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

Abstract

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.

Arylpyridines: A Review from Selective Synthesis to Atropisomerism

“…Therefore, a series of Suzuki-Miyaura cross-coupling reactions under different reaction conditions were performed with the amount of 2-methoxyphenylboronic acid being systematically reduced. 121 The cross-coupling of 3,4,5-tribromo-2,6-dimethylpyridine (134) with a limited amount of 2-methoxyphenylboronic acid (from 3 to 1 equiv) gave a mixture of atropisomeric, differently mono-and disubstituted 2,6-dimethylpyridine derivatives 135-138 (Scheme 33). 121…”

“…121 The cross-coupling of 3,4,5-tribromo-2,6-dimethylpyridine (134) with a limited amount of 2-methoxyphenylboronic acid (from 3 to 1 equiv) gave a mixture of atropisomeric, differently mono-and disubstituted 2,6-dimethylpyridine derivatives 135-138 (Scheme 33). 121…”

“…The preferred formation of syn-syn isomers in the 2methoxy series suggests the influence of an additional palladium O-chelation effect present in the oxidative addition and/or transmetalation step of the reaction (Scheme 34). 121 In order to verify this hypothesis, another arylboronic acid that cannot coordinate to the palladium atom, 2-chlorophenylboronic acid was used (Scheme 35). 121 As expected, the distribution of atropisomeric products was different.…”

“…121 In order to verify this hypothesis, another arylboronic acid that cannot coordinate to the palladium atom, 2-chlorophenylboronic acid was used (Scheme 35). 121 As expected, the distribution of atropisomeric products was different. The main product of coupling was thermodynamically more stable isomer anti-syn-140 ( Figure 13).…”

“…The main product of coupling was thermodynamically more stable isomer anti-syn-140 ( Figure 13). 121 It seems therefore reasonable to assume that the stereochemical outcome of the Suzuki-Miyaura arylation of pyri-dine derivatives depends on the ability of the ortho-substituent of the phenylboronic acid to chelate to the palladium atom. In the case of chelating substrates, the reaction is kinetically governed leading preferentially to syn-atropisomers, whereas non-chelating species lead to more thermodynamically stable anti-products.…”