Structurally diverse arene-fused ten-membered lactams accessed via hydrolytic imidazoline ring expansion

Abstract

Imidazoline-fused [1,4]oxazepines ( prepared in two simple steps from methyl 2-hydroxyaroates, ethylene diamine and bis-electrophilic aromatics) undergo a facile, good-yielding hydrolytic imidazoline ring expansion (HIRE) upon N-alkylation and treatment with aqueous K 2 CO 3 . The resulting arene-fused ten-membered lactams significantly add to the contemporary arsenal of smallmolecule scaffolds where medium-sized ring systems are severely underrepresented.Small molecule libraries containing medium-sized (8-to 11-membered) rings are currently recognized as a drug discovery platform with many advantages compared to linear scaffolds or those based on flat heteroaromatic rings.1 The introduction of a cycle drastically reduces the rotatable bond count (compared to a linear molecule), which improves permeability through cell membranes and intestinal absorption.

Ring‐Expansion Reactions in the Synthesis of Macrocycles and Medium‐Sized Rings

“…An umber of creative ring-expansion strategies have been described in this review, to generateb othc omplex macrocyclic arrays and medium rings. Many recently developed procedures are included, [107] attesting to the currenth igh interest in this area, however,i ti s also important to recognise the key contribution of classical ring expansion methods;i np articular, much is owed to ring expansion pioneers such as Grob, Eschenmoser and Hesse, whose work continues inspire new discoveries to this day. In terms of outlook, we would argue that the development of methods for ring expansion processes that can be performed sequentially may be of the greatestf uture importance.…”

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 .…”

“…Unfortunately, the alkylation of 1 could only be achieved upon treatment with methyl or ethyl sulfate under microwave‐promoted conditions . This limited the diversity of the R' substituents on the lactam nitrogen atom of ring‐expanded products 3 .…”

Characterizations of crystalline structure and catalytic activity of zwitterionic imidazole derivatives

“…The synthesis of 2-(1H-Imidazolin-2-yl) phenol has been widely reported by the authors in the literature [31][32][33][34]. In this work, we have realized this condensation reaction between ethylenediamine and phenyl salicylate.…”

“…The structure of L1 is build by an asymmetric unit containing one phenol molecule and two phenol-imidazole molecules. The carbon atoms (C 31 and C 10 ) in the imidazole rings are nearly coplanar with the largest deviations from the middle plan being 0.0942(13) Å for C 31 and 0.0807(13) Å for C 10…”