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Tetrahedron Letters 54 (2013) 3199–3203 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters

Contents lists available at SciVerse ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier.com/locate/tetlet

Letters journal homepage: www.elsevier.com/locate/tetlet An effective one-pot conversion of acid chlorides to

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 Ko rea

article info

Article history:

Received 2 February 2013 Revised 9 April 2013 Accepted 11 April 2013 Available online 18 April 2013

Keywords:

Diisobutylaluminum hydride (DIBALH) Morpholine amide Acid chloride Aldehyde Ketone

abstract

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%. 2013 Elsevier Ltd. All rights reserved.

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 desirable objectives in the synthesis field. Weinreb amides, 1 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 78 C, in contrast to those of ketones, which can reach 90%. Herein, we report a new and improved method for the one-pot synthesis of aldehydes and ketones from acid chlorides. As an alternative to the use of Weinreb amides, this approach involves

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 agents 3 were employed in the one-pot synthesis of benzaldehyde 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

H N O
H
N
O
O LDBMA O i-Bu i-Bu R H Al i-Bu i-Bu THF R Cl Al N
O
LDBMA
O
i-Bu
i-Bu
R H
Al
i-Bu
i-Bu
THF
R Cl
Al
N
0 °C, 3 h
0 °C, 10 min
H
O
O
R'Li
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).

0040-4039/$ - see front matter 2013 Elsevier Ltd. All rights reserved.

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J. K. Park et al. / Tetrahedron Letters 54 (2013) 3199–3203

aluminum hydride (LDBMA) 4 being the best reducing agent for 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

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

Table 1 Partial reduction of benzoyl chloride under a variety of reaction conditions

O benzoyl chloride hydride DIBALH i -Bu i -Bu Al amine H NR 2 0
O
benzoyl chloride
hydride
DIBALH
i -Bu
i -Bu
Al
amine
H
NR 2
0 °C, 10 min
0 °C, 10 min
0 °C, 3 h

Entry

Amine (equiv)

Amine (equiv)

DIBALH (equiv)

Hydride

Hydride (equiv)

Yield d (%)

1

Morpholine

1.25

1.2

DIBALH

1.5

75

2

LDBMA

a

99

3

LDBMA

b

91

4

LDBMA

c

72

5

LDBMA

98

6

Piperidine

LDBMA

15

7

Diethyl amine

LDBMA

18

a Lithium diisobutylethoxy aluminum hydride .

 

b Lithium diisobutylisopropoxy aluminum hydride .

c 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 reaction 5

 
O H i -Bu i -Bu Al N THF LDBMA O R Cl + DIBALH
O
H
i -Bu
i -Bu
Al
N
THF
LDBMA
O
R
Cl
+
DIBALH
N
0 °C, 3 h
0 °C, 10 min
0 °C, 10 min
R
H
O
(1.25 eq)
(1.2 eq)
O
(1.0 eq)
 

Entry

Acid chloride

Product

LDBMA (equiv)

Yield a (%)

1

O Cl
O
Cl
O H
O
H

1.5

99

2

Cl O Cl
Cl
O
Cl
Cl O H
Cl
O
H

1.5

97

3

O Cl Cl
O
Cl
Cl
O Cl H
O
Cl
H

1.5

98

4

O Cl Cl
O
Cl
Cl
O H Cl
O
H
Cl

1.5

96

5

O Br Cl
O
Br
Cl
O Br H
O
Br
H

1.5

98

6

O Cl Br
O
Cl
Br
O H Br
O
H
Br

1.5

92

J. K. Park et al. / Tetrahedron Letters 54 (2013) 3199–3203

3201

Table 2 (continued )

Entry

 

Acid chloride

Product

LDBMA (equiv)

Yield a (%)

 

7

O O 2 N Cl
O
O 2 N
Cl
O O 2 N H
O
O 2 N
H

1.5

96

8

O Cl O 2 N
O
Cl
O 2 N
O H O 2 N
O
H
O 2 N

1.5

96

9

O Cl
O
Cl
O H
O
H

1.5

97

10

O Cl
O
Cl
O H
O
H

1.5

99

11

O Cl MeO
O
Cl
MeO
O H MeO
O
H
MeO

1.5

81

 

12

O Cl
O
Cl
O H
O
H

1.5

92

13

O O Cl
O
O
Cl
O O H
O
O
H

1.5

83

14

O Cl
O
Cl
O H
O
H

1.7

98

 

O

 

O

 
 

15

Cl

Cl

  15 Cl H   1.7 90

H

 

1.7

90

a Yields were determined by GC with naphthalene as internal standard .

 

Table 3 Yields of ketones from their representative acid chlorides in a one-pot reaction at 0 C 7

 
 
O H i -Bu i -Bu Al N THF R n -BuLi O Cl +
O
H
i -Bu
i -Bu
Al
N
THF
R
n
-BuLi
O
Cl
+
DIBALH
N
0 °C, 3 h
0 °C, 10 min
0 °C
R
Bu
O
(1.25 eq)
(1.2 eq)
O
(1.0 eq)
 

Entry

Acid chloride

Product

 

Rxn condition

Yield a (%)

 

n -BuLi ð equiv Þ = time

ð min Þ

1

O Cl
O
Cl
O Bu
O
Bu
 

2.0/10

98

2

b

O Cl
O
Cl
O Ph
O
Ph

2.5/30

97

3

O Cl F
O
Cl
F
O Bu
O
Bu

2.0/10

98

4

O Cl Cl
O
Cl
Cl
O Cl Bu
O
Cl
Bu

2.0/10

99

5

O Cl Cl
O
Cl
Cl
O Bu Cl
O
Bu
Cl

2.0/10

99

6

2.0/10

98

O Cl
O
Cl
O Bu
O
Bu

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J. K. Park et al. / Tetrahedron Letters 54 (2013) 3199–3203

Table 3 (continued )

Entry

Acid chloride

Product

Rxn condition

Yield a (%)

 

n -BuLi ð equiv Þ = time

ð min Þ

7

O Cl
O
Cl
O Bu
O
Bu

2.0/10

94

8

O Cl MeO
O
Cl
MeO
O Bu MeO
O
Bu
MeO

2.0/10

98

9

O Cl
O
Cl
O Bu
O
Bu

2.0/10

99

10

O O Cl
O
O
Cl
O O Bu
O
O
Bu

2.0/10

85

11

O Cl
O
Cl
O Bu
O
Bu

3.0/10

94

12

b

O Cl
O
Cl
O Ph
O
Ph

3.0/30

94

 

O

O

13

13 3.0/10 95
13 3.0/10 95

3.0/10

95

 

Cl

Bu

a lsolated yields after silica column chromatography.

 

b Used PhLi as nucleophile instead of n -BuLi.

 
 

H

N
N

O

i -Bu

i -Bu

THF

i -Bu

Al N
Al
N

O

i -Bu

 

Ph

O

O

Cl

i -Bu Al O O N Cl
i
-Bu
Al
O
O
N
Cl

Ph

-Bu

i

 
Al
Al

H

0 °C, 3 h

0 °C, 10 min

 

1

2

 
i -Bu O i -Bu LDBMA Al HCl(aq) O O Ph N O Li OMe
i -Bu O i -Bu LDBMA Al HCl(aq) O O Ph N O Li OMe
i
-Bu
O
i
-Bu
LDBMA
Al
HCl(aq)
O
O
Ph
N
O
Li
OMe
0 °C, 10 min
Ph
O
Ph
N
H
 

i -Bu

Al
Al

Cl

i -Bu

H

 

3

4

Scheme 2. Proposed mechanism.

results of the one-pot synthesis of ketones from a representative selection of acid chlorides. 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- bered cyclic form 6 by coordination of the aluminum metal with 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.

Acknowledgments

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.

References and notes

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.

5. 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, 1.25 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, 0.46 M in hexane–THF, 1.5 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 ether (2 10 mL). The combined organic layers were dried over MgSO 4 . GC analysis showed a 99% yield of benzaldehyde. All products in Table 2 were confirmed through comparison with GC data of authentic sample.

7. Partial alkylation of acid chlorides to corresponding ketones . The following experimental procedure for the partial reduction of benzoyl chloride to

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 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