An efficient construction of 4-OXO-4H-chromene-2-carboxylate derivatives via one-pot cascade reaction under solvent-free conditions

Article abstract of DOI:10.3987/COM-15-13191

An efficient synthetic strategy to chromone derivatives from commercially available diethyl acetylenedicarboxylate and phenols via a one-pot cascade reaction has been developed. Performing the reaction using pyridine and polyphosphoric acid as the catalyst at room temperature and 90°C without any solvent gave the chromone derivatives in good to high yields at one time. A possible reaction pathway was also proposed and supported by the experiment. This protocol is environmentally friendly and metal-free, with advantages including short reaction times, convenient operation, and mild reaction conditions.

Full text of DOI:10.3987/COM-15-13191

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HETEROCYCLES, Vol. 91, No. 6, 2015
HETEROCYCLES, Vol. 91, No. 6, 2015, pp. 1204 - 1211. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 11th February, 2015, Accepted, 20th April, 2015, Published online, 11th May, 2015
DOI: 10.3987/COM-15-13191
AN
EFFICIENT
CONSTRUCTION
DERIVATIVES
OF
VIA
4-OXO-4H-
CHROMENE-2-CARBOXYLATE
ONE-POT
CASCADE REACTION UNDER SOLVENT-FREE CONDITIONS
Chao Huang,* Jia-Hui Guo, Huang-Mei Fu, Ming-Long Yuan, and Li-Juan
Yang
Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education, Engineering Research Center of
Functional Materials of Yunnan, Yunnan Minzu University, Kunming, 650500,
China; E-mail: huang.chao@hotmail.com
Abstract – An efficient synthetic strategy to chromone derivatives from
commercially available diethyl acetylenedicarboxylate and phenols via a one-pot
cascade reaction has been developed. Performing the reaction using pyridine and
o
polyphosphoric acid as the catalyst at room temperature and 90 C without any
solvent gave the chromone derivatives in good to high yields at one time. A
possible reaction pathway was also proposed and supported by the experiment.
This protocol is environmentally friendly and metal-free, with advantages
including short reaction times, convenient operation, and mild reaction conditions.
As oxygen-containing heterocyclic compounds, chromones can be found in a large number of natural
products.1 Chromone scaffolds (Figure 1), for example flavones and isoflavones, have a broad range of
biological activities such as anti-inflammatory, antiplatelet, anticancer, antiviral, and antimicrobial
properties.2 Due to their pharmaceutical applications, recently, relevant reports, which focused on the
construction of simple chromones and fused chromones as well as the derivatization and total synthesis,
have gradually increased.3 Among these, considerable efforts have been paid for exploring ideal synthetic
routes to 4-oxo-4H-chromene-2-carboxylates (Figure 1).
Figure 1. Simple chromones and target molecule

HETEROCYCLES, Vol. 91, No. 6, 2015
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In modern organic chemistry, the ideal synthesis should be a combination of a number of environmental,
health, safety, and economic targets, so that meets the principles of green chemistry.4 Accordingly,
synthetic methodologies including bicyclic construction, chromanones transformation, and chromones
derivatization have been designed.1a Actually, few study has been reported on chromanones
transformation, while as for the chromones derivatization has been often used for the formation of
functional compounds and fused heterocyclic compounds.5 Compared with the previous reports, bicyclic
construction has been frequently employed and could be considered as the most efficient strategy for the
construction of simple chromones.6 However, most of the reported methodologies had with limitations,
i.e., they are multi-step and typically carried out with metal catalysts, strong acids, or unconventional
reagents. Furthermore, it often requires high temperature or pressure that makes the synthesis and
isolation of desired products difficult and the yields are low to moderate. Thus, it is highly urgent to
develop some facile alternatives with easily available starting materials and under mild reaction
conditions for fulfilling the principle of efficient and green synthesis.
In the past few decades, cascade reaction has aroused much attention because of the advantages, viz.,
atom economy, step-saving, and efficiency in chemical processes by which avoiding the isolation of
intermediates and change of reaction conditions.7 It has also been regarded as a powerful tool for total
synthesis of natural products and construction of heterocyclic compounds. Stimulated by our prior work,8
we are pleased to introduce the reaction for the construction of chromones. Herein, we design a protocol
for the construction of 4-oxo-4H-chromene-2-carboxylate ring via a cascade reaction between
commercially available phenols 1 and the diethyl acetylenedicarboxylate 2 (Scheme 1).
Scheme 1. Strategies for the synthesis of 4-oxo-4H-chromene-2-carboxylate
At first, we treated 1a with 2 in solvent-free conditions at room temperature and the reaction might
1
proceed by the addition of pyridine as a base; however, the target molecule could not be found by H
NMR analysis. Then some catalysts were added to the reaction mixture, which were expected to get the

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HETEROCYCLES, Vol. 91, No. 6, 2015
4-oxo-4H-chromene-2-carboxylates in one-pot, and we finally used the concentrated sulfuric acid at last.
Next, phenol 1a and diethyl acetylenedicarboxylate 2 were treated to optimize the reaction conditions
(Table 1). The reaction could also proceed in different solvents at room temperature (Table 1, entries 2–5),
but we could not obtain the products 3a in better yields. In the elevated temperature treatment (at 90 oC),
the target product 3 was obtained in the yield of more than 50% under solvent-free conditions (Table 1,
entries 6–7). A study on different catalyst such as concentrated sulfuric acid and diphenyl ether was
examined, and we could find polyphosphoric acid (PPA) as the best catalyst (Table 1, entries 7–9).
Among the basic catalysts, pyridine affords the best result (Table 1, entries 9–11). Thus, we defined the
reaction of the phenol 1a with 1.25 equiv of diethyl acetylenedicarboxylate 2, as catalysts by pyridine and
o
PPA, under solvent-free conditions from room temperature to 90 C as the standard reaction conditions
(Table 1, entry 9).
Table 1. Optimization of the Reaction Conditionsa
Entry
Catalystb
Solvent
Temperaturec
Time (h)d
Yield (%)e
1
2
3
4
5
6
7
8
9
pyridine-H2SO4
pyridine-H2SO4
pyridine-H2SO4
pyridine-H2SO4
pyridine-H2SO4
pyridine-H2SO4
pyridine-H2SO4
pyridine-diphenyl ether
pyridine- PPA
Et3N- PPA
solvent-free
THF
rt
rt
rt
rt
rt
10
10
10
10
10
3
3
3
3
12
12
41
38
36
32
35
52
55
10
82
25
0
acetone
toluene
CH2Cl2
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
90 oC
rt– 90 oC
rt– reflux
rt– 90 oC
rt– 90 oC
rt– 90 oC
10
11
Na2CO3- PPA
aThe reaction was carried out using 1a (1.00 mmol) and 2 (1.25 mmol) in the indicated solvent (1 mL) in
b
a dry Schlenk tube. base (0.50 mmol) and cyclization reagents (6.00 mmol) were added respectively.
cTemperature was adjusted to different catalysts. dThe total reaction time. eIsolated yields.
Under the optimal conditions established, the scope of the one-pot cascade reaction without solvent was
developed using a range of substituted phenols 1 (Scheme 2). They provided the chromone compounds 3
in good to high yields, and the results are summarized in Scheme 2 and the experimental section. All of
1
the products 3a–3k were characterized by IR, H NMR, 13C NMR and the high resolution mass
spectrometry (HRMS). The reaction of substituted phenols 1 and 2 proceeded smoothly, however, the
phenols with active functional group and β-naphthol were not good for this reaction. The presence of
either electron-withdrawing or electron-donating groups on the aromatic ring of phenols 1 played a

HETEROCYCLES, Vol. 91, No. 6, 2015
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significant role in the formation of chromones 3. For example, the reactions of 2 and phenols 1b and 1c
having the electron-donating substituents proceeded in short time (3 h) and afforded 3b and 3c in high
yields (76% and 88%), respectively. However, reversely the reactions of 2 and phenols 1d–1g having the
electron-withdrawing substituted proceeded slowly (5 h) and afforded 3d–3g in moderate yields (from 51%
to 56%). Moreover, the positional isomers (ortho-, meta-, and para- Me) having same methyl group on
phenol ring showed no effect on the yields (from 73% to 76%) of the chromones 3. However, the
regioselectivity of intramolecular Friedel-Crafts reaction was observed in the reaction of 2 and
meta-substituted phenol such as 1j and 1k, and the yields of major product were above 50% yield.
Scheme 2. Construction of 4-oxo-4H-chromene-2-carboxylates 3
A plausible mechanistic pathway for the formation of the desired product 3 is described in Scheme 3.
Activated non-terminal alkyne having electron-withdrawing groups on the acetylene bond facilitated the
nucleophilic addition reaction of diethyl acetylenedicarboxylate 2 and phenols 1 to afford the intermediate
4. Then, using PPA as a catalyst, the product 3 has been afforded by the intramolecular Friedel-Crafts
reaction of 4. To clarify the mechanism of the cascade reaction process, ethyl 4-oxo-4H-chromene-
2-carboxylate 3a was prepared by multi-step method instead of one pot protocol. We found that the
intermediate 4a was easily obtained from the nucleophilic addition reaction of phenol 1a to diethyl
acetylenedicarboxylate 2 in high yield of 80% without solvent at room temperature. Further investigation
implied that the target chromone 3a came from 4a, which was supported by the case that the cascade
reaction through nucleophilic addition of phenol 1 to 2 and following Friedel-Crafts reaction of 4. These
results also suggest that the cascade reaction is an effective method.
Scheme 3. Plausible mechanistic pathway for the formation of 3
In conclusion, we have developed an efficient and facile strategy for the formation of chromone
derivatives. The approach used pyridine and PPA as catalysts, easily accessed diethyl

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acetylenedicarboxylate 2 and simple phenols 1 as the starting materials, and the corresponding chromones
3 were obtained in reasonable yields at one time. This method did not need the aid of any metals and
classical solvents. Generally, the advantages of this environmentally benign procedure over earlier
reported approaches include its simplicity, fast and clean reactions and high yields. Our further
investigation into the application of the strategy for the formation of chromone heterocyclic compounds
and chromone drug are currently on-going.
EXPERIMENTAL SECTION
All compounds were fully characterized by spectroscopic techniques. The NMR spectra were recorded on
a Bruker Avance 400 spectrometer at 400 MHz spectrometer (1H: 400 MHz, 13C: 100 MHz) with
tetramethylsilane (TMS) as the internal standard (δ 0.0 ppm), chemical shifts (δ) are expressed in ppm,
and J values are given in Hz. Deuterated chloroform (CDCl3) was used as a solvent. IR spectra were
recorded on a FT-IR Thermo Nicolet Avatar 360 using a KBr pellet. The melting points were determined
on an XT-4A melting point apparatus and are uncorrected. Alumina N-neutral (100–200 & 200–300
mesh) for column chromatography and silica GF254 for TLC were produced by Qingdao Marine
Chemical Company (China).
Typical Procedure for the Preparation of the Chromone Derivatives 3.
Ethyl 4-oxo-4H-chromene-2-carboxylate (3a). Pyridine (0.50 mmol) was added to a mixture of diethyl
acetylenedicarboxylate 2 (1.00 mmol) and phenol 1a (1.25 mmol). The resulting mixture was stirred at
room temperature for 10 min. Then, PPA (6.00 mmol) was added and the mixture was heated up to 90 oC
for the appropriate amount of time. The process of the reaction was monitored by TLC. And the heating
will be stopped when the intermediate from the reaction of 1a and 2 transformed to the new product
completely, then the mixture was cooled to room temperature. The residue was purified by column
chromatography on silica gel to give 3a (82%); White solid: mp 68–69 qC (lit,9 mp 63 °C); IR (KBr) (νmax
cm-1) 3090, 1739, 1651, 1451, 1251, 1119, 1063, 859; 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J = 7.2 Hz,
3H), 4.11 (q, J = 7.2 Hz, 2H), 5.48 (d, J = 12.6 Hz, 1H), 6.98 (m, 1H), 7.09 (t, J = 7.43 Hz, 1H), 7.28 (t, J
,
= 8.0 Hz, 1H), 7.73 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 60.0, 102.2, 118.1, 118.1, 125.0, 130.0,
130.0, 155.9, 159.0, 159.0, 167.2; HRMS (ESI-TOF) m/z Calcd for C12H10O4 [M+Na]+ 241.0477, found
241.0471.
Ethyl 6-methyl-4-oxo-4H-chromene-2-carboxylate (3b): Yield 76%; White solid: mp 133–134 qC
(lit,10 mp 137–139 °C); IR (KBr) (νmax, cm-1) 3080, 1748, 1651, 1616, 1478, 1287, 1238, 1122, 1045, 867,
833, 737; 1H NMR (400 MHz, CDCl3): δ 1.42 (t, J = 7.1 Hz, 3H), 2.45 (s, 3H), 4.45 (q, J = 7.1 Hz, 2H),
13
7.09 (s, 1H), 7.52 (m, 2H), 7.96 (m, 1H); C NMR (100 MHz, CDCl3): δ 14.1, 21.0, 62.9, 114.6, 118.5,

HETEROCYCLES, Vol. 91, No. 6, 2015
1209
124.0, 125.0, 136.0, 136.1, 152.1, 154.3, 160.6, 178.5; HRMS (ESI-TOF) m/z Calcd for C13H12O4
[M+Na]+ 255.0633, found 240.0627.
Ethyl 6-methoxy-4-oxo-4H-chromene-2-carboxylate (3c): Yield 88%; White solid: mp 102–103 qC
1
(lit,9 mp 98 °C); IR (KBr) (νmax, cm-1) 3085, 1741, 1653, 1451, 1249, 1117, 1064, 862; H NMR (400
MHz, CDCl3): δ 1.44 (t, J = 7.2 Hz, 3H), 3.9 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 7.1 (s, 1H), 7.33 (dd, J =
13
9.2, 3.2 Hz, 1H), 7.55 (s, 1H); C NMR (100 MHz, CDCl3): δ 14.1, 56.0, 63.0, 104.6, 113.9, 115.5,
120.3, 125.0, 150.9, 152.0, 157.5, 160.6, 178.3; HRMS (ESI-TOF) m/z Calcd for C13H12O5 [M+Na]+
271.0582, found 271.0576.
Ethyl 6-bromo-4-oxo-4H-chromene-2-carboxylate (3d): Yield 53%; White solid: mp 136–137 qC (lit,11
1
mp 143–144 °C); IR (KBr) (νmax, cm-1) 3095, 1739, 1652, 1451, 1250, 1119, 1064, 860; H NMR (400
MHz, CDCl3): δ 1.44 (t, J = 7.1 Hz, 3H), 4.49 (q, J = 7.1 Hz, 2H), 7.26 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H),
13
7.74 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H); C NMR (100 MHz, CDCl3): δ 14.2, 63.7, 74.8, 111.9, 119.9,
129.1, 136.4, 136.8, 152.0, 162.8; HRMS (ESI-TOF) m/z Calcd for C12H9BrO4 [M+Na]+ 318.9582, found
318.9576.
Ethyl 6-fluoro-4-oxo-4H-chromene-2-carboxylate (3e): Yield 56%; White solid: mp 128–129 qC; IR
(KBr) (νmax, cm-1) 3075, 1740, 1652, 1450, 1250, 1118, 1064, 860; 1H NMR (400 MHz, CDCl3): δ 1.37 (t,
J = 7.2 Hz, 3H), 4.40 (q, J = 7.2 Hz, 2H), 7.04 (s, 1H), 7.41 (m, 1H), 7.57 (m, 1H), 7.76 (dd, J = 8.0, 3.1
13
Hz, 1H); C NMR (100 MHz, CDCl3): δ 13.0, 62.1, 109.5, 109.7, 112.9, 120.0, 120.1, 121.9, 122.2,
151.4, 159.3, 176.6; HRMS (ESI-TOF) m/z Calcd for C12H9FO4 [M+Na]+ 259.0383, found 259.0377.
Ethyl 4-oxo-6-trifluoromethyl-4H-chromene-2-carboxylate (3f): Yield 53%; White solid: mp 123–124
qC; IR (KBr) (νmax, cm-1) 3080, 1740, 1652, 1450, 1250, 1119, 1064, 859; 1H NMR (400 MHz, CDCl3): δ
1.43 (t, J = 7.1 Hz, 3H), 4.45 (d, J = 7.1 Hz, 2H), 7.15 (s, 1H), 7.26 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 8.40
(q, J = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 13.1, 60.7, 114.1, 118.2, 123.0, 127.1, 130.8, 134.3,
151.5, 157.3, 159.2, 164.0, 176.9; HRMS (ESI-TOF) m/z Calcd for C13H9F3O4 [M+Na]+ 309.0351, found
309.0345.
Ethyl 6-nitro-4-oxo-4H-chromene-2-carboxylate (3g): Yield 51%; White solid: mp 172–173 qC (lit,11
1
mp 178–179 °C); IR (KBr) (νmax, cm-1) 3075, 1739, 1651, 1450, 1250, 1118, 1064, 858; H NMR (400
MHz, CDCl3): δ 1.44 (t, J = 7.0 Hz, 3H), 4.49 (q, J = 7.0 Hz, 2H), 7.17 (s, 1H), 7.78 (d, J = 9.9 Hz, 1H),
13
8.56 (m, 1H), 9.04 (d, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl3): δ 14.1, 63.5, 115.0, 120.7, 122.5,
124.4, 128.9, 145.2, 152.8, 158.7, 159.8, 176.8; HRMS (ESI-TOF) m/z Calcd for C12H9NO6 [M+Na]+
286.0328, found 286.0322.
Ethyl 8-methyl-4-oxo-4H-chromene-2-carboxylate (3h): Yield 73%; White solid: mp 101–103 qC
1
(lit,11 mp 100–101 °C); IR (KBr) (νmax, cm-1) 3085, 1741, 1653, 1454, 1249, 1115, 1065, 863; H NMR

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HETEROCYCLES, Vol. 91, No. 6, 2015
(400 MHz, CDCl3): δ 1.35 (t, J = 7.2 Hz, 3H), 2.43 (s, 3H), 4.36 (q, J = 7.2 Hz, 2H), 6.97 (s, 1H), 7.21 (t,
J = 7.7 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1,
15.5, 62.9, 114.4, 123.2, 124.3, 125.4, 128.4, 135.8, 152.0, 154.4, 160.6, 178.8˗HRMS (ESI-TOF) m/z
Calcd for C13H12O4 [M+Na]+ 255.0633, found 240.0627.
Ethyl 8-bromo-4-oxo-4H-chromene-2-carboxylate (3i): Yield 69%; White solid: mp 124–125 qC (lit,12
1
mp 125–126 °C); IR (KBr) (νmax, cm-1) 3085, 1740, 1653, 1450, 1250, 1118, 1064, 861; H NMR (400
MHz, CDCl3): δ 1.38 (t, J = 7.1 Hz, 3H), 4.41 (q, J = 8.0 Hz, 2H), 7.05 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H),
7.88 (m, 1H), 8.05 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 13.0, 62.1, 111.4, 113.6, 124.0, 124.6, 125.4,
137.1, 151.5, 151.6, 159.0, 176.8; HRMS (ESI-TOF) m/z Calcd for C12H9BrO4 [M+Na]+ 318.9582, found
318.9576.
Ethyl 7-methyl-4-oxo-4H-chromene-2-carboxylate (3j): Yield 76%; White solid: mp 57–58 qC (lit,11
mp 57–58 °C); IR (KBr) (νmax, cm-1) 2968, 1754, 1690, 1625, 1440, 1361, 1318, 1222, 1167, 1055, 1013,
927, 854, 792, 736; 1H NMR (400 MHz, CDCl3): δ 1.37 (m, 3H), 2.43 (s, 3H), 4.39 (q, J = 7.1 Hz, 2H),
13
7.02 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.35 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H); C NMR (100 MHz,
CDCl3): δ 14.1, 21.9, 62.9, 114.7, 118.4, 122.1, 125.4, 127.4, 146.3, 151.9, 156.1, 160.6, 178.3; HRMS
(ESI-TOF) m/z Calcd for C13H12O4 [M+Na]+ 255.0633, found 240.0627.
Ethyl 7-formyl-4-oxo-4H-chromene-2-carboxylate (3k): Yield 55%; White solid: mp 103–104 qC; IR
(KBr) (νmax, cm-1) 3075, 1739, 1651, 1450, 1250, 1119, 1064, 857; 1H NMR (400 MHz, CDCl3): δ 1.44 (t,
J = 7.1 Hz, 3H), 4.47 (q, J = 7.1 Hz, 2H), 7.82 (s, 1H), 7.83 (d, J = 5.3 Hz, 1H), 7.13 (s, 1H), 7.86 (s, 1H),
11.08 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 13.1, 62.2, 114.6, 122.7, 122.8, 124.5, 133.3, 136.6, 151.0,
155.3, 159.0, 178.5, 191.5; HRMS (ESI-TOF) m/z Calcd for C13H10O5 [M+Na]+ 269.0426, found
269.0420.
ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China (No. 21202142), and the
Key Project of Chinese Ministry of Education (No. 212161), Start-up funds of Yunnan Minzu University.
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