One-pot three-component synthesis of 1-amidoalkyl naphthols and polyhydroquinolines using a deep eutectic solvent: a green method and mechanistic insight

Article abstract of DOI:10.1039/d0nj05687a

The multicomponent synthesis of 1-amidoalkyl naphthols and polyhydroquinolines has been developed as an atom-economic procedure catalyzed by a deep eutectic solvent ([CholineCl][ZnCl₂]₃). The reactions proceed smoothly at low temperatures for a short reaction time without the use of toxic and volatile organic solvents. Deep eutectic solvents are capable of not only allowing multicomponent reactions to proceed in high yield but also controlling the selectivity towards desired products. The mechanistic insight was examined by HRMS (ESI) to propose a plausible mechanism. Furthermore, [CholineCl][ZnCl₂]₃can be recycled in up to three consecutive cycles with an insignificant loss of catalytic activity under the optimized conditions.

Full text of DOI:10.1039/d0nj05687a

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DOI: 10.1039/D0NJ05687A
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One-pot three-component synthesis of 1-amidoalkyl naphthols
and polyhydroquinolines using deep eutectic solvent: A green
method and mechanistic insight
Received 00th January 20xx,
Accepted 00th January 20xx
Vu Thanh Nguyen,‡,a,b Hai Truong Nguyen‡,a,b and Phuong Hoang Trana,b,
*
DOI: 10.1039/x0xx00000x
Abstract. The multicomponent synthesis of 1-amidoalkyl naphthols and polyhydroquinolines has been developed as an
atom-economic procedure catalyzed by a deep eutectic solvent ([CholineCl][ZnCl2]3). The reactions proceed smoothly at
low temperatures for a short reaction time without the use of toxic and volatile organic solvents. Deep eutectic solvents
are capable of not only allowing multicomponent reactions to proceed in high yield but also controlling the selectivity
towards desired products. The mechanistic insight was examined by HRMS (ESI) to propose a plausible mechanism.
Furthermore, [CholineCl][ZnCl2]3 can be recycled up to three consecutive cycles with an insignificant loss of catalytic
activity under the optimized conditions.
www.rsc.org/
minimizing the production of hazardous waste.21-23 1-Amidoalkyl-2-
naphthols containing 1,3-amino oxygenated functional groups
possess many biological characteristics and pharmacological
Introduction
Deep eutectic solvents (DESs) are a new class of green solvents
analogous to ionic liquids, which are generally prepared by mixing a
hydrogen bond acceptor with a hydrogen bond donor under a
certain temperature.1 The deep eutectic solvents are generally
based on readily available and low-cost components such as choline
chloride and hydrogen bond donor (urea, ethylene glycol, glycerol,
glucose, etc.), which makes them more suitable for large-scale
applications.2 These compounds played a vital as catalysts or
solvents for organic synthesis reactions.3, 4 DESs have been used in
many areas such as extraction of cellulose,5 extraction of chitin,6
extraction of polysaccharides, lipid, and various polarities
compounds,7-10 electrolyte in dye-sensitized solar cells,11 electrolyte
in lithium-Ion battery,12 and electrolyte in electrochemical double-
layer capacitor.13 Recently, deep eutectic solvent [CholineCl][ZnCl2]3
from choline chloride and zinc chloride emerged as the green
catalyst in organic transformation. [CholineCl][ZnCl2]3 has been
successfully applied on several reactions such as Friedel-Crafts,14-17
Paal-Knorr,18 Diels-Alder,19 aza Diels–Alder.20
25
activities such as antitumor,24,
antibiotics,26 antianginals,27-29
antimalarial,30, 31 and HIV protease inhibitors.32, 33 Various reports
have been published regarding the preparation of
1-amidoalkyl-2-naphthol derivatives through the C-N, C-C coupling
reaction from 2-naphthol, aldehydes, and amides in the presence of
various catalysts such as sulfonated material,34-36 ionic liquid,37-41
nano-S8,42 Brönsted acid,43-45 deep eutectic solvents,46 ZrO(OTf)2,47
metal salt,48 oxide metal,49 thiamine hydrochloride,50 trityl
chloride,51 I2,52 montmorillonite K10 clay,53 cation-exchanged
resins,54 etc. However, many disadvantages existed in these
methods, including prolonged reaction time, low yield, high
reaction temperature, and the formation of by-products.
Polyhydroquinolines were important compounds of N-heterocycles,
which was obtained from the condensation reaction of aldehydes,
dimedone, ethyl acetoacetate, and ammonium acetate. These
compounds exhibited many critical biological activities and were
applied in the pharmaceutical field, such as potential α-amylase and
α-glucosidase inhibitors,55 antitumor,56 calcium antagonists,57
antiplasmodial,58 antibacterial,59 antiproliferative,60 antimalarial,61
antiatherosclerotic,62 and antidiabetic properties.63 There were
many methods for synthesizing polyhydroquinoline derivatives by
using the catalysts such as metal triflates,64 zeolites,65 ionic
Multicomponent reactions allow the rapid synthesis of diverse
compounds in a cost- and time-effective manner from abundant
and available starting materials. The prominent features of
multicomponent reactions are reducing overall steps and
67
69
71
liquids,66,
nanoparticles,68,
heterogeneous nanocatalyst,70,
organic-solid-acid,72 deep eutectic solvents,73,
organocatalysis,75 Brönsted acids,76 etc.
enantioselective
74
a
Department of Organic Chemistry, Faculty of Chemistry, University of Science,
Ho Chi Minh City 721337, Viet Nam.
b Vietnam National University, Ho Chi Minh City 721337, Viet Nam.
In this work, we report the efficient protocol for the
multicomponent synthesis of N-containing heterocyclics, including
‡ These authors contributed equally to this work.
Email: thphuong@hcmus.edu.vn
the
preparation
of
1-amidoalkyl-2-naphthols
and
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
polyhydroquinolines using [CholineCl][ZnCl2]3 as a green catalyst
This journal is © The Royal Society of Chemistry 20xx
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under solvent-free condition. The plausible mechanism was choline chloride, methanesulfonic acid, other deep euVteiecwtiAcrtsicolelvOennlintes
proposed by the mean of HRMS (ESI) analysis.
including [CholineCl][acid oxalic], [CDhOoIl:in10e.C1l0]3[u9r/Dea0]N2,J056a8n7Ad
[CholineCl][ethyleneglycol], and ionic liquids such as [BMIM]Cl and
[EMIM]Cl. No reaction occurred when the reaction was carried out
with [CholineCl][ethyleneglycol] or without a catalyst. The best
result was observed in the presence of 20 mol% of
[CholineCl][ZnCl2]3 at 60 oC for 40 min (Table 1, entry 10). The
Results and discussion
Preparation of [CholineCl][ZnCl2]3
[CholineCl][ZnCl2]3 was prepared from previous reports from
choline chloride and zinc chloride with a molar ratio of 1:3 (Scheme
1).14, 18, 77, 78 The reaction was carried out at 100 oC until a clear
colorless liquid obtained. The structure of the catalyst was
synthesis
of
N-((2-hydroxynaphthalen-1-
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60
yl)(phenyl)methyl)benzamide was also scaled up from 1 mmol scale
to 10 mmol scale without a significant drop in yield.
1
determined by H and 13C NMR spectra, FT-IR, HR-MS (ESI), Raman,
Table 1. The effect of various catalyst for the synthesis of N-((2-
1
and TGA. H and 13C NMR spectra provided signals consistent with
hydroxynaphthalen-1-yl)(phenyl)methyl)benzamide.a
previous literature (Fig. S1 and S2†).79 These results showed that no
impurities were detected by the NMR spectrum. The Fig. S3†
showed the FT-IR spectra of [CholineCl][ZnCl2]3, and reused
[CholineCl][ZnCl2]3 after three cycles. The vibrational band around
3409 cm-1 was from the O–H-stretching of the hydroxyl group.
Moreover, the bands at 30002890 cm-1 and 14381400 cm-1,
indicated the presence of alkyl groups. The peaks at 1125 and
1063 cm-1 were from the C-N vibration. The signals at 1045 and
950 cm-1 were found to correlate the C–O and C–C–O asymmetric
stretching. These results were compared with published works.18, 80
As displayed in Fig. S4†, the Raman spectrum indicated the signal at
130 cm-1, assigned to Zn–Cl stretching modes.81 The absorption
Entry
1
2
3
4
5
6
7
8
Catalysts
ZnCl2
FeCl2
AlCl3
Choline chloride
MsOHb
[CholineCl][acid oxalic]
[CholineCl][urea]2
[CholineCl][ethylene glycol]
[CholineCl][lactic acid]9
[CholineCl][ZnCl2]3
[BMIM]Cl
Isolated yield %
61
65
74
58
60
70
10
NRc
59
94 (83)d
6
8
NRb
9
10
11
12
13
-
peaks of ZnCl3 were found at 280 cm-1 and 340 cm-1.82 Based on
[EMIM]Cl
None
the Thermogravimetric analysis (TGA), the results showed that the
catalyst worked stably to 350-370 oC, responding well to reaction
conditions (Fig. S5†).
a
Reaction conditions: 2-Naphthol (1.0 mmol), aldehydes (1.0 mmol), and
acetamides (1.0 mmol) at 60 oC for 40 min with 20 mol% of catalyst.
b MsOH = Methanesulfonic acid
c NR: No reaction.
Cl
d 10 mmol scale.
N
ZnCl2
HO
To compare the present method with previous literature, the
reaction of 2-naphthol, benzaldehyde, and benzamide afforded N-
((2-hydroxynaphthalen-1-yl)(phenyl)methyl)benzamide in excellent
yield within 15 min under solvent-free condition (Table 2, entry 8).
[CholineCl][ZnCl2]3
In
condition, and simple reaction rendered
attractive from the viewpoint of green chemistry.
general,
the
availability
of
the
this
reagents, mild
method more
Scheme 1. [CholineCl][ZnCl2]3 synthesis process
Synthesis of 1-amidoalkyl naphthol derivatives
The catalytic activity of [CholineCl][ZnCl2]3 was investigated by the
synthesis of N-((2-hydroxynaphthalen-1-
Table 2. Comparison of current work with previous reports for
preparation of 1-amidoalkyl naphthols.
yl)(phenyl)methyl)benzamide, which performed between 2-
naphthol, benzaldehyde, and benzamide. The results were listed in
Table S1†. This reaction was conducted to investigate the influence
of reaction parameters such as reaction temperature, reaction
time, and amount of catalysts. To optimal condition reaction, the C-
N coupling reaction was performed at different temperatures such
as room temperature, 60, 80, 100, and 120 oC for 40 min, giving the
Temp. Time
Yield
(%)
Entry
Catalysts
(oC)
(min)
Fe3O4@C-SO3H MNPs
Solvent-free
[Msim]FeCl4 (5 mol%)
Solvent-free
IL@MNP (1.5 mol%)
Dichloroethane (10 mL)
AIL@MNP
1
2
3
4
80
160
8883
9584
6285
9186
110
30
3
o
best yield of the main product at 60 C (Table S1†, entry 2). Then,
70
22
the reaction time was investigated by varying the time from 10 min
to 60 min (Table S1†, entries 6-10). The amount of the catalyst was
also evaluated, and 20 mol% of [CholineCl][ZnCl2]3 was chosen to
study the reaction between 2-naphthol, benzaldehyde, and
benzamide. As can be seen in Table 1, the effect of various catalyst
was investigated with metal chlorides (ZnCl2, FeCl2, and AlCl3),
90
Solvent-free
Fe3O4@SiO2@IL-PVP
(0.015 g)
Solvent - free
5
6
80
15
20
9587
9788
nano-Fe3O4@ZrO2-
100
2 | J. Name., 2020, 00, 1-3
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H3PO4 (0.06 g)
[C6(MPy)2][CoCl4]2−
(0.2 g)
Solvent-free
This work:
[CholineCl][ZnCl2]3
(20 mol%)
Solvent-free
The reaction mechanism for the preparation of 1V-aiemw iAdrtoicalelkOynll-in2e-
naphthol was illustrated in Scheme 2. FromDtOheI: 1r0e.s1u0l3t9o/Df 0thNeJ0H56R8M7AS
analysis, a plausible reaction mechanism was proposed. Firstly,
benzaldehyde was activated by [CholineCl]-[ZnCl2]3. Then,
benzamide attacked to the carbonyl group of the benzaldehyde to
give intermediate (A), detected by HRMS (m/z 209.0562 [M+H]+,
Cacld. m/z 209.0840). Further, 2-naphthol was attacked and
condensed with intermediate (A). The intermediate (B) was
affirmed by HRMS (m/z 264.0980 [M+H]+, Cacld. m/z 264.1019).
Next, the deprotonation of intermediate (B) generated the desired
product, which was detected by HRMS (m/z 354.1489 [M] Cacld.
m/z 354.1433).
7
8
120
60
25
40
7541
94
10
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The reaction was then conducted with several amides and
aldehydes using [CholineCl][ZnCl2]3 as the catalyst under the
optimal conditions. The results were presented in Table 3. First, the
reaction was performed with aldehydes containing the electron-
donating groups (-CH3, -C(CH3)3) and electron-withdrawing groups (-
Cl, -F, -Br, -NO2, and –N(CH3)2) at the para position on the benzene
ring afforded desired products in high yield (compounds 1-8, Table
3). Next, the reaction was further investigated with furfural; the
yield of the product decreased significantly. The five-membered
heterocyclic compounds containing the oxygen resulted in lower
activity than the benzene ring (compound 9, Table 3). Aldehyde
derivatives containing substituents (-COOH, -OH) at the ortho
position on the benzene ring provided the desired products in low
yields due to steric obstacles (compounds 11-12, Table 3). Next, the
reaction of 2-naphthol, aldehydes, and 2-chloroacetamide in the
presence of [CholineCl][ZnCl2]3 occurred smoothly with good to
excellent yields (compounds 14-16, Table 3).
[CholineCl][ZnCl2]3
O
H
C6H5
N
C6H5
O
O
O
H
C6H5
H
O
H
O
OH
C6H5
NH2
C6H5
N
C6H5
C6H5
N
H
C6H5
H
(A)
H
C6H5
H
N
C6H5
O
C6H5
NH
OH
[CholineCl][ZnCl2]3
O
O
C6H5
H
(B)
Scheme 2. The plausible mechanism for preparation of 1-amidoalkyl
naphthol.
Table 3. Synthesis of 1-amidoalkyl naphthol using
[CholineCl][ZnCl2]3 as the catalysis.a
O
R2
R1 NH
Synthesis of polyhydroquinoline derivatives
OH
OH
O
To evaluate the catalytic activity of [CholineCl][ZnCl2]3, the synthesis
of polyhydroquinolines was carried out with aldehydes (1.0 mmol),
dimedone (1.0 mmol), ethyl acetoacetate (1.0 mmol), and
ammonium acetate (1.0 mmol). The results were described in Table
S2†. Initially, the parameter of condensation reaction was studied
[CholineCl][ZnCl2]3 (20 mol%)
R2 NH2 solvent-free, 60 oC,40-80 min
+ R1 CHO
+
F
O
O
Cl
O
O
NH
OH
NH
OH
NH
OH
NH
OH
o
with different temperatures (RT, 60, 80, 100, and 120 C), different
time (5, 10, 15, 20, 30, and 40 min), and the amount of catalyst (0,
0.5, 1, 2, 5, and 10 mol%). The optimal conditions were observed in
the formation of ethyl 2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydro-quinoline-3-carboxylate in the concentration of 0.5
(4)
87%
40 min,
O
(2)
78%
(3)
88%
50 min,
O
40 min,
O
(1)
94%
40 min,
O
N
O2N
Br
NH
NH
NH
NH
o
OH
OH
OH
OH
mol% of [CholineCl][ZnCl2]3 for 40 min at 100 C. The condensation
reaction was investigated with various catalysts, and the major
product was achieved in the highest yield with [CholineCl][ZnCl2]3
(entry 7, Table 4).
(8)
63%
(7)
89%
65 min,
O
(6)
95%
40 min,
O
(5)
88%
40 min,
O
40 min,
O
NH
NH
NH
NH
O
COOH
OH
Table 4. Effects of different catalysts for the preparation of
OH
OH
OH
OH
polyhydroquinolines.a
Entry
Catalyst
Isolated yield
(11)
50%
60 min,
O
(12)
56%
75 min,
O
(10)
95%
40 min,
O
(9)
45%
80 min,
O
(%)
35
28
54
63
32
32
87
O2N
Cl
Cl
Cl
Cl
1
2
3
4
5
6
7
MgO
Al2O3
ZnCl2
AlCl3
FeCl3
Cu(NO3)2
[CholineCl][ZnCl2]3
NH
NH
NH
NH
OH
OH
OH
OH
(16) 90%
40 min,
(15)
87%
80 min,
(14)
60%
55 min,
(13)
48%
75 min,
a Reaction condition: 2-naphthol (1.0 mmol), aldehydes (1.0 mmol) and amides
(1.0 mmol) in the presence of [CholineCl][ZnCl2]3 (20 mol%) at 100 oC. Isolated
yields.
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a
Reaction condition: Benzaldehyde (1.0 mmol), dimedone (1.0 mmol), ethyl
acetoacetate (1.0 mmol), ammonium acetate (1.0 mmol), and catalysts (0.5
mol%) at 100 oC for 20 min.
yields (compounds 19-25, Table 6). The presence of the substituent
View Article Online
at the ortho position of the aromatic aldehyDdOesI: i1n0c.1r0e3a9s/eDd0tNhJe05s6te8r7iAc
hindrances, which gave the desired products in low yields
(compounds 26-27, Table 6). The heterocyclic aldehydes containing
oxygen showed less reactivity toward condensation reactions for
the synthesis of ethyl 4-(furan-2-yl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate and their derivatives
(compounds 29-34, Table 6).
The preparation of ethyl 2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydro-quinoline-3-carboxylate from benzaldehyde, ethyl
acetoacetate, dimedone, and ammonium acetate under the present
method was compared with previous reports. From the results of
Table 5, the use of [CholineCl][ZnCl2]3 demonstrated some
advantages such as short reaction time, the ease of being recycled,
and economic and environmental efficiency.
10
11
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Table 6. [CholineCl][ZnCl2]3-catalyzed for synthesis of poly-
hydroquinolines.a
R
CHO
O
O
O
O
O
O
NH4OAc
OEt
R
+
+
Table 5. Comparing the current method in the reaction of
benzaldehyde, dimedone, ethyl acetoacetate, and ammonium
acetate with previous literature.
OEt [CholineCl][ZnCl2]3 (0.5 mol%)
solvent-free, 100 oC, 20 min
N
H
Yielda
%
Cl
Temp.
(oC)
Time
(min)
Entry
Catalysts
Cl
O
O
O
O
O
O
O
O
CoFe2O4@Pr (0.04 g)
EtOH (2 mL)
BIL@MNP (0.25 mol%)
solvent-free
1
2
reflux
70
400
15
9189
OEt
OEt
OEt
OEt
N
N
H
N
H
N
H
H
9290
(19) 85%
(20) 80%
(17) 75%
(18) 87%
OMe
TBA-AMPS (Ionic liquid)
(10 mol%)
MeOH
[(CH2)4SO3HMIM][HSO4]
(25 mol%)
F
3
4
reflux
8
9791
9092
O
O
O
O
O
O
O
O
OEt
OEt
OEt
OEt
OEt
OEt
reflux
67
N
H
N
H
N
N
H
H
EtOH (5 mL)
(23) 77%
(24) 75%
(21) 79%
(22) 76%
[TBA]2[W6O19] (7 mol%)
solvent-free
Hf(NPf2)4 (1 mol%)
Perfluorodecalin
Ni@IL-OMO (0.5 mol%)
solvent-free
[BBMIm][HSO4]2
(2.4 mol%) solvent-free
This work:
N
O
9593
9566
9694
9295
O2N
O
5
6
7
8
110
60
20
180
70
O
COOH
OH
O
O
O
O
O
O
O
OEt
OEt
OEt
N
N
H
N
H
N
15
H
H
(28) 71%
(27) 74%
(25) 80%
(26) 65%
OH
60
18
Br
Cl
O
O
O
O
O
O
O
O
O
O
O
O
[CholineCl][ZnCl2]3
(0.5 mol%)
OEt
OEt
OEt
9
100
20
87
N
H
N
N
H
N
H
H
solvent-free
(31) 68%
(29) 68%
(30) 72%
(32) 72%
Cl
With the optimized reaction conditions in hand, various starting
materials were tested to synthesize polyhydroquinoline derivatives
with [CholineCl][ZnCl2]3 under solvent-free conditions. All the
condensation reactions were carried out at 100 C for 20 min. The
results were presented in Table 6. In the case of
O
O
O
O
O
O
OEt
OEt
N
H
N
H
o
(34) 69%
(33) 70%
cyclohexanecarboxaldehyde
, the condensation reaction was
a
Reaction condition: Aldehydes (1.0 mmol), dimedone (1.0 mmol), ethyl
occurred to form ethyl 4-cyclohexyl-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate with good yield
(compound 17, Table 6). The catalytic effect of the
[CholineCl][ZnCl2]3 was then investigated with aromatic aldehydes
containing the electron-withdrawing (e.g., Cl, –F, –OCH3, –N(CH3)2)
and electron-donating groups (e.g., CH3, –C(CH3)3) at the ortho or
para position giving the major products were obtained in good
acetoacetate (1.0 mmol) and ammonium acetate (1.0 mmol) in the presence of
[CholineCl][ZnCl2]3 (0.5 mol%) at 100 oC in 20 min. Isolated yields.
The synthesis of polyhydroquinoline derivatives was carried out
through the reaction of benzaldehyde, ethyl acetoacetate,
dimedone, and ammonium acetate in the presence of
4 | J. Name., 2020, 00, 1-3
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1
2
3
4
[CholineCl][ZnCl2]3 as the green catalyst (Scheme 3), and the 1, and 1475 cm-1. The fresh and reused catalyst showed that the
precursors were monitored by HRMS. First, ethyl acetoacetate structure has remained mostly unchanged.
View Article Online
DOI: 10.1039/D0NJ05687A
interacted with ammonium acetate to form the imine (C), detected
by HRMS (m/z 130.95869). On the other hand, the Knoevenagel
condensation occurred between benzaldehyde and the active
methylene group of dimedone in the presence of [CholineCl][ZnCl2]3
to generate the α,β-unsaturated compound (D) with m/z
229.10520. Next, the imine (C) reacted with α,β-unsaturated
compound (D) to give the intermediate (E), determined by HRMS
(m/z 358.20593). Finally, the ethyl 2,7,7-trimethyl-5-oxo-4-phenyl-
1,4,5,6,7,8-hexahydro-quinoline-3-carboxylate was obtained via the
cyclization reaction, and this product was also detected by HRMS
(m/z 340.19134). Besides, some by-products were observed by
HRMS with different m/z values such as 330.16392 and 350.21205,
which could be assigned for diethyl 2,6-dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-dicarboxylate (from benzaldehyde and ethyl
acetoacetate)96 and 3,3,6,6-tetramethyl-9-phenyl-3,4,6,7,9,10-
5
6
7
8
9
10
11
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59
60
hexahydroacridine-1,8(2H,5H)-dione
(from
benzaldehyde,
dimedone, and ammonium acetate),97 respectively.
Figure 1. Recycling of [CholineCl][ZnCl2]3
H3N
H
AcO-
OH
AcO
NH3
O-
CO2Et
NH3
Me
-[AcOH]
+[AcO-]
O
AcO-
CO2Et
AcO
CO2Et
CO2Et
Me
Me
O
Experimental
General procedure for the preparation of 1-amidoalkyl naphthol
derivatives
Me
+
NH4
CO2Et
NH2
CO2Et
Me
CO2Et
H
CO2Et
NH2
CO2Et
NH3
NH3
H
-O
HO
O
Me
H2N
Me
H2N
Me
In a 25 mL round bottom flask, a mixture of 2-naphthol (1.0 mmol,
0.144 g), benzaldehyde (1.0 mmol, 0.106 g), benzamide (1.0 mmol,
0.121 g), and [CholineCl][ZnCl2]3 (20 mol%, 0.109 g) was heated at
Me
(C)
H3N
H
H2O
H
NH3
[CholineCl][ZnCl2]3
O
o
NH3
100 C for 40 min. The reaction times were monitored in Table 3
H
O
O
O
O
O
O
(checked by TLC). After completion, the reaction mixture was
allowed to cool to room temperature. The reaction mixture was
extracted with ethyl acetate (3 x 30 mL). The ethyl acetate layer was
washed with distilled water (3 x 10 mL). The organic layer was dried
over Na2SO4, and the solvent was recovered by a rotary evaporator.
The desired product was purified by crystallization from hot
ethanol. The structure and purity of the product were determined
by 1H, and 13C NMR, FT-IR, or HRMS (ESI).
H
H
C6H5
H
C6H5
C6H5
H
H
O
H
O
O
NH3
O
O
NH3
H
NH3
(D)
NH3
C6H5
C6H5
O
H3N
O
H
C6H5
H2N
CO2Et
Me
O
O
H
H
CO2Et
Me
CO2Et
Me
H2N
O
O
H2N
(C)
(D)
H3N
(E)
H
General procedure for the preparation of polyhydroquinoline
derivatives
NH3
In a 25 mL round bottom flask, a mixture of benzaldehyde (1.0
mmol, 0.106 g), dimedone (1.0 mmol, 0.140 g), ethyl acetoacetate
(1.0 mmol, 0.027 g), ammonium acetate (1.0 mmol, 0.077 g), and
[CholineCl][ZnCl2]3 (0.5 mol%, 0.0027 g) was heated at 100 oC for 20
min. After completion (checked by TLC), the reaction mixture was
allowed to cool to room temperature. Ethyl acetate was used to
extract the reaction mixture (3 x 30 mL). The ethyl acetate layer was
washed with distilled water (3 x 10 mL). The product was purified
by crystallization from hot ethanol. The structure and purity of the
product were determined by 1H, and 13C NMR, FT-IR, or HRMS (ESI).
C6H5
C6H5
O
H
O
CO2Et
Me
CO2Et
N
N
H
OH
H
H
H3N
H
[CholineCl][ZnCl2]3
Scheme 3. Proposed mechanism for preparation of
polyhydroquinolines
To study the reusability of the catalyst, the recovered
[CholineCl][ZnCl2]3 was tested in the synthesis of 1-amidoalkyl
naphthol and polyhydroquinoline (Fig. 1). The [CholineCl][ZnCl2]3
still remained a good activity after three consecutive runs. The
recovered catalyst was recorded by FT-IR spectroscopy. From Fig.
S3†, FT-IR spectra of fresh and recovered [CholineCl][ZnCl2]3
catalysts showed similar vibration bands within 3500 cm-1, 1619 cm-
Conclusions
In conclusion, we have successfully developed an effective method
for the multicomponent synthesis of 1-amidoalkyl naphthols and
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a Lewis acid 17. X. Jin, A. Wang, H. Cao, S. Zhang, L. Wang, X. VZiehweAnrgticlaenOdnlinXe.
1
2
3
4
5
6
7
8
polyhydroquinolines using [CholineCl][ZnCl2]3 as
catalyst. The process was accomplished under mild conditions, and Zheng, Res. Chem. Intermed., 2018, 44, 55D21O-I5: 1503.100.39/D0NJ05687A
the desired product was isolated easily through the recrystallization 18. H. Truong Nguyen, D.-K. Nguyen Chau and P. H. Tran, New J.
from hot ethanol. The prominent features of the present work are Chem., 2017, 41, 12481-12489.
an inexpensive catalyst, mild condition, and work-up simplicity. The 19. P. Amudha, G. Lavanya, K. Venkatapathy and C. J. Magesh,
straightforward multicomponent synthesis of these compounds Lett. Org. Chem., 2019, 16, 865-873.
from available starting materials is more favorable than the two- 20. A. Penaranda Gomez, O. Rodriguez Bejarano, V. V.
step procedure in terms of eliminating the isolation and purification Kouznetsov and C. Ochoa-Puentes, ACS Sustainable Chem. Eng.,
of precursors and saving energy, time, and chemicals. The plausible 2019, 7, 18630-18639.
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to the industry to reduce costs and to prevent environmental W.-M. He, ACS Sustainable Chem. Eng., 2019, 7, 1574-1579.
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5
O
O
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OH
R
CHO
R1 CHO
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O
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
NH4OAc
OEt
R2 NH2
[CholineCl][ZnCl2]3
O
R2
R1 NH
O
R
O
OEt
OH
N
H