N, N, N&#39;, N&#39;-Tetramethylethylenediamine-Enabled Photoredox-Catalyzed C-H Methylation of N-Heteroarenes

Catalyzed C −H Methylation of N �Heteroarenes

Article

N,N,N’,N’�Tetramethylethylenediamine-Enabled Photoredox-

Fang Liu, Zhi-Peng Ye, Yuan-Zhuo Hu, Jie Gao, Lan Zheng, Kai Chen,* Hao-Yue Xiang,*

Xiao-Qing Chen, and Hua Yang *

Cite This: https://doi.org/10.1021/acs.joc.1c01325

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sı Supporting Information

ABSTRACT: Aiming at the valuable methylation process, readily

available and inexpensive N,N,N�,N�-tetramethylethylenediamine

(

TMEDA) was �rst identi�ed as a new methyl source in photoredox-

catalyzed transformation in this work. By virtue of this simple methylating

reagent, a facile and practical protocol for the direct C−H methylation of

N-heteroarenes was developed, featuring mild reaction conditions, broad

substrate scope, and scalability. Mechanistic studies disclosed that a

sequential photoredox, base-assisted proton shift, fragmentation, and tautomerization process was essentially involved.

INTRODUCTION

cleaved to generate a methyl radical (Scheme 1b, left). In 2018,

by taking advantage of their newly designed cerium-based

photo catalytic system, Zuo and coworkers realized the

�

Methylation is a fundamentally important transformation in

both biological systems and medicinal chemistry. In biology,

the modi�cation by introducing a methyl group plays a vital

utilization of gaseous methane as a methyl radical precursor.

Most recently, Doyle’s group added trimethylorthoformate to

the list of methyl sources for the photo-induced transformation

by developing a radical approach for the methylation of

role in impacting gene expression and mammalian embryo

development. Pharmaceutical sciences leverage this “magic

methyl e�ect” to improve solubility, bioavailability, and

metabolism of drug molecules. For instance, installing a

methyl substituent at the thiophene ring of an inhibitor of

(hetero)aryl chlorides by using nickel/photoredox catalysis.

Despite these encouraging advances, new and readily available

methylating reagents are highly expectable to extend the

chemical dimension of the methylation transformation, thus

o�ering new synthetic opportunities for direct methylation.

N,N,N �, N �- Tetramethylethylenediamine(TMEDA), a readily

available organic base ($ 0.007/mmol), has been extensively

applied in various transformations as ligands for metal-

PTP1B signi�cantly improved its IC value 250-fold (Scheme

a, left). Moreover, a survey of the top 200 selling

pharmaceutical products in 2011 and 2018 respectively

shows that more than 67 and 73% of small-molecule drugs

contain at least one methyl group (Scheme 1a, right).

Additionally, in terms of organic synthesis, the methyl group is

also regarded as a versatile unit, which can be easily converted

to a range of useful functional groups, including halogens,

aldehydes, and carboxylic acids. As a result, general strategies

for direct methylation, especially for N-heterocycles featuring

unique chemical and biological properties, have been greatly

valued and considerably developed in the last decade.

catalyzed reactions or sacri�cing reagents in photo-induced

transformations. Given its salient structural features bearing

four methyl groups, we rationalized that TMEDA might act as

an active methylating agent under speci�c conditions. Very

recently, TMEDA has been identi�ed as a methylene or formyl

source through the C−N bond cleavage under photocatalytic

conditions. Unfortunately, no success has been achieved in

Traditional methylation processes for N-heterocycles mostly

relied upon transition-metal-catalyzed cross-coupling reactions

or C−H alkylation with a set of nucleophilic organometallic

the application of TMEDA as a methylating reagent. The

challenge is attributed to the fact that TMEDA was usually

vulnerable to oxidation by photocatalysts through a single-

electron-transfer (SET) process followed by hydrogen-atom-

transfer (HAT) to generate an aminium ion, which serves as a

reagents. Meanwhile, these approaches usually required toxic

and unstable methylating reagents and/or occurred at high

temperature, thus greatly limiting their substrate scope and

application range. With the blossom of visible-light-induced

photocatalysis, the methylation of N-heterocycles through a

Received: June 7, 2021

radical pathway has become an entirely new option. Up to

now, methylating reagents such as MeOH, peroxide,

MeB(OH)₂, DMSO, and other equivalents have found

applications in photo-induced methylation of N-heterocycles,

in which a C heteroatom or C−C bond was homolytically

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

Scheme 1. Impact of Methylation and Photo-Induced C−H Methylation of N-heterocycles

methylene or formyl source by intercepting by various

nucleophiles such as electron-rich N-heterocycles. Aiming at

addressing this issue, we envisioned that the pathway could be

modulated to proceed a radical transposition process via

deprotonation to form a C-centered radical for direct

alkylation of N-heterocycles, especially for electron-de�cient

substrates (Scheme 1b, right). Following this rationale, we

herein advanced an unprecedented approach for photoredox-

catalyzed direct C−H methylation of a variety of biologically

relevant N-heterocycles using TMEDA as the new methylating

source (Scheme 1c).

Table 1. Optimization of the Reaction Conditions

entry

base

cat

PC-1

temp. (°C) time (h) yield (%)

r.t.

K HPO₄

PC-1

NH HCO₃

KHCO₃

K CO₃

NaHCO₃

RESULTS AND DISCUSSION

�

To test our hypothesis, we sought to study the methylation of

Na CO₃

-methylquinoxalin-2(1H)-one (1a) as the model electron-

Na CO₃

fac-Ir(ppy)₃

Eosin Y

PC-2

de�cient hetereocycle (shown in Table 1). Under irradiation of

0 W blue light-emitting diodes (LEDs) and in the presence of

Na CO₃

TMEDA (2a), the desired product 3a was obtained in 55%

yield as expected (Table 1, entry 1). This result encouraged us

to further optimize the reaction conditions. Then, a careful

screening of various bases in MeCN as solvent revealed that

Na CO was the optimal choice (Table 1, entries 2−7).

Na CO₃

PC-3

PC-1

trace

Na CO₃

Among the surveyed photocatalysts such as fac-Ir(ppy) , eosin

Na CO₃

Y, rhodamine B, and Ru(bpy) (PF ) , Ir[dF(CF )-

Na CO₃

ppy] (dtbbpy)PF was proven to be the best option (Table

Na CO₃

, entries 8−11). An argon atmosphere was essential to this

Reaction conditions: 1-methylquinoxalin-2(1H)-one (1a, 0.2 mmol,

.0 equiv), TMEDA (2a, 0.2 mmol, 1.0 equiv), base (0.6 mmol, 3

reaction system (Table 1, entry, 12). Inspired by the elegant

work of Kim’s group, 10 equiv of water was further added to

this reaction system to facilitate the C−N bond cleavage of

TMEDA, which signi�cantly promoted the chemical yield of

equiv), cat (5 mol %), MeCN (2.0 mL, without puri�cation) 30 W

b c

blue LEDs, argon atmosphere. Yield of isolated product. PC-1:

Ir[dF(CF )ppy] (dtbbpy)PF ; PC-2: Rhodamine B; PC-3:Ru-

bpy) (PF ) . Under air atmosphere. H O (10 equiv) was added.

(

a to 78% (Table 1, entry 13). To further verify the

90 mg of 4 Å molecular sieve was added. 1 mL water was added.

importance of water in promoting this transformation, the

e�ect of the amount of water has been evaluated (Table 1,

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

entries 14 and 15). In the presence of molecular sieve, the

chemical yield of 3a was reduced dramatically to 29%. Excess

water also resulted in lower yield due to the lower solubility for

the substrates. Pleasingly, elevating the reaction temperature

could remarkably shorten the reaction time to 5 h, without

a�ecting the yield of 3a (Table 1, entries 16−18). Finally, the

optimal conditions were determined to be acetonitrile as

solvent, Na CO as the base, and Ir[dF(CF )ppy] (dtbbpy)-

Scheme 2. Scope with Respect to Quinoxalinones and

a b

Pyrazinones

PF as the photocatalyst with the addition of H O in an argon

atmosphere under the irradiation of 30 W blue LEDs.

With these optimized reaction conditions in hand, the

substrate scope and limitations of this protocol were

subsequently investigated (Scheme 2). First, various sub-

stituted 1-methylquinoxalin-2(1H)-ones 1 were prepared and

subjected to the standard conditions. A range of products 3

with varied substituents on the N-1 atom, including Et, allyl,

esters, and benzyl, were obtained with moderate to good yields

(

Schemes 2 and 3b−i). Disubstituted 1-methylquinoxalin-

(1H)-ones 1p−1r were also evaluated and proven to be

suitable substrates. It is noteworthy that tricyclic product 1,3-

dimethylbenzo[g]-quinoxalin-2(1H)-one 3s was able to be

smoothly synthesized in 45% yield as well. However, the nitro

group on the phenyl moiety completely muted the reactivity.

To further demonstrate the compatibility of this trans-

formation, 1-methylquinoxalin-2(1H)-ones 1 with di�erent

substitution patterns on the benzene ring were also examined.

Obviously, the presence of methyl substituent at the 5-position

of the phenyl unit gave a good yield (Schemes 2 and 3j). In

addition, diverse electron-withdrawing groups at the 6-position

of the phenyl unit were well tolerated, giving the correspond-

ing products 3k−3o in 51−79% yields. Furthermore,

encouraged by these results, we turned our attention toward

extending the substrate scope of this photo-induced trans-

formation to other important N-heterocycles (Schemes 2 and

t−y). Pleasantly, both N-unprotected and N-Me pyrazinones

delivered the corresponding methylated products under this

photoredox-catalyzed reaction system (Schemes 2 and 3t−u).

Likewise, unsubstituted imidazo[1,2-b] pyridazine 1v reacted

with TMEDA to successfully a�ord 3v in 73% yield. Other

functional groups such as Cl, Br, and ethynyl group on this

heterocyclic sca�old were also well tolerated. However, this

photocatalyzed transformation was currently limited to N-

heterocycles. Other types of heterocycles such as coumarin

were unable to give the desired product. Ultimately, a scale-up

reaction under standard conditions was conducted to

demonstrate the synthetic potential of the developed protocol,

providing 3a in 54% yield (Scheme 2, bottom).

In order to elucidate the mechanism of this process, several

control experiments were carried out as shown in Scheme 3.

First, N�,N�-dimethylethane-1,2-diamine 2b and 2-

Standard conditions: 1 (0.2 mmol, 1.0 equiv), TMEDA (2a, 0.2

mmol, 1.0 equiv), Na CO (0.6 mmol, 3 equiv), Ir[dF(CF )-

ppy] (dtbbpy)PF (5 mol %), MeCN (2.0 mL), H O (2.0 mmol,

(

dimethylamino)ethan-1-ol 2c were also evaluated as the

methyl source and markedly inferior results were achieved.

However, trimethylamine 2d was unable to give the

methylation product, suggesting that these two nitrogen

atoms were synergistically involved in this transformation.

Otherwise, no conversion was detected using ethyl-substituted

amines 2e and 2f as a methyl source (Scheme 3a). When 2.0

equiv of radical scavenger 2,2,6,6-tetramethylpiperidin-1-oxyl

0 equiv), 30 W blue LED, argon atmosphere, 45 °C (oil bath), 5 h.

Yield of isolated product. fac-Ir(ppy) was used.

330.2146, calcd 330.2176) were clearly identi�ed by mass

analysis (see the Supporting Information for details).

These results indicate that a free-radical pathway is involved

in the photo-induced transformation. Thereafter, the illumina-

tion and photocatalyst were also identi�ed to be necessitated.

Interestingly, upon switching H O to D O in the process, the

(

TEMPO) was added to the model reaction system, the

methylated product 3a was not detected (Scheme 3b). Instead,

the corresponding coupled product TEMPO-I (m/z =

95.2564, calcd 295.2589) and TEMPO-VI (m/z =

corresponding deuterated mixture of 3a was able to be

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

TMEDA (2a ) (see the Supporting Information for details). In

Article

Scheme 3. Control Experiments

addition, the cyclic voltammetry experiments were performed

to further support our speculation (see the Supporting

Information for details).

On the basis of the above experimental results, density

functional theory (DFT) calculations were conducted to gain

insights into the mechanism (see the SI for details). As

shown in Figure 1, TMEDA could undergo single-electron

(

III)

transfer (SET) with the excited Ir photocatalyst to deliver a

N-centered radical I, which was suggested by TEMPO trapping

experiments. The resulting radical cation I was converted to �-

amino radical II through a base-promoted deprotonation step

via I-TS-II with a free energy barrier of 7.3 kcal/mol. Then, a

radical addition of intermediate II to 1a proceeded smoothly

to deliver intermediate III. From radical III, the cleavage of the

�-C-H bond could be achieved by an intramolecular 1,6-

proton shift via III-TS-IV. It is noteworthy that this C−H

cleavage could also be promoted by a base such as Na CO or

TMEDA, with a little higher free energy barrier, which could

account for the reactivity of the substrate 2-(dimethylamino)-

ethan-1-ol 2c (see Figure S12 for details). As the newly formed

C−N bond could be weakened by the protonation of the

nitrogen atom, the fragmentation of intermediate V occurred

easily with a free energy barrier of only 5.7 kcal/mol to deliver

N,N,N �- trimethylethylenediamine and exo-ole�n VI. It is worth

mentioning that the formation of addition intermediate V was

observed through HRMS and HNMR analysis, which hints to

us that protonation process occurred in the generation of the

introduced methyl group. The light on/o� studies and

quantum yield measurement (� = 0.03) were also commenced

for understanding this reaction mechanism, and the conse-

quence excluded the possibility of a radical chain process (see

the Supporting Information for details). Subsequently,

emission quenching experiments (Stern−Volmer Studies) of

a and 2a in acetonitrile solution were conducted. The

uorescence measurements recorded illustrated that photo-

excited Ir[dF(CF )ppy] (dtbbpy)PF could be quenched by

con�rmed by mass analysis ([M + H] , m/z = 276.1920, calcd

276.1945). The reduction of VI by Ir(II) was exogermic by

14.1 kcal/mol to form intermediate VII, which is signi�cantly

larger than a SET process from Ir(II) to III or 1a (see the SI

for details). Presumably, a barrierless protonation of

intermediate VII occurred to a�ord 3-methylene-dihydroqui-

noxalin-2(1H)-one VIII. Finally, tautomerization assisted by

trace NaHCO , which may be generated by Na CO -catalyzed

�

deprotonation of radical cation I, will lead to the observed C3-

methylated quinoxalinone 3a (see details in the SI). This

Figure 1. Free-energy pro�les for the plausible reaction pathway. The relative free energies in MeCN have been present in the unit of kcal/mol.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

intermolecular proton shift is also consistent with the

deuteration experiments.

after �ltering and drying. To a mixture of sodium hydride (182 mg,

.5 mmol, 1.5 equiv, 60% dispersion in mineral oil) in DMF (2 mL)

was added a solution of 1t (516 mg, 3 mmol, 1.0 equiv) in DMF (2

mL) and THF (2 mL) dropwise at 0 °C under an argon atmosphere.

A solution of methyl iodide (3.9 mmol, 1.3 equiv) in THF (1 mL)

was added dropwise to the mixture at 15 min at 0 °C. Then, tetrabutyl

ammonium iodide (111 mg, 0.3 mmol, 0.1 equiv) was added to

reaction mixture followed by stirring at room temperature for 3 h. The

reaction was quenched with ice water and extracted with EtOAc. The

organic extract was washed with brine, dried over Na SO ,

In conclusion, we have established a general visible-light-

driven direct C−H methylation strategy by rationalizing the

reactivity of TMEDA as a new methylating reagent, which

proved valid for a series of signi�cant N-heterocycles, including

quinoxalin-2(1H)-ones, pyrazinones, and imidazo[1,2-b] pyr-

idazines. The present protocol represents the �rst example

using the readily available and inexpensive TMEDA as the

methylating reagent under photocatalytic conditions. Compre-

hensive mechanistic studies disclosed that the inherent

structural feature of TMEDA and base-assisted tautomeriza-

tion were pivotal for this process. The mild reaction

conditions, broad substrate scope, and scalability of this

transformation would greatly broaden the synthetic utilizations

of the developed protocol. Further exploration on the synthetic

potentials of this simple methylation reagent is currently

underway in our group.

concentrated under reduced pressure, and further puri�ed by �ash

column chromatography (CH Cl /acetone or n-hexanes/EtOAc) to

give the corresponding N-methyl 5-phenyl pyrazinones (1u).

General Procedure for the Preparation of 3a−3u. To a 15

mL reaction tube equipped with a magnetic stirring bar,

quinoxalinone or pyrazinones 1a−1u (0.2 mmol, 1.0 equiv),

tetramethylethylenediamine 2a (0.2 mmol, 1.0 equiv), Na CO (0.3

mmol, 1.5 equiv), Ir[dF(CF )ppy] (dtbbpy)PF (4 mg), H O (2.0

mmol, 10.0 equiv), and MeCN (2 mL) were added. The vessel was

evacuated and back�lled with Ar three times. The tube was screw-

capped and stirred in an oil bath (45 °C) under irradiation of 30 W

blue LEDs (distance app. 5 cm) for 5 h. The solvent was removed

under reduced pressure, and then the residue was puri�ed by �ash

column chromatography (PE-PE/EtOAc = 1:9 to 1:4) to a�ord the

desired products 3a−3u.

EXPERIMENTAL SECTION

�

General Experimental Methods. Unless otherwise stated,

reagents commercially available were used without further puri�ca-

tion. H NMR spectra were recorded at 400 MHz. The chemical

shifts were reported in parts per million (ppm) relative to

tetramethylsilane and with the solvent resonance as the interior

standard. Data were recorded as follows: chemical shift, multiplicity (s

General Procedure for the Synthesis of Compounds 3v−3y.

To a 15 mL reaction tube equipped with a magnetic stirring bar,

imidazo[1,2-b]pyridazines 1v−1y (0.2 mmol, 1.0 equiv), tetramethy-

lethylenediamine 2a (0.2 mmol, 1.0 equiv), Na CO (0.3 mmol, 1.5

singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling

constants (Hz), integration. C NMR data were collected at 100

MHz with complete proton decoupling. Chemical shifts were

reported in parts per million (ppm) from tetramethylsilane with the

solvent resonance as the interior standard. For UV−Vis spectra, a

Shimadzu UV-2600 was used. Infrared spectra (IR) were measured by

FT-IR apparatus. High-resolution mass spectroscopy (HRMS) was

recorded on a Bruker Apex II TOF MS ES+ mass spectrometer, and

the samples were dissolved in acetonitrile. About cyclic voltammetry

equiv), fac-Ir(ppy) (4 mg) or Ir[dF(CF )ppy] (dtbbpy)PF (4 mg),

H O (2.0 mmol, 10.0 equiv), and MeCN (2 mL) were added. The

vessel was evacuated and back�lled with Ar three times. The tube was

screw-capped and stirred in an oil bath (45 °C) under irradiation of

0 W blue LEDs (distance app. 5 cm) for 5 h. The solvent was

removed under reduced pressure, and then the residue was puri�ed by

ash column chromatography (PE-PE/EtOAc = 1:9 to 1:4) to a�ord

�

the desired product 3v−3y.

(

CV) experiments, a CHI650D electrochemical workstation was used.

Emission intensities were recorded using a Perkin-Elmer LS 55

uorescence spectrometer. Column chromatography was carried out

Characterization Data of Compound 1e, 1h, and 3a−3y.

Ethyl-2-(2-oxoquinoxalin-1(2H)-yl)propanoate (1e). Red solid; the

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; m.p. 114−115 °C;

�

on silica gel (200−300 mesh). Imidazo[1,2-b] pyridazine was

purchased from Shanghai Haohong Biomedical Technology Co.,

Ltd. and used without any further puri�cation.

−1

IR (neat) v 1741, 1654, 1599, 1216, 1113, 1068, 764 cm ; H NMR

400 MHz, Chloroform-d) �8.32 (s, 1H), 7.94−7.92 (m, 1H), 7.58−

.54 (m, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 5.76

s, 1H), 4.20 (qq, J = 6.3, 3.6 Hz, 2H), 1.73 (d, J = 7.1 Hz, 3H), 1.16

(

General Procedure for the Preparation of quinoxali-

23−28

nones.

To a suspension of O-arylenediamines (5 mmol, 1.0

(

equiv) in ethanol (20 mL) was added ethyl 2-oxoacetate (6 mmol, 1.2

equiv). The mixture was stirred at room temperature for 4 h. The

precipitated solid was �ltered, washed with ethanol, and �nally dried

to a�ord the corresponding products 1aa−1as. To a suspension of

quinoxalinones 1aa−1as (4.3 mmol, 1 equiv) in DMF (20 mL) were

added potassium carbonate (5.2 mmol, 1.2 equiv) and the

corresponding alkyl halides (6.9 mmol, 1.6 equiv). The mixture was

stirred at room temperature overnight. Ethyl acetate (100 mL) and

water (20 mL) were added. The aqueous layer was extracted twice

with EtOAc (50 mL). Also, the combined organic layers were washed

t, J = 7.1 Hz, 3H); C{ H} NMR (100 MHz, Chloroform-d) �

69.6, 154.2, 150.0, 133.9, 131.5−130.9 (m), 123.9, 113.8, 62.0, 50.8,

4.0; HRMS (ESI-TOF) m/z: [M + K] Calcd for C H KN O

85.0636; Found 285.0627.

-(3-Methoxybenzyl)quinoxalin-2(1H)-one (1h). White solid; the

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; m.p. 79−80 °C; IR

−1 1

(

neat) v 1647, 1599, 1460, 1035, 796, 750, 508 cm ; H NMR (400

MHz, Chloroform-d) �8.39 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.46 (t,

J = 7.8 Hz, 1H), 7.33−7.29 (m, 2H), 7.23 (t, J = 7.8 Hz, 1H), 6.82−

with a saturated solution of NH Cl (30 mL) followed by brine (40

.78 (m, 4H), 5.45 (s, 2H), 3.75 (s, 3H); C{ H} NMR (100 MHz,

mL), dried over Na SO , �ltered, and evaporated under reduced

Chloroform-d) � 160.0, 155.1, 150.1, 136.5, 133.4 (d, J = 11.7 Hz),

32.6, 131.1 (d, J = 5.1 Hz), 130.5 (d, J = 6.4 Hz), 130.0, 55.2, 45.5;

pressure. The residue was puri�ed by �ash chromatography (PE/

EtOAc = 1:10 or 1:5) over silica gel to a�ord the desired products

HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H NaN O

a−1s.

16 14

289.0947; Found 289.0952.

,3-Dimethylquinoxalin-2(1H)-one (3a). Yellow solid; the product

General Procedure for the Preparation of pyrazinones. To

a mixture of glycinamide hydrochloride (2.2 g, 20.0 mmol, 1.0 equiv)

in MeOH (18 mL) and water (4.4 mL) was added 12.5 M aqueous

NaOH solution (2.4 mL, 28.6 mmol, 1.4 equiv) at −30 °C, followed

by a solution of NaOH (800 mg, 20.0 mmol, 1.0 equiv) in MeOH (9

mL). Then, benzene glyoxal (3.1 g, 20.0 mmol, 1.0 equiv) was added

at −30 °C and the mixture was allowed to stir at the same

temperature for 2 h. The resulting mixture was further stirred at room

temperature for 1 h and cooled in an ice bath followed by an

acidi�cation with AcOH. The 5-phenyl pyrazinone (1t) was obtained

was puri�ed by �ash column chromatography (PE-PE/EtOAc = 1:9

to 1:4) to a�ord the desired product; 27.2 mg, yield: 78%; m.p. 102−

−

03 °C; IR (neat) v 3468, 3235, 2922, 1642, 1595, 1470, 758 cm ;

H NMR (400 MHz, Chloroform-d) �7.80 (d, J = 7.9 Hz, 1H), 7.52

(t, J = 7.7 Hz, 1H), 7.35−7.30 (m, 2H), 3.70 (s, 3H), 2.60 (s, 3H);

HRMS (ESI-TOF) m/z: [M + H] Calcd for C10

O 175.0866;

Found 175.0877. The NMR data was consistent with the reported

data.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

3H); ¹³C{ H} NMR (100 MHz, Chloroform-d) �160.0, 158.5, 155.2,

1-ethyl-3-methylquinoxalin-2(1H)-one (3b). White solid; the

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 23.9 mg, yield:

136.9, 132.9, 132.7, 130.0, 129.6, 129.5, 123.7, 119.0, 114.4, 112.9,

112.6, 55.2, 45.8, 21.7; HRMS (ESI-TOF) m/z: [M + Na] Calcd for

4%;m.p.103−105 °C;IR (neat) v 3472, 3363, 3212, 1638, 1593, 754

C H N NaO 303.1104; Found 303.1111.

−

1 1

cm ; H NMR(400 MHz, Chloroform-d) �7.82 (dd, J = 8.2, 1.5 Hz,

(3-Bromobenzyl)-3-methylquinoxalin-2(1H)-one (3i). White

H), 7.52 (ddd, J = 7.8, 7.2, 1.5 Hz, 1H), 7.35−7.31 (m, 2H), 4.33 (q,

solid; the product was puri�ed by �ash column chromatography

(PE-PE/EtOAc = 1:9 to 1:4) to a�ord the desired product; 22.0 mg,

yield: 33%; m.p. 120−122 °C; IR (neat) v 2973, 2919, 1646, 1600,

J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); HRMS (ESI-

TOF) m/z: [M + Na] Calcd for C H N NaO 211.0842; Found

−1 1

11.0845. The NMR data was consistent with the reported data.

-allyl-3-methylquinoxalin-2(1H)-one (3c). Yellow solid, the

1466, 1072, 1056, 755 cm ; H NMR (400 MHz, Chloroform-d) �

7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.45−7.39 (m, 3H), 7.34−7.30 (m,

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 19.7 mg, yield:

1H), 7.21−7.14 (m, 3H), 5.46 (s, 2H), 2.66 (s, 3H); C{ H} NMR

(100 MHz, Chloroform-d) �157.5, 155.2, 137.6, 132.9, 132.4, 131.0,

130.5, 129.9, 129.74, 129.72, 125.5, 123.9, 123.1, 114.1, 45.4, 21.7;

−

9%; m.p. 65−66 °C;IR (neat) v 1656, 1644, 1596, 1188, 752 cm ;

H NMR (400 MHz, Chloroform-d) �7.82 (dd, J = 8.0, 1.5 Hz, 1H),

HRMS (ESI-TOF) m/z: [M + H] Calcd for C H BrN O

.49 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.33 (ddd, J = 8.3, 7.4, 1.2 Hz,

H), 7.29−7.27 (m, 1H), 5.94 (ddt, J = 17.3, 10.3, 5.1 Hz, 1H), 5.27

329.0284; Found 329.0284.

1,3,5-Trimethylquinoxalin-2(1H)-one (3j). Yellow solid; the

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 20.8 mg, yield:

55%; m.p. 144−145 °C; IR (neat) v 1636, 1598, 1481, 1212, 785,

(

dq, J = 10.4, 1.4 Hz, 1H), 5.17 (dq, J = 17.2, 1.5 Hz, 1H), 4.91 (dt, J

5.0, 1.6 Hz, 2H), 2.62 (s, 3H); C{ H} NMR (100 MHz,

Chloroform-d) � 158.4, 154.8, 132.8, 132.5, 130.6, 129.5, 129.5,

−1 1

23.6, 118.1, 114.2, 44.5, 21.6; HRMS (ESI-TOF) m/z: [M + Na]

765, 471 cm ; H NMR (400 MHz, Chloroform-d) �7.39 (t, J = 7.9

Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.68 (s,

Calcd for C H N NaO 223.0842; Found 223.0846.

Methyl-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetate (3d).

White solid; the product was puri�ed by �ash column chromatog-

raphy (PE-PE/EtOAc = 1:9 to 1:4) to a�ord the desired product;

3H), 2.67 (s, 3H), 2.60 (s, 3H); C{ H} NMR (100 MHz,

Chloroform-d) � 156.5, 155.1, 138.2, 133.3, 131.3, 129.2, 124.9,

111.5, 29.2, 21.9, 17.6. HRMS (ESI-TOF) m/z: [M + Na] Calcd for

6.0 mg, yield: 56%; m.p. 110−113 °C;IR (neat) v 1749, 1235, 1219,

NaO 211.0842; Found 211.0842.

−

1 1

175, 1068, 763, 617 cm ; H NMR (400 MHz, Chloroform-d) �

.96−7.94 (m, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.61−7.53 (m, 2H),

6-Fluoro-1,3-dimethylquinoxalin-2(1H)-one (3k). Yellow solid;

the product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 24.5 mg, yield:

79%; m.p. 163−165 °C; IR (neat) v 1640, 1598, 1272, 1219, 892, 804

.08 (s, 2H), 3.79 (s, 3H), 2.72 (s, 3H); C{ H} NMR (100 MHz,

Chloroform-d) � 169.0, 154.9, 147.7, 139.3, 139.1, 129.0, 128.1,

−1 1

26.9, 62.6, 52.2, 20.3; HRMS (ESI-TOF) m/z: [M + Na] Calcd for

cm ; H NMR (400 MHz, Chloroform-d) �7.51 (dd, J = 8.6, 2.3 Hz,

C H N NaO 255.0740; Found 255.0749.

1H), 7.31−7.28 (m, 1H), 7.27−7.23 (m, 1H), 3.70 (s, 3H), 2.60 (s,

3H); HRMS (ESI-TOF) m/z: [M + Na] Calcd for C10

Ethyl-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)propanoate (3e).

NaO

Yellow solid; the product was puri�ed by �ash column chromatog-

raphy (PE-PE/EtOAc = 1:9 to 1:4) to a�ord the desired product;

215.0591; Found 215.0599. The NMR data was consistent with the

reported data.

2.5 mg, yield: 43%; m.p. 68−70 °C; IR (neat) v 1738, 1647, 1603,

6-Chloro-1,3-dimethylquinoxalin-2(1H)-one (3l). Yellow solid;

the product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 27.6 mg, yield:

67%; m.p. 162−164 °C; IR (neat) v 1661, 1203, 1101, 1078, 802

−

1 1

223, 1191, 1103, 751 cm ; H NMR (400 MHz, Chloroform-d) �

.85 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.6 Hz,

H), 7.16 (d, J = 8.4 Hz, 1H), 5.73 (brs, 1H), 4.25−4.15 (m, 2H),

−

1 1

.60 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H);

cm ; H NMR (400 MHz, Chloroform-d) �7.79 (d, J = 2.4 Hz, 1H),

7.48 (dd, J = 8.9, 2.4 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 3.69 (s, 3H),

2.59 (s, 3H); HRMS (ESI-TOF) m/z: [M + K]⁺Calcd for

HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H N NaO

83.1053; Found 283.1048. The NMR data was consistent with the

reported data.

ClKN

O 247.0035; Found 247.0037. The NMR data was

tert-Butyl-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetate (3f).

Yellow solid; the product was puri�ed by �ash column chromatog-

raphy (PE-PE/EtOAc = 1:9 to 1:4) to a�ord the desired product;

consistent with the reported data.

6-Bromo-1,3-dimethylquinoxalin-2(1H)-one (3m). White solid;

the product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 28.1 mg, yield:

56%; m.p. 158−160 °C; IR (neat) v 2963, 2922, 1651, 1100, 1075,

6.4 mg, yield: 67%; m.p. 117−119 ;°C; IR (neat) v 1738, 1658,

−1 1

645, 1601, 1237, 1149, 767 cm ; H NMR (400 MHz, Chloroform-

−

1 1

d) � 7.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.49 (ddd, J = 8.5, 7.3, 1.5 Hz,

1066, 1057, 802 cm ; H NMR (400 MHz, Chloroform-d) �7.96 (d,

J = 2.2 Hz, 1H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.17 (d, J = 8.9 Hz₊,

1H), 3.68 (s, 3H), 2.60 (s, 3H); HRMS (ESI-TOF) m/z: [M + Na]

Calcd for C H BrN NaO 274.9790; Found 274.9791. The NMR

H), 7.33 (dd, J = 8.3, 7.4, 1.2 Hz, 1H), 7.05 (dd, J = 8.4, 1.1 Hz,

H), 4.94 (s, 2H), 2.61 (s, 3H), 1.46 (s, 9H); C{ H} NMR (100

MHz, Chloroform-d) �166.1, 158.2, 154.7, 132.7, 132.5, 129.7, 129.7,

23.8, 113.1, 83.2, 44.2, 28.0, 21.5; HRMS (ESI-TOF) m/z: [M +

data was consistent with the reported data.

Na] Calcd for C H N NaO 297.1210; Found 297.1206.

1,3-Dimethyl-6-(tri�uoromethyl)quinoxalin-2(1H)-one (3n).

White solid; the product was puri�ed by �ash column chromatog-

raphy (PE-PE/EtOAc = 1:9 to 1:4) to a�ord the desired product;

24.6 mg, yield: 51%; m.p. 130−131 °C; IR (neat) v 2987, 2901, 1066,

-Benzyl-3-methylquinoxalin-2(1H)-one (3g). White solid; the

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 21.5 mg, yield:

−

1 1

3%; m.p. 107−108 °C;IR (neat) v 1643, 1599, 1569, 757, 751, 603

973, 794, 470 cm ; H NMR (400 MHz, Chloroform-d) �7.92 (d, J

= 8.3 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 3.74 (s, 3H),

2.63 (s, 3H); HRMS (ESI-TOF) m/z: [M+ H]⁺Calcd for

C H F N O 243.0740; Found 243.0743. The NMR data was

−

1 1

cm ; H NMR (400 MHz, Chloroform-d) �7.82 (dd, J = 7.9, 1.5 Hz,

H), 7.40 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.33−7.27 (m, 4H), 7.25−

13 1

.23 (m, 3H), 5.50 (s, 2H), 2.66 (s, 3H); C{ H} NMR (100 MHz,

Chloroform-d) � 158.5, 155.3, 135.2, 132.9, 132.6, 129.57, 129.55,

28.9, 127.7, 126.9, 123.7, 114.4, 45.9, 21.7; HRMS (ESI-TOF) m/z:

consistent with the reported data.

1,3-Dimethyl-2-oxo-1,2-dihydroquinoxalin-6-yl Acetate (3o).

Yellow solid; the product was puri�ed by �ash column chromatog-

raphy (PE-PE/EtOAc = 1:9 to 1:4) to a�ord the desired product;

23.4 mg, yield: 51%; m.p. 160−162 °C; IR (neat) v 2918, 1652, 1261,

[

M + Na] Calcd for C H N NaO 273.0998; Found 273.1005.

16 14 2

-(3-Methoxybenzyl)-3-methylquinoxalin-2(1H)-one (3h). Yellow

solid; the product was puri�ed by �ash column chromatography (PE-

PE/EtOAc = 1:9 to 1:4) to a�ord the desired product; 29.7 mg, yield:

−

1 1

1208, 1106, 1084, 754 cm ; H NMR (400 MHz, Chloroform-d) �

8.01 (d, J = 1.7 Hz, 1H), 7.99 (dd, J = 8.3, 1.7 Hz, 1H), 7.85 (d, J =

8.3 Hz, 1H), 3.99 (s, 3H), 3.76 (s, 3H), 2.63 (s, 3H); HRMS (ESI-

3%; m.p. 119−121 °C; IR (neat) v 1659, 1597, 1252, 1031, 788, 692

−1 1

cm ; H NMR (400 MHz, Chloroform-d) �7.81 (dd, J = 8.0, 1.5 Hz,

H), 7.40 (dd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.31−7.27 (m, 1H), 7.25−

TOF) m/z: [M + Na] Calcd for C H N NaO 255.0740; Found

.21 (m, 2H), 6.82−6.77 (m, 3H), 5.47 (s, 2H), 3.76 (s, 3H), 2.66 (s,

255.0750. The NMR data was consistent with the reported data.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.1c01325.

Article

,3,6,7-Tetramethylquinoxalin-2(1H)-one (3p). Black solid; the

= 0.8 Hz, 1H), 7.81 (d, J = 1.23 Hz, 1H), 6.98 (d, J = 1.2 Hz, 1H),

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 19.8 mg, yield:

9%; m.p. 140−142 °C; IR (neat) v 2969, 1412, 1076, 1066, 1056,

026, 898, 872 cm ; H NMR (400 MHz, Chloroform-d) � 7.54 (s,

H), 7.05 (s, 1H), 3.67 (s, 3H), 2.57 (s, 3H), 2.40 (s, 3H), 2.34 (s,

H); HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H N NaO

25.0998; Found 225.0999. The NMR data was consistent with the

reported data.

2.75 (d, J = 0.9 Hz, 3H); C{ H} NMR (100 MHz, Chloroform-d) �

146.8, 139.1, 138.8, 133.3, 118.0, 117.4, 16.6. HRMS (ESI-TOF) m/

z: [M + H] Calcd for C H ClN 168.0323; Found 168.0330.

−

1 1

3-Bromo-8-methylimidazo[1,2-b]pyridazine (3x). White solid;

the product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 17.1 mg, yield:

40%; m.p. 66−68 °C ; IR (neat) v 2917, 1269, 1065, 929, 834, 630,

−1 1

542, 455 cm ; H NMR (400 MHz, Chloroform-d) �8.34 (d, J = 4.6

Hz, 1H), 7.75 (s, 1H), 6.93−6.91 (m, 1H), 2.68 (d, J = 1.1 Hz, 3H);

6,7-Di�uoro-1,3-dimethylquinoxalin-2(1H)-one (3q). White solid;

the product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 24.3 mg, yield:

8%; m.p. 205−206 °C; IR (neat) v 2986, 2972, 2902, 1225, 1077,

066, 1057, 896 cm ; H NMR (400 MHz, Chloroform-d) � 7.61

dd, J = 10.3, 8.2 Hz, 1H), 7.10 (dd, J = 11.3, 7.1 Hz, 1H), 3.66 (s,

H), 2.57 (s, 3H); HRMS (ESI-TOF) m/z: [M + H] Calcd for

C{ H} NMR (100 MHz, Chloroform-d) � 143.8, 140.8, 137.7,

133.2, 116.3, 100.7, 16.0; HRMS (ESI-TOF) m/z: [M + H] Calcd

(

for C H BrN 211.9818; Found 211.9824.

−1 1

3-Ethynyl-8-methylimidazo[1,2-b]pyridazine (3y). Yellow solid;

the product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 4.0 mg, yield: 57%;

m.p. 177−178 °C ; IR (neat) v 2965, 2920, 1075, 1066, 1057, 1028,

C H F N O 211.0677; Found 211.0680. The NMR data was

−1 1

consistent with the reported data.

,7-Dichloro-1,3-dimethylquinoxalin-2(1H)-one (3r). Yellow

solid, the product was puri�ed by �ash column chromatography

PE-PE/EtOAc = 1:9 to 1:4) to a�ord the desired product; 19.4 mg,

835, 779 cm ; H NMR (400 MHz, Chloroform-d) �8.35 (d, J = 4.5

Hz, 1H), 7.97 (s, 1H), 6.94 (d, J = 4.5 Hz, 1H), 3.81 (s, 1H), 2.69 (s,

3H); C{ H} NMR (100 MHz, Chloroform-d) �143.9, 140.6, 138.0,

137.8, 117.3, 112.4, 87.0, 70.9, 16.4; HRMS (ESI-TOF) m/z: [M +

(

yield: 40%; m.p. 220−222 °C; IR (neat) v 2919, 1652, 1596, 1079,

067, 889 cm ; H NMR (400 MHz, Chloroform-d) �7.89 (s, 1H),

H] Calcd for C H N 158.0713; Found 158.0712.

−

1 1

.39 (s, 1H), 3.66 (s, 3H), 2.58 (s, 3H); HRMS (ESI-TOF) m/z: [M

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge at

�

H] Calcd for C H Cl N O 243.0086; Found 243.0088. The NMR

sı

data was consistent with the reported data.

,3-Dimethylbenzo[g]quinoxalin-2(1H)-one (3s). Black solid; the

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 19.7 mg, yield:

Setup for the photocatalytic procedure; Detailed

optimization of reaction conditions; Mechanistic studies

and computational details; H NMR and C NMR

5%; m.p. 200−202 °C; IR (neat) v 2960, 2918, 1650, 1623, 1600,

−1 1

077, 1066, 1056 cm ; H NMR (400 MHz, Chloroform-d) � 8.30

(

s, 1H), 7.97 (dd, J = 8.3 Hz, 1H), 7.90 (dd, J = 8.3 Hz, 1H), 7.59−

.54 (m, 2H), 7.48 (t, J = 7.4 Hz, 1H), 3.77 (s, 3H), 2.64 (s, 3H);

spectra for compounds 1e, 1h, and 3a-3y (PDF)

C{ H} NMR (100 MHz, Chloroform-d) � 159.0, 155.1, 133.3,

AUTHOR INFORMATION

32.0, 131.9, 130.0, 128.42, 128.39, 127.7, 127.1, 125.3, 110.0, 29.1,

1.8; HRMS (ESI-TOF) m/z: [M+ Na] Calcd for C H N NaO

�

Corresponding Authors

47.0842; Found 247.0840.

-Methyl-5-phenylpyrazin-2(1H)-one (3t). Yellow solid; the

Kai Chen − College of Chemistry and Chemical Engineering,

Central South University, Changsha 410083, P. R. China;

Key Laboratory of Chemical Oncogenomics, Peking

University Shenzhen Graduate School, Shenzhen 518055, P.

R. China; orcid.org/0000-0003-1012-0383;

Email: kaichen@csu.edu.cn

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 14.8 mg, yield:

0%; m.p. 223−225 °C; IR (neat) v 1643, 1255, 1075, 859, 776, 753

−1 1

cm ; H NMR (400 MHz, Chloroform-d) �7.79 (d, J = 7.5 Hz, 2H),

.61 (s, 1H), 7.46−7.42 (m, 4H), 2.59 (s, 3H); HRMS (ESI-TOF)

Hao-Yue Xiang − College of Chemistry and Chemical

Engineering, Central South University, Changsha 410083, P.

R. China; orcid.org/0000-0002-7404-4247;

Email: xianghaoyue@csu.edu.cn

Hua Yang − College of Chemistry and Chemical Engineering

and Key Laboratory of Hunan Province for Water

Environment and Agriculture Product Safety, Central South

University, Changsha 410083, P. R. China; orcid.org/

m/z: [M+ H] Calcd for C H N O 187.0866; Found 187.0892. The

NMR data was consistent with the reported data.

,3-Dimethyl-5-phenylpyrazin-2(1H)-one (3u). Yellow solid; the

product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 37.2 mg, yield:

7%; m.p. 108−109 °C; IR (neat) v 2968, 2919, 1275, 1076, 1066,

−1 1

057, 1028, 692 cm ; H NMR (400 MHz, Chloroform-d) � 7.76−

.73 (m,2H), 7.44−7.40 (m, 3H), 7.35−7.31 (m, 1H), 3.60 (s, 3H),

.56 (s, 3H); HRMS (ESI-TOF) m/z: [M+ Na] Calcd for

0000-0002-5518-5255; Email: hyangchem@csu.edu.cn

C H N NaO 223.0842; Found 223.0823. The NMR data was

consistent with the reported data.

Authors

8-Methylimidazo[1,2-b]pyridazine (3v). Yellow solid; the product

Fang Liu − College of Chemistry and Chemical Engineering,

was puri�ed by �ash column chromatography (PE-PE/EtOAc = 1:9

to 1:4) to a�ord the desired product; 12.2 mg, yield: 46%

Central South University, Changsha 410083, P. R. China

Zhi-Peng Ye − College of Chemistry and Chemical

Engineering, Central South University, Changsha 410083, P.

R. China

(

Ir[dF(CF )ppy] (dtbbpy)PF was used), 19.4 mg, yield: 73% (fac-

3 2 6

Ir(ppy) was used);m.p. 55−56 °C; IR (neat) v 1341, 1272, 843, 726,

(

−

1 1

39, 575,508, 489 cm ; H NMR (400 MHz, Chloroform-d) � 8.18

d, J = 4.6 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 1.1 Hz, 1H),

.84 (dq, J = 4.6, 1.1 Hz, 1H), 2.67 (d, J = 1.0 Hz, 3H); HRMS (ESI-

Yuan-Zhuo Hu − College of Chemistry and Chemical

Engineering, Central South University, Changsha 410083, P.

R. China

Jie Gao − College of Chemistry and Chemical Engineering,

Central South University, Changsha 410083, P. R. China

Lan Zheng − College of Chemistry and Chemical Engineering,

Central South University, Changsha 410083, P. R. China

Xiao-Qing Chen − College of Chemistry and Chemical

Engineering and Key Laboratory of Hunan Province for

TOF) m/z: [M+ Na] Calcd for C H N Na 156.0532; Found

56.0531.The NMR data was consistent with the reported data.

-Chloro-8-methylimidazo[1,2-b]pyridazine (3w). White solid;

the product was puri�ed by �ash column chromatography (PE-PE/

EtOAc = 1:9 to 1:4) to a�ord the desired product; 11.4 mg, yield:

(

4% (Ir[dF(CF )ppy] (dtbbpy)PF was used, 13.7 mg, yield: 41%

3 2 6

fac-Ir(ppy) was used); m.p. 40−41 °C; IR (neat) v 1341, 1272, 843,

−

1 1

26, 639, 575 cm ; H NMR (400 MHz, Chloroform-d) �7.97 (d, J

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

orcid.org/0000-0002-8768-8965

Article

Water Environment and Agriculture Product Safety, Central

South University, Changsha 410083, P. R. China;

Bhowmick, T.; Punniyamurthy, T.; Dey, D.; Nath, J.; Chaudhuri, M.

K. Molybdenum(VI)-Peroxo Complex Catalyzed Oxidation of

Alkylbenzenes with Hydrogen Peroxide. Tetrahedron Lett. 2003, 44,

Complete contact information is available at:

915−4917.

https://pubs.acs.org/10.1021/acs.joc.1c01325

7) (a) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Privileged

Scaffolds for Library Design and Drug Discovery. Curr. Opin. Chem.

Biol. 2010, 14, 347−361. (b) Baumann, M.; Baxendale, I. R. An

Overview of the Synthetic Routes to the Best Selling Drugs

Containing 6-Membered Heterocycles. Beilstein J. Org. Chem. 2013,

Notes

The authors declare no competing �nancial interest.

, 54. (c) Abbas, H.-A. S.; Al-Marhabi, A. R.; Eissa, S. I.; Ammar, Y. A.

Molecular Modeling Studies and Synthesis of Novel Quinoxaline

Derivatives with Potential Anticancer Activity as Inhibitors of c-Met

Kinase. Bioorg. Med. Chem. 2015 , 23 , 6560−6572. (d) Lamberth, C.

Pyridazine Chemistry in Crop Protection. J. Heterocycl. Chem. 2017,

ACKNOWLEDGMENTS

�

We gratefully acknowledge the �nancial support from the

National Natural Science Foundation of China (22078370,

1776318, 22078369, 22003077), the Basic Science Center

Project for the National Natural Science Foundation of China

No. 72088101, the Theory and Application of Resource and

Environment Management in the Digital Economy Era), the

Natural Science Foundation of Hunan Province (2018JJ3868,

4, 2974−2984. (e) Xia, P.-J.; Hu, Y.-Z.; Ye, Z.-P.; Li, X.-J.; Xiang, H.-

Y.; Yang, H. O-Perfluoropyridin-4-yl Oximes: Iminyl Radical

Precursors for Photoor Thermal-Induced N −O Cleavage in C-

(

sp )−C(sp ) Bond Formation. J. Org. Chem. 2020, 85, 3538 −3547.

f) He, Z.-X.; Gong, Y.-P.; Zhang, X.; Ma, L.-Y.; Zhao, W. Pyridazine

as a Privileged Structure: An Updated Review on Anticancer Activity

of Pyridazine Containing Bioactive Molecules. Eur. J. Med. Chem.

020JJ4682), the Fundamental Research Funds for Central

South University (2020zzts401), and Central South University.

2021, 209, 112946.

(8) (a) Ohki, Y.; Hatanaka, T.; Tatsumi, K. C-H Bond Activation of

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