Reaction scope and mechanistic insights of nickel-catalyzed migratory Suzuki–Miyaura cross-coupling

Cross-coupling reactions have developed into powerful approaches for carbon–carbon bond formation. In this work, a Ni-catalyzed migratory Suzuki–Miyaura cross-coupling featuring high benzylic or allylic selectivity has been developed. With this method, unactivated alkyl electrophiles and aryl or vinyl boronic acids can be efficiently transferred to diarylalkane or allylbenzene derivatives under mild conditions. Importantly, unactivated alkyl chlorides can also be successfully used as the coupling partners. To demonstrate the applicability of this method, we showcase that this strategy can serve as a platform for the synthesis of terminal, partially deuterium-labeled molecules from readily accessible starting materials. Experimental studies suggest that migratory cross-coupling products are generated from Ni(0/II) catalytic cycle. Theoretical calculations indicate that the chain-walking occurs at a neutral nickel complex rather than a cationic one. In addition, the original-site cross-coupling products can be obtained by alternating the ligand, wherein the formation of the products has been rationalized by a radical chain process.


Supplementary Figure 3. Investigation the Role of Et3SiH
Conclusion: Et3SiH only play the role of generating the active nickel catalyst from the Ni(II) salt.

Supplementary Figure 4. Investigation the in situ Conversion
Procedure: the two reaction was setup at 0.5 mmol scale in 4.0 mL anhydrous DMA. The conversions were determined by GC analysis. Notice: The formation of alkyl-Br and alkyl-I can also be observed in the standard reaction by GC analysis.
Supplementary Figure 5. Results of without Nickel Catalyst concentrated in vacuo to give a crude material of 3-phenylpropan-1-d-1-ol, which was used without further purification.

Supplementary Figure 7. Reactiom on process
Procedure A: Under N2 atmosphere, into an oven-dried 10 mL reaction tube equipped with a magnetic stir bar and sealed with a rubber stopper sequentially added NiI2 (15.6 mg, 0.05 mmol, 10 mol %), BC (18.0 mg, 0.05 mmol, 10 mol %), anhydrous DMA (4 mL) and Et3SiH (20 L, 0.13 mmol, 25 mol %). The mixture was stirred at 35 °C for 30 min, then TBAB (161.2 mg, 0.5 mmol, 1.0 equiv), LiOH (29.9 mg, 1.25 mmol, 2.5 equiv), alkyl tosylate (0.5 mmol, 1 equiv) and aryl boronic acid (0.75 mmol, 1.5 equiv) were added in this order. The resulting mixture was stirred at 35 °C (if aryl boronic pinacol ester was used, stirred at 60 o C) and monitored by GC until the alkyl tosylate disappeared. After the reaction was complete, the mixture was quenched by saturated brine and extracted with ethyl acetate (20 mL  3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was separated on a silica gel column affording the crosscoupling product.  (600 mg, 25 mmol, 2.5 equiv), (3-bromopropyl)benzene (1.52 mL, 10 mmol), (4-cyanophenyl)boronic acid (2.21 g, 15 mmol, 1.5 equiv) and DMA (80 mL) were added to the resulting mixture in this order. The resulting mixture was stirred at 35 °C and monitored by GC until the alkyl bromoride disappeared. After the reaction was complete, the mixture was quenched by saturated brine and extracted with ethyl acetate (40 mL  3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was separated on a silica gel column, affording the cross-coupling product (1.53 g, 70%). Figure 11. Crude GC Spectrum

Supplementary Figure 27. Investigation the Role of Aryl Group
In glovebox, into an oven-dried 10 mL reaction tube equipped with a magnetic stir bar and sealed with a rubber stopper sequentially added NiI2 (15.6 mg, 0.05 mmol, 10 mol %), BC (18.0 mg, 0.05 mmol, 10 mol %), anhydrous DMA (4 mL) and Et3SiH (20 L, 0.13 mmol, 25 mol %). The mixture was stirred at 35 C for 30 min. Then LiOH (29.9 mg, 1.25 mmol, 2.5 equiv), phenylboronic acid (91.5 mg, 0.5 mmol, 1.5 equiv), 3-bromopentane (62 L, 0.5 mmol, 1 equiv) and L5 (8 L, 0.05 mmol, 10 mol %) were added to the resulting mixture in this order. The tube was sealed with a rubber stopper, stirred at 35 C and monitored by GC. After the reaction was complete, the mixture was quenched by saturated brine and extracted with ethyl acetate (20 mL  3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was separated on a silica gel column affording the cross-coupling product.  4, 127.2, 125.9, 40.8, 39.8, 22.4, 21.0, 14.3. Kinetic Studies: With the optimized reaction condition, the kinetics of the reaction was monitored by gas chromatography with 1,3,5-trimethoxybenzene as internal standard. Each reaction was monitored to 0-20% conversion, and rate constants were calculated for each reaction using the initial rates method. Error analysis was conducted using standard equations and calculations.

2-Fluoro-1-methoxy-4-(1-phenylpropyl)benzene (3a):
The reaction was conducted following the general procedure A in a 0.5 mmol scale. The residue was purified by column chromatography on silica gel to afford the product 3a (

2-Methoxy-5-(1-phenylpropyl)pyridine (3c):
The reaction was conducted following the general procedure A in a 0.5 mmol scale. The residue was purified by column chromatography on silica gel to afford the product 3c (

1, 3-Dimethoxy-5-(1-phenylpropyl)benzene (3d):
The reaction was conducted following the general procedure A in a 0.5 mmol scale. The residue was purified by column chromatography on silica gel to afford the product 3d (

2-(1-(3,5-Dimethoxyphenyl)propyl)dibenzo[b,d]thiophene (3l):
The reaction was conducted following the general procedure A in a 0.5 mmol scale. The residue was purified by column chromatography on silica gel to afford the product 3l (

2-Fluoro-1-methoxy-4-(1-phenylpropyl-3, 3-d2)benzene (3a-D2'):
The reaction was conducted following the general procedure A in a 0.5 mmol scale. The residue was purified by column chromatography on silica gel to afford the product 3a-D2 (88.6 mg, 72% yield, rr Computational Methods: All density functional theory calculations were carried out with the Gaussian 09 programs. 15 Density functional B3-LYP [16][17] with a standard 6-31G(d) basis set (LANL2DZ basis set for Ni) was used for geometry optimizations. Harmonic frequency calculations were performed for all stationary points to confirm them as local minima or transition structures and to derive the thermochemical corrections for the enthalpies and free energies. M06 functional [18][19] was used to calculate the single point energies and provide highly accurate energy information. The solvent effects were considered by single point calculations on the gas-phase stationary points with a continuum solvation model SMD. 20 The larger basis set 6-311+G(d,p) (LANL2DZ basis set for Ni) was used in the solvation single point calculations. The energies given in this report are the M06 calculated Gibbs free energies and enthalpies in DMA solvent. Two explicit DMA molecules were added to each Li atom to make the Li four-coordinated. Outer-shell solvent molecules were treated using the implicit solvation model (SMD).
Supplementary Figure 55. Corresponding calculation of thermodynamic stability comparison between active catalyst CP1 and CP1'.
Usually, the energy profile starts with the most stable catalyst species added/generated in the reaction system. In the experimental report, in the presence of BC ligand and reductive Et3SiH species, the catalyst precursor NiI2 would generate BCNi 0 species by ligand exchange and reduction. As shown in Scheme S4, in the presence of solvent molecules (N, N-dimethylacetamide, DMA), solvent molecular coordination occurs to generate three or four-coordinated nickel species CP1 or CP1'. The free energy of three-coordinated Ni 0 (BC)(DMA) CP1 is 10.8 kcal/mol lower than four-coordinated Ni 0 (BC)(DMA)2 CP1'. Therefore, CP1 is considered to be the active catalyst species and set to relative zero point in the calculated reaction energy profile.
Supplementary Figure 56. Calculation of the combine process of Ph-B(OH)2 and LiOH•3DMA to generate CP20.
In our experimental part, LiOH acts as an additive to active benzene boric acid. Considering charge neutralization and coordination number, we calculated the combine process of PhB(OH)2 and LiOH·3DMA to generate CP20 and find it's 27.9 kcal/mol exoergicity, which indicates the existence and stability of lithium phenyl boronate compounds CP20.