Intermolecular Palladium(0)-Catalyzed Atropo-enantioselective C–H Arylation of Heteroarenes

Abstract

General Methods Experimental Procedures, Reagents and Glassware All commercially available chemicals were used as purchased for the synthesis of substrates. All reactions were carried out under an atmosphere of nitrogen in oven-dried glassware with magnetic stirring, unless otherwise indicated. Acetonitrile (MeCN) was dried over CaH2, distilled and stored inside the N2-filled glovebox. Toluene, THF and dichloromethane were purified by the Innovative Technology Solvent Delivery System. Chemicals were used as obtained from the suppliers unless otherwise stated. Solvent compositions are given in (v/v). Chromatography Flash chromatography was performed with Silicycle silica gel 60 (0.040-0.063 μm grade). Analytical thin-layer chromatography was performed with commercial glass plates coated with 0.25 mm silica gel (E. Merck, Kieselgel 60 F254). Compounds were visualized under UV-light at 254 nm and oxidized in standard KMnO4 dye followed by heating if necessary. NMR Spectroscopy Proton nuclear magnetic resonance (1 H NMR) data were acquired at 400 MHz on a Bruker AVANCEIII-400 spectrometer or at 600 MHz on a Bruker DRX-600 spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) relative to residual chloroform (s, 7.26 ppm) or residual acetone (2.05 ppm). Proton decoupled Carbon-13 nuclear magnetic resonance (13 C NMR) data were acquired at 101 MHz or 126 MHz on a Bruker AVANCEIII-400. Chemical shifts are reported in ppm relative to residual chloroform (77.16 ppm) or residual acetone (29.84 ppm, 206.26 ppm). Proton decoupled Fluorine-19 nuclear magnetic resonance (19 F{ 1 H} NMR) were acquired at 377 MHz on a Bruker AV400 spectrometer. Proton decoupled Phosphorus-31 nuclear magnetic resonance (31P{1H} NMR) were acquired at 162 MHz on a Bruker AV400 spectrometer. The assignment of proton and carbon signals was assisted by COSY, HSQC, HMBC and DEPT-135 experiments where necessary. Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; hept, heptet; dd, doublet of doublets; dt, doublet of triplets; ddd, doublet of doublets of doublets; tt, triplet of triplets; tq, triplet of quartets; qt, quartet of triplets; m, multiplet. All NMR data were recorded at 298 K. Infrared Spectroscopy Infrared (IR) data were recorded on an Alpha-P Bruker FT-IR Spectrometer. Absorbance frequencies are reported in reciprocal centimeters (cm-1). Mass Spectrometry HRMS measurements were performed on an Agilent LC-MS TOF (Multimode: ESI + APCI + APPI). High resolution mass are given in m/z. Melting Points Melting points were measured on a Büchi B-540 and are uncorrected. Enantiomeric excesses Enantiomeric excesses were measured on an Agilent HPLC and Shimadzu HPLC. Optical rotations were measured on a Polartronic M polarimeter using a 0.5 cm cell with a Na 589 nm filter.

Enantioselective Synthesis of Atropisomers with Multiple Stereogenic Axes

“…The following year, Baudoin and Cramer reported an atroposelective intermolecular Pd‐catalyzed C−H arylation of 1,2,3‐triazoles and pyrazoles . They used a Pd 0 complex with the chiral monodentate phosphine ligand L3 for the arylation of a broad range of triazoles and pyrazoles in high enantioselectivity.…”

Challenging Atroposelective C–H Arylation

“…Following the intramolecular C-H arylation described above, Cramer and Baudoin reported in 2020 the more challenging intermolecular atropoenantioselective C-H arylation of electron-deficient heteroarenes. 20 In their initial study, they focused on the synthesis of Ar-HetAr scaffolds via C-H arylation of 1,2,3 triazole derivatives, which are biologically relevant units recognized as bioisosteres and pharmacophores. To achieve a configurational stability of the heterobiaryl axis at 80-100 °C over prolonged reaction times, the coupling between 1-methyl-4-phenyl-1H-1,2,3-triazole and 1-bromo-2-methoxy naphthalene, furnishing a product with four ortho-substituents around the heterobiaryl axis, was selected (Scheme 7).…”

Enantioselective Synthesis of Atropisomers with Multiple Stereogenic Axes

“…Thef ollowing year, Baudoin and Cramer reported an atroposelective intermolecular Pd-catalyzed C À Harylation of 1,2,3-triazoles and pyrazoles. [14] They used aPd 0 complex with the chiral monodentate phosphine ligand L3 for the arylation of ab road range of triazoles and pyrazoles in high enantio- selectivity.I nvestigations of the deuterium kinetic isotope effect revealed that the C À Ha ctivation is the rate-determining but not the enantio-determining step.Interestingly,the CÀ Ha rylation of 1,5-dibromo-2,6-dimethoxynaphthalene 10with two equivalents of 1-methyl-4-phenyl-1H-1,2,3-triazole (9)allowed the synthesis of the double-axis heteroatropisomer (M,M)-11 in good yield (76 %) and excellent enantiocontrol (> 99 % ee)w ithout formation of the meso stereoisomer (Scheme 5).…”