Reactions of 17-chloro-16-formylandrosta-5,16-diene with thiohydrazides of oxamic acids

Article abstract of DOI:10.1007/s11172-013-0384-7

Reactions of thiohydrazides of oxamic acids with 17-chloro-16- formylandrosta-5,16-diene give the corresponding thiohydrazones at the formyl group. Their subsequent reactions with alkali (het)arenethiolates yield 17-het(aryl)thio derivatives, being accomp

Full text of DOI:10.1007/s11172-013-0384-7

Russian Chemical Bulletin, International Edition, Vol. 62, No. 12, pp. 2626—2627, December, 2013
2626
Reactions of 17ꢀchloroꢀ16ꢀformylandrostaꢀ5,16ꢀdiene
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.
Eꢀmail: zavi@ioc.ac.ru
Reactions of thiohydrazides of oxamic acids with 17ꢀchloroꢀ16ꢀformylandrostaꢀ5,16ꢀdiene
give the corresponding thiohydrazones at the formyl group. Their subsequent reactions with
alkali (het)arenethiolates yield 17ꢀhet(aryl)thio derivatives, being accompanied by cyclization
of the thiooxalylhydrazone fragment into a 1,3,4ꢀthiadiazole ring.
Key words: androstane, thiohydrazides, oxamic acids, hydrazones, sulfides, 1,3,4ꢀthiadiꢀ
azoles, heterocyclization.
Continuing our investigations1—3 into the synthesis of
1H and 13C NMR spectra show characteristic signals at 
8.3 (H(1´)) and 132.4 (C(16)). Compounds 3a,b are very
unstable and decompose within 3 h even at room temꢀ
perature.
steroid derivatives containing heterocyclic fragments, we
studied reactions of 17ꢀchloroꢀ16ꢀformylandrostane with
thiohydrazides of oxamic acids. According to the literaꢀ
ture data,4,5 reactions of such 17ꢀchloroꢀ16ꢀformyl derivꢀ
atives with hydrazines and hydrazides afford [17,16ꢀd]ꢀ
pyrazolines and pyrazoles fused to the corresponding steꢀ
roid molecules.
Reactions of chloro aldehyde 1 with thiohydrazides of
oxamic acids 2a,b in ethanol in the presence of a catalytic
amount of TsOH at 20 C for 15 min give hydrazones 3a,b
in quantitative yields (Scheme 1).
We studied reactions of hydrazone 3a with (het)areneꢀ
thiolates 4a—c (Scheme 2). Variation of the solvents
(DMSO, acetonitrile, and acetone) showed that acetoꢀ
nitrile ensures the highest yields of products 5a—c. We
also found that the sulfide bond formation is accompanied
by cyclization of the thiooxalylhydrazone fragment into
1,3,4ꢀthiadiazole. On using sodium pyrimidineꢀ2ꢀthiolꢀ
ate 4a, compound 3a is transformed into sulfide 5a in 86%
yield, which was isolated and characterized by 1H and
13C NMR and mass spectra and elemental analysis. Simiꢀ
lar reactions with (het)arenethiolates 4b,c produce comꢀ
plex mixtures of reaction products; we failed to isolate the
target compounds 5b,c in the individual state. However,
their formation was confirmed by highꢀresolution mass
spectra containing molecular ion peaks with m/z 656 and
647, respectively (see Scheme 2).
Scheme 1
Scheme 2
2, 3: Ar = 4ꢀMeOC6H4 (a), 4ꢀClC6H4 (b)
The structures of the hydrazones obtained were proved
by spectroscopic methods and elemental analysis. Their
4, 5: R = pyrimidinꢀ2ꢀyl (a), Ph (b), 1,2,4ꢀtriazolꢀ3ꢀyl (c);
M = Na, K
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2626—2627, December, 2013.
1066ꢀ5285/13/6212ꢀ2626 © 2013 Springer Science+Business Media, Inc.

Steroid hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 12, December, 2013
2627
2.13—2.41 (m, 6 H); 2.78—2.91 (m, 2 H, C(15)H2); 4.42 (m, 1 H,
C(3)H); 5.35 (s, 1 H, C(6)H); 7.38 (m, 2 H, H arom.); 7.63 (m, 2 H,
H arom.); 8.45 (s, 1 H, C(1´)H); 10.15 (s, 1 H, NHCO); 13.67
(s, 1 H, NHCS). 13C NMR (75 MHz, DMSOꢀd6), : 15.6
(C(19)), 19.5 (C(18)), 20.3 (C(11)), 21.5 (CH3CO), 29.9 (C(15)),
27.5 (C(2)), 30.5 (C(7)), 32.7 (C(8)), 36.5 (C(1)), 37.8 (C(4)),
50.0 (C(10)), 33.0 (C(12)), 49.9 (C(9)), 49.5 (C(13)), 53.5
Experimental
Melting points were determined on a Boetius hot stage (heatꢀ
ing rate near the melting point 4 C min–1) and are given uncorꢀ
rected. Highꢀresolution mass spectra (ESI) were recorded on
a Bruker micrOTOF II instrument in the positive (capillary voltꢀ
age 4500 V) or negative ion mode (capillary voltage 3200 V). The
scan range was 50—3000 Da; the instrument was calibrated exꢀ
ternally or internally using an Electrospray Calibrant Solution
(Fluka). Solutions of samples in acetonitrile, methanol, or water
were infused into the mass spectrometer through a syringe (flow
rate 3 L min–1). Nitrogen was employed as a nebulizing gas
(4 L min–1); the interface temperature was 180 C. 1H NMR
spectra were recorded on Bruker WMꢀ300 (300 MHz) and Brukꢀ
er DRXꢀ500 instruments (500 MHz) at 303 K. 13C NMR spectra
were recorded on a Bruker WMꢀ300 instrument (75 MHz). The
signals of the solvents served as the internal standards. The course
of the reactions was monitored and the purity of the compounds
obtained was checked by TLC on KieselgelꢀG Si 254F plates
(Merck) with hexane—ethyl acetate or light petroleum—ethyl
acetate as an eluent; spots were visualized with a solution of
Ce(SO4)2 in 10% H2SO4. For column chromatography, Acros
60A silica gel (0.060—0.200 mm) was used. Solvents were puriꢀ
fied and dried according to standard procedures. Commercial
chemicals (Acros) were employed. Thiohydrazides of oxamic
acids 2a,b were prepared as described earlier.6
Reactions of 17ꢀchloroꢀ16ꢀformylandrostadiene 1 with thioꢀ
hydrazides of oxamic acids 2a,b. Thiohydrazide of oxamic acid 2
(0.1 or 0.20 mmol) and a catalytic amount of TsOH were added
at room temperature to a solution of 3ꢀacetoxyꢀ17ꢀchloroꢀ16ꢀ
formylandrostaꢀ5,16ꢀdiene (1) (0.0376 g, 0.1 mmol) in ethanol
(30 mL). The reaction mixture was stirred at room temperature
for 10—15 min (monitoring by TLC) and poured into water
(50 mL). The precipitate that formed was filtered off, washed
with water (3×25 mL), and dried in vacuo. Products 3 were puriꢀ
fied by column chromatography on silica gel with light petroꢀ
leum—ethyl acetate as an eluent.
3ꢀAcetoxyꢀ17ꢀchloroꢀ16ꢀ{2ꢀ[2ꢀ(4ꢀmethoxyphenylamino)ꢀ
2ꢀoxoꢀ1ꢀthioxoethyl]hydrazonomethyl}androstaꢀ5,16ꢀdiene (3a).
Yield 86%, m.p. 247—250 C (ethyl acetate—hexane). Found (%):
C, 63.64; H, 6.71; Cl, 6.12; N, 7.15; S, 5.58. C31H38ClN3O4S.
Calculated (%): C, 63.74; H, 6.56; Cl, 6.07; N, 7.19; S, 5.47.
1H NMR (500 MHz, DMSOꢀd6), : 0.92 (s, 3 H, C(19)H3); 0.99
(s, 3 H, C(18)H3); 1.29—1.92 (m, 9 H); 1.96 (s, 3 H, MeCO);
2.13—2.41 (m, 6 H); 2.78—2.91 (m, 2 H, C(15)H2); 3.70 (s, 3 H,
OMe); 4.42 (m, 1 H, C(3)H); 5.35 (s, 1 H, C(6)H); 6.86 (d, 2 H,
H arom., J = 8.6 Hz); 7.59 (d, 2 H, H arom., J = 8.6 Hz); 8.78
(s, 1 H, C(1´)H); 10.33 (s, 1 H, NHCO); 13.70 (s, 1 H, NHCS).
13C NMR (75 MHz, DMSOꢀd6), : 15.1 (C(19)), 19.0 (C(18)),
20.1 (C(11)), 21.2 (CH3CO), 29.9 (C(15)), 27.5 (C(2)), 30.5
(C(7)), 32.7 (C(8)), 36.5 (C(1)), 37.8 (C(4)), 50.0 (C(10)), 33.0
(C(12)), 49.9 (C(9)), 49.5 (C(13)), 53.5 (C(14)), 55.4 (OMe),
73.3 (C(3)), 114.0 (C(6´)Ar, C(8´)Ar), 121.9 (C(5´)Ar, C(9´)Ar),
122.0 (C(6)), 131.42 (C(4´)Ar), 133.1 (C(16)), 140.0 (C(5)), 150.7
(C(1´)), 152.6 (C(17)), 155.8 (C(7´)Ar), 170.0 (MeCO), 172.0
(C(3´)), 183.4 (C(2´)). MS (ESI), m/z: 585.
(C(14)), 73.2 (C(3)), 121.7 (C(16)), 122.0 (C(6)), 122.7 (C(5´)Ar
,
C(9´)Ar), 127.8 (C(6´)Ar, C(8´)Ar), 129.9 (C(4´)Ar), 140.0 (C(5)),
141.3 (C(7´)Ar), 153.8 (C(1´)), 152.6 (C(17)), 170.2 (MeCO),
165.4 (C(3´)), 188.2 (C(2´)). MS (ESI), m/z: 589.
3ꢀAcetoxyꢀ16ꢀ{5ꢀ[Nꢀ(4ꢀmethoxyphenyl)carbamoyl]ꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀyl}ꢀ17ꢀ(pyrimidinꢀ2ꢀylsulfanyl)androstaꢀ5,16ꢀdiene
(5a). 2ꢀMercaptopyrimidine (0.0778 mmol) was dissolved in acꢀ
etonitrile (4 mL). Sodium carbonate (0.0856 mmol) was added.
The mixture was stirred at room temperature for 2 h (monitoring
by TLC) and concentrated in vacuo to give sodium pyrimidineꢀ
2ꢀthiolate (4a). Then thiolate 4a (0.155 mmol) was suspendꢀ
ed in acetonitrile (10 mL), and a solution of hydrazone 3a
(0.171 mmol) in acetonitrile (10 mL) was slowly added. The
reaction mixture was stirred at 20 C for 10—15 min (monitoring
by TLC) and diluted with water (20 mL). The product was exꢀ
tracted with ethyl acetate (3×20 mL). The combined extracts
were dried with MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography on silica gel with ethyl
acetate—hexane as an eluent. The yield of product 5a was 86%,
m.p. 154—157 C (ethyl acetate—hexane). Found (%): C, 63.81;
H, 6.09; N, 10.54; S, 9.82. C35H39N5O4S2. Calculated (%):
C, 63.90; H, 5.98; N, 10.65; S, 9.75. 1H NMR (300 MHz,
CDCl3), : 1.03 (s, 3 H, C(19)H3); 1.12 (s, 3 H, C(18)H3);
1.29—1.93 (m, 7 H); 2.08 (s, 3 H, MeCO); 2.12—2.43 (m, 6 H);
2.74—2.88 (m, 2 H, C(12)H2); 3.30—3.39 (m, 2 H, C(15)H2);
3.85 (s, 3 H, OMe), 4.62 (m, 1 H, C(3)H); 5.44 (s, 1 H, C(6)H);
7.07 (t, 1 H, C(5)H, pyrimidine); 7.37 (d, 2 H, H arom., J = 8.6 Hz);
7.66 (d, 2 H, H arom., J = 8.6 Hz); 8.55 (d, 2 H, C(4)H,
C(6)H, pyrimidine, J = 4.9 Hz); 9.13 (s, 1 H, NHCO).
13C NMR (75 MHz, CDCl3), : 15.1 (C(19)), 19.0 (C(18)), 20.1
(C(11)), 21.2 (CH3CO), 27.5 (C(2)), 30.5 (C(7)), 32.7 (C(8)),
36.5 (C(1)), 37.8 (C(4)), 39.9 (C(15)), 50.0 (C(10)), 33.0 (C(12)),
49.9 (C(9)), 49.5 (C(13)), 53.5 (C(14)), 55.4 (OMe), 73.3 (C(3)),
114.4 (C(6´)Ar, C(8´)Ar), 117.2 (C(5), pyrimidine), 121.5
(C(5´)Ar, C(9´)Ar), 122.0 (C(6)), 131.42 (C(4´)Ar), 138.7 (C(16)),
140.0 (C(5)), 145.2 (C(17)), 155.8 (C(7´)Ar), 156.5 (C(4), C(6),
pyrimidine), 163.2 (C(3´)), 164.3 (C(2´)), 164.7 (C(1´)), 170.6
(MeCO), 175.2 (C(2), pyrimidine). MS (ESI), m/z: 658.
References
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3ꢀAcetoxyꢀ17ꢀchloroꢀ16ꢀ{2ꢀ[2ꢀ(4ꢀchlorophenylamino)ꢀ2ꢀ
oxoꢀ1ꢀthioxoethyl]hydrazonomethyl}androstaꢀ5,16ꢀdiene (3b).
Yield 89%, m.p. 234—236 C (ethyl acetate—hexane). Found (%):
C, 61.31; H, 5.83; Cl, 12.13; N, 7.04; S, 5.52. C30H35Cl2N3O3S.
Calculated (%): C, 61.22; H, 5.99; Cl, 12.05; N, 7.14; S, 5.45.
1H NMR (500 MHz, DMSOꢀd6), : 0.92 (s, 3 H, C(19)H3); 0.99
(s, 3 H, C(18)H3); 1.29—1.92 (m, 9 H); 1.96 (s, 3 H, MeCO);
6. M. M. Krayushkin, V. N. Yarovenko, I. V. Zavarzin, Russ. Chem.
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Received November 11, 2013