2-Pyridones 4-amino

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

The same opinion is held by Hauser and coworkers for the condensation of the ketoaminonitriles 72 with acetophenone in the presence of the polyphosphoric acid66. They assume an initial conversion of precursors 72 into ketoaminoamides 73, which are then condensed with the ketone to give substituted 3-amino-2-pyridones 74 (equation 27). 

Theoretically, three azaquinones (228-230) are possible. Compound 230 was postulated as the oxidation product of 2,5-dihydroxypyridine (1897M613), but that compound was later found to be a dimer (231) (65CB2139). Oxidation of either 3-amino-2-pyridone or 5-amino-2-pyridone, preferably with potassium bromate, gave a product for which an equilibrium between the 6-hydroxy derivative of 228 and the 3-hydroxy derivative of 230 was postulated... 

The regiolsomeric system (II) derived from the readily available 3-amino-2-pyridone is less easy to prepare. Cuillaumet and coworkers reported the synthesis of (II) via a one-step process using diphosgene (Ref. 239). The reaction was carried out in CH2CI2/THF mixture in presence of triethyl amine at-78°C, and the product isolated and purified by flash chromatography [Scheme 187]. 

The tricyclic compound 247 was obtained with an overall yield of 80% by a two-stage synthesis 1) Reaction of anhydride 1 with 3-amino-2-pyridone 2) cyclocondensation of the product formed at the first stage by heating with phosphorus pentoxide [161],... 

Nan and coworkers employed an RCM/oxidation strategy for the synthesis of aromatic 2-pyridones from acrylamides 50. Treating acrylamides 50 with Grubbs second-generation catalyst 3 followed by subsequent oxidation of the dihydropyridone intermediate with 2,3-dichloro-5,6-dicyano-l,4-ben-zoquinone (DDQ) resulted in the synthesis of 3-amino-2-pyridones 51. This methodology was tolerant of a variety of substituents at the 6-position and the resulting pyridones were obtained in moderate to good yields. As shown in Scheme 15, the substituents at the 6-position include aliphatic. 

The cyclization of the condensation product of 3-aminopyridine-l-oxide with diethyl ethoxymethylenemalonate (EMME) yields ethyl 4-hydroxy-1,7-naphthyridine-7-oxide-3-carboxylate (IX-108) the -oxide function need not be present if the o-positions of 3-aminopyridines are blocked. The Skraup reaction with 3-amino-2-pyridone yields l,7-naphthyridin-8-one. Several... 

Alkyl(or aryl)oxazolo[5,4-6-] pyridines (Ml-594) are formed by acylation of 3-amino-2-pyridones followed by distillation from PjOs 6-Bromo-2-phenyloxazolo[5,4-6]pyridine (XH-594 R 6-Br, R = CsH ) is prepared directly from 3-amino-5-bromo-2-pyridone and benzoic anhydride. ... 

The preparation of oxazolo[5,4-i ]pyridin-2(lH)-one 747 from the readily available 3-amino-2-pyridone 746 with triphosgene or CDI at —78 °C has been reported [537]. 

Dimethyl sulphoxide acts as a nucleophile, rather than an oxidant, in the conversion of epoxides into glycols, in the presence of BF3 or tri-nitrobenzenesulphonic add, but the conversion of cyclohexane 1,4-dioxide into pyrocatechol with DMS0-BF8,Et20 implies oxidation. Lead tetra-acetate in DMSO oxidizes JV-amino-pyridones and -phen-anthridones to nitrenes, which can be trapped as sulphoximides R2N-N=S(0)Me2. Diphenylacetylene gives benzil, Ph CO CO Ph, on treatment with JV-bromosuccinimide (more than 2 equiv.) in anhydrous DMSO, while stilbene gives the dibromo-adduct under the same conditions further studies may show this to be a very useful method for preparing 1,2-diketones from acetylenes. 

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

Chemistry, pharmacology, and clinical efficacy of the Chinese nootropic agent huperzine A, alkaloid from Hupenia sermta with annulated 2-pyridone and l-amino-3-methyl-9-ethylidenebicyclo[3.3.l]nona-2,6-diene fragments 99ACR641. 

Syntheses in which a nitrile provides atoms 1 and 2 start from an ylide (82JFC373), or a 1-amino-2-pyridone (82S974) to give compounds 45 and 46. Other two atom fragments used with l-amino-2-pyridones are amides which give compounds such as 47 (86S860). 

Reaction of diphenylcyclopropanone with tutroketene aimnals gives 6-amino-2-pyridones fEq 10 88 ... 

Fluoro-2-pyridone was prepared by a Balz-Schiemann reaction on 4-amino-2-methoxypyridine followed by Me3Sil. BF as counterion gave a better yield than PF 6 (85JHC145). 

Fig. 8 A comparison of the results from microwave and conventional heating for amino-dehalogenation on 2-pyridones...

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

Fig. 9 Examples of Buchwald-Hartwig amination of bromo-pyridines and subsequent hydrogenolysis leading to amino-substituted 2-pyridones...

More general processes rely on variations of the Guareschi-Thorpe reaction [14] where condensations between 1,3-dicarbonyls and cyanoacetamide yield functionalized monocyclic 2(lff)-pyridones (a and b. Scheme 2) [15, 16]. Unless the carbonyls are sufficiently different in reactivity, the reaction suffers from poor regioselectivity. The use of 3-alkoxy or 3-amino enones instead of 1,3-dicarbonyls has proven to be a versatile and reliable synthetic methodology where the 1,4-addition controls the regioselective outcome (c and d. Scheme 2) [17-19]. 

Reaction of 1,3-dicarbonyl compounds with IVJV-dimethylformamide dimethyl acetal followed by malonamide in the presence of sodium hydride gives 5,6-disubstituted 1,2-dihydro-2-oxopyridine-3-carboxamides, whereas reaction of the intermediate enamines with cyanothioacetamide or cyanoacetamide in the presence of piperidine provides 2-thioxopyridine-3-carboxamides and 4,5-disubstituted l,2-dihydro-2-oxopyridine-3-carboxamides, respectively <95S923>. P-Enaminonitriles 14 react with p-ketoesters and alkyl malonates, in the presence of stoichiometric amounts of tin(IV) chloride, to afford 4-aminopyiidines 15 and 4-amino-2-pyridones 16 <95T(51)12277>. 

CioH14N2Os 4-Amino- l- -D-ribofuranosyl-2-pyridone (3-deazacytidine) DAZCYT10 38 490... 

One other, perhaps even more dramatic and common example concerns compounds like 2 and 4 hydroxy- and amino-pyridines. These compounds exhibit tautomeric behaviour and tend to exist in solution as the corresponding pyridone and imine. This reduces the familiar pyridine-like properties of the ring system, accentuating the effects of these substituents (in terms of induced chemical shifts) and at the same time, radically increasing the expected couplings 2 -3 couplings. 

The addition-elimination adducts (143)-(145) are also useful precursors to imidazo[4,5-b]pyridines. Thus, the malonate derived products (143) on treatment with hot ethanolic HC1 [92JCS(P1)2789] or hot ethanolic triethylamine (78H241) gave the imidazo[4,5-b]pyridones (157). The dinitrile derivatives (144) gave the ortho amino nitriles (158) by treatment with hot methanolic sodium hydroxide solution and the nitrile esters (145)... 

Hydroxyl - Exists ca. 99.9% in pyridone-form Compare with carboxylic acid Amino - Exists ca. 0.01% in pyridonimine-form Compare with amide... 

The condensation of 2-amino-6-methylpyridine and EMME was carried out in methyl-phenyl-polysiloxanes at 90-100°C to give high-purity (99%) diethyl A-(6-methyl-2-pyridyl)aminomethylenemalonate in 97% yield (84GEP3308089). 3-Amino-5-(pyridyl)-2-(17/)-pyridones were reacted with dialkyl alkoxymethylenemalonates in boiling ethanol for 6.0-6.5 h to... 

The presence of substituents on the pyridine ring, which reduce the basicity of the annular nitrogen atom, not only shifts the pyridone-hydroxypyridine equilibrium towards the hydroxy form [62], but they also inhibit A-alkylation. Thus, for example, 3,5,6-trichloro-2-hydroxypyridine is alkylated preferentially on the oxygen atom. Predictably, alkylation of 3-hydroxypyridine and of 2-amino-3-hydroxypyridine leads to the 3-alkoxypyridines in high yield under basic conditions [63] (see Chapter 3). 

It has been claimed that cardiotonic activity is retained upon replacement of the pyridone moiety in the amrinone molecule by a 3(2 /)-pyridazinone system (9) [7]. Moreover, the patent literature covers various cardiotonic 6-(pyridyl)-3(2//)-pyridazinones and 4,5-dihydro congeners as exemplified by (10), which have been developed in the United States [8-11], Also 3-amino-... 

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