Hydroquinolines via the Hantzsch Reaction Promoted by SiO2-I

Full text of DOI:10.1080/00304948.2016.1206422

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
Hydroquinolines via the Hantzsch Reaction
Promoted by SiO2-I
Abdul Ahad & Maqdoom Farooqui
To cite this article: Abdul Ahad & Maqdoom Farooqui (2016) Hydroquinolines via the Hantzsch
Reaction Promoted by SiO2-I, Organic Preparations and Procedures International, 48:5, 371-376
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Date: 10 September 2016, At: 02:17

Organic Preparations and Procedures International, 48:371–376, 2016
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2016.1206422
Hydroquinolines via the Hantzsch Reaction
Promoted by SiO2-I
Abdul Ahad and Maqdoom Farooqui
Post Graduate and Research Centre, Dr. Rafiq Zakaria Campus, Maulana Azad
College, Rauza Baugh, Aurangabad (M.S), India
Hydroquinolines that incorporate the 1,4-dihydropyridine motif constitute a privileged
structures with broad biological activities such as in amlodipine, nicardipine, nifedipine
and isra-dipine used in the treatment of hypertension and cardiovascular diseases.1
Recent studies have shown that quinoline scaffolds are of substantial interest as they dis-
play a broad range of properties such as anti-diabetic,2 broncho-dilating,3 neurotropic,4
bactericidal and herbicidal5 and anti-cancer activity6 and can also act as glycoprotein
inhibitors.7 Furthermore, some hydroquinolines may be used as therapeutic agents in the
treatment of Alzheimer’s disease because they reduce cellular t levels.8 2,4-Disubstituted
hydroquinolines have been established as lipid modulating and anti-hyperglycemic
agents.9
This broad range of applications has elicited numerous methods for the preparation of
these compounds. The four-component condensation of aldehydes, a diketone, a b-keto
ester and ammonium acetate is one of the simplest, most common and straightforward
approaches under a variety of conditions such as traditional heating,10 use of micro-
wave,11 of ultrasound 12 and of catalysts and reagents such as cerric ammonium nitrate,13
TMSCl,14 organocatalysts,15 sulfamic acid,16 Al2(SO)3,17 Baker’s yeast,18 ZnO-beta zeo-
lite,19 thiourea dioxide,20 HClO4–SiO2,21 heteropoly acids,22 FeF3,23 molecular iodine,24
ZrCl4,25 PPA-SIO2,26 nano particles,27–29 metal triflates,30–31 thiazolium ion32 and ceric
ammonium nitrate.33 However, several of these procedures suffer from some disadvan-
tages such as hazardous catalysts or solvents, formation of by-products, prolonged reac-
tion times, use of expensive metal precursors and high temperature conditions and in
some cases, the need to use microwave or ultrasonic irradiation. However, some of the
nano particles and heterogeneous acids catalysed procedures provide better yields, but
they are not only expensive, their preparation requires tedious procedure and results in
low yields. Thus the development of a new convenient and efficient protocol that avoids
many of these drawbacks is highly desirable. The present work reports the use of silica
iodide (SiO2-I) as a highly efficient and inexpensive heterogeneous catalyst for the prepa-
ration of hydroquinolines (Scheme. 1). In comparison with mineral acids, metal trifaltes,
nano particles and other heterogeneous catalysts, SiO2-I is non-corrisive, economical,
provide ease of preparation and handling, cleaner reaction profile; can be separated easily
Received November 27, 2015; in final form May 13, 2016.
Address correspondence to Maqdoom Farooqui, Post Graduate and Research Centre, Dr. Rafiq
Zakaria Campus, Maulana Azad College, Rauza Baugh, Aurangabad (M.S), India. E-mail:
maqdoomf789@gmail.com
371

372
Ahad and Farooqui
with high recovery and reusability. These features lead to decreasing environment pollu-
tion and equipment cauterization, as the hallmarks of green chemistry are atom efficiency,
elimination of toxic reagents, safe and cleaner aspects, reduction in the generation of
waste and re-usability of the reagents.34–38 To our knowledge, there is only one report on
the application of silica iodide (SiO2-I) as a catalyst in organic transformations.39
O
R1
O
O
COR4
Me
O
O
O
SiO2- I
R.T
R2
R3
NH4OAc
4
R1
Me
R4
H
R2 R3
2
N
H
1
3
5 (a-q )
a) R1 = C6H5, R2, R3 = Me, R4 = OEt; b) R1 = 4-ClC6H4, R2, R3 = Me, R4 = OEt; c) R1 = 3-NO2-
C6H4, R2, R3 = Me, R4 = OEt; d) R1 = 2-ClC6H4, R2, R3 = Me, R4 = OEt; e) R1 = 4-MeC6H4, R2,
R3 = Me, R4 = OEt; f) R1 = 4-MeOC6H4, R2, R3 = Me, R4 = OEt; g) R1 = 4-HOC6H4, R2, R3 =
Me, R4 = OEt; h) R1 = 4-Me2NC6H4, R2, R3 = Me, R4 = OEt; i) R1 = 4-BrC6H4, R2, R3 = Me, R4
= OEt; j) R1 = 4-HO-3-MeOC6H3, R2, R3 = Me, R4 = OEt; k) R1 = C6H5CH=CH, R2, R3 = Me,
R4 = OEt; l) R1 = Et, R2, R3 = Me, R4 = OEt; m) R1 = n-Pr, R2, R3 = Me, R4 = OEt; n) R1 =
C6H5, R2, R3 = H, R4 = OEt; o) R1 = 3-NO2 C6H4, R2, R3 = H, R4 = OEt; p) R1 = 4-MeOC6H4, R2,
R3 = H, R4 = OEt; q) R1 = 3-MeOC6H4, R2, R3 = Me, R4 = Me;
Scheme 1
We initiated our study with one equivalent (1 mmol) of 4-chlorobenzaldehyde, ethyl
aceto-acetate (1 mmol), dimedone (1 mmol) and ammonium acetate (1 mmol) in ethanol at
room temperature as a model reaction (5b). Various amounts of the catalyst (SiO2-I) ranging
from 0.05 g to 0.15 g were attempted and it was found that the use of 0.1 g of the catalyst
for a one mmol scale proved to be best to lead to the highest yield of 5b (70%). Although a
better yield of product 5b (70% in ethanol) was obtained, some amount of the symmetrical
diethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylate was also
formed as a side-product of reaction of ethyl acetoacetate, 4-chlorobenzaldehyde and
ammonium acetate, it was isolated by column chromatography. It was found that the use of
a 1.5 mmol of dimedone completely minimize the formation of this by-product, therefore,
1.5 mmol of dimedone or 1,3-cyclohexanedione were utilized for all the reactions (5a–5q).
Once the reaction conditions were optimized, the generality and efficiency of the pro-
cedure was explore for the synthesis of a wide variety of substituted corresponding hydro-
quinoline derivatives (Table 1, Entries 1–17). The reaction conditions are sufficiently
mild to tolerate a variety of groups such as OCH3, NO2, OH, Cl, Br on the benzene ring
of aldehydes (Table 1, Entries 1–10 and 14–17). Morever amino (NH2) group substitutd
benzaldehydes were also utilized in this reaction; unfortunately, only sticky materials of
dark colored were obtained and none of the desired products could be formed. The reac-
tions of aliphatic aldehydes such as propionaldehyde and butyraldehyde proceeded more
slowly and gave the corresponding quinolines in somewhat lower yields (Table 1, Entries
12, 13) while cinnamaldehyde reacted more rapidly and gave an excellent yield of the
expected product (Table 1, Entry 11). The cyclic ketone, dimedone was then replaced
with 1,3-cyclohexanedione and the reaction with different aldehydes were performed.
The resulting hydroquinolines were produced in equally high yields (Table 1, Entries
14–16). We then focused our attention on replacing ethyl acetoacetate by acetyl acetone

Hydroquinolines via the Hantzsch Reaction Promoted by SiO2-I
373
Table 1
SiO2-I Catalyzed Synthesis of Hydroquinolines (5) at RT
EtOH
Solvent-free
mpꢀC
Entry Products Time (min) Yield Time (min) Yield
Found
Lit
1
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
80
80
90
90
80
80
80
90
90
90
80
90
90
80
80
80
80
84
85
78
80
85
88
83
80
84
75
86
58
62
81
82
84
83
30
30
40
30
30
30
30
40
40
40
30
40
40
30
30
30
30
90
92
84
88
92
94
90
85
88
80
90
68
72
91
93
94
90
207–209 209–21024
241–243 244–24633
173–175 177–17818
202–204 206–20811
258–260 260–26130
260–262 258–25930
234–236 237–23824
220–222 222–22318
256–258 253–25530
228–230 225–22718
202–204 204–20630
144–145 145–14630
142–144 146–14730
238–240 240–24124
196–198 198–20024
190–192 193–19524
206–208 205–20615
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
in a reaction, here also the corresponding hydroquinoline was synthesized in quantitative
yields (Table 1, Entry 17).
The reactions carried out under solvent-free conditions by grinding the reagents
together in an agate mortar at room temperature proceeded successfully in less time with
increased yields (Table 1, Entries 1–17). All the products (5a–q) are known compounds
and their structures were confirmed by comparison of their physical and spectral data
with those reported previously.24–33,11,15,18 The catalyst SIO2-I was prepared by the
reported method with some minor modifications.39
One of the advantages of using heterogeneous catalysts is their re-cyclability and re-
usability. After completion of the reaction, SiO2-I can be easily separated from the reac-
tion mixture and after drying at 100ꢀC for two hours, it was re-used at least four addi-
tional times with no significant loss of activity (92–85% of 5b).
In conclusion, to the best of our knowledge, this is the first report of the use of silica
iodide as a catalyst in the four-component synthesis of hydroquinolines. The mild reac-
tion conditions, excellent yields obtained at room temperature coupled with the simple
work-up procedure, shorter reaction times, cost effectiveness and re-usability of the cata-
lyst are the key advantages of our protocol over those previously reported. 10–33
Experimental Section
All chemicals and solvents were purchased from Aldrich and Merck and used without fur-
ther purification. Silica gel-coated aluminum sheets (Merck) were used for thin layer
chromatography (TLC). Melting points were determined on a Stuart apparatus and are

374
Ahad and Farooqui
uncorrected. Infrared spectra were recorded as KBr disc on a Shimadzo spectrophotome-
ter (435-U-04). MS were obtained on Shimadzu LC-MS spectrometer.NMR spectra were
recorded on a Bruker advance II 400 NMR Spectrometer. Scanning microscopy with
X-ray microanalyser (SEM/EDS) of Nova FEI Company apparatus was used.
Preparation of Silica Iodide
Silica gel (10 g) was dispersed in dichloromethane (25 ml), and thionyl chloride
(10 ml) was added dropwise (addition funnel) with stirring (stir bar) at 20–30ꢀC. After
1 h, the solvent was removed by rotary evaporation in vacuo to give 13.0 g of silica
chloride (SiO2-Cl) as a dry solid. It was washed with water and dried at 80ꢀC under
vacuo (2 mm Hg, 1 hr). Then a solution of sodium iodide (1.5 g) in a mixture of
EtOH-H2O (4:1, 5 mL) was added to 3.0 g of the solid SiO2-Cl and the suspension
was stirred for 30 min. The solid obtained was collected, washed with water and dried
at 80ꢀC under vacuo (2 mm Hg, 1 hr) to afford 3.5 g of SiO2-I as a colorless solid. In
order to confirm the presence of iodide in SiO2-I, chemical tests of sodium fusion
extract (SFE) were performed. Silver nitrate test gave a very positive result, formed a
yellow precipitate, which confirmed the presence of iodine in the catalyst. Further-
more, the catalyst characterization by scanning electron microscopy with X-ray
anlyser (SEM-EDS) was also performed.
Synthesis of Hydroquinolines (5). General Procedures
In Ethanol
To a stirred (spin bar) mixture of the aldehyde (1 mmol), ethyl acetoacetate (0.130 g,
1 mmol), dimedone (or 1,3-cyclohexanediones) (1.5 mmol), and ammonium acetate
(0.077 g, 1 mmol) in 5 mL of ethanol was added 0.1 g of SiO2-I and the mixture was
stirred at room temprature for an appropriate time (Table 1, Entries 1–17). Upon comple-
tion of the reaction as indicated by TLC (ethyl acetate-hexane, 3:7), the reaction mixture
was poured onto 5 ml ice water and the precipitated solid mixture was collected. The
solid mixture of the product and catalyst was washed with diethyl ether (20 mL) and the
insoluble solid (catalyst) was separated and kept aside for re-use. Evaporation of the ethe-
real solution gave the crude product which after recrystallization from ethanol-water
(4:1), afforded the pure products.
Under Solvent-free Conditions
A mixture of the aldehyde (1 mmol), ethyl acetoacetate (0.130 g, 1 mmol), dimedone (or
1,3-cyclohexanediones) (1.5 mmol), ammonium acetate (0.077 g, 1 mmol) and SiO2-I
(0.1 g) was thoroughly mixed in an agate mortar and ground using a pestle manually at
room temperature for an appropriate time (Table 1, Entries 1–17). Upon completion of
the reaction as indicated by TLC (ethyl acetate-hexane, 3:7), work-up and recrystalliza-
tion procedures were same as described above.
Acknowledgments
Laboratory facilities and financial assistance from the Postgraduate and Research Cen-
tre, Dr. Rafiq Zakaria Campus, Maulana Azad College is gratefully acknowledged. We

Hydroquinolines via the Hantzsch Reaction Promoted by SiO2-I
375
are also grateful to SAIF Punjab University and YB Chavhan College of Pharmacy,
Aurangabad for providing analytical facilities. We sincerely appreciate the help of Prof.
Jean-Pierre Anselme, Executive Editor of the Journal, whose constructive comments
and guidance helped greatly to improve the manuscript.
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