Hantzsch ester derivatives reduction

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. 

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]. 

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). ... 

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). 

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 enantioselective reduction of pyrilium cations has been achieved. For example, the calcone (196) is treated with catalytic chiral acid (BINOL-derived phos-phonic acid or triflimide) and subjected to photolysis in the presence of the Hantzsch ester. A mechanism is proposed involving formation of the pyrilium cation (197). The chiral counterion provides an asymmetric environment around the ion (197) and the hydride is delivered stereoselectively from the Hantzsch ester. Reduction of the pyrilium ion gives product (198). 

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]. 

So far, no example of reduction has been reported in the literature using a catalytic system relying on planar chirality. However, ansa-derivatives of Hantzsch esters were developed by Kanomata and Nagata [58] as NADH model compounds (Scheme 8.20). These reagents displayed excellent hydrogen transfer abilities-reduction of carbonyl compounds was achieved with almost perfect enantioselec-tivily. There is no doubt that, coupled with a proper metal-based hydride-transfer system, such NADH models could perform well in a catalytic version. 

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. 

The high performance of 64 compared to Hantzsch ester 39 was demonstrated by Akiyama and coworkers in the asymmetric transfer hydrogenation of trifluor-omethylacetophenone derivatives (Scheme 11.17a) [31]. Benzothiazoline 64c afforded 68 in 89% yield with 96% ee. In contrast, a significant reduction of reactivity and enantioselectivity was observed when 39 was used (4% yield, 45% ee). Enders and coworkers also reported the superiority of benzothiazoline over Hantzsch ester in a symmetric synthesis of tetrahydroisoquinolines via the reductive amination/aza-Michael addition sequence (Scheme 11.17b) [32]. Benzothiazoline 64d had a beneficial effect on both chemical yield and selectivity (98% yield,... 

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]. 

The first enantioselective imine reduction using Hantzsch esters as hydride donor was carried our by Singh and Batra in Using cysteine-derived catalysts, only moderate,... 

As mentioned. List et al. used TRIP derivative 31 in combination with a Hantzsch ester to perform the first asymmetric, oiganocatalytic reductive amination. Acetophenone was stirred for 9 hours at room temperature with anisi-dine in the presence of 4 A molecular sieves to first form the imine. Subsequently, 5 mol% 31 and 1.4 equivalents... 

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