JACS: photocatalytic carboxylation of benzyl C-H bond

Carbon dioxide provides an ideal but challenging block for organic synthesis Among them, the carboxylation of carbon nucleophiles and carbon dioxide has attracted much attention because it provides a convenient way for the direct synthesis of carboxylic acid derivatives Direct activation of C-H bonds and subsequent carboxylation are attractive and promising strategies for CO2 reactions, compared with the use of pre functionalized starting materials, because the corresponding cost and waste will be reduced as the synthesis steps of the target molecules are reduced Due to the acidity of CO 2, the carboxylation of SP C-H bond and SP 2 C-H bond has been realized in the presence of suitable base However, the direct carboxylation of SP 3 C-H bond and CO 2 is relatively rare Only Murakami group reported the UV excited C-H bond of benzyl SP 3 and the direct carboxylation of allyl C-H bond (scheme 1) Jamison group realized the carboxylation of C-H bond of α - amino SP 3 by photo oxidation-reduction strategy However, no visible light mediated direct carboxylation of SP 3c-h bond has been reported Recently, the research group of Professor Burkhard K ö nig, University of Regensburg, Germany, realized the first visible light mediated carboxylation of benzyl sp 3c-h with CO 2 under the action of photosensitizer and hat catalyst Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b05360) (source: J am Chem SOC.) recently, the research group reported the carboxylation of (pseudo) halide and styrene with CO2 by visible light nickel double Catalysis (J am Chem SOC 2018, 140, 3198) Considering that alkyl can be captured by Ni 0 species produced by Ni I intermediate, it can be used as an active species for carboxylation reaction with CO 2 In order to realize the C-H bond carboxylation with CO2, a photo redox strategy involving hydrogen atom transfer is proposed In order to verify the above conjecture, the author used 2,4,5,6-tetra (carbazole-9-yl) phthalonitrile (4czipn) as photosensitizer, lnibr 2 as catalyst, tri isopropylsilane (HAT1) as catalyst, ethyl benzene as model substrate to investigate the feasibility of the reaction Although the initial attempt did not produce the target product, the author unexpectedly found that 2-phenylpropionic acid was produced without lnibr2, although the yield was slightly lower (Table 1, entry 1) After the selection of catalyst and solvent, the optimum conditions of the reaction were determined as follows: under 4 ATM CO 2 atmosphere, with HAT1 as catalyst, 6 mol% 4czipn as photosensitizer and DMF as solvent, the target product 2A could be obtained in 57% yield at room temperature (source: J am Chem SOC.) then, under the optimal catalytic system, the author investigated the universality of other benzyl substrates As shown in Table 2, a series of 2-arylpropionic acid compounds can be obtained in medium to high yield (2b-2n), and the reaction can be compatible with a variety of functional groups (including halogen, amide, ester, acetal, pyrazole, etc.) By prolonging the length of alkyl side chain, the corresponding product 2O - 2q was still obtained in good yield When there are multiple benzyl C-H sites in the substrate, the reaction only forms mono carboxylated products (2R, 2S, 2T and 2U) Among them, the reaction effect of dibenzene and 9,10-dihydroanthracene is better than that of naphthohexyl and 9,10-Dihydrophenanthrene The benzyl sites of heteroaromatics and saturated oxygen heterocyclic compounds can also be carboxylated successfully to 2V - 2Y in 39% - 85% yield Finally, the method was applied to the synthesis of drugs with 2-phenylpropionic acid structure, and 2AA - 2ad was obtained in good yield (source: J am Chem SOC.) finally, based on mechanism experiments and related literature reports, the author proposed the reaction mechanism as shown in scheme 3 One cyano group in 4czipn is substituted by benzyl group to form 3-benzyl-2,4,5,6-tetra (9h-carbazole-9-yl) benzylnitrile (4czbnbn), which is considered as the main active catalyst for the formation of carbon anion The thiol cation r-sh ● + and the reducing photosensitizer, 4czpebn ● -, are produced by the visible light excited 4czpebn * through the reduction quenching of triesopropylsilane mercaptan by single electron transfer (set) Then, r-sh ● + is deprotonated to produce an electrophilic sulfur radical r-sh ●, which further extracts the hydrogen atom from the benzyl position of ethyl benzene to complete the organic catalytic cycle and form a benzyl radical The previously formed 4czpebn ● - reduces the benzyl radical to complete the catalytic cycle of photo oxidation-reduction and provide the carbon anion of ethyl benzene The anion is easy to be captured by carbon dioxide and then protonated to produce the final product (source: J am Chem SOC.) in a word, the first visible light mediated carboxylation of benzyl C-H bond has been realized by the co catalysis of photoreduction and organic molecules The reaction is simple and novel with high atom economy The reaction can be carried out smoothly without any metal reagent, electron donor or acceptor, stoichiometric additive, and the carboxylic acid needed can be prepared in medium to excellent yield, and the substrate is widely used.