Rhodium-Catalyzed, Remote Terminal Hydroarylation of Activated

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Rhodium-Catalyzed, Remote Terminal Hydroarylation of Activated Olefins through a Long-Range Deconjugative Isomerization Arun Jyoti Borah and Zhuangzhi Shi* State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China S Supporting Information *

ABSTRACT: The Rh-catalyzed, remote terminal hydroarylation of active olefins at the C7-position of indoles and the ortho-position of indolines and anilines with the appropriate choice of a N-PtBu2 directing group through long-range deconjugative isomerization has been reported. This transformation not only overcomes the conjugate rule of Michael acceptors but also controls the positional selectivity of indoles, representing a significant advancement in both alkene isomerization and the C−H alkylation of indoles.

T

he remote functionalization of an organic molecule by alkene isomerization (chain walking) along a carbon skeleton has inspired the development of fascinating and innovative synthetic methods.1 To be synthetically useful, the remote-targeted transformation must display high selectivities in terms of both directionality and positional functionalization.2 In this regard, the remote construction of C(sp3)−C(sp2) bonds triggered by alkene isomerization, including the main processes of dehydrogenative Heck3 and hydroarylation4 reactions, has received considerable attention. Some discriminating functional groups such as alcohol,5 aryl,6 ether,7 ester,8 keto, cyano,9 and cyclopropyl10 functionalities far removed from the olefinic moiety can usually serve as the thermodynamic driving force for the chain walking (Figure 1a). Among these groups, double bonds in conjugation with aryl and ether groups gave α-arylation products,6,7 and carboxylate groups form the conjugate addition products.8 Notably, the reactivity of the alkene is typically reduced with increasing polarity of the olefinic moiety, and not surprisingly, most examples only employ electron-rich alkenes. To overcome the tendency to form conjugated species, electron-poor alkenes possessing terminal moieties such as ether11 and alcohol12 that can be derivatized could allow long-range deconjugative isomerizations. In the absence of such groups, the hydroarylation of the activated alkenes at the remote terminal methyl position by deconjugative isomerization with high selectivity is a significant challenge,13 but it would provide access to many useful products. Alkyl-substituted indoles are often found in biologically active compounds, and the development of effective and regioselective methods for the alkylation of indoles at each position has been of great interest to synthetic chemists.14 In 2015, Sigman and co-workers developed a dehydrogenative Heck reaction of trisubstituted, electron-rich alkenes with © 2018 American Chemical Society

Figure 1. Remote arylation induced by chain walking.

indoles to construct quaternary stereocenters remote to a carbonyl by alkene isomerization (Figure 1b).15 As part of our studies toward regioselective C−H functionalization of the benzene core of indoles,16 herein, we report a highly regioselective hydroarylation of simple activated alkenes at the C7-position of indoles via a long-range deconjugative isomerization triggered by a hydrometalation event (Figure 1c). Challenges in this transformation include (i) overcoming the conjugate rule of Michael acceptors with long-range isomerization and (ii) controlling the positional selectivity of the indole. Compared to the traditional 1,4-addition of activated alkenes to indoles at the C3-position (Figure 1d),17 this C−H activation strategy can alter the regioselectivity of both the indoles and alkenes and generate linear alkylindole products at the C7-position. In 2017, our group discovered that monophosphine ligands could undergo direct arylation by a rhodium-catalyzed, tertiary phosphine-directed C−H activation.18 We envisioned that the Received: April 2, 2018 Published: May 4, 2018 6062

DOI: 10.1021/jacs.8b03560 J. Am. Chem. Soc. 2018, 140, 6062−6066

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Journal of the American Chemical Society Table 2. Scope of the Indoles and Indolinea

installation of a tertiary phosphine group at the N atom of an indole may selectively deliver the rhodium center to the C−H bond at the C7-position for the subsequent chain walking. After a systematic evaluation of the reaction parameters of N-PtBu2 indole 1a with methyl (E)-pent-2-enoate (2a), we found that the simple combination of 5 mol % of [Rh(coe)2Cl]2 and 5 mol % of 2,2′-biphenol (L5) in toluene at 120 °C afforded the desired linear product in 91% yield with excellent regioselectivity (Table 1). In the absence of such a ligand, the reaction Table 1. Evaluating the Reaction Parametersa

a

Standard conditions: [Rh(coe)2Cl]2 (5 mol %), ligand (5 mol %), indole (0.20 mmol), and 2a (0.80 mmol) in 0.4 mL of solvent at 120 °C for 24 h under argon. The yields and relative ratios of products were determined by 19F NMR using PhCF3 as an internal standard. b Isolated yield.

a

Reaction conditions: [Rh(coe)2Cl]2 (5 mol %), L5 (5 mol %), 1 (0.20 mmol), and 2a (0.80 mmol) in 0.4 mL of toluene at 120 °C for 24 h under argon; isolated yields are reported.

phosphine directing group on the nitrogen atom has been proven to be a key factor to this reaction (Scheme 1).

suffered from poor yield and selectivity (60%, L/B = 4:1). Other ligands such as L3, L4, and L6 could also play a critical role to secure high reactivity, but L1 and L2 resulted in diminished reactivity. Moreover, indoles bearing N-directing groups, such as pivaloyl and pyrimidyl groups and our formerly reported TBPO ligand, did not provide any hydroarylation product, which confirms the importance of the N-PtBu moiety for achieving both high reactivity and selectivity. With the best reaction conditions in hand, we investigated the scope of this deconjugative addition process using various indoles with 2a (Table 2). Indoles bearing electron-donating substituents including methyl (3ca−3ea), methoxy (3fa−3ga), and phenyl (3ha) groups exclusively underwent the linear alkylation affording the corresponding products in 64−82% yields. Gratifyingly, halogen-containing motifs (3ia−3la) and a boron functionality (3ma) were well-tolerated under the reaction conditions, highlighting the potential of this process in combination with further conventional cross-coupling transformations. Ester (3na) and acyl (3oa) functionalities that may exhibit competing coordination abilities with the rhodium catalyst were also tolerated, and these substrates were converted in moderate yields. Substrates with highly electronwithdrawing groups such as cyano could also afford a 60% yield of corresponding desired product 3pa. In addition, indoline product 3qa from the linear alkylation at the ortho-position was obtained in 61% yield. By switching the catalytic system to [Rh(cod)2]OTf/L3, deconjugative addition of active olefin 2a with N-PtBu protected aniline 4a could be also achieved exclusively at the ortho-position in 65% yields. The presence of a tertiary

Scheme 1. Hydroarylation of Olefin 2a with Aniline 4a

Afterward, we examined this remote arylation event with olefinic substrates with various chain lengths and double-bond positions (Table 3). Excellent regioselectivities were achieved with α,β-unsaturated esters 2b−2e. The methyl (E)-non-2enoate (2e) afforded product 2e in 62% yield via double bond migration over six positions along the chain. Reactions conducted with (E)-hept-3-en-2-one (2f) produced hydroarylation product 3af with a remote keto group. In contrast to nickel-catalyzed migration/arylations, which occur at the benzylic site,6 the hydroarylation of a mixture of cis/trans isomers of β-methylstyrene 2g with our system provided exclusively linear product 3ag in 65% yield.19 The reactions of internal unactivated olefins (2h and 2i) afforded products 3aa (the same as that from olefin 2a) and 3ai in 60−89% yields. The longer the aliphatic chain, the larger the number of positional and geometric isomers that can be formed, and in a rather extreme case, methyl erucate (2j), with more than 20 C, dominant linear product 4aj was obtained in 42% yield by longrange deconjugative isomerization with concomitant formation of a small amount of the branched product.20 It is noted that 6063

DOI: 10.1021/jacs.8b03560 J. Am. Chem. Soc. 2018, 140, 6062−6066

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Journal of the American Chemical Society Table 3. Scope of the Olefins for the Long-Range Deconjugative Isomerizationa

Reaction conditions: 5 mol % of [Rh(coe)2Cl]2, 5 mol % of L5, 1a (0.20 mmol), and 2 (0.80 mmol) in 0.4 mL of toluene at 120 °C for 24 h, Ar atmosphere; isolated yields are reported. The relative ratios of isomers were determined by GC-MS and NMR analyses. b10 mol % of [Rh(coe)2Cl]2, 10 mol % of L6 as ligand, 2 (0.40 mmol). c10 mol % of [Rh(coe)2Cl]2, 10 mol % of L5 at 140 °C for 48 h. a

Preliminary experiments were performed to establish the mechanism of this reaction. This remote hydroarylation process is highly reversible as evidenced by the significant H/D scrambling of indole D-1b (Scheme 3a) and use of 1b in the

the presence of substituents on the conjugated olefin chain such as (E)-methyl-5-methylhex-2-enoate and (E)-benzyl 2-methylbut-2-enoate could not generate the products (not shown in the table). Finally, olefin 2k bearing a cyano group also reacted smoothly to form 3ak and 3ek with complete linear selectivity. The structure of linear hydroarylation product 3ek was unambiguously confirmed by an X-ray crystallographic analysis. Notably, the reaction of indole 1b on a 3.8 mmol scale with olefin 2b could give 3bb in 62% yield, which was further converted to alcohol 6 by a tandem PtBu2 removal and reduction process in 87% yield. Further mesylation and nucleophilic substitution of 7 produced 1,7-annulated system 5 in 77% yield, which is a building block for highly active 5-HT receptor antagonist and potent kinase inhibitors. In addition, the PtBu2 directing group in 3ag could also be removed by simple TsOH·H2O treatment (Scheme 2).

Scheme 3. Mechanistic Experiments

Scheme 2. Synthetic Applications

presence of D2O (Scheme 3b). Deuterium incorporation was observed at all sites on the alkyl chain of the product. Moreover, a kinetic isotopic effect (KIE) of 1.2 was observed from two parallel reactions using 1b and D-1b (Scheme 3c). These results indicate that the C−H bond cleavage may occur before the rate-determining step of the reaction. From the experimental results and literature precedent, we have proposed a mechanistic pathway for this hydroarylation process (Figure 2). The reaction is triggered by the reversible oxidative addition of Rh species A to the C−H bond of the indole at the C7-position forming metallacycle B. The 6064

DOI: 10.1021/jacs.8b03560 J. Am. Chem. Soc. 2018, 140, 6062−6066

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Journal of the American Chemical Society

Talents Plan”, the “Jiangsu Specially-Appointed Professor Plan”, and National Natural Science Foundation of China (Grant 2167020084) for financial support.

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(1) (a) Franzoni, I.; Mazet, C. Org. Biomol. Chem. 2014, 12, 233. (b) Vasseur, A.; Bruffaerts, J.; Marek, I. Nat. Chem. 2016, 8, 209. (c) Vilches-Herrera, V.; Domke, L.; Börner, A. ACS Catal. 2014, 4, 1706. (d) Sommer, H.; Juliá-Hernández, F.; Martin, R.; Marek, I. ACS Cent. Sci. 2018, 4, 153. (2) For some recent examples, see: (a) Kochi, T.; Hamasaki, T.; Aoyama, Y.; Kawasaki, J.; Kakiuchi, F. J. Am. Chem. Soc. 2012, 134, 16544. (b) Obligacion, J. V.; Chirik, P. J. J. Am. Chem. Soc. 2013, 135, 19107. (c) Larionov, E.; Lin, L.; Guénée, L.; Mazet, C. J. Am. Chem. Soc. 2014, 136, 16882. (d) Hamasaki, T.; Aoyama, Y.; Kawasaki, J.; Kakiuchi, F.; Kochi, T. J. Am. Chem. Soc. 2015, 137, 16163. (e) Dupuy, D.; Zhang, K.-F.; Goutierre, A.-S.; Baudoin, O. Angew. Chem., Int. Ed. 2016, 55, 14793. (f) Martínez, J. I.; Smith, J. J.; Hepburn, H. B.; Lam, H. W. Angew. Chem., Int. Ed. 2016, 55, 1108. (g) Juliá-Hernández, F.; Moragas, T.; Cornella, J.; Martin, R. Nature 2017, 545, 84. (h) Chen, F.; Chen, K.; Zhang, Y.; He, Y.; Wang, Y.-M.; Zhu, S. J. Am. Chem. Soc. 2017, 139, 13929. (3) Le Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170. (4) (a) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.; Dong, G. Chem. Rev. 2017, 117, 9333. (b) Huang, G.; Liu, P. ACS Catal. 2016, 6, 809. (c) Crisenza, G. E. M.; Bower, J. F. Chem. Lett. 2016, 45, 2. (5) (a) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science 2012, 338, 1455. (b) Mei, T.-S.; Werner, E. W.; Burckle, A. J.; Sigman, M. S. J. Am. Chem. Soc. 2013, 135, 6830. (c) Mei, T.-S; Patel, H. H.; Sigman, M. S. Nature 2014, 508, 340. (d) Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P.-O.; Wu, Y.-D.; Sigman, M. S.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 1960. (e) Patel, H. H.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 3462. (6) (a) He, Y.; Cai, Y.; Zhu, S. J. Am. Chem. Soc. 2017, 139, 1061. (b) Lee, W.-C.; Wang, C.-H.; Lin, Y.-H.; Shih, W.-C.; Ong, T.-G. Org. Lett. 2013, 15, 5358. (c) Chen, F.; Chen, K.; Zhang, Y.; He, Y.; Wang, Y.-M.; Zhu, S. J. Am. Chem. Soc. 2017, 139, 13929. (d) Lee, W.-C.; Chen, C.-H.; Liu, C.-Y.; Yu, M.-S.; Lin, Y.-H.; Ong, T.-G. Chem. Commun. 2015, 51, 17104. (7) (a) Ebe, Y.; Onoda, M.; Nishimura, T.; Yorimitsu, H. Angew. Chem., Int. Ed. 2017, 56, 5607. (b) Romano, C.; Mazet, C. J. Am. Chem. Soc. 2018, 140, 4743. (8) Ohlmann, D. M.; Goosen, L. J.; Dierker, M. Chem. - Eur. J. 2011, 17, 9508. (9) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 7290. (10) (a) Masarwa, A.; Didier, D.; Zabrodski, T.; Schinkel, M.; Ackermann, L.; Marek, I. Nature 2014, 505, 199. (b) Singh, S.; Bruffaerts, J.; Vasseur, A.; Marek, I. Nat. Commun. 2017, 8, 14200. (11) Wakamatsu, H.; Nishida, M.; Adachi, N.; Mori, M. J. Org. Chem. 2000, 65, 3966. (12) Lin, L.; Romano, C.; Mazet, C. J. Am. Chem. Soc. 2016, 138, 10344. (13) For a linear-selective hydroarylation of unactivated internal olefins with trifluoromethyl-substituted arenes, see: Bair, J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.; Eisenstein, O.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 13098. (14) For some recent examples, see: (a) Xu, L.; Zhang, C.; He, Y.; Tan, L.; Ma, D. Angew. Chem., Int. Ed. 2016, 55, 321. (b) Leitch, J. A.; McMullin, C. L.; Mahon, M. F.; Bhonoah, Y.; Frost, C. G. ACS Catal. 2017, 7, 2616. (15) Zhang, C.; Santiago, C. B.; Crawford, J. M.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 15668. (16) (a) Yang, Y.; Qiu, X.; Zhao, Y.; Mu, Y.; Shi, Z. J. Am. Chem. Soc. 2016, 138, 495. (b) Yang, Y.; Li, R.; Zhao, Y.; Zhao, D.; Shi, Z. J. Am. Chem. Soc. 2016, 138, 8734. (17) Jiang, H.; Paixão, M. W.; Monge, D.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132, 2775.

Figure 2. Proposed catalytic cycle.

remarkable selectivity stems from the formation of a fivemembered metallacycle through C−H bond cleavage at the C7position (B), which is thermodynamically favored over the formation of a four-membered metallacycle at C2 (B′). Then, regioselective reversible insertion of the alkene into the Rh−H bond generates intermediate C, which undergoes iterative βhydride elimination/migratory insertion sequences and eventually generates terminal olefin complex D. Then, terminal hydroarylation of D can produce intermediate E, which, following reductive elimination, generates desired product 3 and reforms catalytic species A. Notably, we found the olefin 2e was only partially isomerized to a mixture with more than five isomers as detected by GC-MS analysis in 24 h without indole. Therefore, the possibility of a tandem olefin isomerization and hydroarylation process can be ruled out as a main pathway.6b In conclusion, we have developed an effective system for remote terminal hydroarylation of activated olefins by rhodium catalysis. With the aid of a sterically hindered and removable NPtBu2 directing group, we could override electronic biases at the indole C3-position and the conjugate reactivity of active olefins to generate the indole C7-alkylation products with excellent regioselectivity. The present results represent an important discovery that is expected to be substantially extended to other systems for long-range deconjugative isomerization processes.

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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/jacs.8b03560. Experimental procedures, characterization data, and spectra of new compounds (PDF) Crystallographic data for 3ek (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Zhuangzhi Shi: 0000-0003-4571-4413 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Mr. Di Wang in our group for reproducing the results of 3la, 3ek, and 5aa. We thank the “1000-Youth 6065

DOI: 10.1021/jacs.8b03560 J. Am. Chem. Soc. 2018, 140, 6062−6066

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Journal of the American Chemical Society (18) (a) Qiu, X.; Wang, M.; Zhao, Y.; Shi, Z. Angew. Chem., Int. Ed. 2017, 56, 7233. For other representative works on P-directed C−H activation, see: (b) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112. (c) Crawford, K. M.; Ramseyer, T. R.; Daley, C. J. A.; Clark, T. B. Angew. Chem., Int. Ed. 2014, 53, 7589. (d) Yang, J.-F.; Wang, R.-H.; Wang, Y.-X.; Yao, W.-W.; Liu, Q.-S.; Ye, M. Angew. Chem., Int. Ed. 2016, 55, 14116. (19) Ilies, L.; Chen, Q.; Zeng, X.; Nakamura, E. J. Am. Chem. Soc. 2011, 133, 5221. (20) (a) Ghebreyessus, K. Y.; Angelici, R. J. Organometallics 2006, 25, 3040. (b) Behr, A.; Obst, D.; Westfechtel, A. Eur. J. Lipid Sci. Technol. 2005, 107, 213. (c) Jimenéz-Rodriguez, C.; Eastham, G. R.; ColeHamilton, D. J. Inorg. Chem. Commun. 2005, 8, 878. (d) JimenézRodriguez, C.; Eastham, G. R.; Cole-Hamilton, D. J. Chem. Commun. 2004, 1720. (e) Quinzler, D.; Mecking, S. Angew. Chem., Int. Ed. 2010, 49, 4306.

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DOI: 10.1021/jacs.8b03560 J. Am. Chem. Soc. 2018, 140, 6062−6066