Palladium-Catalyzed Cascade Heck Cyclization To Access Bisindoles

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Palladium-Catalyzed Cascade Heck Cyclization To Access Bisindoles Kai Yuan, Lina Liu, Jiayi Chen, Songjin Guo, Hequan Yao,* and Aijun Lin* State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China S Supporting Information *

ABSTRACT: A novel strategy for intercepting the σ-alkylpalladium species generated via a Heck reaction, enabling a palladiumcatalyzed cyclization of o-ethynylanilines, has been described. This direct and operationally simple protocol provided a fundamental platform to synthesize bisindoles with high efficiency, involving one C−N bond and two C−C bond formations.

F

unctional heterocycles bearing indole and oxindole moieties broadly exist in many biologically active natural products and pharmaceutical molecules with anticancer, antivirus, antitumor, and inhibition properties1 (Figure 1). In

Scheme 1. Organopalladium-Mediated Cyclization of oEthynylanilines to the Synthesis of Indoles

Figure 1. Functional heterocycles bearing indole and oxindole moieties existing in selected bioactive compounds.

by taking advantage of highly active and stabilized arylpalladium, vinylpalladium, alkynylpalladium, and allylpalladium species. In contrast, the alkylpalladium species was rarely involved and generally proved challenging due to the inherent instability,5 interference of β-hydride elimination,6 and difficulties associated with the oxidative addition of alkyl electrophiles to Pd(0).7 Moreover, the substituents installed on the C3 position of indoles were frequently simple and nonfunctional. As part of our ongoing project in the synthesis of functional N-heterocycles,8 herein we describe our latest work on the Pd-catalyzed cascade Heck cyclization reaction to construct bisindoles. In this reaction, the cyclization of oethynylanilines was mediated by the in situ generated σalkylpalladium species,9 involving one C−N bond and two C− C bond formations in a one-pot procedure (Scheme 1b).

this context, well-designed methods such as organocatalyzed Diels−Alder reactions of 2-vinylindoles with methyleneindolinones,2 Lewis acid, and organocatalyst cooperatively catalyzed α-alkylation of 2-oxindoles with (3-indolyl)methanols3 have been exploited to target these frameworks. Encouraged by these initial explorations, building a general catalytic platform for the direct generation of such bisindoles with easily prepared materials and further enlarging the substrate diversity remain fascinating and desirable. Recently, organopalladium species in situ generated via the oxidative addition of halohydrocarbons and analogues with Pd(0) have been utilized as versatile synthetic intermediates in the transformations of o-ethynylanilines to construct 2,3disubstituted indoles4 (Scheme 1a). Nevertheless, the synthetic potential of this well-established protocol is usually restricted © XXXX American Chemical Society

Received: April 18, 2018

A

DOI: 10.1021/acs.orglett.8b01235 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Initially, we began our study with N-(2-bromophenyl)-Nmethylmethacrylamide 1a and 4-methyl-N-(2-(phenylethynyl)phenyl)benzenesulfonamide 2a as the model substrates. After intensive investigation, we found that the target product 3aa could be achieved in 96% yield in the presence of 5.0 mol % of Pd(PPh3)4 and 3.0 equiv of K2CO3 at 80 °C in MeCN (Table 1, entry 1). The structure of 3aa was unambiguously identified

Scheme 2. Substrate Scope of Alkene-Tethered Aryl Halogensa,b

Table 1. Optimization of Reaction Conditionsa,b

entry

variations from standard conditions

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

none without Pd(PPh3)4 without K2CO3 Pd(dba)2 + PPh3 instead of Pd(PPh3)4 Pd(dba)2 + Cy-Johnphos instead of Pd(PPh3)4 Pd(dba)2 + CPy3 instead of Pd(PPh3)4 Pd(dba)2 + XPhos instead of Pd(PPh3)4 Pd(OAc)2 + PPh3 instead of Pd(PPh3)4 Pd(PPh3)2Cl2 + PPh3 instead of Pd(PPh3)4 KHCO3 instead of K2CO3 Na2CO3 instead of K2CO3 KOH instead of K2CO3 Et3N instead of K2CO3 toluene instead of MeCN THF instead of MeCN DMF instead of MeCN

98 (96)c nrd trace 85 92 53 30 58 74 94 80 39 91 76 82 88

a

Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (5.0 mol %), ligand (20.0 mol %), K2CO3 (0.6 mmol), MeCN (4.0 mL), 80 °C, 6 h, Ar atmosphere, sealed tube. bThe yield was determined by 1H NMR using CH2Br2 as an internal standard. cIsolated yield. dnr = no reaction.

a

Reaction conditions: X = Br, 1 (0.2 mmol), 2a (0.24 mmol), Pd(PPh3)4 (5.0 mol %), K2CO3 (0.6 mmol), MeCN (4.0 mL), under Ar atmosphere for 6 h, sealed tube. bIsolated yields. cX = I. dX = Cl.

groups installed on the nitrogen atom delivered 3va and 3wa in 95% and 88% yields. Secondary amide 1x could not offer the desired product 3xa. When substrate 1y bearing N-allyl and αmethylacryl moiety10 was tested, 3ya could be selectively formed in 73% yield. Moreover, product 3za with both indole and indoline frameworks could be prepared in a moderate yield. After checking the character of alkene-tethered aryl halogens 1, we then shifted our attention to investigating the substrate scope of o-ethynylanilines 2, and the results are shown in Scheme 3. The benzene ring with various substituents bound to the alkynyl terminal provided 3ab−af in 79−95% yields. The structure of 3af was identified by single-crystal X-ray analysis (see the SI for details). Products 3ag and 3ah with thiophene and silyl groups were obtained in 89% and 93% yields. Although the terminal alkyne is certainly a more challenging substrate due to its inherent stability and activity issues, 3ai could also be isolated in 40% yield. Furthermore, the electronic effects of the substituents attached to the benzene ring of the anilines were also examined, offering 3aj−ar in 51−90% yields. The protecting group Ts of substrates 2 could be changed into Ms, Bz, and Boc groups, offering 3as−au in moderate to high yields. When 2v with CF3CO group was tested, a nitrogen atom deprotected product 3av was formed in 89% yield. To further evaluate the efficiency and practicality of this reaction, a gram-scale experiment was carried out, and 3aa

by single-crystal X-ray analysis (see the Supporting Information (SI) for details). A control experiment revealed that the reaction did not occur in the absence of a Pd(PPh3)4 catalyst (Table 1, entry 2). No better results were obtained when other palladium catalysts and ligands were employed to replace Pd(PPh3)4 (Table 1, entries 4−9). A range of bases were also tested, resulting in 3aa in lower yield, compared to K2CO3 (Table 1, entries 10−13). Screening solvents indicated that MeCN was the optimal choice (Table 1, entries 14−16). With the optimized conditions in hand, we then investigated the substrate scope of the alkene-tethered aryl halogens 1 to test the generality of the reaction, and the results are summarized in Scheme 2. Both aryl bromine and aryl iodine could furnish the reaction well, while aryl chloride was an inactive substrate and could not offer the desired product 3aa under the standard conditions. A variety of substrates containing electron-donating or electron-withdrawing groups at the 4- and 5-positions of the benzene ring could perform well, affording 3ba−na in 94−98% yields. The substrate 1o with a methyl group at the 3-position of the benzene ring offered 3oa in a moderate yield due to the steric hindrance. Products 3qa−sa with a naphthalene ring and pyridines were achieved in 91−94% yields. Substrates 1t and 1u with an aryl or benzyl group at the α-position of the double bond generated 3ta and 3ua in 96% and 91% yields. The n-butyl or benzyl B

DOI: 10.1021/acs.orglett.8b01235 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Substrate Scope of o-Ethynylanilinesa,b

Scheme 4. Gram-Scale Experiment and Further Transformation

Scheme 5. Further Studies of the Reaction

a Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), Pd(PPh3)4 (5.0 mol %), K2CO3 (0.6 mmol), MeCN (4.0 mL), under Ar atmosphere for 6 h, sealed tube. bIsolated yields.

(1.49 g) could be achieved in 95% yield on 3.0 mmol scale under the standard conditions (Scheme 4a). The sulfamide group in 3aa could be conveniently hydrolyzed, producing compound 3av in 95% yield (Scheme 4b). Treatment of 3aa with Lawesson’s reagent in toluene afforded compound 4 in 77% yield (Scheme 4c). The reduction of the amide group with DIBAL-H at −78 °C provided 3za in 86% yield (Scheme 4d). To gain some mechanistic insight into this reaction, further studies and control experiments were carried out. Although the indole 5 could be generated through the cyclization of oethynylaniline 2a in the presence of a base (Scheme 5a), no desired product 3aa could be detected when 1a and 5 were tested under the optimized reaction conditions, with all starting materials recovered (Scheme 5b). When the reaction of 1a and 2a was operated with 1.0 equiv of Pd(PPh3)4 in the absence of a base, product 3aa could be achieved in 87% yield (Scheme 5c). These results could rule out the possibility in which the base-promoted deprotonation of 2a and then the cyclization

occurred to generate indole 5 as an intermediate. Moreover, the o-ethynylaniline derivatives 6 and 7 could offer the corresponding products 3aa and 8 in 5% and 92% yields in the absence of a base (see the SI for details) (Scheme 5d,e). The azide 9,11 without an NH group, could not cyclize under the base conditions (see the SI for details) and led to the corresponding product 3av in 40% yield (Scheme 5f). These results further demonstrated that the cyclization of o-ethynylanilines was mediated by the in situ generated σ-alkylpalladium species. On the basis of the above results of the control experiments and previous works,4,9 a plausible reaction pathway of this C

DOI: 10.1021/acs.orglett.8b01235 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

■

reaction is shown in Scheme 6. Oxidative addition of 1a to the Pd(0) catalyst generates the arylpalladium species A, which

Letter

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]; [email protected]. *E-mail: [email protected].

Scheme 6. Proposed Mechanism

ORCID

Hequan Yao: 0000-0003-4865-820X Aijun Lin: 0000-0001-5786-4537 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Generous financial support from the National Natural Science Foundation of China (NSFC21502232 and NSFC21272276) is gratefully acknowledged.

■

(1) For selected examples, see: (a) Staub, R. E.; Onisko, B.; Bjeldanes, L. F. Chem. Res. Toxicol. 2006, 19, 436. (b) Zhu, Q.; Tang, C.-P.; Ke, C.-Q.; Li, X.-Q.; Liu, J.; Gan, L.-S.; Weiss, H.-C.; Gesing, E.R.; Ye, Y. J. Nat. Prod. 2010, 73, 40. (c) Singh, R.; Masuda, E. S.; Payan, D. G. J. Med. Chem. 2012, 55, 3614. (d) Ma, S.-S.; Mei, W.-L.; Guo, Z.-K.; Liu, S.-B.; Zhao, Y.-X.; Yang, D.-L.; Zeng, Y.-B.; Jiang, B.; Dai, H.-F. Org. Lett. 2013, 15, 1492. (e) Liu, Y.-F.; Chen, M.-H.; Wang, X.-L.; Guo, Q.-L.; Zhu, C.-G.; Lin, S.; Xu, C.-B.; Jiang, Y.-P.; Li, Y.-H.; Jiang, J.-D.; Li, Y.; Shi, J.-G. Chin. Chem. Lett. 2015, 26, 931. (f) Pillaiyar, T.; Köse, M.; Sylvester, K.; Weighardt, H.; Thimm, D.; Borges, G.; Förster, I.; von Kügelgen, I.; Müller, C. E. J. Med. Chem. 2017, 60, 3636. (2) For a selected review, see: (a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. For selected examples, see: (b) Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212. (c) Zhou, L.; Xu, B.; Zhang, J. Angew. Chem., Int. Ed. 2015, 54, 9092. (d) Wang, Y.; Tu, M.-S.; Yin, L.; Sun, M.; Shi, F. J. Org. Chem. 2015, 80, 3223. (e) Ren, J.-W.; Wang, J.; Xiao, J.-A.; Li, J.; Xiang, H.-Y.; Chen, X.-Q.; Yang, H. J. Org. Chem. 2017, 82, 6441. (3) For selected examples, see: (a) Ren, C.-L.; Zhang, T.; Wang, X.Y.; Wu, T.; Ma, J.; Xuan, Q.-Q.; Wei, F.; Huang, H.-Y.; Wang, D.; Liu, L. Org. Biomol. Chem. 2014, 12, 9881. (b) Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2010, 132, 15534. (c) Zhu, G.; Bao, G.; Li, Y.; Sun, W.; Li, J.; Hong, L.; Wang, R. Angew. Chem., Int. Ed. 2017, 56, 5332. (d) Saito, M.; Kobayashi, Y.; Tsuzuki, S.; Takemoto, Y. Angew. Chem., Int. Ed. 2017, 56, 7653. (4) For selected reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, 215. (d) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1. (e) Shiri, M. Chem. Rev. 2012, 112, 3508. (f) Chinchilla, R.; Nájera, C. Chem. Rev. 2014, 114, 1783. For selected examples, see: (g) Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M. Org. Lett. 2002, 4, 1355. (h) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M. J. Org. Chem. 2005, 70, 6213. (i) Lu, B. Z.; Zhao, W.; Wei, H.-X.; Dufour, M.; Farina, V.; Senanayake, C. H. Org. Lett. 2006, 8, 3271. (j) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Perboni, A.; Sferrazza, A.; Stabile, P. Org. Lett. 2010, 12, 3279. (5) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674. (6) Bräse, S.; de Meijere, A. In Metal-catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 3. (7) Patai, S. The Chemistry of the Metal−Carbon Bond; Stille, J. K., Ed.; Wiley: New York, 1985; Vol. 2. (8) (a) Zhao, L.; Li, Z.; Chang, L.; Xu, J.; Yao, H.; Wu, X. Org. Lett. 2012, 14, 2066. (b) Su, Y.; Zhou, H.; Chen, J.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Org. Lett. 2014, 16, 4884. (c) Jiang, H.; Gao, S.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Adv. Synth. Catal. 2016, 358, 188. (d) Guo, S.; Yuan,

undergoes an intramolecular Heck reaction to form the alkylpalladium species B. Coordination of the alkylpalladium intermediate B to the triple bond of 2a enables the intramolecular nucleophilic attack12 of the nitrogen atom and generates the intermediate C. In the presence of a base,13 intermediate C could easily convert to the intermediate D. Finally, reductive elimination of intermediate D produces the product 3aa and simultaneously regenerates the Pd(0) species to the next catalyzed cycle. In conclusion, we have established an unprecedented strategy for a catalytic, in situ generated σ-alkylpalladium species induced, cascade cyclization of o-ethynylanilines. This protocol provided a straightforward platform for the synthesis of biologically interesting bisindoles in high efficiency, exhibiting good functional group tolerance and scalability. The reaction proceeded through an intramolecular Heck reaction, aminopalladation and reductive elimination, involving one C−N bond and two C−C bond formations. Further investigations on the asymmetric version of this reaction and its applications to other functional heterocycles are in progress in our laboratory.

■

REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01235. 1

H and 13C NMR spectra for all new compounds (PDF)

Accession Codes

CCDC 1821767 and 1821768 contain 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033. D

DOI: 10.1021/acs.orglett.8b01235 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters K.; Gu, M.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 5236. (e) Zhang, K.; Xu, X.; Zheng, J.; Yao, H.; Huang, Y.; Lin, A. Org. Lett. 2017, 19, 2596. (f) Zheng, J.; Li, P.; Gu, M.; Lin, A.; Yao, H. Org. Lett. 2017, 19, 2829. (9) For selected examples, see: (a) Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin, M.; Kandur, W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4711. (b) Lu, Z.; Hu, C.; Guo, J.; Li, J.; Cui, Y.; Jia, Y. Org. Lett. 2010, 12, 480. (c) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 1778. (d) Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 14916. (e) Peng, R.; Van Nieuwenhze, M. S. Org. Lett. 2012, 14, 1962. (f) Seashore-Ludlow, B.; Somfai, P. Org. Lett. 2012, 14, 3858. (g) Piou, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2012, 51, 11561. (h) Gao, Y.; Xiong, W.; Chen, H.; Wu, W.; Peng, J.; Gao, Y.; Jiang, H. J. Org. Chem. 2015, 80, 7456. (i) Kong, W.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137, 16028. (j) Wu, X.-X.; Chen, W.-L.; Shen, Y.; Chen, S.; Xu, P.-F.; Liang, Y.-M. Org. Lett. 2016, 18, 1784. (k) Kong, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9714. (l) Pérez-Gómez, M.; García-López, J.A. Angew. Chem., Int. Ed. 2016, 55, 14389. (m) Yao, T.; He, D. Org. Lett. 2017, 19, 842. (n) Schempp, T. T.; Daniels, B. E.; Staben, S. T.; Stivala, C. E. Org. Lett. 2017, 19, 3616. (o) Yao, T.; Liu, T.; Zhang, C. Chem. Commun. 2017, 53, 2386. (p) Shao, C.; Wu, Z.; Ji, X.; Zhou, B.; Zhang, Y. Chem. Commun. 2017, 53, 10429. (q) Yoon, H.; Rölz, M.; Landau, F.; Lautens, M. Angew. Chem., Int. Ed. 2017, 56, 10920. (r) Saha, N.; Wang, H.; Zhang, S.; Du, Y.; Zhu, D.; Hu, Y.; Huang, P.; Wen, S. Org. Lett. 2018, 20, 712 and references cited therein. (10) Liu, X.; Ma, X.; Huang, Y.; Gu, Z. Org. Lett. 2013, 15, 4814. (11) Zhou, Q.; Zhang, Z.; Zhou, Y.; Li, S.; Zhang, Y.; Wang, J. J. Org. Chem. 2017, 82, 48. (12) (a) Martínez, C.; Á lvarez, R.; Aurrecoechea, J. M. Org. Lett. 2009, 11, 1083. (b) Han, X.; Lu, X. Org. Lett. 2010, 12, 3336. (c) Denis, J. G.; Franci, G.; Altucci, L.; Aurrecoechea, J. M.; de Lera, Á . R.; Á lvarez, R. Org. Biomol. Chem. 2015, 13, 2800. (d) Jash, M.; Das, B.; Chowdhury, C. J. Org. Chem. 2016, 81, 10987. (13) (a) Piou, T.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14, 3760. (b) Vachhani, D. D.; Butani, H. H.; Sharma, N.; Bhoya, U. C.; Shah, A. K.; Van der Eycken, E. V. Chem. Commun. 2015, 51, 14862. (c) Sharma, U. K.; Sharma, N.; Kumar, Y.; Singh, B. K.; Van der Eycken, E. V. Chem. - Eur. J. 2016, 22, 481. (d) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.; Schoenebeck, F.; Lautens, M. Nat. Chem. 2017, 9, 361.

E

DOI: 10.1021/acs.orglett.8b01235 Org. Lett. XXXX, XXX, XXX−XXX