# Mild and efficient synthesis of carbamates using dioxazolones as bench-stable isocyanate surrogates: application in AChE-inhibiting agent development

## TL;DR

A new method for making carbamates using stable dioxazolones was developed, offering a safer and efficient way to create insecticides and AChE inhibitors.

## Contribution

The use of dioxazolones as bench-stable isocyanate surrogates for carbamate synthesis is novel and avoids handling volatile isocyanates.

## Key findings

- The method enabled rapid and high-yield synthesis of diverse carbamates, including insecticides like propoxur and carbofuran.
- A 30-compound library was created, with several compounds showing potent nanomolar acetylcholinesterase (AChE) inhibition.
- Molecular docking revealed insights into structure–activity relationships and selectivity between insect and mammalian AChE.

## Abstract

A practical method for carbamate synthesis was developed using 3-substituted dioxazolones as bench-stable isocyanate surrogates. Prepared from hydroxamic acids using triphosgene, these dioxazolones underwent base-promoted decarboxylation to generate isocyanates in situ. The optimized protocol (MeCN, Cs2CO3, 70 °C) enabled rapid (20 min), high-yielding access to diverse carbamates, including commercial insecticides propoxur and carbofuran in both milligram and gram scales. The carbamate-forming step avoided direct handling of volatile isocyanates, generates CO2 as the only byproduct, and exhibited broad substrate scope, affording a 30-compound library. Biological evaluation identified several potent acetylcholinesterase (AChE) inhibitors, with series-5 demonstrating nanomolar-level activity. Molecular docking provided structural insights into structure–activity relationships and potential determinants of insect versus mammalian AChE selectivity. This work offered a scalable route to carbamate agents and a valuable compound library for AChE-targeted discovery.

A practical method for carbamate synthesis was developed using 3-substituted dioxazolones as bench-stable isocyanate surrogates.