Pd-catalyzed Suzuki/Sonogashira cross-coupling reaction and the direct sp3 arylation of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

Article abstract of DOI:10.1016/j.tetlet.2018.02.001

A rapid and efficient method is reported for the synthesis of the [1,2,4]triazolo[1,5-a]pyrimidine motif. Palladium catalyzed Suzuki and Sonogashira cross coupling reactions on 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine were performed. The direct sp³ arylation of compounds resulting from the Suzuki reaction was then carried out.

Full text of DOI:10.1016/j.tetlet.2018.02.001

Accepted Manuscript
Pd-catalyzed Suzuki/Sonogashira cross-coupling reaction and the direct sp3 ar-
ylation of 7-chloro-5-methyl-[1, 2, 4]triazolo[1, 5-a]pyrimidine
Mohammed Loubidi, Anaïs Moutardier, Joana F. Campos, Sabine Berteina-
Raboin
PII:
S0040-4039(18)30158-8
https://doi.org/10.1016/j.tetlet.2018.02.001
TETL 49686
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
1 December 2017
27 January 2018
1 February 2018
Please cite this article as: Loubidi, M., Moutardier, A., Campos, J.F., Berteina-Raboin, S., Pd-catalyzed Suzuki/
Sonogashira cross-coupling reaction and the direct sp3 arylation of 7-chloro-5-methyl-[1, 2, 4]triazolo[1, 5-
a]pyrimidine, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.001
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Pd-catalyzed Suzuki/Sonogashira cross-coupling reaction
and the direct sp3 arylation of 7-chloro-5-methyl-
[1,2,4]triazolo[1,5-a]pyrimidine
Leave this area blank for abstract info.
Mohammed Loubidi, Anaïs Moutardier, Joana F. Campos, Sabine Berteina-Raboin*

1
Tetrahedron Letters
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Pd-catalyzed Suzuki/Sonogashira cross-coupling reaction and the direct sp3 arylation
of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine
Mohammed Loubidi , Anaïs Moutardier, Joana F. Campos , Sabine Berteina-Raboin*
Institute of Organic and Analytical Chemistry, University of Orleans, UMR-CNRS 7311, BP 6759, rue de Chartres, 45067 Orléans cedex 2, France.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Available online
A rapid and efficient method is reported for the synthesis of the [1,2,4]triazolo[1,5-
a]pyrimidine motif. Palladium catalyzed Suzuki and Sonogashira cross coupling
reactions on 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine were performed. The
direct sp3 arylation of compounds resulting from the Suzuki reaction was then carried
out.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Triazolo[1,5-a]pyrimidine
Suzuki
Sonogashira
Palladium
Direct sp3 arylation
N-heterocycles or fused nitrogen heterocycles are
interesting synthetic targets in the search for biologically active
molecules. For this reason, nitrogen bridgehead heterocycles
have received considerable attention in organic synthesis.1
In continuation of our research program, we report
herein a rapid and efficient pathway for the preparation of 7-
(substituted)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine from
[1,2,4]triazolo[1,5-a]pyrimidine by functionalization using
Suzuki and Sonogashira palladium-catalyzed cross coupling
reactions. The direct C-H arylation of 7-(substituted)-5-methyl-
[1,2,4]triazolo[1,5-a]pyrimidine at the sp3 center is also
described.
In particular, the [1,2,4]triazolo[1,5-a]pyrimidine
subunit has displayed a wide range of biological activities, for
example as a PDE2a inhibitor for the treatment of memory
disorders,2 LSD1 inhibitor,3 anti-Alzheimer’s,4 anticancer,5 anti-
malarial,6 anti-tubercular,7 anti-leishmanial,8 anti-bacterial,9 anti-
viral,10 and hypnotic agent,11 and as a CB2 cannabinoid receptor
inverse agonist.12
First, 7-chloro-5-methyl-[1,2,4]triazolo[1,5-
a]pyrimidine 4 was synthesized in a two-step process (Scheme
While condensation reactions are the most widely used
method to prepare the [1,2,4]triazolo[1,5-a]pyrimidine scaffold,13
relatively few publications have reported the functionalization of
this scaffold using transition metals. Among the latter, the
functionalization, or more precisely creation of a carbon-carbon
bond, via a transition metal-catalyzed cross-coupling reaction is
undoubtedly the most important and has been widely exploited in
recent years. Palladium, the most commonly used metal, enables
the synthesis of complex and functionalized organic molecules
and its chemistry possesses interesting properties such as
allowing heterogeneous and homogeneous catalysis under mild
experimental conditions which are compatible with many
functional groups. Several palladium-catalyzed cross-coupling
reactions have been described such as the Suzuki14 or
1).
Scheme 1. Two-step preparation of the intermediate 7-chloro-5-
methyl-[1,2,4]triazolo[1,5-a]pyrimidine 4
The condensation reaction between 2-aminotriazole 1 and ethyl
acetoacetate resulted in the formation of 5-
methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-ol 3 in 83% yield. Next,
chlorination of 5-methyl-[1,2,4]triazolo[1,5-a] pyrimidin-7-ol
with POCl3 gave 7-chloro-5-methyl-[1,2,4]triazolo[1,5-
a]pyrimidine 4 in 65% yield.17
Sonogashira reactions.15 Recently, several heterocyclic systems
have also been functionalized using direct C-H arylation.16
*Corresponding author:
e-mail address: sabine.berteina-raboin@univ-orleans.fr
Tel: +33-238494856
Optimization of the Suzuki cross coupling reaction with
triazolo-pyrimidine skeleton 4 was performed using p-
methoxyphenylboronic acid as a model substrate. The use of

2
different palladium sources (palladium(II) acetate or
determined as: boronic acid (1.5 equiv.), Pd(PPh3)4 (0.10
palladium(0) tetrakis triphenylphosphine) as catalysts, sodium
bicarbonate or cesium carbonate as bases, and 1,4-dioxane or
water as solvents were examined. The best conditions were
equiv.), Na2CO3 (2.0 equiv.) 1,4-dioxane/water (4/1), 105 °C, 24
h (Table 1, entry 3).
Table 1. Reaction conditions optimization for the Suzuki cross coupling reaction
Solvent
(3 mL)
Entry
Pd
Base
T (°C)
Yield 5 (%)a
Pd(PPh3)4
Pd(OAc)2/ Xantphos
Na2CO3 water
Cs2CO3 Dioxane
105
105
49%
61%
1
2
Dioxane/water
(4/1)
3
Pd(PPh3)4
Na2CO3
105
81%
a Isolated yield after column chromatography
Different boronic acids were then used to determine the
reaction scope. Several 5-methyl-7-(aryl)-[1,2,4]triazolo[1,5-
a]pyrimidines were obtained in good to excellent yields, showing
that this strategy was compatible with both electron-rich
(CH3, OCH3) and electron-poor (CN, OCF3) boronic acids.
The trifluoromethoxyphenyl boronic acid is an electron-poor
boronic acid to an extent; however, its inductive electron-
withdrawing ability is moderate compared to fluoride, and is
actually a very weak resonance donor. This potentially
explains the yield of 8 being closer to that of 6 than to that of
7, the latter of which is derived from a more electron-deficient
aryl boronic acid. The examples containing fluorine
derivatives were chosen because of the well-known
improvement of pharmacological properties often promoted
with the introduction of fluorine. These conditions were also
applied to introduce selected heteroarylboronic acids (Table
2).
Table 2. Scope of the Suzuki–Miyaura cross coupling of 7-chloro-5-methyl- [1,2,4]triazolo[1,5-a]pyrimidine 4
Yield (%)a
81%
Entry
5
R-B(OH)2 product
Yield (%)a
51%
Entry
1
R-B(OH)2 product
9
5
6
7
72%
32%
10 65%
2
3
6
7
11 63%
70%
12 46%
4
8
8

3
a Isolated yield after column chromatography
After having successfully achieved the Suzuki cross
coupling reaction of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-
a]pyrimidine 4, we then focused on introducing greater diversity
by employing the Sonogashira coupling reaction. To achieve this
goal, previously described18 conditions were used (alkyne (1.2
equiv.), Pd(PPh3)2Cl2 (5 mol%), CuI (10 mol%), DMF/Et3N
(1/1), reflux, 1.5 h). Three alkynes were successfully introduced
onto [1,2,4]triazolo[1,5-a]pyrimidine 4 with good yields (Table
3, entries 1, 3 and 4), except for the ethynyl benzene bearing a
nitro group in the para position (Table 3, entry 2).
Table 3. Synthesis of 7-alkynyl-substituted-[1,2,4]triazolo[1,5-a]pyrimidines
Yield
Yield
(%)a
Entry
Alkyne
Product
Entry Alkyne
Product
(%)a
13
81%
14
65%
1
3
15
53%
2
-
4
a Isolated yield after column chromatography
The last stage was to study the direct C-H arylation. To
optimize this reaction, 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine
containing a 4-methoxyphenyl group at the 7-position was
used as the starting material, and bromobenzene as the
coupling partner (Table 4). Various reaction conditions were
investigated using different catalyst systems, bases, ligands,
and solvents. Total conversion was obtained when
TTBP•HBF4/Pd(OAc)2 was used as catalyst and K2CO3 as a base
in toluene at 120 °C for 48 h, affording the desired products in
56% yield and an 85:15 ratio of mono vs disubstitution.
Table 4. Optimization of the direct C-H arylation of 7-(4-methoxyphenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine 5
Entry
Ligand
Base
Solvent
Ratio a
Yield (%)b
16-17
16-17
TTBP•HBF4
1
K2CO3
Toluene
85
15
56
9
2
PPh3
K2CO3
Toluene
62
38
36
12
3
4
5
TTBP•HBF4
Cs2CO3
K2CO3
K2CO3
Toluene
Toluene
Toluene
75
80
85
25
20
15
27
38
41
7
-
-
8c
7
d
d
6
7
-
K2CO3
K2CO3
Dioxane
Dioxane
-
-
-
-
-
-
d
d
TTBP•HBF4
-
-

4
a 1H NMR ratio based on integration of the OCH3 resonance;b Isolated yield after column
chromatography; c reaction carried out with Pd(PPh3)4 (10 mol%); d degradation.
a]pyrimidines was prepared using the optimized reaction
conditions. The desired compounds were isolated in acceptable
yields. In entries 3 and 5 (Table 5) only the major products were
recovered.
In order to examine the scope of the direct sp3 arylation
reaction, a series of 5-substituted-[1,2,4]triazolo[1,5-
Table 5. Substrate scope for the direct C-H arylation
R1
R2
Yield (%)a
Entry
1
16, 56%
18, 48%
17, 9%
19, 8%
2
20, 63%
22, 40%
24, 43%
21, 0%
23, 8%
25, 0%
3
4
5
a Isolated yield after column chromatography
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A. Supplementary data
Supplementary data (experimental section and copies of spec-
tra for all of compounds) associated with this article can be
found, in the online version, at https://doi.org/
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HIGHLIGHTS
Heterocyclic nitrogen compounds
Triazolo[1,5-a]pyrimidine synthesis
Palladium cross-coupling
Direct sp3 arylation