Concise and Efficient Access to 5,7-Disubstituted Pyrazolo[1,5-a]pyrimidines by Pd-Catalyzed Sequential Arylation, Alkynylation and SNAr Reaction

Article abstract of DOI:10.1002/ejoc.201701024

A simple and efficient method for synthesis of 5,7-disubstituted pyrazolo[1,5-a]pyrimidines is reported. The synthetic route involved first a one-pot two-step synthesis of 7-substituted pyrazolo[1,5-a]pyrimidin-5-ones from the reaction of 3-aminopyrazole 1 with activated alkynes. These compounds were used as key intermediates to access, with excellent yields, a library of new 5,7-disubstituted pyrazolo[1,5-a]pyrimidines, which are known for their wide range of biological activities, through C–O bond activation with PyBroP (bromotripyrrolidinophosphonium hexafluorophosphate) as an activator reagent.

Full text of DOI:10.1002/ejoc.201701024

A Journal of
Accepted Article
Title: Concise and efficient access to new 5,7-disubstituted
pyrazolo[1,5-a]pyrimidines via Pd-catalyzed sequential arylation,
alkynylation and SNAr reaction
Authors: Mohamed Abarbri, Badr Jismy, Gérald Guillaumet, Hassan
Allouchi, and Mohamed Akssira
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701024
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10.1002/ejoc.201701024
European Journal of Organic Chemistry
FULL PAPER
Concise and efficient access to new 5,7-disubstituted pyrazolo[1,5-
a]pyrimidines via Pd-catalyzed sequential arylation, alkynylation
and SNAr reaction
Badr Jismy,[a], [b] Gérald Guillaumet,[c] Hassan Allouchi,[a] Mohamed Akssira,[b] Mohamed Abarbri*[a]
Abstract: A simple and efficient method for synthesis of 5,7-
disubstituted pyrazolo[1,5-a]pyrimidines is reported. The synthetic
route involved first the one-pot two-step synthesis of 7-substituted
pyrazolo[1,5-a]pyrimidin-5-ones
from
the
reaction
of
3-
aminopyrazole 1 with activated alkynes. These compounds were
utilized as key intermediates to access, with excellent yields, a
library of new 5,7-disubstituted pyrazolo[1,5-a]pyrimidines which are
known for their wide range of biological activities, via C-O bond
activation
using
PyBroP
(Bromotripyrrolidinophosphonium
hexafluorophosphate) as activator reagent.
Introduction
Figure 1. Examples of the drugs with a pyrazolo[1,5-a]pyrimidine scaffold.
Fused nitrogen heterocycles are important scaffolds for the
preparation of compound libraries for medicinal and
pharmaceutical applications.[1] Pyrazolo[1,5-a]pyrimidines are an
important class of such heterocycles possessing diverse
biological properties.[2] For example, they can act as kinase
inhibitors,[3] hepatitis C virus inhibitors,[4] antagonists of serotonin
5-HT6 receptors,[5] PET tumor imaging agents,[6] anticancer
agents,[7] COX-2 inhibitors,[8] antimicrobial[9] and anxiolytic[10]
agents, etc. The structural motif of pyrazolo[1,5-a]pyrimidines
may also be found in a large number of pharmaceutical agents
with a diverse range of physiological activities. For example, the
anxiolytic drug Ocinaplon, and the hypnotic drugs Zaleplon and
Indiplon have this central pattern of pyrazolo[1,5-a]pyrimidines
(Figure 1). Moreover, some pyrazolo[1,5-a]pyrimidine derivatives
have been found to have an antiepileptic effect,[11] and are
antidepressant[12] agents for the treatment of sleep disorders,[13]
and oncolytics.[14]
The condensation of 3(5)-aminopyrazoles with 1,3-dicarbonyl
compound has emerged as the most general approach for the
16]
synthesis of these heterocycles.[2,
Symmetrical β-diketones
react with 3(5)-aminopyrazole to provide only one possible
pyrazolo[1,5-a]pyrimidine. However, when a non-symmetrical
reagent is used, isomeric mixtures are usually obtained.[16a-b,17]
Other 1,3-bis electrophilic compounds, such as alkoxymethylene
β -dicarbonyl derivatives, enaminonitriles and β-enaminones,
have been used to synthesize these fused heterocycles.[18] The
condensation reaction of aminopyrazole with 1,2-allenic
lactones[19] or β-halovinyl aldehydes[20] has also been reported
for the synthesis of pyrazolo[1,5-a]pyrimidines. All of These
strategies have various drawbacks; however, the scope of the
substrate is restricted, synthesis procedures are long and
require several steps, regioselectivity is poor and harsh reaction
conditions are required. Although many methods of synthesis of
substituted pyrazolo[1,5-a]pyrimidines are described in the
literature, to the best of our knowledge there have been few
reports describing the synthesis of 5,7-disubstituted
The interesting biological activities reported for pyrazolo[1,5-
a]pyrimidines have stimulated the development of the chemistry
of this class of compounds. A large number of publications and
patents related to the chemistry or biological activity of
pyrazolo[1,5-a]pyrimidines have therefore been issued.[15]
21]
pyrazolo[1,5-a]pyrimidines.[19,
New, simple and easy
strategies are therefore required to generate a library of new
substituted pyrazolo[1,5-a]pyrimidines that can incorporate a
number of aspects of structural diversity and a variety of
substitution patterns in the target pyrazolo[1,5-a]pyrimidine
library, so that the biological properties of this heterocycle
system can be investigated further. Tautomerizable heterocycles
have recently emerged as an attractive class of substrates for
Pd-catalyzed cross-coupling via in situ C-O activation using
phosphonium salts.[22] In particular, the innovative work of Kang
et al. permitted the direct arylation of tautomerizable
heterocycles using boronic acids as coupling partners.[22a]
We have recently described successful one-pot access to a wide
variety of new fluorinated bicyclic heterocycle compounds
involving nitrogen as the nucleophile in the Michael addition
reaction followed by cyclization of the adduct.[23] Continuing our
longstanding interest in the synthesis and diversification of novel
heterocycles,[24] we report here access to diversified of original
bridgehead nitrogen heterocycle 5,7-disubstituted pyrazolo[1,5-
a]pyrimidines. (Het) aryl, alkynyl, amino and thiol groups were
thus introduced very efficiently at the C-5 position in
pyrazolo[1,5-a]pyrimidines to generate a library of new 5,7-
[a]
Badr Jismy, Hassan Allouchi, Mohamed Abarbri
Département de Chimie Université François Rabelais
Laboratoire d’Infectiologie et Santé Publique (UMR 1282), équipe
Recherche et Innovation en Chimie Médicinale
Parc de Grandmont, 37200 Tours, France
E-mail: mohamed.abarbri@univ-tours.fr badr.jismy@etu.univ-tours.fr
Mohamed Akssira
Département de Chimie Université Hassan II de Casablanca
Laboratoire de Chimie Physique et de Chimie Bioorganique, URAC 22
BP 146, 28800 Mohammedia, Maroc.
[b]
[c]
E-mail: akssira@yahoo.fr
Gérald Guillaumet
Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans,
UMR CNRS 7311
BP 6759 rue de Chartres, 45067 Orléans Cedex2, France
E-mail: gerald.guillaumet@univ-orleans.fr
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10.1002/ejoc.201701024
European Journal of Organic Chemistry
FULL PAPER
disubstituted pyrazolo[1,5-a]pyrimidines whose biological
potential is already well known.
In order to establish the best conditions for the synthesis of
pyrazolo[1,5-a]pyrimidin-5-ones 3 starting from ethyl propiolate
derivatives and 3-aminopyrazole 1, a study of the reaction
conditions was carried out.
Optimization of the Reaction Conditions for
the Synthesis of Pyrazolo[1,5-a]pyrimidin-5-
ones.
As a starting point for the development of this one-pot two-
step sequence, we chose to study the reaction of 3-
aminopyrazole 1 with ethyl propiolate as a model. To optimize
the reaction conditions, we examined a range of solvents,
catalysts, temperatures and reaction times. The reaction
conditions studied to furnish the pyrazolo[1,5-a]pyrimidin-5-one
3a are summarized in Table 1.
We thus examined the efficacy of the type of solvent without
changing other factors for the one-pot addition/lactamization
reaction. After testing different solvents, we reached the
conclusion that the isolated yield of the addition/lactamization
product 3a did not exceed 40% whatever the solvent used.
The resulting intermediate Michael addition (E)-2 failed to cyclize
(Scheme 1). Among the various solvents examined, only
solvents with Lewis basicity properties were practical for this
transformation (Table 1, entries 5, 9, 10 and 11). Dioxane or
THF was therefore the appropriate solvent to provide the best
yield of the heterocycle product 3a (Table 1, entries 5, 9 and 10).
Experiments performed in other solvents (ethanol, DMF, DCE
and toluene) resulted in very low yields (Table 1, entries 1, 2, 6
and 12). Only a complex mixture was obtained using more polar
protic solvents and none of the desired product 3a was isolated
(Table 1, entries 3 and 4).
Results and Discussion
Main Text Paragraph . We initially developed a one-pot two-
step synthesis of pyrazolo[1,5-a]pyrimidin-5-ones 3 via the
condensation of commercially available 3-aminopyrazole 1 with
activated
alkynes.
Pyrazolo[1,5-a]pyrimidin-5-ones
were
subsequently used as key intermediates to lead directly to the
fused pyrazolo[1,5-a]pyrimidines. Although many synthesis
approaches have been described in the case of pyrazolo[1,5-
a]pyrimidin-7-ones 3’, very few syntheses have been reported
for pyrazolo[1,5-a]pyrimidin-5-one regioisomers 3 (Figure 2).[25]
These syntheses are essentially based on the condensation of
aminopyrazole with 1,3-dimethyluracil or with ethyl 3-
ethoxyacrylate.
The addition of catalysts such as AuBr3, CuI, Cu(OAc)2 and
FeCl3 did not improve the yield (Table 1, entries 13-17). On the
contrary, no desired product or decrease in yield of the cyclized
product 3a was detected. Increasing the quantity of catalyst to 1
equivalent did not improve the yield of this reaction (Table 2,
entry 17). We also found that the heating system had a
significant influence, since no cyclized product 3a was formed at
room temperature using dioxane as solvent, and only the
resulting product 2 (E/Z = 60/40) from the Michael addition
reaction was isolated (Table 1, entry 7). This reaction was
carried out by heating in a sealed tube for 24 hours. Prolonging
the reaction time did not improve the yield of the reaction (Table
1, entry 18), but a lower yield was obtained if the reaction time
was reduced (Table 1, entry 8). In order to improve yield and to
reduce the reaction time, conventional thermal heating was
replaced by microwave (MW) irradiation to promote the reaction
(Table 1, entry 10). This resulted in a reduced reaction time (2h)
but afforded a comparable yield of 3a (41%, Table 1, entry 10).
Figure 2. Examples of pyrazolo[1,5-a]pyrimidin-5-ones and pyrazolo[1,5-
a]pyrimidin-7-ones.
To date, there are few references available in the
27]
literature,[26,
which describe the synthesis of pyrazolo[1,5-
a]pyrimidines using ethyl propiolate as the source for the α,β-
unsaturated carbonyl moiety. However, both synthesis routes
have some drawbacks related to either the lack of synthesis
detail and limited yields (e.g. lower than 40%),[26] or to the
functionalization limitation which requires more steps and driven
also by its non-substitution in position 5.[27]
Table 1. Optimization studies for the reaction of 3-aminopyrazole 1 with ethyl propiolate: A comparison of Solvents.
Entry
Solvent
EtOH
T°C
Reflux
120
Time (h)
Cat (20% mol)
Product(s)
3a/E-2 (35/65)
3a/E-2 (32/68)
3a/ E-2 (0/0)
3a/E-2 (0/0)
Yield(%)[a]
1
2
3
4
24
"
-
-
-
-
31
30
0
DMF
H2O
Reflux
Reflux
"
CH3COOH
"
0
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10.1002/ejoc.201701024
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5
THF
Reflux
Reflux
rt
"
"
-
3a/E-2 (42/58)
3a/E-2 (37/63)
3a/2 (0/100) [b]
3a/E-2 (41/59)
3a/E-2 (45/55)
3a/E-2 (47/53)
3a/E-2 (40/60)
3a/E-2 (27/73)
3a/E-2 (43/57)
3a/E-2 (0/100)
3a/E-2 ((17/83)
3a/E-2 (38/62)
3a/E-2 (43/57)
3a/E-2 (48/52)
38
35
0
6
DCE
-
7
Dioxane
Dioxane
Dioxane
Dioxane
CH3CN
Toluène
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
"
-
8
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
16
24
2
24
"
-
36
40[c]
41[d]
36
20
35
0
9
-
10
11
12
13
14
15
16
17
18
-
-
-
AuBr3
"
"
CuI
"
Cu(OAc)
FeCl3
10
30
32
40
"
"
AuBr3 (1 equiv)
-
36
[a] Yield of isolated product 3a.
[b] In this case, (E-2/Z-2 = 60/40)
[c] Reaction conditions: 1 (1 mmol), alkyne (1.2 mmol), 1,4-dioxane, 110°C, 24h.
[d] Conditions: 1 (1 mmol), alkyne (1.2 mmol), MW, 1,4-dioxane, 110°C, 2h.
Upon examination and on the basis of the results obtained, it
appeared that varying the solvent, catalyst or reaction time did
not improve the yield of 3a, and the low yield obtained can be
explained by the formation of the intermediate Michael adduct
(E)-2 accompanying the expected product 3a, whose E-
configuration of the double bond is not favorable for cyclization
(Scheme 1). The low yield of 3a obtained using these conditions
prompted us to find an alternative based on isomerization of the
double bond of intermediate (E)-2 promoting the cyclization
reaction to improve the reaction yield of pyrazolo[1,5-
a]pyrimidin-5-one 3a
reactants were refluxed in dioxane in a sealed tube for 2h using
microwave conditions, followed by addition of 2 equivalents of
sodium methoxide at room temperature for 12h. The synthetic
routes to obtain pyrazolo[1,5-a]pyrimidin-5-one 3a are reported
in Scheme 2.
Scheme 2. Synthetic routes to obtain compound 3a
The spectral data obtained for 3a were in complete agreement
with reported data.[29]
After a careful analysis of our results, the optimum conditions
were found to be 3-aminopyrazole 1 (1 equiv.), alkyne (1.2
equiv.), in refluxing dioxane using microwave-assisted
conditions for 2h, followed by addition of sodium methoxide (2
equiv.) at room temperature for 12h.
Having established the optimum conditions, the scope of the
substrate was next examined. The protocol was found to be
broadly applicable for substituted ethyl propiolate, as ethyl
propiolate substituted with CH3 and Ph groups led to 7-
substituted pyrazolo[1,5-a]pyrimidin-5-ones 3b-c in good yields
(Scheme 3).
Scheme 1. The resulting Michael isomer of product 2 leading to cyclized
compound 3a
As depicted in Scheme 2 and using the isomerization conditions
of enamines,[28] the resulting isolated Michael adduct (E)-2 was
treated by
2 equivalents of sodium methoxide at room
temperature for 12h. After isomerization, this pathway lead to
the expected cyclized product 3a with 66% yield, which means
that the overall yield of product 3a was 76% starting from 3-
aminopyrazole 1 and ethyl propiolate, after the two steps
corresponding to the paths a and b (Scheme 2). 3a was also
obtained with comparable yield (78%) in a one-pot manner when
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Reactivity of pyrazolo[1,5-a]pyrimidin-5-ones
3a-c via cross-coupling reaction
We focused on C-O activation for the synthesis of varied
pyrazolo[1,5-a]pyrimidines 4 having an aryl group in position 5.
Pyrazolo[1,5-a]pyrimidin-5-ones 3 were reacted with boronic
acids to synthesize the target compounds using a combination
of two conditions, i.e the phosphonium coupling condition
(PyBrop 1.3 equiv, Et3N 3 equiv, 1,4-dioxane, rt, 2h) then the
Suzuki-Miyaura cross-coupling condition[30] (PdCl2(PPh3)2,
Na2CO3, 110°C, 24h). Direct arylation proceeded successfully
providing good to excellent isolated yields of 5-arylated
pyrazolo[1,5-a]pyrimidines 4a-q (Table 2).
As shown in Table 2, a number of substituents (including
functionalized ones) were tolerated on the boronic acid under
the conditions presented and provided the desired products 4a-q
in excellent yields. Arylboronic acid bearing electron-donating
groups such as methoxy group at para position were easily
coupled with 3a, 3b and 3c provided the corresponding products
4b (100%), 4c (71%) and 4d (100%), respectively. However,
using ortho-methoxy phenylboronic acid provided only 72% yield
of the expected product 4e. Steric hindrance could explain this
result. Phenylboronic acid substituted with thiomethyl group at
para position led to 82% yield of 5-arylated pyrazoloprymidine 4f.
Boronic acids with halogen substituents, such as fluorine on the
benzene ring were found to be effective and compatible for this
coupling reaction [4j (78%), 4k (95%) and 4l (98%)].
Scheme 3. Synthesis of 7-substituted pyrazolo[1,5-a]pyrimidin-5-ones 3a-c.
As shown in Scheme 3, activated alkynes substituted with an
alkyl or aryl group were effectively condensed with 3-
aminopyrazole
1
to provide 7-substituted pyrazolo[1,5-
a]pyrimidin-5-ones 3b (50%) and 3c (54%), respectively. The
reaction described was extremely versatile and provided a
convenient method for the synthesis of various 7-substituted
pyrazolo[1,5-a]pyrimidin-5-ones 3 with total regioselectivity. In
each case, it can be assumed that the Michael addition occurred
at the heterocyclic nitrogen and was then followed by lactam
formation involving the exocyclic amine function.
Once the synthesis conditions of pyrazolo [1,5-a]pyrimidin-5-
ones 3a-c had been established, these compounds were
subsequently used as key intermediates for the synthesis of
additional heterocycles.
Table 2. Synthesis of 5-(hetero) aryl substituted-pyrazolo[1,5-a]pyrimidines 4a-q. [a]
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Boronic acid with electron-withdrawing functional 4-acetyl was
also tolerated, yielding the desired products 4m (95%).
Importantly, the use of heteroarylboronic acids such as 2-furyl,
3-furyl, 2-thienyl and 3-thienyl was very effective, yielding 4n
(100%), 4o (90%), 4p (95%) and 4q (73%), respectively, thereby
permitting easy diversification into biologically important
biheterocyclic frameworks. Further confirmation of the product
structures was obtained by X-ray crystal structure analysis of
compound 4e (Figure 3).[31]
Having successfully developed the C-5-arylation of pyrazolo[1,5-
a]pyrimidines, we focused on introducing greater diversity
employing this strategy.
One–pot C-5-alkynylation using the Sonogashira coupling
reaction[32] was undertaken, wherein alkyne
(1.5 equiv), PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), Et3N (5
equiv.) and dioxane were added after the prior addition of
ByProP and Et3N at room temperature for 2 h. The mixture was
subsequently heated at 80°C for 12h. This protocol provided
direct access to several new 5-alkynyl pyrazolo[1,5-
a]pyrimidines 5a-e with moderate to excellent yields (Table 3).
Table 3. Synthesis of 5-alkynyl substituted-pyrazolo[1,5-a]pyrimidines 5a-e
Figure 3. X-ray single-crystal structure of 4e
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dioxane, rt, 2h), followed by the addition of 1.5 equiv. of amine in
dioxane at 110°C for 12h.
This one-pot approach successfully afforded excellent yields of
the corresponding 5-aminopyrazolo[1,5-a]pyrimidines (5-APP)
6a-j (Table 4). 5-APP were identified to have inhibitory activity
against Jak2.[27] The one-pot reaction using allylamine or even
benzylamine as the nucleophilic reagent yielded 98%, 77% and
70% 5-aminopyrazolo[1,5-a]pyrimidines 6b, 6c and 6f,
respectively (Table 4). Under the same conditions, aliphatic
compounds such as hexylamine and 2-phenylethylamine
reacted well to give the expected products 6a and 6d with yields
of 90% and 96%, respectively (Table 4). This one-pot SNAr
reaction was also achieved when using secondary amines.
Piperidine generated the desired product 6h with 98% yield and
morpholine afforded 6i with 97% yield. In the presence of N-
phenylpiperazine, this SNAr led to 6j with 95% yield. Also, a non-
cyclic secondary amine such as dibutylamine led to the
expected product with 66% yield. On the other hand no reaction
was observed using aromatic amine such as aniline, presumably
due to the weak nucleophilicity of the amine group. Nor was
there any success using the Buchwald conditions (Pd(OAc)2,
Xantphos, dioxane, 100°C).[33]
Notably, phenyl acetylene was coupled easily with 3a and 3c to
afford 5d (74%) and 5e (72%), respectively.
Homopropargylic alcohol reacted efficiently with 3a to provide
the expected product 5c (80%). In addition, aliphatic alkynes
such as 1-hexyne were coupled to give the expected products
5a with 80% yield while the alkyne possessing bulkier
cyclopropyl substitution was less compatible (5b, 55%).
With a viable protocol to hand, we extended this SNAr reaction to
sulfur compounds. In contrast to aromatic amines, thiophenol
was found to be very reactive, providing excellent yield of the
desired product 6k (88%, Table 4), and 2-mercaptoacetate
provided 83% yield of the C-5 thiolation product 6l, again
demonstrating the potential of this process for the preparation of
a library of original 5,7-disubstituted pyrazolo[1,5-a]pyrimidines.
As depicted in Tables 2, 3 and 4, this strategy represents a
general and effective approach to accessing a library of new 5,7-
disubstituted pyrazolo[1,5-a]pyrimidines whose biological
potential is already well known. All products were new and fully
Direct SNAr of pyrazolo[1,5-a]pyrimidin-5-ones:
Synthesis of 5-amino and 5-mercapto
pyrazolo[1,5-a]pyrimidines 6a-l
To demonstrate the scope of this efficient protocol via C-O bond
activation, we then focused on the C-5 nucleophilic aromatic
substitution reaction using amines as nucleophiles. In fact,
various amines were found to react with 3 using first the C-O
bond activation conditions (PyBrop 1.3 equiv., Et3N 3 equiv, 1,4-
1
characterized by H and 13C spectroscopy as well as by HRMS.
Table 4. Synthesis of 5-amino and 5-mercapto substituted pyrazolo[1,5-a]pyrimidines 6a-l.[a]
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All reactions were carried out under argon atmosphere. Reactions were
monitored by thin-layer chromatography (TLC) using silica gel (60 F254)
plates, and the compounds were visualized by UV irradiation. Column
chromatography was performed with silica gel 60 (230 – 400.13 mesh,
0.040 – 0.063 mm). Absolute ethanol, acetonitrile and toluene were
obtained from commercial sources and were used without further
purification. Triethylamine and DMF were distilled from calcium hydride.
THF was distilled from sodium and benzophenone.
Conclusions
In conclusion, a new practical and simple method of synthesis
for access to
pyrazolo[1,5-a]pyrimidines was developed. We first established
a concise and straightforward one-pot strategy for the synthesis
a wide variety of new 5,7-disubstituted
All 1H NMR and 13C NMR spectra were recorded on a 300 MHz Bruker
Avance FT-NMR spectrometer (300 MHz or 75 MHz, respectively). All
chemical shifts are given as
value (ppm) with reference to
of
7-substituted
pyrazolo[1,5-a]pyrimidin-5-ones
by
tetramethylsilane (TMS) as an internal standard. The peak patterns are
indicated as follows: s, singlet ; d, doublet ; t, triplet ; q, quartet ; m,
multiplet. The coupling constants, J, are reported in Hertz (Hz).
Electrospray ionization high-resolution mass spectrometry experiments
(HRMS) were performed on a hybrid tandem quadrupole/time-of flight (Q-
TOF) instrument, equipped with a pneumatically assisted electrospray (Z-
spray) ion source (Micromass, Manchester, U.K.) operated in positive
mode.
condensation of 3-aminopyrazole with ethyl propiolate
derivatives. These compounds were then used as building
blocks to synthesize C-5 and C-7 disubstituted pyrazolo[1,5-
a]pyrimidines via C-O activation of the amide function using
PyBroP as activating reagent. (Het)aryl, alkynyl, amino and thiol
groups were thus introduced very efficiently at the C-5 position
in pyrazolo[1,5-a]pyrimidines to generate a library of new 5,7-
disubstituted
pyrazolo[1,5-a]pyrimidines.
This
C-5
functionalization was achieved with excellent yields. This
approach is flexible, since a wide variety of groups may be
introduced at the 5 and 7-positions. One-pot strategies, including
reduction of the number of steps and reduction of reaction time,
contributed to these eco-efficient processes. We believe that this
approach would have a wide range of applications in the
synthesis of diversely-based pyrazolo[1,5-a]pyrimidines of
potential medicinal value.
Typical Procedure for the synthesis of 7-substituted pyrazolo[1,5-
a]pyrimdin-5-ones 3:
In a microwave vial, 3-aminopyrazole (1.20 mmol, 100 mg) was dissolved
in 1,4-dioxane (4 mL). Alkyne (1.2 equiv) was then added, and the
mixture was degassed by argon bubbling for 10 min. The sealed tube
was heated at 110 °C for 2 h. After cooling, MeONa (120 mg, 2 equiv)
was added and the reaction was stirred for 12h at room temperature. The
reaction mixture was neutralized with a solution of hydrochloric ether
(2M) and the solvent was removed under reduced pressure. The crude
product was purified using a silica gel column eluting with the mobile
phases given below.
Further exploration of this strategy and biological evaluation of
the compounds thus synthesized are currently under
investigation in our laboratory.
Pyrazolo[1,5-a]pyrimidin-5(4H)-one (3a):[28,34] 3a was obtained as a
white solid with 78 % yield after purification by silica gel chromatography
(AcOEt/MeOH: 9.5/0.5): m.p 245.5 °C; 1H NMR (300 MHz, DMSO-d6): δ
Experimental Section
General considerations
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701024
European Journal of Organic Chemistry
FULL PAPER
= 12.11 (s, 1H), 8.48 (d, J = 7.9 Hz, 2H), 7.76 (d, J = 1.9 Hz, 2H), 5.94 (d,
J = 7.9 Hz, 2H), 5.81 (d, J = 1.9 Hz, 2H); 13C NMR (75 MHz, DMSO-d6):
δ = 160.3, 144.0, 141.1, 138.9, 106.4, 87.7; HR-MS (ESI): m/z =
136.0506, calcd. for C6H5N3O [M+H]+: 136.0505.
7.91 (dd, J = 7.7 Hz, 1.8 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.16 – 7.04 (m,
2H), 6.73 (d, J = 2.2 Hz, 1H), 3.92 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
= 157.4, 156.1, 148.6, 144.9, 133.5, 131.5, 131.0, 127.1, 121.3, 111.5,
110.1, 96.8, 77.5, 77.0, 76.6, 55.6; HR-MS (ESI): m/z = 226.0973, calcd.
for C13H11N3O [M+H]+: 226.0975.
7-Methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (3b):
3b was obtained as a white solid with 50 % yield after purification by
silica gel chromatography (100 % EtOAC): m.p 207 °C; 1H NMR (300
MHz, DMSO-d6) δ 12.02 (s, 1H), 7.76 (d, J = 1.9 Hz, 2H), 5.9 (s, 1H),
5.84 (d, J = 1.9 Hz, 2H), 3.35 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ
160.1, 148.7, 143.2, 141.0, 104.6, 87.8, 16.9; HR-MS (ESI): m/z =
150.0662, calcd. for C7H7N3O [M+H]+: 150.0662.
5-(4-(Methylthio)phenyl)pyrazolo[1,5-a]pyrimidine (4f): 4f was
obtained as a yellow solid with 82 % yield after purification by silica gel
chromatography (cyclohexane /AcOEt: 7.5/2.5): m.p 152.5 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.71 (dd, J = 7.4, 0.7 Hz, 1H), 8.14 (d, J = 2.3 Hz,
1H), 8.05 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 7.2 Hz,
1H), 6.72 (dd, J = 2.3, 0.7 Hz, 1H), 2.57 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ = 155.6, 148.5, 145.6, 142.3, 135.1, 133.5, 127.5 (2C), 126.0
(2C), 105.0, 96.8, 15.2; HR-MS (ESI): m/z = 242.0731, calcd. for
C13H11N3S [M+H]+: 242.0746.
7-Phenylpyrazolo[1,5-a]pyrimidin-5(4H)-one (3c):[35]
3c was obtained as a white solid with 54% yield after purification by silica
1
gel chromatography (petroleum ether/AcOEt : 4/6): m.p 244 °C; H NMR
(300 MHz, DMSO-d6): δ = 12.21 (s, 1H), 7.88 – 7.85 (m, 2H), 7.79 (d, J =
1.9 Hz, 2H), 7.58 – 7.51 (m, 3H), 6.08 (s, 1H), 5.93 (d, J = 2.0 Hz, 2H);
13C NMR (75 MHz, DMSO-d6): δ = 160.1, 149.3, 143.5, 141.9, 131.1,
131.0, 129.9 (2C), 128.7 (2C), 105.5, 88.0; HR-MS (ESI): m/z = 212.0818,
calcd. for C12H9N3O [M+H]+: 212.0818.
5-(p-Tolyl)pyrazolo[1,5-a]pyrimidine (4g): 4g was obtained as a yellow
solid with 87 % yield after purification by silica gel chromatography
(cyclohexane /AcOEt: 7.5/2.5): m.p 157 °C; 1H NMR (300 MHz, CDCl3): δ
= 8.71 (dd, J = 7.4, 0.5 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 8.02 (d, J = 8.3
Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 6.72 (dd, J =
2.3, 0.5 Hz, 1H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 156.3,
148.5, 145.5, 140.9, 135.0, 134.4, 129.7 (2C), 127.2 (2C), 105.4, 96.8,
21.4; HR-MS (ESI): m/z = 210.1012, calcd. for C13H11N3 [M+H]+:
210.1026.
Typical procedure for the synthesis of 5-arylated pyrazolo[1,5-
5-(4-(Hydroxymethyl)phenyl)pyrazolo[1,5-a]pyrimidine (4h):[36] 4h
was obtained as a yellow solid with 82 % yield after purification by silica
gel chromatography (cyclohexane /AcOEt: 6/4): m.p 132 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.68 (dd, J = 7.4 Hz, 0.6 Hz, 1H), 8.15 (d, J = 2.3
Hz, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.5 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 1.8
Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H) 4.80 (s, 2H); 13C NMR (75 MHz, CDCl3):
δ = 155.9, 148.5, 145.5, 143.6, 136.2, 135.0, 132.0, 128.5, 127.3, 105.4,
97.0, 64.7; HR-MS (ESI): m/z = 226.0959, calcd. for C13H11N3O [M+H]+:
226.0975.
a]pyrimdines 4
To a stirred solution of 7-substituted pyrazolo[1,5-a]pyrimidin-5-ones 3
(1.0 equiv) in 1,4-dioxane (3 ml) at room temperature was added PyBroP
(1.3 equiv) and Et3N (3 equiv). The reaction mixture was stirred at room
temperature for 2 h (The progress of the reaction was monitored by TLC).
After completion of the first step, boronic acid (1.5 equiv), Na2CO3 (5
equiv) and PdCl2(PPh3)2 (10 mol %) were added successively at room
temperature. After the mixture had been stirred at 100 °C for 24 h, it was
diluted with CH2Cl2, washed with saturated NH4Cl solution and dried with
MgSO4. The crude product was purified by column chromatography to
give pure 5,7-disubstituted pyrazolo[1,5-a]pyrimidines.
5-(4-(Trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidine (4i): 4i was
obtained as a yellow solid with 93 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 8/2): m.p 101 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.76 (d, J = 7.4 Hz, 1H), 8.17 – 8.14 (m, 3H), 7.38
(d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H); 19
F
NMR (282 MHz, CDCl3): δ = -57.67; 13C NMR (75 MHz, CDCl3): δ =
154.6, 150.9 (q, J = 1.7 Hz), 148.4, 145.8, 135.6, 135.3, 128.9 (2C),
120.4 (q, J = 258.1 Hz), 121.12, 105.1, 97.2; HR-MS (ESI): m/z =
280.0672, calcd. For C13H8F3N3O [M+H]+: 280.0692.
5-Phenylpyrazolo[1,5-a]pyrimidine (4a): 4a was obtained as a yellow
solid with 76 % yield after purification by silica gel chromatography
(cyclohexane/AcOEt: 8/2): m.p 123 °C; 1H NMR (300 MHz, CDCl3): δ =
8.74 (d, J = 7.4 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.13 – 8.10 (m, 2H),
7.56 – 7.53 (m, 3H), 7.31 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H); 13
C
5-(4-Fluorophenyl)pyrazolo[1,5-a]pyrimidine (4j): 4j was obtained as a
yellow solid with 78 % yield after purification by silica gel chromatography
(cyclohexane /AcOEt: 7.5/2.5): m.p 167 °C; 1H NMR (300 MHz, CDCl3): δ
= 8.74 (dd, J = 7.4, 0.5 Hz, 1H), 8.16 – 8.10 (m, 3H), 7.28 – 7.20 (m, 3H),
6.73 (d, J = 2.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ = -110.11; 13C
NMR (75 MHz, CDCl3): δ = 166.0, 162.7, 155.1, 148.4, 145.7, 135.2,
133.3 (d, J = 3.1Hz), 129.3, 129.2, 116.0 (d, J = 21.8 Hz), 105.1, 97.0;
HR-MS (ESI): m/z = 214.0761, calcd. for C12H8FN3 [M+H]+: 214.0775.
5-(4-Fluoro-3-methylphenyl)pyrazolo[1,5-a]pyrimidine (4k): 4k was
obtained as a white solid with 95 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt, 8:2): m.p 164 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.72 (dd, J = 7.4, 0.6 Hz, 1H), 8.15 (d, J = 2.3 Hz,
1H), 8.0 (d, J = 7.2 Hz, 1H), 7.9 – 7.87 (m, 1H), 7.25 (d, J = 7.4 Hz, 1H),
7.16 (t, J = 8.9 Hz, 1H), 6.72 (dd, J = 2.2 Hz, 0.6 Hz, 1H), 2.40 (s, 3H);
19F NMR (282 MHz, CDCl3): δ = -114.3; 13C NMR (75 MHz, CDCl3): δ =
164.6, 161.3, 155.4, 148.5, 145.6, 135.1, 133.0 (d, J = 3.4 Hz), 130.6 (d,
J = 5.8 Hz), 126.5 (d, J = 8.7 Hz), 125.7 (d, J = 17.8 Hz), 115.6 (d, J =
22.9 Hz), 105.2, 96.9, 14.7 (d, J = 3.4 Hz); HR-MS (ESI): m/z = 228.0915,
calcd. for C13H10FN3 [M+H]+: 228.0931.
5-(4-Fluorophenyl)-7-phenylpyrazolo[1,5-a]pyrimidine (4l): 4l was
obtained as a yellow solid with 98 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 9.5/0.5): m.p 137 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.20 – 8.14 (m, 3H), 8.09 – 8.06 (m, 2H), 7.63 –
7.61 (m, 3H), 7.32 (s, 1H), 7.23 (t, J = 8.7 Hz, 2H), 6.81 (d, J = 2.3 Hz,
1H); 19F NMR (282 MHz, CDCl3): δ = –110.5; 13C NMR (75 MHz, CDCl3):
δ = 165.9, 162.6, 155.0, 149.7, 146.9, 145.3, 133.7 (d, J = 3.1 Hz), 131.4,
131.0, 129.3 (d, J = 8.6 Hz), 129.2 (2C), 128.7 (2C), 161.1, 115.8, 104.8,
79.2; HR-MS (ESI): m/z = 290.1084, calcd. for C18H12FN3 [M+H]+:
290.1088.
NMR (75 MHz, CDCl3): δ =156.3, 148.5, 145.6, 137.2, 135.1, 130.5,
129.0 (2C), 127.3 (2C), 105.5, 97.0; HR-MS (ESI): m/z = 196.0858, calcd.
for C12H9N3 [M+H]+: 196.0869.
5-(4-Methoxyphenyl)pyrazolo[1,5-a]pyrimidine (4b): 4b was obtained
as a white solid from 4-methoxyphenylboronic acid with 100 % yield after
purification by silica gel chromatography (petroleum ether /AcOEt: 7/3):
m.p 150 °C; 1H NMR (300 MHz, CDCl3): δ = 8.68 (d, J = 7.4 Hz, 1H),
8.12 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 7.4 Hz, 1H)
7.04 (d, J = 8.7 Hz, 2H) 6.68 (d, J = 2.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ = 161.7, 155.8, 148.5, 145.4, 134.9, 129.6, 128.8, 114.3, 105.0,
96.6, 55.4; HR-MS (ESI): m/z = 226.0957, calcd. for C13H11N3O [M+H]+:
226.0975.
7-Methyl-5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine (4c): 4c was
obtained as a white solid with 71 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 8/2): m.p 130 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.18 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H),
7.12 (s, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.7 (d, J = 2.3 Hz, 1H), 3.9 (s, 3H),
2.85 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 161.4, 155.5, 148.9, 145.6,
144.7, 130.0, 128.8 (2C), 114.3 (2C), 104.6, 96.7, 55.4, 17.6; HR-MS
(ESI): m/z = 240.1115, calcd. for C14H13N3O [M+H]+: 240.1131.
5-(4-Methoxyphenyl)-7-phenylpyrazolo[1,5-a]pyrimidine (4d): 4d was
obtained as a yellow oil with 100 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 8.5/1.5): 1H NMR (300 MHz,
CDCl3): δ = 8.16 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 8.9 Hz, 2H), 8.09 – 8.05
(m, 3H), 7.62 – 7.60 (m, 3H), 7.32 (s, 1H), 7.06 (d, J = 8.9 Hz, 2H), 6.77
(d, J = 2.3 Hz), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 161.5, 155.8,
149.8, 146.7, 145.0, 131.6, 130.8, 130.0, 129.2 (2C), 128.8 (2C), 128.7
(2C), 114.3 (2C), 104.8, 96.7, 55.4; HR-MS (ESI): m/z = 302.1286, calcd.
for C19H15N3O [M+H]+: 302.1288.
5-(4-Acetylphenyl) pyrazolo[1,5-a]pyrimidine (4m): 4m was obtained
as a yellow solid with 95 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 6/4): m.p 183 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.78 (dd, J = 7.4 Hz, 0.6 Hz, 1H), 8.22 (d, J = 8.6
Hz, 2H), 8.19, (d, J = 2.4 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.34 (d, J =
5-(2-Methoxyphenyl)pyrazolo[1,5-a]pyrimidine (4e): 4e was obtained
as a yellow solid with 72 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 8/2): m.p 120 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.66 (d, J = 7.4 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701024
European Journal of Organic Chemistry
FULL PAPER
7.4 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 2.69 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ = 197.6, 154.7, 148.5, 145.9, 141.2, 138.2, 135.3, 128.9 (2C),
127.5(2C), 105.4, 97.5, 26.8; HR-MS (ESI): m/z = 238.0959, calcd. for
C14H11N3O [M+H]+: 238.0975.
2.79 (t, J = 6.3 Hz, 2H), 2.3 (t, J = 6.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ = 148.0, 145.7, 142.3, 134.7, 110.5, 97.2, 91.8, 80.8, 60.5,
23.9; HR-MS (ESI): m/z = 188.0818, calcd. For C10H9N3O [M+H]+:
188.0818.
5-(Furan-2-yl)pyrazolo[1,5-a]pyrimidine (4n): 4n was obtained as a
5-(Phenylethynyl)pyrazolo[1,5-a]pyrimidine (5d): 5d was obtained as
white solid with 100
%
yield after purification by silica gel
a brown solid with 74 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 8/2): m.p 122 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.67 (dd, J = 7.4 Hz, 0.4 Hz, 1H), 8.12 (d, J = 2.3
Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.25 – 7.22 (m, 2H), 6.70 (d, J = 1.9 Hz,
1H), 6.63 – 6.62 (m, 1H); 13C NMR (75 MHz, CDCl3): δ = 151.7, 147.2,
147.6, 145.6, 145.0, 135.1, 112.7, 111.9, 104.1, 96.8; HR-MS (ESI): m/z
= 186.0662, calcd. for C10H7N3O [M+H]+: 186.0662.
chromatography (petroleum ether /AcOEt: 8/2): m.p 178 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.67 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H),
7.66 – 7.64 (m, 3H), 7.0 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H); 13
C
NMR (75 MHz, CDCl3): δ = 148.2, 145.8, 142.2, 134.6, 132.4 (2C), 129.8,
128.6 (2C), 121.53, 110.66, 97.55 , 92.73, 87.53; HR-MS (ESI) m/z =
220.0869 calcd. For C14H9N3 [M+H]+: 220.0869.
5-(Furan-3-yl)pyrazolo[1,5-a]pyrimidine (4o): 4o was obtained as a
white solid with 90 % yield after purification by silica gel chromatography
(petroleum ether /EtOAC: 7.5/2.5): m.p 149 °C; 1H NMR (300 MHz,
CDCl3): δ = 8.6 (dd, J = 7.3 Hz, 0.7 Hz, 1H), 8.11 (d, J = 1.8 Hz, 2H),
7.55 (t, J = 1.7 Hz, 1H), 7.03 (dd, J = 1.8 Hz, 0.7 Hz, 1H), 6.97 (d, J = 7.3
Hz, 1H), 6.65 (dd, J = 2.3 Hz, 0.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ
= 150.8, 148.4, 145.4, 144.5, 142.9, 134.9, 126.0, 108.7, 105.6, 96.5;
HR-MS (ESI): m/z = 186.0650, calcd. for C10H8N3O [M+H]+: 186.0662.
7-Phenyl-5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine (4p): 4p was
obtained as a yellow solid with 95 % yield after purification by silica gel
7-Phenyl-5-(phenylethynyl)pyrazolo[1,5-a]pyrimidine (5e): 5e was
obtained as a black oil with 72 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 9.5/0.5); 1H NMR (300 MHz,
CDCl3): δ = 8.22 (d, J = 2.4 Hz, 1H), 8.10 – 8.06 (m, 2H), 7.69 – 7.66 (m,
2H), 7.62 – 7.60 (m, 3H), 7.44 – 7.42 (m, 3H), 7.12 (s, 1H), 6.82 (d, J =
2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 149.6, 146.4, 145.4, 142.1,
132.3 (2C), 131.2, 130.6, 129.7, 129.30 (2C), 128.7 (2C), 128.6 (2C),
121.5, 110.2, 97.7, 92.3, 87.9; HR-MS (ESI): m/z = 296.1179 calcd. for
C20H13N3 [M+H]+: 296.11822.
1
chromatography (petroleum ether /AcOEt: 9.5/0.5): m.p 100 °C; H NMR
(300 MHz, CDCl3): δ = 8.15 (d, J = 2.3 Hz, 1H), 8.07 – 8.04 (m, 2H), 7.75
(d, J = 3.8 Hz, 1H), 7.61 (m, 3H), 7.54 (d, J = 5.0 Hz, 1H), 7.28 (s, 1H),
7.18 (t, J = 3.8 Hz, 1H), 6.76 (d, J= 2.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ = 151.3, 149.4, 146.7, 145.2, 143.2, 131.3, 131.0, 129.8, 129.3
(2C), 128.7 (2C), 128.3, 127.3, 104.0, 96.9; HR-MS (ESI): m/z =
278.0744, calcd. for C16H11N3S [M+H]+: 278.0746.
5-(Thiophen-3-yl)pyrazolo[1,5-a]pyrimidine (4q): 4q was obtained as a
brown solid with 73 % yield after purification by silica gel chromatography
(petroleum ether /AcOEt: 7.5/2.5): m.p 127 °C; 1H NMR (300 MHz,
CDCl3): δ = 8.66 (dd, J = 7.4 Hz, 0.7 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H),
8.02 (dd, J = 2.9 Hz, 1.3 Hz, 1H), 7.79 (dd, J = 5.0 Hz, 1.3 Hz, 1H), 7.45
(dd, J = 5.0 Hz, 2.9 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.68 (dd, J = 2.3,
0.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 152.1, 148.4, 145.5, 140.4,
135.0, 126.9, 126.4, 126.1, 105.7, 96.8; HR-MS (ESI): m/z = 202.0420,
calcd. for C10H7N3S [M+H]+: 202.0433.
Typical procedure for the synthesis of 5-amino (mercapto or
aryloxy) pyrazolo[1,5-a]pyrimidines 6
In a sealed tube, 3 (1.11 mmol, 150 mg, 1 equiv) and PyBroP (1.44 mmol,
621 mg, 1.3 equiv) were dissolved in 1.4-dioxane 4 ml. Et3N (3.33 mmol,
0.46 ml, 3 equiv) was then added, and the mixture was stirred at room
temperature for 2 h. After cooling, the corresponding amine (1.5 equiv)
was added, and the mixture was stirred for 12h at 110 °C. After cooling,
the solvents were evaporated under reduced pressure, and the crude
residue was purified by silica gel column chromatography to give the
desired 5-aminated products 6.
N-Hexylpyrazolo[1,5-a]pyrimidin-5-amine (6a): 6a was obtained as a
white solid with 90 % yield after purification by silica gel chromatography
(cyclohexane /AcOEt: 5/5): m.p 105 °C: 1H NMR (300 MHz, CDCl3): δ =
8.22 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 6.13 (d, J =1.7 Hz, 1H),
6.01 (d, J = 7.6 Hz, 1H), 4.87 (s, 1H), 3.44 (q, J = 7.1 Hz, 2H), 1.7 – 1.6
(m, 2H), 1.44 – 1.30 (m, 6H), 0.91 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ = 155.4, 148.6, 144.7, 135.1, 98.8, 92.2, 41.6, 31.5, 29.3, 26.7,
22.6, 14.0; HR-MS (ESI): m/z = 219.1601, calcd. for C12H18N4 [M+H]+:
219.1604.
General procedure for the synthesis of 5-alkynyl substituted-
pyrazolo[1,5-a]pyrimidines 5
General procedure: To
a
stirred solution of
2 (7-substituted
pyrazolo[1,5-a]pyrimidin-5-ones) (1.0 equiv) in 1,4-dioxane (3 ml) at room
temperature were added PyBroP (1.3 equiv) and Et3N (3 equiv). The
reaction mixture was stirred at room temperature for 2 h (The progress of
the reaction was monitored by TLC). Next, PdCl2(PPh3)2 (10 mol %), CuI
( 10 mol %) and alkyne (1.5 equiv) were added successively and the
reaction was stirred at 80 °C for 12 h. The reaction was then diluted with
CH2Cl2, washed with saturated NH4Cl solution and dried with MgSO4.
The crude product was purified by column chromatography to give pure
5-alkynylated pyrazolo[1,5-a]pyrimidines 5.
N-Allylpyrazolo[1,5-a]pyrimidin-5-amine (6b): 6b was obtained as a
white solid with 98 % yield after purification by silica gel chromatography
(cyclohexane /AcOEt: 5/5): m.p 210 °C; 1H NMR (300 MHz, CDCl3): δ =
8.26 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 6.15 (d, J = 2.0 Hz, 1H),
6.0 (m, 2H), 5.33 – 5.21 (m, 2H), 4.88 (s, 1H), 4.12 (t, J = 5.6 Hz, 2H);
13C NMR (75 MHz, CDCl3): δ = 155.1, 148.4, 144.7, 135.3, 134.1, 116.8,
98.8, 92.4, 43.8; HR-MS (ESI): m/z = 175.0976, calcd. for C9H10N4
[M+H]+: 175.0978.
N-Benzylpyrazolo[1,5-a]pyrimidin-5-amine (6c): 6c was obtained as a
5-(Hex-1-yn-1-yl)pyrazolo[1,5-a]pyrimidine (5a): 5a was obtained as a
yellow oil with 80 % yield after purification by silica gel chromatography
(petroleum ether/AcOEt: 9.5/0.5): 1H NMR (300 MHz, CDCl3): δ = 8.59 (d,
J = 7.2 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.66 (d,
J = 2.2 Hz, 1H), 2.50 (t, J = 7.0 Hz, 2H), 1.68 – 1.60 (m, 2H), 1.54 – 1.47
(m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ = 148.1,
145.6, 142.8, 134.4, 110.7, 97.4, 79.5, 30.1, 20.0, 19.1, 13.6; HR-MS
(ESI): m/z = 200.1182, calcd. for C12H13N3 [M+H]+: 200.1182.
white solid with 77 % yield after purification by silica gel chromatography
(petroleum ether/AcOEt: 1/1): m.p 139 °C; H NMR (300 MHz, CDCl3): δ
1
= 8.24 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.39 – 7.28 (m, 5H),
6.17 (d, J = 2.1 Hz, 1H), 6.03 (d, J = 2.1 Hz, 1H), 5.18 (s, 1H), 4.67 (d, J
= 5.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ = 155.2, 148.4, 144.7, 138.2,
135.3, 128.8 (2C), 127.9 (2C), 127.6, 99.0, 92.5, 45.6; HR-MS (ESI): m/z
= 225.1131, calcd. for C13H12N4 [M+H]+: 225.1135.
N-Phenethylpyrazolo[1,5-a]pyrimidin-5-amine (6d): 6d was obtained
5-(Cyclopropylethynyl)pyrazolo[1,5-a]pyrimidine (5b):[ 5b was obtained as
a yellow oil with 96 % yield after purification by silica gel
as a yellow oil with 55 % yield after purification by silica gel chromatography chromatography (petroleum ether /AcOEt: 3.5/6.5); 1H NMR (300 MHz,
1
(Cyclohexane /AcOEt: 8.5/1.5): H NMR (300 MHz, CDCl3): δ = 8.57 (d, J = CDCl3): δ = 8.21 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.37 – 7.24
7.1 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 6.8 (d, J = 7.2 Hz, 1H), 6.64 (d, J = 1.9 (m, 5H), 6.16 (d, J = 1.8 Hz, 1H), 5.95 (d, J = 7.6 Hz, 1H), 4.89 (s, 1H),
Hz, 1H), 1.58 – 1.49 (m, 1H), 1.0 – 0.95 (m, 4H); 13C NMR (75 MHz, CDCl3): 3.79 – 3.72 (m, 2H), 2.98 (t, J = 6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3):
δ = 148.1, 145.5, 142.7, 134.4, 110.6, 99.6, 97.0, 74.9, 9.2 (2C), 0.2; HR-MS δ = 155.2, 148.6, 144.6, 138.9, 135.0, 128.8 (2C), 128.7 (2C), 126.6,
(ESI): m/z = 184.0867 calcd. For C11H9N3 [M+H]+: 184.0869
99.2, 92.4, 42.4, 35.2; HR-MS (ESI): m/z = 239.1288, calcd. for C14H14N4
4-(Pyrazolo[1,5-a]pyrimidin-5-yl)but-3-yn-1-ol (5c): 5c was obtained
as a brown solid with 80 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 4/6): m.p 140 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.64 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H),
6.85 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 2.2 Hz, 1H), 3.91 (q, J = 6.3 Hz, 2H),
[M+H]+: 239.1291.
N-(3,4-Dimethoxyphenethyl)pyrazolo[1,5-a]pyrimidin-5-amine (6e):
6e was obtained as a yellow oil with 98 % yield after purification by silica
gel chromatography (petroleum ether /AcOEt: 3/7); 1H NMR (300 MHz,
CDCl3): δ = 8.21 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 6.85 – 6.77
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701024
European Journal of Organic Chemistry
FULL PAPER
(m, 3H), 6.15 (d, J = 1.7 Hz, 1H), 5.97 (d, J = 7.6 Hz, 1H); 4.89 (s, 1H),
3.89 (s, 3H), 3.88 (s, 3H), 3.77 – 3.70 (m, 2H), 2.93 (t, J = 6.8 Hz, 2H);
13C NMR (75 MHz, CDCl3): δ = 155.2, 149.0, 148.5, 147.7, 144.6, 135.1,
131.3, 120.7, 112.0, 111.4, 99.2, 92.4, 55.9, 55.8, 42.4, 34.8; HR-MS
(ESI): m/z = 299.1500, calcd. for C16H18N4O2 [M+H]+: 299.1502.
Keywords: 3-aminopyrazole • activated alkynes • C-O bond
activation • 7-substituted pyrazolo[1,5-a]pyrimidin-5-ones • 5,7-
disubstituted pyrazolo[1,5-a]pyrimidines.
N-(3,5-Dimethoxybenzyl)-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine
(6f): 6f was obtained as a yellow oil with 70 % yield after purification by
silica gel chromatography (petroleum ether/AcOEt: 7/3); 1H NMR (300
MHz, CDCl3): δ = 7.92 – 7.86 (m, 3H), 7.53 – 7.51 (m, 3H), 6.55 (d, J =
2.1 Hz, 2H), 6.61 (t, J = 2.1 Hz, 1H), 6.25 (d, J = 2.1 Hz, 1H), 6.07 (s, 1H),
5.21 (s, 1H), 4.62 (d, J = 5.5 Hz, 2H), 3.79 (s, 6H); 13C NMR (75 MHz,
CDCl3): δ = 161.1 (2C), 155.4, 149.8, 147.0, 144.3, 140.9, 131.7, 130.5,
129.1 (2C), 128.5 (2C), 105.7 (2C), 99.3, 98.3, 92.7, 55.3 (2C), 45.6; HR-
MS (ESI): m/z = 361.1654, calcd. for C21H20N4O2 [M+H]+: 361.1659.
N,N-Dibutylpyrazolo[1,5-a]pyrimidin-5-amine (6g): 6g was obtained as
a yellow oil with 66 % yield after purification by silica gel chromatography
(cyclohexane /AcOEt: 7/3); 1H NMR (300 MHz, CDCl3): δ = 8.25 (d, J =
7.9 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 6.21 (d, J = 7.9 Hz, 1H), 6.06 (d, J =
2.0 Hz, 1H), 3.5 (t, J = 7.6 Hz, 1H), 1.63 (quint, J = 7.6 Hz, 4H), 1.39
(sext, J = 7.4 Hz, 4H), 0.98 (t, J = 7.3 Hz, 6H); 13C NMR (75 MHz,
CDCl3): δ = 154.7, 148.9, 144.7, 134.8, 96.3, 91.5, 48.5 (2C), 30.0 (2C),
20.2 (2C), 13.9 (2C); HR-MS (ESI): m/z = 247.1915, calcd. for C14H22N4
[M+H]+: 247.1917.
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5-(Piperidin-1-yl)pyrazolo[1,5-a]pyrimidine (6h): 6h was obtained as a
yellow solid with 98 % yield after purification by silica gel chromatography
1
(cyclohexane /AcOEt: 6.5/3.5): m.p 89 °C; H NMR (300 MHz, CDCl3): δ
= 8.26 (dd, J =7.9, 0.8 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 6.5 (d, J = 7.9
Hz, 1 H), 6.09 (dd, J = 0.7 Hz, 2.2 Hz, 1H), 3.68 – 3.64 (m, 4H), 1.68 –
1.62 (m, 6H); 13C NMR (75 MHz, CDCl3): δ = 155.4, 148.6, 144.9, 135.2,
96.5, 92.0,
46.0 (2C), 25.6 (2C), 24.6; HR-MS (ESI): m/z = 203.1279, calcd. for
C10H14N4 [M+H]+: 203.1291.
4-(Pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (6i): 6i was obtained as a
brown solid with 97 % yield after purification by silica gel chromatography
1
(cyclohexane /AcOEt: 6/4): m.p 195 °C; H NMR (300 MHz, CDCl3): δ =
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a) T. Asano, H. Yamazaki, C. Kasahara, H. Kubota, T. Kontani, Y.
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8.35 (d, J = 7.8 Hz, 1H), 7.91 (bs, 1H), 6.34 (d, J = 7.7 Hz, 1H), 6.17 (bs,
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5-(4-Phenylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine (6j): 6j was
obtained as a white solid with 95 % yield after purification by silica gel
chromatography (petroleum ether /EtOAC; 4/6): m.p 158 °C; 1H NMR
(300 MHz, CDCl3): δ = 8.36 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H),
7.36 – 7.28 (m, 2H); 7.03 – 6.93 (m, 3H), 6.41 (d, J = 7.9 Hz, 1H), 6.17 (d,
J = 2.1 Hz, 1H), 3.89 (bs, 4H), 3.33 (bs, 4H); 13C NMR (75 MHz, CDCl3):
δ = 155.4, 150.8, 148.4, 145.2, 135.5, 129.3 (2C), 120.6, 116.6 (2C),
96.3, 92.5, 49.3 (2C), 44.8 (2C); HR-MS (ESI): m/z = 280.1554, calcd. for
C16H17N5 [M+H]+: 280.1557.
5-(Phenylthio)pyrazolo[1,5-a]pyrimidine (6k): 6k was obtained as a
white solid with 98 % yield after purification by silica gel chromatography
(petroleum ether /AcOEt: 7/3): m.p 129.5 °C; 1H NMR (300 MHz, CDCl3):
δ = 8.39 (dd, J = 7.1 Hz, 0.7 Hz, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.68 –
7.63 (m, 2H), 7.52 – 7.49 (m, 3H), 6.48 (dd, J = 2.3 Hz, 0.7 Hz, 1H), 6.39
(d, J = 7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 162.0, 148.0, 145.4,
135.5 (2C), 134.3, 130.1, 129.8 (2C), 129.0, 106.0, 95.5; HR-MS (ESI):
m/z = 228.0576, calcd. for C12H9N3S [M+H]+, 228.0590.
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Ethyl 2-(pyrazolo[1,5-a]pyrimidin-5-ylthio)acetate (6l): 6l was
obtained as a gray solid with 83 % yield after purification by silica gel
chromatography (petroleum ether /AcOEt: 8/2): m.p 69 °C; 1H NMR (300
MHz, CDCl3): δ = 8.41 (d, J = 7.3 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 6.67
(d, J = 7.3 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.05
(s, 2H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ = 168.8,
158.1, 148.9, 144.9, 133.7, 106.9, 95.3, 61.8, 32.3, 14.2; HR-MS (ESI):
m/z = 238.0643, calcd. for C10H11N3O2S [M+H]+: 238.0645.
Acknowledgements
We thank the “Département d’analyses Chimiques et Médicales”
(Tours, France) for chemical analyses.
.
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701024
European Journal of Organic Chemistry
FULL PAPER
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5,7-disubstituted pyrazolo[1,5-a]pyrimidines
Badr Jismy, Gérald Guillaumet,Hassan
Allouchi, Mohamed Akssira, Mohamed
Abarbri*
Page No. – Page No.
Title Concise and efficient access to new
5,7-disubstituted pyrazolo[1,5-
a]pyrimidines via Pd-catalyzed sequential
arylation, alkynylation and SNAr reaction
Synthesis of new 5,7-disubstituted pyrazolo[1,5-a]pyrimidines starting from 3-aminopyrazole and activated alkynes, via C-O bond
activation.
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