Mild and green synthesis of tetrahydrobenzopyran, pyranopyrimidinone and polyhydroquinoline derivatives and DFT study on product structures

Article abstract of DOI:10.1007/s11164-015-2079-1

The multicomponent synthesis of 4H-benzo[b]pyran, pyranopyrimidinone and polyhydroquinoline derivatives has been achieved using catalytic amounts of calcium hydrogen phosphate in aqueous medium as a green, inexpensive and environmentally benign media. The

Full text of DOI:10.1007/s11164-015-2079-1

Res Chem Intermed
DOI 10.1007/s11164-015-2079-1
Mild and green synthesis of tetrahydrobenzopyran,
pyranopyrimidinone and polyhydroquinoline
derivatives and DFT study on product structures
1
1
•
Mohammad Ali Bodaghifard
1
•
Mohammad Solimannejad
1
Sajad Asadbegi
•
Samira Dolatabadifarahani
Received: 21 February 2015 / Accepted: 24 April 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract The multicomponent synthesis of 4H-benzo[b]pyran, pyranopyrimidi-
none and polyhydroquinoline derivatives has been achieved using catalytic amounts
of calcium hydrogen phosphate in aqueous medium as a green, inexpensive and
environmentally benign media. The process is operationally simple and has good to
excellent yields. Moreover, computational parameters of some products were ob-
tained using density functional theory at the B3LYP/6-311??G(d,p) basis set and
correlated to experimental results.
Keywords Green synthesis Á Benzopyran Á Pyranopyrimidinone Á DFT study
Introduction
Environmentally benign and clean synthetic procedures have great importance in
organic syntheses. Reactions in solvent-free or aqueous media are environmentally
safe, devoid of any carcinogenic effects, have a simple work up and are especially
important in industry. Thus, development of multicomponent reactions (MCRs)
without the use of any harmful organic solvents and catalysts has become the goal of
present day chemical reactions [1].
Tetrahydrobenzo[b]pyran, pyranopyrimidinone and polyhydroquinoline deriva-
tives are an important class of heterocyclic drugs and pharmaceuticals, and are
widely used as antiallergic, antibacterial, antifungal, diuretic, spasmolytic, hepato-
protective, vasodilator, bronchodilator, antiatherosclerotic, antidiabetic, antitumor,
antihypertensive, antimalarial and antianaphylactic agents [2–8]. Numerous meth-
ods have been reported for the synthesis of these heterocycles [9–19]. However,
&
Mohammad Ali Bodaghifard
mbodaghi2007@yahoo.com; m-bodaghifard@araku.ac.ir
1
Department of Chemistry, Faculty of Science, Arak University, 38156-88349 Arak, Iran
123

M. A. Bodaghifard et al.
some of these methods have drawbacks, such as long reaction times, use of
stoichiometric and/or relatively expensive reagents, low yields, harsh reaction
conditions, effluent pollution and tedious workup procedures. Because of the
drawbacks mentioned above, the search for improved and less hazardous conditions
for the synthesis of these compounds has prime importance.
Hydrogen phosphate slats are inexpensive, easily available and safe salts that are
used in some organic transformations [20–24]. As a continuation of our research
devoted to the development of green organic chemistry and one-pot multicompo-
nent reactions (MCRs) for the synthesis of various heterocyclic compounds [25, 26]
and our interest in computational chemistry, herein we wish to report an efficient
and green procedure for the preparation of 4H-benzo[b]pyrans, pyrano[2,3-
d]pyrimidinones and polyhydroquinolines via a domino Knoevenagel cyclocon-
densation reaction using calcium hydrogen phosphate as an efficient and inexpen-
sive catalyst in aqueous medium, and theoretical study on product structures
(
Schemes 1, 2).
Results and discussion
At first, we optimized reaction condition using various solvent and hydrogen phosphate
salts at different temperatures. For optimization benzaldehyde, dimedone and
malononitrile were chosen as a model reaction and various conditions were evaluated
(
Scheme 3). The best reaction condition for this reaction was 10 wt% CaHPO as a
4
catalyst, Water/ethanol (4:1) as a green solvent, 2 h time and 80 °C (Table 1, entry 12).
To determinetheefficiency ofcatalyst, the model reactionwas carriedout intheabsence
of catalyst and it was revealed that the reaction was not completed in the absence of
catalyst (Table 1, entry 14). The reaction is clean and efficient, and the experimental
procedure is very simple. This method does not require high temperature. Moreover, the
catalyst can be conveniently handled and also recovered and reused for at least three
times without loss of its activity (Table 1, entry 12).
We used this optimized condition for the synthesis of tetrahydrobenzo[b]pyran,
pyrano[2,3-d]pyrimidinone and polyhydroquinoline derivatives. The various aro-
matic aldehydes bearing electron-donating and electron-withdrawing substituent
underwent the condensation with malononitrile and diketone smoothly to afford a
wide range of desired products in good yields. The results are indicated in Tables 2,
3
and 4.
O
O
HN
O
Ar
O
O
Ar
O
N
H
O
CN
O
CN
CN
CN
3
HN
ArCH O +
4
2
°
NH2
°
CaHPO , 80 C
N
H
NH2
CaHPO , 80 C
4
O
O
4
1
2
5
H O/EtOH (4:1)
H O/EtOH (4:1)
2
2
6
Scheme 1 The efficient synthesis of tetrahydrobenzopyran and pyranopyrimidinone derivatives
1
23

Mild and green synthesis of tetrahydrobenzopyran…
O
O
O
Ar
O
O
OEt
+
OEt
8
4
,
CaHPO 80 C
H
°
R1
R2
R1
+
NH4OAc
2O/EtOH (4:1)
N
H
2
O
ArCHO
R
10
1
1
7
9
Scheme 2 The efficient synthesis of polyhydroquinolines
O
O
Ph
O
CHO
CN
CN
+
+
CN
O
NH2
1
5
2
3
Scheme 3 The model reaction for optimization of reaction condition
Table 1 Optimization of reaction condition
b
a
Entry
Solvent
Catalyst
Temp. (°C)
Yield (%)
c
1
2
3
4
5
6
7
8
9
H
H
2
O
O
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
CaHPO
None
4
(20 %)
(20 %)
(20 %)
(20 %)
(20 %)
(20 %)
(20 %)
(20 %)
(20 %)
(20 %)
(20 %)
(10 %)
(10 %)
25
N.C.
2
4
4
4
4
4
4
4
4
4
4
4
4
80
N.C.
N.C.
N.C.
N.C.
N.C.
N.C.
N.C.
84
CH
3
3
OH
CH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
25
CH
2
2
CH OH
CHCl
3
CH CN
3
DMF
Toluene
2 5
C H OH
10
11
12
13
14
15
16
17
H
H
H
H
H
H
H
H
2
O/EtOH (4:1)
2
O/EtOH (4:1)
2
O/EtOH (4:1)
2
O/EtOH (1:1)
2
O/EtOH (4:1)
2
O/EtOH (4:1)
2
O/EtOH (4:1)
2
O/EtOH (4:1)
50
80
92
d
80
91, 89, 90
90
80
Reflux
80
N.C.
(NH
NaHPO
KHPO
4
)
2
HPO
(20 %)
(20 %)
4
(20 %)
N.C.
4
80
N.C.
4
80
N.C.
N.C. means: The reaction was not completed
a
Isolated yields
b
All reactions carried out in 2 h
c
Not completed, as indicated by TLC
d
Catalyst reused for three consecutive reactions
A possible explanation for the mechanism of the one-pot reaction between
aldehyde, malononitrile and dimedone or barbituric acid in the presence of CaHPO4,
is presented in Scheme 4. We suggest that CaHPO is an effective catalyst for the
4
123

M. A. Bodaghifard et al.
Table 2 Synthesis of
tetrahydrobenzo[b]pyrans in
green media
a
Entry
ArCHO
Product
M.P (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
C
6
H
5
–
5a
5b
5c
5d
5e
5f
226–228
202–205
224–226
212–215
210–212
182–184
204–206
228–230
223–226
230–233
91
90
95
92
90
93
91
89
91
91
4-MeO–C
4-(Me) N–C
4-Cl–C
3-NO –C
2,4-Cl –C
4-Br–C
3-Cl–C
2-NO –C
6 4
H –
2
6 4
H –
6 4
H –
2
6 4
H –
2
6 3
H –
6
H
4
–
5g
5h
5i
6 4
H
–
2
6 4
H –
a
Yields refer to isolated
products
1
0
3-OH–C
6
H
4
–
5j
Table 3 Synthesis of
pyrano[2,3-d] pyrimidinones in
green media
a
Entry
ArCHO
Product
M.P (°C)
Yield (%)
1
2
3
4
5
6
7
C
6
H
5
–
6a
6b
6c
6d
6e
6f
226–228
212–215
270–272
239–241
242–245
241–243
226–229
89
92
90
87
93
91
91
4-Cl–C
3-NO –C
3-Cl–C
2,4-Cl –C
4-NO –C
4-Br–C
6 4
H –
2
6 4
H –
6 4
H –
2
6 3
H –
2
6 4
H –
a
Yields refer to isolated
products
6
H
4
–
6g
Table 4 Synthesis of polyhydroquinolines in green media
1
2
R
°
a
Entry
ArCHO
R
Product
M.P ( C)
Yield (%)
1
4
5
5
5
2
3
4
5
6
7
8
9
C
6
H
5
–
H
H
11a
11b
11c
11d
11e
11f
11g
11h
11i
238–240
235–238
242–245
201–203
203–205
252–255
260–263
242–245
178–180
240–243
253–255
180–183
203–205
260–263
89
92
90
91
90
91
91
90
88
92
91
88
91
93
4-Cl–C
4-Me–C
3-NO –C
6
H
4
–
H
H
6
H
4
–
H
H
2
6
H
4
–
H
H
C
6
H
5
–
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
4-MeO–C
4-(Me) N–C
4-Cl–C
3-NO –C
2,4-Cl –C
4-Br–C
3-NO –C
2-Cl–C
4-Me–C
6
H
4
–
2
6
H
4
–
6 4
H –
2
6 4
H –
2
6
H
3
–
11j
6
H
4
–
11k
11l
2
6 4
H –
6
H
4
–
11m
11n
10
6 4
H –
a
Yields refer to isolated products
1
23

Mild and green synthesis of tetrahydrobenzopyran…
formation of malonate anion 7 and facilitates Knoevenagel condensation between
aryl aldehyde 1 and malononitrile 2, which proceeds via intermediate 7 and
produces intermediate 8, which after dehydration produces olefin 9. CaHPO also
4
catalyzes the generation of a proposed enolate intermediate 10, which is formed
from dimedone 3. Enolate intermediate 10 adds to olefin 9 to generate product 5,
after intramolecular cyclization, proton transfer and tautomerization of intermediate
1
1 (Scheme 4).
A DFT study has been carried out on selected molecules of desired products 5a,
g and 11a at 6-311??G(d,p) basis set by assuming Cs point group symmetry.
6
7
O
NC
CN
1
2
NC
CN
Ar
H
H O
2
HO
CN
8
H
Ca2+ + HPO42-
Ar
H
CN
CaHPO + H O
4
2
Ar
CN
9
H
CN
O
Ar
O
O
H
NC
O
1
1
10
N
O
O
Ar
Ca2+ + HPO42-
CaHPO + H O
NC
4
2
O
H N
O
2
5
3
Scheme 4 The proposed mechanism for the reaction in the presense of CaHPO
4
123

M. A. Bodaghifard et al.
Also, the natural bond orbital (NBO) has been done on the optimized structures at
B3LYP/6-311??G(d,p) level. The GIAO/DFT calculations were performed to
1
3
obtain computational C chemical shifts for products at B3LYP level with
-311??G(d,p) basis set. The optimized structures bearing charge density on atoms
6
Fig. 1 Molecular structure of products 5a and 6g, along with numbering and charge density of atoms
Fig. 2 Molecular structure of product 11a, along with numbering and charge density of atoms
1
23

Mild and green synthesis of tetrahydrobenzopyran…
Table 5 Calculated optimized parameter values of product 5a
˚
Bond length (A)
˚
Bond length (A)
˚
Bond length (A)
Bond label
Bond label
Bond label
O1–C2
1.368
1.358
1.366
1.010
1.010
1.415
1.160
1.521
1.093
1.534
1.516
1.344
1.378
1.498
C7–H17
C7–H18
C7–C8
1.098
1.094
1.546
1.542
1.093
1.094
1.093
1.537
1.095
1.094
1.094
1.544
1.520
1.092
C9–H20
1.099
1.218
1.480
1.396
1.084
1.394
1.084
1.393
1.084
1.395
1.084
1.393
1.085
1.399
C2–C3
C10–O11
C10–C5
C2–N12
N12–H15
N12–H16
C3–C13
C13–N14
C3–C4
C8–C21
C21–H23
C21–H24
C21–H25
C8–C22
C22–H26
C22–H27
C22–H28
C8–C9
C30–C31
C31–H36
C31–C32
C32–H37
C32–C33
C33–H38
C33–C34
C34–H39
C34–C35
C35–H40
C35–C30
C4–H29
C4–C38
C4–C5
C5–C6
C6–O1
C9–C10
C9–H19
C6–C7
Table 6 Calculated NBO
charges on atoms of product 5a
in the gas phase
Atom
Charge
Atom
Charge
Atom
Charge
O1
-0.528
0.560
H15
H16
H17
H18
H19
H20
C21
C22
H23
H24
H25
H26
H27
H28
0.408
0.394
0.228
0.225
0.229
0.227
-0.577
-0.566
0.208
0.201
0.208
0.203
0.207
0.201
H29
C30
C31
C32
C33
C34
C35
H36
H37
H38
H39
H40
0.222
-0.240
-0.184
-0.197
-0.201
-0.201
-0.210
0.212
C2
C3
-0.786
0.579
C4
C5
-0.237
0.393
C6
C7
-0.425
-0.068
-0.462
0.551
C8
C9
0.206
C10
O11
N12
C13
N14
0.204
-0.563
-0.777
0.274
0.203
0.202
-0.348
1
3
are depicted in Figs. 1 and 2. Bond orders, charge density on all atoms and C-
NMR data are indicated in Tables 5, 6, 7, 8, 9, 10, 11, 12, and 13. Computational
parameters obtained for product 5a showed that in 4H-benzo[b]pyrans, the C5-C6
bond length is shorter than that of the C2–C3 bond that referred to lone pair electron
sharing from 2-amino group to the C2–C3 double bond and electron demanding of
the 3-cyano substituent (Table 5). On the other hand, NBO analysis indicates
maximum positive charge density on C2 and highly negative charge density on C3
that confirmed the resonance between NH moiety and C2–C3 double bond
2
1
Table 6). The normal C-NMR signals of olefinic carbons often appear in the
3
(
123

M. A. Bodaghifard et al.
1
3
range of 110–140 ppm, but GIAO/DFT calculated C-NMR predicted the C3
signal to appear in high magnetic field, and C2 signal to appear in low magnetic
field, which is in consistent with experimental data and confirmed the highly
negative charge density on C3 and the positive charge on C2 (Table 7). Also, a
13
Table 7 Calculated (dTheo.) and experimental (dExp.) C NMR chemical shifts for product 5a
Atom
Experimental
GIAO/DFT B3LYP/6-311??G(d,p)
dExp–dTheo
Gas phase
DMSO
C21
C22
C8
26.33
27.62
25.542
32.019
25.091
31.046
1.209
-3.446
-7.943
-5.257
-3.012
-4.778
-2.625
-6.605
-5.874
-5.559
-5.591
-7.064
-6.193
-7.633
-8.416
31.27
38.382
39.143
C4
35.04
40.77
40.257
C7
39.83
43.266
42.812
C9
49.91
53.958
54.678
C3
60.33
66.698
62.925
C13
C5
113.07
118.41
126.11
126.65
126.65
127.52
127.52
143.21
157.73
161.37
195.17
119.548
120.804
131.575
132.536
132.732
132.773
136.555
150.402
164.566
166.948
200.905
119.605
124.274
131.659
132.191
133.664
133.693
135.133
151.616
168.277
171.635
205.622
C33
C32
C34
C35
C31
C30
C2
-10.577
-10.335
-10.522
C6
C10
2
R = 0.998
dExp = 0.957 dTheo - 1.606
Table 8 Calculated optimized parameter values of product 6g
˚
Bond length (A)
˚
Bond length (A)
˚
Bond length (A)
Bond label
Bond label
Bond label
O1–C2
1.378
1.357
1.362
1.010
1.010
1.416
1.159
1.523
1.094
1.512
1.458
C5–C6
1.348
1.370
1.010
1.395
1.210
1.381
1.012
1.411
1.216
1.534
1.396
C22–H31
C22–C23
C23–H30
C23–C24
C24–Br29
C24–C25
C25–H28
C25–C26
C26–H27
1.084
1.394
1.082
1.390
1.918
1.392
1.082
1.392
1.085
C2–C3
C6–N7
C2–N15
N15–H16
N15–H17
C3–C18
C18–C19
C3–C4
N7–H14
N7–C8
C8–O13
C8–N9
N9–H12
N9–C10
C10–O11
C4–C21
C21–C22
C4–H20
C4–C5
C5–C10
1
23

Mild and green synthesis of tetrahydrobenzopyran…
Table 9 Calculated NBO
charges on atoms of product 6g
Atom
Charge
Atom
Charge
Atom
Charge
in the gas phase
O1
C2
C3
C4
C5
C6
N7
C8
N9
C10
O11
-0.520
0.569
H12
O13
H14
N15
H16
H17
C18
N19
H20
C21
C22
0.425
-0.606
0.429
C23
C24
C25
C26
H27
H28
Br29
H30
H31
-0.215
0.097
-0.219
0.184
0.206
0.221
0.065
0.224
0.221
-0.296
-0.224
-0.221
0.569
-0.778
0.413
0.398
-0.617
0.811
0.275
-0.329
0.243
-0.638
0.665
-0.034
-0.164
-0.592
13
Table 10 Calculated (dTheo.) C NMR chemical shifts for the compound 6g
Atom
Experimental
GIAO/DFT B3LYP/6-311??G(d,p)
dExp–dTheo
Gas phase
DMSO
C4
32.25
58.38
40.641
68.680
40.134
64.581
-7.884
-6.201
-8.668
-4.711
C3
C5
87.97
96.618
96.638
C18
C26
C23
C25
C22
C21
C24
C8
118.95
119.73
129.63
129.63
131.07
131.07
143.52
149.44
152.32
157.60
162.40
118.856
132.390
136.485
136.855
137.487
146.845
146.960
149.019
154.593
163.918
163.979
123.661
134.320
135.788
136.836
137.367
144.655
149.141
144.655
156.984
165.844
167.993
-14.59
-6.158
-7.206
-6.297
-13.585
-5.621
4.785
C6
-4.654
-8.244
-5.593
C10
C2
2
R = 0.986
dExp = 1.012 dTheo - 8.369
weak resonance has been found among O1–C6–C5 atoms, which gives a slight
negative charge density on C5 (Table 6). The same results have been seen in
pyranopyrimidinone 6g (Tables 8, 9, 10).
Computational parameters obtained for product 11a showed that there is no
difference between C5–C6 and C2–C3 bond lengths, and they are approximately
identical. NBO analysis indicates a slightly negative charge density on C5 due to
weak resonance between the N1 atom and the C5–C6 double bond. The effective
resonance in the ester functional group among O15 and the C13–O14 double bond
and the highly negative charge density on O14 atom can be a good reason for
123

M. A. Bodaghifard et al.
Table 11 Calculated optimized parameter values of product 11a
˚
Bond length (A)
˚
Bond length (A)
˚
Bond length (A)
Bond label
Bond label
Bond label
N1–C2
1.395
1.008
1.359
1.508
1.088
1.092
1.094
1.527
1.090
1.475
1.535
1.520
1.356
1.469
1.383
1.506
C7–H19
C7–H20
C7–C8
1.096
1.099
1.532
1.095
1.094
1.530
1.092
1.098
1.525
1.222
1.213
1.361
1.448
1.092
1.092
1.516
C17–H31
C17–H32
C17–H33
C34–C35
C35–H40
C35–C36
C36–H41
C36–C37
C37–H42
C37–C38
C38–H43
C38–C39
C39–H44
C39–C34
1.093
1.093
1.093
1.398
1.083
1.394
1.085
1.394
1.084
1.394
1.085
1.394
1.085
1.400
N1–H18
C2–C3
C2–C12
C12–H26
C12–H27
C12–H28
C3–C4
C8–H21
C8–H22
C8–C9
C9–H23
C9–H24
C9–C10
C10–O11
C13–O14
C13–O15
O15–C16
C16–H29
C16–H30
C16–C17
C4–H25
C3–C13
C4–C34
C4–C5
C5–C6
C5–C10
C6–N1
C6–C7
Table 12 Calculated NBO
charges on atoms of product 11a
in the gas phase
Atom
Charge
Atom
Charge
Atom
Charge
N1
-0.596
-0.219
0.632
C16
C17
H18
H19
H20
H21
H22
H23
H24
H25
H26
H27
H28
H29
H30
-0.031
-0.588
0.388
0.204
0.218
0.198
0.204
0.227
0.217
0.256
0.241
0.233
0.191
0.184
0.186
H31
H32
H33
C34
C35
C36
C37
C38
C39
H40
H41
H42
H43
H44
0.207
0.200
C2
C3
0.201
C4
-0.423
-0.167
0.249
-0.026
-0.180
-0.196
-0.209
-0.204
-0.209
0.219
C5
C6
C7
-0.408
-0.369
-0.459
0.542
C8
C9
C10
O11
C12
C13
O14
O15
-0.577
-0.610
0.653
0.203
0.201
0.199
-0.615
-0.589
0.200
1
3
inefficient resonance in N1–C2–C3 bonds. The calculated C-NMR signal of
olefinic carbons in polyhydroquinoline in contrast to previous products (5a and 6g)
has not appeared in high field (Table 13), and good correlation has been found
among theoretical and experimental data.
1
23

Mild and green synthesis of tetrahydrobenzopyran…
Table 13 Calculated (dTheo.) 13C NMR chemical shifts for the compound 11a
Atom
Experimental
GIAO/DFT B3LYP/6-311??G(d,p)
dExp–dTheo
Gas phase
DMSO
C17
C12
C8
14.10
19.26
14.483
24.417
26.645
31.484
39.83
13.946
24.257
26.636
30.945
40.994
41.697
64.431
110.477
119.148
130.391
131.437
133.096
133.717
134.1
0.154
-4.997
-5.136
-3.695
-7.514
-4.817
-5.631
-4.627
-5.608
-5.411
-3.387
-4.846
-5.667
-5.850
21.50
C7
27.25
C9
33.48
C4
36.88
41.59
C16
C3
58.80
63.852
113.158
121.331
130.232
131.928
132.027
132.036
137.781
147.497
151.534
154.203
171.16
197.717
105.85
113.54
124.98
128.05
128.25
128.05
128.25
143.05
147.00
148.85
167.05
195.20
C5
C37
C36
C38
C39
C35
C2
153.716
155.261
158.416
173.626
202.67
-10.666
-8.261
-9.566
-6.576
-7.470
C6
C34
C13
C10
2
R = 0.999
dExp = 0.977 dTheo - 3.356
Experimental method
Chemicals were purchased from Merck and Acros chemical companies. All of the
products are known compounds and were identified by their physical and
spectroscopic data reported in literature. Melting points were measured by using
capillary tubes on an electro-thermal digital apparatus and are uncorrected. The
progress of reactions was monitored by thin-layer chromatography (TLC) using n-
hexane/EtOAc (3:1 v/v) as eluent. IR spectra were recorded as KBr disc on a galaxy
series FT-IR 5030 spectrometer. NMR spectra were recorded on a 300 MHz Bruker
spectrometer in DMSO-d with TMS as an internal standard.
6
Theoretical calculations were performed using the GAUSSIAN 98 package and
the Gauss-View molecular visualization program on a personal computer [27]. The
geometry optimization of the products and corresponding energy and harmonic
vibrational frequencies were calculated at 6-311??G(d,p) basis set by assuming Cs
point group symmetry [28, 29]. The absence of imaginary frequency verified that
optimized geometry for the title molecule was a true minimum on the potential
energy surface at their respective levels of theory. The natural bond orbital (NBO)
technique was performed on the optimized structures at B3LYP/6-311??G(d,p)
123

M. A. Bodaghifard et al.
level [30]. The GIAO/DFT method at B3LYP level with 6-311??G(d,p) basis set
1
was used for C chemical shifts predictions [31, 32].
3
General procedure for the synthesis of tetrahydrobenzo[b]pyrans
A mixture of an aromatic aldehyde (1 mmol), malononitrile (1 mmol), dimedone
°
(
1 mmol) and CaHPO (10 mol%) in 5 ml H O/EtOH (4:1) was heated at 80 C
4
2
with stirring for an appropriate time. After completion of the reaction was confirmed
by TLC, for catalyst removal, 10 ml ethanol was added and stirred for 5 min and
filtered. Water (5–10 ml) was added to filtration and the mixture cooled in a fridge
to give the precipitate. The solid product was filtered and washed with cold water
(
2 9 10 ml). The pure product was obtained by recrystallization from ethanol:water
4:1).
(
General procedure for the synthesis of pyrano[2,3-d]pyrimidinones
A mixture of barbituric acid (1 mmol), malononitrile (1 mmol), aromatic aldehyde
(
1 mmol), and CaHPO (10 mol%) was added to a round bottomed flask and 5 ml
4
H O/EtOH (4:1) was added to it and heated on a hot plate at 80 °C. After
2
completion of the reaction was confirmed by TLC, for catalyst removal, 10 ml
ethanol was added and stirred for 5 min and filtered. Water (5–10 ml) was added to
filtration and the mixture cooled in a fridge to give the precipitate. The solid product
was filtered and washed with cold water (2 9 10 ml). The pure product was
obtained by recrystallization from ethanol:water (4:1).
General procedure for the synthesis of polyhydroquinolines
A mixture of dimedone (1 mmol), ethylacetoacetate(1 mmol), aromatic aldehyde
(
round bottomed flask and 5 ml H O/EtOH (4:1) was added to it and heated on a hot
1 mmol), ammonium acetate (1.2 mmol) and CaHPO (10 mol%) was added to a
4
2
plate at 80 °C. After completion of the reaction was confirmed by TLC, for catalyst
removal, 10 ml ethanol was added and stirred for 5 min and filtered. Water
(5–10 ml) was added to filtration and the mixture cooled in a fridge to give the
precipitate. The solid product was filtered and washed with cold water (2 9 10 ml).
The pure product was obtained by recrystallization from ethanol:water (4:1).
Physical and spectroscopic data for selected compounds
Compound 5a (Table 2) IR (KBr) (mmax): 3393, 3317, 3185, 2958, 2196, 1687,
-
1 1
1
652, 1367 cm ; H-NMR (300 MHz, DMSO-d ): dH: 0.94 (3H, s, CH ), 1.04
6
3
(
3H, s, CH ), 2.08 (1H, d, J = 16.0 Hz, H(C-6)), 2.23 (1H, d, J = 16.0 Hz, H(C-
3
6
)), 2.50 (2H, m, CH ), 4.11 (1H, s, H-4), 7.06 (2H, br s, NH ), 7.19 (3H, m, H ),
2 2 Ar
1
3
7
.33 (2H, m, H ) ppm; C-NMR (75 MHz, DMSO-d ) dC: 26.33 (C21), 27.62
Ar
6
(
(
C22), 31.27 (C8), 35.04 (C-4), 39.83 (C7), 49.91 (C9), 60.33 (C3–CN), 113.07
C5), 118.41 (CN), 126.11 (CH ), 126.65 (2CH ), 127.52 (2CH ), 143.21 (C6),
Ar
Ar
Ar
1
23

Mild and green synthesis of tetrahydrobenzopyran…
157.73 (C2–NH ), 161.37 (C ), 195.17 (C=O) ppm; Anal. Calcd. for C H N O :
2 Ar 18 18 2 2
C, 73.45; H, 6.16; N, 9.52. Found: C, 73.61; H, 6.31; N, 9.41.
Compound 5c (Table 2) IR (KBr) (mmax): 3381, 3321, 3209, 2962, 2191, 1682,
-
1 1
1
656, 1367 cm ; H-NMR (300 MHz, DMSO-d ): dH: 0.97 (3H, s, CH ), 1.06
6
3
(
3H, s, CH ), 2.10 (1H, d, J = 16.0 Hz, H(C-6)), 2.27 (1H, d, J = 16.0 Hz, H(C-
3
6
J = 8.7 Hz, H ), 6.95 (2H, br s, NH ), 6.97 (2H, d, J = 8.7 Hz, H ) ppm; Anal.
)), 2.47–2.55 (2H, m, CH ), 2.87 (6H, s, –N(Me) ), 4.06 (1H, s, H-4), 6.66 (2H, d,
2 2
Ar
2
Ar
Calcd. for C H N O : C, 71.19; H, 6.87; N, 12.45. Found: C, 71.33; H, 6.75; N,
2
0 23 3 2
1
2.33.
Compound 5f (Table 2) IR (KBr) (mmax): 3533, 3364, 3153, 2966, 2193, 1685,
-
1 1
1
658, 1367 cm ; H-NMR (300 MHz, DMSO-d ): dH: 1.00 (3H, s, CH ), 1.06
6
3
(
3H, s, CH ), 2.11 (1H, d, J = 16.0 Hz, H(C-6)), 2.27 (1H, d, J = 16.0 Hz, H(C-
3
6
J = 8.4 Hz, H ), 7.39 (1H, d, J = 8.4 Hz, H ), 7.56 (1H, s, H ) ppm; C-NMR
)), 2.47–2.61 (2H, m, CH ), 4.70 (1H, s, H-4), 7.15 (2H, br s, NH ), 7.25 (1H, d,
2 2
1
3
Ar
Ar
Ar
(
CN), 111.8 (C5), 119.5 (CN), 128.1 (C ), 129.2 (C ), 131.9 (C ), 132.2 (C ),
75 MHz, DMSO-d ): dC: 19.0, 27.4, 28.8, 32.2, 33.1 (C7), 50.3 (C9), 56.5 (C3–
6
Ar
Ar
Ar
Ar
1
C H Cl N O : C, 59.52; H, 4.44; N, 7.71. Found: C, 59.79; H, 4.56; N, 7.63.
33.5 (C ), 141.2 (C6), 159.1 (C2–NH ), 163.8 (C ), 196.1 ppm; Anal. Calcd. for
Ar 2 Ar
1
8
16
2 2 2
Compound 5g (Table 2) IR (KBr) (mmax): 3398, 3319, 3211, 2966, 2191, 1683,
-
1 1
1
656, 1369 cm ; H-NMR (300 MHz, DMSO-d ): dH: 0.97 (3H, s, CH ), 1.06
6
3
(
3H, s, CH ), 2.12 (1H, d, J = 16.0 Hz, H(C-6)), 2.28 (1H, d, J = 16.0 Hz, H(C-
3
6
)), 2.54 (2H, m, CH ), 4.21 (1H, s, H-4), 7.13 (2H, br s, NH ), 7.15 (2H, d,
2 2
J = 8.5 Hz, H ), 7.50 (2H, d, J = 8.5 Hz, H ) ppm; Anal. Calcd. for C H
18 17-
Ar
Ar
BrN O : C, 57.92; H, 4.59; N, 7.51. Found: C, 58.11; H, 4.71; N, 7.43.
2
2
Compound 6e (Table 3) IR (KBr) (mmax): 3389, 3305, 3184, 3078, 2193, 1718,
-
1 1
1
7
1
676, 1410, 1282 cm ; H-NMR (300 MHz, DMSO-d ): dH: 4.75 (1H, s, H-5),
6
.25 (2H, br s, NH ), 7.38 (2H, s, H ), 7.57 (1H, s, H ), 11.13 (1H, br s, NH),
2
Ar
Ar
1
3
2.17 (1H, br s, NH) ppm; C-NMR (75 MHz, DMSO-d ): dC: 32.91 (C4), 56.76
6
(
(
C3–CN), 87.22 (C5), 118.74 (C:N), 127.66 (CH ), 128.81 (CH ), 132.03
Ar
Ar
CH ), 133.23 (C –Cl), 140.05 (C –Cl), 149.62 (C6), 152.87 (C=O), 152.90 (C2–
Ar
Ar
Ar
NH ), 157.94 (C=O), 162.41 (C ) ppm; Anal. calcd. for C H Cl N O : C, 47.89;
2
Ar
14
8
2 4 3
H, 2.30; N, 15.96. Found: C, 47.72; H, 2.41; N, 15.85.
Compound 6g (Table 3) IR (KBr) (mmax): 3391, 3302, 3188, 3072, 2197, 1718,
-
1 1
1
s, NH ), 7.22 (2H, d, J = 8.2 Hz, H ), 6.51 (2H, d, J = 8.2 Hz, H ) 11.12 (1H, br
674, 1408, 1280 cm ; H-NMR (DMSO-d ): dH: 4.26 (1H, s, H-5), 7.20 (2H, br
6
2
Ar
3
Ar
1
s, NH), 12.14 (1H, br s, NH) ppm C-NMR (75 MHz, DMSO-d ): dC: 35.25 (C4),
6
5
1
1
8.38 (C3–CN), 87.97 (C5), 118.95 (C:N), 119.73 (C–Br), 129.63 (2 CHAr),
31.07 (2 CH ), 143.52 (C6), 149.44 (C=O), 152.32 (C2–NH ), 157.60 (C=O),
62.40 (C ) ppm; Anal. Calcd. for C H BrN O : C, 46.56; H, 2.51; N, 15.51.
Ar
2
Ar
14
9
4 3
Found: C, 46.81; H, 2.63; N, 15.39.
Compound 11a (Table 4) IR (KBr) (mmax): 3284, 3140, 1691, 1608, 1479, 1379,
-
1
1
1
222, 1180, 1072 cm
;
H-NMR (300 MHz, DMSO-d ): dH: 1.12 (3H, t,
6
123

M. A. Bodaghifard et al.
J = 7.0 Hz, CH ), 1.87–2.27 (6H, m, CH ), 2.46 (3H, s, CH ), 3.97 (2H, q,
3
2
3
J = 7.0 Hz, CH ), 4.90 (1H, s, CH), 7.04–7.20 (5H, m, H ), 9.14 (1H, s, NH) ppm;
2
Ar
1
3
C-NMR (75 MHz, DMSO-d ): dC: 14.10, 19.26, 21.50, 27.25, 33.48, 36.88,
6
5
1
7
8.80, 105.85, 113.54, 124.98, 128.05, 128.25, 143.05, 147.00, 148.75, 167.05,
95.20 ppm; Anal. Calcd. for C H NO : C, 73.29; H, 6.80; N, 4.50. Found: C,
1
9
21
3
3.51; H, 6.85; N, 4.48.
Compound 11e (Table 4) IR (KBr) (mmax): 3288, 2962, 1699, 1610, 1485, 1381,
-
1 1
1
CH ), 1.13 (3H, t, J = 7.1 Hz, CH ), 2.14–2.50 (4H, m, CH ), 3.97 (2H, q, J = 7.1 Hz,
211, 1072 cm ; H-NMR (300 MHz, DMSO-d ): dH: 0.84 (3H, s, CH ), 1.00 (3H, s,
6
3
3
3
2
CH ), 4.84 (1H, s, CH), 7.03–7.20 (5H, m, H ), 9.07 (1H, s, NH) ppm; Anal. Calcd. for
Ar
2
C H NO : C, 74.31; H, 7.42; N, 4.13. Found: C, 74.48; H, 7.51; N, 4.06.
2
1
25
3
Compound 11 k (Table 4) IR (KBr) (mmax): 3280, 3217, 3065, 2951, 1695, 1637,
-
1
1
; H-NMR (300 MHz, DMSO-d6):
1
608, 1489, 1381, 1263, 1210, 1092 cm
dH:0.82 (3H, s, CH ), 1.00 (3H, s, CH ), 1.12 (3H, t, J = 7.0 Hz, CH ), 1.94–2.44
3
3
3
(
4H, m, CH ), 2.29 (3H, s, CH ), 3.96 (2H, q, J = 7.0 Hz, CH ), 4.82 (1H, s, CH),
2 3 2
7
6
.08–7.39 (4H, m, H ), 9.12 (1H, s, NH) ppm; Anal. Calcd. for C H BrNO : C,
Ar 21 24 3
0.29; H, 5.78; N, 3.35. Found: C, 60.41; H, 5.89; N, 3.43.
Compound 11n (Table 4) IR (KBr) (m ): 3277, 3207, 3078, 2962, 1701, 1647,
max
-
1 1
1
604, 1493, 1381, 1280, 1215, 1090 cm ; H-NMR (300 MHz, DMSO-d ): dH:
6
0
m, CH ), 2.24 (3H, s, CH ), 2.29 (3H, s, CH ), 3.96 (2H, q, J = 7.1 Hz, CH ), 4.79
.84 (3H, s, CH ), 1.00 (3H, s, CH ), 1.14 (3H, t, J = 7.1 Hz, CH ), 1.98–2.44 (4H,
3
3
3
2
3
3
2
(
C H NO : C, 74.76; H, 7.70; N, 3.96. Found: C, 74.88; H, 7.81; N, 3.81.
1H, s, CH), 6.95–7.03 (4H, m, H ), 9.03 (1H, s, NH) ppm; Anal. Calcd. for
Ar
2
2
27
3
Conclusion
In conclusion, we have demonstrated a simple and efficient method for the synthesis
of tetrahydrobenzo[b]pyran, pyrano[2,3-d]pyrimidinone and polyhydroquinoline
derivatives. The present method has many obvious advantages compared to those
reported in the previous literature, such as the avoidance of discharging harmful
organic solvents, the simplicity of the methodology and the use of a commercially
available and inexpensive catalyst. Good yields of products and reusability of
catalyst are other advantages of this methodology. Furthermore, DFT-NBO and
GIAO/DFT analysis revealed some facts and good correlation in theoretical and
experimental data for the desired products.
Acknowledgments We gratefully acknowledge the financial support of this work by the Research
Council of Arak University.
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Mild and green synthesis of tetrahydrobenzopyran…
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