Copper-catalyzed oxidative esterification of alcohols with aldehydes activated by Lewis acids

Article abstract of DOI:10.1016/j.tetlet.2006.11.169

An efficient oxidative esterification of aromatic and aliphatic aldehydes with simple alcohols was accomplished using catalytic amounts of Cu(ClO₄)₂·6H₂O and InBr₃ with tert-hydroperoxide as an oxidant.

Full text of DOI:10.1016/j.tetlet.2006.11.169

Tetrahedron Letters 48 (2007) 1033–1035
Copper-catalyzed oxidative esterification of alcohols
with aldehydes activated by Lewis acids
Woo-Jin Yoo and Chao-Jun Li*
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada 3HA 2K6
Received 15 October 2006; revised 29 November 2006; accepted 29 November 2006
Available online 19 December 2006
Abstract—An efficient oxidative esterification of aromatic and aliphatic aldehydes with simple alcohols was accomplished using
catalytic amounts of Cu(ClO4)2Æ6H2O and InBr3 with tert-hydroperoxide as an oxidant.
Ó 2006 Elsevier Ltd. All rights reserved.
C–H bonds are ubiquitous in nature and thus the ability
to perform selective C–H bond functionalization has
long attracted the attention of chemists.1 Recently, we
have described a variety of copper-catalyzed cross-de-
hydrogenative coupling (CDC) protocols in which the
sp3-hybridized C–H bond adjacent to a heteroatom
can be functionalized with a variety of pronucleophiles
in the presence of an oxidant.2 Furthermore, a copper-
catalyzed oxidative allylic alkylation of cyclic alkenes
and activated methylene units was also demonstrated
in the presence of tert-butyl hydroperoxide (TBHP) as
the oxidant.3
gous oxidative esterification of aldehydes required long-
er reaction time and higher temperature. Furthermore,
the reaction performed poorly without the presence of a
carbonyl directing group. Thus, unlike simple alcohols,
the enol forms of 1,3-diketones and b-ketoesters proved
to be excellent substrates for the stereoselective oxida-
tive esterification of aldehydes (Scheme 2).
While a variety of procedures6 exist for the direct oxida-
tive esterification of aldehydes, these protocols are often
hindered by the need for excess reagents and/or expen-
sive catalyst. Furthermore, competing side reactions,
such as the oxidation of the alcohol and aldehyde sub-
strates, often complicate matters and limit the applica-
tion of this functional group transformation. However,
unlike most oxidative esterification protocols, the cop-
per-catalyzed oxidative esterification with b-dicarbonyl
compounds using TBHP as an oxidant do not suffer
from these disadvantages. Thus, we became interested
in utilizing the copper-catalyzed system to induce the
oxidative esterification to occur with aldehydes and sim-
ple alcohols while avoiding the limitations faced by most
oxidative esterification protocols.
During our investigation into the CDC reaction, we
discovered that the acyl C–H bond can be selectively
functionalized with alcohols4 and amines5 to generate
the corresponding esters and amides using copper salts
and TBHP as an oxidant (Scheme 1).
While the oxidative amidation of aldehydes can be
accomplished rapidly under mild conditions, the analo-
cat. [Cu]
TBHP
O
O
+
H
X R'
R'
R
H
R
X
O
O
CuBr
TBHP, 80 oC
O
O
X = O, NH
+
R1
O
O
R1
H
R2
R3
Scheme 1. Copper-catalyzed oxidative esterification and amidation of
R2
R3
aldehydes.
R1 = alkyl, aryl
R2 = alkyl, alkyl halide, aryl
R3 = alkyl, ether
Keywords: Copper; Indium; C–H Transformation; Oxidative esterifi-
cation.
*
Scheme 2. Copper-catalyzed stereoselective oxidative esterification of
aldehydes with b-dicarbonyl compounds.
Corresponding author. Tel.: +1 514 398 8457; fax: +1 514 398
3797; e-mail: cj.li@mcgill.ca
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.169

1034
W.-J. Yoo, C.-J. Li / Tetrahedron Letters 48 (2007) 1033–1035
Table 1. Optimization of the oxidative esterification of benzaldehyde
(entry 11) furnished the desired ester 3a in high yield.
Attempts at improving the yield with the introduction
of a solvent (toluene, acetonitrile, water, etc.) or a
different oxidant (O2, H2O2, cumene hydroperoxide,
tert-butyl peroxybenzoate, etc.) failed.
with 1-butanola
cat. [Cu], cat. [M]
TBHP, 80 oC, 16 h
O
O
+
HO
Ph
H
Ph
O
1a
2a
[Cu]
3a
With the optimized reaction conditions in hand, we
examined the scope of the copper/indium catalyst sys-
tem for the oxidative esterification of aldehydes with
simple alcohols (Table 2).8 In general, the copper/
indium catalyzed oxidative esterification occurs smoothly
to provide the desired ester in good yields. Sterically hin-
dered alcohols diminish the effectiveness of the reaction
(entries 2–4). The oxidative esterification reaction was
amenable to both electron-rich and electron-poor aro-
matic aldehydes (entries 6–9). More gratifying was the
compatibility of the reaction to proceed successfully
with primary and secondary aliphatic aldehydes as
substrates (entries 10–11). Unfortunately, due to the
oxidative nature of the reaction conditions, substrates
containing functional groups that readily oxidizes, such
as allyl alcohols and sulfides were shown to be poor
substrates for the oxidative esterification reaction.
Entry
[M]
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
CuOTfc
CuBr2
Cu(OTf)2
—
33
49
64
45
62
64
56
62
67
78
91
RhCl3ÆH2O
Ga(OTf)3
InCl3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
10
11d
Cu(ClO4)2Æ6H2O
Cu(ClO4)2Æ6H2O
a Benzaldehyde (1.0 equiv), 1-butanol (1.5 equiv), TBHP (1.1 equiv,
C = 5.5 M in decane), copper salt (5.0 mol %), and Lewis acid
(5.0 mol %).
b Reported yields were based on benzaldehyde and determined by
NMR using an internal standard.
c As a toluene complex.
d At 100 °C.
A tentative mechanism for the oxidative esterification of
aldehydes with simple alcohols is proposed in Scheme 3.
The oxidative esterification reaction may precede
through the initial formation of a hemiacetal intermedi-
ate 4, followed by oxidation of 4 by TBHP to generate
the corresponding ester.9
Under the hypothesis that the copper-catalyzed oxida-
tive esterification occurs through a hemiacetal inter-
mediate, we rationalized that a Lewis acid may aid its
development and ultimately lead to the formation of
the desired ester. Thus, we began our study with the
examination of a variety of high-valent metal salts as
co-catalyst for the oxidative esterification of benzalde-
hyde 1a with 1-butanol 2a (Table 1).
In conclusion, we have developed an oxidative esterifica-
tion reaction between aldehydes and alcohols catalyzed
OH
OR'
O
O
[O]
In the presence of Lewis acids, the formation of the
desired ester 3a increased (entries 2–5). Re-investigation
of the copper source demonstrated that both copper(I)
and copper(II) salts were viable catalysts, although
Cu(ClO4)2Æ6H2O proved to be the best choice (entries
6–10).7 Finally, increasing the reaction temperature
+
HO R'
R
R
H
R
OR'
4
Scheme 3. Tentative mechanism for the oxidative esterification of
aldehydes with alcohols.
Table 2. Oxidative esterification of aldehydes with simple alcoholsa
O
O
Cu(ClO4)2 6H2O, InBr3
TBHP, 100 oC, 16 h
+
HO R'
R
H
R
OR'
3a-k
1a-g
2a-e
Entry
Aldehyde
R
Alcohol
R0
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2a
2a
2a
2a
2a
2a
n-Bu
Me
Et
2-Propyl
tBu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
3a
3b
3c
3d
3e
3f
91
83
89
57
Trace
87
65
81
42
4-Me–C6H4
4-MeO–C6H4
4-Cl–C6H4
4-CN–C6H4
n-Pentyl
3g
3h
3i
10
11
3j
3k
91
85
1g
Cyclohexyl
a Aldehyde (1.0 equiv), alcohol (1.5 equiv), TBHP (1.1 equiv, C = 5.5 M in decane), Cu(ClO4)2Æ6H2O (5.0 mol %), and InBr3 (5.0 mol %).
b Isolated yields were based on the aldehyde.

W.-J. Yoo, C.-J. Li / Tetrahedron Letters 48 (2007) 1033–1035
1035
Mekhalfia, A.; Ollis, W. D. Synlett 1990, 347; (g)
Okimoto, M.; Chiba, T. J. Org. Chem. 1998, 53, 218; (h)
Espenson, J. H.; Zuolin, Z.; Zauche, T. H. J. Org. Chem.
1999, 64, 1191; (i) Gopinath, R.; Patel, B. K. Org. Lett.
2000, 2, 577; (j) Traivs, B. R.; Sivakumar, M.; Hollist, G.
O.; Borhan, B. Org. Lett. 2003, 5, 1031; (k) Sharghi, H.;
Sarvari, M. H. J. Org. Chem. 2003, 68, 4096; (l) Kiyooka,
S.; Ueno, M.; Ishii, E. Tetrahedron Lett. 2005, 46, 4639;
(m) Sayama, S.; Onami, T. Synlett 2004, 2739; Mori, N.;
Togo, H. Tetrahedron 2005, 61, 5915.
by a combination of Cu(ClO4)2Æ6H2O and InBr3 using
TBHP as an oxidant. Both aliphatic and aromatic alde-
hydes were compatible to the reaction conditions and
large excess of the alcohol was not required to obtain
the desired ester. Further investigation into the scope
and synthetic application are in progress and will be
reported in due course.
7. Both Cu(I) and Cu(II) salts were viable catalysts for the
oxidative esterification reaction. However, the oxidation
state of the active catalyst species cannot be predicted due
to the ability of Cu(I) salts to oxidatively, and Cu(II) salts
to reductively decompose peresters to generate radicals.
See: Sheldon, R. A.; Kochi, J. K. Metal-catalyzed Oxida-
tion of Organic Compounds; Academic Press: New York,
1981.
Acknowledgments
We thank the Canada Research Chair (Tier I) founda-
tion (to C.-J.L.), the CFI, NSERC, and CIC (AstraZen-
eca/Boehringer Ingelheim/Merck Frosst) for support of
our research.
8. General procedure for oxidative esterification of aldehydes
with alcohols: Under an atmosphere of nitrogen, TBHP
References and notes
(0.99 mmol, 1.1 equiv) was added to
Cu(ClO4)2Æ6H2O (0.046 mmol, 5.0 mol %),
a
mixture of
InBr3
1. Handbook of C–H Transformation: Applications in Organic
Synthesis; Dyker, G., Ed.; Wiley-VCH: New York, 2005.
2. (a) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acd. Sci.
U.S.A. 2006, 103, 8928; (b) Zhang, Y.; Li, C.-J. Angew.
Chem., Int. Ed. 2006, 45, 1949; (c) Li, Z.; MacLeod, P. D.;
Li, C.-J. Tetrahedron: Asymmetry 2006, 17, 590; (d) Li, Z.;
Li, C.-J. Eur. J. Org. Chem. 2005, 3173; (e) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2005, 127, 6968; (f) Li, Z.; Li, C.-J. J.
Am. Chem. Soc. 2005, 127, 3672; (g) Li, Z.; Li, C.-J. Org.
Lett. 2004, 6, 4887; (h) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2004, 126, 11810.
3. Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 56.
4. Yoo, W.-J.; Li, C.-J. J. Org. Chem. 2006, 71, 6266.
5. Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128,
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6. For representative examples, see: (a) Chiba, T.; Okimoto,
M.; Naga, H.; Taka, Y. Bull Chem. Soc. Jpn. 1982, 55,
335; (b) Wuts, P. G. M.; Bergh, C. L. Tetrahedron Lett.
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F. W. Tetrahedron Lett. 1988, 29, 5087; (f) Marko, I. E.;
(0.046 mmol, 5.0 mol %), aldehyde 1a–g (0.93 mmol,
1.0 equiv), and alcohol 2a–e (1.42 mmol, 1.5 equiv) at
room temperature. The reaction vessel was capped and
allowed to stir magnetically for 16 h at 100 °C.10 The
crude reaction mixture was purified by column chromato-
graphy (EtOAc–hexanes mixtures) to provide the esters
3a–k.
9. The oxidation of the hemiacetal intermediate 4 likely
occurs through a radical mechanism since radical scaven-
ger, 2,6-di-tert-butyl-4-methyl phenol (BHT) inhibits the
reaction. Radical based mechanisms have been proposed
for the oxidation of alcohols to aldehydes by galactose
oxidases. For recent mechanstic studies, see: (a) Himo, F.;
Eriksson, L. A.; Maseas, F.; Siegbahn, P. E. M. J. Am.
Chem. Soc. 2000, 122, 8031; (b) Whittaker, M. M.; Ballou,
D. P.; Whittaker, J. W. Biochemistry 1998, 37, 8426; (c)
Wachter, R. M.; Montague-Smith, M. P.; Branchaud, B.
P. J. Am. Chem. Soc. 1997, 119, 7743.
10. While no explosions were experienced during the synthesis
of the esters reported in this letter, great care should
always be exercised when handling peroxides in the
presence of metal salts and high temperatures.