Systematic investigation on the synthesis of androstane-based 3-, 11- and 17-carboxamides via palladium-catalyzed aminocarbonylation

Article abstract of DOI:10.1016/j.steroids.2010.11.008

3,17-Dicarboxamido-androst-3,5,16-triene, 3-carboxamido-androst-3,5-dien- 17-one, 17-carboxamido-androst-4,16-dien-3-one and 11-carboxamido-androst-5, 9(11)-dien-3,17-dione derivatives were synthesized in homogeneous carbonylation reactions from the corre

Full text of DOI:10.1016/j.steroids.2010.11.008

Steroids 76 (2011) 280–290
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Steroids
journal homepage: www.elsevier.com/locate/steroids
Systematic investigation on the synthesis of androstane-based 3-, 11- and
17-carboxamides via palladium-catalyzed aminocarbonylation
Péter Ácsa, Attila Takácsa, Mercédesz Kissa, Noémi Pálinkása, Sándor Mahób, László Kollára,∗
a University of Pécs, Department of Inorganic Chemistry, Ifjúság u. 6. H-7624 Pécs, Hungary
b Gedeon Richter Pharmaceutical Works, Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
3,17-Dicarboxamido-androst-3,5,16-triene, 3-carboxamido-androst-3,5-dien-17-one, 17-carboxamido-
androst-4,16-dien-3-one and 11-carboxamido-androst-5,9(11)-dien-3,17-dione derivatives were syn-
thesized in homogeneous carbonylation reactions from the corresponding 3,17-diiodo-androst-
3,5,16-triene, 3-iodo-androst-3,5-diene-17-ethylene ketal, 17-iodo-androst-5,16-dien-3-ethylene ketal,
11-iodo-androst-5,9(11)-diene-3,17-bis(ethylene ketal) derivatives, respectively. A highly chemoselec-
tive palladium-catalyzed aminocarbonylation of the corresponding iodo-alkene, carried out under mild
reaction conditions, can be considered as the key-step for the introduction of the carboxamide functional-
ities. The synthesis of the iodo-alkene substrate is based on the transformation of the corresponding keto
derivative to hydrazone, which was treated with iodine in the presence of a base (1,1,3,3-tetramethyl
guanidine). The aminocarbonylation reaction is highly tolerant towards the N-nucleophiles, i.e. various
primary and secondary amines including amino acid methyl esters can also be used.
Received 21 October 2010
Received in revised form
18 November 2010
Accepted 29 November 2010
Available online 3 December 2010
Keywords:
Iodo-alkene
Carboxamide
Androstane
Palladium catalyst
Carbonylation
© 2010 Elsevier Inc. All rights reserved.
1. Introduction
reductase inhibitors [12–15]. Recently, aminocarbonylation with
in situ formed palladium catalysts was successfully carried out even
The homogeneous catalytic reactions are widely used both for
the synthesis of simple building blocks and for the functionalization
of various skeletons, among them biologically important backbones
[1–3]. As for the steroidal skeleton, there is an increasing inter-
est in developing new strategies to introduce functional groups
into specific positions (especially into 3-, 11- and 17-positions)
of the steroidal framework in order to improve their pharmaco-
logical efficacy. Starting from the 1970s, various transition metal
catalyzed reactions have been used for the selective modification
of the steroidal backbone. As first examples hydrogenation and var-
ious carbonylation reactions were used, recently dihydroxylations
and several types of coupling reactions proved to sufficient both for
the construction of a steroid framework or for the functionalization
of the steroidal skeleton [4].
at the more hindered 12- and 11-positions of the C-ring [16,17].
A seminal work on the transformation of steroidal 11-ketones
was carried out by Stéphan et al. Various key intermediates were
prepared in methylenation [18], alkinylation [19], aryl- and alkyl-
lithium additions [20,21], and allylation by allyl-Grignard reagents
[22].
In the present paper, we report on the efficient synthesis of
novel androstene derivatives bearing carboxamide functionalities
either at 3-, 11- and/or 17-positions. A systematic investigation on
the selective synthesis of carboxamides with additional keto func-
tionalities, suitable for further transformations at distinguished
positions, was carried out.
2. Experimental
The synthesis of steroidal carboxamides, possessing the amide
functionality either at the A- or the D-ring at the distinguished
position-3 and 17, respectively [5–11], is in the forefront of the
palladium-catalyzed homogeneous reactions. Their importance
lies in the chance of tuning their pharmacological activity as 5␣-
PPh3, 1,1,3,3-tetramethylguanidine (TMG) and adrenosterone
(16) were purchased from Aldrich. Androst-4-ene-3,17-dione (1), a
well-known starting compound for the production of several phar-
maceutically active steroids, was produced by bioconversion of
fitosterols in Gedeon Richter Plc.
Commercial Et3N, primary and secondary amines including
amino acid esters (Aldrich) were used without further purification.
Toluene and DMF were dried according to standard procedures.
The steroidal mono- and diketals (5, 11 and 10, 17, respectively)
were synthesized according to modified conventional synthetic
∗
Corresponding author at: University of Pécs, Department of Inorganic Chemistry,
Ifjúság u. 6. (PO Box 266) H-7624 Pécs, Hungary. Tel.: +36 72 503600;
fax: +36 72 501527.
E-mail address: kollar@ttk.pte.hu (L. Kollár).
0039-128X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2010.11.008

P. Ács et al. / Steroids 76 (2011) 280–290
281
procedures [23] using the corresponding keto derivatives as start-
ing materials. The transformation of the keto functionality to
iodo-alkene moiety was carried out by the modification of the Bar-
ton’s methodology [24,25]. Owing to differences to the previously
published methods, a detailed description of these syntheses will
be given below.
The 1H and 13C NMR spectra were recorded on a VARIAN
INOVA 400 spectrometer at 400 and 100.58 MHz, respectively. The
chemical shifts are given as ı values (ppm) and referenced to
tetramethylsilane. TLC analyses were carried out by using Merck
TLC sheets (Silica gel 60 F254) and chloroform, chloroform/ethanol,
and ethyl acetate/methanol mixtures were used as appropriate elu-
ents. (The exact ratios are given at the corresponding synthetic
procedures.) Mass-spectrometry data have been obtained by using
a GC–MS system consisting of a Perkin Elmer AutoSystem XL gas-
chromatograph and Perkin Elmer TurboMass mass spectrometer.
To a solution of 10 (5 g, 13.4 mmol) in acetone (500 mL) and
water (50 mL), 1 N aqueous HCl (10 mL) was added and stirred
overnight at room temperature. After addition of saturated NaHCO3
(200 mL), the mixture was concentrated under reduced pres-
sure. The residue was dissolved in chloroform (150 mL), washed
with water and brine, dried on sodium sulfate and evaporated.
Purification by column chromatography (silicagel, petroleum ether
(40–70 ◦C):EtOAc 75:25) gave pure 11 as a white solid material.
Yield: 1.76 g; 39.8%.
2.4. Synthesis of 3-iodo-androst-3,5-diene-17-ethylene ketal (7)
Androst-4-ene-3-one-17-ethylene ketal (5) (5 g, 25.2 mmol),
freshly distilled hydrazine hydrate (98%, 3.86 g, 77.3 mmol) and
barium oxide (100 mg) in 2-methoxy-ethanol (70 mL) were heated
for 2 days at 160 ◦C. After completion of the reaction the mixture
was poured onto water and extracted with dichloromethane. The
combined organic layer was washed with water, and brine. It was
dried over sodium sulfate and evaporated to give the 3-hydrazone
derivative (6). The product was used in the next step without fur-
ther purification.
2.1. Synthesis of 3,17-diiodo-androst-3,5,16-triene (3)
Androst-4-en-3,17-dione (1) (5 g, 17.5 mmol), freshly distilled
hydrazine hydrate (98%, 8.92 g, 178.4 mmol) and barium oxide
(100 mg) in 2-methoxy-ethanol (80 mL) were heated for 2 days at
160 ◦C. After completion of the reaction the mixture was poured
onto water and extracted with dichloromethane. The combined
organic layer was washed with water, and brine. It was dried
over sodium sulfate and evaporated to give the 3,17-bis-hydrazone
derivative (2). The product was used in the next step without fur-
ther purification.
To
a stirred solution of iodine (6.50 g, 25.6 mmol) in
dichloromethane (50 mL) 1,1,3,3–tetramethylguanidin (TMG,
12.05 g, 104.6 mmol) was added slowly and cooled by iced water
bath during the addition. The solution of 6 (4 g, 11.6 mmol) in
dichloromethane (20 mL) was added drop-wise at room temper-
ature. After the addition was completed, the mixture was stirred
for an hour. Then the solvent was evaporated and the residue
was heated at 90 ◦C under argon atmosphere for 2 h. The mixture
was poured onto water and extracted with dichloromethane. The
combined organic layer was washed with 1 N aqueous HCl, water,
5% aqueous NaHCO3, water, saturated aqueous Na2S2O3 and water
again, dried on sodium sulfate and evaporated. Purification by col-
umn chromatography (silicagel, petroleum ether (40–70 ◦C):EtOAc
7:3) gave pure 7 as a pale yellow solid material. Yield: 1.59 g;
31.1%.
To
a
stirred solution of iodine (17.80 g, 70.1 mmol) in
(5 g, 15.9 mmol) and
dichloromethane (80 mL) solution of
2
1,1,3,3-tetramethylguanidin (TMG, 16.50 g, 143.3 mmol) in
dichloromethane (30 mL) was added drop-wise at room temper-
ature. After the addition was completed, the mixture was stirred
for an hour. Then the solvent was evaporated and the residue
was heated at 90 ◦C under argon atmosphere for 2 h. The mixture
was poured onto water and extracted with ether. The combined
organic layer was washed with 1 N aqueous HCl, water, 5% aque-
ous NaHCO3, water, saturated aqueous Na2S2O3 and water again,
dried on sodium sulfate and evaporated. Purification by column
chromatography (silicagel, hexane:EtOAc 99:1) gave pure 3 as a
pale yellow solid material. Yield: 1.38 g; 17.1%.
2.5. Synthesis of 17-iodo-androst-5,16-diene-3-ethylene ketal
(13)
The 17-keto-3-ketal derivative (11) (3.3 g, 10 mmol) was trans-
formed to the corresponding 17-iodo-16-ene derivative (13) via
17-hydrazone (12) according to the procedure described for 7.
Yield: 1.54 g; 35%.
2.2. Synthesis of androst-4-ene-3-one-17-ethylene ketal (5)
A solution of androst-4-en-3,17-dione (1) (5.98 g, 20.9 mmol)
in chloroform (100 mL) and 1.40 mL (1.56 g, 25.1 mmol) of ethy-
lene glycol containing p-toluene-sulfonic acid (40 mg) was stirred
under reflux for a day in a Dean–Stark water separator. The
reaction mixture was cooled neutralized and washed with 5%
aqueous NaOH and water. It was dried on sodium sulfate, evapo-
rated and purified by column chromatography (silicagel, petroleum
ether (40–70 ◦C):EtOAc 7:3). Pure 5 as a white solid material was
obtained. Yield: 3.12 g; 45.3%.
2.6. Synthesis of androst-5-ene-11-one-3,17-bis(ethylene ketal)
(17)
A solution of adrenosterone (16) (5 g, 16.6 mmol) in chloroform
(100 mL) and 2.23 mL (2.48 g, 40 mmol) of ethylene glycol contain-
ing p-toluene-sulfonic acid (40 mg) was stirred under reflux for a
day in a Dean–Stark water separator. The reaction mixture was
cooled, neutralized and washed with 5% aqueous NaOH and water.
It was dried on sodium sulfate, evaporated and purified by column
chromatography (silicagel, petroleum ether 70 ◦C:EtOAc 7:3). Pure
17 as a white solid material was obtained. Yield: 2.82 g; 43.8%.
2.3. Synthesis of androst-5-ene-17-one-3-ethylene ketal (11)
A solution of androst-4-en-3,17-dione (1) (10 g, 35.0 mmol)
in chloroform (150 mL) and 4.70 mL (5.24 g, 84.4 mmol) of ethy-
lene glycol containing p-toluene-sulfonic acid (150 mg) was stirred
under reflux for a day in a Dean–Stark water separator. The reac-
tion mixture was cooled, neutralized and washed with 5% aqueous
NaOH and water. It was dried on sodium sulfate, evaporated and
purified by column chromatography (silicagel, petroleum ether
40–70 ◦C:EtOAc 75:25). Pure 3,17-diketal (10) as a white solid
material was obtained. Yield: 8.50 g; 65.1%.
2.7. Synthesis of
11-iodo-androst-5,9(11)-diene-3,17-bis(ethylene ketal) (19)
Androst-5-ene-11-one-3,17-bis(ethylene ketal) (17) (5.50 g,
14.2 mmol), freshly distilled hydrazine hydrate (98%, 60.24 g,
1.21 mol) and barium oxide (100 mg) in di(ethylene glycol) methyl
ether (80 mL) were heated for 5 days at 195 ◦C. After completion
of the reaction the mixture was poured onto water and extracted
with dichloromethane. The combined organic layer was washed

282
P. Ács et al. / Steroids 76 (2011) 280–290
with water, and brine. It was dried over sodium sulfate and evap-
orated to give the 11-hydrazone derivative (18). The product was
used in the next step without further purification.
2.9. Analytical and spectroscopic data of compounds
2.9.1. Ketals
To
a
stirred solution of iodine (5.61 g, 22.1 mmol) in
Androst-4-ene-3-one-17-ethylene ketal (5): 1H NMR (CDCl3,
400 MHz): 5.68 (br s, 1H, 4-CH); 3.79–3.91 (m, 4H, O(CH2)2O);
0.88–2.42 (m, 19H, skeleton protons); 1.16 (s, 3H, 19-CH3); 0.85
(s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 199.3; 171.1;
123.8; 119.0; 65.2; 64.5; 53.6; 49.7; 45.7; 38.6; 35.8; 35.7; 34.0;
33.9; 32.7; 31.3; 30.3; 22.6; 20.4; 17.4; 14.2. MS (m/z/rel.int.):
330/34 (M+), 285/4, 266/9, 99/100. IR (KBr, (cm−1)): 1672 (C O),
1619 (C C). Analysis calculated for C21H30O3 (M = 330.47): C,
76.33; H, 9.15; Found: C, 76.21; H, 9.01. Rf = 0.73 (petroleum ether
(40–70)/EtOAc = 7/3). Mp. 168–170 ◦C. White powder-like material
(as obtained after column chromatography).
dichloromethane (50 mL) 1,1,3,3–tetramethylguanidin (TMG,
10.90 g, 94.7 mmol) was added slowly and cooled by iced water
bath during the addition. The solution of 18 (4.23 g, 10.5 mmol) in
dichloromethane (20 mL) was added drop-wise at room temper-
ature. After the addition was completed, the mixture was stirred
for an hour. Then the solvent was evaporated and the residue
was heated at 90 ◦C under argon atmosphere for 2 h. The mixture
was poured onto water and extracted with dichloromethane. The
combined organic layer was washed with 1N aqueous HCl, water,
5% aqueous NaHCO3, water, saturated aqueous Na2S2O3 and water
again, dried on sodium sulfate and evaporated. Purification by
column chromatography (silicagel, petroleum ether 70 ◦C:EtOAc
7:3) gave pure (19) as an orange oil. Yield: 0.86 g; 16.4%.
Androst-5-ene-17-one-3-ethylene ketal (11): 1H NMR (CDCl3,
400 MHz): 5.35 (br s, 1H, 6-CH); 3.85–3.95 (m, 4H, O(CH2)2O);
0.98–2.56 (m, 19H, skeleton protons); 1.02 (s, 3H, 19-CH3); 0.85 (s,
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 220.9; 140.4; 121.3;
109.3; 64.4; 64.2; 51.8; 49.9; 47.5; 41.8; 36.8; 36.3; 35.8; 31.5;
31.4; 31.0; 30.7; 21.9; 20.3; 18.9; 13.5. MS (m/z/rel.int.): 330/3
(M+), 99/100. IR (KBr, (cm−1)): 1738 (C O). Analysis calculated
for C21H30O3 (M = 330.47): C, 76.33; H, 9.15; Found: C, 76.42;
H, 9.41. Rf = 0.79 (petroleum ether (40–70)/EtOAc = 75/25). Mp.
195–1197 ◦C. White powder-like material (as obtained after col-
umn chromatography).
2.8. General procedure for aminocarbonylation at atmospheric
pressure
A mixture of 7 (or 13 or 19) (1 mmol), palladium(II) acetate
(5.6 mg, 0.025 mmol), and PPh3 (13.1 mg, 0.05 mmol) were
dissolved in 10 mL DMF under argon. NEt3 (0.5 mL) and tert-
butylamine (0.30 mL, 3 mmol) (or another N-nucleophile) were
added. (The amino acid methyl esters (e–g) were used as
hydrochloride salts (1.1 mmol) and were added together with the
catalyst.) The atmosphere was changed to CO (1 bar), and the reac-
tion was conducted at 50 ◦C for the appropriate reaction time (see
Table 1). The composition of the reaction mixture was checked by
TLC. The solvent was evaporated, and the residue was dissolved
in 20 mL of CHCl3. It was washed in turn with 2 mL × 20 mL of
water, 20 mL portions of 5% HCl, saturated NaHCO3, and brine. The
organic layer was separated, dried over Na2SO4 and evaporated.
Column chromatography (silica gel, CHCl3/EtOAc 98/2, 95/5, 90/10,
or 80/20; the exact ratios are given below) resulted in the target
carboxamides (8, 14, and 20).
Androst-5-ene-11-one-3,17-bis(ethylene ketal) (17): 1H NMR
(CDCl3, 400 MHz): 5.30 (br s, 1H, 6-CH); 3.76–3.94 (m, 9H,
2xO(CH2)2O + 9-CH); 2.50–2.62 (m, 2H, 12-CH2); 1.14–2.12 (m,
14H, skeleton protons); 1.20 (s, 3H, 19-CH3); 0.79 (s, 3H, 18-CH3);
13C NMR (100.58 MHz, CDCl3): 211.0; 141.2; 120.5; 117.9; 109.1;
65.3; 64.5; 64.3; 64.2; 60.4; 50.1; 48.9; 48.6; 41.6; 37.0; 35.1;
34.3; 33.8; 31.9; 30.8; 22.5; 18.0; 14.8. MS (m/z/rel.int.): 388/4
(M+), 99/100. IR (KBr, (cm−1)): 1698 (C O). Analysis calculated for
C
23H32O5 (M = 388.50): C, 71.11; H, 8.30; Found: C, 70.95; H, 8.20.
Rf = 0.45 (petroleum ether (40–70)/EtOAc = 7/3). Mp. 180–181 ◦C.
White powder-like material.
The diiodo substrate 3 (0.5 mmol) was dissolved in 10 mL of 2-
butanone. The other reagents and precatalysts were used in the
amount as given above. The work-up procedure was also identical
and resulted in carboxamides 4.
2.9.2. Iodoalkenes
3,17-Diiodo-androst-3,5,16-triene (3): 1H NMR (CDCl3,
400 MHz): 6.55 (br s, 1H, 4-CH); 6.12 (br s, 1H, 16-CH); 5.36 (br s,
1H, 6-CH); 2.58–2.63 (m, 2H, 7-CH2); 1.01–2.22 (m, 13H, skeleton
Table 1
Palladium-catalyzed aminocarbonylation of androstane-based iodo-alkene substrates 3, 7, 13 and 19.a
Entry
Substr.
Amine
Amine:substrate ratio
Reaction time [h]
Conv.b [%]
Isolated yield (amide) [%]
1
2
3
4
5
6
7
8
3d
3d
3d
3d
3d
7
7
7
7
7
13
13
13
13
13
13
13
19
19
t-BuNH2 (a)
piperidine (c)
morpholine (d)
morpholine (d)
ProOMe (g)
3
20
90
200
90
200
90
200
48
48
48
20
20
20
20
20
20
60
90
90
>98c
>98c
>98c
>95c
>98c
>98
>98
55
35
30
>98
>98
60
78 (4a)
80 (4c)
77 (4d)
74 (4d)
75 (4g)
80 (8b)
80 (8c)
n.d.e
30 (8d)
22 (8g)
82 (14a)
80 (14b)
41 (14c)
30 (14d)
81 (14e)
78 (14f)
77 (14g)
82 (20a)
20 (20c)
1.5
1.5
1.5
1.1
2
1.5
1.5
1.5
1.1
3
aniline (b)
piperidine (c)
piperidine (c)
morpholine (d)
ProOMe (g)
t-BuNH2 (a)
aniline (b)
piperidine (c)
morpholine (d)
GlyOMe (e)
AlaOMe (f)
ProOMe (g)
t-BuNH2 (a)
piperidine (c)
9
10
11
12
13
14
15
16
17
18
19
2
1.5
1.5
1.1
1.1
1.1
3
40
>98
>98
>98
>98
30
1.5
a
Reaction conditions: 0.025 mmol Pd(OAc)2; 0.05 mmol PPh3, 1 mmol substrate; 10 mL DMF; reaction temp.: 50 ◦C; p(CO) = 1 bar (unless otherwise stated).
Based on the iodoalkene substrate; determined by GC (unless otherwise stated).
Based on the iodoalkene substrate; determined by 1H NMR.
2-Butanone (10 mL) was used as solvent.
b
c
d
e
Not determined.

P. Ács et al. / Steroids 76 (2011) 280–290
283
protons); 1.00 (s, 3H, 19-CH3); 0.78 (s, 3H, 18-CH3); 13C NMR
(100.58 MHz, CDCl3): 142.8; 139.3; 137.6; 124.2; 112.8; 95.2; 55.0;
50.3; 48.6; 37.4; 36.5; 36.3; 34.7; 33.9; 31.1; 31.0; 21.0; 19.1; 15.4.
MS (m/z/rel.int.): 506/100 (M+), 491/3, 364/2, 219/12, 145/21. IR
1596 (C C). Analysis calculated for C29H44O2N2 (M = 452.68): C,
76.95; H, 9.80; N, 6.19; Found: C, 76.81; H, 9.95; N, 5.96. Rf = 0.74
(CHCl3/EtOH = 8/2). Mp. 116–118 ◦C. White crystalline material (as
obtained after column chromatography).
(KBr, (cm−1)): 1620, 1601 (C C). Analysis calculated for C19H24 2
I
3,17-Bis(N,N-pentan-1,5-diylcarboxamido)-androst-3,5,16-
triene (4c): 1H NMR (CDCl3, 400 MHz): 5.92 (br s, 1H, 16-CH);
5.63 (br s, 1H, 6-CH); 5.44 (br s, 1H, 4-CH); 3.35–3.60 (m,
8H, 2xN(CH2)2); 0.90–2.30 (m, 21H, skeleton protons+ (CH2)3
(piperidine)); 1.02 (s, 3H, 19-CH3); 0.94 (s, 3H, 18-CH3); 13C
NMR (100.58 MHz, CDCl3): 171.3; 167.8; 148.9; 140.6; 130.8;
129.3; 128.4; 126.2; 56.8; 48.5; 48.4 (br); 42.3 (br); 34.9; 34.1;
33.3; 32.0; 31.6; 30.1; 26.2 (br); 24.7; 23.8; 20.6; 19.0; 16.7.
IR (KBr, (cm−1)): 1628 (CON); 1597 (C C). Analysis calcu-
lated for C31H44O2N2 (M = 476.70): C, 78.11; H, 9.30; N, 5.88;
Found: C, 78.01; H, 9.46; N, 5.60. Rf = 0.57 (CHCl3/EtOAc = 7/3).
Pale-yellow viscous material (as obtained after column
chromatography).
3,17-Bis(N,N-3-oxapentan-1,5-diylcarboxamido)-androst-
3,5,16-triene (4d): 1H NMR (CDCl3, 400 MHz): 6.14 (br s, 1H,
16-CH); 6.01 (br s, 1H, 4-CH); 5.55 (br s, 1H, 6-CH); 3.66 (br s,
8H, 2xO(CH2)2); 3.59 (br s, 8H, 2xN(CH2)2); 1.00–2.38 (m, 15H,
skeleton protons); 0.99 (s, 3H, 19-CH3); 0.78 (s, 3H, 18-CH3); 13C
NMR (100.58 MHz, CDCl3): 171.7; 170.5; 140.7; 137.6; 130.0;
127.3; 116.2; 112.8; 67.2 (double intensity); 55.1; 54.0 (br); 50.3;
48.7; 46.5 (br); 36.4; 36.3; 35.2; 33.9; 31.5; 31.0; 23.9; 21.0; 19.3;
15.4. IR (KBr, (cm−1)): 1610 (v br, CON, C C). Analysis calculated
for C29H40O4N2 (M = 480.65): C, 72.47; H, 8.39; N, 5.83; Found:
C, 72.21; H, 8.49; N, 5.62. Rf = 0.73 (CHCl3/EtOAc = 1/1). Orange
viscous material (as obtained after column chromatography).
3,17-Bis(N,N-(1ꢀ-Methoxycarbonyl-butan-1,4-diyl)-
(M = 506.21): C, 45.08; H, 4.78; Found: C, 45.23; H, 4.89. Rf = 0.90
(hexán/EtOAc = 99/1). Mp. 135–136 ◦C. Pale yellow crystalline
material.
3-Iodo-androst-3,5-diene-17-ethylene ketal (7): 1H NMR
(CDCl3, 400 MHz): 6.51 (br s, 1H, 4-CH); 5.32 (br s, 1H, 6-
CH); 3.78–3.93 (m, 4H, –O(CH2)2O–); 2.55–2.63 (m, 2H, 7-CH2);
0.80–2.24 (m, 15H, skeleton protons); 0.90 (s, 3H, 19-CH3); 0.78
(s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 142.3; 139.3;
124.4; 119.3; 94.8; 65.2; 64.5; 50.7; 47.9; 45.8; 37.3; 36.3; 34.3;
34.2; 31.9; 30.9; 30.5; 22.6; 20.4; 18.9; 14.3. MS (m/z/rel.int.):
440/41 (M+), 378/100, 352/66, 337/17, 99/68. IR (KBr, (cm−1)):
1620, 1603 (C C). Analysis calculated for C21H29O2I (M = 440.36):
C, 57.28; H, 6.64; Found: C, 57.12; H, 6.82. Rf = 0.83 (petroleum
ether (40–70)/EtOAc = 7/3). Mp. 144–147 ◦C. Pale yellow crystalline
material.
3-Iodo-androst-2,4-diene-17-ethylene ketal (7ꢀ): 1H NMR
(CDCl3, 400 MHz): 5.17 (br s, 1H, 2-CH); 5.68 (br s, 1H, 4-
CH); 3.80–3.94 (m, 4H, –O(CH2)2O–); 2.53–2.62 (m, 2H, 1-CH2);
0.80–2.24 (m, 15H, skeleton protons); 0.90 (s, 3H, 19-CH3); 0.78 (s,
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 148.7; 131.4; 125.0;
119.2; 88.3; 65.2; 64.5; 54.3; 49.7; 45.8; 36.5; 36.4; 34.2; 34.1;
30.8; 30.5; 30.4; 22.7; 20.9; 17.0; 14.2. MS (m/z/rel.int.): 440/92
(M+), 325/12, 395/7, 99/100. Analysis calculated for C21H29O2I
(M = 440.36): C, 57.28; H, 6.64; Found: C, 57.07; H, 6.85. Rf = 0.79
(petroleum ether (40–70)/EtOAc = 7/3). Yellow viscous material (as
obtained after column chromatography).
carboxamido)-carboxamido-androst-3,5,16-triene (4 g): 1H
NMR (CDCl3, 400 MHz): 6.12 (br s, 1H, 16-CH); 6.00 (br s, 1H,
4-CH); 5.58 (br s, 1H, 6-CH); 5.52 (br s, 2H, NCH); 3.72 (s, 6H, 2x
OCH3); 3.58–3.70 (m, 4H, 2xNCH2); 0.80–2.45 (m, 23H, skeleton
protons+ 2x(CH2)2 (proline)); 0.98 (s, 3H, 19-CH3); 0.78 (s, 3H,
18-CH3); 13C NMR (100.58 MHz, CDCl3): 173.3; 173.1; 170.8;
169.2; 146.8; 141.1; 137.7; 137.6; 116.0; 112.8; 59.0; 55.1; 54.4;
52.4; 50.3; 48.7; 36.4; 35.5; 35.2; 34.0; 33.9; 33.6; 33.5; 31.6; 31.3;
31.1; 31.0; 29.5; 25.6; 23.3; 21.0; 19.2; 15.4. IR (KBr, (cm−1)): 1743
(C O); 1618 (v br, CON, C C). Analysis calculated for C33H44O6N2
(M = 564.72): C, 70.19; H, 7.85; N, 4.96; Found: C, 70.03; H, 7.96;
N, 4.71. Rf = 0.73 (CHCl3/EtOAc = 8/2). Yellow viscous material (as
obtained after column chromatography).
3-(N-phenylcarboxamido)-androst-3,5-diene-17-(ethylene
ketal) (8b): 1H NMR (CDCl3, 400 MHz): 7.52–7.62 (m, 2H,
Ph(ortho)); 7.30–7.38 (m, 2H, Ph(meta)); 7.12 (t, 7.4 Hz, 1H,
Ph(para)); 6.85 (br s, 1H, 4-CH); 5.80 (br s, 2H, 6-CH + NH);
3.80–3.95 (m, 4H, OCH2CH2O); 0.80–2.56 (m, 17H, skeleton
protons); 0.91 (s, 3H, 18-CH3); 0.95 (s, 3H, 19-CH3); 13C NMR
(100.58 MHz, CDCl3): 166.4; 140.8; 138.1; 134.1; 130.8; 129.9;
124.0; 119.9; 119.3; 114.3; 65.2; 64.5; 54.6; 50.6; 49.8; 47.8;
45.8; 36.5; 34.7; 34.1; 33.4; 30.4; 22.6; 21.1; 20.5; 19.0; 14.3.
MS (m/z/rel.int.): 433/30 (M+), 371/13; 341/100; 99/28. IR
(KBr, (cm−1)): 1659 (CON). Analysis calculated for C28H35O3N
(M = 433.59): C, 77.56; H, 8.14; N, 3.23; Found: C, 77.37; H, 8.40; N,
3.01. Rf = 0.70 (CHCl3/EtOAc = 95/5). Mp. 137–139 ◦C. Pale brown
solid material.
17-Iodo-androst-5,16-diene-3-ethylene ketal (13): 1H NMR
(CDCl3, 400 MHz): 6.12 (br s, 1H, 16-CH); 5.35 (br s, 1H, 6-
CH); 3.88–3.97 (m, 4H, –O(CH2)2O–); 2.53–2.60 (m, 2H, 4-CH2);
0.80–2.18 (m, 15H, skeleton protons); 1.05 (s, 3H, 19-CH3); 0.75
(s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 140.6; 137.5;
121.6; 112.7; 109.4; 64.4; 64.2; 54.8; 50.1; 49.9; 41.8; 36.9; 36.2;
36.1; 33.7; 31.1; 31.0 (double intensity); 20.8; 18.8; 15.1. MS
(m/z/rel.int.): 440/5 (M+), 99/100, 55/8. IR (KBr, (cm−1)): 1577
(C C). Analysis calculated for C21H29O2I (M = 440.36): C, 57.28; H,
6.64; Found: C, 57.01; H, 6.80. Mp. 183–186 ◦C. Pale yellow crys-
talline material.
11-Iodo-androst-5,9(11)-diene-3,17-bis(ethylene ketal) (19):
1H NMR (CDCl3, 400 MHz): 6.57 (d, 6.2 Hz, 1H, 4-CH); 3.80-3.98
(m, 8H, O(CH2)2O); 3.62 (dt, 13.5 Hz, 3.5 Hz, 1H); 3.20 (dd, 16.3 Hz,
3.2 Hz, 1H); 2.70 (d, 16.4 Hz, 1H); 2.58 (d, 13.5 Hz, 1H); 1.22–2.15
(m, 12H, skeleton protons); 1.41 (s, 3H, 19-CH3); 0.90 (s, 3H, 18-
CH3); 13C NMR (100.58 MHz, CDCl3): 145.2; 139.6; 121.3; 118.4;
109.1; 93.5; 65.2; 64.4; 64.3; 64.2; 55.2; 51.7; 47.5; 45.3; 42.5;
41.9; 40.8; 34.1; 32.6; 29.4; 23.5; 20.1; 13.9. MS (m/z/rel.int.): 498/2
(M+), 371/3, 99/100. Analysis calculated for C23H31O4I (M = 498.40):
C, 55.43; H, 6.27; Found: C, 55.23; H, 6.40. Rf = 0.72 (petroleum
ether (40–70)/EtOAc = 7/3). Orange oil (as obtained after column
chromatography).
2.10. Carboxamides
3,17-Di-(N-tert-butylcarboxamido)-androst-3,5,16-triene
(4a): 1H NMR (CDCl3, 400 MHz): 6.66 (br s, 1H, NH); 6.20 (br s, 1H,
16-CH); 5.69 (br s, 1H, NH); 5.52 (br s, 1H, 6-CH); 5.45 (br s, 1H,
4-CH); 0.96–2.40 (m, 15H, skeleton protons); 1.34 (s, 9H, tBu); 1.32
(s, 9H, tBu); 1.02 (s, 3H, 19-CH3); 0.92 (s, 3H, 18-CH3); 13C NMR
(100.58 MHz, CDCl3): 167.7; 165.6; 151.7; 141.2; 134.1; 132.7;
129.6; 129.0; 56.8; 51.1; 48.4; 46.5; 34.9; 34.7; 33.4; 31.7; 31.3;
30.0; 28.9; 28.8; 22.0; 20.7; 18.8; 16.4. MS (m/z/rel.int.): 452/100
(M+), 395/21, 380/30, 324/12. IR (KBr, (cm−1)): 1645 (CON);
3-(N-phenylcarboxamido)-androst-2,4-diene-17-(ethylene
ketal) (8ꢀb): 1H NMR (CDCl3, 400 MHz): 1H NMR (CDCl3, 400 MHz):
7.50–7.62 (m, 2H, Ph(ortho)); 7.30–7.40 (m, 3H, Ph(meta)); 7.10
(t, 7.4 Hz, 1H, Ph(para)); 6.81 (br s, 1H, 2-CH); 6.01 (br s, 1H, NH);
5.96 (br s, 1H, 4-CH); 3.80–3.92 (m, 4H, OCH2CH2O); 0.80–2.50 (m,
17H, skeleton protons); 0.93 (s, 3H, 18-CH3); 0.97 (s, 3H, 19-CH3);
13C NMR (100.58 MHz, CDCl3): 165.3; 148.4; 140.8; 138.0; 134.3;
131.7; 130.0; 127.3; 119.3; 114.8; 64.5; 63.7; 54.7; 50.8; 48.0;
45.7; 37.3; 35.8; 34.6; 34.1; 31.5; 30.6; 22.0; 21.0; 17.3; 13.7.

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P. Ács et al. / Steroids 76 (2011) 280–290
MS (m/z/rel.int.): 433/81 (M+), 341/40; 281/39; 207/35; 99/100.
(Identified in the 15/85 mixture of 8ꢀb/8c.)
35.8; 34.9; 33.4; 31.3; 31.2; 22.0; 20.4; 19.0; 13.7. MS (m/z/rel.int.):
389/29 (M+), 297/100. IR (KBr, (cm−1)): 1733 (C O); 1662 (CON);
1595 C C). Analysis calculated for C26H31O2N (M = 389.54): C,
80.17; H, 8.02; N, 3.60; Found: C, 80.02; H, 8.25; N, 3.37. Rf = 0.78
(CHCl3/EtOAc = 95/5). Beige viscous material.
3-(N,N-pentan-1,5-diylcarboxamido)-androst-3,5-diene-17-
(ethylene ketal) (8c): 1H NMR (CDCl3, 400 MHz): 5.89 (br s, 1H,
4-CH); 5.41 (br s, 1H, 6-CH); 3.73–3.90 (m, 4H, OCH2CH2O); 3.40
(br s, 4H, N(CH2)2); 0.80–2.30 (m, 23H, skeleton protons+ (CH2)3);
0.89 (s, 3H, 18-CH3); 0.81 (s, 3H, 19-CH3); 13C NMR (100.58 MHz,
CDCl3): 171.3; 140.2; 130.7; 128.6; 119.3; 116.1; 65.1; 64.5; 54.6;
50.7; 49.8; 48.0; 45.8; 37.2; 36.5; 34.7; 34.1; 33.4; 32.0; 31.3; 30.6;
24.7; 23.8; 22.7; 20.4; 19.1; 14.2. MS (m/z/rel.int.): 425/100 (M+),
363/14; 324/15; 99/38. IR (KBr, (cm−1)): 1633 (CON). Analysis
calculated for C27H39O3N (M = 425.61): C, 76.20; H, 9.24; N, 3.29;
Found: C, 76.00; H, 9.41; N, 3.11. Rf = 0.58 (CHCl3/EtOAc = 8/2).
Yellow highly viscous material.
3-(N,N-pentan-1,5-diylcarboxamido)-androst-2,4-diene-17-
(ethylene ketal) (8ꢀc): 1H NMR (CDCl3, 400 MHz): 5.70 (br s, 1H,
2-CH); 5.47 (br s, 1H, 4-CH); 3.75-3.90 (m, 4H, OCH2CH2O); 3.40
(br s, 4H, N(CH2)2); 0.80–2.30 (m, 23H, skeleton protons+ (CH2)3);
0.89 (s, 3H, 18-CH3); 0.79 (s, 3H, 19-CH3); 13C NMR (100.58 MHz,
CDCl3): 170.0; 147.0; 131.9; 126.5; 122.8; 119.2; 65.1; 64.4; 54.6;
50.7; 49.8; 48.0; 45.8; 37.8; 36.5; 34.7; 34.1; 33.4; 32.0; 31.2; 30.5;
24.6; 23.8; 22.6; 21.1; 19.1; 14.2. MS (m/z/rel.int.): 425/80 (M+),
424/100; 380/53; 362/13; 99/71. IR (KBr, (cm−1)): 1633 (CON).
(Identified in the 15/85 mixture of 8ꢀc/8c.)
3-(N,N-3-oxapentan-1,5-diylcarboxamido)-androst-3,5-
diene-17-(ethylene ketal) (8d): 1H NMR (CDCl3, 400 MHz):
5.97 (br s, 1H, 4-CH); 5.52 (br s, 1H, 6-CH); 3.76–3.92 (m, 4H,
OCH2CH2O); 3.62 (br s, 4H, O(CH2)2); 3.55 (br s, 4H, N(CH2)2);
0.80–2.36 (m, 17H, skeleton protons); 0.90 (s, 3H, 18-CH3); 0.84 (s,
3H, 19-CH3); 13C NMR (100.58 MHz, CDCl3): 171.7; 140.3; 130.2;
129.8; 119.5; 116.0; 67.2; 67.1; 65.4; 64.7; 54.8; 50.9; 48.2; 46.0;
37.4; 35.0; 34.3; 33.6; 32.2; 31.5; 30.8; 24.0; 22.9; 20.7; 19.3; 14.5.
MS (m/z/rel.int.): 427/71 (M+), 382/38; 99/100. IR (KBr, (cm−1)):
1632 (CON). Analysis calculated for C26H37O4N (M = 427.58): C,
73.03; H, 8.72; N, 3.28; Found: C, 72.88; H, 8.89; N, 3.10. Rf = 0.50
(CHCl3/EtOAc = 7/3). Mp. 106–108 ◦C. Yellow crystalline material.
3-(N,N-3-oxapentan-1,5-diylcarboxamido)-androst-2,4-
diene-17-(ethylene ketal) (8ꢀd): 1H NMR (CDCl3, 400 MHz):
5.78 (br s, 1H, 2-CH); 5.52 (br s, 1H, 4-CH); 3.76–3.90 (m, 4H,
OCH2CH2O); 3.62 (br s, 4H, O(CH2)2); 3.55 (br s, 4H, N(CH2)2);
0.80–2.36 (m, 17H, skeleton protons); 0.90 (s, 3H, 18-CH3); 0.82 (s,
3H, 19-CH3); 13C NMR (100.58 MHz, CDCl3): 170.3; 147.8; 132.2;
131.4; 128.7; 119.5; 67.2; 67.1; 65.4; 64.7; 54.8; 50.0; 48.2; 46.0;
38.1; 36.7; 34.4; 33.6; 32.2; 31.6; 30.7; 24.0; 22.8; 21.3; 17.6; 14.5.
(Identified in the 22/78 mixture of 8ꢀd/8d.)
3-(N-phenylcarboxamido)-androst-2,4-diene-17-one (9ꢀb):
MS (m/z/rel.int.): 389/100 (M+), 374/25; 297/67; 281/71; 207/85.
(Identified in the 8/92 mixture of 9ꢀb/9b.)
3-(N,N-pentan-1,5-diylcarboxamido)-androst-3,5-diene-17-
one (9c): 1H NMR (CDCl3, 400 MHz): 5.89 (br s, 1H, 4-CH); 5.42 (br
s, 1H, 6-CH); 3.40 (br s, 4H, N(CH2)2); 0.80–2.41 (m, 23H, skeleton
protons+ (CH2)3); 0.90 (s, 3H, 18-CH3); 0.81 (s, 3H, 19-CH3); 13C
NMR (100.58 MHz, CDCl3): 220.6; 171.2; 140.3; 131.0; 128.3;
125.8; 54.7; 51.7; 50.8; 48.2; 47.5; 37.7; 35.7; 34.7; 33.3; 31.3;
30.7; 26.1; 24.6; 23.7; 21.7; 20.2; 19.0; 17.2; 13.6. MS (m/z/rel.int.):
381/100 (M+), 366/15; 297/22. IR (KBr, (cm−1)): 1736 (C O); 1633
(CON); 1608 C C). Analysis calculated for C25H35O2N (M = 381.56):
C, 78.70; H, 9.25; N, 3.67; Found: C, 78.55; H, 9.43; N, 3.44. Rf = 0.49
(CHCl3/EtOAc = 8/2). Mp. 102–103 ◦C. Yellow crystalline material.
3-(N,N-pentan-1,5-diylcarboxamido)-androst-2,4-diene-17-
one (9ꢀc): 1H NMR (CDCl3, 400 MHz): 5.70 (br s, 1H, 2-CH); 5.48 (br
s, 1H, 4-CH); 3.40 (br s, 4H, N(CH2)2); 0.80–2.41 (m, 23H, skeleton
protons+ (CH2)3); 0.90 (s, 3H, 18-CH3); 0.80 (s, 3H, 19-CH3); 13C
NMR (100.58 MHz, CDCl3): 220.6; 169.8; 146.3; 131.8; 122.8;
116.4; 51.7; 50.8; 47.8; 47.5; 37.2; 35.7; 34.7; 33.3; 31.4; 31.0;
30.0; 26.1; 24.6; 23.7; 21.7; 20.8; 19.0; 17.2; 13.8. MS (m/z/rel.int.):
381/77 (M+), 380/100; 365/40; 281/49; 207/65. (Identified in the
20/80 mixture of 9ꢀc/9c.)
3-(N,N-3-oxapentan-1,5-diylcarboxamido)-androst-3,5-
diene-17-one (9d): 1H NMR (CDCl3, 400 MHz): 6.00 (br s, 1H,
4-CH); 5.56 (br s, 1H, 6-CH); 3.64 (br s, 4H, O(CH2)2); 3.58 (br
s, 4H, N(CH2)2); 0.80–2.36 (m, 17H, skeleton protons); 0.95 (s,
3H, 19-CH3); 0.90 (s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3):
220.9; 171.7; 140.5; 130.2; 130.0; 119.3; 67.2; 52.1; 51.4 (br);
51.2; 48.5; 47.8 (br); 47.9; 42.5 (br); 36.0; 35.1; 34.1; 33.5; 31.6;
31.1; 30.3; 23.9; 22.0; 21.1; 20.5; 19.3; 13.9. MS (m/z/rel.int.):
383/100 (M+), 297/70; 207/31. IR (KBr, (cm−1)): 1736 (C O), 1611
(br, CON, C C). Analysis calculated for C24H33O3N (M = 383.53): C,
75.16; H, 8.67; N, 3.65; Found: C, 75.08; H, 8.82; N, 3.46. Rf = 0.45
(CHCl3/EtOAc = 7/3). Mp. 98–100 ◦C. Yellow crystalline material.
3-(N,N-3-oxapentan-1,5-diylcarboxamido)-androst-2,4-
diene-17-one (9ꢀd): 1H NMR (CDCl3, 400 MHz): 5.84 (br s, 1H,
2-CH); 5.72 (br s, 1H, 4-CH); 3.64 (br s, 4H, O(CH2)2); 3.58 (br
s, 4H, N(CH2)2); 0.80–2.36 (m, 17H, skeleton protons); 0.90 (s,
3H, 18-CH3); 0.88 (s, 3H, 19-CH3); MS (m/z/rel.int.): 383/20 (M+);
382/23; 281/43; 207/100. (Identified in the 18/82 mixture of
9ꢀd/9d.)
3-(N,N-(1ꢀ-methoxycarbonyl-butan-1,4-diyl)-carboxamido)-
androst-3,5-diene-17-(ethylene ketal) (8 g): 1H NMR (CDCl3,
400 MHz): 6.12 (br s, 1H, 4-CH); 5.50 (br s, 1H, 6-CH); 4.40–4.49
(m, 1H, NCH); 3.75–3.90 (m, 4H, OCH2CH2O); 3.63 (s, 3H, OCH3);
3.50–3.62 (m, 2H, N(CH2)2); 0.80–2.36 (m, 21H, skeleton pro-
tons+ (CH2)2); 0.90 (s, 3H, 18-CH3); 0.82 (s, 3H, 19-CH3); 13C
NMR (100.58 MHz, CDCl3): 173.1; 169.3; 140.7; 131.8; 128.1;
119.5; 115.8; 65.4; 64.7; 58.9; 54.8; 50.9; 48.2; 46.0; 37.3; 34.9;
34.3; 33.6; 32.2; 31.6; 30.8; 23.3; 22.9; 22.8; 21.3; 20.8; 19.2;
14.5. MS (m/z/rel.int.): 469/26 (M+); 429/17; 341/60; 281/100. IR
(KBr, (cm−1)): 1740 (C O); 1628 (CON). Analysis calculated for
C28H39O5N (M = 469.62): C, 71.61; H, 8.37; N, 2.98; Found: C, 71.50;
H, 8.59; N, 2.73. Rf = 0.63 (CHCl3/EtOAc = 7/3). Mp. 146–148 ◦C. Pale
yellow crystalline material.
3-(N-phenylcarboxamido)-androst-3,5-diene-17-one (9b):
1H NMR (CDCl3, 400 MHz): 7.52–7.60 (m, 2H, Ph(ortho)); 7.29–7.38
(m, 2H, Ph(meta)); 7.10 (t, 7.4 Hz, 1H, Ph(para)); 6.90 (br s, 1H,
4-CH); 6.40 (br s, 1H, NH); 5.80 (br s, 2H, 6-CH); 0.85–2.60 (m,
17H, skeleton protons); 0.92 (s, 3H, 18-CH3); 0.98 (s, 3H, 19-CH3);
13C NMR (100.58 MHz, CDCl3): 220.9; 166.2; 140.9; 138.0; 134.2;
130.0; 129.0; 124.1; 120.0; 119.3; 54.8; 51.8; 50.9; 49.1; 47.7;
17-(N-tert-butylcarboxamido)-androst-5,16-diene-3-
ethylene ketal (14a): 1H NMR (CDCl3, 400 MHz): 6.12 (br s,
1H, 16-CH); 5.43 (br s, 1H, NH); 5.24 (br d, 4.2 Hz, 1H, 6-CH);
3.80–3.92 (m, 4H, OCH2CH2O); 2.48 (br d, 14.1 Hz, 1H, 7-CHa);
1.02–2.13 (m, 16H, skeleton protons); 1.30 (s, 9H, tBu); 0.98 (s,
3H, 19-CH3); 0.94 (s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3):
165.9; 152.0; 140.7; 134.3; 121.8; 109.5; 64.5; 64.3; 57.0; 51.2;
50.3; 46.6; 42.0; 36.9; 36.4; 34.9; 31.7; 31.5; 31.2; 30.4; 29.1 (triple
intensity); 20.9; 18.9; 16.5. MS (m/z/rel.int.): 413/6 (M+), 99/100.
IR (KBr, (cm−1)): 1652 (CON); 1600 (C C). Analysis calculated for
C26H39O3N (M = 413.60): C, 75.50; H, 9.50; N, 3.39; Found: C, 75.41;
H, 9.65; N, 3.21. Rf = 0.42 (CHCl3/EtOAc = 9/1). Mp. 218–219 ◦C.
Off-white crystalline material.
17-(N-phenylcarboxamido)-androst-5,16-diene-3-ethylene
ketal (14b): 1H NMR (CDCl3, 400 MHz): 7.50–7.58 (m, 3H,
NH + Ph(ortho)); 7.29 (t, 7.4 Hz, 2H, Ph(meta)); 7.05 (t, 7.4 Hz, 1H,
Ph(para)), 6.41 (br s, 1H, 16-CH); 5.35 (br d, 4.0 Hz, 1H, 6-CH);
3.78–3.96 (m, 4H, OCH2CH2O); 2.58 (br d, 14.1 Hz, 1H, 7-CHa);
1.07–2.30 (m, 16H, skeleton protons); 1.04 (s, 3H, 19-CH3); 1.05 (s,

P. Ács et al. / Steroids 76 (2011) 280–290
285
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 164.3; 151.4; 140.9;
138.3; 136.4; 129.2 (double intensity); 124.2; 121.7; 120.0 (double
intensity); 109.6; 64.6; 64.4; 56.9; 50.3; 47.0; 42.1; 37.0; 36.4;
34.9; 32.2; 31.6; 31.2; 30.4; 20.9; 19.0; 16.6. MS (m/z/rel.int.):
433/5 (M+), 281/4; 207/3; 99/100. IR (KBr, (cm−1)): 1663 (CON);
1594 (C C). Analysis calculated for C28H35O3N (M = 433.59): C,
77.56; H, 8.14; N, 3.23; Found: C, 77.43; H, 8.25; N, 3.07. Rf = 0.74
(CHCl3/EtOAc = 9/1). Mp. 256–257 ◦C. Beige crystalline material.
17-(N,N-pentan-1,5-diylcarboxamido)-androst-5,16-diene-
3-ethylene ketal (14c): 1H NMR (CDCl3, 400 MHz): 5.64 (br
s, 1H, 16-CH); 5.29 (br d, 4.2 Hz, 1H, 6-CH); 3.80–3.92 (m, 4H,
OCH2CH2O); 3.40–3.55 (m, 4H, N(CH2)2); 2.51 (br d, 14.1 Hz, 1H,
7-CHa); 1.02–2.13 (m, 22H, skeleton protons+ (CH2)3); 1.01 (s,
3H, 19-CH3); 1.00 (s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3):
168.1; 149.2; 140.8; 129.7; 121.8; 109.6; 64.6; 64.4; 56.9; 51.7;
50.3; 48.7; 42.0; 37.0; 36.4; 34.4; 32.4; 31.7; 31.2; 30.9; 27.9; 26.8
(br); 24.9; 20.8; 19.0; 16.8. MS (m/z/rel.int.): 425/6 (M+), 325/2;
99/100. IR (KBr, (cm−1)): 1626 (CON); 1593 (br) (C C, Ph). Analysis
calculated for C27H39O3N (M = 425.61): C, 76.20; H, 9.24; N, 3.29;
Found: C, 76.03; H, 9.45; N, 3.20. Rf = 0.60 (CHCl3/EtOAc = 7/3). Mp.
212–213 ◦C. Off-white crystalline material.
17-(N,N-3-oxapentan-1,5-diyl-carboxamido)-androst-5,16-
diene-3-ethylene ketal (14d): 1H NMR (CDCl3, 400 MHz): 5.73 (br
s, 1H, 16-CH); 5.32 (br s, 1H, 6-CH); 3.84–3.95 (m, 4H, OCH2CH2O);
3.50–3.66 (m, 8H, 2xNCH2CH2O); 2.54 (br d, 14.1 Hz, 1H, 7-CHa);
1.02-2.25 (m, 16H, skeleton protons); 1.03 (s, 3H, 19-CH3); 1.01 (s,
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 168.2; 148.4; 140.8;
131.3; 121.8; 109.6; 67.3(double intensity); 64.6; 64.4; 56.9; 50.3;
48.8; ca. 48.0 (br); 42.0; 37.1; 36.4; 34.4; 32.5; 31.7; 31.2; 30.5;
20.8; 19.0; 16.9. MS (m/z/rel.int.): 427/3 (M+), 207/3; 99/100. IR
(KBr, (cm−1)): 1633 (CON); 1593 (C C). Analysis calculated for
C26H37O4N (M = 427.58): C, 73.03; H, 8.72; N, 3.28; Found: C, 72.88;
H, 8.61; N, 3.11. Rf = 0.43 (CHCl3/EtOAc = 1/1). Mp. 171–172 ◦C.
Off-white crystalline material.
4.42–4.52 (m, 1H, NCH); 3.87–3.96 (m, 4H, OCH2CH2O); 3.70
(s, 3H, OCH3); 3.45–3.70 (m, 2H, NCH2); 2.53 (br d, 8 Hz, 1H,
7-CHa); 1.03–2.28 (m, 20H, skeleton protons+ CH2CH2); 1.03 (s,
3H, 19-CH3); 1.02 (s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3):
173.2/172.9; 167.3; 149.8/149.5; 140.8; 134.4/133.0; 121.7; 109.5;
64.6; 64.4; 58.8/58.7; 56.7/56.6; 52.3/52.2; 50.3; 49.4; 48.7/48.5;
42.0; 37.0; 36.4; 34.5/34.3; 32.6; 31.8; 31.2; 30.4/30.3; 29.4;
25.6/24.9; 20.8; 19.0; 16.6. MS (m/z/rel.int.): 469/10 (M+), 341/9;
207/12; 99/100. IR (KBr, (cm−1)): 1752 (COO); 1631 (CON);
1595 (C C). Analysis calculated for C28H39O5N (M = 469.62): C,
71.61; H, 8.37; N, 2.98; Found: C, 71.44; H, 8.18; N, 2.83. Rf = 0.51
(CHCl3/EtOAc = 9/1). Mp. 185–186 ◦C. White crystalline material.
17-(N-tert-butylcarboxamido)-androst-4,16-diene-3-one
(15a): 1H NMR (CDCl3, 400 MHz): 6.09 (br s, 1H, 16-CH); 5.63 (br
s, 1H, 16-CH); 5.48 (br s, 1H, NH); 0.83–2.40 (m, 17H, skeleton
protons); 1.30 (s, 9H, tBu); 1.13 (s, 3H, 19-CH3); 0.94 (s, 3H, 18-
CH3); 13C NMR (100.58 MHz, CDCl3): 199.3; 171.0; 165.5; 151.5;
133.6; 123.8; 55.9; 54.0; 51.0; 46.3; 38.6; 35.4; 34.4; 33.8; 33.7;
32.6; 31.7; 31.3; 29.5; 28.8 (triple intensity); 20.6; 17.1; 16.3. MS
(m/z/rel.int.): 369/100 (M+), 352/41, 297/82. IR (KBr, (cm−1)): 1666
(C O); 1652 (CON); 1597 (C C). Analysis calculated for C24H35O2N
(M = 369.55): C, 78.00; H, 9.55; N, 3.79; Found: C, 77.81; H, 9.68;
N, 3.51. Rf = 0.56 (CHCl3/EtOAc = 9/1). Mp. 221–222 ◦C. Pale yellow
solid material.
17-(N-phenylcarboxamido)-androst-4,16-diene-3-one
(15b): 1H NMR (CDCl3, 400 MHz): 7.98 (br s, 1H, NH); 7.58
(d, 7 Hz, 2H, Ph(ortho)); 7.20–7.25 (m, 2H, Ph(meta)); 7.02 (t,
7 Hz, 1H, Ph(para)), 6.38 (br s, 1H, 16-CH); 5.68 (br s, 1H, 4-CH);
0.80-2.41 (m, 17H, skeleton protons); 1.12 (s, 3H, 19-CH3); 1.03 (s,
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 199.7; 171.3; 164.0;
150.6; 138.2; 135.9; 128.8 (double intensity); 123.8; 119.7 (double
intensity); 55.7; 54.1; 46.7; 38.7; 35.5; 34.3; 33.8; 33.7; 32.6; 31.8;
31.7; 20.7; 17.1; 16.3. MS (m/z/rel.int.): 389/44 (M+), 297/100;
281/20; 207/40. IR (KBr, (cm−1)): 1673 (C O); 1651 (CON);
1595 (C C). Analysis calculated for C26H31O2N (M = 389.54): C,
80.17; H, 8.02; N, 3.60; Found: C, 80.01; H, 8.22; N, 3.37. Rf = 0.59
(CHCl3/EtOAc = 9/1). Mp. 172–173 ◦C. Pale brown solid material.
17-(N,N-pentan-1,5-diylcarboxamido)-androst-4,16-diene-
3-one (15c): 1H NMR (CDCl3, 400 MHz): 5.67 (br s, 2H,
4-CH + 16-CH); 3.48 (br s, 4H, N(CH2)2); 1.02–2.13 (m, 23H,
skeleton protons+ (CH2)3); 1.18 (s, 3H, 19-CH3); 1.03 (s, 3H, 18-
CH3); 13C NMR (100.58 MHz, CDCl3): 199.4; 171.0; 167.6; 148.7;
129.4; 123.8; 55.9; 54.1; 48.4; 48.2 (br); 42.1 (br); 38.7; 35.5; 33.9;
33.8 (double intensity); 32.7; 32.0; 31.8; 26.7 (br); 25.8 (br); 24.6;
20.6; 17.1; 16.6. MS (m/z/rel.int.): 381/69 (M+), 366/100; 258/12. IR
(KBr, (cm−1)): 1674 (C O); 1630 (CON); 1596 (C C, Ph). Analysis
calculated for C25H35O2N (M = 381.56): C, 78.70; H, 9.25; N, 3.67;
Found: C, 78.55; H, 9.41; N, 3.50. Rf = 0.34 (CHCl3/EtOAc = 9/1).
Orange viscous material.
17-(N-methoxycarbonylmethylcarboxamido)-androst-5,16-
diene-3-ethylene ketal (14e): 1H NMR (CDCl3, 400 MHz): 6.41
(br s, 1H, 16-CH); 6.19 (br s, 1H, NH); 5.34 (br s, 1H, 6-CH); 4.08
(d, 4.8 Hz, 2H, NCH2); 3.88–3.98 (m, 4H, OCH2CH2O); 3.75 (s, 3H,
OCH3); 2.47 (br d, 14.2 Hz, 1H, 7-CHa); 1.06–2.23 (m, 16H, skeleton
protons); 1.03 (s, 3H, 19-CH3); 1.00 (s, 3H, 18-CH3); 13C NMR
(100.58 MHz, CDCl3): 170.9; 166.0; 150.1; 140.8; 137.0; 121.8;
109.6; 64.6; 64.4; 56.9; 52.5; 50.3; 46.6; 42.0; 41.2; 37.0; 36.4; 34.9;
32.0; 31.5; 31.2; 30.4; 20.9; 19.0; 16.5. MS (m/z/rel.int.): 429/3
(M+), 207/6; 99/100. IR (KBr, (cm−1)): 1735 (COO); 1646 (CON);
1592 (C C). Analysis calculated for C25H35O5N (M = 429.56): C,
69.90; H, 8.21; N, 3.26; Found: C, 69.80; H, 8.35; N, 3.03. Rf = 0.48
(CHCl3/EtOAc = 7/3). Mp. 192–193 ◦C. White crystalline material.
17-(N-(1-methoxycarbonylethyl)-carboxamido)-androst-
5,16-diene-3-ethylene ketal (14f): 1H NMR (CDCl3, 400 MHz):
6.35 (br s, 1H, 16-CH); 6.25 (br d, 7.1 Hz, 1H, NH); 5.30 (br d,
4.2 Hz; 1H, 6-CH); 4.59 (qi, 7.1 Hz; 1H, NCH); 3.85–3.93 (m,
4H, OCH2CH2O); 3.70 (s, 3H, OCH3); 2.50 (br d, 14.0 Hz, 1H,
7-CHa); 1.06–2.22 (m, 16H, skeleton protons); 1.39 (d, 7.1 Hz,
3H, CHCH3); 1.02 (s, 3H, 19-CH3); 0.98 (s, 3H, 18-CH3); 13C NMR
(100.58 MHz, CDCl3): 173.9; 165.5; 150.3; 140.8; 137.0; 121.8;
109.6; 64.6; 64.4; 56.9; 52.6; 50.2; 47.9; 46.6; 42.0; 37.0; 36.4;
34.9; 31.9; 31.5; 31.3; 30.4; 20.9; 19.0; 18.8; 16.5. MS (m/z/rel.int.):
443/3 (M+), 341/5; 208/8; 99/100. IR (KBr, (cm−1)): 1758 (COO);
1639 (CON); 1586 (C C). Analysis calculated for C26H37O5N
(M = 443.58): C, 70.40; H, 8.41; N, 3.16; Found: C, 70.22; H, 8.30;
N, 3.01. Rf = 0.60 (CHCl3/EtOAc = 8/2). Mp. 172–173 ◦C. Off-white
crystalline material.
17-(N,N-3-oxapentan-1,5-diylcarboxamido)-androst-4,16-
diene-3-one (15d): 1H NMR (CDCl3, 400 MHz): 5.73 (br s, 1H,
16-CH); 5.70 (br s, 1H, 6-CH); 3.50–3.68 (m, 8H, 2xNCH2CH2O);
0.93–2.43 (m, 17H, skeleton protons); 1.20 (s, 3H, 19-CH3); 1.08 (s,
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 199.3; 170.7; 167.7;
147.9; 131.0; 123.9; ca. 67.2 (br); 67.0 (double intensity); 55.9;
54.1; ca. 51.0 (br); 48.4; 38.7; 35.5; 33.9; 33.8 (double intensity);
32.6; 32.0; 31.8; 20.6; 17.1; 16.6. MS (m/z/rel.int.): 383/100
(M+), 368/90; 297/31. IR (KBr, (cm−1)): 1675 (C O); 1634 (CON);
1596 (C C). Analysis calculated for C24H33O3N (M = 383.53): C,
75.16; H, 8.67; N, 3.65; Found: C, 75.01; H, 8.79; N, 3.47. Rf = 0.26
(CHCl3/EtOAc = 8/2). Mp. 154–155 ◦C. Off-white solid material.
17-(N-methoxycarbonylmethylcarboxamido)-androst-4,16-
diene-3-one (15e): 1H NMR (CDCl3, 400 MHz): 6.35 (br s, 2H,
16-CH + NH); 5.65 (br s, 1H, 4-CH); 4.01 (d, 4.8 Hz, 2H, NCH2);
3.70 (s, 3H, OCH3); 0.90–2.40 (m, 17H, skeleton protons); 1.15 (s,
3H, 19-CH3); 0.98 (s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3):
17-(N,N-(1ꢀ-methoxycarbonyl-butan-1,4-diyl)-
carboxamido)-androst-5,16-diene-3-ethylene ketal (14g) (ca.
2/1 mixture of two C(O)N rotamers): 1H NMR (CDCl3, 400 MHz):
6.06/5.98 (minor/major) (br s, 1H, 16-CH); 5.32 (br s, 1H, 6-CH);

286
P. Ács et al. / Steroids 76 (2011) 280–290
366/20; 297/100. IR (KBr, (cm−1)): 1747 (COO); 1674 (C O);
1635 (CON); 1590 (C C). Analysis calculated for C26H35O4N
(M = 425.57): C, 73.38; H, 8.29; N, 3.29; Found: C, 73.24; H, 8.15; N,
3.11. Rf = 0.35 (CHCl3/EtOAc = 8/2). Yellow viscous material.
11-(N-tert-butylcarboxamido)-androst-5,9(11)-dien-3,17-
di(ethylene ketal) (20a): 1H NMR (CDCl3, 400 MHz): 5.48 (br d, 1H,
5.1 Hz, 6-CH); 5.19 (br s, 1H, NH); 3.80–3.95 (m, 8H, OCH2CH2O);
1.20–2.55 (m, 16H, skeleton protons); 1.36 (s, 3H, 19-CH3); 1.34
(s, 9H, tBu); 0.95 (s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3):
174.0; 140.1; 139.4; 127.9; 121.8; 119.0; 108.9; 65.1; 64.4; 64.3;
64.2; 51.2; 47.0; 43.8; 42.0; 41.6; 38.0; 36.6; 34.3; 33.4; 31.3; 28.6;
24.3; 23.9; 14.2; 13.3. MS (m/z/rel.int.): 471/15 (M+), 426/8, 399/22,
319/9, 207/21, 99/100. IR (KBr, (cm−1)): 1654 (CON). Analysis cal-
199.5; 171.0; 170.6; 165.7; 149.5; 136.3; 123.9; 55.8; 54.0; 52.3;
46.4; 40.9; 38.7; 35.5; 34.4; 33.9; 33.8; 32.7; 31.7; 31.6; 20.7; 17.2;
16.3. MS (m/z/rel.int.): 385/77 (M+), 370/42; 281/100; 265/91;
207/20. IR (KBr, (cm−1)): 1739 (COO); 1663 (br, C O + CON);
1592 (C C). Analysis calculated for C23H31O4N (M = 385.50): C,
71.66; H, 8.11; N, 3.63; Found: C, 71.48; H, 8.30; N, 3.43. Rf = 0.28
(CHCl3/EtOAc = 8/2). Mp. 192–193 ◦C. White crystalline material.
17-(N-(1ꢀ-methoxycarbonylethyl)-carboxamido)-androst-
4,16-diene-3-one (15f): 1H NMR (CDCl3, 400 MHz): 6.35 (br d,
7.1 Hz, 1H, NH); 6.30 (br s, 1H, 16-CH); 5.62 (br s, 1H, 4-CH);
4.53 (qi, 7.1 Hz; 1H, NCH); 3.66 (s, 3H, OCH3); 0.90–2.40 (m,
17H, skeleton protons); 1.35 (d, 7.1 Hz, 3H, CHCH3); 1.12 (s, 3H,
19-CH3); 0.94 (s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3):
199.3; 173.5; 170.8; 165.0; 149.5; 135.8; 123.7; 55.6; 53.8; 52.2;
47.5; 46.2; 38.5; 35.3; 34.2; 33.7; 33.6; 32.5; 31.5; 31.4; 20.5;
18.2; 16.9; 16.1. MS (m/z/rel.int.): 399/42 (M+), 384/18; 297/100;
282/40. IR (KBr, (cm−1)): 1736 (COO); 1675 (C O); 1655 (CON);
1591 (C C). Analysis calculated for C24H33O4N (M = 399.53): C,
72.15; H, 8.33; N, 3.51; Found: C, 72.24; H, 8.51; N, 3.29. Rf = 0.41
(CHCl3/EtOAc = 8/2). Mp. 169–170 ◦C. Pale yellow solid material.
17-(N,N-(1ꢀ-methoxycarbonyl-butan-1,4-diyl)-
carboxamido-androst-4,16-diene-3-one (15g) (ca. 2/1 mixture
of two C(O)N rotamers): 1H NMR (CDCl3, 400 MHz): 6.06/5.97
(minor/major) (br s, 1H, 16-CH); 5.68 (br s, 1H, 4-CH); 4.40–4.50
(m, 1H, NCH); 3.70/3.68 (s, 3H, OCH3); 3.45–3.70 (m, 2H, NCH2);
0.91–2.42 (m, 21H, skeleton protons+ CH2CH2); 1.13 (s, 3H, 19-
CH3); 1.02/1.04 (s, 3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3):
199.3; 172.9/172.6; 170.9; 166.8/166.6; 149.2/148.9; 134.1/132.6;
123.7; 58.5; 55.6/55.4; 54.0; 51.9; 49.1; 48.3/48.1; 38.5; 35.3;
33.9/33.8; 33.7 (double intensity); 33.6; 32.5; 32.0; 31.7; 29.0;
25.3/24.6; 20.5; 17.0; 16.3. MS (m/z/rel.int.): 425/24 (M+), 410/8;
culated for C28H41O5N (M = 471.64): C, 71.31; H, 8.76; N, 2.97;
Found: C, 71.18; H, 8.82; N, 2.70. Rf = 0.30 (CH2Cl2/EtOAc = 8/2).
Pale yellow viscous material.
11-(N-tert-butylcarboxamido)-androst-5,11-dien-3,17-
di(ethylene ketal) (20ꢀa): 1H NMR (CDCl3, 400 MHz): 6.11 (s, 1H,
12-CH); 5.49 (br d, 1H, 5.1 Hz, 6-CH); 5.31 (br s, 1H, NH); 3.82–3.98
(m, 8H, OCH2CH2O); 1.20–2.55 (m, 15H, skeleton protons); 1.36
(s, 9H, tBu); 1.06 (s, 3H, 19-CH3); 0.95 (s, 3H, 18-CH3); 13C NMR
(100.58 MHz, CDCl3): 172.4; 141.5; 139.7; 136.2; 123.1; 117.9;
109.0; 65.2; 64.3; 64.2; 64.0; 53.3; 51.1; 46.8; 46.0; 42.3; 40.4; 36.9;
34.7; 32.8; 30.8; 28.8; 28.7; 21.6; 18.7; 17.3. MS (m/z/rel.int.): 471/5
(M+), 372/5, 207/22, 99/100. IR (KBr, (cm−1)): 1649 (CON). Analysis
calculated for C28H41NO5 (M = 471.64): C, 71.31; H, 8.76; N, 2.97;
Found: C, 71.22; H, 8.87; N, 2.81. Rf = 0.56 (CH2Cl2/EtOAc = 6/4).
Mp. 253–254 ◦C. Off-white crystalline material.
11-(N,N-pentan-1,5-diylcarboxamido)-androst-5,9(11)-
dien-3,17-di(ethylene
ketal)
(20c):
1H
NMR
(CDCl3,
400 MHz): 5.50 (br d, 1H, 5.3 Hz, 6-CH); 3.80–3.96 (m, 10H,
O
NNH
2
H2NNH
H
2
H
H
H
H
H
O
H2NN
1
2
I2, TMG
NR1R2
I
O
H
H
H
H
H
H
H
O
1 2
R R N
I
1
CO, HNR R2
O
O
3
4
NR1R2
I
Pd(OAc)2
PPh3
H
H
H
H
H
1 2
R R N
I
4'
3'
R1 R2
a
c
H
tBu
-(CH2)5-
-(CH2)2O(CH2)2-
-CH(COOCH3)(CH ) -
d
g
2 3
Scheme 1. Synthesis of 3,17-dicarboxamido-androst-3,5,16-trienes based on androst-4-en-3,17-dione (1) via aminocarbonylation of the corresponding iodoalkene derivative
as key-intermediate.

P. Ács et al. / Steroids 76 (2011) 280–290
287
2xOCH2CH2O + NCH2); 3.10–3.23 (m, 2H, NCH2); 1.20–2.58 (m,
22H, skeleton protons+ (CH2)3); 1.40 (s, 3H, 19-CH3); 0.90 (s,
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 173.4; 140.6; 139.7;
125.6; 121.6; 119.2; 109.0; 65.1; 64.6; 64.4; 64.2; 47.6; ca. 47 (br);
47.1; 44.0; 41.9; 41.4; ca. 41 (br); 37.2; 36.8; 34.4; 32.1; 31.6; 31.2;
26.3; 25.3; 24.6; 23.9; 23.8. MS (m/z/rel.int.): 483/15 (M+), 440/9,
399/14, 99/100. Analysis calculated for C29H41O5N (M = 483.65): C,
72.02; H, 8.54; N, 2.90; Found: C, 71.90; H, 8.62; N, 2.66. Rf = 0.89
(CH2Cl2/EtOAc = 8/2). Pale yellow viscous material (as obtained
after column chromatography).
tBu); 1.47 (s, 3H, 19-CH3); 1.32 (s, 9H, tBu); 0.92 (s, 3H, 18-CH3);
13C NMR (100.58 MHz, CDCl3): 219.9; 198.9; 172.6; 168.2; 139.8;
129.2; 124.9; 51.7; 47.1; 45.1; 43.5; 39.6; 38.2; 35.8; 34.1; 33.5;
30.0; 29.7; 28.4; 22.8; 15.2; 13.7. MS (m/z/rel.int.): 383/9 (M+),
368/11; 311/32, 58/100. IR (KBr, (cm−1)): 1739 (C O); 1646
(br, C O + CON); 1615 (C C). Analysis calculated for C24H33O3N
(M = 383.53): C, 75.16; H, 8.67; N, 3.65; Found: C, 75.03; H, 8.80;
N, 3.44. Rf = 0.48 (CH2Cl2/EtOAc = 1/1). Pale yellow crystalline
solid material (as obtained after column chromatography). Mp.
204–205 ◦C.
11-(N,N-pentan-1,5-diylcarboxamido)-androst-5,11-dien-
3,17-di(ethylene ketal) (20ꢀc): 1H NMR (CDCl3, 400 MHz): 5.94
(s, 1H, 12-CH); 5.46 (d, 5.7 Hz; 1H, 6-CH); 3.80–3.96 (m, 10H,
2xOCH2CH2O + NCH2); 3.10–3.23 (m, 2H, NCH2); 1.20–2.50 (m,
21H, skeleton protons+ (CH2)3); 1.25 (s, 3H, 19-CH3); 0.97 (s,
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 172.4; 142.0; 136.7;
135.4; 122.2; 118.4; 109.2; 65.5; 65.2; 64.4; 64.2; 55.8; ca. 53 (br);
47.6; 46.8; 42.2; ca. 42 (br); 40.2; 35.4; 34.9; 32.6; 31.4; 30.7;
26.5; 25.3; 24.6; 21.5; 18.0; 17.0. MS (m/z/rel.int.): 483/10 (M+),
438/2, 364/21, 204/4, 99/100. Analysis calculated for C29H41O5N
(M = 483.65): C, 72.02; H, 8.54; N, 2.90; Found: C, 71.81; H, 8.70; N,
2.78. Rf = 0.39 (CH2Cl2/EtOAc = 8/2). Pale yellow viscous material
(as obtained after column chromatography).
11-(N-tert-butylcarboxamido)-androst-4,11-dien-3,17-
dione (21ꢀa): 1H NMR (CDCl3, 400 MHz): 6.48 (s, 1H, 12-CH); 5.76
(br s, 1H, 4-CH); 5.44 (br s, 1H, NH); 1.20–2.62 (m, 15H, skeleton
protons); 1.32 (s, 9H, tBu); 1.20 (s, 3H, 19-CH3); 1.02 (s, 3H, 18-
CH3); 13C NMR (100.58 MHz, CDCl3): 215.3; 198.8; 171.0; 167.9;
139.6; 135.9; 126.1; 62.5; 54.7; 51.4; 48.9; 46.5; 41.4; 36.2; 35.1;
34.5; 33.9; 29.5; 28.5; 20.8; 18.2; 17.3. MS (m/z/rel.int.): 383/100
(M+), 368/7; 310/55, 253/22. IR (KBr, (cm−1)): 1742 (COO); 1655
(br, C O + CON); 1613 (C C). Analysis calculated for C24H33O3N
(M = 383.53): C, 75.16; H, 8.67; N, 3.65; Found: C, 75.10; H, 8.82;
N, 3.50. Rf = 0.51 (CH2Cl2/EtOAc = 1/1). Pale yellow crystalline
solid material (as obtained after column chromatography). Mp.
104–105 ◦C.
11-(N-tert-butylcarboxamido)-androst-4,9(11)-dien-3,17-
dione (21a): 1H NMR (CDCl3, 400 MHz): 5.75 (br s, 1H, 4-CH); 5.21
(br s, 1H, NH); 1.10–2.60 (m, 16H, skeleton protons); 1.32 (s, 9H,
11-(N,N-pentan-1,5-diylcarboxamido)-androst-4,9(11)-
dien-3,17-dione (21c): 1H NMR (CDCl3, 400 MHz): 5.74 (s, 1H,
4-CH); 3.80–3.88 (m, 1H, NCHaHb); 3.39–3.45 (m, 1H, NCHaHb);
O
O
H
O
H
O
O
HOCH2CH2OH
H
H2NNH2
H
H
H
H
H
H
O
O
H2NN
1
5
6
I2, TMG
O
O
O
H
O
O
O
H
H
H
H
H
H
H
H
H
H
R1R2N
R1R2N
I
O
O
7
CO, R1R2NH
9
8
H+, H2O
Pd(OAc)2
PPh3
O
H
O
O
O
H
H
H
H
H
H
R1R2N
R1R2N
I
O
O
7'
9'
8'
R1
H
R2
Ph
b
c
-(CH2)5-
-(CH2)2O(CH2)2-
-CH(COOCH3)(CH2)3-
d
g
Scheme 2. Synthesis of 3-carboxamido-androst-3,5-dien-17-ones based on androst-4-en-3,17-dione (1) via aminocarbonylation of the corresponding iodoalkene derivative
as key-intermediate.

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P. Ács et al. / Steroids 76 (2011) 280–290
3.08–3.17 (m, 2H, NCH2); 1.20–2.60 (m, 22H, skeleton protons+
(CH2)3); 1.45 (s, 3H, 19-CH3); 0.93 (s, 3H, 18-CH3); 13C NMR
(100.58 MHz, CDCl3): 219.9; 198.9; 172.1; 168.3; 140.1; 127.4;
124.9; ca. 47 (br); 47.2; 45.1; 43.3; 41.6; ca. 41 (br); 38.4; 35.9; 34.3;
33.6; 32.6; 30.0; 26.0; 25.2; 24.4; 24.2; 22.9; 13.9. MS (m/z/rel.int.):
395/2 (M+), 380/8, 311/11, 84/100. IR (KBr, (cm−1)): 1739 (COO);
1674 (C O + CON); 1616 (C C). Analysis calculated for C25H33O3N
(M = 395.54): C, 75.91; H, 8.41; N, 3.54; Found: C, 75.80; H, 8.64; N,
3.26. Rf = 0.26 (CH2Cl2/EtOAc = 1/1). Mp. 106–107 ◦C. Orange solid
material (as obtained after column chromatography).
11-(N,N-pentan-1,5-diylcarboxamido)-androst-4,11-dien-
3,17-dione (21ꢀc): 1H NMR (CDCl3, 400 MHz): 6.25 (s, 1H, 12-CH);
5.76 (s, 1H, 4-CH); 3.10–3.70 (m, 4H, 2xNCH2); 1.20–2.60 (m,
21H, skeleton protons+ (CH2)3); 1.23 (s, 3H, 19-CH3); 1.06 (s,
3H, 18-CH3); 13C NMR (100.58 MHz, CDCl3): 215.0; 198.4; 170.8;
167.8; 135.2; 135.0; 126.0; 55.4; 48.8; 48.3; 46.4; 42.5; 41.2; 36.2;
35.3; 34.5; 33.8; 33.7; 29.5; 25.9; 25.2; 24.6; 20.8; 18.8; 17.3. MS
(m/z/rel.int.): 396/100 (M+), 380/52, 310/45, 274/55, 84/95. IR (KBr,
(cm−1)): 1742 (C O); 1673 (C O + CON); 1609 (C C). Analysis
calculated for C25H33O3N (M = 395.54): C, 75.91; H, 8.41; N, 3.54;
Found: C, 75.67; H, 8.61; N, 3.33. Rf = 0.30 (CH2Cl2/EtOAc = 1/1). Mp.
106–107 ◦C. Pale yellow solid material (as obtained after column
chromatography).
tion [4,5,12–15]. The transformation of the keto groups at all of
the three positions into the corresponding iodo-alkenes, and by
using the triiodide (3,11,17-triiodo-androst-3,5,9(11),16-tetraene)
as a substrate in palladium-catalyzed carbonylation reaction, the
corresponding 3,11,17-tri-carboxamido-androstane was obtained
in acceptable yield under mild reaction conditions [17]. The selec-
tive aminocarbonylation at one of these distinguished positions,
in the presence of a further keto functionality, still remained a
challenge.
As previously, the appropriate substrates with iodo-alkene func-
tionality(ies) served for the introduction of the carboxamide groups
in the present study. The ketone—hydrazone—iodo-alkene reac-
tion sequence was used for the preparation of the substrate. In
order to preserve the 3-keto and/or 17-keto functionalities, they
were protected as ethylene ketals following conventional synthetic
methodologies (See Section 2).
In order to investigate the possibility of the synthesis of
steroids containing both keto and carboxamide functionalities
from steroids with iodoalkene moieties, 3,17-diiodo-androst-
3,5,16-triene (3), 3-iodo-androst-3,5-diene-17-ethylene ketal (7),
3-iodo-androst-2,4-diene-17-ethylene ketal (7ꢀ), 17-iodo-androst-
5,16-diene-3-ethylene ketal (13) and 11-iodo-androst-5,9(11)-
diene-3,17-bis(ethylene ketal) (19) were synthesized from the
corresponding 3,17-diketo-, 3-keto-, 17-keto- and 11-keto deriva-
tives, respectively. In this way, the hydrazones (2, 6, 12 and 18),
obtained after the protection of one or two keto functionalities as
ethylene ketal, were transformed to the above iodoalkenes in the
presence of TMG and iodine.
3. Results and discussion
The homogeneous catalytic functionalization of steroids via var-
ious carbonylation reactions has been one of our major interest for
a long time [4]. The introduction of a carboxamide (or ester, formyl)
functionality into the distinguished positions 3, 11 and especially
17 is of pharmacological importance as discussed under Introduc-
The iodoalkenes 3, 7 (7ꢀ), 13 and 19 were reacted as substrates in
aminocarbonylation reaction (Schemes 1–4). Various primary and
secondary amines were used as N-nucleophiles (tert-butylamine
O
O
O
H
O
H+, H2O
HOCH2CH2OH
H
H
H
H
H
H
H
H
O
O
O
O
O
1
10
11
H2NNH2
NNH2
O
NR1R2
CO, R1R2NH
I
I2, TMG
H
H
H
H
H
H
H
H
H
Pd(OAc)2
PPh3
O
O
O
O
O
O
12
14
13
H+, H2O
R1
H
H
R2
a
b
c
tBu
Ph
NR1R2
O
H
-(CH2)5-
H
d
e
-(CH2)2O(CH2)2-
H
H
H
CH2COOCH3
O
f
CH(CH3)COOCH3
15
g
-CH(COOCH3)(CH2)3-
Scheme 3. Synthesis of 17-carboxamido-androst-4,16-dien-3-ones based on androst-4-en-3,17-dione (1) via aminocarbonylation of the corresponding iodoalkene derivative
as key-intermediate.

P. Ács et al. / Steroids 76 (2011) 280–290
289
O
O
O
O
H
O
O
O
H2NN
HOCH CH2OH
2
H
H
H2NNH
H
2
H
H
H
H
H
O
O
O
O
O
16
17
18
I2, TMG
O
O
O
O
O
H
O
O
I
R1R2N
R1R2N
H
H
H
H
H
O
O
O
O
O
20
19
21
1
CO, HNR R2
H+, H2O
Pd(OAc)2
PPh3
O
O
O
O
H
O
O
O
I
R1R2N
R1R2N
H
H
H
H
H
H
H
H
O
O
O
O
O
19'
20'
21'
R1 R2
tBu
-(CH2)5-
a
c
H
Scheme 4. Synthesis of 11-carboxamido-androst-4,9(11)-dien-3,17-diones based on androst-4-en-3,9,17-trione (16) via aminocarbonylation of the corresponding
iodoalkene derivative as key-intermediate.
(a), aniline (b), pyperidine (c), morpholine (d), methyl glycinate (e),
methyl alaninate (f), methyl prolinate (g)) in DMF in the presence of
palladium—phosphine ‘in situ’ catalysts under carbon monoxide at
atmospheric pressure. The ‘in situ’ formation of highly active coor-
dinatively unsaturated Pd(0) catalysts with mono- and bidentate
phosphines has been published before [26].
It can be stated, that iodoalkene functionalities in all positions
(3-iodo-3-ene, 17-iodo-16-ene, 11-iodo-9(11)-ene) reacted quan-
titatively under mild conditions. In this way, 3,17-dicarboxamido-
4,16-diene derivatives (4) (Scheme 1), 3-carboxamido-3-ene
derivatives (8) (Scheme 2), 17-carboxamido-16-ene derivatives
(14) (Scheme 3) and 11-carboxamido-9(11)-ene derivatives (20)
(Scheme 4) were synthesized in moderate to high yields depending
on the structure of the amine (Table 1).
diene/3,5-diene ratio of 3-iodo compounds were shifted towards
the 3,5-diene structure of 3-carboxamides. The ratio of 4/4ꢀ felt in
the range of 10/1–12/1. It could be explained by the oxidative addi-
tion of the 3-iodo-2,4-diene (3ꢀ) to Pd(0) forming a Pd(II)-2,4-dienyl
intermediate which underwent isomerization to Pd(II)-3,5-dienyl
derivative. Its aminocarbonylation provided carboxamides 4.
The aminocarbonylation of 7 with secondary amines (c, d, and g)
resulted in conversion of 55, 35, and 30%, respectively. To achieve
higher conversion, and consequently, higher isolated yields, ele-
vated reaction times had to be used (entries 7–10).
As discussed above, the ca. 3/1 mixture of the diiodo compounds
7 and 7ꢀ was used, both iodo-dienes were completely converted
to the corresponding dicarboxamides 8c, 8d, and 8g (Scheme 2).
Again, the isomerization of the conjugated double bond system
from 2,4- to 3,5-positions during palladium-catalyzed reaction took
place, enabling the isolation of 3-carboxamido-3,5-dienes in good
yields. The deprotection at the 17 position led to the corresponding
3-carboxamido-17-keto derivatives (9c, 9d and 9g) in yields higher
than 95%. It is worth noting, that the characterization of 2,4-dienes
in both series of compounds (17-ethylene ketals, 8ꢀ and 17-ketones,
9ꢀ) was successful. Unlike the major products (8 and 9), the isolation
of 8ꢀ and 9ꢀ as pure compounds was failed. However, they could be
characterized in two-component mixtures (See Characterization).
The protection of the 3-keto functionality as an ethylene ketal
in 1 resulted in the formation of a highly reactive iodo-alkene 13
(Scheme 3). The aminocarbonylation of 13 brought about the high-
yielding formation of 17-carboxamides 14a–g. The lowest isolated
yield was obtained with secondary amines, while the highest with
Using 3 as a substrate, the corresponding carboxamides were
isolated in high yields. The secondary amines (c, d and g) have
shown diminished reactivity, i.e. longer reaction times were nec-
essary to achieve high yields (entries 1–5).
When the 3/1 mixture of the diiodo compounds 3 and 3ꢀ
was used, a complete conversion towards dicarboxamides was
obtained (Scheme 1). Two of them, 4a and 4c were isolated as
pure compounds in acceptable yields using column chromatog-
raphy, however, 4d, 4g were obtained in surprisingly low yields.
Although the reaction mixture contained some 2,4-diene isomers
(4ꢀa, 4ꢀc, 4ꢀd and 4ꢀg) as well, their isolation as pure compound
for full characterization was not successful. It is worth noting that
the partial isomerization of the 2,4-diene functionality to 3,5-diene
was observed during aminocarbonylation, i.e. the original 2,4-

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P. Ács et al. / Steroids 76 (2011) 280–290
tert-butyl-amine (82%) (entries 11–17). The corresponding 3-keto-
4-ene derivatives, 15a–g, the potential intermediates for further
functionalization, were obtained in high yields (>95%) upon depro-
tection.
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synthesis of steroidal crown ethers via palladium-catalysed carbonylation reac-
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and androgen-related genes by triiodothyronine in the brain of silurana tropi-
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inflammatory properties of 5␣-reductase inhibitor finasteride in experimental
animals. Eur J Drug Metab Ph 2008;33:181–6.
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[16] Ács P, Müller E, Czira G, Mahó S, Pereira M, Kollár L. Facile synthesis of 12-
carboxamido-11-spirostenes via palladium-catalyzed carbonylation reactions.
Steroids 2006;71:875–9.
[17] Ács P, Jakab B, Takács A, Kollár L. Facile synthesis of 11-carboxamido-
androst-4,9(11)-dienes via palladium-catalyzed aminocarbonylation. Steroids
2007;72:627–32.
[18] Stephan E, Brossat M, Lecomte V, Bouit P-A. Synthesis of the 11␤-
hydroxymethyl-androst-4-en-3,17-dione. Tetrahedron 2006;62:2052–5.
[19] Lecomte V, Stephan E, Jaouen G. Access to 11␤-ethynyl-androst-5-ene. Tetra-
hedron Lett 2005;46:1123–6.
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11-oxo-steroid. Tetrahedron Lett 2001;42:5409–11.
The selective protection of the 3- and 17-keto functionalities
of adrenosterone (16) and the transformation of the 11-keto func-
tionality to 11-iodo-9(11)-ene by standard synthetic procedures,
led to the ca. 5/1 mixture of 19 and 19ꢀ (Scheme 4). The palladium-
catalyzed aminocarbonylation of the iodo-alkenes resulted in the
complete formation of 11-carboxamides 20a/20ꢀa using a primary
amine (a) while much lower yields have been obtained with a
secondary amine (c) as N-nucleophile (entries 18 and 19). The iso-
merization of 11-ene to 9(11)-ene during aminocarbonylation took
place to a very low extent, i.e., a 4/1 mixture of 20/20ꢀ was obtained.
The hydrolysis of the ethylene ketal functionalities provided the
11-carboxamido-3,17-dione derivatives 21/21ꢀ.
As a summary it can be stated, that conjugated unsatu-
rated steroidal carboxamides, possessing both carboxamide and
ketone functionalities, can be synthesized in yields of practical
interest in palladium catalyzed carbonylation of the correspond-
ing iodoalkenes. The iodoalkene functionality, easily accessible
from ketone, provided a clean, high-yielding aminocarbonylation
towards carboxamides. It has been proved that the selective protec-
tion of the keto group(s) via ethylene ketals, enables the synthesis of
carboxamides with additional keto functionality(ies), which could
serve as ideal site for further functionalization of the skeleton. The
aminocarbonylation proved to be highly tolerant towards both the
structure of the amine nucleophiles and the structural variations of
the steroidal backbone.
Acknowledgements
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organolithium reagents to hindered and/or enolisable ketones. Tetrahedron
2003;59:2169–76.
[22] Lecomte V, Stephan E, Vaissermann J, Jaouen G. Are the 11-oxo-steroids really
so hindered towards organometallic compounds? Steroids 2004;69:17–21.
[23] Herzog HL, Jevnik MA, Tully ME, Hershberg EB. Cyclic ketals of 4-androstene-
3,17-dione. J Am Chem Soc 1953;75:4425–7.
The authors thank the Hungarian National Science Foundation
(NKTH-OTKA CK78553) and Science, Please! Research Team on
Innovation (SROP-4.2.2./08/1/2008-0011) for their financial sup-
port.
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