Thio-claisen and cope rearrangements

Abstract

The various modifications of the Cope and Claisen rearrangements have been developed in recent years and these methods have proved very useful for the natural product synthesis owing to their high stereoselectivities. 1 Nozaki et al. 2 Although found the stereoselective trisubstituted olefin synthesis via a thio-Claisen rearrangement in 1973, only a few reports have appeared on this rearrangement so far. 3 Takano et al. reported an a-allylation of thioamides via a thio-Claisen rearrangement 4a and its successful application to the indole alkaloid synthesis. 4b In this communication we wish to report the first example of the double thio-Claisen and Cope rearrangements, which furnish cl,Bc,<-unsaturated thioamides possessing the fundamental terpene skeleton. The total profile of this reaction is illustrated in Scheme I. The S-alkylation of a,B-unsaturated thioamides 1. with allylic halides 2 and subsequent dehydrohalogenation with a base afforded thioamides 4, which appeared to be derived from ketene S,N-ketal intermediates (3E and/or 32) via a thio-Claisen rearrange. ment. This transformation could be undertaken most satisfactorily by the S-allylation in t-BuOH followed by dehydrohalogenation with DBU (1,5-diazabicyclo[5.2.0]undecene-5). For example, o-allylation of thiocrotonoylpyrrolidine g with crotyl chloride 2b in t-BuOH gave 3-methyl-2-vinylthiopent-4-enoylpyrrolidine 4 (R1= R2= H, R3= Me) exclusively in 72% yield (entry 5), 5 while in THF a mixture of 4 and 2-vinylthiohex-4-enoylpyrrolidine 7 were obtained in 30 and 20% yields, respectively, as a result of S-alkylations at both termini of unsymmetrical allylic halide (eq 1). When KOtBu was used instead of DBU, the first formed B,y-unsaturated thioamide 4 was completely isomerized to ct,Bunsaturated thioamide, i.e., in entry 3, 2-isopropylidenethiopent-4-enoylpyrrolidine was obtained in 45% yield as the only isolable product.