Synthesis and Characterization of Binary-Complex Models of Ureas and 1,3-Dicarbonyl Compounds: Deeper Insights into Reaction Mechanisms Using Snap-Shot Structural Analysis

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.