This paper reports on the generation and alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with ω,ω'-dihaloalkanes, followed by a novel ring-expansion protocol toward 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. A variety of halogen, oxygen, nitrogen, sulfur, and carbon nucleophiles was used to trigger this ring rearrangement, resulting in CF3-azaheterocycles bearing different types of functionalized side chains.

Scheme 4. Possible isomerizations of bicyclic aziridiniumi ntermediates 10. Scheme5.Reactiono f1 -azabicyclo[1.1.0]butane 16 with aromatic thiols and amines. Scheme 10. Solvent-dependent transformation of 2-(bromomethyl)aziridines 35. Scheme 9. Reduction of amines 33 and 39 to aziridines 34 and azetidines 38. Scheme 14. Nucleophile-dependent conversion of mesyloxyazetidine 52. Scheme 15. Ring contraction of 3,3-dichloroazetidines 55 to aziridines 60. Scheme 19. Ring expansion of 2-chloromethyl-a nd 2-(methanesulfonyloxymethyl)azetidines 72 to 3-substituted pyrrolidines 73 and 74. Scheme 20. DAST-promoted ring expansion of 2-(hydroxymethyl)azetidines 76. Scheme 40. Conversion of 1-azabicyclo[4.1.0]heptanes 159 to (thio)morpholines 161 and (thi)azepanes 163.

2-(2-Cyanoethyl)aziridines and 2-aryl-3-(2-cyanoethyl)aziridines were deployed as substrates for an In(OTf)3 -mediated regio- and stereoselective ring rearrangement upon treatment with LiAlH4, affording a variety of novel 2-(aminomethyl)pyrrolidines and 3-aminopiperidines, respectively. Further synthetic elaboration of the obtained 3-aminopiperidines resulted in the formation of a peculiar and unexplored conformationally constrained imidazolidinone and diketopiperazine scaffold.

Enantiopure 4-formyl-β-lactams were deployed as synthons for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines via trifluoromethylation through aldehyde modification followed by reductive removal of the β-lactam carbonyl moiety. Subsequent treatment of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur, and fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to excellent yields (45-99%) and high diastereoselectivities (dr >99/1, H NMR) via interception of bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce, for example, a CF-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system.

The front cover picture illustrates the use of 1‐azoniabicyclo[n.1.0]alkane scaffolds (bicyclic aziridinium ions), which have emerged as versatile synthetic intermediates for the construction of a broad variety of nitrogen‐containing heterocycles. The corresponding review article provides a comprehensive survey of all pathways leading to the generation of 1‐azoniabicyclo[n.1.0]alkanes, as well as a discussion on their subsequent ring expansions to relevant azaheterocycles, governed by ring size, substitution pattern, and/or the nature of the applied nucleophiles. Details can be found in the review on pages 3485–3511 (J. Dolfen, N. N. Yadav, N. De Kimpe, M. D'hooghe, H.‐J. Ha, Adv. Synth. Catal. 2016, 358, 3485–3511; DOI: 10.1002/adsc.201600750).