FeSO4-promoted direct arylation of benzoquinones with ArB(OH)2 or ArBF3K

Article abstract of DOI:10.1016/j.tetlet.2012.12.031

FeSO₄·7H₂O was proven to work as effective promoter for the direct arylation of benzoquinones with aryl boronic acids in the presence of K₂S₂O₈. In the arylation, slow addition of iron solution was crucial to efficiently proceed with the reaction. Interestingly, the Fe-mediated arylation could be converted into a catalytic reaction by using hydroquinones, instead of benzoquinones, or addition of ascorbic acid.

Full text of DOI:10.1016/j.tetlet.2012.12.031

Tetrahedron Letters 54 (2013) 1084–1086
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Tetrahedron Letters
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FeSO4-promoted direct arylation of benzoquinones with ArB(OH)2 or ArBF3K q
⇑
Kimihiro Komeyama , Tetsuya Kashihara, Ken Takaki
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, Higashi-Hiroshima 739-8527, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
FeSO4Á7H2O was proven to work as effective promoter for the direct arylation of benzoquinones with aryl
boronic acids in the presence of K2S2O8. In the arylation, slow addition of iron solution was crucial to effi-
ciently proceed with the reaction. Interestingly, the Fe-mediated arylation could be converted into a cat-
alytic reaction by using hydroquinones, instead of benzoquinones, or addition of ascorbic acid.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 9 November 2012
Revised 7 December 2012
Accepted 10 December 2012
Available online 19 December 2012
Keywords:
Iron salt
Direct arylation
Benzoquinones
Aryl boronic acids
Electron transfer reaction
Direct arylation of the C–H bond has emerged as an atom-eco-
nomical alternative to the cross-coupling reaction between orga-
nohalides and organometallic species for the carbon–carbon bond
formation. In this field, the most promising protocol would be
the transition metal-catalyzed coupling reaction through the C–H
bond activation.1 However, most of them require the use of rare
metals and sometimes high reaction temperatures. Therefore, the
development of a more practical method for direct arylation has
been desired.
On the other hand, it is known that aryl radicals can react with
olefins to give coupling arylated products under mild conditions as
shown in Meerwein reactions.2 However, these radical reactions
generally involve the use of aryldiazonium salts, which are difficult
to prepare and handle. Very recently, Baran demonstrated the di-
rect arylation of benzoquinones and heteroarenes using aryl radi-
cals delivered from arylboronic acids by means of AgNO3/
K2S2O8.3 This method is a simple and powerful protocol for access
to mono-arylated benzoquinones, except for the use of the rare
metal like silver. Herein, we would like to report a direct arylation
of benzoquinones with arylboronic acids using the FeSO4/K2S2O8
system.4 In addition, this iron-mediated reaction can be replaced
with a catalytic process by use of hydroquinone substrates instead
of benzoquinone or participation of ascorbic acid as an additive.
First, we investigated an effect of metal complexes and oxidants
in the direct arylation of benzoquinone (1a) with phenylboronic
acid (2a). These results are summarized in Table 1. When an aque-
ous solution of FeSO4Á7H2O (1.0 equiv) was slowly added to a mix-
ture of 1a and 2a (1.5 equiv) in the presence of K2S2O8 (3.0 equiv)
by syringe pump (10 lL/min), the desired 2-phenyl-1,4-benzoqui-
none (3aa) was obtained in 68% yield within a short reaction time
(Table 1, entry 1). Other oxidants such as Na2S2O8 and (NH4)2S2O8
were not effective in this reaction (entries 2 and 3).5 The slow addi-
tion and stoichiometric amount of FeSO4Á7H2O were necessary to
efficiently proceed with this arylation. Thus, the quick addition
caused a low product yield and decomposition of 1a6 (entry 4).
The catalytic reaction (20 mol % FeSO4Á7H2O) and excess loading
of the iron (1.5–2.0 equiv) reduced the yield (entries 5 and 6). Ef-
fects of other iron and transition metal complexes like FeCl2,
Fe(OAc)2, K4[Fe(CN)6], Fe(salen), Fe(Pc), (phen)3FeSO4, CuSO4,
CoSO4, MnSO4, and NiSO4 were examined, but they were not effec-
tive for the direct arylation (entries 7–16). In this reaction, the
addition of water was necessary to dissolve the persulfate oxidant.
Organic solvents such as chlorobenzene, dichloromethane, ben-
zene, and acetonitrile were also effective to afford the product
3aa in 68%, 60%, 48%, and 38% yields, respectively. But dimethyl
sulfoxide and N,N-dimethylformamide afforded the product in
low yields (<1% yield).
With optimized conditions on hand, the scope of arylboronic
acids for the present iron-mediated direct arylation of 1a was
investigated as summarized in Chart 1. Me, MeO, and halogen sub-
stituents were well tolerated, leading to mono-arylated benzoqui-
nones 3ab–3ak. Similar to the arylboronic acids, aryl potassium
trifluoroborates (ArBF3K) were also effective, in which the corre-
sponding arylated benzoquinones 3aa and 3af were provided in
slightly higher yields than boronic acids. However, aryl pinacol
borates and their boroxines did not participate in the reaction. In
all reactions, bi-and multi-arylated benzoquinones were not
q
Part of this work was presented at the 59th Symposium on Organometallic
Chemistry, Japan, Osaka, September 13–15, 2012, abstracts P3A-07.
⇑
Corresponding author. Tel.: +81 82 424 7747; fax: +81 82 424 5494.
E-mail address: kkome@hiroshima-u.ac.jp (K. Komeyama).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.031

K. Komeyama et al. / Tetrahedron Letters 54 (2013) 1084–1086
1085
Table 1
3an. Unfortunately, similar substituents {CN, NO2, CF3, CO2Me,
C(O)Me} at the para- and ortho-positions completely prevented
the reaction, in which these aryl boronic acids or potassium triflu-
oroborates remained unchanged after the reaction. Additionally,
the coupling reaction with styryl and phenylethynyl potassium tri-
fluoroborates failed under similar conditions. Especially, in the lat-
ter transformation a Csp–Csp coupling exclusively occurred to
afford 1,4-diphenyl-1,3-diyne in 30% yield.8
Screening of reaction conditions for the direct arylation of 1a with 2aa
Entry
Metal complex (x)
Oxidant
Yield of 3aab (%)
Next, we examined the compatibility of benzoquinone deriva-
tives as depicted in Chart 2. This arylation favored electron-rich
benzoquinones 1b, 1c, and 1g rather than electron-deficient ones
1d and 1e. Mono-substituted benzoquinone like 1g was converted
into a mixture of regioisomers 3ga, in which the arylation mainly
occurred at the less sterically hindered 5- and 6-positions of the
benzoquinone skeleton. Maleimide 1h proved to be a viable sub-
strate, providing the 3-phenyl maleimide 3ha.9
1
2
FeSO4Á7H2O (1.0)
FeSO4Á7H2O (1.0)
FeSO4Á7H2O (1.0)
FeSO4Á7H2O (1.0)
FeSO4Á7H2O (0.2)
FeSO4Á7H2O (1.5-2.0)
FeCl2Á7H2O (1.0)
Fe(OAc)2 (1.0)
K4[Fe(CN)6] (1.0)
Fe(Salen)d (1.0)
Fe(Pc)e (1.0)
Fe(Phen)3SO4 (1.0)
CuSO4 (1.0)
CoSO4 (1.0)
MnSO4 (1.0)
NiSO4 (1.0)
K2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
68
20
0
28
30
25–44
20
12
12
8
2
8
8
4
1
2
3
4c
5
6
7
8
9
10
11
12f
13
14
15
16
According to these experimental results, a plausible pathway of
the iron-mediated direct arylation of benzoquinone is proposed in
Scheme 1. A single electron transfer of Fe2+ to S2O82À producing sul-
fate radical (SOÁ4À) could initiate the transformation with a libera-
tion of SO24À and Fe3+ as the well-established Fenton process
(step a).10 The generated SOÁ4À would react with aryl boronic acids
2 to give the aryl radical species (step b),3 whose aryl radical gen-
eration has been well studied theoretically and experimentally.11
The aryl radical could attack benzoquinones 1, leading to the inter-
mediate A (step c). Sequent oxidation and deprotonation of A
would provide the arylated benzoquinone 3 (step d). SOÁ4À rather
than Fe3+ species would act as oxidant in this step. Thus, if the
a
An aqueous solution of metal complex was slowly added to the mixture of 1a
(0.25 mmol), 2a (0.38 mmol), and oxidant (0.75 mmol) by syringe pump (10 L/min).
b
GC yield.
c
Aqueous solution of FeSO4Á7H2O was quickly added.
d
Fe(Salen) = Fe(II) N,N-bis(salicylaldehyde)ethylenediamine.
e
Fe(Pc) = Iron(II) phthalocyanine.
Phen = 1,10-phenanthroline. 1.0 mol/L solution was used.
f
intermediate A reduces Fe3+ or S2O2À to give Fe2+ or SOÁ4À, respec-
8
detected.7 In contrast, strong electron-deficient arylboronic acids
possessing NO2, CF3, and C(O)Me groups at the meta-position on
the phenyl ring afforded lower yields of products 3al, 3am, and
tively, the present reaction would be performed by the catalytic
amount of the iron. Furthermore, in the control experiment, we
confirmed that SOÁ4À works as an oxidant of A, 12 that is, the reaction
of 1a and 2a with K2S2O8 proceeded at the elevated temperature
(80 °C), giving rise to the corresponding arylated quinone 3aa, al-
beit in low yields (20%). This experimental result would suggest
a possibility of the oxidation process of A with SO4ÁÀ
.
On the other hand, it is known that Fe3+ can be reduced to form
Fe2+ with suitable reductants such as hydroquinones or ascorbic
acid (Vitamin C).13 Therefore, we envisioned that the addition of
such reductants into the reaction media might be able to replace
the iron-mediated direct arylation to a catalytic one. Based on
Chart 1. Compatibility of aryl boronic acids 2.
Chart 2. Compatibility of benzoquinone 2 and its derivative.

1086
K. Komeyama et al. / Tetrahedron Letters 54 (2013) 1084–1086
of FeSO4Á7H2O and K2S2O8. Moreover, this iron-mediated arylation
could be changed to the catalytic reaction by the replacement of
benzoquinones to hydroquinones as substrates or the addition of
ascorbic acid as reductants. The present protocol, therefore, is
anticipated to be a useful method for the synthesis of aryl benzo-
quinones that are important as pharmacophores with high biolog-
ical activity and as building blocks for natural products.15
Investigation of the mechanistic detail and synthetic applications
of the iron-mediated and -catalyzed radical reaction is in progress.
Acknowledgments
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan. K.K. also acknowledges financial
support for General Sekiyu R & D Encouragement Assistance Foun-
dation. Finally, we thank Professor Manabu Abe (Faculty of Science,
Hiroshima University) for useful discussion on this reaction.
Scheme 1. Plausible reaction mechanism of the iron-mediated direct arylation of
benzoquinones with aryl boronic acids.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.031.
Scheme 2. Iron-catalyzed direct arylation of hydroquinones.
References and notes
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Scheme 3. Iron-catalyzed direct arylation of benzoquinones in the presence of
ascorbic acid.
4. After construction of this paper, we became aware that a research closely
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5. Compared with K2S2O8 and Na2S2O8, (NH4)2S2O8 was highly dissolved in the
reaction media.
these hypothesis, when 1,4-dihydroquinones 4a and 4h, instead of
the corresponding benzoquinones, were treated with FeSO4Á7H2O
catalyst (20 mol %) in the presence of PhB(OH)2 and K2S2O8
(6.0 equiv), the mono-arylated benzoquinones 3aa and 3ha were
obtained in good yields (Scheme. 2). In these reactions, all of the
hydroquinones were converted to the arylated benzoquinones 3
or the naked benzoquinones 1, that is, no remaining hydroqui-
nones were detected after the reaction. Additionally, ascorbic acid
also worked well for the construction of similar catalytic reactions
(Scheme 3), wherein the aryl benzoquinone were provided in good
yields. In the above two types of catalytic reactions, the absence of
the iron afforded traces of the arylated products (<5% yield). The
NMR monitoring of the reaction of 1a with ascorbic acid (25 °C
in CDCl3) indicated the formation of hydroquinone 4a in about
20% yield, albeit with longer reaction times (12 h).14 Although
the role of ascorbic acid in this catalytic reaction might be a reduc-
tion of benzoquinone 3 to form hydroquinone 4, which is an active
reductant of Fe3+ (vide supra), the reduction process of Fe3+ to Fe2+
with ascorbic acid would not be excluded at present.
6. Treatment of 1a with FeSO4Á7H2O and K2S2O8 in the absence of 2a resulted in
60% consumption of 1a.
7. The arylation of the isolated 3aa under similar conditions did not proceed.
8. Martelli, G.; Spangnolo, P.; Tiecco, M. J. Chem. Soc. B 1966, 877.
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Chem. 1977, 42, 832; (b) Giordano, C.; Bellli, A. J. Org. Chem. 1979, 44, 2314.
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In conclusion, we have developed the practical method for the
direct mono-arylation of benzoquinones using the combination