# Synthesis of Substituted 1,4-Benzodiazepines by Palladium-Catalyzed Cyclization of N-Tosyl-Disubstituted 2-Aminobenzylamines with Propargylic Carbonates

## TL;DR

A new palladium-catalyzed method efficiently creates substituted 1,4-benzodiazepines, useful in medicinal chemistry.

## Contribution

A novel palladium-catalyzed cyclization method for synthesizing substituted 1,4-benzodiazepines is introduced.

## Key findings

- The reaction proceeds via π-allylpalladium intermediates and amide nitrogen attack.
- Regioselectivity is influenced by electronic effects of substituents on the aryl groups.
- The method successfully constructs bioactive benzodiazepine frameworks.

## Abstract

A synthesis of substituted 1,4-benzodiazepines has been developed via palladium-catalyzed cyclization of N-tosyl-disubstituted 2-aminobenzylamines with propargylic carbonates. The reaction proceeds through the formation of π-allylpalladium intermediates, which undergo intramolecular nucleophilic attack by the amide nitrogen to afford seven-membered benzodiazepine cores. In reactions involving unsymmetrical diaryl-substituted carbonates, regioselectivity was observed to favor nucleophilic attack at the alkyne terminus substituted with the more electron-rich aryl group, suggesting that electronic effects play a key role in determining product distribution. The versatility of this reaction was further demonstrated by constructing a benzodiazepine framework found in bioactive molecules, indicating its potential utility in medicinal chemistry. Mechanistic insights supported by stereochemical outcomes and X-ray crystallographic analysis of key intermediates reinforce the proposed reaction pathway. This palladium-catalyzed protocol thus offers an efficient and practical approach to access structurally diverse benzodiazepine derivatives.