Pyridone imines

It is well established that for most aminopyridines and their benzo derivatives the amino form greatly predominates over the pyridone-imine tautomer <76AHC(S1)152, 63AHC(l)404>. 

Of the 4-pyridone series, Jackman et al.280 have reported that 1-methyl-4-pyridone sustains a weaker ring current than l-methyl-2-pyridone, and Batts and Spinner281 in a discussion of chemical shifts state that the fractional aromaticity is probably not appreciable for either (4-pyridone or 4-pyridone imine). ... 

The A// values obtained as described in Scheme 20 demonstrate that 2-pyridone and 2-pyridinethione retain most of the aromatic resonance energy of pyridine, and that 2-pyridone imine is also strongly aromatic, while 2-pyridone methide is much less so. 

In preliminary e q)eriments, model reaction mixtures were investigated. Maltose was reacted with amines such as propylamine or a-N-acetyllysine. To detect aU the previously mentioned mahose products at the same time, an HPLC system can be used with a water-acetonitrile gradient (8). To avoid chromatographic problems with metal conq)lexing substances like pyridone or pyridone imine, common RP-18 columns are to be replaced by Uhracarb material. Applying diode-array-detection, peaks can be identified by their characteristic UV-spectra v diich aUows an unequivocal analysis of the substances. 

Comparison of 2- and 4-aminopyridine, 2-dimethylamino- and 4-di-methylamino-pyridine, and 1-methyl-2- and l-methyl-4-pyridone-imine in ether solution shows the primary amines to exist as such, and not as the imines , and the same is certainly true in alcoholic and aqueous solution Table 5.6), For the aminopyridines the long wavelength of maximum absorption varies with the molecular species in the order Z > Ct > NM, and for a particular species these wavelengths depend on the point of attachment of the substituent to the nucleus in the order 3 > 2 > 4. The benzyl anion forms a suitable model for the discussion of these facts. In it, according to non-bonding molecular orbital theory (p. 43), the charge distributions in the non-bonding molecular orbital n) and in the two lowest unoccupied... 

Silver acetate has also been used as the oxidizing reagent Hydrazine analogues of the pyridone imines have been obtained as... 

This method has been extended to include imines other than A -thia-zolines, hence enabling the synthesis of multi ring-fused 2-pyridones (28,30, and 33, Scheme 8). Thus, by reacting dihydroisoquinoUnes 27 or /1-carboUnes 29 with acyl Meldrum s acid derivatives 24, a set of new ring-fused heterocycles was prepared in moderate to excellent yields (a and b. Scheme 8). These systems were prepared by using trifluoro acetic acid (TFA) as a proton source instead of solutions saturated with HCl (g). The switch of acid proved to be advantageous since it reduced the formation of by-products and increased the isolated yields. From a practical point of view, TFA is also su-... 

Scheme 8 2-Pyridone synthesis from the reaction of acylketenes and imines...

As in the case of Diels-Alder reactions, aqueous aza-Diels-Alder reactions are also catalyzed by various Lewis acids such as lanthanide triflates.113 Lanthanide triflate-catalyzed imino Diels-Alder reactions of imines with dienes or alkenes were developed. Three-component aza-Diels-Alder reactions, starting from aldehyde, aniline, and Danishefsky s diene, took place smoothly under the influence of HBL4 in aqueous media to afford dihydro-4-pyridone derivatives in high yields (Eq. 12.46).114... 

Similar aza-Diels-Alder reactions of Danishefsky s diene with imines or aldehydes and amines in water took place smoothly under neutral conditions in the presence of a catalytic amount of an alkaline salt such as sodium triflate or sodium tetraphenylborate to afford dihydro-4-pyridones in high yields (Eq. 12.49).117 Antibodies have also been found to catalyze hetero-Diels-Alder reactions.118... 

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 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. 

Under the influence of zinc chloride, Danishefsky s diene 4 reacts with simple imines to give dihydro-y-pyridones 100 (e.g. R1 = n-Bu, Ph, Bn R2 = Pr, i-Pr, Ph) in 62-76% yields (equation 58)51. In contrast, the Et2AlCl-catalyzed reaction of the diene 86 with benzylidenemethylamine (101) results in the formation of the dihydro-a-pyridone 102 (equation 59)52. 

The first step in the total synthesis of the alkaloid ( )-ipalbidine 104 was the reaction of the diene 103 with A1-pyrrol ine (equation 60)53. The proportions of threo- and m // TO-dihydro- -pyridones, 106 and 107, respectively, produced in the diethylaluminium chloride-catalyzed reactions of the a-benzyloxyimines 105 (R = n-CsHn, i-Pr or i-Bu) with the diene 86 (equation 61), depend on the nature of R and the amount of imine used54. 

The enantioselective (76-90% ee) formation of the dihydro-y-pyridones 113 from various imines 112 (R = Ph, 3,5-xylyl or 3-pyridyl) and Danishefsky s diene 4 in the presence of 4 A molecular sieves and one equivalent of a catalyst prepared from triphenyl... 

Shortly after this reaction was reported, Hegedus found46 that imines undergo a similar insertion process. The products (251) are structurally very similar to the alkyne adducts (247), and decomplexation with iodine, followed by treatment with trimethylamine TV-oxide, afforded a variety of substituted pyridones in good yield. 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

In a reinvestigation of earlier work by McEwen et al. (150), Laude and coworkers (148,149) showed that the product from the reaction between miinchnone imine 245 and several acrylates affords 2-pyridones (e.g., 248) and not a 3-carboethoxypyrrole as originally claimed. Thus, once again, a 1,3-dipolar... 

Reaction of oxazolones with 1-azadienes, for example, imines prepared from 3-(2-furyl)acrolein or cinnamaldehyde, affords 2-pyridones 316. Several mechanisms have been proposed to explain the formation of 316. However, products like 315 have also been isolated. The authors proposed that 315 arises from alkylation at C-4 of the oxazolone by the 1-azadiene. Subsequent nucleophilic attack by the amino group with ring opening then yields the 2-pyridone (Scheme 7.103). Representative examples of 2-pyridones prepared from 1-azadienes are shown in Table 7.28 (Fig. 7.30). 

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). ... 

There is little or no well-defined chemistry of 2-amino-pyrones, -pyrylium salts, etc., because of the ease with which these systems undergo ANRORC reactions to give substituted pyridones (equation 88). 4-Aminopyrylium salts are reversibly deprotonated to the imines (equation 89). Amino groups in the 3- and 5-positions of pyrones can be diazotized normally. 

Cycloadditions where the 2ir component is an inline or iminium species have been much used for the synthesis of reduced pyridines and pyridones (B-87MI505-01), see also a general review of imine cycloadditions (87H(26)777). 

JCS(Pl)677). Presumably cyclization occurs at the nitrile carbon atom and the pyranone is formed via the imine. However, the product from this route sometimes contains a pyridone. In fact, in the above example, the pyridone is formed exclusively when a low concentration of base is used, but at high molarity only the pyranone is formed. 

The profound influence of base on the course of the reaction led to the postulate that at high methoxide molarity it is the anion of the imine (306) which is in equilibrium with the ester anion (305). The former ionic species is readily hydrolyzed by acid to the pyran-2-one. However, at low molarities the unionized imine (307) is the equilibrating species and this is susceptible to nucleophilic attack at C-6 which occurs with ring opening. Subsequent cyclization gives the pyridone (Scheme 87). 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

Vankar and co-workers709 have shown that Nafion-H can catalyze the hetero Diels-Alder reaction between the Danisefsky diene 164 and aromatic imines to form 2,3-dihydro-y-pyridones (Scheme 5.69). The reaction with aromatic aldehydes, however, yields only the Mukaiyama aldol condensation products. 

Cyclocondensation with imines. The diene (1) undergoes a similar [2 + 4] cycloaddition with imines, even nonactivated imines. Use of a three- or fourfold excess of the diene improves the yield of 5,6-dihydro-y-pyridones (equation l).4... 

OT w-2,6-Diaryl-4-piperidones were produced in a [4+2] cycloaddition reaction using aryl-iV-allylimines and a diene in the presence of Cu(OTf)2 in high yield and de (>99%) (Scheme 87) <2004TL4357>. Reaction of imines with /3,7-unsaturated a-bromoketenes yields dihydro-2-pyridones some of which were reacted with allylamines producing aziridines with 99% de in generally high yield <2004TL5031>. 

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