Hantzsch Ester as the Hydride Source

Comprehensive Enantioselective Organocatalysis Catalysts, Reactions, and Applications, First Edition. 

In addition to quinolines, pyridines were also found to be suitable substrates for this cascade reduction. Chiral tetrahydropyridines 36 and 37 were synthesized with up to 92% ee by employing (R)-7 as the catalyst [25]. Phenanthroline, which has the same functional group as quinoline and pyridine, was reported by MetalHnos et al. to undergo transfer hydrogenation to the corresponding octahy-drophenanthroline 38 with up to 99% ee, whereas most other substrates provided moderate ee [26]. 

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Selected recent developments in the area of asymmetric organocatalysis in our laboratory have been briefly summarized. Enamine catalysis, Brpnsted acid catalysis, and iminium catalysis turn out to be powerful new strategies for organic synthesis. Using Hantzsch ester as the hydride source, highly enantioselective transfer hydrogenantion reactions have been developed. We have also developed an additional new con-... 

In 2009, Gong s group reported the dynamic kinetic transfer hydrogenation reaction of 2-methyl-2,4-diaryl-2,3-dihydrobenzo[ )][l,4]diazepines, using chiral phosphoric acids as organocatalysts and Hantzsch ester as the hydride source. ° A 3,3 -H8-BINOL-derived phosphoric acid was identified as the optimal chiral catalyst for this process, affording the corresponding 1,3-diamine derivatives with moderate diastereoselectivities of up to 78% de, and enan-tioselectivities of up to 94% ee, as shown in Scheme 2.107. 

Hantzsch Ester as the Hydride Source 945 B NHR2 NHR2... 

In path A, the substrate is protonated on the more electronegative end of the double bond followed by a hydride transfer to the opposite end. An example of this mechanism type is the reduction of double bonds using a Br0nsted acid for protonation and a Hantzsch ester as the hydride source. The addition of a hydride to the more electropositive end of the double bond followed by subsequent protonation of the anion leads to products on path B. In this case, the silane reduction of imines serves as an example for this reaction type, wherein the subsequent protonation usually proceeds during workup. ... 

The MacMillan laboratory has produced an interesting study on the reductive amination of a broad scope of aromatic and aliphatic methyl ketones catalyzed by ent-lk, utilizing Hantzsch ester as a hydride source (Scheme 5.26) [48]. Apphcation of corresponding ethyl ketones gave very low conversions. Computational studies indicated that while catalyst association with methyl ketones exposes the C=N Si face to hydride addition, substrates with larger alkyl groups are forced to adopt conformations where both enantiofaces of the iminium ir... 

Scheme 42.36 Enantioselective domino reductive amination using the Hantzsch ester as stoichiometric hydride source and catalyzed by a silylated phosphoric acid.

This area has undergone very recent development, with List et al. first reporting the possibility of using ammonium salts as catalysts for the reduction of otf-unsaturated aldehyde in 2004 [12]. These authors used a Hantzsch ester 1 (commercially available) as the hydride source, and preliminary screening showed that several ammonium salts were able to catalyze the reduction in an efficient manner. Some typical examples are indicated in Scheme 11.4, where salt 2 serves as the catalyst. 

In this transfer hydrogenation, aromatization of the dihydropyridine (Hantzsch ester) to form a pyridine derivative is essential for it to act as the hydride source. 

Using catalytic amounts of the morphoUne salt of a chiral phosphoric acid such as compound 241 and Hantzsch ester 242 as the hydride source. List et al. were able to achieve highly selective reductions of a broad variety of a,p-unsaturated carbonyl compounds like famesal (243) as demonstrated in the enantioselective synthesis of the bee pheromone (/ )-244 (210) (Scheme 56). Notably, this method was found to be superior when compared to the use of chiral amine-based catalysts with respect to enantioselectivity in several examples employing stericaUy unhindered aliphatic aldehydes (209). 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

As mentioned above, the asymmetric transfer hydrogenation of Hantzsch ester 39 could be applied to a wide variety of substrates, albeit with some limitations. One of the limitations of 39 is its tunability, which is a fatal drawback to broadening the generality of the asymmetric transfer hydrogenation reaction by 1 and 39. In 2009, Zhu and AMyama developed a highly tunable hydride source, benzothia-zoUne 64, and showed that it could be used in the asymmetric transfer hydrogenation of ketimines by combination with chiral phosphoric acid catalyst 1 (Scheme 11.16) [29, 30]. 

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