Quantitative synthesis of aldehydes from weinreb amides using lithium diisobutyl-t-butoxyaluminum hydride (LDBBA)

Full text of DOI:10.1002/bkcs.10571

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DOI: 10.1002/bkcs.10571
BULLETIN OF THE
J. S. An et al.
KOREAN CHEMICAL SOCIETY
Quantitative Synthesis of Aldehydes from Weinreb Amides Using Lithium
Diisobutyl-t-Butoxyaluminum Hydride (LDBBA)
*
Jae Sung An, Won Kyu Shin, and Duk Keun An
Department of Chemistry, Kangwon National University, and Institute for Molecular Science and Fusion
Technology, Chunchon 200-701, Republic of Korea. *E-mail: dkan@kangwon.ac.kr
Received June 22, 2015, Accepted August 5, 2015, Published online November 8, 2015
Keywords: Lithium diisobutyl-t-butoxyaluminum hydride, Diisobutylaluminum hydride, Weinreb amide,
Partial reduction, Aldehyde synthesis
Over the past several years, we have developed novel reducing
agents for the partial reduction of carboxylic acid derivatives
toaldehydes, whichare valuable intermediatesinthesynthesis
of complex natural products with significant biological activ-
ity as well as other useful materials. Among these reducing
agents, lithium diisobutyl-t-butoxyaluminum hydride
(LDBBA), sodium diisobutyl-t-butoxyaluminum hydride
(SDBBA), and potassium diisobutyl-t-butoxyaluminum
hydride (PDBBA), the t-butoxy derivatives of diisobutylalu-
minum hydride (DIBALH), are particularly effective to pro-
duce aldehydes in synthetically useful yields.1–4 LDBBA is
now commercially available from Sigma-Aldrich Company.
As part of our research program we decided to attempt the
partial reduction of carboxylic acid derivatives of the valuable
Weinreb amides,5 which are versatile building blocks that
could act as useful intermediates for the preparation of alde-
hydes and ketones, using LDBBA, SDBBA, and PDBBA
(Scheme 1).
can achieve 90% yields, although some derivatives are con-
verted to the corresponding aldehydes in excellent yields.6
In addition, Georg and coworkers demonstrated that Weinreb
amides can be readily reduced with Cp2Zr(H)Cl at room tem-
perature to give aldehydes in 85–94% yield.7 And very
recently, Singaram et al. have reported that chloromagnesium
dimethylaminoborohydride (MgAB) is a very useful partial
reducing agent for the synthesis of aldehydes from Weinreb
amides.8 Herein, we report a general and efficient method
for the synthesis of aldehydes from Weinreb amides, through
partial reduction using metal diisobuyl-t-butoxyaluminum
hydrides.
We initially carried out an evaluation of the reducing prop-
erties of LDBBA, SDBBA, and PDBBA for the partial reduc-
tion of representative aromatic and aliphatic Weinreb amides
to aldehydes. Fortunately, we found that LDBBA, SDBBA,
and PDBBA had excellent partial reducing ability for the
desired reaction at a mild reaction temperature (0 ꢀC). Of these
hydrides, we selected LDBBA as the most useful because
SDBBA and PDBBA require longer reaction times (Table 1).
Thus, we used LDBBA for the synthesis of aldehydes from
representative Weinreb amides, under the optimized reaction
conditions, with 1.1 equiv of LDBBA at 0 ꢀC for 30 min. The
results are summarized in Table 2.
Weinreb has described two types of general reducing
agents DIBALH and lithium aluminum hydride (LAH), for
the partial reduction of Weinreb amides to aldehydes.5a How-
ever, the yields of the desired aldehydes are relatively low
(67–76%) even at −78 ꢀC, in contrast to those of ketones that
As shown in Table 2, N-methoxy-N-methylbenzamide and
its derivatives, containing electron-withdrawing and electron-
donating substituents were smoothly converted to the corre-
sponding aldehydes in quantitative yields (entries 1–8,
Table 2). Similarly, all other reactions readily proceeded with
quantitative yields for a range of substrates, including hetero-
aromatics, N-methoxy-N-methylnicotinamide, and N-meth-
oxy-N-methyl-2-furoamide (entries 9 and 10, Table 2); a
polyaromatic, N-methoxy-N-methyl-2-naphthylamide (entry
11, Table 2); aliphatic substrates (entries 12 and 13, Table 2);
and an α,β-unsaturated Weinreb amide (entry 14, Table 2).
This demonstrates the broad scope of the reaction in terms
of the substituent on the Weinreb amide. The isolated yields
correlated well with those determined by GC (entries 1 and
12, Table 2).
i-Bu
i-Bu
Al
H
DIBALH
t-BuOM
THF-hexane
i-Bu
i-Bu
M
O Al
H
O
O
(M=Li, Na, K)
THF-hexane
O
R
N
R
H
Subsequently we studied the reducing characteristics
of LDBBA for the partial reduction of other carboxylic acid
Scheme 1. Synthesis of aldehydes from Weinreb amides using the
novel reducing agent.
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Table 1. Evaluation of metal diisobutyl-t-butoxyaluminum hydrides
Table 2. Synthesis of aldehydes from representative Weinreb amides
for the synthesis of aldehydes from Weinreb amides.
using LDBBA.
Weinreb amide H−
LDBBA
H− (equiv) Time (h) Yield (%)a
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.5
3.0
9.0
0.5
0.5
3.0
0.5
9.0
0.5
3.0
9.0
>99
>99
99
>99
87
>99
5
41
SDBBA
PDBBA
LDBBA
SDBBA
Entry
1
Weinreb amide
Product
Yield (%)a
>99 (98)
PDBBA
LDBBA
SDBBA
PDBBA
>99
>99
94
2
3
4
5
>99
>99
>99
>99
a Yields were determined by GC.
derivatives. We attempted the chemoselective reduction of
Weinreb amides in the presence of a similar ester and standard
N,N-dialkyl tertiary amide, which could be predicted to be
either more reactive or similarly reactive to Weinreb amides.
However, when 1:1 mixtures of the Weinreb amide and the
ester or tertiary amidewere subjected toLDBBA, thereactions
successfully afforded the corresponding aldehyde from the
Weinreb amide with almost no reduction of the other car-
boxylic acid derivatives (Table 3). Thus, gratifyingly, we
found LDBBA to be a promising, and useful chemoselective
reducing agent.
6
7
8
>99
>99 (97)
>99
In conclusion, we have developed a general and
useful method for the selective synthesis of aldehydes from
Weinreb amides, with no over-reduction to the alcohol, using
LDBBA, which can be readily prepared from DIBALH and is
also commercially available. The advantages of the present
method include quantitative product yields, a short reaction
time, and mild reaction conditions (0 ꢀC). Therefore, we
believe that LDBBA has great potential as a broadly applica-
ble, alternative partial reducing agent for the synthesis of
aldehydes from Weinreb amides in organic synthesis. Further-
more, LDBBA could selectively reduce Weinreb amides to
the corresponding aldehydes in the presence of esters and ter-
tiary amides.
9
>99
>99
10
11
12
13
>99
>99 (97)
>99 (96)
Experimental
14
>99
General. All glassware was dried thoroughly in an oven,
assembled hot, and cooled under a stream of dry nitrogen prior
to use. All reactions and manipulation of air- and moisture-
sensitive materials were carried out using the standard techni-
ques for handling air-sensitive materials. All chemicals were
commercial reagents of the highest purity, which were further
purified by standard methods before use. Tetrahydrofuran
a Yields were determined by GC. Isolated yields are shown in
parentheses.
(THF) was dried over sodium-benzophenone and distilled.
Weinreb amides were prepared according to the literature pro-
cedure.2a Gas chromatography (GC) analyses were performed
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Table 3. Chemoselective partial reduction of Weinreb amide to
aldehydewithLDBBAat0 ꢀC inthepresenceofanester orastandard
tertiary amide.
Acknowledgments. This study was supported by a National
Research Foundation of Korea Grant funded by the Korean
Government (2014R1A1A2059124), the Korea Foundation
for the Advancement of Science & Creativity (KOFAC),
and was funded by the Korean Government (MOE).
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Preparation of LDBBA. To a solution of t-butyl alcohol
(5.26 mL, 55 mmol) in THF (25 mL) was added n-
butyllithium (22 mL, 2.5 M in hexane, 55 mmol) at 0 ꢀC. After
stirring for 1 h at room temperature, DIBALH (50 mL, 1.0 M
in hexane, 50 mmol) was added dropwise to the reaction mix-
ture at 0 ꢀC and the mixture was stirred for a further 2 h at room
temperature to obtain a colorless homogeneous solution. The
concentration of LDBBA solution in THF-hexane was meas-
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0 ꢀC. The LDBBA solution was stable in the refrigerator for 6
months without any appreciable reduction of the hydride
content.
Partial Reduction of Weinreb Amides to the Correspond-
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the partial reduction of N-methoxy-N-methylbenzamide
to benzaldehyde is representative. A dry, argon-flushed
flask, equipped with a magnetic stirring bar and a septum,
was charged with N-methoxy-N-methylbenzamide (0.08
mL, 0.5 mmol) and THF (5 mL). After cooling to 0 ꢀC,
LDBBA (1.38 mL, 0.4 M 0.55 mmol) was added
dropwise and the mixture was stirred for 30 min at the same
temperature. The reaction was quenched with 1N aqueous
HCl (5 mL) and the product was extracted with diethyl
ether (10 mL). The organic layer was dried over
anhydrous magnesium sulfate. GC analysis showed quantita-
tive conversion to benzaldehyde. All products in Table 2
were confirmed through a comparison with the GC data of
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