Pyrazines Diels-Alder reactions

In another paper, the same authors investigated the 1,3-dipolar cycloaddition on 2-(lH)-pyrazine scaffolds 72 and electron-rich azides, using Cu(0) and CUSO4 as pre-catalysts. To demonstrate the versatility of this approach, they reported the generation of different templates (73 in Scheme 25) as an application of cUck chemistry . They also investigated the Diels-Alder reaction of the so obtained triazoles with dimethyl acetylenedicarboxylate (DMAD), under microwave irradiation. The latter reaction allowed obtaining various pyridinones in good yields (74 and 75 in Scheme 25) [57]. 

A diastereoselective intramolecular hetero-Diels-Alder reaction of optically active 428 gave unstable 1,3,4,8,9,9a-hexahydropyrido[2,l-f][l,3]oxazin-l-one 429 (X = 0), and l,3,4,8,9,9a-hexahydropyrido[l,2-(z]pyrazin-l-one 429 (X = NTs) (Equation 80) <2003JA4970, 2004T10277>. In the case of pyrido[l,2- ]pyrazine, the reaction was carried out in the presence of 2,6-di- /-butyl-4-methylphenol. 

Novel pyrazine-containing cydoadducts 80a-c were synthesized by Diels-Alder reaction of [60]fullerene with the corresponding 2,3-bis(bromomethyl)pyrazine derivatives 79a-c (Scheme 9.23) [73] the 2,3-pyrazinoquinodimethanes were trapped as the Diels-Alder adducts by reaction with [60]fullerene under reflux in o-dichloroben-zene (ODCB) as solvent with classical heating and under the action of microwave ir-... 

The Mitsunobu reaction of perhydropyrido[l,2-a]pyrazine-l,4-dione 230 at ambient temperature gave dehydrated product 231 in 15% yield. When the reaction was carried out with excess PBu3 and diethyl azodicar-boxylate at 40 °C the incipient 231 spontaneously underwent enolization and tautomerization, [4+2] aza-Diels-Alder reaction to provide a 2.4 1 mixture of diastereomers 232 and 233 (07T6124). No reaction occurred when isolated 231 was treated under similar conditions. 

A Diels-Alder approach to varenicline was recently published by Dr. Reddy s Laboratories. Entry to a key bicyclic intermediate is achieved by an iodide-catalyzed Diels-Alder reaction of tetrabromo dimethyl pyrazine (47) with excess norbomadiene. Dihydroxylation of 48, oxidative cleavage, and reductive amination prepares N-p-methoxybenzyl varenicline (50), which is deprotected under transfer hydrogenation conditions to give varenicline (1) in 10% yield for the sequence.47 This approach continues the theme of building the piperidine of 1 through olefin oxidative cleavage and reductive amination, but by doing so late in the sequence however, the approach... 

Intramolecular hetero-Diels-Alder reactions provide a novel approach to polycyclic pyrazines and lumazines if 1,2,4-triazines contain the dienophilic component in a side chain tethered to the... 

The formation of pyridazines from 1,2-diaza-1,3-butadienes and electron-rich dienophiles has been reported [308] on the other hand, tetrazine and triazole derivatives have been prepared from these heterodienes and azo esters [309]. Aza Diels-Alder reactions of 1,4-diaza-1,3-butadienes have been employed for the synthesis of unsymmetrical pyrazine derivatives by Heathcock et al. [310]. 

An investigation concerning intramolecular aza Diels-Alder reactions of 3-(co-alkynyl)-l,2,4-triazines has been published by Taylor et al. [327] and trichloro-1,2,4-triazine has been introduced as novel triazine diene recently [328]. 1,2,4-Triazines are a useful alternative of 1,4-diaza-l,3-butadienes with regard to the aforementioned synthesis of pyrazines since Taylor s group has found them to undergo cycloadditions with nitriles followed by extrusion of nitrogen [329]. This reaction is noteworthy since it is a Diels-Alder reaction of both electron-deficient diene and dienophile. 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

Heating of 2-(Af-acetyl-3-butynylamino)pyrazine (28 X = NAc) at 165°C brings about an intramolecular Diels Alder reaction followed by loss of hydrogen cyanide leading to the formation of... 

Intramolecular Diels-Alder reactions of the pyrazine derivatives 631 (X = O, S or NAc R = SiMes or HOCH2) yield mixtures of the tricyclic heterocycles 633 and 634. Both arise from the intermediate cycloadducts 632, which can lose the elements of hydrogen cyanide in two ways, as indicated. ... 

L-Pro has been used as an organocatalyst in an inverse-electron-demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines to furnish pyrazines with medicinal interest.The transformation proceeds by the reaction of the diene 1,2,4,5-tetrazine with the enamine formed in situ from the ketone and L-Pro. A retro-Diels-Alder step eliminates nitrogen and forms the pyr-azine product after catalyst elimination. The transformation is, however, not regioselective with unsymmetrical ketones. 

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