Hydrazine hydrate induced reductive cleavage of α,β-epoxy ketones: An efficient procedure for the preparation of β-hydroxy ketones

Article abstract of DOI:10.1016/j.tetlet.2004.12.103

An efficient and general procedure for the reductive cleavage of α,β-epoxy ketones to the corresponding β-hydroxy ketones, using hydrazine hydrate in ethanol at low temperatures, is described.

Full text of DOI:10.1016/j.tetlet.2004.12.103

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1067–1070
Hydrazine hydrate induced reductive cleavage of
a,b-epoxy ketones: an efficient procedure for the
preparation of b-hydroxy ketones
b
b
c
Jorge A. R. Salvador,a, Alcino J. L. Leita˜o, M. Luısa Sa e Melo and James R. Hanson
*
´
´
a
´ ´
Laboratorio de Quımica Farmaceutica, Faculdade de Farmacia, Universidade de Coimbra, 3000-295 Coimbra, Portugal
Centro de Estudos Farmaceuticos, Laboratorio de Quımica Farmaceutica, Faculdade de Farmacia,
ˆ
´
b
ˆ
´
´
ˆ
Universidade de Coimbra, 3000-295 Coimbra, Portugal
´
cSchool of Chemistry, Physics and Environmental Science, University of Sussex, Brighton, Sussex BN1 9QJ, UK
Received 15 October 2004; revised 16 December 2004; accepted 21 December 2004
Available online 11 January 2005
Abstract—An efficient and general procedure for the reductive cleavage of a,b-epoxy ketones to the corresponding b-hydroxy
ketones, using hydrazine hydrate in ethanol at low temperatures, is described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The selective reduction of a,b-epoxy ketones to b-hydr-
oxy ketones is recognized as a synthetically important
process in the construction of a variety of important nat-
ural products, through the use of these aldol key
intermediates.
ported the use of Cp2TiCl for the selective reduction
of a,b-epoxy ketones to b-hydroxy ketones.
In this communication we describe an efficient and ver-
satile procedure for the reductive cleavage of a,b-epoxy
ketones to the corresponding b-hydroxy ketones under
mild conditions using NH2NH2ÆH2O in ethanol as sol-
vent. The steroidal epoxy ketones 1, 7, 10 and 13, were
readily reduced to corresponding b-hydroxy ketones 2,
8, 11, 14 in high isolated yields (Scheme 1, Table 1).
Apart from the reaction with substrate 10 at 0 ꢁC, which
required a mixture of ethanol/MTBE 2:3 as solvent, all
the reactions were performed in ethanol. Temperature
plays an important role in this procedure. Thus, reac-
tions performed at low temperatures (À20 ꢁC, 0 ꢁC)
afforded b-hydroxy ketones as the only product (Table
1 entries 1, 2, 8, 9, 13 and 17). Reactions performed un-
der similar conditions but at room temperature afforded
b-hydroxy ketones as major products (Table 1, entry 3,
ratio b-hydroxy-ketone/allylic alcohol 2:1). In general,
reactions carried out at 50 ꢁC led to the mixtures of
allylic alcohol and b-hydroxy-ketone (except for sub-
strate 13, Table 1, entry 19), while under reflux the
allylic alcohol was the only reaction product (Table 1,
entries 6, 7, 12, 16 and 18).
The aldol process proved to be highly useful for the
preparation of ꢀacyclicꢁ b-hydroxy ketones, however
for cyclic b-hydroxy ketones this method cannot be gen-
erally applied efficiently.
Several methods have been developed to perform the
selective reduction of a,b-epoxy ketones. Use of chro-
mium(II) salts1 and Zn/acetic acid2 as well as electro-
chemical methods3 often result in the formation of
enone among other by products. Other examples include
SmI2,4 Al amalgam,5 Bu3SnH/AIBN,6 H2/Pd/C,7 PET,8
organoselenium reagents,9 photoinduced electron trans-
fer reactions with 2-phenyl-N,N-dimethylbenzimidazo-
line10 and lithium naphalenide,11 but there are many
drawbacks and disadvantages such as the need for the
use of drastic conditions, poor yields, low selectivity,
and the stoichiometric amounts of toxic reagents often
required. Quite recently Doris and co-workers12 re-
The reduction of a,b-epoxy ketones to allylic alcohols
under these reaction conditions, corroborate with previ-
ous findings regarding the similar conditions used in the
*
Corresponding author. Tel.: +351 239 859900; fax: +351 239
827126; e-mail: salvador@ci.uc.pt
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.103

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J. A. R. Salvador et al. / Tetrahedron Letters 46 (2005) 1067–1070
Scheme 1.
Wharton reaction (hydrazine hydrate, ethanol, acetic
acid, reflux).13
In summary, the homogeneous mild reaction conditions
and good yields in product formation, coupled with an
operational simplicity broadness and reproducibility,
in the aforementioned procedure, is a method of choice
for the synthesis of b-hydroxy ketones via reductive
cleavage of the corresponding a,b-epoxy ketones.
The presence of water having no influence upon the
reaction (Table 1 entries 5, 7, 13,15, 16 and 19) allows
the use of a common solvent (ethanol) in this process.
The same outcome was generally observed with a non-
steroid substrate 4, the (S)-(+)-carvone epoxide. When
the reaction was performed with this substrate at 0 ꢁC,
it afforded product 5 in a good yield (72%) and moder-
ate stereoselectivity (Table 1, entry 9).
Typical procedure: To a solution of 4b,5b-epoxy-17b-
hydroxyandrostan-3-one 1 (0.150 g/0.5 mmol) in etha-
nol at 0 ꢁC, hydrazine hydrate (1 mL/20 mmol) was
added. After 2 h under magnetic stirring, the solution
was quenched with HCl (10% aq solution) and after
10 min extracted with CH2Cl2 (3 · 25 mL). The com-
bined organic layer was washed with aqueous saturated
NaHCO3 (2 · 25 mL), water (25 mL), dried over anhy-
drous MgSO4, filtered and evaporated under reduced
pressure to afford 5b,17b-dihydroxyandrostan-3-one 2
(0.131 g, 87%) as a white solid product.
For the pregnane derivative 13, the 20 keto group in a
flexible side chain at C17 allowed to carry out the reac-
tion at 50 ꢁC leading to the formation of the correspond-
ing b-hydroxy-ketone 14 (Table 1, entry 19). However,
when the reaction was performed at reflux it afforded
a mixture of the b-hydroxy-ketone 14 and the allylic
alcohols.
Selected spectroscopic data: Spectroscopic data for 2,9b
5,9a 8,14 119a and 1415 are in agreement with those re-
ported in the literature.
Although the mechanism of this reaction is still unclear,
using substrate 13, we could isolate the 16a-hydroxy-
20-hydrazone as the intermediate of the process before
submitting the reaction solution to the acidic work-up.
Compound 2: 1H NMR (300 MHz, CDCl3): d 0.77 (3H,
s, 18-Me), 1.01 (3H, s, 19-Me), 3.04 (1H, d, J = 15.1 Hz,

J. A. R. Salvador et al. / Tetrahedron Letters 46 (2005) 1067–1070
1069
Table 1. Reductive cleavage of a,b-epoxy ketosteroids and (S)-(+)-carvone epoxide with hydrazine hydrate
Entry Substrate/mmol
Ethanol Water Hydrazine
(mL)
Temperature
(ꢁC)
Time (h)
Product Isolated
yield (%)
Ratioa
(mL)
hydrate (mL)
(hydroxy-ketone/allylic
alcohol)
1
1/0.5
1/0.5
5
––
––
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.3
0.3
0.3
0.3
0.5
0.5
1.0
À20
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
1
2
2
86
87
87
84
86
87
85
70b
72b
73
74
73
84
86
86
88
72d
88
87
1:0
1:0
2:1
1:1
1:1
0:1
0:1
1:0
1:0
2.5:1
1:3.0
0:1
1:0
42:1
2:1
0:1
1:0
0:1
1:0
2
5
0
2
3
1/0.5
1/0.5
5
––
––
rt
50
2
4
5
2+3
2+3
3
5
1/0.5
1/0.5
5
1.0
––
50
Reflux
Reflux
6
5
7
1/0.5
4/1.2
5
1.0
––
3
8
5
À20
5
9
4/1.2
4/1.2
5
––
––
0
5
10
11
12
13
14
15
16
17
18
19
5
rt
50
5
4/1.2
4/1.2
5
––
––
6
5
Reflux
0
6
7/0.16
7/0.16
7/0.16
7/0.16
10/0.25
10/0.25
13/0.45
2.5
2.5
2.5
2.5
2c
5
0.1
––
8
rt
50
8
0.1
0.1
––
8
Reflux
0
9
11
––
0.25
Reflux
50
12
14
7.5
a Determined by 1H NMR in crude product.
b The diastereoisomer (2R) was obtained in 33% yield as a by-product.
c A mixture of MTBE (3 mL) and ethanol (2 mL) was used as solvent.
d After flash chromatography (petroleum benzine–ethyl acetate 9:1–1:1).
4a-H), 3.67 (1H, t, J = 8.5 Hz, 17a-H); 13C NMR
(75.5 MHz, CDCl3): d 78.6 (C5), 81.7 (C17), 211.3 (C3);
IR (ATR): 3365, 2932, 2864, 1703, 1446, 1376, 1132,
Acknowledgements
Financial support from FCT is gratefully acknowledged.
J.A.R.S. thanks Fundac¸a˜o Calouste Gulbenkian for
financial support.
1027, 1007, 955, 911 cmÀ1
.
Compound 5: 1H NMR (300 MHz, CDCl3): d 1.12 (3H,
d, J = 7.0 Hz), 1.76 (3H, s), 4.32 (1H, m), 4.77 (1H, s),
4.80 (1H, s); 13C NMR (75.5 MHz, CDCl3): d 73.6
(C3); 110.0 (C@CH2); 147.2 (C@CH2); 210.9 (C1); IR
(Film): 3462, 3083, 2971, 2936, 1711, 1664, 1450, 1375,
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