Medium‐Sized‐Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion

Abstract

Analogues of dibenzodiazepines,inwhich the sevenmembered nitrogen heterocycle is replaced by a9 -12-membered ring, were made by an unactivated Smiles rearrangement of five-to eight-membered heterocyclic anthranilamides.T he conformational preference of the tertiary amide in the starting material leads to intramolecular migration of ar ange of aryl rings,e ven those lacking electron-withdrawing activating groups,a nd provides am ethod for n!n + 4r ing expansion. The medium-ring products adopt achiral ground state with an intramolecular,t ransannular hydrogen bond. The rate of interconversion of their enantiomeric conformers depends on solvent polarity.R ing size and adjacent steric hindrance modulate this hidden hydrophilicity,thus making this scaffold ag ood candidate for drug development.Scheme 1. Prototypical tricyclic antidepressants, and our approach to their medium-sized-ring analogues.

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

“…9 The latter are normally recognized in polycyclic systems with some degree of instability which is released via breaking of a central bond which leads to energy-lowering transformations such aromatization or strain relief. Recent illustrative examples include synthesis of 10-membered lactam 1 from readily available 2-oxocyclohexancarboxylic acid by Unsworth and co-workers 3 and conformationally induced Smiles ring expansion synthesis of dibenzodiazepine analogs 2 reported by Clayden and co-workers 10 as well as other examples from these two groups. 11 In recent years, we have been involved 12 in exploring N-(hetero)aryl 2-imidazolines as privileged motifs for drug discovery as well as versatile templates for scaffold-oriented synthesis.…”

Electrochemical Ring Expansion to Synthesize Medium-Sized Lactams Through C–C Bond Cleavage

“…Besides thiophene rings as migrating (hetero)aryl groups, substrates bearing electron-rich benzothiophene and anisole also survived and gave the corresponding products in 56-92% yields after electrolysis. Halogen groups, such as F and Cl, could provide extra opportunities for further transformations (12)(13)(14)(15)(16). It was particularly noteworthy that electron-deficient moieties could also be effectively transformed into the corresponding pyridyl-fused lactams with 89% yield (17).…”

“…[7][8][9][10] Therefore, synthetic routes to obtain medium-sized rings avoiding end-to-end cyclization are desirable. With this regard, ring-expansion strategies such as Beckmann rearrangement, 11,12 retro-aldol reaction, 13,14 and others [15][16][17][18][19][20][21][22][23] have proven to be especially useful in recent years. Despite these important advancements, these types of methodologies also show difficulties in requiring multistep preparation for expansion substrates or failing to serve as a practical route toward the broad scope of lactams.…”

Atropisomerism in a 10-Membered Ring with Multiple Chirality Axes: (3Z,9Z)-1,2,5,8-Dithiadiazecine-6,7(5H,8H)-dione Series

“…In addition to compound 16, other 10-membered rings presenting intracyclic amide group (heterocyclic analogues of dibenzodiazepines) 27 or an exocyclic amide bond (10membered benzazecine derivative) 28 and additional insaturations showed enantiomeric conformations, but the enantiomerization barriers obtained by VT-NMR were too low to imagine a room temperature isolation of the corresponding enantiomers.…”