Microwave Assisted, Multi-component Synthesis of Lophine

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The synthesis of imines is generally performed by the acid catalyzed condensation of a carbonyl with a primary amine. org2_imineschiffbase.jpg  When performed using a primary amine, the product can also be referred to as a Schiff base.  The synthesis of imines (or Schiff bases) is highly reversible, meaning reactions can be driven to completion by removal of the water by-product using methods such as azeotropic distillation or molecular sieves.  The reaction involves nucleophilic attack of the primary amine on the carbonyl and proceeds through a hemiaminal intermediate before the loss of water and formation of the imine.
In the case of secondary amines, the imine product is disfavored and results in formation of an aminal or enamine.  Initially, the same steps are followed to reach the hemiaminal, which is then protonated.  In contrast to the case of primary amines, this protonated heminal is unable to lose an N-H proton and must follow a different reaction path.  Nucleophilic attack of a second amine and loss water can result in formation of the aminal product (Scheme 2).  Alternatively, when there is a proton α to the carbonyl, a simple elimination reaction can result in formation of the enamine (Scheme 3).


The synthesis of heterocyclic compounds often requires elevated temperatures and prolonged reaction times, morg2_lophine.jpgaking them well suited for microwave applications.  The synthesis of the nitrogen heterocycle lophine (2,4,5-triphenylimidazole) from benzaldehyde, benzil and ammonium acetate can be performed rapidly using microwave irradiation.
1Experiment adapted from Crouch, R.D.; Howard, J.L.; Zile, J.L.; Barker, K.H. J. Chem. Ed. 2006, 83, 1658.