Catalyst-free green synthesis of tetrahydro-benzo[b]pyrans in magnetized water: experimental aspects and molecular dynamics simulation

Article abstract of DOI:10.1007/s11164-019-03774-8

In this work, magnetized water is applied as a green-promoting medium for the catalyst-free, one-pot, practical, efficient, and environmentally benign multi-component synthesis of tetrahydrobenzo[b]pyrans. Some tetrahydrobenzo[b]pyran derivatives are synt

Full text of DOI:10.1007/s11164-019-03774-8

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03774-8
Catalyst‑free green synthesis of tetrahydro‑benzo[b]pyrans
in magnetized water: experimental aspects and molecular
dynamics simulation
Mohammad Bakherad1 · Fatemeh Moosavi2 · Ali Keivanloo1 · Rahele Doosti1 ·
Elmira Moradian1 · Mahsa Armaghan3
Received: 15 October 2018 / Accepted: 12 February 2019
© Springer Nature B.V. 2019
Abstract
In this work, magnetized water is applied as a green-promoting medium for the cat-
alyst-free, one-pot, practical, efcient, and environmentally benign multi-component
synthesis of tetrahydrobenzo[b]pyrans. Some tetrahydrobenzo[b]pyran derivatives
are synthesized by a three-component reaction of an aldehyde, malononitrile, and
1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione at room temperature.
This method ofers the advantages of short reaction time, low cost, quantitative
yield, simple work-up, and no need for an organic solvent. It is thus enviro-economic
with no dangerous wastes produced. The molecular insight on the system shows that
magnetized water has a dramatic efect on the strength of the interactions between
all organic reagents as well as an increase of a factor of 1.2 in order of the number
of hydrogen bonds between water and each organic reagent. In the presence of mag-
netized water, the reagents are more condensed in the center of the simulation box,
showing a more considerable molecular interaction leading to a more viscous sys-
tem that limits the species movements.
Keywords Magnetized water · Tetrahydrobenzo[b]pyran · Molecular dynamics
simulation · Pair correlation · Hydrogen bond
*
*
Mohammad Bakherad
m.bakherad@yahoo.com
Fatemeh Moosavi
moosavibaigi@um.ac.ir
1
2
3
Faculty of Chemistry, Shahrood University of Technology, Shahrood 3619995161, Iran
Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 91779, Iran
Chemistry Department, Science and Research Branch, Islamic Azad University, Tehran, Iran
Vol.:(0123456789)
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M. Bakherad et al.
Introduction
Tetrahydrobenzo[b]pyrans can be used as efective tools to improve pharmaco-
logical properties of drugs and a lot of natural products [1]. These derivatives
possess a number of signifcant biological roles; for instance, they have anti-
anaphylactic, spamolytic, anti-bacterial, anti-cancer, anti-oxidant, and anti-HIV
activities [2–4]. Various procedures have been suggested for the synthesis of
tetrahydro-4H-benzopyran derivatives [5–14]. These methods, however, have a
number of drawbacks such as high reaction temperature, long reaction time, use
of catalysts, and use of harmful organic solvents.
From the environmental and economic viewpoints, it is advisable to keep away
from the utilization of dangerous and costly organic solvents. The utilization of
water as the solvent shows valuable gains because it is very polar and thus immis-
cible with a majority of organic compounds. Therefore, water-soluble by-prod-
ucts stay and isolation of the organic materials is easy [15, 16]. Some chemical
reactions have been carried out in the presence of water, and this medium has
been reported to increase the reactivity and stereoselectivity of these reactions
[17–19]. However, most chemical reactions could not be carried out in water as a
solvent.
Since the 1950s, we have known that an applied magnetic feld can afect the
properties of water such as light absorbance, pH, zeta potential, conductivity, and
surface tension [20–23] even if the treatment time is short and the magnetic fux
density is not high [24]. A permanent external magnet can be installed on a pre-
viously established water tube system, resulting in no additional energy require-
ment for water magnetization. This green technology is clean and has zero energy
consumption. Pure water, as a polar and associative liquid, can modify its inter-
molecular interactions in an applied magnetic feld, changing to a metastable
state and keeping that state for some time [25]. Based on the Mosin theory [26,
27], the applied magnetic feld directly afects the structure of water due to the
dipole polarization of water molecules. These molecules are bound together via
low-energy intermolecular Van der Waals forces, dipole–dipole interactions, and
hydrogen bonding. The applied magnetic feld can deform the hydrogen bonds
and give rise to some partial ruptures. In this regard, we have reported the multi-
component reactions carried out in magnetized water [28–32].
As another consideration, molecular dynamics (MD) simulation as a powerful
tool allows a general understanding of the molecular structure and molecular level
dynamics. Such valuable information is often desirable to go beyond the generic
models and a reliable prediction of physical properties and molecular organiza-
tions. Even if these predictive calculations have been judged not feasible, a com-
bination of quantum mechanics calculations (to get molecular geometry, internal
torsional potentials, and partial charges) to completely defne a force feld, and
of MD simulation performed on sufciently large samples, and long-time scales
can, in principle, provide the desired answers. In this context, recently, predicting
the magnetized solvent efect on the structural properties have shown that mag-
netization plays a main role in the reaction yield, structure, dynamics, and size
1 3

Catalyst-free green synthesis of tetrahydro-benzo[b]pyrans…
and shape of the nanomaterials [33–38]. Considering all these results, it would be
nice to have a deep insight into the above-mentioned reaction by MD simulation.
Herein, we wish to report a catalyst-free, simple, and green synthetic method for
the synthesis of tetrahydro benzo[b]-pyrans in magnetized water (Scheme 1). Fur-
thermore, the efect of magnetized water on the synthesis of tetrahydrobenzo[b]
pyran derivatives was investigated by theoretical studies.
Results
The choice of an appropriate reaction medium is of crucial importance for a success-
ful synthesis. Firstly, we studied the three-component reaction of 1,3-cyclohexanedi-
one 1a (1.0 mmol), benzaldehyde 2a (1.0 mmol), and malononitrile 3 (1.0 mmol)
at 25 °C in several solvents including toluene, DMF, CH3CN, CH2Cl2, CHCl3,
1,4-dioxane, MeOH, EtOH, and H2O (Table 1). As shown in this table, the yield of
product 4a was susceptible to the change in the polarity of the solvent. Among all
these solvents, water was found to be the most suitable one with respect to the reac-
tion yield (Table 1, entry 10). This efect can be attributed to the existence of strong
hydrogen bond interactions at the organic phase-water interface, which stabilizes the
reaction intermediate [39].
Then we attempted to optimize the reaction conditions using magnetized solvents
in order to improve the yield of the target product 4a. Magnetized solvents were
prepared using a static magnetic system of 0.8 T feld strength at diferent magnetic
feld time exposures (Fig. 1). The solvent (5 mL) was put in a test tube, which was
then put in the magnetic feld for 5 min. The tube was subsequently removed from
the instrument and used for the reaction.
Similarly, the above model reaction was carried out in the magnetized solvents
with a magnetization time of 5 min. As indicated in Table 2, tetrahydrobenzo[b]
pyran 4a was not formed in non-polar magnetized solvents (Table 2, entry 1), and
even magnetized polar solvents were unable to produce the desired 4a in an accept-
able yield (Table 2, entries 2–7). Moreover, when the reaction was carried out in
magnetized methanol and magnetized ethanol, as polar protic solvents, the target
product 4a was obtained in a low yield (Table 2, entries 8 and 9) even after the
reaction time was prolonged to 2 h. Surprisingly, when magnetized water was used
as the solvent (Table 2, entry 10), the product 4a was obtained in an excellent yield
(98%) and with a short reaction time (10 min). It seems that magnetized water is a
suitable solvent with respect to the reaction yield of 4a.
O
O
R2
O
CN
Magnetized water
Catalyst-free, 25 oC
CN
CN
R2CHO
+
+
R1
R1
O
NH2
R1
R1
1
2
3
4
Scheme 1 Three-component synthesis of tetrahydrobenzo [b]pyrans 4 in magnetized water
1 3

M. Bakherad et al.
Table 1 Model reaction, conditions and yield
O
O
R2
O
CN
CN
CN
R2CHO
+
+
O
NH2
Entry
Solvent
Yield (%)a
1
2
3
4
5
6
7
8
9
10
Toluene
DMF
CH3CN
CH2Cl2
CHCl3
THF
1,4-dioxane
MeOH
EtOH
–
–
–
–
–
5
5
12
10
20
H2O
Reaction conditions: 1,3-cyclohexanedione 1a (1.0 mmol), benzaldehyde 2a (1.0 mmol), malononitrile 3
(1.0 mmol), solvent (3 mL), 25 °C, for 2 h
aIsolated yield
Fig. 1 Pilot for solvent magneti-
zation apparatus
50 mm
40 mm
15 mm
Based on the results obtained (Table 2, entry 10), we attempted to optimize the
reaction conditions using magnetized water, which could help to lower the reaction
time and improve the product yield. As indicated in Table 3, the magnetization time
plays a critical role in obtaining a high-yield product 4a. With increase in the water
1 3

Catalyst-free green synthesis of tetrahydro-benzo[b]pyrans…
Table 2 Synthesis of 4a in
magnetized solvents under
various conditions
Entry
Magnetized solvents
Yield (%)a
1
2
3
4
5
6
7
8
Toluene
DMF
CH3CN
CH2Cl2
CHCl3
THF
1,4-dioxane
MeOH
EtOH
–
15
10
10
12
21
24
45
40
98
9
10b
H2O
Reaction conditions: 1,3-cyclohexanedione 1a (1.0 mmol), benzalde-
hyde 2a (1.0 mmol), malononitrile 3 (1.0 mmol), magnetized water
(3 ml), magnetization time (5 min), 25 °C, 2 h
aIsolated yield
bReaction time 10 min
Table 3 The synthesis of
tetrahydrobenzo[b]pyran 4a
under various conditions
Entry
Magnetization time Reaction time
Yield (%)a
(min)
(min)
1
2
3
4
2
5
10
20
10
5
60
98
97
98
5
30
Reaction conditions: 1,3-cyclohexanedione 1a (1.0 mmol), benzalde-
hyde 2a (1.0 mmol), malononitrile 3 (1.0 mmol), magnetized water
(3 ml)
aIsolated yield
magnetization time from 2 to 10 min, the product 4a was obtained in a shorter time
and with more yield (Table 3, entries 1–3). The best reaction yield was found to be
in water magnetized in 5 min and for a reaction time of 10 min (Table 3, entry 2).
Increasing the reaction time did not improve the reaction yield (Table 3, entry 4).
One should pay attention to this fact that in the synthesis of tetrahydrobenzo[b]
pyran derivatives via a one-pot three-component condensation reaction between car-
bonyl compounds, the compounds having reactive α-methylene groups and alkyl-
malonates undergo reactions in the presence of acids or bases or a metal-containing
catalyst with the assistance of organic solvents or ionic liquids [40, 41]. Clearly, syn-
thesis through these reported procedures not only leaves behind a lot of inorganic or
organic wastes during the work-up process but also is troubled with the complication
of carrying away trace amounts of the residue metal species from the target com-
pound when it is used in pharmaceutical synthesis.
Conducting the model reaction in magnetized water not only afords a high
reaction yield but also keeps away (1) production of harmful wastes, (2) use of
1 3

M. Bakherad et al.
a great amount of organic solvent or catalyst, and (3) boring post-treatment. We,
therefore, believe that our proposed system is an appealing policy for the synthe-
sis of the product from the green synthesis viewpoint.
The scope and generality of the process was then explored using the condi-
tions stated in Table 3 (entry 2). As shown in Table 4, various aromatic aldehydes
containing electron-withdrawing substituents, electron-donating substituents,
and halogens on their aromatic rings, hetero-aromatic and aliphatic aldehydes
were utilized successfully in the reaction, and the corresponding products were
obtained in high-to-excellent yields in short reaction times. Aromatic aldehydes
having electron-withdrawing groups (Table 4, entries 13–15 and 33–35) reacted
at faster rates compared to those with electron-donating groups (Table 4, entries
2–4 and 22–24). Furthermore, furfural, which is known as an acid-sensitive spe-
cies, was proved to be applicable in magnetized water (Table 4, entries 16 and
36), indicating the usefulness of our methodology. Also, aliphatic aldehydes such
as propanal, butanal, and 3-methyl butanal were applicable in this system, and the
products were obtained in high yields (Table 4, entries 18–20 and 38–40).
It was also crystallized from ethanol in the form of white needles, and was
characterized by single crystal X-ray crystallography. This analysis showed that
it was crystallized in the monoclinic system with space group C, and there were
also four molecules present in each unit cell. Figure 2 shows a perspective view
of the molecular structure of 4k.
Notably, at the beginning of the reactions, a solution that seemed to be nearly
transparent was observed because both the aldehyde and 1,3-dicarbonyl com-
pounds were soluble in magnetized water. The latter formed a product, which was
found to be insoluble in magnetized water. At the end of the reaction, a large
amount of the solid product was formed. This made stirring of the reaction mix-
ture difcult (Fig. 3).
A comparative study of the reaction conditions for the synthesis of
tetrahydrobenzo[b]pyran 4a using the methods given in Table 5 and reported in
the present letter demonstrates that the proposed protocol is actually better than
several other ones. Most of the listed methodologies sufer from some limita-
tions like the long reaction times, high reaction temperatures, and use of cata-
lysts. Preparation of tetrahydrobenzo[b]pyran was performed in the presence of
catalysts (Table 5, entries 1–9). Additionally, the present protocol is efective in
the catalyst-free synthesis of tetrahydrobenzo[b]pyran 4a in 10 min at room tem-
perature (Table 5, entry 13). The same transformation requires 3.5 h and 24 h for
completion using water at 100 °C and room temperature, respectively (Table 5,
entries 10–12).
Mechanistically, 1,3-cyclohexandione (I) was converted to its corresponding
enolate form (II) in the presence of magnetized water. Magnetized water plays a
major role in its promoting activity for the formation of phenylidenemalononitrile
III, which is readily prepared in situ by the Knoevenagel condensation of benzal-
dehyde 2a with the highly active CH acidic malononitrile 3. Finally, the Michael-
type addition of the enolate form II to phenylidenemalononitrile III followed by
cyclization and tautomerization yielded tetrahydrobenzo[b]pyran 4a (Scheme 2).
1 3

Catalyst-free green synthesis of tetrahydro-benzo[b]pyrans…
Table 4 Synthesis of tetrahydrobenzo[b]pyrans 4
O
R2
O
O
Magnetized water, 25 oC
CN
CN
CN
R2CHO
+
+
R1
R1
NH2
O
R1
R1
1
2
3
4
Entry R1 R2
Product Time (min) Yield (%)a MP (°C) (Lit)[References]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
10
20
20
30
10
30
10
20
5
10
10
5
5
5
98
94
92
90
95
94
90
95
98
97
98
95
97
93
98
92
98
92
93
92
98
93
90
89
98
95
92
98
99
98
97
96
213–215 (213–215) [5]
230–233 (232–233) [5]
197–199 (200–201) [6]
195–197 (198–200) [7]
244–245
4-Me-C6H4-
2-MeO-C6H4-
4-MeO-C6H4-
3,5-(OMe)-OH-C6H2
2,3,4-(OMe)3-C6H2
4-Me2N-C6H4
2-Cl-C6H4-
193–195
165–167 (168–170) [8]
212–214 (209–211) [9]
240–242 (241–243) [10]
221–223 (225–227) [9]
240–242
9
4-Cl-C6H4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
2,4-Cl2-C6H3-
2,6-Cl2-C6H3-
4-Br-C6H4-
2-NO2-C6H4-
3-NO2-C6H4-
4-NO2-C6H4-
2′-furanyl
2′-thiophenyl
CH3CH2-
CH3CH2CH2-
(CH3)2CHCH2-
4j
4k
4l
238–240 (241–242) [7]
195–198 (196–198) [6]
218–220 (221–223) [7]
234–236 (234–236) [7]
197–198 (199–200) [6]
208–209 (204–205) [9]
179–181 (180–182) [10]
183–185 (188–190) [10]
150–153 (155–157) [11]
229–230 (226–228) [5]
208–210 (210–213) [7]
190–194 (194–196) [12]
200–203 (201–202) [7]
191–193 (189–192) [13]
198–200 (200–202) [13]
213–215 (217–218) [12]
190–192 (191–192) [7]
213–216 (213–215) [5]
200–202 (192–194) [12]
249–250 (250–252) [12]
195–197 (196–198) [7]
4m
4n
4o
4p
4q
4r
4 s
4t
4u
4v
4w
4x
5
10
10
20
25
20
7
15
15
20
10
20
10
15
5
Me Ph
Me 4-Me-C6H4-
Me 2-MeO-C6H4-
Me 4-MeO-C6H4-
Me 3,5-(OMe)2-4-OH-C6H2 4y
Me 2,3,4-(OMe)3-C6H2
Me 4-Me2N-C6H4
Me 2-Cl-C6H4-
4z
4aa
4ab
4ac
4ad
4ae
4af
Me 4-Cl-C6H4-
Me 2,4-Cl2-C6H3-
Me 2,6-Cl2-C6H3-
Me 4-Br-C6H4-
10
10
5
1 3

M. Bakherad et al.
Table 4 (continued)
Entry R1 R2
Product Time (min) Yield (%)a MP (°C) (Lit)[References]
33
34
35
36
37
38
39
40
Me 2-NO2-C6H4-
4ag
4ah
4ai
4
5
4
10
10
20
25
20
99
90
98
98
97
96
92
90
230–232 (233–234) [7]
199–201 (204–205) [7]
180–182 (175–177) [7]
203–205 (201–203) [6]
222–224 (220–222) [5]
174–178 (179–180) [14]
188–190 (192–194) [14]
152–154 (156–157) [11]
Me 3-NO2-C6H4-
Me 4-NO2-C6H4-
Me 2′-furanyl
Me 2′-thiophenyl
Me CH3CH2-
Me CH3CH2CH2-
Me (CH3)2CHCH2-
4aj
4ak
4al
4am
4an
Reaction conditions: 1,3-cyclohexanedione or dimedone (1.0 mmol), an aldehyde (1.0 mmol), malononi-
trile (1.0 mmol), magnetization time (5 min), magnetized water (3 mL), 25 °C
aIsolated yield
Discussion
The details of the MD simulation at 300 K can be found elsewhere [32]. The struc-
ture and atomic label for each organic compound is given in Fig. 4. As the fgure
demonstrates, it is possible to face with diferent hydrogen bonds. Notice that the
hydrogen bond (HB) plays the main role in the presence of magnetization [33–38].
As a result, the present study concentrates on the pair correlations that are related to
the HB directly.
According to the mechanism proposed, Scheme 2, the interactions between water
and each organic material has a considerable efect on the reaction. Interestingly, the
results of MD are in accordance with the experimental results. See Fig. 5 for more
details.
According to the fgure, it can be understood that an intermolecular hydrogen
bond has a great efect on the reaction. The strongest interactions are observed
between water and 1,3-cyclohexanedione (HW…O_M) as well as water and benzal-
dehyde (HW…O_MB) whilst the weakest interaction occurs between the water and
alkyl side of 1,3-cyclohexanedione (OW…H_C). However, the intensity of interac-
tion between water and the aldehyde group of the benzaldehyde is lower than that of
water with 1,3-cyclohexanedione. It means that the interaction between malononi-
trile and water is not as important as the other organics. On the other hand, magnet-
ized water owes a stronger interaction with benzaldehyde than 1,3-cyclohexanedi-
one. It can be also stated that the water plays a crucial role in the reaction if it is
magnetized.
Considering the number of water molecules around each organic compound dem-
onstrates that 1,3-cyclohexanedione is a neighbor with one water molecule at a dis-
tance of 2.375 Å, whereas it increases to 1.2 of the number of water molecules, on
average, at the presence of magnetized water, i.e., the number of water molecules
surrounding 1,3-cyclohexanedione enhances by magnetized solvent. In addition,
noticeably, the number of water molecules near malononitrile by magnetization
increases by one. However, the number of water molecules around the benzaldehyde
1 3

Catalyst-free green synthesis of tetrahydro-benzo[b]pyrans…
Fig. 2 ORTEP representation of 4k. Displacement ellipsoids are drawn at 50% probability level, and H
atoms are shown as small spheres of arbitrary radii. CCDC 1527544 contains supplementary crystallo-
graphic data for this article
reagent does not show any signifcant change. On the other hand, the interactions
between all organic reagents enjoy a considerable growth. The number of hydrogen
bonds due to water and each organic reagent shows a rise of about 1.2 times. This
sustainable result has also been verifed with the mechanism proposed.
In order to have a deep insight into the interaction of organics with each other in
the presence and absence of magnetized solvent, the pair correlation functions were
studied. The results are summarized in Table 6.
1 3

M. Bakherad et al.
Fig. 3 Progress of the reaction between 4-nitrobenzaldehyde, malononitrile, and 1,3- cyclohexanedi-
one in magnetized water without any catalyst. [a Beginning of the reaction; b after 2 min of reaction at
25 °C; c the end of the reaction]
Table 5 Comparison between results obtained for the proposed method and those reported for some
other reported ones in the preparation of 4a
Entry
Catalyst
Reaction conditions
Time
Yield (%)
[Refer-
ences]
1
2
3
4
5
6
7
8
Lipase
Na2CO3
LiBr
Fe3O4@SiO2@TiO
SiO2 NPs
MNP@PDMA
Amino-β-cyclodextrin
Fe3O4@SiO2
Nano γ-Fe2O3
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free This work
EtOH/H2O (4:1), 35 °C
Ball milling, RT
H2O, Refux
Solvent-free, 95 °C
EtOH, RT
H2O, RT
Solvent-free, RT
H2O, 80 °C
H2O, RT
Glycerol, 80 °C
H2O, 100 °C
H2O, RT
Magnetized water
1 h
94 [6]
99 [7]
91 [9]
93 [12]
88 [13]
95 [42]
95 [43]
90 [44]
93 [45]
93 [5]
99 [46]
75 [47]
98
10 min
15 min
20 min
30 min
25 min
1 h
25 min
6 h
1 h
9
10
11
12
13
3.5 h
24 h
10 min
According to Table 6, the interactions are stronger, except for H_1B…H_C
that is observed at a longer distance as well as lower intensity. Noticeably, all
correlations are wider with some shoulders due to magnetized water. It can con-
frm the mechanism that the interactions between the reagents is invigorated by
1 3

Catalyst-free green synthesis of tetrahydro-benzo[b]pyrans…
H
H
O
H
H
O
H
O
O
H
O
O
H
O
I
II
H
H
H
O
H
H
O
H
H
O
H
H
H
H
O
H
H
O
O
H
H
CN
CN
H
O
HO
+
CN
H
NC
CN
Ph
H
-H2O
Ph
Ph
CN
III
H
H
H
O
O
H
O
Ph
O
Ph
O
O
Ph
H
H
CN
NH2
CN
NH
CN
H
O
O
N
O
O
H
H
4a
H
Scheme 2 Plausible mechanism for synthesis of tetrahydrobenzo[b]pyran 4a
magnetized water. Furthermore, 1,3-cyclohexanedione and malononitrile interac-
tions are intensifed due to the presence of magnetized water.
The results of the density profle also confrm that the reagents are more con-
centrated in the center of the simulation box by applying magnetized water. See
Fig. 6 for more details.
Based on Fig. 6, the number of reagents in a special position of the z direc-
tion increases as the magnetized water is added that is in accordance with the
more and stronger interactions between the molecules additionally to the more
viscous system that limits the species movements.
1 3

M. Bakherad et al.
Fig. 4 The structure and atomic label of the target organics
(A)
(B)
1.6
1.4
1.2
1
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
H_AB OW
H_1B OW
O_MB HW
O_M HW
N_Y HW
H_AB OW
H_1B OW
O_MB HW
O_M HW
N_Y HW
H_C OW
H_C OW
H_Cm OW
H_Cm OW
0
3
6
9
12
15
0
3
6
9
12
15
r (Å)
r (Å)
Fig. 5 Radial distribution function between atoms of 1,3-cyclohexanedione, benzaldehyde, and malon-
onitrile and water. a Unmagnetized water; b magnetized water
Conclusion
A practical, green, simple, short, and convenient method was proposed for the prepa-
ration of tetrahydrobenzo[b]pyran derivatives in magnetized water. This new process
provides an opportunity to use magnetized water and avoids the use of environmentally
1 3

Catalyst-free green synthesis of tetrahydro-benzo[b]pyrans…
Table 6 Intensity and position
Interaction type
Unmagnetized water
Magnetized water
of the frst peak of radial
distribution function between
atoms of 1,3-cyclohexanedione,
benzaldehyde, and malononitrile
Position
Intensity
Position
Intensity
H_1B…C_T
H_1B…H_C
H_1B…N_Y
O_M…C_Y
O_M…N_Y
3.575
2.625
2.125
3.375
3.525
13.225
11.129
7.740
9.140
10.460
3.475
2.675
2.675
3.575
3.375
9.590
5.403
20.659
10.920
15.810
(A)
(B)
C_B
C_B
O_MB
O_M
C_Tm
C_Y
O_MB
0.004
0.004
O_M
C_Tm
C_Y
0.003
0.003
0.002
0.001
N_Y
N_Y
0.002
0.001
0
0
-15
-10
-5
0
5
10
15
-15
-10
-5
0
5
10
15
z (Å)
z (Å)
Fig. 6 Density profle of 1,3-cyclohexanedione, benzaldehyde, and malononitrile versus z direction. a
Unmagnetized water; b Magnetized water
harmful conventional organic solvents, wide scope of substrates, high reaction yield,
short reaction time, cleaner reaction profle, easy workup, and reduced waste produc-
tion by the lack of a catalyst or an additive agent. Moreover, the proposed method can
be used in a large-scale synthesis. Noticeably, the classical investigation confrms that
the intermolecular interaction is enhanced due to applying magnetized water. In the
presence of treated water, the organic reagents hydrogen bonds increase as well as their
interaction with water. The number of hydrogen bonds levels up by a factor of 1.2 and
the compactness of compounds by magnetization demonstrates that the reagents are
located at a near distance from each other to have a chance for interaction with each
other through water. On the other hand, all the correlations would be greater in the pres-
ence of magnetized water that can confrm the mechanism proposed experimentally.
Experimental
Preparation of magnetized water
In order to prepare a magnetized water sample according to Fig. 1, 5 mL distilled
water was frst put in a test tube, which was then put between two neodymium
1 3

M. Bakherad et al.
magnets NdFeB (10 cm×5 cm×4 cm) with a magnetic feld of 0.8 T. The test tube
was subsequently removed from the instrument and used for the reaction.
General procedure for synthesis of tetrahydrobenzo[b]pyran (5a–an) To
a
10-mL round-bottomed fask containing magnetized water (3 mL) were added a
1,3-dicarbonyl compound (1.0 mmol), an aldehyde (1.0 mmol), and malononitrile
(1.0 mmol). The reaction mixture was left at 25 °C and monitored by the thin layer
chromatography (TLC) technique. After completion of the reaction, the precipitate
thus formed was fltered and subsequently washed with ethanol to aford the desired
product (Table 5).
2‑Amino‑3‑cyano‑4‑phenyl‑5‑oxo‑4H‑5,6,7,8‑tetrahydrobenzo[b]pyran (4a) R(KBr)
υmax 3431, 3310, 2185, 1633, 1626, 1518, 1375, 1257, 1137 cm−1; 1H NMR
(DMSO-d6, 300 MHz) δ 1.95 (s, 2H, CH2), 2.22–2.27 (m, 2H, CH2), 2.62 (s, 2H,
CH2), 4.18 (s, 1H, CH), 7.00 (s, 2H, NH2), 7.14–7.20 (m, 3H, Ar–H), 7.26–7.31
(m, 2H, Ar–H); MS (EI), m/z [M]+ 266; Anal. Calcd. for C16H14N2O2: C, 72.16; H,
5.30; N, 10.52. Found: C, 72.33; H, 5.38; N, 10.66.
2‑Amino‑3‑cyano‑4‑(4‑hydroxy‑3,5‑dimethoxyphenyl)‑5‑oxo‑4H‑5,6,7,8‑tetrahydro‑
1
benzo[b] pyran (4e) IR (KBr) υmax 3395, 3311, 2188, 1646, 1518 cm−1; H NMR
(DMSO-d6, 300 MHz) δ 1.90–1.96 (m, 2H, CH2), 2.30 (d, J=5.4 Hz, 2H, CH2),
2.63 (d, J=5.1 Hz, 2H, CH2), 3.78 (s, 6H, OCH3), 4.13 (s, 1H, CH), 6.37 (s, 2H,
Ar–H), 6.95 (s, 2H, NH2), 8.24 (s, 1H, OH); 13C NMR (DMSO-d6, 75 MHz) δ
20.3 (CH2), 26.9 (CH2), 35.6 (CH2), 36.9 (CH), 56.4 (OCH3), 58.9 (OCH3), 105.0
(C=C), 114.3 (CN), 120.3 (Ar), 134.9 (Ar), 135.3 (Ar), 148.2 (Ar), 158.8 (=C–O),
164.7 (=C–O), 196.4 (C=O); MS (EI), m/z [M]+ 342; Anal. Calcd. for C18H18N2O5:
C, 63.15; H, 5.30; N, 8.18. Found: C, 63.35; H, 5.39; N, 8.01.
2‑Amino‑3‑cyano‑4‑(2,3,4‑trimethoxyphenyl)‑5‑oxo‑4H‑5,6,7,8‑tetrahydrobenzo[b]
pyran (4f) IR (KBr) υmax 3413, 3301, 3174,2954, 2185, 1658, 1637, 1600, 1494,
1
1460, 1400, 1369, 1280, 1089, 1001, 790 cm−1; H NMR (DMSO-d6, 300 MHz)
δ 1.88–1.97 (m, 2H, CH2), 2.22–2.30 (m, 2H, CH2), 2.60 (t, J=5.4 Hz, 2H, CH2),
3.74 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.04 (s, 1H, CH), 6.69
(d, J=10.5 Hz, 1H, Ar–H), 6.72 (d, J=10.5 Hz, 1H, Ar–H), 6.87 (s, 2H, NH2); 13
C
NMR (DMSO-d6, 75 MHz) δ 20.3 (CH2), 26.9 (CH2), 30.5 (CH2), 36.8 (CH), 56.1
(OCH3), 58.5 (OCH3), 60.6 (OCH3), 61.1 (C=C), 108.1 (C=C), 114.1 (CN), 120.4
(Ar), 123.4 (Ar), 130.6 (Ar), 141.8 (Ar), 151.5 (Ar), 152.5 (Ar), 159.1 (=C–O),
164.9 (=C–O), 196.2 (C=O); MS (EI), m/z [M]+ 356; Anal. Calcd. for C19H20N2O5:
C, 64.04; H, 5.66; N, 7.86. Found: C, 64.26; H, 5.75; N, 7.69.
2‑Amino‑3‑cyano‑4‑(2,6‑dichlorophenyl)‑5‑oxo‑4H‑5,6,7,8‑tetrahydrobenzo[b]pyr1an
(4k) IR (KBr) υmax 3462, 3321, 2209, 1633, 1606, 1508, 1398, 1267 cm−1; H
NMR (DMSO-d6, 300 MHz) δ 1.93–2.01 (m, 2H, CH2), 2.22–2.29 (m, 2H, CH2),
2.51–2.58 (m, 2H, CH2), 5.22 (s, 1H, CH), 7.13 (s, 2H, NH2), 7.24 (t, J=7.8 Hz,
1H, Ar–H), 7.35 (d, J=7.5 Hz, 1H, Ar–H), 7.45 (d, J=7.8 Hz, 1H, Ar–H); 13C
1 3

Catalyst-free green synthesis of tetrahydro-benzo[b]pyrans…
NMR (DMSO-d6, 75 MHz) δ 20.3 (CH2), 26.9 (CH2), 32.7 (CH2), 36.7 (CH), 53.9
(C=C), 111.4 (C=C), 119.4 (CN), 128.9 (Ar), 129.3 (Ar), 130.7 (Ar), 134.7 (Ar),
136.2 (Ar), 136.8 (Ar), 159.6 (=C–O), 166.0 (=C–O), 196.2 (C=O); MS (EI), m/z
[M]+ 334; Anal. Calcd. for C16H12Cl2N2O2: C, 57.33; H, 3.61; N, 8.36. Found: C,
57.50; H, 3.51; N, 8.19.
2‑Amino‑3‑cyano‑4‑ethyl‑5‑oxo‑4H‑5,6,7,8‑tetrahydrobenzo[b]pyran (4r) IR (KBr)
υmax 3400, 3320, 2183, 1675, 1650, 1600, 1380 cm−1; 1H NMR (DMSO-d6,
300 MHz) δ 0.773 (m, 3H, CH3), 1.37–1.53 (m, 2H, CH2), 1.88–1.96 (m, 2H, CH2),
2.34 (d, J=5.7 Hz, 2H, CH2), 2.51 (m, 2H, CH2), 3.18 (s, 1H, CH), 6.91 (s, 2H,
NH2); MS (EI), m/z [M]+ 218; Anal. Calcd. for C12H14N2O2: C, 66.04; H, 6.47; N,
12.84. Found: C, 66.22; H, 6.38; N, 12.69.
5‑Oxo‑4H‑5,6,7,8‑tetrahydrobenzo[b] pyran (4w) IR (KBr) υmax 3375, 3321, 3186,
1
2962, 2192, 1683, 1654, 1510, 1369 cm−1; H NMR (DMSO-d6, 300 MHz) δ 0.97
(s, 3H, CH3), 1.05 (s, 3H, CH3), 2.06 (d, J=16.2 Hz, 1H, CH2), 2.26 (d, J=16.2 Hz,
1H, CH2), 2.48 (s, 2H, CH2), 3.75 (s, 3H, OCH3), 4.48 (s, 1H, CH), 6.85 (s, 1H,
Ar–H), 6.88 (s, 2H, NH2), 6.94–7.01 (m, 2H, Ar–H), 7.17 (t, J=7.2 Hz, 1H, Ar–H);
MS (EI), m/z [M]+ 324; Anal. Calcd. for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64.
Found: C, 70.52; H, 6.30; N, 8.81.
2‑Amino‑3‑cyano‑4‑(4‑bromophenyl)‑7,7‑dimethyl‑5‑oxo‑4H‑5,6,7,8‑
tetrahydrobenzo[b]pyran1(4af) IR (KBr) υmax 3504, 3312, 3168, 2208, 1673, 1641,
1378, 1281, 1097 cm−1; H NMR (DMSO-d6, 300 MHz) δ 1.04 (s, 3H, CH3), 1.07
(s, 3H, CH3), 2.10 (d, J=16.2 Hz, 1H, CH2), 2.26 (d, J=16.2 Hz, 1H, CH2), 2.51
(s, 2H, CH2), 4.19 (s, 1H, CH), 7.09 (s, 2H, NH2), 7.13 (d, J=6.6 Hz, 2H, Ar–H),
7.49 (d, J=6.6 Hz, 2H, Ar–H); 13C NMR (DMSO-d6, 75 MHz) δ 27.3 (CH3), 28.7
(CH3), 32.2 (CH2), 35.6 (CH), 50.4 (CH2), 58.1 (CH2), 79.6 (C=C), 112.7 (CN),
120.0 (Ar), 130.0 (Ar), 131.6 (Ar), 144.6 (Ar), 158.9 (=C–O), 163.1 (=C–O), 196.1
(C=O); MS (EI), m/z [M]+ 372; Anal. Calcd. for C18H17BrN2O2: C, 57.92; H, 4.59;
N, 7.51. Found: C, 57.74; H, 4.50; N, 7.70.
2‑Amino‑3‑cyano‑4‑(2‑nitrophenyl)‑7,7‑dimethyl‑5‑oxo‑4H‑5,6,7,8‑tetrahydrob
enzo[b]‑pyran (4ag) IR (KBr) υmax 3406, 3325, 3182, 3080, 2964, 2190, 1681,
1519, 1367 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ 0.88 (s, 3H, CH3), 1.02 (s, 3H,
CH3), 2.02 (d, J=16.2 Hz, 1H, CH2), 2.21 (d, J=16.2 Hz, 1H, CH2), 2.49 (s, 2H,
CH2), 4.94 (s, 1H, CH), 7.22 (s, 2H, NH2), 7.38 (t, J=8.7 Hz, 1H, Ar–H), 7.44 (d,
J=6.6 Hz, 1H, Ar–H), 7.67 (t, J=7.5 Hz, 1H, Ar–H), 7.44 (t, J=8.1 Hz, 1H, Ar–H);
MS (EI), m/z [M]+ 339; Anal. Calcd. for C18H17N3O4: C, 63.71; H, 5.05; N, 12.38.
Found: C, 63.53; H, 5.15; N, 12.52.
2‑Amino ‑3‑ c yano ‑4‑(thiophen‑2‑yl)‑7, 7‑ dimethyl‑5‑ oxo ‑4H‑5, 6, 7, 8‑
tetrahydrobenzo[b]‑ pyran (4ak) IR (KBr) υmax 3384, 3132, 2964, 2198, 1676,
1662, 1637, 1400, 1384, 1215, 1110, 1004, 854 cm−1; 1H NMR (DMSO-d6,
300 MHz) δ 0.99 (s, 3H, CH3), 1.05 (s, 3H, CH3), 2.15 (d, J=16.2 Hz, 1H,
1 3

M. Bakherad et al.
CH2), 2.37 (d, J=16.2 Hz, 1H, CH2), 2.46 (s, 2H, CH2), 4.54 (s, 1H, CH), 6.88
(d, J=9.6 Hz, 1H, thiophene), 6.92 (d, J=3.6 Hz, 1H, thiophene), 7.13 (s, 2H,
NH2), 7.33 (d, J=4.5 Hz, 1H, thiophene); MS (EI), m/z [M]+ 300; Anal. Calcd. for
C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33. Found: C, 63.80; H, 5.28; N, 9.49.
Acknowledgements We gratefully acknowledge the fnancial support of the Research Council of the
Shahrood University of Technology.
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