Suzuki–Miyaura Coupling of Halophenols and Phenol Boronic Acids: Systematic Investigation of Positional Isomer Effects and Conclusions for the Synthesis of Phytoalexins from Pyrinae

Abstract

The Suzuki-Miyaura couplings of o-, m-, and p-halophenols with o-, m-, and p-phenol boronic acids were investigated for all combinations under standardized conditions, using Pd/C as a heterogeneous catalyst and water as a solvent. In the case of iodophenols, conventional heating was used, while for bromophenols significantly better results could be obtained using microwave irradiation. This systematic study revealed that 2,4'-biphenol is particularly difficult to access, irrespective of the starting materials used, but that these difficulties can be overcome by using different additives. The conclusions drawn from this investigation allowed us to identify conditions for the protecting group-free or minimized total synthesis of biaryl-type phytoalexins. These compounds possess antibacterial activity and are produced by fruit trees as a response to microbial infection.

Synthesis of Magnaldehydes B and E and Dictyobiphenyl B by Microwave‐Promoted Cross‐Coupling of Boronophenols

“…[37] In the next step, the o,pЈ-biphenol moiety was constructed by a Suzuki-Miyaura coupling reaction. [38] Fluorides are believed to coordinate to the Pd, increase the nucleophilicity of the solvent, that is, water, through hydrogen bonding, and thereby facilitate the formation of the crucial Pd-hydroxy intermediates [40][41][42] without extensive deprotonation of the boronophenol. [39] We found that bases such as NaOH or K 2 CO 3 that are typically used in Suzuki-Miyaura reactions give very low yields when combined with p-boronophenols such as 7, and this might be attributed to the deprotonation of the phenol under these reaction conditions.…”

High Throughput Experimentation and Continuous Flow Validation of Suzuki–Miyaura Cross‐Coupling Reactions

“…Our results show that both electron‐rich and electron‐deficient aryl halides ( 2 – 12 ) were tolerated to produce cross‐coupled products in moderate to good yield as assessed by product peak intensities (Figure A–D). Comparison of the anisole family of precursors ( 2 – 5 ) revealed that the meta ‐positioned methoxy group ( 4 , Figure C) provided more desired product than ortho ( 5 , Figure D) or para ( 2 & 3 , Figure 3 A&B) due to the reduced electron donating contribution from the meta placement of this substituent …”

Pd/C Catalysis under Microwave Dielectric Heating

“…A careful evaluation on how the substituent position in 9 influenced the reaction efficiency was also reported: the m-boronophenol was the most reactive substrate, followed by the p-isomer. The optimized MW accelerated cross-coupling conditions were applied to the synthesis of nine naturally occurring phytoalexins with biaryl structures (Scheme 4) [22]. The cross-coupling occurred also under conventional heating (2.5 h at 80 °C vs. 30 min at 150 °C under MW irradiation) while, with the corresponding bromophenols, the products were obtained in acceptable yields only using MWs.…”