C–H γ,γ,γ-Trifluoroalkylation of Quinolines via Visible-Light-Induced

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C−H γ,γ,γ-Trifluoroalkylation of Quinolines via Visible-Light-Induced Sequential Radical Additions Yuhei Kumagai, Nanami Murakami, Futa Kamiyama, Ryo Tanaka, Tatsuhiko Yoshino,* Masahiro Kojima,* and Shigeki Matsunaga* Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

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ABSTRACT: The photocatalyst-free C−H γ,γ,γ-trifluoroalkylation of quinolines under visible light irradiation is reported. By the combination of readily available alkenes and Umemoto’s reagent II, a variety of γ,γ,γ-trifluoroalkyl groups were installed into quinolines via chemoselective sequential radical processes. This transformation provides rapid access to a variety of quinoline derivatives with scarcely explored fluoroalkyl groups, affording a novel library of N-heteroaromatic compounds and versatile building blocks for applications in medicinal chemistry.

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Therefore, we were motivated to develop a novel synthetic method that allows access to drug-like molecules bearing γ,γ,γtrifluoroalkyl groups. Given the prevalence of quinolines in medicinal chemistry,5 we initially aimed our investigation toward the C−H γ,γ,γ-trifluoroalkylation of quinolines. Relevant precedence for such alkylation of electron-deficient N-heteroaromatics has been reported by MacMillan, who showed that the C−H 3,3,3-trifluoropropylation of isoquinoline can be accomplished by photoredox/thiol dual catalysis using 3,3,3-trifluoropropanol (Scheme 1, (1)).6a The mild reaction conditions are favorable in terms of functional-group compatibility, but the preparation of the respective γ,γ,γtrifluoroalcohols is required to construct a large compound library. Studer has developed multicomponent radical reactions that involve trifluoromethyl radicals, alkenes, and quinoxalinones which proceed via electron catalysis7 (Scheme 1, (2)).6b While the ready availability of the reaction components is advantageous, this method was applied only to quinoxalin2(1H)-one, presumably because the basic reaction conditions hampered the Minisci-type C−H alkylation of electrondeficient N-heterocycles,8,9 in which activation of N-heteroaromatics by protonation plays a vital role. Moreover, the intrinsically gaseous iodotrifluoromethane employed as a source of trifluoromethyl radical is not a tractable reagent in laboratory-scale experiments. Although not directly applicable to C−H γ,γ,γ-trifluoroalkylation, Minisci has reported a relevant C−H alkylation strategy based on perfluoroalkyl iodide and alkenes that proceeds via a three-component radical addition (Scheme 1, (3)).6c Nevertheless, an elevated temperature was necessary to achieve the C−H functionalization of quinolines, and the functional-group tolerance as well as the substrate scope were limited. In order to achieve C−H γ,γ,γ-trifluoroalkylations of quinolines with a broad substrate scope, we envisioned that

rganofluorine compounds represent a frequently encountered class of biologically active synthetic small molecules.1 Among these, the trifluoromethyl group has been intensively employed to improve the bioactivity and pharmacodynamics of drug lead compounds, which has resulted in the discovery and marketing of several medicinal agents (Figure 1). Behind the success, development of practical

Figure 1. Trifluoroalkyl groups in biologically active compounds.

trifluoromethylation reactions has made a substantial contribution.2 On the other hand, the γ,γ,γ-trifluoroalkyl group represents a scarcely studied structural motif in medicinal chemistry (Figure 1). As the terminal position of a linear alkyl chain is vulnerable against metabolic C−H oxidation by cytochrome P450, the introduction of fluorine atoms at their terminal position is a feasible strategy to prolong in vivo activity of such lead compounds. In addition, pioneering studies have confirmed the enhanced bioactivity of compounds with γ,γ,γtrifluoroalkyl groups due to additional electrostatic interactions with target proteins and improved lipophilicity.3 Nevertheless, vast areas of chemical space4 including this fluorine-containing functional group remain to be investigated. © XXXX American Chemical Society

Received: March 22, 2019

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DOI: 10.1021/acs.orglett.9b01015 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 1. C−H γ,γ,γ-Trifluoroalkylation of ElectronDeficient N-Heteroarenes

process.13 The overall reaction process can also be classified as the “electron-catalyzed” transformation.7 Based on this proposed reaction design, we started our investigation on the C−H γ,γ,γ-trifluoroalkylation of quinolines using methyl quinoline-4-carboxylate (1a) and allyltrimethylsilane (2a) in the presence of trifluoroacetic acid (TFA) (Table 1). An evaluation of electrophilic trifluoromethylating reagent Table 1. Optimization of Reaction Conditionsa

catalyst-free sequential radical reactions under precisely controlled acidic conditions could potentially realize Miniscitype alkylations with a high functional-group tolerance. Our reaction design for the C−H γ,γ,γ-trifluoroalkylation of quinolines is proposed in Scheme 2. In the presence of an Scheme 2. Reaction Design for the C−H γ,γ,γTrifluoroalkylation of Quinolines a Reactions were run with 1a (0.050 mmol), 2a (X equiv), CF3 source (Y equiv), and additive (1.2 equiv) in the indicated solvent (0.1 M to 1a) under irradiation from blue LED (λmax = 447 nm) for 20 h. b Determined by 1H NMR. cIsolated yield in 0.20 mmol scale. d1b was used instead of 1a. eYield of 3ba.

revealed that benzothiophene-based reagent 4c (Umemoto’s reagent II)14 exhibited the best performance for the desired transformation compared to hypervalent iodine-based reagents (Togni’s reagent I or II)15 (entries 1−3). This difference in reactivity might be due to the facile photoinduced homolysis of the S−CF3 bond of 4c compared to the homolysis of the I− CF3 bonds of 4a or 4b.16,17 Surprisingly, an evaluation of the Brønsted acids revealed that an additional acid is not necessary for this γ,γ,γ-trifluoroalkylation (entries 3−5). We assume that trifluoromethanesulfonic acid slowly generated in situ from 4c sufficiently protonated 1a, activating the N-heteroaromatic toward addition of nucleophilic radicals. While no 3aa was obtained when the reaction was performed in dioxane, a comparable yield was observed when acetone was used as a solvent (entries 5−7). Increasing the amount of 2a18 and 4c increased the product yield, and 3aa was isolated in 84% yield (entry 8). Notably, the conditions established for C(2)−H alkylation were equally suitable for the C(4)−H alkylation of quinolines. Thus, when methyl quinoline-2-carboxylate (1b) was used instead of 1a under otherwise identical conditions to

electrophilic trifluoromethyl radical source (CF3−X), the homolysis of the C−X bond could be induced by irradiation with visible light, affording the trifluoromethyl radical during the initiation step. A subsequent addition of the electrophilic trifluoromethyl radical to alkenes would then serve as the first step for the radical-propagation sequence.10,11 The γ,γ,γtrifluoroalkyl radicals thus generated are nucleophilic, and an addition of the radical to protonated quinolines would confer α-aminoalkylradicals,12 which would subsequently be deprotonated to confer a C−N based radical anion. A final electron transfer from these intermediates to the electrophilic trifluoromethylating reagent would deliver the γ,γ,γ-trifluoroalkylated quinoline under concomitant regeneration of the trifluoromethyl radical, thus completing the radical chain B

DOI: 10.1021/acs.orglett.9b01015 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 4. Scope with Respect to Quinolinesa

those of entry 8, the corresponding C(4)−H alkylated product (3ba) was obtained in 84% isolated yield (entry 9).19,20 With the optimized reaction conditions in hand, we examined the substrate scope of the C−H γ,γ,γ-trifluoroalkylation with respect to alkenes (Scheme 3). In addition to Scheme 3. Scope with Respect to Alkenesa

a

Reactions were run with 1 (0.20 mmol), 2a (5.0 equiv), and 4c (3.0 equiv) in MeCN (0.1 M to 1) under blue LED irradiation (λmax = 447 nm) for 20 h unless otherwise noted. b3.0 equiv of 2a was used. cAt a 1.0 mmol scale. d1-Octene (2b) was used instead of allyltrimethylsilane (2a).

derivatizations. The presence of an electron-withdrawing cyano group enhanced the C(4)−H alkylation, and 3ga was obtained in excellent yield. 2-Trifluoromethylquinoline was alkylated under the standard reaction conditions to afford 3ha in a reduced isolated yield after intensive purification. Considering several established methods for the derivatization of 2-haloquinolines, their C(4)−H alkylation should allow access to versatile building blocks for applications in medicinal chemistry. Gratifyingly, the C(4)-trifluoroalkylation of 2chloroquinoline and 2-bromoquinoline proceeded in synthetically useful yields using 1-octene and 4c, which delivered 3ib and 3jb, respectively.21,22 Since a rich variety of established methods are available for modifications of quinoline derivatives, the C−H γ,γ,γtrifluoroalkylated products serve as versatile intermediates for further transformations (Scheme 5). For example, the incorporation of an aryl group into C−H γ,γ,γ-trifluoroalkylated product 3ib was readily achieved under Suzuki−Miyaura coupling conditions, affording 5a in 98% yield. The alkynylation of 3ib occurred smoothly under Sonogashira

a

Reactions were run with 1a or 1b (0.20 mmol), 2 (3.0 equiv), and 4c (3.0 equiv) in MeCN (0.1 M to 1a or 1b) under blue LED irradiation (λmax = 447 nm) for 20 h.

allylsilanes, unactivated nonpolar alkenes afforded the C(2)−H alkylated products in good yield (3ab, 3ac). The chloroalkyl group, which is vulnerable under ionic reaction conditions, was successfully installed under the applied reaction conditions (3ad). An internal alkene was also a viable substrate, delivering 3ae in high yield and excellent diastereoselectivity. Other allyl silanes used were also suitable substrates, and the C(4)−H alkylation occurred to confer 3bf and 3bg in 73% and 74% yield, respectively. Alkenes with polar functional groups afforded products with ester (3bh) or acetoxy (3bi) groups in good yield. An alkene with a nitrogen-containing functional group smoothly participated in the alkylation as well (3bj). Encouraged by these results, we also evaluated the substrate scope in terms of quinolines (Scheme 4). A C(4)-substituted quinoline with an amide group afforded the C(2)−H alkylated product in 72% yield (3ca). The synthetically versatile Weinreb amide was also tolerated in this alkylation method (3da). Phenanthridine, which is a frequently found core structure in biologically active substances, could also be employed as a substrate in this C−H alkylation reaction (3ea). The C(2)−H alkylation of 4-bromoquionoline afforded the corresponding product (3fa) in modest yield, albeit that it represents a synthetically useful intermediate for further

Scheme 5. Transformations of 3ib

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Organic Letters

drugs introduced to the market in the last decade (2001−2011). Chem. Rev. 2014, 114, 2432. (e) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 8315−8359. (2) Selected general reviews of trifluoromethylation and related transformations: (a) Prakash, G. K. S.; Yudin, A. K. Perfluoroalkylation with organosilicon reagents. Chem. Rev. 1997, 97, 757−786. (b) Ma, J.-A.; Cahard, D. Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions. Chem. Rev. 2004, 104, 6119−6146. (c) Ma, J.-A.; Cahard, D. Update 1 of: Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions. Chem. Rev. 2008, 108, PR1−PR43. (d) Kirk, K. L. Fluorination in medicinal chemistry: methods, strategies, and recent developments. Org. Process Res. Dev. 2008, 12, 305−321. (e) Furuya, T.; Kamlet, A. S.; Ritter, T. Catalysis for fluorination and trifluoromethylation. Nature 2011, 473, 470−477. (f) Tomashenko, O. A.; Grushin, V. V. Aromatic trifluoromethylation with metal complexes. Chem. Rev. 2011, 111, 4475−4521. (g) Studer, A. A “Renaissance” in radical trifluoromethylation. Angew. Chem., Int. Ed. 2012, 51, 8950−8958. (h) Chen, P.; Liu, G. Recent advances in transition-metal-catalyzed trifluoromethylation and related transformations. Synthesis 2013, 45, 2919−2939. (i) Xu, J.; Liu, X.; Fu, Y. Recent advance in transitionmetal-mediated trifluoromethylation for the construction of C(sp3)CF3 bonds. Tetrahedron Lett. 2014, 55, 585−594. (j) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 2015, 115, 826−870. (k) BarataVallejo, S.; Cooke, M. V.; Postigo, A. Radical fluoroalkylation reactions. ACS Catal. 2018, 8, 7287−7307. (3) Selected examples of γ,γ,γ-trifluoroalkyl groups in bioactive compounds: (a) Woo, L. W. L.; Fischer, D. S.; Sharland, C. M.; Trusselle, M.; Foster, P. A.; Chander, S. K.; Di Fiore, A.; Supuran, C. T.; De Simone, G.; Purohit, A.; Reed, M. J.; Potter, B. V. L. Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography. Mol. Cancer Ther. 2008, 7, 2435−2444. (b) Sittaramane, V.; Padgett, J.; Salter, P.; Williams, A.; Luke, S.; McCall, R.; Arambula, J. F.; Graves, V. B.; Blocker, M.; van Leuven, D.; Bowe, K.; Heimberger, J.; Cade, H. C.; Immaneni, S.; Shaikh, A. Discovery of quinoline-derived trifluoromethyl alcohols, determination of their in vivo toxicity and anticancer activity in a zebrafish embryo model. ChemMedChem 2015, 10, 1802−1807. (4) Selected reviews of chemical space in drug discovery: (a) Lipinski, C.; Hopkins, A. Navigating chemical space for biology and medicine. Nature 2004, 432, 855−861. (b) Dandapani, S.; Marcaurelle, L. A. Accessing new chemical space for ‘undruggable’ targets. Nat. Chem. Biol. 2010, 6, 861−863. (c) Reymond, J.-L.; van Deursen, R.; Blum, L. C.; Ruddigkeit, L. Chemical space as a source for new drugs. MedChemComm 2010, 1, 30−38. (5) Reviews of biologically active quinoline derivatives: (a) Vandekerckhove, S.; D’hooghe, M. Quinoline-based antimalarial hybrid compounds. Bioorg. Med. Chem. 2015, 23, 5098−5119. (b) Afzal, O.; Kumar, S.; Haider, M. R.; Ali, M. R.; Kumar, R.; Jaggi, M.; Bawa, S. A review on anticancer potential of bioactive heterocycle quinoline. Eur. J. Med. Chem. 2015, 97, 871−910. (c) Hu, Y.-Q.; Gao, C.; Zhang, S.; Xu, L.; Xu, Z.; Feng, L.-S.; Wu, X.; Zhao, F. Quinoline hybrids and their antiplasmodial and antimalarial activities. Eur. J. Med. Chem. 2017, 139, 22−47. (6) (a) Jin, J.; MacMillan, D. W. C. Alcohols as alkylating agents in heteroarene C-H functionalization. Nature 2015, 525, 87−90. (b) Zheng, D.; Studer, A. photoinitiated three-component αperfluoroalkyl-β-heteroarylation of unactivated alkenes via electron catalysis. Org. Lett. 2019, 21, 325−329. (c) Antonietti, F.; Mele, A.; Minisci, F.; Punta, C.; Recupero, F.; Fontana, F. Enthalpic and polar effects in the reactions of perfluoroalkyl radicals: new selective synthetic developments with alkenes and heteroaromatic bases. J. Fluorine Chem. 2004, 125, 205−211.

coupling conditions to deliver 5b in 69% yield. The introduction of heteroatoms was also accomplished successfully: A 2-aminated quinoline (5c) was obtained in 81% yield from a Buchwald−Hartwig amination. An oxygen-containing functional group was successfully installed by treating 3ib with NaOMe in MeOH to furnish 5d in 89% yield. The products of the current C−H γ,γ,γ-trifluoroalkylation reaction thus not only serve as members of a novel library of N-heteroaromatics but also as key building blocks for the preparation of bioactive substances with potential applications in medicinal chemistry. In summary, we have achieved a photocatalyst-free, visiblelight-mediated C−H γ,γ,γ-trifluoroalkylation of quinolines with high functional-group tolerance.23 The use of readily available alkenes and the easy-to-handle trifluoromethylating reagent 4c provides rare access to quinoline derivatives substituted with γfluorinated alkyl chains in an operationally simple manner. In addition, the corresponding products of the C−H γ,γ,γtrifluoroalkylation of halogenated quinolines can be readily modified using well-established transformations, thus allowing access to medicinally relevant but scarcely studied quinoline derivatives. Investigations into the applicability of this C−H γ,γ,γ-trifluoroalkylation protocol to other N-heteroaromatics24 as well as the introduction of other fluorinated alkyl groups via C−H functionalization reactions are currently in progress in our group.

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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.9b01015. Full spectra of all new compounds, additional investigations on reaction conditions, and mechanistic studies (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Shigeki Matsunaga: 0000-0003-4136-3548 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by JSPS KAKENHI grant JP15H05802 within the remit of Precisely Designed Catalysts with Customized Scaffolding as well as JSPS KAKENHI grants JP17H03049 and JP18H06097.

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DOI: 10.1021/acs.orglett.9b01015 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters alkyl-substituted 1,4-naphthoquinone derivatives. J. Org. Chem. 2019, 84, 1006−1014. (13) Relevant C−H alkylation of quinolines via sequential radical additions: (a) McCallum, T.; Barriault, L. Direct alkylation of heteroarenes with unactivated bromoalkanes using photoredox gold catalysis. Chem. Sci. 2016, 7, 4754−4758. (b) Liu, Z.; Liu, Z.-Q. An intermolecular azidoheteroarylation of simple alkenes via free-radical multicomponent cascade reactions. Org. Lett. 2017, 19, 5649−5652. (14) Reviews of Umemoto’s reagents: (a) Zhang, C. Recent advances in trifluoromethylation of organic compounds using Umemoto’s reagents. Org. Biomol. Chem. 2014, 12, 6580−6589. (b) Ni, C.; Hu, M.; Hu, J. Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis. Chem. Rev. 2015, 115, 765−825. See also: (c) Umemoto, T.; Ishihara, S. Power-variable electrophilic trifluoromethylating agents. S-, Se-, and Te-(trifluoromethyl)dibenzothio-, -seleno-, and -tellurophenium salt system. J. Am. Chem. Soc. 1993, 115, 2156−2164. (d) Umemoto, T.; Zhang, B.; Zhu, T.; Zhou, X.; Zhang, P.; Hu, S.; Li, Y. Powerful, thermally stable, one-potpreparable, and recyclable electrophilic trifluoromethylating agents: 2,8-difluoro- and 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium salts. J. Org. Chem. 2017, 82, 7708−7719. (15) A review of Togni’s reagents: Charpentier, J.; Früh, N.; Togni, A. Electrophilic trifluoromethylation by use of hypervalent iodine reagents. Chem. Rev. 2015, 115, 650−682. (16) 4c has essentially no absorbance in the visible light region (see the Supporting Information for its UV−vis spectra), but its activation by blue LED without photocatalyst is inconsistent with a literature precedent. See: Egami, H.; Ito, Y.; Ide, T.; Masuda, S.; Hamashima, Y. Simple photo-induced trifluoromethylation of aromatic rings. Synthesis 2018, 50, 2948−2953. (17) Intermediacy of trifluoromethyl radical was supported by a trapping experiment with TEMPO. See the Supporting Information for details. (18) Excess alkenes might compensate for competitive consumption of alkenes by radical-mediated side reactions. Indeed, 3 was obtained in a lower yield with reduced amounts of 2a or 2b. See the Supporting Information for details. (19) Umemoto’s reagent I was also applicable to this reaction, but showed less reactivity compared to 4c (73% 1H NMR yield of 3aa under the conditions in Table 1, entry 8). (20) Addition of photoredox catalysts did not accelerate the reaction. See the Supporting Information for details. (21) When unsubstituted quinoline was treated with 2a and 4c under the standard conditions, a mixture of C(4)- and C(2)-alkylated products was obtained in 31% and 22% 1H NMR yield, respectively (C4/C2 = 1.4/1). The yield and the regioselectivity did not improve in the presence of Lewis acidic additives. See the Supporting Information for details. (22) Electron-withdrawing groups on 1 improved the yield of 3 presumably by facilitating nucleophilic addition of γ,γ,γ-trifluoroalkyl radicals. Alkylation of 1 with electron-donating group was more challenging: 4-Methylquinoline afforded the corresponding product in 23% yield. See the Supporting Information for details. (23) A selected review of photocatalyst-free transformations mediated by electron donor−acceptor complexes: (a) Lima, C. G. S.; de M. Lima, T.; Duarte, M.; Jurberg, I. D.; Paixão, M. W. Organic synthesis enabled by light-irradiation of EDA complexes: theoretical background and synthetic applications. ACS Catal. 2016, 6, 1389− 1407. Selected examples: (b) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. Unusual ipso substitution of diaryliodonium bromides initiated by a single-electron-transfer oxidizing process. Angew. Chem., Int. Ed. 2010, 49, 3334−3337. (c) Arceo, E.; Jurberg, I. D.; Á lvarez-Fernández, A.; Melchiorre, P. Photochemical activity of a key donor-acceptor complex can drive stereoselective catalytic α-alkylation of aldehydes. Nat. Chem. 2013, 5, 750−756. (d) Silvi, M.; Arceo, E.; Jurberg, I. D.; Cassani, C.; Melchiorre, P. Enantioselective organocatalytic alkylation of aldehydes and enals driven by the direct photoexcitation of enamines. J.

Am. Chem. Soc. 2015, 137, 6120−6123. (e) Cheng, Y.; Yuan, X.; Ma, J.; Yu, S. Direct aromatic C-H trifluoromethylation via an electrondonor-acceptor complex. Chem. - Eur. J. 2015, 21, 8355−8359. (f) Liu, B.; Lim, C.-H.; Miyake, G. M. Visible-light-promoted C−S cross-coupling via intermolecular charge transfer. J. Am. Chem. Soc. 2017, 139, 13616−13619. (g) Zhu, M.; Zhou, K.; Zhang, X.; You, S.L. Visible-light-promoted cascade alkene trifluoromethylation and dearomatization of indole derivatives via intermolecular charge transfer. Org. Lett. 2018, 20, 4379−4383. (24) In our preliminary study, isoquinoline and quinoxaline afforded the respective alkylated products in modest isolated yield, while methyl pyridine-4-carboxylate or pyrazine gave a complex mixture. See the Supporting Information for details.

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DOI: 10.1021/acs.orglett.9b01015 Org. Lett. XXXX, XXX, XXX−XXX