2-Pyridone, catalysis

A direct substitution mechanism was indicated for the 2-pyridone catalysis of aminolysis of methyl acetate by methylamine." This mechanism is represented in Figure 7.9. It avoids a tetrahedral intermediate and describes a concerted displacement process that is facilitated by proton transfer involving 2-pyridone. Two very closely related TSs involving either the 2-hydroxypyridine or 2-pyridone tautomers were found. These TSs show extensive cleavage of the C-0 bond (2.0-2.2 A) and formation... 

In this solvent the reaction is catalyzed by small amounts of trimethyl-amine and especially pyridine (cf. 9). The same effect occurs in the reaction of iV -methylaniline with 2-iV -methylanilino-4,6-dichloro-s-triazine. In benzene solution, the amine hydrochloride is so insoluble that the reaction could be followed by recovery. of the salt. However, this precluded study mider Bitter and Zollinger s conditions of catalysis by strong mineral acids in the sense of Banks (acid-base pre-equilibrium in solution). Instead, a new catalytic effect was revealed when the influence of organic acids was tested. This was assumed to depend on the bifunctional character of these catalysts, which act as both a proton donor and an acceptor in the transition state. In striking agreement with this conclusion, a-pyridone is very reactive and o-nitrophenol is not. Furthermore, since neither y-pyridone nor -nitrophenol are active, the structure of the catalyst must meet the conformational requirements for a cyclic transition state. Probably a concerted process involving structure 10 in the rate-determining step... 

The azinones and their reaction characteristics are discussed in some detail in Section II, E. Because of their dual electrophilic-nucleophilic nature, the azinones may be bifunctional catalysts in their own formation (cf. discussion of autocatalysis below) or act as catalysts for the desired reaction from which they arise as byproducts. The uniquely effective catalysis of nucleophilic substitution of azines has been noted for 2-pyridone. 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

Three salicylate (2-hydroxybenzoate) anions, which have unusual reactivity towards bromine that has been attributed to intramolecular proton transfer assisting electrophilic attack (Tee and Iyengar, 1985, 1990), exhibit modest catalysis (k /k2u = 3 to 10) and have KTS values similar to phenols. Pyridones and their /V-methyl derivatives, three heteroaromatic acid anions, and four phenoxy derivatives show comparable catalysis (k //c2u = 1.7 to 9.5) and Krs values (Table A4.4). 

The action of the valine derivatives 87 on the diene 86 under EtAlCU catalysis resulted in a mixture of cycloadducts 88, which on hydrolysis with aqueous methanolic sodium carbonate furnished a mixture of the dihydro-2-pyridones 89 and 90 and the esters 91 and 92. In the case of imines derived from aliphatic aldehydes, e.g. 87 (R = Pr), all four types of product were isolated, whereas imines from aromatic aldehydes, 87 (R = Ph, 3-CIC6H4 etc.), gave only the esters 91 and 92 (equation 55). All products were formed in yields of 64-84% and in high de49. 

Scheme 2.5 Self-assembly through hydrogen bonding of the 2-pyridone/2-hydroxypyridine system 1 (6-DPPon) to generate bidentate ligand metal complexes 3 for homogeneous catalysis.

In the course of the reaction, Michael adduct 43 cyclizes initially under base catalysis to the dihydropyridone 45, which forms dianion 46. Electron transfer (an SET process leads to radical anion 47, which is finally transformed into pyridone 44 through an aromati/ation that includes hydrogen transfer and another SET process. 

Related co-cyclotrimerizations of two alkyne molecules with limited isocyanates have also been achieved using cobalt and nickel catalysts. With respect to intramolecular versions, two examples of the cobalt(I)-catalyzed cycloaddition of a,m-diynes with isocyanates have been reported to afford bicyclic pyri-dones only in low yields, although 2,3-dihydro-5(lff)-indolizinones were successfully obtained from isocyanatoalkynes and several silylalkynes with the same cobalt catalysis [19]. On the other hand, the ruthenium catalysis using Cp RuCl(cod) as a precatalyst effectively catalyzed the cycloaddition of 1,6-diynes 21 with 4 equiv. of isocyanates in refluxing 1,2-dichloroethane to afford bicyclic pyridones 25 in 58-93% yield (Eq. 12) [20]. In this case,both aryl and aliphatic isocyanates can be widely employed. 

Palladium catalysis can also be used for the introduction of nitrogen substituents, e.g., Scheme 161 <2004TL769>. 3-Bromothiophene can be coupled with 2-pyridone to form the A-(3-thienyl) derivative using a catalyst consisting of Cul in the presence of N,A-dimethylcyclohexane-1,2-diamine and KOAc or K2C03 <2005T2931>. 

Figure 1.20 Possible transition states in the catalysis of tetramethyl glucose muta-rotation by 2-pyridone, and calculated transition state for formic acid catalysis of 2-hydroxytetrahydropyran ring opening. In the calculated transition state, the proton is largely transferred to the endocyclic oxygen, the endocyclic C-O bond has started to break, but the hydroxyl proton is not transferred to the catalyst, i.e. the reaction is concerted but not synchronous.

As a variation on the theme, instead of a zinc(II)-salophen unit, receptor 9 features a 2-pyridone unit, that is a known bifunctional catalyst for the rate limiting breakdown of the tetrahedral intermediate involved in the aminolysis of active esters in aprotic solvents. Turnover catalysis was indeed observed when the reaction between propylamine and PNPCC (Equation 8.5) was carried out in CH2CI2/CH3CN 99 1 in the presence of receptor 9. It was estimated that the reaction inside 9 is ca. 6000 times faster than the reaction in the bulk solvent. 

Small hydrogen isotope effects have been found in a nucleophilic substitution of an aromatic heterocycle, the reaction of cyanuric chloride with aniline-N,N-d2 in benzene solution (Zollinger, 1961a). As the effects are small (5%), it is difficult to draw definite mechanistic conclusions. The reactions of cyanuric chloride and other halogenated triazine derivatives are subject to bifunctional catalysis (e.g. by carboxylic acids and by a -pyridone) and to catalysis by monofunctional bases like pyridine (Bitter and Zollinger, 1961). Reinheimer et al. (1962) measured the solvent isotope effect in the hydrolysis of 2-chloro-5-nitro-pyridine (A h,o/ d.o = 2 36). The result makes it probable, but... 

Similar catalysis could be achieved with several other N-hydroxy compounds, for instance with l-hydroxy-2-pyridone. 

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