Facile Synthesis of Steroidal Vicinal Hydroxysulfides via the Reaction of Steroidal Epoxides with Thiols in the Presence of an Ionic Liquid

Abstract

Ring-opening of steroidal 2,3-epoxides with thiols can be carried out effectively in the Brønsted acidic ionic liquid [Hmim] + [BF 4 ] -as a recyclable solvent and catalyst. The use of other ionic liquids/molten salts resulted in a decrease in the conversion and/or in reduced selectivity. In [bmim] + Br -, a conversion of 2,3-epoxy-17-ones into 2,17-and 3,17-diones was also observed.Ring-opening of epoxides in the presence of various nucleophiles such as amines, thiols and alcohols, is an important synthetic transformation leading to a great variety of functionalized intermediates. 1 However, this reaction is usually carried out with either a large excess of the nucleophile at elevated temperatures or using relatively high, often equimolar amounts of Lewis acids as promoters. In order to minimize the amount of harmful reagents and solvents, much attention has recently been paid to the use of alternative reaction media. Ionic liquids have been shown to promote ring-opening of epoxides leading to 1,2-aminoalcohols, 2 1,2-azido-or thiocyanoalcohols 3 and 1,2-haloalcohols. 4-6 Recently, we have synthesized several 2b-arylamino-3a-hydroxy steroids, which are close analogues of well-known compounds used as neuromuscular blocking agents, 7 by the cleavage of steroidal 2,3-epoxides with arylamines using 1-butyl-3-methylimidazolium tetrafluoroborate {[bmim] + BF 4 -} as both solvent and catalyst. 8As numerous 3a-hydroxy-2b-substituted steroid derivatives, some of them bearing thioether linkages, have been shown to possess anaesthetic activity, 9 we decided to investigate a similar reaction of steroidal 2,3-epoxides with thiols as nucleophiles. Thiolysis of epoxides is usually achieved in the presence of acids, 10 bases, 11 or Lewis acids such as lithium-12 or zinc perchlorate, 13 AlPW 12 O 40 , 14 BF 3 , 15 or InCl 3 . 16 Cleavage has also been achieved by microwave irradiation, 17 or by the use of alternative reaction media, such as water, 18 fluoroalcohols 19 or ionic liquids. 20,21 However, the results obtained so far by the use of ionic liquids are somewhat contradictory. Thiolysis of cyclohexene oxide with thiophenol was reported to take place smoothly at room temperature in [bmim] + Br -. 20 At the same time, however, this solvent was found to be only moderately effective by Yang et al. in the reaction of the same epoxide with 4-methylthiophenol, leading to the product in only 43% yield at 50°C. 21 On comparing the results obtained in [bmim] + X -type ionic liquids (X = Cl, Br, BF 4 ), [bmim] + [BF 4 ] -was found to be superior compared to the other two solvents. 21 Based on these results and our previous findings concerning the ring-opening of steroidal epoxides, 8 a systematic investigation into the thiolysis of 2b,3b-epoxy-5a-androstan-17-one (1; Scheme 1) was carried out in [bmim] + [BF 4 ] -as solvent and catalyst.Scheme 1 Reaction of 2b,3b-epoxy-5a-androstan-17-one (1) with thiols in [bmim] + [BF 4 ] -Optimal conditions for ring-opening of 1 were determined for the reaction with thiophenol (Table 1). In contr...

Metal‐Free Ring‐Opening of Epoxides

“…Yang and co-worker [39] reported a highly regioselective ringopening reactions of 1,2-epoxides (19) with ArSH (23) and ArSeH (40) promoted by ionic liquid [Bmim]BF 4 (12)which acted as both solvent as well as catalysts. The corresponding βhydroxy sulfides (39) and β-hydroxy selenides (41) were obtained in good to excellent yields (81-99 % and 91-99 %, respectively) and regioselectivity (10 : 90-99 : 1 and 22 : 78-99 : 1), respectively.…”

“…Brønsted acidic ionic liquid of the type [Hmim]BF 4 ( 42 ) have also been used [40] to efficiently realize the thiolysis of 2 β ,3 β ‐epoxy‐5 α ‐androstan‐17‐one ( 43 a ) and 2 α ,3 α ‐epoxy‐5 α ‐androstan‐17‐one ( 43 b ) steroidal epoxide. [Hmim]BF 4 was shown to act both as a catalyst and solvent.…”

“…Brønsted acidic ionic liquid of the type [Hmim]BF 4 (42) have also been used [40] to efficiently realize the thiolysis of 2β,3βepoxy-5α-androstan-17-one ( Kantamet al [41] reported a simple, efficient, and recyclable protocol for a facile Friedel-Crafts alkylation of nitrogen heterocycles such as indoles (46) and pyrroles (47) with epoxides (13) using [bmim][OTf] ionic liquid (48) which acted both as catalyst and reaction medium. The corresponding Friedel-Crafts adducts (49 and 50) were obtained in poor to good yield (18-90 %) with high regioselectivity.…”

“… Synthesis of steroidal vicinal hydroxysulfides via . the reaction of steroidal epoxides with thiols in the presence of an [Hmim]BF 4 ,ionic liquid [40] …”

Ionic Liquids-Assisted Ring Opening of Three-Membered Heterocycles with Thio- and Seleno-Silanes

“…However, only few examples are reported on the reaction of epoxides with thiols in ionic liquids. In some cases, addition of a catalyst was not necessary, while for some ring opening reactions of epoxides or thiols heating was required [49][50][51][52]. The most common ILs consist of dialkylimidazolium cations and [BF 4 − ], with [Br − ] or [Cl − ] as the counter-anion.…”