Mechanistic Studies of the Palladium-Catalyzed Desulfinative Cross-Coupling of Aryl Bromides and (Hetero)Aryl Sulfinate Salts

Pyridine and related heterocyclic sulfinates have recently emerged as effective nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with (hetero)aryl halides. These sulfinate reagents are straightforward to prepare, stable to storage and coupling reaction conditions, and deliver efficient reactions, thus offering many advantages, compared to the corresponding boron-derived reagents. Despite the success of these reactions, there are only scant details of the reaction mechanism. In this study, we use structural and kinetic analysis to investigate the mechanism of these important coupling reactions in detail. We compare a pyridine-2-sulfinate with a carbocyclic sulfinate and establish different catalyst resting states, and turnover limiting steps, for the two classes of reagent. For the carbocyclic sulfinate, the aryl bromide oxidative addition complex is the resting state intermediate, and transmetalation is turnover-limiting. In contrast, for the pyridine sulfinate, a chelated Pd(II) sulfinate complex formed post-transmetalation is the resting-state intermediate, and loss of SO2 from this complex is turnover-limiting. We also investigated the role of the basic additive potassium carbonate, the use of which is crucial for efficient reactions, and deduced a dual function in which carbonate is responsible for the removal of free sulfur dioxide from the reaction medium, and the potassium cation plays a role in accelerating transmetalation. In addition, we show that sulfinate homocoupling is responsible for converting Pd(OAc)2 to a catalytically active Pd(0) complex. Together, these studies shed light on the challenges that must be overcome to deliver improved, lower temperature versions of these synthetically important processes.

H NMR spectra were obtained on a Brüker AVIII HD 400 (400 MHz), AVII 500 (500 MHz) or AVIII HD 500 (500 MHz) spectrometer using the residual solvent as an internal standard. 13 C{ 1 H} NMR spectra were obtained on a Brüker AVIII HD 400 (101 MHz), AVII 500 (126 MHz) or AVIII HD 500 (126 MHz) spectrometer using the 1 H decoupling method and the residual solvent as an internal standard. 19 F NMR spectra were obtained on a Brüker AVIII HD 400 (377 MHz) spectrometer using the 1 H decoupling method. Acquisitions were carried out at room temperature unless otherwise stated. Chemical shifts ( ) are reported in parts per million (ppm) from the residual solvent peak and coupling constants (J) were given in Hertz (Hz) and rounded to the nearest 0.5 Hz. Proton multiplicity is assigned using the following abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), quintet (p), multiplet (m), broad (br), apparent (app.). High resolution mass spectra were recorded either on a Brüker MicroTOF spectrometer under electrospray ionization conditions (ESI) or on a Waters LCT Premier spectrometer under the conditions of chemical ionization (CI) by the internal service at Chemistry Research Laboratory, University of Oxford. Samples for mass spectra were prepared as 1 mg/mL solution in MeOH (HRMS-ESI). Values quoted are a ratio of mass to charge in Daltons. High resolution values are calculated to four decimal places from the molecular formula, all found within a tolerance of five ppm. Infrared spectra were recorded on a Brüker Tensor 27 FT-IR spectrometer. Melting points were determined using a Stuart Scientific Melting Point Apparatus SMP1.

[(4-Me-C6H4)Pd(PCy3)2(Br)] (8b)
Cyclopentadienyl allyl palladium (100 mg, 0.47 mmol, 1.0 equiv.), tricyclohexylphosphine (283 mg, 1.00 mmol, 1.1 equiv.) and 1-bromo-4-methylbenzene (164 mg, 0.96 mmol, 2.0 equiv.) were introduced in a 25 mL round bottom flask. The flask was sealed with a septum, evacuated (< 0.1 mbar) and back-filled with argon twice, then benzene (3.5 mL) was added. The reaction was stirred at room temperature for 16 hours. Pentane (20 mL) was added resulting in the precipitation of a yellow solid. The reaction mixture was filtered, the filtrate was concentrated, and the resulting yellow slurry was triturated in pentane (20 mL) resulting in the precipitation of a solid an off white micro crystalline solid. The mixture was filtered and the solid dried under high vacuum to yield the title compound in

Sodium 4-methoxybenzenesulfinate (16)
4-Bromoanisole (1.50 g, 8.02 mmol, 1.0 equiv.) was added to a solution of CuI (4.58 g, 24.1 mmol, 3.0 equiv.) and SMOPS (4.19 g, 24.1 mmol, 3.0 equiv.) in DMSO (24 mL). The reaction was stirred under a nitrogen atmosphere at 110 °C for 16 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered through a pad of silica. The filtrate was washed with water (3 x 50 mL), brine (3 x 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography (Gradient of EA 30% to 40% in PE) to yield 45% (939 mg, 3.64 mmol) of methyl 3-((4-methoxyphenyl)sulfonyl)propanoate as a white solid.  A solution of methyl 3-((4-methoxyphenyl)sulfonyl)propanoate (500 mg, 1.94 mmol, 1.0 equiv.) in ether (39 mL) was slowly added to a flask containing sodium hydride (60% in mineral oil, 77.4 mg, 1.94 mmol, 1.0 equiv.) and 3 Å activated molecular sieves (5.00 g) under nitrogen atmosphere at 0 °C. The resulting mixture was stirred for 16 hours at room temperature, then quenched with MeOH at 0 °C, filtered through a pad of Celite® which was flushed with methanol, and concentrated under S11 reduced pressure. The resulting solid was dissolved in water (5 mL), washed with dichloromethane (3 x 5 mL), and the solvents were removed under reduced pressure by forming an azeotrope with acetonitrile to yield the title compound in 96% (360 mg, 1

Sodium 4-(trifluoromethyl)benzenesulfinate (19)
The reaction was performed under air. Hydrogen peroxide solution (30% wt. in water, 271 µL, 2.80 mmol, 1.0 equiv.) was slowly added to a solution of 4-(trifluoromethyl)benzenethiol and sodium hydroxide (101 mg, 2.53 mmol, 0.9 equiv.) in methanol (12 mL) and water (12 mL) at 0 °C. The resulting mixture was allowed to warm to room temperature over 16 hours. The solvent was removed under reduced pressure, and the solid was washed with ethyl acetate (ether should be used instead to avoid formation of sodium acetate). The obtained off-white solid was dissolved in a minimum amount of water and precipitated by addition of acetonitrile leading to 49% (275 mg, 1.

Sodium pyridine-4-sulfinate (21)
The reaction was performed under air. Pyridine-4-thiol (1.03 g, 9.3 mmol, 1.0 equiv.) and sodium hydroxide (445 mg, 11.1 mmol, 1.2 equiv.) were dissolved in methanol (45 mL) and water (45 mL). The reaction mixture was cooled to 0 °C, and hydrogen peroxide 30% wt. in water (1.6 mL, 18.2 mmol, 2.0 equiv.) was added dropwise. The reaction was allowed to warm to room temperature over 16 hours. The solvents were removed under vacuum by forming an azeotrope with acetonitrile. The crude off-white solid was recrystallized in a mixture of acetone/

Lithium 6-(tert-butyl)pyridine-2-sulfinate (22)
A solution of n-BuLi (2.15 M in Hexane) (1.3 mL, 2.80 mmol, 0.93 equiv.) was added to a solution of 2bromo-6-(tert-butyl)pyridine (650 mg, 3.04 mmol, 1.0 equiv.) in THF at -78 °C. The reaction was stirred at -78 °C for 40 minutes before slow addition of TIMSO (450 mg, 3.02 mmol, 1.0 equiv.) at -78 °C. The mixture was allowed to warm to room temperature over 10 minutes. The reaction mixture was quenched with MeOH, and the solvents were removed under reduced pressure. The residue was suspended in Et2O, loaded on a silica plug, and washed thoroughly with Et2O. The Et2O fractions were all discarded, then MeOH was added and the product was collected.

General Procedure A: Synthesis of 4-methylphenylsulfinate salts with different counter cations
The reaction was performed under air. Sodium 4-methylbenzene sulfinate (1.0 equiv.) was dissolved in a 1:1 mixture of water and dichloromethane (0.06 M). The reaction mixture was cooled to 0 °C before addition of HCl (2.0 equiv.). The reaction mixture was stirred for 5 minutes at 0 °C, then transferred to a separating funnel. The organic layer was quickly collected and cooled to 0 °C. The aqueous layer was discarded. Water (25 mL per gram of sodium sulfinate introduced) was added and the base XOH was added (0.5 equiv.) and stirred for 5 minutes at 0 °C. The reaction was transferred to a separating funnel, and layers were quickly separated. The organic layer was discarded, and the aqueous layer was concentrated under vacuum by forming an azeotrope with acetonitrile to yield the title compound without further purification.

Potassium pyridine-2-sulfinate (26)
Pyridine-2-thiol (1.00 g, 9.0 mmol, 1.0 equiv.) and potassium hydroxide (454 mg, 8.1 mmol, 0.9 equiv.) were dissolved in methanol (40 mL) and water (5.0 mL). The reaction mixture was cooled to 0 °C, and hydrogen peroxide 30% wt. in water (1.7 mL, 17.5 mmol, 2.0 equiv.) was added dropwise. The reaction was allowed to warm to room temperature over 16 hours, after which 30 mL of water and 100 mL of dichloromethane were added. The aqueous layer was concentrated under vacuum by forming an azeotrope with acetonitrile to yield the title compound without further purification as an extremely hygroscopic off white solid in 69% yield (1.13 g, 6.

Lithium 4-methoxybenzenesulfinate 4-OMe
A solution of n-BuLi (2.50 M in Hexane) (3.4 mL, 8.5 mmol, 0.9 equiv.) was added to a solution of 1bromo-4-methoxybenzene (1.2 mL, 9.6 mmol, 1.0 equiv.) in THF at -78 °C. The reaction was stirred at -78 °C for 40 minutes before slow addition of TIMSO (1.43 g, 9.6 mmol, 1.0 equiv.) at -78 °C. The mixture was allowed to warm to room temperature and stirred for 10 minutes. The reaction mixture was quenched with MeOH, and the solvents were removed under reduced pressure. The residue was suspended in a 1:1 mixture of acetone/diethyl ether and stirred for 2 hours. The suspension was filtered and washed extensively with acetone and diethyl ether, then dried under high vacuum to yield the title compound as a white solid in 74% yield (1.12 g, 6.3 mmol). 1

Sodium 5-(trifluoromethyl)pyridine-2-sulfinate
Procedure performed under air. Hydrogen peroxide solution (30% wt. in water, 590 µL, 6.11 mmol, 2.0 equiv.) was slowly added to a solution of 5-(trifluoromethyl)pyridine-2-thiol (547 mg, 3.05 mmol, 1.0 equiv.) and sodium hydroxide (147 mg, 3.68 mmol, 1.2 equiv.) in methanol (15 mL) and water (15 mL) at 0 °C. The resulting mixture was allowed to warm to room temperature over 16 hours. The solvents were removed under reduced pressure by forming an azeotrope with acetonitrile. The crude solid was recrystallized in acetone (100 mL) and water (6 mL Thanks to the Willis group for proofreading all this looooooong SI! Although you didn't spot this one!
This linear correlation between the amount of Pd(OAc)2 introduced and the amount of 4,4'dimethylbiphenyl 5b formed suggests that the formation of the active Pd(0) species from the Pd(II) precatalyst is mediated by the homocoupling of two sulfinate substrates. The gradient was found to be 0.76, which can be explained by the existence of minor reduction pathways or by catalyst deactivation/decomposition.  The vial was sealed with a microwave vial cap, evacuated (< 0.1 mbar) and back-filled with argon twice, then 1,4-dioxane (4.6 mL) and 1-bromo-4-fluorobenzene (25 µL, 0.23 mmol, 1.0 equiv.) were added. The vial was then placed in a preheated heating block at 150 °C and stirred for 16 hours. The yield of products 3 or 5 were determined by HPLC using 1,3,5-trimethoxybenzene as the internal standard.

DOSY NMR Data
DOSY experiments used the Bruker Double Stimulated Echo (DSTE) pulse sequence with solvent suppression by presaturation during the relaxation delay. 16 spectra with 32K data points were collected for each experiment. The duration of the pulsed field gradient (P30) was 1 ms, and the diffusion time (D2O) was varied between 100-120 ms to allow 5% residual signal with the maximum gradient strength. The gradient strength was incremented in 16 steps from 5% to 95% of the maximum value in a squared ramp. The diffusion data was analysed using the Dynamics module in Topspin 3.

For 11
Average diffusion constant = 3.16E-10 m 2 s -1 Predicted molecular weight from diffusion constant = 853 g.mol -1 Actual molecular weight = 1274 g.mol -1 For 12 Average diffusion constant = 4.27 E-10 m 2 s -1 Predicted molecular weight from diffusion constant = 445 g.mol -1 Actual molecular weight = 624 g.mol -1 Although the predicted molecular weight values are significantly different compared to the actual molecular weight values, they show that compound 11 is approximately two times heavier than compound 12, suggesting that compound 11 is dimeric in solution. The NMR tube was evacuated (< 0.1 mbar) and back-filled with argon twice. 1,4-Dioxane (500 µL) and benzene-d6 (100 µL) were then added to the Young's NMR tube. The NMR tube was sealed, vigorously shaken, and set of NMR spectra ( 1 H, 19 F, 31 P{ 1 H}) was immediately recorded. The NMR tube was evacuated (< 0.1 mbar) and back-filled with argon twice. 1,4-Dioxane (500 µL) and benzene-d6 (100 µL) were then added to the Young's NMR tube. The NMR tube was sealed, vigorously shaken, and set of NMR spectra ( 1 H, 19 F, 31 P{ 1 H}) was immediately recorded. The 19 F NMR and 31 P{ 1 H} NMR spectra of compounds 11 and 17 are very similar and inconclusive. However, the aromatic protons of compounds 11 and 17 are significantly different in CDCl3. Although these experiments were performed in a different solvent (1,4-dioxane/benzene-d6 5:1), the proton NMR spectrum suggests that the sulfinate exchange does not happen at room temperature. Pyridine was introduced as a 1.3*10 -2 mM solution in CDCl3 (600 µL, 0.0079 mmol, 2.0 equiv.), after which a first set of NMR spectra ( 1 H, 19 F, 31 P{ 1 H}) was recorded (t1). As the data suggested that 18 had formed, but was in equilibrium with 11 and free pyridine (broad peaks), a large excess of pyridine (10 µL, 0.12 mmol, 32 equiv.) was added to the NMR tube, and a second set of NMR spectra was recorded (t2). Consumption of 11 was this time total. The NMR sample was subsequently concentrated under reduced pressure, washed with diethyl ether, and compound 11 was reformed as shown in the third set of NMR spectra (t3). Crystallization of compound 18 from dichloromethane/hexane or pyridine/hexane proved to be unsuccessful. and tricyclohexylphosphine (0-12 mg, 0-0.043 mmol, 2.2-11 equiv.) were introduced into a Young's NMR tube. The NMR tube was evacuated (< 0.1 mbar) and back-filled with argon twice. A 0.013 M solution of 1,3,5-trifluorobenzene in toluene-d8 (600 µL, 0.0077 mmol, 2.0 equiv.) was added to the Young's NMR tube. The NMR tube was sealed, vigorously shaken, and placed in a 500 MHz NMR spectrometer that had been pre-equilibrated at 90 °C. NMR experiments were then collected at 90 °C. Conversion of the starting material and yield of product were measured against 1,3,5-trifluorobenzene as the internal standard. (5.4 mg, 0.0078 mmol, 1.0 equiv.) and tricyclohexylphosphine (0-12 mg, 0-0.043 mmol, 2.2-11 equiv.) were introduced into a Young's NMR tube. The NMR tube was evacuated (< 0.1 mbar) and back-filled with argon twice. A 0.013 M solution of 1,3,5-trifluorobenzene in toluene-d8 (600 µL, 0.0077 mmol, 1.0 equiv.) was added to the Young's NMR tube. The NMR tube was sealed, vigorously shaken, and placed in a 500 MHz NMR spectrometer that had been pre-equilibrated at 110 °C. NMR experiments were then collected at 110 °C. Conversion of the starting material and yield of product were measured against 1,3,5-trifluorobenzene as the internal standard. (4.9 mg, 0.0079 mmol, 1.0 equiv.) and tricyclohexylphosphine (0-12 mg, 0-0.043 mmol, 2.2-11 equiv.) were introduced into a Young's NMR tube. The NMR tube was evacuated (< 0.1 mbar) and back-filled with argon twice. A 0.013 M solution of 1,3,5-trifluorobenzene in toluene-d8 (600 µL, 0.0077 mmol, 1.0 equiv.) was added to the Young's NMR tube. The NMR tube was sealed, vigorously shaken, and placed in a 500 MHz NMR spectrometer that had been pre-equilibrated at 110 °C. NMR experiments were then collected at 110 °C. Conversion of the starting material and yield of product were measured against 1,3,5-trifluorobenzene as the internal standard.  ) in 1,4-dioxane (500 µL) was added, followed by 100 µL of benzene-d6. The NMR tube was sealed, vigorously shaken, and heated at 150 °C for 14 hours. The NMR tube was allowed to cool to room temperature, and a set of NMR spectra ( 19 F, 31 P{ 1 H}) was recorded.

Calibration Curves for HPLC Analysis General Method
A 0.04 M solution of substrate in 1,4-dioxane and a 0.04 M solution of 1,3,5-trimethoxybenzene in 1,4-dioxane were prepared. Using a 100 µL glass syringe, six different ratios of these solutions were mixed in six different vials which were topped up with an ~ 10:1 acetonitrile/water mixture.
A linear relation between the ratios of the peak areas obtained and the substrate/standard ratio was obtained using Microsoft ® Excel. Data for the kinetic studies will be directly reported in mM.

Influence of the Addition Order of the Reagents on the Initial Rate
As demonstrated in section 2.2.1, the active Pd(0) species are generated in situ by homo-coupling of two (hetero)aryl sulfinate substrates. Therefore, it is possible to follow the rate of catalyst activation by monitoring the formation of the homocoupling product 5b.
The following data was obtained by injecting a solution of Pd(OAc)2 and PCy3 to a preheated solution of aryl bromide 2, sulfinate 4 and K2CO3. This shows that with this addition order, catalyst activation affects the initial rate of the reaction, as product formation happens concurrently with the reduction of Pd(OAc)2: induction and turnover are conflated, potentially giving misleading initial rate data.  ) and PCy3 (6.4 mg, 0.023 mmol, 0.10 equiv.) were added to a microwave vial equipped with a stirrer bar. The vial was sealed with a microwave vial cap, evacuated (< 0.1 mbar) and back-filled with argon twice, then 1,4-dioxane (4.6 mL) was added and a first aliquot was taken. The vial was then placed in a preheated heating block at 150 °C and stirred for 10 minutes, aliquots were taken every two minute during this period. Then, 1-bromo-4-fluorobenzene (25 µL, 0.23 mmol, 1.0 equiv.) was injected and aliquots were taken every two minutes for 12 more minutes. The amounts of product 5 and 4,4'-dimethylbiphenyl 5b were measured by HPLC against 1,3,5-trimethoxybenzene as the internal standard.
Initial rates were obtained from the first four points of the plot of product formation against time with Microsoft ® Excel as described in the following figure.

S50
The 1 : 2 ratio palladium/ligand ratio was kept constant, and each concentration was repeated three times (runs 1, 2 and 3).
Initial rates were obtained from the first four points of the plot of product formation against time with Microsoft ® Excel as described in the following figure.

S53
The 1 : 2 ratio palladium/ligand ratio was kept constant, and each concentration was repeated three times (runs 1, 2 and 3).
Initial rates were obtained from the first four points of the plot of product formation against time with Microsoft ® Excel as described in the following figure.
Initial rates were obtained from the first four points of the plot of product formation against time with Microsoft ® Excel as described in the following figure.

S59
Each concentration was repeated two times (runs 1 and 2).
Initial rates were obtained from the first four points of the plot of product formation against time with Microsoft ® Excel as described in the following figure.
Representative plot for five concentrations of Pd(OAc)2.

S62
The palladium/ligand ratio was kept ≤ 0.1, and each concentration was repeated two times (runs 1 and 2).
Initial rates were obtained from the first four points of the plot of product formation against time with Microsoft ® Excel as described in the following figure.
Plot for five concentrations of Ar-Br.

Homogeneous vs Heterogeneous Catalysis
The nature of the active species in palladium-catalyzed cross-couplings can be ambiguous. 12 In order to verify that our interpretation of the initial rate studies was not biased by a possible heterogeneous component, we performed a mercury test. The introduction of Hg(0) in the reaction mixture entirely stopped the reactivity, suggesting that the reaction could follow a heterogeneous pathway. However, the mercury poisoning test can sometimes lead to false positives, as Hg(0) can decompose Pd(0)/L and Pd(II)/L systems. 13

Filtration Test
A filtration test was performed to gather more information on the nature of the true catalyst species. A reaction using typical stoichiometry and concentration was halted after 20 minutes at which point the conversion was 20% based on an internal standard (0.0023 mmol.min -1 ). The solution was cooled, filtered through a 0.22 µm PTFE syringe filter under an inert atmosphere, and the filtrate was introduced in a new reaction vial containing K2CO3 and the sulfinate coupling partner 4. Upon heating, the reaction started again with a similar rate of 0.0020 mmol.min -1 , as 41% conversion were reached after 20 minutes and 88% after 120 minutes. Although it is not possible to fully exclude a heterogeneous pathway, we propose, based on the isolation of discrete homogenous intermediates and the filtration test, that the major catalytic pathway is homogenous for the cross-coupling reaction.

Crystallographic and Refinement Data Crystal Structure Determinations
Single crystal X-ray diffraction data for all samples were collected as follows: a typical crystal was mounted on a MiTeGen micromounts using perfluoropolyether oil and cooled rapidly in a stream of nitrogen gas using an Oxford Cryosystems unit. 14 Data were collected with an Agilent SuperNova diffractometer (Cu Kα radiation, λ = 1.54180 Å), a Rigaku XtaLAB Mini II diffractometer (Mo Kα radiation, λ = 0.71073 Å) or a Rigaku XtaLAB Synergy diffractometer (Mo Kα radiation, λ = 0.71073 Å). Raw frame data were reduced using CrysAlisPro. 15 The structures were solved using SHELXT 16 and refined using full-matrix least squares refinement on all F 2 data using the SHELXL-18 17 using the interface OLEX2. 18 All hydrogen atoms were placed in calculated positions (riding model). Further comments regarding individual crystal structures can be found below. Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre under CCDC 1964568-1964578. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Full bond length and bond angle data may be found in the CIFs.

Further Comments on Individual Crystal Structures Compound 6:
The asymmetric unit contains two independent half molecules. One acetate was modelled as disordered over two sites. Restraints were applied with the aid of the FragmentDB module. 19 The second acetate is likewise incompletely occupied, however, attempts to introduce a disorder model were not successful, giving rise to the two Level B Checkcif alerts. Compound 10: A disordered molecule of dichloromethane in the lattice was modelled over two sites. Restraints were applied with the aid of the FragmentDB module. 19 Compound 11-CF3: Minor peaks of electron density were observed adjacent to F1 and C31 atom of the aryl. This was modelled as a substitutional disorder of the CF3 and F units. The occupancies in the final model are 0.77/0.23. Compound 12: A disordered molecule of hexane lying on a special position in the lattice modelled over two sites. Restraints were applied with the aid of the FragmentDB module. 19 Compound 12-OMe: A molecule of dichloromethane lying on a special position in the lattice was modelled with the aid of the FragmentDB module. 19 Compound 13: The sulfinate was modelled as disordered over two sites. A molecule of chloroform in the lattice was modelled as disordered over three sites with the aid of the FragmentDB module. 19 Compound 14: The sulfinate was found to be incompletely occupied (0.85). This was modelled as substitutional disorder with the starting bromide (0.15). The bromide was modelled with isotropic displacement parameters as the refinement became unstable when anisotropic displacement parameters were employed in the refinement. The data was also modelled as an inversion twin. Compound 17: The collected crystal was found to be twinned. The twin matrix [-1.000, 0.000, 0.000, 0.000, -1.000, 0.000, -0.351, -0.922, 1.000] was applied with the twin scale factor refining to 0.16. The sulfinate and aryl groups displayed prolate displacement ellipsoids. These were modelled over two sites employing restraints to geometries and displacement parameters. Compound 20: The asymmetric unit contains two independent molecules.