Efficient synthesis of diversely substituted pyrimidines by palladium catalyzed Suzuki-Miyaura coupling

Article abstract of DOI:10.1016/j.tetlet.2014.01.042

An efficient synthesis of 2-aryl/heteroaryl substituted pyrimidinyl ethanones 4(a-t) was developed using a palladium-catalyzed Suzuki-Miyaura coupling reaction strategy. Use of Pd(OAc)₂ in the presence of PPh₃ and Na₂CO₃ in 1,4-dioxane solvent was found to be the most effective reaction condition.

Full text of DOI:10.1016/j.tetlet.2014.01.042

Accepted Manuscript
Efficient synthesis of diversely substituted pyrimidines by palladium catalyzed
Suzuki-Miyaura coupling
Viral J. Faldu, Pratik K. Talpara, Viresh H. Shah
PII:
S0040-4039(14)00075-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.042
TETL 44074
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 November 2013
10 January 2014
13 January 2014
Please cite this article as: Faldu, V.J., Talpara, P.K., Shah, V.H., Efficient synthesis of diversely substituted
pyrimidines by palladium catalyzed Suzuki-Miyaura coupling, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.01.042
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Efficient synthesis of diversely substituted pyrimidines by palladium catalyzed Suzuki-
Miyaura coupling
Viral J. Faldua, Pratik K. Talparaa, Viresh H. Shaha*
aDepartment of Chemistry, Saurashtra University, Rajkot-360005.
*Email: drvireshshah@gmail.com
Abstract- An efficient synthesis of 2-aryl/heteroaryl substituted pyrimidinyl ethanones 4(a-t)
was developed using a palladium-catalyzed Suzuki-Miyaura coupling reaction strategy. Use
of Pd(OAc)2 in presence of PPh3 and Na2CO3 in 1,4-dioxane solvent was found to be the most
effective reaction condition.
Keywords: Suzuki-Miyaura coupling, Palladium catalyst, Triphenylphosphine.
Palladium-catalyzed formation of carbon–carbon bonds have become an extremely powerful
tool in modern synthetic organic chemistry.1–4 In recent years, palladium-catalyzed Suzuki
cross-coupling reactions have been increasingly employed for the construction of
unsymmetrical biaryl units which have a wide range of applications in various areas such as
pharmaceutical, herbicides, natural products.5–10 The recent identification of a DHPM
(dihydropyrimidine) analog as a potential new anticancer lead is involved in blocking mitosis
by inhibition of a kinesin motor protein.11
The Suzuki reaction is an extremely powerful technique for the formation of biaryl
compounds, consequently there has been significant attention focused on the development of
catalysts that are able to promote the coupling of aryl halide substrates. Hence the
development of catalysts for promoting Suzuki coupling of aryl halide substrates has attracted
considerable interest. Suzuki-Miyaura coupling reactions are more efficient in organic media
while employing Pd(OAc)2, Pd(PPh3)4 and PdCl2 as catalyst and among them use of PdCl2 is
found to be more efficient in the case of biphasic media.12
There are a number of drugs which possess pyrimidine derivatives, responsible for biological
and therapeutic activities.13 In view of the above, the present article reports an efficient
regioselective approach for the synthesis of diversely substituted pyrimidinyl ethanones using
Suzuki-Miyaura coupling. The effects of solvent, temperature and catalyst on the efficiency
of the Suzuki-Miyaura coupling reaction have been studied.
The present work reports an efficient four-step approach for the synthesis of tetra substituted
pyrimidinyl ethanones. The first step involves the Biginelli synthesis of 3,4-
dihydropyrimidin-2(1H)-ones14 1(a-c) followed by the oxidation with 60% nitric acid15 to
generate 2-oxo pyrimidinyl ethanones 2(a-c). The method in general provides moderate to
good yields of oxidized products. However, factors such as steric hindrance, the presence of
electron withdrawing substituents on phenyl ring and solubility of DHPMs
(dihydropyrimidines) affect the yield and rate of reaction.
1

2-Oxo-pyrimidinyl ethanones 2(a-c) were then chlorinated with POCl3 in N,N-dimethyl
o
o
aniline at 100 -105 C16 to obtain 2-chloro-pyrimidinyl ethanones 3(a-c). Suzuki–Miyaura
cross-coupling reaction of aryl boronic acids with 2-chloro pyrimidinyl ethanones 3(a-c)
afforded title 2-aryl/heteroaryl substituted pyrimidinyl ethanones 4(a-t) in good to excellent
yields. The overall synthetic protocol along with the target molecules synthesized, reagents
and conditions are shown in (Scheme 1).
[Insert Scheme-1 and Table-1 here]
The studies reveal that Suzuki–Miyaura cross-coupling of aryl boronic acids with 2-chloro
pyrimidinyl ethanones 3(a-c) in the presence PPh3 with Pd(OAc)2 as catalyst, Na2CO3 as base
afford good yields of products as shown in Table 1.
To explore the effect of reaction parameters such as solvent, temperature and catalyst on the
Suzuki–Miyaura cross-coupling of aryl boronic acids with 2-chloro pyrimidinyl ethanones
3(a-c), we chose coupling of 2-chloro pyrimidinyl ethanone (3c) and 4-ethyl phenyl boronic
acid as the model reaction.
To optimize the Suzuki coupling reaction with different catalytic system, we employed
Pd(OAc)2, PdCl2(PPh3)2, Pd(PPh3)4 and Pd(dba)3 as Pd(0) and Pd(II) catalyst as shown in
Table 2.
[Insert Table-2 and Scheme-2 here]
The Suzuki–Miyaura cross-coupling reaction using PdCl2(PPh3)2 (entry 4b, Table 2) afforded
good yield but the reaction was slower. Use of Pd(PPh3)4 (entry 7c, Table 2) did not afford
higher yields than by use of Pd(OAc)2 (entry 20, Table 1) which might be due to slow initial
dissociation for Pd(PPh3)4. The formation of some by-products such as self-coupling
products, and coupling products of phosphine-bound phenyls may also attribute for lower
yield while using Pd(PPh3)4.17,18 Coupling using Pd(dba)3 required more time and gave
moderate to lower yields with different bases (entry 10d, 11d and 12d, Table 2) which might
be attributed to slow initial dissociation as well. Based on experimental data reported in Table
1 and Table 2 it was concluded that Pd(OAc)2 is the most efficient palladium source.
It is well known that the base is involved in the coordination sphere of the palladium in trans-
metallation step where hydrolysis of the Ar-PdL2–X from Ar-PdL2–OR takes place which is
known to enhance the rate of reaction.18 In case of the triphenylphosphine the rate of reaction
shows a remarkable decrease in presence of K3PO4 (entry 3a and 12d, Table-2). Among the
bases tested, Na2CO3 and K2CO3 have proved to be better (entry 1a, 4b, 5band 7c, Table-2).
[Insert Table-3 here]
Among the commonly used organic solvents (toluene, DMF, THF, and dioxane) the best
results were obtained with toluene and dioxane (Table 3). Partial product formation was
observed in THF and DMF, but use of a DMF:water mixture (entry 3a, Table 3) gave good
yield. It was observed that higher water content led to higher conversion of aryl-halides with
good yields. Very low conversion was observed in case of methanol and acetone as solvents
(entry 6a and 7a, Table 3).
2

To summarise our results (Table 1, Table 2, Table 3) it was found that an efficient Suzuki–
Miyaura cross-coupling reaction of 2-chloro pyrimidinyl ethanones with aryl boronic acids is
achieved in the presence of Pd(OAc)2/PPh3 and saturated aqueous solution of Na2CO3 in 1,4-
dioxane to afford good to excellent yields.
Acknowledgements: We acknowledge the support of UGC through grant no. 41-
198/2012(SR), New Delhi, India, for financial support and for providing instrumental support
under FIST and SAP program and SAIF, Punjab University-Chandigarh. I also wish to
acknowledge Professor and head, Department of Chemistry, Saurashtra University-Rajkot for
providing research facility.
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3.
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4.
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Suzuki, A., Cross‐Coupling Reactions Of Organoboranes: An Easy Way To Construct
C-C Bonds (Nobel Lecture). Angewandte Chemie International Edition 2011, 50 (30),
6722-6737.
(a) Diederich, F.; Stang, P., Metal-catalyzed cross-coupling reactions. Wiley. com:
2008; (b) Miyaura, N.; Suzuki, A., Palladium-catalyzed cross-coupling reactions of
organoboron compounds. Chemical reviews 1995, 95 (7), 2457-2483; (c) Suzuki, A.,
For reviews: (a) J. Organomet. Chem 1999, 576, 147-168.
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7.
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and versatile replacements for air-sensitive trialkylphosphines. Applications in
stoichiometric and catalytic processes. Organic letters 2001, 3 (26), 4295-4298.
(a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L., Highly active palladium
catalysts for Suzuki coupling reactions. Journal of the American Chemical Society
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active catalyst for palladium-catalyzed cross-coupling reactions: room-temperature
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(phosphinite)‘PCP’-pincer complexes and their application as catalysts in the Suzuki
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reaction. New Journal of Chemistry 2000, 24 (10), 745-747; (b) Bedford, R. B.;
Welch, S. L., Palladacyclic phosphinite complexes as extremely high activity catalysts
in the Suzuki reaction. Chemical Communications 2001, (1), 129-130.
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a) Molander, G. A.; Katona, B. W.; Machrouhi, F., Development of the Suzuki-
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in aryl alkynylations. The Journal of organic chemistry 2002, 67 (24), 8416-8423; (b)
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Graphical Abstract
4

Scheme-1
R1
O
R1
O
R1
H
O
O
H2N
ii
i
N
NH
O
N
H
O
N
H
O
O
H2N
1(a-c)
2(a-c)
O
R1
N
O
R1
iv
N
N
iii
Cl
N
R2
4(a-t)
3(a-c)
3a-R1=4-CH3-Ph
3b-R1=4-OCH3-Ph
3c-R1=3-Ph-O-Ph
Scheme 1. Reagents and conditions; (i) Aryl aldehyde (1.0 equiv), acetyl acetone (1.0 equiv),
urea (1.0 equiv), con. HCl (1-2 drops) and ethanol (94%, 5 vol.) reflux, 3 h, 85-92%; (ii) 1(a-c),
°
HNO3 (60%) 0 C - r.t. (Ref. 15), 90-92%; (iii) 2(a-c) (1.0 equiv), N,N-dimethylaniline (1.4
equiv), POCl3 (20 mL), reflux, 12 h, (Ref. 16), 80-85%; (iv) 3(a-c) (1.0 equiv), arylboronic acid
(1.2 equiv), Pd(OAc)2 (0.04 equiv), PPh3 (0.2 equiv), satd. aqueous solution of Na2CO3 (17 mL)
and 1,4-dioxane (26 mL), reflux, 5 h, 70-93%.
Table 1
Entry
1
R1
R2
Product
Yield
(%)
92
CH3
O
N
N
O
4a

CH3
2
89
O
N
N
4b
CH3
3
85
S
O
N
N
S
4c
CH3
4
90
O
N
N
4d
CH3
5
6
78
87
O
N
N
4e
H3C
O
O
S
O
N
N
S
4f

H3C
H3C
H3C
H3C
7
82
80
88
86
O
N
O
O
O
O
O
N
N
4g
8
O
N
O
N
H
N
4h
9
O
N
CH3
O
O
N
O
4i
10
O
N
O
N
Br
4j

H3C
11
91
O
N
O
O
N
CH3
4k
4l
12
13
14
85
77
86
N
S
S
O
O
O
O
O
N
N
O
O
N
4m
Cl
N
O
CH3
O
N
N
4n
4o
15
16
87
78
O
O
O
O
O
N
O
N
O
Cl
O
N
4p

F
17
18
84
73
HO
O
O
N
O
F
O
N
4q
F
F
F
N
N
O
O
O
O
N
N
4r
4s
F
19
20
78
92
O
O
CH3
N
O
O
N
4t
Scheme 2
CH3
Condition
N
N
Cl
O
O
a, b, c and d
O
N
O
N
3c
4t

Table 2
Effect of various bases and catalysts in the Suzuki reaction of aryl halide (3c) and 4-ethyl
phenylboronic acid
Entry
1a
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2 Na2CO3
PdCl2(PPh3)2 K2CO3
PdCl2(PPh3)2 K3PO4
Base
Na2CO3
K2CO3
K3PO4
Conversion
100
%Yielde Entry Catalyst
Base
Pd(PPh3)4 Na2CO3
Conversion %Yielde
92
45
50
81
73
64
7c
8c
9c
100
90
80
65
66
60
45
55
2a
70
80
100
100
Pd(PPh3)4
Pd(PPh3)4
K2CO3
K3PO4
Na2CO3
K2CO3
K3PO4
3a
100
80
4b
10d Pd(dba)3
11d Pd(dba)3
12d Pd(dba)3
5b
60
70
6b
100
Condition:a Reaction was conducted in 1,4-dioxane (26 mL) employing arylboronic acid (1.2 equiv), Pd(OAc)2 (0.04
equiv), PPh3(0.2 equiv), satd. aqueous solution of base (17 mL), at 120 °C for 5h reflux, 80-93%.
b Reaction was conducted in 1,4-dioxane at 110 °C for 3h employing 1 mol% of PdCl2(PPh3)2, 1M base (2.5 equiv),
aryl halide (3c) (1 equiv) and 4-ethyl phenylboronic acid (1 equiv).
c
°
Reaction was conducted in DMF:water (5:1 v/v) at 120 C for 3h using Pd(PPh3)4 (0.02 equiv), base (2 equiv),
TBAB (0.12 equiv), aryl halide (3c) (1 equiv) and 4-ethyl phenylboronic acid (1.3equiv).
d
°
Reaction was conducted in Toluene:Water (9:1 v/v) at 100 C for 14h using Pd(dba)3 (0.02 equiv), base (3equiv),
PPh3 (0.2 equiv), aryl halide (3c) (1 equiv) and 4-ethyl phenylboronic acid (3 equiv).
e Isolated yield
Table 3
Effect of Solvent on Suzuki reaction of aryl halide (3c) and 4-ethyl phenylboronic acid
Entry
1a
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Solvent
1,4-dioxane
THF
DMF:Water
Toluene:Water
THF:Water
Methanol
Conversion % Yieldb
100
Partially
80
92
20
66
54
59
30
25
2a
3a
4a
60
62
5a
6a
50
7a
Acetone
partially
Condition:a Reaction was conducted in Solvent (4:6 v/v) employing arylboronic acid (1.2 equiv), Pd(OAc)2 (0.04
equiv), PPh3(0.2 equiv), satd. aqueous solution of base, at 120 °C for 5h reflux.
b Isolated yield