Thionation of some α,β-unsaturated steroidal ketones

Article abstract of DOI:10.3390/molecules15053462

The reactions of selected α,β-unsaturated steroidal ketones with Lawesson's reagent (LR) in CH₂Cl₂ and toluene under the standard reaction conditions and with a combination of phosphorus pentasulfide with hexamethyldisiloxane (P₄S₁₀/HMDO) in 1,2-dichlorobenzene (ODCB) under microwave irradiation were investigated and for this purpose several cholestane, androstane and pregnane carbonyl derivatives were chosen. Depending on the reagent and the solvent, 19 new sulfur containing compounds, including dithiones 4c and 4d, α,β-unsaturated 3-thiones 3a-e, dimer-sulfides 2a-e, 1,2,4-trithiolanes 5a-e and phosphonotrithioates 6b-e were synthesized. All newly prepared compounds were characterized by IR, ¹H- and ¹³C-NMR spectroscopy and elemental analysis.

Full text of DOI:10.3390/molecules15053462

Molecules 2010, 15, 3462-3477; doi:10.3390/molecules15053462
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Thionation of Some α,β-Unsaturated Steroidal Ketones
Natalija M. Krstić 1,*, Mira S. Bjelaković 1, Milan M. Dabović 1 and Vladimir D. Pavlović 2
1
Center for Chemistry, Institute of Chemistry, Technology and Metallurgy, University of Belgrade,
Studentski trg 12-16, P. O. Box. 473, 11001 Belgrade, Serbia;
E-Mails: mbjelak@chem.bg.ac.rs (M.S.B.); mdabovic@chem.bg.ac.rs (M.M.D.)
2
Faculty of Chemistry, University of Belgrade, Student ski trg 12-16, P. O. Box 158, 11001
Belgrade, Serbia; E-Mail: pavlovic@chem.bg.ac.rs (V.D.P.)
* Author to whom correspondence should be addressed; E-Mail: nkrstic@chem.bg.ac.rs;
Tel.: +381-11-3336-666; Fax: +3811-11-2636-061.
Received: 16 April 2010; in revised form: 30 April 2010 / Accepted: 10 May 2010 /
Published: 12 May 2010
Abstract: The reactions of selected α,β-unsaturated steroidal ketones with Lawesson’s
reagent (LR) in CH2Cl2 and toluene under the standard reaction conditions and with a
combination of phosphorus pentasulfide with hexamethyldisiloxane (P4S10/HMDO) in 1,2-
dichlorobenzene (ODCB) under microwave irradiation were investigated and for this
purpose several cholestane, androstane and pregnane carbonyl derivatives were chosen.
Depending on the reagent and the solvent, 19 new sulfur containing compounds, including
dithiones 4c and 4d, α,β-unsaturated 3-thiones 3a-e, dimer-sulfides 2a-e, 1,2,4-trithiolanes
5a-e and phosphonotrithioates 6b-e were synthesized. All newly prepared compounds were
characterized by IR, 1H- and 13C-NMR spectroscopy and elemental analysis.
Keywords: α,β-unsaturated steroidal ketones; α,β-unsaturated 3-thiones; Lawesson’s
reagent; P4S10/HMDO; dimerization, microwave irradiation
1. Introduction
Steroids are an important group of natural compounds possessing a variety of biological activities.
The replacement of one or more carbon atoms in a steroid molecule by a heteroatom affects the
chemical properties of that particular steroid and often results in alterations of its biological activity,

Molecules 2010, 15
3463
which sometimes may be useful. Also, the addition of heterocyclic rings or new functional groups to
steroid molecules often leads to changes in their physiological activity. Thionation is one possible
modification that could have some influence on such activity. The larger and less electronegative
sulfur atom, relative to oxygen, might alter the hydrogen-bonding ability and/or induce conformational
changes in the modified molecule. In addition the increased reactivity of the thione function should
make these derivatives useful intermediates for further transformations. Recently we reported synthesis
of 6-thioxo-7-aza-B-homocholest-4-ene and 6-aza-7-thioxo-B-homocholest-4-ene using Lawesson’s
reagent [1]. Continuing this investigation and our previous work on modified steroid compounds as
biologically active molecules [1–4], the goal of this study was to synthesize some new
thioxosteroid derivatives.
Several methods are reported in the literature for the thionation of organic compounds. Phosphorus
pentasulfide (P4S10) was first reported in 1869 by Henry [5] and Wislicenus [6]. The usual procedure,
which involves boiling toluene, xylene or pyridine as solvent, requires a large excess of reagent, long
reaction timed, and results in low and variable yields [7–9]. Recently Curphey [10–12] has shown that
a combination of P4S10 with hexamethyldisiloxane (HMDO) efficiently converts esters, lactones,
amides and ketones into their corresponding thio derivatives. Under the standard reaction conditions
(dry toluene/xylene, thermal heating) this method has provided an increase in the selectivity and yield.
Kaushik et al. developed a new thionating reagent by encapsulating the P4S10 in basic alumina [13].
The reactions were carried out in good to excellent yields by refluxing mixture of ketone and
P4S10/Al2O3 in acetonitrile, but this method needs some more investigation. In 1978, Lawesson and
coworkers developed a new reagent, 2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide,
commonly named Lawesson’s reagent (LR, Figure 1) [14–16].
Figure 1. Lawesson’s reagent.
S
S P
P S
S
OMe
MeO
The attractiveness of LR is associated with its commercial availability, simplicity and convenience
of use, high yields and especially soft thionation reactions. In some cases the main disadvantage of this
reagent is the formation of byproducts or stable heterocyclic intermediates. However, some of these
sulfur and phosphorus containing products can be very useful as they have showed a promising anti-
microbial and anti-inflammatory activity [17–20]. Since all described procedures require the use of dry
aromatic hydrocarbon solvents and lengthy reaction times, microwave assistance has been applied to
thionate a wide variety of substrates [21–25].
α,β-Unsaturated thiones are relatively little known, presumably due to their instability as
monomeric species. Thus, the conversion of α,β-unsaturated ketones into corresponding thiones
remains a challenging problem for organic chemists. Thionation of some steroidal ketones is already
described in literature. Barton and coworkers synthesized several Δ1,4-diene-3-thioxo corticosteroids
using P4S10 in pyridine as a reagent [26]. Weis et al. also described the regioselective thionation of
3-oxo-1,4-diene steroid systems with LR in anhydrous THF [27]. Although several simple alicyclic

Molecules 2010, 15
3464
α,β-unsaturated thiones have been prepared, 3-thioxocholest-4-ene [28], 17-thioxoandrost-4-en-3-one
[19] and 3,17-dithioxoandrost-4-ene [19] remain the only characterized steroidal examples. As far as
we know there is no report dealing with the synthesis of thiono analogues of steroidal ketones under
the microwave irradiation.
Herein we report on the reaction of several α,β-unsaturated cholestane, androstane and pregnane
carbonyl derivatives 1a-e (Figure 2) with LR (in CH2Cl2 and toluene) under the standard reaction
conditions and with
microwave irradiation.
a
combination of P4S10/HMDO in 1,2-dichlorobenzene under
Figure 2. Substrates 1a-e.
CH3
CH3
CH3
C8H17
O
O
H3C
H3C
H
O
O
O
1a
1b
1c
CH3
CH3
O
O
O
H3C
H3C
O
O
1d
1e
2. Results and Discussion
The reactions of α,β-unsaturated ketones 1a-e with LR gave different products, depending on the
solvent and duration of the reaction. Due to the instability of the unsaturated thioketones or dimers
formed and their easy reconversion to the starting compounds a certain amount (8–52%) of the parent
compounds was isolated in all cases.
At the beginning, the reaction procedure for thionation was carried out in refluxing toluene.
Instantaneous reaction took place (the purple color of reaction mixture) with simultaneous formation of
thionated products. Although there was no complete consumption of 1a-e, the reaction was quenched
after 25-45 min (depending on substrate, see Experimental), while the solution was still purple, which
was the evidence of the presence of thioketones. After flash column chromatography, besides
corresponding dimer-sulfides 2a-e (7–56%), thioketones 3a-e were isolated in 11–27% yields (Scheme
1). When the reaction procedure was carried out in refluxing toluene for 8 h initially formed unstable
α,β-unsaturated thioketones either dimerize to give corresponding dimer-sulfides 2a-e (30–51%), or
decompose to a more stable starting ketones 1a-e (26–52%) (Scheme 1).

Molecules 2010, 15
3465
Scheme 1. Thionation of 1a-e with LR in toluene.
CH3
R1
R2
R
O
1a R=CH3, R1=C8H17, R2=H
1b R=CH3, R1R2=O,
1c R=H, R1R2=O,
1d R=CH3, R1=COCH3, R2=H,
1e R=CH3, R1=COCH3, 1617-epoxy
LR, Toluene
i) 25-45 min
ii) 8 h
CH3
R1
R2
R
R
SM
+
+
S
S
2
2a i) 56% ii) 30%
2b i) 21% ii) 50%
2c i) 7% ii) 43%
2d i) 16% ii) 51%
2e i) 25% ii) 41%
3a i) 11% ii) -
3b i) 27% ii) -
3c i) 25% ii) -
3d i) 22% ii) -
3e i) 20% ii) -
1a i) 18% ii) 52%
1b i) 8% ii) 38%
1c i) 37% ii) 26%
1d i) 38% ii) 34%
1e i) 36% ii) 31%
All obtained thioketones 3a-e were pink oils and their structures were determined on the basis of
1
their spectral data (IR, H-NMR, 13C-NMR). In the IR spectra the absorption for the original
13
unsaturated 3-oxo group, was missing, as well as the singlet for C-3 in the C-NMR spectra at about
199 ppm. Instead, the new singlet at δ 236.7, 237.0, 237.8, 236.9 and 237.4 ppm for C(3)=S, for
1
compounds 3a-e, respectively, appeared. In the H-NMR spectra signal for H-4 at δ 6.63, 6.69, 6.74,
6.66 and 6.63 ppm was situated downfield comparing to the resonance for the corresponding proton in
starting compounds 1a-e (at δ 5.72, 5.74, 5.84, 5.80 and 5.70 ppm, respectively). In addition, in all
thioketones, both protons at C-2 (α-position to the C=S group) resonate well-separated downfield from
the other ring protons due to the strong C=S anisotropy, H-equatorial as a td at about δ 3.15 ppm,
H-axial as a dtd, at about δ 2.50 ppm both with corresponding JHH coupling constants.
In the IR spectra of 2a-e the absorptions for the original unsaturated 3-oxo groups at 1667, 1665,
1667, 1665 and 1661 cm-1 for 1a-e, respectively, were missing, as well as the singlet for C-3 in the
13C-NMR spectra at about δ 199 ppm. Instead, the new C-3 singlet at δ 129.4, 129.5, 129.5, 129.3,
129.4 ppm and the C-6 doublet at δ 124.3, 123.3, 124.8, 123.8 and 123.6 ppm for compounds 2a-e,
respectively, appeared indicating the formation of a new double bond and Δ3,5-diene structure. New
1
signal had also appeared in the H-NMR spectra: the broad triplet at δ 5.47, 5.45, 5.50, 5.42 and
5.39 ppm for H-6 for compounds 2a-e, respectively. On the other hand, the H-4 signal at δ 6.11, 6.13,
6.14, 6.11 and 6.10 ppm for compounds 2a-e, respectively, was shifted downfield comparing with that
in starting compounds 1a-e (at δ 5.72, 5.74, 5.84, 5.80¸ 5.70 ppm, respectively). This can be explained
by anisotropy effect of the new double bond in the dimers. On the basis of the COSY correlations
between the vinylic H-6 and H2-7 together with the key HMBC correlations from H-6 to C-7 and C-8

Molecules 2010, 15
3466
the alternative Δ2,4-isomer was ruled out. Furthermore, the elemental analyses for 2a-e were in
agreement with the proposed structures.
In order to increase the yield of thioketones we performed the same reactions under milder
conditions, in CH2Cl2 as a solvent (refluxing for 45 min) and the thioketones 3a-e were obtained in
much higher yield, 28–70%. Besides, steroids 1c-e gave corresponding 1,2,4-trithiolanes 5c-e. The
steroids 1b and 1e gave also the (4-methoxy-phenyl)phosphonotrithioates 6b and 6e. In this reaction
the formation of dithioketones 4c and 4d was observed as well and these products were also isolated
but due to their instability we were able to record only IR spectra in which the absorption for the
original unsaturated 3-oxo group was missing as well as the absorptions for carbonyls at C-17 for 4c
and C-20 for 4d (Scheme 2).
Scheme 2. Thionation of 1a-e with LR in CH2Cl2.
CH3
R1
R2
R
O
1a R=CH3, R1=C8H17, R2=H
1b R=CH3, R1R2=O
1c R=H, R1R2=O
1d R=CH3, R1=COCH3, R2=H
1e R=CH3, R1=COCH3, 1617-epoxy
LR, CH2Cl2
i) 45 min
ii) 4-8 h
CH3
CH3
R1
R1
R2
R2
R
R
R
+
+
+
S
S
S
2
2a i) 25% ii) -
2b i) 5% ii) -
3a i) 70% ii) 5%
4b R=CH3, R1R2=S
-
3b i) 33% ii)
-
4c R=H, R1R2=S i) 5% ii) -
4d R=CH3, R1=CSCH3, R2=H i) 9% ii) -
4e R=CH3, R1=CSCH3,1617-epoxy -
2c
2d
2e
-
-
-
3c i) 38% ii) 8%
3d i) 28% ii) 12%
3e i) 35% ii)
-
R
R
R
R
S S
S
SM
+
+
S
S
S
P
OCH3
5a i)
5b i)
5c i) 16% ii) 11%
5d i) 16% ii) 27%
5e i) 6% ii) 36%
-
-
ii) 79%
ii) 35%
6a
-
1a -
6b i) 4%) ii) 36%
1b i) 40% ii) 8%
1c i) 24% ii) 27%
1d i) 28% ii) 19%
1e i) 27% ii) 10%
6c i)
6d i)
6e i) 7% ii) 28%
-
-
ii) 8%
ii) 13%
With a prolonged time of reaction in CH2Cl2 (reflux 4–8 h, depending on substrate, see
Experimental) all unsaturated ketones 1a-e gave as a main product the corresponding 1,2,4-trithiolanes
5a-e (11–79%). Besides, steroids 1b-e gave also the (4-methoxyphenyl)phosphonotrithioates 6b-e

Molecules 2010, 15
3467
(8–36%) as a result of further reaction of firstly formed thioketones with LR. In some cases (1a, 1c and
1d) the thioketones, 3a, 3c and 3d were still present in the reaction mixture and isolated in very poor
yield (5–12%) (Scheme 2).
Support for the structures 5a-e was found from the 13C- and 1H-NMR spectral data as well as from
the elemental analysis which showed that they contain three additional sulfur atoms (at two steroid
1
molecules). NMR spectral data showed the absence of α,β-unsaturated 3-oxo group. In the H-NMR
spectra signal for H-4 at δ 5.45, 5.44, 5.60, 5.47 and 5.46 ppm for 5a-e, respectively, was situated
upfield comparing with that in the starting compounds 1a-e (at δ 5.72, 5.74, 5.84, 5.80¸ 5.70 ppm,
respectively), demonstrating the effect of an absence of the deshielding influence of 3-oxo group. In
the 13C-NMR spectra the singlet for C-5 at δ 152.5, 149.8 147.0, 151.9 and 151.8 ppm for 5a-e,
respectively, was also situated upfield when compared to the corresponding resonance in 1a-e,
indicated the absence of α,β-unsaturated carbonyl group. In addition, the singlet for C-3 at about
199 ppm for starting compounds was missing and instead the new singlet at δ 81.3, 80.2, 80.9, 81.1
and 81.1 ppm, respectively for 5a-e, appeared indicating the formation of 1,2,4-trithiolane ring.
In the IR spectra of phosphonotrithioates 6b-e the original C(3)=O absorption band disappeared,
13
1
while in the C-NMR spectra the singlet for C-3 at about δ 199 ppm was also absent. The H-NMR
spectra showed the new olefinic H-6 proton signal, a broad triplet at δ 5.52, 5.61, 5.49 and 5.47 ppm
for 6b-e, respectively. On the other hand, the resonance for the olefinic H-4 proton appeared like two
sets of signals, two doublets at δ 6.30 and 6.34 ppm, 6.38 and 6.40 ppm, 6.28 and 6.32 ppm, 6.28 and
6.31 ppm for compounds 6b-e, respectively, with JPH about 4 Hz indicated two different protons, both
with the long range coupling with phosphorus. The signal for 19-Me group also appeared in pairs, two
singlets at δ 0.92 and 0.96 ppm for 6b, 0.89 and 0.92 ppm for 6d and 0.89 and 0.94 ppm for 6e.
Besides, the new singlet at δ 3.87, 3.86, 3.86 and 3.87 ppm (OCH3) appeared as well as two doublets
of doublets at δ 6.96 and 8.02, 7.00 and 8.01, 6.96 and 8.02 and 6.95 and 8.01 ppm for aromatic
protons for 6b-e, respectively, and these signals had corresponding JHH and JPH coupling constants. On
basis of the peak areas ratio of the olefinic, methoxy and aromatic protons (H-4/H-
6/OCH3/ArH(3,5)/ArH(2,6)=2:2:3:2:2) it was deduced that two steroid molecules are attached with
one monomeric species of LR to gave (4-methoxyphenyl)phosphonotrithioates 6b-e. The difference
between H-4 protons and 19-methyl groups is attributed to the molecular asymmetry. This was
confirmed by the 13C-NMR spectra in which the C-3 carbon atoms appeared like two doublets at
δ 124.5 and 124.8 ppm, 124.7 and 125.2 ppm, 124.4 and 124.5 ppm, 122.4 and 124.7 ppm for 6b-e,
respectively, with 2JPC about 10 Hz. Furthermore, the signals for C-1, C-2, C-4, C-5, C-6, C-10 and 19-
Me appeared like two sets of signals confirming proposed structures. Also, there were the signals for
aromatic carbon atoms with corresponding 1-4JPC coupling constants at δ 162.9, 133.7, 129.6 and 113.9
ppm for compound 6b, at δ 162.9, 133.4, 129.6, 113.6 ppm for 6c, at δ 162.6, 133.4, 128.1 and 113.6
ppm for 6d, and at δ 162.6, 133.4, 127.7 and 113.6 ppm for 6e.
Thionation of steroidal ketones 1a-e with a combination of P4S10/HMDO under microwave
irradiation in all cases gave two products: 3-thioketones 3a-e (11–26%) and dimer-sulfides 2a-e
(7–42%). The yield of thioketones obtained was lower than in the reaction with LR in CH2Cl2. In one
case, in the reaction of 19-norandrost-4-ene-3,17-dione (1c) the 3,17-dithioketone 4c was isolated as
well (3%) (Scheme 3).

Molecules 2010, 15
Scheme 3. Thionation of 1a-e with P4S10/HMDO under the microwave irradiation.
3468
CH3
R1
R2
R
O
1a R=CH3, R1=C8H17, R2=H
1b R=CH3, R1R2=O
1c R=H, R1R2=O
1d R=CH3, R1=COCH3, R2=H
1e R=CH3, R1=COCH3, 1617-epoxy
P4S10/HMDO
ODCB, MW, Ar, 90 sec
CH3
CH3
R1
R1
R2
R2
R
R
R
+
+
+
SM
S
S
S
2
2a (42%)
3a (19%)
3b (17%)
3c (26%)
3d (11%)
3e (12%)
1a (32%
1b (34%)
1c (16%)
1d (28%)
1e (24%)
4b R=CH3, R1R2=S -
4c R=H, R1R2=S (3%)
4d R=CH3, R1=CSCH3, R2=H -
4e R=CH3, R1=CSCH3, 1617-epoxy -
2b (19%)
2c (7%)
2d (25%)
2e (26%)
3. Experimental Section
3.1. General
Removal of solvents was carried out under reduced pressure. Melting points were determined on an
electrothermal capillary melting point apparatus and are uncorrected. IR spectra were recorded on a
Perkin-Elmer spectrophotometer FT-IR 1725X: ν in cm-1. 1H- and 13C-NMR spectra were recorded on
a Varian Gemini-200 spectrometer (at 200 and 50 MHz, respectively) and/or a Bruker Avance
13
500 MHz spectrometer (1H at 500 MHz; C at 125 MHz) in CDCl3 and/or C6D6 at room temperature
using TMS as internal standard. Chemical shifts are expressed in ppm (δ) values and coupling
constants (J) in Hz. Mass spectra were taken on Finnigan-MAT 8230. Thin-layer chromatography was
performed on precoated Merck silica gel 60 F254 plates in toluene/EtOAc (9:1, 8:2) and in n-
hexane/EtOAc (8:2, 6:4), detection with 50% aq. H2SO4 and/or with CAM solution. Flash column
chromatography (FCC) was performed on silica gel Merck 0.040–0.063 mm under the Ar atmosphere.
Elemental analyses were determined on Vario EL III. All starting steroid compounds were
commercially available products.
3.2. General procedure for thionation with LR
LR (1 mmol) was added to a solution of steroidal ketone (1 mmol) in dichloromethane or toluene
(15 mL). The reaction mixture was refluxed (duration mentioned in each experiment) with stirring and
monitored by TLC. After the completion of reaction the rest of reagent was removed by filtration and

Molecules 2010, 15
3469
evaporated. The residue was chromatographed by FCC using toluene/EtOAc or n-hexane/EtOAc (ratio
mentioned in each experiment) as eluent.
3.3. General procedure for thionation with combination of P4S10/HMDO under the microwave
irradiation
All microwave assisted reactions were carried out using a modified Panasonic NN-S255W domestic
microwave oven (2450 MHz, 800 W) which was adapted for laboratory applications with an external
reflux condenser. The oven was perforated at the top for a condenser tube and external steel tube of the
same diameter (~30 mm) was welded in order to eliminate possible microwave leakage.
P4S10 (0.5 mmol) was added to a solution of steroidal ketone (2 mmol) in ODCB (5 mL) placed in a
20 mL quartz vessel. The reaction mixture was stirred under the argon (Ar) for 10 minutes at room
temperature and then HMDO (3.5 mmol) was added. The content was irradiated at 600 W for
90 seconds under Ar atmosphere with a pause of 2 min after every 20 seconds, monitored by TLC.
After the completion of reaction the mixture was chromatographed by FCC using toluene/EtOAc or
n-hexane/EtOAc (ratio mentioned in each experiment) as eluent.
3.3.1. Thionation of cholest-4-en-3-one (1a)
In toluene 45 min: Starting with 384 mg of 1a, elution with n-hexane gave dimer-sulfide 2a (216 mg,
1
56%). Oil. IR (CHCl3): 2935, 1465, 732. H-NMR (500 MHz, CDCl3): 0.70 (s, 6H, 2×H3C(18)), 0.86
and 0.87 (2d, 12H, 2×H3C(26), 2×H3C(27)), 0.92 (d, 6H, 2×H3C(21)), 0.94 (s, 6H, 2×H3C(19)), 5.41
13
(br.t, J = 4.5 Hz, 2H, 2×H-C(6)), 6.11 (2H, 2×H-C(4)). C-NMR (125 MHz): 141.6 (s, C(5)), 131.7
(d, C(4)), 129.4 (s, C(3)) 124.3 (d, C(6)), 56.9 (d, C(14)), 56.2 (d, C(17)), 48.1 (d, C(9)), 42.5 (s,
C(13)), 39.8 (t, C(12)), 39.5 (t, C(24)), 36.2 (t, C(22)), 35.8 (d, C(20), 34.7 (s, C(10)), 34.7 (t, C(1)),
31.9 (t, C(7)), 31.8 (d, C(8)), 28.2 (t, C(16)), 28.0 (d, C(25)), 27.8 (t, C(2)), 24.2 (t, C(15)), 23.8 (t,
C(23)), 22.8 (q, C(27)), 22.6 (q, C(26)), 21.1 (t, C(11)), 19.0 (q, C(19)), 18.7 (q, C(21)), 12.0 (q,
C(18)). Anal. calcd for C54H86S: C 84.52; H 11.30; S 4.18. Found: C 84.07; H 11.56; S 4.28. Further
elution with n-hexane/toluene (70:30) gave 3-thioxocholest-4-ene (3a) (45 mg, 11%). Pink oil. IR
(CHCl3): 2931, 1582, 1024. 1H-NMR (200 MHz, C6D6): 0.61 (s, 3H, H3C(18)), 080 (s, 3H, H3C(19)),
0.92 (d, 6H, H3C(26), H3C(27)), 0.97 (d, 3H, H3C(21)), 2.50, (dtd, J=18.6, 15.3, 4.6, 1H, Hβ-C(2)),
3.11 (dt, J=18.0, 3.4, 1H, Hα-C(2)), 6.63 (br.s, 1H, H-C(4)). 13C NMR (50 MHz, C6D6): 236.7 (s,
C(3)), 161.8 (s, C(5)), 135.4 (d, C(4)), 56.4 (d, C(14)), 56.0 (d, C(17)) 53.9 (d, C(9)), 43.6 (t, C(2)),
42.6 (s, C(13)), 39.9 (2t, C(12) and C(24)), 38.5 (s, C(10)), 36.7 (t, C(22)), 36.6 (t, C(6)), 36.1 (d,
C(20)), 35.7 (d, C(8)), 32.7 (t, C(7)), 32.2 (t, C(1)), 28.5 (t, C(16)), 28.4 (d, C(25)), 24.3 (2t, C(15) and
C(23)), 23.0 (q, C(27)), 22.8 (q, C(26)), 21.2 (t, C(11)), 18.9 (q, C(21)), 16.7 (q, C(19)), 12.1 (q,
C(18)). Anal. calcd for C27H44S: C 80.93; H 11.07; S 8.00. Found: C 8.67; H 11.22; S 8.18.
Additionally starting material (70 mg, 18%) was recovered.
In toluene 8 h: Starting with 384 mg of 1a, elution with n-hexane gave dimer-sulfide 2a (112 mg,
30%) and starting material (200 mg, 52%).

Molecules 2010, 15
3470
In CH2Cl2 45 min: Starting with 380 mg of 1a, elution with n-hexane gave dimer-sulfide 2a (95 mg,
25%). Further elution with n-hexane/toluene (70:30) gave 3-thioxocholest-4-ene (3a) (279 mg, 70%).
In CH2Cl2 4 h: Starting with 380 mg of 1a, elution with n-hexane and crystallization from MeOH gave
1
1,2,4-trithiolane 5a (330 mg, 79% ). m.p. 134–136 ºC. IR (CHCl3): 2929, 1464, 733. H-NMR (200
MHz, CDCl3): 0.67 (s, 6H, 2×H3C(18)), 086 (d, 12H, 2×H3C(26), 2×H3C(27)), 0.93 (d, 6H,
13
2×H3C(21)), 1.03 (s, 6H, 2×H3C(19)), 5.45 (s, 2H, 2×H-C(4)). C-NMR: 152.5 (s, C(5)), 119.1 (d,
C(4)), 81.3 (s, C(3)), 56.1 (d, C(17)), 55.9 (d, C(14)), 54.4 (d, C(9)), 42.4 (s, C(13)), 39.7 (t, C(12)),
39.5 (t, C(24)), 37.6 (s, C(10)), 37.3 (t, C(2)), 36.1 (t, C(22)), 35.8 (d, C(20)), 35.7 (d, C(8)), 35.0 (t,
C(1)), 32.7 (t, C(7)), 32.4 (t, C(6)), 28.2 (t, C(16)), 28.0 (d, C(25)), 24.2 (t, C(15)), 23.8 (t, C(23)), 22.8
(q, C(27)), 22.5 (q, C(26)), 21.2 (t, C(11)), 18.6 (q, C(21)), 18.5 (q, C(19)), 11.9 (q, C(18)). Anal. calcd
for C54H88S3: C 77.82; H 10.61; S 11.54. Found: C 77.61; H 10.78; S 11.39. Further elution with n-
hexane/toluene (70:30) gave 3-thioxocholest-4-ene (3a) (20 mg, 5%).
Under microwave irradiation: Starting with 762 mg of 1a, elution with n-hexane gave dimer-sulfide
2a (323 mg, 42%). Further elution with n-hexane/toluene (70:30) gave 3-thioxocholest-4-ene (3a)
(153 mg, 19%). Starting material (244 mg, 32%) was also obtained.
3.3.2. Thionation of androst-4-ene-3,17-dione (1b)
In toluene 45 min: Starting with 860 mg of 1b, elution with toluene/EtOAc (97:3) and crystallization
from MeOH gave dimer-sulfide 2b (182 mg, 21%). m.p. > 126 ºC (decomp.). IR (CHCl3): 2940, 1737,
1
732. H-NMR (200 MHz, CDCl3): 0.91 (s, 6H, 2×H3C(18)), 0.97 (s, 6H, 2×H3C(19)), 5.45 (br. s, 2H,
2×H-C(6)), 6.13 (s, 2H, 2×H-C(4)). 13C-NMR: 221.1 (s, C(17)), 141.6 (s, C(5)), 131.4 (d, C(4)), 129.5
(s, C(3)), 123.3 (d, C(6)), 51.7 (d, C(14)), 48.0 (d, C(9)), 47.6 (s, C(13)), 35.7 (t, C(12)), 34.7 (s,
C(10)), 34.5 (t, C(1)), 31.3 (t, C(7)), 31.3 (d, C(8)), 30.6 (t, C(16)), 27.6 (t, C(2)), 21.7 (t, C(15)), 20.3
(t, C(11)), 18.9 (q, C(19)), 13.6 (q, C(18)). Anal. calcd for C38H50O2S: C 79.95; H 8.83; S 5.62. Found:
C 79.80; H 9.06; S 5.70. Further elution with toluene/EtOAc (95:5) afforded 3-thioxoandrost-4-en-17-
1
one (3b) (242 mg, 27%). Pink oil. IR (C6D6): 2936, 1735, 1579, 1010. H NMR (200 MHz, C6D6):
0.63 (s, 3H, H3C(18)), 0.74 (s, 3H, H3C(19)), 2.52 (dtd, J=17.6, 15.6, 5.0, 1H, Hβ-C(2)), 3.15 (dt,
J = 17.4, 3.4 Hz, 1H, Hα-C(2)), 6.69 (s, 1H, H-C(4)). 13C NMR (50 MHz, C6D6): 237.0 (s, C(3)), 217.7
(s, C(17)), 161.3 (s, C(5)), 135.4 (d, C(4)), 53.7 (d, C(9)), 50.6 (d, C(14)), 47.2 (s, C(13)), 43.5 (t,
C(2)), 38.4 (s, C(10)), 36.5 (t, C(16)), 35.5 (t, C(6)), 34.9 (d, C(8)), 32.3 (t, C(7)), 31.7 (t, C(12)), 30.6
(t, C(1)), 21.6 (t, C(15)), 20.3 (t, C(11)), 16.7 (q, C(19)), 13.5 (q, C(18)). Starting material (69 mg, 8%)
was also recovered.
In toluene 8h: Starting with 572 mg of 1b, elution with toluene/EtOAc (97:3) and crystallization from
MeOH gave dimer-sulfide 2b (290 mg, 50%) and starring material (217 mg, 38%).
In CH2Cl2 45 min: Starting with 572 mg of 1b, elution with toluene/EtOAc (97:3) gave dimer-sulfide
2b (27 mg, 5%). Further elution with toluene/EtOAc (95:5) afforded 3-thioxoandrost-4-en-17-one (3b)
(197 mg, 33%). Elution with toluene/EtOAc (93:7) gave phosphonotrithioate 6b (27 mg, 4%). Starting
material (228 mg, 40%) was also obtained.

Molecules 2010, 15
3471
In CH2Cl2 8 h: Starting with 572 mg of 1b, elution with toluene/EtOAc (95:5) and crystallization from
MeOH gave 1,2,4-trithiolane 5b (220 mg, 35%). m.p. 148–150 ºC. IR (CHCl3): 2929, 1738, 1439, 732.
1H-NMR (200 MHz, CDCl3): 0.87 (s, 6H, 2×H3C(18)), 1.06 (s, 6H, 2×H3C(19)), 5.44 (s, 2H, 2×H-
C(4)). 13C-NMR: 220.9 (s, C(17)), 149.8 (s, C(5)), 119.2 (d, C(4)), 80.2 (s, C(3)), 53.9 (d, C(9)), 50.9
(d, C(14)), 47.6 (s, C(13)), 37.2 (s, C(10)), 39.7 (t, C(16)), 35.7 (t, C(1)), 35.2 (d, C(8)), 34.9 (t, C(2)),
32.2 (t, C(6)), 31.3 (t, C(7)), 29.6 (t, C(12)), 21.7 (t, C(15)), 20.4 (t, C(11)), 18.5 (q, C(19)), 13.69 (q,
C(18)). Anal. calcd for C38H52O2S3: C 71.65, H 8.23, S15.10. Found: C 71.19, H 8.27, S 14.84. Further
elution with toluene/EtOAc (93:7) gave phosphonotrithioate 6b (280 mg, 36%).
m.p. >133 ºC (decomp.). IR (CHCl3): 2936, 1733, 1254, 1096, 828. 1H-NMR (500 MHz, CDCl3): 0.89
and 0.90 (2s, 6H, 2×H3C(18)), 0.92 and 0.96 (2s, 6H, 2×H3C(19)), 3.87 (s, 3H, OCH3), 5.52 (br.s, 2H,
4
4
2×H-C(6)), 6.30 and 6.34 (2d, JPH = 3.0 and 4.5 Hz, 2H, 2×H-C(4)), 6.96 (dd, JPH = 3.5 Hz,
JHH = 9.0 Hz, 2H, 2×Ar-H), 8.02 (dd, JPH = 14.0 Hz, JHH = 9.0 Hz, 2H, 2×Ar-H). 13C-NMR
3
4
(125 MHz): 220.2 (s, C(17)), 162.9 (sd, JPC = 2.9 Hz, ArC-OCH3), 142.08 and 142.05 (2sd,
4JPC = 3.6 and 4.6 Hz, 2×C(5)), 141.46 and 141.38 (2dd, both JPC = 5.5 Hz, 2×C(4)), 133.7 (dd,
3
3JPC = 12.5 Hz, 2×ArC-H), 129.6 (sd, JPC = 91.8 Hz, ArC-P), 126.83 and 126.80 (2d, 2×C(6)), 124.7
and 124.5 (2sd, 2JPC=12.8 and 9.1, 2×C(3)), 113.9 (dd, 2JPC=15.0, 2×ArC-H), 55.7 (q, OCH3), 52.0 (d,
C(14)), 48.2 (d, C(9)), 47.9 (s, C(13)), 36.0 (t, C(16)), 35.0 and 34.9 (2t, 2×C(1)), 34.73 and 34.70 (2s,
2×C(10)), 31.6 (d, C(7)), 31.5 (t, C(8)), 31.4 and 31.2, 2t, 2×C(2)), 31.06 (t, C(12)), 22.0 (t, C(15)),
20.6 (t, C(11)), 19.16 and 19.22 (2q, 2×C(19)), 13.9 (q, C(18)). ESI-TOF-MS: m/z calcd for
C45H57O3PS3: 773.3286 [M+H]+, found 773.2404. Starting material (46 mg, 8%) was recovered too.
Under microwave irradiation: Starting with 572 mg of 1b, elution with toluene/EtOAc (97:3) gave
dimer-sulfide 2b (105 mg, 19%). Further elution with toluene/EtOAc (95:5) afforded 3-thioxoandrost-
4-en-17-one (3b) (100 mg, 17%). Starting material (195 mg, 34%) was isolated.
3.3.3. Thionation of 19-norandrost-4-ene-3,17-dione (1c)
In toluene 25 min: Starting with 540 mg of 1c, elution with toluene/EtOAc (98:2) afforded dimer-
1
sulfide 2c (37 mg, 7%). IR (CHCl3): 2928, 1737. H-NMR (200 MHz, CDCl3): 0.92 (s, 6H,
13
2×H3C(18)), 5.55 (br. s, 2H, 2×H-C(6)), 6.14 (s, 2H, 2×H-C(4)). C-NMR: 221.01 (s, C(17)), 141.6
(s, C(5)), 131.4 (d, C(4)), 129.5 (s, C(3)), 124.8 (d, C(6)), 50.1 (d, C(14)), 49.4 (d, C(9)), 47.7 (s,
C(13)), 42.4 (s, C(10)), 42.4 (d, C(8)), 36.4 (t, C(16)), 31.3 (t, C(7)), 30.6 (t, C(12)), 29.6 (t, C(2)),
26.5 (t, C(1)), 25.6 (t, C(11)), 21.7 (t, C(15)), 13.6 (q, C(18)). Anal. calcd for C36H36O2S: C 79.66; H
8.54; S 5.91. Found: C 79.80; H 8.72; S 6.00. Further elution with toluene/EtOAc (97:3) afforded 3-
thioxo-19-norandrost-4-en-17-one (3c) (140 mg, 25%). Pink oil. IR (C6D6): 2929, 1731, 1560, 1034.
1H-NMR (500 MHz, C6D6): 0.60 (s, 3H, H3C(18)), 2.35 (dtd, J = 15.8, 14.5, 4.5 Hz, 1H, Hβ-C(2)),
13
3.15 (dt, J = 16.5, 4.0 Hz, 1H, Hα-C(2)), 6.75 (s, 1H, H-C(4)). C-NMR (125 MHz, C6D6): 237.8 (s,
C(3)), 217.8 (s, C(17)), 156.9 (s, C(5)), 136.6 (d, C(4)), 50.3 (d, C(14)), 49.7 (d, C(9)), 47.8 (s, C(13)),
46.5 (t, C(2)), 42.9 (d, C(10)), 40.1 (d, C(8), 35.9 (t, C(16)), 35.4 (t, C(6)), 32.1(t, C(7)), 30.2 (t,
C(12)), 27.9 (t, C(1)), 26.0 (t, C(15)), 21.9 (t, C(11)), 14.0 (q, C(18)). Anal. calcd for C18H24OS: C
74.95; H 8.39; S 11.12. Found: C 75.10; H 8.68; S 11.27. Starting material (200 mg, 37%)
was isolated.

Molecules 2010, 15
3472
In toluene 8 h: Starting with 540 mg of 1c, elution with toluene/EtOAc (98:2) afforded dimer-sulfide
2c (230 mg, 43%) and starting material (140 mg, 26%).
In CH2Cl2 45 min: Starting with 544 mg of 1c, elution with toluene/EtOAc (99:1) gave 3,17-dithioxo-
19-norandrost-4-ene (4c) (29 mg, 5%). IR (KBr): 2845, 1582. Further elution with toluene/EtOAc
(97:3) afforded 3-thioxo-19-norandrost-4-en-17-one (3c) (220 mg, 38%). Further elution with
toluene/EtOAc (95:5) gave 1,2,4-trithiolane 5c (99 mg, 16%). IR (CHCl3): 2928, 1737, 1403. 1H-NMR
(200 MHz, CDCl3): 0.90 (s, 6H, 2×H3C(18)), 5.60 (s, 2H, 2×H-C(4)). 13C-NMR: 221.0 (s, C(17)),
147.0 (s, C(5)), 120.5 (d, C(4)), 80.9 (s, C(3)), 50.1 (d, C(9)), 50.1 (d, C(14)), 47.7 (s, C(13)), 41.3 (d,
C(10)), 39.9 (d, C(8)), 37.5 (t, C(2)), 36.6 (t, C(16)), 34.8 (t, C(6)), 31.3 (t, C(7)), 30.1 (t, C(12)), 28.0
(t, C(1)), 25.4 (t, C(11)), 21.5 (t, C(15)), 13.7 (q, C(18)). Anal. calcd for C36H48O2S3: C 71.00; H 7.94;
S 15.80. Found: C 71.42; H 7.88; S 15.56. Starting material recovery: 130 mg, (24%).
In CH2Cl2 7 h: Starting with 544 mg of 1c, elution with toluene/EtOAc (97:3) afforded 3-thioxo-19-
norandrost-4-en-17-one (3c) (47 mg, 8%). Further elution with toluene/EtOAc (95:5) gave 1,2,4-
trithiolane 5c (65 mg, 11%). Further elution with toluene/EtOAc (94:6) gave phosphonotrithioate 6c
1
(59 mg, 8%). IR (CHCl3):2929, 1730, 1439, 1096, H-NMR (200 MHz, CDCl3): 0.89 (s, 6H,
2×H3C(18)), 3.86 (s, 3H, OCH3), 5.61 (br.s, 2H, 2×H-C(6)), 6.38 and 6.40 (2d, both 4JPH = 4.4 Hz, 2H,
2×H-C(4)), 7.00 (dd, 4JPH = 3.4 Hz, JHH = 8.4 Hz, 2H, 2×Ar-H), 8.01 (dd, 3JPH = 14.0 Hz, JHH = 9.0 Hz,
13
2H, 2×Ar-H). C-NMR(50 MHz): 220.9 (s, C(17)), 162.9 (s, ArC-OCH3) 142.1 (s, C(5)), 141.6 and
3
141.7 (2d, 2×C(4)), 133.4 (dd, JPC = 12.8 Hz, 2×ArC-H), 129.6 (sd, JPC = 91.8 Hz, ArC-P), 126.9 (d,
C(6)), 125.2 and 124.7 (2sd, both 2JPC = 12.0 Hz, 2×C(3)), 113.6 (dd, 2JPC = 14.6 Hz, 2×ArC-H), 55.4
(q, OCH3), 50.8 (d, C(14)), 49.9 (d, C(9)), 47.7 (s, C(13)), 43.5 (d, C(10)), 39.9 (d, C(8)), 35.7 (t,
C(16)), 31.2 (2t, C(2) and C(7)), 30.3 (t, C(12)), 28.0 (t, C(1)), 25.4 (t, C(11)), 21.4 (t, C(15)), 13.7 (q,
C(18)). Starting material (147 mg, 27%) was also obtained.
Under the microwave irradiation: Starting with 540 mg of 1c, elution with toluene/EtOAc (99:1) gave
3,17-dithioxo-19-norandrost-4-ene (4c) (18 mg, 3%). IR: 2845, 1582, 1035. Further elution with
toluene/EtOAc (98:2) afforded dimer-sulfide 2c (38 mg, 7%). Further elution with toluene/EtOAc
(97:3) afforded 3-thioxo-19-norandrost-4-en-17-one (3c) (149 mg, 26%). Starting material (86 mg,
16%) was isolated.
3.3.4. Thionation of progesterone (1d)
In toluene 45 min: Starting with 314 mg of 1d, elution with toluene/EtOAc (99:1) gave 3-
1
thioxoprogesterone (3d) (73 mg, 22%). Pink oil. IR (C6D6): 2936, 1702, 1579, 1010. H-NMR (200
MHz, C6D6): 0.54 (s, 3H, H3C(18)), 076 (s, 3H, H3C(19)), 1.86 (s, 3H, H3C(21)), 2.52 (dtd, J = 16.5,
13
15.5, 5.0 Hz, 1H, Hβ-C(2)), 3.14 (dt, J = 17.8, 3.6 Hz, 1H, Hα-C(2), 6.66 (s, 1H, H-C(4)). C-NMR
(50 MHz, C6D6): 236.9 (s, C(3)), 206.9 (s, C(20)), 161.9 (s, C(5)), 135.4 (d, C(4)), 63.3 (d, C(17)),
55.9 (d, C(14)), 53.7 (d, C(9)), 43.7 (s, C(13)), 43.6 (t, C(2)), 38.6 (t, C(12)), 38.4 (s, C(10)), 36.6 (t,
C(6)), 35.4 (d, C(8)), 32.6 (t, C(7)), 31.9 (t, C(1)), 31.1 (q, C(21)), 24.4 (t, C(15)), 23.1 (t, C(16)), 21.1
(t, C(11)), 16.8 (q, C(19)), 13.4 (q, C(18)). Further elution with toluene/EtOAc (98:2) afforded dimer-
1
sulfide 2d (50 mg, 16%). IR (CHCl3): 2939, 1703, 1257. H-NMR (200 MHz, CDCl3): 0.65 (s, 6H,

Molecules 2010, 15
3473
2×H3C(18)), 0.94 (s, 6H, 2×H3C(19)), 2.13 (s, 6H, 2×H3C(21)), 5.42 (br. s, 2H, 2×H-C(6)), 6.11 (s,
2H, 2×H-C(4)). 13C-NMR: 209.4 (s, C(20)), 141.4 (s, C(5)), 131.6 (d, C(4)), 129.3 (s, C(3)), 123.8 (d,
C(6)), 63.5 (d, C(17), 56.9 (d, C(14)), 47.8 (d, C(9)), 44.0 (s, C(13)), 38.7 (t, C(12)), 34.6 (s, C(10)),
34.6 (t, C(1)), 31.6 (d, C(8)), 31.6 (q, C(21)), 31.4 (t, C(7)), 27.6 (t, C(2)), 24.3 (t, C(15)), 22.7 (t,
C(16)), 21.0 (t, C(11)), 18.9 (q, C(19)), 13.2 (q, C(18)). Anal. calcd for C42H58O2S: C 80.46; H 9.32; S
5.11. Found: C 80.68; H 9.41; S 13.69. Starting material recovered: 119 mg (38%).
In toluene 8 h: Starting with 314 mg of 1d, elution with toluene/EtOAc (98:2) gave dimer-sulfide 2d
(160 mg, 51%) and starting material (106 mg, 34%).
In CH2Cl2 45 min:Starting with 630 mg of 1d, elution with toluene/EtOAc (99:1) gave 3,20-
dithioxoprogesterone (4d) (66 mg, 9%). IR (KBr): 2939, 1576, 1010. Further elution with
toluene/EtOAc (98:2) afforded 3-thioxoprogesterone (3d) (185 mg, 28%). Further elution with
1
toluene/EtOAc (97:3) gave 1,2,4-trithiolane 5d (114 mg, 16%). IR (CHCl3): 2934, 1702, 1492. H-
NMR (200 MHz, CDCl3): 0.63 (s, 6H, 2×H3C(18)), 1.03 (s, 6H, 2×H3C(19)), 2.13 (s, 6H, 2×H3C(21)),
13
5.47 (s, 2H, 2×H-C(4)). C-NMR: 209.5 (s, C(20)), 151.9 (s, C(5)), 119.3 (d, C(4)), 81.1 (s, C(3)),
63.5 (d, C(17), 56.0 (d, C(14)), 54.2 (d, C(9)), 44.0 (s, C(13)), 38.7 (t, C(12)), 37.2 (s, C(10)), 37.2 (t,
C(2)), 35.6 (d, C(8)), 34.9 (t, C(1)), 32.5 (t, C(6)), 32.1 (t, C(7)), 31.4 (q, C(21)), 24.3 (t, C(15)), 22.7
(t, C(16)), 21.1 (t, C(11)), 16.5 (q, C(19)), 13.2 (q, C(18)). Anal. calcd for C42H60O2S3: C 72.78; H
8.73; S 13.88. Found: C 72.91; H 8.67; S 13.80. Recovered starting material: 176 mg (28%).
In CH2Cl2 7 h: Starting with 630 mg of 1d, elution with toluene/EtOAc (99:1) gave 3-
thioxoprogesterone (3d) (78 mg, 12%). Further elution with toluene/EtOAc (97:3) gave 1,2,4-
trithiolane 5d (185 mg, 27%). Further elution with toluene/EtOAc (96:4) gave phosphonotrithioate 6d
1
(110 mg, 13%). IR (CHCl3): 2936, 1702, 1257, 1098, 830. H-NMR (500 MHz, CDCl3): 0.637 and
0.640 (2s, 6H, 2×H3C(18)), 0.89 and 0.92 (2s, 6H, 2×H3C(19)), 2.117 and 2.120 (2s, 6H, 2×H3C(21)),
4
3.86 (s, 3H, OCH3), 5.49 (br.s, 2H, 2×H-C(6)), 6.28 and 6.32 (2d, JPH = 4.5 and 6.0 Hz, 2H, 2×H-
C(4)), 6.96 (dd, 4JPH = 3.2 Hz, JHH = 9.0 Hz, 2H, 2×Ar-H), 8.02 (dd, 3JPH = 14.0 Hz, JHH = 9.0 Hz, 2H,
4
2×Ar-H). 13C NMR (125 MHz): 209.4 (s, C(20)), 162.6 (sd, JPC = 2.9 Hz, ArC-OCH3), 141.6 and
4
3
141.7 (2sd, both JPC = 3.7 Hz, 2×C(5)), 141.27 and 141.35 (2dd, JPC = 5.5 Hz, 2×C(4)), 133.4 (dd,
3JPC = 12.8 Hz, 2×ArC-H), 128.1 (sd, JPC = 84.6 Hz, ArC-P), 127.23 and 127.20 (2dd, JPC = 3.7 and
5
2
2
5.0 Hz, 2×C(6)), 124.5 and 124.4 (2sd, JPC = 8.7 and 10.0 Hz, 2×C(3), 113.6 (d, JPC = 15.0 Hz,
2×ArC-H)), 63.5 (d, C(17), 56.9 (d, C(9)), 55.5 (q, OCH3), 47.7 (d, C(14)), 44.1 (s, C(13)), 38.7 (t,
C(12)), 34.80 and 34.78 (2t, 2×(C(1)), 34.34 and 34.31 (2s, 2×C(10)), 31.8 (t, C(7)), 31.6 (d, C(8)),
31.5 (q, C(21)), 31.3 and 31.1 (2t, 2×C(2)), 24.2 (t, C(15)), 22.6 (t, C(16)), 20.9 (t, C(11)), 18.93 and
18.88 (2q, 2×C(19)), 13.3 (q, C(18)). ESI-TOF-MS: m/z calcd for C49H65O3PS3: 829.39062 [M+H]+,
found 829.38920. In addition starting material (120 mg, 19%) was isolated.
Under microwave irradiation: Starting with 630 mg of 1d, elution with toluene/EtOAc (99:1) gave 3-
thioxoprogesterone (3d) (72 mg, 11%). Further elution with toluene/EtOAc (98:2) afforded gave
dimer-sulfide 2d (152 mg, 25%). Starting material (158 mg, 28%) was also recovered.

Molecules 2010, 15
3474
3.3.5. Thionation of 16α,17α-epoxyprogesterone (1e)
In toluene 25 min: Starting with 500 mg of 1e, elution with toluene/EtOAc (99:1) gave 3-thioxo-
1
16α,17α-epoxyprogesterone (3e) (105 mg, 20%). Pink oil. IR (C6D6): 2942, 1701, 1574, 1075. H-
NMR (500 MHz, C6D6): 0.67 (s, 3H, H3C(18)), 098 (s, 3H, H3C(19)), 1.77 (s, 3H, H3C(21)), 2.44 (dtd,
J = 16.2, 15.8, 5.0 Hz, 1H, Hβ-C(2)), 3.04 (s, H-C(16)), 3.09 (dt, J = 17.5, 3.5 Hz, 1H, Hα-C(2)), 6.63
13
(s, 1H, H-C(4)). C-NMR (125 MHz, C6D6): 237.4 (s, C(3)), 204.0 (s, C(20)), 161.3 (s, C(5)), 135.8
(d, C(4)), 71.1 (s, C(17)), 60.4 (d, C(16)), 54.1 (d, C(9)), 45.4 (d, C(14)), 43.9 (t, C(2)), 42.1 (s, C(13)),
38.8 (t, C(12)), 38.8 (s, C(10)), 33.6 (d, C(8)), 32.8 (t, C(6)), 31.9 (t, C(7)), 31.8 (t, C(1)), 27.7 (t,
C(15)), 25.9 (q, C(21)), 21.8 (t, C(11)), 17.0 (q, C(19)), 15.7 (q, C(18)). Further elution with
toluene/EtOAc (98:2) afforded gave dimer-sulfide 2e (122 mg, 25%). IR (CHCl3): 2939, 1703, 1376.
1H-NMR (200 MHz, CDCl3): 0.95 (s, 6H, 2×H3C(19)), 1.06 (s, 6H, 2×H3C(18)), 2.02 (s, 6H,
13
2×H3C(21)), 3.68 (s, 2H, 2×H-C(16)), 5.39 (br. s, 2H, 2×H-C(6)), 6.10 (s, 2H, 2×H-C(4)). C-NMR
(50 MHz, CDCl3): 204.8 (s, C(20)), 141.6 (s, C(5)), 131.4 (d, C(4)), 129.4 (s, C(3)), 123.3 (d, C(6)),
70.8 (s, C(17)), 60.3 (d, C(16)), 48.1 (d, C(14)), 45.4 (d, C(9)), 41.5 (s, C(13)), 34.7 (s, C(10)), 34.4 (t,
C(1)), 31.2 (t, C(12)), 31.1 (t, C(2)), 31.1 (t, C(7)), 29.4 (d, C(8)), 27.2 (t, C(15)), 25.8 (q, C(21)), 21.3
(t, C(11)), 18.8 (q, C(19)), 15.1 (q, C(18)). Anal. calcd for C42H54O4S: C 77.02; H 8.31; S 4.90. Found:
C 77.38; H 8.53; S 5.10. Starting material recovered: 180 mg (36%).
In toluene 8 h: Starting with 500 mg of 1e, elution with toluene/EtOAc (98:2) afforded gave dimer-
sulfide 2e (202 mg, 41%) and starting material (155 mg, 31%).
In CH2Cl2 45 min: Starting with 500 mg of 1e, elution with toluene/EtOAc (99:1) gave 3-thioxo-
16α,17α-epoxyprogesterone (3e) (185 mg, 35%). Further elution with toluene/EtOAc (98:2) and
crystallization from CH3OH afforded 1,2,4-trithiolane 5e (62 mg, 6%). m.p. > 147 ºC (decomp.). IR
1
(CHCl3): 2936, 1705, 1377, 733. H-NMR (200 MHz, CDCl3): 1.03 (s, 6H, 2×H3C(19)), 1.04 (s, 6H,
2×H3C(18)), 2.02 (s, 6H, 2×H3C(21)), 3.66 (s, 2H, 2×H-C(16)), 5.46 (s, 2H, 2×H-C(4)). 13C-NMR (50
MHz, CDCl3): 204.9 (s, C(20)), 151.8 (s, C(5)), 119.5 (d, C(4)), 81.1 (s, C(3)), 70.8 (s, C(17)), 60.4 (d,
C(16)), 54.5 (d, C(9)), 44.8 (d, C(14)), 41.6 (s, C(13)), 37.3 (t, C(2)), 37.3 (s, C(10)), 34.9 (t, C(1)),
33.3 (d, C(8)), 32.2 (t, C(6)), 32.2 (t, C(7)), 31.2 (t, C(12)), 27.3 (t, C(15)), 25.9 (q, C(21)), 20.5 (t,
C(11)), 18.3 (q, C(19)), 15.2 (q, C(18)). Anal. calcd for C42H56O4S3: C 69.96; H 7.83; S 13.34. Found:
C 69.68; H 8.11; S 13.47. Further elution with same eluent gave phosphonotrithioate 6e (42 mg, 7%).
1
Oil. IR (CHCl3): 2941, 1701, 1135, 984, 723. H-NMR (200 MHz, CDCl3): 0.89 and 0.94 (2s, 6H,
2×H3C(19)), 1.05 (s, 6H, 2×H3C(18)), 2.02 (s, 6H, 2×H3C(21)), 3.69 (s, 2H, 2×H-C(16)), 3.87 (s, 3H,
OCH3), 5.47 (br.s, 2H, 2×H-C(6)), 6.28 and 6.31 (2sd, 4JPH = 5.8 and 6.0 Hz, 2H, 2×H-C(4)), 6.95 (dd,
3
13
4JPH = 3.0 Hz, JHH = 8.8 Hz, 2H, 2×Ar-H), 8.01 (dd, JPH = 14.0 Hz, JHH = 8.8 Hz, 2H, 2×Ar-H). C-
NMR (50MHz, CDCl3): 204.8 (s, C(20)), 162.6 (s, ArC-OCH3), 141.85 and 141.78 (2s, C(5)), 141.3
and 141.1 (2d, 2×C(4)), 133.4 (dd, 3JPC = 12.8 Hz, 2×ArC-H), 127.7 (sd, JPC = 84.7 Hz, ArC-P), 126.7
(d, C(6)), 124.7 and 124.4 (2sd, both 2JPC = 9.1 Hz, 2×C(3)), 113.6 (dd, 2JPC=14.6, 2×ArC-H), 70.8 (s,
C(17)), 60.3 (d, C(16)), 55.4 (q, OCH3), 47.9 (d, C(9)), 45.4 (d, C(14)), 41.5 (s, C(13)), 34.6 (t, C(1)),
34.4 (s, C(10)), 31.4 (t, C(12)), 31.2 (t, C(7)), 31.0 (t, C(2)), 29.3 (d, C(8)), 27.3 (t, C(15)), 25.8 (q,
C(21)), 20.3 (t, C(11)), 18.8 (q, C(19)), 15.1 (q, C(18)). Starting material obtained: 135 mg (27%).

Molecules 2010, 15
3475
In CH2Cl2 8h: Starting with 500 mg of 1e, elution with toluene/EtOAc (98:2) gave 1,2,4-trithiolane 5e
(200 mg, 36%). Further elution with same eluent gave phosphonotrithioate 6e (180 mg, 28%). Starting
material: 50 mg (10%).
Under microwave irradiation: Starting with 500 mg of 1e, elution with toluene/EtOAc (99:1) gave 3-
thioxo-16α,17α-epoxyprogesterone (3e) (63 mg, 12%). Further elution with toluene/EtOAc (98:2)
afforded dimer-sulfide 2e (127 mg, 26%). Starting material isolated: 120 mg (24%).
4. Conclusions
In this work we showed that Lawesson’s reagent can be suitable for preparation of α,β-unsaturated
steroidal thioketones as well as different, depending on the solvent, sulfur steroid derivatives. α,β-
Unsaturated ketones 1a-e in boiling toluene gave, besides dimer-sulfides 2a-e, the thioketones 3a-e in
11–27% yields. Much higher yields of thioketones were obtained when thionation was carried out in
CH2Cl2 (28–70%). In this reaction the dithioketones 4c and 4d were isolated as well. With prolonged
reaction times in both solvents and due to the enethiones instability and formation of by-products
neither thioketone could be isolated. In toluene, the initially formed unstable enethiones dimerize to
give only the corresponding dimer-sulfides 2a-e (30–51%). In CH2Cl2 all unsaturated ketones 1a-e
gave as a main product the corresponding dimers with 1,2,4-trithiolane ring 5a-e in 11-79% yields, and
(4-methoxyphenyl)phosphonotrithioates 6b-e (8–36%) as a result of further reaction of the initially
formed thioketones with LR.
The combination of P4S10/HMDO under the microwave irradiation can also be applied for
thionation of α,β-unsaturated steroids. This reaction gave two main products, 3-thioketones 3a-e and
dimer-sulfides 2a-e. However, the yields of synthesized thioketones (11–26%) were lower than in the
reaction with LR
Although all obtained products were separated using flash column chromatography partial
decomposition to the more stable starting α,β-unsaturated ketones took place in all cases. The synthetic
results of this work could be useful for chemists in general, not only those working in the field of
steroid chemistry. It could be used for preparation of α,β-unsaturated thioketones as well as new sulfur
and/or phosphorus containing compounds.
Acknowledgements
The authors acknowledge the financial support of the Ministry of Science and Technological
Development of Serbia (Part of the project “Synthesis of different useful products from steroidal
molecules” - Project No. 142033).
References
1. Krstić, N.M.; Bjelaković, M.S.; Žižak, Ž.; Pavlović, M.D.; Juranić, Z.D.; Pavlović, V.D.
Synthesis of some steroidal oximes, lactams, thiolactams and their antitumor activities. Steroids
2007, 72, 406–414.

Molecules 2010, 15
3476
2. Krstić, N.M.; Bjelaković, M.S.; Dabović, M.M.; Lorenc, Lj.B.; Pavlović, V.D. Photochemical and
Beckmann rearrangement of (Z)-cholest-4-en-6-one oxime. J. Serb. Chem. Soc. 2004, 69,
413–420.
3. Pavlović, V.D.; Dabović, M.M.; Martinović, S.; Lorenc, Lj.B.; Kalvoda, J. Synthesis of 5-
azaandrostane-3β,17β-diol protected at the 17β-hydroxyl group. J. Serb. Chem. Soc. 2004, 69,
861–869.
4. Bjelaković, M.S.; Krstić, N.M.; Juranić, N.; Dabović, M.M.; Gojković, S.V.; Kessler, M.;
Kalvoda, J.; Pavlović, V.D. Steroid template associated peptides: design, synthesis and 2D NMR
characterization of a novel protected 18-Phe,19-Gly-containing steroidal compound. Tetrahedron
2007, 63, 9960–9969.
5. Henry, L. Ueber eine neue Bildungs- und Darstellungsweise der Nitrile. Ann. Chem. Pharm. 1869,
152, 148–152.
6. Wislicenus, J. Vorläufige Mittheilungen. Z. Chem. 1869, 12, 324-326.
7. Schmidt, U.; Luttringhaus, A.; Trefzger, H. Über Trithone, XII Trithione aus β-Ketoestern. Justus
Liebigs Ann. Chem. 1960, 631, 129–138.
8. Brillon, D. Recent Developments in the Area of Thionation Methods and Related Synthetic
Applications. J. Sulfur Chem. 1992, 12, 297–332.
9. Machiguchi, T.; Hasegawa, T.; Kano, Y. General Synthesis, Spectroscopic Properties, and Dipole
Moments of 2-Substituted Tropothiones. Bull. Chem. Soc. Jpn. 1993, 66, 3699–3706.
10. Curphey, T.J. A superior procedure for the conversion of 3-oxoesters to 3H-1,2-dithiole-3-thiones.
Tetrahedron Lett. 2000, 41, 9963–9966.
11. Curphey, T.J. Thionation with the Reagent Combination of Phosphorus Pentasulfide and
Hexamethyldisiloxane. J. Org. Chem. 2002, 67, 6461–6473.
12. Curphey, T.J. Thionation of esters and lactones with the reagent combination of phosphorus
pentasulfide and hexamethyldisiloxane. Tetrahedron Lett. 2002, 43, 371–373.
13. Polshettiwar, V.; Kaushik, M.P. A new, efficient and simple method for the thionation of ketones
to thioketones using P4S10/Al2O3. Tetrahedron Lett. 2004, 45, 6255–6257.
14. Pedersen, B.S.; Scheibye, S.; Nilsson, N.H.; Lawesson, S.O. Studies on organophosphorus
compounds. XX. Syntheses of thioketones. Bull. Soc. Chim. Belg. 1978, 87, 223–228.
15. Pedersen, B.S.; Lawesson, S.O. Studies on organophosphorus compounds —XXVIII: Syntheses
of 3H-1,2-dithiole-3-thiones and 4H-1,3,2,-oxazaphosphorine derivatives from the dimer of p-
methoxyphenyl-thionophosphine sulfide and derivatives of 3-oxo carboxylic acids. Tetrahedron
1979, 35, 2433–2437.
16. Cava, M.P.; Levinson, M.I. Thionation reactions of Lawesson’s reagents. Tetrahedron 1985, 41,
5061–5087.
17. Venkateswarlu, P.; Venkata, S.C. Studies on organophosphorus compounds: reactions of
benzosuberones
with
2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide
(Lawesson’s reagent). Tetrahedron Lett. 2004, 45, 3207–3209.
18. Cava, M.P.; Lau, J.; Simonsen, K.B. Cholestano-Fused Electron Donors and Acceptors J. Org.
Chem. 1997, 62, 6814–6819.
19. Mohamed, N.R.; Elmegeed, G.A.; Younis, M. Studies on Organophosphorus Compounds VII1,2:
Transformations of Steroidal Ketones With Lawesson’s Reagent into Thioxo and Heterofused

Molecules 2010, 15
3477
Steroids. Results of Antimicrobial and Antifungal Activity. Phosphorus Sulfur Silicon 2003, 178,
2003–2017.
20. Mohamed, N.R.; Elmegeed, G.A.; Abd-ElMalek, H.A.; Younis, M. Synthesis of biologically
active steroid derivatives by the utility of Lawesson’s reagent. Steroids 2005, 70, 131–136.
21. Olsson, R.; Hansen, H.C.; Andersson, C-M. Microwave-assisted solvent-free parallel synthesis of
thioamides. Tetrahedron Lett. 2000, 41, 7947–7950.
22. Heravi, M.M.; Rajabzadeh, G.; Rahimizadeh, M.; Bakavoli, M.; Ghassemzadeh, M. Thiation of
heterocycles using silica gel supported P2S5 under microwave irradiation in solventless system.
Synth. Commun. 2001, 31, 2231–2234.
23. Varma, R.S.; Kumar, D. Microwave-Accelerated Solvent-Free Synthesis of Thioketones,
Thiolactones, Thioamides, Thionoesters and Thioflavonoids. Org. Lett. 1999, 1, 697–700.
24. Filippi, J-J.; Fernandez, X.; Lizzani-Cuvelier, L.; Loiseau, A-M. Solvent-free thionation of γ-
lactones under microwave irradiation. Tetrahedron Lett. 2003, 44, 6647–6650.
25. Nivsarkar, M.; Gupta, A.K.; Kaushik, M.P. Thionation of phosphoramidodichloridates and
phosphoramidate diesters using phosphorus pentasulfide and hexamethyldisiloxane under
microwave irradiation. Part 1. Tetrahedron Lett. 2004, 45, 6863–6866.
26. Barton, D.H.R.; Choi, L.S.L.; Hesse, R.H.; Pechet, M.M.; Wilshire, C. Preparation and Reactions
of α,β-Unsaturated and Cross-conjugated Diene Thiones. J. Chem. Soc., Perkin Trans. 1 1979,
1166–1175.
27. Weiß, D.; Gaudig, U.; Beckert, R. A new method for the preparation of cross conjugated 3-
thioxosteroids [Eine neue Methode zur Herstellung von gekreuzt-konjugierten 3-
Thioxosteroiden]. Synthesis 1992, 8, 751–752.
28. Bourdon, R.; Preparation of sterol thiols. II. 3-Thiono and 3β-mercapto-4-cholestenes. [No 130. –
Préparation de thiols stéroliques. II.– 3-thioxo-cholesta 4-ène et 3β-mercapto-cholesta]. Bull. Soc.
Chim. France 1958, 722–725.
Sample Availability: Samples of the compounds are available from the authors.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an Open Access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).