Synthesis of MAPA Reagents and 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine Using the Goldberg Reaction.

Daniel L Comins

doi:10.3390/molecules27061833

Abstract

A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5–3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2-N-substituted aminopyridines from various secondary N-alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.

Highlights

When t-AmOH was the solvent with potassium phosphate as the base, the reaction proceeded well in 8 h; a significant amount of deformylation of the initial formamide product occurred, to give
When t-AmOH was the solvent with potassium phosphate as the base, the reaction proceeded well in 8 h; a significant amount of deformylation of the initial formamide product occurred, to give 2-methylaminopyridine (MAP) as a byproduct
N-Methylbenzamide [22], N-benzylformamide [23], Nbutylformamide [24], and N-tert-butylformamide [25] were made according to procedures outlined in the literature

Summary

Introduction

LuzCitation: Comins, D.L. Synthesis zio and Damian Winston Young of MAPA Reagents and. 2-methylaminopyridine formamide formamide 11 and and related related amides amides 22 (MAPA). The 2-methylaminopyridine widely used as reagents for for formylation formylation and and acylation acylation of ofvarious variousorganometallic organometallicreagents, reagents, amines, and other nucleophiles [1–5] (Figure 1). Publisher’s Note: MDPI stays neu27061833 tral with regard to jurisdictional Academic

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Conclusion