Hantzsch ester derivatives

Double bonds conjugated with aldehydes or ketones can selectively be reduced with two different catalytic systems. Both systems use Hantzsch ester derivatives (HEH, 1) as hydride donor, analogous to nicotinamide adenine dinucleotide (NADH, 2), nature s reducing agent (Figure 32.1). These esters were first prepared by Hantzsch in 1882 from ethyl acetoacetate, formaldehyde, and ammonia. The... 

List was the first to explore this possibility, examining the Hantzsch ester mediated reduction of a,P-unsaturated aldehydes [209], Using 20 mol% of the binaphthyl derived phosphonate salt of morpholine (153) in dioxane at 50 °C, a series of P-aryl a,P-unsaturated aldehydes underwent transfer hydrogenation with Hantzsch ester 154 with excellent levels of absolute stereocontrol (96-98% ee) (Scheme 63). The method was also applied to the aliphatic substrates ( )-citral and famesal to give the mono-reduced products in 90% and 92% ee, respectively. Significantly, in line with many of the chiral secondary amine catalysed transformations described above the reactions follow a simple and practical procedure without the need for exclusion of moisture and air. 

Kumar A, Maurya RA (2008) Efficient synthesis of Hantzsch esters and polyhydroquinoline derivatives in aqueous micelles. Synlett 883-885... 

In 2005, both Rueping et al. and List et al. reported the first transfer hydrogenation with Hantzsch ester 1 of several N-protected ketimines catalyzed by chiral Bronsted acids derived from l,l -binaphthol [17, 18]. The reaction typically requires 1 to 20 mol% of catalyst, is performed in benzene at 60 °C, and enantio-selectivities of up to 90% are obtained. The chiral Bronsted acid protonates the lcetimine at nitrogen, giving an ion-pair which is reduced by Hantzsch ester 1. (For experimental details see Chapter 14.21.2). A preferred transition state has... 

Chlorotrimethylsilane with zinc in THF reduces 3-oxo-5 a-steroids directly to A2-olefinic derivatives, but most other oxo-groups are unreactive, allowing selective attack on the 3-oxo-group in diones.178 The 5)8-steroidal iminium perchlorate (204), obtained179 by reduction of the A4-unsaturated analogue with the Hantzsch ester (a dihydropyridine), can be reduced further with the same reagent to give the 3/3-pyrrolidinium salt (205) stereospecifically.180... 

A brief discussion of some aspects of alcohol dehydrogenase will be used to illustrate the potential for catalysis. This system is chosen for illustration because it has been studied so extensively. Lessons drawn can be applied in a broader context. The 1,4-dihydropyridine (2a) is the reductant and this affords a nico-tinium ion (1) on transfer of hydride, as illustrated in equation (1). This process is mimicked in many abiotic systems by derivatives of (2 R = alkyl or benzyl), by Hantzsch esters (7), which are synthetically readily accessible, and 1,4-dihydro derivatives (8) of pyridine-3,5-dicarboxylic acid. A typical abiotic reaction is the reduction of the activated carbonyl group of an alkyl phenylglyoxylate (9), activated by a stoichiometric amount of the powerful electrophile Mg(CI04)2, by, for example, (2b equation 8). After acrimonious debate the consensus seems to be that such reactions involve a one-step mechanism (i.e. equation 5), unless the reaction partner strongly demands a radical intermediate, as in the reduction of iron(II) to iron(III). 

In a similar manner, iminium salts derived from a, -unsaturated aldehydes and ketones are reduced by Hantzsch ester (Scheme 79). The ratio between the 1,4- and 1,2-reduction products depends upon the p/(a of the amine component. a-Keto-P,y-unsaturated esters are reduced by NAD(P)H models in the presence of Mg(Cl04)2- At room temperature 1 equiv. of the reducing agent effects 1,4-reduction of the... 

Since CIgSiH is known to be activated by DMF and other Lewis bases to effect hydrosilylation of imines (Scheme 4.2) [8], it is hardly surprising that chiral formamides, derived from natural amino adds, emerged as prime candidates for the development of an asymmetric variant of this reaction [8]. It was assumed that, if successful, this approach could become an attractive altemative to the existing enzymatic methods for amine production [9] and to complement another organo catalytic protocol, based on the biomimetic reduction with Hantzsch ester, which is being developed in parallel [5]. 

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. 

Hydrogenation and reduction of C=N bond. Chiral Bronsted acids possessing a bulky backbone such as VAPOL derivative 9 attract and hold imine molecules in the concave space, and this reasoning has led to successful development of a protocol for the s3mthesis of a-amino acid derivatives from imino precursors by transfer hydrogenation (from Hantzsch ester). ... 

The transfer hydrogenation of 3-substituted quinolines was also studied, with the particularity that the stereogenic center was generated in this case during the conjugate addition step (Scheme 4.60). ° The reaction needed for a more sterically demanding catalyst such as partially hydrogenated derivative 60f and, in addition, the nature of the Hantzsch ester required further optimization in order to achieve the best enantioselectivities, which still remained in values around 80% ee. In this case, the scope of the reaction was limited to the use of quinolines with aromatic or heteroaromatic substituents at the 3-position. 

The asymmetric counteranion directed organocatalysis has been also applied to the enantioselective transfer hydrogenation of a,f)-unsaturated ketones employing catalyst 11, which involves a chiral cation such as a valine ester anunonium salt and a chiral binaphthol derived phosphate [23]. This combination, in the presence of the Hantzsch ester 4, is a very active and enantioselective system for the transfer hydrogenation of a variety of cyclic a,P-unsaturated ketones (Scheme 2.5). Acyclic ketones are also reduced but with slightly lower enantioselectivities. 

Nature makes use of NADH (reduced nicotinamide adenine dinucleotide) as a cofactor for enantioselective biochemical hydrogenations, which are typical hydride-transfer reactions. Dihydropyridines and benzimidazolines derivatives are active hydride donors due to the presence of the nitrogen atom and the ability of the molecule to undergo aromatisation. Organocatalytic enantioselective reductions carried out using hydride donors has been studied, and effective reductions have been achieved with imidazoli-dinone organocatalysts, both with a,p unsaturated aldehydes and ketones. Generally, a stoichiometric quantity of reductant (Hantzsch ester 4) is required for these transformations (Scheme 18.5). 

Dihydrobenzodiazepine derivatives, which are generated from phenylene-diamine and substituted acetophenone, are racemized by the intramolecular retro-Mannich/Mannich process. Combination of this racemization with chiral phosphoric acid-catalysed transfer hydrogenation by Hantzsch ester gave cyclic 1,3-diamine having a quaternary stereogenic centre (Scheme 5.41) [114]. 

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. 

Within a molecule of NAD(P)H, the 1,4-dihydronicotinamide moiety acts as a reducing reagent. Thus, a 1,4-dihydropyridine derivative where the ring nitrogen is substituted by a simple substituent, such as 1-propyl-1,4-dihydronicotinamide (PNAH), 1-benzyl-1, 4-dihydro-nicotinamide (BNAH), or Hantzsch ester (HEH), can be considered as a model compound for NAD(P)H. 

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]. 

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