Pyridinones synthesis

The only synthesis which corresponds with this description formally, though not mechanistically, resulted in formation of (385) from a side reaction in the attempted esterification of the pyridinone acid (383) with diazoethane, via ring expansion of the putative intermediate (384) (76CPB1870). 

Dipoles can also be built into heterocyclic systems, and though of limited use, they may also be utilized for the synthesis of [5,6] ring-fused systems. Reaction of 2 3H)-benzothiazolethione with (chlorocarbonyl)phenylketene in warm anhydrous benzene gave the heteroaromatic betaine (416). On heating with DMAD in boiling toluene the tricyclic pyridinone (418) was obtained, presumably by elimination of COS from the intermediate cycloadduct (417) (80JOC2474). 

Fig. 39 Microwave-assisted synthesis of pyridinones from resin-bonnd 2(iH)-pyrazinones. Reagents and conditions a dimethyl acetylenedicarboxylate, chlorobenzene, reflux (132 °C), 1-2 days or 1,2-dichlorobenzene, MW 220 °C, 20-40min b bromobenzene, reflux (156 °C), 2h or 1,2-dichlorobenzene, MW 220 °C, 10min R = OC2H4C2H c TFA, reflux (72 °C), 20-24 h or TFA/Ch2Cl2, MW 120 °C, 10-40min. R=OMe or Ph, R = methoxyphenyl. All microwave-assisted reactions were rim in sealed vessels...

Imanishi, T, Yagi, N., Shin, H., Hanaoka, M. (1981) 1.6-Dihydro-3(2H)-Pyridinones as Synthetic Intermediates. A Novel Total Synthesis of ( )-Ibogamine and ( )-Epiibogamine. Tetrahedron Letters, 22, 4001-4004. 

In Scheme 6.230, the multistep synthesis of 2,3-dihydro-4-pyridones is highlighted [411]. The pathway described by Panunzio and coworkers starts from a dioxin-4-one precursor, which is readed with 2 equivalents of benzyl alcohol under solvent-free microwave conditions to furnish the corresponding /1-diketo benzyl esters. Subsequent treatment with 1 equivalent of N,N-dimethylformamide dimethyl acetal (DMFDMA), again under solvent-free conditions, produces an enamine, which is then cyclized with an amine building block (1.1 equivalents) to produce the desired 4-pyridinone produds. All microwave protocols were conducted under open-vessel conditions using power control. 

In conclusion, structures containing polyiodide anions, with cationic aromatic ligands as counter parts of formulae [(L)(HL+)] (I ) are known to be synthesized by the treatment of the appropriate amide with HI [26-28], In contrast, the complexes with PYOH, in the present case, were formed by the direct reaction of 2-hydroxypyridine with di-iodine in a molar ratio of 2 1 and 1 2. This is a redox reaction, where 2-hydroxy-pyridine firstly is oxidized to pyridinone-2 radical cation. In the case of 2-hydroxy-pyridine however, peroxide structures are not formed like disulphides in the case of PYSH. Polyiodide anions are simultaneously produced in this case This should be a consequence of redox differences between -SH and OH groups and may be proven a useful pathway for the synthesis of polyiodide materials. 

The fact that pyromeconic acid and allomaltol were only available with difficulty meant that direct synthesis of certain 3-hydroxy-4-pyridinones was not possible. However the demonstration that some of these compounds were accessible from maltol or ethylmaltol by functionalizing the position adjacent to the ring-oxygen by an aldol condensation and N-oxide intermediates led to the preparation of 2-(l -hydroxyalkyl) and 2-amido derivatives with usefully high affinities for Fe + (70). 

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. 

The construction of an indolizidine skeleton has been successfully obtained by radical cyclizations mediated by (TMS)3SiH. Reaction (7.44) represented a key step in the total synthesis of (—)-slaframine. The two pairs of diastereomers were first separated and then hydrolysed to the corresponding alcohols in a 76% overall yield [55]. On the other hand the cyclization of the A-iodopropyl pyridinones in Reaction (7.45) occurs smoothly at room temperature using Et3B/02 as initiator, to give the desired products with a trifluoromethyl group at the bridgehead position in a syn/anti ratio of 7 3 [56]. 

The preparation of metal complexes from hydroxypyridinones is usually simple and straightforward—the more difficult task is generally the synthesis of the required ligand. There may also be difficulties in separating complex from ligand, especially for the more lipophilic complex S sublimation, used in the case of A -n-hexyl, may be more successful than recrystallization. 3-Hydroxy-4-pyridinones are for the most part accessible from hydroxypyranones. Reagents developed for analytical and separation purposes (preparative methods may be traced back... 

Senda, T. Ogasawara, M. Hayashi, T. Rhodium-Catalyzed Asymmetric 1,4-Addition of Organoboron Reagents to 5,6-Dihydro-2(lH)-pyridinones. Asymmetric Synthesis of 4-Aryl-2-piperidinones. ]. Org. Chem. 2001, 66, 6852-6856. 

Finally, by placing the additional carbonyl in the carboxylic component, a synthesis of pyridinones 131 has been realized [115]. In this case, the nucleophilic carbon is not the one derived from the acid, but the one initially embedded in the starting aldehyde. Moreover, here a vinylogous Knoevenagel is operating, which is clearly favoured over the reaction involving the carbon a to the amide, thanks to the formation of a stable aromatic 6-membered ring. 

An alternative method for the synthesis of amrinone from 3-cyano-5-(4-piridyl)-2(l//)-pyridinone (17.2.2) is based on it s acidic hydrolysis to the corresponding acid, 3-carboxy-5-(4-piridyl)-2(l//)-pyridinone (17.2.5), nitration of which with nitrous acid in the presence of sulfuric acid forms 3-nitro-5-(4-piridyl)-2(l//)-pyridinone (17.2.6). Reducing the nitro group of this product with hydrogen gives the desired amrinone (17.2.4) [19, 20]. 

Acyl-2-phenyloxazole derivatives undergo a reductive photocyclization in the presence of sodium borohydride to generate a bicychc oxazoline with a cis-fused pyridinone ring 307. The stereochemistry of the product is consistent with hydride attack from the less hindered surface of the cyclic intermediate 306. The oxazoline containing pyridinone is a key intermediate used for the synthesis of pseudodisto-mins 308 (Scheme 8.85, p. 415). ° ... 

Another related photocyclodehydrogenation synthesis uses an N- styrylpyridinone (164 Scheme 92), which is generated by N- alkylation of pyridinone with a styryl bromide. Irradiation in acid solution in the presence of oxygen causes isomerization and cyclodehydrogenation to afford 4//-benzo[a]quinolizin-4-one (165) and its 7-phenyl derivative (166) in yields of 37% and 60% respectively (77JOC1122). 

Furo[2,3- ]pyridines can be synthesized from alkynylpyridones and iodonium sources (Scheme 31) <20060L1113>. Iodine proved to be much more effective at promoting the iodocyclization reaction than other iodonium sources (ICl, A -iodosuccinimide (NIS)). The pyridinium triiodide salt, 104, can be converted into the corresponding pyridinone by treatment with an external source of iodide. In a variation of the reaction, a one-pot synthesis of the furopyridine derivatives 105 can be achieved, with overall yields of 79-92%, by treatment with iodine followed by sodium iodide without isolation of the triiodide salt. Another similar one-pot synthesis involves 3-iodo-2-pyridones, terminal alkynes, and organic halides in a series of two palladium cross-coupling reactions (Equation 45) <20030L2441>. This reaction could also be carried out in a two-step sequence, but the overall reaction yields were typically improved for the one-pot method. 

An oxidative coupling reaction of hydroxypyridinones with /5-dicarbonyl compounds leads to the formation of dihydrofuro[3,2- ]pyridinone derivatives (Equation 48) <2005TL5085>. The reaction is carried out as a one-pot synthesis. 

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