Azasteroids. synthesis by Diels-Alder reaction between maleimides, citraconimide, and triazolindiones and 1-(1-trialkylsiloxyvinyl)-3,4- dihydronaphthalene derivatives

Article abstract of DOI:10.1007/s00706-005-0344-5

18-Nor-16-azaestrane derivatives with 8β, 13β, and 14β orientation were isolated from Diels-Alder reactions between maleimides or citraconimide and 1-(1-siloxyvinyl)naphthalene derivatives. (8RS)-13,14,16- Triazaestrane derivatives were synthesized from 1,2,4-triazolin-3,5-diones. The parent 11-oxo derivatives were obtained by desilylation, and they were transformed into 11-hydroxyimino derivatives. 3-Hydroxy derivatives, finally were synthesized by cleavage of the 3-methoxy group with BBr₃. During these transformations the stereochemistry of the steroidal skeleton was not changed. The stereochemistry of these "unnatural" steroids was elucidated by spectroscopic methods, and compared with results from calculations, and with the configuration of natural estrane derivatives. Finally, an improved method for the synthesis of the starting material, 6-methoxy-1-[(1-trialkylsiloxy)-vinyl]-3,4-dihydronaphthalene was developed. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-005-0344-5

Monatshefte f€ur Chemie 136, 1651–1669 (2005)
DOI 10.1007/s00706-005-0344-5
Azasteroids. Synthesis by Diels-Alder
Reaction between Maleimides,
Citraconimide, and Triazolindiones
and 1-(1-Trialkylsiloxyvinyl)-3,4-
dihydronaphthalene Derivatives
Adnan Sultani, Harald Dietrich, Friedrich Richter,
ꢀ
and Hans-Hartwig Otto
Department of Pharmaceutical=Medicinal Chemistry (PMC), Institute of Pharmacy,
Ernst-Moritz-Arndt-University, DE-17487 Greifswald, Germany
Received December 27, 2004; accepted January 3, 2005
Published online July 22, 2005 # Springer-Verlag 2005
Summary. 18-Nor-16-azaestrane derivatives with 8ꢀ, 13ꢀ, and 14ꢀ orientation were isolated from
Diels-Alder reactions between maleimides or citraconimide and 1-(1-siloxyvinyl)naphthalene deriva-
tives. (8RS)-13,14,16-Triazaestrane derivatives were synthesized from 1,2,4-triazolin-3,5-diones. The
parent 11-oxo derivatives were obtained by desilylation, and they were transformed into 11-hydroxy-
imino derivatives. 3-Hydroxy derivatives, finally were synthesized by cleavage of the 3-methoxy group
with BBr3. During these transformations the stereochemistry of the steroidal skeleton was not changed.
The stereochemistry of these ‘‘unnatural’’ steroids was elucidated by spectroscopic methods, and
compared with results from calculations, and with the configuration of natural estrane derivatives.
Finally, an improved method for the synthesis of the starting material, 6-methoxy-1-[(1-trialkylsiloxy)-
vinyl]-3,4-dihydronaphthalene was developed.
Keywords. 2-Trialkylsiloxy-1,3-diene; Maleimide; Triazolindione; Azasteroid; Cycloaddition.
Introduction
Natural steroids with 8ꢀ, 9ꢁ, 13ꢀ, and 14ꢁ configuration, and partially modified
derivatives are used as highly potent drugs [1]. During the last decades derivatives
with a partial natural configuration but unusual substitution patterns became valu-
able therapeutics like the 5ꢁ-reductase inhibitor finasteride [2] and the anti-
gestagene mifepristone [3]. Whereas the structure of mifepristone shows an unusual
substituent, a para-dimethylaminophenyl group at position C-11, finasteride
ꢀ
Corresponding author. E-mail: ottohh@pharmazie.uni-greifswald.de

1652
A. Sultani et al.
belongs to the important group of 4-azasteroids [4]. There are many potent synthe-
ses described for those systems containing the nitrogen atom either in ring A or in
ring B of the steroid skeleton [5]. We have described Diels-Alder reactions between
1-(1-siloxyvinyl)cyclohexene and dienophiles [6] and reactions between cyclopen-
tadiene and maleimides [7]. Here we report about our studies of the reaction
between 1-(1-siloxyvinyl)-3,4-dihydronaphthalene derivatives and maleimides
and related dienophiles.
Results and Discussion
Synthesis
Starting materials for the synthesis of the 1-(1-trialkylsiloxyvinyl)-3,4-dihydro-
naphthalenes 4a, 4c, 4d, and 4b were the acetyl derivatives 2a and 2b which could
be prepared from the tetralones 1a and 1b by reaction with sodium acetylide
followed by a Rupe rearrangement [8, 9], but the reaction needs drastic and dan-
gerous conditions, and the yields of 2a and 2b were not satisfying. The Friedel-
Crafts acylation of 1-trimethylsilyl-3,4-dihydronaphthalenes with acetyl chloride
could be an alternative route [10] but yielded a number of by-products. Therefore,
we prepared 2a and 2b from 1 following Ref. [11] by reaction with Me3SiCN and
ZnI2 without isolation of the intermediates followed by a reaction with MeMgBr,
and finally hydrolysis. We modified the reaction conditions, the procedure, and
replaced MeMgBr by MeLi, which allowed working at more convenient tempera-
tures, and improved the yields. Therefore, we give the detailed procedure in the
experimental part. The overall yield was in all experiments higher than 65%. The
final silylation step was done in the usual way [12, 13] in THF at ꢁ78ꢂC with LDA
and ClSiR3. The dienes 4a–4d were isolated as light yellow viscous liquids with
yields higher than 90%. They were relatively stable when stored at ꢁ20ꢂC under
N2. As known from other experiments, 4d is the most stable compound of this
group, and cleavage of the Si–O bond is extremely difficult because of the bulky
silyl moiety [14].
From the reaction between 2a and diethylchlorophosphate the phosphorylated
diene 3 was obtained as a reddish liquid, yield 50%, which was very air-sensitive,
whereby we did not use this compound for further reactions.
The IR spectra of the siloxydienes 4a–4d were characterized by two bands at
1625 and 1610 cmꢁ1 caused by the asymmetrically substituted olefinic double
1
bond. In the H NMR spectra a triplet from the proton at C-2 of the naphthalene
ring, the signals of the silyl group, and two singlets of the olefinic protons at C-20
confirmed the structure.
The cycloadditions between 4a–4c and maleimides were done by refluxing
equivalent amounts in toluene with TLC control. After evaporation of the solvent
the 11-trialkylsiloxy-16-azasteroids 5a, 5c–5h were obtained with yields of 40% to
>95%. Using these conditions, the yields of reactions between 4d and maleimides
were not satisfying. Therefore, these reactions were done at ꢁ78ꢂC in CH2Cl2 in
the presence of EtAlCl2 yielding compounds 6a–6c with yields up to 65%.
Trialkylsilyl groups used as protecting groups very often can be cleaved by
mild methods. We tried to desilylate the cycloaddition products by many different

Azasteroids
1653
Scheme 1
methods. Finally, short-time refluxing of 5a–5e, 5g, and 5h in a mixture of conc.
HCl and MeOH yielded the crystalline and uniform 11-oxo derivatives 7a–7g with
yields of 75–99%. But when we tried to deprotect the other siloxy compounds
using these conditions we failed completely. Compounds 6a–6c and 5f resisted the
desilylation, and even other methods like TBAF in THF with AcOH, or KF, or
TBAF=SiO2 were not successful.
The IR spectra of 7a–7g showed an intensive carbonyl band at 1720 cmꢁ1, and
the C¼C band around 1620 cmꢁ1 was missing in the spectra. 7a–7c and 7f showed
good solubility in CHCl3 and similar solvents, whereas 7d, 7e, and 7g were soluble
only in DMSO or DMF. Finally, 4 derivatives, 7a, 7b, 7d, and 7e were transformed
with H2NOH ꢃ HCl into the crystalline 11-hydroxyimino derivatives 8a–8d using
the standard procedure in EtOH with aqueous AcONa or a modified procedure in
THF (Scheme 2). An appropriate method to deprotect the 3-hydroxy group was the
reaction with BBr3 in CH2Cl2 at 0ꢂC. When we applied this method to 7a and 7d
the crystalline phenols 9a and 9b were isolated with yields of ca. 40%. Applying
the reaction to the 11-hydroxyimino derivative 8b not only the methoxy group was
deprotected, but even the hydroxyimino group was transformed into the ketone
function, and we obtained 9c with 44% yield. As we deduced from spectroscopic
data, the stereochemistry of the starting material was not changed during anyone of
the described transformations (Scheme 2).
By the reactions with maleimides one nitrogen atom was introduced into posi-
tion 16 of the steroid skeleton, whereas reactions between 4a, 4b and azadieno-
philes should give the possibility for the introduction of additional nitrogen atoms
into positions 13 and 14. Therefore, we started experiments with the usually highly

1654
A. Sultani et al.
Scheme 2
reactive azodicarboxylates, but we failed completely. Either no product was
obtained or the starting materials were reisolated. More successful were reactions
between 4a and 4b and 4-phenyl- or 4-methyl-1,2,4-triazolin-3,5-diones, but these
very reactive dienophiles afforded special reaction conditions. All reactions had to
be done under N2 at ꢁ60ꢂC in THF. Using these conditions we obtained the siloxy
derivatives 10a–10c with yields of ca. 75%. As these siloxy derivatives are very
air-sensitive, they were immediately, without further purification, hydrolyzed to the
11-oxo derivatives 11a–11c, isolated as colorless crystals with ca. 80% yield
(Scheme 3).

Azasteroids
1655
Scheme 3
Scheme 4
The IR spectra confirmed the general structures. In the spectra of 10a and 10b
we detected the C¼C band at 1620 cmꢁ1, and in the spectra of 11a–11c the car-
bonyl band at 1720 cmꢁ1 caused by the 11-oxo group was a characteristic element.
The reaction between 4a and ꢁ-methyl-N-phenylmaleimide (citraconimide)
was successful when we used our standard procedure, refluxing in toluene for
3.5 h, and gave 30% of the starting material 4a, and about 40% of a crystalline,
1
conform product 12 showing in the MS spectra m=z ¼ 461 (Mþ). In the H NMR
spectrum we found one singlet for the methoxy group at ꢂ ¼ 3.76 ppm, and one
singlet for a methyl group at ꢂ ¼ 1.46 ppm. These were interpreted as hints for the
formation of only one of the two possible regioisomers. The question which one
1
was formed could be answered by the analysis of the H NMR spectra. We found
an AB system for 8-H and 14-H at ꢂ ¼ 2.68 and 2.86 ppm with a coupling constant
J ¼ 3.4 Hz, torsion angle ꢄ30ꢂ, and positive NOE between 8-H and one 7-H, one
12-H, and 14-H. Considering these results, and the endo addition, 8-H should be
ꢀ-orientated, and the methyl group should be fixed to C-13 in a pseudoaxial orienta-
tion (ꢀ). This result was supported by a calculation of the electron densities and the
coefficients of the starting materials explaining the regioselectivity [15]. Comparing
the diene 4a with the analogue vinylnaphthalene, explains the opposite regioselec-
tivity in the reaction between citraconimide and the vinylnaphthalene [15].
Experiments to hydrolyze the silylenol group of 12 by MeOH=Hþ at 60ꢂC, or
with TBAF=THF, or by H2=Pd in CH2Cl2 failed. This might be explained by the
half-chair conformation of ring B, and the pseudoaxial orientation of the methyl
group prohibiting an attack of the reagent from the upper side and from the down-
side of the molecule. Furthermore, this result confirmed the proposal that in the
hydrolysis of compounds with an H atom at C-13 the attack of the reagent occurred

1656
A. Sultani et al.
Scheme 5
from the upper side of the molecule, which was found even in reductions of the
11-oxo and 17-oxo group yielding in all experiments the ꢁ-orientated hydroxyl
group [15].
Finally, reactions between the 1-(1-methoxyvinyl) derivative 13 [9] and sub-
stituted maleimides opened a route to 11-methoxy derivatives, whereby we isolated
14a, 14b, and 15 with yields of 50–60%. Reductive demethylation either by
H2=Pd-C or by BH3=THF gave the 11-oxo derivatives 7a, 7e, and 11b with quan-
titative yields. Furthermore, 14a, 14b, and 15 were prepared from the parent
11-oxo derivatives by reaction with methyl orthoformiate in MeOH with high
yields (Scheme 5).
Stereochemistry and Spectroscopy
Considering the mechanism of the cycloaddition [16] the reaction between the
siloxy dienes and maleimides should have occurred as an endo addition yielding
at least two possible structures for all trialkylsiloxy derivatives: either the relative
Table 1. 1H NMR data of 5a, 6b, 5f (250 MHz), 5d (200 MHz), and 5e (300 MHz); CDCl3; ꢂ (ppm)
Proton
5a
6b
5f
5d
5e
7ꢀ
7ꢁ
2.10
2.32
2.52
2.62
2.68
2.74
2.92
3.22
3.34
2.07
2.21
2.47
2.51
2.59
2.71
2.98
3.10
3.14
2.14
2.38
2.50
2.57
2.71
2.71
2.97
3.21
3.36
2.04
2.23
2.50
2.52
2.72
2.72
2.79
3.10
3.22
2.11
2.31
2.56
2.58
2.68
2.73
2.85
3.12
3.20
12ꢀ
6ꢀ
8ꢀ
6ꢁ
12ꢁ
14ꢀ
13ꢀ

Azasteroids
1657
Table 2. 1H NMR data (300 MHz, CDCl3, H,H-COSY) of 5e
Proton
ꢂ (ppm)
2J (Hz)
3J (Hz)
7ꢀ
7ꢁ
2.11 (dddd)
2.31 (dddd)
2.56 (ddd)
2.58 (ddd)
2.68 (dddd)
2.73 (ddd)
2.85 (dd)
12.6
12.6
15.4
14.6
5.8, 3.5, 3.5
12.6, 12.6, 3.5
7.0
12ꢀ
6ꢀ
12.6, 3.5
12.6, 5.8, 5.8
3.5, 3.5
8ꢀ
6ꢁ
14.6
15.4
12ꢁ
14ꢀ
13ꢀ
1.6
3.12 (dd)
8.8, 5.8
3.20 (ddd)
8.8, 7.0, 1.6
structure with 8ꢀ, 13ꢀ, and 14ꢀ orientation, or the relative structure with 8ꢁ, 13ꢀ,
and 14ꢀ orientation. As the 1H NMR data of all trialkylsiloxy compounds (Tables 1,
and 2, and Exp.) of this reaction showed an analogous pattern of shift values and
coupling constants, the structure elucidation is demonstrated for compound 5e
(Table 2).
The signals of 13-H and 14-H in the spectra of 5e at ꢂ ¼ 3.20 and 3.12 ppm,
showed a coupling constant J ¼ 8.8 Hz, confirming the cis orientation. The signal at
ꢂ ¼ 2.68 ppm (8-H) exhibited a coupling with the signal of 14-H, J ¼ 5.8 Hz, which
agreed with the cis orientation.
A further support for this structure was obtained by NOE experiments. Irradia-
tion at ꢂ ¼ 2.68 ppm (8-H) caused positive effects on the signals at ꢂ ¼ 2.11 ppm
(7-H) and ꢂ ¼ 3.12 ppm (14-H), and irradiation at ꢂ ¼ 3.12 ppm (14-H) caused a pos-
itive NOE at ꢂ ¼ 2.68 ppm (8-H) and ꢂ ¼ 3.20 ppm (13-H). Both effects should be
possible only if 8-H, 13-H, and 14-H are situated at the same side of the molecule.
Irradiation on the signal of 13-H enlarged the signals of 14-H, 12-H, and 7ꢀ-H, and
irradiation at the signal of 7ꢀ-H enlarged the signals of 14-H, 8ꢀ-H, and 7ꢁ-H. All
data fit to a structure with cis-syn-cis-connection of the rings B, C, and D, and 8ꢀ,
13ꢀ, and 14ꢀ-orientation.
Interpretation of the coupling constants following the Karplus-Conroy rules
enabled us to construct a favored form of 5e (under NMR conditions in CDCl3),
showing ring C in a flat boot form connected endo-cis with ring D, and ring B
Fig. 1. Calculated structure of 5e (MMþ, HYPERCHEM)

1658
A. Sultani et al.
Table 3. 1H NMR data of 7a, 7c (300 MHz, CDCl3), 7a (400 MHz, pyridine-d5), and 7d, 7e
(400 MHz, DMSO-d6); shift values, ꢂ (ppm); coupling constants of the proton with the proton in
position noted, J (Hz)
ꢀ
Proton
7a
7a
7c
7d
7e
ꢂ
J
ꢂ
J
ꢂ
J
ꢂ
J
7ꢁ
7ꢀ
1.55
2.06
2.90
2.90
2.90
3.46
3.46
3.46
1.70
2.10
3.01
3.12
3.30
3.74
3.90
4.00
8ꢀ ¼ 15
1.38
1.84
2.88
2.84
2.84
3.44
3.35
3.35
8ꢀ ¼ 12
1.33
1.76
2.76
2.67
2.76
3.52
3.50
3.50
8ꢀ ¼ 15
1.26
1.62
2.61
2.61
2.61
3.58
3.50
3.50
8ꢀ ¼ 15
8ꢀ
9ꢀ ¼ 4.1
13ꢀ ¼ 6
13ꢀ ¼ 2
9ꢀ ¼ 4.5
13ꢀ ¼ 6
9ꢀ ¼ 4.5
13ꢀ ¼ 6
13ꢀ ¼ 2
9ꢀ ¼ 4
12ꢀ
12ꢁ
9ꢀ
13ꢀ ¼ 6
13ꢀ ¼ 2
13ꢀ ¼ 1.5
14ꢀ
13ꢀ
8ꢀ ¼ 6
8ꢀ ¼ 6
8ꢀ ¼ 6
8ꢀ ¼ 6
14ꢀ ¼ 9
14ꢀ ¼ 9
14ꢀ ¼ 9
14ꢀ ¼ 9
ꢀ
In pyridine-d5
existing in a half-chair conformation. This proposal was in agreement with the
result of a MMþ calculation (HYPERCHEM, Fig. 1).
From the shift values of other 11-trialkylsiloxy derivatives like 5a, 5d, 5f, and
3
3
6b (Table 1), and the coupling constants J13ꢀ=14ꢀ ¼ 8–9 Hz, J13ꢀ=12ꢀ ¼ 6 Hz,
3
3J8ꢀ=14ꢀ ¼ 6 Hz, and J8ꢀ=7ꢀ ¼ 6 Hz in these spectra we deduced that all isolated
11-trialkylsiloxy compounds independently from the synthetic route showed the
relative structure with the orientation 8ꢀ, 13ꢀ, and 14ꢀ demonstrating that in these
examples the cycloaddition strictly had followed the endo-rule of Alder [17].
An additional stereocenter at C-9 was generated by the desilylation reaction,
whereby for the 11-oxo derivatives two isomers could be formed. If 9-H is cis
related to 8ꢀ-H, the structure would show 8ꢀ, 9ꢀ, 13ꢀ, and 14ꢀ orientation, and if
9-H is trans related to 8ꢀ-H, the overall relative structure would be 8ꢀ, 9ꢁ, 13ꢀ,
1
and 14ꢀ. Shift values of the H NMR spectra of selected 11-oxo derivatives are
collected in Table 3. Comparing these values with those of 5e clearly demonstrated
the different structures. Whereas the values of the signals of 8ꢀ-H and 12-H are
only slightly influenced by the carbonyl group, the signals of 7-H, 13ꢀ-H, and 14ꢀ-H
exhibited greater differences. NOE experiments showed that the proton 9-H in
CDCl3 solution of the isolated 11-oxo compounds was ꢀ-orientated. Irradiation at
ꢂ ¼ 2.88 ppm (8ꢀ-H, 7c) showed a positive effect on the signals of 9-H and 14ꢀ-H,
and vice versa. In addition, the coupling constants 3J ¼ 3 Hz (7a, 7d), and 4.15 Hz
(7c, torsion angle ꢄ44ꢂ) between the signals of 8ꢀ-H and 9-H confirmed a pseu-
doaxial orientation of both protons and thereby the relative conformation 8ꢀ, 9ꢀ,
13ꢀ, and 14ꢀ with cis-syn-cis connection of the rings B, C, and D. The cou-
3
pling J13ꢀ=14ꢀ ¼ 9 Hz, torsion angle ꢄ9ꢂ, was interpreted as resulting from an
3
axial=axial orientation, and J8ꢀ=14ꢀ ¼ 3J12ꢀ=13ꢀ ¼ 6 Hz, torsion angle ꢄ30ꢂ, and
3
3J12ꢁ=13ꢀ ¼ 1.5 Hz, torsion angle ꢄ62ꢂ, and J8ꢀ=9ꢀ ¼ 4.5 Hz, torsion angle ꢄ41ꢂ
were interpreted as the result of a flattened boat conformation of ring C. The
stereochemistry of the triaza derivatives 11a, 10b, and 11b was deduced from their
1H NMR data (Table 4) confirming the 8ꢀ and 9ꢀ orientation, and suggesting that
the overall conformation equals that of the other 11-oxo compounds. Characteristic

Azasteroids
Table 4. Selected H NMR data of 11a, 10b, and 11b (250 MHz, CDCl3); ꢂ (ppm); J (Hz)
11a 10b
1.75
1659
1
11b
ꢂ (7ꢁ-H)
ꢂ (7ꢀ-H)
ꢂ (9ꢀ-H)
ꢂ (12ꢀ-H)
ꢂ (12ꢁ-H)
ꢂ (8ꢀ-H)
J (8ꢀ/9ꢀ)
J (8ꢀ/7ꢀ)
J (8ꢀ/7ꢁ)
2.50
1.90
1.92
2.35
4.07
4.35
4.34
4.78
5.5
2.20
3.96
4.21
4.25
4.60
6
–
4.00
4.40
4.46
–
3
1.5
12
1.5
12
15
for the ꢀ orientation seemed to us the couplings J8ꢀ=7ꢀ, J8ꢀ=7ꢁ, and J8ꢀ=9ꢀ ¼ 6.0 and
5.5 Hz indicating a torsion angle of ꢄ30ꢂ between 8-H and 9-H.
Comparing the spectroscopic data of the 11-hydroxyimino derivatives and of
the 3-hydroxy derivatives allowed us to postulate identical configuration and con-
formation as deduced for the 11-trialkylsiloxy and 11-oxo derivatives.
The formation of the 9ꢀ orientation in the desilylation reaction may be under-
stood by the stereochemistry of the 11-trialkylsiloxy compounds. Considering the
deduced stereochemistry (Fig. 1) is correct, the addition of a proton on C-9
occurred kinetically controlled from the downside of the conformative strained
and fixed molecule (anti) yielding the 9ꢀ orientation as an attack from the upper
side and thereby formation of the thermodynamically preferred 9ꢁ orientation is
blocked by the bulky silyloxy substituent at C-11.
Whereas the natural estrogenes like estrone and estradiol are characterized by
an all-trans connection of the rings B, C, and D [18], our unnatural derivatives
show an all-cis connection between these rings or a trans-cis-cis connection. And
whereas the natural estrogenes act as activators in the system of sexual hormons
[19], some of the unnatural derivatives act as inhibitors of enzymes of this system
like cleaving enzyme, aromatase, and 5ꢁ-reductase, and thereby might be starting
materials for optimized inhibitor drugs [20].
Experimental
Melting points: Linstr€om apparatus; IR spectra (KBr): Perkin-Elmer IR 1310, Nicolet 205, Beckmann
1
IR 4240, IR 33; NMR spectra: H: Varian T 60 (60 MHz), Bruker WP 80 (80 MHz), ARX 200
(200 MHz), WP 250 (250 MHz), ARX or WM 300 (300MHz), AM 400 (400 MHz), 13C: Bruker
WH 90 (22.63 MHz), WM 250 (62.80 MHz), AM 400 (100.61 MHz), 27ꢂC, internal TMS, CDCl3,
values from 250 MHz spectra, CDCl3, if not otherwise noted; MS spectra: Finnigan MAT 44 S, EI,
70eV; elemental analyses: Pharmazeutisches Institut, University of Freiburg or Pharmazeutisches
Institut, University of Greifswald, Perkin Elmer Analyzer 2400 CHN; the results agreed with the
calculated values within experimental error. Column chromatography (CC): silica gel 60 Merck
7734. Lithium diisopropylamide (LDA) was freshly prepared by mixing of equimolar amounts of
diisopropylamine in THF and n-butyl lithium (BuLi, 1.6M solution in n-hexane) at ꢁ78ꢂC. Solvents
were purified=dried according to literature procedures. Abbreviations: AcOEt¼ ethyl acetate;
al¼ aliphatic; ar¼ aromatic; DME ¼ dimethoxyethane; HMPT¼ hexamethylphosphortrisamide;

1660
A. Sultani et al.
PE¼ petroleum ether; TBAF¼ tetrabutylammonium fluoride (1M solution in THF); TLC ¼ thin layer
chromatography (pre-coated silica gel plates 60 F254, Merck 5554 or 5550). Note that all stereoche-
mical notations describe relative stereochemistry.
1-Acetyl-6-methoxy-3,4-dihydronaphthalene (2a) [11]
At 60ꢂC, under N2 and stirring, trimethylsilylcyanide (19 cm3, 150 mmol) was added to a mixture from
a solution of 6-methoxytetralone (22.6 g, 128mmol) in 50cm3 DME and 0.8 g ZnI2. After stirring for
90min, the mixture was cooled to 0ꢂC, and with vigorous stirring MeLi (100cm3, 1.6 M in Et2O,
160 mmol) was dropwise added, stirring was continued for 1 h at 0ꢂC, and 12 h at room temperature.
Then the mixture was cooled to 0ꢂC, and very slowly hydrolyzed by dropwise adding of a satd.
aqueous solution of NaHCO3 (ꢄ100 cm3), and then extracted with 6 ꢃ 50cm3 Et2O. The combined
organic layers were dried (MgSO4), and evaporated in vacuo. 150 cm3 HCl (10%) were added to the
residue, and the mixture was refluxed for 3 h, cooled to room temperature, and extracted with
8 ꢃ 50cm3 Et2O. The combined organic layers were washed with 250 cm3 of a satd. aqueous solution
of NaHCO3, dried (MgSO4), and evaporated in vacuo. The residue crystallized on cooling. Yield 21.4 g
(83%); beige crystals; mp 74–76ꢂC (MeOH).
1-Acetyl-3,4-dihydronaphthalene (2b) [11]
As described for 2a from ꢁ-tetralone (13.5 cm3, 100 mmol), 0.7 g ZnI2 in 25cm3 DME, and trimethyl-
silylcyanide (15 cm3, 100 mmol), at 60ꢂC for 3.5h, MeLi (100 cm3, 160 mmol), and stirring for 12 h. A
mixture from 300 cm3 EtOH, and 300 cm3 dil. HCl was added to the first residue, reflux 3.5 h, and
work-up as for 2a. The final residue was distilled in vacuo. Yield 14 g (81%); light yellow air-sensitive
liquid; bp 180ꢂC=267 Pa; IR: ꢃꢀ¼ 3060, 3020 (ar CH), 2940, 2900, 2840 (al CH), 1670 (CO), 1610
1
(C¼C), 1600, 1490, 1450, 1260, 770 (ar) cmꢁ1; H NMR: ꢂ ¼ 2.40 (m, Me, 3-Hax, 3-Heq), 2.75 (m,
4-Hax, 4-Heq), 7.0 (t, J ¼ 6 Hz, 2-H), 7.1 (m, 5-H, 6-H, 7-H), 7.72 (t, J ¼ 9 Hz, 8-H) ppm; 13C NMR:
ꢂ ¼ 23.47 (C-3), 27.28 (C-4), 29.49 (Me), 126.26 (C-5), 126.45 (C-7), 127.38 (C-8), 127.49 (C-4a),
130.68 (C-1), 133.21 (C-2), 136.26 (C-8a), 139.13 (C-6), 199.18 (CO) ppm.
1-(ꢁ-Diethylphosphoryloxyvinyl)-6-methoxy-3,4-dihydronaphthalene (3, C17H23O5P)
Under N2 and at ꢁ78ꢂC, a solution of 2a (4.1g, 20mmol) in 10cm3 THF was added dropwise and
with stirring to a solution of LDA (25 mmol) in 10cm3 THF. After stirring for 20min diethyl chloro-
phosphate (6.9g, 40mmol) was added in one portion, stirring was continued for 12 h, while the mixture
warmed to room temperature. Then, 50 cm3 of n-pentane were added, and the mixture was poured into
50cm3 of an aqueous satd. solution of NaHCO3, the organic layer was separated, washed with 100cm3
of an aqueous satd. solution of NaCl, dried (MgSO4), and evaporated in vacuo. The residue was
purified by Kugelrohr distillation. Yield 3.1g (50%); bp 200ꢂC=133 Pa; IR: ꢃꢀ¼ 2980 (al CH), 1610
(C¼C), 1500, 1250 (O–P) cmꢁ1; 1H NMR (80 MHz): ꢂ ¼ 1.46 (t, J ¼ 11, 4.5 Hz, Me), 2.65 (m, 3-Hax,
3-Heq), 2.75 (m, 6-Hax, 6-Heq), 3.75 (s, OMe), 4.62 (dt, J ¼ 11, 4.5 Hz, 3 Hz, CH2), 4.59, 5.17 (2 t,
J ¼ 2.5, 1 Hz, 1 H, CH2vinyl), 6.25 (dd, J ¼ 5.5, 3 Hz, 1 H, CH2vinyl), 6.75 (m, 5-H, 7-H), 7.32 (t, J ¼ 9,
2 Hz, 8-H) ppm.
1-(ꢁ-Trimethylsiloxyvinyl)-6-methoxy-3,4-dihydronaphthalene (4a)
See Ref. [21]
1-(ꢁ-Trimethylsiloxyvinyl)-3,4-dihydronaphthalene (4b, C15H20OSi)
A solution of 2b (3.4g, 20mmol) in 10cm3 THF was dropwise added at ꢁ78ꢂC and under N2 to a
solution of LDA (25 mmol) in 10 cm3 THF. After 10min, ClSi(Me)3 (4cm3, 32mmol) was added in
one portion. After warming to room temperature (after 12 h), work-up as described for 4a. Yield 4.4g
(90%); light yellow air-sensitive liquid; bp 280ꢂC=133 Pa; IR: ꢃꢀ¼ 3120, 3000 (ar CH), 2940 (al CH),
1620 (¼C-OSi), 1480, 1450, 1250, 1020, 850 (ar) cmꢁ1; 1H NMR: ꢂ ¼ 0.2 (s, SiMe3), 2.32 (m, 3-Hax,
3-Heq), 2.73 (m, 4-Hax, 4-Heq), 4.50, 4.62 (2s, CH2), 6.13 (dd, J ¼ 10, 3 Hz, 2-H), 7.25 (m, 4 ar H) ppm.

Azasteroids
1661
1-(ꢁ-Triisopropylsiloxyvinyl)-6-methoxy-3,4-dihydronaphthalene (4c, C19H28O2Si)
From 2a (4.1g, 20 mmol) and chlorotriisopropylsilane (6.0 cm3, 30mmol) in 20cm3 HMPT as
described for 4a, purification by CC (Al2O3). Yield 6.5g (90%); yellow viscous liquid; IR (film):
ꢃꢀ¼ 2960 (al CH), 1625 (¼C-OSi), 1470, 1260, 1050, 890 (ar) cmꢁ1; 1H NMR (80 MHz): ꢂ ¼ 1.0 (s,
Si(CHMe2)3), 2.2 (m, 3-He, 3-Ha), 2.74 (m, 4-Ha, 4-He), 3.77 (s, OMe), 6.17 (t, J ¼ 10Hz, 2-H), 6.75
(m, 5-H, 7-H), 7.37 (d, J ¼ 9 Hz, 8-H) ppm.
1-(ꢁ-tert-Butyldimethylsiloxyvinyl)-6-methoxy-3,4-dihydronaphthalene (4d, C19H28O2Si)
From 2a (4.1g, 20mmol) and t-butylchlorodimethylsilane (6.0g, 30mmol) in 15cm3 HMPT as
described for 4a, purification by CC (FlorisilR, n-hexane). Yield 6.3 g (99%); light yellow viscous
liquid; IR (film): ꢃꢀ¼ 3120, 3040, 3000 (ar CH), 2960, 2940, 2890, 2860, 2840 (al CH), 1625, 1610
(¼C-OSi), 1570, 1500, 840 (ar) cmꢁ1; 1H NMR (60 MHz): ꢂ ¼ 0.1 (s, SiMe2), 0.9 (s, CMe3), 2.0–2.9
(m, 3-H, 4-H), 3.80 (s, OMe), 4.45, 4.55 (2s, 20-H), 6.15 (t, J ¼ 4.5 Hz, 2-H), 6.7 (m, 5-H, 7-H), 7.35
(m, 8-H) ppm.
General Procedure for the Reaction between ꢁ-Trialkylsiloxyvinylcycloalkenes
and Maleinimides
Equivalent amounts of the siloxydiene and of the maleimide in toluene were refluxed as noted (TLC
control). After cooling to room temperature, the solvent was evaporated in vacuo, and the residue was
purified as noted.
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-16-phenyl-11-trimethylsiloxy-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (5a, C26H29NO4Si)
From 4a (1.43 g, 5.1 mmol) and N-phenylmaleimide (0.9g, 5.2 mmol), 30cm3 of toluene, 8 h. Yield
1.6 g (72%); colorless crystals; mp 105ꢂC (PE); IR: ꢃꢀ¼ 3070, 3050 (ar CH), 2960, 2900, 2840 (al
1
CH), 1770, 1710 (CO), 1630 (¼C-OSi), 1610, 1570, 1490, 1190, 850, 650 (ar) cmꢁ1; H NMR:
ꢂ ¼ 0.15 (s, SiMe3), 2.10 (dddd, J ¼ 12, 6, 3, 3 Hz, 7ꢀ-H), 2.32 (dddd, J ¼ 12, 12, 12, 3 Hz, 7ꢁ-H), 2.52
(dd, J ¼ 15, 6 Hz, 12ꢀ-H), 2.62 (ddd, J ¼ 15, 12, 3 Hz, 6ꢀ-H), 2.68 (ddd, J ¼ 12, 6, 6, 1.5 Hz, 8ꢀ-H),
2.74 (ddd, J ¼ 15, 3, 3 Hz, 6ꢁ-H), 2.92 (dd, J ¼ 15, 1.5 Hz, 12ꢁ-H), 3.22 (dd, J ¼ 9, 6 Hz, 14ꢀ-H), 3.34
(ddd, J ¼ 9, 6, 1.5 Hz, 13ꢀ-H), 3.80 (s, OMe), 6.61 (d, J ¼ 2 Hz, 4-H), 6.63 (dd, J ¼ 2, 9 Hz, 2-H), 7.1
(m, 2 ar H), 7.36 (m, 3 ar H), 7.81 (d, J ¼ 9 Hz, 1-H) ppm; 13C NMR (62.80MHz): ꢂ ¼ 0.67 (SiMe3),
25.17 (C-7), 31.20 (C-6), 31.62 (C-12), 38.52 (C-8), 41.52 (C-13), 43.51 (C-14), 55.07 (OMe), 111.43
(C-4), 112.67 (C-2), 113.25 (C-9), 125.58 (C-10), 126.70 (C-20, C-60), 128.50 (C-1), 129.05 (C-40),
129.69 (C-30, C-50), 132.09 (C-10), 139.99 (C-5), 143.98 (C-11), 157.36 (C-3), 176.72 (C-15), 178.34
(C-17) ppm; DEPT 135: ꢂ ¼ 0.65 (SiMe3), 25.15 (CH2, C-7), 31.19 (CH2, C-6), 31.61 (CH2, C-12),
38.50 (C-8), 41.51 (C-13), 43.50 (C-14), 55.08 (OMe), 111.42 (C-4), 112.66 (C-2), 126.70 (C-20, C-60),
128.49 (C-1), 129.05 (C-40), 129.68 (C-30, C-50) ppm; MS: m=z (%) ¼ 447 (62) [Mþ], 261 (22), 260
(100), 73 (48), 45 (8).
(8ꢀ,13ꢀ,14ꢀ)-16-(4-Bromophenyl)-3-methoxy-11-trimethylsiloxy-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (5b, C26H28BrNO4Si)
From 4a (10.0 g, 37 mmol) and N-(4-bromophenyl)maleimide (9.2 g, 37 mmol), 70 cm3 of toluene,
4.5 h reflux, and stirring for 12 h at room temperature. The precipitate was separated and washed with a
few cm3 of cold PE. Yield 11.6g (60%); colorless needles; mp 172–174ꢂC (toluene); IR: ꢃꢀ¼ 3097,
1
2956, 2906, 2838 (CH), 1768, 1700 (CO), 1621 (¼C-OSi), 1488 (ar), 1262 (SiMe3) cmꢁ1; H NMR
(200 MHz): ꢂ ¼ 0.11 (s, SiMe3), 2.11 (dddd, J ¼ 12.3, 6.0, 3.0, 3.0 Hz, 7ꢀ-H), 2.27 (dddd, J ¼ 12.2,
12.2, 12.2, 3.5Hz, 7ꢁ-H), 2.47–2.81 (m, 6ꢁ-H, 6ꢀ-H, 8ꢀ-H, 12ꢀ-H), 2.90 (dd, J ¼ 15.1, 1.7 Hz,
12ꢁ-H), 3.23 (dd, J ¼ 8.8, 5.5 Hz, 14ꢀ-H), 3.36 (ddd, J ¼ 8.6, 6.6, 1.8 Hz, 13ꢀ-H), 3.78 (s, OMe),
6.63 (d, J ¼ 2.7 Hz, 4-H), 6.66 (dd, J ¼ 8.8, 2.7 Hz, 2-H), 7.01 (d, J ¼ 8.8 Hz, 30-H, 50-H), 7.51 (d,
J ¼ 8.6 Hz, 20-H, 60-H), 7.80 (d, J ¼ 8.4 Hz, 1-H) ppm; 13C NMR (75 MHz): ꢂ ¼ 0.64 (SiMe3), 25.09

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A. Sultani et al.
(C-7), 31.11 (C-6), 31.58 (C-12), 38.49 (C-8), 41.53 (C-13), 43.52 (C-14), 55.12 (OMe), 111.38 (C-4),
112.68 (C-2), 113.19 (C-9), 122.36 (C-40), 125.41 (C-10), 128.15 (C-20, C-60), 129.59 (C-1), 130.92
(C-10), 132.24 (C-30, C-50), 139.94 (C-5), 143.91 (C-11), 157.37 (C-3), 176.42 (C-15), 178.02 (C-17)
ppm; DEPT 135: ꢂ ¼ 0.64 (SiMe3), 25.08 (CH2, C-7), 31.10 (CH2, C-6), 31.57 (CH2, C-12), 38.48
(C-8), 41.52 (C-13), 43.51 (C-14), 55.11 (OMe), 111.37 (C-4), 112.67 (C-2), 128.15 (C-20, C-60),
129.57 (C-1), 132.23 (C-30, C-50) ppm.
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-16-ethyl-11-(trimethylsiloxy)-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (5c, C22H29NO4Si)
From 4a (1.4g, 5.3 mmol) and N-ethylmaleimide (0.6g, 5 mmol), 30cm3 of toluene, 4 h. The product
was immediately used for the synthesis of 7c. Yellow liquid; IR: ꢃꢀ¼ 2942, 2838 (al CH), 1771, 1698
(CO), 1605 (¼C-OSi), 1570, 1408, 1251, 974, 882, 754, 696 (ar) cmꢁ1; 1H NMR: ꢂ ¼ 0.2 (s, SiMe3),
1.0 (t, J ¼ 7.5 Hz, Me), 2.60 (m, 9 al H), 3.50 (q, J ¼ 7.5 Hz, CH2), 3.75 (s, OMe), 6.72 (m, 2-H, 4-H),
7.75 (d, J ¼ 9 Hz, 1-H) ppm.
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-11-(trimethylsiloxy)-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (5d, C20H25NO4Si)
From 4a (7.6g, 28 mmol) and maleimide (2.7g, 28mmol), 130 cm3 of toluene, 2–3 h. Yield 9.4 g
(92%); colorless crystals; mp 221–223ꢂC (n-pentane=acetone); IR: ꢃꢀ¼ 3180 (ar CH), 2980, 2880,
1
2820 (al CH), 1776, 1701 (CO), 1628 (¼C-OSi), 1610, 1570, 1490, 1360, 1250, 850 (ar) cmꢁ1; H
NMR (200 MHz): ꢂ ¼ 0.12 (s, SiMe3), 2.04 (dddd, J ¼ 12.7, 5.9, 3.3, 3.3 Hz, 7ꢀ-H), 2.23 (dddd,
J ¼ 12.3, 12.3, 12.3, 3.4 Hz, 7ꢁ-H), 2.50 (dd, J ¼ 15.7, 6.7 Hz, 12ꢀ-H), 2.52–2.76 (m, 6ꢁ-H, 6ꢀ-H,
8ꢀ-H), 2.79 (dd, J ¼ 15.3, 1.6 Hz, 12ꢁ-H), 3.10 (dd, J ¼ 8.9, 5.6 Hz, 14ꢀ-H), 3.22 (ddd, J ¼ 8.8, 7.0,
1.6 Hz, 13ꢀ-H), 3.78 (s, OMe), 6.61 (d, J ¼ 2.2 Hz, 4-H), 6.65 (dd, J ¼ 8.8, 2.7 Hz, 2-H), 7.85 (d,
J ¼ 8.4 Hz, 1-H), 8.25 (bs, H–N) ppm; 13C NMR (DMSO-d6): ꢂ ¼ 0.48 (SiMe3), 24.64 (C-7), 30.56
(C-6), 30.79 (C-12), 36.97 (C-8), 41.91 (C-13), 43.89 (C-14), 54.78 (OMe), 111.03 (C-4), 111.50
(C-9), 112.46 (C-2), 125.45 (C-10), 129.07 (C-1), 139.56 (C-5), 143.56 (C-11), 156.57 (C-3), 179.47
(C-15), 180.74 (C-17) ppm; DEPT 135 (DMSO-d6): ꢂ ¼ 0.45 (SiMe3), 24.59 (C-7), 30.50 (C-6), 30.74
(C-12), 36.91 (C-8), 41.86 (C-13), 43.85 (C-14), 54.75 (OMe), 110.99 (C-4), 112.42 (C-2), 129.02
(C-1) ppm; MS: m=z (%) ¼ 372 (30) [Mþþ1], 371 (100) [Mþ], 184 (32), 73 (68), 45 (16).
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-11-(trimethylsiloxy)-16-methyl-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (5e, C21H27NO4Si)
From 4a (1.45 g, 5.3 mmol) and N-methylmaleimide (0.55 g, 5 mmol), 30cm3 of toluene, 2.5 h. Yield
1.35g (70%); colorless crystals; mp 178ꢂC (n-hexane=acetone); IR: ꢃꢀ¼ 2958, 2836 (al CH), 1770
(CO), 1692, 1630 (¼C-OSi), 1607, 1568, 1492, 1378, 1286, 1157, 994, 720, 695 (ar) cmꢁ1; 1H NMR:
ꢂ ¼ 0.09 (s, SiMe3), 2.11 (dddd, J ¼ 12.6, 5.8, 3.5, 3.5 Hz, 7ꢀ-H), 2.31 (dddd, J ¼ 12.6, 12.6, 3.5Hz,
7ꢁ-H), 2.56 (ddd, J ¼ 15.4, 7.0, 1.5 Hz, 12ꢀ-H), 2.58 (ddd, J ¼ 14.6, 12.6, 3.5 Hz, 6ꢀ-H), 2.68
(dddd, J ¼ 12.6, 5.8, 5.8, 1.5Hz, 8ꢀ-H), 2.73 (ddd, J ¼ 14.6, 3.5, 3.5 Hz, 6ꢁ-H), 2.85 (dd, J ¼ 15.4,
1.6 Hz, 12ꢁ-H), 2.93 (s, NMe), 3.12 (dd, J ¼ 8.8, 5.8Hz, 14ꢀ-H), 3.20 (ddd, J ¼ 8.8, 7.0, 1.6Hz,
13ꢀ-H), 3.77 (s, OMe), 6.60 (d, J ¼ 2.5 Hz, 4-H), 6.41 (dd, J ¼ 8.8, 2.5 Hz, 2-H), 7.80 (d, J ¼ 8.8 Hz,
1-H) ppm.
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-16-phenyl-11-(triisopropylsiloxy)-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (5f, C32H41NO4Si)
From 4c (1.8g, 5 mmol) and N-phenylmaleimide (0.9g, 5.2 mmol), 30cm3 of toluene, 8 h. Yield 1.0 g
(40%); colorless crystals; mp 205ꢂC (MeOH); IR: ꢃꢀ¼ 2860, 2840 (al CH), 1770, 1720 (CO), 1610
1
(¼C-OSi), 1570, 1500, 1410, 1050, 880, 710 (ar) cmꢁ1; H NMR: ꢂ ¼ 1.0 (s, Si(CHMe2)3), 2.14
(dddd, J ¼ 15, 6, 3.5, 3.5 Hz, 7ꢀ-H), 2.38 (dddd, J ¼ 15, 15, 15, 3.5 Hz, 7ꢁ-H), 2.50 (dd, J ¼ 15, 7 Hz,
12ꢀ-H), 2.57 (ddd, J ¼ 15, 15, 3.5 Hz, 6ꢀ-H), 2.71 (m, 8ꢀ-H, 6ꢁ-H), 2.97 (dd, J ¼ 15, 1.5 Hz, 12ꢁ-H),

Azasteroids
1663
3.21 (dd, J ¼ 9, 6 Hz, 14ꢀ-H), 3.36 (ddd, J ¼ 9, 7, 1.5 Hz, 13ꢀ-H), 3.76 (s, OMe), 6.59 (d, J ¼ 3 Hz,
4-H), 6.64 (dd, J ¼ 9, 3 Hz, 2-H), 7.21 (m, 5 ar H), 7.78 (d, J ¼ 9 Hz, 1-H) ppm; MS: m=z (%) ¼ 531
(92) [Mþ], 488 (30), 315 (54), 73 (46), 59 (100).
(8ꢀ,13ꢀ,14ꢀ)-16-Phenyl-11-(trimethylsiloxy)-18-nor-16-azaestra-1,3,5(10),9(11)-tetraene-
15,17-dione (5g, C25H27NO3Si)
From 4b (1.22 g, 5 mmol) and N-phenylmaleimide (0.9g, 5 mmol), 30cm3 of toluene, 5–8 h. The
product was immediately used for the synthesis of 7f. Yield 0.85g (40%); colorless crystals; mp
113ꢂC (toluene); IR: ꢃꢀ¼ 3100, 3060, 3040 (ar CH), 2960, 2840 (al CH), 1780, 1730 (CO), 1630
(¼C-OSi), 1600, 1500, 700 (ar) cmꢁ1; 1H NMR: ꢂ ¼ 0.1 (s, SiMe3), 2.0–3.5 (m, 9 al H), 7.0–8.0 (m, 8
ar H) ppm.
(8ꢀ,13ꢀ,14ꢀ)-11-(Trimethylsiloxy)-18-nor-16-azaestra-1,3,5(10),9(11)-tetraene-
15,17-dione (5h, C19H23NO3Si)
From 4b (0.8g, 3.3 mmol) and maleimide (0.32 g, 32 mmol), 10cm3 of toluene, 3 h. Yield 0.60 g
(53%); colorless crystals; mp 220ꢂC (n-hexane=acetone); IR: ꢃꢀ¼ 3167 (NH), 3060 (ar CH), 2958,
2844 (al CH), 1777, 1702 (CO), 1624 (¼C-OSi), 1597, 1482, 1440, 1364, 1321, 1265, 1252, 1220,
1189, 1049, 1010, 999, 966, 949, 878, 849, 820 (ar) cmꢁ1; 1H NMR (acetone-d6): ꢂ ¼ 0.25 (s, SiMe3),
2.25 (m, 7ꢀ-H, 6ꢁ-H), 2.70 (m, 6ꢀ-H, 7ꢁ-H, 8ꢀ-H, 12ꢀ-H, 14ꢀ-H), 3.25 (m, 12ꢁ-H, 13ꢀ-H), 7.0 (m,
2-H, 3-H, 4-H), 7,87 (m, 1-H) ppm; MS: m=z (%) ¼ 341 (100) [Mþ], 326 (6), 229 (12), 185 (10), 184
(56), 75 (30), 73 (92), 45 (16).
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-16-phenyl-11-(tert-butyldimethylsiloxy)-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (6a, C29H35NO4Si)
At ꢁ78ꢂC and under N2, a solution of EtAlCl2 (3cm3, 5.4 mmol, 1.8% in toluene) was added with
stirring to a solution of N-phenylmaleimide (0.9g, 5.2mmol) in 20 cm3 CH2Cl2, and after stirring for
30min a solution of 4d (1.65 g, 5 mmol) in 10cm3 CH2Cl2 was added. The mixture was stirred for 2 h
at ꢁ78ꢂC, hydrolyzed with dil. HCl, and extracted with 2 ꢃ 100 cm3 CH2Cl2. The combined organic
layers were dried (MgSO4), and evaporated in vacuo. Yield 1.2 g (49%); light yellow crystals; mp
180ꢂC (MeOH=AcOEt); IR: ꢃꢀ¼ 3010 (ar CH), 2950, 2935, 2860 (al CH), 1770, 1705 (CO), 1600,
1570, 1490, 830, 760, 700 (ar) cmꢁ1; 1H NMR (80 MHz): ꢂ ¼ 0.05, 0.20 (2s, SiMe2), 0.95 (s, CMe3),
2.0–3.5 (m, 9 al H), 3.8 (s, OMe), 6.55–7.95 (m, 8 ar H) ppm.
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-16-ethyl-11-(tert-butyldimethylsiloxy)-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (6b, C25H35NO4Si)
From 4d (1.65 g, 5 mmol) and N-ethylmaleimide (0.57 g, 5 mmol), as described for 6a. Yield
1.4 g (65%); colorless crystals; mp 120ꢂC (CHCl3); IR: ꢃꢀ¼ 2960, 2940, 2860, 2840 (al CH), 1770
(CO), 1630 (¼C-OSi), 1610, 1490, 1410, 780 (ar) cmꢁ1; 1H NMR: ꢂ ¼ 0.08 (s, SiMe2), 0.88 (s, CMe3),
1.0 (t, J ¼ 7 Hz, Me), 2.07 (dddd, J ¼ 15, 6, 3, 3 Hz, 7ꢀ-H), 2.21 (dddd, J ¼ 15, 12, 12, 3 Hz, 7ꢁ-H),
2.47 (ddd, J ¼ 15, 6, 1.5 Hz, 12ꢀ-H), 2.51 (ddd, J ¼ 15, 12, 3 Hz, 6ꢀ-H), 2.59 (dddd, J ¼ 12, 6, 6,
1.5 Hz, 8ꢀ-H), 2,71 (ddd, J ¼ 15, 3, 3 Hz, 6ꢁ-H), 2.98 (dd, J ¼ 15, 1.5 Hz, 12ꢁ-H), 3.10 (dd, J ¼ 9,
6 Hz, 14ꢀ-H), 3.14 (ddd, J ¼ 9, 6, 1.5 Hz, 13ꢀ-H), 3.42 (q, J ¼ 7 Hz, CH2), 3.75 (s, OMe), 6.57
(m, 2-H, 4-H), 7.71 (dd, J ¼ 9, 3 Hz, 1-H) ppm; MS: m=z (%) ¼ 441 (100) [Mþ], 384 (56), 259 (60),
73 (64).
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-11-(tert-butyldimethylsiloxy)-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (6c, C23H31NO4Si)
From 4d (0.86 g, 5.1 mmol) and maleimide (0.25 g, 5 mmol), as described for 6a. Yield 0.6 g (30%);
1
light yellow liquid; H NMR (90 MHz): ꢂ ¼ 0.1 (s, SiMe2), 0.9 (s, CMe3), 3.3–1.9 (m, 9 al H), 3.72
(s, OMe), 6.6 (m, 2-H, 4-H), 7.72 (d, J ¼ 9 Hz, 1-H), 8.3 (bs, H–N) ppm.

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(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-16-phenyl-18-nor-16-azaestra-1,3,5(10)-triene-
11,15,17-trione (7a, C23H21NO4)
Compound 5a (1.0g, 2.2mmol) in 30cm3 MeOH and 1.5cm3 of conc. HCl were refluxed for 30min,
the hot solution was filtered, and cooled until crystallization was completed. Yield 0.71g (85%);
colorless crystals; mp 181ꢂC (MeOH); IR: ꢃꢀ¼ 3060 (ar CH), 2940, 2860, 2840 (al CH), 1780,
1740, 1710 (CO), 1610, 1500, 1380, 1280, 1180, 1040, 870 (ar) cmꢁ1 1H NMR (300MHz):
;
ꢂ ¼ 1.55 (m, 7ꢀ-H), 2.06 (m, 7ꢁ-H), 2.90 (m, 6ꢁ-H, 6ꢀ-H, 8ꢀ-H, 12ꢀ-H, 12ꢁ-H), 3.46 (m, 9ꢀ-H,
13ꢀ-H, 14ꢀ-H), 3.76 (s, OMe), 6.6 (d, J ¼ 3 Hz, 4-H), 6.76 (dd, J ¼ 9, 3 Hz, 2-H), 7.22 (d, J ¼ 9 Hz,
1
1-H), 7.3–7.52 (m, 5 ar H) ppm; H NMR (400MHz, pyridine-d5): ꢂ ¼ 1.70 (dddd, J ¼ 15, 15, 7.5,
3 Hz, 7ꢀ-H), 2.1 (m, 7ꢁ-H), 2.8 (m, 6ꢁ-H, 6ꢀ-H), 3.01 (dddd, J ¼ 15, 9, 7.5, 3 Hz, 8ꢀ-H), 3.12 (dd,
J ¼ 16, 6 Hz, 12ꢀ-H), 3.30 (ddd, J ¼ 16, 16, 6.0Hz, 12ꢁ-H), 3.6 (s, OMe), 3.74 (dd, J ¼ 6, 3 Hz, 9ꢀ-H),
3.90 (dd, J ¼ 9, 6 Hz, 14ꢀ-H), 4.0 (dd, J ¼ 16, 9 Hz, 13ꢀ-H), 6.72 (d, J ¼ 3 Hz, 4-H), 6.9 (dd, J ¼ 9,
3 Hz, 2-H), 7.6–7.3 (m, 5 ar H) ppm; 13C NMR (100.61 MHz): ꢂ ¼ 22.91 (C-7), 29.15 (C-8), 35.40
(C-12), 36.67 (C-13), 37.83 (C-14), 42.91 (C-6), 50.78 (C-9), 55.29 (OMe), 76.78 (C-11), 112.45
(C-4), 113.59 (C-2), 123.63–128.96 (ar C), 129.38 (C-3), 132.09 (C-1), 136.34 (C-5), 158.92 (C-10),
176.22, 177.22, 206.60 (CO) ppm; DEPT 135 (DMSO-d6): ꢂ ¼ 22.1 (CH2, C-7), 28.6 (CH2, C-6), 35.4
(CH2, C-12), 35.8 (C-8), 37.3 (C-9), 42.1 (C-14), 50.0 (C-13), 54.9 (OMe), 111.7 (C-2), 112.8 (C-4),
127.0 (C-20, C-60), 128.4 (C-40), 129.0 (C-30, C-50), 132.0 (C-1) ppm; MS: m=z (%) ¼ 375 (100) [Mþ],
198 (68), 159 (38), 43 (20).
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-16-(4-Bromophenyl)-3-methoxy-18-nor-16-azaestra-1,3,5(10)-triene-
11,15,17-trione (7b, C23H20BrNO4)
From 5b (1.9g, 3.6 mmol) in 50cm3 MeOH, room temperature, and warming for a few min in a boiling
water-bath. Yield 0.7 g (54%); colorless needles; mp 185–192ꢂC (AcOEt); IR: ꢃꢀ¼ 2936, 2860 (CH),
1776, 1714 (CO), 1608, 1504, 1491 (ar) cmꢁ1; 1H NMR (300 MHz): ꢂ ¼ 1.54 (m, 7ꢁ-H), 2.01 (m, 7ꢀ-H),
2.91 (m, 6ꢁ-H, 6ꢀ-H, 8ꢀ-H, 12ꢁ-H, 12ꢀ-H), 3.52 (m, 9ꢀ-H, 13ꢀ-H, 14ꢀ-H), 3.77 (s, OMe), 6.62
(d, J ¼ 2.6 Hz, 4-H), 6.78 (dd, J ¼ 8.5, 2.7 Hz, 2-H), 7.32 (d, J ¼ 8.8 Hz, 1-H), 7.16–7.65 (m, 4 ar H)
ppm.
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-16-Ethyl-3-methoxy-18-nor-16-azaestra-1,3,5(10)-triene-
11,15,17-trione (7c, C19H21NO4)
From 5c (1.2g, 3 mmol) as described for 7a. Yield 0.89g (90%); colorless crystals; mp 179ꢂC
(MeOH); IR: ꢃꢀ¼ 3080, 3000 (ar CH), 2960, 2940, 2840 (al CH), 1770, 1710, 1690 (CO), 1610,
1505, 1400, 1350, 1110, 820 (ar) cmꢁ1; 1H NMR (300MHz): ꢂ ¼ 1.23 (t, J ¼ 7 Hz, Me), 1.38 (dddd,
J ¼ 12, 12, 12, 2.6 Hz, 7ꢁ-H), 1.84 (dddd, J ¼ 12, 6, 3, 3 Hz, 7ꢀ-H), 2.82 (ddd, J ¼ 12, 12, 3 Hz, 6ꢀ-H),
2.84 (m, 12ꢁ-H, 12ꢀ-H), 2.86 (m, 6ꢁ-H), 2.88 (m, 8ꢀ-H), 3.35 (dd, J ¼ 9, 6 Hz, 13ꢀ-H), 3.35 (dd,
J ¼ 9, 6 Hz, 14ꢀ-H), 3.44 (dd, J ¼ 4.5, 1.5 Hz, 9ꢀ-H), 3.64 (dq J ¼ 7, 1 Hz, CH2), 3.77 (s, OMe), 6.60
(d, J ¼ 3 Hz, 4-H), 6.72 (dd, J ¼ 9, 3 Hz, 2-H), 7.25 (d, J ¼ 9 Hz, 1-H) ppm; 13C NMR (100.61 MHz):
ꢂ ¼ 13.20 (Me), 22.82 (C-7), 29.16 (C-8), 34.03 (CH2), 35.48 (C-12), 35.99 (C-13), 37.47 (C-14),
42.58 (C-6), 50.62 (C-9), 55.25 (OMe), 112.32 (C-4), 113.48 (C-2), 123.75 (C-2), 132.10 (C-1), 136.39
(C-5), 158.85 (C-10), 177.07, 178.07, 206.83 (CO) ppm; MS: m=z (%) ¼ 328 (25) [Mþþ1], 327 (100)
[Mþ], 173 (30), 159 (56).
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-16-azaestra-1,3,5(10)-triene-11,15,17-trione
(7d, C17H17NO4)
From 5d (1.0g, 2.7 mmol), as described for 7a. Yield 0.74 g (92%); colorless crystals; mp 218ꢂC
(MeOH); IR: ꢃꢀ¼ 3180 (NH), 3060 (ar CH), 2940, 2840, 2790 (al CH), 1780, 1720, 1710 (CO), 1610,
1580, 1500, 1360, 840, 820 (ar) cmꢁ1
;
1H NMR (400MHz, CDCl3=DMSO-d6): ꢂ ¼ 1.33 (dddd,
J ¼ 15, 15, 7.5, 3 Hz, 7ꢀ-H), 1.76 (m, 7ꢁ-H), 2.52 (m, 6ꢀ-H), 2.70 (ddd, J ¼ 15, 3, 3 Hz, 6ꢁ-H),
2.67, 2.76 (2dd, J ¼ 15, 6, 1.3Hz, 12ꢁ-H, 12ꢀ-H), 2.76 (m, 8ꢀ-H), 3.50 (2dd, J ¼ 9, 6 Hz, 13ꢀ-H, 14ꢀ-H),

Azasteroids
1665
3.52 (dd, J ¼ 4.5, 1.3 Hz, 9ꢀ-H), 3.70 (s, OMe), 6.60 (dd, J ¼ 9, 3 Hz, 4-H), 6.70 (dd, J ¼ 9, 3 Hz, 2-H),
7.08 (d, J ¼ 9 Hz, 1-H), 11.40 (bs, H–N) ppm; 13C NMR (DMSO-d6): ꢂ ¼ 22.12 (C-7), 28.55 (C-6),
35.13 (C-8), 35.23 (C-12), 37.70 (C-9), 43.04 (C-14), 49.88 (C-13), 54.80 (OMe), 111.50 (C-2), 112.66
(C-4), 125.02 (C-10), 131.98 (C-1), 136.27 (C-5), 157.83 (C-3), 178.92 (C-17), 180.15 (C-15), 207.48
(C-11) ppm; DEPT 135 (DMSO-d6): ꢂ ¼ 22.1 (CH2, C-7), 28.6 (CH2, C-6), 35.1 (C-8), 35.2 (CH2,
C-12), 37.7 (C-9), 43.0 (C-14), 49.9 (C-13), 54.8 (OMe), 111.5 (C-2), 112.7 (C-4), 132.0 (C-1) ppm;
MS: m=z (%) ¼ 300 (20) [Mþ], 299 (100), 271 (35), 200 (25), 159 (76), 115 (38).
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-16-methyl-18-nor-16-azaestra-1,3,5(10)-triene-
11,15,17-dione (7e, C18H19NO4)
From 5e (1.2g, 3 mmol), as described for 7a. Yield 0.71 g (75%); colorless crystals; mp 159ꢂC
(MeOH); IR: ꢃꢀ¼ 3060, 3000 (ar CH), 2940, 2840 (al CH), 1770, 1720, 1690 (CO), 1610, 1500,
1380, 1270, 820 (ar) cmꢁ1; 1H NMR (400MHz, DMSO-d6): ꢂ ¼ 1.26 (m, 7ꢀ-H), 1.62 (m, 7ꢁ-H), 2.61
(m, 6ꢁ-H, 6ꢀ-H, 8ꢀ-H, 12ꢁ-H, 12ꢀ-H), 2.85 (s, Me), 3.50 (m, 13ꢀ-H, 14ꢀ-H), 3.58 (dd, J ¼ 6, 2 Hz,
9ꢀ-H), 3.70 (s, OMe), 6.62 (d, J ¼ 3 Hz, 4-H), 6.71 (dd, J ¼ 9, 3 Hz, 2-H), 7.05 (d, J ¼ 9 Hz, 1-H) ppm;
MS: m=z (%) ¼ 314 (20) [Mþþ1], 313 (100) [Mþ], 285 (30), 159 (90), 115 (58), 91 (25).
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-16-Phenyl-18-nor-16-azaestra-1,3,5(10)-triene-
11,15,17-trione (7f, C22H19NO3)
From crude 5g as described for 7a. Yield 0.40 g (25%); colorless crystals; mp 90ꢂC (MeOH); IR:
ꢃꢀ¼ 3060, 3020 (ar CH), 2940 (al CH), 1780, 1720, 1700 (C¼O), 1600, 1500, 1380, 1180, 740, 690
1
(ar) cmꢁ1; H NMR: ꢂ ¼ 1.1–3.65 (m, 10 al H), 7.0–7.65 (m, 9 ar H) ppm.
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-18-Nor-16-azaestra-1,3,5(10)-triene-11,15,17-dione (7g, C16H15NO3)
From 5h (0.30 g, 0.9 mmol) in 15cm3 MeOH, as described for 7a. Yield 0.12g (50%); colorless
crystals; mp 206ꢂC (CHCl3); IR: ꢃꢀ¼ 3276 (NH), 2945 (al CH), 1770, 1722 (CO), 1485, 1437,
1414, 1338, 1294, 1261, 1182, 1035, 1005, 938, 845, 776, 735, 648, 625 (ar) cmꢁ1 1H NMR
;
(DMSO-d6): ꢂ ¼ 1.84 (ddd, J ¼ 15, 6, 4.5 Hz, 7ꢀ-H), 2,1 (ddd, J ¼ 14, 6, 3 Hz, 6ꢀ-H), 2.76–3.0
(m, 4 al H), 3.30 (dd, J ¼ 9, 5 Hz, 14ꢀ-H), 3.44 (m, 9ꢀ-H, 12ꢀ-H, 13ꢀ-H), 7.08 (m, 2-H, 3-H, 4-H),
7.32 (dd, J ¼ 9, 3 Hz, 1-H), 11.50 (s, H–N) ppm; MS: m=z (%) ¼ 271 (4) [Mþþ2], 270 (16) [Mþþ1],
269 (100) [Mþ], 251 (10), 180 (26), 170 (26), 129 (72), 112 (44), 99 (18), 98 (10), 77 (12), 71 (10),
55 (12), 42 (18).
General Procedure for the Synthesis of Oximes
a. A mixture from H2NOH ꢃ HCl (0.35 g, 5 mmol) and AcONa (1.0g, 10mmol) was refluxed in
10cm3 EtOH and then filtered. The ketone (1mmol) was added to the filtrate, and the reaction mixture
was refluxed for 40 min, filtered, and a few cm3 H2O were added to the filtrate until it became milky.
Cooling to 0–5ꢂC for 24–48 h resulted in a precipitate which was crystallized as noted.
b. An aqueous solution of AcONa (0.86 g, 10.5 mmol) in 2.5 cm3 H2O was added to an aqueous
solution of H2NOH ꢃ HCl (0.73 g, 10.5mmol) in 2 cm3 H2O. The mixture was added with stirring to a
solution of the ketone or the trialkylsilyl compound in THF, MeOH was added until a clear solution
was obtained, and stirring was continued at room temperature for 16h. Then H2O was added until the
precipitate was complete.
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-11-Hydroxyimino-3-methoxy-16-phenyl-18-nor-16-azaestra-
1,3,5(10)-triene-15,17-dione (8a, C23H22N2O4)
a. From 7a (0.38 g, 1.1 mmol). b. From 7a (0.75 g, 2 mmol), 15 cm3 THF. Yield a. 0.4 g (50%), b. 0.5 g
(63%); colorless crystals; mp 222ꢂC (MeOH); IR: ꢃꢀ¼ 3428 (OH), 2938 (al CH), 1777, 1712 (CO),
1608 (C¼N), 1500 (ar), 1250 (C–O), 693 (ar) cmꢁ1; 1H NMR: ꢂ ¼ 1.52 (m, 7ꢁ-H), 1.86 (m, 7ꢀ-H),
2.7–2.9 (m, 6ꢁ-H, 6ꢀ-H, 12ꢀ-H), 3.00 (m, 8ꢀ-H), 3.35 (m, 12ꢁ-H, 14ꢀ-H), 3.50 (dd, J ¼ 8.8, 6.8Hz,

1666
A. Sultani et al.
13ꢀ-H), 3.63 (d, J ¼ 3.7 Hz, 9ꢀ-H), 3.77 (s, OMe), 6.63 (d, J ¼ 2.6 Hz, 4-H), 6.73 (dd, J ¼ 8.4, 2.6 Hz,
2-H), 7.06 (d, J ¼ 8.4 Hz, 1-H), 7.26–7.5 (m, 5 ar H), 7.59 (bs, H–O) ppm.
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-16-(4-Bromophenyl)-11-hydroxyimino-3-methoxy-18-nor-16-
azaestra-1,3,5(10)-triene-15,17-dione (8b, C23H21BrN2O4)
b. From 7b (0.4g, 0.9 mmol), 10cm3 THF. Yield 0.3 g (71%); colorless crystals; mp 255–260ꢂC
(MeOH); IR: ꢃꢀ¼ 3244 (OH), 2990, 2941, 2889, 2832 (CH), 1774, 1706 (CO), 1612, 1503, 1489
(ar) cmꢁ1; 1H NMR (300MHz, DMSO-d6): ꢂ ¼ 1.42 (m, 7ꢁ-H), 1.67 (m, 7ꢀ-H), 2.55 (dddd, J ¼ 12.6,
6.2, 3.2, 3.2 Hz, 6ꢁ-H), 2.74 (m, 6ꢀ-H, 8ꢀ-H, 12ꢀ-H), 3.13 (dd, J ¼ 17.6, 5.1 Hz, 12ꢁ-H), 3.50 (dd,
J ¼ 9.3, 5.6 Hz, 14ꢀ-H), 3.58 (dd, J ¼ 9, 7 Hz, 13ꢀ-H), 3.68 (s, OMe), 3.70 (d, J ¼ 5 Hz, 9ꢀ-H), 6.60 (d,
J ¼ 2.5 Hz, 4-H), 6.65 (dd, J ¼ 8.4, 2.7 Hz, 2-H), 7.00 (d, J ¼ 8.5 Hz, 1-H), 7.23–7.73 (m, 4 ar H) ppm;
13C NMR (75 MHz, DMSO-d6): ꢂ ¼ 19.07 (C-7), 20.63 (C-6), 27.91 (C-12), 35.30 (C-8), 36.40 (C-9),
41.95 (C-14), 42.66 (C-13), 54.81 (OMe), 111.23 (C-2), 112.71 (C-4), 121.19, 127.99, 128.95, 131.22,
131.36, 131.84, 136.06 (ar C), 155.56 (C-3), 157.71 (C-11), 176.70 (C-17), 178.00 (C-15) ppm; DEPT
135 (DMSO-d6): ꢂ ¼ 19.07 (CH2, C-7), 20.63 (CH2, C-6), 27.91 (CH2, C-12), 35.30 (C-8), 36.40 (C-9),
41.95 (C-14), 42.66 (C-13), 54.81 (OMe), 111.23 (C-2), 112.71 (C-4), 128.95, 131.22, 131.84 (ar C)
ppm.
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-11-Hydroxyimino-3-methoxy-16-methyl-18-nor-16-azaestra-
1,3,5(10)-triene-15,17-dione (8c, C18H20N2O4)
a. From 7e (0.32 g, 1.1mmol). Yield 0.09 g (26%); colorless crystals; mp 225ꢂC (EtOH); IR: ꢃꢀ¼ 3417
1
(OH), 2942 (al CH), 1777, 1706 (CO), 1610 (C¼N), 1501 (ar) cmꢁ1; H NMR (DMSO-d6=acetone-
d6): ꢂ ¼ 1.32 (m, 7ꢁ-H), 1.60 (m, 7ꢀ-H), 2.79 (m, 8ꢀ-H, 6ꢁ-H, 6ꢀ-H), 2.81 (s, NMe), 2.95 (dd, J ¼ 15,
3.4 Hz, 12ꢀ-H), 3.35 (m, 12ꢁ-H, 13ꢀ-H), 3.45 (dd, J ¼ 9, 6 Hz, 14ꢀ-H), 3.65 (d, J ¼ 6.8 Hz, 9ꢀ-H),
3.78 (s, OMe), 6.60 (d, J ¼ 2 Hz, 4-H), 6.65 (dd, J ¼ 9, 2 Hz, 2-H), 7.00 (d, J ¼ 9 Hz, 1-H) ppm.
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-11-Hydroxyimino-3-methoxy-18-nor-16-azaestra-1,3,5(10)-triene-
15,17-dione (8d, C17H18N2O4)
a. From 7d (0.30 g, 1.0 mmol). b. From 7d (1.3g, 3.3 mmol), 40 cm3 THF. Yield a. 0.25g (70%), b.
0.8 g (77%); colorless crystals; mp 250ꢂC (MeOH); IR: ꢃꢀ¼ 3400 (OH), 3265 (NH), 2935 (al CH),
1
1769, 1711 (CO), 1612 (C¼N), 1579 (ar) cmꢁ1; H NMR (DMSO-d6): ꢂ ¼ 1.35 (m, 7ꢁ-H), 1.65 (m,
7ꢀ-H), 2.40 (m, 8ꢀ-H), 2.74 (m, 6ꢁ-H, 6ꢀ-H, 12ꢀ-H), 2.91 (dd, J ¼ 18, 1.5 Hz, 12ꢁ-H), 3.35 (m, 13ꢀ-H,
14ꢀ-H), 3.62 (d, J ¼ 4.5 Hz, 9ꢀ-H), 3.68 (s, OMe), 6.61 (d, J ¼ 2.5Hz, 4-H), 6.64 (dd, J ¼ 9, 2.5 Hz, 2-H),
7.0 (d, J ¼ 9 Hz, 1-H), 11.15 (s, 16-H) ppm; 13C NMR: ꢂ ¼ 19.72 (C-7), 20.91 (C-12), 28.14 (C-6),
34.88 (C-8), 37.16 (C-13), 42.01 (C-9), 43.83 (C-14), 54.90 (OMe), 111.20 (C-4), 112.82 (C-2), 128.25
(C-3), 131.48 (C-1), 136.08 (C-5), 155.95 (C-10), 157.75 (C-11), 179.20, 180.57 (CO) ppm.
General Procedure for the Reaction with BBr3
A solution of BBr3 (1 M in CH2Cl2) was dropwise added at 0ꢂC to a solution of the methoxy
compound in CH2Cl2, stirring was continued for 3–4 h, then 20 cm3 CH2Cl2 were added, and the
mixture was poured onto 30–50g of crashed ice. After warming to room temperature, the organic layer
was separated, and the aqueous layer was extracted with 4 ꢃ 50cm3 AcOEt. The combined organic
layers were washed with H2O and a satd. aqueous solution of NaCl, dried (MgSO4), and evaporated in
vacuo (max. 50ꢂC, preferred 20ꢂC).
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-3-Hydroxy-16-phenyl-18-nor-16-azaestra-1,3,5(10)-triene-
11,15,17-trione (9a, C22H19NO4)
From 7a (0.4g, 1.1 mmol) in 30 cm3 CH2Cl2 and 4.5 cm3 BBr3. Yield 0.2 g (42%); colorless crystals;
mp 217–221ꢂC (AcOH); IR: ꢃꢀ¼ 3338 (OH), 2922 (CH), 1773, 1712 (CO), 1684, 1606, 1499 (ar)
cmꢁ1
.

Azasteroids
1667
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-3-Hydroxy-18-nor-16-azaestra-1,3,5(10)-triene-11,15,17-trione
(9b, C16H15NO4)
From 7d (0.3g, 1 mmol) in 30cm3 CH2Cl2 and 4.0cm3 BBr3. Yield 0.1 g (30%); yellow-brownish
crystals; mp 225–236ꢂC (AcOEt); IR: ꢃꢀ¼ 3188 (OH), 1750, 1704 (CO), 1614, 1597, 1578 (ar) cmꢁ1
;
HPLC: k10 ¼ 4.75, t0 ¼ 3.09 (RP-18, MeCN=H2O 37); k10 1 ¼ 1.24, t0 ¼ 2.17 ((S,S)-Whelk-O1,
n-hexane=2-propanol 7=3); k10 1 ¼ 6.99, t0 ¼ 1.83 (Chiralcel OJ-R, MeCN=H2O 3=7).
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-16-(4-Bromophenyl)-3-hydroxy-18-nor-16-azaestra-1,3,5(10)-
triene-11,15,17-trione (9c, C22H18BrNO4)
From 5b (1.0g, 2 mmol) and 11 cm3 BBr3 in 60 cm3 CH2Cl2. Yield 0.3 g (44%); yellow crystals; mp
295–300ꢂC (MeCN); IR: ꢃꢀ¼ 3391 (OH), 2933 (CH), 1763, 1703 (CO), 1611, 1595, 1490 (ar) cmꢁ1
;
HPLC: k10 ¼ 1.53, t0 ¼ 2.09 (RP-18, MeCN=H2O 7:3); k10 1 ¼ 3.57, t0 ¼ 2.17 ((S,S)-Whelk-O1,
n-hexane=2-propanol 7=3); k10 1 ¼ 14.10, t0 ¼ 2.09 (Chiralcel OJ-R, MeCN=H2O 1=1).
(RS)-3-Methoxy-16-methyl-11-(trimethylsiloxy)-18-nor-13,14,16-triazaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (10a, C19H25N3O4Si)
Compound 4a (1.45 g, 5.3 mmol) and 4-methyl-1,2,4-triazolin-3,5-dione (0.57 g, 5.5 mmol) in 20cm3
THF were stirred at ꢁ60ꢂC for 1 h. When the reaction was complete (TLC control), the solvent was
concentrated in vacuo, and the residue was immediately used for the synthesis of 11a.
(RS)-3-Methoxy-16-phenyl-11-(trimethylsiloxy)-18-nor-13,14,16-triazaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (10b, C24H27N3O4Si)
4-Phenyl-1,2,4-triazolin-3,5-dione (0.96 g, 5.5 mmol) and 4a (1.45 g, 5.3 mmol) in 30 cm3 THF were
stirred at ꢁ60ꢂC for 2 h. Then the solvent was evaporated in vacuo. Yield 1.8 g (75%); colorless
crystals; mp 112ꢂC (MeOH); IR: ꢃꢀ¼ 3010 (ar CH), 2960, 2820 (al CH), 1790, 1730 (CO), 1620
(¼C-OSi), 1590, 1470 (ar), 1270 (C–O) cmꢁ1; 1H NMR (400MHz): ꢂ ¼ 0.10 (s, SiMe3), 1.90 (dddd,
J ¼ 15, 3, 3, 1.5 Hz, 7ꢀ-H), 2.50–3.07 (m, 6ꢁ-H, 6ꢀ-H, 7ꢁ-H), 3.81 (s, OMe), 4.00 (dd, J ¼ 15, 1.5Hz,
12ꢀ-H), 4.40 (dd, J ¼ 15, 1.5 Hz, 12ꢁ-H), 4.46 (ddd, J ¼ 12, 7.5, 1.5 Hz, 8ꢀ-H), 6.64 (d, J ¼ 3 Hz,
4-H), 6.75 (dd, J ¼ 3, 9 Hz, 2-H), 7.5 (m, 5 ar HPh), 7.90 (d, J ¼ 9 Hz, 1-H) ppm.
(8ꢀ,9ꢀ)-3-Methoxy-16-methyl-18-nor-13,14,16-triazaestra-1,3,5(10)-triene-
11,15,17-trione (11a, C16H17N3O4)
4-Methyl-1,2,4-triazolin-3,5-dione (0.57 g, 5.5mmol) and 4a (1.45 g, 5.3 mmol) in 20cm3 THF were
stirred for 1–2 h at ꢁ60ꢂC. After warming to room temperature, 30cm3 MeOH and 1.5cm3 of conc.
HCl were added, and the mixture was refluxed for 10–30min, the hot solution was filtered, and
evaporated in vacuo. Yield 0.59 g (80%); colorless crystals; mp 159ꢂC (MeOH); IR: ꢃꢀ¼ 3005 (ar
CH), 2960, 2940, 2840 (al CH), 1780, 1720, 1710 (CO), 1620, 1580, 1510, 1470, 1270, 880 (ar) cmꢁ1
;
1H NMR: ꢂ ¼ 1.75 (dddd, J ¼ 18, 12, 12, 3 Hz, 7ꢁ-H), 2.20 (m, 7ꢀ-H), 2.92 (ddd, J ¼ 15, 12, 3 Hz, 6ꢁ-H,
6ꢀ-H), 3.13 (s, Me), 3.80 (s, OMe), 3.96 (dd, J ¼ 6, 1.5 Hz, 9ꢀ-H) 4.21, 4.25 (2d, J ¼ 15Hz, 12ꢀ-H,
12ꢁ-H), 4.60 (dddd, J ¼ 12, 6, 3, 1.5Hz, 8ꢀ-H), 6.67 (d, J ¼ 3 Hz, 4-H), 6.79 (dd, J ¼ 9, 3 Hz, 2-H), 7.0
(d, J ¼ 9 Hz, 1-H) ppm.
(8ꢀ,9ꢀ)-3-Methoxy-16-phenyl-18-nor-13,14,16-triazaestra-1,3,5(10)-triene-
11,15,17-trione (11b, C21H19N3O4)
From 10b (1.71 g, 3.8 mmol), as described for 7a. Yield 1.1g (77%); colorless crystals; mp 163ꢂC
(MeOH); IR: ꢃꢀ¼ 3060, 3000 (ar CH), 2940, 2840 (al CH), 1770, 1740, 1720 (CO), 1610, 1500 (ar)
cmꢁ1; 1H NMR: ꢂ ¼ 1.92 (dddd, J ¼ 15, 12, 12, 6 Hz, 7ꢁ-H), 2.35 (dddd, J ¼ 15, 3, 3, 1.5 Hz, 7ꢀ-H),
2.96 (ddd, J ¼ 15, 15, 6 Hz, 6ꢁ-H, 6ꢀ-H), 3.80 (s, OMe), 4.07 (dd, J ¼ 5.5, 1.5 Hz, 9ꢀ-H), 4.35, 4.34
(2d, J ¼ 15Hz, 12ꢀ-H, 12ꢁ-H), 4.78 (dddd, J ¼ 12, 5.5, 3, 1.5 Hz, 8ꢀ-H), 6.70 (d, J ¼ 2 Hz, 4-H), 6.78
(dd, J ¼ 9, 2 Hz, 2-H), 7.0 (d, J ¼ 9 Hz, 1-H), 7.50 (m, 5 ar H) ppm; MS: m=z (%) ¼ 378 (6) [Mþþ1],
377 (20) [Mþ], 160 (100), 93 (18).

1668
A. Sultani et al.
(8ꢀ,9ꢀ)-16-Phenyl-18-nor-13,14,16-triazaestra-1,3,5(10)-triene-11,15,17-trione
(11c, C20H17N3O3)
From 4b (0.50 g, 1.7 mmol) and 4-phenyl-1,2,4-triazolin-3,5-dione (0.3g, 1.7 mmol), time 1 h, as de-
scribed for 11a. Yield 0.35 g (60%); colorless crystals; mp 177ꢂC (MeOH); IR: ꢃꢀ¼ 2936 (al CH), 1773,
1712 (CO), 1501 (ar) cmꢁ1; 1H NMR: ꢂ ¼ 1.70 (dddd, J ¼ 15, 15, 15, 3 Hz, 7ꢁ-H), 2.27 (m, 7ꢀ-H), 2.9
(m, 6ꢁ-H, 6ꢀ-H), 3.30 (s, OMe), 4.27 (d, J ¼ 16 Hz, 12ꢀ-H), 4.6 (dd, J ¼ 6, 1.5 Hz, 9ꢀ-H), 4.64 (d,
J ¼ 16Hz, 12ꢁ-H), 4.75 (dddd, J ¼ 15, 7.5, 3, 3 Hz, 8ꢀ-H), 7.15 (m, 4 ar H), 7.5 (m, 5 ar H) ppm; MS:
m=z (%) ¼ 347 (50) [Mþ], 191 (15), 190 (20), 130 (100), 129 (80), 115 (40), 91 (25), 77 (10), 51 (5).
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-16-phenyl-11-(trimethylsiloxy)-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione (12, C27H31NO4Si)
From 4a (450mg, 1.65mmol) and ꢁ-methyl-N-phenylmaleimide (0.28 g, 1.50 mmol) in 20cm3 of
toluene under N2, reflux for 1.2 h, as described for 5a. Yield 0.30 g (40%); colorless crystals; mp
168ꢂC (MeOH); IR: ꢃꢀ¼ 2959, 2837 (al CH), 1775, 1710 (CO), 1632 (¼C-OSi), 1607 (ar), 1570, 1492,
1454, 1390, 1362, 1304, 1251, 1214, 1199, 1151, 1135, 1054, 985, 932, 881, 849, 760, 696 (ar) cmꢁ1
;
1H NMR: ꢂ ¼ 0.04 (s, SiMe3), 1.46 (s, Me), 2.02 (dddd, J ¼ 12.8, 12.8, 12.8, 3.0 Hz, 7ꢁ-H), 2.16 (dddd,
J ¼ 12.8, 6.7, 6.7, 3.6 Hz, 7ꢀ-H), 2.48 (m, 6ꢀ-H, 6ꢁ-H), 2.62 (dd, J ¼ 20.9, 1.5 Hz, 12ꢀ-H), 2.68 (ddd,
J ¼ 12.8, 6.7, 3.4Hz, 8ꢀ-H), 2.86 (d, J ¼ 3.4 Hz, 14ꢀ-H), 2.90 (dd, J ¼ 20.9, 2.15Hz, 12ꢁ-H), 3.76 (s,
OMe), 6.60 (d, J ¼ 2 Hz, 4-H), 6.66 (dd, J ¼ 9, 2 Hz, 2-H). 7.06 (m, 2 ar HPh), 7.35 (m, 3 ar HPh), 7.78
(d, J ¼ 9 Hz, 1-H) ppm; 13C NMR: ꢂ ¼ 0.15 (SiMe3), 22.04 (C-18), 22.68 (C-7), 30.43 (C-6), 30.84
(C-12), 44.99 (C-8), 46.85 (C-14), 49.90 (C-13), 54.69 (OMe), 101.88 (C-11), 110.99 (C-9), 111.93
(C-2), 113.26 (C-4), 125.15-129.32 (ar C), 131.68 (C-3), 139.49 (C-5), 144.53 (C-10), 156.89 (C-1Ph),
176.99, 179.07 (CO) ppm; MS: m=z (%) ¼ 464 (2) [Mþþ3], 463 (6) [Mþþ2], 462 (30) [Mþþ1], 461
(100) [Mþ], 275 (10), 274 (40), 259 (8), 243 812), 75 (10), 73 (50), 45 (6).
1-(1-Methoxyvinyl)-3,4-dihydro-6-methoxynaphthalene (13)
See Ref. [9]
(8ꢀ,13ꢀ,14ꢀ)-3,11-Dimethoxy-16-methyl-18-nor-16-azaestra-1,3,5(10),9(11)-tetraene-
15,17-dione (14a, C19H21NO4)
a. From 13 (1.0g, 4.5 mmol) and N-methylmaleimide (0.45 g, 3.5 mmol) as described for 5a, 8 h. b. 7e
(0.15 g, 0.45mmol) in 5 cm3 MeOH and 2 cm3 HC(OMe)3 were stirred at room temperature for
12–15 h. Then the solvent was evaporated. Yield a. 0.43g (30%), b. 0.14 g (91%); colorless crystals;
mp 161ꢂC (MeOH=H2O); IR: ꢃꢀ¼ 2936, 2839 (al CH), 1769, 1692 (CO), 1603, 1566 (ar), 1266, 1241,
1223 (C–O), 785, 661 (ar) cmꢁ1; 1H NMR: ꢂ ¼ 2.10 (m, 7ꢀ-H), 2.25 (m, 7ꢁ-H), 2.48 (ddd, J ¼ 15, 6,
1.5 Hz, 12ꢀ-H), 2.57 (m, 6ꢁ-H, 6ꢀ-H, 8ꢀ-H), 3.09 (dd, J ¼ 9, 6 Hz, 14ꢀ-H), 3.14 (dd, J ¼ 15, 1.5Hz,
12ꢁ-H), 3.21 (ddd, J ¼ 9, 6, 3 Hz, 13ꢀ-H), 3.60 (s, 11-OMe), 3.77 (s, 3-OMe), 6.60 (d, J ¼ 3 Hz, 4-H),
6.67 (dd, J ¼ 9, 3 Hz, 2-H), 7.79 (d, J ¼ 9 Hz, 1-H) ppm.
(8ꢀ,13ꢀ,14ꢀ)-3,11-Dimethoxy-16-phenyl-18-nor-16-azaestra-1,3,5(10),9(11)-tetraene-
15,17-dione (14b, C24H23NO4)
From 13 (1.0g, 4.5 mmol) and N-phenylmaleimide (0.90 g, 5.2 mmol), 6 h, as described for 5a. Yield
1.5 g (56%); colorless crystals; Rf ¼ 0.52 (neutral Al2O3, CHCl3); mp 162ꢂC (MeOH); IR: ꢃꢀ¼ 2933
1
(OMe), 2840 (al CH), 1709 (CO), 1621 (¼C–O), 1604 (ar), 1305 (C–O), 693 (ar) cmꢁ1; H NMR:
ꢂ ¼ 2.10 (dddd, J ¼ 15, 6, 3, 3 Hz, 7ꢀ-H), 2.35 (dddd, J ¼ 15, 12, 12, 3 Hz, 7ꢁ-H), 2.45 (ddd, J ¼ 15, 6,
1.5 Hz, 12ꢀ-H), 2.65 (ddd, J ¼ 15, 12, 3 Hz, 6ꢀ-H), 2.72 (ddd, J ¼ 12, 6, 1.5 Hz, 8ꢀ-H), 2.78 (ddd,
J ¼ 15, 3, 3 Hz, 6ꢁ-H), 3.20 (dd, J ¼ 9, 6 Hz, 14ꢀ-H), 3.22 (dd, J ¼ 15, 1.5 Hz, 12ꢁ-H), 3.40 (ddd,
J ¼ 9, 6, 1.5 Hz, 13ꢀ-H), 3.62 (s, 11-OMe), 3.80 (s, 3-OMe), 6.55 (d, J ¼ 3 Hz, 4-H), 6.70 (dd, J ¼ 9,
3 Hz, 2-H), 7.1 (m, 2 ar H), 7.4 (m, 3 ar H), 7.80 (d, J ¼ 9 Hz, 1-H) ppm.

Azasteroids
1669
(8ꢀ)-3,11-Dimethoxy-16-phenyl-18-nor-13,14,16-triazaestra-1,3,5(10),9(11)-tetraene-
15,17-dione (15, C22H21N3O4)
13 (1.0g, 4.5 mmol) and 4-phenyl-1,2,4-triazolin-3,5-dione (1.05 g, 5.75mmol) in 30cm3 of toluene
were stirred at ꢁ78ꢂC for 2–5 h. Then 50cm3 MeOH were added, and the solvent was evaporated
in vacuo. Yield 950 mg (55%); colorless crystals; mp 142ꢂC (MeOH); IR: ꢃꢀ¼ 2937 (al CH), 1776,
1712 (CO), 1650 (¼C-OSi), 1607, 1497, 767, 692, 647 (ar) cmꢁ1; 1H NMR: ꢂ ¼ 1.85 (m, 7ꢀ-H), 3.06
(m, 6ꢁ-H, 6ꢀ-H, 7ꢁ-H), 3.66 (s, 11-OMe), 3.81 (s, 3-OMe), 4.24 (dd, J ¼ 15.6, 1.7 Hz, 12ꢀ-H), 4.40
(dd, J ¼ 15.6, 1.9 Hz, 12ꢁ-H), 4.46 (ddd, J ¼ 10.2, 7.3, 2.6 Hz, 8ꢀ-H), 6.65 (d, J ¼ 3 Hz, 4-H), 6.80 (dd,
J ¼ 9, 3 Hz, 2-H), 7.5 (m, 5 ar H), 7.90 (d, J ¼ 9 Hz, 1-H) ppm.
Acknowledgments
We thank Degussa AG for generous support with chemicals, E. Merck KGaG, Darmstadt, for
continuous support with chromatography materials and biological testing, the ‘‘Fonds der Chemischen
Industrie’’ for financial support, and Dr. M. Kindermann, Chemistry Dept. University of Greifswald,
for some NMR experiments.
References
€
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