Tetrahedron Letters
Palladium/NHC-catalyzed oxidative esterification of aldehydes with phenols
Manli Zhang a, Shouhui Zhang a, Guoying Zhang a, Fan Chen a, , Jiang Cheng a,b,
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a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, PR China
b State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed oxidative esterification of aldehydes with phenols is described, using air as the
clean oxidant. This reaction tolerates many functional groups, providing esters with yields ranging from
moderate to excellent.
Received 26 December 2010
Revised 21 February 2011
Accepted 3 March 2011
Available online 11 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Carboxylic acid esters are not only important building blocks in
the synthesis of natural and pharmacologically active compounds,1
but are also used as protecting groups in synthesis.2 Esters are gen-
erally prepared from acyl chlorides and mixed anhydrides, which
are commonly derived from free carboxylic acids, or with carbodii-
mides, 1-hydroxybenzotriazoles and other expensive coupling
agents.3 Oxidative esterification has received increasing attention
and has become an economical alternative to traditional ester syn-
thesis.4 Among these, the use of heterocyclic carbenes as catalysts
provided elegant access to esters.5 In 2008, we described an NHC-
palladium-catalyzed aromatic esterification of aldehydes with
organoboronic acids and molecular oxygen.6 Subsequently, Gois
disclosed the NHC-iron-catalyzed aerobic oxidative aromatic ester-
ification of aldehydes with boronic acids.7 The direct transforma-
tion of aldehydes with alcohols accessing esters would be
attractive from an atom economic point of view. Recently, Rovis
and Bode demonstrated the NHC-catalyzed oxidative esterifica-
tions of aldehydes with alcohols by the internal redox and in situ
Initially, we studied the reaction of benzaldehyde (1a) with 4-
nitrophenol (2a) as the model reaction for screening the reaction
parameters (Table 1). To our delight, the product (3aa) was isolated
in 48% yield by using the combination of Pd(OAc)2 (5.0 mol %), L1
as precursor of N-heterocyclic carbene (NHC) (Fig. 1) (5.0 mol %)
and Na2CO3 (3.0 equiv) in dry xylene at 100 °C under air. Ligand
played a significant role in the esterification of aldehydes. After
screening the imidazolium salts, we found that L2 was better than
other ligands, producing 3aa in 74% yield (Table 1, entry 2).
Increasing the amount of L2 in the system had little influence on
the yield. The yield greatly improved to 87% using 4 equiv of
Na2CO3 (Table 1, entry 6). However, the yield decreased to 68%
when 5 equiv of Na2CO3 was employed (Table 1, entry 7). Notably,
Na2CO3 gave a significantly higher yield than other inorganic bases
(Table 1, entries 10–13). In the absence of base, product 3aa could
be gained in only 10% yield (Table 1, entry 8). A compatible yield
was obtained under O2, however, the yield dramatically decreased
to 25% under N2 (Table 1, entry 6). This result indicated the air may
serve as the terminal oxidant in the reaction. Next, the solvent ef-
fect was studied, and xylene was the best (Table 1, entries 14–17).
Among the palladium species screened, Pd(OAc)2 was superior to
PdCl2, Pd2(dba)3 and Pd(dppf)Cl2 (Table 1, entries 18–20). The
product 3aa was isolated in 40% yield in the absence of Pd (Table 1,
entry 21), suggesting that L2 could catalyze the reaction to some
extent. The NHC was essential for the esterification reaction since
no product was observed without NHC (Table 1, entry 9). The
employment of 1.5 equiv of benzaldehyde was optimal, since more
or less amount of benzaldehyde resulted in decreased yields. Nota-
bly, the reaction conducted on a 10 mmol scale produced the ester-
ification product 3aa in 80% yield.
activation of
a
-functionalized aldehydes, respectively.8 However,
-functional group in the aldehydes would
the requirement of an
a
greatly diminish the substrate scope. Accordingly, the NHC-
catalyzed oxidative esterification of aldehydes with transition-metal
based oxidants9 or organic oxidants10 has been investigated. Nev-
ertheless, the excess or stoichiometry oxidant was used for the
aforementioned transformation. Very recently, Studer reported
the NHC-catalyzed oxidation of aldehydes to esters by quinone
derivatives. The quinone derivatives could be recovered by air oxi-
dation, rendering the process economically attractive.11 However,
to develop a facile and versatile procedure on such transformation
still remains a highly desired goal for organic chemists. Herein, we
report our study on the palladium/NHC-catalyzed oxidative ester-
ification of aldehydes with phenols, which used air as the clean
oxidant and did not require special functional group and oxidant.12
Having identified the optimal reaction conditions, the substitu-
ent effects of aldehydes were examined as shown in Figure 2. The
aromatic esterification of aldehydes with phenols proceeded
smoothly in good to excellent yields. The electronic properties of
the substituents on the phenyl ring of aldehydes had some effect
on the reaction. Generally, the aldehydes possessing electron-
withdrawing groups gave slightly higher yields than those of
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Corresponding authors. Fax: +86 577 56998939.
Cheng).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.