COMMUNICATION DOI: 10.1002/asia.201301733
IrACHTUNGRE(III)-Catalyzed C7-Position-Selective Oxidative C H Alkenylation of Indolines with Alkenes in Air Shiguang Pan,[a] Takayuki Wakaki,[a] Naoto Ryu,[a] and Takanori Shibata*[a, b]
Abstract: An efficient method for C7-position-selective alkenylation of N-substituted indolines with alkenes is reported. Various 7-alkenylindolines were obtained in moderate to excellent yields in air in the presence of catalytic amounts of [Cp*IrCl2]2, AgOTf, and CuACHTUNGRE(OAc)2. The protocol relies on the use of a carbonyl or carbamoyl group on the nitrogen atom of indoline as a directing group and is potentially applicable to the synthesis of 7-alkenylindoles and 7-alkylindoles.
lyzed C7-alkenylation of indolines, which was followed by oxidation to 7-alkenylindoles in one-pot.[9] In all of these examples, more than stoichiometric amounts of oxidants, such as N-fluoro-2,4,6-trimethylpyridinium triflate ([F + ]), benzoquinone (BQ), and copper acetate, were generally used. Herein, we report the iridiumACHTUNGRE(III)-catalyzed C7-alkenylation of indolines in air using a catalytic amount of copper acetate as a reoxidant and a carbonyl group as a directing group (Scheme 1, bottom). Our recent studies have focused on the development of cationic iridium(I)-catalyzed synthesis initiated by the cleavage of inactive bonds, such as C H, N H, and C O bonds.[10] Recently, we developed a C2-position-selective alkylation of indoles with alkenes using cationic Ir-diphosphine catalysts.[10k] This protocol relies on the use of a carbonyl group on the nitrogen atom of indoles as a directing group. More recently, the C7-position-selective alkylation of indolines was achieved, also with the use of cationic Ir catal-
The indoline skeleton is very important due to its ubiquity in numerous natural products and pharmaceutically important compounds.[1, 2] Thus, atom-economical and green methods for the synthesis of functionalized indoline derivatives have been strongly desired. The installation of desired substituents along with the construction of the indoline skeleton has been a conventional protocol for regioselective synthesis.[3] However, a more straightforward approach is the C H bond functionalization of indoline derivatives. Among the extensive studies over the past decade in which various transition metal catalysts were used,[4] Ru-catalyzed carbonylation and Pd-catalyzed arylation and methylation of indolines at the C7-position have been reported.[5] We also reported a cationic Ir(I)-catalyzed C7-position-selective alkylation of N-substituted indolines with alkenes.[6] By contrast, the C7position-selective C H alkenylation of indolines is a potentially useful transformation and has been a hot topic since 2013: Arrays and Carretero et al. reported the first example of an oxidative C H alkenylation using a Pd catalyst, in which a pyridylsulfonyl group was used as a directing group (Scheme 1, top).[7] Oestreich et al. reported a milder procedure for the Pd-catalyzed C H alkenylation of indolines using N-carbamoyl indolines.[8] While this manuscript was being prepared, Antonchick et al. reported a rhodium-cata[a] Dr. S. Pan, T. Wakaki, N. Ryu, Prof. Dr. T. Shibata Department of Chemistry and Biochemistry Waseda University Shinjuku, Tokyo 169-8555 (Japan) Fax: (+ 81) 3-5286-8098 E-mail: [email protected] [b] Prof. Dr. T. Shibata Japan Science and Technology Agency (JST) 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201301733.
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Scheme 1. Examples of C7-position-selective alkenylation of indolines.
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salt acted as a reoxidant, but the choice of Cu(II) salts was important (entries 6 and 7). Notably, a catalytic amount of NaOAc facilitated the reaction (entry 8). These results suggested that CuACHTUNGRE(OAc)2 acted as a base, which assisted hydrogen abstraction, as well as a reoxidant of the iridium complex.[10e] Furthermore, the reaction of 1 a and 2 a was examined under an oxygen atmosphere, but the yield was slightly decreased (entry 9). We used the conditions in entry 3 for further investigations. With the optimized conditions in hand, we explored the scope of N-substituted indolines (Table 2). First, we examined a variety of carbonyl functionalities on the nitrogen atom of indoline. As a result, the corresponding C7-alkenylated indolines 3 b–3 e were obtained, and the highest yield
Scheme 2. Ir-Catalyzed C7-selective C H bond activation of indoline: alkylation (previous work) and alkenylation (this work).
ysis (Scheme 2, upper).[6] The reaction of N-substituted indolines with alkenes under similar reaction conditions gave various 7-alkylindolines in moderate to high yields. Against this background, we hypothesized that an oxidative C7-alkenylation of N-substituted indolines with alkenes would also proceed with the use of appropriate iridium catalysts (Scheme 2, bottom). We initiated our study of C7-position-selective alkenylation with the reaction of N-acetylindoline (1 a) with styrene (2 a) (Table 1). The reaction of 1 a and 2 a in the presence of [Cp*IrCl2]2 (5 mol %) and anhydrous CuACHTUNGRE(OAc)2 (10 mol %) in 1,2-dichloroethane (DCE) at 100 8C in air resulted in the
Table 2. Scope of the directing group and substituent on indoline.[a]
Table 1. Optimization of reaction conditions.[a]
Entry
Ag salt
Additive
Yield [%]
1 2 3 4 5 6 7 8 9[b]
none AgBF4 AgOTf AgSbF6 AgOTf AgOTf AgOTf AgOTf AgOTf
CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 none CuCl2 CuACHTUNGRE(OTf)2 NaOAc CuACHTUNGRE(OAc)2
15 89 95 85 34 31 39 61 72
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Yield [%]
1 2 3 4 5 6 7 8 9 10 11[b] 12[c]
Et iPr tBu cyclopropyl NMe2 NEt2 piperidinyl Me Me Me Me Me
H H H H H H H 2-Me 2-Ph 3-Me 5-Br 6-F
86 (3 b) 84 (3 c) 93 (3 d) 90 (3 e) 79 (3 f) 72 (3 g) 65 (3 h) 96 (3 i) 84 (3 j) 88 (3 k) 64 (3 l) 61 (3 m)
of 93 % was achieved with a bulky pivaloyl group (entries 1– 4). Carbamoyl groups were also effective as directing groups, and the desired products 3 f–3 h were obtained in moderate to good yields (entries 5–7). In contrast to the C7alkylation of indoline,[6] a wide range of directing groups could be used in the C7-alkenylation of indoline. We determined that an acetyl group was the directing group of choice and further investigated the effect of the substituents on the indoline skeleton. Methyl and phenyl groups at the 2- or 3-position gave no effect in this reaction and the corresponding alkenylated products 3 i, 3 j, and 3 k were obtained in high yields (entries 8–10). By contrast, an electron-withdrawing group at the 5- or 6-position decreased the reactivity: 5-bromoindoline could also undergo the oxidative C H alkenylation to give the product 3 l, but a longer reaction time was required (entry 11). In the case of 6-fluoroindoline,
formation of the desired product 3 a, albeit in low yield (entry 1). When Ag salts were added for the formation of cationic Ir species, the yields were drastically improved, and AgOTf led to an excellent yield (95 %) (entries 2–4). In the absence of CuACHTUNGRE(OAc)2, the catalytic reaction proceeded, but the yield was significantly decreased (entry 5). The copper
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[a] The reaction conditions were as follows: N-substituted indoline 1 (0.1 mmol), styrene (2 a) (0.4 mmol), [Cp*IrCl2]2 (0.005 mmol), CuACHTUNGRE(OAc)2 (0.01 mmol), AgOTf (0.02 mmol), DCE (0.2 mL), 100 8C, 48 h, in air. [b] The reaction time was 96 h. [c] The reaction was carried out using CuACHTUNGRE(OAc)2 (2.0 equiv) under an argon atmosphere.
[a] The reaction conditions were as follows: N-acetylindoline (1 a) (0.1 mmol), styrene (2 a) (0.4 mmol), [Cp*IrCl2]2 (0.005 mmol), additive (0.01 mmol), Ag salt (0.02 mmol), solvent (0.2 mL), 100 8C, 48 h, in air, unless otherwise noted. [b] The reaction was examined under an oxygen atmosphere.
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Table 3. Scope of alkenes.[a]
A plausible mechanistic pathway for the synthesis of 7-alkenylindolines is proposed that involves catalytic dehydrogenative cross-coupling (Scheme 4). First, an active cationic complex A is generated by the combination of [Cp*IrCl2]2 and AgOTf. This species is coordinated by the carbonyl
Entry
R
Yield [%]
1 2 3 4 5 6 7[b] 8
3-MeOC6H4 4-MeC6H4 4-ClC6H4 4-BrC6H4 CO2Et CO2c-Hex SO2Ph P(O)ACHTUNGRE(OEt)2
59 (3 n) 94 (3 o) 88 (3 p) 92 (3 q) 75 (3 r) 89 (3 s) 60 (3 t) 86 (3 u)
[a] The reaction conditions were as follows: N-acetylindoline (1 a) (0.1 mmol), alkene 2 (0.4 mmol), [Cp*IrCl2]2 (0.005 mmol), CuACHTUNGRE(OAc)2 (0.01 mmol), AgOTf (0.02 mmol), DCE (0.2 mL), 100 8C, 48 h, in air. [b] The reaction time was 72 h.
two equivalent amounts of CuACHTUNGRE(OAc)2 were required for high conversion (entry 12).[11] We next examined the scope of the alkene in the C7-alkenylation of N-acetylindoline (1 a) (Table 3). In place of the parent styrene, several functionalized styrenes were used: both electron-donating groups, such as methoxy and methyl groups, and electron-withdrawing groups, such as halogens, could be installed at the meta- and para-positions, and the corresponding products 3 n–3 q were obtained in good to excellent yields (entries 1–4).[12] Acrylates were also good coupling partners, and ethyl acrylate and cyclohexyl acrylate gave the desired products 3 r and 3 s (entries 5 and 6). As for other electron-deficient alkenes, phenyl vinylsulfone and vinyl phosphonate could be used, and C7-functionalized products 3 t and 3 u were obtained (entries 7 and 8).[13] To demonstrate the utility of the present reaction, transformations of product 3 a obtained above were investigated (Scheme 3). Hydrogenation of compound 3 a in the presence of Pd/C and hydrogen afforded 7-alkylindoline 4 in 91 % yield under mild reaction conditions. Conversion of 3 a using DDQ as an oxidant easily gave 7-alkenylindole 5 in moderate yield. Furthermore, hydrogenation and DDQ oxidation provided 5 and 7-alkylindole 6 in respective yields of 15 % and 38 %.
Scheme 4. Proposed mechanism.
oxygen of the acetyl group, and subsequent C H bond activation at the C7-position via concerted metalation/deprotonation provides aryliridium B. Alkene insertion into the carbon-iridium bond of B along with b-hydride elimination then provides the desired product 3 and the iridium(I) complex D, which is oxidized to the iridiumACHTUNGRE(III) complex A by Cu(II). The resulting Cu(I) is reoxidized by air. In summary, we have developed an IrACHTUNGRE(III)-catalyzed regioselective C7-alkenylation of N-acyl- and carbamoyl indolines with alkenes. The catalyst prepared from [Cp*IrCl2]2 and AgOTf afforded various 7-alkenylindolines in moderate to high yields in air with a catalytic amount of CuACHTUNGRE(OAc)2. The present results represent a new entry for C7-alkenylated indoline synthesis. Further studies on the scope of the substrates, applications, and the precise mechanism are underway in our laboratory.
Experimental Section General Experimental Procedure for Products 3: [Cp*IrCl2]2 (0.005 mmol), AgOTf (0.02 mmol), CuACHTUNGRE(OAc)2 (0.01 mmol), and N-substituted indoline 1 (0.1 mmol) were placed in a Schlenk tube with a cold finger condenser. Subsequently, alkene 2 (0.4 mmol) and 1,2-dichloroethane (0.2 mL) were added to the reaction vessel. The solution was then stirred in air at 100 8C (bath temperature) for 48 h. The resultant mixture was cooled to room temperature, and the solvent was evaporated to dryness. The crude products were purified by thin-layer chromatography (nhexane or dichloromethane/ethyl acetate) to yield analytically pure 3 (see the Supporting Information for details).
Scheme 3. Synthetic transformations of 3 a.
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Acknowledgements This work was supported by Grand-in-aid for Scientific Research on Innovative Area, “Molecular Activation Directed toward Straightforward Synthesis”, MEXT, JST, ACT-C, and grants for Excellent Graduate School (Practical Chemical Wisdom), Waseda University, MEXT, Japan.
[6]
Keywords: alkenes · alkenylation · C–H activation · indoline · iridium
[7] [8] [9]
[1] a) T. Wang, Q. Xu, P. Yu, X, Liu, J. M. Cook, Org. Lett. 2001, 3, 345 – 348; b) M. E. Kuehne, W. G. Bornmann, I, Marko, Y. Qin, K. L. LeBoolluec, D. A. Frasier, F. Xu, T. Mulamba, C. L. Ensinger, L. S. Borman, A. E. Huot, C. Exon, F. T. Bizzarro, J. B. Cheung, S. L. Bane, Org. Biomol. Chem. 2003, 1, 2120 – 2136; c) R. Iyengar, K. Schildknegt, M. Morton, J. Aube, J. Org. Chem. 2005, 70, 10645 – 10652; d) L. Xiang, D. Xing, W. Wang, R. Wang, Y. Ding, L. Du, Phytochemistry 2005, 66, 2595 – 2601; e) H. Zhang, J. Boonsombat, A. Padwa, Org. Lett. 2007, 9, 279 – 282; f) T. Bui, S. Syed, C. F. Barbas, III., J. Am. Chem. Soc. 2009, 131, 8758 – 8759; g) Y.-C. Xiao, C. Wang, Y. Yao, J. Sun, Y.-C. Chen, Angew. Chem. Int. Ed. 2011, 50, 10661 – 10664; Angew. Chem. 2011, 123, 10849 – 10852. [2] a) A. Rakhit, M. E. Hurley, V. Tipnis, J. Coleman, A. Rommel, H. R. Brunner, J. Clin. Pharmacol. 1986, 26, 156 – 164; b) J. Dunlop, K. L. Marquis, H. K. Lim, L. Leung, J. Kao, C. Cheesman, S. Rosenzweig-Lipson, CNS Drug Rev. 2006, 12, 167 – 177. [3] a) S. Anas, H. B. Kagan, Tetrahedron: Asymmetry 2009, 20, 2193 – 2199; b) B. M. Trost, M. K. Brennan, Synthesis 2009, 3003 – 3025; c) D. Liu, G. Zhao, L. Xiang, Eur. J. Org. Chem. 2010, 3975 – 3984. [4] a) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873 – 2920; b) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Chem. Rev. 2007, 107, 5318 – 5365; c) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173 – 1193; d) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147 – 1169. [5] For Ru-catalyzed carbonylation and Pd-catalyzed arylation and methylation of the C H bond at the C7-position of indoline, see: a) N. Chatani, S. Yorimitsu, T. Asaumi, F. Kakiuchi, S. Murai, J.
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Org. Chem. 2002, 67, 7557 – 7560; b) D. Kalyani, N. R. Deprez, L. V. Desai, M. S. Sanford, J. Am. Chem. Soc. 2005, 127, 7330 – 7331; c) Z. Shi, B. Li, X. Wan, J. Cheng, Z. Fang, B. Cao, C. Qin, Y. Wang, Angew. Chem. Int. Ed. 2007, 46, 5554 – 5558; Angew. Chem. 2007, 119, 5650 – 5654; d) T. Nishikata, A. R. Abela, S. Huang, B. H. Lipshutz, J. Am. Chem. Soc. 2010, 132, 4978 – 4979; e) L. Jiao, M. Oestreich, Chem. Eur. J. 2013, 19, 10845 – 10848; f) S. R. Neufeldt, C. K. Seigerman, M. Sanford, Org. Lett. 2013, 15, 2302 – 2305. S. Pan, N. Ryu, T. Shibata, Adv. Synth. Catal. 2014, 356, in press, DOI: 10.1002/adsc.201300917. B. Urones, R. G. Arrays, J. C. Carretero, Org. Lett. 2013, 15, 1120 – 1123. L. Jiao, M. Oestreich, Org. Lett. 2013, 15, 5374 – 5377. Z. Song, R. Samanta, A. P. Antonchick, Org. Lett. 2013, 15, 5662 – 5665. a) K. Tsuchikama, M. Kasagawa, Y. Hashimota, K. Endo, T. Shibata, J. Organomet. Chem. 2008, 693, 3939 – 3942; b) K. Tsuchikama, Y. Hashimota, K. Endo, T. Shibata, Adv. Synth. Catal. 2009, 351, 2850 – 2854; c) K. Tsuchikama, M. Kasagawa, K. Endo, T. Shibata, Org. Lett. 2009, 11, 1821 – 1823; d) K. Tsuchikama, M. Kasagawa, K. Endo, T. Shibata, Synlett 2010, 97 – 100; e) T. Shibata, Y. Hashimoto, M. Otsuka, K. Tsuchikama, K. Endo, Synlett 2011, 2075 – 2079; f) T. Shibata, H. Hirashima, M. Kasagawa, K. Tsuchikama, K. Endo, Synlett 2011, 2171 – 2176; g) S. Pan, K. Endo, T. Shibata, Org. Lett. 2011, 13, 4692 – 4695; h) S. Takebayashi, T. Shibata, Organometallics 2012, 31, 4114 – 4117; i) S. Pan, Y. Matsuo, K. Endo, T. Shibata, Tetrahedron 2012, 68, 9009 – 9015; j) S. Pan, K. Endo, T. Shibata, Org. Lett. 2012, 14, 780 – 783; k) S. Pan, N. Ryu, T. Shibata, J. Am. Chem. Soc. 2012, 134, 17474 – 17477; l) S. Pan, N. Ryu, T. Shibata, Org. Lett. 2013, 15, 1902 – 1905. Under the standard reaction conditions, the desired product 3 m was obtained in 10 % yield along with the recovery of substrate. p-Methoxystyrene was very reactive under the present reaction conditions and was completely consumed in the absence of indoline 1 a. Non-1-ene, cyclohexene, allylbenzene, vinyl acetate, and n-butyl vinyl ether were inappropriate alkenes under the present reaction conditions. Received: December 31, 2013 Published online: && &&, 0000
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COMMUNICATION C H Activation Shiguang Pan, Takayuki Wakaki, Naoto Ryu, &&&&—&&&& Takanori Shibata* Lettin’ the cat outta the bag: An efficient IrIII-catalyzed oxidative coupling of N-substituted indolines with various alkenes at the C7-position in air assisted by a carbonyl or carbamoyl group as a directing group is reported. The catalyst was prepared from
[Cp*IrCl2]2 and AgOTf. A variety of 7alkenylindolines were obtained in moderated to high yields. The reaction is potentially applicable to the synthesis of 7-alkylindoles and 7-alkenylindoles.
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IrACHTUNGRE(III)-Catalyzed C7-Position-Selective Oxidative C H Alkenylation of Indolines with Alkenes in Air
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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IrACHTUNGRE(III)-Catalyzed C7-Position-Selective Oxidative C H Alkenylation of Indolines with Alkenes in Air Shiguang Pan,[a] Takayuki Wakaki,[a] Naoto Ryu,[a] and Takanori Shibata*[a, b]
Abstract: An efficient method for C7-position-selective alkenylation of N-substituted indolines with alkenes is reported. Various 7-alkenylindolines were obtained in moderate to excellent yields in air in the presence of catalytic amounts of [Cp*IrCl2]2, AgOTf, and CuACHTUNGRE(OAc)2. The protocol relies on the use of a carbonyl or carbamoyl group on the nitrogen atom of indoline as a directing group and is potentially applicable to the synthesis of 7-alkenylindoles and 7-alkylindoles.
lyzed C7-alkenylation of indolines, which was followed by oxidation to 7-alkenylindoles in one-pot.[9] In all of these examples, more than stoichiometric amounts of oxidants, such as N-fluoro-2,4,6-trimethylpyridinium triflate ([F + ]), benzoquinone (BQ), and copper acetate, were generally used. Herein, we report the iridiumACHTUNGRE(III)-catalyzed C7-alkenylation of indolines in air using a catalytic amount of copper acetate as a reoxidant and a carbonyl group as a directing group (Scheme 1, bottom). Our recent studies have focused on the development of cationic iridium(I)-catalyzed synthesis initiated by the cleavage of inactive bonds, such as C H, N H, and C O bonds.[10] Recently, we developed a C2-position-selective alkylation of indoles with alkenes using cationic Ir-diphosphine catalysts.[10k] This protocol relies on the use of a carbonyl group on the nitrogen atom of indoles as a directing group. More recently, the C7-position-selective alkylation of indolines was achieved, also with the use of cationic Ir catal-
The indoline skeleton is very important due to its ubiquity in numerous natural products and pharmaceutically important compounds.[1, 2] Thus, atom-economical and green methods for the synthesis of functionalized indoline derivatives have been strongly desired. The installation of desired substituents along with the construction of the indoline skeleton has been a conventional protocol for regioselective synthesis.[3] However, a more straightforward approach is the C H bond functionalization of indoline derivatives. Among the extensive studies over the past decade in which various transition metal catalysts were used,[4] Ru-catalyzed carbonylation and Pd-catalyzed arylation and methylation of indolines at the C7-position have been reported.[5] We also reported a cationic Ir(I)-catalyzed C7-position-selective alkylation of N-substituted indolines with alkenes.[6] By contrast, the C7position-selective C H alkenylation of indolines is a potentially useful transformation and has been a hot topic since 2013: Arrays and Carretero et al. reported the first example of an oxidative C H alkenylation using a Pd catalyst, in which a pyridylsulfonyl group was used as a directing group (Scheme 1, top).[7] Oestreich et al. reported a milder procedure for the Pd-catalyzed C H alkenylation of indolines using N-carbamoyl indolines.[8] While this manuscript was being prepared, Antonchick et al. reported a rhodium-cata[a] Dr. S. Pan, T. Wakaki, N. Ryu, Prof. Dr. T. Shibata Department of Chemistry and Biochemistry Waseda University Shinjuku, Tokyo 169-8555 (Japan) Fax: (+ 81) 3-5286-8098 E-mail: [email protected] [b] Prof. Dr. T. Shibata Japan Science and Technology Agency (JST) 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201301733.
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Scheme 1. Examples of C7-position-selective alkenylation of indolines.
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salt acted as a reoxidant, but the choice of Cu(II) salts was important (entries 6 and 7). Notably, a catalytic amount of NaOAc facilitated the reaction (entry 8). These results suggested that CuACHTUNGRE(OAc)2 acted as a base, which assisted hydrogen abstraction, as well as a reoxidant of the iridium complex.[10e] Furthermore, the reaction of 1 a and 2 a was examined under an oxygen atmosphere, but the yield was slightly decreased (entry 9). We used the conditions in entry 3 for further investigations. With the optimized conditions in hand, we explored the scope of N-substituted indolines (Table 2). First, we examined a variety of carbonyl functionalities on the nitrogen atom of indoline. As a result, the corresponding C7-alkenylated indolines 3 b–3 e were obtained, and the highest yield
Scheme 2. Ir-Catalyzed C7-selective C H bond activation of indoline: alkylation (previous work) and alkenylation (this work).
ysis (Scheme 2, upper).[6] The reaction of N-substituted indolines with alkenes under similar reaction conditions gave various 7-alkylindolines in moderate to high yields. Against this background, we hypothesized that an oxidative C7-alkenylation of N-substituted indolines with alkenes would also proceed with the use of appropriate iridium catalysts (Scheme 2, bottom). We initiated our study of C7-position-selective alkenylation with the reaction of N-acetylindoline (1 a) with styrene (2 a) (Table 1). The reaction of 1 a and 2 a in the presence of [Cp*IrCl2]2 (5 mol %) and anhydrous CuACHTUNGRE(OAc)2 (10 mol %) in 1,2-dichloroethane (DCE) at 100 8C in air resulted in the
Table 2. Scope of the directing group and substituent on indoline.[a]
Table 1. Optimization of reaction conditions.[a]
Entry
Ag salt
Additive
Yield [%]
1 2 3 4 5 6 7 8 9[b]
none AgBF4 AgOTf AgSbF6 AgOTf AgOTf AgOTf AgOTf AgOTf
CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 none CuCl2 CuACHTUNGRE(OTf)2 NaOAc CuACHTUNGRE(OAc)2
15 89 95 85 34 31 39 61 72
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Yield [%]
1 2 3 4 5 6 7 8 9 10 11[b] 12[c]
Et iPr tBu cyclopropyl NMe2 NEt2 piperidinyl Me Me Me Me Me
H H H H H H H 2-Me 2-Ph 3-Me 5-Br 6-F
86 (3 b) 84 (3 c) 93 (3 d) 90 (3 e) 79 (3 f) 72 (3 g) 65 (3 h) 96 (3 i) 84 (3 j) 88 (3 k) 64 (3 l) 61 (3 m)
of 93 % was achieved with a bulky pivaloyl group (entries 1– 4). Carbamoyl groups were also effective as directing groups, and the desired products 3 f–3 h were obtained in moderate to good yields (entries 5–7). In contrast to the C7alkylation of indoline,[6] a wide range of directing groups could be used in the C7-alkenylation of indoline. We determined that an acetyl group was the directing group of choice and further investigated the effect of the substituents on the indoline skeleton. Methyl and phenyl groups at the 2- or 3-position gave no effect in this reaction and the corresponding alkenylated products 3 i, 3 j, and 3 k were obtained in high yields (entries 8–10). By contrast, an electron-withdrawing group at the 5- or 6-position decreased the reactivity: 5-bromoindoline could also undergo the oxidative C H alkenylation to give the product 3 l, but a longer reaction time was required (entry 11). In the case of 6-fluoroindoline,
formation of the desired product 3 a, albeit in low yield (entry 1). When Ag salts were added for the formation of cationic Ir species, the yields were drastically improved, and AgOTf led to an excellent yield (95 %) (entries 2–4). In the absence of CuACHTUNGRE(OAc)2, the catalytic reaction proceeded, but the yield was significantly decreased (entry 5). The copper
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[a] The reaction conditions were as follows: N-substituted indoline 1 (0.1 mmol), styrene (2 a) (0.4 mmol), [Cp*IrCl2]2 (0.005 mmol), CuACHTUNGRE(OAc)2 (0.01 mmol), AgOTf (0.02 mmol), DCE (0.2 mL), 100 8C, 48 h, in air. [b] The reaction time was 96 h. [c] The reaction was carried out using CuACHTUNGRE(OAc)2 (2.0 equiv) under an argon atmosphere.
[a] The reaction conditions were as follows: N-acetylindoline (1 a) (0.1 mmol), styrene (2 a) (0.4 mmol), [Cp*IrCl2]2 (0.005 mmol), additive (0.01 mmol), Ag salt (0.02 mmol), solvent (0.2 mL), 100 8C, 48 h, in air, unless otherwise noted. [b] The reaction was examined under an oxygen atmosphere.
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Table 3. Scope of alkenes.[a]
A plausible mechanistic pathway for the synthesis of 7-alkenylindolines is proposed that involves catalytic dehydrogenative cross-coupling (Scheme 4). First, an active cationic complex A is generated by the combination of [Cp*IrCl2]2 and AgOTf. This species is coordinated by the carbonyl
Entry
R
Yield [%]
1 2 3 4 5 6 7[b] 8
3-MeOC6H4 4-MeC6H4 4-ClC6H4 4-BrC6H4 CO2Et CO2c-Hex SO2Ph P(O)ACHTUNGRE(OEt)2
59 (3 n) 94 (3 o) 88 (3 p) 92 (3 q) 75 (3 r) 89 (3 s) 60 (3 t) 86 (3 u)
[a] The reaction conditions were as follows: N-acetylindoline (1 a) (0.1 mmol), alkene 2 (0.4 mmol), [Cp*IrCl2]2 (0.005 mmol), CuACHTUNGRE(OAc)2 (0.01 mmol), AgOTf (0.02 mmol), DCE (0.2 mL), 100 8C, 48 h, in air. [b] The reaction time was 72 h.
two equivalent amounts of CuACHTUNGRE(OAc)2 were required for high conversion (entry 12).[11] We next examined the scope of the alkene in the C7-alkenylation of N-acetylindoline (1 a) (Table 3). In place of the parent styrene, several functionalized styrenes were used: both electron-donating groups, such as methoxy and methyl groups, and electron-withdrawing groups, such as halogens, could be installed at the meta- and para-positions, and the corresponding products 3 n–3 q were obtained in good to excellent yields (entries 1–4).[12] Acrylates were also good coupling partners, and ethyl acrylate and cyclohexyl acrylate gave the desired products 3 r and 3 s (entries 5 and 6). As for other electron-deficient alkenes, phenyl vinylsulfone and vinyl phosphonate could be used, and C7-functionalized products 3 t and 3 u were obtained (entries 7 and 8).[13] To demonstrate the utility of the present reaction, transformations of product 3 a obtained above were investigated (Scheme 3). Hydrogenation of compound 3 a in the presence of Pd/C and hydrogen afforded 7-alkylindoline 4 in 91 % yield under mild reaction conditions. Conversion of 3 a using DDQ as an oxidant easily gave 7-alkenylindole 5 in moderate yield. Furthermore, hydrogenation and DDQ oxidation provided 5 and 7-alkylindole 6 in respective yields of 15 % and 38 %.
Scheme 4. Proposed mechanism.
oxygen of the acetyl group, and subsequent C H bond activation at the C7-position via concerted metalation/deprotonation provides aryliridium B. Alkene insertion into the carbon-iridium bond of B along with b-hydride elimination then provides the desired product 3 and the iridium(I) complex D, which is oxidized to the iridiumACHTUNGRE(III) complex A by Cu(II). The resulting Cu(I) is reoxidized by air. In summary, we have developed an IrACHTUNGRE(III)-catalyzed regioselective C7-alkenylation of N-acyl- and carbamoyl indolines with alkenes. The catalyst prepared from [Cp*IrCl2]2 and AgOTf afforded various 7-alkenylindolines in moderate to high yields in air with a catalytic amount of CuACHTUNGRE(OAc)2. The present results represent a new entry for C7-alkenylated indoline synthesis. Further studies on the scope of the substrates, applications, and the precise mechanism are underway in our laboratory.
Experimental Section General Experimental Procedure for Products 3: [Cp*IrCl2]2 (0.005 mmol), AgOTf (0.02 mmol), CuACHTUNGRE(OAc)2 (0.01 mmol), and N-substituted indoline 1 (0.1 mmol) were placed in a Schlenk tube with a cold finger condenser. Subsequently, alkene 2 (0.4 mmol) and 1,2-dichloroethane (0.2 mL) were added to the reaction vessel. The solution was then stirred in air at 100 8C (bath temperature) for 48 h. The resultant mixture was cooled to room temperature, and the solvent was evaporated to dryness. The crude products were purified by thin-layer chromatography (nhexane or dichloromethane/ethyl acetate) to yield analytically pure 3 (see the Supporting Information for details).
Scheme 3. Synthetic transformations of 3 a.
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Acknowledgements This work was supported by Grand-in-aid for Scientific Research on Innovative Area, “Molecular Activation Directed toward Straightforward Synthesis”, MEXT, JST, ACT-C, and grants for Excellent Graduate School (Practical Chemical Wisdom), Waseda University, MEXT, Japan.
[6]
Keywords: alkenes · alkenylation · C–H activation · indoline · iridium
[7] [8] [9]
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COMMUNICATION C H Activation Shiguang Pan, Takayuki Wakaki, Naoto Ryu, &&&&—&&&& Takanori Shibata* Lettin’ the cat outta the bag: An efficient IrIII-catalyzed oxidative coupling of N-substituted indolines with various alkenes at the C7-position in air assisted by a carbonyl or carbamoyl group as a directing group is reported. The catalyst was prepared from
[Cp*IrCl2]2 and AgOTf. A variety of 7alkenylindolines were obtained in moderated to high yields. The reaction is potentially applicable to the synthesis of 7-alkylindoles and 7-alkenylindoles.
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IrACHTUNGRE(III)-Catalyzed C7-Position-Selective Oxidative C H Alkenylation of Indolines with Alkenes in Air
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