2-Pyridones, bicyclic

The gas-phase equilibrium between 2-hydroxypyridine and 2-pyridone favours the hydroxy-form, but in the equilibrium between 2-hydroxypyridine iV-oxide and N-hydroxy-2-pyridone, the major tautomer is the hydroxy-pyridone. Bicyclic adducts between 2-pyridones and dimethyl acetylene-dicarboxylate, unobtainable at atmospheric pressure, have been obtained at 10—15 kbar. A novel route to iV-hydroxy-2-pyridone involves the trimethyl-silylation of 2-pyridone followed by oxidation of the resulting 2-(trimethyl-silyloxy)pyridine with the DMF complex of molybdenum pentoxide. p-Nitro-phenols (45) and nitro-acetamides (46) are formed from the reaction of 3,5-dinitro-2-pyridones (43) with the sodium salts of /3-keto-esters (44) (Scheme 20). ... 

Tlie existence of the ylide 19, which can formally be interpreted as the deprotonation product from the corresponding salt 7a, has been claimed by trapping chlorocarbene with pyridine during the laser-flash photolysis of e do-7-chlorodibenzo[n,c]bicyclo[4.1.0]heptane (18) (96JPC18426). Bromination of l-vinyl-2-pyridone (20) yields the bicyclic pyridinium bro-... 

It was shown in the same article that the decarboxylation could also be performed by conventional heating but then copper cyanide was required and a mixture of saturated and imsaturated 2-pyridones 65 and 66 was obtained in a ratio of 1 10 (Fig. 10). A tentative mechanism was suggested for the reagent-free MAOS method where the carbonyl in the 2-pyridone ring is supposed to assist in the decarboxylation yielding an yUde 67 (Fig. 11). The decarboxylated bicyclic 2-pyridone 68 is thereafter obtained after protonation by the solvent. In agreement with the mechanistic suggestion, it was shown that a selective deuteration occurred when deuterated dimethyl sulfoxide (DMSO-de) was used as solvent. 

Bicyclic 2-pyridones fused over the nitrogen is another important heterocyclic scaffold. In the quest towards the total synthesis of Camptothecin, Danishefsky and co-workers developed a method where a vinylogous urethane was reacted with 1,3-dicarboxymethoxyallene generated in situ from dimethyl 3-chloroglutaconate to a bicyclic 2-pyridone intermediate [31-34]. This method has later been successfully applied in the synthesis of other... 

Scheme 4 Synthesis of bicyclic 2-pyridones fused over the nitrogen...

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

Hoomaert has studied Diels-Alder reactions of pyridine oquinodimethane analogs generated from functionalized o-bis(chloromethyl)pyridines <96T(52)11889>. The photochemical cycloaddition of 2-alkoxy-3-cyano-4,6-dimethylpyridine with methacrylonitrile gives a bicyclic azetine, 6-alkoxy-3,5-dicyano-2,5,8-trimethyl-7-azabicyclo[4.2.0]octa-2,7-diene, in moderate yield <96CC1349>. Regiospecific hydroxylation of 3-(methylaminomethyl)pyridine to 5-(methylaminomethyl)-2-(17/)-pyridone by Arthrobacter ureafaciens has been reported <96MI173>. 

Treatment of pyridones 638a (X = CH) <1997CHE596> and pyrazinones 638b (X = N) <1998JHC655> with - V-alkyl and W-aryl triazolidinediones provides tricyclic derivatives 639 containing the title bicyclic moiety in good yields (Equation 94). 

The same group subsequently described the rapid functionalization of the bicyclic 2-pyridone ring, in particular various aminomethylation pathways (Scheme 6.217)... 

Itoh and co-workers reported the ruthenium(n)-catalyzed [2 + 2 + 2]-cycloaddition of 1,6-diynes with isocyanates to afford the corresponding bicyclic pyridones 163 (Scheme 72).356 357 For previously reported ruthenium-catalyzed [2 + 2 + 2]-cycloaddition of 1,6-diynes see Refs 358 and 358a, and for theoretical calculations of the cyclocotrimer-ization of alkynes with isocyanates, isothiocyanates, and carbon disulfide see Refs 359 and 359a. 

The assumed mechanism proceeds via ruthenacyclopentadiene intermediates of type 160 or structure 161 as possible intermediates. Subsequently, the common bicyclic intermediate 162 is formed through insertion of the C=N double bond into the C-Ru bond, and reductive elimination of the ruthenium fragment gives rise to the desired bicyclic pyridones 163. 

The bicyclic 2-pyridone-containing 3CP (human rhinovirus 3C protease) inhibitor 279 displayed improved inhibition properties and exhibited potent antirhinoviral activity in cell culture when tested against a number of different human rhinovirus (HRV) serotypes <2002BML733>. 

This strategy is a powerful route to bicyclic pyridones and their transformation products. Thus, these workers (40,41) applied this methodology to formal syntheses of the lupinine alkaloids ( )-lupinine and ( )-anagyrine (89) (Scheme 10.14). Imidosulfoxide (82) is converted to the corresponding isomiinchnone that is trapped with methyl acrylate to give 85. Oxidation, ring opening, and triflate formation... 

Enamine exchange with the weakly basic amino group of 4-(aminomethylene)-2-phenyl-5(477)-oxazolone 418 leads to the 4-[(A-cycloalkenyl)aminomethylene]-5(47/)-oxazolones 422, that thermally cyclize to afford [h]-fused bicyclic 4-pyridones 423 (Scheme 7.138). ... 

Bicyclic pyridones have been prepared (Scheme 73) and found to be potent orally bioavailable thrombin inhibitors <2000BML1069>. 

Bicyclic /3-lactams have been produced by photochemical closure of the 3,4-bond on the irradiation of pyridone (155) and related derivatives (72CB2780, 72TL3563). In the case of pyrimid-4-ones (156) in alcoholic solution, the intermediate bicyclic azetine (157) undergoes ring opening (79JOC2083, 80JOC936). 

Mechanistically the ring expansion of the 2-pyridone (278) to the novel 2,2-disubstituted azepin-3-one (281) is reminiscent of the preparation of 3//-azepin-2-ones outlined in Scheme 28. Steric crowding in the carbanion (279) is held to be responsible for cyclization to the bicycle (280) and hence ring expansion (Scheme 39) <80JCS(Pi)285l). 

Heteroaromatic vinyl isocyanates have been used as a source of bicyclic pyridones. In the preparation of the l-methylpyrazolo[4,3-c]pyridone 153 the isocyanate 152b, obtained by Curtius rearrangement of the corresponding acid azide 152a, was heated at 220°C in diphenyl ether to furnish the product in good yield.143,144 Several 2-alkyl derivatives were also prepared.144... 

The photoisomer of 4-methyl-2-pyridone has been used to synthesize functionalized /3-lactams (81CC880). Ozonolysis followed by reduction of (698) yielded a 1 1 mixture of (699) and (700). Monotosylation and cyclization of these products gave rise to an isomeric mixture of bicyclics (701 Scheme 164). 

Methyl-4,6-pyrimidinedione (214) adds DMAD to give the pyridone 216 via the unstable bicyclic adduct (215).340... 

---