Imines metal-free reduction

METAL-FREE REDUCTION OF IMINES ENANTIOSELECTIVE BR0NSTED ACID CATALYZED TRANSFER HYDROGENATION USING CHIRAL BINOL-PHOSPHATES AS CATALYSTS... 

The isolation of product is usually possible after evaporation of the solvent and extraction with hexane, ether, or toluene. Supported versions, for example on polystyrene grafted with PPh2 groups, have proved unsatisfactory because the rate of deactivation is greatly enhanced under these conditions [37]. Asymmetric versions exist, but the ee-values tend to be lower than in the Rh series [38]. With acid to neutralize the basic N lone pair, imine reduction is fast. Should it be necessary to remove the catalyst from solutions in order to isolate a strictly metal-free product, a resin containing a thiol group should prove satisfactory. A thiol group in the substrate deactivates the catalyst, however. 

A mild, acid- and metal-free direct reductive amination of ketones has been achieved that relies on selective imine activation by hydrogen bond formation and utilizes the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea as hydrogen bond donor. The mechanism in Scheme 18, supported by ab initio calculations, has been suggested.358... 

Asymmetric variants of imine reduction have also been developed towards enantiopure aziridines. Reduction of chiral /V-tert-butanesulfinyl a-halo imines afforded enantiopure aziridines in good to excellent yields <07JOC3211>. Enantioselective catalytic reduction of a-chloroimines utilizing metal-free L-valine-derived formamide 45 followed by base-mediated ring closure provided aziridines with preserved enantiopurity <07AG(I)3722>. 

Silanes are widely recognized as efficient reagents for reduction of carbonyl and heterocarbonyl functionality. In the case of alkyl and arylsilanes, the reaction requires catalysis by Lewis acids or transition metal complexes 1, 3] however, with more Lewis acidic trichloro or trialkoxysilanes, an altemative metal free activation can be accomplished. Thus, it has been demonstrated that extracoordinate silicon hydrides, formed by the coordination of silanes to Lewis bases, such as tertiary amines 7a], DMF [7b] or MeCN, and so on [7], can serve as mild reagents for the reduction of imines to amines [8]. In the case of trichlorosilane, an inexpensive and relatively easy to handle reducing reagent, and DMF as a Lewis basic promoter, the intermediacy of hexacoordinate species has been confirmed by Si NMR spectro scopy [7b]. 

More recent efforts to effect metal-free hydrogenations have fallen in the realm of organo-catalysts. For example, the hydrogenation of enones, imines, unsaturated a,P-aldehydes, and quinolines have been achieved without a metal, however, in these cases the stoichiometric source of H2 was a Hantzsch ester (Scheme 11.3) [10-14], Such a protocol can be applied to asymmetric reductions, as substituted enones can be reduced with reasonable enantiomer excesses between 73 and 91%. A variety of organocatalyst systems have been reviewed [15, 16]. 

The reactions of simple imine complexes are mainly restricted to hydrogenation or reduction by hydrides or by addition of nucleophiles such as alcohols. For example, complexes of macrocycles (18) undergo catalytic reduction to generate two chiral centres.66 Sodium borohydride has been used to reduce the imine complexes shown in equation (3).67 This technique enables convenient removal of the metal and the consequent synthesis of the reduced free macrocycles. Complexes of the aldimine (20) undergo nucleophilic addition of alcohols.49... 

The metal ion does, however, introduce a new subtlety into these reductions. The reduction of the two imine groups in the nickel(n) complex 4.10 is readily achieved with Na[BH4], The free tetraamine ligand would be expected to exhibit a facile pyramidal inversion at each nitrogen atom, whereas in the nickel(n) complex this inversion is not possible without significant weakening (or breaking) of the Ni-N bonds. In macrocyclic complexes it is very often found that the complex obtained by the reduction of a co-ordinated imine does not possess the same stereochemistry as that obtained by the direct reaction of the free amine with metal ion. 

The synthetic method may be seen to be complementary to direct nucleophilic displacement. Whereas amines often react relatively sluggishly in metal-mediated nucleophilic displacements, they usually undergo facile reaction with carbonyls to form imines. The reduction of the imines (free or co-ordinated) may then be achieved by reduction with Na[BH4] or (less conveniently) by direct hydrogenation. This provides a very convenient method for the preparation of cyclic amines (Fig. 6-14). 

However, when bound to a higher metal oxidation state center, with a limited tt-electron donor ability, the nitriles display v (N C) higher than in the free state and can be activated toward nucleophilic attack, as observed for the reactions of cfr-[ReCLi(NCMe)2] (formed by spontaneous reduction of ReCls in NCMe) with oximes, HON=CRR, amino-alkylated adenines, or alcohols, which behave as protic nucleophiles (reaction 2) to yield, for example, in the flrst case, the imine complexes cA-[ReCl4 NH=C(Me)ON=CRR 2]. 

A transition metal catalyst has also been used to effect the reductive alkylation of amino groups on proteins [41], This reaction uses [Cp Ir(4-4 -dimethoxybipy)(H20)]S04 31 as a mild transfer hydrogenation catalyst and formate ion as the stoichiometric hydride source, in Fig. 10.3-11 (a). Presumably, this reaction occurs via the reversible formation of imine 33 with free amino groups on the protein surface, followed by reduction of iridium hydride 32. For most proteins, multiple modifications are observed (Fig. 10.3-ll(b)), although the overall level of conversion can be altered through variation of either the reaction temperature or the concentrations of the aldehyde and catalyst. In general, the reaction has shown excellent reliability for protein alkylation between pH 5 and 7.4. 

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