Bifunctional Primary Amino‐thiourea Asymmetric Catalysis: The Imine‐Iminium Ion Mechanism in the Michael Addition of Nitromethane to Enone

Abstract

Primary-amine thioureas are preeminent organocatalysts used in challenging asymmetric Michael-type reactions, such as in the addition of nitromethane to enones. However, the complete reaction mechanism of this reaction has not yet been fully elucidated. Considering that the primary-amine group could act via both base and iminium ion catalysis, both mechanisms were investigated in this work using theoretical methods. The calculations have indicated that the base catalysis is kinetically unfeasible, with very high overall ΔG � . An imine-iminium ion catalysis is a viable route. This mechanism requires the participation of an acid as a cocatalyst (additive) in several steps, including the formation of the imine. The rate-determining step corresponds to the proton transfer from the nitromethane to the imine, forming the nitronate-iminium ion-pair intermediate. This complex reacts via nucleophilic attack of the nitronate ion to the electrophilic carbon of the iminium ion, forming a new CÀ C bond that determines the enantioselectivity of the reaction.

Highly Stereoselective, Organocatalytic Mannich-type Addition of Glyoxylate Cyanohydrin: A Versatile Building Block for the Asymmetric Synthesis of β-Amino-α-ketoacids

“…Since the substituent on the amine moiety of the catalyst did not influence the enantioselectivity (Table , entry 6 vs 7), we used N , N -dimethylamino thiourea C7 and benzothiadiazine C10 as catalysts to simplify the reaction systems. A conformational search for the TS that provides adduct ent -39 revealed that the unprecedented conformers TS2 and TS4 , in which the thiourea and benzothiadiazine moiety is flipped relative to TS1 and TS3 , are the most stable TSs. , The patterns of intermolecular hydrogen bonding in the most favorable TSs TS2 and TS4 are similar to those of TS1 and TS3 ; on the other hand, characteristic intramolecular hydrogen-bond interactions in the catalyst structures are observed in TS2 and TS4 ; the α-C–H bond of the ammonium moiety interacts with the sulfur atom of thiourea in TS2 and the nitrogen atom of sulfonamide in TS4 . Importantly, the intramolecular hydrogen bond in TS4 is much shorter than that in TS2 (2.27 Å vs 2.56 Å), which would result in a more vacant catalytic pocket and decrease the steric repulsion between the catalyst and substrate in TS4 relative to that in TS2 .…”

Thiourea modified low molecular polyamide as a novel room temperature curing agent for epoxy resin

“…20 At the same time, because LMPA itself is a kind of polymer and its specific molecular weight is difficult to measure, the modified TLMPA is a mixture, so it is difficult to measure the probability of the occurrence of –SH group in the curing process. As can be seen from the references, 21–24 the nucleophilic reaction between the C atom in thiourea and the N atom with strong electronegativity in the primary amine is relatively complete in the oil bath heating environment. At the same time, because thiourea itself is a solid, if the reaction had not been completed, the mechanical properties of E-51/TLMPA would have been reduced, but such a situation was not found in the test, so the modification of thiourea was relatively complete.…”

Stereoselective Three‐Step One‐Pot Cascade Combining Amino‐ and Biocatalysis to Access Chiral γ‐Nitro Alcohols**

“…Recent efforts by the groups of Hilvert, Poelarends, and others have shown that this reaction can also be performed via enzymatic catalysis using different biocatalysts such as carboligases and tautomerases, [18–21] or artificial enzymes bearing non‐natural cofactors that enable iminium catalysis [22] . However, the use of prolinol [23] and thiourea‐based [24] organocatalysts continues to be the preferred method as they have been shown to be a very efficient tool to enable this transformation through a bifunctional mechanism involving carbonyl activation via iminium ion formation and nitro group activation via hydrogen‐bonding interactions [25] …”