Report of the research group of Professor Mo Dongliang of Guangxi Normal University on the synthesis of 2-aminobenzonitrile derivatives by the cleavage of a new C − C bond of 2-arylindole catalyzed by iron

The author: Professor Mo Dongliang's group 2-aminobenzonitrile compounds are not only a kind of important organic synthesis intermediates, but also most of their derivatives have biological activities, such as anti-inflammatory effect and can be used as DPP-IV inhibitors The traditional synthesis of 2-aminobenzonitrile is mainly through the reduction of o-nitrobenzonitrile or the coupling reaction of o-haloaromatic amines Compared with the traditional synthesis method, Professor Zeng Xiaoming of Xi'an Jiaotong University recently developed the cyaniding reaction between arylalkyne and arylcyanamide under the condition of no metal, and realized the synthesis of 2-aminobenzonitriles (scheme 1-A) by n-cn bond breaking In 2015, Professor Sun Peipei of Nanjing Normal University developed rhodium catalyzed nitroso directed C-H bond cyanidation to construct 2-aminobenzonitriles (scheme 1-B) In 2016, Professor ranu of India reported the continuous C-H amination and cyanidation to synthesize 2-aminobenzonitriles (scheme 1-C) using catelani reaction Although these strategies have successfully constructed a variety of 2-aminobenzonitrile compounds containing amino and nitrile bifunctional groups, there are still some limitations, such as the raw materials (arylalkyne and n-nitrosoarylamine) are not easy to obtain, and expensive metal catalysts (rhodium or palladium) are required Therefore, it is still a challenge to develop an efficient and simple synthesis method of 2-aminobenzonitrile from easily available raw materials (source: org Lett.) recently, Professor Mo Dongliang's research group of Guangxi Normal University reported the strategy of "one pot" synthesis of 2-aminobenzonitrile derivatives (scheme 1-D) under mild conditions, using 2-arylindole as raw material, through nitrification and iron catalyzed C − C bond breaking This method has many advantages, such as easy to get raw materials, wide range of substrates, gram scale preparation, cheap metal catalyst, and involving the breaking of new C − C bond of indole This paper is entitled "synthesis of 2-aminobenzonitriles through nitrosation reaction and sequential iron (III) - catalyzed C − C bonds clearance of 2-aryindoles" and published on org Lett The first author of this paper is Chen Weili, a postgraduate, Wu Siyi, an undergraduate, and Professor Mo Dongliang, a corresponding author (DOI: 10.1021 / ACS Orglett 8b01294) Firstly, the author found that oxime 2A could be obtained by nitration of 2-Phenylindole 1A with TBN in 99% yield, but 2A could not be converted into 2-aminobenzonitrile 3A under heating conditions Then, using oxime 2A as raw material, the author optimized the C − C bond breaking step by adding metal catalyst (Table 1) It was found that 2-aminobenzonitrile 3A could be obtained in 93% yield when 10 mol% Fe (OTF) 3 was added However, other iron salts, palladium and copper catalysts did not promote the cleavage of C-C bond Finally, the author used 2-Phenylindole 1A as the raw material to carry out the "one pot" reaction of nitration and iron catalyzed C − C bond breaking, and found that 2-aminobenzonitrile 3A could still be obtained in 92% yield (source: org Lett.) next, the author investigated the substrate applicability of the reaction (scheme2) For 2-arylindoles substituted by different groups, the corresponding 2-aminobenzonitrile derivative 3 can be obtained in medium to excellent yields, no matter whether there are donor or acceptor groups on the aromatic ring In addition, the gram scale preparation of compound 3A has been realized (source: org Lett.) later, the author studied the reaction mechanism (scheme3) The author determined that the compound 2 obtained from the nitrification of indole was scheme 3-1 through the single crystal of 2C compound When methyl protected 2-phenylindole 1n reacts with TBN, only 3-nitrosoindole 4N (scheme 3-2) can be obtained In the absence of iron catalyst, only when the temperature rises to 120 ° C, can 2-aminobenzonitrile 3N be produced in 16% yield; in the optimal condition of adding iron catalyst, 3N (scheme 3-3) can be obtained in 89% yield This shows that iron catalyst can accelerate the formation of 2-aminobenzonitrile 3N from oxime 4N The oxime 2AA protected by methyl is also difficult to react smoothly under the optimal conditions, and only the raw material remains (scheme3-4) It was further found that 18 o-label (scheme3-5) was found in the product 3a of unprotected 2-Phenylindole 1A reaction when heavy water was added to the reaction conditions, while 18 o-label (scheme3-6) was not found in the product 3N when methyl protected indole 1n was used This shows that the formation of product 3A undergoes the process of intermolecular hydrolysis, while the formation of 3N is the process of intramolecular o-transfer (source: org Lett.) based on the above mechanism research and related literature, the author proposed the possible mechanism of the reaction (scheme 4) When r = h, indole 1 reacts with TBN to form nitro compound 4, and then [1,5] - H migrates to form oxime 2; oxime coordinates with Fe (OTF) 3 to form intermediate a, which is broken by C − C bond to form intermediate B and releases Fe (OH) (OTF) 2; B hydrolyzes and isomerizes under Fe (OH) (OTF) 2 to form 2-aminobenzonitrile 3 When R ≠ h, iron promoted the isomerization of nitro compound 4 to obtain intermediate C, and C through intramolecular nucleophilic reaction to obtain intermediate D under the promotion of iron, D broke n − O bond and C − C bond to form 2-aminobenzonitrile 3 (source: org Lett.) finally, the author found that 2-aminobenzonitrile-3 reacts with sulfuric acid at 100 ° C, which is easy to undergo intramolecular cyclization and hydrolysis to produce 2-aryl substituted benzoxazinone-5 Different substituted 2-aminobenzonitrile-3 can obtain corresponding benzoxazinone-5 in good to excellent yield At the same time, benzoxazinone was prepared on the scale of 5A gram (source: org Lett.) conclusion: the research group of Professor Mo Dongliang of Guangxi Normal University has realized the series strategy of nitration and iron catalyzed C − C cracking, and synthesized 2-aminobenzonitrile derivatives by "one pot" method with 2-arylindole as raw material This method has many advantages, such as easy to get raw materials, wide range of substrates, gram scale preparation, cheap metal catalyst, and involving the breaking of new C − C bond of indole.