2 -Pyrazinones, formation

Keyhani, A. Yaylayan, V. Elucidation of the mechanism of pyrazinone formation in glycine model systems using labeled sugars and amino acids. Submitted to J. Agric. Food Chem. 

The dechlorination of the C-3 and C-5 position of the pyrazinone system was described to be fast under microwave irradiation [29]. Contrary to the reported de-chlorination [26] via palladium-catalyzed reaction with sodium formate 100 °C for 2-4 h and at the C-5 position in 2-3 days, a dramatic rate enhancement was observed under microwave irradiation (Scheme 12). The mono-reduction at C-3 was performed at 190 °C in DMF in merely 5 min, and the reduction of C-5, starting from the mono-reduction product, was performed in n-butanol in 55 min to afford the fois-reduction product in good overall yield. 

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. 

Alternatively, 3-phenyl pyrazinone was prepared via Suzuki reaction, when a polymer-bound pyrazinone was irradiated with 4 equiv of phenylboronic acid, 5 equiv of Na2C03 and 20 mol % of Pd[P(Ph)3]4 as the catalyst in DMF as the solvent (Scheme 36). Contrary to the results obtained in solution phase [29], all attempts to drive the reaction toward the formation of disub-stituted compound, using higher equivalents of reagents or longer reaction times, were unsuccessful. Apphcation of aqueous conditions afforded mixtures of 3-mono and 3,5-disubstituted pyrazinones. 

C=N bond formation has also been achieved starting from two additional carbonyl functions properly installed in an Ugi component. Cyclization has been accomplished in this case through a Paal-Knorr reaction of the dicarbonyl compound generated by the Ugi condensation, leading to pyrazinones [107]. 

Although methylation of 2(l//)-pyrazinones with diazomethane gives a mixture of O- and N-methylated pyrazines as the fixed tautomers (Equation 20) <1993JOC7542>, the trimethylsilylation leads to the exclusive formation of 0-silyl compounds, which are effectively converted to bromopyrazines 42 (Scheme 33) <1999JHC783>. In the same... 

Studies directed toward the synthesis of bicyclomycin have resulted in the discovery of efficient routes to the construction of the 2-oxa-8,10-diazabicyclo[4.2.2]decane system (160). Thus, the monolactim ether (155) with a hydroxypropyl side chain at position 3, on oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), gave the product (156) in good yield, presumably via an iminium species (Scheme 51). No trace of the spiro compound (157) could be detected in this reaction. The formation of (156) is probably kinetically controlled. Prior protection of the alcohol as a silyl ether, followed by DDQ oxidation, gave the pyrazinone (158) subsequent deprotection and acid treatment gave the thermodynamically preferred spiro compound (159). The method has been extended to the synthesis of (160), having an exocyclic methylene this compound is a key intermediate in the total synthesis of bicyclomycin [88JCS(P1)2585]. 

Conversion of pyrazinones into bromopyrazines is known (82MI2), as is side-chain bromination, particularly when NBS is used under conditions conducive to radical formation. Thus, 2-ethyl-3-methylpyrazine was converted into the l -bromoethyl derivative (72JOC511). 

Af-(2-Aminoethyl)-Ai-carboxymethylglycine (31) gave 4-carboxymethyl-3,4,5, 6-tetrahydro-2(177)-pyrazinone (32) (Me2NCHO, reflux %).820 Also the formation of bis(3,6-dioxopiperazin-2-ylmethyl)disulfide (33)1440 and... 

Diphenyl-3-nitro-2-pyrazinone (85) undergoes displacement of the nitro group (cf. Section II,D,2,c) by halide ion in aqueous acid (protonation of the 0x0 oxygen atom), with thionyl chloride (formation of —0—SO—Cl which in this case does not go to chloro), and with phosphorus oxychloride [formation of —0— POCl2 (86) which goes to chloro, but more slowly than nitro displacement occurs]. 

Najera and coworkers introduced a new class of cyclic alanine templates (227, equation 59), the structure of which was anchored on Schollkopf s bislactim ether . Palladium-catalyzed allylations of the chiral pyrazinone derivative 227 with allylic carbonates (228) as substrates led to the formation of y,i5-unsaturated amino acids (229a-c) under very mild and neutral reaction conditions, whereas the required base for enolate preparation has been generated in situ from the allylic carbonate during jr-allyl complex formation. With this protocol in hand, the alkylated pyrazinones 229 were obtained with excellent regio- and diastereoselectivities (>98% ds). Finally, hydrolysis with 6 N aqueous HCl under relatively drastic conditions (150 °C) led to the free amino acids. 

A second example is evident from the work of Singh et al.68 on the pyrazinone-containing thrombin inhibitor 2, which is associated with irreversible incorporation of radioactivity to human microsomal tissue and in vivo in the rat. Visual inspection of the structure as well as analysis in the DEREK program does not raise any concern with regards to the presence of structural alerts. However, mechanistic studies on reactive metabolite formation depict de novo metabolic routes of bioactivation on the latent pyrazinone-ring system, leading to the formation of reactive metabolites that adduct to GSH (Figure 6.6). 

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