Ketimine reduction

To improve upon the selectivity of the ketimine reduction process further, the hydrosilylation of a range of substrates derived from (/ )- -phenylethylamine were examined [37]. Optimization of the reaction conditions allowed obtaining complete diastereoselective reduction of a wide range of acetophenone-derived ketimines as well as a-imino esters, demonstrating the cooperative effect of catalyst and the (/ )-methyl benzyl residue at the imine nitrogen. In this context, we reported also a low cost protocol for a highly stereoselective reduction of ketimines bearing a very cheap and removable chiral auxiliary, promoted by an achiral inexpensive Lewis base, such as DMF [38]. 

The insertion of alkynes into a chromium-carbon double bond is not restricted to Fischer alkenylcarbene complexes. Numerous transformations of this kind have been performed with simple alkylcarbene complexes, from which unstable a,/J-unsaturated carbene complexes were formed in situ, and in turn underwent further reactions in several different ways. For example, reaction of the 1-me-thoxyethylidene complex 6a with the conjugated enyne-ketimines and -ketones 131 afforded pyrrole [92] and furan 134 derivatives [93], respectively. The alkyne-inserted intermediate 132 apparently undergoes 671-electrocyclization and reductive elimination to afford enol ether 133, which yields the cycloaddition product 134 via a subsequent hydrolysis (Scheme 28). This transformation also demonstrates that Fischer carbene complexes are highly selective in their reactivity toward alkynes in the presence of other multiple bonds (Table 6). 

Scheme 31 Auxiliary-induced diastereoselective reduction of a-amino ketimines...

Rather than preforming the a-amino ketimines to be reduced, it is often advantageous to form in situ the more reactive iminium ions from a-aminoketones and primary amines or ammonium salts in the presence of the reducing agent, e.g., sodium cyanoborohydride. Use of this procedure (reductive amination) with the enantiopure a-aminoketone 214 and benzylamine allowed the preparation of the syn diamines 215 with high yields and (almost) complete diastereoselectivities [100] (Scheme 32). Then, the primary diamines 216 were obtained by routine N-debenzylation. Similarly, the diamine 217 was prepared using ammonium acetate. In... 

The first example of an asymmetric reduction of C=N bonds proceeding via DKR was reported in 2005 by Lassaletta et al. In this process, the transfer hydrogenation of 2-substituted bicyclic and monocyclic ketimines could be accomplished via DKR by using a HCO2H/TEA mixture as the hydrogen source and a chiral ruthenium complex including TsDPEN ligand,... 

Scheme 9.25 Ru-catalysed DKR-reductions of cyclic ketimines with TsDPEN ligand.

In 1994, the scope of this p-hydroxy sulfoximine ligand was extended to the borane reduction of ketimine derivatives by these workers. The corresponding chiral amines were formed with enantioselectivities of up to 72% ee, as shown in Scheme 10.57. It was found that the A -substituent of the ketimine had a major influence on the asymmetric induction, with a ketoxime thioether (SPh) being the most successful substrate. 

Scheme 10.57 Borane reductions of ketimine derivatives with P-hydroxy sulfoximine ligand.

As can be seen in the scheme below, insertion reactions of aldehydes to the C-H bond of aromatic ketimines by using a rhenium catalyst provided benzo[c]furans via a mechanism involving consecutive steps of C-H bond activation, insertion of aldehyde, intramolecular nucleophilic cyclization, reductive elimination, and elimination of aniline <06JA12376>. 

A mechanism has been proposed for this, and related transformations, involving a chelation assisted C-H bond functionalization. Following hydride addition to the solvent, acetone, and a transmetallation reaction, reductive elimination yields the ketimine. Hydrolysis of the latter affords the ketone (Equation (131)).114 114a... 

Addition of RMgBr to nitriles. Grignard reagents react with nitriles slowly if at all, but even r-butylmagnesium chloride will add to nitriles in refluxing THF when catalyzed by a copper(I) salt. The adduct can be converted to a ketimine by anhydrous protonation, to a primary amine by reduction (Li/NH,), or to a ketone by hydrolysis. The actual reagent may be a cuprate such as R3Cu(MgX)2. 

More recently, an important chiral titanium catalyst for the asymmetric reduction with hydrogen of /V-substi luted dialkyl ketimines to enantioenriched amines has been... 

Coordination of the aluminum atom of the reducing complex was proposed to take place both to the oxygen atom of the hydroxy group and to the nitrogen atom of the amino group. The asymmetric reduction of enamine perchlorates and ketimines with menthol and bomeol chiral auxiliary reagents (50,51) presumably involves coordination of aluminum to the nitrogen atom of the substrate. 

For the reduction of ketimines with trichlorosylane via a possible hydrogen-bonding activation, see Maikov, A. V. Mariani, A. MacDougall, K. N. Kocovsky, P. Org. Lett. 2004, 6, 2253-2256. 

Ketimines are reduced to amines very easily by catalytic hydrogenation, by complex hydrides and by formic acid. They are intermediates in reductive amination of ketones (p. 134). An example of the reduction of a ketimine is conversion of 3-aminocarbonyl-2,3-diphenylazirine to the corresponding aziridine by sodium borohydride (yield 73%), by potassium borohydride (yield 71%) and by sodium bis (2-methoxyethoxy) aluminum hydride (yield 71%) [939]. 

Hydrazones treated with alkalis decompose to nitrogen and hydrocarbons [845, 923] Woljf-Kizhner reduction) (p. 34), and p-toluenesulfonylhydra-zones are reduced to hydrocarbons by lithium aluminum hydride [812], sodium borohydride [785] or sodium cyanoborohydride [813]. Titanium trichloride hy-drogenolyzes the nitrogen-nitrogen bond in phenylhydrazones and forms amines and ketimines which are hydrolyzed to the parent ketones. Thus 2,4-dinitrophenylhydrazone of cycloheptanone afforded cycloheptanone in 90% yield [202]. 

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