Bismuth-Catalyzed Oxidative Coupling of Arylboronic Acids with Triflate and Nonaflate Salts

Herein we present a Bi-catalyzed cross-coupling of arylboronic acids with perfluoroalkyl sulfonate salts based on a Bi(III)/Bi(V) redox cycle. An electron-deficient sulfone ligand proved to be key for the successful implementation of this protocol, which allows the unusual construction of C(sp2)–O bonds using commercially available NaOTf and KONf as coupling partners. Preliminary mechanistic studies as well as theoretical investigations reveal the intermediacy of a highly electrophilic Bi(V) species, which rapidly eliminates phenyl triflate.

NMR spectra were recorded using 300 MHz Bruker Avance III and 500 MHz Bruker Avance III NMR spectrometers. 1 H NMR spectra (300.13 MHz, 500.1 Hz) were referenced to the residual protons of the deuterated solvent, 1 and are reported to tetramethylsilane (δTMS = 0 ppm), chloroform-d (δTMS = 7.26 ppm) or acetonitrile-d3 (δTMS = 1.94 ppm). 13 C{ 1 H} NMR spectra (75.47 MHz, 125 MHz) were referenced internally to the D-coupled 13 C resonances of the NMR solvent and are reported to tetramethylsilane (δTMS = 0 ppm), chloroform-d (δTMS = 77.16 ppm) or acetonitrile-d3 (δTMS = 1.32 ppm). 19 19 F resonances of CFCl3. Chemical shifts (δ) are given in ppm, relative to deuterated solvent residual peak, and coupling constants (J) provided in Hz. For aryl nonaflates 5a-e and bismine nonaflate 4d, 13 C NMR spectra were acquired with a Bruker BB-1H/19F TBO Probe with inverse gated decoupling. For 1 H NMR waltz16 was used for decoupling. For 19 F the decoupling scheme bi_p5m4sp_4sp.2 with adiabatic chirp pulses was used to ensure the broadband decoupling on 19 F. Sometime small artifacts can be seen in the spectra. 19 F-HMQCs were acquired to show which 19 F signals correlate with the corresponding 13 C nuclei. Figure S1. Ligands utilized in this study.
Ligands L5 and L6 were synthesized by oxidation of the corresponding thioether 5 with metachloroperbenzoic acid (mCPBA). 6 Characterization and spectroscopic data for all of them matches those described in the literature. Ligand L7 was synthesized using the same protocol, which is described below.

Synthesis of diarylsulfone ligand L7
A round bottomed flask equipped with a stir bar was charged with bis(4-(trifluoromethyl)phenyl)sulfane 7 (2.3 g, 7.1 mmol, 1.0 equiv.) and 20 mL of CH2Cl2 under air. The reaction mixture was cooled to 0 °C, and mCPBA (3.7 g, 21.4 mmol, 3.0 equiv.) was added in portions as a solid. The reaction is stirred overnight slowly warming to room temperature. Then, a solution of saturated Na2CO3 was added slowly (vigorous CO2 evolution) and the resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to give L7 as a white solid (2.245 g, 6.3 mmol, 89%). The product obtained was used without further purification.   Phenylbismines 9a-d were synthesized according to a previously reported protocol. 8 Phenylbismines 9e, 9f and 6 were synthesized following the procedure described below.

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General procedure for the synthesis of phenylbismines. 9 A Schlenk flask equipped with a stir bar was charged with BiBr3 (0.66 equiv.), BiPh3 (0.33 equiv.) and Et2O (8 mL) under an Ar atmosphere and stirred at room temperature for 3 h. THF (10 mL) was added to completely dissolve the yellow precipitate, and this solution was added dropwise to a -78 °C dilithiated ligand solution. The dilithiated ligand was prepared in a separate Schlenk flask from the corresponding ligand (1 equiv.), dissolved in THF (30 mL), with nbutyllithium (2.6 M in hexanes, 2.1 equiv.) at -78 °C for 1 h. Following the addition of the bismuth compound to the dilithiated ligand, the reaction was stirred overnight, slowly warming to room temperature. The reaction was quenched by the addition of brine (20 mL), extracted with EtOAc (40 mL), and re-extracted with CH2Cl2 (2 × 50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to give a thick yellow residue. The crude material was purified by flash chromatography (silica gel, hexanes/EtOAc) to give the corresponding phenylbismine as a white solid.
As shown in Table 1, bismine containing CF3 groups furnished 2a in high yields after the oxidation-reductive elimination sequence. Although 9a also generated 2a in good yields, it was partially decomposed after reaction completion, and a significant amount of benzene was detected (>10%). On the other hand, when 6 was oxidized in presence of NaOTf at 90 °C, an excellent yield S14 of 2a was obtained , together with the corresponding Bi(III)-OTf (4c) and trace amounts of benzene ( Figure S3). Similar results were obtained with 9f. Figure S3. 1 H NMR (top) and 19 F NMR (bottom) analysis of the reaction crude after the oxidation-reductive elimination sequence with 6 using 1-fluoro-2,6-dichloropyridinium tetrafluoroborate (1.0 equiv.) and NaOTf (5.0 equiv.) in CDCl3 at 90 °C.
Based on these results, the corresponding triflates of 9f and 6 (4b and 4c, respectively) were synthesized to be tested in the catalytic reaction, together with the corresponding triflate of 9c (4a) as a control catalyst (see below). This experiment corresponds to the data shown in Figure 2A in the manuscript.
In a culture tube, bismine triflate 4c (17.7 mg, 0.025 mmol), phenylboronic acid (1a, 3.1 mg, 0.025 mmol), Na3PO4 (8.2 mg, 0.05 mmol) and 20 mg of MS were mixed with anhydrous CDCl3 under an Ar atmosphere and the reaction was stirred for 3 h at 60 °C. Then, 1,3,5trimethoxybenzene was added as internal standard and the crude reactions were analyzed by 1 H NMR to determine the yield of 6 (see Table S2). CDCl3 under an Ar atmosphere and the reaction was stirred for 3 h at 60 °C. Then, 1,3,5trimethoxybenzene was added as internal standard and the crude reactions were analyzed by 1 H NMR to determine the yield of 6 (see Table S3). This experiment corresponds to the data shown in Figure 2B in the manuscript.
First, we performed a one-pot protocol consisting in a first oxidation with XeF2 at 0 °C, followed by the addition of 1.0 equiv. of TMSOTf.

Synthesis and isolation of 14
The synthesis and isolation of the Bi(V) difluoride species 14 was attempted following the protocol described below.
In a 10 mL Schlenk flask, phenyl bismine 6 (128 mg, 0.2 mmol) was mixed with anhydrous CHCl3 (5 mL) under an Ar atmosphere and the reaction was cooled to 0 °C. Then. XeF2 (34 mg, 0.2 mmol) was added at once as a solid, and the mixture was stirred for 1 h at 0 °C. Then, pentane was added to the suspension (3 mL), and the solid was separated by decantation. The pale-yellow solid was washed with pentane (2 × 2mL), and dried under vacuum for a period of 2 h. The title compound was obtained in >95% yield.

Reductive elimination from 7a -HRMS studies
This experiment corresponds to the data shown in Figure 2B in the manuscript.

Oxidation-reductive elimination sequence
This experiment corresponds to the data shown in Figure 2B in the manuscript.

Optimization for the Bi-catalyzed coupling of arylboronic acids and NaOTf
General Procedure: A culture tube equipped with a stir bar was charged with phenylboronic acid (3.1 mg, 0.025 mmol). A teflon cap was fitted, and the tube was evacuated and refilled with Ar (3 cycles). The tube was transferred to a glove box, bismine catalyst (X mol%), 1-fluoro-2,6dichloropyridinium tetrafluoroborate (7.0 mg, 1.1 equiv.), NaOTf (4.7 mg, 1.1 equiv.), base (Y equiv.) and additive (Z mg) were added. The tube was removed from the glove box and subjected to a positive pressure of Ar. CDCl3 (0.5 mL) was added and the reaction was then stirred 16 h at the indicated temperature. Then, the yield was calculated by 19 F NMR using 1-fluoro-4nitrobenzene as internal standard (addition by weight).       General Procedure: A culture tube equipped with a stir bar was charged with phenylboronic acid (3.1 mg, 0.025 mmol). A teflon cap was fitted, and the tube was evacuated and refilled with Ar (3 cycles). The tube was transferred to a glove box, bismine catalyst (X mol%), 1-fluoro-2,6dichloropyridinium tetrafluoroborate (7.0 mg, 1.1 equiv.), KONf (9.3 mg, 1.1 equiv.), Na3PO4 (Y equiv.) and 5Å molecular sieves (Z mg) were added. The tube was removed from the glove box and subjected to a positive pressure of Ar. CDCl3 (0.5 mL) was added and the reaction was then stirred 16 h at the corresponding temperature. After the indicated time, the yield was calculated by 19 F NMR using 1-fluoro-4-nitrobenzene as internal standard (addition by weight).

Computational details
All calculations were perfomed using the development version of ORCA 4.2. [26][27] Geometries were optimized using the hybrid Perdew-Burke-Ernzerhof functional (PBE0) [28][29] in conjunction with the def2-TZVP basis set, 30 the auxiliary def2/J basis set 31 and the default effective core potential (ECP) for Bi. 32 Fine integration grids (grid6) were applied. The dispersion correction by  Figure S14). However, 7a could also undergo isomerization to 7a-trans through a kinetic barrier of G ‡ = 5.8 kcal/mol (TSra). The trans isomer 7a-trans is computed to be 2.7 kcal/mol higher in energy than 7a, being the latter the most stable species. This extra stabilization of the cis form is suggested to be a result of the coordination of the -SO2moiety in 7a, thus providing electronic density to the highly electrophilic Bi V center. Other isomers were also evaluated (see Figure S15), but 7a resulted to be the most stable conformer. Bismines locating two phenyl groups in apical were not considered, as they are predicted to be highly energetic and therefore unlikely to be formed according to the polarity rule Then, 7a can undergo reductive elimination either through a 3-membered ring transition state (TS1a, G ‡ = 24.7 kcal/mol) or through a 5-membered ring transition state (TS2a, G ‡ = 21.2 kcal/mol). As shown in Figure S13, the 5-membered TS2a is slightly favored over the 3-membered TS1a (G ‡ = 3.5 kcal/mol), pointing towards TS2a as the preferable pathway for the C-O bond forming event. Furthermore, the reductive elimination from 7a, which was detected by HRMS (see section 3.3.3), proceeds in less than 10 minutes at room temperature (ca. 22 °C). This result agrees with the theoretical results depicted in Figure S14.
Similar results were obtained when the DFT profile of the reaction starting from ditriflate bismine 7b was studied ( Figure S16). Similarly to 7a, 7b can also undergo isomerization via turnstile pseudo-rotation to furnish 7b-trans (G = 2.8 kcal/mol) through a kinetic barrier of G ‡ = 6.1 kcal/mol (TSrb). In this case, the cis isomer is also the most stable form probably due to coordination of the -SO2moiety to the electrophilic Bi(V) center. In line with the reactivity observed with 7a, 7b could also undergo reductive elimination through two different cyclic transition states. Indeed, a 3-membered ring transition state (TS1b) would yield 4c and 2a through a kinetic barrier of G ‡ = 24.5 kcal/mol, while a 5-membered transition state (TS2b) would yield the same products through a pathway with a lower activation barrier (G ‡ = 22.9 kcal/mol). In this case, although TS2b it is slightly favored over TS1b, the energetic difference between both routes (G ‡ = 1.6 kcal/mol) is not sufficient to fully rule out TS1b. Also, it is important to note than in both profiles the reaction is highly exergonic (Figures S14 and S16, G = -40.8 and -43.2 kcal/mol, respectively), showing that this reductive elimination is thermodynamically favored independently of the anions bonded to 7.
The most relevant structures of the reductive elimination profiles from species 7a and 7b are shown in Figures S17 and S18, together with selected structural parameters.   Figure S19). As reported in the main text, the natural charge on the Bi center decreased from 2.179 in 7a, to 1.849 and 1.884 in TS1a and TS2a, respectively, to finally 1.499 in 8. This progressive change of charge at the Bi center points out to a concerted reductive elimination. In addition, the C atom directly attached to the Bi center (C1) also experienced a substantial change, becoming positively charged at the transition state (see Figure S19 and Table S8). This buildup of positive charge on the C atom directly bound to the Bi center was also observed experimentally in previous reductive elimination studies from Bi V species. 8    Figure S19 and Table S8). This result, together with the WBI > 0 for the respective C-O bonds being formed in TS1a and TS2a (see Figure S19 and Table S9) indicate that the C1-Bi cleavage happens simultaneously with the O1(')-C1 bond forming event, as expected in a concerted reductive elimination step.

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Similar results were obtained when NBO analysis was performed on the most relevant species involved in the reductive elimination from 7b (see Figure S20 and Table S9).