stoichiometric
amount of N-iodosuccinimide by a simple and energy-saving
protocol (Table 2, entry 7). With the optimized reaction condi-
tions, we explored the scope of this one-pot synthesis with
diverse N-halosuccinimides and pyrazolo[1,5-a]pyrimidines
preformed. The microwave-assisted reaction between b-enami-
nones 2 and NH-5-aminopyrazoles (3) afforded the crude
products 4, which were subsequently halogenated using diverse
N-halosuccinimides in 1,2-dichloroethane as solvent at room
temperature for 20 min. As shown in Scheme 4, the 3-halopyr-
azolo[1,5-a]pyrimidines 5a–i were successfully obtained in 89–
96% yields. The structure of the 3-iodopyrazolo[1,5-a]pyrimi-
dine 5g was solved by single-crystal X-ray diffraction analysis.26
Although some publications are devoted to the linear
synthesis of halogenated pyrazolo[1,5-a]pyrimidines, the regio-
selective incorporation of others functional groups such as
nitroso, nitro, sulphonyl and amine have been poorly explored.
In fact, most of the existing reports are patents. Thereby, we
propose the introduction of diverse functional groups on this
heterocyclic core through a one-pot approach according to our
former results, starting from b-enaminone 2 (or another 1,3-bis-
electrophilic reagents) and the appropriate NH-5-
aminopyrazole (3). Particularly, nitroaromatic compounds
have been employed to develop not only bioreductive pro-
drugs27a but also uorescent probes for the detection of nitro-
reductase and tumor hypoxia.27b,c These results encouraged us
to investigate the cyclocondensation-nitration sequence under
microwave irradiation in order to afford 3-nitropyrazolo[1,5-a]
pyrimidines 6 within a single reaction vessel (Scheme 5). Our
initial testing of the nitration reaction proceeded under
conventional heating, attempting to carry out the reaction in the
same microwave tube. The crude product 4 with 4 equiv. of the
nitrating mixture (HNO3 : H2SO4, 2 : 1) in 2.0 mL of EDC or
water as solvent, and with temperatures between 5–45 ꢀC for 1–3
hours, did not work without microwave irradiation. However,
microwave-assisted reactions at 60 ꢀC for 10 min under solvent-
free conditions, enabled the regioselective formation of the 3-
nitrosubstituted products 6a–d in yields up to 89% (Scheme 5).
Remarkably, these 3-nitropyrazolo[1,5-a]pyrimidines 6 could be
used as potential colorimetric or uorescent probes for the
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7a and 7b in 75% and 60% yields, respectively (Scheme 6, right).
Further applications of this methodology is under active
investigation due to their interesting extended p-conjugation.27c
Furthermore, the palladium-catalyzed reduction of representa-
tive 3-nitropyrazolo[1,5-a]pyrimidines 6a and 6b was explored.
As expected, the reduction of the nitro group was achieved at
25 ꢀC under H2 atmosphere at ambient pressure using Pd/C as
catalyst in ethanol, giving the corresponding pyrazolo[1,5-a]
pyrimidin-3-amines 8a and 8b in good yields, which have
inherent synthetic utility (Scheme 6, le).
Scheme 5 Synthesis of 3-nitropyrazolo[1,5-a]pyrimidines. Reaction
conditions: b-enaminone 2 (0.50 mmol) and NH-5-aminopyrazole 3
(0.50 mmol) at 180 ꢀC under microwave irradiation for 2 min; after
cooling by airflow addition of nitric acid (2.0 mmol) and sulfuric acid
(1.0 mmol) at 60 ꢀC under solvent-free microwave irradiation for
10 min.
Conclusions
In summary, b-enaminones and pyrazolo[1,5-a]pyrimidines can
be easily and conveniently prepared in excellent yields from
methylketones via microwave irradiation under catalyst- and
solvent-free conditions, and easy purication. These protocols
provide a better and practical alternative to existing procedures.
Likewise, we have developed an efficient and expeditious
microwave-assisted synthesis of functionalized pyrazolo[1,5-a]
pyrimidines in good to excellent yields with the formation of
three new bonds in a one-pot manner. Interestingly, the time-
efficient construction of a pyrazolo[1,5-a]pyrimidine core and
subsequent regioselective functionalization on the pyrazole
moiety with functional groups such as halogen or nitro in
a single reaction vessel has not been previously reported. This
cyclocondensation-electrophilic substitution sequence offers
marked improvements in terms of general applicability, effi-
cacy, simplicity, and eco-compatibility. Also, this one-pot
methodology could be used to introduce others electrophilic
substituents on the pyrazolo[1,5-a]pyrimidine core. Finally,
some representative post-functionalization reactions have also
been developed, affording heteroamines and p-extended
heterocycles of valuable synthetic and medicinal interest.
detection of nitroreductase and hypoxic tumor cell imaging,
because the reduced systems have interesting photophysical
properties, as well as their unsubstituted precursors 4 (Image 1
in the ESI†).
Notably, the synergy between functionality and modularity is
the key aspect of this consecutive one-pot approach towards the
syntheses of properly functionalized pyrazolo[1,5-a]pyrimidines
5a–i and 6a–d. This is important because such structures are
attractive scaffolds for medicinal chemistry and can be
prepared by convenient and eco-compatible one-pot synthetic
methods. For example, the chemically manipulating the
halogen and nitro groups in the functionalized heterocycles 5
and 6 was briey explored. Because of easy availability of water,
we choose to use this green solvent and microwave heating in
order to start our studies using some iodine-derivatives 5.
Gratifyingly, the palladium-catalyzed Sonogashira cross-
coupling reaction of phenylacetylene with 3-iodopyrazolo[1,5-
a]pyrimidines 5f and 5g using 10% Pd/C–PPh3–CuI as a catalyst
system, afforded the corresponding 3-phenylethynyl derivatives
Acknowledgements
The authors are grateful for the nancial support from Uni-
versidad de los Andes and Colombian Institute for Science and
Research (COLCIENCIAS). We also acknowledge Edwin Guevara
for acquiring the high-resolution mass spectra, Dr Eduardo C.
Escudero-Adan (X-ray Diffraction Unit of Institute of Chemical
Research of Catalonia (ICIQ) in Tarragona-Spain) and Dr Mario
Macias (Universidad de los Andes) for their help with the
analysis of the X-ray crystallographic data.
Notes and references
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Scheme 6 Post-functionalization of 3-halo- and 3-nitropyrazolo[1,5-
a]pyrimidines. Reaction conditions: (i) substrate 5f or 5g (0.25 mmol),
phenylacetylene (0.38 mmol), 1 : 4 : 2 ratio of 10% Pd/C–PPh3–CuI
and Et3N (5.0 equiv.) in water (2.0 mL) at 80 ꢀC under microwave
irradiation for 1 h; (ii) substrate 6a or 6b (0.50 mmol) and 10% Pd/C (5
wt%) under an H2 atmosphere in EtOH (5.0 mL) at 25 ꢀC for 3 h.
´
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28488 | RSC Adv., 2017, 7, 28483–28488
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