Chiral Phosphoric-Acid-Catalyzed Regioselective and

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

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Chiral Phosphoric-Acid-Catalyzed Regioselective and Enantioselective C7-Friedel−Crafts Alkylation of 4‑Aminoindoles with Trifluoromethyl Ketones Lu Cai,†,‡,§ Yunlong Zhao,†,§ Tongkun Huang,† Shanshui Meng,*,† Xian Jia,‡ Albert S. C. Chan,*,† and Junling Zhao*,† †

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China

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ABSTRACT: A highly regioselective and enantioselective C7-Friedel−Crafts alkylation of 4-aminoindoles with trifluoromethyl ketones promoted by a spirocyclic phosphoric acid was developed. This strategy was applicable to various substituted trifluoromethyl ketones and 4-aminoindole derivatives, affording the corresponding C7-functionalized indole derivatives, bearing a pharmaceutically interesting trifluoromethylated tertiary alcohol scaffold, in 21%−98% yields with up to >99% enantiomeric excess (ee). ompared to their fluorine-free analogues, the fluorinated compounds often have increased metabolic stability and bioavailability, because of the unique physical and chemical properties of the F atom (such as small size, high electronegativity, and high C−F bond dissociation energy).1 As a result, more than 20% of the modern pharmaceuticals and agrochemicals contain F atoms.2 For example, efavirenz (antiHIV),3 sorafenib (anticancer),4 mefloquine (antimalaria),5 and fluralaner (insecticide)6 are all trifluoromethyl-bearing compounds. Consequently, the development of new synthetic methodologies that allow the incorporation of F atoms, especially trifluoromethyl scaffold, on pharmaceutically interesting frameworks are in great need. Indole is one of the most important nitrogen-containing heterocycles, and it has been regarded as “a privileged structure” in natural products and drug discovery.7,8 The catalytic asymmetric Friedel−Crafts alkylation of indoles with prochiral trifluoromethylated electrophiles is a reliable approach for the synthesis of chiral trifluoromethyl-containing indole derivatives.9 Among which, reaction using trifluoromethyl ketones as Friedel−Crafts acceptors has attracted considerable attention,10 because the resulting optically active trifluoromethyl-substituted tertiary alcohols are valuable pharmaceutical intermediates and chiral building blocks.11 Even many elegant protocols have been documented using different catalytic strategies, but the electrophilic substitution occurred dominantly at the more nucleophilic C3 position of indoles.10 In some specific cases, the alkylation could switched to C2 position when using C3-substituted indoles or 4,7dihydroindole (a pyrrole derivative) as nucleophiles.12 To the best of our knowledge, there are no reports on the direct catalytic asymmetric Friedel−Crafts alkylation of indoles with

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© XXXX American Chemical Society

trifluoromethyl ketones at the less-reactive carbocyclic positions. In fact, the functionalization of indole carbocycle is still a difficult and hot topic in indole chemistry. Taking advantage of the activating/directing ability of the hydroxyl group, the asymmetric functionalization of indole carbocyclic positions were recently reported using hydroxyindoles as nucleophiles, and the alkylation will occur regioselectively at the ortho position of the hydroxyl group.13 However, only limited electrophiles were applicable, and C3 substitution products were obtained in the case of Friedel−Crafts alkylation of trifluoromethyl ketones with hydroxyindoles.10h,13b As our continuing research interest in the asymmetric functionalization of indole derivatives,13d,14 we recently reported an example of regioselective and enantioselective C7 functionalization of indoles with 4-aminoindoles as Friedel−Crafts donors.15 In order to expand the substrate scope of our strategy, we herein reported the regioselective and enantioselective Friedel−Crafts alkylation 4-aminoindoles with trifluoromethyl ketones, to provide an efficient method for the synthesis of optically enriched trifluoromethylated 7-indolylmethanol derivatives. Initially, 2,2,2-trifluoroacetophenone (2a) and 4-aminoindole 3a were treated with BINOL-derived chiral phosphoric acid 1a in dichloromethane at room temperature. Gratifyingly, the corresponding C7-functionalized product 4aa was produced as the only adduct in 37% yield and 38% enantiomeric excess (ee). Encouraged by this result, a series of BINOL- and SPINOL-derived chiral phosphoric acids have been examined, and the results are summarized in Table 1. It Received: March 6, 2019

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DOI: 10.1021/acs.orglett.9b00821 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

entry

catalyst

solvent

yieldb (%)

enantiomeric excess, eec (%)

1 2 3 4 5 6 7 8 9 10 11 12 13e 14 15e 16e 18

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1i 1i 1i 1i 1i

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 EtOAc CHCl3 toluene CH3CN ClCH2CH2Cl

37 61 31 73 27 37 92 68 71 81 84 85 54 60 30 24 86

38d 4d 21d 43d 11d 28d 85d 59d 97 4 64 60 66 93 75 96 98

Scheme 1. Scope of Trifluoromethyl Ketonesa

a

Reactions conditions: 2 (0.15 mmol), 3a (0.1 mmol), 1i (0.01 mmol), 1,2-dichloroethane (0.5 mL), room temperature, 4−48 h. Isolated yields are given. Enantiomeric excess was determined by HPLC on a chiral stationary phase.

a

Reactions were performed on a 0.1 mmol scale in 0.5 mL solvent at room temperature, unless otherwise noted. bIsolated yields are given. c Enantiomeric excess was determined by high-performance liquid chromatography (HPLC) on a chiral stationary phase. dOpposite configuration. eReaction time is 48 h.

bearing electron-donating (4ba and 4ca) or ortho (4ja and 4ka) substituents at the aromatic ring. Heteroaromatic ketones, such as 2-furyl (2p), 2-thienyl (2q), 2-benzofuryl (2s), reacted smoothly with 3a under the optimal conditions to furnish the corresponding products with high yields and excellent enantioselectivity. Aliphatic trifluoromethyl ketones are also applicable in our strategy; however, relatively lower yields were obtained due to the low electrophilic activities of those substrates. For example, when trifluoromethyl methyl ketone (2t) was used, product 4ta was isolated in only 42% yield and 33% ee, and the use of ethyl trifluoroacetoacetate (2u) gave 4ua in 45% yield with 80% ee. It was noteworthy that the reaction works well for substrates with the trifluoromethyl moiety being replaced with a difluoromethyl group (2w) or an ester moiety (2v), to give the corresponding products 4wa and 4va in 69% and 42% yields with 87% and 78% ee, respectively. More importantly, propargyl ketone (2x) is also a good acceptor in this reaction, and the corresponding tertiary 7-indolyl propargylic trifluoromethyl alcohol (4xa) was formed in 85% yield with 96% ee. The propargyl moiety is a versatile building block and enables many further transformations,16 which makes this strategy more attractive. The application of highly reactive ethyl trifluoropyruvate (2z) in this C7-Friedel−Crafts alkylation was also studied, furnishing C7-substituted product 4za in 56% yield and 63% ee.17 The absolute configuration of 4fa was determined to be S by X-ray crystallographic analysis. The configuration of the rest of the

was found that this reaction has good regioselectivity, and SPINOL-derived catalyst 1i proved to be the best, to give 4aa in 71% yield with 97% ee (Table 1, entry 9). After the determination of the catalyst, the effect of the reaction solvent was then studied. As shown in Table 1, both the yield and enantioselectivity were strongly affected by the reaction media, solvents such as ethyl acetate and toluene gave relatively lower yields and ee values, even with prolonged reaction time (Table 1, entries 13 and 15), while 1,2-dichloroethane was found to be the optimal, affording the product 4aa in 86% yield and 98% ee (Table 1, entry 18). With the optimal reaction conditions established, we subsequently examined the substrate scope of this transformation, with respect to different substituted trifluoromethyl ketones (Scheme 1). Generally, our methodology was applicable to various substituted trifluoromethyl ketones (2) with excellent regioselectivity, producing the corresponding tertiary 7-indolyl trifluoromethyl alcohols in good to high yield with high enantioselectivity in most cases. In the case of aromatic ketones, the electron nature of substituents and substitution patterns at the aromatic ring has little effect on the stereoselectivity, both electron-donating and electron-withdrawing groups were well-tolerated to give the corresponding products with excellent enantioselectivity (80% ee → 99% ee). However, relatively lower yields were observed with ketones B


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Organic Letters

states were depicted in Scheme 3. In this transformation, chiral phosphoric acid acted as a bifunctional catalyst, and both

products was assigned assuming a uniform stereochemical mechanism. The substrate scope of 4-aminoindoles was also studied, and the results are presented in Scheme 2. The results indicated

Scheme 3. Proposed Transition State

Scheme 2. Scope of 4-Aminoindolesa

substrates were activated through hydrogen-bonding interactions with the catalyst. Besides the traditional nucleophilic C3 position, the indole C7 position is also activated because of the para activating effect of the amino moiety. Accordingly, there are two possible pathways in this transformation, TS-I and TS-II, which respectively give C3 alkylation product 4′ and C7 alkylation product 4. In this case, electrophilic substitution at the C3 is becoming difficult, because of the steric hindrance caused by the substituted amino moiety at C4 position, while the alkylation at the C7 position gains an upper hand to give product 4 in excellent regioselectivity. The utility of this C7-Friedel−Crafts alkylation was finally explored. The reaction of 2a and 3a was performed on a 2 mmol scale, producing 4aa in 93% yield with the high enantioselectivity retained (Scheme 4a). The 2-chlorobenzyl

a

Reactions conditions: 2a (0.15 mmol), 3 (0.1 mmol), 1i (0.01 mmol), 1,2-dichloroethane (0.5 mL), room temperature, 24−48 h. Isolated yields are given. Enantiomeric excess was determined by HPLC on a chiral stationary phase.

that variations of the functional groups on the amino moiety has little effect on the reaction efficiency, the corresponding C7-substituted products were synthesized in moderate to high yields with excellent regioselectivity and enantioselectivity. For example, N-(cyclopropylmethyl)-1H-indol-4-amine (3f) and ethyl 2-((1H-indol-4-yl)amino)acetate (3i) gave products 4af and 4ai both in 73% yields and 94% and 90% ee, respectively. However, unsubstituted amino moiety will somehow suppress the reaction, and this was exemplified by the reaction of 4aminoindole (3j). In this specific case, only trace amounts of product were detected via thin-layer chromatography (TLC) after three days, because of the condensation of the primary amino group and the carbonyl moiety. 4-Diallylaminoindole (3k) produced 4ak in 48% yield with 48% ee. Then, the effect of substituents on the pyrrole ring of indole was examined. Probably because of the steric hindrance, the presence of a phenyl group at the indole C2 position significantly decreased the nucleophilic activity of 3c, and the corresponding product 4ac was produced in only 21% yield and 91% ee even with a prolonged reaction time. However, when less sterically hindered methyl group was used, excellent results are obtained. 2-Methyl substrate (3d) gave a high yield (87%) of 4ad with excellent enantioselectivity (99% ee). Bulky substituent at C3 position, such as isopropyl (3e), also led to a decreased yield (49%). It is also noteworthy that N1 methylated substrate 3l did not react with 2a under the optimal conditions. Based on our experimental results together with previous reports on phosphoric acid catalysis,18 the plausible transition

Scheme 4. (a) Scale-Up Synthesis of 4aa, and (b) Transformation of 4aa

moiety on the amino group could be readily removed. For example, when 4aa was treated with ammonium formate and Pd/C in methanol at reflux, the corresponding product 5 was formed in 95% yield and 97% ee (Scheme 4b). In conclusion, we have successfully applied our strategy for the high regioselective C7-Friedel−Crafts alkylation of indoles C


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Organic Letters

(4) Keating, G. M.; Santoro, A. Sorafenib A Review of its Use in Advanced Hepatocellular Carcinoma. Drugs 2009, 69, 223. (5) Müller, M.; Orben, C. M.; Schützenmeister, N.; Schmidt, M.; Leonov, A.; Reinscheid, U. M.; Dittrich, B.; Griesinger, C. The Absolute Configuration of (+)- and (−)-erythro-Mefloquine. Angew. Chem., Int. Ed. 2013, 52, 6047. (6) Asahi, M.; Kobayashi, M.; Matsui, H.; Nakahira, K. Differential Mechanisms of Action of the Novel γ-Aminobutyric Acid Receptor Antagonist Ectoparasiticides Fluralaner (A1443) and Fipronil. Pest Manage. Sci. 2015, 71, 91. (7) (a) Sundberg, R. J. In The Chemistry of Indoles; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Academic Press: New York, 1996. (b) Ryan, K. S.; Drennan, C. L. Divergent Pathways in the Biosynthesis of Bisindole Natural Products. Chem. Biol. 2009, 16, 351. (c) Brown, R. K. In Indoles; Houlihan, W. J., Ed.; Wiley− Interscience: New York, 1972. (8) (a) Cacchi, S.; Fabrizi, G. Synthesis and Functionalization of Indoles Through Palladium-catalyzed Reactions. Chem. Rev. 2005, 105, 2873. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures. Chem. Rev. 2003, 103, 893. (c) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances, 4th Edition; Thieme: New York, 2001. (d) Bonjoch, J.; Solé, D. Synthesis of Strychnine. Chem. Rev. 2000, 100, 3455. (e) Humphrey, G. R.; Kuethe, J. T. Practical Methodologies for the Synthesis of Indoles. Chem. Rev. 2006, 106, 2875. (9) Nie, J.; Guo, H. C.; Cahard, D.; Ma, J. A. Asymmetric Construction of Stereogenic Carbon Centers Featuring a Trifluoromethyl Group from Prochiral Trifluoromethylated Substrates. Chem. Rev. 2011, 111, 455. (10) For selected examples on Friedel−Crafts alkylation of indoles with trifluoromethyl ketones, see: (a) Török, B.; Abid, M.; London, G.; Esquibel, J.; Török, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Highly Enantioselective Organocatalytic Hydroxyalkylation of Indoles with Ethyl Trifluoropyruvate. Angew. Chem., Int. Ed. 2005, 44, 3086. (b) Nakamura, S.; Hyodo, K.; Nakamura, Y.; Shibata, N.; Toru, T. Novel Enantiocomplementary C2-Symmetric Chiral Bis(imidazoline) Ligands: Highly Enantioselective Friedel−Crafts Alkylation of Indoles with Ethyl 3,3,3-Trifluoropyruvate. Adv. Synth. Catal. 2008, 350, 1443. (c) Nie, J.; Zhang, G. W.; Wang, L.; Fu, A.; Zheng, Y.; Ma, J. A. A Perfect Double Role of CF3 Groups in Activating Substrates and Stabilizing Adducts: the Chiral Brønsted Acid-Catalyzed Direct Arylation of Trifluoromethylketones. Chem. Commun. 2009, 2356. (d) Ma, J.; Kass, S. R. Asymmetric Arylation of 2,2,2-Trifluoroacetophenones Catalyzed by Chiral Electrostatically-Enhanced Phosphoric Acids. Org. Lett. 2018, 20, 2689. (e) Kasztelan, A.; Biedrzycki, M.; Kwiatkowski, P. High-Pressure-Mediated Asymmetric Organocatalytic Hydroxyalkylation of Indoles with Trifluoromethyl Ketones. Adv. Synth. Catal. 2016, 358, 2962. (f) Kashikura, W.; Itoh, J.; Mori, K.; Akiyama, T. Enantioselective Friedel−Crafts Alkylation of Indoles, Pyrroles, and Furans with Trifluoropyruvate Catalyzed by Chiral Phosphoric Acid. Chem. - Asian J. 2010, 5, 470. (g) Biedrzycki, M.; Kasztelan, A.; Kwiatkowski, P. High-Pressure Accelerated Enantioselective Addition of Indoles to Trifluoromethyl Ketones with a Low Loading of Chiral BINOL-Derived Phosphoric Acid. ChemCatChem 2017, 9, 2453. (h) Han, X.; Ouyang, W.; Liu, B.; Wang, W.; Tien, B.; Wu, S.; Zhou, H. B. Enantioselective Inhibition of Reverse Transcriptase (RT) of HIV-1 by Non-Racemic Indole-Based Trifluoropropanoates Developed by Asymmetric Catalysis Using Recyclable Organocatalysts. Org. Biomol. Chem. 2013, 11, 8463. (11) (a) Mü l ler, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881. (b) Thayer, A. M. Constructing Life Sciences Compounds. Chem. Eng. News 2006, 84, 15. (12) (a) Huang, B. B.; Wu, L.; Liu, R. R.; Xing, L. L.; Liang, R. X.; Jia, Y. X. Enantioselective Friedel−Crafts C2-Alkylation of 3Substituted Indoles with Trifluoropyruvates and Cyclic N-Sulfonyl α-Ketiminoesters. Org. Chem. Front. 2018, 5, 929. (b) Wang, T.; Zhang, G. W.; Teng, Y.; Nie, J.; Zheng, Y.; Ma, J. A. Chiral Brønsted

with trifluoromethyl ketones as electrophiles. This transformation was efficiently catalyzed by a spirocyclic phosphoric acid catalyst, yielding the corresponding products in moderate to high yields with excellent enantioselectivity in most cases. This strategy was not only applicable to various substituted trifluoromethyl ketones, but also difluoromethyl ketones and benzoylformates. More importantly, the resulting products are optically active trifluoromethyl and 7-indolyl-substituted tertiary alcohols, which are of interest in medicinal chemistry. The possible mechanism of this reaction was also discussed.

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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.9b00821. Typical experimental procedure and characterization for all products (PDF) Accession Codes

CCDC 1895141 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] (S. Meng). *E-mail: [email protected] (A. S. C. Chan). *E-mail: [email protected] (J. Zhao). ORCID

Shanshui Meng: 0000-0002-3334-0648 Junling Zhao: 0000-0002-2960-0830 Author Contributions §

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Grant No. 21772199) and the Research Foundation for Advanced Talents of Sun Yat-sen University (No. 3600018821101) for financial support of this program.

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REFERENCES

(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320. (b) Isanbor, C.; O’Hagan, D. Fluorine in Medicinal Chemistry: A Review of Anti-Cancer Agents. J. Fluorine Chem. 2006, 127, 303. (c) Prakash, G. K. S.; Wang, F. Fluorine: The New Kingpin of Drug Discovery. Chim. Oggi. 2012, 30, 30. (2) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Trifluoromethyltrimethylsilane: Nucleophilic Trifluoromethylation and Beyond. Chem. Rev. 2015, 115, 683. (3) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, N. A.; Bacheler, L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova, B. C.; Garber, S.; Logue, K.; Trainor, G. L.; Anderson, P. S.; EricksonViitanen, S. K. Inhibition of Clinically Relevant Mutant Variants of HIV-1 by Quinazolinone Non-Nucleoside Reverse Transcriptase Inhibitors. J. Med. Chem. 2000, 43, 2019. D


Letter

Organic Letters Acid-Catalyzed Enantioselective Friedel−Crafts Reaction of 4,7Dihydroindoles with Trifluoromethyl Ketones. Adv. Synth. Catal. 2010, 352, 2773. (13) (a) Montesinos-Magraner, M.; Vila, C.; Rendón-Patiño, A.; Blay, G.; Fernández, I.; Muñoz, M. C.; Pedro, J. R. Organocatalytic Enantioselective Friedel−Crafts Aminoalkylation of Indoles in the Carbocyclic Ring. ACS Catal. 2016, 6, 2689−2693. (b) MontesinosMagraner, M.; Vila, C.; Blay, G.; Fernández, I.; Muñoz, M. C.; Pedro, J. R. Hydroxy-Directed Enantioselective Hydroxyalkylation in the Carbocyclic Ring of Indoles. Org. Lett. 2017, 19, 1546−1549. (c) Vila, C.; Rostoll-Berenguer, J.; Sánchez-García, R.; Blay, G.; Fernández, I.; Muñoz, M. C.; Pedro, J. R. Enantioselective Synthesis of 2-Amino-1,1diarylalkanes Bearing a Carbocyclic Ring Substituted Indole through Asymmetric Catalytic Reaction of Hydroxyindoles with Nitroalkenes. J. Org. Chem. 2018, 83, 6397−6407. (d) Xiao, M. J.; Xu, D. F.; Liang, W. H.; Wu, W. Y.; Chan, A. S. C.; Zhao, J. L. Organocatalytic Enantioselective Friedel−Crafts Alkylation/Lactonization Reaction of Hydroxyindoles with Methyleneoxindoles. Adv. Synth. Catal. 2018, 360, 917. (e) Liu, J. Y.; Yang, X. C.; Lu, H.; Gu, Y. C.; Xu, P. F. Organocatalytic, Enantioselective Friedel−Crafts Reaction of Indoles in the Carbocyclic Ring and Electron-Rich Phenols. Org. Lett. 2018, 20, 2190. (14) (a) Bi, B.; Lou, Q. X.; Ding, Y. Y.; Chen, S. W.; Zhang, S. S.; Hu, W. H.; Zhao, J. L. Chiral Phosphoric Acid Catalyzed Highly Enantioselective Friedel−Crafts Alkylation Reaction of C3-Substituted Indoles to β,γ-Unsaturated α-Ketimino Esters. Org. Lett. 2015, 17, 540. (b) Ding, Y. Y.; Xu, D. F.; Meng, S. S.; Li, Y.; Zhao, J. L. Chiral Phosphoric Acid Catalyzed Enantioselective Friedel−Crafts Reaction of N-Protected 4-Aminoindoles with β,γ-Unsaturated αKetimino Esters. Adv. Synth. Catal. 2018, 360, 664. (c) Lou, Q. X.; Ding, Y. Y.; Xu, D. F.; Liu, G. K.; Zhao, J. L. Organocatalytic Enantioselective Synthesis of Dihydropyrano-indole Derivatives Bearing Trifluoromethylated All-Carbon-Substituted Stereocenters. Adv. Synth. Catal. 2017, 359, 2557. (d) Zhao, Y. L.; Wang, L. S.; Zhao, J. L. Chiral phosphoric acid catalyzed aza-Friedel−Crafts alkylation of indoles with cyclic aryl α-ketimino esters. Tetrahedron Lett. 2017, 58, 213. (15) Xun, W.; Xu, B.; Chen, B.; Meng, S. S.; Chan, A. S. C.; Qiu, F. G.; Zhao, J. L. Regio and Enantioselective Organocatalytic Friedel− Crafts Alkylation of 4-Aminoindoles at the C7-Position. Org. Lett. 2018, 20, 590. (16) Chen, L.; Chen, K.; Zhu, S. Transition-Metal-Catalyzed Intramolecular Nucleophilic Addition of Carbonyl Groups to Alkynes. Chem. 2018, 4, 1208. (17) The reaction was completed within 40 min with a total yield of 28% polysubstituted products formed. (18) Fu, A.; Meng, W.; Li, H.; Nie, J.; Ma, J. A. A Density Functional Study of Chiral Phosphoric Acid-catalyzed Direct Arylation of Trifluoromethyl Ketone and Diarylation of Methyl Ketone: Reaction Mechanism and the Important Role of the CF3 Group. Org. Biomol. Chem. 2014, 12, 1908.

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Chiral Phosphoric-Acid-Catalyzed Regioselective and

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