Asymmetric remote C-H borylation of internal alkenes via alkene isomerization

Recent years have witnessed the growing interest in the remote functionalization of alkenes for it offers a strategy to activate the challenging C–H bonds distant from the initiation point via alkene isomerization/functionalization. However, the catalytic enantioselective isomerization/functionalization with one single transition metal catalyst remains rare. Here we report a highly regio- and enantioselective cobalt-catalyzed remote C–H bond borylation of internal alkenes via sequential alkene isomerization/hydroboration. A chiral ligand featured twisted pincer, anionic, and non-rigid characters is designed and used for this transformation. This methodology, which is operationally simple using low catalyst loading without additional activator, shows excellent enantioselectivity and can be used to convert various internal alkenes with regio- and stereoisomers to valuable chiral secondary organoboronates with good functional group tolerance.


General Information
Ether, tetrahydrofuran, 1,4-dioxane and toluene were distilled from sodium benzophenoneketyl prior to use and dichloromethane was distilled from CaH 2 . Pinacolborane (HBpin) (97%) was purchased from TCI and used as received. NaHBEt 3 (1.0 M in THF) were purchased from Aldrich and used as received. Co(OAc) 2 (99%) were purchased from Alfa and used as received. The other commercial available chemicals were used as received. NMR spectra were recorded on a Bruker-400 instrument. 1 H NMR chemical shifts were referenced to tetramethylsilane signal (0 S249 ppm), 13 C NMR chemical shifts were referenced to the solvent resonance (77.00 ppm, CDCl 3 ). The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br = broad. IR spectra were recorded on a Perkin-Elmer Spectrum One FTIR spectrometer with diamond ATR accessory. High-resolution mass spectra (HRMS) were recorded on EI-TOF (electrospray ionization-time of flight). X-ray diffraction data was obtained on Gemini A Ultra. L1-L3 were prepared according to the methods reported by our group. 1-3 S1-S5 were prepared according to the literature. 4

General procedure for the preparation of L4 -L5, Lsa-Lsh
A 50 mL oven-dried round-bottom flask was charged with amine S1 (5.0 mmol), picolinic acid (8.0 mmol) and DCM (25 mL). After stirred at room temperature for 5 min, DCC (8.0 mmol) and DMAP (8 mmol) was added to this reaction mixture and stirred at room temperature for 24 h.

Synthesis of L6-L9: (S)-N-(1-hydroxy-3-phenylpropan-2-yl)-2-iodobenzamide (S6b):
2-Iodobenzoic acid (24.80 g, 100 mmol) was dissolved in dichloromethane (200 mL) in a 250 mL roundbottomed flask and cooled on an ice bath. Oxalyl chloride (13.0 mL, 150 mmol) and DMF (5 drops) was added in sequence under stirring, and the reaction was allowed to come to room temperature. After 8 hours the reaction mixture was evaporated to give the crude product without purification and used in the next step. The acyl chloride was dissolved in dichloromethane (30 mL) and added dropwise to a solution of the amino alcohol S6a (

Procedures for Synthesis of Starting Materials
General procedure A for preparation of alkenes: Under N 2 atmosphere, a 100 mL flame-dried Schlenk flask was charged with RP + Ph 3 X -(12mmol, 1.2 eq.) and 30 mL of THF. n-BuLi (14.4 mmol,5.8 mL,2.5 M in THF) was added dropwise over 10 min at -20 o C. After stirred at -20 o C for 40 min, the corresponding aldehyde in 10 mL of THF was added dropwise. Then the mixture was warmed to room temperature slowly and stirred for another 18 h. After completion of the reaction, the reaction mixture was quenched with saturated solution of NH 4 Cl (25~30 mL) under ice cooling and the organic layer was separated. The aqueous layer was extracted with EtOAc (2x30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 200-300 mesh) to afford the corresponding alkene (a mixture of E/Z isomer and the ratio is unknown).

General procedures B for preparation of alkenes:
Under N 2 atmosphere, a 100 mL flame-dried Schlenk flask was charged with RP + Ph 3 X -(12mmol, 1.2 eq.), NaH (14.4 mmol) and 30 mL of THF. The mixture was refluxed for 2 h. Then the corresponding aldehyde in 10 mL of THF was S268 added dropwise at 0 o C. Then the mixture was warmed to room temperature and refluxed for [4][5][6][7][8][9][10][11][12] h. After completion of the reaction, the reaction mixture was quenched with saturated solution of NH 4 Cl (25~30 mL) under ice cooling and the organic layer was separated. The aqueous layer was exracted with EtOAc (2x20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 200-300 mesh) to afford the corresponding alkene (a mixture of E/Z isomer and the ratio is unknown).   3-(m-tolyl)
The reaction mixture was refluxed for 20 h. After cooling to room temperature, the mixture was concentrated and purified by column chromatography using PE/EA = 20:1 as the eluent to afford S275 ester as a light yellow oil.
Under N 2 atmosphere, a 50 mL flame-dried Schlenk flask was charged with ester and 10 mL Et 2 O.
To this reaction mixture, CH 3 MgBr (4.2 mL, 3.0 mol/L) was added slowly at 0 o C. Then the mixture was warmed to room temperature and stirred for 20 h. After completion of the reaction, the reaction mixture was quenched with saturated solution of NH 4 Cl ( 25-30 mL) and the organic layer was separated. The aqueous layer was exracted with EtOAc (3x20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 200-300 mesh) using PE/EA = 10/1 as the eluent to afford the alkene (1.1181 g, 90% yield for two steps, Z/E ratio: 4.0/1) as a colorless oil. 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 7.32-7.14 (m, 2H), 7. 24-7.14 (m, 3H), 5.49-5.44 (m, 0 (m, 7H), 1.18 (s, 6H). All the spectroscopic data were in agreement with the reported ones. 13
The mixture was extracted with EtOAc (3x60 mL) and the organic phases were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The resulting crude product was purified by column chromatography using PE/EA = 5/1 as the eluent to afford alkene 1v (4.2942 g, 19.7
Then the mixture was filtered and the filtrate was evaporated to give the crude alcohol without purification and used in the next step.

Linear effect reaction
L7 with different ee value was prepared by mixing L7 and L7 rac in THF solution.
Prepared according to the general procedure using Co(OAc) 2 (0.025 mmol), L7 (0.030 mmol), Et 2 O (1 mL), 1a (0.5 mmol) and HBpin (90 μL, 0.6 mmol). After 20 h, the resulting solution was added 20 mL of ether and filtered through a pad of silica gel, washed by ether (10 mL × 2). The combined filtrates were concentrated and purified by flash column chromatography using PE/EtOAc = 20/1 as the eluent to afford 2a as a colorless oil and ee value was determined by HPLC.