Copper(ii) ketimides in sp3 C–H amination

Commercially available benzophenone imine (HN 
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Created by potrace 1.16, written by Peter Selinger 2001-2019
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 CPh2) reacts with β-diketiminato copper(ii) tert-butoxide complexes [CuII]–OtBu to form isolable copper(ii) ketimides [CuII]–NCPh2. Structural characterization of the three coordinate copper(ii) ketimide [Me3NN]Cu–NCPh2 reveals a short Cu-Nketimide distance (1.700(2) Å) with a nearly linear Cu–N–C linkage (178.9(2)°). Copper(ii) ketimides [CuII]–NCPh2 readily capture alkyl radicals R˙ (PhCH(˙)Me and Cy˙) to form the corresponding R–NCPh2 products in a process that competes with N–N coupling of copper(ii) ketimides [CuII]–NCPh2 to form the azine Ph2CN–NCPh2. Copper(ii) ketimides [CuII]–NCAr2 serve as intermediates in catalytic sp3 C–H amination of substrates R–H with ketimines HNCAr2 and tBuOOtBu as oxidant to form N-alkyl ketimines R–NCAr2. This protocol enables the use of unactivated sp3 C–H bonds to give R–NCAr2 products easily converted to primary amines R–NH2via simple acidic deprotection.


General Procedures and Instrumentation
All catalytic reactions were carried out in a nitrogen-filled glovebox. 4A molecular sieves were activated in vacuo at 180 ºC for 24 h. Celite was dried overnight at 200 ºC under vacuum.
Benzophenone imine (97%) was purchased from Acros, purged with nitrogen and stored over 4A molecular sieves prior to use. para-substituted benzonitriles, aryl halides and Grignard reagents for benzophenone imine derivative synthesis were purchased from Sigma and used as  1 H, 13 C{H} and 19 F NMR spectra were recorded on a 400 MHz Varian Spectrometer (400, 100.47 and 376 MHz respectively). All NMR spectra were recorded at room temperature unless otherwise noted. 1 H NMR and 13 C{H} NMR spectra were indirectly referenced to tetramethylsilane using residual solvent signal as the internal standard. 19  EPR spectra were collected on a JEOL continuous wave spectrometer JES-FA200 equipped with an X-band Gunn oscillator bridge, a cylindrical mode cavity, and a liquid nitrogen cryostat. EPR measurements were performed in sealed quartz tubes. All spectra were obtained on freshly prepared solutions (1-3 mM in toluene) of at least 2 independently synthesized batches and were checked carefully for reproducibility. Background spectra were obtained on clean solvents at the same measurement conditions. Spectral simulation was performed using the program QCMP 136 by Prof. Dr. Frank Neese from the Quantum Chemistry Program Exchange as used by Neese et al. in J. Am. Chem. Soc. 1996, 118, 8692-8699. The fittings were performed by the "chi by eye" approach and always taking all available spectra at different temperatures into account. S4

Synthesis of [Me 3 NN]Cu-O t Bu (2a).
Scheme S1. Synthesis of [Me 3  After stirring for 15 minutes, the solution was filtered through a syringe filter and volatiles were removed in vacuo to get a reddish-brown oil in 94% yield. While usually isolated as an oil, a few X-ray quality crystals could be obtained from toluene at -37 °C. This intermediate was further characterized with UV-visible spectroscopy (Figure S1), EPR spectroscopy (Figure S14), and Xray crystallography ( Figure S17).

Reaction of [Me 3 NN]Cu-O t Bu (2a) with benzophenone imine
In a nitrogen filled glovebox, a stock solution of [Me 3 Figure S3), EPR spectroscopy ( Figure S15), and X-ray crystallography ( Figure S18). Due to high thermal sensitivity, this species could not be characterized by elemental analysis.

Reaction of [Cl 2 NN]Cu-O t Bu (2b) with benzophenone imine.
[Cl 2 NN]Cu-O t Bu (2b) was synthesized following a reported procedure. 6  Attempts to crystalize this species from pentane at -37 °C afforded red color crystals in a very low yield. Due to high thermal sensitivity of crystals this species could not be characterized with X-ray crystallography or elemental analysis. This species was further characterized with UV-vis spectroscopy ( Figure S5) and EPR spectroscopy ( Figure S16).   13 C NMR, and UV-vis spectroscopies ( Figure S6) as well as X-ray crystallography ( Figure S19).
The filtrate was concentrated in vacuo to 2 mL. Bright red crystals were isolated in 98% yield after allowing the solution to stand overnight at -35 °C. This species was further characterized by X-ray crystallography ( Figure S20).    In a nitrogen filled glovebox, [Cl 2 NN]Cu-N=CPh 2 (3b) (51 mg, 0.08 mmol, 1 equiv.) was dissolved in benzene (1.00 mL) in a thick walled 5 mL pressure vessel and (E/Z)-azobis(phenylethane) (20 mg, 0.08 mmol, 5 equiv.) was added. The mixture was stirred for 18 h at 90 °C. Reaction mixture was cooled to room temperature quenched by opening to air. Naphthalene (10 mg, 0.08 mmol, 1 equiv.) was added to the quenched reaction mixture as an internal standard. The yield was determined by 1 H NMR in CDCl 3 against the internal standard to be 74% considering the peak at δ 4.58 ppm (benzylic 1H).

Catalytic C-H amination
Optimization of the amination protocol Scheme S10. Representative reaction for optimization of C-H amination reaction.
To the solution, t BuOO t Bu (90.0 μL, 0.490 mmol, 1.2 equiv.) was added and the pressure vessel was immediately sealed, heated at 90 °C. After 24 h, the reaction was allowed to cool to room temperature and quenched by exposure to air. Naphthalene (52 mg, 0.408 mmol, 1 equiv.) was added to the quenched reaction mixture as an internal standard. The yield was determined by 1 H NMR spectroscopy considering the peak at δ 4.58 ppm (1H) with naphthalene (1 equiv. based on the imine) as a standard. S18

Catalytic C-H amination with benzophenone imine derivatives
Representative procedure for catalytic C-H amination of ethylbenzene with benzophenone imine derivatives Scheme S11. Catalytic C-H amination reaction of ethylbenzene with benzophenone imine derivatives. sealed, heated at 90 °C. After 24 h the reaction mixture was cooled down to room temperature and exposed to air to quench the reaction. Naphthalene (52 mg, 0.408 mmol, 1 equiv.) was added to the quenched reaction mixture as an internal standard and yield was determined with 1 H NMR.

Catalytic C-H amination with benzophenone imine
Scheme S13. Representative C-H amination reaction of ethylbenzene.

Representative procedure for C-H amination of ethylbenzene.
In down to room temperature and exposed to air to quench the reaction.

Purification of amination products was carried out following three general procedures.
General purification procedure A -Isolation of ketimine products R-N=CAr 2

S23
Products were isolated via fast column chromatography with 5% EtOAc in hexanes on silica.* *A high flow rate (50 mL/min) should be used to ensure product separation from the benzophenone azine byproduct and to minimize ketimine hydrolysis to primary amines.
General purification procedure B -Isolation of ketimine products R-N=CAr 2 The reaction mixture was transferred into a 4 dram vial with dichloromethane. One eighth of the reaction mixture was used to run a preparatory TLC with 3% triethyl amine, 5% ethyl acetate in hexane. TLC plates were basified with a solution of 5% triethyl amine in hexane prior to use.
General purification procedure C -Isolation of deprotected amines as HCl acid salts R-NH 3 + Cl -Following a reported procedure, 11  and it was filtered off to isolate the amination products as hydrochloric acid salts.  Figure S21.

EPR Spectra of Cu(II) Intermediates
EPR spectra were collected on a JEOL continuous wave spectrometer JES-FA200 equipped with an X-band Gunn oscillator bridge, a cylindrical mode cavity, and a liquid nitrogen cryostat. EPR measurements were performed in sealed quartz tubes. All spectra were obtained on freshly prepared solutions (1 -3 mM in toluene) of at least 2 independently synthesized batches and were checked carefully for reproducibility. Background spectra were obtained on clean solvents at the same measurement conditions. Spectral simulation was performed using the    program. Structure solutions were performed using the SHELXTL/PC suite. 12 Intensities were corrected for Lorentz and polarization effects and an empirical absorption correction was applied using Blessing's method as incorporated into the program SADABS. 13 Non-hydrogen atoms were refined with anisotropic thermal parameters and hydrogen atoms were included in idealized positions unless otherwise noted. Structures were rendered with POV-Ray in Mercury using 50% probability ellipsoids unless otherwise mentioned. Further comments on disorder models:

[Me 3 NN]Cu-O t Bu (2a):
The t-butyl group is disordered over two orientations. The like O-C distances and C-C distances were restrained to be similar (esd 0.01 Å). Similar displacement amplitudes were imposed on disordered sites overlapping by less than the sum of van der Waals radii.

[Me 3 NN]Cu(NH=CPh 2 ) •THF (4a•THF):
The amine H atom was located in the difference map and its position was allowed to freely refine. The amine H atom U's were assigned as 1.5 times the U eq of the N3. This H atom refined to good intermolecular hydrogen bonding position with the THF solvate molecule.

[Cl 2 NN]Cu(NH=CPh 2 ) (4b):
The amine H atom was located in the difference map and its position was allowed to freely refine. The amine H atom U's were assigned as 1.5 times the U eq of the N3.   u1-N2