Direct synthesis of ortho-dihalogenated arylpyrimidines using calcium halides as halogen sources

Article abstract of DOI:10.1016/j.tetlet.2010.10.061

Pyrimidines and their derivatives have been used as important motifs in materials and medicinal chemistry. In this Letter, a wide variety of ortho-dihalogenated arylpyrimidines were synthesized with high yields and functional-group tolerance using calcium

Full text of DOI:10.1016/j.tetlet.2010.10.061

Tetrahedron Letters 51 (2010) 6641–6645
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Tetrahedron Letters
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Direct synthesis of ortho-dihalogenated arylpyrimidines using calcium
halides as halogen sources
Xiaojian Zheng a, Bingrui Song a, Guifei Li a, Bingxin Liu a, Hongmei Deng b, Bin Xu a,
⇑
a Department of Chemistry, Shanghai University, Shanghai 200444, China
b Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrimidines and their derivatives have been used as important motifs in materials and medicinal chem-
istry. In this Letter, a wide variety of ortho-dihalogenated arylpyrimidines were synthesized with high
yields and functional-group tolerance using calcium halides as crucial halogenating agents and cupric tri-
fluoroacetate as oxidant in the presence of air. The generated dichlorinated products could be further
manipulated by stepwise Suzuki–Miyaura reaction to afford a wide range of ortho-functionalized arylpyr-
imidines amenable to physical and biological evaluations.
Received 27 August 2010
Revised 25 September 2010
Accepted 12 October 2010
Available online 20 October 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Calcium halides
C–H activation
Cross-coupling
Halogenation
Nitrogen heterocycles
Aryl or heteroaryl halides are extremely valuable starting mate-
rials or intermediates for synthetic elaboration, as well as important
structural motifs in many natural products and manufactured
drugs.1 They have been broadly utilized to construct complex struc-
tures in organic chemistry via transition-metal catalyzed cross-cou-
pling reactions, such as Buchwald–Hartwig amination, Heck,
Negishi, and Suzuki reactions.2,3 This class of materials could be tra-
ditionally achieved by Friedel–Crafts halogenation4 or Sandmeyer
reaction5 or through directed ortho-lithiation reactions.6 However,
these commonly used methods sometimes suffer from several
drawbacks, such as limited substrates’ scope, low selectivity, te-
dious and somehow dangerous procedures and thus restrict their
applications in organic synthesis.
Remarkable progress has been made during the past decades in
catalytic C–H activation directed by functional groups.7,8 Recently,
ortho halogenated arenes were selectively synthesized through
metal-catalyzed halogenation of C–H bonds with the assistance
of some directing groups, including amide,9c,f,h carboxylic acid,9a,g
pyridine,9b,d,i,j and oxazoline.9k Pyrimidines are important compo-
nents for a variety of biological active molecules and pharmaceuti-
cal agents,10 as well as potential OLED materials,11 thus, the
development of readily available functionalized arylpyrimidines
will be very important. In this event, the pyrimidine-directed C–
H functionalization approach will be one of the best synthetic
pathways leading to efficient construction of pyrimidine deriva-
tives. However, only few examples involving pyrimidine as direct-
ing group for C–H functionalization were reported8e,h,i,k,m and one
of the reasons may be due to the formation of a dual metal
complex.12
Generally, for biaryl substrates, such as arylpyridines or aryl-
pyrimidines with electron-donating property and particularly for
those with para-substitution in the aromatic ring, ortho-dihalogen-
ated product could often be achieved more easily through C–H
halogenation.9b,i,j,l However, ortho-dihalogenation is dramatically
restrained or completely inhibited for those substrates bearing
meta-substituents in the aromatic ring even under harsh condi-
tions,7c,9g,i,l which may be due to the occurence of steric hindrance
between the meta-substituents of the substrates and the catalyst
during the transition state of the reaction. Thus, developing highly
efficient catalytic systems for direct C–H halogenation with diverse
directing groups and expanding the reaction scopes to steric sub-
strates remain a challenge.
We have made some efforts to develop efficient methods for the
construction of nitrogen-containing heterocycles13 and recently
focused our research on the metal-catalyzed regioselective C–H
functionalization of arylpyrimidines.14 Among them, a palladium-
catalyzed highly monoselective C–H halogenation of arylpyrimi-
dines was developed using commonly available calcium halides
as crucial halogenating agents, and a palladacycle complex derived
from arylpyrimidine and Pd(OAc)2 might be the active species
during the reaction (Scheme 1).14a We envisioned that the use of
this palladacycle might promote the reaction.15 In this Letter, we
report a direct ortho C–H dihalogenation of arylpyrimidines, using
⇑
Corresponding author. Tel./fax: +86 21 66132065.
E-mail address: xubin@shu.edu.cn (B. Xu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.061

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X. Zheng et al. / Tetrahedron Letters 51 (2010) 6641–6645
calcium halides as halogenating agents and cupric trifluoroacetate
as oxidant in the presence of air.
N
N
O
O
O
O
At the outset of this investigation, we used meta-substituted
2-(3-methoxyphenyl) pyrimidine 1a as model substrate under
the catalysis of palladium. In the previous study, we have found
that ortho-dichlorinated products could be produced exclusively
from 2-phenylpyrimidine in the presence of calcium chloride,
using Pd(OAc)2 as the catalyst and Cu(OTFA)2 as the oxidant.14a
However, the dichlorination of sterically hindered substrate 1a
turned out to be much more difficult and afforded the correspond-
ing dichlorinated product 2a in 67% yield after reacted for a period
of 90 h under the same condition (Table 1, entry 1) and no better
result was given when PdCl2 was used instead (Table 1, entry 2).
To our delight, the ortho-dichlorination reaction was improved in
the presence of palladacycle I (2.5 mol %) with decreased reaction
time (Table 1, entry 3). Other solvents, such as toluene, dioxane,
and acetonitrile, were almost totally ineffective for this transfor-
mation (Table 1, entries 4–6). The use of CuCl2, NaCl, and KCl as
chlorinating agent resulted in lower yields even with more equiv-
alents of chloride ions, which indicated that the use of CaCl2 was
crucial for this chlorination reaction (Table 1, entries 7–9). Switch
of Cu(OTFA)2 to Cu(OTf)2 and Cu(OAc)2 could not significantly in-
crease the yields of 2a (Table 1, entries 10 and 11), and when Ox-
one and K2S2O8 were employed as oxidants, the reaction gave only
trace amount of dichlorinated product (Table 1, entries 12 and 13).
Further screens concerning the amount of CaCl2 gave similar re-
sults; more amount of CaCl2 could not increase the yield dramati-
cally (Table 1, entries 14 and 15). Compound 2a could be afforded
in 79% yield in the absence of palladium after reacted for 7 days9e
(Table 1, entry 16) and 40% of 2a could be isolated together with
48% of mono-chlorinated product when CuCl2 was used instead
of Cu(OTFA)2 and CaCl2 (Table 1, entry 17).
Pd
Pd
N
N
Palladacycle I
Scheme 1. Active species for C–H halogenation of arylpyrimidines.
Table 1
Optimization of dichlorination reaction of 1aa
Palladacycle I (2.5 mol%)
Oxidant (1.0 equiv.)
N
Cl
N
MeO
MeO
N
N
Cl source (X equiv.)
Solvent, air, 110 o
C
Cl
1a
Oxidant
2a
Entry
Cl Source (equiv)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Cu(OTFA)2
Cu(OTFA)2
Cu(OTFA)2
Cu(OTFA)2
Cu(OTFA)2
Cu(OTFA)2
Cu(OTFA)2
Cu(OTFA)2
Cu(OTFA)2
Cu(OTf)2
Cu(OAc)2
Oxone
CaCl2 (4.0)
CaCl2 (4.0)
CaCl2 (4.0)
CaCl2 (4.0)
CaCl2 (4.0)
CaCl2 (4.0)
CuCl2 (4.0)
NaCl (8.0)
KCl (8.0)
CaCl2 (4.0)
CaCl2 (4.0)
CaCl2 (4.0)
CaCl2 (4.0)
CaCl2 (5.0)
CaCl2 (3.0)
CaCl2 (4.0)
CuCl2 (4.0)
HOAc
HOAc
HOAc
Toluene
Dioxane
MeCN
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
90
80
54
48
48
48
60
60
60
57
65
60
60
53
70
7 days
56
67c
61d
72
<5
<5
<5
52
40
37
70
56
Trace
5
K2S2O8
Cu(OTFA)2
Cu(OTFA)2
Cu(OTFA)2
/
76
62
79e
40f
Having optimized the reaction conditions, we prepared a variety
of arylpyrimidines14 with different substituents and explored the
scope and generality of this dichlorination reaction. As shown in
Table 2, substrates bearing meta- (Table 2, entries 1–4), para- (Table
2, entries 6–12) substituents on aryl ring, as well as naphthalene-
containing pyrimidine (Table 2, entry 13), gave dichlorinated prod-
ucts in good to excellent yields. Arylpyrimidines containing both
electron-donating (Table 2, entries 1, 2, 6 and 7) and electron-
withdrawing groups (Table 2, entries 3, 4 and 8–12) could react
a
Reaction conditions: substrate of 1a (0.30 mmol), palladacycle I (2.5 mol %),
oxidant (1.0 equiv), HOAc (5.0 mL), 110 °C, under air. Cu(OTFA)2 = cupric
trifluoroacetate.
b
Isolated yield.
c
5 mol % of Pd(OAc)2 was used.
d
5 mol % of PdCl2 was used.
e
Without palladium
f
Monochlorinated product was also isolated in 48% yield
Table 2
Direct C–H dichlorination of arylpyrimidinesa
Cl
N
R2
I
N
Palladacycle (2.5 mol% )
Cu(OTFA)2 (1.0 equiv.)
R2
N
R1
N
R1
CaCl2 (4.0-6.0 equiv.)
HOAc, air, 110 oC
Cl
2
1
Entry
1
Substrate
Product
Time (h)
54
Yieldb (%)
72
N
Cl
N
MeO
MeO
Me
N
N
1a
Cl
2a
N
Cl
N
Me
N
N
2
3
36
98
92
1b
Cl
2b
N
Cl
N
OHC
OHC
86c
N
N
1c
Cl
2c

X. Zheng et al. / Tetrahedron Letters 51 (2010) 6641–6645
6643
Table 2 (continued)
Entry
Substrate
Product
Time (h)
108
Yieldb (%)
N
Cl
N
O2N
Cl
O2N
60d
89
N
4
5
N
1d
Cl
2d
N
N
N
N
11
10
11
38
21
96
28
21
1e
Cl
Cl
2e
N
N
N
N
6
83
Me
MeO
Cl
Me
Cl
2f
1f
N
Cl
N
N
N
7
88
MeO
Cl
Cl
N
1g
2g
N
Cl
N
8
88e
86e
90e
86e
84e
N
Cl
1h
2h
N
Cl
N
N
N
9
F
Cl
F
2i
1i
N
Cl
Cl
N
N
N
10
11
12
F3C
F3C
Cl
N
1j
2j
N
N
N
TsO
TsO
Cl
1k
2k
N
Cl
N
N
N
EtO2C
Cl
EtO2C
1l
2l
N
Cl
N
N
N
N
13
14
48
6
89
89
86
1m
Cl
2m
Ph
Ph
N
N
Cl
Cl
N
N
N
1n
Cl
N
2n
2o
N
Ph
Ph
15
21
1o
Cl
a
Reaction conditions: substrate of 1 (0.30 mmol), palladacycle I (2.5 mol %), Cu(OTFA)2 (0.30 mmol), CaCl2 (1.2–1.8 mmol), HOAc (5.0 mL), 110 °C, under air.
Isolated yield.
7.5 mol % of palladacycle I, Cu(OTFA)2 (0.45 mmol), CaCl2 (2.4 mmol) were used.
7.5 mol % of palladacycle I, Cu(OTFA)2 (0.60 mmol), CaCl2 (2.4 mmol) were used.
6.0 equiv of CaCl2 was used.
b
c
d
e
smoothly and afford corresponding products predominately. The
substrates with formyl and nitro groups attached could also pro-
ceed well to give 2c and 2d in good yields (Table 2, entries 3 and
4) although a long reaction time was needed for completion. The ac-
tive formyl group in compound 1c remained intact under the reac-
tion condition and mono-chlorinated product could be isolated in
89% yield after reacted for 4 h, which indicated that further chlori-
presence of functional groups, such as formyl (Table 2, entry 3),
nitro (Table 2, entry 3), halogen (Table 2, entries 8 and 9), tosylate
(Table 2, entry 11), and ester (Table 2, entry 12) were all compatible
with this C–H chlorination reaction under optimized conditions. It
should be noted that inactive meta-substituted electron-deficient

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X. Zheng et al. / Tetrahedron Letters 51 (2010) 6641–6645
nation from mono-chlorinated product is more sluggish. In partic-
ular, high yields of dichlorinated products 2n and 2o could be
achieved for dual phenyl substituted pyrimidines (Table 2, entries
14 and 15).
To further expand the scope of the reaction, we treated several
arylpyrimidines with CaBr2 to form dibrominated products.16 Grat-
ifyingly, the corresponding dibrominated products 3a–d could also
be well achieved in high yields using CaBr2 as brominating reagent,
which validates the reaction as a practically convenient method for
both chlorination and bromination (Table 3). Substrates with both
electron-donating (Table 3, entry 2) and electron-withdrawing
(Table 3, entries 3 and 4) groups on aromatic ring could convert
into dibromides in good to excellent yields.
Metal-catalyzed nitrogen-directed ortho-arylation of aromatic
rings has been well documented,7c,h,17 however, few exam-
ples8i,m,17e have been reported for the preparation of ortho-arylated
2-phenylpyrimidines11a,b and most of them gave mono-phenylated
product predominantly. Recently, Nakamura and co-workers
reported an iron-catalyzed direct arylation of 2-phenylpyrimidine
and afforded mono-phenylated product in 81% yield together with
9% of diphenylated product.8i To increase the synthetic utility of
these dihalogenated products and synthesize ortho-functionalized
arylpyrimidines, 2e was successfully converted into corresponding
diphenylated arylpyrimidine 4 by Suzuki–Miyaura reaction with
phenylboronic acid underthe catalysis of Pd(OAc)2 and PCy3 in diox-
ane (Scheme 2). Furthermore, two different kinds of arylboronic
Table 3
Direct C–H dibromination of arylpyrimidinesa
N
Br
N
Palladacycle I (2.5 mol%)
Cu(OTFA)2 (1.0 equiv.)
R2
R2
N
N
R1
R1
CaBr2 (4.0-6.0 equiv.)
Br
HOAc, air, 110 o
C
1
3
Entry
1
Substrate
Product
Time (h)
22
Yieldb (%)
72
N
Br
N
N
N
1e
Br
3a
N
Br
N
N
N
2
3
4
12
32
64
94
86c
79c
Me
Me
Br
3b
1f
N
Br
N
N
N
Cl
Br
Br
Cl
1h
3c
N
N
N
N
EtO2C
Br
EtO2C
1l
3d
a
b
c
Reaction conditions: substrates of 1 (0.30 mmol), palladacycle (2.5 mol %), Cu(OTFA)2 (0.30 mmol), CaBr2 (1.2–1.8 mmol), HOAc (5.0 mL), 110 °C.
Isolated yield.
6.0 equiv of CaBr2 was used.
Pd(OAc)2 (5 mol%)
Cl
N
N
B(OH)2 PCy3-HBF4 (10 mol%)
N
+
N
Cs2CO3 (5.0 equiv.)
dioxane, 110 oC, N2, 10 h
60% yield
Cl
2e
4
Me
1) Pd(dba)2 (5 mol%), PCy3-HBF4 (10 mol%)
Cs2CO3 (2.0 equiv.), dioxane, 110 oC, N2, 10 h
4-Methoxylphenylboronic acid (2.0 equiv.)
Cl
N
N
N
N
2) Pd(dba)2 (5 mol%), PCy3-HBF4 (10 mol%)
Cs2CO3 (2.5 equiv.), dioxane, 110 oC, N2, 10 h
4-Methylphenylboronic acid (2.5 equiv.)
37% yield for two steps
Cl
2e
OMe
5
Scheme 2. Application of dichlorinated product.

X. Zheng et al. / Tetrahedron Letters 51 (2010) 6641–6645
6645
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demonstrates the superiority of our prepared dichlorinated
products.
In summary, we have developed an efficient and direct C–H
halogenation reaction for the synthesis of ortho-dihalogenated
arylpyrimidines using calcium halides as crucial halogenating
agents in the presence of palladacycle and cupric trifluoroacetate.
This ortho C–H halogenation reaction may go through either
Pd(0)–Pd(II) or Pd(II)–Pd(IV) intermediates with Cu(OTFA)2 and
air as co-oxidant to complete the catalytic cycle.14a The tolerance
of this protocol toward a wide variety of functional groups enables
the synthesis of a broad spectrum of valuable compounds. The gen-
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Miyaura reaction to afford a wide range of substituted arylpyrim-
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studies are in progress in our laboratory to extend this process to
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We thank the National Natural Science Foundation of China
(No. 20972093) and Shanghai Municipal Education Commission
(No. J50102 and 10YZ06) for financial support. X.Z. is supported
by the Graduate Student Creative Foundation of Shanghai Univer-
sity (No. SHUCX102026).
Supplementary data
Supplementary data (experimental details, spectroscopic char-
acterization data, copies of the 1H NMR, 19F NMR, and 13C NMR
spectra of all products) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2010.10.061.
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