2-Iodo-4-methylthiophene synthesis

Yield:16488-58-7 73%

Reaction Conditions:

Stage #1: 3-Methylthiophenewith lithium diisopropyl amide in tetrahydrofuran;n-heptane;ethylbenzene at -25 - 0; for 1.08333 h;
Stage #2: with iodine in tetrahydrofuran;n-heptane;ethylbenzene at -15 - 10; for 2 h;

Steps:

1

Example 1 2-iodo-4-methyl-thiophene; A 3 L 4-Neck flask, equipped with overhead stirring, rubber septum, thermocouple and nitrogen inlet/outlet is charged with 3-methylthiophene (135 mL, 1.38 mol) and THF (1 L). The mixture is cooled to -20⁰C and LDA (800 mL of Aldrich 2.5 M solution in THF/Heptane/ethylbenzene) is added via 12 gauge cannula over 35 minutes, adjusting the addition rate and cooling as necessary to maintain the reaction temp between -25°C and -15°C. The mixture is allowed to stir for 30 min after conclusion of addition, keeping the temperature below 0 ⁰C.In a separate 5 L flask equipped with overhead stirring, cooling bath, nitrogen flow and thermocouple, iodine (454 g, 1.3 equiv) is dissolved in THF (1.65 L), stirred at rt for 20 min to ensure complete dissolution and cooled to -20⁰C. By the time the solution had cooled to -10⁰C, iodine began to precipitate.The anion solution is brought to 0⁰C and cannulated over 40 minutes into a solution of the iodide, adjusting the rate as necessary to keep the reaction at or below -15°C. At the conclusion of the addition, the mixture is allowed to warm to 10⁰C over 2h. The reaction is diluted with MTBE (1.0 L) and the reaction is quenched with ¹A sat'd ammonium chloride (500 mL). The organic layer is washed with 0.5 N sodium thiosulfate (2 x 750 mL), 2 x 1 L water (2 x IL) and brine (200 mL). The organic layers are allowed to sit in the separator for 4h and any separated water is drawn-off. The organic layers are concentrated by rotary evaporation at 30⁰C and 175 mbar to 1.2 L. Essentially no product is detected by HPLC in either the aqueous phase or distillates. A small and unquantifable amount of unreacted 3-methylthiophene is lost to the washes and evaporation. Based on recovered starting material, off-isomer formation, and the absence of product in either washings or rotovap distillates, the yield for this reaction is calculated as 73% for the purposes of estimating the reagents for the Ullmann coupling.¹H NMR (CDCl₃, δ) 7.05 (IH, tight m), (6.91 (IH, tight m), (2.21, 3H, s)

References:

WO2008/121666,2008,A1 Location in patent:Page/Page column 8-9