C-O bond Formation in a Microfluidic Reactor: High Yield SNAr Substitution of Heteroaryl Chlorides

Abstract

This study describes our development of a novel and efficient procedure for C-O bond formation under mild conditions, for coupling heteroaryl chlorides with phenols or primary aliphatic alcohols. We utilized a continuous-flow microfluidic reactor for C-O bond formation in electron-deficient pyrimidines and pyridines in a much more facile manner with a cleaner reaction profile, high yield, quick scalability and without the need for the transition metal catalyst. This approach can be of general utility to make C-O bond containing intermediates of industrial importance in a continuous and safe manner.

Keywords: C–O bond; Flow chemistry; Micro-fluidic reactor; SNAr reaction.

Figure 1

Examples of bioactive molecules containing C–O bond.

Scheme 1

C–O bond formation using compound 1 with different phenols and alcohols.a,b ^aFor synthesis of various 3 derivatives, two solutions were prepared and introduced by Pump A & B into the Asia microfluidic reactor; one contained the aryl halide 1 (0.56 mmol, 1.0 equivalent) in THF–H₂O (2.5 mL, 3:2 v/v) and the other contained a mixture of corresponding phenols (0.84 mmol, 1.5 equivalent) and NaOH (0.84 mmol, 1.5 equivalent) in THF–H₂O (2.5 mL, 3:2 v/v) ^bProduct yield determined by LCMS.

Scheme 2

C–O bond formation using mono chloropyrimidine and pyridine. a,b,c ^aFor synthesis of 5 & 7, two solutions were prepared and introduced by Pump A & B into the Asia microfluidic reactor; one contained the aryl halide 1 (0.56 mmol, 1.0 equivalent) in THF–H₂O (2.5 mL, 3:2 v/v) and the other contained a mixture of phenol 2a (0.84 mmol, 1.5 equivalent) and NaOH (0.84 mmol, 1.5 equivalent) in THF–H₂O (2.5 mL, 3:2 v/v). ^bFor attempted synthesis of 7 Toulene, DMF and DMSO neat were also used ^cYield determined by LCMS.

Scheme 3

C–O bond formation using 2-chloro-5-nitropyridine with different phenols. a,b ^aFor synthesis of various 9 derivatives, two solutions were prepared and introduced by Pump A & B into the Asia microfluidic reactor; one contained the aryl halide 1 (0.56 mmol, 1.0 equivalent) in THF–H₂O (2.5 mL, 3:2 v/v) and the other contained a mixture of corresponding phenols (0.84 mmol, 1.5 equivalent) and NaOH (0.84 mmol, 1.5 equivalent) in THF–H₂O (2.5 mL, 3:2 v/v) ^bYield determined by LCMS.