C–H Activation as a Quick Access to

Letter Cite This: Org. Lett. 2018, 20, 712−715

pubs.acs.org/OrgLett

Domino Carbopalladation/C−H Activation as a Quick Access to Polycyclic Frameworks Nemai Saha,†,‡,§ Haiwen Wang,†,§ Shengyi Zhang,† Yongliang Du,† Daqian Zhu,† Yumin Hu,† Peng Huang,*,†,‡ and Shijun Wen*,†,‡ †

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China ‡ School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Road, Guangzhou 510006, China S Supporting Information *

ABSTRACT: A new type of domino reaction for synthesis of heterocycles fusing the important bioactive cores, such as oxindole, indoline, and isoquinoline, is presented. Upon exposure to the very common palladium catalyst, the conceptually designed N-alkenyl iodobiaryls undergo a sequential carbopalladation/C−H activation to build polycyclic frameworks. These novel unique frameworks may provide structure sources in fragment-based drug discovery. fficient synthesis of heterocyclic frameworks are in demand as they are widely present in natural products and pharmaceuticals.1 Recently, fragment-based drug discovery (FBDD) has become a powerful strategy to generate drug-hits toward the development of potential clinical drugs.2 Key features of FBDD require high-quality fragments with reasonable molecular weights, hydrogen bond donors/acceptors, and rigidity/flexibility. The development of novel frameworks is of importance to provide fragment sources in FBDD. In this regard, heterocyclic fragments are good candidates. We are interested in seeking compounds exhibiting antiproliferative ability against malignant cancers by targeting tumorigenic pathways.3 In the past, a series of heterocycles containing a biaryl system were made in our laboratory.4 Thus, we envisioned that some novel alkaloid-like scaffolds could be constructed by incorporating a biaryl with naturally important heterocycles like oxindole and isoquinoline (Figure 1).

E

offer a great avenue toward synthesis of oxindole derivatives mediated by palladium catalysis.8 Oxindole constitutes an essential core in natural products and biological useful compounds,9 and it may provide a structural basis in FBDD. Numerous synthetic methods are developed to build up the oxindole framework.10 The majority of the reported methods often involve external nucleophilic trapping of transient σ-alkyl PdII I-a arising from an intramolecular Heck reaction,11 resulting in several seminal synthetic pathways to oxindole derivatives II (Scheme 1a). In this regard, cyanides,12 hydrazones,13 CO,14 allenes,15 isocyanides,16 and others17 might be used. While R is an aryl group, I-a might also undergo another intramolecular C− H activation ready for further transformation.18 Scheme 1. Directed Cascade Pathways Initiated by an Intramolecular Heck Reaction

Figure 1. Heterocyclic frameworks fusing oxindole or isoquinoline motifs.

Domino reactions are able to construct modular molecular frameworks by forming multiple bonds in a single operation.5 Synthetic chemists continue to develop novel protocols to prepare heterocycles, especially employing transition-metalmediated domino transformations.6 Among them, the wellknown Heck reaction has received great attention.7 Haloarenes with a pendant olefin motif are useful substrates for potential intramolecular cascade reactions. For example, ortho-haloanilides © 2018 American Chemical Society

Received: December 8, 2017 Published: January 10, 2018 712

DOI: 10.1021/acs.orglett.7b03843 Org. Lett. 2018, 20, 712−715

Letter

Organic Letters

smoothly even at 60 °C, with 60% yield. This high spontaneity of the domino process was encouraging because C−H activation often demands high temperature.21 Notably, the reaction did not need additional ligands. Solvent had a pronounced effect on this cascade reaction. Protic methanol suppressed C−H activation and favored protonolysis of III-a to form 3,3-dimethyl oxindole. Acetonitrile, dioxane, and toluene gave low yields (Table S1). Having the optimal condition in hand, we next focused on the scope of substrates to explore the transformation generality (Figure 2). The functionality on the N-atom, viz, methyl, ethyl, and removable benzyl and 4-methoxybenzyl (PMB), was very tolerable (2a−2e). Remarkably, N-allyl was also compatible, providing an oxindole with an allyl untouched (2f). Substrates 1c−1g with more congested Ar1 containing additional Me and Ph provided the desirable oxindoles in excellent yields. Substituents on the Ar2 ring, including electron-donating groups (Me, t-Bu, dimethyl, OMe) and electron-withdrawing groups (F, CN, CO2Et), were also studied. When placed in the 4-position, all the substrates underwent the domino process with high efficiency (2h−2l). The substrate with a methyl at the ortho position also underwent the transformation smoothly (2m). Substrates containing a CN at the meta position led to regioselective preference to the ortho-isomer (2n/2n′ or 2o/ 2o′), likely attributed to the palladium chelation by ortho-CN in the transition state III-b. The ethyl and phenyl exhibited a similar result, generating the expected oxindoles (2q−2t) in excellent to moderate yields. The substrate bearing an allyl instead of acryloyl also underwent the domino process to afford indoline derivative 2u, of which the structure was confirmed by X-ray crystallography (Figure 2). It is noteworthy that the intramolecular carbopalladation was preferential to acryloyl in the presence of allyl, as documented in the formation of 2f. Increasing the number of heteroatoms at a proper range is of great importance in fragment scaffolds of FBDD and pharmaceuticals. Therefore, more heterocyclic moieties were investigated (Figure 3). The new substrates containing thienyl and pyridyl satisfactorily afforded the expected skeletons in good to excellent yields (4a−4e). The pyridyl substrate required additional Ph3P to achieve a good yield (4e) because coordination of a transition metal by pyridyl often compromises

Since 2-iodobiaryls were often used to prepare cyclic diaryliodoniums in our laboratory,19 we became interested in the construction of alkaloid-like polycyclic scaffolds from 2iodobiaryl III (Scheme 1b). It was our hypothesis that installation of an aryl ortho to the iodine in III would provide a potential C−H activation site for in situ generated palladium species III-a. Finally, reductive elimination of III-b would furnish tetracycle IV. With this strategy, several series of novel polycyclic frameworks could be obtained by using an approach of diversityoriented synthesis, providing chemical libraries for biological interrogation.20 To test our concept, the study began with 1a for the survey of reaction conditions. To our satisfaction, a tetracyclic oxindole 2a was successfully obtained quantitatively using catalytic Pd(OAc)2 with Na2CO3 as base in DMF at 95 °C (Scheme 2). Both Scheme 2. Domino Reaction under the Optimal Condition

NMR and mass spectroscopy unambiguously suggested the skeleton of 2a, further validated by a single-crystal X-ray analysis of its analogue 2c (Figure 2). The transformation also occurred

Figure 3. Substrate scope with phenyl−aryl/heteroaryl systems. a75 °C, 2 h. bAdditional PPh3 (0.2 equiv).

Figure 2. Substrate scope with biphenyl systems of 1. 713

DOI: 10.1021/acs.orglett.7b03843 Org. Lett. 2018, 20, 712−715

Letter

Organic Letters the catalyst reactivity.22 Other biaryl acrylamides containing an α- or a β-naphthyl moiety also underwent the transformation smoothly (4f, 4g). To gain more diversified fragments, different skeletons were considered to incorporate the biaryls by C−N bond connection. A pyrrole ring is present in a broad spectrum of biologically active compounds.23 Thus, N-arylpyrroles 5a,b were synthesized to test our domino reaction (Figure 4). Under the standard reaction

8c). Installation of an electron-donating or -withdrawing group did not impact the domino transformation (8d−8f). In our domino process, β-H elimination would compete with intramolecular C−H activation if there was a β-H present in the N-alkenyl motif of 1. Thus, two control experiments were then performed (Scheme 3). The C−H activation was disrupted, Scheme 3. Mechanistic Study

Figure 4. Transformation with the N-arylpyrrolyl system.

condition, the expected skeleton featuring a hybridized pyrrolyl/ piperidyl/oxindole was obtained in excellent yields (6a, 6b). The new results demonstrated that intramolecular C−H activation could proceed in the pyrrole ring at high efficacy. Ring size variation is a general strategy to ensure exploitation of the developed method. Thus, a new series of N-alkenyl biphenyl carboxamides 7a−7f were designed to build isoquinoline frameworks with a middle 6/6 ring system (Figure 5).

whereas β-H elimination was possible in substrate 9, leading completely to the formation of 10. When 11 with a cycloalkene motif was examined, a γ-H elimination was still dominant to produce 12, although α-H was absent. To gain further understanding of the kinetic pathways, we measured the kinetic isotope effect (KIE) of this domino process by performing two parallel reactions with either 1c or 1c-d5. The value of kH/kD (KIE = 2.76) implied that the C−H activation might be rate limiting in the domino process. In summary, we have developed a new type of domino reaction to access polycyclic frameworks catalyzed by a very common palladium species. A α-halobiaryl system is designed to realize domino Heck carbopalladation, C−H activation, and cyclization, forming two cycles and a quaternary center. Applying this approach, we have successfully constructed a series of novel ringfused heterocycles including oxindole, indoline, and isoquinoline. Our constructed molecular frameworks may provide fragment sources in FBDD. Moreover, preliminary biological evaluation indeed found some hits with obvious anticancer capacity (Figure S1).

■

ASSOCIATED CONTENT

S Supporting Information *

Figure 5. Domimo transformation with substrates 7.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03843. Experimental details, data characterization, and spectra copies (PDF)

Compared to those of aryl acryloylamide 1, the reactions with Nallyl aryl carboxamide 7 were sluggish and required more catalyst loading to complete the conversion. The NMR spectra of 7 recorded at room temperature showed signal multiplication, implying that 7 might have a torsional rotation to suppress the reaction. Under modified conditions, the expected isoquinoline skeletons were finally delivered in a good manner (8a−8f). As demonstrated in Figure 5, functionalities on the N-atom were well tolerated to give ring-fused isoquinoline derivatives (8a−

Accession Codes

CCDC 1557338 and 1557349 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. 714

DOI: 10.1021/acs.orglett.7b03843 Org. Lett. 2018, 20, 712−715

Letter

Organic Letters

■

(11) Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 14916−14919. (12) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. - Eur. J. 2007, 13, 961− 967. (13) (a) Xia, Y.; Wang, J. Chem. Soc. Rev. 2017, 46, 2306−2362. (b) Gao, Y.; Xiong, W.; Chen, H.; Wu, W.; Peng, J.; Gao, Y.; Jiang, H. J. Org. Chem. 2015, 80, 7456−7467. (14) (a) Liao, G.; Yin, X.-S.; Chen, K.; Zhang, Q.; Zhang, S.-Q.; Shi, B.F. Nat. Commun. 2016, 7, 12901−13000. (b) Frutos-Pedreno, R.; García-Lόpez, J.-A. Adv. Synth. Catal. 2016, 358, 2692−2700. (15) (a) Elboray, E. E.; Gao, C.; Grigg, R. Tetrahedron 2012, 68, 3103− 3111. (b) Volla, C. M. R.; Bäckvall, J.-E. ACS Catal. 2016, 6, 6398−6402. (16) Kong, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9714−9718. (17) (a) Kong, W.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137, 16028−16031. (b) Wang, M.; Zhang, X.; Zhuang, Y.-X.; Xu, Y.-H.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 1341−1347. (c) Sickert, M.; Weinstabl, H.; Peters, B.; Hou, X.; Lautens, M. Angew. Chem. 2014, 126, 5247−5251. (18) (a) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.; Schoenebeck, F.; Lautens, M. Nat. Chem. 2017, 9, 361−368. (b) PérezGόmez, M.; García-Lόpez, J.-A. Angew. Chem., Int. Ed. 2016, 55, 14389− 14393. (c) Piou, T.; Bunescu, A.; Wang, Q.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2013, 52, 12385−12389. (d) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460− 7461. (19) (a) Luo, B.; Cui, Q.; Luo, H.; Hu, Y.; Huang, P.; Wen, S. Adv. Synth. Catal. 2016, 358, 2733−2738. (b) Wu, Y.; Wu, F.; Zhu, D.; Luo, B.; Wang, H.; Hu, Y.; Wen, S.; Huang, P. Org. Biomol. Chem. 2015, 13, 10386−10391. (c) Liu, Z.; Zhu, D.; Luo, B.; Zhang, N.; Liu, Q.; Hu, Y.; Pi, R.; Huang, P.; Wen, S. Org. Lett. 2014, 16, 5600−5603. (20) Schreiber, S. L. Science 2000, 287, 1964−1969. (21) Bera, M.; Agasti, S.; Chowdhury, R.; Mondal, R.; Pal, D.; Maiti, D. Angew. Chem., Int. Ed. 2017, 56, 5272−5276. (22) Shang, M.; Wang, M.-M.; Saint-Denis, T. G.; Li, M.-H.; Dai, H.X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 5317−5321. (23) (a) Santhini, P. V.; Babu, S. A.; Krishnan, R. A.; Suresh, E.; John, J. Org. Lett. 2017, 19, 2458−2461. (b) Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868− 9878.

AUTHOR INFORMATION

Corresponding Authors

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

Shijun Wen: 0000-0002-9347-8243 Author Contributions §

N.S. and H.W. contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported in part by National Natural Science Foundation of China (81672952, 81430060), Guangdong Science and Technology Program (2017A020215198), and Guangzhou Science and Technology Program (201504010038, 201508020250, LCY201317).

■

REFERENCES

(1) (a) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369−375. (b) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960−9009. (c) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885−1898. (2) (a) Murray, C. W.; Rees, D. C. Nat. Chem. 2009, 1, 187−192. (b) Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. J. Med. Chem. 2008, 51, 3661−3680. (c) Nie, F.; Kunciw, D. L.; Wilcke, D.; Stokes, J. E.; Galloway, W. R. J. D.; Bartlett, S.; Sore, H. F.; Spring, D. R. Angew. Chem., Int. Ed. 2016, 55, 11139−11143. (d) Hung, A. W.; Ramek, A.; Wang, Y.; Kaya, T.; Wilson, J. A.; Clemons, P. A.; Young, D. W. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 6799−6804. (3) (a) Trachootham, D.; Zhou, Y.; Zhang, H.; Demizu, Y.; Chen, Z.; Pelicano, H.; Chiao, P. J.; Achanta, G.; Arlinghaus, R. B.; Liu, J.; Huang, P. Cancer Cell 2006, 10, 241−52. (b) Luo, B.; Wang, J.; Li, X.; Lu, W.; Yang, J.; Hu, Y.; Huang, P.; Wen, S. Molecules 2017, 22, 773. (4) (a) Zhu, D.; Liu, P.; Lu, W.; Wang, H.; Luo, B.; Hu, Y.; Huang, P.; Wen, S. Chem. - Eur. J. 2015, 21, 18915−18920. (b) Peng, X.; Luo, H.; Wu, F.; Zhu, D.; Ganesan, A.; Huang, P.; Wen, S. Adv. Synth. Catal. 2017, 359, 1152−1156. (5) For domino reactions, see: (a) Blouin, S.; Blond, G.; Donnard, M.; Gulea, M.; Suffert, J. Synthesis 2017, 49, 1767−1784 and references therein. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115−136. (6) For metal-catalyzed domino cascade, see: (a) Düfert, A.; Werz, D. B. Chem. - Eur. J. 2016, 22, 16718−16732. (b) Ardkhean, R.; Caputo, D. F. J.; Morrow, S. M.; Shi, H.; Xiong, Y.; Anderson, E. A. Chem. Soc. Rev. 2016, 45, 1557−1569. (c) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072− 3081. (7) (a) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320−2322. (b) Heck, R. F. Org. React. 1982, 27, 345. (c) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062−5085. (8) (a) Lee, Y.-C.; Patil, S.; Golz, C.; Strohmann, C.; Ziegler, S.; Kumar, K.; Waldmann, H. Nat. Commun. 2017, 8, 14043−14055. (b) Huang, J.R.; Sohail, M.; Taniguchi, T.; Monde, K.; Tanaka, F. Angew. Chem., Int. Ed. 2017, 56, 5853−5857. (c) Le, C. M.; Sperger, T.; Fu, R.; Hou, X.; Lim, Y. H.; Schoenebeck, F.; Lautens, M. J. Am. Chem. Soc. 2016, 138, 14441−14448. (9) (a) Shimizu, S.; Tsubogo, T.; Xu, P.; Kobayashi, S. Org. Lett. 2015, 17, 2006−2009. (b) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F. ACS Catal. 2014, 4, 743−762. (c) Trost, B. M.; Masters, J. T.; Burns, A. C. Angew. Chem., Int. Ed. 2013, 52, 2260−2264. (d) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247−7290. (10) (a) Kong, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2017, 56, 3987−3991. (b) Kong, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9714−9718. 715

DOI: 10.1021/acs.orglett.7b03843 Org. Lett. 2018, 20, 712−715