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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Org. Chem. 2014, 79, 4, 1805-1817
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Synthesis and Characterization of Binary-Complex Models of Ureas and 1,3-Dicarbonyl Compounds: Deeper Insights into Reaction Mechanisms Using Snap-Shot Structural Analysis

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† Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
‡ Faculty of Pharmaceutical Sciences, Hoshi University, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
§ Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
*E-mail: [email protected]
Cite this: J. Org. Chem. 2014, 79, 4, 1805–1817
Publication Date (Web):January 22, 2014
https://doi.org/10.1021/jo4028775
Copyright © 2014 American Chemical Society
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Abstract

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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.

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Results of catalyst screening in hydrazination and Mannich reaction of 8, copies of 1H and 13C NMR spectra for all new compounds, and the computational details, and X-ray crystal structures analysis data of 9K, 10, and 11E (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.

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