Bench-Stable Nickel Precatalysts with Heck-type Activation

Herein, we report the synthesis and characterization of a new class of air- and moisture-stable phosphine-containing nickel(II) precatalysts, which activate through a Heck-type mechanism. The activities of the precatalysts are demonstrated with a carbonyl–ene coupling reaction.

Characterization of the Cabonyl -Ene Reaction pg. S7 IV.
Procedure and Characterization for Authentic Heck Product Synthesis pg. S10 V.
X-Ray Diffraction Characterization of the Precatalysts pg. S12 VI.
GC/MS Spectra of Heck Activation Product pg. S23 VII. NMR Spectra of Aryl Precursors and Nickel Complexes pg. S25 VIII. References pg. S58
Purity was determined by 31 P, 1 H and 13 C NMR. NMR spectra were obtained in CD 2 Cl 2 , C 6 D 6, or toluene-d 8 purchased from Cambridge Isotope Laboratories and used as received. Norell 5mm NMR tubes with standard septa caps were used. 1 H NMR Spectra were obtained at 400 MHz, 13 C spectra were obtained at 101 MHz with 1 H decoupling, and 31 P spectra were obtained at 126 MHz with 1 H decoupling. 1 H chemical shifts are reported in parts per million relative to TMS (δ = 0.00 ppm) and were referenced to the residual solvent peak. 31 P chemical shifts are reported in parts per million relative to 85% phosphoric acid (δ = 0.00 ppm). The following designations are used to describe multiplicities: s (singlet), brs (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), m (multiplet). For 1 H NMR yields, nitromethane (1 equiv) was used as an internal standard added post reaction, added after dilution with CDCl 3 . Unless otherwise noted, NMR spectra were collected at room temperature (23-27 °C).
Gas chromatography (GC) analyses were performed on an Agilent 7890A GC system with an autosampler and (5%-phenyl)-methylpolysiloxane column coupled to a flame ionization detector. Gas chromatography/ mass spectroscopy (GC/MS) analyses were performed on an Agilent 5975C with a triple-axis detector using an autosampler and (5%phenyl)-methylpolysiloxane column coupled to a quadrupole MSD. Dodecane (1 equiv) was used as an internal standard for determination of yields. Authentic samples of compounds 9 and 10 were synthesized via a previously published method and used to make a calibration curve used to determine yield. 1 Melting points were collected on eletrothermal apparatus using glass capillaries. The meting points were determined open to air on recrystallized material. Infrared spectroscopy (IR) spectra were collected using an Agilent Cary 630 FT-IR spectrometer equipped with an ATR accessory. Peaks from the fingerprint region were omitted from the report for clarity. Elemental analyses (EA) were obtained for the complexes that did not successfully crystallize. EA was performed at Atlantic Microlabs, Inc. High-Resolution Mass Spectroscopy (HRMS) was obtained on a Bruker Daltonics APEXIV 4.7 Tesla FT-ICR-MS outfitted with either an electrospray ionization (ESI) or an IonSense DART ion source. X-Ray diffraction was performed on a Bruker APEX.

II. Synthesis and Characterization of the Aryl Precursors.
Procedure

1-(allyloxy)-2-bromo-4-(tert-butyl)benzene (4):
Under Ar, in an oven-dried round bottom flask charged with a stir bar, 2-bromo-4-(tert-butyl)phenol (20.62 g, 1 equiv, 90 mmol) 3 was added to a round bottom flask containing K 2 CO 3 (37.3 g, 3 equiv) and allyl bromide (21.78 g, 2 equiv). The reaction was stirred for 24 h at room temperature after which H 2 O was added until the salt was dissolved. The desired product was extracted with 3 x 25 mL of DCM. The organic layer was then dried with Na 2 SO 4, filtered, and concentrated. The desired product 4 (19.8 g, 82% yield over two steps) was isolated via automated flash chromatography to as a clear oil. R f = 0.39 in 10% EtOAc/Hexanes. 1

1-chloro-2-(pent-4-en-1-yloxy)naphthalene:
Under Ar, 1-bromo-2-(pent-4-en-1yloxy)naphthalene 5 (2.91 g, 1 equiv, 10 mmol) and CuCl (1.09 g, 1.1 equiv, 11 mmol) were added to an oven dried round bottom flask with a stir bar. The flask was evacuated and refilled with Ar three times. DMF (60 mL) was added and a reflux condenser was fitted to the flask. The flask was evacuated and refilled with Ar three times. The reaction was then heated to reflux and stirred for 18 h. The reaction was then taken off heat and quenched with NH 4 OH and extracted with 25 mL Et 2 O. The organic solution was washed once each with 30% aq NH 4 OH and water. The organic layer was dried over Na 2 SO 4,  (6): Under Ar, in an oven-dried round bottom flask charged with a stir bar, 1.2M i-PrMgBr LiCl (6 mL, 7.8 mmol, 1.3 equiv) is added to 1-chloro-2-iodo benzene (0.72 g, 6 mmol, 1 equiv) in THF (5 mL) at 0 °C. This reaction was stirred for 2h and monitored for conversion. Then prenylbromide (2.1 g, 18 mmol, 3 equiv) was added, the reaction is warmed to room temperature and stirred for 3 h. Then the reaction was filtered through silica with 100% hexanes and then the solvent was removed via rotary evaporation. Compound 6 (0.35 g, 32% yield) was purified via automated column chromatography with 100% hexanes to give a light yellow oil. R f = 0.63 in 100% hexanes 1

III. Characterization of the Cabonyl -Ene Reaction
Synthesized via previously reported procedure in a 78% yield.  In a round bottom flask, p-toluenesulfonic acid (4 mg, 0.022 mmol, 0.1 equiv) was added via syringe to a stirred solution of 3,3-dimethyl-2,3-dihydroinden-1-ol (36 mg, 1 equiv 0.22 mmol) in 5 mL of toluene. The reaction was then heated to 60 °C for 2 h. The reaction is then cooled to room temperature and quenched with aq. NaOH. The product is extracted with 2 x 5 mL portions of Et 2 O and washed with 1 x 5 mL portion of brine. The product is dried over NaSO 4 and purified via automated column chromatography to give desired product 11 as a clear oil (11 mg, 35% yield). Heat activation: In an oven-dried 2 dram vial, 3 mL of toluene was added to precatalyst Ni-6 (20 mg, 1 equiv). The reaction was heated to 60 °C for 24 hours. The reaction was then cooled to room temperature and filtered through a plug of silica. The contents were then analyzed by GC/MS and HRMS.
TESOTf activation: In an oven-dried 2 dram vial, TESOTf (2 equiv) was added to precatalyst Ni-6 (20 mg, 1 equiv) in toluene (3 mL). The reaction was stirred for 24 hours. The reaction was then opened to air and filtered through a plug of silica. The Ni-6 S12

V. X-Ray Diffraction Characterization of the Precatalysts.
General Information: Low temperature diffraction data (φ-and ω-scans) was collected on a Bruker X8 Kappa DUO four-cycle diffractometer coupled to a Smart Apex2 CCD detector for complexes Ni-2, Ni-3a, Ni-3b, Ni-5a, and Ni-6 with Mo Kα radiation (λ = 0.71073 Å) from an IµS micro-source. The crystal structures were then solved using SHELXS 7 and refined against F 2 on all data by full-matrix least squares with SHELXL-97, 8 following established refinement strategies. 9 All hydrogen atoms bound to carbon atoms were included into the model at geometrically calculated positions using AFIX/HFIX commands and refined using a riding model. The isotropic displacement parameter of all hydrogen atoms was fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). All non-H atoms were refined anisotropically. Figure S1. Thermal ellipsoid depiction of compound Ni-2. ORTEP at 50% probability. Figure S2. Thermal ellipsoid depiction of compound Ni-2. ORTEP at 50% probability with disorder omitted.
The crystal structure of Ni-2 was disordered over the aliphatic side chain.  Figure S3. Thermal ellipsoid depiction of compound Ni-3a. ORTEP at 50% probability.
The crystal structure of Ni-5a was disordered over the aliphatic side chain.  Figure S7. Thermal ellipsoid depiction of compound Ni-6. ORTEP at 50% probability. The crystal structure of Ni-6 was disordered over the aliphatic side chain. The disorder was omitted for clarity. Figure S8. Thermal ellipsoid depiction of compound Ni-6 with disorder. ORTEP at 50% probability.
The structure was refined as a two-component non-merohedral twin against the HKLF4 reflections file. Refinement against the HKLF5 file was also attempted but resulted in a poorer fit. The structure contained two molecules in the asymmetric unit, each of which exhibited an alkyl group disordered over two positions; this disorder was modeled with the help of similarity restraints on 1,2-and 1,3-distances and displacement parameters as well as enhanced rigid-bond restraints.