DOI: 10.1002/chem.201405695
Communication
& Pericyclic Reaction
An Iron-Catalyzed Cascade Approach to Benzo[b]carbazoles Synthesis Followed by 1,4-Sulfonyl Migration Siva Senthil Kumar Boominathan,[a] Gopal Chandru Senadi,[a] Jaya Kishore Vandavasi,[a] Jeff YiFu Chen,[b] and Jeh-Jeng Wang*[a] lization of alkynes gives a reactive vinylidene intermediate that is subsequently captured in pericyclic reactions for generating complex molecules in a single operation from easily accessible starting materials.[9] Although this approach is a useful tool for constructing various heterocycles, the existing strategies have been insufficiently addressed, and there is still room to develop this area of research. Based on these facts and our ongoing research in these field,[10] we constructed benzo[b]carbazole-6ol derivatives by a metal-mediated 5-exo-dig annulation followed by an electrocyclization in a cascade manner (Scheme 2). Instead of the expected product (2), the reaction proceeded further to give an unprecedented [1,4]-N-O sulfonyl migrated product 3. The starting materials were prepared from Sonogashira coupling between commercially available 2-iodoanilines with corresponding terminal alkynes. This was followed by N-tosylation
Abstract: A simple and straightforward approach was developed to construct 5H-benzo[b]carbazole derivatives by iron catalysis in a cascade sequence. The notable features of this work include an atom-economical cascade sequence, unprecedented 1,4-sulfonyl migration, tolerance of a variety of functional groups, good yields, and an economical catalytic system.
Benzo[b]carbazoles are a type of polycyclic skeleton found in many naturally occurring alkaloids and biologically active molecules.[1] The co-planar structure of these molecules has profound applications in materials science due to its chemiluminescent and optoelectronic properties.[2] Thus, these scaffolds are attractive targets in organic synthesis. The common methods to prepare these molecules include the cycloaromatization of keteneimines,[3] intramolecular dehydro Diels–Alder cycloaddition reactions using ynamides,[4] benzannulation reactions with indoles,[5] naphthalenes,[6a,b] or carbazoles,[6c] and some other methods[7] (Scheme 1). Due to their significant importance, efforts are still being made to develop benzo[b]carbazoles using simple precursors, inexpensive catalysts, and atom economy. Pericyclic reactions have long been regarded as an atom-economical bond-forming process, and they are most frequently encountered in cascade reactions.[8] Scheme 1. Previous approaches to benzo[b]carbazoles. The metal-catalyzed exo-dig cyc-
and a base-mediated N-alkylation with various a-bromoaryl (heteroaryl) ketones. This gave compound 1 a–u in quantitative yields (Supporting Information, Scheme S1). We began our studies using 1 a as a model substrate, and the results are summarized in Table 1. The reaction was carried out with 10 mol % FeCl3 in toluene at reflux for 30 h, which produced the compound 3 a in 48 % yield (Table 1, entry 1; the structure of 3 a was confirmed by X-ray analysis).[11] To improve the yield, various iron salts were tested, among which Fe(OTf)2
[a] S. S. K. Boominathan, G. C. Senadi, Dr. J. K. Vandavasi, Prof. Dr. J.-J. Wang Department of Medicinal and Applied Chemistry Kaohsiung Medical University 100, Shih-Chuan 1st Road, Kaohsiung (Taiwan) E-mail: [email protected] [b] Dr. J. Y.-F. Chen Department of Biotechnology, Kaohsiung Medical University 100, Shih-Chuan 1st Road, Kaohsiung (Taiwan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405695. Chem. Eur. J. 2015, 21, 1 – 6
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Communication failed to proceed under the standard reaction conditions. The probable reason could be the low acidity of the a-CH proton, which may reduce the enolization. We carried out control experiments, as shown in Scheme 3, to
Scheme 2. Iron-catalyzed approach to benzo[b]carbazoles.
was found to give the best yield (entries 2–8). We also screened different solvents, and toluene had the best performance in terms of yield (entries 9–12). The temperature was examined, and 130 8C was suitable in terms of reaction time and yield (entry 13), whereas lower temperatures reduced the reaction yield (entry 14). When the catalyst loading was increased to 20 mol %, the yield was further improved to 75 % (entry 15). Subsequently, we tested the reaction with other Lewis acids AgOTf, Zn(OTf)2, PdCl2, In(OTf)3, Sc(OTf)3, Cu(OTf)2, iodine, and BF3·Et2O, but all of them failed to produce the desired products (entries 17–24). Since Brønsted acid present in the metal salt could catalyze the reaction, we performed a control experiment with TfOH, but there was no reaction (entry 25). Based on the screening results, we selected 20 mol % Fe(OTf)2 in toluene at 130 8C as the optimal reaction condition (entry 15). To explore the substrate scope, a range of 5H-benzo[b]carbazoles were synthesized, as shown in Table 2. First, R1 was replaced at different positions with various substituents, such as methyl, methoxy, fluoro, chloro, cyano, and nitro. These gave the corresponding products in moderate to good yields (3 a–i). Of note, the phenyl group (R1) appended with electron-withdrawing groups reacted well to give greater yields than the electron-donating groups. Next, R2 was substituted with methyl, fluoro, and chloro, and the respective products were isolated in good yields (3 j–m). R3 was replaced with phenyl groups containing electron-donating and -withdrawing groups, which were successfully converted to the products (3 n,o). However, when R3 was replaced with alkyl groups such as H, TMS, n-butyl, and cyclopropyl, the reactions failed to proceed. We extended the scope to aroyl units containing heterocycles, such as furan and thiophene (1 p,q). Under optimized conditions, these substrates underwent cyclization (2 p,q), but the N O tosyl shift did not occur in both cases. The reason could be the partial coordination of Lewis acid with the adjacent heteroatom. The nitrogen replaced with other sulfonyl groups such as 4-bromophenylsulfonyl and phenylsulfonyl were compatible with our reaction conditions, and corresponding products were isolated (3 r,s). In contrast, the reaction with nitrogen substituted with methyl sulfonyl or 4-nitrophenylsulfonyl groups failed to proceed, and the reaction turned into a complex mixture (3 t,u). The representative compounds 3 a, 3 f, and 3 h were unambiguously confirmed by X-ray analysis.[11] Further, we attempted to construct the oxygen heterocycles and prepared the respective starting material 2-(2-(2-phenylethynyl)phenoxy)-1-phenylethanone. Unfortunately, the reaction &
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Table 1. Optimization studies.[a]
Entry
Catalyst
Solvent
T [8C]
t [h]
Yield [%] 3 a (2 a)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15[b] 16[b] 17 18 19 20 21 22 23 24[c] 25[c] 26
FeCl3 FeCl2 Fe(OTf)2 Fe(acac)3 FeBr3 FeCl3·6 H2O FeSO4 Fe(OTf)3 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)3 AgOTf Zn(OTf)2 PdCl2 In(OTf)3 Sc(OTf)3 Cu(OTf)2 I2 BF3·Et2O TfOH –
toluene toluene toluene toluene toluene toluene toluene toluene benzene DMF DMSO PhCl toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene
110 110 110 110 110 110 110 110 110 120 120 120 130 90 130 130 110 110 110 110 110 110 110 110 110 130
30 30 30 30 30 30 30 30 30 24 24 30 24 30 24 24 24 24 24 24 24 24 24 24 24 30
48 22 (trace) 54 45 (20) – – – 20 22 trace trace 32 66 15 75 40 – – – – – – – – – –
[a] Reaction conditions: 1 a (0.5 mmol), catalyst (10 mol %), and solvent (2 mL) in seal tube and heated to given temperature; [b] reaction carried out with 20 mol % of catalyst; [c] 50 mol % catalyst was used.
understand the reaction mechanism and the role of the catalyst. To identify the reaction intermediate, we stopped the reaction at 12 h and isolated the intermediate 2 o in 32 % yield [Scheme 3, Eq. (1)]. Then, the intermediate was treated under standard reaction conditions, and the expected N O tosyl-migrated product 3 o was obtained [Scheme 3, Eq. (2)]. However, in the absence of iron catalyst, the intermediate failed to proceed to the final product [Scheme 3, Eq. (3)]. Thus, we confirmed that the catalyst is necessary for the cascade process and tosyl migration. In addition, the compound 2 o was unambiguously confirmed by 1H NMR spectroscopy and X-ray analysis.[11] 2
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Communication Table 2. Substrate scope of benzo[b]carbazoles.[a]
Scheme 3. Control experiments.
intermediate B converts to its enol form C and then undergoes a 6p electrocyclization, giving the intermediate D, and aerial oxidative aromatization[12] gave the hydroxy 5H-benzo[b]carbazole intermediate 2. Then the sulfonyl oxygen of intermediate 2 coordinated with Fe(OTf)2 and resulted in the intermediate E, and the sequential nucleophilic attack of phenolic OH gave the five-member intermediate F. Finally, the rearrangement of intermediate F afforded the desired product 3, and the catalyst was regenerated for the next cycle. In summary, we have developed a simple and straightforward procedure for the synthesis of benzo[b]carbazoles by iron-catalyzed 5-exo-dig cyclization and a subsequent 6p electrocyclization. The reaction underwent an unprecedented [1,4]tosyl migration from nitrogen to oxygen with the aid of the same catalytic system. Additional features of this transformation include good substrate scope compatibility, simple precursors, relatively tolerable reaction conditions, and an environmentally benign iron catalytic system. Further studies to expand this methodology and biological evaluation are under way in our laboratory.
[a] Reaction conditions: 1 a (0.5 mmol), catalyst (20 mol %), and solvent (2 mL) in seal tube and heated at 130 8C for given time; [b] reaction turned to a complex mixture.
To find out whether the sulfonyl migration occurs in an intramolecular or intermolecular pathway, we performed a crossover experiment as shown in Scheme 4. The equimolar quantities of 2 o and 2 r were treated under the standard reaction conditions, giving the direct products (3 o and 3 r); the crossover products (3 o’ and 3 r’) were not detected by 1H NMR spectroscopy and LC-MS analysis. The results suggest that the sulfonyl group migration proceeds via an intramolecular pathway. Based on the literature[8, 9, 12, 13] and our experimental results, we tentatively propose the reaction mechanism in Scheme 5.[14] Initially, the carbonyl group of 1 converted to its enol form A, and then the Lewis acid coordinated on the alkyne, which facilitates a 5-exo-dig cyclization and subsequent protodemetallation gives the vinylidene intermediate B. Next, Chem. Eur. J. 2015, 21, 1 – 6
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Experimental Section General experimental procedure for 5H-benzo[b]carbazoles (3 a–3 o and 2 p,q) An oven-dried seal tube was charged with 1 a (0.5 mmol) in toluene (2 mL) and Fe(OTf)2 (20 mol %) was added. The reaction mixture was stirred at 130 8C for the respective time and was monitored by TLC. Upon completion, the reaction mass was poured into water and extracted into EtOAc (15 mL). The combined organic layer was washed with brine solution (10 mL) and the aqueous layer was washed with EtOAc (2 10 mL). The combined organic extract was dried on sodium sulfate and concentrated under vacuo. The obtained crude residue was passed through the flash column chromatograph (silica gel; EtOAc/hexane) to afford the title compound in moderate to good yields.
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Communication ChemMedChem 2011, 6, 1872; g) A. W. Schmidt, K. R. Reddy, H. J. Knçlker, Chem. Rev. 2012, 112, 3193; h) K. Kinoshita, T. Kobayashi, K. Asoh, N. Furuichi, T. Ito, H. Kawada, S. Hara, J. Ohwada, K. Hattori, T. Miyagi, W. S. Hong, M. J. Park, K. Takanashi, T. Tsukaguchi, H. Sakamoto, T. Tsukuda, N. Oikawa, J. Med. Chem. 2011, 54, 6286. [2] a) Y. Wu, Y. Li, S. Gardner, B. S. Ong, J. Am. Chem. Soc. 2005, 127, 614; b) M. T. Levick, S. C. Coote, I. Grace, C. Lambert, M. L. Turner, D. J. Procter, Org. Lett. 2012, 14, 5744; c) M. T. Levick, I. Grace, S. Y. Dai, N. Kasch, C. Muryn, C. Lambert, M. L. Turner, D. J. Procter, Org. Lett. 2014, 16, 2292; d) P. Balczewski, Chemik 2012, 66, 11. [3] a) M. Schmittel, J. P. Steffen, M. Angel, B. Engels, C. Lennartz, M. Hanrath, Angew. Chem. Int. Ed. 1998, 37, 1562; Angew. Chem. 1998, 110, 1633; b) C. Shi, K. K. Wang, J. Org. Chem. 1998, 63, 3517; c) Y. P. Xing, B. B. Hu, Q. J. Yao, P. Lu, Y. G. Wang, Chem. Eur. J. 2013, 19, 12788. [4] a) M. F. Martnez-Espern, D. Rodriguez, L. Castedo, C. Sa, Org. Lett. 2005, 7, 2213; b) M. F. Martnez-Espern, D. Rodriguez, L. Castedo, C. Sa, Tetrahedron 2006, 62, 3843. [5] a) H. L. Fraser, G. W. Gribble, Can. J. Chem. 2001, 79, 1515; b) C. K. Sha, K. S. Chuang, S. J. Wey, J. Chem. Soc. Perkin Trans. 1 1987, 977; c) K. Paul, K. Bera, S. Jalal, S. Sarkar, U. Jana, Org. Lett. 2014, 16, 2166; d) A. Surez, P. Garca-Garca, A. Fernndez-Rodrguez, R. Sanz, Adv. Synth. Catal. 2014, 356, 374; e) J. Wu, D. Wang, H. Wang, F. Wu, X. Li, B. Wan, Org. Biomol. Chem. 2014, 12, 6806; f) V. Dhayalan, J. A. Clement, R. Jagan, A. Mohanakrishnan, Eur. J. Org. Chem. 2009, 531; g) R. Y. Tang, J. H. Li, Chem. Eur. J. 2010, 16, 4733. [6] a) M. E. Buden, V. A. Vaillard, S. E. Martin, R. A. Rossi, J. Org. Chem. 2009, 74, 4490; b) P. Appukkuttan, E. Vander Eycken, W. Dehaen, Synlett 2005, 127; c) K. S. Prakash, R. Nagarajan, Adv. Synth. Catal. 2012, 354, 1566. [7] M. F. Martnez-Espern, D. Rodrguez, L. Castedo, C. Sa, Tetrahedron 2008, 64, 3674 and references therein. [8] a) S. Sankararaman, Pericyclic Reactions: A Textbook, Wiley-VCH, Weinheim, 2005; b) L. M. Bishop, J. E. Barbarow, R. G. Bergman, D. Trauner, Angew. Chem. Int. Ed. 2008, 47, 8100; Angew. Chem. 2008, 120, 8220; c) J. K. Lee, D. J. Tantillo, Annu. Rep. Prog. Chem. Sect. B 2008, 104, 260; d) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49; e) S. Arns, L. Barriault, Chem. Commun. 2007, 2211; f) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. Int. Ed. 2006, 45, 7134; Angew. Chem. 2006, 118, 7292; g) J. Poulin, C. M. Gris-Bard, L. Barriault, Chem. Soc. Rev. 2009, 38, 3092. [9] a) E. A. Anderson, Org. Biomol. Chem. 2011, 9, 3997; b) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993; c) Z. Q. Wang, Y. Liang, Y. Lei, M. B. Zhou, J. H. Li, Chem. Commun. 2009, 5242; d) Z. Q. Wang, Y. Lei, M.-B. Zhou, G. X. Chen, R. J. Song, Y. X. Xie, J. H. Li, Org. Lett. 2011, 13,
Scheme 4. Crossover experiments.
Scheme 5. Proposed reaction mechanism.
Acknowledgements The authors gratefully acknowledge funding from the Ministry of Science and Technology (MOST), Taiwan. Keywords: alkynes · benzo[b]carbazoles · iron · pericyclic reaction · sulfonyl migration
[1] a) C. M. Miller, F. O. McCarthy, RSC Adv. 2012, 2, 8883; b) G. W. Gribble, M. J. Saulnier, J. Chem. Soc. Chem. Commun. 1984, 168; c) C. Asche, W. Frank, A. Albert, U. Kucklaender, Bioorg. Med. Chem. 2005, 13, 819; d) K. R. Hande, Update Cancer Ther. 2008, 3, 13; e) N. Ramkumar, R. Nagarajan, J. Org. Chem. 2014, 79, 736; f) M. G. Ferlin, O. Gia, L. D. Via,
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Communication 14; e) R. Grigg, U. Sakee, V. Sridharan, S. Sukirthalingam, R. Thangavelauthum, Tetrahedron 2006, 62, 9523; f) S. Schweizer, Z. Z. Song, F. E. Meyer, P. H. Parsons, A. Meijere, Angew. Chem. Int. Ed. 1999, 38, 1452; Angew. Chem. 1999, 111, 1550. [10] a) G. C. Senadi, W. P. Hu, J. S. Hsiao, J. K. Vandavasi, C. Y. Chen, J. J. Wang, Org. Lett. 2012, 14, 4478; b) S. S. K. Boominathan, W. P. Hu, G. C. Senadi, J. J. Wang, Adv. Synth. Catal. 2013, 355, 3570; c) B. Barve, Y. C. Wu, M. El-Shazly, M. Korinek, Y. B. Cheng, J. J. Wang, F. R. Chang, Org. Lett. 2014, 16, 1912. [11] CCDC 1024284 (3 a), 1024283 (3 f), 1024269 (3 h) and 1024282 (2 o) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [12] a) P. Xie, Y. Huang, R. Chen, Chem. Eur. J. 2012, 18, 7362; b) A. Diallo, Y. L. Zhao, H. Wang, S. S. Li, C. Q. Ren, Q. Liu, Org. Lett. 2012, 14, 5776;
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c) T. Narender, S. Sarkar, K. Rajendar, S. Tiwari, Org. Lett. 2011, 13, 6140; d) G. Rajeshwaran, A. K. Mohanakrishnan, Org. Lett. 2011, 13, 1418. [13] For tosyl migration, see: a) M. D. Mertens, M. Pietsch, G. Schnakenburg, M. Gtschow, J. Org. Chem. 2013, 78, 8966; b) Y. Horino, M. Kimura, Y. Wakamiya, T. Okajima, Y. Tamaru, Angew. Chem. Int. Ed. 1999, 38, 121; Angew. Chem. 1999, 111, 123; c) S. Bravermana, M. Cherkinskya, R. Raj, Sulfur Rep. 1999, 22, 49; d) S. S. P. Chou, H. C. Wang, P. W. Chen, C. H. Yang, Tetrahedron 2008, 64, 5291. [14] We have proposed two alternative mechanistic pathway for the conversion of compound 1 to 2 in the Supporting Information (Schemes S2 and S3).
Received: October 17, 2014 Published online on && &&, 0000
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Communication
COMMUNICATION & Pericyclic Reaction S. S. K. Boominathan, G. C. Senadi, J. K. Vandavasi, J. Y.-F. Chen, J.-J. Wang* && – && An Iron-Catalyzed Cascade Approach to Benzo[b]carbazoles Synthesis Followed by 1,4-Sulfonyl Migration
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Chem. Eur. J. 2015, 21, 1 – 6
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It’s iron, man: A simple and straightforward approach was developed to obtain 5H-benzo[b]carbazole derivatives by iron catalysis in a cascade sequence. The notable features of this work in-
clude an atom-economical cascade sequence, unprecedented 1,4-tosyl migration, tolerance of a variety of functional groups, good yields and an economic catalytic system.
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Communication
& Pericyclic Reaction
An Iron-Catalyzed Cascade Approach to Benzo[b]carbazoles Synthesis Followed by 1,4-Sulfonyl Migration Siva Senthil Kumar Boominathan,[a] Gopal Chandru Senadi,[a] Jaya Kishore Vandavasi,[a] Jeff YiFu Chen,[b] and Jeh-Jeng Wang*[a] lization of alkynes gives a reactive vinylidene intermediate that is subsequently captured in pericyclic reactions for generating complex molecules in a single operation from easily accessible starting materials.[9] Although this approach is a useful tool for constructing various heterocycles, the existing strategies have been insufficiently addressed, and there is still room to develop this area of research. Based on these facts and our ongoing research in these field,[10] we constructed benzo[b]carbazole-6ol derivatives by a metal-mediated 5-exo-dig annulation followed by an electrocyclization in a cascade manner (Scheme 2). Instead of the expected product (2), the reaction proceeded further to give an unprecedented [1,4]-N-O sulfonyl migrated product 3. The starting materials were prepared from Sonogashira coupling between commercially available 2-iodoanilines with corresponding terminal alkynes. This was followed by N-tosylation
Abstract: A simple and straightforward approach was developed to construct 5H-benzo[b]carbazole derivatives by iron catalysis in a cascade sequence. The notable features of this work include an atom-economical cascade sequence, unprecedented 1,4-sulfonyl migration, tolerance of a variety of functional groups, good yields, and an economical catalytic system.
Benzo[b]carbazoles are a type of polycyclic skeleton found in many naturally occurring alkaloids and biologically active molecules.[1] The co-planar structure of these molecules has profound applications in materials science due to its chemiluminescent and optoelectronic properties.[2] Thus, these scaffolds are attractive targets in organic synthesis. The common methods to prepare these molecules include the cycloaromatization of keteneimines,[3] intramolecular dehydro Diels–Alder cycloaddition reactions using ynamides,[4] benzannulation reactions with indoles,[5] naphthalenes,[6a,b] or carbazoles,[6c] and some other methods[7] (Scheme 1). Due to their significant importance, efforts are still being made to develop benzo[b]carbazoles using simple precursors, inexpensive catalysts, and atom economy. Pericyclic reactions have long been regarded as an atom-economical bond-forming process, and they are most frequently encountered in cascade reactions.[8] Scheme 1. Previous approaches to benzo[b]carbazoles. The metal-catalyzed exo-dig cyc-
and a base-mediated N-alkylation with various a-bromoaryl (heteroaryl) ketones. This gave compound 1 a–u in quantitative yields (Supporting Information, Scheme S1). We began our studies using 1 a as a model substrate, and the results are summarized in Table 1. The reaction was carried out with 10 mol % FeCl3 in toluene at reflux for 30 h, which produced the compound 3 a in 48 % yield (Table 1, entry 1; the structure of 3 a was confirmed by X-ray analysis).[11] To improve the yield, various iron salts were tested, among which Fe(OTf)2
[a] S. S. K. Boominathan, G. C. Senadi, Dr. J. K. Vandavasi, Prof. Dr. J.-J. Wang Department of Medicinal and Applied Chemistry Kaohsiung Medical University 100, Shih-Chuan 1st Road, Kaohsiung (Taiwan) E-mail: [email protected] [b] Dr. J. Y.-F. Chen Department of Biotechnology, Kaohsiung Medical University 100, Shih-Chuan 1st Road, Kaohsiung (Taiwan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405695. Chem. Eur. J. 2015, 21, 1 – 6
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Communication failed to proceed under the standard reaction conditions. The probable reason could be the low acidity of the a-CH proton, which may reduce the enolization. We carried out control experiments, as shown in Scheme 3, to
Scheme 2. Iron-catalyzed approach to benzo[b]carbazoles.
was found to give the best yield (entries 2–8). We also screened different solvents, and toluene had the best performance in terms of yield (entries 9–12). The temperature was examined, and 130 8C was suitable in terms of reaction time and yield (entry 13), whereas lower temperatures reduced the reaction yield (entry 14). When the catalyst loading was increased to 20 mol %, the yield was further improved to 75 % (entry 15). Subsequently, we tested the reaction with other Lewis acids AgOTf, Zn(OTf)2, PdCl2, In(OTf)3, Sc(OTf)3, Cu(OTf)2, iodine, and BF3·Et2O, but all of them failed to produce the desired products (entries 17–24). Since Brønsted acid present in the metal salt could catalyze the reaction, we performed a control experiment with TfOH, but there was no reaction (entry 25). Based on the screening results, we selected 20 mol % Fe(OTf)2 in toluene at 130 8C as the optimal reaction condition (entry 15). To explore the substrate scope, a range of 5H-benzo[b]carbazoles were synthesized, as shown in Table 2. First, R1 was replaced at different positions with various substituents, such as methyl, methoxy, fluoro, chloro, cyano, and nitro. These gave the corresponding products in moderate to good yields (3 a–i). Of note, the phenyl group (R1) appended with electron-withdrawing groups reacted well to give greater yields than the electron-donating groups. Next, R2 was substituted with methyl, fluoro, and chloro, and the respective products were isolated in good yields (3 j–m). R3 was replaced with phenyl groups containing electron-donating and -withdrawing groups, which were successfully converted to the products (3 n,o). However, when R3 was replaced with alkyl groups such as H, TMS, n-butyl, and cyclopropyl, the reactions failed to proceed. We extended the scope to aroyl units containing heterocycles, such as furan and thiophene (1 p,q). Under optimized conditions, these substrates underwent cyclization (2 p,q), but the N O tosyl shift did not occur in both cases. The reason could be the partial coordination of Lewis acid with the adjacent heteroatom. The nitrogen replaced with other sulfonyl groups such as 4-bromophenylsulfonyl and phenylsulfonyl were compatible with our reaction conditions, and corresponding products were isolated (3 r,s). In contrast, the reaction with nitrogen substituted with methyl sulfonyl or 4-nitrophenylsulfonyl groups failed to proceed, and the reaction turned into a complex mixture (3 t,u). The representative compounds 3 a, 3 f, and 3 h were unambiguously confirmed by X-ray analysis.[11] Further, we attempted to construct the oxygen heterocycles and prepared the respective starting material 2-(2-(2-phenylethynyl)phenoxy)-1-phenylethanone. Unfortunately, the reaction &
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Table 1. Optimization studies.[a]
Entry
Catalyst
Solvent
T [8C]
t [h]
Yield [%] 3 a (2 a)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15[b] 16[b] 17 18 19 20 21 22 23 24[c] 25[c] 26
FeCl3 FeCl2 Fe(OTf)2 Fe(acac)3 FeBr3 FeCl3·6 H2O FeSO4 Fe(OTf)3 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)3 AgOTf Zn(OTf)2 PdCl2 In(OTf)3 Sc(OTf)3 Cu(OTf)2 I2 BF3·Et2O TfOH –
toluene toluene toluene toluene toluene toluene toluene toluene benzene DMF DMSO PhCl toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene
110 110 110 110 110 110 110 110 110 120 120 120 130 90 130 130 110 110 110 110 110 110 110 110 110 130
30 30 30 30 30 30 30 30 30 24 24 30 24 30 24 24 24 24 24 24 24 24 24 24 24 30
48 22 (trace) 54 45 (20) – – – 20 22 trace trace 32 66 15 75 40 – – – – – – – – – –
[a] Reaction conditions: 1 a (0.5 mmol), catalyst (10 mol %), and solvent (2 mL) in seal tube and heated to given temperature; [b] reaction carried out with 20 mol % of catalyst; [c] 50 mol % catalyst was used.
understand the reaction mechanism and the role of the catalyst. To identify the reaction intermediate, we stopped the reaction at 12 h and isolated the intermediate 2 o in 32 % yield [Scheme 3, Eq. (1)]. Then, the intermediate was treated under standard reaction conditions, and the expected N O tosyl-migrated product 3 o was obtained [Scheme 3, Eq. (2)]. However, in the absence of iron catalyst, the intermediate failed to proceed to the final product [Scheme 3, Eq. (3)]. Thus, we confirmed that the catalyst is necessary for the cascade process and tosyl migration. In addition, the compound 2 o was unambiguously confirmed by 1H NMR spectroscopy and X-ray analysis.[11] 2
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Communication Table 2. Substrate scope of benzo[b]carbazoles.[a]
Scheme 3. Control experiments.
intermediate B converts to its enol form C and then undergoes a 6p electrocyclization, giving the intermediate D, and aerial oxidative aromatization[12] gave the hydroxy 5H-benzo[b]carbazole intermediate 2. Then the sulfonyl oxygen of intermediate 2 coordinated with Fe(OTf)2 and resulted in the intermediate E, and the sequential nucleophilic attack of phenolic OH gave the five-member intermediate F. Finally, the rearrangement of intermediate F afforded the desired product 3, and the catalyst was regenerated for the next cycle. In summary, we have developed a simple and straightforward procedure for the synthesis of benzo[b]carbazoles by iron-catalyzed 5-exo-dig cyclization and a subsequent 6p electrocyclization. The reaction underwent an unprecedented [1,4]tosyl migration from nitrogen to oxygen with the aid of the same catalytic system. Additional features of this transformation include good substrate scope compatibility, simple precursors, relatively tolerable reaction conditions, and an environmentally benign iron catalytic system. Further studies to expand this methodology and biological evaluation are under way in our laboratory.
[a] Reaction conditions: 1 a (0.5 mmol), catalyst (20 mol %), and solvent (2 mL) in seal tube and heated at 130 8C for given time; [b] reaction turned to a complex mixture.
To find out whether the sulfonyl migration occurs in an intramolecular or intermolecular pathway, we performed a crossover experiment as shown in Scheme 4. The equimolar quantities of 2 o and 2 r were treated under the standard reaction conditions, giving the direct products (3 o and 3 r); the crossover products (3 o’ and 3 r’) were not detected by 1H NMR spectroscopy and LC-MS analysis. The results suggest that the sulfonyl group migration proceeds via an intramolecular pathway. Based on the literature[8, 9, 12, 13] and our experimental results, we tentatively propose the reaction mechanism in Scheme 5.[14] Initially, the carbonyl group of 1 converted to its enol form A, and then the Lewis acid coordinated on the alkyne, which facilitates a 5-exo-dig cyclization and subsequent protodemetallation gives the vinylidene intermediate B. Next, Chem. Eur. J. 2015, 21, 1 – 6
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Experimental Section General experimental procedure for 5H-benzo[b]carbazoles (3 a–3 o and 2 p,q) An oven-dried seal tube was charged with 1 a (0.5 mmol) in toluene (2 mL) and Fe(OTf)2 (20 mol %) was added. The reaction mixture was stirred at 130 8C for the respective time and was monitored by TLC. Upon completion, the reaction mass was poured into water and extracted into EtOAc (15 mL). The combined organic layer was washed with brine solution (10 mL) and the aqueous layer was washed with EtOAc (2 10 mL). The combined organic extract was dried on sodium sulfate and concentrated under vacuo. The obtained crude residue was passed through the flash column chromatograph (silica gel; EtOAc/hexane) to afford the title compound in moderate to good yields.
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Scheme 4. Crossover experiments.
Scheme 5. Proposed reaction mechanism.
Acknowledgements The authors gratefully acknowledge funding from the Ministry of Science and Technology (MOST), Taiwan. Keywords: alkynes · benzo[b]carbazoles · iron · pericyclic reaction · sulfonyl migration
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Received: October 17, 2014 Published online on && &&, 0000
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COMMUNICATION & Pericyclic Reaction S. S. K. Boominathan, G. C. Senadi, J. K. Vandavasi, J. Y.-F. Chen, J.-J. Wang* && – && An Iron-Catalyzed Cascade Approach to Benzo[b]carbazoles Synthesis Followed by 1,4-Sulfonyl Migration
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It’s iron, man: A simple and straightforward approach was developed to obtain 5H-benzo[b]carbazole derivatives by iron catalysis in a cascade sequence. The notable features of this work in-
clude an atom-economical cascade sequence, unprecedented 1,4-tosyl migration, tolerance of a variety of functional groups, good yields and an economic catalytic system.
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