Cu(OTf)2-mediated Chan-Lam reaction of carboxylic acids to access phenolic esters

Article abstract of DOI:10.1021/jo101558s

A Cu(OTf)₂-mediated Chan-Lam reaction of carboxylic acids with arylboronic acids is described. It represents a facile and practical methodology to access phenolic esters in moderate to good yields. The procedure tolerates a series of functional groups, such as methoxycarbonyl, acetoxy, free phenolic hydroxyl, vinyl, nitro, trifluoromethyl, methoxyl, bromo, chloro, iodo, and acetyl groups.

Full text of DOI:10.1021/jo101558s

pubs.acs.org/joc
synthesis of natural and pharmacological compounds.3 How-
Cu(OTf)2-Mediated Chan-Lam Reaction of
Carboxylic Acids to Access Phenolic Esters
ever, the direct esterification of benzoic acid and phenol4 as well
as transesterification reactions5 were often conducted under
strongly acidic or basic conditions, which might limit the scope
of functional groups and cause side reactions, such as carboni-
zation, oxidation, etc.6 The Baeyer-Villiger oxidation7 reac-
tion may suffer from low regioselectivity. From the synthetic
point of view, it is a highly desirable goal to develop a versatile
approach to the synthesis of phenolic esters in a simple and mild
way. Very recently, we reported a copper-catalyzed esterifica-
tion of carboxylic acids or anhydrides with aryl and alkenyl
trimethoxysilane.8 However, 3 equiv of expensive AgF are
required for the aforementioned transformations. Herein, we
report a Cu(OTf)2-mediated Chan-Lam reaction of carboxylic
acids with boronic acids.
Lingli Zhang,† Guoying Zhang,† Manli Zhang,† and
Jiang Cheng*,†,‡
†College of Chemistry and Materials Engineering, Wenzhou
University, Wenzhou 325027, People’s Republic of China, and
‡State Key Laboratory of Coordination Chemistry, Nanjing
University, Nanjing 210093, People’s Republic of China
jiangcheng@wzu.edu.cn
Received August 9, 2010
We initiated our investigation by examining the reaction
of benzoic acid and phenylboronic acid (Table 1). During the
survey of additives, to our delight, phenyl benzoate was pro-
duced in 25% yield in the presence of 1 equiv of urea as an
additive in ethyl acetate (entry 2, Table 1). Benzamide was
also effective for this transformation, while thiourea and
acetamide inhibited the reaction. The influence of copper
catalysts was investigated, and Cu(OTf)2 turned out to be the
best (entries 6-9, Table 1). Several solvents, such as toluene,
THF, MeNO2, and MeCN, were also examined. No product
was formed in the absence of copper (entry 14, Table 1).
Compatible yield was gained when the reaction was con-
ducted under oxygen. We believed the urea may at least act
A Cu(OTf)2-mediated Chan-Lam reaction of carboxylic
acids with arylboronic acids is described. It represents a
facile and practical methodology to access phenolic esters in
moderate to good yields. The procedure tolerates a series of
functional groups, such as methoxycarbonyl, acetoxy, free
phenolic hydroxyl, vinyl, nitro, trifluoromethyl, methoxyl,
bromo, chloro, iodo, and acetyl groups.
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The construction of carbon-oxygen bonds is a central
theme in organic synthesis. Among these, the transition-
metal-catalyzed reaction of ArX and alcohols or phenols is
one of the most powerful methods for the forming of C-O
bonds.1 However, the employing of a strong base, such as
KOtBu and NaOMe, as well as the elevated reaction tempera-
ture, would diminish the functional compatibility and the
reaction practicality. Alternative transformation involves the
copper-catalyzed Chan-Lam reaction of arylboronic acids
with alcohols or phenols,2 which may run under room tem-
perature. However, to the best of our knowledge, the employ-
ing of carboxylic acids as an O-donor in Chan-Lam reaction
has never been studied or reported before. The formed
benzoate derivatives are important building blocks in the
(1) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
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7472 J. Org. Chem. 2010, 75, 7472–7474
Published on Web 10/13/2010
DOI: 10.1021/jo101558s
r
2010 American Chemical Society

Zhang et al.
JOCNote
TABLE 1. Selected Results for Optimal Reaction Conditionsa
TABLE 2. Reaction of Carboxylic Acids with Phenylboronic Acida
entry
catalyst
additive
solvent
yield (%)
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
Cu(acac)2
Cu2O
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
toluene
THF
<5
25
15
<5
<5
95
33
7
<5
<5
90
56
20
NH2CONH2
PhCONH2
NH2CSNH2
CH3CONH2
NH2CONH2
NH2CONH2
NH2CONH2
NH2CONH2
NH2CONH2
NH2CONH2
NH2CONH2
NH2CONH2
NH2CONH2
9
CuI
10
11
12
13
14
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CH3NO2
MeCN
EtOAc
<5
aReaction conditions: benzoic acid (0.2 mmol), phenylboronic acid
(0.6 mmol), Cu source (40 mol %), and additive (1.0 equiv) in solvent
(2 mL), 60 °C; 12 h under air.
as a ligand to copper under this transformation. The reac-
tion conducted on a 2 mmol scale formed the product in an
acceptable 65% yield.
Finally, the optimized conditions were found as following:
under air, Cu(OTf)2 (40 mol %) as the catalyst, and urea
(1 equiv) in ethyl acetate at 60 °C.
With the established optimal parameters, we turned our
attention to investigate the scope of carboxylic acids. The
results were summarized in Table 2. The electronic property
of the groups on the phenyl ring of carboxylic acids had
some effect on the reaction. Generally, the carboxylic acids
possessing electron releasing groups produced the phenolic
esters with higher yields (e.g., entries 1, 11, and 15, Table 2).
The procedure tolerated a range of functional groups, such
as iodo, chloro, bromo, nitro, free phenolic hydroxyl, and
acetyloxy groups. The compatible of halo groups is synthet-
ically useful since the products could be easily further modi-
fiable. The hindrance on the phenyl ring of carboxylic acids
had a limited effect on the reaction. For example, 1b and 1g
produced the products 3ba and 3ga in 94 and 78% yields,
respectively (entries 1 and 6, Table 2). Salicylic acid 1k deliv-
ered the phenolic ester 3ka in moderate yield, however,
when the phenolic hydroxyl was masked with acetyl, the
esterification yield dramatically increased to 88% (entries
10 and 11, Table 2). Notably, the hetero aromatic carboxylic
acid, such as furan-2-carboxylic acid 1n, cinnamic acid 1o,
and 2-phenylacetic acid 1p ran smoothly under the standard
conditions, producing the esters in 95, 96, and 98% yields,
respectively (entries 12, 13 and 14, Table 2). The yield de-
creased to 50 and 70% under the presence of molecular sieves
or using the dry EtOAc as solvents, respectively. This transfor-
mation is very practical, as it could be conducted under air,
and the rigorous exclusion of air/moisture is not required
either.
aReaction conditions: carboxylic acid (0.2 mmol), phenylboronic acid
(73 mg, 0.6 mmol), Cu(OTf)2 (29 mg, 40 mol %), urea (12 mg, 1.0 equiv)
in EtOAc (2 mL), 60 °C, 12 h under air.
Next, the esterification of benzoic acid with several aryl-
boronic acids was investigated (Table 3). We found 24 h was
required to complete the reaction. For example, the reac-
tion of benzoic acid and 4-vinylphenyl boronic acid afforded
the products in 65 and 90% at 12 and 24 h, respectively. As
expected, the groups on the phenyl ring of arylboronic acids,
such as chloro, trifluoromethyl, acetyl, and methoxycarbonyl
were well compatible under the standard procedure. Notably,
vinyl in 2j survived under the reaction procedure, producing
3aj in 90% yield (entry 9, Table 3). 2-Methylphenylboronic
acid delivered the ester in 38% yield. Disappointingly,
4-hydroxyphenylboronic acid and other ortho-substituted
J. Org. Chem. Vol. 75, No. 21, 2010 7473

Zhang et al.
JOCNote
TABLE 3. Reaction of Benzoic Acid with Arylboronic Acidsa
The phenol was detected as a byproduct during the
procedure. However, when benzoic acid and phenol were
subjected to the standard reaction condition in the absence
or presence of phenylboronic acid (10 and 20 mol %, respec-
tively), a trace of ester (<1%) was formed. This result ruled
out the possibility of a hydroxylation of boronic acids9/
esterification pathway.
In conclusion, we have developed a Cu(OTf)2-mediated
Chan-Lam reaction of carboxylic acid and arylboronic acids,
affording the phenolic esters in moderate to good yields. The
reaction showed remarkably broad substrate scope and good
functional group tolerance.
Experimental Section
Typical Experimental Procedure for the Reaction of Arylboron-
ic Acids with Carboxylic Acids to Esters. Under air, a reaction
tube was charged with carboxylic acid (0.2 mmol), arylboronic
acid (0.6 mmol), Cu(OTf)2 (29 mg, 40 mol %), urea (0.2 mmol),
and ethyl acetate (2 mL). The mixture was stirred at 60 °C. After
the mixture was kept stirring for 12 or 24 h, the solvent was
evaporated under reduced pressure and the residue was purified
by flash column chromatography on silica gel to give the product.
Phenyl 2-Acetoxybenzoate (3ma). Compound 3ma is a white
solid; 1H NMR (CDCl3, 500 MHz): δ 8.15 (d, J = 7.9 Hz, 1H),
7.58-7.54 (m, 1H), 7.36-7.31 (m, 3H), 7.21-7.17 (m, 1H),
7.11-7.09 (m, 3H), 2.23 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ
169.7, 162.9, 151.2, 150.6, 134.5, 132.2, 129.5, 126.1, 126.0,
124.0, 121.7, 21.0. IR (prism, cm-1): 3058, 1739, 1694, 1483,
1188, 740. MS (EI) 256 (Mþ); HRMS Calcd for C15H12O4 (Mþ),
256.0736; found, 256.0730.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20972115), the Key Project of
Chinese Ministry of Education (No. 209054), and State Key
Laboratory of Coordination Chemistry of Nanjing Univer-
sity for financial support.
Supporting Information Available: Experimental proce-
dures along with copies of spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
aReaction conditions: benzoic acid (24 mg, 0.2 mmol), arylboronic
acid (0.6 mmol), Cu(OTf)2 (29 mg, 40 mol %), urea (12 mg, 1.0 equiv) in
EtOAc (2 mL), 60 °C, 24 h, under air.
(9) The transition-metal catalyzed hydroxylation of boronic acids, please
see: (a) Xu, J.; Wang, X.; Shao, C.; Su, D.; Cheng, G.; Hu, Y. Org. Lett. 2010,
12, 1964. (b) Kianmehr, E.; Yahyaee, M.; Tabatabai, K. Tetrahedron Lett.
2007, 48, 2713. (c) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith,
M. R., III. J. Am. Chem. Soc. 2003, 125, 7792. (d) Benjamin, R.; Travis,
B. R.; Ciaramitaro, B. P.; Borhan, B. Eur. J. Org. Chem. 2002, 3429. (e)
Simon, J.; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. J. Org.
Chem. 2001, 66, 633.
phenylboronic such as 2-chlorophenylboronic, 2-methoxy-
phenylboronic, and naphthaleneboronic acid failed to deliver
the desired esters.
7474 J. Org. Chem. Vol. 75, No. 21, 2010