SOME SYNTHETIC LIMITATIONS IN THE USE OF STERICALLY HINDERED AMINES IN THE UGI REACTION

V. Klymenko, I. Piontkovskyy, M. Tupychak, N. Pokhodylo


DOI: http://dx.doi.org/10.30970/vch.6601.215

Abstract


Multicomponent reactions are powerful synthetic methods where multiple starting components combine to form multifunctional compounds in a single procedure. The four-component Ugi reaction, which includes a primary amine, carbonyl compound, carboxylic acid, and isonitrile, yields highly substituted α-aminoacyl amides, offering unique advantages for diversity-oriented synthesis. Recently, the literature on the Ugi reaction in organic synthesis has expanded significantly, introducing a variety of precursors. However, some simple reagents, like tert-butylamine, are underrepresented in studies, indicating limitations in their application. This article presents examples where tertiary amines fail to yield the expected Ugi adducts, instead forming carboxylic acid amides.

Previously, we established that 2-azido-3-arylpropanoic acids are highly reactive precursors in the Ugi reaction. However, attempts to introduce sterically hindered 2-methylbut-3-yn-2-amine and tert-butylamine into the Ugi reaction with 2-azido-3-arylpropanoic acids did not result in the formation of Ugi adducts; instead, the main product of the reaction was the corresponding amides with moderate yields.

We also observed similar results when introducing an equimolar mixture of 2-(2-bromophenyl)cyclopropan-1-carboxylic acid, tert-butylamine, p-methoxybenzaldehyde, and  tert-butylisonitrile into the Ugi reaction. The main product of the reaction was an amide. Another example of obtaining N-tert-butylamide under Ugi reaction conditions was the interaction of 1-oxo-1H-isothiophen-3-carboxylic acid, tert-butylamine, p-methylbenzaldehyde, and p-tolyl isonitrile.

The obtained results suggest that the steric factors of the amine component in the Ugi reaction may hinder its progression and promote an alternative reaction pathway resulting in amides, which are apparently the products of the interaction of Schiff base intermediates with carboxylic acids. These results not only reveal synthetic limitations of the Ugi reaction but may also be applied to develop a synthetic approach for obtaining amides directly from carboxylic acids under mild conditions.

 

Keywords: Ugi reaction, tert-butylamine, amides, steric factor.


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