Organocatalytic Enantioselective γ-Position-Selective Mannich Reactions of β-Ketocarbonyl Derivatives

Abstract

Catalytic asymmetric Mannich reactions of β-ketocarbonyl derivatives (such as β-ketoesters and (2-oxopropyl)phosphonate), resulting in the formation of a C–C bond at the γ-position of the β-ketocarbonyl derivatives with high enantioselectivities, are reported. The bond formation at the α-position of the β-ketoester was reversible, and the γ-position-reacted product δ-amino β-ketoester derivative was kinetically formed and was stable. The dynamic kinetic process was key for the direct access to the γ-position-reacted products from β-ketocarbonyls under catalytic conditions.

On the Topic of Substrate Scope

“…An additional table of all other unreactive substrates attempted (eight examples) is listed in the Supporting Information in Scheme S1. Further examples published at Organic Letters within the past month, where the scope has largely been selected to provide the most information with fewer examples, typically illustrate 26–29 substrate combinations. − …”

1,3-Diamine-Derived Catalysts: Design, Synthesis, and the Use in Enantioselective Mannich Reactions of Ketones

“…β-Ketophosphonates, including those bearing chiral centers, have been used in the Horner–Wadsworth–Emmons version of Wittig reactions to form enone derivatives and in other reactions. − Previously, only three substrate examples of the enantioselective γ-position-selective Mannich reaction of a β-ketophosphonate were reported, in which a cinchona-derived amine with an acid was used as a catalyst . While the catalyst system was useful for the corresponding reactions of β-ketoesters, it was less efficient for the reactions of β-ketophosphonates, and further development was required. Among the catalysts 1 and conditions tested, the reactions in the presence of 1a ·CF 3 COOH with dibenzyl phosphate or of 1a with CF 3 COOH and dibenzyl phosphate at room temperature (25 °C) afforded 9a in high yields with high enantioselectivities (Table , entries 4 and 6).…”

“…First, we evaluated the use of 1 in the presence or absence of acids in catalysis of the Mannich reaction of β-ketophosphonate 7a with imine 8a to afford γ-position-selective reaction product 9a (Table ). β-Ketophosphonates, including those bearing chiral centers, have been used in the Horner–Wadsworth–Emmons version of Wittig reactions to form enone derivatives and in other reactions. − Previously, only three substrate examples of the enantioselective γ-position-selective Mannich reaction of a β-ketophosphonate were reported, in which a cinchona-derived amine with an acid was used as a catalyst . While the catalyst system was useful for the corresponding reactions of β-ketoesters, it was less efficient for the reactions of β-ketophosphonates, and further development was required.…”

“…Thus, the 1,3-diamine moiety of 1 was necessary for the catalysis. While the reaction of 7a and 8a affording 9a catalyzed by a cinchona-derived amine with an acid was previously reported, the reaction catalyzed by 1,3-diamine derivative 1a with the acids under the optimized conditions was faster to afford 9a and provided 9a with higher enantioselectivity than the previously reported reaction catalyzed by the cinchona-derived amine with the acid.…”

Kinetic and Thermodynamic Evidence of the Paal–Knorr and Debus–Radziszewski Reactions Underlying Formation of Pyrroles and Imidazoles in Hydrothermal Liquefaction of Glucose–Glycine Mixtures

“…Despite the lack of mechanistic explanations in the acid-catalyzed HTL literature, the reaction mechanisms associated with the formation of five-membered N-heterocycles have been discussed in the general chemistry literature. − Considering the involved organic macromolecules and derivatives and the resulting structures of the five-membered N-heterocycles, the Paal–Knorr (i.e., a mechanism involving α-dicarbonyls and primary amine or ammonia) and Debus–Radziszewski (i.e., a three-reactant mechanism involving α-dicarbonyls, formaldehyde, and primary amine or ammonia) reactions are the most relevant to be referred to as the underlying mechanisms. However, this assumption requires a careful and comprehensive validation because the reaction kinetic and thermodynamic behaviors under near-supercritical water conditions were significantly different from those reported under milder reaction conditions in general chemistry literature.…”