Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Enantioselective Cyclization of 3‑Allenylindoles: Access to Functionalized Tetrahydrocarbazoles Christian P. Grugel and Bernhard Breit* Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertrstr. 21, Freiburg 79104, Germany
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S Supporting Information *
ABSTRACT: A highly selective rhodium-catalyzed cyclization of tethered 3-allenylindoles is reported. In a smooth reaction, 1-vinyltetrahydrocarbazoles are obtained in excellent yields and enantioselectivities. Aside from a great functional group tolerance, this method requires neither the Schlenk technique nor the use of anhydrous solvents. Preliminary mechanistic investigations proved that the reaction proceeds via an intermediary formed spiroindolenine which rapidly undergoes an acid-catalyzed stereospecific migration.
T
Scheme 1. Transition-Metal Catalyzed Strategies for the Synthesis of Enantioenriched 1-Vinyltetra-hydrocarbazoles
he indole framework represents one of the most widely distributed structural features among heteroaromatic compounds in nature.1 Given their widespread occurrence in biologically active agents, tetrahydrocarbazoles (THCs) represent an important subclass among indole-based natural products (Figure 1) as they constitute key features in many alkaloids.2
Figure 1. Selected tetrahydrocarbazole (THC) natural products and structurally related alkaloids.
In this fashion, Bandini and co-workers recently reported on an allylic alkylation of allylic alcohols by means of a bimetallic gold cataylst.5 The You group then progressed on the initial concept and developed a strategy for an iridium-catalyzed dearomatization of indoles to obtain 5-membered spiroindolenines. Moreover, they observed a stereospecific migration of
For this, selective functionalizations of indoles have drawn the attention of synthetic organic chemists for many years. In this respect, various groups aimed at a selective synthesis of the tetrahydrocarbazole core. Among different strategies, such as Friedel−Crafts type arylations,3 a powerful tool for their synthesis is represented by intramolecular allylic substitution reactions from 3-functionalized indoles (Scheme 1).4 © XXXX American Chemical Society
Received: May 16, 2019
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DOI: 10.1021/acs.orglett.9b01721 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
this intermediate to the corresponding 1-vinyltetrahydrocarbazole upon exposure to catalytic amounts of a Brønstedt acid.4c,6 Despite their respective synthetic utility and their excellent stereoelectivities, these methods represent allylic substitution reactions and thus violate the principle of atom economy7 by releasing stoichiometric amounts of a side product in the course of the reaction. Throughout the last years, we reported on a series of intermolecular rhodium-catalyzed chemo-, regio-, and enantioselective coupling reactions involving allenes8,9 and alkynes10,11 as allylic electrophile precursors with various pronucleophiles, thus establishing a more atom-economic alternative to the classic allylic alkylation. Meanwhile, we were also able to expand this methodology toward asymmetric intramolecular transformations.12 Addressing this strive for sustainability, Liu and Wiedenhoefer similarly developed a gold(I)-catalyzed strategy that allowed for the intramolecular hydroarylation of allenes.13 However, despite its synthetic elegance, this method is rather limited with respect to a synthetic applicability as only Nmethylindoles could serve as nucleophiles and terminal allenes mostly provided the cyclization product only in moderate enantioselectivies. That being stated, we sought to disclose a more general, convenient approach toward functionalized tetrahydrocarbazoles by making use of our previously developed rhodium-based strategy. Combined with the findings of the You group that 5-membered spiroindolenines rapidly undergo a stereospecific rearrangement to the isomeric 1-vinyltetrahydrocarbazoles,6b we envisioned to develop a tandem spirocyclization/stereospecific migration procedure starting from readily available, tethered 3-allenylindoles. Herein, we report our preliminary results. We initiated our investigations by drafting 3-allenylindole 1a as the model substrate for the envisioned cyclization. In an initial attempt with 2.5 mol % [Rh(cod)Cl]2 and 7.5 mol % rac-BINAP (L1) in the presence of 50 mol % pyridinium 4toluenesulfonate (PPTS) as weakly acidic cocatalyst, the desired vinyl tetrahydrocarbazole 2a was already formed in an excellent yield of 89% (Table 1, entry 1). With this outcome in hand, we subsequently sought to examine the potential for a development of an enantioselective version thereof. In light of the high structural diversity of commercially available and, thus, easily accessible ligands with axial chirality, we examined a variety of members of this family for their capability to catalyze the given transformation enantioselectively. To our delight, by making use of (R)-BINAP (L2), tetrahydrocarbazole 2a was already formed in a quite promising enantiomeric ratio of 77:23 (entry 2). Unfortunately, the reaction’s enantioselectivity remained almost unaffected when changing the axial chiral backbone from BINAP to MeO-BIPHEP (L3) or Segphos (L4)-type ligands (entries 3 and 4). In light of this outcome, we envisioned to increase the enantioselectivity of the present cyclization by selectively modifying the substituents at the ligands’ phosphine moiety. However, more bulky (R)-Tol-BINAP (L5, entry 5) and (R)-DM-BINAP (L6, entry 6) showed similar or only slightly better results than (R)-BINAP. The same held for (R)-DMSegphos (L7), which promoted the product formation in a marginally higher er but at the cost of isolated yield of tetrahydrocarbazole 2a. Gratifyingly, by increasing the steric bulk even further by implementing DTBM aryls in the ligand (L8), not only was the excellent reactivity maintained, but also 2a formed in a drastically improved er of 97:3. Finally, we also
entry
ligand
yieldb/%
erc
1 2 3 4 5 6 7 8 9d
rac-BINAP (L1) (R)-BINAP (L2) (R)-MeOBiphep (L3) (R)-Segphos (L4) (R)-Tol-BINAP (L5) (R)-DM-BINAP (L6) (R)-DM-Segphos (L7) (S)-DTBM-Segphos (L8) (R)-DTBM-Segphos (L8)
89 89 90 98 92 83 81 99 93
77:23 71.5:28.5 62:38 80:20 32.5:26.5 70:30 97:3 (−) 97.5:2.5
a
Reaction conditions: 1a (0.2 mmol), [Rh(cod)Cl]2 (2.5 mol %), ligand (7.5 mol %), PPTS (50 mol %), DCE (1.0 mL), 40 °C, 16 h. b Isolated yields. cDetermined by chiral HPLC. dReaction performed in DCM.
could replace the toxic solvent 1,2-dichloroethane (DCE) for more benign DCM without negatively affecting the outcome of the reaction (entry 9). With these optimized conditions in hand, we sought to examine the reaction scope (Scheme 2). In this respect, we subjected a variety of differently substituted indoles to the indicated reaction conditions. Halogen-bearing substrates reacted smoothly and furnished the desired 1-vinyltetrahydrocarbazoles 2b−e in excellent yields and enantioselectivities. Notably, even an iodidesubstituted indole could be implemented in the catalysis without observing any side reactions stemming from a potential oxidative addition of the Rh(I) catalyst into the C(sp2)-I bond as 2e was obtained in almost quantitative yield and 98:2 er. Indoles with electron-rich residues, such as methoxy groups (2f−h) or alkyl groups (2i−j) were also found to be excellent coupling partners as the reaction provided the desired cyclized products in excellent yields and enantioselectivities regardless of the respective substitution pattern. On the other hand, electron-withdrawing groups such as nitrile (2k) or nitro groups (2l) were also well tolerated in this cyclization. Next, we examined the influence of different tethers which link the indole and the allene part (Scheme 3). In this respect, we exchanged methyl malonate for its ethyl (2m), iso-propyl (2n), and tert-butyl (2o) analogues, all of which provided the desired tetrahydrocarbazoles smoothly in a clean reaction almost quantitatively and up to 99:1 er. In order to highlight the mildness of the present protocol, we subjected a potentially acid-sensitive acetal 2p to the reaction conditions. To our delight, no deprotection occurred during the catalysis as 2p was isolated in 98% yield and 93.5:6.5 er. Additionally, malononitrile (2q) also proved to be a decent tether, as did benzoylacetonitrile (2r). B
DOI: 10.1021/acs.orglett.9b01721 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Reaction Scopea
Table 2. Demonstration of the Reaction’s Robustness and Convenience for the Conversion of 1a to 2aa entry
modifications to the general procedure
yield/%
er
1 2 3 4 5 6
1 mol % [Rh], 3 mol % ligand 20 mol % PPTS analytical grade DCM (stab. with amylene) no flame drying no Schlenk technique, only Ar-balloon aerobic conditions
95 94 95 94 86 n.r.
98:2 96:4 97.5:2.5 97:3 97.5:2.5
a
See Table 1.
1) resulted in essentially the same outcome as lowering the amount of PPTS (entry 2). Performing the reaction in (neither anhydrous nor degassed) analytical grade DCM or waive previous flame-drying procedures also showed comparable results (entries 3 and 4). Interestingly, using the Schlenk technique is also not required even though the corresponding yield of the cyclization product is slightly compromised (entry 5). However, rapid catalyst decomposition was observed upon a reaction under aerobic conditions, most likely owing to ligand oxidation (entry 6). With this reduced catalyst loading (Table 2, entry 1), we perfomed the cyclization of 1d on a gram scale and were able to isolate 1.14 g of tetrahydrocarbazole 2d in an enantiomeric ratio of 95.5:4.5, thus highlighting the synthetic utility of this protocol (Scheme 4). a
Reaction conditions: 1 (0.2 mmol), [Rh(cod)Cl]2 (2.5 mol %), ligand (7.5 mol %), PPTS (50 mol %), DCM (1.0 mL), 40 °C, 16 h. All yields given as isolated yields. The absolute configuration of the tetrahydrocarbazoles 2 was assigned as (S) by means of a crystal structure analysis of 2d. For details, see the Supporting Information.
Scheme 4. Gram-Scale Catalysis
Scheme 3. Reaction Scope (Continued)a
In order to prove our initial assumption of an intermediary formed spiroindolenine 3, we performed in situ NMR monitoring experiments and were able to observe the formation (and consumption) of 3a.14 Furthermore, by stopping the reaction after 15 min, we could isolate the aspired intermediate 3a in 44% yield with a 9:1 dr and 99:1 er, which clearly indicates that the present rhodium-catalyzed intramolecular hydroarlyation of allenes proceeds via an initial alkylation of the (more nucleophilic) 3-position followed by a stereospecific migration rather than a direct allylation of the 2position (Scheme 5). On the basis of these observations and previous studies of this catalytic system,15 we propose the following mechanism for this transformation (Scheme 6). After initial catalyst preformation from [Rh(cod)Cl]2 and (R)-DTBM-Segphos Scheme 5. Isolation of Sprioindolenine Intermediate 3a
a
Reaction conditions: 1 (0.2 mmol), [Rh(cod)Cl]2 (2.5 mol %), ligand (7.5 mol %), PPTS (50 mol %), DCM (1.0 mL), 40 °C, 16 h. All yields given as isolated yields. [b] Reaction performed at 30 °C.
In order to demonstrate the robustness and convenience of the reaction, we performed several experiments under certain perturbations to the initial reaction conditions (Table 2). Reducing the amount of rhodium precatalyst and ligand (entry C
DOI: 10.1021/acs.orglett.9b01721 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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Scheme 6. Proposed Reaction Mechanism
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Bernhard Breit: 0000-0002-2514-3898 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the DFG and the Fonds der Chemischen Industrie. C.P.G. is grateful for a Ph.D. fellowship from the Fonds der Chemischen Industrie. Dr. Manfred Keller and Dr. Daniel Kratzert (both from the University of Freiburg) are acknowledged for providing highly qualified NMR measurements and X-ray crystal structure analyses. Technical support by Gamze Ciplak and Joshua Emmerich (both from the University of Freiburg), specifically for laboratory assistance and HPLC separations, is acknowledged.
(L8), a rhodium(III) hydride complex A is generated upon reaction with PPTS,16 followed by a hydrometalation of the allene moiety in 1 to give the allylrhodium(III) intermediate B. Subsequent nucleophilic attack of the indole at its C3-position releases the spirocycle 3 in its protonated form, while simultaneously regenerating the Rh(I) catalyst. This observed regioselectivity is explicable by the greater nucleophilicity at the C3-position compared to C2, despite its increased steric hindrance.6b The spiroindoleneine 3 then undergoes an acidcatalyzed stereospecific migration, after which the better migrating group (higher lying HOMO of the migrating σbond) is attached to C2 of the indole scaffold. Finally, elimination of HX then releases the 1-vinyltetrahydrocarbazole 2. To conclude, we have accomplished a highly enantioselective tandem spirocyclization/stereospecific migration starting from tethered, readily available 3-allenylindoles. The reaction proceeds with perfect atom economy and only requires low loadings of a commercially available catalyst. The mildness of the present protocol is exemplified by a great functional group tolerance. Further investigations regarding the expansion of this method to alkynes as coupling partners or other heteroatom-based tethers as well as its application in synthesis will be the objective of future research in our laboratories.
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REFERENCES
(1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: London, 1970. (b) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996. (c) Dewick, P. M., Ed. Medicinal Natural Products: A Biosynthetic Approach; Wiley: New York, 2002. (d) Fattorusso, E., Scafati, O. T., Eds. Modern Alkaloids; Wiley-VCH: Weinheim, 2008. (2) For a review on the significance of tetrahydrocarbazole natural products, see: Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303. (3) For selected review articles on Friedel−Crafts-type reactions with indoles, see: (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. (c) Zeng, M.; You, S.-L. Synlett 2010, 2010, 1289. (4) For selected reviews on allylic alkylation, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (b) Falciola, C. A.; Alexakis, A. Eur. J. Org. Chem. 2008, 2008, 3765. (c) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47, 2558. (d) Butt, N. A.; Zhang, W. Chem. Soc. Rev. 2015, 44, 7929. (e) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. ACS Catal. 2016, 6, 6207. (5) (a) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424. (b) Bandini, M.; Eichholzer, A. Angew. Chem. 2009, 121, 9697;(c) Angew. Chem., Int. Ed. 2009, 48, 9533. (d) Cera, G.; Crispino, P.; Monari, M.; Bandini, M. Chem. Commun. 2011, 47, 7803. (e) Bandini, M.; Gualandi, A.; Monari, M.; Romaniello, A.; Savoia, D.; Tragni, M. J. Organomet. Chem. 2011, 696, 338. (6) (a) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418. (b) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem. 2012, 124, 1712;(c) Angew. Chem., Int. Ed. 2012, 51, 1680. (7) Trost, B. M. Science 1991, 254, 1471. (8) For a recent review, see: Koschker, P.; Breit, B. Acc. Chem. Res. 2016, 49, 1524. (9) For examples of C−C bond formation, see: (a) Li, C.; Breit, B. J. Am. Chem. Soc. 2014, 136, 862. (b) Beck, T. M.; Breit, B. Angew. Chem. 2017, 129, 1929;(c) Angew. Chem., Int. Ed. 2017, 56, 1903. (d) Grugel, C. P.; Breit, B. Org. Lett. 2018, 20, 1066. (e) Bora, P. P.; Sun, G.-J.; Zheng, W.-F.; Kang, Q. Chin. J. Chem. 2018, 36, 20. (f) Grugel, C. P.; Breit, B. Chem. - Eur. J. 2018, 24, 15223. (10) For a recent review, see: Haydl, A. M.; Breit, B.; Liang, T.; Krische, M. J. Angew. Chem. 2017, 129, 11466; Angew. Chem., Int. Ed. 2017, 56, 11312. (11) For examples of C−C bond formation, see: (a) Beck, T. M.; Breit, B. Org. Lett. 2016, 18, 124. (b) Cruz, F. A.; Chen, Z.; Kurtoic, S. I.; Dong, V. M. Chem. Commun. 2016, 52, 5836. (c) Li, C.; Grugel, C. P.; Breit, B. Chem. Commun. 2016, 52, 5840. (d) Beck, T. M.; Breit, B. Eur. J. Org. Chem. 2016, 2016, 5839. (e) Cruz, F. A.; Dong, V. M. J.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01721. Experimental procedures and analytical data for the synthesized compounds, including 1H and 13C NMR spectra (PDF) Accession Codes
CCDC 1899363 and 1909597 contain 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
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. D
DOI: 10.1021/acs.orglett.9b01721 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Am. Chem. Soc. 2017, 139, 1029. (f) Cruz, F. A.; Zhu, Y.; Tercenio, Q. D.; Shen, Z.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 10641. (12) For recent examples on rhodium-catalyzed diastereo- and enantioselective cyclizations with allenes, see: (a) Haydl, A. M.; Berthold, D.; Spreider, P. A.; Breit, B. Angew. Chem. 2016, 128, 5859; Angew. Chem. Int. Ed. 2016, 55, 5765. (b) Ganss, S.; Breit, B. Angew. Chem. 2016, 128, 9890; Angew. Chem. Int. Ed. 2016, 55, 9738. (c) Spreider, P. A.; Haydl, A. M.; Heinrich, M.; Breit, B. Angew. Chem. 2016, 128, 15798; Angew. Chem., Int. Ed. 2016, 55, 15569. (d) Steib, P.; Breit, B. Angew. Chem. 2018, 130, 6682; Angew. Chem., Int. Ed. 2018, 57, 6572. (e) Schmidt, J. P.; Breit, B. Chem. Sci. 2019, 10, 3074. (13) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935. (14) For details, see the Supporting Information. (15) Gellrich, U.; Meißner, A.; Steffani, A.; Kähny, M.; Drexler, H.J.; Heller, D.; Plattner, D. A.; Breit, B. J. Am. Chem. Soc. 2014, 136, 1097. (16) Sulfonic acids are known for their ability to generate [Rh]−H species. For recent literature in this field, see: Yang, Y.; Moschetta, E. G.; Rioux, R. M. ChemCatChem 2013, 5, 3005.
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DOI: 10.1021/acs.orglett.9b01721 Org. Lett. XXXX, XXX, XXX−XXX
