Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Cu-Catalyzed Denitrogenative Transannulation of 3‑Aminoindazoles To Assemble 1‑Aminoisoquinolines and 3‑Aminobenzothiophenes Yao Zhou,† Ya Wang,† Yixian Lou,‡ and Qiuling Song*,†,‡,§
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†
Institute of Next Generation Matter Transformation, College of Materials Science & Engineering at Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, China ‡ Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang 310000, China § Fujian University Key Laboratory of Molecule Synthesis and Function Discovery, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China S Supporting Information *
ABSTRACT: We disclose a novel Cu-catalyzed denitrogenative transannulation of 3-aminoindazoles to afford diverse functionalized 3-aminobenzothiophenes and 1-aminoisoquinolines, in which denitrogenative transannulation of 3-aminoindazoles is reported for the first time. This transformation proceeds via an “extrude-and-sew” strategy with an unprecedented radical reactivity of 3-aminoindazoles.
T
displaying high atom economy and providing an efficacious and direct approach to access intricate frameworks, it is still a powerful tool to acquire complicated compounds.1 Another alternative tactic involves cleavage of two bonds and extrusion of a small molecule (such as CO, N2, CO2, etc.) from the parent substrates, followed by introduction of a new group from another reactant, named “extrude-and-sew” transformations (Scheme 1b).2 3-Aminobenzothiophene and 1-aminoisoquinoline derivatives are widely found as privileged core structural motifs in many bioactive compounds.3,4 Meanwhile, they also serve as versatile building blocks for the generation of isoquinoline and benzothiophene derivatives.5,6 In this letter, we demonstrate a novel “extrude-and-sew” transformation of 3aminoindazoles to assemble the valuable 3-aminobenzothiophene and 1-aminoisoquinoline derivatives. Since the research groups of Gevorgyan,7 Fokin,8 and Murakami9 reported the pioneering studies on denitrogenation reaction of triazoles to generate highly electrophilic α-imino metal carbenoid species, during the past decades, myriads of work based on the transition-metal-catalyzed denitrogenative transannulation of triazoles have been reported for the synthesis of azo-heterocyclic compounds.10,11 In addition to the triazoles, the denitrogenative transannulation of benzotriazinones was also developed,12 in which diverse isoquinolone derivatives were produced via regioselective insertion of benzotriazinones with various unsaturated compounds. In 2018, Murakami disclosed a Rh-catalyzed enantioselective denitrogenative transannulation of 1H-tetrazoles with styrenes for the construction of 3,5-diaryl-
he development of new strategies for successive multiple bond cleavage and multiple bond formation to forge complex molecules is an important goal in organic chemistry. Recently, a variety of “cut-and-sew” reactions have been developed by organic chemists1 as the “cut-and-sew” tactics could rapidly construct complex molecules by incorporating two skeletons and reorganizing bond connections. This “cut-andsew” strategy typically involves oxidative addition of transition metals into strained C−C bonds followed by 2π unit insertion (Scheme 1a). Although most excellent “cut-and-sew” transformations design and prepare special strained substrates,
Scheme 1. “Cut-and-Sew” Transformations and “Extrudeand-Sew” Transformations
Received: July 2, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.9b02288 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 2-pyrazolines.13a In the same year, Chattopadhyay demonstrated an excellent Ir-catalyzed intramolecular transannulation of tetrazoles.13b Very recently, Chattopadhyay’s group also disclosed the Fe(II)-mediated intermolecular denitrogenative transannulation of 1,2,3,4-tetrazoles, overriding traditional click chemistry.13c Although the denitrogenative transannulations of triazoles, benzotriazinones, and tetrazoles have been previously studied, the denitrogenative transannulation of 3-aminoindazoles has never been reported so far. As part of our ongoing interest in exploring new reactions of 3-aminoindazoles,14 herein, we describe a novel Cu-catalyzed denitrogenative transannulation of 3-aminoindazoles to afford diverse functionalized 3-aminobenzothiophenes and 1-aminoisoquinolines (Scheme 1c). To experimentally verify our hypothesis, we selected the commercially available 3-amino-1H-indazole (1a) as a model substrate to react with (Z)-ethyl 3-amino-3-phenyl acrylate (2a). At the outset, when the reaction was performed in the presence of Cu(OAc)2 and tert-butyl peroxybenzoate (TBPB) in CH3CN at 60 °C using K2CO3 as the base, desired product ethyl 1-amino-3-phenylisoquinoline-4-carboxylate (3aa) was obtained in 47% yield (Table 1, entry 1). Subsequently, the model reaction was subjected to various oxidants to investigate the effect of the oxidants (Table 1, entries 2−10). Among the oxidants tested, tert-butyl hydroperoxide (TBHP) demonstrated the optimal efficiency (Table 1, entry 3). We then screened
several copper catalysts. Disappointingly, only marginal improvements were obtained when other Cu salts, such as CuCl2, CuI, and CuBr2, were used in place of Cu(OAc)2 (Table 1, entries 11−13). To enhance the reaction yield, we also inspected a series of bases (Table 1, entries 14−19). Organic bases, such as DBU, just lead to a stagnant reaction. The yield of 3aa was significantly increased to 81% when Cs2CO3 was employed as the base (Table 1, entry 19). The attempt to increase the amount of Cs2CO3 resulted in a lower yield of 3aa (Table 1, entry 20). The model reaction failed to deliver higher yields whether we increased or decreased the temperature (entries 21 and 22). Having identified the optimal reaction conditions, the scope of this Cu-catalyzed oxidative transannulation of 3-aminoindazoles to afford 1-aminoisoquinoline derivatives was evaluated (Scheme 2). A variety of functionalized enamines Scheme 2. Substrate Scope with Respect to Enamines*
Table 1. Optimization of the Reaction Conditions
entrya
[Cu]
oxidant
base
yield (%) of 3aab
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20e 21f 22g
Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 CuCl2 CuI CuBr2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
TBPB DTBP TBHP O2 K2S2O8 Na2S2O8 LPO PIFA IBX PhIO TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 DBU NaOAc NaOH Li2CO3 K3PO4 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
47 27 61 31c 36 25
