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. 2023 Nov 14;28(22):7587. doi: 10.3390/molecules28227587

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

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, Jin-Jing Li 2,*
Editor: Dingyi Wang
PMCID: PMC10673412  PMID: 38005308

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.

Keywords: Csp3-H oxidation, pyridin-2-yl-methanones, copper catalysis, water, mechanism study

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.

Scheme 1.

Scheme 1

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The oxidation of benzylic C(sp3)-H bond to aromatic ketones with copper catalysts [20,24,25,28,31,32,33,37].

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.

Table 1.

Optimization of the reaction a.

graphic file with name molecules-28-07587-i001.jpg

Entry Cu Salt (mol %) Water Solvent Time/h Yield/%
1 Cu(NO3)2·3H2O (10 mol%) 5.0 equiv. DMA 20 69
2 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. DMA 20 68
3 Cu(NO3)2·3H2O (10 mol%) - DMA 20 36
4 Cu(NO3)2 (10 mol%) - DMA 20 8
5 Cu(NO3)2 (10 mol%) 2.5 equiv. DMA 20 59
6 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. DMA 20 70 b
7 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. DMA 20 43 c
8 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. DMA 12 41
9 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. DMA 30 61
10 Cu(NO3)2·3H2O (5 mol%) 2.5 equiv. DMA 20 40
11 Cu(NO3)2·3H2O (20 mol%) 2.5 equiv. DMA 20 68
12 Cu(OAc)·H2O (10 mol%) 2.5 equiv. DMA 20 42
13 CuCl2·2H2O (10 mol%) 2.5 equiv. DMA 20 45
14 CuSO4 (10 mol%) 2.5 equiv. DMA 20 36
15 CuBr2 (10 mol%) 2.5 equiv. DMA 20 40
16 Cu(CF3SO3)2 (10 mol%) 2.5 equiv. DMA 20 22
17 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. DMF 20 45
18 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. DMSO 20 30
19 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. NMP 20 21
20 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. PhCl 20 23
21 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. Et3N 20 trace
22 Cu(NO3)2·3H2O (10 mol%) 2.5 equiv. H2O 20 trace
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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.

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.

Table 2.

Scope of the Cu catalyzed oxidation of benzylpyridines.

graphic file with name molecules-28-07587-i002.jpg

Entry 1 Ar Time/h 2 Yield/%
1 Inline graphic
1a–1o 		Ph 20 2a 68
2 4-t-BuC6H4 38 2b 76
3 2-naphthyl 30 2c 85
4 4-PhC6H4 30 2d 92
5 4-OCF3C6H4 25 2e 65
6 4-ClC6H4 20 2f 48
7 3-ClC6H4 20 2g 63
8 3-BrC6H4 30 2h 62
9 2-CH3COC6H4 50 2i 63
10 4-CH3OOCC6H4 23 2j 60
11 3-CNC6H4 39 2k 68
12 3-NO2C6H4 30 2l 54
13 2-thiophenyl 25 2m 65
14 2-thiazolyl 24 2n 51
15 3-pyridyl 20 2o 60
16 Inline graphic
1p 		- 30 2p 62
17 Inline graphic
1q 		- 40 2q trace
18 Inline graphic
1r 		- 10 2r 66
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Reaction conditions: 1 (1 mmol), Cu(NO3)2.3H2O (10 mol%), solvent (3 mL), H2O (2.5 equiv.), 100 °C, argon atmosphere.

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].

Scheme 2.

Scheme 2

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Controlled experiments.

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].

Scheme 3.

Scheme 3

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Plausible mechanism.

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.

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.

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).

Click here for additional data file. (14.6MB, zip)

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.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

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

Footnotes

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