Abstract
Heteroaryl <i>ortho</i>-phenoxyethylamines have been extensively employed in medicinal chemistry as privileged scaffolds for the design of highly potent and selective ligands. Herein an efficient, fast, and general method for the synthesis of heteroaryl phenoxyethylamines via Suzuki cross-coupling is reported. This approach offers the opportunity to obtain a large variety of biaryls incorporating five-membered (thiophene, furan, thiazole, pyrazole, imidazole) or six-membered (pyridine, pyrimidine) heteroaromatic rings for appropriate libraries of ligands. All the compounds presented here have never been synthesized before and a full structural characterization is given.
Highlights
R coupling in the case of electron-rich substrates or was converted into the corresponding pinacolboronic ester 10 and coupled with the electron-poor aryl halide, as described in Scheme 1
Heteroaryl ortho-phenoxyethylamines have been extensively employed in medicinal chemistry as privileged scaffolds for the design of highly potent and selective ligands (Figure 1) for glycine transporter GlyT1 (1),[1] α1 adrenergic receptor 2,2 DNA topoisomerases 3,3 AMPA receptor 4,4 and 5-HT2A receptor 5.5,6 Trifenagrel (6), a potent inhibitor of arachidonate-induced platelets aggregation,[7] moPhpC 7, fluorescent pyrrolocytosine nucleobases designed for tight binding to guanine,[8] and some 2,3- and 3,4diarylfurans, for example, 89 with anti-implantation activity, belong to this versatile class of heteroaryl ortho-phenoxyethylamines
We describe the synthesis of several heteroaryl ortho-phenoxyethylamines via Suzuki cross-coupling
Summary
Alkylation of 2-iodophenol in the standard conditions reported for the Williamson reaction provided the aryl iodide 9 in high yield (89%). Since the presence of an alcohol may improve water/toluene miscibility and the activation of the boronic acid to boronate by the hydroxyl anion, in order to prevent the formation of the ethyl ester, the amount of ethanol was lowered (toluene–ethanol, 3:1 v/v) Under these conditions the ester was found in trace amounts and 11 was isolated in good yield (70%). 12 was synthetized in excellent yield (93%) without any optimization steps These coupling conditions allow a variety of heterobiaryls to be obtained in good/high yields, starting from the corresponding electron-rich boronic acids, even in the presence of a base sensitive group. A molar ratio of 4:1 ligand (Cy-JohnPhos) to catalyst [Pd(OAc)2] afforded 10 with the highest yield (95%) and the lowest reaction time (2 h) (Table 1, entry 8)
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