2.3- Dihydro-4-pyridones, addition

Allyltrimethylsilanes react with triplet excited 2,3-dicyano-5,6-dimethylpyra-zine to give diazatricyclooctenes (115), possibly via intermediate (114) formed from ring-opening of an initially-formed [2+2]adduct. Intramolecular [2+2]-cycloaddition yields the pentacyclic compound (116) on irradiation of the corresponding tethered enantiopure bis-2,3-dihydro-4-pyridone. Addition of ethylene to the corresponding a,P-unsaturated-y-lactams in acetone yields (117) and (118) as the major photoproducts. ... 

Figure 3.31. Scope of Rh/(i )-binap-catalyzed asymmetric 1,4-addition of ArZnCl to 2,3-dihydro-4-pyridones.

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also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15).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. 

The mechanism of the reactions of aromatic unsaturated ketones with malonamide was described in [154]. The expected product of (3-addition— <5-ketamide—was isolated and fully characterized. The proposed mechanism of the formation of the terahydropyridone cycle in [154] was similar to one suggested in [134, 153] for cyanamide. The first stage of the reaction is an addition of the CH-acid to the ethylene bond of the unsaturated ketone and generation of the (3-adduct, which can easily undergo a cyclization leading to dihydro derivatives of 2-pyridone 146 (Scheme 3.45). 

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. 

Addition of pyrrolyl and indolyl Grignard reagents to 1-acyl salts of 4-methoxy-3-(triisopropylsilyl)pyridine affords the corresponding l-acyl-2-heteroaryl-2,3-dihydro-4(17/)-pyridones, e.g., 443 (main product) and 444... 

A convenient synthesis of thiazolo-fused 2-pyridones 41 has been developed <07JOC4917>. Thus, A2-thiazolines 39 undergo acyl ketene imine cyclocondensation with Meldrum s acid derivatives 38 to give the dihydro thiazolo-fused 2-pyridones 40, which transform to 41 via bromination-elimination process. Pyridones 41 are converted to the 2-substituted analogs 43 and the saturated products 42 by Heck coupling and conjugate addition, respectively. 

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. ... 

The same strategy has been used to prepare trans bicyclic enones. The protected C5 phosphonylated aldehyde is obtained in 84% yield by a CuBr SMe2-mediated Michael addition of the Grignard reagent derived from 4-chlorobutyraldehyde diethyl acetal to a 5-phosphonylated 2,3-dihydro-4-pyridone in THF. Subsequent room-temperature hydrolysis of the acetal using aqueous oxalic acid in THF affords a near-quantitative yield of the crude aldehyde, which undergoes an intramolecular Homer-Wadsworth-Emmons reaction under treatment with Et3N/LiCl in THF at room temperature (89%). ... 

The nucleophilic reactivity of 17 can be increased by N-deprotonation and the best results were obtained with the in situ generated lithium salts. The latter react with acrylates by Michael addition and ring closure to give a single product. The problem of regioselectivity arises because the enamine anion 47 is delocalized and can react both at the nitrogen anion and/or at the enamine carbon. Both cases are known in the literature with similar substrates (ref. 49). These two pathways should lead to the isomeric dihydro a- or y-pyridones (Scheme 53). 

To a solution of 100 mg (2R)-2-((lR)-hydroxy-l-hept-3-yn-2-one)-l-[((15, 2R)-2-(1-methyl- 1-phenylethyl) cyclohexyoxy) carbonyl]-5-(triisopropylsilyl)-2,3-ciihydro-4-pyridone (0.161 mmol) in 7 mL methanol was added 66 mg cerium(III) chloride heptahydrate (CeCl3 7H20, 0.177 mmol) in one portion. After being stirred for 10 min, the mixture was cooled to —50°C, and 9 mg sodium borohydride (0.241 mmol) was added. The reaction mixture was stirred for an additional 10 min, quenched with 10 mL water, and extracted with CH2CI2 (3 x 10 mL). The combined extracts were dried over MgS04 and concentrated under reduced pressure. The residue was purified by radial PLC (silica gel, 30% EtOAc/hexanes) to give 96 mg (2R)-2-((lR,25)-dihydroxy-hept-3-yne)- -[((15,2R)-2-( 1-methyl- 1-phenylethyl)-cyclohexyloxy)carbonyl]-5-(triisopropylsilyl)-2,3-dihydro-4-pyridone as a colorless oil, in a yield of 96%. 

Comins et al. [70] showed that V-acetyl-2,3-dihydro-4-pyridone reacts in a regio- and stereoselective manner to give the 5-exo-cyclization products. Product 80 is obtained under Jeffrey conditions, whereas hydride capture delivers the formal 1,4-addition product 81 (Scheme 6.22). 

Without additional reagents 2,3-Dihydro-5(4//)-pyridone 1-oxides... 

Two one-pot procedures for the preparation of 3,4-dihydro-2( 1 H )-pyridones, based upon 1,4-addition of ketones to substituted acrylamides, have been reported (Scheme 26). Using methacrylamide as the Michael acceptor, 1,4-addition of ketones (330) catalysed by... 

Vinyl ketones, ethyl cyanoacetate and atnncaiixin acetate give 4,6-disubsti-tuted 3-cyano-2-pyridones (XU-142) by a reaction path that includes a Michael addition and a dehydrogenation. The intermediate 3,4-dihydro-2-pyridones were not detected. When benzylideneacetophenone was used in benzene, the reaction proceeded by a Knoevenagel condensation and it was possible to isolate the intermediate 3-cyano-5,6-dihydro-4,6-diphenyl-2-pyridone, which was dehydrogenated to MI-142 by boiling in acetone. ... 

Treatment of 5,6-dialkyl-3,4-dihydro-2-pyridones (XII-464 Rj = Rg = CH3, R5 = C3H7, Rfi = CH3) with bromine or sulfuryl chloride " results in addition of halogen, which is followed by dehydrohalogenation to the 2-pyridone. The tetrahydroquinolone (XII-463, m = 2) was also prepared by this route from XII-462. ... 

First, we carried out the reactions of a p-methyl-VJ TSA (lb) and the unsubstituted VKSA (Ic) with cinnamaldimine-TiCl4 complexes (5a) in a manner similar to that of the simple imine cases (Scheme 3). The reactions gave 3-(E -2-phenyl-ethenyl)-5,6-dihydro-2-pyridones (8) and/or 5-amino-7-phenyl-2,6-hexadienoates (9) in moderate to excellent yields through exclusive y-/, 2 addition. The results are summarized in Table IL... 

Hydrogenation over Pt in acetic acid gave a tetrahydro derivative while a similar reduction in ethanol gave a dihydro derivative in which the Zl --double bond was saturated. The fact that all three compounds had identical UV-spectra is in accord with the presence of two isolated double bonds in selagine in addition to the a-pyridone grouping. With the number and nature of its functional groups established it was apparent that selagine was tricyclic. 

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. 

Cheng has published a convenient and synthetically useful alternative method to the NHK reaction for the arylation of aromatic aldehydes in a mild and selective way with nickel(ll) bromide/zinc/dppe mediated protocol for the synthesis of diaryl carbinols. Durandetti reported an electrochemical coupling of aryl halides with aldehydes for the synthesis of diaryl carbinols which was catalytic in chromium and nickel salts. Comins utilized the NHK reaction to prepare 5-(l-hydroxyalkyl)-2,3-dihydro-4-pyridones, which were then explored in reductive, oxidative and substitutive reactions. " The first asymmetric catalytic synthesis of 5y -alk-l-ene-3,4-diols was developed the regio-, diastereo- and enantioselective addition of 3-chloropropenyl pivaloate to aldehydes was made possible by exploiting Salen r(II) species in a catalytic version of the NHK reaction. ... 

Inter- and intramolecular HWE reactions of 5-(diethoxyphosphoryl)-l-acyl-2-alkyl(aryl)-2,3-dihydro-4-pyridones showed very interesting results by Comins and Ollinger. Treating phosphomate 38 with f-BuOK forms anion, followed by addition of the aldehyde, and raising the reaction temperature to 35 °C gave good yields of the desired enones 39. An... 

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