Cp*Co(III)-catalyzed C-H bond amination of indoles with arylazide compounds

Indoles are an important class of intermediates found in drug molecules and functional materials, so structural modification of indoles is necessary. We have developed an inexpensive and readily available transition metal cobalt(III) catalyzed selective C-H amination reaction of indoles with azides at the C2 position, which has high functional group tolerance. It provides an effective way to synthesize a range of 2-aminoindole derivatives using an environmentally friendly and resource-efficient catalytic system, paving the way for expanding the application of indole structures.


Introduction
Indoles are important precursors for the synthesis of many drugs and are widely found in drug molecules [1-5]   .For example, indomethacin is currently one of the strongest non-steroidal drugs with antiinflammatory effects.In addition, indomethacin has analgesic and antipyretic effects, inhibits leukocyte chemokines, antagonizes inflammatory factors, and reduces immune responses.Indomethacin has been widely used in ophthalmic diseases, such as ophthalmic inflammation, cataracts, glaucoma, and other areas, with good therapeutic effects.In recent years, new formulations of indomethacin have been developed in ophthalmology, further expanding the application field of indomethacin.Therefore, the structural modification of indole is very important.Among the various functionalized indole compounds, 2-aminoindole is a very important structural unit that serves as the core backbone of various drug molecules, with potential pharmacological activity and wide application in areas such as chemical and materials engineering (Figure 1) [6][7] .The diagram shows the active compounds of several 2-aminoindole derivatives such as Mollenine A, a natural fungal-like product, Pyrroloindole, a common intermediate in drug development, Physostigmine, a reversible acetylcholinesterase (AchE) inhibitor, and Cruciferane, a natural plant component, Chaetominine, which is cytotoxic to human leukemia K562 and colon cancer SW1116 cell lines, and Robustanoid B, a novel alkaloid.Considering the extensive uses of 2-aminoindole derivatives, it is particularly important to develop additional methods for the synthesis of 2-aminoindoles.
Therefore, the synthesis and selective carbon-hydrogen bond functionalization of indoles has therefore become a comprehensive research target in the field of organic synthesis.Traditionally, the synthesis of functionalized indoles has fallen into two categories: (1) the construction of indole frameworks from other substrates, and (2) the direct functionalization of existing indole frameworks.
Molecular synthesis mainly involves the interconversion of pre-existing functional groups.The introduction of these functional groups requires many reaction steps and some by-products are generated during this time, however, we can directly use C-H bonds as potential functional groups, which prevents lengthy synthetic steps and has fewer side reactions, thereby enabling the activation of C-H bonds in step is more economical.
Because of their importance, the synthesis of indoles has been of interest to organic chemists for more than 100 years.The earliest and most classic of these is the Fischer synthesis.In 1883 Fischer et al. used phenylhydrazone to form the indole ring by nucleophilic ring closure through rearrangement catalyzed by protonic or Lewis acids, followed by the elimination of ammonia.This is the famous Fischer synthesis.Because of the importance of indoles, we wanted to complete the synthesis of indoles using a transition metal catalytic system.Through research in the literature, we have found that 2aminoindoles are a very useful class of pharmaceutical intermediates.Therefore we would like to complete the synthesis of 2-aminoindole compounds on the basis of transition metal catalysis.Transition metal catalysis has become an effective tool for the functionalization and late modification of indole structure-related molecules over the past decades, this method offers higher atomic economy and synthetic utility than conventional organic reactions.This reaction can be used in organic synthesis, drug synthesis, and polymer chemistry, it is one of the key steps in the synthesis of many complex organic compounds.This approach has made great progress in recent years and can simplify the synthesis steps of organic target products and improve the atomic economy.This is achieved by introducing a localization group into the reaction substrate and a reaction between the transition metal and the C-H bond to produce a C-M bond intermediate and the C-M bonded intermediates are produced by the reaction between a metal catalyst and a C-H bond, where the transition metal is coordinated to the localization atom on the localization group to achieve localization revitalization of the specific C-H bond, thus accomplishing good regioselectivity.
In transition metals, the Cp*Rh(III) catalysts show very good performance, including C2 amination of indoles (Figure 2a) [8] .In view of the necessity of developing environmentally friendly, atomically economical and recyclable catalytic systems, Matsunaga and Kanai's group has also made relevant progress in recent years (Figure 2b).Hereto, we have implemented a new method for the direct selective C-H amination of indoles with azides at the C2 position using cheap and readily available Cp*Co(III) catalysts to obtain a series of 2-aminoindoles (Figure 2c).

Results and Discussion
Satoh and Miurain's seminal reports on the targeted C-H functionalization catalyzed by Cp*Rh(III) and Cp*Ir(III) species reports prompted much research into the application of these catalysts in a variety of useful synthetic reactions.The catalytic activity of cobalt, which is also a Group IX transition metal and much cheaper, has also been demonstrated, with cobalt-catalyzed C-H functionalizations falling into two categories: low-valent methods (where the active cobalt catalyst is usually in the zero or monovalent oxidation state) and high-valent methods (where the active cobalt catalyst is usually in the trivalent oxidation state).
In 2013, Matsunaga and Kanai's group made a major catalytic breakthrough in the field of trivalent cobalt.The first report demonstrating that a similar cobalt complex, Cp*Co(III), is also an effective catalyst for C-H functionalization was published.The first Cp*Co(III)-type catalyst [Cp*Co(benzene)](PF6)2 was introduced for the functionalization of 2-aryl pyridines with sulfonimides.Since then, this field has received a lot of attention from chemists.To date, more than ten different types of Cp*Co(III) catalysts have been synthesized, the more commonly used ones being [Cp*Co(C6H6)](PF6)2, [Cp*Co(C6H6)][B(C6F5)4]2, Cp*Co(CO)I2 and [Cp*CoI2]2, as shown in Figure 3.
Using these catalysts, chemists have developed a variety of hydrocarbon bond activation reactions.Depending on the type of bond formation, these reactions can be classified into five types.In the present study, we will examine the composition of the C-N bond.We first screened the reaction conditions (Table 1) and tried different cationic cobalt complexes, Co(acac)3, [Co(NH3)6Cl3], Co2(CO)8 and CoI2 did not react (Entries 1-4).However, the catalytic system of [Cp*CoI2]2 complexes with Ag salts was observed to produce the product, evidence that Cp*Co(III) species play a decisive role in the reaction.Under these conditions, a 96% yield was obtained with KOAc (Entry 5).We then screened the range of silver salts.In the screened Ag salts (Entries 5-8), AgSbF6 was the best, with 2.5 mol% of [Cp*CoI2]2 and 10 mol% of AgSbF6 giving the amination product in 96% yield (Entry 5).The cationic Cp*Co(III) material generated with AgPF6 was slightly less reactive.The reactivity of the reaction with the catalytic system formed by AgBF4 and Cp*Co(III) was substantially lower, with a yield of only 49% (Entry 7), while for the AgOAc-only system, the reaction yielded only trace amounts of product (Entry 8).Subsequent reaction yields were also low in the absence of KOAc or AgSbF6 (Entry 11: 8%, Entry 9: 0%), suggesting that the catalytic system of AgSbF6 and KOAc is essential.After screening a series of conditions, the optimum reaction conditions were determined to be 2.5 mol% [Cp*CoI2]2 as the catalyst, 10 mol% AgSbF6 as silver salt, and 30 mol% KOAc as an additive in 0.2 M concentration of 1,4-dioxane at 80 ℃ for 24 h.At this time, a 96% yield was achieved, which gave good results.The corresponding target product of amination.After obtaining the optimum reaction conditions, a wider range of substrates was tried to determine the applicability of the method (Figure 4).The indole backbone has multiple C-H bonds, including a pyrrole ring (C2-C3 positions) and a benzene ring (C4-C7 positions), and we decided to attach different substituents to different positions of the indole and use them as substrates for the catalytic reaction.Indole C4 position with Br attached 85% yield, with Cl 89% yield and 79% yield with OMe.Indole C5 with methyl in 90% yield, OMe in 80% yield, F in 90% yield, Cl in 85% yield, and CO2Me in 78% yield.Indole C6 with Me 79% yield, with F 83% yield, with Cl 71% yield, with OBn 85% yield.The results show that the indole derivatives studied (the system is suitable for a wide range of substrates) show tolerance to both electron-absorbing and electron-donating substituents.This result proves that the catalytic system is highly effective and we are pleased with the result.Subsequently, we intend to expand the range of substrates for amine derivatives.To complete the range of substrates for catalytic reactions, we then extended the range of substrates for the azide and the results are shown in Figure 6.When base group CO2Me, SO2Me and NO2 are attached to the azobenzene counterpart, the reaction yields are good and the amination products can be acquired in yields of 73%-75%.When CF3 is attached to the azobenzene counterpart, the catalyst and silver salt loadings can be reduced to 2.5 mol% and 10 mol% and the reaction time to 36h, the product yield can then be 78%.The results showed good tolerance to amination reagents as well.The above results demonstrate that the reaction can be extended to many different indole substrates and that satisfactory yields can be achieved.

Conclusions
In summary, the work we did was as follows: After screening a series of conditions, the optimum reaction conditions were determined to be 2.5 mol% [Cp*CoI2]2 as the catalyst, 10 mol% AgSbF6 as silver salt and 30 mol% KOAc as an additive in 0.2 M concentration of 1,4-dioxane at 80 ℃ for 24 h.At this time, a 96% yield was achieved, which gave good results.The corresponding target product of amination.Indole C4 position with Br attached 85% yield, with Cl 89% yield and 79% yield with OMe.Indole C5 with methyl in 90% yield, OMe in 80% yield, F in 90% yield, Cl in 85% yield, and CO2Me in 78% yield.Indole C6 with Me 79% yield, with F 83% yield, with Cl 71% yield, with OBn 85% yield.When base group CO2Me, SO2Me, and NO2 are attached to the azobenzene counterpart, the reaction yields are good and the amination products can be acquired in yields of 73%-75%.When CF3 is attached to the azobenzene counterpart, the catalyst and silver salt loadings can be reduced to 2.5 mol% and 10 mol% and the reaction time to 36h, the product yield can then be 78%.
In summary, we have provided an efficient method for obtaining 2-position amino-substituted indole derivatives using inexpensive and readily available metallic cobalt as a catalyst, which is environmentally friendly, atomically economical, and functional group tolerant to the substrate, suggesting a usable route for the structural modification of indoles.And we expect that this selective amination reaction will lead to a wider range of synthetic applications.The next step is to screen the product for biological activity and find the structure of the potential drug and explore better reaction systems, such as using cheaper catalytic systems and expanding the range of substrates.
In conclusion, the reaction achieves the C-H bonded amination of indole derivatives at the C2 position catalyzed by a trivalent cobalt catalyst, a catalytic system with good functional group tolerance, high substrate universality, and excellent yields.This method may suggest some novel approaches for the further development of indoline alkynyl structures, opening up further possibilities for related structures and application values.

Figure 1 .
Figure 1.Selected examples of the 2-amido indole unit.Transition metal catalysis has become an effective tool for the functionalization and late modification of indole structure-related molecules over the past decades, this method offers higher atomic economy and synthetic utility than conventional organic reactions.This reaction can be used in organic synthesis, drug synthesis, and polymer chemistry, it is one of the key steps in the synthesis of many complex organic compounds.This approach has made great progress in recent years and can simplify the synthesis steps of organic target products and improve the atomic economy.This is achieved by introducing a localization group into the reaction substrate and a reaction between the transition metal and the C-H bond to produce a C-M bond intermediate and the C-M bonded intermediates are produced by the reaction between a metal catalyst and a C-H bond, where the transition metal is coordinated to the localization atom on the localization group to achieve localization revitalization of the specific C-H bond, thus accomplishing good regioselectivity.In transition metals, the Cp*Rh(III) catalysts show very good performance, including C2 amination of indoles (Figure2a)[8] .In view of the necessity of developing environmentally friendly, atomically economical and recyclable catalytic systems, Matsunaga and Kanai's group has also made relevant progress in recent years (Figure2b).Hereto, we have implemented a new method for the direct selective C-H amination of indoles with azides at the C2 position using cheap and readily available Cp*Co(III) catalysts to obtain a series of 2-aminoindoles (Figure2c).

Figure 3 .
Figure 3. Structure of the Cp*Co(III) catalyst.We first screened the reaction conditions (Table1) and tried different cationic cobalt complexes, Co(acac)3, [Co(NH3)6Cl3], Co2(CO)8 and CoI2 did not react (Entries 1-4).However, the catalytic system of [Cp*CoI2]2 complexes with Ag salts was observed to produce the product, evidence that Cp*Co(III) species play a decisive role in the reaction.Under these conditions, a 96% yield was obtained with KOAc (Entry 5).We then screened the range of silver salts.In the screened Ag salts (Entries 5-8),

Figure 5 .
Figure 5. Indole substrate scope.To complete the range of substrates for catalytic reactions, we then extended the range of substrates for the azide and the results are shown in Figure6.When base group CO2Me, SO2Me and NO2 are attached to the azobenzene counterpart, the reaction yields are good and the amination products can be acquired in yields of 73%-75%.When CF3 is attached to the azobenzene counterpart, the catalyst and silver salt loadings can be reduced to 2.5 mol% and 10 mol% and the reaction time to 36h, the product yield can then be 78%.The results showed good tolerance to amination reagents as well.The above results demonstrate that the reaction can be extended to many different indole substrates and that satisfactory yields can be achieved.