Copper(I)-catalyzed C-C and C-O coupling reactions using hydrazone ligands

Article abstract of DOI:10.1055/s-0029-1217822

Copper-catalyzed C-C coupling reaction of aryl iodides with diethylmalonate in toluene at 90C gave arylated malonates using 5 mol% of CuI with hydrazone 1a as a ligand in good yields under an aerobic atmosphere. We also found CuI/hydrazone 1b in toluene to be an efficient catalytic system for C-O coupling reactions of aryl bromides with phenols to give aryl ethers in good yields at 110C under an aerobic atmosphere.

Full text of DOI:10.1055/s-0029-1217822

LETTER
2457
Copper(I)-Catalyzed C–C and C–O Coupling Reactions Using Hydrazone
Ligands
C
u(I)-Catalyzed
a
C
–C
a
ndC
k
–O
C
ouplin
a
gReaction
s
s
hi Mino,* Fumitoshi Yagishita, Masanori Shibuya, Kenji Kajiwara, Hiroaki Shindo, Masami Sakamoto,
Tsutomu Fujita
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33, Yayoi-cho, Inage-ku,
Chiba 263-8522, Japan
Fax +81(43)2903401; E-mail: tmino@faculty.chiba-u.jp
Received 29 May 2009
Table 1 Optimization of the Reaction Conditions for Copper-Cata-
Abstract: Copper-catalyzed C–C coupling reaction of aryl iodides
lyzed C-Arylation of Diethyl Malonate with Iodobenzenea
with diethylmalonate in toluene at 90 °C gave arylated malonates
Cu catalyst, ligand
base, solvent
using 5 mol% of CuI with hydrazone 1a as a ligand in good yields
under an aerobic atmosphere. We also found CuI/hydrazone 1b in
toluene to be an efficient catalytic system for C–O coupling reac-
tions of aryl bromides with phenols to give aryl ethers in good yields
at 110 °C under an aerobic atmosphere.
O
O
O
O
PhI
+
EtO
OEt
EtO
OEt
90 °C, 24 h, air
Ph
2a
Key words: copper catalyst, hydrazone, C–C coupling, C–O cou-
pling, malonate, aryl ether
Entry Ligand Cu catalyst Base
Solventb Yield (%)c
1
2
1a
1b
1c
1d
–
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
55
39
45
35
32
46
29
44
32
7
In recent years, great advances have been achieved on the
modification of copper-catalyzed Ullmann-type coupling
reactions.1 By using some special ligands such as N,N-
and N,O-bidentate compounds, many CuI-catalyzed C–N,2
C–C,3 and C–O2b,c,4 bond formation reactions could be
carried out at relatively low temperatures. We recently re-
ported on CuI-catalyzed C–N bond formation reactions
such as Goldberg-type N-arylation of amides and Ull-
mann-type N-arylation of azoles, using phosphine-free
hydrazone ligands.5 We now report the use of air-stable,
phosphine-free hydrazone ligands 1a–d6 for copper-cata-
lyzed C–C and C–O bond formation reactions (Figure 1).
3
4
5
6
1a
1a
1a
1a
1a
1a
1a
1a
1a
7
8
9
10
11
12
13
14
t-BuOK CPME
Ph
Ph
Ph
Ph
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
30
39
67
73
N
N
N
N
N
N
N
N
Me
Me
Me
Me
DMSO
toluene
toluene
Me
Me
1a
1c
1b
1d
d
N
N
N
N
N
N
N
N
a Reaction conditions: Iodobenzene (2 mmol), diethyl malonate
(4 mmol), base (3 mmol), solvent (2 mL), Cu source (0.10 mmol),
ligand (0.20 mmol).
Figure 1
b CPME: cyclopentyl methyl ether.
c GC yield; 2-methoxynaphthalene was used as an internal standard.
d Cs2CO3 (4 mmol) was added.
Initially, we examined the copper-catalyzed C–C bond
formation reaction – the Hurtley reaction7 – using hydra-
zone ligand. We optimized the conditions for C-arylation
of diethyl malonate with iodobenzene using 5 mol% of
CuI as a catalyst for 24 hours at 90 °C under an aerobic at-
mosphere (Table 1). In the presence of Cs2CO3 as base in
cyclopentyl methyl ether (CPME) as solvent, hydrazone
1a was found to be the most appropriate ligand (entry 1 vs.
entries 2–4). In the absence of ligand 1a, the yield was de-
creased (entry 1 vs. entry 5). We then investigated the ef-
fect of copper catalysts (entries 1, and 6–8). In the case of
using CuBr, CuCl, and Cu2O, the yields were decreased;
CuI proved to be the best copper source for the C-aryla-
tion (entry 1). The effect of various bases was investigated
(entries 1, and 9–10) and Cs2CO3 proved to be the most
successful. The effect of various solvents was also inves-
SYNLETT 2009, No. 15, pp 2457–2460
x
x
.x
x
.2
0
0
9
Advanced online publication: 17.08.2009
DOI: 10.1055/s-0029-1217822; Art ID: U05809ST
© Georg Thieme Verlag Stuttgart · New York

2458
T. Mino et al.
LETTER
tigated (entries 1, and 11–13) and toluene was found to be 1d (entry 2 vs. entries 1, 3, and 4). In the absence of
the most suitable (entry 13). After increasing the added ligand, the yield was decreased (entry 5). We investigated
amount of Cs2CO3, we obtained diethyl phenylmalonate the effect of copper catalysts, bases, and solvents in this
2a with good yield (entry 14).
reaction (entries 2, and 6–14). In the presence of CuI as
catalyst and K3PO4 as a base in toluene, product 3a was
obtained in good yield (entry 2).
With the best reaction conditions established (Table 2, en-
try 1),8 we screened a range of different aryl iodides in or-
der to explore the scope of the C-arylation of diethyl
malonate (Table 2).9 Using 4-substituted aryl iodides led
to good yields of the desired products (entries 2–5). More-
over, the reaction of 3-substituted and 2-substituted aryl
iodides also led to good yields (entries 6–10). In the reac-
tions of 1-iodonaphthalene, the corresponding product 2k
was obtained in 58% (entry 11).
Table 3 Optimization of Reaction Conditions for the Copper-Cata-
lyzed O-Arylation of p-Cresol with Bromobenzenea
Cu catalyst, ligand,
base, solvent
+
PhBr
HO
Me
PhO
Me
110 °C, 5 h, air
3a
Entry Ligand Cu catalyst Base
Solvent Yield (%)b
toluene 78
toluene 83
toluene 71
toluene 74
toluene 67
toluene 80
toluene 69
toluene 58
Table 2 Copper-Catalyzed C-Arylation of Diethyl Malonate with
Aryl Iodidesa
1
2
1a
1b
1c
1d
–
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CuI (5 mol%)
CuI
ligand 1a (10 mol%)
Cs2CO3 (2 equiv)
PhMe (1.0 M)
O
O
O
O
3
CuI
+
ArI
EtO
OEt
90 °C, 24 h, air
EtO
OEt
4
CuI
2 equiv
Ar
2
5
CuI
Entry
1
Ar
Ph
Product
2a
Yield (%)b
6
1b
1b
1b
1b
1b
1b
1b
1b
1b
CuBr
CuOAc
Cu2O
CuI
69
68
59
50
62
53
67
64
52
50
58
7
2
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
4-AcC6H4
3-MeC6H4
3-F3CC6H4
3,5-Me2C6H3
2-MeC6H4
2-MeOC6H4
1-Naph
2b
2c
8
3
9
Cs2CO3 toluene trace
K2CO3 toluene 59
4
2d
2e
10
11
12
13
14
CuI
5c
6
CuI
t-BuOK toluene no reaction
2f
CuI
K3PO4
K3PO4
K3PO4
DMF
NMP
10
18
7
2g
CuI
8
2h
2i
CuI
DMSO 20
a Reaction conditions: Bromobenzene (0.5 mmol), p-cresol (1.0
mmol), base (1 mmol), solvent (1 mL), Cu source (0.025 mmol),
ligand (0.0.25 mmol).
9
10
11
2j
b Isolated yield.
2k
a Reaction conditions: Aryl iodide (2 mmol), diethyl malonate (4
In an attempt to probe the generality of the method, the
reaction of phenols with a variety of aryl bromides was
conducted (Table 4).11 The reaction of bromobenzene and
para-substituted aryl bromides with p-cresol gave the cor-
responding products in good yields (entry 1–6). The reac-
tion of 1-bromonaphthalene, with meta- and ortho-
substituted aryl bromides such as 3-bromotoluene and 2-
bromotoluene gave moderate to good yields of the corre-
sponding products (entries 7–9). Furthermore, the reac-
tion of 4-bromotoluene with 4-chlorophenol and m-cresol
also gave the corresponding products with good to high
yields (entries 10 and 11).
mmol), Cs2CO3 (4 mmol), toluene (2 mL), CuI (0.10 mmol), ligand
1a (0.20 mmol).
b Isolated yield.
c This reaction was carried out at 80 °C.
We next investigated the copper-catalyzed C–O bond for-
mation reaction using hydrazones 1a–d as ligands. Al-
though Liu recently reported C–O bond formation with
hydrazone-type ligands such as glyoxal bis(phenylhydra-
zone), 10 mol% of CuI was used as a catalyst under N2 at-
mosphere.10 We wanted to find the optimal reaction
conditions using 5 mol% of CuI as a catalyst under an aer-
obic atmosphere. Bromobenzene and p-cresol were cho-
sen as model substrates, and the reactions were carried out
for five hours at 110 °C (Table 3). When the reaction was
carried out using hydrazone ligand 1b, the product 3a was
obtained in higher yield than in the the case of 1a, 1c or
In conclusion, we have found that hydrazone 1a is useful
as an air-stable, phosphine-free ligand for the copper-
catalyzed C–C coupling reaction of aryl iodides with di-
ethyl malonate. Hydrazone 1b was an efficient ligand for
C–O coupling reactions of aryl bromides with phenols.
Synlett 2009, No. 15, 2457–2460 © Thieme Stuttgart · New York

LETTER
Cu(I)-Catalyzed C–C and C–O Coupling Reactions
2459
(3) (a) Yip, S. F.; Cheung, H. Y.; Zho, Z.; Kwong, F. Y. Org.
Lett. 2007, 9, 3469. (b) Xie, X.; Cai, G.; Ma, D. Org. Lett.
2005, 7, 4693. (c) Bate, C. G.; Saejueng, P.; Verkataraman,
D. Org. Lett. 2004, 4, 1441. (d) Ma, D.; Liu, F. Chem.
Commun. 2004, 1934. (e) Zanon, J.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 2890. (f) Hennessy,
E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
(4) (a) Nonappa, P. D.; Pandurangan, K.; Maitra, U.; Wailes, S.
Org. Lett. 2007, 9, 2767. (b) Ma, D.; Cai, Q.; Xie, X. Synlett
2005, 1767. (c) Cristau, H.-J.; Cellier, P. P.; Hamada, S.;
Spindler, J.-F.; Taillefer, M. Org. Lett. 2004, 6, 913.
(d) Wan, Z.; Jones, C. D.; Koenig, T. M.; Pu, Y. J.; Mitchell,
D. Tetrahedron Lett. 2003, 44, 8257. (e) Nordmann, G.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978.
(f) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799. (g) Buck, E.;
Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.;
Reider, P. J. Org. Lett. 2002, 4, 1623.
Table 4 Copper-Catalyzed O-Arylation of Phenols with Aryl Bro-
midesa
CuI (5 mol%)
ligand 1b (5 mol%)
K3PO4 (2 equiv)
PhMe (0.5 M)
+
Ar1
O
3
Ar2
Ar1Br
Ar2OH
110 °C, 5 h, air
2 equiv
Entry Ar1
Ar2
Product Yield (%)b
1
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
3-MeC6H4
3a
3b
3c
3d
3e
3f
83
69
71
94
86
81
74
78
75
78
90
2
4-MeC6H4
4-t-BuC6H4
4-NCC6H4
4-O2NC6H4
4-MeOC6H4
1-Naph
3
4
(5) Mino, T.; Harada, Y.; Shindo, H.; Sakamoto, M.; Fujita, T.
5
Synlett 2008, 614.
(6) (a) Mino, T.; Shirae, Y.; Sakamoto, M.; Fujita, T. Synlett
2003, 882. (b) Mino, T.; Shirae, Y.; Sakamoto, M.; Fujita, T.
J. Org. Chem. 2005, 70, 2191. (c) Mino, T.; Shirae, Y.;
Sasai, Y.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2006, 71,
6834.
(7) (a) Hurtley, W. R. H. J. Chem. Soc. 1929, 1870.
(b) Bruggink, A.; Ray, S. J.; McKillop, A. Org. Synth. 1978,
58, 52.
6c
7c
8
3g
3h
3i
3-MeC6H4
2-MeC6H4
4-MeC6H4
4-MeC6H4
9c
10
11c
3j
(8) We tried the reaction at 110 °C in toluene for 24 h, however,
the yield of 2a decreased to 28% and ethyl phenylacetate
was also obtained (8% NMR yield).
3h
a Reaction conditions: Aryl bromide (0.5 mmol), phenol (1.0 mmol),
K3PO4 (1 mmol), toluene (1 mL), CuI (0.025 mmol), ligand 1b (0.025
mmol).
(9) General procedure for copper-catalyzed C-arylation of
diethyl malonate with aryl iodides (Table 2): Under an
atmosphere of air, aryl iodide (2.0 mmol) was added to a
mixture of diethyl malonate (4.0 mmol), Cs2CO3 (4.0
mmol), ligand 1a (0.20 mmol), and CuI (0.10 mmol) in
toluene (2 mL) at r.t. The mixture was stirred at 90 °C for 24
h, then diluted with EtOAc and H2O. The organic layer was
washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The resulting residue was purified
by silica gel chromatography (hexane–EtOAc) to provide
the desired product. All prepared compounds 2, except 2f,
b Isolated yields.
c This reaction was carried out for 18 h.
References and Notes
(1) (a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
42, 5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem.
Rev. 2004, 248, 2337.
were previously known and identified by 1H NMR, 13
NMR and MS.
C
Compound 2f (Table 2, entry 6): Yield: 53%; brown liquid;
(2) (a) Buchwald, S. L.; Altman, R. A. J. Org. Chem. 2007, 72,
6190. (b) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863.
(c) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609.
(d) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779.
(e) Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth.
Catal. 2006, 348, 2197. (f) Zhang, H.; Cai, Q.; Ma, D. W.
J. Org. Chem. 2005, 70, 5164. (g) Buchwald, S. L.; Antilla,
J. C.; Baskin, J. M.; Barder, T. E. J. Org. Chem. 2004, 69,
5578. (h) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.;
Taillefer, M. Eur. J. Org. Chem. 2004, 695. (i) Ma, D.; Cai,
Q. Synlett 2004, 128. (j) Ma, D.; Cai, Q.; Zhang, H. Org.
Lett. 2003, 5, 2453. (k) Kwong, F. Y.; Buchwald, S. L. Org.
Lett. 2003, 5, 793. (l) Antilla, J. C.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 11684. (m) Buchwald,
S. L.; Klapars, A.; Huang, X. H. J. Am. Chem. Soc. 2002,
124, 7421. (n) Kwong, F. Y.; Klapars, A.; Buchwald, S. L.
Org. Lett. 2002, 4, 581. (o) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727.
1H NMR (CDCl3): d = 1.26 (t, J = 7.1 Hz, 6 H), 2.35 (s, 3 H),
4.16–4.27 (m, 4 H), 4.57 (s, 1 H), 7.13–7.28 (m, 4 H); 13
C
NMR (CDCl3): d = 14.0, 21.4, 57.9, 61.7, 126.3, 128.4,
128.9, 129.9, 132.6, 138.2, 168.2; EI-MS: m/z (%) = 250
(25) [M+]; HRMS (FAB-MS): m/z calcd for C14H19O4:
251.1283; found: 251.1284.
(10) Liu, Y.-H.; Li, G.; Yang, L.-M. Tetrahedron Lett. 2009, 50,
343.
(11) General procedure for copper-catalyzed O-arylation of
phenols with aryl bromides (Table 4): Under an
atmosphere of air, aryl bromide (0.5 mmol) was added to a
mixture of phenol (1.0 mmol), K3PO4 (1.0 mmol), ligand 1b
(0.025 mmol), and CuI (0.025 mmol) in toluene (1 mL) at r.t.
The mixture was stirred at 110 °C for either 5 h or 18 h, then
the mixture was diluted with EtOAc and H2O. The organic
layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue
was purified by silica gel chromatography (hexane–EtOAc)
to provide the desired product. All prepared compounds 3,
except 3g and 3h, were known and identified by 1H NMR,
13C NMR and MS.
Compound 3g (Table 4, entry 7): Yield: 74%; colorless oil;
1H NMR (CDCl3): d = 2.34 (s, 3 H), 6.88 (d, J = 7.6 Hz,
Synlett 2009, No. 15, 2457–2460 © Thieme Stuttgart · New York

2460
T. Mino et al.
LETTER
2 H), 6.94–6.97 (m, 2 H), 7.15 (d, J = 8.6 Hz, 2 H), 7.35 (t,
J = 8.0 Hz, 1 H), 7.45–7.54 (m, 2 H), 7.58 (d, J = 8.2 Hz,
1 H), 7.84–7.87 (m, 1 H), 8.22–8.25 (m, 1 H); 13C NMR
(CDCl3): d = 20.7, 112.6, 118.8, 122.1, 122.9, 125.8, 125.8,
126.5, 126.7, 127.7, 130.3, 132.8, 134.9, 153.6, 155.3; EI-
MS: m/z (%) = 234 (100) [M+]; HRMS (FAB-MS): m/z calcd
for C17H14O: 234.1045; found: 234.1027.
Compound 3h (Table 4, entry 8): Yield: 78%; colorless oil;
1H NMR (CDCl3): d = 2.31 (s, 3 H), 2.33 (s, 3 H), 6.77–6.80
(m, 2 H), 6.87–6.93 (m, 3 H), 7.12–7.21 (m, 3 H); 13C NMR
(CDCl3): d = 20.7, 21.4, 115.3, 119.0, 119.1, 123.6, 129.3,
130.2, 132.7, 140.0, 154.8, 157.7; EI-MS: m/z (%) = 198
(100) [M+]; HRMS (FAB-MS): m/z calcd for C14H14O:
198.1045; found: 198.1046.
Synlett 2009, No. 15, 2457–2460 © Thieme Stuttgart · New York

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