Catalytic Enantio‐ and Diastereoselective Mannich Addition of TosMIC to Ketimines

Abstract

Chiral amines bearing a stereocenter in the α position are ubiquitous compounds with many applications in the pharmaceutical and agrochemical sectors, as well as in catalysis. Catalytic asymmetric Mannich additions represent a valuable method to access such compounds in enantioenriched form. This work reports the first enantio‐ and diastereoselective addition of commercially available p‐toluenesulfonylmethyl isocyanide (TosMIC) to ketimines, affording 2‐imidazolines bearing two contiguous stereocenters, one of which is fully‐substituted, with high yields and excellent stereocontrol. The reaction, catalyzed by silver oxide and a dihydroquinine‐derived N,P‐ligand, is broad in scope, operationally simple, and scalable. Derivatization of the products provides enantioenriched vicinal diamines, precursors to NHC ligands and sp3‐rich heterocyclic scaffolds. Computations are used to understand catalysis and rationalize stereoselectivity.

Recent Developments in Enantioselective Transition Metal Catalysis Featuring Attractive Noncovalent Interactions between Ligand and Substrate

“… 40 Variation in the pronucleophile component was also studied, and p -toluenesulfonyl isocyanide (TosMIC) was a competent pronucleophile for the Mannich transformation with a variety of DPP-protected imines ( Figure 4 g). 41 …”

“…In the more recent report using TosMIC as the pronucleophile, DFT was used to rationalize the formation of the major enantiomer ( Figure 4 h). 41 In the two lowest-energy transition states, in which the ketimine adopts the E -configuration, the strongly hydrogen bond-accepting phosphine oxide interacts with both silver and the amide of the ligand through hydrogen bonding.…”

Recent Advances in the Chemistry of Isocyanides with Activated Methylene Group

“…However, Trulli and colleagues have shown that presence of a steric hindrance on the pronucleophile carbon of α-substituted methyl isocyanoacetates leads to formation of both isomers (Scheme 48 Franchino et al applied catalytic Mannich addition of TosMIC 1m to N-phosphonyl ketimines 99 in the presence of silver(I) oxide and N,P-ligands 16 for enantio-and diastereoselective preparation of 5-alkyl-5-aryl-4-tosyl-2-imidazolines 100 in high yields and stereopurity. [60] Computational analysis confirmed the key role of silver oxide-N,P-ligands complexes in streoselectivity of the reaction and substrate activation during C-C bond formation (Scheme 49). N-phosphonyl imines 101 were also involved in sterecontrolled preparation of N-phosphonyl-4-carboxymethyl-5-aryl-(alkyl)-2-imidazolines 102, 103 described by Qiao and colleagues.…”

“…Franchino et al applied catalytic Mannich addition of TosMIC 1m to N‐phosphonyl ketimines 99 in the presence of silver(I) oxide and N,P‐ligands 16 for enantio‐ and diastereoselective preparation of 5‐alkyl‐5‐aryl‐4‐tosyl‐2‐imidazolines 100 in high yields and stereopurity. [ 60 ] Computational analysis confirmed the key role of silver oxide‐N,P‐ligands complexes in streoselectivity of the reaction and substrate activation during C–C bond formation (Scheme 49).…”

TosMIC: A Powerful Synthon for Cyclization and Sulfonylation

“…All compounds were characterized by spectroscopic analysis and stereoselectivity was confirmed by computation approach and X-ray diffraction method. [17] A. M. van Leusen and his co-workers reported the synthesis of imidazole derivatives from aldimine derivative and tosylmethyl isocyanide. Diverse range of aldimines was prepared from readily available aldehyde and N-dimethylsulfamoyl amide in refluxing toluene.…”