Atropisomerism in 3,4,5‐Tri‐(2‐methoxyphenyl)‐2,6‐lutidine

Abstract

Suzuki reaction of tribromo‐2,6‐lutidine with (2‐methoxyphenyl)boronic acid gave 3,4,5‐tris(2‐methoxyphenyl)‐2,6‐lutidine in the form of a mixture of three atropisomers that were stable at room temperature. Each isomer was isolated and fully characterized, including by X‐ray structure determination. One of the isomers, being a racemic mixture, was separated into individual enantiomers by using semipreparative chiral HPLC. Their absolute stereochemistry was initially assigned on the basis of computational calculation of the CD spectra and finally confirmed by X‐ray analysis.

Efficient synthesis of differently substituted triarylpyridines with the Suzuki-Miyaura cross-coupling reaction

“…Our previous results 29 as well as data collected in Table 1 (entries 4, 6, 9, 10) indicated that some catalytic systems with a properly chosen base could be suitable for regioselective diarylation of 8 and 9. In a subsequent study we decided to apply ready to use ferrocenylphosphine-based catalyst Pd(dppf)Cl 2 ×CH 2 Cl 2 , mainly because of its air stability and high activity.…”

“…In a recent paper we demonstrated that Buchwald ligand S-Phos in connection with palladium donor Pd(OAc) 2 in the presence of K 3 PO 4 allows Suzuki cross-coupling of pyridine 3 with 2-methoxyphenylboronic acid in less than an hour. 29 During an optimization study, this catalytic system proved superior to others, e. g.…”

“…We have already described a similar phenomenon in the presence of stable atropoisomers of related oligoaryl pyridines. 22,29 In the case of compound 1c two diastereomers were detected in the reaction mixture. After their chromatographic separation we recorded their NMR spectra, but apparently due to fast atropoisomerization we were unable to prepare crystals suitable for X-ray study.…”

“…The preparation of 3,4,5-tribromo-2,6-dimethylpyridine 3, 2,3,5-tribromo-4,6-dimethylpyridine 4, 2-chloro-3,5-dibromo-4,6-dimethylpyridine 5, 4-chloro-3,5-dibromo-2,6-dimethylpyridine 6, were carried out by our already reported method. 17,19,29 The reagents and solvents were commercially available and were used without further purification. All cross-coupling reactions were carried out in 22 mL vials (Supelco) closed with solid cups sealed with PTFE/silicone septa under argon or nitrogen atmosphere.…”

“…We already reported on the preparation of 3,4,5-tris-(2-methoxyphenyl)-2,6-dimethylpyridine from 3,4,5-tribromo-2,6-dimethylpyridine 3 via Suzuki reaction with 2-methoxyphenylboronic acid in the presence of palladium acetate and the Buchwald ligand S-Phos. 29 The positive outcome of this reaction was due to the use of 3 as a starting material and careful optimization of the reaction conditions. Considering the easy availability of differently substituted arylboronic acids, our method would be suitable for the preparation of a wide library of 3,4,5-triaryl-2,6-dimethylpyridines P5 (1a-m).…”