Synthesis of α‑(Pentafluorosulfanyl)- and α‑(Trifluoromethyl)-Substituted Carboxylic Acid Derivatives by Ireland–Claisen Rearrangement

Earlier studies have shown that [3,3]-sigmatropic rearrangements of allyl esters are useful for the construction of fluorine-containing carboxylic acid derivatives. This paper describes the synthesis of 3-aryl-pent-4-enoic acid derivatives bearing either a pentafluorosulfanyl (SF₅) or a trifluoromethyl (CF₃) substituent in the 2-position by treatment of corresponding SF₅- or CF₃-acetates of <i>p</i>-substituted cinnamyl alcohols with triethylamine followed by trimethylsilyl triflate (TMSOTf). This Ireland–Claisen rearrangement delivered approximate 1:1 mixtures of syn/anti diastereoisomers due to tiny differences (<0.5 kcal/mol) both in the energy of (<i>Z</i>)/(<i>E</i>)-isomeric ester enolates and in the alternative Zimmerman–Traxler transition states of model compounds as shown by DFT calculations. Acidic reaction conditions have to be avoided since addition of the reagents in opposite sequence (first TMSOTf then Et₃N) led to oligomerization of the cinnamyl SF₅- and CF₃-acetates. Treatment of the corresponding regioisomeric 1-phenyl-prop-2-en-1-yl acetates under the latter conditions resulted in [1,3]-sigmatropic rearrangement and subsequent oligomerization of the intermediately formed cinnamyl esters. When Et₃N was added first followed by TMSOTf, no further reaction of the formed ester was detected

<i>Anti</i>-Selective Aldol Reactions of Pentafluorosulfanylacetic Acid Esters with Aldehydes Mediated by Dicyclohexylchloroborane

Aldol reactions of pentafluorosulfanyl (SF₅)-substituted acetic acid esters with both aromatic and aliphatic aldehydes proceeded with excellent <i>anti</i>-diastereoselectivity and good to high yields using dicyclohexylchloroborane/triethylamine. This methodology enabled the synthesis of hitherto unknown α-SF₅-β-hydroxy esters. Using a norephedrine-based auxiliary, high asymmetric induction was observed. The stereochemistry of products was assigned by NMR spectroscopy and proved by X-ray diffraction analysis. The intermediate enolate was identified as a highly unstable species