Synthesis of 1H-isochromenes, 4H-chromenes, and ortho-aminocarbonitrile tetrahydronaphthalenes from the same reactants by using metal-free catalyst

Article abstract of DOI:10.1002/jhet.3742

A facile and rapid multicomponent synthesis of pharmaceutically diverse 1H-isochromenes, 4H-chromenes, and ortho-aminocarbonitrile tetrahydronaphthalenes has been developed from benzaldehyde, malononitrile, and cyclohexanone. Three different methods from the same reactants, solvent, temperature, and catalyst lead to three products with excellent yields. All the reactions were followed with the Michael addition and cyclization. In this study, morpholine was used as an active metal-free base catalyst that increases the yields of products and decreases the time of reactions.

Full text of DOI:10.1002/jhet.3742

Received: 17 July 2019
DOI: 10.1002/jhet.3742
Revised: 25 August 2019
Accepted: 27 August 2019
A R T I C L E
Synthesis of 1H-isochromenes, 4H-chromenes, and ortho-
aminocarbonitrile tetrahydronaphthalenes from the same
reactants by using metal-free catalyst
Hossein Naeimi
| Somaye Mohammadi
Department of Organic Chemistry,
Abstract
Faculty of Chemistry, University of
Kashan, Kashan, Iran
A facile and rapid multicomponent synthesis of pharmaceutically diverse 1H-
isochromenes, 4H-chromenes, and ortho-aminocarbonitrile tetrahydronaph-
thalenes has been developed from benzaldehyde, malononitrile, and
cyclohexanone. Three different methods from the same reactants, solvent, tem-
perature, and catalyst lead to three products with excellent yields. All the reac-
tions were followed with the Michael addition and cyclization. In this study,
morpholine was used as an active metal-free base catalyst that increases the
yields of products and decreases the time of reactions.
Correspondence
Hossein Naeimi, Department of Organic
Chemistry, Faculty of Chemistry,
University of Kashan, Kashan
87317-51167, Iran.
Email: naeimi@kashanu.ac.ir
Funding information
University of Kashan, Grant/Award
Number: 159148/96
1 | INTRODUCTION
products such as an antitumor compound.[19–22] 4H-
Chromenes can be employed as cognitive enhancers for
Multicomponent reactions (MCRs) are a great idea for
the synthesis of a complicated organic product. Mul-
ticomponent reactions have three or more reactants to
form a new applied product. This reaction converts all or
most material atoms to a new form of atom. The products
that are synthesized from the MCR are used in medicine,
pharmacology, and industries.[1–3] The optimum condi-
tions for MCR to find high yield, low cost, shorter reaction
time, energy conservation, and comfortable and cheap
purification processes have been explored.[4–8] One of the
famous MCRs was the synthesis of α,β-unsaturated
nitrile, which was synthesized from Michael reaction
as the active intermediate for the synthesis of several
useful products.[9–11] Derivatives of bicyclic ortho-
aminocarbonitrile from cyclic ketones, malononitrile, and
benzaldehyde create important organic products.[12–14]
Some of these products were tetrahydronaphthalene, 1H-
isochromene, and 4H-chromene. Ortho-aminocarbonitrile
tetrahydronaphtha-lene is useful as a precursor and signif-
icant for its optical properties.[15,16] The various derivatives
of 1H-isochromene are present in a diversity of natural
products, pharmaceuticals, and bioactive molecules.[17,18]
These benefit structure applied in biological and pharmacy
cure of neurodegenerative illnesses (such as Huntington
disease, Parkinson disease, Alzheimer disease, and
amyotrophic lateral sclerosis) and other dangerous neuro-
degenerative illnesses such schizophrenia.[23–26] Numer-
ous methods and catalyst are reported for the synthesis of
the α,β-unsaturated nitrile and the related product, for
example, nanocatalyst, transition metal catalyst, and
metal-free catalyst. One special straightforward and
economical reaction has been the use of a metal-free
catalyst.[27,28] This catalyst has high activity without any
heavy metal such as Et3N, guanidine, and morpholine.
Morpholine is a great base catalyst that can be applied in
different MCRs.[29] In the present report, we hope to study
the MCRs of cyclohexanone, malononitrile, and benzalde-
hyde for the synthesis of three products with excellent
yield using different methods.
2 | RESULTS AND DISCUSSION
2.1 | Investigation of various methods
At the beginning of our study, all the reactants were
mixed at the same time, and the reaction flowed under
J Heterocyclic Chem. 2019;1–10.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
NAEIMI AND MOHAMMADI
different acid and base catalysts, solvents, and tempera-
tures. Consequently, in a better condition, we obtained
three products in low yields (Scheme 1).
For the synthesis of ortho-aminocarbonitrile
tetrahydronaphthalene (6a), two equivalents of
malononitrile was used: one reacts with cyclohexanone,
and the other with benzaldehyde. So the two methods
was examined increasing the yield of the product. The
first was a one-pot reaction with cyclohexanone, benzal-
dehyde, and two equivalents of malononitrile under the
best condition. The product of this reaction was obtained
in good yields (Scheme 5).
For increase of the yield of ortho-aminocarbonitrile
tetrahydronaphthalene (6a), another method was
probed. In this method, first, the intermediate from the
reaction of cyclohexanone and malononitrile, also the
intermediate forms of benzaldehyde and malononitrile
were synthesized. Then, both of the intermediates were
mixed together to form the final product (Scheme 6). The
yield of the reaction under the best condition was
excellent.
Since malononitrile is the active reactant and was
rapidly added to the Michael addition with a double-bond
or carbonyl compound, the reaction was probed step by
step. In the first reaction, cyclohexanone was mixed to
malononitrile under different catalysts and solvents, and
after 10 to 20 minutes, benzaldehyde was added to the
mixture. In this reaction, under the best conditions, 1H-
isochromene (4a) was synthesized in excellent yield
(Scheme 2).
In the other reaction, first, benzaldehyde and
malononitrile were mixed under different conditions;
and after 20 to 25 minutes, cyclohexanone was added to
the mixture; and then the reaction followed for 15 to
20 minutes. In the best condition, the 4H-chromene (5a)
product was formed with good yield (Scheme 3).
To increase the yield of 4H-isochromene, another
method was used. In this reaction, the first benzaldehyde
and cyclohexanone were mixed under several conditions.
After formation of the α,β-unsaturated carbonyl com-
pound during 15 to 20 minutes, malononitrile was added
to the mixture. So 4H-chromene (5a) was a product in
excellent yield (Scheme 4).
2.2 | Investigation of catalytic activity
To select the best condition for the desired reactions, they
were examined in the presence of different catalysts, sol-
vents, and temperatures for the reaction. To analyze the
SCHE ME 1 Synthesis of three products
from cyclohexanone, benzaldehyde, and
malononitrile [Color figure can be viewed at
wileyonlinelibrary.com]
SCHEME 2 Synthesis of 1H-isochromene from
cyclohexanone, malononitrile, and benzaldehyde [Color
figure can be viewed at wileyonlinelibrary.com]
SCHEME 3 Synthesis of 4H-chromene from
benzaldehyde, malononitrile, and cyclohexanone [Color figure
can be viewed at wileyonlinelibrary.com]
SCHEME 4 Synthesis of 4H-chromene from
cyclohexanone, benzaldehyde, and malononitrile
[Color figure can be viewed at wileyonlinelibrary.com]

NAEIMI AND MOHAMMADI
3
the reactions. So the reactions were tested in ethanol with
morpholine catalyst under various temperature, with the
reactions at room temperature having excellent yield
(Table 2).
After optimization of the reactions by the different
catalysts, solvents, and temperatures, the reaction
condition was determined. So the best catalyst that was
selected for the synthesis of 1H-isochromene and 4H-
SCHEME 5 One-pot synthesis of ortho-aminocarbonitrile
tetrahydronaphthalene from cyclohexanone, malononitrile, and
benzaldehyde [Color figure can be viewed at wileyonlinelibrary.
com]
isochromene
from
cyclohexanone
(1
mmol),
malononitrile (1 mmol), and benzaldehyde (1 mmol) and
for ortho-aminocarbonitrile tetrahydronaphthalene from
cyclohexanone (1 mmol), malononitrile (2 mmol), and
benzaldehyde (1 mmol) was morpholine, and the best
solvent was ethanol. Therefore, the different derivatives
of 1H-isochromene, 4H-isochromene, and ortho-
aminocarbo-nitrile tetrahydronaphthalene (Table 3) were
synthesized at room temperature in 30 to 50 minutes.
2.3 | Proposed reaction mechanism
Synthesis of 1H-isochromene was done in two steps: the
first included the mixing of cyclohexanone with
malononitrile in ethanol under a great base condition
from morpholine. The reaction was followed by
vinylogous Michael addition for the synthesis of vin-
ylmalononitriles A. Then benzaldehyde was added to the
mixture, and the processes were followed by cycle crea-
tion of C–C (D) and C–O (E) bonds. In the end, 1H-
isochromene (4a) was synthesized with cyclization and
loss the hydrogen from intermediate via the base catalyst
(Scheme 7).
SCHEME 6 Synthesis of ortho-aminocarbonitrile
tetrahydronaphthalene in two steps from cyclohexanone,
malononitrile, and benzaldehyde [Color figure can be viewed at
wileyonlinelibrary.com]
For the synthesis of 4H-chromene, the first cyclohexa-
none and benzaldehyde were mixed in ethanol using
morpholine as a catalyst for synthesis of desired chalcone
(F) from condensation reaction. Then malononitrile was
added to the mixture for the synthesis of intermediate G
from Michael addition. The processes were flowing by
the formation of C–O bond, and at the end of reaction,
4H-chromene (5a) was synthesized with the
rearrangement of double bonds (Scheme 8).
The first step for synthesis of ortho-aminocarbonitrile
tetrahydronaphthalene (6a) includes the Michael
addition of cyclohexanone and malononitrile with the
formation of intermediate A. Another equivalent of
malononitrile concurrently reacts with benzaldehyde 2a
to obtain intermediate I. Then, by the action of
morpholine, intermediate J forms, which attack anion B
to intermediate I, and the processes were flowing by
cyclization of two C–C bonds. At the end of the processes,
ortho-aminocarbonitrile tetrahydronaphthalene (6a) was
formed with losses in hydrogen via base catalyst and
rearrangement of the molecules (Scheme 9).
applicants of catalyst, first, the reactions were studied
without catalyst at ambient and reflux temperatures
(Table 1, entry 1), but the yield of the product was very
low. The reactions were probed by altering the acid and a
base catalyst such as p-toluenesulfonic acid (PTSA),
Fe2O3, Et3N, guanidine, morpholine, NaOH, and MgO
(Table 1). The observation of the small amount of prod-
uct was noticed in the presence of acid catalysts, such as
PTSA and Fe2O3 (Table 1 entries 2 and 3), and clearly
shows that yields were increased under the bases of MgO
and NaOH and nitrogen-containing bases such as guani-
dine, Et3N, and morpholine. Among the base catalysts,
morpholine was found superior with the increase of yield
and decrease of reaction time. Also, different amounts of
catalyst (mmol) were studied, and the results are reported
in Table 1, entries 9 to 11.
The reactions were studied in several solvents such as
chloroform, dichloromethane, acetonitrile methanol, and
ethanol. Consequently, ethanol has the best condition for

4
NAEIMI AND MOHAMMADI
TABLE 1 Analysis of catalytic activity and catalyst amount (mmol) for synthesis of 1H-isochromene,a 4H-chromene,b and
ortho-aminocarbonitrile tetrahydronaphthalenec
Entry
Catalyst
None
Yield, %d/Tim,e h4a
10/24
Yield, %d/Time, hd5a
5/24
Yield, %d/Time, h6a
-/24
Catalyst Amount, mmol
1
-
2
PTSA
5/24
5/24
-/24
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.05
3
Fe2O3
7/24
6/25
-/24
4
NaOH
50/1.5
70/1
65/2
60/1.45
75/1
5
Et3N
73/1.5
6
Pyridine
Guanidine
MgO
65/1
60/1.5
70/1
7
80/0.6
76/1
83/0.75
70/1.5
85/0.6
80/1.5
95/0.3
95/0.3
90/0.75
8
9
Morpholine
Morpholine
Morpholine
93/0.3
93/0.3
93/0.75
92/0.3
10
11
92/0.3
87/0.6
Abbreviation: PTSA, p-toluenesulfonic acid.
aReaction conditions: cyclohexanone (1 mmol), malononitrile (1 mmol), benzaldehyde (1 mmol), and 5 mL of solvent.
bReaction conditions: benzaldehyde (1 mmol), cyclohexanone (1 mmol), malononitrile (1 mmol), and 5 mL of solvent.
cReaction conditions: benzaldehyde (1 mmol), cyclohexanone (1 mmol), malononitrile (2 mmol), and 5 mL of solvent.
dIsolated yield.
TABLE 2 Analysis of the solvent role and the reaction temperature for the synthesis of 1H-isochromene,a 4H-chromene,b and
ortho-aminocarbonitrile tetrahydronaphthalenec
Entry
Solvent
Temperature, ꢀC
Yield, %d/Time, h4a
75/0.66
78/0.75
89/0.58
75/0.83
93/0.5
Yield, %d/Time, h5a
60/0.70
Yield, %d/Time, h6a
65/0.75
65/0.83
85/0.6
1
2
3
4
5
6
7
8
Chloroform
Dichloromethane
Methanol
Acetonitrile
Ethanol
25
25
25
25
25
40
50
60
65/0.8
80/0.66
75/0.85
70/0.6
92/0.5
95/0.33
87/0.6
Ethanol
85/0.75
83/1
84/0.8
Ethanol
82/0.75
85/0.6
Ethanol
80/1
75/1.5
83/1
aReaction conditions: cyclohexanone (1 mmol), malononitrile (1 mmol), benzaldehyde (1 mmol), and 0.1 mmol of morpholine.
bReaction conditions: benzaldehyde (1 mmol), cyclohexanone (1 mmol), malononitrile (1 mmol), and 0.1 mmol of morpholine.
cReaction conditions: benzaldehyde (1 mmol), cyclohexanone (1 mmol), malononitrile (2 mmol), and 0.1 mmol of morpholine.
dIsolated yield.
3 | CONCLUSIONS
4 | EXPERIMENTAL SECTION
4.1 | Chemicals
In summary, we have investigated three reactions from
the same reactants by using the different methods for
obtaining the specific product with excellent yield. The
products contain 1H-isochromene, 4H-chromene, and
ortho-aminocarbonitrile tetrahydronaphthalene that
were synthesized from cyclohexanone, malononitrile,
and benzaldehyde. All the reactions were in an ethanol
solvent under a base condition at room temperature. In
the end, the products from three reactions were recog-
nized by melting points and IR and 1H NMR spectra.
All reactants and solvents were used as the starting
resources; cyclohexanone, benzaldehyde, and mor-
pholine were acquired from Sigma; malononitrile and
ethanol were purchased from Merck Chemical Company.
The products were assessed with 1H NMR, Fourier trans-
form infrared (FTIR), and melting point analysis; 1H
NMR spectra were register in DMSO-d6 and chloroform-
d solvents with a Bruker DRX-400 spectrometer with

NAEIMI AND MOHAMMADI
5
TABLE 3 Synthesis of various derivatives of 1H-isochromene, 4H-chromene, and ortho-aminocarbonitrile tetrahydronaphthalene and
determination of the yield and reaction time in the presence of morpholine catalyst
4a-h,a Yield %,d Time min
5a-h,b Yield %,d Time min
6a-h,c Yield %,d Time min
(Continues)

6
NAEIMI AND MOHAMMADI
TABLE 3 (Continued)
4a-h,a Yield %,d Time min
5a-h,b Yield %,d Time min
6a-h,c Yield %,d Time min
aReaction conditions: cyclohexanone (1 mmol), malononitrile (1 mmol), benzaldehyde (1 mmol), 0.1 mmol of morpholine, and ethanol solvent (5 mL), rt.
bReaction conditions: benzaldehyde (1 mmol), cyclohexanone (1 mmol), malononitrile (1 mmol), 0.1 mmol of morpholine, and ethanol solvent (5 mL), rt.
cReaction conditions: benzaldehyde (1 mmol), cyclohexanone (1 mmol), malononitrile (2 mmol), 0.1 mmol of morpholine, and ethanol solvent (5 mL), rt.
dIsolated yield.
SCHEME 8 Reaction mechanism for synthesis of 4H-
chromene [Color figure can be viewed at wileyonlinelibrary.com]
was added to the mixture and followed by the reaction
for 10 to 20 minutes at room temperature. In the end,
5 mL water was added to the mixture for the formation
of the pure product. The product was characterized by
melting points and IR and 1H NMR spectra.
SCHEME 7 Reaction mechanism for synthesis of 1H-
isochromene [Color figure can be viewed at wileyonlinelibrary.com]
tetramethylsilane as the internal reference. Fourier trans-
form infrared spectra were reached as KBr pellets and
register with PerkinElmer 781 spectrophotometer by an
Impact 400 Nicolet FTIR spectrophotometer. Melting
points were measured on a Yanagimoto micromelting
point apparatus.
4.2.1 | 3-Amino-1-phenyl-
5,6,7,8-tetrahydro-1H-isochromene-
4-carbonitrile (4a)
4.2 | General multicomponent
procedure for synthesis of 1H-isochromene
White solid; mp: 280-282ꢀC (lit. mp 285-288ꢀC)[13]; IR
(KBr) v = 3418, 3339, 3253, 2933, 2210, 1648, 1601 1451,
1392, 1276, 1080, 713, 581 cm−1, 1H NMR (400 MHz,
chloroform-d) δ 7.46-7.58 (m, 5H), 6.05 (s. 1H), 4.86
(s, 2H, NH2), 3.07-3.10 (d, J = 12.5 Hz, 1H), 2.88-2.91
(m, 1H), 2.27-2.32 (m, 1H), 2.15-2.18 (m, 1H), 1.79-1.82
(m, 1H), 1.67-1.70 (m, 1H), 1.49-1.58 (m, 1H), 0.91-1.00
(m, 1H).
1H-Isochromene was synthesized from the MCR. In this
reaction, 1 mmol of cyclohexanone (1a) with 1 mmol of
malononitrile was mixed in an ethanol solvent. Then,
0.1 mmol of morpholine was added to the mixture and
stirred for 10 to 20 minutes at ambient temperature. After
the reaction is completed, 1 mmol of benzaldehyde (2a-f)

NAEIMI AND MOHAMMADI
7
SCHEME 9 Reaction mechanism for synthesis of ortho-
aminocarbonitrile tetrahydronaphthalene [Color figure can
be viewed at wileyonlinelibrary.com]
4.2.2 | 3-Amino-1-(4-bromophenyl)-
5,6,7,8-tetrahydro-1H-isochromene-
4-carbonitrile (4b)
829, 515 cm−1, 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.64
(m, 6H, CH, NH2), 5.71 (s, 1H), 3.60-3.62 (d, J = 12.2 Hz,
1H), 2.77-2.79 (d, J = 13.3 Hz, 1H), 2.18-2.20 (d, J = 18.8 Hz,
1H), 2.06 (s, 1H), 1.67 (s, 1H), 1.36-1.58 (m, 2H), 0.82-0.86
(q, J = 12.5, 12.1 Hz, 1H).
White solid; mp: 260-263ꢀC; IR (KBr) v = 3422, 3343,
3250, 2928, 2210, 1643, 1600, 1488, 1390, 1274, 1075,
834, 509 cm−1, 1H NMR (400 MHz, chloroform-d) δ
7.42-7.78 (m, 3H), 7.17-7.19 (d, J = 8.3 Hz, 1H), 6.10-6.05
(m, 1H). 4.85 (s, 2H, NH2), 3.05-3.09 (d, J = 12.3 Hz, 1H),
2.85-2.88 (d, J = 12.5 Hz, 1H), 2.29-2.33 (m, 1H),
2.03-2.26 (m, 1H), 1.80-1.86 (m, 1H), 1.41-1.73 (m, 2H),
0.73-1.09 (m, 1H).
4.2.5 | 3-Amino-1-(4-(dimethylamino)
phenyl)-5,6,7,8-tetrahydro-1H-isochromene-
4-carbonitrile (4e)
White solid; mp: 248-250ꢀC; IR (KBr) v = 3447, 3355,
3206, 2916, 2213, 1617, 1525, 1446, 1357, 1271, 1116,
947, 524 cm−1. 1H NMR (400 MHz, chloroform-d) δ
7.34-7.71 (m, 1H), 7.16-7.12 (d, J = 8.5 Hz, 1H), 6.60-6.88
(m, 2H), 6.01-6.05 (m, 1H), 4.87 (s, 2H, NH2), 3.00
(s, 6H), 2.75-2.91 (m, 1H), 2.25-2.33 (m, 1H), 2.14
(m, 1H), 1.76-1.81 (m, 2H), 1.42-1.65 (m, 2H), 0.86-1.03
(m, 1H).
4.2.3 | 3-Amino-1-(3-nitrophenyl)-
5,6,7,8-tetrahydro-1H-isochromene-
4-carbonitrile (4c)
White solid; mp: 248-250ꢀC; IR (KBr) v = 3440, 3356,
3249, 2948, 2209, 1638, 1530, 1441, 1351, 906, 828,
1
546 cm−1, H NMR (400 MHz, chloroform-d) δ 7.46-7.48
(d, J = 8.2 Hz, 2H), 7.35-7.21 (m, 2H), 6.03-6.06 (m, 1H),
4.87 (s, 2H, NH2), 3.04-3.07 (d, J = 12.4 Hz, 1H), 2.77-2.93
(m, 1H), 2.15-2.19 (m, 1H), 1.81-1.83 (m, 1H), 1.70-1.73
(m, 1H), 1.47-1.63 (m, 2H), 0.89-1.02 (m, 1H).
4.2.6 | 3-Amino-1-(2,4-dichlorophenyl)-
5,6,7,8-tetrahydro-1H-isochromene-
4-carbonitrile (4f)
White solid; mp: 276-279ꢀC; IR (KBr) v = 3445, 3355,
3203, 2942, 2214, 1624, 1592, 1475, 1338, 1269, 11088,
1051, 879, 562 cm−1, 1H NMR (400 MHz, chloroform-d) δ
7.52-7.68 (m, 2H), 7.41-7.43 (m, 1H), 6.06-6.10 (m, 1H),
4.88 (s, 2H, NH2), 3.95-3.99 (d, J = 12.3 Hz, 1H), 2.80-2.97
(t, J = 12.2 Hz, 1H), 2.31-2.33 (m, 1H), 2.09-2.24 (m, 1H),
1.75-1.87 (m, 1H), 1.44-1.60 (m, 2H), 0.96-0.99 (m, 1H).
4.2.4 | 3-Amino-1-(4-fluorophenyl)-
5,6,7,8-tetrahydro-1H-isochromene-
4-carbonitrile (4d)
White solid; mp: 262-265ꢀC; IR (KBr) v = 3421, 3336,
3250, 2948, 2212, 1648, 1599, 1454, 1390, 1272,

8
NAEIMI AND MOHAMMADI
4.2.7 | 3-Amino-1-(4-nitrophenyl)-
5,6,7,8-tetrahydro-1H-isochromene-
4-carbonitrile (4g)
4.3.3 | 2-Amino-4-(3-nitrophenyl)-
5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (5c)
White solid; mp: 229-232ꢀC (lit. mp 232-236ꢀC)[13]; IR
White solid; mp: 120-122ꢀC; IR (KBr) v = 3460, 3363,
(KBr) v = 3418, 3347, 3286, 2938, 2206, 1644, 1523, 1448,
3085, 2931, 2863, 2189, 1669, 1633 1527, 1410, 1349, 1130,
1
1
1348, 1132, 1041, 859, 558 cm−1, H NMR (400 MHz,
809, 735, 680 cm−1, H NMR (400 MHz, chloroform-d) δ
DMSO-d6) δ 8.28-8.54 (m, 2H), 8.18-8.22 (t, J = 7.8 Hz,
1H), 7.70-8.05 (m, 1H), 7.35-7.70 (m, 1H), 6.67 (s, 2H,
NH2), 5.67 (s, 1H), 3.49-3.51 (d, J = 12.5 Hz, 1H), 3.42
(s, 1H), 2.85-3.87 (d, J = 12.5 Hz, 1H), 2.11-2.15 (m, 1H),
1.61-1.71 (m, 1H), 1.41-1.45 (t, J = 19.3 Hz, 1H), 0.85-0.88
(m, 1H).
8.11-8-17 (d, J = 22.4 Hz, 1H), 7.63-7.65 (m, 2H), 6.95 (s,
1H), 4.68 (s, 2H, NH2), 4.16 (s, 1H), 2.66-2.79 (m, 1H),
2.59-2.62 (d, J = 11.7 Hz, 1H), 2.06-2.10 (d, J = 17.6 Hz,
1H), 1.83-1.99 (m, 1H), 1.45-1.77 (m, 4H).
4.3 | General multicomponent
procedure for synthesis of 4H-chromene
4.3.4 | 2-Amino-4-(4-fluorophenyl)-
5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (5d)
4H-Chromene was synthesized from the three-
component reaction. For this reaction, 1 mmol of cyclo-
hexanone (1) with 1 mmol of benzaldehyde (2a-h) was
mixed in an ethanol solvent, and then 0.15 mmol of mor-
pholine as a catalyst was added to the mixture. After
15 to 20 minutes, 1 mmol of malononitrile was added to
the mixture. The reaction was followed with thin-layer
chromatography (TLC). At the end of the reaction, 5 mL
of water was added to the mixture for the formation
of the pure product. The product was filtered and
White solid; mp: 223-225ꢀC; IR (KBr) v = 3448, 3346,
3057, 2955, 2863, 2187, 1671, 1635 1592, 1412, 1254, 1139,
700, 515 cm−1, 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.37
(d, J = 8.2 Hz, 1H), 7.20 (s, 2H, NH2), 6.93 (s, 1H), 6.81 (s,
2H), 4.00 (s, 1H), 3.34 (s, 1H), 2.59-2.62 (d, J = 15.3 Hz,
1H), 2.43-2.46 (d, J = 10.4 Hz, 1H), 2.01-2.05 (d,
J = 17.1 Hz, 1H), 1.76-1.77 (d, J = 6.5 Hz, 2H), 1.39-1.61
(m, 2H).
1
recognized with FTIR and H NMR spectra and melting
point.
4.3.5 | 2-Amino-4-(4-(dimethylamino)
phenyl)-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (5e)
4.3.1 | 2-Amino-4-phenyl-
5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (5a)
White solid; mp: 223-225ꢀC; IR (KBr) v = 3445, 3325,
3021, 2892, 2835, 2192, 1668, 1635 1595, 1417, 1247, 1133,
1
754, 699, 561 cm−1, H NMR (400 MHz, chloroform-d) δ
White solid; mp: 233-235ꢀC (lit. mp 240-241ꢀC)[30]; IR
7.18-7.19 (d, J = 7.0 Hz, 1H), 7.14 (s, 2H), 6.84 (s, 1H),
4.49 (s, 2H, NH2), 3.93 (s, 1H), 2.69-2.72 (d, J = 9.0 Hz,
1H), 2.58 (m, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 1.97-1.99 (d,
J = 5.1 Hz, 2H), 1.62 (m, 4H).
(KBr) v = 3453, 3317, 3177, 2954, 2828, 2183, 1668, 1629
1483, 1411, 1382, 1253, 1132, 1069, 819, 514 cm−1, H
1
NMR (400 MHz, chloroform-d) δ 7.33-7.37 (m, 4H), 6.88
(s, 1H), 4.52 (s, 1H), 3.97 (s, 2H, NH2), 2.68-2.77 (m, 1H),
2.54-2.64 (m, 1H), 1.93-2.05 (m, 2H), 1.46-1.72 (m, 4H).
4.3.6 | 2-Amino-4-(2,4-dichlorophenyl)-
5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (5f)
4.3.2 | 2-Amino-4-(4-bromophenyl)-
5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (5b)
White solid; mp: 130-132ꢀC; IR (KBr) v = 3466, 3319,
3180, 2942, 2836, 2186, 1669, 1631 1596, 1486, 1410, 1259,
1090, 824, 512 cm−1,1H NMR (400 MHz, chloroform-d) δ
7.38-7.45 (m, 1H), 7.20-7.24 (dd, J = 18.6, 10.7 Hz, 1H),
6.85 (s, 1H), 4.64-4.67 (s, 2H, NH2), 3.70-3.74 (q,
J = 7.0 Hz, 1H), 2.34-2.65 (m, 2H), 2.18-2.01 (m, 1H), 1.87
(m, 1H), 1.59-1.62 (d, J = 12.2 Hz, 2H), 1.37-1.52 (m, 1H),
1.23-1.26 (t, J = 7.0 Hz, 1H).
White solid; mp: 220-222ꢀC; IR (KBr) v = 3446, 3335,
3235, 2935, 2863, 2214, 1667, 1663 1595, 1484, 1413, 1258,
1128, 1008, 822, 512 cm−1
,
1H NMR (400 MHz,
chloroform-d) δ 7.47 (m, 1H), 7.13-7.17 (m, 2H), 6.79
(s, 1H), 4.54 (s, 2H, NH2), 3.95 (s, 1H), 2.66 (s, 1H), 2.54
(s, 1H), 1.94-1.98 (d, J = 17.5 Hz, 2H), 1.57-1.63
(d, J = 24.8 Hz, 4H).

NAEIMI AND MOHAMMADI
9
4.3.7 | 2-Amino-4-(4-nitrophenyl)-
5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (5g)
2.01-2.20 (m, 2H), 1.67 (s, 1H), 1.43-1.50 (m, 1H),
0.72-0.97 (m, 1H).
White solid; mp: 180-183ꢀC; IR (KBr) v = 3466, 3378,
4.4.3 | 2-Amino-4-(3-nitrophenyl)-
4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-
tricarbonitrile (6c)
2934, 2191, 1640, 1517, 1443, 1343 11032, 855, 705 cm−1
,
1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 2H, NH2)
7.57-7.59 (d, J = 8.5 Hz, 1H), 7.49-7.50 (d, J = 8.3 Hz,
1H), 7.07 (s, 1H), 7.02 (s, 1H), 4.27 (s, 1H) , 2.62-2.77
(m, 1H), 2.54-2.56 (d, J = 7.1 Hz, 1H), 2.03-2.19 (m, 2H),
1.71-1.88 (m, 2H), 1.56-1.57 (d, J = 4.6 Hz, 2H).
White solid; mp: 265-267ꢀC (lit. mp 262-264ꢀC)[32]; IR
(KBr) v = 3445, 3356, 2949, 2853, 2216, 1622, 1472, 1389,
1270, 1023, 746, 506 cm−1,1H NMR (400 MHz, DMSO-d6)
δ 7.64-7.71 (m, 2H), 7.54-7.56 (d, J = 7.9 Hz, 1H), 7.39
(s, 3H), 5.72 (s, 1H), 3.60-3.63 (d, J = 12.5 Hz, 1H),
2.76-2.61 (t, J = 10.1 Hz, 1H), 2.24-1.92 (m, 2H), 1.65
(s, 1H), 1.43-1.45 (d, J = 9.9 Hz, 2H), 0.79-0.88
(q, J = 12.1 Hz, 1H).
4.4 | General multicomponent
procedure for synthesis of ortho-
aminocarbonitrile tetrahydronaphthalene
For
the
synthesis
of
ortho-aminocarbonitrile
tetrahydronaphthalene with a four-component reaction,
cyclohexanone (1 mmol) (1) was reacted with
malononitrile (1 mmol), and at the same time, benzalde-
hyde (1 mmol) (2a-h) was reacted with malononitrile
(1 mmol). This was followed with both reactions in etha-
nol solvent with 0.1 mmol of morpholine. After comple-
tion of the reactions, both intermediate products were
mixed and the processes monitored by TLC. At the end of
the reaction, 5 mL water was added to the reaction mix-
ture for the formation of the pure product. The final
product was determined with a melting point and FTIR
and 1H NMR spectra.
4.4.4 | 2-Amino-4-(4-fluorophenyl)-
4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-
tricarbonitrile (6d)
White solid; mp: 264-266ꢀC (lit. mp 262-264ꢀC)[31]; IR
(KBr) v = 3448, 3356, 3210, 2957, 2839, 2212, 1618, 1518,
1449, 1387, 1230, 1120, 930, 824, 525 cm−1 1H NMR
,
(400 MHz, DMSO-d6) δ 7.34-7.38 (d, J = 20.5 Hz, 2H),
7.29-7.20 (m, 1H), 7.05-6.91 (m, 1H), 5.69 (s, 1H), 3.73
(s, 2H, NH2), 3.40-3.33 (m, 1H), 2.84-2.63 (m, 1H),
2.08-2.14 (dd, J = 47.5, 12.6 Hz, 2H), 1.65 (s, 1H),
1.43-1.47 (d,
J
=
20.9 Hz, 1H), 0.80-0.84 (d,
J = 12.5 Hz, 1H).
4.4.1 | 2-Amino-4-phenyl-
4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-
tricarbonitrile (6a)
4.4.5 | 2-Amino-4-(4-(dimethylamino)
phenyl)-4a,5,6,7-tetrahydronaphthalene-
1,3,3(4H)-tricarbonitrile (6e)
White solid; mp: 256-260ꢀC (lit. mp 255-257ꢀC)[31]; IR
(KBr) v = 3446, 3356, 2950, 2856, 2216, 1623, 1525 1477,
1
1390, 1271, 1040, 748, 501 cm−1, H NMR (400 MHz,
White solid; mp: 263-265ꢀC; IR (KBr) v = 3447, 3355,
2952, 2803, 2214, 1617, 1525, 1272, 1168, 947, 816,
525 cm−1, 1H NMR (400 MHz, DMSO-d6) δ 7.32 (s, 3H,
NH2, CH), 7.17-7.19 (d, J = 8.5 Hz, 1H), 6.76-6.89
(m, 1H), 6.62-6.76 (m, 1H), 5.69 (s, 1H), 3.32-3.33
(d, J = 7.9 Hz, 1H), 2.91 (s, 6H), 2.70 (s, 1H), 2.14-2.19
(d, J = 18.1 Hz, 1H), 2.04 (s, 1H), 1.65 (s, 1H), 1.50-1.53
(d, J = 10.6 Hz, 1H), 1.44 (s, 1H), 0.73-0.97 (m, 1H).
DMSO-d6) δ 7.25-7.65 (m, 7H, NH2, CH), 5.72 (s, 1H),
3.52-3.55 (d, J = 12.3 Hz, 1H), 2.80 (s, 1H), 2.06-2.15
(d, J = 36.6 Hz, 2H), 1.64-1.68 (d, J = 12.8 Hz, 1H), 1.44
(s, 2H), 0.83-0.86 (d, J = 11.4 Hz, 1H).
4.4.2 | 2-Amino-4-(4-bromophenyl)-
4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-
tricarbonitrile (6b)
White solid; mp: 251-253ꢀC (lit. mp 244-246ꢀC)[31]
IR (KBr) v = 3421, 3336, 3250, 2947, 2865, 2212, 1646,
1599 1454, 1390, 1037, 830, 586 cm−1 1H NMR
;
4.4.6 | 2-Amino-4-(2,4-dichlorophenyl)-
4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-
tricarbonitrile (6f)
,
(400 MHz, DMSO-d6) δ 7.41-7.48 (m, 1H), 7.35 (s, 2H,
NH2), 7.33-7.24 (m, 2H), 7.22 (s, 1H), 5.71 (s, 1H),
3.44-3.47 (d, J = 12.5 Hz, 1H), 2.76 (s, 1H), 2.49 (s, 1H),
White solid; mp: 260-264ꢀC (lit. mp 262-264ꢀC)[31]; IR
(KBr) v = 3446, 3357, 2943, 2860, 2214, 1623, 1593, 1476,

10
NAEIMI AND MOHAMMADI
1388, 1268, 1109, 880, 562, 501 cm−1, 1H NMR (400 MHz,
DMSO-d6) δ 7.72-7.94 (m, 2H), 7.63-7.65 (d, J = 8.2 Hz,
1H), 7.44 (s, 2H, NH2), 5.75 (s, 1H), 3.85-3.88 (d,
J = 12.3 Hz, 1H), 2.85 (s, 1H), 2.09-2.14 (d, J = 23.6 Hz,
2H), 1.64 (s, 1H), 1.39-1.41 (d, J = 18.9 Hz, 2H), 0.78-0.81
(d, J = 11.9 Hz, 1H).
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4.4.7 | 2-Amino-4-(4-nitrophenyl)-
4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-
tricarbonitrile (6g)
White solid; mp: 256-260ꢀC (lit. mp 264-266ꢀC)[31]; IR
(KBr) v = 3419, 3343, 3252, 2943, 2867, 2212, 1645, 1602
1492, 1390, 1094, 837, 567 cm−1
,
1H NMR
(400 MHz, DMSO-d6) δ 7.56-7.63 (q, J = 8.2 Hz, 2H),
7.51-7.53 (d, J = 8.1 Hz, 1H), 7.44-7.46 (d, J = 7.8 Hz,
1H), 7.39 (s, 2H, NH2), 5.72 (s, 1H), 3.62-3.65 (d,
J = 12.5 Hz, 1H), 2.79 (s, 1H), 2.07-2.15 (m, 2H), 1.65
(s, 1H), 1.43-1.46 (d, J = 9.7 Hz, 2H), 0.79-0.88
(q, J = 11.7 Hz, 1H).
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ACKNOWLEDGMENT
The authors are grateful to the University of Kashan for
supporting this work by grant 159148/96.
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ORCID
Hossein Naeimi https://orcid.org/0000-0002-9627-596X
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
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How to cite this article: Naeimi H,
Mohammadi S. Synthesis of 1H-isochromenes, 4H-
chromenes, and ortho-aminocarbonitrile
tetrahydronaphthalenes from the same reactants
by using metal-free catalyst. J Heterocyclic Chem.
2019;1–10. https://doi.org/10.1002/jhet.3742
[14] S. Rostamnia, A. Nuri, H. Xin, A. Pourjavadi, S. H. Hosseini,
Tetrahedron Lett. 2013, 54, 3344.