Cobalt catalyzed sp3 C–H amination utilizing aryl azides

A dinuclear Co(ii) complex supported by a modular, tunable redox-active ligand system is capable of selective C–H amination to form indolines from aryl azides in good yields at low (1 mol%) catalyst loading.

Procedures

2,2'-Bis(diphenylacetamido)diphenylamine (HN(o-PhNHC(O)Ph) 2 ) [H 3 L Ph ].
A suspension of HN(o-PhNH 2 ) 2 1 (6.31 g, 31.7 mmol) in dichloromethane (DCM, 50 mL) was lowered to 0 C under an atmosphere of N 2 . Triethylamine (9.75 mL, 63.4 mmol) was then added, followed by benzoyl chloride (8.10 mL, 63.4 mmol). The mixture was stirred at 0 C for 1 h. The reaction mixture was slowly warmed to room temperature and stirred for an additional 20 h. The resulting pale brown solution was extracted with saturated aqueous NaHCO 3 (3 x 30 mL), and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude solid was recrystallized by layering hexanes over a concentrated DCM solution of the product (10.98 g, 85 %

b) Co(II) Complexes
The cobalt complexes are all prepared by similar procedures. The cobalt complexes can be prepared as either dipotassium or bistetraethylammonium salts. The choice of counter cation does not impact the amination reactions.
. To a solution of [HN(o-PhNHC(O) t Bu) 2 ] (120 mg, 0.327 mmol) in dry dimethylformamide (DMF, 10 mL) was added potassium hydride (39.3 mg, 0.971 mmol) inside a nitrogen-filled atmosphere dry box. When gas evolution ceased, CoBr 2 (71 mg, 0.327 mmol) was added as a solid and the mixture stirred. After stirring for 3 h, DMF was removed under high vacuum and the resulting solid was dissolved in CH 3 CN (15 mL), filtered through a medium porosity frit, and the filtrate was concentrated to dryness. Deep green X-ray diffraction quality crystals were obtained by slow diffusion of diethyl ether into a concentrated CH 3 CN solution of K 2 [Co 2 (L tBu ) 2 ] (65 %, 179 mg). IR (KBr, cm -1 ) (CO) 1664;  eff = 4.67(6) B (Evans Method, CD 2 Cl 2 , 298K);  max , nm (, M -1 cm -1 ) (CH 3  After stirring for 3 h, DMF was removed under high vacuum and the resulting solid was dissolved in CH 3 CN (15 mL), filtered through a medium porosity frit, and the filtrate was concentrated to dryness. Deep green X-ray diffraction quality crystals were obtained by slow diffusion of diethyl ether into a concentrated CH 3 CN solution of (Et 4 N) 2   When gas evolution ceased, CoBr 2 (78 mg, 0.358 mmol) was added as a solid, and the mixture was stirred for 1 h. Tetraethylammonium bromide (75 mg, 0.358 mmol) was then added to the deep magenta-teal solution. After stirring for 3 h, DMF was removed under high vacuum and the resulting solid was dissolved in CH 3 CN (15 mL), filtered through a medium porosity frit, and the filtrate was concentrated to dryness. Deep teal X-ray diffraction quality crystals were obtained by slow diffusion of diethyl ether into a concentrated CH 3 CN solution of (Et 4 N) 2

c) Azides
General Procedure A. Procedure from the literature 2 was modified as follows: alkyne (1.2 equiv.) was added to a solution of 2-bromoaniline (1.0 equiv.), PdCl 2 (PPh 3 ) 3 (5 mol %), and CuI (2 mol %) in THF at room temperature. N 2 was bubbled through the stirring mixture for 30 mins, after which a solution of ethanolamine in H 2 O (3.0 M, 12 equiv.) was added slowly. The mixture was heated to reflux until thin layer chromatography indicated complete consumption of starting material. The reaction was cooled to room temperature and extracted with DCM. The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. Purification by flash chromatography on silica gel as indicated afforded the desired product.

S7
General Procedure B. Aniline (1.0 equiv.) and Pd/C (10 wt. %, 0.1 equiv.) in THF (0.12 M) were stirred at room temperature under a balloon of H 2 . After thin layer chromatography indicated complete consumption of the starting material, the mixture was filtered through Celite and washed with Et 2 O to afford crude product. NaNO 2 (1.2 equiv.) was added to a stirring solution of crude aniline (1.0 equiv.) in a 1:1 mixture of AcOH and H 2 O (0.8 M) at 0 °C. The mixture was stirred for two hours, and NaN 3 (1.4 equiv.) was added. The reaction was warmed to room temperature. After 30 minutes, H 2 O and Et 2 O were added. Na 2 CO 3 was added slowly to neutralize the solution until pH 7 was reached. The phases were separated, and the aqueous phase was extracted with Et 2 O . The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. Purification by flash chromatography on silica gel as indicated afforded the azide.

d) Amination Reactions
General Procedure C. Inside a nitrogen-filled atmosphere dry box, a 20 mL scintillation vial was charged with a magnetic stir bar, aryl azide (1.0 equiv.), (Et 4 N) 2 [Co 2 (L iPr ) 2 ] (1 mol%) 1 , and a 4:1 mixture of toluene and DMF, respectively. To the reaction mixture was added freshly activated 4 Å molecular sieves. The reaction vial was sealed with a Teflon cap and the reaction mixture was heated to 110 °C for 24 h inside the dry box on a DynaBloc heating block. After 24 h, the reaction vial was removed from the heating block and allowed to stir at room temperature for 30 minutes. After reaction mixture cooled to room temperature, the molecular sieves were removed by filtration, and the solvent was removed under vacuum. Purification by flash chromatography on silica gel (7:1 hexanes/EtOAc) as indicated afforded the desired product.

2-phenylindoline (6).
General procedure C was modified as follows: to a mixture of azide 5 2 (170 mg, 0.761 mmol) and (Et 4 N) 2 [Co 2 (L iPr ) 2 ] 1 (8.0 mg, 0.0076 mmol) was added 0.06 mL of pyridine (0.761 mmol) in 5.0 mL of a 4:1 mixture of toluene and DMF, respectively. Purification by flash chromatography (7:1 hexanes/EtOAc) afforded the title compound (133 mg, 78 % yield). 2 S14 e) Control reactions. Several control reactions were conducted to ensure the cobalt catalysts were required for amination. Heating azide 5 at 110 °C for 48 hours in the presence of molecular sieves in a toluene:DMF (4:1) mixture did not lead to the formation of indoline 6; starting material was isolated in greater than 95% yield. Heating azide 5 at 110 °C for 48 hours in the presence of molecular sieves and CoBr 2 in a toluene:DMF (4:1) mixture did not lead to the formation of indoline 6; starting material was isolated in greater than 95% yield. Similarly, azide 5 does not react under similar conditions in the presence of free ligand.  N-(2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)