Synthesis of steroidal thiadiazoles from steroidal ketones.

Syntheses of steroidal heterocycles containing a five-membered N,S- heterocycle attached at the 6,7 positions of the B ring are reported. 5Alpha-cholestane-6-one (1), its 3beta-acetoxy- (2) and 3beta-chloro- (3) analogues reacted with semicarbazide and aqueous sodium acetate in refluxing ethanol to yield 5alpha-cholestan-6-one-semicarbazone 1a and its 3-beta-acetoxy and 3beta-chloro derivatives 2a and 3a, respectively. The reactions of 1a, 2a and 3a with thionyl chloride in dichloromethane at low temperature afforded the cyclized thiadiazole 4 and its 3beta-acetoxy- and 3beta-chloro analogues 5 and 6 in good yields.

Introduction

Important biological activities like antibacterial, antiviral, anticonvulsant, analgesic, antithrombotic and antitumour properties [1,2,3,4,5,6,7,8] associated with molecules incorporating nitrogen and sulfur atoms individually or in combinations thereof have been the focus for the ongoing synthesis of a number of thiadiazole derivatives [9,10,11,12,13,14]. A literature survey reveals that little attention has been paid however to the synthesis of systems containing 1,2,3-and other thiadiazoles at various steroidal positions [15], which are good candidates for possessing the aforementioned biological properties. Another notable feature of the thiadiazole moiety was also observed recently when it was found to possess male contraceptive properties [16]. Synthetically, heterocyclic steroidal compounds have generated a great deal of interest in exploiting more than one proximal functional group in designing novel structures for performing a variety of synthetic functions in transformations and synthesis. One such functionality is the α-ketomethylene group which has been used as a building block for thiadiazole systems [17,18]. We now report the preparation of the desired steroidal thiadiazoles. The reaction of 5α-cholestane-6- one (1) and its 3β-acetoxy- and 3β-chloro- analogues 2 and 3 [19,20,21] with semicarbazide and sodium acetate gave semicarbazones 1a, 2a and 3a, respectively [22]. Further reaction of 1a. 2a and 3a with thionyl chloride in dichloromethane at -10 °C yielded the desired products 4, 5 and 6, with a fused heterocycle attached at the C-6 and C-7 positions of the cholestane skeleton B ring.

Results and Discussion

Steroidal semicarbazones 1a, 2a and 3a were prepared starting from α-cholestane-6-one (1) and its 3β-acetoxy and 3β-chloro analogues 2 and 3 following the Hurd-Mori procedure [23] to furnish steroidal thiadiazoles 4, 5 and 6, respectively (Scheme 1).

Scheme 1

 

The structure of compound 4 was established by IR, 1H-NMR spectra and elemental analyses (Table II and Table III). The IR spectrum displayed bands at 1615 cm-1(C=C), 1565 cm-1(N=N), 1380 cm-1(C-N) and 715 cm-1(C-S), indicating the presence of a thiadiazole ring. The 1H-NMR spectrum of 4 showed a triplet at δ 2.9 and a double doublet at δ 3.5, assigned to C5-αH and C8-βH, respectively. Methyl protons were observed at δ 1.12 (C10-CH3), 0.70 (C13-CH3), 0.90 and 0.83 (C20-CH3 and C25 (-CH3)2). The elemental analyses and remaining IR absorption bands are in complete agreement with the proposed possible structures 4 and 4a.

Table II

Physical properties and analytical data of compounds 4 - 6.

Compound	Physical state	Molecularformula (Mol. Wt.)	Yield (%)	% found (calcd.)				Rf value	TLCa (mL)
				C	H	N	S
5α-cholest-6-eno[6,7- d] thiadiazole (4)	Glossy semi-solid	C27H44N2S (428)	58	75.66(75.70)	10.24(10.28)	6.54(6.50)	7.42(7.48)	0.155	2:1.00:0.10
3β-acetoxy-5α-cholest-6-eno [6,7-d] thiadiazole (5)	Glossy semi-solid	C29H46N2OS (486)	62	71.56(71.60)	9.41(9.46)	5.72(5.76)	6.51(6.58)	0.301	2 : 0.6: 0.10
3β-chloro-5α-cholest-6-eno [6,7-d] thiadiazole (6)	Glossy semi-solid	C27H43N2ClS (462/464)	58	69.78(70.08)	9.48(9.50)	6.02(6.05)	6.78(6.91)	0.492

a Solvents: Petroleum ether -AcOEt -AcOH

Table III

Spectral data for compounds 4-6

Compound	IR (KBr, cm-1)	1H-NMR(δ, ppm)	MS (EI):mz (%)
4	1615 (C=C)	2.9 (t, C5-αH)	428 (M+.),
	1380 (C-N)	3.5 (dd, C8-βH)	400 (100) (base peak),
	1565 (N=N)	1.12 (C10-CH3)	368 (30) (M+-N2 and S),
	715 (C-S)	0.70 (C13-CH3)	386 (10) (M+-N2 and CH3),
		0.90 (C20-CH3) and	287 (7) (M+-N2 and C8H17),
		0.83 (C25-CH3).
5	1615 (C=C)	4.9 (m, W1/2 =17 Hz, C3-αH A/B	486 (M+.),
	1374 (C-N)	ring junction trans) [26]	365 (100) (base peak),
	1570 (N=N)	2.75 (t, C5-αH), 2.95 (dd, C8-βH),	458 (20) (M+-N2),
	711 (C-S)	2.1 (s, 3H, CH3COO), 1.13 (C10-	442 (5) (M+-N2 and CH3),
		CH3), 0.67 (C13-CH3), 0.91 (C20-	426 (8) (M+-AcOH),
		CH3) and 0.87 (C25-CH3).	398 (30) (M+-N2 and AcOH),
			345 (7) (M+-N2 and C8H17)
6	1623 (C=C)	2.7 (t, C5-αH), 3.0 (dd, C8-βH)	462/464[35/37Cl] (M+.)/(M++2)
	1370 (C-N)	4.2 (br, m, W1/2 =16Hz C3-αH	(3/0.96) (0.25/0.08 peak’s value),
	1550 (N=N)	A/B ring junction trans) [ 26]	394 (100) (base peak),
	705 (C-S)	1.15 (C10-CH3), 0.68 (C13-CH3),	434/436 (12/3.8) (M+-N2),
		0.93 (C20-CH3) and 0.83 (C25-	418/420 (10/3.5) (M+-N2 and CH3),
		CH3)	400/402 (30/(9.1) (M+-N2 and S),
			321/323 (8/2.3) (M+-N2 and C8H17)

The reaction mechanism [23,24,25] clearly shows that the C6-N bond in the imino intermediate 1a remains intact and further two α-hydrogens are required. These facts favour structure 4 rather than 4a. The ring is planar and must be stable due to aromatization. Therefore, the product is characterized as 5α-cholest-6-eno[6,7-d]-thiadiazole (4), satisfying all observed spectral properties. The products 5 and 6 were also characterized on the basis of similar spectroscopic analyses and mechanistic accounts.

Table I

Physical properties of the semicarbazones 1a-3a

Starting Ketone	Products	Yield (%)	M.p. (°C)	Rf	TLCa (mL)
α-cholestan-6-one (1)	α-cholestan-6-one-semicarbazone (1a)	80	190	0.206	2: 1.00 :0.10
3β-acetoxy-α-cholestan-6-one (2)	3β-acetoxy-α-cholestan-6-one-semicarbazone (2a)	83	242	0.428	2 : 0.6: 0.10
3β-chloro-α-cholestan-6-one (3)	3β-chloro-α-cholestan-6-one-semicarbazone (3a)	75	152	0.603	2 : 0.6: 0.10

a Solvents: Petroleum ether -AcOEt -AcOH