Anatomy of the Ugi Reaction and Attempted Cyclization to Diketopiperazines


Abstract

Reaction profiling using H NMR spectroscopy was used to elucidate the kinetics and progression of the 4-component Ugi reaction, involving a carbonyl compound, an amine, a carboxylic acid and an isonitrile. Aromatic aldehydes such as benzaldehyde, veratraldehyde and piperonal were found to react smoothly with 5-methylfurfurylamine and t-butylamine to yield imines in methanol. Phenylacetaldehyde led to intractable product mixtures within minutes of adding to the amine component. The addition of boc-gly alone led to a reversal of the imine formation, while the addition of boc-gly with t-butyl isonitrile or benzyl isonitrile led to a more limited reversal to the aldehyde that peaked after about 30 min before diminishing again over several days. The Ugi products started to crystallize within hours or days. 2-morpholinoethyl isonitrile did not generate Ugi products, apparently due to its instability in the presence of boc-gly.

Introduction

The Ugi reaction is a versatile four component reaction between a carbonyl compound, an amine, a carboxylic acid and an isonitrile. (Ugi 2003) It has been prized in drug discovery for its applicability to combinatorial libraries and simplicity, generally being carried out in one step at ambient temperature. Post condensation modification of the products can also be implemented systematically to generate even larger libraries of compounds.(Hulme 2004)

For example, the UDC (Ugi - deboc - cyclize) strategy has been reported as a convenient route to diketopiperazines (DKPs) (Hulme 1999 and Hulme 1998), synthetic targets proposed to inhibit malarial enoyl reductase (PfENR) (find-a-drug ref). This approach to attacking the proliferation of the malarial parasite has already been shown to be effective with other agents (triclosan ref).

Scheme 1.



Results


Discussion


Conclusion

Experimental


References

Ugi (2003) Molecules