The CSIC [ Carbanion mediated Sulfonate ( Sulfonamido) Intramolecular Cyclization] reaction: Scope and limitations

Abstract

The CSIC (Carbanion-mediated Sulfonate -Sulfonamide- Intramolecular Cyclization) reaction has been extended to new carbonyl containing substrates, showing the scope and limitations of this process. Suitable derivatives of ketones (e.g acetophenone ( 1)), β-keto esters (e.g ethyl acetoacetate ( 4)), γ-keto esters (e.g ethyl 2-oxocyclohexaneacetate ( 5) and ethyl levulinate ( 6)) proved reluctant to undergo this protocol. Cyclopropyl methyl ketone ( 2) gave the heterocycle ( 3), only in the “sulfonamide” synthetic sequence of the CSIC reaction. Cyclic azaketones (e.g tropinone ( 7)) failed also, but 4-piperidones ( 9, 10) afforded the novel 3,8-disubstituted 4-amino-8-aza-1-oxa-2-thiaspiro[4.5]dec-3-ene 2,2-dioxide ( 12, 15a-c) and 8-substituted 4-amino-1,8-diaza-2-thiaspiro[4.5]dec-3-ene 2,2-dioxide ( 18a, 18b, 21a, 21b) ring systems; the former compounds are the first examples of such ring systems substituted at the 3-position, whereas the latter represent the first ever representatives of spiro fused systems containing the 4-amino-2,3-dihydroisothiazole 1,1-dioxide moiety. Base promoted (NaH or DBU) cyclization of precursors 11b, 14a-c, 17b, 17c and 20 give the final adducts in good overall yield. Finally, we were unsuccessful with some conveniently functionalized anthranilonitrile derivatives ( 8a-d), in an attempt to extend the CSIC reaction to β-aminonitriles. As a result of these studies the substrate dependent reactivity in the CSIC reaction has been analyzed in depth and some restrictions and limitations have been observed and discussed.