Microwave-assisted synthesis of 2,5-disubstituted pyrimidine derivatives via Buchwald-Hartwig amination

Article abstract of DOI:10.1016/j.tetlet.2019.151406

Various 2,5-disubstituted pyrimidine derivatives were synthesized under microwave irradiation via Buchwald-Hartwig amination. This concise approach provides interesting scaffolds in good to high yields and with large functional group compatibility. These

Full text of DOI:10.1016/j.tetlet.2019.151406

Journal Pre-proofs
Microwave-assisted synthesis of 2,5-disubstituted pyrimidine derivatives via
Buchwald-Hartwig amination
Bo Li, Mélanie Etheve-Quelquejeu, Expédite Yen Pon, Christiane Garbay,
Huixiong Chen
PII:
S0040-4039(19)31197-9
DOI:
https://doi.org/10.1016/j.tetlet.2019.151406
TETL 151406
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 October 2019
8 November 2019
13 November 2019
Please cite this article as: Li, B., Etheve-Quelquejeu, M., Pon, E.Y., Garbay, C., Chen, H., Microwave-assisted
synthesis of 2,5-disubstituted pyrimidine derivatives via Buchwald-Hartwig amination, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.151406
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Bo Li, Mélanie Etheve-Quelquejeu, Expédite Yen Pon, Christiane Garbay and Huixiong Chen

1
Tetrahedron Letters
Microwave-assisted synthesis of 2,5-disubstituted pyrimidine derivatives via
Buchwald-Hartwig amination
Bo Li, Mélanie Etheve-Quelquejeu, Expédite Yen Pon, Christiane Garbay and Huixiong Chen
Chemistry of RNA, nucleosides, peptides and heterocycles, CNRS UMR8601, Université Paris Descartes, 45 rue des Saints-Pères, Paris 75006, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Various 2,5-disubstituted pyrimidine derivatives were synthesized under microwave irradiation
via Buchwald-Hartwig amination. This concise approach provides interesting scaffolds in good
to high yields and with large functional group compatibility. These novel chemical entities could
be used as building blocks in drug design.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimidine
Pd-catalyzed
C-N cross-coupling
Microwave synthesis
1. Introduction
Pyrimidines are one of two biologically important families of
nitrogenous bases, which include cytosine and thymine in DNA
and cytosine and uracil in RNA. Substituted pyrimidines have
been found in a large variety of biologically active natural and
synthetic products [1–3], and are also used as building blocks for
a number of commercial drugs including the tyrosine kinase
inhibitor Gleevec® [4], the HMG-CoA reductase inhibitor
Crestor® [5], the 5-HT1A receptor agonist Buspirone [6], and the
dihydrofolate reductase inhibitor Trimethoprim [7]. Several
pyrimidine derivatives possess medicinal properties such as anti-
cancer [1], anti-bacterial [8], antiviral [9], anti-inflammatory
[10], anti-arthritic [11], anti-diabetic [12], antihypertensive [13],
anti-analgesic [14], antipyretic [15] and antiplatelet activities
[16]. Among them, 2,5-disubstituted pyrimidine-containing small
molecules have also attracted significant attention due to their
interesting pharmacological activities (Fig. 1) [5, 17–21].
Our interest in the development of 2,5-disubstituted
pyrimidine scaffolds prompted us to develop a scalable method
for their synthesis. Despite the simple structural features of these
scaffolds, our synthetic efforts encountered major setbacks, due
to low reactivity at the 5 position of the pyrimidine ring. A
review of the literature for the Pd-catalyzed amination of aryl
halides and heteroaryl halides provided few successful examples
of C-N cross-couplings with 2-substituted-5-bromopyrimidines,
which have been less explored and usually gave modest yields
[22].
Figure 1. Selected bioactive compounds containing 2,5-disubstituted
pyrimidine frameworks.
In recent decades, palladium-catalyzed C-N coupling under
microwave (MW) irradiation has become a powerful technique
for the synthesis of various heterocyclic compounds [23, 24].
Herein, we report optimized conditions, substrate scope, and
———
Corresponding author.
E-mail address: huixiong.chen@parisdescartes.fr (H. Chen)

2
Tetrahedron Letters
applications of the Pd-catalyzed C-N cross-coupling of 2-
substituted-5-bromo-pyrimidines under MW irradiation, which
provided facile access to these compounds with good to high
yields.
With the optimized conditions in hand (Table 1, entry 9), we
explored the substrate scope of the amine to assess the generality
of the reaction (Table 2). Firstly, electron-donating groups
(EDGs) on the aromatic ring of different arylamines, such as m-
methyl (Table 2, entry 1), o-methoxy (Table 2, entry 2), p-
methoxy (Table 2, entry 3) and m-methoxy groups (Table 2,
entry 4) provided the desired products 2b–e in high yields.
Heteroarylamines with EDGs such as methoxy (Table 2, entry 5)
and alkyl groups (Table 2, entry 6) reacted with 5-bromo-2-
methylpyrimidine 1a, affording the corresponding products 2f–g
in 64−84% yield. Aniline reacted well with 2-methyl-5-
bromopyrimidine (Table 2, entry 7) giving the corresponding
product 2h in 82% yield. On the other hand, the arylamines
bearing strong electron withdrawing groups (EWGs) including
m-CF3 (Table 2, entry 8), p-CF3 (Table 2, entry 9) and m-CN
(Table 2, entry 10) were tolerated, leading to the corresponding
products 2i–k in 59−82% yield. In addition, the arylamine
bearing o-CO2H also reacted well with 1a affording the desired
product 2m in 67% yield (Table 2, entry 12). The reaction of 4-
aminobenzoate ester with 1a gave a mixture of the desired
product and its hydrolyzed compound with a poor yield. When
the MW irradiation time was shortened to 30 minutes, we were
pleased to obtain the product in 55% yield. In particular,
arylamines bearing an inductive electron-withdrawing o-F group
(Table 2, entry 13) gave the desired product in a nearly
quantitative yield. Finally, the substrate scope of the amine was
also extended to several secondary amines such as morpholine
(Table 2, entry 14) and a piperidine derivative (Table 2, entry
15), providing the desired coupling products in good to excellent
yields.
2. Results and Discussion
Initially, the palladium-catalyzed C-N cross-coupling reaction
of commercially available 5-bromo-2-methylpyrimidine 1a with
4-aminobenzonitrile was selected as a model reaction to optimize
the MW conditions. Upon performing the reaction in a sealed
tube, we noted that the optimal yields were achieved when the
reaction was performed at 120 °C. The reaction time was
adjusted to 1 h in order to obtain maximum conversion without
causing decomposition of the products. Then, we examined the
reaction in the presence of different palladium catalysts using
XPhos and Cs2CO3 in 1,4-dioxane (Table 1, entries 1–3). We
were delighted to find that the reaction successfully proceeded
with Pd2dba3 as the Pd source and furnished the desired cross-
coupling product 2a in 65% yield (Table 1, entry 3). We
subsequently investigated the effect of various ligands and bases
on the yield; however, the results were not satisfactory and
SPhos, XantPhos, BINAP and P(tBu)3 all gave lower yields
(Table 1, entries 4–7). Sodium tert-butoxide was superior to all
of the other bases tested (Table 1, entries 7–9). Strong bases such
as NaOtBu promoted the reaction affording product 2a in 92%
yield, whereas weak bases such as K3PO4 and Cs2CO3 were less
favorable for the reaction yield. In addition, we used different
organic solvents (Table 1, entries 9, 11–12) and identified 1,4-
dioxane as the most effective solvent which gave a better yield
(Table 1, entry 9) in comparison with toluene and DMF (Table 1,
entries 11 and 12). Finally, the reaction with Pd/XPhos (1:1)
resulted in a reduced yield (Table 1, entry 10).
Table 2
Preparation of 2-methyl-5-substituted pyrimidines 2b–p.
Table 1
Optimization of the C-N-coupling conditions.
Entry
1
RR’NH
Product
Yield [%]a,b
85
Entry Catalyst
Ligand
Base
Solvent
Yield 2a [%]a,b
2b
1
Pd(PPh3)4 XPhos
Pd(OAc)2 XPhos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
12
29
65
26
14
9
2
2
2c
86
3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
XPhos
SPhos
4
5
XantPhos Cs2CO3
3
4
5
2d
2e
2f
81
83
64
6
BINAP
P(tBu)3
XPhos
XPhos
XPhosc
XPhos
XPhos
Cs2CO3
Cs2CO3
K3PO4
7
15
45
92
76
57
trace
8
9
NaOtBu
NaOtBu
NaOtBu
NaOtBu
10
11
12
DMF
6
7
2g
2h
84
82
a Reagents and conditions: 1a (0.3 mmol), 4-aminobenzonitrile (0.33 mmol),
Pd-catalyst (2 mol%), L/Pd = 2/1, base (0.42 mmol), solvent (2 mL), 1 h,
120 °C.
b Isolated yield.
c
L/Pd = 1/1

3
8
9
2i
2j
2k
2l
82
59
Entry
1
R
H
Product
Yield [%]a,b,c
84
10
11
69
3b
2
3
3c
86
90
55c
3d
4
5
CH3NH--
(CH3)2N--
3e
3f
44
81
12c
13
14
15
2m
2n
2o
67
98
93
77
6
7
3g
3h
99
89
8
9
3i
93
2p
3j (3j’)b
62 (52)
a Reagents and conditions: 1a (0.3 mmol), RR’NH (0.33 mmol), Pd2dba3
(2 mol%), XPhos (8 mol %), NaOtBu (0.42 mmol), 1,4-dioxane (2 mL), 1 h,
120 oC;
10
11
CH3O--
3k
3l
65
55
b Isolated yield;
c Reaction time 30 min.
Next, we extended the Pd-catalyzed amination to 5-
bromopyrimidines bearing a variety of substituents at the 2-
position (1b–m, Table 3). These substrates reacted well with 4-
aminobenzonitrile and provided the corresponding products in
rather good to excellent yields (3b–m, Table 3). Notably, the
reaction of 5-bromopyrimidine with 4-aminobenzonitrile
proceeded well giving 3b in 84% yield, which is better than that
obtained using Okada’s method [25]. 5-Bromopyrimidine
substituted by phenyl or p-methoxyphenyl groups (Table 3,
entries 2–3) afforded the corresponding products in high yields.
In addition, 5-bromopyrimidines substituted by a secondary
amino group (alkyl, cyclic and phenylalkyl amino) provided the
desired products in 81–99% yield (Table 3, entries 5–8). In
contrast, a primary amino group at the 2-position of 5-
12
3m
51
a
Reagents and conditions: 1b–m (0.3 mmol), 4-aminobenzonitrile (0.33
mmol), Pd2dba3 (2 mol%), XPhos (8 mol %), NaOtBu (0.42 mmol), 1,4-
dioxane (2 mL), 1 h, 120 oC;
b Isolated yield;
c 3j was treated with TFA to give 3j’, yield in parentheses was calculated for
3j’ over two steps. 3j’, 4-((2-((3,4,5-trimethoxyphenyl)amino) pyrimidin-5-
yl)amino)benzonitrile.
3. Conclusion
bromopyrimidine resulted in
a lower yield. Indeed, 2-
methylamino-5-bromopyrimidine gave the corresponding product
in 44% yield (Table 3, entry 4), while 2-phenylamino-5-
bromopyrimidine led to low conversion (data not shown). Thus,
the arylamino group at the 2-position of 5-bromopyrimidine was
protected with Boc and then reacted with 4-aminobenzonitrile,
giving the product 3j in 62% yield. This was subsequently treated
with TFA leading to the deprotected product 3j’ (Table 3, entry
9). On the other hand, 5-bromopyrimidine substituted by
alkyloxy, phenyloxy and aryloxy groups were also suitable for
this reaction, with the target compounds 3k–m formed in 51–
65% yield (Table 3, entries 10–12).
A concise approach was developed for the synthesis of 2,5-
disubstituted pyrimidine derivatives via palladium catalyzed C-N
coupling under microwave irradiation in good to high yields.
This coupling reaction has a wide range of substrate scope and
good functional group tolerance, leading to versatile building
blocks for assembling interesting heterocyclic molecules. We
believe that this study would supply new chemical entities
(NCEs) for drug discovery.
Acknowledgments
This study is supported by Ligue Paris Ile-de-France. BL
thanks the China Scholarship Council (CSC) for financial
support.
Table 3.
Preparation of various 2,5-disubstituted pyrimidines 3b-m.

4
Tetrahedron Letters
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5
HIGHLIGHTS



A practical procedure was developed to prepare
2,5-disubstituted pyrimidines.
The method has a wide range of substrate
scope and good functional group tolerance.
The reaction occurred generally in good to
excellent yields.

The products of this reaction could be used as
the building blocks in drug design.