Aryl ketimines, reductions

The Br0nsted acid catalyzed enantioselective reduction of several methyl-aryl ketimines affords the corresponding amines in good yields and enantioselectivities (Table 4.1). The mild reaction conditions and generally good chemoselectivity of this transfer hydrogenation render this transformation an attractive and metal-free approach to optically active amines. 

Alkyl aryl ketimines were reduced with up to 99% ee (Scheme 8) [24]. The high enantioselectivity was not affected by the E Z ratio of the imines. For example, a 1.8 1 E Z mixture of the N-propylimine of 4 -methoxy-3-methyIbuty-rophenone was converted to the desired product in 97% optical yield. Hydrosilylation of the N-propylimine of cyclohexyl methyl ketone with a substrate to Ti molar ratio of 2,000 1 was completed to give the product in 98% ee [24]. N-Benzylimine of 2-octanone, a simple aliphatic ketimine, was reduced with 69% optical yield. The reduction of W-benzyl-l-indanimine gave the corresponding amine in 92% ee (Scheme 9) [24]. 

Sun and co-workers developed a novel Lewis basic organocatalyst 86 (Scheme 31), easily synthesized from commercially available L-pipecolinic acid. The catalyst 86 promoted the reduction of IV-aryl ketimines 85 with HSiCl3 2 in high yield and... 

In addition, the asymmetric reduction of A7-aryl ketimines with tri-chlorosilane could be achieved on polymer-supported organocatalysts by Kocovsky et alP Indeed, 7V-methylvaline-derived formamide anchored to a polymeric support, used at a catalyst loading of 15 mol %, allowed good enantioselectivities of up to 82% ee combined with good yields to be obtained for the formed chiral amines (Scheme 8.3). This novel methodology simplified the recovery of the catalyst, which could be reused at least five times without any loss of the activity. The best results were obtained with the catalysts directly attached to the polymer or via a suitable spacer. A strong influence of the solvents on the catalytic performance was observed with chloroform giving the... 

Scheme 8.3 Reductions of 7V-aryl ketimines catalysed by polymer-supported organocatalyst.

To test this possibility, Ba ckvaU studied the reduction of the A -aryl ketimine 19 in which the imine and intramolecular amine trap are linked by a saturated cyclohexane ring. Reduction of 19 by 2 occurred at 80°C to give exclusively 20, in which the newly reduced amine was coordinated to ruthenium (Scheme 17) [25]. Upon warming to 8°C, 20 rearranged to 21. NMR experiments were also carried out where the imine nitrogen part of 19 was marked with At —80°C, only 20 could be observed in the NMR. Backvall concluded that these experiments support the inner-sphere mechanism. 

Scheme 2.9 Brtinsted acid-catalyzed reduction of N-aryl ketimines and 2-substituted quinolines. PMP=p-methoxyphenyl...

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... 

Arylation reactions of aromatic ketimines were developed, and in many cases the products of the reaction were isolated after subsequent hydrolysis. Therefore, these arylations constitute an indirect method for the preparation of arylated aromatic ketones, the direct functionalizations of which are often more difficult. Thus, direct arylation of imine 42 with sodium tetraphenylborate catalyzed by [RhCl(cod)]2 afforded a mixture of mono- and diarylated benzophenone imines (44 and 45) (Scheme 9.16) [53]. The formation of the corresponding amine 46 clearly indicated that 42 also acted as a hydride acceptor in this transformation. Most likely, the reaction occurs via initial coordination by the benzophenone imine to a phenylrho-dium intermediate followed by orfho-rhodation to afford the five-membered rhoda-cyde intermediate 47 (Scheme 9.16). Subsequent reductive elimination generates the monophenylated product 44 and a rhodium hydride, which then reduces imine 42 in the presence of ammonium chloride as proton donor to regenerate the catalytically active speties. 

Johnston demonstrated the applicability of a conceptually novel process for aryl amination using free radical intermediates for the preparation of indoles <010L1009>. In this approach, ketimines derived from o-bromophencthylamines 111 cyclize via a reductive 5-exo radical process to A -substituted indolines 112 when treated with n-BujSnH and a radical initiator. 

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. 

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