Facile synthesis of 17-formyl steroids via palladium-catalyzed homogeneous carbonylation reaction.

Article abstract of DOI:10.1016/S0039-128X(02)00035-1

17-formyl-androst-16-ene and its analogues were synthesized from the corresponding 17-iodo-16-ene derivatives in palladium-catalyzed formylation reaction using tributyltin hydride as hydrogen source under mild reaction conditions. The formation of androst-16-ene and its isomerization products, as well as that of analogous steroidal olefins as side-products, was found to be dependent on the reaction conditions. The formylation reaction tolerates various functional groups on the A and B rings of the steroids. Copyright 2002 Elsevier Science Inc.

Full text of DOI:10.1016/S0039-128X(02)00035-1

Steroids 67 (2002) 777–781
Facile synthesis of 17-formyl steroids via palladium-catalyzed
homogeneous carbonylation reaction
Andrea Petza, Judit Horváthb, Zoltán Tubab, Zoltán Pintérc, László Kollára,c,∗
a
Department of Inorganic Chemistry, University of Pécs, Ifjúság u. 6, P.O. Box 266, H-7624 Pécs, Hungary
b
Chemical Works of Gedeon Richter Ltd., Budapest, Hungary
c
Research Group for Chemical Sensors of the Hungarian Academy of Sciences, P.O. Box 266, H-7624 Pécs, Hungary
Received 29 June 2001; received in revised form 6 March 2002; accepted 20 March 2002
Abstract
17-Formyl-androst-16-ene and its analogues were synthesized from the corresponding 17-iodo-16-ene derivatives in palladium-catalyzed
formylation reaction using tributyltin hydride as hydrogen source under mild reaction conditions. The formation of androst-16-ene and its
isomerization products, as well as that of analogous steroidal olefins as side-products, was found to be dependant on the reaction conditions.
The formylation reaction tolerates various functional groups on the A and B rings of the steroids. © 2002 Elsevier Science Inc. All rights
reserved.
Keywords: Steroids; 17-Iodo-16-enes; 17-Formyl-steroids; Tributyltin hydride; Palladium catalysts; Carbonylation
1. Introduction
on the application of simple starting materials like easily
accessible iodoalkenes [7] provides a novel approach for
the synthesis of formyl steroids. Furthermore, the unde-
sired side-reactions and the effect of some of the reaction
parameters on yields will also be discussed.
The homogeneous catalytic functionalization of bio-
logically important skeletons, among them steroids, is an
efficient method for the synthesis of new derivatives. The
formyl group (especially at the distinguished position-17
of an androstane-skeleton) may serve as a functionality
for further build-up of a steroid. Although steroidal formyl
derivatives, which possess formyl group attached to the
D-ring, are available via homogeneous hydroformylation of
steroidal alkenes, in most cases rather complex mixture of
formyl stereoisomers has been obtained [1].
The palladium-catalyzed carbon monoxide-based formy-
lation reaction [2] involves either the use of CO/H2 mixture
[3], sodium formate [4] or that of poly(methylhydrosiloxane)
[5] as hydrogen source and aryl or allyl halides as sub-
strates. A low-pressure versatile formylation reaction has
also been developed for the conversion of aryl, benzyl, and
vinyl halides using tributylstannane as a hydrogen donor and
Pd(PPh3)4 as catalyst [6].
2. Experimental
Pd(OAc)2, PPh3, dppp, dppb, and tributyltin hydride were
commercial products. Commercial DMF and Et3N were
used without further purification. Toluene was dried over
sodium and distilled under argon. Steroidal 17-iodo-16-enes
were synthesized according to an analogous method by
using the 17-keto derivatives. They were converted into
hydrazones, those were treated with iodine in the presence
of a base resulting in the formation of the corresponding
17-iodo-16-enes, 1–5 [7–10].
1
The H and 13C NMR spectra were recorded on a VAR-
IAN INOVA 400 spectrometer at 400 and 100.58 MHz,
respectively. The chemical shifts are given as δ values
(ppm), with tetramethylsilane as the internal standard. GLC
analyses were carried out with a HP-5890/II gas chromato-
graph using a 15 m HP-5 column (temperature program:
initial temperature: 200 ◦C ((2 min), rate: 10 ◦C/min, fi-
nal temperature: 300 ◦C, flow rate: 0.976 ml/min (constant
flow))).
In the present paper, we report on the efficient novel syn-
thesis of steroids possessing 17-formyl-16-ene moiety in
palladium-catalyzed carbonylation of ‘iodo-vinyl’ steroids
bearing 17-iodo-16-ene functionality. Our method based
∗
Corresponding author. Tel.: +36-72-327622; fax: +36-72-501527.
E-mail address: kollar@ttk.pte.hu (L. Kolla´r).
0039-128X/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.
PII: S0039-128X(02)00035-1

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A. Petz et al. / Steroids 67 (2002) 777–781
2.1. General procedure for the synthesis of steroidal
formyl derivatives
C, 75.71; H, 9.03; N, 4.65; Found: C, 75.49; H, 9.31;
N, 4.33.
2.2.4. 17-Formyl-3-methoxy-estra-1,3,5(10),16-tetraene (9)
1H NMR (CDCl3, 400 MHz): 9.73 (s, 1H, CHO); 6.70
(d, 8.4 Hz, 1H, 1-CH); 7.19 (dd, 3.2 Hz, 8.4 Hz, 1H, 2-CH);
6.81 (dd, 2.0 Hz, 3.6 Hz, 1H, 16-CH); 6.62 (d, 3.2 Hz, 1H,
4-CH); 3.76 (s, 3H, OCH3); 2.86 (m, 2H, 6-CH2); 2.3
(m, 4H; skeleton protons); 2.05 (ddd, 1H, 15-HaHb); 1.9
(m, 1H, 15-HaHb); 1.6 (m, 4H; skeleton protons); 1.4 (m,
1H; skeleton proton); 0.96 (s, 3H, 18-CH3); MS (m/z/rel.
int.): 296/100 (M+); 173/50; 160/62. Analysis calculated
for C20H24O2 (M = 296.41): C, 81.04; H, 8.16; Found: C,
80.83; H, 8.40.
A mixture of an ‘iodo-vinyl’ derivative (1 mmol), palla-
dium(II) acetate (11.2 mg, 0.05 mmol), and triphenylphos-
phine (26.2 mg, 0.1 mmol) (or 1,4-bis(diphenylphosphino)-
butane (dppb), 1,3-bis(diphenylphosphino)-propane (dppp)
0.05 mmol)) were dissolved in 14 ml toluene under argon.
The atmosphere was changed to carbon monoxide (1 bar),
then tributyltin hydride (0.32 ml, 1.2 mmol) dissolved in
3 ml toluene was added dropwise to the reaction mixture at
50 ◦C in 2 h. The reaction was conducted for an additional
6 h. (The composition of the reaction mixture was checked
by TLC and determined by GC-MS.) The solvent was evap-
orated to dryness, and the rest was dissolved in 10 ml of
chloroform. Potassium fluoride (0.2 g) dissolved in 10 ml
water was added and stirred vigorously for 10 h. The organic
layer was separated, dried on sodium sulfate and evapo-
rated. The chromatography (silicagel, toluene/methanol =
4/1) resulted in the formyl-products in 50–75% isolated
yields.
2.2.5. 17-Formyl-6b-hydroxy-3a,5a-cycloandrost-
16-ene (10)
1H NMR (CDCl3, 400 MHz): 9.73 (s, 1H, CHO); 6.80
(dd, 2.0 Hz, 3.4 Hz, 1H, 16-CH); 4.30 (m, 1H, 6-H); 3.3 (t,
1H, 6-OH); 2.20–0.80 (16H; skeleton protons); 1.10 (s, 3H,
18-CH3); 0.97 (s, 3H, 19-CH3); 0.54 (t, 6.5 Hz, 1H, 3-CH);
0.30 (dd, 6 Hz, 11 Hz, 1H, 4-Ha); MS (m/z/rel. int.): 282/55
(M+–H2O); 267/30 ((M+–H2O–CH3); 145/65; 121/100.
Analysis calculated for C20H28O2 (M = 300.44): C, 79.96;
H, 9.39; Found: C, 79.71; H, 9.15.
2.2. Analytical and spectroscopic data of compounds
2.2.1. 17-Formyl-androst-16-ene (6)
1H NMR (CDCl3, 400 MHz): 9.68 (s, 1H, CHO); 6.76
(dd, 1.7 Hz, 3.4 Hz, 1H, 16-CH); 2.34 (ddd, 3.4 Hz, 6.4 Hz,
17.5 Hz, 1H, 15-CHaHb); 2.04 (ddd, 1.7 Hz, 11.9 Hz,
17.5 Hz, 1H, 15-CHaHb); 0.88 (s, 3H, 18-CH3); 0.80 (s, 3H,
19-CH3); 13C NMR (100.58 MHz, CDCl3): 190.1 (CHO);
157.2 (17-C); 153.1 (16-C); 56.6; 55.4; 47.5; 47.2; 38.5;
36.5; 34.4; 33.8; 32.7; 32.1; 29.1; 28.9; 26.8; 22.0; 20.6;
13.6 (18-CH3); 12.2 (19-CH3); MS (m/z/rel. int.): 286/62
(M+); 271/40 (M+–CH3); 257/90 (M+–CHO), 189/100.
Analysis calculated for C20H30O (M = 286.46): C, 83.86;
H, 10.56; Found: C, 83.58; H, 10.28.
2.3. MS data for the side-products (m/z/rel. int.)
2.3.1. Androst-16-ene (1a)
258/46 (M+); 243/100 (M+–CH3); 148/72; 94/86; re-
tention time (RT, under GC conditions specified above):
9.7 min.
2.3.2. Androst-15-ene (1b)
258/69 (M+); 243/45 (M+–CH3); 148/70; 94/100; RT:
10.8 min.
2.2.2. 17-Formyl-4-aza-4-methyl-androst-16-en-3-one (7)
1H NMR (CDCl3, 400 MHz): 9.69 (s, 1H, CHO); 6.77
(dd, 1.6 Hz, 3.2 Hz, 1H, 16-CH); 3.03 (m, 1H, 5-CH); 2.91
(s, 3H, N-CH3); 1.2–2.5 (m, 17H, ring protons); 1.05 (s,
3H, 18-CH3); 0.89 (s, 3H, 19-CH3). MS (m/z/rel. int.):
315/66 (M+); 300/12 (M+–CH3); 286/22 (M+–CHO);
70/100. Analysis calculated for C20H29NO2 (M = 315.46):
C, 76.15; H, 9.27; N, 4.44; Found: C, 75.90; H, 9.02;
N, 4.26.
2.3.3. 4-Aza-4-methyl-androst-16-en-3-one (2a)
287/80 (M+); 272/45 (M+–CH3); 124/50; 70/100; RT:
14.4 min.
2.3.4. 4-Aza-4-methyl-androst-15-en-3-one (2b)
287/52 (M+); 272/5 (M+–CH3); 112/100; 70/41; RT:
14.9 min.
2.3.5. 4-Aza-androst-16-en-3-one (3a)
273/82 (M+); 258/100 (M+–CH3); 147/70; 91/96; RT:
14.3 min.
2.2.3. 17-Formyl-4-aza-androst-16-en-3-one (8)
1H NMR (CDCl3, 400 MHz): 9.60 (s, 1H, CHO);
6.70 (dd, 1.7 Hz, 3.4 Hz, 1H, 16-CH); 6.4 (brs, 1H,
NH); 3.06 (dd, 4.4 Hz, 11.6 Hz, 1H, 5-CH); 2.40 (m,
2H, 2-CH2); 2.10 (ddd, 1H, 15-CHaHb); 1.95 (ddd, 1H,
15-CHbHb); 1.80–0.80 (13H; skeleton protons); 0.99 (s,
3H, 18-CH3); 0.94 (s, 3H, 19-CH3); MS (m/z/rel. int.):
301/60 (M+); 286/38 (M+–CH3); 272/51 (M+–CHO);
56/100. Analysis calculated for C19H27NO2 (M = 301.43):
2.3.6. 4-Aza-androst-15-en-3-one (3b)
273/100 (M+); 258/53 (M+–CH3); 180/55; 98/76; RT:
14.9 min.
2.3.7. 3-Methoxy-estra-1,3,5(10),16-tetraene (4a)
268/100 (M+); 253/20 (M+–CH3); 173/56; 147/40; RT:
15.2 min.

A. Petz et al. / Steroids 67 (2002) 777–781
779
2.3.8. 3-Methoxy-estra-1,3,5(10),15-tetraene (4b)
268/42 (M+); 253/3 (M+–CH3); 173/22; 147/100; RT:
16.1 min.
2.3.9. 6β-Hydroxy-3α,5α-cycloandrost-16-ene (5a)
254/45 (M+–H2O); 239/41 (M+–H2O–CH3); 145/100;
133/84; RT: 10.1 min.
Fig. 2. Products formed in palladium-catalyzed reactions of 17-iodo-
16-enes (1–5).
2.3.10. 6β-Hydroxy-3α,5α-cycloandrost-15-ene (5b)
254/42 (M+–H2O); 239/100 (M+–H2O–CH3); 145/10;
133/21; RT: 10.6 min.
action of palladium–alkenyl intermediate with tributyltin
hydride results in the formation of the 16-ene and via
their isomerization the 15-ene olefinic side products
(androst-16-ene (1a), 4-aza-4-methyl-androst-16-en-3-one
(2a), 4-aza-androst-16-en-3-one (3a), 3-methoxy-estra-1,3,5
(10),16-tetraene (4a), 6␤-hydroxy-3␣,5␣-cycloandrost-
16-ene (5a) and androst-15-ene (1b), 4-aza-4-methyl-and-
rost-15-en-3-one (2b), 4-aza-androst-15-en-3-one (3b),
3-methoxy-estra-1,3,5(10),15-tetraene (4b), 6␤-hydroxy-3␣,
5␣-cycloandrost-15-ene (5b), respectively). The forma-
tion of 16-ene derivatives might occur also via radical
dehalogenation. The olefinic side-products possessing 16-
and 15-ene functionalities were not isolated as pure sub-
stances from the reaction mixtures. They were identified
after base-line separation by GC–MS (see analytical data)
and by using the corresponding reference compounds for
GC and TLC. The reference 16-ene compounds (1a–5a)
of known structure were synthesized from the correspond-
ing iodoalkenes by the method of Cox and Turner [7] and
Barton et al. [8]. The formation of 15-ene side-products
(1b–5b) upon isomerization of 16-ene compounds (1a–5a)
has also been observed for estradiol [12]. The analogous
dehydratation of the corresponding 17-hydroxy steroids
also served as an applicable procedure in our case for
the synthesis of the mixture of 16- and 15-ene derivatives
[12,13]. The 15-ene byproducts show characteristic olefinic
3. Results and discussion
17-Iodo-androst-16-ene (1), 17-iodo-4-aza-4-methyl-and-
rost-16-en-3-one (2), 17-iodo-4-aza-androst-16-en-3-one
(3), 17-iodo-3-methoxy-estra-1,3,5(10),16-tetraene (4),
and 17-iodo-6␤-hydroxy-3␣,5␣-cycloandrost-16-ene (5)
(Fig. 1) were reacted with carbon monoxide and tributyltin
hydride in toluene in the presence of palladium–phosphine
‘in situ’ catalysts. (The ‘in situ’ formation of highly active
Pd(0) catalyst with mono and bidentate phosphines has
been published before [11].) The corresponding 17-formyl-
16-ene derivatives (17-formyl-androst-16-ene (6), 17-
formyl-4-aza-4-methyl-androst-16-en-3-one (7), 17-formyl-
4-aza-androst-16-en-3-one (8), 17-formyl-3-methoxy-estra-
1,3,5(10),16-tetraene
(9),
17-formyl-6␤-hydroxy-3␣,
5␣-cycloandrost-16-ene (10)) were synthesized in moder-
ate to good yields, which depend strongly on the reaction
conditions (Fig. 2, Table 1).
The formation of the two types of products (unsatu-
rated formyl and olefinic derivatives) can be explained
by the following two different reaction mechanisms. The
palladium–alkenyl intermediate which is formed in the
oxidative addition of the ‘iodo-vinyl’ substrate onto the
‘in situ’ formed palladium(0) species may react in two
pathways (Fig. 3). (i) It may insert CO and the acyl in-
termediate formed this way undergoes hydrostannolysis
yielding the target compounds, 6–10. (ii) The direct re-
1
signals in the H NMR of the crude reacion mixtures. The
broad singlets at around 6.6 ppm (6.60, 6.58, 6.60, 6.60,
and 6.63 ppm for 1b, 2b, 3b, 4b, and 5b, respectively) are
characteristic for the 15-ene isomerization compounds. (In
1
addition to GC–MS analysis, the H NMR, based on the
integrals of the olefinic protons, also served as a useful tool
for the quantitative analysis of the product distribution.)
It turned out, that both the conversion and the chemos-
electivity of the reaction is mainly determined by two
factors: (i) the rate of the addition of tributyltin hydride
solution and (ii) the type of the bidentate phosphine.
Upon slow addition of tributyltin hydride to the reac-
tion mixture (see general procedure) hydrogenolysis takes
place to a small extent (15–30%) and the appropriate
17-formyl-derivatives (6–10) are the only formyl-products.
However, when the tributyltin hydride solution was added
within 10 min, the amount of the hydrodehalogenation
products (1a–5a and 1b–5b) predominates (55–65% of the
products) over that of 6–10, especially in case of 3 and 5
Fig. 1. Steroidal 17-iodo-16-ene derivatives (1–5) used as substrates.

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A. Petz et al. / Steroids 67 (2002) 777–781
Table 1
Formylation of 17-iodo-16-enes (1–5) in the presence of Pd(OAc)2 + phosphine catalystsa
Run
Substrate
Methodb
Phosphine
Conversionc (%)
Product distributionc (%)
17-CHO, 6–10
1a–5a
1b–5b
(isolated yields in brackets)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1
1
1
1
1
1
1
1
2
2
2
3
3
3
4
4
5
5
5
A
B
B
A
B
B
B
B
B
A
B
A
A
B
B
B
A
B
B
PPh3
PPh3
dppp
dppb
83
89
90
60
97
43
35
60
81
99
68
54
38
82
88
90
77
92
83
45
23
14
13
36
15
4
14
14
16
32
12
38
41
12
18
8
32
15
10
21
6
27
18
14
21
28
8
47
34
10
23
7
51
18
11
71 (52)
77 (58)
43
79 (70)
69 (53)
68 (52)
72 (55)
63 (52)
40
80 (72)
15
25
78 (70)
59
85 (75)
22
dppb
PPh3 + dppb
dpdcf
PPh3 + dpdcf
PPh3
dppb
dppb
PPh3
dppb
dppb
PPh3
dppb
PPh3
PPh3
dppb
37
17
15
65 (54)
74 (68)
a Reaction conditions: 0.05 mmol Pd(OAc)2, 0.1 mmol PPh3 (or 0.05 mmol diphosphine); 14 ml toluene; 1.2 mmol HSnBu3 (in 3 ml toluene), 50 ◦C,
1 bar CO.
b Method A: HSnBu3 solution added in 10 min; method B: HSnBu3 solution added in 2 h.
c Determined by GC.
Fig. 3. A mechanistic representation of the elementary catalytic steps of formylation and hydrostannolysis resulting in 6–10 and 1a–5a, respectively.
as substrates (80–85% olefinic products). Probably due to
the presence of the NH group of the lactame (4-NH) and
6␤-hydroxy functionalities tributyltin hydride acts mainly
as a hydrodehalogenation agent. The application of flexi-
ble chelating phosphines like dppb and dppp proved to be
superior both to rigid bidentate diphosphine (e.g. dpdcf =
1-diphenylphosphino-2,1ꢀ-[(1-dicyclohexylphosphino)-1,3-
propanediyl]-ferrocene) and monodentate phosphine (PPh3).
The best conversions and selectivities, which enable facile
isolation of the formyl products in good yields (70–75%),
were obtained with palladium–dppb in situ systems.
des (versatile intermediates of potential pharmacologically
important derivatives) can be synthesized in yields of prac-
tical interest in palladium-catalyzed carbonylation reaction
of easily available iodoalkenes as substrates. The reaction
tolerates various functional groups on the A and B rings of
the steroids.
Acknowledgments
L.K. thanks the Hungarian National Science Foundation
(OTKA T35047) and Ministry of Education (FKFP 0242)
for the financial support.
As a summary, it can be stated that under appropriate re-
action conditions conjugated unsaturated steroidal aldehy-

A. Petz et al. / Steroids 67 (2002) 777–781
781
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