Nickel-Catalyzed Suzuki Coupling of Phenols Enabled by SuFEx of Tosyl Fluoride

A practical and efficient Suzuki coupling of phenols has been developed by using trans-NiCl(o-Tol)(PCy3)2/2PCy3 as a catalyst in the presence of tosyl fluoride as an activator. The key for the direct use of phenols lies in the compatibility of the nickel catalyst with tosyl fluoride (TsF) and its sulfur(VI) fluoride exchange (SuFEx) with CAr-OH. Water has been found to improve the one-pot process remarkably. The steric and electronic effects and the functional group compatibility of the one-pot Suzuki coupling of phenols appear to be comparable to the conventional one of pre-prepared aryl tosylates. A series of electronically and sterically various biaryls could be obtained in good to excellent yields by using 3–10 mol% loading of the nickel catalyst. The applications of this one-pot procedure in chemoselective derivatization of complex molecules have been demonstrated in 3-phenylation of estradiol and estrone.

Sulfur(VI) fluoride exchange (SuFEx), the so-called second generation of click reaction [36][37][38][39], has proven to be a privileged protocol in activating phenolic C Ar -OH group via chemoselective formation of sulfonates with SO 2 F-containing reagents in the presence of various other nucleophiles [37,40]. As a part of our continuous efforts to develop practical procedures for construction of biaryls from pseudohalides [41][42][43][44], we report herein a SuFEx enabled, nickel/phosphine catalyzed Suzuki coupling of phenols via in situ formation of tosylates with tosyl fluoride (TsF) using trans-NiCl(o-Tol)(PCy 3 ) 2 /2PCy 3 as a catalyst to practically and efficiently synthesize various biaryls with good functional group comparability.

Scheme 1.
Cross-coupling of 1a with alternative phenyl boron compounds.
A plausible mechanism has been proposed for the nickel-catalyzed Suzuki couplin of phenols enabled by SuFEx of tosyl fluoride (Scheme 2). Given the observation of th homocoupling product of aryl boronic acids, the aryl nickel(II) di(phosphine) complexe Scheme 1. Cross-coupling of 1a with alternative phenyl boron compounds.
Molecules 2023, 28, 636 6 of 10 A plausible mechanism has been proposed for the nickel-catalyzed Suzuki coupling of phenols enabled by SuFEx of tosyl fluoride (Scheme 2). Given the observation of the homocoupling product of aryl boronic acids, the aryl nickel(II) di(phosphine) complexes are most likely reduced to nickel(0) phosphine complexes, which require 2 equiv. more phosphine ligand to be stable, by aryl boronic acids via sequential transmetalation and reductive elimination. The facts that sharply different structural effects of phenol vs. boron counterparts, as well as the isolation of biphenyl-2-yl tosylate as a sole product from catechol, imply that the oxidative addition of nickel to tosylate intermediates, instead of the SuFEx or aryl transmetalation from boron, should be the rate-determining step in the catalytic cycle. The better performance of electron-richer PCy 3 than PPh 3 and the requirement of extra 2 equiv. PCy 3 with respect to trans-NiCl(o-Tol)(PCy 3 ) 2 support the speculation of rate-determining oxidative addition of tosylate intermediate to the nickel(0) species.
Molecules 2023, 28, x FOR PEER REVIEW 6 of 9 are most likely reduced to nickel(0) phosphine complexes, which require 2 equiv. more phosphine ligand to be stable, by aryl boronic acids via sequential transmetalation and reductive elimination. The facts that sharply different structural effects of phenol vs. boron counterparts, as well as the isolation of biphenyl-2-yl tosylate as a sole product from catechol, imply that the oxidative addition of nickel to tosylate intermediates, instead of the SuFEx or aryl transmetalation from boron, should be the rate-determining step in the catalytic cycle. The better performance of electron-richer PCy3 than PPh3 and the requirement of extra 2 equiv. PCy3 with respect to trans-NiCl(o-Tol)(PCy3)2 support the speculation of rate-determining oxidative addition of tosylate intermediate to the nickel(0) species.

Scheme 2.
A plausible catalytic cycle for the nickel-catalyzed Suzuki coupling of phenols enabled by SuFEx of tosyl fluoride.

General Information
All reactions were carried out under nitrogen by using standard Schlenk techniques unless otherwise stated. Commercially available chemicals were used as received without further purification. Nickel complexes, Cat 1-Cat 9, were prepared according to previously reported procedures [45,50,51]. The reaction progress was monitored by TLC. Column chromatograph was performed on 300-400 mesh silica gel. 1 H and 13 C NMR spectra were recorded in CDCl3 or Acetone-d6 at ambient temperature on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Germany). Chemical shifts (δ) in NMR are reported in ppm, relative to the internal standard of tetramethylsilane (TMS) or residues of the deuterated solvents. Coupling constants J are reported in Hz. Proton coupling patterns were described as singlet (s), doublet (d), triplet (t), quartet (q), and multiple (m). High-resolution mass spectra (HRMS) were measured with an Agilent mass spectrometer (HR-TOF-MS, EI).

General Information
All reactions were carried out under nitrogen by using standard Schlenk techniques unless otherwise stated. Commercially available chemicals were used as received without further purification. Nickel complexes, Cat 1-Cat 9, were prepared according to previously reported procedures [45,50,51]. The reaction progress was monitored by TLC. Column chromatograph was performed on 300-400 mesh silica gel. 1 H and 13 C NMR spectra were recorded in CDCl 3 or Acetone-d 6 at ambient temperature on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Germany). Chemical shifts (δ) in NMR are reported in ppm, relative to the internal standard of tetramethylsilane (TMS) or residues of the deuterated solvents. Coupling constants J are reported in Hz. Proton coupling patterns were described as singlet (s), doublet (d), triplet (t), quartet (q), and multiple (m). High-resolution mass spectra (HRMS) were measured with an Agilent mass spectrometer (HR-TOF-MS, EI).

General Procedure for Nickel/Phosphine Catalyzed Suzuki Coupling of Phenols with Aryl Boronic Acids Enabled by SuFEx of TsF
To a 25 mL dry flask were added phenol 1 (1.0 mmol), aryl boronic acid 2 (1.3 mmol), TsF (1.1 mmol, 0.193g), trans-NiCl(o-Tol)(PCy 3 ) 2 (3 mol%, 0.022g), PCy 3 (6 mol%, 0.017g), and K 3 PO 4 ·3H 2 O (5.0 mmol, 1.332g). The air in the flask was replaced by N 2 using standard Schlenk techniques before solvents THF (4.0 mL) and H 2 O (1.0 mL) were added by a syringe. The mixture was stirred under N 2 atmosphere at 70 • C (bath temperature) for a given time or monitored by TLC until the reaction completed. The reaction mixture was diluted with CH 2 Cl 2 (15 mL), followed by washing with H 2 O (3 × 10 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to afford biaryl compound 3.
All known products were characterized by comparing their NMR with those reported in literature and the new compound, 2-tosyloxybiphenyl (3sa), was further characterized by HRMS. For details, see Supplementary Materials.

Conclusions
In summary, a practical Suzuki coupling of phenols enabled by SuFEx of tosyl fluoride has been developed by using trans-NiCl(o-Tol)(PCy 3 ) 2 /2PCy 3 as catalyst in the presence of 5 equiv. K 3 PO 4 ·3H 2 O in aqueous THF. Both aryl and phosphine ligands in the aryl nickel complexes have proven to affect their catalytic performance significantly. Water in the system has also been found to play an important role for high catalytic efficiency. Large structural effects from phenols have been observed while the electronic and steric influences from the boron counterpart appeared to be comparably small, if not negligible. A series of electronically and sterically various biaryls could be obtained in good to excellent yields by using the SuFEx enabled, nickel-catalyzed one-pot Suzuki coupling, eliminating the pre-preparation of tosylates. The potentials to apply the practical one-pot procedure in derivatization of complex molecules have also been demonstrated.