Synthesizing Highly Fluorinated Oligophenyls via Negishi Coupling of Fluoroarylzinc Pivalates

Abstract

Previously established general synthetic methods for the synthesis of highly fluorinated biphenyls using Suzuki-Miyaura protocols require the use of organoboron compounds which are not very stable under reactions conditions and thus need to be used in large excess. Herein we report an improved general strategy for the synthesis of highly fluorinated biphenyls, terphenyls and phenyl-substituted terphenyls using organozinc pivalates. The influence of several parameters was investigated: a) in a series of different monodentate phosphine ligands, X-Phos showed the best performance; b) a higher yield could be obtained for substrates bearing less steric hindrance or lower amount of fluorine substitution; c) as iodinated substrates decomposed during the reaction, brominated electrophiles were found to be superior. The presented protocol is scalable, versatile, and works with commonly used and commercially available phosphine ligands (X Phos) and palladium sources (Pd2dba3). Also, it does not need excess nucleophile usage for terphenyl synthesis and only a slight such excess for the preparation of phenyl substituted terphenyls.

A halogen bonding molecular tweezer

“…15 c ,18 In contrast to previous studies, we now needed to further functionalize these terphenyls. The synthesis of these structures is usually approached by Suzuki–Miyaura or Negishi cross-coupling, 19 and the assembled structure is then periodinated using harsh reaction conditions with N -iodosuccinimide (NIS) and trifluoromethanesulfonic acid (HOTf) as solvent based on a protocol by Olah and coworkers. 20…”

“…Biphenyls 4 were synthesized as previously reported. 18,19 We used symmetrical biphenyls 4 to avoid the formation of difficult to separate atropisomers during iodination, as the iodinated molecule can no longer rotate freely. Our reasoning led us to assume that the “outside” monodentate binding site would be much weaker coordinating than the “inside” bidentate one.…”

“…Our reasoning led us to assume that the “outside” monodentate binding site would be much weaker coordinating than the “inside” bidentate one. Applying our previously established methods 19 for the construction of perfluorinated polycyclic compounds, we were able to synthesize 5 in good yields (up to 97% via Suzuki coupling, up to 74% via Negishi coupling, see ESI† for experimental details). With terphenyl 5 in hand, we attempted iodination as previously mentioned using NIS and HOTf.…”