Claisen‐Schmidt Condensation and Domino Claisen‐Schmidt Condensation ‐ Michael Addition of 16‐Formyl Steroids in the Presence of Switchable Polarity Solvents

Abstract

Switchable polarity solvents (reversible ionic liquids) have been used to replace conventional catalysts and solvents in Claisen-Schmidt condensation reactions of 16-formyl steroids and aromatic ketones. The primarily formed α,β-unsaturated ketones may undergo a Michael addition with the aromatic ketone reaction partner. By the proper choice of the reaction conditions, either the α,β-unsaturated ketone or the products of the domino Claisen-Schmidt condensation -Michael addition could be obtained with good selectivity. The catalyst could successfully be recovered and reused. The steroidal products with androstane and estrane skeleton were characterized by different spectroscopic methods (NMR, IR, MS).

Diols Speed Up Guanidine Base Catalyzed Claisen‐Schmidt Condensation to Produce New 15‐Arylidene Steroids

“…Previously, it was demonstrated that the two-component system containing tBu-TMG (5) and ethylene glycol is not reusable due to the difficulties in the removal of carbon dioxide from the mixture in the ionic state. [31] According to the present experiments, the MTBD (6)/ethylene glycol mixture showed equally excellent activity (Table 1, entries 22,23). If this mixture, in contrast to tBu-TMG/ ethylene glycol offers the advantage of re-usability by absorption and removal of carbon dioxide, it can be an excellent catalyst/solvent for synthesis of steroid derivatives in the Claisen-Schmidt condensation.…”

“…catalysts in the Claisen-Schmidt condensation of 17-oxo- [30] and 16-formyl steroids [31] in the presence of methanol [30] or ethylene glycol. [30,31] As the nBu-TMG/ethylene glycol mixture had been found to form a readily reversible system, [30,31] and made it possible to recycle both the base and the alcohol, the reaction of 17α-methyl-18-nor-13α-16-oxo steroid (1) and benzaldehyde (2 a) was first carried out in the presence of a mixture of these components (Table 1, entry 1). Unfortunately, only low conversion was achieved under conditions identical to those applied in the synthesis of 16-arylidine derivatives before.…”

“…These results clearly show the lower reactivity of compound 1 compared to 17-oxo- [30] or 16-formyl steroids. [31] To achieve higher conversion in the condensation, the applicability of tBu-TMG (5) was investigated because of its higher basicity compared to nBu-TMG (entries 7 and 8). Although only a moderate improvement could be observed when substrate 1 and reagent 2 a were used in a ratio of 1/1 (entry 7), the application of a fivefold excess of aldehyde 2 a led to product 3 a in excellent yield (entry 8).…”

“…Earlier, this approach was applied successfully in our group in the Claisen-Schmidt condensation of 17-oxo steroids and aromatic aldehydes, [30] as well as that of 16-formyl steroids and aromatic ketones. [31] Based on these findings, the synthesis of 17α-methyl-18-nor-5α,13α-15-arylidene-steroids was planned via the guanidine-base catalysed reaction of an 17α-methyl-18nor-5α,13α-16-oxo steroid (For numbering see Supporting Information) and aromatic aldehydes in order to produce some new derivatives bearing the 18-nor-5α,13α-androstane core. Product separation and catalyst recycling was planned to be realised by the switch between the molecular and ionic states of guanidine/alcohol mixtures (Figure 1).…”

Synthetic methods towards steroid-ferrocene conjugates

“…Steroid-ferrocene derivatives 111 and 112 were obtained via the Claisen-Schmidt condensation of the corresponding 16-formyl steroids and acetylferrocene (110), carried out in a nBu-TMG (2-n-butyl-1,1,3,3tetramethylguanidine) and ethylene glycol mixture (Scheme 20). 54 nBu-TMG can play a dual role of co-solvent and catalyst to substitute the usual alkali hydroxides. In similar reactions, both nBu-TMG and ethylene glycol can be recycled via the formation of a reversible ionic liquid in the presence of CO2.…”