Unprecedented ortho-acylation of azoxybenzenes with α-oxocarboxylic acids by Pd-catalyzed C-H activation and decarboxylation

Article abstract of DOI:10.1039/c3cc45492d

A palladium-catalyzed ortho-acylation reaction of azoxybenzenes with α-oxocarboxylic acids was developed in the presence of K₂S ₂O₈. The established methodology provides a direct approach to obtain acylated azoxybenzenes in good yields.

Full text of DOI:10.1039/c3cc45492d

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Unprecedented ortho-acylation of azoxybenzenes with
a-oxocarboxylic acids by Pd-catalyzed C–H activation
and decarboxylation†
Cite this: Chem. Commun., 2013,
49, 9170
Received 19th July 2013,
Accepted 5th August 2013
Hongji Li,a Pinhua Li,a Qiong Zhaoa and Lei Wang*ab
DOI: 10.1039/c3cc45492d
www.rsc.org/chemcomm
A palladium-catalyzed ortho-acylation reaction of azoxybenzenes with
a-oxocarboxylic acids was developed in the presence of K2S2O8.
The established methodology provides a direct approach to obtain
acylated azoxybenzenes in good yields.
Scheme 1 Resonance structures for azoxybenzenes.
Transition metal-catalyzed C–H bond activation and functionaliza-
tion1 in recent years have been broadly explored for the efficient materials in electronic devices because of their liquid crystalline
construction of complex molecules and natural products.2 In parti- properties12 and have also been used as polymer inhibitors, stabilizers
cular, the employment of directing groups in substrates can facilitate and dyes.13 In spite of numerous methods for the preparation of azoxy
C–H activation and control the reaction selectivity, because the compounds being developed,14 reports on the synthesis of sterically
function group often binds with transition metal to form an active hindered ortho-acylated azoxybenzenes are rare.
species which can furnish the catalytic cycle.3 The utilization of
As far as we know, the azoxy group has never been studied in
directing groups in transition metal-catalyzed C–H activation has group-directed C–H activation. It should be noted that two kinds of
been successfully applied in construction of C–C and C–heteroatom potential C–H bonds exist in the azoxybenzene, which may be
bonds, and these groups mainly include pyridines, azobenzenes, involved in the subsequent C–H functionalization (Scheme 2). Hence,
amides, oximes, alcohols, amines, carboxylic acids, esters, aldehydes, the control of C–H activation and functionalization is extremely
ketones, nitriles, triazenes, alkenes and so on.4 Presently, we success- challenging in azoxybenzenes. As part of our ongoing interest in
fully realized the ortho-C–H functionalization of azobenzenes.4o Based C–H activation and decarboxylation reaction,4o,15 we herein report
on these findings, we envisioned that the azoxy compounds, with two the first Pd-catalyzed site-selective ortho-acylation of azoxybenzenes
proposed resonance structures (Scheme 1),5 can also provide a with a-oxocarboxylic acids under mild reaction conditions.
coordinating site (oxygen or nitrogen) to complex with transition
Initially, we examined the model acylation of azoxybenzene (1a)
with 2-oxo-2-phenylacetic acid (2a) in DCE using Pd(OAc)2 as catalyst
metal4 and enable the next ortho-C–H bond functionalization.
We recently noted that the decarboxylative cross-coupling reac- at 60 1C for 24 h, as shown in Table S1 (ESI†). We found that the
tions, involving readily available carboxylic acids as coupling partners, acylated product 3a was isolated in 16% yield when using (NH4)2S2O8
have been paid much attention in organic synthesis.6,7 For example, as an oxidant (Table S1, entry 1). Gratifyingly, 72% yield of 3a was
Myers,7a,b Goossen,7c–g Li,7h Liu7i and Miura7j completed the obtained in the presence of K2S2O8 (entry 2). However, the use of
decarboxylative biaryl coupling, alkynylation, olefination and Cu(OAc)2 as an oxidant did not improve the yield of 3a (entry 3). Other
ketone formation. Most recently, Ge,8 Duan,9 Kim10 and Tan11 inorganic oxidants, such as AgOAc and Mn(OAc)3, were found to be
developed the decarboxylative acylation of unactivated arenes with ineffective in the reaction (entries 4 and 5). Meanwhile, it was also
a-oxocarboxylic acids via group-directed C–H activation and function- found that TBHP (tert-butyl hydroperoxide) or DTBP (di-tert-butyl
alization. Additionally, it is well known that azoxy compounds are key peroxide) could not promote the reaction (entries 6 and 7). When
the reaction was performed under 1.0 atm of an oxygen atmosphere,
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000,
P R China. E-mail: leiwang@chnu.edu.cn; Fax: +86-561-309-0518;
Tel: +86-561-380-2069
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China
† Electronic supplementary information (ESI) available. CCDC 950406. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc45492d
Scheme 2 Site-selective ortho-acylation of azoxybenzenes with a-oxocarboxylic acids.
c
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3a was isolated in 30% yield (entry 8). The effect of the palladium a-oxoarylcarboxylic acids were used as substrates in the reaction
source on the reaction was also examined, and the results demon- (3d vs. 3k, 3e vs. 3h, and 3g vs. 3i). However, when azoxybenzene
strated that Pd(TFA)2 gave lower yield of 3a, compared with Pd(OAc)2 (1a) was coupled with more steric and electron attractive 2-oxo-2-(2-
(entry 2 vs. 9). However, other commercially available Pd catalysts, (trifluoromethyl)phenyl)acetic acid (2j) under the optimized reaction
such as Pd(PPh3)2Cl2, Pd(CH3CN)2Cl2 and PdCl2, exhibited poor conditions, a satisfactory yield of the corresponding product 3j was
performance in the model reaction (entries 10–12). The general achieved. Fortunately, a representative structure of 3j was confirmed
additives, Ag2O and PivOH, were also investigated and the results by X-ray single-crystal analysis.16 It was worth noting that the use of
indicated that the addition of Ag2O into the reaction did not affect the disubstituted a-oxocarboxylic acids 2l and 2m provided the desired
yield of 3a obviously (entry 13). In addition, the introduction of PivOH products in 82% (3l) and 81% (3m) yields, respectively. When
resulted in an inferior yield of 3a (entry 14). Furthermore, the 2-(naphthalen-1-yl)-2-oxoacetic acid 2n was tested in the reaction,
optimization of reaction time did not help in promoting the model 63% of the product 3n was obtained. Encouraged by the above results,
reaction under the above reaction conditions (entries 15 and 16). To the heterocyclic-substituted a-oxocarboxylic acid 2o was evaluated and
further optimize the reaction conditions for the reaction of 1a with 2a, a moderate yield of the product 3o was obtained at the enhanced
a variety of solvents were examined. DCE was found to be the best one reaction temperature. Finally, it was observed that the simple aliphatic
for the reaction and the detailed results are listed in Table S2 (ESI†). a-oxocarboxylic acids 2p could react with azoxybenzene (1a) at 100 1C,
The optimized reaction conditions were obtained as follows: affording the acylated product 3p in 44% yield. To expand the
5.0 mol% of Pd(OAc)2 as catalyst, K2S2O8 as oxidant, and DCE scope of this method, some typical disubstituted azoxybenzenes
as solvent, at 60 1C under air for 24 h.
were synthesized and examined. The results demonstrated that the
Under the above optimized reaction conditions, we then examined disubstituted azoxybenzenes with electron-donating and electron-
the scope of decarboxylative acylation reactions with respect to withdrawing substituents at the para-positions of phenyl rings,
a-oxocarboxylic acids, and the results are summarised in Scheme 3. such as MeO, i-Pr, Et, Me and F, afforded the desired products
It was found that substrates with both electron-donating and electron- (3q–u) in good yields. Obviously, the steric hindrance effect of the
withdrawing groups on the benzene rings of 2-oxo-2-arylacetic acids azoxy compound, 1g, was observed, and its reaction with 2-oxo-2-
were tolerated and afforded good yields of the corresponding acylated phenylacetic acid (2a) led to lower yield of product 3v under the
products. Notably, compared to the electron-donating groups, includ- present reaction conditions.
ing MeO, t-Bu and Me, the electron-withdrawing groups, such as
Although the exact reaction mechanism is not clear to date, a
halogens at the para-positions of the phenyl rings in a-oxocarboxylic possible pathway is described in Scheme 4. It is known that N is
acids, exhibited higher activity when they reacted with azoxybenzenes, generally considered to be a better coordinating atom than O when
furnishing the corresponding products in enhanced yields (3e–g). The complexed with Pd(II). Hence, azoxybenzene 1a firstly reacted with
steric hindrance effect was observed when meta- and ortho-substituted Pd(OAc)2 to form an active complex I through the ortho-C–H inser-
tion,17 which accounts for the high regioselectivity in the reactions.
Then, the obtained I underwent an anion exchange with a-keto acid 2a
to generate a cyclopalladated complex II along with release of HOAc.
Subsequently, the decarboxylation of complex II led to CO218 and a
complex III, which underwent reductive elimination to afford the
acylated product 3a and Pd(0). Finally, the regeneration of Pd(II) from
Pd(0) was realized in the presence of K2S2O8. However, the Pd(III) or
Pd(IV) intermediate could not be absolutely ruled out in the system.19
Moreover, the further transformation of the acylated
azoxybenzenes into an indazole backbone was examined.4o,4q
Scheme 4 Proposed reaction mechanism.
Scheme 3 The scope of azoxybenzenes and a-oxocarboxylic acids in the reaction.
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transformation of acylated azoxybenzenes (3a–f) into indazoles
4 was completed in 2 h with excellent yields (Scheme 5).
In summary, we have disclosed an ortho-acylation reaction of azoxy-
benzenes with a-oxocarboxylic acids through palladium-catalyzed direct
C–H activation and decarboxylation in the presence of K2S2O8. This
simple methodology employs readily available azoxy compounds and
a-oxocarboxylic acids as starting materials to obtain acylated azoxy-
benzenes in good yields with high regioselectivity. The detailed
mechanistic investigations and further applications of these azoxy-
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This work was financially supported by the National Science
Foundation of China (No. 21172092) and the Department of
Education, Anhui Province (No. KJ2013B246).
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