Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Bromides with Pyrimidin-2-yl Tosylates

Article abstract of DOI:10.1002/cjoc.201700071

A new protocol for the NiCl₂-catalyzed cross-electrophile coupling of aryl bromides with pyrimidin-2-yl tosylates to give the corresponding C2-arylation pyrimidine derivatives has been developed. This study provides an improvement over previous methods by using pyrimidin-2-yl tosylates instead of halides as coupling partners that are stable and easily available.

Full text of DOI:10.1002/cjoc.201700071

COMMUNICATION
DOI: 10.1002/cjoc.201700071
Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Bromides
with Pyrimidin-2-yl Tosylates
Chunyu Gong, Congde Huo, Xicun Wang,* and Zhengjun Quan*
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education of China; Key Laboratory
of Polymer Materials of Gansu Province; College of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou, Gansu 730070, China
A new protocol for the NiCl2-catalyzed cross-electrophile coupling of aryl bromides with pyrimidin-2-yl tosyl-
ates to give the corresponding C2-arylation pyrimidine derivatives has been developed. This study provides an im-
provement over previous methods by using pyrimidin-2-yl tosylates instead of halides as coupling partners that are
stable and easily available.
Keywords pyrimidin-2-yltosylates, functional pyrimidines, cross-electrophile coupling, aryl bromides, Nick-
el-catalyst
Introduction
mide esters[16] as the electrophiles.
Heterobiaryl compounds are common structure in
many bioactive molecule and pharmaceuticals, which
have attracted much attention in the relevant research
fields.[17] 3,4-Dihydropyrimidineone (DHPM) is a spe-
cial heterocyclic structure which has a wide range of
pharmacological products[18] such as α1a-adrenergic re-
ceptor antagonists, B virus replication inhibitors, cal-
cium channel modulators and mitotic kinesin inhibi-
tors.[19,20] In general, the methods to convert DHPM to
2-substituted pyrimidines involve sequential dehydro-
genation, tautomerization and activation coupling pro-
cess including chlorination[21] or sulfonylation,[22] then
coupling with a nucleophile. Chlorination of DHPMs
normally uses POCl3 under high temperature. Compara-
tively speaking, sulfonylation is often conducted under
room temperature, which is a safer method.
We have been working on developing a safe, effi-
cient and simple method to prepare tetrasubstituted py-
rimidines under mild conditions. In 2013, we reported
the process of synthesis of tetrasubstituted pyrimidines
by palladium(II) catalyzed cross-coupling reactions of
pyrimidin-2-yl tosylates with aryboronic acids and ter-
minal alkynes.[23] Then, we reported the coupling reac-
tion of pyrimidin-2-yl tosylates with a series of nucleo-
philes such as Grignard reagents,[24] phenols and ani-
lines[25] (Scheme 1, path A). In order to bypass the in-
convenience associated with reaction of organometallic
nucleophiles, we present the nickel-catalyzed cross-
electrophile coupling of pyrimidin-2-tosylates with aryl
bromides (Scheme 1, path B).
Transition-mental-catalyzed coupling reactions pro-
vide universal tools for construction of carbon-carbon
bonds.[1] Most of the processes require the use of or-
ganometallic reagents such as RB(OH)2, RBF3K, RZnI,
RMgBr, etc. in conjunction with an electrophile. In
general, these organometallic reagents are prepared
from the corresponding organic halides in separate
step.[2] Meanwhile, these kind of reagents are usually
air- and moisture-sensitive. In order to avoid the use of
unstable organometallic reagents, reductive cross-cou-
pling of two different electrophiles has been devel-
oped.[3]
In recent years, several groups have shown several
cases of coupling of two different aryl or alkyl halides
under cobalt-,[4] iron-,[5] palladium-[6] and nickel-cata-
lyzed[7] methods, especially nickel-catalyzed aryl-alkyl[8]
or alkyl-alkyl[9] cross-coupling of two electrophiles has
attracted wide attentions. Catalysts comprising a nick-
el(II) precursor and chelating nitrogen-based ligands
(bipyridine, phenanthroline) have proven to be espe-
cially active when using metallic manganese or zinc as
reductant. For instance, Gong’s group have showed
many cases of Ni-catalyzed cross-coupling of several
electrophiles such as allyl methyl carbonate, acyl chlo-
ride and allyl acetate.[10,11] Other researchers also pro-
vided some novel catalytic strategy. MacMillan,[12] Mo-
lander[13] and Lei[14] have showed photoredox/nickel
dual catalytic cross-coupling reaction to construct C－C
bond using two electrophiles. Weix has also showed
cross-coupling of epoxides[15] and N-hydroxyphthali-
*
E-mail: wangxicun@nwnu.edu.cn
Received January 23, 2017; accepted February 26, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201700071 or from the author.
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Gong et al.
COMMUNICATION
Scheme 1 Synthesis of C2-arylpyrimidine derivatives
try 7). However, when other solvents such as dioxane,
DMA and DMSO were used, there occurred almost no
reaction. We found that the base also plays an important
role in this reaction (Entries 8－13) and K3PO4 remark-
ably enhanced the yield of 3a to 73% (Entry 13). Finally,
when o-phenanthroline was used instead of bpy, the best
78% yield of 3a was observed (Entry 15). We also take
phosphorous ligands into consideration, when 1,3-bis-
(diphenylphosphino)propane (DPPP) was used as the
ligand, there was no reaction detected by TLC. Mean-
while, no improvement was found when the reaction
conditions changed.
Upon the establishment of viable reaction conditions,
several pyrimidin-2-yl tosylates (1) and aryl bromides
(2) were employed as substrates in this reaction
(Scheme 2). In general, yields from moderate to excel-
lent (30%－92%) were obtained under the standard re-
action conditions. Pyrimidin-2-yl tosylates containing
electron-donating groups (Me and MeO) on the phenyl
ring decreased the yield of C－C cross coupling prod-
ucts, which indicated that the electron-donation groups
would affect stability of the intermediate in this reaction.
When pyrimidin-2-yl tosylates contains electron-with-
drawing groups such as F atoms, the yield of corre-
sponding product has improved. In addition, 3-bromo-
thiophene as the aryl bromides also gave excellent
yields of C－C coupling products with several pyrim-
idin-2-yl tosylates. Moreover, pyrimidin-2-yl tosylates
containing Br or Cl group on the phenyl gave the
cross-coupling products 3j, 3k and 3l in low yields
(26%－38%) with forming of byproducts, which may
be biaryl compounds or homocoupling products.[26]
Generally, there are two different mechanisms of the
cross-electrophile coupling reaction proposed, the radi-
cal-chain[27] and double oxidative addition[26] mecha-
nisms. When we added 1 equiv. amount of 2,2,6,6-tetra-
methylpiperidinooxy (TEMPO) into the reaction mix-
ture of 1a with 1b under the standard conditions, only
slight decrease of yield was observed, this result indi-
cates this reaction likely performs through a Ni-cata-
lyzed oxidation and reduction elimination procedure
rather than the radical process.
Results and Discussion
We selected the coupling of pyrimidin-2-yl tosylates
1a and bromobenzene 2a as our test system to optimize
the reaction conditions (Table 1). When the reaction was
carried out in DMF at 40 ℃ in the presence of KF as a
base and 2,2'-bipyridine (bpy) as a ligand, the yield was
low (Entry 1) although the experiment was prolonged to
72 h. When the temperature reached to 80 ℃, the yield
increased to 50% (Entry 2). Meanwhile, the 3a was iso-
lated in 71% yield when THF was used as solvent (En-
Table 1 Optimization of the C2-arylation of DMHPs
Entry Ligand
Base
KF
KF
KF
KF
KF
KF
KF
Solvent Yieldb/%
1
bpy
DMF
＜10c
50
0d
0
2
bpy
DMF
3
bpy
DMF
4
bpy
Dioxane
DMA
DMSO
THF
5
bpy
24
0
6
bpy
7
bpy
71
0
8
bpy
t-BuOK THF
t-BuONa THF
9
bpy
0
10
11
12
13
14
15
bpy
K2CO3
THF
THF
0
According to our experiments and reported results,[26]
we proposed two processes for the Ni-catalyzed cross-
electrophile coupling of aryl bromides with pyrim-
idin-2-yl tosylates. NiII was first reduced to NiI by Zn
powder, which then oxidatively added to 1 to generate a
NiIII complex A, which was then once again reduced by
Zn to produce NiI intermediate B. This intermediate
underwent oxidative addition to aryl bromides 2, form-
ing a NiIII complex C. Subsequent reductive elimination
of C gave C2-arylation pyrimidine derivatives 3 and
NiIX (Scheme 4, path A). Alternatively, Ni0/ NiII process
was also considerable, NiII was first reduced to Ni0 with
Zn powder, which then oxidatively added to 1 to gener-
ate a NiII complex A, which was then once again re-
bpy
Cs2CO3
0
bpy
t-BuOK THF
0
bpy
K3PO4
K3PO4
K3PO4
K3PO4
THF
THF
THF
THF
73
0
dppp
o-phenanthroline
o-phenanthrolinee
78
72
16
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst
(10%, 0.05 mmol), ligand (10 mol%, 0.05 mmol), base (0.5
mmol), Zn powder (1 mmol), solvent (2 mL), 80 ℃, 12 h. b Iso-
c
lated yield after column chromatography. The reaction was car-
ried out under 60 ℃. d The reaction was carried out under 100 ℃.
e Catalyst (5 mol%, 0.025 mmol), ligand (5 mol%, 0.025 mmol).
2
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Chin. J. Chem. 2017, XX, 1—5

Cross-Electrophile Coupling of Aryl Bromides with Pyrimidin-2-yl Tosylates
duced by Zn to produce NiI intermediate B. B under-
went oxidative addition to aryl bromides 2, forming a
NiIII complex C. Subsequent reductive elimination of C
gave C2-arylation pyrimidine derivatives 3 and NiIX.
NiIX was subsequently reduced to Ni0 by Zn powder
(Scheme 4, path B).
Scheme 2 Synthesis of C2-pyridimidine derivatives from pyrimidin-2-yl tosylates and aryl bromides
R1
R1
O
O
Br
NiCl2 (10% mol)
o-Phenanthroline (10% mol)
R4O
N
R4O
N
+
R3
N
Zn (2 equiv.), K3PO4 (1 equiv.)
THF, reflux, 12 h
R3
N
OTs
R2
R2
1
2
3
F
Cl
Br
OMe
O
O
Cl
O
O
O
O
EtO
Me
N
EtO
N
EtO
Me
N
EtO
Me
N
EtO
Me
N
N
EtO
N
Ph
Me
N
Ph
N
Ph
N
Ph
N
Ph
Me
N
Ph
3f, 65%
3a, 78%
3b, 81%
3c, 48%
3d, 30%
3e, 26%
Me
Me
O
EtO
Ph
N
O
O
Ph
N
O
O
O
N
MeO
Me
N
EtO
Me
Me
EtO
Me
N
MeO
N
Me
Me
MeO
N
Me
N
Ph
N
N
Ph
Me
N
Ph
Me
Me
N
Ph
3g, 46%
3h, 79%
3i, 44%
3j, 41%
3k, 35%
3l, 49%
O
Ph
N
O
Ph
N
O
EtO
Me
N
EtO
Me
O
EtO
N
N
EtO
Me
N
N
OMe
Me
N
OMe
OMe
Me
3m, 60%
3n, 62%
3o, 83%
3p, 32%
F
O
O
O
O
O
EtO
Me
N
MeO
Me
N
N
EtO
Me
N
MeO
Me
N
N
EtO
Me
N
N
OMe
N
N
S
S
S
3s, 87%
3t, 92%
3u, 71%
3r, 63%
3q, 82%
Scheme 3 Control experiments
O
Ph
O
Ph
Br
NiCl2 (10% mol)
o-Phenanthroline (10% mol)
EtO
N
EtO
N
+
Zn (2 equiv.), K3PO4 (1 equiv.)
THF, reflux, 12 h
TEMPO (1 equiv.)
Me
N
Ph
Me
N
OTs
3a, 69% 75%
2a
1a
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3

Gong et al.
COMMUNICATION
Scheme 4 Proposed mechanism
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Conclusions
In summary, we developed a method to synthesize
C-2 substituted pyrimidines by using the cross-electro-
phile coupling of pyrimidin-2-yl tosylates with aryl and
heteroaryl bromides. A wide range of C-2 substituted
pyrimidines were obtained in good yields. This mild
reaction condition provides an extension to get C-2 sub-
stituted pyrimidines by utilizing easily prepared pyrimi-
dine-2-yl tosylates and less expensive, commercially
available (hetero) aryl bromides.
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We are thankful for the financial support from the
National Natural Science Foundation of China (Nos.
21362032, 21362031 and 21562036) and Northwest
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