Highly stereoselective oxidative esterification of aldehydes with β-dicarbonyl compounds

Article abstract of DOI:10.1021/jo0606103

Copper-catalyzed oxidative esterification of aldehydes with β-dicarbonyl compounds was developed using tert-butyl hydroperoxide as an oxidant. In general, the enol esters were synthesized in good yields (up to 87%) and high stereoselectivity under the optimized reaction conditions.

Full text of DOI:10.1021/jo0606103

SCHEME 1. CDC Reactions for C-C Bond Formation
Highly Stereoselective Oxidative Esterification of
Aldehydes with â-Dicarbonyl Compounds
Woo-Jin Yoo and Chao-Jun Li*
SCHEME 2. Oxidative Esterification of Aldehydes
Department of Chemistry, McGill UniVersity, 801 Sherbrooke
Street West, Montreal, Quebec H3A 2K6, Canada
cj.li@mcgill.ca
ReceiVed March 20, 2006
derivatives such as acid anhydrides or chlorides.2 Direct
oxidative transformation of an aldehyde moiety to an ester has
been accomplished in a variety of ways, such as electrochemical
oxidation or through the use of transition metals as catalyst in
the presence of an oxidant.3 Often, these procedures involve
the use of a large excess of reagents and expensive catalysts.
Furthermore, competing side reactions, such as the oxidation
of the alcohol and aldehyde substrates, complicate matters.
Copper-catalyzed oxidative esterification of aldehydes with
â-dicarbonyl compounds was developed using tert-butyl
hydroperoxide as an oxidant. In general, the enol esters were
synthesized in good yields (up to 87%) and high stereose-
lectivity under the optimized reaction conditions.
Recently, there has been a concerted effort in developing
facile conversion of aldehydes to esters. Such protocols involve
the use of Oxone,4 pyridinium hydrobromide perbromide,5 I2,6
Al2O3/CH3SO3H,7 and H2O2 as oxidants for the esterification
8
of aldehydes. While these methods have been demonstrated to
be useful for simple alcohol substrates, to the best of our know-
ledge, there are no published examples in which a â-dicarbonyl
or its corresponding enol form are used as substrates for
oxidative esterification. As part of our continuing interest in
the utilization of C-H bonds for bond formation processes, we
wish to report an effective copper-catalyzed oxidative esterifi-
cation of aldehydes with â-dicarbonyl compounds.
To begin our study, the effect of the various reaction
parameters on the oxidative esterification of benzaldehyde 3a
with â-diketone 4a was examined (Table 1). Initially, on the
basis of our earlier report1a on the CDC reaction of allylic C-H
bond with activated methylene compounds, the combination of
CuBr and CoCl2 was examined as cocatalyst (entry 1).
Subsequently, it became apparent that CoCl2 was not required
for the esterification reaction (entry 2). Furthermore, decreasing
The development of efficient methods for bond formation
processes is of great interest to chemists. Carbon-carbon (C-
C) bond formation often involves prefunctionalized starting
materials and thus requires additional synthetic steps toward
the formation of a single chemical bond. The direct utilization
of carbon-hydrogen (C-H) bonds to from C-C bonds would
be highly desirable since it would eliminate prefunctionalization
of the substrates and make synthetic steps shorter. With respect
to this goal, we and others have been developing cross-
dehydrogenative coupling (CDC) reactions for C-C bond
formation (Scheme 1).1
During the course of our investigations on the CDC reaction
between cyclic alkene substrates 1 with activated methylene
compounds 2,1c we uncovered an interesting competing reaction
pathway when an aldehyde was introduced into the system. With
catalytic amounts of copper and cobalt salts, in the presence of
an oxidant such as tert-butyl hydroperoxide (TBHP), oxidative
esterification of the aldehyde occurred (Scheme 2).
(2) Larock, R. C. ComprehensiVe Organic Transformation; VCH: New
York, 1999.
(3) 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. 1986, 27, 3995. (c) Connor, B.; Just, G.
Tetrahedron Lett. 1987, 28, 3235. (d) Murahashi, S.; Naota, T.; Ito, K.;
Maeda, Y.; Taki, H. J. Org. Chem. 1987, 52, 4319. (e) William, D. R.;
Klingler, F. D.; Allen, E. E.; Lichtenthaler Tetrahedron Lett. 1988, 29, 5087.
(f) Marko, I. E.; 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) Kiyooka, S.; Ueno, M.;
Ishii, E. Tetrahedron Lett. 2005, 46, 4639.
Traditionally, synthesis of esters often involves the nucleo-
philic addition of an alcohol to activated carboxylic acid
(1) For representative examples, see the following. sp3 C-H and sp3
C-H: (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 56. (b) Li, Z.; Li,
C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (c) Zhang, Y.; Li, C.-J. Angew.
Chem., Int. Ed. 2006, 45, 1949. (d) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc.
2006, 128, 4242. sp3 C-H and sp C-H: (e) Li, Z.; Li, C.-J. Org. Lett.
2004, 6, 4997. (f) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (g)
Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003,
125, 15312. (h) Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. J. Chem.
Res. Miniprint 1993, 2827. sp2 C-H and sp2 C-H: (i) Li, Z.; Li, C.-J. J.
Am. Chem. Soc. 2005, 127, 6968. (j) Hatamoto, Y.; Sakaguchi, S.; Ishii, Y.
Org. Lett. 2004, 6, 4623. (k) Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y.
J. Am. Chem. Soc. 2003, 125, 1476. (l) Jia, C.; Kitamura, T.; Fujiwara, Y.
Acc. Chem. Res. 2001, 34, 633. (m) Tsuji, J.; Nagashima, H. Tetrahedron
1984, 40, 2699. (n) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem.
Soc. 2004, 126, 6556. sp C-H and sp C-H: (o) Nicolaou, K. C.; Zipkin,
R. E.; Petasis, N. A. J. Am. Chem. Soc. 1982, 104, 5558.
(4) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett.
2003, 5, 1031.
(5) Sayama, S.; Onami, T. Synlett 2004, 2739.
(6) (a) Mori, N.; Togo, H. Tetrahedron 2005, 61, 5915. (b) Inch, T. D.;
Ley, R. V.; Rich, P. J. Chem. Soc. C 1968, 1693. (c) Eliel, E. L.; Clawson,
L.; Knox, D. E. J. Org. Chem. 1985, 50, 2707.
(7) Sharghi, H.; Sarvari, M. H. J. Org. Chem. 2003, 68, 4096.
(8) (a) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567. (b)
Gopinath, R.; Patel, B. K. Org. Lett. 2000, 2, 577. (c) Sato, K.; Hyodo, M.;
Takagi, J.; Aoki, M.; Noyori, R. Tetrahedron Lett. 2000, 41, 1439. (d)
Gopinath, R.; Barkakaty, B.; Talukdar, B.; Patel, B. K. J. Org. Chem. 2003,
68, 2944.
10.1021/jo0606103 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/08/2006
6266
J. Org. Chem. 2006, 71, 6266-6268

TABLE 1. Optimization of Reaction Conditionsa
TABLE 2. Copper-Catalyzed Oxidative Esterification of
Aldehydesa
alde-
entry hyde
â-dicarb-
yieldb
prod (%)
yield (%)
yield (%)
conversionc
(%)
R
onyl
R′
Me
Et
Me
CH2Cl OEt
Ph
Me
Me
Me
Me
Me
R′′
entry
catalyst
of 5ab
of 6b
1
2
3
4
5
6
7
8
9
3a Ph
4a
4b
4c
4d
4e
4c
4c
4c
4c
4c
Me
Et
OMe
5a
5b
5c
5d
5e
5f
57c
80
84
49
86
81
81
72
80
89
1d
2d
3
CuBr/CoCl2
CuBr
CuBr
CuBr
CuCl
51
51
64
53
54
26
54
49
0
10
10
7
10
18
9
7
19
0
100
100
92
83
100
70
95
91
95
95
3a Ph
3a Ph
3a Ph
3a Ph
3b 4-F-C6H4
3c 4-OMe-C6H4
3d C5H11
4e
5
OEt
OMe
OMe 5g
OMe 5h
OMe
OMe
6
CuI
7
CuBr2
8
9
10
Cu(OAc)2
Cu(OTf)2
CuOTff
3e cyclohexyl
3f CH(CH2CH3)2
5i
5j
10
0
0
a Aldehyde (1 equiv), â-carbonyl (1.1 equiv), CuBr (2.5 mol %), and
TBHP (1.5 equiv). b Isolated yields were based on the aldehyde. c The (E)-
stereoisomer was also isolated with a yield of 9%.
a Benzaldehyde (1 equiv), 2,4-pentanedione (1.1 equiv), TBHP (1.5
equiv), cobalt(II) chloride (10.0 mol %), and copper salt (2.5 mol %).
b Reported yields were based on benzaldehyde and determined by NMR
using as internal standard. c Conversion was based on benzaldehyde. d TBHP
(2.0 equiv). e TBHP (1.0 equiv). f As a toluene complex.
SCHEME 3. Oxidative Esterification of a Simple Alcohol
the amount of TBHP to 1.5 equiv improved the yield (entry 3).
After a variety of copper salts were screened, CuBr was found
to be the most effective (entries 3 and 5-9).9 Attempts to
improve the yield through the use of different oxidants (O2,
H2O2, cumene hydroperoxide, tert-butyl peroxybenzoate, etc.)
and solvents (toluene, dioxane, DMSO, water, etc.) were
unsuccessful. The reaction temperature played an important role
in the esterification. At lower temperatures (20, 50 °C) lower
yields were obtained, while increasing the temperature to 100
°C resulted in the complete loss of stereoselectivity with no
improvement in the overall yield.
Under the standard conditions, various â-dicarbonyl com-
pounds 4a-f were used as substrates for the oxidative esteri-
fication of aldehydes 3a-f (Table 2). In general, the reaction
proved to be highly stereoselective for the (Z)-enol esters 5a-
j, and the level of stereoselectivity was dependent on the nature
of the â-dicarbonyl substrates. With â-diketones, the level of
stereoselectivity varies (entries 1-2). However, with â-ke-
toesters 4c-e, the oxidative esterification was shown to be
highly stereoselective to furnish (Z)-enol esters exclusively
(entries 3-11). When the reaction was carried out with
substituents on the active methylene position, the desired ester
was not obtained. Both aliphatic and aromatic aldehydes were
amenable to the reaction conditions and the electronic nature
of the aldehydes did not appear to greatly influence the yield
of the reaction. When the reaction was extended to simple
primary alcohol systems such as 1-butanol, the oxidative
esterification also proceeded, albeit at a lower yield (Scheme
3). Furthermore, when a cyclic â-diketone was subjected to the
optimized reaction conditions, esterification was not observed.
Thus, it appears that substrates that can bind to the copper metal
in a bidentate fashion, such as â-diketones and â-ketoesters,
are good substrates for the esterification reaction.
Possible reaction mechanisms to explain the results of the
copper-catalyzed oxidative esterification of aldehydes with
â-dicarbonyl compounds are proposed in Scheme 4. Copper
complex 6 generated from a copper salt with â-dicarbonyl
compounds 4a-e may coordinate with aldehydes 3a-f and
undergo an internal nucleophilic addition to form copper
hemiacetal 7. H-abstraction of copper complex 7 by a radical
generated from the copper-catalyzed decomposition of TBHP
followed by a single-electron transfer (SET) of the hemiacetal
radical to the copper metal leads to the desired ester 5a-j.10
Alternatively, copper complex 6 can decompose TBHP to
generate a radical, which can then abstract the hydrogen of
aldehydes 3a-f. The newly formed acyl radical can undergo
SET with copper to produce a Cu(III) complex 8 that can
reductively eliminate to release the desired ester 5a-j.11 For
metal-catalyzed oxidation reactions involving TBHP, a radical
mechanism is often invoked. Indeed, the introduction of a radical
scavenger, 2,6-di-tert-butyl-4-methyl phenol (BHT), to the
reaction between aldehyde 3a and â-diketone 4a prevented the
esterification process and provided only trace amounts of 5a
with nearly quantitative recovery of the unreacted aldehyde 3a.
In conclusion, we have developed a copper-catalyzed oxida-
tive esterification between an aldehyde and a â-dicarbonyl
compound using TBHP as an oxidant. The reaction was found
to be highly stereoselective to provide the enol esters in good
yields. Further investigations into the scope, mechanism, and
(10) SET of ketyl radical intermediates have been proposed in the
oxidation of alcohols to aldehydes by galactose oxidases. For recent
mechanistic 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.
(11) Copper(III) intermediates have been proposed for copper-catalyzed
allylic oxidation of alkenes with peresters. See: Eames, J.; Watkinson, M.
Angew. Chem., Int. Ed. 2001, 40, 3567.
(9) Both Cu(I) and Cu(II) salts were viable catalysts for the esterification
reaction. However, the oxidation state of the active catalytic 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 Oxidations of Organic Compounds;
Academic Press: New York, 1981.
J. Org. Chem, Vol. 71, No. 16, 2006 6267

SCHEME 4. Proposed Mechanism for Copper-Catalyzed Oxidative Esterification of Aldehydes
(Z)-4-Oxopent-2-en-2-yl benzoate (5a) (Table 2, entry 1): Rf
0.30 (EtOAc/hexane ) 1:4); H NMR (CDCl3, 400 MHz) δ 8.19
synthetic application of this reaction are currently under
investigation in our laboratory.
1
(m, 2H), 7.69 (m, 1H), 7.58 (m, 2H), 5.99 (s, 1H), 2.29 (s, 3H),
2.25 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 195.0, 163.1, 157.8,
133.5, 129.9, 128.7, 128.4, 117.1, 31.0, 21.5. The spectral data are
consistent with those reported in the literature.12
Experimental Section
General Procedure for the Copper-Catalyzed Oxidative
Esterification of Aldehydes with â-Dicarbonyl Compounds. To
a mixture of CuBr (3.3 mg, 0.025 mmol, 2.5 mol %), aldehyde 3a
(0.100 mL, 0.985 mmol), and â-diketone 4a (0.11 mL, 1.1 mmol)
was added tert-butyl hydroperoxide (TBHP, 5.5 M in decanes, 0.27
mL, 1.5 mmol) under an inert atmosphere (N2) at room temperature.
The reaction vessel was capped and stirred overnight at 80 °C. The
crude reaction mixture was purified by column chromatography
on silica gel (EtOAc/hexane ) 1:4) to provide 6 (18.3 mg, 0.0896
mmol, 9%) and 5a (114.0 mg, 0.558 mmol, 57%) as a clear
colorless oil.
Acknowledgment. We thank the Canada Research Chair
(Tier I) foundation (to C.J.L.), the CFI, NSERC, and CIC
(AstraZeneca/Boehringer Ingelheim/Merck Frosst) for support
of our research.
Supporting Information Available: Representative experi-
mental procedure and characterization of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(Z)-4-Oxopent-2-en-2-yl benzoate (6): Rf 0.44 (EtOAc/hexane
1
) 1:4); H NMR (CDCl3, 400 MHz) δ 8.07 (m, 2H), 7.63 (m,
JO0606103
1H), 7.49 (m, 2H), 6.23 (s, 1H), 2.45 (s, 3H), 2.26 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 197.1, 163.7, 162.7, 133.7, 129.9, 128.9,
128.5, 116.5, 32.3, 18.8. The spectral data are consistent with those
reported in the literature.12
(12) Negishi, E.; Liou, S.; Xu, C.; Shimoyama, I.; Makabe, H. J. Mol.
Catal. Chem. A. 1999, 143, 279.
6268 J. Org. Chem., Vol. 71, No. 16, 2006