Iodine-promoted cleavage of the C-17-dihydroxyacetone side chain of corticosteroids in aqueous ammonia water

Article abstract of DOI:10.3184/030823409X393664

A convenient approach to 17-ketosteroids by the iodine-promoted cleavage of the C-17-dihydroxy acetone side chain of corticosteroids is described. Treatment of steroids containing the C-17-dihydroxyacetone side chain with iodine and an excess of aqueous ammonia in acetonitrile at 50°ffords high yields of the corresponding 17-ketosteroids.

Full text of DOI:10.3184/030823409X393664

22 RESEARCH PAPER
JANUARY, 22–23
JOURNAL OF CHEMICAL RESEARCH 2009
Iodine-promoted cleavage of the C-17-dihydroxyacetone side chain of
corticosteroids in aqueous ammonia water
Liang Sun, Xin Geng, Lanhai Liu, Chenggang Jiang and Cunde Wang*
School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P. R. China
A convenient approach to 17-ketosteroids by the iodine-promoted cleavage of the C-17-dihydroxy acetone side
chain of corticosteroids is described. Treatment of steroids containing the C-17-dihydroxyacetone side chain
with iodine and an excess of aqueous ammonia in acetonitrile at 50°C, affords high yields of the corresponding
17-ketosteroids.
Keywords: corticosteroids, 17-ketosteroids, molecular iodine, cleavage reaction
17-Ketosteroids and corticosteroids bearing
a
C-17-
C-17-dihydroxyacetone side chain to afford 17-ketosteroids
promoted by molecular iodine under ambient conditions with
excellent yields. Scheme 1.
dihydroxyacetone side chain are some of the most important
compounds in steroid chemistry.1,2 The degradation of
steroids having the two-carbon side chain at the 17-position is
an important reaction because the products play an important
role as key intermediates in the biological conversion of
steroidal hormones.3-5 These reactions have therefore attracted
considerable attention. Various methods for the chemical
transformation of corticosteroids to form 17-ketosteroids
have been reported.6-12 These reactions are normally carried
out in the presence of a strong base or by using oxidative
methods. Although earlier reactions for the transformation of
corticosteroids to form 17-ketosteroids are still considered to
be useful, they require harsh reaction conditions and the yields
are often unsatisfactory. Recently a new simple and elegant
transformation of corticosteroids to form 17-ketosteroids has
been described.6 The procedure used sodium methoxide as a
strong base which attacked the C-17-dihydroxyacetone side.
The development of new approaches using mild reaction
FRQGLWLRQVꢀLVꢀDQꢀDFWLYHꢀUHVHDUFKꢀ¿HOGꢁꢀ5HFHQWO\ꢀLRGLQHꢀKDVꢀEHHQꢀ
used as a mild promoter for various organic transformations to
afford the products in excellent yields with high selectivity. It
has also been reported to be a mild, cheap and easily available
oxidising reagent and is less toxic than molecular bromine or
chlorine. Iodine has been explored as a powerful catalyst for
various organic transformations.13-16 To our knowledge, there
are no reports of the iodine-promoted cleavage of the C-17-
dihydroxyacetone side chain of corticosteroids in aqueous
ammonia. In continuation of our studies with molecular iodine
mediated reactions, we reasoned that iodine might be used
to effect the C–C bond cleavage reactions of corticosteroids
in the presence of aqueous ammonia. We report here a
novel chemical transformation of corticosteroids bearing a
Results and discussion
In our initial work, based on the classical method using a base
as a catalyst, 11E,17,21-trihydroxy-pregn-4-ene-3,20-dione 1a
and 35% aqueous ammonia were stirred at room temperature in
CH3CN in the absence of iodine. After 24 hours, only 10% of
the starting material was consumed; then at elevated temperature
50°C, only 18% of product 2a was obtained after workup of the
reaction after the same reaction time. To improve the product
yields and to optimise the reaction conditions, iodine was used
in an equiomolar amount. The reaction was carried out under
VLPLODUꢀFRQGLWLRQVꢁꢀ7RꢀRXUꢀVXUSULVHꢂꢀDꢀVLJQL¿FDQWꢀLPSURYHPHQWꢀ
in the yield of the product 2a (64% in yield) was observed.
Encouraged by these results, we investigated the reaction
further using different amounts of iodine. The increase in the
quantity of iodine from 1.0 to 1.5 equiomolar enhanced the
product yield from 64 to 72%. We varied the solvent and found
that acetonitrile gave the best result. We found that CH3CN,
DMF, THF, or DMSO gave the product 2a in yield at 72%,
50%, 59% and 31% respectively. Furthermore, faster reaction
occurred on increasing the temperature from room temperature
to 50°C and the reaction time was reduced to 24 h. In order to
HYDOXDWHꢀWKHꢀHI¿FLHQF\ꢀRIꢀLRGLQHꢀDVꢀDꢀSURPRWHUꢂꢀWKHꢀUHDFWDQWVꢀ1a–
c were treated with ammonia in the presence of 1.5 equiomolar
of iodine to generate product 2a–c. The results are summarised
in Scheme 1.
The products 2a–c were fully characterised by spectroscopic
analysis. The IR spectra of the products showed C17=O
stretching band at 1736–1740 cm-1 and C3=O stretching in
OH
O
O
X
X
Y
Y
.
OH
I2, NH3 H2O, CH3CN,
50 oC, 24 h
72–78 %
O
O
1a–c
2a–c
Entry
X
Y
17-Ketosteroids (2)(%)
a
b
c
HO
H
H
H
72
78
76
-O-
Scheme 1
* Correspondent. E-mail:tianranyaowu@zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2009 23
OH
OH
O
N
H
OH
OH
I2
NH3
-HI
-H2O
O
O
O
OH
O
N
I
O H
-HI
O
Scheme 2 Plausible reaction pathway for cleavage of the side chain of corticosteroids
the band at 1654–1672 cm-1. 1H NMR spectra, C4-alkene
proton was observed as singlet at 5.69–5.75 ppm. The protons
belonging to D-methylene adjacent to the carbonyls were
observed within the expected chemical shift values.
The mechanism for the conversion of the corticosteroids
to 17-ketosteroids can be tentatively explained as shown in
6FKHPHꢀꢃꢁꢀ$QꢀLPLQHꢀLVꢀ¿UVWꢀIRUPHGꢀE\ꢀQXFOHRSKLOLFꢀDGGLWLRQꢀ
of ammonia to the 20-carbonyl, followed by iodo-substitution
LQꢀQLWURJHQꢀRIꢀWKHꢀLPLQHꢀDQGꢀWKHꢀHI¿FLHQWꢀFOHDYDJHꢀRIꢀ&ꢄꢅ±&ꢃꢆꢀ
bond.17
In conclusion, we have successfully developed an easy and
HI¿FLHQWꢀ PHWKRGꢀ WRꢀ SUHSDUHꢀ Dꢀ YDULHW\ꢀ RIꢀ ꢄꢅꢇNHWRVWHURLGVꢀ E\ꢀ
the reaction of different corticosteroids with ammonia in the
presence of 1.5 equiomolar of iodine at 50°C. The promoting
activity of iodine is remarkable and affords an environmentally
benign process.
53.9, 51.0, 47.6, 38.7, 35.8(2C), 35.3, 34.0, 32.7, 31.4, 30.9, 21.8,
20.4, 17.5, 13.8; IR (KBr, cm-1): Q 1740, 1672, 1448. Anal. Calcd for
C19H26O2: C, 79.68; H, 9.15; Found: C, 79.44; H, 9.32%.
4-Androstene-3,11,17-trione (2c): 76% yield; white crystals, m.p.
1
218–220°C (EtOAc–hexanes) (lit.6: 218–220°C); H NMR (CDCl3,
300 MHz) G 5.74 (s, 1H), 1.44 (s, 3H), 0.88 (s, 3H); 13C NMR (CDCl3,
75 MHz) G 216.7, 207.5, 199.4, 167.8, 124.9, 63.4, 50.5, 50.4, 49.9,
38.4, 36.4, 36.0, 34.8, 33.8, 32.1, 31.0, 21.6, 17.4, 14.7; IR (KBr, cm-1):
Q 1740, 1702, 1665, 1447. Anal. Calcd for C19H24O3: C, 75.97; H,
8.05; Found: C, 75.69; H, 8.33%.
We are grateful to the Natural Science Foundation of Jiangsu
(GXFDWLRQꢀ 0LQLVWU\ꢀ RIꢀ &KLQDꢀ IRUꢀ ¿QDQFLDOꢀ VXSSRUWꢁꢀ ꢈ*UDQWꢀ
07KJB150135)
Received 15 October 2008; accepted 10 November 2008
Paper 08/0227 doi: 10.3184/030823409X393664
Published online: 23 January 2009
Experimental
Elemental analytical data were obtained by using a model 240
analytical instrument, IR spectra were measured with a model 408
infrared spectrometer, 1H NMR and 13C NMR spectra were recorded
on a JNM-90Q spectrometer by using TMS as an internal standard
(CDCl3 as solvent).
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A
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7KHꢀSURGXFWꢀZDVꢀSXUL¿HGꢀE\ꢀFROXPQꢀFKURPDJUDSK\ꢀꢈVLOLFDꢀJHOꢂꢀ(W2$Fꢉ
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