Letter Cite This: Org. Lett. 2018, 20, 930−933
pubs.acs.org/OrgLett
TEMPO-Catalyzed Aerobic Oxidative Selenium Insertion Reaction: Synthesis of 3‑Selenylindole Derivatives by Multicomponent Reaction of Isocyanides, Selenium Powder, Amines, and Indoles under Transition-Metal-Free Conditions Huan Liu, Yi Fang, Shun-Yi Wang,* and Shun-Jun Ji* Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, P. R. China S Supporting Information *
ABSTRACT: A novel and efficient approach for the selenium functionalization of indoles was developed with selenium powder as the selenium source, catalyzed by 2,2,6,6tetramethylpiperidinooxy (TEMPO) and employing O2 as the green oxidant. This protocol provides a practical route for the synthesis of 3-selenylindole derivatives and has the advantages of readily available starting materials, mild reaction conditions, and a wide scope of substrates. Electron spin-resonance (ESR) studies reveal that the approach involves the formation of nitrogen-centered radicals and selenium radicals via oxidation of in situ generated selenoates.
T
Braga and co-workers reported the selenium functionalization of indoles with diselenides, employing an equivalent amount of DMSO as a stoichiometric oxidant catalyzed by I2 (Scheme 1a).9c Subsequently, Wu’s group reported copper-catalyzed C 3 selenylation of indoles using elemental selenium as the selenium source (Scheme 1b).10 Despite these prominent achievements, until now, there have been no efficient methods for the C3
he development of novel and efficient methods for the formation of C−Se bonds has been the subject of intense recent research efforts, because selenium-containing skeletons are widespread in medicine candidates, bioactive compounds, and other organic materials.1 The past decades have witnessed great progress in the transition-metal-catalyzed C−Se bondforming reactions of aryl or alkyl halides with selenium reagents, such as PhSeH,2 PhSeSnBu3,3 and diselenides.4 However, these selenium reagents are usually unstable under an air atmosphere and difficult to prepare and handle, which limit their further applications. In recent years, transition-metal-catalyzed insertion reactions utilizing selenium powder have emerged as a powerful tool for the construction of C−Se bonds, due to the selenium powder was hypotoxic, commercially available, and easy to handle.5 Whereas, the reported methods often require high temperature and utilization of aryl/alkyl halides as a synthon, which may hamper their application to some extent. In addition, several complementary methods involving direct selenylation of aromatic C(sp2)−H with diselenides have also been reported.6 However, most of these reactions are also limited in their substrate scope, poor atom economy, and transition metal residue. Thus, the development of facile and transition-metalfree methods for the construction of the C−Se bond from readily available starting materials is still highly desirable. The indole skeletons are recognized as versatile and important building blocks in organic synthesis and are prevalent in a series of natural products, agrochemicals, and pharmaceuticals.7 Especially, chalcogenylindoles have gained increasing attention due to their therapeutic value in the treatment of HIV, cancer, heart disease, and allergies.8 To date, the reported approaches for the synthesis of 3-selenylindoles are still rare.9 For instance, © 2018 American Chemical Society
Scheme 1. Approaches for Formation of C−Se Bonds
Received: December 5, 2017 Published: February 2, 2018 930
DOI: 10.1021/acs.orglett.7b03783 Org. Lett. 2018, 20, 930−933
Letter
Organic Letters Scheme 2. Scope of Isocyanidesa,b
selenylation of indoles under transition-metal-free conditions with elemental selenium as the selenium source. More recently, our group reported the approach for the synthesis of 1,2,4selenadiazol-5-amine derivatives through the aerobic radicalcascade multicomponent reactions of isocyanides, selenium powder, and imidamides under metal-free conditions (Scheme 1c).11 Inspired by this work, we questioned whether indoles could be selenium-functionalized directly at the C3 position by the reaction of isocyanides, selenium powder, indoles, and amines under transition-metal-free conditions. Herein, we developed a novel and facile transition-metal-free approach for the synthesis of 3-selenylindoles through TEMPO-catalyzed oxidative selenylation of indoles with isocyanides, selenium powder, and amines (Scheme 1d). We initiated our study by investigating the reaction of 1isocyano-3-nitrobenzene 1a, elemental selenium 2, indole 3a, and diethylamine 4a under metal-free conditions. Gratifyingly, the desired product 5a was formed in 57% LC-yield in acetonitrile (Table 1, entry 1). Encouraged by this result, we
a
Reaction conditions: 1 (0.30 mmol), 2 (0.36 mmol), 3a (0.36 mmol), 4a (0.36 mmol), Cs2CO3 (0.60 mmol), THF (2 mL), 40 °C, 16 h under air. bIsolated yields.
Table 1. Optimization of the Reaction Conditionsa
entry
solvent
base
TEMPO (mol %)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13d 14e 15f
CH3CN DMF DMSO 1,4-dioxane THF THF THF THF THF THF THF THF THF THF THF
Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Et3N DBU K2CO3 t-BuONa Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
− − − − − − − − − 10 20 30 20 20 20
57 51 35 74 77 0 50 47 13 83 91(85)c 73 92c 94c 93c
(5b) positions afforded the desired products in 94% and 54% yields, respectively. This result indicated that electronic effect greatly affected the efficiency of the reaction. Other substrates bearing electron-withdrawing groups, such as cyano (5c), acetyl (5d), amido (5e), ester (5f), trifluoromethyl (5g), bromo (5h and 5j), and chloro (5i) moieties, were also compatible with the reaction, resulting in 5c−5j in 53%−92% yields. Generally, substrates bearing weak electron-withdrawing groups (5g−5j) gave higher yields than those bearing strong electron-withdrawing groups (5b−5f). Substrates bearing electron-donating groups, such as methyl (5k and 5l) and methoxy (5m), led to the desired products in 91%, 96%, and 98% yields, respectively. Similar yields of 5k and 5l showed that steric hindrance did not affect the transformation. In addition, we also investigated the scope of aliphatic isocyanides. Disappointedly, we could only isolate the corresponding selenourea derivatives, which might be due to the instability of the alkyl nitrogen radical intermediates. Next, the substrate scope of the reaction was further expanded to a range of substituted indoles. As shown in Scheme 3, both substrates bearing electron-donating (6b−6h) and electronScheme 3. Scope of Indolesa,b
a
All reactions were performed with 1a (0.30 mmol), 2 (0.36 mmol), 3a (0.36 mmol), 4a (0.36 mmol), and base (0.60 mmol) in solvent (2 mL) at 40 °C for 12 h under air unless otherwise noted. bYields were determined by LC-MS analysis using biphenyl as an internal standard. c Isolated yields. dRun for 14 h. eRun for 16 h. fRun for 18 h.
screened a series of solvents. Tetrahydrofuran was determined to be the optimal solvent, affording 5a in 77% LC-yield (Table 1, entries 2−5). Next, other organic bases (Table 1, entries 6−7) and inorganic bases (Table 1, entries 8−9) were investigated, of which no better result was obtained. It is noteworthy that the LCyield of 5a dramatically increased to 91% (85% isolated yield) when 20 mol % TEMPO was added (Table 1, entry 11). Finally, the highest isolated yield (94%) was obtained by extending the reaction time to 16 h (Table 1, entry 14). With the optimized reaction conditions in hand (Table 1, entry 14), we explored the scope of various isocyanide derivatives 1 (Scheme 2). Satisfactorily, both electron-deficient and -rich aromatic isocyanides proceeded well to give the corresponding products in moderate to excellent yields. The aromatic isocyanides with nitro substituents in the meta (5a) and para
a Reaction conditions: 1a (0.30 mmol), 2 (0.36 mmol), 3 (0.36 mmol), 4a (0.36 mmol), Cs2CO3 (0.60 mmol), THF (2 mL), 40 °C, 16 h under air. bIsolated yields.
931
DOI: 10.1021/acs.orglett.7b03783 Org. Lett. 2018, 20, 930−933
Letter
Organic Letters
corresponding products in good yields. It is notable that aromatic secondary amines (7k and 7l) were suitable candidates for this one-pot reaction, affording the desired 3-selenylindoles in moderate yields. Unfortunately, the primary amines, such as aniline (7m) and n-butylamine (7n) failed to result in the desired products under the optimal reaction conditions. Because of the presence of NH, the selenium of the selenourea intermediates was easily eliminated to form carbodiimide intermediates under basic conditions. Subsequent intermolecular nucleophilic addition between indoles and carbodiimides afford corresponding addition products. To gain a deep insight into the reaction mechanism, several electron spin-resonance (ESR) experiments were carried out (see Supporting Information for details). In the tested system of isocyanide, selenium, amine, and cesium carbonate in the presence of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), a typical ESR signal of a DMPO-trapped nitrogen-centered radical was observed (g = 2.0056). Besides, a strong ESR signal was detected in the model reaction system, which might result from DMPO-trapped selenium radical. As for the other reaction mixtures in the absence of selenium, almost no ESR signal was observed. This result indicated that the reaction underwent a radical pathway. Thus, we proposed that selenoate intermediate was oxidized to generate a nitrogen-centered radical, which converted to the selenium radical in the process of reaction. Next, the model reaction was carried out under argon (Scheme 5). It
withdrawing groups (6i−6n) could react smoothly to give the desired products in high yields. In addition, the structure of 6j was unambiguously determined by X-ray crystallography (CCDC 1559791; see Supporting Information for details). To our delight, the expected products were observed in 91%−98% yields when a methyl substituent located on the C2, C4, C5, C6, or C7 position of indole (6c−6g) was applied to the reaction. In addition, the reaction of 2-phenyl-1H-indole proceeded smoothly to afford 6b in 97% yield. The high yield of 6b indicated that there was no notable effect on the reaction from steric hindrance. A halogen substituent, such as fluoro (6l), bromo (6m), and iodo (6n), could also be tolerated in these reactions and resulted in the desired products in 91%, 91%, and 94% yields, respectively. It is noteworthy that the free NH group plays a crucial role in this transformation. N-Methyl substituted indole (3o) could not participate in this reaction. According to this result, we proposed that the free (NH) indole would undergo a process of cleavage of the acidic N−H bond in the presence of a base, resulting in enhancing the nucleophilicity of the C3 position. Furthermore, 3-methyl-1H-indole (3p) failed to furnish the corresponding 2-selenylindole under standard conditions, which strongly indicates that the reactive sites of indoles are located on the C3 position. Furthermore, the scope of amines was further investigated under the optimized reaction conditions. A number of secondary amines including aliphatic amines and aromatic amines were subjected to the reactions, and all the reactions proceeded smoothly to afford the corresponding products in moderate to high yields (Scheme 4). The application of dipropylamine (4b),
Scheme 5. Investigation of the Reaction Mechanism
Scheme 4. Scope of Aminesa,b was found that only a trace amount of 5a was observed. This result proved that an oxidant is crucial for this cascade reaction. It should be noted that when 2.0 equiv of TEMPO were added to the model reaction under an argon atmosphere, the reaction proceeded well, affording the desired product 5a in 83% yield. Thus, we believed that TEMPO/O2 acted as the synergistic catalyst in this reaction. On the basis of the above experiment results and previous literature,11,12 we proposed a plausible mechanism in Scheme 6. Scheme 6. Plausible Reaction Mechanism
a
Reaction conditions: 1a (0.30 mmol), 2 (0.36 mmol), 3a (0.36 mmol), 4 (0.36 mmol), Cs2CO3 (0.60 mmol), THF (2 mL), 40 °C, 16 h under air. bIsolated yields.
dibutylamine (4c), and diisopropylamine (4d) furnished 7b−7d in 89% and 92% yields, respectively. Methylamine derivatives could also be tolerated in the reaction, leading to the expected products (7f and 7g) in 66% and 60% yields, respectively. Pleasingly, several cyclic aliphatic secondary amines such as pyrrolidine (7h), morpholine (7i), and 1,2,3,4-tetrahydroisoquinoline (7j) could be smoothly transformed to the
Initially, the reaction of isocyanide 1 with elemental selenium 2 generates isoselenocyanate A under the basic conditions. Next, A reacts with an amine to produce selenoate B, resulting in equilibrium between selenium anion intermediate B and nitrogen anion intermediate C. Subsequently, oxidation of intermediate C by O2/TEMPO generates nitrogen-centered radical D, which resonates to the more active selenium radical 932
DOI: 10.1021/acs.orglett.7b03783 Org. Lett. 2018, 20, 930−933
Letter
Organic Letters
(2) (a) Gao, G. Y.; Colvin, A. J.; Chen, Y.; Zhang, X. P. J. Org. Chem. 2004, 69, 8886. (b) Gujadhur, R. K.; Venkataraman, D. Tetrahedron Lett. 2003, 44, 81. (3) (a) Nishiyama, Y.; Tokunaga, K.; Sonoda, N. Org. Lett. 1999, 1, 1725. (b) Nishiyama, Y.; Tokunaga, K.; Kawamatsu, H.; Sonoda, N. Tetrahedron Lett. 2002, 43, 1507. (c) Bonaterra, M.; Martın, S. E.; Rossi, R. A. Tetrahedron Lett. 2006, 47, 3511. (4) (a) Singh, D.; Alberto, E. E.; Rodrigues, O. E. D.; Braga, A. L. Green Chem. 2009, 11, 1521. (b) Ricordi, V. G.; Freitas, C. S.; Perin, G.; Lenardao, E. J.; Jacob, R. G.; Savegnago, L.; Alves, D. Green Chem. 2012, 14, 1030. (c) Li, Y.; Wang, H.; Li, X.; Chen, T.; Zhao, D. Tetrahedron 2010, 66, 8583. (d) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 951. (e) Chatterjee, T.; Ranu, B. C. J. Org. Chem. 2013, 78, 7145. (f) Taniguchi, N.; Onami, T. J. Org. Chem. 2004, 69, 915. (g) Ajiki, K.; Hirano, M.; Tanaka, K. Org. Lett. 2005, 7, 4193. (h) Becht, J. M.; Le Drian, C. J. Org. Chem. 2011, 76, 6327. (i) Saba, S.; Rafique, J.; Braga, A. L. Adv. Synth. Catal. 2015, 357, 1446. (5) (a) Singh, D.; Deobald, A. M.; Camargo, L. R. S.; Tabarelli, G.; Braga, A. L. Org. Lett. 2010, 12, 3288. (b) Li, Y.; Nie, C.; Wang, H.; Li, X.; Verpoort, F.; Duan, C. Eur. J. Org. Chem. 2011, 2011, 7331. (c) Zhang, S. Z.; Karra, K.; Heintz, C.; Kleeker, E.; Jin, J. Tetrahedron Lett. 2013, 54, 4753. (d) Chen, C. H.; Hou, C.; Wang, Y. G.; Andy Hor, T. S.; Weng, Z. Q. Org. Lett. 2014, 16, 524. (e) Min, L.; Wu, G.; Liu, M. C.; Gao, W. X.; Ding, J. C.; Huang, X. B.; Wu, H. Y. J. Org. Chem. 2016, 81, 7584. (f) Sun, P. F.; Jiang, M.; Wei, W.; Min, Y. Y.; Zhang, W.; Li, W. H.; Yang, D. S.; Wang, H. J. Org. Chem. 2017, 82, 2906. (g) Gao, C.; Wu, G.; Min, L.; Liu, M. C.; Gao, W. X.; Ding, J. C.; Chen, J. X.; Huang, X. B.; Wu, H. Y. J. Org. Chem. 2017, 82, 250. (6) (a) Iwasaki, M.; Tsuchiya, Y.; Nakajima, K.; Nishihara, Y. Org. Lett. 2014, 16, 4920. (b) Qiu, R.; Reddy, V. P.; Iwasaki, T.; Kambe, N. J. Org. Chem. 2015, 80, 367. (c) Yu, S.; Wan, B.; Li, X. Org. Lett. 2015, 17, 58. (d) Ricordi, V. G.; Thurow, S.; Penteado, F.; Schumacher, R. F.; Perin, G.; Lenardao, E. J.; Alves, D. Adv. Synth. Catal. 2015, 357, 933. (e) Zhu, L.; Qiu, R.; Cao, X.; Xiao, S.; Xu, X.; Au, C.-T.; Yin, S. F. Org. Lett. 2015, 17, 5528. (7) (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (b) Hassam, M.; Basson, A. E.; Liotta, D. C.; Morris, L.; van Otterlo, W. A. L.; Pelly, S. C. ACS Med. Chem. Lett. 2012, 3, 470. (c) Tanaka, H.; Noguchi, H.; Abe, I. Org. Lett. 2005, 7, 5873. (8) (a) Ragno, R.; Coluccia, A.; La Regina, G.; De Martino, G.; Piscitelli, F.; Lavecchia, A.; Novellino, E.; Bergamini, A.; Ciaprini, C.; Sinistro, A.; Maga, G.; Crespan, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2006, 49, 3172. (b) De Martino, G.; La Regina, G.; Coluccia, A.; Edler, M. C.; Barbera, M. C.; Brancale, A.; Wilcox, E.; Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2004, 47, 6120. (c) La Regina, G.; Edler, M. C.; Brancale, A.; Kandil, S.; Coluccia, A.; Piscitelli, F.; Hamel, E.; De Martino, G.; Matesanz, R.; Díaz, J. F.; Scovassi, A. I.; Prosperi, E.; Lavecchia, A.; Novellino, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2007, 50, 2865. (d) Unangst, P. C.; Connor, D. T.; Stabler, S. R.; Weikert, R. J.; Carethers, M. E.; Kennedy, J. A.; Thueson, D. O.; Chestnut, J. C.; Adolphson, R. L.; Conroy, M. C. J. Med. Chem. 1989, 32, 1360. (e) Avis, I.; Martinez, A.; Tauler, J.; Zudaire, E.; Mayburd, A.; Abu-Ghazaleh, R.; Ondrey, F.; Mulshine, J. L. Cancer Res. 2005, 65, 4181. (9) (a) Ferreira, N. L.; Azeredo, J. B.; Fiorentin, B. L.; Braga, A. L. Eur. J. Org. Chem. 2015, 2015, 5070. (b) Gao, Z.; Zhu, X.; Zhang, R. RSC Adv. 2014, 4, 19891. (c) Azeredo, J. B.; Godoi, M.; Martins, G. M.; Silveira, C. C.; Braga, A. L. J. Org. Chem. 2014, 79, 4125. (10) Luo, D. P.; Wu, G.; Liu, M. C.; Gao, W. X.; Huang, X. B.; Chen, J. C.; Wu, H. Y. J. Org. Chem. 2016, 81, 4485. (11) Fang, Y.; Zhu, Z.-L.; Xu, P.; Wang, S.-Y.; Ji, S.-J. Green Chem. 2017, 19, 1613. (12) (a) Asanuma, Y.; Fujiwara, S.; Shin-ike, T.; Kambe, N. J. Org. Chem. 2004, 69, 4845. (b) Fang, Y.; Wang, S.-Y.; Shen, X.-B.; Ji, S.-J. Org. Chem. Front. 2015, 2, 1338. (c) Fujiwara, S.-i.; Asanuma, Y.; Shin-ike, T.; Kambe, N. J. Org. Chem. 2007, 72, 8087.
intermediate E. Meanwhile, deprotonation of indole in the presence of Cs2CO3 gives nitrogen anion intermediate F and carbon anion intermediate G. Next, the cross-coupling of radical E with G affords nitrogen radical cation H. Finally, the single electron transfer of intermediate H furnishes the desired product. In summary, we have successfully realized selenium functionalization at the C3 position of indoles under transitionmetal-free conditions with chemically stable and easily available elemental selenium as the selenium source. The reaction proceeds under mild conditions with O2 as the green oxidant. The 3-selenylindoles derivatives were obtained in moderate to high yields with excellent functional group tolerance. Studies to further understand the mechanisms and explore further potential applications of this reaction in medicinal chemistry are currently in progress.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03783. Detailed experimental procedures and characterization datum (PDF) Accession Codes
CCDC 1559791 contains 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 data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Shun-Yi Wang: 0000-0002-8985-8753 Shun-Jun Ji: 0000-0002-4299-3528 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We gratefully acknowledge Professor B.-Z. Zhu and Dr. C.-H. Huang (RCEES, CAS, CN) for helpful discussions, the National Natural Science Foundation of China (21772137, 21672157, 21372174), the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 16KJA150002), the Ph.D. Programs Foundation of PAPD, the project of scientific and technologic infrastructure of Suzhou (SZS201708), and Soochow University for financial support. We thank Fang-Hui Li in this group for reproducing the result for 5a.
■
REFERENCES
(1) (a) Mugesh, G.; du Mont, W.; Sies, H. Chem. Rev. 2001, 101, 2125. (b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004, 104, 6255. (c) Sarma, B. K.; Mugesh, G. J. Am. Chem. Soc. 2005, 127, 11477. (d) Bhabak, K. P.; Mugesh, G. Chem. - Eur. J. 2007, 13, 4594. (e) Bhabak, K. P.; Mugesh, G. Acc. Chem. Res. 2010, 43, 1408. (f) Manjare, S. T.; Kim, Y.; Churchill, D. G. Acc. Chem. Res. 2014, 47, 2985. (g) Muller, A.; Cadenas, E.; Graf, P.; Sies, H. Biochem. Pharmacol. 1984, 33, 3235. (h) Parnham, M.; Sies, H. Expert Opin. Invest. Drugs 2000, 9, 607. 933
DOI: 10.1021/acs.orglett.7b03783 Org. Lett. 2018, 20, 930−933
