Ketimines unsymmetrical

We have previously discussed that keto-aldehydes react with anilines first at the aldehyde carbon to form the aldimine. Subsequent condensation with another aniline formed a bis-imine or enamino-imine. The aniline of the ketimine normally cyclizes on the aldimine (24 —> 26). Conversely, cyclization of the aldimine could be forced with minimal aniline migration to the ketimine using PPA (30 —> 31). The use of unsymmetrical ketones has not been thoroughly explored a few examples are cited below. One-pot enamine formation and cyclization occurred when aniline 48 was reacted with dione 49 in the presence of catalytic p-TsOH and heat. Imine formation occurred at the less-hindered ketone, and cyclization with attack on the reactive carbonyl was preferred. ... 

Whereas branched ketimines are metalated at the less substituted carbon, metalation and alkylation of unsymmetric imines leads to regioisomers2,4,27. For this reason, only symmetrical ketones and unsymmctrical ketones with one substituent having no a-hydrogens have been applied in alkylation reactions via imines (see Table 4). 

The reaction seems to be limited to this very special functional group of the ketimines whereas the terminal alkene component can be varied somewhat. The scope of the reaction is rather limited based on the number of isomers generated from symmetrical (two isomers) and unsymmetrical alkenes (up to six isomers) and, as a consequence, the usefulness of this reaction for the synthesis of more complex molecules is uncertain at the moment. A theoretical investigation has been undertaken to elucidate the reaction pathway and the role of the ketimine subunit. It could be shown that the ketimine functionality is important as it acts as a bidentate ligand... 

Recent research by Bergbreiter, Newcomb, Meyers and their respective coworkers has shown that a variety of factors, such as the base, the temperature of deprotonation, and the size of the substituent on nitrogen, control the structure of the metallated imine and ultimately the regiochemistry of the alkylation reaction. In contrast to metal enolates, where the more-substituted species is usually the more thermodynamically stable, less-substituted sy/i-metallated ketimines, e.g. (89), are the most thermodynamically stable of the possible isomers of unsymmetrical systems. An explanation for the greater stability of syn imine anions compared with anti imine anions has been presented by Houk, Fraser and coworkers. ... 

The first examples of alkylations at the more-substituted position of an unsymmetrical ketimine were actually reported by Hosomi et al., who carried out deprotonations with alkyllithium reagents at lower temperatures (Scheme 47). 

Grignard reagents as bases alkyllithium reagents are not generally useful because of competing addition to the carbon-nitrogen double bond. Depending upon the experimental conditions e.g. solvent, temperature and base) and the nature of the N-substituent, deprotonation of the unsymmetrical ketimines (2 =... 

It was recently shown that the addition of metal salts dramatically increased the diastereoselectivity on sulfinyl ketimine enolates, which provides a rapid route to syn- and anri-1,3-amino alcohols (Scheme 3, eq 1). For two other recent examples, a silver nitrate (AgNOsj/LDA combination has been used in the formation of selenium containing heterocycles as potential antitumor agents (Scheme 3, eq 2), while an LDA/HMPA combination was used to fragment aromatic thioacetals to form unsymmetrically substituted thiothionophthalicanhydrides (Scheme 3, eq 3). ... 

Alternative precursors for the synthesis of NHCs are thiourea derivatives of type 14. Kuhn and Kratz first reported a facile method for the synthesis of symmetrically substituted imidazol-2-thiones by the reaction of 3-hydroxy-2-butanone with suitable thiourea derivatives (Scheme 1.8a). Related saturated imidazolin-2-thiones 15 or benzimidazol-2-thiones 16 were obtained by reaction of aliphatic or aromatic 1,2-diamino compounds with thiophosgene (Scheme 1.8b). Unsymmetrically substituted imidazolin-2-thiones 17 were obtained by the reaction of lithium-A-lithiomethyldithiocarbamates with aldimines and ketimines, respectively (Scheme 1.8c). ... 

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