One-pot microwave-assisted synthesis of benzopyrano[2,3-c]pyrazol-3-one derivatives

Article abstract of DOI:10.1002/jhet.1801

A convenient one-pot microwave-assisted synthesis of Benzopyrano[2,3-c] pyrazol-3-one derivatives was developed, where Knoevenagel condensation and hydrazinolysis reactions were continuously performed under microwave irradiation without separation and purification of the intermediates until the last cyclocondensation reaction except the substrates addition. The one-pot procedure exhibited shorter reaction times and higher yields (25-55%) of the objects than the conventional heating method.

Full text of DOI:10.1002/jhet.1801

1210
One-Pot Microwave-Assisted Synthesis of Benzopyrano[2,3-c]pyrazol-
Vol 51
3-one Derivatives
a
a
a
a,b
Pei Chen, Yan Li, Xinbing Chen, Zhongwei An, Yiwei Xu,a and Xiaojun Hea
*
aKey Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education, School of Materials
Science and Engineering, Shaanxi Normal University, Xi’an 710062, People’s Republic of China
bXian Modern Chemistry Research Institute, Xi’an 710065, People’s Republic of China
*
E-mail: chenxinbing@snnu.edu.cn
Received December 16, 2011
DOI 10.1002/jhet.1801
Published online 16 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
A convenient one-pot microwave-assisted synthesis of Benzopyrano[2,3-c]pyrazol-3-one derivatives was
developed, where Knoevenagel condensation and hydrazinolysis reactions were continuously performed under
microwave irradiation without separation and purification of the intermediates until the last cyclocondensation
reaction except the substrates addition. The one-pot procedure exhibited shorter reaction times and higher yields
(25–55%) of the objects than the conventional heating method.
J. Heterocyclic Chem., 51, 1210 (2014).
general strategy of producing Benzopyrano-based fused
heterocycles, Knoevenagel condensation reaction was the
main step to realize the construction of the Benzopyrano
framework. Khodairy reported the preparation of BPP from
the hydrazinolysis reaction of 3-carbethoxy-benzopyran-
2-thione with hydrazine hydrate.[2] It is known that
Knoevenagel condensation and hydrazinolysis reactions can
be carried out under microwave irradiation,[4] respectively,
where the reaction time is shorter than the conventional heat-
ing method. It should be a convenient and fast procedure for
the preparation of BPP via microwave-assisted Knoevenagel
condensation and hydrazinolysis reactions under microwave
irradiation. However, to date, there has been no report.
In this context, we report a rapid one-pot microwave
synthesis of various functional BPP derivatives, where the
reactions will be continuously performed without separation
and purification of the intermediates until the last cyclocon-
densation reaction except the substrates addition (Scheme 1).
INTRODUCTION
The fused aromatic heterocycles have especially
attracted much attention because they are important
moieties in many compounds that exhibit useful applica-
tions in medicine, agriculture, and industry. Among the
polyheterocyclics, coumarin derivatives is one of the
widespread investigated molecules due to their biological
activity as nervous system depressants and antibacterial
agent, and promising applications as mesogenic core for
liquid crystal.[1] As one of coumarin derivatives,
Benzopyrano[2,3-c]pyrazol-3-one (BPP) framework has
potential for functional materials application, because advan-
tages of this structure are to allow further selective functiona-
lizations, which could be envisioned using regioselective
reactions on pyrazole moiety or/and on phenyl ring. [2,3]
To our knowledge, only a few papers described the
preparation of substituted BPP.[2] According to the
© 2013 HeteroCorporation

July 2014
One-Pot Microwave-Assisted Synthesis
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Scheme 1. Synthetic route of BPP derivatives under microwave irradiation.
RESULTS AND DISCUSSION
and conventional heating conditions. The activated 4Å
molecular sieves were found to be helpful in improving
the conversion because of the efficient adsorption of water
produced in Knoevenagel condensation, and DMF was the
best solvent for both Knoevenagel condensation and
hydrazinolysis reactions (Tables 2 and 3). In a typical
procedure, the successive reactions in a suitable solvent were
irradiated in a sealed Teflon vessel at 600 W maximum
power or heated in an oil bath (Table 3). First, we tried the
one-pot procedure in ethanol under conventional heating
without separation process and purification of the intermedi-
ate. However, the reaction was found to be sluggish, and
after 8 h of heating at 60ꢀC, only 14% of BPP5 was isolated
next to a considerable amount of unreacted starting material
(Table 3, entry 1). Changing the solvent to DMF afforded
BPP5 in 16% yield within 8 h (Table 3, entry 2), and increas-
ing the temperature to 100ꢀC gave BPP5 in 30% yield
(Table 3, entry 5), which was much lower than that of multi-
step synthesis under conventional heating (46%, Table 2).
After the conventional heating attempts, we decided to carry
out the one-pot procedure under microwave irradiation.
Unfortunately, irradiating the successive reactions for 1.2 h
at 60ꢀC provided the product in a disappointingly low yield
of 22% (Table 3, entry 6). However, the reaction was much
faster at 100ꢀC as monitored by TLC (Table 3, entries 9
A variety of BPP derivatives were smoothly prepared
via the microwave-assisted one-pot preparation method
(Scheme 1). Comparisons between microwave irradiation
method and conventional heating method (Scheme 2) are
listed in Table 1. The present microwave-assisted one-pot
procedure exhibited 25–55% yields, which was slightly
higher than the multistep conventional heating method
(17–46%). In addition, the microwave synthetic method
avoided a lengthy separation process and purification of
the intermediate and only needed much shorter overall
reaction time (50 min) than the conventional heating
method (490 min). The results indicated that the one-pot
microwave synthesis is convenient for BPP derivatives.
However, in our experiments, it failed to construct BPP
skeleton when 2-hydroxybenzaldehyde with electron-
withdrawing group (such as nitro group) was chosen as
starting material, whether via microwave irradiation method
or conventional heating method, although a number of
reports had been published regarding Knoevenagel conden-
sation based on this kind of substrate.
To optimize the procedure, we studied Knoevenagel
condensation and hydrazinolysis reactions in one-pot
under a variety of conditions and compared microwave
Scheme 2. Synthesis of BPP via multisteps conventional heating method.
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Vol 51
Table 1
The results of the microwave-assisted one-pot method and the conventional heating method for the preparation of BPP derivatives.
Reaction time (min)/yield (%)a
Melting point
(ꢀC)
Purification method
Code
MW methodb
50/52
CH method 1c
490/43
CH method 2d
490/28
(eluent or solvent)
BPP1
219–220 (lit. e
219–220)
204–206
269–270
>300
CC (DCM)
BPP2
BPP3
BPP4
BPP5
BPP6
50/50
50/40
50/25
50/55
50/41
490/42
490/32
490/17
490/46
490/33
490/31
490/22
490/10
490/30
490/23
CC (DCM/PE = 3/2)
Rec (EA)
CC (EA/PE = 1/3)
CC (DCM)
204–205
>300
Rec (EA)
BPP, Benzopyrano[2,3-c]pyrazol-3-one; CC, column chromatography; Rec, recrystalization; DCM, dichloromethane; PE, petroleum ether; EA, ethyl acetate.
aOverall reaction time and overall isolated yield (average of three runs) with GC or HPLC purity of the objects higher than 98%.
bOne-pot procedure under microwave irradiation with an output of 600 W (Scheme 1).
cMutistep procedure under conventional heating (Scheme 2).
dOne-pot procedure under conventional heating without separation process and purification of the intermediate.
eReference [2].
EXPERIMENTAL
and 10). Finally, one-pot microwave procedure in DMF at
100ꢀC was found to be highly effective for synthesis of
BPP derivatives.
IR spectra were recorded on a Nicolet Avatar 360E spectrometer
(Thermo Electron Corporation, Madison, Wis., USA). H-NMR
1
In conclusion, the present one-pot procedure provided
a convenient synthesis of coumarin-based fused polycy-
clic compounds, BPP derivatives. Under microwave irra-
diation, Knoevenagel condensation and hydrazinolysis
reactions could be continuously performed without
separation and purification of the intermediates except
the substrates addition. Although the overall yields of
the three reactions were below 55% for this procedure,
it is expected that the yields of the procedure can be
further improved by rational adjustment of the reaction
conditions.
spectra, with TMS as internal standard, were recorded on a Bruker
AV 300 (300 MHz) instrument (Bruker Corporation, Karlsruhe,
Germany). Elemental analysis was performed for C, H, and N in a
Elementar Vario EL III instrument (Elementar Analysensysteme
GmbH, Hanau, Germany). The purities of the target compounds
were measured by Shimatsu GC-2014C and LC-20AT (Shimadzu
Corporation, Kyoto, Japan). Melting points were determined by
using X-5 melting point apparatus with microscope from Beijing
Taike and were uncorrected. Microwave-assisted reactions were
carried out in a MDS-6 microwave oven (Sineo Microwave
Chemical Technology Co. Ltd, Shanghai, China) with an
output of 600 W. 2,4-Dihydroxybenzaldehyde, 2-hydroxy-4-
Table 2
Conversion of the microwave synthesis in different solvents for Knoevenagel condensation and hydrazinolysis reactions.
Time (min)/temperature (ꢀC)
a
Substrate
R1
Substituent
R1 = H
R2 = H
R3 = H
R4 = H
(reaction type)
Solvent
Conversion (%)
Absolute ethanol
Absolute ethanol (4 Å MS) b
DMF
DMF (4 Å MS)
No solvent
Absolute ethanol
Absolute ethanol (4 Å MS)
DMF
DMF (4 Å MS)
No solvent
80
91
73
95
75
82
85
76
92
69
93
96
95
97
30/100 (Knoevenagel condensation)
R2
OH
R3
CHO
R4
R1 = H
R2 = OCH3
R3 = H
30/100
(Knoevenagel Hcondensation)
R4 =
R1 = R2 = H
R3 = R4 = H
R1 = H; R2 = OCH3
R3 = R4 = H
10/80
(Hydrazinolysis)
10/80
Absolute ethanol
DMF
Absolute ethanol
DMF
R3 R4
c
R2
COOC2H5
(Hydrazinolysis)
R1
O
O
MS, molecular sieves.
aBased on GC or HPLC analysis.
b4 Å MS was added in solvent.
cThe purified substrate was prepared and used.
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Table 3
Optimization of the conditions for one-pot synthesis of BPP5.
Entry
Conditions
Solvent
EtOH
Temperature (ꢀC)
Time (h)a
Yield (%)b
1
2
3
4
5
6
7
8
9
Δ
60
60
80
80
100
60
8
8
8
12
8
1.2
1.2
1.2
40 min
40 min
14
16
23
24
30
22
34
45
51
55
DMF
DMF(4 Å MS)
DMF(4 Å MS)
DMF(4 Å MS)
EtOH
DMF(4 Å MS)
DMF(4 Å MS)
DMF(4 Å MS)
DMF(4 Å MS)
MW
60
80
100
c
10
100/80
Δ, one-pot conventional heating; MW, microwave experiments with 600 W power.
aOverall time for Knoevenagel condensation and hydrazinolysis, where 2 h and 10 min under conventional heating and microwave irradiation conditions
were needed for hydrazinolysis, respectively.
bOverall isolated yield.
c100ꢀC and 80ꢀC for Knoevenagel condensation and hydrazinolysis, respectively.
methoxybenzaldehyde, 2-hydroxybenzaldehyde, 2-hydroxy-3-
methoxybenzaldehyde, 2-hydroxy-3,5-dichlorobenzaldehyde,
2-hydroxy-5-chlorobenzaldehyde, piperidine, and hydrazine
hydrate were purchased from Aladdin Reagent Co. (Shanghai,
China) and were used as received. Acetic acid, absolute ethanol,
diethylmalonate, N,N-DMF, tetrabutyl ammonium bromide,
hydrochloric acid, 4Å molecular sieves, and CH2Cl2 were
purchased from Sinopharm Chemical Reagent Co. (Shanghai,
China), and DMF was dehydrated by predried 4Å molecular
sieves that were activated at 350ꢀC for 4 h prior to use.
BPP derivatives (BPP1 to BPP6) were prepared through one-
pot synthesis under microwave irradiation (Scheme 1), as well
as via multistep or one-pot synthesis with traditional heating
method (Scheme 2). As an example, the preparation procedure
of BPP5 is described as follows.
One-pot synthesis under microwave irradiation. Reaction
mixture of 2-hydroxy-4-methoxybenzaldehyde (20mmol), diethyl
malonate (24 mmol), piperidine (0.25 mL), two drops of acetic
acid, predried 4-Å molecular sieves (5g), and DMF (10 mL) was
added into a sealed Teflon vessel (Yuhua Co., Henan, China) and
then irradiated in a microwave oven to perform the Knoevenagel
condensation at 100ꢀC with an output of 600 W for 30min. Then,
Taking out the Teflon vessel from microwave oven, hydrazine
hydrate (85%) (2.5mL) was added. The reaction mixture was
irradiated in a microwave oven to perform hydrazinolysis reaction
at 80ꢀC with an output of 600 W for 10min. After cooling to
room temperature, taking out the Teflon vessel, the mixture was
filtrated through Celite (Xian Bomei Tiancheng United States
Glass Co., Ltd., Xi’an, China) to remove molecular sieves and
insoluble matter with washing by DMF. To the combined organic
filtrate, some amounts of 2M hydrochloric acid solution were
added to adjust pH value below 3 with appearance of yellow
precipitate. The resulting mixture was stirred about 10 min for
further cyclocondensation reaction. The precipitate was collected
by filtration and purified by column chromatography on silica gel
using CH2Cl2 as eluent. The overall yield for BPP5 was 55% of
pale yellow crystals with GC purity of 99.4%. mp 204–205ꢀC.
1H-NMR (300 MHz, CDCl3): d 11.78 (s, NH, 1H), 8.54 (s, 1H),
7.21 (s, 1H), 6.46 (m, 2H), 3.82 (s, 3H);IR (KBr, pellet, cmÀ1):
3400 (NH), 2982, 2937, 1625 (C═O and C═N), 1568, 1386,
1283, 1199, 964, 837; Elem. Anal.: Calcd C11H8N2O3: C 61.11,
H 3.73, N 12.96; found C 61.33, H 3.81, N 12.72.
BPP1 was obtained in 52% overall yield by using a similar method
to that used for BPP5. mp 219–220ꢀC. 1H-NMR (300 MHz, CDCl3):
d 11.39 (s, NH, 1H), 8.71 (s, 1H), 7.37 (m, 2H), 7.01 (m, 2H);IR
(KBr, pellet, cmÀ1): 3443 (NH), 3042, 1624 (C═O and C═N),
1572, 1278, 893, 752; Elem. Anal.: Calcd C10H6N2O2: C 64.52, H
3.25, N 15.05; found C 64.63, H 3.35, N 14.96.
BPP2 was obtained in 50% overall yield by using a similar
method to that used for BPP5. mp 204–206ꢀC. 1H-NMR
(300 MHz, CDCl3): d 11.50 (s, NH, 1H), 8.71 (s, 1H), 6.96
(m, 3H), 3.94 (s, 3H);IR (KBr, pellet, cmÀ1): 3443 (NH), 2963,
1624 (C═O and C═N), 1577, 1463, 1381, 1263, 1079, 964,
735; Elem. Anal.: Calcd C11H8N2O3: C 61.11, H 3.73, N 12.96;
found C 61.38, H 3.86, N 12.68.
BPP3 was obtained in 40% overall yield by using a similar
method to that used for BPP5. mp 204–206ꢀC. 1H-NMR
(300 MHz, CDCl3): d 11.78 (s, NH, 1H), 9.07 (s, 1H), 7.74
(m, 2H);IR (KBr, pellet, cmÀ1): 3424 (NH), 3073, 1625 (C═O
and C═N), 1563, 1450, 1209, 1176, 868, 728; Elem. Anal.: Calcd
C10H4Cl2N2O2: C 47.09, H 1.58, N 10.98; found C 46.89, H
1.65, N 10.77.
BPP4 was obtained in 25% overall yield by using a similar
method to that used for BPP5. mp >300ꢀC. 1H-NMR
(300 MHz, CDCl3): d 11.47 (s, NH, 1H), 11.27(s, 1H), 8.84
(s, 1H),7.47 (m, 1H), 6.40 (m, 2H);IR (KBr, pellet, cmÀ1): 3330
(NH), 3328, 2923, 2851, 1730, 1620 (C═O and C═N), 1215,
967; Elem. Anal.: Calcd C10H6N2O3: C 59.41, H 2.99, N 13.86;
found C 59.63, H 3.06, N 13.65.
BPP6 was obtained in 41% overall yield by using a similar
method to that used for BPP5. mp >300ꢀC. 1H-NMR (300MHz,
CDCl3): d 11.73 (s, NH, 1H), 8.90 (s, 1H), 7.53 (m, 2H), 7.15
(s, 1H);IR (KBr, pellet, cmÀ1): 3444 (NH), 2992, 1628 (C═O and
C═N), 1568, 1267, 1183, 745; Elem. Anal.: Calcd C10H5ClN2O2:
C 54.44, H 2.28, N 12.70; found C 54.29, H 2.42, N 12.54.
Multistep synthesis via conventional heating. To a 100 mL,
three-neck, round-bottom flask equipped with an overhead stirrer
and condenser, 0.50 g of 2-hydroxy-4-methoxybenzaldehyde
(3.6mmol), 0.64 g of diethyl malonate (0.61 mL, 4.0 mmol,
10mol% excess), and 20 mL of absolute ethanol were added. The
mixture was heated with stirring until dissolution occurred. Then,
0.34g of piperidine (0.4mL, 4.0 mmol) was added, and the
resulting solution was refluxed for 6 h, and on cooling, a yellow
crystalline solid formed. Crystals of ethyl 7-methoxycoumarin-3-
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P. Chen, Y. Li, X. Chen, Z. An, Y. Xu, and X. He
Vol 51
carboxylate were isolated by filtration and washed with cold
ethanol. The solid was recrystallized from ethanol (75%), filtered,
and washed with cold ethanol (75%) again. The crystals were
dried in a vacuum oven at 50ꢀC. The yield was 75% with GC
purity more than 99%.
To a 100mL, three-neck, round-bottom flask equipped with an
overhead stirrer and condenser, 2 mmol of the aforementioned ethyl
7-methoxycoumarin-3-carboxylate, 15mL of absolute ethanol, and
0.6 mL of hydrazine hydrate (85%) were added. The reaction
mixture was stirred at reflux for 2 h. Then, some amounts of 2M
hydrochloric acid solution were added into the mixture to adjust pH
value below 3. The resulting mixture was stirred for another 10 min
and transferred to a separatory funnel with 60 mL of CH2Cl2. The
organic layer was washed several times with water to neutral and
dried over anhydrous sodium sulfate. The solvent was removed
under reduced pressure, and the residue was purified by column chro-
matography on silica gel using CH2Cl2 as eluent. The yield was 68%.
Acknowledgments. The authors are grateful to the National Science
Foundation Committee of China (no. 50802058), Program for
Changjiang Scholars and Innovative Research Team in University
(IRT1070), and the Fundamental Research Funds for the Central
Universities (no. GK200902002, GK201002002) for financial
support of this work.
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Other BPP derivatives (BPP1 to BPP6) were obtained in 17–46%
overall yield by using a similar conventional heating method to that
used for BPP5.
One-pot synthesis via conventional heating. The procedure
was similar to multistep synthetic method but without separation
process and purification of the intermediate.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet