Methylation using dimethylcarbonate catalysed by ionic liquids under continuous flow conditions

Toma N. Glasnov,C. Oliver Kappe,John D. Holbrey,Kenneth R. Seddon,Ting Yan

doi:10.1039/c2gc36226k

Toma N. Glasnov, C. Oliver Kappe + Show 3 more

Open Access

https://doi.org/10.1039/c2gc36226k

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Journal: Green Chem.	Publication Date: Jan 1, 2012
Citations: 50	License type: cc-by

Affiliation: University of Graz, Queen's University Belfast

Abstract

The ionic liquid, tributylmethylammonium methylcarbonate, has been employed as a catalytic base for clean N-methylation of indole with dimethylcarbonate. The reaction conditions were optimised under microwave heating to give 100% conversion and 100% selectivity to N-methylindole, and subsequently transferred to a high temperature/high pressure (285 °C/150 bar) continuous flow process using a short (3 min) residence time and 2 mol% of the catalyst to efficiently methylate a variety of different amines, phenols, thiophenols and carboxylic acid substrates. The extremely short residence times, versatility, and high selectivity have significant implications for the synthesis of a wide range of pharmaceutical intermediates, as high product throughputs can be obtained via this scalable continuous flow protocol. It has also been shown that the ionic liquid can be generated in situ from tributylamine, which has the net effect of transforming an ineffective stoichiometric base into a highly efficient catalyst for this broad class of reactions.

Highlights

Dimethylcarbonate (DMC) is a valuable green reagent with versatile and tunable chemical reactivity[1,2] and can be used either as a methoxycarbonylating agent (at lower temperatures, by nucleophilic attack at the carbonyl carbon of DMC) or as a methylating agent (at higher temperatures, typically above 120 °C, via nucleophilic attack at the methyl carbon of DMC)
Dimethylcarbonate (DMC) is a valuable green reagent with versatile and tunable chemical reactivity[1,2] and can be used either as a methoxycarbonylating agent or as a methylating agent
The reaction conditions were optimised under microwave heating to give 100% conversion and 100% selectivity to N-methylindole, and subsequently transferred to a high temperature/high pressure (285 °C/150 bar) continuous flow process using a short (3 min) residence time and 2 mol% of the catalyst to efficiently methylate a variety of different amines, phenols, thiophenols and carboxylic acid substrates

Summary

Introduction

Dimethylcarbonate (DMC) is a valuable green reagent with versatile and tunable chemical reactivity[1,2] and can be used either as a methoxycarbonylating agent (at lower temperatures, by nucleophilic attack at the carbonyl carbon of DMC) or as a methylating agent (at higher temperatures, typically above 120 °C, via nucleophilic attack at the methyl carbon of DMC). The reaction conditions were optimised under microwave heating to give 100% conversion and 100% selectivity to N-methylindole, and subsequently transferred to a high temperature/high pressure (285 °C/150 bar) continuous flow process using a short (3 min) residence time and 2 mol% of the catalyst to efficiently methylate a variety of different amines, phenols, thiophenols and carboxylic acid substrates.

Results

Conclusion