Copper-mediated radical alkylarylation of unactivated alkenes with acetonitrile leading to fluorenes and pyrroloindoles

Abstract

A Cu-mediated/catalyzed selective oxidative dual C–H bond cleavage of an arene and alkylnitrile or acetone is reported. This method provides a novel approach to highly functionalized fluorene and pyrroloindole derivatives, which are useful in pharmaceutical and photoelectronic areas. In this reaction, two new C(sp³)–C(sp³) and C(Ar)–C(sp³) bonds, a quaternary center and a five-membered ring are simultaneously formed.

---

Polycyclic aromatic hydrocarbons (PAHs) have been playing increasingly important roles in organic, medicinal and materials chemistry over the past few decades.¹ Representative examples are fluorene and pyrroloindole derivatives (Fig. 1, I and II), which have excellent anti-inflammatory (III),² antitumor (VII),³ and anticancer (VIII) activities⁴ and were confirmed as the cholesterol acyltransferase (ACAT) inhibitor (IV),⁵ cyclophilin A inhibitor (V)⁶ or S1P1 receptor agonist (VI),⁷etc. In addition, while these structural motifs are privileged in naturally occurring and biological active molecules, they also exhibit unique electrical and optical properties.⁸ As such, the development of practical and efficient methods for the synthesis of functionalized PAHs is urgently demanded.

Fig. 1 Representative bioactive related compounds exhibiting the fluorene or pyrroloindole motifs.

Several synthetic procedures to build fused cyclic compounds which suffered from limitations, such as tedious multistep synthesis, harsh reaction conditions, lack of regioselectivity, and poor functional group tolerance, were reported.^9,10 Recently, extensive research attention has been paid to transition-metal-mediated cyclizations utilizing C–H bond activation (Scheme 1, A)¹¹ or a direct dehydrogenative aryl–aryl coupling strategy (Scheme 1, B).¹² Although intermolecular catalytic reactions were also reported (Scheme 1, C),¹³ the fast assembly of diverse fluorenes commencing from suitably functionalized starting materials is still an exciting goal because of its simple operation and atom economy.¹⁴ In this regard we report: (1) an autotandem radical process for the construction of polycyclic aromatic compounds through an oxidative C–C/C–C cross-coupling sequence with the participation of unactivated alkenes (it should be noted that the documented intermolecular dicarbonation is still restricted to oxindoles¹⁵ and related heterocycles¹⁶ using activated substrates); (2) an inexpensive Cu-mediated/catalyzed¹⁷ selective oxidative C–H bond cleavage of an arene and alkylnitrile; (3) two new C–C bonds, a quaternary center and a five-membered ring are simultaneously formed in one reaction; (4) an operationally simple and air benign catalyst system allowing access to various condensed carbo- or heterocycles as a promising scaffold for synthetic intermediates, pharmacophores, and organic photoelectronic materials (Scheme 1, D).

Scheme 1 Metal-mediated routes to fluorenes.

The sequence of domino oxidative coupling of alkene 1a with acetonitrile (2a) and subsequent aryl intramolecular incorporation was established after conducting a variety of reactions (for detailed information on the optimization of the reaction conditions, see Table S1, ESI†). It was found that the presence of the nitrogen-containing ligand (1,10-phenanthroline) was critical to obtaining high yields of the target product. A reasonable explanation is that the cyano group of acetonitrile might coordinate strongly to a metal leading to catalyst poisoning.¹⁸ Screening of other parameters (ligand, base, catalyst, oxidant, etc.) substantially increased the yield of 3aa to 78%. In addition, this one-pot reaction can be scaled up to 2 mmol (70% yield) under an air atmosphere (Table 1, product 3aa).

Table 1 Rapid assembly of fluorenes from alkenes 1 and acetonitrile 2a ^a

a Reaction conditions: alkene 1 (0.2 mmol), 2a (2 mL), Cu(OTf)₂ (0.1 mmol), 1,10-phenanthroline (0.2 mmol), K₂CO₃ (0.6 mmol) and di-tert-butyl peroxide (0.5 mmol) at 140 °C under air for 19 h; yields of the isolated products. b 2 mmol scale. c Determined by ¹H NMR analysis of the isolated products; only the major products are shown.

---

Encouraged by these results, next we set out to investigate the scope of various alkenes 1 in acetonitrile (Tables 1 and 2). As shown in Table 1, the substrates bearing electron-withdrawing or electron-donating groups always afforded the desired products in moderate to good yields (3aa–3na). The functionalities such as halogen, cyano, and ester groups at the p-(3aa–3ha), m-(3ia–3ka), or o-positions (3la–3na) of the aryl rings have no significant influence on the efficiency, thereby facilitating a chance for further modifications of the embedded functional groups. Notably, the use of substrates containing meta-substituents gave a mixture of two regioselective products (3ja/3ja′ and 3ka/3ka′). Moreover, substrates bearing heterocyclic rings including pyridine (1o), pyrimidine (1p) and thiophene (1q) were proven to be appropriate candidates, delivering the corresponding products 3oa–3qa in 37–68% yields. To our delight, when the benzene ring of 1 was changed to naphthalene (1r), phenanthrene (1s), dibenzo[b,d]furan (1t), dibenzo[b,d]thiophene (1u), triphenylamine (1v), and 9-phenyl-9H-carbazole (1w), the substrates were also successfully converted into the alkylarylated products 3ra–3wa. This methodology provides a concise entry to methylene-disubstituted fluorenes which are not easily accessed by the reported methods. More importantly, these new members of the family of π-conjugated polycyclic derivatives could be used as potential optoelectronic materials.^1h,8d

Table 2 Substrate scope for the reaction of various alkenes 1 with 2a ^a

a Reaction conditions: alkene 1 (0.2 mmol), 2a (2 mL), Cu(OTf)₂ (0.1 mmol), 1,10-phenanthroline (0.2 mmol), K₂CO₃ (0.6 mmol) and di-tert-butyl peroxide (0.5 mmol) at 140 °C under air for 19 h; yields of the isolated products. b Diastereomeric ratio was determined by ¹H NMR spectroscopy of the isolated products. c 30 mol% of Cu(OTf)₂ was used.

---

The synthesis of fluorene 4aa with an ethyl group at the methylene moiety proceeded smoothly under optimal conditions, whereas simple styrene failed to afford the product 4ba (Table 2, 4aa–4ba). In addition, it was found that 2-vinylbiphenyls containing halogen atoms or derived from 1-(biphenyl-2-yl)propan-1-one were also compatible with the reaction conditions, leading to the tricyclic products 4ca and 4da in 66% and 57%, respectively. Interestingly, pyrroles and indoles could be facilely incorporated into these skeletons, which greatly streamlined the access to such fused pyrroloindoles (as electroluminescence materials^8b and pharmaceutically relevant molecules^3,4,7). Unfortunately, a series of other types of alkenes having an aliphatic chain (6–7) or double bonds (8) as the tether were not suitable. Apart from acetonitrile 2a, acetone 2b could also act as an effective substrate in this system with alkenes 1 (Table 3).¹⁹ The aryl-substituted alkenes 1 also worked well and mainly offered the desired products 5ab, 5db and 5sb in medium yield. Gratifyingly, the reaction was applicable to 5-(2-(prop-1-en-2-yl)phenyl)pyrimidine (1s), furnishing the product 5pb in 47% yield.

Table 3 Rapid assembly of fluorenes from alkenes 1 and acetone 2b ^a

a Reaction conditions: alkene 1 (0.3 mmol), 2a (2 mL), Cu(OTf)₂ (0.03 mmol), 1,10-phenanthroline (0.06 mmol), Na₃PO₄ (0.3 mmol) and di-tert-butyl peroxide (0.75 mmol) at 120 °C under air for 24 h; yields of the isolated products.

---

It is noteworthy that the cyanomethylated products were widely applied in synthetic transformations (Scheme 2).²⁰ For instance, an unexpected product of 9H-fluoren-9-ol 10 was synthesized from 3aa with the reduction of lithium aluminium hydride (Scheme 2, a). In addition, the cyano group can be easily hydrolyzed to amide in the KOH/tBuOH system (Scheme 2, b). Moreover, the photophysical properties of the prepared polycyclics were analysed by UV-Vis absorption photoluminescence measurements at room temperature in CH₂Cl₂ (Fig. 2).

Scheme 2 Further synthetic transformations and mechanism studies.

Fig. 2 The fluorescence spectra of the prepared polycyclic compounds.

To get insight into the mechanism, a kinetic isotopic effect (KIE) study was conducted. The intermolecular k_H/k_D (3.3) indicated that the C(sp³)–H bond cleavage of acetonitrile should be the rate-determining step (Scheme 2, c). Furthermore, the reactions were completely inhibited in the presence of a radical scavenger 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) (Scheme 2, d), implying that a radical process might be involved in this transformation (for detailed information, see Fig. S2 and S3, ESI†). Initial mechanistic studies suggested that a free radical pathway (Scheme 3, path b) was more likely than a process involving the formation of an organocopper species (path a).¹⁷ Thus, initially, acetonitrile radical B (SOMO-π delocalization)^17g which is thermodynamically stable, adds to alkene 1 to form a free radical D. Subsequently, an intramolecular cyclization from active alkyl radical D to intermediate E occurs; the former is kinetically competitive with TEMPO trapping, thus the TEMPO adduct of D was not observed.²¹ Finally, radical E was oxidized and followed by deprotonation to furnish fluorene 3.^15,16

Scheme 3 Proposed reaction mechanism.

In conclusion, we have developed a copper-mediated/catalyzed selective oxidative C–H bond functionalization reaction for a rapid assembly of fluorene and pyrroloindole derivatives from unactivated alkenes and acetonitrile. The reaction is general and practical because of its high reaction efficiency, broad substrate scope, the use of an inexpensive Cu-catalyst, and simple operation under air. More importantly, this methodology provides chemists an alternative method for designing new pharmaceutical frameworks and photoelectronic devices. Further studies to elucidate the detailed reaction mechanism and its application to the synthesis of complex products are ongoing in our group and will be disclosed in the near future.

We gratefully acknowledge the Natural Science Foundation of China (no. 21172162, 21372174), the Young National Natural Science Foundation of China (no. 21202113), the Ph.D. Programs Foundation of Ministry of Education of China (2013201130004), the Research Grant from the Innovation Project for Graduate Student of Jiangsu Province (KYZZ15_0322), PAPD, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials and Soochow University for financial support.

Notes and references

1. (a) R. G. Harvey, Polycyclic Aromatic Hydrocarbons, Wiley-VCH, Weinheim, 1997; (b) M. Toyota and N. Ihara, Nat. Prod. Rep., 1998, 15, 327; (c) M. Bendikov, F. Wudl and D. F. Perepichka, Chem. Rev., 2004, 104, 4891; (d) D. Pérez and E. Guitián, Chem. Soc. Rev., 2004, 33, 274; (e) J. E. Anthony, Chem. Rev., 2006, 106, 5028; (f) Carbon-Rich Compounds, ed. M. M. Haley and R. R. Tykwinski, Wiley-VCH, Weinheim, 2006; (g) S. Sergeyev, W. Pisula and Y. H. Geerts, Chem. Soc. Rev., 2007, 36, 1902; (h) C. Wang, H. Dong, W. Hu, Y. Liu and D. Zhu, Chem. Rev., 2012, 112, 2208; (i) J. R. Fulton, M. W. Bouwkamp and R. G. Bergman, J. Am. Chem. Soc., 2000, 122, 8799; (j) C. A. Fleckenstein and H. Plenio, Chem. – Eur. J., 2007, 13, 2701.
2. R. M. Burch, M. Weitzberg, N. Blok, R. Muhlhauser, D. Martin, S. G. Farmer, J. M. Bator, J. R. Connor, M. Green and C. Ko, Proc. Natl. Acad. Sci. U. S. A., 1991, 88, 355.
3. R. Kakadiya, H. Dong, P.-C. Lee, N. Kapuriya, X. Zhang, T.-C. Chou, T.-C. Lee, K. Kapuriya, A. Shah and T.-L. Su, Bioorg. Med. Chem., 2009, 17, 5614.
4. (a) M. Tomasz and Y. Palom, Pharmacol. Ther., 1997, 76, 73; (b) W. T. Bradner, Cancer Treat. Rev., 2001, 27, 35.
5. A. K. Banala, B. A. Levy, S. S. Khatri, C. A. Furman, R. A. Roof, Y. Mishra, S. A. Griffin, D. R. Sibley, R. R. Luedtke and A. H. Newman, J. Med. Chem., 2011, 54, 3581.
6. S. Ni, Y. Yuan, J. Huang, X. Mao, M. Lv, J. Zhu, X. Shen, J. Pei, L. Lai, H. Jiang and J. Li, J. Med. Chem., 2009, 52, 5295.
7. R. M. Jones, D. J. Buzard, A. M. Kawasaki, H. S. Kim, L. Thoresen, J. Lehmann and X. Zhu, WO2010027431, 2010.
8. For selected examples, see: (a) U. Scherf and E. J. W. List, Adv. Mater., 2002, 14, 477; (b) T. Yoshihara, S. I. Druzhinin and K. A. Zachariasse, J. Am. Chem. Soc., 2004, 126, 8535; (c) R. Rathore, V. J. Chebny and S. H. Abdelwahed, J. Am. Chem. Soc., 2005, 127, 8012; (d) Y.-X. Xu, C.-C. Chueh, H.-L. Yip, F.-Z. Ding, Y.-X. Li, C.-Z. Li, X. Li, W.-C. Chen and A. K.-Y. Jen, Adv. Mater., 2012, 24, 6356; (e) M. J. Ingleson, D. Crossley, I. A. Cade, E. Clark, A. Escande, M. Humphries, S. King, I. Vitorica-Yrzebal and M. Turner, Chem. Sci., 2015, 6, 5144; (f) G.-F. Zhang, T. Chen, Z.-Q. Chen, M. P. Aldred, X. Meng and M.-Q. Zhu, Chin. J. Chem., 2015, 33, 939.
9. For selected examples for the synthesis of fluorenes, see: (a) S. Merlet, M. Birau and Z. Y. Wang, Org. Lett., 2002, 4, 2157; (b) D. L. J. Clive and R. Sunasee, Org. Lett., 2007, 9, 2677; (c) D. J. Gorin, I. D. G. Watson and F. D. Toste, J. Am. Chem. Soc., 2008, 130, 3736; (d) L. Xu, W. Yang, L. Zhang, M. Miao, Z. Yang, X. Xu and H. Ren, J. Org. Chem., 2014, 79, 9206; (e) Y. Wang, P. R. McGonigal, B. Herlé, M. Besora and A. M. Echavarren, J. Am. Chem. Soc., 2014, 136, 801; (f) X. Qin, X. Li, Q. Huang, H. Liu, D. Wu, Q. Guo, J. Lan, R. Wang and J. You, Angew. Chem., Int. Ed., 2015, 54, 7167.
10. For selected examples for the synthesis of pyrroloindoles, see: (a) G. Abbiati, A. Casoni, V. Canevari, D. Nava and E. Rossi, Org. Lett., 2006, 8, 4839; (b) M. Tanaka, M. Ubukata, T. Matsuo, K. Yasue, K. Matsumoto, Y. Kajimoto, T. Ogo and T. Inaba, Org. Lett., 2007, 9, 3331; (c) S. J. Hwang, S. H. Cho and S. Chang, J. Am. Chem. Soc., 2008, 130, 16158; (d) L. Hao, Y. Pan, T. Wang, M. Lin, L. Chen and Z.-P. Zhan, Adv. Synth. Catal., 2010, 352, 3215; (e) N. Kern, M. Hoffmann, A. Blanc, J.-M. Weibel and P. Pale, Org. Lett., 2013, 15, 836.
11. (a) L. C. Campeau, M. Parisien, A. Jean and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 581; (b) S. J. Hwang, H. J. Kim and S. Chang, Org. Lett., 2009, 11, 4588; (c) M. Tobisu, Y. Kita, Y. Ano and N. Chatani, J. Am. Chem. Soc., 2008, 130, 15982; (d) K. Fuchibe and T. Akiyama, J. Am. Chem. Soc., 2006, 128, 1434.
12. (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (b) M. Itoh, K. Hirano, T. Satoh, Y. Shibata, K. Tanaka and M. Miura, J. Org. Chem., 2013, 78, 1365.
13. (a) T.-P. Liu, C.-H. Xing and Q.-S. Hu, Angew. Chem., Int. Ed., 2010, 49, 2909; (b) Y.-B. Zhao, B. Mariampillai, D. A. Candito, B. Laleu, M. Li and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 1849; (c) C.-G. Dong and Q.-S. Hu, Angew. Chem., Int. Ed., 2006, 45, 2289; (d) C.-G. Dong and Q.-S. Hu, Org. Lett., 2006, 8, 5057; (e) R. Barroso, R. A. Valencia, M.-P. Cabal and C. Valdes, Org. Lett., 2014, 16, 2264.
14. (a) A.-H. Zhou, F. Pan, C. Zhu and L.-W. Ye, Chem. – Eur. J., 2015, 21, 10278; (b) Z. Liu, H. Tan, L. Wang, T. Fu, Y. Xia, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2015, 54, 3056.
15. For reviews, see: (a) W. Mai, J. Wang, L. Yang, J. Yuan, P. Mao, Y. Xiao and L. Qu, Chin. J. Org. Chem., 2014, 34, 1958; (b) J.-R. Chen, X.-Y. Yu and W.-J. Xiao, Synthesis, 2015, 604. For selected examples, see: (c) S. Jaegli, J. Dufour, H. Wei, T. Piou, X. H. Duan, J. P. Vors, L. Neuville and J. Zhu, Org. Lett., 2010, 12, 4498; (d) T. Wu, X. Mu and G. Liu, Angew. Chem., Int. Ed., 2011, 50, 12578; (e) X. Mu, T. Wu, H. Wang, Y. Guo and G. Liu, J. Am. Chem. Soc., 2012, 134, 878; (f) W.-T. Wei, M.-B. Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P. Xie and J.-H. Li, Angew. Chem., Int. Ed., 2013, 52, 3638; (g) S. L. Zhou, L. N. Guo, H. Wang and X. H. Duan, Chem. – Eur. J., 2013, 19, 12970; (h) H. Wang, L. N. Guo and X. H. Duan, Chem. Commun., 2013, 49, 10370; (i) X. Xu, Y. Tang, X. Li, G. Hong, M. Fang and X. Du, J. Org. Chem., 2014, 79, 446; (j) J.-H. Fan, W.-T. Wei, M.-B. Zhou, R.-J. Song and J.-H. Li, Angew. Chem., Int. Ed., 2014, 53, 6650; (k) M.-Z. Lu and T.-P. Loh, Org. Lett., 2014, 16, 4698; (l) Y. Liu, J.-L. Zhang, R.-J. Song and J.-H. Li, Org. Chem. Front., 2014, 1, 1289; (m) H. Zhang, P. Chen and G. Liu, Synlett, 2012, 2749.
16. (a) B. Zhang and A. Studer, Chem. Soc. Rev., 2015, 44, 3505; (b) U. Wille, Chem. Rev., 2013, 113, 813; (c) K. C. Majumdar, P. K. Basu and P. P. Mukhopadhyay, Tetrahedron, 2004, 60, 6239; (d) X. Dong, R. Sang, Q. Wang, X.-Y. Tang and M. Shi, Chem. – Eur. J., 2013, 19, 16910; (e) S.-L. Zhou, L.-N. Guo, S. Wang and X. H. Duan, Chem. Commun., 2014, 50, 3589; (f) Y. Li, Y. Lu, G. Qiu and Q. Ding, Org. Lett., 2014, 16, 4240; (g) G. Han, Y. Liu and Q. Wang, Org. Lett., 2014, 16, 3188; (h) H. Wang, Y. Yu, X. Hong and B. Xu, Chem. Commun., 2014, 50, 13485; (i) T. F. Jamison, Angew. Chem., Int. Ed., 2014, 53, 14451; (j) B. Zhang and A. Studer, Org. Lett., 2014, 16, 1216; (k) L. Lv, S. Lu, Q. X. Guo and Z. Li, J. Org. Chem., 2015, 80, 698; (l) N. Fuentes, W. Kong, L. Fernández-Sánchez, E. Merino and C. Nevado, J. Am. Chem. Soc., 2015, 137, 964; (m) Q.-H. Deng, J.-R. Chen, Q. Wei, Q.-Q. Zhao, L.-Q. Lu and W.-J. Xiao, Chem. Commun., 2015, 51, 3537; (n) X.-Q. Chu, H. Meng, Y. Zi, X.-P. Xu and S.-J. Ji, Org. Chem. Front., 2015, 2, 216; (o) W.-T. Wei, R.-J. Song, X.-H. Ouyang, Y. Li, H.-B. Li and J.-H. Li, Org. Chem. Front., 2014, 1, 484.
17. For recent Cu-catalyzed selective oxidative C–H bond cleavages, see: (a) Y. Zhu and Y. Wei, Chem. Sci., 2014, 5, 2379; (b) A. K. Yadav and L. S. Yadav, Org. Biomol. Chem., 2015, 13, 2606; (c) B. D. Barve, Y.-C. Wu, M. El-Shazly, M. Korinek, Y.-B. Cheng, J.-J. Wang and F.-R. Chang, Tetrahedron, 2015, 71, 2290; (d) S. Manna and A. P. Antonchick, Angew. Chem., Int. Ed., 2015, 54, 14845; (e) W.-T. Wei, H.-B. Li, R.-J. Song and J.-H. Li, Chem. Commun., 2015, 51, 11325; (f) A. Bunescu, Q. Wang and J. Zhu, Org. Lett., 2015, 17, 1890; (g) Z. Li, Y. Xiao and Z.-Q. Liu, Chem. Commun., 2015, 51, 9969; (h) C. Chatalova-Sazepin, Q. Wang, G. M. Sammis and J. Zhu, Angew. Chem., Int. Ed., 2015, 54, 5443.
18. (a) S.-I. Murahashi, T. Naota, H. Taki, M. Mizuno, H. Takaya, S. Komiya, Y. Mizuho, N. Oyasato, M. Hiraoka, M. Hirano and A. Fukuoka, J. Am. Chem. Soc., 1995, 117, 12436; (b) D. M. Tellers, J. C. M. Ritter and R. G. Bergman, Inorg. Chem., 1999, 38, 4810; (c) T. Naota, A. Tannna and S.-I. Murahashi, J. Am. Chem. Soc., 2000, 122, 2960; (d) T. Naota, A. Tannna and S.-I. Murahashi, Chem. Commun., 2001, 63; (e) M. Kujime, S. Hikichi and M. Akita, Organometallics, 2001, 20, 4049; (f) M. Purzycki, W. Liu, G. Hilmersson and F. F. Fleming, Chem. Commun., 2013, 49, 4700.
19. X.-W. Lan, N.-X. Wang, W. Zhang, J.-L. Wen, C.-B. Bai, Y. Xing and Y.-H. Li, Org. Lett., 2015, 17, 4460.
20. (a) K. Friedrich and K. Wallenfels, The Chemistry of the Cyano Group, Wiley-Interscience, New York, 1970; (b) R. J. H. Gregory, Chem. Rev., 1999, 99, 3649.
21. Trace amounts of the final products were observed suggesting that the acetonitrile radical is not completely consumed by TEMPO before the active alkyl radical D is generated.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00329f

---