Some mechanistic aspects regarding the Suzuki–Miyaura reaction between selected ortho-substituted phenylboronic acids and 3,4,5-tribromo-2,6-dimethylpyridine

Background: Atropisomers are very interesting stereoisomers having axial chirality resulting from restricted rotation around single bonds and are found in various classes of compounds. ortho-Substituted arylpyridines are an important group of them. A regio- and atropselective Suzuki–Miyaura cross-coupling reaction on 3,4,5-tribromo-2,6-dimethylpyridine was studied. Results: Reactions with various amounts of ortho-substituted phenylboronic acids with 3,4,5-tribromo-2,6-dimethylpyridine gave a series of mono- di- and triarylpyridine derivatives which allowed to draw conclusions about the order of substitution. Also, the observed selectivity in the case of ortho-methoxyphenylboronic acid suggested an additional metal O-chelation effect in the transition state, apparently not present in the ortho-chloro analogues. The rotational barrier in selected atropisomers was determined on the basis of HT NMR and thermal epimerisation experiments. The structure of most presented atropisomeric derivatives of 2,6-dimethylpyridine was confirmed by single-crystal X-ray analysis. Racemic chiral, differently substituted atropisomers were also examined by 1H NMR spectroscopy in the presence of a chiral solvating agent. Conclusion: This regio- and atropselectivity may be generally applicable to other arylpyridine systems. A regio- and atropselective Suzuki–Miyaura cross-coupling process has been observed, giving an efficient access to a class of atropisomeric compounds. An opposite selectivity using a differently ortho-substituted phenylbornic acid was observed.


Experimental section:
All reactions were carried out in oven-dried pressure tube under argon atmosphere in order to simultaneously exclude oxygen and water. Solvents for the reactions were commercially available and were used without further purification. THF or toluene were dried and distilled by standard methods. All solvents were purchased from Sigma Aldrich. TLC analyses were performed on Merck Kieslgel 60 F-254 plates. The visualization of plates was done under UV light or under iodine vapor. All chemicals employed, including ligands, pre-catalyst, boronic acids and bases, were purchased from commercial sources (Sigma Aldrich and Fluorochem) and used without further purification.
Melting points were determined on an Electrothermal Model IA 9200 apparatus and are uncorrected.
NMR spectra were recorded on a Bruker AVANCE 300 MHz spectrometer operating at 300 MHz for 1 H NMR and 75 MHz for 13 C NMR. The spectra were measured in CDCl 3 and are given as δ values (in ppm) relative to TMS. Peak characterization: s = singlet, brs = broad singlet, d = doublet, brd = broad doublet, t = triplet, dd = doublet of doublets, q = quartet, m = multiplet HRMS spectra were collected on Quattro LC Micromass and LCT Micromass TOF HiRes apparatuses.
X-ray crystallographic data were collected using Xcalibur-R -axis single crystal diffractometer from Oxford Diffraction. Data were measured at room temperature using Cu K monochromatic radiation. After initial corrections the collected data were used to solve crystal structures and then to refine models. SHELXS-97 and SHELXL-97 software was applied for these purposes. Full structural data have been deposited with Cambridge Structural Data Centre under respective deposit numbers.

General procedure of Suzuki-Miyaura reaction:
A mixture of 4 (500 mg, 1.45 mmol), arylboronic acid (1.0-12.0 equiv), palladium catalyst (5.0 mol %), ligand (5.0 mol %) and base (9.0 equiv) in 10 mL of solvent was stirred at required temperature under argon atmosphere for required time. The reaction was monitored by TLC. After completion of the reaction, the mixture was cooled and quenched with cold water (5 mL). The organic phase was extracted with toluene (3 × 5 mL). Combined organic extracts were dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel (230−400 mesh) using ethyl acetate in hexane to obtain pure compound different-substituted compound in moderate or good yield.