Heteroarylation of Indoles: Access to 2

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Letter Cite This: Org. Lett. 2018, 20, 7332−7335

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Palladium-Catalyzed Arylation/Heteroarylation of Indoles: Access to 2,3-Functionalized Indolines Nicolas Zeidan, Tamara Beisel, Rachel Ross, and Mark Lautens* Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada

Org. Lett. 2018.20:7332-7335. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/16/18. For personal use only.

S Supporting Information *

ABSTRACT: A palladium-catalyzed diastereoselective dearomatization of N-(2-bromobenzoyl)indoles by an arylation/ heteroarylation sequence is reported. Diverse functionalized indolines are accessed in good to excellent yields and selectivity. Studies conducted on the effects of copper in the reaction revealed that, along with improving conversions, the additive inhibits epimerization of the product.

D

Scheme 1. Literature Precedence of 1,2-Difunctionalizations of Olefins

eveloping modified scaffolds based on biologically relevant compounds is an important task for the discovery of new therapeutic agents. Accessing highly functionalized heterocycles, including indoles and indolines, which are prominent in many natural products and pharmaceutical agents, is of particular interest.1 Some of the most widely used syntheses and functionalizations of indoles rely on transition metal chemistry, as it allows for unique disconnections and atom economy.2 Our group and others have extensively investigated the intramolecular 1,2-carbofunctionalization of olefins.3 Utilizing this approach, Fagnou,4a Zhu,4b and Sharma and Van der Eycken4c have reported trapping of the σ-Pd intermediate with activated heterocycles (Scheme 1a). These direct C−H activations allow for rapid access to diverse compounds without the need for prefunctionalization of the reagent.5 Metal-catalyzed dearomatization of indoles has also been used to access complex indolines in a relatively short number of steps.6 In a similar manner to 1,1-disubstituted olefins, N-(2bromobenzoyl)indoles undergo a 1,2-difunctionalization by a sequential carbopalladation, and nucleophilic trapping of the benzylic-palladium intermediate to access 2,3-substitued indolines bearing proximate sterically congested carbon centers (Scheme 1b).7 We report herein a palladium-catalyzed dearomatization by sequential arylation/direct heteroarylation of indoles using activated heterocycles as the coupling partners (Scheme 1c). We began our studies with benzothiazole (BTA) as the coupling partner for its potentially useful therapeutic effects.8 After screening the reaction parameters, we found that 0.2 mmol of 1a with 5 mol % Pd(t-Bu3P)2, 8 equiv of BTA, 2 equiv of Cs2CO3, and 40 mol % CuCl2 in toluene at 120 °C for 15 h © 2018 American Chemical Society

provided the dearomatized product 2aa in quantitative yield as a single diastereomer, as confirmed by single-crystal X-ray Received: October 16, 2018 Published: November 7, 2018 7332

DOI: 10.1021/acs.orglett.8b03310 Org. Lett. 2018, 20, 7332−7335

Letter

Organic Letters analysis.9 To assess the importance of the reaction parameters, we altered the conditions and evaluated the impact (Table 1).

Scheme 2. Varying the Indole Core in the Dearomative Arylation/Heteroarylation of Indolesa

Table 1. Effects of Reaction Parameters in the Dearomative Arylation/Heteroarylation of Indolesa

entry

change to standard condition

2aa (%)b

drc

1 2 3 4 5 6 7

none 1.2 equiv of Cs2CO3 4 equiv of BTA no CuCl2 CuCl instead of CuCl2 PivOH instead of CuCl2 added 10 μL of H2O (2.8 equiv)

>99 67 83 60 62 74 97

>20:1 >20:1 >20:1 3.2:1 5.6:1 4.6:1 >20:1

a

Reactions run on 0.2 mmol scale. bYield of 2aa determined by NMR using trimethoxybenzene as an internal standard. cDiastereomeric ratio determined by NMR. BTA = benzothiazole

Lowering the equivalents of base (Table 1, entry 2) or BTA (Table 1, entry 3) resulted in a slightly diminished yield, with no impact on dr. Omitting CuCl2 from the reaction (Table 1, entry 4) resulted in diminished yields as well as lower dr, suggesting the additive influences the rate or longevity of the catalyst as well as affects epimerization. Notably, CuCl (Table 1, entry 5) as well as various Cu(I or II), Zn(II), Fe(III), and Yb(III) salts (not shown) did not improve the yield or dr. Pivalic acid, a common additive in C−H activation,10 improves the yield, but at the expense of poor diastereoselectivity (Table 1, entry 6). Finally, we found that the reaction tolerates a modest amount of water without catalyst deactivation (Table 1, entry 7). With the optimized conditions in hand, we investigated the scope with respect to the indole (Scheme 2). Product 2aa could be accessed on a 1 g scale, or by using the aryl iodide or aryl chloride variants of 1a in good yield with excellent dr. An electron-withdrawing group para- to the acyl linker (2b) or an electron-donating group para- to the halide (2e) was tolerated; however, the opposite electronic pattern provided products 2c and 2d with diminished yields. Substitution at the 5-position of the indole provided products 2f and 2g, albeit in reduced stereoselectivity. However, excellent dr was observed for the difluoro product 2h. A longer alkyl chain at the 2-position, as in the case of 2i or protected amine 2j, was tolerated. Additionally, Weinreb amide 2k, and a variety of 2-aryl indoles (2l−2o), all participated in the reaction. Finally, vinyl halide 1p was a compatible substrate in the diarylation reaction providing product 2p in good yield. Slow hydrolysis was observed for electron-deficient starting materials providing 2methylindole as a side product. In all other cases, only product was observed by crude NMR suggesting other decomposition pathways are operative. Next, we examined the scope with respect to the C−H partner. Pyridine-N-oxide as well as pentafluoro benzene provided products 2ab and 2ac, respectively, in good yield and excellent selectivity (Scheme 3). Under the standard conditions, benzoxazole provided the dearomatized product

a

Unless otherwise noted, reactions run on a 0.2 mmol scale. Reaction run using 10 mol % catalyst cReaction run at 100 °C. d Reaction run on 0.1 mmol scale. b

(2ad) in quantitative yield, albeit with poor selectivity. The diastereomers converged to a single diastereomer by alkylating the acidic position to give two fully substituted contiguous centers (3).11 Finally, no selectivity was seen with 4methylthiazole, providing both C2 and C5 arylation products in 62% (2ae) and 31% (2af) yields, respectively; however, they could be easily separated by column chromatography. Indoles, benzofurans, and benzothiophenes were not tolerated in the reaction, and only trace product could be observed. Finally, we investigated the role of copper(II) chloride on the reaction as both the yield and dr of the product increased when used (vide supra). We subjected a sample of the product to Cs2CO3 in toluene at 120 °C for 15 h (Table 2, entry 1). Although full recovery of the product was seen, the dr eroded to 2.4:1. The addition of 40 mol % copper gave a similar outcome (Table 2, entry 2). However, in the presence of 2 equiv of copper, full recovery of the material was achieved with no erosion in dr (Table 2, entry 7333

DOI: 10.1021/acs.orglett.8b03310 Org. Lett. 2018, 20, 7332−7335

Letter

Organic Letters

In conclusion, we have developed a palladium-catalyzed diastereoselective dearomatization of indoles by a 1,2arylation/direct heteroarylation sequence. Functionalized indolines are accessed in good to excellent yields and selectivity. The role of copper(II) chloride was investigated and was found to prevent epimerization of the easily epimerizable dibenzylic center, as well as improve conversions.

Scheme 3. Varying the Activated Heterocycle in the Dearomative Arylation/Heteroarylation of Indolesa

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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.8b03310. Experimental procedures, optimization, mechanistic studies, characterization data, X-ray data, and 1H/13C NMR spectra (PDF) Accession Codes

CCDC 1858836 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 [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 Author a

Reactions run on 0.2 mmol scale. bReactions run using 10 mol % catalyst. cNaH (1.2 equiv), alkyl-bromide (2 equiv), TBAI (20 mol %), DMF, 0 °C to rt.

*E-mail: [email protected]. ORCID

Nicolas Zeidan: 0000-0002-7959-5005 Mark Lautens: 0000-0002-0179-2914

Table 2. Epimerization Studies and Probing of the Effects of Cu(II) Chloridea

Notes

The authors declare no competing financial interest.

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a

ACKNOWLEDGMENTS We thank the Natural Science and Engineering Research Council (NSERC), the University of Toronto (UofT), and Alphora Inc. for financial support. N.Z. thanks the Province of Ontario for a graduate scholarship (OGS). T.B. thanks the Alexander von Humboldt Foundation for the Feodor Lynen Research Fellowship. R.R. thanks the NSERC and the University of Toronto for financial support. Thanks to Dr. Darcy Burns and the NMR team (University of Toronto), as well as Dr. Alan Lough (University of Toronto)for singlecrystal X-ray results.

3). We attribute the need for 2 equiv to the relative concentrations of copper and the product relative to the base during the progress of the reaction. That is, during the standard reaction, as the concentration of product increases, the concentration of base decreases, and hence, a smaller amount of copper is sufficient to maintain high dr values. The possibility of a diastereomeric resolution by copper was investigated (Table 2, entry 4), but no resolution was achieved. However, there was no change in dr suggesting epimerization is suppressed in both diastereomers.

(1) (a) Hino, T.; Nakagawa, M. In The Alkaloids: Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press: New York, 1989; Vol. 34, pp 1−410. (b) Taylor, A. P.; Robinson, R. P.; Fobian, Y. M.; Blakemore, D. C.; Jones, L. H.; Fadeyi, O. Org. Biomol. Chem. 2016, 14, 6611. (2) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (3) (a) Giri, R.; KC, S. J. Org. Chem. 2018, 83, 3013. (b) Yoon, H.; Marchese, A. D.; Lautens, M. J. Am. Chem. Soc. 2018, 140, 10950. (c) Yen, A.; Lautens, M. Org. Lett. 2018, 20, 4323. (4) (a) René, O.; Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4560. (b) Kong, W.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137, 16028. (c) Sharma, U. K.; Sharma, N.; Kumar, Y.; Singh, B. K.; Van Der Eycken, E. V. Chem. - Eur. J. 2016, 22, 481.

entry

additive

2aa + 2aa′ (%)b

drc

1 2 3 4d

none CuCl2 (40 mol %) CuCl2 (2 equiv) CuCl2 (2 equiv)

98 79 97 89

2.4:1 2.3:1 >20:1 4:1

■

Reactions run on 0.1 mmol scale. bYield of 2aa determined by NMR using trimethoxybenzene as an internal standard. cDiastereomeric ratio determined by NMR. dSample of 2aa used was 4:1 dr.

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REFERENCES

DOI: 10.1021/acs.orglett.8b03310 Org. Lett. 2018, 20, 7332−7335

Letter

Organic Letters (5) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Mei, T. S.; Kou, L.; Ma, S.; Engle, K.; Yu, J. Q. Synthesis 2012, 44, 1778. (c) Xue, X. S.; Ji, P.; Zhou, B.; Cheng, J. P. Chem. Rev. 2017, 117, 8622. (6) Zheng, C.; You, S. L. Chem. 2016, 1, 830. (7) (a) Petrone, D. A.; Kondo, M.; Zeidan, N.; Lautens, M. Chem. Eur. J. 2016, 22, 5684. (b) Liu, R. R.; Wang, Y. G.; Li, Y. L.; Huang, B. B.; Liang, R. X.; Jia, Y. X. Angew. Chem., Int. Ed. 2017, 56, 7475. (c) Shen, C.; Liu, R. R.; Fan, R. J.; Li, Y. L.; Xu, T. F.; Gao, J. R.; Jia, Y. X. J. Am. Chem. Soc. 2015, 137, 4936. (d) Zhao, L.; Li, Z.; Chang, L.; Xu, J.; Yao, H.; Wu, X. Org. Lett. 2012, 14, 2066. (e) Petrone, D. A.; Yen, A.; Zeidan, N.; Lautens, M. Org. Lett. 2015, 17, 4838. (f) Qin, X.; Lee, M. W. Y.; Zhou, J. S. Angew. Chem., Int. Ed. 2017, 56, 12723. (8) Kamal, A.; Syed, M. A. H.; Mohammed, S. M. Expert Opin. Ther. Pat. 2015, 25, 335. (9) CCDC Deposition Number: 1858836. (10) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496. (11) Only one isomer was observed under these reaction conditions. Alkylation proposed to occur stereoselectively from the convex face due to the rigid structure of the molecule (see ref 7e).

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DOI: 10.1021/acs.orglett.8b03310 Org. Lett. 2018, 20, 7332−7335