Nature catalysis: intermingled pumperer reaction activated metal free photocatalytic C-H / C-H coupling of aromatics

The construction of (hetero) diaryls is a key application of cross coupling reaction, because the structure of (hetero) diaryls is common in drugs, pesticides and functional materials Traditional cross coupling reactions require two pre functionalized components and the catalysis of platinum group metals In order to simplify the synthesis process, the method of directly activating the C-H bond of the reaction substrate and selectively coupling C-H / C-H to obtain (hetero) diaryl structure has become more and more mature in recent years However, these methods still need platinum group metals, high temperature or guiding groups to ensure site selectivity The use of photocatalysts has become a supplementary method for the construction of (hetero) diaryls The reaction conditions are milder and transition metals are not needed in some cases However, such methods still need guiding groups (Fig 1a) Recently, the David J.Procter research team at University of Manchester in the United Kingdom reported the construction of a heteroaromatic two aryl structure (Fig 1b) by using visible light catalysis to achieve chemical and regioselectivity C-H/C-H coupling of non functionalized aromatics Relevant results were published on nature Catalysis (DOI: 10.1038/s41929-019-0415-3) (source: nature Catalysis) the author's blueprint for this reaction is to activate nucleophilic aromatic hydrocarbons with sulfoxide, that is, to generate corresponding aryl dibenzothiophene salts (AR DBT +; FIG 2B, a → b) through the interrupted Pummerer reaction The excited state of 10 phenylphenothiazine (PTH) transfers single electron to AR DBT +, resulting in the formation of Dibenzothiophene and aryl radicals (Fig 2B, B → C) The (hetero) arene substrate then captures the aryl radicals (Fig 2B, C → d) The newly formed free radical adducts are oxygenated and aromatized to obtain the coupling products (Fig 2B, D → e → f) After optimization, tert butyl benzene 1 and N-methyl pyrrole were coupled to form (hetero) diaryl 3 (Fig 2C) by this metal free one pot method (source: nature Catalysis) subsequent mechanism study experiments confirmed the reaction mechanism proposed by the author Firstly, the feasibility of the single electron transfer path in the reaction mechanism was evaluated by cyclic voltammetry Consistent with this, stern Volmer experiment also confirmed that AR DBT + salt 2 effectively quenched the excited state Photocatalyst (Fig 3a) The formation of (hetero) diaryl 3 was inhibited by the presence of free radical scavenger tempo in the reaction mixture (Fig 3b), while free radical scavenger 1,1-diphenylethyl produced free radical scavenger 4 (Fig 3C) Finally, AR DBT + salt 5 (containing N-allyl ether) was reduced to 5-exo-trig free radical cyclization / addition product 6 (Fig 3D), which provided further support for the proposed mechanism The measurement results of quantum yield of 3 (0.18) support the closed cycle proposed by the author, and exclude the free radical chain process of reducing d to B, then generating C to E (source: nature catalyst) after determining the best reaction conditions and getting the experimental support of the proposed reaction mechanism, the author expanded the application scope of the reaction substrate (Table 1) The aromatization of N-methylpyrrole with alkylsubstituted aromatic hydrocarbons resulted in a high yield (3 and 7-10) Electron rich phenol and aniline derivatives were also coupled in good yields (11-17) A series of substituted anisole was used to participate in the arylation reaction in order to evaluate the compatibility of various functional groups The substrates containing halogen, trifluoromethylsulfonate, methanesulphonyl, ketone, amide, ester, trifluoromethyl and cyano all provide heterodiaryl products (18-28) with complete chemical selectivity In addition, without changing the reaction conditions, 26 samples were prepared at the scale of 10 mmol, which revealed that the scheme was scalable Next, the authors turn their attention to the electron rich heteroaromatic substrates Although thiophene substrates showed some compatibility (31-33), furan and pyrrole did not react (34, 35) The next step is to evaluate the range of (hetero) aromatics A series of substituted pyrrole (36-39), thiophene (40-42), furan (43-47), benzofuran (48) and indole (49) were successfully used in the coupling reaction Complete domain control was observed in 3-substituted heterocyclic compounds (42, 46 and 47) Ar DBT + salt can also be used in Minisci coupling reaction (50) Finally, in addition to being activated by the interrupted Pummerer reaction, aromatics can also be used as a free radical capture substrate to generate biaryl compounds (52-55) (source: nature catalyst) in order to show the potential of this reaction, the author applied this strategy to the synthesis and modification of multiple complex molecules The author first aimed at pseudo Lin, a natural marine product (FIG 4A) Because of its unique highly halogenated structure, it has attracted extensive attention in recent years, and has been found to have antibiotic, antitumor and phytotoxic activities In the past, the synthetic route of pseudo ilin was to construct heterocycles from benzaldehyde or phenyl ketone, and the shortest synthetic step so far is seven Using commercial 2,4-dichloroanisole as starting material, N-H heterodiaryl structure 56 was obtained after the removal of TERT butoxycarbonyl The natural pentachloropseudilin 57 was obtained by subsequent chlorination and demethylation, while the dichloro tribromopseudilin 58 was obtained by bromination of pyrrole ring, both of which had high overall yield This method is also suitable for the selective modification of complex skeleton compounds with biological activity (Fig 4b) Pentaacetate salicylin (59), boscalid (60), fenofibrate (61), clofibutyl (62) and n-acetylmexiletine (63) can be successfully arylated by this two-step, one pot process Complete chemical and regional control can be observed in all reactions X-ray crystal analysis confirmed the structure of 60 (source: nature Catalysis) Summary: a one pot method has been developed by the author to construct (hetero) diaryl structure compounds from nonfunctional substrates by combining photocatalysis with the activated substrate of interrupted Pummerer reaction In the absence of metal, C-H / C-H cross coupling can be realized to construct (hetero) diaryl carbon framework without multi-step synthesis The combination of organic photocatalyst 10-phenylphenothiazine and intermediate aryl dibenzothiophene salt is unique, and it has a wide range of substrate application in high selectivity process Pentachloropseulin with biological activity was synthesized, and the complex molecules with biological activity were modified, which proved the practicability of the reaction.