Lithium diisobutyl-t-butoxyaluminum hydride, a new and efficient reducing agent for the conversion of esters to aldehydes

Article abstract of DOI:10.1016/j.tetlet.2007.05.091

Lithium diisobutyl-t-butoxyaluminum hydride (LDBBA), easily prepared by reaction of lithium t-butoxide with DIBALH, readily reacts with common aromatic and aliphatic esters to give the corresponding aldehydes in 74-88% yield at 0 °C. Especially, this reagent proved to be the most effective partial reducing agent for conversion of isopropyl esters to aldehydes, in most cases, with >90% yield under the same reaction temperature.

Full text of DOI:10.1016/j.tetlet.2007.05.091

Tetrahedron Letters 48 (2007) 5061–5064
Lithium diisobutyl-t-butoxyaluminum hydride, a new and
efficient reducing agent for the conversion of esters to aldehydes
Min Sung Kim, Young Mi Choi and Duk Keun An*
Department of Chemistry, Kangwon National University, Chunchon 200-701, Republic of Korea
Received 18 April 2007; revised 14 May 2007; accepted 15 May 2007
Available online 18 May 2007
Abstract—Lithium diisobutyl-t-butoxyaluminum hydride (LDBBA), easily prepared by reaction of lithium t-butoxide with
DIBALH, readily reacts with common aromatic and aliphatic esters to give the corresponding aldehydes in 74–88% yield at
0
ꢀC. Especially, this reagent proved to be the most effective partial reducing agent for conversion of isopropyl esters to aldehydes,
in most cases, with >90% yield under the same reaction temperature.
2007 Elsevier Ltd. All rights reserved.
ꢁ
Partial reduction of ester to aldehyde is one of the most
important and highly desirable methods in organic syn-
thesis, and a large number of reducing agents for this
diisobutyl-t-butoxyaluminum hydride (LDBBA) pre-
pared from DIBALH smoothly reduced esters to alde-
hydes in very good yields at 0 ꢀC. Herein, we wish to
report a new alternative and efficient method for partial
reduction of esters to aldehydes by LDBBA under mild
conditions.
1
purpose have been reported. Among them, diisobutyl-
2
aluminum hydride (DIBALH), which is commercially
available, is used as the most popular reducing agent,
although this reagent provides moderate yields (48–
8
8%) and requires a very low temperature (À78 ꢀC). It
Scheme 1 outlines the preparation of lithium diiso-
butylalkoxyaluminum hydrides from DIBALH. Thus,
when an equimolar amount of easily preparable lithium
alkoxide derived from common alcohols and n-butyl-
lithium was reacted with DIBALH in THF at 0 ꢀC or
room temperature, these reagents such as lithium di-
isobutylmethoxyaluminum hydride (LDBMA), lithium
diisobutylethoxyaluminum hydride (LDBEA), lithium
has also been reported that several other reducing
agents for partial reduction of esters, such as lithium
tri-t-butoxyaluminum hydride (LTBA), bis(4-methyl-
3
1
-piperazinyl)aluminum hydride,4 lithium tris(diethyl-
5
amino)aluminum hydride (LiAlH(NEt ) ), and sodium
2
3
6
diethylpiperidinohydroaluminate (SDPA), can be used.
However, these reagents cannot achieve very general
reduction of both aliphatic and aromatic esters, and
additionally sodium diethyldihydroaluminate (SDDA),
which is the precursor for synthesis of SDPA, is not com-
mercially available. Recently, we have reported that lith-
ium diisobutyldialkylaminohydroaluminates, the amino
derivatives of DIBALH, are new partial reducing agents
which can reduce various esters to aldehydes. Among them,
lithium diisobutylpiperidinohydroaluminate (LDBPA)
was the most effective for partial reduction of esters to
i-Bu
DIBALH
ROH
+
n-BuLi
ROLi
RO Al i-Bu Li
H
i-Bu
i-Bu
EtO Al i-Bu
H
i-Bu
H CO Al i-Bu Li
3
Li
O
Al i-Bu
H
Li
7
a
H
aldehydes in moderate to good yields at 0 ꢀC, and also
LDBPA was effective for partial reduction of aromatic
nitriles and tertiary amides in almost quantitative
7
b,c
i-Bu
yield.
In the course of our program for developing a
O
Al i-Bu Li
H
new selective reducing agent, we found that lithium
LDBBA
*
0
Corresponding author. Tel.: +82 33 250 8494; fax: +82 33 253
582; e-mail: dkan@kangwon.ac.kr
7
Scheme 1. Preparation of lithium diisobutylalkoxyaluminum hydrides.
040-4039/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.091

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M. S. Kim et al. / Tetrahedron Letters 48 (2007) 5061–5064
a,b
Table 1. Reduction of representative aromatic and aliphatic esters with lithium diisobutylalkoxyaluminum hydrides at 0 ꢀC
Compound
Product
LDBMA (%)
LDBEA (%)
LDBIPA (%)
LDBBA (%)
c
Ethyl benzoate
Ethyl caproate
Benzaldehyde
Caproaldehyde
7
19
9
29
23
31
74
87
d
a
b
c
Reduction of esters by using 1.2 equiv of lithium diisobutylalkoxyaluminum hydrides.
Yields were determined by GC.
Reacted for 3 h.
d
Reacted for 1 h.
diisobutylisopropoxyaluminum hydride (LDBIPA), and
aliphatic esters such as ethyl caproate, ethyl undecano-
ate, and ethyl cyclohexanecarboxylate were smoothly
reduced to the corresponding aldehydes in 81–88%
yields. Especially, LDBBA showed much improved
yields for isopropyl esters such as isopropyl benzoate
and isopropyl caproate. Therefore, we tested the alde-
hyde synthesis from the representative isopropyl esters
with LDBBA. The results are summarized in Table 3.
8
9
LDBBA were obtained quantitatively. Next, we exam-
ined partial reduction of representative aromatic and ali-
phatic esters to aldehydes by using these hydride
reagents in THF at 0 ꢀC. The results are summarized
in Table 1.
As shown in Table 1, the bulky t-butanol derivative was
most effective the reduction of esters to aldehydes. Of
these hydrides examined, we found that LDBBA pro-
vided the best results. So, we applied LDBBA for the syn-
thesis of aldehydes from various esters at 0 ꢀC. The results
for representative esters are summarized in Table 2.
As shown in Table 3, LDBBA reduced various aliphatic
1
0
and aromatic isopropyl esters to aldehydes, in most
cases, with >90% yield at 0 ꢀC. However, isopropyl 4-
methoxybenzoate under the same conditions was
reduced somewhat slowly and gave 85% yield of 4-meth-
oxybenzaldehyde after 24 h. This is attributable to its
lower reactivity than that of the other esters, because
methoxy is a very good electron-donating substituent.
Furthermore, isopropyl cinnamate, an a,b-unsaturated
isopropyl ester, gave 79% yield.
As shown in Table 2, ethyl benzoate was smoothly
reduced to produce benzaldehyde in 74% yield. Under
identical conditions, reduction with DIBALH itself pro-
vided only benzyl alcohol. The case of t-butyl benzoate
showed very slow reduction, in rather lower yield (63%
and 69%), presumably due to the bulk of the t-butyl
group. Also, benzoates with an electron-withdrawing
substituents such as ethyl 4-fluorobenzoate, methyl
In summary, we easily prepared a series of lithium di-
isobutylalkoxyaluminum hydrides by the reaction of
commercially available DIBALH with lithium alkox-
ides. Among them, LDBBA was the most effective for
reduction of esters to aldehydes in good yield. As a
substrate for the reaction with LDBBA, the isopropyl
esters were more effective than the methyl and ethyl
esters. Another great advantage of this reagent is that
this aldehyde synthesis can be carried out at 0 ꢀC instead
of a very low temperature (À78 ꢀC) or a very high
3
2
4
-chlorobenzoate, ethyl 4-chlorobenzoate, ethyl
-bromobenzoate, ethyl 4-bromobenzoate, and ethyl
-nitrobenzoate, and electron-donating substituent
such as ethyl 2-toluate were readily reduced to the
corresponding aldehydes in 81–85% yields. Similarly,
reduction of other aromatic esters such as ethyl 2-naph-
thoate and ethyl 2-furoate gave the corresponding alde-
hydes in 80% and 81% yield, respectively. Furthermore,
Table 2. Yields of aldehydes in the reduction of representative esters with LDBBA at 0 ꢀC
a
Entry
Compound
Reaction conditions
Yield of aldehyde (%)
À
H /ester
Time (h)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
Ethyl benzoate
1.2
(1.2)
1.3
3.0
4.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.3
1.2
1.2
3
(3)
3
3
3
3
3
3
3
3
3
3
3
1
1
1
1
1
74
(0)
b
Isopropyl benzoate
t-Butyl benzoate
89
63
69
83
81
83
85
83
85
82
80
81
87
98
88
81
Ethyl 4-fluorobenzoate
Methyl 3-chlorobenzoate
Ethyl 4-chlorobenzoate
Ethyl 2-bromobenzoate
Ethyl 4-bromobenzoate
Ethyl 4-nitrobenzoate
Ethyl 2-toluate
Ethyl 2-naphthoate
Ethyl 2-furoate
Ethyl caproate
1
1
1
1
1
1
1
1
1
Isopropyl caproate
Ethyl undecanoate
Ethyl cyclohexanecarboxylate
a
Yields were determined by GC.
Yield obtained by DIBALH alone is shown in parentheses.
b

M. S. Kim et al. / Tetrahedron Letters 48 (2007) 5061–5064
5063
Table 3. Yields of aldehydes in the reduction of representative isopropyl esters with LDBBA at 0 ꢀC
a
Entry
Compound
Reaction conditions
Yield of aldehyde (%)
À
H /ester
Time (h)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
Isopropyl benzoate
1.3
(1.3)
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
3
(3)
3
3
3
3
24
3
3
3
89
(0)
93
92 (77)
94
92 (78)
85
90
94
91
98
94
79
93
b
Isopropyl 4-fluorobenzoate
Isopropyl 4-chlorobenzoate
Isopropyl 4-bromobenzoate
Isopropyl 3-nitrobenzoate
Isopropyl 4-methoxybenzoate
Isopropyl 3-toluate
Isopropyl 2-naphthoate
Isopropyl 2-furoate
Isopropyl caproate
c
c
1
1
1
1
1
1
1
1
1
Isopropyl dodecanoate
Isopropyl cinnamate
Isopropyl cyclohexanecarboxylate
a
b
c
Yields were determined by GC.
Yield obtained by DIBALH alone is shown in parentheses.
Isolated yield.
temperature (reflux). In total, we believe that the
LDBBA reagent developed here is an efficient alterna-
tive to other agents for partial reduction of carboxylic
esters.
was stable in the refrigerator for 6 months without any
appreciable loss of hydride content.
9
. When equimolar LDBBA and terminal acetylene such as
-hexyne were reacted, 1 mol of hydrogen evolved rapidly.
However, DIBALH could not evolve hydrogen with 1-
1
1
1
hexyne, indicating hydroalumination of Al(III) complex.
Consequently, LDBBA is to be Al(IV) complex.
Acknowledgement
10. Reduction of esters with LDBBA to aldehydes. The
following procedure for the reduction of isopropyl benzo-
ate with LDBBA is representative. To a solution of
isopropyl benzoate (0.082 mL, 0.5 mmol) in THF (5 mL)
containing naphthalene as an internal standard was added
LDBBA (1.3 mL, 0.5 M in THF–hexane) at 0 ꢀC. After
This work was supported by the Research Institute for
Basic Science, Kangwon National University, Korea.
3
h, the reaction mixture was hydrolyzed with 5 mL of 1 N
References and notes
HCl (aq) and the product was extracted with 10 mL of
diethyl ether. The ether layer was dried over anhydrous
magnesium sulfate. GC analysis showed an 89% yield of
benzaldehyde. Isopropyl esters were prepared by methods
1
2
3
. Malek, J. Org. React. 1988, 36, 249; Cha, J. S. Org. Prep.
Proced. Int. 1989, 21, 451.
. Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962,
1
2
given in the literature.
6
19.
. Weissman, P. M.; Brown, H. C. J. Org. Chem. 1966, 31,
83.
Preparation of 4-chlorobenzaldehyde from isopropyl 4-
chlorobenzoate. To a solution of isopropyl 4-chlorobenzo-
ate (1.99 g, 10 mmol) in THF (50 mL) was added LDBBA
(26 mL, 0.5 M in THF–hexane) at 0 ꢀC. After 3 h, the
reaction mixture was hydrolyzed with 50 mL of 1 N HCl
(aq) and the product was extracted three times with 50 mL
of diethyl ether. The ether layer was dried over anhydrous
magnesium sulfate. After removal of the ether, the residue
was dissolved in 30 mL of ethanol, and upon addition of
water, a crystalline product appeared. The solid was
collected and sublimed at 55 ꢀC under high vacuum, and
pure 4-chlorobenzaldehyde (1.08 g, 77%) was obtained:
2
4
5
. Muraki, M.; Mukaiyama, T. Chem. Lett. 1975, 215.
. Cha, J. S.; Kwon, S. S. J. Org. Chem. 1987, 52, 5487; Cha,
J. S.; Kwon, S. S. J. Org. Chem. 1990, 55, 1692.
6
. Yoon, N. M.; Ahn, J. H.; An, D. K.; Shon, Y. S. J. Org.
Chem. 1993, 58, 1941; Yoon, N. M.; Shon, Y. S.; Ahn, J.
H.; An, J. W. Bull. Korean Chem. Soc. 1993, 14, 522.
. (a) Ahn, J. H.; Song, J. I.; Ahn, J. E.; An, D. K. Bull.
Korean Chem. Soc. 2005, 26, 377; (b) Ha, J. H.; Ahn, J. H.;
An, D. K. Bull. Korean Chem. Soc. 2006, 27, 121; (c) Woo,
S. M.; Kim, M. E.; An, D. K. Bull. Korean Chem. Soc.
7
1
3
1
mp 47 ꢀC (lit. mp 47.5 ꢀC). The H NMR spectrum
agreed with that of an authentic sample.
2
006, 27, 1913.
8
. Preparation of lithium diisobutyl-t-butoxyaluminum hydride
Preparation of 3-nitrobenzaldehyde from isopropyl 3-nitro-
benzoate. To a solution of isopropyl 3-nitrobenzoate
(2.09 g, 10 mmol) in THF (50 mL) was added LDBBA
(26 mL, 0.5 M in THF–hexane) at 0 ꢀC. After 3 h, the
reaction mixture was hydrolyzed with 50 mL of 1 N HCl
(aq) and the product was extracted three times with
100 mL of diethyl ether. The ether layer was poured into
150 mL of saturated sodium bisulfite (aq) solution. To this
solution was added 100 mL of THF, and the mixture was
stirred for 2 h. At this time the crystalline bisulfite adduct
of 3-nitrobenzaldehdye was apparent. The solution was
cooled in an ice bath to ensure complete crystallization of
(
5
LDBBA). To a solution of t-butyl alcohol (5.16 mL,
5 mmol) in THF (25 mL) was added n-butyllithium
(
20 mL, 2.5 M in hexane, 55 mmol) at 0 ꢀC. After being
stirred for 1 h at room temperature, DIBALH (50 mL,
.0 M in hexane, 50 mmol) was added dropwise to the
reaction mixture at 0 ꢀC and the mixture was stirred for
h at room temperature to give a colorless homogeneous
1
2
solution. The concentration of LDBBA solution in THF–
hexane was measured gasometrically by hydrolysis of an
aliquot of the solution with a hydrolyzing mixture of t-
butyl alcohol–THF (1:1) at 0 ꢀC. The LDBBA solution

5064
M. S. Kim et al. / Tetrahedron Letters 48 (2007) 5061–5064
1
3
1
the adduct. The adduct was collected by filtration, washed
with pentane (3 · 50 mL), and dried. The adduct was
placed in 100 mL of aqueous magnesium sulfate solution,
mp 58 ꢀC (lit. mp 58.5 ꢀC). The H NMR spectrum
agreed with that of an authentic sample.
11. Utimoto, K.; Uchida, K.; Yamaya, M.; Nozaki, H.
Tetrahedron Lett. 1977, 3641.
100 mL of pentane and 20 mL of a 37% formaldehyde
solution was added, and the mixture was stirred for 1 h.
The pentane layer was separated and dried over anhy-
drous magnesium sulfate. Evaporation of all volatile
materials gave a pure 3-nitrobenzaldehyde (1.18 g, 78%):
12. Growther, G. P.; Kaiser, E. M.; Woodruff, R. A.; Hauser,
C. R. Org. Synth., Coll. 1988, 6, 259.
13. Handbook of Chemistry and Physics, 87th ed.; CRC Press:
Boca Raton, FL, 2006.