Reactivity of Some Unsaturated 17-Oxo Steroids under Conditions of Diimide Reduction

Article abstract of DOI:10.1039/a706570a

The olefinic double bond in 17-oxo steroids 1,5 and 7 is either reduced with diimide very slowly (compound 1) or it cannot be reduced at all (compounds 5 and 7), thus enabling hydrazine (accumulated by disproportionation of the diimide) to react with their respective 17-oxo groups to give hydrazones 3,6 and 8.

Full text of DOI:10.1039/a706570a

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102 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 102±103
Reactivity of Some Unsaturated 17-Oxo Steroids under
Conditions of Diimide Reduction{
Ljubinka Lorenc, Lidija Bondarenko-Gheorghiu and
Mihailo Lj. Mihailovic*
aFaculty of Chemistry, University of Belgrade, Studentski trg12^16, P.O. Box158,YU-11001, Belgrade,
Yugoslavia
bCenter for Chemistry, ICTM, P.O. Box 815,YU-11001, Belgrade,Yugoslavia
The olefinic double bond in 17-oxo steroids 1, 5 and 7 is either reduced with diimide very slowly (compound 1) or it cannot be
reduced at all (compounds 5 and 7), thus enabling hydrazine (accumulated by disproportionation of the diimide) to react with their
respective17-oxo groups to give hydrazones 3, 6 and 8.
1
and 1661 cm assignable to the hydrazone NH2 group and
C1N bond, respectively, while its H NMR spectrum, con-
taining parts of two singlets for the CH3-18 group (at d 0.92
and 0.98), indicated that this product consisted of the Z and
E stereoisomers.
It is known that the diimide reduction of a carbon±carbon
multiple bond can be selectively carried out in the presence
1
of
a
variety of reactive functional groups,1 including
allylic halides,2,3 ethers,2 amines,2 disul®des,4 unsaturated
ketones,2,5 peroxides6,7 and some other functions.1 A limi-
tation of the use of diimide as a reducing agent is the com-
petition between hydrogenation of the carbon±carbon
multiple bond and disproportionation,1,8 i.e., hydrogenation
of the diimide nitrogen±nitrogen double bond by another
diimide molecule to form nitrogen and hydrazine (Scheme
1). Which of these processes will prevail depends on the
relative rate at which diimide reacts with the unsaturated
substrate. If the rate of reduction is suciently slower than
the rate of disproportionation of diimide, the latter reaction
will dominate and no reduction will be accomplished. For
these particular cases it was anticipated1 that if the substrate
contains any other functional group capable of reacting
with hydrazine, reaction at that function with hydrazine
formed by diimide disproportionation would occur.
Me
C
Me
•
N
N
•
•
O
•
O
O
AcO
AcO
O
O
1
4 one isomer
HN NH
acetone
O
NNH2
+
O
O
AcO
AcO
O
2 (~16%)
O
Z and E isomer
3 (~58%)
Scheme 1
Scheme 2
In this paper we report on the diimide reactions of some
unsaturated 17-oxo steroids, i.e., 17-oxo-5,8a-epidioxy-5a-
androst-6-en-3b-yl acetate (1), 17-oxoandrost-5-en-3b-yl
acetate (5) and 17-oxo-7-norandrost-5-en-3b-yl acetate (7)
(Schemes 2 and 3), which illustrate the reactivity of such
substrates.
In an attempt to purify the hydrazone 3 by recrystal-
lization from an acetone±methanol mixture, it was
spontaneously transformed to the corresponding isopropyli-
denehydrazono derivative 4. This compound was obtained
in only one, Z or E, stereoisomeric form, and its identi®-
cation based on elemental microanalysis (C24H36N2O4) and
spectral characteristics (see Experimental section) con®rmed
the hydrazone structure 3.
On the other hand, when the D5-unsaturated androstene
and B-norandrostene derivatives 5 and 7, respectively, were
subjected to the diimide reaction as above, they gave
(Scheme 3) the D5-unsaturated hydrazones 6 and 8, respect-
ively, in quantitative yield. Signals for the ole®nic HC(6)
protons in the 1H NMR spectra of 6 and 8 (at d 5.39 for
the former and at d 5.44 for the latter compound) clearly
indicated that the D5-double bond in both substrates
remained unattacked by the diimide molecule.9 Other spec-
tral data were also in full agreement with the structures 6
and 8, respectively.
When the 17-oxo epidioxide 1 was treated with an excess
of diimide, generated in situ from dipotassium azodicarboxy-
late and acetic acid (for details see Experimental section), it
gave, after column chromatography on SiO2 (Scheme 2), the
expected saturated 17-oxo epidioxide 2 in only 16% yield,
the major reaction product being a Z±E mixture of the cor-
responding hydrazone 3 (isolated in 58% yield). The 17-oxo
compound 2 was identi®ed by comparison with an authentic
sample,7 while the structure 3 was deduced as follows. In
product 3 the original ole®nic D6-double bond (1H NMR:
AB quartet centred at d 6.42) and the ®ve-membered-ring
17-oxo group (IR: absorption at 1748 cm 1) were missing,
indicating that both these functions had participated in the
diimide reaction. In accordance with the proposed structure,
the IR spectrum of 3 contained new absorptions at 3450
These results have unequivocally con®rmed the validity of
the above mentioned assumption. Since the ole®nic double
bond in the investigated 17-oxo steroids is either reduced
with diimide very slowly (compound 1) or it cannot be
reduced at all (compounds 5 and 7), reaction of their
To receive any correspondence.
This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1998 103
Diimide Reaction of 17-Oxoandrost-5-en-3 -yl Acetate (5).ÐTo a
stirred solution of 5 (200 mg, 0.6 mmol) in CH2Cl2 (10 ml) and
absolute MeOH (15 ml) dipotassium azodicarboxylate (1.0 g,
2.7 mmol) was added and the suspension cooled in an ice-bath.
To this mixture was added dropwise a solution of AcOH (0.6 ml)
in MeOH (6 ml) within ca. 30 min and stirring was continued
overnight at room temperature. Work-up as above a€orded a
crystalline solid (220 mg) which was chromatographed on SiO2
(12 g). Elution with EtOAc gave a mixture of (Z)- and (E)-
hydrazones 6 (167 mg, 80.1%), mp 275±276 8C (decomp.);
/
max
0.87, 0.92 (3 H, parts of
1
cm (KBr) 3344, 1733, 1669, 1250;
H
two s, H-18 of Z and E isomers), 1.05 (3 H, s, H-19), 2.04 (3 H, s,
OCOCH3), 4.61 (1 H, m, H-3), 5.39 (1 H, d, J 5.0 Hz, H-6);
C
16.4, 16.6 (q, C-18), 19.2 (q, C-19), 20.5 (t, C-11), 21.3 (q,
OCOCH3), 23.2, 23.3 (t, C-15), 24.3 (t, C-2) 27.6 (t, C-7), 31.2
(d, C-8), 31.2 (t, C-12), 33.7, 33.9 (t, C-16), 36.6 (t,
C-1), 36.8 (s, C-10), 38.0 (t, C-4), 43.7, 43.9 (s, C-13), 50.2
(d, C-9), 53.5, 53.8 (d, C-14), 73.7 (d, C-3), 122.0 (d, C-6),
139.8 (s, C-5), 170.5 (s, OCOCH3), 165.9 173.6 (s, C-17); m/z 344
(M+).
Scheme 3
respective 17-oxo groups with hydrazine (accumulated by
diimide disproportionation) is the main process.
Diimide Reaction of 17-Oxo-7-norandrost-5-en-3 -yl Acetate (7).Ð
A
stirred ice-cooled suspension of
potassium azodicarboxylate (1.0 g, 2.7 mmol) in CH2Cl2 (10 ml) and
MeOH (15 ml) was treated with solution of AcOH (0.6 ml)
7 (200 mg, 0.63 mmol) and
a
Experimental
and MeOH (15 ml) as above. The mixture was left overnight at
room temperature and worked up as above. The residue (210 mg)
was puri®ed by column chromatography on SiO2 (12 g). Toluene±
Mps are uncorrected. IR spectra were recorded on a Perkin-
Elmer 337 spectrometer and NMR spectra on a Varian Gemini
2000 spectrometer (1H at 200 MHz, 13C at 50 MHz) in CDCl3
solution at room temperature, using SiMe4 as internal standard
(d in ppm, J in Hz). Mass spectra were measured on a Finnigan-
MAT 8230 spectrometer at 70 eV. Column chromatography was
carried out on silica gel 0.063±0.200 mm. TLC (control of reactions
and separation of products) was performed on silica gel G (Stahl)
(detection with 50% aqueous H2SO4).
EtOAc (6:4 and 1:1) eluted the hydrazone 8 (201 mg, 96.2%), mp
1
224±225 8C (decomp.); max/cm 3445, 1733, 1662, 1245;
0.92
(3 H, s, H-18), 0.93 (3 H, s, H-19), 2.04 (3 H, s, OCOCH3), 4.64
H
(1 H, m, H-3), 5.44 (1 H, br, s, H-6); 14.4 (q, C-18), 17.1 (q,
C
C-19), 20.5 (t, C-11), 21.3 (q, OCOCH3), 23.5 (t, C-15), 27.8 (t,
C-2), 29.6 (t, C-12), 32.7 (t, C-4), 34.1 (t, C-16), 36.7 (t, C-1), 44.7
(d, C-14), 45.6 (s, C-10), 45.7 (s, C-13), 51.3 (d, C-8), 62.5 (d, C-9),
73.5 (d, C-3), 125.1 (d, C-6), 148.5 (s, C-5), 170.4 (s, OCOCH3),
173.1 (s, C-17); m/z 330 (M+).
17-Oxo-5,8 -epidioxy-5 -androst-6-en-3 -yl Acetate (1)11.ÐMp
239±240 8C (from acetone±methanol); [ ]D= + 66.0 (c, 0.50 in
1
CHCl3); max/cm (KBr) 1748, 1735, 1248;
0.93 (3 H, s, H-18),
1.00 (3 H, s, H-19), 2.03 (3 H, s, OCOCH3), 5.00 (1 H, m, H-3),
H
6.32, 6.52 (2 H, AB, J 8.6 Hz, H-6, H-7) (Found: C, 69.75: H, 7.79.
C21H28O5 requires C, 69.98; H, 7.83%).
Diimide Reduction of 17-Oxo-5,8 -epidioxy-5 -androst-6-en-3 -yl
We thank the Serbian Academy of Sciences and Arts and
the Ministry of Sciences and Technology of Serbia for ®nan-
cial support.
Acetate (1).ÐTo a stirred solution of 1 (1.08 g, 3 mmol) in CH2Cl2
(50 ml) and absolute MeOH (70 ml) dipotassium azodicarboxylate
(5 g, 13.5 mmol) was added and the suspension cooled in an ice-
bath. To this mixture was added dropwise a solution of AcOH
(3 ml) in absolute MeOH (30 ml) within ca. 1 h. Stirring was
continued at room temperature for an additional 20 h, when the
yellow colour disappeared. The mixture was taken up in water
(250 ml) and extracted twice with CH2Cl2, the combined organic
extract was washed with saturated aq. NaHCO3 solution and water,
Received, 9th September 1997; Accepted, 31st October 1997
Paper E/7/06570A
References
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dried (Na2SO4) and evaporated and the residue
( 1.2 g) was
chromatographed on SiO2 (50 g). Elution with toluene±EtOAc 9:1
and 8:2 a€orded 5,8 -epidioxy-17-oxo-5 -androstan-3 -yl acetate
(2) (182 mg, 16.1%), mp (141 8C), IR and 1H NMR identical with
those of an authentic sample.7
3 S. Uemura, A. Onoe, H. Okazaki, M. Okano and K. Ichikawa,
Bull. Chem. Soc. Jpn., 1976, 49, 1437.
Toluene±EtOAc 2:8 and EtOAc eluted a mixture of (Z)- and (E)-
hydrazone 3 (655 mg, 58.1%): max/cm (KBr) 3450, 1733, 1661,
4 E. E. van Tamelen, R. S. Dewey, M. F. Lease and W. H. Pirkle,
J. Am. Chem. Soc., 1961, 83, 4302.
1
1252; dH 0.92, 0.98 (3 H, parts of two s, H-18 of Z and E isomers),
1.03 (3 H, s, H-19), 2.00 (3 H, s, OCOCH3), 4.81 (1 H, m, H-3).
5 G. Dauben and C. H. Schallhorn, J. Am. Chem. Soc., 1971, 93,
2254.
Upon recrystallization from acetone±methanol, hydrazone
3
6 W. Adam and H. J. Eggelte, J. Org. Chem., 1977, 42, 3987.
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a€orded 5,8a-epidioxy-17-isopropylidenehydrazono-5a-androstan-3b-
1
yl acetate 4 (384 mg), mp 205 8C; max/cm (KBr) 1742, 1670,
1254; dH 0.98 (3 H, s, H-18), 1.04 (3 H, s, H-19), 1.81, 1.99 [6 H,
2 s, N=C(CH3)2],, 2.00 (3 H, s, OCOCH3), 4.82 (1 H, m, H-3); dC
17.3 (q, C-18), 17.5 (q, C-19), 18.0 (q, CH3C=N), 19.3 (t, C-11),
20.9 (t, C-2), 21.0 (q, OCOCH3), 21.5 (t, C-15), 24.7 (q, CH3C=N),
25.7 (t, C-1), 26.4 (t, C-6), 27.9 (t, C-16), 33.5 (t, C-4) 35.4 (t, C-7),
35.5 (s, C-10), 36.0 (t, C-12), 44.8 (s, C-13), 51.7 (s, C-9), 51.9 (d,
C-14), 69.4 (d, C-3), 78.5 (s, C-8), 80.4 (s, C-5), 159.3 [s,
8 R. Tang, M. L. McKee and D. M. Stanbury, J. Am. Chem.
Soc., 1995, 117, 8967.
9 A successful diimide reduction of the ole®nic double bond in
some
5-B-nor-steroids has been recently reported,10 using
toluene-p-sulfonyl hydrazide in collidine at 150 8C.
10 A. Kasal, H. Chodounska and W. J. Szczepek, Tetrahedron
Lett., 1996, 37, 6221.
N=C(CH3)2], 169.7 (s, OCOCH3), 173.2 (s, C-17); m/z 416 (M+
)
(Found: C, 68.83; H, 8.50; N, 7.11. C24H36N2O4 requires C, 69.20;
H, 8.71; N, 7.44%).
11 L. Bondarenko-Gheorghiu, Ph.D. Thesis, University of
Belgrade, 1986.