Hantzsch ester derivatives reaction

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. 

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... 

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). 

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]. 

The unsubstituted 5,5 -isomer (76) is not readily available by the Hantzsch method. It was first prepared (Scheme 29) by diazotization of a diamino derivative (53HCA354) obtained by a benzidine-like rearrangement (51CB518), and has since been prepared by cross-coupling of the chloro- and trimethylstannyl-thiazoles (87S185). The 4,4 -bis(ethoxycar-bonyl) derivative has been prepared from thiooxalic esters by reaction... 

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. 

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). 

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. 

A wide range of 4-thio-substituted 2-aryl-4H-chromenes is formed when 2-hydroxychalcone derivatives react with various thiols (Scheme 27). Two new C-S and C-O bonds are formed in this catalyst-free domino reaction (13T2430). Chiral phosphoric acids catalyze the photocyclization reduction of 2-hydroxychalcones (13CEJ13658) and the 1,4-reduction of racemic 2,4-diaryl-2H-chromen-2-ols (13CEJ9775), both in the presence of the Hantzsch ester, to provide 2,4-diaryl-4H-chromenes in good yields and with excellent enantioselectivity. 

The asymmetric-transfer hydrogenation of aromatic compounds to enantiopure cyclic nitro compounds with two contiguous stereocentres in benzene is catalysed by H8-BfNOL-derived phosphoric acid with Hantzsch ester as the hydrogen source. The 1,4-// addition intermediate, formed in the initial step of the reaction, was isolated. The product is obtained with 97% yield and 99% ee. ... 

Halogenation, maleic acid derivatives, 60 Hammett equation, 138, 139 Hammett sigma values, 372 Hantzsch ester hyrogen donor, 43 MA reduction, 43 Heat of copolymerization MA-allyl chloride pair, 405 MA-yV-butyl vinyl ether pair, 405 MA-isopropenyl acetate pair, 333 MA-a-methylstyrene pair, 404, 405 MA-styrene pair, 404, 405 MA-vinyl acetate pair, 333, 405 polyester-styrene mixtures, 487 vinyl acetate with maleates and fumarates, 333 Heat of polymerization MA-epoxide reactions, 482 MA monomer, 244... 

The first case in which organocatalysis by halogen bonding was postulated, a report by Bolm et al. in 2008 [124], in fact involves C-X-based halogen-bond donors. As a test reaction, the reduction of quinoline derivatives by a Hantzsch Ester was chosen. Previously, this type of reaction had been reported to proceed enantioselectively with Ir[COD]Cl2/(5)-SegPhos or chiral Brpnsted acids (Scheme 13) [125]. 

At almost the same time, MacMillan and coworkers found that the reductive amination starting from aldehyde, amine, and Hantzsch ester 39 also proceeded smoothly by means of 1 in the presence of 5 A MS to afford benzylic amines 43 with 83-97% ee (Scheme 11.11) [22]. They proved that dialkyl ketones as well as alkyl aryl ketones were suitable substrates even methyl ethyl ketone was reduc-tively aminated with 83% ee. They also reported the asymmetric reduction of pyruvic-acid-derived cyclic imino ester 44. In this reaction, the structure of 44 exhibited a remarkable correlation to MM3 calculations in terms of both hydrogen bond orientation and specific architectural elements that dictate iminium enan-tiofacial discrimination. 

A successful asymmetric organocatalytic based C=0 reduction with the Hantzsch ester was not reported until very recently. Terada and Toda developed a relay catalysis that combined Rh(ll) and a chiral phosphoric acid catalyst in a one-pot reaction (Scheme 32.15). In this reaction sequence, a rhodium carbene (I) forms in the first step and is followed with an intramolecular cyclization to afford carbonyl ylide intermediate II or oxidopyrylium III. These intermediates are protonated by 7 to yield the chiral ion pair between isobenzopyrylium and the conjugate base of 7 (IV). Intermediate IV is further reduced in situ by Hantzsch ester Id to produce the isochroman-4-one derivative 67, which is finally trapped with benzoyl chloride to afford the chiral product 68. Surprisingly, the reaction sequence proceeds well to give racemic product even without the addition of chiral 7, while giving rise to the desired product with high enantioselectivity in the presence of chiral Br0nsted acid 7 [38]. 

BINOL-derived phosphoric acids have proven to be versatQe and powerful catalysts for various organic transformations. Usually, to obtain high enantioselectivities, suitable substituents at the 3,3 -positions of the BINOL backbone are necessary. Since several steps are required to prepare such catalysts, the development of recoverable chiral phosphoric acids would be highly desirable. In 2010 [40] Rueping et al. prepared copolymer catalyst 69, in which 7 is immobilized (Scheme 32.16). The effect of 69 has been tested in the asymmetric reduction of benzoxazine 41 with Hantzsch ester la and was found to be highly efficient even after 12 runs. The recovery of 69 is quite easy and simple filtration is needed since the reaction is heterogeneous. 

Subsequently, the same group disclosed that in the presence of 10mol% of 5b, diketones 39, primary amine 40, and Hantzsch ester 37b could also undergo a cascade aldol-reduction reaction to provide cyclohexylamine derivatives 41 with up to 96% ee (Scheme 2.11) [18]. 

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