Tandem oxidation-oxidative C-H/C-H cross-coupling: Synthesis of arylquinones from hydroquinones

Article abstract of DOI:10.1039/c3cc41067f

A concise and efficient approach to arylquinones from widely available hydroquinones has been developed through a tandem reaction involving the oxidation of hydroquinones and subsequent oxidative C-H/C-H cross-coupling of the resulting quinones with arenes.

Full text of DOI:10.1039/c3cc41067f

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Tandem oxidation–oxidative C–H/C–H cross-coupling:
synthesis of arylquinones from hydroquinones†
Shuai Zhang,ab Feijie Song,*ab Dongbing Zhaoab and Jingsong You*ab
Cite this: Chem. Commun., 2013,
49, 4558
Received 7th February 2013,
Accepted 25th March 2013
DOI: 10.1039/c3cc41067f
www.rsc.org/chemcomm
A concise and efficient approach to arylquinones from widely avail-
A more efficient approach to arylquinones is probably the
able hydroquinones has been developed through a tandem reaction transition-metal-catalyzed oxidative C–H/C–H cross-coupling of
involving the oxidation of hydroquinones and subsequent oxidative quinones with arenes that does not need preactivation of each
C–H/C–H cross-coupling of the resulting quinones with arenes.
coupling partner. However, the capability of quinones to oxidize
and coordinate with transition metals10 makes this type of coupling
The quinone derivatives are widely distributed in natural challenging, and thus very limited success has been obtained in the
products1 and exhibit various biological activities.2 They are past years,11 although the transition-metal-catalyzed oxidative Heck
also involved in many bioenergetic processes due to the electron- coupling has made significant progress.12 Given the fact that many
transport properties.3 Furthermore, aryl substituted quinones are quinones are synthesized via the oxidation of hydroquinones13 and
very useful in the dye industry owing to their important coloring oxidation conditions are necessary for the oxidative C–H/C–H cross-
properties.4 Thus, the synthesis of aryl substituted quinones has coupling of quinones with arenes, we rationalized that these two
attracted significant attention and many methods have been reactions could be conducted in one pot and thus enhance the
developed. Among these, the reaction of quinones with aryl synthetic efficiency of arylquinones. Herein, we report a one-pot
radicals has become an important protocol. Traditionally, diazo- synthesis of arylquinones starting from hydroquinones through the
nium salts are used as the aryl radical sources,5 which are usually tandem reaction of oxidation of hydroquinones–oxidative C–H/C–H
unstable, synthetically difficult, and sometimes explosive. To cross-coupling of quinones with arenes (Scheme 1). It is noteworthy
address this issue, commercially available, non-toxic, and stable that the reactions can be carried out under an air atmosphere.
boronic acids are found to be ideal radical sources to react with
The reaction of 1,4-naphthalenediol 1a with benzene 2a was
quinones in the presence of catalytic amounts of AgNO3, which is used to optimize the reaction conditions (eqn (1); Table S1,
to date the most efficient, general, and mild synthetic route to ESI†). After screening various parameters, it was found that
arylquinones.6 Alternative approaches to arylquinones include oxidant, palladium species and PivOH were crucial for this
the Lewis acid-catalyzed nucleophilic addition of arenes to qui- tandem reaction to proceed smoothly. The yield of the desired
nones,7 the transition-metal-catalyzed addition of boronic acids product 2-phenyl-1,4-naphthoquinone 3a could reach 97% in
or their salts to quinones,8 and the palladium-catalyzed cross- the presence of 5 mol% Pd(acac)2, 3.0 equiv. of Ag2CO3,
coupling of halogenated quinones with boronic acids or 3.5 equiv. of DMSO, and 2.0 equiv. of PivOH using benzene as
stannanes.9 However, these addition approaches often require the solvent. The addition of DMSO was beneficial to the reaction.
an oxidation step to convert the resulting arylated hydroquinones Using more economical Cu(OAc)2, PhI(OAc)2, or O2 as oxidant
to quinones. Besides, the Lewis acid-catalyzed addition approach could not provide the desired arylquinone 3a in satisfactory yields
is limited to electron-rich arenes such as amino and/or methoxy- due to the inefficiency of the second-step oxidative coupling,
substituted arenes due to the low nucleophilicity of electron-
deficient arenes. The palladium-catalyzed cross-coupling reac-
tions require tedious prefunctionalization of both substrates.9
a Key Laboratory of Green Chemistry and Technology of Ministry of Education,
College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064,
P. R. China. E-mail: fsong@scu.edu.cn, jsyou@scu.edu.cn; Fax: +86 28-85412203
b State Key Laboratory of Biotherapy, West China Medical School,
Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data. See DOI: 10.1039/c3cc41067f
Scheme 1 The one-pot synthesis of arylquinones from hydroquinones.
c
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Table 2 The tandem reaction of various 1,4-hydroquinones with benzenea
although they could oxidize 1,4-naphthalenediol 1a to
1,4-naphthoquinone 5a.
(1)
The scope of arene coupling partners was examined next
under the optimal conditions (Table 1). Arenes with electron-rich
or neutral groups such as methyl and methoxy groups could all
couple with the in situ generated 1,4-naphthoquinone 5a to afford
the desired arylquinones in good to excellent yields (Table 1,
3b–3f). However, a moderate yield of 40% was obtained when
N,N-dimethylaniline was employed as the substrate (Table 1, 3g).
a
Reaction conditions: hydroquinone 1 (0.4 mmol), Pd(acac)2 (5 mol%),
Table 1 The scope of different arenesa
Ag2CO3 (1.2 mmol), PivOH (0.8 mmol), DMSO (1.4 mmol) and benzene
b
2a (3.0 mL) at 140 1C for 24 h. Starting from 1,4-hydroquinone.
c
d
Starting from 2-phenyl-1,4-hydroquinone. 10 mol% of Pd(acac)2,
4.0 equiv. of PivOH, 48 h.
Arenes with electron-withdrawing substituents including chloro-,
fluoro-, nitro- and trifluoromethyl groups could also provide the
desired products under the present catalytic conditions, although
10 mol% of Pd(acac)2 was often required to obtain synthetically
useful yields (Table 1, 3h–3m). 2,3-Dimethyl-1,4-hydroquinone
showed similar reactivity to 1,4-naphthalenediol 1a towards the
reaction with both electron-rich and electron-deficient arenes
(Table 1, 3n–3p). When heteroarenes such as indoles or furans
instead of arenes were subjected to the standard conditions, only
the homocoupling products of heteroarenes were obtained.14 By
decreasing the amount of heteroarenes to 2.0 equiv. and
changing the solvent to DCE, the desired heteroarylquinones
were obtained, albeit in low yields (Table 1, 3q and 3r).
Subsequently, the feasibility of this reaction to other hydro-
quinones was examined (Table 2). Besides benzannulated
hydroquinones, alkyl, aryl, and methoxy substituted hydro-
quinones could all smoothly undergo the tandem reaction of
oxidation–oxidative cross-coupling to afford the desired arylated
quinones in good to excellent yields (Table 2, 4a–4e). Interest-
ingly, the treatment of 2,6-dimethyl-1,4-hydroquinone 1f and
trimethyl-1,4-hydroquinone 1g with benzene provided the
ortho-methyl pivaloxylated arylquinones 4f and 4g under the
standard conditions, respectively. Monitoring of the reaction
mixture did not show the phenyl quinone or ortho-methyl
pivaloxylated quinone intermediates except the final product,
implying that the pivaloxyl and phenyl groups might be intro-
duced to the quinone core from the same intermediate.
The study of the mechanism was mainly focused on the
second-step oxidative C–H/C–H cross-coupling of quinones with
arenes because the oxidation of hydroquinones to quinones is
well known.13 Considering that quinones can react easily with
radicals, a radical scavenger TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy, 20 mol%) was added to the reaction mixture of
1,4-naphthoquinone 5a and benzene under standard conditions.
A slightly decreased yield of 78% was obtained, indicating that a
radical pathway might not be involved in this process.15
a
Reaction conditions: hydroquinone 1 (0.4 mmol), Pd(acac)2 (5 mol%),
Ag2CO3 (1.2 mmol), PivOH (0.8 mmol), DMSO (1.4 mmol) and arene 2
b
(3.0 mL) at 140 1C for 24 h. The ratio of two isomers was determined
using 1H NMR. 10 mol% of Pd(acac)2. 10 mol% of Pd(acac)2, 4.0 equiv.
c
d
e
of PivOH, 48 h. 2.0 equiv. of heteroarenes, 1,2-dichloroethane as solvent.
c
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cross-coupling of the resulting quinones with arenes in one
pot. Further studies to apply this methodology to the synthesis
of arylquinone-containing natural products are in progress.
We thank the National Basic Research Program of China
(973 Program, 2011CB808600) and the National NSF of China
(21202105, 21025205, 21272160, and 21021001) for their financial
support.
Scheme 2 Proposed mechanism for the oxidative C–H/C–H cross-coupling of
Notes and references
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16 For selected examples involving the alkenyl C–H cleavage, see:
In conclusion, a concise and efficient protocol for the
synthesis of arylquinones from widely available hydroquinones
has been developed. The reaction proceeds through the oxida-
tion of hydroquinones and subsequent oxidative C–H/C–H
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c
4560 Chem. Commun., 2013, 49, 4558--4560
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