An effective one-pot conversion of acid chlorides to aldehydes and ketones

Article abstract of DOI:10.1016/j.tetlet.2013.04.041

Aldehydes and ketones were synthesized from their respective acid chlorides via a one-pot protocol. Morpholine amide intermediates that were readily prepared by the aminolysis of various acid chlorides with diisobutyl(morpholino) aluminum smoothly reacted with the reducing agent LDBMA and the organolithium reagents under mild reaction conditions (0 C), giving almost excellent product yields of up to 95%.

Full text of DOI:10.1016/j.tetlet.2013.04.041

Tetrahedron Letters 54 (2013) 3199–3203
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Tetrahedron Letters
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An effective one-pot conversion of acid chlorides to aldehydes and ketones
⇑
Jae Kyo Park, Won Kyu Shin, Duk Keun An
Department of Chemistry, Kangwon National University and Institute for Molecular Science and Fusion Technology, Chuncheon 200-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 February 2013
Revised 9 April 2013
Accepted 11 April 2013
Available online 18 April 2013
Aldehydes and ketones were synthesized from their respective acid chlorides via a one-pot protocol. Mor-
pholine amide intermediates that were readily prepared by the aminolysis of various acid chlorides with
diisobutyl(morpholino)aluminum smoothly reacted with the reducing agent LDBMA and the organolith-
ium reagents under mild reaction conditions (0 °C), giving almost excellent product yields of up to 95%.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Diisobutylaluminum hydride (DIBALH)
Morpholine amide
Acid chloride
Aldehyde
Ketone
Aldehydes and ketones are highly valuable building blocks and
reactive intermediates in a wide variety of organic syntheses. The
establishment of a simple, general, and practical method for pre-
paring these molecules is one of the most important and highly
the reaction of a reducing agent and organolithium reagents with
morpholine amide intermediates under mild conditions (0 °C),
resulting in excellent yields (Scheme 1).
We previously carried out the synthesis of tertiary amides from
the reaction of benzoyl chloride and diisobutyl(morpholino)alumi-
num. The corresponding morpholine amides could be obtained in
99% yield. And we found that the morpholine amide was an effective
precursor to the synthesis of aldehydes and ketones through the
reaction of morpholine amide with DIBALH and n-BuLi.
Furthermore, to demonstrate the feasibility of performing the de-
sired reaction under a variety of conditions, various reducing
1
desirable objectives in the synthesis field. Weinreb amides, which
are generally synthesized from acid chlorides, are recognized as
reliable intermediates for the preparation of aldehydes and
ketones from carboxylic acid derivatives, and their synthetic utility
has been widely demonstrated.2 However, reactions involving
Weinreb amides are not always suited to large-scale practical
applications because of the high cost factor involved. Further, the
yields of the desired aldehydes are fairly low (67–76%) even at
3
agents were employed in the one-pot synthesis of benzaldehyde
ꢀ
78 °C, in contrast to those of ketones, which can reach 90%.
Herein, we report a new and improved method for the one-pot
via amide intermediates prepared by the reaction of
a
diisobutyl(amino)aluminum reagent and benzoyl chloride. Diisobu-
tyl(morpholino)aluminum was the most effective reagent for syn-
thesizing the amide intermediate, with lithium diisobutylmethoxy
synthesis of aldehydes and ketones from acid chlorides. As an
alternative to the use of Weinreb amides, this approach involves
O
LDBMA
R'Li
O
i-Bu
i-Bu
H
R
H
Al
N
N
i-Bu
i-Bu
THF
R
Cl
0 °C, 10 min
Al
H
0
°C, 3 h
O
O
O
R
R'
Scheme 1. New synthetic method of aldehydes and ketones from acid chlorides.
⇑
Corresponding author. Tel.: +82 33 250 8494; fax: +82 33 253 7582.
E-mail address: dkan@kangwon.ac.kr (D.K. An).
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.041

3
200
J. K. Park et al. / Tetrahedron Letters 54 (2013) 3199–3203
4
aluminum hydride (LDBMA) being the best reducing agent for the
corresponding aldehydes in 92% and 83% yields, respectively
(entries 12 and 13). Furthermore, aliphatic acid chlorides were
smoothly reduced to the corresponding aldehydes in 98% and
90% yields, respectively, under similar reaction conditions (entries
14 and 15).
From these results, it was anticipated that treatment of mor-
pholine amide intermediates with n-BuLi or PhLi would be effec-
tive for the one-pot synthesis of ketones from their respective
aromatic and aliphatic acid chlorides. As expected, the correspond-
ing ketones were isolated in 85–99% yields; however, with bromo-
substituted esters, metal–halogen exchange products were
obtained instead of the desired ketones. Table 3 summarizes the
partial reduction of benzoyl chloride to benzaldehyde at 0 °C (Table
1).
The next step was to synthesize different aldehydes from their
respective aromatic and aliphatic acid chlorides using the condi-
tions optimized in the first set of experiments. The results for a
number of representative esters are summarized in Table 2.
As shown in Table 2, various aromatic acid chlorides with elec-
tron-withdrawing and electron-donating substituents were
observed to smoothly undergo conversion to the corresponding
aldehydes in 92–99% yields at mild reaction temperature (entries
1
–11). The polyaromatic compound, 2-naphthoyl chloride, and
the heterocyclic aromatic compound, 2-furoyl chloride, gave the
Table 1
Partial reduction of benzoyl chloride under a variety of reaction conditions
O
i-Bu
i-Bu
benzoyl chloride
0 °C, 10 min
hydride
DIBALH
°C, 3 h
Al
amine
H
NR2
0 °C, 10 min
0
Entry
Amine (equiv)
Amine (equiv)
1.25
DIBALH (equiv)
Hydride
DIBALH
Hydride (equiv)
1.5
Yieldd (%)
1
2
3
4
5
6
7
Morpholine
1.2
75
99
91
72
98
15
18
a
LDBMA
b
LDBMA
c
LDBMA
LDBMA
LDBMA
LDBMA
Piperidine
Diethyl amine
a
b
c
Lithium diisobutylethoxy aluminum hydride.
Lithium diisobutylisopropoxy aluminum hydride.
Lithium diisobutyl-t-butoxy aluminum hydride.
d
Yields were determined by GC with naphthalene as internal standard.
Table 2
Yields of aldehydes from representative acid chlorides in a one-pot reaction5
O
H
i-Bu
i-Bu
Al
N
N
THF
O
LDBMA
R
Cl
+
DIBALH
(1.2 eq)
0
°C, 3 h
0 °C, 10 min 0 °C, 10 min
R
H
O
(
1.25 eq)
O
(1.0 eq)
Entry
1
Acid chloride
Product
LDBMA (equiv)
1.5
Yielda (%)
99
O
O
Cl
H
Cl
O
Cl
O
2
3
1.5
1.5
97
98
Cl
H
O
O
Cl
Cl
Cl
Cl
H
O
O
4
5
6
H
1.5
1.5
1.5
96
98
92
Cl
Br
Cl
Br
O
O
O
O
Cl
Cl
H
H
Br
Br

J. K. Park et al. / Tetrahedron Letters 54 (2013) 3199–3203
3201
Table 2 (continued)
Entry
Acid chloride
Product
LDBMA (equiv)
1.5
Yielda (%)
O
O
O N
O N
2
7
8
9
2
96
96
Cl
Cl
H
H
O
O
1.5
O N
O N
2
2
O
O
O
O
1.5
1.5
97
99
Cl
H
1
0
1
Cl
H
O
O
1
Cl
H
1.5
81
MeO
O
MeO
O
O
O
O
O
1
1
2
3
1.5
1.5
92
83
Cl
H
O
O
Cl
H
1
1
4
5
1.7
1.7
98
90
Cl
H
O
O
Cl
H
a
Yields were determined by GC with naphthalene as internal standard.
Table 3
7
Yields of ketones from their representative acid chlorides in a one-pot reaction at 0 °C
O
H
i-Bu
i-Bu
Al
N
N
THF
O
R
Cl
n-BuLi
+
DIBALH
(1.2 eq)
0
°C, 3 h
0 °C, 10 min
(1.0 eq)
0 °C
R
Bu
O
(
1.25 eq)
O
Entry
1
Acid chloride
Product
Rxn condition
Yielda (%)
98
n-BuLi ðequivÞ=time ðminÞ
O
O
2.0/10
Cl
Bu
O
O
2b
3
2.5/30
2.0/10
2.0/10
2.0/10
2.0/10
97
98
99
99
Cl
Ph
O
O
Cl
Bu
F
O
O
Cl
Cl
4
Cl
Bu
Bu
O
O
5
Cl
Cl
Cl
O
O
6
98
Cl
Bu
(
continued on next page)

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202
J. K. Park et al. / Tetrahedron Letters 54 (2013) 3199–3203
Table 3 (continued)
Entry
Acid chloride
Product
Rxn condition
Yielda (%)
94
n-BuLi ðequivÞ=time ðminÞ
O
O
7
8
9
2.0/10
2.0/10
Cl
Bu
O
O
Cl
Bu
98
MeO
MeO
O
O
Cl
Bu
2.0/10
2.0/10
99
85
O
O
1
0
O
O
Cl
Bu
O
O
O
1
1
1
1
3.0/10
3.0/30
3.0/10
94
94
95
Cl
Cl
Bu
O
2b
3
Ph
O
O
Cl
Bu
a
lsolated yields after silica column chromatography.
Used PhLi as nucleophile instead of n-BuLi.
b
O
i-Bu
i-Bu
i-Bu
Al
H
Al
N
i-Bu
O
N
i-Bu
i-Bu
THF
Ph
Cl
O
Al
H
0
°C, 3 h
0 °C, 10 min
Ph
Cl
O
N
O
1
2
i-Bu
Al
OMe
O
i-Bu
O
LDBMA
HCl(aq)
O
O
Ph
N
Li
0
°C, 10 min
Ph
H
O
Ph
i-Bu
i-Bu
N
Al
Cl
H
3
4
Scheme 2. Proposed mechanism.
results of the one-pot synthesis of ketones from a representative
selection of acid chlorides.
Acknowledgments
The proposed reaction mechanism is shown in Scheme 2, with
the conversion of benzoyl chloride to the corresponding aldehyde
shown as an example. Initially, the acid chloride is attacked by
the morpholide anion of diisobutyl(morpholino)aluminum 1 to
give intermediate 2, which is possibly stabilized in a seven-mem-
This research was supported by the National Research Founda-
tion of Korea Grant funded by the Korean Government
(2012R1A1B6000451). We are also grateful for the support
extended by Brain Korea 21.
6
bered cyclic form by coordination of the aluminum metal with
References and notes
the morpholine oxygen. Morpholine amide intermediate 3 is pro-
duced through the release of an aluminum complex from interme-
diate 2, and then, intermediate 3 gives adduct 4 in the presence of
LDBMA. Finally, hydrolysis of 4 affords the benzaldehyde product.
In conclusion, we have developed a facile, alternative method
for the direct synthesis of aldehydes and ketones by partial reduc-
tion and partial alkylation of morpholine amide intermediates of
common acid chlorides under mild reaction temperature (0 °C).
This novel methodology has broad scope in the synthesis of alde-
hydes and ketones from acid chlorides, as an alternative to the
use of Weinreb amides. The present method has a number of valu-
able advantages, including high product yields (almost up to 95%),
mild reaction conditions, low costs, and process simplicity.
1
2
.
.
Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
For a review, see: (a) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15; (b) Mentzel,
M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339, 517; (c) Singh, J.; Satyamurthi,
N.; Aidhen, I. S. J. Prakt. Chem. 2000, 342, 340.
(a) Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 619; (b) Ahn, J. H.;
Song, J. I.; Ahn, J. E.; An, D. K. Bull. Korean Chem. Soc. 2005, 26, 377; (c) Kim, M. S.;
Choi, Y. M.; An, D. K. Tetrahedron Lett. 2007, 48, 5061; (d) Song, J. I.; An, D. K.
Chem. Lett. 2007, 36, 886.
3
.
4. Preparation of LDBMA. A dry and argon-flushed flask, equipped with a magnetic
stirring bar and a septum, was charged with methanol (2.23 mL, 55 mmol) and
25 mL of THF. After cooling to 0 °C, n-BuLi (20 mL, 2.5 M in hexane, 50 mmol)
was added dropwise and stirred for 1 h at room temperature. To the reaction
mixture was slowly added DIBALH (50 mL, 1.0 M in hexane, 50 mmol) and
stirred for 2 h at same temperature to give a colorless homogeneous solution.
The concentration of LDBMA solution in THF–hexane was measured
gasometrically by hydrolysis of an aliquot of the solution with a hydrolyzing

J. K. Park et al. / Tetrahedron Letters 54 (2013) 3199–3203
3203
mixture of t-butyl alcohol–THF (1:1) at 0 °C. The LDBMA solution was stable in
the refrigerator for 6 months without any appreciable loss of hydride content.
Partial reduction of acid chlorides to corresponding aldehydes. The following
experimental procedure for the partial reduction of benzoyl chloride to
benzaldehyde is representative. A dry and argon-flushed flask, equipped with
a magnetic stirring bar and a septum, was charged with morpholine (0.11 mL,
1-phenylpentanone is representative. A dry and argon-flushed flask, equipped
with a magnetic stirring bar and a septum, was charged with morpholine
(0.11 mL, 1.25 mmol) and 10 mL THF. After cooling to 0 °C, DIBALH (1.2 mL,
1.0 M in hexane, 1.2 mmol) was added dropwise and stirred for 3 h at same
temperature. To the reaction mixture was slowly added benzoyl chloride
(0.116 mL, 1.0 mmol) and stirred for 10 min. Then, n-BuLi (1.25 mL, 1.6 M in
hexane, 2.0 mmol) was added and the mixture was stirred for 10 min again. The
reaction was stopped by aqueous 1 N HCl (10 mL) and extracted with diethyl
5
.
1
.25 mmol) and THF (10 mL). After cooling to 0 °C, DIBALH (1.2 mL, 1.0 M in
hexane, 1.2 mmol) was added dropwise and the mixture was stirred for 3 h at
the same temperature. Benzoyl chloride (0.116 mL, 1.0 mmol) was added slowly
to the reaction mixture, which was stirred for 10 min. Then, LDBMA (3.3 mL,
ether (2 ꢁ 10 mL). The combined organic layers were dried over MgSO
4
, filtered
and concentrated under reduced pressure. Purification of the residue by column
chromatography on silica gel yielded 1-phenylpentanone (159 mg, 98%). All
products in Table 3 were confirmed by comparison with NMR data reported in
the literature.8
0
1
.46 M in hexane–THF, 1.5 mmol) was added and the mixture was stirred for
0 min again. The reaction was stopped by aqueous 1 N HCl (10 mL) and
extracted with diethyl ether (2 ꢁ 10 mL). The combined organic layers were
dried over MgSO . GC analysis showed a 99% yield of benzaldehyde. All products
4
8. (a) Yoshida, J.; Itoh, M.; Matsunaga, S.; Isoe, S. J. Org. Chem. 1992, 57, 4877; (b)
Fausett, B. W.; Liebeskind, L. S. J. Org. Chem. Soc. 2005, 70, 4851; (c) Oh, C. H.;
Kim, A.; Park, W.; Park, D. I.; Kim, N. Synlett 2006, 2781; (d) James, J. J.;
Henderson, K. W.; Kerr, W. J. Org. Lett. 2006, 8, 5073; (e) Genna, D. T.; Posner, G.
H. Org. Lett. 2011, 13, 5358.
in Table 2 were confirmed through comparison with GC data of authentic
sample.
Badioli, M.; Ballini, R.; Bartolacci, M.; Bosica, G.; Torregiani, E.; Marcantoni, E. J.
Org. Chem. 2002, 67, 8938.
Partial alkylation of acid chlorides to corresponding ketones. The following
experimental procedure for the partial reduction of benzoyl chloride to
6
7
.
.