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DOI: 10.1039/C4CC06929C
Graphical Abstract
Minyoung Kim, Neeraj Kumar Mishra, Jihye Park, Sangil Han, Youngmi Shin, Satyasheel Sharma, Youngil Lee, Eui-Kyung Lee, Jong Hwan Kwak and In Su Kim*
H H H
N H
O H
cat. Pd(TFA)2 (NH4)2S2O8 DCE, 80 oC O R HO O
oxidation
N
N R
OO
Ph
R
OO
Ph
C7-acylated indoles
30 examples up 85% yield
The palladium-catalyzed decarboxylative acylation of highly substituted indolines with αketo acids via C–H bond activation is described.
ChemComm Accepted Manuscript
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Decarboxylative acylation of indolines with α-keto acids under palladium catalysis: facile strategy to 7-substituted indoles
Journal Name
ChemComm
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DOI: 10.1039/C4CC06929C
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ARTICLE TYPE
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Minyoung Kim,a Neeraj Kumar Mishra,a Jihye Park,a Sangil Han,a Youngmi Shin,a Satyasheel Sharma,a Youngil Lee,b Eui-Kyung Lee,a Jong Hwan Kwaka and In Su Kim*,a 5
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x The palladium-catalyzed decarboxylative acylation of highly substituted indolines with α-keto acids via C–H bond activation is described. This protocol provides efficient access to C7-carbonylated indoles known to have diverse biological profiles. Since the pioneering works of Myers1 and Goossen,2 the transition-metal-catalyzed decarboxylative cross-coupling reactions using carboxylic acids, such as aryl, alkenyl and alkynyl surrogates, have emerged as one of the most attractive tools for the formation of C–C and C–heteroatom bonds in organic synthesis.3 Recently, the decarboxylative cross-coupling reactions on a sp3-hybridized carbon were also reported.4 However, decarboxylative acylations using α-keto acids are relatively less explored. For instance, Goossen et al. first described the Pd/Cucatalyzed decarboxylative acylation reaction of aryl bromides with α-keto carboxylate salts as acyl equivalents to afford diaryl ketones.5 Shortly thereafter, Ge and coworkers demonstrated an elegant result on the palladium-catalyzed decarboxylative acylation of acetanilides6a and phenylpyridines6b with αoxocarboxylic acids as acyl sources via C–H bond activation. Guo and Duan reported the palladium-catalyzed decarboxylative coupling between cyclic enamides and α-oxocarboxylic acids to afford β-keto enamides.7 Inspired by these works, our group has developed the decarboxylative acylation reactions of aromatic C– H bonds with various directing groups, e.g., ketoximes,8a phenylacetamides,8b and O-phenylcarbamates,8c with α-keto acids. Later, some literatures on the directing group-assisted decarboxylative acylations of aldoximes,9a anilides,9b benzoic acids,9c azobenzenes,9d,e azoxybenzenes,9f and 9g phenoxypyridines were also reported. In addition, a mild silvercatalyzed acylarylation of acrylamides with α-oxocarboxylic acids was described via a tandem decarboxylative radical cyclization strategy.10 The 7-acylated indoles are ubiquitous structural motifs found in a number of natural and synthetic molecules.11 With the development of catalytic C–H bond functionalization, it has become the most straightforward protocol leading to acylated indoles. In general, acylation of indoles occurs preferentially at the more electron-rich C3-position due to the premier site for electrophilic substitution. The traditional methods for the This journal is © The Royal Society of Chemistry [year]
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synthesis of 3-acylindoles are Friedel-Crafts reactions,12 Vilsmeier-Haack reactions,13 and the reaction of indoles with nitrilium14 or N-(α-haloacyl)-pyridinium salts15 (Scheme 1). The other protocols include the Ru- or Fe-catalyzed C3carbonylations of indoles with anilines as carbonyl equivalents,16 the Pd-catalyzed addition of indoles to nitriles,17 and the Cumediated decarboxylative acylation of indolic C3-position with αoxocarboxylic acids.18 The common routes to 2-aroylindoles involve the direct addition of acyl electrophiles into the 2lithioindole species19 or the Pd-catalyzed tandem cyclization reactions.20 Recently, the directing group-assisted catalytic C2acylations of indoles using aldehydes21 or α-keto acids22 have been an intensive research area to override the inherent selectivity of indoles. However, to the best of our knowledge, there has been no previous report on catalytic C–H acylation at the C7-position of indoles. Herein, we described a facile approach for the C7selective decarboxylative C–H acylation of indolines with αoxocarboxylic acids.23 Notably, the formed C7-aroylated indolines can be readily converted to C7-aroylated indoles under the oxidative conditions.
Scheme 1 Pd-catalyzed C7-acylation of indolines.
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Our investigation was initiated by exploring the coupling of 1(indolin-1-yl)ethanone (1a) and 2-oxo-2-phenylacetic acid (2a). After extensive screening of reaction conditions, we found that Pd(TFA)2 catalyst efficiently catalyzed the coupling of 1a and 2a in the presence of (NH4)2S2O8 as an external oxidant in DCE solvent at 80 oC to afford our desired product 3a in 65% yield, as shown in Table 1 (see ESI for the details). However, pivaloyl or [journal], [year], [vol], 00–00 | 1
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Decarboxylative acylation of indolines with α-keto acids under palladium catalysis: facile strategy to 7-substituted indoles
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noted that the bromo moiety of 3j remained intact during the course of the reaction, providing the opportunity for further transformation on the product. This reaction was also compatible with C2- or C3-substituted indolines 1k–1p furnishing the corresponding products 3k–3p in high yields. In addition, Nbenzolylated carbazole 1q participated in the decarboxylative acylation reaction to provide 3q with slightly decreased reactivity under the present reaction conditions. We were pleased to observe C7-acylation of C6-substituted indolines 1r and 1s, which provided the corresponding products 3r and 3s in 49% and 34% yields, respectively. Table 3 Scope of α-keto acidsa
a
Table 1 Screening of directing groups
O +
N H
O 1e
Pd(TFA)2 (5 mol %)
R
HO O
Ph
DCE, 80 oC, 15 h
2b-2m
MeO
X
OO
Cl Ph
OO
Table 2 Scope of indolinesa
4k, 66%
4e, 75%
N OO
N Ph
OO
4i, 79%
N OO
S
OO
Ph
4j, 57%
N Ph
Ph
F3C
4f, 85% (X = Me) 4g, 81% (X = F) 4h, 81% (X = NO2)
With the optimized reaction conditions in hand, the scope and limitations of N-benzoylated indolines were examined (Table 2).
OO
4c, 68% (X = Br) 4d, 82% (X = F)
N
Reaction conditions: 1a–1g (0.2 mmol), 2a (0.3 mmol), Pd(TFA)2 (5 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 oC for 15 h in sealed tubes. b Yield isolated by column chromatography.
N Ph
X 4b, 78%
Ph
OO
N Ph
OO
a
R
4b-4m, %b
N
15
N
(NH4)2S2O8 (200 mol %)
N Ph
4l, 30% (43%)c
Me
OO
Ph
4m, 15%
a 40
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a
Reaction conditions: 1e and 1e–1s (0.2 mmol), 2a (0.3 mmol), Pd(TFA)2 (5 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 oC for 15 h in sealed tubes. b Yield isolated by column chromatography.
Indolines 1h–1j with substitutents (OMe, Cl and Br) on aromatic ring was found to be favoured in the decarboxylative C7-acylation reaction to afford the desired products 3h–3j with an excellent level of regioselectivity in high yields. It should be
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Reaction conditions: 1e (0.2 mmol), 2b–2m (0.3 mmol), Pd(TFA)2 (5 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 oC for 15 h in sealed tubes. b Yield isolated by column chromatography. c 2l (0.6 mmol), (NH4)2S2O8 (300 mol %), 20 h.
To further explore the substrate scope and limitations of this process, a broad range of α-keto acids under the standard reaction conditions was screened, as shown in Table 3. The coupling of indoline 1e and phenylglyoxylic acids 2b–2i with electrondonating and electron-withdrawing groups (MeO, Me, Br, Cl, F, CF3 and NO2), regardless of the position of the substituent on the aromatic ring, affording the corresponding products 4b–4i in high yields. The halogen moieties on phenylglyoxylic acids were all tolerated under the present reaction conditions. This transformation also showed good reactivity toward naphthalenyl oxoacetic acids 2j and 2k. In addition, 2-oxo-2-(thiophen-2yl)acetic acid (2l) was also found to be favoured in the decarboxylative acylation reaction to afford the desired product 4l with slightly decreased reactivity. However, aliphatic α-keto acid 2m underwent the decarboxylative acylation in low yield. Next, we investigated a large-scale experiment to highlight the robustness and practicality of this transformation. Thus one-pot transformation was performed to provide 7-acylated indole 5a in 62% isolated yield via the decarboxylative acylation followed by oxidation using DDQ (Scheme 2). This journal is © The Royal Society of Chemistry [year]
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N,N-dimethylcarbamoyl directing groups were found to be far less effective in the C7-acylation of indolines under identical reaction conditions. Moreover, pyrimidinyl-protected indoline 1d did not deliver the corresponding product. Interestingly, Nbenzoylated indolines 1e–1g displayed high reactivity to afford our desired C7-aroylated products 3e–3g. It is noteworthy to mention that the ortho-C–H bonds in N-benzoyl groups were untouched, although they were found to be reactive in C–H funtionalization protocols.24 The regioselectivity of this reaction was further confirmed by removing N-benzoyl units of 3e–3g in ethanolic KOH solution to give C7-benzoylated free-(NH)indoline 5b.
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Scheme 2 One-pot scale-up experiment for the formation of 7-acylated indoles.
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To demonstrate the further transformation of C7-acylated indolines, a removal of N-benzoyl protection group of 3e under standard hydrolysis conditions was first subjected to give free(NH)-indoline 5b in 81% yield (Scheme 3, Eq. 1). Finally, we sought to explore the possibility of performing sequential C–H functionalization, wherein a newly installed functional group would serve as the directing group for an additional C–H activation (Scheme 3, Eq. 2). Thus, we performed the olefination of 3a with n-butyl acrylate under ruthenium catalysis25 to afford product 5c in 45% isolated yield with a high regioselectivity. The starting material 3a was recovered in 38% yield. Though the conversion yield is low, a slower reaction rate can be expected presumably due to the nonproductive multidentate coordination of the substrate with Ru catalyst.
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Scheme 3 Synthetic transformations of C7-acylated indolines. 20
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A plausible reaction mechanism is outlined in Scheme 4. First, a coordination of 1e to Pd(II) catalyst and the subsequent cyclopalladation at the indolinic C7-position provides a 6membered palladacycle I, which reacts with 2a to afford dimeric Pd(III) or Pd(IV) intermediate II along with decarboxylation.9a,d,e Finally, 7-acylated indoline 3e is formed by reductive elimination, and meanwhile a Pd(II) sepecies is regenerated to complete the catalytic cycle. Alternatively, the reaction mechanism involving a Pd(0/II) catalytic cycle cannot be excluded.6,8,9g
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Scheme 4 Plausible reaction mechanism.
This journal is © The Royal Society of Chemistry [year]
In conclusion, we disclosed the palladium-catalyzed decarboxylative acylation of highly substituted indolines with αoxocarboxylic acids as acyl sources. These transformations have been applied to a wide range of substrates, and allow the generation of an array of C7-acylated indoles, which are known to be crucial scaffolds of biologically active compounds. Further applications of this method to the preparation of bioactive compounds and a detailed mechanistic study are currently underway. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2013R1A2A2A01005249)
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a
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Fax: 82 31 292 8800; Tel: 82 31 290 7788; E-mail: [email protected] b Department of Chemistry, University of Ulsan, Ulsan 680-749, Republic of Korea † Electronic Supplementary Information (ESI) available: Experimental procedures and spectroscopic data for all compounds. See DOI: 10.1039/b000000x/ 1 (a) A. G. Myers, D. Tanaka and M. R. Mannion, J. Am. Chem. Soc., 2002, 124, 11250; (b) D. Tanaka, S. P. Romeril and A. G. Myers, J. Am. Chem. Soc., 2005, 127, 10323. 2 (a) L. J. Goossen, G. J. Deng and L. M. Levy, Science, 2006, 313, 662; (b) L. J. Goossen, N. Rodríguez, B. Melzer, C. Linder, G. J. Deng and L. M. Levy, J. Am. Chem. Soc., 2007, 129, 4824; (c) L. J. Goossen, N. Rodríguez and C. Linder, J. Am. Chem. Soc., 2008, 130, 15248; (d) L. J. Goossen, N. Rodríguez, P. P. Lange and C. Linder, Angew. Chem., Int. Ed., 2010, 49, 1111. 3 For selected reviews, see: (a) O. Baudoin, Angew. Chem., Int. Ed., 2007, 46, 1373; (b) L. J. Goossen, N. Rodríguez and K. Goossen, Angew. Chem., Int. Ed., 2008, 47, 3100; (c) T. Satoh and M. Miura, Synthesis, 2010, 3395; (d) J. D. Weaver, A. Recio III, A. J. Grenning and J. A. Tunge, Chem. Rev., 2010, 111, 1846; (e) N. Rodríguez and L. J. Goossen, Chem. Soc. Rev., 2011, 40, 5030; (f) J. Cornella and I. Larrosa, Synthesis, 2012, 44, 653; (g) W. I. Dzik, P. P. Lange and L. J. Goossen, Chem. Sci., 2012, 3, 2671. 4 For selected examples, see: (a) T. Tsuda, M. Tokai, T. Ishida and T. Saegusa, J. Org. Chem., 1986, 51, 421; (b) T. Tsuda, M. Tokai, T. Ishida and T. Saegusa, J. Org. Chem., 1986, 51, 5216; (c) R. Shang, Y. Fu, J.-B. Li, S.-L. Zhang, Q.-X. Guo and L. Liu, J. Am. Chem. Soc., 2009, 131, 5738. 5 L. J. Goossen, F. Rudolphi, C. Oppel and N. Rodríguez, Angew. Chem., Int. Ed., 2008, 47, 3043. 6 (a) P. Fang, M. Li and H. Ge, J. Am. Chem. Soc., 2010, 132, 11898; (b) M. Li and H. Ge, Org. Lett., 2010, 12, 3464. 7 H. Wang, L.-N. Guo and X.-H. Duan, Org. Lett., 2012, 14, 4358. 8 (a) M. Kim, J. Park, S. Sharma, A. Kim, E. Park, J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun., 2013, 49, 925; (b) J. Park, M. Kim, S. Sharma, E. Park, A. Kim, S. H. Lee, J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun., 2013, 49, 1654; (c) S. Sharma, A. Kim, E. Park, J. Park, M. Kim, J. H. Kwak, S. H. Lee, Y. H. Jung and I. S. Kim, Adv. Synth. Catal., 2013, 355, 667. 9 (a) Z. Yang, X. Chen, J. Liu, Q. Gui, K. Xie, M. Li and Z. Tan, Chem. Commun., 2013, 49, 1560; (b) S. Sharma, I. A. Khan and A. K. Saxena, Adv. Synth. Catal., 2013, 355, 673; (c) J. Miao and H. Ge, Org. Lett., 2013, 15, 2930; (d) H. Li, P. Li, H. Tan and L. Wang, Chem.–Eur. J., 2013, 19, 14432; (e) Z.-Y. Li, D.-D. Li and G.-W. Wang, J. Org. Chem., 2013, 78, 10414; (f) H. Li, P. Li, Q. Zhao and L. Wang, Chem. Commun., 2013, 49, 9170; (g) J. Yao, R. Feng, Z. Wu, Z. Liu and Y. Zhang, Adv. Synth. Catal., 2013, 355, 1517. 10 H. Wang, L.-N. Guo and X.-H. Duan, Adv. Synth. Catal., 2013, 355, 2222.
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ChemComm Accepted Manuscript
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11 (a) K. Mahmood, M. Pais, C. Fontaine, H. M. Ali, A. H. A. Hadi and E. Gulttet, Tetrahedron Lett., 1993, 34, 1795; (b) D. R. Beukes, M. T. Davies-Coleman, M. Kelly-Borges, M. K. Harper and D. J. Faulkner, J. Nat. Prod., 1998, 61, 699; (c) B. Meseguer, D. Alonso-Díaz, N. Griebenow, T. Herget and H. Waldmann, Angew. Chem., Int. Ed., 1999, 38, 2902; (d) C. B. Hartline, E. A. Harden, S. L. Williams-Aziz, N. L. Kushner, R. J. Brideau and E. R. Kern, Antiviral Res., 2005, 65, 97; (e) Z. Wang and R. Vince, Bioorg. Med. Chem., 2008, 16, 3587; (f) C. Ma, X. Yang, H. Kandemir, M. Mielczarek, E. B. Johnston, R. Griffith, N. Kumar and P. J. Lewis, ACS Chem. Biol., 2013, 8, 1972. 12 (a) R. J. Sundberg, The Chemistry of Indoles, Academic Press, New York, 1970; (b) O. Ottoni, A. de V. F. Neder, A. K. B. Dias, R. P. A. Cruz and L. B. Aquino, Org. Lett., 2001, 3, 1005; (c) S. K. Guchhait, M. Kashyap and H. Kamble, J. Org. Chem., 2011, 76, 4753. 13 (a) R. A. Heacock and S. Kasparek, Advances in Heterocyclic Chemistry, Eds.: A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1969, pp. 43; (b) J. Bergman and L. Venemalm, Tetrahedron Lett., 1987, 28, 3741. 14 S. C. Eyley, R. G. Giles and H. Heaney, Tetrahedron Lett., 1985, 26, 4649. 15 J. Bergman, J.-E. Bäckvall and J.-O. Lindström, Tetrahedron, 1973, 29, 971. 16 (a) W. Wu and W. Su, J. Am. Chem. Soc., 2011, 133, 11924; (b) L.-T. Li, J. Huang, H.-Y. Li, L.-J. Wen, P. Wang and B. Wang, Chem. Commun., 2012, 48, 5187; (c) J. Chen, B. Liu, D. Liu, S. Liu and J. Cheng, Adv. Synth. Catal., 2012, 354, 2438. 17 Y. Ma, J. You and F. Song, Chem.–Eur. J., 2013, 19, 1189. 18 L. Yu, P. Lia and L. Wang, Chem. Commun., 2013, 49, 2368. 19 (a) M. Saulnier and G. Gribble, J. Org. Chem., 1982, 47, 757; (b) A. R. Katritzky and K. Akutagawa, Tetrahedron Lett., 1985, 26, 5935. 20 (a) M. Ishikura and M. Terashima, J. Org. Chem., 1994, 59, 2634; (b) R. Soley, F. Albericio and M. Alvarez, Synthesis, 2007, 1559; (c) M. Arthuis, R. Pontikis and J. C. Florent, Org. Lett., 2009, 11, 4608. 21 B. Zhou, Y. Yang and Y. Li, Chem. Commun., 2012, 48, 5163. 22 C. Pan, H. Jin, X. Liu, Y. Cheng and C. Zhu, Chem. Commun., 2013, 49, 2933. 23 For catalytic C7-arylation of indolines, see: (a) D. Kalyani, N. R. Deprez, L. V. Desai and M. S. Sanford, J. Am. Chem. Soc., 2005, 127, 7330; (b) Z. Shi, B. Li, X. Wan, J. Cheng, Z. Fang, B. Cao, C. Qin and Y. Wang, Angew. Chem., Int. Ed., 2007, 46, 5554; (c) T. Nishikata, A. R. Abela, S. Huang and B. H. Lipshutz, J. Am. Chem. Soc., 2010, 132, 4978; (d) L.-Y. Jiao and M. Oestreich, Chem.–Eur. J., 2013, 19, 10845; (e) S. De, S. Ghosh, S. Bhunia, J. A. Sheikh and A. Bisai, Org. Lett., 2012, 14, 4466; For catalytic C7-olefination of indolines, see: (f) L.-Y. Jiao and M. Oestreich, Org. Lett., 2013, 15, 5374; (g) Z. Song, R. Samanta and A. P. Antonchick, Org. Lett., 2013, 15, 5662; For catalytic C7-alkylation of indolines, see: (h) S. Pan, S. Ryu and T. Shibata, Adv. Synth. Catal., 2014, 356, 929; For catalytic C7-amidation of indolines, see: (i) C. Pan, A. Abdukader, J. Han, Y. Cheng and C. Zhu, Chem.–Eur. J., 2014, 20, 3606. 24 For selected examples, see: (a) M. Kim, S. Sharma, N. K. Mishra, S. Han, J. Park, M. Kim, Y. Shin, J. H. Kwak, S. H. Han and I. S. Kim, Chem. Commun., 2014, 50, 11303; (b) J. Park, E. Park, A. Kim, Y. Lee, K.-W. Chi, J. H. Kwak, Y. H. Jung and I. S. Kim, Org. Lett., 2011, 13, 4390. 25 For a selected example on Ru-catalyzed C–H olefination of arenes containing a ketone directing group, see: P. Kishor and M. Jeganmohan, Org. Lett., 2011, 13, 6144.
This journal is © The Royal Society of Chemistry [year]
ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: I. S. Kim, M. Kim, N. K. Mishra, J. Park, S. Han, Y. Shin, S. Sharma, Y. Lee, E. Lee and J. H. Kwak, Chem. Commun., 2014, DOI: 10.1039/C4CC06929C.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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DOI: 10.1039/C4CC06929C
Graphical Abstract
Minyoung Kim, Neeraj Kumar Mishra, Jihye Park, Sangil Han, Youngmi Shin, Satyasheel Sharma, Youngil Lee, Eui-Kyung Lee, Jong Hwan Kwak and In Su Kim*
H H H
N H
O H
cat. Pd(TFA)2 (NH4)2S2O8 DCE, 80 oC O R HO O
oxidation
N
N R
OO
Ph
R
OO
Ph
C7-acylated indoles
30 examples up 85% yield
The palladium-catalyzed decarboxylative acylation of highly substituted indolines with αketo acids via C–H bond activation is described.
ChemComm Accepted Manuscript
Published on 25 September 2014. Downloaded by University of Windsor on 29/09/2014 16:06:03.
Decarboxylative acylation of indolines with α-keto acids under palladium catalysis: facile strategy to 7-substituted indoles
Journal Name
ChemComm
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DOI: 10.1039/C4CC06929C
Cite this: DOI: 10.1039/c0xx00000x
ARTICLE TYPE
www.rsc.org/xxxxxx
Minyoung Kim,a Neeraj Kumar Mishra,a Jihye Park,a Sangil Han,a Youngmi Shin,a Satyasheel Sharma,a Youngil Lee,b Eui-Kyung Lee,a Jong Hwan Kwaka and In Su Kim*,a 5
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x The palladium-catalyzed decarboxylative acylation of highly substituted indolines with α-keto acids via C–H bond activation is described. This protocol provides efficient access to C7-carbonylated indoles known to have diverse biological profiles. Since the pioneering works of Myers1 and Goossen,2 the transition-metal-catalyzed decarboxylative cross-coupling reactions using carboxylic acids, such as aryl, alkenyl and alkynyl surrogates, have emerged as one of the most attractive tools for the formation of C–C and C–heteroatom bonds in organic synthesis.3 Recently, the decarboxylative cross-coupling reactions on a sp3-hybridized carbon were also reported.4 However, decarboxylative acylations using α-keto acids are relatively less explored. For instance, Goossen et al. first described the Pd/Cucatalyzed decarboxylative acylation reaction of aryl bromides with α-keto carboxylate salts as acyl equivalents to afford diaryl ketones.5 Shortly thereafter, Ge and coworkers demonstrated an elegant result on the palladium-catalyzed decarboxylative acylation of acetanilides6a and phenylpyridines6b with αoxocarboxylic acids as acyl sources via C–H bond activation. Guo and Duan reported the palladium-catalyzed decarboxylative coupling between cyclic enamides and α-oxocarboxylic acids to afford β-keto enamides.7 Inspired by these works, our group has developed the decarboxylative acylation reactions of aromatic C– H bonds with various directing groups, e.g., ketoximes,8a phenylacetamides,8b and O-phenylcarbamates,8c with α-keto acids. Later, some literatures on the directing group-assisted decarboxylative acylations of aldoximes,9a anilides,9b benzoic acids,9c azobenzenes,9d,e azoxybenzenes,9f and 9g phenoxypyridines were also reported. In addition, a mild silvercatalyzed acylarylation of acrylamides with α-oxocarboxylic acids was described via a tandem decarboxylative radical cyclization strategy.10 The 7-acylated indoles are ubiquitous structural motifs found in a number of natural and synthetic molecules.11 With the development of catalytic C–H bond functionalization, it has become the most straightforward protocol leading to acylated indoles. In general, acylation of indoles occurs preferentially at the more electron-rich C3-position due to the premier site for electrophilic substitution. The traditional methods for the This journal is © The Royal Society of Chemistry [year]
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synthesis of 3-acylindoles are Friedel-Crafts reactions,12 Vilsmeier-Haack reactions,13 and the reaction of indoles with nitrilium14 or N-(α-haloacyl)-pyridinium salts15 (Scheme 1). The other protocols include the Ru- or Fe-catalyzed C3carbonylations of indoles with anilines as carbonyl equivalents,16 the Pd-catalyzed addition of indoles to nitriles,17 and the Cumediated decarboxylative acylation of indolic C3-position with αoxocarboxylic acids.18 The common routes to 2-aroylindoles involve the direct addition of acyl electrophiles into the 2lithioindole species19 or the Pd-catalyzed tandem cyclization reactions.20 Recently, the directing group-assisted catalytic C2acylations of indoles using aldehydes21 or α-keto acids22 have been an intensive research area to override the inherent selectivity of indoles. However, to the best of our knowledge, there has been no previous report on catalytic C–H acylation at the C7-position of indoles. Herein, we described a facile approach for the C7selective decarboxylative C–H acylation of indolines with αoxocarboxylic acids.23 Notably, the formed C7-aroylated indolines can be readily converted to C7-aroylated indoles under the oxidative conditions.
Scheme 1 Pd-catalyzed C7-acylation of indolines.
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Our investigation was initiated by exploring the coupling of 1(indolin-1-yl)ethanone (1a) and 2-oxo-2-phenylacetic acid (2a). After extensive screening of reaction conditions, we found that Pd(TFA)2 catalyst efficiently catalyzed the coupling of 1a and 2a in the presence of (NH4)2S2O8 as an external oxidant in DCE solvent at 80 oC to afford our desired product 3a in 65% yield, as shown in Table 1 (see ESI for the details). However, pivaloyl or [journal], [year], [vol], 00–00 | 1
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Decarboxylative acylation of indolines with α-keto acids under palladium catalysis: facile strategy to 7-substituted indoles
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DOI: 10.1039/C4CC06929C
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noted that the bromo moiety of 3j remained intact during the course of the reaction, providing the opportunity for further transformation on the product. This reaction was also compatible with C2- or C3-substituted indolines 1k–1p furnishing the corresponding products 3k–3p in high yields. In addition, Nbenzolylated carbazole 1q participated in the decarboxylative acylation reaction to provide 3q with slightly decreased reactivity under the present reaction conditions. We were pleased to observe C7-acylation of C6-substituted indolines 1r and 1s, which provided the corresponding products 3r and 3s in 49% and 34% yields, respectively. Table 3 Scope of α-keto acidsa
a
Table 1 Screening of directing groups
O +
N H
O 1e
Pd(TFA)2 (5 mol %)
R
HO O
Ph
DCE, 80 oC, 15 h
2b-2m
MeO
X
OO
Cl Ph
OO
Table 2 Scope of indolinesa
4k, 66%
4e, 75%
N OO
N Ph
OO
4i, 79%
N OO
S
OO
Ph
4j, 57%
N Ph
Ph
F3C
4f, 85% (X = Me) 4g, 81% (X = F) 4h, 81% (X = NO2)
With the optimized reaction conditions in hand, the scope and limitations of N-benzoylated indolines were examined (Table 2).
OO
4c, 68% (X = Br) 4d, 82% (X = F)
N
Reaction conditions: 1a–1g (0.2 mmol), 2a (0.3 mmol), Pd(TFA)2 (5 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 oC for 15 h in sealed tubes. b Yield isolated by column chromatography.
N Ph
X 4b, 78%
Ph
OO
N Ph
OO
a
R
4b-4m, %b
N
15
N
(NH4)2S2O8 (200 mol %)
N Ph
4l, 30% (43%)c
Me
OO
Ph
4m, 15%
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a
Reaction conditions: 1e and 1e–1s (0.2 mmol), 2a (0.3 mmol), Pd(TFA)2 (5 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 oC for 15 h in sealed tubes. b Yield isolated by column chromatography.
Indolines 1h–1j with substitutents (OMe, Cl and Br) on aromatic ring was found to be favoured in the decarboxylative C7-acylation reaction to afford the desired products 3h–3j with an excellent level of regioselectivity in high yields. It should be
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Reaction conditions: 1e (0.2 mmol), 2b–2m (0.3 mmol), Pd(TFA)2 (5 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 oC for 15 h in sealed tubes. b Yield isolated by column chromatography. c 2l (0.6 mmol), (NH4)2S2O8 (300 mol %), 20 h.
To further explore the substrate scope and limitations of this process, a broad range of α-keto acids under the standard reaction conditions was screened, as shown in Table 3. The coupling of indoline 1e and phenylglyoxylic acids 2b–2i with electrondonating and electron-withdrawing groups (MeO, Me, Br, Cl, F, CF3 and NO2), regardless of the position of the substituent on the aromatic ring, affording the corresponding products 4b–4i in high yields. The halogen moieties on phenylglyoxylic acids were all tolerated under the present reaction conditions. This transformation also showed good reactivity toward naphthalenyl oxoacetic acids 2j and 2k. In addition, 2-oxo-2-(thiophen-2yl)acetic acid (2l) was also found to be favoured in the decarboxylative acylation reaction to afford the desired product 4l with slightly decreased reactivity. However, aliphatic α-keto acid 2m underwent the decarboxylative acylation in low yield. Next, we investigated a large-scale experiment to highlight the robustness and practicality of this transformation. Thus one-pot transformation was performed to provide 7-acylated indole 5a in 62% isolated yield via the decarboxylative acylation followed by oxidation using DDQ (Scheme 2). This journal is © The Royal Society of Chemistry [year]
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N,N-dimethylcarbamoyl directing groups were found to be far less effective in the C7-acylation of indolines under identical reaction conditions. Moreover, pyrimidinyl-protected indoline 1d did not deliver the corresponding product. Interestingly, Nbenzoylated indolines 1e–1g displayed high reactivity to afford our desired C7-aroylated products 3e–3g. It is noteworthy to mention that the ortho-C–H bonds in N-benzoyl groups were untouched, although they were found to be reactive in C–H funtionalization protocols.24 The regioselectivity of this reaction was further confirmed by removing N-benzoyl units of 3e–3g in ethanolic KOH solution to give C7-benzoylated free-(NH)indoline 5b.
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Scheme 2 One-pot scale-up experiment for the formation of 7-acylated indoles.
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To demonstrate the further transformation of C7-acylated indolines, a removal of N-benzoyl protection group of 3e under standard hydrolysis conditions was first subjected to give free(NH)-indoline 5b in 81% yield (Scheme 3, Eq. 1). Finally, we sought to explore the possibility of performing sequential C–H functionalization, wherein a newly installed functional group would serve as the directing group for an additional C–H activation (Scheme 3, Eq. 2). Thus, we performed the olefination of 3a with n-butyl acrylate under ruthenium catalysis25 to afford product 5c in 45% isolated yield with a high regioselectivity. The starting material 3a was recovered in 38% yield. Though the conversion yield is low, a slower reaction rate can be expected presumably due to the nonproductive multidentate coordination of the substrate with Ru catalyst.
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Scheme 3 Synthetic transformations of C7-acylated indolines. 20
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A plausible reaction mechanism is outlined in Scheme 4. First, a coordination of 1e to Pd(II) catalyst and the subsequent cyclopalladation at the indolinic C7-position provides a 6membered palladacycle I, which reacts with 2a to afford dimeric Pd(III) or Pd(IV) intermediate II along with decarboxylation.9a,d,e Finally, 7-acylated indoline 3e is formed by reductive elimination, and meanwhile a Pd(II) sepecies is regenerated to complete the catalytic cycle. Alternatively, the reaction mechanism involving a Pd(0/II) catalytic cycle cannot be excluded.6,8,9g
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Scheme 4 Plausible reaction mechanism.
This journal is © The Royal Society of Chemistry [year]
In conclusion, we disclosed the palladium-catalyzed decarboxylative acylation of highly substituted indolines with αoxocarboxylic acids as acyl sources. These transformations have been applied to a wide range of substrates, and allow the generation of an array of C7-acylated indoles, which are known to be crucial scaffolds of biologically active compounds. Further applications of this method to the preparation of bioactive compounds and a detailed mechanistic study are currently underway. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2013R1A2A2A01005249)
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School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Fax: 82 31 292 8800; Tel: 82 31 290 7788; E-mail: [email protected] b Department of Chemistry, University of Ulsan, Ulsan 680-749, Republic of Korea † Electronic Supplementary Information (ESI) available: Experimental procedures and spectroscopic data for all compounds. See DOI: 10.1039/b000000x/ 1 (a) A. G. Myers, D. Tanaka and M. R. Mannion, J. Am. Chem. Soc., 2002, 124, 11250; (b) D. Tanaka, S. P. Romeril and A. G. Myers, J. Am. Chem. Soc., 2005, 127, 10323. 2 (a) L. J. Goossen, G. J. Deng and L. M. Levy, Science, 2006, 313, 662; (b) L. J. Goossen, N. Rodríguez, B. Melzer, C. Linder, G. J. Deng and L. M. Levy, J. Am. Chem. Soc., 2007, 129, 4824; (c) L. J. Goossen, N. Rodríguez and C. Linder, J. Am. Chem. Soc., 2008, 130, 15248; (d) L. J. Goossen, N. Rodríguez, P. P. Lange and C. Linder, Angew. Chem., Int. Ed., 2010, 49, 1111. 3 For selected reviews, see: (a) O. Baudoin, Angew. Chem., Int. Ed., 2007, 46, 1373; (b) L. J. Goossen, N. Rodríguez and K. Goossen, Angew. Chem., Int. Ed., 2008, 47, 3100; (c) T. Satoh and M. Miura, Synthesis, 2010, 3395; (d) J. D. Weaver, A. Recio III, A. J. Grenning and J. A. Tunge, Chem. Rev., 2010, 111, 1846; (e) N. Rodríguez and L. J. Goossen, Chem. Soc. Rev., 2011, 40, 5030; (f) J. Cornella and I. Larrosa, Synthesis, 2012, 44, 653; (g) W. I. Dzik, P. P. Lange and L. J. Goossen, Chem. Sci., 2012, 3, 2671. 4 For selected examples, see: (a) T. Tsuda, M. Tokai, T. Ishida and T. Saegusa, J. Org. Chem., 1986, 51, 421; (b) T. Tsuda, M. Tokai, T. Ishida and T. Saegusa, J. Org. Chem., 1986, 51, 5216; (c) R. Shang, Y. Fu, J.-B. Li, S.-L. Zhang, Q.-X. Guo and L. Liu, J. Am. Chem. Soc., 2009, 131, 5738. 5 L. J. Goossen, F. Rudolphi, C. Oppel and N. Rodríguez, Angew. Chem., Int. Ed., 2008, 47, 3043. 6 (a) P. Fang, M. Li and H. Ge, J. Am. Chem. Soc., 2010, 132, 11898; (b) M. Li and H. Ge, Org. Lett., 2010, 12, 3464. 7 H. Wang, L.-N. Guo and X.-H. Duan, Org. Lett., 2012, 14, 4358. 8 (a) M. Kim, J. Park, S. Sharma, A. Kim, E. Park, J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun., 2013, 49, 925; (b) J. Park, M. Kim, S. Sharma, E. Park, A. Kim, S. H. Lee, J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun., 2013, 49, 1654; (c) S. Sharma, A. Kim, E. Park, J. Park, M. Kim, J. H. Kwak, S. H. Lee, Y. H. Jung and I. S. Kim, Adv. Synth. Catal., 2013, 355, 667. 9 (a) Z. Yang, X. Chen, J. Liu, Q. Gui, K. Xie, M. Li and Z. Tan, Chem. Commun., 2013, 49, 1560; (b) S. Sharma, I. A. Khan and A. K. Saxena, Adv. Synth. Catal., 2013, 355, 673; (c) J. Miao and H. Ge, Org. Lett., 2013, 15, 2930; (d) H. Li, P. Li, H. Tan and L. Wang, Chem.–Eur. J., 2013, 19, 14432; (e) Z.-Y. Li, D.-D. Li and G.-W. Wang, J. Org. Chem., 2013, 78, 10414; (f) H. Li, P. Li, Q. Zhao and L. Wang, Chem. Commun., 2013, 49, 9170; (g) J. Yao, R. Feng, Z. Wu, Z. Liu and Y. Zhang, Adv. Synth. Catal., 2013, 355, 1517. 10 H. Wang, L.-N. Guo and X.-H. Duan, Adv. Synth. Catal., 2013, 355, 2222.
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