Efficient one-pot selective reduction of esters in β-ketoesters using LiHMDS and lithium aluminium hydride

Article abstract of DOI:10.1016/j.tetlet.2011.01.030

The ester functionality in β-keto esters is selectively reduced in one-pot, first by enolization using LiHMDS and then reduced with lithium aluminium hydride. This method produces β-hydroxyl ketones from the corresponding β-keto esters in high yield.

Full text of DOI:10.1016/j.tetlet.2011.01.030

Tetrahedron Letters 52 (2011) 1205–1207
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Tetrahedron Letters
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Efficient one-pot selective reduction of esters in b-ketoesters using LiHMDS
and lithium aluminium hydride
K. Sivagurunathan a,b, S. Raja Mohamed Kamil a, S. Syed Shafi a, F. Liakth Ali Khan a, R. Venkat Ragavan c,
⇑
a Department of Chemistry, Islamiah College, Vaniyambadi 635 752, India
b Syngene International Pvt. Ltd, Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigini Link Road, Bangalore 560 099, India
c Organic Chemistry Division, School of Advanced Sciences, VIT University 632 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The ester functionality in b-keto esters is selectively reduced in one-pot, first by enolization using
LiHMDS and then reduced with lithium aluminium hydride. This method produces b-hydroxyl ketones
from the corresponding b-keto esters in high yield.
Received 12 July 2010
Revised 29 December 2010
Accepted 8 January 2011
Available online 14 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Key words:
b-Keto esters
Selective reduction
LiHMDS and LAH
Selective reduction (or) oxidation of one functional group over
the other functional groups in a molecule plays an important role
in synthesizing the target molecules, particularly in the synthesis
of natural products. Selective reduction of esters in the presence
of ketone is always a challenging task because of the easy reducing
nature of ketone than ester. There are some methods for this selec-
tive reduction,1 but unfortunately all these reports are step-inten-
sive. There are a few reports in which ketones are selectively
reduced over the ester and other ketone in pyruvic acid deriva-
tives.2 This method also suffers through long reaction time, tedious
work-up, and usage of enzymes. To the best of our knowledge
there are two reports in which ester in long chain b-keto ester
has been selectively reduced by enolizing the ketone by trimethyl
silyl chloride followed by the reduction using LAH.3 Here-in we
report the fast and one-pot selective reduction of esters in the
presence of aryl ketones in b-keto esters, using which a number
of b-hydroxy ketones were synthesized. There are a number of
reports for the synthesis of b-hydroxy ketones.4
like lithium aluminium hydride. We have optimized the reaction
conditions using different solvents and different reducing agents
(Table 1). Among the reducing agents, LAH produced the best re-
sults with a shorter reaction time. Sodium borohydride did not give
any product under the same conditions, while lithium borohydride
gave only 34% of product.
After finding the suitable solvent and reducing agent, we
screened different bases for enolization (Table 2). KHMDS and
LiHMDS were found to be equally good for enolization, compared
to other bases. Use of both sodium hydride and potassium tert-
butoxide resulted in poor yield.
The required b-keto esters were synthesized using two different
methods (Method A6 and Method B7). The synthesized b-keto es-
ters and their yields are given in Table 3. The ketones in the b-keto
esters enolize under the reaction conditions and these enolized b-
keto esters were selectively reduced by adding suitable reducing
agent (LAH) in one-pot.8 We carried out a number of experiments
with aliphatic b-keto esters (Table 4, entries 23–25). In all these
cases both the ester and ketone were reduced under the reaction
conditions. In entries 24 and 25 diastereomeric mixtures of 1,3-
dihydroxy compounds were observed. In entry 26, bulky tert-butyl
ester did not undergo this selective reduction under these condi-
tions as expected. The enol in this case is not stabilized by conju-
gation. To prove the generality of this approach various aromatic
b-keto esters were examined under these conditions and the re-
sults are given in Table 4. In some cases we observed the formation
of 1,3-dihydroxy compounds. Almost all the b-keto esters were
selectively reduced smoothly, and b-keto esters having halogens
and heterocyclic b-keto esters did not produce any by-products.
As part of our research program,5 in the synthesis of pyrazoles
from b-keto esters, we were interested in the reactivity of enolates
of b-keto esters with hydrazines. In this process we were interested
in checking the stability and reactivity of ketone enolates. The aryl
ketone enolates 2 in aryl b-keto esters were stabilized by their ex-
tended conjugation with aromatic systems (Fig. 1) which reduces
the reactivity of the ketone to a great extent. These enolized aryl
ketones 2 were intact even in presence of strong reducing agent
⇑
Corresponding author.
E-mail address: ragavachem@gmail.com (R.V. Ragavan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.030

1206
K. Sivagurunathan et al. / Tetrahedron Letters 52 (2011) 1205–1207
O
O
OLi O
O
OLi
OC2H5
3
LiHMDS
OC2H5
OC2H5
R
R
R
THF
1
2
THF
LAH
O
OH
R
4
Figure 1. Stabilization of enol 2 by conjucation with aromatic system.
Table 1
Table 3 (continued)
Effect of solvent and reducing agents on the yield of 18
Entry
9
Substrate
COOCH3
Product
Yielda (%)
78c
Entry
Reducing agent
Solvent
Yielda (%)
O
O
O
1
2
3
4
5
LAH (1 M soln in THF)
LAH (1 M soln in THF)
LAH (1 M soln in THF)
NaBH4
THF
Diethyl ether
THF
THF
THF
81
34
23b
0
OC2H5
O
N
N
COOCH3
LiBH4
34
OC2H5
10
11
67c
87b
Cl
a
Isolated yield.
1 equiv of LAH used.
Cl
N
b
N
O
O
OCH3
O
Table 2
Effect of base on the yield of 18
a
b
c
Isolated yield.
Synthesized by Method A.
Synthesized by Method B.
Entry
Base
Solvent
Yielda (%)
1
2
3
4
5
LiHMDS (1 M in THF)
KHMDS (1 M in THF)
NaHMDS (1 M in THF)
NaH
THF
THF
THF
THF
THF
81
78
53
27
34
t-BuOK
a
Isolated yield.
Table 4
Selective reduction of esters in b-keto esters
Entry
Substrate
Product
Yielda (%)
78
O
O
O
Table 3
Synthesis of b-ketoesters
OH
O
O
12
Entry
Substrate
Product
Yielda (%)
88b
O
O
O
O
O O
Cl
Cl
13
14
81
78
1
O
OH
OCH3
O
O
O
O
O
O
O
2
3
4
84b
81b
89b
Cl
Cl
OCH3
O
OH
OH
O
Cl
O
Cl
O
Cl
Cl
OCH3
O
O
O
O
O
O
15
84
H3CO
H3CO
OCH3
OMe
OMe
O
O
O
O O
5
91b
O
OH
16
17
87
76
OCH3
F
F
F
F
O
O
O
O
O
O
O
6
7
8
76b
87c
76c
OH
OCH3
Cl
O
Cl
O
Cl
O
Cl
COOCH3
O
O
18
19
74
70
OH
O
O
OC2H5
O
N
N
N
N
N
N
O
O
COOCH3
O
O
OH
OC2H5
N
N

K. Sivagurunathan et al. / Tetrahedron Letters 52 (2011) 1205–1207
1207
Authors are also thankful to the Management, Islamiah College
for providing the lab facilities.
Table 4 (continued)
Entry
Substrate
Product
Yielda (%)
72
O
O
O
References and notes
20
O
OH
1. (a) Martin, A.; Murray, H.; Pratt, E.; Zaho, Y. B.; Albizati, F. J. Am. Chem. Soc. 1990,
112, 6965; (b) Lavallee, F.; Spino, C.; Ruel, R.; Hogan, K. T.; Deslongchamps, P.
Can. J. Chem. 1992, 70, 1406; (c) Hitchcock, S. R.; Perron, F.; Martin, V. A.;
Albizati, K. F. Synthesis 1990, 1059; (d) Yun, J.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 5640; (e) Johnson, C. R.; Dutra, G. A. J. Am. Chem. Soc. 1973, 95, 7777;
(f) Choshi, T.; Matsuya, Y.; Okita, M.; Inada, K.; Sugino, E.; Hibino, S. Tetrahedron
Lett. 1998, 39, 2341; (g) Martin, V. A.; Albizati, K. F. J. Org. Chem. 1988, 53, 5986;
(h) Hankovszky, H. O.; Hideg, K.; Lex, L.; Kulcsar, G.; Halasz, A. H. Can. J. Chem.
1982, 60, 1432.
2. Fadravis, N. W.; Radhika, K. R. Tetrahedron: Asymmetry 2004, 14, 3443.
3. (a) Alderdice, M.; Spino, C.; Weiler, L. Can. J. Chem. 1993, 71, 1955; (b) Srikrishna,
A.; Krishnan, K. J. Org. Chem. 1993, 58, 7751.
4. (a) Yoshio, U.; Makoto, O. Tetrahedron Lett. 1976, 17, 4597; (b) Hasegawa, E.;
Ishiyama, K.; Horaguchi, T.; Shimizu, T. J. Org. Chem. 1991, 56, 1631; (c) Smith, A.
B., III; Levenberg, P. A. Synthesis 1981, 567.
5. (a) Ragavan, R. V.; Vijayakumar, V.; Kumari, N. S. Eur. J. Med. Chem. 2009, 44,
3852; (b) Ragavan, R. V.; Vijayakumar, V.; Kumari, N. S. Eur. J. Med. Chem. 2010,
45, 1173.
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H.; Homeyer, A. H.; David, M. J. J. Am. Chem. Soc. 1941, 63, 2252.
7. General procedure to synthesize b-keto esters (Method B): To the solution of ethyl
acetate (60 mol), aryl ester (10 mol) in dry THF (20 mL), LiHMDS (30 mol) was
added quickly at À50 °C and stirred at this temperature for 30 min. The reaction
was monitored by TLC and it was quenched with acetic acid (20 mol) and water
(25 mL), basified with sat. solution of sodium bicarbonate (20 ml) and extracted
with ethyl acetate (2 Â 20 mL). The combined organic extract was washed with
water (10 mL) and brine solution (10 mL) and dried over anhyd Na2SO4. The
crude product was purified by column chromatography (hexane/ethyl acetate,
20:80) to get the pure product.
N
N
N
O
O
O
Cl
Cl
21
22
65
82
OH
OH
O
N
O
O
O
O
O
O
OH
OH
OH
23
24
88
38
OC2H5
OH
O
O
O
O
OH
O
25
26
45
0
OC2H5
OH
O
O
O
O
OH
a
Isolated yield.
In summary we have developed an efficient, simple, one-pot
8. General procedure for the selective reduction of esters in b-keto esters: LiHMDS
(10 mol) was added to the solution of b-keto ester (10 mol) in THF (20 mL) at
0 °C. After stirring at this temperature for 30 min LAH (20 mol, 1 M solution in
THF) was added at 0 °C and stirred at this temperature for 30 min. The reaction
was monitored by TLC. After completion of the reaction, the reaction mixture
was quenched with cold water (30 mol) and the resulting solid was filtered
through Celite bed and washed with ethyl acetate (20 mL). Filtrate was dried
over anhyd Na2SO4 and the crude product was purified by column
chromatography to get the pure product.
method for selective reduction of esters in the presence of aryl ke-
tone in b-keto esters using LiHMDS and LAH. At present we are
applying this strategy to b-diketones and further work in this area
is under progress.
Acknowledgments
Authors are grateful to Syngene International Pvt. Ltd, (Dr. Gou-
tham Das and Dr. P. Sathya shanker) for their invaluable support.