Merging Regiodivergent Catalysis with Atom‐Economical Radical Arylation

Abstract A titanocene‐catalyzed regiodivergent radical arylation is described that allows access to either enantiomerically pure tetrahydroquinolines or indolines from a common starting material. The regioselectivity of epoxide opening that results in the high selectivity of heterocycle formation is controlled by two factors, the absolute configuration of the enantiopure ligands of the (C5H4R)2TiX2 catalyst and the inorganic ligand X (X=Cl, OTs). The overall reaction is atom‐economical and constitutes a radical Friedel–Crafts alkylation.


General Information
All Reactions involving air-and moisture sensitive substances were carried out in flame dried glassware under argon atmosphere using standard Schlenk technique. The THF used in the reactions was freshly distilled over Na before use. All reactions were monitored by thin-layer chromatography (TLC) on Merck silica gel F 254 plates using UV light as visualizing agent (if applicable) and a solution of ammoniummolybdate tetrahydrate (25g/L) and Ce(SO 4 ) 2 •4H 2 O (10g/L) in 10% aqueous H 2 SO 4 followed by heating as developing agents. The crude products were purified by Flash column chromatography on Merck silica gel 50 if not stated otherwise.

1
H NMR and 13 C NMR spectra were measured on Bruker AMX 300 MHz, 400 MHz or 500 MHz spectrometers. 1 H NMR chemical shifts (δ H ) are given in ppm and calibrated by using the residual peak of the undeuterated solvent (CHCl 3 7.26 ppm or C 6 H 5 D 7.16 ppm) as internal reference. 13 C NMR shifts are noted in ppm (δ C ) using the solvent peak as internal reference (CDCl 3 77.0 ppm or C 6 D 6 128.0 ppm). Coupling constants are reported in Hz and represent J H,H couplings, unless explicitly stated otherwise. The diastereomeric and regioisomeric ratios of the products were determined by 13 C NMR spectroscopy of the crude mixtures. It has been demonstrated that the NMR techniques used here are accurate for the determination of diastereomeric and regioisomeric ratios. [1] Compared to 1 H NMR spectroscopy the errors of the ratios in 13 C NMR spectroscopy are typically less than 2% and therefore within experimental error. IR spectra were recorded on Nicolet ATR-IR-Spectrometer TM 380 as neat films on KBr plates. High resoltution mass spectra were measured using a Thermo Fisher Scientific Orbitrap XL mass spectrometer by ESI (+) measurement.
Enantiomeric ratios were determined by chiral HPLC on a Daicel Chiralpak IC-U column. The α D 20 values were measured in chloroform (10 g/L) on the MCP 150 polarimeter by Anton Paar.
The data collection for the single crystal x-Ray analysis was performed on a Bruker D8-Venture diffractometer using multi-layer optics monochromated Cu-K irradiation ( = 1.54178 Å). The diffractometer was equipped with a low-temperature device (Oxford Cryostream 800er series, Oxford Cryosystems, 100(2) K). Intensities were measured by fine-slicing  and -scans and S6 corrected for background, polarization and Lorentz effects. For all data sets an empirical absorption correction was applied. The structures were solved by intrinsic phasing methods and refined anisotropically by the least-square procedure implemented in the SHELX program system. [2] All hydrogen atoms were included using the riding model on the bound carbon atoms. CCDC numbers 1910522 (2g) and 1910523 (3a) contain the supplementary crystallographic data for this paper, which can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

General procedure for bromination-epoxidation reaction sequence of allylic alcohols (GP1).
A solution of allylic alcohol (1.0 eq.) in CH 2 Cl 2 (0.5 mmol/mL) is cooled to -78°C. Over a period of 1h bromine (1.0 eq.) is added via dropping funnel and the reaction is stirred for 1h at -78°C. The reaction is quenched by addition of saturated NaHSO 3 solution (2 mL/mmol substrate). After warming up to room temperature ¾ of the solvent is removed, phases are separated, and the aqueous phase is extracted twice with CH 2 Cl 2 . The combined organic extracts are dried over MgSO 4 and the solvent is removed under reduced pressure. The product was used without further purification. [3] α-bromo alcohol (1.0 eq.) is dissolved in methanol (2 mL/mmol) and finely ground K 2 CO 3 (2.0 eq.) is added. The mixture is stirred for 3 h and the reaction progress is monitored by TLC. After complete conversion ¾ of the methanol is removed in vacuo and the residue is mixed with ethyl acetate (2 mL/mmol). K 2 CO 3 is removed via vacuum filtration and the solvent is evaporated. The crude product is purified via flash column chromatography (silica, Eluent: CH : MTBE 98:2) or distillation (60°C, 10 mbar) depending on reaction scale. [4] S7 2.2 General procedure for the hydrolytic kinetic resolution of terminal epoxides (GP2).
(S,S)-or (R,R)-oligomeric Jacobsen catalyst (0.05 mg/mmol substrate) is added to the racemic terminal epoxide (1.0 eq.). H 2 O (0.53 eq.) is added dropwise and after completed addition the reaction mixture is stirred for 16h. The crude product is purified via flash column chromatography (silica, Eluent: CH : MTBE 98:2). [5] The er of the product is determined via chiral HPLC.

General procedure for the addition of anilinide derivatives to terminal epoxides (GP3a).
A solution of aniline derivative (1.0 eq.) in THF (0.5 mmol/mL) is cooled down to -78°C and nBuLi solution (2.5M in hexane, 1.2 eq.) is added dropwise. The mixture is stirred for 30 min followed by addition of the terminal syn-bromo-epoxide (1.2 eq.). The reaction is allowed to warm to room temperature over 16h. The reaction is quenched by addition of saturated NH 4 Cl solution (2 mL/mmol aniline). The phases are separated, and the aqueous layer is extracted with diethylether three times.
The combined organic extracts are washed with water and brine, then dried over Na 2 SO 4 and the solvent is removed. The crude product is purified via flash column chromatography (silica, Eluent: CH : MTBE, 98:2). The resulting compounds can be air sensitive. [6] S8

General procedure for the aminolysis-epoxidation reaction sequence (GP3b).
A round bottom flask is charged with Aniline derivative (1.0 eq.), terminal syn-bromo-epoxide (1.0 eq.) and SiO 2 (20% of the weight of both reactants). If not stated otherwise the reaction mixture is stirred at room temperature for 24-48h and progress is monitored via TLC. 5 mL of DCM are added, and the suspension is allowed to stir for another 30 min. The mixture is filtered, and all volatiles are removed in vacuo. The crude is purified via flash column chromatography (SiO 2 , Eluent: CH : MTBE, 97:3). The obtained syn-bromo-alcohol (1.0 eq.) is dissolved in 5 mL MeOH and freshly ground K 2 CO 3 (2.0 eq.) is added. The mixture is heated to 40°C and is stirred for 1h. The reaction progress is monitored via TLC. After cooling to room temperature 50 mL of Et 2 O are added, K 2 CO 3 is removed via filtration and the solution is concentrated in vacuo. The crude product is purified via flash column chromatography (SiO 2 , eluent: CH : MTBE 99:1). [7] 2.4 General procedures for the regiodivergent arylation of epoxides.

General procedure for the formation of tetrahydroquinolines GP4.
A Schlenk tube is charged with cat-(OTs) 2 (= L-Kagan-(OTs) 2 ) (L-cat-OTs2 40 mg, 0.05 mmol, 0.1 eq.) and zinc powder (10 mg, 0.15 mmol, 0.3 eq.). The tube is evacuated for 15 min and then flushed with argon. Afterwards 1 mL of dry THF is added, which results in a red solution. The solution is stirred for at least five minutes. Once the color of the solution has changed from red to turquoise the substrate (0.5 mmol, 1.0 eq.) is added via syringe. The syringe is flushed with 1.5 mL of THF and the reaction mixture is allowed to stir for 48 h at room temperature. Afterwards the reaction mixture is filtered through a silica plug and flushed with Diethylether. The solvent is removed under reduce pressure and the crude product is purified via flash column chromatography (silica, Eluent: CH : MTBE 9:1).
The diastereoselectivity and the regioselectivity is determined by 13 C NMR analysis of the crude product.

General procedure for the formation of indolines (GP5).
A Schlenk tube is charged with lutidine hydrochloride (Lut•HCl 22 mg, 0.15 mmol, 0.3 eq.), which is resublimed in vacuo. Zinc powder (10 mg, 0.15 mmol, 0.3 eq.) and ent-cat-Cl 2 (= D-Kagans-complex) 18.4 mg, 0.035 mmol, 0.07 eq.) are added and the Schlenk tube is evacuated for 15 min. Afterwards 1 mL of dry THF is added, which results in a red solution. The solution is stirred until the color of the solution has changed from red to green. Then the substrate (0.5 mmol, 1.0 eq.) is added via syringe.
The syringe is flushed with 1.5 mL of THF and the reaction mixture is allowed to stir for 48 h at room temperature. Afterwards the reaction mixture is filtered through a silica plug and flushed with Diethylether. The solvent is removed under reduce pressure and the crude product is purified via flash column chromatography (silica, Eluent: CH : MTBE 9:1). The diastereoselectivity and the regioselectivity is determined by 13 C NMR analysis of the crude product.

Structural assignment of the tetrahydroquinoline-scaffold and configurational analysis with tetrahydroquinolines 2a and 2g.
The constitution of the THQ scaffold was elucidated by single crystal X-ray diffraction of purified Nmethyl-tetrahydroquinoline 2g (pure trans- isomer: trans-2g). The X-ray also revealed the transconfiguration and the axial orientation of the hydroxy group in the pseuso-chairlike 1,2,3,4tetrahydro-pyridine ring of the THQ 2g.
In the