A general method for copper-catalyzed arene cross-dimerization

Article abstract of DOI:10.1021/ja2047717

A general method for a highly regioselective copper-catalyzed cross-coupling of two aromatic compounds using iodine as an oxidant has been developed. The reactions involve an initial iodination of one arene followed by arylation of the most acidic C-H bon

Full text of DOI:10.1021/ja2047717

ARTICLE
pubs.acs.org/JACS
A General Method for Copper-Catalyzed Arene Cross-Dimerization
Hien-Quang Do and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S Supporting Information
b
ABSTRACT:
A general method for a highly regioselective copper-catalyzed cross-coupling of two aromatic compounds using iodine as an oxidant
has been developed. The reactions involve an initial iodination of one arene followed by arylation of the most acidic CꢀH bond of
the other coupling component. Cross-coupling of electron-rich arenes, electron-poor arenes, and five- and six-membered
heterocycles is possible in many combinations. Typically, a 1/1.5 to 1/3 ratio of coupling components is used, in contrast to
existing methodology that often employs a large excess of one of the arenes. Common functionalities such as ester, ketone, aldehyde,
ether, nitrile, nitro, and amine are well-tolerated.
(pathway E) is perhaps the most efficient method for biaryl
synthesis.4,9 Functionalized starting materials are not required,
and a stoichiometric oxidant is needed. However, this pathway
presents the most formidable difficulties with respect to regios-
electivity and selectivity for cross-coupling over homocoupling.
Often up to 100 equiv of one of the coupling components is
required to achieve a good yield of the cross-coupling product. A
few recent reports have shown that in special cases, a minimal
excess of one of the coupling components can be used.9d,m,n
Achieving good coupling regioselectivity is also problematic
unless five-membered-ring heterocycles, directing-group-con-
taining arenes, or polyfluorobenzenes are employed. Besides
the above-mentioned issues, in most of the published cases
palladium catalysts are used in conjunction with several equiva-
lents of heavy-metal (silver or copper) reoxidants. However,
oxygen can sometimes be used as the stoichiometric oxidant,
avoiding the generation of heavy-metal waste.10
The generality of direct dehydrogenative arene coupling is
relatively low. Success has been achieved either in the arylation of
electron-rich heterocycles and directing-group-containing arenes
with simple benzenes or cross-coupling of five-membered-ring
heterocycles. Therefore, the development of a new, general
catalytic system for dehydrogenative cross-coupling would be
quite appealing. In view of the existing limitations, the new
reaction system should deliver highly efficient cross-coupling
with good regioselectivity while involving a readily available
copper catalyst and a transition-metal-free oxidant. Additionally,
the method should be highly general, allowing for cross-coupling
of many arene types.
1. INTRODUCTION
The biaryl moiety is a ubiquitous structural motif in natural
products, pharmaceuticals, and functional materials.1 As a con-
sequence, formation of arylꢀaryl bonds has interested chemists
since Ullmann reported a copper-catalyzed method for biaryl
synthesis more than a century ago.2a The following methods can
be used for creating an arylꢀaryl bond (Scheme 1). Ullmann
coupling is an example of the coupling of two aryl halides to give a
biaryl (pathway A). A stoichiometric reducing agent is necessary,
and achieving selective cross-coupling is difficult for most inter-
molecular cases.2 Presently, the most widely used method for
arylꢀaryl bond formation is the coupling of an arylmetal with an
aryl halide (pathway B). Reactions such as Stille, Suzuki, Kuma-
da, Negishi, and others allow for a highly controlled synthesis of
biaryls possessing virtually any structural motif.3 However, this
methodology requires functionalized starting materials that may
not be readily available, resulting in longer synthetic sequences.
Coupling of an aryl halide with an arene CꢀH bond is also
possible (pathway C). Reoxidation is not required. Excellent
regioselectivity with respect to the arene CꢀH bond-coupling
component has been achieved for arylation of heterocycles4,5 and
directing-group-containing arenes4,6 as well as deprotonative aryla-
tion that includes functionalization of polyfluorobenzenes.4,7
However, for many simple substrates, the regioselectivity of the
arylation is still problematic. Often only symmetric arenes such as
benzene or p-xylene are employed as CꢀH coupling compo-
nents because of the formation of regioisomeric mixtures.4
Pathway D involves the coupling of an arylmetal or carboxylic
acid with an arene CꢀH bond.4,8 The regioselectivity issues for
this pathway are similar to the ones observed for pathway C.
Additionally, a stoichiometric oxidant, typically a transition-
metal salt, is required. Direct dehydrogenative arene coupling
Received: May 24, 2011
Published: August 08, 2011
r
2011 American Chemical Society
13577
dx.doi.org/10.1021/ja2047717 J. Am. Chem. Soc. 2011, 133, 13577–13586
|

Journal of the American Chemical Society
ARTICLE
Scheme 1. Methods for ArylꢀAryl Bond Formation
Scheme 2. Reaction Development Considerations
partners could be employed. The oxidant must be able to
functionalize a broad range of aromatic compounds regioselec-
tively, affording intermediates that are reactive toward subse-
quent copper-catalyzed direct arylation.7bꢀj Iodination usually
occurs with high regioselectivity.11,12 Electron-rich and electron-
poor arenes can be iodinated under electrophilic and deproto-
native reaction conditions, respectively.11,12 Aryl iodides can be
employed as substrates in highly regioselective copper-catalyzed
arylation of CꢀH bonds, which has been found to be successful
in the arylation of a variety of heterocycles and electron-deficient
arenes.7bꢀj The combination of a copper-catalyzed direct aryla-
tion reaction with an in situ iodination should allow the creation
of a general method for oxidative cross-coupling of two arenes.
The iodinating reagent must be compatible with the copper(I)
catalyst. Strong oxidants must be avoided, since they efficiently
convert catalytically active Cu(I) to inactive Cu(II). We have
reported a sequential iodination/cross-coupling method that
employs ICl as the oxidant.7i However, because ICl is incompa-
tible with the Cu(I) catalyst, the reaction must be carried out in
two steps. With those considerations in mind, we chose to use I2,
since it is a weaker oxidant than ICl and delivers an C(sp2)ꢀI
functionality that is reactive under copper catalysis.
We report here a method for highly regioselective copper-
catalyzed cross-coupling of arene CꢀH bonds that employs
iodine as the terminal oxidant.
2. METHOD DEVELOPMENT CONSIDERATIONS
As mentioned above, most of the existing dehydrogenative
arene cross-coupling methods are palladium-catalyzed, and the
scope of the published reactions is rather limited. The explana-
tion for the lack of generality can be inferred from the proposed
mechanisms, in which the palladium catalyst governs both the
arylation selectivity and the available substrate scope. The
oxidant reoxidizes Pd(0) to Pd(II) and must be inert with
respect to the substrates and reaction products. Alternatively,
one can envision reaction conditions under which one of the
coupling partners instead of the catalyst would be oxidized,
affording a functionalized intermediate that could participate in
further reaction to form a cross-coupling product (Scheme 2).
The oxidative direct arylation can be dissected into two
consecutive in situ processes: oxidation and direct arylation.
This approach may result in several advantages if the substrate
oxidation step is designed correctly. Fast and selective oxidation
of only one of the coupling components should result in
minimization of the amount of the homodimerization byproduct.
Additionally, a large excess of one of the coupling components
should not be necessary. Regioselective oxidation would result in
selective activation of only one of the many CꢀH bonds in the
substrate. Consequently, diverse and nonsymmetric coupling
3. RESULTS
3.1. Optimization of the Iodination Step. The method
for oxidative arene cross-coupling consists of iodination followed
by direct arylation, which should be mutually compatible. The
conditions for direct arylation employing copper catalysis
have been investigated extensively.7 The iodination method
and its compatibility with the arylation step had to be investi-
gated, taking into account that iodination may proceed by
different mechanisms for various arene types. Iodinations of
electron-rich arenes, electron-deficient arenes, five-membered-
ring heterocycles, and six-membered-ring heterocycles are dis-
cussed below according to the mechanisms by which these
halogenations occur.
The iodination of electron-rich arenes proceeds through electro-
philic aromatic substitution.11 Our initial attempts were directed
toward developing optimized conditions for the iodination of
electron-rich arenes by iodine that would be compatible with the
subsequent cross-coupling step. 1,3-Dimethoxybenzene was
13578
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586

Journal of the American Chemical Society
ARTICLE
Scheme 3. Optimization of Iodination Conditions for Elec-
tron-Rich Arenes
Scheme 5. Pyridine Iodination
required in the cross-coupling step and by employing a mixture of
tBuOLi and K3PO4 as the base. Huang and co-workers have
reported that in nonpolar solvents, the acidity of five-membered-
ring heterocycles is increased by copper complexation, thus
facilitating the deprotonation step.15
Finally, a method was developed for iodination of pyridines at
the 2-position. Conditions similar to the ones used for the
iodination of electron-poor arenes afforded reasonable conver-
sions to 2-iodopyridines. Only pyridines possessing electron-
donating substituents or halogens are reactive (Scheme 5).
Interestingly, in this case the CuI/phenanthroline additive
slightly decreases the conversion, in contrast to the iodination
of electron-poor arenes.
Scheme 4. Influence of Copper Catalyst on Iodination of
Electron-Poor Arenes and Acidic Heterocycles
3.2. Oxidative Arene Cross-Dimerization. The wide scope
of iodination combined with the generality of copper-catalyzed
CꢀH bond arylation results in a very general method that allows
the cross-coupling of many arene types. For example, by employ-
ing this methodology, one can cross-couple electron-rich arenes
with electron-poor arenes as well as five- and six-membered-ring
heterocycles. Any combinations of cross-coupling of electron-
poor arenes, five-membered-ring heterocycles, and six-mem-
bered-ring heterocycles should also be possible. The types of
cross-coupling reactions that are not possible with this metho-
dology include cross-coupling of electron-rich arenes. Addition-
ally, electron-neutral arenes such as benzene cannot be used as
either of the coupling components because of the requirement of
a relatively acidic CꢀH bond with a DMSO pKa of 35ꢀ37 or
below16 for the copper-catalyzed arylation step and their lack of
reactivity in the iodination step. For convenience, the cross-
coupling examples below are classified according to arene type
rather than the iodination mechanism.
3.2.1. Coupling of Electron-Rich Arenes with Heterocycles
and Electron-Poor Arenes. The reaction between 1,3-dimethox-
ybenzene and 3,5-difluoronitrobenzene was performed under
the conditions developed for iodination of electron-rich arenes.
The arenes were cross-coupled using 10 mol % CuI/phenanthro-
line as the catalyst, K3PO4 as the base, iodine as the oxidant, and
pyridine as an additive in 1,2-dichlorobenzene, and an excellent
yield of the product was obtained (Table 1, entry 1). When the
CuI/phenanthroline catalyst was omitted, the cross-coupling
product was not formed. A number of electron-rich arenes were
then cross-coupled with five- and six-membered-ring hetero-
cycles as well as electron-poor arenes. Typically, an arene ratio of
1/1.5 to 1/3 was used, and no homocoupling products were
observed. A single product regioisomer was obtained in each
case. Electron-rich arenes possessing either one dialkylamino or
alkoxy substituent with an additional electron-donating group were
reactive. 2,5-Dimethylanisole was coupled with 2-cyanothio-
phene, affording the coupling product in a good yield (entry 2).
The coupling of 3-methylanisole with a uracil derivative gave the
product in 61% yield (entry 3). Dimethylaniline derivatives were
arylated with phenyloxazole (entry 4), 3,5-difluoropyridine
(entry 5), and thiophene-2-carbaldehyde (entry 8). Couplings
used as the model substrate for iodination. A number of bases and
additives were screened in dioxane and 1,2-dichlorobenzene
solvent (Scheme 3).
The best conversion in dioxane was obtained when Na3PO4
was used as a base in the presence of 0.5 equiv of pyridine as an
additive. However, the use of excess pyridine resulted in lower
conversions. Unfortunately, Na3PO4 is not an efficient base for
the subsequent cross-coupling step, and thus, the reaction was
examined in 1,2-dichlorobenzene. To our delight, the conversion
was improved to 90% when K3PO4 was employed as the base in
the presence of pyridine as an additive. Thus, the conditions for
iodination of electron-rich aromatic compounds involve K3PO4
as the base, I2, dichlorobenzene as the solvent, and pyridine as an
additive. For more reactive substrates, iodination can be per-
formed in dioxane. These conditions can be used for iodination
of electron-rich arenes such as methoxy- or aminobenzenes as
well as five-membered-ring heterocycles such as thiophenes,
indoles, pyrazoles, pyrroles, furans, and indolizines.
In contrast, iodination of electron-deficient arenes by electro-
philic pathways requires harsh reaction conditions that are
incompatible with the subsequent cross-coupling step.13 Conse-
quently, a deprotonative halogenation pathway should be
employed.12 As reported previously, use of dioxane as the solvent
in combination with an alkoxide base and iodine proved to be
efficient for regioselective iodination of the most acidic arene
CꢀH bond (Scheme 4).14 The reaction conditions are applicable
to the iodination of electron-poor arenes that contain several
electron-withdrawing groups as well as the most acidic hetero-
cycles, such as oxazoles and thiazoles. Interestingly, the best
results were obtained in the presence of the copper catalyst that is
13579
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586

Journal of the American Chemical Society
ARTICLE
Table 1. Arylation of Electron-Rich Arenesa
a Conditions: copper(I) iodide (0.1 mmol), phenanthroline (0.1 mmol), electron-rich arene (1ꢀ3 mmol), coupling partner (1ꢀ2 mmol), iodine (1.2ꢀ
1.3 mmol), 1,2-dichlorobenzene solvent (0.7ꢀ1.0 mL), pyridine additive (0.5ꢀ1.0 mmol), 1ꢀ7 days. Yields are isolated yields. See the Supporting Information
for details. b Sequential iodination/cross-coupling. c Dioxane solvent. d Less than 3% of perfluoro-4,40-bitolyl was also formed.
13580
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586

Journal of the American Chemical Society
ARTICLE
Table 2. Arylation of Electron-Deficient Arenesa
a Conditions: copper(I) iodide (0.1 mmol), phenanthroline (0.1 mmol), electron-poor arene (1ꢀ4 mmol), coupling partner (1ꢀ3 mmol), iodine
(1.2ꢀ2.6 mmol), dioxane solvent (0.8ꢀ2.0 mL), K3PO4 or tBuOLi/K3PO4 base, 5 hꢀ5 days. Yields are isolated yields. See the Supporting Information
c
d
for details. b Pyridine additive (0.5 mmol), 1,2-dichlorobenzene solvent. Pyridine additive (1.0 mmol), 20 mol % CuI/phenanthroline. 4,40,5,50-
e
f
Tetramethyl-2,20-bithiazole byproduct (13%) was formed. 2,20-Bibenzothiazole byproduct (15%) was formed. 2,20,3,30,5,50,6,60-Octafluoro-4,40-
dimethoxybiphenyl byproduct (12%) was formed. 20,200,30,300,50,500,60,600-Octafluoro-p-quaterphenyl byproduct (8%) was formed. h 2,3,5,6-Tetra-
g
fluoro-40-cyanobiphenyl dimer byproduct (12%) was formed. i 2,20,3,30,5,50,6,60-Octafluoro-4,40-dimethoxybiphenyl byproduct (18%) was formed.
of 1- and 2-methoxynaphthalene with a polyfluorinated arene
and 2,3,5,6-tetrafluoropyridine, respectively, were also suc-
cessful (entries 6 and 7). Some polycyclic hydrocarbons such
as azulene and pyrene were arylated with polyfluorinated arenes
(entries 9 and 10). The method appears to have good func-
tional group tolerance, with nitro, cyano, amide, chloro, and
aldehyde substituents being compatible with the reaction
conditions. In all of these examples, the reactions proceeded
13581
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586

Journal of the American Chemical Society
ARTICLE
Table 3. Arylation of Five-Membered Ring Heterocyclesa
a Conditions: copper(I) iodide (0.1 mmol), phenanthroline (0.1 mmol), heterocycle (1ꢀ3 mmol), coupling partner (1ꢀ4 mmol), iodine (1.2ꢀ
2.5 mmol), 1,2-dichlorobenzene solvent (0.7ꢀ1.0 mL), K3PO4 or tBuOLi/K3PO4 base, 2 hꢀ9 days. Yields are isolated yields. See the Supporting
Information for details. b Dioxane solvent. Less than 5% of 2-phenyloxazole dimer was formed. c 20 mol % CuCl/phenanthroline. d Dioxane/DMF mixed
solvent (9/1). e Sequential iodination/cross-coupling. f A minor amount of regioisomer (<5%) was formed. g 20 mol % CuCl/phenanthroline catalyst.
h
Decafluorobiphenyl byproduct (<3%) was formed. Dioxane solvent. 2,20,3,30,5,50,6,60-Octafluoro-4,40-dimethoxybiphenyl byproduct (16%) was
formed. i Dioxane solvent. 2,20-Bibenzothiazole byproduct (15%) was formed.
by initial iodination of the electron-rich arene followed by copper-
catalyzed cross-coupling. In only one case was the formation
of a minor amount of a homocoupling byproduct observed:
1-methoxynaphthalene arylation by heptafluorotoluene (entry 6)
afforded <3% of perfluoro-4,40-bitolyl in addition to the cross-
coupling product.
3.2.2. Arylation of Electron-Deficient Arenes. A wide range of
aromatic compounds bearing at least two electron-withdrawing
13582
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586

Journal of the American Chemical Society
ARTICLE
Table 4. Pyridine Arylationa
a Conditions: copper(I) iodide (0.1 mmol), phenanthroline (0.1 mmol), pyridine substrate (1.5ꢀ3.0 mmol), coupling partner (1.0 mmol), iodine
(1.3ꢀ1.8 mmol), dioxane solvent (0.9ꢀ1.6 mL), K3PO4 or tBuOLi/K3PO4 base, 5 hꢀ7 days. Yields are isolated yields. See the Supporting Information
for details. b 1,2-Dichlorobenzene solvent. c Mixed 1,2-dichlorobenzene/DMF solvent (9.5/0.5). d 1,2-Dichlorobenzene solvent, pyridine additive
(0.5 mmol). e 2,20-Difluoro-6,60-dinitrobiphenyl byproduct (16%) was formed.
groups such as chloro, fluoro, nitro, cyano, and ester were
selectively arylated at the most acidic CꢀH bond (Table 2).
The entries are arranged with respect to the mechanism of
iodination pathway involved in the coupling. The iodination
occurred by electrophilic aromatic substitution (entries 1 and 2),
deprotonation/iodination (entries 3ꢀ8), and iodination of six-
membered ring heterocycles (entries 9 and 10). In entries 5ꢀ8,
the electron-deficient arene was iodinated. In all other cases, the
coupling partner was iodinated. Only one regioisomer of the
coupling product was observed.
and several halogenated nitrobenzenes with five-membered-ring
heterocycles such as cyanoindoline (entry 2), dimethylthiazole
(entry 3), and benzothiazole (entry 4) were successful. Interest-
ingly, selective cross-coupling of two electron-deficient arenes
was possible when there was a sufficient CꢀH bond acidity
difference between the coupling partners. For example, tetra-
fluorobiphenyl could be coupled with 1-fluoro-3-nitrobenzene
(entry 6). Coupling of a cyanated tetrafluorobiphenyl with 1,3,5-
trifluorobenzene delivered the cross-coupling product selectively
(entry 7). Finally, coupling of an arene possessing four fluorine
substituents with an arene possessing three fluorines occurred in
a moderate yield (entry 8). The cross-coupling product can be
3,5-Difluorobenzonitrile was coupled with N-methylcarbazole
in an acceptable yield (entry 1). Coupling of pentafluorobenzene
13583
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586

Journal of the American Chemical Society
ARTICLE
obtained because the iodination step requires electron-deficient
arenes possessing at least four fluorine substituents. The more
acidic arene is converted to an aryl iodide, which then couples with
the less acidic arene to afford the cross-coupling product. Arylation
of pyridine derivatives with electron-deficient arenes affords
2-arylpyridines in moderate yields (entries 9 and 10). In cases
where the deprotonation/iodination pathway was operative, homo-
coupling byproduct formation was observed (entries 3ꢀ8).
3.2.3. Arylation of Five-Membered-Ring Heterocycles. The
reaction scope for the arylation of five-membered-ring hetero-
cycles is summarized in Table 3. The entries are arranged with
respect to the mechanism of the iodination pathway involved in
the cross-coupling. The iodination occurred by electrophilic
aromatic substitution (entries 1ꢀ8) or deprotonation/iodina-
tion (entries 9 and 10). In all cases except entry 9, the five-
membered-ring heterocycle was iodinated.
Thiophenes were arylated by other five-membered-ring het-
erocycles, such as 2-phenyloxadiazole (entry 1) and 2-cyanothio-
phene (entry 5), as well as electron-deficient arenes (entry 6).
Especially interesting is the cross-coupling of two electronically
different thiophenes (entry 5). This reaction proceeded with an
excellent cross-coupling selectivity, and no homocoupling pro-
ducts were observed in the crude reaction mixture. Double
arylation of 1,2,4,5-tetrafluorobenzene with N-butylpyrazole
afforded the coupling product in an excellent yield (entry 2).
Arylations of N-methylindole and 1-methyl-2-acetylpyrrole with
electron-deficient arenes were successful (entries 3 and 4).
Furan derivatives were arylated with electron-deficient arenes
(entries 7 and 8). Caffeine was functionalized in a good yield
(entry 9). Benzothiazole was coupled with N-methyl-1,2,
4-triazole, and the product was obtained in a moderate yield. Two
examples in Table 3 show a fourfold CꢀH bond functionalization
wherein the substrate was diarylated (entries 2 and 6). In some
cases, minor amounts of arene homodimerization products were
observed (entries 1, 6, 9, and 10).
3.2.4. Pyridine Arylation by Heterocycles and Electron-Defi-
cient Arenes. Table 4 summarizes the scope for arylation of
pyridine derivatives. The data are arranged according to the
mechanism of the iodination pathway involved in the cross-
coupling. The iodination occurred by electrophilic aromatic
substitution (entries 1ꢀ3), deprotonation/iodination (entry 4),
and pyridine iodination (entries 6ꢀ9). In entries 1ꢀ4, the
coupling partner was iodinated. In all other cases, the pyridine
derivative was iodinated. Only one product isomer was observed
in each case.
Polyfluoropyridines were arylated with 2-butylthiophene
(entry 1), 1,3-dimethylindole (entry 2), and N-butylpyrazole
(entry 3). 3-Chloro-5-cyanopyridine was also reactive and could
be coupled with tetrafluorocyanobiphenyl (entry 4). Pyridine
itself was not reactive toward iodination/cross-coupling. How-
ever, pyridine derivatives possessing a halogen, methoxy, or alkyl
substituent at the 3- or 4-position could be iodinated/cross-
coupled under the general conditions with moderate yields and
high selectivities (entries 5ꢀ8). Only monoarylation was ob-
served even in the presence of excess iodine. Interestingly,
isoquinoline was arylated regioselectively with 3-fluoronitroben-
zene, albeit in a moderate yield (entry 9). The low efficiency of
isoquinoline iodination was responsible for the diminished yield
in the latter case. The 2,20-difluoro-6,60-dinitrobiphenyl bypro-
duct was formed in entry 9.
Table 5. Influence of Additives
Entry
Additive
Time (h)
Conversion (%)a
1
2
3
4
5
6
7
none
none
5
12
12
5
68
>98
88
LiI (1 equiv)
I2 (0.5 equiv)
<1
I2 (0.5 equiv)
24
5
<1
I2 (0.5 equiv) + LiI (1 equiv)
I2 (0.5 equiv) + LiI (1 equiv)
<1
24
12
a Determined by GC using an internal standard.
to 9 days. Both the iodination and subsequent copper-catalyzed
cross-coupling7d proceeds on a time scale of hours. For the
methodology to be useful and predictable, the factors causing the
long reaction times must be understood. Several control experi-
ments were run to determine which components of the reaction
mixture inhibit the reaction (Table 5).
The cross-coupling of 1,3-dimethoxybenzene with 3,5-difluor-
onitrobenzene required 5 days to achieve an 82% yield (Table 1,
entry 1). In contrast, 3,5-difluoronitrobenzene arylation of 2,4-
dimethoxyiodobenzene proceeded to complete conversion in 12
h (Table 5, entry 2). Iodination of 1,3-dimethoxybenzene to
produce the intermediate 2,4-dimethoxyiodobenzene required 1
h to achieve 90% conversion (Scheme 3). Clearly, one of the
reaction components inhibits the copper-catalyzed cross-cou-
pling of 1,3-dimethoxybenzene with 3,5-difluoronitrobenzene.
Addition of LiI somewhat slowed the reaction (entry 3). How-
ever, addition of 0.5 equiv of I2 shut the reaction down
completely (entries 4 and 5). Interestingly, when both LiI and
I2 were added to the reaction mixture, some activity was restored
(entries 6 and 7). The mechanism of inhibition most likely
involves oxidation of catalytically active Cu(I) to inactive Cu-
(II).7i,17 Analysis of the data in Tables 1ꢀ4 allows us to conclude
that the reaction time depends on the efficiency of the iodination
process. If iodination is either slow or inefficient, resulting in the
presence of residual iodine in the reaction mixture, the reactions
are slow. Diarylation examples such as those shown in entries 2 and
6 of Table 3 were among the slowest reactions. The shortest reaction
times were generally observed for examples where the acidic
heterocycle or polyfluoroarene coupling component was iodinated.
4. SUMMARY
An operationally simple and general method for copper-
catalyzed cross-coupling of two aromatic compounds that em-
ploys iodine as the oxidant has been developed. The reactions
proceed by iodination of one of the coupling components
followed by arylation of the most acidic CꢀH bond of the other
coupling component. Electron-rich arenes can be coupled with
electron-poor arenes as well as five- and six-membered-ring
heterocycles. Additionally, any combinations of five- and six-
membered-ring heterocycles and electron-poor arenes can also
3.2.5. General Considerations. Copper-catalyzed arene cross-
dimerization required reaction times anywhere from a few hours
13584
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586

Journal of the American Chemical Society
ARTICLE
be cross-coupled. In many cases, formation of homocoupling
products is not observed. The coupling components are used in a
ratio of 1/1.5 to 1/3, in contrast to existing methodology that
often employs one of the arenes as the solvent. Most common
functionalities, such as ester, ketone, aldehyde, ether, nitrile,
nitro, and amine, are well-tolerated. For arenes containing
multiple active CꢀH bonds, polyfunctionalization is possible.
Commun. 2010, 46, 677. (k) Livendahl, M.; Echavarren, A. M. Isr. J.
Chem. 2010, 50, 630. (l) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(5) For selected examples, see: (a) Akita, Y.; Inoue, A.; Yamamoto,
K.; Ohta, A.; Kurihara, T.; Shimizu, M. Heterocycles 1985, 23, 2327. (b)
Catellani, M.; Chiusoli, G. P.; Ricotti, S. J. Organomet. Chem. 1985,
296, C11. (c) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. (d) Rieth, R. D.;
Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett. 2004, 6, 3981. (e)
Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (f) Lewis, J. C.;
Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 2493. (g) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem.
2006, 1379. (h) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (i)
Huestis, M. P.; Fagnou, K. Org. Lett. 2009, 11, 1357. (j) Gracia, S.;
Cazorla, C.; Mꢀetay, E.; Pellet-Rostaing, S.; Lemaire, M. J. Org. Chem.
2009, 74, 3160. (k) Ackermann, L.; Vicente, R.; Born, R. Adv. Synth.
Catal. 2008, 350, 741. (l) Park, C.-H.; Ryabova, V.; Seregin, I. V.;
Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159. (m) Ohnmacht,
S. A.; Culshaw, A. J.; Greaney, M. F. Org. Lett. 2010, 12, 224.
(6) For selected examples, see: (a) Bedford, R. B.; Coles, S. J.;
Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112.
(b) Caron, L.; Campeau, L.-C.; Fagnou, K. Org. Lett. 2008, 10, 4533.
(c) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007,
129, 9879. (d) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 11234. (e) Kwak, J.; Kim, M.; Chang, S. J. Am. Chem. Soc. 2011,
133, 3780. (f) Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L.
J. Am. Chem. Soc. 2010, 132, 468. (g) Scarborough, C. C.; McDonald,
R. I.; Hartmann, C.; Sazama, G. T.; Bergant, A.; Stahl, S. S. J. Org. Chem.
2009, 74, 2613. (h) Shabashov, D.; Daugulis, O. J. Org. Chem. 2007,
72, 7720. (i) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetra-
hedron Lett. 2000, 41, 2655. (j) Ackermann, L.; Vicente, R.; Potukuchi,
H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032.
(7) For palladium catalysis, see: (a) Lafrance, M.; Rowley, C. N.;
Woo, T. K; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. For copper
catalysis, see:(b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007,
129, 12404. (c) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008,
130, 1128. (d) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem.
Soc. 2008, 130, 15185. (e) Ackermann, L.; Potukuchi, H. K.; Landsberg,
D.; Vicente, R. Org. Lett. 2008, 10, 3081. (f) Yotphan, S.; Bergman, R. G.;
Ellman, J. A. Org. Lett. 2009, 11, 1511. (g) Yoshizumi, T.; Tsurugi, H.;
Satoh, T.; Miura, M. Tetrahedron Lett. 2008, 49, 1598. (h) Besseliꢁevre,
F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson, D. S. Org. Lett. 2008,
10, 4029. (i) Do, H.-Q.; Daugulis, O. Chem. Commun. 2009, 6433. (j)
Chen, X.; Dobereiner, G.; Hao, X.-S.; Giri, R.; Maugel, N.; Yu, J.-Q.
Tetrahedron 2009, 65, 3085. For nickel catalysis, see:(k) Canivet, J.;
Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733. (l) Hachiya, H.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737.
(8) For selected examples, see: (a) Oi, S.; Fukita, S.; Inoue, Y. Chem.
Commun. 1998, 2439. (b) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.;
Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78. (c) Giri, R.; Maugel, N.; Li,
J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510. (d) Kirchberg, S.; Tani, S.; Ueda, K.;
Yamaguchi, J.; Studer, A.; Itami, K. Angew. Chem., Int. Ed. 2011, 50, 2387.
(e) Zhao, H.; Wei, Y.; Xu, J.; Kan, J.; Su, W.; Hong, M. J. Org. Chem.
2011, 76, 882. (f) Tredwell, M. J.; Gulias, M.; Gaunt Bremeyer, N.;
Johansson, C. C. C.; Collins, B. S. L.; Gaunt, M. J. Angew. Chem., Int. Ed.
2011, 50, 1076. (g) Chu, J.-H.; Lin, P.-S.; Wu, M.-J. Organometallics
2010, 29, 4058. (h) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.;
Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473. (i) Cornella, J.; Lu, P.;
Larrosa, I. Org. Lett. 2009, 11, 5506. (j) Vogler, T.; Studer, A. Org. Lett.
2008, 10, 129. (k) Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010,
49, 2768. (l) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 17676. (m) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H.
J. Am. Chem. Soc. 2010, 132, 4978. (n) Wang, C.; Piel, I.; Glorius, F.
J. Am. Chem. Soc. 2009, 131, 4194. (o) Shuai, Q.; Yang, L.; Guo, X.; Basle,
O.; Li, C.-J. J. Am. Chem. Soc. 2010, 132, 12212.
4. EXPERIMENTAL SECTION
General Procedure for Coupling Reactions. Outside the
glovebox, a 1 dram vial equipped with a magnetic stir bar was charged
with 1,10-phenanthroline (10 mol %), CuI (10 mol %), iodine (1.2ꢀ2.6
equiv), the arene substrates in the indicated ratio, pyridine (0ꢀ1.0
equiv), and 1,4-dioxane or 1,2-dichlorobenzene solvent. The vial was
flushed with nitrogen, capped, and placed inside the glovebox. To this
mixture was added base (K3PO4 or a tBuOLi/K3PO4 mixture). The
sealed vial was then taken out of the glovebox and stirred at the
appropriate temperature. After the completion of the reaction, the
mixture was cooled to room temperature, diluted with CH2Cl2
(1.0 mL), and subjected to column chromatography on silica gel in
hexanes followed by an appropriate solvent to elute the products. After
concentration of the fractions containing the product, the residue was
dried under reduced pressure to yield the pure product.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and characterization data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
olafs@uh.edu
’ ACKNOWLEDGMENT
We thank the Welch Foundation (Grant E-1571), the National
Institute of General Medical Sciences (Grant R01GM077635),
the Alfred P. Sloan Foundation, the Camille and Henry Dreyfus
Foundation, and the Norman Hackerman Advanced Research
Program for supporting this research.
’ REFERENCES
(1) Hassan, J.; Sꢀevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
(2) (a) Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174.
(b) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
(3) For reviews, see: (a) Suzuki, A. Chem. Commun. 2005, 4759.
(b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442. (c) Miura, M. Angew. Chem., Int. Ed. 2004, 43, 2201.
(d) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
(4) For reviews, see: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Angew. Chem., Int. Ed. 2009, 48, 9792. (c) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (d) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (e) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (f) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (g) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (h) Messaoudi, S.; Brion,
J.-D.; Alami, M. Eur. J. Org. Chem. 2010, 6495. (i) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (j) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
(9) (a) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008,
130, 9254. (b) Itahara, T. J. Chem. Soc., Chem. Commun. 1981, 254. (c)
Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (d) Xi, P.; Yang, F.;
13585
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586

Journal of the American Chemical Society
ARTICLE
Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010,
132, 1822. (e) Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.;
Dohi, T. J. Am. Chem. Soc. 2009, 131, 1668. (f) Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 9651. (g) Li, R.; Jiang, L.; Lu, W.
Organometallics 2006, 25, 5973. (h) He, C.-Y.; Fan, S.; Zhang, X. J.
Am. Chem. Soc. 2010, 132, 12850. (i) Izawa, Y.; Stahl, S. S. Adv. Synth.
Catal. 2010, 352, 3223. (j) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010,
132, 16377. (k) Malakar, C. C.; Schmidt, D.; Conrad, J.; Beifuss, U. Org.
Lett. 2011, 13, 1378. (l) Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.;
Miura, M. J. Am. Chem. Soc. 2011, 133, 2160. (m) Han, W.; Mayer, P.;
Ofial, A. R. Angew. Chem., Int. Ed. 2011, 50, 2178. (n) Brasse, M.; Ellman,
J. A.; Bergman, R. G. Chem. Commun. 2011, 47, 5019. (o) Takahashi, M.;
Masui, K.; Sekiguchi, H.; Kobayashi, N.; Mori, A.; Funahashi, M.;
Tamaoki, N. J. Am. Chem. Soc. 2006, 128, 10930. (p) Gong, X.; Song,
G.; Zhang, H.; Li, X. Org. Lett. 2011, 13, 1766. (q) Wang, Z.; Li, K.; Zhao,
D.; Lan, J.; You, J. Angew. Chem., Int. Ed. 2011, 50, 5365. (r) Yamaguchi,
A. D.; Mandal, D.; Yamaguchi, J.; Itami, K. Chem. Lett. 2011, 40, 555.
(10) (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef,
B. Org. Lett. 2007, 9, 3137. (b) Yokota, T.; Sakaguchi, S.; Ishii, Y. Adv.
Synth. Catal. 2002, 344, 849. (c) Brasche, G.; Garcia-Fortanet, J.;
Buchwald, S. L. Org. Lett. 2008, 10, 2207. (d) Liꢀegault, B.; Lee, D.;
Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022. (e)
Basle, O.; Li, C.-J. Chem. Commun. 2009, 4124. (f) Hagelin, H.; Oslob,
J. D.; Åkermark, B. Chem.—Eur. J. 1999, 5, 2413. (g) Do, H.-Q.;
Daugulis, O. J. Am. Chem. Soc. 2009, 131, 17052.
(11) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 1487.
(12) (a) Do, H.-Q.; Daugulis, O. Org. Lett. 2009, 11, 421. (b) Popov,
I.; Do, H.-Q.; Daugulis, O. J. Org. Chem. 2009, 74, 8309.
(13) (a) Prakash, G. K. S.; Mathew, T.; Hoole, D.; Esteves, P. M.;
Wang, Q.; Rasul, G.; Olah, G. A. J. Am. Chem. Soc. 2004, 126, 15770. (b)
Deacon, G. B.; Smith, R. N. M. Aust. J. Chem. 1982, 35, 1587.
(14) Do, H.-Q.; Daugulis, O. Org. Lett. 2010, 12, 2517.
(15) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.;
Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674.
(16) (a) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron
2007, 63, 1568. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(17) For examples of copper (II) iodideꢀphenathroline complexes,
see: (a) Ainscough, E. W.; Plowman, R. A. Aust. J. Chem. 1970, 23, 691.
(b) Percy, G. C.; Thornton, D. A. J. Mol. Struct. 1972, 14, 313.
13586
dx.doi.org/10.1021/ja2047717 |J. Am. Chem. Soc. 2011, 133, 13577–13586