Pyridone 1-alkyl, arylation

Comins, D.L., and Olhnger, C.G., Inter- and intramolecular Homer-Wadsworth-Emmons reactions of 5-(diethoxyphosphoryl)-l-acyl-2-alkyl(aryl)-2,3-dihydro-4-pyridones, Tetrahedron Lett., 42, 4115, 2001. 

Comins, D. L. Kuethe, J. T. Miller, T. M. Fevrier, F. C. Brooks, C. A. "Diels-Ader Reactions of A/-Acyl-2-alkyl(aryl)-5-vinyl-2,3-dihydro-4-pyridones" J. Org. Chem. 2005, 70, 5221 -5234. For addition work see Comins, D. L. Joseph, S. P. Peters, D. D. "Preparation of 2,6-Disubstituted 2,3-Dihydro-4-pyridones Dehydrogenation ofTrimethylsilyl Enol Ethers with Palladium(ll) Acetate" Tetrahedron Lett. 1995, 36, 9499-9452. 

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). 

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... 

Finally, reaction of 2,4-diphenyl-5(4//)-oxazolone 322 with 4-phenyl-A -tosyl-1-azabuta-1,3-diene was found to be highly dependent on the experimental conditions. At room temperature the sole product was 323 that arises from alkylation of 322 by addition at the imine carbon. However, heating 322 and 4-phenyl-A-tosyl-1-azabuta-1,3-diene gave rise to several products including a 2-pyridone 324, 2,3,6-triphenylpyridine 325, and the pentasubstituted pyrroles 326 and 327. The authors postulated two different reaction mechanisms. Here, both a 1,3-dipolar cycloaddition of the oxazolone and a nucleophilic addition of the oxazolone are possible and that may account for the formation of 324—327. The marked differences in reactivity of 4-phenyl-A-tosyl-l-azabuta-l,3-diene relative to A-alkyl- or A-aryl-1-aza-1,3-dienes was attributed to the powerful electron-withdrawing nature of the tosyl group (Scheme 7.107). ... 

Recently, it has been shown that 2-pyridones with the nitrogen atom substituted by alkyl,262 aryl, or methoxyl265 do undergo Diels-Alder reactions. Heating l-methyl-2-pyridone with DMAD to 195°, the first successful example studied,262 gave 51, which was thought to be formed via 49 as shown. Under milder conditions,265 Diels-Alder adducts (cf. 49) can be isolated and, on further heating, yield phthalic esters and isocyanates. 

Microwave reaction conditions have been reported for the synthesis of 2-pyridones in a modern version of the traditional three-component condensation reaction (Scheme 108) <2004T8633>. A library of 18 3,5,6-trisubstituted pyridines was generated and includes aryl, alkyl, and fused derivatives. 

Nitrogen-based heterocycles can also be prepared through Ni/NHC-catalyzed cyclo addition reactions. For example, Ni/SIPr catalyzed the cycloaddition of diynes with isocyanates under the mildest conditions to date [26]. In particular, excellent yields of pyridones are obtained from diynes and isocyanates at room temperature using only 3 mol % catalyst. As shown in Eq. 8, a variety of diynes were subjected to these optimized conditions. Both aryl and alkyl isocyanates were readily converted to the respective 2-pyridone. Sterically hindered substrates appeared to have very little effect on the reaction, as excellent yields of product were obtained with bulky isocyanates and bulky diynes. 

In an analogous manner, the generation of alkyl radicals in benzene solution by the O-acyl oxime method results in the formation of alkylbenzenes with moderate to good yields for simple acids (equation 55). Use of pyridine as solvent leads to the formation of alkylpyridines as mixtures of ortho, meta and para isomers in which the para isomer predominates. The 0-acyI benzophenone oxime chemistry can also be applied to aryl acids in benzene or pyridine, resulting in the formation of mixed biaryls. A closely related method involves photolysis of mixed anhydrides of arenecarboxylic acids with the hydrox-amic acid A -hydroxy-Z-pyridone in benzene solution (equation 56). 

Like pyridones, oxy-diazines are readily deprotonated under mild conditions, to give ambident anions which can be alkylated conveniently by phase-transfer methods, alkylation usually occurring at nitrogen. " M-Arylations of uracils also proceed in this way with, for example, l-fluoro-4-nitrobenzene."" 3-Pyridazinones alkylate cleanly on N-2 under phase-transfer conditions," but the regiochemistry of uracil alkylation is sometimes difficult to control (see also below). Uracils are sufficiently acidic to take part in Mitsunobu reactions." ... 

A -Methylnicotinamide (7a) is oxidized predominantly at position 6 by rabbit liver aldehyde oxidase [60, 196, 197], As the size of the alkyl substituent increases (7b-7d), oxidation at carbon 4 becomes more favourable, and with the r-butyl analogue (7e) only 4-pyridone is produced (Table 3.7) [60, 197]. The Km for compounds (7a-7e) decreases with increasing size of the alkyl group, pointing to a higher affinity for those compounds with more hydrophobic substituents. However, the larger branched alkyl groups not only sterically hinder oxidation at carbon 6 but also decrease the overall oxidation rate. The major products of aryl or arylalkyl-substituted 3-carbamoylpyridinium chlorides (7f-7n) with rabbit liver aldehyde are also 6-pyridones [51]. 

Other methods for one-step pyridone formation include aza-annulation with either 57 or 86. The reaction of tetralone 83 and ammonia generated an imine that underwent aza-annulation with 57 to give 84, which was used as a key intermediate in the synthesis of derivatives of antitumor and antiviral alkaloid fagaronine (eq. 22).35 Reagent 86 converted 85 to the corresponding pyridone 87 by aza-annulation and subsequent elimination of MeSH (eq. 23).6 Reaction of 86 with other aryl alkyl ketones, such as a-tetralone and 2-acetyl thiophene, only produced yields of 28% and 36%, respectively. 

Diethyl oxalate reacts with 3,4-diaminopyridines having an alkyl or aryl substituent on the 4-amino group to provide 1-substituted 2,3-dioxo compounds. Thus the pyridines 13 yield the compounds 14, and the pyridones 15 give the corresponding trioxo products 16. ... 

On irradiation in dilute solution, A -alkyl- und A -aryl-2-pyridones are converted into Dewar pyridones (2-azabicyclo[2.2.0]hex-5-en-3-ones). For instance, 4,6-dimethyl-l-phenyl-2-pyridone 18 affords product 19 ... 

Cu(OAc)2-oxidized annulations of (di)aryl- and (di)alkyl-substituted alkynes by various electron-rich and electron-deficient acrylamides using [RuCl2(p-cymeme)]2 as the catalyst in the presence of f-AmOH as a solvent result in the formation of 2-pyridones. The catalyst displayed a notable chemo- and regio-selectivity. °... 

The trisodio salts of W-5 6 are also alkylated with a,a)-dibromoalkanes to give the corresponding bis(triketones), which can be converted to the polymethylene-bis-2-(6-aryl-4-pyridones) f W-55 i = 5,6) with ammonia. "... 

Primary and secondary enamines and anils (XII-163) react with carbon suboxide (MI-164) to form 3-unsubstituted-4-hydroxy-2-pyridones (XII-16S), with carbethoxy ethyl ketene (XI-166) to form 3-ethyl-4-hydroxy-2-pyridones (XII-167), and with malonyl chloride (MI-168) or malonic acids and acetic anhydride (XI-169)to give 3-substituted4-hydroxy-2-pyridones (XII-ITO) " (Table XII-1). Anils of cyclic ketones (MI-163, Rj Re = (CH,) where n = 3,4,5,6 Ri = aryl) and substituted malonyl chlorides (R3 = alkyl) give 5,6-polymethylene-4-hydroxy-2-pyridones. A comparison... 

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. ... 

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