Rare Medium-Sized Rings Prepared via Hydrolytic Imidazoline Ring Expansion (HIRE)

Abstract

The hydrolytic imidazoline ring expansion (HIRE) methodology was extended to readily available tetracyclic [1,4]thiazepines as well as sulfoxide and sulfone analogs thereof. The reactions resulted in the facile formation of a rare medium-sized [1,4,7]thiazecine ring system that has an emerging utility in bioactive compound design. Comparing the HIRE rates for representative compounds in the three groups of substrates allowed drawing some generalizations about the substituent effects on the course of the reaction.

An Alternative Approach to the Hydrated Imidazoline Ring Expansion (HIRE) of Diarene‐Fused [1.4]Oxazepines

“…However, when “quaternized” by alkylation at the imidazoline nitrogen atom, treatment of the resulting imidazolinium salts 2 with 0.1 % w/v aqueous K 2 CO 3 solution rapidly converted them to ring‐expanded 1,4,7‐oxadiazecines 3 . Since the formation of a putative “hydrated imidazoline” (HI) intermediate was evoked, with the energetically favored[7c] breakage of the central a bond leading to 3 , the approach was dubbed the “ h ydrated i midazoline r ing e xpansion” (HIRE) . The reversible breakage of the other C‐N bond ( b ) in HI could, in principle, lead to N ‐(2‐aminoethyl) [1.4] oxazepinones 4 , which was not observed over the formation of 3 .…”

Rethinking Hydrolytic Imidazoline Ring Expansion: A Common Approach to the Preparation of Medium-Sized Rings via Side-Chain Insertion into [1.4]Oxa- and [1.4]Thiazepinone Scaffolds

“…Recently, we described a ring-expansion strategy involving nucleophilic addition of hydroxide anion to an imidazoline moiety (activated by N -alkylation) in diarene-fused [1.4]­oxazepines ( 1 ) or [1.4]­thiazepines ( 2 ) leading to rare, medium-sized [1,4,7]­oxazecines 3 and [1,4,7]­thiazecines 4 , respectively. Such a ring-expansion strategy clearly belongs to type A (Figure ) as it presumably involves the breaking of the central bond in putative intermediate 5 through which the ring-expansion process is thought to proceed.…”

Significant Broadening of the Substrate Scope for the Hydrated Imidazoline Ring Expansion (HIRE) via the Use of Lithium Hexamethyldisilazide

“…This process has been successfully applied to ring expansion in oxa, 4b c thia, 4d dioxathia 4a and aza 4e analogs of substrates 1 , which were either obtained via N -alkylation of the respective imidazoline-fused substrates 4c d or, more conveniently, were elaborated from the respective azepinones 3 via a straightforward sequence of forming an amidine with 2-aminoethanols 4 followed by an intramolecular S N 2 process. 4b e However, it turned out that certain substrates, insufficiently activated towards rupture of the central ‘ a ’ bond (usually oxa 4b or aza 5 analogs with insufficiently electron-poor fused (hetero)aromatic moieties 6 ) failed to undergo the HIRE process and delivered solely the product resulting from expulsion of the aminoalkyl side chain 5 , i.e., from alternative rupture of the ‘ b ’ bond.…”