Enantioselective Nickel‐Catalyzed anti‐Arylmetallative Cyclizations onto Acyclic Ketones

Abstract Domino reactions involving nickel‐catalyzed additions of (hetero)arylboronic acids to alkynes, followed by cyclization of the alkenylnickel intermediates onto tethered acyclic ketones to give chiral tertiary‐alcohol‐containing products in high enantioselectivities, are described. The reversible E/Z isomerization of the alkenylnickel intermediates enables overall anti‐arylmetallative cyclization to occur. The ring system of the products are substructures of certain diarylindolizidine alkaloids.


General Information
All air-sensitive reactions were carried out under an inert atmosphere using oven-dried apparatus.
2,2,2-Trifluoroethanol (TFE) was purchased from Fluorochem and degassed before use using a stream of argon gas (20 min). All commercially available reagents were used as received unless otherwise stated. Petroleum ether refers to Sigma-Aldrich product 24587 (petroleum ether boiling point 40−60 °C). Thin layer chromatography (TLC) was performed on Merck DF-Alufoilien 60F254 0.2 mm precoated plates. Compounds were visualized by exposure to UV light or by dipping the plates into solutions of potassium permanganate or vanillin followed by gentle heating. Flash column chromatography was carried out using silica gel (Fisher Scientific 60 Å particle size 35-70 micron or Fluorochem 60 Å particle size 40-63 micron). Melting points were recorded on a Gallenkamp melting point apparatus and are uncorrected. The solvent of recrystallization is reported in parentheses.

4-Methyl-N-(pent-4-en-2-yn-1-yl)benzenesulfonamide (S9)
. 9 To a solution of carbamate S8 (1.00 g, 2.98 mmol) in CH2Cl2 (10 mL) under an argon atmosphere at 0 C was added TFA (1.40 mL, 17.9 mmol). The ice bath was removed and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (15 mL), washed with H2O (15 mL) and brine (15 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to give the sulfonamide S9 (485 mg, 69%) as an off-white solid. The analytical data were consistent with those reported previously. 9

N-(2,2-Dimethoxypropyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide
(S11). To a suspension of alkyne S3 5 (1.00 g, 4.78 mmol) and K2CO3 (793 mg, 5.73 mmol) in acetone (15 mL) at room temperature was added chloroacetone (0.42 mL, 5.26 mmol) and the resulting mixture was stirred at room temperature for 24 h. Further chloroacetone (0.21 mL, 2.58 mmol) was added and the mixture was stirred at 50 C for a further 3 h. The reaction mixture was filtered through celite (EtOAc) and the filtrate was concentrated in vacuo to leave the ketone S10, which was used directly in the next step without further purification. The flask containing the ketone S10 was evacuated and backfilled with argon three times, and anhydrous MeOH (25 mL), followed by p-toluenesulfonic acid monohydrate (46 mg, 0.24 mmol) were added. The solution was heated to 70 C and trimethyl orthoformate (1.57 mL, 14.3 mmol) was added, and the mixture was stirred at 70 C for 3 h. The reaction was cooled to room temperature, diluted with Et2O (70 mL), and then washed with saturated aqueous NaHCO3 (20 mL), H2O (20 mL), and brine (20 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (15% EtOAc/pet. ether) to give the dimethyl acetal S11 (

N-(3-Chloroprop-2-yn-1-yl)-4-methyl-N-(2-oxopropyl)benzenesulfonamide (1l).
To a solution of alkyne S11 (467 mg, 1.50 mmol) in acetone (5 mL) under an argon atmosphere at room temperature was added NCS (721 mg, 5.40 mmol) and AgNO3 (300 mg, 1.80 mmol), and the resulting mixture was stirred at 70 °C for 18 h. The reaction was filtered through celite (EtOAc) and concentrated in vacuo to leave the chloroalkyne S12, which was used directly in the next step without further purification. To the chloroalkyne S12 was added MeOH (5 mL) and 10% aqueous HCl (1 mL) and the resulting suspension was stirred at room temperature for 10 min. Saturated aqueous NaHCO3 (10 mL) was added and the volatiles were removed in vacuo. The mixture was extracted with EtOAc (20 mL) and the organic layer was washed with brine (10 mL

4-Methyl-N-(3-oxobutyl)-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (9)
To a suspension of alkyne S1 3 (500 mg, 1.75 mmol) and K2CO3 (363 mg, 2.62 mmol) in acetone (4 mL) at room temperature was added but-3-en-2-one (0.17 mL, 2.10 mmol) and the resulting mixture stirred at room temperature for 36 h and then at 50 C for 20 h. The mixture was filtered through celite (using EtOAc as eluent) and the filtrate was concentrated in vacuo.      Slow diffusion of pentane into a solution of 2j in CH2Cl2 gave crystals that were suitable for X-ray crystallography: ORTEP with ellipsoid probabilities at 50% analysis of the crude material showed the ratio of major:minor products was >19: