2-Pyridone Mannich reaction

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

Table 3 Highly substituted 2-pyridones were aminomethylated by utilizing a microwave-assisted Mannich reaction...

Quinolone (122), 2-pyridone (123), kojic acid (124) and 4-hydroxycoumarin (125) couple with diazonium salts (to form azo compounds, e.g. 126) and undergo Mannich reactions (e.g. with HCHO + HNMe2 to form -CH2NMe2 derivatives) at the positions indicated. Chromones undergo the Mannich reaction to give, for example, (127). 

Enantioselective silver-catalyzed aza-Diels-Alder reactions have also been described. Whereas the use of BINAP as the chiral ligand gave only unsatisfactory enantioselectivities,367,367a Hoveyda etal 6 used the peptidic phosphine 373 which has already been used for silver-catalyzed asymmetric Mannich reactions (see Scheme 108) in the efficient Ag(i)-catalyzed cycloaddition of arylimines 449 with Danishefsky s diene (Scheme 135). After acidic work-up, the chiral pyridones 450 were obtained with excellent yields and enantioselectivities. The presence of isopropanol as a proton source is essential for obtaining high conversions and stereoselectivities. Similar to the Mannich reactions, the cycloaddition is not affected by the presence of air or the use of undistilled THF. 

Pyridines, pyridones, and pyrones containing an amino or hydroxy group also undergo diazo coupling, nitrosation, and Mannich reactions, as do their benzenoid analogues, phenol or aniline. Such reactions take place under conditions of relatively low acidity where less of the compound is in the form of an unreactive cation. 

Tomisawa, H., Wang, C. H., and Kato, H., l-Alkyl-2(lH)pyridone derivatives. XXI. Mannich reaction of 2-methyl-l(2H)-thioiso-quinolone, Yakugaku 2asshi, 94, 124, 1974 Chem. Ahstr., 80, 133215, 1974. 

The first systematic investigation toward Lewis acid catalyzed vinylogous Mukaiya ma Mannich reactions was reported by the group of Ojima in 1987 who showed that acyclic vinylketene silyl 0,0 acetals 10 reacted with imines activated by stoichio metric amounts of TiCU to furnish either 5 amino 2 alkenoates 11 or 5,6 dihydro pyridones 12 selectively in excellent yields depending upon the substitution of the silyl dienolate employed (Scheme 5.4) [5]. Although 2 methyl substituted vinylketene acetal 10a gave rise to acyclic 5 amino 2 alkenoates 11 exclusively, 3 methyl substi tuted vinylketene acetal 10b furnished 5,6 dihydropyridones 12 as the sole products. 

The 2-pyridone core structure is present in a wide range of compounds with antibacterial, antifungal, and antitumor activity members of this family also play an important role in Alzheimer s disease. By employing microwave-assisted organic synthesis, efficient conditions have been established for introduction of ami-nomethylene substituents in highly substituted bicyclic 2-pyridones. To incorporate tertiary aminomethylene substituents in the 2-pyridone framework, a microwave-assisted Mannich reaction using preformed imminium salts proved to be effective. Primary amino methylene substituents were introduced via cyanodehalogenation then borane dimethyl sulfide reduction of the afforded nitrile (Scheme 10.36) [78]. Microwave irradiation proved superior to traditional conditions for these transformations. 

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