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

Abstract

The previously reported ring-expansion strategy involving hydrolytically prone imidazoline rings was thought to include the formation of a hydrated imidazoline intermediate. In this work, we accessed the latter via the addition of a 2-aminoethyl side chain onto a lactam moiety. This led to an efficient three-atom ring expansion of diarene-fused [1.4]oxazepines and [1.4]thiazepines and led us to propose to term this common approach the hydrated imidazoline ring expansion (HIRE) reaction. The strategy was extended to the insertion of longer (containing up to five atoms) side chains, and thus, larger (11to 12-membered) diarene-fused rings were obtained via the homo-HIRE and homo 2 -HIRE reactions, respectively. This underscores the utility of the HIRE reaction for the preparation of medium-sized rings, an important class of chemical tools for interrogation of various biological targets.

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

“…According to DFT calculations conducted at B3LYP/6‐31G* level of theory, (see Supporting information), evolution of HI‐y into 4y is marginally different in energy effect from an alternative pathway HI‐y → 3y (Δ G –15.7 kcal/mol and –14.9 kcal/mol, respectively). However, the formation of 3y is probably irreversible, despite its being nearly equal in free energy to 4y .…”

“…Not unexpectedly, the highest yields over four steps were obtained with pyridine‐ and pyrazine‐containing substrates 5d – f (Table , Entries 11–19). Also notable is the fact the ring expansion approach was found applicable not only to the n + 3 ring expansion (delivering 10‐membered [1,4,7]oxadiazecin‐9‐ones, Figure ) but also to the n + 4 ring expansion in a process we termed “ homo ‐HIRE” (Table , Entries 10 and 16). The formation of the resulting [1]oxa[4,8]diazacycloundecin‐10‐ones 3j and 3p likely occurs with the intermediacy of the respective “hydrated tetrahydropyrimidines” (in analogy to the HI intermediates postulated in all other cases).…”

“…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 .…”

“…On the contrary, primary and secondary amines 4 smoothly underwent ring expansion in aqueous alkaline acetonitrile to give 3 . Under dehydrative conditions, primary amines 4 gave respective imidazolines 1 which could not undergo the HIRE process without being activated by alkylation …”

“…This limited the diversity of the R' substituents on the lactam nitrogen atom of ring‐expanded products 3 . At the same time, obtaining secondary amines 4 entailed lengthy synthesis . This prompted us to consider an alternative approach to constructing imidazolinium salts 2 , which would allow for a much greater flexibility of the R' substituents as well as a shorter route to ring‐expanded products 3 obtained upon hydration of 2 .…”