Base-mediated [4+2] annulation of electron-deficient nitrobenzoheterocycles and α,α-dicyanoalkenes in water: Facile access to structurally diverse functionalized dibenzoheterocyclic compounds
Graphical abstract
Introduction
Polycyclic heterocycles are ubiquitous and important structural motifs found in a wide range of natural products, pharmaceuticals, agrochemicals, and organic functional materials [1]. In particular, functionalized dibenzoheterocyclic compounds, such as dibenzofuran[2], dibenzothiophene [3] and carbazole derivatives [4], are quite important heterocyclic compounds that have attracted much interest over the years due to their extensive application in biologically active compounds and materials science (Fig. 1). A number of methodologies have been developed for the synthesis of various functionalized dibenzofuran, dibenzothiophene and carbazole derivatives [5,6]. However, we noticed that the protocols developed to date have more or less certain aspects of limitations, such as lack of generality, unsatisfactory scope, harsh reaction conditions, multistep operation, and inevitable of using transition metal. Therefore, in view of their promising potential applications in the area of drug discovery and the development of new materials, the exploitation of efficient and eco-friendly synthetic methods employing mild reaction conditions for the generation of structurally diverse functionalized dibenzoheterocyclic compounds is still highly in demand.
In recent years, the reports regarding to the application of electron-deficient nitrobenzoheterocycles, including 2- and 3-nitroindoles[7,8], 2-nitrobenzofurans [9], 2- and 3-nitrobenzothiophenes [8e, 8p], [9], [9](a), [9](e), [9](f), [10], as robust electrophiles for the construction of various polycyclic heterocyclic skeletons illustrate the continued interest from synthetic chemists. On the other hand, α,α-dicyanoalkenes have been widely used as highly reactive vinylogous nucleophiles for the Michael addition and the subsequent cyclization reaction to access various cyclic compounds [11]. As a continuation of our investigation on the synthesis of polycyclic heterocycles[12], we envisioned that electron-deficient 2-nitrobenzofurans could react with α,α-dicyanoalkenes through a tandem reaction process (Scheme 1, top). As depicted in Scheme 1, at first, the α,α-dicyanoalkene would be easily deprotonated by a suitable base to furnish the corresponding vinylogous carbanion. And then, a vinylogous Michael addition between the vinylogous carbanion and 2-nitrobenzofurans should give the corresponding intermediate A. Afterwards, the attack of carbanion in the intermediate A to one of the cyano groups would give rise to the intramolecular cyclization, affording the primary [4 + 2] annulation products. Ultimately, the molecular tautomerization and subsequent elimination of nitrous acid would lead to the formation of the desired dibenzofuran derivatives.
To our great delight, we have recently found that this strategy for the formation of dibenzofurans can be smoothly implemented even with water as the reaction medium (Scheme 1, top). As we all know, water is abundant, environmentally benign, and low cost solvent in nature [13]. More importantly, we also demonstrate that the developed tandem vinylogous Michael addition/cyclization/tautomerization/elimination process can be extended to 2-nitrobenzothiophenes, 3-nitrobenzothiophenes and 3-nitroindoles to generate dibenzothiophene and carbazole derivatives (Scheme 1, bottom). Herein, we wish to report our research on this subject.
Section snippets
Results and discussion
Initially, 2-nitrobenzofuran 1a and α,α-dicyanoalkene 2a were chosen as model substrates to optimize the reaction conditions (Table 1). With DABCO in CH2Cl2 at room temperature for 36 h, the reaction afforded the pentacyclic heterocyclic product 3aa in 34% yield (Table 1, entry 1), while with triethylamine as base, 3aa could be obtained in 46% yield (Table 1, entry 2). Using K2CO3 for the reaction, 3aa was isolated in 60% yield (Table 1, entry 3). The increased reactivity and yield could be
Conclusion
In summary, we have successfully developed an efficient and eco-friendly [4 + 2] annulation of 2-nitrobenzofurans, 2-nitrobenzothiophenes, 3-nitrobenzothiophenes, and 3-nitroindoles with α,α-dicyanoalkenes for the synthesis of structurally diverse dibenzoheterocyclic compounds. The reaction proceeded smoothly via a tandem vinylogous Michael addition/cyclization/tautomerization/elimination process in water with cesium carbonate as base. This methodology provides a simple and convenient access to
General experimental information
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by TLC. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3 and DMSO‑d6. 1H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl3 at 7.26 ppm, DMSO‑d6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet,
Declaration of interest statement
We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
We declare that there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled.
Acknowledgements
We are grateful for financial support from the National NSFC (21871252 and 21901024), the National Key R&D Program of China (2018YFC0807301-3), the Project of Youth Science and Technology Innovation Team of Sichuan Province (2016TD0027).
References (16)
- et al.
Inside Chem.
(2017)et al.Org. Lett.
(2018)et al.Chem. Commun.
(2019)et al.Org. Lett.
(2019)et al.J. Org. Chem.
(2019)et al.Org. Biomol. Chem.
(2019)et al.Chem. Commun.
(2019) - CCDC-1964645 (3ea) Contains the Supplementary Crystallographic Data for This Paper. These Data Can Be Obtained Free of...
- et al.
Nat. Prod. Rep.
(2004)Nat. Prod. Rep.
(2006)et al.Chem. Rev.
(2007)et al.Heterocycles
(2009)et al.Nat. Prod. Rep.
(2009)et al.Chem. Rev.
(2014)et al.Chem. Soc. Rev.
(2015) - et al.
Dibenzofurans
et al.Phytochemistry
(1995)et al.J. Med. Chem.
(2000)et al.J. Nat. Prod.
(2002)Eur. J. Med. Chem.
(2015) - et al.
J. Med. Chem.
(1995)et al.Bioorg. Med. Chem. Lett
(2005)et al.J. Org. Chem.
(2007) - et al.
Chem. Mater.
(2001)et al.Chem. Rev.
(2002)et al.J. Org. Chem.
(2004)et al.Chem. Rev.
(2012)et al.Tetrahedron
(2012) - For selected reviews,... et al.
Chem. Rev.
(2002)et al.Curr. Org. Chem.
(2005)et al.Chem. Commun.
(2006)Tetrahedron
(2006)et al.Chem. Rev.
(2007)et al.Tetrahedron
(2007)Chem. Pharm. Bull.
(2008) - For selected examples,... et al.
Synlett
(2003)et al.Angew. Chem. Int. Ed.
(2003)et al.Tetrahedron Lett.
(2005)et al.J. Am. Chem. Soc.
(2005)et al.Org. Lett.
(2006)et al.J. Org. Chem.
(2006)et al.J. Org. Chem.
(2018)et al.J. J. Org. Chem.
(2018)et al.Org. Biomol. Chem.
(2015)et al.J. Org. Chem.
(2015)et al.J. Org. Chem.
(2008)
Cited by (12)
Annulation reactions of electrophilic benzannulated heterocycles towards heteroacenes
2024, Chemical CommunicationsRecent advances in the synthesis of benzo[b]thiophene fused polycyclic derivatives: Strategies and reactions
2023, Chinese Chemical LettersBase-Mediated Annulation of Electrophilic Benzothiophene with Naphthols and Phenols: Accessing Benzothiophene-Fused Heteroacenes
2022, Journal of Organic ChemistryDearomatization of Nitro(hetero)arenes through Annulation
2022, European Journal of Organic ChemistryFive-membered ring systems: furans and benzofurans
2021, Progress in Heterocyclic ChemistryCitation Excerpt :The reaction proceeded smoothly via a tandem vinylogous Michael addition/cyclization/tautomerization/elimination process in water with cesium carbonate as base, affording a wide range of dibenzofurans in good to high yields. The optical properties of the polycyclic aromatic products were preliminarily investigated by UV/Vis and fluorescence experiments, indicating the potential values of these compounds for photoluminescence materials (20T131115). Image 071239780323984102