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

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.


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 Csp 3 -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  (Scheme 1).Among all the oxidants, oxygen is more conveniently and readily available.Nevertheless, extra additives, such as NHPI, ClCH 2 COOEt, 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 N 2 ,N 2 -dimethyl-N 4 -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 Csp 3 -H oxidation with water.To the best of our knowledge, a water-involved oxidation approach for pyridin-2-yl-methanones has never been reported.
Molecules 2023, 28, x FOR PEER REVIEW 2 of 11 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 N 2 ,N 2 -dimethyl-N 4 -phenyl-6-(1-(pyridin-2yl)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-ylmethanones via direct Csp 3 -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.The oxidation of benzylic C(sp 3 )-H bond to aromatic ketones with copper catalysts [20,24,25,28,[31][32][33]37].

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

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(NO 3 ) 2 .3H 2 O/H 2 O/N 2 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(NO 3 ) 2 (Table 1, entries 2-4).However, a slightly lower yield was observed in the presence of anhydrous Cu(NO 3 ) 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(NO 3 ) 2 3H 2 O 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(NO 3 ) 2 3H 2 O was proved to be the best choice for this transformation (Table 1, entries [12][13][14][15][16]. Finally, the influence of the solvents was investigated (Table 1, entries [17][18][19][20][21][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 H 2 O or Et 3 N.It is clear that DMA was considered to be optimal for this oxidation process.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][18][19][20][21][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 (1al) were performed to test the scope of our oxidation methodology.As shown in Table 2, 2benzylpyridines 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 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 electronwithdrawing (-Cl, -Br, -COMe, -COOMe, -CN, -NO 2 ) 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.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 chromatographymass spectrometry (LCMS) for capturing the possible intermediates and by-products,  Subsequently, we turned our attention to probe the reaction mechanism of this oxidic process.Firstly, we monitored the reaction mixture over time via liquid chromatographymass spectrometry (LCMS) for capturing the possible intermediates and by-products, spite 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.   1 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 chromatographymass spectrometry (LCMS) for capturing the possible intermediates and by-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 chromatographymass spectrometry (LCMS) for capturing the possible intermediates and by-products, 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 18 O-labeled water instead of water (Scheme 2, Equations ( 3) and ( 4)); both intermediate IV (IV-1 or IV-2) and 18 O-labeled products were confirmed via LCMS, further proving that water participated in the reaction and acted as oxygen donor in the reaction [37].

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 Scheme 3. Plausible mechanism.

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 13 C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer in CDCl 3 or DMSO-d 6 with Me 4 Si 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.

General Procedure for the Synthesis of 2
To a mixture of pyridyl-methanes (1.0 mmol), H 2 O (2.5 mmol), and DMA (3 mL), we added Cu(NO 3 ) 2 •3H 2 O (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 Na 2 SO 4 .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.

Conclusions
In conclusion, we have demonstrated an efficient copper-catalyzed oxygen-free synthesis of pyridin-2-yl-methanones via the direct oxidation of Csp 3 -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.

1 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.

1
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 chromatographymass spectrometry (LCMS) for capturing the possible intermediates and by-products, 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 1 .
Optimization of the reaction a .

Table 1 .
Optimization of the reaction a .

Table 2 .
Scope of the Cu catalyzed oxidation of benzylpyridines.

Table 2 .
Scope of the Cu catalyzed oxidation of benzylpyridines.

Table 2 .
Scope of the Cu catalyzed oxidation of benzylpyridines.

Table 2 .
Scope of the Cu catalyzed oxidation of benzylpyridines.

Table 2 .
Scope of the Cu catalyzed oxidation of benzylpyridines.

Table 2 .
Scope of the Cu catalyzed oxidation of benzylpyridines.