Construction of substituted benzene rings by palladium-catalyzed direct cross-coupling of olefins: A rapid synthetic route to 1,4-naphthoquinone and its derivatives

Article abstract of DOI:10.1002/anie.201103380

Ring the changes: The direct cross-coupling of electron-deficient 1,4-benzoquinone or its derivatives with electron-rich alkyl vinyl ethers proceeds in a tandem manner to produce substituted benzene rings with good selectivity and in good to excellent yields (see scheme). The reaction has the potential for the rapid synthesis of diverse substituted benzene rings as it is not limited by substituent effects. Copyright

Full text of DOI:10.1002/anie.201103380

Communications
DOI: 10.1002/anie.201103380
Cross-Coupling
Construction of Substituted Benzene Rings by Palladium-Catalyzed
Direct Cross-Coupling of Olefins: A Rapid Synthetic Route to
1,4-Naphthoquinone and Its Derivatives**
Peng Hu, Shijun Huang, Jing Xu, Zhang-Jie Shi,* and Weiping Su*
Dedicated to Professor Christian Bruneau on the occasion of his 60th birthday
Benzene rings can be found in about 30% of all industrial
chemicals and in over half of the top 50 drugs.[1] This fact
clearly illustrates the immense scientific and commercial
value of aromatic compounds in modern society. These
compounds usually bear more than one substituent on the
benzene ring, and are traditionally constructed by the
stepwise introduction of substituents through electrophilic
aromatic substitution (Scheme 1a). Because the substituents
on benzene rings strongly influence both the reactivity of the
rings toward further substitution and the orientation of that
substitution, careful choice of the reagents and the synthetic
route is crucial to achieve high regioselectivities in the
syntheses of polysubstituted benzene rings. Furthermore, in
cases in which the substitution pattern of an aromatic
compound would direct new substituents into the wrong
positions, tedious synthetic routes that involve conversion
and/or protection–deprotection of functional groups are often
required to access the desired products. An alternative
approach to polysubstituted benzene rings is the transition-
metal-catalyzed [2+2+2] cyclotrimerization of alkynes.[2] This
route has the advantage of the rapid construction of highly
functionalized molecular frameworks in one step compared
with electrophilic aromatic substitution reactions (Sche-
me 1a). By using this strategy, intermolecular reactions
provide a versatile tool for the ring synthesis of complex
molecular products.[2a] However, intermolecular three-com-
ponent cross-coupling reactions of alkynes are strictly
restricted to specific substrates, and in most cases suffer
from a lack of control of chemo- and regioselectivity.[2b]
The metal-catalyzed direct functionalization of aromatic
À
À
carbon hydrogen (C H) bonds is emerging as an effective
means for the elaboration of arenes.[3–6] Despite significant
advances in this field, the vast majority of metal-catalyzed
À
aromatic C H functionalization reactions have focused on
[3a–f]
C H arylation
and C H olefination,[3h,6a] and intermolec-
À
À
Scheme 1. a) Existing synthetic routes to substituted benzene rings.
Route a: stepwise introduction of substituents to benzene through
À
ular reactions for the transformation of C H bonds into
À
À
À
À
carbon heteroatom bonds such as C O and C N bonds are
mainly limited to benzene derivatives that bear pyridyl
electrophilic aromatic substitution or C H functionalization; route b:
[2+2+2] cycloaddition of alkynes. b) Construction of substituted
groups,[6b,c] and heterocycles (such as azoles) that bear acidic
benzene rings by cross-coupling of olefins: direct conversion of olefinic
À
À
C H bonds to C C bonds.
[6d]
À
C H bonds.
Both electrophilic aromatic substitution reactions and
À
metal-catalyzed aromatic C H functionalization reactions
[*] P. Hu, S. Huang, J. Xu, Prof. W. Su
State Key Laboratory of Structural Chemistry
Fujian Institute of Research on the Structure of Matter
Chinese Academy of Sciences
produce benzene derivatives by modifying parent aromatic
rings, and thus depend on the nature of the existing
substituents. Our interest in the rapid synthesis of substituted
benzene rings with diverse substituents and substitution
patterns led us to question whether a direct cross-coupling
of olefins to generate polysubstituted benzene rings through
Yangqiao West Road 155, Fuzhou, Fujian 350002 (China)
E-mail: wpsu@fjirsm.ac.cn
Prof. Z.-J. Shi
College of Chemistry, Peking University
Beijing 100871 (China)
E-mail: zshi@pku.edu.cn
À
À
the conversion of olefinic C H bonds to C C bonds might be
possible (Scheme 1b). This cross-coupling reaction of three
olefin components would result in substituted products
through the actual formation of benzene rings, therefore
presenting a fundamentally new approach for the construc-
tion of these compounds. However, achievement of this target
reaction with high selectivity remains a great challenge
because the successive cross-coupling of olefins would be
required in this process. Even the metal-catalyzed direct
[**] Financial support from the 973 Program (2011CB932404,
2011CBA00501), the NSFC (20821061, 20925102), the “Distin-
guished Overseas Scholar Project”, the “One Hundred Talent
Project”, the Knowledge Innovation Program of CAS, and the Key
Project of CAS is greatly appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103380.
9926
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9926 –9930

coupling between two different olefin components has hardly
been developed, though this reaction provides a highly
efficient approach to a diene moiety that is commonly
found in naturally occurring compounds. Only four examples
of metal-catalyzed cross-coupling of olefins to dienes have
been reported since Ishii and co-workers presented the first
example in 2004.[7] The paucity of methods for the catalytic
cross-coupling of olefins indicates the difficulty for olefins to
undergo this type of transformation. In addition to the
reactivity issue, another challenge in achieving the cross-
coupling of three olefin components is the control of
selectivity. All the reported metal-catalyzed cross-coupling
reactions of olefins produce the dimerization products with-
out further incorporation of the third olefin component into
the molecular framework. For example, ruthenium- or
rhodium-catalyzed couplings of two different olefins results
construction of benzene rings. This method allows the
reaction to occur under mild conditions, and is compatible
with a broad range of functional groups. Notably, no product
from olefin dimerization was detected in the crude reaction
mixture, thus illustrating that this cross-coupling reaction of
olefins to produce benzene rings proceeds in a domino
manner.
Initially, the reaction of 1,4-benzoquinone (1a) with
cyclohexyl vinyl ether (2a) was chosen as a model reaction
for optimization of the reaction conditions. The product of
this model reaction, 6-cyclohexyloxy-1,4-naphthoquinone
(3a), was characterized by NMR spectroscopy and X-ray
single-crystal diffraction analysis;[9] the results confirmed that
the cross-coupling of olefins to substituted benzene ring was
accompanied by loss of an alkoxyl group. Avariety of reaction
parameters were observed to have an impact on the efficiency
of this reaction. Among the palladium sources that were
examined, Pd(OAc)2 afforded the best catalytic reactivity.
Control experiments showed that palladium sources were
indispensable for this reaction to occur. In contrast, other
additives, such as silver salts, were not crucial to achieve
catalytic turnover. For example, the reaction of two equiv-
alents of 1a with 2a, in which 1a acted as both the reagent and
the oxidant, provided 3a in 44% yield in the absence of
AgOAc. However, addition of AgOAc or a combination of
Ag2CO3 with carboxylic acids considerably enhanced the
turnover when 1a was the limiting reagent. Other oxidants
that were commonly used for reoxidation of Pd0 to PdII, for
example, various CuII salts, also worked for this reaction but
were inferior to AgOAc.[9] A survey of solvents showed that
coordinating DMSO was required for this reaction to occur.
However, the introduction of DMF or 1,2-dimethoxyethane
(DME) as a cosolvent with DMSO significantly improved this
reaction compared with the use of DMSO alone, and the
variation of concentration of DMSO in a mixed solvent
influenced the reaction outcomes. The optimum reaction
medium was found to be 5% (v/v) DMSO in DMF. These
observations suggested that a palladium complex with DMSO
as the ligand may be involved in the catalytic process. This
hypothesis was supported by the fact that replacement of
DMSO with its analogue tetramethylene sulfoxide gave a
comparable result. The combination of these efforts estab-
lished that the best yield of 3a (64%) could be achieved by
the reaction of 1a with four equivalents of 2a conducted in a
mixed solvent of DMSO in DMF (5% v/v) at 608C for 12 h
with 8 mol% Pd(OAc)2 as a catalyst and six equivalents of
AgOAc as an oxidant (Scheme 3).[10]
À
in the alkylation of one coupling partner by addition of a C H
[8]
=
bond across a C C double bond, and palladium-catalyzed
reactions generate diene compounds.[7] Therefore, the key to
constructing substituted benzene rings by cross-coupling of
olefins is to identify an active catalyst system that is capable of
catalyzing the cross-coupling of olefins in a domino manner.
There are two possible ways to achieve this goal: 1) the
catalyst system preferentially promotes the reaction of diene
B with an olefin rather than the initial formation of diene B
(path A, Scheme 2); 2) the catalyst system enables the olefin
Scheme 2. Construction of substituted benzene rings by cross-coupling
of olefins.
to intercept intermediate A prior to its b-hydrogen elimina-
tion (path B, Scheme 2). For path B, a strategy to intercept
intermediate A is the use of a cyclic olefin as one of the
coupling partners. The metal/cycloalkyl-complex intermedi-
ate derived from the cyclic olefin through the carbometala-
tion of the double bond is reluctant to form a syn-coplanar
conformation for b-hydrogen elimination and consequently
reacts with an additional olefin molecule.
Herein, we verify the feasibility of the catalytic cross-
coupling of olefins to furnish substituted benzene rings with
high selectivity. A versatile catalyst system has been devel-
oped for the direct coupling of electron-deficient cyclic olefins
(1,4-benzoquinone or its derivatives) with electron-rich
olefins (alkyl vinyl ethers) to produce alkoxy-substituted
1,4-naphthoquinones or 9,10-anthraquinones through the
With the optimized reaction conditions established, we
next examined the generality of this transformation. As
shown in Scheme 3, both mono- and disubstituted 1,4-
benzoquinones underwent smooth coupling with 2a to form
the desired products in good yields (3b–3e). Reactions of
monosubstituted 1,4-benzoquinones resulted in a regioiso-
meric mixture of 6- and 7-substituted 1,4-naphthoquinones
with 6-substituted isomers as main products. Interestingly, the
regioselectivity toward 6-substituted products could be
improved by increasing the steric bulk of the substituents in
monosubstituted 1,4-benzoquinones, as illustrated by a com-
parison between the yields of 2-tert-butyl-1,4-benzoquinone
Angew. Chem. Int. Ed. 2011, 50, 9926 –9930
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9927

Communications
tionally simple. As a result, the reaction reported here will
find applications in organic synthesis.
Inspired by the fact that the cross-coupling of olefins to
substituted benzene rings occurred between two electroni-
cally different olefins, we further expanded the substrate
scope of this reaction. As an electron-rich olefin, N-vinyl-2-
pyrrolidone (2p) reacted with 1a to produce the correspond-
ing product 3u in 36% yield [Eq. (1)]. N-phenylmaleimide
(1g) could serve as an electron-deficient olefin in the cross-
coupling reaction with 2d, although 3v was produced in much
lower yield [Eq. (2)]. Our attempts to improve the yields of
these reactions failed at this stage.
Scheme 3. Substrate scope of Pd-catalyzed direct cross-coupling of
olefins for the synthesis of substituted benzene rings. Yields of
isolated products are given. The 6-substituted products 3b, 3c, and
3d were formed together with their corresponding 7-substituted
isomers 3b’, 3c’, and 3d’ (3b/3b’=2:1, 3c/3c’=5:1, 3d/3d’=6:1).
DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide, Piv=
pivaloyl.
Because the cross-coupling of olefins to substituted
benzene rings is similar to the Nenitzecu indole synthesis
with respect to the selectivity and the nature of the
reactants,[14] it is reasonable to assume that these two
reactions share common elementary steps in the initial
stages of their catalytic cycles. As in the Nenitzecu indole
synthesis, the cross-coupling reaction could be initiated by a
palladium-promoted conjugate addition of an electron-rich
vinyl ether to 1,4-benzoquinone to generate intermediate H
(Scheme 4); the Pd salt would act as a Lewis acid catalyst in
(3d) and 2-methyl-1,4-benzoquinone (3b). As a coupling
partner, 1,4-naphthoquinone exhibited an excellent reactivity
in the direct cross-coupling of olefins to substituted benzene
rings (3 f). This reaction tolerated a broad range of substrates
with regard to alkyl vinyl ethers (3g–3t), and was compatible
with a variety of functional groups on the alkyl portion of
alkyl vinyl ethers; these groups include trifluoromethyl,
chlorine, fluorine, alkene, ether, ester, and amide. Although
good yields were generally obtained with the examined alkyl
vinyl ethers, the observed effects that functional groups had
on the reactivity of alkyl vinyl ethers were presumably a result
of the electronic factors. For instance, alkyl vinyl ethers with
aryl groups at the b position of the ether linkage afforded
higher yields than ethers with aryl groups at the a position of
the ether linkage (3n versus 3o).
this reaction.[15] Olefin insertion into the Pd C bond in
À
intermediate H followed by Pd–OR elimination and depro-
tonation would lead to the formation of p-allyl–palladium
complex K, which could undergo intramolecular olefin
insertion via its tautomer L and subsequent b-hydrogen
elimination to form intermediate N. Finally, oxidative dehy-
drogenation of intermediate N would take place to form the
product. Intermediate N may form 1,4-naphthoquinone by
elimination of ROH, thus explaining the observation that 1,4-
naphthoquinone or 9,10-anthraquinone are generated as side
products in these transformations (less than 2% yield in all
cases).
The obtained products, both alkoxy-substituted 1,4-naph-
thoquinones and 9,10-anthraquinones, are prevalent as build-
ing blocks in natural products.[11] Additionally, nickel- or
To support the mechanistic hypothesis, we carried out the
reaction of 1,4-benzoquinone with isobutyl vinyl ether at
varied temperatures. We anticipated that the reactions at low
temperatures may be slow and thus allow us to capture
reaction intermediates. GC–MS analysis[9] showed that the
reaction that was run for 12 h at room temperature produced
À
palladium-catalyzed cross-coupling through C O bond cleav-
age allows these products to be further elaborated.[12]
Compared with the Dçtz benzannulation reaction,[13] which
produces a substituted hydroquinone by using stoichiometric
amounts of toxic chromium carbenes, our protocol is opera-
9928 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9926 –9930

and its derivatives with a variety of electron-rich vinyl ethers.
These reactions occur under mild conditions and furnish
substituted benzene rings with high selectivity and in good
yields. This work provides the first example of the direct
cross-coupling of olefins to substituted benzene rings, and
may open up new routes for the synthesis of the latter
compounds. Ongoing work is focused on expanding the scope
of this transformation with respect to both electron-rich and
electron-deficient olefins.
Scheme 4. Proposed mechanism for Pd-catalyzed cross-coupling of
olefins to substituted benzene rings.
not only the target compound 3i but also the two by-products
5h and 5j [Eq. (3)]. Compound 5h may derive from the
intermediate H by Pd–H elimination and subsequent hydro-
Experimental Section
In a glove box, a 25 mL tube equipped with a stirrer bar was charged
with Pd(OAc)2 (0.02 mmol), 1,4-benzoquinone (0.2 mmol), AgOAc
(1.2 mmol or 1.4 mmol), vinyl ethers (0.8 mmol or 1.2 mmol), DMSO
(0.1 mL), and DMF (2 mL). The tube was fitted with a Teflon screw
cap and removed from the glove box. The reaction mixture was
stirred at 60–908C for 12–24 h. After cooling, the reaction mixture
was diluted with diethyl ether (10 mL) and filtered through a pad of
silica gel, which was then washed with the same solvent (20–50 mL).
The filtrate was washed with saturated aqueous solution of NaCl
(30 mL). The organic phase was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was then purified
by column chromatography on silica gel with 3–30% diethyl ether in
hexane as eluent to provide the corresponding product.
Received: May 17, 2011
Revised: July 22, 2011
Published online: August 31, 2011
lysis. Compound 5j may derive from the intermediate J by
demetalation and hydrogenation. These two by-products,
which were closely related to the above-mentioned reaction
intermediates, provided circumstantial evidence for the
proposed mechanism. Compound 5h was also observed in
the reaction of 1a with 2d at room temperature when
10 mol% of other Lewis acids such as ZnCl2 and AgOTf were
used in place of Pd(OAc)2 and AgOAc.[9] In addition, the
reaction of 1a with 1,4-butanediol divinyl ether (2q) afforded
four products [Eq. (4)], and the formation of 3w and 3x
clearly illustrated the fate of one of the alkoxy groups of
alkoxy vinyl ethers; the group was liberated as ROH during
the reaction, a result that was consistent with the mechanistic
hypothesis.
Keywords: benzoquinones · cross-coupling · olefins ·
.
palladium · vinyl ethers
[1] R. E. Maleczka, Jr., Science 2009, 323, 1572.
[2] a) S. Saito, Y. Yamamoto, Chem. Rev. 2000, 100, 2901; b) B. R.
Galan, T. Rovis, Angew. Chem. 2009, 121, 2870; Angew. Chem.
Int. Ed. 2009, 48, 2830; c) for a recent example, see: A.
Jeevanandam, R. P. Korivi, I.-W. Huang, C.-H. Cheng, Org.
Lett. 2002, 4, 807.
[3] a) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 949; b) X. Chen,
K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121,
5196; Angew. Chem. Int. Ed. 2009, 48, 5094; c) T. W. Lyons, M. S.
Sanford, Chem. Rev. 2010, 110, 1147; d) G. Brasche, J. Garcia-
In summary, we have established the palladium-catalyzed
direct cross-coupling of electron-deficient 1,4-benzoquinone
Angew. Chem. Int. Ed. 2011, 50, 9926 –9930
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9929

Communications
Fortanet, S. L. Buchwald, Org. Lett. 2008, 10, 2207; e) O.
[7] a) Y. Hatamoto, S. Sakaguchi, Y. Ishii, Org. Lett. 2004, 6, 4623;
b) M. Li, L. Li, H. Ge, Adv. Synth. Catal. 2010, 352, 2445; c) Y.-
H. Xu, J. Lu, T.-P. Loh, J. Am. Chem. Soc. 2009, 131, 1372;
d) H. F. Yu, W. W. Jin, C. L. Sun, J. P. Chen, W. M. Du, S. B. He,
Z. K. Yu, Angew. Chem. 2010, 122, 5928; Angew. Chem. Int. Ed.
2010, 49, 5792.
[8] a) B. M. Trost, K. Imi, I. W. Davies, J. Am. Chem. Soc. 1995, 117,
5371; b) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am. Chem.
Soc. 2006, 128, 5604.
Daugulis, V. G. Zaitsev, D. Shabashov, Q.-N. Pham, A. Lazareva,
Synlett 2006, 3382; f) L.-C. Campeau, D. R. Stuart, K. Fagnou,
Aldrichimica Acta 2007, 40, 35; g) D. A. Colby, R. G. Bergman,
J. A. Ellman, Chem. Rev. 2010, 110, 624; h) Y. Yokota, M. Tani,
S. Sakaguchi, Y. Ishii, J. Am. Chem. Soc. 2003, 125, 1476; i) P.
Gandeepan, K. Parthasarathy, C.-H. Cheng, J. Am. Chem. Soc.
2010, 132, 8569.
[4] a) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2008, 130, 1128;
b) Y. Wei, H. Zhao, J. Kan, W. Su, M. Hong, J. Am. Chem. Soc.
2010, 132, 2522; c) Y. Wei, W. Su, J. Am. Chem. Soc. 2010, 132,
16377; d) D. Garcꢀa-Cuadrado, A. A. C. Braga, F. Maseras,
A. M. Echavarren, J. Am. Chem. Soc. 2006, 128, 1066.
[5] a) J.-Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka, Jr., M. R.
Smith III, Science 2002, 295, 305; b) J. M. Murphy, X. Liao, J. F.
Hartwig, J. Am. Chem. Soc. 2007, 129, 15434; c) R. J. Phipps,
M. J. Gaunt, Science 2009, 323, 1593; d) Y.-H. Zhang, B.-F. Shi,
J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 5072; e) D. R. Stuart, K.
Fagnou, Science 2007, 316, 1172; f) S.-D. Yang, C.-L. Sun, Z.
Fang, B.-J. Li, Y.-Z. Li, Z.-J. Shi, Angew. Chem. 2008, 120, 1495;
Angew. Chem. Int. Ed. 2008, 47, 1473.
[9] See the Supporting Information for details.
[10] An excess of the vinyl ether was required to afford a good yield,
presumably because the vinyl ether decomposed under the
reaction conditions. The best results were obtained when four
equivalents of the vinyl ether were used. Optimization studies
showed that six equivalents of AgOAc were required to obtain
the best yield, and that the use of less than six equivalents of
AgOAc decreased the yields significantly, presumably because
several Pd0–PdII oxidation cycles were involved in this reaction.
See the Supporting Information for details.
[11] a) I. Fujii, Y. Ebizuka, Chem. Rev. 1997, 97, 2511; b) M. Isaka, P.
Kittakoop, K. Kirtikara, N. L. Hywel-Jones, Y. Thebtaranonth,
Acc. Chem. Res. 2005, 38, 813.
[12] D.-G. Yu, B.-J. Li, Z.-J. Shi, Acc. Chem. Res. 2010, 43, 1486.
[13] K. H. Dçtz, Angew. Chem. 1975, 87, 672; Angew. Chem. Int. Ed.
Engl. 1975, 14, 644.
[6] a) For a recent example, see: K. M. Engle, D.-H. Wang, J.-Q. Yu,
J. Am. Chem. Soc. 2010, 132, 14137; b) for a recent example of
À
pyridyl-directed intermolecular C O bond formation, see: A. R.
Dick, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2004, 126,
2300; c) for a recent example of functional-group-directed
[14] G. R. Allen, Jr., Org. React. 1973, 20, 337.
À
intermolecular C N bond formation, see: H. Y. Thu, W. Y. Yu,
C. M. Che, J. Am. Chem. Soc. 2006, 128, 9048; d) H. Zhao, M.
Wang, W. Su, M. Hong, Adv. Synth. Catal. 2010, 352, 1301.
[15] N. Asao, T. Nogami, K. Takahashi, Y. Yamamoto, J. Am. Chem.
Soc. 2002, 124, 764.
9930 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9926 –9930