Novel 13β- and 13α-d-homo steroids: 17a-carboxamido-d-homoestra- 1,3,5(10),17-tetraene derivatives via palladium-catalyzed aminocarbonylations

Article abstract of DOI:10.1016/j.steroids.2010.07.002

17a-Methoxycarbonyl- and 17a-carboxamido-d-homoestra-1,3,5(10),17-tetraene derivatives were synthesized by palladium-catalyzed carbonylation reactions of the corresponding 17a-iodo-d-homoestra-1,3,5(10),17-tetraene derivatives using methanol and various a

Full text of DOI:10.1016/j.steroids.2010.07.002

Steroids 75 (2010) 1075–1081
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Steroids
journal homepage: www.elsevier.com/locate/steroids
Novel 13␤- and 13␣-d-homo steroids:
17a-carboxamido-d-homoestra-1,3,5(10),17-tetraene derivatives via
palladium-catalyzed aminocarbonylations
Attila Takácsa, Péter Ácsa, Zoltán Berenteb, János Wölflingc, Gyula Schneiderc, László Kollára,∗
a Department of Inorganic Chemistry, University of Pécs, Ifjúság u. 6, PO Box 266, H-7624 Pécs, Hungary
b Institute of Biochemistry and Medical Chemistry, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary
c Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2010
Received in revised form 29 June 2010
Accepted 5 July 2010
Available online 13 July 2010
17a-Methoxycarbonyl- and 17a-carboxamido-d-homoestra-1,3,5(10),17-tetraene derivatives were syn-
thesized by palladium-catalyzed carbonylation reactions of the corresponding 17a-iodo-d-homoestra-
1,3,5(10),17-tetraene derivatives using methanol and various amines as O- and N-nucleophiles,
respectively. Both the natural (13␤) and the epi (13␣) series of compounds were isolated. The 17a-iodo-
17-ene functionalities in the two 13-epimer series differ in reactivity. While the aminocarbonylations
were practically complete in the 13␤ series in reasonable reaction time under mild conditions and high
isolated yields were achieved, the corresponding 13␣-17a-iodo-17-ene substrate has shown decreased
reactivity resulting in moderate to low yields. However, under high carbon monoxide pressure (40
bar) excellent yields can be obtained even in the 13␣ series. The aminocarbonylation was completely
chemoselective in both series, i.e., the corresponding 17a-carboxamido-17-ene derivatives were formed
exclusively.
Keywords:
Iodoalkene
Carboxamide
13␣-Steroid
d-Homosteroid
Palladium
Carbonylation
© 2010 Published by Elsevier Inc.
1. Introduction
for the homogeneous catalytic synthesis of 12-carboxamido-11-
spirostenes and 11-carboxamido-androst-9(11)-enes, respectively
The homogeneous catalytic functionalization of steroids with
regular skeleton (13␤-methyl group and five-membered d-ring) is
well-established and was reviewed in 2003 [1]. Among the func-
tionalities introduced, carboxamido group is of special interest
due to the high pharmacological importance of 17-carboxamido-
androstanes and estra-1,3,5(10)-trienes as 5␣-reductase inhibitors.
The corresponding 13-epimer, 13␣-estra-1,3,5(10)-triene is also
known as the framework of 13␣-estrone and its derivatives;
much less efforts have been made towards its functionalization
[2,3].
Palladium-catalyzed aminocarbonylation of steroidal sub-
strates with 3-trifloxy-3-ene or 17-trifloxy/17-iodo-16-ene moi-
eties (where trifloxy stands for trifluoromethylsulphonyloxy, ‘TfO’
as its acronym used usually) proved to be an efficient tool for
the introduction of carboxamide functionalities into positions-
3 and -17, respectively [4–10]. Recently, the high reactivity of
the iodo-ene moiety in more hindered positions, i.e., 12-iodo-
11-ene and 11-iodo-9(11)-ene functionalities, have been utilized
[11,12]. Furthermore, similar methodology was exploited for the
functionalization of estra-1,3,5(10),16-tetraene and androsta-5,16-
diene derivatives in the 13␣ series [13].
The search for steroids with novel pharmacological effects led
to the synthesis of d-homo derivatives both in the androstane and
estrane series. The isolation from natural sources and the syn-
thetic approaches to d-homosteroids were reviewed recently [14].
An efficient methodology was developed for the synthesis of 16-
halogenated d-homoestrone and its 13␣-epimer by using Lewis
acid-catalyzed intramolecular Prins reaction, that is, the cyclization
of the corresponding unsaturated secoestrone aldehyde [15]. d-
Homoestrone 3-methyl and 3-benzyl ethers were synthesized both
in the natural and 13-epi series and tested in vitro in a radioligand-
binding assay [16]. Nitrogen-containing d-homo and condensed
d-homo compounds belonging to the 13␣-estrone series with sub-
stituted nitroaniline moieties at position-17a have been described
[17]. 2-Phenethyl-d-homoestrone and related compounds were
synthesized and tested as 17␤-hydroxysteroid dehydrogenase type
1 inhibitors [18].
17-Aminophenyl-17-aza-d-homoestrones were synthesized
via ␦-alkenyl phenylhydrazones and the corresponding cyclic
iminium salts [19]. 3␤-Hydroxy-17-oxa-d-homoandrost-5-ene-
∗
Corresponding author. Tel.: +36 72 503600; fax: +36 72 501527.
E-mail address: kollar@ttk.pte.hu (L. Kollár).
0039-128X/$ – see front matter © 2010 Published by Elsevier Inc.
doi:10.1016/j.steroids.2010.07.002

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A. Takács et al. / Steroids 75 (2010) 1075–1081
16-one served as a starting compound for the synthesis of novel
4- and 6-nitro d-homo derivatives [20].
months. No changes either in color or in analytical characteristics
were observed within this time interval).
Prompted by the pharmacological potential of 17-carboxamides
and by the facile palladium-catalyzed carbonylations of the
iodoalkene functionality, we report on the synthesis of novel
17a-carboxamido-d-homoestratetraenes from the corresponding
17a-17-ene derivatives.
2.1.2. Synthesis of
3-methoxy-17a-iodo-13˛-d-homoestra-1,3,5(10),17-tetraene (6)
via the corresponding hydrazone
3-Methoxy-17a-iodo-13␣-d-homoestra-1,3,5(10),17-tetraene
(6) was prepared according to a known method described above
for 5. The only difference is in the final isolation step, that is, the
17a-iodo-17-ene product (6) was purified by column chromatog-
raphy (silica gel, petroleum ether (40–60): EtOAc 97:3). Yield:
2.05 g; 62.9%.
2. Experimental
PPh3 and 1,1,3,3-tetramethylguanidine (TMG) were purchased
from Aldrich. Commercial NEt3, and primary and secondary
amines, including amino acid ester hydrochlorides (Aldrich), were
used without further purification. DMF was dried according to
a standard procedure. 3-Methoxy-d-homoestra-1,3,5(10)-triene-
17a-one (1) and 3-methoxy-13␣-d-homoestra-1,3,5(10)-triene-
17a-one (2) were synthesized as described previously in Ref.
[16].
2.1.3. General procedure for aminocarbonylation at atmospheric
pressure
A
mixture of 5 (or 6) (408 mg, 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 alanine and proline methyl ester N-nucleophiles were
used as hydrochloride salts (1.1 mmol) and 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 off, and the residue was dissolved
in 20 mL of CHCl3. It was washed in turn with 2 × 50 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, 98/2, 95/5, 90/10 or 80/20 CHCl3/EtOAc
mixtures) resulted in the target 17a-carboxamido-17-ene deriva-
tives (7a–e, 8a–e).
3-Methoxy-17a-iodo-d-homoestra-1,3,5(10),17-tetraene (5)
and 3-methoxy-17a-iodo-13␣-d-homoestra-1,3,5(10),17-tetraene
(6), used as substrates in the present work, were synthesized in
a modified conventional three-step synthetic procedure [20,21]
from the corresponding 17a-keto derivatives, 1 and 2, respec-
tively. A detailed description of the synthesis 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 with Merck TLC
sheets (Silica gel 60 F254) and CHCl3/EtOAc mixtures (98/2, 95/5,
90/10 or 80/20) as appropriate eluents. Elemental analyses were
measured on a 1108 Carlo Erba apparatus. Mass-spectrometric data
have been obtained by using a GC–MS system consisting of a Perkin
Elmer AutoSystem XL gas chromatograph and a Perkin Elmer Tur-
boMass mass spectrometer.
2.1.4. General procedure for aminocarbonylation at high pressure
The DMF solution of the catalyst precursor and reactants
(amounts as above) was transferred under argon into a 100 mL
stainless steel autoclave. The reaction vessel was pressurized up
to 40 bar with CO and the magnetically stirred mixture was heated
in an oil bath at 50 ◦C for the given reaction time. The work-up
procedure was identical with that given above for atmospheric
aminocarbonylation.
2.1.1. Synthesis of 3-methoxy-17a-iodo-d-homoestra-1,3,5(10),17-
tetraene (5) via the corresponding hydrazone
A
mixture of 3-methoxy-d-homoestra-1,3,5(10)-triene-17a-
one (1) (2.60 g, 8.7 mmol), freshly distilled hydrazine hydrate (98%,
2.22 g, 44.5 mmol) and BaO (100 mg) in 2-methoxy-ethanol (50 mL)
was heated for 2 days at 110 ◦C. After completion of the reaction,
the mixture was poured into water and extracted with CH2Cl2.
The combined organic phase was washed successively with water
and brine, dried over Na2SO4, and evaporated to give the 17a-
hydrazone derivative (3). This product was used in the next step
without further purification.
To a stirred solution of I2 (4.27 g, 16.8 mmol) in CH2Cl2 (50 mL),
1,1,3,3-tetramethylguanidine (TMG, 8.30 g, 72.0 mmol) was added
slowly the mixture being cooled in an ice-water bath during the
addition. A solution of 3 (2.50 g, 8.0 mmol) in CH2Cl2 (20 mL) was
added dropwise at 0 ◦C. After the addition was completed, the mix-
ture was stirred for 1 h. The solvent was then evaporated off and
the residue was heated at 90 ◦C under an argon atmosphere for
3 h, after which the mixture was poured into water and extracted
with CH2Cl2. The combined organic layer was washed successively
with 1N aqueous HCl, water, 5% aqueous NaHCO3, water, saturated
aqueous Na2S2O3 and water again, dried over Na2SO4 and evapo-
rated. The residue was purified by column chromatography (silica
gel, petroleum ether (40–60): EtOAc 95:5) resulting in 17a-iodo-
17-ene product (5) as a white solid material. Yield: 1.20 g; 36.8%.
(In order to avoid oxidative and photochemical decomposition, 5
must be kept under argon in a refrigerator. When used in carbony-
lation reactions, reproducible results can be obtained even after 2
2.1.5. General procedure for methoxycarbonylation at
atmospheric pressure
A mixture of 5 (or 6) (408 mg, 1 mmol), palladium(II) acetate
(5.6 mg, 0.025 mmol) and PPh3 (13.1 mg, 0.05 mmol) was dissolved
in 10 mL of DMF under argon, and NEt3 (0.5 mL) and methanol
(0.13 mL, 5 mmol). The atmosphere was changed to CO (1 bar), and
the reaction was conducted at 50 ◦C for the appropriate reaction
time. The composition of the reaction mixture was checked by TLC.
Work-up procedure was identical with that given above for the
17a-carboxamides.
2.1.6. General procedure for methoxycarbonylation at high
pressure
A mixture of 6 (408 mg, 1 mmol), palladium(II) acetate (5.6 mg,
0.025 mmol) and PPh3 (13.1 mg, 0.05 mmol) was dissolved in
10 mL of DMF under argon, and NEt3 (0.5 mL) and methanol
(0.13 mL, 5 mmol). The reaction mixture was then transferred
under argon into a 100 mL stainless steel autoclave, which was
pressurized to 40 bar with CO and the magnetically stirred
mixture was heated in an oil bath at 50 ◦C for 40 h. Work-up

A. Takács et al. / Steroids 75 (2010) 1075–1081
1077
Table 1
Palladium-catalyzed aminocarbonylation of 3-methoxy-17a-iodo-d-homoestra-1,3,5(10),17-tetraene (5) and 3-methoxy-17a-iodo-13␣-d-homoestra-1,3,5(10),17-tetraene
(6)a.
Run
Amine
Substr.
Amine: 5(6) ratio
Reaction time [h]
p(CO) [bar]
Conv.b [%]
Isolated yield (amide) [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
t-BuNH2 (a)
t-BuNH2 (a)
t-BuNH2 (a)
t-BuNH2 (a)
t-BuNH2 (a)
t-BuNH2 (a)
t-BuNH2 (a)
Aniline (b)
5
5
5
5
6
6
6
5
6
5
5
6
6
5
6
5
6
6
6
3
3
3
3
3
3
3
2
20
0.25
0.5
1
20
20
45
20
20
20
0.25
20
20
20
20
20
20
20
110
1
1
1
1
1
40
40
1
1
1
1
1
40
1
1
1
1
40
40
>98
41
83
89
45
87
97
>98
71
>98
97
25
61
>98
20
55
84 (7a)
NDc
NDc
NDc
NDc
76 (8a)
82 (8a)
80 (7b)
55 (8b)
80 (7c)
NDc
Aniline (b)
2
Piperidine (c)
Piperidine (c)
Piperidine (c)
Piperidine (c)
AlaOMe (d)
AlaOMe (d)
ProOMe (e)
ProOMe (e)
ProOMe (e)
ProOMe (e)
1.5
1.5
1.5
1.5
1.1
1.1
1.1
1.1
1.1
1.1
20 (8c)
55 (8c)
82 (7d)
16 (8d)
40 (7e)
–
0
66d
98d
NDc
76 (8e)
a
Reaction conditions: 0.025 mmol Pd(OAc)2; 0.05 mmol PPh3, 1 mmol substrate (5 or 6); 10 mL DMF; Reaction temp.: 50 ◦C.
Determined by GC.
b
c
ND = isolated yields were not determined in these runs.
d
Determined by 1H NMR.
procedure was identical with that given above for the 17a-
carboxamides.
found: C, 78.54; H, 9.36; N, 3.49. Rf = 0.80 (CHCl3/EtOAc = 90/10);
mp. 184–185 ◦C. White crystalline material.
3-Methoxy-17a-(N-tert-butylcarboxamido)-13␣-d-homoestra-
1,3,5(10),17-tetraene (8a): 1H NMR (CDCl3): 7.22 (d, 8.4 Hz, 1H,
1-H); 6.73 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.63 (d, 2.6 Hz; 1H, 4-H);
5.91 (br s, 1H, 17-H); 5.38 (br s, 1H, NH); 3.78 (s, 3H, OCH3);
2.83–2.90 (m, 2H, 6-H2); 1.88–2.40 (m, 6H, skeleton protons);
1.08–1.50 (m, 7H, skeleton protons); 1.43 (s, 3H, 18-H3);1.37 (s,
9H, tBu); 13C NMR (CDCl3): 170.6; 157.5; 144.4; 137.9; 133.0;
128.6; 126.5; 113.4; 111.6; 55.1; 51.0; 46.5; 42.6; 37.6 (double
intensity); 36.5; 31.8; 30.4; 28.8; 29.7 (triple intensity); 26.8;
21.0; 18.9. IR (KBr (cm−1)): 3451 (NH); 1659 (NCO); 1613 (C C);
1590 (A-ring). MS (m/z/rel. int.): 381/100 (M+), 366/6; 324/10;
309/8; 280/20. Analysis calculated for C25H35O2N (M = 381.56): C,
78.70; H, 9.25; N, 3.67; found: C, 78.60; H, 9.39; N, 3.45. Rf = 0.65
(CHCl3/EtOAc = 95/5); mp. 115–116 ◦C. Pale yellow crystalline
material.
2.2. Analytical and spectroscopic data
3-Methoxy-17a-iodo-d-homoestra-1,3,5(10),17-tetraene (5):
1H NMR (CDCl3): 7.22 (d, 8.0 Hz, 1H, 1-H); 6.75 (br d, 8.0 Hz, 1H,
2-H); 6.65 (br s, 1H, 4-H); 6.36 (br s, 1H, 17-H); 3.80 (s, 3H, OCH3);
2.82–2.95 (m, 2H, 6-H2); 1.95–2.40 (m, 6H, skeleton protons);
1.22–1.60 (m, 7H, skeleton protons); 1.02 (s, 3H, 18–H3); 13C NMR
(CDCl3): 157.8; 138.0; 137.5; 132.9; 126.4; 118.6; 113.7; 111.9;
55.5; 49.1; 44.1; 42.6; 41.6; 39.8; 30.8; 30.4; 27.0; 26.6; 20.2;
18.8. IR (KBr (cm−1)): 1610 (C C); 1576 (A-ring). MS (m/z/rel.
int.): 408/100 (M+), 281/2; 171/32; 147/14. Analysis calculated for
C
20H25OI (M = 408.32): C, 58.83; H, 6.17; found: C, 58.70; H, 6.36.
Rf = 0.71 (petroleum ether (40–60)/EtOAc = 95/5); mp. 108–109 ◦C.
Off-white crystalline material.
3-Methoxy-17a-(N-phenylcarboxamido)-d-homoestra-
3-Methoxy-17a-iodo-13␣-d-homoestra-1,3,5(10),17-tetraene
(6): 1H NMR (CDCl3): 7.22 (d, 8.4 Hz, 1H, 1-H); 6.73 (dd, 8.4 Hz,
2.6 Hz, 1H, 2-H); 6.63 (d, 2.6 Hz; 1H, 4-H); 6.40 (br d, 3.1 Hz, 1H,
17-H); 3.80 (s, 3H, OCH3); 2.81–2.91 (m, 2H, 6-H2); 1.90–2.37 (m,
6H, skeleton protons); 1.20–1.67 (m, 7H, skeleton protons); 1.18
(s, 3H, 18-H3); 13C NMR (CDCl3): 157.6; 139.2; 137.9; 133.1; 126.4;
115.0; 113.5; 111.5; 55.3; 45.6; 43.0; 42.2; 42.0; 37.6; 30.3; 29.9;
27.1; 26.9; 26.1; 19.5. IR (KBr (cm−1)): 1610 (C C); 1575 (A-ring).
MS (m/z/rel. int.): 408/100 (M+), 281/8; 173/44; 147/13. Analysis
calculated for C20H25OI (M = 408.32): C, 58.83; H, 6.17; found: C,
58.66; H, 6.26. Rf = 0.66 (petroleum ether (40–60)/EtOAc = 97/3);
mp. 135–136 ◦C. White crystalline material.
3-Methoxy-17a-(N-tert-butylcarboxamido)-d-homoestra-
1,3,5(10),17-tetraene (7a): 1H NMR (CDCl3): 7.22 (d, 8.4 Hz, 1H,
1-H); 6.73 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.62 (d, 2.6 Hz; 1H, 4-H);
5.83 (br s, 1H, 17-H); 5.48 (br s, 1H, NH); 3.80 (s, 3H, OCH3);
2.83–2.91 (m, 2H, 6-H2); 1.88–2.33 (m, 6H, skeleton protons);
1.20–1.60 (m, 7H, skeleton protons); 1.40 (s, 9H, tBu); 1.25 (s,
3H, 18-H3); 13C NMR (CDCl3): 170.8; 157.5; 148.0; 137.9; 133.0;
126.6; 126.3; 113.5; 111.5; 55.2; 51.2; 47.5; 43.7; 38.2; 36.6; 35.2;
30.2; 28.9 (triple intensity); 26.4; 26.1; 25.4; 19.8; 19.6. IR (KBr
(cm−1)): 3412 (NH); 1663 (NCO); 1636 (C C); 1608 (A-ring). MS
(m/z/rel. int.): 381/100 (M+), 366/11; 309/22; 280/20. Analysis
calculated for C25H35O2N (M = 381.56): C, 78.70; H, 9.25; N, 3.67;
1,3,5(10),17-tetraene (7b): 1H NMR (CDCl3): 7.58 (d, 8.0 Hz,
2H, Ph(ortho)); 7.30–7.40 (m, 3H, Ph(meta) +NH); 7.22 (d, 7.8 Hz,
1H, 1-H); 7.10 (t, 7.8 Hz, 1H, Ph(para)); 6.73 (dd, 7.6 Hz, 2.6 Hz,
1H, 2-H); 6.62 (d, 2.6 Hz; 1H, 4-H); 6.12 (br s, 1H, 17-H); 3.79
(s, 3H, OCH3); 2.84–2.91 (m, 2H, 6-H2); 1.92–2.36 (m, 6H, skele-
ton protons); 1.24–1.61 (m, 7H, skeleton protons); 1.32 (s, 3H,
18-H3); 13C NMR (CDCl3): 168.5; 157.6; 147.5; 138.3; 137.8;
132.9; 129.0 (double intensity); 128.7; 126.2; 124.1; 119.8 (dou-
ble intensity); 113.5; 111.6; 55.2; 47.6; 43.7; 38.3; 36.9; 35.4;
30.1; 26.4; 26.0; 25.6; 19.9; 19.6. IR (KBr (cm−1)): 3328 (NH);
1675 (NCO); 1608 (C C); 1595 (A-ring). MS (m/z/rel.int.): 401/65
(M+), 309/100; 281/8; 207/48; 171/61. Analysis calculated for
C
27H31O2N (M = 401.55): C, 80.76; H, 7.78; N, 3.49; found: C, 80.58;
H, 7.86; N, 3.30. Rf = 0.77 (CHCl3/EtOAc = 95/5); mp. 210–211 ◦C.
Off-white crystalline material.
3-Methoxy-17a-(N-phenylcarboxamido)-13␣-d-homoestra-
1,3,5(10),17-tetraene (8b): 1H NMR (CDCl3): 7.53 (d, 7 Hz, 2H,
Ph(ortho)); 7.26–7.32 (m, 3H, Ph(meta) +NH); 7.20 (d, 8.4 Hz, 1H,
1-H); 7.08 (t, 7 Hz, 1H, Ph(para)); 6.70 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H);
6.62 (d, 2.6 Hz; 1H, 4-H); 6.19 (br s, 1H, 17-H); 3.79 (s, 3H, OCH3);
2.84–2.92 (m, 2H, 6-H2); 1.90–2.47 (m, 6H, skeleton protons);
1.07–1.50 (m, 7H, skeleton protons); 1.51 (s, 3H, 18-H3); 13C
NMR (CDCl3): 168.5; 157.6; 143.9; 138.2; 138.0; 133.0; 131.0;

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A. Takács et al. / Steroids 75 (2010) 1075–1081
129.0 (double intensity); 126.6; 124.1; 119.7 (double intensity);
113.5; 111.6; 55.2; 46.6; 42.6; 37.9; 37.7; 36.4; 31.9; 30.4; 28.9;
26.9; 21.4; 18.8. IR (KBr (cm−1)): 3425 (NH); 1668 (NCO); 1602
(C C); 1590 (A-ring). MS (m/z/rel. int.): 401/100 (M+), 309/86;
281/14; 173/93. Analysis calculated for C27H31O2N (M = 401.55):
C, 80.76; H, 7.78; N, 3.49; found: C, 80.50; H, 7.92; N, 3.23. Rf = 0.59
(CHCl3/EtOAc = 98/2); Mp. 223–224 ◦C. Off-white crystalline
material with pinkish tinge.
3-Methoxy-17a-[N,N-(1ꢀ-methoxycarbonyl-1ꢀ,4ꢀ-
butanediyl)carboxamido]-d-homoestra-1,3,5(10),17-tetraene
(7e, 85/15 mixture of two isomers due to C(O)–N hindered rota-
tion): 1H NMR (CDCl3) (major/minor isomer): 7.20 (d, 8.4 Hz, 1H,
1-H); 6.71 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.60 (d, 2.6 Hz; 1H, 4-H);
5.68/5.52 (br s, 1H, 17-H); 4.42 (d, 7.2 Hz, 1H, NCH); 3.78 (s, 3H,
OCH3); 3.76 (s, 3H, OCH3); 3.50–3.70 (m, 2H, NCH2); 2.82–2.87
(m, 2H, 6-H2); 1.80–2.37 (m, 10H, skeleton protons + (CH2)2);
1.20–1.55 (m, 7H, skeleton protons); 1.24/1.25 (s, 3H, 18-H3). 13C
NMR (CDCl3) (major/minor isomer): 172.7/173.3; 170.1/170.3;
157.3; 144.4/144.8; 137.6; 132.8/132.6; 126.3/127.0; 126.0/125.9;
113.3; 111.3; 58.1/57.8; 55.0; 51.8/52.0; 49.3; 47.2/46.9; 43.5/43.4;
38.2; 36.9/36.6; 35.2; 29.9/30.8; 29.3; 26.2; 25.9/25.7; 25.1/24.8;
24.4; 19.9/20.2; 19.5. IR (KBr (cm−1)): 1747 (COO); 1657 (NCO);
1614 br (C C + A-ring). MS (m/z/rel. int.): 437/70 (M+), 422/100;
378/15; 309/76. Analysis calculated for C27H35O4N (M = 437.58):
C, 74.11; H, 8.06; N, 3.20; found: C, 74.02; H, 8.27; N, 3.11. Rf = 0.61
(CHCl3/EtOAc = 80/20). Yellow highly viscous material.
3-Methoxy-17a-[(N,N-(1ꢀ,5ꢀ-pentanediyl)carboxamido)]-d-
homoestra-1,3,5(10),17-tetraene (7c): 1H NMR (CDCl3): 7.20 (d,
8.4 Hz, 1H, 1-H); 6.72 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.62 (d, 2.6 Hz;
1H, 4-H); 5.52 (br s, 1H, 17-H); 3.78 (s, 3H, OCH3); 3.40–3.70
(m, 4H, 2NCH2); 2.85–2.90 (m, 2H, 6-H2); 1.20-2.33 (m, 19H,
skeleton protons + (CH2)3); 1.28 (s, 3H, 18-H3). 13C NMR (CDCl3):
170.4; 157.6; 143.7; 137.9; 133.0; 126.2; 125.0; 113.5; 111.6; 55.2;
48.5; 47.1; 43.7; 42.1; 38.5; 36.7; 35.4; 30.1; 26.6; 26.4 (double
intensity); 25.9; 25.2; 24.8; 20.3; 19.8. IR (KBr (cm−1)): 1655
(NCO); 1618 (C C); 1608 (A-ring). MS (m/z/rel. int.): 393/49 (M+),
378/100; 308/5. Analysis calculated for C26H35O2N (M = 393.57):
C, 79.35; H, 8.96; N, 3.56; found: C, 79.30; H, 9.14; N, 3.41. Rf = 0.69
(CHCl3/EtOAc = 80/20). Mp. 154–155 ◦C. White crystalline material.
3-Methoxy-17a-[(N,N-(1ꢀ,5ꢀ-pentanediyl)carboxamido)]-13␣-
d-homoestra-1,3,5(10),17-tetraene (8c): 1H NMR (CDCl3): 7.19 (d,
8.4 Hz, 1H, 1-H); 6.70 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.60 (d, 2.6 Hz;
1H, 4-H); 5.63 (br s, 1H, 17-H); 3.76 (s, 3H, OCH3); 3.20–3.90 (m,
4H, 2NCH2); 2.80–2.85 (m, 2H, 6-H2); 1.30–2.30 (m, 19H, skeleton
protons + (CH2)3); 1.45 (br s, 3H, 18-H3). 13C NMR (CDCl3): 169.9;
157.3; 139.6; 137.8; 133.0; 128.7; 126.2; 113.1; 111.3; 54.9; 48.6
(br); 47.1 (br); 42.4 (double intensity); 37.6; 36.5 (br); 33.0 (br);
30.1; 28.4; 26.7; 26.3; 25.6; 24.6 (double intensity); 20.7; 18.7.
IR (KBr (cm−1)): 1645 (NCO); 1603 (C C); 1608 (A-ring). MS
(m/z/rel. int.): 393/67 (M+), 378/100; 308/10. Analysis calculated
for C26H35O2N (M = 393.57): C, 79.35; H, 8.96; N, 3.56; found:
C, 79.21; H, 9.18; N, 3.40. Rf = 0.59 (CHCl3/EtOAc = 90/10). Mp.
96–97 ◦C. White crystalline material.
3-Methoxy-17a-[N,N-(1ꢀ-methoxycarbonyl-1ꢀ,4ꢀ-
butanediyl)carboxamido]-13␣-d-homoestra-1,3,5(10),17-
tetraene (8e, 80/20 mixture of two isomers due to C(O)–N
hindered rotation): 1H NMR (CDCl3) (major/minor isomer): 7.18
(d, 8.4 Hz, 1H, 1-H); 6.70 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.60 (d,
2.6 Hz; 1H, 4-H); 5.98/5.86 (br s, 1H, 17-H); 4.58 (t, 7.4 Hz, 1H,
NCH); 3.76 (s, 3H, OCH3); 3.74 (s, 3H, OCH3); 3.45–3.65 (m, 2H,
NCH2); 2.78–2.87 (m, 2H, 6-H2); 1.80–2.37 (m, 10H, skeleton pro-
tons + (CH2)2); 0.96–1.50 (m, 7H, skeleton protons); 1.45/1.40 (s,
3H, 18-H3). 13C NMR (CDCl3) (major/minor isomer): 173.1/172.1;
169.7; 157.3; 141.8/140.4; 137.9/137.7; 133.1/132.9; 130.9/129.9;
126.4/126.1; 113.2; 111.4; 58.2/58.5; 55.0; 52.0; 49.8; 46.9;
42.7/42.5; 37.8; 36.5/36.3; 32.5; 30.7/30.2; 29.1; 28.5/27.9; 26.8;
25.6/24.8; 22.2/21.0; 18.7/18.4; 14.1. IR (KBr (cm−1)): 1747 (COO);
1679 (NCO); 1611 br (C C + A-ring). MS (m/z/rel. int.): 437/65
(M+), 422/100; 378/10; 309/39. Analysis calculated for C27H35O4N
(M = 437.58): C, 74.11; H, 8.06; N, 3.20; found: C, 73.98; H, 8.29;
N, 3.01. Rf = 0.72 (CHCl3/EtOAc = 80/20). Mp. 78–80 ◦C. White
crystalline material.
3-Methoxy-17a-methoxycarbonyl-d-homoestra-1,3,5(10),17-
tetraene (9): 1H NMR (CDCl3): 7.22 (d, 8.4 Hz, 1H, 1-H); 6.66–6.73
(m, 2H, 2-H + 17-H); 6.62 (br s, 1H, 4-H); 3.80 (s, 3H, OCH3); 3.72
(s, 3H, COOCH3); 2.82–2.91 (m, 2H, 6-H2); 2.49 (d, 13.0 Hz, 1H,
16-Ha); 1.90–2.35 (m, 5H, skeleton protons); 1.20–1.65 (m, 7H,
skeleton protons); 1.21 (s, 3H, 18-H3); 13C NMR (CDCl3): 168.0;
157.55; 141.2; 137.6; 133.0; 126.3; 126.21; 113.48; 111.56; 55.2;
51.2; 48.1; 43.6; 39.2; 38.2; 36.6; 35.2; 30.1; 26.5; 26.2; 19.3; 19.0.
IR (KBr (cm−1)): 1709 (COO); 1612 br (C C + A-ring). MS (m/z/rel.
int.): 340/100 (M+), 312/2, 281/10; 228/40; 213/11. Analysis
calculated for C22H28O3 (M = 340.46): C, 77.61; H, 8.29; found:
C, 77.49; H, 8.39. Rf = 0.70 (CHCl3/EtOAc = 98/2). Mp. 95–98 ◦C.
Off-white crystalline material.
3-Methoxy-17a-[N-(1ꢀ-methoxycarbonylethyl)carboxamido]-
d-homoestra-1,3,5(10),17-tetraene (7d): 1H NMR (CDCl3): 7.21 (d,
8.4 Hz, 1H, 1-H); 6.73 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.62 (d, 2.6 Hz;
1H, 4-H); 6.19 (br d, 7.5 Hz; 1H, NH); 6.00 (br s, 1H, 17-H); 4.60 (qi,
7.5 Hz, 1H, NHCH); 3.78 (s, 6H, 2xOCH3); 2.83–2.90 (m, 2H, 6-H2);
1.90–2.33 (m, 6H, skeleton protons); 1.20–1.55 (m, 7H, skeleton
protons); 1.42 (q, 7.5 Hz, 3H, CHCH3); 1.25 (s, 3H, 18-H3). 13C NMR
(CDCl3): 173.6; 170.1; 157.4; 146.4; 137.7; 132.9; 128.6; 126.1;
113.4; 111.5; 55.1; 52.3; 47.7; 47.4; 43.5; 38.2; 36.5; 35.1; 30.0;
26.3; 26.0; 25.5; 19.6; 19.4; 18.3. IR (KBr (cm−1)): 3347 (NH); 1747
(COO); 1660 (NCO); 1632 (C C); 1612 (A-ring). MS (m/z/rel.int.):
411/100 (M+), 396/10; 309/42; 294/24; 280/18. Analysis calcu-
lated for C25H33O4N (M = 411.54): C, 72.96; H, 8.08; N, 3.40; found:
C, 72.80; H, 8.22; N, 3.29. Rf = 0.76 (CHCl3/EtOAc = 80/20); Mp.
159–160 ◦C. White crystalline material.
3-Methoxy-17a-[N-(1ꢀ-methoxycarbonylethyl)carboxamido]-
13␣-d-homoestra-1,3,5(10),17-tetraene (8d): 1H NMR (CDCl3):
7.20 (d, 8.4 Hz, 1H, 1-H); 6.71 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.61 (d,
2.6 Hz; 1H, 4-H); 6.12 (br s, 1H, 17-H); 6.05 (br d, 7.6 Hz; 1H, NH);
4.60 (qi, 7.4 Hz, 1H, NHCH); 3.78 (s, 3H, OCH3); 3.73 (s, 3H, OCH3);
2.83–2.87 (m, 2H, 6-H2); 1.88–2.35 (m, 6H, skeleton protons);
1.02–1.40 (m, 7H, skeleton protons); 1.42 (s, 3H, 18-H3); 1.38 (d,
7.4 Hz, 3H, CHCH3). 13C NMR (CDCl3): 173.5; 169.9; 157.5; 142.7;
137.9; 132.9; 130.7; 126.4; 113.4; 111.5; 55.1; 52.2; 47.6; 46.4;
42.6; 37.5; 37.4; 36.5; 31.7; 30.3; 28.7; 26.8; 21.1; 18.7; 18.3. IR
(KBr (cm−1)): 3392 (NH); 1717 (COO); 1664 (NCO); 1632 (C C);
1608 (A-ring). MS (m/z/rel.int.): 411/100 (M+), 396/5; 309/25;
294/19; 280/23. Analysis calculated for C25H33O4N (M = 411.54):
C, 72.96; H, 8.08; N, 3.40; found: C, 72.77; H, 8.23; N, 3.25. Rf = 0.60
(CHCl3/EtOAc = 90/10); Mp. 152–153 ◦C. Pale yellow crystalline
material.
3-Methoxy-17a-methoxycarbonyl-13␣-d-homoestra-
1,3,5(10),16-tetraene (9ꢀ): 1H NMR (CDCl3): 7.22 (d, 8.4 Hz,
1H, 1-H); 6.73 (dd, 8.4 Hz, 2.6 Hz, 1H, 2-H); 6.62 (br s, 1H, 4-H);
5.82 (br s, 1H, 16-H); 5.61 (br d, 10.0 Hz, 1H, 17-H); 3.80 (s, 3H,
OCH3); 3.71 (s, 3H, COOCH3); 3.00 (br s, 1H, 17a-H); 2.82–2.90 (m,
2H, 6-H2); 1.90–2.35 (m, 6H, skeleton protons); 1.20–1.65 (m, 7H,
skeleton protons); 0.87 (s, 3H, 18-H3); 13C NMR (CDCl3): 174.0;
157.57; 137.3; 134.3; 132.7; 126.30; 126.2; 113.50; 111.67; 55.2;
51.2; 45.5; 42.8; 40.1; 39.2; 38.2;35.4; 30.1; 26.7; 26.3; 26.1; 13.5.
IR (KBr (cm−1)): 1732 (COO); 1612 bar (C C + A-ring). MS (m/z/rel.
int.): 340/100 (M+), 312/2, 281/10; 228/40; 213/11. Analysis
calculated for C22H28O3 (M = 340.46): C, 77.61; H, 8.29; found:
C, 77.35; H, 8.44. Rf = 0.70 (CHCl3/EtOAc = 98/2). Mp. 127–129 ◦C.
White crystalline material.
3-Methoxy-17a-methoxycarbonyl-13␣-d-homoestra-
1,3,5(10),17-tetraene (10): 1H NMR (CDCl3): 7.20 (d, 8.4 Hz,

A. Takács et al. / Steroids 75 (2010) 1075–1081
1079
of the molar ratio of hydrazine (from 5- to 10-fold related to the
starting ketone, 1) nor the increase in the reaction temperature
of hydrazone (3) formation (from 110 ◦C (in 2-methoxy-etanol) to
135 ◦C (in 2-ethoxy-ethanol)) resulted in higher isolated yield of 5.
However, the transformation of 2–6 (via hydrazone 4) was prac-
tically complete under standard hydrazone formation–iodination
conditions and two dehydroiodination products were detected
by GC–MS in traces only (less than 2% each). The high-purity
iodoalkene (6) was isolated by column chromatography in up to
63% yields in a highly reproducible reaction.
Compound 5 and 6 were reacted with CO at atmospheric pres-
sure and various primary or secondary amines as N-nucleophiles
(tert-butylamine (a), aniline (b), piperidine (c), methyl alaninate
(d) or methyl prolinate (e)) in DMF in the presence of palladium(II)
acetate–PPh3 catalyst formed in situ (Scheme 1). The in situ for-
mation of highly reactive, coordinately unsaturated palladium(0)
complexes from palladium(II) acetate has been investigated in
detail [23]. The aminocarbonylation of both 5 and 6 was chemo-
specific resulting in the exclusive formation of the corresponding
17a-carboxamido-16-ene derivatives, 7a-e and 8a-e, respectively.
However, the two substrates differ substantially in reactivity: while
practically complete conversions were obtained in reasonable reac-
tion times by using 5 (run 1, 8, 10 and 14) except for the case when
proline methyl ester was used as N-nucleophile (run 16), up to 71%
conversions were obtained only with 6 under the same reaction
conditions (run 5, 9, 12 and 15) (Table 1).
The smooth work-up procedure of the reaction mixtures, as
well as the isolation of the target amides in excellent purity has
proved that the substrates with iodo-vinyl functionality are good
enol-triflate surrogates. Using the naturally configured 5 (13␤), the
highest reactivities were observed with sterically less hindered pri-
mary and secondary amines such as tert-butyl-amine (a), aniline
(b), piperidine (c) and methyl alaninate (d). The corresponding car-
boxamides were isolated in yields of up to 84%. The amino acid ester
with a sterically hindered secondary amine functionality (methyl
prolinate, e) resulted in definitely lower yield. Surprisingly, aniline
(b) with low basicity (usually being less reactive than the other pri-
mary amines) reacted with practically complete conversion. It was
revealed by detailed GC–MS studies on the aminocarbonylation of
5 with a (runs 2–4) and c (run 11) as N-nucleophiles, that high con-
versions can be obtained even much shorter reaction times than
the normally used 20 h.
Although the order of reactivity is very similar to that of the
natural 13␤ series, that is, a being most and e less reactive, much
lower conversions and, consequently, isolated yields were obtained
(Table 1). Under carbon monoxide at atmospheric pressure, 45%
conversion was obtained with a (run 5), and practically no reaction
was observed with e (run 17). It is worth noting that the conversions
can be increased substantially by applying higher carbon monoxide
pressure (40 bar), and as a consequence of that, isolated yields of
practical importance were obtained with a (runs 6 and 7), with c
(run 13), and even with the less reactive e (run 18).
Scheme 1. Synthesis of 3-methoxy-17a-carboxamido-d-homoestra-1,3,5(10),17-
tetraene (7a–e) and 3-methoxy-17a-carboxamido-13␣-d-homoestra-1,3,5(10),17-
tetraene (8a–e) derivatives via aminocarbonylation of 5 and 6, respectively.
1H, 1-H); 6.70–6.76 (m, 2H, 2-H, 6.62 (br s, 1H, 17-H); 3.79 (s,
3H, OCH3); 3.69 (s, 3H, COOCH3); 2.80–2.90 (m, 2H, 6-H2); 2.67
(d, 13.0 Hz, 1H, 16-Ha); 1.90–2.37 (m, 5H, skeleton protons);
0.98–1.40 (m, 7H, skeleton protons); 1.39 (s, 3H, 18-H3); 13C NMR
(CDCl3): 167.9; 157.4; 139.1; 137.8; 137.1; 133.1; 126.2; 113.3;
111.9; 55.1; 51.0; 46.8; 42.7; 37.2; 37.1; 36.4; 30.9; 30.2; 27.9;
26.8; 21.9; 18.5. IR (KBr (cm−1)): 1708 (COO); 1609 br (C C + A-
ring). MS (m/z/rel. int.): 340/100 (M+), 325/3, 293/5; 225/10;
186/32. Analysis calculated for C22H28O3 (M = 340.46): C, 77.61; H,
8.29; found: C, 77.40; H, 8.51. Rf = 0.70 (CHCl3/EtOAc = 98/2). Mp.
135–136 ◦C. Pale-brown crystalline material.
3. Results and discussion
According to
a general carbonylation methodology, the
iodoalkene functionality undergoes various carbonylation reac-
tions in the presence of amines, alcohols or H2O as HX-type
nucleophiles resulting in a facile synthesis of the corresponding
amides, esters or carboxylic acids, respectively. Two 13-epimers
of 3-methoxy-17a-iodo-d-homoestra-1,3,5(10),17-tetraene (13␤,
In addition to the N-nucleophiles, methanol as O-nucleophile
was also used in alkoxycarbonylation of 5 and 6 carried out under
carbon monoxide at atmospheric pressure (Scheme 2). Even more
pronounced difference in reactivity was observed in methoxy-
carbonylation than in aminocarbonylations, that is, while 5 was
completely converted in 20 h, 6% conversion was achieved with
6 under same conditions. Similarly to aminocarbonylation, the
conversion of 6 into the methoxycarbonylated product 10 was effi-
ciently increased to 88% rising the carbon monoxide pressure to 40
bar.
‘natural’,
5 and 13␣, ‘epi’, 6) were used as substrates in
homogeneous carbonylations. They were synthesized from the
corresponding 17a-ketone epimers (1 and 2, respectively) via
their hydrazones (3 and 4, respectively) (Scheme 1). A published
method based on the ketone–hydrazone–iodoalkene reaction path-
way with some modifications was used [21,22]. Using the similar
procedure for the synthesis of 5 and 6, significant differences in
yields were observed. Low yields (up to 64%, isolated yields up
to 37%) were obtained for 5. Detailed GC–MS studies revealed
that the formation of the target compound (5) is always accom-
panied by that of the four different dehydroiodination products
possessing carbon–carbon double bonds in different positions of
the d-ring. Furthermore, it turned out that neither the increase
Surprisingly, the product composition differ completely: while
the alkoxycarbonylation of 6 (13␣-epimer) resulted in the forma-
tion of 10 with the expected 17-ene structure exclusively, that
of the 5 gave two products in a ratio of 55/45. Detailed NMR

1080
A. Takács et al. / Steroids 75 (2010) 1075–1081
Scheme 2. Synthesis of 3-methoxy-17a-methoxycarbonyl-d-homoestra-1,3,5(10),17-tetraene (9) and 3-methoxy-17a-methoxycarbonyl-13␣-d-homoestra-1,3,5(10),17-
tetraene (10) via alkoxycarbonylation of 5 and 6, respectively.
investigations, including 2D techniques such as NOESY and ROESY,
revealed that in addition to the expected ␣-unsaturated ester (17-
ene derivative, 9) its 16-ene isomer (9ꢀ) was also formed.
tions can be proved also by the acceptable yields in the sterically
hindered 13␣ series which could not be achieved by conventional
reactions.
The significant difference between the reactivity of 5 and 6 both
in amino- and alkoxycarbonylations can be explained by the dif-
ferent C/D-ring anellations. The cis-C/D anellation in 6 resulted
in a sterically congested arrangement of ring C and D. The close
proximity of the axial 11␤-H of the methylene group in position-
11 and the axial H atom at C-8, makes the oxidative addition
of the 17a-iodo-17-ene moiety to palladium(0)-complex forming
an alkenyl-palladium(II) complex (A) sterically highly disfavored
(Scheme 3). Therefore, the consecutive catalytic steps, the activa-
tion and insertion of carbon monoxide, resulting in the terminal
carbonyl complex (B) and the acyl-palladium(II) complex (C),
respectively, and the product forming reductive elimination are
also much slower than the corresponding elementary steps involv-
ing 5. All of the latter elementary steps are facile reactions due
to the trans anellation of the C/D-rings and therefore, less steric
congestion.
Acknowledgments
The authors thank the Hungarian Scientific Research Fund
(NKTH-OTKA CK78553, K72309), the Joint Project of the Euro-
pean Union—Hungarian National Development Program and
Science (GVOP-3.2.1-2004-04-0168/3), Research Team on Inno-
vation (SROP-4.2.2./08/1/2008-0011) for financial support, and
Johnson Matthey for the generous gift of palladium(II) acetate.
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