Letter pubs.acs.org/OrgLett
Heteroannulation of 3‑Nitroindoles and 3‑Nitrobenzo[b]thiophenes: A Multicomponent Approach toward Pyrrole-Fused Heterocycles P. V. Santhini,†,‡ Sheba Ann Babu,† Akhil Krishnan R,† E. Suresh,§ and Jubi John*,†,‡ †
Organic Chemistry Section, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 19, India ‡ Academy of Scientific and Innovative Research (AcSIR), CSIR-NIIST, Thiruvananthapuram 19, India § Central Salt and Marine Chemicals Research Institute, Bhavnagar 364 002, India S Supporting Information *
ABSTRACT: A simple, efficient, and general multicomponent reaction involving an enolizable ketone, a primary amine, and an N-protected 3-nitroindole was developed for the synthesis of a range of functionalized pyrrolo[3,2-b]indoles. The methodology was efficaciously utilized for the “pyrroloindoliztion” of natural products, the pyrrolization of 3-nitrobenzo[b]thiophene, and the gram-scale synthesis of pyrroloindole. Furthermore, a “one-pot” approach for accessing indolo[3,2b]indoles was realized. obtained from the reactions of these enamines with β-nitro styrenes.11 Based on these literature leads, we envisioned that a multicomponent reaction involving an enolizable ketone, a primary amine, and N-tosyl-3-nitroindole would result in a new methodology for the heteroannulation of indole to give pyrrolo[3,2-b]indole12 heterocycles (Scheme 1). The reported routes toward this fused indole moiety are scarce, and some of them involve tedious and multistep processes like the intramolecular nucleophilic substitution of substituted pyrrole derivatives12a and reaction of N-acetylindoxyl hydrazone with ketones under acidic conditions.12b Metal-catalyzed routes toward pyrrolo[3,2-b]indole include Pd-catalyzed intramolecular
F
or over 150 years, organic chemists have exploited multicomponent reactions (MCRs)1 for the preparation of libraries of pharmacophores, natural products, functional chromophores, polymeric materials, etc.2 The indole core is one of the most studied moieties due to its wide spectrum of biological activities, which is evident from its applications in pharmaceuticals and agrochemicals.3 Hence, interest remains high in finding novel routes for the synthesis and functionalization of these bioactive scaffolds. MCRs continue to be effectively utilized for the functionalization of indole4 following the report by Yonemitsu et al. on a 3-CR involving an aldehyde, indole, and Meldrum’s acid.5 In the present paper, we disclose a novel metalfree multicomponent method for the pyrrolo-annulation of Nprotected 3-nitroindoles. Indole is generally considered as an electron-rich heterocycle due to its reactivity as a nucleophile (at the C-3 position) in the majority of reported reactions.6 This inherent nucleophilicity can be reversed by the installation of electron-withdrawing groups on the N atom and C-2 or C-3 carbon atoms.7 For example, N-tosyl3-nitroindole, an electrophilic indole, was thoroughly studied for its reactivity by different groups for generating highly functionalized indole derivatives.8 We were interested in exploiting the reactivity of electrophilic indoles for the development of a facile method for fusing the pyrrole9 moiety onto the indole core. The synthesis of pyrroloindolines by the dipolar cycloaddition of 2and 3-nitroindoles with azomethine ylides was first described by Gribble8k and later asymmetric versions by different groups.8n,p,v Lately, a highly regio- and diastereoselective addition of nucleophilic enamines derived from 2° amines with 3-nitroindoles was reported, generating a new C−C bond along with dearomatization of the indole ring.8u The chemistry of enamines derived from 1° amines and enolizable ketones was investigated in detail by several groups for the generation of functionalized Nheterocycles.10 In particular, substituted pyrrole moieties were © XXXX American Chemical Society
Scheme 1. Synthetic Routes toward Pyrrolo[3,2-b]indole
Received: April 15, 2017
A
DOI: 10.1021/acs.orglett.7b01147 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Scheme 3. Generality of the Pyrrolo[3,2-b]indole Synthesisa
cyclization of bromoanilinoalkenenitriles12d and Cu-catalyzed intramolecular C−N coupling.12e The investigations to validate our hypothesis commenced with the multicomponent reaction of N-tosyl-3-nitroindole 1a, cyclohexanone 2a, and p-methoxybenzylamine 3a. Initially, 2a and 3a were treated in toluene at 60 °C in the presence of 4 Å molecular sieves, with 3-nitroindole 1a being added to the reaction after 1 h and the reactants being allowed to stir at the same temperature. After 12 h, the expected pyrrolo[3,2-b]indole 4a was isolated from the reaction mixture in 24% yield (Scheme 2). The structure of the fused indole 4a was assigned on the basis of various spectroscopic analyses, and final confirmation was obtained from X-ray crystal data. Scheme 2. MCR toward Pyrrolo[3,2-b]indole 4a
Detailed optimization studies were performed to find the best conditions for the heteroannulation with 1a, 2a, and 3a as substrates.13 With the optimal conditions [combination of 1 equiv of 1, 2 equiv of 2, 2 equiv of 3, 4 Å MS (50 mg), toluene, 60 °C, 12 h] in hand, we subsequently explored the substrate scope of the present heteroannulation reaction, the results of which are summarized in Scheme 3. The multicomponent process was found to be general with different benzylamines substituted with both electron-donating (4a and 4b) and -withdrawing substituents (4d) furnishing pyrroloindoles in good yields. Fused indoles were obtained in excellent yields of 90% for 4e and 81% for 4f when linear amines such as hexyl- and dodecylamines were used. Propargyl- and allylamine were also well tolerated under the reaction conditions, furnishing the respective pyrroloindoles 4g and 4h in good yields. Next, we studied the effect of steric bulk on the amine moiety on the outcome of the MCR. As expected, 2-phenylethylamine furnished the product 4i in good yield. It was found that the yield of pyrroloindole 4j diminished to 45% with 1-phenylethylamine. With cyclohexylamine, the product 4k was obtained in moderate yield (53%) and with adamantylamine the MCR failed, hence proving that the reactivity decreases with an increase in the steric bulk of the amine component. Anilines with both electron-donating and -withdrawing substituents furnished the respective fused indole derivatives (4m,o) in good yields. Further studies were performed to evaluate the reactivity of different cyclic ketones. To our dismay, MCR with cyclopentanone resulted in an intractable reaction mixture within 1 h of the addition of the 3nitroindole 1a. As expected, both cycloheptanone and cyclooctanone reacted well, affording the products 4q and 4r in 60% and 50% yields, respectively. Starting with 1,4-cyclohexanedione monoethylene acetal, the fused indole 4s was obtained in 68% yield. Installation of additional heterocyclic rings to the pyrroloindole moiety with O (4t), N (4u), and S (4v) atoms was effected with success by the MCR involving the respective heteroatom-containing cyclic ketone. Our next attempt was to check the reactivity of 2-indanone and α-tetralone toward the heteroannulation process. Both of these ketones failed to furnish the expected products even at reflux, which might be due to the
a
Reaction conditions: 1 (50 mg), 2 (2 equiv), 3 (2 equiv), 4 Å MS (50 mg), toluene (0.3 mL), 60 °C, 12 h. bReflux, 24 h.
inability of the aromatic enamine to add to the electrophilic indole.14 In subsequent reactions, the substitution pattern in electrophilic indole was varied. As anticipated, the reactions with halogen (Br and Cl)-substituted nitroindoles proceeded well, affording the products 4y, 4z, and 4aa in excellent yield. The possibility of synthesizing halogen-substituted fused indoles increases the impact of the developed methodology, as these molecules can be further functionalized by metal-catalyzed transformations. From the MCR with 5-methoxy-3-nitroindole, the product 4ab was formed only in trace amounts (not in isolable yields) even after being heated at reflux in toluene for a prolonged period of time. Finally, when the electron-withdrawing group at the N atom of indole was changed to Boc and CO2Et, both substrates afforded the products 4ac and 4ad in 60% and 75% yield, respectively. It should be noted that the generality of the reaction has been designed in such a way that the products of these reactions can be further synthetically manipulated toward molecules of interest. Subsequently, the scope of the reaction was examined with different acyclic ketones (Scheme 4). In our initial experiment, acetone was used both as a reagent and as the medium for the MCR, from which the corresponding pyrrolo[3,2-b]indole 4ae was isolated in 65% yield. 4-Heptanone also afforded the expected product 4af in good yield. Next, we evaluated the reactivity of acetophenone under the optimized conditions and also at reflux in toluene; both reactions failed to afford the B
DOI: 10.1021/acs.orglett.7b01147 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Generality of the Pyrrolo[3,2-b]indole Synthesisa
Scheme 5. Mechanism of the Heteroannulation Reaction
forms the intermediate F. This is followed by the attack of the enamine on the C-3 carbon of the nitronate F to furnish the pyrroline intermediate G. Elimination of hyponitrous acid and water from the intermediate G results in the formation of the final compound pyrroloindole H. Our success in the heteroannulation of N-protected-3-nitroindole encouraged us to check the reactivity of 3-nitrobenzo[b]thiophene 5 in the present MCR (Scheme 6). The reactions of enamines derived from acetone and cyclohexanone proceeded well under the optimized conditions, furnishing the expected benzothieno[3,2-b]pyrroles 6a and 6b.
a
Reaction conditions: 1 (50 mg), 2 (2 equiv), 3 (2 equiv), 4 Å MS (50 mg), toluene (0.3 mL), 60 °C, 12 h. bReflux, 24 h.
anticipated fused indole.14 Inseparable mixtures of regioisomers (4ah, 4ah′, 4ai, 4ai′) were obtained in good yields from unsymmetrical acyclic ketones like 2-butanone and 2-hexanone. The uniqueness of the developed methodology was further illustrated by carrying out the “pyrroloindolization” of natural products either containing a primary amine or an enolizable ketone (Table 1). Tyramine, a trace amine derived from tyrosine,
Scheme 6. MCR toward Pyrrolization of Benzothiophene
Table 1. Generality of “Pyrroloindolization” of Natural Productsa
Any developed methodology will only be valuable if it can be scaled up. Hence, we attempted the gram-scale synthesis (starting from 1 g of 1a) of pyrrolo[3,2-b]indole 4e, and the compound was obtained in 86% yield (Scheme 7). The tosyl Scheme 7. Scale-up and N-Ts Deprotection of Pyrroloindoles and Synthesis of Indolo[3,2-b]indole
a
Reaction conditions: 1 (50 mg), 2 (2 equiv), 3 (2 equiv), 4 Å MS (50 mg), toluene (0.3 mL), 60 °C, 12 h.
was first subjected to the MCR conditions from which the expected pyrroloindole compound 4aj was obtained in 51% yield. The primary amine part of tryptamine was also successfully incorporated into the pyrrole ring by the “pyrroloindolization” process. Next, we checked the reactivity of menthone (mixture of isomers) with hexylamine and 5-chloro-3-nitro-1-tosylindole in the multicomponent process. We were delighted that the expected product 4al was formed, albeit in moderate yield. Finally, 5α-cholestan-3-one was also subjected to “pyrroloindolization”, which afforded a single regioisomeric product 4am in good yield. A plausible mechanism for this multicomponent reaction analogous to the one proposed by Jana et al. is outlined in Scheme 5.11c The first step of the reaction is the formation of imine C by the condensation of ketone and amine which will be in equilibrium with the enamine form D. Next, Michael addition of enamine D to the C-2 position the 3-nitro-N-tosylindole E
(Ts) group of pyrroloindole 4e could be easily removed by treatment with NaOH in a mixture of MeOH−THF.15 We also assumed that by starting from cyclohexanone indolo[3,2b]indoles16 could be generated in a “one-pot” process involving successive MCR and oxidation steps. We tested our hypothesis with 1a, cyclohexanone, and hexylamine as substrates. After completion of the MCR, DDQ was added, and the reaction was left at 60 °C for 12 h. As expected, the fused heteroacene 8 was obtained in 25% yield. Detailed studies on the optimization and generality of this one-pot indolo[3,2-b]indole synthesis are underway. C
DOI: 10.1021/acs.orglett.7b01147 Org. Lett. XXXX, XXX, XXX−XXX
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(c) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449. (7) Bandini, M. Org. Biomol. Chem. 2013, 11, 5206 and references cited therein. (8) (a) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Am. Chem. Soc. 1988, 110, 7188. (b) Pelkey, E. T.; Chang, L.; Gribble, G. W. Chem. Commun. 1996, 1909. (c) Pelkey, E. T.; Gribble, G. W. Chem. Commun. 1997, 1873. (d) Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603. (e) Biolatto, B.; Kneeteman, M.; Mancini, P. M. E. Tetrahedron Lett. 1999, 40, 3343. (f) Pelkey, E. T.; Gribble, G. W. Synlett 1999, 7, 1117. (g) Chataigner, I.; Hess, E.; Toupet, L.; Piettre, S. R. Org. Lett. 2001, 3, 515. (h) Biolatto, B.; Kneeteman, M.; Paredes, E.; Mancini, P. M. E. J. Org. Chem. 2001, 66, 3906. (i) Kishbaugh, T. L. S.; Gribble, G. W. Tetrahedron Lett. 2001, 42, 4783. (j) Chrtien, A.; Chataigner, I.; Helias, N. L’.; Piettre, S. R. J. Org. Chem. 2003, 68, 7990. (k) Roy, S.; Kishbaugh, T. L. S.; Jasinski, J. P.; Gribble, G. W. Tetrahedron Lett. 2007, 48, 1313. (l) Chataigner, I.; Panel, C.; Gerard, H.; Piettre, S. R. Chem. Commun. 2007, 3288. (m) Chataigner, I.; Piettre, S. R. Org. Lett. 2007, 9, 4159. (n) Lee, S.; Diab, S.; Queval, P.; Sebban, M.; Chataigner, I.; Piettre, S. R. Chem. - Eur. J. 2013, 19, 7181. (o) Beemelmanns, C.; Gross, S.; Reissig, H.-U. Chem. - Eur. J. 2013, 19, 17801. (p) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462. (q) Trost, B. M.; Ehmke, V.; O’Keefe, B. M.; Bringley, D. A. J. Am. Chem. Soc. 2014, 136, 8213. (r) Zhao, J.-Q.; Zhou, M.-Q.; Wu, Z.-J.; Wang, Z.-H.; Yue, D.-F.; Xu, X.Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2015, 17, 2238. (s) Andreini, M.; De Paolis, M.; Chataigner, I. Catal. Commun. 2015, 63, 15. (t) Li, Y.; Tur, F.; Nielsen, R. P.; Jiang, H.; Jensen, F.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 1020. (u) Andreini, M.; Chapellas, F.; Diab, S.; Pasturaud, K.; Piettre, S. R.; Legros, J.; Chataigner, I. Org. Biomol. Chem. 2016, 14, 2833. (v) Gerten, A. W.; Stanley, L. M. Org. Chem. Front. 2016, 3, 339. (w) Liu, X.; Yang, D.; Wang, K.; Zhang, J.; Wang, R. Green Chem. 2017, 19, 82. (x) Rivinoja, D. J.; Gee, Y. S.; Gardiner, M. G.; Ryan, J. H.; Hyland, C. J. T. ACS Catal. 2017, 7, 1053. (9) (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402. (b) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2014, 43, 4633. (10) (a) Grob, C. A.; Camenish, K. Helv. Chim. Acta 1953, 36, 49. (b) Thomas, J.; Jana, S.; John, J.; Liekens, S.; Dehaen, W. Chem. Commun. 2016, 52, 2885. (c) Jana, S.; Thomas, J.; Dehaen, W. J. Org. Chem. 2016, 81, 12426. (11) (a) Trautwein, A. W.; Jung, G. Tetrahedron Lett. 1998, 39, 8263. (b) Ranu, B. C.; Dey, S. S. Tetrahedron Lett. 2003, 44, 2865. (c) Maiti, S.; Biswas, S.; Jana, U. J. Org. Chem. 2010, 75, 1674. (d) Guan, Z. H.; Li, L.; Ren, Z.-H.; Li, J.; Zhao, M.-N. Green Chem. 2011, 13, 1664. (12) For the synthesis of pyrrolo[3,2-b]indole, see: (a) Aiello, E.; Dattolo, G.; Cirrincione, G. J. Chem. Soc., Perkin Trans. 1 1981, 1. (b) Grinev, A. N.; Ryabova, Y. S. Chem. Heterocycl. Compd. 1982, 18, 155. (c) Aiello, E.; Dattolo, G.; Cirrincione, G.; Almerico, A. M. J. Heterocycl. Chem. 1984, 21, 721. (d) Yang, C.-C.; Tai, H.-M.; Sun, P.-J. J. Chem. Soc., Perkin Trans. 1 1997, 1, 2843. (e) Karkhelikar, M. V.; Rao, V. V.; Shinde, S.; Likhar, P. R. Tetrahedron Lett. 2016, 57, 4803. (13) See the Supporting Information. (14) We have found that the aromatic enamine generated from primary amine and ketones like α-tetralone and acetophenone would easily react with β-nitrostyrene to furnish functionalized pyrrole in good yields (unpublished results). 3-Nitroindole is less reactive than β-nitro styrene due to the electron-donating influence of the indole nitrogen, which explains why aromatic enamines derived from acetophenone and analogues do not react. (15) Liu, Y.; Shen, L.; Prashad, M.; Tibbatts, J.; Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 2008, 12, 778. (16) For the synthesis of indolo[3,2-b]indole see: Samsoniya, S. A; Trapaidze, M. V. Russ. Chem. Rev. 2007, 76, 313 and references cited therein.
In conclusion, we have developed a general method for the heteroannulation of N-protected 3-nitroindoles and 3nitrobenzo[b]thiophenes. The methodology was applied for the synthesis of a number of pyrroloindoles starting from different cyclic and acyclic ketones, primary amines, and 3nitroindoles. Another notable achievement was the application of the MCR for the “pyrroloindolization” of natural products. We have also demonstrated the applicability of the heteroannulation strategy for the generation of pyrrolo[3,2-b]indoles on a gram scale. In addition, a “one-pot” process for accessing indolo[3,2b]indoles was realized, the detailed investigations of which will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01147. Synthetic procedures, analytical details, NMR spectra for all the compounds, and crystallographic data for 4a (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jubi John: 0000-0003-0483-2026 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Dr. K. V. Radhakrishnan, Principal Scientist, CSIRNIIST, for the constructive discussions. P.V.S. thanks UGC for a research fellowship. J.J. thanks the Department of Science and Technology (DST)-SERB, India, for a Young Scientist Start-Up Research Grant (SB/FT/CS-107/2014). We also thank Mrs. Saumini Mathew, Mr. Saran P. R., Mrs. Viji S., and Ms. Aathira S. of CSIR-NIIST for recording NMR and mass spectra, respectively.
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REFERENCES
(1) Multicomponent Reactions; Zhu, J., Bienaym, H., Eds.; Wiley-VCH: Weinheim, 2005. (2) For selected reviews on applications of MCR, see: (a) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083. (b) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (c) Levi, L.; Muller, T. J. J. Chem. Soc. Rev. 2016, 45, 2825. (d) Kakuchi, R. Angew. Chem., Int. Ed. 2014, 53, 46. (3) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970. (b) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 4. (c) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Bird, C. W., Eds.; Pergamon Press: Oxford, 1996; Vol. 2. (d) Sundberg, R. J. Indoles; Academic Press: London, 1996. (f) Gribble, G. W. Heterocyclic Scaffolds II: Reactions and Applications of Indole. Topics in Heterocyclic Chemistry; Springer-Verlag, Berlin, 2010; Vol. 26. (g) KochanowskaKaramyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. (4) (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (b) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (5) (a) Shiri, M. Chem. Rev. 2012, 112, 3508. (b) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Chem. Pharm. Bull. 1982, 30, 3092. (6) (a) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903. (b) You, S. L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190. D
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