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Article

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

by
Jianwei Shi
1,†,
Zhichuan Wang
2,†,
Xiaoxu Teng
1,
Bing Zhang
3,*,
Kai Sun
2 and
Xin Wang
2,*
1
School of Chemistry and Chemical Engineering, Yangtze Normal University, Chongqing 408100, China
2
College of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China
3
College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(5), 2206; https://doi.org/10.3390/molecules28052206
Submission received: 30 January 2023 / Revised: 22 February 2023 / Accepted: 23 February 2023 / Published: 27 February 2023
(This article belongs to the Special Issue Catalytic Green Reductions and Oxidations)
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Abstract

:
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.

1. 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.
Selenium-containing compounds play important roles in organic synthesis, medicinal chemistry, and biochemistry [17,18,19,20,21]. In particular, researchers have demonstrated that N-heterocycles modified with organylselanyl groups exhibit unique pharmacological activities and physicochemical properties and thereby have higher applied value (Figure 1B). In the long history of selenium chemistry, diselenides as readily available substrates [22,23,24,25,26,27,28] or precatalysts [29,30,31,32,33,34] have garnered considerable attention for use in various reactions. Especially in the last five years, electrochemistry-induced C-H bond selenylation for the synthesis seleno-heterocycles has been booming [35,36,37,38,39,40,41,42,43,44]. Although selenium can bring positive physiochemical properties of bioactive molecules and drugs, the methods for direct selenylation of pyrido[1,2-a]pyrimidin-4-ones are still limited. Until 2021, the only two examples for C-3 selenylation of pyrido[1,2-a]pyrimidin-4-ones by Das group was established (Scheme 1A) [45,46]. These achievements may be important; however, practical applications of the above-mentioned synthetic strategies are limited to the stoichiometric or excessive oxidants, diselenides, harmful halogenated solvents and the difficult collection of the target products from large amounts of unexpected byproducts and unconsumed reagents. Electrochemical technology employe traceless electrons as redox reagents, avoiding extra chemical oxidants, reductants, and transition-metal catalysts, and more importantly, it bears the unique advantage of controlling reactivity by “dialing-in” the specific potential on demand [47,48,49,50,51,52,53,54]. We envisioned whether a more easy-going radical selenylation of the pyrido[1,2-a]pyrimidones via electrochemical technology may be realized, which would afford a sustainable and universal selenylation method (Scheme 1B).

2. 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-4H-pyrido[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, nBu4NBF4 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 nBu4NI, nBu4NPF6 and nBu4NClO4 were then tested. The results showed that nBu4NPF6 exhibited a positive effect, leading to the isolated 3a with a satisfactory 66% yield, while nBu4NI and nBu4NClO4 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).
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.
We next focused our attention toward evaluating the scope of various diselenides (Table 3). Regardless of electron-donating (2-OMe, 3-Me, 4-Me, 4-OMe,) or electron-withdrawing groups (2-CF3, 3-Br, 4-Cl, 4-Br) on the phenyl ring of the selenide moiety, this electro-oxidative C3-selenylation could proceed smoothly, giving the corresponding products 3k−3r in moderate to excellent yields (60–97%). Multi-substituted diselenides, 1,2-di(naphthalen-2-yl)diselane, 1,2-di(pyridin-2-yl)diselane and 1,2-dimethyldiselane were also compatible with this transformation, producing the corresponding products 3s−3y in moderate to excellent yields (40–97%). Possibly due to the strong oxidation environment, the selenylation yields with the electron-rich diaryl diselenides were significantly lower (3t and 3u). The electronic and steric effects with diselenides have no obvious effects on the reaction. When substituents at the 7-position varied from aryl to methyl, the electro-oxidative C3-selenylation with 3-Br, 3-Me, 4-Me and 4-Cl substituted diselenides and 1,2-dimethyldiselane proceeded smoothly, delivering the desired products 3aa−3ad in 73−95% yields. Meanwhile, 7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one was also a good partner in this transformation, and selenylated 3ae could be isolated in 85% yield.
Mechanistic information was collected to elucidate the detailed reaction pathways. First, radical trapping experiments were performed. When 2 equiv of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (2,4-di-tert-butyl-4-methylphenol) was added into the reaction system, the desired product 3a was totally suppressed. Furthermore, adduct 4 was observed through GC-MS analysis (Scheme 2a,b). When 2 equiv of stilbene was added, adducts 5 and 6 were observed through GC-MS analysis (Scheme 2c). These results indicated that this reaction mostly proceeds via a radical pathway.
Second, the cyclic voltammetry (CV) experiments on both reactants were carried out. The measured oxidation peak of 1a presented at 1.98 V (Figure 2, blue line), and an obvious oxidation peak of diphenyl diselenide 2a could be observed at 1.88 V (Figure 2, red line). Since the reactions were performed under 5V constant voltage, both 1a and 2a may undergo single-electron oxidation, and the radical trapping experiments also demonstrated this result (Scheme 2b,c).
On the basis of mechanistic studies and previous literature reports [45,46,55,56,57], the proposed mechanism of electro-oxidative C3-selenylation of pyrido[1,2-a]pyrimidin-4-ones is depicted in Scheme 3. Firstly, the anodic oxidation of diselenide 2a could deliver PhSe. and PhSe+. Secondly, the addition of RSe. on the C-3 position of 2-phenyl-4H-pyrido[1,2-a] pyrimidin-4-one 1a generates the radical intermediate A. Anodic oxidation of A and the subsequent deprotonation results in the final products 3a. At the cathode, protons and PhSe+ are reduced to H2 and PhSe. at the surface of the cathode to complete this conversion.
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.

3. Materials and Methods

3.1. Materials and Instruments

All reagents were purchased from commercial sources and used without further purification. 1H NMR, 13C 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 1H NMR and 13C 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 gel-coated TLC plates. Purification by flash column chromatography was performed over SiO2 (silica gel 200−300 mesh).

3.2. 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).

3.3. 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), nBu4NPF6 (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.
2-Phenyl-3-(phenylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3a). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 129–130 °C) in 94% yield (71.11 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.24; 1H NMR (500 MHz, CDCl3) δ 9.08 (d, J = 7.1 Hz, 1H), 7.80–7.76 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 6.5, 3.1 Hz, 2H), 7.43–7.39 (m, 3H), 7.32–7.28 (m, 2H), 7.18 (td, J = 7.1, 1.4 Hz, 1H), 7.15 (dd, J = 6.3, 2.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 168.10, 157.78, 150.25, 140.24, 136.87, 131.83, 131.08, 129.33, 128.99, 128.89, 128.00, 127.89, 126.68, 126.64, 116.08, 105.70; HRMS (ESI) calcd for C20H15N2OSe [M+H]+: 379.0344, found: 379.0338.
6-Methyl-2-phenyl-3-(phenylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3b). 6-Methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 47.25 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 171–172 °C) in 96% yield (74.90 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.45; 1H NMR (500 MHz, CDCl3) δ 7.59 (dd, J = 6.5, 2.9 Hz, 2H), 7.51–7.46 (m, 2H), 7.41–7.35 (m, 3H), 7.28 (dd, J = 6.5, 2.9 Hz, 2H), 7.16–7.09 (m, 3H), 6.76–6.70 (m, 1H), 2.99 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.91, 161.42, 152.72, 144.17, 139.86, 135.92, 132.26, 130.49, 129.28, 128.97, 128.90, 127.82, 126.39, 125.35, 118.85, 107.00, 24.54; HRMS (ESI) calcd for C21H17N2OSe [M+H]+: 393.0501, found: 393.0494.
7-Chloro-2-phenyl-3-(phenylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3c). 7-Chloro-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 51.26 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 169–170 °C) in 70% yield (59.32 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.56; 1H NMR (500 MHz, CDCl3) δ 9.07 (d, J = 1.0 Hz, 1H), 7.70–7.65 (m, 2H), 7.59 (dd, J = 6.7, 2.6 Hz, 2H), 7.42 (dd, J = 5.1, 1.5 Hz, 3H), 7.31 (dd, J = 6.5, 2.9 Hz, 2H), 7.17–7.13 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 167.52, 156.78, 148.46, 139.86, 137.89, 131.52, 131.34, 129.55, 129.01, 128.94, 127.96, 127.61, 126.97, 125.64, 124.64, 107.00; HRMS (ESI) calcd for C20H14ClN2OSe [M+H]+: 412.9954, found: 412.9948.
7-Methyl-2-phenyl-3-(phenylselanyl)-4H-pyrido [1,2-a]pyrimidin-4-one (3d). 7-Methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 47.25 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 190–191 °C) in 95% yield (74.49 mg). Rf (petroleum ether/ethyl acetate = 5:1): 0.14; 1H NMR (500 MHz, CDCl3) δ 8.90 (s, 1H), 7.66 (s, 2H), 7.58 (dd, J = 6.5, 2.8 Hz, 2H), 7.43–7.39 (m, 3H), 7.30 (dd, J = 6.4, 2.8 Hz, 2H), 7.16–7.12 (m, 3H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.74, 157.65, 149.19, 140.34, 139.81, 131.98, 131.00, 129.23, 128.95, 128.87, 127.87, 126.60, 126.49, 126.08, 125.46, 105.30, 18.43; HRMS (ESI) calcd for C21H17N2OSe [M+H]+: 393.0501, found: 393.0495.
8-Methoxy-2-phenyl-3-(phenylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3e). 8-Methoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 50.45 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 179–180 °C) in 67% yield (54.82 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.31; 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J = 2.6 Hz, 1H), 7.68 (d, J = 9.6 Hz, 1H), 7.61–7.54 (m, 3H), 7.43–7.39 (m, 3H), 7.31 (dd, J = 6.4, 3.0 Hz, 2H), 7.17–7.13 (m, 3H), 3.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.72, 157.57, 151.26, 147.29, 140.26, 132.12, 131.94, 131.02, 129.21, 128.98, 128.90, 127.89, 127.34, 126.63, 107.49, 105.10, 56.57; HRMS (ESI) calcd for C21H17N2O2Se [M+H]+:409.0450, found: 409.0444.
7-Phenyl-6-(phenylselanyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (3f). 7-Phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one (0.20 mmol, 45.65 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 161–162 °C) in 82% yield (62.71 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.24; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 4.9 Hz, 1H), 7.59–7.54 (m, 2H), 7.43–7.39 (m, 3H), 7.32 (dd, J = 6.5, 3.0 Hz, 2H), 7.18–7.14 (m, 3H), 7.01 (d, J = 4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 1166.97, 162.25, 158.15, 139.56, 131.54, 131.25, 129.51, 129.04, 128.97, 127.87, 126.86, 122.68, 112.29, 107.05; HRMS (ESI) calcd for C18H13N2OSSe [M+H]+: 384.9908, found: 384.9902.
2-(4-Methoxyphenyl)-3-(phenylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3g). 2-(4-Methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 50.45 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 161–162 °C) in 67% yield (54.75 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.18; 1H NMR (500 MHz, CDCl3) δ 9.05 (d, J = 7.1 Hz, 1H), 7.79–7.74 (m, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.31 (dd, J = 6.6, 2.7 Hz, 2H), 7.15 (dd, J = 6.7, 3.9 Hz, 4H), 6.93 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 167.48, 160.70, 157.86, 150.13, 136.74, 132.59, 132.05, 130.86, 130.75, 129.00, 127.99, 126.58, 126.55, 115.81, 113.25, 104.92, 55.39; HRMS (ESI) calcd for C21H17N2O2Se [M+H]+: 409.0450, found: 409.0444.
2-(3-Fluorophenyl)-3-(phenylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3h). 2-(3-Fluorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 48.05 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 133–134 °C) in 96% yield (54.75 mg). Rf (petroleum ether/ethyl acetate = 5:1): 0.11; 1H NMR (500 MHz, CDCl3) δ 9.08 (d, J = 7.1 Hz, 1H), 7.83–7.76 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 5.4 Hz, 2H), 7.30 (dd, J = 8.6, 5.5 Hz, 3H), 7.19 (t, J = 6.9 Hz, 1H), 7.16–7.06 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 166.44 (d, J = 2.4 Hz), 163.46, 161.01, 157.76, 150.27, 142.23, 142.15, 137.12, 131.53, 131.33, 129.49 (d, J = 8.3 Hz), 129.06, 128.00, 126.75 (d, J = 26.9 Hz), 124.77 (d, J = 3.0 Hz), 116.30 (d, J = 9.8 Hz), 116.08 (d, J = 7.2 Hz), 115.89, 105.97; 19F NMR (471 MHz, CDCl3) δ −113.07; HRMS (ESI) calcd for C20H14FN2OSe [M+H]+: 397.0250, found: 397.0244.
2-Methyl-3-(phenylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3i). 2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 32.04 mg) was reacted with PhSeSePh (0.20 mmol, 74.91 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 136–137 °C) in 78% yield (49.24 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.24; 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J = 7.1 Hz, 1H), 7.79–7.75 (m, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.41–7.35 (m, 2H), 7.22–7.12 (m, 4H), 2.73 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 169.50, 157.25, 150.25, 136.98, 131.48, 130.58, 129.20, 128.21, 126.62, 125.86, 115.74, 105.71, 26.82; HRMS (ESI) calcd for C15H13N2OSe [M+H]+: 317.0188, found: 317.0182.
7-Methyl-6-(phenylselanyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (3j). 7-Methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (0.20 mmol, 33.24 mg) was reacted with PhSeSePh (0.20 mmol, 62.43 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 187–188 °C) in 77% yield (49.67 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.21; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 4.9 Hz, 1H), 7.59–7.54 (m, 2H), 7.43–7.39 (m, 3H), 7.32 (dd, J = 6.5, 3.0 Hz, 2H), 7.18–7.14 (m, 3H), 7.01 (d, J = 4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.54, 162.33, 157.74, 131.11, 130.84, 129.21, 126.79, 122.88, 111.52, 107.06, 26.41; HRMS (ESI) calcd for C13H11N2OSSe [M+H]+: 322.9752, found: 322.9745.
3-((2-Methoxyphenyl)selanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3k). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-bis(2-methoxyphenyl)diselane (0.20 mmol, 74.44 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 156–157 °C) in 87% yield (70.96 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.16; 1H NMR (500 MHz, CDCl3) δ 9.08 (d, J = 7.1 Hz, 1H), 7.81–7.73 (m, 2H), 7.63 (dd, J = 6.5, 3.0 Hz, 2H), 7.37 (dd, J = 7.0, 3.7 Hz, 3H), 7.20–7.08 (m, 2H), 6.95 (dd, J = 7.8, 1.3 Hz, 1H), 6.78–6.73 (m, 2H), 3.79 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.01, 157.79, 156.62, 150.46, 140.22, 137.01, 129.35, 128.84, 128.73, 128.03, 127.84, 127.07, 126.64, 121.50, 121.24, 116.08, 110.45, 103.08, 55.73; HRMS (ESI) calcd for C21H17N2O2Se [M+H]+: 409.0450, found: 409.0443.
2-Phenyl-3-((2-(trifluoromethyl)phenyl)selanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3l). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-bis(2-(trifluoromethyl)phenyl)diselane (0.20 mmol, 89.6 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 151–152 °C) in 65% yield (57.71 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.14; 1H NMR (500 MHz, CDCl3) δ 9.07 (dd, J = 7.1, 0.6 Hz, 1H), 7.86–7.81 (m, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.62–7.57 (m, 3H), 7.42–7.37 (m, 3H), 7.26–7.19 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 168.78, 157.69, 150.60, 139.74, 137.39, 131.93 (d, J = 6.9 Hz), 131.02, 129.62, 129.28, 129.03, 128.80, 127.98 (d, J = 6.8 Hz), 126.89 (q, J = 5.4 Hz), 126.74, 125.96, 125.15, 122.97, 116.39, 104.13 (d, J = 2.8 Hz); 19F NMR (471 MHz, CDCl3) δ −61.18; HRMS (ESI) calcd for C21H14F3N2OSe [M+H]+: 447.0218, found: 447.0212.
2-Phenyl-3-(m-tolylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3m). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-di-m-tolyldiselane (0.20 mmol, 68.04 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 126–127 °C) in 60% yield (49.21 mg). Rf (petroleum ether/ethyl acetate = 5:1): 0.11; 1H NMR (500 MHz, CDCl3) δ 9.08 (d, J = 7.1 Hz, 1H), 7.80–7.72 (m, 2H), 7.60 (dd, J = 6.4, 2.9 Hz, 2H), 7.44–7.38 (m, 3H), 7.20–7.15 (m, 1H), 7.13–7.07 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 2.23 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.96, 157.80, 150.21, 140.24, 138.67, 136.79, 131.78, 131.52, 129.26, 128.89, 128.78, 128.13, 128.01, 127.86, 127.63, 126.63, 116.03, 105.88, 21.33; HRMS (ESI) calcd for C21H17N2OSe [M+H]+: 393.0501, found: 393.0496.
3-((3-Bromophenyl)selanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3n). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-bis(3-bromophenyl)diselane (0.20 mmol, 93.99 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 96–97 °C) in 90% yield (81.84 mg). Rf (petroleum ether/ethyl acetate = 5:1): 0.11; 1H NMR (500 MHz, CDCl3) δ 9.08 (d, J = 6.9 Hz, 1H), 7.84–7.79 (m, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.61–7.54 (m, 2H), 7.46–7.35 (m, 4H), 7.25–7.19 (m, 3H), 7.00 (t, J = 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 168.16, 157.64, 150.37, 139.97, 137.16, 133.80, 133.32, 130.27, 129.72, 129.48, 129.06, 128.79, 128.02, 127.97, 126.71, 122.83, 116.31, 105.02; HRMS (ESI) calcd for C20H14BrN2OSe [M+H]+: 456.9449, found: 456.9439.
2-Phenyl-3-(p-tolylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3o). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-di-p-tolyldiselane (0.20 mmol, 68.04 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 157–158 °C) in 94% yield (73.34 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.27; 1H NMR (500 MHz, CDCl3) δ 9.06 (d, J = 7.1 Hz, 1H), 7.78–7.70 (m, 2H), 7.60 (dd, J = 6.4, 2.8 Hz, 2H), 7.45–7.40 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 6.97 (d, J = 7.9 Hz, 2H), 2.25 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 167.82, 157.74, 150.13, 140.32, 136.74, 136.71, 131.64, 129.80, 129.30, 128.95, 127.94, 127.91, 127.88, 126.60, 115.99, 106.20, 21.12; HRMS (ESI) calcd for C21H17N2OSe [M+H]+: 393.0501, found: 393.0494.
3-((4-Methoxyphenyl)selanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3p). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-bis(4-methoxyphenyl)diselane (0.20 mmol, 74.44 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 191–192 °C) in 68% yield (55.56 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.17; 1H NMR (500 MHz, CDCl3) δ 9.06 (d, J = 6.8 Hz, 1H), 7.77–7.74 (m, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.60–7.56 (m, 2H), 7.45–7.42 (m, 3H), 7.30 (d, J = 8.8 Hz, 2H), 7.17–7.13 (m, 1H), 6.69 (d, J = 8.8 Hz, 2H), 3.73 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.39, 159.11, 157.77, 149.99, 140.35, 136.55, 134.44, 129.24, 128.94, 127.90, 126.59, 121.51, 115.90, 114.60, 107.17, 55.22; HRMS (ESI) calcd for C21H17N2O2Se [M+H]+: 409.0450, found: 409.0446.
3-((4-Chlorophenyl)selanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3q). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-bis(4-chlorophenyl)diselane (0.20 mmol, 76.21 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 187–188 °C) in 97% yield (79.88 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.32; 1H NMR (500 MHz, CDCl3) δ 9.07 (d, J = 7.1 Hz, 1H), 7.83–7.79 (m, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.60–7.55 (m, 2H), 7.45–7.40 (m, 3H), 7.25–7.18 (m, 3H), 7.11 (d, J = 8.5 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 168.05, 157.64, 150.28, 140.08, 137.02, 132.85, 132.60, 129.92, 129.46, 129.10, 128.83, 127.96, 126.69, 116.22, 105.47; HRMS (ESI) calcd for C20H14ClN2OSe [M+H]+: 412.9954, found: 412.9949.
3-((4-Bromophenyl)selanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3r). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-bis(4-bromophenyl)diselane (0.20 mmol, 93.99 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 198–199 °C) in 77% yield (70.53 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.21; 1H NMR (500 MHz, CDCl3) δ 9.07 (d, J = 6.7 Hz, 1H), 7.83–7.80 (m, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.59–7.55 (m, 2H), 7.44–7.40 (m, 3H), 7.26–7.23 (m, 2H), 7.22–7.19 (m, 1H), 7.18–7.14 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 168.11, 157.63, 150.30, 140.06, 137.08, 132.76, 132.01, 130.68, 129.49, 128.83, 127.97, 126.69, 120.86, 116.26, 105.28. 19F NMR (471 MHz, CDCl3) δ −40.57; HRMS (ESI) calcd for C20H14BrN2OSe [M+H]+: 456.9449, found: 456.9440.
3-((3,5-Dimethylphenyl)selanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3s). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-bis(3,5-dimethylphenyl)diselane (0.20 mmol, 73.65 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 105–106 °C) in 95% yield (76.78 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.32; 1H NMR (500 MHz, CDCl3) δ 9.08 (d, J = 7.2 Hz, 1H), 7.79–7.75 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 6.5, 2.9 Hz, 2H), 7.43–7.38 (m, 3H), 7.19–7.15 (m, 1H), 6.90 (s, 2H), 6.76 (s, 1H), 2.18 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 167.83, 157.82, 150.17, 140.26, 138.43, 136.72, 131.24, 129.20, 128.92, 128.87, 128.74, 128.01, 127.83, 126.62, 115.99, 106.03, 21.21; HRMS (ESI) calcd for C22H19N2OSe [M+H]+: 407.0657, found: 407.0652.
3-(Mesitylselanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3t). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-dimesityldiselane (0.20 mmol, 82.60 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 251–252 °C) in 40% yield (35.23 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.45; 1H NMR (500 MHz, CDCl3) δ 8.97 (d, J = 7.2 Hz, 1H), 7.70–7.64 (m, 2H), 7.55–7.51 (m, 2H), 7.44–7.40 (m, 3H), 7.10–7.06 (m, 1H), 6.76 (s, 2H), 2.29 (s, 6H), 2.18 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.71, 156.74, 149.12, 142.29, 140.14, 137.78, 135.70, 129.23, 128.54, 128.45, 128.13, 127.81, 127.56, 126.44, 115.49, 108.00, 24.10, 20.92; HRMS (ESI) calcd for C23H21N2OSe [M+H]+: 421.0814, found: 421.0808.
3-(Naphthalen-1-ylselanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3u). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-di(naphthalen-2-yl)diselane (0.20 mmol, 82.46 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 161–162 °C) in 48% yield (41.28 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.24; 1H NMR (500 MHz, CDCl3) δ 9.05 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.77–7.73 (m, 2H), 7.68 (dd, J = 13.1, 8.5 Hz, 2H), 7.57 (dd, J = 7.5, 1.8 Hz, 2H), 7.53 (d, J = 6.5 Hz, 1H), 7.43–7.39 (m, 2H), 7.36 (q, J = 5.3 Hz, 3H), 7.22 (t, J = 7.7 Hz, 1H), 7.17–7.13 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 168.00, 157.75, 150.13, 140.10, 136.74, 133.97, 133.49, 131.12, 130.40, 129.28, 128.87, 128.41, 127.99, 127.93, 127.85, 127.27, 126.60, 126.29, 125.94, 125.74, 116.00, 105.86; HRMS (ESI) calcd for C24H17N2OSe [M+H]+: 429.0501, found: 429.0494.
2-Phenyl-3-(pyridin-2-ylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3v). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-di(pyridin-2-yl)diselane (0.20 mmol, 62.83 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:3) to afford the title compound as a yellow solid (m. p. 178–179 °C) in 97% yield (73.24 mg). Rf (petroleum ether/ethyl acetate = 5:3): 0.1; 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J = 7.1 Hz, 1H), 8.32 (dd, J = 4.7, 0.9 Hz, 1H), 7.84–7.79 (m, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 6.5, 3.0 Hz, 2H), 7.40–7.35 (m, 4H), 7.20 (td, J = 7.1, 1.3 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.00–6.95 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 168.36, 157.74, 156.65, 150.51, 150.02, 140.18, 137.20, 136.36, 129.43, 128.89, 128.02, 127.88, 126.70, 124.32, 120.59, 116.27, 104.21; HRMS (ESI) calcd for C19H14N3OSe [M+H]+: 380.0297, found: 380.0290.
3-(Methylselanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3w). 2-Phenyl-8,9-dihydro-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 44.42 mg) was reacted with 1,2-dimethyldiselane (0.24 mmol, 37.60 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 117–118 °C) in 95% yield (59.96 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.28; 1H NMR (500 MHz, CDCl3) δ 9.10–9.05 (m, 1H), 7.75–7.68 (m, 2H), 7.67–7.61 (m, 2H), 7.50–7.45 (m, 3H), 7.17 (s, 1H), 2.21 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 165.88, 157.36, 149.36, 140.26, 135.93, 129.47, 128.93, 128.03, 127.23, 126.59, 115.85, 106.24, 7.97; HRMS (ESI) calcd for C15H13N2OSe [M+H]+: 317.0188, found: 317.0182.
6-Methyl-3-(methylselanyl)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3x). 6-Methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 47.25 mg) was reacted with 1,2-dimethyldiselane (0.20 mmol, 37.60 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as yellow liquid in 94% yield (61.77 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.26; 1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 7.5, 1.8 Hz, 2H), 7.44 (dd, J = 11.8, 5.3 Hz, 5H), 6.70 (t, J = 4.0 Hz, 1H), 3.06 (s, 3H), 2.12 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.41, 161.15, 151.80, 143.42, 139.93, 135.00, 129.34, 128.93, 127.97, 125.37, 118.59, 108.02, 24.65, 7.93; HRMS (ESI) calcd for C16H15N2OSe [M+H]+: 331.0344, found: 331.0337.
6-(Methylselanyl)-7-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3y). 7-Phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one (0.20 mmol, 45.65 mg) was reacted with 1,2-dimethyldiselane (0.20 mmol, 37.60 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as an orange solid (m. p. 147–148 °C) in 87% yield (56.03 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.26; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 4.9 Hz, 1H), 7.60 (dd, J = 6.5, 2.9 Hz, 2H), 7.48–7.43 (m, 3H), 7.02 (d, J = 4.9 Hz, 1H), 2.19 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 164.71, 160.91, 158.00, 139.57, 129.59, 129.01, 127.96, 122.13, 112.15, 107.18, 8.00; HRMS (ESI) calcd for C13H11N2OSSe [M+H]+: 322.9752, found: 322.9746.
3-((3-Bromophenyl)selanyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3z). 2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 32.04 mg) was reacted with 1,2-bis(3-bromophenyl)diselane (0.20 mmol, 93.99 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to afford the title compound as a yellow solid (m. p. 97–98 °C) in 77% yield (60.93 mg). Rf (petroleum ether/ethyl acetate = 10:1): 0.42; 1H NMR (500 MHz, CDCl3) δ 9.07–9.01 (m, 1H), 7.81–7.78 (m, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.46 (t, J = 1.7 Hz, 1H), 7.31–7.26 (m, 2H), 7.17 (td, J = 7.0, 1.2 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 2.73 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ 169.73, 157.11, 150.44, 137.31, 133.62, 132.52, 130.47, 129.63, 128.78, 128.25, 125.94, 123.13, 115.97, 104.80, 26.81; HRMS (ESI) calcd for C15H12BrN2OSe [M+H]+:394.9293, found: 394.9284.
3-((3-Methoxyphenyl)selanyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3aa). 2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 32.04 mg) was reacted with 1,2-bis(3-methoxyphenyl)diselane (0.20 mmol, 74.44 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:2) to afford the title compound as yellow liquid in 84% yield (58.14 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.11; 1H NMR (500 MHz, CDCl3) δ 9.05 (dd, J = 7.1, 0.6 Hz, 1H), 7.80–7.77 (m, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.16 (td, J = 7.0, 1.2 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.96–6.90 (m, 2H), 6.73–6.68 (m, 1H), 3.73 (s, 3H), 2.73 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.52, 159.96, 157.19, 150.23, 137.17, 132.57, 129.93, 128.27, 125.77, 122.58, 116.03, 115.87, 112.02, 105.44, 55.27, 26.75; HRMS (ESI) calcd for C16H15N2O2Se [M+H]+: 347.0293, found: 347.0287.
2-Methyl-3-(p-tolylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3ab). 2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 32.04 mg) was reacted with 1,2-di-p-tolyldiselane (0.20 mmol, 68.04 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 128–129 °C) in 73% yield (48.21 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.15; 1H NMR (500 MHz, CDCl3) δ 9.08–9.03 (m, 1H), 7.8.-7.76 (m, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.16 (td, J = 7.1, 1.2 Hz, 1H), 7.02 (d, J = 7.9 Hz, 2H), 2.74 (s, 3H), 2.27 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.83, 157.14, 149.98, 137.11, 136.78, 131.26, 130.03, 128.24, 127.43, 125.63, 115.87, 106.30, 26.70, 21.07; HRMS (ESI) calcd for C16H15N2OSe [M+H]+: 331.0344, found: 331.0337.
3-((4-Chlorophenyl)selanyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3ac). 2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 32.04 mg) was reacted with 1,2-bis(4-chlorophenyl)diselane (0.20 mmol, 76.21 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to afford the title compound as a white solid (m. p. 121–122 °C) in 67% yield (47.07 mg). Rf (petroleum ether/ethyl acetate = 10:1): 0.51; 1H NMR (500 MHz, CDCl3) δ 9.04 (d, J = 7.1 Hz, 1H), 7.81–7.78 (m, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.35–7.30 (m, 2H), 7.17 (dd, J = 9.1, 4.8 Hz, 3H), 2.74 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.42, 157.10, 150.31, 137.17, 132.73, 131.98, 129.66, 129.29, 128.15, 125.90, 115.90, 105.36, 26.79; HRMS (ESI) calcd for C15H12ClN2OSe [M+H]+: 350.9798, found: 350.9790.
2-Methyl-3-(methylselanyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3ad). 2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.20 mmol, 32.04 mg) was reacted with 1,2-dimethyldiselane (0.20 mmol, 37.60 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a white solid (m. p. 73–74 °C) in 73% yield (37.12 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.17; 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J = 7.1 Hz, 1H), 7.72–7.68 (m, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H), 2.73 (s, 3H), 2.32 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.24, 156.77, 149.48, 136.09, 127.41, 125.79, 115.47, 106.25, 26.62, 7.16; HRMS (ESI) calcd for C10H11N2OSe [M+H]+: 255.0031, found: 255.0027.
7-Methyl-6-(methylselanyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (3ae). 7-Methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (0.20 mmol, 33.24 mg) was reacted with 1,2-dimethyldiselane (0.20 mmol, 37.60 mg) according to General Procedure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford the title compound as a yellow solid (m. p. 131–132 °C) in 85% yield (43.86 mg). Rf (petroleum ether/ethyl acetate = 5:2): 0.24; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 4.9 Hz, 1H), 6.96 (d, J = 4.9 Hz, 1H), 2.65 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.21, 161.15, 157.52, 122.30, 111.38, 107.08, 77.40, 7.17; HRMS (ESI) calcd for C8H9N2OSSe [M+H]+: 260.9595, found: 260.9593.

4. Conclusions

We have presented a practical and sustainable C3 selenylation of pyrido[1,2-a]pyrimidin-4-ones under electrochemically driven external oxidant-free conditions. Various structurally diverse seleno-substituted products were obtained with broad substrate scope and with good functional group compatibility in 31 examples. A preliminary mechanism study revealed a radical pathway maybe involved under this catalytic system. Further mechanistic studies and applications of this strategy to more complicated drug candidates are underway in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28052206/s1, Copies of 1H NMR, 13C NMR, and 19F 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.

Funding

This work was supported by the National Natural Science Foundation of China (21801007), the Projects of Chongqing Education Board (CXQT21037, KJQN201901428), the Natural Science Foundation Project of Chongqing CSTC (2022NSCQ-MSX0304) and the Fuling Science and Technology Commission Project (2021ABB1041).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the article and Supplementary Material.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of compounds 3a–3f are available from the authors.

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Molecules 28 02206 g001 550
Figure 1. Representative biological skeletons.
Figure 1. Representative biological skeletons.
Molecules 28 02206 g001
Molecules 28 02206 sch001 550
Scheme 1. C-3 selenylation of pyrido[1,2-a]pyrimidin-4-ones.
Scheme 1. C-3 selenylation of pyrido[1,2-a]pyrimidin-4-ones.
Molecules 28 02206 sch001
Molecules 28 02206 sch002 550
Scheme 2. Radical trapping experiments. (a: The control experiment in the presence of TEMPO; b: The control experiment in the presence of BHT. c: The control experiment in the presence of stilbene.)
Scheme 2. Radical trapping experiments. (a: The control experiment in the presence of TEMPO; b: The control experiment in the presence of BHT. c: The control experiment in the presence of stilbene.)
Molecules 28 02206 sch002
Molecules 28 02206 g002 550
Figure 2. Cyclic voltammograms of substrates.
Figure 2. Cyclic voltammograms of substrates.
Molecules 28 02206 g002
Molecules 28 02206 sch003 550
Scheme 3. Proposed mechanism.
Scheme 3. Proposed mechanism.
Molecules 28 02206 sch003
Molecules 28 02206 sch004 550
Scheme 4. Synthesis of substrate 1.
Scheme 4. Synthesis of substrate 1.
Molecules 28 02206 sch004
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 28 02206 i001
EntryElectrolyteSolvent (mL)ElectrodeTime (h)Yield (%) b
1nBu4NBF4MeCNPt(+)/Pt(−)342
2nBu4NIMeCNPt(+)/Pt(−)30
3nBu4NPF6MeCNPt(+)/Pt(−)366
4nBu4NClO4MeCNPt(+)/Pt(−)319
5nBu4NPF6DMFPt(+)/Pt(−)30
6nBu4NPF6DMSOPt(+)/Pt(−)30
7nBu4NPF6MeOHPt(+)/Pt(−)30
8nBu4NPF6HFIPPt(+)/Pt(−)339
9nBu4NPF6MeCNC(+)/C(−)316
10nBu4NPF6MeCNC(+)/Pt(−)30
11nBu4NPF6MeCNPt(+)/Pt(−)3Trace c
12nBu4NPF6MeCNPt(+)/Pt(−)30 d
13nBu4NPF6MeCNPt(+)/Pt(−)594
14nBu4NPF6MeCNPt(+)/Pt(−)50 e
a Reactions conditions: 1a (0.2 mmol), 2a (0.2 mmol), supporting electrolyte (0.2 mmol), solvent (5 mL), 5 V cell voltage, rt −60 °C, 3 h. b Isolated yield. c Reaction performed at 40 °C. d Reaction performed at room temperature. e Without electricity.
Table
Table 2. Substrate scope of pyrido[1,2-a]pyrimidin-4-ones a,b.
Table 2. Substrate scope of pyrido[1,2-a]pyrimidin-4-ones a,b.
Molecules 28 02206 i002
entrysubstrateproductentrysubstrateproduct
1Molecules 28 02206 i003
 1a		Molecules 28 02206 i004
 3a, 94%c		2Molecules 28 02206 i005
 1b		Molecules 28 02206 i006
 3b, 96%
3Molecules 28 02206 i007
 1c		Molecules 28 02206 i008
 3c, 70%		4Molecules 28 02206 i009
 1d		Molecules 28 02206 i010
 3d, 95%
5Molecules 28 02206 i011
 1e		Molecules 28 02206 i0123e, 67%6Molecules 28 02206 i013
 1f		Molecules 28 02206 i014
 3f, 82%
7Molecules 28 02206 i0151gMolecules 28 02206 i0163g, 67%8Molecules 28 02206 i0171hMolecules 28 02206 i0183h, 96 %
9Molecules 28 02206 i019
 1i		Molecules 28 02206 i020
 3i, 82%		10Molecules 28 02206 i021
 1j		Molecules 28 02206 i022
 3j, 77%
a Reaction conditions: In an undivided two-necked bottle, with Pt(+)/Pt(−) as the anode and cathode, 1 (0.2 mmol), 2a (0.2 mmol), nBu4NPF6 (0.2 mmol), MeCN (5 mL), 60 °C, 5 h. b Isolated yield. c 5 mmol 1a was added, 3a with 91% isolated yield.
Table
Table 3. Substrate scope of diselenides and pyrido[1,2-a]pyrimidin-4-ones a,b,c,d,e.
Table 3. Substrate scope of diselenides and pyrido[1,2-a]pyrimidin-4-ones a,b,c,d,e.
Molecules 28 02206 i023
entrysubstrateproductentrysubstrateproduct
1Molecules 28 02206 i024
 2b		Molecules 28 02206 i025
 3k, 87%		2Molecules 28 02206 i026
 2c		Molecules 28 02206 i027
 3l, 65%
3Molecules 28 02206 i028
 2d		Molecules 28 02206 i029
 3m, 60%		4Molecules 28 02206 i030
 2e		Molecules 28 02206 i031
 3n, 90%
5Molecules 28 02206 i032
 2f		Molecules 28 02206 i033
 3o, 94%		6Molecules 28 02206 i034
 2g		Molecules 28 02206 i035
 3p, 68%
7Molecules 28 02206 i036
2h		Molecules 28 02206 i0373q, 97%8Molecules 28 02206 i038
 2i		Molecules 28 02206 i039
 3r, 77%
9Molecules 28 02206 i040
 2j		Molecules 28 02206 i041
 3s, 95%		10Molecules 28 02206 i042
 2k		Molecules 28 02206 i043
 3t, 40%
11Molecules 28 02206 i044
 2l		Molecules 28 02206 i045
 3u, 48%		12Molecules 28 02206 i046
 2m		Molecules 28 02206 i047
 3v, 97%
13Molecules 28 02206 i048
 2n		Molecules 28 02206 i049
 3w, 84%		14Molecules 28 02206 i050
 1b		Molecules 28 02206 i051
 3x, 77%
15Molecules 28 02206 i052
 1f		Molecules 28 02206 i053
 3y, 73%		16Molecules 28 02206 i054
 2e		Molecules 28 02206 i055
 3z, 67%
17Molecules 28 02206 i056
 2o		Molecules 28 02206 i057
 3aa, 95%		18Molecules 28 02206 i058
 2f		Molecules 28 02206 i059
 3ab, 94%
19Molecules 28 02206 i060
 2h		Molecules 28 02206 i061
 3ac, 73%		20Molecules 28 02206 i062
 1i		Molecules 28 02206 i063
 3ad, 87%
21Molecules 28 02206 i064
 1j		Molecules 28 02206 i065
 3ae, 85%
a Reaction conditions: In an undivided two-necked bottle, with Pt(+)/Pt(−) as the anode and cathode, 1 (0.2 mmol), 2a (0.2 mmol), nBu4NPF6 (0.2 mmol), MeCN (5 mL), 60 °C, 5 h. b Isolated yield. c The substrate 1 of entry 1-13 is 1a. d The substrate 1 of entry 16-19 is 1i. e The substrate 2 of entry 14-15 and entry 20-21 is 2n.
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MDPI and ACS Style

Shi, J.; Wang, Z.; Teng, X.; Zhang, B.; Sun, K.; Wang, X. Electro-Oxidative C3-Selenylation of Pyrido[1,2-a]pyrimidin-4-ones. Molecules 2023, 28, 2206. https://doi.org/10.3390/molecules28052206

AMA Style

Shi J, Wang Z, Teng X, Zhang B, Sun K, Wang X. Electro-Oxidative C3-Selenylation of Pyrido[1,2-a]pyrimidin-4-ones. Molecules. 2023; 28(5):2206. https://doi.org/10.3390/molecules28052206

Chicago/Turabian Style

Shi, Jianwei, Zhichuan Wang, Xiaoxu Teng, Bing Zhang, Kai Sun, and Xin Wang. 2023. "Electro-Oxidative C3-Selenylation of Pyrido[1,2-a]pyrimidin-4-ones" Molecules 28, no. 5: 2206. https://doi.org/10.3390/molecules28052206

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