Pd/Xiang-Phos-catalyzed enantioselective intermolecular carboheterofunctionalization under mild conditions† †Electronic supplementary information (ESI) available. CCDC 1981382 (3ac) and 1981384 (3aa). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0sc01391a

A highly chemo-, regio-, enantio-selectivitive Pd/Xiang-Phos-catalyzed intermolecular carboheterofunctionalization of 2,3-dihydrofurans for the synthesis of polysubstituted benzofused heterocycles mild conditions.


General Information
Unless otherwise noted, all reactions were carried out under a nitrogen atmosphere; materials obtained from commercial suppliers were used directly without further purification. The [α]D was recorded using PolAAr 3005 High Accuracy Polarimeter. 1 H NMR spectra and 13 C NMR spectra were recorded on a Bruker 400 MHz or 500 MHz spectrometer in chloroform-d3, and were calibrated with CDCl3 (δ = 77.00 ppm). 19 F NMR spectra were recorded on a Bruker 400 MHz spectrometer in chloroform-d3. Chemical shifts (in ppm) were referenced to tetramethylsilane (δ = 0 ppm) in CDCl3 as an internal standard. The data is being reported as (s = singlet, d = doublet, dd = doublet of doublet, t = triplet, m = multiplet or unresolved, br = broad signal, coupling constant(s) in Hz, integration).
Reactions were monitored by thin layer chromatography (TLC) using silicycle pre-coated silica gel plates. Flash column chromatography was performed on silica gel 60 (particle size 200-400 mesh ASTM, purchased from Yantai, China) and eluted with petroleum ether/ethyl acetate. All reagents and solvents were used as received from commercial sources (Energy Chemical, J&K ® , Adamas-beta ® , Bidepharm) without further purification. The substrates 2b-f were synthesized according to published procedures 1 . The spectral data of the substrates were consisted with that reported in the literature 2 Table S1. Detailed optimization of the enantioselective intermolecular carboamination of 2,3-dihydrofuran and 1a [a] Entry Pd L* Base Solvent Temp.

Experimental procedures
3.1 General procedure for the synthesis of (S, R S )-N-Me-X4/X5.
To a solution of di-1-adamantylphosphine borane (5 mmol) in dry THF (25 mL) was added n BuLi (1.2 eq, 1.6 M in hexane) dropwise under argon at -78 °C. The resulting solution at this temperature during 1 hour and 1,2-dibromo compound (5 mmol) was added dropwise followed by n BuLi (1.2 eq, 1.6 M in hexane). After 10 minutes at -78 °C, (RS)-sulfinyl imine (6 mmol) was added and the reaction mixture was warmed to room temperature overnight. The reaction mixture was quenched by the addition of NH4Cl (aq.) and diluted with EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated. The crude product was dealed with Et2NH (15 mL) and the resulting solution was stirred under argon at 55 °C. After the reaction was complete (monitored by TLC), solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography on silica gel (Petroleum ether : EtOAc = 10:1) to afford the desired Xiang-Phos.
To a solution of Xiang-Phos (2 mmol) in dry THF (5 mL) was added n BuLi (1.5 eq, 1.6 M in hexane) dropwise under argon at -30 °C. The resulting solution was stilled at this temperature for 1 hour and then MeI (2 eq) was added dropwise at -50 °C. The resulting solution was stilled at this temperature for 1.5 hours and then stilled at 0 °C for another 1.5 hours. The reaction mixture was quenched by the addition of NH4Cl (aq.) and diluted with EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated.
The crude product was then purified by flash column chromatography on silica gel (Petroleum ether: EtOAc = 10:1) to afford the desired N-Me-Xiang-Phos.
NaOPh (4 eq) and H2O (2 eq) were subsequently added under a flow of argon, followed by 2a (4 eq). The mixture was stirred at 20 or 60 o C for 12-36 h. After the reaction was complete (monitored by TLC), solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography on silica gel using hexane/EtOAc as the eluent to afford the desired product 3.
The mixture was stirred at 20 or 50 o C for 24-48 h. After the reaction was complete (monitored by TLC), solvent was removed under reduced pressure. The crude product was then purified by flash column chromatography on silica gel using hexane/Et2O as the eluent to afford the desired product 6.