Dihydropyridin-2 -ones, synthesis

Besides being useful precursors to pyrroles pyridine-2-ones -4-ones, -4-thiones. and -4-imines 4-alkylidene-dihydropyridines thiophenes 1,2,4-triazoles thiapyrane-2-thiones, isoquinoline-3-ones isoben-zothiophenes and 4-mercaptoimidazolium hydroxide inner salts, mesoionic thiazoles are potentially useful in the construction of molecules with herbicidic (39). central nerve stimulating, and antiinflammatory properties (40,41). Application in dye synthesis has likewise been reported (42). 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

An important extension of this work deals with the preparation of N-substituted l,4-dihydropyridine-3,5-diearboxylates. Tliirty examples have been deseribed (92SC3291). In most eases the reported yields (10-95%) are higher than those mentioned in the literature. Tire most signifieant results eoneern the synthesis of 1-aryl derivatives, whieh are hardly aeeessible by elassie methods. One should mention that the aminoeyelohexadiene 84 has been isolated as a by-produet when starting from ethyl A-benzylaminobut-3-enoate (Seheme 26). 

Another approach to the generation of an iminium cation suitable for cyclization is the protonation of dihydropyridine derivatives. One example can be found in Scheme 48, where treatment of compound 243 with acid induced its cyclization to indoloquinolizine 244, a precursor in the first total synthesis of (i)-tangutorine 245, an alkaloid isolated from a traditional Chinese medicinal plant <2001TL6593>. 

A one-pot synthesis of N-substituted 4-aryl-l,4-dihydropyridines (Scheme 8.34) was recently [52] mentioned at the Fifth International Electronic Conference on Syn-... 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

The Hantzsch reaction that allows the synthesis of pyridine derivatives, is a condensation involving two equivalents of a yS-ketoester or a yS-ketoamide, one equivalent of an aldehyde and ammonia. The Hantzsch reaction was used by Patel et al. for the synthesis of a 300 member dihydropyridine library (Scheme 3.27) [287]. 

As six-membered heterocycles are present in a number of natural products and biologically important molecules, solid-phase synthesis of these has been reported very often (Fig. 3.9). Solid-phase synthesis for nearly every six-membered ring including one nitrogen atom are known piperidines (272) [376], tetrahydropyridines (273) [377, 378], dihydropyridines (274) [219, 379, 380], pyridines (275) [349, 381-386], (Scheme 3.37), piperidinones (276) [387], dihydropyridones (277-279) [313, 378, 388-390], pyridinones (280-281) [328, 329] and piperidindiones (282) [391] derivatives. In contrast, the synthesis of six-membered rings with one single oxygen is rarely described. Nevertheless, solid-phase synthesis of dihydropyrans (283-284) [392-394] and tetrahydropyrans (285) [335, 336] has been reported. 

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). 

Das Sharma S, Hazarika P, Konwar D (2008) A simple, green and one-pot four-component synthesis of 1,4-dihydropyridines and their aromatization. Catal Commun 9 709-714... 

Debache A, Boulcina R, Belfaitah A, Rhouati S, Carboni B (2008) One-pot synthesis of 1,4-dihydropyridines via a phenylboronic acid catalyzed Hantzsch three-component reaction. Synlett 509-512... 

Akbari JD, Tala SD, Dhaduk MF, Joshi HS (2008) Molecular iodine-catalyzed one-pot synthesis of some new Hantzsch 1,4-dihydropyridines at ambient temperature. Arkivoc... 

Sabitha G, Arundhathi K, Sudhakar K, Sastry BS, Yadav JS (2009) CeC13 center dot 7H20-Catalyzed one-pot synthesis of Hantzsch 1,4-dihydropyridines at room temperature. Synth Commun 39 2843-2851... 

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... 

Xia JJ, Wang GW (2005) One-pot synthesis and aromatization of 1,4-dihydropyridines in refluxing water. Synthesis 2379-2383... 

Utilization of acetic acid (90CCC718, 95BML2783) and mixtures of acetic and sulfuric acids (81JHC309), as well as triphenylmethylborofluor-ide (86JPR35), leads to 3-cyano-3,4-dihydropyridin-2-ones, which can be oxidized into the corresponding cyanopyridones by nitrosylsulfuric acid. Authors (81JHC309) have studied the synthesis of 3-cyanopyridones 264 systematically, and have shown that the latter can be obtained by different routes from 2-amino-4H-pyrans 59, as well as from related dihydro- 265 and tetrahydropyridone 266 (Scheme 104). 

Bazureau s group reported extensive work with TSILs for synthesis of various 4-thiazolidinones, 1,4-dihydropyridines, 3,4-dihydropyrimidin-2(lH)-ones and polyhydroquinones. They functionalized imidazole compounds with esters, which were then reacted with reagents to afford the target compound. They report that microwave dielectric heating is a useful aid to rapidly produce the desired product in high yields. 

The great majority of 1,4-dihydropyridines are prepared using classical Hantzsch pyridine synthesis or one of its variants. The first dihydropyridine was in fact isolated back in 1882 as a stable intermediate from that method. In its simplest form, the synthesis involves heating an aldehyde such a orf/io-nitrobenzaldehyde (12-1) with ethyl acetoacetate (12-2) and ammonia. The reaction almost certainly involves, as the first... 

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