Organic letters: cobalt catalyzes the decarboxylation of benzo heterocycles and aromatic carboxylic acids to form biarylhydrocycles

Biarylhydrocyclic compounds have unique biological and physical properties and are widely used in organic functional materials, drugs and ligands Transition metal catalyzed cross coupling reactions are often used to synthesize these compounds The classical methods usually use halogenated hydrocarbons and functionalized aromatics as reaction substrates In recent years, the direct functionalization of aromatic heterocyclic C-H has made a breakthrough Among them, the strategy of direct functionalization of C-H by decarboxylation of aromatic carboxylic acid substrate can minimize the dimerization in the coupling process, which is an ideal method for the construction of C-C bond of biaryl heterocyclic compounds In the past, palladium catalyst system was widely used in the decarboxylation of C-H (Fig 1a) In 2010, Greaney et al reported the direct aromatic heterocyclization of oxazole C-H catalyzed by Pd (OAC) 2 / CuCo 3 system In 2012, su et al reported the related reactions with thiophene as the substrate, and the catalytic system was PD (OAC) 2 / Ag 2CO3 Palladium catalyst is suitable for a narrow range of substrates, and benzo aromatic heterocyclic substrates are usually not good for reaction Therefore, it is of great value to develop the method of decarboxylation of C-H aromatic heterocycles Fig 1 Decarboxylation and coupling of aromatic heterocycles catalyzed by transition metals: Recently, Li guigen and Lu Hongjian, from the school of chemistry and chemical engineering, Nanjing University, used cheap and low-toxic cobalt catalyst to decarboxylate C-H aromatic heterocycles and obtained a series of diarylhydrocycles (Fig 1b) Relevant papers are published online on organizational letters Firstly, a series of cobalt catalysts, ligands and solvents were screened by using benzothiazole (1a) and 3-methylbenzothiophene-2-carboxylic acid (2a) as the substrates for decarboxylation coupling The experimental results are shown in Fig 2 Under the action of catalyst system cobr 2 / IPR · HCl and solvent 2-f-trifluorotoluene, the yield of product 3A can reach 82% Fig 2 Screening source of reaction conditions: after organic letters had the best conditions, the author expanded the benzo heterocyclic substrate (Fig 3) Benzothiazole with different substituents in benzene ring reacts with aromatic heterocyclic carboxylic acid in medium to good yield, and benzoxazole also has good reactivity There are also a wide range of carboxylic acid substrates Benzothiophenic acid, benzofuranic acid, indolic acid, benzothiazolic acid, thiazolic acid and other aromatic heterocyclic acids can realize the decarboxylation coupling process Further studies have found that benzoic acids with electron withdrawing groups, such as Nitrobenzoic Acid and fluorobenzoic acid, are also suitable for such decarboxylation of C-H aromatic heterocyclization (Fig 4) Fig 3 Synthesis source of diarylhydrocycles: Organic letters Fig 4 Synthesis source of phenyl aromatic heterocycles: in order to study the mechanism of catalytic decarboxylation coupling reaction, the author designed a series of control experiments On the basis of the standard conditions, the author added the free radical trapping agent tempo, and the yield of the product was only 7% Therefore, it was speculated that the reaction might be a free radical mechanism (Fig 5a) H / D experiments show that there is no h / D exchange between d-1n and 2A (Fig 5b) The first-order kinetic isotopic effect was observed in parallel experiments, indicating that the C-H bond fracture of benzoxazole is the rate controlling step of the reaction (Fig 5C) The intermolecular competitive reaction shows that the electron density of the aromatic ring does not affect the reaction rate (Fig 5d) Figure 5 Experimental source of mechanism research: Based on the above research and previous reports, the author proposed the catalytic cycle mechanism As shown in path 1 in Figure 6 At first, CO (II) catalyst was oxidized to CO (III) by Ag 2CO 3, and the intermediate a was formed by Ag 2CO 3 and benzothiazole 1 On the other hand, aromatic carboxylic acids are converted into aromatic radicals under the action of Ag 2CO 3, and then react with a to obtain CO (IV) intermediate B Subsequently, the target product 3 was obtained by CO elimination and the CO (II) catalyst was regenerated Because silver salts can promote the decarboxylation of aromatic acids and form Ag aryl intermediates, the catalytic cycle in the reaction may also follow path 2 Figure 6 Source of catalytic cycle process: summary of organic letters: Li guigen and Lu Hongjian team realized the decarboxylation coupling reaction of benzo aromatic heterocycles and aromatic carboxylic acids catalyzed by cobalt The catalyst used in the new method is cheap and the substrate selection range is wide, which provides a new idea for the synthesis of biaryl heterocycles and phenyl heterocycles Paper link: http://pubs.acs.org/doi/10.1021/acs.orglett.7b02730