Pyrazinones, Diels-Alder

Keywords 2(lH)-Pyrazinone Diels-Alder reaction Microwave Solid support ... 

Scheme 7.58 General reaction sequence for 2(1 H)-pyrazinone Diels-Alder cycloadditions with acetylenic dienophiles.

Case study pyrazinone Diels-Alder chemistry... 

Scheme 7.45 Intermolecular 2(liT)-pyrazinone Diels-Alder reactions on solid support. Reagents and conditions (i) CS2CO3, DMF, MW, 70° C, 5 min (ii) dimethyl acetylene dicarboxylate (DMAD), 1,2-dichlorobenzene, MW, 220°C, 20-40 min (iii) TFA-CH2C12 (1 4 or 1 9), MW, 120°C, 10-40 min.

Diels-Alder Reactions of the 2(lH)-Pyrazinone Scaffold in Solution. . . 280... 

Diels-Alder Reactions of the 2(llT)-Pyrazinone Scaffold with Ethylenes. . 281... 

Abstract An overview on the microwave-enhanced synthesis and decoration of the 2(lH)-pyrazinone system is presented. Scaffold decoration using microwave-enhanced transition-metal-catalyzed reactions for generating structural diversity, as well as the conversion of the 2(lH)-pyrazinone skeleton applying Diels-Alder reactions to generate novel heterocyclic moieties are discussed. The transfer of the solution phase to polymer-supported chemistry (SPOS) is also described in detail. 

An interesting parallel was found while the microwave-enhanced Heck reaction was explored on the C-3 position of the pyrazinone system [29]. The additional problem here was caused by the capability of the alkene to undergo Diels-Alder reaction with the 2-azadiene system of the pyrazinone. An interesting competition between the Heck reaction and the Diels-Alder reaction has been noticed, while the outcome solely depended on the substrates and the catalyst system. Microwave irradiation of a mixture of pyrazinone (Re = H), ethyl acrylate (Y = COOEt) and Pd(dppf)Cl2 resulted in the formation of a mixture of the starting material together with the cycloaddition product in a 3 1 ratio (Scheme 15). On the contrary, when Pd(OAc)2 was used in combination with the bulky phosphine ligand 2-(di-t-butylphosphino)biphenyl [41-44], the Heck reaction product was obtained as the sole product. When a mixture of the pyrazinone (Re = Ar) with ethyl acrylate or styrene and Pd(dppf)Cl2 was irradiated at 150 °C for 15 min, both catalytic systems favored the Heck reaction product with no trace of Diels-Alder adduct. 

Diels-Alder Reactions of 2(1//)-Pyrazinone Scaffold with Acetylenes... 

However, most of the reactions are reported to be slow, taking up to 12 h for complete conversion of the starting materials. A Diels-Alder reaction of the pyrazinone scaffold with dimethyl acetylenedicarboxylate (DMAD) [57] has been studied in view of investigating the swiftness of this cycloaddition-fragmentation protocol (Scheme 20). The authors investigated the reaction with DMAD (lOequiv) under microwave irradiation at an elevated temperature of 190 °C, using small amounts of ionic liquid (bmimPFe) in... 

Scheme 19 Diels-Alder reactions of the 2(lH)-pyrazinone scaffold with acetylenes...

Scheme 20 Microwave-enhanced Diels-Alder reaction of the pyrazinone scaffold with DMAD...

Scheme 21 Diels-Alder reactions of the pyrazinone scaffold with ethylene gas...

As the Diels-Alder reactions of 2( lff)-pyrazinones with richly substituted acetylenes can be used to generate diversely substituted pyridines and pyridi-nones, these cyclo additions were investigated under microwave irradiation conditions on the 1,2,3-triazole decorated pyrazinone scaffold. As a proof of concept, the pyrazinones bearing a 1,4-disubstituted-1,2,3-triazole unit, linked via a C-0 bond, were reacted with the symmetrical dienophile dimethyl acetylenedicarboxylate (DMAD), in view of minimizing regioselect-ivity problems (Scheme 28). 

Scheme 28 Diels-Alder reactions of C - O linked 2( l//)-pyrazinone-triazoles with DMAD...

These triazolo-pyrazinones were reacted with DMAD under microwave irradiation (Scheme 32). The reactions were carried out in o-DCB at a slightly elevated temperature of 200 °C for 15 min. Interestingly, the opposite selectivity to the C-C linked analogues was observed during the Diels-Alder reactions of C - N linked pyrazinone-triazoles with DMAD, as pyridines were found to prevail over the corresponding pyridinones. These compounds were isolated in combined yields of 39-68%. 

A very detailed comparison for every single step of the whole sequence (linking of a pyrazinone to the solid support, Diels-Alder reaction with acetylenic dienophile and cleavage of a formed pyridinone from the resin) was made between microwave irradiation and conventional heating conditions [115]. 

To perform Diels-Alder reactions on solid phase, the 2(lH)-pyrazinone scaffold is linked to a suitable support via its amide nitrogen atom. While N-l-substituted pyrazinones are readily accessible by the choice of an appropriate amine, it is not possible to prepare N-l-unsubstituted pyrazinones using the general strategy as previously outlined in the introduction. How-... 

Scheme 39 Diels-Alder reaction of 2(114)-pyrazinones with acetylenes on solid support...

To avoid problems with the separation of regiomers, dimethyl acetylene dicarboxylate (DMAD) was chosen as a dienophile. The intermolecular Diels-Alder reactions were performed in refluxing dichlorobenzene (bp 132 °C), while the intramolecular reaction of alkyne tethered pyrazinone required a solvent with a higher boiling point (bromobenzene, bp 156 °C). In the case of 3-methoxy or 3-phenyl pyrazinones a mixture of pyridinones and pyridines was obtained, while for the alkyne tethered analogue only the di-hydrofuropyridinone was isolated as the single reaction product. 

For the microwave-assisted experiments, both solvents were replaced by 1,2-dichlorobenzene, as it couples very effectively with microwaves (loss-tangent (tan 5) at 20 °C 1,2-dichlorobenzene 0.280 as compared to 0.101 for chlorobenzene). Diels-Alder reactions of 3-methoxy or 3-phenyl pyrazinones with DMAD were performed at a pre-selected maximum temperature of 200 °C, whereas the intramolecular reaction of alkyne tethered pyrazinone required a higher temperature (220 °C). The yields obtained under microwave irradiation are comparable with those obtained under conventional conditions, while for the dihydrofuropyridinone the yield was improved from... 

As in the case of the solution-phase protocol, Diels-Alder reactions of the polymer-bound pyrazinones la,b were carried out in refluxing chlorobenzene (132 °C) and it required 1-2 days to drive these reactions to the completion (Scheme 44). Intramolecular cycloaddition of pyrazinone Ic was carried out in refluxing bromobenzene (bp 156 °C). Microwave-assisted cycloadditions of these substrates were performed in 1,2-dichlorobenzene at 220 °C and in significantly shorter reaction times (10-40 min). The product distribu-... 

Scheme 44 Diels-Alder reactions of resin-bound pyrazinones...

It has to be noted that the temperatures up to 220 °C involved in the transformations on polystyrene-based support do not affect the resin stabihty. The controlled microwave irradiation appeared to be very effective in speeding up the linking of 2(lH)-pyrazinones to an appropriate resin as well as in accelerating the rate of subsequent solid-phase Diels-Alder reaction and the following cleavage of a resulting pyridinone from the sohd support. 

Another approach towards monocyclic N-unsubstituted 2-pyridones is based on a solid-phase supported Diels-Alder reaction where a resin-bound 2(lH)-pyrazinone 9 is reacted with acetylenic dienophiles (Fig. 4) [43]. The initially formed cycloadduct then undergoes a retro Diels-Alder reaction and depending on the substitution pattern of the starting pyrazinone the reaction... 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

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