Letter Cite This: Org. Lett. 2018, 20, 2997−3000
pubs.acs.org/OrgLett
Palladium-Catalyzed Tandem Reaction of Three Aryl Iodides Involving Triple C−H Activation Xiai Luo,†,‡ Yankun Xu,† Genhua Xiao,† Wenjuan Liu,† Cheng Qian,† Guobo Deng,† Jianxin Song,† Yun Liang,*,† and Chunming Yang*,† †
National & Local Joint Engineering Laboratory for New Petro-chemical Materials and Fine Utilization of Resources, Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of the Assembly and Application of Organic Functional Molecules, Hunan Normal University, Changsha, Hunan 410081, China ‡ Hunan University of Medicine, Huaihua 418000, China S Supporting Information *
ABSTRACT: A novel palladium-catalyzed tandem reaction of N-(2-iodoaryl)acrylamides with two aryl iodides for the synthesis of spirooxindole has been achieved. The reaction underwent the process of triple C−H activation and four C−C bond formations based on the double trapping of transient spirocyclic palladacycles which are obtained through remote C−H activation.
A
Further intermolecular reactions were achieved by Lautens: (1) two structurally distinguishable aryl iodoides reacted together through a carbopalladation and a sequence of C−H activations formed three new C−C bonds;12 (2) aryl iodoides reacted with alkyl iodoides via a sequence of C−H activations and following C−C bond cleavage formed four new C−C bonds.13 These methods can efficiently construct the complex organic molecular by tandem C−H activation. Therefore, developing multi-C−H functionalization and multi-C−C formation between structurally distinguishable aryl iodides is important and remains challenging. N-2-Halophenylacrylamides,14−18 as important synthons for construction of spirooxindole, were widely used. In the presence of Pd(0) catalysts, they readily transformed into spirocyclic palladacycles through a Heck-type reaction and following remote C−H activation which was trapped by alkynes,15 arynes,16 CH2Br2,17 disilanes,18 and diazo19 compounds to spirocyclic oxindoles. Inspired by these previous studies, we envision that the iodobenzene can insert into the spirocyclic palladacycles for synthesis of spirocyclic oxindoles (Scheme 1). Herein, we wish to detail our results.
spiral ring skeleton is ubiquitous in organic molecules and found in a wide range of natural products, pharmaceuticals, agrochemicals, and materials.1 For this reason, substantial efforts have been directed toward the development of stepeconomical and atom-economical strategies for the construction of spirocyclic compounds. C−H functionalization reactions2 involving tandem processes3 have emerged as powerful tools to reach this near-ideal goal. In the past, tremendous progress has been made in the area of directing group-assisted C−H bond activation.2 However, the installation and removal of directing groups is a major drawback for synthetic applications. Alternatively, utilizing a transient directing group instead of the covalent directing group can avoid this limitation.4 Pioneering and systematic research has been carried out by Catellani and co-workers, who discovered and developed a Pd/norbornene catalytic system that could combine selective C−H bond activation with sequential reactions for ortho-C−H functionalization.5 Meanwhile, many chemists developed this reaction and applied it to activate the ortho-C−H bond in organic synthesis.6 On the basis of this research, a strategy of remote C−H functionalization was developed that utilized the tethered alkene moiety of aryl halides serving as a surrogate of norbornene to generate σalkylpalladium species. The σ-alkylpalladium species can achieve remote C−H activation via spirocyclic palladacycles or 1−4 palladium shift.7−13 Recently, outstanding work using mono-C−H functionalization for the synthesis of spirocyclic and polycyclic compounds has been reported.8,15−19 However, selective multi-C−H functionalization reactions are quite rare.9−13 In a pioneering study, Larock synthesized a tetracyclic compounds via a sequence of intramolecular C−H activation which is facilitated by a net 1,4-palladium shift.9 Utilizing a similar strategy, Zhu synthesized tetracyclic [3,4]-fused oxindoles;10 Wang and Ji synthesized pentacyclic compounds.11 © 2018 American Chemical Society
Scheme 1. Intermolecular Multi-C−H Functionalization
Received: April 1, 2018 Published: May 7, 2018 2997
DOI: 10.1021/acs.orglett.8b00982 Org. Lett. 2018, 20, 2997−3000
Letter
Organic Letters
respectively. Regrettably, the N-free and N-tosyl-substituted acrylamides were unfavorable substrates for this cyclization reaction. Subsequently, our study focused on the substitution effect on the 2-iodophenyl of N-(2-iodophenyl)-N-benzyl-2phenylacrylamide. It was observed that substrates containing electron-donating groups (including methyl and methoxyl) and electron-withdrawing groups (including chloro, fluoro, and trifluoromethyl) could be smoothly transformed into the corresponding products in good yields. Unfortunately, the substrate bearing a cyano group could not be tolerated well, and the corresponding products 3ma were formed in 38% yield. Furthermore, the compatibility of functionalities on the phenyl groups linked to the double bonds was checked. The substrates containing the electron-donating group such as methoxyl and the electron-withdrawing group such as fluoro were well tolerated, and the corresponding products were given in 79% (3na) and 63% (3oa) yields, respectively. When a fluorine atom was introduced to the ortho-position of benzene ring, the reaction proceeded with high efficiency, and the monoarylated product 3pa was afforded in 87% yield. We next explored the generality of substituted iodobenzenes (Scheme 4). For para-substituted iodobenzenes, we found that
We began our investigation using the easily accessible N-(2iodophenyl-N-methyl-2-phenylacrylamide and iodobenzene as model substrates. Under the reaction conditions we developed previously in the related studies20 [Pd(OAc)2 as catayst, PPh3 as ligand, K2CO3 as base, DMSO as solvent, at 120 °C, under nitrogen atmosphere], the unexpected phenyl-substituted spirocyclic oxindole 3aa was isolated in 35% yield, while no expected 1-methyl-10′H-spiro[indoline-3,9′-phenanthren]-2one (3aa′) was observed. We reasoned that the reaction underwent remote C−H bond activation twice via formation of twice spirocyclic palladacycles. Encouraged by this interesting result, screening of various reaction conditions, including Pd catalysts, P-ligands, bases, solvents, and additives, revealed the optimal reaction conditions (see the Supporting Information (SI) for details), and the expected arylated spirooxindole 3aa was obtained in 65% yield (Scheme 2). It is noteworthy that the reaction could also be performed in 61% yield at a scale of 1 mmol of N-(2-iodophenyl)-N-methyl-2-phenylacrylamide 1a. Scheme 2. Optimization of Reaction Conditions
Scheme 4. Variation of the Iodobenzenes 2a
With the optimized conditions in hand, a series of substituted N-(2-iodophenyl)-2-phenylacrylamides 1 were first examined to study the scope of tandem process, and the results are summarized in Scheme 3. When electron-donating groups such as ethyl (1b), benzyl (1c), 4-fluorobenzyl (1d), and 4methylbenzyl (1e) N-substituted acrylamides were subjected to the reaction conditions, the desired products 3ba, 3ca, 3da, and 3ea were obtained in 61%, 81%, 71%, and 65% yields, Scheme 3. Variation of the Acrylamides 1a
a
Reaction conditions: 1a or 1c (0.2 mmol), 2 (0.8 mmol), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cs2CO3 (1.0 mmol), TBAI (0.1 mmol), DMSO (2 mL) at 120 °C under nitrogen atmosphere for 12 h. Isolated yield are given.
both electron-donating substituents (Me, OMe, N(Me)2) and electron-withdrawing substituents (F, Cl, CF3, Ph) were well tolerated, and moderate yields of corresponding spirooxindoles were obtained (52%−67%). The structure of spirooxindole product 3ac was unambiguously confirmed by single-crystal Xray analysis (CCDC: 1825599). However, methyl 4-iodobenzoate was not a suitable arylating reagent, and only 36% yield of 3ci was given. Happily, the iodobenzene containing two methyl groups in the meta-position afforded the desired product 3cj in 65% yield when the reaction time extended to 24 h. When the reaction of 1-iodo-2-methylbenzene or 1-chloro-2-iodobenzene
a
Reaction conditions: 1 (0.2 mmol), 2a (0.8 mmol), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cs2CO3 (1.0 mmol), TBAI (0.1 mmol), DMSO (2 mL) at 120 °C under nitrogen atmosphere for 12 h. Isolated yield are given. 2998
DOI: 10.1021/acs.orglett.8b00982 Org. Lett. 2018, 20, 2997−3000
Letter
Organic Letters was performed under standard reaction conditions, no desired product was isolated. This result indicated that the steric effect affected the reaction dramatically. To investigate the reaction intermediates, several control experiments were performed (Scheme 5). First, the spiropalla-
Scheme 6. Possible Reaction Mechanism
Scheme 5. Control Experiments
dacycle 4 was independently synthesized, which could efficiently react with iodobenzene to give desired product 3aa in 42% yield. This result indicated that the reaction was initiated by the spiropalladcycle 4, which was generated by an intramolecular Heck-type reaction followed by remote C−H activation. Then the possible intermediates 5 and 6 were synthesized as well. The reaction of 4-methyliodobenzene with 5 was investigated first, and a pair of isomers of 7 and 7′ was obtained in a 1:2 ratio. This result showed that the final C−H activation could take place from the phenyl or 4-methylphenyl. Finally, it was found that the intermediate 5 could not react with iodobenzene. These findings suggested that the reaction underwent a phenylation followed by the other phenylation. On the basis of the present experimental results, as well as previous reported mechanisms,7−20 the hypothetical catalytic cycle is shown in Scheme 6. The reaction starts with oxidative addition of Pd(0) to the C−I bond of N-(2-iodophenyl)-Nmethyl-2-phenylacrylamide 1a followed by a tandem intramolecular Heck reaction and C−H activation to form the key intermediate of five-membered palladacycle E.15−18 In general, two reaction pathways for the arylation of the palladacycle are considered. Path A: E undergoes oxidative addition with iodobenzene to give Pd(IV) complex H, and subsequent reductive elimination generates alkylpalladium species G. Path B: A transmetalation-type exchange may occur between the palladacycle E and arylpalladium species N, and following aryl− aryl reductive elimination it gives the intermediate G, which takes place without a formal change of the oxidation state of palladium. The arylated intermediate G forms a new spirocyclic palladacycle I via a second C−H activation.13 Likewise, two reaction pathways [A′, Pd(IV), versus B′, Pd(II)−Pd(II)] for the cyclization cannot be ruled out, and the seven-membered palladacycle K can be achieved through the third C−H activation.12 Finally, intermediate K undergoes reductive elimination, which regenerates the Pd(0) catalyst and affords the product of 3aa.
In conclusion, a novel, efficient method for the synthesis of spirooxindoles has been developed. In this reaction, three C−H bond activations and four C−C bond formations are involved. In the presence of palladium catalyst, N-(2-halophenyl)-2phenylacrylamides transform into spirooxindole via a sequence of formation of spirocyclic palladacycles that is generated by an intramolecular remote C−H activation. We anticipate that this approach will show its application in a series of directing-groupfree remote C−H functionalization reactions.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00982. Experimental procedures, full characterization of products, and NMR spectra (PDF) Accession Codes
CCDC 1825599 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. 2999
DOI: 10.1021/acs.orglett.8b00982 Org. Lett. 2018, 20, 2997−3000
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Organic Letters *E-mail:
[email protected].
P.-X.; Wang, X.-C.; Wang, P.; Zhu, R.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 11574. (d) Dong, Z.; Wang, J.; Dong, G. J. Am. Chem. Soc. 2015, 137, 5887. (e) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle, K. M.; Yu, J.-Q. Nature 2015, 519, 334. (f) Cárdenas, D. J.; Martín-Matute, B.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 5033. (g) Wu, T.; Mu, X.; Liu, G. Angew. Chem., Int. Ed. 2011, 50, 12578. (h) Mu, X.; Wu, T.; Wang, H.-L.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc. 2012, 134, 878. (7) (a) Mehta, V. P.; García-López, J.-A. ChemCatChem 2017, 9, 1149. (b) Franzoni, I.; Yoon, H.; Garcíıa-López, J.-A.; PobladorBahamonde, A. I.; Lautens, M. Chem. Sci. 2018, 9, 1496. (8) (a) Wang, M.; Zhang, X.; Zhuang, Y.-X.; Xu, Y.-H.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 1341. (b) Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin, M.; Kandur, W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4711. (c) Zheng, H.; Zhu, Y.; Shi, Y. Angew. Chem., Int. Ed. 2014, 53, 11280. (d) Piou, T.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14, 3760. (e) Hu, Y.; Yu, C.; Ren, D.; Hu, Q.; Zhang, C.; Cheng, D. Angew. Chem., Int. Ed. 2009, 48, 5448. (f) Kim, K. H.; Lee, H. S.; Kim, S. H.; Kim, S. H.; Kim, J. N. Chem. - Eur. J. 2010, 16, 2375. (g) Grigg, R.; Fretwell, P.; Meerholtz, C.; Sridharan, V. Tetrahedron 1994, 50, 359. (h) Lu, Z.; Hu, C.; Guo, J.; Li, J.; Cui, Y.; Jia, Y. Org. Lett. 2010, 12, 480. (i) Yao, T.; He, D. Org. Lett. 2017, 19, 842. (9) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460. (10) (a) Piou, T.; Bunescu, A.; Wang, Q.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2013, 52, 12385. (b) Bunescu, A.; Piou, T.; Wang, Q.; Zhu, J. Org. Lett. 2015, 17, 334. (11) Gu, Z.-Y.; Liu, C.-G.; Wang, S.-Y.; Ji, S.-J. Org. Lett. 2016, 18, 2379. (12) Sickert, M.; Weinstabl, H.; Peters, B.; Hou, X.; Lautens, M. Angew. Chem., Int. Ed. 2014, 53, 5147. (13) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.; Schoenebeck, F.; Lautens, M. Nat. Chem. 2017, 9, 361. (14) For representative papers, see: (a) Vachhani, D. D.; Butani, H. H.; Sharma, N.; Bhoya, U. C.; Shah, A. K.; Van der Eycken, E. V. Chem. Commun. 2015, 51, 14862. (b) Kong, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9714. (c) Liu, X.; Ma, X.; Huang, Y.; Gu, Z. Org. Lett. 2013, 15, 4814. (d) Tong, S.; Limouni, A.; Wang, Q.; Wang, M.-X.; Zhu, J. Angew. Chem., Int. Ed. 2017, 56, 14192. (e) Zhou, M.-B.; Huang, X.-C.; Liu, Y.-Y.; Song, R.-J.; Li, J.-H. Chem. - Eur. J. 2014, 20, 1843. (f) Wang, D.-C.; Wang, H.-X.; Hao, E.-J.; Jiang, X.-H.; Xie, M.-S.; Qu, G.-R.; Guo, H.-M. Adv. Synth. Catal. 2016, 358, 494. (g) Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-J.; Liu, Y.; Hu, M.; Xie, P.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52, 3638. (h) Kong, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9714. (i) Kong, W.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137, 16028. (15) Yoon, H.; Rölz, M.; Landau, F.; Lautens, M. Angew. Chem., Int. Ed. 2017, 56, 10920. (16) (a) Pérez-Gómez, M.; García-López, J.-A. Angew. Chem., Int. Ed. 2016, 55, 14389. (b) Yoon, H.; Lossouarn, A.; Landau, F.; Lautens, M. Org. Lett. 2016, 18, 6324. (17) Shao, C.; Wu, Z.; Ji, X.; Zhou, B.; Zhang, Y. Chem. Commun. 2017, 53, 10429. (18) (a) Lu, A.; Ji, X.; Zhou, B.; Wu, Z.; Zhang, Y. Angew. Chem., Int. Ed. 2018, 57, 3233. (b) Xiao, G.; Chen, L.; Deng, G.; Liu, J.; Liang, Y. Tetrahedron Lett. 2018, 59, 1836. (19) Pérez-Gómez, M.; Hernández-Ponte, S.; Bautista, D.; GarcíaLópez, J.-A. Chem. Commun. 2017, 53, 2842. (20) Wu, L.; Deng, G.; Liang, Y. Org. Biomol. Chem. 2017, 15, 6808.
ORCID
Guobo Deng: 0000-0002-5470-5706 Jianxin Song: 0000-0002-1756-5898 Yun Liang: 0000-0002-2550-9220 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21572051, 21602057), Opening Fund of Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education of China), and H u n a n No r m a l U n i v e r si t y ( K L C B T C M R 2 0 17 0 7 , KLCBTCMR201708).
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REFERENCES
(1) For representative reviews, see: (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748. (b) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (c) Klajn, R. Chem. Soc. Rev. 2014, 43, 148. (d) Rios, R. Chem. Soc. Rev. 2012, 41, 1060. (e) Yu, B.; Yu, D.-Q.; Liu, H.-M. Eur. J. Med. Chem. 2015, 97, 673. (2) For representative reviews, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (d) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (e) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (f) Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G. Chem. Soc. Rev. 2015, 44, 7764. (g) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev. 2016, 45, 2900. (h) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155. (i) He, J.; Wasa, M.; Chan, K. L.; Shao, Q.; Yu, J.-Q. Chem. Rev. 2017, 117, 8754. (3) For representative reviews, see: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390. (c) Platon, M.; Amardeil, R.; Djakovitch, L.; Hierso, J.-C. Chem. Soc. Rev. 2012, 41, 3929. (d) Sears, J. E.; Boger, D. L. Acc. Chem. Res. 2016, 49, 241. (e) Chauhan, P.; Mahajan, S.; Enders, D. Acc. Chem. Res. 2017, 50, 2809. (4) (a) Jun, C.-H.; Lee, H.; Hong, J.-B. J. Org. Chem. 1997, 62, 1200. (b) Mo, F.; Dong, G. Science 2014, 345, 68. (c) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112. (d) Lightburn, T. E.; Dombrowski, M. T.; Tan, K. L. J. Am. Chem. Soc. 2008, 130, 9210. (e) Grünanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 7346. (f) Luo, J.; Preciado, S.; Larrosa, I. J. Am. Chem. Soc. 2014, 136, 4109. (g) Mo, F.; Dong, G. Science 2014, 345, 68. (h) Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.; Dong, G. Angew. Chem., Int. Ed. 2016, 55, 9084. (i) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Science 2016, 351, 252. (j) Saidi, O.; Marafie, J.; Ledger, A. E. W.; Liu, P. M.; Mahon, M. F.; Kociok-Köhn, G.; Whittlesey, M. K.; Frost, C. G. J. Am. Chem. Soc. 2011, 133, 19298. (k) Paterson, A. J.; St John-Campbell, S.; Mahon, M. F.; Press, N. J.; Frost, C. G. Chem. Commun. 2015, 51, 12807. (l) Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. (m) Warratz, J.; Li, S.; Zell, D.; De Sarkar, S.; Ishikawa, E. E.; Ackermann, L. J. Am. Chem. Soc. 2015, 137, 13894. (5) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119. (b) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2004, 126, 78. (c) Della Ca’, N.; Fontana, M.; Motti, E.; Catellani, M. Acc. Chem. Res. 2016, 49, 1389. (d) Zhang, H.; Chen, P.; Liu, G. Angew. Chem., Int. Ed. 2014, 53, 10174. (e) Zhang, H.; Wang, H.-Y.; Luo, Y.; Chen, C.; Cao, Y.; Chen, P.; Guo, Y.-L.; Lan, Y.; Liu, G. ACS Catal. 2018, 8, 2173. (6) (a) Ye, J.; Lautens, M. Nat. Chem. 2015, 7, 863. (b) Martins, A.; Mariampillai, B.; Lautens, M. Top. Curr. Chem. 2009, 292, 1. (c) Shen, 3000
DOI: 10.1021/acs.orglett.8b00982 Org. Lett. 2018, 20, 2997−3000
