Hantzsch hydride source

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... 

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. 

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 2005, the groups of List and McMillan simultaneously described excellent results in the asymmetric reduction of a,/ -unsaturated aldehydes with a prochiral center in the ft position [14, 15]. (For experimental details see Chapters 14.22.1 and 14.22.2). In both cases the catalyst used was a chiral imidazolidinone (6 or 8), and some representative examples are listed in Tables 11.1 and 11.2. The reactions were run at 10-20 mol% of catalyst, at moderate temperature (13 °C or 4 °C) over several hours. The hydride source (Hantzsch ester) was utilized in stoichiometric quantities, and the chemical yields and enantiomeric excesses proved to be... 

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

Later on, the Rueping group reported an organocatalytic enantioselective reduction of pyridine 180 (Scheme 17.30) [74], according to the procedure described by Bohlmann and Rahtz [75]. The key step in the synthesis of decahydroquinolines from the pumiliotoxin family involved Hantzsch dUiydropyridine 172 as the hydride source and involved BINOL-phosphoric acid 181 as a chiral Br0nsted acid catalyst... 

The iminium-catalyzed reduction of ot,p-unsaturated carbonyl compotmds using Hantzsch dihydropyridines as the hydride source was reported independently by the List and MacMillan groups at the end of 2004 and the beginning of 2005 203-205). 

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). 

Reductive amination of a-branched ketones and p-anisidine using Hantzsch ester as a hydride source and chiral Bronsted acid, TRIP, as a catalyst gave chiral p-branched amine (Scheme 5.17) [58]. This catalyst system was extended to three-component Kabachnik-Eields reaction, which uses phosphite as nucleophile instead of hydride, to give p-branched a-amino phosphonate [59]. Reductive ami-nation of p-keto ester or p-keto nitrile with trichlorosilane as a hydride source... 

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. 

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]. 

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

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

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. ... 

A major drawback should be noted. No organocatalyst has been known to activate dihydrogen until now, solely transition metals and metalloids have been suitable catalysts. All organocatalytic reductions rely on organic hydride sources like silanes and Hantzsch esters. The fact that metalloid boron species (which are much more closely related to organocatalysts) are known to activate dihydrogen makes it very likely that in a few years, the first all-organic catalysts will be used. 

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