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Different 2‐arylated oxazolo[4,5‐b]pyrazines, obtained by palladium(II)‐catalysed domino reaction from 2,3‐dichloropyrazine and the corresponding carboxamides, were functionalized by deprotometallation. Employing lithium 2,2,6,6‐tetramethylpiperidine, in order to form a lithio derivative, and then trapping it by iodolysis, proved to be inefficient. However, the presence of a zinc‐based in situ trap allowed most substrates to be functionalized. Deprotonation of the pyrazine ring was observed in the presence of tolyl and anisyl groups at the oxazole 2‐position. In contrast, with chlorophenyl and thienyl groups in this 2‐position, deprotonation rather occurred on these groups either competitively or exclusively. The regioselectivities were discussed in the light of calculated pKa values of the substrates in THF. Finally, in the case of 2‐phenyloxazolo[4,5‐b]pyrazine, we converted the mixture of 5‐ and 6‐iodinated products into the corresponding 5,6‐diiodide which was further functionalized by a double Suzuki coupling.
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... reaction of 1 with 4 to give 6). We are unaware of any direct reaction of 2 with four nucleophiles; in systems where the chlorines and hydrogens of 2 are all replaced, the reaction of C-5 and C-6 (the hydrogen-bearing carbons) involves reaction with an oxidant (e.g., a molecular halogen), sometimes followed by an organometallic coupling [22,23]. On the other hand, pyrazines bearing leaving groups readily undergo displacement of those leaving groups, by either SNAr or Addition of the Nucleophile, Ring Opening, and Ring Closure (ANRORC) mechanisms [24][25][26]. ...
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... The use of in situ metal traps avoids the use of cryogenic conditions to achieve these reactions [16,17]. We have developed mixed lithium-zinc combinations based on TMP (TMP = 2,2,6,6-tetramethylpiperidino) capable of deprotonating sensitive substrates at temperatures close to rt [18][19][20][21]. In order to obtain original scaffolds such as pyrazino-fused carbazoles and carbolines, we decided to combine this deprotometalation under in situ trapping conditions with palladium-and copper-catalyzed coupling reactions. ...
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