Chlorotrimethylsilane → 2-Fluoro-3-(1,4-dioxaspiro[4.5]decan-8-YL)pyrazine

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Reaction Steps

To a suspension of activated zinc dust (51 g, 0.78 mol, 1.94 eq.) in anhydrous DMA (100 mL) was added 1,2-dibromoethane (5.5 mL, 0.064 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (8.1 mL, 0.064 mol, 0.16 eq.) over 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of 8-iodo-1,4-dioxaspiro[4.5]decane (172 g, 0.639 mol, 1.59 eq.) in anhydrous DMA (300 mL) was added to the above suspension over 30 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour and cooled to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2-fluoro-3-iodopyrazine (see PREPARATION P6.2; 90 g, 0.402 mol, 1.0 eq.), PdCl2(dppf)CH2Cl2 (9.8 g, 0.012 mol, 0.03 eq.), and CuI (4.75 g, 0.025 mol, 0.062 eq.) in anhydrous DMA (300 mL) using a cannula. DMA (100 mL) was used to rinse the remaining zinc dust and the solution was added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight.

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