Methyl Hantzsch ester

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... 

Cyano-5-(3,4-dimethoxyphenyl)-l-methylpyrazinium iodide (356) gave 6-(3,4-dimethoxyphenyl)-4-methyl-4,5-dihydro-2-pyrazinecarbonitrile (357) [ Hantzsch ester (diethyl 2,6-dimethyl-l,4-dihydro-3,5-pyridinedicar-boxylate) (1 mol), MeCN, 20°C, 3 h 80% or NaBH4, MeCN, 20°C, 30 min 83%], and thence 6-(3,4-dimethoxyphenyl)-4-methyl-l,4,5,6-tetrahydro-2-pyrazinocarbonitrile (357a) (repeat procedures for 24 and 3 h, respectively, both affording 72%).1262... 

In 2005, Rueping et al. reported that chiral phosphoric acids function as an efficient catalyst for the enantioselective reduction of ketimines (Scheme 3.40a 1) [87]. A variety of aryl methyl ketimines were reduced to the corresponding amines in optically active forms using Hantzsch ester as the hydrogenation transfer reagent (HEH) [88]. Subsequently, List and coworkers improved the catalytic efficiency and enantioselectivity by thorough optimization of the substituents (G) that were introduced to the phosphoric acid catalyst (Scheme 3.40a 2) [89]. Almost simulta neously, MacMillan and coworkers successfully developed the enantioselective... 

A soln. of startg. 4-aryl-1,4-dihydropyridine in DMF treated with NaCN at 60°, and stirred for 20 min - 3-methyl 5-(isopropyl) 2-(fluoromethyl)-6-methylpyridine-3,5-dicarboxylate and l-chloro-4-fluoro-2-(trifluoromethyl)benzene (Y 72%). This is the first generally applicable fragmentation-type aromatization of a Hantzsch ester under mild, basic, non-oxidative conditions. F.e.s. T. Mclnally, A.C. Tinker, J. Chem. Soc. Perkin Trans. I 1988, 1837-44. 

Within the context of chiral secondary amine-catalyzed conjugate reduction, the polyethylene glycol grafted polystyrene resin-supported peptide 18 was developed as an effective catalyst for the 1,6-selective transfer hydrogenation of 3-methyl-2,4-dienals with Hantzsch ester, followed by enantioselective 1,4-reduction (Scheme 14) [26]. The combination of the five terminal residues of the catalyst. 

The chiral phosphoric acid (218)-catalysed enantioselective transfer hydrogenation of unprotected disubstituted 2-(imino (phenyl) methyl) phenol using a Hantzsch ester (2, R = BuO as the hydrogen source gave the corresponding chiral Af,0-unprotected amines in high yields with excellent ee. The presence of the ortho-OW group enabled conversion to medicinally relevant compounds. ... 

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. 

In 2007, Ramachary et al. reported an asymmetric Knoevenagel/hydrogenation/Robinson annulation sequence to obtain Wieland-Miescher ketone 189 [88] (Scheme 2.62). The reaction of 5 equiv of aldehyde 9 with the 1,3-dicarbonyl compounds 186 (with CH acid) and Hantzsch ester 187 under proline catalysis furnished the expected cyclo-hexane-1,3-dione B in good yields. Once the solvent was removed by vacuum pump, the crude reaction mixture was diluted with DMF and treated with methyl vinyl ketone 188 in the presence of (S)-proline (1) furnishing the expected... 

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. 

Esters show similar behaviour. Hantzsch found the /-factor for ethyl acetate to be close to 2, and accurate determinations by Leisten also gave values close to 2 for ethyl and methyl benzoate and p-nitrobenzoate. In a solvent containing sufficient water, hydrolysis of the ester occurs. The reaction of methyl benzoate has a time of half-change of a few hours at 25°C in sulphuric acid containing about 0.07 M water, and Leisten actually used the increase in the / -factor, from 2 to 3, to follow the hydrolysis reaction, viz. 

Khadilkar, B.M., Gaikar, V.G. and Chitnavis, A.A., Aqueous hydrotrope solution as a safer medium for microwave enhanced Hantzsch dihydropyridine ester synthesis, Tetrahedron Lett., 1995, 36, 8083-8083 Khadilkar, B.M. and Chitnavis, A.A., Rate enhancement in the synthesis of some 4-aryl- 1,4-dihydropyridines using methyl 3-aminocrotonate, under microwave irradiation, Indian J. Chem., Sect. B, 1995, 34, 652-653. 

As well as being intermediates for the synthesis of pyridines, these dihydropyridines are themselves an important class of heterocycles. For instance, dihydropyridine 5.14 is a drug for lowering blood pressure. In the synthesis of 5.14 note that carrying out the Hantzsch synthesis stepwise allows for the preparation of an unsymmetrical dihydropyridine, having both a methyl and an ethyl ester. 

The acidic character of hexyl is one of its most important features. It was first observed by Aleksandrov [24] when preparing ammonium salt of hexyl. Later this property was investigated by Hantzsch and Opolski [25], who obtained the O-methyl ether of the aci-form of hexyl, according to Hantzsch s nomenclature (la). The aci-form of the compound can yield salts and O-ethers (esters). It is intensely coloured due to the presence of the quinonoid ring. 

Thiazole esters 252a-c were prepared by Hantzsch condensation with a thioamide in good yield except in the case of 252c, bearing a methyl ester (Scheme 101) <2006JA2995>. 

A new strategy for the synthesis of heterocyclic a-amino acids utilizing the Hantzsch dihydropyridine synthesis was developed in the laboratory of A. Dondoni." ° The enantiopure oxazolidinyl keto ester was condensed with benzaldehyde and fert-butyl amino crotonate in the presence of molecular sieves in 2-methyl-2-propanol to give a 85% yield of diastereomeric 1,4-dihydropyridines. The acetonide protecting group was removed and the resulting amino alcohol was oxidized to the target 2-pyridyl a-alanine derivative. 

Carbon-11 labelled calcium channel antagonists C-nifedipine, C-nisoldipine, C-nitrendipine and C-CFj-nifedipine possessing vasodilating and hypotensive properties have been synthesized using a modified Hantzsch-type cyclocondensation proce-dure . Condensation of aldehydes 242, 243 and 244 with 3-aminocrotonic acid esters 245, 246, 247 and with acetoacetic ester 248 produced in one pot after 12 hours reflux in dry ethanol the methyl sulphonylethyl protected dihydropyridines 249-252. Deprotection of the carboxylic acids by alkaline hydrolysis followed by conversion into the dihydropyridine monocarboxylic acids 253-256 gave potassium salts in situ, and subsequent methylation with CH3I produced the corresponding labelled title compounds 257-260 (equation 102),... 

Extending the Hantzsch synthesis and in the course of producing new 4-aryl-l,4-dihydropyridines related to the powerful calcium antagonist Nifedipine (Adalat),16 arylalkylideneacetoacetates, ketones, and malonic esters (18 and 21) have been treated with ketenaminals (19) to give 2-amino-l,4-dihydropyridine-3-carboxylic esters 20 and 2217 (Scheme 7). This reaction was also applied to 4-arylalkylidene-2-methyl-l,3-oxazolinone-5.18... 

Stetinova and co-workers used the Hantzsch synthesis to prepare 1,2,4-trisubstituted pyrroles as part of their ongoing efforts to produce novel pyrrole derivatives with antihypertensive activity. Reaction of aldehyde 274 with methyl acetoacetate 180 and glycine methyl ester hydrochloride 275 in sodium methoxide in methanol gave the corresponding 1,4-dihydropyridine 276 in 43% yield. 

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