Copper-catalyzed 8-amido chelation-induced regioselective C–H fluoroalkylation of quinolines

Abstract

An efficient and highly regioselective protocol for copper(II)-catalyzed remote C–H fluoroalkylation of 8-aminoquinoline amides with R_fSO₂Na (R_f = CF₃, CF₂H, C₄F₉, C₅F₁₁, and C₆F₁₃) is described. This reaction provides an effective strategy for the direct construction of fluorine-containing six-membered heteroaromatic core structures.

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To date, the incorporation of fluorine-containing groups into biologically active molecules has emerged as a widely employed strategy in medicinal chemistry, in order to perturb the chemical, physical, and biological properties of parent compounds.¹ Among them, the trifluoromethyl group is of extensive interest owing to its strong electron-withdrawing power and high lipophilicity.² Therefore, substantial efforts have been devoted to the development of new synthetic methods for the direct assembly of CF₃-containing small molecules.³

Transition-metal-catalyzed or -mediated trifluoromethylations of aryl halides,^4a–c alkynes^4d–f and the corresponding boronic acids^4g,h are all early examples of this transformation. In recent years, transition-metal-catalyzed C–H functionalization has become a facile and robust approach to the construction of C–C and C-heteroatom bonds.⁵ Its power originates in the ability to accomplish site-selective derivatization of inert C–H bonds without the need for prefunctionalized starting materials. As such, new approaches of direct transformation from C–H to C–CF₃ have been realized, including palladium-catalyzed ortho C–H trifluoromethylation by Pd^II/Pd^IV redox catalysis,^6a–c copper-catalyzed or -mediated trifluoromethylation of heterocyclic compounds,^6d,e as well as methods which take advantage of CF₃ radical formation.^6f–h

Derivatives of quinolines are ubiquitously found in naturally occurring and synthetic bioactive compounds (Scheme 1).⁷ Straightforward access for their functionalization has aroused great interest based on the C–H activation strategy.⁸ However, the implementation of such an atom-economical technique is challenging due to the uncontrolled regioselectivity problem. Although the direct functionalization of C–H bonds at the C2-,^8d,eC4-,^8f,g and C8-positions^8h,i of quinolines has been well-developed, the selective functionalization at the C5-position remains an intriguing problem. Pioneered by the work of Stahl and co-workers demonstrated in 2013,⁹ some progress has been made focused on the functionalization of this distal and geometrically inaccessible C–H bond in quinolines. Zeng and coworkers demonstrated a C5-allylation of quinolines in the presence of an iron catalyst.^10a Shortly thereafter, the copper-catalyzed direct C–H bond sulfonylation of aminoquinolines with arylsulfonyl chlorides was reported by the Wei and Wu group, which has a broad substrate scope for both aromatic and aliphatic sulfonyl chlorides.^10b–d Very recently, Baidya and coworkers developed a direct C(sp²)–H amination of quinolines by the use of azodicarboxylates.^10e However, not a single approach for the direct selective remote C–H fluoroalkylation of quinolines has been reported (Scheme 2).

Scheme 1 Direct C–H functionalization of quinolines.

Scheme 2 Chelation-induced remote C–H functionalization of quinolines.

Our previous studies on the selective introduction of fluorine-containing groups into inert C–H bonds¹¹ led us to wonder if the CF₃ group could be inserted into quinoline derivatives and thus offer a direct entry towards the C5-functionalized aminoquinoline-derived antimalarial and anti-cancer drug candidates. It was anticipated that the formation of a metal-chelated complex would affect the electron contribution in quinoline, which ends up with the regioselective assembly of the CF₃ group at the C5-position. Herein, we detailed a highly regioselective C5–H trifluoromethylation of 8-aminoquinolines by using NaSO₂CF₃ as a trifluoromethylating reagent in the presence of AIBN as an oxidant. This protocol tolerates a wide range of functional groups and is also compatible with R_fSO₂Na to offer perfluoroalkylated quinolines.

We commenced our investigation by examining the reaction of 8-aminoquinoline derivative 1a with NaSO₂CF₃ (2a) (Table 1). After a careful evaluation of various reaction parameters, the desired trifluoromethylated quinoline 3a was isolated in 73% yield in the presence of CuBr₂ as a catalyst and AIBN as an oxidant under air for 12 h (Table 1, entry 4). However, compared to other copper salts such as Cu(OAc)₂, CuCl₂, CuO, and Cu(OTf)₂, CuCl showed lower reactivity (entries 1–3, 5–6). As expected, copper played a pivotal role in this reaction, the desired product could not be obtained under copper-catalyst-free conditions and reducing the catalyst loading resulted in a decreased yield of the C5-trifluoromethylation product (entries 7 and 8), while using 50 mol% CuBr₂ resulted in a mixture of trifluoromethylation and bromination products 3a and 4a (entry 9). Control experiments suggest that 3a formed under these conditions arises from direct C–H trifluoromethylation, not C–H bromination followed by CF₃ substitution of bromide in 4a. Among the oxidants examined, including TBHP, K₂S₂O₈, AIBN, and H₂O₂, AIBN was the best choice (entry 4 vs. 10–12). Besides, the addition of a base (e.g., K₂CO₃, Na₂CO₃, and Cs₂CO₃) would disfavor the generation of the desired product but promote the bromination at the C5 position (entries 13–15). The reaction yield showed a decrease in DCE (entry 16), while screening of other solvents resulted in recovery of the starting material 1a (entries 17–19). Finally, air can be well-tolerated in the process, and the yield of 3a dropped to 51% when the reaction temperature was altered from 120 °C to 100 °C (entry 20).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Base	Oxidant	Solvent	Yield^b (%)
					3a	4a
a Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), copper catalyst (10 mol%), oxidant (0.24 mmol), base (0.20 mmol), solvent (1 mL) at 120 °C under air for 12 h. b Isolated yield. c Copper catalyst (5 mol%). d Copper catalyst (50 mol%). e At 100 °C.
1	Cu(OAc)2		AIBN	MeCN	31
2	Cu(OTf)2		AIBN	MeCN	53
3	CuCl2		AIBN	MeCN	15
4	CuBr2		AIBN	MeCN	73
5	CuO		AIBN	MeCN	12
6	CuCl		AIBN	MeCN	36
7			AIBN	MeCN
8	CuBr2		AIBN	MeCN	58^c
9	CuBr2		AIBN	MeCN	68^d	21
10	CuBr2		TBHP	MeCN	<5	17
11	CuBr2		K2S2O8	MeCN	12	15
12	CuBr2		H2O2	MeCN	Trace
13	CuBr2	K2CO3	AIBN	MeCN	24	35
14	CuBr2	Na2CO3	AIBN	MeCN	22	40
15	CuBr2	Cs2CO3	AIBN	MeCN	13	51
16	CuBr2		AIBN	DCE	56
17	CuBr2		AIBN	PhCl	Trace
18	CuBr2		AIBN	DME
19	CuBr2		AIBN	Dioxane	Trace
20	CuBr2		AIBN	MeCN	51^e

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With the optimized reaction conditions in hand, we next sought to investigate the substrate scope. As shown in Table 2, the reaction was quite general for a wide variety of 8-amino-quinolines. Aliphatic amides (1a–1i), aromatic amides (1j–1l, 1n), and carboxamides with heterocyclic substitutions (1m) are compatible with the reaction, though aliphatic amides would generate the corresponding product in relatively lower yields. Aliphatic amides bearing either linear chains or cyclic chains with different ring-sizes were trifluoromethylated in satisfactory yields. Note that the amide with an electrophile-sensitive functional group, 4-(1H-indol-3-yl)-butanamide (1i), remained intact in the reaction. Besides, the electronic effect was not obvious on the benzene ring of benzamides, such desired products were afforded in moderate to good yields (3j–3l). The functional groups such as Me and MeO on the quinoline ring would change the electron contribution which showed increases of product yields (3o–3r). In addition, compound 3k was crystallized and X-ray analysis unambiguously confirmed the regioselective C-5 trifluoromethylation of the quinoline (Scheme 3).

Scheme 3 The crystal structure of 3k.

Table 2 Substrate scope of amides, quinolines, and sulfinates

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Moreover, the reaction is not restricted only to NaSO₂CF₃ (2a), we further extended the substrate scope to investigate the direct introduction of CH₂F, CHF₂, and R_f groups into the C5-position of quinolines by using CH₂FSO₂Na, CHF₂SO₂Na and R_fSO₂Na as fluorinating reagents (Table 2). Sodium perfluoroalkanesulfinates (R_fSO₂Na) with different R_f groups were synthesized according to the procedure reported by Hu and DesMarteau.¹² Remarkably, it turns out that this single-electron transfer activation mode enables the formation of fluoroalkyl radicals and further facilitates bond formation regioselectively at the C5-position of quinolines. In each case, perfluoroalkylation products were forged with moderate levels of efficiency (3u–3w), while the reactions proceeded less effectively with CH₂FSO₂Na. In the case of CHF₂SO₂Na, only a trace amount of 3s was produced, probably because CH₂FSO₂Na is less reactive in generating fluoroalkyl radicals.¹³

To gain some insight into the mechanism of the copper-catalyzed 8-amido chelation-induced remote C–H trifluoromethylation of quinolines, control experiments were carried out (Scheme 4). It should be mentioned that coordination of 1a to Cu^II as an amidate is prior to trifluoromethylation, which can be supported by the lack of reaction of the N-methyl substrate 5a under standard conditions. Meanwhile, if the C5–H position was blocked by a bromo group (4a), the target product would not occur, which demonstrates that the trifluoromethylation product is formed not by CF₃ substitution of 4a. The addition of the radical inhibitor TEMPO resulted in an obvious inhibition of the reaction, indicating that a radical pathway might be involved in the process. Besides, in the case of non-protecting 8-aminoquinoline, the reaction gave a 1 : 2 mixture of 7-CF₃ and 5-CF₃ products, respectively, with 16% yield of the mixture.

Scheme 4 Control experiment.

When the quinoline trifluoromethylation reaction was performed in the presence of D₂O, no deuterium incorporation was observed in the recovered starting material or the product (Scheme 5). This result indicates that cleavage of the C–H bond is irreversible. Besides, an intermolecular competition experiment was carried out to obtain the kinetic isotope effect (KIE). Analysis of the H/D ratio of quinoline revealed a nearly equal mixture of isotopes, corresponding to a K_H/K_D = 1.17.

Scheme 5 Deuteration and isotope effect experiments.

This observation implies that the cleavage of C–H is not the rate-limiting step in the nonchelate-directed trifluoromethylation process.

On the basis of the above-mentioned results and related precedents,^8a,9,10a–e a tentative mechanism is proposed as shown in Scheme 6. We believe that the quinoline trifluoromethylation in our study is governed by a single-electron transfer (SET) mechanism. The process is initiated from the coordination of 8-aminoquinoline derived 1 with CuBr₂ and subsequently deprotonation to afford the chelated intermediate B. Meanwhile, the homolytic cleavage of AIBN releases 2-cyano-2-propyl radicals which are employed to initiate the trifluoromethyl radical via a single electron transfer process. Then, the addition of the trifluoromethyl radical to the intermediate B occurs at the C5 position to form the complex C. Thereafter, the Cu^I complex C is oxidized followed by the generation of complex E through a proton transfer process. Finally, the decomposition of E provides the desired product 3, along with the regeneration of intermediate A to continue the catalytic cycle.

Scheme 6 Plausible mechanism for the remote C–H trifluoromethylation of quinolines.

Conclusions

In conclusion, an efficient copper-catalyzed 8-amido chelation induced strategy is described to realize the C-5 direct C–H functionalization of quinolines with fluorinated sulfinate salts R_fSO₂Na. The reaction features a broad substrate scope, excellent functional group tolerance and high regioselectivity. Considering the critical role of fluoro-containing moieties in pharmaceutical and agrochemical research, this approach could potentially offer new strategies to the synthesis of fluoroalkylated quinolines. Further efforts in our laboratory are devoted to the exploitation of regio- and stereocontrol in fluoroalkylation reactions, particularly regarding the direct functionalization of more challenging inactive sp³ C–H bonds.

Acknowledgements

We gratefully acknowledge the Natural Science Foundation of Jiangsu Province (BK 20131346, BK 20140776) for financial support. This work was also supported by the National Natural Science Foundation of China (21476116, 21402093) and the Chinese Postdoctoral Science Foundation (2015M571761, 2016T90465).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data for all products. CCDC 1478785. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00369a

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