Three-component synthesis of 4H-pyran scaffolds accelerated by a gabapentin-based natural deep eutectic solvent

Article abstract of DOI:10.1039/d0nj05342b

The development of environmentally benign synthetic protocols has attracted increasing attention in recent organic syntheses. As a part of this concept, our group synthesized a new natural deep eutectic solvent (NADES) by using gabapentin and choline chlo

Full text of DOI:10.1039/d0nj05342b

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Three-component synthesis of 4H-pyran scaffolds
accelerated by a gabapentin-based natural deep
eutectic solvent†
Cite this: New J. Chem., 2021,
45, 3138
Meysam Alipour Khoshdel, Farhad Shirini, * Mohaddeseh Safarpoor Nikoo Langarudi,
Mehdi Zabihzadeh
and Mohammad Biglari
The development of environmentally benign synthetic protocols has attracted increasing attention in
recent organic syntheses. As a part of this concept, our group synthesized a new natural deep eutectic
solvent (NADES) by using gabapentin and choline chloride. After characterization by FTIR, 1H and 13C
NMR, and mass spectra, the prepared NADES was utilized as an efficacious catalyst for the synthesis of
4H-pyran scaffolds such as tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone(thione) derivatives.
The use of inexpensive and bio-compatible reagents for the synthesis of the catalyst, a simple and green
procedure for the preparation of the catalyst and products, short reaction times, high yields of the products,
and applicability to large-scale synthesis are the prominent features of this protocol. Also, the catalyst could
be recovered easily and recycled up to five times without significant loss of its catalytic activity.
Received 31st October 2020,
Accepted 29th December 2020
DOI: 10.1039/d0nj05342b
rsc.li/njc
as very important biodegradable types of DESs. Amino acids are
highly abundant molecules which are well-known as the sub-
Introduction
For up to two decades, ionic liquids (ILs) have been selected as units of proteins. Amino acids hold an acidic (COOH) and a basic
green solvents for the replacement of traditional organic solvents (NH2) functional group in their structures. This special structure
in synthetic methodologies. For years, scientists’ attempts have causes brilliant properties in these materials. Because of these
led to less moisture-sensitive ionic liquids and metal-free ones groups, amino acids can be convenient H-bond donors for the
designed for specific tasks. However, the sustainability and preparation of DESs. Based on the relative position of the COOH
greenness of ILs have grown dubiously and chemists struggle and NH2 groups, amino acids are divided into a, b, g, and d ones
to find novel solvent–catalysts to use in organic syntheses. To (Fig. 1). Although a-amino acids are known as protein-building
develop eco-friendly solvents, deep eutectic solvents (DESs) have amino acids (proteinogenic), non-proteinogenic amino acids are
attracted a great deal of attention because they show ionic used as intermediates in metabolic pathways (e.g. b-alanin is an
character like ILs. However, they are more cost-saving (because intermediate in the synthesis of vitamin B5 in plants and
of the use of inexpensive raw materials), less toxic, and more microorganisms)5 or as medications in the drug industry (gaba-
biodegradable than ILs. DESs consist of a mixture of compounds pentin is e.g. used to treat neuropathic pain6 and pregabalin is a
possessing lower melting points than their ingredients. This cut medication for treating epilepsy and fibromyalgia).7
in the melting point is due to the formation of hydrogen bonding
between H-bond donor and acceptor species used for the the B complex vitamins, that plays key roles in many biological
preparation of the requested DES.1
processes. It is a constituent of sphingomyelin and lecithin and
Choline is an essential nutrient, commonly grouped with
In recent years, Dai and co-workers focused on natural a precursor of acetylcholine. Choline plays a vital role in methyl
compounds that can be used as H-bond donors such as organic group metabolism, carcinogenesis, and lipid transport. Its
acids, amino acids, and sugars.2,3 Use of these compounds along deficiency is associated with a fatty liver.8 It can be used for
with a natural H-bond acceptor like choline chloride, betaine, bodybuilding and delaying fatigue in endurance sports. On the
glycerol, and lactic and malic acids3,4 causes the development of other hand, researchers showed that taking choline can loosen
a novel category named Natural Deep Eutectic Solvents (NADESs) the symptoms of asthma in people who have this disease.9 In
recent years, the choline chloride reagent as a bi-functional
Department of Chemistry, College of Sciences, University of Guilan, Rasht,
compound containing quaternary ammonium and alcoholic
41335-19141, Iran. E-mail: shirini@guilan.ac.ir; Fax: +98 131 3233262;
groups is widely used in the synthesis of DESs.10–13 4H-Pyrans
Tel: +98 1313233262
† Electronic supplementary information (ESI) available: FT-IR, 1H NMR & 13C
and pyran-annulated heterocyclic scaffolds have attracted great
attention due to their diverse useful biological and pharmacological
NMR of new products. See DOI: 10.1039/d0nj05342b
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Fig. 1 Amino acids, categorized based on the relative position of the functional groups (NH2 and COOH).
activities such as antimicrobial,14 anti-cancer,15,16 antiviral, and
antileishmanial properties.17
FT-IR spectra were recorded with a PerkinElmer Spectrum
BX series and KBr pellets were used for solid samples. 1H NMR
They are also used as cognition-enhancing drugs for the and 13C NMR spectra were determined on a Bruker AV-400 and
treatment of neurodegenerative disease, including schizophrenia, 500 using TMS (0.00 ppm) as an internal standard and DMSO-
Alzheimer’s disease, Parkinson’s disease, Huntington’s disease d6 and CDCl3 as solvents. Mass spectra were measured using an
and Down’s syndrome.18
Agilent Technologies 5975C spectrometer via a mass selective
In this study, a new natural deep eutectic solvent was prepared detector operating at an ionization potential of 70 eV.
from gabapentin and choline chloride. After identification its
Preparation of the [Ch]Cl:Gab NADES
catalytic activity was investigated in the synthesis of 4H-pyran
scaffolds such as tetrahydrobenzo[b]pyran and pyrano[2,3-d]-
pyrimidinone(thione) derivatives.
A mixture of choline chloride ([Ch]Cl) (6.98 g, 50 mmol) and
gabapentin (Gab) (8.56 g, 50 mmol) was ground in a mortar at
room temperature for 30 min until a homogeneous white highly
viscous liquid appeared. Then, the reaction was stopped and the
prepared NADES was collected without any further purification.
The characterization of the obtained NADES was done using
Experimental
Materials
1
FT-IR, mass, H NMR, and 13C NMR spectroscopic techniques.
All of the aldehydes, malononitrile, C–H activated acidic compounds,
gabapentin, and choline chloride were purchased from Sigma-
Aldrich (Mumbai) and Merck (Munich) chemical companies and
were used without further purification. The purity of the substrates
was monitored by thin-layer chromatography (TLC). All solvents were
purchased from Merck (Munich) and were kept sealed in airtight
bottles as well to minimize the absorption of atmosphere moisture.
Moreover, they were distilled before being used.
General procedure for the synthesis of tetrahydrobenzo[b]pyran
and pyrano[2,3-d]pyrimidinone(thione) derivatives
In a round-bottomed flask (10 mL) a mixture of aldehyde 1
(1 mmol), the requested C–H activated acidic compound 2
(1 mmol), malononitrile 3 (1 mmol), and the prepared NADES
(0.031 g, 10 mol%) was stirred and heated in an oil-bath at 75 1C
for an appropriate period of time. After completion of the reaction
(monitored by TLC [n-hexane–EtOAc (10 : 2)]), water was added to
separate the catalyst. Then, the precipitated product was filtered,
dried, and subsequently recrystallized from ethanol (4a–y).
Characterization techniques
The products were characterized by their physical constants,
comparison with authentic samples, and IR and NMR spectro-
scopies. The purity determination of the substrate and reaction
monitoring were accomplished by TLC on silica-gel polygram
SILG/UV 254 plates. Melting points were measured using an electro-
Results and discussion
thermal IA9100 melting point apparatus in capillary tubes. The In recent years the use of organocatalysts in organic transfor-
starting temperature of the approximate melting range was input mations has become an important part of our ongoing research
via the keyboard and the melting point range was spotted visually. program.19,20 In this line, very recently we have reported the
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spectrum of the [Ch]Cl:Gab NADES, the broad peak in the 2500–
3500 cmÀ1 region is related to the vibrations of –OH in choline
chloride and gabapentin. Also, the average peak observed at
3020 cmÀ1 is related to the vibrations of the aliphatic CH bonds.
Also, the sharp peaks at 955 and 1080 cmÀ1 are related to the C–N
and C–O tensile vibrations, respectively.
Scheme 1 Preparation of the [Ch]Cl:Gab NADES.
Mass spectroscopy
The mass spectrum of the [Ch]Cl:Gab NADES is shown in Fig. 3.
The molecular ion peak (M+) appearing at m/z = 311 with relative
intensity up to 0.40 corresponds to the molecular weight of the
catalyst. Other ion peaks at m/z = 171 (11.2, gabapentin), m/z =
140 (5.6, [Ch]Cl[OH]), m/z = 128 (1.2, C8H17N), and m/z = 44
(24.8, C2H5O) and the base peak at m/z = 81.0 (100, C6H12) are
also observed clearly.
preparation of a choline chloride, urea, and thiourea based DES
and its ability in the promotion of some multi-component
reactions.21 Herein and in continuation of these studies we
wish to report the preparation, identification, and application
of the [Ch]Cl:Gab NADES as a new, green, and efficient natural
deep eutectic solvent in the promotion of the synthesis of
tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone(thione)
derivatives.
NMR spectroscopy
1
In the H NMR spectrum, of the prepared [Ch]Cl:Gab NADES,
Catalyst characterization
the aliphatic hydrogens of the are appeared as multiplet in the
range of 1.41 to 1.21 ppm. The H7 and H8 peaks are seen at
2.22 ppm and 2.64 ppm, respectively. The peak related to H13
appears with coupling constant 4 Hz at 3.44 ppm as a triple and
the quadrated H14 peak comes up with coupling constant
4 Hz at 3.82 ppm. The weakness of the OH and NH peaks also
indicates the formation of hydrogen bonds in this compound
(Fig. 4).
After preparation of the [Ch]Cl:Gab NADES (Scheme 1), various
spectroscopic techniques were used to characterize its structure.
Here are some elucidations in detail.
FT-IR analysis
The FT-IR spectra of the prepared [Ch]Cl:Gab NADES, choline
chloride, and gabapentin are shown in Fig. 2. In the FT-IR
In the 13C NMR spectrum of the prepared DES the number
of peaks observed is equal to the number of carbons of the
compound, and the peak corresponding to the carboxyl group
appears at 175.1 ppm (Fig. 5).
Catalytic activity
The obtained data from the structural studies pointed out that
the [Ch]Cl:Gab NADES is successfully synthesized. In the next
step and in order to show the catalytic ability of this new
NADES the promotion of the synthesis of tetrahydrobenzo[b]-
pyran and pyrano[2,3-d]pyrimidinone(thion) derivatives in the
presence of this reagent was investigated. The study was started
by the optimization of the three-component reaction of 4-chloro-
benzaldehyde, dimedone, and malononitrile as a model one. In
this regard, the effect of different factors such as the catalyst
loading, temperature, and solvent in this reaction was studied.
Preliminary experiments revealed that only a trace amount of the
desired product can be obtained when the reaction proceeded in
aprotic solvents such as CH3CN and CH3Cl at reflux temperature.
Next, the reaction was tested in protic solvents, water, and EtOH,
at room temperature and under reflux conditions.
In these cases, the reactions were not completed after a
prolonged time of reaction (60 min). When the reaction was
carried out under solvent-free conditions, both the reaction
times and yields were drastically improved. Further studies, as
shown in Table 1 (entry 7), clarified that the best result can be
obtained in the presence of 10 mol% of the [Ch]Cl:Gab NADES
at 75 1C in the absence of solvent. It is very important to note
Fig. 2 FT-IR spectra of gabapentin (a), choline chloride (b) and the
[Ch]Cl:Gab NADES (c).
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Fig. 3 Mass spectrum of the [Ch]Cl:Gab NADES.
Fig. 4 1H NMR spectrum of the [Ch]Cl:Gab NADES.
that when the reaction proceeded in the presence of choline scope and generality of this protocol, different types of aro-
chloride or gabapantine, it was not completed even after long matic aldehydes containing electron-withdrawing or electron-
reaction times (Table 1, entries 11 and 12). To demonstrate the donating groups in the ortho, meta, and para positions of the
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Fig. 5 13C NMR spectrum of the [Ch]Cl:Gab NADES.
Table 1 Optimization of the amounts of the catalyst, temperature and solvent in the synthesis of the tetrahydrobenzo[b]pyran derivative of 4-
chlorobenzaldehyde
Entry
Catalyst (mol%)
Solvent
Temp. (1C)
Time (min)
Conversion (%)
1
2
3
4
5
6
7
8
[Ch]Cl:Gab NADES (10)
[Ch]Cl:Gab NADES (10)
[Ch]Cl:Gab NADES (10)
[Ch]Cl:Gab NADES (10)
[Ch]Cl:Gab NADES (10)
[Ch]Cl:Gab NADES (5)
[Ch]Cl:Gab NADES (10)
[Ch]Cl:Gab NADES (20)
[Ch]Cl:Gab NADES (30)
[Ch]Cl:Gab:H2O (30)
Gabapentin (10)
H2O
H2O
C2H5OH
CH3CN
CH3Cl
—
—
—
—
—
r.t.
60
60
60
60
60
11
7
10
15
20
60
60
60
Trace
Reflux
Reflux
Reflux
Reflux
75
75
75
75
75
100
100
100
Not completed
Not completed
Trace
Trace
100 (87)a
100 (95)a
100 (90)a
100 (85)a
100 (85)a
Not completed
Not completed
Trace
9
10
11
12
13
—
—
—
[Ch]Cl (10)
—
a
The yields are related to the isolated products.
aromatic ring and other C–H activated acidic compounds such
as 1,3-cyclohexanedione and (thio)barbituric acid were reacted
with malononitrile under the same reaction conditions in the
presence of the prepared DES to obtain tetrahydrobenzo[b]pyran
and pyrano[2,3-d]-pyrimidinone(thione) derivatives, respectively
(Scheme 2 and Table 2). As indicated in Table 2, all of the selected
starting materials reacted smoothly during acceptable reaction
Scheme 2 Synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyr-
times with high yields. Furthermore, pyridine-4-carbaldehyde imidinone derivatives catalyzed by the [Ch]Cl:Gab NADES.
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Table 2 Preparation of tetrahydrobenzo[b]pyran (entries 4a–l) and pyrano[2,3-d]pyrimidinone(thione) (entries 4m–y) derivatives using [Ch]Cl:Gab
NADES as the catalyst
Melting point (1C)
Time
(min)
TOF
Entry
Aldehyde
Product
Yielda (%)
(minÀ1)/100
Obs.
Lit. [ref.]
1
4-ClC6H4CHO
7
18
28
95
1.357
0.478
0.325
208–210
208–21024
2
2-Carboxy benzaldehyde
86
189–192
New
3
Cinamaldehyde
91
198–200
189–19125
4
4-NMe2C6H4CHO
27
89
0.333
198–200
199–20326
5
4-SMeC6H4CHO
14
88
0.628
210–212
211–21219
6
2-Naphthaldehyde
16
92
0.575
260–262
255–25726
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Table 2 (continued)
Melting point (1C)
Time
(min)
TOF
Entry
Aldehyde
Product
Yielda (%)
(minÀ1)/100
Obs.
Lit. [ref.]
7
3-CHOC6H4CHOb
19
90
0.473
243–245
243–24426
8
4-CHOC6H4CHOb
18
91
0.506
267–268
264–26626
9
4-OMeC6H4CHO
3-NO2C6H4CHO
4-SMeC6H4CHO
16
11
27
92
94
90
0.575
0.855
0.333
203–205
214–216
216–218
202–20419
212–21425
217–21919
10
11
12
Pyridine-4-carbaldehyde
23
88
0.382
228–231
New
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Table 2 (continued)
Melting point (1C)
Time
(min)
TOF
Entry
13
Aldehyde
C6H5CHO
Product
Yielda (%)
(minÀ1)/100
Obs.
Lit. [ref.]
14
90
0.643
224–226
224–22524
14
4-ClC6H4CHO
8
94
1.175
237–240
237–24024
15
16
17
3-OHC6H4CHO
2-NO2C6H4CHO
3-BrC6H4CHO
12
13
13
91
92
92
0.758
0.708
0.708
160–161
248–250
245–247
160–16227
249–25127
254–25628
18
4-NMe2OC6H4CHO
16
90
0.563
230–232
231–23329
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Table 2 (continued)
Melting point (1C)
Time
(min)
TOF
Entry
Aldehyde
Product
Yielda (%)
(minÀ1)/100
Obs.
Lit. [ref.]
19
4-CHOC6H4CHOb
16
90
0.563
4300
430026
20
21
22
23
2-MeC6H4CHO
12
15
19
23
90
87
91
89
0.750
0.580
0.479
0.387
222–224
210–213
242–244
243–245
223–22529
211–21229
242–24526
245–24730
Pyridine-4-carbaldehyde
2-NO2C6H4CHO
3-BrC6H4CHO
24
3-OMeC6H4CHO
21
22
89
88
0.424
0.400
235–238
New
New
25
2-ClC6H4CHO
240 (dec.)
a
b
Isolated yield. In this case 2 mmol of malononitrile and 2 mmol dimedone were used.
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was used as a heterocyclic aldehyde under the same conditions,
and the related derivatives were successfully obtained in high
yields during short reaction times (Table 2, entries 12 and 21).
In order to show the reusability potential of the catalyst, the
syntheses of 2-amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile 4a (Table 2, entry 1) and
7-amino-5-(4-chlorophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano-
[2,3-d]pyrimidine-6-carbonitrile 4n (Table 2, entry 14) were studied
again. For this purpose, after completion of the reaction, the solid
product was washed with water to separate the catalyst ([Ch]Cl:Gab
NADES is soluble in water). Then, the filtrate was evaporated under
reduced pressure. The obtained catalyst was washed with diethyl
ether and dried. No appreciable change in the color and the
physical properties of the recovered [Ch]Cl:Gab NADES was
observed. The FT-IR spectrum of the recycled catalyst was the
same as the freshly prepared one, showing the stability of this
reagent in the reaction media. The recovered catalyst was reused
for at least five runs without appreciable loss of its catalytic activity
(Fig. 6 and 7).
Fig. 7 Reusability of [Ch]Cl:Gab NADES in the synthesis of 4n.
The mechanism of the reaction passes through two distinct
routes as soon as the carbonyl group of aldehyde 1 gets
H-bonded by the NADES (intermediate a). What makes a
difference between routes 1 and 2 is the difference between
the attack speed of b or d to a. So, the rate of formation of
intermediates b and d from 1,3-diketone 2 and malononitrile 3,
respectively, affects the reaction rate. Two factors can impact
the formation of b and d in acidic media, provided by DES.
First, in malononitrile 3, acidic hydrogens (–CH2–) are bonded
with two sp carbons (–CN), whereas, in 1,3-diketone 2, these
hydrogens are in correlation with two sp2 carbons (–CQO). The
higher s-character in an orbital, the more electronegative it will
be. Therefore, because of the two more electron-withdrawing
functional groups (–CN) in malononitrile 3, it shows more
acidic character than 1,3-diketone 2. Losing an acidic hydrogen,
malononitrile 3 changes to a weak base (b), which is reversed by
retrieving a hydrogen. In a more acidic medium, this reaction
increasingly undergoes a reverse. Second, the sp orbital in
nitrogen decreases the energy level of its lone pairs to bond
with hydrogen, so oxygen is H-bonded more rapidly.
On the other hand, oxygen can form a bifurcated H-bond22,23
(depicted in red dashed lines) which causes intermediate d to
become more stable. As a result, the formation of intermediate
d takes place in a shorter time. According to the reaction rate
equation (eqn (1)), where A and B represent the concentration of
the reactants, exponents x and y are the partial reaction orders
for reactants A and B, respectively, and k is the reaction rate
constant for a reaction, the rate of the reaction is correlated with
the concentration of the reactants. So when the concentration of
intermediate d is increased, the Knoevenagel condensation of
aldehyde 1 and 1,3-diketone 2 occurred at a rapid rate.
r = k[A]x[B]y
(1)
This fact that oxygen forms a stronger and more rapid H-bond
impacts the mechanism till the product (4a–y) produces. In the
Michael-addition, oxygen H-bonding in intermediate 5 causes
the Michael-addition product (intermediate e) to generate d
more quickly. In this step, b and d have already been produced
and the rate of H-bonding in them is not effective. All outcomes
result in route 2 being a shorter and faster pathway to produce
the products (4a–y) in acidic media (S-17).
To highlight the efficiency of the presented method, we
compared some of the results obtained in the presence of the
[Ch]Cl:Gab NADES with the same ones obtained in the presence
of other catalysts as reported in the literature. As shown in
Table 3 the [Ch]Cl:Gab NADES can be proposed as a useful
catalyst in terms of the reaction times, amounts of the catalyst
and yields. Moreover, the preparation of this reagent is straight-
forward, and does not require further purification steps which
is very worthwhile from the viewpoint of economic and envir-
onmental issues (green chemistry).
We also examined the possibility of the present method for
large-scale performance via the reaction of 4-chlorobenzaldehyde
Fig. 6 Reusability of [Ch]Cl:Gab NADES in the synthesis of 4a.
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Table 3 Comparison of the catalytic activity of the [Ch]Cl:Gab NADES with some reported catalysts in the synthesis of 4-chlorophenyl derivatives of
tetrahydrobenzo[b]pyran (entries 1–9) and pyrano[2,3,d] pyrimidinone (entries 10–17)
Entry
Catalystref.
Amount Conditions
Time (min) Yield (%) TOF (minÀ1)/100
1
2
3
4
5
6
7
8
9
Urea31
10 mol% EtOH : H2O (1 : 1)/r.t.
20 mol% H2O : EtOH (2 : 1)/40 1C
20 mol% EtOH/reflux
180
80
40
87
78
91
80
95
94
90
92
95
0.048
0.049
0.114
—
0.122
0.078
—
Fructose32
Glutamic acid33
SO42À/MCM-4134
2,2,2-Trifluoroethanol35
DABCO36
25 mg
2 mL
EtOH/reflux
Reflux
60
300
120
10
120
7
10 mol% H2O/reflux
Fe3O4@MCM-41@Zr-piperazine37 30 mg
H2O : EtOH (7 : 3)/reflux
80 1C
[Ch]Cl/urea38
2 mL
0.837
1.357
[Ch]Cl:Gab NADESa
10 mol% Solvent free/75 1C
10
11
12
13
14
15
16
17
18
19
Urea31
10 mol% EtOH : H2O (1 : 1)/r.t.
10 mol% THF : H2O (8 : 2)/reflux
840
110
720
20
86
85
92
95
89
92
82
93
93
92
0.010
0.077
—
—
—
0.077
0.820
0.245
0.152
0.460
Boric acid39
Al-HMS-2040
30 mg
EtOH/r.t.
H2O/80 1C
41
Fe3O4@SiO2-Propyl-Pip-SO3HÁHSO4 30 mg
Nano-titania sulfuric acid39
20 mg
EtOH : H2O (19 : 1)/reflux 60
42
CaHPO4
10 mol% H2O : EtOH (4 : 1)/80 1C 120
50 mol% EtOH/75 1C
20 mol% H2O/90 1C
36 mol% H2O/reflux
10 mol% Solvent free/75 1C
43
[Ch]Cl/ZnCl2
2
19
17
20
Taurine/ChCl DES44
ChCl/urea/thiourea DES21
[Ch]Cl:Gab NADESa
a
This work.
(10 mmol), malononitrile (10 mmol), and dimedone or barbituric Acknowledgements
acid (10 mmol) using 10 mol% [Ch]Cl:Gab NADES in an oil-bath
We are thankful to the Research Council of University of Guilan
for the partial support of this research.
at 75 1C. The reactions were found to proceed smoothly in both
cases affording the desired products, 2-amino-4-(4-chlorophenyl)-
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile 4a
(10 min, 95%) and 7-amino-5-(4-chlorophenyl)-2,4-dioxo-1,3,4,5-
tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile 4n (25 min,
94%), almost similar in all respects to the 1 mmol scale (Table 2,
entries 1 and 14). The above results indicate that a large-scale
reaction is achievable using the [Ch]Cl:Gab NADES as the catalyst.
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There are no conflicts to declare.
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