2-Position-Selective C–H Perfluoroalkylation of Quinoline Derivatives

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2‑Position-Selective C−H Perfluoroalkylation of Quinoline Derivatives Takahiro Shirai,† Motomu Kanai,*,†,§ and Yoichiro Kuninobu*,‡,§ †

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan § ERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan ‡

S Supporting Information *

ABSTRACT: We developed 2-position-selective, direct C−H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of quinoline derivatives. Regioselective transformation was achieved without derivatization of the quinolines. The reaction proceeded at room temperature with high functional group tolerance, even in gram scale. Notably, the reaction was applicable to substrates containing a functional group sensitive to oxidation and a drug molecule.

fluoride (HF) through the formation of a six-membered transition state (Figure 1e). Herein, we report 2-positionselective direct C−H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of quinoline derivatives (Figure 1e). Treatment of quinoline (1a) with trifluoromethyltrimethylsilane (2a) in the presence of trifluoroacetic acid and cesium fluoride as a potential HF source in dimethylformamide (DMF) did not afford the desired product (Scheme 1, entry 1). When toluene was used as the solvent, a mixture of 2-trifluoromethyldihydroquinoline (3a) and 2-trifluoromethylquinoline (4a) formed in 10% yield (3a + 4a, Scheme 1, entry 2). In this reaction, no other regioisomers formed. The total yield of 3a + 4a was improved to 38% by replacing the fluoride source with potassium hydrogen fluoride (KHF2) and adding 3.0 equiv of DMF (Scheme 1, entry 3). The reaction temperature was decreased to 25 °C by changing the solvent to dioxane, but the yield of 3a + 4a was still unsatisfactory (42%: Scheme 1, entry 4). The additive was crucial for this reaction (Scheme 1, entries 5−7), and the best results (73% yield of 3a + 4a) were achieved by adding 3 equiv of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU) (Scheme 1, entry 7). We speculated that DMPU acts as a Lewis base to form hypervalent silicon9 and increase the reactivity of Me3SiCF3 (see the proposed mechanism section). Aromatized 4a should be obtained by involuntary oxidation of 3a with aerobic oxygen during either the reaction or workup. Next, we investigated the substrate scope of six-membered N-heteroaromatic compounds under the optimized conditions (Scheme 2). To simplify product isolation, we added PhI(OAc)2 to the reaction mixture before workup to converge

T

he introduction of perfluoroalkyl groups can significantly improve the functions of organic molecules, such as drugs,1 agrochemicals,2 and organic functional materials,3 due to their special properties, including strong electron-withdrawing ability and stability. An ideal method of introducing perfluoroalkyl groups is direct C−H perfluoroalkylation. For example, C−H trifluoromethylation reactions with trifluoromethyl radical species proceed under mild conditions with a broad substrate scope.4 Regioselective C−H trifluoromethylation of six-membered N-heteroaromatic compounds such as pyridine and quinoline derivatives under radical trifluoromethylation conditions is quite difficult, however, mainly due to the high reactivity of the CF3 radical (Figure 1a).4 On the other hand, several examples of 2-position-selective C−H trifluoromethylation of six-membered N-heteroaromatic compounds using a less reactive CF3 anionic species are reported. In 2007, Makosza and co-workers reported a method involving the preparation of N-(4-methoxybenzyl)azinium salts: treatment of the salts with a CF3 anion and successive oxidation (Figure 1b).5 In 2014, we reported a method involving N-oxide formation, activation of N-oxides with a BF2CF3 Lewis acid, and treatment of the BF2CF3 complex with a CF3 anion (Figure 1c).6,7 Subsequently, Larionov revealed a 2-position-selective C−H trifluoromethylation of six-membered heteroaromatic Noxides (Figure 1d).8 Those reactions, however, have the following drawbacks: (1) several steps to the trifluoromethylated products; (2) increased production costs due to the need for a BF2CF3 source (Figure 1c); and (3) difficult applications to N-heteroaromatic compounds containing oxidation-sensitive functional group(s), such as a formyl group. To address these points, we envisioned that 2-position-selective C−H trifluoromethylation would be possible through dual activation of both N-heteroaromatic substrates and trifluoromethyltrimethylsilane by hydrogen © XXXX American Chemical Society

Received: January 30, 2018

A

DOI: 10.1021/acs.orglett.8b00339 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Substrate Scope of 2-Position-Selective Trifluoromethylation of Quinoline Derivatives 1

Figure 1. C−H trifluoromethylation reactions of six-membered Nheteroaromatic compounds.

Scheme 1. Optimization of the Reaction Conditions for 2Position-Selective Trifluoromethylation of Quinoline (1a)

a

Me3SiCF3 (6.0 equiv). PhI(OAc)2.

b1

methoxy, formyl, carbonyl, methoxycarbonyl, acetyloxy, amide, alkenyl, and alkynyl groups and fluorine, chlorine, bromine, and iodine atoms, remained unchanged. Specifically, an oxidationsensitive formyl group was tolerated under the reaction conditions, albeit with a moderate product yield (33%: 4m). Moreover, trifluoromethylation of the formyl group hardly proceeded in this case. The reaction also proceeded using other quinoline derivatives, such as phenanthroline derivatives and 1,5-naphthyridine (products: 4x−4z). Ditrifluoromethylated products of 1x and 1z were not formed. In all entries, only single regioisomers were formed, and almost all starting substrates were recovered except the formation of the

H NMR yield of 4a after oxidation with

the products to 4a. In the case of quinoline derivatives 1a−1g having a methyl substituent at the 3-, 4-, 5-, 6-, 7-, or 8-position, the product was obtained in 56%−67% yield. Based on the results using 3-methylquinoline (1b) and 8-methylquinoline (1g), the reaction was not affected by steric hindrance around the nitrogen atom of the substrates. The reaction proceeded with high functional group tolerance: functional groups, such as B

DOI: 10.1021/acs.orglett.8b00339 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters trifluoromethylated products. Pyridine derivatives, however, produced a low yield (e.g., 4,4′-di-tert-butyl-2,2′-dipyridyl: 10%).10,11 We then expanded the scope of the nucleophiles to other perfluoroalkylation reactions using 6-methylquinoline (1e) as a substrate (Scheme 3). 6-Methyl-2-pentafluoroethylquinoline

Scheme 5. Gram-Scale Experiment

Scheme 3. Perfluoroalkylation Reactions Scheme 6. Trifluoromethylation of Quinine

(5) and 6-methyl-2-heptafluoropropylquinoline (6) were obtained in 83% and 85% yields, respectively, when pentafluoroethyltrimethylsilane (2b) and heptafluoropropyltrimethylsilane (2c) were used as perfluoroalkylation reagents. A working hypothesis for the reaction mechanism is proposed in Scheme 4. After the formation of HF from

substrate containing an sp3 nitrogen atom with higher Brønsted basicity than that of N-heteroaromatics even though the reaction is supposed to be promoted by HF. Other functional groups also remained unchanged during the reaction. In summary, we developed 2-position-selective, direct C−H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of quinoline derivatives using perfluoroalkyltrimethylsilane, trifluoroacetic acid, KHF2, and DMPU. The reaction proceeded with high functional group tolerance, including an oxidation-sensitive formyl group, which might not be tolerated under the previous conditions. Because the present reaction does not require the preparation of activated substrates, it is more practical than previously reported reactions with regard to the number of steps, time, and cost required to synthesize 2-perfluoroalkylated quinoline derivatives.

Scheme 4. Proposed Mechanism for 2-Position-Selective Trifluoromethylation

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CF3COOH and KHF2,12 2-position-selective trifluoromethylation proceeds through a six-membered transition state A comprising a hexavalent silicon center derived by the assembly of substrate 1, HF, Me3SiCnF2n+1 (2), and DMPU.13−16 The transfer ability of a perfluoroalkyl group on a silicon atom increases by the coordination of DMPU which coordinates to a hypervalent silicon atom.13 Then, the nucleophilic attack of the perfluoroalkyl group to a 2-position of the quinoline derivative, where it is electrophilically activated by HF, occurs to give intermediate 3. The resulting dihydroquinoline 3 is converted to 2-trifluoromethylated quinoline 4 via oxidation of 3 with PhI(OAc)2. The trifluoromethylation reaction proceeded even in gram scale (Scheme 5). Thus, starting from 1.43 g of 6-methylquinoline (1e), 0.96 g of 6-methyl-2-trifluoromethylquinoline (4e) was obtained in 45% yield. The method was applied to the late-stage trifluoromethylation of a drug molecule, quinine (7), affording trifluoromethylated quinine (8) in 24% yield (Scheme 6). Although the yield was low, it is noteworthy that the reaction proceeded from a

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00339.

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General experimental procedure and characterization data for trifluoromethylated products (PDF)

AUTHOR INFORMATION

Corresponding Authors

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

Motomu Kanai: 0000-0003-1977-7648 Yoichiro Kuninobu: 0000-0002-8679-9487 Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.8b00339 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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(16) The trifluoromethylation of quinoline (1a) proceeded using DMPU-HF reagent (3.0 equiv) instead of CF3COOH, KHF2, and DMPU, and the desired product 4a was obtained in 28% yield. This result will support the proposed mechanism.

ACKNOWLEDGMENTS This work was supported in part by ERATO from JST (grant number: JPMJER1103), JSPS KAKENHI Grant Number JP 16K13946, and Yakugaku Shinkoukai.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00339 Org. Lett. XXXX, XXX, XXX−XXX