Iminium cation, hydrogenation

Norton and coworkers found that catalytic enantioselective hydrogenation of the C=N bond of iminium cations can be accomplished using a series of Ru complexes with chiral diphosphine ligands such as Chiraphos and Norphos [68], Even tetra-alkyl-substituted iminium cations can be hydrogenated by this method. These reactions were carried out with 2 mol.% Ru catalyst and 3.4—3.8 bar H2 at room temperature in CH2C12 solvent (Eq. (39)). 

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. 

Whether these radicals serve as electron donors (to yield iminium cations) or as hydrogen atom donors (to yield vinylamines) will depend on the nature of the reaction partner, particularly on its reduction potential. In any case, the quantum yield of C N cleavage reactions are low, since they require several consecutive processes, i.e. successive transfer of an electron, a proton, and a second electron, or a mechanistic equivalent thereof. 

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... 

CpRu(P-P)H as a Catalyst for Ionic Hydrogenation of Iminium Cations... 

We have reported that the ionic hydrogenation of iminium cations occurs catalytically and with enantioface selectivity when a piano-stool ruthenium hydride complex is used [91] isolated yields range from 60-80% with 2 mol % catalyst. Furthermore, enantiopure bisphosphines give enantioenriched product (eq 51) base workup yields enantioenriched amines (eq 52). 

Crucial to the course of the hydrogenation reaction is the formation of the iminium cation, which competes with the formation of ammonium salts. The hydrogenation of aniline derivatives could be readily accomplished, which copes most probably with the fact that aryl-substituted imines are more basic than aryl-substituted amines. The iminium cations are therefore always accessible in kinetically relevant... 

The enol form of the active hydrogen compound reacts with the iminium cation to form a -aminocarbonyl compound (a Mannich base). 

Fig. 27. Proposed mechanism for the ionic hydrogenation of C=N double bonds of iminium cations.

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. 

The possible reaction mechanism for a cascade olefination-hydrogenation reaction is illustrated in Scheme 1.21. First, the reaction of proline with ciis-isomer 67 generates the iminium cation 68, which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69. A retro-Mannich or base-induced elimination reaction of amine 69 would furnish active olefin 70. The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situ-generated conjugated system or, more precisely, the HOMO-LUMO gap of reactants 65 and 70. 

A different type of photoreaction in ILs has been studied by Jones and co-workers the photoreduction of benzophenones by primary amines. Prior work by Cohen demonstrated that photolysis of benzophe-none in benzene in the presence of sec-butylamine afforded benzopinacol (and an imine). This reaction proceeds through a radical pair formed by hydrogen-atom abstraction by the triplet excited state ben-zophenone from the amine. In the much more polar environment of an IL, the radical pair may instead undergo single electron transfer to form an iminium cation and a hydroxyl-substituted carbanion. Proton transfer from the cation to the anion will yield benzhydrol and an imine. 

The electrophile 4 adds to the aromatic ring to give a cationic intermediate 5. Loss of a proton from 5 and concomitant rearomatization completes the substitution step. Subsequent hydrolysis of the iminium species 2 yields the formylated aromatic product 3. Instead of the highly toxic hydrogen cyanide, zinc cyanide can be used. The hydrogen cyanide is then generated in situ upon reaction with the hydrogen chloride. The zinc chloride, which is thereby formed, then acts as Lewis acid catalyst. 

The reaction was rationalized in terms of electron transfer from the olefin 71-systems to a singlet excited iminium salt moiety, followed by nucleophilic attack of the solvent (CH3OH or water) on the cation diradical and subsequent 1,5-radical coupling. The same protocol was extended to the transformation of N-prenylquino-linium perchlorate (192) and N-prenylpyridinium perchlorates (194) into the corresponding cyclic compounds which, upon hydrogenation, produced benzoin-dolizidines (1 1.6) and perhydroindolizines, respectively (Scheme 8.53) [87]. 

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). 

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