Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 2‑Aminobenzonitriles through Nitrosation Reaction and Sequential Iron(III)-Catalyzed C−C Bond Cleavage of 2‑Arylindoles Wei-Li Chen,† Si-Yi Wu,† Xue-Ling Mo, Liu-Xu Wei, Cui Liang, and Dong-Liang Mo* State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China; School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin, 541004, China S Supporting Information *
ABSTRACT: A variety of 2-aminobenzonitriles were prepared from 2-arylindoles in good to excellent yields through tertbutylnitrite (TBN)-mediated nitrosation and sequential iron(III)catalyzed C−C Bond cleavage in a one-pot fashion. The 2aminobenzonitriles can be used to rapidly synthesize benzoxazinones by intramolecular condensation. The present method features an inexpensive iron(III) catalyst, gram scalable preparations, and novel C−C bond cleavage of indoles.
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Scheme 1. Strategies To Access 2-Aminobenzonitriles
he cyano and amino groups not only are extensively found in various biologically active molecules and functionalized materials but also are used as powerful building blocks.1,2 2Aminobenzonitriles are one of the most important types of these compounds, have favorable anti-inflammatory effects, and serve as DPP-IV inhibitors.3 Although many cyanation or amination strategies were developed to introduce cyano and amino groups into aromatic compounds, traditional methods to prepare 2-aminobenzonitriles were usually through reduction or coupling reactions from ortho-nitrobenzonitriles, ortho-nitro derivatives, or ortho-halo anilines.4 Recently, Zeng and coworker developed an efficient metal-free chemoselective aminocyanation of arynes to prepare 1,2-bifunctional aminobenzonitriles by N−CN bond cleavage (Scheme 1A).5 In 2015, Sun’s group reported a rhodium-catalyzed direct cyanation of the aromatic C−H bond to access 2-alkylaminobenzonitriles using N-nitroso as a directing group (Scheme 1B).6 In 2016, Ranu and co-workers found that regioselective synthesis of 2aminobenzonitriles can be achieved through palladiumcatalyzed norbornene-mediated tandem ortho-C−H amination/ipso-C−I cyanation of iodoarenes. Single and double C− H aminations were observed (Scheme 1C).7 Although these efficient methods toward 2-aminobenzonitriles were successfully developed, the reaction suffered from limited or not easily available starting materials (arynes and N-nitrosoarylamines), unnecessary byproducts, and requiring expensive metal catalysts (rhodium or palladium). Therefore, development of efficient and practical strategies to prepare 2-aminobenzonitriles from easily accessible starting materials and inexpensive catalysts remains desirable. Recently, C−C bond cleavage to access new and reactive intermediates through transition-metal catalysts has attracted much attention in organic synthesis.8 As the most abundant transition metal on earth, using iron catalysts in synthetic chemistry has clear advantages because of the inexpensive, nontoxic, and environmentally benign properties of iron species.9 N−O bond cleavage and sequential amination to form the C−N bond through iron catalysts have been © XXXX American Chemical Society
reported.10 2-Arylindoles have been identified to go through C−C bond cleavage by the oxidation of PhI(OAc)2 and copper salts.11 During studies of selective N−O bond cleavage in our group,12 we envisioned that 2-arylindoles would go through nitrosation to provide oxime intermediates using tert-butylnitrite (TBN).13 Then, C−C bond cleavage under iron catalysts would deliver 2-aminobenzonitriles (Scheme 1D). It is noteworthy that 2-arylindoles were easily obtained on gram scales from aryl hydrazines and ketones through Fischer indole Received: April 23, 2018
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DOI: 10.1021/acs.orglett.8b01294 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters synthesis.14 Herein, we report a novel and efficient method to afford various 2-aminobenzonitriles from indoles through onepot TBN-mediated nitrosation and iron-catalyzed C−C bond cleavage. Initially, oxime 2a was chosen as a model substrate for investigating the key C−C bond cleavage step. Oxime 2a was prepared in 99% yield by treating indole 1a with 2.0 equiv of TBN in MeCN at 80 °C for 30 min. When oxime 2a was heated at 100 °C without a catalyst for 24 h, compound 3a was not observed and only oxime 2a was recovered (Table 1, entry
equiv of H2SO4 and TfOH were tested (Table 1, entries 19− 20). Product 3a could not be observed using H2SO4, while TfOH delivered 3a in 16% yield. Based on the best solvent for the formation of 3a in accordance with the formation of oxime 2a, a one-pot reaction to prepare 3a from 1a was performed. Indole 1a was treated with TBN in MeCN at 80 °C until 1a was consumed completely. Then, Fe(OTf)3 was added directly and the reaction ran at 100 °C for 18 h giving 3a in 92% yield (Table 1, entry 21). Hence, the optimal conditions for preparing 3a was that indole 1a reacted with TBN in MeCN at 80 °C, and then, the reaction was added with 10 mol % of Fe(OTf)3 and heated at 100 °C. With the optimal conditions established, a variety of aryl moieties at the 2-position of indoles 1 were evaluated. As shown in Scheme 2, indoles 1a−k containing electron-donating
Table 1. Optimization of the C−C Bond Cleavage Conditionsa
Scheme 2. Scope of Forming 2-Aminobenzonitriles 3 for 2Arylindoles 1a,b entry
cat. (10 mol %)
solvent
temp (°C)
3a (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19c 20c 21e
− FeCl2 Fe(OAc)2 Fe(OTf)2 Fe(OTf)3 FeCl3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Pd(OAc)2 Cu(OTf)2 CuCl H2SO4 TfOH Fe(OTf)3
MeCN MeCN MeCN MeCN MeCN MeCN DCE THF toluene DMSO MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN
100 100 100 100 100 100 100 100 100 100 120 80 60 40 25 100 100 100 100 100 100
− 6 10 69 95 73 14
