Indium-catalyzed reductive esterification of a carboxylic acid: Sequential preparation of an ester and symmetrical ether

Article abstract of DOI:10.1002/adsc.201100524

An unprecedented reductive dimerization of two carboxylic acids to produce ester derivatives by a combination catalyst involving InBr₃ and sulfuric acid is described. A sequential conversion of the in-situ formed ester to a symmetrical ether by indium-catalyzed deoxygenation of the ester with a hydrosilane in the same pot was also demonstrated. Copyright

Full text of DOI:10.1002/adsc.201100524

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DOI: 10.1002/adsc.201100524
Indium-Catalyzed Reductive Esterification of a Carboxylic Acid:
Sequential Preparation of an Ester and Symmetrical Ether
Norio Sakai,a,* Yuta Usui,a Reiko Ikeda,a and Takeo Konakaharaa
a
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science
(RIKADAI), Noda, Chiba 278-8510, Japan
Fax : (+81)-4-7123-9890; e-mail: sakachem@rs.noda.tus.ac.jp
Received: July 4, 2011; Revised: August 1, 2011; Published online: December 8, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100524.
Abstract: An unprecedented reductive dimerization
of two carboxylic acids to produce ester derivatives
by a combination catalyst involving InBr3 and sulfu-
ric acid is described. A sequential conversion of the
in-situ formed ester to a symmetrical ether by
indium-catalyzed deoxygenation of the ester with a
hydrosilane in the same pot was also demonstrated.
an equimolar condensation of a carboxylic acid and
an alcohol has been widely developed.[3] Another ap-
proach has been to establish a disproportionation re-
action that consists of the condensation of two identi-
cal molecules. For example, the Tishchenko reaction,
which involves dimerization of two aldehydes to di-
rectly produce a functionalized ester, has been devel-
oped by the employment of various Lewis acids or
transition metal catalysts (path b in Scheme 1).[4]
Metal-catalyzed oxidative dimerization of primary al-
cohols to esters has also been achieved using transi-
tion metal complexes (path c in Scheme 1).[5]
Keywords: esterification; esters; etherification;
ethers; indium; reduction; silanes
Despite the fact that the various synthetic ap-
proaches to ester derivatives by the conventional con-
The synthesis of esters has a fundamentally important densation and metal-catalyzed dimerization method
and central position in organic synthesis.[1] During the described above have well-established scope and utili-
past two decades, the synthetic approach to esters has ty, as far as can be ascertained, there is no reported
attracted much attention, from the viewpoint of envi- example of the direct synthesis of ester derivatives
ronmental-friendly and atom-efficient preparations. from two identical carboxylic acids in one pot (path d
The conventional access to an ester derivative is in Scheme 1). Herein we report that the addition of a
made possible via condensation of a carboxylic acid, Brønsted acid (sulfuric acid) to a reaction mixture, in
or its acid derivative, with excess amounts of an alco- which InBr3 catalyzes the reduction of a carboxylic
hol in the presence of an acid catalyst or a dehydrat- acid by a hydrosilane leading to a primary alcohol,
ing agent (path a in Scheme 1).[2] Recently, to avoid undergoes unprecedented esterification of two car-
the use of excess amounts of condensing substrates, boxylic acids to directly produce ester derivatives.[6]
We also disclose a sequential conversion of the in-situ
formed ester to a symmetrical ether by indium-cata-
lyzed deoxygenation of the ester with a hydrosilane in
a same pot.
The esterification of 3-phenylpropionic acid with
InBr3, Et3SiH and several Brønsted acids was investi-
gated as a model reaction (Table 1). When the reac-
tion was conducted with 5 mol% of InBr3, 4 equiv. of
Et3SiH in the presence of 0.2 equiv. of 98% sulfuric
acid in CHCl3 under an air atmosphere, the ester 1a
was obtained in 85% yield as a major product (run 1).
Decreasing the amounts of both the reducing agent
and the Brønsted acid to 3 equiv. and 0.1 equiv. result-
Scheme 1. Several approaches to an ester derivative.
ed in the maintenance of high reactivity of this reduc-
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Norio Sakai et al.
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Table 1. Examination of the reaction conditions.
Table 2. Single-step synthesis of various esters from a car-
boxylic acid.[a]
Run Et3SiH [equiv.] Promoter [equiv.]
Yield [%][a]
1a
2a
1
2
3
4
5
6
7
8
4
3
3
4
4
4
3
4
H2SO4
H2SO4
H2SO4
HCl
AcOH
PTS
N
85
84
90
trace
trace
trace
NR NR
NR NR
11
38
76
40
4 ꢁ MS
–
ND 40 [46]b)
[a]
[b]
NMR yield.
The yield of the corresponding silyl ether 2a’ is given in
parentheses.
tion (runs 2 and 3). Running this reaction with hydro-
chloric acid and acetic acid retarded the reduction to
a completely inactive state (runs 4 and 5). The use of
p-toluenesulfonic acid (PTS) showed a slight effect,
but the primary alcohol 2a was obtained as a major
product (run 6). Because the addition of 4ꢁ MS in-
stead of PTS apparently improved the yield of the
ester, sulfuric acid may function as a dehydrating
agent between the formed primary alcohol and a car-
boxylic acid to drive the equilibrium to completion
(run 7).[7] When the reduction was performed without
sulfuric acid, the ester was not formed at all, and a
mixture of the corresponding alcohol 2a and silyl
ether derivative 2a’ was obtained after aqueous work-
up (run 8). As described above, this reaction proceed-
[a]
Isolated yield.
[b]
Yield of the corresponding alcohol derivative is in paren-
theses.
Et3SiH=4 equiv.
[c]
ed cleanly under an air atmosphere, whereas under ring would not be reduced with the present reducing
inert gases, such as nitrogen and argon, the progress system. With the substrate having a nitro group, the
of the esterification was remarkably retarded. Conse- corresponding ester derivative 1k was obtained in
quently, the dehydration and absorption functions of 46% yield with the recovery of the starting material.
sulfuric acid are an essential for this esterification.
Consequently, a nitro group is slightly sensitive to the
A series of results of the indium-catalyzed esterifi- reducing system. Use of an aliphatic carboxylic acid
cation of an identical carboxylic acid in the presence having a thiophene ring gave the ester in practically
of sulfuric acid are summarized in Table 2. In all cases useful yield.
using a linear aliphatic carboxylic acid, the reductive
Strangely, the reducing system was not applicable
esterification proceeded cleanly, producing the corre- to an aromatic carboxylic acid such as benzoic acid,
sponding ester derivatives in moderate to good yields. resulting in the recovery of the stating material as
A branched carbon chain next to a carbonyl moiety well as the results reported previously.[8] Thus, we at-
sterically affected the approach between the carboxyl- tempted the crossed esterification of an aliphatic car-
ic acid and in-situ formed alcohol, resulting in a de- boxylic acid with the aromatic carboxylic acid, benzo-
crease in the yield of the product 1e. The use of 2- ic acid (Scheme 2).[9] Although a hydrosilane (TMDS:
phenylbutyric acid produced only primary alcohol 2f tetramethyldisiloxane) and solvent required tuning
in 62% yield. A halogen substituent on the benzene up, preparation of the crossed ester, 3-phenylpropyl
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Indium-Catalyzed Reductive Esterification of a Carboxylic Acid
Scheme 2. Crossed esterification of an aliphatic acid with an
aromatic acid.
Scheme 3. Plausible reaction path for esters.
benzoate (3) was successful in a 72% yield. As ex-
pected, the primary alcohol, which was reduced from
the aliphatic carboxylic acid, immediately reacted direct synthesis of symmetrical ethers from an identi-
with benzoic acid rather than the unreacted aliphatic cal carboxylic acid.
acid to produce the corresponding ester.
To understand the reaction pathway for the esterifi-
Previously, the direct conversion of an ester into an cation, several control experiments were conducted.[12]
ether was achieved through reductive deoxygenation When 3-phenylpropionic acid was treated with
using an InBr3/Et3SiH system.[8,10] Therefore, the pres- 5 mol% of InBr3 and 1 equiv. of Et3SiH in CDCl3 at
ent method was applied to the direct conversion of a room temperature, a nearly quantitative formation of
carboxylic acid into a symmetrical ether in one-pot the corresponding silyl ester was observed by
(Table 3). The aliphatic acid 1a was initially treated 13C NMR. Additionally, when 2 more equivalents of
with the reducing system containing InBr3/Et3SiH/ Et3SiH were added to the resulting mixture involving
H2SO4, without isolation of the formed ester, followed the silyl ester, a smooth transformation from the silyl
by the addition of 4 equiv. (SiH) of polymethylhydro- ester to the silyl ether 2a’ was observed.[13] For the
siloxane (PMHS) to produce the expected symmetri- role of sulfuric acid, when the reaction of 3-phenyl-
cal ether 4a in 86% yield. Consequently, the indium propionic acid with the isolated silyl ether 2a’ was
salt remained intact during the total reaction and conducted using 0.1 equiv. of sulfuric acid, the corre-
maintained its high catalytic activity. This procedure sponding ether 1a was obtaained in 83% NMR
also accommodated other aliphatic carboxylic acids to yield.[14] By contrast, running a similar reaction with
produce the corresponding ethers in 50–85% yields.[11] only InBr3 did not produce the ether at all. On the
This serves as a novel and convenient method for the basis of these results, we present a plausible mecha-
nism for the esterification as shown in Scheme 3. A
carboxylic acid was sequentially reduced to the corre-
sponding silyl ether through the formation of a silyl
Table 3. One-pot synthesis of several symmetrical ethers.[a]
ester and a silyl acetal with liberation of H2 and
(Et3Si)2O.[15] The formed silyl ether was quite immedi-
ately reacted with another carboxylic acid to produce
the desired ester. It was found that the indium salt
mainly activated a carbonyl moiety of a formed silyl
À
ester and a C O bond on a silyl acetal, facilitating the
attack of a hydrosilane, and that sulfuric acid promot-
ed the hydrolysis of a silanol by condensation.
In summary, a cooperative catalytic system involv-
ing InBr3 and H2SO4 has been described that allows
for the direct synthesis of esters from readily available
carboxylic acids through reduction and condensation.
After the further addition of a hydrosilane, the one-
pot conversion of the in-situ formed ester into a sym-
metrical ether was accomplished. The scope and syn-
thetic applications for this reaction are under investi-
gation.
[a]
Isolated yield.
Et3SiH (4 equiv.) instead of PMHS.
[b]
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2008, 73, 4882–4887; b) I. Shiina, R. Ibuka, M. Kubota,
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Experimental Section
Typical Procedure for Table 2
To a 5-mL screw-capped vial (or a 10-mL flask) containing
freshly distilled CHCl3 (0.6 mL) were successively added
carboxylic acid (0.60 mmol), InBr3 (0.030 mmol, 11 mg), sul-
furic acid (0.060 mmol, 3.2 mL) and Et3SiH (1.8 mmol,
290 mL) under an air atmosphere. The resulting mixture was
stirred at room temperature or 608C (bath temperature),
and monitored by TLC analysis until completion. After the
reaction, the resulting mixture was cooled to room tempera-
ture, and directly poured to a separatory funnel containing
H2O (10 mL). The aqueous layer was extracted with CHCl3
(5 mLꢂ3). The organic phases were combined, dried over
anhydrous Na2SO4, filtered, and evaporated under reduced
pressure. The crude product was purified by silica gel
column chromatography (eluent: hexane-AcOEt) to give
the corresponding ester 1.
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Typical Procedure for Table 3
To a 5-mL screw-capped vial (or a 10-mL flask) containing
freshly distilled CHCl3 (0.6 mL) were successively added
carboxylic acid (0.60 mmol), InBr3 (0.030 mmol, 11 mg), sul-
furic acid (0.06 mmol, 3.2 mL) and Et3SiH (1.8 mmol,
290 mL) under an air atmosphere. The resultant mixture was
stirred at room temperature or 608C (bath temperature) for
20–24 h with monitoring by TLC analysis. After completion
of the first step, polymethylhydrosiloxane (PMHS)
(2.4 mmol) was added to the resulting mixture which was
further stirred at 608C for 4–20 h. The mixture was cooled
to room temperature, and directly poured to a separatory
funnel containing H2O (10 mL). The aqueous layer was ex-
tracted with CHCl3 (5 mLꢂ3), and the organic phases were
combined, dried over anhydrous Na2SO4, filtered, and
evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography (eluent:
hexane-AcOEt) to give the corresponding symmetrical
ether 4.
Acknowledgements
This work was partially supported by a grant from the Japan
Private School Promotion Foundation supported by MEXT,
and by a grant from CCIS program supported by MEXT.
The authors thank Shin-Etsu Chemical Co., Ltd., for the gift
of hydrosilanes.
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