Palladium-Catalyzed Direct C3-Selective Arylation of N-Unsubstituted

Letter pubs.acs.org/OrgLett

Palladium-Catalyzed Direct C3-Selective Arylation of N‑Unsubstituted Indoles with Aryl Chlorides and Triflates Miyuki Yamaguchi, Kohei Suzuki, Yusuke Sato, and Kei Manabe* School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan S Supporting Information *

ABSTRACT: The direct C3-arylation of N-unsubstituted indoles with aryl chlorides and triflates has been realized using a palladium−dihydroxyterphenylphosphine (DHTP) catalyst. The site selectivity is different from that obtained with other structurally related ligands. This unique feature of the DHTP ligand is attributed to complex formation between the lithium salts of the ligand and the indole. The method was applied to the late-stage derivatization of pharmaceuticals having a chloro group.

A

Scheme 1. Pd-Catalyzed Arylation of N-Unsubstituted Indoles with Aryl Halides and Triflates

rylindoles are key structural components of many natural products and pharmaceuticals, and considerable effort has been devoted to developing efficient synthetic methods for their preparation.1 C3-arylated indoles are a particularly important class of compounds with diverse biological activities such as antimicrobial,2 anti-inflammatory,3 and anticancer activities.4 Late-stage functionalization by direct arylation of indoles provides a powerful tool for the synthesis of C3-arylated indoles.5 The introduction of an aromatic moiety at the C-3 position of indoles is typically achieved by transition-metalcatalyzed cross-coupling reactions,6 such as palladium-catalyzed direct C−H functionalization. Transition-metal-free processes have also been reported; however, some drawbacks, such as the need for highly reactive arylating agents (e.g., hypervalent iodine reagents7 and diazonium salts8) and low regioselectivity due to benzyne-like intermediates,9 limit their application. In Pdcatalyzed direct C−H functionalization reactions, aryl halides are often used as reactants. However, in the reaction of Nunsubstituted indoles, control of site selectivity is an important issue, as arylation occurs also at the C-2 or N-1 position of the indole moiety (Scheme 1a).5a,b In addition, arylating agents for the C3-arylation of N-unsubstituted indoles are limited to aryl iodides and bromides,10 and only a few reactions with less reactive but readily available aryl chlorides have been reported,9,11 which usually result in N-arylation (Scheme 1b).12 Recently, Veisi and co-worker reported the direct arylation of indoles at the C-3 position with aryl chlorides using a catalyst derived from palladium nanoparticles immobilized on single-wall carbon nanotubes.11 However, the development of efficient methods with a broad substrate scope for the synthesis of C3-arylated indoles is still highly desirable. Moreover, no examples of C3-arylation using aryl triflates as arylating agents, which are readily prepared from the corresponding phenols, have been reported, as the reaction provides exclusively the corresponding N-arylated product (Scheme 1b).12b © 2017 American Chemical Society

Over the past decade, we have developed various hydroxylated terphenylphosphine ligands such as dihydroxyterphenylphosphine (DHTP), which have been successfully applied to site-selective Pd-catalyzed cross-coupling reactions of halophenols and haloanilines.13 In these reactions, the Pd−DHTP catalyst and halophenol or haloaniline form a heteroaggregate via a metal phenoxide or anilide intermediate, bringing the halogen in the ortho position to the hydroxy or amino group close to the palladium atom for site-selective oxidative addition. In our investigations, we have now found that Cy-DHTP (1a)13e,j also enables site-selectivity switching in Pd-catalyzed arylation reactions of indoles (Scheme 1c). Herein, we report a Pd−1a-catalyzed C3-selective direct arylation of N-unsubstituted indoles with aryl chlorides and triflates. Received: August 28, 2017 Published: September 12, 2017 5388

DOI: 10.1021/acs.orglett.7b02669 Org. Lett. 2017, 19, 5388−5391

Letter

Organic Letters

11). Hydroxyterphenylphosphine 1c13a,f bearing one hydroxy group did not show C3-selectivity (entry 12), demonstrating the superiority of 1a over 1c, which was also observed in our previous studies on Kumada−Tamao−Corriu13e and Sonogashira couplings.13h,k,l Next, the effect of base was examined using the Pd−1a catalyst. Interestingly, no reaction occurred when sodium or potassium tert-butoxide was used instead of lithium tert-butoxide (entries 13 and 14), which prompted us to screen other lithium bases. However, the reaction in the presence of Li2CO3 or LiOH gave only small amounts of 4 (entries 15 and 16), and the use of Li3PO4 was found to be ineffective (entry 17). With the optimized conditions in hand, the scope of the arylating agents was examined (Scheme 2). First, the reaction

First, the effect of ligands and bases was studied (Table 1). Unsubstituted indole (2) and 4-chlorotoluene (3) were selected Table 1. Effect of Ligands and Bases in the Pd-Catalyzed C3Arylation of N-Unsubstituted Indole with Chlorotoluene

yield (%)a

a

entry

ligand

base

4

5

6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

no ligand PCy3 P(t-Bu)3·HBF4 PPh3 Cy-JohnPhos XPhos SPhos Xantphos DPPE 1a·HBF4 1b 1c·HBF4 1a·HBF4 1a·HBF4 1a·HBF4 1a·HBF4 1a·HBF4

t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuONa t-BuOK Li2CO3 LiOH Li3PO4

1 18 nd nd nd nd nd nd nd 85 (81)b 19 12 nd nd 1 2 nd

nd 6 nd nd 86b 62b 76b nd nd 1 1 31 nd nd nd nd nd

nd trace nd nd 4 8 2 nd nd 3 trace 2 nd nd nd nd nd

Scheme 2. Scope of Aryl Chlorides and Triflatesa

NMR yield. bIsolated yield. nd = not detected.

as model substrates, and the reactions were carried out under the conditions based on our previous study of site-selective cross-couplings,13h,i,k using catalysts derived from palladium acetate and a phosphine ligand, lithium tert-butoxide as a base, and toluene as a solvent. In the absence of ligand, the arylation reaction did not proceed (entry 1). When tricyclohexylphosphine was used, the desired C3-arylated product 4 was obtained in low yield along with a small amount of N-arylated 5 (entry 2). Under these conditions, tri-tert-butylphosphine and triphenylphosphine were ineffective (entries 3 and 4). Moreover, the use of Cy-JohnPhos,14 XPhos,12c or SPhos15 afforded N-arylated 5 selectively in good yield (entries 5−7), whereas the reaction using bidentate ligands failed to provide arylated products (entries 8 and 9). On the other hand, when the HBF4 salt of Cy-DHTP (1a) was used, the C3-selective reaction proceeded smoothly to give the desired 4 in good yield (entry 10). Notably, although structurally related, 1a and 2phosphinobiphenyl ligands such as Cy-JohnPhos gave opposite selectivities. DHTP 1b13e,j bearing a diphenylphosphino group also promoted the arylation reaction at the C-3 position selectively, although the yield of 4 was significantly lower (entry

a

Isolated yield. b1 mmol scale. c1.2 equiv of 3-chlorobenzotrifluoride were used. d1.2 equiv of 2 were used. ePd(OAc)2 (4 mol %), 1a·HBF4 (8 mol %). f1.5 equiv of 2 were used. 48 h.

using 4-bromotoluene or p-tolyl triflate instead of 3 was carried out. In both cases, the arylation proceeded selectively at the C-3 position, with p-tolyl triflate giving the desired 4 in higher yield (75%). To the best of our knowledge, this is the first example using aryl triflates in Pd-catalyzed direct C3-arylation of Nunsubstituted indoles. Moreover, chlorobenzene and aryl chlorides bearing an electron-donating group reacted smoothly with 2 to afford C3-arylated 7−10 in high yields. Next, aryl chlorides having an electron-withdrawing group were tested. 15389

DOI: 10.1021/acs.orglett.7b02669 Org. Lett. 2017, 19, 5388−5391

Letter

Organic Letters Chloro-4-fluorobenzene and 1-chloro-3-(trifluoromethyl)benzene gave 11 and 12, respectively, in moderate yields, whereas 1-chloro-4-nitrobenzene did not give the desired product 13. The reactions using heteroaryl chlorides afforded C3-arylated 14−16; however, 16 was accompanied by a significant amount of the corresponding N-arylated product (25%), which was separable from the desired product. The arylation of 2 using various aryl triflates was also carried out. Notably, higher yields of 10 and 11 were obtained with 4methoxyphenyl and 4-fluorophenyl triflate than with the corresponding aryl chlorides. In addition, benzo[d][1,3]dioxole, tetrahydronaphthalene, and Indane moieties could be successfully introduced into the 3-position of indoles using triflates as arylating agents, which were readily prepared from the corresponding hydroxy compounds, to afford the desired 17− 19, respectively. Next, the scope of indoles was investigated (Scheme 3). Indoles bearing substituents at various positions were reacted

Scheme 4. C3-Arylation of Indole with Pharmaceuticals Containing an Aryl Chloride Moiety

Scheme 3. Scope of Indolesa

yield along with a small amount of N-arylated product. In the case of (±)-chlorpheniramine (30), C3-arylated product 31 was obtained in 53% yield without formation of the N-arylated product, although a longer reaction time was required. Chlorine is one of the frequently used elements in pharmaceuticals, much more frequently than bromine or iodine, and the majority of the chlorine atoms are attached to an aromatic carbon.17 Therefore, this catalytic system will find further synthetic applications in late-stage introduction of an indole moiety to pharmaceuticals. A catalytic cycle is proposed in Scheme 5. First, the NH of indole 2 and the hydroxy groups of ligand 1a are deprotonated Scheme 5. Proposed Catalytic Cycle

a

Isolated yield. bPd(OAc)2 (4 mol %), 1a·HBF4 (8 mol %), t-BuOLi (3.5 equiv). The yield was determined after reduction to the corresponding indoline with NaBH3CN.16b

with 3 using the Pd−1a catalyst. 5-Methoxyindole and 5fluoroindole gave the corresponding products 20 and 21 in high and moderate yield, respectively. Indoles bearing substituents at the C-7 position also afforded the desired products (22 and 23) in moderate to good yields. When C2-substituted indoles were used, the yields of products (24 and 25) decreased, suggesting a steric hindrance effect on the reaction. On the other hand, Nmethylindole did not react, and 26 was not formed. Surprisingly, the reaction of 3-methylindole also proceeded, and 3,3disubstituted indolenine 27 was obtained. Although the yield and site selectivity of the reaction still need to be improved, to the best of our knowledge, this is the first example of C3arylation of 3-substituted indoles to synthesize 3,3-disubstituted compounds with simple aryl halides.16 The utility of this catalytic system was demonstrated by reacting indole with pharmaceuticals containing an aryl chloride moiety (Scheme 4). When 1 equiv of chlorpromazine (28) was used as a reactant, arylation proceeded selectively at the C-3 position of the indole to afford the desired product 29 in 65%

by t-BuOLi, and the obtained lithium salts form heteroaggregate A.18 Oxidative addition of aryl chloride or triflate to Pd gives intermediate B, in which the C-3 position of indole is close to the Pd atom thus promoting selective palladation to form intermediate C. This intermediate, which would be formed without significant strain according to a molecular model, 5390

DOI: 10.1021/acs.orglett.7b02669 Org. Lett. 2017, 19, 5388−5391

Letter

Organic Letters

(5) (a) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673. (b) Lebrasseur, N.; Larrosa, I. Adv. Heterocycl. Chem. 2012, 105, 309. (c) Sandtorv, A. H. Adv. Synth. Catal. 2015, 357, 2403. (6) Selected recent reviews: (a) Gribble, G. W. In Palladium in Heterocyclic Chemistry, 2nd ed.; Li, J. J., Gribble, G. W., Eds.; Elsevier: Amsterdam, 2007; p 303. (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (d) El Kazzouli, S.; Koubachi, J.; El Brahmi, N.; Guillaumet, G. RSC Adv. 2015, 5, 15292. (7) (a) Gu, Y.; Wang, D. Tetrahedron Lett. 2010, 51, 2004. (b) Ackermann, L.; Dell’Acqua, M.; Fenner, S.; Vicente, R.; Sandmann, R. Org. Lett. 2011, 13, 2358. (8) Zhang, Y.-P.; Feng, X.-L.; Yang, Y.-S.; Cao, B.-X. Tetrahedron Lett. 2016, 57, 2298. (9) Chen, J.; Wu, J. Angew. Chem., Int. Ed. 2017, 56, 3951. (10) Selected examples: (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (b) Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48, 2415. (c) Bellina, F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529. (d) Cusati, G.; Djakovitch, L. Tetrahedron Lett. 2008, 49, 2499. (e) Nikulin, M. V.; Lebedev, A. Y.; Voskoboinikov, A. Z.; Beletskaya, I. P. Dokl. Chem. 2008, 423, 326. (f) Ackermann, L.; Barfüßer, S. Synlett 2009, 2009, 808. (g) Joucla, L.; Batail, N.; Djakovitch, L. Adv. Synth. Catal. 2010, 352, 2929. (h) Perato, S.; Large, B.; Lu, Q.; Gaucher, A.; Prim, D. ChemCatChem 2017, 9, 389. (11) Veisi, H.; Morakabati, N. New J. Chem. 2015, 39, 2901. (12) (a) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575. (b) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403. (c) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (d) Suzuki, K.; Hori, Y.; Kobayashi, T. Adv. Synth. Catal. 2008, 350, 652. (e) Crawford, S. M.; Lavery, C. B.; Stradiotto, M. Chem. - Eur. J. 2013, 19, 16760. (f) Fareghi-Alamdari, R.; Haqiqi, M. G.; Zekri, N. New J. Chem. 2016, 40, 1287. (13) (a) Ishikawa, S.; Manabe, K. Chem. Lett. 2007, 36, 1302. (b) Ishikawa, S.; Manabe, K. Chem. Lett. 2007, 36, 1304. (c) Ishikawa, S.; Manabe, K. Org. Lett. 2007, 9, 5593. (d) Wang, J.-R.; Manabe, K. J. Org. Chem. 2010, 75, 5340. (e) Ishikawa, S.; Manabe, K. Angew. Chem., Int. Ed. 2010, 49, 772. (f) Ishikawa, S.; Manabe, K. Tetrahedron 2010, 66, 297. (g) Ishikawa, S.; Manabe, K. Tetrahedron 2011, 67, 10156. (h) Yamaguchi, M.; Katsumata, H.; Manabe, K. J. Org. Chem. 2013, 78, 9270. (i) Yamaguchi, M.; Manabe, K. Org. Lett. 2014, 16, 2386. (j) Yamaguchi, M.; Suzuki, K.; Manabe, K. Tetrahedron 2015, 71, 2743. (k) Yamaguchi, M.; Akiyama, T.; Sasou, H.; Katsumata, H.; Manabe, K. J. Org. Chem. 2016, 81, 5450. (l) Yamaguchi, M.; Manabe, K. Org. Biomol. Chem. 2017, 15, 6645. (14) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413. (15) Walker, S. D.; Barder, T. E.; Martnelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871. (16) C3-arylation reactions of 3-substituted indoles with hypervalent bismuth and iodine reagents were reported: (a) Barton, D. H. R.; Finet, J.-P.; Giannotti, C.; Halley, F. J. Chem. Soc., Perkin Trans. 1 1987, 241. (b) Eastman, K.; Baran, P. S. Tetrahedron 2009, 65, 3149. (17) Smith, B. R.; Eastman, C. M.; Njardarson, J. T. J. Med. Chem. 2014, 57, 9764. (18) Lithium salts of phenols and indoles are known to form homoaggregates through a four-membered Li−O(N)−Li−O(N) structure. For example, see: (a) De Vries, T. S.; Goswami, A.; Liou, L. R.; Gruver, J. M.; Jayne, E.; Collum, D. B. J. Am. Chem. Soc. 2009, 131, 13142. (b) Frenzel, A.; Herbst-Irmer, R.; Klingebiel, U.; Noltemeyer, M.; Schäfer, M. Z. Naturforsch., B: J. Chem. Sci. 1995, 50, 1658.

undergoes reductive elimination followed by deprotonation by t-BuOLi (or deprotonation followed by reductive elimination) to give the desired C3-arylated product. In this mechanism, binding of 1a to 2 via their lithium salts suppresses arylation at the N-1 position and promotes arylation at the C-3 position. Our hypothesis that complex formation between the NH of the indole and the hydroxy groups of the Pd−1a catalyst via the corresponding lithium salts is the key to successful arylation is supported by the lack of product formation in the reaction of Nmethylindole (Scheme 3). In summary, we have developed a direct C3-arylation of Nunsubstituted indoles with aryl chlorides and triflates using the Pd−1a catalyst. Complex formation between the Pd−1a catalyst and the indole via lithium salts is assumed to be the key to achieve C3-selectivity. This method enables the C3-functionalization of N-unsubstituted indole with readily available aryl chlorides and triflates, including bioactive compounds such as pharmaceuticals.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02669. Experimental procedures and characterization data, 1H and 13C NMR spectra (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kei Manabe: 0000-0002-9759-1526 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors thank Ryoya Hagiwara (University of Shizuoka) for his assistance in the indolenine synthesis. This work was partially supported by JSPS KAKENHI (Grant Numbers 15H04634, 15K18833, and 17K08214), the Society of Synthetic Organic Chemistry (Japan), the Uehara Memorial Foundation, and the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Japan Agency for Medical Research and Development (AMED).

■

REFERENCES

(1) (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (b) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29. (c) Gribble, G. W. Indole Ring Synthesis: From Natural Products to Drug Discovery; John Wiley & Sons Ltd.: West Sussex, 2016. (d) Joule, J. A. In Science of Synthesis, Vol. 10; Thomas, E. J., Ed.; Georg Thieme Verlag: Stuttgart, 2001; p 526. (e) Joule, J. A. In Science of Synthesis Knowledge Updates 2010/2, Vol. 10; Thomas, E. J., Ed.; Georg Thieme Verlag: Stuttgart, 2010; p 243. (2) Hoppe, H. H.; Kerkenaar, A.; Sijpesteijn, K. A. Pestic. Biochem. Physiol. 1976, 6, 422. (3) Hu, W.; Guo, Z.; Yi, X.; Guo, C.; Chu, F.; Cheng, G. Bioorg. Med. Chem. 2003, 11, 5539. (4) Brancale, A.; Silvestri, R. Med. Res. Rev. 2007, 27, 209. 5391

DOI: 10.1021/acs.orglett.7b02669 Org. Lett. 2017, 19, 5388−5391