Photoinitiated decarboxylative C3-difluoroarylmethylation of quinoxalin-2(1H)-ones with potassium 2,2-difluoro-2-arylacetates in water

Abstract

An efficient and green strategy for the preparation of C3-difluoroarylmethylated quinoxalin-2(1H)-one via a visible-light-induced decarboxylative C3-difluoroarylmethylation of quinoxalin-2(1H)-one with potassium 2,2-difluoro-2-arylacetate in water at room temperature was developed. This photoinduced reaction generated the desired products in good yields under simple and mild conditions.

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Introduction

Organic compounds containing fluorine have been widely found in pharmaceuticals, agrochemicals and materials.¹ The incorporation of fluorine atoms could remarkably change the physical and biological properties of its parent compounds, such as lipophilicity, stability, and bioavailability.² Among various fluoroalkyl groups, the benzylic difluoromethylene group (ArCF₂) has attracted much attention in medicinal chemistry, due to the fact that the ArCF₂ moiety has unique stability, and isosteric properties as an ethereal oxygen atom or a carbonyl group.³ So, it is of great value for the construction of fluorinated molecules, especially in the designed structure of drugs. Traditionally, difluoromethylene groups are introduced into the molecular skeleton by a deoxyfluorination of aldehydes or ketones with aminosulfur trifluorides, XeF₂, or F₂.⁴ Most recently, transition metals including Cu-, Pd-, and Ni-catalyzed difluoroalkylation reactions have been developed.⁵ As a distinct type of difluorobenzylic compound, difluoroalkylated arenes are present in many bioactive compounds. Therefore, the exploration of practical and broadly applicable methods for the introduction of the ArCF₂ group into target molecules is in high demand. α,α-Difluoroarylacetic acids and their salts are inexpensive, easy to store and simple to handle fluorine-containing regents, can be readily converted to a variety of useful ArCF₂-containing compounds. Recently, the decarboxylative coupling of gem-difluoroarylacetic acids and their salts have been well established. For example, Wu's group reported a direct decarboxylative alkynylation of α,α-difluoroarylacetic acids under transition metal-free conditions.⁶ Hashmi's group developed a silver-catalyzed decarboxylative alkynylation of α,α-difluoroarylacetic acids with ethynyl-benziodoxolone reagents,⁷ and Hao's group disclosed a silver-catalyzed decarboxylative difluoroarylmethylation of difluoroacetates with isocyanides for constructing 6-gem-difluoromethylenated phenanthridines (Scheme 1a).⁸ Very recently, Wan and Hao's group demonstrated a palladium(II)-catalyzed decarboxylative meta-selective C–H difluoromethylation of arenes from easily accessible difluoroacetic acids, and then a Ag-catalyzed minisci C–H difluoromethylarylation of N-heteroarenes was also developed by the group.⁹ Despite these achievements, it is still desirable to develop practical and mild synthetic methods for the preparation of CF₂-containing scaffolds.

Scheme 1 Decarboxylative difluoroarylmethylation reactions.

Quinoxalin-2(1H)-ones, especially the C3-functionalized derivatives are important moieties in pharmaceuticals and materials (Fig. 1).¹⁰ In the past few years, the C3-functionalizations of quinoxalin-2(1H)-ones have become a hot topics,¹¹ including C3-arylation,¹² C3-alkylation,¹³ C3-acylation,¹⁴ C3-amination,¹⁵ C3-phosphonation,¹⁶ C3-alkoxylation,¹⁷ C3-sulfenylation¹⁸ and C3-di/trifluoromethylation,¹⁹ have been extensive investigated. More recently, Zhang et al. reported a decarboxylative C3-difluoroarylmethylation of quinoxalin-2(1H)-ones with α,α-difluoroarylacetic acids in the presence of (NH₄)₂S₂O₈ (3.0 equiv.) in DMSO at 60 °C for 18 h (Scheme 1b),²⁰ while an excessive dose of oxidant and high temperature was still need in this transformation.

Fig. 1 C3 benzyl/alkyl substituted bioactive quinoxalin-2(1H)-ones.

As we all known, visible-light photocatalysis as a powerful tool for organic synthesis²¹ have met to the demands of reaction economy, operational simplicity and environmental friendliness. The organic transformations under visible-light irradiation in the absence of additional photocatalysts have received considerable attention, providing a challenging but meaningful direction for further photochemistry research. Because of our interest in visible-light-induced organic reactions without the photosensitizer,²² we here wish to describe a simple and efficient method for the direct C3-difluoroarylmethylation of quinoxalin-2(1H)-ones with potassium 2,2-difluoro-2-arylacetates via photochemical process without the additional photosensitizer in water under ambient conditions (Scheme 1c).

Results and discussion

First, N-methyl-quinoxalin-2(1H)-one (1a) and potassium α,α-difluoro-2-(4-methoxyphenyl)acetate (2a) were used as the model substrates to optimize the reaction conditions, and the results were shown in Table 1. When the model reaction was conducted with 1.0 equivalent of K₂S₂O₈ in DCE at room temperature under the irradiation of blue LED (420–425 nm) for 10 h, only trace amount of the desired product 3a was detected (Table 1, entry 1). To improve yield of the product, a number of solvents were examined. Organic solvents, such as DCE, DMSO, acetone and CH₃CN show all negative effect to the reaction. To our delight, H₂O exhibits excellent reactivity, delivering good yield of product 3a in 91% yield. However, co-solvents (DCE/H₂O and CH₃CN/H₂O in 1 : 1 volume ratio) give poor reactivity (Table 1, entries 2–7). The structure of 3a was characterized by ¹H, ¹³C and ¹⁹F NMR, and the structure of 3i was further confirmed by X-ray single crystal analysis.²⁴ In the absence of visible-light irradiation, no desired product was formed (Table 1, entry 8). A number of oxidants were also tested for the model reaction, and the results indicated that (NH₄)₂S₂O₈ is another effective oxidant, while no reactivity of BPO, DCP, BI-OH, TBHP and DTBP, and less reactivity of BQ, H₂O₂, generating 3a in 54% and 47% yields, respectively (Table 1, entries 9–16). When the model reaction was performed in the presence of oxygen atmosphere without K₂S₂O₈, only 31% yield of 3a was isolated (Table 1, entry 17). It is worth noting that the desired product 3a was also obtained in 90% yield when the reaction was performed under a nitrogen atmosphere, which indicates that oxygen is not required in this transformation (Table 1, entry 18). Subsequently, the wavelength of light source was investigated and blue LED (420–425 nm) was the best choice for the reaction. When the wavelength was less than 420–425 nm or more than 420–425 nm, the results exhibited the less reactivity (Table 1, entries 19–23). Moreover, when sodium α,α-difluoro-2-(4-methoxyphenyl)acetate and α,α-difluorophenylacetic acid were used as substrate, the product 3a was obtained in 89% and 86% yield, respectively (entries 24–25). The loading of oxidant, the ratio of 1a to 2a, as well as the reaction time were optimized, which are also summarized in Table 1 (entries 26–28).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Oxidant	Light source	Yield^b (%)
a Reaction conditions: N-methyl-quinoxalin-2(1H)-one (1a, 0.10 mmol), potassium 2,2-difluoro-2-(4-methoxyphenyl)acetate (2a, 0.15 mmol), oxidant (1.0 equiv.), solvent (3.0 mL) at room temperature under light irradiation (1.5 W) in air for 10 h.b Isolated yield. NR = no reaction.c Oxygen balloon instead of K2S2O8.d Nitrogen atmosphere.e Sodium α,α-difluoro-2-(4-methoxyphenyl) acetate was instead of 2a.f α,α-Difluorophenylacetic acid was instead of 2a.g K2S2O8 (0.75 equiv.).h K2S2O8 (1.5 equiv.).i 2a (0.1 mmol, 1.0 equiv.).j 2a (0.2 mmol, 2.0 equiv.).k 8 h.l 12 h.
1	DCE	K2S2O8	420–425 nm	Trace
2	DMSO	K2S2O8	420–425 nm	Trace
3	Acetone	K2S2O8	420–425 nm	NR
4	CH3CN	K2S2O8	420–425 nm	NR
5	H2O	K2S2O8	420–425 nm	91
6	DCE : H2O (1 : 1)	K2S2O8	420–425 nm	42
7	CH3CN : H2O (1 : 1)	K2S2O8	420–425 nm	<5
8	H2O	K2S2O8	In dark	0
9	H2O	BPO	420–425 nm	Trace
10	H2O	DCP	420–425 nm	Trace
11	H2O	BI-OH	420–425 nm	Trace
12	H2O	TBHP	420–425 nm	NR
13	H2O	DTBP	420–425 nm	NR
14	H2O	(NH4)2S2O8	420–425 nm	82
15	H2O	BQ	420–425 nm	54
16	H2O	H2O2	420–425 nm	47
17	H2O	O2	420–425 nm	31^c
18	H2O	K2S2O8	420–425 nm	90^d
19	H2O	K2S2O8	380–385 nm	75
20	H2O	K2S2O8	390–395 nm	74
21	H2O	K2S2O8	410–415 nm	84
22	H2O	K2S2O8	450–455 nm	86
23	H2O	K2S2O8	Sunlight	65
24	H2O	K2S2O8	420–425 nm	89^e
25	H2O	K2S2O8	420–425 nm	86^f
26	H2O	K2S2O8	420–425 nm	64^g, 90^h
27	H2O	K2S2O8	420–425 nm	61^i, 91^j
28	H2O	K2S2O8	420–425 nm	75^k, 89^l

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With the optimized reaction conditions in hand, we next investigated the generality of this direct C3-difluoroarylmethylation reaction. A variety of N-substituted quinoxalin-2(1H)-ones were subjected to the reaction, and the results are listed in Scheme 2. In general, all the selected quinoxalin-2(1H)-one derivatives could reacted with potassium 2,2-difluoro-2-(4-methoxyphenyl)acetate (2a) very smoothly under the standard conditions, indicating a broad tolerance of substituted groups including an electron-donating and an electron-withdrawing group on aromatic rings of quinoxalin-2(1H)-ones. Initial studies were focused on various N-protected quinoxalin-2(1H)-ones and the desired products 3a–3h were obtained in good to excellent yields. Next, a series of quinoxalin-2(1H)-ones bearing substituents on the benzene ring were also investigated under the optimal reaction conditions. In general, the C6-position substituted quinoxalin-2(1H)-ones bearing an electron-deficient group (F, Cl, Br, CF₃, CO₂CH₃) could generate the desired products 3i–3m in good to excellent yields (79–91%). Moreover, the dimethyl-substituted substrate 1n, was compatible with the reaction as well, and provided the desired product 3n in 93% yield, while the dichloro-substituted substrate 1o furnished the product 3o in a lower yield of 70%. It should be noted that quinoxalin-2(1H)-ones without protecting group were also well matched with the transformation, while the expected products 3p–3s were obtained in middle yields because of the poor solubility of the starting materials and products in water and commonly used organic solvents.

Scheme 2 The scope of quinolin-2(1H)-ones [reaction conditions: quinoxalin-2(1H)-one (1, 0.10 mmol), potassium 2,2-difluoro-2-phenylacetate (2a, 0.15 mmol), K₂S₂O₈ (1.0 equiv.), H₂O (3.0 mL) at room temperature with blue LED (420–425 nm, 1.5 W) irradiation in air for 10 h; isolated yield of the product].

Subsequently, the universality of potassium difluoroarylacetates were further explored, as shown in Scheme 3. Various para-substituted potassium α,α-difluoroarylacetates were used as difluoroarylmethylation reagent to react with N-methyl-quinoxalin-2(1H)-one (1a) to afford the corresponding difluoroarylmethylated quinoxalin-ones 3t–3aa in moderate to high yields. Generally, potassium α,α-difluoroarylacetates with electron-donating groups (3u–3y) gave higher yields than those with electron-withdrawing groups (3z–3aa). Compared with the corresponding 4-substituted potassium α,α-difluoroarylacetates. 2-Methyl, 2-methoxyl and 3-methyl substitutions in the arene ring of potassium α,α-difluoroarylacetates could provide the corresponding products in slightly lower yields. Moreover, the di-substituted substrates were also compatible with the reaction as well, and provided the desired product 3ae–3ag in good yields. To our delight, when the heterocyclic potassium difluoroarylacetate was employed, the transformation could also proceed smoothly and the corresponding product 3ah in 78% yield. In particular, naphthyl-based substrate was also examined and showed good reactivity in the reaction, providing 3ai in 87% yield.

Scheme 3 The scope of 2,2-difluoro-2-phenylacetate [reaction conditions: N-methyl-quinoxalin-2(1H)-one (1a, 0.10 mmol), 2,2-difluoro-2-phenylacetate (2, 0.15 mmol), K₂S₂O₈ (1.0 equiv.), H₂O (3.0 mL) at room temperature with blue LED (420–425 nm, 1.5 W) irradiation in air for 10 h; isolated yield of the product].

It is important to note that quinoxaline (4a) could also been involved in this direct C3-difluoroarylmethylation reaction, which reacted with potassium 2,2-difluoro-2-(4-methoxyphenyl)acetate (2a) under the standard conditions, providing the corresponding product 5a in 61% yield. However, when 2H-benzo[b][1,4]oxazin-2-one (6a) was employed in this transformation, no desired product 7a was detected (Scheme 4).

Scheme 4 Decarboxylative difluoroarylmethylation of 4a and 6a.

To further clarify the mechanism of this transformation, the control experiment was conducted, as shown in Scheme 5. When the model reaction was carried out in the presence of radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 2.5 equiv.) under the standard conditions, no desired product was found, suggesting that a radical process might involve in the reaction. An aryl difluoromethyl radical was trapped with TEMPO under standard reaction conditions to generate the corresponding adduct 8, which was detected by HRMS analysis.

Scheme 5 The control experiment.

On the basis of above experimental results and relevant literature,²³ a plausible mechanism is proposed in Scheme 6. The radical anion SO₄⁻˙ was firstly generated from K₂S₂O₈ under visible-light irradiation. With the assistance of radical anion SO₄⁻˙, the potassium 2,2-difluoro-2-phenylacetate 2t undergoes a decarboxylation process to generate a radical intermediate I, releasing carbon dioxide. Then the radical intermediate attacks quinoxalin-2(1H)-one 1a at C3-position to generate the radical intermediate II, which is further undergoes single-electron oxidation by loss of H⁺ to afford the product 3t.

Scheme 6 The proposed mechanism.

Conclusions

In summary, we have developed an efficient and environment-friendly synthetic protocol for the preparation of C3-difluoroarylmethylated quinoxalin-2(1H)-one via a visible-light-induced decarboxylative difluoroarylmethylation of quinoxalin-2(1H)-one with potassium 2,2-difluoro-2-arylacetate in water under simple and mild conditions. The reaction proceeds smoothly at room temperature afford the corresponding products in moderate to good yields with a broad substituent group tolerance. Further application of this photo-generated difluoroarylmethyl radical to other organic transformations and a detailed mechanistic study are underway in our laboratory.

Experimental section

General remarks

The ¹H NMR, ¹³C NMR and ¹⁹F NMR spectra were recorded on a 400 MHz or a 600 MHz Bruker FT-NMR spectrometer (400/100/376 MHz or 600/150/564 MHz, respectively). All chemical shifts are given as δ value (ppm) with reference to tetramethylsilane (TMS) as an internal standard. The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; q, quartet. The coupling constants, J, are reported in hertz (Hz). High resolution mass spectroscopy data of the product were collected on an Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS (ESI). Melting points (uncorrected) were obtained on WRS-1B digital melting point apparatus. The quinoxalin-2(1H)-ones and potassium 2,2-difluoro-2-(4-methoxyphenyl)acetates were prepared according to the reported literature.^8,19a All the solvents and commercially available reagents were purchased from commercial suppliers. Products were purified by flash chromatography on 200–300 mesh silica gels, SiO₂.

Typical procedure for the photoinitiated decarboxylative C3-difluoroarylmethylation

A 5 mL oven-dried reaction vessel equipped with a magnetic stirrer bar was charged with N-methyl-quinoxalin-2(1H)-one (1a, 0.10 mmol), potassium 2,2-difluoro-2-(4-methoxyphenyl)acetate (2a, 0.15 mmol), K₂S₂O₈ (0.10 mmol) and H₂O (3.0 mL). The reaction vessel was exposed to a blue LED (420–425 nm, 1.5 W) irradiation at room temperature in air with stirring for 10 h. After completion of the reaction, the mixture was extracted with ethyl acetate and concentrated to yield the crude product, which was further purified by flash chromatography (silica gel, petroleum ether/ethyl acetate = 20 : 1 to 9 : 1) to give the desired product 3a.

Characterization data for products

3-(Difluoro(4-methoxyphenyl)methyl)-1-methylquinoxalin-2(1H)-one (3a). Yellow solid. Mp 181.4–182.7 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.02–8.00 (m, 1H), 7.67–7.65 (m, 2H), 7.63–7.61 (m, 1H), 7.42–7.38 (m, 1H), 7.32–7.30 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.9, 152.0, 150.7 (t, J = 29.2 Hz), 134.1, 132.1, 131.2, 127.4 (t, J = 5.8 Hz), 126.9 (t, J = 26.6 Hz), 124.0, 117.5 (t, J = 245.4 Hz), 113.7, 113.5, 55.2, 28.8; ¹⁹F NMR (376 MHz, CDCl₃) δ: −98.33. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₇H₁₄F₂N₂NaO₂]⁺: 339.0916, found: 339.0915.

3-(Difluoro(4-methoxyphenyl)methyl)-1-ethylquinoxalin-2(1H)-one (3b). Yellow solid. Mp 202.1–202.7 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.04–8.02 (m, 1H), 7.68–7.61 (m, 3H), 7.41–7.37 (m, 1H), 7.36–7.33 (m, 1H), 6.94–6.92 (m, 2H), 4.26 (t, J = 7.2 Hz, 2H), 3.81 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.9, 151.5, 150.6, 133.2, 132.0, 131.7, 131.6, 127.5 (t, J = 5.8 Hz), 127.1, 126.8, 123.8, 117.5 (t, J = 245.2 Hz), 113.6, 55.2, 37.3, 12.3; ¹⁹F NMR (376 MHz, CDCl₃) δ: −98.03. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₈H₁₆F₂N₂NaO₂]⁺: 353.1072, found: 353.1070.

3-(Difluoro(4-methoxyphenyl)methyl)-1-propylquinoxalin-2(1H)-one (3c). Yellow solid. Mp 170.4–170.6 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.02–8.00 (m, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.62–7.60 (m, 1H), 7.38–7.36 (m, 1H), 7.31–7.30 (m, 1H), 6.92–6.91 (m, 2H), 4.14–4.12 (m, 2H), 3.80–3.79 (m, 3H), 1.76–1.70 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 160.8, 151.6, 150.5 (t, J = 28.2 Hz), 133.3, 131.9, 131.5, 131.4, 127.3 (t, J = 5.4 Hz), 127.0 (t, J = 26.9 Hz), 123.7, 117.5 (t, J = 245.1 Hz), 113.7, 113.5, 55.1, 43.6, 20.4, 11.1; ¹⁹F NMR (564 MHz, CDCl₃) δ: −97.93. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₉H₁₈F₂N₂NaO₂]⁺: 367.1229, found: 367.1223.

1-Allyl-3-(difluoro(4-methoxyphenyl)methyl)quinoxalin-2(1H)-one (3d). Yellow solid. Mp 117.7–118.9 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.02–8.00 (m, 1H), 7.68–7.65 (m, 2H), 7.61–7.56 (m, 1H), 7.39–7.35 (m, 1H), 7.31–7.29 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H), 5.90–5.81 (m, 1H), 5.24–5.22 (m, 1H), 5.16–5.11 (m, 1H), 4.83–4.81 (m, 2H), 3.78 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.8, 151.4, 150.5 (t, J = 28.9 Hz), 133.3, 131.9, 131.4, 131.2, 130.1, 127.4 (t, J = 5.7 Hz), 126.9 (t, J = 27.0 Hz), 123.9, 118.3, 117.5 (t, J = 245.5 Hz), 114.2, 113.5, 55.1, 44.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: −97.82. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₉H₁₆F₂N₂NaO₂]⁺: 365.1072, found: 365.1077.

3-(Difluoro(4-methoxyphenyl)methyl)-1-(prop-2-yn-1-yl)quinoxalin-2(1H)-one (3e). Yellow solid. Mp 165.5–166.7 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.02 (d, J = 7.8 Hz, 1H), 7.67–7.65 (m, 3H), 7.49–7.47 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 6.92–6.91 (m, 2H), 4.97–4.96 (m, 2H), 3.79 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 160.9, 150.9, 150.5 (t, J = 29.3 Hz), 132.6, 132.1, 131.5, 131.3, 127.5 (t, J = 5.6 Hz), 126.7 (t, J = 26.9 Hz), 124.4, 117.4 (t, J = 245.4 Hz), 114.3, 113.6, 76.2, 73.6, 55.2, 31.2; ¹⁹F NMR (564 MHz, CDCl₃) δ: −97.93. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₉H₁₄F₂N₂NaO₂]⁺: 363.0916, found: 363.0911.

1-Benzyl-3-(difluoro(4-methoxyphenyl)methyl)quinoxalin-2(1H)-one (3f). Yellow solid. Mp 147.8–150.1 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.02–8.00 (m, 1H), 7.70–7.68 (m, 2H), 7.51–7.46 (m, 1H), 7.35–7.31 (m, 1H), 7.28–7.21 (m, 4H), 7.16–7.15 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.40 (s, 2H), 3.79 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.9, 152.1, 150.8 (t, J = 29.0 Hz), 134.7, 133.5, 132.0, 131.6, 131.3, 128.9, 127.7, 127.5 (t, J = 5.6 Hz), 127.0 (t, J = 26.9 Hz), 126.8, 124.0, 117.6 (t, J = 245.5 Hz), 114.5, 113.6, 55.2, 45.6; ¹⁹F NMR (376 MHz, CDCl₃) δ: −97.76. HRMS (ESI) ([M + Na]⁺) calcd for [C₂₃H₁₈F₂N₂NaO₂]⁺: 415.1229, found: 415.1232.

Ethyl 2-(3-(difluoro(4-methoxyphenyl)methyl)-2-oxoquinoxalin-1(2H)-yl)acetate (3g). Yellow solid. Mp 119.1–120.2 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 4.94 (s, 2H), 4.18, (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 166.4, 160.8, 151.5, 150.3 (t, J = 28.9 Hz), 133.2, 132.1, 131.4, 131.3, 127.3 (t, J = 5.6 Hz), 126.7 (t, J = 26.4 Hz), 124.2, 117.3 (t, J = 245.2 Hz), 113.5, 113.2, 62.0, 55.1, 43.1, 13.8; ¹⁹F NMR (376 MHz, CDCl₃) δ: −97.76. HRMS (ESI) ([M + Na]⁺) calcd for [C₂₀H₁₈F₂N₂NaO₄]⁺: 411.1127, found: 411.1125.

1-Benzoyl-3-(difluoro(4-methoxyphenyl)methyl)quinoxalin-2(1H)-one (3h). Yellow solid. Mp 185.6–186.3 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.06–8.04 (m, 1H), 8.00–7.98 (m, 2H), 7.66–7.62 (m, 3H), 7.52–7.48 (m, 3H), 7.40–7.36 (m, 1H), 6.97–6.95 (m, 1H), 6.92–6.90 (m, 2H), 5.67 (s, 2H), 3.79 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 190.5, 160.9, 151.8, 150.4, 134.4, 134.2, 133.7, 132.1, 131.6, 131.5, 129.0, 128.1, 127.4 (t, J = 5.6 Hz), 126.9, 124.2, 117.4 (t, J = 245.3 Hz), 113.7, 113.6, 55.2, 48.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: −97.83. HRMS (ESI) ([M + Na]⁺) calcd for [C₂₄H₁₈F₂N₂NaO₃]⁺: 443.1178, found: 443.1174.

3-(Difluoro(4-methoxyphenyl)methyl)-6-fluoro-1-methylquinoxalin-2(1H)-one (3i). Yellow solid. Mp 191.1–192.4 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.73–7.70 (m, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.42–7.37 (m, 1H), 7.31–7.26 (m, 1H), 6.92 (m, 2H), 3.80 (s, 3H), 3.63 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.0, 159.9, 157.4, 152.0 (t, J = 29.2 Hz), 151.6, 131.9 (d, J = 13.2 Hz), 127.5 (t, J = 5.6 Hz), 126.6 (t, J = 26.9 Hz), 120.0 (d, J = 24.0 Hz), 117.4 (t, J = 245.8 Hz), 116.5 (d, J = 22.5 Hz), 114.9 (d, J = 8.6 Hz), 113.6, 55.2, 29.1; ¹⁹F NMR (376 MHz, CDCl₃) δ: −98.33, −117.88. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₇H₁₃F₃N₂NaO₂]⁺: 357.0821, found: 357.0822.

6-Chloro-3-(difluoro(4-methoxyphenyl)methyl)-1-methylquinoxalin-2(1H)-one (3j). Yellow solid. Mp 254.3–255.6 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.02 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59–7.57 (m, 1H), 7.26–7.25 (m, 1H), 6.93–6.92 (m, 2H), 3.81 (s, 3H), 3.62 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 161.0, 152.0 (t, J = 29.3 Hz), 151.6, 132.9, 132.1, 131.9, 130.5, 129.4, 127.5 (t, J = 5.4 Hz), 126.6 (t, J = 26.7 Hz), 117.4 (t, J = 245.9 Hz), 114.9, 113.6, 55.3, 29.1; ¹⁹F NMR (564 MHz, CDCl₃) δ: −98.71. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₇H₁₃ClF₂N₂NaO₂]⁺: 373.0526, found: 373.0528.

6-Bromo-3-(difluoro(4-methoxyphenyl)methyl)-1-methylquinoxalin-2(1H)-one (3k). Yellow solid. Mp 204.7–205.4 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.15–8.14 (m, 1H), 7.71–7.68 (m, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.20–7.18 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.0, 151.8 (t, J = 39.3 Hz), 151.6, 134.7, 133.5, 133.3, 132.0, 127.5 (t, J = 5.6 Hz), 126.5 (t, J = 26.9 Hz), 117.3 (t, J = 245.8 Hz), 115.2, 113.6, 55.2, 29.0; ¹⁹F NMR (376 MHz, CDCl₃) δ: −98.62. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₇H₁₃BrF₂N₂NaO₂]⁺: 417.0021, found: 417.0020.

3-(Difluoro(4-methoxyphenyl)methyl)-1-methyl-6-(trifluoromethyl)quinoxalin-2(1H)-one (3l). Yellow solid. Mp 164.8–167.2 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.302–8.300 (m, 1H), 7.85–7.83 (m, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.43–7.42 (m, 1H), 6.92–6.91 (m, 2H), 3.80 (s, 3H), 3.65 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 161.1, 152.3 (t, J = 29.6 Hz), 151.7, 136.4, 130.6, 128.7 (q, J = 3.3 Hz), 127.5 (t, J = 5.4 Hz), 126.4 (t, J = 33.6 Hz), 126.2 (q, J = 26.7 Hz), 124.3, 122.5, 117.3 (t, J = 246.0 Hz), 114.5, 113.6, 55.2, 29.1; ¹⁹F NMR (564 MHz, CDCl₃) δ: −62.13, −98.78. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₈H₁₃F₅N₂NaO₂]⁺: 407.0789, found: 407.0793.

Methyl 3-(difluoro(4-methoxyphenyl)methyl)-1-methyl-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (3m). Yellow solid. Mp 178.7–180.4 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.67–8.66 (m, 1H), 8.26–8.24 (m, 1H), 7.65–7.64 (m, 2H), 7.36–7.35 (m, 1H), 6.92–6.91 (m, 2H), 3.96 (s, 3H), 3.80 (s, 3H), 3.65 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 165.5, 161.0, 151.5 (t, J = 29.3 Hz), 137.3, 132.9, 132.5, 130.6, 127.5 (t, J = 5.4 Hz), 126.5 (t, J = 26.7 Hz), 125.9, 117.3 (t, J = 245.9 Hz), 113.8, 113.6, 55.2, 52.4, 29.1; ¹⁹F NMR (564 MHz, CDCl₃) δ: −98.63. HRMS (ESI) ([M + H]⁺) calcd for [C₁₉H₁₇F₂N₂O₄]⁺: 375.1151, found: 375.1152.

3-(Difluoro(4-methoxyphenyl)methyl)-1,6,7-trimethylquinoxalin-2(1H)-one (3n). Yellow solid. Mp 164.8–167.2 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.77 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.92 (d, J = 8.4 Hz, 2H), 3.81–3.80 (m, 3H), 3.61–3.60 (m, 3H), 2.43 (s, 3H), 2.37 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.8, 152.2, 149.3, 148.9, 142.4, 133.1, 132.3, 131.2, 129.8, 127.4 (t, J = 5.7 Hz), 127.0, 117.6 (t, J = 244.8 Hz), 114.2, 113.5, 55.2, 28.8, 20.7, 19.1; ¹⁹F NMR (376 MHz, CDCl₃) δ: −102.79. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₉H₁₈F₂N₂NaO₂]⁺: 367.1229, found: 367.1224.

6,7-Dichloro-3-(difluoro(4-methoxyphenyl)methyl)-1-methylquinoxalin-2(1H)-one (3o). Yellow solid. Mp 191.6–192.7 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.40 (s, 1H), 6.91 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.57 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.0, 151.9 (t, J = 29.4 Hz), 151.3, 136.3, 133.4, 131.9, 130.3, 127.9, 127.5 (t, J = 5.7 Hz), 126.3 (t, J = 26.7 Hz), 117.2 (t, J = 246.2 Hz), 115.2, 113.6, 55.2, 29.1; ¹⁹F NMR (376 MHz, CDCl₃) δ: −98.07. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₇H₁₂Cl₂F₂N₂NaO₂]⁺: 407.0136, found: 407.0137.

3-(Difluoro(4-methoxyphenyl)methyl)quinoxalin-2(1H)-one (3p). Yellow solid. Mp 174.3–175.6 °C. ¹H NMR (400 MHz, d₆-DMSO) δ: 12.72 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.65–7.61 (m, 1H), 7.55–7.53 (m, 2H), 7.38–7.34 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H); ¹³C NMR (100 MHz, d₆-DMSO) δ: 160.6, 151.9, 133.1, 132.1, 130.3, 129.5, 127.2 (t, J = 5.2 Hz), 126.6, 123.7, 117.7 (t, J = 243.5 Hz), 113.7, 55.2; ¹⁹F NMR (376 MHz, d₆-DMSO) δ: −95.09. HRMS (ESI) ([M + H]⁺) calcd for [C₁₆H₁₃F₂N₂O₂]⁺: 303.0940, found: 303.0945.

3-(Difluoro(4-methoxyphenyl)methyl)-6-fluoroquinoxalin-2(1H)-one (3q). Yellow solid. Mp 190.1–191.8 °C. ¹H NMR (600 MHz, d₆-DMSO) δ: 12.81 (s, 1H), 7.81–7.79 (m, 1H), 7.60–7.57 (m, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.39–7.37 (m, 1H), 7.02 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H); ¹³C NMR (150 MHz, d₆-DMSO) δ: 161.2, 159.2, 157.6, 152.7 (t, J = 28.5 Hz), 152.1, 131.0 (d, J = 12.0 Hz), 130.6, 127.7 (t, J = 4.5 Hz), 126.9 (t, J = 27.0 Hz), 120.9 (d, J = 25.5 Hz), 118.1 (t, J = 243.0 Hz), 117.5 (d, J = 9.0 Hz), 115.0 (d, J = 22.5 Hz), 114.3, 55.8; ¹⁹F NMR (564 MHz, d₆-DMSO) δ: −95.19, −118.50. HRMS (ESI) ([M + H]⁺) calcd for [C₁₆H₁₁F₃N₂O₂]⁺: 320.0733, found: 320.0776.

6-Bromo-3-(difluoro(4-methoxyphenyl)methyl)quinoxalin-2(1H)-one (3r). Yellow solid. Mp 200.5–201.9 °C. ¹H NMR (600 MHz, d₆-DMSO) δ: 12.86 (s, 1H), 8.131–8.129 (m, 1H), 7.81–7.94 (m, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.30–7.29 (m, 1H), 7.02 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H); ¹³C NMR (150 MHz, d₆-DMSO) δ: 161.2, 162.6 (t, J = 28.5 Hz), 162.2, 135.2, 133.0, 131.9, 131.7, 127.7 (t, J = 4.5 Hz), 126.8 (t, J = 27.0 Hz), 118.03 (t, J = 243.0 Hz), 118.0, 115.5, 114.3, 55.8; ¹⁹F NMR (564 MHz, d₆-DMSO) δ: −95.23. HRMS (ESI) ([M + H]⁺) calcd for [C₁₆H₁₁BrF₂N₂O₂]⁺: 379.9972, found: 379.9971.

3-(Difluoro(4-methoxyphenyl)methyl)-6,7-difluoroquinoxalin-2(1H)-one (3s). Yellow solid. Mp 187.3–187.9 °C. ¹H NMR (600 MHz, d₆-DMSO) δ: 12.87 (s, 1H), 8.12–8.10 (m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.29–7.26 (m, 1H), 7.02 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H); ¹³C NMR (150 MHz, d₆-DMSO) δ: 161.2, 152.1, 151.9 (t, J = 25.5 Hz), 147.3 (d, J = 13.5 Hz), 145.7 (d, J = 13.5 Hz), 131.5 (d, J = 10.5 Hz), 127.7 (t, J = 4.5 Hz), 127.2 (d, J = 9.0 Hz), 126.8 (t, J = 31.5 Hz), 118.0 (t, J = 243.0 Hz), 117.8 (d, J = 18.0 Hz), 114.3, 103.8 (d, J = 21.0 Hz), 55.8; ¹⁹F NMR (564 MHz, d₆-DMSO) δ: −95.19, −129.94 (d, J = 23.0 Hz); −143.37 (d, J = 23.0 Hz). HRMS (ESI) ([M + H]⁺) calcd for [C₁₆H₁₀F₄N₂O₂]⁺: 338.0678, found: 338.0674.

3-(Difluoro(phenyl)methyl)-1-methylquinoxalin-2(1H)-one (3t). Yellow solid. Mp 161.1–161.9 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.05–8.03 (m, 1H), 7.75–7.73 (m, 2H), 7.67–7.64 (m, 1H), 7.43–7.42 (m, 3H), 7.41–7.40 (m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 3.64 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.1, 150.6, 134.9 (t, J = 26.3 Hz), 134.2, 132.2, 131.5, 131.4, 130.2, 128.2, 125.9 (t, J = 5.6 Hz), 124.1, 117.4 (t, J = 245.9 Hz), 113.7, 28.9; ¹⁹F NMR (564 MHz, CDCl₃) δ: −99.63. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₆H₁₂F₂N₂NaO]⁺: 309.0810, found: 309.0814.

3-(Difluoro(p-tolyl)methyl)-1-methylquinoxalin-2(1H)-one (3u). Yellow solid. Mp 171.4–172.8 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.05–8.02 (m, 1H), 7.66–7.63 (m, 2H), 7.61 (s, 1H), 7.43–7.39 (m, 1H), 7.33–7.31 (m, 1H), 7.24–7.22 (m, 2H), 3.63 (s, 3H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 152.0, 150.7 (t, J = 28.2 Hz), 140.3, 134.2, 132.1, 132.0 (t, J = 26.4 Hz), 131.4 (double), 128.9, 125.8 (t, J = 5.6 Hz), 124.0, 117.5 (t, J = 245.2 Hz), 113.7, 28.9, 21.3; ¹⁹F NMR (100 MHz, CDCl₃) δ: −99.21. HRMS (ESI) ([M + H]⁺) calcd for [C₁₇H₁₄F₂N₂NaO₂]⁺: 339.0916, found: 339.0915.

2-((4-Ethylphenyl)difluoromethyl)-1-methylquinoxalin-2(1H)-one (3v). Yellow solid. Mp 171.4–172.8 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.05–8.03 (m, 1H), 7.66–7.62 (m, 3H), 7.43–7.39 (m, 1H), 7.33–7.31 (m, 1H), 7.26–7.24 (m, 2H), 3.64 (s, 3H), 2.66 (t, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 152.1, 150.7 (t, J = 28.3 Hz), 146.5, 134.2, 132.2 (t, J = 26.3 Hz), 132.1, 131.5, 131.4, 127.7, 125.9 (t, J = 5.7 Hz), 124.0, 117.5 (t, J = 245.5 Hz), 113.7, 28.9, 28.7, 15.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: −99.13. HRMS (ESI) ([M + H]⁺) calcd for [C₁₈H₁₇F₂N₂O]⁺: 315.1303, found: 315.1304.

3-((4-Butylphenyl)difluoromethyl)-1-methylquinoxalin-2(1H)-one (3w). Yellow solid. Mp 106.7–107.4 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.04–8.02 (m, 1H), 7.65–7.63 (m, 3H), 7.42–7.39 (m, 1H), 7.32–7.30 (m, 1H), 7.23 (d, J = 7.8 Hz, 2H), 3.63 (s, 3H), 2.61 (t, J = 7.8 Hz, 2H), 1.61–1.56 (m, 2H), 1.37–1.31 (m, 2H), 0.91 (t, J = 8.4 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.0, 150.7 (t, J = 28.2 Hz), 145.2, 134.2, 132.1 (t, J = 26.7 Hz), 132.08, 131.4, 131.3, 128.3, 125.8 (t, J = 5.4 Hz), 124.0, 117.5 (t, J = 245.6 Hz), 113.7, 35.4, 33.3, 28.9, 22.3, 11.9; ¹⁹F NMR (564 MHz, CDCl₃) δ: −99.05. HRMS (ESI) ([M + H]⁺) calcd for [C₂₀H₂₁F₂N₂O]⁺: 343.1616, found: 343.1617.

((4-(tert-Butyl)phenyl)difluoromethyl)-1-methylquinoxalin-2(1H)-one (3x). Yellow solid. Mp 129.9–130.7 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.04–8.02 (m, 1H), 7.69–7.67 (m, 2H), 7.64–7.61 (m, 1H), 7.45–7.43 (m, 2H), 7.41–7.39 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3.63 (s, 3H), 1.30 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ: 153.3, 152.0, 150.7 (t, J = 28.2 Hz), 134.2, 132.1, 131.7 (t, J = 26.9 Hz), 131.5, 131.4, 125.7 (t, J = 5.6 Hz), 125.2, 124.0, 117.5 (t, J = 245.7 Hz), 113.7, 34.7, 31.2, 28.9; ¹⁹F NMR (564 MHz, CDCl₃) δ: −99.08. HRMS (ESI) ([M + H]⁺) calcd for [C₂₀H₂₁F₂N₂O]⁺: 343.1616, found: 343.1615.

3-([1,1′-Biphenyl]-4-yldifluoromethyl)-1-methylquinoxalin-2(1H)-one (3y). Yellow solid. Mp 143.0–144.3 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.03–8.01 (m, 1H), 7.82–7.80 (m, 2H), 7.64–7.59 (m, 3H), 7.57–7.55 (m, 2H), 7.42–7.37 (m, 3H), 7.34–7.28 (m, 2H), 3.61 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 152.0, 150.4 (t, J = 28.3 Hz), 143.0, 140.2, 134.1, 133.7 (t, J = 26.8 Hz), 132.2, 131.4, 131.3, 128.7, 127.7, 127.0, 126.4 (t, J = 5.5 Hz), 124.0, 117.4 (t, J = 245.7 Hz), 113.7, 28.5; ¹⁹F NMR (376 MHz, CDCl₃) δ: −99.24. HRMS (ESI) ([M + Na]⁺) calcd for [C₂₂H₁₆F₂N₂NaO]⁺: 385.1123, found: 385.1126.

3-((4-Chlorophenyl)difluoromethyl)-1-methylquinoxalin-2(1H)-one (3z). Yellow solid. Mp 231.1–231.4 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.03–8.02 (m, 1H), 7.69–7.67 (m, 2H), 7.66–7.65 (m, 1H), 7.44–7.41 (m, 1H), 7.40–7.39 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.0, 150.1 (t, J = 28.1 Hz), 136.4, 134.2, 133.4 (t, J = 27.0 Hz), 132.4, 131.4 (double), 128.5, 127.5 (t, J = 5.6 Hz), 124.2, 117.0 (t, J = 246.0 Hz), 113.8, 29.0; ¹⁹F NMR (564 MHz, CDCl₃) δ: −99.69. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₆H₁₁ClF₂N₂NaO]⁺: 343.0420, found: 343.0423.

3-((4-Bromophenyl)difluoromethyl)-1-methylquinoxalin-2(1H)-one (3aa). Yellow solid. Mp 185.8–187.2 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.04–8.02 (m, 1H), 7.68–7.65 (m, 1H), 7.62–7.61 (m, 2H), 7.57–7.55 (m, 2H), 7.44–7.42 (m, 1H), 7.35–7.34 (m, 1H), 3.65 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.0, 150.2 (t, J = 28.1 Hz), 134.2, 133.9, 132.4, 131.5 (double), 131.4, 130.9, 128.8, 127.8 (t, J = 5.6 Hz), 124.8, 117.1 (t, J = 246.0 Hz), 113.8, 29.0; ¹⁹F NMR (564 MHz, CDCl₃) δ: −99.92. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₆H₁₁BrF₂N₂NaO]⁺: 386.9915, found: 386.9918.

3-(Difluoro(o-tolyl)methyl)-1-methylquinoxalin-2(1H)-one (3ab). Yellow solid. Mp 154.2–155.3 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.01–7.99 (m, 1H), 7.86–7.85 (m, 1H), 7.66–7.64 (m, 1H), 7.42–7.39 (m, 1H), 7.34–7.29 (m, 3H), 7.17–7.16 (m, 1H), 3.64 (s, 3H), 2.38 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.1, 150.2 (t, J = 28.4 Hz), 136.2 (t, J = 3.0 Hz), 134.2, 132.7 (t, J = 24.2 Hz), 132.2, 131.5, 131.4, 131.2, 130.1, 127.5 (t, J = 8.1 Hz), 125.5, 124.0, 118.2 (t, J = 245.6 Hz), 113.7, 28.9, 20.2; ¹⁹F NMR (564 MHz, CDCl₃) δ: −97.61. HRMS (ESI) ([M + H]⁺) calcd for [C₁₇H₁₅F₂N₂O]⁺: 301.1147, found: 301.1146.

3-(Difluoro(2-methoxyphenyl)methyl)-1-methylquinoxalin-2(1H)-one (3ac). Yellow solid. Mp 151.4–152.7 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.03–8.01 (m, 1H), 7.88–7.87 (m, 1H), 7.64–7.61 (m, 1H), 7.41–7.37 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 3.56 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 156.4 (t, J = 4.7 Hz), 152.2, 150.7 (t, J = 26.7 Hz), 133.9, 131.7, 131.5, 131.4, 131.0, 127.1 (t, J = 7.4 Hz), 123.8, 123.7 (t, J = 24.8 Hz), 120.6, 116.0 (t, J = 242.6 Hz), 113.6, 113.4, 55.7, 28.7; ¹⁹F NMR (564 MHz, CDCl₃) δ: −98.27. HRMS (ESI) ([M + H]⁺) calcd for [C₁₇H₁₅F₂N₂O₂]⁺: 317.1096, found: 317.1097.

3-(Difluoro(m-tolyl)methyl)-1-methylquinoxalin-2(1H)-one (3ad). Yellow solid. Mp 143.4–144.3 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.03–8.01 (m, 1H), 7.64–7.61 (m, 1H), 7.54–7.52 (m, 2H), 7.41–7.38 (m, 1H), 7.31–7.29 (m, 2H), 7.23–7.22 (m, 1H), 3.61 (s, 3H), 2.36 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 151.9, 150.5 (t, J = 28.1 Hz), 138.0, 134.7 (t, J = 26.1 Hz), 134.1, 132.1, 131.3, 131.2, 130.9, 128.1, 126.2 (t, J = 5.4 Hz), 124.0, 123.0 (t, J = 5.6 Hz), 117.3 (t, J = 245.6 Hz), 113.7, 28.8, 21.3; ¹⁹F NMR (564 MHz, CDCl₃) δ: −99.20. HRMS (ESI) ([M + H]⁺) calcd for [C₁₇H₁₅F₂N₂O]⁺: 301.1147, found: 301.1149.

3-((2,4-Dimethoxyphenyl)difluoromethyl)-1-methylquinoxalin-2(1H)-one (3ae). Yellow solid. Mp 191.3–192.4 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.03–8.02 (m, 1H), 7.80–7.79 (m, 1H), 7.64–7.61 (m, 1H), 7.41–7.38 (m, 1H), 7.33–7.32 (m, 1H), 6.61 (dd, J₁ = 9.0 Hz, J₂ = 2.4 Hz, 1H), 6.40–6.39 (m, 1H), 3.80 (s, 3H), 3.62 (s, 3H), 3.54 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 162.3, 157.7 (t, J = 4.7 Hz), 152.2, 150.8 (t, J = 27.0 Hz), 133.9, 131.6, 131.4, 131.0, 128.3 (t, J = 7.2 Hz), 123.8, 116.2 (t, J = 25.0 Hz), 116.19 (t, J = 242.0 Hz), 113.6, 104.4, 98.8, 55.6, 55.2, 28.7; ¹⁹F NMR (564 MHz, CDCl₃) δ: −97.04. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₈H₁₆F₂N₂NaO₃]⁺: 369.1021, found: 369.1025.

3-((3,4-Dimethylphenyl)difluoromethyl)-1-methylquinoxalin-2(1H)-one (3af). Yellow solid. Mp 206.7–207.1 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.02–8.01 (m, 1H), 7.63–7.60 (m, 1H), 7.46–7.45 (m, 2H), 7.40–7.37 (m, 1H), 7.30–7.28 (m, 1H), 7.17–7.16 (m, 1H), 3.60 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 151.9, 150.6 (t, J = 28.2 Hz), 138.9, 136.5, 134.1, 132.2 (t, J = 26.1 Hz), 132.0, 131.3, 131.2, 129.4, 126.6 (t, J = 5.4 Hz), 123.9, 123.2 (t, J = 5.6 Hz), 117.4 (t, J = 245.4 Hz), 113.7, 28.8, 19.7, 19.6; ¹⁹F NMR (564 MHz, CDCl₃) δ: −98.82. HRMS (ESI) ([M + H]⁺) calcd for [C₁₈H₁₇F₂N₂O]⁺: 315.1303, found: 315.1304.

3-((3,5-Dimethylphenyl)difluoromethyl)-1-methylquinoxalin-2(1H)-one (3ag). Yellow solid. Mp 186.7–188.4 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.06–8.05 (m, 1H), 7.66–7.64 (m, 1H), 7.43–7.41 (m, 1H), 7.34–7.32 (m, 3H), 7.05 (s, 1H), 3.64 (s, 3H), 2.33 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.1, 150.7 (t, J = 28.1 Hz), 137.9, 134.7 (t, J = 25.7 Hz), 134.2, 132.1, 131.9, 131.4 (double), 124.0, 123.4 (t, J = 5.6 Hz), 117.44, 117.4 (t, J = 245.0 Hz), 113.7, 28.9, 21.3; ¹⁹F NMR (564 MHz, CDCl₃) δ: −99.00. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₈H₁₆F₂N₂NaO]⁺: 337.1123, found: 337.1127.

3-(Difluoro(thiophen-2-yl)methyl)-1-methylquinoxalin-2(1H)-one (3ah). Yellow solid. Mp 121.4–122.8 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.01–7.99 (m, 1H), 7.79–7.78 (m, 1H), 7.67–7.63 (m, 1H), 7.42–7.37 (m, 2H), 7.35–7.31 (m, 2H), 3.67 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 152.0, 150.2 (t, J = 28.1 Hz), 136.2 (t, J = 29.4 Hz), 134.2, 132.2, 131.4, 131.3, 126.0, 125.9 (t, J = 6.6 Hz), 125.8, 124.1, 115.9 (t, J = 244.3 Hz), 113.7, 29.0; ¹⁹F NMR (376 MHz, CDCl₃) δ: −94.82. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₄H₁₀F₂N₂NaOS]⁺: 315.0374, found: 315.0371.

3-(Difluoro(naphthalen-1-yl)methyl)-1-methylquinoxalin-2(1H)-one (3ai). Yellow solid. Mp 148.7–149.5 °C. ¹H NMR (600 MHz, CDCl₃) δ: 8.36–8.35 (m, 1H), 8.23–8.22 (m, 1H), 8.09–8.07 (m, 1H), 7.94–7.93 (m, 1H), 7.85–7.83 (m, 1H), 7.63–7.59 (m, 2H), 7.43–7.39 (m, 3H), 7.27–7.25 (m, 1H), 3.55 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.0, 150.5 (t, J = 28.1 Hz), 134.3, 133.8, 132.3, 131.4, 131.3 (double), 129.8 (t, J = 24.6 Hz), 129.5, 128.8, 126.7, 126.6 (t, J = 8.8 Hz), 125.6, 125.0, 124.7, 124.0, 118.1 (t, J = 246.8 Hz), 113.7, 28.8; ¹⁹F NMR (564 MHz, CDCl₃) δ: −96.21. HRMS (ESI) ([M + Na]⁺) calcd for C₂₀H₁₄F₂N₂NaO: 359.0966, found: 359.0967.

2-(Difluoro(4-methoxyphenyl)methyl)quinoxaline (5a). Yellow solid. Mp 121.5–123.8 °C. ¹H NMR (600 MHz, CDCl₃) δ: 9.19 (s, 1H), 8.17–8.15 (m, 2H), 7.85–7.81 (m, 2H), 7.59 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 3.83 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 161.1, 150.3 (t, J = 31.5 Hz), 142.7, 142.0 (t, J = 4.5 Hz), 141.1, 131.2, 130.8, 129.9, 129.3, 127.8 (t, J = 27.3 Hz), 127.5 (t, J = 5.6 Hz), 118.6 (t, J = 242.7 Hz), 113.9, 55.4; ¹⁹F NMR (564 MHz, CDCl₃) δ: −93.48. HRMS (ESI) ([M + Na]⁺) calcd for [C₁₆H₁₂F₂N₂NaO]⁺: 309.0810, found: 309.0809.

Conflicts of interest

There are no conflicts to declare

Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China (21772062), the Young Talent Key Project of Anhui Province (170808J02) and the Scientific Research Project of Anhui Provincial Education Department (KJ2015TD002) for financial support of this work.

Notes and references

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24. X-Ray single crystal structure 3i (CCDC number: 1961424).†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1961424. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0ra02059a

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