Palladium-catalyzed cross-coupling reaction of 2- and/or 5-substituted 4,6-dichloropyrimidines with arylboronic acids

Article abstract of DOI:10.1002/jhet.184

(Chemical Equation Presented) The Suzuki-Miyaura reaction of some 4,6-dichloropyrimidines bearing methylthio-, methyl-, amino-, cyano-, formyl-, and nitro groups in positions 2 and/or 5 of the pyrimidine ring with arylboronic acids has been investigated. Influence of palladium catalyst, ligand, base, and solvent on the reaction outcome was studied. The reaction was found to give the corresponding 4,6-diarylpyrimidines in reasonable yields using Pd(OAc) ₂/PPh₃/K₃PO₄ or Pd(PPh ₃)₂Cl₂/K₃PO₄ as catalyst systems.

Full text of DOI:10.1002/jhet.184

960
Palladium-Catalyzed Cross-Coupling Reaction of 2- and/or 5-
Substituted 4,6-Dichloropyrimidines with Arylboronic Acids
Vol 46
S. Tumkevicius,* J. Dodonova, I. Baskirova, and A. Voitechovicius
Department of Organic Chemistry, Vilnius University, Naugarduko 24, Vilnius LT-03225,
Lithuania
*E-mail: sigitas.tumkevicius@chf.vu.lt
Received January 14, 2009
DOI 10.1002/jhet.184
Published online 3 September 2009 in Wiley InterScience (www.interscience.wiley.com).
The Suzuki-Miyaura reaction of some 4,6-dichloropyrimidines bearing methylthio-, methyl-, amino-,
cyano-, formyl-, and nitro groups in positions 2 and/or 5 of the pyrimidine ring with arylboronic acids
has been investigated. Influence of palladium catalyst, ligand, base, and solvent on the reaction outcome
was studied. The reaction was found to give the corresponding 4,6-diarylpyrimidines in reasonable
yields using Pd(OAc)2/PPh3/K3PO4 or Pd(PPh3)2Cl2/K3PO4 as catalyst systems.
J. Heterocyclic Chem., 46, 960 (2009).
INTRODUCTION
Initially, compound 1a [9] was coupled with a slight
excess of phenylboronic acid using Pd(OAc)2/PPh3/
Na2CO3 (aqueous 1M solution) as a catalyst system in
tetrahydrofurane. However, conversion of 1a was very
slow and led to a complex mixture of products from
which any product was isolated (Table 1, entry 1).
Almost the same result was obtained when Cs2CO3 was
used as a base instead Na2CO3. Change of Pd(OAc)2 to
Pd2(dba)3 did not give the desirable result again—a mix-
ture of 2a and 3a with the latter compound as major
product was isolated in negligible amount.
In the past two decades, the Suzuki-Miyaura cross-cou-
pling reaction has evolved into one of the most widely used
carbon-carbon bond forming processes [1,2]. Its impact on
organic synthesis is largely attributed to the fact that it pro-
vides an applicable method for the preparation of biaryls.
Aryl- and heteroarylpyrimidine derivatives have found
applications in many contemporary areas of chemistry, such
as, ligands for coordination to metal ions [3], components
for molecular recognition studies involving hydrogen bond-
ing and p–p interactions [4], compounds with therapeutic
and agrochemical properties [5], fluorophores and electron-
transporting compounds in organic light-emitting devices
[6]. Although the direct arylation of simple chloropyrimi-
dines is well documented [7], arylation of chloropyrimidines
containing various reactive groups and application of the
Suzuki-Miyaura reaction for the synthesis of densely substi-
tuted arylpyrimidines is explored insufficiently. Continuing
our studies on the synthesis of pyrimidine derivatives and
related heterocycles [8] in this communication, we present
the results of investigation of the palladium-catalyzed cross-
coupling reaction of some 4,6-dichloropyrimidines (1a–f)
bearing methylthio-, methyl-, amino-, cyano-, formyl-, and
nitro groups in positions 2 and/or 5 of the pyrimidine ring
with selected arylboronic acids.
It should be mentioned that in spite of the fact that equiv-
alent amount of phenylboronic acid was used both chlorine
groups of compound 1a took part in the coupling reaction
(entries 2 and 3). When 2.16 equiv. of phenylboronic acid
was used in the reaction the corresponding 4,6-diphenylpyri-
midine 3a was isolated in 29% low yield (entry 4). We
decided that a reason of such poor reaction course can be
due to the presence of water in the reaction mixture. Chlo-
rine groups in positions 4 and 6 of the pyrimidine ring are
very reactive toward various nucleophiles [11]. Thus, in
addition to other possible side reactions, such as, dehaloge-
nation, homocoupling, etc., hydrolysis of chlorine groups
under the alkaline reaction conditions could also occur to
give several side products. Therefore, for further study,
K3PO4/anhydrous dioxane was chosen as a base/solvent sys-
tem. Using Pd(OAc)2/PPh3/K3PO4 as a catalyst system, the
reaction of 1a with 1.08 equiv. of phenylboronic acid gave a
complex mixture of products from which compound 2a was
isolated in 26% yield (entry 5). When the coupling was car-
ried out with 2.16 equiv. of phenylboronic acid in an
RESULTS AND DISCUSSION
Our investigation started with the cross-coupling of
4,6-dichloropyrimidines 1a–f with phenylboronic acid
(Scheme 1).
C
V
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Palladium-Catalyzed Cross-Coupling Reaction of
2- and/or 5-Substituted 4,6-Dichloropyrimidines with Arylboronic Acids
961
Scheme 1
pling reaction with 1.08 equiv. phenylboronic acid did
not give monophenyl derivatives 2c,d. With both sub-
strates 1c,d, the side reactions competed with the cross-
coupling reaction and, at best, formation of both mono-
phenyl and diphenyl derivatives were observed. How-
ever, performing the reaction of 1c,d with double
amount of phenylboronic acids using Pd(OAc)2/PPh3/
K3PO4 gave 3c,d in 68% and 59% yields, respectively
(entries 10 and 15). To increase the yield of the cross-
coupling product 3c bidentate ligand—1,4-di(triphenyl-
phosphino)butane (dppb) and more electron rich and
sterically hindered ligands—tri(o-tolyl)phosphane and
(2-biphenyl)dicyclohexylphosphine were used in the
reaction. However, the side reactions competed again
and complex mixtures of products were formed (entries
11 and 12) or no reaction was observed (entry 13). It
was found that using Pd(PPh3)2Cl2 instead Pd(OAc)2
sometimes gives better results (entries 14 and 16) and
there is no necessity to add an additional amount of
ligand when Pd(PPh3)2Cl2 is used as a catalyst. Under
these conditions, 4,6-diphenyl-2-methylpyrimidine (3e)
was obtained in 73% yield (Table 1, entry 17). The
cross-coupling of 4,6-dichloro-5-nitropyrimidine (1f)
[15] with phenylboronic acid proceeded ambiguously.
Nitro group due to its electron-withdrawing nature acti-
vates chlorine groups in the positions 4 and 6 of the py-
rimidine ring, but this, perhaps, increases chances of
side reactions to take place. Thus, after 2 h substrate 1f
anhydrous dioxane with K3PO4 as a base twofold coupling
occurred to give compound 3a in 51% yield (entry 6).
The cross-coupling reaction of 4,6-dichloro-2-methyl-
thiopyrimidine-5-carbaldehyde (1b) [9] with 1.08 equiv.
phenylboronic acid using Pd(OAc)2/PPh3/K3PO4 in
dioxane at 70ꢀC furnished 4-chloro-2-methylthio-6-phe-
nylpyrimidine-5-carbaldehyde (2b) in 34% yield (entry
7). A slightly better yield of 2b (42%) was obtained
when Pd2(dba)3 was used as a catalyst and when the
reaction was carried out at room temperature (entry 8).
In the reaction of 1b with 2.16 equiv. of phenylboronic
acid at the reflux temperature of dioxane, the corre-
sponding 4,6-diphenylpyrimidine 3b was obtained in
62% yield (entry 9). Compounds 1c,d [12,13] bearing
strong electron-donating and capable to form complexes
with palladium species amino group [14] in the position
2 of the pyrimidine ring reacted with phenylboronic acid
only at elevated temperatures. Moreover, possibly due to
decreased reactivity of chlorine groups, the cross-cou-
Table 1
Results of the Suzuki-Miyaura reaction of compounds 1a–f with phenylboronic acid.
PhB(OH)2
Equiv.
Reaction temp.
(ꢀC)/duration (h)
Product
(yield, %)a
Entry
Compd.
Catalyst/ligand
Pd(OAc)2/PPh3
Base/solvent
1
2
3
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1c
1d
1d
1e
1f
1.08
1.08
1.08
2.16
1.08
2.16
1.08
1.08
2.16
2.16
2.16
2.16
2.16
2.16
2.16
2.16
2.16
2.16
Na2CO3/H2O/THF
Cs2CO3/H2O/THF
Cs2CO3/H2O/THF
Cs2CO3/H2O/THF
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
K3PO4/dioxane
D/35
D/33
D/28
D/11
70ꢀC/25
D/2.7
70ꢀC/35
r.t./72
D/2.75
D/13
D/3
D/13
D/5
D/7
D/25
D/3.5
D/3
ND
Pd(OAc)2/PPh3
Pd2(dba)3/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd2(dba)3/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/dppb
Pd(OAc)2/P(o-tol)3
Pd(OAc)2/(2-biPh)PCy2
Pd(PPh3)2Cl2
2a þ 3a (traces)b
2a:3a ¼ 1:3b
3a (29)
4
5
2a (26)
3a (51)
2b (34)
2b (42)
3b (62)
3c (68)
ND
ND
6
7
8
9
10
11
12
13
14
15
16
17
18
Recovered 1c
3c (85)
Pd(OAc)2/PPh3
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
3d (59)c
3d (51)
3e (73)c
3f (21)
Pd(OAc)2/PPh3
D/2
a The yields reported are after isolation and purification by the column chromatography.
b Determined by 1H NMR spectra.
c Physical properties of compounds 3d,e corresponded the reported data [10] where they were synthesized from acyclic precursors by cycloconden-
sation reactions.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

962
S. Tumkevicius, J. Dodonova, I. Baskirova, and A. Voitechovicius
Vol 46
Scheme 2
vis spectrophotometer Lambda 20 in ethanol solutions. IR
spectra were run on a PerkinElmer FTIR spectrophotometer
Spectrum BX II in nujol. 1H and 13C NMR spectra were
recorded on a Varian INOVA spectrometer (300 MHz and 75
MHz, respectively). Chemical shifts are reported in ppm rela-
tive to tetramethylsilane. Mass spectrum was obtained on a
mass spectrometer Kratos 115-30 (70 eV) by direct insertion
probe. Elemental analysis (C and H) were found to be in good
agreement (ꢁ0.4%) with the calculated values. Column chro-
matography was performed using Silica gel 60 (0.040–0.063
mm) (Merck). All reactions and purity of the synthesized com-
pounds were monitored by TLC using Silica gel 60 F254 alu-
minum plates (Merck). Visualization was accomplished by UV
light.
Typical procedure for the synthesis of compounds 2a,b
and 3a–d,f using Pd(OAc)2/PPh3/K3PO4. A solution of com-
pound 1a–d,f (0.45 mmol) in anhydrous dioxane (20 mL) was
flushed with argon and K3PO4 (0.61 g, 2.9 mmol), phenylbor-
onic acid (0.118 g, 0.97 mmol) (in case of synthesis 2a,b 0.3
g, 1.47 mmol K3PO4, and 0.06 g, 0.49 mmol phenylboronic
acid was used), 2.5 mol % Pd(OAc)2 and 5 mol % PPh3 were
added under stirring and argon flow. The reaction mixture was
stirred under argon at a temperature indicated in Table 1. Then
dioxane was evaporated under reduced pressure to dryness. To
dissolve inorganic salts the residue was treated with water (5
mL) and stirred for 0.5 h. The obtained solution was extracted
with chloroform (3 ꢂ 25 mL), organic layer was dried with
Na2SO4, chloroform removed by distillation under reduced
pressure, and the solid was purified by column chromatography
to give compounds 2a,b, and 3a–d,f.
disappeared from the reaction mixture (TLC data), but
the desirable 4,6-diphenyl-5-nitropyrimidine (3f) was
isolated only in 21% yield (Table 1, entry 18).
Taking into account, the results of the cross-coupling
reactions of 1a–e with phenylboronic acid some 4,6-dia-
rylpyrimidines 4–6 using Pd(PPh3)2Cl2/K3PO4 as a cata-
lyst system were synthesized (Scheme 2, Table 2).
In conclusion, the performed investigation showed that
the synthesis of 6-aryl-4-chloropyrimidines bearing various
substituents in the second and fifth positions of the pyrimi-
dine ring by the Suzuki-Miyaura cross-coupling reaction is
problematic. The reaction proceeds with the formation of
mixtures of mono- and di-arylpyrimidines. Otherwise, the
Suzuki-Miyaura cross-coupling reaction of the correspond-
ing 4,6-dichloropyrimidines with double amount of arylbor-
onic acids using Pd(OAc)2/PPh3/K3PO4 or Pd(PPh3)2Cl2/
K3PO4 as catalyst systems in dioxane furnishes the corre-
sponding 2- and/or 5-substituted 4,6-diarylpyrimidines in
reasonable yields.
Typical procedure for the synthesis of compounds 3c–e,
4–6 using Pd(PPh3)2Cl2/K3PO4. A suspension of compounds
1c–e (0.51 mmol) in dioxane (25 mL) was flushed with argon.
Then, K3PO4 (3.16 mmol), arylboronic acid (1.1 mmol), 2.5
mol % Pd(PPh3)2Cl2 were added under stirring and argon
flow. The reaction mixture was refluxed under stirring and ar-
gon until compounds 1c–e consumed (TLC control). Then
EXPERIMENTAL
Melting points were determined in open capillaries and are
uncorrected. UV spectra were obtained on a PerkinElmer UV-
Table 2
Coupling of compounds 1c,e with arylboronic acids.
Compound
Arylboronic acid
Duration (h)
2
Product
Yield (%)
50
4
7
65
50
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DOI 10.1002/jhet

September 2009
Palladium-Catalyzed Cross-Coupling Reaction of
2- and/or 5-Substituted 4,6-Dichloropyrimidines with Arylboronic Acids
963
dioxane was evaporated under reduced pressure. To dissolve
inorganic salts, the residue was treated with water (5 mL) and
stirred for 0.5 h. The solid obtained was filtered off and puri-
fied by crystallization or column chromatography.
4-Chloro-2-methylthio-6-phenylpyrimidine-5-carbonitrile
(2a). Compound 2a was purified by column chromatography
using benzene, yield 26%, mp 95–96ꢀC. 1H NMR (deuterio-
chloroform): d 2.69 (s, 3H, SCH3), 7.59–7.63 (m, 3H, 30,40,50-
H), 8.08–8.11 (m, 2H, 20, 60-H). 13C NMR (deuteriochloro-
form): d 14.99, 101.0, 114.9, 129.0, 129.6, 131.9, 134.5,
163.8, 168.8, 176.7. Anal. Calcd. for C12H8ClN3S: C, 55.07;
H, 3.08. Found: C, 55.42; H, 3.01.
form. Yield 50%, mp 248–251ꢀC (from chloroform). UV: kmax
204 (e 67,000), 287 (e 42,000). IR: 3492, 3400 sh., 3290
(NH2), 1688 cmꢃ1 (C¼¼O). 1H NMR (deuteriochloroform): d
6.10 (s, 2H, NH2), 7.44–7.46 (m, 2H, 2 ꢂ 400-H), 7.50–7.55
(m, 4H, 2 ꢂ 300,500-H), 7.68–7.71 (m, 4H, 2 ꢂ 200,600-H), 7.77
(s, 8H, 2 ꢂ 20,30,50,60-H), 10.01 (s, 1H, CHO). 13C NMR (di-
methyl sulfoxide-d6): d 116.99, 126.8, 127.6, 128.6, 129.8,
131.1, 137.5, 140.1, 142.0, 163.4, 171.6, 188.9. ms (ESI): m/z
(%) 428 (100) (M þ1). Anal. Calcd. for C29H21N3O: C, 81.48;
H, 4.95. Found: C, 81.64; H, 5.04.
4,6-Di(4-tert-butylphenyl)-2-methylpyrimidine (5). Compound
6 was purified by column chromatography using chloroform.
Yield 65%, mp 110–111ꢀC. UV: kmax 206 (e 34,000), 255 (e
25,000), 283 sh. (e 21,000), 297 sh. (e 24,000), 306 (e
27,000). 1H NMR (deuteriochloroform): d 1.41 [s, 18H, 2ꢂ
C(CH3)3], 2.88 (s, 3H, 2-CH3), 7.58 (d, J ¼ 8.7 Hz, 4H, 2 ꢂ
30,50-H), 7.88 (s, 1H, 5-H), 8.08 (d, J ¼ 8.7 Hz, 4H, 2 ꢂ 20,60-
H). 13C NMR (deuteriochloroform): d 26.72, 31.50, 35.13,
109.91, 126.17, 127.29, 135.00, 154.33, 164.97, 168.63. Anal.
Calcd. for C25H30N2: C, 83.75; H, 8.43. Found: C, 84.06; H,
8.62.
4-Chloro-2-methylthio-6-phenylpyrimidine-5-carbaldehyde
(2b). Compound 2b was synthesized by the typical procedure
using Pd(OAc)2 (yield 34%) or by analogous procedure using 2.5
mol % Pd2(dba)3 under conditions presented in Table 1 (yield
42%). Compound 2b was purified by column chromatography
using benzene. mp 140–141ꢀC. UV: kmax 266 (e 17,000), 287 (e
1
15,000). IR: 1694 cmꢃ1 (CHO). H NMR (deuteriochloroform): d
2.69 (s, 3H, SCH3), 7.57–7.62 (m, 5H, C6H5), 10.09 (s, 1H,
CHO). 13C NMR (deuteriochloroform): d 14.85, 120.7, 129.0,
130.5, 131.6, 135.2, 160.9, 170.1, 176.2, 188.2. Anal. Calcd. for
C12H9ClN2OS: C, 54.44; H, 3.43. Found: C, 54.78; H, 3.64.
2-Methylthio-4,6-diphenylpyrimidine-5-carbonitrile (3a). Com-
pound 3a was purified by column chromatography using benzene.
Yield 29%, mp 220–221ꢀC. UV: kmax 277 (e 30,000), 339
4,6-Bis(3,5-dichlorophenyl)-2-methylpyrimidine (6). Yield
50%, mp 230–231ꢀC (from toluene). UV: kmax 219 (e 29,000),
247 (e 12,000), 260 sh. (e 8100), 295 (e 12,000), 318 (e 4600).
1H NMR (deuteriochloroform): d 2.91 (s, 3H, 2-CH3), 7.56 (t,
4
4J ¼ 1.8 Hz, 2H, 2 ꢂ 40-H), 7.82 (s, 1H, 5-H), 8.07 (d, J ¼
1.8 Hz, 4H, 2 ꢂ 20,60-H). 13C NMR (deuteriochloroform): d
26.6, 110.2, 126.0, 131.0, 136.1, 140.2, 162.9, 169.50. ms
(ESI): m/z (%) 384 (100) (Mþ). Anal. Calcd. for C17H10Cl4N2:
C, 53.16; H. 2,62. Found: C, 53.23; H, 2.57.
1
(e 2500). IR: 2220 cmꢃ1 (CN). H NMR (deuteriochloroform): d,
2.73 (s, 3H, SCH3), 7.59–7.62 (m, 6H, 2 ꢂ 30,40,50-H), 8.07–8.10
(m, 4H, 2 ꢂ 20,60-H). 13C NMR (deuteriochloroform), d, ppm:
14.8, 98.4, 117.7, 129.0, 129.6, 131.96, 135.8, 169.4, 175.9. Anal.
Calcd. for C18H13N3S: C, 71.26; H, 4.32. Found: C, 71.17; H, 4.55.
2-Methylthio-4,6-diphenylpyrimidine-5-carbaldehyde (3b). Com-
pound 3b was purified by column chromatography using ben-
zene. Yield 62%, mp 112–113ꢀC. UV: kmax 275 (e 20,000).
Acknowledgment. J. Dodonova and I. Baskirova gratefully
acknowledge Lithuanian Science Council for student research
fellowship awards.
1
IR: 1697 cmꢃ1 (CHO). H NMR (deuteriochloroform): d 2.73
(s, 3H, SCH3), 7.54–7.57 (m, 6H, 30,40,50-H), 7.68–7.71 (m,
4H, 20,60-H), 10.05 (s, 1H, CHO). 13C NMR (deuteriochloro-
form): d 14.73, 121.8, 128.7, 130.4, 130.9, 136.8, 168.8,
175.1, 190.6. Anal. Calcd. for C18H14N2OS: C, 70.56; H, 4.61.
Found: C, 70.79; H, 4.49.
REFERENCES AND NOTES
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2-Amino-4,6-diphenylpyrimidine-5-carbaldehyde (3c). Yield
85% using Pd(PPh3)2Cl2 and 68% using Pd(OAc)2/PPh3, mp
149–150ꢀC (dec.) (from 2-propanol). UV: kmax 259 (e 22,000),
276 sh. (e 21,000), 314 sh. (e 11,000). IR: 3468, 3380 sh,
3277 (NH2), 1687 cmꢃ1 (C¼¼O). 1H NMR (deuteriochloro-
form): d 5.96 (s, 2H, NH2), 7.50–7.63 (m, 10H, 2ꢂ C6H5),
[2] (a) Miyaura, N.; Suzuki, A. Chem Rev 1995, 95, 2457; (b)
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9.89 (s, 1H, CHO). 13C NMR (deuteriochloroform):
d
117.9, 128.6, 129.5, 130.4, 137.5, 162.4, 172.5, 189.2. Anal.
Calcd. for C17H13N3O: C, 74.17; H, 5.11. Found: C, 74.00;
H, 4.95.
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1H NMR (deuteriochloroform):
d
7.52–7.60 (m, 6H,
2ꢂ[30,40,50-H]), 7.73–7.76 (m, 4H, 2ꢂ[20,60-H]), 9.41 (s, 1H,
2-H). 13C NMR (deuteriochloroform): d 128.1, 129.3, 131.5,
133.6, 143.99, 158.3, 158.4. ms (ESI): m/z (%) 278 (100) (M
þ1). Anal. Calcd. for C16H11N3O2: C, 69.31; H, 4.00. Found:
C, 69.22; H, 4.08.
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S. Tumkevicius, J. Dodonova, I. Baskirova, and A. Voitechovicius
Vol 46
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet