Visible light-induced aerobic C–N bond activation: a photocatalytic strategy for the preparation of 2-arylpyridines and 2-arylquinolines

Abstract

An efficient method for accessing arylpyridines and arylquinolines via visible light-induced aerobic C–N bond activation is described. The applicability of different kinds of simple ketones, easily available amines, and the use of air as the sole oxidant make this transformation very attractive.

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Pyridines and quinolines are the most important moieties found in natural products, pharmaceuticals¹ and organometallic catalysts.² Therefore, the preparation of their derivatives has been an area of intense interest for synthetic organic chemists.³ A number of approaches for their synthesis have been developed, which involve transition-metal-catalyzed cross-coupling,⁴ cycloadditions,⁵ ring-closing metathesis,⁶ and radical reactions.⁷ Given their importance, the development of a new efficient method from easily accessible starting materials is still in demand.

To date, the aerobic oxidation reaction of C–N bonds, such as transition metal-catalyzed or metal-free aerobic oxidation and so on, have attracted considerable attention for the construction of C–C bonds.⁸ There is a common superiority that oxygen is used, which is considered as a highly atom-economical, environmentally friendly and abundant oxidant.⁹ Besides that, because primary alkyl amines represent the most simple and common amines, the cleavage of the C–N bond of them for the construction of pyridines or quinolines is especially desirable. Acetophenones were also considered as easily available starting materials. Therefore, the combination of acetophenones and amines, such as 1,3-diaminopropane or benzylamine, will be one of the elegant strategies for the direct building of nitrogen-containing heterocycles, such as 2-arylpyridines and 2-arylquinolines, via a domino C–N cleavage/cyclization/aromatization reaction. Recently, several groups have successively reported for the synthesis of them via different reaction conditions in low to high yields (Scheme 1a–c).¹⁰ However, to the best of our knowledge, the direct C–N bond activation of simple primary alkyl amines for synthesis of them under visible-light photoredox reaction has not been established yet. Recently, visible-light photoredox reaction has revealed the power in organic synthesis,¹¹ especially in the C–X (X = C, S, N, O) bond-forming reactions.¹² Here in, we present a direct C–N bond activation of simple alkyl amines under aerobic conditions for the generation of 2-arylpyridines and 2-arylquinolines utilizing visible-light photoredox reaction (Scheme 1d).

Scheme 1 Synthesis of 2-arylquinolines and 2-arylpyridines.

Initially, we tested the reaction of acetophenone (1a) and 1,3-diaminopropane (2a) using Ru(bpy)₃Cl₂ (2 mol%) as photocatalyst and CH₃CN as solvent under the irradiation of a 23 W household compact fluorescent lamp (CFL) at room temperature. Unfortunately, no desired product was obtained (Table 1, entry 1). We thought a catalytic acid may play an important role in the formation of an imine intermediate.^10a,10d While the catalytic p-methylbenzenesulfonic acid was considered as additive to promote this transformation, there is still no product to be observed (Table 1, entry 2). We then conducted the reaction by heating it to reflux at 82 °C. To our delight, the reaction occurred in 37% yield (Table 1, entry 3). When we changed the amount of acid, the addition of one equivalent of p-methylbenzenesulfonic acid was most effective and a 51% isolated yield was obtained (Table 1, entries 4 and 5). Besides that, a major byproduct, (E)-1-phenylethan-1-one oxime, was found with 20% yield. Other additives, such as acetic acid, TFA, MSA, benzoic acid, were also tested for this transformation, but lower yields were obtained (Table 1, entries 6–9). Besides that, solvent screening proved CH₃CN superior to other solvents (Table 1, entries 10–13). Further optimization of reaction conditions did not improve the yield of product (see ESI†). Control experiments showed that both Ru(bpy)₃Cl₂ and visible light are essential for this reaction (Table 1, entries 14 and 15).

Table 1 Optimization of the reaction conditions^a

Entry	Additive	Solvent	Yield^b (%)
a Conditions: 1a (0.5 mmol), 2a (1.5 mmol), Ru(bpy)3Cl2 (0.01 mmol), additive (0.5 mmol), solvent (2 mL), O2 balloon, irradiation with a 23 W household light bulb at about 82 °C for 48 h.b GC yield based on dibenzyl ether as an internal standard.c Room temperature.d 0.3 mmol TsOH was used.e Isolated yield.f 1 mmol TsOH was used.g Without light.h Without catalyst.
1^c		CH3CN	0
2^c^,^d	TsOH	CH3CN	0
3^d	TsOH	CH3CN	37
4^e	TsOH	CH3CN	53 (51)
5^f	TsOH	CH3CN	39
6	Acetic acid	CH3CN	16
7	TFA	CH3CN	15
8	MSA	CH3CN	17
9	Benzoic acid	CH3CN	10
10	TsOH	DMF	11
11	TsOH	MeOH	33
12	TsOH	DMSO	29
13	TsOH	CHCl3	17
14^g	TsOH	CH3CN	0
15^h	TsOH	CH3CN	0

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Under the optimized reaction conditions, we started to explore the substrate scope. The reaction proceeds smoothly with various substituted aryl ketones (Table 2). Acetophenones with an electron-donating or weak electron-withdrawing group on the para-position of the benzene ring afforded the desired products in low to good yields (3b–3j). Of them, substrate with strong electron-withdrawing group showed an obvious negative effect on the yield (3d). It is noteworthy that trifluoromethyl, fluoro, chloro, bromo, hydroxy on the phenyl ring were well tolerated, which enabled potential applications in further functionalization (3d–3h). It seemed that steric hindrance did have some influence on the reaction. Thus, 3k–3n were obtained in low yields. Besides that, 1-tetralone was also a suitable substrate for this transformation to well construct 2,3-disubstituted pyridine (3q).

Table 2 Substrate scope of reactions^ab

a Reaction conditions: 1 (0.5 mmol), 2a (1.5 mmol), Ru(bpy)₃Cl₂ (0.01 mmol), TsOH (0.5 mmol), CH₃CN (2 mL) at 82 °C irradiated by a 23 W fluorescent lamp for 48 h under O₂ balloon.b Isolated yield.

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In order to further explore the applicability of ketones, when 1,3-propanediamine (2a) was replaced by 2-amino benzylamine (2b), the corresponding quinoline products could be obtained in good yields (Table 3). Under the same optimized conditions, acetophenone (1a) could react well with 2b to afford the desired product 4a in 65% yield. Ketones bearing an electron-withdrawing or electron-donating substituent also provided the corresponding products in good to excellent yields (4b–4f).

Table 3 Substrate scope of reactions^ab

a Reaction conditions: 1 (0.5 mmol), 2b (1.5 mmol), Ru(bpy)₃Cl₂ (0.01 mmol), TsOH (0.5 mmol), CH₃CN (2 mL) at 82 °C irradiated by a 23 W fluorescent lamp for 48 h under O₂ balloon.b Isolated yield.

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This reaction also tolerated a wide range of functional groups, including fluoro, chloro, bromo moieties. There was no obvious steric hindrance effect on the reaction and 4g–4i were generated in good yields. Additionally, heterocyclic methyl ketones could react with 2b smoothly to give the corresponding product 4l in good yield, which may have a potential application as a ligand in the organometallic catalysts. 1-Tetralone also underwent such transformation, providing the corresponding polycyclic compound 4m in 76% yield.

Based on the above results, a plausible mechanism was proposed to account for these aerobic C–N bond activation reactions (Scheme 2). Initially, condensation occurred between acetophenone (1a) and 1,3-propanediamine (2a) to afford imine intermediate I at high temperature. Excitation of ruthenium catalyst under the visible light generated the excited [Ru(bpy)₃]²⁺* species, which oxidized intermediate I to form the radical cation of amine II, along with active single electron transfer species, [Ru(bpy)₃]⁺. The species [Ru(bpy)₃]⁺ then reduced oxygen to furnish the radical anion of oxygen and regenerated catalyst [Ru(bpy)₃]²⁺. The imine intermediate III was formed by losing one hydrogen free radical, which immediately underwent cyclization, elimination and aromatization to afford the desired product 3a.

Scheme 2 Proposed mechanism.

Conclusions

In summary, we have developed a visible light-catalyzed aerobic C–N bond activation to well construct 2-arylpyridines and 2-arylquinolines, which are useful synthetic intermediates and important skeletons of biologically active molecules in organic synthesis. The applicability of various easily accessible starting materials and the use of air as the sole oxidant make this transformation very attractive. Further work towards expanding the use of photoredox catalysis in the construction of heterocyclic product is underway.

Acknowledgements

The authors acknowledge the financial support provided by the National Natural Science Foundation of China (No. 21232003). We thank the Instrumental Analysis Center for microanalysis.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra07962h

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