Copper(I) Iodide-Catalyzed (Het)arylation of Diethyl Malonate with (Het)aryl Bromides by Using 1,3-Benzoxazole as a Ligand

Article abstract of DOI:10.1055/s-0036-1591210

An efficient Ullmann-type coupling of aryl bromides with diethyl malonate in the presence of copper(I) iodide and 1,3-benzoxazole is presented. This method has a broad substrate scope (heterocyclic and phenyl bromides) and good functional-group tolerance (OMe, Me, Ac, CN, NO ₂, F, and Cl). Moreover, less time is needed to reach full conversion (3-9 hours).

Full text of DOI:10.1055/s-0036-1591210

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
de
Y. Zeng et al.
Letter
Synlett
Copper(I) Iodide-Catalyzed (Het)arylation of Diethyl Malonate
with (Het)aryl Bromides by Using 1,3-Benzoxazole as a Ligand
Yu Zenga
Hao-liang Zhengb
Zhao Yangc
Cheng-Kou Liua
Zheng Fang*a
Kai Guo*a,d
O
O
O
O
CuI/K3PO4/DMSO
Ar Br
+
R1
OEt
R1
OEt
O
Ligand =
Ar
N
23 examples
up to 91% yield
broad substrate scope (heterocyclic and benzene ring bromides)
good functional group tolerance (OMe, Me, Ac, CN, NO2, F, Cl)
less time consumed to reach the full conversion (3–9 h)
a College of Biotechnology and Pharmaceutical Engineering,
Nanjing Tech University, 30 Puzhu South Road, Nanjing,
211816, P. R. of China
fzcpu@163.com
guok@njtech.edu.cn
b School of Chemistry and Molecular Biosciences, Faculty of
Chemistry, The University of Queensland, Brisbane,
Queensland, Australia
c College of Engineering, China Pharmaceutical University,
24 Tongjiaxiang, Nanjing, 210003, P. R. of China
d State Key Laboratory of Materials-Oriented Chemical
Engineering, Nanjing Tech University, 30 Puzhu South Road,
Nanjing, 211816, P. R. of China
Received: 20.06.2017
Accepted after revision: 26.07.2017
Published online: 26.10.2017
α-Aryl carboxylic acids are usually synthesized by hy-
drolysis and decarboxylation of arylmalonates, which is an
effective method. Moreover, arylmalonates can also serve as
useful precursors for the construction of various heterocy-
cles,3 such as indoles,4 isoquinolines,5 quinoxalinones,6 or
chromenes.7 The Ullmann-type coupling of malonates with
aryl halides has generally been used to synthesize α-aryl
carbonyl compounds. Initially, this reaction was restricted
by the harsh conditions necessary (high temperatures, long
reaction times),8 the need for equivalent or even excess
amounts of copper salts, and low yields. Later, a break-
through was achieved by the development of palladium-
catalyzed coupling reactions.9 However, the use of the noble
medal palladium is uneconomical. In addition, the need for
strong alkalis such as t-BuOK impairs the scope and func-
tional-group tolerance of the reaction. In recent decades,
many efforts have been devoted to the development of
copper-catalyzed Ullmann-type coupling reactions. The
Hurtley reaction permits the arylation of malonates
(Scheme 1, eq. 1), but only 2-bromobenzoic acid and closely
related bromides can be transformed into the desired prod-
ucts. Numerous efforts have been devoted to expanding the
substrate scope of the Hurtley reaction. Later, it was found
that many aryl halides besides 2-bromobenzoic acid could
be successfully coupled with enolate anions (Scheme 1,
eq. 2), but this method is limited by the multistep process
and the use of a stoichiometric amount of the copper salt.
At the end of 20th century, Okuro and co-workers reported
the first coupling reaction of aryl iodides with activated
methylene compounds in the presence of a catalytic
amount of copper(I) iodide (Scheme 1, eq. 3).10 This
DOI: 10.1055/s-0036-1591210; Art ID: st-2017-w0499-l
Abstract An efficient Ullmann-type coupling of aryl bromides with di-
ethyl malonate in the presence of copper(I) iodide and 1,3-benzoxazole
is presented. This method has a broad substrate scope (heterocyclic
and phenyl bromides) and good functional-group tolerance (OMe, Me,
Ac, CN, NO2, F, and Cl). Moreover, less time is needed to reach full con-
version (3–9 hours).
Key words Ullmann coupling, benzoxazole, copper catalysis, aryl
bromides, hetarylation, arylation
α-Aryl carboxylic acids are key structural elements of
many natural products1 and pharmaceuticals,2 especial
nonsteroidal anti-inflammatory drugs (Figure 1).
O
Cl
F
HO
N
OH
S
O
O
MeO
O
indomethacin
sulindac
Cl
O
N
H
Cl
OH
OH
O
ibufenac
diclofenac
Figure 1 Marketed drugs with α-aryl carboxylic acid structures
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
Y. Zeng et al.
Letter
Synlett
O
O
Cu
Cu
OH
CH2(COOEt)2
+
R1
(1)
(2)
OH
R1
COOEt
X
COOEt
R1
R1
+
NaCH2(COOEt)2
COOEt
COOEt
X
Cu
ligand free, X = I, Br, 120 °C (3)
Cu La, X = I, 24–29 h, 70 °C (4)
Cu Lb, X = I, 24–30 h, 70 °C, (5)
R1
COOEt
COOEt
Cu Lc, X = I, Br, (6)
CH2(COOEt)2
+
R1
when X = Br, 24–48 h, 50 °C
X
Cu Ld, X = I, Br (7)
when X = Br, 32 h, refluxing 1,4-dioxane
Cu Le, X = I, 24 h, 90 °C (8)
O
OH
O
OH
N
N
N
OH
N
N
N N
N
H
Me
Me
N
N
Me
Me
La (2001)
Lb (2004)
Lc (2005)
Ld (2007)
Le (2009)
Scheme 1 Previous methods
reaction was carried out at 120 °C and gave low to moder-
ate yields, as the coupling products tended to decompose
under these conditions. Moreover, only 16% yield of the de-
sired product was obtained when bromobenzene was used.
It is noteworthy that no ligand was added in this reaction,
which might explain why a high temperature was neces-
sary. In recent years, it has been shown that the use of a li-
gand is crucial to the success of the reaction.11 Many cata-
lytic reactions that occur under mild conditions in the pres-
ence of certain ligands, such as N,N-12 or N,O-bidentate13
compounds, have been reported (Scheme 1, eqs. 4–8). Re-
cently, several copper-nanoparticle-catalyzed coupling re-
actions of aryl halides with diethyl malonate to effect the
arylation of malonates under ligand-free conditions have
been established.14 Although considerable progress has
been achieved by these methods, several drawbacks re-
main. First, the reactivity is still a slightly unsatisfactory,
and many methods are limited to aryl iodides (Scheme 1,
eqs. 4, 5, and 8) as, although aryl bromides are compatible
with some reactions, longer times (20–36 h) and higher
temperatures are necessary (Scheme 1, eqs. 6 and 7). Sec-
ondly, as far as we know, there have been only a few reports
on the coupling of malonates with heterocyclic halides. Be-
cause, many heterocyclic compounds have physiological ac-
tivities, particular attention has been paid to the design and
synthesis of heterocyclic compounds with potential physio-
logical activities. Furthermore, the development of more ef-
fective approaches with broad substrate scopes compatible
with various heterocyclic halides is still an attractive goal.
Here, we describe the use of 1,3-benzoxazole as ligand to
achieve an effective Ullmann-type C–C bond formation.
We examined the coupling reaction of 3-bromopyridine
with diethyl malonate to optimize the reaction conditions,
as summarized in Table 1. Initially, various N,N- and N,O-
bidentate ligands were tested (Table 1, entries 1–8). 1,3-
Benzoxazole was the most effective ligand, giving an 86%
yield of the desired product in DMSO (Table 1, entry 8).
Only a trace of the desired product was detected in the ab-
sence of a ligand (Table 1, entry 9). Subsequently, the effect
of the base was investigated (Table 1, entries 8 and 10–15).
Soluble organic bases failed to give the desired product
(Table 1, entries 13–15), whereas inorganic bases tended to
exhibit superior reactivities (Table 1, entries 8 and 10–15).
However, the reaction gave a significantly lower yield (15%)
in the presence of Cs2CO3 (Table 1, entry 10), and only trac-
es of the desired product were obtained when the reaction
was performed in the presence of K2CO3 or NaOAc (Table 1,
entries 11 and 12). K3PO4 turned out to be the best base,
giving an 86% isolated yield (Table 1, entry 8). Next, we ex-
amined various solvents (Table 1, entries 8 and 16–19). Sur-
prisingly, other solvents gave poorer yields than DMSO.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
Y. Zeng et al.
Letter
Synlett
Table 1 Optimization of the Conditions for the Coupling of Diethyl Malonate with 3-Bromopyridinea
O
O
N
Br
O
O
EtO
OEt
CuI/ligand
+
EtO
OEt
N
Entry
Catalyst
Ligand
Catalyst/Ligand
(equiv)
Base
Solvent
Temp (°C)
Yieldb (%)
1
CuI
L1
L2
L3
L4
L5
L6
L7
L8
–
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
–
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
NaOAc
Et3N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
80
70
60
40
30
50
50
50
50
50
50
50
50
22
2
CuI
16
3
CuI
30
4
CuI
43
5
CuI
11
6
CuI
14
7
CuI
24
8
CuI
86
9
CuI
trace
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29c
30d
31c
32c
CuI
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1.5
1:1.2
CuI
trace
trace
NO
NO
NO
32
CuI
CuI
CuI
DIPEA
py
CuI
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CuI
1,4-dioxane
toluene
THF
NO
NO
trace
74
CuI
CuI
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CuI
79
CuI
87
CuI
71
CuI
17
CuBr
CuBr2
Cu(OAc)2
CuO
CuI
24
12
19
8
85
CuI
76
CuI
88
CuI
79
H
OH
N
N
COOH
H
N
O
N
N
COOH
N
N
COOH
N
NH2
N
N
L1
L2
L3
L4
L7
L8
L5
L6
a Reaction conditions: 3-bromopyridine (1 mmol), diethyl malonate (1.5 mmol), CuI (0.1 mmol), ligand (0.2 mmol), base (3 mmol), solvent (2 mL), under argon, 6 h.
b Isolated yield.
c CuI (0.08 mmol) was used.
d CuI (0.05 mmol) was used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
Y. Zeng et al.
Letter
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O
O
When the temperature was increased to 60 °C, a compa-
rable yield was obtained (Table 1, entry 22), but a further
increase in the temperature resulted in a decrease in the
yield (Table 1, entries 20 and 21), possibly because of de-
composition of the product. Lower temperatures gave lower
yields than that obtained at 50 °C (Table 1, entries 8, 23, and
24). Next, the catalytic activity of various copper salts was
explored (Table 1, entries 8, 25–28). Markedly lower yields
were obtained when CuI was replaced by other copper
compounds such as CuBr, CuBr2, Cu(OAc)2, or CuO. Screen-
ing of the catalyst load showed that 8 mol% catalyst was
necessary (Table 1, entries 8, 29, and 30). Moreover, the ra-
tio of the concentration of the catalyst to that of the ligand
was examined (Table 1, entries 8, 31, 32), and a ratio of 1 to
1.5 was found to be the best choice. Therefore, the screen-
ing of the reaction parameters showed that the optimal re-
action conditions are as follows: ArBr (1.0 mmol), diethyl
malonate (1.5 mmol), CuI (0.08 mmol), 1,3-benzoxazole
(0.12 mmol), K3PO4 (3 mmol), and DMSO (2 mL) at 50 °C
under argon for six hours.
By using these optimized conditions, we examined the
scope and functional-group tolerance of the reaction. To
our delight, moderate to good yields (64–91%) were ob-
tained when electron-deficient or electron-rich hetaryl
bromides were used (Scheme 2; 3a–s). However, the elec-
tron-rich hetaryl bromides showed inferior reactivities to
the electron-deficient ones. Despite lower reactivities of the
electron-rich hetaryl bromides, good yields of products 3g,
3h, and 3r were nevertheless obtained by prolonging the
reaction time. Moreover, substituents at various positions
on the pyridine ring did not affect the reaction efficiency
(3d–f). Generally, the reaction efficiency was affected by
steric hindrance but, fortunately, sterically hindered pyri-
dine ring bromides still gave good yields (3d, 3f, and 3q).
Notably, 2-bromopyridine showed a lower activity than 4-
bromopyridine or 3-bromopyridine (3a, 3l, and 3o), and a
longer time was necessary to reach the full conversion with
the 2-bromo isomers (3o–r). A number of functional
groups, including F, Cl, MeCO, NO2, CN, Me, and OMe, were
tolerated under our reaction conditions (3a–v). Good to ex-
cellent yields were also obtained when 3-bromoquinoline
or some bromobenzene derivatives were used (3s–v). How-
ever, bromobenzene and electron-rich bromobenzenes
failed to give the corresponding products, and almost no
product was detected when electron-rich or electron-defi-
cient aryl chloride was used. When diethyl malonate was
replaced by ethyl cyanoacetate, a good yield of the corre-
sponding product 3w was obtained.
O
O
O
CuI
Ar Br
R1
OEt
+
O
N
R1
OEt
Ligand =
Ar
1
2
3
O
O
O
O
O
N
O
O
EtO
OEt
EtO
OEt
EtO
OEt
EtO
OEt
N
N
N
NO2
91% (3c)
Cl
83% (3b)
86% (3a)
71% (3d)
O
O
O
O
O
O
N
O
O
EtO
OEt
EtO
OEt
EtO
OEt EtO
OEt
N
N
N
MeO
OMe
72% (3e)
74% (3f)
78% (3g)
78% (3h)
O
O
O
O
N
O
O
O
O
EtO
OEt
OEt
EtO
F
EtO
OEt EtO
OEt
N
N
NC
N
O
81% (3i)
85% (3j)
87% (3k)
81% (3l)
O
O
O
O
O
O
O
O
EtO
OEt EtO
OEt
EtO
OEt EtO
OEt
N
N
N
Cl
N
83% (3m)
75% (3n)
68% (3o)
65% (3p)
O
O
N
O
O
O
O
O
O
N
EtO
OEt
EtO
OEt
EtO
OEt
EtO
Cl
OEt
N
OMe
O
NO2
91% (3t)
67% (3q)
64% (3r)
70% (3s)
O
O
O
O
EtO
OEt
EtO
OEt
NC
OEt
N
CN
70% (3v)
O
78% (3u)
78% (3w)
Scheme 2 Copper-catalyzed (het)arylations of diethyl malonate and
ethyl cyanoacetate. Reagents and conditions: ArBr (1.0 mmol), diethyl
malonate (1.5 mmol), CuI (0.1 mmol), 1,3-benzoxazole (0.2 mmol),
K3PO4 (3 mmol), DMSO (2 mL) at 50 °C under Ar. Yields of the isolated
products are reported.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
Y. Zeng et al.
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Synlett
A proposed mechanism, shown in Scheme 3 9a,12a,14b in-
volves oxidative addition, ligand substitution by the eno-
late, and reductive elimination. The ligand assists by pre-
venting aggregation of the metal and by increasing its solu-
bility or stability.
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CuI + L
O
O
EtO
OEt
ArX
LCuI
Ar
reductive
elimination
oxidative
addition
O
N
L =
Ar
Ar
LCu(III)I
LCu(III)I
OEt
X
O
EtO
O
ligand substitution
by enolate
X
O
O
O
O
base
EtO
OEt
EtO
OEt
Scheme 3 Proposed mechanism
(4) (a) Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115. (b) Chen, Y.; Xie, X.;
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In summary, a practical and effective CuI/1,3-benzoxazole-
promoted Ullmann-type coupling method has been devel-
oped.15 This method features a higher efficiency (shorter
time to reach full conversion), a broad substrate scope (phe-
nyl and heterocyclic bromides), good functional-group tol-
erance, and offers a potential protocol for the synthesis of
heterocyclic drugs.
Funding Information
The research has been supported by National Natural Science Founda-
tion of China (Grant No.U1463201, 21522604 and 21402240) and
Jiangsu Province Natural Science Fund (Grant No.BK20150031)
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591210.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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1993, 58, 7606.
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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Y. Zeng et al.
Letter
Synlett
(14) (a) Pai, G.; Chattopadhyay, A. P. Synthesis 2013, 45, 1475.
(b) Kidwai, M.; Bhardwaj, S.; Poddar, R. Beilstein J. Org. Chem.
2010, 6, No 35.
separated organic layer was then dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified
by chromatography (silica gel, hexane/EtOAc).
(15) Diethyl (Het)arylmalonates 3a–v; General Procedure
DMSO (2 mL), the appropriate (het)aryl bromide 1 (1.0 mmol),
diethyl malonate (2; 1.5 mmol), CuI (0.1 mmol), 1,3-benzo-
xazole (0.2 mmol), and K3PO4 (3 mmol) were successively added
to a sealed tube under argon. The mixture was stirred at 50 °C
for 3–9 h until the reaction was complete (TLC) and then poured
into sat. aq NH4Cl (20 mL). The mixture was extracted with
EtOAc (3 × 20 mL), and the organic phases were combined and
washed with sat. aq NH4Cl (2 × 20 mL) and H2O (2 × 20 mL). The
Diethyl Pyridin-3-ylmalonate (3a)
Purified by column chromatography [silica gel, hexane/EtOAc
(6:1)] to give a yellowish oil; yield: 204 mg (86%).
1H NMR (400 MHz, CDCl3): δ = 8.55–8.51 (m, 2 H), 7.80 (dt,
J = 8.0, 2.0 Hz, 1 H), 7.27 (dd, J = 7.9, 4.8 Hz, 1 H), 4.59 (s, 1 H),
4.24–4.11 (m, 4 H), 1.21 (t, J = 7.1 Hz, 6 H). 13C NMR (101 MHz,
CDCl3): δ = 167.43, 150.28, 149.53, 136.93, 128.97, 123.52,
62.19, 55.43, 13.97. HRMS (TOF): m/z [M + H]+ calcd for C12H15
NO4: 238.1074; found: 238.1084.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F