Modular Synthesis of Biaryl‐Substituted Phosphine Ligands: Application in Microwave‐Assisted Palladium‐Catalyzed C–N Cross‐Coupling Reactions

Abstract

Biaryl‐substituted monophosphine‐based ligands have been synthesized by transition‐metal‐free “ARYNE” cross‐coupling reaction of aryllithiums with 1,2‐dibromobenzene and subsequent regioselective functionalization through bromine–lithium interconversion. These ligands were employed in palladium‐catalyzed C–N bond‐forming reactions. The reaction was found to be general with wide substrate applicability. A wide variety of both primary and secondary amines were successfully coupled with an array of differently substituted halobenzenes under microwave irradiation to give the expected products in good to excellent yields. A number of biaryl‐substituted phosphine ligands screened for the coupling reaction showed that steric bulk and the electronic properties of substituents on phosphorus play a crucial role in governing the catalytic activity of C–N cross‐coupling reactions.

Phosphines with N‐Heterocyclic Boryl‐Substituents: Ligands for Coordination Chemistry and Catalysis

“…For a proof of principle, we performed an exemplary study of the Pd‐catalyzed Buchwald–Hartwig coupling of bromobenzene with 2,6‐diisopropylaniline (Dipp‐NH 2 ) in refluxing toluene [reaction (1), Scheme ]. The reaction protocol copies a known synthesis of target amine 11 using a bulky Buchwald‐type phosphine as activating ligand , . For our studies, phosphine 5a was deemed to provide the best compromise between optimum ligand properties, chemical stability, and easy synthetic accessibility.…”

“…Performing the reaction with the reported catalyst load [2 mol‐% Pd(OAc) 2 and 3 mol‐% phosphine] led to quantitative conversion of the aryl halide within two hours. Work‐up afforded the product in a yield 72 % (Table , entry 1), which is slightly smaller than the reported yield of 82 % after 8 hours reaction using a Buchwald‐type phosphine.…”

“…Expectedly, NHB‐phosphine 5a promotes also the amination of iodobenzene with Dipp‐NH 2 (quantitative conversion within <30 min), while no activity at all was observed with fluoro‐ or chlorobenzene as substrates. The efficacy of 5a in syntheses of tertiary amines is illustrated in the coupling of bromobenzene with 11 [reaction (2)] and piperidine [reaction (3)]; both reactions mimic reported syntheses with Buchwald‐type ligands as auxiliary . Because conducting C–N cross‐coupling reactions under microwave (MW) irradiation enables substantial time savings,, we studied the synthesis of 11 in a MW reactor.…”

“…The efficacy of 5a in syntheses of tertiary amines is illustrated in the coupling of bromobenzene with 11 [reaction (2)] and piperidine [reaction (3)]; both reactions mimic reported syntheses with Buchwald‐type ligands as auxiliary . Because conducting C–N cross‐coupling reactions under microwave (MW) irradiation enables substantial time savings,, we studied the synthesis of 11 in a MW reactor. Interestingly, quantitative reaction occurred within 10 min at 200 °C in the presence of Pd(OAc) 2 and 5a as pre‐catalysts (entry 5 in Table ), but 67 % conversion to 11 was also achieved when the reaction was carried out under more forcing conditions (40 min at 270 °C; entry 6 in Table ) in the absence of both Pd(OAc) 2 and 5a .…”

Solvent‐Free Ruthenium‐Catalyzed Direct Coupling of Phosphines and Aryl Chlorides via C−H Activation: An Efficient and Straight Access to Aryl‐Substituted Biarylphosphines

“…Recent years, late-stage modification via selective CÀ H bond functionalization [3] has emerged as a novel strategy for the preparation of biarylphosphines, [4] which enables more efficient chemical synthesis by avoiding the traditional pre-functionalization of substrates. [5] Among various functionalizations, [6] arylation reaction of biarylphosphines has received much attention as it could easily tune the steric and electronic properties phosphines by installing various aryl groups. [7] With this strategy, Yang group developed a O-directed Pd-catalyzed ortho-CÀ H arylation of biarylphosphine oxides with aryl iodides, in which additional synthetic steps for pre-oxidation of phosphines and late-stage reduction of phosphine oxides were required to obtain tertiary phosphines.…”