Hantzsch dihydropyridines hydrogenation

Recently, we established that several proton acids catalyze the metal-free reduction of ketimines under hydrogen-transfer conditions with Hantzsch dihydropyridine as the hydrogen source.Additionally, we were able to demonstrate a catalytic enantioselective procedure of this new transformation by employing a chiral Br0nsted acid as catalyst.(see Chapter 4.1). 

The Brpnsted acid catalyzed hydrogenation of quinolines with Hantzsch dihydropyridine as reducing agent provides a direct access to a variety of substituted tetrahydroquinolines (Table 4.2). The mild reaction conditions of this metal-free reduction of heteroaromatic compounds, high yields, operational simplicity and practicability, broad scope, functional group tolerance and remarkably low catalyst loading render this environment-friendly process an attractive approach to optically active tetrahydroquinolines and their derivatives (Table 4.3) (see page 176). ... 

Dissymmetric ferrocenyldiphosphines have been synthesized from (R)-(+)-N, N -dimethylaminoethylferrocene. The diphosphines have been used as ligands in asymmetric transfer hydrogenation of acetophenone in the presence of ruthenium catalysts.297 Asymmetric transfer hydrogenation of a,/S-unsaturated aldehydes with Hantzsch dihydropyridines and a catalytic amount of MacMillan imidazolidinone salt (12) leads to the saturated carbonyl compounds in high yields and excellent chemo-and enantio-selectivities.298 ... 

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

Inspired by the recent observation that imines are reduced with Hantzsch esters in the presence of achiral Lewis or Brpnsted acid catalysts (Itoh et al. 2004), we envisioned a catalytic cycle for the reductive amination of ketones which is initiated by protonation of the in situ generated ketimine 10 from a chiral Brdnsted acid catalyst (Scheme 13). The resulting iminium ion pair, which may be stabilized by hydrogen bonding, is chiral and its reaction with the Hantzsch dihydropyridine 11 could give an enantiomerically enriched amine 12 and pyridine 13. 

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. ... 

In 2005 Rueping s group reported the first enantioselective Brpnsted acid-catalyzed reduction of ketoimines [53]. Under hydrogen-transfer conditions with Hantzsch dihydropyridine as the hydrogen source, phosphoric acid 17f as best-performing catalyst was selected, showing that not only steric but also electronic effects of the 3,3 substituents on binaphthol scaffold played a role in this transformation, while a screening of solvents established that nonpolar solvents are essential (Scheme 15.22). 

In 2006 List and Mayer [66] reported that the organic salt of (R) 3,3 -bis(2,4,6-triisopropylphenyl)-l,l -binaphthyl-2,2 -diyl hydrogen phosphate (TRIP) and morpholine was able to promote the transfer hydrogenation via Hantzsch dihydropyridine of a, 3-unsaturated aldehydes with high levels of enantioselectivity, ranging between 96% and >98% ee (Scheme 15.31). 

Mimicking Nature s reducing agent NADH (nicotinamide adenine dinucleotide), the Hantzsch dihydropyridines were found to be very useful transfer hydrogenation agents enabling highly stereoselective reductions of a,p-unsaturated electrophiles in combination with a chiral catalyst. 

The use of iminium-catalysis to facilitate highly asymmetric transfer hydrogenations has already been covered in some detail previously (Sect. 3.2.1) (203-205, 210) and the interested reader is referred to the original literature cited therein. Besides iminium activation in combination with Hantzsch dihydropyridines as hydride donors, the use of chiral phosphoric acids in... 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

Torchy, S., Cordonnier, G., Barbry, D. and Van den Eynde, J.J., Hydrogen transfer from Hantzsch 1,4-dihydropyridines to carbon-carbon double bonds under microwave irradiation, Molecules, 2002, 7, 528-533. 

Zhang D, Wu L-Z, Zhou L, et al. Photocatalytic hydrogen production from Hantzsch 1,4-dihydropyridines by platinum(II) terpyridyl complexes in homogeneous solution. / Am Chem Soc 2004 126 3440-1. 

The first important MCR was developed by Strecker in 1850 (Scheme 1) [20]. In this reaction ammonia, an aldehyde and hydrogen cyanide combine to form a-cyano amines 1, which upon hydrolysis form a-amino acids 2. Also, heterocyclic compounds were obtained using MCRs. An example of this is the Hantzsch reaction, discovered in 1882 [21]. This reaction is a condensation of an aldehyde with two equivalents of a (3-ketoester in the presence of ammonia resulting in the formation of dihydropyridines 3. A comparable reaction is the Biginelli reaction, founded in 1893 ([22] and see for review [23]). This reaction is a 3-component reaction (3CR) between an aldehyde, a (3-ketoester and urea to afford dihydropyrimidines 4. 

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. 

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