Angelw: visible light induced pyridination of long-range C (SP3) - H bond

In general, the functionalization of inactive long-range C-H bonds can be realized by free radical transfer of N and O centers, and the site selectivity of the reaction is controlled by intramolecular 1,5-hydrogen atom transfer (1,5-hat) In view of the widespread presence of hydroxyl groups in organic molecules, the development of a mild catalytic strategy for the direct conversion of O-H bonds to O-centered radicals is an effective way to achieve remote C-H bond activation Recently, Chen and Meggers used IR photocatalysis to generate o-center radicals from n-alkoxy-phthalimide, respectively, and then functionalized the remote C-H bond via 1,5-hat The above methods usually need Hantzsch ester as reducing agent to promote the catalytic reaction, and the by-product phthalimide is formed Although great progress has been made in functionalization of remote C-H bonds, the introduction of pyridine via remote C (SP 3) - H bond activation is still very challenging Recently, Professor Sungwoo Hong and Professor Mu Hyun baik of the Korean Academy of science and Technology (KAIST) designed a class of n-alkoxypyridinium salts, and realized the remote selective pyridylation of C (SP 3) - H bond under the mild and no transition metal conditions by using the organic catalytic photo oxidation reduction strategy Relevant articles were published on angelw Chem Int ed (DOI: 10.1002 / anie 201809879) Recently, the research team of Sungwoo Hong reported that quinolinone 3-phosphonate (Q 1) can make n-ethoxypyridinium salt form reactive ethoxyl radical after photoexcitation under mild reaction conditions (org Lett 2017, 19, 1394) Therefore, it is suggested that n-alkoxypyridinium salt substrate can be used not only as a precursor of alkoxy radicals, but also as a heteroaryl source of pyridination The author conjectures that the alkyl radical is produced by the single electron reduction and 1,5-hat of n-alkoxypyridinium salt 1 and the photoexcited Q 1 * species, and then the alkyl radical B may be added with 1 to form the product 2 (scheme 1) (source: angelw Chem Int ed.) in order to verify the above conjecture, the author uses n-alkoxypyridinium salt 1A as the model substrate to explore the feasibility of the free radical series reaction After the selection of various catalytic systems, the author found that when Q 1 was used as photocatalyst, CH 3CN was used as solvent, blue LED was used to irradiate 1a to initiate the pyridination of long-range C (SP 3) - H bond, and the corresponding product 2A (Table 1) was formed in excellent yield (93%) It is speculated that the reaction process includes continuous cracking / 1,5-hat / pyridylation The addition of tempo can completely inhibit the reaction, which shows that the free radical mechanism is reliable (source: angelw Chem Int ed.) after determining the optimal reaction conditions, the author next investigated the application scope of n-alkoxypyridinium salt 1 (Table 2) The 4-heteroaryl alcohols (2a-2c, 2e-2h, 2m-2o) can be successfully obtained from a variety of substrates including alkyl, phenyl and halogen in good to excellent yields Substrates (2i-2l and 2P) with aliphatic or nitrogen heterocycles, such as cyclohexyl, cyclopentyl, cyclobutyl, and BOC protected piperidine groups, can also participate in the reaction and obtain the target product In addition, the substrate can be extended to the secondary alkoxy structure, and the corresponding secondary alcohol product (2q) can be obtained Other heteroaromatics containing pyridine ring were also compatible with the reaction system, and the product (2R - 2V) was obtained in good yield It is important that not only the C (SP 3) - H bond of the tertiary alkane, but also the C (SP 3) - H bond of the secondary alkane and the C (SP 3) - H bond of the primary alkane can be functionalized in this reaction system, and the corresponding products (2v-2ag and 2aj) can be obtained in medium to good yields (source: angelw Chem Int ed.) next, the author tried to prove the practicability of the free radical reaction by post modification of bioactive molecules (scheme 2) Under slightly changed reaction conditions, the target product 2ak can be successfully obtained in 70% yield of steroid derivatives with complex structure We also investigated the substrate for deriving theobromine (xanthine drugs), and obtained the pyridine product 2Al in 70% yield In addition, the substrates derived from pyridine drugs such as pyrrolidol and verodge can also effectively form the corresponding products 2am and 2An (source: angelw Chem Int ed.) then, after a lot of mechanism experiments, the author proposed a possible reaction pathway (scheme 3) Under visible light irradiation, the catalytic cycle starts from Q 1 excitation to Q 1 * Q 1 * then provides a single electron reduction of n-alkoxypyridinium salt 1 and triggers N-O bond cleavage to release pyridine and produce living alkoxy radical a After 1,5-hat process, a is transformed into activated carbon radical B Then, nucleophilic alkyl radical B is added with n-alkoxypyridinium salt 1 to form free radical cation C The N-O bond of C is cleaved to form the final product and alkoxy radical A A may undergo a 1,5-hat process to form B and start a new reaction cycle The above mechanism is also verified by DFT calculation (source: angel Chem Int ed.) Summary: Professor Sungwoo Hong and Professor Mu Hyun baik have developed a new class of n-alkoxyheteroarylium salts In the presence of 3-quinolinone phosphonate (Q 1), it can provide alkoxy radicals and be applied to the selective heteroaromatization of remote C (SP 3) - H bonds This method is simple and efficient 4-heteroaryl alcohol can be obtained in one step, and it is suitable for the later functionalization of complex bioactive molecules.