One-Pot SNAr/Direct Pd-Catalyzed CH Arylation Functionalization of Pyrazolo[1,5-a]pyrimidine at the C3 and C7 Positions

Article abstract of DOI:10.1002/ejoc.201800580

An efficient and original synthesis of various 3,7-substituted pyrazolo[1,5-a]pyrimidines is reported. First, a two-step process by an S_NAr amination followed by a Pd-catalyzed direct CH-arylation was developed, then a parallel single-pot S_NAr amination/CH arylation sequence was performed starting from 7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine to obtain highly functionalized products with good yields.

Full text of DOI:10.1002/ejoc.201800580

A Journal of
Accepted Article
Title: One pot SNAr/Direct Pd-catalyzed CH arylation functionalization
of pyrazolo[1,5-a]pyrimidine in C3 and C7 positions
Authors: Mohammed Loubidi, Catherine Manga, Zahira Tber, Ibtissam
Bassoude, El Mokhtar Essassi, and Sabine Berteina-Raboin
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800580
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800580
Supported by

10.1002/ejoc.201800580
European Journal of Organic Chemistry
FULL PAPER
One pot SNAr/Direct Pd-catalyzed CH arylation functionalization
of pyrazolo[1,5-a]pyrimidine in C3 and C7 positions
Mohammed Loubidi[a], Catherine Manga[a], Zahira Tber[a], Ibtissam Bassoude[b], El Mokhtar Essassi[b]
and Sabine Berteina-Raboin*[a]
CH-arylation was developed, then a parallel single-pot SNAr
Abstract: An efficient and original synthesis of various 3,7-
amination / CH arylation sequence was performed starting from
substituted pyrazolo[1,5-a]pyrimidines is reported. First, a two-
7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine 2 to obtain
step process via SNAr amination followed by a Pd-catalyzed direct
highly functionalized products with good yields.
nowadays as one of the most important methods in organic
chemistry.[11] Pd-catalyzed C–H activation is an attractive method
to access rapidly aryl-heteroarenes and unsymmetrical bis-
Introduction
heteroaryls without the need for the prior functionalization of
reagents and substrates for the cross-coupling reaction, allowing
a high atom economy. During the last decade many efforts to
develop the direct arylation of 6,5, 6,6 and 5,5 heterocyclic
Heterocyclic scaffolds are versatile molecules which are found in
numerous biological, pharmaceutical, and materials science
applications.[1] The synthesis of these scaffolds has been
extensively reported usually through various transformations
involving condensation or substitution reactions then using
transition-metal-catalyzed cross-coupling methodologies. Among
the broad range of templates, pyrazolopyrimidines[2] and
systems have been reported using various palladium catalysts.
[12]
especially pyrazolo[1,5-a]pyrimidines[3] demonstrate
a
high
Considering the biological interest of these poly-nitrogenated
heterocycles, it is necessary to develop new efficient and practical
routes for the synthesis of functionalized pyrazolo[1,5-
a]pyrimidines. We report in this paper a novel and efficient
protocol for the synthesis of a 3,7-disubstituted pyrazolo[1,5-
a]pyrimidine library via a SNAr amination followed by palladium-
catalyzed direct arylation. Then a one-pot Amination / Arylation
approach was developed to obtain highly functionalized products
in good yields (Scheme 1).
pharmaceutical and biological potential. This core structure has
been reported as a CoX-2 selective inhibitor,[4] and as an
antianxiety[5] or antimicrobial agent.[6] Several synthetic drugs
exhibiting a pyrazolo[1,5-a]pyrimidine motif have already been
commercialized, among which the hypnotic drug Zaleplon (I),[7]
the fungicide Pyrazophos (II),[8] and the hypnotic sedative Indiplon
(III) [9] (Figure 1).
Figure 1. Therapeutic agents based on pyrazolo[1,5-a]pyrimidine
The synthesis and functionalization of these core-structures
has already received considerable attention. [10] For many years,
direct arylation has attracted a lot of interest and is considered
Figure 2. “One-pot” or two step functionalization of pyrazolo[1,5-a]pyrimidines.
Results and Discussion
[a]
M. Loubidi, C. Manga, Z. Tber, S. Berteina-Raboin
Institut de Chimie Organique et Analytique, Université d’Orléans,
UMR-CNRS 7311, BP 6759, rue de Chartres, 45067 Orléans cedex
2, France
Synthesis of the key intermediate
To carry out our study we synthesized the pyrazolo[1,5-
E-mail: sabine.berteina-raboin@univ-orleans.fr.
[3f]
a]pyrimidine 2 using the chemistry already described
condensing the commercially available
by
[b]
I. Bassoude, E-M. Essassi,
3-amino-5-
Laboratoire de chimie organique heterocyclique URAC 21, Pole de
competences pharmacochimie, Mohammed V University in Rabat,
BP 1014, avenue Ibn-Batouta, Rabat, Morocco
phenylpyrazole with ethyl acetoacetate (1.2 equiv) acetic acid at
110°C for 20h to lead to the desired product 1 with a good yield
(90%) (Scheme 1).
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800580
European Journal of Organic Chemistry
FULL PAPER
Table 1 : Optimization of the regioselective Pd C-H direct arylation
Scheme 1: Synthesis of 7-chloro pyrazolo[1,5-a]pyrimidine 2.
Product 1[13] then underwent the classical halogenation procedure
in presence of phosphorus(V) oxychloride (POCl3) to provide the
expected chloroderivative 2 [13] in 97% yield.
Entry
1
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
Pd(OH)2/C
Pd(OH)2/C
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ligand
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
-
Base
K2CO3
K2CO3
K2CO3
KOAc
Na2CO3
NaH
Solvent
Dioxane
DMF
Yield[a]
23%
5%
2
Two-step functionalization of pyrazolo[1,5-a]pyrimidine
3
DMA
4%
[14]
Using the conditions described in our previous work
the
4
Toluene
Toluene
Toluene
Toluene
Toluene
DMA
40%
8%
precursor of palladium CH direct arylation, 4-(5-methyl-2-phenyl-
1H-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine (3) was synthesized
by SNAr with morpholine as amine reagent in toluene, in 69% yield
after 24 hours of heating at 130 ° C, (Scheme 2).
5
[b]
6
-
[c]
7
K2CO3
K2CO3
KOAc
K2CO3
K2CO3
K2CO3
-
[c]
8
-
-
9
-
14%
22%
62
10
11
12
AsPPh3
PtBu3HBF4
PtBu3HBF4
Toluene
Toluene
Toluene
Scheme 2: Synthesis of 7-morpholinopyrazolo[1,5-a]pyrimidine 3.
74[d]
Regioselective Pd-catalyzed C-H direct arylation on the
pyrazolo[1,5-a]pyrimidine 3 was then studied. We started using
the conditions already described by our team[11a] with
bromobenzene (1.5 equiv.) in the presence of palladium(II)
acetate (10 mol%), triphenylphosphine (20 mol-%), and K2CO3 (2
equiv.) in dioxane, reflux, for 48 h. Under these experimental
conditions, the Pd-catalyzed direct C–H arylation took place at the
C3-position to give compound 4 in only 23% yield (Table 1, Entry
1). Encouraged by this initial result, we decided to evaluate the
influence of each reaction parameter, catalyst, ligand, base, and
solvent. Results are summarized in Table 1. Toluene was found
to be the best solvent tested while DMF and DMA drastically
lowered the yield to 5 or 4%, respectively (Table 1, Entries 2 and
3). Other catalyst systems such as Pd(PPh3)Cl2 and Pd(OH)2/C
[15] (Table 1, Entries 7–8) were also tested but were inefficient in
toluene. A low quantity of the expected compound was obtained
using Pd(OH)2/C in DMA (Table 1, Entry 9). We also investigated
the role of ligand and/or base on this cross-coupling Pd-catalyzed
direct arylation reaction and we found that the use of PtBu3HBF4
[a] Isolated yield after column chromatography, [b] degradation, [c] 100%
of the starting material was recovered, the reaction was carried out
with 2 equiv. of bromobenzene.
[d]
These optimal conditions were used to explore the scope and
limitations of the regioselective Pd-catalyzed C-H direct arylation
reaction (Table 2). Whatever the substituent on the bromoaryl
reagent (i.e., electron-donating or electron-withdrawing), the
efficiency of the direct coupling remained acceptable ranging from
49% to 88% yields (Table 2, product 5-11).
Table 2. Scope and limitations of the regiodselective C-H direct arylation of 3
[14,16]
instead of PPh3 in the presence of 10 mol-% of Pd(OAc)2,
bromobenzene (1.5 equiv.), and K2CO3 (2 equiv.) in toluene at
130 °C for 48 h provided 3 in 62% yield (Table 1, Entry 11).
Increasing the quantity of bromobenzene from 1.5 to 2.0 equiv.,
under same reaction conditions, improved the yield to 74% (Table
1, Entry 12).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800580
European Journal of Organic Chemistry
FULL PAPER
Entry
Morpholine
2.1 equiv.
1.5 equiv.
1.1 equiv.
1.1 equiv.
Bromobenzene
2 equiv.
Time (h)
48
Yield[a]
17%
35%
54%
69%
1
2
3
4
2 equiv.
48
2 equiv.
48
3 equiv.
24
[a] Isolated yield after column chromatography
Table 4. Scope and limitations of the functionalization of 2 in one-pot process
Entry
1
Amine
R-Br
Product
Yield[a]
One-pot functionalization of pyrazolo[1,5-a]pyrimidine
4,71%
As our team is involved in the search for synthetic methodologies
that have a low environmental impact, we were concerned to
develop a method that was economic in terms of energy, time and
atoms. For this reason, we planned to do the two reaction steps
in a one-pot process.
Compound 2 underwent the one-pot process using 2.1 equiv. of
morpholine, 2 equiv. of bromobenzene in presence of 10 mol %
of Pd(OAc)2, 20 mol % of PtBu3HBF4 then 2 equiv. of K2CO3 in
toluene at 130 °C, but unfortunately after 48h of reaction time only
17% of the desired product was isolated (Table 3, entry 1).
To avoid the possible poisoning of the catalyst by an excess of
amine we reduced the amount of morpholine to 1.5 equiv. then to
1.1 equiv. (Table 3, entries 2-3) to obtain the bi-functionalized
product in 54% yield.
An increase in the quantity of bromobenzene to 3 equivalent
allowed us to considerably improve the yield and to decrease the
reaction time from 48 to 24h.
The following conditions, bromobenzene (3 equiv.), morpholine
(1.1 equiv), Pd(OAc)2 (0.10 equiv.), PtBu3HBF4 (0.20 equiv.) and
K2CO3 (2 equiv.) in toluene, at 130°C for 24 hours (Table 3, entry
4) were therefore used for the generation of the small library
(Table 4).
2
3
4
5
6
7
11,82%
5,67%
17,86%
18,79%
19,64%
20,72%
Table 3. Optimization of the one-pot reaction conditions
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800580
European Journal of Organic Chemistry
FULL PAPER
dd: double doublet, ddd: double double doublet, d: doublet, t: triplet,
dt: double triplet, m: multiplet. Coupling constants (J) are reported in
Hertz (Hz). High-resolution mass spectra (HRMS) were per-formed on
a Q-TOF mass spectrometer.
8
21,45%
22,88%
5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol (1):
A
round-
bottomed flaskunder argon, a mixture of ethyl acetoacetate (7,53
mmol, 1mL), 3-Amino-5-phenylpyrazole (6,28 mmol, 1g) in acetic acid
(1mL) was heated at 110 °C for 20 h. After cooling to room
temperature the reaction mixture was filtrated, washed with ethanol,
then crystallized in the mixture DMF/ water (2:1) to give compound 1.
Beige solid (83 %; 117 mg); mp: 325-326 °C; 1H NMR (400 MHz,
DMSO-d6) δ 2.31 (s, 3H), 6.57 (s, 1H), 7.36 – 7.45 (m, 2H), 7.43 –
7.52 (m, 3H), 7.96 – 8.00 (m, 2H), 12.34 (s, 1H) ppm. 13C NMR (101
MHz, DMSO-d6) δ 18.61, 85.40, 95.28, 126.11, 128.70, 128.83,
132.46, 142.76, 150.16, 152.85, 156.09 ppm. MS (IS): m/z = 226 [M
+ 1].
9
10
23,41%
7-Chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine (2): Under
argon, a mixture of phosphorus(V) oxychloride (13.20mmol, 1.3 mL),
triethylamine (10.4 mmol, 1.5 mL), and dioxane (7,3 mL) were added
to the compound 1 (5.2mmol, 1.17g) then heated at 110°C for 3hours
and 30minutes. After cooling to room temperature the reaction mixture
was evaporated under reduced pressure then the residue was cooled
to 0 °C with water then with a saturated solution of NaHCO3 to pH=8.
After the extraction with dichloromethane (3 × 15 mL), the combined
organic layers were dried with anhydrous MgSO4. The solvent were
evaporated and the crude product was purified by column
chromatography on silica gel to give compound 2. Yellow solid (87 %;
1.1 g) mp: 180-181 °C;1H NMR (400 MHz, CDCl3) δ 2.60 (s, 3H), 6.82
(s, 1H), 6.94 (s, 1H), 7.40 – 7.50 (m, 3H), 8.00 – 8.04 (m, 2H) ppm.
13C NMR (101 MHz, CDCl3) δ 24.75, 94.27, 108.83, 126.90 (2C),
128.93(2C), 129.40, 132.60, 138.25, 150.80, 156.94, 158.55 ppm. MS
(IS): m/z = 244 [M + 1].
11
12
24,78%
25,58%
Various amine and substituted bromide halides were successfully
introduced in moderate to good yields ranging from 41% to 88%.
The morpholine was tested with bromobenzene, 4-bromotoluene
and 2-fluorobenzene leading to the desired compounds 4, 5 and
11 in good yields. We pursued the generalization with other
amines such as piperidine, 2,6-dimethylmorpholine, pyrrolidine,
1-phenylpiperazine and thiomorpholine in combination with two
aryl-bromides, either 4-bromotoluene or 4-cyanobenzene, under
the reaction conditions to obtain the expected products 17 to 25
(Table 4, entries 4-12).
4-(5-methyl-2-phenyl-1H-pyrazolo[1,5-a]pyrimidin-7-
yl)morpholine (3): Under argon, the morpholine (751mg, 8.62mmol)
was added to the compound 2 (1g, 4.10mmol) in toluene 2ml then
heated at 130°C for 25hours. After the extraction with
dichloromethane (3 × 15 mL), the combined organic layers were dried
with anhydrous MgSO4. The solvent were evaporated and the crude
product was purified by column chromatography on silica gel
(EtOAc/petroleum ether 4:6) to give compound 3. White solid (69 %;
Conclusions
1
833 mg); H NMR (400 MHz, CDCl3) δ 2.54 (s, 4H), 3.75 – 3.82 (m,
In conclusion, we have reported here a novel and efficient method
3H), 3.97 – 4.05 (m, 3H), 5.98 (s, 1H), 6.76 (s, 1H), 7.34 – 7.43 (m,
1H), 7.40 – 7.50 (m, 2H), 7.97 (dd, J = 8.4, 1.4 Hz, 2H) ppm. 13C NMR
(101 MHz, CDCl3) δ 25.10, 48.61 (2C), 66.49 (2C), 91.91, 93.16,
126.58 (2C), 128.79 (2C), 128.92, 133.29, 150.01, 152.01,
154.92,159.47 ppm. MS (IS): m/z = 295 [M + 1].
to access
a new library of 3,7-disubstitutedpyrazolo[1,5-
a]pyrimidines. The functionalization of this heterocycle was
developed in two steps then in a one-pot process. The
methodology described is original, complete regioselectivity was
obtained and various electron-rich and electron-poor substituents
were successfully introduced in good yields. The one-pot SNAr
amination/CH direct arylation allowed us to efficiently prepare
some 3,7-disubstituted pyrazolo[1,5-a]pyrimidines.
General
procedure
for
the
preparation
via C-H
of
3-
(substituted)pyrazolo[1,5-a]pyrimidine
arylation
(products 4-16)
Under an atmosphere of argon, a mixture of 3 (50.00 mg, 0.34 mmol),
aryl or heteroaryl bromide (0.68 mmol, 2.00 equiv.), K2CO3 (0.68 mmol,
2.00 equiv.), PtBu3HBF4 (0.068 mmol, 0.20 equiv.), and Pd(OAc)2
(0.034 mmol, 0.10 equiv.) in toluene (0.50 mL), was heated to 130 °C
for 48h. The mixture was then allowed to cool to room temperature.
After evaporation of the solvent under reduced pressure and the
addition of water (10 ml), the residue was extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were dried with MgSO4 and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (EtOAc/petroleum ether 4:6).
General information
All reagents were purchased from commercial suppliers and were
used without further purication. The reactions were monitored by thin-
layer chromatography (TLC) analysis using silica gel (60 F254) plates.
Compounds were visualized by UV irradiation. Flash column
chromatography was performed on silica gel 60 (230/ 400 mesh,
0.040, 0.063 mm). Melting points (mp [°C]) were taken on samples in
open capillary tubes and are uncorrected. he infrared spectra of
compounds are given in cm-1. 1H and 13C NMR spectra were recorded
on a spectrometer at 250 MHz (13C, 62.9 MHz) or 400 MHz (13C, 100
MHz). Chemical shifts are given in parts per million from
tetramethylsilane(TMS) as internal standard. The following
abbreviations are used for the proton spectra multiplicities: s: singlet,
4-(5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7-
yl)morpholine (4): Beige solid (74 %; 56 mg); mp 159-162 °C; H
1
NMR (400 MHz, CDCl3) δ 2.50 (s, 3H), 3.74 (dd, J = 3.7, 5.9 Hz, 4H),
3.91 – 3.98 (m, 4H), 5.98 (s, 1H), 7.19 – 7.24 (m, 1H), 7.27 – 7.35 (m,
5H), 7.46 – 7.53 (m, 2H), 7.56 – 7.63 (m, 2H) ppm.13C NMR (101 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800580
European Journal of Organic Chemistry
FULL PAPER
CDCl3) δ 25.38, 48.61 (2C), 66.51 (2C), 93.77, 107.37, 126.45, 128.37
(2C), 128.40 (2C), 129.18 (2C), 130.31 (2C), 132.62, 133.84, 148.95,
149.87, 152.78, 159.75 ppm. HRMS (m/z) [M+H]+ calcd for
C23H23N4O: 371.2023; found: 371.2026.
162.96 (d, J = 244.3 Hz) ppm. HRMS (m/z) [M+H]+ calcd for
C23H22FN4O: 389.1770; found: 389.1770.
4-(3-(2-fluorophenyl)-5-methyl-2-phenylpyrazolo[1,5-
a]pyrimidin-7-yl)morpholine (11): Beige solid (67 %; 44.5 mg); mp:
223-229°C;1H NMR (400 MHz, CDCl3) δ 2.52 (s, 3H), 3.80 (dd, J =
3.7, 5.9 Hz, 4H), 4.00 (dd, J = 3.7, 5.9 Hz, 4H), 6.02 (s, 1H), 7.07 –
7.14 (m, 1H), 7.21 (td, J = 1.3, 7.5 Hz, 1H), 7.30 – 7.35 (m, 4H), 7.51
(td, J = 1.9, 7.5 Hz, 1H), 7.60 – 7.68 (m, 2H) ppm. 13C NMR (101 MHz,
CDCl3) δ 25.35, 48.62 (2C), 66.51 (2C), 93.80, 101.28, 116.03 (d, J =
22.4 Hz), 120.76, 124.25 (d, J = 3.7 Hz), 128.08 (2C), 128.39 (2C),
128.46, 129.03 (d, J = 8.1 Hz), 133.27 (d, J = 3.3 Hz), 133.86, 149.48,
149.83, 153.11, 159.99, 160.64 (d, J = 247.2 Hz) ppm. HRMS (m/z)
[M+H]+ calcd for C23H22FN4O: 389.1772; found: 389.1769.
4-(5-methyl-2-phenyl-3-(p-tolyl)pyrazolo[1,5-a]pyrimidin-7-
yl)morpholine (5): Beige solid (72 %; 57 mg); mp 190-192 °C;1H
NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 2.53 (s, 3H), 3.74 – 3.82 (m,
4H), 3.99 (dd, J = 3.8, 5.8 Hz, 4H), 6.01 (s, 1H), 7.17 (d, J = 8.0 Hz,
2H), 7.30 – 7.38 (m, 3H), 7.42 (d, J = 8.0 Hz, 2H), 7.65 (td, J = 2.1,
4.0, 4.4 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 21.42, 25.35,
48.59 (2C), 66.50 (2C), 93.69, 107.38, 128.33, 128.35 (2C), 129.12
(2C), 129.17 (2C), 129.56, 130.16 (2C), 133.92, 136.04, 148.95,
149.84, 152.59, 159.56 ppm HRMS (m/z) [M+H]+ calcd for C24H25N4O:
385.2023; found: 385.2021.
4-(5-methyl-2-phenyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-
1
4-(5-methyl-2-phenyl-3-(m-tolyl)pyrazolo[1,5-a]pyrimidin-7-
yl)morpholine (6): Yellow solid (60 %; 35 mg); mp 174-177 °C; H
yl)morpholine (12): Beige solid (49 %; 37 mg); mp: 231-233°C; H
1
NMR (400 MHz, CDCl3) δ 2.58 (s, 3H), 3.77 – 3.82 (m, 4H), 3.95 –
4.00 (m, 4H), 6.09 (s, 1H), 7.38 – 7.43 (m, 3H), 7.54 – 7.61 (m, 4H),
8.52 (d, J = 5.3 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 25.39,
48.65 (2C), 66.43 (2C), 94.35, 104.03, 124.09 (2C), 128.68 (2C),
128.99, 129.36 (2C), 133.32, 149.25,149.51 (2C), 150.00, 150.83,
153.69, 160.87 ppm. HRMS (m/z) [M+H]+ calcd for: C22H23N5O:
372.1866; found: 372.1865.
NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 2.54 (s, 3H), 3.78 (dd, J = 3.7,
5.8 Hz, 4H), 3.99 (dd, J = 3.7, 5.8 Hz, 4H), 6.01 (s, 1H), 7.08 (d, J =
7.4 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.32 –
7.36 (m, 3H), 7.38 (s, 1H), 7.62 – 7.69 (m, 2H) ppm. 13C NMR (101
MHz, CDCl3) δ 21.36, 25.05, 48.27 (2C), 66.18 (2C), 93.38, 107.19,
127.02, 127.19, 127.94, 127.98 (2C), 128.02, 128.78 (2C), 130.66,
132.13, 133.54, 137.50, 148.64, 149.51, 152.36, 159.31 ppm. HRMS
(m/z) [M+H]+ calcd for C24H25N4O: 385.2023; found: 385.2021.
4-(5-methyl-3-(4-(methylthio)phenyl)-2-phenylpyrazolo[1,5-
a]pyrimidin-7-yl)morpholine (13): Beige solid (56 %; 41 mg); mp:
164-175°C;1H NMR (400 MHz, CDCl3) δ 2.50 (s, 3H), 2.54 (s, 3H),
3.78 (dd, J = 3.7, 5.9 Hz, 4H), 3.98 (dd, J = 3.6, 5.8 Hz, 4H), 6.02 (s,
1H), 7.26 (d, J = 8.4 Hz, 2H), 7.33 – 7.39 (m, 3H), 7.47 (d, J = 8.4 Hz,
2H), 7.64 (dt, J = 3.0, 4.2 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ
16.18, 25.37, 48.58 (2C), 66.48 (2C), 93.78, 106.69, 126.93 (2C),
128.43 (2C), 128.45, 129.16 (2C), 129.59, 130.57 (2C), 133.76,
136.04, 148.89, 149.86, 152.68, 159.75 ppm. HRMS (m/z) [M+H]+
calcd for C24H25N4OS: 417.1744; found: 417.1740.
4-(5-methyl-2-phenyl-3-(o-tolyl)pyrazolo[1,5-a]pyrimidin-7-
yl)morpholine (7): Beige solid (47 %; 40 mg); mp 218-220°C;1H NMR
(400 MHz, CDCl3) δ 2.10 (s, 3H), 2.52 (s, 3H), 3.64 – 3.95 (m, 4H),
4.02 – 4.05 (m, 4H), 6.04 (s, 1H), 7.22 – 7.37 (m, 7H), 7.53 – 7.65 (m,
2H) ppm. 13C NMR (101 MHz, CDCl3) δ 20.53, 25.35, 48.66 (2C),
66.55 (2C), 93.58, 107.26, 125.99, 127.70 (2C), 127.95, 128.30,
128.40 (2C), 130.42, 132.13, 132.31, 133.90, 138.28, 149.14, 149.78,
152.36, 159.40 ppm. HRMS (m/z) [M+H]+ calcd for C24H25N4O:
385.2023; found: 385.2023.
1-(4-(5-methyl-7-morpholino-2-phenylpyrazolo[1,5-a]pyrimidin-
3-yl)phenyl)ethan-1-one (14): Yellow solid (88 %; 64 mg); mp: 264-
267°C;1H NMR (400 MHz, CDCl3) δ 2.56 (s, 3H), 2.60 (s, 3H), 3.79
(dd, J = 3.7, 5.9 Hz, 4H), 3.98 (dd, J = 3.7, 5.9 Hz, 4H), 6.07 (s, 1H),
7.38 (dd, J = 2.1, 5.2 Hz, 3H), 7.58 – 7.64 (m, 2H), 7.68 (d, J = 8.6 Hz,
2H), 7.93 (d, J = 8.6 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 25.40,
26.71, 48.64, 66.47, 94.14, 106.06, 128.52, 128.57, 128.75, 129.31,
129.87, 133.54, 134.78, 138.09, 149.10, 149.95, 153.28, 160.43,
198.06 ppm. HRMS (m/z) [M+H]+ calcd for C25H25N4O2: 413.1897;
found: 413.1969.
4-(3-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-
a]pyrimidin-7-yl)morpholine (8): Beige solid (68 %; 56 mg); mp:
219-220°C;1H NMR (400 MHz, CDCl3) δ 2.53 (s, 3H), 3.75 – 3.80 (m,
4H), 3.83 (s, 3H), 3.96 – 4.01 (m, 4H), 6.01 (s, 1H), 7.31 – 7.38 (m,
3H), 7.44 (d, J = 8.9 Hz, 2H), 7.64 (dd, J = 3.1, 6.6 Hz, 2H) ppm. 13
C
NMR (101 MHz, CDCl3) δ 25.35, 48.58 (2C), 55.39, 66.50 (2C), 93.65,
107.09, 114.04 (2C), 124.97, 128.33, 128.36 (2C), 129.08 (2C),
131.41 (2C), 133.89, 148.87, 149.84, 152.49, 158.40, 159.50 ppm.
HRMS (m/z) [M+H]+ calcd for C24H25N4O2: 401.1794; found: 401.1793.
4-(3-(4-fluorophenyl)-5-methyl-2-phenylpyrazolo[1,5-
4-(5-methyl-7-morpholino-2-phenylpyrazolo[1,5-a]pyrimidin-3-
yl)benzonitrile (15): Yellow solid (71 %; 48 mg); mp: 247-250°C; 1H
NMR (250 MHz, CDCl3) δ 2.56 (s, 3H), 3.80 (s, 4H), 3.98 (s, 4H), 6.08
a]pyrimidin-7-yl)morpholine (9): Beige solid (77 %; 61 mg); mp:
213-215°C; 1H NMR (400 MHz, CDCl3) δ 2.54 (s, 3H), 3.76 – 3.81 (m,
4H), 3.97 – 4.01 (m, 4H), 6.03 (s, 1H), 7.05 (t, J = 8.8 Hz, 2H), 7.35
(dd, J = 2.4, 4.1 Hz, 3H), 7.49 (dd, J = 5.5, 8.9 Hz, 2H), 7.61 (ddd, J =
1.4, 2.4, 5.1 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 25.36, 48.60
(2C), 66.49 (2C), 93.81, 106.33, 115.38 (d, J = 21.3 Hz, 2C), 128.46
(2C), 128.51, 129.13 (2C), 128.58 (d, J = 3.3 Hz), 131.81 (d, J = 8.1
Hz, 2C), 133.63, 148.89, 149.88, 152.69, 159.88, 161.80 (d, J = 245.4
Hz) ppm. HRMS (m/z) [M+H]+ calcd for C23H22FN4O: 389.1770; found:
389.1752.
(s, 1H), 7.39 (m, 3H), 7.59 (m, 4H), 7.70 (d, J = 8.1 Hz, 2H) ppm. 13
C
NMR (101 MHz, CDCl3) δ 25.35, 48.64 (2C), 66.42 (2C), 94.28,
105.21, 109.15, 119.60, 128.66 (2C), 128.92, 129.29 (2C), 130.16
(2C), 132.07 (2C), 133.30, 137.92, 149.03, 149.96, 153.34, 160.74
ppm. HRMS (m/z) [M+H]+ calcd for C24H22N5O: 396.1819; found:
396.1815.
4-(3-(3-fluoro-4-methylphenyl)-5-methyl-2-phenylpyrazolo[1,5-
a]pyrimidin-7-yl)morpholine (16): Beige solid (67 %; 44 mg); mp:
189.-192°C;1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.55 (s, 3H),
3.78 (dd, J = 3.7, 5.9 Hz, 4H), 3.98 (dd, J = 4.1, 5.4 Hz, 4H), 6.03 (s,
1H), 7.09 – 7.20 (m, 2H), 7.26 (dd, J = 1.7, 11.2 Hz, 1H), 7.34 – 7.40
(m, 3H), 7.60 – 7.67 (m, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 14.50,
14.54, 25.36, 48.60 (2C), 66.48 (2C), 93.84, 106.20 (d, J = 2.2 Hz),
116.53 (d, J = 22.7 Hz), 122.71 (d, J = 17.2 Hz), 125.61 (d, J = 3.3
Hz), 128.45 (2C), 128.54, 129.17 (2C), 131.24 (d, J = 5.9 Hz), 132.03
(d, J = 8.8 Hz), 148.92, 149.87, 152.75, 159.92, 161.38 (d, J = 243.2
4-[3-(3-fluorophenyl)-5-methyl-2-phenyl-pyrazolo[1,5-
a]pyrimidin-7-yl]morpholine (10): Beige solid (72 %; 44.5 mg); mp:
198-201°C;1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 3.80 (d, J = 4.9
Hz, 4H), 3.99 (d, J = 5.0 Hz, 4H), 6.05 (s, 1H), 6.95 (dd, J = 4.5, 9.0
Hz, 1H), 7.27 – 7.40 (m, 6H), 7.59 – 7.67 (m, 2H) ppm. 13C NMR (101
MHz, CDCl3) δ 25.36, 48.60 (2C), 66.47 (2C), 93.93, 106.01 (d, J =
2.6 Hz), 113.15 (d, J = 21.3 Hz), 116.84 (d, J = 22.0 Hz), 125.81 (d, J
= 2.9 Hz), 128.48 (2C), 128.62, 129.22 (2C), 129.66 (d, J = 8.4 Hz),
133.54, 134.87 (d, J = 8.8 Hz), 148.91, 149.88, 152.95, 160.12,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800580
European Journal of Organic Chemistry
FULL PAPER
Hz) ppm. HRMS (m/z) [M+H]+ calcd for C24H24FN4O: 403.1917; found:
403.1925.
ppm. HRMS (m/z) [M+H]+ calcd for C24H25N4: 369.2074; found:
369.2073.
General procedure for the Amination and the C-H arylation in
“one-pot” reaction (products 17-25)
4-(5-methyl-2-phenyl-7-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-
3-yl)benzonitrile (22): Yellow solid (88 %; 72 mg); mp: 223-227°C;
1H NMR (400 MHz, CDCl3) δ 1.71 – 1.86 (m, 6H), 2.54 (s, 3H), 3.71 –
3.80 (m, 4H), 6.08 (s, 1H), 7.38 – 7.40 (m, 2H), 7.58 – 7.61 (m, 3H),
7.67 – 7.73 (m, 3H), 7.76 – 7.79 (m, 1H) ppm. 13C NMR (101 MHz,
CDCl3) δ 24.60, 25.31, 25.52 (2C), 49.75 (2C), 94.47, 104.78, 108.87,
119.71, 128.05, 128.60 (2C), 128.75, 129.29 (2C), 130.14 (2C),
132.05 (2C), 133.00, 133.55, 149.25, 150.40, 160.54 ppm. HRMS
(m/z) [M+H]+ calcd for C25H24N5: 394.2026; found: 394.2026.
In a sealed tube and under an atmosphere of argon, a mixture of 3
(50.00 mg, 0.34 mmol), amine (1.1 equiv. 0.37 mmol), aryl or
heteroaryl bromide (1.02 mmol, 3.00 equiv.), K2CO3 (0.68 mmol, 2.00
equiv.), PtBu3HBF4 (0.068 mmol, 0.20 equiv.), and Pd(OAc)2 (0.034
mmol, 0.10 equiv.) in toluene (0.5 mL), was heated to 130 °C for 24h.
The mixture was then allowed to cool to room temperature. After
evaporation of the solvent under reduced pressure and the addition of
water (10 mL), the residue was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were dried with MgSO4 and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (EtOAc/petroleum ether 4:6).
4-(5-methyl-2-phenyl-7-(4-phenylpiperazin-1-yl)pyrazolo[1,5-
a]pyrimidin-3-yl)benzonitrile (23): Beige solid (41 %; 40 mg); mp:
245-250°C;1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 3.42 – 3.49 (m,
4H), 3.94 – 4.01 (m, 4H), 6.14 (s, 1H), 6.93 (t, J = 7.3 Hz, 1H), 7.02
(s, 2H), 7.29 – 7.34 (m, 2H), 7.40 (dd, J = 2.1, 5.1Hz, 3H), 7.58 – 7.62
(m, 4H), 7.72 (d, J = 8.6 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ
31.06, 48.32 (2C), 49.19 (2C), 94.57, 105.20, 109.13, 116.75 (2C),
119.65, 120.78, 128.68 (2C), 128.92, 129.31 (2C), 129.44 (2C),
130.19 (2C), 132.11 (2C), 133.38, 138.00, 149.11, 149.92, 151.09,
153.30, 160.72 ppm. HRMS (m/z) [M+H]+ calcd for C30H27N6:
471.2292; found: 471.2288.
5-methyl-2-phenyl-7-(piperidin-1-yl)-3-(p-tolyl)pyrazolo[1,5-
a]pyrimidine (17): Yellow solid (86 %; 68.5 mg); mp: 174-176°C; 1H
NMR (400 MHz, CDCl3) δ 1.73 – 1.88 (m, 6H), 2.37 (s, 3H), 2.51 (s,
3H), 3.73 (t, J = 5.4 Hz, 4H), 6.01 (s, 1H), 7.16 (d, J = 7.9 Hz, 2H),
7.30 – 7.37 (m, 3H), 7.40 – 7.46 (m, 2H), 7.66 – 7.71 (m, 2H) ppm.
13C NMR (101 MHz, CDCl3) δ 21.42, 24.71, 25.32, 25.54 (2C), 49.64
(2C), 93.88, 106.98, 128.14, 128.27 (2C), 129.11 (2C), 129.13 (2C),
129.90, 130.20 (2C), 134.19, 135.82, 149.16, 150.39, 152.19, 159.40
ppm. HRMS (m/z) [M+H]+ calcd for C25H27N4: 383.2230; found:
383.2232.
4-(7-(2,6-dimethylmorpholino)-5-methyl-2-phenylpyrazolo[1,5-
a]pyrimidin-3-yl)benzonitrile (24): Beige solid (78 %; 68 mg); mp:
1
240-244°C; H NMR (400 MHz, CDCl3) δ 1.28 (s, 3H), 1.30 (s, 3H),
3-(4-methoxyphenyl)-5-methyl-2-phenyl-7-(piperidin-1-
2.56 (s, 3H), 2.73 (dd, J = 10.4 , 12.3 Hz, 2H), 3.98 (ddd, J = 2.3, 6.3,
10.5 Hz, 2H), 4.37 – 4.44 (m, 2H), 6.07 (s, 1H), 7.40 (dd, J = 2.0, 5.2
Hz, 3H), 7.55 – 7.61 (m, 4H), 7.68 – 7.72 (m, 2H) ppm. 13C NMR (101
MHz, CDCl3) δ 19.04 (2C), 25.32, 53.62 (2C), 71.30 (2C), 94.40,
105.13, 109.11, 119.62, 128.67 (2C), 128.88 (2C), 129.25, 130.18
(2C), 132.08 (2C), 133.32, 137.98, 149.10, 149.60, 153.21, 160.67
ppm. HRMS (m/z) [M+H]+ calcd for C26H26N5O: 424.2132; found:
424.2130.
yl)pyrazolo[1,5-a]pyrimidine (18): Beige solid (79 %; 64 mg); mp:
170-177°C;1H NMR (400 MHz, CDCl3) δ 1.73 – 1.87 (m, 6H), 2.51 (s,
3H), 3.72 – 3.75 (m, 3H), 3.83 (s, 4H), 6.00 (s, 1H), 6.89 – 6.93 (m,
2H), 7.33 (dd, J = 1.8, 5.2 Hz, 3H), 7.45 (d, J = 8.9 Hz, 2H), 7.65 –
7.70 (m, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 24.73, 25.34, 25.55
(2C), 44.87, 49.65 (2C), 55.40, 93.84, 100.14, 112.08, 114.01 (2C),
115.92, 125.35, 128.15, 128.31 (2C), 129.08 (2C), 131.45 (2C),
143.29, 152.91, 158.30 ppm. HRMS (m/z) [M+H]+ calcd for
C25H27N4O: 399.2179; found: 399.2176.
4-(5-methyl-2-phenyl-7-thiomorpholinopyrazolo[1,5-a]pyrimidin-
3-yl)benzonitrile (25): Yellow solid (58 %; 49 mg); mp: 226-230°C;
1H NMR (400 MHz, CDCl3) δ 2.55 (s, 3H), 2.87 – 2.93 (m, 4H), 4.04 –
4.10 (m, 4H), 6.09 (s, 1H), 7.40 (dd, J = 2.2, 5.1 Hz, 3H), 7.56 – 7.61
(m, 4H), 7.69 – 7.72 (m, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 25.21,
26.98 (2C), 50.94 (2C), 94.86, 105.12, 109.04, 119.49, 128.56 (2C),
128.79, 129.10 (2C), 130.05 (2C), 131.98 (2C), 133.18, 137.80,
149.00, 149.70, 160.54, 153.08 ppm. HRMS (m/z) [M+H]+ calcd for
C24H22N5S: 412.1590; found: 412.1588.
2,6-dimethyl-4-(5-methyl-2-phenyl-3-(p-tolyl)pyrazolo[1,5-
a]pyrimidin-7-yl)morpholine (19): Brown solid (64 %; 54 mg); mp:
1
182-186°C; H NMR (400 MHz, CDCl3) δ 1.32 (s, 3H), 1.33 (s, 3H),
2.40 (s, 3H), 2.56 (s, 3H), 2.73 (t, J = 11.3 Hz, 2H), 4.05 (td, J = 3.1,
6.4 Hz, 2H), 4.43 (d, J = 11.9 Hz, 2H), 6.02 (s, 1H), 7.20 (d, J = 7.9
Hz, 2H), 7.36 – 7.40 (m, 3H), 7.46 (d, J = 7.9 Hz, 2H), 7.69 (dd, J =
3.1, 6.7Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 19.07 (2C), 21.40,
25.31, 53.57 (2C), 71.31 (2C), 93.77, 107.30, 128.26, 128.33 (2C),
129.05 (2C), 129.15 (2C), 129.62, 130.17 (2C), 133.94, 135.98,
149.03, 149.46, 152.41, 159.48 ppm. HRMS (m/z) [M+H]+ calcd for
C26H29N4O: 413.2336; found: 413.2338.
Acknowledgements
4-(5-methyl-2-phenyl-3-(p-tolyl)pyrazolo[1,5-a]pyrimidin-7-
yl)thiomorpholine (20): Beige solid (72 %; 59 mg); mp: 260-264°C;
1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 2.52 (s, 3H), 2.89 – 2.94
(m, 4H), 4.02 – 4.08 (m, 4H), 6.01 (s, 1H), 7.17 (d, J = 8.1 Hz, 2H),
7.32 – 7.36 (m, 3H), 7.42 (d, J = 8.2 Hz, 2H), 7.64 – 7.69 (m, 2H) ppm.
13C NMR (101 MHz, CDCl3) δ 21.42, 25.34, 27.15 (2C), 50.94 (2C),
94.41, 128.31, 128.36 (2C), 129.05 (2C), 129.18 (2C), 129.55,
129.60, 130.18 (2C), 133.95, 136.03, 149.05, 149.74, 152.42, 159.49
ppm. HRMS (m/z) [M+H]+ calcd for C24H25N4S: 401.17944; found:
401.17934.
We acknowledge the Region Centre for financial support.
Conflicts of interest
The authors declare no conflict of interest.
Keywords: • pyrazolo[1,5-a]pyrimidine , • C-H arylation • one-
pot • Pd-catalysed • Amination
5-methyl-2-phenyl-7-(pyrrolidin-1-yl)-3-(p-tolyl)pyrazolo[1,5-
1
a]pyrimidine (21): Beige solid (45 %; 34 mg); mp: 178-180°C; H
NMR (400 MHz, CDCl3) δ 2.01 – 2.07 (m, 4H), 2.36 (s, 3H), 2.44 (s,
3H), 3.98 – 4.08 (m, 4H), 5.66 (s, 1H), 7.15 (d, J = 8.1 Hz, 2H), 7.33
(dd, J = 2.0, 5.1 Hz, 3H), 7.42 (d, J = 8.1 Hz, 2H), 7.62 – 7.69 (m, 2H)
ppm. 13C NMR (101 MHz, CDCl3) δ 21.40, 25.21, 25.61 (2C), 50.84
(2C), 89.64, 105.80, 128.04, 128.26 (2C), 128.99 (2C), 129.07 (2C),
129.44, 130.14 (2C), 134.40, 135.56, 147.28, 149.58, 152.01, 159.52
Reference
[1]
a) J. A. Joule, K. Mills, Heterocyclic Chemistry, 4th ed., Black Sciences
Oxford, UK, 2000. b) N. A. McGrath, M. Brichacek, J. T. Njardarson, J.
Chem. Educ. 2010, 87, 1348-1349.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800580
European Journal of Organic Chemistry
FULL PAPER
[2]
a) M.H. Elnagdi, M. R. H. Elmoghayar, G. H. Elgemeie, Adv. Heterocycl.
Chem., 1987, 41,319-376. b) V.S. Dinakaran, B. Bomma, K. K.
Srinivasan, Der Pharm. Chem., 2012, 4, 255-265. c) V. Masevicius, R.
Juskenas, S. Tumkevicius, J. Heterocycl. Chem., 2012, 49, 315-320. d)
M. Chauhan, R. Kumar, Bioorg. Med. Chem., 2013, 21, 5657-5668. e) M.
C. Bagley, M. Baashen, V. L. Paddock, D. Kipling, T. Davis, Tetrahedron,
2013, 39, 8429-8438. f) M. Drev, U. Groselj, S. Mevec, E. Pusavec, J.
Strekelj, A. Golobic, G. Dahmann, B. Stanovnik, J. Svete, Tetrahedron,
2014, 70, 8267-8279.
Shankaraiah Guruvaiah, Eur. J. Chem. 2014, 5, 676-680. c) Saikia,
Pallabi; Kaishap, Partha Pratim; Prakash, Rashmi; Shekarrao, Kommuri;
Gogoi, Sanjib; Boruah, Romesh C. Tetrahedron Lett., 2014, 55, 3896-
3900. d) D. Marzouq, Z. Salman, S. Omniya, A. A. Al Najjar, K. U. Sadek,
Eur. J. Chem. 2016, 7, 347-351. e) J-C. Castillo, D. Estupinan, M.
Nogueras, J. Cobo, J. Portilla, J. Org. Chem. 2016, 81, 12364-12373. f)
P. Golubev, E. A. Karpova, A. S. Pankova, M. Sorokina, M. A. Kuznetsov,
J. Org. Chem. 2016, 81, 11268-11275. g) J. Sun, J-K. Qiu, B. Jiang, W-
J. Hao, C. Guo, S-J. Tu, J. Org. Chem., 2016, 81, 3321-3328. h) I.
Bassoude, Z. Tber, E. Essassi, G. Guillaumet, S. Berteina-Raboin, RSC
Advances. 2016, 6, 3301-3306. i) Z. Li, D. Xie, J. He, Yan. Du, J. Yang,
J. Chem. Sci. 2017, 129, 1579-1586.
[3]
a) T. M. A. Elmaati, F. M. A. El-Taweel, J. Chin. Chem. Soc., 2003, 50,
413-418. b) G. Lavecchia, S. Berteina-Raboin, G. Guillaumet,
Tetrahedron Lett. 2004, 45, 6633-6636. c) G. Lavecchia, S. Berteina-
Raboin, G. Guillaumet, Tetrahedron Lett. 2004, 45, 2389-2392. d) Y. D.
Wang, E. Honores, B. Wu, S. Johnson, D. Powell, M. Miranda, J. P.
Mcginnis, C. Discafani, S. K. Rabindran, W. Cheng., G. Krishnamurthy,
Bioorg. Med. Chem., 2009, 17, 2091-2100. e) A. M. Hussein, J. Saudi
Chem. Soc, 2010, 14, 61-68. f) M.P. Dwyer, K. Paruch, M. Labroli, C.
Alvarez, K. M. Keertikar, C. Poker, R. Rossman, T. O. Fischmann, J. S.
Duca, V. Madison, D. Parry, N. Davis, W. Seghezzi, D. Wiswell, T. J.
Guzi, Bioorg. Med. Chem. Lett., 2011, 21, 467-470. g) A. Hassan,
D .Masoud, F. Sroor, A. Askar. Med. Chem. Res, 2017, 11, 2909-2919.
h) C. Bagul, G. Koteswara Rao, V. K. K.Makani, J. R. Tamboli, M. Pal-
Bhadra, A. Kamal, Med. Chem. Commun., 2017, 8, 1810-1816. i)
B.Carbain, J. Fankrlik, L. Musilova, S. Haldar, C. Kopruluoglu, H.Ajani,
P.S.Brahmkshatriya, R. Jorda, V. Krystof, P. Hobza, A. Echalier, K.
Paruch, M. Lepsik, Eur. J. Med. Chem, 2017, 126, 1118-1128.
C. Almansa, A. F. de Arriba, F. L. Cavalcanti, L.A. Gomez, A. Miralles,
M. Merlos, J.G. Rafanell, J. Forn, J. Med. Chem. 2001, 44, 350-361.
W. E. Kirkipatrick, T. Okabe, I. W. Hillyard, R. K. Robins, A. T. Dren, T.
Novinson, J. Med. Chem. 1977, 20, 386-393.
[11] a) J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib, G.
Guillaumet, Synlett 2006, 3237-3242. b) J. Koubachi, S. El Kazzouli, S.
Berteina-Raboin, A. Mouaddib, G. Guillaumet, J. Org. Chem. 2007, 72,
7650-7655. c) N. Lebrasseur, I. Larrosa, A. R. Katritzky, Ed. Adv.
Heterocycl. Chem. 2012, 105, 309-351. d) L. G. Mercier, M. Leclerc, Acc.
Chem. Res. 2013, 46, 1597-1605. e) R Rossi, F. Bellina, M. Lessi, C.
Manzini, L. A. Perego, Synthesis 2014, 46, 2833-2883. f) R. Rossi, M.
Lessi, C. Manzini, G. Marianetti, F. Bellina, Adv. Synth. Catal. 2015, 357,
3777-3814.
[12] a) L. Ackermann, Chem. Rev., 2011, 111, 1315-1345. b) K. M. Engle, T.
S. Mei, M. Wasa, J. Q. Yu, Acc. Chem. Res., 2012, 45, 788-802. c) S. R.
Neufeldt, M. S. Sanford, Acc. Chem. Res., 2012, 45, 936-946. d) X. X.
Cuo, D. W. Gu, Z. Wu, W. Zhang, Chem. Rev. 2015, 115,1622-1651. e)
T. Gensch, M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc.
Rev. 2016, 45, 2900-2936. f) Y. Park, Y. Kim, S. Chang, Chem. Rev.,
2017, 117, 9247-9301. g) Z. Dong, Z. Ren, S.J. Thompson, Y. Xu, G.
Dong, Chem. Rev., 2017, 117, 9333-9403. h) R.B. Bedford, S.J. Durrant,
M. Montgomery Angew. Chem. Int. Ed 2015, 54, 8787-8790.
[13] I. Bassoude, S. Berteina-Raboin, El M. Essassi, G. Guillaumet, L. El
Ammari, Acta Crystallogr. E 2013, 69, 749.
[4]
[5]
[6]
[7]
B. M. Shaikh, S. G. Konda, S. S. Chobe, G. G. Mandawad, O. S. Yemul,
B. S. Dawane, J. Chem. Pharm. Res. 2011, 3, 435-443.
a) E. Sanna, F. Busonero, G. Talani, M. Carta, F. Massa, M. Peis, E.
Maciocco, Eur. J. Pharmacol. 2002, 2, 103-110. b) P. G. Baraldi, F.
Fruttarolo, M. A. Tabrizi, R. Romagnoli, D. Preti, E. Ongini, H. El-Kashef,
M. D. Carrion, P. A. Borea, J. Heterocyclic. Chem. 2007, 44, 355-361.
a) J. Castillo-Sánchez, A. A-d. Real, M. Rodriguez-Sánchez, A.
Valverde-García, J. Agric. Food Chem. 2000, 48, 2991-2994. b) A. S.
Hassan, T. S. Hafez, S. A. Osman, Sci. Pharm., 2015, 83, 27-39.
a) J.K. Walsh, A. Moscovitch, J. Burke, R. Farber, T. Roth, Sleep Med,
2007, 8, 753. b) P. Kaswan, K. Pericherla, D. Purohit, A. Kumar,
Tetrahedron Lett. 2015, 56, 549-553.
[14] J.F. Campos, M.J.R.P Queiroz, S. Berteina-Raboin, Catalysts, 2018, 8,
137.
[15] M. Parisien, D. Valette, K. Fagnou, J. Org. Chem. 2005, 70, 7578–
7584.
[8]
[9]
[16] M. Loubidi, A. Moutardier, J. F. Campos, S. Berteina-Raboin,
Tetrahedron Lett. 2018, 59, 1050-1054
.
[10] a) I. Bassoude, S. Berteina-Raboin, S. Massip, J. M. Leger, C. Jarry, E.
Essassi, G. Guillaumet, Eur. J. Org. Chem. 2012, 2572-2578. b) K.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800580
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
We report in this paper a novel and
efficient protocol for the synthesis of a
3,7-disubstituted pyrazolo[1,5-
a]pyrimidine library via a SNAr
amination followed by palladium-
catalyzed direct arylation.
Mohammed Loubidi[a], Catherine
Manga[a], Zahira Tber[a], Ibtissam
Bassoude[b], El Mokhtar Essassi[b] and
Sabine Berteina-Raboin[a]*
Page No. – Page No.
One pot SNAr/Direct Pd-catalyzed CH
arylation functionalization of
pyrazolo[1,5-a]pyrimidine in C3 and
C7 positions
Layout 2:
FULL PAPER
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here; max. width: 11.5 cm; max. height: 2.5 cm))
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.