3-Formylpyrazolo[1,5- a]pyrimidines as Key Intermediates for the Preparation of Functional Fluorophores

Article abstract of DOI:10.1021/acs.joc.8b01571

A one-pot route for the regioselective synthesis of 3-formylpyrazolo[1,5-a]pyrimidines 4a-k in good yields through a microwave-assisted process is provided. The synthesis proceeds via a cyclocondensation reaction between β-enaminones 1 with NH-3-aminopyrazoles 2, followed by formylation with an iminium salt moiety (Vilsmeyer-Haack reagent). These N-heteroaryl aldehydes 4 were successfully used as strategic intermediates for the preparation of novel functional fluorophores with yields up to 98%. The structures of the products obtained and regioselectivity of the reactions were determined on the basis of NMR measurements and X-ray diffraction analysis. Since pyrazolo[1,5-a]pyrimidines (PPs) 3 have shown an important fluorescence, photophysical properties of four 2-methylderivatives substituted at position 7 with different acceptor (A) or donor (D) groups were investigated. The compounds evaluated exhibited large Stokes shift in different solvents, but only the substituted p-methoxyphenyl (4-An) showed a strong fluorescence intensity with quantum yields up to 44% due to its greater ICT. Therefore, hybrid systems based on pyrazolo[1,5-a]pyrimidines could be used as fluorescent probes to detect biologically or environmentally relevant species.

Full text of DOI:10.1021/acs.joc.8b01571

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Article
3-Formylpyrazolo[1,5-a]pyrimidines as Key Intermediates
for the Preparation of Functional Fluorophores
Juan-Carlos Castillo, Alexis Tigreros, and Jaime Portilla
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01571 • Publication Date (Web): 27 Jul 2018
Downloaded from http://pubs.acs.org on July 27, 2018
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3-Formylpyrazolo[1,5-a]pyrimidines as Key Intermediates for the
Preparation of Functional Fluorophores
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Juan-Carlos Castillo,†, ‡ Alexis Tigreros,† and Jaime Portilla*,†
† Bioorganic Compounds Research Group, Department of Chemistry, Universidad de los
Andes, Carrera 1 No. 18A-10, Bogotá, Colombia
‡
Escuela de Ciencias Químicas, Facultad de Ciencias, Universidad Pedagógica y
Tecnológica de Colombia UPTC, Avenida Central del Norte, Tunja, Colombia
*Email: jportill@uniandes.edu.co
Keywords: 5-Aminopyrazole, -Enaminone, Fluorescence, 3-Formilpyrazolo[1,5-
a]pyrimidine, Microwave chemistry, Quantum yields
TOC graphic & Abstract
A one-pot route for the regioselective synthesis of 3-formylpyrazolo[1,5-a]pyrimidines 4a−k in
good yields through a microwave-assisted process is provided. The synthesis proceeds via a
cyclocondensation reaction between β-enaminones 1 with NH-3-aminopyrazoles 2, followed by
formylation with an iminium salt moiety (Vilsmeyer-Haack reagent). These N-heteroaryl
aldehydes 4 were successfully used as strategic intermediates for the preparation of novel
functional fluorophores with yields up to 98%. The structures of the products obtained and
regioselectivity of the reactions were determined on the basis of NMR measurements and
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X-ray diffraction analysis. Since pyrazolo[1,5-a]pyrimidines (PPs) 3 have shown an important
fluorescence, photophysical properties of four 2-methylderivatives substituted at position 7 with
different acceptor (A) or donor (D) groups were investigated. The compounds evaluated
exhibited large Stokes shift in different solvents, but only the substituted p-methoxyphenyl (4-
An) showed a strong fluorescence intensity with quantum yields up to 44% due to its greater
ICT. Therefore, hybrid systems based on pyrazolo[1,5-a]pyrimidines could be used as
fluorescent probes to detect biologically or environmentally relevant species.
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INTRODUCTION
Functionalized N-heterocycles are of notable interest to organic chemists to both uncover
novel derivatives and explore new applications in drug delivery and biomedical research.
The functional groups may expand the applicability and scope of such compounds.1 The
synthesis of N-heteroaryl aldehydes is an important focus of research for synthetic organic
chemists due to their presence in biologically active compounds, as well as other functional
molecules.2 In addition, the carbonyl group can undergo a variety of transformations such
as C-C, C-N and C-O coupling reactions, and also participate in redox reactions;3 thus, the
biological and physicochemical effect of such post-functionalized compounds would be
improved. Particularly, pyrazolo[1,5-a]pyrimidine derivatives has received augmented
interest in recent years due to their broad range of biological and pharmacological
activities.4 For example, the hypnotic drug Indiplon (I),5a diamide derivative (II) (good
anticancer activity),5b and anxiolytic agent Ocinaplon (III)5c have this structural scaffold 7-
aryl substituted, as well as diverse carbonyl derivatives at position 3 (Figure 1). In addition,
pyrazolo[1,5-a]pyrimidines (PPs) have found applications in material sciences because of
their interesting photophysical properties.6
Figure 1. Examples of biologically active 3-funtionalized 7-arylpyrazolo[1,5-a]pyrimidines
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Consequently, the development of efficient and sustainable methods for the synthesis and
derivatization of pyrazolo[1,5-a]pyrimidines are still highly desirable. Synthetic approaches
to PPs have largely relied on the condensation reaction between NH-3-aminopyrazoles with
1,3-bis-electrophilic compounds (e.g., β-dicarbonyl compounds,7 β-enaminones,8 β-
ketonitriles,9 β-haloenones,10 among others11). Interestingly, microwave12 and ultrasonic13
irradiation using β-enaminones as precursor have been successfully used to facilitate the
reaction. A less obvious approach was the KOtBu-induced condensation reaction between
1,3,5-triaryl-pentane-1,5-diones with NH-3-aminopyrazoles, which proceeds with loss of
one molecule of aryl methyl ketone.14 Besides other stepwise approaches using single
bond-forming reactions, a couple of tricomponent procedures have been developed in
recent years to prepare PPs.15 In spite the existence of diverse pyrazolo[1,5-a]pyrimidines
synthesis, efficient methods which can introduce a broad range of functional groups on the
ring in a one-step or single pot have remained largely unexplored. Most of these methods
involve the synthesis of halo-derivatives by multistep sequences that proceed with the
preformation of the pyrazolo[1,5-a]pyrimidine core and subsequent regioselective
halogenation.16 However, the incorporation of others functional groups such as hydrazone,
carboxyl, enone and nitroso have been poorly explored. In fact, most of the existing reports
are pharmaceutical patents. Thus, to develop an operationally simple and time-efficient
method for preparing functionalized PPs by employing a single step or one-pot procedure is
desirable.
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Our lab previously reported a microwave-assisted synthesis of 6-aryldiazenylpyrazolo[1,5-
a]pyrimidin-7-amines from α-arylhydrazinylidene-β-ketonitriles, and their use in the
preparation of pyrazolo[5,1-b]purine derivatives (Scheme 1a).17 More recently, we reported
our initial results on the time-efficient synthesis of 3-halo and 3-nitro-pyrazolo[1,5-
a]pyrimidines in stepwise and one-pot manner. The reactions were carried out from β-
enaminones and NH-3-aminopyrazoles, followed by a regioselective electrophilic
substitution with easily available reagents in the same reaction vessel (Scheme 1b).18 Over
the past several years we have been quite interested in the synthesis of heteroaryl
aldehydes19 due to useful for their use in numerous transformations such as condensations
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or redox reactions.3 Inspired by these results, and our continuing interest on the search for
novel and greener methods for the syntheses of N-heterocycles,20 we proposed the
microwave-assisted consecutive synthesis of 3-formylpyrazolo[1,5-a]pyrimidines via a
Vilsmeyer-Haack formylation (Scheme 1c). It is important to mention that few examples of
such compounds were reported in the literature, and multistep procedures were used for
their selective preparation in all cases in medium-good yields (50-81%).21 Moreover, we
were unable to find any examples for the direct and regioselective formylation of
pyrazolo[1,5-a]pyrimidines at position 3. To the best of our knowledge, this is the first
report of using microwave-assisted one-pot reaction for the synthesis of 3-
formylpyrazolo[1,5-a]pyrimidines.
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Scheme 1. Synthesis of functionalized pyrazolo[1,5-a]pyrimidines under mild conditions
RESULTS AND DISCUSSION
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Given our previous results regarding the consecutive synthesis of 3-halo- and 3-nitro-
pyrazolo[1,5-a]pyrimidines (Scheme 1b),18 we planned to study an analogous approach
toward 3-formylpyrazolo[1,5-a]pyrimidines 4 in a single reaction vessel. The synthesis was
carried out starting from -enaminones 1 and NH-3-aminopyrazoles 2, and finishing with
the addition of 2 equiv. of Vilsmeier-Haack reagent generated in situ from POCl3 and
DMF. It is important to mention that the first step reaction was performed using conditions
of our previously developed protocol, where the crude intermediate 3a was obtained almost
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1
pure, according to H NMR analysis, by high vacuum removal of all volatiles of the
reaction mixture.18 In this way, the second step was optimized in the same microwave tube
as indicated below (Table 1). We carried out the optimization by varying the temperature
and testing the effect of microwave irradiation in contrast to conventional heating. As a test
reaction, we submitted an equimolar mixture of the β-anaminone 1a and 5-amino-3-methyl-
1H-pyrazole (2a) at 180 °C under microwave irradiation for 2 min in a sealed tube, after
cooling by airflow addition of 2 equiv. of preformed Vilsmeier-Haack reagent at 40 °C for
10 min provided the desired product 4a in 45% yield as the only detectable regioisomer
(Table 1, entry 1). The structure of 4a was confirmed by NMR and mass spectroscopy. We
continue our study using microwave irradiation at temperatures between 60−80 °C for 10
min. Pleasingly, the highest yield (91%) was achieved at 80 °C, while at lower
temperatures, the formylated product 4a was obtained in acceptable yields together with the
intermediate 3a (Table 1, entries 2−4). Reaction times longer than 10 min resulted in lesser
yields of desired product 4a (Table 1, entries 5−6). In order to determine the specific
microwave effect on accelerating the reaction versus conventional heating, a pre-heated
sand bath was used as a source of heat in comparative experiments (Table 1, entries 4 vs 7).
Pleasingly, the heteroaryl aldehyde 4a was also successfully obtained using conventional
heating at 80 °C for 60 min, but this method was not completely satisfactory due to loss of
intermediate mass during the transfer process from the microwave tube to the round-
bottom. Consequently, we corroborated the feasibility of our hypothesis to perform reliable
cyclocondensation-formylation sequence in the same microwave tube without further
isolation of 3a.
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Table 1. Optimization of the reaction parameters for the one-pot synthesis of 3-
formylpyrazolo[1,5-a]pyrimidine 4a.a
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Entry
T (°C)
40b
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80c
Time t
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15 min
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60 min
Yield (%)
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7d
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Reaction conditions: -enaminone 1a (0.50 mmol) and 5-amino-3-methyl-1H-pyrazole (2a, 0.50 mmol) at
180 °C under microwave irradiation for 2 min, after cooling by airflow addition of 2 equiv. of preformed
Vilsmeier-Haack reagent (2 equiv. POCl3 and 4 equiv. DMF). b Run in 10 mL sealed tubes at a power of 300
c
d
W. Conventional heating with a sand bath. Run in a 10 mL round-bottom flask with 0.5 mL of anhydrous
DMF at 80 °C for 60 min (not one-pot procedure).
Once the reaction conditions have been optimized (Table 1, entry 4), we then examined the
scope of this synthesis with a variety of preformed pyrazolo[1,5-a]pyrimidines 3a−k. The
results are summarized in Scheme 2. In general, the microwave-assisted reaction of -
enaminones 1a−g with NH-3-aminopyrazoles 2a−d afforded the crude intermediate 3a−k,
which were successfully formylated under microwave irradiation to provide the heteroaryl
aldehydes 4a−k in good yields. These results evidenced the high electron density of carbon
atom at position 3 of intermediates 3a−k (see 13C NMR spectra of PPs 3 in Supporting
Information),18 from which some representative derivatives were isolated in this work. The
previously reported PPs 3a, 3d and 3f were obtained18 to complement the subsequent
photophysical studies, while the novel derivatives 3c, 3e, 3g, and 3i were synthesized and
completely characterized accordingly. The structure of the 3-formylpyrazolo[1,5-
a]pyrimidine 4a was solved by single-crystal X-ray diffraction analysis.22 It was found that
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the pyrazolyl group well tolerated either alkyl or aryl substituents (R1), and almost no loss
of efficiency was observed for the -enaminones tested, which indicated the low electronic
influence of the aryl (or heteroaryl) group on their reactivity. Albeit when the -enaminone
4-pyridyl substituted 1f was used, the one-pot reaction afforded the lowest yields toward
the formation of the products 4f (72%) and 4k (74%). This novel synthetic methodology to
obtain the heteroaryl aldehydes 4a−k was distinguished by its operational simplicity, short
reaction times, and eco-compatibility in terms of waste and energy.
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Scheme 2. Microwave-assisted synthesis of 3-formylpyrazolo[1,5-a]pyrimidines 4a−ka
Reaction conditions: -enaminone 1 (0.50 mmol) and NH-3-aminopyrazole 2 (0.50 mmol) at 180 °C for 2
min; after cooling by airflow addition of 2 equiv. of Vilsmeier-Haack reagent at 80 °C under microwave
irradiation for 10 min. (See the Experimental Section for details.)
Once 3-formylpyrazolo[1,5-a]pyrimidines 4 were obtained we developed some post-
functionalization reactions to generate novel PPs derivatives, knowing that the nitrogenous
heteroaryl aldehydes are important intermediates in organic and medicinal chemistry.19,23
The formyl group can be converted into hydrazone, imine, enone, alcohol, and carboxylic
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acid among other important functional groups; though, the incorporation of such functional
groups on the pyrazolo[1,5-a]pyrimidine core have been poorly explored. Therefore, we
study the possibility of chemically manipulating the formyl group in the representative
aldehydes 4a, 4b and 4j by an environmentally friendly synthetic protocols. As expected,
the Knoevenagel condensation of 4 with malononitrile (5) using piperidine as catalyst in
absolute ethanol at 80 °C under microwave irradiation for 10 min, afforded the dicyanovinyl
derivatives 6 in nearly quantitative yields (Scheme 3a). Equally, when 2-hydrazinylpyridine
(7) was used as nucleophile under analogous conditions without catalyst, heteroaryl
aldehydes 4 were efficiently converted to 2-pyridilhydrazones 8 in excellent yields
(Scheme 3b). Curiously, novel functional derivatives 6 and 8 could be used as fluorescent
probes for selective recognition of cyanide or for the detection of metal ions respectively,
somewhat similar to our previous reports with analogous structures (Scheme 3, gray).19b-c
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Scheme 3. Synthesis of post-functionalized pyrazolo[1,5-a]pyrimidines 6 and 8a
a Reaction conditions: (a) 4 (0.50 mmol), malononitrile (5, 0.50 mmol) and piperidine (0.10 mmol) in EtOH
(2.0 mL); (b) 4 (0.50 mmol) and 2-hydrazinylpyridine (7, 0.50 mmol) in EtOH (2.0 mL). (See the
Experimental Section for details.)
The formyl moiety of 4 also suffered a condensation reaction using p-chloroacetophenone
(9), allowing the incorporation of enone functional group. The Claisen-Schmidt reaction of
heteroaryl aldehydes 4a−b with 9 using sodium hydroxide as base at room temperature led
to the formation of the expected hetero-chalcones 10a−b in high yields (Scheme 4a). These
chalcones 10 bearing pyrazolo[1,5-a]pyrimidine moiety could be used as building blocks
for the development of potential antitumor agents, among other valuable compounds.24 On
the other hand, we investigated the transition metal-free oxidation of the formyl group of
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4a−b to carboxylic acids 11a−b with Oxone in DMF at room temperature. Oxone is a
tradename for the potassium triple salt with formula 2KHSO5·KHSO4·K2SO4, commonly
used as an oxidizing agent for numerous organic transformations, and whose active
ingredient is potassium peroxymonosulfate (KHSO5). This salt may be used as an
alternative to common transition-metal oxidants for the transformation of aldehydes to
carboxylic acids.25 As expected, the 3-formylpyrazolo[1,5-a]pyrimidines 4a−b were
oxidized effortlessly to their carboxylic acids 11a−b in good yields using 1 equiv. of
Oxone (Scheme 4b). This transformation resulted in a protocol where: (a) there is no need
for rigorous exclusion of air or moisture, (b) the oxidation process is highly efficient, and
(c) the replacement of expensive and toxic transition-metal oxides by environmentally
benign reagent Oxone.25 It is important to note that pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid 11 could be used as reagents for the synthesis of amide derivatives with potential
biological activity.5b,21c In addition, Yoshida and co-workers also reported a transition-
metal-free oxidation of a 3-formylpyrazolopyrimidine to the corresponding carboxylic acid
but using a large excess of oxidizing reagent (NaClO2:NaH2PO4, ~10:5 equiv.).21c
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Scheme 4. Synthesis of post-functionalized pyrazolo[1,5-a]pyrimidines 10 and 11a
a
Reaction conditions: (a) 4 (0.50 mmol), p-chloroacetophenone (9, 0.55 mmol) and 20% aqueous NaOH
(0.20 mL) in MeOH (5.0 mL); (b) 4 (0.50 mmol) and Oxone (0.50 mmol) in DMF (3.0 mL). (See the
Experimental Section for details.)
Given our interesting synthetic results (obtaining 4, 6, 8, 10, and 11), we consider precise to
carry out a photophysical studies of some non-functionalized PPs 3, in order to establish the
scope of the pyrazolo[1,5-a]pyrimidine core as a new organic fluorophore. This study was
done to categorize N-heteroaryl aldehydes 4 as key intermediates of novel functional
fluorophores, since they have the respective heterocyclic core. Functional fluorophores are
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sophisticated structures for photophysical applications, often difficult to access by
conventional synthetic strategies from simple starting materials.26 In this way, we selected
compounds 3a and 3d−f to carry out the corresponding studies because their structures are
substituted at position 7 with different electron-donor (D) and electron-acceptor (A) groups
(Figure 2). This structural feature is crucial in fluorescence phenomena that involve charge
transfer (CT), and has been often observed in various N-heterocycles suitably substituted.27
The UV-vis and fluorescence emission spectra of PPs 3a and 3d−f were achieved in
toluene (PhMe), dichloromethane (DCM), acetonitrile (ACN), dimethylsulfoxide (DMSO),
and ethanol (EtOH) as solvents of different polarity (See Supporting Information, Figures
S2-S6 and Table S1). Fluorophores 3a and 3d−f exhibited large Stokes shift (7187-9240
cm-1) and without any tendency of solvatochromic shift in the different solvents evaluated.
In addition, the compound 3d exhibited the strongest fluorescence intensity with quantum
yields (F) up to 44%. This fluorophore (D-A) is quite significant versus that of 3a and 3e-f due
to the presence of a strong donating group like the 4-methoxyphenyl that favors a higher
intramolecular charge transfer (ICT).19c,28 The quantum yields of 3d in PhMe, DCM, ACN,
DMSO, and EtOH are 34, 44, 17, 23, and 19% respectively. Compounds 3a and 3e have
similar fluorescence intensity between them, but lower than fluorophore 3d, while 3f presented
a very weak fluorescence due to the electronic effect of the 7-aryl substituent. The
difference between 3d and 3e is because the m-methoxy substituents only contribute to
inductive effects (A) whereas the p-methoxy substituent contribute both inductive (A) and
resonance effects (D).29 These findings confirm that the fluorescence phenomenon of these
compounds is governed by an ICT mechanism sensitive to the electronic nature of the 7-
aryl substituent group on the pyrazolo[1,5-a]pyrimidine core (Figure 2). Therefore, these
fluorophores could be used as building blocks of novel fluorescent probes to detect
biologically or environmentally relevant species. In fact, the heteroaryl aldehydes 4a-k retain
the fluorescent characteristics of their precursors 3 (Figures S7).
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Figure 2. Structure of fluorophores 3a and 3d−f. Relative quantum yields were obtained
with anthracene (ϕF = 0.28 in ethanol)30 as reference. Photograph was taken using 20 µM
solutions in DCM. A hand-held UV lamp under long wavelength (λ = 365 nm) was used.
CONCLUSIONS
In summary, we have developed an efficient and expeditious microwave-assisted synthesis
of 3-formylpyrazolo[1,5-a]pyrimidine 4a-k in good to excellent yields with the formation
of three new bonds in a one-pot manner. The construction of heteroaryl aldehydes 4 via a
sequential cyclocondensation reaction of β-enaminones 1 with NH-3-aminopyrazoles 2,
followed by formylation with Vilsmeyer-Haack reagent in a single reaction vessel has not
been previously reported. This one-pot sequence offers improvements in terms of broad
substrate scope, operational simplicity, short reaction times, high-yield, environmentally
sustainable and highly atom economical. Pleasingly, aldehydes 4 readily engage in nucleophilic
addition reactions with malononitrile, 2-hydrazinylpyridine and p-chloroacetophenone for the
synthesis of dicyanovinyl 6, hydrazone 8 and hetero-chalcone 10 derivatives respectively, in
excellent yields (90−98%). Likewise, we have developed an efficient and simple protocol for
the Oxone-induced oxidation of 4 to the respective carboxylic acids 11 in good yields, which is
a valuable alternative to traditional metal-mediated oxidations. Besides the great synthetic and
biological interest of the novel synthesized compounds, its photophysical importance is
highlighted because the pyrazolo[1,5-a]pyrimidine core proved to be an ICT modulable
fluorophore. Consequently, these compounds could be used to design fluorescent probes in
the detection of various relevant species; thus, we expect to extend our studies toward the
synthesis of chemosensors based on PPs for anions or metal ion detection.
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EXPERIMENTAL SECTION
General information. All reagents were purchased from commercial sources and used
without further purification unless otherwise noted. All starting materials were weighed and
handled in air at room temperature. The reactions were monitored by TLC visualized by
UV lamp (254 or 365 nm). Flash chromatography was performed on silica gel (230-400
mesh). All reactions under microwave irradiation were performed using a sealed reaction
vessel (10.0 mL, max pressure = 300 psi) containing a Teflon-coated stir bar (obtained
from CEM). Microwave-assisted reactions were performed in a CEM Discover SP focused
microwave (ν = 2.45 GHz) reactor equipped with a built-in pressure measurement sensor
and a vertically focused IR temperature sensor. Controlled temperature, power, and time
settings were used for all reactions. NMR spectra were recorded at 400 MHz (1H) and 101
MHz (13C) at 298 K using tetramethylsilane (0 ppm) as the internal reference. NMR
spectroscopic data were recorded in CDCl3 or DMSO-d6 using as internal standards the
residual non-deuteriated signal for 1H NMR and the deuteriated solvent signal for 13C NMR
spectroscopy. DEPT spectra were used for the assignment of carbon signals. Chemical
shifts () are given in ppm and coupling constants (J) are given in Hz. The following
abbreviations are used for multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd
= doublet of doublets, and m = multiplet. Melting points were collected using a capillary
melting point apparatus and are uncorrected. High resolution mass spectra (HRMS) were
recorded using a Q-TOF spectrometer via electrospray ionization (ESI). Crystallographic
data were recorded on a diffractometer using graphite-monochromated Mo K radiation
(= 0.71073 Å). Structures were solved using an interactive algorithm,31a subsequently
completed by a difference Fourier map, and refined using the program SHELXL2014,31b
and the graphic material was prepared using the Mercury 3.8 sofware.31c Non-
commercially available NH-3-aminopyrazoles 2 were prepared using known procedures.32
The non-commercially available 2-hydrazinylpyridine 7 was prepared by a method
developed in our laboratory.19a The electronic absorption and fluorescence emission spectra
were recorded in quartz cuvettes having a path length of 1 cm. UV-vis and fluorescence
measurements were performed at room temperature (20 ºC). For fluorescence
measurements, both the excitation and emission slit widths were 5 nm.
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Synthesis and Characterization
General procedure for the synthesis of -enaminones 1a–g. A mixture of the corresponding
methyl ketone (8.0 mmol) and N,N-dimethylformamide dimethyl acetal (DMF–DMA, 8.8
mmol) was subjected to microwave irradiation under solvent-free conditions at 150 °C (160
W, monitored by an IR temperature sensor) and maintained at this temperature for 15 min
in a sealed tube containing a Teflon-coated magnetic stir bar. The resulting reaction mixture
was cooled to 55 °C by airflow and the excess of DMF–DMA was removed under reduced
pressure. The resulting clean crude product was used without further purification following
the method developed in our laboratory.18 However, herein we report the synthesis and
characterization of β-enaminones 1c, 1e and 1f, which were obtained by this new method.18
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(E)-1-(4-Bromophenyl)-3-(dimethylamino)prop-2-en-1-one 1c. By following the general
procedure at 160 °C and maintaining that temperature for 15 min in the reaction with 4-
bromoacetophenone (1642 mg, 8.25 mmol) and DMF–DMA (1661 L, 12.5 mmol), the -
enaminone 1c was obtained as a yellow solid (2034 mg, 97%). Mp 81–82 °C (amorphous)
(Lit.33 82–83 °C). 1H NMR (400 MHz, CDCl3):  = 2.92 (s, 3H), 3.14 (s, 3H), 5.64 (d, J =
12.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.75–7.81 (m, 3H) ppm. 13C{1H} NMR (101 MHz,
CDCl3):  = 37.2 (CH3), 45.1 (CH3), 91.7 (CH), 125.4 (C), 129.1 (CH), 131.3 (CH), 139.3
(C), 154.5 (CH), 187.2 (C) ppm. HRMS (ESI+): calcd. for C11H13BrNO+ 254.0181 [M +
H]+; found 254.0189. These NMR data matched previously reported data.33
(E)-3-(Dimethylamino)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 1e. By following the
general procedure at 160 °C and maintaining that temperature for 15 min in the reaction
with 3,4,5-trimethoxyacetophenone (1713 mg, 8.15 mmol) and DMF–DMA (1621 L, 12.2
mmol), the -enaminone 1e was obtained as a yellow solid (2076 mg, 96%). Mp 127–129
°C (amorphous) (Lit.34 128–130 °C). 1H NMR (400 MHz, CDCl3):  = 2.94 (s, 3H), 3.14 (s,
3H), 3.87 (s, 3H), 3.91 (s, 6H), 5.64 (d, J = 12.2 Hz, 1H), 7.15 (s, 2H), 7.80 (d, J = 12.3
13
Hz, 1H) ppm. C{1H} NMR (101 MHz, CDCl3):  = 37.2 (CH3), 45.0 (CH3), 56.2 (CH3),
60.8 (CH3), 91.6 (CH), 104.8 (CH), 136.0 (C), 140.5 (C), 152.7 (C), 154.2 (CH), 187.6 (C)
+
ppm. HRMS (ESI+): calcd. for C14H20NO4 266.1392 [M + H]+; found 266.1401. These
NMR data matched previously reported data.34
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(E)-3-(Dimethylamino)-1-(thiophen-2-yl)prop-2-en-1-one 1g. By following the general
procedure at 160 °C and maintaining that temperature for 15 min in the reaction with 4-
acetylthiophene (873 L, 8.08 mmol) and DMF–DMA (1621 L, 12.2 mmol), the -
enaminone 1g was obtained as a yellow solid (1435 mg, 98%). Mp 100 °C (amorphous)
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(Lit.35 101 °C). H NMR (400 MHz, CDCl3):  = 2.91 (s, 3H), 3.12 (s, 3H), 5.62 (d, J =
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12.3 Hz, 1H), 7.07 (t, J = 4.4 Hz, 1H), 7.46 (d, J = 4.7 Hz, 1H), 7.62 (d, J = 4.2 Hz, 1H),
13
7.77 (d, J = 12.2 Hz, 1H) ppm. C{1H} NMR (101 MHz, CDCl3):  = 37.2 (CH3), 44.9
(CH3), 91.5 (CH), 127.5 (CH), 128.3 (CH), 130.2 (CH),147.3 (C), 153.5 (CH), 180.7 (C)
ppm. HRMS (ESI+): calcd. for C9H12NOS+ 182.0640 [M + H]+; found 182.0648. These
NMR data matched previously reported data.35
General procedure for the synthesis of 7-aryl-2-methylpyrazolo[1,5-a]pyrimidines 3a, 3c-g
and 3i. A mixture of -enaminone 1 (0.50 mmol) and NH-3-aminopyrazole (2, 0.50 mmol)
was subjected to microwave irradiation under solvent-free conditions at 180 °C (190 W,
monitored by an IR temperature sensor) and maintained at this temperature for 2 min in a
sealed tube containing a Teflon-coated magnetic stirring bar. The resulting reaction mixture
was cooled to 55 °C by airflow and the precipitated product formed upon the addition of
cold EtOH/H2O (1:1, 1.0 mL) was filtered off, washed and dried to give the pure product 3.
The previously reported compounds by us 3a, 3d and 3f, the novel derivatives 3e and 3i,
and compounds made by our method 3c and 3g are representative compounds in this work.
These seven pyrazolopyrimidines were isolated and characterized following the method
developed in our laboratory.18
7-(4-Bromophenyl)-2-methylpyrazolo[1,5-a]pyrimidine 3c. The general procedure at 180
°C and maintaining that temperature for 2 min in the reaction with 1c (140 mg, 0.55 mmol)
and 2a (54 mg, 0.56 mmol) afforded product 3c as a yellow solid (152 mg, 96%). Mp 149–
1
150 °C (amorphous) (Lit.16d 148–150 °C). H NMR (400 MHz, CDCl3):  = 2.52 (s, 3H),
6.57 (s, 1H), 6.79 (d, J = 4.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H),
8.44 (d, J = 4.5 Hz, 1H) ppm.13C{1H} NMR (101 MHz, CDCl3):  =14.7 (CH3), 96.5 (CH),
106.2 (CH), 125.4 (C), 130.0 (C), 130.7 (CH), 131.9 (CH), 144.9 (C), 148.5 (CH), 150.6
+
(C), 155.1 (C) ppm. HRMS (ESI+): calcd. for C13H11BrN3 288.0136 [M + H]+; found
288.0140.
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2-Methyl-7-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidine 3e. The general procedure
at 180 °C and maintaining that temperature for 2 min in the reaction with 1e (141 mg, 0.53
mmol) and 2a (54 mg, 0.56 mmol) afforded product 3e as a yellow solid (155 mg, 98%).
Mp 124–126 °C (amorphous). 1H NMR (400 MHz, CDCl3):  = 2.54 (s, 3H), 3.94 (s, 9H),
6.57 (s, 1H), 6.80 (d, J = 4.5 Hz, 1H), 7.33 (s, 2H), 8.44 (d, J = 4.5 Hz, 1H) ppm.13C{1H}
NMR (101 MHz, CDCl3):  = 14.8 (CH3), 56.2 (CH3), 60.8 (CH3), 96.2 (CH), 106.2 (CH),
106.7 (CH), 126.2 (C), 140.2 (C), 145.8 (C), 148.5 (CH), 150.7 (C), 153.1 (C), 154.9 (C)
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ppm. HRMS (ESI+): calcd. for C16H18N3O3 300.1348 [M + H]+; found 300.1351.
2-Methyl-7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine 3g. The general procedure at 180 °C
and maintaining that temperature for 2 min in the reaction with 1g (92 mg, 0.51 mmol) and
2a (51 mg, 0.53 mmol) afforded product 3g as a yellow solid (101 mg, 92%). Mp 120–121
1
°C (amorphous) (Lit.16d 106–108 °C). H NMR (400 MHz, CDCl3):  = 2.61 (s, 3H), 6.56
(s, 1H), 7.14 (d, J = 4.6 Hz, 1H), 7.26 (t, J = 4.5 Hz, 1H), 7.71 (d, J = 5.0 Hz, 1H), 8.34 (d,
J = 3.8 Hz, 1H), 8.42 (d, J = 4.6 Hz, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3):  =14.8
(CH3), 96.1 (CH), 102.9 (CH), 127.5 (CH), 131.2 (CH), 131.5 (C), 132.0 (CH), 139.2 (C),
147.8 (CH), 150.5 (C), 154.8 (C) ppm. HRMS (ESI+): calcd. for C11H10N3S+ 216.0595 [M
+ H]+; found 216.0593.
2-(4-Bromophenyl)-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine 3i. The general
procedure at 180 °C and maintaining that temperature for 2 min in the reaction with 1d
(105 mg, 0.51 mmol) and 2c (126 mg, 0.53 mmol) afforded product 3i as a yellow solid
1
(184 mg, 95%). Mp 165–166 °C (amorphous). H NMR (400 MHz, CDCl3):  = 3.92 (s,
3H), 6.88 (d, J = 4.3 Hz, 1H), 7.01 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.3 Hz,
2H), 7.88 (d, J = 8.3 Hz, 2H), 8.19 (d, J = 8.7 Hz, 2H), 8.46 (d, J = 4.4 Hz, 1H) ppm.
13C{1H} NMR (101 MHz, CDCl3):  = 55.5 (CH3), 93.4 (CH), 106.5 (CH), 114.0 (CH),
123.0 (C), 128.1 (CH), 131.2 (CH), 131.5 (C), 131.8 (CH), 146.1 (C), 149.1 (CH), 151.3
(C), 154.5 (C), 161.9 (C) ppm. HRMS (ESI+): calcd. for C19H15BrN3O+ 380.0398 [M +
H]+; found 380.0405.
General procedure for the synthesis of pyrazolo[1,5-a]pyrimidine-3-carbaldehydes 4a–j. A
mixture of -enaminone 1 (0.50 mmol) and NH-3-aminopyrazole (2, 0.50 mmol) was
subjected to microwave irradiation under solvent-free conditions at 180 °C (190 W,
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monitored by an IR temperature sensor) and maintained at this temperature for 2 min in a
sealed tube containing a Teflon-coated magnetic stirring bar. Later cooling to room
temperature, 300 L of anhydrous N,N-dimethylformamide cooled to 0 °C was added into
the tube and subsequently, the formylating agent solution was added dropwise with stirring
at 0 °C―this reagent was prepared by adding phosphoryl chloride (2.0 mmol, 187 L) to
310 L of cool anhydrous N,N-dimethylformamide (4.0 mmol) over a period of 10 min,
maintaining the temperature at 0°C for an additional 30 min. After stirring the formylation
for 15 minutes at 0 ° C, the reaction mixture was warmed to room temperature and stirred
for additional 15 min. Then, the solution was irradiated with microwaves at 80 °C (90 W,
monitored by an IR temperature sensor) and maintained at this temperature for 10 min in a
sealed tube containing a Teflon-coated magnetic stirring bar and the resulting reaction
mixture was cooled to 55 °C by airflow. The pH of the solution was maintained at 7 by
adding an aqueous solution of sodium bicarbonate (20%), and the reaction mixture was
vigorously stirred at room temperature for 30 min. The resulting precipitated was filtered,
washed with cold water (2 x 5.0 mL), and purified by flash chromatography on silica gel
(eluent: CH2Cl2) to afford the corresponding heteroaryl aldehydes 4.
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2-Methyl-7-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4a. By following the general
procedure in the reaction between -enaminone 1a (88 mg, 0.50 mmol), NH-3-
aminopyrazole 2a (49 mg, 0.51 mmol), N,N-dimethylformamide (310 L, 4.00 mmol) and
phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4a as a yellow solid (108
1
mg, 91%). Mp 167–168 °C (amorphous). H NMR (400 MHz, CDCl3):  = 2.74 (s, 3H),
7.10 (d, J = 4.5 Hz, 1H), 7.58–7.61 (m, 3H), 8.02–8.06 (m, 2H), 8.71 (d, J = 4.5 Hz, 1H),
13
10.43 (s, 1H) ppm. C{1H} NMR (101 MHz, CDCl3):  = 14.5 (CH3), 108.8 (C), 109.4
(CH), 128.8 (CH), 129.4 (CH), 129.9 (C), 131.7 (CH), 147.4 (C), 152.0 (C), 152.2 (CH),
157.3 (C), 183.9 (CH) ppm. HRMS (ESI+): calcd. for C14H12N3O+ 238.0980 [M + H]+;
found 238.0981.
7-(4-Chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4b. By following
the general procedure in the reaction between -enaminone 1b (111 mg, 0.53 mmol), NH-
3-aminopyrazole 2a (53 mg, 0.55 mmol), N,N-dimethylformamide (310 L, 4.00 mmol)
and phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4b as a yellow solid
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(128 mg, 89%). Mp 212–213 °C (amorphous). H NMR (400 MHz, CDCl3):  = 2.74 (s,
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3H), 7.07 (d, J = 4.5 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 8.70 (d, J
= 4.6 Hz, 1H), 10.4 (s, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3):  = 14.5 (CH3), 108.9
(C), 109.2 (CH), 128.3 (C), 129.1 (CH), 130.8 (CH), 138.0 (C), 146.2 (C), 152.0 (C), 152.1
(CH), 157.4 (C), 183.9 (CH) ppm. HRMS (ESI+): calcd. for C14H11ClN3O+ 272.0591 [M +
H]+; found 272.0594.
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7-(4-Bromophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4c. By following
the general procedure in the reaction between -enaminone 1c (124 mg, 0.49 mmol), NH-3-
aminopyrazole 2a (49 mg, 0.51 mmol), N,N-dimethylformamide (310 L, 4.00 mmol) and
phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4c as a yellow solid (125 mg,
1
81%). Mp 221–222 °C (amorphous). H NMR (400 MHz, CDCl3):  = 2.74 (s, 3H), 7.08
(d, J = 4.5 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 8.72 (d, J = 4.6 Hz,
1H), 10.43 (s, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 14.6 (CH3), 108.9 (C),
109.2 (CH), 126.5 (C), 128.7 (C), 130.9 (CH), 132.1 (CH), 146.3 (C), 152.0 (C), 152.2
(CH), 157.4 (C), 183.9 (CH) ppm. HRMS (ESI+): calcd. for C14H11BrN3O+ 316.0085 [M +
H]+; found 316.0089.
7-(4-Methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4d. By following
the general procedure in the reaction between -enaminone 1d (103 mg, 0.50 mmol), NH-
3-aminopyrazole 2a (51 mg, 0.52 mmol), N,N-dimethylformamide (310 L, 4.00 mmol)
and phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4d as a white solid (104
1
mg, 78%). Mp 181–182 °C (amorphous). H NMR (400 MHz, CDCl3):  = 2.75 (s, 3H),
3.91 (s, 3H), 7.07–7.11 (m, 3H), 8.09 (d, J = 9.0 Hz, 2H), 8.66 (d, J = 4.6 Hz, 1H), 10.42 (s,
13
1H) ppm. C{1H} NMR (101 MHz, CDCl3):  = 14.6 (CH3), 55.5 (CH3), 108.6 (CH),
108.6 (C), 114.3 (CH), 122.0 (C), 131.3 (CH), 147.2 (C), 152.0 (CH), 152.2 (C), 157.1 (C),
+
162.4 (C), 183.9 (CH) ppm. HRMS (ESI+): calcd. for C15H14N3O2 268.1086 [M + H]+;
found 268.1080.
2-Methyl-7-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4e. By
following the general procedure in the reaction between -enaminone 1e (143 mg, 0.54
mmol), NH-3-aminopyrazole 2a (55 mg, 0.57 mmol), N,N-dimethylformamide (310 L,
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4.00 mmol) and phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4e as a
yellow solid (161 mg, 91%). Mp 216–217 °C (amorphous). 1H NMR (400 MHz, CDCl3): 
= 2.75 (s, 3H), 3.94 (s, 6H), 3.95 (s, 3H), 7.10 (d, J = 4.5 Hz, 1H), 7.30 (s, 2H), 8.70 (d, J =
4.5 Hz, 1H), 10.42 (s, 1H) ppm.13C{1H} NMR (101 MHz, CDCl3):  = 14.7 (CH3), 56.4
(CH3), 60.9 (CH3), 107.0 (CH), 108.8 (C), 109.3 (CH), 124.8 (C), 140.9 (C), 147.2 (C),
152.1 (C), 152.2 (CH), 153.3 (C), 157.3 (C), 184.0 (CH) ppm. HRMS (ESI+): calcd. for
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C17H18N3O4 328.1297 [M + H]+; found 328.1297.
2-Methyl-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4f. By following the
general procedure in the reaction between -enaminone 1f (88 mg, 0.50 mmol), NH-3-
aminopyrazole 2a (50 mg, 0.52 mmol), N,N-dimethylformamide (310 L, 4.00 mmol) and
phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4f as a yellow solid (86 mg,
1
72%). Mp 233–234 °C (amorphous). H NMR (400 MHz, CDCl3):  = 2.75 (s, 3H), 7.16
(d, J = 4.4 Hz, 1H), 7.94 (d, J = 4.7 Hz, 2H), 8.78 (d, J = 4.4 Hz, 1H), 8.89 (d, J = 4.7 Hz,
2H), 10.44 (s, 1H) ppm.13C{1H} NMR (101 MHz, CDCl3):  =14.5 (CH3), 109.1 (C), 109.5
(CH), 123.1 (CH), 137.4 (C), 144.5 (C), 150.6 (CH), 151.8 (C), 152.2 (CH), 157.7 (C),
183.9 (CH) ppm. HRMS (ESI+): calcd. for C13H11N4O+ 239.0933 [M + H]+; found
239.0940.
2-Methyl-7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4g. By following the
general procedure in the reaction between -enaminone 1g (100 mg, 0.55 mmol), NH-3-
aminopyrazole 2a (55 mg, 0.57 mmol), N,N-dimethylformamide (310 L, 4.00 mmol) and
phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4g as a yellow solid (120
1
mg, 90%). Mp 196–197 °C (amorphous). H NMR (400 MHz, CDCl3):  = 2.81 (s, 3H),
7.30 (t, J = 5.0 Hz, 1H), 7.38 (d, J = 4.7 Hz, 1H), 7.80 (d, J = 5.0 Hz, 1H), 8.38 (d, J = 3.5
Hz, 1H), 8.64 (d, J = 5.0 Hz, 1H), 10.41 (s, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3): 
= 14.6 (CH3), 105.7 (CH), 108.5 (C), 128.0 (CH), 130.4 (C), 132.6 (CH), 133.9 (CH),
140.6 (C), 151.4 (CH), 151.8 (C), 157.1 (C), 184.0 (CH) ppm. HRMS (ESI+): calcd. for
C12H10N3OS+ 244.0545 [M + H]+; found 244.0535.
2-(4-Chlorophenyl)-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4h. By
following the general procedure in the reaction between -enaminone 1d (98 mg, 0.48
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mmol), NH-3-aminopyrazole 2b (97 mg, 0.50 mmol), N,N-dimethylformamide (310 L,
4.00 mmol) and phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4h as a
yellow solid (148 mg, 85%). Mp 227–228 °C (amorphous). 1H NMR (400 MHz, CDCl3): 
= 3.93 (s, 3H), 7.11 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 4.6 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H),
8.08 (d, J = 8.5 Hz, 2H), 8.16 (d, J = 8.8 Hz, 2H), 8.75 (d, J = 4.6 Hz, 1H), 10.46 (s, 1H)
ppm. 13C{1H} NMR (101 MHz, CDCl3):  = 55.5 (CH3), 107.5 (C), 109.4 (CH), 114.3
(CH), 121.7 (C), 128.6 (CH), 129.9 (C), 130.9 (CH), 131.5 (CH), 136.1 (C), 147.3 (C),
152.5 (CH), 152.9 (C), 156.4 (C), 162.4 (C), 183.5 (CH) ppm. HRMS (ESI+): calcd. for
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C20H15ClN3O2 364.0853 [M + H]+; found 364.0861.
2-(4-Bromophenyl)-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4i. By
following the general procedure in the reaction between -enaminone 1d (113 mg, 0.55
mmol), NH-3-aminopyrazole 2c (138 mg, 0.58 mmol), N,N-dimethylformamide (310 L,
4.00 mmol) and phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4i as a
yellow solid (195 mg, 87%). Mp 230–231 °C (amorphous). 1H NMR (400 MHz, CDCl3): 
= 3.93 (s, 3H), 7.11 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 4.6 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H),
8.01 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 8.9 Hz, 2H), 8.76 (d, J = 4.5 Hz, 1H), 10.46 (s, 1H)
ppm. 13C{1H} NMR (101 MHz, CDCl3):  = 55.5 (CH3), 107.5 (C), 109.4 (CH), 114.3
(CH), 121.7 (C), 124.5 (C), 130.3 (C), 131.2 (CH), 131.5 (CH), 131.6 (CH), 147.3 (C),
152.5 (CH), 152.9 (C), 156.5 (C), 162.4 (C), 183.5 (CH) ppm. HRMS (ESI+): calcd. for
+
C20H15BrN3O2 408.0348 [M + H]+; found 408.0350.
2,7-bis(4-Methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4j. By following the
general procedure in the reaction between -enaminone 1d (103 mg, 0.50 mmol), NH-3-
aminopyrazole 2d (98 mg, 0.52 mmol), N,N-dimethylformamide (310 L, 4.00 mmol) and
phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4j as a yellow solid (149 mg,
83%). Mp 171–172 °C (amorphous). 1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3H), 3.90 (s,
3H), 7.01 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 4.4 Hz, 1H), 8.07 (d, J
= 8.9 Hz, 2H), 8.16 (d, J = 8.9 Hz, 2H), 8.70 (d, J = 3.7 Hz, 1H), 10.43 (s, 1H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 55.3 (CH3), 55.4 (CH3), 107.2 (C), 109.1 (CH),
113.8 (CH), 114.1 (CH), 121.8 (C), 123.7 (C), 131.1 (CH), 131.5 (CH), 147.0 (C), 152.1
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(CH), 152.6 (C), 157.6 (C), 161.0 (C), 162.3 (C), 183.7 (CH) ppm. HRMS (ESI+): calcd.
+
for C21H18N3O3 360.1348 [M + H]+; found 360.1351.
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2-(4-Methoxyphenyl)-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4k. By
following the general procedure in the reaction between -enaminone 1f (92 mg, 0.52
mmol), NH-3-aminopyrazole 2d (104 mg, 0.55 mmol), N,N-dimethylformamide (310 L,
4.00 mmol) and phosphoryl chloride (187 L, 2.00 mmol) afforded compound 4k as a
yellow solid (127 mg, 74%). Mp 181–182 °C (amorphous). 1H NMR (400 MHz, CDCl3): δ
= 3.88 (s, 3H), 7.03 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 4.3 Hz, 1H), 8.05 (d, J = 8.8 Hz, 2H),
8.12 (d, J = 4.9 Hz, 2H), 8.86 (d, J = 4.4 Hz, 1H), 8.92 (d, J = 5.0 Hz, 2H), 10.48 (s, 1H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 55.4 (CH3), 107.9 (C), 110.2 (CH), 114.0
(CH), 123.2 (C), 123.7 (CH), 131.2 (CH), 143.8 (C), 149.4 (CH), 149.5 (C), 152.2 (CH),
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152.4 (C), 158.2 (C), 161.4 (C), 183.7 (CH) ppm. HRMS (ESI+): calcd. for C19H15N4O2
331.1195 [M + H]+; found 331.1199.
General procedure for the synthesis of dicyanovinyl derivatives 6a–b. A solution of
pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4 (0.50 mmol), malononitrile (5, 0.50 mmol)
and piperidine (0.10 mmol) in 2.0 mL of ethanol absolute was irradiated with microwaves
at 80 °C (90 W, monitored by an IR temperature sensor) and maintained at this temperature
for 10 min in a sealed tube containing a Teflon-coated magnetic stirring bar and the
resulting reaction mixture was cooled to 55 °C by airflow, concentrated under reduced
pressure, and the residue was directly purified by flash chromatography on silica gel
(eluent: CH2Cl2) to afford the pure product 6.
2-((7-(4-Chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methylene)-malononitrile
6a. By following the general procedure at 80 °C and by maintaining that temperature for 10
min in the reaction with pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4b (135 mg, 0.50
mmol), malononitrile 5 (34 mg, 0.52 mmol) and piperidine (10 L, 0.10 mmol) in 2.0 mL
of ethanol absolute afforded compound 6a as a yellow solid (153 mg, 96%). Mp 237–238
1
°C (amorphous). H NMR (400 MHz, CDCl3): δ = 2.67 (s, 3H), 7.14 (d, J = 4.2 Hz, 1H),
7.59 (d, J = 8.2 Hz, 2H), 7.95 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 8.78 (d, J = 4.2 Hz, 1H)
13
ppm. C{1H} NMR (101 MHz, CDCl3):  = 15.0 (CH3), 78.6 (C), 104.5 (C), 109.9 (CH),
113.9 (C) 115.5 (C), 127.9 (C), 129.3 (CH), 130.9 (CH), 138.5 (C), 146.7 (C), 148.6 (CH),
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+
149.5 (C), 152.0 (CH), 156.9 (C) ppm. HRMS (ESI+): calcd. for C17H11ClN5 320.0703 [M
+ H]+; found 320.0700.
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2-((2,7-bis(4-Methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-malononitrile 6b.
By following the general procedure at 80 °C and by maintaining that temperature for 10
min in the reaction between pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4j (179 mg, 0.50
mmol), malononitrile 5 (34 mg, 0.52 mmol) and piperidine (10 L, 0.10 mmol) in 2.0 mL
of ethanol absolute afforded compound 6b as a yellow solid (200 mg, 98%). Mp 204–205
°C (amorphous). 1H NMR (400 MHz, CDCl3):  = 3.90 (s, 3H), 3.92 (s, 3H), 7.05–7.11 (m,
4H), 7.19 (d, J = 4.7 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.85 (s, 1H), 8.15 (d, J = 8.9 Hz,
2H), 8.78 (d, J = 4.6 Hz, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3):  = 55.4 (CH3), 55.5
(CH3), 80.2 (C), 102.5 (C), 109.4 (CH), 113.7 (C), 114.3 (CH), 114.7 (CH), 115.6 (C),
121.8 (C), 123.1 (C), 130.9 (CH), 131.6 (CH), 147.7 (C), 149.1 (C), 149.8 (CH), 151.4
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(CH), 158.1 (C), 161.4 (C), 162.5 (C) ppm. HRMS (ESI+): calcd. for C24H18N5O2
408.1460 [M + H]+; found 408.1463.
General procedure for the synthesis of 2-pyridilhydrazone derivatives 8a–b. A solution of
pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4 (0.50 mmol) and 2-hydrazinylpyridine (7,
0.50 mmol) in 2.0 mL of ethanol absolute was irradiated with microwaves at 80 °C (90 W,
monitored by an IR temperature sensor) and maintained at this temperature for 10 min in a
sealed tube containing a Teflon-coated magnetic stirring bar and the resulting reaction
mixture was cooled to 55 °C by airflow and the precipitated product formed was filtered
off, washed with cold EtOH (2 x 1.0 mL), and dried to afford the pure product 8.
(E)-7-(4-Chlorophenyl)-2-methyl-3-((2-(pyridin-2-yl)hydrazono)methyl)pyrazolo[1,5-
a]pyrimidine 8a. Following the general procedure, the reaction between pyrazolo[1,5-
a]pyrimidine-3-carbaldehyde 4b (130 mg, 0.48 mmol) and 2-hydrazinylpyridine 7 (56 mg,
0.51 mmol) in 2.0 mL of ethanol absolute afforded compound 8a as an orange solid (165
mg, 95%). Mp 240–241 °C (amorphous). 1H NMR (400 MHz, DMSO-d6):  = 2.69 (s, 3H),
6.71 (t, J = 5.9 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 7.61–7.69 (m,
3H), 8.08 (d, J = 4.1 Hz, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.47 (s, 1H), 8.59 (d, J = 4.0 Hz,
1H), 10.7 (br s, 1H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6):  = 15.4 (CH3), 104.2 (C),
105.8 (CH), 107.9 (CH), 114.1 (CH), 128.5 (CH), 129.1 (C), 131.1 (CH), 132.2 (CH),
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135.8 (C), 137.8 (CH), 144.1 (C), 147.5 (CH), 147.6 (C), 149.8 (CH), 151.6 (C), 157.1 (C)
+
ppm. HRMS (ESI+): calcd. for C19H16ClN6 363.1125 [M + H]+; found 363.1134.
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(E)-2,7-bis(4-Methoxyphenyl)-3-((2-(pyridin-2-yl)hydrazono)methyl)pyrazolo[1,5-
a]pyrimidine 8b. Following the general procedure, the reaction between pyrazolo[1,5-
a]pyrimidine-3-carbaldehyde 4j (180 mg, 0.50 mmol) and 2-hydrazinylpyridine 7 (56 mg,
0.51 mmol) in 2.0 mL of ethanol absolute afforded compound 8b as an orange solid (209
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mg, 93%). Mp 223–224 °C (amorphous). H NMR (400 MHz, CDCl3):  = 3.85 (s, 3H),
3.87 (s, 3H), 6.71 (t, J = 3.4 Hz, 1H), 7.00–7.17 (m, 5H), 7.31 (t, J = 4.9 Hz, 1H), 7.61 (t, J
= 3.0 Hz, 1H), 7.99–8.07 (m, 3H), 8.26 (d, J = 7.8 Hz, 2H), 8.53 (s, 1H), 8.63 (d, J = 3.5
13
Hz, 1H), 10.83 (br s, 1H) ppm. C{1H} NMR (101 MHz, CDCl3):  = 55.2 (CH3), 55.4
(CH3), 102.8 (C), 106.3 (CH), 107.8 (CH), 113.4 (CH), 113.9 (CH), 114.1 (CH), 122.1 (C),
125.1 (C), 130.7 (CH), 131.2 (CH), 132.7 (CH), 138.0 (CH), 145.1 (C), 146.8 (CH), 148.6
(C), 149.9 (CH), 152.6 (C), 156.7 (C), 159.8 (C), 161.5 (C) ppm. HRMS (ESI+): calcd. for
C26H23N6O2 451.1882 [M + H]+; found 451.1885.
+
General procedure for the synthesis of chalcones 10a–b. A mixture of pyrazolo[1,5-
a]pyrimidine-3-carbaldehyde 4 (0.50 mmol), p-chloroacetophenone 9 (0.55 mmol) and
20% aqueous NaOH (0.20 mL) in MeOH (5.0 mL) was stirred at room temperature for 12
h. After the reaction was complete (monitored by TLC), the volume of the reaction mixture
was reduced to 1.0 mL under reduced pressure, and water (5.0 mL) was added. The
aqueous solution was extracted with ethyl acetate (2 x 5.0 mL), the combined organic
extracts were dried over anhydrous Na2SO4, and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography on silica gel employing
CH2Cl2/MeOH (40:1, v/v) as eluent to afford the corresponding chalcone 10.
(E)-1-(4-Chlorophenyl)-3-(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-3-yl)prop-2-en-1-
one 10a. Following the general procedure, the reaction between pyrazolo[1,5-a]pyrimidine-
3-carbaldehyde 4a (118 mg, 0.50 mmol), p-chloroacetophenone 9 (71 µL, 0.55 mmol) and
20% aqueous NaOH (200 µL) in 5.0 mL of MeOH afforded compound 10a as a yellow
solid (174 mg, 93%). Mp 201–203 °C (amorphous). 1H NMR (400 MHz, CDCl3):  = 2.65
(s, 3H), 7.00 (d, J = 4.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.58–7.62 (m, 3H), 8.04–8.11
(m, 5H), 8.24 (d, J = 15.3 Hz, 1H), 8.67 (d, J = 4.3 Hz, 1H) ppm. 13C{1H} NMR (101
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MHz, CDCl3):  = 13.3 (CH3), 105.4 (C), 108.4 (CH), 119.0 (CH), 128.7 (CH), 128.8
(CH), 129.4 (CH), 129.9 (CH), 130.4 (C), 131.4 (CH), 134.5 (CH), 137.2 (C), 138.6 (C),
147.0 (C), 148.6 (C), 150.4 (CH), 156.7 (C), 189.3 (C) ppm. HRMS (ESI+): calcd. for
C22H17ClN3O+ 374.1060 [M + H]+; found 374.1057.
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(E)-1-(4-Chlorophenyl)-3-(7-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-3-
yl)prop-2-en-1-one 10b. Following the general procedure, the reaction between
pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4b (133 mg, 0.49 mmol), p-chloroacetophenone
9 (71 µL, 0.55 mmol) and 20% aqueous NaOH (200 µL) in 5.0 mL of MeOH afforded
1
compound 10b as a yellow solid (180 mg, 90%). Mp 259–260 °C (amorphous). H NMR
(400 MHz, CDCl3):  = 2.66 (s, 3H), 6.99 (d, J = 4.3 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H),
7.58 (d, J = 8.4 Hz, 2H), 8.02–8.09 (m, 5H), 8.24 (d, J = 15.3 Hz, 1H), 8.68 (d, J = 4.4 Hz,
1H) ppm. 13C{1H} NMR (101 MHz, CDCl3):  = 13.3 (CH3), 105.5 (C), 108.2 (CH), 119.4
(CH), 128.7 (CH), 129.1 (CH), 129.9 (CH), 130.8 (CH), 134.4 (CH), 137.1 (C), 137.8 (C),
144.2 (C), 145.8 (C), 148.6 (C), 150.4 (CH), 153.6 (C), 156.8 (C), 189.3 (C) ppm. HRMS
(ESI+): calcd. for C22H16Cl2N3O+ 408.0670 [M + H]+; found 408.0675.
General procedure for oxidation of aldehyde to carboxylic acid 11a–b. A mixture of
pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 4 (0.50 mmol) and Oxone (0.50 mmol) in 3.0
mL of anhydrous DMF was stirred at room temperature for 12 h. Then, 1.0 mL of 1 N HCl
was added to dissolve the salts and the reaction mixture was stirred at room temperature for
30 min. The desired product was extracted with ethyl acetate (2 x 5.0 mL), the combined
organic extracts were washed with brine (1 x 5.0 mL), dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure. The crude product was purified by flash
chromatography on silica gel employing CH2Cl2/MeOH (30:1, v/v) as eluent to afford the
corresponding carboxylic acid 11.
2-Methyl-7-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 11a. Following the general
procedure, the reaction between heterocyclic aldehyde 4a (116 mg, 0.49 mmol) and oxone
(154 mg, 0.50 mmol) in 3.0 mL of anhydrous DMF afforded compound 11a as an orange
solid (105 mg, 85%). Mp 173–174 °C (amorphous). 1H NMR (400 MHz, CDCl3):  = 2.54
(s, 3H), 6.65 (d, J = 4.4 Hz, 1H), 7.54–7.56 (m, 3H), 8.03–8.06 (m, 2H), 8.27 (d, J = 4.4
13
Hz, 1H), 9.31 (br s, 1H) ppm. C{1H} NMR (101 MHz, CDCl3):  = 11.3 (CH3), 105.2
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(CH), 128.2 (C), 128.6 (CH), 129.1 (CH), 131.0 (C), 131.1 (CH), 136.9 (C), 143.7 (C),
+
145.7 (CH), 145.7 (C), 146.5 (C) ppm. HRMS (ESI+): calcd. for C14H12N3O2 254.0930 [M
+ H]+; found 254.0925.
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7-(4-Chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 11b. Following
the general procedure, the reaction between heterocyclic aldehyde 4b (130 mg, 0.48 mmol)
and oxone (154 mg, 0.50 mmol) in 3.0 mL of anhydrous DMF afforded compound 11b as a
yellow solid (110 mg, 80%). Mp 204–205 °C (amorphous). 1H NMR (400 MHz, CDCl3): 
= 2.44 (s, 3H), 6.83 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H),
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8.45–8.49 (m, 2H) ppm. C{1H} NMR (101 MHz, CDCl3):  = 11.7 (CH3), 107.0 (CH),
120.8 (C), 128.5 (C), 129.0 (CH), 130.6 (CH), 137.4 (C), 140.5 (C), 145.1 (C), 146.5 (C),
+
148.9 (CH), 158.7 (C) ppm. HRMS (ESI+): calcd. for C14H11ClN3O2 288.0540 [M + H]+;
found 288.0536.
Photophysical properties
UV-vis absorption and fluorescence studies. The solvochromic studies of the compounds
3a and of 3d-f was carried out with 10 µM solutions in toluene (PhMe), dichloromethane
(DCM), acetonitrile (ACN), dimethylsulfoxide (DMSO), and ethanol (EtOH). Fluorescence
response in photographs was excitation at 365 nm using a UV lamp. The relative quantum
yields were obtained by using anthracene (ϕF = 0.28 in ethanol at 340 nm)30 as reference
and calculated according to the following equation.19b-c,30,36
where x and st indicate the sample and standard solution, respectively, ϕ is the quantum
yield, F is the integrated area of the emission, A is the absorbance at the excitation
wavelength, and η is the index of refraction of the solvents.
AUTOR INFORMATION
Corresponding Author
*E-mail: jportill@uniandes.edu.co
ORCID
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Jaime Portilla: 0000-0002-8206-7481
Juan-Carlos Castillo: 0000-0002-6060-2578
Notes
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The authors declare no competing financial interest.
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ASSOCIATED CONTENT
Supporting Information
CIF for compound 4a and copies of H and C{1H} NMR spectra for all compounds and
spectroscopic properties. The Supporting Information is available free of charge on the
ACS Publications website at DOI:
1
13
ACKNOWLEDGEMENTS
We thank the Department of Chemistry and Vicerrectoría de Investigaciones at Universidad
de los Andes for financial support. Our gratitude to Colombian Institute for Science and
Research (COLCIENCIAS) for the financial support and for the postdoctoral fellowships
conferred to Dr. Alexis Tigreros (Con. 784 of 2017). We also acknowledge B.Sc. Hernán-
Alejandro Rosero for preliminary experiments, Edwin Guevara for acquiring the mass
spectra, and Dr. Mario Macías (Universidad de los Andes) for his help with the analysis of
the X-ray crystallographic data.
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