Catalytic Application of 1,4-Piperazinediethanesulfonic Acid (PIPES) for the One-pot Multicomponent Synthesis of Pyrano[4,3-b]pyrans

Full text of DOI:10.1080/00304948.2020.1761228

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Catalytic Application of 1,4-
Piperazinediethanesulfonic Acid (PIPES) for the
One-pot Multicomponent Synthesis of Pyrano[4,3-
b]pyrans
Nader Ghaffari Khaligh, Taraneh Mihankhah & Mohd Rafie Johan
To cite this article: Nader Ghaffari Khaligh, Taraneh Mihankhah & Mohd Rafie Johan
(2020): Catalytic Application of 1,4-Piperazinediethanesulfonic Acid (PIPES) for the One-pot
Multicomponent Synthesis of Pyrano[4,3-b]pyrans, Organic Preparations and Procedures
International, DOI: 10.1080/00304948.2020.1761228
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1761228
OPPI BRIEF
Catalytic Application of 1,4-Piperazinediethanesulfonic
Acid (PIPES) for the One-pot Multicomponent Synthesis
of Pyrano[4,3-b]pyrans
Nader Ghaffari Khaligha , Taraneh Mihankhahb , and Mohd Rafie Johana
aNanotechnology and Catalysis Research Center, Institute of Postgraduate Studies, University of Malaya,
b
Kuala Lumpur, Malaysia; Environmental Research Laboratory, Department of Water and Environmental
Engineering, School of Civil Engineering, Iran University of Science and Technology, Tehran, Iran
ARTICLE HISTORY Received 6 May 2019; Accepted 3 December 2019
Pyrans have been extensively explored in both academic organizations and pharmaceut-
ical industries owing to their biological characteristics, including anticancer activity.1,2
Among the pyrans, pyrano[4,3-b]pyran derivatives have shown such pharmacological
properties as antiviral,3 antimicrobial,4 antifungal,5,6 and antioxidant7 activities. Due to
their wide range of applications, several methods have been developed for the synthesis
of pyrano[4,3-b]pyrans as valuable lead compounds; and all of these methods have their
merits and limitations.3,8–16 Some of the drawbacks include: the use of catalysts contain-
ing metals, which are not desirable because of their toxicity or waste generation; high
costs and time-consuming procedures for the preparation of catalysts; long reaction
times; high temperatures or low yields.
Good and coworkers had earlier suggested 1,4-piperazinediethanesulfonic acid
(PIPES) as a buffer for biological applications.17 PIPES is not prone to complex forma-
tion with metal ions and has a pKa near to physiological pH, so PIPES has been used as
a buffering agent in biological, biochemical and environmental studies.18 PIPES is a sub-
stance which is commercially available, non-toxic, thermally stable, inexpensive, easy to
handle and easy to store. In past efforts, we have used the planetary ball mill for the
synthesis of pyrano[4,3-b]pyrans,15–16 Schiff bases,19,20 and arylidene analogues of
Meldrum’s acid.21 We would now like to report on the catalytic efficiency of PIPES for
the synthesis of pyrano[4,3-b]pyrans under mild conditions. To the best of our know-
ledge, PIPES has not been exploited previously in organic synthesis as an organocatalyst.
This is part of a wider exploration by our laboratory to develop more reactions using
PIPES as a desirable organocatalyst in organic transformations.
In order to establish the optimum conditions, 4-chlorobenzaldehyde (1a), malononi-
trile, and 4-hydroxy-6-methyl-2-pyrone were chosen as the model reactants. The model
reactants were ground through the ball milling process at room temperature under cata-
lyst-free and solvent-free conditions. With no catalyst, even after 4 hours, TLC analysis
showed that the aldehyde remained, and there was no new spot for the putative product
2-amino-4-(4-chlorophenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile
CONTACT Nader Ghaffari Khaligh,
ngkhaligh@gmail.com
Nanotechnology and Catalysis Research Center, 3rd
Floor, Block A, Institute of Postgraduate Studies, University of Malaya, 50603 Kuala Lumpur, Malaysia
ß 2020 Taylor & Francis Group, LLC

2
N. G. KHALIGH ET AL.
Table 1. Optimization of the synthesis of pyrano[4,3-b]pyrans.a
Loading TMDPS
Number of
milling ball
Speed
(rpm)
Milling ball
diameter (mm)
Milling time
(min)
Entry
(mol%)
Yield (%)b
c
1
2
3
4
5
6
7
8
0
5
5
5
5
5
5
5
5
5
2
300
300
300
300
300
400
500
600
600
600
7
7
7
7
7
7
7
7
5
240
240
60
30
30
30
30
30
30
-
10
10
10
5
10
10
10
10
10
78
77
73
61
77
88
94
42
81
9
10
10
30
aReaction conditions: 4-chlorobenzaldehyde (1a) (5.0 mmol), 4-hydroxy-6-methyl-2-pyrone (5.0 mmol), malononitrile
(5.0 mmol), room temperature.
bIsolated yield.
cMonitored by TLC, see Experimental section.
(2a) (Table 1, Entry 1). By manipulating the parameters shown in Table 1, we deduced
that Entry 8 represented the optimized reaction conditions.
Then we studied the scope and generality of the present protocol for the synthesis of
pyrano[4,3-b]pyran derivatives through our ball milling process under optimized reac-
tion conditions (Scheme 1).
Substituted pyrano[4,3-b]pyrans (2a-o) were obtained in good to excellent yields
(Table 2). The electron-withdrawing substituents on the benzaldehyde ring afforded
higher yields than electron-donating substituents at the same positions, probably due to
the enhanced electrophilicity of the aldehyde (Table 2, Entries 1,4,9,13 versus 5,7,10,12).
Even the benzaldehydes bearing acid-sensitive methoxy substituents gave the respective
products in good yield without decomposition (Table 2, Entries 5,7,12).
A comparison of the current method with a few previously reported methods is
shown in Table 3.
A scale up experiment was carried out through the condensation reaction of 4-chlor-
obenzaldehyde (50.0 mmol), malononitrile (50.0 mmol), and 4-hydroxy-6-methyl-2-
pyrone (50.0 mmol) under optimized reaction conditions. This afforded 2a in 83% yield
within 30 min.
We found that the recovered PIPES (see Experimental section) could be dried and
re-used in subsequent runs. During three subsequent runs, representative products 2a,
2b, and 2c were obtained in the presence of recycled PIPES in a range of yields of 94-
90%, 85-83%, and 86-82%, respectively.
In conclusion, the catalytic efficiency of PIPES was demonstrated for the synthesis of
pyrano[4,3-b]pyrans using the ball milling process for the first time. The current proto-
col has such advantages as simplicity, solvent-free conditions at room temperature, high
yields, short reaction times, and recyclability. We hope that these promising results will
foster further research for the catalytic applications of PIPES in organic synthesis.
Experimental section
All chemicals were analytical grade and purchased from Sigma Aldrich, Merck, and
Fluka Chemical Companies and used without further purification. All the products are
known compounds and were characterized by their melting points. The purity

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
OH
O
O
R
CN
R
PIPES (10 mol%)
O
+
+
O
NC
H
O
Ball mill (600 rpm), r.t., 30 min
CN
H3C
H3C
O
NH2
1(a-o)
2(a-o)
Scheme 1. Over-all reaction.
Table 2. The catalytic application of PIPES in the synthesis of pyrano[4,3-b]pyran derivatives.a
Melting point (ꢀC)
Entry
Aldehydes 1(a-o)
Pyrano[4,3-b]pyran 2(a-o)
Yield (%)b
Found
Reportedref.
1
2
3
4
5
6
7
8
4-Cl-C6H4-
C6H5-
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
94
85
86
94
86
84
82
88
92
84
87
80
92
89
90
221-223
247-248
225-226
218-220
205-207
260-261
228-230
219-221
220-222
222-223
212-214
238-239
215-216
241-243
243-244
228-23022
23622
4-CH3-C6H4-
4-NO2-C6H4-
4-(CH3O)-C6H4-
2-Cl-C6H4-
3,4,5-(CH3O)3-C6H2-
4-Br-C6H4-
218-22022
220-22222
210-21212
258-26014
227-22914
217-21912
223-2253
220-22214
212-21414
242-24414
217-21914
240-24114
245-24714
9
4-F-C6H4-
10
11
12
13
14
15
4-(CH3)2CH-C6H4-
3,5-Cl2-C6H4-
2-(CH3O)-C6H4-
4-CF3-C6H4-
3,5-F2-C6H3-
3,5-(CF3)2-C6H4-
aReaction conditions: aldehyde 1(a-o) (5.0 mmol), malononitrile (5.0 mmol), 4-hydroxy-6-methyl-2-pyrone (5.0 mmol),
PIPES (0.5 mmol), revolution rate (600 rpm), five milling balls with diameter 7 mm, milling time (30 min), room
temperature.
bIsolated yield.
Table 3. Comparison of the present protocol with other reported strategies for the synthesis of 2-
amino-4-phenyl-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carbonitriles.
Catalyst
loading (mol%)
Entry
Catalyst
[BMIM][BF4]
[NH4][OAc]
Conditions
Time (min) Yield (%)
Ref.
3
1
2
3
664
10
4.2
80 ꢀC
180
10
85
94
88
7
Solvent-free, grinding, r.t.
10
4-(Succinimido)-1-butane
Neat, 60 ꢀC
60
sulfonic acid
[BBMIm][HSO4]
TMDPS
BBSI-HSO4
TMDP
12
14
15
16
22
4
5
6
7
8
120.5
5
5
20
10
Solvent-free, 60 ꢀC
Milling, r.t.
Milling, r.r.
35
30
30
90
35
94
84
89
85
94
Milling, r.t.
Succinimide-N-sulfonic acid
Solvent-free, 60 ꢀC
(Solar energy)
24
25
26
27
28
29
30
9
KF-Al2O3
Piperidine
Thiourea dioxide
Urea
50 mg per mmol EtOH, reflux
1-2 drops per mmol MeOH, reflux
480a
60
40
420
60
600
630
30
76a
79
92
81
77
89
65
85
10
11
12
13
14
15
16
10
10
1.0
120 U
–
H2O, 80 ꢀC
EtOH:H2O (1:1 v/v), r.t.
Solvent-free, 100 ꢀC
i-Propanol, 60 ꢀC
H2O, 80 ꢀC
TMGT
Porcine pancreas lipase
–
PIPES
10
Milling, r.t.
This work
a2-Amino-4-(4-chlorophenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile.

4
N. G. KHALIGH ET AL.
determination of the substrates and reaction monitoring were accomplished by TLC
using silica gel SIL G/UV 254 plates and eluent (ethyl acetate:n-hexane 2:8). Melting
€
points were recorded on a Buchi B-545 apparatus in open capillary tubes and are uncor-
1
rected. In all the cases the H NMR spectra were recorded with Bruker 400 MHz instru-
ments. All chemical shifts are quoted in parts per million (ppm) relative to TMS using
deuterated solvent. Ball-milling was performed in a Retsch PM100 planetary ball mill
using the stainless steel chamber and two or five stainless steel balls (diameter: 5, 7 or
10 mm) with 300-600 rpm.
Typical catalytic application of PIPES for the synthesis of pyrano[4,3-b]pyran
derivatives
The aldehyde (5.0 mmol), malononitrile (5.0 mmol), 4-hydroxy-6-methyl-2-pyrone
(5.0 mmol) and PIPES (10 mol%) were milled vigorously using the planetary ball mill at
room temperature for 30 min. The reaction mixture was washed with dilute hydro-
chloric acid (5%) and the product was separated by simple filtration. The dry solid
crude product was purified by recrystallization from ethanol and did not require further
1
purification. All the compounds had melting points and H NMR spectra identical to
the literature values.3,12,14,22 The PIPES could be regenerated from the aqueous acid
wash through neutralizing by NaHCO3 and washing with methanol and evaporating of
solvent. The regenerated PIPES was applied for another run. Listed below are represen-
1
tative H NMR spectra of less common products.
2-Amino-4-(4-fluorophenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carboni-
trile (2i)
1H NMR (400 MHz, DMSO-d6) d ¼ 7.25-7.12 (m, 6H), 6.28 (s, 1H), 4.31 (s, 1H), 2.22
(s, 3H) ppm.
2-Amino-4-(4-isopropylphenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carboni-
trile (2j)
1H NMR (400 MHz, DMSO-d6) d ¼ 7.20-7.18 (m, 3H), 7.10 (d, 2H, J ¼ 8.8 Hz), 6.28 (s,
1H), 4.25 (s, 1H), 2.85 (s, 1H), 2.21 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H) ppm.
2-Amino-4-(3,5-dichlorophenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carboni-
trile (2k)
1H NMR (400 MHz, DMSO-d6) d ¼ 7.46 (t, J ¼ 1.8 Hz, 1H), 7.20-7.18 (m, 2H), 6.98 (s,
2H), 6.30 (s, 1H), 4.46 (s, 1H), 2.28 (s, 3H) ppm.
2-Amino-4-(2-methoxyphenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carboni-
trile (2l)
1H NMR (400 MHz, DMSO-d6) d ¼ 7.20-7.18 (m, 1H), 7.05-6.98 (m, 2H), 6.92-6.87 (m,
3H), 4.70 (s, 1H), 3.68 (s, 3H), 2.30 (s, 3H) ppm.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
2-Amino-4-(4-trifluoromethyl-phenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-
carbonitrile (2m)
1H NMR (400 MHz, DMSO-d6) d ¼ 7.70 (d, J ¼ 8.4 Hz, 2H), 7.51 (s, 2H), 7.46 (d,
J ¼ 8.4 Hz, 2H), 4.58 (s, 1H), 2.91 (s, 3H) ppm.
2-Amino-4-(3,5-difluorophenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carboni-
trile (2n)
1H NMR (400 MHz, DMSO-d6) d ¼ 7.33 (s, 2H), 7.16-7.08 (m, 1H), 7.01-6.94 (m, 2H),
6.30 (s, 1H), 4.43 (s, 1H), 2.25 (s, 3H) ppm.
2-Amino-4-(3,5-bis(trifluoromethyl)phenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-
3-carbonitrile (2o)
1H NMR (400 MHz, DMSO-d6) d ¼ 8.02 (s, 1H), 7.96 (s, 2H), 7.41 (s, 2H), 6.32 (s,
1H), 4.72 (s, 1H), 2.25 (s, 3H) ppm.
Acknowledgments
The authors are grateful to staff members in the Analytical and Testing Center, Malaya
University, for partial support.
ORCID
Nader Ghaffari Khaligh
Taraneh Mihankhah
Mohd Rafie Johan
http://orcid.org/0000-0001-9585-9253
http://orcid.org/0000-0003-3104-5220
http://orcid.org/0000-0003-1133-9977
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