FeCl3-catalyzed cascade reaction: An efficient approach to functionalized coumarin derivatives

Article abstract of DOI:10.1080/00397911.2013.862833

An efficient and environmentally benign synthesis of 3-substituted or 3,4-disubstituted coumarins was accomplished via iron(III) chloride-catalyzed cascade reactions of salicylaldehydes and activated methylene compounds. The reaction preceded cleanly under mild reaction conditions to provide the desired coumarin derivatives in good to excellent yields.

Full text of DOI:10.1080/00397911.2013.862833

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FeCl3-Catalyzed Cascade Reaction: An
Efficient Approach to Functionalized
Coumarin Derivatives
Xinwei He a , Zhenglei Yan a , Xiaoqian Hu a , Yin Zuo a , Chang Jiang
a , Lei Jin a & Yongjia Shang a
a Key Laboratory of Functional Molecular Solids, Ministry of
Education, Anhui Key Laboratory of Molecule-Based Materials,
College of Chemistry and Materials Science , Anhui Normal
University , Wuhu , China
Accepted author version posted online: 10 Feb 2014.Published
online: 29 Apr 2014.
To cite this article: Xinwei He , Zhenglei Yan , Xiaoqian Hu , Yin Zuo , Chang Jiang , Lei Jin &
Yongjia Shang (2014) FeCl3-Catalyzed Cascade Reaction: An Efficient Approach to Functionalized
Coumarin Derivatives, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 44:10, 1507-1514, DOI: 10.1080/00397911.2013.862833
To link to this article: http://dx.doi.org/10.1080/00397911.2013.862833
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Synthetic Communications1, 44: 1507–1514, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.862833
FeCl3-CATALYZED CASCADE REACTION: AN EFFICIENT
APPROACH TO FUNCTIONALIZED COUMARIN
DERIVATIVES
Xinwei He, Zhenglei Yan, Xiaoqian Hu, Yin Zuo, Chang Jiang,
Lei Jin, and Yongjia Shang
Key Laboratory of Functional Molecular Solids, Ministry of Education,
Anhui Key Laboratory of Molecule-Based Materials, College of Chemistry
and Materials Science, Anhui Normal University, Wuhu, China
GRAPHICAL ABSTRACT
Abstract An efficient and environmentally benign synthesis of 3-substituted or 3,4-
disubstituted coumarins was accomplished via iron(III) chloride–catalyzed cascade
reactions of salicylaldehydes and activated methylene compounds. The reaction preceded
cleanly under mild reaction conditions to provide the desired coumarin derivatives in good
to excellent yields.
Keywords Activated methylene compounds; cascade reaction; catalysis; coumarins;
iron(III) chloride
Received July 23, 2013.
Address correspondence to Y. Shang, Key Laboratory of Functional Molecular Solids, Ministry of
Education, Anhui Key Laboratory of Molecule-Based Materials, College of Chemistry and Materials
Science, Anhui Normal University, Wuhu 241000, China. E-mail: shyj@mail.ahnu.edu.cn
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1507

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X. HE ET AL.
INTRODUCTION
Coumarins, which are chemical derivatives of benzo-2-pyrones or chromen-2-
ones, are widely distributed in various species of plants.[1] Coumarins have been
reported to exhibit antibacterial, anticarcinogenic, and analgesic activity.[2] In
addition, they also serve as antioxidant and anti-inflammatory agents and HIV pro-
tease inhibitors.[3] The major synthetic methods for the preparation of coumarins
include the Pechmann reaction and its modifications,[4] the Knoevenagel conden-
sation,[5] the Wittig reaction,[6] the Claisen rearrangement,[7] the Vilsmeier–Haack
and Suzuki cross-coupling reactions,[8] Pd-catalyzed site-selective cross-coupling
reactions,[9] nickel-catalyzed cycloaddition reaction,[10] as well as other reactions.[11]
However, there are usually some drawbacks including demanding reaction
conditions, tedious manipulation, long reaction time, and poor overall yield in these
reported methods. Thus, the development of novel, concise, and efficient synthetic
methods for 3-substituted=3,4-disubstituted coumarins is desirable and significant
from both chemical and biological viewpoints.
In recent years, environmental concerns have directly influenced the develop-
ment of new methodologies, which requires higher standards for synthetic efficiency,
atom economy, and reaction costs. Because iron is one of the most abundant metals
on the earth, many iron complexes could be obtained for relatively low costs and are
usually environmentally benign: therefore, they have been regarded as promising
alternatives to many other widely used traditional metal complexes in the catalysis
of various reactions.[12] Despite these advantages and recent impressive progress in
related fields, iron was still relatively underrepresented in the field of catalysis com-
pared to other transition metals.[13] Very recently, iron trichloride has received much
attention in the catalytic synthesis of heterocyclic compounds,[14] multicomponent
reactions,[15] cross-coupling reactions,[16] and cyclization reactions.[17] Herein, we
report a new method for the synthesis of 3-substituted=3,4-disubstituted coumarins
via a FeCl3-catalyzed cascade reaction of commercially available salicylaldehydes
and activated methylene compounds. This methodology represents a simple route
to 3-substituted=3,4-disubstituted coumarins in good to excellent yields under mild
reaction conditions (Scheme 1).
RESULTS AND DISCUSSION
At first the reaction conditions were explored using the commercially available
substrates salicylaldehyde (1a) and malononitrile (2a) by varying the loading amount
Scheme 1. Synthesis of coumarins via FeCl3-catalyzed cascade reactions.

FeCl3-CATALYZED CASCADE REACTION
1509
of the catalyst FeCl3 in ethanol (Table 1). It is found that 5 mol% of the catalyst is
optimal for the reaction (Table 1, entry 1). While the use of several other solvents
such as methanol, acetonitrile, tetrahydrofuran (THF), dimethylformamide
(DMF), H2O, toluene, and dimethylsulfoxide (DMSO) did not improve the yield
(Table 1, entries 8–14), prolonging the reaction time to 24 h led to improved yield.
Thus the reaction was best performed with 5 mol% of FeCl3 in ethanol, producing
the coumarin (3a) in 72% yield after 24 h at 80 ꢀC (Table 1, entry 7).
Following the optimal reaction conditions, we next examined the scope of
this reaction by reacting various salicylaldehydes with malononitrile (2a) or ethyl
2-cyanoacetate (2b), and the results are summarized in Table 2. Generally, the yields
obtained with malononitrile (Table 2, entries 1–3) were less than those obtained with
ethyl 2-cyanoacetate (Table 2, entries 10–12). As to malononitrile (2a), when
salicyladehydes bearing a strong electron-donating group at the para position of
the aldehydes or a strong electron-withdrawing group at the para position of the phe-
nol hydroxyl group were used, the reaction hardly took place (Table 2, entries 6–9).
Interestingly, for ethyl 2-cyanoacetate (2b), the reaction was not affected by such
substituent effects, while the reaction in this case was extremely sensitive to the
sterical factors of the salicylaldehyde (Table 2, entry 13). The structure of the product
3b was confirmed by x-ray crystallographic analysis as shown in Fig. 1.
To test the versatility of this reaction, the optimized reaction condition was
further applied to the reaction of other activated methylene compounds such as
2-cyanoacetamide and diethyl malonate with 2-hydroxy acetophenone (1h) or
Table 1. Optimization of the reaction conditionsa
Entry
FeCl3 (mol %)
Solvent
Temp. (ꢀC)
Time (h)
Yield (%)b
1
2
5
10
25
50
100
5
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
CH3OH
CH3CN
THF
80
80
80
80
80
80
80
60
80
60
80
80
80
80
8
10
10
10
10
16
24
24
24
24
24
24
24
24
60
58
3
45
52
4
5
50
65
6
7
5
72
60
8
5
9
5
48
18
10
11
12
13
14
5
5
DMF
H2O
Trace
Trace
25
5
5
Toluene
DMSO
5
15
aReaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), solvent (5 mL), 80 ꢀC.
bYield of the isolated product.

1510
X. HE ET AL.
Table 2. Synthesis of a series of 3-substituted coumarin derivatives
Entry
2 (R1)
1 (R2, R3, R4, R5)
1a (H, H, H, H)
1b (H, H, Cl, H)
Product
Yield (%)a
1
2
2a (CN)
2a
3a
3b
3c
3d
3e
—
—
—
—
3f
72
75
3
2a
2a
1c (H, H, Br, H)
1d (C(CH3)3, H, C(CH3)3, H)
75
93
4
5
2a
2a
1e (H, OCH3, H, H)
1f (H, H, NO2, H)
80
6
Trace
Trace
Trace
Trace
95
7
2a
2a
1h (H, H, F, H)
1g (H, NEt2, H, H)
1i (H, NMe2, H, H)
8
9
2a
2b (CO2Et)
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1f
2b
2b
2b
2b
2b
2b
3g
3h
—
3i
89
85
Trace
80
70
3j
3k
1g
80
aReaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), FeCl3 (0.05 mmol), EtOH (5 mL), 80 ꢀC, 24 h.
salicyladehydes such as 2-hydroxy-1-naphthaldehyde (Table 3). Except for when
compared to salicylaldehyde 1a, its ketone counterpart 2-hydroxy acetophenone
(1h) showed significantly lower reactivity in that an additional base was usually
required to give acceptable yields of the desired product (Table 3, entries 1–3).
Likewise, diethyl malonate and 2-hydroxy-1-naphthaldehyde (Table 3, entries 12,
Figure 1. X-ray single-crystal structure of 3b.

FeCl3-CATALYZED CASCADE REACTION
1511
Table 3. Synthesis of 3=3,4-disubstituted coumarins with various substrates via FeCl3-catalyzed cascade
reaction
Entry
2 (X, Y)
1 (R1, R2, R3, R4, R5)
1h (CH3, H, H, H, H)
1h
Product
Yield (%)a
1
2
2a (CN, CN)
2b (CO2Et, CN)
3l
3l
50c
63c
41c
73
3
2c (CONH2, CN)
2c
1h
3m
3g
3h
3i
4
1b (H, H, H, Cl, H)
1c (H, H, H, Br, H)
1f (H, H, H, NO2, H)
1e (H, H, OCH3, H, H)
1g (H, H, NEt2, H, H)
5
2c
2c
71
68
6
7
2c
2c
3j
72
58
8
3n
3o
3p
3q
3f
=
1i (H, H, H, -CH CH-CH CH-)
=
9
2a
2b
75
10
11
12
13
14
1i
1g
92
2c
85b
96
2d (CO2Et, CO2Et)
2e (CH3CO, COOEt)
2e
1a (H, H, H, H, H)
1c
1g
3r
3s
53c
38c
aReaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), FeCl3 (0.05 mmol), EtOH (5 mL), 80 ꢀC, 24 h.
bMethanol as solvent.
cNa2CO3 (1.0 mmol) was used as an additive.
9, and 10) also reacted efficiently to produce the expected coumarins 3f, 3o, and 3p in
96%, 75%, and 92%, respectively. When ethyl acetoacetate was used as substrate, the
reaction appeared to be quite general with respect to the activemethylene compounds.
The activity of ethyl acetoacetate is much less than malononitrile or ethyl
2-cyanoacetate, for sodium carbonate is necessary in this reaction. Furthermore,
salicyladehydes bearing Br and NEt2 groups could undergo smooth conversion in
the present reaction condition to yield the desired compounds in 53% and 38%
(Table 3, entries 13 and 14).
Interestingly, when 2-cyanoacetamide was used, the major isolated product
was not the expected 3-formamide coumarins, but instead the same products as those
Scheme 2. FeCl3-catalyzed cascade reaction of salicyladehyde and ethyl acetoacetate to form ethyl
2-ethoxy-2-methyl-6-nitro-2H-chromene-3-carboxylate (3t).

1512
X. HE ET AL.
Scheme 3. Plausible reaction pathway for the formation of compound 3t.
obtained using ethyl 2-cyanoacetate (Table 3, entries 4–7) in moderate yields. This
result might be attributed to alcoholysis of the acetamide functionality under the
reaction conditions (Table 3, entry 11). When 2-hydroxy-5-nitrobenzaldehyde was
used (Scheme 2), the major isolated product was not coumarin or chromenol but
only obtained ethyl 2-ethoxy-2-methyl-6-nitro-2H-chromene-3-carboxylate (3t) in
95% yield. This result might be attributed to the strong electron-withdrawing ability
of the NO2 group.
A plausible mechanism was proposed for the formation of the compound 3 t.
First, 2-hydroxy-5-nitrobenzaldehyde (1f) reacted with ethyl acetoacetate (2e) in
the presence of Na2CO3 to form the intermediate A (Knoevenagel condensation).
Subsequently, the oxygen of hydroxyl attacked the carbanyl group of the intermedi-
ate A to form the intermediate B (intermolecular cyclization reaction). Then, alcohol
reacted with the intermediate B in the presence of FeCl3 to generate the desired
compound 3t through dehydration process.
On the basis of these experimental results, we proposed a plausible mechanism
for this FeCl3-catalyzed cascade reaction as shown in Scheme 4. First, salicyladehyde
1 reacted with the activated methylene compounds 2 in the presence of FeCl3 to form
benzylidene compounds 4 (Knoevenagel condensation). Subsequently, the oxygen of
hydroxyl attacked the cyano- group of the intermediate 4 to form the intermediate 5,
which then underwent hydrolysis to give the corresponding coumarin products.
Scheme 4. Plausible mechanism leading to coumarins via FeCl3-catalyzed cascade reaction.

FeCl3-CATALYZED CASCADE REACTION
1513
EXPERIMENTAL
General Procedure for the Synthesis of Substituted Coumarin
Derivatives 3
Anhydrous FeCl3 (0.05 mmol) was added to a stirred solution of salicyladehyde
1a (1 mmol) and malononitrile 2a (1.2 mmol) in ethanol (3 mL). The mixture was
heated in an oil bath at 80 ꢀC for 24 h and cooled down to room temperature. The
solvent was removed under vacuum, and the residue was directly purified by flash col-
umn chromatography on silica gel (200–300 mesh) with ethyl acetate and petroleum
ether (1:6–1:8, v=v) as eluting solvent to afford the product 3a (123 mg, 0.72 mmol) in
72% yield.
2-Oxo-2H-chromene-3-carbonitrile (3a)[18]
White solid; yield: 123 mg (72%); mp 175–176 ꢀC. IR (KBr) v: 3107, 3072, 3045,
2924, 2229, 1774, 1728, 1604, 1560, 1446, 1369, 1288, 1257, 1188, 1149, 1051, 972,
1
763 cmꢁ1. H NMR (300 MHz, CDCl3) d: 8.22 (s, 1H, CH), 7.67 (t, J ¼ 7.5 Hz, 1H,
ArH), 7.56 (d, J ¼ 7.4 Hz, 1H, ArH), 7.35 (d, J ¼ 4.6 Hz, 2H, ArH) ppm. 13C NMR
(75 MHz, CDCl3) d: 151.9, 135.6, 129.3, 125.8, 117.5, 113.5, 106.8, 101.0 ppm. HRMS
(ESI) calcd for C10H5NO2 (MþHþ) 172.0398, found 172.0393.
CONCLUSIONS
In summary, we have successfully developed a novel, operationally simple,
FeCl3-catalyzed cascade reaction for the synthesis of 3-substituted=3,4-disubstituted
coumarins from salicyladehydes and cyanide methylene compounds under mild reac-
tion conditions. This synthetic approach was also applicable to the corresponding
reaction with ethyl acetoacetate to synthesize substituted chromenols.
FUNDING
This work was partially supported by the National Natural Science Foun-
dation of China (No. 21172001), the Program for the NCET (NCET-10-0004),
and the Anhui Provincial Natural Science Foundation (No. 1308085QB39).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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