Copper-catalyzed synthesis of esters from ketones. Alkyl group as a leaving group

Article abstract of DOI:10.1021/ol800576w

The conversion of ketones to esters has been achieved through the use of Cu catalyst and tetrabutylammonium nitrite. This reaction involves the activation of the less activated C-C bond, and the alkyl group is removed as a leaving group. Various isopropyl ketones are found to be good substrates for this reaction.

Full text of DOI:10.1021/ol800576w

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2067-2070
Copper-Catalyzed Synthesis of Esters
from Ketones. Alkyl Group as a Leaving
Group
Yuji Nakatani, Yuichiro Koizumi, Ryu Yamasaki, and Shinichi Saito*
Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science,
Kagurazaka, Shinjuku, Tokyo 162-8601, Japan
ssaito@rs.kagu.tus.ac.jp
Received March 13, 2008
ABSTRACT
The conversion of ketones to esters has been achieved through the use of Cu catalyst and tetrabutylammonium nitrite. This reaction involves
the activation of the less activated C-C bond, and the alkyl group is removed as a leaving group. Various isopropyl ketones are found to be
good substrates for this reaction.
The catalytic cleavage of a carbon-carbon single bond
by transition-metal complexes is a potentially useful
transformation, and extensive studies have been carried
out.1 In most reactions, however, highly strained com-
pounds such as three- or four-membered carbocycles,2
compounds with good leaving groups which contain a
carbon atom,3 or chelating compounds4 have been utilized
as the substrates, and the catalytic cleavage of a less
activated carbon-carbon bond5 remains a challenging
issue. Recently, we developed the copper-catalyzed nitra-
tion of aryl iodides by tetrabutylammonium nitrite.6 When
we carried out the Cu-catalyzed nitration of 4-iodoac-
etophenone, we noticed that the acetyl group was con-
verted to butoxycarbonyl group and a small amount of a
butyl ester instead of the expected nitro compound (4-
nitroactophenone) was isolated. The result indicated that
C-C bond was activated and an unusual alkoxylation-
dealkylation reaction proceeded. We examined the reaction
in detail and developed an efficient method for the
conversion of ketones to esters. In this paper, we report
the copper-catalyzed synthesis of esters from ketones by
formal alkoxylation-dealkylation.
We studied the reaction of various aryl ketones with
tetrabutylammonium nitrite (2a, 1.2 equiv). The results
are summarized in Table 1. The reactions were carried
out at 150 °C in o-xylene. The reaction of methyl ketone
1a without catalyst did not proceed at all (entry 1). When
the reaction was carried out in the presence of CuI (10
mol %),7 however, the desired ester 3a was isolated in
21% yield (entry 2). We also carried out the screening of
the ligands (entries 3-9). Though various ligands were
evaluated, most ligands were not effective (entries 3-7).
The best result was achieved when the reaction was
performed in the presence of 1,10-phenanthroline (L1, 20
mol %) (entry 8), and decreasing the amount of L1 to 10
mol % did not affect the yield of 3a (entry 9). Next, we
(1) (a) Murai, M.; Ito, Y. ActiVation of UnreactiVe Bonds and Organic
Synthesis; Murai, M., Ed.; Springer: Berlin, 1999; pp 99-129. (b) Jun, C.-H
Chem. Soc. ReV. 2004, 33, 610–618.
(2) (a) Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117–3179.
(b) Bart, S. C.; Chirik, P. J. J. Am. Chem. Soc. 2003, 125, 886–887. (c)
Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124, 13976–
13977.
(3) (a) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126,
13904–13905. (b) Tobisu, M.; Kita, Y.; Chatani, N. J. Am. Chem. Soc.
2006, 128, 8152–8153.
(4) (a) Jun, C. -H.; Moon, C. W.; Lee, D.-Y. Chem. Eur. J. 2002, 8,
2422–2428. (b) Wakui, H.; Kawasaki, S.; Satoh, T.; Miura, M.; Nomura,
M. J. Am. Chem. Soc. 2004, 126, 8658–8659.
(5) Few examples on the cleavage of an unreactive carbon-carbon bond
are known, see: (a) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem.
Soc. 2006, 128, 11368–11369. (b) Shimada, T.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 6646–6647.
(7) Though Cu(OAc)2 and Cu(OTf)2 were as effective as CuI, we chose
CuI as a catalyst for this reaction due to its stability and low price. Cu
bronze, CuCl, CuO, and Cu2O were less effective.
(6) Saito, S.; Koizumi, Y. Tetrahedron Lett. 2005, 46, 4715–4717.
10.1021/ol800576w CCC: $40.75
Published on Web 04/19/2008
2008 American Chemical Society

was ranked as follows: secondary alkyl > primary alkyl
. aryl, tertiary alkyl. On the other hand, the migratory
amplitude of the alkyl groups in the Baeyer-Villiger
reaction follows the general order: tertiary alkyl >
secondary alkyl, aryl > primary alkyl.9
Table 1. Copper-Catalyzed Synthesis of Esters from Ketonesa
As the isopropyl ketone was found to be most reactive,
we next examined the generality of this reaction, and the
results are summarized in Table 2. Isobutyrophenone 1h
entry compd
R
ligand (mol %)
yieldb (%)
1c
2
3
1a Me
1a Me
1a Me
none
none
0
21
21
tri-o-tolylphosphine (20)
tris(2,4-di-tert-butylphenyl)
phosphate (20)
TMEDAd (20)
Table 2. Copper-Catalyzed Synthesis of Esters from Ketonesa
4
5
6
7
8
9
10
11
12
13
14
15
16
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
23
19
22
17
26
25
3
DABCOe (20)
L-proline (20)
1,10-phenanthroline (L1) (20)
L1 (10)
L1 (10)
1b
1c
H
Et
L1 (10)
14f
76
81
64h
0
1d i-Pr L1 (10)
1dg i-Pr L1 (10)
1eg Cy
L1 (10)
t-Bu L1 (10)
1g Ph L1 (10)
1f
0
a All reactions were carried out using 1 mmol of 1 in o-xylene (0.5
mL) at 150 °C in a test tube sealed with a screw-cap under argon. b Isolated
yields. A significant amount of the starting material remained unchanged
when the yield of 3a was low. c The reaction was carried out without
catalyst. d TMEDA ) N,N,N′,N′-tetrametylethylenediamine. e DABCO
) 1,4-diazabicyclo[2.2.2]octane. f R-Oximino ketone (4) was isolated
as the main product (54% yield). g A larger amount (1.8 equiv) of 2a was
used. h Yield determined by NMR.
carried out the conversion of other ketones in the presence
of CuI (10 mol %) and 1,10-phenanthroline (10 mol %).
Aldehyde 1b was not reactive under the reaction condi-
tions, and only a small amount of the ester 3a was isolated
(entry 10). Though the reaction of ethyl ketone 1c
proceeded, the isolated yield of the ester 3a was low (14%
yield): the ketone 1c was nitrosated, and R-oximino ketone
(4) was isolated as the main product (entry 11).8 To our
surprise, isopropyl ketone 1d was converted to the ester
in high yield (entry 12). Furthermore, the yield improved
by increasing the amount of 2 to 1.8 equiv (entry 13).
Cyclohexyl ketone was also converted to 3a in moderate
yield (entry 14). On the other hand, the reaction of tert-
butyl ketone 1f or phenyl ketone 1g did not proceed at
all (entries 15 and 16). It is noteworthy that the observed
leaving group ability of alkyl groups for this reaction is
quite different from the migratory apititude of alkyl groups
in the Baeyer-Villiger reaction.9 Thus, the leaving group
ability of alkyl groups for the copper catalyzed reaction
a All reactions were carried out using 1 mmol of 1 in o-xylene (0.5
mL) at 150 °C in a test tube sealed with a screw-cap under argon. b Isolated
yields. c Determined by GC-MS analysis. d n-Butyl benzoate was isolated
in 12% yield.
was converted to the corresponding ester in 80% yield
(entry 2). Aryl isopropyl ketones substituted with an
electron-donating group such as methyl, methoxy, or tert-
butyl group were converted to the corresponding esters
in high yields (entries 3-5). Ketones substituted with an
(8) It is known that the R-position of ketone was easily nitrosated by
nitrites, see: Ru¨edi, G.; Oberli, M. A.; Nagel, M.; Weymuth, C.; Hansen,
H.-J. Synlett 2004, 13, 2315–2318.
2068
Org. Lett., Vol. 10, No. 10, 2008

electron-withdrawing group such as chloro, trifluorometh-
yl, or nitro also gave the corresponding esters in good
yields (entries 6-8). However, amino ketone 1o was not
a proper substrate for this transformation: the amino group
was eliminated by the Sandmeyer-type reaction,10 and
n-butyl benzoate was isolated in 12% yield (entry 9).
Naphthyl ketone 1p also gave the corresponding ester
(entry 10). As for heteroaromatic derivatives, benzofuryl,
pyridyl, and quinolyl ketones were converted to the
corresponding esters in moderate yields (entries 11-13),
while the reactivity of N-methyl indolyl ketone 1t was
low. The reaction of N-methyl indolyl ketone (1t) stopped
in 6 h, and further conversion was not observed even after
prolonged heating (entry 14).
Scheme 1
.
Isolation of the Products Derived from the Reaction
of 1w
We next carried out the reaction of alkyl-alkyl ketone
using 2-methyl-5-phenylpentan-3-one (1u) (eq 1). The iso-
propyl group was eliminated preferentially, and the corre-
sponding ester 3u was isolated in 61% yield. The trifluoro-
methyl group, as well as the isopropyl group, could be the
leaving group in this reaction, and the reaction of 1v
proceeded smoothly under similar reaction conditions to give
the ester in high yield (eq 2).
to other ketones could be explained in terms of the
bulkiness of the isopropyl group: the bulky isopropyl
group would facilitate the conversion of the tetrahedral
intermediate (9) to the ester (3),13 and therefore, the rate
of the reaction would be accelerated. On the other hand,
tert-butyl ketone is so bulky that the addition of butoxy
copper does not proceed to form the corresponding copper
complex 9. Although the acid-catalyzed formation of
R-ketooxime from ketone in the presence of NaNO2 has
been reported in the literature8 and a similar mechanism
which involves the oxidation of the R-position of the
ketone could be postulated, this reaction would not
proceed via this pathway. It is difficult to suppose the
preferential oxidation of the secondary alkyl group (iso-
propyl group) bound to the carbonyl group, since it was
reported that the primary alkyl group, not the secondaty
alkyl group, was prone to be oxidized.8 If this reaction
proceeds via the oxidation, primary alkyl groups would
be better leaving groups. Furthermore, the result of the
reaction of a trifluoromethyl ketone indicates that the
In order to understand the fate of the volatile leaving
group (isopropyl group) in this reaction, we carried out
the reaction of ketone 1w and analyzed the products
(Scheme 1). We obtained 3a (78% yield), benzylacetone
(5), and other derivatives 6 and 78 from the reaction
mixture.
Based on these results, a possible mechanism of the
reaction is shown in Scheme 2. Initially, the reaction of
tetrabutylammonium nitrite 2a and Cu(I) species would
occur to afford the copper complex (8),11 which subse-
quently inserted into the carbonyl group (1),12 and the
ester (3) would be generated by the elimination of the
alkyl copper species (10). Finally, the reductive elimina-
tion proceeded and the copper catalyst would be regener-
ated. The higher reactivity of isopropyl ketones compared
Scheme 2. Mechanistic Hypothesis for the Conversion of
Ketones to Esters
(9) For reviews, see: (a) ten Brink, G. J.; Arends, I. W. C. E.; Sheldon,
R. A. Chem. ReV. 2004, 104, 4105–4124. (b) Heaney, H. Top. Curr. Chem.
1993, 164, 1–19.
(10) Shin, H. H.; Park, Y. J.; Kim, Y. H. Heteroatom Chem. 1993, 4,
259–262.
(11) It is known that nitrite is reduced by copper complex such as copper-
containig nitrite reductase to afford a Cu-NO complex, see: (a) Tocheva,
E. I.; Rosell, F. I.; Mauk, A. G.; Murphy, M. E. P. Science 2004, 304,
867–870. (b) Burg, A.; Lozinsky, E.; Cohen, H.; Meyerstein, D. Eur.
J. Inorg. Chem. 2004, 367, 5–3680.
Org. Lett., Vol. 10, No. 10, 2008
2069

reaction proceeds via the addition-elimination pathway,
rather than the oxidation pathway, since the trifluoromethyl
group is a better leaving group and would not be oxy-
genated easily.
Finally, we carried out the synthesis of esters by using
other tetraalkylammonium nitrites. Nitrite 2b showed high
reactivity as well as 2a, and the ketone 1d was converted to
the ethyl ester 11 in 81% yield (eq 3). Although the ketone
1d was converted to benzyl ester 12 by using 2c, the yield
was low (eq 4).
In summary, we developed an efficient method for the
conversion of ketones to esters by using a copper catalyst
and tetrabutylammonium nitrite. A less activated C-C
bond is cleaved catalytically in the presence of a Cu
catalyst, and an alkyl group is the leaving group in this
reaction. The detailed mechanistic studies of this reaction
are in progress.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) An example of the insertion of an alkoxy copper complex to the
carbonyl group exists, see: Kubota, M.; Yamamoto, T.; Yamamoto, A. Bull.
Chem. Soc. Jpn. 1979, 52, 146–150.
(13) This process would be the rate-determining step of this reaction.
OL800576W
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Org. Lett., Vol. 10, No. 10, 2008