Metal-free oxidative para cross-coupling of phenols

Article abstract of DOI:10.1002/chem.201301028

C-C coupling: Direct oxidative coupling reactions are an attractive tool for environmentally benign chemistry. The oxidative biaryl coupling reaction of phenols with various arenes at the para positions with hypervalent iodine reagents may also be included in this category. The reaction proceeds under very mild conditions without metal catalysts in a very short time under ambient conditions (see scheme; HFIP=hexafluoroisopropanol). Copyright

Full text of DOI:10.1002/chem.201301028

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DOI: 10.1002/chem.201301028
Metal-Free Oxidative para Cross-Coupling of Phenols
Koji Morimoto, Kazuma Sakamoto, Yusuke Ohnishi, Takeshi Miyamoto, Motoki Ito,
Toshifumi Dohi, and Yasuyuki Kita*[a]
Biaryls are an important group found in a wide range of
compounds such as natural products, polymers, liquid crys-
tals, and ligands for transition-metal catalysts.[1] The direct
phenolic derivatives for the synthesis of several pharmaco-
logically interesting natural products.[8] However, the inter-
molecular oxidative biaryl coupling reaction of phenols by
cross-coupling[2] of arene C H bonds is an attractive and
C H/C H’ coupling has remained unexplored. Because the
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convenient method for the synthesis of biaryls that avoids
the prefunctionalization of the starting materials (Scheme 1)
oxidative C H/C H’ cross-coupling of two aromatic com-
pounds has several drawbacks, including the formation of
undesired homo-coupling products derived from the oxida-
tion of the starting materials and over-oxidation of the cou-
pling products due to oxidation potentials lower than those
of the corresponding starting materials, especially, for oxy-
genated aryl compounds, the development of an efficient ox-
idative cross-coupling reaction is challenging. In spite of
this, Canesi and co-workers have demonstrated the oxidative
cross-coupling reaction of phenols and anilines with a hyper-
valent iodine reagent.[9] Waldvogel and co-workers reported
an electrochemical phenol–arene cross-coupling reaction
with boron-doped diamond electrodes.[10] However, these
coupling methods are mostly limited coupling at the ortho
position of phenols. Therefore, an efficient oxidative cross-
coupling reaction of phenols at the para position remains
unreported under metal-free conditions.[11]
À
À
Scheme 1. Oxidative C H/C H’ cross-coupling of aromatic compounds.
required for conventional cross-coupling reactions[3] between
aryl halides and organometallic reagents. Therefore, these
protocols are highly desirable from both synthetic and
atom-economic points of view.
In 2007, Fagnou and co-workers reported a metal-cata-
lyzed selective oxidative cross-coupling reaction with stoi-
chiometric amounts of oxidants.[4a] Since then, the oxidative
cross-coupling method has received considerable attention.[4]
Recently, we developed a new synthetic method that ena-
Herein, we describe a broadly applicable oxidative cross-
coupling reaction of phenols (at the para position) with vari-
ous arenes (Scheme 2). This versatile hypervalent-iodine-
À
À
bles the metal-free C H/C H’ cross-coupling of two aro-
matic compounds with hypervalent iodine
AHCTUNGTRENNUNG
These reactions proceeded with excellent regiocontrol and
high selectivity for the cross-coupling products was generally
observed.
On the other hand, the oxidation of phenol rings often
constitutes a key transformation in the biogenesis of natural
products and a powerful strategy for the construction of
functionalized intermediates in the development of complex
organic molecules.[6] The environmentally benign hyperva-
lent-iodine-based oxidation of phenol derivatives has been
very widely used for the synthesis of natural products,[7] and
has also been applied to the oxidative coupling of various
Scheme 2. The oxidative para cross-coupling of phenols.
AHCTUNGTREG(NNUN III)-induced oxidative coupling operates under mild reac-
tion conditions without the use of expensive catalysts, and
tolerates a diverse range of the arene coupling partners. We
have used this principle to demonstrate the iterative aryla-
tion of phenol, which enables the selective arylation of the
para and ortho positions by repeated oxidative coupling
with the same method.
[a] Dr. K. Morimoto, K. Sakamoto, Y. Ohnishi, T. Miyamoto, Dr. M. Ito,
Dr. T. Dohi, Dr. Y. Kita
College of Pharmaceutical Sciences, Ritsumeikan University
1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577 (Japan)
Fax: (+81)77-561-5829
Based on our previous results[12] and the recent success of
the ortho cross-coupling of methoxy arenes,[5b] we first ex-
amined the coupling reaction of 2,6-dimethoxyphenol (1a)
E-mail: kita@ph.ritsumei.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301028.
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and 1,2,4-trimethoxybenzene (2a) with the combination of
phenyliodine bis(trifluoroacetate) (PIFA) and a Lewis acid,
such as BF3·Et2O and trimethylsilyl triflate (TMSOTf;
Table 1, entries 1 and 2). However, these reaction conditions
nary organic solvents, such as toluene, diethyl ether, dime-
thoxyethane, dioxane, dichloromethane, and another fluo-
roalcohol, CF3CH2OH, were less effective than HFIP. After
the optimization process, the cross-coupling of various phe-
nols was carried out under our standard conditions (AcOH
(2 equiv), PIDA (1 equiv) as the oxidant, and HFIP as the
solvent).
Table 1. Optimization of reaction conditions.[a]
Pyrogallols are frequently found in nature[14] and their de-
rivatives recently showed the ability to assemble into struc-
tures on a multi nanometer scale that can serve specific
functions.[15] Therefore, we tested the para coupling reaction
with pyrogallol derivatives. The reaction of the phenol 1a
with various arenes (2) gave the cross-coupling products
3ab–an in good yields and the results are summarized in
Table 2. Phenol 1a reacted smoothly with various arenes, re-
Entry
Iodine
Reagent
Solvent
Additive
T
Yield [%][b]
3aa/4aa
Table 2. Substrate scope.[a,b]
[oC]
1
2
3
4
5
6
7
8
9
PIFA
PIFA
PIFA
PIFA
PIDA
HTIB
PIDA
PIDA
PIDA
CH2Cl2
CH2Cl2
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
BF3·Et2O
TMSOTf
none
BF3·Et2O
none
À78
À78
RT
RT
RT
RT
RT
RT
RT
36
24
62
55
68
trace
86
67
trace
12
17
n.d.
11
n.d.
n.d.
n.d.
n.d.
n.d.
none
CH3COOH
CH2ClCOOH
CH3SO3H
[a] PIFA=phenyliodine
bis(trifluoroacetate),
HTIB=hydroxy-
ACHTUNGTRENNUNG(tosyloxy)iodobenzene, PIDA=phenyliodine diacetate, HFIP=hexa-
fluoroisopropanol. [b] Yields of isolated product after chromatography.
were ineffective for producing the cross-coupling product
3aa and gave <20% yields of the homo-coupling product
4aa. On the other hand, a previous study in our group has
shown that a fluoroalcohol can enhance the reactivity of the
hypervalent iodine reagent.[13] Therefore, we performed the
coupling reaction of 1a and 2a with PIFA in a fluoroalcohol
at room temperature. As a result, the desired cross-coupling
product 3aa was obtained in 62% yield without forming the
homo-coupling product 4aa (Table 1, entry 3). When PIFA
with BF3·Et2O in hexafluoroisopropanol (HFIP) was em-
ployed, a small amount of the homo-coupling product 4aa
was detected (Table 1, entry 4).
To improve the yield of the coupling product 3aa, a varie-
ty of iodineACHTUNGTRENNUNG(III) reagents were evaluated. With phenyliodine
diacetate (PIDA) as an oxidant, the yield of the coupling
product 3aa (Table 1, entry 5) increased, whereas hydroxy-
[a] Reactions were carried out by adding the iodine reagent (0.2 mmol)
to a stirred solution of the phenol in (CF3)2CHOH (2 mL) in the pres-
ence of CH3COOH (0.4 mmol) at room temperature. [b] Yield of isolated
product. pin=pinacolate.
ACHTUNGTRENNUNG(tosyloxy)iodobenzene (HTIB) decreased the yield of the
3aa (Table 1, entry 6). Other hypervalent-iodine-based oxi-
dants and various oxidizing agents, such as MoCl4 and Pb-
ACHTUNGTRENNUNG(OAc)4, did not promote the desired cross-coupling reaction
and over-oxidations sometimes occurred (see the Supporting
Information).
With PIDA as the clear choice of oxidant, we examined
the role of additives. The use of AcOH increased the yield
of the coupling product 3aa to 86% (Table 1, entry 7). The
use of other Brønsted acids did not increase the yield of
coupling product 3aa (Table 1, entries 8 and 9). Other ordi-
gardless of the electronic and steric properties of the sub-
stituents, thus providing the cross-coupling products in good
yields. Notably, in the case of iodine-substituted substrate
2c, deiodination of which usually occurs under oxidative
coupling conditions,[16] the coupling reaction proceeded effi-
ciently and the corresponding coupling product 3ac was ob-
tained in 81% yield. The arylboron compound 2d, which
could be activated with metal catalysts in the Suzuki cou-
pling reaction,[3a] was well-tolerated under the present condi-
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Table 3. Substrate scope.[a]
tions. Electron-rich naphthalenes possessing either a dialky-
lamino or a methoxy substituent (2 f and 2g, respectively)
could be coupled with a phenol 1a, affording 3af and 3ag in
good yields.
For electron-poorer mesitylene (2h) only the cross-cou-
pling product 3ah was detected. When 1-methoxy-3-methyl-
benzene (2i) was used, the cross-coupling product 3ai could
be isolated as an isomeric mixture (5:2 para/meta to the
OMe group) in 75% total yield. Heteroaromatic com-
pounds, such as the thiophene 2j, indole 2k, benzofuran 2l,
and benzothiophene 2m, were found to react smoothly with
1a to furnish the corresponding coupling products, 3aj–am.
The carbazole 2n was also effective in this reaction, yielding
3an in 84% yield. In each case, no homo-coupling products
were observed.
Entry
Substrate (Phenol)
Time [h]
Yield [%][b]
1
2
3
4
R1 =Me, R2 =H (1b)
R1 =tBu, R2 =H (1c)
R1 =I, R2 =H (1d)
3
3
6
3
52
62
52
58
R1 =tBu, R2 =tBu (1e)
5
5
46
The scope of the present cross-coupling reaction was fur-
ther examined by testing various substituted phenols and
the results of these studies are presented in Table 3. Because
simple ortho-substituted phenols have frequently led to mul-
tiple arylations with metal catalysts,[11] the concentration of
phenol 1b–f in this reaction was decreased to 0.02m. Under
these conditions, the coupling products were obtained in sat-
isfactory yields without over-oxidation. The alkyl-substituted
phenols 1b and 1c, having a smaller and bulkier substituent,
respectively, gave the corresponding para-arylated products
3bh and 3ch in good yields (Table 3, entries 1 and 2). The
iodine-substituted phenol, 1d, was tolerated under the reac-
tion conditions, resulting in the desired cross-coupled prod-
uct 3dh in 52% yield (Table 3, entry 3). The naphthol, 1 f,
which is easy to over-oxidize, can also be incorporated
(Table 3, entry 5).
[a] Reactions were carried out by adding iodine reagent (0.2 mmol) to a
stirred solution of phenol in (CF3)2CHOH (10 mL) in the presence of
CH3COOH (0.4 mmol) at room temperature. [b] Yield of the isolated
product.
species are generated in the coupling process. Additionally,
when 1a was coupled with 2a in the presence of 3aa in
HFIP for 2 h as a control experiment, only phenol 1a was
completely consumed and gave the coupling product 3aa in
75% yield, whereas the added coupling product 3aa re-
mained unreacted. This result clearly indicated that PIDA
can differentiate between the two distinct phenol units of
the substrates 1 and products 3. The rapid formation of the
intermediate (A) prevented the over-oxidation of the cross-
coupling products (3).
Our coupling reaction is para selective, but reactivity is
not limited to the position para to the OH group, but also
may occur at the position ortho to the OH group when the
para position is already substituted (Table 4). Employing 2a
A plausible mechanism for the present oxidative para
coupling reaction of phenols is illustrated in Scheme 3. First,
PIDA reacts with a phenol to give intermediate A. The phe-
noxenium cation is generated
by ligand exchange followed by
reductive elimination.[17] The
phenoxenium cation intermedi-
ate reacts selectively at the
para position of arenes to give
the corresponding cross-cou-
pling products (3). On the
other hand, formation of cation
radical B[5] steers the product
distribution toward the unde-
sired homo-coupling. Therefore,
the controllable two-electron
oxidizing ability of the reagent
is important for successful
cross-coupling of phenols. We
found that for the coupling re-
action of 1a with 2a in the
presence of a radical scavenACTHNUTRGENUGgN er,
such as galvinoxyl, the yield of
the coupling product 3aa did
not decrease. This experimental
Scheme 3. Plausible reaction mechanisms for a) the cross-coupling reaction described in this work and b) the
result indicated that no radical previously described[12] single electron oxidative homo-coupling.
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Y. Kita et al.
Table 4. Cross-coupling of para-substituted phenols.[a,b]
Scheme 5. One-pot sequential arylation of a phenol.
coupling partner under our coupling conditions. We found
that the second reaction proceeded smoothly to give the un-
symmetrical terphenyl coupling product 5b in 55% yield.
In conclusion, we have developed an efficient method for
the cross-coupling of phenols with various aromatic com-
pounds. This method consists of two sequential steps, first a
cationic phenoxenium intermediate is generated with an
[a] Reactions were carried out by adding iodine reagent (0.2 mmol) to a
stirred solution of the phenol in (CF3)2CHOH (10 mL) in the presence of
CH3COOH (0.4 mmol) at room temperature. [b] Yield of the isolated
product.
iodineACHTNUTRGNE(NUG III) reagent and then the cation reacts with another
arene. As the phenol rapidly interacts with the iodine re-
agent, homo-coupling of the starting materials and over-oxi-
dation of the coupling products are avoided. The reaction
has the additional benefit of being free of metal catalysts
and not requiring prefunctionalization of the starting materi-
als. We are currently examining the scope of this reaction
with a range of phenols and related substrates and a variety
of coupling partners, with the goal of applying our method
to the synthesis of biaryls with interesting functionality and
biological activity.
with para-substituted phenols 1g–i afforded the cross-cou-
pling products 3ga–ia in good yields. Electron-rich arenes,
such as 1,3-dimethoxybenzene (2b) and 2-methoxynaphtha-
lene (2o), arylated 1g ortho to the phenol to give biaryls
3gb and 3go in moderate yields. Mesitylene (2h) was also
effective in this reaction. In all cases, the resulting coupling
products contained 1% or less contamination by other re-
gioisomers or over-oxidation products.
To further explore its applicability, we sought to combine
the controllable para and ortho arylations of phenols into an
iterative process.[18] Starting from 2-methyl phenol (1b), the
selective para-arylation produced 3bh in 52% yield, and a
second arylation added 2a at the ortho position, to give the
differentially diarylated product 5a (Scheme 4).[19]
Experimental Section
Acetic acid (0.3 mmol, 1.5 equiv) was added to a stirred solution of 1a
(0.2 mmol, 1 equiv) and 2a (0.3 mmol, 1.5 equiv) in HFIP (2 mL) and,
CH3COOH (0.4 mmol, 2 equiv) at room temperature. PIDA (0.2 mmol,
1 equiv) was subsequently added and then the mixture was stirred for an
additional 3 h under the same conditions, during which time the reaction
progress was checked by TLC. Saturated aqueous sodium hydrogen car-
bonate was added to the mixture when the reaction was complete. The
aqueous phase was extracted with CH2Cl2. The extract was dried over an-
hydrous Na2SO4 and then evaporated to dryness. The crude residue was
purified by column chromatography on silica-gel (eluent: n-hexane/ethyl
acetate) to give the pure coupling product 3aa in 86% yield.
With a cross-coupling protocol in hand, we subsequently
À
investigated two sequential one-pot C H arylation reactions
of phenol to install two different arenes (Scheme 5). 4-Me-
thoxyphenol (1h) first underwent ortho arylation, giving
3hh in 62% yield. With this intermediate, we attempted to
perform a second one-pot arylation reaction with 2a as a
Acknowledgements
This work was partially supported by
Grants-in-Aid for Scientific Research
(A) from the Japan Society for the
Promotion of Science (JSPS), a Grant-
in-Aid for Scientific Research on In-
novative Areas ꢁꢁAdvanced Molecular
Transformation by Organocatalystsꢂꢂ
from The Ministry of Education, Cul-
ture, Sports, Science and Technology
(MEXT), and the Ritsumeikan Global
Innovation Research Organization (R-
GIRO) project. K. M. also acknowl-
Scheme 4. Iterative para and ortho arylation of a phenol.
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Metal-Free Cross-Coupling of Phenols
COMMUNICATION
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Keywords: aromatic
cross-coupling
substitution
iodine
·
biaryls
phenols
·
·
·
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À
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[19] We examined the one-pot ortho and para arylations of phenol 1b. In
this case, the yield of coupling product 5a was slightly lower than
for the two-step synthesis shown in Scheme 4.
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Received: March 18, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

Y. Kita et al.
Cross-Coupling
K. Morimoto, K. Sakamoto,
Y. Ohnishi, T. Miyamoto, M. Ito,
T. Dohi, Y. Kita* ............. &&&& — &&&&
À
C C coupling: Direct oxidative cou-
reagents may also be included in this
category. The reaction proceeds under
very mild conditions without metal
catalysts in a very short time under
ambient conditions (see scheme;
HFIP=hexafluoroisopropanol).
pling reactions are an attractive tool
for environmentally benign chemistry.
The oxidative biaryl coupling reaction
of phenols with various arenes at the
para positions with hypervalent iodine
Metal-Free Oxidative para Cross-
Coupling of Phenols
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www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!