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z Sustainable Chemistry

One-pot Synthesis of 2-Amino-4H-chromenes Derivatives in

Aqueous Solution of Choline Hydroxide
Lingjun Li,* Lili Bai, Jingjing Li, Wanlu Feng, Dongshuang Fan, Qixing Li, and Anlian Zhu*[a]

2-Amino-4H-chromenes have showed broad bioactivities and Its operation and work-up procedures were very simple, and
attracted great attention in synthetic chemistry. Here, the importantly, the target compounds could be obtained from
aqueous solution of choline hydroxide was found to be an simple centrifugation and washing procedures, no column
efficient catalytic system for the one-pot synthesis of 2-amino- purification was needed. In addition, the catalytic system
4H-chromenes under room temperature. Various aldehydes, involving choline hydroxide and water could be easily reused
malononitrile and phenols could be converted to the corre- for at least five cycles with high activity. The above advantages
sponding 2-amino-4H-chromenes smoothly with good to made this catalytic system promising in the industrial produc-
excellent isolated yields. This catalytic system had high chemo- tion of 2-amino-4H-chromenes.
selectivity with biocompatible catalyst in green solvents, water.

high reaction temperature, utilization of hazard volatile organic

Introduction
solvents or expensive metal precursors, and as we know, even
4H-chromene skeleton is the key building block for many trace residual of transition metals in final products will lead to
important natural heterocyclic products with wide pharmaco- the undesired harmful effects towards human health. There-
logical and biological activities.[1–6] Some of these natural fore, a more eco-friendly method with cheap and biocompat-
compounds such as 2-amino-4H-chromenes have showed ible catalyst at ambient reaction conditions is still in great
antitumor,[7,8] antibacterial,[9–11] antiviral,[12] antioxidant,[13,14] demand.
anticoagulant[15,16] and antiallergenic activities.[17] In addition, The results from our continuous interests in the utilization
they have also been utilized as laser dyes,[18] pigments, of basic ionic liquids in the catalysis suggested that the related
fluorescence markers[19] and cosmetics. So, the synthesis for the catalytic procedures benefit from excellent reactivity and
derivatives of 2-amino-4H-chromenes has received great special selectivity.[36–39] Some basic ionic liquids have the ability
attention and many methods have been developed for this to modulate the catalytic activity of various metals as ligands
purpose,[20] in which, the MCR synthesis strategies based on the or solvents in the related reaction systems.[40–44] Here, it was
reaction of malononitrile, aromatic aldehydes and phenols found that the aqueous solution of choline hydroxide could
have showed great attraction due to its efficient construction efficiently promote the one-pot three components reactions of
of several new chemical bonds in a one-pot with high atom various aldehydes, malononitrile and phenols for the synthesis
efficiency. Various catalytic systems have been developed for of 2-amino-4H-chromenes under moderated conditions. This
this conversion, like Fe(HSO4)3,[21] MeSO3H,[22] p-toluenesulfonic catalytic system had high chemoselectivity and various alde-
acid,[23] heteropolyacid,[24] sulfonic acid functionalized PEG,[25] hydes could react smoothly to produce the target 2-amino-4H-
sulfonic acid functionalized silica,[26] tungstic acid functionalized chromenes with good to excellent isolated yields at room
mesoporous SBA-15,[27] iodine,[28] and nanosized MgO,[29] temperature. When the reaction completed, the target com-
hydrotalcite,[30] DBU,[31] Et3N,[32] 4-dimethylaminopyridine,[33] pounds could be isolated from the aqueous solution of choline
DABCO entrapped in agar,[34] amino-appended cyclodextrin, hydroxide through simple centrifugation and decantation. The
and CoFe2O4, CuO/CeO2, supported copper iodide, Bimetallic remaining aqueous solution of choline hydroxide could be
PdRu/graphene oxide.[35] These catalysts have made structurally recycled and reused for at least five cycles without significant
diverse synthesis of 2-amino-4H-Chromene derivatives with catalytic activity decrease. These results showed that this
satisfactory isolated yields, but most of them suffered from catalytic system is promising for the eco-friendly synthesis of 2-
amino-4H-chromenes with high atom efficiency.
[a] Prof. L. Li, L. Bai, J. Li, W. Feng, D. Fan, Q. Li, Dr. A. Zhu
School of Chemistry and Chemical Engineering, Key Laboratory of Green Results and Discussion
Chemical Media and Reactions, Ministry of Education, Collaborative
Innovation Center of Henan Province for Green Manufacturing of Fine Firstly, the reaction of p-nitrobenzaldehyde, malononitrile and
Chemicals, Henan Normal University, Xinxiang, Henan 453007, P. R. China
resorcinol were selected as the model to investigate the
E-mail: [email protected]
[email protected] influence of the concentration and catalyst loading of choline
Supporting information for this article is available on the WWW under hydroxide and the results were collected in Table 1. The results
https://doi.org/10.1002/slct.202003076 showed that both the concentration and the loading of choline

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ChemistrySelect doi.org/10.1002/slct.202003076

Table 1. Effect of the concentration and catalyst loading of choline reaction system through centrifugation and decantation after
hydroxide. the completion of reaction, leaving the aqueous solution of
choline hydroxide reused directly for the next run. The
reutilization results illustrated in Figure 1 suggested that the
catalytic activity could be well maintained for at least five
cycles without noticeable decrease.
The plausible reaction mechanism of this catalytic proce-
Entry[a] Conc.(%)[b] Molar ratio[c] Time(h) Yield(%)[d] dure was proposed and illustrated in Scheme 1. The α-H of
malonitrile was deprotonated by the hydroxide anion to form
1 47 1.0 0.5 85
2 40 1.0 0.5 86
the carbon anion. The carbon anion then attacked the C=O of
3 30 1.0 0.5 91 aldehyde which was activated by the hydroxyl group on the
4 20 1.0 0.5 83 choline cation through the formation of hydrogen bond to
5 10 1.0 0.5 85 form the Knoevenagel intermediate. Meanwhile, Phenoxy anion
6 30 0.5 0.5 89
7 30 0.3 0.5 93
was also formed under the catalysis of choline hydroxide,
8 30 0.1 0.5 85 which then reacted with Knoevenagel intermediate and the
target product was formed after the following cyclization
[a]Reaction conditions: p-nitrobenzaldehyde (0.5 mmol, 75.6 mg), malono-
nitrile (0.5 mmol, 33.0 mg), resorcinol (0.5 mmol, 55.0 mg), aqueous rearrangement procedures.
solution of choline hydroxide (0.5 mmol, 1.0 eq), room temperature; [b]The
concentration of choline hydroxide in water; [c]Molar ratio of choline
hydroxide to substrates; [d]Isolated yields. Conclusion
In conclusion, this work has developed an efficient one-pot
multicomponent catalytic system for the synthesis of 2-amino-
hydroxide have significant influence on its catalysis for the 4H-chromenes in aqueous solution under room temperature. In
target compounds and when the mass concentration of choline this catalytic system, various benzyaldehyde and heteroaro-
hydroxide in water is at 30 %, and its molar ratio to reactants is matic aldehydes could react with malononitrile, and activate
at 0.3eq, the product can arrive at 93 % isolated yields at room phenols efficiently, giving the target 2-amino-4H-chromenes
temperature within half an hour. with good to excellent isolated yields. After the reactions were
The above results showed that the aqueous solution of
choline hydroxide have excellent potentials for the production
of 2-amino-4H-chromenes under mild conditions, so its gen-
erality of this catalytic system was further investigated using
different aldehydes and phenols under the optimized reaction
conditions and the results were collected in Table 2. The results
showed that various benzaldehydes with strong electro-with-
drawing groups like NO2 and F can reacted with malononi-
trile and resorcinol fluently and the target compounds can
reach excellent isolated yields within half an hour(entries 1–4,
Table 2). The benzaldehydes with halides groups like –Cl and
-Br at ortho-position also have good reactivity which could
converted to the target compounds with isolated yields above
93 % within 0.5 hours (entries 6, 8, Table 2), while at para-
position, the reaction rate was a little sluggish, but could still
give good yields when the reaction time was prolonged to
5 hours(entries 7, 9, Table 2). The benzaldehyde and its deri-
vates with electro-donating groups was not profitable in this Figure 1. Reusability of the aqueous solution of choline hydroxide.
catalytic system but could still reach good to excellent yields
after prolonged reaction time (entries 10–12, Table 2). Hetero-
aromatic aldehydes such as 2-furaldehyde and 4-pyridinecar-
boxaldehyde could also react with malononitrile and resorcinol
smoothly, reaching the target 2-amino-4H-chromenes with
excellent yields (entries 13, 14, Table 2). When it comes to the
steric 2-methylresorcinol, it could still react with various
aldehydes and malononitrile smoothly (entries 15–18, Table 2).
Then the recyclability and reusability of the aqueous
solution of choline hydroxide were investigated using the
model reaction in Table 1. Due to the product is insoluble in
the aqueous solutions, so it could be separated from the Scheme 1. The plausible reaction mechanism.

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Table 2. The reaction of phenol, aromatic aldehydes and malononitrile catalyzed by choline hydroxide.

Time Yield M.p.(°C)

Entrya Aldehyde R1 Product Found Report(Lit)
(h) (%) b

1 H 0.5 91 208–210 208–210[45]

4a

2 H 0.5 83 228–230 235–237[2]

4b

3 H 0.5 96 164–166 163–165[35]

4c

4 H 0.5 87 167–169 167–169[2]

4d

5 H 0.5 91 216–218 191–192[2]

4e

6 H 0.5 94 222–224 200–204[45]

4f

7 H 5 83 146–148 158–160[45]

4g

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Table 2. continued

Time Yield M.p.(°C)

Entrya Aldehyde R1 Product Found Report(Lit)
(h) (%) b

8 H 0.5 93 206–208 205–206[46]

4h

9 H 5 78 146–148 226–228[45]

4i

10 H 9 85 182–184 184–186[45]

4j

11 H 7 78 210–212 212–214[47]

4k

12 H 7 93 192–194 192–194[47]

4l

13 H 0.5 88 216–218 218–210[48]

4m

14 H 1.5 87 215–216 214–215[47]

4n

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Table 2. continued

Time Yield M.p.(°C)

Entrya Aldehyde R1 Product Found Report(Lit)
(h) (%) b

15 CH3 4.5 94 110–112 –

4o

16 CH3 1 98 158–160 –

4p

17 CH3 1 97 222–224 220–221[49]

4q

18 CH3 1 70 182–184 –

4r

[a] Reaction conditions: phenol (0.5 mmol), aromatic aldehydes (0.5 mmol), malononitrile (0.5 mmol), aqueous solution of choline hydroxide (0.3eq, 30 % wt),
room temperature; [b] Isolated yields.

completed, the pure products can be gotten by simple washing

Supporting Information Summary
after they were separated from the reaction system through
centrifugation and decantation, no column chromatography The experimental section and selected products NMR data and
purification procedure is needed. The catalyst plus solvent can spectrum can be found in supporting information.
be recycled and reused for at least five cycles without
significant activity decrease. In addition, the catalyst, choline
Acknowledgement
hydroxide, is commercial available with low cost and excellent
biocompatibility. The benefits from the utilization of biocom- This work was financially supported by the National Natural
patible and reusable catalyst, easy operation and work-up Science Foundation of China (No. 21373079) and S&T Research
procedures, simple purification of product and the moderate Foundation of Education Department of Henan Province (No.
reaction conditions, all made this catalytic system promising for 20A150022).
the production of 2-amino-4H-chromenes in industrial.
Conflict of Interest
The authors declare no conflict of interest.

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