Interaction of 16-hydroxymethylidene derivatives of androstane and estrone with thiohydrazides of oxamic acids

Article abstract of DOI:10.1007/s11172-013-0379-4

Reaction of thiohydrazides of oxamic acids with 16-hydroxymethylidene derivatives of androstane and estrone involves the hydroxymethylidene group and leads to thiohydrazones, which undergo heterocyclization to give 16-(1,3,4-thiadiazol-2-yl)-substituted steroids.

Full text of DOI:10.1007/s11172-013-0379-4

Russian Chemical Bulletin, International Edition, Vol. 62, No. 12, pp. 2603—2608, December, 2013
2603
Interaction of 16ꢀhydroxymethylidene derivatives of androstane
and estrone with thiohydrazides of oxamic acids
I. V. Zavarzin, Ya. S. Antonov, E. I. Chernoburova, M. A. Shchetinina, N. G. Kolotyrkina, and A. S. Shashkov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: zavi@ioc.ac.ru
Reaction of thiohydrazides of oxamic acids with 16ꢀhydroxymethylidene derivatives of
androstane and estrone involves the hydroxymethylidene group and leads to thiohydrazones,
which undergo heterocyclization to give 16ꢀ(1,3,4ꢀthiadiazolꢀ2ꢀyl)ꢀsubstituted steroids.
Key words: androstane, estrone, thiohydrazides of oxamic acids, thiohydrazones,
1,3,4ꢀthiadiazols.
1
Reaction of steroids, which have active groups in the
ring D, with thiohydrazides of oxamic acids is different
from the reaction with hydrazines and carboxhydrazides.1—5
For example, reactions of dehydropregnenolone with hyꢀ
drazines and hydrazides usually result in formation of pyraꢀ
zoles.3—5 In similar conditions thiohydrazides of oxamic
acids give 2´ꢀ(Nꢀarylcarbamoyl)ꢀ5´ꢀmethylꢀ16ꢀhydroxyꢀ
spiro(androstꢀ4ꢀeneꢀ17,6´ꢀ[1,3,4]ꢀthiadiazinꢀ3ꢀones).4,5
Proceeding our study6—8 of steroids with heterocyclic
substituents, we studied the reaction of 16ꢀhydroxymethꢀ
ylidene derivatives of androstane (1) and estrone (2) with
thiohydrazides of oxamic acids 3a,b.
Compounds 1 and 2 exist in dynamic equilibrium of
ketoꢀaldehyde and ketoꢀenol tautomers9 (see Scheme 1).
As known,9—12 16ꢀhydroxymethylidene derivatives of anꢀ
drostane (1) and estrone (2) react with hydrazines and
hydrazides to give corresponding [17,16ꢀc] pyrazoles.
We have found, that the presence of the thioxo group
in compounds 3a,b changes the direction of the reaction,
and the cyclization takes place in the side chain giving the
1,3,4ꢀthiadiazole fragment. For example, heating of comꢀ
pounds 1 and 2 with equimolar amount of thiohydrazides
3a,b in ethanol in the presence of the catalytic amount of
TsOH gave the corresponding steroid thiohydrazones 4a,b
and 5a,b with 8090% yields (see Scheme 1). When the
twofold excess of the thiohydrazides was used, compounds
4 and 5 were obtained as only products evidencing the
17ꢀpositioned keto group left intact.
detail.13 The H NMR spectrum of the form A had charꢀ
acteristic signals at  8.58 and 11.1 attributed to the proꢀ
tons of the groups N=CH and NHC=S, correꢀ
spondingly. The 13C NMR spectrum of the form B has
a signal at  167.2, which is assigned to the CSH moiety.
The 1H NMR spectrum of the form C has the signal of the
heterocyclic proton at  5.6.
The cyclization of the thiohydrazone fragment in diꢀ
oxane under reflux in the presence of TsOH occurs in the
side chain of the steroid thiohydrazones 4 and 5 to give the
corresponding thiadiazoles 6 and 7 in 6064% yields
(Scheme 3). The cyclization is oxidative and may be air
promoted.
Synthesis of hydrazones 4 and 5 and the following cyꢀ
clization can be combined into a oneꢀpot procedure, which
is refluxing of the mixture of compounds 1 or 2 with the
corresponding thiohydrazides in acetic acid. In this case
3ꢀOH acetylation of the steroid part takes place along
with the cyclization, and the acetates 8 and 9 are obtained
(Scheme 4).
In contrast to the transformations of the steroids 1
and 2, interaction of the related 2ꢀhydroxymethylideneꢀ
1ꢀindanone (10) with the thiohydrazide 3a leads to the
cleavage of the molecule and removal of indanone along
with the formation of the 1,3,4ꢀthiadiazole cycle (Scheme 5).
For example, heating of compound 10 with the equimoꢀ
lar quantity of the thiohydrazide 3a in ethanol in the
presence of the catalytic amount of TsOH leads to
Nꢀ(4ꢀmethoxyphenyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide 11
in a yield of 69%. Also, 1ꢀindanone (12) was isolated from
the reaction mixture.
In the solution, compounds 4 and 5 exist in three basic
tautomeric forms, which are the thioxo (A), the thiol (В)
and the cyclic form (C) (see Scheme 2).
Initially, the dissolved compounds 4 and 5 take the
form A, which is readily tautomerized to the forms B and
C. This type of tautomerism is characteristic of hydrazones
of thiohydrazides of oxamic acid and was described in
Transformations of this type, which include the reꢀ
moval of the 1,3,4ꢀthiadiazole fragment, have been deꢀ
scribed earlier14 for the derivatives of 3ꢀformylꢀ4ꢀhydrꢀ
oxycoumarin.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2603—2608, December, 2013.
1066ꢀ5285/13/6212ꢀ2603 © 2013 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 12, December, 2013
Zavarzin et al.
Scheme 1
3—5: Ar = 4ꢀMeOC6H4 (a), 4ꢀFC6H4 (b)
Scheme 2
Scheme 3
Reagents and conditions: i. TsOH, dioxane, reflux.
In the opinion of the authors,14 the oxidation is acꢀ
complished by DMSO, which is used as a solvent. In our
case, in the absence of DMSO the air oxygen can be an
oxidant.
On the other hand, we can conjecture, that losing of
the thiadiazole fragment during the cyclization can result
from sixꢀmembered ring sigmatropic rearrangement. The
detailed mechanism is beyond the scope of this study.
Interaction of compounds 1, 2, 10 with thiohydrazides 3
in different conditions, in particular in toluene in the
presence of the catalytic amount of AcOH, or in benzene
in the presence the catalytic amount of BF3•Et2O, leads

1,3,4ꢀThiadiazole steroids
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 12, December, 2013
2605
Scheme 4
the external and internal calibration was performed (Electroꢀ
spray Calibrant Solution, Fluka); solutions of samples in acetoꢀ
nitrile, methanol or water were syringed; the flow rate was
3 L min–1, nitrogen was used as the nebulizing gas (4 L min–1);
1
the temperature of the interface 180 C. H NMR spectra were
recorded on NMR spectrometers Bruker WMꢀ300 (300 МHz) and
Bruker DRXꢀ500 (500 MHz) at 303 K, and 13C NMR spectra
were measured on a Bruker WMꢀ300 (75 MHz). The signals of
the solvents were used as the references. The course of the reacꢀ
tions and purity of products was monitored by TLC on Kieselꢀ
gelꢀG (Merck Si 254F) using a AcOEthexane mixture as an
eluent, the spots were visualised with Ce(SO4)2 solution in 10%
H2SO4. Column chromatography was carried out on silica gel
Acros 60A (0.0600.200). Solvents were purified and dried usꢀ
ing standard procedures. The reagents were purchased from
Acros. The starting thiohydrazides 3a,b were obtained as deꢀ
scribed.16 16ꢀHydroxymethylidene derivatives of androstane (1)
and estrone (2) were obtained by Claisen condensation of ethyl
formate with 3ꢀhydroxyꢀ5ꢀandrostanꢀ17ꢀone and estrone.10
3ꢀHydroxyꢀ16ꢀhydroxymethylideneꢀ5ꢀandrostanꢀ17ꢀone
(1). To a stirred solution of 3ꢀhydroxyꢀ5ꢀandrostanꢀ17ꢀone
(1.8 mmol) in pyridine (20 mL) ethyl formate (11.9 mmol) and
sodium methoxide (27 mmol) were added slowly under N2 atmosꢀ
phere at room temperature. The reaction mixture was stirred for
18 h at room temperature; the course of the reaction was moniꢀ
tored by TLC. After that the reaction mixture was poured to the
solution of AcOH (9 mL) in water (80 mL), the mixture was
extracted with dichloromethane (320 mL). The combined orꢀ
ganic fractions were washed with water (3×70 mL) and extracted
with 2% KOH in water (3100 mL). The basic fractions were
combined and washed with diethyl ether (3×15 mL). The basic
layer was separated and AcOH was added until the pH 5. The
precipitate was separated, washed with heptane (3×30 mL), dried
in vacuo and recrystallized from acetone. The yield of comꢀ
pound 1 was 96%, m.p. 167—169 С (acetone). 1H NMR
(300 MHz, DMSOꢀd6), : 0.68 (m, 1 Н, H(9)); 0.77 (s, 3 Н,
C(13)Me); 0.79 (s, 3 Н, C(10)Me); 0.91, 1.61 (m, 2 Н, H(1));
0.95, 1.72 (m, 2 Н, H(7)); 1.07 (m, 1 Н, H(5)); 1.13, 1.43 (m, 2 Н,
H(4)); 1.15 (s, 1 Н, H(14)); 1.15, 1.65 (m, 2 Н, H(2)); 1.24, 1.26
(m, 2 Н, H(6)); 1.26, 1.65 (m, 2 Н, H(12)); 1.28, 1.58 (m, 2 Н,
H(11)); 1.52 (s, 1 Н, H(8)); 1.88, 2.46 (m, 2 Н, H(15)); 3.35
(m, 1 Н, Н(3)); 7.34 (s, 1 Н, H(1´)). 13C NMR (75 MHz,
DMSOꢀd6), : 11.9 (C(19)); 14.1 (C(18)); 20.0 (C(11)); 24.1
(C(15)); 28.1 (C(6)); 30.4 (C(7)); 31.2 (C(12)); 31.3 (C(2)); 34.0
(C(8)); 35.2 (C(10)); 36.4 (C(1)); 38.0 (C(4)); 44.3 (C(5)); 47.4
(C(13)); 49.3 (C(14)); 53.9 (C(9)); 69.1 (C(3)); 113.1 (C(16));
149.8 (C(1´)); 208.4 (C(17)). Found (%): С, 74.63; Н, 9.39.
C20H30O3. Calculated (%): С, 75.43; Н, 9.50. MS (ESI),
m/z: 319.
8, 9: Ar = 4ꢀMeOC6H4 (a), 4ꢀFC6H4 (b)
Reagents and conditions: i. 3a,b, AcOH, reflux.
Scheme 5
Reagents and conditions: i. 3a, TsOH, EtOH, reflux.
to complex mixtures, which were resolved to give 12—20%
of isolated products 6, 7 and 11.
Thus, we have shown that compounds 3a,b with the
thioxo group interact with ꢀketo aldehydes 1, 2, 10 in
a special way which includes the cyclization of the thioꢀ
oxamidic fragment into the 1,3,4ꢀthiadiazole group.
Reaction of compound 1 with thiohydrazides 3a,b in ethanol.
To a stirred and heated (70 С) solution of compound 1
(1.32 mmol) in ethanol (40 mL) thiohydrazide 3a,b (1.58 mmol)
and a catalytic amount of TsOH were added. The mixture was
stirred at this temperature for 7 h, kept for 12 h at 20 С and
poured onto the ice. The precipitate was filtered off, washed
with water (3×50 mL), hexane (3×30 mL), airꢀdried and the
residue was subjected to column chromatography on silica gel
(the eluent was AcOEthexane, 1 : 1) and products 4а,b were
obtained.
Experimental
Melting points were measured on a Boetius hot stage with
a heating rate of 4 C min–1 and are uncorrected. High resolution
mass spectra were recorded on a Bruker micrOTOF II instruꢀ
ment using the electrospray ionization (ESI) technique.15 The
measurements were done in the positiveꢀion mode (capillary
voltage was 4500 V) and in the ionꢀnegative mode (capillary
voltage was 3200 V); the mass scan range was m/z: 503000 D;
3ꢀHydroxyꢀ16ꢀ{2ꢀ[2ꢀ(4ꢀmethoxyphenylamino)ꢀ2ꢀoxoꢀ1ꢀ
thioxoethyl]hydrazonomethyl}androstanꢀ17ꢀone (4а). Yield 86%,

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Zavarzin et al.
m.p. 239—241 С (AcOEthexane). 1H NMR (500 MHz,
DMSOꢀd6), : 0.67 (s, 1 Н, Н(9)); 0.76 (s, 3 Н, С(13)Ме); 0.78
(s, 3 Н, С(10)Ме); 0.89, 1.59 (m, 2 Н, Н(1)); 0.92, 1.71 (m, 2 Н,
Н(7)); 1.04 (s, 1 Н, Н(5)); 1.14, 1.41 (m, 2 Н, Н(4)); 1.21, 1.70
(m, 2 Н, Н(2)); 1.23, 1.25 (m, 2 Н, Н(6)); 1.25, 1.61 (m, 2 Н,
Н(12)); 1.27, 1.58 (m, 2 Н, Н(11)); 1.29 (s, 1 Н, Н(14)); 1.49
(s, 1 Н, Н(8)); 1.74, 2.03 (m, 2 Н, Н(15)); 3.08 (m, 1 Н, Н(16));
3.44 (s, 1 Н, Н(3)); 3.72 (s, 3 Н, ОМе); 5.60 (s, 1 Н, Н(1´) (С));
6.87 (d, 2 Н, HAr, J = 8.7 Hz); 7.60 (d, 2 Н, HAr, J = 8.7 Hz);
8.58 (s, 1 Н, Н(1´) (А, В)); 10.00 (s, 1 Н, NHСО); 11.10 (s, 1 Н,
NHCS (А)). 13C NMR (75 MHz, DMSOꢀd6), : 12.0 (C(18)),
12.9 (C(19)), 20.1 (C(11)), 23.9 (C(15)), 28.1 (C(6)), 30.7 (C(7)),
31.3 (C(12)), 32.9 (C(2)), 33.7 (C(8)), 35.3 (C(10)), 36.5 (C(1)),
38.0 (C(4)), 44.2 (C(13)), 44.4 (C(5)), 48.3 (C(14)), 49.4 (C(16)),
53.9 (C(9)), 55.1 (OMe), 69.2 (C(3)), 113.8 (CAr), 121.6 (CAr),
131.3 (CAr), 155.6 (CAr), 157.4 (C(3´)), 167.2 (С(2´) (B)), 190.3
(С(2´) (A)), 217.9 (C(17)). Found (%): С, 66.08; Н, 7.62; N, 7.78;
S, 6.23. С29Н39N3О4S. Calculated (%): С, 66.26; Н, 7.48; N,
7.99; S, 6.10. MS (ESI), m/z: 526.
3ꢀHydroxyꢀ16ꢀ{2ꢀ[2ꢀ(4ꢀfluorophenylamino)ꢀ2ꢀoxoꢀ1ꢀthiꢀ
oxoethyl]hydrazonomethyl}androstanꢀ17ꢀone (4b). Yield 79%,
m.p. 228—232 С (ethyl acetate—hexane). 1H NMR (500 MHz,
DMSOꢀd6), : 0.78 (s, 3 Н, C(13)Ме); 0.81 (s, 3 Н, С(10)Ме);
3.44 (s, 1 Н, Н(3)); 5.60 (s, 1 Н, Н(1´) (C)); 7.42 (m, 2 Н, HAr);
7.69 (m, 2 Н, HAr); 8.61 (s, 1 Н, H(1´) (A, B)); 10.13 (s, 1 Н,
NHСО); 10.95 (s, 1 Н, NHCS (A)). 13C NMR (DMSOꢀd6),
: 12.2 (C(18)), 12.9 (C(19)), 20.0 (C(11)), 23.9 (C(15)),
28.3 (C(6)), 30.6 (C(7)), 31.1 (C(12)), 32.9 (C(2)), 33.6 (C(8)),
35.3 (C(10)), 36.5 (C(1)), 38.0 (C(4)), 44.0 (C(13)), 44.4 (C(5)),
48.5 (C(14)), 49.2 (C(16)), 53.9 (C(9)), 69.2 (C(3)), 122.9 (CAr),
127.1 (CAr), 129.5 (CAr), 141.3 (CAr), 163.4 (C(3´)), 167.4 (С(2´)
(B)), 190.5 (С(2´) (A)), 218.1 (C(17)). Found (%): С, 65.65;
Н, 7.22; F, 3.52; N, 7.99; S, 6.45. С28Н36FN3О3S. Calculated (%):
С, 65.47; Н, 7.06; F, 3.70; N, 8.18; S, 6.24. MS (ESI), m/z: 514.
Cyclization of thiohydrazones 4a,b. The solution of thiohyꢀ
drazones 4a,b (1.32 mmol) and the catalytic amount of TsOH
was kept in refluxing dioxane for 8 h in contact with atmosphere
and the course of the reaction was monitored by TLC. Then the
reaction mixture was poured onto ice, the precipitate was filꢀ
tered off, washed with water (3×20 mL), heptane (3×20 mL) and
airꢀdried. The residue was subjected to column chromatography
on silica gel (the eluent was AcOEthexane, 1 : 1) and products
6а,b were obtained.
5ꢀ(3ꢀHydroxyꢀ17ꢀoxoandrostanꢀ16ꢀyl)ꢀNꢀ(4ꢀmethoxypheꢀ
nyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (6a). Yield 76%, m.p.
176—179 С (AcOEthexane). 1H NMR (500 MHz, DMSOꢀd6),
: 0.74 (m, 1 Н, H(9)); 0.81 (s, 3 Н, C(10)Me); 0.84, 1.05 (s, 3 Н,
C(13)Me); 0.93, 1.61 (m, 2 Н, H(1)); 1.05, 1.73 (m, 2 Н, H(7));
1.09 (m, 1 Н, H(5)); 1.16, 1.44 (m, 2 Н, H(4)); 1.23, 1.70 (m, 2 Н,
H(2)); 1.25, 1.65 (m, 2 Н, H(12)); 1.27, 1.28 (m, 2 Н, H(6));
1.32, 1.62 (m, 2 Н, H(11)); 1.53 (s, 1 Н, H(14)); 1.63 (s, 1 Н,
H(8)); 2.28, 2.53 (m, 2 Н, H(15)); 3.30 (s, 1 Н, H(3)); 3.75 (s, 3 Н,
OMe); 4.41 (m, 1 Н, H(16)); 6.94 (m, 2 Н, HAr); 7.72 (m, 2 Н,
HAr); 10.93, 10.95 (s, 1 Н, NHСО). 13C NMR (75 MHz,
DMSOꢀd6), : 12.2 (C(19)), 14.3 (C(18)), 20.1 (C(11)), 28.1
(C(6)), 30.9 (C(7)), 31.0 (C(12)), 33.0 (C(2)), 34.0 (C(8)), 35.4
(C(10)), 36.7 (C(1)), 38.0 (C(4)), 38.3 (C(15)), 44.1 (C(13)),
44.4 (C(5)), 48.1 (C(14)), 49.9 (C(16)), 54.1 (C(9)), 55.1 (OMe),
69.3 (C(3)), 114.0 (CAr), 122.1 (CAr), 130.4 (CAr), 156.1 (CAr),
156.2 (C(3´)), 164.3 (C(2´)), 164.7 (C(1´)), 217.5, 217.8 (C(17)).
Found (%): С, 66.38; Н, 7.32; N, 7.88; S, 6.33. С29Н37N3О4S.
Calculated (%): С, 66.51; Н, 7.12; N, 8.02; S, 6.12. MS (ESI),
m/z: 524.
5ꢀ(3ꢀHydroxyꢀ17ꢀoxoandrostanꢀ16ꢀyl)ꢀNꢀ(4ꢀfluorophenꢀ
yl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (6b). Yield 79%, m.p.
186—188 С (AcOEthexane). 1H NMR (500 MHz, DMSOꢀd6),
: 0.83 (s, 3 Н, C(10)Me); 1.06 (s, 3 Н, C(13)Me); 3.32 (s, 1 Н,
H(3)); 4.35 (m, 1 Н, H(16)); 7.42 (m, 2 Н, HAr); 7.81 (m, 2 Н,
HAr); 10.19 (s, 1 Н, NHСО). 13C NMR (75 MHz, DMSOꢀd6),
: 12.2 (C(19)), 14.6 (C(18)), 20.1 (C(11)), 28.4 (C(6)), 30.9
(C(7)), 31.3 (C(12)), 33.0 (C(2)), 34.0 (C(8)), 35.5 (C(10)), 36.7
(C(1)), 38.0 (C(4)), 38.6 (C(15)), 44.1 (C(13)), 44.4 (C(5)), 48.5
(C(14)), 49.2 (C(16)), 54.1 (C(9)), 69.3 (C(3)), 121.2 (CAr), 125.5
(CAr), 133.7 (CAr), 141.7 (CAr), 159.6 (C(3´)), 164.5 (C(2´)),
164.7 (C(1´)), 217.3, 217.8 (C(17)). Found (%): С, 65.61; Н, 6.87;
F, 3.54; N, 8.09; S, 6.46. С28Н34FN3О3S. Calculated (%):
С, 65.73; Н, 6.70; F, 3.71; N, 8.21; S, 6.27. MS (ESI), m/z: 512.
Reaction of compound 1 with thiohydrazides 3a,b in acetic
acid. To the stirred solution of compound 1 (1.0 mmol) in acetic
acid (25 mL) thiohydrazide 3а,b (1.1 mmol) was added, the
mixture was refluxed for 1—2 h and the course of the reaction
was monitored by TLC. Then the reaction mixture was poured
onto the ice, the precipitate was filtered off, washed with water
(3×50 mL), heptane (3×25 mL) and airꢀdried. The residue was
subjected to column chromatography on silica gel (the eluent
was AcOEthexane, 1 : 1) and products 8а,b were obtained.
5ꢀ(3ꢀAcetoxyꢀ17ꢀoxoandrostanꢀ16ꢀyl)ꢀNꢀ(4ꢀmethoxypheꢀ
nyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (8a). Yield 76%, m.p.
185—188 С (AcOEthexane, 1 : 1). 1H NMR (500 MHz,
DMSOꢀd6), : 0.74 (m, 1 Н, H(9)); 0.81 (s, 3 Н, C(10)Me);
0.84, 1.05 (s, 3 Н, C(13)Me); 0.93, 1.61 (m, 2 Н, H(1)); 1.05,
1.73 (m, 2 Н, H(7)); 1.09 (m, 1 Н, H(5)); 1.16, 1.44 (m, 2 Н,
H(4)); 1.23, 1.70 (m, 2 Н, H(2)); 1.25, 1.65 (m, 2 Н, H(12));
1.27, 1.28 (m, 2 Н, H(6)); 1.32, 1.62 (m, 2 Н, H(11)); 1.53 (s, 1 Н,
H(14)); 1.63 (s, 1 Н, H(8)); 1.96 (s, 3 Н, CH3 (ОAc)); 2.28, 2.53
(m, 2 Н, H(15)); 3.30 (s, 1 Н, H(3)); 3.75 (s, 3 Н, OMe); 4.41
(m, 1 Н, H(16)); 4.69 (s, 1 Н, H(3)); 6.94 (m, 2 Н, HAr);
7.72 (m, 2 Н, HAr); 10.93, 10.95 (s, 1 Н, NHСО).13C NMR
(75 MHz, DMSOꢀd6), : 12.2 (C(19)), 14.3 (C(18)), 20.1 (C(11)),
21.2 (СН3 (АсО)); 28.1 (C(6)), 30.9 (C(7)), 31.0 (C(12)), 33.0
(C(2)), 34.0 (C(8)), 35.4 (C(10)), 36.7 (C(1)), 38.0 (C(4)), 38.3
(C(15)), 44.1 (C(13)), 44.4 (C(5)), 48.1 (C(14)), 49.9 (C(16)),
54.1 (C(9)), 55.1 (OMe), 73.3 (C(3)), 114.0 (CAr), 122.1 (CAr),
130.4 (CAr), 156.1 (CAr), 156.2 (C(3´)), 164.3 (C(2´)), 164.7
(C(1´)), 170.0 (C=O (AcO)), 217.5, 217.8 (C(17)). Found (%):
С, 65.94; Н, 6.86; N, 7.54; S, 5.56. С31Н39N3О5S. Calculatꢀ
ed (%): С, 65.82; Н, 6.95; N, 7.43; S, 5.67. MS (ESI), m/z: 566.
5ꢀ(3ꢀAcetoxyꢀ17ꢀoxoandrostanꢀ16ꢀyl)ꢀNꢀ(4ꢀfluorophenyl)ꢀ
1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (8b). Yield 79%, m.p. 194—197 С
(AcOEthexane). 1H NMR (500 MHz, DMSOꢀd6), : 0.83
(s, 3 Н, C(10)Me); 1.06 (s, 3 Н, C(13)Me); 4.71 (s, 1 Н, H(3));
4.35 (m, 1 Н, H(16)); 7.42 (m, 2 Н, HAr); 7.81 (m, 2 Н, HAr);
10.19 (s, 1 Н, NHСО). 13C NMR (75 MHz, DMSOꢀd6), : 12.2
(C(19)), 14.6 (C(18)), 20.1 (C(11)), 21.4 (СН3 (АсО)), 28.4
(C(6)), 30.9 (C(7)), 31.3 (C(12)), 33.0 (C(2)), 34.0 (C(8)), 35.5
(C(10)), 36.7 (C(1)), 38.0 (C(4)), 38.6 (C(15)), 44.1 (C(13)),
44.4 (C(5)), 48.5 (C(14)), 49.2 (C(16)), 54.1 (C(9)), 73.3 (C(3)),
121.2 (CAr), 125.5 (CAr), 133.7 (CAr), 141.7 (CAr), 159.6 (C(3´)),
164.5 (C(2´)), 164.7 (C(1´)), 170.0 (C=O (AcO)), 217.3, 217.8
(C(17)). Found (%): С, 65.19; Н, 6.43; F, 3.54; N, 7.46; S, 5.67.
С30Н36FN3О4S. Calculated (%): С, 65.08; Н, 6.55; F, 3.43;
N, 7.59; S, 5.79. MS (ESI), m/z: 554.

1,3,4ꢀThiadiazole steroids
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 12, December, 2013
2607
3ꢀHydroxyꢀ16ꢀhydroxymethylideneꢀ1,3,5(10)ꢀestratrienꢀ17ꢀ
one (2). Ethyl formate (14.5 mmol) and sodium methoxide
(33 mmol) were slowly added to the stirred solution of estrone
(2.2 mmol) in pyridine (20 mL) under argon atmosphere at room
temperature, the reaction mixture was stirred for 18 h, and the
course of the reaction was monitored by TLC. Then the mixture
was poured to the solution of AcOH (9 mL) in water (80 mL),
the mixture was extracted with dichloromethane (320 mL). The
combined organic fractions were washed with water (3×70 mL)
and extracted with 2% KOH in water (3×100 mL). The basic
water fractions were combined and washed with diethyl ether
(3×15 mL). The basic layer was separated and AcOH was added
until the pH 5. The precipitate was separated, washed with hepꢀ
tane (3×30 mL), dried in vacuo and recrystallized from acetone.
The yield of compound 2 was 78%, m.p. 229—231 С (acetone).
1H NMR (300 MHz, DMSOꢀd6), : 0.81 (s, 3 Н, C(13)Me);
1.34, 1.91 (m, 2 Н, H(7)); 1.39, 2.30 (m, 2 Н, H(11)); 1.39, 1.77
(m, 2 Н, H(12)); 1.39 (m, 1 Н, H(14)); 1.49 (m, 1 Н, H(8));
1.98, 2.59 (m, 2 Н, H(15)); 2.16 (m, 1 Н, H(9)); 2.77 (m, 2 Н,
H(6)); 6.47 (s, 1 Н, H(4)); 6.52 (m, 1 Н, H(2)); 7.03 (m, 1 Н,
H(1)); 7.40 (s, 1 Н, H(1´)). 13C NMR (75 MHz, DMSOꢀd6), :
14.2 (C(18)), 23.8 (C(15)), 25.5 (C(11)), 26.1 (C(7)), 28.8 (C(6)),
31.3 (C(12)), 37.4 (C(8)), 43.3 (C(9)), 47.6 (C(13)), 48.3 (C(14)),
112.6 (C(2)), 113.0 (C(16)), 114.8 (C(4)), 125.6 (C(1)), 130.0
(C(10)), 136.9 (C(5)), 150.1 (C(1´)), 154.8 (C(3)), 208.3 (C(17)).
Found (%): С, 76.65; Н, 7.39. C19H22O3. Calculated (%):
С, 76.48; Н, 7.43. MS (ESI), m/z: 299.
Reaction of compound 2 with thiohydrazides 3a,b in ethanol.
To the stirred and heated (70 С) solution of compound 2
(1.67 mmol) in ethanol (40 mL) thiohydrazide 3a,b (1.84 mmol)
and the catalytic amount of TsOH were added. The reaction
mixture was stirred at this temperature for 7 h and kept for 12 h at
20 С, and the course of the reaction was monitored by TLC.
Then the reaction mixture was poured onto ice, the precipitate
was filtered off, washed with water (3×50 mL), and airꢀdried.
The residue was subjected to column chromatography on silica
gel (the eluent was AcOEthexane, 1 : 1) and products 5а,b
were obtained.
DMSOꢀd6), : 0.80 (s, 3 Н, C(13)Me); 2.75 (m, 2 Н, H(6)); 5.62
(s, 1 Н, Н(1´) (C)); 6.44 (m, 1 Н, H(4)); 6.52 (s, 1 Н, H(2)); 7.04
(s, 1 Н, H(1)); 7.40 (m, 2 Н, HAr); 7.72 (m, 2 Н, HAr); 8.52
(s, 1 Н, H(1´) (A, B)); 10.21 (s, 1 Н, NHСО). 13C NMR
(75 MHz, DMSOꢀd6), : 12.8 (C(18)), 23.9 (C(15)), 25.7 (C(11)),
26.9 (C(7)), 29.2 (C(6)), 31.3 (C(12)), 37.5 (C(8)), 43.7 (C(9)),
44.1 (C(13)), 47.6 (C(14)), 49.2 (C(16)), 112.8 (C(2)),
115.0 (C(4)), 122.4 (CAr), 125.9 (C(1)), 126.8 (CAr), 129.5 (CAr),
129.9 (C(10)), 137.2 (C(5)), 141.3 (CAr), 155.0 (C(3)), 163.1
(C(3´)), 167.2 (С(2´)), 190.1 (C(2´) (A)); 217.3, 217.7 (C(17)).
Found (%): С, 65.82; Н, 5.67; F, 3.93; S, 6.40. C27H28FN3O3S.
Calculated (%): С, 65.70; Н, 5.72; F, 3.85; S, 6.50. MS (ESI),
m/z: 494.
Cyclization of compounds 5a,b. The solution of thiohydrꢀ
azone 5a,b (0.132 mmol) in dioxane (10 mL) was refluxed in the
presence of the catalytic amount of TsOH, and the course of the
reaction was monitored by TLC. The reaction mixture was
poured onto ice, the residue was filtered off, washed with water
(3×50 mL), hexane (3×25 mL), airꢀdried and subjected to colꢀ
umn chromatography on silica gel (the eluent was ethyl aceꢀ
tate—hexane, 1 : 1) and products 7а,b were obtained.
5ꢀ[3ꢀHydroxyꢀ17ꢀoxoestraꢀ1,3,5(10)ꢀtrienꢀ16ꢀyl]ꢀNꢀ(4ꢀ
methoxyphenyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (7a). Yield
72%, m.p. 162—166 С (AcOEthexane). 1H NMR (500 MHz,
DMSOꢀd6), : 0.82 (s, 3 Н, C(13)Me); 1.37, 1.92 (m, 2 Н,
H(7)); 1.42, 1.75 (m, 2 Н, H(12)); 1.42, 2.31 (m, 2 Н, H(11));
1.47 (s, 1 Н, H(14)); 1.56 (s, 1 Н, H(8)); 2.19 (m, 1 Н, H(9));
2.76 (m, 2 Н, H(6)); 3.75 (s, 3 Н, ОМе); 4.33 (m, 1 Н, H(16));
6.47 (m, 1 Н, H(4)); 6.53 (s, 1 Н, H(2)); 6.95 (m, 2 Н, HAr); 7.05
(s, 1 Н, H(1)); 7.73 (m, 2 Н, HAr); 10.96 (s, 1 Н, NH). 13C NMR
(75 MHz, DMSOꢀd6), : 13.5 (C(18)), 25.5 (C(11)), 26.3 (C(7)),
38.5 (C(15)), 29.0 (C(6)), 31.8 (C(12)), 37.2 (C(8)), 47.3 (C(13)),
43.7 (C(9)), 49.3 (C(14)), 49.8 (C(16)), 55.2 (ОМе), 112.8 (C(2)),
113.9 (CAr), 114.9 (C(4)), 120.9 (CAr), 122.2 (CAr), 125.9 (C(1)),
129.9 (C(10)), 137.2 (C(5)), 155.0 (C(3)), 156.0 (CAr),
156.2 (C(3´)), 164.3 (C(2´)), 164.5 (C(1´)), 219.8 (C(17)).
Found (%): С, 66.67; Н, 5.88; N, 8.48; S, 6.29. С28Н29N3О4S.
Calculated (%): С, 66.78; Н, 5.80; N, 8.34; S, 6.37. MS (ESI),
m/z: 504.
3ꢀHydroxyꢀ16ꢀ{2ꢀ[2ꢀ(4ꢀmethoxyphenylamino)ꢀ2ꢀoxoꢀ1ꢀthiꢀ
oxoethyl]hydrazonomethyl}ꢀ1,3,5(10)ꢀestratrienꢀ17ꢀone (5a).
Yield 61%, m.p. 153—156 С (AcOEthexane). 1H NMR
(500 MHz, DMSOꢀd6), : 0.83 (s, 3 Н, C(13)Me); 1.44, 1.76
(m, 2 Н, H(12)); 1.34, 1.91 (m, 2 Н, H(7)); 1.40, 2.31 (m, 2 Н,
H(11)); 1.47 (s, 1 Н, H(8)); 1.57 (m, 1 Н, H(14)); 1.72, 2.08
(m, 2 Н, H(15)); 2.16 (s, 1 Н, H(9)); 2.74 (m, 2 Н, H(6)); 3.15
(m, 1 Н, H(16)); 3.75 (s, 3 H, OMe); 5.60 (s, 1 Н, Н(1´) (C));
6.45 (s, 1 Н, H(4)); 6.52 (s, 1 Н, H(2)); 6.94 (m, 2 Н, HAr);
7.04 (s, 1 Н, H(1)); 7.73 (m, 2 Н, HAr); 8.51 (s, 1 Н, H(1´)
(A, B)); 9.98 (s, 1 H, NHCO); 10.91 (s, 1 H, NHCS (A)).
13C NMR (75 MHz, DMSOꢀd6), : 12.8 (C(18)), 24.0 (C(15)),
25.5 (C(11)), 26.5 (C(7)), 29.0 (C(6)), 31.5 (C(12)), 37.1 (C(8)),
43.5 (C(9)), 44.3 (C(13)), 47.4 (C(14)), 49.3 (C(16)), 55.2 (OMe),
112.8 (C(2)), 113.9 (CAr), 115.0 (C(4)), 122.3 (CAr), 125.9 (C(1)),
129.9 (C(10)), 130.7 (CAr), 137.1 (C(5)), 155.0 (C(3)),
156.2 (CAr), 157.6 (C(3´)), 167.1 (С(2´) (B)), 190.1 (C(2´) (A)),
217.3 (C(17)). Found (%): С, 66.45; Н, 6.27; S, 6.42.
C28H31N3O4S. Calculated (%): С, 66.51; Н, 6.18; S, 6.34. MS
(ESI), m/z: 506.
5ꢀ[3ꢀHydroxyꢀ17ꢀoxoestraꢀ1,3,5(10)ꢀtrienꢀ16ꢀyl]ꢀNꢀ(4ꢀfluꢀ
orophenyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (7b). Yield 69%,
m.p. 174—176 C (AcOEthexane). 1H NMR (500 MHz,
DMSOꢀd6), : 0.81 (s, 3 Н, C(13)Me); 2.76 (m, 2 Н, H(6)); 3.75
(s, 3 Н, ОMe); 4.38 (m, 1 Н, H(16)); 6.47 (m, 1 Н, H(4)); 6.57
(s, 1 Н, H(2)); 7.42 (m, 2 Н, HAr); 7.05 (s, 1 Н, H(1)); 7.84 (m, 2 Н,
HAr); 10.89 (s, 1 Н, NH). 13C NMR (75 MHz, DMSOꢀd6),
: 13.1 (C(18)), 25.7 (C(11)), 26.3 (C(7)), 29.0 (C(6)), 31.5 (C(12)),
37.4 (C(8)), 38.5 (С(15)), 43.7 (C(9)), 47.3 (C(13)), 49.3 (C(14)),
49.8 (C(16)), 112.8 (C(2)), 114.9 (C(4)), 121.3 (CAr), 125.9
(C(1)), 126.5 (CAr), 129.6 (CAr), 130.0 (C(10)), 137.2 (C(5)),
141.3 (CAr), 155.0 (C(3)), 156.6 (C(3´)), 164.5 (C(2´)), 164.8
(C(1´)), 219.8 (C(17)). Found (%): С, 66.11; Н, 5.27; F, 3.97;
N, 8.43; S, 6.42. С27Н26FN3О3S. Calculated(%): С, 65.97;
Н, 5.33; F, 3.86; N, 8.55; S, 6.52. MS (ESI), m/z: 492.
Reaction of compound 2 with thiohydrazides 3a,b in acetic
acid. To the stirred solution of ketone 2 (1.2 mmol) in acetic acid
(25 mL), thiohydrazide 3a,b (1.3 mmol) was added, the reaction
mixture was refluxed for 1—2 h, and the course of the reaction
was monitored by TLC. The reaction mixture was poured onto
ice, the residue was filtered off, washed with water (3×50 mL),
hexane (3×25 mL), airꢀdried and subjected to column chromatoꢀ
3ꢀHydroxyꢀ16ꢀ{2ꢀ[2ꢀ(4ꢀfluorophenylamino)ꢀ2ꢀoxoꢀ1ꢀthioxoꢀ
ethyl]hydrazonomethyl}ꢀ1,3,5(10)ꢀestratrienꢀ17ꢀone (5b). Yield
58%, m.p. 141—143 С (AcOEthexane). 1H NMR (500 MHz,

2608
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 12, December, 2013
Zavarzin et al.
graphy on silica gel (the eluent was AcOEthexane, 1 : 1) and
the products 9а,b were obtained.
References
5ꢀ[3ꢀAcetoxyꢀ17ꢀoxoestraꢀ1,3,5(10)ꢀtrienꢀ16ꢀyl]ꢀNꢀ(4ꢀmethꢀ
oxyphenyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (9a). Yield 72%,
m.p. 170—173 С (AcOEthexane). 1H NMR (500 MHz,
DMSOꢀd6), : 0.82 (s, 3 Н, C(13)Me); 1.37, 1.92 (m, 2 Н,
H(7)); 1.42, 1.75 (m, 2 Н, H(12)); 1.42, 2.31 (m, 2 Н, H(11));
1.47 (s, 1 Н, H(14)); 1.56 (s, 1 Н, H(8)); 1.96 (s, 3 Н, CH3
(ОAc)); 2.19 (m, 1 Н, H(9)); 2.76 (m, 2 Н, H(6)); 3.75 (s, 3 Н,
ОМе); 4.33 (m, 1 Н, H(16)); 6.47 (m, 1 Н, H(4)); 6.53 (s, 1 Н,
H(2)); 6.95 (m, 2 Н, HAr); 7.05 (s, 1 Н, H(1)); 7.73 (m, 2 Н,
HAr); 10.96 (s, 1 Н, NH). 13C NMR (75 MHz, DMSOꢀd6),
: 13.5 (C(18)), 21.2 (СН3 (АсО)), 25.5 (C(11)), 26.3 (C(7)), 29.0
(C(6)), 31.8 (C(12)), 37.2 (C(8)), 38.2 (C(15)), 47.3 (C(13)),
43.7 (C(9)), 49.3 (C(14)), 49.8 (C(16)), 55.2 (ОМе), 112.8 (C(2)),
113.9 (CAr), 114.9 (C(4)), 120.9 (CAr), 122.2 (CAr), 125.9 (C(1)),
129.9 (C(10)), 137.2 (C(5)), 149.0 (C(3)), 156.0 (CAr), 156.2
(C(3´)), 164.3 (C(2´)), 164.5 (C(1´)), 170.2 (C=O (AcO)), 219.8
(C(17)). Found (%): С, 66.13; Н, 5.65; N, 7.61; S, 5.99.
С30Н31N3О5S. Calculated (%): С, 66.04; Н, 5.73; N, 7.70;
S, 5.88. MS (ESI), m/z: 546.
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5ꢀ[3ꢀAcetoxyꢀ17ꢀoxoestraꢀ1,3,5(10)ꢀtrienꢀ16ꢀyl]ꢀNꢀ(4ꢀfluꢀ
orophenyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (9b). Yield 69%,
m.p. 182—185 C (AcOEthexane). 1H NMR (500 MHz,
DMSOꢀd6), : 0.81 (s, 3 Н, C(13)Me); 2.76 (m, 2 Н, H(6)); 3.75
(s, 3 Н, OMe); 4.38 (m, 1 Н, H(16)); 6.47 (m, 1 Н, H(4)); 6.57
(s, 1 Н, H(2)); 7.42 (m, 2 Н, HAr); 7.05 (s, 1 Н, H(1)); 7.84 (m, 2 Н,
HAr); 10.89 (s, 1 Н, NH). 13C NMR (75 MHz, DMSOꢀd6), :
13.1 (C(18)), 21.4 (СН3 (АсО)), 25.7 (C(11)), 26.3 (C(7)),
29.0 (C(6)), 31.5 (C(12)), 37.4 (C(8)), 38.2 (C(15)), 43.7 (C(9)),
47.3 (C(13)), 49.3 (C(14)), 49.8 (C(16)), 112.8 (C(2)),
114.9 (C(4)), 121.3 (CAr), 125.9 (C(1)), 126.5 (CAr), 129.6 (CAr),
130.0 (C(10)), 137.2 (C(5)), 141.3 (CAr), 149.0 (C(3)), 156.6
(C(3´)), 164.5 (C(2´)), 164.8 (C(1´)), 170.1 (C=O (AcO)), 219.8
(C(17)). Found (%): С, 65.39; Н, 5.18; F, 3.67; N, 7.74; S, 6.14.
С29Н28FN3О4S. Calculated (%): С, 65.27; Н, 5.29; F, 3.56;
N, 7.87; S, 6.01. MS (ESI), m/z: 534.
7. A. V. Kamernitskii, E. I. Chernoburova, V. V. Chertkova,
V. N. Yarovenko, I. V. Zavarzin, M. M. Krayushkin, Bioorꢀ
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Chernoburova, V. N. Yarovenko, M. M. Krayushkin, V. V.
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M. J. Reed, B. V. L. Potter, Chem. Med. Chem., 2006, 1, 464.
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2004, 491].
2ꢀHydroxymethylideneꢀ1ꢀindanone (10) was obtained by the
reaction of 1ꢀindanone with ethyl formate in the presence of
sodium methoxide.17
Nꢀ(4ꢀMethoxyphenyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (11).
To the stirred solution of 2ꢀhydroxymethylideneꢀ1ꢀindanone (10)
(1.25 mmol) in ethanol (35 mL), thiohydrazide 3а (1.5 mmol)
and catalytic amount of TsOH were added at room temperature
and the mixture was stirred and refluxed for 1—2 h (TLC moniꢀ
toring). Then the reaction mixture was poured into water
(70 mL), extracted with ethyl acetate (3×30 mL), combined orꢀ
ganic fractions were washed with water (3×35 mL), dried over
MgSO4 and the solvent was evaporated. The residue was subꢀ
jected to column chromatography on silica gel (the eluent was
AcOEt—hexane, 1 : 1). Product 11 was obtained with the yield
69%, m.p. 192—194 С (AcOEt—hexane). 1H NMR (300 MHz,
CDCl3), : 3.86 (s, 3 Н, OMe); 6.95 (d, 2 Н, HAr, J = 8.7 Hz);
7.62 (d, 2 Н, HAr, J = 8.7 Hz); 9.11 (s, 1 Н, NH); 9.33 (s, 1 Н,
H(1)). 13C NMR (75 MHz, CDCl3), : 56.8 (OMe), 112.6 (CAr),
122.3 (CAr), 135.1 (CAr), 155.5 (CAr), 156.2 (C(3)), 159.3 (C(1)),
164.3 (C(2)). Found (%): С, 51.13; Н, 3.74; N, 17.78; S, 13.74.
C10H9N3O2S. Calculated (%): С, 51.05; Н, 3.86; N, 17.86;
S, 13.63. MS (ESI), m/z: 236.
17. C. Asche, W. Frank, A. Albert, U. Kucklaender, Bioorg. Med.
Chem., 2005, 13, 81.
Received October 30, 2013