“On Water” Nucleophilic Addition of Formaldehyde N,N‐Dialkylhydrazones to α‐Keto Esters

Abstract

Water solves the problem: The use of pure water as the reaction mixture is key for the nucleophilic addition of formaldehyde hydrazones to α‐keto esters, leading to highly functionalized carbinols in high yields and short reaction times. The need for heterogeneous conditions and the observed solvent kinetic isotope effect are in agreement with the proposed “on water” activation.

Unprecedented Nucleophilic Additions of Highly Polar Organometallic Compounds to Imines and Nitriles Using Water as a Non‐Innocent Reaction Medium

“…Remarkably, a significant solvent deuterium isotope effect was detected: the yield of 2 a dropped considerably to 57 % vs. 96 % for the on‐H 2 O reaction (Table , entry 4). These reproducible data are consistent with a proton transfer at the water–organic interface (cleavage of an O−D bond) in the rate‐limiting step, and thus with the active participation of water . On the other hand, upon replacing water with MeOH, a higher degree of protonation was observed as the formation of 2 a was suppressed dramatically (15 % yield) (Table , entry 5).…”

Water as the reaction medium in organic chemistry: from our worst enemy to our best friend

“…25). 98 These results suggest that interfacial water molecules gure prominently in the mechanistic pathway. The authors postulated that water brings the two substrates in close proximity while activating the ketone.…”

Catalytic Asymmetric Construction of Chiral Hydropyridazines via Conjugate Addition of N-Monosubstituted Hydrazones to Enones

“…Conventionally, N , N -dialkylhydrazones were applied in the total synthesis of natural products as practical chiral auxiliary reagents and have been reported as useful ligands and catalysts in asymmetric reactions. Besides, differing from the reactions where they acted as electrophiles, conjugate additions where N , N -dialkylhydrazones were used as nucleophiles have been realized recently. − In comparison, asymmetric conjugate addition of N -monosubstituted hydrazones in organocatalysis still remains problematic and challenging due to the competitive aza-Michael addition and carbo-Michael addition (formal diaza-ene reaction). The site selectivity was dependent on the N -monosubstituted hydrazones used in each organocatalytic reaction.…”