Copper-assisted nickel catalyzed ligand-free C(sp2)-O cross-coupling of vinyl halides and phenols

Article abstract of DOI:10.1021/ol500134p

A convenient and efficient protocol has been achieved for the cross-coupling of phenols and vinyl halides by a unique Ni/Cu catalytic system for the first time, where the reaction is catalyzed by Ni and Cu is involved in the transmetalation process. This

Full text of DOI:10.1021/ol500134p

Letter
pubs.acs.org/OrgLett
Copper-Assisted Nickel Catalyzed Ligand-Free C(sp2)−O Cross-
Coupling of Vinyl Halides and Phenols
Debasish Kundu, Pintu Maity, and Brindaban C. Ranu*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
S
* Supporting Information
ABSTRACT: A convenient and efficient protocol has been
achieved for the cross-coupling of phenols and vinyl halides by a
unique Ni/Cu catalytic system for the first time, where the
reaction is catalyzed by Ni and Cu is involved in the
transmetalation process. This procedure provides an easy access
to a library of aryl-vinyl and aryl-styrenyl ethers.
he vinyl C(sp2)−O bond forming reaction is of much
interest as vinyl/styrenyl ethers are employed as useful
Scheme 1. Cross-Coupling of Vinyl Halides and Phenols
T
intermediates in a wide variety of reactions such as cyclo-
addition,1 cyclopropanation,2 metathesis reaction,3 etc. They
are also found as core units of several biologically active
molecules and natural products.4 In addition, vinyl groups act
as efficient protecting groups for phenol derivatives.5 Although
several multistep protocols have been reported for the synthesis
of vinyl ethers,6 transition metal catalyzed cross-coupling of
vinyl halides and phenols has been found to be more effective.
Earlier palladium-based catalysts have been employed for
vinylation of phenols.7 However, use of expensive palladium
is not cost-effective for industry. Thus use of other less
expensive metals received attention. Only recently, a few
reports on Cu-catalyzed vinylation of phenols and N-hetero-
cycles in the presence of a variety of ligands have appeared.8
The essential feature of all these protocols is the necessity of a
ligand to activate the Cu-catalysts toward reaction. The N-
containing ligands, commonly employed, are not always easily
accessible and are relatively expensive when they are
commercially available. Moreover, the presence of a large
amount of ligands also posed difficulty in the purification of
products. In addition, a couple of these methods8a,b required a
longer reaction time (24−48 h). Recently Ni-catalysts have
received much attention due to their relatively low cost and
interesting catalytic features. Several Ni catalysts have been
successfully used for the synthesis of important organic
molecules.9 This prompted us to explore the hitherto
unreported application of a Ni-catalyst for the vinylation of
phenols without using any ligand. In a preliminary experiment
we found that Ni-salt alone cannot initiate the reaction of vinyl
bromide and phenol. However, the presence of a Cu-salt in the
system triggered the reaction. Thus, as a part of our continuing
program on transition metal catalyzed reactions10 we report
here a Cu-assisted Ni- catalyzed ligand free cross-coupling of
aromatic alcohols with styrenyl and vinyl halides (I and Br)
(Scheme 1).
representative coupling of 4-methoxy phenol (1a) and (E)-4-
methyl styrenyl bromide (2a). The results are summarized in
Table 1. The reaction did not proceed using NiCl2, NiBr2, or
Ni(acac)2 alone (Table 1, entries 1−3). However the presence
of CuI in Ni(acac)2 triggered the reaction although solvent has
a significant influence. The best yield of product was obtained
by using 5 mol % of Ni(acac)2, 5 mol % of CuI, and 2.0 equiv of
Cs2CO3 at 100 °C for 8 h in N-methylpyrrolidinone (NMP)
(Table 1, entry 4). NMP was found to be more efficient
compared to DMSO, dioxane, and DMF (Table 1, entries 7−
9). Other nickel salts such as NiCl2 and NiBr2 under identical
conditions are not very effective (Table 1, entries 16−17). The
reaction at lower temperature (80 °C) takes a longer period
(25 h) (Table 1, entry 5). At rt only a trace amount of product
(5%) was isolated (Table 1, entry 6). CuBr and CuCl were
found to be less active in comparison to CuI (Table 1, entries
10 and 11). Weaker bases such as K2CO3 and K3PO4 failed to
initiate the reaction (Table 1, entries 12 and 13). Only a trace
of product (<5%) was isolated when the reaction was carried
out using CuI alone in the absence of Ni(acac)2 (Table 1, entry
14). A lower catalyst loading (2%) leads to lower conversion
(Table 1, entry 15). Thus, in a typical procedure a mixture of
phenol and styrenyl (or vinyl) halide (I and Br) was heated at
100 °C under argon in the presence of Ni(acac)2 (5 mol %)
and CuI (5 mol %) for a certain period of time to complete the
reaction (TLC). A series of diversely substituted styrenyl and
vinyl halides underwent coupling with a variety of phenols by
this procedure to produce the corresponding styrenyl aryl
To standardize the reaction conditions a series of experi-
ments were performed with variation of reaction parameters
such as catalyst, solvent, base, temperature, and time for a
Received: November 20, 2013
Published: February 6, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
a
Table 1. Standardization of Reaction Conditions
Scheme 3. Ni−Cu Catalyzed O-Styrylation
b
entry
catalyst
NiCl2
solvent
temp [°C] time [h] yield (%)
1
2
3
NMP
NMP
NMP
NMP
NMP
NMP
DMSO
Dioxane
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
100
100
100
100
80
20
20
20
8
0
NiBr2
0
Ni(acac)2
0
c
4
Ni(acac)2/CuI
Ni(acac)2/CuI
Ni(acac)2/CuI
Ni(acac)2/CuI
Ni(acac)2/CuI
Ni(acac)2/CuI
Ni(acac)2/CuBr
Ni(acac)2/CuCl
Ni(acac)2/CuI
Ni(acac)2/CuI
CuI
92
60
0
c
5
25
30
16
16
16
18
18
15
15
15
15
20
20
12
c
6
rt
c
7
100
100
100
100
100
100
100
100
100
100
100
100
25
trace
55
71
45
c
8
c
9
c
10
c
11
c
d
12
0
c
e
13
trace
trace
20
f
14
g
15
Ni(acac)2/CuI
NiCl2/CuI
c
16
trace
trace
c
17
NiBr2/CuI
h
18
NiCl2/CuI
40
a
Reaction conditions: A mixture of 1a (1.0 mmol), 2a (1.0 mmol),
and Cs2CO3 (2.0 mmol) was heated under an argon atmosphere.
b
c
Yields of isolated pure products. 5 mol % of Ni and Cu catalysts
d
e
f
were used. K2CO3 was used as base. K3PO4 was used as base. 10
mol % CuI was used. 2 mol % of Ni and Cu catalyst were used. 20
mol % of Zn powder was used as an additive.
g
h
ethers (Scheme 3, Scheme 5) and vinyl aryl ethers (Scheme 4).
All the products were obtained with high stereoselectivity.
The (E)-styrenyl halides produced the corresponding (E)-
styrenyl aryl ethers. However the reaction of (Z)-styrenyl
bromide did not produce the corresponding (Z)-styrenyl aryl
ethers; instead the corresponding 1,3-diyne was obtained.
Possibly, the (Z)-styrenyl bromide underwent rapid E2 type
elimination11 in the presence of a strong base such as Cs2CO3
to form the aryl acetylene which is then converted to the 1,3-
diyne via homocoupling by the Ni/Cu catalytic system
(Scheme 2).
a
Reaction conditions: aryl alcohol (1.0 mmol), styrenyl halide (1.0
mmol), Ni(acac)2 (0.05 mmol), CuI (0.05 mmol), Cs2CO3 (2.0
mmol), NMP (3.0 mL), 100 °C, 8 h, under argon. b 10 h. c 2.0 mmol
d
of aryl alcohols used. Reaction conditions: aryl alcohol (1.5 mmol),
styrenyl halide (1.0 mmol), Ni(acac)2 (0.1 mmol), CuI (0.1 mmol),
K3PO4 (2.0 mmol), NMP (3.0 mL), 100 °C, 24 h, under argon.
Scheme 2. Outcome of Reaction of (Z)-Styrenyl Bromide
a
Scheme 4. Ni−Cu Catalyzed O-Vinylation
A variety of functionalized styrenyl aryl ethers bearing
important functionalities such as F, Br, and OMe were obtained
by this procedure (Scheme 3, 3aa, 3ae, 3cc). The naphthyl
vinyl aryl ethers were also accomplished without any difficulty
(Scheme 3, 3fg, 3ig, 3cg, 3hg). The efficiency of this protocol
for the synthesis of sterically hindered styrenyl and vinyl aryl
ethers by the coupling of 2,6-dimethoxy phenol and 2,4-di-tert-
butyl phenol is noteworthy (Scheme 3, 3cc, 3ci, 3ji; Scheme 4,
5jb). Several 1-phenyl-1,3-butadienyl aryl ethers were also
obtained (Scheme 3, 3ah, 3ci, 3ji, 3gi). The synthesis of these
conjugated dienyl ethers were not addressed earlier by other
procedures using this reaction.
a
Reaction conditions: aryl alcohol (1.0 mmol), vinyl halide (1.0
mmol), Ni(acac)2 (0.05 mmol), CuI (0.05 mmol), Cs2CO3 (2.0
mmol), NMP (3.0 mL), 100 °C, 6 h, under argon. 10 h.
b
Moreover, these compounds possess great potential in
organic synthesis.12 A couple of bis-styrenyl aryl ethers
(Scheme 3, 3af and 3bf) which are of biological importance13
were also synthesized. Although poor reactivity from acidic
phenols in Ullmann type coupling is quite common14 this
protocol is successfully employed for the synthesis of vinyl
ethers by the reaction of substituted vinyl halides with acidic
and electron-deficient phenols such as 3-nitrophenol, 3-hydroxy
acetophenone, and 4-hydroxy benzonitrile (Scheme 3, 3hg, 3hj,
3ki, 3kj, 3lj, 3lk, 3hj; Scheme 5, 3km, 3hm, 3lm). Significantly,
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In general, all the reactions are clean and high yielding. The
reaction is compatible with diversely substituted phenols
bearing electron-donating and -withdrawing groups in the
-ortho, -meta and -para positions of the aromatic ring. Although
the products were obtained by a homogeneous metal catalysis
pathway, ICP-MS studies of purified products showed the
absence of any metal impurities (nickel or copper). All of these
products are reported for the first time with full characterization
Scheme 5. Ni−Cu Catalyzed O-Styrylation with
a
,b
Trisubstituted Halo-olefins
1
data (IR, H NMR, 13C NMR, and HR-MS).
The N-heterocycles such as pyrazole and 2-pyrrolidinone
also underwent coupling with vinyl halides by this catalytic
system quite easily (Scheme 7).
Scheme 7. Ni−Cu Catalyzed N-Vinylation of Pyrazole and 2-
Pyrrolidinone
a
Reaction conditions: aryl alcohol (1.0 mmol), vinyl halide (1.0
mmol), Ni(acac)2 (0.05 mmol), CuI (0.05 mmol), Cs2CO3 (2.0
b
mmol), NMP (3.0 mL), 100 °C, 12 h, under argon. Reaction
conditions: aryl alcohol (1.5 mmol), vinyl halide (1.0 mmol),
Ni(acac)2 (0.1 mmol), CuI (0.1 mmol), K3PO4 (2.0 mmol), NMP
(3.0 mL), 100 °C, 24 h, under argon (for 3km).
the coupling of 4-hydroxy benzonitrile with E-bromostilbene
(Scheme 5, 3km) furnished the corresponding (E) isomer in
better (76%) yield compared to that (56%) reported by
Limberger et al.8c The more challenging reactions of vinyl
halides bearing substituents at the α- and β-positions relative to
the halide are also successful by this protocol (Scheme 5). All of
these compounds are obtained in single stereoisomers with an
(E)-configuration as revealed by the NOE, NOESY, and COSY
experiments (see SI) of a representative molecule, 3lm, and
authentication of 3km with a reported one.8c
To understand the reaction mechanism we considered the
possibility of a radical as well as an ionic pathway. It was
observed that the reaction rate and yield remained unaffected
when the reaction was performed in the presence of nitroarene
(electron acceptor) or THF (electron trapper)17 or TEMPO
(radical quencher). Moreover, high stereoselectivity in O-
styrenylation and vinylation reactions achieved in this process
does not support the radical mechanism, as vinyl radicals
undergo rapid inversion of configuration.17 Thus, involvement
of a radical pathway is unlikely. We observed a decreasing rate
of reaction with the enhancement of steric hindrance and
acidity of phenols. This is usually indicative of an oxidative
addition−reductive elimination pathway.17
Interestingly, the reaction of 2,6-dimethoxyphenol with (Z)-
ethyl-3-iodo-acrylate (Scheme 6) provided the corresponding
Scheme 6. O-Vinylation with (Z)-Ethyl 3-Iodo-acrylate
As the reaction did not proceed in the presence of either
Ni(acac)2 or CuI alone under ligand-free conditions it is likely
that each of these two metals has its specific role in the
oxidative−reduction process. Thus we focused our attention to
find the primary catalytic species in this reaction. If we consider
the reaction to be catalyzed by Cu the involvement of CuI/CuIII
in oxidative addition appears very unlikely due to the high
redox potential of the CuI−CuIII system in ligand-free
conditions.18a Usually in the presence of a N-containing ligand
the coordination of the ligand with the CuI-center leads to a
sharp decrease in CuI−CuIII redox potential and facilitates the
process.18b Next we considered the catalysis by Ni. We have
observed that NiCl2 alone cannot initiate the reaction (Table 1,
entry 18). However when the reaction was performed in
presence of Zn the reaction proceeds to the extent of 40%
(unoptimized).
Thus it may be suggested that the active species in this
process is Ni(0) which is generated in situ in the presence of a
base under the reaction conditions. To obtain more convincing
evidence we performed a few UV experiments. A solution of
Ni(acac)2 in NMP at 100 °C (reaction temperature) shows a
peak at 298 nm, whereas when Cs2CO3 was added into the
solution immediately a new peak appeared at 376 nm which
corresponds to that of Ni(0) nanoparticles.19 This proves the
formation of Ni(0) from Ni(II) in the presence of Cs2CO3 in
the reaction mixture. The UV studies of the vinylation reaction
(E)-vinyl ether with an inverted trans configuration. The
identity of this compound was satisfactorily established by IR,
1H NMR, 13C NMR, and HRMS. The coupling constant (J
value) for the olefinic protons adjacent to −CO2Et is found to
be 12.2 Hz which is characteristic for a trans configuration. This
value is in good agreement with trans coupling (J = 12.0−12.4
Hz) observed in closely related molecules.15 On the other hand
the cis olefinic protons in analogous (Z)-compounds show a
coupling constant (J) of 6.8 Hz.16 In contrast, Cook et al.
reported complete retention of stereochemistry in a similar Cu-
catalyzed coupling of (Z)-ethyl 3-iodo-acrylate with phenols to
provide (Z)-vinyl ethers even though all of these vinyl ethers
showed a coupling constant of 12 Hz for olefinic protons which
indicate a trans configuration.8b A controlled experiment for a
reaction of (Z)-ethyl 3-iodo-acrylate in the absence of phenol
virtually showed no isomerization (Z/E = 98:2) of the starting
material, and thus it is likely that the reaction proceeds via the
addition elimination pathway.
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also show the appearance of the same Ni(0) peak just after 1
min which remains until the end of the reaction (see SI).20 The
Ni(0) undergoes fast oxidative addition with styrenyl and vinyl
halides leading to the intermediate A. In the other cycle, it is
most likely that CuI interacts with a nucleophile, phenol in the
presence of base (Cs2CO3), to form the intermediate B
(Scheme 8) and subsequently the nucleophile is transferred
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provides the product.
In conclusion, we have developed a convenient and efficient
protocol for the synthesis of vinyl aryl ether catalyzed by a
unique Ni−Cu homogeneous catalytic system. The significant
feature of this protocol is the catalysis by Ni and participation
of Cu in the transmetalation process under ligand-free
conditions. We are not aware of any C−O bond formation
catalyzed by Ni metal salt, and thus this report of C(sp2)−O
cross-coupling is the first one. The other advantages of this
protocol are broad functional group tolerance including strong
electron-withdrawing functionality, high stereoselectivity, use of
an inexpensive and relatively benign catalyst with low loading,
ligand-free conditions, operational simplicity, and high yields.
This concept of catalysis by Ni with the assistance of another
transition metal such as Cu is of high potential, and further
investigation for other useful cross-coupling reactions is
currently in progress.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Typical experimental procedure and characterization data of all
1
products and copies of their H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(20) See Supporting Information for full reference.
*E-mail: ocbcr@iacs.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are pleased to acknowledge the financial support from
DST, New Delhi through an award of JCB Fellowship to B.C.R.
(Grant No. SR/S2/JCB-11/2008). D.K. and P.M. thank CSIR
for their fellowships.
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