Cine-Substitutions at Five-Membered Hetarenes Enabled by Sulfonium Salts

We report a nucleophilic substitution reaction of five-membered hetarylsulfonium salts that results in a change of the substitution pattern on the arene. The products of these cine-substitutions are hard to access synthetically otherwise. The sulfonium salts that serve as starting materials are generated by a highly site-selective C–H functionalization reaction.

integration. Multiplets resulting from coupling to several magnetically non identical atoms with a coincidentally equal (within the limits of detection) coupling constant are indicated with ψ as well as splittings not resulting from a coupling to another spin.

Massspectrometry
High-resolution mass spectra were acquired using a Q Exactive Plus Orbitrap manufactured by Thermo Scientific, Bremen, Germany or a Q Exactive GC Orbitrap manufactured by Thermo Scientific, Bremen, Germany in combination with the gas-chromatograph Trace 1310 manufactured by Thermo Scientific, Bremen, Germany.
Subsequently, EtOAc (10 ml) and aqueous NaHCO 3 solution (saturated, 10 ml) were added under vigorous stirring. The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 20 ml

Imidazopyridine-derived dibenzothiophenium salt S8
Under an ambient atmosphere, a 20 ml glass vial equipped with a teflon coated stir bar was charged with imidazopyridine (590 mg, 5.0 mmol, 1.0 equiv.), dibenzothiophene-S-oxide (1.0 g, 5.0 mmol, 1.0 equiv.), and MeCN (15 ml, c = 0.33 M). The mixture was cooled to -78 °C, subsequently trifluoroacetic acid anhydride (1.0 ml, 1.6 g, 7.5 mmol, 1.5 eq.) was added dropwise. Subsequently, the reaction mixture was allowed to warm to 25 °C, over a period of 1 h. The reaction mixture was stirred at 25 °C for 24 h. Subsequently, the reaction mixture was diluted with DCM (15 ml) and washed with water (30 ml). The organic layer was dried with MgSO 4 . The organic phase was directly loaded onto a silica column and eluted with DCM / MeOH (1 / 0 gradient to 4 / 1) to afford 1.50 g (72 %) of compound S8 as colorless crystals.
Subsequently, the reaction mixture was allowed to warm to 25 °C, over a period of 1 h. Subsequently, the reaction mixture was diluted with DCM (10 ml) and washed with water (2 × 30 ml). The organic layer was dried with MgSO 4 . The organic phase was directly loaded onto a silica column and eluted with DCM / MeOH (1 / 0 gradient to 4 / 1) to afford 1.17 g (82 %) of compound S10 as pale yellow highly viscous oil.
Subsequently, the reaction mixture was allowed to warm to 25 °C, over a period of approximately 20 min, and subsequently stirred for 1 h at 25 °C. Subsequently, the reaction mixture was diluted with DCM (30 ml) and washed with water (2 × 50 ml). The organic layer was dried with MgSO 4 . The organic phase was directly loaded onto a silica column and eluted with EtOAc / DCM / MeOH (1 / 0 / 0, then 0 / 1 / 0 gradient to 0 / 4 / 1) to afford 4.05 g (88 %) of compound 1 as a brown solid.

Side reaction with the methoxymethylbenzoate-derived thianthrenium salt, compound 4
Under an ambient atmosphere, a 20 ml glass vial equipped with a teflon coated stir bar was charged with 2methoxymethylbenzoate-derived thianthrenium salt 3 (375 mg, 0.80 mmol, 1.0 equiv.), KCN (104 mg, 1.60 mmol, 2.0 equiv.), and DMSO (10 ml, c = 0.08 M). The vial was sealed, and the reaction mixture was subsequently stirred for 20 h at 60 °C. Subsequently, the reaction mixture was diluted aqueous Fe(OAc) 2 solution (200 mg Fe(OAc) 2 in 5 ml H 2 O). The mixture was stirred for 10 min at ambient temperature, and subsequently poured onto a biphasic mixture of EtOAc (150 ml) and water (150 ml). The layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 ml). The combined organic layers were washed with water (50 ml) and subsequently dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes / EtOAc (19 / 1 gradient to 3 / 2 (v/v)) to afford 32 mg (21 %) of compound 4 as colorless oil.

X-ray crystallography:
Sample preparation: Vapor diffusion technique was used to grow the crystals. Compound 5 (approx. 5mg) was dissolved in 1.5 mL DCM in a 4 mL glass vial. The vial with the solution was placed inside a 20 mL glass vial filled with 3 mL pentane. The 20 ml vial was sealed and the vials were left at ambient temperature for three days to yield the crystals that were used for the analysis.     Under an ambient atmosphere, a 20 ml glass vial equipped with a teflon coated stir bar was charged with imidazopyridazine-derived dibenzothiophenium salt S1 (200 mg, 0.48 mmol, 1.0 equiv.), K 2 CO 3 (266 mg, 1.93 mmol, 4.0 equiv.), benzotriazol (172 mg, 1.44 mmol, 3.0 equiv.), and DMSO (10 ml, c = 0.05 M). The vial was sealed and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (10 ml). The reaction mixture was extracted with EtOAc (4 × 20 ml). The combined organic layers were dried with MgSO 4 , filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes / EtOAc (4 / 1 gradient to 7 / 13 (v/v)) to afford 75 mg (66 %) of compound 6 as colorless solid and 10 mg (9 %) of compound S14 as colorless solid.

X-ray crystallography:
Sample preparation: Vapor diffusion technique was used to grow the crystals. Compound 6 (approx. 5mg) was dissolved in 1.5 mL DCM in a 4 mL glass vial. The vial with the solution was placed inside a 20 mL glass vial filled with 3 mL pentane. The 20 ml vial was sealed and the vials were left at ambient temperature for three days to yield the crystals that were used for the analysis.

S35
vial was sealed and the reaction mixture was stirred at 80 °C for 12 h. Subsequently, the reaction mixture was directly loaded onto a column of silica gel and purified by chromatography eluting with hexanes / EtOAc (4 / 1 gradient to 1 / 1 (v/v)) to afford 45 mg (78 %) of compound 8 as colorless solid.

Phthalimide-substituted imidazopyridine 17
Under an ambient atmosphere, a 20 ml glass vial equipped with a teflon coated stir bar was charged with
The vial was sealed, and subsequently stirred for 2 d at 80 °C. Subsequently, the reaction mixture was poured onto a biphasic mixture of EtOAc (50 ml), water (50 ml) and sulfuric acid (1M, 10 ml). The layers were separated, and the aqueous layer was extracted with EtOAc (30 ml). The combined organic layers were washed with water (10 ml), and subsequnlty dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes / EtOAc (9 / 1 gradient to 6 / 4 (v/v)) to afford 100 mg (68 %) of compound 20 as colorless solid.

Diphenylhydantoin-substituted bithiophene 21
Under an ambient atmosphere, a 20 ml glass vial equipped with a teflon coated stir bar was charged with
The vial was sealed, and subsequently stirred for 23 h at 80 °C. Subsequently, the reaction mixture diluted with EtOAc (50 ml) and washed with water (50 ml). The aqueous layer was extracted with EtOAc (30 ml). The combined organic layers were washed with water (20 ml). The organic layer was dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes / EtOAc (9 / 1 gradient to 1 / 4 (v/v)) to afford 125 mg (88 %) of compound 22 as colorless solid.