Indium-catalyzed retro-claisen condensation

Article abstract of DOI:10.1002/anie.200702798

(Chemical Equation Presented) Retro-aldol reaction: Indium-catalyzed reaction of a 1,3-diketone with an alcohol proceeds under solvent-free conditions by nucleophilic attack of the alcohol on a carbonyl group of the 1,3-diketone and carbon-carbon bond cleavage by a retro-Claisen condensation to give an ester in high yield (see scheme). Using water and an amine as nucleophiles instead of an alcohol gave the corresponding carboxylic acid and amide.

Full text of DOI:10.1002/anie.200702798

Angewandte
Chemie
DOI: 10.1002/anie.200702798
Synthetic Methods
Indium-Catalyzed Retro-Claisen Condensation**
Atsushi Kawata, Kazumi Takata, Yoichiro Kuninobu,* and Kazuhiko Takai*
Esters are indispensable compounds both in daily life and in
academic and industrial laboratories. Thus, efficient methods
for synthesizing esters are important.[1] To date, various
methods have been employed for this purpose, including
condensation of alcohols and carboxylic acids,[2,3] acid anhy-
drides,[4] or acyl halides;[5] transesterification;[6] ester-inter-
change reactions;[7] mercury-catalyzed reaction of carboxylic
acids with acetylenes;[8] and enzyme-catalyzed methods.[9]
Recently, chemical transformations via carbon–carbon bond
cleavage have received much attention, because new skel-
etons can be constructed directly by using such reactions.[10]
We report herein indium-catalyzed synthesis of esters via
carbon–carbon bond cleavage, that is, retro-Claisen conden-
sation.[11]
several Lewis acids were investigated (Table 1, entries 2–8).
Scandium(III) triflate provided 3a in 72% yield (Table 1,
entry 2). This reactivity differs from that of ytterbium(III)
triflate, despite the fact that scandium and ytterbium belong
to the same group. Ytterbium(III) triflate provides a b-keto
enol ether through nucleophilic attack of an alcohol on a 1,3-
diketone followed by dehydration,[12] whereas lanthanum(III)
triflate provided 3a in 22% yield (Table 1, entry 3). The
reaction proceeded smoothly with copper(II) triflate, and 3a
was obtained in 92% yield (Table 1, entry 4); however,
copper(II) acetate did not catalyze the reaction (Table 1,
entry 5). Silver(I) triflate gave 3a in low yield (Table 1,
entry 6). When indium(III) triflate was used as catalyst, 3a
was formed quantitatively (Table 1, entry 7).
The reaction of 2,4-pentanedione (1a) with 2-phenyl-
ethanol (2a) in the presence of [{ReBr(CO)3(thf)}2] as the
catalyst at 808C for 24 h gave phenethyl acetate (3a) in 49%
yield (Table 1, entry 1). In this reaction, starting materials 1a
and 2a remained, and acetone was formed as a single side
product. The reaction did not proceed in the absence of the
catalyst (Table 1, entry 9). To improve the yield of the acetate,
The treatment of dissymmetric 1,3-diketone 1b with 2-
phenylethanol (2a) in the presence of 3 mol% of indium(III)
triflate under solvent-free conditions at 808C for 24 h
afforded phenethyl acetate (3a) with high selectivity, and
benzoate 3b was obtained as a side product (Table 2, entry 1).
The 1,3-diketone bearing two phenyl groups provided the
corresponding benzoate 3b in 90% yield (Table 2, entry 2).
Cyclohexane-1,3-dione (1d) afforded d-keto ester 3c by a
ring-opening reaction in 95% yield, without any side products
(Table 2, entry 3). A 1,3-diketone with a substituent on the
active methylene moiety, namely, 1e, gave the corresponding
acetate 3a in 95% yield (Table 2, entry 4). On using 2-
acetylcyclopentanone (1 f), the five-membered ring was
opened, and e-keto ester 3d was produced in 86% yield
(Table 2, entry 5).
Next we investigated several alcohols (Table 3). Alkyl
alcohols 2a and 2b furnished acetates 3a and 3e in 95% and
94% yields, respectively (Table 3, entries 1 and 2).[13] Allyl
alcohol afforded the corresponding allyl ester in 78% yield.
However, it was difficult to isolate the allyl ester because of its
low boiling point. Thus, 1,3-diketone 1a was changed to 2-
acetylcyclohexanone (1g). Treatment of 1g with allyl alcohol
2c provided allyl ester 3 f in 90% yield of isolated product
(Table 3, entry 3). Alcohols containing functional groups such
as carbon–carbon double and triple bonds, bromide, and ether
groups remained unchanged during the reaction, and the
corresponding acetates were formed in good to excellent
yields (Table 3, entries 4–8).
Table 1: Catalytic activity of metal complexes.
Entry Catalyst
Yield[%] [a]
Entry Catalyst Yield[%] [a]
1[b]
2
3
4
5
[{ReBr(CO)3(thf)}2] 49
6
7
8
9
AgOTf
In(OTf)3 98
InCl3
none
4
Sc(OTf)3
La(OTf)3
Cu(OTf)2
Cu(OAc)2
72
22
92
0
20
0
[a] Determinedby 1H NMR spectroscopy. [b] 1.5 mol%.
[*] A. Kawata, K. Takata, Dr. Y. Kuninobu, Prof. Dr. K. Takai
Division of Chemistry andBiochemistry
Graduate School of Natural Science and Technology
Okayama University
Tsushima, Okayama 700-8530 (Japan)
Fax: (+81)86-251-8094
E-mail: kuninobu@cc.okayama-u.ac.jp
ktakai@cc.okayama-u.ac.jp
The proposed reaction mechanism (Scheme 1) is as
follows: 1) coordination of a 1,3-dicarbonyl compound to a
metal center (Lewis acid), 2) nucleophilic attack of an alcohol
on a carbonyl group of 1,3-dicarbonyl compounds, 3) carbon–
carbon bond cleavage in a retro-aldol-type reaction to give an
ester, and 4) quenching of the resulting enolate by a proton to
regenerate the metal catalyst. In this reaction, step 3 is
important because it leads to the formation of esters and
determines the activity of the reaction.
[**] Financial support by a Grant-in-Aidfor Scientific Research on
Priority Areas (No. 18037049, “Advanced Molecular Transforma-
tions of Carbon Resources”) from the Ministry of Education,
Culture, Sports, Science, andTechnology of Japan, andfor Young
Scientists (B) (No. 18750088) from Japan Society for the Promotion
of Science, andOkayama Foundation for Science andTechnology is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 7793 –7795
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7793

Communications
Table 2: Indium-catalyzed reaction of a 1,3-dicarbonyl compound 1 with
2-phenylethanol (2a).
Entry 1,3-Dicarbonyl
compound
Yield[%] [a]
1
3a 90 (93)
3b 90 (92)
3b 0 (2)
2[b]
Scheme 1. Proposedmechanism for the formation of esters.
3[c]
On using water (4) or amine 6 instead of alcohols 2,
similar reactions proceeded, and the corresponding carbox-
ylic acid 5 and amide 7 were obtained in 85% and 99% yields,
respectively [Eqs. (1) and (2)].
3c 95 (98)
3a 95 (98)
4
5[d]
3a 4 (9)
3d 86 (88)
[a] Yieldof isolatedproduct. Yielddeterminedby
1H NMR spectroscopy
is reportedin parentheses. [b] 2a (1.2 equiv), 1158C. [c] 2a (1.5 equiv),
1158C. [d] 2a (1.2 equiv).
Table 3: Indium-catalyzed reaction of 2,4-pentanedione (1a) with alco-
hol 2.[a]
In summary, we have developed the indium-catalyzed
synthesis of esters by reactions of 1,3-dicarbonyl compounds
with alcohols. These reactions proceed by nucleophilic attack
of alcohols on a carbonyl group of 1,3-diketones and carbon–
carbon bond cleavage in a retro-aldol-type reaction. From a
different viewpoint, this can be regarded as a deacylation
reaction. Water and an amine could also be used as
nucleophiles, and resulted in the corresponding carboxylic
acid and amide.
Entry
1[c]
Alcohol
Yield[%] [b]
3a 95 (98)
2
3e 94 (96)
3[d]
3 f 90 (93)
4
5
3g 93 (>99)
Experimental Section
Synthesis of ester 3a (Table 3, entry 1): A mixture of 2,4-pentane-
dione (1a, 0.5 mmol), 2-phenylethanol (2a, 0.25 mmol), and In(OTf)3
(4.2 mg, 0.0075 mmol) was stirred at 808C for 24 h. The product was
isolated by column chromatography on silica gel to give 3a as a
colorless liquid.
3h 97 (>99)
3i 85 (86)
6
Received: June 25, 2007
Published online: September 4, 2007
7
8
3j 91 (95)
3i 90 (91)
[a] 1a (2.0 equiv), 2 (1.0 equiv). [b] Yieldof isolatedproudct. Yield
determined by 1H NMR is reportedin parentheses. [c] In(OTf)
(3.0 mol%). [d] 2-Acetylcyclohexanone was used as 1,3-diketone.
À
Keywords: C C activation · esters · indium · retro reactions ·
synthetic methods
3
.
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Angewandte
Chemie
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these results elsewhere.
Angew. Chem. Int. Ed. 2007, 46, 7793 –7795
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7795