Direct Imine Acylation: A Versatile Method for the Synthesis of Nitrogen-Containing Heterocycles, Spirocycles and Natural Products

Abstract

Diverse nitrogen-containing heterocyclic compounds can be synthesised by the N-acylation of imines using functionalised carboxylic acids (Direct Imine Acylation, DIA). The carboxylic acids are activated in situ using the coupling agent propylphosphonic acid anhydride (T3P), before reacting with the imine coupling partner to generate N-acyl­iminium ions in situ, that can then be trapped by oxygen-, nitrogen-, sulfur- or carbon-based nucleophiles built into the carboxylic acid. This versatile, convergent method has been used to generate a wide range of products, including aromatic and aliphatic heterocycles, β-lactams, azaspirocycles and natural products.

1 Introduction

2 DIA in the Total Synthesis of ‘Upenamide

3 DIA with Benzoic Acid Derivatives

4 DIA with Aliphatic Carboxylic Acids

5 DIA in the Synthesis of β-Lactams

6 DIA in the Synthesis of Azaspirocycles

7 Mechanistic Studies

8 Conclusion

Key words

N-heterocycles - spirocycles - natural products - N-acyliminium ions - ‘upenamide - evodiamine - cavidine

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