Electro-Oxidative C3-Selenylation of Pyrido[1,2-a]pyrimidin-4-ones

In this work, we achieved a C3-selenylation of pyrido[1,2-a]pyrimidin-4-ones using an electrochemically driven external oxidant-free strategy. Various structurally diverse seleno-substituted N-heterocycles were obtained in moderate to excellent yields. Through radical trapping experiments, GC-MS analysis and cyclic voltammetry study, a plausible mechanism for this selenylation was proposed.


Introduction
N-heterocycles hold a privileged position in the preparation of drugs, agrochemicals, polymers, and other functional materials [1,2]. According to statistics, nitrogen species are presented in more than 80% of the top 200 pharmaceuticals, and two thirds of these N-containing medicines contain N-heterocyclic skeletons [3]. Among these, N-fused pyrido[1,2-a]pyrimidin-4-ones are one of the most prominent classes of structural motifs due to their ubiquity and bioactivity as the backbones of many natural and pharmacologic products [4][5][6]. A variety of derivatives based on this backbone show versatile bioactivities, including antioxidants, antipsychotics, and antiulcer drugs, etc. ( Figure 1A) [7][8][9][10]. During the past decades, many efforts have been devoted to the construction and derivatization of such N-fused heterocycles, mainly including multicomponent cyclization, metal catalyzed direct C−H functionalization and metal-free chalcogenation with extra stoichiometric oxidants [11][12][13][14][15][16]. However, inevitable metal residue, extra stoichiometric oxidants, harmful halogenated solvents and inert gas conditions seriously restrict use for pharmaceutical chemistry applications. Thus, the development of modular approaches that provide facile and practical access to functionalized pyrido[1,2-a]pyrimidin-4-ones continues to be in high demand.

Results and Discussion
In order to optimize the reaction conditions for the anticipated selenylation of pyrido[1,2-a]pyrimidin-4-ones, we commenced our study by employing 2-phenyl-4Hpyrido[1,2-a]pyrimidin-4-one 1a and diphenyl diselenide 2a as model substrates in this reaction. As shown in Table 1, Pt(+)/Pt(−) were chosen as both the anode and cathode, n Bu 4 NBF 4 as the supporting electrolyte, reactions were performed in MeCN at 60 • C under 5V constant voltage in an undivided three-necked bottle, for 3 h, and the target 3a could be isolated in 42% isolated yield (entry 1). Other electrolytes commonly used for electrochemical conditions such as n Bu 4 NI, n Bu 4 NPF 6 and n Bu 4 NClO 4 were then tested. The results showed that n Bu 4 NPF 6 exhibited a positive effect, leading to the isolated 3a with a satisfactory 66% yield, while n Bu 4 NI and n Bu 4 NClO 4 did not proceed efficiently (entries 2−4). Further solvent screening revealed that DMF, DMSO, MeOH and HFIP are not ideal options for this transformation (entries 5−8). Moreover, the effects of the electrode materials were explored. However, lower reaction yields were obtained when the Pt(+)/Pt(−) was replaced by C(+)/C(−) and C(+)/Pt(−) (entries 9 and 10). When the reaction temperature was adjusted from 60 to 40 • C or to room temperature, the yields dramatically decreased (entries 11 and 12). When the reaction time is extended to 5 h, the yield of 3a can be increased sharply to 94% (entry 13). The control experiment also showed that no desired product 3a was generated without electricity (entry 14). ical conditions such as n Bu4NI, n Bu4NPF6 and n Bu4NClO4 were then tested. The results showed that n Bu4NPF6 exhibited a positive effect, leading to the isolated 3a with a satisfactory 66% yield, while n Bu4NI and n Bu4NClO4 did not proceed efficiently (entries 2−4). Further solvent screening revealed that DMF, DMSO, MeOH and HFIP are not ideal options for this transformation (entries 5−8). Moreover, the effects of the electrode materials were explored. However, lower reaction yields were obtained when the Pt(+)/Pt(−) was replaced by C(+)/C(−) and C(+)/Pt(−) (entries 9 and 10). When the reaction temperature was adjusted from 60 to 40 °C or to room temperature, the yields dramatically decreased (entries 11 and 12). When the reaction time is extended to 5 h, the yield of 3a can be increased sharply to 94% (entry 13). The control experiment also showed that no desired product 3a was generated without electricity (entry 14).

Entry
Electrolyte With the optimized conditions in hand, we further evaluated the scope of the substrates by examining various functionalized pyrido[1,2-a]pyrimidin-4-ones 1, and the results are illustrated in Table 2. As can be seen, for substrates bearing 2-Me, 3-Me, 3-Cl and 4-OMe on the pyridine ring, this transformation could be proceeded smoothly to provide the corresponding 3b−3e in 67−96% yields. Furthermore, 7-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one 1f was compatible with this conversion, giving the corresponding product 3f in 82% yield. Substituents at the 7-position can also vary from aryl to methyl, with the desired products 3g−3j isolated in 67−96% yields. In further demonstration of the utility and applicability of this method, a gram-scale selenylation reaction with 1a was performed. The gram-scale reaction proceeded well to form the corresponding product 3a in 91% yield, demonstrating the capacity to apply the protocol. With the optimized conditions in hand, we further evaluated the scope of the substrates by examining various functionalized pyrido[1,2-a]pyrimidin-4-ones 1, and the results are illustrated in Table 2. As can be seen, for substrates bearing 2-Me, 3-Me, 3-Cl and 4-OMe on the pyridine ring, this transformation could be proceeded smoothly to provide the corresponding 3b−3e in 67−96% yields. Furthermore, 7-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one 1f was compatible with this conversion, giving the corresponding product 3f in 82% yield. Substituents at the 7-position can also vary from aryl to methyl, with the desired products 3g−3j isolated in 67−96% yields. In further demonstration of the utility and applicability of this method, a gram-scale selenylation reaction with 1a was performed. The gram-scale reaction proceeded well to form the corresponding product 3a in 91% yield, demonstrating the capacity to apply the protocol.
However, according to radical trapping experiments, the other pathway involved the anodic oxidation of both 1a and 2a, which cannot be ruled out. The cross-coupling of the corresponding PhSe . and carbon-centered radicals could also quickly deliver the final products 3a.

Materials and Instruments
All reagents were purchased from commercial sources and used without further purification. 1 H NMR, 13 C NMR spectra were recorded on a Bruker Ascend™ 400 or Bruker Ascend™ 500 spectrometer (Billerica, MA, USA) in deuterated solvents containing TMS Scheme 3. Proposed mechanism.
Molecules 2023, 28, 2206 8 of 17 However, according to radical trapping experiments, the other pathway involved the anodic oxidation of both 1a and 2a, which cannot be ruled out. The cross-coupling of the corresponding PhSe . and carbon-centered radicals could also quickly deliver the final products 3a.

Materials and Instruments
All reagents were purchased from commercial sources and used without further purification. 1 H NMR, 13 C NMR spectra were recorded on a Bruker Ascend™ 400 or Bruker Ascend™ 500 spectrometer (Billerica, MA, USA) in deuterated solvents containing TMS as an internal reference standard. All high-resolution mass spectra (HRMS) were measured on a mass spectrometer by using electrospray ionization orthogonal acceleration time-of-flight (ESI-OA-TOF), and the purity of all samples used for HRMS (>95%) was confirmed by 1 H NMR and 13 C NMR spectroscopic analysis. Melting points were measured on a melting point apparatus equipped with a thermometer and were uncorrected. All the reactions were monitored by thin-layer chromatography (TLC) using GF254 silica gelcoated TLC plates. Purification by flash column chromatography was performed over SiO 2 (silica gel 200−300 mesh).

General Procedure for the Synthesis of 1
A mixture of 2-aminopyridines (3.00 mmol) and the appropriate β-keto esters (4.50 mmol) in PPA (6.00 g) was heated at 100 • C for 1 h while stirring with a glass stick. The thick syrup thus obtained was slowly poured into crushed ice, and the resulting suspension was neutralized with 10% aqueous sodium hydroxide. The solid precipitate was collected by filtration, washed with water, and recrystallized to give 1 (Scheme 4). A mixture of 2-aminopyridines (3.00 mmol) and the appropriate β-keto esters (4.50 mmol) in PPA (6.00 g) was heated at 100 °C for 1 h while stirring with a glass stick. The thick syrup thus obtained was slowly poured into crushed ice, and the resulting suspension was neutralized with 10% aqueous sodium hydroxide. The solid precipitate was collected by filtration, washed with water, and recrystallized to give 1 (Scheme 4).

The General Procedure for the Synthesis of 3
Various 2-(aryl/alkyl) substituted 4H-Pyrido-[1,2-a]-Pyrimidin-4-ones 1 (0.20 mmol), diselenide 2 (0.20 mmol), n Bu4NPF6 (0.20 mmol) and MeCN (5.0 mL) were placed in a 10 mL two-necked round-bottomed flask. The flask was equipped with a stir bar, a platinum plate (1 cm × 1 cm) anode and a platinum plate (1 cm × 1 cm) cathode. The electrolysis was carried out under air atmosphere at 60 °C using a constant potential of 5 V until complete consumption of the substrate 1 (monitored by TLC, about 5 h). After the completion of the reaction, the mixture was quenched by NaHCO3 (sat. aq. 150 mL) and extracted with CH2Cl2 (50 mL × 3). Then, the organic solvent was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate and petroleum ether as eluent to give 3.

The General Procedure for the Synthesis of 3
Various 2-(aryl/alkyl) substituted 4H-Pyrido-[1,2-a]-Pyrimidin-4-ones 1 (0.20 mmol), diselenide 2 (0.20 mmol), n Bu 4 NPF 6 (0.20 mmol) and MeCN (5.0 mL) were placed in a 10 mL two-necked round-bottomed flask. The flask was equipped with a stir bar, a platinum plate (1 cm × 1 cm) anode and a platinum plate (1 cm × 1 cm) cathode. The electrolysis was carried out under air atmosphere at 60 • C using a constant potential of 5 V until complete consumption of the substrate 1 (monitored by TLC, about 5 h). After the completion of the reaction, the mixture was quenched by NaHCO 3 (sat. aq. 150 mL) and extracted with CH 2 Cl 2 (50 mL × 3). Then, the organic solvent was concentrated in vacuo. The residue was purified by flash column chromatography with ethyl acetate and petroleum ether as eluent to give 3.

2-Phenyl
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules28052206/s1, Copies of 1 H NMR, 13 C NMR, and 19 F NMR spectra of the products are included in the Supporting Information.
Author Contributions: J.S. and Z.W. contributed equally to this work; J.S., Z.W. and X.T. performed the experiments; X.T. and Z.W. prepared the supporting information; B.Z., K.S. and X.W. supervised the project, provided resources and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.