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F.-F. Yong et al. / Tetrahedron Letters 52 (2011) 1169–1172
Table 2
coupling reaction; KOH and Cs2CO3 were shown to be ineffective
(entries 6 and 7). Next, we probed the effect of the PTC on the
reaction (entries 8 and 9). TPAB proved to be the PTC of choice
giving the product in an excellent yield of 78% under ligand-free
conditions (entry 9). Lower yields were obtained in the case of
TBAC (entry 4) and TBAB (entry 8). Finally, an attempt to lower
the catalyst loading to 10 mol % with reduced solvent volume
gave the product in an optimum yield of 80% (entry 10). To rule
out the possibility that the catalysis was assisted by other con-
taminants that might be present in the system, control experi-
ments revealed that no product was obtained in the absence of
the copper source (entry 11). The optimized conditions for our
ligand-free copper-catalyzed cross-coupling reaction are as fol-
low: Cu2O8 (10 mol %), TPAB (10 mol %), and K3PO4 (2 equiv) in
H2O (0.40 ml) at 130 °C (entry 10).
To investigate the generality of this protocol, various func-
tionalized aryl halides were coupled with 2-pyrrolidinone under
the optimized conditions. The results are summarized in Table 2.
In general, good to excellent yields were obtained in most in-
stances (Table 2, entries 1–10). ortho-Substituted aryl iodides
did not significantly hamper the cross-coupling reaction, afford-
ing the expected products in good yields (Table 2, entries 2
and 3), and no significant electronic effects were observed for
meta- (entries 4–6), and para- (entries 7–10) substituted aryl io-
dides. This proved that aryl iodides were efficient electrophilic
coupling partners for this catalytic system. However, this proto-
col was limited to aryl iodides as the use of bromobenzene as
the coupling partner gave only a small amount of the product
(entry 11). This difference in reactivity of the halide substituent
in the electrophilic counterpart was confirmed by the chemose-
lective reaction of amide 1 with the iodo functionality of the
mixed aryl halides in entries 8 and 9.
In order to expand the scope of this ligand-free Cu2O-catalyzed
amidation, the method was tested using a series of amide deriva-
tives. The arylation of a representative cyclic secondary amide, d-
valerolactam, and heterocyclic amide, thiophene-2-carboxamide
gave the respective arylated products in good yields (Table 3, en-
tries 1–8). Moreover, the aromatic amide 4-methoxybenzamide
gave the corresponding N-arylated product in moderate yield un-
der the influence of ligand-free Cu2O catalysis (entries 9–12). No
significant electronic effects were observed for the cross-coupling
of the amide derivatives with the selected meta-substituted aryl io-
dides. Currently, this catalytic system is not effective when ali-
phatic amides are employed, as only trace amounts of products
are observed.
In summary, a simple and practical strategy was developed
for the N-arylation of various amides with substituted aryl
iodides using a ligand-free Cu2O catalyst in water. In most cases,
the N-arylated derivative was obtained in good to excellent
yield. This ligand-free catalytic system which utilizes inexpen-
sive and commercially available cuprous oxide as the catalyst,
and water is expected to be particularly useful in industrial
applications. Adaptation of this ligand-free Cu catalytic system
to other cross-coupling reactions is ongoing in our laboratory.
N-Arylation of 2-pyrrolidinone with aryl halides catalyzed by ligand-free Cu2O in
watera
Cu2O (10 mol%)
O
N Ar
3a-j
O
NH
K3PO4 (2 equiv)
ArX
+
TPAB (10 mol%)
H2O
130 oC, 24 h
1
Entry
ArX
Product
Yieldb (%)
O
I
I
80
1
2
3a
3b
80c
N
O
N
85
Cl
Cl
O
I
46
N
3
4
3c
96c
MeO
MeO
O
I
46
N
3d
60c
Me
Me
O
I
I
N
5
6
3e
3f
73
74
Cl
Cl
O
N
CF3
O
CF3
I
OMe
7
8
3g
3h
3i
70
85
88
74
31
N
OMe
O
I
F
N
F
O
I
CI
9
N
Cl
O
I
CF3
10
11
3j
N
CF3
O
Br
3a
N
a
Unless otherwise stated, the reaction was carried out with 2-pyrrolidinone
(2.21 mmol), aryl halide (1.47 mmol), K3PO4 (2.94 mmol), Cu2O (10 mol %), TPAB
(10 mol %), H2O (0.40 ml), 130 °C, 24 h.
b
Isolated yield after column chromatography.
The reaction was performed with Cu2O (20 mol %) and TPAB (20 mol %).
c
Acknowledgments
We thank the National Institute of Education and Nanyang
Technological University for their generous support.
catalyst, K3PO4 as base and tetrabutylammonium chloride (TBAC)
as phase-transfer catalyst (PTC) in water gave a promising yield
of 62% (Table 1, entry 1). Encouraged by this result, optimization
studies were initiated to evaluate the efficiency of various cop-
per sources for the arylation reaction. Among the copper salts
screened (entries 1–5), Cu2O proved to be the best catalyst (en-
try 4), affording the N-arylated product in a good yield of 70%.
Among the bases studied, K3PO4 plays an important role in this
Supplementary data
Supplementary data (experimental procedures and compound
characterization data) associated with this article can be found,