Dihydro-a-pyridones

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 A -pyrrol ine (equation 60)" . The proportions of threo- and ezyt/zro-dihydro-a-pyridones, 106 and 107, respectively, produced in the diethylaluminium chloride-catalyzed reactions of the a-benzyloxyimines 105 (R = n-CsHn, /-Pr or /-Bu) with the diene 86 (equation 61), depend on the nature of R and the amount of imine... 

The oxidation of silyl enol ethers 111 with palladium(n) acetate is a convenient nnethod for the preparation of synthetically useful 2,6-disubstituted 2,3-dihydro-4-pyridones 112 <95TL(36)9449>. 

The montmorillonite KlO-catalyzed aza-Diels-Alder reaction of Danishefsky s diene with aldimines, generated in situ from aliphatic aldehydes and p-anisidine, proceeded smoothly in H20 or in aqueous CH3CN to afford 2-substituted 2,3-dihydro-4-pyridones in excellent yields (Eq. 12.47).115 Also, complex [(PPh3)Ag(CBiiH6Br6)] was shown to be an effective and selective catalyst (0.1 mol% loading) for a hetero-Diels-Alder reaction with Danishefsky s diene and the reaction showed a striking dependence on the presence of trace amounts of... 

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... 

In Scheme 6.230, the multistep synthesis of 2,3-dihydro-4-pyridones is highlighted [411]. The pathway described by Panunzio and coworkers starts from a dioxin-4-one precursor, which is readed with 2 equivalents of benzyl alcohol under solvent-free microwave conditions to furnish the corresponding /1-diketo benzyl esters. Subsequent treatment with 1 equivalent of N,N-dimethylformamide dimethyl acetal (DMFDMA), again under solvent-free conditions, produces an enamine, which is then cyclized with an amine building block (1.1 equivalents) to produce the desired 4-pyridinone produds. All microwave protocols were conducted under open-vessel conditions using power control. 

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. 

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... 

As a general rule, in the case of CSPs featuring hydrophobic pockets, a decrease of mobile phase flow-rate results in an increase of chromatographic resolution (Rs), as a consequence of better stationary phase mass transfer [78]. This change has significant impact mostly in RP mode [17]. In the NP enantioselective separations of two test solutes (4-hexyl-5-cyano-6-methoxy-3,4-dihydro-2-pyridone and... 

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. 

Acyl-2-alkyl-2,3-dihydro-4( 1 //)-pyridones A are readily available heterocycles in both racemic and chiral form. l-Acyl-2-alkyl-l,2-dihydropyridines B are much less readily accessible, especially enantiopure, but are much sought after building blocks for alkaloid synthesis. A very efficient (83-96%) and simple procedure has now been developed for the A — B transformation, illustrated as follows treatment of l-allyloxycarbonyl-2-cyclohexyl-2,3-dihydro-4-pyridone with one equivalent of the Vilsmeier reagent in trichloroethylene at room temperature gave l-allyloxycarbonyl-4-chloro-2-cyclohexyl-l,2-dihydropyridine in 92% yield. 

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... 

A two-electron reduction of activated pyridinium salt 178 forms an intermediate enolate 179, which, upon quenching with a number of electrophiles, yields dihydro l-pyridones 180 after hydrolysis. These compounds are notable because they contain a variety of groups a to the nitrogen (Table 5 Equation (94) <20050L435, 20060BC1071>. 

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>. 

A simple diastereoselective route to 2,3,6-trisubstituted-2,3-dihydro-4-pyridones from a diketoester, aryl aldehydes, and ammonium acetate has been reported (Equation 168) <2005TL5511>. 

The importance of ring size holds for the tautomerism of J2-pyrrol-5-ones and A 2-dihydro-6-pyridones. Whilst the former compounds behave as cyclic l-methyl-2-alkyl-2-hydroxy-5-pyrrolidones82 (or, on distillation, as dehydrated 1 -methyl-2-alkyl-d 2-pyrrolones), the latter compounds exist preferentially in the form of acyclic N-methylamides of 8-oxo-acids53 (as shown by infrared spectroscopy) dehydration to A 2-dihydro-6-pyridones is achieved only with difficulty. 

Although the mechanism of chlorination of pyridine A-oxides by the action of phosphorus oxychloride, phosphorus pentachloride, or sulfuryl chloride has not been established, it seems most likely that some of these reactions involve intra- or inter-molecular attack by chloride ion or potential chloride ion following complexing at oxygen (see Sections II and IV). With a few exceptions, they are therefore more appropriately discussed under the heading of nucleophilic substitutions (Section IV, A, 3). One such exception may be the reaction of A-hydroxy-4-pyridone with sulfuryl chloride, which ultimately gives l,2,2,3,3,5,6-heptachloro-2,3-dihydro-4-pyridone (65). It has been proposed that the first step in this reaction is the formation of 3,5-dichIoro-AT-hydroxy-4-pyridone.157 If this is so, then it must involve electrophilic attack at the two /3-positions, followed by the more usual nucleophilic substitutions. 

Phenylacetylene on heating with NIS in methanol and catalytic amounts of HTI was transformed to the diiodo acetal PhC(OMe)2CHI2 (95%) under similar conditions, iodo-phenylacetylene afforded PhC(OMe)2COOMe (86%) [56]. Other reactions using NBS or NIS and catalytic HTI resulted in bromination and iodination of, respectively, polyalkylbenzenes [57] and A-acyl-2,3-dihydro-4-pyridones [58]. 

Conjugate addition.s The key step in a stereocontrolled synthesis of the Lyth-raceae alkaloid lasubine II (4) is the conjugate addition of an alkylcopper complexed with BF3 to the N-acyl-2,3-dihydro-4-pyridone 1 to give the d.v-product 2 in 56% yield and >96% stereoselectivity. Hydrogenation in the presence of Li2C03 effects cyclization and deprotection of nitrogen to give the ketone 3, which is reduced stereoselectively by lithium trisiamylborohydride to the desired alcohol 4. 

There is complete parallelism here with strychnine thus, dihydro-vomicine gives an 11-benzylidene derivative (196). Deoxyvomicine (CCXLII) gives a product which may be the simple benzylidine compound CCXLIII or the rearranged a-pyridone CCXLIV (197) deoxy-dihydrovomicine behaves similarly. 

The acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic /3 lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (-)-lasubine (I). Tin tetrachloride mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be aUylated with high diastereoselectivity to give optically active homoaUyhc amines (Scheme 87). 

Lewis acid-promoted asymmetric conjugate addition of an aUylsilane to a series of 8-arylmentbol-derived iV-acyl-2,3-dihydro-4-pyridones (122) has been reported to lead to 2-aUyl-4-piperidones with moderate to high levels of asymmetric induction the highest levels were attained with Ar = 2-naphthyl. The stereochemical course of the reaction was attributed to 7t-stacking and the method was applied to the asymmetric synthesis of (—)-iV-methylconiine. ... 

Cycloadditions. Both hetero-Diels-Alder reactions of polymer-bound aldimines with Danishefsky s diene to afford 2-aryl-2,3-dihydro-4-pyridones and 1,3-dipolar cycloadditions of nitrones with a, 3-unsaturated amides are catalyzed by YbfOTflj. Remarkable switch in diastereoselectivity by solvent is observed in the latter reactions. 

Under thermal conditions the heterocyclic spiro[2.4]heptene system undergoes rearrangement to a 5,6-dihydro-4-pyridone. This reaction is very useful when alkanenitrile oxides with appropriate leaving groups in the side chain are used because they lead to annulated dihydro-4-pyridones with a bridgehead nitrogen atom. - ... 

In a study of the Lewis-acid catalyzed formation of optically active dihydro-j -pyridones 118 from the imines 117 (R = Ts. Ph. Bn or CO2L11 and the diene 4 in the presence of chiral Lewis acids, it was found that only the tosyl compound reacted diastereoselectively,... 

Akiyama et al. have reported that the cycloaddition of 102 to imines is effectively accelerated by 10 mol% of a Bronsted acid such as HBF4 in aqueous media, affording dihydro-4-pyridones in good to high yield (Scheme 10.109) [295]. This catalytic system is applicable to three-component synfhesis of dihydro-4-pyridones from aldehydes, anilines, and 102. The three-component coupling can be achieved efficiently in water without any organic solvent by using SDS as surfactant. 

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