Ester Hantzsch

The first synthesis of a 1,4-dihydropyridine, which is known as the Hantzsch ester, is attributed to Arthur Hantzsch (1882LA1, 1885CB1744). Since then,... 

The desulphonylation of /J-ketosulphones with the Hantzsch ester is described in Reference 226. 

Dehydrogenation of the Hantzsch ester in a melt with the oxide at 130-140°C proceeded explosively. 

The authors used for the first time aromatic hydrotope solution system such as 50% sodium p-toluene sulfonate aqueous solution (NaPTSA), 40% sodium cumene sulfonate aqueous solution (NaCuS), and 20% sodium p-xy-lene sulfonate (NaXS) aqueous solution to perform Hantzsch ester synthesis. 

Complex hydrides have been used rather frequently for the conjugate reduction of activated dienes92-95. Just and coworkers92 found that the reduction of a,ft-unsaturated ketene 5,5-acetals with lithium triethylborohydride provided mixtures of 1,4- and 1,6-reduction products which were transformed into enals by treatment with mercuric salts (equation 27). Likewise, tetrahydro-3//-naphthalen-2-ones can be reduced with L-Selectride to the 1,6-reduction products93 -95 this reaction has been utilized in the stereoselective synthesis of several terpenes, e.g. of (/ )-(—)-ligularenolide (equation 28)95. Other methods for the conjugate reduction of acceptor-substituted dienes involve the use of methylcopper/diisobutylaluminum hydride96 and of the Hantzsch ester... 

Jprgensen has also developed a one-pot three component coupling of 1,3-dicarbonyl compounds, a,P-unsaturated aldehydes and primary amines to give a series of Hantzsch ester analogues [99],... 

Combination of the Hantzsch ester mediated transfer hydrogenation together with chlorine (116) or fluorine (117) electrophiles allows for the formal addition of HCl or HF aaoss a double bond in a catalytic asymmetric manner (Scheme 48) [178], Within this paper the reactions were further refined by the use of two cycle-specific secondary amines which effectively operated independently within the same reaction mixture. Impressively, this allowed access to either diastereoisomer of the product depending upon the absolute configuration of the catalyst used in the second step of the sequence. 

Cordova has described a reductive Mannich protocol that proceeds with high chemo-, diastereo- and enantioselectivity [179]. Conjugate reduction of p,p-disub-stituted enal 118 with Hantzsch ester 119 in the presence of 30 (10 mol%) and benzoic acid (10 mol%) (63 h, -20 °C) followed by addition of a-iminoglyoxylate 120 and stirring for a further 24 h gave the product (121) with excellent levels of relative and absolute stereocontrol (10 1-50 1 dr 95-99% ee) (Scheme 49). 

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. 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

Detailed mechanistic investigations of transfer hydrogenations with Hantzsch ester by means of DFT computational studies were carried out by the groups of Goodman and Himo [42, 43]. 

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

Simon L, Goodman JM (2008) Theoretical study of the mechanism of Hantzsch ester hydrogenation of imines catalyzed by chiral BINOL-phosphoric acids. J Am Chem Soc 130 8741-8747... 

Franke PT, Johansen RL, Bertelsen S, Jorgensen KA (2008) Organocatalytic enantioselective one-pot synthesis and application of substituted 1,4-dihydropyridines - Hantzsch ester analogues. Chem Asian J 3 216—224... 

Photoinduced electron transfer [22] from reductants such as l-benzyl-l,4-di-hydronicontinamide [27], the Hantzsch-ester [22] (diethyl-2,6-dimethyl-l,4-di-hydropyridine-3,5-dicarboxylate) or 10-methyl-9,10-dihydroacridine [27, 28] to the fullerene and successive proton transfer leads selectively to l,2-dihydro[60]fullerene. These reductions usually proceed under mild conditions. 

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... 

Scheme 6.24 Amines obtained from the transfer hydrogenation of aldimines in the presence of catalyst 9 and Hantzsch ester 19.

Correlations with effective model for the NAD/NADH coenzyme system, and this work provides detailed analysis of H and 13C NMR of such compounds. 

Diethoxycarbonyl-2,6-dimethyl-l,4-dihydro-pyridin (Hantzsch-Ester)... 

Reductive amination of ketones using p-anisidine and the Hantzsch ester for transfer hydrogenation is a low-yielding reaction in toluene at room temperature, but thiourea is an efficient catalyst, and yields of up to 94% are reported at 50 °C.334 A mechanism involving thiourea hydrogen bonding to the intermediate imine is supported by ab initio calculations. 

A mild, acid- and metal-free direct reductive amination of ketones has been achieved that relies on selective imine activation by hydrogen bond formation and utilizes the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea as hydrogen bond donor. The mechanism in Scheme 18, supported by ab initio calculations, has been suggested.358... 

An enantioselective organocatalytic reductive amination has been achieved using Hantzsch ester for hydrogen transfer and compound (21) as catalyst. This mild and operationally simple fragment coupling has been accomplished with a wide range of ketones in combination with aryl and heterocyclic amines.359... 

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

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