K2S2O8 mediated C-3 arylation of quinoxalin-2(1H)-ones under metal-, photocatalyst- And light-free conditions

Article abstract of DOI:10.1039/d0ra00013b

Two facile and effective C-3 arylation protocols of quinoxalin-2(1H)-ones with arylhydrazines and aryl boronic acids respectively via free radical cross-coupling reactions under metal-, photocatalyst- and light-free conditions have been unveiled. K_2<

Full text of DOI:10.1039/d0ra00013b

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K2S2O8 mediated C-3 arylation of quinoxalin-2(1H)-
ones under metal-, photocatalyst- and light-free
Cite this: RSC Adv., 2020, 10, 3615
conditions†
ab
Nibedita Baruah Dutta,abc Mayurakhi Bhuyanab and Gakul Baishya
*
Two facile and effective C-3 arylation protocols of quinoxalin-2(1H)-ones with arylhydrazines and aryl
boronic acids respectively via free radical cross-coupling reactions under metal-, photocatalyst- and
light-free conditions have been unveiled. K2S2O8 has been used as an efficient oxidant to generate aryl
radicals from arylhydrazines and aryl boronic acids under two different reaction conditions. The
generated aryl radicals undergo a free radical coupling reaction at the C-3 position of quinoxalin-2(1H)-
ones producing 3-arylquinoxalin-2(1H)-ones in good to excellent yields. The involvement of radicals in
the course of the reaction has been demonstrated by radical trapping experiments with 2,2,6,6-
tetramethylpiperidine-1-oxyl.
Received 26th November 2019
Accepted 8th January 2020
DOI: 10.1039/d0ra00013b
rsc.li/rsc-advances
C–C bond formation reaction at C-3 position of quinoxalin-
2(1H)-ones by involving different aryl radical sources such as
Introduction
arylboronic acids, diaryliodonium salts, arylhydrazine/
iodosobenzene, and aniline/alkyl nitrite. Very recently, Kim's
group used the technique of visible light-mediated redox
catalysis to obtain 3-arylquinoxalin-2(1H)-ones from arylqui-
noxalin-2(1H)-ones by using arenediazonium salt as an aryl
radical source.6 Although these methods have their own merits,
there is a need for further improvement concerning the prac-
tical and operational simplicity as well as the use of non-toxic
oxidant (previous reports, Scheme 1).
Quinoxalin-2(1H)-ones have emerged as an important class of
heterocyclic compounds because of their broad biological
activities and other chemical properties.1 More specically, the
skeleton of 3-arylquinoxalin-2(1H)-one is found in a variety of
potential biological entities, and they exhibit a broad spectrum
of pharmaceutical properties.2 Anti-tryposomal,3a anti-plasmo-
dial,3b anti-histamine,3c anticancer,3d anti-viral,3e,f antitumor
and antimicrobial,3g CFTR activators,3h FXa coagulation inhib-
itors2b and PDGF-bR inhibitor2c are a few of them reported in the
literature. Besides, polymers obtained from these compounds
can be used as semiconductors which also sets up their
importance in the eld of materials science.4
It has been well established that compared to the classical
cross-coupling methods to form carbon–carbon and carbon-
Owing to their broad biological properties, synthetic and
medicinal chemists all over the world are putting effort into
developing easy-to-handle and practical methods for the
synthesis of 3-arylquinoxalin-2(1H)-ones. Generally, the aryla-
tion of quinoxalin-2(1H)-ones with versatile aryl source under
suitable reaction conditions produces 3-arylquinoxalin-2(1H)-
ones in a single step chemical process. Recently, several
research groups have highlighted the importance of this skel-
eton and also reported a handsome number of synthetic
methodologies.5 Most of these methods undergo the radical
aChemical Science & Technology Division, CSIR-North East Institute of Science and
Technology, Jorhat-785006, India. E-mail: b.gakul@gmail.com; Fax: +91
3762370011; Tel: +91 3762372948
bAcademy of Scientic and Innovative Research, Ghaziabad, Uttar Pradesh-201002,
India
cRain Forest Research Institute, Jorhat-785001, India
† Electronic supplementary information (ESI) available: Experimental data of all
new compounds; 1H and 13C NMR spectra of all compounds. See DOI:
10.1039/d0ra00013b
Scheme 1 C-3 arylation of quinoxalin-2(1H)-ones.
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Table 1 Reaction optimization studiesa
Entry
PhNH2NH2 (equiv.)
K2S2O8 (equiv.)
Solvent
Time (h)
Yieldsb (%)
1
2
3
4
5
6
7
8
1.2
1.5
1.2
1.5
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
—
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
ClCH2H2Cl
ClCH2CH2Cl–H2O
THF
Acetone
CH3CN
CH3CN
CH3CN
CH3CN
DMSO–H2O
CH3CN
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
n.r.
n.r.
49
57
61
62
1.5
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
3.0
3.0
3.0
3.0
3.0
Complex mixture
Trace
Complex mixture
n.r.
81
53
78
61
61
9
10
11c
12c
13d
14e
15e
16f
17g
Trace
Trace
CH3CN
a
Reaction conditions: a mixture of 1a (0.2 mmol) and 2a in the presence of K2S2O8 was stirred as mentioned above in the table. b Isolated yields.
Reaction is carried out at 50 ꢀC. d Additive K2CO3 was used. e NH4S2O8. f Mn(OAc)3$2H2O. g PhI(OCOCF3)2 were used instead of K2S2O8.
c
heteroatom bonds, the coupling reactions involving free- different organic and inorganic oxidants, potassium persulfate
radicals have emerged as modern synthetic methods in (K2S2O8) has come out as a suitable oxidant for many oxidative
organic and medicinal chemistry.7 Generally, bromo- and transformations since the discovery of Minisci reaction.13,14
iodoarenes are used as traditional aryl radicals sources for Because of inexpensive, readily available and easy-to-handling
various arylation reaction under different metal-catalyzed properties it has been widely used as an oxidant in both labo-
conditions.8 In recent years, back to back publications estab- ratory experiments and industrial processes.14 Although several
lish arylhydrazine as a readily available aryl radical source in the reports on the synthesis of 3-arylquinoxalin-2(1H)-ones are
presence of either an oxidizing agent or a base which undergoes known in the literature, there is no such report on the use of
C–H functionalization reaction at an active C-centre of different arylhydrazine and arylboronic acid in the presence of the
organic compounds.9 However, the use of excess bases and toxic oxidizing agent K2S2O8 as aryl radical source for the C-3 aryla-
transition metals, longer reaction hours and low yield of the tion reaction of quinoxalin-2(1H)-ones. Again, the reagent
desired products are a few major drawbacks of these reported system arylhydrazine/K2S2O8 has been utilized for the rst time
methods. Recently, Akamanchi's group has published a series for any arylation reaction.
of articles where they used the mixture of arylhydrazine and
In continuation of our ongoing research program on the
iodoxybenzoic acid as an aryl radical source for the arylation synthesis of various heterocycles,15 we, herein, report two new
reaction of different organic compounds.10 Similarly, arylbor- methods for the synthesis of 3-arylquinoxalin-2(1H)-ones via the
onic acids are also used as aryl radical sources under different radical coupling reaction of quinoxalin-2(1H)-ones with arylhy-
metal as well as metal-free reaction conditions for the arylation drazines and arylboronic acids as radical counterparts in the
of different organic compounds such as naphthoquinone, presence of sole oxidant K2S2O8 (this report, Scheme 1).
benzoquinone, quinazoline, quinoline, quinoxalin-2(1H)-ones,
imidazopyridines, etc.11 Additionally, stability, as well as easy
availability in different substituted forms, makes aryl boronic
acids more convenient and practical to use as aryl radical
Results and discussion
To nd the optimal reaction conditions for the synthesis of 3-
arylquinoxalin-2(1H)-one derivatives, we rst attempted the
cross-coupling reaction of quinoxalin-2(1H)-one (1a, 0.2 mmol)
with phenylhydrazine (2a, 0.24 mmol) in acetonitrile at room
temperature under open-air atmosphere. No reaction was
counterparts for synthesizing versatile building blocks and
structural scaffolds. Even, several important organic trans-
formations involving aryl boronic acids can be performed in
water which proves their water stability as well.12 Among
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perceived as both starting materials remained unchanged aer bulky groups namely n-butyl, prenyl, homoallyl, ethox-
6 h of reaction time (Table 1, entry 1). We also performed the ycarbonylmethyl and phenacyl groups (1c, 1f, 1g & 1i–j). Further,
same reaction by adding 1.5 equiv. of 2a, but the same result we noticed that quinoxalin-2(1H)-ones bearing more bulky
was obtained (Table 1, entry 2). When the reaction was carried groups such as 20-bromophenacyl (1k) and naphthalene-2-acyl
out in the presence of 1.5 equiv. of K2S2O8, aer 6 hours of (1l) at the N-1 position also afforded the respective products
reaction, a new spot above the starting compound 1a was 3ka & 3la in good yields. It would be worth mentioning that
noticed in the TLC which was isolated in 49% yield and quinoxalin-2(1H)-one having N-propargyl group (1h) also took
conrmed as the product 3aa by 1H and 13C NMR spectral place in the reaction and produced the product 3ha in 60% yield
analysis as well as by comparing with the known spectral data (Table 2).
(Table 1, entry 3). To improve the yield of the reaction, the ratio
Aer exemplication of our protocol with different N-
of K2S2O8 and phenylhydrazine were increased; and accord- substituted quinoxalin-2(1H)-one, we explored the scope of N-
ingly, two sets of the same reaction were performed by using 1.5 unsubstitued quinoxalin-2(1H)-one with a variety of phenyl-
equiv. of phenylhydrazine in the presence of 2.0 and 3.0 equiv. hydrazines. We rst performed the reaction of quinoxalin-
of K2S2O8. As expected, both the reactions smoothly underwent 2(1H)-one (1m) with phenylhydrazine (2a) under the standard
affording the product in 57% and 61% yield (Table 1, entry 4 &
5). Again, use 2.0 equiv. of 2a with 3.0 equiv. of K2S2O8 did not
signicantly enhance the yield of the reaction, and we obtained
the product in 62% yield (Table 1, entry 6). Other solvents like
DCE, 1 : 1 mixture of DCE: water, THF, and acetone were also
employed, but none of them were successful (Table 1, entry 7, 8,
9, 10). Therefore, we selected acetonitrile as the solvent of
choice. Surprisingly, when we warmed the reaction up to 50 ꢀC,
a signicant enhancement of the yield was perceived and an
81% yield of the product was obtained (Table 1, entry 11). In
a further improvement of the yield of 3aa, an additive like
K2CO3 was also used, but we did not notice any increment
(Table 1, entry 13). Instead of K2S2O8 we also used (NH4)2S2O8 as
an oxidant and performed the same reaction in two different
solvent systems viz. acetonitrile and 1 : 1 mixture of DMSO and
water, but both experiments failed to give a better yield of 3aa
(Table 1, entry 14 & 15). Oxidants like Mn(OAc)3$2H2O and
PhI(OCOCF3)2 have also been screened for the same reaction
under the optimized reaction conditions, however, they only
produced a trace amount of 3aa (Table 1, entry 16 & 17). Thus,
the optimized reaction conditions involve the simple stirring of
quinoxalin-2(1H)-one (1a, 1.0 equiv.) with phenylhydrazine (2a,
1.5 equiv.) in the presence of K2S2O8 (3.0 equiv.) in acetonitrile
at 50 ꢀC for 6 h under open-air atmosphere (Table 1, entry 11).
With optimized conditions in hand, we rst examined the
scope and general applicability of different N-substituted qui-
noxalin-2(1H)-one with the radical counterpart phenylhydrazine
(2a). Different N-substituted quinoxalin-2(1H)-ones such as N-
ethyl (1b), N-n-butyl (1c), N-benzyl (1d), N-allyl (1e), N-prenyl (1f)
and N-homoallyl (1g) quinoxalin-2(1H)-ones smoothly under-
went the reaction producing the respective 3-phenylquinoxalin-
2(1H)-ones 3ba–3ga in very good to excellent yields. Other
substituents like ethoxycarbonylmethyl and phenacyl groups at
the N-1 position of quinoxalin-2(1H)-one were also well toler-
ated under the optimized reaction conditions and the respective
N-substituted quinoxalin-2(1H)-ones (1i & 1j) produced the 3-
phenylated products 3ia & 3ja in good yields. It was observed
that the substituents present at the N-1 atom showed a signi-
cant variation of the yield of the product under the reaction
conditions. For example, N-substituted quinoxalin-2(1H)-ones
bearing N-alkyl groups like methyl, ethyl, benzyl and allyl (1a,
1b, 1d & 1e) gave more yield of the respective phenylated
products (3aa, 3ba, 3da & 3ea) rather than those bearing little
Table 2 Scope of N-substituted quinoxalin-2(1H)-one.a,b
a
Reaction condition: a mixture of 1 (0.5 mmol) and 2a (0.75 mmol) in
the presence of K2S2O8 (1.5 mmol) was stirred in acetonitrile at 50 ꢀC
for 6–9 hours under air exposure. b Isolated yields.
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Table 3 Scope of N-unsubstituted quinoxalin-2(1H)-one with diverse Table
4
Scope of N-methyl quinoxalin-2(1H)-ones with diverse
phenylhydrazines.a,b
phenylhydrazines.a,b
a
Reaction conditions: a mixture of 1m (0.5 mmol) and 2a–f (0.75 mmol)
in the presence of K2S2O8 (1.5 mmol) was stirred in acetonitrile at 50 ꢀC
for 6–9 hours under air exposure. b Isolated yields.
a
Reaction conditions: a mixture of 1 (0.5 mmol) and 2a–e (0.75 mmol)
in the presence of K2S2O8 (1.5 mmol) was stirred in acetonitrile at 50 ꢀC
for 6–9 hours under air exposure. b Isolated yields.
reaction conditions. Unexpectedly, the reaction smoothly
underwent affording the corresponding product 3ma in very
good yield (71%). To prove the efficacy of the protocol, a variety
of substituted phenylhydrazines were also reacted with 1m
under the optimized reaction conditions, and all the reactions
underwent smoothly affording the respective products 3mb–
3mf in very good yields. In contrary to the earlier reports, this
protocol is equally suitable for N-unsubstitued quinoxalin-
2(1H)-one and we obtained 3-arylated products in very good
yields. The results were presented in Table 3.
Next, we checked the compatibility of our developed protocol
with a variety of quinoxalin-2(1H)-one with unsubstituted and
substituted phenylhydrazines (Table 4). Different arene ring-
substituted 1-methylquinoxalin-2(1H)-one for example 6-nitro-
1-methylquinoxalin-2(1H)-one (1n), 6,7-dichloro-1-methyl-
quinoxalin-2(1H)-one (1o), 6,7-dimethyl-1-methylquinoxalin-
2(1H)-one (1p) also underwent the reaction with 2a producing
the respective phenylated products 3na, 3oa & 3pa in very good
yields. Quinoxalin-2(1H)-one bearing electron-donating group
(1p) gave higher yields than those bearing electron-withdrawing
groups (1n & 1o). In further exploration, a variety of phenyl-
hydrazines bearing electron-withdrawing and electron-
donating groups in the arene ring (2b, 2c, 2d & 2e) were reac-
ted with different 1-methylquinoxalin-2(1H)-one 1a, 1o & 1p. As
expected, all the reactions proceeded well and afforded the
respective products 3oc, 3pb, 3ab, 3ac, 3ad & 3ae in good to very
good yields (Table 4). Arylhydrazines having an electron-
donating group at para-position (2c) and electron-withdrawing
groups at meta-position (2b & 2d) worked better and produced
higher yields than that having an electron-withdrawing group at
para-position (2e).
Once the exploration of our protocol with a variety of phe-
nylhydrazines was completed, we next examined the efficacy of
the arylation reaction of quinoxalin-2(1H)-ones with different
aryl boronic acid. Accordingly, we performed the reaction of 1a
with phenyl boronic acid (4a) in acetonitrile at room tempera-
ture under the optimized reaction conditions of Table 1. The
reaction did not yield the product 3aa and both the starting
materials 1a & 4a remained intact in the reaction mixture
(Table 5, entry 1). As is known from the literature that aryl
boronic acids form aryl radicals in the presence of excess K2S2O8
at higher temperature, hence we checked the feasibility of the
reaction at a little higher temperature.16 Accordingly, we carried
out the same reaction at 80 ꢀC. This time, a very little conversion
was observed in TLC, but we were not able to isolate the product
3aa (Table 5, entry 2). In further optimization, the effect of
solvent on the yield of the product was also examined and
accordingly, we performed the same reaction in different
solvents like dichloroetꢀhane and a 1 : 1 mixture of dichloro-
ethane and water at 80 C. Surprisingly, a signicant improve-
ment of the yield was observed in the 1 : 1 mixture of
dichloroethane and water (Table 5, entry 4). To further improve
the yield, we also added a base K2CO3 in different amounts. To
our delight, an addition of 1.0 equiv. of K2CO3 to the reaction
mixture considerably enhanced the yield (Table 5, entry 6).
Given curiosity, we also performed the same reaction in pure
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Table 5 Reaction optimization studies with phenylboronic acid.a,b
Entry
Solvent
Additive
Temp (ꢀC)
Time (h)
Yieldb (%)
n.r.
1
2
3
4
5
6
7
8
9d
CH3CN
CH3CN
—
—
—
—
30
80
80
80
80
80
80
80
80
12
12
6
6
6
6
6
2
6
c
—
—
c
ClCH2CH2Cl
ClCH2CH2C–H2O
ClCH2CH2Cl–H2O
ClCH2CH2Cl–H2O
ClCH2CH2C–H2O
H2O
40
57
66
67
80
n.r.
K2CO3 (0.25 mmol)
K2CO3 (0.50 mmol)
K2CO3 (0.75 mmol)
K2CO3 (0.50 mmol)
K2CO3 (0.50 mmol)
H2O
a
Reaction conditions: a mixture of 1a (0.5 mmol), 4a (0.75 mmol) and K2S2O8 (1.0 mmol) in solvent was stirred as mentioned in the table above.
Isolated yield. n.r.: no reaction. c Product 3aa could not be isolated. d Reaction was performed without K2S2O8.
b
Table 6 Substrate scope with variation of quinoxalin-2(1H)-one and
arylboronic acids.a,b
water keeping the other conditions unchanged and surpris-
ingly, the reaction underwent very smoothly producing 80%
yield of 3aa (Table 5, entry 8). Thus the optimized reaction
conditions involve the stirring of the reaction mixture of N-
methylquinoxalin-2(1H)-ones (1a, 0.5 mmol) and phenylboronic
acid (4a, 0.75 mmol) in the presence of 2.0 equiv. of K2S2O8 and
ꢀ
1.0 equiv. of K2CO3 in water (5 mL) at 80 C for 2 h (Table 5,
entry 8). However, no reaction took place in the absence of
K2S2O8 under standard reaction conditions and the starting
compounds remained unchanged (Table 5, entry 9).
Aer optimization of the reaction conditions with phenyl-
boronic acid, we engaged different aryl boronic acids bearing
both electron-donating and -withdrawing substituents in the
arene ring to react with quinoxalin-2(1H)-ones (Table 6).
Accordingly, a series of experiments were conducted by reacting
1a with a variety of aryl boronic acids such as 3-uo-
rophenylboronic (4d), 4-methoxylphenylboronic acid (4g), 3-
methylphenylboronic acid (4h), 4-chlorophenylboronic acid (4i)
and 4-bromophenylboronic acid (4j); and all the reaction
underwent smoothly producing the respective arylated quinox-
alin-2(1H)-ones 3aa, 3ad, 3ag, 3ah, 3ai & 3aj in very good to
excellent yields. Aryl boronic acid bearing electron-withdrawing
group in meta-position (4d) gave a better yield than those of
para-position (4i & 4j). Similarly, aryl boronic acid with electron-
donating group in para-position (4g) afforded a better yield than
that of meta-position (4h). N-Benzyl and N-ethylcarboxymethyl
quinoxalin-2(1H)-ones (1d & 1i) were also reacted with 4a under
the optimized reaction conditions and both substrates
produced the corresponding 3-phenylquinoxalin-2(1H)-ones
3da & 3ia in very good yields. In the next couple of experiments,
we also examined the efficacy of N-unsubstituted quinoxalin-
2(1H)-one 3m and performed the reaction of 3m with 4a, 4h & 4j.
Surprisingly, we obtained very good yields of the respective
products 3ma, 3mh & 3mj.
a
Reaction conditions: a mixture of 1 (0.5 mmol), 4 (0.75 mmol), K2S2O8
(1.5 mmol) and K2CO3 (0.5 mmol) in H2O was stirred at 80 ꢀC for 2–6
hours. b Isolated yield.
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Scheme 2 Gram-scale synthesis of 3ma.
In another experiment, the robustness of the above protocol
was proved by performing a gram-scale reaction with quinox-
alin-2(1H)-one (3m) and phenylboronic acid (4a) under optimal
reaction conditions. As expected, the product 3ma was obtained
in 51% yield which is comparable to the yield obtained in the
small scale preparation (Scheme 2).
To nd out a plausible reaction mechanism, a radical scav-
enger effect was explored by performing the arylation reaction
of quinoxalin-2(1H)-one (1a) with phenylhydrazine (2a) in the
presence
of
a
radical
trapping
reagent
2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) under the standard
reaction conditions. As expected, the yield of the product 3aa
sharply reduced from 81% to 19% on the addition of 2.0 equiv.
of TEMPO. The same reaction was also repeated at room
temperature to trap the radical, but we could not isolate the
radical trapping product, however, the yield of 3aa was drasti-
cally affected affording only a 10% yield. Another radical trap-
ping experiment was performed by reacting TEMPO with 2,4-
dinitrophenylhydrazine (2g) under the optimized reaction
conditions, this furnished the TEMPO adduct 1-(2,4-
dinitrophenoxy)-2,2,6,6-tetramethylpiperidine (5) in 67% yield.
The above experiments proved the involvement of radicals in
the course of the reaction (Scheme 3).
Scheme 4 Plausible reaction mechanism.
2ꢁ
S2O8 to the sulfate radical anion SO4cꢁ which reacts with
phenylhydrazine to form the phenylhydrazine radical I. Again,
one more sulfate anion radical reacts with I to give phenyl-
diazene II, which in turn reacts with another sulfate anion
radical and forms III. The removal N2 gas from III produces the
phenyl radical IV which undergoes Minisci-type13 radical addi-
tion reaction on to C-3 position of quinoxalin-2(1H)-one (1a),
thus affording the nitrogen radical intermediate V. The formed
intermediate V undergoes 1,2-hydrogen shi and produces the
carbon radical VI which is again oxidized by persulfate via SET
to form the carbon cation intermediate VII. Finally, the
abstraction of b-H from intermediate VII by SO42ꢁ produces the
desired product 3aa. In an alternative path, Hc radical abstrac-
tion by SO4cꢁ from V could also furnish 3aa. Similarly, aryl
boronic acid also forms aryl radical which undergoes the radical
addition reaction and nally produces the 3-arylquinoxalin-
2(1H)-one (Scheme 4).11f
Based on the above result as well as literature's supports,17
a plausible mechanism has been proposed in Scheme 4. The
reaction commences with the decomposition of persulfate
In view of the importance of 1,2,3-triazoles compounds and
their uses as linkers for various applications in diverse areas of
chemistry such as medicinal chemistry, agrochemistry, and
material chemistry,18 we, herein, attempted to synthesize qui-
noxalinone linked triazole derivative and accordingly, we carried
out the reaction between 3ha and commercially available 1-azi-
doadamantane (6) under standard reaction conditions of Huis-
gen [2 + 3]-cycloaddition reaction.19 The reaction smoothly
underwent furnishing the product 7 in 82% yield (Scheme 5).
A comparison of our both protocols with the reported
methods in terms of yield, reaction temperature and time has
been given in Table 7. From the data presented in Table 7, it can
be concluded that both methodologies show tremendous
potential over earlier reported methods. These two protocols
Scheme 3 Radical scavenger effect.
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substituents in the arene ring have undergone the arylation
reaction with various arylhydrazines and aryl boronic acids
producing 3-arylquinoxalin-2(1H)-ones in very good to excellent
yields. N-Unsubstituted quinoxalin-2(1H)-ones also work well
under the optimized conditions of both protocols. Huisgen [2 +
3]-cycloaddition reaction on 3-arylquinoxalin-2(1H)-one derived
alkyne was also accomplished to reveal its synthetic application.
Further applications of these two reactions are under investiga-
tion in our laboratory.
Scheme 5 Synthesis of 3-phenylquinoxalin-2(1H)-one linked triazole.
have not used any hazardous organic or inorganic oxidants like
PhIO and Mn(OAc)3, transition metal catalyst viz. Pd(OAc)2,
extremely corrosive and explosive reagent t-BuONO (used in 6
equiv.), strong Brønsted acid such as methane sulfonic acid and
very high temperature, etc. Again, PhIO and Ar2IBF4 are not
commercially available reagents. Use of cheap, readily available
and non-toxic oxidant K2S2O8, mild reaction conditions (50–80
ꢀC), shorter reaction hours (2–9 h) and environmentally benign
solvents make these two transformations an alternative meth-
odology for the construction of various 3-arylquinoxalin-2(1H)-
ones from readily available starting materials.
Experimental section
General experimental details
1H NMR and 13C NMR spectra were recorded in CDCl3, DMSO-
d6 on 500, 400 and (125, 100) MHz NMR spectrometer, respec-
tively, using TMS as internal standard. HRMS (ESI) data were
recorded on Mass spectrometer. All the commercially available
reagents were used without further purication. All experiments
were monitored by thin layer chromatography using aluminium
pre-coated silica gel TLC plates. Aer elution, plate was visual-
ized under UV illumination at 254 nm for UV active materials.
Column chromatography was performed on silica gel (100–200
mesh) eluting appropriate ethyl acetate–hexane mixture.
Conclusions
In conclusion, we have established the reagent system
comprising of arylhydrazine and K2S2O8 as a versatile reagent
Preparation of starting materials
system for the rst time to promote the free radical arylation The starting compounds quinoxalin-2(1H)-one (1a–1p) were
reaction on to C-3 position of quinoxalin-2(1H)-ones. Similarly, prepared in accordance with literature methods.2c,5g
K2S2O8/arylboronic acid has also been found to be an efficient
General procedure for the preparation of compound 3 with
reagent system to drive the same arylation reaction. In both the arylhydrazines. To a solution of quinoxalin-2(1H)-one (1, 0.5
methods K2S2O8 took part in the reaction as a sole oxidant mmol) and arylhydrazine 2 (0.75 mmol) in acetonitrile (5 mL)
producing aryl radicals from arylhydrazines and aryl boronic was added K2S2O8 (1.5 mmol). Then the reaction mixture was
acids under metal-, photocatalyst- and light-free conditions in stirred at 50 ꢀC for 6–9 hours under air exposure. Aer
environmentally benign solvents acetonitrile and water respec- completion of the reaction (as monitored by TLC) water (10 mL)
tively. Both the methodologies are operationally very simple and was added to the reaction mixture and extracted with ethyl
robust, and they do not require any dry reaction conditions and acetate (3 ꢂ 10 mL). The organic layer was washed with brine (1
special reaction set up. A wide range of N-substituted quinoxalin- ꢂ 10 mL) and dried over anhydrous sodium sulfate. The organic
2(1H)-ones bearing both electron-donating and withdrawing layer was concentrated under rotary evaporator and column
Table 7 Comparison of our protocols vs. reported methods for the preparation of 3aa
Entry
Reagent system
Temp. (ꢀC)
Time (h)
Yield (%)
Ref.
1
2
3
4
5
6
7
8
9
ArB(OH)2/Pd(OAc)2/phenanthroline/O2
ArB(OH)2/Mn(OAc)2.
Ar2IBF4/Cs2CO3
ArNHNH2/PhIO
ArNH2/t-BuONO/CH3SO3H
ArNH2/t-BuONO
ArN2BF4/Eosin-Y/blue LED
ArNHNH2/K2S2O8
ArB(OH)2/K2S2O8/K2CO3
100
120
r. t.
r. t.
r. t.
r. t.
r. t.
50
20
12
72
9
1.5
48
3
85
80
80
81
81
89
71
81
80
5g
5m
5i
5j
5k
5l
6
6
2
This report
This report
80
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chromatographed on silica gel (100–200 mesh) using 2 : 8 ethyl 128.2, 128.1, 123.9, 113.4, 48.6. HRMS (ESI): calculated m/z for
acetate–hexane as the eluent to get the pure 3-aryl quinoxalin-
2(1H)-ones 3. Products 3aa, 3ba, 3da, 3ea, 3ia, 3ma, 3mc, 3me,
C
22H16N2O2 [M + H]+: 341.1292, found: 341.1285.
1-(2-(2-Bromophenyl)-2-oxoethyl)-3-phenylquinoxalin-2(1H)-one
3nd, 3oa, 3pa, 3ab, 3ac, 3ad & 3ae are known in the literature5,6 (3ka). Yellow solid, mp 168.6–172.5 C, 65% yield. IR (CHCl3):
ꢀ
and the spectral data of unknown compounds 3ca, 3fa, 3ga, 3ha, 3059.5, 2949.1, 1960.7, 1711.9, 1648.6, 1440.2, 1217.1, 986.5,
1
3ja, 3ka, 3la, 3mb, 3md, 3mf, 3oc, 3pb, 5 & 7 have been given 763.6, 430.9 cmꢁ1. H NMR (CDCl3, 500 MHz): d 8.31–8.29 (m,
here.
2H), 7.99 (dd, 1H, J ¼ 8.0, 1.5 Hz), 7.72–7.67 (m, 2H), 7.56–7.52
1-Butyl-3-phenylquinoxalin-2(1H)-one (3ca). Orange liquid, (m, 1H), 7.49–7.44 (m, 4H), 7.41–7.37 (m, 2H), 7.23 (dd, 1H, J ¼
73% yield. IR (CHCl3): 3057.5, 2959.1, 1652.0, 1603.5, 1465.3, 8.5, 1.0 Hz), 5.67 (s, 2H). 13C NMR (CDCl3, 125 MHz): d 195.1,
1295.3, 1180.7, 763.5, 692.2, 426.7 cmꢁ1. H NMR (CDCl3, 500 154.2, 153.7, 138.6, 135.6, 133.8, 133.2, 132.68, 132.62, 130.6,
1
MHz): d 8.30 (dd, 2H, J ¼ 7.0, 3.5 Hz), 7.95 (dd, 1H, J ¼ 8.0, 1.5 130.4, 130.3, 129.4, 128.0, 127.7, 123.9, 118.9, 113.4, 51.2. HRMS
Hz), 7.56 (t, 1H, J ¼ 8.5 Hz), 7.47–7.46 (m, 3H), 7.36–7.32 (m, (ESI): calculated m/z for C22H15BrN2O2 [M + H]+: 419.0390,
2H), 4.32 (t, 2H, J ¼ 8.0 Hz), 1.81 (p, 2H, J ¼ 7.5 Hz), 1.55 (sextet, found: 419.0392.
2H, J ¼ 7.5 Hz), 1.02 (t, 3H, J ¼ 7.5 Hz). 13C NMR (CDCl3, 125
1-(2-(Naphthalen-2-yl)-2-oxoethyl)-3-phenylquinoxalin-2(1H)-
MHz): d 154.3, 154.0, 135.9, 133.2, 132.4, 130.5, 130.16, 130.12, one (3la). Brown solid, mp 207.0–219.4 ꢀC, 56% yield. IR (KBr):
129.4, 127.9, 123.4, 113.4, 42.3, 29.2, 20.2, 13.7. HRMS (ESI): 3245.5, 2938.3, 2220.9, 1650.5, 1601.5, 1464.1, 1241.0, 1176.6,
calculated m/z for C18H18N2O [M + H]+: 279.1492, found: 750.5, 693.7, 534.2 cmꢁ1.1H NMR (CDCl3, 500 MHz): d 8.67 (s,
279.1493.
1-(3-Methylbut-2-enyl)-3-phenylquinoxalin-2(1H)-one
1H), 8.33 (dd, 2H, J ¼ 6.0, 2.5 Hz), 8.10 (dd, 1H, J ¼ 9.0, 2.0 Hz),
(3fa). 8.03–7.98 (m, 3H), 7.93 (d, 1H, J ¼ 8.0 Hz), 7.68–7.59 (m,
Orange solid, mp 97.9–115.2 ꢀC, 61% yield. IR (CHCl3): 3295.8, 2H),7.49–7.45 (m, 4H), 7.38 (t, 1H, J ¼ 7.5 Hz), 7.05 (dd, 1H, J ¼
2916.7, 1652.0, 1604.4, 1466.3, 1293.8, 1178.5, 762.3, 692.1, 8.5,1.0 Hz), 5.94 (s, 2H). 13C NMR (CDCl3, 125 MHz): d 191.1,
425.2 cmꢁ1 1H NMR (CDCl3, 500 MHz): d 8.31–8.29 (m, 2H), 154.4, 153.7, 135.9, 135.7, 133.2, 132.7, 132.3, 131.8, 130.6,
.
7.95 (dd, 1H, J ¼ 7.5, 1.0 Hz), 7.55–7.52 (m, 1H), 7.48–7.45 (m, 130.3, 130.0, 129.6, 129.4, 129.3, 129.0, 128.9, 127.9, 127.8,
3H), 7.36–7.29 (m, 2H), 5.23–5.20 (m, 1H), 4.96 (d, 2H, J ¼ 6.5 127.1, 123.8, 123.3, 123.0, 113.7, 113.4, 48.6. HRMS (ESI):
Hz), 1.92 (s, 3H), 1.74 (s, 3H). 13C NMR (CDCl3, 125 MHz): calculated m/z for C26H18N2O2 [M + H]+: 391.1441, found:
d 154.2, 154.1, 137.2, 136.0, 133.2, 132.5, 130.4, 130.1, 130.0, 391.1450.
129.4, 127.9, 123.4, 117.8, 113.8, 40.8, 25.5, 18.3.
1-(But-3-enyl)-3-phenylquinoxalin-2(1H)-one (3ga). Yellow mp 233.6–237.7 ꢀC, 70% yield. IR (KBr): 3421.8, 2926.4, 1667.3,
liquid, 61% yield. IR (CHCl3): 3075.0, 2976.6, 1651.9, 1602.8, 1610.8, 1417.9, 1116.5, 902.2, 754.6, 618.5 cmꢁ1 1H NMR
3-(3-Chlorophenyl) quinoxalin-2(1H)-one (3mb). Brown solid,
.
1465.3, 1295.7, 919.1, 762.9, 692.1, 428.4 cmꢁ1. 1H NMR (CDCl3, (DMSO-d6, 500 MHz) d 12.67 (s, 1H), 8.38 (s, 1H), 8.30 (dd, 1H, J
500 MHz): d 8.31–8.29 (m, 2H), 7.96 (dd, 1H, J ¼ 8.0, 1.5 Hz), ¼ 8.0, 1.5 Hz), 7.87 (d, 1H, J ¼ 7.5 Hz), 7.59–7.52 (m, 3H), 7.36 (d,
7.57–7.54 (m, 1H), 7.49–7.46 (m, 3H), 7.37–7.32 (m, 2H), 5.96– 2H, J ¼ 7.0 Hz). 13C NMR (DMSO-d6, 125 MHz): d 154.8, 152.7,
5.87 (m, 1H), 5.17–5.09 (m, 2H), 4.40 (t, 2H, J ¼ 8.0 Hz), 2.58 (q, 137.8, 132.9, 132.5, 132.2, 131.1, 130.28, 130.21, 129.2, 129.1,
2H, J ¼ 7.0 Hz). 13C NMR (CDCl3, 125 MHz): d 154.2, 154.0, 128.0, 123.8, 115.5. HRMS (ESI): calculated m/z for C14H9ClN2O
135.9, 133.8, 133.2, 132.3, 130.6, 130.2, 130.1, 129.4, 127.9, [M + H]+: 257.0476, found: 257.0486.
123.5, 117.6, 113.4, 41.7, 31.4. HRMS (ESI): calculated m/z for
18H16N2O [M + H]+: 277.1335, found: 277.1346.
3-(3-Fluorophenyl) quinoxalin-2(1H)-one (3md). Brownish
yellow solid, mp 225.6–227.5 ꢀC, 76% yield. IR (KBr): 3433.8,
C
3-Phenyl-1-(prop-2-ynyl) quinoxalin-2(1H)-one (3ha). Yellow 3068.5, 2848.7, 1668.5, 1607.8, 1475.1, 1246.5, 896.9, 783.0,
solid, mp 139.9–143.2 ꢀC, 60% yield. IR (CHCl3): 3282.6, 1651.3, 555.4 cmꢁ1.1H NMR (DMSO-d6, 500 MHz) d 12.66 (s, 1H), 8.20–
1603.4, 1464.3, 1173.9, 1029.8, 753.8, 427.0 cmꢁ1
.
1H NMR 8.31 (m, 2H), 7.86 (dd, 1H, J ¼ 8.0, 2.5 Hz), 7.58–7.52 (m, 2H),
(CDCl3, 400 MHz): d 8.31 (dd, 2H, J ¼ 6.4, 2.0 Hz), 7.96 (dd, 1H, J 7.38–7.32 (q, 3H, J ¼ 6.5 Hz). 13C NMR (DMSO-d6, 125 MHz):
¼ 8.4, 1.6 Hz), 7.61–7.57 (m, 1H), 7.48–7.46 (m, 4H), 7.41–7.37 d 162.9 (d, J ¼ 240.625 Hz), 154.8, 152.7, 138.1 (d, J ¼ 8.125 Hz),
(m, 1H), 5.12 (d, 2H, J ¼ 2.8 Hz), 2.30 (t, 1H, J ¼ 2.4 Hz). 13C NMR 132.5, 132.1, 131.1, 130.2 (d, J ¼ 8.0 Hz), 129.2, 125.5 (d, J ¼
(CDCl3, 100 MHz): d 154.1, 153.8, 135.8, 133.9, 131.9, 130.7, 2.625 Hz), 123.8, 117.4 (d, J ¼ 21.0 Hz), 116.1(d, J ¼ 23.375 Hz),
130.6, 130.5, 129.6, 128.2, 124.2, 114.1, 76.9, 73.2, 31.7. HRMS 115.5. HRMS (ESI): calculated m/z for C14H9FN2O [M + H]+:
(ESI): calculated m/z for C17H12N2O [M + H]+: 261.1022, found: 241.0772, found: 241.0775.
261.1032.
1-(2-Oxo-2-phenylethyl)-3-phenylquinoxalin-2(1H)-one
3-(4-(Triuoromethyl) phenyl) quinoxalin-2(1H)-one (3mf).
(3ja). Brown solid, mp 291.7–294.7 ꢀC, 59% yield. IR (KBr): 3434.6,
Brownish yellow solid, mp 198.1–201.3 ꢀC, 71% yield. IR 2850.5, 1663.3, 1610.8, 1330.1, 1114.8, 906.5, 760.1, 618.6 cmꢁ1
.
(CHCl3): 3058.5, 1691.3, 1648.6, 1446.9, 1227.4, 989.1, 754.6, 1H NMR (500 MHz, DMSO-d6) d 12.70 (s, 1H), 8.51 (d, 2H, J ¼ 8.5
423.5 cmꢁ1
.
1H NMR (CDCl3, 500 MHz): d 8.33–8.30 (m, 2H), Hz), 7.86 (d, 3H, J ¼ 8.5 Hz), 7.59 (t, 1H, J ¼ 8.0 Hz), 7.36–7.33
8.10 (dd, 2H, J ¼ 8.0, 0.5 Hz), 7.99 (dd, 1H, J ¼ 8.0, 1.0 Hz), 7.69 (m, 2H). 13C NMR (DMSO-d6, 125 MHz): d 154.8, 153.1, 139.6,
(tt, 1H, J ¼ 7.5, 2.0 Hz), 7.57 (t, 2H, J ¼ 8.0 Hz), 7.49–7.44 (m, 132.6, 132.2, 131.3, 130.2, 129.3, 125.1, 125.0, 123.9, 115.5.
4H), 7.37–7.33 (m, 1H), 6.99 (dd, 1H, J ¼ 8.5, 1.0 Hz), 5.79 (s, HRMS (ESI): calculated m/z for C15H9F3N2O [M + H]+: 291.0740,
2H). 13C NMR (CDCl3, 125 MHz): d 191.2, 154.4, 153.8, 135.8, found: 291.0750.
134.6, 134.3, 133.3, 132.8, 130.7, 130.43, 130.4, 129.6, 129.0,
6,7-Dichloro-1-methyl-3-p-tolylquinoxalin-2(1H)-one
(3oc).
Brown solid, mp 180.9–183.4 ꢀC, 61% yield. IR (CHCl3): 3394.4,
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2919.5 1661.6, 1417.7, 1294.6, 94.2, 883.3, 427.0 cmꢁ1. 1H NMR (dd, 1H, J ¼ 8.0, 1.5 Hz), 7.75 (s, 1H), 7.60–7.56 (m, 1H), 7.49–
(CDCl3, 500 MHz): d 8.22 (d, 2H, J ¼ 8.5 Hz), 7.95 (s, 1H), 7.36 (s, 7.48 (m, 3H), 7.36–7.33 (m, 1H), 5.58 (s, 2H), 2.20–2.16 (m, 9H),
1H), 7.27 (d, 2H, J ¼ 7.5 Hz), 3.67 (s, 3H), 2.41 (s, 3H). 13C NMR 1.76–1.70 (m, 6H). 13C NMR (CDCl3, 125 MHz): d 154.4, 153.8,
(CDCl3, 125 MHz): d 154.7, 154.1, 141.4, 133.9, 132.6, 132.5, 141.3, 135.8, 133.1, 132.4, 130.5, 130.2, 130.1, 129.3, 128.0,
132.1, 130.8, 129.6, 128.9, 127.3, 114.9, 29.5, 21.5. HRMS (ESI): 123.8, 120.2, 114.8, 59.7, 42.7, 38.3, 35.7, 29.2. HRMS (ESI):
calculated m/z for C16H12Cl2N2O [M + H]+: 319.0399, found: calculated m/z for C27H27N2O [M + H]+: 438.2288, found:
319.0407.
3-(3-Chlorophenyl)-1,6,7-trimethylquinoxalin-2(1H)-one (3pb).
Yellow solid, mp 172.0–173.8 ꢀC, 73% yield. IR (CHCl3): 3366.3,
438.2293.
Conflicts of interest
2919.5 1637.7, 1419.4, 1298.8, 1011.1, 677.0, 431.0 cmꢁ1 1H
.
NMR (CDCl3, 500 MHz): d 8.34 (t, 1H, J ¼ 2.0 Hz), 8.26 (dt, 1H, J There are no conicts to declare.
¼ 7.5, 1.5 Hz), 7.67 (s, 1H), 7.43–7.37 (m, 2H), 7.08 (s, 1H), 3.72
(s, 3H), 2.42 (s, 3H), 2.35(s, 3H). 13C NMR (CDCl3, 125 MHz):
d 154.5, 151.0, 140.9, 137.9, 134.0, 132.9, 131.47, 131.40, 130.5,
Acknowledgements
129.9, 129.4, 129.2, 127.6, 114.1, 29.2, 20.7, 19.2. HRMS (ESI): Authors are grateful to the Council of Scientic and Industrial
calculated m/z for C17H15ClN2O [M + H]+: 299.0946, found: Research (CSIR), New Delhi, for nancial support under the In-
299.0958.
1-(2,4-Dinitrophenoxy)-2,2,6,6-tetramethylpiperidine
house Project OLP 2020. MB thanks DST, New Delhi for INSPIRE
(5). fellowship. Authors also thank the Director, CSIR-NEIST for his
Yellow liquid, 67% yield. IR (CHCl3): 3115.7, 2977.2, 2938.4, continuous support and encouragement.
1602.1, 1533.0 (N–O stretch), 1470.2, 1365.5(N–O stretch),
1271.3, 426.9 cmꢁ1. 1H NMR (CDCl3, 500 MHz): d 8.06 (dd, 1H, J
Notes and references
¼ 2.5, 2.0 Hz), 8.36 (dd, 1H, J ¼ 9.5, 3.0 Hz), 8.09 (d, 1H, J ¼ 9.5
Hz), 1.68–1.65 (m, 6H), 1.31 (s, 6H), 1.02 (s, 6H). 13C NMR
(CDCl3, 125 MHz): d 161.4, 139.6, 135.1, 128.6, 121.1, 118.3, 61.7,
39.4, 31.8, 20.7, 16.5.
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General procedure for the preparation of compound 3 with
arylboronic acid. To a solution of quinoxalin-2(1H)-one 1, (0.5
mmol) and arylboronic acid 4 (0.75 mmol) in water (3 mL) in
a reaction vial was added K2S2O8 (1.0 mmol) and K2CO3 (0.5
mmol). Then the reaction vial was screwed and stirred at 80 ꢀC
for 2–6 hours. Aer completion of the reaction (as monitored by
TLC) water (10 mL) was added to the reaction mixture and
extracted with ethyl acetate (3 ꢂ 10 mL). The organic layer was
washed with brine (1 ꢂ 10 mL) and dried over anhydrous
sodium sulfate. The organic layer was concentrated under
rotary evaporator and column chromatographed on silica gel
(100–200 mesh) using 2 : 8 ethyl acetate–hexane as the eluent to
get the pure 3-aryl quinoxalin-2(1H)-ones 3. Products 3aa, 3ad,
3ag, 3ah, 3ai, 3aj, 3ia, 3ja, 3oi, 3ma, 3mh & 3mj are known in the
literature.5
´
´
¨
Procedure for the preparation of the compound 7.
Compound 3ha (0.138 mmol) and 1-azidoadamantane (6, 0.138
mmol) were taken in CH2Cl2 and H2O (2 mL, 1 : 1) system in
a 25 mL round-bottomed ask and stirred for 5 min. CuSO4-
$5H2O (0.150 mmol) and sodium ascorbate (2.8 mmol) were
added and the reaction mixture was stirred at r.t. for 12 h. The
progress of the reaction was monitored by TLC. Aer comple-
tion of the reaction, the crude mixture was partitioned between
H2O (15 mL) and CH2Cl2 (20 mL). The aqueous layer was
extracted with ethyl acetate (3 ꢂ 15 mL). The combined organic
phases were dried over anhydrous sodium sulphate and
concentrated under rotary evaporator and column chromato-
graphed on silica gel (100–200 mesh) using 2 : 8 ethyl acetate–
hexane as the eluent to get the pure compound 7. Yellow liquid,
82% yield. IR (CHCl3): 3400.8, 2911.7, 1651.8, 1604.2, 1444.4,
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d 8.31 (dd, 2H, J ¼ 7.0, 3.5 Hz), 8.01 (dd, 1H, J ¼ 8.5, 1.0 Hz), 7.92
This journal is © The Royal Society of Chemistry 2020
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3624 | RSC Adv., 2020, 10, 3615–3624
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