Enamines transfer hydrogenation

The nicotinamide ring of nicotinamide adenine dinucleotide can exist in both oxidized (NAD+) and reduced (NADH) forms, where the reduced form can be viewed as a double vinylogous amine, i.e. a double enamine. The hydrogen transfer from the C4 atom is widely believed to proceed by a hydride transfer mechanism, reminiscent of the mechanism of carbonyl reduction by metal hydrides. 

An intermediate at the same oxidation level can be produced in a totally different manner via the ready condensation of an rr/i >-nitrobenzaldehyde with nitromethane reduction to an anilino-enamine has been achieved traditionally with metal/acid combinations, and more recently by catalytic transfer hydrogenation. 

By combining regioselective Au(l)-catalyzed enamine synthesis with enantiose-lective transfer hydrogenation, the asymmetric synthesis of tetrahydroquinolines from simple 2-(2-propynyl)aniline derivatives has been achieved (Scheme 15.94). Here, a chiral Bronsted acid is used in combination with the Hantzsch ester to install the chiral center with up to 99% ee [316]. 

In 2006, Hoffmann et al. described an efficient reductive amination of racemic aldehydes via dynamic kinetic resolution (Scheme 2.10). In the presence of 5mol% Brpnsted acid 5b, a-branched aldehydes 36 condensed with amines to form two imine enantiomers XI and X3 with different reaction rates in a transfer hydrogenation reaction, which then underwent a fast racemization via an imine-enamine tautomerization and resulted in enantioenriched P-branched chiral amine products 38 [17]. 

Asymmetric hydrogenation of heteroaromatic compounds provides a straightforward synthetic pathway to access enantioenriched heterocycles, which are of great importance in the synthesis of pharmaceuticals and natural products. Rueping et al. reported several examples of enantioselective cascade transfer hydrogenation reaction of heteroaromatic substrates under metal-free conditions [19,20]. The same group also developed a cascade reaction between enamines 42 and oc,P-unsaturated... 

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. 

The optically active Schiff bases containing intramolecular hydrogen bonds are of major interest because of their use as ligands for complexes employed as catalysts in enantioselective reactions or model compounds in studies of enzymatic reactions. In the studies of intramolecularly hydrogen bonded Schiff bases, the NMR spectroscopy is widely used and allows detection of the presence of proton transfer equilibrium and determination of the mole fraction of tautomers [21]. Literature gives a few names of tautomers in equilibrium. The OH-tautomer has been also known as OH-, enol- or imine-form, while NH tautomer as NH-, keto-, enamine-, or proton-transferred form. More detail information concerning the application of NMR spectroscopy for investigation of proton transfer equilibrium in Schiff bases is presented in reviews.42-44... 

The crude enamine is dissolved in 450 ml. of ether, and the solution is transferred to a 1-1. three-necked flask equipped with a sealed stirrer, a 250-ml. dropping funnel, and a two-necked adapter fitted with a calcium chloride tube and a thermometer immersed in the solution. A solution of 71-76 g. (0.85-0.90 mole) (Note 5) of methyl propiolate (Caution Methyl propiolate is a severe lachrymator and should he handled only in the hood.) in 150 ml. of ether is added dropwise. During the addition the temperature of the mixture is maintained at 25-30° by periodic cooling of the reaction flask in a dry ice-acetone bath. When the addition is almost complete, a white solid begins to separate. The mixture is stirred at 25-30° for an additional hour, cooled to 0°, and filtered to remove the solid. This is dissolved in 700 ml. of 6% hydrochloric acid (Note 6), the acidic solution is warmed at 55-60° for 1 hour, and the mixture is cooled and extracted with two 100-ml. portions of ether. The ether is removed on a steam bath, and the residue of crude methyl 10-oxocyclodec-2-ene-l-carboxylate is dissolved in 300 ml. of methanol and hydrogenated over 5 g. of 5% palladium-on-alumina catalyst at 40 p.s.i. pressure and room temperature. 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

Scheme 6.104 Key intermediates of the proposed catalytic cycle for the 100-catalyzed Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes Formation of imine (A) and F-enamine (B), double hydrogen-bonding activation of the nitroalkene and nucleophilic enamine attack (C), zwitterionic structure (D), product-forming proton transfer, and hydrolysis.

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