Reduction of ketimines

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.

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. 

Recently, we established that several proton acids catalyze the metal-free reduction of ketimines under hydrogen-transfer conditions with Hantzsch dihydropyridine as the hydrogen source.Additionally, we were able to demonstrate a catalytic enantioselective procedure of this new transformation by employing a chiral Br0nsted acid as catalyst.(see Chapter 4.1). 

Reduction of ketimines.1 Reduction of N-cyclohexylideneaniline (1) with aluminum isopropoxide and isopropyl alcohol (Meerwein-Ponndorf reduction, 1, 35-36) results in N-isopropylaniline as the major product (equation I). However, if... 

A hindered BINAP-phosphoric acid catalyst allows the enantioselective reduction of ketimines via transfer hydrogenation.307 Imines can be generated in situ from either aliphatic or aromatic ketones, with low catalyst loading. 

Scheme 7.18 Asymmetric reduction of ketimines see Table 7.5 for R]-R3, and Figure 7.4 for catalysts.

Only limited success has been reported in the reduction of ketimines due to the low electrophilicity of the imine carbon and the rapid equilibration between the (E)- and (Z)-isomers. However, high enantioselectivity was achieved in catalytic reduction of imines of keto esters (Equation (261))1125 and oximes of acetophenone (Equation (262))1089,1125-1131 cyclic ketones (Equation (263)),1127 and a ketone possessing a boryl group (Equation (264)).1128... 

Development of the First Highly Enantioselective Organocatalytic Reduction of Ketimines... 

From this survey we found that several proton acids catalyze the reduction of ketimines using Hantzsch dihydropyridine 2 as the hydride donor. With regard to the different acids tested diphenyl phosphate... 

In 2005, Rueping et al. reported that chiral phosphoric acids function as an efficient catalyst for the enantioselective reduction of ketimines (Scheme 3.40a 1) [87]. A variety of aryl methyl ketimines were reduced to the corresponding amines in optically active forms using Hantzsch ester as the hydrogenation transfer reagent (HEH) [88]. Subsequently, List and coworkers improved the catalytic efficiency and enantioselectivity by thorough optimization of the substituents (G) that were introduced to the phosphoric acid catalyst (Scheme 3.40a 2) [89]. Almost simulta neously, MacMillan and coworkers successfully developed the enantioselective... 

Table 4.1 Reduction of ketimines 6a and 6b with trichlorosilane (Scheme 4.2), catalyzed by formamides 16 21 (Figure 4.1).

The reduction of ketimines (Scheme 4.2 and Tables 4.3 4.7) was carried out under standard conditions [12], that is, with 2 equiv of CI jSiH (this excess could be considerably lowered for larger scale operations) in toluene (an optimized solvent) at room temperature (15 20 ° C) overnight (a compromise to attain both good reaction rates and enantioselectivities) with Sigamide (35) as catalyst at 5 mol% loading (although 1 mol% was also shown to be equally effective [12c]) under an argon atmosphere. In some cases, acetic acid (<1 equiv) was added to the reaction mixture (see below). 

Table4.11 Reduction of ketimines 6 with trichlorosilane, catalyzed by the valine derived N methyl formamides (S) 23, (S) 48 52 ...

Asymmetric reduction of ketimines to sec-aminesf Of the various hydride reagents found to achieve high enantioselective reduction of ketones, the oxazaborolidine 1 of Itsuno, prepared from BH3 and (S)-(—)-2-amino-3-methyl-I,l-diphenylbutane-l-ol, derived from (S)-valine, (12,31), is the most effective in terms of asymmetric induction. Like Corey s oxazaborolidines derived from (S)-proline, 1 can also be used in catalytic amounts. The highest enantioselectivities obtain in reduction of N-phenylimines of aromatic ketones (as high as 88% ee). The enantioselectivities are lower in the case of N-t-butylimines of aryl ketones (80% ee). Reduction of N-phenylimines of prochiral dialkyl ketones with 1 results in 10-25% ees. 

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]. 

Scheme 3 Proposed catalytic cycle for the reduction of ketimines...

Maikov, Kocovsky, and co-workers have developed different L-valine-based Lewis basic catalysts such as 81 [176, 177], for the efficient asymmetric reduction of ketimines 76 with trichlorosilane 2, or catalyst 82 [178] with a fluorous tag, which allows an easy isolation of the product and can be used in the next cycles, while preserving high enantioselectivity in the process. Sigamide catalyst 83 [179, 180] and Lewis base 84 [181] were employed in a low amount (5 mol%) affording final chiral amines 80 with high enantioselectivity (Scheme 30) [182]. Interestingly, 83 was used for the enantioselective preparation of vicinal a-chloroamines and the subsequent synthesis of chiral 1,2-diaryl aziridines. In these developed approaches the same absolute enantiomer was observed in the processes. 

Figure11.2 OAB-induced asymmetric reduction of ketimine derivatives.

In contrast to the numerous known asymmetric ketone reductions, only limited success has been achieved in the reduction of ketimines. This is due to the low elec-trophilicity of the imine carbon and rapid equilibrium between the E and Z isomers [80]. In addition, most chiral Lewis acids, including OABs, are trapped by the basic nitrogen atoms of imines and/or product amines, leading to a decreased catalytic effect. 

Figure 15.5 Formamides and related catalysts for asymmetric reduction of ketimines.

Figure 15.6 Nitrogen Lewis bases used in the enantioselective reduction of ketimines.

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