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Communication

Oxygen-Free Csp3-H Oxidation of Pyridin-2-yl-methanes to Pyridin-2-yl-methanones with Water by Copper Catalysis

by
Ming Zeng
1,
Jia-Le Chen
1,
Xue Luo
2,
Yan-Jiao Zou
1,
Zhao-Ning Liu
2,
Jun Dai
3,
Deng-Zhao Jiang
1,4 and
Jin-Jing Li
2,*
1
School of Pharmacy and Life Science, Jiujiang University, Jiujiang 332005, China
2
College of Pharmacy, Jiamusi University, Jiamusi 154007, China
3
Analytical and Testing Center, Jiujiang University, Jiujiang 332005, China
4
Jiujiang Key Laboratory for the Development and Utilization of Traditional Chinese Medicine Resources in Northwest Jiangxi, Jiujiang 332005, China
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(22), 7587; https://doi.org/10.3390/molecules28227587
Submission received: 12 October 2023 / Revised: 3 November 2023 / Accepted: 7 November 2023 / Published: 14 November 2023
(This article belongs to the Special Issue Recent Advances in Transition Metal Catalysis)
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Abstract

:
Aromatic ketones are important pharmaceutical intermediates, especially the pyridin-2-yl-methanone motifs. Thus, synthetic methods for these compounds have gained extensive attention in the last few years. Transition metals catalyze the oxidation of Csp3-H for the synthesis of aromatic ketones, which is arresting. Here, we describe an efficient copper-catalyzed synthesis of pyridin-2-yl-methanones from pyridin-2-yl-methanes through a direct Csp3-H oxidation approach with water under mild conditions. Pyridin-2-yl-methanes with aromatic rings, such as substituted benzene, thiophene, thiazole, pyridine, and triazine, undergo the reaction well to obtain the corresponding products in moderate to good yields. Several controlled experiments are operated for the mechanism exploration, indicating that water participates in the oxidation process, and it is the single oxygen source in this transformation. The current work provides new insights for water-involving oxidation reactions.

Graphical Abstract

1. Introduction

The synthesis of aromatic ketones has attracted great consideration in recent decades [1,2,3,4,5,6,7,8]. The strategy of direct oxidation of Csp3–H provided a powerful and promising method for the transformation of diarylmethane to aromatic ketones. However, an excess of hazardous and dangerous oxidants and a much higher temperature are always introduced due to the low reactivity of C-H bonds [9,10,11,12,13]. As a result, unwanted wastes and by-products are produced, which makes it difficult to obtain desired products in good yields. With the development of organometallic chemistry, the use of transition metals has been investigated in the synthesis of N-heterocyclic ketones with molecule oxygen, iodine, and peroxides as oxidants under mild conditions [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34] (Scheme 1). Among all the oxidants, oxygen is more conveniently and readily available. Nevertheless, extra additives, such as NHPI, ClCH2COOEt, and AcOH, are essential for some of the examples [24,25,28,29]. According to these reports, peroxy acid intermediate is formed with oxygen via a radical pathway for the transformation, providing an impressive protocol for the synthesis of pyridin-2-yl-methanones. Despite all this, innovative approaches with greener additives by means of metal catalysis are still in great demand. In 2022, Liu has reported the selective oxidation of alkylarenes to aromatic ketones or benzaldehydes with water [35]. In this transformation, water participates in the reaction and offers the oxygen for the process with a palladium catalyst, producing phenyl(pyridin-2-yl)methanone in 44% yield, which inspires us to take water as an oxygen donor for an oxidation reaction in the presence of non-noble metals. More recently, our research group has reported a copper-catalyzed synthesis of aroyl triazines and terminal olefin-substituted triazines [36,37]. Surprisingly, in our attempt to obtain N2,N2-dimethyl-N4-phenyl-6-(1-(pyridin-2-yl)vinyl)-1,3,5-triazine-2,4-diamine, the corresponding oxidation product was observed instead, so we proved that water can provide oxygen for the curtain oxidation transformation. The unexpected findings encourage us to probe the possibility of transforming pyridin-2-yl-methanes to pyridin-2-yl-methanones catalyzed by a copper catalyst in the presence of water. Here, we report an efficient copper-catalyzed synthesis of pyridin-2-yl-methanones via direct Csp3-H oxidation with water. To the best of our knowledge, a water-involved oxidation approach for pyridin-2-yl-methanones has never been reported.

2. Results and Discussion

We initially conducted the reaction through choosing 1a as substrate for the optimization study. To our delight, the reaction was smoothly carried out in N,N-dimethylacetamide (DMA) under a Cu(NO3)2 . 3H2O/H2O/N2 catalytic system after 20 h and gave the desired product in 69% yield (Table 1, entry 1). Lowering the amount of water to 2.5 equiv. gave a similar result, but a dramatically decreased yield of 2a was observed without the use of additional water or anhydrous Cu(NO3)2 (Table 1, entries 2–4). However, a slightly lower yield was observed in the presence of anhydrous Cu(NO3)2 and water (Table 1, entry 5). These results suggested that water was essential for the oxidation process. It was worth noting that prolonging the reaction time or elevating the temperature could not help increase the production; contrarily, a shorter reaction time or lower temperature resulted in a decreased yield of 2a (Table 1, entries 6–9). However, the lower loading of the Cu(NO3)2 3H2O led to a slower reaction, and a 68% yield of 2a was obtained when increasing the amount of the catalyst (Table 1, entries 10–11). Next, we paid attention to the various copper (II) catalysts; Cu(NO3)2 3H2O was proved to be the best choice for this transformation (Table 1, entries 12–16). Finally, the influence of the solvents was investigated (Table 1, entries 17–22). The results showed that the replacement of DMA with DMF, DMSO, or PhCl gave a much lower yield, while the reaction could hardly occur due to the lower solubility in H2O or Et3N. It is clear that DMA was considered to be optimal for this oxidation process.
With the optimized condition in hand, a variety of substituted 2-benzylpyridines (1a-l) were performed to test the scope of our oxidation methodology. As shown in Table 2, 2-benzylpyridines with electron-donating (-t-Bu, -Naphthyl, Ph) and electron-withdrawing (-Cl, -Br, -COMe, -COOMe, -CN, -NO2) groups underwent the reaction to afford desired oxidation products in moderate to good yields. Gratifyingly, when 2-(thiophen-2-ylmethyl)pyridine (1m), 2-(pyridin-2-ylmethyl)thiazole (1n), and 2-(pyridin-3-ylmethyl)pyridine (1o) were subjected to the oxidation protocol, the corresponding oxidation products were obtained in 65%, 51%, an 60% yield, respectively. Then, 4-benzylpyridine was tested under the optimized conditions, giving the corresponding product (2q) in 62% yield. Despite much effort, 3-benzylpyridine cannot undergo the reaction under the current conditions to form the desired product. Instead, 3-pyridine with triazine substrate (1r) could easily transfer into the corresponding product in 66% yield.
Subsequently, we turned our attention to probe the reaction mechanism of this oxidic process. Firstly, we monitored the reaction mixture over time via liquid chromatography–mass spectrometry (LCMS) for capturing the possible intermediates and by-products, suggesting that IV (IV-1 or IV-2) should be a vital intermediate for this transformation (Scheme 2, Equation (1)). A treatment of IV (IV-1 or IV-2) under the standard conditions gave the desired product in 46% yield (Scheme 2, Equation (2)). What puzzled us was where the source of oxygen came from. Moreover, several labeling experiments were preformed to investigate the source of oxygen for our oxidation protocol. The reaction was performed in the presence of deuterium oxide or 18O-labeled water instead of water (Scheme 2, Equations (3) and (4)); both intermediate IV (IV-1 or IV-2) and 18O-labeled products were confirmed via LCMS, further proving that water participated in the reaction and acted as oxygen donor in the reaction [37].
Based on the results above and previous work [25,37], a plausible mechanism of the water-involved oxidation process was proposed (Scheme 3). Initially, 1a was activated by a hydrogen proton to give 1a’ [24,25,26,28], which subsequently reacted with CuX2 to afford I and II [33]. Then, the reaction between II and H2O generating III and IV (IV-1 or IV-2) was formed through the reductive elimination process [14,36,37,38]. In the presence of a metal catalyst, oxygen, or sodium nitrite [39,40,41,42,43,44,45,46,47,48], IV (IV-1 or IV-2) underwent dehydrogenation to afford the desired product 2a [41,46,47,48] (Scheme 3). Notably, Cu(I) would be reoxidized to Cu(II) in the H2/H2O/H+ system, closing the catalytic cycle [14,37,49].

3. Materials and Methods

3.1. General Information

Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. All reactions were performed in a heating mantle in a sealed tube unless otherwise noted. Thin layer chromatography (TLC) was performed using silica gel 60 F254 and was visualized using UV light. Column chromatography was performed with silica gel (mesh 300–400). 1H NMR and 13C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer in CDCl3 or DMSO-d6 with Me4Si as an internal standard. Data were reported as follows: a chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, and m = multiplet), coupling constant in Hertz (Hz), and integration. The HRMS and mass data were recorded via ESI on a TOF mass spectrometer.

3.2. General Procedure for the Synthesis of 2

To a mixture of pyridyl-methanes (1.0 mmol), H2O (2.5 mmol), and DMA (3 mL), we added Cu(NO3)2·3H2O (10 mol%). The resulting mixture was then sealed and stirred for 20–40 h at 100 °C under argon. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4. The crude residue was obtained after evaporation of the solvent in a vacuum, and the residue was purified via flash chromatography with petroleum ether and ethyl acetate (v/v 20/1~5/1) as the eluent to give the pure product.
Phenyl(pyridin-2-yl)methanone (2a) [34] 1H NMR (400 MHz, CDCl3) δ 8.77–8.64 (m, 1H), 8.05 (dd, J = 8.2, 1.0 Hz, 2H), 8.02 (dd, J = 7.9, 0.8 Hz, 1H), 7.88 (td, J = 7.7, 1.7 Hz, 1H), 7.61–7.54 (m, 1H), 7.50–7.43 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 193.9, 155.1, 148.6, 137.0, 136.2, 132.9, 130.9, 128.1, 126.1, 124.6.
(4-(Tert-butyl)phenyl)(pyridin-2-yl)methanone (2b) [50] 1H NMR (400 MHz, CDCl3) δ 8.77–8.71 (m, 1H), 8.06–8.01 (m, 3H), 7.91 (td, J = 7.7, 1.7 Hz, 1H), 7.57–7.46 (m, 3H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 193.5, 156.6, 155.4, 148.5, 137.0, 133.5, 130.9, 126.0, 125.2, 124.5, 35.1, 31.1.
Naphthalen-2-yl(pyridin-2-yl)methanone (2c) [10] 1H NMR (400 MHz, CDCl3) δ 8.74–8.69 (m, 1H), 8.30–8.24 (m, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.00–7.90 (m, 2H), 7.74 (dd, J = 7.1, 1.1 Hz, 1H), 7.60–7.49 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 196.5, 155.5, 149.1, 137.0, 134.7, 133.8, 132.2, 131.2, 129.9, 128.4, 127.4, 126.5, 126.3, 125.6, 124.6, 124.1.
[1,1′-Biphenyl]-4-yl(pyridin-2-yl)methanone (2d) [10] 1H NMR (400 MHz, CDCl3) δ 8.81–8.75 (m, 1H), 8.21–8.16 (m, 2H), 8.11 (d, J = 7.8 Hz, 1H), 7.95 (td, J = 7.8, 1.7 Hz, 1H), 7.77–7.71 (m, 2H), 7.69–7.64 (m, 2H), 7.54 (dd, J = 4.7, 1.2 Hz, 1H), 7.53–7.47 (m, 2H), 7.43 (ddd, J = 7.3, 4.7, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.3, 155.2, 148.5, 145.6, 140.1, 137.1, 134.9, 131.6, 128.9, 128.1, 127.3, 126.9, 126.2, 124.6.
Pyridin-2-yl(4-(trifluoromethoxy)phenyl)methanone (2e) [51] 1H NMR (400 MHz, CDCl3) δ 8.73 (dd, J = 4.7, 0.6 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 8.06 (dt, J = 7.7, 1.2 Hz, 1H), 8.02 (br, 1H), 7.93 (td, J = 7.7, 1.7 Hz, 1H), 7.56–7.48 (m, 2H), 7.48–7.43 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 191.1, 148.9, 148.5, 138.1, 137.2, 129.6, 129.5, 126.6, 125.0, 124.7, 124.3, 120.5 (q, J = 257.8 Hz); 19F NMR (376 MHz, CDCl3) δ -57.8.
(4-Chlorophenyl)(pyridin-2-yl)methanone (2f) [28] 1H NMR (400 MHz, CDCl3) δ 8.75 (dd, J = 4.4, 0.7 Hz, 1H), 8.13–8.05 (m, 3H), 7.95 (td, J = 7.6, 0.7 Hz, 1H), 7.54 (ddd, J = 7.6, 4.4, 1.2 Hz, 1H), 7.51–7.46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 192.3, 154.6, 148.5, 139.4, 137.2, 134.6, 132.5, 128.4, 126.4, 124.7.
(3-Chlorophenyl)(pyridin-2-yl)methanone (2g) [52] 1H NMR (400 MHz, CDCl3) δ 8.79–8.74 (m, 1H), 8.12–8.07 (m, 2H), 8.00 (dt, J = 8.0, 1.1 Hz, 1H), 7.94 (td, J = 7.6, 1.7 Hz, 1H), 7.59 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.54 (ddd, J = 7.6, 5.0, 1.2 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 192.3, 154.4, 148.6, 137.9, 137.2, 134.3, 132.7, 130.9, 129.5, 129.1, 126.5, 124.7.
(3-Bromophenyl)(pyridin-2-yl)methanone (2h) [53] 1H NMR (400 MHz, CDCl3) δ 8.70 (ddd, J = 4.7, 1.5, 0.8 Hz, 1H), 8.18 (dd, J = 7.8, 0.7 Hz, 1H), 7.92 (td, J = 7.7, 1.7 Hz, 1H), 7.65 (dd, J = 7.9, 0.7 Hz, 1H), 7.52–7.48 (m, 1H), 7.49–7.42 (m, 2H), 7.41–7.34 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 195.8, 153.5, 149.3, 140.3, 137.0, 133.0, 131.5, 129.8, 127.0, 126.9, 123.9, 120.0.
1-(2-Picolinoylphenyl)ethan-1-one (2i) [54] 1H NMR (400 MHz, CDCl3) δ 8.79–8.73 (m, 1H), 8.67 (t, J = 1.5 Hz, 1H), 8.31 (dt, J = 7.7, 1.3 Hz, 1H), 8.24–8.18 (m, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.96 (td, J = 7.7, 1.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.54 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 2.67 (s, 3H). 13C NMR (100MHz, CDCl3) δ 197.4, 192.9, 154.4, 148.6, 137.2, 136.9, 136.7, 135.3, 132.1, 130.9, 128.6, 126.6, 124.7, 26.7.
Methyl 4-picolinoylbenzoate (2j) [24] 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.7 Hz, 1H), 8.21–8.10 (m, 5H), 7.95 (td, J = 7.7, 1.7 Hz, 1H), 7.54 (ddd, J = 7.7, 4.7, 1.2 Hz, 1H), 3.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.2, 166.4, 154.4, 148.6, 139.9, 137.2, 133.5, 130.8, 129.2, 126.6, 124.7, 52.4.
3-Picolinoylbenzonitrile (2k) [24] 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.5 Hz, 1H), 8.50 (t, J = 1.4 Hz, 1H), 8.39 (dt, J = 7.8, 1.4 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.98 (td, J = 7.6, 1.7 Hz, 1H), 7.88 (dt, J = 7.8, 1.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.58 (ddd, J = 7.6, 4.5, 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 191.2, 153.7, 148.6, 137.4, 137.2, 135.5, 135.0, 134.9, 129.1, 126.9, 124.8, 118.2, 112.5.
(3-Nitrophenyl)(pyridin-2-yl)methanone (2l) [24] 1H NMR (400 MHz, CDCl3) δ 9.08–8.97 (m, 1H), 8.77 (dd, J = 2.7, 2.0 Hz, 1H), 8.57–8.42 (m, 2H), 8.20 (d, J = 8.0 Hz, 1H), 7.99 (td, J = 7.7, 1.7 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.59 (ddd, J = 7.7, 4.8, 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 191.0, 153.6, 148.7, 147.9, 137.6, 137.4, 136.6, 129.2, 127.0, 126.9, 126.2, 124.8.
Pyridin-2-yl(thiophen-2-yl)methanone (2m) [55] 1H NMR (400 MHz, CDCl3) δ 8.76 (ddd, J = 4.7, 1.6, 0.8 Hz, 1H), 8.41 (dd, J = 3.9, 1.2 Hz, 1H), 8.19 (dt, J = 7.7, 1.2 Hz, 1H), 7.90 (td, J = 7.7, 1.6 Hz, 1H), 7.76 (dd, J = 5.0, 1.2 Hz, 1H), 7.51 (ddd, J = 7.7, 4.7, 1.2 Hz, 1H), 7.20 (dd, J = 5.0, 3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 183.5, 154.0, 148.2, 140.0, 137.1, 136.7, 136.3, 127.6, 126.6, 123.8.
Pyridin-2-yl(thiazol-2-yl)methanone (2n) [56] 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 4.5 Hz, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.22 (d, J = 3.0 Hz, 1H), 7.96 (td, J = 7.6, 1.7 Hz, 1H), 7.80 (d, J = 3.0 Hz, 1H), 7.59 (ddd, J = 7.6, 4.5, 1.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 181.5, 161.7, 152.4, 148.8, 144.9, 137.2, 127.5, 127.3, 124.9.
Pyridin-2-yl(pyridin-3-yl)methanone (2o) [10] 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.79 (d, J = 3.9 Hz, 1H), 8.73 (d, J = 4.3 Hz, 1H), 8.43 (dt, J = 7.9, 1.9 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.93 (td, J = 7.7, 1.7 Hz, 1H), 7.53 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 7.44 (dd, J = 7.9, 4.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 192.0, 153.9, 152.8, 152.1, 148.6, 138.2, 137.2, 132.0, 126.8, 124.5, 123.0.
Phenyl(pyridin-4-yl)methanone (2p)[14] 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 4.7 Hz, 2H), 7.84 (d, J = 7.5 Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 4.7 Hz, 2H), 7.54 (t, J = 7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 195.1, 150.3, 144.4, 135.92, 133.5, 130.1, 128.8, 128.6, 122.8.
(4-(Dimethylamino)-6-(phenylamino)-1,3,5-triazin-2-yl)(pyridin-3-yl)methanone (2r) 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.17 (d, J = 1.4 Hz, 1H), 8.86 (dd, J = 4.7, 1.4 Hz, 1H), 8.46–8.27 (m, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.61 (dd, J = 7.8, 4.7 Hz, 1H), 7.31 (t, J = 7.2 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 3.20 (s, 3H), 3.12 (s, 3H); 13C NMR (100 MHz, DMSO) δ 190.6, 168.5, 164.9, 163.7, 154.5, 151.5, 139.7, 138.1, 130.4, 129.0, 124.3, 123.0, 120.4, 36.6, HRMS (ESI) [M + H]+, calcd for C17H17N6O: 321.1464, found: 321.1468.

4. Conclusions

In conclusion, we have demonstrated an efficient copper-catalyzed oxygen-free synthesis of pyridin-2-yl-methanones via the direct oxidation of Csp3-H with water. Further mechanism studies proved that the oxygen of the products came from water. This work provided a powerful approach for certain oxidation reactions. Detailed mechanistic studies and substrate expansion are in progress.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28227587/s1, Figure S1, 1H NMR spectrum of phenyl(pyridin-2-yl)methanone (2a); Figure S2, 13C NMR spectrum of phenyl(pyridin-2-yl)methanone (2a); Figure S3, 1H NMR spectrum (4-(tert-butyl)phenyl)(pyridin-2-yl)methanone (2b); Figure S4, 13C NMR spectrum of (4-(tert-butyl)phenyl)(pyridin-2-yl)methanone (2b); Figure S5, 1H NMR spectrum of naphthalen-2-yl(pyridin-2-yl)methanone (2c); Figure S6, 13C NMR spectrum of naphthalen-2-yl(pyridin-2-yl)methanone (2c); Figure S7, 1H NMR spectrum of [1,1′-biphenyl]-4-yl(pyridin-2-yl)methanone (2d); Figure S8, 13C NMR spectrum of [1,1′-biphenyl]-4-yl(pyridin-2-yl)methanone (2d); Figure S9, 1H NMR spectrum of pyridin-2-yl(4-(trifluoromethoxy)phenyl)methanone (2e); Figure S10, 13C NMR spectrum of pyridin-2-yl(4-(trifluoromethoxy)phenyl)methanone (2e); Figure S11, 19F NMR spectrum of pyridin-2-yl(4-(trifluoromethoxy)phenyl)methanone (2e); Figure S12, 1H NMR spectrum of (4-chlorophenyl)(pyridin-2-yl)methanone (2f); Figure S13, 13C NMR spectrum of (4-chlorophenyl)(pyridin-2-yl)methanone (2f); Figure S14, 1H NMR spectrum of (3-chlorophenyl)(pyridin-2-yl)methanone (2g); Figure S15, 13C NMR spectrum of (3-chlorophenyl)(pyridin-2-yl)methanone (2g); Figure S16, 1H NMR spectrum of (2-bromophenyl)(pyridin-2-yl)methanone (2h); Figure S17, 13C NMR spectrum of (2-bromophenyl)(pyridin-2-yl)methanone (2h); Figure S18, 1H NMR spectrum of 1-(2-picolinoylphenyl)ethan-1-one (2i); Figure S19, 13C NMR spectrum of 1-(2-picolinoylphenyl)ethan-1-one (2i); Figure S20, 1H NMR spectrum of methyl 4-picolinoylbenzoate (2j); Figure S21, 13C NMR spectrum of methyl 4-picolinoylbenzoate (2j); Figure S22, 1H NMR spectrum of 3-picolinoylbenzonitrile (2k); Figure S23, 13C NMR spectrum of 3-picolinoylbenzonitrile (2k); Figure S24, 1H NMR spectrum of (3-nitrophenyl)(pyridin-2-yl)methanone (2l); Figure S25, 13C NMR spectrum of (3-nitrophenyl)(pyridin-2-yl)methanone (2l); Figure S26, 1H NMR spectrum of pyridin-2-yl(thiophen-2-yl)methanone (2m); Figure S27, 13C NMR spectrum of pyridin-2-yl(thiophen-2-yl)methanone (2m); Figure S28, 1H NMR spectrum of pyridin-2-yl(thiazol-2-yl)methanone (2n); Figure S29, 13C NMR spectrum of pyridin-2-yl(thiazol-2-yl)methanone (2n); Figure S30, 1H NMR spectrum of pyridin-2-yl(pyridin-3-yl)methanone (2o); Figure S31, 13C NMR spectrum of pyridin-2-yl(pyridin-3-yl)methanone (2o); Figure S32, 1H NMR spectrum of phenyl(pyridin-4-yl)methanone (2q); Figure S33, 13C NMR spectrum of phenyl(pyridin-4-yl)methanone (2q); Figure S34, 1H NMR spectrum of (4-(dimethylamino)-6-(phenylamino)-1,3,5-triazin-2-yl)(pyridin-3-yl)methanone (2r); Figure S35, 13C NMR spectrum of (4-(dimethylamino)-6-(phenylamino)-1,3,5-triazin-2-yl)(pyridin-3-yl)methanone (2r).

Author Contributions

Reaction optimization, J.-L.C.; synthesis investigation, Y.-J.Z.; mechanism studies, X.L.; NMR and HRMS analysis, J.D. and D.-Z.J.; writing—original draft preparation, Z.-N.L.; writing—review and editing, supervision, M.Z. and J.-J.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Natural Science Foundation of Heilongjiang Province of China, grant number LH2022H094 and The APC was funded by LH2022H094.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

We are grateful for support from the Analytical and Testing Center of Jiujiang University and Jiujiang key laboratory for the development and utilization of traditional Chinese medicine resources in Northwest Jiangxi. And we appreciate for finical support of the Natural Science Foundation of Heilongjiang Province of China.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Molecules 28 07587 sch001
Scheme 1. The oxidation of benzylic C(sp3)-H bond to aromatic ketones with copper catalysts [20,24,25,28,31,32,33,37].
Scheme 1. The oxidation of benzylic C(sp3)-H bond to aromatic ketones with copper catalysts [20,24,25,28,31,32,33,37].
Molecules 28 07587 sch001
Molecules 28 07587 sch002
Scheme 2. Controlled experiments.
Scheme 2. Controlled experiments.
Molecules 28 07587 sch002
Molecules 28 07587 sch003
Scheme 3. Plausible mechanism.
Scheme 3. Plausible mechanism.
Molecules 28 07587 sch003
Table 1. Optimization of the reaction a.
Table 1. Optimization of the reaction a.
Molecules 28 07587 i001
EntryCu Salt (mol %)WaterSolventTime/hYield/%
1Cu(NO3)2·3H2O (10 mol%)5.0 equiv.DMA2069
2Cu(NO3)2·3H2O (10 mol%)2.5 equiv.DMA2068
3Cu(NO3)2·3H2O (10 mol%)-DMA2036
4Cu(NO3)2 (10 mol%)-DMA208
5Cu(NO3)2 (10 mol%)2.5 equiv.DMA2059
6Cu(NO3)2·3H2O (10 mol%)2.5 equiv.DMA2070 b
7Cu(NO3)2·3H2O (10 mol%)2.5 equiv.DMA2043 c
8Cu(NO3)2·3H2O (10 mol%)2.5 equiv.DMA1241
9Cu(NO3)2·3H2O (10 mol%)2.5 equiv.DMA3061
10Cu(NO3)2·3H2O (5 mol%) 2.5 equiv.DMA2040
11Cu(NO3)2·3H2O (20 mol%) 2.5 equiv.DMA2068
12Cu(OAc)·H2O (10 mol%)2.5 equiv.DMA2042
13CuCl2·2H2O (10 mol%) 2.5 equiv.DMA2045
14CuSO4 (10 mol%)2.5 equiv.DMA2036
15CuBr2 (10 mol%) 2.5 equiv.DMA2040
16Cu(CF3SO3)2 (10 mol%)2.5 equiv.DMA2022
17Cu(NO3)2·3H2O (10 mol%)2.5 equiv.DMF2045
18Cu(NO3)2·3H2O (10 mol%)2.5 equiv.DMSO2030
19Cu(NO3)2·3H2O (10 mol%)2.5 equiv.NMP2021
20Cu(NO3)2·3H2O (10 mol%)2.5 equiv.PhCl2023
21Cu(NO3)2·3H2O (10 mol%)2.5 equiv.Et3N20trace
22Cu(NO3)2·3H2O (10 mol%)2.5 equiv.H2O20trace
a Reaction conditions: 1 (1 mmol), CuX2 (10 mol%), solvent (3 mL), H2O (2.5 equvi.), 100 °C, 20 h, argon atmosphere. b 120 °C. c 80 °C.
Table 2. Scope of the Cu catalyzed oxidation of benzylpyridines.
Table 2. Scope of the Cu catalyzed oxidation of benzylpyridines.
Molecules 28 07587 i002
Entry1ArTime/h2Yield/%
1Molecules 28 07587 i003
1a–1o		Ph202a68
24-t-BuC6H4382b76
32-naphthyl302c85
44-PhC6H4302d92
54-OCF3C6H4252e65
64-ClC6H4202f48
73-ClC6H4202g63
83-BrC6H4302h62
92-CH3COC6H4502i63
104-CH3OOCC6H4232j60
113-CNC6H4392k68
123-NO2C6H4302l54
132-thiophenyl252m65
142-thiazolyl242n51
153-pyridyl202o60
16Molecules 28 07587 i004
1p		-302p62
17Molecules 28 07587 i005
1q		-402qtrace
18Molecules 28 07587 i006
1r		-102r66
Reaction conditions: 1 (1 mmol), Cu(NO3)2.3H2O (10 mol%), solvent (3 mL), H2O (2.5 equiv.), 100 °C, argon atmosphere.
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Zeng, M.; Chen, J.-L.; Luo, X.; Zou, Y.-J.; Liu, Z.-N.; Dai, J.; Jiang, D.-Z.; Li, J.-J. Oxygen-Free Csp3-H Oxidation of Pyridin-2-yl-methanes to Pyridin-2-yl-methanones with Water by Copper Catalysis. Molecules 2023, 28, 7587. https://doi.org/10.3390/molecules28227587

AMA Style

Zeng M, Chen J-L, Luo X, Zou Y-J, Liu Z-N, Dai J, Jiang D-Z, Li J-J. Oxygen-Free Csp3-H Oxidation of Pyridin-2-yl-methanes to Pyridin-2-yl-methanones with Water by Copper Catalysis. Molecules. 2023; 28(22):7587. https://doi.org/10.3390/molecules28227587

Chicago/Turabian Style

Zeng, Ming, Jia-Le Chen, Xue Luo, Yan-Jiao Zou, Zhao-Ning Liu, Jun Dai, Deng-Zhao Jiang, and Jin-Jing Li. 2023. "Oxygen-Free Csp3-H Oxidation of Pyridin-2-yl-methanes to Pyridin-2-yl-methanones with Water by Copper Catalysis" Molecules 28, no. 22: 7587. https://doi.org/10.3390/molecules28227587

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