Two General Routes to 1,4-Disubstituted-2,3,4,5-tetrahydro- 1H-3-benzazepines

Abstract

[structure] Two general routes to 1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepines are described. Both routes utilize an appropriately functionalized phenethylamino alcohol as the penultimate intermediate: the first route makes use of the reductive amination of a benzyl alkyl ketone with alpha-(aminomethyl)benzyl alcohol, while the second route utilizes the addition of a Grignard reagent to the oxazolidine derived from a substitued phenylacetaldehyde and alpha-(methylaminomethyl)benzyl alcohol. In all cases studied, the cis-1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepine was obtained as the major product.

Calcium‐Catalyzed Synthesis of 1,2‐Disubstituted 3‐Benzazepines

“…A transition‐metal‐free alternative is an acid‐mediated Friedel–Crafts cyclization5 using a large excess of acid, traditionally as the solvent. Unfortunately, these S N 1 processes suffer from poor diastereoselectivity, generally in the range of 1:16 to 3:1,7 thereby precluding the formation of enantiopure 3‐benzazepines through operationally simple chiral pool synthesis. First diastereoselective transformations proceeding by an S N 1 mechanism, were published only recently 8…”

Diastereoselective Synthesis of 1,2‐Disubstituted 2,3,4,5‐Tetrahydro‐1H‐3‐benzazepines by Means of the Stevens Rearrangement

“…Synthetic approaches to 1H-3-benzazepines include different strategies, most of them based on two disconnections (Figure 2). Disconnection (a), which is the most common route, makes use of Friedel-Crafts-type reactions implying halogen, [7] alcohol, [8] or carbamate compounds.…”

Palladium‐Catalyzed Oxidative Cycloaddition through CH/NH Activation: Access to Benzazepines

“…[11] In addition to Anafranil, its analogues, Tienopramine and Amezepine, are also classified as antidepressants. [13] A direct synthetic method utilizing simple and readily available starting materials, would not only enable the construction of a new class of scaffolds, but would also facilitate late-stage modification of existing compounds that are biologically active. [13] A direct synthetic method utilizing simple and readily available starting materials, would not only enable the construction of a new class of scaffolds, but would also facilitate late-stage modification of existing compounds that are biologically active.…”

“…[12] Preparation of such benzazepine-containing compounds generally requires multiple synthetic steps. [13] A direct synthetic method utilizing simple and readily available starting materials, would not only enable the construction of a new class of scaffolds, but would also facilitate late-stage modification of existing compounds that are biologically active. To address this limitation, we devised a direct CÀH/NÀH activation method to construct a benzazepine scaffold.…”