# Oxidative Dehydrogenation of N‐Heteroaromatic Alkyl Alcohols and Amines Facilitated by Dearomative Tautomerization

## TL;DR

This paper introduces a simple and eco-friendly method to convert N-heteroaromatic alcohols and amines into aldehydes using acidic or basic aqueous solutions, without over-oxidation.

## Contribution

A novel oxidation method for N-heteroarenes using dearomative tautomerization under mild conditions is introduced.

## Key findings

- 9-acridinemethanol is fully oxidized to 9-acridinecarboxaldehyde in 3 hours using 5% acetic acid.
- The reaction proceeds via acid-catalyzed dearomative tautomerization and enol/enamine intermediates.
- No over-oxidation to carboxylic acids is observed, and the method is applicable to various N-heteroarenes.

## Abstract

The oxidation of alcohols, amines, and halides is a fundamental transformation in organic chemistry with significant applications in the synthesis of fine chemicals, pharmaceuticals, and natural products. Here we show that a broad variety of N‐heteroarenes bearing hydroxymethyl, aminomethyl, or halomethyl groups are oxidatively dehydrogenated to their respective aldehydes by simply heating them in acidic or basic aqueous solution under ambient atmosphere. The quantitative oxidation of 9‐acridinemethanol to 9‐acridinecarboxaldehyde serves as an illustrative example, proceeding to completion within 3 hours in refluxing 5% aqueous acetic acid or even household vinegar. Quinoline derivatives may be similarly oxidized but require higher temperatures and longer reaction times, while indole derivatives are oxidized under basic conditions. Based on comprehensive regioselectivity screens, internal kinetic isotope competition, and density functional theory (DFT) calculations, we propose a mechanism in which migration of a methylene hydrogen to the pyridinic nitrogen by acid‐catalyzed dearomative tautomerization yields an unstable enol or enamine intermediate that then irreversibly loses two hydrogen atoms to atmospheric oxygen. In addition to the simplicity and environmentally benign nature of our method, we observe no indication of any over‐oxidation to carboxylic acids. Finally, we demonstrate the synthetic utility of this reaction through two different one‐pot formylations of acridine.

N‐heteroaromatic alkyl alcohols and amines are inherently unstable in acidic and/or basic solution due to an irreversible dehydrogenation that proceeds from a minority tautomer. In many cases, this reaction results in quantitative oxidation to the corresponding aldehyde, providing a simple, convenient, and green approach for preparing versatile synthetic building blocks.