Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enamine Catalytic Annulation of Azonaphthalenes: An Access to Indole Derivatives Hanhui Zhao, Huijun Yuan, Yanru Zhang, Rongshi Li,* and Wenjun Li* Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao 266021, P. R. China
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S Supporting Information *
ABSTRACT: The secondary-amine mediated [3 + 2] annulation of azonaphthalenes with aldehydes and ketones is described for the first time, which provides an alternative protocol for the synthesis of indole derivatives. It features a cheap and readily available catalyst, a broad scope of reactants, very mild reaction conditions, and high efficiency. Significantly different from the transition-metal-mediated processes, the enamine activation represents the first organic base-catalytic protocol for indole synthesis.
T
practical protocol for accessing N-substituted-1-aminoindoles from readily available precursors has become an urgent task. With the aim to find suitable synthons for the construction of the indole ring system, especially N-substituted-1-aminoindoles, we focused much attention toward azonaphthalenes because this class of reactants can play the role of carbon− carbon−nitrogen building blocks in [3 + 2] annulations with unsaturated compounds.14,15 In particular, Tan and co-workers have elegantly disclosed a chiral phosphoric acid catalyzed [3 + 2] annulation of azonaphthalenes with 2-substituted indoles to construct axially chiral benz[e]indole derivatives (Scheme 1A).16a Independently, Shi et al. have also reported the chiral phosphoric acid catalyzed [3 + 2] annulations of azonaphthalenes with 3-vinylindoles,17 leading to the formation of chiral dihydrobenzo[e]indole scaffolds (Scheme 1B). Very recently, Wang et al. have developed a carbene-catalyzed [4 + 2] annulation of azonaphthalenes with α-chloroaldehydes for assembly of chiral dihydrocinnolinone derivatives.18 Based on these pioneering reports and as a part of our ongoing interest in the construction of heterocyclic compounds,19 we designed an enamine catalyzed [3 + 2] annulation of azonaphthalenes with enolizable carbonyl compounds (Scheme 1C). In this reaction, aldehyde/ketone was activated by an amine via enamine catalysis,20 followed by reacting with azonaphthalene to form the desired N-substituted-1-aminoindoles. Notably, our designed reaction not only represents the first enamine
he importance of an indole nucleus and its broad spectrum of application justifies it being a privileged structure in numerous research areas including pharmaceuticals, fragrances, agrochemicals, pigments, and material science.1 Accordingly, the construction of the indole nucleus has been a major area of focus for synthetic organic chemists and numerous synthetic methods have been developed.2 In particular, as one of the most important subfamilies of indoles, N-substituted-1-aminoindoles exhibit promising biological activities, such as antidepressant,3 serotonin 5-HT2 antagonists,4 antioxidant effects,5 and potential therapeutic reagents for treatment of Alzheimer’s disease.6 In addition, Nsubstituted-1-aminoindoles also acted as highly valuable intermediates for the construction of many important nitrogen-containing cyclic frameworks.7 Despite N-substituted-1-aminoindoles derivatives holding great potential applications, to date, their synthetic methods are nearly still limited to transition-metal-mediated reactions,8 including Pd-catalyzed cyclization of N,N′-dimethyl-ochloroarylacetaldehyde hydrazones,9 Cu-catalyzed intramolecular cyclization of a suitable Boc-protected enehydrazine and subsequent deprotection,10 the Pd-catalyzed intramolecular cyclization of 2-halo-phenylacetylenes and N,N-disubstituted hydrazines,11 Rh-catalyzed annulation of 2-acetyl-1-arylhydrazines with diazo compounds,12 and so on.13 Notably, these methods suffer from disadvantages such as multistep syntheses, harsh reaction conditions, moderate to poor yields, and limited substrate scope. Therefore, developing a direct, versatile, and © XXXX American Chemical Society
Received: July 19, 2019
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DOI: 10.1021/acs.orglett.9b02507 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Organocatalytic Synthesis of N-Substituted-1aminoindoles
conditions including additive, reaction media, and reaction time revealed that pyrrolidine combined with AcOH enabled the formation of N-substituted-1-aminobenzo[e]indole 3aa in 95% yield in CH2Cl2 at room temperature for 24 h (entry 8; see Supporting Information for details). Under the optimal reaction conditions, we then investigated the substrate scope of aldehydes 2 in the C1 mediated [3 + 2] annulation for the construction of N-substituted-1-aminobenzo[e]indole frameworks, and the results were summarized in Scheme 2. It was found that this catalytic strategy was Scheme 2. Scope of Reactions Azonaphthalenes and Aldehydesa
catalyzed [3 + 2] annulation of azonaphthalene and enolizable carbonyl compounds but also provides an efficient and practical method for the construction of the indole ring system, especially 1-aminobenzoindole and 7-aminobenzotetrahydrocarbazole frameworks. At the outset of this study, we investigated the reaction between 2-azonaphthalene 1a and butyraldehyde 2a in CH2Cl2 at room temperature (Table 1). Gratifyingly, the annulation Table 1. Condition Optimization of Reaction between 1a and 2aa
Entry
Catalyst
Additive
Solvent
Time [h]
1 2 3 4 5 6 7 8
C1 C1 C2 C3 C4 C5 C6 C1
− AcOH AcOH AcOH AcOH AcOH AcOH AcOH
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
12 12 12 12 12 12 12 24
Yield [%]b 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa,
35 85 33 57
