One-pot synthesis of 3,4-disubstituted coumarins under catalysis of Mn 3O4 nanoparticles

Article abstract of DOI:10.1002/ejoc.201101578

The one-pot synthesis of 3,4-disubstituted coumarins from substituted 2-(hydroxymethyl)phenols with β-keto esters catalyzed by Mn ₃O₄ nanoparticles was developed. A series of 3,4-disubstituted coumarin derivatives were obtained in good yields. A new method for the one-pot synthesis of 3,4-disubstituted coumarins from substituted 2-(hydroxymethyl)phenols with β-keto esters catalyzed by Mn ₃O₄ nanoparticles has been developed. A series of 3,4-disubstituted coumarin derivatives were synthesized from substituted 2-(hydroxymethyl)phenols and β-keto esters in good yields. Copyright

Full text of DOI:10.1002/ejoc.201101578

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101578
One-Pot Synthesis of 3,4-Disubstituted Coumarins under Catalysis of Mn3O4
Nanoparticles
Huayin Sun,[a] Yonghui Zhang,[a] Fengfeng Guo,[a] Yizhe Yan,[a] Changfeng Wan,[a]
Zhenggen Zha,*[a] and Zhiyong Wang*[a]
Keywords: Manganese / Nanoparticles / Natural products / Heterogeneous catalysis
The one-pot synthesis of 3,4-disubstituted coumarins from
substituted 2-(hydroxymethyl)phenols with β-keto esters cat-
alyzed by Mn3O4 nanoparticles was developed. A series of
3,4-disubstituted coumarin derivatives were obtained in
good yields.
coumarins. For instance, a microporous polymer based on
Nafion resin/silica,[5a] Well–Dawson heteropolyacid,[5b]
montmorillonite KSF,[8a] and calcined Mg-Al hydrotal-
cite[11a] have all been used as heterogeneous catalysts for the
synthesis of coumarins.
Introduction
Coumarin and its derivatives are important chemicals in
natural and synthetic organic chemistry.[1] Their applica-
tions range from pharmaceuticals, food additives, cosme-
tics,[1] optical brightening agents,[2] and insecticides to plant
growth regulators.[3] For example, dihydrofurocoumarins
show significant ability to inhibit c-AMP synthetase and
polycyclic coumarins present potent anti-HIV activity in
addition to other activities.[4] 3-Arylcoumarins show both
antioxidant activity and lipoxygenase inhibitory activity.[1]
These applications and properties render coumarins very
interesting targets to organic chemists. As a result, a variety
of methods, including the Pechmann reaction,[5] the Perkin
reaction,[6] the Claisen rearrangement,[7] the Knoevenagel
reaction,[8] the Reformatsky reaction,[9] and the Wittig reac-
tion,[10] have been developed to synthesize coumarins. Re-
cently, metal-catalyzed multicomponent reactions (usually
involving alkynes, carbon monoxide, aryls) were investi-
gated and widely employed in the synthesis of 3,4-disubsti-
tuted coumarins.[11] Among these methods, the Pechmann
reaction, a two-component (phenols and β-keto esters) cou-
pling under acid catalysis, is a very well-established method
for the preparation of multisubstituted coumarin
rings.[5b–5e] However, this reaction usually involves the use
of acidic catalysts, and mineral acid in an excess amount is
necessary in the classical preparations, resulting in environ-
mental pollution. For eco-friendly reasons, some solid-
phase catalysts have been employed for the preparation of
Nevertheless, substituent diversity and regioselectivity in
the synthesis of 3,4-disubstituted coumarins remain a chal-
lenge, and restricted reaction conditions are often involved
in the preparation.[11] Therefore, a simpler and more effec-
tive synthetic method for the preparation of 3,4-disubsti-
tuted coumarin derivatives is highly desirable, with the hope
of finding derivatives with more potent biological activities.
Recently, nanoparticles have been widely used in organic
synthesis.[12] Our group has paid particular attention to
nanoparticle-catalyzed organic reactions.[13] To the best of
our knowledge, the synthesis of 3,4-disubstituted coumarins
catalyzed by nanoparticles has not been reported, except
for the synthesis of coumarins catalyzed by heterobimetallic
Co/Rh nanoparticles.[11g] Here we report an efficient, one-
pot synthesis of 3,4-disubstituted coumarin derivatives by
reaction of substituted 2-(hydroxymethyl)phenols with β-
keto esters catalyzed by Mn3O4 nanoparticles under mild
reaction conditions. The experimental procedure is very
simple, and the catalyst can be removed easily by centrifu-
gation. Moreover, substituent diversity and regioselectivity
can be realized.
Results and Discussion
Initially, we prepared the Mn3O4 nanoparticles according
to a previously established procedure,[14] and the nanopar-
ticles were characterized by TEM (Figure 1a).
Afterwards, the Mn3O4 nanoparticles and a series of Mn
species were examined as the primary catalysts for the
model reaction of 2-[hydroxy(phenyl)methyl]phenol (1a)
with ethyl acetoacetate (2a, Table 1). It was found that
Mn3O4 nanoparticles gave the best result as a catalyst in
[a] Hefei National Laboratory for Physical Sciences at the
Microscale, CAS Key Laboratory of Soft Matter Chemistry,
Joint-lab of Green Synthetic Chemistry and Department of
Chemistry, University of Science and Technology of China
Hefei 230026, China
Fax: +86-551-360-3185
E-mail: zgzha@ustc.edu.cn
zwang3@ustc.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101578.
480
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Eur. J. Org. Chem. 2012, 480–483

Mn3O4 Nanoparticle Catalyzed Synthesis of 3,4-Disubstituted Coumarins
KOH, and NaOH, were also examined in this reaction. Af-
ter optimization, K2CO3 proved to be the best base for this
reaction (Table 2, Entries 6, 10–13). Also, the molecular ra-
tio of the reaction substrates to the base had an influence
on the reaction. It was found that a ratio of 1:3:3 1a/2a/
K2CO3 afforded 3a in a yield of 78% (Table 2, Entry 16).
Finally, the optimal conditions were obtained, that is,
10 mol-% catalyst loading, 1 equiv. of 1a, 3 equiv. of 2a, and
3 equiv. of K2CO3, and the reaction was carried out at
80 °C for 12 h.
Figure 1. TEM images of (a) fresh Mn3O4 nanoparticles and
(b) Mn3O4 nanoparticles after the fifth cycle.
Table 2. Effect of solvents and the amount of the catalyst.[a]
the reaction (Table 1, Entry 1), whereas commercial Mn3O4
powder and other manganese oxides showed low catalytic
activity (Table 1, entries 2–4). For instance, manganese salts
such as MnCl2·4H2O and Mn(OAc)2·4H2O gave product 3a
in only 15 and 10% yield, respectively (Table 1, Entries 5
and 6). In the absence of a catalyst or base (Table 1, En-
tries 7 and 8), 3a was not obtained at all.
Entry
Catalyst
loading [mol-%]
Solvent
Base
Yield
[%][b]
Table 1. Reaction of 2-[hydroxy(phenyl)methyl]phenol (1a) with
ethyl acetoacetate (2a) catalyzed by various Mn catalysts.[a]
1
2
3
4
5
6
7
8
5
5
5
5
CH3CN
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOH
NaOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
43
–
dioxane
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
28
58
12
72
68
60
52
54
43
57
34
–
26
78
42
53
32
5
10
15
20
30
10
10
10
10
10
10
10
10
10
10
9
10
11
12
13
14[c]
15[d]
16[e]
17[f]
18[g]
19[h]
[a] Reaction conditions: 1a (1 mmol), 2a (2 mmol), Mn3O4 nano-
particles, K2CO3 (2 mmol), solvent (2 mL), 80 °C. [b] Isolated
yield. [c] 100 °C. [d] 1a/2a/K2CO3 = 1:2:3. [e] 1a/2a/K2CO3 = 1:3:3.
[f] 1a/2a/K2CO3 = 1:3:4. [g] 1a/2a/K2CO3 = 1:4:2. [h] 1a/2a/K2CO3
= 1:4:3.
With the optimal conditions in hand, the substrate scope
was investigated (Table 3). Different substituents on the
phenyl ring affected the reaction slightly. For instance, when
the substituents were at the para position with respect to
the hydroxy group, there was little influence on the reaction,
regardless of the electronic effects of the substituents
[a] Reaction conditions: 1a (1 mmol), 2a (2 mmol), catalyst (5 mol-
%), K2CO3 (2 mmol), CH3CN (2 mL), 80 °C. [b] Isolated yield.
[c] Commercial Mn3O4. [d] In the absence of a catalyst. [e] In the
absence of K2CO3.
With this promising result in hand (Table 1, Entry 1), we (Table 3, Entries 4, 6, 7, 9, and 10).
optimized the reaction conditions further. Among various
However, substitution at the ortho position to the hy-
solvents examined, DMF proved to be the best solvent, af- droxy group on the phenyl ring led to a lower yield com-
fording 3a in 58% yield (Table 2, Entry 4). Upon optimizing pared to that obtained with substituents at the para position
the catalyst loading, 10 mol-% of Mn3O4 nanoparticles pro- (Table 3, Entries 2, 4–6, 8, and 9). This indicated that the
vided a satisfactory yield (Table 2, Entry 6). Both an in- steric hindrance on the phenyl ring had a small influence
crease and a decrease in the loading of the Mn3O4 nanopar- on the reaction. On the other hand, the effect of the R2
ticles resulted in lower yields (Table 2, Entries 4, 7, 8, and substituent was investigated. Usually, R2 = aryl, but when
9). Bases additives, including Na2CO3, Cs2CO3, K2CO3, R2 = alkyl, the reaction did not proceed, except when R2 =
Eur. J. Org. Chem. 2012, 480–483
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481

H. Sun, Y. Zhang, F. Guo, Y. Yan, C. Wan, Z. Zha, Z. Wang
SHORT COMMUNICATION
Table 3. Reaction of substituted 2-(hydroxymethyl)phenols 1 with indicated that the Mn3O4 nanoparticle catalyst had great
β-keto esters 2.[a]
recyclability in this reaction. The TEM image of the Mn3O4
nanoparticles after the fifth round is shown in Figure 1b.
Table 4. Recycling of the catalyst.[a]
[a] Reaction conditions: 1a (1 mmol), 2a (3 mmol), Mn3O4 nano-
particles (10 mol-%), K2CO3 (3 mmol), DMF (2 mL) at 80 °C. Iso-
lated yields are given.
The XRD and XPS[15] patterns of the Mn3O4 nanopar-
ticles after the fifth round were similar to those of the fresh
Mn3O4 nanoparticles (see the Supporting Information),
which demonstrated that the structure of the Mn3O4 nano-
particles was maintained after the recycling reactions.
To study the reaction mechanism, control experiments
were carried out (Scheme 1). In the presence of Mn3O4
nanoparticles, 1a was converted into 1aЈ in air in 75% yield.
Without the Mn3O4 nanoparticles, no oxidation product
was observed. This indicated that the Mn3O4 nanoparticles
acted as the catalyst in the first oxidation step. Then, 1aЈ
reacted with 2a to give rise to product 3a in the presence of
K2CO3. In this step, in the presence of the Mn3O4 nanopar-
ticles, 70% yield of 3a was obtained, whereas 45% yield was
reached in the absence of Mn3O4 nanoparticles. this shows
that the Mn3O4 nanoparticles can still be the catalyst, act-
ing as a Lewis acid, for the second cyclization step of the
whole reaction.
[a] Reaction conditions: 1 (1 mmol), 2 (3 mmol), Mn3O4 nanopar-
ticles (10 mol-%), K2CO3 (3 mmol), DMF (2 mL), 80 °C. [b] Iso-
lated yield. [c] tert-Butyl acetoacetate was used.
Me (Table 3, Entry 11). However, substitution of the aryl
had little influence on this reaction. For example, when a
methyl group located at the para-position of the phenyl
ring, a good yield was still obtained (Table 3, Entry 12). Fi-
nally, the generality of β-keto esters was examined. It was
found that R3 can be different alkyl groups (Table 3, En-
tries 13 and 14). Moreover, substrate 2d (R3 = phenyl) gave
Scheme 1. Steps of the reaction.
product 3o in 60% yield (Table 3, Entry 15). Nevertheless,
the steric effect of R3 had a negative influence on this reac-
tion. When R3 = tBu, no desired product was obtained
Conclusions
(Table 3, Entry 16). When tert-butyl acetoacetate 2e was
used in the reaction, the corresponding reaction could be
carried out smoothly to give 3a in good yield (Table 3, En- catalytic system for the one-pot synthesis of 3,4-disubsti-
try 17). tuted coumarins by using Mn3O4 nanoparticles as a hetero-
In conclusion, we have successfully developed a new
The recyclability of the catalyst was also investigated. geneous catalyst. A variety of 3,4-disubstituted coumarin
The reaction of 2-[hydroxy(phenyl)methyl]phenol (1a) with derivatives were synthesized from substituted 2-(hy-
ethyl acetoacetate (2a) was employed as a model reaction. droxymethyl)phenols and β-keto esters in good yields.
When Mn3O4 nanoparticles were over six runs, no obvious Compared with previous catalytic systems, Mn3O4 nano-
loss in the catalytic activity was observed (Table 4). This particles display important advantages, including low cata-
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Mn3O4 Nanoparticle Catalyzed Synthesis of 3,4-Disubstituted Coumarins
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is in progress in our laboratory.
Experimental Section
Preparation of Mn3O4 Nanoparticles:[14] Mn(OAc)2·4H2O (0.50 g)
and DMSO (30 mL) were added into a 30-mL, Teflon-lined stain-
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nanoparticles were precipitated after keeping it at room tempera-
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for 10 min, then washed with water and anhydrous ethanol (3ϫ)
and dried at 60 °C for 6 h in vacuo. Typical XRD and XPS patterns
of the nanoparticles are shown in Figures S2a and S3a (see the
Supporting Information). All the strong and shape diffraction
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General Working Procedure for the Preparation of 3a–o: The Mn3O4
nanoparticles (22.9 mg, 10 mol-%) and the appropriate 2-(hy-
droxymethyl) phenol (1 equiv.) in DMF (2 mL) were heated at
80 °C for 6 h. Then, the β-keto ester (3 mmol) and K2CO3 (3 mmol)
were added to the mixture. The mixture was stirred for 6 h. After
completion of the reaction, the catalyst was separated by centrifu-
gation. Then, the solution was extracted with ethyl acetate
(3ϫ20 mL). The combined organic layer was washed with water
and brine and dried with anhydrous sodium sulfate. The organic
phase was concentrated under vacuum and purified with column
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental details; characterization data; and the 1H NMR,
13C NMR, and mass spectra of all compounds.
Acknowledgments
We are grateful for the financial support of the National Science
Foundation of China (No. J1030412, 20772118, 20932002,
20972144, 21172205, 90813008), Ministry of Science and Technol-
ogy (010CB912103), and the Chinese Academy of Sciences.
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Received: October 30, 2011
Published Online: December 9, 2011
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