Generation of Organozinc Reagents by Nickel Diazadiene Complex Catalyzed Zinc Insertion into Aryl Sulfonates

Abstract The generation of arylzinc reagents (ArZnX) by direct insertion of zinc into the C−X bond of ArX electrophiles has typically been restricted to iodides and bromides. The insertions of zinc dust into the C−O bonds of various aryl sulfonates (tosylates, mesylates, triflates, sulfamates), or into the C−X bonds of other moderate electrophiles (X=Cl, SMe) are catalyzed by a simple NiCl2–1,4‐diazadiene catalyst system, in which 1,4‐diazadiene (DAD) stands for diacetyl diimines, phenanthroline, bipyridine and related ligands. Catalytic zincation in DMF or NMP solution at room temperature now provides arylzinc sulfonates, which undergo typical catalytic cross‐coupling or electrophilic substitution reactions.


S3
Phenylacetic acid S-thiophenylester was prepared following a literature procedure. 6

Chromatography
Column chromatography (CC) on silica gel 60 (35-70 µm particle size) was performed under flash conditions with 0.2 bar pressure. Thin layer chromatography was performed on glass plates coated with silica gel 60 F254 and visualized with UV light (254 nm) and molybdenum stain (Mostain). 7

q-NMR analysis:
Product quantification by quantitative NMR (qNMR) analysis was carried out as follows: the crude reaction mixture was homogeneously dissolved in an appropriate solvent (CDCl3, if suitable). An internal standard (see below) was added by Hamilton µL syringe (or as weighed amount of solid) and the solution was homogenized by swirling. A sample of the reaction mixture (250-350 µL) was placed into an NMR tube containing CDCl3 (250 µL). The sample was well shaken and a proton NMR (delay d1 = 20 s, 16 scans) was recorded. 8 The yield of the reaction is determined by comparison of the integral of the internal standard with the integral of characteristic signals of the reaction product(s) and starting material(s) in the 1

S6
(4 mL) were added and the organic phase was analysed by gas chromatography (GC-MS). The amount substance was determined by integration of the peak areas and calculation of its percentage.

Experimental reaction design
The experimental design consisted in exposing model substrate 1-naphthyl tosylate (1a) to zinc dust in the presence of additives and potential catalysts (complexes, precursors + ligands). After heating overnight, the reaction was quenched with iodine solution to convert any 2a formed to 3a, and the reaction mixture was analyzed by GC-MS. The results are expressed in area-% of detected peaks and thus only give a semiquantitative indication of the composition of the product mixture.

Zincation screening in MeCN solution
The initial experiments included attempted catalytic zincation in MeCN   In ensuing experiments, various transition metal complexes were screened for activity in zincation, but with little success (Table S2). We then returned to nickel catalysts, which had shown some activity in MeCN splitting and focused the screen to NiCl2(PR3)2 complexes, which showed expected activity in reductive coupling (entries 16-19), but also for imine formation, and eventually also some zincation (detected by ArI generation; entry 17). Since imine formation is likely competing with metalation, MeCN appeared as less desirable solvent.
The results of Table S3 confirm that the reaction is more selective in THF than MeCN (Tables S1, S2), and that certain Ni-bisphosphanes give relatively high levels of metalation, besides reduction to naphthalene and biaryl coupling; the latter corresponds to the results reported by Jutand et al, where biaryl coupling was the target reaction. 12 It appeared, however, that ligand effects might divert the reaction away from reductive coupling to metalation or reduction; in particular, an experiment with a diazadiene ligand (entry 14) appeared promising.

Focus ligand screening in nickel-catalyzed zincation of naphthyl tosylate
Based on the initial results in Table S3, a ligand screen for nickel was initiated in THF solution. The nickel-ligand complexes were generated by in situ procedures.

Additional metal screening
With the standard reaction conditions now changed to THF solution, another round of metal complex screening was undertaken (compare Table S2 for initial results in MeCN solution). However, no activity for any other metal was detected. Compared to the preliminary screening (Section 2), the refined screening involved reactions with better soluble NiCl2(dme) as precursor under exclusion of water in all steps, and using accurate quantification of components in the reaction mixture by qNMR (±1-2 mol%).

General screening procedure 4 (GSP4)
A 20 mL Schlenk tube equipped with a stir bar and a glass stopper with Teflon sleeve was evacuated and flooded with argon (3 ´). Zinc powder (262 mg, 4.00 mmol, 4.0 equiv.) [and additive NaI (225 mg, 1.50 mmol, 1.5 equiv.), in case it was used], were placed in the tube, dried by heating under vacuum with a heat gun for two minutes, and allowed to cool to room temperature in vacuum with magnetic stirring. Solvent (3 mL) and activator (iodine: 127 mg, 500 µmol, 0.5 equiv.; or 1,2dichloroethane, 0.2 equiv.) were added, and the suspension was stirred until the brown colour vanishes (iodine), or heated to reflux for 2 min (1,2-dichloroethane). The Ni precursor complex and ligand were added, and the reaction mixture was stirred for 30 minutes at the indicated reaction temperature. Finally, 1-naphthyl tosylate (1a; 298 mg, 1.00 mmol, 1.0 equiv.) was added, and the reaction mixture was stirred at the given temperature for 20 h. The reaction mixture was cooled to 0 °C in an ice/water bath before adding iodine (1.02 g, 4.00 mmol, 4.0 equiv.) and stirring for ten minutes at 0 °C. 13 The mixture was quenched by addition of sat aq NH4Cl (10 mL), followed by Na2SO3 (ca. 500 mg) and Et2O (10 mL) and stirred while the dark brown colour faded. After ca.
5 min, the aqueous phase was separated from the organic phase, and the organic phase was washed with sat aq NH4Cl (2×20 mL) and sat aq NaCl (1×20 mL). The organic phase was dried (MgSO4), filtered and carefully evaporated (ca. 45 °C, 500 mbar) to give crude product, which was analysed by qNMR. S13

qNMR analysis of the reaction mixture
Unless specified otherwise, the crude product was dissolved in CDCl3 (800 µL), and the walls of the flask were carefully rinsed with the resultant solution. The internal standard 1,1,2,2-tetrachloroethane (50 µL) was added using a microliter syringe (50 µL, Hamilton), and the solution was mixed vigorously. The prepared sample was measured without further dilution. 1 H (20 s relaxation delay).
Where possible, the signals of the anticipated products were identified using reported spectroscopic data. Figure S1 shows the aromatic region of an example spectra: Figure S1. Expansion of the aromatic region and the internal standard peak with integrals of relevant peaks for analysis.
The putative peak group of 1-NapOH (black frame) is further magnified. The signals with an asterisk (*) are due to 2,6diisopropylamine from hydrolysed ligand.
The yield of the reaction is determined by comparison of the integral of the internal standard with the integral of characteristic signals of the reaction product(s) and starting material(s) in the 1 H-NMR spectra. Area integration of the signals for internal standard (1,1,2,2-tetrachloroethane in the above case) did not include the 13 C satellites. The shifts of the characteristic crude material components are listed in Table S6. Since 1-naphthol is a very minor product with less than 1% yield in all cases in the catalytic zincation conducted, it will not be listed in the screening tables.

Basic reaction conditions and ligand-to-metal ratio
The first screen with improved experimental design (Table S7, upcoming page) pointed out that: • L1 is superior to L2 from the preliminary screen • additive NaI is not required • use of DMF instead of THF allows performing reactions at r.t.
A systematic variation of the ligand-to-metal ratio (Table S8, upcoming page) with L1 next found that this ligand performs best at a 1:2 nickel-to-ligand ratio as opposed to 1:1 or 1:3 ratios. Likewise, the Ni-L1 system does not require the presence of iodide, since it yields virtually identical results whether Zn is activated with I2 or 1,2-dichloroethane. S15

1 H NMR (500 MHz, [D7]-DMF)
The 1 H NMR spectrum ( Figure S2) is characterized by broadened peaks which may in part be due to paramagnetic residues from the nickel catalyst.      Figure S4. Peak assignments for 1-naphthylzinc tosylate (2a) as derived from 2D NMR data. Assignments for signals with asterisk (*) may be exchangeable.  Figure S5. Full COSY with expansion of the aromatic region (inset); connectivity of the three-spin system in black.

Nickel precatalyst
The nickel precatalyst (NiCl2·dme) was prepared according to the Inorganic Syntheses procedure from NiCl2·6 H2O via partial dehydration, then reaction with trimethyl orthoformate and dme in MeOH. 5 It is also commercially available. Traces of water present in this (hygroscopic) precursor will increase the amount of hydrocarbon in the product at the cost of zinc reagent.

Solvent
Commercial, dry solvent (DMF, NMP) was used and checked for water content by coulometric Karl-Fischer-titration. Any water present in the solvent will increase the amount of hydrocarbon in the product at the cost of zinc reagent.
1,2-Dibromoethane (98%, 17.6 µL, 37.6 mg, 200 µmol, 0.2 equiv.) was added and the walls were rinsed with dry DMF (1 mL) (heat and gas evolution were observed). After stirring at 60 °C for 20 minutes, the reaction mixture was cooled down to room temperature for five minutes in a water bath.
Then it was cooled to 0 °C before adding iodine (1.02 g, 4.00 mmol, 4.0 equiv.) and stirring for ten  Purification by CC gave the desired product. and stirring for ten minutes at 0 °C. Sat aq NH4Cl (10 mL) and sodium sulfite (ca. 1 g) were added and the reaction mixture was stirred until most of the brown color had faded. Et2O (10 mL) was added and the suspension was filtered. Additionally, the pad of Celite was rinsed with Et2O (3´5 mL). The organic phase was separated, washed with a saturated solution of NH4Cl (2´20 mL) and NaCl     iodobenzoate (262 mg, 1.00 mmol, 1.0 equiv.) in DMF (3 mL). After stirring for five minutes at room temperature, the above naphthylzinc tosylate solution (4.5 mL) was added dropwise and the brownish reaction mixture was stirred for 1 h at r.t. After quenching with sat aq NH4Cl (10 mL) and Et2O (10 mL), the suspension was filtered. The organic phase was separated, washed with sat aq NH4Cl (2´20 mL), aq HCl (6 M, 20 mL), water (20 mL) and sat aq NaCl (20 mL 10 mol%) in DMF (6 mL) were reacted according to GP1. After catalytic zincation, a second pre-dried (3·10 -2 mbar, heat-gun) Schlenk tube was charged with Pd(OAc)2 (6.7 mg, 20.0 µmol, 2 mol%), S-Phos (24.6 mg, 40.0 µmol, 4 mol%) and p-bromobenzonitrile (182 mg, 1.00 mmol, 1.0 equiv.) in DMF (3 mL). After stirring for five minutes at room temperature, the above naphthylzinc tosylate solution (4.5 mL) was added dropwise and the brownish reaction mixture was stirred for 1 h at r.t. After addition of sat aq NH4Cl (10 mL) and Et2O (10 mL), the resulting suspension was filtered. The organic phase was separated, washed with a sat aq NH4Cl (2 ´ 20 mL),