NMR Spectroscopic and Computational Study of Conformational Isomerism in Substituted 2-Aryl-3H-1-benzazepines: Toward Isolable Atropisomeric Benzazepine Enantiomers

Abstract

Certain 2-aryl-3H-1-benzazepines are conformationally mobile on the NMR time scale. Variable-temperature NMR experiments bolstered by calculations indicate that alkylation of the azepine ring will slow the interconversion of conformational enantiomers markedly. DFT studies show that, while the substitution patterns of the aryl groups at C2 and C4 do not exert large effects on the rate of enantiomerization, alkylation at C5 slows it appreciably. Alkylation at C3 slows enantiomerization even more, possibly to the extent that isolation of atropisomers might be attempted.

Interplay of Nitrogen-Atom Inversion and Conformational Inversion in Enantiomerization of 1H-1-Benzazepines

“…We note that, in many cases, the transition states deviate somewhat from planarity. This is a common phenomenon in seven-membered heterocycles of these types. ,, …”

“…The B3LYP functional , and the 6-31G­(d) basis set were used together with standard protocols. The combination of the B3LYP functional and the 6-31G­(d) basis set reproduces the geometries and energetics of the ring-flip of benzazepines well . All structures were optimized without constraints.…”

“…The azepine rings of both 1 and 2 are nonplanar, and because the nitrogen atom breaks symmetry, they exhibit planar chirality . We have shown that the enantiomers of 3 H -benzazepine 1 and its derivatives interconvert rapidly at room temperature by a ring-flipping process. , The case of N-alkylated 1 H -benzazepines such as 2 might be complicated by the nitrogen atom, which, if it is nonplanar, becomes a chiral center that could undergo stereochemical inversion. Thus, benzazepines 2 could exist as a mixture of four stereoisomersthat is, two pairs of enantiomersinterconverting at rates which may depend strongly on the surrounding structural features.…”

“…26 A systematic experimental and computational study of the relationship between ring-flip and N-inversion and how these affect the energy barrier to enantiomerization is desirable considering the ever increasing importance of seven-membered-ring heterocycles in pharmacology. 8 It is well-known that varying the steric bulk of the groups attached to atoms around the ring juncture of the 1,4-benzodiazepine system 27 and other benzodiazepine 16 and benzazepine systems 4,16 will strongly affect the rate of the ring-flip. A systematic study of the steric effects of groups around the ring juncture, where one of the atoms bearing those groups is stereolabile, is lacking.…”

Construction of 5H‐Dibenzo[c,e]azepine Framework from Dibenzothiophene Dioxides andN‐Benzylimines through SNAr Reactions

“…344.1560). Atropisomerism of rigid seven-membered rings including benzazepines [4,31,32] and dibenzocycloheptanes [33][34][35] were reported in the literature. We also investigated the atropisomerism of 3aa and 4 computationally, which is described in Supporting Information.…”