Hantzsch-type esters

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),... 

The reaction mixture was irradiated in a domestic MW oven for 5 min on a surface of bentonite clay. Not only traditional j8-keto esters, but also, for example, cyclic 1,3-diketones can participate in this MCR, thus enabling a four-component Hantzsch-type synthesis of unsymmetrically substituted 1,4-pyridines 20 (Scheme 17.15) [29, 37]. 

When some dihydropyridines were prepared by the Hantzsch one-pot synthesis from alkyl 3-aminocrotonates (85CPB3787), the same type of products were formed by Michael addition of esters of amidinoacetic acid to aralkylidene-/3-ketoesters (81AF1173). 

Correlations with Hantzsch esters) (70) (77BSB267). This latter type of compound is of interest as an effective model for the NAD/NADH coenzyme system, and this work provides detailed analysis of H and 13C NMR of such compounds. 

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... 

The most commonly used method for the preparation of fused thiazoles involves the reaction of a-mercapto N-heterocyclic compounds of type (138) with an a-halocarbonyl compound or ester to give S-alkylated intermediates (139) which can be dehydrated to (140). When R2 is alkoxy, thiazolones (141) are formed (Hantzsch synthesis). Strong dehydrating agents are necessary to cyclize aldehydes and ketones (139) to fused thiazoles. The method has been used to prepare (dihydro) imidazo[2,l-6]thiazoIes and thiazolo[3,2- ]-s-triazoles (80JHC1321, 78JHC401, 82IJC(B)243). 

Biomimetic-type reduction of preformed eniminium salts with the Hantzsch ester or 1-benzyl-1,4-dihydronicotinamide results in stereospecific formation of cis ring fused ketones23 (Scheme 14). 

Hantzsch has adduced as further evidence for the existence of these aci- and pseudo-compounds the fact that he has prepared esters of both types of substances, the aci-ester being yellow and the other being colorless. 

Nifedipine 218 and other related 1,4-dihydropyridines are important as antihypertensive agents (Ca antagonists). They are prepared by a classical Hantzsch synthesis from acetoacetic ester, arylaldehyde and NH3 [72]. Sulfapyridine 219 was one of the first sulfonamide antibacterial agents to be used. Cerivastatin (Lipobay) 220, a powerful HMG-CoA reductase inhibitor, is applied for treatment of primary hypercholesteremia types Ila and b. 

Our own approach to the combination of crown ether and dihydropyridine chemistry has involved constructing the dihydropyridine as an integral portion of the macrocyclic crown ether ring (see 24b, for example). The first synthetic approach involved ring-closure of an alicyclic precursor by means of the Hantzsch 1,4-dihydropyridine synthesis as illustrated for the preparation of (50, eq. 24). Such Hantzsch esters (general type 46) are attractive in that the acid functionalities at the 3,5-positions can be used as handles for attaching the (dihydro)pyridine... 

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. 

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]. 

Further adaptation of the Hantzsch dihydropyridine synthesis has opened up synthetic routes to annelated 1,4-dihydropyridines, e.g. (25), in which the nitrogen is at a bridgehead position, " and to 2-amino-l,4-dihydropyridine-3,5-dicarboxylates of type (26)/ The former are prepared by Michael addition of /3-amino-acrylates (27) to alkylideneacetoacetic esters R CH=C(C02Me)C0CH3, whereas the latter involve a similar reaction of the acetoacetate with an amidinoacetic ester (NH2)2C=CHC02R. ... 

In path A, the substrate is protonated on the more electronegative end of the double bond followed by a hydride transfer to the opposite end. An example of this mechanism type is the reduction of double bonds using a Br0nsted acid for protonation and a Hantzsch ester as the hydride source. The addition of a hydride to the more electropositive end of the double bond followed by subsequent protonation of the anion leads to products on path B. In this case, the silane reduction of imines serves as an example for this reaction type, wherein the subsequent protonation usually proceeds during workup. ... 

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