2-Pyridones amides

GUARESKY - THORPE Pyridone Synthesis Synthesis of pyndones from beta diketones and activated amides... 

R-methyl-2-pyridone- N-methyl-2-pyridone-3-carboxylic acid 3-carhoxylic acid amide... 

From monoalkylammobutenones and diketene at —5°C in benzene 3-acetyl-4-methyl-2(l//)-pyridones 300 are formed via the intermediate amides 299 (80MI1). 

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). 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

Some heterocyclic amides, in principle similar to those described above, were shown to cyclize in a Michael type reaction to give anellated pyridones in excellent yield 1-1393... 

Fig. 8. N Is XANES spectra of (a) fulvic acid isolated from a glucose-glycine-S-Mn02 system and (b) the lyophilized solid phase (Jokic et al. 2004b). The peaks are assigned to pyridinic (398.6 eV), pyridone (400.7 eV), amide (401.3 eV) and pyrrolic (402.0 eV) moieties.

During their studies with 1,5-diaminoimidazoles (96 R = NHR, R2 = Ph), French workers isolated the amide (118 R = NHPh, R2 = Ph, R3 = COCH2COMe) (5%) after heating a solution of compound (96 R1 = NHPh, R2 = Ph) in xylene with ethyl acetoacetate. The major product of the reaction was an imidazo[4,5-6]pyridone (Section V,B,8,a) (78JHC937). 

Followed by the X-ray studies on cc-pyridonate-blue, various platinum-blues and the related complexes of exocyclic amidate and imidate ligands (see Fig. 3) have been prepared and structurally ana-... 

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

Di-2-pyridyl sulphite (343) (from 2-pyridone and thionyl chloride in the presence of triethylamine) transforms primary aliphatic and aromatic amines RNH2 into N-sulphinylamines RN=S=0 and it dehydrates amides ArCONH2 to aryl cyanides, aldehyde oximes RCH=NOH (R = Cxlf 7. 4-MeOCgH4 or PhCH=CH) to the cyanides RCN and A-alkyl- and TV-ary Iformamides RNHCHO to isocyanides RNC. Aliphatic and aromatic... 

When two carbon atoms of an aromatic six-membered ring are replaced by an amide group (—CONH—) as in 2-pyridone, the aromatic character of the ring is not lost, owing to the importance of... 

Hydroxy- and 4-hydroxy-pyridines are in equilibrium with their tautomeric amide structures containing a carbonyl. These tautomers are called 2-pyridone and 4-pyridone respectively. This type of tautomerism does not occur with the corresponding benzene derivative phenol, since it would destroy the stabilization conferred by aromaticity. 

Like amides, 2- and 4-pyridones are also very weak bases, mnch weaker than amines. Like amides, they actnally protonate on oxygen rather than nitrogen (see Section 4.5.4). This fnrther emphasizes that the nitrogen lone pair is already in nse and not available for protonation. On the other hand, the N-H can readily be deprotonated pyridones are appreciably acidic abont 11). The conjngate base benefits from considerable resonance stabilization, both via... 

We have seen that 2- and 4-hydroxypyridines exist primarily in their tautomeric amide-like pyridone forms (see Section 11.4.3). This preference over the phenolic tautomer was related to these compounds still retaining their aromatic character, with further stabilization from the carbonyl group. 3-Hydroxypyridine cannot benefit from this additional stabilization. In contrast, 2-aminopyridine and 4-aminopyridine exist almost entirely as the amino... 

Attempts to extend this process to the related 2-pyridone system have been less successful, with only a small proportion of C-6 lithiation being observed with l-methyl-2-pyridone [85CC1021 88JCS(P1)1]. In fact, the major mode of reaction involves lithiation of the exocyclic methyl group, to give a carbanionic species that is dipole-stabilized by the heterocyclic amide group (Scheme 120) (83MI1). 

The synthesis of cis-1,4 polymers was also tried by e use of monomers with an s-cis conformation. The solid-state photopolymerization of pyridone derivatives, which is a six-membered cyclic diene amide and is a tautomer of 2-hydroxypyridine, was attempted [100]. Pyridones make hydrogen-bonded cocrystals with a carboxylic acid in the crystalline state. Because the cyclic structure fixes its s-cis conformation, if the polymerization proceeds, a cis-2,5 polymer would be obtained. Actually, however, the photopolymerization did not occur, contrary to our expectation, but [4-1-4] photodimerization proceeded when the carbon-to-carbon distance for the dimerization was small (less than 4 A) [101]. A closer stacking distance of the 2-pyridone moieties might be required for the topochemical polymerization of cychc diene monomers. 

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