Selective Synthesis of N-[1,3,5]Triazinyl-α-Ketoamides and N-[1,3,5]Triazinyl-Amides from the Reactions of 2-Amine-[1,3,5]Triazines with Ketones

In this study, we report a selective approach for synthesizing N-([1,3,5]triazine-2-yl) α-ketoamides and N-([1,3,5]triazine-2-yl) amides from ketones with 2-amino[1,3,5]triazines through oxidation and oxidative C−C bond cleavage reaction, respectively. The transformation proceeds under mild conditions, provides good functional group tolerance and chemoselectivity, and will serve as a valuable tool for the synthesis of bioactive products.


Results
In a recent paper, we reported the annulation of 2-amino- [1,3,5]triazines and k to construct imidazo [1,2-a] [1,3,5]triazines. However, trace unexpected α-ketoam and amides 4 were found as byproducts. Interestingly, α-ketoamides 3a became vored product using CuCl (20 mol%) along with iodine (2 eq.) in DMSO at 120 °C h under a nitrogen atmosphere (90%) (  [11][12][13][14]. We also ob that the yield of the product was lower when CuCl, I2 or 2a was reduced ( Table 1, [15][16][17]. Notably, 3a was afforded in 75% or 48% yield when running the reaction air or O2 ( Having established the optimal conditions, the substrate scope was examined (Scheme 2). Various electron-donating substituents on the aryl unit of ketones were investigated and furnished the respective products in 67-93% yields (3b-f). In addition, aryl ketones with electron-withdrawing substituents also work well in the reaction. For example, aryl ketones substituted with halogens at either the meta or para positions successfully underwent amidation to give α-ketoamides 3g-j in good yields. In addition, thiophone was found to be suitable reaction partner and afforded the desired product 3k with a 59% yield. Next, we surveyed the scope of 2-amino [1,3,5]triazine derivatives with different substituents on the C4-position. The derivatives with N,N-diethylamino, morpholino, pyrrolidino, and piperidino substituents were also competent starting materials for this strategy and performed the corresponding products 3l-o in 75-99% yields. 2-Amine- [1,3,5]triazines with phenylamino substituent at the C4-position were also tolerated under the standard reaction conditions, giving the desired product 3p with an 82% yield. Additionally, the structure of 3a was unambiguously confirmed using the single crystal X-ray analysis (CCDC 2180473). Having established the optimal conditions, the substrate scope was examined (Scheme 2). Various electron-donating substituents on the aryl unit of ketones were investigated and furnished the respective products in 67-93% yields (3b-f). In addition, aryl ketones with electron-withdrawing substituents also work well in the reaction. For example, aryl ketones substituted with halogens at either the meta or para positions successfully underwent amidation to give α-ketoamides 3g-j in good yields. In addition, thiophone was found to be suitable reaction partner and afforded the desired product 3k with a 59% yield. Next, we surveyed the scope of 2-amino [1,3,5]triazine derivatives with different substituents on the C4-position. The derivatives with N,N-diethylamino, morpholino, pyrrolidino, and piperidino substituents were also competent starting materials for this strategy and performed the corresponding products 3l-o in 75-99% yields. 2-Amine- [1,3,5]triazines with phenylamino substituent at the C4-position were also tolerated under the standard reaction conditions, giving the desired product 3p with an 82% yield. Additionally, the structure of 3a was unambiguously confirmed using the single crystal X-ray analysis (CCDC 2180473). After demonstrating the reaction scope for the synthesis of N-( [1,3,5]triazine-2-yl) αketoamides, we decided to pursue an oxidative C−C bond cleavage approach with N-([1,3,5]triazine-2-yl) amides formation. Using the above reaction conditions, we failed to obtain the desired product 4a ( Table 2, entry 1). The use of other copper salts such as CuI, CuBr, and Cu(OAc)2 was also found ineffective for the reaction ( Table 2, entries 2-5). After demonstrating the reaction scope for the synthesis of N-([1,3,5]triazine-2-yl) α-ketoamides, we decided to pursue an oxidative C−C bond cleavage approach with N-([1,3,5]triazine-2-yl) amides formation. Using the above reaction conditions, we failed to obtain the desired product 4a ( Table 2, entry 1). The use of other copper salts such as CuI, CuBr, and Cu(OAc) 2 was also found ineffective for the reaction ( Table 2, entries 2-5). Employing CuCl 2 along with 1,2-DCB or Diethylene glycol dimethyl ether (diglyme) solvent afforded the desired product 4a with 27% and 11% yields, respectively ( Table 2, entries 6-7). However, the other solvent (1,2,4-trichlorobenzene (1,2,4-TCB), DMF, NMP, and toluene) proved to be unproductive for the reaction ( Table 2, entries [8][9][10][11]. Increasing the amount of CuCl 2 to 40 mol% and the temperature to 140 • C in the mixture of 1,2-DCB and diglyme afforded product 4a with a 63% yield ( Table 2, entry 13). The amount of I 2 was screened, and the results showed that 1.5 equiv of I 2 was optimal for this reaction (Table 2,  entry 15). Stirring the reaction for a longer time and a shorter time gave product 4a in lower yields (Table 2, entries [18][19]. The reaction did not proceed either in the absence of copper salts and I 2 , and control experiments showed that oxygen was needed to perform the reaction (Table 2, entries 20-23). Table 2. Optimization of the reaction conditions for the formation of 4a a .
Employing CuCl2 along with 1,2-DCB or Diethylene glycol dimethyl ether (diglyme) solvent afforded the desired product 4a with 27% and 11% yields, respectively ( Table 2, entries 6-7). However, the other solvent (1,2,4-trichlorobenzene (1,2,4-TCB), DMF, NMP, and toluene) proved to be unproductive for the reaction (  [8][9][10][11]. Increasing the amount of CuCl2 to 40 mol% and the temperature to 140 °C in the mixture of 1,2-DCB and diglyme afforded product 4a with a 63% yield ( Table 2, entry 13). The amount of I2 was screened, and the results showed that 1.5 equiv of I2 was optimal for this reaction ( Table 2, entry 15). Stirring the reaction for a longer time and a shorter time gave product 4a in lower yields ( Table 2, entries [18][19]. The reaction did not proceed either in the absence of copper salts and I2, and control experiments showed that oxygen was needed to perform the reaction ( Table 2, entries 20-23). With a set of optimized conditions for the construction of N-( [1,3,5]triazine-2-yl) amides in hand, the generality and scope of this protocol were explored (Scheme 3). Methyl and methoxy substituted aryl ketones reacted smoothly under the standard reaction conditions to deliver the desired products 4b-d. Likewise, aryl ketones with electron-withdrawing groups such as F, Cl, and Br illustrated similar reactivity and afforded the corresponding amides 4e-j with 53-63% yields. Regarding the scope of 2-amine- With a set of optimized conditions for the construction of N-([1,3,5]triazine-2-yl) amides in hand, the generality and scope of this protocol were explored (Scheme 3). Methyl and methoxy substituted aryl ketones reacted smoothly under the standard reaction conditions to deliver the desired products 4b-d. Likewise, aryl ketones with electronwithdrawing groups such as F, Cl, and Br illustrated similar reactivity and afforded the corresponding amides 4e-j with 53-63% yields. Regarding the scope of 2-amine- [1,3,5]triazines, the reaction proceeded well for substrates with morpholino, pyrrolidino, and piperidino groups.
To probe the reaction mechanistic path, a series of control experiments were further conducted (Scheme 4). For α-ketoamidation reaction, treatment of 2a in the absence of 1a under the standard condition gave phenyl glyoxal (5) (63%), and then 5 treated with 1a to isolate the desired product 3a with a 97% yield, indicating that 5 should be an intermediate for the formation of 3a (Equations (1) and (2)). For the amidation reaction, first, when the reaction of 1a with 2a was carried out under the standard conditions, the trace of benzoic acid could be detected using 1 H NMR (Equation (3)). However, no desired product 4a was obtained from benzoic acid with 1a, indicating that it is a byproduct for the formation of amides (Equation (4)). Next, the reaction of 5 that is potentially generated with 1a did not give the amide 4a, indicated that this compound was not the intermediate (Equation (5)). Furthermore, the reaction failed to furnish desired amide 4a using TEMPO as a radical scavenger, suggesting that a radical pathway might be involved in this C-C single cleavage reaction (Equation (6)).
Molecules 2023, 28, x FOR PEER REVIEW 5 of 13 [1,3,5]triazines, the reaction proceeded well for substrates with morpholino, pyrrolidino, and piperidino groups. To probe the reaction mechanistic path, a series of control experiments were further conducted (Scheme 4). For α-ketoamidation reaction, treatment of 2a in the absence of 1a under the standard condition gave phenyl glyoxal (5) (63%), and then 5 treated with 1a to isolate the desired product 3a with a 97% yield, indicating that 5 should be an intermediate for the formation of 3a (Equations (1) and (2)). For the amidation reaction, first, when the reaction of 1a with 2a was carried out under the standard conditions, the trace of benzoic acid could be detected using 1 H NMR (Equation (3)). However, no desired product 4a was obtained from benzoic acid with 1a, indicating that it is a byproduct for the formation of amides (Equation (4)). Next, the reaction of 5 that is potentially generated with 1a did not give the amide 4a, indicated that this compound was not the intermediate (Equation (5)). Furthermore, the reaction failed to furnish desired amide 4a using TEMPO as a radical scavenger, suggesting that a radical pathway might be involved in this C-C single cleavage reaction (Equation (6)). On the basis of our study and related reports, a plausible mechanism is depicted (Scheme 5) [14,17,20,23,29,30]. Initially, acetophenone 2 with I 2 produced intermediate A, followed by the oxidation to produce intermediate B. The latter then reacted with 2-amino [1,3,5]

General Experiment
Under otherwise noted, materials were obtained from commercial suppliers and used without further purification. Thin layer chromatography (TLC) was performed using silica gel 60 F254 and visualized using UV light. Column chromatography was performed with silica gel (mesh 300-400). 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance 500 MHz spectrometer in CDCl3 with Me4Si as an internal standard. Data were reported as follows: chemical shift in parts per million (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, and m = multiplet), coupling constant in Hertz (Hz) and integration. IR spectra were recorded on an FT-IR spectrometer, and only major peaks are reported in cm −1 . HRMS and mass data were recorded via ESI on a TOF mass spectrometer.

General Procedure for the Synthesis of N-([1,3,5]Triazine-2-yl) α-Ketoamides 3
A mixture of 1,3,5-triazine (0.5 mmol), ketone (1.1 mmol), CuCl (0.10 mmol) and I2 (1.00 mmol) was added in DMSO (4 mL). The resulting mixture was then stirred at 120 °C under N2. After the completion of the reaction, the reaction mixture was cooled to room temperature, 10% Na2S2O3 was added and the mixture was extracted with ethyl acetate (4 × 20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using flash chromatography with petroleum ether and ethyl acetate as the eluent to give the pure product.

General Experiment
Under otherwise noted, materials were obtained from commercial suppliers and used without further purification. Thin layer chromatography (TLC) was performed using silica gel 60 F254 and visualized using UV light. Column chromatography was performed with silica gel (mesh 300-400). 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance 500 MHz spectrometer in CDCl 3 with Me 4 Si as an internal standard. Data were reported as follows: chemical shift in parts per million (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, and m = multiplet), coupling constant in Hertz (Hz) and integration. IR spectra were recorded on an FT-IR spectrometer, and only major peaks are reported in cm −1 . HRMS and mass data were recorded via ESI on a TOF mass spectrometer.

General Procedure for the Synthesis of N-([1,3,5]Triazine-2-yl) α-Ketoamides 3
A mixture of 1,3,5-triazine (0.5 mmol), ketone (1.1 mmol), CuCl (0.10 mmol) and I 2 (1.00 mmol) was added in DMSO (4 mL). The resulting mixture was then stirred at 120 • C under N 2 . After the completion of the reaction, the reaction mixture was cooled to room temperature, 10% Na 2 S 2 O 3 was added and the mixture was extracted with ethyl acetate (4 × 20 mL). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified using flash chromatography with petroleum ether and ethyl acetate as the eluent to give the pure product. A mixture of 1,3,5-triazine (0.5 mmol), ketone (1.1 mmol), CuCl 2 (0.20 mmol), and I 2 (0.75 mmol) was added in 1,2-dichlorobenzene (2 mL) and bis(2-methoxy ethyl)ether (1 mL). The resulting mixture was then sealed and stirred at 140 • C under O 2 . After completion of the reaction, the reaction mixture was cooled to room temperature, 10% Na 2 S 2 O 3 was added and the mixture was extracted with ethyl acetate (4 × 20 mL). The organic phase was dried over anhydrous Na 2 SO 4 . The crude residue was obtained after the evaporation of the solvent in vacuum, and the residue was purified using flash chromatography with petroleum ether/ethyl acetate as the eluent to give the pure product.

Conclusions
In summary, we found that oxidative α-ketoamidation and oxidative C−C bond cleavage amidation of ketones with 2-amino [1,3,5]triazines to form N-([1,3,5]triazine-2yl) α-ketoamide and N-([1,3,5]triazine-2-yl) amide derivatives are available by using a suitable reaction condition. The new method tolerates a variety of functional groups of the substrate and furnished moderate to good yields of the corresponding products under mild conditions. Work is currently ongoing to investigate the use of afforded products in the fields of medicinal chemistry.
Author Contributions: Conceptualization and methodology D.C.; conceptualization, supervision, writing-reviewing and editing, C.Z.; data curation and writing-original draft preparation, Y.L. and P.Z.; visualization and investigation, J.Z. and Z.P. All authors have read and agreed to the published version of the manuscript.