Ionic liquid-promoted green synthesis of biologically relevant diaryl thioethers

Abstract

This study reports an ionic liquid (IL) promoted green method to obtain diaryl thioethers useful as key intermediates for the synthesis of matrix metalloproteinase (MMP) inhibitors. The synthetic pathway includes a sequential Ullmann reaction and Suzuki cross-coupling. The Ullmann conditions were optimized as regards the catalyst, the ionic liquid, reaction time, and temperature. Under optimal conditions (1-butyl-3-methylimidazolium bromide ([BMIM]Br) as solvent; catalyst, Cu; base, K 2 CO 3 ; reaction time, 22 h; reaction temperature, 150°C) the aryl iodide conversion was 95%. The Suzuki cross-coupling was conducted in 1-butyl-3methylimidazolium tetrafluoroborate ([BMIM]BF 4) at 110°C, using Pd(PPh 3) 4 as catalyst and Na 2 CO 3 as base. For both reactions, a combination of ILs with microwave (MW) irradiation determined a substantial improvement of reaction time and yields compared to conventional heating. This multi-step process reduces reaction times and removes organic solvents providing a more eco-friendly alternative for the synthesis of important pharmaceutical building blocks.

Modern Development in Copper‐ and Nickel‐Catalyzed Cross‐Coupling Reactions: Formation of Carbon‐Carbon and Carbon‐Heteroatom bonds under Microwave Irradiation Conditions

“…Likewise, ionic liquid (1‐butyl‐3‐methylimidazolium bromide) was recently evaluated in relatively similar reaction conditions of coupling of 2‐iodophenylacetic acid and 4‐bromothiophenol. High yield was achieved of the desired product in only 40 min [129] . Another method for C−S bond formation was reported from the coupling of a wide spectrum of aryl iodides with thiols using catalytic amount of copper(II) oxide with 1,10‐phenanthroline as a ligand and potassium tert ‐butoxide as a base in water at 120 °C for 30 min [130] .…”

“…High yield was achieved of the desired product in only 40 min. [129] Another method for CÀ S bond formation was reported from the coupling of a wide spectrum of aryl iodides with thiols using catalytic amount of copper(II) oxide with 1,10-phenanthroline as a ligand and potassium tertbutoxide as a base in water at 120 °C for 30 min. [130] Chiosis and coworkers have disclosed a microwave-assisted synthetic protocol for the S-arylation of 8-mercaptoadenine, employing CuI and n-Bu 4 NBr with sodium tert-butoxide in DMF.…”