Mild Copper(I) iodide/β-keto ester catalyzed coupling reactions of styryl bromides with phenols, thiophenols, and imidazoles

Article abstract of DOI:10.1055/s-2008-1067082

An efficient and mild vinylation of O-, S-, and N-nucleophiles is reported. Copper(I) iodide/ethyl 2-oxocyclohexanecarboxylate is used as the catalytic system. The protocol tolerates a broad range of functional groups on the substrates, and gives the corr

Full text of DOI:10.1055/s-2008-1067082

PAPER
1911
Mild Copper(I) Iodide/b-Keto Ester Catalyzed Coupling Reactions of Styryl
Bromides with Phenols, Thiophenols, and Imidazoles
C
oupling of Styryl Brom
e
ide
s
w
ith
P
i
henols
l
,
T
hiop
i
henols,
a
and Imida
n
z
oles g Bao,* Yunyun Liu, Xin Lv
Department of Chemistry, Zhejiang University, Xi Xi Campus, Hangzhou, Zhejiang 310028, P. R. of China
Fax +86(571)88273814; E-mail: wlbao@css.zju.edu.cn; E-mail: wbao@hzcnc.com
Received 14 December 2007; revised 21 March 2008
that this catalytic system was applicable to the formation
Abstract: An efficient and mild vinylation of O-, S-, and N-nucleo-
philes is reported. Copper(I) iodide/ethyl 2-oxocyclohexanecarbox-
ylate is used as the catalytic system. The protocol tolerates a broad
range of functional groups on the substrates, and gives the corre-
of C–N,8b C–O,8c C–S,8d and C–C8e bonds. Cristau and
Taillefer et al. disclosed that copper-catalyzed arylation of
pyrazoles with aryl halides was facilitated by oxime and
sponding aryl styryl ethers, aryl styryl sulfides, and N-styrylimida- Schiff base under mild conditions.9 Buchwald and co-
zoles in moderate to excellent yields as well as with good
stereoselectivity.
workers found that diamine- and diol-type compounds
could serve as excellent supporting ligands in copper-cat-
alyzed C–N bond-formation reactions.10 Recently, they
Key words: b-keto esters, Ullmann coupling reaction, copper ca-
talysis, vinylation
developed a highly selective copper-catalyzed C–N cou-
pling reaction. The ligand they used was cyclic b-diketone
and the reaction can be carried out at room temperature.11
Aryl vinyl ethers, vinyl sulfides, and N-vinylimidazoles The abovementioned reports reveal that the selection of a
are useful intermediates or building blocks in organic syn- proper ligand is of importance in Ullmann coupling and
thesis.1 In addition, aryl vinyl ethers and vinyl sulfides indicate the possibility to introduce new ligands to pro-
have found application in the synthesis of biologically ac- mote copper-catalyzed coupling reactions.
tive molecules and natural product analogues.2 N-Vi-
Recently, we reported that ethyl 2-oxocyclohexanecar-
boxylate is a very efficient ligand in the copper-catalyzed
nylimidazoles have also been used in medicine and
agriculture.3 Various methods for the synthesis of these
coupling reactions for the synthesis of N-arylamides, N-
compounds have been reported. The most straightforward
arylimidazoles, aryl ethers, and aryl thioethers.12 This suc-
of these involve the addition of phenols, thiophenols, and
cess prompted us to examine whether the new ligand is fit
imidazoles to alkynes.4 Although this protocol is particu-
for the coupling of vinyl bromides with phenol, thiophe-
larly important, because the addition reaction proceeds in
nols, and imidazoles. Herein, we wish to report these re-
an atom-efficient way, without waste, it suffers from ei-
sults.
ther harsh reaction conditions or lack of stereocontrol of
In our initial screening experiment, the coupling of (E)-b-
bromostyrene with phenol was used as a model reaction to
the double-bond geometry. Another noteworthy method-
ology to gain aryl vinyl ethers, vinyl sulfides, and N-vi-
explore the suitable reaction conditions (Table 1). When
the reaction was conducted under the action of copper(I)
iodide and ethyl 2-oxocyclohexanecarboxylate at 60 °C in
N,N-dimethylformamide, the corresponding product was
obtained in 30% yield (Table 1, entry 1). Several solvents
such as dimethyl sulfoxide, N-methylpyrrolidin-2-one, di-
oxane, toluene, acetonitrile, and 1-butyl-3-methylimida-
zolium tetrafluoroborate ([Bmim]BF4) were tested.
Dimethyl sulfoxide and N-methylpyrrolidin-2-one pro-
vided almost the same yields (Table 1, entries 3 and 5),
but the other solvents were inferior (Table 1, entries 2, 4,
6, and 7). To our disappointment, although the reaction
time was prolonged, poor conversion was observed when
this coupling reaction was carried out at 45 °C (Table 1,
entry 9). With regard to yield, copper(I) iodide is a better
catalyst than copper(I) bromide in this reaction (Table 1,
entries 5 and 8).
nylimidazoles is copper-catalyzed Ullmann coupling.5
However, these reactions usually proceed at relatively
high temperatures or have been limited to vinyl iodides as
substrates. More recently, a similar copper-catalyzed pro-
tocol enabled the O-vinylation of phenols under milder
temperatures.6 Unfortunately, only (E)-b-bromostyrene
can be used as the substrate, and there was no example of
a reaction of a substituted vinyl bromide with a phenol.
During the past few years, significant progress has been
made on the development of a copper-catalyzed Ullmann-
type coupling reaction.7 This progress has relied greatly
on the use of some special ligands, such as N,N-, O,O-,
and N,O-bidentate compounds, as well as phosphines and
carbenes. Ma and co-workers reported that the structures
of a- and b-amino acids could induce acceleration of Ull-
mann-type aryl amination and the coupling reactions of
amino acids with aryl halides could be carried out at rela-
tively low temperatures.8 Further exploration revealed
On the basis of the above studies, the optimized condi-
tions can be set as follows: N-methylpyrrolidin-2-one as
solvent, copper(I) iodide/ethyl 2-oxocyclohexanecarbox-
ylate as catalytic system, and reaction temperature 60 °C.
These reaction conditions were applied to the coupling of
SYNTHESIS 2008, No. 12, pp 1911–1917
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1067082; Art ID: F23007SS
© Georg Thieme Verlag Stuttgart · New York

1912
W. Bao et al.
PAPER
Table 1 Coupling Reaction of (E)-b-Bromostyrene and Phenol Catalyzed by Copper Salts and a b-Keto Estera
O
OH
O
Br
O
OEt
CuI, ligand
+
Cs2CO3, solvent
ligand
Entry
Solvent
Catalyst
Temp (°C)
Time (h)
24
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMF
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuI
60
60
60
60
60
60
60
60
45
30
40
MeCN
DMSO
[Bmim]BF4
NMP
24
24
90
c
24
trace
95
24
dioxane
toluene
NMP
24
30
40
15
24
55
DMSO
40
10
a Reagents and conditions: CuX (15 mol%), ligand (30 mol%), Cs2CO3 (2 mmol), (E)-b-bromostyrene (1 mmol), PhOH (1.2 mmol), solvent (2
mL).
b Isolated yield.
c Bmim = 1-butyl-3-methylimidazolium.
different phenols with different (E)-b-bromostyrenes Table 3, entry 4). The reaction of (E)-4-chloro-b-bro-
(Table 2). The coupling reactions performed well for all mostyrene with thiophenol gave the corresponding prod-
the substrates examined, affording the target products in uct with full retention of stereochemistry (Table 3, entry
moderate to excellent yields. Electron-deficient (E)-b- 2). The catalytic system is even milder than the L-proline/
bromostyrenes were generally superior to electron-rich copper(I) iodide/ILs system we previously reported for
ones, giving better yields (Table 2, compare entries 2, 3, the coupling of (E)-b-bromostyrenes and thiophenols.5a
and 4, as well as 7 and 8). Similar results were observed
The optimized reaction conditions were also used to ex-
in the coupling of substituted (E)-b-bromostyrenes and 4-
amine the coupling of (E)-b-bromostyrenes with imida-
methylphenol (Table 2, entries 5, 7, and 8). Other phenols,
zoles (Table 4). Because the separation of product from
whether electron-donating or electron-withdrawing, all
the solvent N-methylpyrrolidin-2-one was difficult, we
worked well under these conditions (Table 2, entries 5 and
tried to use dimethyl sulfoxide as solvent instead. By this
1
6). The stereoselectivity was good, as determined by H
protocol, we were able to couple electron-rich and -poor
NMR spectroscopy. With the exception of the reactions
(E)-b-bromostyrenes with imidazoles, producing the cor-
responding N-vinylimidazoles in good yields (Table 4,
represented by entries 5 and 7 (Table 2), the stereochem-
istry of the double bond was retained under the reaction
entries 2–4 and 6–8). The reaction was slightly disfavored
conditions.
by the steric hindrance of nucleophilic reagents. For ex-
A second part of our work involved the application of the ample, when benzimidazole was used as the substrate, a
method to the synthesis of vinyl sulfides (Table 3). (E)-b- higher reaction temperature than used with imidazole was
Bromostyrenes bearing an electron-withdrawing group on necessary to ensure good conversion (Table 4, entries 5–
the benzene ring showed higher reactivity than those bear- 8). Electron-rich (E)-4-(2-bromovinyl)toluene reacted
ing an electron-donating group (Table 3, compare entries well with benzimidazole, but a longer reaction time was
2, 3, and 4). In addition, thiophenol with electron-with- required (Table 4, entry 6). Significantly, (E)-b-bro-
drawing group worked well under the current conditions, mostyrenes furnished (E)-N-vinylimidazoles exclusively,
giving the desired product in reasonable yield (Table 3, except for the reaction shown in entry 7 (Table 4), which
entry 5). Furthermore, this reaction is also applicable to gave the product in an E/Z ratio of 97:3 (by 1H NMR). The
(E)-b-bromostyrene and thiol (Table 3, entry 6). Fortu- catalytic system for this reaction is even milder than that
nately, the conversion of (E)-b-bromostyrenes was re- used in the L-proline/copper(I) iodide/ILs system we pre-
markably stereoselective, giving (E)-vinyl sulfides; for viously reported for the coupling of (E)-b-bromostyrenes
example, when (E)-4-methyl-b-bromostyrene was cou- and imidazoles.5c
pled with thiophenol, the ratio of (E)-4-methylstyryl phe-
Limitations in the method were found when (Z)-b-bro-
1
nyl sulfide to the (Z)-isomer was 95:5 (by H NMR;
mostyrene was used as substrate. For example, the cou-
Synthesis 2008, No. 12, 1911–1917 © Thieme Stuttgart · New York

PAPER
Coupling of Styryl Bromides with Phenols, Thiophenols, and Imidazoles
1913
Table 2 Coupling Reactions of (E)-b-Bromostyrenes with Phenols Catalyzed by Copper(I) Iodide/Ethyl 2-Oxocyclohexanecarboxylatea
Br
HO
O
CuI, ligand
R1
R2
R1
R2
Cs2CO3, NMP, 60 °C
Entry
Bromostyrene
Phenol
Product
Yieldb (%)
95
E/Zc
OH
O
Br
1
2
3
4
100:0
OH
OH
OH
OH
Br
O
81
84
91
100:0
100:0
100:0
Me
Cl
F
Me
Cl
F
Br
O
Br
O
O
O
Br
Br
5
6
7
89
79
85
97:3
100:0
100:0
94:6
Me
Me
OH
Cl
Cl
OH
Br
O
Me
Me
Me
Me
OH
Br
O
8
9
91
Cl
Cl
Me
Me
OH
0d
O
Br
a Reagents and conditions: CuI (15 mol%), ligand (30 mol%), Cs2CO3 (2 mmol), (E)-b-bromostyrene (1 mmol), phenol (1.2 mmol), NMP (2
mL), 60 °C, 24 h.
b Isolated yield.
c The ratio was based on the 1H NMR spectrum.
d Reaction performed at 90 °C.
pling of (Z)-b-bromostyrene with thiophenol proceeded In summary, we have reported here a mild and efficient
well (Table 3, entry 7), but the reaction of (Z)-b-bro- catalytic system for the coupling reactions of phenols, thi-
mostyrene with phenol and imidazole failed to give any ols, and imidazoles with (E)-b-bromostyrenes at relative-
product, even at 90 °C (Table 2, entry 9 and Table 4, entry ly low temperature, and which is applicable to a number
9). We reason that this might result from the different nu- of substrates. The yields are good to excellent, and the ste-
cleophilicity of these substrates.
reoselectivity is satisfactory.
Synthesis 2008, No. 12, 1911–1917 © Thieme Stuttgart · New York

1914
W. Bao et al.
PAPER
Table 3 Coupling Reactions of (E)-b-Bromostyrenes with Thiophenols Catalyzed by Copper(I) Iodide/Ethyl 2-Oxocyclohexanecarboxylatea
Br
HS
S
CuI, Ligand
R1
R2
R1
R2
Cs2CO3, NMP,60 °C
Entry
Bromostyrene
Thiophenol
Product
Yieldb (%)
86
E/Zc
SH
Br
S
1
2
3
4
89:11
SH
SH
SH
SH
Br
S
88
92
85
100:0
93:7
95:5
Cl
F
Cl
F
Br
S
Br
S
Me
Me
S
S
Br
Br
5
82
83:17
Cl
Cl
CH2SH
6
7
75
76
97:3
98:2
SH
S
Br
a Reagents and conditions: CuI (15 mol%), ligand (30 mol%), Cs2CO3 (2 mmol), (E)-b-bromostyrene (1 mmol), thiophenol (1.2 mmol), NMP
(2 mL), 60 °C, 24 h.
b Isolated yield.
c The ratio was based on the 1H NMR spectrum.
Table 4 Coupling Reactions of (E)-b-Bromostyrenes with Imidazoles Catalyzed by Copper(I) Iodide/Ethyl 2-Oxocyclohexanecarboxylatea,b
N
Br
N
N
CuI, ligand
+
Cs2CO3, DMSO, 60–80 °C
N
H
Entry
1
Bromostyrene
Imidazole
Product
Yieldc (%)
88
E/Zd
N
Br
N
N
100:0
HN
N
Br
N
N
2
85
100:0
HN
Me
Me
Synthesis 2008, No. 12, 1911–1917 © Thieme Stuttgart · New York

PAPER
Coupling of Styryl Bromides with Phenols, Thiophenols, and Imidazoles
1915
Table 4 Coupling Reactions of (E)-b-Bromostyrenes with Imidazoles Catalyzed by Copper(I) Iodide/Ethyl 2-Oxocyclohexanecarboxylatea,b
(continued)
N
Br
N
N
CuI, ligand
+
Cs2CO3, DMSO, 60–80 °C
N
H
Entry
3
Bromostyrene
Imidazole
Product
Yieldc (%)
87
E/Zd
N
Br
N
N
100:0
HN
Cl
Cl
F
N
Br
N
N
4
5
6
7
90
82
85e
84
100:0
100:0
100:0
97:3
HN
F
N
HN
HN
HN
HN
N
N
N
N
Br
N
N
Br
N
Me
Cl
Me
Cl
F
N
Br
N
N
Br
N
8
9
88
0f
100:0
F
N
N
HN
Br
N
a Reagents and conditions: CuI (15 mol%), ligand (30 mol%), Cs2CO3 (2 mmol), (E)-b-bromostyrene (1 mmol), imidazole (1.2 mmol), DMSO
(2 mL), 24 h.
b Temp: imidazole, 60 °C; benzimidazole, 80 °C.
c Isolated yield.
d The ratio was based on the 1H NMR spectrum.
e Reaction time: 40 h.
f Reaction performed at 90 °C.
All reactions were carried out in Schlenk or test tubes under a N2 at-
mosphere. All the copper sources, ligands, and bases were commer-
cially available. Organic solvents, also commercially available,
were dried over 4-Å MS before use. All phenols, thiophenols, and
imidazoles were used as received. TLC was carried out on 0.2-mm
thick silica gel plates (GF 254) and visualized by UV light. The col-
umns were packed with silica gel 60 (200–300). All products were
confirmed by 1H NMR and IR spectroscopy. Unknown compounds
were additionally confirmed by 13C NMR spectroscopy and ele-
mental analysis. All melting points are uncorrected. The NMR spec-
tra of samples in CDCl3 with TMS as internal standard were
recorded on a Bruker Avance 400-MHz NMR instrument. IR spec-
tra were recorded on a Bruker Vector 22 FT-IR spectrometer, and
samples were prepared as KBr plates.
Coupling of Styryl Bromides with Phenols, Thiophenols, and
Imidazoles; General Procedure
An oven-dried Schlenk tube was back-filled with N2 and charged
with Cs2CO3 (650 mg, 2.0 mmol), CuI (30 mg, 0.15 mmol, 15
mol%), ethyl 2-oxocyclohexanecarboxylate (50 mg, 0.30 mmol, 30
mol%), the appropriate (E)-b-bromostyrene (1 mmol), the nucleo-
philic reagent (phenol, thiophenol, or imidazole for C–O, C–S, or
C–N coupling, respectively; 1.2 mmol), and anhyd solvent (2 mL)
under a stream of N2. The reaction tube was quickly sealed and the
contents were stirred at the temperature indicated in Tables 2–4 for
24 h. The cooled reaction mixture was dissolved in H2O and extract-
ed with EtOAc. The combined organic layer was dried (MgSO4).
The product was further purified by column chromatography (silica
gel, PE–EtOAc).
Synthesis 2008, No. 12, 1911–1917 © Thieme Stuttgart · New York

1916
W. Bao et al.
PAPER
(E)-4-(2-Phenoxyvinyl)toluene (Table 2, entry 2)
Oil.
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Solid; mp 67–68 °C.
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(E)-1-(4-Fluorostyryl)-1H-imidazole (Table 4, entry 4)
Solid; mp 78–79 °C.
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808 cm–1.
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7.30–7.26 (m, 2 H), 7.16 (s, 1 H), 7.09–7.05 (m, 2 H), 6.72 (d,
J = 14.4 Hz, 1 H).
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Evano, G.; Panek, J. S. J. Am. Chem. Soc. 2005, 127, 15026.
(h) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117.
(i) Yang, T.; Lin, C. X.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F.
Org. Lett. 2005, 7, 4781. (j) Gorobets, E.; McDonald, R.;
Keay, B. A. Org. Lett. 2006, 8, 1483. (k) Miyamoto, H.;
Okawa, Y.; Nakazaki, A.; Kobayashi, S. Angew. Chem. Int.
Ed. 2006, 45, 2274. (l) Cai, Q.; He, G.; Ma, D. J. Org.
Chem. 2006, 71, 5268. (m) Altman, R. A.; Buchwald, S. L.
Org. Lett. 2006, 8, 2779. (n) Taillefer, M.; Xia, N.; Ouali, A.
Angew. Chem. Int. Ed. 2007, 46, 934.
Anal. Calcd for C11H9FN2: C, 70.20; H, 4.82; N, 14.88; Found: C,
70.18; H, 4.82; N, 14.93.
(E)-1-(4-Fluorostyryl)-1H-benzo[d]imidazole (Table 4, entry 8)
Solid; mp 122–123 °C.
IR (KBr): 3089, 2964, 1659, 1610, 1492, 1290, 947, 808, 742 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.22 (s, 1 H), 7.86 (d, J = 7.0 Hz,
1 H), 7.61 (d, J = 7.0 Hz, 1 H), 7.48–7.44 (m, 3 H), 7.41–7.34 (m, 2
H), 7.11 (t, J = 12.4 Hz, 2 H), 6.95 (d, J = 14.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 163.79, 161.33, 144.01, 140.70,
132.66, 130.92, 127.84, 127.76, 123.91, 123.16, 120.81, 119.03,
116.11, 115.89, 110.24.
Anal. Calcd for C15H11FN2: C, 75.62; H, 4.65; N, 11.76; Found: C,
75.63; H, 4.69; N, 11.71.
Synthesis 2008, No. 12, 1911–1917 © Thieme Stuttgart · New York

PAPER
Coupling of Styryl Bromides with Phenols, Thiophenols, and Imidazoles
1917
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Synthesis 2008, No. 12, 1911–1917 © Thieme Stuttgart · New York