From aniline to phenol: carbon-nitrogen bond activation via uranyl photoredox catalysis

Abstract Carbon-nitrogen bond activation, via uranyl photoredox catalysis with water, enabled the conversion of 40 protogenetic anilines, 8 N-substituted anilines and 9 aniline-containing natural products/pharmaceuticals to the corresponding phenols in an ambient environment. A single-electron transfer process between a protonated aniline and uranyl catalyst, which was disclosed by radical quenching experiments and Stern-Volmer analysis, facilitated the following oxygen atom transfer process between the radical cation of protonated anilines and uranyl peroxide originating from water-splitting. 18O labeling and 15N tracking unambiguously depicted that the oxygen came from water and amino group left as ammonium salt. The 100-fold efficiency of the flow operation demonstrated the great potential of the conversion process for industrial synthetic application.

To further demonstrate the application potential of anilines, flow reactions were conducted, which were more efficient (0.68 mmol/h for 2a, 20 mmol scale) than those done with parallel reactors (0.04 mmol/h for 2a, 10 mmol scale). It is noteworthy that clinically applied pharmaceuticals, i.e. propofol and paracetamol by flow reactions could be, at most, 315 times as efficient as by tube operation, though the residue volume of flow pipeline was only ∼4.7 mL (<1/10 of the total volume) (Scheme 4).
The mechanistic study was carried out to understand the process. Firstly, radical quenching experiments with 2,2,6,6-tetramethyl-1-piperinedinyloxy (TEMPO) and butylated hydroxytoluene (BHT) suggested the radical property of this system (Scheme 5a, supplementary information (SI), Section IV-1). UV-vis absorption between catalyst and each component demonstrated that uranyl salt served as a photosensor. The addition of aniline salt to uranyl solution enhanced the absorption efficiency, illustrating the interaction between the uranyl species and aniline complex (Scheme 5b, SI, Section IV-2). Active uranyl cation was quenched by aniline/TFA complex, as detected by Stern-Volmer analysis (Scheme 5c, SI, Section IV-3), and energy transfer process was ruled out considering the lower value of the lowest triplet energy of the uranyl cation (E T = 58.5 kcal/mol) compared with that of anilines [41,42]. Meanwhile, the ammonium salt was instantaneously generated, as was monitored by 1 H NMR experiments before C−N bond activation (Scheme 5d, SI, Section IV-4). Furthermore, the quenching effect between uranyl species and protonated anilines was much stronger than in those with Ir[dF(CF 3 )ppy] 2 dtbpy . PF 6 , Ru(bpy) 3   atom of the product phenols originated from water rather than oxygen atmosphere (Scheme 6a, SI, Section IV-5). According to previous studies [38,43,44], uranyl peroxide complexes were obtained from uranyl photolysis of water, which is responsible for the oxygen atom transfer. 15 N NMR tracking experiments showed that only ammonium trifluoroacetate was obtained, which indicated that the amino group on anilines left in the form of ammonia followed by neutralization with TFA (Scheme 6b, SI, Section IV-6). In addition, both on-off experiments (SI, Section IV-6) and the quantum yield of 8.4 (SI, Section IV-7) demonstrated the existence of a radical chain propagation process during the transformation.
Based on the mechanistic study, a possible reaction pathway was depicted as shown in Scheme 7. Under blue light, uranyl photoredox catalysis was stimulated and generated * UO 2 2+ through the LMCT process. Then, the single electron transfer process between * UO 2 2+ and protonated anilines A brought forth UO 2 + and radical cation B. Another uranyl peroxide dimer was generated from watersplitting [43,44], capturing B with C−O bond formation and C−N bond fracture to get the radical cation of phenol C. Single electron transfer between C and UO 2 + afforded the desired product 2 and regenerated the catalyst. Meanwhile, the radical chain propagation process was also in progress during this transformation owing to the higher oxidation potential of intermediate C (E 1/2 = 1.56 V) [45] compared with protonated anilines A (E 1/2 = 0.89 V).

CONCLUSION
In summary, oxygen atom transfer from water to organic molecules via uranyl photoredox catalysis was discovered in photoredox circulation. Accordingly, C−N bond activation in undecorated anilines was systematically established at ambient conditions, generating a series of sensitive and fragile phenols. The 100-fold efficiency of the flow set-up indicated the industrial application potential of the strategy. Radical trapping experiments, Stern-Volmer analysis and 1 H NMR experiments demonstrated the interaction between active uranyl species and protonated anilines. Further studies in uranyl catalysis are on-going in our laboratory.

SUPPLEMENTARY DATA
Supplementary data are available at NSR online.