Photo-induced oxidant-free oxidative C–H/N–H cross-coupling between arenes and azoles

Direct cross-coupling between simple arenes and heterocyclic amines under mild conditions is undoubtedly important for C–N bonds construction. Selective C(sp2)-H amination is more valuable. Herein we show a selective C(sp2)-H amination of arenes (alkyl-substituted benzenes, biphenyl and anisole derivatives) accompanied by hydrogen evolution by using heterocyclic azoles as nitrogen sources. The reaction is selective for C(sp2)-H bonds, providing a mild route to N-arylazoles. The KIE (kinetic isotope effect) experiment reveals the cleavage of C–H bond is not involved in the rate-determining step. Kinetic studies indicate the first-order behaviour with respect to the arene component. It is interesting that this system works without the need for any sacrificial oxidant and is highly selective for C(sp2)-H activation, whereas C(sp3)-H bonds are unaffected. This study may have significant implications for the functionalization of methylarenes which are sensitive to oxidative conditions.


Supplementary Methods
General information: All manipulations were carried out by standard Schlenk techniques. Unless otherwise stated, analytical grade solvents and commercially available reagents were used to conduct the reactions. Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates.
Flash chromatography columns were packed with 200-300 mesh silica gel in petroleum ether (bp. 60−90 ºC). Gradient flash chromatography was conducted eluting with a continuous gradient from petroleum ether to the ethyl acetate. All new compounds were characterized by 1 H NMR, 13 C NMR and HRMS. The known compounds were characterized by 1 H NMR and 13 C NMR. The 1 H and 13 C NMR spectra were recorded on a Bruker 400 MHz NMR spectrometer. High resolution mass spectra (HRMS) were measured with a Waters Micromass GCT instrument and accurate masses were reported for the molecular ion + Hydrogen (M+H). Hydrogen gas content was analyzed by gas chromatography (7890-II, Tianmei, China, TCD, nitrogen as a carrier gas and 5 Å molecular sieve column, a thermal conductivity detector).

Conditions Screening:
A solution of p-xylene 1a (X equiv), 1H-pyrazole 2a (0.3 mmol), photocatalyst (Y mol%) and Co III (dmgH)2Cl2 (8 mol%) in degassed dry CH3CN were stirred under nitrogen atmosphere and irradiated by 3W blue LEDs at 25 o C for 24 h. After completion of the reaction, the yield of desired product 3a was determined by GC with naphthalene as the internal standard. The results were summarized in Supplementary Table 1.

Reaction conditions for Substrate Scope:
A solution of arenes 1 (1.2 mmol or 2.0 mL), azoles 2 (0.3 mmol), photocatalyst (7 mol%) and Co III (dmgH)2Cl2 (8 mol%) in degassed dry CH3CN (5.0 mL or 3.0 mL) were stirred under nitrogen atmosphere and irradiated by 3W blue LEDs at 25 o C for 24 h. After completion of the reaction, H2 was detected by GC-TCD. The aqueous solution was extracted with ethyl acetate (3 × 10 mL) and the combined extracts were dried with anhydrous Na2SO4. The solvent was removed under reduced pressure by rotary evaporation. Then, the pure product was obtained by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate= 25:1).

Procedure for Kinetic Order in biphenyl substrate:
The order in substrate arene was determined by studying the initial rate of reaction with different concentrations of arene. Under nitrogen atmosphere, biphenyl (0.3 ~ 1.8 mmol, 0.3 mmol, 0.6mmol, 1.2 mmol, 1.5 mmol, 1.8 mmol), 1Hpyrazole 2a (0.3 mmol), Acr + -Mes ClO4 -(0.021 mmol, 7 mol %), Co III (dmgH)2Cl2 (8 mol%) and degassed dry CH3CN (5.0 mL) were added to the reaction vessel one by one. The reaction was carried out under irradiation by a commercially available blue LEDs at 25 o C for 1 h. The GC yields were determined using naphthalene as an internal standard. Finally, the initial rate for different concentration of biphenyl vs relative concentrations could be obtained.

Analytical Data of Compounds
Amination of p-xylene with pyrazole 1 : Reaction was proceeded with 1.2 mmol p-xylene and 5.0 mL CH3CN. After 24 h, the reaction mixture was purified by silica gel column chromatography to afford the product 3a. 36

Amination of 1-(tert-butyl)-4-methylbenzene with pyrazole:
Reaction was proceeded with 1.2 mmol 1-(tertbutyl)-4-methylbenzene and 5.0 mL CH3CN. After 24 h, the reaction mixture was purified by silica gel column chromatography to afford the product 3d as an inseparable mixture. The ratio of the mixture was 19:1 (CA:CB) determined by 1    Amination of cumene with pyrazole 4 : Reaction was proceeded with 2.0 mL cumene and 3.0 mL CH3CN. After 24 h, the reaction mixture was purified by silica gel column chromatography to afford the product 3h as an inseparable mixture. The ratio of the mixture was 1:6.1 (ortho:para) as determined by 1  as an inseparable mixture. The ratio of the mixture was 1:11 (CA:CB) as determined by 1  Amination of m-xylene with 3-phenyl-1H-pyrazole: Reaction was proceeded with 2.0 mL m-xylene and 3.0 mL CH3CN. After 24 h, the reaction mixture was purified by silica gel column chromatography to afford the N isomerous products 3n1 56.6 mg colorless liquid (yield: 76%, 0.3 mmol scale) and 3n2 17.1 mg colorless liquid (yield: 23%, 0.3 mmol scale). The ortho:para ratio of the 3n1 was 1:8 (CA:CB) and the ortho:para ratio of the 3n2 was 1:11.5 (CA:CB) as determined by 1  Amination of m-xylene with 4-methyl-1H-pyrazole: Reaction was proceeded with 2.0 mL m-xylene and 3.0 mL CH3CN. After 24 h, the reaction mixture was purified by silica gel column chromatography to afford the product 3o as an inseparable mixture. The ortho:para ratio of the mixture was 1:14 (CA:CB) as determined by 1 H NMR. 50.3mg colorless liquid (yield: 90%, 0.3 mmol scale).