Iminium catalysts transfer hydrogenation

The imidazoline salt 253 was reported recently by Willis et al. to be the catalyst of choice in an iminium-catalyzed transfer hydrogenation (using ester 247 as a hydride donor) of an ( )/(Z)-mixture of the a,(3-unsatuiated aldehyde 254 to furnish the chiral aldehyde 255 in good yield and enantioselectivity (221). With compound... 

The TEAF system can be used to reduce ketones, certain alkenes and imines. With regard to the latter substrate, during our studies it was realized that 5 2 TEAF in some solvents was sufficiently acidic to protonate the imine (p K, ca. 6 in water). Iminium salts are much more reactive than imines due to inductive effects (cf. the Stacker reaction), and it was thus considered likely that an iminium salt was being reduced to an ammonium salt [54]. This explains why imines are not reduced in the IPA system which is neutral, and not acidic. When an iminium salt was pre-prepared by mixing equal amounts of an imine and acid, and used in the IPA system, the iminium was reduced, albeit with lower rate and moderate enantioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Nevertheless, as other kinetic studies have indicated a pre-equilibrium with imine, it is possible that the proton formally sits on the catalyst and the iminium is formed during the catalytic cycle. It is, of course, possible that the mechanism of imine transfer hydrogenation is different to that of ketone reduction, and a metal-coordinated imine may be involved [55]. 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

A new approach to stereoselective transfer hydrogenation of imines was the application of chiral phosphoric acid esters as organocatalysts [50-52]. The mechanism is based on the assumption that the imine is protonated by a chiral Bronsted acid, which acts as the catalyst. The resulting diastereomeric iminium ion pairs, which may be stabilized by hydrogen bonding, react with the Hantzsch dihydropyridine at different rates to give an enantiomerically enriched amine and a pyridine derivative [50-52]. The exact mechanism is still under discussion however computational density functional theory (DFT) studies ]53, 54] suggest a three-point contact model. ... 

On the other hand, the use of chiral anions in conjunction achiral or chiral ammonium ion catalysts has been pioneered by List and co-workers. In 2006, Mayer and List [ 166] hypothesized that catalytic salts of achiral amines and chiral phosphoric acids could induce asymmetry in the transfer hydrogenation of p,p-disubstituted-a,p-unsaturated aldehydes, in a process that would be complementary to the previously developed chiral iminium catalysis (see Section 2.2.1.4) of this process [68,167]. The experimental verification of this hypothesis demonstrated that excellent yields and enantioselectivities (90-98% ee) could be achieved in these hydrogenations. The fact that with an achiral secondary amine such as morpholine the process was highly stereoselective led the authors to postulate that ion-pairing and not Brpnsted acid... 

In addition to the example discussed in section 1.2.3, the complementary character of iminium and enamine mechanisms was also exploited for the transfer hydrogenation of C=N bonds. Reaction of 8-diketones with aromatic amines in the presence of a Hantzsch ester and an acid catalyst yields prevalently tra 5-disubstitued cyclohexylamines [74] (Scheme 2.16). In this transformation, the initially formed enamine undergoes cyclization yielding an a, 3-unsaturated iminium ion which in turn reacts with two molecules of Hantzsch ester to liberate the final product. The acid catalyst is crucial to maintain a high concentration of the iminium ion in the reaction mixture. 

Asymmetric hydride reduction using Hantzsch ester has recently been extensively explored in organocatalysis using iminium-based catalysts or Brpnsted acid catalysts [72a-c], As an advance to their asymmetric conterion-directed catalysis (ACDC), List and coworkers found that the combination of simple primary amino acids such as L-valine with a chiral phosphoric acid led to an effective primary aminocatalyst for asymmetric transfer hydrogenation of a,P-unsaturated ketones (Scheme 5.43) [72d]. The catalysis could be applied to a range of substrates with good yields and excellent enantioselectivity. 

The scope and mechanism of ionic hydrogenation of iminium cations have been investigated for a CpRuH catalyst bearing a chelating diphosphine.64 The mechanism involves three steps hydride transfer (from the catalyst) to form an amine, coordination of H2 to the resulting ruthenium cation, followed by proton transfer from the dicoordinated H2 to the amine. The cationic intermediate [e.g. CpRu(dppm)( 72-H2)+] can be used to hydrogenate enamines provided that the latter are more basic than the product amine. The relative reactivity of C=C and C=N bonds in a, ft -unsaturated iminium cations has also been investigated. 

Wilkinson s catalyst mediates a Cannizzaro-like process with benzaldehyde in ethanol the aldehyde serves as a dihydrogen source to reduce itself, and the benzoic acid formed is esterified by the solvent (eq 8). Pyrrolidine is IV-methylated by methanol in the presence of RhCl(PPh3)3, a reaction that presumably occurs via hydrogen transfer from methanol, condensation of the formaldehyde formed with pyrrolidine, then hydrogen transfer to the iminium intermediate (eq 9). ... 

The rate-limiting and stereo-determining stage in this catalytic cycle is the hydride transfer to the iminium salt. Since the iminium salt in the intermediate C is not bound to the iridium atom, addihonal orientations of the C=N double bond are available. Computational study showed that the enantioselectivity is determined in the competition of transihon states in either of which the NH-hydrogen is positioned nearby the largest substituent (Figure 1.31). The reasons for the different stabilihes of iminium cations and corresponding transition states are far from evident in this case. Hence, computations of similar level are necessary for each particular combination of a catalyst and a substrate. 

The proposed catalytic cycle is shown in Figure 1.34. ° The catalytic cycle starts with intermediate a, obtained from [Pd(OCOCF3)2 (P)-BINAP)] via dissociation of one OCOCF3. The reaction of intermediate a with molecular H2 (possibly solvent-assisted) affords monohydride intermediate b. Substrate (2-methylindole in Figure 1.34) enters the cycle in the proton-ated form (from organic acid presented at stoichiometric amount) of iminium cation a, which forms hydrogen-bonded adduct c. After rate-and enantio-determining hydride transfer, catalyst-product complex d is formed. The cycle restarts after product dissociation into solution. 

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