Metal-Free Triple Annulation of Ene–Yne–Ketones with Isocyanides

Letter Cite This: Org. Lett. 2018, 20, 6750−6754

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Metal-Free Triple Annulation of Ene−Yne−Ketones with Isocyanides: Domino Access to Furan-Fused Heterocycles via Furoketenimine Zhongyan Hu, Jinhuan Dong, Zhaoyang Li, Bo Yuan, Ruyue Wei, and Xianxiu Xu*

Org. Lett. 2018.20:6750-6754. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 11/02/18. For personal use only.

College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China S Supporting Information *

ABSTRACT: A new furoketenimine intermediate from the coupling of ene-yne-ketones and o-alkenyl arylisocyanides, which enables the efficient synthesis of a wide range of tetracyclic and pentacyclic furan-fused heterocycles in a onepot domino process under catalyst-free conditions, is disclosed. Based on the control experiments, a cascade of 1,6-addition, cyclization, intramolecular Diels−Alder reaction, and oxidative aromatization was proposed for the mechanism.

A

right).15b To date, only these two domino transformations of isocyanides and ene-yne-ketones have been reported, and both of these reactions are initiated by an 1,4-addition onto the conjugated ketones.15 Considering that isocyanide possesses a unique α-addition reactivity,12,15b,16 we hypothesized that ketenimines (Int III) could be generated from isocyanides and ene-yne-ketones if a cascade 1,6-addition and cyclization sequence could be facilitated (see Scheme 1d). As a continuation of our studies on the domino reaction of functionalized isocyanides,17 we herein report an unprecedented catalyst-free triple annulation of o-alkenylaryl isocyanides with ene-yne-ketones, in which furoketenimine Int III is involved as the key intermediate (Scheme 1c). Thus, a wide range of furocarbazoles, furoacridinone, and related fused heterocycles are efficiently synthesized through the successive formation of four bonds and three rings in a single operation. In contrast to the well-established metal- and Lewis basemediated process (see Schemes 1a−c), and to the best of our knowledge, this is the first example of the formation of furoketenimine intermediate from the coupling of isocyanides with ene-yne-ketones.15,18 The furocarbazole scaffold is frequently found in carbazole alkaloids,19 such as furostifoline, eustifoline-D, furoclausine-A, and furoclausine-B (see Figure 1).20 Some synthesized furocarbazole derivatives exhibit valuable biological activities.21 Therefore, the construction of furocarbazole derivatives has drawn considerable attention in recent years.19−21 The present domino reaction not only disclosed a new reactivity profile of ene-yne-ketones and isocyanides, but also provided an efficient and straightforward protocol for the rapid assembly of

s an atom-economical process, the domino reaction has attracted much attention for its potential in the construction of natural productlike scaffolds from simple substrates in a single operation.1 In such reactions, multiple bonds are generally formed in a sequential manner in that the latter bond-forming transformation occurs at the functionalities obtained in the former step. In this context, ene−yne−ketones, bearing conjugated ketone, alkenyl, and alkyne functionalities, are promising feedstocks in such process, and have been extensively explored during the past decade.2−11 One of the most widely studied transformations is the transition-metalcatalyzed cyclization of ene-yne-ketones to generate functionalized furan derivatives via an α-furyl metal carbenoid intermediate Int I (see Scheme 1a). 2 Representative contributions were documented by the research groups of Uemura,3 Vicent,4 Zhang,5 Wang,6 Zhu,7 Zhou,8 and other researchers.9 Meanwhile, another novel transformation of eneyne-ketones is the phosphine/sulfur-catalyzed or mediated synthesis of 5-functionalized furan10 or benzofuran derivatives11 via the key yilde Int II, which is generated by the 1,6addition-initiated domino process (Scheme 1b). In the aforementioned chemistry of ene-yne-ketone, a metal or a Lewis base is required as a promoter or catalyst, and the catalyst- and promoter-free transformation of these valuable synthons has been elusive. Because of their versatile reactivities, isocyanides are valuable building blocks for the synthesis of heterocycles,12 and domino reactions of functionalized isocyanides have been well-established.13 Our group has been interested in the isocyanide-based domino annulation for years.14 Very recently, we reported a double annulation of ene-yne-ketones with αacidic isocyanides (see Scheme 1c, left).15a Subsequently, Li and co-workers documented a double isocyanide insertion and cyclization cascade of ene-yne-ketones (see Scheme 1c, © 2018 American Chemical Society

Received: September 7, 2018 Published: October 17, 2018 6750

DOI: 10.1021/acs.orglett.8b02870 Org. Lett. 2018, 20, 6750−6754

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa,b

Scheme 1. Reactivities of Ene-Yne-Ketones

entry

solvent

temperature (°C)

yield of 3a (%)

1 2 3 4 5 6 7 8 9 10

EtOH 1,4-dioxane CH3CN DCE DCM toluene THF DMF CH3CN CH3CN

100 100 100 100 100 100 100 100 120 80

34 80 83 58 50 68 60 63 79 51

a Reaction conditions: 1a (1.5 equiv), 2a (0.25 mmol), solvent (2 mL) in an air atmosphere. bIsolated yields.

Scheme 2. Scope of Ene-Yne-Ketones 1a,b

Figure 1. Natural furocarbazole alkaloids.

structurally complex natural-product-inspired furocarbazole scaffolds. Very recently, we reported a formal [1 + 2 + 3] annulation of o-alkenyl arylisocyanides with α,β-unsaturated ketones for the expedient synthesis of carbazoles in ethanol at 100 °C.22 Herein, when the reaction of ene-yne-ketone 1a and isocyanide 2a was treated with our previous conditions, furo[2,3b]carbazole 3a was obtained in 34% yield (see Table 1, entry 1). Solvent screening revealed that the yield of 3a was improved to 83% when acetonitrile was used as the reaction media (see Table 1, entries 2−8). Elevating the temperature to 120 °C led to a slightly lower yield of 3a (Table 1, entry 3 vs entry 9). Decreasing the temperature to 80 °C led to a low yield of 3a (see Table 1, entry 3 vs entry 10). With the optimal conditions in hand, the scope of ene-yneketones 1 was first examined and the results are summarized in Scheme 2. First, the triple annulation tolerates substrate 1 bearing a broad range of groups (R3) on the alkyne terminus, including electron-neutral, electron-rich, and electron-deficient aryl (1a−1e in Scheme 2), naphthyl (1f in Scheme 2), styryl (1g in Scheme 2), and alkyl groups (1i−1k in Scheme 2).

a

Reaction conditions: 1a (1.5 equiv), 2 (0.25 mmol) in CH3CN (2 mL) at 100 °C. bIsolated yields. cGram-scale synthesis. dThreecomponent reaction from 1,3-diketone, propiolaldehyde, and isocyanide 2a.

Interestingly, when ene-yne-ketone 1h with a TMS group at the alkyne terminus was used as a substrate, the desilylation furocarbazole 3h was obtained in 72% yield. Then, ene-yneketone compounds derived from various 1,3-diketones (1l−1n in Scheme 2), β-ketonesters (1o−1q in Scheme 2), 1,3-diester (1r in Scheme 2), β-nitroketone (1s in Scheme 2), β6751

DOI: 10.1021/acs.orglett.8b02870 Org. Lett. 2018, 20, 6750−6754

Letter

Organic Letters cyanoketones (1t and 1u in Scheme 2), and ketones (1v and 1w in Scheme 2) undergo this triple annulation process to result the furocarbazole derivatives (1l−1w in Scheme 2) in good to high yields. Furthermore, ene-yne-ketones from cyclic 1,3-diketones (1x−1aa in Scheme 2), dimethyl barbituric acid (1ab in Scheme 2), and pyrazol-5(4H)-one (1ac in Scheme 2) also tolerate this domino reaction, and structurally complex pentacyclic and hexacyclic frameworks 3x−3ac resulted in good to high yields. In addition, a gram-scale synthesis of 3a (1.389 g, 70% yield) was also performed to demonstrate the practicability of this triple annulation. Next, the scope of the triple annulation was evaluated, with respect to isocyanides 2; the results are summarized in Scheme 3. A variety of o-alkenyl arylisocyanides 2 tolerate this domino

Scheme 4. Control Experiments

Scheme 3. Scope of Isocyanides 2a,b

detected. This result indicates that the triple annulation may not proceed through a carbene pathway.7 Based on present results, and the literature precedent,10,11,23 a possible mechanistic pathway for the generation of furocarbazoles 3 and 4 is proposed (see Scheme 5). The 1,6Scheme 5. Proposed Mechanism

a Reaction conditions: 1 (1.5 equiv), 2a (0.25 mmol) in CH3CN (2 mL) at 100 °C. bIsolated yields.

addition of isocyanide 2 to ene-yne-ketone 1 generates zwitterionic species I, which forms the furan ketenimine intermediate II upon cyclization.10 An intramolecular Diels− Alder reaction (IMDA), in which the furoketenimine moiety acts as the diene and the alkene group as dienophile, then occurs to give the tetracyclic intermediate III. A 1,3-proton shift and oxidative aromatization successively occur to produce the final furocarbazoles 3 and 4.23 Notably, this is the first time that the reactive ketenimine is generated from the coupling of ene-yne-ketone and isocyanide. Finally, the synthesis of furoacridinones was also accomplished by this novel triple annulation strategy. As shown in Scheme 6, the reaction of ene-yne-ketones 1 with o-enoyl arylisocyanides 824 gives furoacridinones 9a−9h, bearing various substituents in good yields (for optimization of the reaction conditions, see the Supporting Information). In summary, an unprecedented catalyst-free triple annulation of o-alkenylaryl isocyanides with ene-yne-ketones has been developed as a general protocol for the efficient and practical synthesis of furocarbazoles, furoacridinone, and related fused heterocycles. This domino reaction enables one to access structural complex frameworks through the successive

reaction, and the corresponding furocarbazole derivatives 4b− 4r are given in good to high yields. The R2 group of isocyanides 2 is compatible with both electron-donating and electron-withdrawing groups at the 4- and 5-positions of the benzene ring (2b−2g in Scheme 3). The R1 group of isocyanides 2 tolerates ester (2i in Scheme 3), amide (2j in Scheme 3), cyano (2k in Scheme 3), as well as electron-rich and electron-deficient aryl groups (2l−2p in Scheme 3). When isocyanide 2q with a phenylsulfonyl group at the double bond was used as the substrate, the desulfonylation product 4q was obtained in moderate yield. In addition, benzo[g]furo[2,3b]carbazole 4r was obtained in 69% yield, when 3-(2isocyanonaphthalen-1-yl)acrylate 2r was employed as feedstocks. Since ene-yne-ketones are often used as nondiazo precursors of carbenes,2−9 a control experiment was performed to identify the possibility of a carbene mechanism (see Scheme 4). When ene-yne-ketone 5 tethered to an alkene group was used as a substrate under standard conditions, the triple annulation product furocarbazole 6 was obtained in 68% yield, whereas the furan carbene cyclopropanation product 7 was not 6752

DOI: 10.1021/acs.orglett.8b02870 Org. Lett. 2018, 20, 6750−6754

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Organic Letters

(2) For reviews, see: (a) Siva Kumari, A. L.; Siva Reddy, A.; Swamy, K. C. K. Org. Biomol. Chem. 2016, 14, 6651. (b) Ma, J.; Zhang, L.; Zhu, S. Curr. Org. Chem. 2015, 20, 102. (3) (a) Miki, K.; Washitake, Y.; Ohe, K.; Uemura, S. Angew. Chem., Int. Ed. 2004, 43, 1857. (b) Miki, K.; Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 5260. (4) (a) Vicente, R.; González, J.; Riesgo, L.; González, J.; López, L. A. Angew. Chem., Int. Ed. 2012, 51, 8063. (b) González, J.; González, J.; Pérez-Calleja, C.; López, L. A.; Vicente, R. Angew. Chem., Int. Ed. 2013, 52, 5853. (5) (a) Zhou, L.; Zhang, M.; Li, W.; Zhang, J. Angew. Chem., Int. Ed. 2014, 53, 6542. (b) Zhang, Z.-M.; Chen, P.; Li, W.; Niu, Y.; Zhao, X.L.; Zhang, J. Angew. Chem., Int. Ed. 2014, 53, 4350. (c) Liu, F.; Qian, D.; Li, L.; Zhao, X.; Zhang, J. Angew. Chem., Int. Ed. 2010, 49, 6669. (d) Liu, F.; Yu, Y.; Zhang, J. Angew. Chem., Int. Ed. 2009, 48, 5505. (e) Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903. (6) (a) Xia, Y.; Qu, S.; Xiao, Q.; Wang, Z.-X.; Qu, P.; Chen, L.; Liu, Z.; Tian, L.; Huang, Z.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2013, 135, 13502. (b) Xia, Y.; Liu, Z.; Ge, R.; Xiao, Q.; Zhang, Y.; Wang, J. Chem. Commun. 2015, 51, 11233. (7) (a) Zhu, D.; Ma, J.; Luo, K.; Fu, H.; Zhang, L.; Zhu, S. Angew. Chem., Int. Ed. 2016, 55, 8452. (b) Ma, J.; Jiang, H.; Zhu, S. Org. Lett. 2014, 16, 4472. (8) Yang, J.-M.; Li, Z.-Q.; Li, M.-L.; He, Q.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2017, 139, 3784. (9) (a) Song, B.; Li, L.-H.; Song, X.-R.; Qiu, Y.-F.; Zhong, M.-J.; Zhou, P.-X.; Liang, Y.-M. Chem. - Eur. J. 2014, 20, 5910. (b) Smith, C. D.; France, D. J. ChemCatChem 2014, 6, 711. (c) Zhan, H.; Lin, X.; Qiu, Y.; Du, Z.; Li, P.; Li, Y.; Cao, H. Eur. J. Org. Chem. 2013, 2013, 2284. (d) Casey, C. P.; Strotman, N. A. J. Org. Chem. 2005, 70, 2576. (e) Cao, H.; Zhan, H.; Cen, J.; Lin, J.; Lin, Y.; Zhu, Q.; Fu, M.; Jiang, H. Org. Lett. 2013, 15, 1080. (10) Clark, J. S.; Boyer, A.; Aimon, A.; García, P. E.; Lindsay, D. M.; Symington, A. D. F.; Danoy, Y. Angew. Chem., Int. Ed. 2012, 51, 12128. (11) Liang, L.; Dong, X.; Huang, Y. Chem. - Eur. J. 2017, 23, 7882. (12) For recent reviews, see: (a) Isocyanide Chemistry Applications in Synthesis and Materials Science;Nenajdenko, V., Ed.; Wiley−VCH: Weinheim, Germany, 2012. (b) Boyarskiy, V. P.; Bokach, N. A.; Luzyanin, K. V.; Kukushkin, V. Y. Chem. Rev. 2015, 115, 2698. (13) (a) Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.; Novellino, G.; Tron, C.; Zhu, J. Chem. Soc. Rev. 2017, 46, 1295. (b) Lygin, A. V.; de Meijere, A. Angew. Chem., Int. Ed. 2010, 49, 9094. (14) (a) Hu, Z.; Yuan, H.; Men, Y.; Liu, Q.; Zhang, J.; Xu, X. Angew. Chem., Int. Ed. 2016, 55, 7077. (b) Xu, X.; Zhang, L.; Liu, X.; Pan, L.; Liu, Q. Angew. Chem., Int. Ed. 2013, 52, 9271. (c) Li, Y.; Xu, X.; Tan, J.; Xia, C.; Zhang, D.; Liu, Q. J. Am. Chem. Soc. 2011, 133, 1775. (d) Tan, J.; Xu, X.; Zhang, L.; Li, Y.; Liu, Q. Angew. Chem., Int. Ed. 2009, 48, 2868. (15) (a) Dong, J.; Bao, L.; Hu, Z.; Ma, S.; Zhou, X.; Hao, M.; Li, N.; Xu, X. Org. Lett. 2018, 20, 1244. (b) Li, F.; Hu, P.; Sun, M.; Li, C.; Jia, X.; Li, J. Chem. Commun. 2018, 54, 6412. (16) Tong, S.; Wang, Q.; Wang, M.-X.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 1293. (17) (a) Bao, L.; Liu, J.; Xu, L.; Hu, Z.; Xu, X. Adv. Synth. Catal. 2018, 360, 1870. (b) Zhang, L.; Li, J.; Hu, Z.; Dong, J.; Zhang, X.-M.; Xu, X. Adv. Synth. Catal. 2018, 360, 1938. (c) Zhang, X.; Wang, X.; Gao, Y.; Xu, X. Chem. Commun. 2017, 53, 2427. (d) Hu, Z.; Dong, J.; Xu, X. Adv. Synth. Catal. 2017, 359, 3585. (e) Gao, Y.; Hu, Z.; Dong, J.; Liu, J.; Xu, X. Org. Lett. 2017, 19, 5292. (f) Hu, Z.; Dong, J.; Men, Y.; Li, Y.; Xu, X. Chem. Commun. 2017, 53, 1739. (g) Men, Y.; Dong, J.; Wang, S.; Xu, X. Org. Lett. 2017, 19, 6712. (h) Lin, Z.; Hu, Z.; Zhang, X.; Dong, J.; Liu, J.-B.; Chen, D.-Z.; Xu, X. Org. Lett. 2017, 19, 5284. (18) One-pot processes involving in situ generation of ketenimines from isocyanides have recently been reported. See: (a) Hu, Z.; Dong, J.; Men, Y.; Lin, Z.; Cai, J.; Xu, X. Angew. Chem., Int. Ed. 2017, 56, 1805. (b) Qiu, G.; Mamboury, M.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 15377. (c) Qiu, G.; Wang, Q.; Zhu, J. Org. Lett.

Scheme 6. Synthesis of Furoacridinones 9

formation of four bonds and three rings in a single operation. Notably, furoketenimine is generated for the first time from a 1,6-addition-initiated domino process of isocyanide with eneyne-ketones. The reaction features metal-, acid- and base-free conditions, readily available starting materials, wide substrate scope, high chemical efficiency, and amenability to gram-scale synthesis. Further studies on the new reactivity profile of functionalized isocyanides are ongoing.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02870. Experimental procedures and characterization data for all compounds (PDF) Accession Codes

CCDC 1854626 and 1865240 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xianxiu Xu: 0000-0001-7435-7449 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support provided by the NSFC (No. 21672034) and Shandong Normal University (No. 108-100801) is gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02870 Org. Lett. 2018, 20, 6750−6754

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DOI: 10.1021/acs.orglett.8b02870 Org. Lett. 2018, 20, 6750−6754