Direct C?H Trifluoromethylation of Quinoxalin-2(1H)-ones under Transition-Metal-Free Conditions

Title: Direct C-H Trifluoromethylation of Quinoxalin-2(1H)-ones under

Transition-Metal-Free Conditions

Authors: Liping Wang, yuecheng Zhang, Fanfan Li, Xinyu Hao, Hong-

Yu Zhang, and Jiquan Zhao

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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800863

Link to VoR: http://dx.doi.org/10.1002/adsc.201800863

10.1002/adsc.201800863

Advanced Synthesis & Catalysis

FULL PAPER

DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Direct C-H Trifluoromethylation of Quinoxalin-2(1H)-ones

under Transition-Metal-Free Conditions

Liping Wang,^aYuecheng Zhang,^{a, b}Fanfan Li,^aXinyu Hao,^aHong-Yu Zhang^a* and

Jiquan Zhao^a*

a

School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300130, PR China.

Phone: 86-22-60204726, E-mail: zhanghy@hebut.edu.cn; jqzhao@hebut.edu.cn

National-Local Joint Engineering Laboratory for Energy Conservation of Chemical Process Integration and Resources

b

Utilization, Hebei University of Technology, Tianjin 300130, PR China.

Received: ((will be filled in by the editorial staff))

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please

delete if not appropriate))

Abstract.

Disclosed

herein

is

a

direct

C-H catalysts, mild reaction conditions and high functional

trifluoromethylation of quinoxalin-2(1H)-ones with sodium group tolerance, which promises a convenient and efficient

trifluoromethanesulfinate. This protocol affords a series of 3- access to pharmaceutically interesting quinoxalinones.

trifluoromethylquinoxalin-2(1H)-one derivatives in moderate

to excellent yields under transition-metal-free conditions.

The present methodology features utilization of the

inexpensive trifluoromethyl source without transition-metal-

Keywords: C-H Trifluoromethylation; Transition-Metal-

Free; Sodium trifluoromethanesulfinate; Quinoxalin-2(1H)-

ones

trifluoromethyl in the 3-position of quinoxalin-2(1H)-

ones with various functional groups, which would

promise its applications in new drug discovery and

synthesis.

Introduction

The quinoxalin-2(1H)-one skeleton is a crucially

structural motif widely distributed in natural products

as well as pharmaceutical molecules.^[1]Owing to their

remarkable properties, extensive efforts have been

devoted to the preparation of diverse 3-substituted

quinoxalin-2(1H)-ones. For instance, one of the

conventional strategy involves construction of the

heterocycle from 1,2-diaminobenzenes (Scheme 1,

strategy a).^[2]The other classical strategy is

functionalization of 3-haloquinoxalin-2(1H)-ones via

transition-metal-catalyzed cross-coupling reactions

(Scheme 1, strategy b).^[3]However, several

limitations still remain in the aforementioned

strategies, including the requirement of pre-

functionalized starting materials, poor atom economy

and harsh reaction conditions. In contrast, the direct

strategy for modification of available quinoxalin-

2(1H)-ones has recently emerged as an efficient and

ideal approach to 3-substituted quinoxalin-2(1H)-

ones. But, only a handful of types of direct

functionalization of quinoxalin-2(1H)-ones have been

achieved, including C₃-H arylation^[4], alkylation^[5],

acylation^[6], phosphonation^[7]and amination^[8]of

quinoxalin-2(1H)-ones (Scheme 1, strategy c).

Despite the significance of the achievements, the

direct C₃-H trifluoromethylation of quinoxalin-2(1H)-

ones remains scarce. Due to importance of 3-

Scheme 1. Different strategies for synthesis of 3-

substituted quinoxalin-2(1H)-ones.

The trifluoromethyl group has raised widespread

concerns in pharmaceutical and agrochemical fields

because of its outstanding performance in altering the

trifluoromethyl-quinoxalin-2(1H)-one derivatives^[1a-b]

it is urgent in demand to conveniently embed the

,

1

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Advanced Synthesis & Catalysis

lipophilicity, metabolic activity, and bioavailability of

potential drug candidates.^[9]Therefore, several

versatile trifluoromethyl reagents, such as Togni’s

reagent^[10], Umemoto’s reagent^[11], Ruppert-Prakash

reagent^[12]and Langlois reagent^[13], have been

invented for the incorporation of trifluoromethyl into

nominated pharmaceutical molecules, especially

improved to 80% by using of 3 equiv of CF₃SO₂Na

(Table 1, entry 14). The screening of reaction

temperature showed room temperature was optimal.

Finally, a survey of different solvents indicated that

CH₃CN was more suitable than EtOAc and DMF

(Table 1, entries 14-16). Overall, the reaction

proceeded efficiently in the presence of 1a (0.3

mmol), CF₃SO₂Na (3.0 equiv.) and PhI(OTFA)₂(3.0

equiv.) in CH₃CN (3.0 mL) at room temperature.

heteroarenes^[14]

and

N,N-dialkylhydrazones^[15]

.

Among these trifluoromethyl reagents, Langlois

reagent takes the advantage of the low cost, good

stability, easily handing and high efficiency.

Consequently, a series of significant methodologies

using Langlois reagent as the trifluoromethyl source

have been accomplished.^[16]However, most of the

reaction systems involve transition-metal-catalysts

which are costly, toxic and recognized as undesirable

residual impurities in pharmaceutical products.

Recently, hypervalent iodine oxidants have drawn

extensive attention due to their low toxicity and high

reactivity.^[17]Hence, with the purpose of establishing

an economical and transition-metal-free method for

the synthesis of 3-trifluoromethylquinoxalinones, we

envision that sodium trifluoromethanesulfinate is the

Table 1. Selected reaction conditions optimization.^a)

1a/2a/

Oxidant

1/2/2

1/2/2.5

1/2/3

1/2/3.5

1/3/3

Yield

(%)^b)

51

15

59

Entry

Oxidant

Solvent

1^c)

2^c)

3^c)

4

5

6

7

8

9

10

11

12

13

14

15

TBHP

K₂S₂O₈

PhI(OTFA)₂

TBHP

CH₃CN

49

K₂S₂O₈

trace

58

ideal

trifluoromethyl

source

with

PhI(OTFA)₂

PhI(OAc)₂

CHP^e)

CH₃CN N. D.^d)

[bis(trifluoroacetoxy)iodo]benzene (PhI(OTFA)₂) as

the oxidant. To the best of our knowledge, there is no

precedent for a direct C-H trifluoromethylation of

quinoxalin-2(1H)-ones.

CH₃CN

EtOAc

DMF^f

37

N. D.

68

75

66

80

69

41

TBPB

DTBP

PhI(OTFA)₂

Results and Discussion

We started our research with 1-methylquinoxalin-

2(1H)-one (1a) as the model substrate and CF₃SO₂Na

(2a) as the trifluoromethyl source. Referring to our

recent works on difunctionalization of alkenes

involving CF₃SO₂Na^[18], our initial experiments were

performed with tert-butyl hydroperoxide (TBHP,

70% solution in H₂O), K₂S₂O₈or PhI(OTFA)₂as the

oxidant in the present of Mn(OAc)₂▪4H₂O (20

mol %). As expected, the target molecule was

obtained in 59% yield when PhI(OTFA)₂was used as

the oxidant (Table 1, entry 3). K₂S₂O₈and TBHP also

promoted the transformation but were not as efficient

as PhI(OTFA)₂(Table 1, entries 1-2). Considering our

purpose of transition-metal-free conditions, we

demonstrated the parallel experiments in the absence

of Mn(OAc)₂▪4H₂O. To our delight, TBHP or

PhI(OTFA)₂itself was found to be sufficient to

prompt the transformation without an apparent

decrease in yield (Table 1, entries 4, 6). Inspired by

this result, we screened other oxidants and found that

PhI(OTFA)₂was still the best. As results showed,

cumyl hydroperoxide (CHP) was less effective than

PhI(OTFA)₂, and the other oxidants including

PhI(OAc)₂, tert-butyl peroxybenzoate (TBPB) and di-

tert-butyl peroxide (DTBP) were invalid for this

reaction (Table 1, entries 7-10). Then the loading of

PhI(OTFA)₂was further evaluated. 3 equiv of

PhI(OTFA)₂was appropriate for the reaction and the

yield of 3a increased to 75% (Table 1, entries 11-13).

Subsequently, the yield of desired product was

16

a)

Unless specifically noted otherwise, reaction conditions:

1a (0.3 mmol), 2a, oxidant and solvent (3 mL), stirred at

room temperature under an argon atmosphere. ^b)Yield of

isolated product. In the present of Mn(OAc)₂▪4H₂O (20

mol %). N. D. = No detected. Cumyl hydroperoxide

c)

d)

e)

f)

(contains ca. 20% aromatic hydrocarbon).

dimethylformamide.

N, N-

After the optimal conditions were established, we

examined the substrate scope of this reaction by using

different quinoxalin-2(1H)-one derivatives (1a-1w)

and 2H-benzo[b][1,4]oxazin-2-one (1x) (Table 2).

Initial studies were focused on a series of quinoxalin-

2(1H)-ones with different N-protecting groups and

they were all suitable substrates, affording the

anticipated products in good to excellent yields (3a-

3e). When quinoxalin-2(1H)-one (1f) was chosen as

the substrate, due to its poor solubility, the result was

disappointing. But the yield of 3f was improved from

20% to 64% by replacing CH₃CN with DMF.

Subsequently, various quinoxalin-2(1H)-ones with

electron-donating or electron-withdrawing groups on

the 7-position of quinoxalin-2(1H)-ones were tested.

The substrates bearing electron-donating or

moderately electron-withdrawing groups engaged in

this reaction efficiently, affording the corresponding

products in good yields (3g, 3h and 3k).

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Advanced Synthesis & Catalysis

Unfortunately, for the strongly electron-deficient

substrates, the corresponding products were provided

in moderate yields (3i and 3m). When investigating

the quinoxalin-2(1H)-ones with different groups on

the 6-position, we observed similar results that the

substrates bearing CF₃or F substituent furnished the

desired products in higher yields compared with the

substrates bearing CN or Br substituent (3n-3q).

Moreover, reaction could also proceed smoothly in

the case of 5-chloro-1-methylquinoxalin-2(1H)-one

(1r) as the substrate and the corresponding 3-

trifluoromethylated product was obtained in 61%

yield (3r). In addition, disubstituted quinoxalin-

2(1H)-ones were also used as substrates and the

expected products were received in moderate to good

yields (3s-3w). In general ， our protocols have

several advantages. Firstly, halogen moieties for

further functionalization, including F, Cl and Br,

were tolerated well with moderate to good yields (3k,

3l, 3p-3r and 3t-3w). Additionally, characteristic

functional groups such as CF_3,CN and NO₂were

compatible in this transformation (3h, 3i and 3m-3o).

Encouraged by these results on quinoxalin-2(1H)-

ones, we further tested 2H-benzo[b][1,4]oxazin-2-one

(1x) under the standard conditions, and found that the

After the test of substrate scope, several control

experiments were carried out to elucidate the

preliminary mechanism of this transformation

(Scheme 2). The transform was completely

suppressed in the presence of 1.0 equivalent of 2,6-

di-tert-butyl-p-cresol (BHT) as a radical inhibitor

(Equation 1). Besides, when 2,2,6,6-tetramethyl-1-

piperidinyloxy (TEMPO) as anther radical inhibitor

was added under standard conditions, the reaction

was partially suppressed. Only 36% yield of the

desired products were obtained and 57% of model

substrate 1a were recovered (Equation 2). Moreover,

in the presence of 1.0 equivalent of 1,1-

diphenylethylene, another radical scavenger, the CF₃-

trapped compound 4a was observed^[16p], and the

target product was isolated in 46% yield with the

starting material being recovered in 43% (Equation 3).

These results indicated that the trifluoromethyl

radical might be involved in the transformation.

corresponding

3-(trifluoromethyl)-2H-

benzo[b][1,4]oxazin-2-one (3x) was obtained in an

acceptable yield.

Table 2. Substrate scope.^{a), b)}

Scheme 2. Control experiments.

Based on our controlled experiments and previous

reports^{[15, 17a-c, 19]}, a tentative mechanism is proposed

in Scheme 3. Initially, CF₃SO₂Na reacts with

PhI(OTFA)₂to afford iodine(III) sulfinate

intermediate A. Decomposition of A gives two free

radicals which are the CF₃radical (B) and I-radical

C^[19], meanwhile, releasing SO₂. Subsequently, the

CF₃radical attacks quinoxalin-2(1H)-one 1a to

generate the aminyl radical intermediate D. Finally,

oxidation of this intermediate followed by

deprotonation in the presence of I-radical C furnishes

the target product, leaving CF₃COOH and PhI.

a)

Unless specifically noted otherwise, reaction conditions:

1a (0.3 mmol), 2a (0.9 mmol), PhI(OTFA)₂(0.9 mmol)

and solvent (3 mL), stirred at room temperature under

b)

c)

argon atmosphere.

dimethylformamide.

Isolated yield.

In N, N-

Scheme 3. Tentative mechanism.

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Advanced Synthesis & Catalysis

In order to demonstrate the application of our

DSQ II mass spectrometer. Melting points (uncorrected)

were obtained on Shanghai Inesa WRS-3 melting point

apparatus. The starting materials were purchased from

Energy Chemical or J&K Chemicals and used without

further purification. Solvents were dried and purified

according to the procedure from “Purification of

Laboratory Chemicals book”. The reaction procedure was

monitored through thin-layer chromatography (TLC),

which was performed using 0.25 mm silica gel plates (60

F254) and was visualized with UV lamp (254 nm). The

crude products were purified by flash column

chromatography on silica gel using petroleum ether/ethyl

acetate as an eluent, and the reported yields are the actual

isolated yields of pure products.

protocol in pharmaceutical synthesis, we chose the N-

SEM protected quinoxalin-2(1H)-one (1y) as a

special substrate. As expected, the reaction also

proceeded well and afforded the desired products (3y)

in 81% yield. According to the previous report^[1a], the

pivotal precursor 3y undergoes a sequence of addition

of lithium cyclopropylacetylide, alkylation (acylation

or sulfonylation) and deprotection to furnish a series

of

3-trifluoromethyl-quinoxalin-2(1H)-one

derivatives (I) as HIV-1 reverse transcriptase

inhibitors. The aforementioned synthetic method for

3y involved a condensation of 1,2-diaminobenzene

with hexafluoropropylene oxide (HFPO), followed by

N-protection using 2-(trimethylsilyl)ethoxymethyl

chloride (SEM-Cl). It is cautionary that HFPO is an

expensive, irritant and gaseous reagent, and not easy

to operate in laboratories.^[20]Obviously, our method

provides a convenient and economical approach to 3-

trifluoromethyl-quinoxalin-2(1H)-ones.

General procedures for the direct trifluoromethylation

of quinoxalin-2(1H)-ones

To a Schlenk tube charged with a magnetic stirring bar,

quinoxalin-2(1H)-ones (1a-1w, 1y) or its derivatives (1x)

(0.3

mmol),

CF₃SO₂Na

(0.9

(PhI(OFA)₂)

mmol),

(0.9

[Bis(trifluoroacetoxy)iodo]benzene

mmol) were added successively and the Schlenk tube was

purged with argon for three times. Anhydrous CH₃CN (3

ml) was then added via syringe and the mixture was stirred

at room temperature in water bath under argon atmosphere

until the substrate was consumed (12 h~18 h, monitored by

TLC). Then the solvent was removed under reduced

pressure and the resulting residue was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate) to afford the corresponding 3-trifluoromethylated

products (3a-3y).

Scheme 4. The application in pharmaceutical synthesis.

Characterization of the Products

Conclusion

1-methyl-3-(trifluoromethyl)quinoxalin-2(1H)-one (3a):

The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3a (80%

yield, 54.8 mg) as light yellow solid, m. p. = 134-136 °C.

¹H NMR (400 MHz, CDCl₃) δ: 8.05 (dd, J = 1.2 Hz, J = 44

Hz, 1H), 7.76-7.72 (m, 1H), 7.48-7.40 (m, 2H), 3.77 (s,

3H); ¹³C NMR (100 MHz, CDCl₃) δ: 150.59, 142.81 (q, J

= 33.7 Hz), 133.54, 132.56, 130.72, 129.85, 123.52,

118.87 (q, J = 274.8 Hz), 113.02, 28.15; ¹⁹F NMR (376

MHz, CDCl₃) δ: -70.12 (s, 3F); HRMS (ESI): m/z calcd

for C₁₀H₇F₃N₂KO⁺[M+K]⁺267.0142. Found 267.0148.

In summary, we have developed an original direct C-

H trifluoromethylation of quinoxalin-2(1H)-ones

under transition-metal-free conditions. Both the

trifluoromethyl source and oxidant are low-cost and

readily available. A variety of 3-trifluoromethyl-

quinoxalin-2(1H)-ones with different functional

groups are obtained in moderate to excellent yields

under mild conditions. Predictably, this protocol

would offer a cheap, practical and efficient access to

pharmaceutically

active

3-trifluoromethyl-

quinoxalin-2(1H)-one derivatives without transition-

metal residues.

1-ethyl-3-(trifluoromethyl)quinoxalin-2(1H)-one (3b):

The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3b (71%

yield, 51.6 mg) as white solid, m. p. = 98-100 °C. ¹H NMR

(400 MHz, CDCl₃) δ: 8.00 (d, J = 8 Hz, 1H), 7.75-7.71 (m,

1H), 7.45-7.41 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.42 (t, J

= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 151.18,

143.88 (q, J = 33.6 Hz), 133.64, 133.51, 132.02, 131.21,

124.33, 119.96 (q, J = 274.7 Hz), 37.68, 12.36; ¹⁹F NMR

(376 MHz, CDCl₃) δ: -70.01 (s, 3F); HRMS (ESI): m/z

calcd for C₁₁H₉F₃N₂KO⁺[M+K]⁺281.0299. Found

281.0303.

Experimental Section

General Experimental Details

All reactions involving air- and moisture-sensitive reagents

were carried out under an argon atmosphere. H and ¹³C

1

NMR spectra were recorded on a Bruker AC-P 400

1

spectrometer (400 MHz for H, 100 MHz for ¹³C and 376

MHz for ¹⁹F) in CDCl₃(with TMS as internal standard) or

DMSO-d6. Chemical shifts (δ) were measured in ppm

relative to TMS δ = 0 for ¹H, or to chloroform δ = 77.0 for

¹³C as internal standard. Coupling constants, J, are reported

in hertz. Mass data were measured with Thermo Scientific

4

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Advanced Synthesis & Catalysis

1-benzyl-3-(trifluoromethyl)quinoxalin-2(1H)-one (3c):

The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3c (81%

yield, 73.8 mg) as light yellow solid, m. p. = 103-104°C.

¹H NMR (400 MHz, CDCl₃) δ: 8.00 (dd, J = 1.2 Hz, J =

8.0 Hz, 1H), 7.63-7.58 (m, 1H), 7.42-7.26 (m, 7H), 5.53 (s,

2H); ¹³C NMR (100 MHz, CDCl₃) δ: 151.77, 144.10 (q, J

= 34.6 Hz), 134.46, 134.02, 133.48, 131.90, 131.21,

129.11, 128.09, 127.06, 124.54, 119.93 (q, J = 274.8 Hz),

114.81, 46.06; ¹⁹F NMR (376 MHz, CDCl₃) δ: -69.91 (s,

3F); HRMS (ESI): m/z calcd for C₁₆H₁₁F₃N₂NaO⁺

[M+Na]⁺327.0716. Found 327.0713.

1,7-dimethyl-3-(trifluoromethyl)quinoxalin-2(1H)-one

(3g): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3g (75%

1

yield, 54.8 mg) as white solid, m. p. = 170-171°C. H

NMR (400 MHz, CDCl₃) δ: 7.86 (d, J = 8.4 Hz, 1H), 7.27

(d, J =7.2 Hz, 1H), 7.19 (s, 1H), 3.75 (s, 3H), 2.58 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ: 151.83, 145.14, 142.54 (q,

J = 33.5 Hz), 134.57, 131.41, 129.20, 126.01, 120.09 (q, J

= 274.5 Hz), 114.04, 29.07, 22.45; ¹⁹F NMR (376 MHz,

CDCl₃) δ: -69.94 (s, 3F); HRMS (ESI): m/z calcd for

C₁₀H₆F₃N₂KO⁺[M+K]⁺281.0299. Found 281.0284.

1-methyl-3,7-bis(trifluoromethyl)quinoxalin-2(1H)-one

(3h): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3h (67%

yield, 59.3 mg) as pale yellow solid, m. p. = 148-149°C.

¹H NMR (400 MHz, CDCl₃) δ: 8.29 (s, 1H), 7.95 (dd, J =

1.6 Hz, J = 8.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 3.79 (s,

3H); ¹³C NMR (100 MHz, CDCl₃) δ: 151.32, 145.53 (q, J

= 34.3 Hz), 136.80, 130.17, 129.71 (d, J = 3.1 Hz), 129.23

(d, J = 3.8 Hz), 126.94 (q, J = 34.0 Hz), 123.26 (q, J =

270.5 Hz), 119.52 (q, J = 275.2 Hz), 114.92, 29.47; ¹⁹F

NMR (376 MHz, CDCl₃) δ: -62.31 (s, 3F), -70.39 (s, 3F);

HRMS (ESI): m/z calcd for C₁₁H₆F₆N₂NaO⁺[M+Na]⁺

319.0277. Found 319.0244.

methyl 2-(2-oxo-3-(trifluoromethyl)quinoxalin-1(2H)-

yl)acetate (3d): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3d (85%

yield, 73.2 mg) as pale yellow solid, m. p. = 139-141°C.

¹H NMR (400 MHz, CDCl₃) δ: 8.03 (d, J = 8 Hz, 1H),

7.73-7.69 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8

Hz, 1H), 5.09 (s, 2H), 3.81 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ: 166.90, 151.17, 143.85 (q, J = 34.6 Hz), 133.76,

132.14, 131.02, 124.86, 119.73 (q, J = 274.9 Hz), 53.12,

43.27; ¹⁹F NMR (376 MHz, CDCl₃) δ: -69.99 (s, 3F);

+

HRMS (ESI): m/z calcd for C₁₂H₉F₃N₂NaO₃[M+Na]⁺

309.0457. Found 309.0455.

tert-butyl 2-(2-oxo-3-(trifluoromethyl)quinoxalin-1(2H)-

yl)acetate (3e): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3e (91%

4-methyl-3-oxo-2-(trifluoromethyl)-3,4-

dihydroquinoxaline-6-carbonitrile (3i): The crude

product was purified by column chromatography on silica

gel (petroleum ether/ethyl acetate = 3:1 to 1:1 as an eluent)

to afford the product 3i (39% yield, 29.7 mg) as white solid,

m. p. = 223-224°C. ¹H NMR (400 MHz, CDCl₃) δ: 8.32 (d,

J = 1.6 Hz, 1H), 7.95 (dd, J =1.6 Hz, J = 8.4 Hz, 1H), 7.50

(d, J = 8.8 Hz, 1H), 3.78 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ: 151.04, 146.09 (q, J = 34.6 Hz), 137.58, 136.06,

135.56, 130.37, 119.35 (q, J = 275.3 Hz), 117.08, 115.35,

108.36, 29.54; ¹⁹F NMR (376 MHz, CDCl₃) δ: -70.39 (s,

3F); HRMS (ESI): m/z calcd for C₁₁H₇F₃N₃O⁺[M+H]⁺

254.0536. Found 254.0544.

1

yield, 90 mg) as light yellow solid, m. p. = 87-89°C. H

NMR (400 MHz, CDCl₃) δ: 8.00 (dd, J = 0.8 Hz, J = 8.0

Hz, 1H), 7.72-7.68 (m, 1H), 7.46-7.42 (m, 1H), 7.15 (d, J

= 8.4 Hz, 1H), 4.97 (s, 2H), 1.46 (s, 9H); ¹³C NMR (100

MHz, CDCl₃) δ: 164.33, 150.16, 142.78 (q, J = 34.0 Hz),

132.84, 132.60, 130.97, 129.93, 123.68, 118.75 (q, J =

274.8 Hz), 112.57, 43.04, 26.91; ¹⁹F NMR (376 MHz,

CDCl₃) δ: -70.00 (s, 3F); HRMS (ESI): m/z calcd for

C₁₅H₁₅F₃N₂NaO₃⁺[M+Na]⁺351.0927. Found 351.0931.

3-(trifluoromethyl)quinoxalin-2(1H)-one (3f): After

substrate 1f was completed consumed (in N,N-

dimethylformamide), water was added and the mixture was

extracted with dichloromethane for three times, the

combined organic solution was washed with saturated

aqueous NaCl solution, dried over Na₂SO₄. The solvent

was removed under reduced pressure, then the residue

product was purified by column chromatography on silica

gel (petroleum ether/ethyl acetate = 1:1 as an eluent) to

afford the product 3f (64% yield, 41.2 mg) as yellow solid,

methyl

4-methyl-3-oxo-2-(trifluoromethyl)-3,4-

dihydroquinoxaline-6-carboxylate (3j): The crude

product was purified by column chromatography on silica

gel (petroleum ether/ethyl acetate = 3:1 as an eluent) to

afford the product 3j (52% yield, 44.6 mg) as white solid,

m. p. = 166-167°C. ¹H NMR (400 MHz, CDCl₃) δ: 8.65 (d,

J = 1.6 Hz, 1H), 8.35 (dd, J = 1.6 Hz, J = 9.2 Hz, 1H), 7.44

(d, J = 8.8 Hz, 1H), 3.97 (s, 3H), 3.77 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ: 165.38, 151.44, 147.41 (q, J = 34.1

Hz), 137.62, 133.99, 133.54, 130.26, 126,54, 119.65 (q, J

= 275.0 Hz), 114.21, 52.63, 29.49; ¹⁹F NMR (376 MHz,

CDCl₃) δ: -70.28 (s, 3F); HRMS (ESI): m/z calcd for

C₁₂H₉F₃N₂NaO₃⁺[M+Na]⁺309.0457, found 309.0454.

1

m. p. = 183-185°C. H NMR (400 MHz, DMSO-d6) δ:

13.06 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 8.0 Hz,

J = 7.2 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 3.37 (s, 3H); ¹³C

NMR (100 MHz, DMSO-d6) δ: 151.63, 143.96 (q, J =

32.3 Hz), 133.66, 133.42, 129.84, 129.81, 124.10, 120.02

(q, J = 274.5 Hz), 115.80; ¹⁹F NMR (376 MHz, DMSO-d6)

δ: -68.55 (s, 3F); HRMS (ESI): m/z calcd for C₉H₆F₃N₂O⁺

[M+H]⁺215.0427. Found 215.0427.

7-fluoro-1-methyl-3-(trifluoromethyl)quinoxalin-2(1H)-

one (3k): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3k (70%

yield, 51.7 mg) as pale yellow solid, m. p. = 155-156°C.

¹H NMR (400 MHz, CDCl₃) δ: 7.99 (dd, J = 6.0 Hz, J =

5

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Advanced Synthesis & Catalysis

8.8 Hz, 1H), 7.19-7.14 (m, 1H), 7.08 (dd, J = 2.4 Hz, J =

10.0 Hz, 1H), 3.71 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ:

165.40 (d, J = 254.7 Hz), 151.46, 142.79 (q, J = 33.8 Hz),

136.46 (d, J = 12.0 Hz), 134.14 (d, J = 10.9 Hz), 127.73,

119.86 (q, J = 274.7 Hz), 112.89 (d, J = 23.6 Hz), 101.05

(d, J = 27.9 Hz), 29.45; ¹⁹F NMR (376 MHz, CDCl₃) δ: -

70.302 (s, 3F), -116.97 (s, 1F); HRMS (ESI): m/z calcd for

C₁₀H₆F₄N₂KO⁺[M+K]⁺285.0048. Found 285.0032.

6-fluoro-1-methyl-3-(trifluoromethyl)quinoxalin-2(1H)-

one (3p): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3p (63%

1

yield, 46.6 mg) as yellow solid, m. p. = 114-116°C. H

NMR (400 MHz, CDCl₃) δ: 7.68 (dd, J = 2.8 Hz, J = 8.0

Hz, 1H), 7.51-7.46 (m, 1H), 7.38 (d, J = 4.8 Hz, J = 9.2 Hz,

1H), 3.74 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.10,

157.65, 151.22, 145.29 (q, J = 33.9 Hz), 131.33 (d, J =

11.1 Hz), 121.65 (d, J = 24.1 Hz), 119.69 (q, J = 275.0 Hz),

116.87 (d, J = 22.5 Hz), 115.35 (d, J = 8.7 Hz), 29.46; ¹⁹F

NMR (376 MHz, CDCl₃) δ: -70.08 (s, 3F), -101.07 (s, 1F);

HRMS (ESI): m/z calcd for C₁₀H₇F₄N₂O⁺[M+H]⁺

247.0489. Found 247.0492.

7-bromo-1-methyl-3-(trifluoromethyl)quinoxalin-

2(1H)-one (3l): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3l (54%

yield, 49.8 mg) as pale yellow solid, m. p. = 143-145°C.

¹H NMR (400 MHz, CDCl₃) δ: 8.14 (d, J = 2.0 Hz, 1H),

7.81 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz,

1H), 3.73 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 151.20,

145.03 (q, J = 33.9 Hz), 136.28, 133.94, 133.71, 131.57,

119.62 (q, J = 275.1 Hz), 117.11, 115.49, 29.36; ¹⁹F NMR

(376 MHz, CDCl₃) δ: -70.27 (s, 3F); HRMS (ESI): m/z

calcd for C₁₀H₆F₃BrN₂NaO⁺[M+Na]⁺328.9508. Found

328.9499.

6-bromo-1-methyl-3-(trifluoromethyl)quinoxalin-

2(1H)-one (3q) ： The crude product was purified by

column chromatography on silica gel (petroleum

ether/ethyl acetate = 3:1 as an eluent) to afford the product

3q (41% yield, 37.9 mg) as light yellow solid, m. p. = 188-

190°C. ¹H NMR (400 MHz, CDCl₃) δ: 7.83 (d, J = 9.2 Hz,

1H), 7.55 (dd, J = 1.6 Hz, J = 7.2 Hz, 2H), 3.72 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ: 151.27, 144.10 (q, J =

34.3 Hz), 135.50, 132.86, 129.70, 128.37, 128.00, 119.76

(q, J = 274.8 Hz), 117.19, 29.32; ¹⁹F NMR (376 MHz,

CDCl₃) δ: -70.17 (s, 3F); HRMS (ESI): m/z calcd for

C₁₀H₇F₃BrN₂O⁺[M+H]⁺306.9688. Found 306.9677.

1-methyl-7-nitro-3-(trifluoromethyl)quinoxalin-2(1H)-

one (3m): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3m (49%

1

yield, 40.2 mg) as yellow solid, m. p. = 186-187°C. H

NMR (400 MHz, CDCl₃) δ: 8.30-8.25 (m, 2H), 8.19 (d, J =

8.4 Hz, 1H), 3.84 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ:

150.94, 149.88, 147.36 (q, J = 34.5 Hz), 135.01, 133.82,

133.16, 119.32 (q, J = 277.5 Hz), 118.72, 109.94, 29.75;

¹⁹F NMR (376 MHz, CDCl₃) δ: -70.44 (s, 3F); HRMS

5-chloro-1-methyl-3-(trifluoromethyl)quinoxalin-2(1H)-

one (3r): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 5:1 as an eluent) to afford the product 3r (61%

yield, 48.1 mg) as light yellow solid, m. p. = 124-126°C.

¹H NMR (400 MHz, CDCl₃) δ: 7.91 (dd, J = 1.2 Hz, J =

8.0 Hz, 1H), 7.74 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 7.35 (t,

J = 8.0 Hz, 1H), 4.10 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

δ: 152.53, 144.21 (q, J = 34.0 Hz), 136.59, 133.28, 132.87,

131.38, 124.78, 120.07, 119.60 (q, J = 275.0 Hz), 35.52;

¹⁹F NMR (376 MHz, CDCl₃) δ: -70.23 (s, 3F); HRMS

(ESI): m/z calcd for C₁₀H₆F₃ClN₂NaO⁺[M+Na]⁺285.0013.

Found 284.9999.

+

(ESI): m/z calcd for C₁₀H₆F₃N₃NaO₃[M+Na]⁺296.0253.

Found 296.0232.

1-methyl-3,6-bis(trifluoromethyl)quinoxalin-2(1H)-one

(3n): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 5:1 as an eluent) to afford the product 3n (75%

1

yield, 66.7 mg) as white solid, m. p. = 162-164°C. H

NMR (400 MHz, CDCl₃) δ: 8.14 (d, J = 8.4 Hz, 1H), 7.69

(d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 3.80 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ: 151.19, 146.36 (q, J = 34.0 Hz),

134.79 (q, J = 33.1 Hz), 134.66, 132.68, 132.39, 123.15 (q,

J = 271.9 Hz), 120.95, 119.53 (q, J = 277.1 Hz), 111.68,

111.54, 29.43; ¹⁹F NMR (376 MHz, CDCl₃) δ: -62.83 (s,

3F), -70.40 (s, 3F); HRMS (ESI): m/z calcd for

C₁₁H₇F₆N₂O⁺[M+H]⁺297.0457. Found 297.0433.

1,6,7-trimethyl-3-(trifluoromethyl)quinoxalin-2(1H)-

one (3s): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3s (81%

yield, 62.4 mg) as light yellow solid, m. p. = 148-150°C.

¹H NMR (400 MHz, CDCl₃) δ: 7.70 (s, 1H), 7.14 (s, 1H),

3.71 (s, 3H), 2.45 (s, 3H), 2.36 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) δ: 151.79, 144.39, 142.76 (q, J = 33.3 Hz),

133.89, 132.73, 131.47, 129.42, 120.17 (q, J = 274.4 Hz),

114.44, 29.05, 20.96, 19.17; ¹⁹F NMR (376 MHz, CDCl₃)

δ: -69.90 (s, 3F); HRMS (ESI): m/z calcd for

C₂₄H₂₂F₆N₄O₂Na⁺[2M+Na]⁺535.1539. Found 535.1558.

1-methyl-2-oxo-3-(trifluoromethyl)-1,2-

dihydroquinoxaline-6-carbonitrile (3o): The crude

product was purified by column chromatography on silica

gel (petroleum ether/ethyl acetate = 3:1 as an eluent) to

afford the product 3o (44% yield, 33.5 mg) as pale yellow

1

solid, m. p. = 176-177°C. H NMR (400 MHz, CDCl₃) δ:

6,7-difluoro-1-methyl-3-(trifluoromethyl)quinoxalin-

2(1H)-one (3t): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3t (83%

8.10 (d, J = 8.4 Hz, 1H), 7.71-7.67 (m, 2H), 3.76 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ: 150.93, 146.90 (q, J =

34.3 Hz), 134.93, 132.77, 127.06, 119.36 (q, J = 275.5 Hz),

118.34, 117.37, 116.57, 29.48; ¹⁹F NMR (376 MHz, CDCl₃)

δ: -70.40 (s, 3F); HRMS (ESI): m/z calcd for

C₁₁H₆F₃N₃NaO⁺[M+Na]⁺276.0355. Found 276.0350.

1

yield, 65.5 mg) as white solid, m. p. = 134-135°C. H

NMR (400 MHz, CDCl₃) δ: 7.82 (dd, J = 8.0 Hz, J = 9.6

Hz, 1H), 7.21 (dd, J = 6.8 Hz, J = 12.0 Hz, 1H), 3.71 (s,

6

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Advanced Synthesis & Catalysis

3H); ¹³C NMR (100 MHz, CDCl₃) δ: 152.71 (dd, J = 14.4

Hz, J = 257.8 Hz), 150.09, 146.22 (dd, J = 14.0 Hz, J =

248.8 Hz), 143.32 (q, J = 34.0 Hz), 131.35 (d, J = 9.0 Hz),

126.06 (d, J = 6.9 Hz), 118.60 (q, J = 274.9 Hz), 118.24

(dd, J = 2.6 Hz, J = 18.2 Hz), 101.75 (d, J = 23.2 Hz),

28.72; ¹⁹F NMR (376 MHz, CDCl₃) δ: -70.25 (s, 3F), -

3-(trifluoromethyl)-1-((2-

(trimethylsilyl)ethoxy)methyl)quinoxalin-2(1H)-one

(3y): The crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 10:1 as an eluent) to afford the product 3y (81%

1

yield, 83.6 mg) as yellow oil. H NMR (400 MHz, CDCl₃)

124.08 (d, J = 22.56 Hz, 1F), -139.53 (d, J = 22.56 Hz, 1F); δ: 7.98 (dd, J = 0.8 Hz, J = 8.4 Hz, 1H), 7.73-7.62 (m, 2H),

HRMS (ESI): m/z calcd for C₁₀H₅F₅N₂NaO⁺[M+Na]⁺

287.0214. Found 287.0202.

7.47-7.43 (m, 1H), 5.76 (s, 2H), 3.37-3.69 (m, 2H), 0.97-

0.93 (m, 2H), -0.03 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ:

153.29, 145.56 (q, J = 33.8 Hz), 134.96, 134.88, 133.01,

132.46, 126.32, 121.28 (q, J = 275.0 Hz), 116.85, 72.98,

69.03, 19.41, -0.01; ¹⁹F NMR (376 MHz, CDCl₃) δ: -70.04

6,7-dichloro-1-methyl-3-(trifluoromethyl)quinoxalin-

2(1H)-one (3u): The crude product was purified by

column chromatography on silica gel (petroleum

ether/ethyl acetate = 3:1 as an eluent) to afford the product

3u (51% yield, 45.5 mg) as yellow solid, m. p. = 156-

158°C. ¹H NMR (400 MHz, CDCl₃) δ: 8.09 (s, 1H), 7.51 (s,

1H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 149.92,

144.06 (q, J = 34.3 Hz), 137.17, 132.80, 131.31, 128.73,

127.71, 144.06 (q, J = 275.1 Hz), 114.56, 28.46; ¹⁹F NMR

(376 MHz, CDCl₃) δ: -70.25 (s, 3F); HRMS (ESI): m/z

calcd for C₁₀H₅Cl₂F₃N₂NaO⁺[M+Na]⁺318.9623. Found

318.9627.

+

(s, 3F); HRMS (ESI): m/z calcd for C₁₅H₁₉F₃SiN₂NaO₂

[M+Na]⁺367.1060. Found 367.1045.

Acknowledgements

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, B2016202393, B2015202284) and the Program

for the Top Young Innovative Talents of Hebei Province (CN)

(Grant No. BJ2017010).

6-bromo-1,7-dimethyl-3-(trifluoromethyl)quinoxalin-

2(1H)-one (3v): he crude product was purified by column

chromatography on silica gel (petroleum ether/ethyl

acetate = 3:1 as an eluent) to afford the product 3v (62%

yield, 59.6 mg) as light yellow solid, m. p. = 156-158°C.

¹H NMR (400 MHz, CDCl₃) δ: 7.82 (s, 1H), 7.60 (d, J =

2.8 Hz, 1H), 3.70 (s, 3H), 2.50 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) δ: 151.26, 144.07 (q, J = 33.9 Hz), 134.75,

133.31, 132.44, 131.25, 129.96, 119.84 (q, J = 274.8 Hz),

117.66, 29.26, 22.32; ¹⁹F NMR (376 MHz, CDCl₃) δ: -

70.12 (s, 3F); HRMS (ESI): m/z calcd for

C₁₁H₈F₃BrN₂KO⁺[M+K]⁺358.9404. Found 358.9406.

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FULL PAPER

Direct C-H Trifluoromethylation of Quinoxalin-

2(1H)-ones under Transition-Metal-Free

Conditions

Adv. Synth. Catal. Year, Volume, Page – Page

Liping Wang,^aYuecheng Zhang,^{a, b}Fanfan Li,^a

Xinyu Hao,^aHong-Yu Zhang^a* and Jiquan Zhao^a*

10

Article Doi

Direct C?H Trifluoromethylation of Quinoxalin-2(1H)-ones under Transition-Metal-Free Conditions

DOI: 10.1002/adsc.201800863

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