Angelw: Professor Burkhard K ö nig, University of Regensburg, Germany

Cyclopropane structure is widely found in natural products and drugs, and it is also an important synthesis precursor, which can be converted by ring opening reaction Therefore, the ring opening modification of cyclopropane is of great significance for the search of new bioactive molecules, functional materials and the synthesis of complex molecules Organic halogenated compounds are a kind of important compounds Carbon halogenated bonds are widely found in many drug molecules and agricultural chemicals, among which β - chloroketone, as a structural unit of many chemical transformations, has attracted the attention of organic chemists Aromatic β - chloroketones are usually synthesized by Friedel crafts acylation, but their substrates are limited and have the problem of regioselectivity (scheme 1a) Recently, Professor Burkhard Ko ̈ nig, University of Regensburg, Germany, reported a new strategy (scheme 1c) for the synthesis of β - chloroketone from arylcyclopropane under visible light The related research results were published in angelw Chem Int ed (DOI: 10.1002/anie.201902473) (picture source: angelw Chem Int ed.) firstly, the author used cyclopropylbenzene (1a) as the reaction substrate, NaCl as the chlorine source, anthraquinone-2-sulfonate hydrate (SAS) as the strong oxidation photosensitizer and trifluoroacetic acid (TFA) as the SAS activator to carry out the pre experiment (Table 1) β - chloroketone 2A (Table 1, entry 1) was obtained in 53% yield Based on this, the author selected chlorine source, acid, photocatalyst and irradiation wavelength, and finally determined that when hydrochloric acid as chlorine source and 395 nm as irradiation wavelength, the highest yield (77%) of product 2A could be obtained (picture source: angelw Chem Int ed.) under the optimal reaction conditions, the author investigated the substrate range of the reaction (Figure 1) The results showed that the yield of the corresponding product (2b-2d) could be increased when the substrate containing the electron donating substituent participated in the reaction, while the substrate containing the electron donating substituent could inhibit the reaction (2e-2m) except for the 4-chlorine substituent In addition, the corresponding products (2n-2p, 2R) were obtained in good yields, whether it was the substrate containing alkyl substituents, aryl or heteroaryl substituents Next, the author applied the synthesis strategy to the synthesis of drugs Although the reaction can only get cyclopropyl Beite with low yield, it can get its corresponding methyl ester and tramadol derivative 2x - 2Y with high yield In order to prove the practicability of this method, a gram scale reaction (10 mmol) was carried out The yield of 2a was 79% When SAS is added as photosensitizer, the corresponding product (3a - 3I) can be obtained in good yield by the reaction of nucleophiles (such as bromide, water or methanol) (image source: angel Chem Int ed.) later, the author obtained 2-isoxazoline derivative 4A or 2-pyrazoline derivative 4B and phosphine chloride 4C in good yield through a series of transformations of β - chloroketone In addition, β - chloroketone can be used as the precursor of conjugated antibody or biological probe to explore the receptor function (4D) (Figure 2) In order to study the reaction mechanism, 18 o labeling experiment, UV-Vis determination experiment, cyclic voltammetry and control experiment were carried out The results of 18O labeling experiments show that the carbonyl oxygen atoms are from oxygen, not from H 2O nucleophilic attack The results of UV-vis and cyclic voltammetry showed that the reaction was initiated by CL In order to further study this point, the author carried out a control experiment with ultrastoichiometric and catalytic chlorine (Figure 3a) The results show that when excessive chlorine and HCl are used, only polychlorination by-products are produced, while when catalytic amount of Cl 2 and excessive HCl are used, 2 a can be obtained in 50% yield with less by-products The author speculates that there is an intermediate of arylcyclopropyl radical cation in the reaction, which can be observed in the reaction of 4-bromocyclopropylbenzene (1ab) (Figure 3B) In addition, when the substituted starting material 1Ac or 1AD is used, only 1Ac produces the decarboxylation product 2a, but 1AD does not react at all, which indicates that the substrate needs to contain a good leaving group at the benzyl position to react (photo source: angelw Chem Int ed.) finally, the author proposed the following reaction mechanism (Figure 4) First, Cl 2 is produced by the reaction of dilute hydrochloric acid and nitric acid, and it is broken down into CL free radical by light Then, Cl · oxidizes arylcyclopropane (a) to form cyclopropyl radical cation (b) Cl - opens the ring of cyclopropane in B to obtain instantaneous benzyl radical (c), which can be trapped by persistent triplet dioxygen radicals to obtain benzyl peroxy radical (d) D reacts with Cl 2 rapidly, and the resulting hydrogen peroxide chlorine (E) can undergo isomeric cracking to obtain ketone (f) (photo source: angelw Chem Int ed.) Summary: Professor Burkhard Ko ̈ nig, University of Regensburg, has reported a new strategy of synthesizing β - chloroketone from arylcyclopropane by visible light The reaction strategy is easy to operate and the functional groups are well tolerated The reaction products can be used as valuable precursors for the synthesis of drugs and bioactive molecules.