Alkyne Indol-2-yl Cation

Sep 22, 2017 - A Lewis acid promoted cascade Friedel-Craft/alkyne indol-2-yl cation cyclization/vinyl cation trapping for an efficient and divergent s...
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Lewis Acid Mediated Cascade Friedel−Craft/Alkyne Indol-2-yl Cation Cyclization/Vinyl Cation Trapping for the Synthesis of N‑Fused Indole Derivatives Santosh J. Gharpure* and Yogesh G. Shelke Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai - 400076, India S Supporting Information *

ABSTRACT: A Lewis acid promoted cascade Friedel-Craft/alkyne indol-2-yl cation cyclization/vinyl cation trapping for an efficient and divergent synthesis of N-fused indoles is developed. The present study illustrates the first example of an alkyne as a nucleophile on the less explored indol-2-yl cation. The method efficiently affords pharmaceutically important pyrrolizino-quinolines and complex fused indole derivatives in high yields.

F

used indole scaffold is ubiquitous in pharmaceuticals, fragrances, agrochemicals, and pigments.1 Among these, pyrrolo[1,2-a]indoles are of particular interest as they are a part of a large number of natural products of biological interest such as mitosanes and mitosenes (1) (antitumor),2 isatisine A (2) (antiviral),3 goniomitine (3) (antiproliferative),4 and Yuremamine (4/5) (hallucinogenic and psychoactive) (Figure 1).5,6

Figure 2. Indolidenium cations.

to the difficulty associated with obtaining them from 2indolylmethanols.9 This is further accentuated by the step economy associated with the synthesis of the latter. As a result, the full potential of indol-2-yl cation 7 to provide a powerful platform for the construction of polycyclic as well as complex indole derivatives remains largely unrealized. There are only a handful of reports on its use in the synthesis of N-fused indole derivatives.10 Recently, we have developed a novel and efficient protocol for the stereoselective synthesis of dihydrobenzofurans, indolines, pyrrolidines, and pyrrolo[1,2-a]indole derivatives using an alkyne Prins type reaction or iminium ion cyclization.11 In continuation of our interest, we envisioned that intermolecular Friedel−Craft reaction of indole 8 with the aldehyde 9 in the presence of Lewis/Brønsted acid would generate the indol-2-yl cation (7′). Its intramolecular reaction with tethered alkyne, a πnucleophile, followed by the trapping of the intermediate vinyl cation by a tethered nucleophile or counteranion of the Lewis/ Brønsted acid would furnish the N-fused indole 10 (Scheme 1).12 Such an approach will add to the repertoire of the chemistry of indol-2-yl cation 7, as, to the best of our knowledge, indol-2-yl cation trapping with an alkyne is hitherto unexplored. In order to determine the feasibility of this proposed retrosynthetic analysis, the propargylindole 8a was reacted with p-tolualdehyde (9a) in the presence of TMSOTf, which led to the formation of the vinylidene triflate 10a, albeit in poor yield.

Figure 1. Natural products bearing pyrrolo[1,2-a]indole core.

Even though enormous synthetic efforts have been devoted to the synthesis of the pyrrolo[1,2-a]indole core, its construction, especially in a stereoselective and chemo-divergent manner, remains a long-standing challenge in synthetic chemistry.7 Indolidenium cations (indolyl cation) are attractive reactive intermediates for the formation of C−C bonds on an indole framework (Figure 2). Indol-3-yl cation 6 is a commonly used indolidenium ion for various synthetic transformations.8 This is not particularly surprising, as the indol-3-yl cations are rather easily generated from 3-indolylmethanols in the presence of a Lewis/Brønsted acid. Interestingly, corresponding indol-2-yl cations 7 have gained traction only in recent years, perhaps owing © 2017 American Chemical Society

Received: August 28, 2017 Published: September 22, 2017 5406

DOI: 10.1021/acs.orglett.7b02680 Org. Lett. 2017, 19, 5406−5409

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Organic Letters

Scheme 3. Scope of Synthesis of Pyrrolo[1,2-a]indolea,b

Scheme 1. Retrosynthetic Analysis for N-Fused Indoles

After some experimentation, we observed that the addition of 10 mol % of benzyl alcohol along with TMSOTf gave the desired vinylidene triflate 10a in excellent yield (see Supporting Information for detailed reaction optimization). While the vinylidene triflate 10a is potentially useful and could be isolated by flash column, its purification by column chromatography proved to be challenging in other cases and varying amounts of hydrolyzed ketones 11 were obtained. To circumvent this problem, we decided to hydrolyze the triflate derivative. After a quick search of acidic/basic conditions, it was found that Et3N in DMF gave the ketone 11a in excellent yield and good diastereoselectivity without any associated decomposition or side products (Scheme 2). The success of this reaction is quite Scheme 2. Synthesis of Pyrrolo[1,2-a]indole Based Triflate 10a and Its Hydrolysis to Ketone 11a

a

Yield refers to that of isolated cis-isomer. inseparable mixture of diastereomers.

interesting, as the reaction of indole derivative with aldehyde in the presence of Lewis acid generally gives bis-indolylmethane.13 Even though alkynes are weak nucleophiles as compared to indole, the intramolecular tethering favors the trapping with an alkyne. Having the optimized conditions for the synthesis of ketone 11 in hand, attention was turned toward studying the substrate scope. Initial efforts focused on the use of aldehydes bearing different electronic substitutions. The reaction was found to be generally efficient with electron-rich aldehydes as well as aldehydes with halide substitutions, and corresponding N-fused indole derivatives 11b−e, 11h were obtained in good yield and diastereoselectivity. The yield and diastereoselectivity for the formation of the ketone 11f was found to drop when an aldehyde bearing an electron-withdrawing substituent was used. N-Fused indole derivatives 11g, 11i with pyrene and heteroaryl substitutions were synthesized in good yield and diastereoselectivity (Scheme 3). Subsequently, we investigated the scope of the method by varying the substituents on the indole ring. Typically, the indole nucleophiles with a variety of substituents such as Ph, Cy, iPr at the third position of indole gave corresponding pyrrolo[1,2-a]indoles 11j−n in good yield, while a trace of pyrrolo[1,2-a]indole 11o was obtained with OMe at the fifth position of indole. Next, the effect of the nature of the aryl group attached to the alkyne was examined. An electron-rich aryl group on the alkyne worked efficiently and furnished the N-fused indole derivatives 11p−s in good yield and diastereoselectivity. When a strong electron-withdrawing group such as a nitro group was used as a substituent, exclusive formation of triaryl methane derivative 12 was observed. This observation could be attributed to the presence of a nitro aryl group on the alkyne making the latter

b

Isolated yield of

much more electron-deficient and thus reducing its nucleophilicity. As a result, intermolecular trapping of the indol-2-yl cation with another molecule of indole becomes faster than intramolecular trapping with an electron-deficient alkyne. Formation of triaryl methane was not observed in any other case. It is pertinent to mention that, in the case of propargylindole having tethered alcohol 8j, corresponding pyrrolo indole derivatives 11t−u were obtained in good yield without the addition of benzyl alcohol. This example involves an initial oxa-Pictet− Spengler reaction followed by the generation of the indol-2-yl cation. It is also pertinent to mention that the compounds 11t−u possess the core of the putative structure of yuremamine (4). In all the cases, the stereochemistry of the major stereoisomer was assigned using coupling constants, which was further unambiguously confirmed by single crystal X-ray diffraction studies on Nfused indole derivatives 11b−d, 11h.14 During the hydrolysis of the vinyl triflate derivatives 10a, it was observed that prolonging the reaction time led to the isomerization of cis-isomer cis-11a to the more stable transisomer trans-11a (Scheme 4). This indicates that cis-11a is a product of the kinetic pathway of the hydrolysis reaction and isomer trans-11a is a thermodynamic product. Next, we attempted the reaction of secondary propargylindole 13 with p-tolualdehyde (9a) under optimized conditions. Interestingly, while the use of TMSOTf as a Lewis acid resulted in decomposition, the use of the milder Cu(OTf)2 resulted in the formation of pyrrolo indole 14 (Scheme 5). A similar outcome was observed when the tertiary propargyl indole 15 was used and the pyrrolo indole 16 was obtained with a higher yield. This clearly indicates that this system can give divergent reaction 5407

DOI: 10.1021/acs.orglett.7b02680 Org. Lett. 2017, 19, 5406−5409

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Organic Letters Scheme 4. Synthesis of trans-Isomer of Pyrrolo[1,2-a]indole

Scheme 7. Scope of Synthesis of Pyrrolizino-quinolines

Scheme 5. Reaction of Secondary and Tertiary Propargylindoles

quinolines 18f−h in excellent yield. Thus, this method delivers a rapid, high yielding access to pharmaceutically important pyrrolizino-quinolines. In order to showcase the utility of the method, the N-fused indole derivative 11c was converted to hexacyclic skeleton 19 with a linear aza-triquinane embedded in it and in excellent yield and diastereoselectivity, after using a reduction-Friedel−Craft reaction sequence (Scheme 8). In another direction, dearoma-

outcomes when subtle deviations in the conformational preferences of propargylindoles 8, 13, and 15 are present. To further expand the scope of the method, we examined aldehydes which have a nucleophilic group, so that a nucleophile will trap the vinyl cation generated during the course of reaction. Thus, when indole derivative 8a was subjected to reaction with salicylaldehyde (9j) in the presence of TMSOTf, a series of cascade reactions such as Friedel−Craft reaction/alkyne indol-2yl cation cyclization/vinyl cation trapping with phenolic −OH and attack of benzyl alcohol on oxonium ion generated under acidic conditions ensued and indolochroman 17 was obtained in good yield (Scheme 6). It is interesting to note that the obtained

Scheme 8. Functionalization of Pyrrolo[1,2-a]indoles

Scheme 6. Synthesis of Core of Revised Structure of Yuremamine (5) tization of pyrroloindole trans-11t in the presence of an iodonium salt and Cu(OTf)2 gave a tetracyclic structure possessing an angularly fused aza-oxa-triquinane 20.15 From a mechanistic point of view, the present cascade Friedel−Craft/alkyne indol-2-yl cation cyclization/vinyl cation trapping can be rationalized as depicted in Scheme 9. In particular, the initial activation of the aldehyde 9 by benzyl

indolochroman 17 is the core of the revised structure of yuremamine (5). This example highlights the versatility of the method, as by simply changing the tethering of the nucleophile, the developed method can be tuned to give access to the core of the putative as well as the revised structure of yuremamine. After successfully synthesizing the core of yuremamine (5), 2azidobenzaldehyde 9ka was used as an aldehyde partner in the cascade process. To our delight, 2-azidobenzaldehyde 9ka when subjected to reaction with propargyl indole derivative 8a in the presence of benzyl alcohol and TMSOTf furnished the pyrrolizino-quinoline 18a in excellent yield (Scheme 7). The generality of this pyrrolizino-quinoline synthesis was studied briefly. In the case of propargyl indoles 8b, 8k, 8h, and 8f having an aromatic ring at the third position of indole, mild electrondeficient and electron-rich alkyne partners reacted with 2azidobenzaldehyde 9ka under optimized conditions to give the corresponding pyrrolizino-quinoline derivatives 18b−e in excellent yield. Electron-rich as well as electron-deficient 2azidobenzaldehyde 9kb−9kd gave corresponding pyrrolizino-

Scheme 9. Possible Mechanism

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DOI: 10.1021/acs.orglett.7b02680 Org. Lett. 2017, 19, 5406−5409

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Organic Letters

(8) For review, see: (a) Palmieri, A.; Petrini, M.; Shaikh, R. R. Org. Biomol. Chem. 2010, 8, 1259. (b) Wang, L.; Chen, Y.; Xiao, J. Asian J. Org. Chem. 2014, 3, 1036. (c) Mei, G.-J.; Shi, F. J. Org. Chem. 2017, 82, 7695. For selected examples of reactions on the indol-3-yl cation, see: (d) Harisson, C.-A.; Leineweber, R.; Moody, C. J.; Williams, J. M. J. Tetrahedron Lett. 1993, 34, 8527. (e) Yokosaka, T.; Nakayama, H.; Nemoto, T.; Hamada, Y. Org. Lett. 2013, 15, 2978. (f) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593. (g) Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.; Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett. 2009, 11, 4620. (h) Sun, F.-L.; Zeng, M.; Gu, Q.; You, S.-L. Chem. - Eur. J. 2009, 15, 8709. (i) Wang, D.-S.; Tang, J.; Zhou, Y.-G.; Chen, M.-W.; Yu, C.-B.; Duan, Y.; Jiang, G.-F. Chem. Sci. 2011, 2, 803. (j) Gong, W.; Liu, Y.; Zhang, J.; Jiao, Y.; Xue, J.; Li, Y. Chem. - Asian J. 2013, 8, 546. (k) Zhuo, M.-H.; Jiang, Y.-J.; Fan, Y.-S.; Gao, Y.; Liu, S.; Zhang, S. Org. Lett. 2014, 16, 1096. (l) Follet, E.; Berionni, G.; Mayer, P.; Mayr, H. J. Org. Chem. 2015, 80, 8643. (m) Fan, T.; Zhang, H.-H.; Li, C.; Shen, Y.; Shi, F. Adv. Synth. Catal. 2016, 358, 2017. (n) Santhini, P. V.; Chand, S. S.; John, J.; Varma, R. L.; Jaroschik, F.; Radhakrishnan, K. V. Synlett 2017, 28, 951. (9) For reactions on indol-2-yl cation, see: (a) Kutney, J. P.; Beck, J.; Bylsma, F.; Cretney, W. J. J. Am. Chem. Soc. 1968, 90, 4504. (b) Pearson, W. H.; Fang, W.-K.; Kampf, J. W. J. Org. Chem. 1994, 59, 2682. (c) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137. (d) Vallakati, R.; May, J. A. J. Am. Chem. Soc. 2012, 134, 6936. (e) Qi, S.; Liu, C.-Y.; Ding, J.-Y.; Han, F.-S. Chem. Commun. 2014, 50, 8605. (f) Li, H.; Li, X.; Wang, H.-Y.; Winston-McPherson, G. N.; Geng, H.-M. J.; Guzei, I. A.; Tang, W. Chem. Commun. 2014, 50, 12293. (g) Feldman, K. S.; Gonzalez, I. Y.; Glinkerman, C. M. J. Am. Chem. Soc. 2014, 136, 15138. (h) Dhiman, S.; Ramasastry, S. S. V. Chem. Commun. 2015, 51, 557. (i) Liu, C.-Y.; Han, F.-S. Chem. Commun. 2015, 51, 11844. (j) Dhiman, S.; Mishra, U. K.; Ramasastry, S. S. V. Angew. Chem., Int. Ed. 2016, 55, 7737. (10) (a) Dethe, D. H.; Boda, R.; Das, S. Chem. Commun. 2013, 49, 3260. (b) Chiarucci, M.; Matteucci, E.; Cera, G.; Fabrizi, G.; Bandini, M. Chem. - Asian J. 2013, 8, 1776. (c) Wang, T.; Shi, S.; Pflasterer, D.; Rettenmeier, E.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Chem. Eur. J. 2014, 20, 292. (d) Sun, X.-X.; Li, C.; He, Y.-Y.; Zhu, Z.-Q.; Mei, G.-J.; Shi, F. Adv. Synth. Catal. 2017, 359, 2660. (11) (a) Gharpure, S. J.; Prasath, V. J. Chem. Sci. 2011, 123, 943. (b) Gharpure, S. J.; Prasath, V.; Kumar, V. Chem. Commun. 2015, 51, 13623. (c) Gharpure, S. J.; Shelke, Y. G.; Kumar, D. P. Org. Lett. 2015, 17, 1926. (12) For selected examples of vinyl cation trapping, see: (a) Lolkema, L. D. M.; Hiemstra, H.; Semeyn, C.; Speckamp, W. N. Tetrahedron 1994, 50, 7115. (b) Metais, E.; Overman, L. E.; Rodriguez, M. I.; Stearns, B. A. J. Org. Chem. 1997, 62, 9210. (c) Chavre, S. N.; Choo, H.; Lee, J. K.; Pae, A. N.; Kim, Y.; Cho, Y. S. J. Org. Chem. 2008, 73, 7467. (d) Xu, T.; Yu, Z.; Wang, L. Org. Lett. 2009, 11, 2113. (e) Yeh, M.-C. P.; Liang, C.-J.; Fan, C.-W.; Chiu, W.-H.; Lo, J.-Y. J. Org. Chem. 2012, 77, 9707. (f) Jin, T.; Himuro, M.; Yamamoto, Y. Angew. Chem., Int. Ed. 2009, 48, 5893. (g) Jin, T.; Himuro, M.; Yamamoto, Y. J. Am. Chem. Soc. 2010, 132, 5590. (h) Jin, T.; Uchiyama, J.; Himuro, M.; Yamamoto, Y. Tetrahedron Lett. 2011, 52, 2069. (13) Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Chem. Rev. 2010, 110, 2250. (14) CCDC 1564356−1564360 for compounds 11b−d, 11h, and 20 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. (15) Liu, C.; Zhang, W.; Dai, L.-X.; You, S.-L. Org. Lett. 2012, 14, 4525.

alcohol and TMSOTf triggers the Friedel−Craft reaction of indole 8 on oxonium ion 21. An extended iminium ion, i.e. indol2-yl cation 7′, generated after elimination of alcohol from indolyl methanol derivative 22, is trapped with the tethered alkyne giving rise to vinyl cation 23. The trapping of the vinyl cation, either intermolecularly with a counteranion of a Lewis acid or intramolecularly with a nucleophile attached to aldehyde, furnishes the functionalized N-fused indole derivative 10, 17, and 18. In summary, we have established a novel and an efficient protocol for the stereoselective synthesis of N-fused indole derivatives using cascade Friedel−Craft/alkyne indol-2-yl cation cyclization/vinyl cation trapping sequence. This study represents the first example in which alkyne is used as a nucleophile for indol-2-yl cation trapping. The utility of this process has been demonstrated in the synthesis of hexacyclic and tetracyclic motifs bearing heteroatom-substituted linear and angular triquinane.

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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.7b02680. Synthetic procedures and characterization data of products (PDF) Crystallographic data for 11b−d, 11h, and 20 (ZIP)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Santosh J. Gharpure: 0000-0002-6653-7236 Yogesh G. Shelke: 0000-0003-3157-1159 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank BRNS, Mumbai, CSIR and SERB, New Delhi for financial support. We thank Mr. Darshan Mhatre of the X-ray facility of the Department of Chemistry, IIT Bombay for collecting the crystallographic data and IRCC, IIT Bombay for funding. We are grateful to CSIR, New Delhi for the award of research fellowships to Y.G.S.

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DEDICATION Dedicated to Professor S. Sankararaman, IIT Madras on the occasion of his 60th birthday. REFERENCES

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DOI: 10.1021/acs.orglett.7b02680 Org. Lett. 2017, 19, 5406−5409