An efficient one-step chemoselective reduction of alkyl ketones over aryl ketones in β-diketones using LiHMDS and lithium aluminium hydride

Article abstract of DOI:10.1016/j.tetlet.2012.06.057

β-Hydroxy ketones were synthesized in one-pot from β-diketones by reducing alkyl ketones chemoselectively by keeping aryl ketone intact. Initially, β-diketones were enolized using LiHMDS and later alkyl ketone was chemoselectively reduced efficiently by lithium aluminium hydride. This method produces β- hydroxyl ketones from the corresponding β-diketones in high yield.

Full text of DOI:10.1016/j.tetlet.2012.06.057

Tetrahedron Letters 53 (2012) 4651–4653
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Tetrahedron Letters
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An efficient one-step chemoselective reduction of alkyl ketones over aryl
ketones in b-diketones using LiHMDS and lithium aluminium hydride
S. Veeraswamy a,b, K. Indrasena Reddy a, R. Venkat Ragavan a, , K. Tirumal Reddy a,
⇑
Satyanarayana Yennam a, A. Jayashree b
a Chemistry Services, GVK Biosciences Pvt. Ltd, Plot No. 28, IDA, Nacharam, Hyderabad 500076, AP, India
b Centre for Chemical Sciences & Technology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
b-Hydroxy ketones were synthesized in one-pot from b-diketones by reducing alkyl ketones chemoselec-
tively by keeping aryl ketone intact. Initially, b-diketones were enolized using LiHMDS and later alkyl
ketone was chemoselectively reduced efficiently by lithium aluminium hydride. This method produces
b- hydroxyl ketones from the corresponding b-diketones in high yield.
Received 10 May 2012
Revised 11 June 2012
Accepted 13 June 2012
Available online 28 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Chemoselective reduction
b-Diketones
b-Hydroxy ketones
LiHMDS and LAH
Chiral b-hydroxy ketones are useful synthetic intermediates
and have been used widely in the synthesis of natural products.1
b-Hydroxy ketones are very important synthetic intermediates in
the synthesis of 1,3-diols, which are basic skeleton of polyene
and poly macrolide antibiotics, for example, compactin, Rifamy-
cin,2 and Lonomycin A,3 etc.
O
O
O
OH
2e
LiHMDS / THF
LAH / THF
1e
Scheme 1. Synthesis of 1-(4-tert-butylphenyl)-3-hydroxybutan-1-one (2e).
There are many reported methods to synthesize b-hydroxy
ketones, among them traditional aldol condensation, Mukaiyama
aldol reactions,4 and boron mediated aldol condensations5 of an
aldehyde with ketone have been most widely studied. There are
methods to synthesize b-hydroxy ketones starting from b-dike-
tones such as ruthenium-BINAP catalyzed hydrogenation,6
Pt/Al2O3 catalyzed hydrogenation,7 and reduction of both the ke-
tones followed by selective oxidation,8 but these methods are poor
chemo selective and step intensive. Enzymatic chemo selective
reduction of b-diketones to b-hydroxy ketones is also reported,9
this method suffers from long reaction time and tedious work-
up. To the best of our knowledge there is only one chemo selective
chemical reduction of b-diketones to b-hydroxy ketones using
zirconium and hafnium complexes,10 and this requires the synthe-
sis of these metallocene complexes.
By applying this methodology a series of b-diketones were che-
moselectively reduced to get the b-hydroxy ketones in good yield.
To test our hypothesis, initially we tried a reaction on compound
1e (Scheme 1) using LiHMDS and LAH and the result was encourag-
ing. Later we tried to optimize the reaction conditions with differ-
ent reducing agents (Table 1), among them lithium aluminium
hydride produced the best results in shorter reaction time (entry
1). DIBAL-H reaction gave only 23% of yield and sodium borohy-
dride did not give any product and starting material remained as
such even at room temperature.
After finding the suitable reducing agent the reaction was car-
ried out in different temperatures (Table 1). Reactions at 0, À50
and À78 °C all found to be equally good, reaction at room temper-
ature produced 15% of 1,3-dihydroxy compound.
b-Diketones were synthesized by treating the acid chlorides on
the acetophenone enolates by following the procedure reported by
Heller et al.12 Aryl ketones in b-diketones using LiHMDS at 0 °C
deprotonate to form enolates and these enolates were chemoselec-
tively reduced by the addition of LAH in one-step (see Fig 1).13 To
test the generality of this method we carried out a number of reac-
tions with different b-diketones and the results are summarized in
In continuation of our earlier research work,11 herein we wish
to report the efficient one-step, chemoselective reduction of alkyl
ketone over aryl ketone using LiHMDS and LAH in b-diketones.
⇑
Corresponding author. Tel.: +91 6628 1348; fax: +91 6628 1505.
E-mail addresses: ragavachem@gmail.com, venkatragavan.r@gvk.bio.com (R.
Venkat Ragavan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.057

4652
S. Veeraswamy et al. / Tetrahedron Letters 53 (2012) 4651–4653
Table 1
Table 2
Effect of reducing agents and temperature on the yield of 2e
Chemoselective reduction of b-diketones
Entry
Reducing agent
Temp. (°C)
Yielda
Entry
1
Substrate
Product
Yielda (%)
80
1
2
3
4
5
LAH (1 M sol. in THF)
DIBAL-H
LAH (1 M sol. in THF)
LAH(1 M sol. in THF)
LAH(1 M sol. in THF)
0
0
À50
À78
rt
81
23
75
69
56
O
O
O
OH
MeO
MeO
MeO
MeO
1a
2a
OMe
OMe
O
O
O
OH
a
2
3
78
75
Isolated yield.
1b
2b
OH
OMe
OMe
O
O
O
MeO
MeO
MeO
MeO
O
O
OLi O
O
OLi
R2
R2
R2
LiHMDS
THF
1c
2c
R1
R1
R1
OMe
OMe
O
O
O OH
enolate - 1
1
enolate - 2
4
5
0
2d
THF
1d
LAH
OH
F3C
F3C
O
O
O OH
O
81
R2
1e
2e
R1
2
O
O
O
O
OH
OH
6
7
72
70
2f
Figure 1. Stabilization of enolate 1 by conjugation with aromatic system.
1f
O
F
O
F
1g
2g
Table 2. Almost all the substrates reacted smoothly and produced
b-hydroxy ketones in good yield. Chemoselective reduction of alkyl
ketones was further confirmed by the NOE experiment in com-
pounds 2a, 2c, 2k, and 2m. Substrates having the highly electron
withdrawing groups did not work (entries 4 and 14) and starting
material was intact even at room temperature. In a few cases very
small amount of 1,3-dihydroxy compounds was observed, when
reactions continued for more than 45 min after adding LAH.
In summary, we have developed an efficient, simple, fast one-
step method for chemoselective reduction of alkyl ketones in the
presence of aryl ketone in b-diketones using LiHMDS and LAH. This
method will help researchers to prepare various b-hydroxy ke-
tones, which are basic skeleton of many natural products and
important synthetic intermediates in the synthesis of 1,3-diols.
O
O
O
O
8
76
O
O
OH
OH
1h
1i
2h
9
78
72
2i
O
O
O OH
10
1j
2j
F
F
O
O
O
OH
11
12
80
74
1k
2k
OMe
OMe
O
O
O
OH
2l
1l
O
O
O OH
Acknowledgments
13
14
70
0
F
F
F
F
1m
2m
Authors are grateful to GVK Biosciences Pvt. Ltd, for the finan-
cial support and encouragement. We thank Dr. Balram Patro for
his motivation and help from the analytical department for the
analytical data is appreciated.
O
O
O
F
OH
1n
1o
1p
2n
F
O
O
O
OH OH
15
16
78
82
2o
O
OH OH
Supplementary data
2p
Supplementary data (Copies of 1H NMR and 13C NMR of all new
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.057.
O
O
O
O
OH
17
18
72
68
2q
1q
O
O
OH
References and notes
1r
2r
OMe
OMe
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13. General procedure for chemoselective reduction of b-diketones: LiHMDS
(2.5 mmol) was added to the solution of b-diketone (2.3 mmol) in THF
(10 mL) at 0 °C. After stirring at this temperature for 30 minutes LAH
(4.6 mmol, 1 M solution in THF) was added at 0 °C and stirred at this
temperature for 30 min., Reaction was monitored by TLC, after completion of
the reaction, reaction mixture was quenched with cold water (4 mL) and the
resulting solid was filtered through celite bed and washed with ethyl acetate
(20 mL). Filtrate was dried over anhydrous Na2SO4, and purification of crude by
column chromatography on silica gel (10% ethyl acetate in pet ether) afforded
the pure product.