Letter Cite This: Org. Lett. 2019, 21, 675−678
pubs.acs.org/OrgLett
Metal-Free C−H Functionalization and Aromatization Sequence for the Synthesis of 1‑(Indol-3-yl)carbazoles and Total Synthesis of 7‑Bromo-1-(6-bromo‑1H‑indol-3-yl)‑9H‑carbazole Ganapathy Ranjani and Rajagopal Nagarajan*
Org. Lett. 2019.21:675-678. Downloaded from pubs.acs.org by SWINBURNE UNIV OF TECHNOLOGY on 02/03/19. For personal use only.
School of Chemistry, University of Hyderabad, Hyderabad 500046, India S Supporting Information *
ABSTRACT: An operationally simple, metal-free, costeffective, and mild oxidative cross-coupling protocol for the synthesis of 1-indolyl tetrahydrocarbazoles to afford 1-(indol3-yl)carbazoles is developed. N-Chlorosuccinimide is used as a mild oxidant for the functionalization of the 1-position of tetrahydrocarbazoles, aromatization of which furnished 1(indol-3-yl)carbazoles in good to moderate yields without employing protection/deprotection strategy. A naturally rare dibromo 1-(indol-3-yl)carbazole alkaloid was synthesized for the first time in two steps with an overall yield of 64% by applying the same methodology. rom the isolation of the first carbazole alkaloid murrayanine in 1965, there has been immense growth in the carbazole chemistry.1 Researchers isolated large numbers of carbazolebased alkaloids exhibiting a wide spectrum of biological activities and developed various metal-mediated/catalyzed and metal-free protocols for their synthesis to date.2 Another big wheel of the heterocyclic family is indole. It exhibits a variety of application in various fields such as biology, medicine, dyes, and agrochemistry.3 Moreover, many biologically potent indole- and carbazole-fused alkaloids also exist in the literature, the most extensively studied category of which is indolocarbazoles.4 Among the biologically active substituted carbazole alkaloids, 1-(indol-3-yl)carbazoles are very rare.5 Very few reports are available in the literature for the construction of the 1-(indol-3yl)carbazole core (Figure 1) and involve either the use of an expensive metal catalyst, prefunctionalized and complex starting materials, a protection strategy, or are applicable to only symmetric bisindoles.6,7 Consequently, the development of alternative methods for the synthesis of 1-(indol-3-yl)carbazoles becomes essential in commercial and environmentally benign points of view.
F
Pityriazole (1) and 7-bromo-1-(6-bromo-1H-indol-3-yl)-9Hcarbazole (2) are the only known naturally available 1-(indol-3yl)carbazoles (Figure 2). The first total synthesis of pityriazole
Figure 2. Naturally available 1-(indol-3-yl)carbazoles.
was reported by Knölker and co-workers using a Pd-catalyzed Suzuki−Miyaura coupling reaction, and so far, this is the only synthetic report available for this alkaloid.8 Stonik and coworkers isolated 7-bromo-1-(6-bromo-1H-indol-3-yl)-9H-carbazole from the marine sponge Penares sp. in 2012, and it is the first alkaloid isolated from the genus Penares. It is cytotoxic to HL-60 and HeLa tumor cell lines with an IC50 of 16.1 and 33.2 μM, respectively, and to the best of our knowledge there is no report for its synthesis to date.9 As our research group focus is on the development of methodologies for the total synthesis of biologically active alkaloids,10 we wanted to synthesize 7-bromo-1-(6-bromo-1Hindol-3-yl)-9H-carbazole and its derivatives to evaluate their biological spectrum. 7-Bromo-1-(6-bromo-1H-indol-3-yl)-9Hcarbazole constitutes of two bromine atoms and an indole moiety in the 1-position of the carbazole in its structure. Hence, the selectivity becomes uncertain while accompanying metalReceived: December 3, 2018 Published: January 24, 2019
Figure 1. Comparison of present work with the previous literature. © 2019 American Chemical Society
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DOI: 10.1021/acs.orglett.8b03848 Org. Lett. 2019, 21, 675−678
Letter
Organic Letters catalyzed C−C cross-coupling strategies,11 and an indirect methodology has to be designed for its synthesis. When considering selectivity, toxicity, and cost, the metal-free oxidative cross-coupling is preferable in such cases.12 We envision that the C−H functionalization of tetrahydrocarbazoles at the 1-position using mild oxidizing reagents followed by aromatization will afford the required 1-substituted carbazoles. Moreover, this approach will provide 1-substituted tetrahydrocarbazoles and 1-substituted carbazoles where both of the scaffolds are biologically potent.13 Tetrahydrocarbazoles can be activated via thionium or peroxo- or chloroindolenine intermediates.14 The available methods for the activation of tetrahydrocarbazole at its 1-position require (1) combination of reagents/oxidizing agents, (2) low temperature, (3) higher equivalents of nucleophiles, (4) longer reaction time, (5) protection of N−H. Chloroindolenines have been known in the literature for more than five decades and are used in the total synthesis of many alkaloids.15 Chloroindolenines are very reactive intermediates and result in many possible products, and it is difficult to control their reactivity. tBuOCl is the conventional reagent used for the generation of chloroindolenine, which is a flammable chemical.16 Hence, the development of an alternative reaction condition which involves a mild, cheap, and single oxidizing reagent for easy handling, avoiding of side reactions, controlling the selectivity, and overcoming the limitations of the previous accessible methods is anticipated. N-Chlorosuccinimide is a mild, inexpensive, and commercially available oxidizing reagent. When NCS is used in the reaction, succinimide is the by-product that can be easily converted back to NCS. Hence, NCS can be an excellent alternative to tBuOCl for the generation of chloroindolenine from tetrahydrocarbazoles. Keeping all these aims and limitations in mind, we started the investigation of oxidative coupling of tetrahydrocarbazoles (synthesized by Fisher indolization)17 with indoles using different halosuccinimides, solvents, and temperature conditions (Table 1). When NBS was used for the oxidative coupling of tetrahydrocarbazole with indole, 40% of the desired product 5a (Table 1, entry 1), and no product formation was observed when NIS was used (Table 1, entry 2). When the reaction was carried out with NCS in THF, 70% of product 5a was formed (Table 1, entry 3). When the solvent was changed from THF to 1,4-dioxane, NCS furnished 75% of 5a (Table 1, entry 4). At the same time, reaction with NCS in acyclic ether solvents such as DME or diglyme resulted in a diminished yield of 5a (Table 1, entries 5 and 6). In addition, NCS with other solvents like DMSO, DCM, and DCE also resulted in a lower yield of 5a (Table 1, entries 7−9). All of these observations confirm that cyclic ether solvents favor the reaction, and when the number of oxygen in the solvent increases, the yield of product 5a also increases. When the reaction was conducted at 0 °C or 0 °C to rt, the product formation was slightly decreased (Table 1, entries 10 and 11). The reaction was carried out in open air and oxygen atmosphere to find the role of oxygen on the reactivity, which also reduced the formation of 5a (Table 1, entries 12 and 13). The same reaction was done under dark, dark−light, and light− dark conditions to understand the role of light on the reaction yield, and 24%, 45%, and 54% of 5a was formed, respectively (Table 1, entries 14−16). From these observations, it is clear that light has some role in the formation of chloroindolenine intermediate and product 5a. We also found that 5a is air and light sensitive and starts decomposing when kept open in air or
Table 1. Optimization of Reaction Conditions: Synthesis of 1-(Indol-3-yl)tetrahydrocarbazoles (5a)
entrye
reagent
solvent
temp (°C)
time
yield (%) of 5ag
1 2 3 4 5 6 7 8 9 10 11 12a,b 13a,c 14a,d 15a,e 16a,f 17
NBS NIS NCS NCS NCS NCS NCS NCS NCS NCS NCS NCS NCS NCS NCS NCS NCS
THF THF THF 1,4-dioxane DME diglyme DMSO DCM DCE 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane
rt rt rt rt rt rt rt rt rt 0 °C 0 to rt rt rt rt rt rt rt
1.5 h 1.5 h 1.5 h 1.5 h 1.5 h 1.5 h 1.5 h 1.5 h 1.5 h 2h 1.5 h 1.5 h 1.5 h 1.5 h 1.5 h 1.5 h 10 min
40 0 70 75 40 30 10 30 5 70 72 60 58 24 45 54 79
a
Reaction conditions: 3a (0.6 mmol, 1 equiv), 4a (0.9 mmol, 1.5 equiv), halosuccinimide (0.6 mmol, 1.0 equiv), solvent (3 mL). b− d Reaction conducted in the open air, under O2 atmosphere, in the dark, respectively. eNCS was added in the dark, and the indole was added in the presence of normal light, fNCS was added in the presence of normal light, and the indole was added in the dark. g Isolated yields.
light. Since product formation is favored by light and also decomposes by light, reaction time becomes crucial to avoid the decomposition of 5a. With this objective, we optimized the reaction conditions at various time intervals and found that 10 min was sufficient to obtain the maximum yield of 5a, no impurity formation was observed within this reaction time (Table 1, entry 17). To our delight, a maximum of 79% of 5a was obtained with NCS in 1,4-dioxane within 10 min (Table 1, entry 17). With the optimized reaction conditions for oxidative crosscoupling of tetrahydrocarbazole and indole in hand, we further moved to analyze the aromatization of 5a to obtain 1-(indol-3yl)carbazole 6a (Table S1). Other than DDQ, none of the available oxidizing reagents in the literature18 aromatized the coupled product 5a satisfactorily and furnished the product 6a in a good amount (Table S1, entries 1−7). DDQ in 1,4-dioxane within 10 min resulted in the formation of 1-(indol-3yl)carbazole 6a in 81% of yield (Table S1, entry 8). After the optimization of reaction conditions for the synthesis of 1-(indol-3-yl)carbazole 6a was complete, we began the investigation of substrate scope of NCS-mediated C−H indolylation of tetrahydrocarbazole by varying the substitutions on both tetrahydrocarbazole and indole (Scheme 1). Indoles with an electron-donating group afforded excellent to good yield of the product (5b, 5c), and indoles with electrondonating substitutions at the second position also resulted in a good yield of the product (5d, 5e), Due to the combined effect of the electron-donating and electron-withdrawing nature of halogens, moderate yields of the product were obtained when halogens were present on indole and tetrahydrocarbazole (5f−i and 5o−q). Halogens on indoles (5f−i) afforded comparatively less yield than the substrates, which contain halogen in 676
DOI: 10.1021/acs.orglett.8b03848 Org. Lett. 2019, 21, 675−678
Letter
Organic Letters Scheme 1. Substrate Scope (Synthesis of Derivatives of 5a)a,b
Scheme 2. Synthesis of Derivatives of 6aa,b
a
a
Reaction conditions: 3a−f (1.46 mmol), NCS (1.46 mmol), indoles (2.19 mmol), and 1,4-dioxane (4.0 mL). bIsolated yields. cReaction time is 20 min.
Reaction conditions: 5a−u (1.0 mmol), DDQ (2.0 mmol), 1,4dioxane (5.0 mL), bIsolated yields.
Scheme 3. Total Synthesis of 7-Bromo-1-(6-bromo-1Hindol-3-yl)-9H-carbazole (2)
tetrahydrocarbazole (5o−q) as the presence electronegative atom on the indole decreases the product yield. As expected, indoles with strong electron-withdrawing substituents further resulted in moderate to lower yield of the product (5j, 5l−n). A few more reactions were carried out to understand the electronic effect of the substituent present on indole and tetrahydrocarbazole on the reactivity. Gratifyingly, when a methyl group was introduced at the 2-position of the 5-nitroindole, the yield of the product 5k was increased more than that of 5j. Unsurprisingly, electron-withdrawing substituents on tetrahydrocarbazole and electron-donating groups on indole affected the yield of the product according to their electronic balance (5r, 5s). NBenzylindole afforded 73% yield of 5t, whereas 1-(4-nitrophenyl)-1H-indole resulted in a trace amount of product. NMethyl tetrahydrocarbazole gave only 50% of 5u, and with Nboc tetrahydrocarbazole no product was formed. It was also observed that 7-azaindole, 3-methylindole, ethyl indole-2carboxylate, and 5-benzyloxyethyl indole-2-carboxylate are not viable substrates for this conversion. In addition, a gram-scale synthesis of 5a was performed and resulted in 75% yield (see SI). All of the tetrahydrocarbazole derivatives (5a−u) were aromatized using DDQ, and derivatives of 1-(indol-3-yl)carbazoles (6a−u) were obtained in excellent to moderate yield (Scheme 2). 7-Bromo-1-(6-bromo-1H-indol-3-yl)-9H-carbazole (2) is a cytotoxic marine alkaloid. It is the second known alkaloid of the class of 1-(indol-3-yl)-9H-carbazole alkaloid until to date. We have synthesized the alkaloid via NCS-mediated C−H indolylation followed by aromatization, with an overall yield of 64% in two steps without employing any protection strategy (Scheme 3), its structure was also confirmed by X-ray crystallography (CCDC 1847790). Furthermore, the proposed mechanism of the reaction is depicted in Figure 3. NCS on reaction with tetrahydrocarbazole forms chloroindolenine intermediate (i), which on nucleophilic attack by indole can
Figure 3. Proposed mechanism of the reaction.
afford compound 5a. Compound 5a upon aromatization conditions can furnish the 1-(indol-3-yl)carbazole 6a. In summary, we have developed a practical, straightforward, efficient, metal-free oxidative coupling followed by aromatization protocol for the synthesis of 1-(indol-3-yl)carbazoles in excellent to moderate yields without any protection/deprotection. Bioactive alkaloid 7-bromo-1-(6-bromo-1H-indol-3-yl)9H-carbazole was synthesized in just two steps with an overall yield of 64% for the first time. The developed methodology allows a wide range of substrate scope and can be applied in the large-scale synthesis, which will be helpful for the in-depth and 677
DOI: 10.1021/acs.orglett.8b03848 Org. Lett. 2019, 21, 675−678
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Organic Letters
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detailed evaluation of the biological spectrum and other applications of 1-(indol-3-yl)carbazoles and 7-bromo-1-(6bromo-1H-indol-3-yl)-9H-carbazole.
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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.8b03848. Experimental details and data (PDF) Accession Codes
CCDC 1847790 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.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Rajagopal Nagarajan: 0000-0002-4471-8933 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge Dr. S. Sathiyaraj, School of Chemistry, University of Hyderabad, for assistance, DST-SERB, India, for financial support (EEQ/2017/000422), and DST, India, for a fellowship.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b03848 Org. Lett. 2019, 21, 675−678
