# Promotion of Water as Solvent in Amination of 4-Chloropyrrolopyrimidines and Related Heterocycles under Acidic Conditions

## TL;DR

This study shows that using water as a solvent improves the amination of certain heterocycles under acidic conditions, offering safer and more cost-effective chemical processes.

## Contribution

The paper demonstrates that water is a superior solvent for acid-promoted amination of 4-chloropyrrolopyrimidines and related compounds compared to traditional organic solvents.

## Key findings

- Amination of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine with aniline derivatives proceeds faster in water than in alcoholic solvents and DMF.
- 14 out of 20 aniline derivatives were successfully aminated in water, while ortho-substituted anilines with pKa below 1 were unsuitable.
- Amination of quinazoline, thienopyrimidine, and purine derivatives also worked well in water, but highly lipophilic compounds were more efficient in 2-propanol.

## Abstract

A switch of reaction
medium from organic solvents to water can
improve the safety and lower the cost of production processes. Hydrochloric
acid-promoted amination of fused pyrimidines has been studied using
4-chloro-7H-pyrrolo[2,3-d]pyrimidine
and aniline as model compounds. Higher rate was observed in water
than in four alcoholic solvents and DMF. An important aspect is that
the amount of acid should be kept low to minimize the competing solvolysis.
The substrate scope for the amination in water was evaluated by reacting
4-chloro-7H-pyrrolo[2,3-d]pyrimidine
with 20 aniline derivatives with variance in steric and electronic
properties. Preparative useful reactions were seen for 14 of the 20
derivatives. Unsuited nucleophiles are ortho-substituted
anilines with a pKa below 1. Amination
of the corresponding quinazoline, thienopyrimidine, and purine also
proceeded well in water. Highly lipophilic and crystalline compounds
are more efficiently aminated in 2-propanol. Aliphatic and benzylic
amines react poorly under acidic conditions, but these aminations
can be done in water without acid.