Rhodium‐Catalyzed Synthesis of 2,3‐Disubstituted Indoles from β,β‐Disubstituted Stryryl Azides
2011; Wiley; Volume: 50; Issue: 7 Linguagem: Inglês
10.1002/anie.201006917
ISSN1521-3773
AutoresKe Sun, Sheng Liu, Patryk M. Bec, Tom G. Driver,
Tópico(s)Cyclopropane Reaction Mechanisms
ResumoAngewandte Chemie International EditionVolume 50, Issue 7 p. 1702-1706 CommunicationOpen Access Rhodium-Catalyzed Synthesis of 2,3-Disubstituted Indoles from β,β-Disubstituted Stryryl Azides† Ke Sun, Ke Sun Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverSearch for more papers by this authorSheng Liu, Sheng Liu Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverSearch for more papers by this authorPatryk M. Bec, Patryk M. Bec Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverSearch for more papers by this authorProf. Tom G. Driver, Corresponding Author Prof. Tom G. Driver tgd@uic.edu Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverDepartment of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverSearch for more papers by this author Ke Sun, Ke Sun Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverSearch for more papers by this authorSheng Liu, Sheng Liu Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverSearch for more papers by this authorPatryk M. Bec, Patryk M. Bec Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverSearch for more papers by this authorProf. Tom G. Driver, Corresponding Author Prof. Tom G. Driver tgd@uic.edu Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverDepartment of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago (USA), Fax: (+1) 312-996-0431 http://www.chem.uic.edu/driverSearch for more papers by this author First published: 14 January 2011 https://doi.org/10.1002/anie.201006917Citations: 141 † We are grateful to the National Institutes of Health NIGMS (R01M984945) and the University of Illinois at Chicago for their generous support. We also thank Prof. L. Anderson (UIC) for insightful discussions. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract Rings à la carte: Rhodium carboxylate complexes catalyze selective cascade reactions to produce a range 2,3-disubstituted indoles from β,β-disubstituted stryryl azides. The selective migration of aryl groups appears to originate from a putative phenonium ion reactive intermediate (see scheme). Transition metal-catalyzed migratorial processes that form new carbon–carbon bonds can enable the formation of complex products from readily accessible, simple starting materials. Controlling the selectivity of the migration step is critical to the success of these transformations.1 Sequential reaction processes that involve metal nitrenes are rare despite their electrophilicity,2 which enables reaction with carbon–hydrogen bonds or olefins.3–6 Our mechanistic study of rhodium(II)-catalyzed carbazole formation from biaryl azides which suggested that CN bond formation preceded CH bond cleavage through a 4π-electron–5-atom electrocyclization.7 Consequently, we anticipated that substrates lacking functionalizable CH bonds might participate in a migratorial process where a new CC bond is formed in addition to the CN bond. In support of this hypothesis, rhodium octanoate catalyzed the conversion of β,β-diphenylstryryl azide 1 to 2,3-diphenylindole 3 (Scheme 1).8 This result, however, does not indicate whether this process can be rendered selective for styryl azides 4 that contain two different β-substituents to form 2,3-disubstituted indoles. Because these N-heterocycles are important pharmaceutical scaffolds,9 new methods, which streamline their synthesis, remain an ongoing goal.10, 11 Herein, we report our initial studies that resulted in the development of a general method to form 2,3-disubstituted indoles—as single regioisomers—from readily available β,β-disubstituted stryryl azides. Scheme 1Open in figure viewerPowerPoint Potential for selective 2,3-disubstituted indole formation. The effect of transition metal complexes on the desired migration was investigated using a mixture of the E- and Z-isomer of β,β-disubstituted aryl azide 8 (Table 1). This azide is readily accessible in two steps from commercially available 2-nitrobenzaldehyde.12 Examination of a range of dirhodium(II) complexes revealed that selective formation of 9 was obtained using with [Rh2(O2CC3F7)4],8, 13 [Rh2(O2CC7H15)4], or [Rh2(esp)2]14 (Table 1, entries 1–7).15 Importantly, both the E- and Z-isomer of 8 were converted to indole 9 revealing that the selectivity of the reaction did not depend on the stereochemistry of the starting material. Other rhodium carboxylate complexes provided attenuated selectivities or reduced yields. Other transition metal complexes, such as [(cod)Ir(OMe)2],16 [Co(tpp)],17 RuCl3,18 or copper salts,19 known to decompose azides or π-Lewis acids,20 did not promote indole formation (Table 1, entries 8–13). Consequently, the reaction conditions were further optimized using rhodium hexaflourobutyrate, and incomplete conversions were observed when either the catalyst loading or the reaction temperature was lowered (<5 mol %; 95:5 2 b H MeO H 97 >95:5 3 c H Cl H 99 >95:5 4[c] d H MeO2C H 94 >95:5 5 e H F3C H 90 >95:5 6[d] f H MeO2S H 95 >95:5 7 g H H Br 95 >95:5 8[d] h H H MeO2C 95 >95:5 [a] Yield after Al2O3 chromatography. [b] As determined by using 1H NMR spectroscopy. [c] X-ray structure of product indole obtained. [d] 5 mol % of [Rh2(esp)2] used. The nature of the migrating group on the aryl azide was subsequently investigated (Table 3). For these substrates, only aryl group migration was observed. While rhodium perfluorobutyrate was a competent catalyst, [Rh2(esp)2] provided the highest yields of the reaction. Only indole 15 a was observed when the tether was shortened (Table 3, entry 1). Appending the electron-withdrawing trifluoromethyl group or the electron-donating methoxy group to the migrating arene did not change the outcome of the reaction (Table 3, entries 2 and 3). In both cases, only aryl group migration was observed. High yields and selective formation of indole 15 d was obtained when an oxygen atom was incorporated into the tether. The reaction was not limited to ring expansion: despite changing the electronic nature of the migrating aryl group, only indoles 15 e and 15 f were formed from azides 14 e and 14 f. Table 3. Scope of Rh2II-catalyzed 2,3-disubstituted indole formation. Entry 14, 17 Styryl azide Indole product Yield [%][a] 1 a 88 2 b 78 3 c 92 4 d 94 5 e 91 6 f 93 7 a 98 8 b 93 9 c 93 10 d 18[b,c] 11 e quant. 12 f quant. 13 g 88 14 h 97 [a] Yield after Al2O3 chromatography. [b] As determined by using 1H NMR spectroscopy. [c] 35 % remaining 17 d. DCE=dichloroethane. The effect of ring size on the reaction efficiency was further examined using styryl azides 17. For this series of substrates, rhodium octanoate proved to be the most reliable catalyst. While ring-expanded products were formed from 4-, 5-, and 6-membered substrates, poor conversion was observed for 7-membered 17 d (Table 3, entries 7–10). Varying the electronic nature of the aryl azide did not attenuate the yield of the reaction (Table 3, entries 11–13). Oxygen atoms were tolerated in the tether without lowering the yield of the ring expansion (Table 3, entry 14). While many mechanisms are possible to explain the reaction outcome, our data suggests that the migration occurs once an intermediate (21) is generated with positive charge on the benzylic carbon. We propose that this intermediate is formed by the mechanism outlined in Scheme 2. Coordination of the rhodium carboxylate complex to the azide produces either α-19 or γ-19.21 Extrusion of N2 from 19 forms rhodium nitrene 20,22 which participates in a 4π-electron–5-atom electrocyclization to establish the carbon–nitrogen bond in 21.7 Aryl migration forms the more stable tertiary iminium ion 22, which tautermizes to produce 9. Alternatively, the ortho-double bond could assist in N2 extrusion to form the intermediate 23, or this intermediate could be formed from [2+1] cycloaddition of the pendant double bond with the electrophilic metallonitrene 20. While 23 is strained,23 its intermediacy would account for the enhanced reactivity of azides with unsaturated ortho-substituents. Scheme 2Open in figure viewerPowerPoint Potential mechanisms for indole formation. We performed several experiments to test the validity of our mechanism. To examine whether N2 was lost before CN bond formation, we performed an intermolecular competition experiment between azides 11 a and 8 (Scheme 3). Our previous Hammett correlation study indicated that N2 extrusion occurred faster with electron-rich aryl azides.7 Acceleration of metallonitrene formation was attributed to the ability of the electron-donating group to assist in N2 loss (24 to 25). In contrast, if N2 loss occurred simultaneously with CN bond formation, we anticipated that 8 would react faster because the azide moiety was more electrophilic than in 11 a. To test these assertions, a 1:1 mixture of styryl azides 11 a and 8 were exposed to reaction conditions. Despite the increased steric pressure around the azide, the more electron-rich substrate reacted faster to produce indole 12 a as the major product to support our proposed electrocyclization mechanism. Scheme 3Open in figure viewerPowerPoint Intermolecular competition experiment. If the migration mechanism involved the formation of a partial positive charge on the α-carbon, we anticipated that electron-rich aryl groups would migrate preferentially. To test this hypothesis, a series of styryl azides, which systematically varied the identity of the para-substituent R, were exposed to reaction conditions (Figure 1). Examination of the product ratios using the Hammett equation revealed that the best linear correlation was obtained with σpara values to give a ρ value of −1.49. The greater propensity of the more electron-rich aryl group to participate in the 1,2-shift was interpreted to suggest that the migration occurs through phenonium ion reactive intermediate 30,24, 25 where the more stable ion leads to the major product. Figure 1Open in figure viewerPowerPoint Correlation of product ratios with the Hammett equation. y=−1.49 x+0.17; R2=0.98. In conclusion, we have demonstrated that rhodium carboxylate complexes catalyze cascade reactions of β,β-disubstituted styryl azides to selectively produce 2,3-disubstituted indoles. Our data suggests that the selectivity of the migratorial process is controlled by the formation of a phenonium ion. Future experiments will be aimed at clarifying the mechanism of this reaction as well as determining if the benzylic cation can be intercepted with additional nucleophiles to produce complex, functionalized N-heterocycles from simple, readily available styryl azides. Supporting Information Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Filename Description anie_201006917_sm_miscellaneous_information.pdf11.1 MB miscellaneous_information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1For reviews of migratorial processes, see: 1aB. Crone, S. F. Kirsch, Chem. Eur. J. 2008, 14, 3514; 1bL. E. Overman, L. D. Pennington, J. Org. Chem. 2003, 68, 7143. 2For cascade reactions involving metal nitrenes, see: 2aA. R. Thornton, V. I. Martin, S. B. Blakey, J. Am. Chem. Soc. 2009, 131, 2434; 2bA. R. Thornton, S. B. Blakey, J. Am. Chem. Soc. 2008, 130, 5020. 3For recent reviews, see: 3aF. Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009, 5061; 3bP. Dauban, R. H. Dodd in Amino Group Chemistry (Ed.: ), Wiley-VCH, Weinheim, 2008, p. 55; 3cJ. Du Bois, Chemtracts 2005, 18, 1. 4For reviews of metal nitrenes from azides, see: 4aT. G. 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