2- Aryl-2,3-dihydro-4-pyridones

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. 

Hetero-Diels-Alder reaction. The condensation of Danishefsky s diene with imines to generate TV-substituted 2-aryl-2,3-dihydro-4-pyridones at room temperature is effected by this salt. A mixture of aldehydes, amines, and the dehydrant MgS04 can be employed instead of imines. 

Acylium salts undergo aza-Nazarov cyclization under similar conditions to form varied five-membered IV-heterocycles.339 Aryl-tethered pyrrolinones and dihydro-pyridones [Eq. (5.132)] were induced to cyclize with triflic acid to afford tri- and tetracyclic products.340... 

This same sequence, however, has been used successfully to prepare (60) [67]. Conversion of (65a, R = NH2) to the corresponding pyridone (65b, R = OH) was accomplished with isoamyl nitrite-H2S04. Arylation of (64) with (65b, R = OH) yielded (66b, R = OH) from which (60) was obtained as described (vide supra). Catalytic reduction of (60) then gave the 7,8-dihydro derivative (69). 

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>. 

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. 

Comins, D.L., and Olhnger, C.G., Inter- and intramolecular Homer-Wadsworth-Emmons reactions of 5-(diethoxyphosphoryl)-l-acyl-2-alkyl(aryl)-2,3-dihydro-4-pyridones, Tetrahedron Lett., 42, 4115, 2001. 

The use of a scandium trifluoromethanesulfonate catalyst has also been reported for aza-Diels-Alder reactions. The reaction of benzaldehyde and amine 104 in [emim][OTf] as the ionic liquid led to the in situ formation of the corresponding imine. Cycloaddition of this imine with Danishefsky s diene gave the A -aryl-6-phenyl-5,6-dihydro-4-pyridone 105 in a quantitative yield (Scheme 44). 

A convenient synthesis of highly functionalized dihydropyrido[2,3-tfjpyrimidines via a double [5 + l]-annulations stoategy was developed. The double annulation route starts from easily available a-alkenoyl-a-carbamoyl ketene-(5,S)-acetals. 2-Amino-3-carbamoyl-5,6-dihydro-4-pyridones was firstly created in excellent yield by a formal [5C + IN] annulation reaction of ketene-(iS. 5)-acetals with ammonia. In the second step, 7,8-dihydropyrido[2,3-d]pyrimidin-4(3/f)-ones (when R = aryl) and 7,8-dihydropyrido[2,3-d]pyrimidines (when R = H), were prepared in good yields by reacting 2-amino-3-carbamoyl-5,6-dihydro-4-pyridones with excessive Vilsmeier reagent (DMF/POCI3) via a second [5 + 1] annulation step. 

Scheme 8.26 Rhodium-catalyzed enantioselective arylation of 2,3-dihydro-4-pyridone 109.

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. ... 

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