Migratory functionalization of unactivated alkyl bromides for construction of all-carbon quaternary centers via transposed tert-C-radicals

Despite remarkable recent advances in transition-metal-catalyzed C(sp3)−C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary-C(sp3)−C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp3) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis. This strategy is complementary to the existing coupling protocols with tert-alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials.

The mixture was extracted with petroleum ether (3 ×15 mL). The combined organic layers were dried with Na2SO4, filtered, evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether) to afford compound S7 (5. 2) An oven-dried 150 mL round-bottom flask equiped with magnetic stirring bar was evacuated and refilled with nitrogen (3 times). To the flask a solution of S7 (3.24 g, 10 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added via syringe. After cooling to 0 °C and stirring for 5 min, to this solution 9-BBN solution in THF (0.5 mol/L, 30 mL, 15 mmol, 1.5 equiv) was added dropwise. The reaction mixture was then stirred at 0 °C additional 30 min, followed by stirring at 35 °C for 8 h. After cooled to 0 °C, the reaction was quenched by adding a NaOH solution (3 mol/L, 16 mL, 48 mmol) followed by the slow addition of H2O2 (30 wt%, 16 mL) solution. After stirring at room temperature for 90 min, the aqueous layer was separated and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, evaporated to dryness under reduced pressure.
The crude residue was purified by flash chromatography (petroleum ether/ethyl acetate = 10 : 1) to give S8 (3.10 g, 9. 3) An oven-dried 50 mL round-bottom flask equiped with magnetic stirring bar was evacuated and refilled with nitrogen (3 times). To the flask was charged S8 (1.70 g, 5.0 mmol, 1.0 equiv), PPh3 (1.57, 6.0 mmol, 1.2 equiv) and DCM (12 mL) against a nitrogen flow. The resulting clear solution was cooled to 0 °C and stirred for 5 min. NBS (1.07 g, 6 mmol, 1.2 equiv) was then added by portions at 0 °C under a nitrogen flow over 5 min. The reaction was allowed to warm to room temperature and stirred for 3 hours. Then the reaction mixture was quenched by adding H2O (10 mL), followed by extraction with DCM (3 × 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 50 : 1) to afford compound 1l (1.

Preparation of compound 1m
An oven-dried 25 mL Schlenk tube equipped with magnetic stirring bar was charged 4-amino-2methyl-1-butanol (1.13 g, 11 mmol, 1.1 equiv) and succinic anhydride (1.48 g, 10 mmol, 1.0 equiv). The Schlenk tube was sealed, evacuated and refilled with nitrogen (3 times). The reaction mixture was stirred at 165 o C for 2 hours. The reaction was cooled to room temperature. Without any treatment, the crude alcohol (1.17 g, 5 mmol, 1.0 equiv) and PPh3 (1.57 g, 6.0 mmol, 1.2 equiv) was added to an oven-dried 50 mL round-bottom flask equipped with magnetic stirring bar, the flask was sealed, evacuated and refilled with nitrogen (3 times). Anhydrous DCM (12 mL) was added via syringe. The resulting clear 9 solution was cooled to 0 °C and stirred for 5 min. NBS (1.07 g, 6.0 mmol, 1.2 equiv) was then added by portions at 0 °C over 5 min under a nitrogen flow. The reaction was allowed to warm to room temperature and stirred for 3 hours. Then the reaction mixture was quenched by adding H2O (10 mL) followed by extraction with DCM (3 × 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20 : 1) to afford compound 1m (1.

Preparation of compound 1n
1) To an oven-dried 150 mL round-bottom flask equipped with magnetic stirring bar was charged cycloheptanecarboxylic acid (0.47 g, 3 mmol, 1.0 equiv). The flask was sealed, evacuated and refilled with nitrogen (3 times). Anhydrous THF (10 mL) was added via syringe and the resulting clear solution was cooled to 0 °C and stirred for 5 min at the same temperature. LiAlH4 (0.19 g, 5.1 mmol, 1.7 equiv) in anhydrous THF (10 mL) was then added dropwise at 0 °C over 10 minutes. After stirring at 0 °C for 1 hour, the mixture was allowed to stir at room temperature for additional 16 hours. The reaction was quenched by adding H2O (0.7 mL) dropwise over 10 min. Then 15% w/w NaOH (0.7 mL) was added and the reaction was allowed to stirred at room temperature for 20 minutes. Then the resulting suspension was diluted with H2O (10 mL) followed by extraction with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10 : 1) to afford compound S9 (0.40 g, 2.9 mmol) in 95% yield as colorless liquid. 1  2) An oven-dried 50 mL round-bottom flask equiped with magnetic stirring bar was evacuated and refilled with nitrogen (3 times). To the flask was charged S9 (0.43 g, 3.0 mmol, 1.0 equiv), PPh3 (0.94 g, 3.6 mmol, 1.2 equiv) and DCM (10 mL) under a nitrogen flow. The resulting clear solution was cooled to 0 °C and stirred for 5 min. NBS (0.64 g, 3.6 mmol, 1.2 equiv) was then added by portions at 0 °C over 5 min under a nitrogen flow. The reaction was allowed to warm to room temperature and stirred for 3 hours. Then the reaction mixture was quenched by adding H2O (10 mL) followed by extraction with DCM (3 × 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether) to afford compound 1n (0.51 g, 2.5 mmol) in 84% yield as colorless liquid. 1

Preparation of compound 1q
An oven-dried 150 mL round-bottom flask equipped with magnetic stirring bar was evacuated and refilled with nitrogen (3 times). To the flask was charged 2,4-dimethyl-3-pentanol (2.8 mL, 20 mmol, 1.0 equiv) and Et2O (40 mL). The resulting clear solution was cooled to 0 °C and stirred for 5 min. After PBr3 (0.75 mL, 8 mmol, 0.4 equiv) was added dropwise at 0 °C, the reaction mixture was allowed to warmed to room temperature and stirred for additional 3 h.

Preparation of compound 1r
An oven-dried 50 mL round-bottom flask equipped with magnetic stirring bar was evacuated and refilled with nitrogen (3 times). To the flask was charged S10 4 (0.64 g, 5.0 mmol, 1.0 equiv), PPh3 (1.57 g, 6.0 mmol, 1.2 equiv) and DCM (10 mL) under nitrogen atmosphere. The resulting clear solution was cooled to 0 °C and stirred for 5 min. NBS (1.07 g, 6.0 mmol, 1.2 equiv) was added by portions at 0 °C over 5 min. The reaction was allowed to warm to room temperature and stirred for 3 hours. Then the reaction mixture was quenched by adding H2O (10 mL) followed by extraction with DCM (3 × 10 mL).
The combined organic layers were dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether) to afford compound 1r (0.38 g, 2.0 mmol) in 40% yield as colorless liquid. 1

Preparation of compound 1s
An oven-dried 50 mL round-bottom flask equipped with magnetic stirring bar was evacuated and refilled with nitrogen (3 times). To the flask was charged S11 5 (0.36 g, 2.0 mmol, 1.0 equiv), PPh3 (0.63 g, 2.4 mmol, 1.2 equiv) and DCM (5 mL) under nitrogen atmosphere. The resulting clear solution was cooled to 0 °C and stirred for 5 min. NBS (0.43 g, 2.4 mmol, 1.2 equiv) was added by portions at 0 °C over 5 min. The reaction was allowed to warm to room temperature and stirred for 3 hours. Then the reaction mixture was quenched by adding H2O (10 mL) followed by extraction with DCM (3 × 10 mL).
The combined organic layers were dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel
The crude residue was purified by flash column chromatography (ethyl acetate) to afford compound S12 (1.10 g, 3.0 mmol) in 60% yield as white solid. 1  2) An oven-dried 50 mL round-bottom flask equipped with magnetic stirring bar was charged S12 (0.73 g, 2 mmol, 1.0 equiv) and PPh3 (0.63 g, 2.4 mmol, 1.2 equiv). The flask was sealed, evacuated and refilled with nitrogen (3 times). DCM (5 mL) was added under a nitrogen flow. The resulting clear solution was cooled to 0 °C and stirred for 5 min. NBS (0.43 g, 2.4 mmol, 1.2 equiv) was added by portions at 0 °C under a nitrogen flow over 5 min. The reaction was allowed to warm to room temperature and stirred for 3 hours. Then the reaction mixture was quenched by adding H2O (10 mL) followed by extraction with DCM (3 × 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1 : 1) to afford compound 1x (0.51 g, 1.
The crude residue was purified by flash column chromatography (ethyl acetate) to afford compound S13  2) An oven-dried 50 mL round-bottom flask equipped with magnetic stirring bar was charged S13 (0.91 g, 2 mmol, 1.0 equiv) and PPh3 (0.63 g, 2.4 mmol, 1.2 equiv). The flask was sealed, evacuated and refilled with nitrogen (3 times). DCM (5 mL) was added under a nitrogen flow. The resulting clear solution was cooled to 0 °C and stirred for 5 min. NBS (0.43 g, 2.4 mmol, 1.2 equiv) was added by portions at 0 °C under a nitrogen flow over 5 min. The reaction was allowed to warm to room temperature and stirred for 3 hours. Then the reaction mixture was quenched by adding H2O (10 mL) followed by extraction with DCM (3 × 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1 : 1) to afford compound 1y (0.

Preparation of compound 1z
An oven-dried 50 mL round-bottom flask equipped with magnetic stirring bar was evacuated and refilled with nitrogen (3 times). To the flask was charged S14 6 (0.56 g, 4.0 mmol, 1.0 equiv), 33% w/w HBr in HOAc (12 mL) and HOAc (5 mL) under a nitrogen flow. The resulting clear solution was stirred at room temperature for 2 hours, then heated to 70 °C and stirred for 1.5 hours, after that stirred at room temperature for 8 hours. After diluted with H2O (10 mL), extraction with ethyl acetate (3 × 10 mL) and H2O (3 × 10 mL), the combined organic layers were dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The crude residue was dissolved in Et2O (12 mL) and

Structure of ligands
L1, L9-L14 were purchased from the commercial supplier and used as received. L8 was prepared according to the literature method. 13 General procedure for the preparation of L2-L7 Step A. To an oven-dried 150 mL round-bottom flask equipped with magnetic stirring bar was charged 2,6-dichloropyridine (0.7400 g, 5 mmol, 1.0 equiv), ferric acetylacetonate (0.0883g, 0.25 mmol, 0.05 equiv). The flask was sealed, evacuated and refilled with nitrogen (3 times). Anhydrous THF (20 mL) and NMP (4.3 mL, 45 mmol, 9 equiv) was added via syringe and the resulting solution was cooled to 0 °C and added corresponding Grignard reagent (7.5 mL, 1M in THF, 1.5 equiv) slowly. After stirring at 0 °C for 1 hour, the mixture was allowed to stir at room temperature for additional 2 hours. The reaction was quenched by adding saturated NH4Cl solution (5 mL). Then the resulting suspension was diluted 18 with H2O (15 mL) followed by extraction with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel to afford corresponding compound.
Step B. To an oven-dried 50 mL round-bottom flask equipped with magnetic stirring bar was charged Ni(PPh3)2Cl2 (0.2 mmol, 0.2 equiv), TBAB (0.3 mmol, 0.3 equiv), Zn (1.0 mmol, 1.0 equiv), the flask was sealed, evacuated and refilled with nitrogen (3 times). Anhydrous DMF (5 mL) and the product of Step A (1 mmol, 1.0 equiv) was added via syringe, the flask was stirred at 55 o C for 24 hours. The resulting suspension was diluted with H2O (10 mL) followed by extraction with ethyl acetate (3 × 10 mL) and H2O (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel to afford corresponding compound.
To an oven-dried 50 mL round-bottom flask equipped with magnetic stirring bar was charged 2,4,6trichloropyridine (1.82 g, 10 mmol, 1.0 equiv) and the flask was sealed, evacuated and refilled with nitro (3 times). Anhydrous DMF (10 mL) was added via syringe and the resulting solution was cooled to 0 °C.
To the suspension, a solution of NaH (0.42g, 2.1 mmol, 1.05 equiv) in MeOH (0.34g, 10.5 mmol, 1.05 equiv) was added dropwise under nitrogen. The resulting mixture was stirred at room temperature for 16 hours, then the mixture was diluted with H2O (15 mL), the organic phase was extracted with ethyl acetate (3 × 10 mL), the combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to afford S19 (1.07 g, 6

Optimization of reaction conditions
To an oven-dried Schlenk tube equipped with a magnetic stir bar was added Ni salt (0.01 mmol, 5.0 mol%), ligand (0.012 mmol, 6.0 mol%), Mn powder (16.5 mg, 0.3 mmol, 1.5 equiv). After the tube was evacuated and refilled with nitrogen (3 times), solvent (1.0 mL), compound 1a (106.2 mg, 0.6 mmol, 3.0 equiv), compound 2a (46.0 mg, 0.2 mmol, 1.0 equiv) was added under nitrogen atmosphere. The tube was capped and stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was analyzed by 19 F NMR with 1-iodo-4-(trifluoromethyl)benzene as internal standard. The pure product was then isolated by column chromatography or preparative TLC on silica gel to afford the desired product.

Representative example of assay yield determination by 19 F NMR
To the crude products was added 1-iodo-4-(trifluoromethyl)benzene (36.3mg, 0.133 mmol) as internal standard. The resulting mixture was analyzed by 19 F NMR and the assay yield was calculated by comparing the integration of signals of the standard (s, 63.0 ppm) and the desired products (d, 87.5 ppm, d, 90.3 ppm). For example, the assay yield of the reaction shown in entry 1 of Table S1 was calculated by the equation "assay yield = integration (3a)/integration (standard)×100%" as 64%.

General procedure for the difluoroallylation reaction
To an oven-dried 10 mL Schlenk tube (see below) equipped with a magnetic stirring bar was added

mmol scale reaction
To an oven-dried 50 mL long-necked flask (see below) with branch equipped with a magnetic

Mechanistic study a) D-labelling experiment
To an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar was added NiBr2·glyme
The flask was sealed, evacuated and refilled with nitrogen (3 times). After S3 (0.88 g, 5 mmol, 1.0 equiv) and anhydrous THF (2 mL) were added, the resulting solution was cooled to 0 °C and stirred for 5 min.
BF3·Et2O (0.39 g, 2.75 mmol, 0.55 equiv) was then added dropwise. The reaction mixture was allowed to stir at room temperature for 3 h. After quenching by adding aqueous solution of NaOH (3 mol/L, 5 mL) followed by H2O2 (36%, 5 mL), the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over Na2SO4. After To an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar was added NiBr2·glyme h. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude residue was analyzed by 19 F NMR which indicated no desired product formed and 97% of 2a remained.

Eq. 2
To an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar was added NiCl2·glyme The tube was capped and stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude residue was purified by preparative TLC on silica gel to afford the compound 9 in

Determination of regioisomeric ratio by 19 F NMR
To identify the regioisomeric ratio of product obtained from the present reaction, the ipsodifluoroallylated product 3a' was isolated. The rr of 3a was calculated by comparing the integral of respective peak in the crude 19 F NMR.