Facile ring opening of 2,3-epoxy-steroids with aromatic amines in ionic liquids

Article abstract of DOI:10.1016/j.steroids.2006.04.006

Efficient ring opening of steroidal 2,3-epoxides with stoichiometric amount of aromatic amines has been carried out using an ionic liquid ([bmim]⁺[BF₄]^-) both as solvent and catalyst. The reactions were completely regio- a

Full text of DOI:10.1016/j.steroids.2006.04.006

steroids 7 1 ( 2 0 0 6 ) 706–711
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/steroids
Facile ring opening of 2,3-epoxy-steroids with aromatic
amines in ionic liquids
a
a,b,∗
c
d
d
Anita Horv a´ th , Rita Skoda-F o¨ ldes
, S a´ ndor Mah o´ , Zolt a´ n Berente , L a´ szl o´ Koll a´ r
a
University of Veszpr e´ m, Department of Organic Chemistry and Research Group for Petrochemistry of the Hungarian Academy of
Sciences, Egyetem u. 10. (P.O. Box 158) H-8200 Veszpr e´ m, Hungary
b
Research Group for Petrochemistry of the Hungarian Academy of Sciences, Egyetem u. 10. (P.O. Box 158) H-8200 Veszpr e´ m, Hungary
Chemical Works of Gedeon Richter Ltd., Budapest, Hungary
University of P e´ cs, Department of Inorganic Chemistry and Research Group for Chemical Sensors of the Hungarian Academy of
c
d
Sciences, Ifj u´ s a´ g u. 6. (P.O. Box 266) H-7624 P e´ cs, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient ring opening of steroidal 2,3-epoxides with stoichiometric amount of aromatic
+
−
Received 29 March 2006
Accepted 25 April 2006
Published on line 5 June 2006
amines has been carried out using an ionic liquid ([bmim] [BF4] ) both as solvent and
catalyst. The reactions were completely regio- and stereoselective in each case. The aminoal-
cohol products have chair conformations in ring A. The ionic liquid-mediated ring opening
can efficiently be carried out with aliphatic amines like morpholine as well.
©
2006 Elsevier Inc. All rights reserved.
Keywords:
Steroids
2,3-Epoxy derivatives
Aminoalcohols
Ionic liquids
1
.
Introduction
phenylamino steroid was synthesized by heating the corre-
sponding 5␣,10␣-epoxide for 100 h at 60 C in the presence
◦
The vicinal amino alcohol moiety is a main structural fea-
ture in a vast number of naturally occurring and synthetic
molecules. Among the synthetic derivatives, chiral auxil-
iaries for asymmetric synthesis and pharmacologically active
compounds represent the two most prominent groups of
compounds [1]. Derivatives of pharmacological importance
include various androstanes with 2-amino-3-ol functionality
that are used as potent neuromuscular blocking agents [2].
Similar steroidal compounds have been shown to inhibit pro-
liferation of leukemia cells [3,4]. Accordingly, several patents
and publications report on methods leading to steroidal amino
alcohols [5–9], but there are only a few examples for the syn-
thesis of aryl amino derivatives [10,11]. A 5␣-hydroxy-10␤-
of boron–trifluoride–etherate reagent and a 100-fold excess
of aniline [10]. The formation of amino alcohols instead of
the expected aziridines was reported in the reaction of 5␣,6␣-
epoxy steroids in the presence of five equivalents of aniline
and boron–trifluoride–etherate reagent in dichloromethane
[11].
One of the most widely used methods for the synthesis
of vicinal amino alcohols is the direct aminolysis of the cor-
responding epoxy-derivatives, mainly due to the facile syn-
thesis of the latter compounds from the readily available
olefins in an optically pure form [1]. However, the ring open-
ing of epoxides usually requires the use of high excess of
the amine, elevated temperature and long reaction time. The
∗
Corresponding author at: University of Veszpr e´ m, Department of Organic Chemistry and Research Group for Petrochemistry of the
Hungarian Academy of Sciences, Egyetem u. 8. (P.O. Box 158) H-8200 Veszpr e´ m, Hungary. Tel.: +36 88 624719; fax: +36 88 624469.
E-mail address: skodane@almos.vein.hu (R. Skoda-F o¨ ldes).
0039-128X/$ – see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2006.04.006

steroids 7 1 ( 2 0 0 6 ) 706–711
707
aminolysis with deactivated or aromatic amines as reagents
is especially problematic. Subsequently, several methods have
been developed to enhance the reactivity of epoxides towards
nucleophilic cleavage by aromatic amines. These include the
use of metal triflates [12,13], metal halides [14], zirconium
sulfophenyl phosphonate [15], transition metal based Lewis
acids [16], fluoro alcohols [17] and silica gel [18]. Currently,
ionic liquids are widely used both as solvents and catalysts
in several reactions because of the enhanced reaction rates
and improved selectivities that can be achieved by these
protocols [19,20]. Simple epoxides have also been shown to
undergo smooth ring-opening with aryl amines in various
ionic liquids like 1-butyl-3-methylimidazolium tetrafluorobo-
30.7; 27.8; 21.7; 20.3; 20.2; 15.1; 13.9. MS (m/z/rel. int.): 395
+
(M )/100, 377/23, 364/8, 349/11, 308/13, 160/27, 107/36, 43/28.
IR(CH Cl , ꢀ (cm 1): 3608, 3481, 3419. Analysis calculated for
−
2
2
C26H37NO2 (395.58): C, 78.94; H, 9.43; N, 3.54; found: C, 78.52;
H, 9.68; N, 3.24. Yield: 82%.
ꢀ
3˛-Hydroxy-2ˇ-((4 -hydroxy-phenyl)-amino)-5˛-androst-17-
one (3b). 1H NMR (ı,CDCl ): 6.67(d, 8.3 Hz, 2H, 3 ,5 -H); 6.45(d,
ꢀ
ꢀ
3
ꢀ
ꢀ
8.3 Hz, 2H, 2 ,6 -H); 3.97(brs, 1H, 3-H); 3.45(brs, 1H, 2-H);
2.50–0.60(m, 26H, ring protons); 0.95(s, 3H, 19-H ); 0.80(s, 3H,
3
+
18-H ). MS (m/z/rel. int.): 397(M )/100, 306/34, 162/23, 109/35.
3
Analysis calculated for C25H35NO3 (397.56): C, 75.53; H, 8.87;
N, 3.52; Found: C, 75.20; H, 9.11; N, 3.31. Yield: 56%
3˛-Hydroxy-2ˇ-(phenyl-amino)-5˛-androst-17-one (3c). 1H
+
−
ꢀ ꢀ
rate ([bmim] [BF4] ) or 1-butyl-3-methylimidazolium hexaflu-
NMR(ı,CDCl ): 7.13(t, 8.4 Hz, 2H, 3 ,5 -H); 6.66(t, 8.4 Hz, 1H,
3
+
−
ꢀ
ꢀ
ꢀ
orophosphate ([bmim] [PF6] ) as solvent [21].
4 -H); 6.55(d, 8.4 Hz, 2H, 2 ,6 -H); 3.96(s, 1H, 3-H); 3.55(s, 1H,
In this paper, the application of this latter method to the
regio- and stereoselective ring opening of 2,3-epoxy-steroids
with aromatic amines is presented. The results are compared
to those obtained using conventional organic solvents.
2-H); 2.50–0.60(m, 26H, ring protons); 0.98(s, 3H, 19-H ); 0.82(s,
3
3H, 18-H3) 13C NMR(ı,CDCl ): 220.1; 147.1; 129.3; 117.4; 112.8;
3
68.3; 55.4; 54.4; 51.3; 47.8; 38.8; 38.3; 36.1; 35.2; 34.6; 32.1;
31.5; 30.7; 27.8; 21.7; 20.2; 15.0; 13.9. MS (m/z/rel. int.): 381
+
(
M )/73, 306/100, 288/40, 243/43, 93/72. Analysis calculated for
C25H35NO2 (381.56): C, 78.70; H, 9.24; N, 3.67; found: C, 78.49;
2
.
Experimental
H, 9.01; N, 3.85. Yield: 48%.
ꢀ
3
˛-Hydroxy-2ˇ-((4 -acetyl-phenyl)-amino)-5˛-androst-17-one
1H and 13C NMR spectra were recorded in CDCl3 on a Varian
Inova 400 spectrometer at 400.13 and 100.62 MHz, respectively.
Chemical shifts ı are reported in ppm relative to CHCl3 (7.26
and 77.00 ppm for H and 13C, respectively). GLC analyses were
carried out with a HP-5890/II gas chromatograph using a 15 m
HP-5 column. Infrared (IR) spectra were recorded in KBr pellets
using an Avatar330 FT-IR instrument. Elemental analyses were
measured on a 1108 Carlo Erba apparatus.
1
ꢀ
ꢀ
(3d). H NMR(ı,CDCl ): 7.78(d, 8.4 Hz, 2H, 3 ,5 -H); 6.52(d, 8.4 Hz,
3
ꢀ
ꢀ
2H, 2 ,6 -H); 3.98(brs, 1H, 3-H); 3.67(brs, 1H, 2-H); 2.50–0.65(m,
26H, ring protons); 2.48(s, 3H, C(O)CH ); 0.99(s, 3H, 19-H );
0.83(s, 3H, 18-H3). 13C NMR(ı,CDCl ): 220.1; 196.4; 150.9; 130.9;
3
3
1
3
127.9; 111.5; 67.9; 55.3; 53.8; 51.3; 47.8; 38.6; 37.6; 36.0; 35.7;
34.6; 32.1; 31.5; 30.6; 27.7; 26.0; 21.7; 20.1; 15.1; 13.8. MS (m/z/rel.
+
int.): 423 (M )/78, 408/6, 395/10, 336/8, 308/16, 288/100, 218/55,
139/30. Analysis calculated for C27H37NO3 (423.59): C, 76.56;
H, 8.80; N, 3.31; found: C, 76.11; H, 9.01; N, 3.58.Yield: 45%.
ꢀ
2
.1.
General procedure for the ring opening of epoxides
3˛-Hydroxy-2ˇ-((4 -nitro-phenyl)-amino)-5˛-androst-17-one
1
ꢀ ꢀ
in ionic liquid
(3e). H NMR(ı,CDCl ): 8.05(d, 8.5 Hz, 2H, 3 ,5 -H); 6.62(d, 8.5 Hz,
2
3
ꢀ
ꢀ
H, 2 ,6 -H); 3.97(brs, 1H, 3-H); 3.48(brs, 1H, 2-H); 2.48–0.60(m,
26H, ring protons); 0.95(s, 3H, 19-H ); 0.82(s, 3H, 18-H ). 13C
In a typical procedure, the steroidal epoxide (0.2 mmol), the
3
3
+
−
aromatic amine (0.2 mmol) and 600 mg [bmim] [BF4] were
placed under argon in a Schlenk-tube equipped with a mag-
netic stirrer and a septum inlet and a reflux condenser with
NMR(ı,CDCl ): 221.2; 152.1; 138.0; 126.4; 111.2; 67.7; 55.2; 53.9;
3
51.4; 47.8; 38.5; 37.4; 36.0; 35.7; 34.5; 32.0; 31.4; 30.8; 27.8; 21.7;
20.1; 15.0; 13.8. MS (m/z/rel. int.): 426(M )/100, 396/55, 339/17,
+
a balloon on the top. The reaction mixture was heated at
208/35, 191/50. Analysis calculated for C25H34N O4 (426.55): C,
70.40; H, 8.03; N, 6.57; found: C, 70.77; H, 8.15; N, 6.75. Yield:
56%.
2
◦
1
3
00 C for 8 h. The mixture was extracted three times with
ml diethyl ether. The etheral extract was analyzed by TLC
and after removal of diethyl ether, by 1H NMR. The prod-
ucts were purified by column chromatography (silica gel, ethyl
acetate/hexane (30:70)) and were crystallized from diethyl
ether.
Any volatiles were removed from the ionic liquid in vacuo
and new load of starting materials (steroid and aromatic
amine) for the next run were added to the ionic liquid and
the atmosphere was changed to argon. The consecutive runs
were conducted for the same reaction time.
2ˇ,3˛-Dihydroxy-5˛-androst-17-one (4) was obtained as a side
product and was characterized by 1H and 13C NMR only. The
chemical shifts of 2-H and 3-H as well as those of C-2 and C-3
correspond well to the chemical shifts of the analogous 2␤,3␣-
dihydroxy-cholestane [22]. 1H NMR(ı,CDCl ): 3.88(m, 2H, 2-H,
3
3-H); 2.50–0.75(m, 26H, ring protons); 0.98(s, 3H, 19-H ); 0.84(s,
3
3H, 18-H3). 13C NMR(ı,CDCl ): 221.2; 71.7; 70.5; 55.3; 51.5; 47.8;
3
40.5; 39.0; 36.2; 35.8; 34.5; 31.8; 31.6; 30.8; 27.9; 21.7; 20.2; 14.5;
13.9.
ꢀ
2
˛,3˛-Epoxy-17-((4 -methyl-phenyl)-imino)-5˛-androstane (5)
2
.2.
Characterization of the products
was obtained as a side product and was characterized by 1H
1
ꢀ
ꢀ
NMR and GC-MS. H NMR(ı,CDCl3): 6.965(d, 8.0 Hz, 2H, 3 ,5 -H);
6.59(d, 8.0 Hz, 2H, 2 ,6 -H); 3.12 (m, 2H, 2-H, 3-H); 2.50–0.60(m,
26H, ring protons); 2.22(s, 3H, 4 -H3); 0.95(s, 3H, 19-H3); 0.78(s,
3H, 18-H3). MS (m/z/rel. int.): 377(M )/83; 362/93; 186/100;
ꢀ
ꢀ
ꢀ
3
(
2
2
3
6
˛-Hydroxy-2ˇ-((4 -methyl-phenyl)-amino)-5˛-androst-17-one
1
ꢀ
ꢀ
ꢀ
3a). H NMR(ı,CDCl3): 6.95(d, 8.4 Hz, 2H, 3 ,5 -H); 6.50(d, 8.4 Hz,
H, 2 ,6 -H); 3.98(brs, 1H, 3-H); 3.51(brs, 1H, 2-H); 2.50–0.75(m,
6H, ring protons); 2.20(s, 3H, 4 -H3); 0.99(s, 3H, 19-H3); 0.83(s,
H, 18-H3). 13C NMR(ı,CDCl3): 221.0; 144.9; 129.9; 126.7; 113.0;
ꢀ
ꢀ
+
ꢀ
144/21; 91/31.
ꢀ
2ˇ-Hydroxy-3˛-((4 -methyl-phenyl)-amino)-5˛-androst-17-one
ꢀ ꢀ
(7). 1H NMR(ı,CDCl3): 6.96(d, 8.4 Hz, 2H, 3 ,5 -H); 6.52(d, 8.4 Hz,
8.4; 55.5; 54.7; 51.3; 47.8; 38.9; 38.5; 36.2; 35.8; 34.6; 32.2; 31.6;

7
08
steroids 7 1 ( 2 0 0 6 ) 706–711
ꢀ
ꢀ
2
2
3
6
2
H, 2 ,6 -H); 4.02(brs, 1H, 2-H); 3.51(brs, 1H, 3-H); 2.50–0.75(m,
Poor results were obtained using the other room tem-
ꢀ
+
−
6H, ring protons); 2.20(s, 3H, 4 -H3); 1.06(s, 3H, 19-H3); 0.85(s,
H, 18-H3). 13C NMR(ı,CDCl3): 221.0; 144.7; 129.8; 126.6; 113.1;
9.4; 55.4; 53.7; 51.4; 47.8; 40.8; 40.5; 35.9; 35.8; 34.5; 31.6; 30.8;
9.1; 28.0; 21.7; 20.2; 20.1; 14.6; 13.9. MS (m/z/rel. int.): 395
M )/100, 377/24, 362/6, 324/7, 288/15, 172/81, 107/82, 83/37.
Analysis calculated for C26H37NO2 (395.58): C, 78.94; H, 9.43;
N, 3.54; found: C, 79.15; H, 9.12; N, 3.35. Yield: 45%.
perature ionic liquid [bmim] [PF6] , only 30% conversion
◦
was achieved under the same reaction conditions (100 C,
2 h). Bu4NBr completely failed to induce any ring opening.
The low reactivity of 1 in epoxide ring opening reaction in
+
+
−
(
[bmim] [PF6] can be explained by the fact that this IL cannot
be considered as innocent solvent due to partial hydrolysis
and formation of species with ‘PF2’ fragments [23].
As a comparison, ring opening was attempted in 1,2-
ethanediol, a usual solvent for the synthesis of 2-alkylamino-
3-ol derivatives [8]. In the presence of a five-fold excess of
3
.
Results and discussion
4
-methyl-aniline 40% conversion was observed after 8 h heat-
◦
3
1
.1.
Ring opening of 2˛,3˛-epoxy-5˛-androstan-
ing at 100 C. The two products, 3a and 4 were obtained in a
7-one with 4-methyl-aniline
1/1 ratio. Upon addition of water (10% based on the amount of
1,2-ethanediol) to the mixture composed of the substrate, 4-
2
␣,3␣-Epoxy-5␣-androstan-17-one (1, Scheme 1) was reacted
methyl-aniline (five equivalent based on the amount of epox-
ide) and of 1,2-ethanediol (0.5 ml/0.1 mmol epoxide), 60% con-
version was achieved and the 3a/4 ratio changed to 1/2. The
use of aprotic solvents, like 1,4-dioxane [24] was completely
inefficient. According to GC and GC-MS measurements, only
3% of ring-opening product 3a was obtained upon heating
the epoxide with five-fold excess of 4-methyl-aniline (2a) at
+
−
+
−
with 4-methyl-aniline (2a) in [bmim] [BF4] , [bmim] [PF6]
and Bu4NBr at 100 C. At this temperature all of the ionic
liquids gave homogeneous solutions of the reagents. In
◦
+
−
[
bmim] [BF4] ring opening took place smoothly with total
conversion of the steroidal epoxide in 2 h using only one
equivalent of the amine reagent. The products (and any unre-
acted starting material) were extracted by diethyl ether and
the extracts were analyzed by TLC and 1H NMR to deter-
mine the conversion of the substrate and the selectivity of the
reaction. Ring opening was completely regio- and stereoselec-
◦
100 C for 8 h. However, a new derivative, which was proved
to be the imine 5 (Scheme 2) according to 1H NMR and GC-
MS measurements, was obtained in 73% yield. (Formation of
imine as a side reaction was observed before, during the con-
densation of 2␣,3␣-epoxy-5␣-androstan-17-one with boiling
aqueous n-butylamine [9].) The use of one equivalent of 2a led
to 5 in 40% yield and no ring-opening product was detected.
As water have been found to catalyze ring-opening in several
cases [9,24], the reaction of 4-methyl-aniline (2a) and 1 was
carried out again under similar conditions (four equivalents
ꢀ
tive, affording 3␣-hydroxy-2␤-((4 -methyl-phenyl)-amino)-5␣-
androst-17-one (3a, Scheme 1) together with 2␤,3␣-dihydroxy-
5␣-androst-17-one (4) as a side product (in less than 5%). The
+
−
ionic liquid [bmim] [BF4] could be reused several times and
no loss of activity or selectivity was observed even after the
third run. 3a was purified by column chromatography and
the exact structure was determined by various spectroscopic
methods ( H, 13C, 31P NMR, 2D NMR techniques including 1H-
1H-COSY, HSQC, HMBC and NOESY, as well as MS, see below).
The formation of 4 can be explained by the presence of
water impurity in ILs. This assumption is supported by the
fact that the deliberate addition of water to the 1,2-ethanediol
solution of 1 and 2a resulted in an increase in the yield of 4
◦
of 2a, 100 C, 8 h in 1,4-dioxane), but in this case in the pres-
1
ence of 10% water (based on the amount of 1,4-dioxane). The
results were almost the same as before, the formation of 3a
and 5 was observed in 4% and 63% yields, respectively.
3.2.
Determination of the structure of the ring
opening-product (3a)
(
see below). A product with an analogous structure had been
1
13
obtained before in the acid-catalyzed ring opening of 2␣,3␣-
epoxycholestane in the presence of water [22].
The H and C chemical shifts of the A-ring nuclei have been
1
1
assigned unequivocally by using H- H COSY, HSQC and HMBC
+
−
Scheme 1 – Ring opening of 2␣,3␣-epoxy-5␣-androstan-17-one (1) with aromatic amines in [bmim] [BF4] .

steroids 7 1 ( 2 0 0 6 ) 706–711
709
Scheme 2 – Reaction of 2␣,3␣-epoxy-5␣-androstan-17-one (1) with 4-methyl-aniline (2a) in 1,4-dioxane.
spectra (in CDCl3 as solvent). The two protons with high chem-
ical shifts (3.51 ppm and 3.98 ppm) correspond to 2-H and 3-H,
respectively. 2-H was distinguished by the coupling with a
geminal pair at 1.70 ppm attached to a carbon with a chemi-
cal shift of 38.5 ppm. This carbon nucleus gave a cross peak
with 19-H3 (at 0.99 ppm) in the HMBC spectrum, so it was
assigned as C-1. On the other hand, the carbon atom that is
attached to the geminal pair at 1.40 ppm and 1.80 ppm, giving
cross peaks with the proton at 3.98 ppm in the 1H- H COSY
spectrum, showed no coupling to 19-H3 in HMBC, so it can
be assigned as C-4. Accordingly, the product is a 2-amino-3-
ol derivative. In the NOESY spectrum, 3-H (at 3.98 ppm) gave
intense cross peaks with both of the protons of the geminal
pair at C-4 (1.40 and 1.80 ppm) and also with 2-H (3.51 ppm). A
weak interaction was also observed between 3-H and 19-H3 (at
conformation of ring A of 3f had been interpreted by the sta-
bilization of this conformation by a combination of relief of
steric strain on the ␤-face of ring A and formation of a hydro-
gen bond between the 3␣-OH and 2␤-N. However, in polar
solvents like DMSO, where intermolecular hydrogen bonds
with the solvent molecules are dominating, the A-ring of 3f
has been reported to exist in chair conformation [28].
In our case, the chair conformation of ring A observed even
in apolar solvents can be explained by the poor nucleophilic
nitrogen of the arylamino group. The lack of an intramolecular
hydrogen bond is confirmed by the infrared spectrum of 3a in
1
−
1
CH2Cl2 that contains three sharp bands at 3608 cm (ꢀOH),
−
1
−1
3481 cm (ꢀasNH2) and 3419 cm (ꢀsNH2).
3.3. Other ring opening reactions in ionic liquids
0
.99 ppm). This is in accordance with a 2␤-amino-3␣-ol struc-
ture where the A-ring is in a chair conformation and both 2-H
and 3-H are in equatorial positions.
Ring opening of 2␣,3␣-epoxy-5␣-androstan-17-one (1) has
been carried out using various other aromatic amine nucle-
+
−
The stereoselectivity of the reaction is consistent with the
classical trans-diaxial opening of cyclic epoxides which max-
imizes orbital overlap and controls regioselectivity (forma-
tion of 3␣-ol products) in spite of the presence of the 19-CH3
group in ␤ position [25–27]. However, it should be noted that
in contrast with 3␣-hydroxy-2␤-arylamino steroids 3a–3e, 3␣-
hydroxy-2␤-alkylamino derivatives adopt a twist-boat confor-
mation of A-ring in CDCl3 as it has been reported for 3␣-
hydroxy-2␤-(4-morpholinyl)-5␣-androst-17-one (3f) [28]. This
is in accordance with our own results that showed prominent
cross peaks between 3-H (3.89 ppm) and 19-H3 (0.90) as well
as between 3-H and 4␤-H (1.84 ppm) in the NOESY spectra of
ophiles (2b–2e, Scheme 1) in [bmim] [BF ] as solvent. The
4
amines 2b–2d were considerably less reactive than 2a (Table 1),
both conversions and selectivities were poorer than with 2a
and there was also a considerable loss of activity when the
ionic liquid was reused (Table 1, entries 2, 4). The only side
product was 2␤,3␣-dihydroxy-5␣-androst-17-one (4) again. No
aminoalcohol was obtained in the presence of 2e, even when
it was used in five-fold excess compared to the epoxide 1.
Although epoxide ring opening in the presence of 4-nitro-
aniline is usually problematic, there are a few examples when
the reaction had been carried out successfully using BiCl [29]
3
and Sn(OTf) or Cu(OTf) [12] as catalysts. In our case, Sn(OTf)
2
2
2
3
f, while no interactions were observed between the 3-H–2-H
was completely ineffective even when it was used in two-fold
excess compared to the epoxide. However, the use of the same
(
2.58 ppm) and the 3-H–4␣-H (1.51 ppm) pairs. The twist-boat
+
−a
Table 1 – Reaction of 2␣,3␣-epoxy-5␣-androstan-17-one (1) with aromatic amines (2a–2e) in [bmim] [BF4]
Entry Product Run 1 Run 2 Run 3
Conversion (%)b Selectivity (%)b,c Conversion (%)b Selectivity (%)b,c Conversion (%)b Selectivity (%)b,c
1
2
3
4
5
6
3a
3b
3c
3d
3e
3e
100
70
75
66
20
>95
86
80
78
<5
73
100
55
>95
84
100
40
>95
85
50
79
35
76
d
d,e
100
a
b
c
◦
+
−
Reaction conditions: 1/amine = 1/1; 100 C, 8 h in [bmim] [BF4] .
Determined by 1H NMR.
Side product: 2␤,3␣-dihydroxy-5␣-androst-17-one (4).
Reaction time: 24 h.
d
e
In the presence of LiOTf. 1/LiOTf = 1/2.

7
10
steroids 7 1 ( 2 0 0 6 ) 706–711
in stoichiometric amount to the epoxide substrate. Also, the
comparison of our results with those obtained in the reaction
of the 2␣,3␣-epoxy-steroid with 4-methylaniline in conven-
tional organic solvents, clearly shows the superiority of the
use of ionic liquids. It has been shown that LiOTf dissolved in
+
−
[
bmim] [BF4] can even induce ring opening in the presence
of 4-nitroaniline.
Acknowledgments
The authors thank the Hungarian National Science Founda-
tion for the financial support (OTKA T048391 and T044800).
R.S.-F. thanks the Hungarian Academy of Sciences for J. Bolyai
fellowship. The MS measurements is kindly acknowledged to
G. Czira (G. Richter Ltd.)
Scheme 3 – Ring opening of 2␣,3␣-epoxy-5␣-androstan-
7-one (1) with morfoline.
1
r e f e r e n c e s
[
[
1] Bergmeier SC. The synthesis of vicinal amino alcohols.
Tetrahedron 2000;56:2561–76.
2] Tuba Z, Mah o´ S, Vizi ES. Synthesis and structure–activity
relationships of neuromuscular blocking agents. Curr Med
Chem 2002;9:1241–53.
[
3] He Q, Jiang DZ. A novel aminosteroid is active for
proliferation inhibition and differentiation induction of
human acute myeloid leukemia HL-60 cells. Leuk Res
1
999;23:369–72.
4] He Q, Na X. The effects and mechanisms of a novel
-aminosteroid on murine WEHI-3B leukemia cells in vitro
Scheme 4 – Ring opening of 2␤,3␤-epoxy-5␣-androstan-
7-one (6) with 4-methyl-aniline (2a).
[
[
1
2
and in vivo. Leuk Res 2001;25:455–61.
5] Hewett CL, Savage DS, inventors; Organon Laboratories
Ltd., United Kingdom, assignee. Improvements in or
relating to new 2␤,16␤-diamino-androstanes. GB Patent
ꢀ
amount of LiOTf led to the formation of 3␣-hydroxy-2␤-((4 -
nitro-phenyl)-amino)-5␣-androst-17-one (3e) in 73% yield (in
1
,138,605 (January 1, 1969).
◦
1
2
4 h at 100 C) according to the H NMR spectrum of the crude
[
6] Savage DS, Sleigh T, Taylor R, inventors; Akzo NV, The
Netherlands, assignee. Novel 2␤,16␤-diamino-androstanes.
Eur Patent 0,288,102 (October 26, 1988).
[7] Sleigh T, Savage DS, Clark JK, inventors; Akzo NV, The
Netherlands, assignee. Novel 16-homo-piperidino-
androstane derivatives and processes for their preparation.
Eur Patent 0,330,253 (30 August 1989).
8] Campbell AC, inventor; Akzo Nobel NV, The Netherlands,
assignee. Substituted 2␤-morfolino-androstane derivatives.
Eur Patent 0,656,365 (7 January 1995).
[9] Hewett CL, Savage DS. Amino-steroids. Part III. 2- and
3-Amino-5␣-androstanes. J Chem Soc (C) 1968:1134–40.
[10] Ponsold K, Schade W, Wunderwald M. Darstellung von
reaction mixture (Table 1, entry 6). At the same time, LiOTf
dissolved in dioxane was equally effective leading to the same
product in 65% after heating the reaction mixture for 24 h.
The products 3b–3e were all proved to be the 3␣-hydroxy-
2␤-amino derivatives according to their NMR spectra.
As a comparison, 2␣,3␣-epoxy-5␣-androstan-17-one (1)
[
was also reacted with an aliphatic amine, morpholine.
+
−
No reaction was observed either in [bmim] [BF4] or 1,2-
ethanediol with one equivalent of the amine. Upon using mor-
pholine in five-fold excess, 3f (Scheme 3) was obtained in 70%
◦
+
−
and 80% yield after heating at 100 C for 8 h in [bmim] [BF4]
and 1,2-ethanediol, respectively.
1
1
0␤-heterosubstituierten Steroiden. J Prakt Chem
975;317:307–18.
2␤,3␤-Epoxy-5␣-androstan-17-one (6) was found to be less
[
11] Agarwal V, Husain S, Gupta KC. Reaction of aniline with
steroidal ␣-epoxides. J Indian Chem Soc 1995;72:639–40.
12] Sekar G, Singh VK. An efficient method for cleavage of
epoxides with aromatic amines. J Org Chem 1999;64:
287–9.
ꢀ
reactive than 1. It could be converted to 2␤-hydroxy-3␣-((4 -
methyl-phenyl)-amino)-5␣-androst-17-one (7, Scheme 4) in
[
4
5 % isolated yield in the presence of one equivalent of 4-
methylaniline.
[
[
[
13] Ollevier T, Lavie-Compin G. Bismuth triflate-catalyzed mild
and efficient epoxide opening by aromatic amines under
aqueous conditions. Tetrahedron Lett 2004;45:49–52.
14] Ollevier T, Lavie-Compin G. An efficient method for the
ring opening of epoxides with aromatic amines catalyzed
by bismuth trichloride. Tetrahedron Lett 2002;43:7891–3.
15] Curini M, Epifano F, Marcotullio MC, Rosati O. Zirconium
sulfophenyl phosphonate as a heterogeneous catalyst in
the preparation of ␤-amino alcohols from epoxides. Eur J
Org Chem 2001:4149–52.
4
.
Conclusion
Ionic liquid promoted ring opening can be successfully
used for the conversion of steroidal 2,3-epoxides into vici-
nal arylamino-alcohols. The strength of this methodology is
shown by its tolerance towards the various functional groups
of the aromatic amine, as well as by the application of amine

steroids 7 1 ( 2 0 0 6 ) 706–711
711
[16] Zhao PQ, Xu LW, Xia CG. Transition metal-based
[23] Rangits G, Pet o˝ cz G, Berente Z. Koll a´ r. NMR investigation
Lewis acid catalyzed ring opening of epoxides using
amines under solvent-free conditions. Synlett 2004:
of platinum-diphosphine complexes in [BMIM] [PF6] ionic
liquid. Inorg Chim Acta 2003;353:301–5.
8
46–50.
[24] Klimstra PD, Counsell RE, inventors; Searle & Co., Chicago,
USA, assignee. Optionally N-substituted
[
[
17] Das U, Crousse B, Kesavan V, Bonnet-Delpon D, B e´ gu e´ JP.
Facile ring opening of oxiranes with aromatic amines in
fluoro alcohols. J Org Chem 2000;65:6749–51.
17-oxygenated-2-amino-5␣-androstan-3-ols. US Patent
3,238,194 (December 12 1962).
18] Chakraborti AK, Rudrawar S, Kondaskar A. An efficient
synthesis of 2-amino alcohols by silica gel catalysed
opening of epoxide rings by amines. Org Biomol Chem
[25] F u¨ rst A, Plattner PA. U¨ ber Steroide und Sexualhormone.
2␣,3␣- und 2␤,3␤-Oxido-cholestane; Konfiguration der
2-oxy-cholestane. Helv Chim Acta 1949;32:275–83.
[26] Barton DHR. The stereochemistry of cyclohexane
derivatives. J Chem Soc 1953:1027–40.
2
004;2:1277–80.
19] Welton T. Ionic liquids in catalysis. Coord Chem Rev
004;248:2459–77.
20] Gordon CM. New developments in catalysis using ionic
liquids. Appl Catal A 2001;222:101–17.
[
[
[
2
[27] Campbell MM, Craig RC, Boyd AC, Gilbert IM, Logan RT,
Redpath J, et al. J Chem Soc Perkin Trans 1979;1:2235–47.
[28] Fielding L, Grant GH. Conformational equilibria in amino
1
13
21] Yadav JS, Reddy BVS, Basak AK, Narsaiah AV. [Bmim]BF4
ionic liquid: a novel reaction medium for the synthesis of
steroids. 1. A H and C NMR spectroscopy and molecular
mechanics study of 3␣-hydroxy-2␤-(4-morpholinyl)-5␣H-
androst-17-one. J Am Chem Soc 1991;113:9785–90.
␤-amino alcohols. Tetrahedron Lett 2003;44:1047–50.
3+
[
22] Cruz Silva MM, Riva S, S a´ e Melo ML. Regioselective
enzymatic acylation of vicinal diols of steroids.
Tetrahedron 2005;65:3065–73.
[29] Swamy NR, Kondaji G, Nagaiah K. Bi catalyzed
regioselective ring opening of epoxides with aromatic
amines. Synth Commun 2002;32:2307–12.