Asymmetric transfer hydrogenation of imines

Much like the direct hydrogenation of imines, the transfer hydrogenation of imines has seen a number of recent attempts to use less toxic solvents and to recycle catalysts, and many of the same methods employed to improve the former reaction have also been applied to the latter. 

There have been multiple efforts toward supported catalysts for asymmetric transfer hydrogenation, and the 4 position on the aryl sulfonate group of 26 has proven a convenient site for functionalization. Thus far, this ligand has been supported on dendrimers [181,182], polystyrenes [183], silica gel [184], mesoporous siliceous foam [185], and mesoporous siliceous foam modified with magnetic particles [186]. The resulting modified ligands have been used in combination with ruthenium, rhodium, and iridium to catalyze the asymmetric transfer of imines and, more commonly, ketones. 

Haraguchi et al. recently supported 26 on three different types of cross linked polystyrenes standard cross linked polystyrene, cross linked polystyrene with 

SOjNa on some aryl groups, and cross linked polystyrene with SO j Bn BU j + 

CH2CI2 solution and was reused for several reductions of B. After three reuses, the catalyst maintained its activity, but the enantiopurity of the products decreased by --10%. The complex did not catalyze the reductions of A, C, or 2 methylquinoxaline, and it was inactive in aqueous solution. On the other hand, the catalysts supported on cross linked polystyrenes with hydrophilic SOjNa or amphiphilic 

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Asymmetric transfer hydrogenation of imines catalyzed by chiral arene-Ru complexes achieves high enantioselectivity (Figure 1.34). Formic acid in aprotic dipolar solvent should be used as a hydride source. The reaction proceeds through the metal-ligand bifunctional mechanism as shown in the carbonyl reduction (Figure 1.24). 

Figure 1.34. Asymmetric transfer hydrogenation of imines catalyzed by chiral Ru complexes.

Anomalous concentration dependence observed in the asymmetric transfer hydrogenation of imines with formic acid, catalysed by chiral rhodium-diamine complexes, has been attributed to the participation of both reactant and product in the formation of formate salt. The probable resting state of the catalyst is a rhodium hydride species.373... 

Phosphoric acid catalysts, bearing bulky groups, have been devised for the asymmetric transfer hydrogenation of imines with Hantsch ester. With the catalyst (14), (g) enantioselectivity up to 93% has been achieved in the reduction of aromatic imines. 

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

Hoffmann S, Seayad AM, List B (2005) A powerful Brpnsted acid catalyst for the organocatalytic asymmetric transfer hydrogenation of imines. Angew Chem Int Ed Engl 44 7424-7427... 

Bianchini, C., Glendenning, L. Ruthenium(ll)-catalyzed asymmetric transfer hydrogenation of ketones using a formic acid-triethylamine mixture. Asymmetric transfer hydrogenation of imines. Chemtracts 1997, 10, 333-338. 

Table 6,10 Asymmetric transfer hydrogenation of imines using HCO2H/NEt3 as the hydrogen source.

Table 6.11 Rhodium catalyzed asymmetric transfer hydrogenation of imines.

Syntheses Using the Asymmetric Transfer Hydrogenation of Imines as a Key Step... 

The past 35 years have seen both the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines develop into useful methods for the synthesis of chiral amines. Particularly, focused research over the past 15 years has led to highly enantioselective examples of both reaction types and has added aza aromatics, activated imines, and iminium cations to their purview. In addition, the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines have both been apphed to total syntheses. Because they are necessarily isomeri... 

Ligands with one R2NH terminus and one ArSO2NR terminus have only recently been used in the asymmetric transfer hydrogenation of imines. See Martins, J.E.D.. Clarkson, G.J.. Wills, M. (2009) Org. Lett. 11, 847. 

Asymmetric Transfer Hydrogenation of Imines. In spite of the great importance of optically active amines for pharmaceutical and agrochemical industries, the ATH of C=N imine bonds has been much less studied than that of ketone bonds (278,280,284,289,340). Cyclic imines are reduced with greater ee values than their acyclic counterparts. The existence of geometrical isomers for the latter is based on the encountered difference in selectivity. 

Asymmetric Transfer Hydrogenation of Imines in Water. The catalytic ATH of imines in aqueous solution has been, so far, much less studied than that of the ketones (289). The tried imines are shown in Figure 89. 

Fig. 11 Asymmetric transfer hydrogenation of imines in aqueous solution...

Ru has been used frequently for obtaining chiral amine units, in asymmetric transfer hydrogenations of imine substrates [40], aldol-type reactions with imine electrophiles [41], and C-H bond arylation (see Chapter 4) [42]. There are very few reports in the literature on the use of ruthenium cattilysts for imine arylation. 

Blackmond, D. G. Ropic, M. Stefinovic, M. Kinetic studies of the asymmetric transfer hydrogenation of imines with formic acid catalyzed by Rh-diamine catalysts. Org. Process Res. Dev. 2006,10,457-463. 

Mao, J. Baker, D. C. A chiral rhodium complex for rapid asymmetric transfer hydrogenation of imines with high enantioselectivity. Org. Lett. 1999,1, 841-843. 

Vdclavik, J. Sot, R Pechiiek, J. Vilhanova, B. Matuska, O. Kuzma, M. Kafier, R Experimental and theoretical perspectives of the Noyori-Ikariya asymmetric transfer hydrogenation of imines. Molecules 2014,19,6987-7007. 

Vdclavik, J. L Kuzma, M. Pfech, J. Kader, P. Asymmetric transfer hydrogenation of imines and ketones using chiral RuIICl(T 6-p-cymene)[(S, S)-N-TsDPEN] as a catalyst A computational study. Organometallics 2011, 30, 4822-4829. 

Haraguchi N, Tsuru K, Arakawa Y, Itsuno S. Asymmetric transfer hydrogenation of imines catalyzed by a polymer-immobilized chiral catalyst. Org. Biomol. Chem. 2009 7 69 75. 

Asymmetric transfer hydrogenation of imines using HC02H/Et3N as a hydrogen donor and catalyzed by suitably designed chiral Ru(II)-complexes was developed by Noyori et al., and since then, it has become the method of choice in enantioselective reduction of cyclic imines. Using this protocol, several asymmetric syntheses of... 

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