Synthesis of Bis-heteroaryls Using Grignard Reagents and Pyridylsulfonium Salts

Herein are reported ligand-coupling reactions of Grignard reagents with pyridylsulfonium salts. The method has wide functional group tolerance and enables the formation of bis-heterocycle linkages, including 2,4′-, 2,3′-, and 2,2′-bipyridines, as well as pyridines linked to pyrimidines, pyrazines, isoxazoles, and benzothiophenes. The methodology was successfully applied to the synthesis of the natural products caerulomycin A and E.

The reaction was heated to 140 °C for 7 h. The reaction was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (3 x 30 mL) and dried over Na2SO4. The solvent was evaporated and purification by FCC (5% Et2O in pentane) gave pyridylsulfide 1li as a white solid (0.75 g, 79%).

Synthesis of sulfonium salts
General procedure C: Sulfide (1.1 equiv.), Ph2IOTf (1.0 equiv.) and Cu(OTf)2 (5 mol%) were added to a crimptop vial and sealed. The vial was evacuated and purged with N2 three times. Dry DCE (0.6 M) was added to the vial and the reaction was heated to 95 °C for 16 h (the vial sitting in an aluminium block placed on a stirrer hotplate). Then the reaction was allowed to cool and sat. aq. NH4Cl (20 mL) was added. The product was extracted using CH2Cl2 (3 x 20 mL) and washed with H2O (2 x 20 mL) and brine (20 mL). The solvent was evaporated and product was isolated by FCC.

Synthesis of bis-heteroaryls
General procedure D: Halopyridine (0.45 mmol, 1.5 equiv.) was added to an oven-dried crimptop vial and sealed. The vial was evacuated and purged with N2 three times. The halopyridine was dissolved in dry THF (1.5 mL) and heated/cooled to a given temperature. i-PrMgCl•LiCl (0.38 mL, 0.45 mmol, 1.5 equiv., 1.2 M in THF) was added dropwise to the stirring solution over 2 min. The reaction was allowed to stir for a given time at the specified temperature. Sulfonium salt (0.3 mmol, 1.0 equiv.) was added to a separate oven-dried crimptop vial and dissolved in dry THF (1.5 mL). The solution of sulfonium salt was added dropwise down the side of the vial to the Grignard reagent solution over 2 min. The reaction was allowed to stir for 2 h. Sat. aq. NH4Cl (3 mL) was added slowly to quench any excess Grignard reagent. The product was extracted with EtOAc (3 x 10 mL), the combined organic layers were washed with H2O (20 mL) and brine (20 mL). The solvent was evaporated, and the product was isolated by FCC.
General procedure E: Pyridine (0.45 mmol, 1.5 equiv.) was added to an oven-dried crimptop vial and sealed. The vial was evacuated and purged with N2 three times. The pyridine was dissolved in dry THF (1.5 mL) and heated/cooled to a given temperature. TMPMgCl•LiCl (0.41 mL, 0.45 mmol, 1.5 equiv., 1.1 M in THF) was added dropwise to the stirring solution over 2 min. The reaction was allowed to stir for a given time at the specified temperature. Sulfonium salt (0.3 mmol, 1.0 equiv.) was added to a separate oven-dried crimptop vial and dissolved in dry THF (1.5 mL). The solution of sulfonium salt was added dropwise down the side of the vial to the Grignard reagent solution over 2 min. The reaction was allowed to stir for 2 h. Sat. aq. NH4Cl (3 mL) was added slowly to quench any excess Grignard reagent. The product was extracted with EtOAc (3 x 10 mL), the combined organic layers were washed with H2O (20 mL) and brine (20 mL). The solvent was evaporated, and the product was isolated by FCC.

119.2.
Spectra were consistent with literature data. 11