Facile synthesis of steroidal vicinal hydroxysulfides via the reaction of steroidal epoxides with thiols in the presence of an ionic liquid

Article abstract of DOI:10.1055/S-0029-1217031

Ring-opening of steroidal 2,3-epoxides with thiols can be carried out effectively in the Bronsted acidic ionic liquid [Hmim] ⁺[BF₄]^- as a recyclable solvent and catalyst. The use of other ionic liquids/molten salts resulte

Full text of DOI:10.1055/S-0029-1217031

PAPER
4037
Facile Synthesis of Steroidal Vicinal Hydroxysulfides via the Reaction of
Steroidal Epoxides with Thiols in the Presence of an Ionic Liquid
S
ynthesis of Steroi
n
dal
H
ydroxy
i
sulfide
t
s
a Horváth,a,b Dávid Frigyes,c Sándor Mahó,b Zoltán Berente,d László Kollár,e Rita Skoda-Földes*a
a
University of Pannonia, Institute of Chemistry, Department of Organic Chemistry, P.O. Box 158, 8201 Veszprém, Hungary
Fax +36(88)624469; E-mail: skodane@almos.uni-pannon.hu
b
c
d
e
Chemical Works of Gedeon Richter Ltd., P.O. Box 27, 1475 Budapest 10, Hungary
Eötvös Loránd University, Institute of Chemistry, Department of Inorganic Chemistry, Pázmány P. sétány 1/A, 1117 Budapest, Hungary
University of Pécs, Department of Biochemistry and Medical Chemistry, Szigeti u. 12, 7624 Pécs, Hungary
University of Pécs, Department of Inorganic Chemistry, P.O. Box 266, 7624 Pécs, Hungary
Received 20 April 2009
media, such as water,18 fluoroalcohols19 or ionic liq-
uids.20,21
Abstract: Ring-opening of steroidal 2,3-epoxides with thiols can
be carried out effectively in the Brønsted acidic ionic liquid
[Hmim]+[BF4]– as a recyclable solvent and catalyst. The use of other
ionic liquids/molten salts resulted in a decrease in the conversion
and/or in reduced selectivity. In [bmim]+Br–, a conversion of 2,3-
epoxy-17-ones into 2,17- and 3,17-diones was also observed.
However, the results obtained so far by the use of ionic
liquids are somewhat contradictory. Thiolysis of cyclo-
hexene oxide with thiophenol was reported to take place
smoothly at room temperature in [bmim]+Br–.20 At the
same time, however, this solvent was found to be only
moderately effective by Yang et al. in the reaction of the
same epoxide with 4-methylthiophenol, leading to the
product in only 43% yield at 50 °C.21 On comparing the
results obtained in [bmim]+X– type ionic liquids (X = Cl,
Br, BF4), [bmim]+[BF4]– was found to be superior com-
pared to the other two solvents.21 Based on these results
and our previous findings concerning the ring-opening of
steroidal epoxides,8 a systematic investigation into the
thiolysis of 2b,3b-epoxy-5a-androstan-17-one (1;
Scheme 1) was carried out in [bmim]+[BF4]– as solvent
and catalyst.
Key words: catalysis, epoxides, ionic liquids, ring-opening, ste-
roids, thiols
Ring-opening of epoxides in the presence of various nu-
cleophiles such as amines, thiols and alcohols, is an im-
portant synthetic transformation leading to a great variety
of functionalized intermediates.1 However, this reaction is
usually carried out with either a large excess of the nu-
cleophile at elevated temperatures or using relatively
high, often equimolar amounts of Lewis acids as promot-
ers. In order to minimize the amount of harmful reagents
and solvents, much attention has recently been paid to the
use of alternative reaction media. Ionic liquids have been
shown to promote ring-opening of epoxides leading to
1,2-aminoalcohols,2 1,2-azido- or thiocyanoalcohols3 and
1,2-haloalcohols.4–6 Recently, we have synthesized sever-
al 2b-arylamino-3a-hydroxy steroids, which are close
analogues of well-known compounds used as neuromus-
cular blocking agents,7 by the cleavage of steroidal 2,3-
epoxides with arylamines using 1-butyl-3-methylimida-
O
11
H
16
2
Δ
O
H
H
+
RSH
ionic liquid
7
H
1
HO
HO
RS
–
zolium tetrafluoroborate {[bmim]+BF4 } as both solvent
+
and catalyst.8
HO
H
H
As numerous 3a-hydroxy-2b-substituted steroid deriva-
tives, some of them bearing thioether linkages, have been
shown to possess anaesthetic activity,9 we decided to in-
vestigate a similar reaction of steroidal 2,3-epoxides with
thiols as nucleophiles. Thiolysis of epoxides is usually
achieved in the presence of acids,10 bases,11 or Lewis acids
such as lithium-12 or zinc perchlorate,13 AlPW12O40,14
BF3,15 or InCl3.16 Cleavage has also been achieved by mi-
crowave irradiation,17 or by the use of alternative reaction
2a R = Ph
3
2b R = 2-naphthyl
2c R = 2-MeOC6H4
2d R = s-Bu
Scheme 1 Reaction of 2b,3b-epoxy-5a-androstan-17-one (1) with
thiols in [bmim]+[BF4]–
Optimal conditions for ring-opening of 1 were determined
for the reaction with thiophenol (Table 1). In contrast to
the ionic liquid promoted reactions of steroidal epoxides
with aromatic amines,8 thiols had to be used in at least in
five-fold excess in order to obtain the product with good
selectivity (entries 1–3). The side product was 2b,3a-di-
hydroxy-5a-androstan-17-one (3), which is presumably
formed by ring-opening induced by water impurity. The
SYNTHESIS 2009, No. 23, pp 4037–4041
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.10.2009
DOI: 10.1055/s-0029-1217031; Art ID: T07909SS
© Georg Thieme Verlag Stuttgart · New York

4038
A. Horváth et al.
PAPER
Table 1 Reaction of 2b,3b-Epoxy-5a-androstan-17-one (1) with Thiols in [bmim]+[BF4]–a
Entry
R (thiol)
Thiol (equiv)
Conv (%)b
Selectivity (%)b
Yield of 2 (%)
2
3
4
1
Ph
1
2
5
5
5
5
5
5
100
100
100
100
100
100
90
20
35
90
85
81
73
63
70
80
65
10
15
19
27
–
–
2
Ph
–
3
Ph
–
80 (2a)
4c
5d
6
Ph
–
Ph
–
2-naphthyl
2-MeOC6H4
s-Bu
–
70 (2b)
54 (2c)
55 (2d)
7
37
–
8e
80
30
a Reaction conditions: 1 (0.2 mmol), [bmim]+[BF4]– (600 mg), 100 °C, 24 h.
b Determined by 1H NMR.
c Ionic liquid reused after reaction of entry 3.
d Ionic liquid reused after reaction of entry 4.
e Reaction time: 30 h.
ionic liquid could be reused with some loss of selectivity liquids/molten salts or organic solvents did not improve
(entries 4 and 5). As a comparison, when the reaction of 1 the results obtained for these reactions (entries 3–7).
with thiophenol was carried out in toluene (conditions
Interestingly, in the ionic liquid [bmim]+Br–, which was
identical to those in entry 3) a 51% conversion in 24 hours
successfully used before in ring-opening of cyclohexene
was achieved but with total selectivity towards 2a.
oxide,20,21 the prevailing reaction was the formation of an
Ring-opening with other thiols took place with similar re- approximately equimolar mixture of diones 7 and 8
sults in [bmim]+[BF4]– (entries 6–8) except for the reac- (Figure 2, Table 2, entry 4). The same phenomenon was
tion of 2-methoxythiophenol (entry 7). Surprisingly, observed in tetrabutylammonium bromide (TBAB;
2b,3a-bis[(2¢-methoxyphenyl)thio]androstan-17-one (4; Table 2, entry 5). The formation of diones was also ob-
Figure 1) was obtained as a side-product. No formation of served in the absence of thiols. Heating of 5 for 24 hours
diol 3 was observed in this case.
resulted in complete conversion of the epoxide into a
O
2-MeO
2-MeO
C6H4S
C H S
H
Δ
6
4
+
RSH
O
H
H
H
ionic liquid
4
H
5
Figure 1 Side-product formed in the reaction of 2b,3b-epoxy-5a-
androstan-17-one (1) with 2-methoxythiophenol
RS
HO
+
3
When a racemic mixture of sec-thiobutanol (s-BuSH) was
used as the reagent, 2d was formed as a non-separable
mixture of two epimers that could be clearly detected only
in the 13C NMR spectrum of the product.
H
6a R = Ph
6b R = 2-naphthyl
6c R = 2-MeOC6H4
Scheme 2 Reaction of 2a,3a-epoxy-5a-androstan-17-one (5) with
Structures of the new products 2a–d and 4 were deter-
mined through a range of spectroscopic measurements in-
cluding 2D NMR techniques (HSQC, HMBC, TROESY).
Ring-opening was found to be completely regio- and ste-
reoselective in each case, and led to trans-diaxially substi-
tuted products, which is typical of such reactions of
steroidal epoxides.22
thiols in ionic liquids
O
O
O
O
H
H
In contrast to the ring-opening of 1, similar reactions of 5
(Scheme 2) in [bmim]+[BF4]– led to the 3a-hydroxy-2b-
sulfide derivatives 6a and 6c with poor selectivities
(Table 2, entries 1 and 2). The use of other common ionic
7
8
Figure 2 5a-Androstanediones formed from 2a,3a-epoxy-5a-an-
drostan-17-one (5) in [bmim]+Br–
Synthesis 2009, No. 23, 4037–4041 © Thieme Stuttgart · New York

PAPER
Synthesis of Steroidal Hydroxysulfides
4039
Table 2 Reaction of 2a,3a-Epoxy-5a-androstan-17-one (5) with Thiols in Ionic Liquidsa
Entry
R (thiol)
Solvent
Conv (%)b
Selectivity (%)b
Yield of 6 (%)
6
3
1
2
Ph
[bmim]+[BF4]–
[bmim]+[BF4]–
[bmim]+[PF6]–
[bmim]+Br–
TBAB
100
100
–
50
45
50
55
–
2-MeOC6H4
3
Ph
–
4
Ph
100
100
<5
25c
35c
–
5
Ph
–
6
Ph
DMF
7
Ph
toluene
37
93
100
100
100
–
7
8
Ph
[Hmim]+[BF4]–
[Hmim]+[BF4]–
[Hmim]+[BF4]–
[Hmim]+[BF4]–
100
100
92
85 (6a)
88 (6b)
74 (6c)
9
2-naphthyl
2-MeOC6H4
s-Bu
10
11
–
–
a Reaction conditions: 2 (0.2 mmol), thiol (1.0 mmol), ionic liquid (600 mg), 100 °C, 24 h.
b Determined by 1H NMR.
c Diones 7 and 8 were obtained as side products.
53/47 and 49/51 mixture of 7/8 in [bmim]+Br– and TBAB, between Hmim and the corresponding epoxides, as well
respectively.
as by the change in the nucleophilic strength of the nu-
cleophiles upon changing the cation of the IL. The follow-
ing observations may be made with respect to steric
crowding of the cation–epoxide adducts and nucleophilic
strength of the nucleophiles: (i) The coordination of the
[bmim]+ cation to the epoxide functionality should result
in a less crowded arrangement than that of the 1,3-dialkyl-
imidazolium cation (e.g. bmim). Therefore, due to the less
crowded epoxide–monoalkylimidazolium adduct, the nu-
cleophilic attack of the sulfide nucleophile leading to hy-
droxy sulfides 2 and 6 is more favored than in [bmim]+-
based ILs. (ii) The protonated imidazolium cation ‘sol-
vates’ the hard water nucleophile more strongly than the
dialkylated imidazolium derivatives, therefore the sul-
fides behave as much stronger nucleophiles under these
conditions, resulting in the preferred formation of 2 or 6.
Conversely, ‘softer’ 1,3-dialkyl-imidazolium cations such
as alkylimidazolium salts {e.g. [Hmim]+}, more efficient-
ly solvate the softer sulfide nucleophile leading to a de-
crease in its nucleophilic strength. In this way, the
nucleophilic attack of water becomes more pronounced,
resulting in the formation of some dihydroxy derivative 3.
It should be noted that a similar reaction was observed
upon heating epoxide 1 in [bmim]+Br–, resulting in a
62/38 mixture of 7 and 8.
Diones 7 and 8 were identified using MS and NMR spec-
troscopy; their 1H NMR spectra were found to be identical
to previously reported data.23,24
As the rate of epoxide ring-opening in ionic liquids is
thought to be accelerated by hydrogen bond interactions
between the imidazolium cation and the epoxide oxygen,
which facilitates C–O bond cleavage,21 we decided to car-
ry out thiolysis of 5 in the Brønsted acidic ionic liquid N-
methylimidazolium tetrafluoroborate {[Hmim]+[BF4]–}.25
The reactions of thiophenol, 2-thionaphthol and 2-meth-
oxythiophenol took place with good conversion and ex-
cellent selectivity, and led to compounds 6a–c in 74–85%
isolated yields (Table 2, entries 8–10). Unfortunately, no
ring-opening was observed with s-BuSH (Table 2, entry
11), which is consistent with the somewhat reduced reac-
tivity compared to other reagents in the thiolysis of 1 de-
scribed above (Table 1, entry 8).
As a conclusion, it can be stated that ring-opening of ste-
roidal 2,3-epoxides with thiols can be carried out effec-
tively in Brønsted acidic ionic liquid [Hmim]+[BF4]–.
Ionic liquids formerly used in such reactions gave poorer
results. Thiolysis in [bmim]+[BF4]– leads to formation of
the products with acceptable and poor selectivities in the
reactions of 1 and 5, respectively. In [bmim]+Br–, a side-
reaction leading to diones 7 and 8 can be observed.
As a comparison, when the reaction of 1 and thiophenol
was carried out in [Hmim]+[BF4]–, compound 2a was ob-
tained in 90% isolated yield with total conversion and ex-
cellent selectivity. Practically no formation of 3 was
observed.
Since the water content in Hmim- and bmim-type ionic
liquids are very similar, the high selectivity towards hy-
droxy sulfides 2 (in case of 1 as substrate) or 6 (in case of
5 as substrate) can be explained by the strong interaction
Synthesis 2009, No. 23, 4037–4041 © Thieme Stuttgart · New York

4040
A. Horváth et al.
PAPER
1H and 13C NMR spectra were recorded in CDCl3 on a Varian Inova
400 spectrometer at 400.13 MHz and 100.62 MHz, respectively.
Chemical shifts (d) are reported in ppm relative to CHCl3 (d = 7.26
and 77.00 ppm for 1H and 13C, respectively). GC analyses were car-
ried out with a HP-5890/II gas chromatograph using a 15 m HP-5
column. EI MS (70 eV) measurements were performed on a
FISONS TRIO 1000 spectrometer using direct inlet. High-resolu-
tion MS measurements of 6a and 6b were carried out on a Thermo
LTQ FT Ultra mass spectrometer (APCI, 4.8 mA discharge current,
300 °C vaporizer temperature, 320 °C capillary temperature, 50 V
tube lens voltage, solvent: MeOH). The protonated molecular ion
peaks were fragmented by CID at a normalized collision energy of
35%. Elemental analyses were measured on a 1108 Carlo Erba ap-
paratus.
Ionic liquids [bmim]+[BF4]–, [bmim]+[PF6]– and [bmim]+Br– were
commercial products purchased from Fluka, [Hmim]+[BF4]– was
synthesized as described previously,26 by reacting 1-methylimid-
azole with tetrafluoroboric acid. The halide content of the ionic liq-
uids were determined by ion chromatography using a suppressed
conductivity detector {[bmim]+[BF4]–: Cl– = 52.9 ppm, Br– = 237.3
ppm; [bmim]+[PF6]–: Cl– = <13 ppm, Br– = <19 ppm; [bmim]+Br–:
Cl– = <13 ppm; [Hmim]+[BF4]–: Cl– = <13 ppm, Br– = <19 ppm}.
H2O content was measured by the Karl–Fischer method using an
amperometric end-point detection {[bmim]+[BF4]–: 0.44%;
[bmim]+[PF6]–: 0.58%; [bmim]+Br–: 2.4%; [Hmim]+[BF4]–:
0.55%}.
MS (EI): m/z (%) = 448 (8) [M+], 288 (5), 160 (100), 128 (12), 115
(17).
Anal. Calcd for C29H36O2S: C, 77.63; H, 8.09. Found: C, 77.81; H,
7.87.
2b-Hydroxy-3a-(2¢-methoxyphenyl)thioandrostan-17-one (2c)
Yield: 46 mg (54%).
1H NMR (400 MHz, CDCl3): d = 7.36 (d, J = 7.5 Hz, 1 H, 6¢-H),
7.20 (t, J = 7.5 Hz, 1 H, 4¢-H), 6.92 (t, J = 7.5 Hz, 1 H, 5¢-H), 6.84
(d, J = 7.5 Hz, 1 H, 3¢-H), 4.05 (br s, 1 H, 2-H), 3.86 (s, 3 H, OCH3),
3.45 (br s, 1 H, 3-H), 2.40 (dd, J = 8.2, 19.1 Hz, 1 H, 16-Ha), 0.75–
2.20 (m, 19 H, ring protons), 1.02 (s, 3 H, 19-CH3), 0.81 (s, 3 H, 18-
CH3).
13C NMR (100 MHz, CDCl3): d = 221.3, 158.2, 131.8, 128.1, 123.5,
121.1, 110.8, 70.7, 55.8, 55.0, 51.4, 48.1, 47.8, 41.1, 40.5, 36.1,
35.8, 34.5, 31.6, 30.6, 29.0, 27.9, 21.7, 20.1, 14.6, 13.9.
MS (EI): m/z (%) = 428 (18) [M+], 410 (2), 288 (4), 270 (4), 140
(100), 125 (18).
Anal. Calcd for C26H36O3S: C, 72.86; H, 8.47. Found: C, 72.52; H,
8.27.
2b-Hydroxy-3a-(2¢-butyl)thioandrostan-17-one (2d)
Mixture of 2¢-epimers; yield: 42 mg (55%).
1H NMR (400 MHz, CDCl3): d = 4.05 (br s, 1 H, 2-H), 2.82 (br s,
1 H, 3-H), 2.68 (m, 1 H, CH-S), 2.40 (dd, J = 8.8, 19.3 Hz, 1 H, 16-
Ha), 0.75–2.20 (m, 24 H, ring protons, CH3CHS, CH2CHS), 1.00 (s,
3 H, 19-CH3), 0.95 (t, J = 8.0 Hz, 3 H, CH3CH2CHS), 0.84 (s, 3 H,
18-CH3).
13C NMR (100 MHz, CDCl3): d = 221.2, 72.5/72.3, 55.1, 51.4, 47.8,
46.6/46.4, 42.7/42.6, 41.3/41.2, 40.6/40.5, 35.9, 35.8, 34.4, 31.6,
30.6/30.4, 30.2, 30.0, 28.0, 21.7, 21.4/21.1, 20.1, 14.8/14.7, 13.9,
11.4/11.3.
Thiolysis in Ionic Liquids; General Procedure
The steroidal epoxide (0.2 mmol), thiophenol or thiol (1.0 mmol)
and ionic liquid (600 mg) were placed under argon in a Schlenk tube
equipped with a magnetic stirrer, a septum inlet and a reflux con-
denser attached to a balloon. The reaction mixture was heated at
100 °C for 24 h, then cooled and extracted with Et2O (3 × 3 mL).
The organic extract was analyzed by TLC and, after removal of the
Et2O, by 1H NMR. The products were purified by column chroma-
tography (silica gel; EtOAc–hexane, 30:70).
MS (EI): m/z (%) = 378 (10) [M+], 360 (8), 349 (3), 331 (3), 303 (3),
288 (40), 270 (30), 105 (50), 91 (60), 57 (60), 41 (100).
Analytical data of the side-products 3,8 723 and 824 corresponded
well to literature data.
Anal. Calcd for C23H38O2S: C, 72.96; H, 10.12. Found: C, 73.21; H,
10.01.
2b-Hydroxy-3a-phenylthioandrostan-17-one (2a)
Yield: 72 mg (90%) (in [Hmim]+[BF4]–).
2b,3a-Bis[(2¢-methoxyphenyl)thio]androstan-17-one (4)
Yield: 17 mg (15%).
1H NMR (400 MHz, CDCl3): d = 7.37 (d, J = 8.0 Hz, 2 H, o-Ph),
7.27 (t, J = 8.0 Hz, 2 H, m-Ph), 7.20 (t, J = 8.0 Hz, 1 H, p-Ph), 4.06
(br s, 1 H, 2-H), 3.45 (br s, 1 H, 3-H), 2.42 (dd, J = 8.0, 18.0 Hz,
1 H, 16-Ha), 0.80–2.20 (m, 19 H, ring protons), 1.04 (s, 3 H, 19-
CH3), 0.85 (s, 3 H, 18-CH3).
13C NMR (100 MHz, CDCl3): d = 221.2, 135.6, 130.9, 129.0, 126.7,
70.6, 55.1, 51.4, 50.4, 47.8, 41.2, 40.3, 36.1, 35.8, 34.4, 31.5, 30.6,
29.0, 27.9, 21.7, 20.1, 14.5, 13.8.
1H NMR (400 MHz, CDCl3): d = 7.10–7.21 (m, 3 H, aryl), 6.91 (dd
J = 1.6, 7.6 Hz, 1 H, aryl), 6.64–6.77 (m, 4 H, aryl), 3.66 (s, 3 H,
OCH3), 3.65 (s, 3 H, OCH3), 3.55–3.58 (m, 1 H, 3-H), 3.51–3.54
(m, 1 H, 2-H), 0.74–2.47 (m, 20 H, ring protons), 1.10 (s, 3 H, 19-
CH3), 0.85 (s, 3 H, 18-CH3).
13C NMR (100 MHz, CDCl3): d = 221.2, 158.5, 158.2, 133.3, 132.4,
128.6, 128.1, 123.8, 123.1, 120.9, 120.8, 110.8, 110.6, 55.6 (2 × C),
55.0, 51.4, 47.9, 47.3, 46.2, 41.4, 38.5, 36.7, 35.8, 34.7, 31.6, 30.6,
29.3, 27.8, 21.7, 20.1, 14.5, 13.9.
MS (EI): m/z (%) = 398 (20) [M+], 380 (2), 288 (10), 270 (10), 110
(100).
MS (EI): m/z (%) = 550 (12) [M+], 411 (100), 278 (42), 272 (68),
218 (41), 140 (25).
Anal. Calcd for C25H34O2S: C, 75.33; H, 8.60. Found: C, 75.08; H,
8.78.
Anal. Calcd for C33H42O3S2: C, 71.96; H, 7.69; Found: C, 72.27; H,
7.51.
2b-Hydroxy-3a-(2¢-naphthyl)thioandrostan-17-one (2b)
Yield: 63 mg (70%).
3a-Hydroxy-2b-phenylthioandrostan-17-one (6a)
Yield: 68 mg (85%).
1H NMR (400 MHz, CDCl3): d = 7.70–7.82 (m, 4 H, naphthyl),
7.40–7.55 (m, 3 H, naphthyl), 4.10 (br s, 1 H, 2-H), 3.58 (br s, 1 H,
3-H), 2.43 (dd, J = 8.7, 19.5 Hz, 1 H, 16-Ha), 0.75–2.25 (m, 19 H,
ring protons), 1.05 (s, 3 H, 19-CH3), 0.87 (s, 3 H, 18-CH3).
13C NMR (100 MHz, CDCl3): d = 221.2, 133.8, 133.1, 132.1, 129.2,
128.7, 128.6, 127.7, 127.2, 126.6, 126.0, 70.6, 55.1, 51.4, 50.3,
47.8, 41.3, 40.4, 36.1, 35.8, 34.5, 31.6, 30.7, 29.0, 27.9, 21.7, 20.2,
14.6, 13.9.
1H NMR (400 MHz, CDCl3): d = 7.38 (d, J = 7.8 Hz, 2 H, o-Ph),
7.25 (t, J = 7.8 Hz, 2 H, m-Ph), 7.18 (t, J = 7.8 Hz, 1 H, p-Ph), 3.95
(br s, 1 H, 3-H), 3.42 (br s, 1 H, 2-H), 2.41 (dd, J = 8.2, 19.1 Hz,
1 H, 16-Ha), 0.70–2.20 (m, 19 H, ring protons), 1.05 (s, 3 H, 19-
CH3), 0.84 (s, 3 H, 18-CH3).
Synthesis 2009, No. 23, 4037–4041 © Thieme Stuttgart · New York

PAPER
Synthesis of Steroidal Hydroxysulfides
4041
13C NMR (100 MHz, CDCl3): d = 221.2, 136.9, 130.4, 129.0, 126.6,
69.6, 55.2, 51.4, 49.4, 47.8, 38.9, 38.7, 36.4, 35.7, 34.7, 31.8, 31.6,
30.8, 27.8, 21.7, 20.1, 14.2, 13.9.
References
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(2) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.
Tetrahedron Lett. 2003, 44, 1047.
(3) Ranu, B. C.; Adak, L.; Banerjee, S. Can. J. Chem. 2007, 85,
366.
HRMS: m/z [M + H] calcd for C25H35O2S: 399.23523 (delta: 1.53
ppm); found: 399.23584.
MS-MS: m/z 399, m/z 381.
(4) Yadav, J. S.; Reddy, B. V. S.; Reddy, C. S.; Rajasekhar, K.
Chem. Lett. 2004, 33, 476.
(5) Yoshino, H.; Nomura, K.; Matsubara, S.; Oshima, K.;
Matsumoto, K.; Hagiwara, R.; Ito, Y. J. Fluorine Chem.
2004, 125, 1127.
Anal. Calcd for C25H34O2S: C, 75.33; H, 8.60. Found: C, 75.54; H,
8.34.
3a-Hydroxy-2b-(2¢-naphthyl)thioandrostan-17-one (6b)
Yield: 79 mg (88%).
(6) Xu, L.-W.; Li, L.; Xia, C.-G.; Zhao, P.-Q. Tetrahedron Lett.
1H NMR (400 MHz, CDCl3): d = 7.70–7.85 (m, 4 H, naphthyl),
7.40–7.55 (m, 3 H, naphthyl), 4.05 (br s, 1 H, 2-H), 3.57 (br s, 1 H,
3-H), 2.41 (dd, J = 8.4, 19.3 Hz, 1 H, 16-Ha), 0.80–2.15 (m, 19 H,
ring protons), 1.05 (s, 3 H, 19-CH3), 0.5 (s, 3 H, 18-CH3).
13C NMR (100 MHz, CDCl3): d = 221.4, 134.4, 134.0, 132.31,
128.8, 128.7, 128.6, 127.9, 127.5, 126.8, 126.2, 69.8, 55.4, 51.6,
49.6, 48.1, 39.2, 38.9, 36.7, 36.0, 35.0, 32.0, 31.8, 31.0, 28.0, 21.9,
20.4, 14.5, 14.1.
2004, 45, 2435.
(7) Tuba, Z.; Mahó, S.; Vizi, E. S. Curr. Med. Chem. 2002, 9,
1507.
(8) Horváth, A.; Skoda-Földes, R.; Mahó, S.; Berente, Z.;
Kollár, L. Steroids 2006, 71, 706.
(9) Phillips, G. H.; Newall, C. E.; Ayres, B. E. (Glaxo
Laboratories Ltd.) UK 1376892, 1970.
(10) Misra, L.; Lal, P.; Chaurasia, N. D.; Sangwan, R. S.; Sinha,
S.; Tuli, R. Steroids 2007, 73, 245.
HRMS: m/z [M + H] calcd for C29H37O2S: 449.25088 (delta: –1.49
ppm); found: 449.25155.
(11) Ponsold, K.; Schade, W.; Wunderwald, M. J. Prakt. Chem.
1975, 317, 307.
MS-MS: m/z 449, m/z 431.
(12) Azizi, N.; Saidi, M. R. Catal. Commun. 2006, 7, 224.
(13) Shivani Chakraborti, A. K. J. Mol. Catal., A 2007, 263, 137.
(14) Firouzabadi, H.; Iranpoor, N.; Jafari, A. A.; Makarem, S.
J. Mol. Catal., A 2006, 250, 237.
Anal. Calcd for C29H36O2S: C, 77.63; H, 8.09. Found: C, 77.42; H,
7.99.
(15) Concellón, J. M.; el Solar, V.; Suárez, J. R.; Blanco, E. G.
Tetrahedron 2007, 63, 2805.
(16) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L.
Tetrahedron Lett. 2003, 44, 6785.
(17) Mojtahedi, M. M.; Ghasemi, M. H.; Abaee, M. S.;
Bolourtchian, M. ARKIVOC 2005, (xv), 68.
(18) Mukherjee, C.; Maiti, G. H.; Misra, A. K. ARKIVOC 2008,
(xi), 46.
(19) Kesavan, V.; Bonnet-Delpon, D.; Bégué, J. P. Tetrahedron
Lett. 2000, 41, 2895.
3a-Hydroxy-2b-(2¢-methoxyphenyl)thioandrostan-17-one (6c)
Yield: 63 mg (74%).
1H NMR (400 MHz, CDCl3): d = 7.34 (d, J = 7.2 Hz, 1 H, 6¢-H),
7.21 (t, J = 7.2 Hz, 1 H, 4¢-H), 6.91 (t, J = 7.2 Hz, 1 H, 5¢-H), 6.86
(d, J = 7.2 Hz, 1 H, 3¢-H), 3.95 (br s, 1 H, 3-H), 3.88 (s, 3 H, OCH3),
3.41 (br s, 1 H, 2-H), 2.42 (dd, J = 8.6, 19.1 Hz, 1 H, 16-Ha), 0.80–
2.20 (m, 19 H, ring protons), 1.04 (s, 3 H, 19-CH3), 0.85 (s, 3 H, 18-
CH3).
13C NMR (100 MHz, CDCl3): d = 221.2, 158.3, 132.4, 128.4, 124.0,
121.0, 110.9, 69.7, 55.8, 55.3, 51.4, 47.8, 47.6, 38.9, 38.5, 36.4,
35.7, 34.7, 31.9, 31.6, 30.7, 27.8, 21.7, 20.1, 14.4, 13.8.
(20) Ranu, B. C.; Mandal, T.; Banerjee, S.; Dey, S. S. Aust. J.
Chem. 2007, 60, 278.
(21) Yang, M.-H.; Yan, G.-B.; Zheng, Y.-F. Tetrahedron Lett.
2008, 49, 6471.
(22) Kirk, D. N.; Hartshorn, M. P. In Steroid Reaction
Mechanisms; Elsevier: New York, 1968, Chap. 3, 112.
(23) Kametani, T.; Suzuki, Y.; Furuyama, H.; Honda, T. J. Org.
Chem. 1983, 48, 31.
MS (EI): m/z (%) = 428 (6) [M+], 410 (3), 288 (4), 270 (7), 140
(100), 125 (35).
Anal. Calcd for C26H36O3S: C, 72.86; H, 8.47. Found: C, 72.61; H,
8.61.
(24) Abraham, R. J.; Ainger, N. J. J. Chem. Soc., Perkin Trans. 2
Acknowledgment
1999, 441.
(25) Wu, H.-H.; Yang, F.; Cui, P.; Tang, J.; He, M.-Y.
Tetrahedron Lett. 2004, 45, 4963.
(26) Janus, E.; Goc-Maciejewska, I.; Łożyński, M.; Pernak, J.
The authors thank the Hungarian National Science Foundation for
financial support (OTKA NK71906, NI61591) as well as L. Nagy
for ion chromatography measurements.
Tetrahedron Lett. 2006, 47, 4079.
Synthesis 2009, No. 23, 4037–4041 © Thieme Stuttgart · New York