Synthesis of tetrahydrobenzo[b]pyran and 3,4-dihydropyrimidinone derivatives using glutamic acid as an efficient catalyst

Article abstract of DOI:10.1080/15533174.2016.1212233

The efforts to use green catalysts for organic synthesis are undeniable. Natural catalysts are biodegradable and easy to access. Herein, glutamic acid was applied as a natural and green catalyst for the synthesis of tetrahydrobenzo[b]pyran and 3,4-dihydro

Full text of DOI:10.1080/15533174.2016.1212233

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Synthesis of tetrahydrobenzo[b]pyran and 3,4-dihydropyrimidinone derivatives using
glutamic acid as an efficient catalyst
a
a
a
a
Khatereh Khandan-Barani *, Mehrnoosh Kangani , Maryam Mirbaluchzehi , Zahra Siroos
Department of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978,
Zahedan, Iran
*
Corresponding author E-mail: kh_khandan_barani@yahoo.com
Abstract: The efforts to use green catalysts for the organic synthesis are undeniable. Natural
Catalysts are biodegradable and easy access. Herein, glutamic acid was applied as a natural and
green catalyst for the synthesis of tetrahydrobenzo[b]pyran and 3,4-dihydropyrimidinone
derivatives under solvent-free and thermal conditions. The most advantages of this research are:
use of natural, green and biodegradable catalyst, easy work-up and high yields.
Keywords: Glutamic acid, tetrahydrobenzo[b]pyran, 3,4-dihydropyrimidinone, solvent-free and
thermal conditions
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1
. Introduction
Glutamic acid is one of the most common non-essential amino acids; German chemist Karl
Ritthausen first isolated Glutamic acid from the wheat gluten in 1866, but its chemical structure
was identified only in 1890; Glutamic acid is an excitatory neurotransmitter increasing the firing
of neurons in the human central nervous system; This amino acid is also known for its ability to
detoxify muscle cells [1,2].
Glutamic acid has one additional methylene group in its side chain than aspartic acid; the side
chain carboxyl of aspartic acid is referred to as the β carboxyl group, while that of glutamic acid
is referred to as the γ carboxyl group (Figure 1). The pKa of the γ carboxyl group for glutamic
acid in a polypeptide is about 4.3, significantly higher than that of aspartic acid [3-5].
Because of the broad pharmacological activities of pyrimidinones and pyranes, different
synthetic methods have been introduced by research groups [6-13]. Usually, these synthetic
approaches are including a multi-step procedure [14]. Among the 12 principles of green
chemistry, utilizing ‘‘safer solvents’’ (or solvents elimination) and to ‘‘design for energy
efficiency’’ can be considered the most important ones for the synthetic chemists [15, 16], the
catalysts which make the organic reactions environmentally benign and economically feasible
are extremely demanded by chemical industries [17, 18].
According to mentioned reasons and in continue of our research on multi-component reactions
[
19-22] we herein report green synthesis of tetrahydrobenzo[b]pyran- and 3,4-
dihydropyrimidinone derivatives under solvent-free and thermal conditions in the presence of
glutamic acid as a natural and green catalyst via the condensation between aryl aldehydes,
2
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dimedone and malononitrile and the reaction between aryl aldehydes, urea and ethyl acetoacetate
(Scheme 1).
2
2
. Experimental
.1.General
Melting points and IR spectra of all compounds were measured on an Electro thermal 9100
1
apparatus and FT-IR-JASCO-460 plus spectrometer. The H NMR spectra were obtained on
Bruker DRX-400 Avance instruments with DMSO as a solvent. All reagents and solvents were
obtained from Aldrich and Merck and used without further purification.
2
.2.General procedure for synthesis of tetrahydrobenzo[b]pyrans
Glutamic acid (5 mol%) was added to a mixture of benzaldehyde (1 mmol), dimedone (1 mmol)
and malononitrile (1 mmol), the reaction mixture was heated to 50°C and maintained for the
appropriate time (Table 2). After completion of the reaction as monitored by thin-layer
chromatography (TLC), the reaction mixture was washed with H O (3× 10 mL) to remove the
2
catalyst. Then, the residue was recrystallized from EtOH. The structures of the synthesized
1
13
compounds were characterized by their IR, melting points and H NMR spectra ( C NMR for
c) and were found to be identical with data described in the literature.
.3.General procedure for synthesis of 3,4- dihydropyrimidin-2(1H)-ones
4
2
A mixture of ethyl acetoacetate (2 mmol), aldehyde (2 mmol), urea (2 mmol) and catalytic
amount of glutamic acid (5 mol%) was heated to 100°C under solvent-free conditions and
maintained for the appropriate time (Table 4). After completion of the reaction as monitored by
thin-layer chromatography (TLC), the residue was washed with water (3× 10 mL) and
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recrystallized from ethanol to afford 3,4-dihydropyrimidinone in excellent yields. The structures
1
of the synthesized compounds were characterized by their IR, melting points and H NMR
spectra and were found to be identical with data described in the literature.
Selected spectroscopic data of some products is given below:
2
-Amino-3-cyano-4-phenyl-7,7-dimethyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran (4a): FT-
-1
2
3
IR: (KBr, νmax/cm ): 3395, 3324 (NH ), 3209 (CH ), 2963, 2882 (CH ), 2198 (CN), 1664
2
sp
sp
1
(
C=O). H NMR (400.1MHz, DMSO-d ): δ=0.94 (s, 3H), 1.02 (s, 3H), 2.09 (d. J= 15.9 Hz, 1H),
6
2
.24 (d, J = 16.0 Hz, 1H), 2.65 (s,2H ), 4.15 (s,1H), 6.99 (br, 2H), 7.11-7.29 (m, 5H) ppm.
2
-Amino-3-cyano-4-(2'-hydroxy-5'-nitrobenzyl)-7,7-dimethyl-5-oxo-4H-5,6,7,8-
-1
tetrahydrobenzo[b]pyran (4c): Yellow Solid, FT-IR (KBr, νmax/cm ): 3433, 3333 (NH ), 3059
2
2
3
1
(
CH ), 2960 (CH ), 2190 (CN), 1669 (C=O). H NMR (400.1MHz, DMSO-d ): δ=1.04 (s,
sp sp 6
3
7
2
1
2
H), 1.09 (s, 3H), 2.08 (d, J = 16.1 Hz, 1H), 2.21 (d, J = 16.1 Hz, 1H), 2.55 (s, 2H), 4.28 (s, 1H),
13
.14 (s, 2H), 7.18-7.31 (m, 3H), 10.43 (s, 1H) ppm. C NMR (100.6 MHz, DMSO-d ): δ= 26.5,
6
7.9, 31.2, 35.7, 40.1, 49.3, 61.4, 112.8, 119.0 (CN), 119.7, 120.04, 130.8, 132.7, 139.4, 158.4,
61.8, 165.5, 194.8 (C=O) ppm.
-Amino-3-cyano-4-(4'-methylbenzyl)-7,7-dimethyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b] pyran
-1
2
3
(
4e): FT-IR (KBr, νmax/cm ): 3425, 3327 (NH ), 3042 (CH ), 2958 (CH ), 2191 (CN), 1676
2 sp sp
1
(
C=O). H NMR (400.1 MHz, DMSO-d ): 1.02 (s, 3H), 1.06 (s, 3H), 2.12 (d, J = 16.0 Hz, 1H),
6
2
.25 (d, J = 16.0 Hz, 1H), 2.29(s, 3H), 2.56 (s, 2H), 4.33 (s, 1H), 4.52 (s, 2H), 7.09 (d, J = 7.6
Hz, 2H), 7.11-7.14 (m, 2H) ppm.
-Amino-3-cyano-4-(4'-chlorobenzyl)-7,7-dimethyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b] pyran
2
-1
2
3
(
4h): FT-IR (KBr, νmax/cm ): 3394, 3312 (NH ), 3060 (CH ), 2962 (CH ), 2190 (CN), 1666
2 sp sp
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1
(
C=O). H NMR (400.1 MHz, DMSO-d ): δ = 0.95 (s, 3H), 1.04 (s, 3H), 2.10 (d, J = 16.1 Hz,
6
1
7
H), 2.19 (d, J = 16.1 Hz, 1H), 2.51 (s, 2H), 4.19 (s, 1H), 7.08 (s, 2H), 7.20 (d, J = 8.1 Hz, 2H),
.31 (d, J = 8.1 Hz, 2H) ppm.
-
5
-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (8a): FT–IR (KBr, νmax/cm
1
1
)
: 3332 (NH), 3320 (NH), 1697 (2C=O). HNMR (400.1 MHz, DMSO-d ):δ=1.08 (t, J = 7.1 Hz,
6
3
1
5
H), 2.24 (s,3H), 3.97 (q, J = 7.1 Hz, 2H), 5.13 (s,1H), 7.21-7.33 (m, 5H), 7.77(s, 1H), 9.23 (s,
H).
-(Ethoxycarbonyl)-4-(4-nitrophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (8c):
-1
1
FT–IR (KBr, νmax/cm ): 3241 (NH), 3110 (NH), 1705 and 1648 (2C=O). H NMR (400.1 MHz,
DMSO-d ): δ=1.10 (t, J =7.0 Hz, 3H), 2.30 (s, 3H), 4.05 (q, J = 7.1 Hz,2H), 5.69 (d, J = 2.3 Hz,
6
1
H,), 7.48 (d, J = 9.2 Hz, 2H), 7.56 (s, 1H), 8.20 (d, J = 9.2 Hz, 2H), 9.10 (s, 1H).
-(Ethoxycarbonyl)-4-(4-chlorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (8d):
5
-1
1
FT–IR (KBr, νmax/cm ): 3332 (NH), 3218 (NH), 1666 (2C=O). H NMR (400.1 MHz, DMSO-
d6): δ=1.12 (t, J =7.1 Hz, 3H), 2.28 (s, 3H), 3.98 (q, J = 7.1 Hz, 2H), 5.36 (d, J = 2.2, 1H), 7.18
(d, J = 9.1, 2H),7.60 (s, 1H), 7.75 (d, J = 9.1, 2H), 9.15 (s, 1H).
5
-(Ethoxycarbonyl)-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (8f):
-1
1
FT–IR (KBr, νmax/cm ): 3245 (NH), 3110 (NH), 1710 and 1648 (2C=O). HNMR (400.1 MHz,
DMSO-d ):δ=1.15 (t, J = 6.8 Hz, 3H), 2.29 (s, 3H), 3.66 (s, 3H), 3.71 (q, J = 6.7 Hz, 2H), 5.05
6
(s, 1H), 6.79-7.12 (m, 4H), 7.59 (s, 1H), 9.24 (s, 1H).
5
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3
. Result and discussion
The reaction between benzaldehyde, dimedone and malononitrile was chosen as a model. The
reaction was performed in different temperature and amount of catalyst.
As can be seen in Table 1 the best results was obtained in the presence of 5 mol% of catalyst at
૦
5
0 C.
Encouraged by the remarkable results obtained from above conditions, and in order to show the
generality and scope of this protocol, we used various aldehydes. Thus, a variety of aromatic
aldehydes, including those with electron withdrawing and electron-donating groups, were tested
using this method. The desired products were obtained in good yields using catalytic amount of
glutamic acid and the results are shown in Table 2.
We proposed mechanism for the synthesis of tetrahydrobenzo[b]pyrans in the presence of
glutamic acid as catalyst. First, Knoevenagel condensation between 1 and 2 produced 2-
benzylidene malononitrile 3, Michael addition of 3 with 5 (1,3-dicarbonyl compound), and
followed cyclization and tautomerization afforded the corresponding product. Glutamic acid can
hold molecules and further catalyze reactions possible activated by hydrogen bonds (Scheme 2).
Next, the reaction conditions were optimized for the synthesis of 3,4-dihydropyrimidinone
derivatives. The reaction between benzaldehyde, urea and ethylacetoacetate was chosen as a
model reaction (Scheme 3). The reaction was performed in different temperature and amount of
૦
catalyst (Table 3). The best results were obtained with 5 mol % of catalyst at 100 C.
Using the optimized reaction condition in the hand (Table 3, Entry 2), a variety of
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3
,4-dihydropyrimidinones were synthesized and the results are summarized in Table 4. A variety
of 3,4-dihydropyrimidinones with ortho, meta and para substitutions on the benzene ring were
examined. Nitro and halogen substitutions were tolerated very well and gave excellent yields in
shorter reaction times than those of methyl and methoxy, groups (Table 4).
The accessibility of the present work in comparison with the reported results in the literature,
some of the results has been accumulated in Table 5. The results show that glutamic acid is a
more efficient catalyst with respect to the reaction time exhibits broad applicability in similar
yield.
Conclusion
We have developed a simple, efficient, and green protocol for the synthesis of
tetrahydrobenzo[b]pyran- and 3,4-dihydropyrimidinone derivatives using glutamic acid catalyst
under solvent-free conditions. The short reaction times, simple work-up in the isolation of the
products in high yields with high purity, solvent-free conditions, and using a green and natural
catalyst are noteworthy features of this new procedure.
Acknowledgment
Financial support from the Research Council of the Islamic Azad University, Zahedan Branch is
gratefully acknowledged.
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Table 1. Optimization of the reaction conditions and amount of catalyst for the synthesis of
tetrahydrobenzo[b]pyrans
Entry
Catalyst (mol %)
T(˚C)
25
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
5
5
50
40
15
15
15
25
45
45
24
65
70
35
5
50
95
5
60
90
5
70
80
10
15
20
-
50
75
50
65
50
55
50
Trace
1
2
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Table 2. synthesis of tetrahydrobenzo[b]pyran derivatives
Entry
R
Product
Time
Isolated
Yield
M.p (°C)
M.p reported
(°C)
(min)
(%)
1
2
3
C H
4a
4b
4c
15
20
15
90
82
85
227-229
191-193
208-210
226-228 [23]
194-196 [23]
-
6
5
4-OCH -C H
4
3
6
2-OH-4-NO2-
C H
6
3
4
5
6
7
4-Br-C H
4d
4e
4f
10
20
10
25
92
80
95
75
198-200
206-208
183-185
202-204
201-203 [24]
208-210 [23]
181-183 [25]
198-200 [26]
6
4
4-CH -C H
4
3
6
4-NO -C H
4
2
6
4-(Me) N-
4g
2
C H
6
4
8
9
4-Cl-C H
4h
4i
4j
15
10
15
90
93
90
214-217
217-219
228-230
215-217 [27]
214-215 [23]
224-226 [28]
6
4
4
2-Cl-C H
6
1
0
2-NO -C H
2 6 4
1
3
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Table 3. Optimization of the reaction conditions and the amount of catalyst for the synthesis of
3
,4-dihydropyrimidinone derivatives
Entry
Catalyst (mol %)
૦
Time (h)
Yield (%)
T( C)
1
2
3
4
5
6
7
8
9
5
5
80
5
3
80
96
100
115
120
130
100
100
100
100
5
3
96
5
3
90
5
3
85
10
15
20
-
5
75
5
70
5
65
24
Trace
1
4
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Table 4. Synthesis of 3,4-dihydropyrimidinonederivatives
Entry
R
Product Time (h)
Isolated
Yield (%)
M.p (°C)
M.p reported
°C)
(
1
2
3
4
5
H
8a
8b
8c
8d
8e
3
3
2
2
1.5
95
85
95
90
92
203-206
213-215
208-210
214-215
195-197
201-203 [29]
214-215 [30]
209-210 [31]
212-213 [32]
197-200 [33]
4-CH3
4-NO2
4-Cl
4-Br
6
7
8
9
4-OMe
4-F
4-NMe2
3-NO2
3-Cl
8f
8g
8h
8i
4
2
4
2
2
80
93
80
92
90
201-203
182-184
252-254
229-231
188-190
202-204 [34]
183-185 [35]
255-256 [36]
227-229 [37]
191-193 [38]
1
0
8j
1
5
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Table 5 . Comparison the result of glutamic acid with other catalysts reported in the literature for
preparation of tetrahydrobenzo[b]pyran and 3,4-dihydropyrimidinone derivatives
Entry Product
Catalysts
conditions
Time
Yield Ref
%)
(
1
4
HDBMB
12 mol%; water; 80
6 h
94
[39]
૦
C
2
3
4
5
6
4
4
4
4
4
TBAB
TBAF
10 mol%; ethanol;
reflux
10 mol %; water;
30 min
30 min
1 h
95
94
91
90
95
[28]
[40]
[41]
[42]
reflux
[TEBSA] HSO4
૦
1
0 mol%; H 0; 90 C
2
Na SeO4
0.1 g; H O-C H OH;
3 h
2
2
2
5
reflux
5mol %; Solvent-
Glutamic Acid
InBr3
10 min
This
work
૦
free; 50 C
7
8
9
8
8
Ethanol, reflux
Ethanol, reflux
420
min
98
91
89
94
91
93
79
[43]
[44]
[45]
[46]
[47]
[48]
[8]
P2O5
240
min
8
8
8
8
8
Bioglycerol-based Acetonitrile, reflux,
240
min
sulfonic acid
N atm
2
1
0
1
2
3
sulfonic acidsilica
Ethanol, reflux
Ethanol, reflux
360
min
1
1
1
p-Toluene
sulfonic acid
150
min
0
Dowex-50W
Solvent-free, 130 C
180
min
Cu(NH SO )
Acetone, reflux
300
min
2
3 2
1
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
8
1
1
1
4
5
6
Zeolite
Cu(OTF)3
toluene, reflux
720
min
80
94
92
[49]
[50]
8
8
0
Acetonitrile, 25 C
360
min
0
Glutamic Acid
Solvent-free, 100 C 90 min
This
work
1
7
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Figure 1. The structure of glutamic acid
1
8
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
R
CHO
O
O
O
CN
CN
+
+
Glutamic acid (5 mol%)
solvent-free, heat
CN
R
O
NH2
1
2
3
4a-j
R
CHO
O
O
6
Glutamic acid (5 mol%)
solvent-free, heat
O
O
EtO
NH
+
H N
2
NH2
+
OEt
R
N
H
O
7
5
8a-j
Scheme 1. Synthesis of tetrahydrobenzo[b]pyran and 3,4-dihydropyrimidinone derivatives in the
presence of glutamic acid as catalyst under solvent-free and thermal conditions
1
9
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ACCEPTED MANUSCRIPT
Scheme 2. Proposed mechanism for the synthesis tetrahydrobenzo[b]pyran in the presence of
glutamic acid as catalyst
2
0
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ACCEPTED MANUSCRIPT
CHO
O
O
Glutamic acid
O
O
EtO
NH
+
H N
2
NH2
+
OEt
solvent-free, heat
N
O
H
7
6
5
Scheme 3. Model reaction for the synthesis of 3,4-dihydropyrimidinone derivatives
2
1
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