Microwave-assisted synthesis of phenylpyrimidine derivatives via Suzuki-Miyaura reactions in water

Article abstract of DOI:10.1016/j.tetlet.2021.152903

An efficient method was developed to prepare biphenylpyrimidine scaffolds via a Suzuki-Miyaura coupling reaction. In this procedure, the products were synthesized under microwave irradiation in water and analogues of biguanidine were employed as ligands.

Full text of DOI:10.1016/j.tetlet.2021.152903

Tetrahedron Letters 68 (2021) 152903
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of phenylpyrimidine derivatives
via Suzuki-Miyaura reactions in water
b,c,
Yi Le a,b,c,1, Yan Zhang b,1, Qin Wang b, Nian Rao b, Dan Li b, Li Liu b,c, Guiping Ouyang a,b,c, , Longjia Yan
⇑
⇑
a State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of
Education, State-Local Joint Laboratory for Comprehensive Utilization of Biomass, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, China
b School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China
c Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method was developed to prepare biphenylpyrimidine scaffolds via a Suzuki-Miyaura cou-
pling reaction. In this procedure, the products were synthesized under microwave irradiation in water
and analogues of biguanidine were employed as ligands.
Received 25 December 2020
Revised 27 January 2021
Accepted 1 February 2021
Available online 9 February 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Phenylpyrimidine
Microwave
Suzuki-Miyaura
Water
Biguanidine
Introduction
achievements indicate that microwave irradiation is a useful and
efficient method for organic synthesis [17–19].
Phenylpyrimidine is an essential skeleton, which has been
widely used due to its physicochemical and pharmaceutical prop-
erties [1–3]. Fenclorim (Fig. 1) is a common herbicide used in agri-
culture for the protection of plants [4]. Additionally, AS1269574 [5]
and PRA-1 (Fig. 1) [6] were also studied for GPCR (G Protein-Cou-
pled Receptor) agonist activity and as an orally reversal agent
against multidrug resistance in cancer, respectively. In 2014, Balla-
tore and co-workers reported a novel candidate drug Cevipabulin
[7] for the treatment of Alzheimer’s disease (AD). Recently, Kumar
and co-workers developed BD-14 as a acetylcholinesterase enzyme
(AChE) inhibitor for the treatment of AD [8].
Our group has been focused on the synthesis of various biolog-
ical compounds, such as diazepines [20], oxadiazoles [21], thiadia-
zoles and quinazolinones [22]. Recently, we reported a microwave-
assisted cycloaddition reaction of 7-azaindoles [23].
Based on the potential bioactivities of phenylpyrimidine deriva-
tives and our previous research, we became interested in the
development of phenylpyrimidines under microwave irradiation.
Herein, we report a facile method to prepare derivatives of
phenylpyrimidine under MW conditions in water.
Microwave irradiation (MW) is a powerful technique in modern
synthetic chemistry [9–13]. For example, Cravotto and co-workers
reviewed the microwave-assisted synthesis of heterocyclic com-
pounds via 1,3-dipolar cycloaddition [14]; Anilkumar and co-work-
ers summarized the latest progress in the synthesis of five
membered nitrogen heterocycles under MW conditions [15]; Chen
and co-workers reported the microwave-assisted Buchwald-Hart-
wig reaction for the synthesis of pyrimidine derivatives [16]. These
Results and discussion
Initially, we chose the commercially available compounds 5-
bromo-2-methyl-pyrimidine 1a and phenylboronic acid 2a as
model starting materials. Under classical conditions (K3PO4, Pd
(dppf)Cl2, dioaxane/H2O, 100 °C, 6 h), the product 2-methyl-5-
phenylpyrimidine 3a was obtained in 85% yield (Table 1, entry
1). The 1H NMR and 13C NMR spectra were consistent with the lit-
erature [24].
Recently, many research groups have focused their interest on
the development of active catalytic systems for the Suzuki-
Miyaura reaction [25–27]. A number of water-soluble ligands have
been explored to favour this reaction in aqueous media, such as
⇑
Corresponding authors at: School of Pharmaceutical Sciences, Guizhou Univer-
sity, Guiyang 550025, China.
E-mail addresses: oygp710@163.com (G. Ouyang), ylj1089@163.com (L. Yan).
Yi Le, and Yan Zhang contributed equally to this work.
1
https://doi.org/10.1016/j.tetlet.2021.152903
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Y. Le, Y. Zhang, Q. Wang et al.
Tetrahedron Letters 68 (2021) 152903
(metformin), 2.0 equiv K2CO3, dioxane/deionized water (1:1, v:v)
at 100 °C under microwave irradiation for 10 min. Compound 3a
was isolated with 66% yield (Table 1, entry 3). Under the same con-
ditions, when the ligand was dppf, the yield was only 36% (Table 1,
entry 2). We also examined the reaction under conventional ther-
mal heating conditions and the yield of the desired product was
43% (Table 2, entry 4). We subsequently investigated the effect of
various biguanidine derivatives as ligands, where phenylbiguanide
L3 gave 86% yield (Table 1, entry 7) and no product was obtained
without a ligand (Table 1, entry 5). Different Pd-sources were also
examined, and Pd(OAc)2 was the best with 88% yield (Table 1,
entry 10). Replacement of K2CO3 by K3PO4, KOtBu, or NaOAc led
to lower yields and KOAc gave the highest yield for this reaction
(Table 1, entries 12–15). Next, H2O was identified as the most
effective solvent (Table 1, entry 20), while dioxane gave 72% yield
(Table 1, entry 19).
NH
N
CN
N
N
N
NH
N
S
N
N
N
Br
N
Cl
Cl
Fenclorim
OH
Cl
AS1269574
PRA-1
HN
F
CF3
O
NH
N
N
N
N
N
F
N
N
Cl
O
O
BD-14
Cevipabulin
Interestingly, the use of tap water gave slightly higher yields
than deionized water (Table 1, entry 21). The reaction yield
decreased significantly when the temperature was 80 °C (Table 1,
entry 24), and the yield was similar in the range of 90 to 110 °C
(Table 1, entries 22–23). The optimal reaction conditions were con-
firmed as 5 mol% Pd(OAc)2, 5 mol% L3, and 2.0 equiv. KOAc, in tap
water at 100 °C under microwave irradiation for 10 min (Table 1,
entry 21).
Fig. 1. Selected bioactive skeletons containing phenylpyrimidine.
metformin [28]. Due to environmental, economical, and safety con-
cerns, we tried to employ biguanide as a ligand in the Suzuki-
Miyaura reaction under MW irradiation for the preparation of 3a.
Therefore, the reaction proceeded using 5 mol% PdCl2, 5 mol% L1
Table 1
Optimization of the Suzuki-Miyaura reaction for the synthesis of 3a.
OH
MW
[Pd]/Ligand
B
Br
N
OH
N
+
Base/Solvent
N
N
1a
Ligand
2a
3a
Entry
[Pd]
Base
Solvent
T (oC)
Yield 3a (%)a,b
1
2
3
4
5
6
7
8
5 mol% PdCl2
5 mol% PdCl2
5 mol% PdCl2
5 mol% PdCl2
5 mol% PdCl2
5 mol% PdCl2
5 mol% PdCl2
5 mol% PdCl2
dppf
dppf
L1
L1
–
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
KOAc
NaOAc
KOtBu
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
THF/H2O
Toluene/H2O
DMF/H2O
Dioxane
H2O
H2O
H2O
H2O
H2O
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
110
90
85c
36d
66
43e
0
L2
L3
L4
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
72
86
85
76
88
trace
82
89
83
78
76
65
68
72
89
90f
88
89
71
9
5 mol% Pd2dba3
5 mol%Pd(OAc)2
5 mol% Pd/C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
5 mol%Pd(OAc)2
80
NH NH
NH NH
NH NH
NH NH
H N
2
N
H
N
H N
N
H
N
H N
N
H
N
2
H N
2
N
H
N
H
2
H
O
CH
3
L1
L2
L3
L4
a
b
c
d
e
f
Reagents and conditions: 1a (1 mmol), 2a (1.2 mmol), Pd-catalyst (5 mol%), ligand (5 mol%), base (2 mmol), solvent (3 mL), Ar, microwave,10 min;
Isolated yields;
Reagents and conditions: 1a (1 mmol), 2a (1.2 mmol), Pd(dppf)Cl2 (5 mol%), K3PO4 (2 mmol), solvent (3 mL), Ar, oil bath, 6 h;
Recovered 47% compound 1a;
Reagents and conditions: 1a (1 mmol), 2a (1.2 mmol), PdCl2, L1 (5 mol%), K2CO3 (2 mmol), solvent (3 mL), Ar, oil bath,10 min, recovered 42% compound 1a;
Tap water.
2

Y. Le, Y. Zhang, Q. Wang et al.
Tetrahedron Letters 68 (2021) 152903
Table 2
Synthesis of phenylpyrimidines 3a-k.
R1
MW
Br
OH
B
N
N
5 mol% L3
+
R1
OH
5 mol% Pd(OAc)2
KOAc, tap water
100 oC, 10 min
N
N
1a
2a-k
3a-k
Entry
1
2
R1B(OH)2
Product
Yield (%)a,b
90
2a
3a
OH
B
OH
2
3
2b
2c
3b
3c
91
93
OH
B
H C
3
OH
OH
B
OH
O
4
5
2d
2e
3d
3e
81
84
OH
B
OH
F3C
OH
B
OH
F
F
6
7
8
2f
3f
83
74
76
OH
B
OH
2g
2h
3g
3h
F
OH
B
OH
OH
B
OH
F
F
F
9
2i
3i
78
OH
B
F
F
OH
10
2j
3j
85
81
OH
B
OH
N
11
2k
3k
OH
B
OH
S
a
Reagents and conditions: 1a (1 mmol), 2 (1.2 mmol), Pd(OAc)2 (5 mol%), L3 (5 mol%), KOAc (2 mmol), tap water (3 mL), Ar, microwave, 100 °C, 10 min;
Isolated yields.
b
With the optimized reaction condition in hand, the scope was
heteroarylboronic acids such as 3-pyridinylboronic acid 2j and 2-
thiophenylboric acid 2k gave the corresponding products in 81–
85% yield (Table 2, entries 10–11).
explored with different boronic acids 2 (Table 2). Arylboronic acids
2b and 2c with electron-donating groups gave higher yields than
2a (Table 2, entries 1–3). Remarkably, product 3c was obtained
in 93% yield (Table 2, entry 3). Arylboronic acids 2d and 2e with
electron-withdrawing groups gave lower yields than 2a (Table 2,
entries 4–5). The steric effect of substituents on the aromatic ring
also affected the coupling reaction (Table 2, entries 5–7). Com-
pound 1a reacted with o-fluorophenylboronic acid 2g leading to
the desired product 3g in 74% yield (Table 2, entry 7). On the other
hand, 3,4-difluorosubstituted or 3,4,5-trifluorosubstituted phenyl-
boronic acids 2h and 2i also afforded the corresponding products
3h and 3i in decreased yields (Table 2, entries 8–9). In addition,
Next, a variety of differently substituted pyrimidines and aryl-
boronic acids were used to extend the developed Suzuki-Miyaura
reaction. As shown in Table 3, 2-bromopyrimidine 1b was reacted
with compounds 2a-b, 2e-g and 2k giving products 3l-3q in 72–
85% yield. Substrates containing electron-donating groups, such
as methyl (2b), gave higher yield than those containing electron-
withdrawing groups, such as fluoride (2f). The yield was also was
influenced by the steric hindrance of compounds 2. Compound
2g with large steric hindrance gave a lower yield than 2f. Subse-
quently, the chloride substituted pyrimidine 1 was also studied
3

Y. Le, Y. Zhang, Q. Wang et al.
Tetrahedron Letters 68 (2021) 152903
Table 3
Acknowledgments
Synthesis of phenylpyrimidines 3l-y.
This project is supported by the Guizhou Provincial Natural Science
Foundation [2020]1Y109 and the GZU (Guizhou University) Found
for Newly Enrolled Talent (No. 201915).
MW
HO
N
5 mol% L3
R1
N
R2
R1
B
+
R2
X
5 mol% Pd(OAc)2
KOAc, tap water
100 oC, 10 min
HO
N
N
2
3l-y
1b-c
1b: 2-bromopyrimidine; X: Cl, Br;
1c: 4,6-dichloro-2-methylpyrimidine;
1d: 4,6-dichloro-pyrimidin-5-ylamine;
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152903.
aReagents and conditions: 1 (1 mmol), 2 (1.2 mmol), Pd(OAc)2 (5 mol%), L3 (5 mol
%), KOAc (2 mmol), tap water (3 mL), Ar, microwave, 100 °C, 10 min;
bReagents and conditions: 1 (1 mmol), 2 (1.2 mmol), Pd(OAc)2 (5 mol%), L3 (5 mol
%), KOAc (2 mmol), tap water (3 mL), Ar, microwave, 110 °C, 20 min.
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The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
4