Pd-catalyzed decarboxylative cross-coupling of sodium pyrimidinecarboxylates with (hetero)aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2017.05.086

A straightforward method for the synthesis of functionalized 4- or 5-(hetero)arylpyrimidines via decarboxylative cross-coupling reaction from readily available pyrimidine-4- and pyrimidine-5-carboxylates was described. In the presence of dual-catalyst system of Pd(PPh₃)₄/Cu₂O, the reaction proceeds smoothly, tolerates a variety of functional groups, and provides easy access to the synthesis of different (hetero)arylpyrimidines compounds.

Full text of DOI:10.1016/j.tetlet.2017.05.086

Accepted Manuscript
Pd-Catalyzed Decarboxylative Cross-Coupling of Sodium Pyrimidinecarboxy-
lates with (Hetero)arylBromides
Shengqiang Wang, Hongtao Lu, Jingya Li, Dapeng Zou, Yusheng Wu, Yangjie
Wu
PII:
S0040-4039(17)30688-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.086
TETL 48979
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 April 2017
24 May 2017
25 May 2017
Please cite this article as: Wang, S., Lu, H., Li, J., Zou, D., Wu, Y., Wu, Y., Pd-Catalyzed Decarboxylative Cross-
Coupling of Sodium Pyrimidinecarboxylates with (Hetero)arylBromides, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.05.086
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Pd-Catalyzed Decarboxylative Cross-Coupling of Sodium
Pyrimidinecarboxylates with (Hetero)arylBromides
Leave this area blank for abstract info.
Shengqiang Wang, Hongtao Lu, Jingya Li, Dapeng Zou*, Yangjie Wu*, Yusheng Wu*
N
Pd(PPh3)4, Cu2O
DMA, 160 oC, 24 h
N
COONa
30 examples
up to 85% yield
+
Het/Ar
Br
Ar/Het
N
N
1
2
3

1
Tetrahedron Letters
Pd-Catalyzed Decarboxylative Cross-Coupling of Sodium Pyrimidinecarboxylates with
(Hetero)arylBromides
Shengqiang Wanga, Hongtao Lua, Jingya Lib,c, Dapeng Zoua,b,, Yusheng Wub,d,, Yangjie Wua,
a The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, PR China
bCollaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China
c Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou 450052, PR China
dTetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ08901, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A straightforward method for the synthesis of functionalized 4- or 5-(hetero)arylpyrimidines via
decarboxylative cross-coupling reaction from readily available pyrimidine-4- and pyrimidine-5-
carboxylates was described. In the presence of dual-catalyst system of Pd(PPh3)4/Cu2O, the
reaction proceeds smoothly, tolerates a variety of functional groups, and provides easy access to
the synthesis of different (hetero)arylpyrimidines compounds.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalysis
Pyrimidinecarboxylates
Arylpyrimidines
Decarboxylative cross-coupling
 Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327(Y.Wu.). E-mail: zdp@zzu.edu.cn, yusheng.wu@tetranovglobal.com,
wyj@zzu.edu.cn.

2
Tetrahedron
Introduction
as shown in Table 1. When the reaction was carried out under 5
mol % PdCl2/Cu2O (1.0 equiv) catalysis in DMA using K2CO3 as
base and BINAP as ligand, only a 15% yield of the desired
product was detected (3a) (entry 1). Subsequently, PPh3, PCy3,
SPhos, XPhos, RuPhos, and other bidentate phosphine ligands
such as bis(diphenylphosphino)methane (dppm) and XantPhos
were evaluated but failed to improve the yield (entries 2-8).
Switching the Pd sources to other commercially available
palladium catalysts (Pd(OAc)2, Pd(TFA)2, Pd2(acac)3,
Pd(dppf)2Cl2 and Pd(PPh3)4), the yield was not improved.
Meanwhile, the combination of Pd(PPh3)4 with BINAP was
shown to be nearly as efficient as Pd(PPh3)4 alone (entries 9-14).
Our previous work indicated that bases play an obvious
influences on the transformation of the pyridazines acids,12 so a
series of bases were screened, but all failed to afford a better
yield (entries 15-20).
Pyrimidines are important heterocyclic scaffolds and have
attracted much attention due to their remarkable biological and
pharmacological activities.1 In addition, arylpyrimidines are also
broadly applied in organometallic chemistry,2 photophysical
materials3 and supramolecular chemistry (Figure 1).4 The
traditional route to the synthesis of arylpyrimidines by careful
synthetic design and ring formation usually suffers from tedious
steps and the limited substrate scope.5 Additionally, the classical
metal-catalyzed cross-coupling reaction is reported to be an
effective methodology for the synthesis of arylpyrimidines from
halopyrimidines and other organometallic reagents.6 But the
utility of the pyrimidines organometallic reagents were hampered
due to their difficult synthesis and lack of stability.7 Recently,
several direct C-H arylation methodologies were actively
developed. In 2006, Fagnou and co-workers reported the direct
arylation of diazine N-oxides with abroad range of aryl halides as
an efficient alternative to standard cross-couplings reaction.8 In
2010, Baran group reported the direct C-H arylation of electron-
deficient heterocycles with arylboronic acids via radical addition
which was similar to Minisci type reactions, but the reaction still
give low regioselectivities.9 Obviously, developing a general and
efficient method for the synthesis of arylpyrimidines from readily
available starting materials remains highly desirable.
Table 1. Optimization of reaction conditionsa
[Pd] (5 mol %)
Ligand (10 %)
Cu2O (1.0 equiv)
N
COOH
Br
N
+
DMA, Base
160 oC, 24 h
N
1 eq
N
2 eq
a
1
a
a
3
2
Entry
1
Catalyst
PdCl2
Ligand
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Na2CO3
Yieldb(%)
In the past few years, transition-metal mediated
decarboxylative coupling reactions have been established as a
powerful and effective method for the construction of C-C
bonds.10 Meanwhile, as far as we know, the coupling of the π-
deficient heteroaryl carboxylic acids remains a challenging goal
due to the instability of the metalated azinyl intermediates.11 Very
recently, our group reported the decarboxylative cross-coupling
reactions of pyridazine-3-carboxylic acid with a variety of
(hetero)aryl halides via a bimetallic Pd/Cu catalysis to afford 3-
arylpyridazines.12 To continue our research in palladium-
catalyzed decarboxylative cross-coupling reactions,13 herein, we
would like to report the first decarboxylative cross-coupling
reaction of pyrimidine-4 and pyrimidine-5-carboxylates with a
variety of (hetero)aryl halides for the synthesis of arylpyrimidine
derivatives.
BINAP
PPh3
15
8
2
PdCl2
3
PdCl2
PCy3
10
8
4
PdCl2
SPhos
XPhos
RuPhos
Dppm
XantPhos
BINAP
BINAP
BINAP
BINAP
BINAP
--
5
PdCl2
9
6
PdCl2
10
7
7
PdCl2
8
PdCl2
11
14
16
13
15
21
20
17
18
9
Pd(OAc)2
Pd(TFA)2
Pd2(acac)3
Pd(dppf)2Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
10
11
12
13
14
15
16
F
N
O
HN
O
OH OH
N
--
N
N
HO
N
N
N
--
H
N
N
17
18
Pd(PPh3)4
Pd(PPh3)4
--
--
Cs2CO3
K3PO4
21
18
SO2Me
Imatinb (Gleevec, Novartis)
O
Rosuvastatin (Crestor, Astrazeneca,)
NMe2
19
20
Pd(PPh3)4
Pd(PPh3)4
--
--
NaOH
26
19
t-BuOK
N
aReaction conditions:1a (0.6 mmol), 2a (1.2 mmol), catalyst (5 mol%), ligand
(10 mol %), Cu2O (0.6 mmol), base (1.8 mmol) and 3Å MS (200 mg) in
DMA (4.0 mL) at 160 oC under N2 for 24 h.
N
CF3
N
N
N
N
N
bDetected by HPLC.
O
F3C
H2N
Generally, the salts form of aryl carboxylic acid were also
used in the decarboxylative cross coupling to reduce the yield of
NVP-BKM120 (PI3K inhibitor, Novartis)
Fluoroscence max = 469 nm (blue)
F = 0.58 (CHCl3)
the protodecarboxylation.14 So
a pre-formed pyrimidine-4-
Fig. 1 Bioactive compounds and materials contained pyrimidines
carboxylate salt instead of the in situ generated counterpart was
employed under the Pd(PPh3)4/Cu2O conditions (Table 2).
Delightedly, the desired product was obtained in a moderate yield,
and the sodium pyrimidine-4-carboxylate gave a better yield
(entries 1-3). Encouraged by this promising result, various other
additives such as CuI, CuBr, Cu(OAc)2, Ag2O and Ag2CO3 were
derivatives.
Results and Discussion
Initially, the decarboxylative cross-coupling reaction of
pyrimidine-4-carboxylic acid (1a) with bromobenzene (2a) was
selected as a model reaction to optimize the reaction conditions

3
also screened to find that even lower yields were observed
(entries 4-8). The Cu2O loading was also examined, and the
yields could be enhanced to 75% by using 0.5 equiv of Cu2O
(entry 9). However, the reaction did not proceed smoothly
without Pd(PPh3)4 or Cu2O indicated that Pd(PPh3)4 and Cu2O
were critical in this reaction (entries 10 and 11). Decreasing the
reaction temperature to 150 °C resulted in a lower yield of 45%
(entry 12). A subsequent survey on the role of solvents revealed
that DMA was the optimal candidate (entries 13-15). The
conclusion for this study is that the substrate sodium pyrimidine-
4-carboxylate combined with 5 mol % Pd(PPh3)4, 2.0 equiv aryl
halides, 0.5 equiv Cu2O in DMA at 160 C is the optimum
condition.
proceed smoothly to afford the corresponding product in 63%
and 78% yield respectively (3r, 3s). Other heteroaryl bromides
such as 6-bromoquinoline and 5-bromopyrimidine could also
afford the desired product in yields of 63% and 76% (3u, 3v). It
is noticeable that the sodium 2-methylpyrimidine-4-carboxylate
as the coupling substrate with 4-bromobenzonitrile can also gave
a 63% yield (3w).
Table 3. Scope of sodium pyrimidine-4-carboxylate and
(hetero)aryl bromides coupling partners a, b
Pd(PPh3)4, Cu2O
N
COONa
Het/Ar
N
+
Het/Ar
Br
DMA, 160 oC, 24 h
N
N
2a-v
1a
3a-w
CN
NC
Table 2. Optimization of reaction conditionsa
N
N
N
N
N
N
NC
N
N
N
N
3b 73%
N
N
Pd(PPh3)4
3c 52%
3d 76%
N
COOM
3a 71%
N
+
Br
additive
F
F
CHO
N
N
solvent, 160 oC
2 eq
1 eq
F
N
N
N
N
1a
Entry
1
2a
3a
Yieldb (%)
3e
3i
3g 83%
3h
Trace
75%
3f
58%
M
Additive
Solvent
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
OHC
O
O
K
Cu2O
Cu2O
Cu2O
CuI
61
N
N
OHC
N
N
O
N
N
N
N
N
N
N
2
Na
Li
69
3l 55%
3j 76%
3k 45%
60%
3
59
F
F
F
O
4
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
43
O2N
F
N
N
N
N
N
N
N
5
CuBr
Cu(OAc)2
Ag2CO3
Ag2O
Cu2O
--
35
F
3m 68%
3n 56%
3o 85%
3p 60%
6
28
F3C
NC
N
7
26
N
N
N
N
N
N
N
N
N
N
N
8
15
75c
3q 61%
3r 63%
3s 78%
3t 58%
9
N
N
N
NC
10
11
12
13
14
15
Trace
Traced
45e
N
N
N
3u
3w
63%
63%
3v
76%
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
aReaction conditions:1a (0.6 mmol), 2a-v (1.2 mmol), Pd(PPh3)4 (5 mol %),
Cu2O (0.3 mmol) and 3Å MS (200 mg) in DMA (4.0 mL) under N2 for 24 h.
43
NMP
28
bIsolated yields.
DMSO
Trace
To further examine the versatility of this methodology, the
decarboxylative cross-coupling reaction of sodium 4-methyl-2-
phenylpyrimidine-5-carboxylate (4a) with
aReaction conditions: 1a (0.6 mmol), 2a (1.2 mmol), Pd(PPh3)4 (5 mol%),
additive and 3Å MS (200 mg) in solvent (4.0 mL) under N2 for 24 h.
a
variety of
bDetected by HPLC.
cCu2O 0.3 mmol.
dAbsent Pd(PPh3)4.
eTemp150 oC.
(hetero)aryl bromides were also explored under the optimal
conditions. The desired products were obtained in moderate
yields and the results were summarized in Table 4. Generally,
electron-deficient substrates showed better reactivity than that
electron-rich ones (5a-5h). The sodium pyrimidine-5-carboxylate
Table 4. Scope of substituted sodium pyrimidine-5-
With the optimal conditions in hand, the scope of the reaction
was then explored and the results were summarized in Table 3.
Firstly, extending the model reaction to other aryl bromides
showed that both electron-rich and electron-deficient aryl
bromides could be successfully converted to the corresponding
products in moderate to good yields. A wide range of functional
groups, such as nitriles, fluoro, ketones, esters, ethers,
trifluoromethyl, and nitro were all tolerated under the reaction
conditions. Generally, it was found that electron-rich aryl
bromides have a relatively lower reactivity than that electron-
deficient ones (3k vs 3d, 3g, 3j). The ortho- cyano or fluoro
substituted aryl bromides did not affect the reactivity (3b, 3e),
while the 2-bromobenzaldehyde provided only trace amount of
the desired product (3h). In addition, the aryl bromides bearing
two halogen atoms could be converted to the desired product in
good yields of 85% and 60% (3o, 3p). Secondly, the heteroaryl
bromides were proved to be good substrates for this reaction too.
For example, 3-bromopyridine and 3-bromo-5-fluoropyridine
carboxylate and (hetero)aryl bromides coupling partners a,b
R
R
N
N
Pd(PPh3)4, Cu2O
COONa
+
Het/Ar Br
Het/Ar
DMA, 160 oC, 24 h
N
N
4a
2a-h
5a-j
N
N
N
O
N
N
N
NC
O
Ph F3C
Ph
Ph
F
Ph
Ph
N
O
N
5a 51%
5e 48%
5i 58%
5b 55%
5f 65%
5c 45%
5g 51%
5d 53%
5h Trace
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
O
N
N
N
N
NC
NC
N
5j
52%
aReaction conditions: 4a (0.6 mmol), 2a-h (1.2 mmol), Pd(PPh3)4 (5 mol %),
Cu2O (0.3 mmol) and 3Å MS (200 mg) in DMA (4.0 mL) under N2 for 24 h.
bIsolated yields.

4
Tetrahedron
76759-76763. (f) Deibl, N.; Ament, K.; Kempe, R. J. Am. Chem.
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11994-12000.
and sodium 2-methylpyrimidine-5-carboxylate could also
provide moderate yields (5j, 5k). LC-MS analysis of the crude
reaction system showed that the by-products were derived from
protodecarboxylations15 of 4a and the Ullmann-type16
dimerization of aryl bromides under copper-mediated cross-
coupling reaction which resulted in the lower chemical yield.
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Conclusion
In conclusion, we have developed a novel synthetic route to 4-
or 5-(hetero)arylpyrimidines via Pd-catalyzed decarboxylative
cross-coupling of pyrimidine-4- and pyrimidine-5-carboxylates
with a variety of (hetero)aryl bromides. The present method
potentially useful for high-efficiency synthesis of versatile of
(hetero)arylpyrimidines derivatives. In addition, stable and
available sodium pyrimidine carboxylates have been used. Under
the optimal conditions, the reaction exhibits good substrate scope.
This is a valuable new route to (hetero)arylpyrimidines which are
commonly found in drug candidates.
Acknowledgments
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We are grateful to the National Natural Science Foundation of
China (21172200) for financial support.
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5
Research highlights
1. An efficient method for the synthesis of 4- or 5-
(hetero)arylpyrimidines has been developed.
3. The stable and easily available carboxylate salts
were used as the nucleophilic coupling partner.
2. Pd-catalyzed decarboxylative cross-coupling was
compatible with many functional groups.

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template box below.
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Graphical Abstract
Pd-Catalyzed Decarboxylative Cross-Coupling of Sodium
Pyrimidinecarboxylates with (Hetero)arylBromides
Shengqiang Wang, Hongtao Lu, Jingya Li, Dapeng Zou*, Yangjie Wu*, Yusheng Wu*
Leave this area blank for abstract info.
N
Pd(PPh3)4, Cu2O
DMA, 160 oC, 24 h
N
COONa
30 examples
up to 85% yield
+
Het/Ar
Br
Ar/Het
N
N
1
2
3