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Experiment 6, page 1

Department of Chemistry, Imperial College
Third Year Advanced Practical Organic Chemistry

EXPERIMENT 6: MULTI-COMPONENT SYNTHESIS - AZOMETHINE YLIDE 1,3-DIPOLAR CYCLOADDITIONS

Aims of the experiment
To demonstrate the three component, one pot assembly of substituted pyrrolidines by way of an azomethine ylide cycloaddition.

Techniques used/learned:
Fractional crystallisation; nmr analysis of diastereomeric mixtures of compounds.

Introduction
Most organic syntheses involve the stepwise construction of target skeletons by either linear or convergent sequences of reactions.¹This approach has served well for many years (and continues to serve well!), but can lead to lengthy synthetic routes to the target molecules. Recently, there has been much interest in the development of methods which encompass 'multi-component synthesis' - reactions involving the combination of three or more separate components in a single synthetic transformation. This interest has come about for two reasons. Firstly, such reactions offer the potential for very short and convergent synthetic sequences (thus offering time, energy and reagent economies). Secondly, the demands of combinatorial synthesis²require that synthetic routes to target compounds offer the scope for maximum diversity of substituents:clearly this is efficiently achieved if one can combine three (or more!) commercially available or simple components. Chemists have thus begun to think of innovative ways to perform multi-component syntheses and Professor Ivar Ugi of the Technical University of Munich has recently developed a SEVEN component synthesis of dihydro-1,3-thiazines and oxazines!³
Impressive as this example is, perhaps of greater utility are reactions which provide compounds which relate closely to molecules with known biological activity. In this experiment, you will be using a three component condensation to prepare substituted pyrrolidines. Many compounds containing pyrrolidine rings have potent biological activity, egnicotine (1) and the neuroexcitatory kainic acid (2). The reaction involves the condensation of an amine (in this case an amino acid) and an aromatic aldehyde to generate a reactive azomethine ylide, which then undergoes a [3+2] cycloaddition reaction with an electron poor diene (dimethyl fumarate) to generate the pyrrolidines (3, Scheme 1).⁴

H₂N