Tuning the Reactivity of Radical through a Triplet Diradical Cu(II) Intermediate in Radical Oxidative Cross-Coupling

Highly selective radical/radical cross-coupling is paid more attention in bond formations. However, due to their intrinsic active properties, radical species are apt to achieve homo-coupling instead of cross-coupling, which makes the selective cross-coupling as a great challenge and almost untouched. Herein a notable strategy to accomplish direct radical/radical oxidative cross-coupling has been demonstrated, that is metal tuning a transient radical to a persistent radical intermediate followed by coupling with another transient radical. Here, a transient nitrogen-centered radical is tuned to a persistent radical complex by copper catalyst, followed by coupling with a transient allylic carbon-centered radical. Firstly, nitrogen-centered radical generated from N-methoxybenzamide stabilized by copper catalyst was successfully observed by EPR. Then DFT calculations revealed that a triplet diradical Cu(II) complex formed from the chelation N-methoxybenzamide nitrogen-centered radical to Cu(II) is a persistent radical species. Moreover, conceivable nitrogen-centered radical Cu(II) complex was observed by high-resolution electrospray ionization mass spectrometry (ESI-MS). Ultimately, various allylic amides derivatives were obtained in good yields by adopting this strategy, which might inspire a novel and promising landscape in radical chemistry.


General procedure of the EPR experiments
(A) Detecting organic radical: to an oven-dried tube equipped a stir bar, metal additives (5 mol%, as required with no addition), N-methoxybenzamide (38.0 mg, 0.25 mmol) was added 1,2-dichloroethane (0.25 mL) under N 2 atmosphere, then DTBP (91 mg, 0.625 mmol) was injected via a microsyringe continuously. After that, the Schlenk tube was allowed to be heated to 120 o C for 50 min. 10 μL DMPO (5,5-dimethyl-1-pyrroline N-oxide) was added into the system, followed by 10 μL of the solution was taken out into a small tube. Then, this mixture was analyzed by EPR at room temperature. The EPR spectrums are shown in Fig. S1 and Fig.   S2 (B) Detecting [Cu] radical: to an oven-dried tube equipped a stir bar, Cu(OTf) 2 (4.5 mg, 0.0125mmol), N-methoxybenzamide (38.0 mg, 0.25 mmol) was added 1,2 dichloroethane (0.25 mL) under N 2 atmosphere. After that, the Schlenk tube was allowed to be heated to 120 o C for 50 min, followed by 10 μL of the solution was taken out into a small tube. Then, this mixture was analyzed by EPR at 150 K (C) Detecting [Cu] radical: to an oven-dried tube equipped a stir bar, Cu(OTf) 2 (4.5 mg, 0.0125mmol), N-methoxybenzamide (38.0 mg, 0.25 mmol) was added 1,2 dichloroethane (0.25 mL) under N 2 atmosphere, then DTBP (91 mg, 0.625 mmol) was injected via a microsyringe.
After that, the Schlenk tube was allowed to be heated to 120 o C for 50 min, followed by 10 μL of the solution was taken out into a small tube. Then, this mixture was analyzed by EPR at 150 K S3 Figure   The nitrogen radical 6, which is thermodynamically 14.7 kcal/mol more stable than tertbutyloxyl radical, could be formed via transition state 1a-ts by the radical substitution between 1a and t BuO radical with a barrier of 6.8 kcal/mol. On the other hand, cyclohexene carbon radical 9 could also be generated with 15.9 kcal/mol exothermic through transition state 2a-ts. The corresponding activation free energy is 12.1 kcal/mol, which is 5.3 kcal/mol higher than that of 1a-ts. Therefore, the generation of 6 is favorable compared with that of 9. Figure S4. Grubbs free energy about Cu(II) complex coordinated by nitrogen-centered radical 6a and the interaction between carbon-centered radical 9 and Cu(OTf)2. Table S1. Optimization of the reaction conditions. a We started our research by applying N-methoxybenzamide 1a and cyclohexene 2a in a model reaction to test different reaction conditions (Table S1). For the optimization study, we focused our attention on the catalysis precursors. The metal played an important role on the selectivity and yield. When Cu(acac) 2 was used, the moderate yield was obtained (Table S1, entry 4). Ni,

S6
Fe, Mn all gave poor yield (Table S1, entry 1-3). Next, the different Copper catalysis precursors were tried. The use of 2 mol% of Cu(OTf) 2 and TMEDA gave the more better result (Table S1, entry 13). Other copper catalysis was not able to facilitate the reaction (Table S1, entry 5-12).
To be satisfactory, The applying of only Cu(OTf) 2 with on TMEDA increased the yield (Table   S1, entry 14) .Maybe, the coordination of the Cu(OTf) 2 and TMEDA blocked the role of Cu(OTf) 2 . But, CuOTf only gave the poor selectivity (Table S1, entry 15). When the Cu(OTf) 2 was not added, there was only trace 3aa obtained (Table S1, entry 16). On the other hand, HOTf instead of Cu(OTf) 2 was used, but we only got traceless product. To our exciting, an increasing yield and selectivity was obtained with the 2a increased (Table S1, entry 18-20). The best yield was got when 2a was used for 2 mL (Table S1, entry 20). At last, the different metal cations were examined, but the yield was dramatically reduced (Table S1, entry 21-24).

General procedure for the C(sp 3 )-H/N-H radical oxidative cross-coupling
In an oven-dried tube equipped with a stir bar, Cu(OTf) 2 (3.6 mg, 0.01 mmol) and Nmethoxybenzamide 1a (75.5 mg, 0.50 mmol) were combined and sealed. The tube was then charged with nitrogen, ethyl acetate (0.5 mL) and cyclohexene 2a (2.0 mL) were successively injected into the tube by syringe. Under the protection by nitrogen, DTBP (183 mg, 1.25 mmol) was slowly injected into the reaction tube. The reaction was then put into oil bath under 120 o C.
After stirring for 9 h, the reaction was cooled down to room temperature and quenched with saturated Na 2 S 2 O 3 solution. After extraction with ethyl acetate (3 x 10 mL), the organic layers were combined and dried over anhydrous Na 2 SO 4 . The pure product was obtained by flash column chromatography on silica gel (petroleum: ethyl acetate = 50:1 -5:1). The product was isolated as a colourless oil (93.0 mg, 81%)

B3LYP absolute calculation energies, enthalpies, and free energies
All the density functional theory (DFT) calculations were carried out with the GAUSSIAN 09 series of programs. DFT method B3LYP with a standard 6-31G(d) basis set was used for geometry optimizations. Harmonic frequency calculations were performed for all stationary points to confirm them as a local minima or transition structures and to derive the thermo chemical corrections for the enthalpies and free energies.