Caffeine-H3PO4: a novel acidic catalyst for various one-pot multicomponent reactions

Article abstract of DOI:10.1007/s11164-017-3002-8

Caffeine-H₃PO₄ along with caffeine-HClO₄ and caffeine-HNO₃ have been prepared and applied for one-pot preparation of bis(indolyl) methanes, 4,4′-(arylmethylene) bis(1H-pyrazol-5-ols), 3,3′-(arylmethylene) bis(4-hydroxycoumarins), 2,4,5-trisubstituted imidazoles, 1‐amidoalkyl‐2‐naphthols, and polyhydroquinolines. The catalysts were characterized using Fourier-transform infrared (FTIR) spectroscopy, ¹H and ¹³C nuclear magnetic resonance (NMR), powder X-ray diffraction (PXRD) analysis, thermogravimetric analysis (TGA), and liquid chromatography (LC)–mass spectroscopy (MS) techniques. The results indicated high product yield, short reaction time, facile separation of catalyst, and easy work-up procedure, suggesting that caffeine-H₃PO₄ can be considered to be an efficient acidic catalyst for organic transformations.

Full text of DOI:10.1007/s11164-017-3002-8

Res Chem Intermed
DOI 10.1007/s11164-017-3002-8
Caffeine-H3PO4: a novel acidic catalyst for various
one-pot multicomponent reactions
Seyyed Jafar Saghanezhad1
Mohammad Hosein Sayahi2
•
•
Iman Imanifar2 Mostafa Mombeni2 Sajedeh Deris Hamood2
•
•
Received: 3 May 2017 / Accepted: 6 June 2017
Ó Springer Science+Business Media B.V. 2017
Abstract Caffeine-H3PO4 along with caffeine-HClO4 and caffeine-HNO3 have
been prepared and applied for one-pot preparation of bis(indolyl) methanes, 4,40-
(arylmethylene) bis(1H-pyrazol-5-ols), 3,30-(arylmethylene) bis(4-hydroxy-
coumarins), 2,4,5-trisubstituted imidazoles, 1-amidoalkyl-2-naphthols, and poly-
hydroquinolines. The catalysts were characterized using Fourier-transform infrared
(FTIR) spectroscopy, 1H and 13C nuclear magnetic resonance (NMR), powder X-ray
diffraction (PXRD) analysis, thermogravimetric analysis (TGA), and liquid chro-
matography (LC)–mass spectroscopy (MS) techniques. The results indicated high
product yield, short reaction time, facile separation of catalyst, and easy work-up
procedure, suggesting that caffeine-H3PO4 can be considered to be an efficient
acidic catalyst for organic transformations.
Keywords Caffeine-H3PO4 Á One-pot reaction Á Solvent-free Á Bis(indolyl)
methanes Á 1-Amidoalkyl-2-naphthols Á Multicomponent reaction
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-3002-8)
contains supplementary material, which is available to authorized users.
&
&
Seyyed Jafar Saghanezhad
saghanezhad@acecr.ac.ir
Mohammad Hosein Sayahi
sayahymh@pnu.ac.ir
1
2
ACECR-Production Technology Research Institute, Ahvaz, Iran
Department of Chemistry, Payame Noor University (PNU), P.O. Box 19395-3697, Tehran, Iran
123

S. J. Saghanezhad et al.
Introduction
The design of novel catalysts for particular tasks has attracted attention due to
industrial needs for higher product yield and/or purity in shorter reaction time [1, 2].
Meanwhile, research on preparation of novel acidic catalysts such as ionic liquids
[3], zeolites [4], metal–organic frameworks (MOFs) [5], and organocatalysts [6] has
drawn attention recently.
Multicomponent reactions (MCRs) have been a focus of interest for organic and
medicinal chemists recently, due to the simplicity and diversity they offer [7, 8].
Apart from their applications in synthesis, MCRs have also been applied as criteria
for benchmarking novel catalysts, including acidic [9], basic [10], magnetic
nanoparticle-supported [11], SBA-15-supported [12], and MOF-supported materials
[13], as well as ionic liquids [14].
Solvent-free organic reactions have been proposed as a solution to environmental
concerns regarding use of organic solvents [15]. Solvent-free multicomponent
synthesis enables organic and medicinal chemists to prepare biologically active
scaffolds that are traditionally synthesized using a sequence of separate reaction
steps. The synergism of performing multicomponent reactions under solvent-free
conditions would be considered beneficial due to the simple monitoring of the
reaction, ability to perform the reaction at any temperature due to the absence of
solvent, simple reaction setup, and easy workup [16].
In continuation of our previous work on applications of novel catalysts in organic
synthesis [17, 18], we decided to investigate one-pot preparation of bis(indolyl)
methanes, 4,40-(arylmethylene) bis(1H-pyrazol-5-ols), 3,30-(arylmethylene) bis(4-
hydroxycoumarins), 2,4,5-trisubstituted imidazoles, 1-amidoalkyl-2-naphthols, and
polyhydroquinolines in presence of catalytic amount of caffeine-H3PO4 under
solvent-free conditions (Scheme 1).
Results and discussion
In the first step, caffeine-H3PO4, caffeine-HClO4, and caffeine-HNO3 were prepared
by dropwise addition of concentrated phosphoric acid, perchloric acid, and nitric
acid, respectively, to solution of caffeine in CHCl3. The mixture was stirred
overnight, and the precipitate was filtered and washed with acetone (Scheme 2). The
catalysts were characterized by FTIR spectroscopy. The characteristic peaks of
caffeine due to amide functional groups at 1654 and 1697 cm-1 were apparent in
the spectra, with a slight shift to higher wavenumber (Figs. 1, 2, 3).
The thermal stability of the catalysts was evaluated by thermogravimetric
analysis (TGA). Degradation of caffeine-H3PO4, caffeine-HClO4, and caffeine-
HNO3 was observed to start at 268, 306, and 250 °C.
To confirm that the caffeine molecule remained intact, 13C NMR of caffeine-
H3PO4 was carried out, revealing the characteristic peaks in the spectrum (Fig. S1).
In the LC–MS spectrum, the caffeine-H? peak was seen at m/z of 194.9 (100 %)
and 195.9 (11.4 %).
123

Caffeine-H3PO4: a novel acidic catalyst for various one-pot…
Scheme 1 One-pot preparation of bis(indolyl) methanes, 4,40-(arylmethylene) bis(1H-pyrazol-5-ols), 3,30-
(arylmethylene) bis(4-hydroxycoumarins), 2,4,5-trisubstituted imidazoles, 1-amidoalkyl-2-naphthols, and
polyhydroquinolines
Finally the powder X-ray diffraction (XRD) patterns of caffeine and caffeine-
H3PO4 were recorded (Fig. 4).
After successful characterization of caffeine-H3PO4, caffeine-HClO4, and
caffeine-HNO3, it was decided to utilize these catalysts for synthesis in various
one-pot organic reactions.
First, preparation of polyhydroquinoline via reaction of benzaldehyde (1 mmol),
dimedone (1 mmol), ethyl acetoacetate (1 mmol), and NH4OAc (1.5 mmol) in
presence of caffeine-H3PO4, caffeine-HClO4, and caffeine-HNO3 was utilized to
benchmark the catalysts. The catalytic activity of caffeine-H3PO4 was superior
compared with the other catalysts. It appears that caffeine-HClO4 and caffeine-
HNO3, which have a nonacidic counterion, did not show good catalytic activity. In
contrast, caffeine-H3PO4, which has an acidic counterion, showed excellent acidic
123

S. J. Saghanezhad et al.
Scheme 2 One-pot preparation of caffeine-H3PO4, caffeine-HClO4, and caffeine-HNO3
Fig. 1 FTIR spectra of a caffeine, b caffeine-H3PO4, c caffeine-HClO4, and d caffeine-HNO3
123

Caffeine-H3PO4: a novel acidic catalyst for various one-pot…
20
0
-20
a)
-40
-60
b)
CAHClO4
-80
CAH3PO4
-100
CAHNO3
c)
-120
50
150
250
350
450
550
650
Temperature (ºC)
Fig. 2 Thermogravimetry of a caffeine-HClO4, b caffeine-H3PO4, and c caffeine-HNO3
O
N
O
N
N
H
N
Fig. 3 LC–MS spectrum of caffeine-H?
activity. Thus, considering that the catalyst remained intact in the reaction medium,
it seems that caffeine-HClO4 and caffeine-HNO3 act as organocatalysts via the
caffeine-H? core. On the other hand, caffeine-H3PO4, which has an acidic
counterion, can act as both an organocatalyst and Brønsted acid. These synergistic
effects make caffeine-H3PO4 the preferred catalyst. The optimized condition was
found to be reaction temperature of 100 °C and amount of catalyst of 7.5 mol%.
Increasing the amount of catalyst or temperature neither increased the yield nor
shortened the time substantially (Table 1). Therefore, with the optimized reaction
condition in hand, we explored the efficiency of caffeine-H3PO4 for one-pot
preparation of polyhydroquinoline derivatives via Hantzsch condensation (Table 2).
After this successful preparation of polyhydroquinoline derivatives using the
catalyst, it was decided to explore its activity in one-pot preparation of
1-amidoalkyl-2-naphthols. The results are summarized in Table 3.
Using the same method as mentioned above, the catalytic activity of caffeine-
H3PO4 was also evaluated in one-pot synthesis of 2,4,5-trisubstituted imidazoles,
showing satisfactory results (Table 4).
123

S. J. Saghanezhad et al.
Fig. 4 Powder XRD patterns of a caffeine and b caffeine-H3PO4
Table 1 Optimization of conditions for preparation of polyhydroquinoline via reaction of benzaldehyde
(1 mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol), and NH4OAc (1.5 mmol)
Entry
Catalyst
Catalyst (mol%)
Temp. (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
–
–
R.T.
60
120
60
60
60
30
30
30
25
20
20
–
Caffeine-H3PO4
Caffeine-HClO4
Caffeine-HNO3
Caffeine-H3PO4
Caffeine-HClO4
Caffeine-HNO3
Caffeine-H3PO4
Caffeine-H3PO4
Caffeine-H3PO4
5
68
35
42
85
54
50
96
91
97
5
60
5
60
5
100
100
100
100
100
100
5
5
7.5
10
15
For the last set of reactions to assess the catalyst’s activity, we selected one-pot
preparation of bis(indolyl) methanes (Table 5), 4,40-(arylmethylene) bis(1H-pyra-
zol-5-ols) (Table 6), and 3,30-(arylmethylene) bis(4-hydroxycoumarins) (Table 7).
The optimum reaction temperature was found to be 80 °C. The corresponding
products were prepared in presence of caffeine-H3PO4.
123

Caffeine-H3PO4: a novel acidic catalyst for various one-pot…
Table 2 Conditions for preparation of polyhydroquinolines via reaction of aromatic aldehydes
(1 mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol), and NH4OAc (1.5 mmol) in presence of
caffeine-H3PO4 (7.5 mol%) at 100 °C under solvent-free conditions
R
R
O
O
O
O
H
O
O
Caffeine-H3PO4 (7.5 mol%)
Solvent-free, 100oC
OEt
OEt
O
N
H
NH4OAc
Product
Entry
R
Time (min)
Yield (%)
Melting point (°C)
Obtained
Reported
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
R
H
25
18
19
22
27
24
18
18
17
21
22
96
94
91
89
86
90
92
95
92
89
87
203–205
261–263
256–257
229–231
208–210
231–233
242–244
237–239
182–184
254–255
233–235
202–204 [19]
260–262 [19]
255–257 [19]
230–231 [19]
207–209 [19]
230–232 [19]
242–243 [20]
238–240 [19]
178–180 [19]
252–254 [19]
239–240 [20]
4-Me
4-OMe
4-OH
2-Cl
O
O
OEt
N
H
4-Cl
2,4-Cl2
4-NO2
3-NO2
4-Br
S
O
O
OEt
N
H
Given the increasing regard being paid to green chemistry, we decided to study
the recyclability and reusability of the catalyst in preparation of 3,30-(aryl-
methylene) bis(4-hydroxycoumarins). After completion of the reaction, water was
evaporated and the catalyst was reused for four subsequent cycles. A small decrease
in performance of the catalyst was observed in subsequent cycles (Fig. 5).
To confirm the intactness of the catalyst, the FTIR spectrum of caffeine-H3PO4
was recorded (Fig. 6). The catalyst did not change during the course of the reaction.
Thus, caffeine-H3PO4 can be considered to be an efficient recyclable green catalyst
for organic synthesis.
To identify the advantages of using caffeine-H3PO4 compared with reported
catalysts, the model reaction of aromatic aldehydes, dimedone, ethyl acetoacetate,
and NH4OAc for preparation of polyhydroquinolines was considered as a
123

S. J. Saghanezhad et al.
Table 3 Conditions for preparation of 1-amidoalkyl-2-naphthols via reaction of aromatic aldehydes
(1 mmol), b-naphthol (1 mmol), and acetamide (1.5 mmol) in presence of caffeine-H3PO4 (7.5 mol%) at
100 °C under solvent-free conditions
R
O
R
O
O
H2N
NH
Caffeine-H3PO4 (7.5 mol%)
Solvent-free, 100oC
H
OH
OH
Entry
Product
R
Time (min)
Yield (%)
Melting point (°C)
Obtained
Reported
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
R
H
40
40
40
60
40
30
30
40
30
30
25
90
87
88
88
90
92
90
95
88
89
85
244–246
217–219
181–183
204–206
215–217
223–224
229–230
226–227
237–238
244–245
222–223
242–243 [21]
220–221 [21]
184–186 [21]
203–205 [22]
210–211 [21]
224–226 [21]
225–227 [22]
226–229 [23]
243–245 [21]
245–246 [21]
222–224 [33]
O
4-CH3
4-OCH3
3-OCH3
2-Cl
NH
OH
4-Cl
2,4-Cl2
4-Br
3-NO2
4-NO2
O
NH
OH
S
representative example (Table 8). Compared with the caffeine-H3PO4-catalyzed
procedure, some of the reported procedures required prolonged reaction time
(entries 1, 2, 5) or gave lower product yield (entries 1, 2, 4, 5). These results
obviously demonstrate that caffeine-H3PO4 could be used as a novel catalyst for
organic transformations.
Experimental
General
All commercially available chemicals were purchased from Sigma and Merck
companies and used without further purification. Products were characterized based
123

Caffeine-H3PO4: a novel acidic catalyst for various one-pot…
Table 4 Conditions for preparation of 2,4,5-trisubstituted imidazoles via reaction of aromatic aldehydes
(1 mmol), benzil (1 mmol), and NH4OAc (1.5 mmol) in presence of caffeine-H3PO4 (7.5 mol%) at
120 °C under solvent-free conditions
NH4OAc
O
O
N
Caffeine-H3PO4 (7.5 mol%)
Solvent-free, 120oC
O
H
N
H
R
R
NH4OAc
Product
Entry
R
Time (min)
Yield (%)
Melting point (°C)
Obtained
Reported
1c
2c
3c
4c
5c
6c
7c
8c
9c
10c
11c
H
50
100
100
100
100
100
110
90
93
91
95
89
94
92
93
94
94
92
74
269–270
229–230
226–228
258–260
192–193
260–261
175–177
261–263
261–262
232–264
260–262
272–274 [24]
232–234 [24]
230–231 [24]
259–262 [25]
192–193 [26]
261–263 [24]
170–172 [25]
263–265 [25]
262–264 [24]
236–238 [26]
261–264 [25]
4-CH3
4-OCH3
3-OCH3
2-Cl
N
N
H
R
4-Cl
2,4-Cl2
4-Br
3-NO2
4-NO2
55
100
40
N
S
N
H
on their physical constants and comparison with authentic samples. Reaction
monitoring was carried out by TLC on silica gel POLYGRAM SIL G/UV254
plates. FTIR spectra were recorded on a BOMEM MB-Series 1998 spectropho-
tometer using KBr pellets as samples in the range of 4000 to 400 cm-1. 1H and 13
C
NMR spectra were recorded in dimethylsulfoxide (DMSO)-d6 on a Bruker
250 MHz spectrometer using tetramethylsilane (TMS) as internal standard. The
¨
thermal stability of the supported catalyst was examined using a BAHR SPA 503
thermogravimetric analyzer at heating rate of 10 °C min-1 over the temperature
range of 40–600 °C under nitrogen atmosphere. The LC-MS spectrum was recorded
using an Agilent 6410 triple-quadrupole LC/MS.
General procedure for preparation of caffeine-H3PO4, caffeine-HClO4, and
caffeine-HNO3 In a 25-mL round-bottomed flask, caffeine (1.94 g, 10 mmol)
was dissolved in 20 mL CHCl3, and the solution was stirred for 1 h. Concentrated
phosphoric/perchloric/nitric acid (10 mmol) was added to the flask. The mixture
was stirred overnight at room temperature. The precipitate was centrifuged and
123

S. J. Saghanezhad et al.
Table 5 Conditions for preparation of bis(indolyl) methanes via reaction of aromatic aldehydes
(1 mmol) and indole (2 mmol) in presence of caffeine-H3PO4 (7.5 mol%) at 80 °C under solvent-free
conditions
R
O
Caffeine-H3PO4 (7.5 mol%)
Solvent-free, 80oC
H
2
N
H
R
HN
Melting point (°C)
NH
Entry
Product
R
Time (min)
Yield (%)
Obtained
Reported
1d
2d
3d
4d
5d
6d
7d
8d
9d
10d
11d
R
H
75
70
64
70
65
60
55
65
70
65
55
95
80
82
89
93
92
94
96
93
89
85
129–131
96–98
128–130 [27]
90–92 [28]
4-Me
4-OMe
3-OMe
2-Cl
185–187
164–166
91–92
186–188 [27]
163–165 [27]
94–95 [27]
HN
NH
4-Cl
82–84
86–88 [27]
2,4-Cl2
4-NO2
3-NO2
4-Br
105–108
236–238
219–221
110–112
144–146
103–106 [28]
237–239 [27]
220–222 [27]
110–112 [27]
140–143 [28]
S
HN
NH
washed several times with CHCl3 and finally with acetone. Finally, white solid
powder (caffeine-H3PO4, caffeine-HClO4, or caffeine-HNO3) was obtained and
dried at 60 °C for 12 h.
Spectra of catalysts
Caffeine-H3PO4, white powder, M.P. 138 °C, IR (KBr, cm-1): 3171, 2960, 2857,
2360, 1717, 1666, 985, 745, 484; 1H NMR (250 MHz, DMSO-d6): d (ppm) 3.12 (s,
3H, CH3), 3.31 (s, 3H, CH3), 3.79 (s, 3H, CH3), 7.8 (s, 1H, ArH), 9.1 (s, 3H,
H3PO4); 13C NMR (62.5 MHz, DMSO-d6): d (ppm) 155.2, 151.72, 148.7, 143.4,
107.3, 33.8, 30.1, 28.2; LC-MS (ESI, positive mode) m/z (%): 194.9 (M?, 100),
195.9 (M?1?, 11).
Caffeine-HNO3, white powder, M.P. 145 °C (color change to orange), IR (KBr,
1
cm-1): 3083, 2958, 2344, 1726, 1688, 1549, 1406, 1390, 1110, 763, 623; H NMR
(250 MHz, DMSO-d6): d (ppm) 3.11 (s, 3H, CH3), 3.31 (s, 3H, CH3), 3.79 (s, 3H,
123

Caffeine-H3PO4: a novel acidic catalyst for various one-pot…
Table 6 Conditions for preparation of 4,40-(arylmethylene) bis(1H-pyrazol-5-ols) via reaction of aro-
matic aldehydes (1 mmol) and 3-methyl-5-pyrazolone (2 mmol) in presence of caffeine-H3PO4
(7.5 mol%) at 80 °C under solvent-free conditions
R
O
Caffeine-H3PO4 (7.5 mol%)
Solvent-free, 80oC
O
H
2
N
N
Ph
N
N
R
N
N
OH
HO
Ph
Ph
Entry
Product
R
Time (min)
Yield (%)
Melting point (°C)
Obtained
Reported
1e
2e
3e
4e
5e
6e
7e
8e
9e
R
H
75
65
60
55
60
70
70
60
60
91
92
80
83
85
85
91
82
90
167–169
206–208
148–150
224–226
201–202
192–194
173–175
167–169 [27]
206–208 [27]
148–150 [27]
224–226 [27]
202–204 [29]
192–194 [27]
173–175 [27]
228–230 [30]
181–183 [29]
4-Cl
3-NO2
4-NO2
4-CH3
3-CH3O
4-CH3O
2,4-Cl2
N
N
Ph
N
N
OH
HO
Ph
183–184
S
N
N
N
N
OH
HO
Ph
Ph
CH3), 7.94 (s, 1H, ArH), 11.85 (s, 1H, HNO3); 13C NMR (62.5 MHz, DMSO-d6): d
(ppm) 155.8, 152.4, 149.2, 144.0, 107.9, 34.5, 30.8, 28.8; LC-MS (ESI, positive
mode) m/z (%): 194.9 (M?, 100), 195.9 (M?1?, 11).
Caffeine-HClO4, white powder, M.P. [150 °C, IR (KBr, cm-1): 3165, 3076,
1
2960, 2890, 1723, 1680, 1646, 1540, 1448, 1100, 763, 622; H NMR (250 MHz,
DMSO-d6): d (ppm) 3.15 (s, 3H, CH3), 3.35 (s, 3H, CH3), 3.82 (s, 3H, CH3), 6.43
(s, 1H, HClO4), 7.95 (s, 1H, ArH); 13C NMR (62.5 MHz, DMSO-d6): d (ppm)
155.9, 152.4, 149.4, 144.1, 107.9, 34.6, 30.8, 28.9; LC-MS (ESI, positive mode) m/
z (%): 194.9 (M?, 100), 195.9 (M?1?, 11).
General procedure for preparation of polyhydroquinolines Mixture of dimedone
(0.14 g, 1 mmol), ethyl acetoacetate (0.13 g, 1 mmol), aromatic aldehydes
(1 mmol), ammonium acetate (0.115, 1.5 mmol), and caffeine-H3PO4 (0.022 g,
7.5 mol%) was heated at 100 °C. Reaction completion was indicated by TLC
[EtOAc/n-hexane (3:10)], after which the mixture was washed with water and the
crude product was recrystallized in hot ethanol to afford the pure product.
123

S. J. Saghanezhad et al.
Table 7 Conditions for preparation of 3,30-(arylmethylene) bis(4-hydroxycoumarins) via reaction of
aromatic aldehydes (1 mmol) and 4-hydroxycoumarin (2 mmol) in presence of caffeine-H3PO4
(7.5 mol%) at 80 °C under solvent-free conditions
R
OH
O
OH
O
OH
O
Caffeine-H3PO4 (7.5 mol%)
Solvent-free, 80oC
H
2
O
O
R
O O
Entry
Product
R
Time (min)
Yield (%)
Melting point (°C)
Obtained
Reported
R
1f
2f
3f
4f
5f
6f
7f
8f
9f
H
60
60
48
45
60
50
65
60
60
95
87
86
90
80
92
88
95
89
228–230
256–258
235–236
227–231
266–268
255–257
244–246
201–203
199–201
232–234 [27]
257–259 [27]
236–238 [27]
233–235 [27]
266–268 [31]
256–258 [27]
249–251 [27]
200–202 [32]
210–212 [32]
4-Cl
OH
O
OH
O
3-NO2
4-NO2
4-CH3
3-CH3O
4-CH3O
2,4-Cl2
O O
S
OH
OH
O
O
O
O
95
94
88
85
100
80
60
40
20
0
75
60
60
60
60
60
Yield, %
Time, min
1
2
3
4
5
Run
Time, min
Yield, %
Fig. 5 Reusability of catalyst in reaction of 4-hydroxycoumarin (2.0 mmol) and benzaldehyde
(1.0 mmol) in presence of caffeine-H3PO4 (7.5 mol%) at 80 °C under solvent-free conditions
123

Caffeine-H3PO4: a novel acidic catalyst for various one-pot…
120
100
80
60
40
1717, 33.58
20
1666, 25.28
0
4000
3600
3200
2800
2400
2000
1600
1200
800
400
Wavenumber, cm-1
Fig. 6 FTIR spectra of fresh (above) and recycled (below) caffeine-H3PO4 catalyst
2,7,7-Trimethyl-5-oxo-4-thiophen-2-yl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic
acid ethyl ester (11a) 1H NMR (DMSO-d6, 250 MHz): d 0.92 (s, 3H), 0.99 (s,
3H), 1.16 (t, J = 7 Hz, 3H, -OCH2CH3), 2.12 (dd, J = 22 Hz, 2H), 2.27 (s, 3H),
2.41 (dd, J = 15 Hz, 2H), 4.04 (q, J = 7 Hz, 2H, -OCH2CH3), 5.18 (s, 1H),
6.65–7.14 (m, 3H, thiophene), 9.23 (s, 1H); 13C NMR (DMSO-d6, 62.5 MHz): d
194.7, 167.1, 152, 150.3, 145.9, 126.7, 123.7, 123, 109.9, 103.5, 59.6, 50.6, 32.5, 31,
29.6, 27, 18.7, 14.7.
123

S. J. Saghanezhad et al.
Table 8 Comparison of caffeine-H3PO4 with reported catalysts for preparation of polyhydroquinolines
via reaction of aromatic aldehydes, dimedone, ethyl acetoacetate, and NH4OAc
Entry Catalyst/temp. (°C)
Catalyst loading
(mol%)
Time
(min)
Yield
(%)
Refs.
[34]
1
Glucosulfonic acid@Fe3O4/ethanol,
reflux
0.05 g
240
90
2
3
Sc(OTf)3/ethanol, R.T.
5
240
50
93
96
[35]
[36]
Fe3O4–DETA–Cu(II)/90 °C
solvent-free
0.22
4
5
6
PPA-SiO2/80 °C solvent-free
p-TSA, ethanol, R.T.
0.03 g
10
45
120
25
92
90
96
[37]
[38]
This
Caffeine-H3PO4/100 °C solvent-free
7.5
work
General procedure for preparation of 2,4,5-trisubstituted imidazoles Mixture of
benzil (0.21 g, 1 mmol), aromatic aldehydes (1 mmol), ammonium acetate (0.19 g,
2.5 mmol), and caffeine-H3PO4 (0.022 g, 7.5 mol%) was heated at 120 °C.
Reaction completion was indicated by TLC [EtOAc/n-hexane (3:10)], after which
the mixture was washed with water and the crude product was recrystallized in hot
ethanol to afford the pure product.
4,5-Diphenyl-2-(thiophen-2-yl)-1H-imidazole (11c) 1H NMR (DMSO-d6,
250 MHz): d 7.11–8.64 (m, 13H, ArH), 12.76 (s, 1H, NH); 13C NMR (DMSO-d6,
62.5 MHz): d 192.2, 142, 137.6, 135.9, 134.4, 131.3, 130, 129.9, 128.9, 128.6,
128.3, 127.5, 126.7, 124.7, 124.5.
General procedure for preparation of 1-amidoalkyl-2-naphthols Mixture of b-
naphthol (0.14 g, 1 mmol), aromatic aldehydes (1 mmol), acetamide (0.09 g,
1.5 mmol), and caffeine-H3PO4 (0.022 g, 7.5 mol%) was heated at 100 °C.
Reaction completion was indicated by TLC [EtOAc/n-hexane (3:10)], after which
the mixture was washed with water and the crude product was recrystallized in hot
ethanol to afford the pure product.
N-((2-Hydroxynaphthalen-1-yl)(thiophen-2-yl)methyl)acetamide (11b) 1H NMR
(DMSO-d6, 250 MHz): d 1.92 (s, 3H), 6.71 (s, 1H), 6.86–7.79 (m, 9H, ArH), 8.6
(d, 1H, ArOH), 12.76 (s, 1H, NH); 13C NMR (DMSO-d6, 62.5 MHz): d 192.3,
169.3, 153.5, 147.5, 135.3, 132.4, 131.4, 129, 128.8, 124.8, 124.5, 123.5, 122.9,
118.8, 45.4, 23.
General procedure for preparation of bis(indolyl) methanes, 4,40-(arylmethylene)
bis(1H-pyrazol-5-ols), or 3,30-(arylmethylene) bis(4-hydroxycoumarins) In a test
tube, a mixture of indole or 3-methyl-1-phenyl-5-pyrazolone or 4-hydroxycoumarin
(2 mmol), aromatic aldehydes (1 mmol), and caffeine-H3PO4 (0.022 g, 7.5 mol%)
was heated at 80 °C in an oil bath. Reaction completion was indicated by TLC
[EtOAc/n-hexane (3:10)], after which the mixture was washed with water and the
crude product was recrystallized in hot ethanol to afford the pure product.
123

Caffeine-H3PO4: a novel acidic catalyst for various one-pot…
Selected spectra
4,40-[(2-Thienyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (9e) 1H NMR
(DMSO-d6, 250 MHz): d 2.30 (s, 6H), 5.12 (s, 1H), 6.74–7.71 (m, 13H, ArH), 13.99
(brs, 2H); 13C NMR (DMSO-d6, 62.5 MHz): d 147.91, 146.29, 137.70, 129.39,
127.22, 126.11, 124.60, 1211.02, 105.46, 29.9, 11.93.
3,30-(Thiophen-2-ylmethylene)bis(4-hydroxy-2H-chromen-2-one) (9f) 1H NMR
(DMSO-d6, 250 MHz): d 6.50 (s, 1H), 6.71–7.92 (m, 11H, ArH), 10.33 (brs, 2H);
13C NMR (DMSO-d6, 62.5 MHz): d 166.1, 164.8, 152.6, 145.8, 132.4, 126.9, 124.5,
124.4, 124.2, 124.1, 118.4, 116.4, 104.7, 33.14.
3,30-(Thiophen-2-ylmethylene)bis(1H-indole) (11d) 1H NMR (DMSO-d6,
250 MHz): d 6.16 (s, 1H), 6.86–7.42 (m, 11H, ArH), 10.89 (s, 2H); 13C NMR
(DMSO-d6, 62.5 MHz): d 150.0, 136.9, 126.8, 125.1, 124.2, 123.7, 121.4, 119.6,
118.7, 118.6, 111.9, 35.4.
Conclusions
Caffeine-H3PO4 was prepared and applied for one-pot preparation of bis(indolyl)
methanes, 4,40-(arylmethylene) bis(1H-pyrazol-5-ols), 3,30-(arylmethylene) bis(4-
hydroxycoumarins), 2,4,5-trisubstituted imidazoles, 1-amidoalkyl-2-naphthols, and
polyhydroquinolines. The high product yield, short reaction time, facile separation
of catalyst, and easy workup procedure indicate that caffeine-H3PO4 can be
considered to be an efficient acidic catalyst for organic transformations.
Acknowledgements We gratefully acknowledge the support of this work by Payame Noor University
(PNU). S.J.S. is also grateful to PTRI of ACECR research council, for financial support.
References
1. L. Lloyd, Industrial catalysts, in Handbook of Industrial Catalysts (Springer, 2011), pp. 1–22
2. J.N. Armor, Catalysis 163, 3–9 (2011)
3. A.S. Amarasekara, Chem. Rev. 116(10), 6133–6183 (2016)
4. A.N. Primo, H. Garcia, Chem. Soc. Rev. 43(22), 7548–7561 (2014)
5. J. Jiang, O.M. Yaghi, Chem. Rev. 115, 6966–6997 (2015)
6. S. Rostamnia, E. Doustkhah, RSC Adv. 4(54), 28238–28248 (2014)
7. R.P. Herrera, Multicomponent Reactions: Concepts and Applications for Design and Synthesis
(Wiley, Hoboken, New Jersey, 2015)
8. J. Zhu, Q. Wang, M.X. Wang (eds.), Multicomponent Reactions in Organic Synthesis (Wiley-VCH,
Weinheim, Germany, 2015)
9. A. Pourjavadi, S.H. Hosseini, R. Soleyman, J. Mol. Catal. A Chem. 365, 55–59 (2015)
10. R.M.N. Kalla, A. Varyambath, M.R. Kim, I. Kim, Appl. Catal. A Gen. 538, 9–18 (2017)
11. J. Safari, Z. Zarnegar, J. Mol. Catal. A Chem. 379, 269–276 (2013)
12. S. Rostamnia, A. Hassankhani, H.G. Hossieni, B. Gholipour, H. Xin, J. Mol. Catal. A Chem. 395,
463–469 (2014)
13. L. Lili, Z. Xin, G. Jinsen, X. Chunming, Green Chem. 14(6), 1710–1720 (2012)
14. S. Sayyahi, A. Azin, S.J. Saghanezhad, J. Mol. Liq. 198, 30–36 (2014)
123

S. J. Saghanezhad et al.
15. K. Tanaka, F. Toda, Chem. Rev. 100, 1025–1074 (2000)
16. M.S. Singh, S. Chowdhury, RSC Adv. 2, 4547–4592 (2012)
17. S.J. Saghanezhad, Y. Nazari, F. Davod, RSC Adv. 6(30), 25525–25530 (2016)
18. S.J. Saghanezhad, S. Sayyahi, Res. Chem. Intermed. 43, 2491–2500 (2017)
19. S. Igder, A.R. Kiasat, M.R. Shushizadeh, Res. Chem. Intermed. 41(10), 7227–7244 (2015)
20. M. Maheswara, V. Siddaiah, G.L.V. Damu, C.V. Rao, Arkivoc 2, 201–206 (2006)
21. A.R. Kiasat, A. Mouradzadegun, S.J. Saghanezhad, Chin. J. Catal. 34(10), 1861–1868 (2013)
22. H. Alinezhad, M. Tajbakhsh, M. Norouzi, S. Baghery, M. Akbari, C. R. Chimie 17(1), 7–11 (2014)
23. F. Moeinpour, N. Dorostkar-Ahmadi, A. Sardashti-Birjandi, A. Khojastehnezhad, M. Vafaei, Res.
Chem. Intermed. 40(8), 3145–3152 (2014)
24. S.J. Saghanezhad, A. Kiasat, Org. Chem. Res. 2(1), 57–63 (2016)
25. J. Safari, S. Dehghan Khalili, M. Rezaei, S.H. Banitaba, F. Meshkani, Monatsh. Chem. 141,
1339–1345 (2010)
26. F. Nemati, M.M. Hosseini, H. Kiani, J. Saudi Chem. Soc. 20, S503–S508 (2016)
27. M. Seddighi, F. Shirini, M. Mamaghani, RSC Adv. 3(46), 24046–24053 (2013)
28. N. Azizi, N. Gholibeghlo, Z. Manocheri, Scientia Iranica 19(3), 574–578 (2012)
29. K. Niknam, S. Mirzaee, Synth. Commun. 41(16), 2403–2413 (2011)
30. W. Wang, S. Wang, X. Qin, J. Li, Synth. Commun. 35(9), 1263–1269 (2005)
31. A.R. Kiasat, L. Hemat-Alian, Res. Chem. Intermed. 41(2), 873–880 (2015)
32. P. Singh, P. Kumar, A. Katyal, R. Kalra, S.K. Dass, S. Prakash, R. Chandra, Catal. Lett. 134(3–4),
303–308 (2010)
33. R.K. Singh, B. Singh, R. Duvedi, S. Kumar, Res. Chem. Intermed. 41(7), 4083–4099 (2015)
34. M. Hajjami, B. Tahmasbi, RSC Adv. 5, 59194–59203 (2015)
35. J.L. Donelson, A.G. Richard, S.K. De, J. Mol. Catal. A Chem. 256, 309–311 (2006)
36. L. Shiri, A. Ghorbani-Choghamarani, M. Kazemi, Monatsh. Chem. 148, 1131–1139 (2017)
37. S.R. Cherkupally, R. Mekala, Chem. Pharm. Bull. 56, 1002–1004 (2008)
38. A. Khojastehnezhad, F. Moeinpour, A. Davoodnia, Chin. Chem. Lett. 22, 807–810 (2011)
123