Synthesis and characterization of binary-complex models of ureas and 1,3-dicarbonyl compounds: deeper insights into...

The mechanism of the enantioselective Mannich reaction catalyzed by a hydrogen-bond (HB)-donor bifunctional organocatalyst has been fully investigated using experimental evidence and computational analysis. Several binary complexes have been designed as models of a catalyst and a nucleophile, where the urea moieties were linked to a 1,3-dicarbonyl compound through the diphenylacetylene motif. X-ray analysis of models 9 and 10 showed that the two N-H protons of the ureas interacted with the same carbonyl group via a double HB interaction. Further investigation of the crystallographic structure of 11 allowed for the direct observation of the labile ammonium-enolate intermediate formed between a bifunctional amino urea and 1,3-diketone. The β-keto ester-amino urea complex 12 reacted with several electrophiles at a remarkably fast rate to provide the corresponding adducts 15 and 17 as single diastereomers in excellent yields, respectively. A density functional theory calculation disclosed the details of the deprotonation and C-C bond-forming steps of the enantioselective Mannich reaction. The deprotonation of the 1,3-dicarbonyl moiety occurred predominantly via the enol form to give the ammonium--enolate intermediate. These results should provide a deeper and more accurate understanding of the functional roles of the HB-donor and Brønsted base moieties of the catalyst.