Nickel-catalyzed migratory alkyl–alkyl cross-coupling reaction†

The selective cross-coupling of activated electrophiles with unactivated ones has been regarded as a challenging task in cross-electrophile couplings. Herein we describe a migratory cross-coupling strategy, which can overcome this obstacle to access the desired cross-coupling products. Accordingly, a selective migratory cross-coupling of two alkyl electrophiles has been accomplished by nickel catalysis. Remarkably, this alkyl–alkyl cross-coupling reaction provides a platform to prepare 2°–2° carbon–carbon bonds from 1° and 2° carbon coupling partners. Preliminary mechanistic studies suggest that chain-walking occurs at both alkyl halides in this reaction, thus a catalytic cycle with the key step involving two alkylnickel(ii) species is proposed for this transformation.


General Information
General information: All reactions were run under a dry argon atmosphere fitted on 8 mL vials unless otherwise noted. Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates.

Reaction Optimization
(1.5 mL). Yields were determined by GC with naphthalene as the internal standard. [b] Isolated yield.

General Procedure (B) for Synthesis of Alkyl Bromines
General procedure for the reduction of carboxylic acid 1 : To a stirred solution of LiAlH4 (1.0 equiv) in THF (0.4 M) was added a solution of carboxylic acid (1.0 equiv) in THF dropwise at 0 °C. The mixture was stirred at 0 °C for another 1 h and then allowed to warm to room temperature for 12 h. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was quenched with 10% NaOH, then the mixture was extracted with EtOAc (3  40 mL), and the organic layers were combined and concentrated in vacuo to give a crude material of alcohol, which was used directly in the next step without further purification.
General procedure for the alcohol tosylation 2 : To a solution of corresponding starting alcohol (1.0 equiv) in DCM (0.4 M), TsCl (1.2 equiv), DMAP (10 mol %) and Et3N (2 equiv) were added. The reaction mixture was stirred rapidly at room temperature for 12 h. The reaction progress was monitored by thin-layer chromatography (TLC). After completion of the reaction, the mixture was extracted with DCM (3  40 mL), and the organic layers were combined and concentrated in vacuo to give a crude material of alkyl tosylate. The crude product was purified via flash chromatography over silica gel.
General procedure for the alkyl bromines: To a solution of corresponding starting alcohol tosylate (1.0 equiv) in Acetone (0.4 M), TBAB (1.2 equiv) was added. The reaction mixture was stirred rapidly at 40 °C for 2 h. The reaction progress was monitored by thin-layer chromatography (TLC). After completion of the reaction, the mixture was concentrated in vacuo to give a crude material of alkyl tosylate. The crude product was then purified via flash chromatography over silica gel.

General Procedure (C) for Synthesis of Alkyl Bromines
To a solution of PPh3 (1.3 equiv) and imidazole (1.3 equiv) in anhydrous DCM (0.4 M), Br2 was added slowly. The reaction mixture was stirred rapidly at 0 °C . Then alcohol was added dropwise. The mixture was stirred at 0 °C for another 1 h and then allowed to warm to room temperature for 12 h. The reaction progress was monitored by thin-layer chromatography (TLC). After completion of the reaction, the mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (3  40 mL), and the organic layers were combined and concentrated in vacuo to give a crude material of alkyl bromine. The crude product was purified via flash chromatography over silica gel.

Synthesis of Dueterium-Labeled Alkyl Bromides
General procedure for the dueterium-labeled alkyl bromides: According to the general procedure B.
Note: one aryl carbon signal is missing due to overlapping, which is consistent with a precedent report (Org. Lett. 2012, 14, 4842-4845. See: SI page 2)

Synthesis of (3-Bromopropyl-3-d)benzene
Procedure for the reduction of 3-phenylpropanal 1 : To a stirred solution of LiAlD4 (210 mg, 5 mmol, 1.0 equiv) in THF (20 mL) was added a solution of 3-phenylpropanal (0.7 mL, 5 mmol, 1.0 equiv) in THF dropwise at 0 °C . The mixture was stirred at 0 °C for another 1 h and then allowed to warm to room temperature for 12 h. The reaction progress was monitored by thin-layer chromatography (TLC).The reaction was quenched with 10% NaOH, then the mixture was extracted with EtOAc (3  40 mL), and the organic layers were combined and concentrated in vacuo to give a crude material of 3-phenylpropan-1-d-1-ol, which was used without further purification.
After completion of the reaction, the mixture was extracted with DCM (3  40 mL), and the organic layers were combined and concentrated in vacuo to give a crude material. The crude product was purified via flash chromatography over silica gel.

Procedure for (3-bromopropyl-3-d)benzene:
To a solution of corresponding 3-phenylpropan-1-d-1ol tosylation (1.0 equiv) in Acetone (0.4 M), TBAB (1.2 equiv) was added. The reaction mixture was stirred rapidly at 40 °C for 2 h. The reaction progress was monitored by thin-layer chromatography (TLC). After completion of the reaction, the mixture was concentrated in vacuo to give a crude material of alkyl tosylate. The crude product was then purified via flash chromatography over silica gel.

Synthesis of Ligands
Synthesis of 6-methoxyquinoline-2-carbonitrile : Under O2, a 200 mL of Schlenk flask equipped with a stir bar was charged with 6-methoxy-2-methylquinoline (5.2 g ,30 mmol), I2 (10.2 mg, 0.04 mmol), NH4F (4.5 g, 120 mmol), TBHP (70% in water, 48.6 mL, 260 mmol), DMSO (50 mL). The reaction mixture was stirred at 70 °C for 48 h in oil bath. After the completion of the reaction (monitored by TLC), the solvent was extracted by EtOAc (3  40 mL) and the organic layers were combined and concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with petroleum ether-EtOAc as the eluent to give the desired product(3.0 g, 54%, a white solid).