Synthesis and X-ray crystal structures of polyfunctionalized 4H-chromene derivatives via tricomponent reaction with Knoevenagel adducts as intermediates in aqueous medium

Article abstract of DOI:10.1016/j.molstruc.2020.129226

Chromenes and their derivatives are an important class of compounds known for their biological properties. In this study, synthetic methodologies were described to obtain 4H-chromene derivatives. Two routes were investigated, the first being a bicomponent

Full text of DOI:10.1016/j.molstruc.2020.129226

Journal of Molecular Structure 1223 (2020) 129226
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis and X-ray crystal structures of polyfunctionalized
4H-chromene derivatives via tricomponent reaction with Knoevenagel
adducts as intermediates in aqueous medium
Lucas Lima Zanina, David Esteban Quintero Jimenezb, Matheus Pereira de Jesusa,
Luan Farinelli Dinizc, Javier Ellenad, André Luiz Meleiro Portoa,∗
a Laboratório de Química Orgânica e Biocatálise, Instituto de Química de São Carlos, Universidade de São Paulo, Av. João Dagnone, 1100, Ed. Química
Ambiental, Santa Angelina, 13563-120, São Carlos, São Paulo, Brazil
b Universidade Federal do Amapá, Rodovia Juscelino Kubitscheck, KM 02, S/N - Jardim Marco Zero, 68903-419, Macapá, Amapá, Brazil
c Laboratório de Controle de Qualidade de Medicamentos e Cosméticos, Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade
Federal de Minas Gerais, 31270-901, Belo Horizonte, Minas Gerais, Brazil
d Laboratório Multiusuário de Cristalografia Estrutural, Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São-carlense, 400,
Parque Arnold Schimidt, 13566-590, São Carlos, São Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Chromenes and their derivatives are an important class of compounds known for their biological prop-
erties. In this study, synthetic methodologies were described to obtain 4H-chromene derivatives. Two
routes were investigated, the first being a bicomponent reaction using Knoevenagel adducts as reagents
and the second using one-pot tricomponent reactions, both under microwave irradiation, using H2O as
solvent and triethylamine as catalyst. Twenty 4H-chromene derivatives were synthesized with 50–95%
yields from aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexadione and malononitrile or methyl cyanoac-
etate, being further characterized by Fourier Transform Infrared and Nuclear Magnetic Resonance. We
also report three crystal structures from the synthesized chromene derivatives, by single-crystal X-ray
diffraction, showing the main supramolecular features of each structure – a poorly unexplored approach
involving this class of compounds so far.
Received 27 July 2020
Revised 5 September 2020
Accepted 7 September 2020
Available online 9 September 2020
Keywords:
Microwave irradiation
Benzopyran
Green solvent
X-ray structures
Tricomponent reaction
© 2020 Published by Elsevier B.V.
1. Introduction
chromene nucleus is a quickly and efficient way to obtain potential
bioactive molecules.
Benzopyran is a polycyclic nucleus resulting from the fusion of
a benzene ring with a pyran ring. According to IUPAC, this nucleus
is named chromene. There are two benzopyran isomers that vary
according to the orientation of the unsaturation and the position
of the oxygen atom in the pyran ring, resulting in 1-benzopyran
(chromene) and 2-benzopyran (isochromene) [1].
A practical route to obtain this type of compound uses a Kno-
evenagel adduct as a synthetic intermediate, which, upon reaction
with dicarbonyl compounds, produces a 4H-chromene derivative.
There are efficient methodologies described in the literature using
this route with different catalysts, and recently, the scientific com-
munity has sought the development of environmentally-friendly
studies [11,12,13].
The chromene nucleus is found in a variety of natural products
and in synthetic compounds with relevant biological applications
[1,2]. Several activities can be highlighted for this class of com-
pounds, such as antitumor [3], antifungal [4], antibacterial [5,6],
anti-inflammatory [7], antioxidants [8,9], antiviral [10], among oth-
ers. Most of the compounds with these highlighted biological ac-
tivities are chromenes of the 4H-pyran ring type. Thus, the de-
velopment of sustainable synthetic methodologies for this type of
In this direction, Azizi et al. [14] reported a tricomponent syn-
thesis of 4H-chromene derivatives, using a magnetite-supported
graphitic carbon nitride as catalyst. Twenty-one examples have
been synthesized with good yields (72–97%), using EtOH as sol-
vent at 60 °C, with a reaction time between 30–190 min. More-
over, Maddila et al. [15] developed an efficient methodology for the
synthesis of 4H-chromene derivatives under ultrasound radiation.
Eleven compounds were obtained with excellent yields (92–98%),
using a mixture of EtOH and H2O as solvent and it is noteworthy
that the reactions showed 94% atomic economy.
∗
Corresponding author.
E-mail address: almporto@iqsc.usp.br (A.L.M. Porto).
https://doi.org/10.1016/j.molstruc.2020.129226
0022-2860/© 2020 Published by Elsevier B.V.

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L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
Once synthesized, the chromenes and their derivatives were
2.3. General procedure for the synthesis of 4H-chromene derivatives
using benzylidene-malononitrile derivatives and
generally studied by a combination of characterization techniques,
including Fourier Transform Infrared (FTIR), Nuclear Magnetic Res-
onance (NMR) and Mass Spectrometry (MS). However, the struc-
tural determination of these compounds by single-crystal X-ray
diffraction (SCXRD) is rare in the literature, mainly due to the dif-
ficulty in obtaining single-crystals.
5,5-dimethylcyclohexane-1,3-dione
Benzylidene malononitrile derivatives 4a-j were obtained by
methodology described by Jimenez et al. [16].
In
a reactional flask (25 mL) were added benzylidene-
An efficient strategy, widely applied in organic synthesis to im-
prove reaction yields or decrease reaction time, is the use of mi-
crowave (MW) irradiation as a heating source. Herein, we report
a sustainable synthetic methodology of 4H-chromene derivatives
using aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexadione, mal-
ononitrile or methyl cyanoacetate and H2O as solvent, under MW
irradiation.
malononitrile derivatives (1.0 mmol), 5,5-dimethylcyclohexane-1,3–
dione (1.0 mmol), triethylamine/H2O (10 mol% - 15 μL/4 mL). After
the reactional flask was put in the MW reactor (55 W) for 25 min
and stirred using internal magnetic stirring at 50 °C. The reactional
time was monitored by TLC using mixture of hexane and ethyl ac-
etate (8:2) and the plates were revealed with sublimated iodine
supported on silica gel. At the end of the reaction, was effectu-
ated an extraction with ethyl acetate (3 × 15 mL). The combined
organic phases were concentrated by vacuum until total evapora-
tion of the solvent and the product was purified by wash with heat
hexane and dichloromethane (1:1). All compounds were character-
ized by 1H and 13C NMR, FTIR and melting point (Supplementary
Material).
2. Experimental
2.1. General methods
Fourier Transform Infrared (FTIR) spectra were recorded on Shi-
madzu IRAffinity-1 spectrometer model. Analysis were performed
using compressed tablets disks prepared with KBr. The transmit-
2.4. General procedure for the synthesis of 4H-chromene derivatives
via one-pot reaction using aromatic aldehydes, malononitrile and
5,5-dimethylcyclohexane-1,3-dione
tance was expressed in cm−1 of band between 4000 and 450 cm−1
.
NMR spectra were recorded on an Agilent Technologies 500/54
Premium Shielded or Agilent Technologies 400/54 Premium
Shielded spectrometer, with DMSO-d6 or acetone-d6 as solvent
and tetramethylsilane (TMS) as the internal standard. The chemi-
cal shifts were expressed in ppm and coupling constants (J) val-
ues were reported in Hz. The chemical shifts (δ) were expressed
in parts per million (ppm) and referenced to the tetramethylsilane
internal standard (TMS) signal and the deuterated solvent used
DMSO-d6 (δH 2.50, δC 39.52) and acetone-d6 (δH 2.84 and 2.05, δC
206.26 e 29.8). For 1H NMR spectra the number of scans was 120.
For 13C NMR spectra the number of scans was 881.
In a reactional flask (25 mL) were added aromatic aldehydes
(1.0 mmol), malononitrile (1.0 mmol), 5,5-dimethylcyclohexane-
1,3–dione (1.0 mmol), triethylamine/H2O (20 mol% - 30 μL/4 mL).
After the reactional flask was put in the MW (55 W) for 60 min
and stirred by internal magnetic stirring at 50 °C. The reactional
time was monitored by TLC using a mixture of hexane and ethyl
acetate (8:2) and the plates were revealed with sublimated iodine
supported on silica flash. At end of the reaction, was effectuated an
extraction with ethyl acetate (3 × 15 mL). The combined organic
phases were concentrated by vacuum until total evaporation of the
solvent and the product was purified by wash with heat hexane
and dichloromethane (1:1). All compounds were characterized by
1H and 13C NMR, FTIR and melting point (Supplementary Material).
The microwave irradiation experiments were performed using
a Discover System from CEM Corporation at a 2.45 GHz frequency
with maximal power output of about 200 W with internal mag-
netic stirring. For the reactions the power of the microwave reactor
used was 55 W.
2.5. General procedure for the synthesis of 4H-chromene derivatives
via one-pot reaction between aromatic aldehydes methyl
cyanoacetate and 5,5-dimethylcyclohexane-1,3-dione
Melting points were measured in a Fisatom model 431 melting
point apparatus.
The single-crystal X-ray diffraction data were collected at
room temperature on an Agilent-Rigaku Super Nova diffractome-
ter equipped with CCD detector system and using Mo radiation
(λ = 0.71073A).
In
a reaction flask (25 mL) were added aromatic alde-
hydes (1.0 mmol), methyl cyanoacetate (1.0 mmol), 5,5-
dimethylcyclohexane-1,3–dione (1.0 mmol), triethylamine/H2O
(20 mol% - 30 μL/4 mL). After the reaction flask was put in the
MW reactor (55 W) for 180 min and stirred (internal magnetic
stirring) at 85 °C. The reaction progress was monitored by TLC
using a mixture of hexane and ethyl acetate (7:3) and the plates
were revealed with sublimated iodine immobilized on silica. At
end of the reaction time, was effectuated an extraction with
ethyl acetate (3 × 15 mL). The combined organic phases were
concentrated by vacuum until total evaporation of the solvent. The
product was purified by column chromatography with silica gel
using a mixture of hexane-ethyl acetate in varying proportions
from 7:3 to 1:1. All compounds were characterized by 1H and
13C NMR, HRMS, FTIR and when it was possible by melting point
(Supplementary Material).
2.2. Chemical reagents
Benzaldehyde (98%) 1a, 4-bromobenzaldehyde (97%) 1b, 4-
methylbenzaldehyde (99%) 1c, 4-chlorobenzaldehyde (99%) 1d, 4-
fluorobenzaldehyde (97%) 1e, 4-nitrobenzaldehyde (97%) 1f, 4-
hydroxybenzaldehyde (97%)
1 g, 3,4,5-trimethoxybenzaldehyde
(98%) 1 h, p-anisaldehyde (98%) 1i, furfural (99%) 1j, vanillin (99%)
1k, 5,5-dimethyl-1,3-cyclohexadione (99%) 2, malononitrile (99%)
3 and methyl cyanoacetate (99%) 6 were purchased from Sigma-
Aldrich.
All the reagents and solvents (hexane, ethyl acetate, triethy-
lamine, methanol, acetone and dichloromethane) were purchased
and were used without further purification (Aldrich, Fluka, Synth,
Merck e Vertec).
2.6. Crystallization protocols of 4H-chromene derivatives 5a, 5e and
The deuterated solvent, DMSO-d6 (99.9%) and acetone-d6
(99.9%) were purchased from Cambridge Isotope Laboratories.
5 g
The TLC analysis was performed in
GRAM® XTra SIL G/UV254, with layer of 0.20 mm of silica gel 60
and with fluorescent indicator of UV254
a
DC-Fertigfolien ALU-
The crystallization of the 4H-chromene derivatives 5a, 5e and
5 g followed the same protocols. First, 50 mg of each compound
was dissolved in 10 mL of methanol or acetone and stirred at soft
.

L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
3
Table 1
Study of the reactional conditions for the synthesis of 4H-chromene derivative 5a using 5,5-dimethyl-1,3-
cyclohexadione 2, Knoevenagel adduct 4a and H2O as solvent by conventional heating (CH) or under MW
irradiation.
Entry
Heating source
Time (min)
Temperature (°C)
Yield 5a (%)
1a
2
3
4
5
6
7
8
9
CH
30
15
30
30
30
10
30
20
10
50
85
85
50
r.t.
50
50
50
50
50a
79
90
94
57
77
95
95
92
CH
CH
CH
CH
CH
MW
MW
MW
a
= without N(Et)3;.
heating conditions (50 °C) for 5 min or until complete solubiliza-
tion. Then, the crystallization batches were allowed to cool down
slowly and covered with Parafilm® for slow evaporation of the sol-
vent. All these systems were maintained at room temperature until
the appearance of suitable single-crystals, which occurs within 5–
10 days.
accessible methodology, triethylamine (TEA) was chosen as the cat-
alyst for the reactions in this study.
Initially, via a bicomponent pathway, the compound 5a was
synthetized using benzylidene-malononitrile (Knoevenagel adduct)
4a and 5,5-dimethyl-1,3-cyclohexadione 2, by conventional heating
(CH) for 30 min, in the absence of TEA, at 50 °C and a moderate
yield of 50% was obtained (Table 1 - Entry 1). In sequence, exper-
iments were carried out in the presence of 10 mol% of TEA, us-
ing CH or MW irradiation as a heating source, with different reac-
tion times ranging from 10 to 30 min and temperatures from room
temperature (r.t.) to 85 °C (Table 1 - Entries 2–9).
2.7. Single-crystal structure determination of 4H-chromene
derivatives 5a, 5e and 5g
X-ray diffraction data collection, cell determination and fi-
nal were obtained using the software CrysAlisPro [17]. Using
Olex2 [18], the structure was solved by direct methods (SHELXT–
14) and the model obtained was refined by full–matrix least
squares on F2 (SHELXL–17) [19]. The non-hydrogen atoms were re-
fined anisotropically. Then, all hydrogen atoms were located from
electron-density difference maps and were positioned geometri-
cally and refined using the riding model [Uiso(H) = 1.2Ueq or
1.5Ueq]. MERCURY 4.0 [20] and ORTEP [21] were used for analysis
and visualization of the structures and for graphic material prepa-
ration. The CIF files of 4H-chromene derivatives 5a, 5e and 5g were
deposit in the Cambridge Structural Data Base [22] under the CCDC
numbers 1999056, 1998987 and 1998988, respectively. Copies of
the data can be obtained, free of charge, viawww.ccdc.cam.ac.uk.
It was observed that the best condition for the synthesis of the
4H-chromene derivative 5a was at 50 °C, employing MW as heat-
ing source for only 10 min and using 10 mol% of TEA (Table 1 -
Entry 9), resulting in 92% yield. This result also demonstrated a
three-fold reduction in reaction time when MW was used com-
pared to CH conditions (Table 1 - Entries 4 and 9). After the op-
timization process, the reaction scope was expanded using several
benzylidene-malononitrile derivatives 4a-j (Table 2).
It was observed that the optimized methodology worked well
for the substrates used. In all cases, the reactions were almost
completed, with yields greater than 92%, showing that the pres-
ence of electron-donor or electron-withdrawing groups did not in-
fluence the reaction kinetics. It should also be noted that com-
pounds 5a-j were easily purified by washing with a heat mixture
of hexane and dichloromethane (1:1).
After observing the success of the bicomponent synthesis route
of the 4H-chromene derivatives 5a-j, the one-pot, tricomponent
route was also analyzed, in which aldehydes 1a-j, dimedone 2 and
malononitrile 3 were added in the same reaction system via a one-
pot reaction.
3. Results and discussion
The Knoevenagel adducts are very relevant compounds in or-
ganic synthesis, because they are considered building blocks to
obtain several polyfunctionalized molecules. An example of a re-
action in which they can act as intermediates is the synthesis
of 4H-chromene derivatives, and this route was initially used in
this work. At first, an optimization procedure was developed to
establish the best reactional conditions for the synthesis of 4H-
chromene derivatives. In a previous study, our research group re-
ported the efficiency of H2O as a solvent in Knoevenagel conden-
sations [16,23]. Therefore, this work also explored the evaluation
of H2O as a solvent in the synthesis of 4H-chromene derivatives.
It is known that the Knoevenagel condensation, and conse-
quently the formation of the 4H-chromene derivatives, can be cat-
alyzed by a distinct range of catalysts. So, in order to develop an
Not surprisingly, the tricomponent reaction had a longer reac-
tion time compared to the two-component route, because the reac-
tion involves one more reaction step, which is the formation of the
Knoevenagel adduct. Therefore, different reaction times of 30, 40
and 50 min were evaluated (Table 3 - Entries 1–3). Among these,
the best condition was found in 60 min, in which 5a was obtained
with 94% yield.
From this result, the scope of the reaction has been expanded
using several aromatic aldehydes and can be observed in Table 4.
It was observed that excellent yields ≥90% were obtained
in 60 min, showing that the synthetic methodology used was

4
L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
Table 2
Synthesis of 4H-chromene derivatives 5a-j using Knoevenagel adducts 4a-j and 5,5-dimethyl-1,3-
cyclohexadione 2 under MW irradiation.
Entry
Ar = aromatic group
C6H5 (4a)
Yield (%)
92 (5a)
95 (5b)
95 (5c)
95 (5d)
95 (5e)
95 (5f)
94 (5 g)
95 (5 h)
95 (5i)
92 (5j)
1
2
4-Br-C6H4 (4b)
–
4-CH3 C6H4 (4c)
3
–
4
4-Cl-C6 H4 (4d)
5
4-F-C6H4 (4e)
–
4-NO2 C6H4 (4f)
6
–
7
4-OH C6H4 (4g)
3–OCH3,4–OCH3,5–OCH3 C6H2 (4 h)
–
8
–
9
4–OCH3 C6H4 (4i)
10
Furan (4j)
Table 3
One-pot synthesis of 4H-chromene derivative 5a in different times using benzaldehyde 1a, 5,5-dimethyl-
1,3-cyclohexadione 2 and malononitrile 3 in H2O under MW irradiation.
Entry
Time (min)
Yield 5a (%)
1
2
3
40
50
60
79
88
94
Table 4
One-pot synthesis of 4H-chromene derivatives 5a-j using aromatic aldehydes 1a-j, 5,5-dimethyl-1,3-
cyclohexadione 2 and malononitrile 3 in H2O under MW irradiation.
Entry
Ar = aromatic group
C6H5 (1a)
Yield (%)
94 (5a)
95 (5b)
93 (5c)
95 (5d)
95 (5e)
95 (5f)
90 (5g)
94 (5h)
95 (5i)
90 (5j)
1
2
4-Br-C6H4 (1b)
–
3
4-CH3 C6H4 (1c)
4
4-Cl-C6H4 (1d)
4-F-C6H4 (1e)
5
–
4-NO2 C6H4 (1f)
6
–
7
4-OH C6H4 (1g)
3–OCH3,4–OCH3,5–OCH3 C6H2 (1 h)
–
8
–
9
4–OCH3 C6H4 (1i)
10
Furan (1j)
efficient for both bi or tricomponent routes in the synthesis of 4H-
chromene derivatives 5a-j. After purification of the compounds, we
observed that the 4H-chromene derivatives 5a, 5e and 5 g crystal-
ized after carrying out their crystallization protocols (see section
4.6). Hence, good-quality single-crystals were collected and sub-
jected to X-ray diffraction analysis.
in Table 5. In Table 6, the geometric parameters of the main H-
bonds for each 4H-chromene derivatives are listed. As depicted by
the ORTEP [21] diagrams (Fig. 1), all compounds exhibit only one
molecule per asymmetric unit. Although compounds 5a and 5e al-
ready have their ORTEPS structures deposited, in this study de-
tailed experiments were carried out regarding the spatial confor-
mations of all crystalline structures [24,25].
Crystallographic analysis of 4H-chromene derivatives 5a, 5e
and 5 g
As the synthesized crystals are racemic because both R and S
forms are present in the crystal structures, the superposing of the
molecules was performed considering only the S enantiomers. In
Fig. 2a, the 4H-chromene derivatives molecular structure displaying
The molecular structures of the 4H-chromene derivatives 5a,
5e and 5g have been successfully confirmed by X-ray crystallogra-
phy analysis. Crystal data and refinement details are summarized

L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
5
Fig. 1. ORTEP type diagrams showing atomic numbering scheme and 50% probability ellipsoids for 4H-chromene derivatives: (a) 5a, (b) 5e and (c) 5g.
the different substituents attached to the carbon of the chiral cen-
ter is presented. Thus, the overlay of the three molecules through
N2, C3, C2, C16, and N1 atoms of the amine and cyano moieties,
respectively, showed that even though the chromene derivatives
are considered conformationally flexible molecules, the orientation
of the aromatic groups as well as the pyran rings are quite sim-
ilar to each other. (Fig. 2b). Hence, the aromatic rings - being 4-
substituted or not - are disposed of in the same direction into
the crystalline structures with the pyran plane rings almost semi-
perpendicularly oriented concerning these moieties. Furthermore,
the mean plane of the 4-substituted aromatic group in the com-
pound 5e is nearly perpendicular compared to the ones observed
in the other chromenes derivatives (5a and 5g), being this struc-
tural attribute motived by the free rotation of the C1–C10 bond.
On the other hand, the 5,5-dimethyl-1,3-cyclohexadione portion
assumes, in all cases, a quasi-planar conformation with respect to
the pyran rings, not being entirely superposed due to the presence
of discreet torsions on these moieties. As a consequence of these
slight conformational differences, the chromene structures present
a great supramolecular diversity, allowing each molecule to have
Table 5
Crystallographic parameters of 4H-chromene derivatives 5a, 5e and 5 g.
4H-chromene derivative
Empirical formula
Molecular weight
Crystal system
5a
5e
5g
C18H18N2O2
294.34
Monoclinic
P21/c
C18H17FN2O2
312.33
Monoclinic
P21/n
C18H18N2O3
310.34
Triclinic
¯
P1
Space group
˚
a (A)
11.3117(8)
9.4717(6)
14.9166(9)
90
9.4283(6)
17.1030(9)
10.4996(7)
90
8.0907(4)
10.0215(5)
10.1440(5)
86.548(4)
85.054(4)
78.343(4)
801.75(7)
2
˚
b (A)
˚
c (A)
α (°)
β (°)
γ (°)
99.356(6)
90
113.622(8)
90
3
˚
Volume (A)
1576.92(18)
4
1551.22(19)
4
Z
ρcalc (g cm3)
μ (mm-1
1.240
1.337
1.286
)
0.082
0.096
0.089
Reflections collected
Independent reflections
R1 [I≥2σ(I)]
18632
25944
15936
3225
3525
3822
0.0572
0.1522
1.095
0.0552
0.1460
1.039
0.0475
wR2 [all data]
0.1279
Goodness-of-fit on F2
1.049
Table 6
Main hydrogen bonds and their geometric parameters in the 4H-chromene derivatives 5a, 5e and 5 g.
˚
˚
•••
•••
5a
•••
D − H A(°)
Interaction
D
A(A)
H
A(A)
Symmetry Code
•••
N2−H2A
N2−H2B
O2
N1
3.005(3)
3.020(3)
2.129(2)
2.155(2)
5e
168.75(13)
168.49(14)
x,-y + 1/2 + 1,+z-1/2
-x,-y + 2,-z + 1
•••
•••
C17−H17C
N2−H2A
O2
2.921(3)
3.542(3)
2.148(2)
2.695(2)
5 g
149.07 (13)
147.49 (15)
x-1/2,-y + 1/2,+z + 1/2
•••
N1
-x + 1/2,+y + 1/2,-z + 1/2 + 1
•••
N1
N2−H2A
O2
2.896(2)
2.837(2)
2.034(1)
2.022(2)
165.56(10)
172.47(11)
x + 1,+y,+z
•••
O3−H3
-x,-y + 1,-z + 2

6
L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
Fig. 2. (a) Molecular structure of 4H-chromene derivatives highlighting the fragments cyano (red), aromatic substituents (orange), carbonyl (pink) and chiral center (denoted
by an asterisk). (b) Overlay of the S enantiomers from the crystal structures of the compounds 5a (yellow), 5e (green) and 5 g (light blue), using the amine and cyano
moieties as the common reference.
•••
Fig. 3. Crystal packing view of the compound 5a highlighting: (a) the formation and extension of molecular dimeric units via N–H
the assembly of the columns and zigzag chains along the diagonal of bc plane.
N and π•••π interactions and (b)
its own pattern of interactions and crystalline packing, as shown
below.
ular similarities with the previously described chromene 5a, the
compound 5e displayed its own hydrogen-bonding pattern as well
as its crystalline arrangement, which was quite different from the
chromene 5a.
The 4H-chromene derivative 5a crystallizes in the monoclinic
P21/c space group. Crystal packing analysis showed that symmetry-
dependent adjacent molecules (related by an inversion center)
were engaged by classical N–H•••N H-bonds (N2−H2A•••N1, d:
Packing analysis revealed that the molecules were associated
with each other by classical N–H•••O H-bonds (N2−H2A•••O2, d:
2
˚
˚
3.020 A; θ: 168.5°) to form a R2(12) homosynthon. As a result,
2.921 A; θ: 149.1°), forming 1D helical-like chains in the crystalline
dimeric molecular units were formed, as illustrated in Fig. 3a.
These dimers of molecules were also connected by π•••π in-
teractions with an intercentroid distance between aromatic rings
structure. Since these infinite 1D chains of helices were also sym-
metrically related to each other via non-classical C–H•••N H-bonds
˚
(C17−H17C•••N1, d: 3.542 A; θ: 147.5°), as shown in Fig. 4a, they
˚
of neighboring molecules of ~4.41 A, leading to the formation of
exhibited the same pattern of intermolecular interactions but ran
in opposite directions, resulting in the crystal structure shown in
Fig. 4b. In summary, the 3D assembly of the 4H-chromene deriva-
tive 5e could be described in terms of these helical chains, as they
were the ones that predominate in the structure.
infinite 1D chains that propagate in zigzags along the diagonal
of the bc crystallographic plane. Thus, the overall 3D-assembly of
chromene derivative 5a was characterized by the stacking of the
zigzag chains along the [010] direction, which was further stabi-
˚
lized by classical N–H•••O H-bonds (N2−H2B•••O2, d: 3.005 A;
In contrast to the 5a and 5e compounds, already discussed,
the 4H-chromene derivative 5g crystallized in the triclinic space
group P1. In its crystal structure, the chromene molecules were
θ: 168.8°), giving rise to a columnar-like crystal structure, as pre-
sented in Fig. 3b.
The 4H-chromene derivative 5e also crystallized in the mono-
clinic system, but in the P21/n space group. Despite the molec-
connected to each other through classical N–H•••O H-bonds
˚
(N2−H2A•••O2, d: 2.896 A; θ: 165.6°). As a consequence, two

L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
7
Fig. 4. Partial packing view of the compound 5e showing: (a) the main H-bonds that stabilize and bridge independent helical chains (represented in green and red) and (b)
the propagation of these chains into crystal structure.
Fig. 5. Main H-bonds representation of the compound 5 g highlighting: (a) how the antiparallel 1D chains are linked to each other, allowing (b) their stacking into the
crystalline structure, as shown from (c) the crystal packing perspective view at bc plane.
infinite 1D chains were formed and extended along the [100] di-
rection. These chains were considered antiparallel to one another
because not only were they symmetrically related via strong O–
alternative, the concentration of TEA in the system was increased,
and the result was positive. By doubling the amount of catalyst
(20 mol%), the reaction achieved 70% of compound 7f (Table 5 -
Entry 2). It was also observed that by increasing the catalyst con-
centration again from 20 to 40 mol%, the yield remained virtually
constant (Table 5 - Entry 3). Finally, tests with a shorter reaction
time and a lower temperature were performed (Table 5 - Entries 4
and 5), however, the yields were lower than entry 2 Table 7.
It is important to mention that, even though the reaction
medium is basic and aqueous, no hydrolysis reaction was observed
in the ester portions of the 4H-chromene derivatives.
˚
H•••N H-bonds (O3−H3•••N1, d: 2.837 A; θ: 172.5°) but they also
propagated in opposite directions in the crystal (Fig. 5a). Addi-
tionally, these chains were thoroughly stacked at the bc crystallo-
graphic plane, so that the 3D crystal packing perspective shown in
Fig. 5b was achieved.
Synthesis of 4H-chromene derivatives 7a-b, 7d-k via a one-
pot tricomponent reaction using aromatic aldehydes 1a-b, 1d-k,
5,5-dimethylcyclohexane-1,3-dione 2 and methyl cyanoacetate 6
under microwave irradiation
In sequence, the reaction scope was expanded and ten 4H-
chromene derivatives 7a-b, 7d-k were synthesized, using the opti-
mized conditions (Table 7 - Entry 2), and moderate to good yields
were obtained (50–70%). The results can be seen in Table 8.
Regarding the difference in reaction conditions, we can high-
light some features that justify the difference in the reactivity
between the methylene active compounds. Malononitrile 2 has a
The versatility of the methodology was verified using another
methylene compound, methyl cyanoacetate 6. So, the optimized
synthetic conditions of compounds 5a-j were extrapolated for this
series. However, it was observed that the results were not simi-
lar. For the synthesis of 4H-chromene derivative 7f, in 180 min,
only 54% yield was obtained (Table 5 - Entry 1). Then, as an

8
L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
Table 7
Optimization of 4H-chromene derivative 7f synthesis using 4-nitrobenzaldehyde 1f, 5,5-dimethyl-1,3-
cyclohexadione 2 and methyl cyanoacetate 6, in H2O under MW irradiation.
Entry
Time (min)
180
TEA (mol%)
Yield (%)
54
1
2
3
4
5
10
20
40
20
20
180
70
180
72
90
56
50a
180
a
performed at 50 °C.
Fig. 6. Proposed three-component formation of 4H-chromene derivatives with Knoevenagel adduct as intermediate formed in situ in presence of TEA.

L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
9
Table 8
Synthesis one-pot of 4H-chromene derivatives 7a-b, 7d-k using aromatic aldehydes 1a-b, 1d-k 5,5-dimethyl-1,3-
cyclohexadione 2 and methyl cyanoacetate 6 in H2O under MW irradiation.
Entry
Ar = aromatic group
C6H5 (1a)
Yield (%)
64 (7a)
63 (7b)
60 (7d)
66 (7e)
70 (7f)
50 (7g)
62 (7h)
66 (7i)
59 (7j)
51 (7k)
1
2
4-Br-C6H4 (1b)
4-Cl-C6H4 (1d)
4-F-C6H4 (1e)
3
4
–
4-NO2 C6H4 (1f)
5
–
6
4-OH C6H4 (1g)
3–OCH3,4–OCH3,5–OCH3 C6H2 (1 h)
–
7
–
8
4–OCH3 C6H4 (1i)
9
furan (1j)
10
vanillin (1k)
lower acidity constant than methyl cyanoacetate 6 (pKa 11 and pKa
13, respectively, in H2O) [26,27] and these values may be justified
due to the difference in electron withdrawing capacity of the cyano
and ester groups. The cyano group is a stronger electron withdraw-
ing group than the ester group, which gives malononitrile a lower
pKa value than methyl cyanoacetate and, consequently, explains
its higher reactivity, given the shorter reaction times and lower
amounts of catalyst required.
5. Supplementary material
All experimental characterization data are contained in the Sup-
plemental Material.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Our proposal for the one-pot 4H-chromene derivatives forma-
tion is shown in Fig. 6. The first step involves the formation of
the Knoevenagel adduct, from the reaction between the aldehyde
and the active methylene compound. In the sequence, a Michael
type addition reaction occurs [28], which is followed by cycliza-
tion and tautomerization processes, resulting in formation of the
4H-chromene derivatives.
CRediT authorship contribution statement
Lucas Lima Zanin: Conceptualization, Methodology, Formal
analysis, Data curation, Writing - original draft, Writing - re-
view & editing. David Esteban Quintero Jimenez: Conceptualiza-
tion, Methodology, Formal analysis, Data curation, Writing - orig-
inal draft, Writing - review & editing. Matheus Pereira de Jesus:
Methodology. Luan Farinelli Diniz: Methodology, Formal analy-
sis, Data curation, Writing - original draft, Writing - review &
editing. Javier Ellena: Project administration, Funding acquisition.
André Luiz Meleiro Porto: Conceptualization, Project administra-
tion, Funding acquisition.
It was observed that the three-component reaction were effec-
tively catalyzed by TEA (Table 1), which presented itself as an ac-
cessible and easy-to-handle catalyst. The capacity of H2O as an al-
ternative and extremely low-cost solvent for organic synthesis re-
actions can also be highlighted.
4. Conclusion
In this study, we have demonstrated an eco-friendly and effi-
cient synthetic protocol of polyfunctionalized 4H-chromene deriva-
tives via bicomponent or tricomponent reactions, using TEA as
catalyst and H2O as a green and accessible solvent. Malononi-
trile 3 and cyano methylacetate 6 were used as methylene ac-
tive compounds, and twenty 4H-chromene derivatives were ob-
tained with good yields of between 50–95%. Additionally, a com-
parison study of the efficiency of MW irradiation in relation of
CH was performed for this reaction class. The results demon-
strated a significant increase in product yields when MW irradi-
ation was used as the heating source (92% yield under MW ir-
radiation, in 10 min against 79% yield under CH, in 15 min for
compound 5a).
Acknowledgments
This study was financed in part by the Coordenação de Aper-
feiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance
Code 001, Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP) projects 2019-07654-2/2016-20155-7 and Conselho Na-
cional de Desenvolvimento Científico e Tecnológico (CNPq) projects
302528/2017-2 (Porto, A. L. M.) and 305190/2017-2 (Ellena, J.).
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2020.129226.
Furthermore, three chromene derivatives crystal structures were
elucidated, with compound 5g being reported for the first time,
and their crystallographic attributes explored in detail. Analysis
of the crystal structures and packing revealed that the chromene
derivatives (5a, 5e and 5g) are mainly stabilized by classical N–
H•••O, N–H•••N, and O–H•••N hydrogen bonds, and in all cases a
distinct 3D crystal structure assembly can also be achieved due to
the conformational flexibility of the molecules.
References
[1] H.A. Favre, W.H. Powell, Nomenclature of Organic chemistry: IUPAC Recom-
mendations and Preferred Names 2013, The Royal Society of Chemistry, Cam-
bridge, 2014.
[2] R. Pratap, V.J. Ram, Natural and synthetic chromenes, fused chromenes, and
versatility of dihydrobenzo[h]chromenes in organic synthesis, Chem. Rev. 114
(2014) 10476–10526.

10
L.L. Zanin, D.E.Q. Jimenez and M.P. de Jesus et al. / Journal of Molecular Structure 1223 (2020) 129226
[3] H. Itokawa, Z.Z. Ibrageim, Y.F. Qiao, K. Takeya, Anthraquinones, naphthohydro-
aqueous ethanol under ultra-sonication with 94% atom economy, J. Mol. Struct.
quinones and naphthohydroquinone dimers from rubia cordifolia and their cy-
1185 (2019) 357–360.
totoxic activity, Chem. Pharm. Bull. 41 (1993) 1869–1872.
[16] D.E.Q. Jimenez, L.L. Zanin, L.F. Diniz, J. Ellena, A.L.M. Porto, Green synthetic
methodology of (E)-2-cyano-3-aryl selective Knoevenagel adducts under mi-
crowave irradiation, Curr. Microw. Chem. 6 (2019) 54–60.
[17] O.D. CrysAlisPRO, Agilent Technologies UK Ltd: Yarnton, (2012).
[18] O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, OLEX2:
a complete structure solution, refinement and analysis program, J. Appl. Crys-
tallogr. 42 (2009) 339–341.
[4] D.C. Baldoqui, M.J. Kato, A.J. Cavalheiro, V.D.S. Bolzani, M.C.M. Young, M. Furlan,
A chromene and prenylated benzoic acid from Piper aduncum, Phytochemistry
51 (1999) 899–902.
[5] H. Tanaka, I. Atsumi, O. Shirota, S. Sekita, E. Sakai, M. Sato, J. Murata, H. Mu-
rata, D. Darnaedi, I.S. Chen, Three new constituents from the roots of erythrina
variegata and their antibacterial activity against methicillin-resistant staphylo-
coccus aureus, Chem. Biodivers. 8 (2011) 476–482.
[6] G. Appendino, S. Gibbons, A. Giana, A. Pagani, G. Grassi, M. Stavri, E. Smith,
M.M. Rahman, Antibacterial cannabinoids from cannabis sativa: a structure-ac-
tivity study, J. Nat. Prod. 71 (2008) 1427–1430.
[19] G.M. Sheldrick, Crystal structure refinement with SHELXL, Acta Crystallogr. C
71 (2015) 3–8.
[20] C.F. Macrae, I. Sovago, S.J. Cottrell, P.T.A. Galek, P. Mccabe, E. Pidcock, M. Plat-
ings, G.P. Shields, J.S. Stevens, M. Towler, P.A. Wood, Mercury 4.0: from vi-
sualization to analysis, design and prediction, J. Appl. Crystallogr. 53 (2020)
226–235.
[7] I.
T.
Il’Ina,
Tolstikova,
O.
Mikhalchenko,
Volcho, N.
A.
Salakhutdinov,
activity of
Pavlova,
D.
E.
Korchagina,
Pokushalov,
K.
Highly
potent
analgesic
monoterpene-derived
[21] L.J. Farrugia, WinGX and ORTEP for windows: an update, J, Appl. Crystallogr.
45 (2012) 849–854.
[22] C.R. Groom, I.J. Bruno, M.P. Lightfoot, S.C. Ward, The Cambridge structural
database, Acta Crystallogr. B. 72 (2016) 171–179.
[23] D.E.Q. Jimenez, I.M. Ferreira, W.G. Birolli, L.P. Fonseca, A.L.M. Porto, Synthe-
sis and biocatalytic ene-reduction of Knoevenagel condensation compounds
by the marine-derived fungus Penicillium citrinum CBMAI 1186, Tetrahedron 72
(2016) 7317–7322.
(2S,4aR,8R,8aR)-2-aryl-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols,
Med. Chem. Res. 23 (2014) 5063–5073.
[8] K.H. Jang, B.H. Lee, B.W. Choi, H.-.S. Lee, J. Shin, Chromenes from the brown
alga Sargassum s iliquastrum, J. Nat. Prod. 68 (2005) 716–723.
[9] Y. Wang, K. Xu, L. Lin, Y. Pan, X. Zheng, Geranyl flavonoids from the leaves of
artocarpus altilis, Phytochemistry 68 (2007) 1300–1306.
[10] Y.R. Lee, Y.M. Kim,
A novel method for the synthesis of substituted ben-
zochromenes by ethylenediamine diacetate-catalyzed cyclizations of naph-
thalenols to α, β-unsaturated aldehydes. Concise synthesis of the natural
products, Helv. Chim. Acta. 90 (2007) 2401–2413.
[24] G. Brahmachari, S. Laskar, B. Banerjee, Eco-friendly, one-pot multicomponent
synthesis of pyran annulated heterocyclic scaffolds at room temperature using
ammonium or sodium formate as non-toxic catalyst, J. Heterocycl. Chem. 51
(2014) 303–308.
[11] I. Kharbangar, R. Rohman, H. Mecadon, B. Myrboh, KF-Al2O3 as an efficient
and recyclable basic catalyst for the synthesis of 4H-pyran-3-carboxylates and
5-acetyl-4H-pyrans, Int. J. Org. Chem. 2 (2012) 282–286.
[25] J. Li, C.W. Lv, X.J. Li, D. Qu, Z. Hou, M. Jia, X.X. Luo, X. Lie, M.K. Li, Synthesis of
biscoumarin and dihydropyran derivatives and evaluation of their antibacterial
activity, Molecules 20 (2015) 17469–17482.
[12] J.M. Khurana, B. Nand, P. Saluja, 1, 8-Diazabicyclo[5.4.0]undec-7-ene:
a
highly efficient catalyst for one-pot synthesis of substituted tetrahy-
dro-4H-chromenes, tetrahydro[b] pyrans, pyrano[d]pyrimidines, and 4H-pyrans
in aqueous medium, J. Heterocycl. Chem. 51 (2013) 618–624.
[26] W.S. Matthews, J.E. Bares, J.E. Bartmess, F.J. Cornforth, G.E. Drucker, R.J. Mc-
Callum, G.J. McCollum, N.R. Vanier, F.G. Bordwell, Z. Margolin, Equilibrium
acidities of carbon acids. VI. Establishment of an absolute scale of acidities in
dimethyl sulfoxide solution, J. Am. Chem. Soc. 97 (1975) 7006–7014.
[27] F.G. Bordwell, H.E. Fried, Acidities of the H-C protons in carboxylic esters,
amides, and nitriles, J. Org. Chem. 46 (1981) 4327–4331.
[13] A. Thangamani, Grindstone Chemistry : an efficient and green synthesis of
2-amino-4H-benzo[b]pyrans, J. Appl. Adv. Res. 2 (2017) 78–85.
[14] N. Azizi, T.S. Ahooie, M.M. Hashemi, I. Yavari, Magnetic graphitic carbon ni-
tride-catalyzed highly efficient construction of functionalized 4H-pyrans, Syn-
lett 29 (2018) 645–649.
[28] J. Clayden, N. Greeves, S. Warren, Organic Chemistry, 2nd ed., Oxford Univer-
sity Press, Oxford, 2012.
[15] S.N. Maddila, S. Maddila, M. Khumalo, S.V.H.S. Bhaskaruni, S.B. Jonnalagadda,
An eco-friendly approach for synthesis of novel substituted 4H-chromenes in