Homogeneous catalytic hydroaminomethylation of steroids with aminoalcohols

Article abstract of DOI:10.1016/S0022-328X(99)00226-0

Rhodium-catalyzed carbonylation of several Δ¹⁶ steroids was carried out in the presence of aminoalcohols and new hydroxy-aminomethyl derivatives have been obtained in moderate to good yields. The multi-step reaction is highly chemo- and regioselective. The new compounds containing the hydroxy function can serve as starting materials for further functionalization of the steroid skeleton.

Full text of DOI:10.1016/S0022-328X(99)00226-0

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 586 (1999) 101–105
Homogeneous catalytic hydroaminomethylation of steroids with
aminoalcohols
Emese Nagy a, Ba´lint Heil b, Szila´rd Toro¨s b,*
3
a Research Group for Petrochemistry of the Hungarian Academy of Sciences, H-8201 Veszpre´m PO Box 158, Hungary
b Uni6ersity of Veszpre´m, Department of Organic Chemistry, H-8201 Veszpre´m PO Box 158, Hungary
Received 10 November 1998; received in revised form 25 March 1999
Dedicated to: Professor La´szlo´ Marko´ on the occasion of his 70th birthday in recognition of his outstanding contribution to organometallic
chemistry.
Abstract
Rhodium-catalyzed carbonylation of several D16 steroids was carried out in the presence of aminoalcohols and new
hydroxy-aminomethyl derivatives have been obtained in moderate to good yields. The multi-step reaction is highly chemo- and
regioselective. The new compounds containing the hydroxy function can serve as starting materials for further functionalization
of the steroid skeleton. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Steroid; Homogeneous catalysis; Hydroformylation–aminomethylation; Rhodium catalyst
further acyclic and cyclic alkenes were also transformed
[2]. The international interest in this field is obvious
from the patent literature [3–5]. Laine and coworkers
enhanced the catalytic activity of the system using a
variety of Group 8 transition metal carbonyl precursors
including the mixed ruthenium–iron catalyst [6].
Japanese authors successfully applied the Co2(CO)8-
1,2bis(diphenylphosphino)ethane system in amino-
methylation of propene with morpholine or piperidine
as amines [7]. The isomer distribution of the reaction
product was similar to that for hydroformylation of the
same substrate with Co catalysts. In our laboratory
1. Introduction
As early as 1949, Reppe discovered [1] that
aminomethylation offers a general one-pot process for
the synthesis of amines from olefins and primary or
secondary amines.
The reaction pathways can be formally divided into
three steps: first hydroformylation of the alkene occurs
followed by condensation of the aldehyde formed with
the amine used and finally, subsequent hydrogenation
of the imine or enamine intermediate results in the
product.
The reaction catalyzed by iron pentacarbonyl was
limited to ethylene and propene and required large
quantities of the catalyst in a long reaction. Later,
rhodium
catalysts
prepared
in
situ
from
[{Rh(diene)Cl}2] and tertiary phosphines were proved
to be efficient not only in hydroformylation of unsatu-
rated D16 steroids [8] but also in aminomethylation of
these derivatives [9], producing steroidal compounds
previously synthesised only in a multi-step classical
syntheses [10]. Kalck reported that the [Rh2(m-S-
tBu)2(CO)2(PPh3)2] complex catalyses the aminomethy-
lation of terminal alkenes under low pressure of carbon
monoxide and hydrogen [11]. He pointed out that the
nature of the solvent has a strong influence on the
course of the reaction. In THF, 98% of 1-octene was
* Corresponding author. Tel.: +36-88-422-022; fax: +36-88-427-
492.
E-mail address: toros@almos.vein.hu (S. To3 ro¨s)
0022-328X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00226-0

102
E. Nagy et al. / Journal of Organometallic Chemistry 586 (1999) 101–105
converted with diethylamine and the aminomethyl com-
pound was produced in 80% yield with 98% selectivity
of the linear derivative. A two-step route towards pri-
mary amines was recently presented by Knifton [12].
Ruthenium-catalyzed aminomethylation was reported
to be highly chemo- and regioselective [13].
Aminomethylation has been extended to produce
tertiary polyamines as well [14]. The polymers can be
obtained by condensation of olefines with secondary
polyamines or by the reaction of polyalkenes with
primary or secondary amines.
expected. Conversely, with the functional group on the
16-C, in addition to the coupling with CH2–N– pro-
tons, the 16-H gives further cross-peaks with the 17-
(a,b)H protons as well as with the 15-(a,b)H protons
(max. five cross-peaks). In the COSY spectrum regis-
tered four cross-peaks can definitely be detected: the H
coupling with CH2–N– protons gives three further
couplings (0.72; 1.28; 1.56 ppm). This fact throws light
on the presence of the hydroxy-aminomethyl group in
position 16; from the four possible isomers (16 and 17
a, b) only the 16-hydroxy-aminomethyl derivatives were
formed, proving the high regioselectivity of the
reaction.
As far as the stereoselectivity of the reaction is con-
cerned, the a and b isomers are present in a 60/40%
ratio (Table 2). This is in accordance with our earlier
results in hydroformylation [8] of the same systems.
Varying the phosphine ligand of the catalytic system
from the highly basic PBu3 to the less basic PPh3 the
ratio of the 16a isomer could be enhanced. An attempt
with the well-known (S,S)-DIOP reduced the hydro-
genation activity of the catalyst, but the ratio of the
stereoisomers was only slightly influenced.
Good yields, high chemo- and regioselectivities were
achieved in hydroformylation–aminomethylation of 1
applying aminoalcohols other than 2-(methyl-
amino)ethanol (Table 1, runs 2–5). Similar results have
been obtained with 2 as substrate.
Using 3b-hydroxy-pregna-5,16-diene-20-one (3), the
isolated product (e) turned out to be predominantly 16a
(\95%) according to the NMR measurements. The
double bond in position 5 remains intact even under
relatively severe reaction conditions because of steric
hindrance. The presence of the substituent at C-17 in
In our latest efforts, carbonylation of several D16
steroids was carried out with the rhodium system in
presence of aminoalcohols and new hydroxy-
aminomethyl derivatives were synthesised in good
yields. Some of these results will be described in the
present paper.
2. Results and discussion
Our aim was to study the aminomethylation reaction
of some androstene and pregnene derivatives with the
rhodium catalyst described using hydroxyalkyl-amines
instead of amines. Applying 3b-hydroxy-5a-androst-16-
ene (1) as the model compound (Scheme 1) we carried
out the reaction with 2-(methylamino)-ethanol in the
presence of an Rh–PBu3 catalyst prepared in situ,
under hydroformylation conditions. As shown in Table
1, Scheme 2, high conversion was achieved and 78.4%
of 3b-hydroxy-16a(b)-[N,N-(methyl, 2-hydroxy-ethy-
lamino)methyl]-5a-androstane (see Section 3.2.4,
product (d)) was obtained. The reaction of the 16, 17
double bond was highly chemoselective; no by-products
were detected.
The structure of the product (d) formed was deter-
mined by NMR (1H–1H COSY, HETCOR, NOE)
measurements after isolation. The presence of a hy-
droxy-aminomethyl moiety in position 17 would result
in coupling of the 17-H proton both with CH2–N–
(2.2–2.4 ppm) protons and with the equatorial (a) and
axial (b) protons of 16-C (see Scheme 3). Thus, in the
COSY spectrum a maximum of three cross-peaks is
the pregnadiene
stereoselectivity.
3
has
a
direct influence on
3. Experimental
[{Rh(nbd)Cl}2] (where nbd is 1,5-norbornadiene) was
prepared according to the literature [15].
Scheme 1. Substrates used in our study.

E. Nagy et al. / Journal of Organometallic Chemistry 586 (1999) 101–105
103
Table 1
Aminomethylation of steroids in presence of aminoalcohols a
Run
Substrate
Aminoalcohol
Conv. (%)
Product distribution (%) b
A
B
C
1
2
3
4
5
6
7
8
1
1
1
1
1
2
2
2
2
2
3
CH3NH(CH2)2OH
CH3CH2CH(NH2)CH2OH
H2N–C6H4–OH
86
100
82
96
100
83
80.4
70.2
93
86
75
13.7
7.4
19
8.2
6.5
16.6
19.6
29.8
7.6
7.8
0
0
0
4.4
0
17.4
0
0
78.4
92.6
81
91.8
89.0
83.3
62.9
70.2
92.4
H2N(CH2)3OH
CH3(CH2)2NH(CH2)2OH
CH3NH(CH2)2OH
H2N(CH2)3OH
CH3CH2CH(NH2)CH2OH
H2N–C6H4–OH
9
10
11
CH3(CH2)2NH(CH2)2OH
CH3NH(CH2)2OH
13.7
5
81.1
c
c
c
a Reaction conditions: 1.5 mmol steroid and 3 mmol of aminoalcohol in 10 ml benzene at 120°C and 80 atm of CO/H2 (1:1). Reaction time:
6 h. Catalyst: 0.0375 mmol of [{Rh(nbd)Cl}2]+0.15 mmol of PBu3.
b Determined by GC.
c Not detectable by GC, isolated yield of product C: 32%.
Benzene was dried over sodium and distilled under
argon. Aminoalcohols were purchased from Aldrich and
distilled prior to use.
3.2. Characterisation of the products
3.2.1. (a) 16h,(i)-[N-(3-Hydroxy-propylamino)-
methyl]-5h-androstane
1H- and 13C-NMR spectra were recorded in CDCl3 on
a Varian Unity 300 (Palo Alto, CA) spectrometer at 300
and 75.5 MHz, respectively. Chemical shifts are reported
in l ppm. Gas–liquid chromatographic (GLC) analyses
were performed on a Shimadzu GC-14A gas chro-
matograph fitted with a 5 m HP-1 column. Gas chro-
matography–mass spectroscopy (GC-MS) measure-
ments were made on a Hewlett–Packard 5971 A GC-
MSD spectrometer.
1H-NMR (CDCl3): 0.69 (s, 3H, 18-CH3), 0.76 (s, 3H,
19-CH3), 1.62 (q, 2H, NH–CH2–CH2), 2.86 (t, 2H,
NH–CH2–CH2–), 3.79 (t, 2H, –CH2–OH).
Infrared (IR) spectra were recorded in KBr pellets on
a Specord-IR 75 instrument.
All manipulations were performed under argon using
standard inert techniques.
13C-NMR (CDCl3): 12.2 (C-19), 18.0, 20.0 (C-18),
20.62, 20.75 (C-11), 22.18 (C-2), 26.80 (C-3), 29.04 (C-6),
30.52, 30.73 (C-15), 31.85 (C-4), 32.42, 32.54 (C-7), 35.19,
35.3 (C-16), 35.73 (C-10), 36.36, 36.51 (C-8), 38.71 (C-1),
38.89, 39.49 (C-12), 40.56, 41.42 (C-13), 44.66 (C-5), 46.6,
47.0 (C-17), 50.2, 50.6 (–C
54.99 (C-9), 56.7, 57.2 (N–C
Anal. Calc. for C23H41NO (347.31): C, 79.47; H, 11.90;
N, 4.03. Found: C, 79.39; H, 12.10; N, 3.95%.
Isolated yield: 50%; m.p.: 134–137°C.
6
H2–OH), 53.29 (C-14), 54.83,
H2–CH2–), 64.5 (CH2–N).
6
6
3.1. General procedure
In a typical experiment a mixture of the steroid (1.5
mmol), [{Rh(nbd)Cl}2] (17.4 mg, 0.0375 mmol), the
phosphine ligand (0.15 mmol) and 3 mmol of aminoal-
cohol in benzene (10 ml) was transferred under argon
into a stainless steel autoclave. The autoclave was pres-
surised to 80 bar with 1:1 CO–H2 and placed into an oil
bath. The reaction was followed by GC. Completing the
reaction, the autoclave was cooled, vented and the
reaction mixture subjected to column chromatography
on silica gel with different eluents (hexane, benzene, ethyl
acetate, acetone, methyl alcohol). The separated and
isolated products were characterised by IR, MS and
various NMR techniques, including 2D NMR experi-
ments.
3.2.2. (b) 16h(i)-[N,N-(Methyl, 2-hydroxy-
ethylamino)methyl]-5h-androstane
1H-NMR (CDCl3): 0.69 (s, 3H, 18-CH3), 0.76 (s, 3H,
19-CH3), 2.23 (s, 3H, N–CH3), 2.50 (m, 2H, N–CH2),
3.54 (t, 2H, –CH2–OH).

104
E. Nagy et al. / Journal of Organometallic Chemistry 586 (1999) 101–105
Scheme 2. Aminomethylation reaction of steroids in presence of aminoalcohols.
13C-NMR (CDCl3): 12.2 (C-19), 18.0, 20.0 (C-18),
CH2–CH2–), 44.88 (C-5), 46.6 (C-17), 50.2 (CH2–OH),
53.18, 54.44 (C-14), 54.59, 54.72 (C-9), 56.7 (NH–
CH2–CH2–), 64.5 (CH2–NH), 71.3 (C-3).
Anal. Calc. for C23H41NO2 (363.31): C, 75.97; H,
11.37; N, 3.85. Found: C, 75.63; H, 11.55; N 3.65%.
Isolated yield: 85%; m.p.: 167–169°C.
20.64, 20.75 (C-11), 22.19 (C-2), 26.81 (C-3), 29.05
(C-6), 29.21 (C-4), 30.86, 32.25 (C-15), 32.42, 32.56
(C-7), 32.93, 34.12 (C-16), 35.31 (C-10), 35.77, 36.37
(C-8), 38.73 (C-1), 38.95, 39.52 (C-12), 40.56, 41.36
(C-13), 41.81 (N–C
53.06, 54.86 (C-14), 54.91, 55.03 (C-9), 58.77 (N–C
CH2–OH), 58.13 (N–CH2–CH2–OH), 65.17 (–C
N).
6
H3), 44.92 (C-5), 47.07 (C-17),
6
H2–
H2–
6
6
3.2.4. (d) 3i-Hydroxy-16h(i)-[N,N-(methyl, 2-
hydroxy-ethylamino)methyl]-5h-androstane
Anal. Calc. for C23H41NO (347.31): C, 79.47; H,
11.90; N, 4.03. Found: C, 79.10; H, 12.0; N, 3.85%.
MS (m/z, relative intensity): 316/82, 257/4, 218/4,
88/100, 41/10.
Isolated yield: 62%; m.p.: 154–157°C.
3.2.3. (c) 3i-Hydroxy-16h,(i)-[N-(3-hydroxy-
propylamino)methyl]-5h-androstane
1H-NMR (CDCl3): 0.68 (s, 3H, 18-CH3), 0.76 (s, 3H,
19-CH3), 1.84 (q, 2H, –CH2–CH2–CH2–), 2.50 (m,
2H, –NH–CH2), 2.86 (t, 2H, –CH2–NH), 3.56 (m,
1H, 3a-H), 3.8 (t, 2H, –CH2–OH).
13C-NMR (CDCl3): 12.2 (C-19), 18.0, 20.0 (C-18),
21.07, 21.20 (C-11), 28.68 (C-6), 30.74 (C-2), 31.51,
31.88 (C-15), 32.32, 32.4 (C-7), 35.20, 35.25 (C-16),
35.58, 35.70 (C-8), 36.52 (C-10), 37.05 (C-4), 38.2 (C-1),
38.81, 39.41 (C-12), 40.46, 41.43 (C-13), 44.6 (–CH2–
Scheme 3. Possible regioisomers of the product.

E. Nagy et al. / Journal of Organometallic Chemistry 586 (1999) 101–105
105
Table 2
Dependence of the 16a/16b ratio on the type of the phosphine ligand a
Run
Ligand
Conv. (%)
Product distribution (%)
16a/16b (%)
A
B
C
1
2
3
PBu3
PPh3
(S,S)-DIOP
86
98.5
96
13.7
3.7
9
7.8
17.9
48
78.5
78.4
43
60/40
50/50
55/45
a Reaction conditions: 1.5 mmol 3b-hydroxy-5a-androst-16-ene and 3 mmol of 2-(methylamino)-ethanol in 10 ml benzene at 120°C and 80 atm
of H2/CO (1:1). Reaction time: 6 h. Catalyst: 0.0375 mmol [{Rh(nbd)Cl}2]+0.15 mmol of ligand.
1H-NMR (CDCl3): 0.68 (s, 3H, 18-CH3), 0.76 (s, 3H,
19-CH3), 3.54 (m, 1H, 3a-H), 2.23 (s, 3H, N-CH3), 3.54
(t, 2H, –CH2–OH), 2.52 (t, 2H, N–CH2).
MS (m/z, relative intensity): 372/55, 254/8, 169/7,
88/100, 43/85.
Isolated yield: 32%; m.p.: 197–199°C.
13C-NMR (CDCl3): 12.2 (C-19), 18.0, 20.0 (C-18),
21.04, 21.15 (C-11), 28.64 (C-6), 30.79 (C-2), 31.47, 32.18
(C-15), 32.28, 32.41 (C-7), 32.90, 34.10 (C-16), 35.23,
35.64 (C-8), 35.71 (C10), 37.00 (C-4), 38.15 (C-1), 38.82,
Acknowledgements
39.40 (C-12), 40.56, 41.36 (C-13), 41.73, 41.79 (N–C
44.76 (C-5), 44.83 (N–CH2–CH2–OH), 46.91 (C-17),
52.86, 54.39 (C-14), 54.56, 54.70 (C-9), 58.1, 58.66
(N–CH2–CH2–OH), 65.09, 65.28 (–CH2–N), 71.22
(C-3).
Anal. Calc. for C23H41NO2 (363.31): C, 75.97; H,
11.37; N, 3.85. Found: C, 75.55; H, 11.45; N, 3.40%.
MS (m/z, relative intensity): 332/38, 254/10, 176/13,
149/20, 88/100, 43/100, 41/52.
6 H3),
The authors thank Z. Tuba and S. Maho´ (Chemical
Works of Gedeon Richter Ltd.) for the steroids and Zs.
Cso´k (University of Veszpre´m) for carrying out the
NMR measurements. This work was supported by the
Hungarian National Science Foundation (OTKA grant
T 020185).
6
6
6
References
Isolated yield: 75%; m.p.: 119–121°C.
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