Radical-mediated direct C–H amination of arenes with secondary amines† †Electronic supplementary information (ESI) available: Full experimental procedures, spectral characterisation and details of DFT calculations. See DOI: 10.1039/c8sc01747f

Direct radical-based substitution of aryl C–H bonds allows one-pot access to valuable polycyclic aryl amines from simple secondary amines.


General Procedure E: TBTU mediated peptidic coupling
To a solution of acid (1.0 eq.) in anhydrous DCM (0.25 M) was added TBTU (1.6 eq.), DIPEA (4.0 eq.) and NH2Me•HCl (1.5 eq.). The reaction mixture was stirred at rt for 20 h then was quenched with sat. aqueous NaHCO3 solution (1 vol) and the phases separated. The aqueous phase was extracted with DCM (× 3) and the combined organic extracts were washed with sat. brine solution (1 vol), dried over Na2SO4 and concentrated in vacuo. Purification afforded the desired product.

General Procedure F: LiAlH4 reduction
To a stirred suspension of LiAlH4 (2.0-4.0 eq.) in THF (1.0 M) at 0 °C was added a solution of reactant in THF (0.5 M) dropwise. The reaction mixture was then heated at reflux for 2-6 h. The reaction mixture was cooled to 0 °C the quenched sequentially with the dropwise addition of H2O (1.0 eq.), 2 M aqueous NaOH (1.0 eq.) and H2O (5.0 eq.) then stirred for 1 h at rt until the reaction S7 mixture had turned colourless. The resultant slurry was dried over Na2SO4, filtered through a pad of Celite and the pad of Celite was washed with EtOAc. The filtrate was concentrated in vacuo.
Purification afforded the desired products.

General Procedure G: Borane reduction
To a stirred solution of amide (1.0 eq.) in THF (0.25 M) at 0 °C was added a solution of BH3 (4.0 eq.) dropwise. The reaction mixture was stirred at 0 °C for 15 mins, then heated to reflux and stirred for 6 h, after which it was cooled to 0 °C and the reaction was quenched with the dropwise addition of 4 M aqueous NaOH (1 vol). The phases were then separated, and the aqueous phase was extracted with EtOAc (× 3) then the combined organic extracts were washed with sat. brine solution (1 vol), dried over Na2SO4 and concentrated in vacuo. Purification afforded the desired product.
Purification by flash chromatography on silica gel, eluting with 50% EtOAc in pentane afforded the title compound (975 mg, 3.85 mmol, 69%) as an amorphous solid.  Following general procedure F,propanamide (

Route C (E)-N-Methylbut-2-enamide
Following a procedure by Greaney et al., 8 to a stirred solution of methylamine (5.50 mL of a 40% w/w in H2O, 1.1 eq.) and Et3N (7.67 mL, 50 mmol, 1 eq.) in DCM (100 mL) at 0 °C, was added crotonyl chloride (4.79 mL, 50 mmol, 1 eq.) dropwise. The reaction mixture was stirred at 0 °C for 30 min, then warmed to rt and stirred for 24 h. The reaction was quenched with sat. aqueous NaHCO3 (50 mL) and the phases separated. The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with EtOAc afforded the title compound (3.46

General Procedure H: Grignard addition to sulfinimine 13
To a stirred solution of sulfinimine 13 (1.0 eq.) in THF (0.5 M) at -78 °C was added a solution of Grignard reagent (1.5 eq.) dropwise. The reaction mixture was stirred at -78 °C for 2 h after which it was warmed to rt and quenched with sat. aqueous NaHCO3 solution (1 vol). The phases were separated and the aqueous phase was extracted with EtOAc (× 3), then the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification afforded the desired product.

General Procedure I: N-Alkylation and deprotection
To a stirred solution of sulfinamide (1.0 eq.)

General Procedure K: Grignard addition to benzyl bromide
To a stirred solution of benzyl bromide (1.0 eq.) in THF (0.5 M) at 0 °C was added a solution of Grignard reagent (1.1 eq.) dropwise. The reaction mixture was stirred at 0 °C for 30 min then warmed to rt and stirred for 1.5 h after which the reaction was quenched with sat. aqueous NH4Cl (2 vol). The aqueous phase was extracted with EtOAc (× 3) and the combined organic extracts were washed with brine (1 vol), dried over Na2SO4 and concentrated in vacuo. Purification afforded the desired product.

General Procedure L: Ozonolysis reaction
A stream of O2 gas was bubbled through a solution of alkene (1.0 eq.) in DCM (0.2 M) at -78 °C for 5 min. After, O3 gas was bubbled through the solution until the solution turned blue. O2 was then bubbled through the reaction mixture until the solution turned colourless and then PPh3 (1.05 eq.) was added and the reaction mixture was stirred until no peroxides remained (starch/I2 test).
The reaction mixture was warmed to rt and concentrated in vacuo. Purification afforded the desired products.
Purification by flash chromatography on silica gel, eluting with 10% Et2O in hexane afforded the title compound (596 mg, 2.83 mmol, 79%) as a colourless oil.
Purification by flash chromatography on silica gel, eluting with 5% Et2O in hexane afforded the title compound (640 mg, 3.04 mmol, 84%) as a colourless oil. The data is in accordance with the literature.
Purification by flash chromatography on silica gel, eluting with 10% Et2O in hexane afforded the
Purification by flash chromatography on silica gel, eluting with 10% Et2O in hexane afforded the title compound (766 mg, 4.54 mmol, 76%) as a colourless oil. The data is in accordance with the literature.
Purification by flash chromatography on silica gel, eluting with a gradient of 20-40% Et2O in hexane afforded the title compound (7.13 g, 33.5 mmol, 88%) as a pale yellow oil. The data is in accordance with the literature.
Purificatiom by SCX-cartridge afforded the title compound (253 mg, 0.92 mmol, 86%) as a yellow oil. eq.) and H2O (5.0 eq.) then stirred for 1 h at rt until the reaction mixture had turned colourless.
The resultant slurry was dried over Na2SO4, filtered through a pad of Celite and the Celite was washed with EtOAc. The filtrate was concentrated in vacuo. Purification afforded the desired products.

Synthesis of methyl(1-phenyloctan-3-yl)amine
To a stirred solution of 3-phenyl propionitrile (1.00 g, 7.51 mmol, 1.0 eq.) in toluene (15 mL The reaction mixture was heated at reflux for 2 h, then cooled to 0 °C and EtO2CCl (0.72 mL, 7.51 mmol, 1.0 eq.) was added dropwise. The reaction mixture was warmed to rt and stirred for 2 h, after which it was transferred by canular to a suspension of LiAlH4 (1.14 g, 30.0 mmol, 4.0 eq.) in THF (30 mL) at 0 °C. The reaction mixture was then heated at reflux for 4 h, after which it was cooled to 0 °C and the reaction was quenched with H2O (4 mL), 2.0 M aqueous NaOH (2 mL) and H2O (2 mL
Purification by flash chromatography on silica gel, eluting with 10% EtOAc in hexane afforded the title compound 1a (565 mg, 3.08 mmol, 92%) as a colourless oil. HRMS data could not be obtained.
Purification by flash chromatography on silica gel, eluting with 10% EtOAc in hexane afforded the title compound 1f (350 mg, 1.77 mmol, 58%) as a pale yellow oil.

N-Chloro-2-phenethylpyrrolidine 4a
Following general procedure b, using 2-phenethylpyrrolidine (100 mg, 0.48 mmol). The reaction mixture was filtered through celite then the filtrate was collected then concentrated at room temperature in vacuo to afford the crude N-chloroamine 4a as a colourless gum, which was used immediately without further purification.

N-Chloro-2-phenethylpiperidine 4b
Following general procedure b, using 2-phenethylpiperidine (150 mg, 0.67 mmol). The reaction mixture was filtered through celite then the filtrate was collected then concentrated at room temperature in vacuo to afford the crude N-chloroamine 4b as a colourless gum, which was used immediately without further purification.

(1R*,2S*)-2-Benzyl-N-chloro-N-methylcyclohexan-1-amine 6
To a stirred solution of 2-benzylcyclohexan-1-one (2.80 g, 14.9 mmol, 1.0 eq.) in MeOH (30 mL) at rt was added NH2Me (12 mL of an 8.0 M solution in EtOH, 10 eq.) and Ti(O i Pr)4 (9.04 mL, 29.8 mmol, 2.0 eq.). The reaction mixture was stirred for 16 h at rt, then it was cooled to 0 °C and NaBH4 (845 mg, 22.4 mmol, 1.5 eq.) was added portionwise then the reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was concentrated in vacuo then the crude gum was taken up in EtOAc (50 mL) and a 2 M aqueous NH4OH (40 mL) and Na2SO4 were added. The resultant slurry was filtered through a pad of Celite, the Celite washed with EtOAc (400 mL) and the filtrate collected and concentrated in vacuo to afford the crude amine as an inseparable mixture of diastereoisomers (confirmation by LC-MS analysis).
Following general procedure B, using the crude amine mixture (350 mg, 1.72 mmol). Purification by flash chromatography on silica gel, eluting with a gradient of 20-40% DCM in hexane afforded the title compound 6 (280 mg, 1.18 mmol, 69%) as a yellow oil.

Reaction optimisation: equivalents of methanesulfonic acid
The cartridge was washed with MeOH and the filtrate was collected. The cartridge was then washed with sat. methanolic NH3 and the filtrate was collected and concentrated in vacuo.

Workup B: Basic aqueous workup
The crude reaction mixture was taken up in H2O and washed with EtOAc. The aqueous phase was then basified with 2 M aqueous NaOH and extracted with EtOAc (× 3). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo.

1,2,3,4-tetrahydroquinoline 12b
Following general procedure O, using chloroamine 10 (100 mg, 0.37 mmol). Workup A followed by purification by flash chromatography on silica gel, eluting with a gradient of 2-10% EtOAc in pentane afforded an inseparable 91:9 mixture of the regioisomeric title compounds (57 mg, 0.24 mmol, 65%) as a colourless gum. Ratio determined by comparison of aromatic signals in the 1 H NMR spectrum; only signals for the major isomer reported.

Description of theoretical method
Electronic structure calculations using the Gaussian 09 suite of programs [Frisch et al.,Gaussian 09,Revision A.1,Gaussian,Inc.,Wallingford CT] were used to map the stationary points on the electronic potential energy surface (PES) for the cyclization of the aminyl radical, and then for the cyclization of the protonated aminium radical. Molecular geometries were first optimised using hybrid density functional theory, which includes some exact Hartree-Fock exchange. The B3LYP method was used together with the 6-311+G(2d,p) triple zeta basis set. This large, flexible basis set has both polarization and diffuse functions added to the atoms. The resulting rotational constants and vibrational frequencies were then used to compute the enthalpy (H) and Gibbs free energy (G) at 298 K. The calculations were performed in the presence of the solvent, dichloromethane, using the Polarizable Continuum Model which places the solute in a cavity within the solvent reaction field [Tomasi et al., Chem. Rev., 2005, 105, 2999Frisch et al. J. Chem. Phys., 2010, 132, 114110]. Table S1. Molecular geometries for the neutral aminyl radical (element followed by Cartesian co-ordinates in Ångstroms) Table S2. Molecular geometries for the protonated aminium radical (element followed by Cartesian co-ordinates in Ångstroms)