Metal-free C3-H acylation of quinoxalin-2(1: H)-ones with α-oxo-carboxylic acids

Article abstract of DOI:10.1039/d0ob01423k

Direct C3-H acylation of quinoxalin-2(1H)-ones with α-oxocarboxylic acids under thermo conditions promoted by PIDA has been achieved in a moderate to good yield in a very fast manner. Mechanistic study revealed that the reaction proceeds via a radical pro

Full text of DOI:10.1039/d0ob01423k

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DOI: 10.1039/D0OB01423K
ARTICLE
Metal-free C3-H acylation of quinoxalin-2(1H)-ones with α-oxo-
carboxylic acids
Hangcheng Ni,* Xingzi Shi, Yu Li, Xiaoning Zhang, Jingwei Zhao* and Fei Zhao*
Received 00th January 20xx,
Accepted 00th January 20xx
Direct C3-H acylation of quinoxalin-2(1H)-ones with α-oxocarboxylic acids under thermo conditions promoted by PIDA has
been achieved in moderate to good yield in a very fast manner. Mechanistic study revealed that the reaction proceeds via
radical process. In addition, this method could be applied to gram-scale reaction and antitumor agent synthesis. This work
represents a simple, convenient and efficient synthesis of 3-acylated quinoxalin-2(1H)-ones.
DOI: 10.1039/x0xx00000x
O
O
N
N
TBHP (4.0 eq.)
DCE, 70 oC, 5 h
Ar
a)
Introduction
R2
R2
+
Ar
H
N
R1
O
O
N
R1
O
O
Among nitrogen-containing heterocycles, quinoxalin-2(1H)-one
core is widely found in various pharmacologically compounds
with biological and pharmaceutical applications.1 A variety of
bioactive compounds like benzodiazepine receptor panadiplon
with this important pharmacophore have entered into clinical
trials.2 Hence, this privileged skeleton has caught considerable
attention with respect to the development of new synthetic
methodology for its functionalization.3 In recent years, direct
C3-H functionalization of quinoxalin-2(1H)-ones including
alkylation,4 arylation,5 alkoxycarbonylation,6 amidation,7
amination8 and phosphonation9 have been well developed to
access 3-substituted quinoxalin-2(1H)-ones.
With the development of radical reactions,10 C3-H acylation
via radical process are becoming a viable tool for the
preparation of C3-acylated quinoxalin-2(1H)-ones. Generally,
arylaldehydes and α-oxo-carboxylic acids are utilized as the
radical precursors for the generation of acyl radical through
hydrogen atom transfer (HAT) and oxidative decarboxylative
process. In 2018, Qu and Yuan reported a TBHP promoted direct
C3-H acylation of quinoxalin-2(1H)-ones with arylaldehydes as
the radical precursors (Scheme 1a).11 For α-oxo-carboxylic acids
as radical precursors, oxidative decarboxylative strategy was
employed with transition metal catalysts and photoredox
catalysts. For example, Wang and Hu disclosed a Ag(I)-mediated
decarboxylative acylation with K2S2O8 as oxidant (Scheme 1b).12
In 2020, Wei discovered a visible-light-catalyzed aerobic
oxidative C3-H decarboxylative acylation with acridine red as
the photocatalyst (Scheme 1b),13 though N1 unprotected
ref. 11
N
N
O
R3
Condition
R2
R2
b)
+
R3 COOH
N
R1
N
R1
O
Condition: 1. Ag catalyst (10%), K2S2O8 (2.0 eq.)
aq. MeCN, 100 oC, 3 h, ref. 12
2. Acridine Red (1%), O2, DCE, Blue LED, 8 h, ref. 13
3. PIDA (4.0 eq.), H2O, Blue LED, 24 h, ref. 14
This work
O
N
N
O
R3
PIDA (2.0 eq.)
R2
R2
c)
+
MeCN, 80 o
C
R3 COOH
N
R1
O
N
R1
O
Fast, 0.5 h-1.5 h
Transition metal free
Unprotected N-H
Gram scale reaction
Antitumor agent synthesis
Scheme 1. Methods towards the synthesis of 3-acyl quinoxalin-2(1H)-ones.
quinoxalin-2(1H)-ones were not tolerated. Recently, Xu and
Xuan reported a visible-light-promoted C3-H decarboxylative
acylation with α-oxo-carboxylic acids as radical precursors
(Scheme 1b).14 However, excess amount of α-oxo-carboxylic
acids (4 equiv.) and phenyliodine (III) diacetate (PIDA, 4 equiv.)
and long reaction time (24 h) were required for this reaction.
Herein, we described a simple, efficient and convenient
synthesis of 3-substituted quinoxalin-2(1H)-ones under thermo
condition promoted by PIDA in a very fast manner (Scheme 1c).
Results and discussion
As shown in Table 1, reaction of unprotected quinoxalin-2(1H)-
one 1a with 2 equiv. of 2-oxo-2-phenylacetic acid 2a in the
presence of 2 equiv. of PIDA under nitrogen atmosphere at 80
oC for 16 h gave the desired 3-acylated product 3a in 76%
isolated yield (entry 1). Yield was slightly improved to 77% with
1.5 equiv. of PIDA while 1 equiv. gave the product in lower yield
Jinhua Branch, Sichuan Industrial Institute of Antibiotics, Chengdu University, 888
West Hai Tang Road, Jinhua321007, China. E-mail: nihc@hotmail.com;
zhaojingwei_siia@126.com; zhaofei@cdu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 1. Optimization of reaction conditionsa
Table 2. Scope of quinoxalin-2(1H)-ones and α-oxocarboxylicacidsa,b
View Article Online
DOI: 10.1039/D0OB01423K
O
O
N
N
O
R3
N
PIDA
CH3CN, 80 o
N
O
PIDA (equiv)
T (oC), t (h)
R2
+
Ph
R2
R3 COOH
+
C
N
R1
O
N
R1
O
Ph
COOH
2a
0.5 h
N
H
O
N
H
O
1
2
O
3
1a
3a
O
O
O
O
N
N
N
N
N
2
PIDA
(equiv.)
Ph
Ph
Ph
Ph
Ph
Entry
t (h)
Solvent
Yield (%)b
(equiv.)
N
H
O
O
N
N
O
Me
2.0
1.5
1.0
16 h
16 h
16 h
CH3CN
CH3CN
CH3CN
1
2
3
2.0
2.0
2.0
76
77
68
Ph
3a
, 87%
3b
3d
, 87%
, 69%
N
3c
, 88%
O
O
O
O
O
O
O
O
N
N
N
N
N
Me
Me
Ph
Ph
Ph
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
16 h
CH3CN
CH3CN
CH3CN
CH3CN
DCE
4
5
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
72
85
87
52
84
86
66
6
N
N
H
3 h
COPh
, 79%
COOEt
, 90%
c
3e
, 79%
N
3g
3h
3f
, 77%
30 min
10 min
30 min
30 min
30 min
30 min
30 min
30 min
6
O
O
7
c
3j
3n
N
R = p-OMe, , 93% R = p-Ph, , 59%
Cl
Cl
Ph
c
c
3k
3o
R = p-Me, , 71% R = p-Cl, , 35%
R
8
c
c
3l
R = o-Me, , 84%
3p
R = p-Br, , 43%
N
H
O
N
H
O
c
c
toluene
DMF
3m
3q
R = m-Me,
, 64% R = p-CF3, , <10%
9
c
3i
, 71%
N
10
11
12 c
13 d
O
O
O
N
N
H2O
Me
CH3CN
CH3CN
42
29
N
H
O
N
O
N
H
O
Me
c
c
c,d
3r
, 24%
3s
, 70%
3t
, 36%
a All reactions were conducted at 0.3 mmol scale of 1 in 3.0 mL of acetonitrile
in a closed flask under nitrogen atmosphere at 80 oC. b Isolated yield. c Reaction
conducted under air. d Reaction conducted at 60 oC.
a All reactions were conducted at 0.3 mmol scale of 1 in 3.0 mL of acetonitrile with
2 equiv. of 2 and 1.5 equiv. of PIDA in a closed flask under nitrogen atmosphere. b
Isolated yield. c Reacting for 1.5 h. d With 4 equiv. of 2 and 3 equiv. of PIDA.
(entry 2-3). 2.0 equiv. of 2a was essential for this reaction as 1.5
equiv. of 2a provided the product in lower yield (entry 4). Then,
reaction time was investigated for this reaction (entry 5-7).
Unexpectedly, the acylation reaction was completed in 30 min,
and the desired product was obtained in 87% yield (entry 6).
Results of solvent optimization indicated that acetonitrile was
the best choice, though other solvents like 1,2-dichloroethane
and toluene also gave the desired product in good yield (entry
8-11). This reaction was very sensitive to air, since the product
was formed only in 42% yield under air (entry 12). In addition,
yield decreased dramatically at lower temperature (60 oC)
(entry 13).
Under the optimal reaction condition, the substrate scope
was examined, and results were compiled in Table 2. Generally,
the acylation reaction proceeded well to give the product in
moderate to good yield. N-substituted quinoxalin-2(1H)-ones
gave the product in 69%-90% yield (3a-3g). It was noteworthy
that various important and active functional groups, such
alkenyl, alkynyl, ketyl and esteryl groups were well tolerated in
this reaction, though lower yield were obtained for substrates
with alkenyl (3d) and alkynyl (3e) group, which might be due to
the radical addition of the acyl radical to reactive unsaturated
bonds.10a Unprotected quinoxalin-2(1H)-ones with methyl or
chloride group on the benzene ring gave the desired product 3h
and 3i in 77% and 71% yield, respectively.
This might be attributed to that the reactivity of the nucleophilic
acyl radical was reduced due to the attached electron-
withdrawing group.14 Naphthyl substituted α-oxo-carboxylic
acids were well tolerated the acylation reaction to deliver the
desired product (3r and 3s), and higher yield was obtained with
2-(naphthalen-1-yl)-2-oxoacetic acid. Apart from the aromatic
α-oxocarboxylic acids, C3 acylated product (3t) could be
synthesized with aliphatic α-oxocarboxylic acid, though in lower
yield.
To demonstrate the utility of the acylation reaction, a gram-
scale reaction was carried out under the standard condition. To
our delight, this scale-up acylation reaction provided the
desired product 3a in an acceptable 72% isolated yield (1.08 g)
(Scheme 2a). In addition, potential antitumor agent15 was
synthesized in a total 59% yield in three steps using our method
as a key step, which indicated the practicality of our
decarboxylative acylation method (Scheme 2b).
O
N
N
O
PIDA
CH3CN, 80 o
30 min
Ph
+
a)
C
Ph
COOH
2a
N
H
O
N
H
O
1a
, 6 mmol
3a
1.08 g, 72%
O
O
O
N
N
N
Ph
COOH
Ph
b)
Ph
POCl3
120 oC, 3 h
76%
key step
87%
N
O
N
H
3a
O
Subsequently, various α-oxocarboxylic acids
2
were
N
Cl
H
1a
4
investigated under standard reaction condition. The electronic
property of α-oxocarboxylic acids affected greatly on the
efficiency of the acylation reaction. α-Oxocarboxylic acids 2 with
electron-donating group (3j-3n) gave the desired products in
higher yield than 2 with electron-withdrawing group (3o-3q).
O
N
1-Phenylpiperazine
Ph
N
100 oC, 2 h
89%
N
N
Ph
5
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Scheme 2. Gram scale reaction and synthesis of the potential antitumor agent.
protocol very attractive both in pharmaceutical cVhieewmAirstitcrleyOanlninde
organic chemistry.
O
DOI: 10.1039/D0OB01423K
N
N
O
O
PIDA
CH3CN, 80 o
Ph
+
N
C
Ph
COOH
Ph
O
N
H
1a
O
N
H
3a
O
30 min
TEMPO
2a
6a
, detected by HRMS
Experimental
1.0 eq. 36%
2.0 eq. trace
Scheme 3. Mechanistic study.
General experimental method
1H NMR spectra were recorded on
a Bruker DPX600
Ph
I
spectrometer at 600 MHz or a Bruker DPX500 spectrometer at
500 MHz. 13C NMR spectra were recorded on a Bruker DPX600
spectrometer at 600 MHz or a Bruker DPX500 spectrometer at
151 MHz or 125 MHz. All chemical shifts were reported in δ
units with references to the residual solvent resonances of the
deuterated solvents for proton and carbon chemical shifts.
HRMS spectra were obtained on a Thermo Q Exactive
spectrometer. Compounds 1b-1i and 2b-2k were prepared
using literature methods.15 All other chemicals were purchased
from Chemical Co. and used as received unless otherwise
specified.
O
O
Ph
I
O
AcO
OAc
(PIDA)
Ph
Ph
thermal I-O
homolysis
Ph
COOH
O
O
2
O
O
A
O
CO2
O
Ph
O
O
B
O
N
Ph
1a
Ph
O
N
O
O
Ph
H
Ph
I
D
E
O
PhI + CO2
C
H+
O
O
H
N
General procedure for the synthesis of product (3a-3t)
N
1,2-H migration
Ph
Ph
H
O
A flame-dried Schlenk-tube equipped with a magnetic stir bar
was charged with 1 (0.3 mmol), 2 (0.6 mmol, 2.0 equiv) and PIDA
(0.45 mmol, 1.5 equiv). Then, the resulting mixture was
evacuated and purged with nitrogen for 3 times. The reaction
N
H
O
N
H
-
C
OAc +
C
PIDA or
F
B
or PhI +
Scheme 4. Proposed mechanism.
o
mixture was stirred at 80 C for 0.5 h -1.5 h. After that, 20 mL
sat. NaHCO3 aq. was added to the reaction mixture, and the
resulting solution was extracted with ethyl acetate (20 mL* 3).
The combined organic solvent was dried over Na2SO4, and then
removed under reduced pressure with a rotary evaporator. The
crude residue was purified by silica gel column chromatography
with ethyl acetate and petrol ether or dichloromethane and
ethyl acetate to give the pure product 3.
In order to gain some insight into the reaction mechanism,
radical trapping experiments were carried out with 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) as the radical scavenger
(Scheme 3). Addition of 1 equiv of TEMPO into the standard
reaction greatly decreased the yield to 36%, and the TEMPO
adduct 6a was detected by HRMS. The reaction was completely
inhibited with 2 equiv of TEMPO. These experiments indicated
that radical process was likely to be involved in this acylation
reaction.
According to the preliminary mechanistic studies and
literature,10-14 a plausible mechanism is proposed in Scheme 4.
Reaction of PIDA with α-oxocarboxylic acid gives the
hypervalent iodine(III) reagent A, which undergoes thermo C-I
bond homolysis to generate the oxygen-centered radical B and
C. Fragment of B and C gives the acyl radical D, and addition of
D to C=N bond of quinoxalin-2(1H)-one affords the nitrogen-
centered radical E. 1,2-H migration of E and the following
oxidative deprotonation of F forms the final product.
3-Benzoylquinoxalin-2(1H)-one (3a):
Yellow solid. Yield: 87%. 1H NMR (600 MHz, DMSO-d6): δ 12.87
(s, 1H) (NH), 7.97 (d, J = 7.7 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.74
(t, J = 7.4 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H),
7.41 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H) (aromatic H). 13
C
NMR (151 MHz, DMSO-d6): δ 192.49, 156.30 (CO), 153.42,
134.66, 134.59, 132.71, 131.79, 131.25, 129.69, 129.14, 129.06,
123.86, 115.94 (aromatic C). This is a known structure. These
data are similar to the reported one.14
3-Benzoyl-1-methylquinoxalin-2(1H)-one (3b):
1
Pale yellow solid. Yield: 87%. H NMR (600 MHz, DMSO-d6): δ
7.98 – 7.96 (m, 2H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.79 – 7.73 (m,
2H), 7.70 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 7.9 Hz, 2H), 7.48 – 7.45
(m, 1H) (aromatic H), 3.67 (s, 3H) (CH3). 13C NMR (151 MHz,
DMSO-d6): δ 192.28, 154.82 (CO), 152.89, 134.67, 134.46,
133.94, 132.03, 131.72, 129.90, 129.72, 129.03, 123.98, 115.25
(aromatic C), 28.99 (CH3). This is a known structure. These data
are similar to the reported one.14
Conclusions
In summary, metal-free C3-H acylation of quinoxalin-2(1H)-ones
with α-oxocarboxylic acid under thermo conditions promoted
by PIDA has been achieved in a simple, convenient and efficient
way. Under the standard condition, a variety of versatile
functional groups were tolerated in this reaction to give the
desired product in moderate to good yield. In addition, this
method could be applied to gram-scale reaction and antitumor
agent synthesis. These features including simplicity, high
efficiency and excellent functional group tolerance make our
3-Benzoyl-1-benzylquinoxalin-2(1H)-one (3c):
1
Yellow solid. Yield: 88%. H NMR (600 MHz, DMSO-d6): δ 8.04
(d, J = 7.9 Hz, 2H), 7.92 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H),
7.67 (t, J = 7.1 Hz, 1H), 7.59 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.37
– 7.33 (m, 4H), 7.28 (t, J = 6.6 Hz, 1H) (aromatic H), 5.54 (s, 2H)
(CH2). 13C NMR (151 MHz, DMSO-d6): δ 192.07, 154.86 (CO),
153.07, 135.47, 134.74, 134.45, 133.09, 132.09, 132.03, 130.24,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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129.81, 129.08, 128.80, 127.50, 126.89, 124.20, 115.53 125.61, 116.93 (aromatic C). This is a known structure. These
View Article Online
(aromatic C), 45.00 (CH2). This is a known structure. These data data are similar to the reported one.12
DOI: 10.1039/D0OB01423K
are similar to the reported one.14
3-(4-Methoxybenzoyl)-quinoxalin-2(1H)-one (3j):
White solid. Yield: 93%. MP: 242.7-243.5 oC. 1H NMR (600 MHz,
1-Allyl-3-benzoylquinoxalin-2(1H)-one (3d):
1
Yellow solid. Yield: 69%. H NMR (600 MHz, DMSO-d6): δ 7.99 DMSO-d6): δ 12.81 (s, 1H) (NH), 7.93 (d, J = 8.9 Hz, 2H), 7.81 (d,
(d, J = 7.8 Hz, 2H), 7.90 (d, J = 7.9 Hz, 1H), 7.76 – 7.73 (m, 2H), J = 7.9 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.53 – 7.27 (m, 2H), 7.08
7.63 (d, J = 8.5 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H), 7.46 (t, J = 7.6 Hz, (d, J = 8.8 Hz, 2H) (aromatic H), 3.87 (s, 3H) (CH3).13C NMR (151
1H) (aromatic H), 6.01 – 5.95 (m, 1H), 5.24 – 5.16 (m, 2H) MHz, DMSO-d6): δ 190.75, 164.27 (CO), 156.65, 153.39, 132.63,
(olefinic H), 4.93 (d, J = 5.3 Hz, 2H) (CH2). 13C NMR (151 MHz, 132.19, 131.55, 131.21, 129.03, 127.59, 123.75, 115.85, 114.34
DMSO-d6): δ 192.14, 154.79 (CO), 152.51, 134.72, 134.45, (aromatic C), 55.74 (OCH3). HRMS (ESI): m/z calcd for
133.04, 132.02, 131.91, 131.33, 130.11, 129.76, 129.06 C16H12N2O3 [M+H]+: 281.0921. Found: 281.0914.
(aromatic C), 124.08, 117.46, 115.54 (olefinic C), 43.90 (CH2).
3-(4-Methylbenzoyl)-quinoxalin-2(1H)-one (3k):
This is a known structure. These data are similar to the reported Yellow solid. Yield: 71%. 1H NMR (600 MHz, DMSO-d6): δ 12.84
one.14
3-Benzoyl-1-(2-propynyl)quinoxalin-2(1H)-one (3e):
(s, 1H) (NH), 7.85 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.65
(t, J = 7.7 Hz, 1H), 7.44 – 7.30 (m, 4H) (aromatic H), 2.41 (s, 3H)
Yellow solid. Yield: 79%. 1H NMR (600 MHz, DMSO-d6): δ 8.07 – (CH3). 13C NMR (151 MHz, DMSO-d6): δ 191.99, 156.50 (CO),
7.94 (m, 2H), 7.92 (dd, J = 8.0, 1.3 Hz, 1H), 7.87 – 7.80 (m, 1H), 153.39, 145.39, 132.67, 132.20, 131.67, 131.23, 129.80, 129.59,
7.77 – 7.70 (m, 2H), 7.58 (t, J = 7.8 Hz, 2H), 7.50 (t, J = 7.6 Hz, 129.09, 123.81, 115.91 (aromatic C), 21.37 (CH3). This is a known
1H) (aromatic H), 5.13 (d, J = 2.5 Hz, 2H) (CH2), 3.43 (t, J = 2.5 Hz, structure. These data are similar to the reported one.11
1H) (alkynyl H). 13C NMR (151 MHz, DMSO-d6): δ 191.80, 154.58
3-(2-methylbenzoyl)-quinoxalin-2(1H)-one (3l):
(CO), 151.95, 134.81, 134.31, 132.31, 132.24, 131.86, 130.21, White solid. Yield: 84%. MP: 202.1-204.6 oC. 1H NMR (600 MHz,
129.81, 129.08, 124.47, 115.41 (aromatic C), 77.66, 75.64 DMSO-d6) : δ 12.84 (s, 1H) (NH), 7.81 (d, J = 8.0 Hz, 1H), 7.69 (d,
(alkynyl C), 31.35 (CH2). This is a known structure. These data J = 7.8 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),
are similar to the reported one.14
7.43 – 7.34 (m, 3H), 7.32 (d, J = 7.5 Hz, 1H) (aromatic H), 2.57 (s,
3H) (CH3). 13C NMR (151 MHz, DMSO-d6): δ 194.35, 156.99 (CO),
Ethyl 2-(3-benzoyl-2-oxoquinoxalin-1(2H)-yl)acetate (3f):
1
Yellow solid. Yield: 90%. H NMR (600 MHz, DMSO-d6): δ 7.94 153.28, 139.43, 133.94, 133.23, 132.65, 132.43, 132.10, 131.70,
(d, J = 8.0 Hz, 3H), 7.81 – 7.71 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 131.14, 129.09, 126.13, 123.82, 115.86 (aromatic C), 21.13
7.59 (t, J = 7.8 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H) (aromatic H), 5.18 (CH3). HRMS (ESI): m/z calcd for C16H12N2O2 [M+H]+: 265.0972.
(s, 2H), 4.19 (q, J = 7.1 Hz, 2H) (CH2), 1.22 (t, J = 7.1 Hz, 3H) (CH3). Found: 265.0966.
13C NMR (151 MHz, DMSO-d6): δ 191.72, 167.22, 154.39 (CO),
3-(3-Methylbenzoyl)-quinoxalin-2(1H)-one (3m):
152.61, 134.85, 134.31, 133.17, 132.39, 131.68, 130.27, 129.64, Yellow solid. Yield: 64%. MP: 182.0-182.7 oC. 1H NMR (600 MHz,
129.14, 124.45, 115.09 (aromatic C), 61.58 (CH2), 43.67, 14.00 DMSO-d6): δ 12.84 (s, 1H) (NH), 7.83 (d, J = 7.9 Hz, 1H), 7.78 (s,
(CH3). This is a known structure. These data are similar to the 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.55 (d, J =
reported one.14
1-Acetylphenyl-3-benzoylquinoxalin-2(1H)-one (3g):
7.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.43 – 7.34 (m, 2H) (aromatic
H), 2.37 (s, 3H) (CH3). 13C NMR (151 MHz, DMSO-d6): δ 192.63,
Yellow solid. Yield: 79%. 1H NMR (600 MHz, DMSO-d6): δ 8.17 – 156.49 (CO), 153.37, 138.58, 135.27, 134.65, 132.67, 131.66,
8.15 (m, 2H), 7.97 – 7.95 (m, 3H), 7.78 – 7.74 (m, 2H), 7.72 – 131.24, 129.87, 129.10, 128.89, 126.90, 123.79, 115.90
7.70 (m, 1H), 7.66 – 7.58 (m, 5H), 7.47 – 7.50 (m, 1H) (aromatic (aromatic C), 20.71 (CH3). HRMS (ESI): m/z calcd for C16H12N2O2
H), 6.01 (s, 2H) (CH2). 13C NMR (151 MHz, DMSO-d6): δ 192.03, [M+H]+: 265.0972. Found: 265.0966. This is a known structure.
191.85, 154.37 (CO), 152.67, 134.81, 134.37, 134.29, 133.59, These data are similar to the reported one.16
132.30, 131.76, 130.20, 129.60, 129.15, 129.00, 128.40, 124.31,
3-(1-Biphenylcarbonyl)quinoxalin-2(1H)-one (3n):
1
115.39 (aromatic C), 49.08 (CH2). This is a known structure. Yellow solid. Yield: 71%. MP: 287.3-290 oC. H NMR (600 MHz,
These data are similar to the reported one.14
DMSO-d6): δ 12.88 (s, 1H) (NH), 8.05 (d, J = 8.3 Hz, 2H), 7.87 (d,
J = 8.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 2H),
3-Benzoyl-6,7-dimethylquinoxalin-2(1H)-one (3h):
1
White solid. Yield: 77%. H NMR (600 MHz, DMSO-d6): δ 12.75 7.66 (t, J = 7.7 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.48 – 7.36 (m,
(s, 1H) (NH), 7.93 (d, J = 8.3 Hz, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.60 3H) (aromatic H). 13C NMR (151 MHz, DMSO-d6): δ 191.98,
(s, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.16 (s, 1H) (aromatic H), 2.36 (s, 156.27 (CO), 153.43, 145.93, 138.72, 133.43, 132.74, 131.79,
3H), 2.30 (s, 3H) (CH3). 13C NMR (151 MHz, DMSO-d6): δ 192.58, 131.27, 130.41, 129.16, 128.69, 127.24, 127.16, 123.85, 115.94
154.80 (CO), 153.46, 141.80, 134.78, 134.50, 132.77, 130.77, (aromatic C). HRMS (ESI): m/z calcd for C21H14N2O2 [M+H]+:
129.75, 129.62, 129.00, 128.83, 115.81 (aromatic C), 19.95, 327.1128. Found: 327.1121.
18.87 (CH3). This is a known structure. These data are similar to
the reported one.14
3-Benzoyl-6,7-dichloroquinoxalin-2(1H)-one (3i):
3-(4-Chlorobenzoyl)-quinoxalin-2(1H)-one (3o):
Yellow solid. Yield: 35%. MP: 250.4-252.1 oC. 1H NMR (600 MHz,
DMSO-d6): δ 12.87 (s, 1H) (NH), 8.01 (d, J = 8.5 Hz, 2H), 7.83 (d,
Yellow solid. Yield: 71%. 1H NMR (600 MHz, DMSO-d6): δ 13.00 J = 7.6 Hz, 1H), 7.67 – 7.64 (m, 3H), 7.42 – 7.35 (m, 2H) (aromatic
(s, 1H) (NH), 8.17 (s, 1H), 8.00 (d, J = 7.3 Hz, 2H), 7.75 (t, J = 7.4 H). 13C NMR (126 MHz, DMSO-d6): δ 191.39, 155.66 (CO),
Hz, 1H), 7.58 (t, J = 7.9 Hz, 2H), 7.55 (s, 1H) (aromatic H). 13C 153.40, 139.66, 133.32, 132.82, 131.94, 131.58, 131.26, 129.23,
NMR (151 MHz, DMSO-d6): δ 191.86, 157.66 (CO), 153.07, 129.20, 123.87, 115.93 (aromatic C). HRMS (ESI): m/z calcd for
134.87, 134.29, 133.81, 132.67, 130.72, 130.13, 129.79, 129.06,
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
C15H9ClN2O2 [M+H]+: 285.0425. Found: 285.0424. This is a 129.16, 128.21 (aromatic C). This is a known structure. These
View Article Online
known structure without spectra.17
data are similar to the reported one.17
DOI: 10.1039/D0OB01423K
3-(4-Bromobenzoyl)-quinoxalin-2(1H)-one (3p):
A mixture of chloroquinoxaline (4a, 0.3 mmol) and 1-
1
Pale yellow solid. Yield: 43%. H NMR (600 MHz, DMSO-d6): δ phenylpiperazine (1.5mmol) was stirred under heating at 100 °C
12.88 (s, 1H) (NH), 7.93 (dd, J = 8.5, 1.5 Hz, 2H), 7.83 (d, J = 7.9 for 2 h. On cooling, the mixture was taken up with water, and
Hz, 1H), 7.81 – 7.72 (m, 2H), 7.66 (t, J = 7.7 Hz, 1H), 7.45 – 7.32 the aqueous solution was extracted with ethyl acetate for 3
(m, 2H) (aromatic H). 13C NMR (151 MHz, DMSO-d6): δ 191.61, times. The combined organic solvent was dried over Na2SO4,
155.62 (CO), 153.39, 133.64, 132.81, 132.17, 131.95, 131.71, and then removed under reduced pressure with a rotary
131.60, 131.25, 129.20, 128.99, 123.87, 115.93 (aromatic C). evaporator. The crude residue was purified by silica gel column
This is a known structure. These data are similar to the reported chromatography with ethyl acetate and petrol ether to give the
one.11
3-(β-naphthoyl)-quinoxalin-2(1H)-one (3r):
pure product 5a as a yellow solid.
3-Benzoyl-2-(4-phenylpiperazine)quinoxaline (5a):
Yellow solid. Yield: 24%. 1H NMR (600 MHz, DMSO-d6): δ 12.90 Yellow solid. Yield: 89%. H NMR (600 MHz, Chloroform-d): δ
(s, 1H) (NH), 8.63 (s, 1H), 8.17 – 8.08 (m, 2H), 8.07 – 7.99 (m, 8.05 (d, J = 7.9 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.4
2H), 7.86 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.68 (t, J = Hz, 1H), 7.74 – 7.61 (m, 2H), 7.59 – 7.42 (m, 3H), 7.35 – 7.13 (m,
7.7 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.40 2H), 7.03 – 6.76 (m, 3H) (aromatic H), 3.70 (t, J = 5.1 Hz, 4H),
(t, J = 7.6 Hz, 1H) (aromatic H). 13C NMR (151 MHz, DMSO-d6): δ 3.18 (t, J = 5.1 Hz, 4H) (CH2). 13C NMR (151 MHz, DMSO-d6): δ
192.60, 156.56 (CO), 153.54, 135.65, 133.32, 132.80, 132.12, 192.76 (CO), 151.40, 150.57, 144.14, 140.97, 135.28, 134.88,
131.99, 131.72, 131.40, 129.84, 129.45, 129.19, 128.84, 127.84, 134.48, 131.58, 130.47, 129.00, 128.95, 128.74, 126.31, 126.06,
127.20, 123.82, 123.48, 115.93 (aromatic C). HRMS (ESI): m/z 119.06, 115.42 (aromatic C), 47.49, 47.29 (CH2). This is a known
1
calcd for C9H12N2O2 [M+H]+: 301.0965. Found: 301.0972.
structure. These data are similar to the reported one.17
3-(α-naphthoyl)-quinoxalin-2(1H)-one (3s):
1
Yellow solid. Yield: 70%. MP: decomposed. H NMR (600 MHz,
Conflicts of interest
There are no conflicts to declare.
DMSO-d6): δ 12.88 (s, 1H) (NH), 9.01 (d, J = 8.6 Hz, 1H), 8.29 (d,
J = 8.2 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.08 (s, 1H), 7.83 (d, J =
7.9 Hz, 1H), 7.80 – 7.74 (m, 1H), 7.72 – 7.64 (m, 2H), 7.59 (t, J =
7.7 Hz, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.40 – 7.33 (m, 1H) (aromatic
H).13C NMR (151 MHz, DMSO-d6): δ 194.45, 157.05 (CO), 153.47,
135.05, 134.13, 133.60, 132.77, 131.72, 131.24, 130.69, 130.10,
129.15, 129.02, 128.92, 126.89, 125.12, 124.94, 123.82, 115.87
(aromatic C). HRMS (ESI): m/z calcd for C9H12N2O2 [M+H]+:
301.0965. Found: 301.0972.
Acknowledgements
We gratefully acknowledge the financial support from Start-up
Funding from Jinhua Branch of Sichuan Industrial Institute of
Antibiotics (Grant 1004).
1-Methyl-3-methoxyquinoxalin-2(1H)-one (3t):
1
Yellow solid. Yield: 36%. H NMR (600 MHz, DMSO-d6): δ 7.89
Notes and references
(dd, J = 8.0, 1.5 Hz, 1H), 7.80 – 7.68 (m, 1H), 7.63 (d, J = 8.5 Hz,
1H), 7.52 – 7.32 (m, 1H) (aromatic H), 3.64 (s, 3H), 2.58 (s, 3H)
(CH3). 13C NMR (151 MHz, DMSO-d6): δ 198.67, 152.93 (CO),
152.24, 134.18, 132.48, 131.22, 130.23, 123.94, 115.08
(aromatic C), 28.90, 28.55 (CH3). This is a known structure.
These data are similar to the reported one.12
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A mixture of 3a (0.5 mmol) and an excess of POCl3 (1.25 mmol)
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1
Yellow solid. Yield: 76%. H NMR (600 MHz, Chloroform-d): δ
8.17 – 8.10 (m, 2H), 8.93 – 7.88 (m, 3H), 7.86 (t, J = 7.5 Hz, 1H),
7.68 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H). (aromatic H). 13
NMR (151 MHz, DMSO-d6): δ 191.32 (CO), 149.89, 142.89,
141.67, 139.30, 135.16, 134.26, 132.81, 131.65, 130.38, 129.21,
C
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DOI: 10.1039/D0OB01423K