Nucleophile‐Directed Selective Transformation of cis‐1‐Tosyl‐2‐tosyloxymethyl‐3‐(trifluoromethyl)aziridine into Aziridines, Azetidines, and Benzo‐Fused Dithianes, Oxathianes, Dioxanes, and (Thio)morpholines

Abstract

A five-step procedure for the synthesis of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine was developed, starting from 1-ethoxy-2,2,2-trifluoroethanol, involving imination, aziridination, ester reduction, hydrogenation, and N-,O-ditosylation steps. Further synthetic elaborations revealed a remarkable difference in the reactivity of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine with respect to aromatic sulfur and oxygen nucleophiles, thus enabling the selective deployment of this versatile substrate as a building block for the synthesis of functionalized aziridines, azetidines, and benzo-fused dithianes, oxathianes, dioxanes, and (thio)morpholines.

Ring Expansions of Activated Aziridines and Azetidines

“…Very recently, De Kimpe and co-workers demonstrated an unprecedented synthesis of cis-2-CF 3 -azetidines 18 from cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl) aziridine 16 via a base-mediated ring opening of the activated aziridines with aromatic oxygen nucleophile followed by an intramolecular cyclization of the intermediate 17 (Scheme 5) [43]. The regio-and stereospecific synthetic methodology furnished the cis-azetidines 18 in excellent yields.…”

Recent applications of aziridine ring expansion reactions in heterocyclic synthesis

“…38 A similar treatment of these aziridines with aryl thiols leads to the formation of N-tosyl-2-arylthiomethyl-3-trifluoromethylaziridines. The phenolate ion attacks at C-2 position of the aziridine ring leading to cleavage of the C-N bond resulting into formation of an intermediate 44.…”

“…38 A regioselective ring-opening occurs either directly forming intermediate 259 or through another aziridine 258 depending on the nucleophile used. The sulfur-nucleophile led to nucleophilic substitution on aziridine followed by ring-opening whereas the oxygen nucleophile led to ring-opening first.…”

Synthesis of trifluoromethyl γ-aminophosphonates by nucleophilic aziridine ring opening

“…14,17 Then, an ester group was reduced to provide the corresponding alcohol 2 in 84% yield. 18,19 Swern oxidation of 2 gave the respective aldehyde 3 (Scheme 1). Aldehyde 3 was used directly to introduce C-P bond by two distinct methods, using different bases and conditions, to yield 1-hydroxyphosphonates (Scheme 2).…”