Palladium-catalyzed aromatic esterification of aldehydes with organoboronic acids and molecular oxygen

Article abstract of DOI:10.1021/ol800176p

A palladium-catalyzed aromatic esterification reaction of aldehydes with arylboronic acids under an air atmosphere was achieved. This reaction tolerates many functional groups and provides aryl benzoate derivatives with yields ranging from moderate to good. Dioxygen takes part in the reaction and is crucial for this transformation.

Full text of DOI:10.1021/ol800176p

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1537-1540
Palladium-Catalyzed Aromatic
Esterification of Aldehydes with
Organoboronic Acids and Molecular
Oxygen
Changming Qin, Huayue Wu,* Jiuxi Chen, Miaochang Liu, Jiang Cheng,*
Weike Su, and Jinchang Ding
College of Chemistry and Materials Engineering, Wenzhou UniVersity,
Wenzhou 325027, P. R. China
huayuewu@wzu.edu.cn; jiangcheng@wzu.edu.cn
Received January 24, 2008
ABSTRACT
A palladium-catalyzed aromatic esterification reaction of aldehydes with arylboronic acids under an air atmosphere was achieved. This reaction
tolerates many functional groups and provides aryl benzoate derivatives with yields ranging from moderate to good. Dioxygen takes part in
the reaction and is crucial for this transformation.
Direct transformation of aldehydes to esters under mild
conditions holds promise in organic synthesis, particularly
in the synthesis of natural products.1 In the past few years,
great progress has been made in the synthesis of alkyl
benzoate derivatives through aldehydes.2 Recently, Wolf and
co-workers reported an efficient oxidative conversion of
aldehydes to ester using siloxanes and palladium-phosphi-
nous acid.3 More recently, Kiyooka and co-workers reported
[IrCl(cod)]2-catalyzed direct oxidative esterification of alde-
hydes with alcohols.4
However, less attention has been paid to the synthesis of
aryl benzoate derivatives, which are important building
blocks in the synthesis of natural and pharmacological
compounds.5 Traditional methods for preparation of these
compounds include esterification6 and transesterification
reactions7 as well as Baeyer-Villiger oxidation reactions.8
The esterification and transesterification reactions were often
conducted under strongly acidic or basic conditions, which
might limit the scope of functional groups. In the Baeyer-
(4) Kiyooka, S. -I.; Wada, Y.; Ueno, M.; Yokoyama, T.; Yokoyama, R.
Tetrahedron 2007, 63, 12695.
(1) (a) Larock, R. C. ComprehensiVe Organic Transformation; VCH:
New York, 1989; p 840. (b) McDonald, C.; Holcomb, H.; Kennedy, K.;
Kirkpatrick, E.; Leathers, T.; Vanemon, P. J. Org. Chem. 1989, 54, 1213.
(c) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968, 90,
5616. (d) Ogawa, T.; Matsui, M. J. Am. Chem. Soc. 1976, 98, 1629. (e)
Garegg, P. J.; Olsson, L.;. Oscarson, S. J. Org. Chem. 1995, 60, 2200. (f)
Sundararaman, P.; Walker, E. C.; Djerassi, C. Tetrahedron Lett. 1978, 19,
1627.
(2) (a) Gopinath, R.; Patel, B. K. Org. Lett. 2000, 5, 577. (b) Gopinath,
R.; Paital, A. R.; Patel, B. K Tetrahedron Lett. 2002, 43, 5123. (c) Espenson,
J. H.; Zhu, Z.; Zauche, T. H. J. Org. Chem. 1999, 64, 1191. (d) Barkakaty,
B.; Talukdar, B.; Patel, B. K. J. Org. Chem. 2003, 68, 2944. (e) Travis, B.
R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett. 2003, 5, 1031. (f)
Okimoto, M.; Chiba, T. J. Org. Chem. 1988, 53, 218. (g) Wuts, P. G. M.;
Bergh, C. L. Tetrahedron Lett. 1986, 27, 3995. (h) McDonald, C. E.; Nice,
L. E.; Shaw, A. W.; Nestor, N. B. Tetrahedron Lett. 1993, 34, 2741.
(3) Lerebours, R.; Wolf, C. J. Am. Chem. Soc. 2006, 128, 13052.
(5) (a) Moretto, A.; Nicolli, A.; Lotti, M. Toxicol. Appl. Pharm. 2007,
219, 196. (b) Berndt, M. C.; Bowles, M. R.; King, G. J.; Zerner, B. Biochim.
Biophys. Acta 1996, 1298, 159. (c) Barratt, M. D.; Basketter, D. A; Roberts,
D. W. Toxicol. in Vitro 1994, 8, 823. (d) Child, J. J.; Oka, T.; Simpson, F.
J.; Krishnamurty, H. G. Can. J. Microbiol. 1971, 17, 1455.
(6) (a) Sarvari, M. H.; Sharghi, H. Tetrahedron 2005, 61, 10903. (b)
Tamaddon, F.; Amrollahi, M. A.; Sharafat, L. Tetrahedron Lett. 2005, 46,
7841. (d) Shah, S. T. A.; Khan, K. M.; Hussain, H.; Anwar, M. U.; Fecker,
M.; Voelter, W. Tetrahedron 2005, 61, 6652.
(7) Oohashi, Y.; Fukumoto, K.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
2005, 78, 1508.
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1991, 739. (b) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.
Chem. Lett. 2004, 33, 248. (c) Kotsuki, H.; Arimura, K.; Araki, T.;
Shinohara, T. Synlett 1999, 462. (d) Toda, F.; Yagi, M.; Kiyoshige, K. J.
Chem. Soc., Chem. Commun. 1988, 958.
10.1021/ol800176p CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/18/2008

Scheme 1. Regioselectivity in the Baeyer-Villiger Oxidation
Table 1. Effects of Pd Source, Base, Solvent, Imidazolium
Salts L, and Ratio of L/Pd on the Palladium-Catalyzed
Esterifications of Aldehydes with Organoboronic Acidsa
Reaction
Villiger oxidation reaction (Scheme 1), given that the
migratory rate of R1 is faster than that of R2, it is hard to
synthesize 3 via this route. Moreover, if R1 and R2 have
similar migratory rates, the mixtures of 2 and 3 will be
obtained with low regioselectivity. An alternative approach
for the synthesis of esters from aromatic aldehydes involves
the Tischenko-Claisen dismutation reaction, which was
limited in the synthesis of benzyl esters. Thus, developing
versatile approaches to the synthesis of aryl benzoate
derivatives is still a highly desired goal in organic synthesis.
In our previous work, we reported the palladium-catalyzed
synthesis of carbinol derivatives and diaryl ketone derivatives
by employing aromatic boronic acids,9 which enjoy high
prestige in metal-catalyzed C-C bond formation thanks to
their advantages of low toxicity, stability to air and moisture,
and good functional group tolerance.10 Our interest in the
development of organoboron reactions led us to explore the
potential reactions between organoboron reagents and alde-
hydes. Herein, we report a palladium-catalyzed aromatic
esterification reaction of aldehydes with aromatic boronic
acids under an air atmosphere, affording aryl benzoate
derivatives in moderate to good yield.
Initial studies were concentrated on reactions between
phenylboronic acid (1a) and piperonal (2a) as a model reac-
tion. After careful screening, to our delight, a 28% yield of
phenyl benzo[d][1,3]dioxole-5-carboxylate (3aa) was ob-
tained by employing the combination of Pd(OAc)2 (5.0 mol
%), L1 as a precursor of an N-heterocyclic carbene (NHC),
(5.0 mol %), and CsF (3.0 equiv) in refluxing dry toluene
under air. Encouraged by this result, we further optimized
the reaction conditions using some other NHC precur-
sors (Figure 1). The selected results, such as palladium
catalysts, the ratio of L/Pd, bases, and solvents, are listed in
Table 1.
L/Pd yield
ligand ratio (%)b
entry
Pd source
PdCl2
Pd(OAc)2
Pd2(dba)3
base
CsF
CsF
CsF
solvent
toluene
toluene
toluene
toluene
toluene
toluene
DMA
toluene
toluene
toluene
toluene
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
16
28
<5
<5
16
Pd2(dba)3‚CHCl3 CsF
Pd(PPh3)4
PdCl2(Py)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CsF
CsF
CsF
Csl
CsCl
KF
17
<5
<5
<5
<5
<5
18
<5
16
59
(53)c
57
52
<5
<5
<5
10 Pd(OAc)2
11 Pd(OAc)2
12 Pd(OAc)2
13 Pd(OAc)2
14 Pd(OAc)2
15 Pd(OAc)2
LiF
Cs2CO3 toluene
CsF
CsF
CsF
toluene
toluene
toluene
16 Pd(OAc)2
17 Pd(OAc)2
18 Pd(OAc)2
19 Pd(OAc)2
20 Pd(OAc)2
CsF
CsF
CsF
CsF
CsF
toluene
toluene
DMF
L4
L4
L4
2
3
1
1
1
1,4-dioxane L4
MeOCH2-
CH2OMe
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
L4
21 Pd(OAc)2
22 Pd(OAc)2
23 Pd(OAc)2
24 Pd(OAc)2
25 Pd(OAc)2
26 Pd(OAc)2
27 Pd(OAc)2
28 Pd(OAc)2
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
L4
L4
L4
1
1
1
1
1
1
1
1
<5
54d
<5e
<5
7f
L1
L1
L1
L4
8g
9h
41i
a All reactions were run with piperonal (75 mg,0.5 mmol), phenylboronic
acid (122 mg, 1.0 mmol), base (1.5 mmol), Pd source (5.0 mol %), and
indicated L/Pd ratio in 3 mL of dry solvent in air at 120 °C for 24 h. b GC
yield. c Undried toluene. d O2 atm. e N2 atm. f 5.0 mol % AgBF4 was added.
g 5.0 mol % AgSbF6was added. h 5.0 mol % AgPF6 was added. i 80 °C
Among the palladium sources used, such as PdCl2,
Pd(OAc)2, PdCl2(Py)2, Pd2(dba)3, Pd2(dba)3‚CHCl3, and
Pd(PPh3)4, Pd(OAc)2 exhibited the highest catalytic reactivity.
The imidazolium chlorides L3 and L1 with bulky aromatic
substituent groups on their nitrogen atoms gave poor to
moderate results, respectively, and imidazolium salts L2
containing N-alkyl groups turned out to be totally ineffective.
Interestingly, only when the ligand changed to the imida-
zolium salts L4 did the yield dramatically increase to 59%.
(9) (a) Qin, C. M.; Wu, H. Y.; Cheng, J.; Chen, X. A.; Liu, M. C.; Zhang,
W. W.; Su, W. K.; Ding, J. C. J. Org. Chem. 2007, 72, 4102. (b) Qin, C.
M.; Chen, J. X.; Wu, H. Y.; Cheng, J.; Zhang, Q.; Zuo, B.; Su, W. K.;
Ding, J. C. Tetrahedron Lett. 2008, 49, 1884.
(10) (a) Suzuki, A. Acc. Chem. Res. 1982, 15, 178. (b) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457. (c) Suzuki, A. J. Organomet. Chem.
1998, 576, 147. (d) Darses, S.; Genet, J. P. Eur. J. Org. Chem. 2003, 4313.
Figure 1. Selected imidazolium salts screened.
1538
Org. Lett., Vol. 10, No. 8, 2008

However, no good yield was obtained when AgBF4, AgSbF6,
or AgPF6 was added with L1 in the system, respectively.
We also found that no desired product was delivered when
AgBF4 was added with L2 in the reaction.
Table 2. Substrate Scope in the Palladium-Catalyzed Aromatic
Esterification of Aromatic Aldehydes with Arylboronic Acidsa
Increasing the amount of L4 in the system had little
influence on the yield (Table 1, entries 16 and 17), which
might be owing to its difficulty to dissociate from the metal
center to produce the bulk metal.11 CsF was superior to some
other cesium or fluoride salts such as Cs2CO3, KF, LiF, CsCl,
and CsI. The choice of solvent was also crucial to the success
of the catalytic reaction. Toluene appeared to be the best
among the common solvents such as DMF, DMA, 1,4-diox-
ane, and 1,2- dimethoxyethane. Moreover, dioxygen played
a significant role in the reaction since no desired products
were obtained under a N2 atmosphere. It should be noted
that 3aa was still obtained in 41% yield at 80 °C for 30 h.
Under the optimized conditions, various aromatic alde-
hydes and aromatic boronic acids were subjected to this kind
of esterification process (Table 2).
As expected, the reaction proceeded smoothly with yields
ranging from moderate to good and tolerated various func-
tional groups such as nitro, cyano, acetoxy, trifluoromethyl,
chloro, and fluoro groups. Electron-rich aldehydes reacted
with aromatic boronic acids easily and gave the desired
products in good yields. Nevertheless, the reaction became
sluggish by using aldehydes with electron-withdrawing
groups. Aliphatic aldehydes, such as 2i, were not good sub-
strates in the reaction. Arylboronic acids with electron-
withdrawing substituted groups, which are less nucleophilic
and transmetalate more slowly than electron-neutral ana-
logues, are prone to homocoupling and protodeboronation
side reactions.12 In our system, however, 1b and 1c could
proceed smoothly with 2a, and the products 3ba and 3ca
were isolated in 68% and 62% yields, respectively (Table
2, entries 9 and 10).
It is noteworthy that 3ca is difficult to prepare from
corresponding diaryl ketones via Baeyer-Villiger oxidation
since the electron-withdrawing groups on the aryl will
decrease its migratory rate. However, in our procedure, 1c
reacted smoothly with 2a and produced 3ca in 62% isolated
yield. The ortho substituents on the aromatic boronic acids
had little effect in the reaction. For example, 3da and 3dd
were isolated in 55% and 56% yield, respectively (Table 2,
entries 11, 16). Since the aromatic aldehydes can be facilely
synthesized from a lot of functional groups such as methyl,
hydroxylmethyl, carboxyl, cyano, and ester,13 this method
appears to be versatile and might provide potential oppor-
tunities in the synthesis of complex molecules possessing
interesting biological and pharmacological properties.
Employing benzoic acid or benzophenone instead of
benzaldehyde under the same procedure, no target product
was detected in this reaction. This result suggested that they
might not be the intermediates of the reaction. Analysis of
the crude reaction mixtures between phenyl boronic acids
a All reactions were run with aldehyde (0.5 mmol), arylboronic acid (1.0
mmol), CsF (228 mg, 1.5 mmol), Pd(OAc)2 (5.6 mg, 5 mol %), L4 (9.9
mg, 5 mol %) in 3 mL of dry toluene in air at 120 °C for 24 h. b Isolated
yield. c 36 h.
and benzaldehyde by GC-MS showed that the 2-hydroxy-
1,2-diphenylethanone was produced in situ, which was
formed due to the NHC-mediated benzil condensation.14
However, 2-hydroxy-1,2-diphenylethanone or benzil did not
deliver the desired product under the standard reaction
conditions either.
To understand the mechanism more clearly, labeling
studies were conducted using 18O2 (Scheme 2). We found
that the reaction proceeded smoothly under an 18O2 atmo-
Scheme 2. Study on 18O2 Incorporation into the Desired
Product
(11) Herrmann, W. A.; Ko¨cher, C. Angew. Chem., Int. Ed. 1997, 36,
2163.
(12) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685 and references therein.
(13) Ferguson, L. N. Chem. ReV. 1946, 38, 227.
Org. Lett., Vol. 10, No. 8, 2008
1539

sphere to provide the desired product in 53% yield. The ESI-
MS spectrum showed that m/z at 244.8 and 266.8 were
attributed to [M + H]+ and [M + Na]+ ions, respectively.
The MS2 spectrum of the precursor ion at m/z 244.8 exhibited
intensive characteristic fragment at m/z 148.7, which was
attributed to the fragment of [244.8 - Ph18OH]+. This result
showed that dioxygen took part in this reaction and was
essential for the transformation.
In summary, we have demonstrated a palladium-catalyzed
aromatic esterification reaction between aldehydes and
organoboronic acids under an air atmosphere. This procedure
represents a simple, direct method in the synthesis of
functionalized phenyl benzoate derivatives from the bulky
commercially available aldehydes. Indeed, this method
appears to be versatile and might have potential application
in the synthesis of complex natural compounds. Furthermore,
this transformation might involve a new type of dioxygen
activity, and further investigation to understand this mech-
anism as well as its application are ongoing in our laboratory.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (nos. 20504023 and 20676123)
for financial support.
Supporting Information Available: Experimental pro-
cedures along with copies of spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606.
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