A combination of heterogeneous catalysis and photocatalysis for the olefination of quinoxalin-2(1H)-ones with ketones in water: a green and efficient route to (Z)-enaminones

Article abstract of DOI:10.1039/d0gc04235h

Herein, a novel aqueous reaction for the olefination of quinoxalin-2(1H)-ones with ketones through a combinational strategy is described. This reaction features very mild conditions using a simple and cheap catalyst for the synthesis of (Z)-enaminones with moderate-to-good yields. Such a methodology successfully combines the heterogeneous Mannich reaction with photocatalysis, and provides a green and practical approach for the synthesis of potentially bioactive (Z)-enaminones with a 3,4-dihydroquinoxalin-2(1H)-one skeleton.

Full text of DOI:10.1039/d0gc04235h

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A combination of heterogeneous catalysis and
photocatalysis for the olefination of quinoxalin-
2(1H)-ones with ketones in water: a green and
efficient route to (Z)-enaminones†
Cite this: Green Chem., 2021, 23,
2123
Jun Xu, Lin Huang, Lei He, Zhigang Ni,
Wanmei Li * and Pengfei Zhang
Jiabin Shen, Xiaoling Li, Kaixian Chen,
*
Herein, a novel aqueous reaction for the olefination of quinoxalin-2(1H)-ones with ketones through a
combinational strategy is described. This reaction features very mild conditions using a simple and
cheap catalyst for the synthesis of (Z)-enaminones with moderate-to-good yields. Such a methodology
successfully combines the heterogeneous Mannich reaction with photocatalysis, and provides a green
and practical approach for the synthesis of potentially bioactive (Z)-enaminones with a 3,4-dihydro-
quinoxalin-2(1H)-one skeleton.
Received 15th December 2020,
Accepted 11th February 2021
DOI: 10.1039/d0gc04235h
rsc.li/greenchem
reactions are generally conducted in volatile and toxic organic
solvents, which not only consume plenty of non-renewable
Introduction
(Z)-Enaminones are an important class of organic compounds, fossil fuels but also cause environmental pollution. Therefore,
which play a central role in organic synthesis and medicinal considerable efforts are being made to develop green reaction
chemistry.1 For example, antibacterial drugs such as pefloxa- media6 (water,6a–f ionic liquids6g–j and so on6k–m) so as to meet
cin, ofloxacin and norfloxacin all contain the (Z)-enaminone ‘Principle 1, Waste Prevention’ and ‘Principle 5, Safer Solvents
framework. In particular, (Z)-enaminones with a 3,4-dihydro- and Auxiliaries’ of Green Chemistry.7
quinoxalin-2(1H)-one skeleton are discovered to display anti-
Photocatalysis has become a powerful methodology for
cancer, antimicrobial, antidiabetic, and antiviral activities organic synthesis because it features low energy consumption
(Scheme 1a).2 In addition, (Z)-enaminones are also commonly and environmental protection to some degree.8 Although
used as building blocks for the synthesis of various valuable elegant, this strategy usually needs an additional photocatalyst
classes of N-heterocycles.3 However, conventional synthesis
methods of these compounds are the cyclization reactions of
o-phenylenediamines with acylpyruvic acids, furan-2,3-diones
or acetylenedicarboxylates, which generally suffer from harsh
reaction conditions and a limited substrate scope.4 Thus, the
development of sustainable and efficient approaches for the
synthesis of these compounds is of great importance.
Owing to the increasing awareness of the importance of
green and sustainable development of chemicals, environ-
ment-friendly synthesis methods to minimise chemical waste
and meet the 12 principles of Green Chemistry have been
attracting interest over the past few decades.5 However, organic
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 311121, China. E-mail: liwanmei@hznu.edu.cn,
pfzhang@hznu.edu.cn
†Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data. For ESI or other electronic format. CCDC
2042085. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d0gc04235h
Scheme 1 Application and synthesis of (Z)-enaminones with a hetero-
cycle skeleton.
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or oxidant, which will not only increase the manufacturing 12 h (Table 1, entry 1). Other supported sulfonic acid catalysts
costs but also cause environmental pollution. From the per- such as Amberlyst®15, Amberlyst®16 and Dowex 50WX2 gave
spective of green chemistry, organic synthesis through the lower yields (Table 1, entries 2–4). No corresponding product
irradiation of visible light without an additional photocatalyst was generated without a catalyst (Table 1, entry 5). The
or oxidant has attracted extensive attention in recent years.9 In product yield could not be enhanced obviously when the start-
the meantime, heterogeneous catalysis has become a sustain- ing-material or catalyst dose was increased or when the reac-
able and practical strategy for the construction of valuable tion time was extended (Table 1, entries 6–8). Instead, the yield
compounds.10 Specifically, ion-exchange resin catalysts have was dramatically decreased by reducing the dose of the start-
received considerable attention due to their low cost, metal- ing-material or catalyst (Table 1, entries 9 and 10). We also per-
free composition, easy product purification, catalyst recover- formed the reaction in organic solvents, such as acetone and
ability and reusability.11 We are interested in developing acetonitrile, and 88% and 85% yields were obtained, respect-
green catalytic systems12 for the direct modification of ively (see the ESI†). To meet the demand of green synthesis, we
N-containing heterocycles,13 herein, we report a reusable sulfo- finally chose water as the solvent for the reaction.
nic ion-exchange resin promoted, photocatalysis method for
With the optimized reaction conditions in hand, we next
the direct olefination of quinoxalin-2(1H)-ones with ketones in explored the substrate scope of quinoxalin-2(1H)-ones with
water (Scheme 1b). The recyclable aqueous phase reaction was acetone (Table 2). Initially, a wide range of N-substituted qui-
performed under very mild conditions, providing a green and noxalin-2(1H)-ones were studied. Various N-substituted groups
n
i
practical route to various (Z)-enaminones bearing 3,4-dihydro- such as methyl, ethyl, butyl, butyl, cyclopropylmethyl, cyclo-
quinoxalin-2(1H)-one in moderate-to-good yields. Recently, hexylmethyl, ester and keto were well tolerated under standard
there has been significant progress in the direct C3–H conditions, providing the corresponding (Z)-enaminones
functionalization of quinoxalin-2(1H)-ones since they are a (3–12) in 73–85% yields. It is worth mentioning that quinoxa-
valuable class of heterocycles,14–20 and to the best of our lin-2(1H)-one with a sensitive allyl group, which could be
knowledge, however, direct C3–H olefination has never been further functionalized, gave product (13) in 70% yield.
reported yet.
N-Phenylquinoxalin-2(1H)-one also could undergo the reaction
smoothly, giving target product (14) in 59% yield. A number of
quinoxalin-2(1H)-ones with different benzyl groups, bearing
both electron-donating and electron-withdrawing substituents
at the ortho-, meta-, or para-position, gave the corresponding
products (15–28) in 48–77% yields. The transformations of
acetone (2a) with quinoxalin-2(1H)-one containing a methyl,
Results and discussion
The reaction conditions of the olefination of quinoxalin-2(1H)-
one (1a) with acetone (2a) were optimised by changing the type
and dose of the supported sulfonic acid catalyst, the dose of
the starting-material and the reaction time. As outlined in
Table 1, (Z)-enaminones (3) were isolated in 83% yield by per-
forming the reaction of 1a (0.2 mmol), 2a (0.6 mmol), and
Amberlyst 15 (50 mg) in H2O (3 mL) under visible light for
t
methoxy butyl, halogen or ester group at the C5-, C6-, or C7-
position yielded target (Z)-enaminones (29–35) in 69–78%
Table 2 Substrate scope of quinoxalin-2(1H)-onesa,b
Table 1 Screening of reaction conditionsa
Entry
Variation from the given conditions
Yieldb [%]
1
2
3
4
5
6
7
8
9
10
None
83
72
50
36
0
85
83
86
52
62
Amberlyst®15 instead of Amberlyst 15
Amberlyst®16 instead of Amberlyst 15
Dowex 50WX2 instead of Amberlyst 15
without Amberlyst 15
100 mg of Amberlyst 15 was used
6.0 equivalents of acetone was used
extended reaction time (24 h)
25 mg of Amberlyst 15 was used
1.5 equivalents of acetone was used
a Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Amberlyst 15 a Reaction conditions: 1 (0.2 mmol), 2a (0.6 equiv.), Amberlyst 15
(50 mg), H2O (3 mL), visible light (LEDs, 420 nm, 5 W), open flask, rt, (50 mg), H2O (3 mL), visible light (LEDs, 420 nm, 5 W), open flask, rt,
air, 12 h. b Isolated yields.
air, 12 h. b Isolated yields.
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yields. The molecular structure of (Z)-enaminone 20 was con- raspberry ketone and pregnenolone were selected to react with
firmed by X-ray crystallographic analysis (CCDC 2042085†). quinoxalin-2(1H)-one directly, giving new (Z)-enaminone mole-
According to the crystal structure, we thought that the effect of cules (61–64) in 53–71% yields. The successful transformations
the hydrogen bond interaction between the amine and carbo- demonstrate that the present strategy has a good application
nyl groups makes the molecules more stable in the (Z)- value for the synthesis of potentially bioactive quinoxalin-2
configuration.
(1H)-one containing (Z)-enaminones.
Subsequently, the substrate scope of ketones for the reac-
To demonstrate the practicality and efficiency of the reac-
tion was studied under the standard reaction conditions tion, a gram-scale synthesis experiment was performed. As
(Table 3). Both long-chain and cycloalkyl methyl ketones could shown in Scheme 2a, a scaled-up model transformation was
undergo the reaction smoothly, affording the corresponding performed effectively to give target product 3 in 75% yield
(Z)-enaminones (36–47) in 65–83% yields. Then, some methyl (1.3 g). Furthermore, the obtained (Z)-enaminone could be
aryl ketones were explored. 1-(Thiophen-3-yl)ethan-1-one could further converted into various quinoxaline derivatives (65–68)
be converted into target product (48) with a slightly lower using different reaction conditions, which clearly revealed the
yield, probably because of its relatively poor solubility. A wide synthetic utility of this protocol (Scheme 2b).
range of acetophenones, which bear substituents at the ortho-
The recyclable experiment was further studied in order to
or para-position with both electron-donating and electron- test the recyclability of the present catalytic system (Fig. 1).
withdrawing characteristics, gave the corresponding products After completion, the reaction mixture was extracted with ethyl
(49–56) in 49–78% yields. We were pleased to find that the acetate, and the organic layer containing the product was puri-
cyclopentanone skeleton could also react with quinoxalin-2 fied. Then, the aqueous phase was reutilized to catalyse the
(1H)-one smoothly to deliver target products (57 and 58) in transformation by directly adding starting materials. A slight
moderate yields. Interestingly, the anticancer molecule (59) loss of catalytic activity in the second run and an obvious loss
and antimicrobial molecule (60) could also be synthesized in of catalytic activity in the third and fourth runs were observed.
moderate yields using the straightforward strategy. Since (Z)- The deactivation of the catalyst is probably caused by active
enaminones bearing a 3,4-dihydroquinoxalin-2(1H)-one frame- site loss and channel plugging of the heterogeneous cata-
work are a promising class of biologically active compounds, lyst.11d Retreatment of the catalyst that used for three or four
several bioactive molecules such as nabumetone, zingiberone, times could regenerate the catalyst with relatively good cata-
lytic activity.
A range of control experiments were then carried out to
study the reaction mechanism. Initially, the Mannich-type
product 66 was generated instead of target product 3 in 53%
Table 3 Substrate scope of ketonesa,b
yield if the reaction was performed under a nitrogen atmo-
sphere (Scheme 3a). This result indicates that oxygen in air
may play a central role in the subsequent dehydrogenation
process, which can be verified by the following control experi-
ments using compound 66 as the starting material. First,
target product 3 was formed in 0%, 50% and 59% yields when
the reaction was performed under a nitrogen, air and oxygen
atmosphere, respectively, showing that oxygen acts as the
a Reaction conditions: 1a (0.2 mmol), 2 (0.6 equiv.), Amberlyst 15
(50 mg), H2O (3 mL), visible light (LEDs, 420 nm, 5 W), open flask, rt,
air, 12 h. b Isolated yields. c The reaction was performed for 24 h.
Scheme 2 Gram-scale synthesis and further transformation.
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singlet dioxygen (see the ESI, Table S1†). The subsequent elec-
tron spin resonance (ESR) experiments further confirmed this
conclusion (see the ESI, Scheme S1–3†).
1-Methyl-3,4-dihydroquinoxalin-2(1H)-one (1z) was also
tested under standard conditions, but both Mannich-type
product 66 and target product
3 were not obtained
(Scheme 3e). A further ESR experiment confirmed the gene-
ration of O2•− (see the ESI, Scheme S4†). Some important inter-
mediates have been determined theoretically by DFT calcu-
lations. In addition, ADCH atomic charge analyses showed
that the charge on the O2 fragment changes from 0.041 to
−0.430.22 These results indicate that a single electron transfer
(SET) process is involved. Subsequently, an HOO• radical (part
of complex Int2) is formed by a proton transfer process. The
electron spin density of Int2 (Fig. 2) confirms the formation of
HOO•. Similarly, an HOO•− radical anion is formed through
another SET process, and finally H2O2 is formed through a
proton transfer process.
Fig. 1 Recyclability test.
According to the mechanistic studies and a previous
report,23 a plausible mechanism for the reaction is suggested
(Scheme 4). In this transformation, Amberlyst 15 acts as the
protonic acid to catalyse the Mannich-type reaction. Initially,
acetone 2a is converted to the enol form (A), which is sub-
sequently attacked by protonated imine B to give intermediate
C. Then, Mannich-type product 66 is generated through depro-
tonation of intermediate C. Meanwhile, substrate 1 is excited
by visible light to generate the excited-species 1*, which acts as
a photocatalyst and undergoes an energy transfer (ET) process
with triplet oxygen to give singlet oxygen, along with the regen-
eration of ground-state substrate 1.9g Finally, the reaction
undergoes two SET processes with singlet oxygen 1O2 to
produce the target product with the generation of H2O2
Scheme 3 Control experiments.
Fig. 2 Optimized geometries of three intermediates. The isosurface of
the electron spin density of Int2 is also shown.
oxidant in the dehydrogenation reaction (Scheme 3b). Second,
the reactions that involve a singlet oxygen inhibitor (DABCO,
1,4-diazabicyclooctane triethylenediamine or NaN3) or no
visible light did not give target product 3, demonstrating that
singlet oxygen 1O2, which was generated from triplet oxygen
3O2 through photocatalysis, serves as the real oxidant
(Scheme 3c and d). To further confirm the assumption,
density functional theory (DFT) calculations using the M06-2X
functional21 (see the ESI† for computational details) were per-
formed. We calculated the triplet energy (ET) and singlet–
triplet energy gap (ΔEST) of 1a, 3, and 66. The results demon-
strate that the triplet energies of all three compounds are
higher than the excitation energy required for the generation
of singlet oxygen (95 kJ mol−1), indicating that all three com-
pounds could act as photosensitizers for the generation of Scheme 4 Plausible mechanism.
2126 | Green Chem., 2021, 23, 2123–2129
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(detected by hydrogen peroxide test paper). The obtained inter-
mediate 66 and product 3 also can act as photocatalysts to
promote the photocatalytic cycle.
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Conclusions
This study describes a novel aqueous reaction for the synthesis
of potentially bioactive (Z)-enaminones with a 3,4-dihydro-
quinoxalin-2(1H)-one skeleton through a combination of hetero-
geneous catalysis and photocatalysis. As demonstrated using
model systems, various (Z)-enaminones were obtained in mod-
erate-to-good yields when different substrates were used.
Control experiments revealed that the Mannich type mechanism
and subsequent SET process were responsible for the reaction.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 21871071) and the Natural Science Foundation of
Zhejiang Province (No. LY21B060009) for financial support.
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