Direct C3 alkoxylation of quinoxalin-2(1H)-ones with alcohols via

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Direct C3 alkoxylation of quinoxalin-2(1H)-ones with alcohols via cross-dehydrogenative coupling under catalyst-free conditions Qiming Yang, Xulin Han, Jiquan Zhao, Hong-Yu Zhang, and Yuecheng Zhang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01181 • Publication Date (Web): 16 Aug 2019 Downloaded from pubs.acs.org on August 16, 2019

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The Journal of Organic Chemistry

Direct C3 alkoxylation of quinoxalin-2(1H)-ones with alcohols via cross-dehydrogenative coupling under catalyst-free conditions Qiming Yang,⊥ Xulin Han,⊥ Jiquan Zhao, Hong-Yu Zhang* and Yuecheng Zhang* School of Chemical Engineering and Technology, Hebei Provincial Key Lab of Green Chemical Technology & High Efficient Energy Saving, Hebei University of Technology, Tianjin 300130, P. R. China. *E-mail: [email protected]; [email protected] N

H

R2 N R1

+ HOR3

O

N

PhI(OTFA)2 CH2Cl2, 50 C, Ar

OR3

R2 O N R1 34 examples up to 91% yield

1. catalyst-free cross-dehydrogenative coupling 2. various alcohols and broad substrate scope

ABSTRACT: A facile and effective alkoxylation protocol of quinoxalin-2(1H)-ones with primary or secondary alcohols via crossdehydrogenative coupling under catalyst-free conditions has been disclosed. This method provides a powerful and convenient access to 3-alkoxylquinoxalin-2(1H)-ones in good to excellent yields by utilizing PhI(OTFA)2 as oxidant, and potential drug molecules containing 3-alkoxylquinoxalin-2(1H)-one skeletons would be easily obtained.

INTRODUCTION H N O F

O

Cl O

N H3C

O

HN

HN O NH2

synthesis of aryl alkyl ethers avoiding poisonous metal residues is highly desired.

N HCl

Anlotinib Hydrochloride

O H3C

N Pyrotinib

N

Scheme 1. Alkoxylation with alcohol via cross coupling

O N

OH O

N

O

a) cross coupling X +

Aryl alkyl or aryl ethers are structural constituents in various bioactive natural products and pharmaceuticals, such as Anlotinib Hydrochloride1, Pyrotinib2 and Aldose Reductase inhibitors3 (Figure 1). Over the past years, typical methodologies for their preparation have been adequately developed, such as the cross coupling reaction catalyzed by transition metals.4 This strategy was efficient for the coupling of aryl halides with phenols or alcohols to synthesize aryl alkyl ethers (Scheme 1a). However, the harsh reaction conditions and prefunctionalized substrates limited the reaction scopes.5 Over the past decade, owing to the high atom and step economy, the cross-dehydrogenation coupling (CDC) strategy has drawn a broad attention.6 From this view, C-H/OH CDC alkoxylation emerges as one of the most simple and efficient access to target ethers in minimum synthetic steps.7 Although glorious achievements have been accomplished, the application of these methods is restricted by the requirement of expensive transition-metal-catalysts or complex photocatalysts in practice especially in the pharmaceutical synthesis (Scheme 1b). So, a direct and simple procedure for the

OR

transition-metal catalyst ligand, base

Aldose Reductase inhibitors

Figure 1. Pharmaceutical molecules containing ethers

HOR

X = I, Br or Cl b) catalytic cross-dehydrogenative coupling H +

HOR

transition-metal catalyst or photo-catalyst

OR

oxidant or oxidant-free c) catalyst-free cross-dehydrogenative coupling N

H

R2

+ HOR3 N R1

O

catalyst-free PhI(OTFA)2

N

OR3

N R1

O

R2

Meanwhile, quinoxalin-2(1H)-ones are also crucial class of bioactive skeletons that are widely present in pharmaceutical molecules, especially in the areas such as antineoplastic8, antidiabetic9, antimicrobial10, anti-inflammatory11 and antithrombotic12 agents. The modification of the quinoxalin2(1H)-one skeleton made it easy to obtain some valuable molecules, and offered a variety of possibilities for the discovery of potential drugs. Especially in recent years, plentiful methods about the direct C3-H functionalization of easily available quinoxalin-2(1H)-ones have been reported, such as introducing alkyl13, (hetero)aryl14, acyl15, trifluoromethyl16, difluoroacetyl17, difluoroarylmethyl18, 19 20 amino and phosphonate groups into the C3 position of

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quinoxalin-2(1H)-ones in succession to obtain a series of valuably functional quinoxalin-2(1H)-ones. However, while congratulating the great achievements on the C3-H functionalization of quinoxalin-2(1H)-ones that have been made, we noted that there was still no report on introducing alkoxy groups into the C3 position of quinoxalin-2(1H)-ones. Hence, we firstly disclosed a facile and highly effective way to directly synthesize 3-alkoxylquinoxalin-2(1H)-ones with alcohols via CDC reactions under catalyst-free conditions (Scheme 1c).

76% to 80% (Table 1, entry 10). Finally, a survey of oxidant loading revealed that 1.5 equivalent of PhI(OCOCF3)2 was the most suitable (Table 1, entry 14-15). In conclusion, the optimized conditions were summarized as: 1a (0.4 mmol), 2a (10 equiv.) and PhI(OCOCF3)2 (1.5 equiv.) in CH2Cl2 at 50 °C under an argon atmosphere. Table 2. Substrate scope with alcoholsa, b N N

N

O

oxidant solvent, t, Ar

1a

N

O

N

O

Oxidant

T(℃ )

Solvent

1 2c 3c 4c 5c 6c 7c 8 9 10 11 12 13 14e 15f

CAN CAN CAN CAN CAN CAN CAN CAN PhI(OAc)2 PhI(OCOCF3)2 IBX K2S2O8 TBPB PhI(OCOCF3)2 PhI(OCOCF3)2

50 50 50 50 50 50 40 50 50 50 50 50 50 50 50

iPrOH

DCM Toluene DMF DCE 1,4-Dioxane DCM DCM DCM DCM DCM DCM DCM DCM DCM

O

N

O 80%

Initially, we investigated the feasibility of CDC reaction by choosing 1-methylquinoxalin-2(1H)-one (1a) as a model substrate, iPrOH as an alkoxy source (2a), and ceric ammonium nitrate (CAN) as an oxidant (Table 1). To our delight, the target product 3a was readily obtained in 77% yield using 1.5 equiv. of CAN and iPrOH itself as solvent at 50 °C (Table 1, entry 1). Other solvents were also screened in the presence of 20 equivalents of iPrOH including CH2Cl2, toluene, DMF, ClCH2CH2Cl and 1,4-dioxane at 50 °C. Reaction in CH2Cl2 afforded 77% yield of target product same as that in iPrOH as both solvent and alkoxy source, which was better than the ones in other solvents (Table 1, entries 2-6). In view of the inconvenience of post processing using highboiling alcohols as solvents, we decided to use CH2Cl2 as selected solvent of this reaction. Subsequently, we tried to perform the reaction at low temperature, however, a lower yield 73% of the target product 3a was received at 40 °C (Table 1, entry 7). Furthermore, reaction under 10 equivalents iPrOH afforded 76% yield of expected product 3a, being only slight decrease compared to that under 20 equivalents iPrOH (Table 1, entry 8). Therefore, we selected 10 equivalents of iPrOH as the suitable loading. Further screening of various oxidants indicated that PhI(OCOCF3)2 was the most appropriate oxidant and the yield of 3a was improved from

3d

N N 3b

OnC7H15

N

71%

N

O

N

O

N 3m

N

O 3i

O O

N

O

O

N

O

73% N O

N

O

81%

O 77%

N

70% N O

O

3n

OnC6H13

N

53%

46%, ee> 99%

O 83%

O

N

O

N

3f

3k

3j 66%

N

O

N

N

O

N

81%

3h

OR3

N

3c

OnC5H11

N

O

N 3g

3e

3a-3o

O 85%, 79% c

N

78%

N R2

O

N

O

N

a Unless specifically noted otherwise, reaction conditions are: 1a (0.4 mmol), 2a (4 mmol), oxidant (0.6 mmol) and solvent (4 mL), stirred at 50 °C under an argon atmosphere about 10 hours. b Yields of isolated product. c 20 equiv. of iPrOH was used. d N. D. = No detected. e 1.3 equiv. of PhI(OCOCF3)2 was used. f 1.7 equiv. of PhI(OCOCF3)2 was used.

CH2Cl2, 50 C, Ar

O nC 4H 9

N

3a

Entry

N

3a

Yield (%)b 77 77 62 68 71 65 73 76 35 80 N. D.d N. D.d N. D.d 55 72

PhI(OTFA)2

+ HOR3 2a-2o

Table 1. Selected reaction conditions optimizationa H + HO O 2a

H

1a

RESULTS AND DISCUSSION N

Page 2 of 8

3l

OH

3o

O 70%

N

O

N

O

36%

Unless specifically noted otherwise, reaction conditions are: 1methylquinoxalin-2(1H)-one 1a (0.4 mmol), 2 (4 mmol), PhI(OCOCF3)2 (0.6 mmol) and DCM (4 mL) at 50 °C under an argon atmosphere. b Yields of isolated product. c A gram-scale. a

With the optimized conditions on hand, we tried to examine the CDC reactions of 1-methylquinoxalin-2(1H)-one (1a) with various alcohols and the results are summarized in Table 2. Initially, primary alcohols from ethanol to n-heptanol were investigated, and the yields of corresponding products were generally high (from 71% to 85%), but decreased slightly along with the carbon chain lengthening (3b-3g). Notably, cyclohexanemethanol and benzyl alcohol as alkoxy sources under the standard conditions also underwent smoothly, affording the corresponding products in excellent yields (3h3i). Subsequently, several secondary alcohols were investigated but generally low yields of the target products were received compared to the corresponding primary alcohols with the same carbon numbers (3j-3k). For cyclohexanol, owing to its cyclic structure with small steric hindrance, the yield of the corresponding product was higher than the corresponding yields in the cases of 2-butanol and 3pentanol (3l). Inspired by these results, we applied this protocol to L-menthol, being a representative of complicated alcohols, and a 46% yield of the target product was received (3m). Thereafter, we selected 1,3-propanediol as a representative of diols, and a yield as high as 81% was obtained under the standard conditions (3n). Finally, some unsaturated alcohols were examined. When pent-2-yn-1-ol was used as the representative of propargyl alcohols, the target product was obtained in 36% yield (3o). But the 3-methylbut2-en-1-ol as the representative of the allyl alcohol failed to give the desired product.


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The Journal of Organic Chemistry In addition, reactions of various quinoxalin-2(1H)-one derivatives (1) with ethanol (2b) were carried out and the results are shown in Table 3. The yields of the corresponding products remained about 80% when the benzyl, methyl acetate and t-butyl acetate N-substituted quinoxalin-2(1H)-ones were used as substrates (3p-3r). Encouraged by these results, we also tested N-SEM protected quinoxalin-2(1H)-one under standard conditions, and a 63% yield of the corresponding product was received (3s). Subsequently, quinoxalin-2(1H)one without protecting group was tested in the reaction and the reaction also proceeded smoothly, providing the expected product in a good yield of 76%. Afterwards, C6 or C7 substituted quinoxalin-2(1H)-ones were investigated. All the substituted substrates, whether the substituents are electronrich or electron-deficient, underwent smoothly to provide the target products in good to excellent yields (3u-3y, 3ac). Besides, substrates with substituents at C5 or C8 also were explored, and the corresponding products were obtained in moderate to good yields (3z-3ab). Next, a series of N-ethyl quinoxalin-2(1H)-ones were also found to be highly matching with the standard conditions, and good yields were achieved in these cases (3ad-3af). Finally, we selected 1methylbenzo[g]quinoxalin-2(1H)-one and 4-ethylpyrido[2,3b]pyrazin-3(4H)-one as respective representatives to screen the compatibility of this method on fused aromatic cycles and polynitrogen heterocycles, and the expected products were successfully isolated in moderate yields (3ag-3ah). Table 3. Substrate scope with quinoxalin-2(1H)-onesa, b H

N R2 N R1

1 N

O

+ C2H5OH 2b

N

O

N

O

3s 63%

Cl O

CH2Cl2, 50 C, Ar

O

N

O

3q 85%

N

Si

O

N

3t

N H

O R 76%

O

N

O

N

O

N

O

Br

3z 82% N

O

N 3ac

O O 80%

N

O

N

O 75%

N

O COOtBu

H

N

+ N

OH

O

1a

standard conditions

N

O

TEMPO (2 equiv.)

N

O

H OH

+ N

O

1a

adduct 4b

3b N.D. 1a recovery :0 %

2b N

+ TEMPO-OCH2CH3 (1)

standard conditions

N

O

BHT (2 equiv.)

N

O

detected by LC-MS

3b N.D. 1a recovery : >99%

2b

+ BHT-OCH2CH3 (2) adduct 5b detected by LC-MS

Based on the aforementioned radical trapping experiments and previous reports19a-b, 21, plausible mechanism about alkoxylation of 1-methylquinoxalin-2(1H)-one with alcohols is proposed in Scheme 3. Initially, PhI(OCOCF3)2 reacts with an alcohol to give I-radical A, alkoxy radical B and trifluoroacetic acid. Subsequently, alkoxy radical B is trapped by substrate 1a to afford the aminyl radical intermediate C (Scheme 3, Path A). In addition, an alternative route to the intermediate C is also feasible (Scheme 3, Path B), namely, in the presence of PhI(OCOCF3)2, the substrate 1a is oxidized to generate the radical cation D, which is captured by nucleophilic alcohols to furnish intermediate E. The key intermediate C is obtained via the deprotonation of intermediate E with the assistance of the trifluoroacetate. Afterwards, the key intermediate C undergoes 1,2-hydrogen shift to produce carbon radical intermediate F, which reacts with I-radical A through a single electron transfer (SET) process to give carbon cation intermediate G, in combination with the release of iodobenzene and trifluoroacetate. Finally, the target product 3 is obtained from deprotonation of intermediate G in the presence of the trifluoroacetate. Scheme 3. Proposed reaction mechanism

N

O

N

O 3ab 60% N

Br

O

N

O

N 3ad 83%

N

O

N

O

F

N

O

N

O

3ag 61%

O

Scheme 2. Radical trapping experiments

Br

F

3af 88%

N

3u : R = Me, 75% 3v : R = F, 88% 3w: R = Cl, 89% 3x : R = COOMe, 75% 3y : R = NO2, 91%

3aa 86%

Br

O

N

3u

N

N 3p-3ah R1

3r 82%

COOMe

O

O

R2



O

O N 3p Bn 78%

N

PhI(OTFA)2

desired product 3b or starting material 1a was observed, instead, TEMPO-OCH2CH3 adduct 4b was detected by LCMS (Scheme 2, equation 1). Besides, when 2.0 equivalent of BHT (2,6-di-tert-butyl-p-cresol), another well-known radical inhibitor, was added under standard conditions, no desired product 3b was detected, but the starting material 1a was almost completely recovered. Moreover, a BHT-captured adduct 5b was also detected by LC-MS (Scheme 2, equation 2). These experiments results indicated that a radical pathway was involved in this transformation.

3ae 74% N

N

N

O O

O

3ah 60%

Unless specifically noted otherwise, reaction conditions are: 1methylquinoxalin-2(1H)-one 1 (0.4 mmol), 2b (4 mmol), PhI(OCOCF3)2 (0.6 mmol) and DCM (4 mL) at 50 °C under an argon atmosphere. b Yields of isolated product.

a

After exploration of the substrate scopes, two radical trapping experiments were carried out to probe the primary mechanism of the C-H alkoxylation reaction. When 2.0 equivalent of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a radical inhibitor was added under the standard reaction system, the desired reaction was completely suppressed. No

OCOCF3 I OCOCF3

N

H

N

O

1a Ph

O

Ph

ROH + 2

Ph

OCOCF3 I OCOCF3

OCOCF3

N

H OR

N

O

+ CF3CHOOH

+ RO B

A

RO Path A

I

1,2-H Shift

H N

OR

N

O

F

C CF3COOH

A

CF3COO

N

H

N

O

D + A + CF3CHOO

ROH Path B

E

N

H H OR

H N

N

O

N O G + PhI + CF3CHOO

OR CF3COO

CF3COOH

N

OR

N

O

3

In summary, we have developed a facile and effective protocol to directly synthesize 3-alkoxylquinoxalin-2(1H)ones with primary or secondary alcohols via CDC reaction under catalyst-free conditions using readily available PhI(OCOCF3)2 as oxidant. The protocol features easy operation, simple reaction system, and broad functional group tolerance, by which a series of potential drug molecules



containing 3-alkoxylquinoxalinone skeletons would be easily achieved in excellent yields.

EXPERIMENTAL SECTION General. All reactions involving air- and moisture-sensitive reagents were carried out under an argon atmosphere. 1H and 13C NMR spectra were recorded on Bruker AC-P 400 spectrometer (400 MHz for 1H and 100 MHz for 13C {1H}) in CDCl3 with TMS as internal standard. Chemical shifts () were measured in ppm relative to TMS  = 0 for 1H, or to chloroform  = 77.0 for 13C as internal standard. Data are reported as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants, J, are reported in hertz. High resolution mass spectra (HRMS) were recorded on quadrupole time of-flight mass spectrometer (Q-TOF-MS) using electrospray ionization (ESI) as an ionization method. Enantiomeric excesses were determined by high performance liquid chromatography (HPLC) with a Shimadzu HPLC system. Optical rotations were measured in CH2Cl2 on an Anton Paar Polarimeter (MCP100) with a 10 cm cell (c given in g/100 mL). Melting points (uncorrected) were obtained on Shanghai Inesa WRS-3 melting point apparatus. The starting materials were purchased from J&K Chemicals or TCI and used without further purification. Some reactions were tried on microreactor (Chemtrix BV, Kilo Flow, Labtrix Start or Protrix) in order to obtain the product in a better yield during the preparation of the substrates. Solvents were dried and purified according to the procedure from “Purification of Laboratory Chemicals book”. Thin-layer chromatography (TLC) was performed using 60 mesh silica gel plates visualized with short-wavelength UV light (254 nm). General procedures for the product 3a. In a dried Schlenk tube, 1 (0.4 mmol) and PhI(OCOCF3)2 (0.6 mmol, 1.5 equiv., 258.0 mg) were added. Then, the tube was evacuated and backfilled with argon for five times. Finally, CH2Cl2 (4.0 mL) and the alcohol (4 mmol) were added in turn via syringes. The mixture was stirred at 50 °C in an oil bath under argon atmosphere. When the substrate was consumed (monitored by TLC), the reaction mixture was cooled to room temperature. The solvent was removed by rotary and the resulting residue was purified by flash column chromatography to afford the final product (3a-3ah). A gram-scale synthesis of 3b. In a dried Schlenk flask, 1a (5 mmol, 0.801g) and PhI(OCOCF3)2 (7.5 mmol, 1.5 equiv., 3.23g) were added. Then, the flask was evacuated and backfilled with argon for five times. Finally, CH2Cl2 (50 mL) and ethanol (50 mmol, 2.30g) were added in turn via syringes. The mixture was stirred at 50 °C in an oil bath under argon atmosphere. When the substrate was consumed (monitored by TLC), the reaction mixture was cooled to room temperature. The solvent was removed by rotary and the resulting residue was purified by flash column chromatography to afford the product 3b in 79% yield (0.81 g, petroleum ether/ethyl acetate = 3:1 as an eluent). Radical trapping experiments. In a dried Schlenk tube, 1a (0.4 mmol, 64.1 mg), the radical inhibitor (TEMPO or BHT) (0.8 mmol, 2 equiv.) and PhI(OCOCF3)2 (0.6 mmol, 1.5 equiv., 258.0 mg) were added. Then, the tube was evacuated and backfilled with argon for five times. Finally, CH2Cl2 (4.0 mL) and the alcohol (4 mmol) were added in turn via syringes. The mixture was stirred at 50 °C in an oil bath under argon atmosphere. After reacting for 12 hours, the mixture was cooled to room temperature. The solvent was removed by rotary and the resulting residue was purified by flash column chromatography. At the same time, a parallel reaction was carried out under the same conditions. After reacting for 4 hours, the mixture was cooled to room temperature

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and detected by LC-MS. 4b: HRMS (ESI): m/z calcd for C11H24NO2 [M+H]+ 202.1802, found 202.1808; 5b: HRMS (ESI): m/z calcd for C17H28NaO2 [M+Na]+ 287.1982, found 287.1982. Characterization of the products. 3-isopropoxy-1methylquinoxalin-2(1H)-one (3a): 80% yield (69.8 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), gray solid, m. p. = 9698 °C. 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, J = 7.9 Hz, 1H), 7.41-7.37 (m, 1H), 7.30-7.23 (m, 2H), 5.53-5.44 (m, 1H), 3.71 (s, 3H), 1.46 (d, J = 6.2 Hz, 6H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.4, 151.4, 131.4, 131.3, 127.4, 126.7, 123.8, 113.3, 70.4, 29.5, 21.6; HRMS (ESI): m/z calcd for C12H14N2O2Na [M+Na]+ 241.0947, found 241.0950. 3-ethoxy-1-methylquinoxalin-2(1H)-one (3b): 85% yield (69.4 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), white solid, m. p. = 126-128 °C. 1H NMR (400 MHz, CDCl3) δ: 7.64-7.61 (m, 1H), 7.43-7.39 (s, 1H), 7.31-7.25 (m, 2H), 4.58-4.53 (m, 2H), 3.73 (s, 3H), 1.51-1.48 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.6, 151.0, 131.3, 131.0, 127.3, 126.6, 123.6, 113.3, 63.2, 29.2, 13.9; HRMS (ESI): m/z calcd for C11H12N2O2Na [M+Na]+ 227.0791, found 227.0788. 1-methyl-3-propoxyquinoxalin-2(1H)-one (3c): 83% yield (72.4 mg, petroleum ether/ethyl acetate = 4:1 as an eluent), white solid, m. p. = 91-93 °C. 1H NMR (400 MHz, CDCl3) δ: 7.62 (d, J = 7.9 Hz, 1H), 7.42-7.39 (m, 1H), 7.32-7.25 (m, 2H), 4.45-4.42 (m, 2H), 3.73 (s, 3H), 1.97-1.88 (m, 2H), 1.08-1.04 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.1, 151.2, 131.6, 131.3, 127.5, 126.9, 123.9, 113.6, 69.1, 29.5, 21.8, 10.5; HRMS (ESI): m/z calcd for C12H14N2O2Na [M+Na]+ 241.0947, found 241.0949. 3-butoxy-1-methylquinoxalin-2(1H)-one (3d): 78% yield (72.4 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), light yellow solid, m. p. = 63-65 °C. 1H NMR (400 MHz, CDCl3) δ: 7.63 (d, J = 7.9 Hz, 1H), 7.42-7.38 (m, 1H), 7.32-7.25 (m, 2H), 4.50-4.46 (m, 2H), 3.72 (s, 3H), 1.91-1.84 (m, 2H), 1.56-1.47 (m, 2H), 1.010.97 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.1, 151.2, 131.5, 131.2, 127.5, 126.9, 123.9, 113.6, 67.4, 30.5, 29.4, 19.2, 13.8; HRMS (ESI): m/z calcd for C13H16N2O2Na [M+Na]+ 255.1104, found 255.1106. 1-methyl-3-(pentyloxy)quinoxalin-2(1H)-one (3e): 81% yield (79.7 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 65-67 °C. 1H NMR (400 MHz, CDCl3) δ: 7.63-7.61 (m, 1H), 7.42-7.38 (m, 1H), 7.31-7.24 (m, 2H), 4.49-4.45 (m, 2H), 3.72 (s, 3H), 1.91-1.86 (m, 2H), 1.46-1.36 (m, 4H), 0.95-0.91 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.1, 151.2, 131.5, 131.1, 127.5, 126.8, 123.9, 113.6, 67.7, 29.4, 28.2, 28.1, 22.4, 14.0; HRMS (ESI): m/z calcd for C14H18N2O2Na [M+Na]+ 269.1260, found 269.1262. 3-(hexyloxy)-1-methylquinoxalin-2(1H)-one (3f): 77% yield (80.1 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 47-48 °C. 1H NMR (400 MHz, CDCl3) δ: 7.63 (d, J = 7.8 Hz, 1H), 7.43-7.39 (m, 1H), 7.32-7.25 (m, 2H), 4.48-4.45 (m, 2H), 3.73 (s, 3H), 1.92-1.85 (m, 2H), 1.49-1.33 (m, 6H), 0.920.90 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.1, 151.2, 131.5, 131.3, 127.5, 126.9, 123.9, 113.6, 67.7, 31.5, 29.5, 28.5, 25.6, 22.6, 14.0; HRMS (ESI): m/z calcd for C15H20N2O2Na [M+Na]+ 283.1417, found 283.1418. 3-(heptyloxy)-1-methylquinoxalin-2(1H)-one (3g): 71% yield (77.9 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 37-38 °C. 1H NMR (400 MHz, CDCl3) δ: 7.64-7.62 (m, 1H), 7.43-7.39 (m, 1H), 7.32-7.25 (m, 2H), 4.50-4.46 (m, 2H), 3.73 (s, 3H), 1.94-1.87 (m, 2H), 1.52-1.27 (m, 10H), 0.92-0.88 (m,


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The Journal of Organic Chemistry 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.1, 150.1, 130.5, 130.2, 126.5, 125.8, 122.9, 112. 6, 66.7, 30.7, 28.4, 28.0, 27.5, 24.9, 21.6, 13.1; HRMS (ESI): m/z calcd for C16H22N2O2Na [M+Na]+ 297.1573, found 297.1570. 3-(cyclohexylmethoxy)-1-methylquinoxalin-2(1H)-one (3h): 70% yield (76.2 mg, petroleum ether/ethyl acetate = 4:1 as an eluent), white solid, m. p. = 93-94 °C. 1H NMR (400 MHz, CDCl3) δ: 7.62 (d, J = 7.7 Hz, 1H), 7.41-7.38 (m, 1H), 7.31-7.23 (m, 2H), 4.27 (d, J = 6.5 Hz, 2H), 3.71 (s, 3H), 1.99-1.90 (m, 3H), 1.77-1.68 (m, 3H), 1.34-1.19 (m, 3H), 1.12-1.04 (m, 2H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.2, 151.1, 131.6, 131.3, 127.5, 126.8, 123.9, 113.6, 72.7, 36.9, 29.9, 29.4, 26.5, 25.7; HRMS (ESI): m/z calcd for C16H20N2O2Na [M+Na]+ 295.1417, found 295.1421. 3-(benzyloxy)-1-methylquinoxalin-2(1H)-one (3i): 73% yield (77.7 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 148-150 °C. 1H NMR (400 MHz, CDCl3) δ: 7.667.64 (m, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.43-7.24 (m, 6H), 5.55 (s, 2H), 3.71 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.6, 151.1, 136.0, 131.7, 131.0, 128.6, 128.4, 127.6, 127.2, 124.0, 113.6, 68.8, 29.5; HRMS (ESI): m/z calcd for C16H14N2O2Na [M+Na]+ 289.0947, found 289.0943. 3-(sec-butoxy)-1-methylquinoxalin-2(1H)-one (3j): 66% yield (61.3 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), gray solid, m. p. = 98-99 °C. 1H NMR (400 MHz, CDCl3) δ: 7.61 (d, J = 7.8 Hz, 1H), 7.41-7.38 (m, 1H), 7.31-7.24 (m, 2H), 5.34-5.28 (m, 1H), 3.72 (s, 3H), 1.96-1.85 (m, 1H), 1.79-1.68 (m, 1H), 1.42 (d, J = 6.2 Hz, 3H), 1.02-0.98 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.6, 151.4, 131.4, 127.4, 126.7, 123.9, 113.6, 75.2, 29.5, 28.7, 19.1, 10.0; HRMS (ESI): m/z calcd for C13H17N2O2 [M+H]+ 233.1285, found 233.1287. 1-methyl-3-(pentan-3-yloxy)quinoxalin-2(1H)-one (3k): 53% yield (52.2 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), gray solid, m. p. = 75-77 °C. 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, J = 7.8 Hz, 1H), 7.41-7.37 (m, 1H), 7.31-7.24 (m, 2H), 5.295.23 (m, 1H), 3.73 (s, 3H), 1.87-1.74 (m, 4H), 1.00-0.96 (m, 1H); 13C {1H} NMR (101 MHz, CDCl ) δ: 154.0, 151.4, 131.4, 131.4, 3 127.4, 126.6, 123.8, 113.5, 79.7, 29.5, 26.1, 9.8; HRMS (ESI): m/z calcd for C14H18N2O2Na [M+Na]+ 269.1260, found 269.1261. 3-(cyclohexyloxy)-1-methylquinoxalin-2(1H)-one (3l): 70% yield (72.3 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 97-98 °C. 1H NMR (400 MHz, CDCl3) δ: 7.61 (d, J = 7.9 Hz, 1H), 7.41-7.37 (m, 1H), 7.30-7.24 (m, 2H), 5.255.18 (m, 1H), 3.72 (s, 3H), 2.12-2.09 (m, 2H), 1.87-1.84 (m, 2H), 1.71-1.62 (m, 2H), 1.50-1.26 (m, 4H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.4, 151.4, 131.5, 131.4, 127.4, 126.7, 123.8, 113.5, 75.6, 31.4, 29.5, 25.5, 24.2; HRMS (ESI): m/z calcd for C15H18N2O2Na [M+Na]+ 281.1260, found 281.1266. 3-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-1methylquinoxalin-2(1H)-one (3m): 46% yield (57.8 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 116-117 °C. 1H NMR (400 MHz, CDCl3) δ: 7.65-7.62 (m, 1H), 7.42-7.38 (m, 1H), 7.32-7.25 (m, 2H), 5.28-5.21 (m, 1H), 3.73 (s, 3H), 2.25-2.22 (m, 1H), 2.11-2.05 (m, 1H), 1.79-1.74 (m, 3H), 1.64-1.58 (m, 1H), 1.27-1.13 (m, 3H), 0.97-0.91 (m, 6H), 0.80 (d, J = 7.0 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 152.6, 150.3, 130.4, 130.3, 126.4, 125.6, 122.7, 112.5, 46.0, 39.0, 33.4, 30.5, 28.4, 25.1, 22.5, 21.1, 19.7, 15.4; HRMS (ESI): m/z calcd for C19H26N2O2Na [M+Na]+ 337.1886, found 337.1881. HPLC: a Chiralcel AS-H column (n-hexane/i-PrOH, 80:20, flow rate = 1 mL/min, λ =254 nm), tR (major) = 3.943 min, tR (minor) = 4.490 min; ee > 99%, [α]D25 -109.6 (c 0.10, CH2Cl2).

3-(3-hydroxypropoxy)-1-methylquinoxalin-2(1H)-one (3n): 81% yield (75.8 mg, petroleum ether/ethyl acetate = 1:2 as an eluent), colourless oil. 1H NMR (400 MHz, CDCl3) δ: 7.63-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.33-7.27 (m, 2H), 4.71-4.68 (m, 2H), 3.813.78 (m, 2H), 3.73 (s, 3H), 2.45 (s, 1H), 2.15-2.09 (m, 2H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.2, 151.1, 131.6, 130.7, 127.4, 127.3, 124.2, 113.7, 64.9, 59.3, 31.8, 29.6; HRMS (ESI): m/z calcd for C12H14N2O3Na [M+Na]+ 257.0897, found 257.0897. 1-methyl-3-(pent-2-yn-1-yloxy)quinoxalin-2(1H)-one (3o): 36% yield (34.9 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), yellow solid, m. p. = 107-109 °C. 1H NMR (400 MHz, CDCl3) δ: 7.66-7.64 (m, 1H), 7.44-7.40 (m, 1H), 7.32-7.25 (m, 2H), 5.08 (t, J = 2.0 Hz, 2H), 3.71 (s, 3H), 2.26-2.20 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 151.8, 149.8, 130.7, 129.8, 126.7, 126.3, 122.9, 112.6, 88.2, 72.5, 54.6, 28.5, 12.5, 11.5; HRMS (ESI): m/z calcd for C14H14N2O2Na [M+Na]+ 265.0947, found 265.0947. 1-benzyl-3-ethoxyquinoxalin-2(1H)-one (3p): 78% yield (87.4 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 145-146 °C. 1H NMR (400 MHz, CDCl3) δ: 7.64-7.62 (m, 1H), 7.33-7.19 (m, 8H), 5.52 (s, 2H), 4.61-4.55 (m, 2H), 1.551.52 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.0, 151.4, 135.2, 131.5, 130.8, 128.9, 127. 7, 127.7, 127.0, 126.9, 123.9, 114.5, 63.6, 46.2, 14.2; HRMS (ESI): m/z calcd for C17H17N2O2 [M+H]+ 281.1285, found 281.1289. methyl 2-(3-ethoxy-2-oxoquinoxalin-1(2H)-yl)acetate (3q): 85% yield (89.1 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 140-142 °C. 1H NMR (400 MHz, CDCl3) δ: 7.64 (d, J = 7.6 Hz,1H), 7.39-7.27 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 5.07 (s, 2H), 4.59-4.54 (m, 2H), 3.77 (s, 3H), 1.52-1.49 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 167.6, 153.6, 151.0, 131.3, 130.7, 127.9, 127.1, 124.3, 113.0, 63.7, 52.8, 43.7, 14.2; HRMS (ESI): m/z calcd for C13H14N2O4Na [M+Na]+ 285.0846, found 285.0848. tert-butyl 2-(3-ethoxy-2-oxoquinoxalin-1(2H)-yl)acetate (3r): 82% yield (99.8 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 118-119 °C. 1H NMR (400 MHz, CDCl3) δ: 7.63 (d, J = 7.8 Hz,1H), 7.38-7.27 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 4.96 (s, 2H), 4.58-4.53 (m, 2H), 1.52-1.48 (m, 3H), 1.45 (s, 9H); 13C {1H} NMR (101 MHz, CDCl3) δ: 166.0, 153.7, 150.9, 131.3, 130.8, 127.8, 127.0, 124.1, 113.1, 83.1, 63.6, 44.5, 28.0, 14.2; HRMS (ESI): m/z calcd for C16H20N2O4Na [M+Na]+ 327.1315, found 327.1317. 3-ethoxy-1-((2-(trimethylsilyl)ethoxy)methyl)quinoxalin-2(1H)one (3s): 63% yield (80.7 mg, petroleum ether/ethyl acetate = 8:1 as an eluent), colourless oil. 1H NMR (400 MHz, CDCl3) δ: 7.61 (d, J = 7.9 Hz,1H), 7.51 (d, J = 8.3 Hz, 1H), 7.41-7.37 (m, 1H), 7.32-7.28 (m, 1H), 5.76 (s, 2H), 4.58-4.53 (m, 2H), 3.72-3.68 (m, 2H), 1.54-1.50 (m, 3H), 0.97-0.93 (m, 2H), -0.03 (s, 9H); 13C {1H} NMR (101 MHz, CDCl3) δ: 155.1, 153.0, 132.6, 131.7, 128.8, 128.4, 125.6, 116.4, 73.3, 68.5, 65.2, 19.5, 15.6, 0.0; HRMS (ESI): m/z calcd for C16H24N2O3Si [M+Na]+ 343.1448, found 343.1452. 3-ethoxyquinoxalin-2(1H)-one (3t): 76% yield (57.8 mg, petroleum ether/ethyl acetate = 1:1 as an eluent), white solid, m. p. = 200-201 °C. 1H NMR (400 MHz, CDCl3) δ: 11.76 (s, 1H), 7.62 (d, J = 7.8 Hz,1H), 7.37-7.27 (m, 3H), 4.63-4.58 (m, 2H), 1.551.52 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.2, 152.6, 131.4, 129.2, 127.0, 126.7, 124.4, 115.7, 63.7, 14.2; HRMS (ESI): m/z calcd for C10H11N2O2 [M+H]+ 191.0815, found 191.0819.



3-ethoxy-1,7-dimethylquinoxalin-2(1H)-one (3u): 75% yield (65.4 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), white solid, m. p. = 146-147 °C. 1H NMR (400 MHz, CDCl3) δ: 7.50 (d, J = 7.1 Hz, 1H), 7.12-7.05 (m, 2H), 4.55-4.52 (m, 2H), 3.70 (s, 3H), 2.48 (s, 3H), 1.50-1.47 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.3, 151.3, 137.2, 131.3, 129.1, 127.2, 125.0, 113.9, 63.3, 29.4, 21.8, 14.2; HRMS (ESI): m/z calcd for C12H14N2O2Na [M+Na]+ 241.0947, found 241.0949. 3-ethoxy-7-fluoro-1-methylquinoxalin-2(1H)-one (3v): 88% yield (78.1 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), white solid, m. p. = 171-173 °C. 1H NMR (400 MHz, CDCl3) δ: 7.60-7.56 (m, 1H), 7.03-6.94 (m, 2H), 4.55-4.50 (m, 2H), 3.68 (s, 3H), 1.51-1.47 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 161.2 (d, J = 244.8 Hz), 153.2 (d, J = 2.1Hz), 151.1, 132.6 (d, J = 11.0 Hz), 128.9 (d, J = 9.9 Hz), 127.7 (d, J = 2.1 Hz), 111.3 (d, J = 23.0 Hz), 100.8 (d, J = 27.8 Hz), 63.5, 29.7, 14.2; HRMS (ESI): m/z calcd for C11H11N2O2FNa [M+Na]+ 245.0701, found 245.0701. 7-chloro-3-ethoxy-1-methylquinoxalin-2(1H)-one (3w): 89% yield (84.7 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), white solid, m. p. = 173-174 °C. 1H NMR (400 MHz, CDCl3) δ: 7.53 (d, J = 8.9 Hz, 1H), 7.25 (d, J = 9.0 Hz, 2H), 4.56-4.51 (m, 2H), 3.69 (s, 3H), 1.51-1.48 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.9, 150.9, 132.5, 132.4, 129.8, 128.5, 124.1, 113.7, 63.7, 29.6, 14.1; HRMS (ESI): m/z calcd for C11H11N2O2ClNa [M+Na]+ 261.0401, found 261.0405. methyl 2-ethoxy-4-methyl-3-oxo-3,4-dihydroquinoxaline-6carboxylate (3x): 75% yield (78.8 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), white solid, m. p. = 169-171 °C. 1H NMR (400 MHz, CDCl3) δ: 8.30 (d, J = 1.6 Hz, 1H), 8.06 (dd, J = 1.6 Hz, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.56 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.74 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 166.3, 154.3, 151.1, 134.9, 130.8, 129.2, 127.9, 125.8, 113.6, 63.8, 52.3, 29.8, 14.1; HRMS (ESI): m/z calcd for C13H14N2O4Na [M+Na]+ 285.0846, found 285.0846. 3-ethoxy-1-methyl-7-nitroquinoxalin-2(1H)-one (3y): 91% yield (90.7 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), light yellow solid, m. p. = 183-185 °C. 1H NMR (400 MHz, CDCl3) δ: 8.47 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 155.1, 150.8, 143.7, 136.3, 131.0, 123.0, 121.7, 114.1, 64.4, 30.1, 14.1; HRMS (ESI): m/z calcd for C11H11N3O4Na [M+Na]+ 272.0642, found 272.0632 8-chloro-3-ethoxy-1-methylquinoxalin-2(1H)-one (3z): 82% yield (78.4 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), light yellow solid, m. p. = 171-172 °C. 1H NMR (400 MHz, CDCl3) δ: 7.39 (d, J = 8 Hz 1H), 7.32-7.28 (m, 1H), 7.16 (d, J = 8 Hz 1H), 4.63 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.9, 150.8, 132.8, 132.0, 128.2, 126.8, 124.8, 112.4, 64.1, 29.9, 14.0; HRMS (ESI): m/z calcd for C11H11ClN2O2Na [M+Na]+ 261.0401, found 261.0402. 8-bromo-3-ethoxy-1-methylquinoxalin-2(1H)-one (3aa): 86% yield (97.7 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), light yellow solid, m. p. = 157-159 °C. 1H NMR (400 MHz, CDCl3) δ: 7.55-7.52 (m, 1H), 7.22-7.16 (m, 2H), 4.60 (q, J = 7.2 Hz, 2H), 3.68 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.9, 150.8, 132.6, 129.1, 127.9, 127.2,

122.7, 113.1, 64.2, 29.9, 14.0; HRMS (ESI): m/z calcd for C11H11BrN2O2Na [M+Na]+ 304.9896, found 304.9896. 5-bromo-3-ethoxy-1-methylquinoxalin-2(1H)-one (3ab): 60% yield (68.1 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), yellow solid, m. p. = 138-140 °C. 1H NMR (400 MHz, CDCl3) δ: 7.64-7.62 (m, 1H), 7.56-7.52 (m, 1H), 7.12-7.08 (m, 1H), 4.54 (q, J = 7.2 Hz, 2H), 4.04 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.7, 152.5, 134.2, 134.0, 131.3, 127.5, 124.7, 107.1, 63.6, 37.1, 14.1; HRMS (ESI): m/z calcd for C11H11BrN2O2Na [M+Na]+ 304.9896, found 304.9896. methyl 3-ethoxy-1-methyl-2-oxo-1,2-dihydroquinoxaline-6carboxylate (3ac): 80% yield (83.8 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), white solid, m. p. = 171-173 °C. 1H NMR (400 MHz, CDCl3) δ: 7.96-7.93 (m, 2H), 7.64 (d, J = 8 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.76 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 166.4, 155.3, 151.0, 134.7, 131.4, 128.2, 127.4, 124.9, 115.3, 64.0, 52.5, 29.7, 14.1; HRMS (ESI): m/z calcd for C13H14N2O4Na [M+Na]+ 285.0846, found 285.0847 6-bromo-3-ethoxy-1-ethylquinoxalin-2(1H)-one (3ad): 83% yield (98.3 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), white solid, m. p. = 128-130 °C. 1H NMR (400 MHz, CDCl3) δ: 7.48 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 11.1 Hz, 2H), 4.55-4.50 (m, 2H), 4.32-4.26 (m, 2H), 1.51-1.48 (m, 3H), 1.40-1.36 (m, 3H); 13C {1H} NMR (101 MHz, CDCl ) δ: 154.0, 150.4, 131.5, 130.6, 3 129.1, 126.9, 120.3, 116.4, 63.7, 37.8, 14.1, 12.3; HRMS (ESI): m/z calcd for C12H13N2O2BrNa [M+Na]+ 319.0053, found 319.0057. 6-bromo-3-ethoxy-1-ethyl-7-methylquinoxalin-2(1H)-one (3ae): 74% yield (91.8 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), yellow solid, m. p. = 105-107 °C. 1H NMR (400 MHz, CDCl3) δ: 7.48 (s, 1H), 7.43 (s, 1H), 4.54-4.48 (m, 2H), 4.30-4.24 (m, 2H), 2.44 (s, 3H), 1.51-1.48 (m, 3H), 1.38-1.35 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.1, 150.3, 133.3, 130.7, 129.3, 129.0, 123.0, 116.8, 63.6, 37.8, 22.3, 14.1, 12.3; HRMS (ESI): m/z calcd for C13H15N2O2BrNa [M+Na]+ 333.0209, found 333.0212. 3-ethoxy-1-ethyl-6,7-difluoroquinoxalin-2(1H)-one (3af): 88% yield (89.5 mg, petroleum ether/ethyl acetate = 3:1 as an eluent), yellow solid, m. p. = 185-186 °C. 1H NMR (400 MHz, CDCl3) δ: 7.46-7.41 (m, 1H), 7.10-7.05 (m, 1H), 4.54-4.48 (m, 2H), 4.294.24 (m, 2H), 1.51-1.48 (m, 3H), 1.39-1.35 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 154.1, 150.4 (d, J = 14.8 Hz), 150.2, 148.0 (d, J = 14.8 Hz), 145.5 (d, J = 13.7 Hz), 127.6 (d, J = 86.7 Hz), 115.5 (d, J = 18.5 Hz), 102.2 (d, J = 23.0 Hz), 63.8, 38.3, 14.1, 12.2; HRMS (ESI): m/z calcd for C12H12N2O2F2Na [M+Na]+ 277.0759, found 277.0765. 3-ethoxy-1-methylbenzo[g]quinoxalin-2(1H)-one (3ag): 61% yield (62.0 mg, petroleum ether/ethyl acetate = 5:1 as an eluent), white solid, m. p. = 137-139 °C. 1H NMR (400 MHz, CDCl3) δ: 8.06 (s, 1H), 7.89-7.85 (m, 2H), 7.51-7.43 (m, 3H), 4.61-4.55 (m, 2H), 3.75 (s, 3H), 1.55-1.51 (m, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ: 153.6, 151.3, 131.8, 130.9, 130.7, 130.1, 127.6, 127.2, 126.5, 125.3, 125.2, 110.1, 63.6, 29.5, 14.2; HRMS (ESI): m/z calcd for C15H14N2O2Na [M+Na]+ 277.0947, found 277.0950. 2-ethoxy-4-ethylpyrido[2,3-b]pyrazin-3(4H)-one (3ah): 60% yield (52.6 mg, petroleum ether/ethyl acetate = 8:1 as an eluent), yellow solid, m. p. = 83-84 °C. 1H NMR (400 MHz, CDCl3) δ: 8.43-8.42 (m, 1H), 7.91-7.88 (m, 1H), 7.27-7.23 (m, 1H), 4.594.53 (m, 4H), 1.53-1.50 (m, 3H), 1.38-1.35 (m, 3H); 13C {1H}


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The Journal of Organic Chemistry NMR (101 MHz, CDCl3) δ: 154.6, 151.6, 146.0, 142.2, 134.5, 127.0, 119.6, 63.9, 36.7, 14.1, 12.9; HRMS (ESI): m/z calcd for C11H13N3O2Na [M+Na]+ 242.0900, found 242.0903.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. HPLC Chromatograms for the product 3m, copies of 1H and 13C {1H} NMR spectra for all products. (PDF)

AUTHOR INFORMATION Corresponding Author *Email:[email protected]; [email protected]

Author Contributions ⊥Q.

Yang and X. Han contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We acknowledge the financial support from the National Natural Science Foundation of China (Grant No. 21776056), the Natural Science Foundation of Hebei Province (CN) (Grant No. B2018202253) and the Program for the Top Young Innovative Talents of Hebei Province (CN) (Grant No. BJ2017010).

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