PhI(OAc)₂ oxidative C5 halogenation of quinolines using copper halides under mild conditions

Abstract

A concise and efficient protocol for PhI(OAc)₂ oxidation halogenation of quinoline at the C5 position was developed, affording the desired remote C–H activation products in moderate to excellent yields. This reaction proceeds with copper halides as the halogenating reagent to afford the halogenated quinolines and features excellent substrate tolerance, providing a facile pathway for the C5 halogenation of quinoline.

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Quinolines, especially those halogenated on their phenyl counter parts, are important structural motifs in many biologically active natural products¹ and pharmaceuticals.^2,3 The use of halogenated quinolines as intermediates in the synthesis of substituted quinolines has also been widely investigated.⁴ Because of their important role in biomedical and organic synthesis, they have attracted considerable attention. In recent years, transition-metal-catalyzed selective halogenation through the use of C–H activation as a strategic reaction instead of traditional halogenating methods has attracted wide attention.^5–8 Very recently, Liu and co-workers reported a remote C–H activation of quinolines through copper-catalyzed radical cross-coupling.⁶ Meanwhile, Zhang demonstrated a copper(II)-catalyzed C-5 and C-7 halogenation of quinolines using sodium halides under mild conditions.⁷ Subsequently, the Mu's team developed a copper-catalyzed regioselective C–H iodination of aromatic carboxamides.⁸ However, these methods have obvious shortcomings such as the use of extra halogenating reagents except the metal catalysts. Therefore, a much more simple and efficient method should be developed to build versatile C–X (X = halogen) bonds. Herein, we report a direct and selective C–H halogenation on the C-5 position of quinolines by using copper halides (X = Cl, Br, I). Notably, the coupling reactions could be carried out in open air at room temperature. The reaction condition was mild and easy to handle.

Encouraged by previous work of C–CF₃ coupling of quinolines,⁹ our studies were initiated by the reaction of N-(quinolin-8-yl)benzamide 1a with 0.5 equivalent of CuBr₂ in DCE under air at room temperature in the presence of 2.0 equivalent of PhI(OAc)₂ and 1.0 equivalent NH₂SO₃H. Surprisingly, the brominated product 2a could be obtained in 90% isolated yield (Table 1, entry 1). Moreover, the structure of 2a was confirmed by X-ray crystallography (CCDC 1439736†) (Scheme 1). Encouraged by this result, we continued optimizing the other reaction parameters. Several other brominated reagents such as CuBr, NBS, KBr and NaBr were screened, nevertheless, the yields of 2a were 25%, 54%, 15%, and 18%, respectively (Table 1, entries 2–5). Screening revealed that the amount of CuBr₂ affected the reaction, the yield of 2a could be increased to 98% by employing 1.0 equivalent CuBr₂ (Table 1, entries 6–8). Subsequently, some other solvents had been used in this transformation including DMF, DCM, toluene and MeCN, but lower yields were obtained (Table 1, entries 11–14). Then we tested the reaction time, neither a longer reaction time (4 h) nor a shorter one (1 h) furnished higher yields than 2 h (Table 1, entries 9–10). After exploring different parameters, the highest yield of 2a was achieved when the reaction was carried out with CuBr₂ (1.0 equiv.), PhI(OAc)₂ (2.0 equiv.) and NH₂SO₃H (1.0 equiv.) in DCE under air at room temperature (Table 1, entry 8).

Table 1 Screening of reaction conditions for bromination of quinolines^a

Entry	[Br] (equiv.)	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.20 mmol), [Br], PIDA (0.40 mmol), NH2SO3H (0.20 mmol) in 1 mL solvent at r.t. under air for 2 h.b Yields of isolated products.c Reaction time was 1 h.d Reaction time was 6 h.
1	CuBr2 (0.5)	DCE	90
2	CuBr (1.0)	DCE	25
3	NBS (1.0)	DCE	54
4	KBr (1.0)	DCE	15
5	NaBr (1.0)	DCE	18
6	CuBr2 (0.2)	DCE	22
7	CuBr2 (0.6)	DCE	93
8	CuBr2 (1.0)	DCE	98
9^c	CuBr2 (1.0)	DCE	74
10^d	CuBr2 (1.0)	DCE	84
11	CuBr2 (1.0)	DMF	85
12	CuBr2 (1.0)	DCM	78
13	CuBr2 (1.0)	Toluene	68
14	CuBr2 (1.0)	CH3CN	67

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Scheme 1 Single-crystal X-ray structure of 2a.

With the optimum reaction conditions in hand, we proceeded to investigate the substrate scope. The brominated transformation showed excellent functional group tolerance; both electron-donating (Table 2, 2b–2h) and electron-withdrawing (Table 2, 2i–2l) benzamides were turned into the corresponding products in moderate to excellent yields, and the reactants with electron-donating substituents afforded the desired products in higher yields relative to those with electron-withdrawing groups. Furthermore, substituents at different positions did not affect the efficiency of the reaction. For example, the substrates of benzamides bearing an electron-donating methyl group at the ortho, meta, and para position had high reactivity to afford the brominated products 2b–2d in good to excellent yields (Table 2, 2b–2d). In addition, the heteroarene carboxamides containing thenoyl amide and furoyl amide moieties were also tolerated and proved to be suitable substrates for this transformation, giving the desired products in 99% and 63%, respectively (Table 2, 2m–2n). Moreover, N-(5-bromoquinolin-8-yl)methacrylamide could react smoothly under the procedure to provide the desired product 2o in 84% yield (Table 2, 2o).

Table 2 Substrate scope of the bromination reaction^a

a Reaction conditions: 1 (0.2 mmol), CuBr₂ (1.0 equiv.), PhI(OAc)₂ (2.0 equiv.), NH₂SO₃H (1.0 equiv.), DCE (1.0 mL), stirred at room temperature, under air, 2 h.b Isolated yields.

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In the further study, we found that chlorination and iodination could also be achieved as well as bromination at the C5 position of quinolines through the same condition (Tables 3 and 4). We conducted the iodination and chlorination transformations by using the CuI and CuCl₂ in the presence of PhI(OAc)₂ and NH₂SO₃H, affording the desired products in moderate to excellent yields. These results demonstrated an easy remote access to quinoline derivatives at the C5 position under relatively mild conditions. Furthermore, we illustrated the scope and limitation of these halogenations. These reactions revealed good functional group tolerance, including aromatic groups and non-aromatic groups. Both electron-donating (Table 3, 3b–3g; Table 4, 4b–4g) and electron-withdrawing (Table 3, 3h–3l; Table 4, 4h–4l) benzamides could react smoothly to give the desired products in moderate to good yields; electron-rich groups gave slightly higher yields compared to electron-poor groups. Satisfactorily, heterocyclic amides were also gained at synthetically good yields (Table 3, 3n–3o; Table 4, 4n). Additionally, N-(5-bromoquinolin-8-yl)methacrylamide was also suitable substrate for these transformations (Table 3, 3m; Table 4, 4m).

Table 3 Substrate scope of the iodination reaction^a

a Reaction conditions: 1 (0.2 mmol), CuI (1.0 equiv.), PhI(OAc)₂ (2.0 equiv.), NH₂SO₃H (1.0 equiv.), DCE (1.0 mL), stirred at room temperature, under air, 2 h.b Isolated yields.

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Table 4 Substrate scope of the iodination reaction^a

a Reaction conditions: 1 (0.2 mmol), CuCl₂ (1.0 equiv.), PhI(OAc)₂ (2.0 equiv.), NH₂SO₃H (1.0 equiv.), DCE (1.0 mL), stirred at room temperature, under air, 2 h.b Isolated yields.

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To gain more insight into the reaction mechanism, radical inhibition experiments had been performed to investigate that whether these reactions proceeded via radical pathway (Scheme 2). We added 2.0 equiv. radical-trapping reagents TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) and BHT (2,6-di-tert-butyl-p-cresol) into the reaction system, respectively. The yield of the desired product decreased sharply to 23% and 25%. The results implied that the radical mechanism might be responsible for the reaction.

Scheme 2 Control experiments.

According to the results of the above reactions and the previous reports,^6,8,10 we proposed that a single electron transfer (SET) mechanism was involved in the halogenation of quinolines (Scheme 3). The halogen radical was produced in the presence of PhI(OAc)₂ with X⁻ (X = Cl, Br, I). We speculated the NH₂SO₃H could promote this procedure. Substrate 1 combined with Cu^II producing the aryl–Cu^II complex A. Subsequently, complex A worked through deprotonation to generate complex B. Then, complex B was attacked by the halogen radical, and the intermediate turned into complex C by single electron transfer (SET). Soon afterwards, the complex C transformed into D through oxidation. After generation of the intermediate E through the proton transfer process (PT), the terminal product 3 was gained via a metal dissociation process, and the catalytic cycle was completed.

Scheme 3 Plausible mechanism.

In summary, we have developed a general PhI(OAc)₂ oxidation approach for highly regioselective C–H activation halogenation of quinolines at the C-5 position using easily available copper halides (X = Cl, Br, I) as “X” sources. This transformation showed high efficiency, a broad substrate scope, and well-tolerated functionalization. Meanwhile, the reaction also offered some other attractive advantages such as simplicity of operation and the direct use of copper halides as halogenating reagent without adding the other halogenating reagents. Thus, it represents a facile pathway for the halogenation of quinolines at the C-5 position.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1439736. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra14863h

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