Development of an efficient, one-pot, multicomponent protocol for synthesis of 8-hydroxy-4-phenyl-1,2-dihydroquinoline derivatives

Article abstract of DOI:10.1002/jhet.4193

A one-pot quick and efficient multicomponent reaction has been developed for the synthesis of a new series of functionalized 8-hydroxy-4-phenyl-1,2-dihydroquinoline derivatives using 30 mol% ammonium acetate in ethanol as solvent. This economical protocol

Full text of DOI:10.1002/jhet.4193

Development of an Efficient, One-Pot, Multicomponent Protocol for Synthesis
of 8-Hydroxy-4-Phenyl-1,2-Dihydroquinoline Derivatives
a,
a,
b
Rukhsana Tabassum *, Muhammad Ashfaq *, Hiroyuki Oku
Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur, 36100, Pakistan
Division of Molecular Science, Graduate School of Science &Engineering Gunma University, Gunma
76-8515, Japan
a
b
3
Abstract
A one pot quick and efficient multicomponent reaction has been developed for the synthesis of a
new series of functionalized 8-hydroxy-4-phenyl-1,2-dihydroquinoline derivatives using 30
mol% ammonium acetate in ethanol as solvent. This economical protocol run smoothly to give
variety of quinoline derivatives in 55-98% yield from inexpensive reagents and catalyst in mild
1
13
reaction conditions. Various spectroscopic techniques like FTIR, H NMR and C NMR,
MALDI-TOF-MS and EI-MS were employed to study and confirm their structure.
Keywords: Quinoline derivatives, 8-hydroxyquinoline, economical, heterocyclic, efficient
protocol.
*
Corresponding authors:
Mailing address: Department of Chemistry, The Islamia University of Bahawalpur, Pakistan
Tel.: +92 03336368347, +92 3006829307.
Email: rukhsana.tabassum@iub.edu.pk
chashfaqiub@yahoo.com
This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1002/jhet.4193
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1
. Introduction
Multicomponent reactions attracted a great attention in recent years due to their simplicity, atom
economy, and greater efficiency due to reduced number of intermediate purification steps that
increase the yield of target products. These reactions are very useful for generation of a variety
of heterocyclic compounds in one pot through one step or by many successive steps protocol
[1-18]
from simple and inexpensive starting materials
. Quinoline derivatives are heterocyclic
compounds that are used as selective and potent drugs against many diseases. They show
[
19-21]
excellent antiviral activity against dengue Zika and avian influenza virus
and now in
[
22-24]
current year even against COVID-19
. Modification of quinoline moiety through
substitution can improve its physical and chemical properties and also pharmacological behavior.
Due to its wide range of pharmaceutical applications it is very popular compound to design new
drugs for treatment of multiple diseases like cancer, dengue fever, malaria, tuberculosis, fungal
[
25-56]
infections, AIDS, Alzheimer’s disease and diabetes etc.
. 8-Hydroxy quinoline is a vital
part of various natural and pharmaceutically active compounds exhibiting a wide-range
[
57-59]
[60-64]
of biological activities
. On account of their vital role as medicinal agents
(Figure 1),
8
-hydroxyquinolines have become important synthetic targets for chemists. No doubt a diverse
range of synthetic protocols including both catalytic and non-catalytic have been developed for
construction of new compounds with virtually boundless combinations of functionality having
[
8, 65-72]
quinoline and 8-hydroxy quinoline scaffold
synthesis of quinoline derivatives from anilines but reaction time was 8-12h
ammonium acetate as catalyst in one pot protocol which reduced the reaction time to 20min-
. L-proline as catalyst was reported for the
[
66]
so we use
1
20min. Ammonium acetate is used as catalyst as well as reagent in synthesis of a wide range of
[
73, 74]
heterocyclic compounds
. In this paper we report a quick and efficient three component
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reaction of malononitrile, 2-aminophenol and functionalized aldehydes for the synthesis of 8-
hydroxy-4-phenyl-1,2-dihydroquinoline derivatives catalyzed by ammonium acetate.µ
Cl
N
Cl
Cl
N
O
N
OH
OH
NH
HO
MAO B
IC50 = 110µM
IC50 = 0.8 µM
N
Anti
O
Anti Mtb
neurodegenerative
Cl
NH
HO
Cl
Raji cells
IC50 = 1.44 µM
N
OH
N
O
8
-HQ
OH
Pim-1
Anticancer
derivatives
Kinase inhibitors
NO 2
OH
HO OH
IC50 = 0.2 µM
Raji cells
IC50 = .0438 µM
OH
OH
N
Anti
bacterial
Br
Anti
HIV
OH
F
OH
N
O
NH
OH
OH
O
IC50 = 0.4 µM
N
Br
N
N
OH
S. aureus
MIC = 6.25 µM
OH IC = 2 µM
OH
IC = 0.30 µM
5
0
COOH
50
Figure. 1: 8-Hydroxy quinoline derivatives with potential pharmacological applications
2
. Results and discussion
Our research work started with screening of catalyst for model reaction of benzaldehyd (1a)
malononitrile (2) and 2-aminophenol (3) (Scheme 1) in the absence and presence of different
[
66]
catalysts. Surprisingly we did not get the product 5a as reported
instead 6a was produced in
1
13
all screening protocols confirmed by H-NMR and C-NMR spectral analysis. To our delight
according to screening results (Table 1 entry 1) without using any catalyst 43% of product was
obtained in one hour at reflux temperature. This reaction proceeded through single step i.e.
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benzylidenemalononitrile was not separated by the reaction of 1a and 2 but when 3 was added,
firstly intermediate was produced at room temperature then on reflux it yielded the product 6a,
that showed that 2-aminophenol itself acted as catalyst for Knoevenagel condensation of
benzaldehyde and malononitrile. So to increase the yield we tried different catalyst and recorded
results in Table 1 and found that when Et N 10 mol% and 20 mol% (Table 1 entry 2 and 3) was
3
used as catalyst product was obtained in 56% yield and increasing the amount of catalyst did not
increase the yield of 6a. With L. proline (Table 1 entry 4) Knoevenagel condensation reaction
was not accomplished and benzaldehyde and malononitrile remained as such even after 24 hours
of stirring. Then we tried different ammonium salts (Table 1 entries 5-9) as catalyst and
amazingly got 68% yield of product with ammonium acetate in one hour at reflux temperature.
Then we performed reaction with different quantities of ammonium acetate and best result was
obtained with 30 mol% of ammonium acetate (Table 1 entry 12) which was 98% yield of product
in just 20 min (5min stirring at room temperature (step 1) and 15 minutes stirring at reflux
temperature(step 2)).
N
5
a
O
H
N
NH2
N
OH
CN
CN+
Catalyst(mol %)
Solvent
+
NH2
N
H
NH2
N
OH
OH
1a
2
3
4
a
N
H
a
NH2
OH
6
Scheme 1: Synthesis of 6a as model reaction
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a
Table 1. Screening of catalysts for model reaction.
Conditions
C amount
b
Entry
Yield %
Catalyst (C)
Solvent
Ethanol
Time
1h
mol%
c
1
-
-
43
56
56
2
3
4
5
6
7
8
9
Et N
10
20
20
10
20
20
20
20
20
25
30
35
Ethanol
2h
3
Et N
Ethanol
2h
3
d
L-Proline
Ethanol
24h
NR
NH OAc
Ethanol
1h
68
37
4
(NH ) CO
Ethanol: Water(4:1)
Ethanol: Water(4:1)
Ethanol: Water(4:1)
Ethanol
1h
4
2
3
d
NH Cl
24h
NR
4
d
(NH ) SO
24h
NR
4
2
4
d
AcOH
24h
NR
1
1
1
1
0
1
2
3
NH OAc
Ethanol
40min
30min
20min
20min
83
90
98
98
4
NH OAc
Ethanol
4
NH OAc
Ethanol
4
NH OAc
Ethanol
4
a
Reaction conditions: 1a (2mmol), 2 (2mmol), catalyst, Solvent (5mL) Stirred at room temperature then
added 3 (2mmol) dissolved in 5mL solvent and refluxed.
Isolated yield in hot reaction mixture.
Without any catalyst.
NR stands for no reaction.
b
c
d
After the selection of appropriate catalyst we further investigated different solvents for reaction
Table2 entries 1-9) and found that ethanol was the most suitable solvent for reaction as product
(
separated during heating and no further purification was required except washing the product
with hot ethanol In water and methanol(Table 2 entries 1 & 2) reaction was not proceeded while
n
n
in propanol and butanol (Table 2 entries 4 & 5) product was separated after cooling and in very
low yield i.e. 25% and 18% respectively. When THF and DMSO was used as solvent reaction
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was accomplished as monitored by TLC but product was not separated even after cooling that
might be due to the high solubility of products in these solvents.
a
Table 2. Screening of solvents for model reaction.
Conditions
b
Entry
Yield %
Solvent
Water
Time
2h
c
1
2
3
4
5
6
7
NR
c
Methanol
Ethanol
2h
NR
20 min
2h
98
n
d
Propanol
25
n
d
Butanol
2h
18
DCM
40min
1h
53
70
Ethanol: Water(1:1)
a
Reaction conditions: 1a (2mmol), 2 (2mmol), catalyst (30 mol% NH OAc), Solvent (5mL) Stirred at room
4
temperature then added 3 (2mmol) dissolved in 5mL solvent and refluxed.
b
Isolated yield in hot reaction mixture.
NR stands for no reaction.
Product was isolated after cooling the reaction mixture at room temperature.
c
d
With optimized reaction conditions i.e. reaction of 1 and 2 at room temperature using ethanol as
solvent in the presence of 30 mol% catalyst and then addition of 3 and reflux for required time,
we further investigated the scope and generality of aldehydes for this multicomponent reaction
and results are enlisted in Table 3. A variety of aldehydes non-substituted (1a, 1k) and
substituted with electron withdrawing groups such as NO , Cl, Br, F and electron donating
2
groups like OCH , CH and OH reacted efficiently with 2-amino phenol(3) and malononitrile (2)
3
3
and produced the corresponding 8-hydroxy-4-phenyl-1,2-dihydroquinoline derivatives in
moderate to excellent yield (55-98%) under mild reaction conditions. Benzaldehyde (1a)
st
produced the required products 6a in highest yields which is 98% in just 20 minutes (1 step was
completed in 5 minutes and second step was completed in15 minutes). Substitution on aldehydes
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effected the time of completion of reaction, for example non substituted aldehydes (1a, 1k) and
para substituted aldehyde 1n converted into products in 20 minutes while all other para
substituted aldehydes yield product in 25 minutes, meta substituted aldehydes took 30-40
minutes for completion of reaction and for ortho substituted aldehydes longest time was required
to convert the reactants into desired product (90-120 minutes). Substitution on aldehydes
irrespective of electron withdrawing or electron donating groups, also effected the yield of
corresponding quinoline derivatives 6, such as meta substituted aldehydes like1c, 1d, 1f, 1i, 1k
and 1l furnished their corresponding products 6c, 6d, 6f, 6i, 6k and 6l in higher yield 83%, 86%,
8
5%, 89%, 82% and 69% respectively as compared to para substituted aldehydes 1b, 1e, 1g, 1j
and 1m which furnished the required products 6b, 6e, 6g, 6j and 6m in 74%, 78%, 82%, 65%
and 67% yields respectively only P-tolualdehyde (1n) produced the required products 6n in
highest yields which is 96%. Ortho substituted aldehydes 1h and 1o produced the lowest yield of
products which was for 6h 58% and for 6o 55%. Steric effect may be aroused due to steric
hindrance of groups present at ortho, meta and para position of 1 as in para substituted
aldehydes this effect is lowest as compared to meta substituted aldehydes while in ortho
substituted aldehydes steric hindrance is highest which could be the reason of lowest yield. Some
aldehydes did not gave the corresponding products, for example para dimethyl amino
benzaldehyde only furnished the intermediate which did not get dissolved in hot ethanol and
ultimately not reacted with 3 to yield product 6, similarly heterocyclic aldehydes like 2-pyridine
aldehyde, furfural aldehyde did not reacted with 2 to produce the intermediate which could yield
the corresponding products.
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Table 3. Substrate scope for synthesis of 8-hydroxy-4-phenyl-1,2-dihydroquinoline derivatives
a
(6a-o).
OH
R
N
O
NH OAc (30 mol %)
4
CN
NH2
Ethanol
H+
+
1. Room temp., 5-10 min.
. Reflux, 15-120 min.
R
N
H
NH2
CN
2
1a-o
3
OH
2
6a-o
b
Entry
Aldehyde
1a
R
Time(min.)
Product
6a
Yield (%)
1
2
3
4
5
6
7
8
9
-C H5
20
25
40
35
25
30
25
90
30
25
20
40
25
20
120
98
6
1b
p-OCH -C H
5
3
6
6b
6c
74
1c
m-OCH -C H
5
3
6
83
1d
m-Br-C H5
6
6d
6e
86
1e
p-NO -C H
2
6
5
78
1f
m-NO -C H
5
2
6
6f
85
1g
p-Cl-C H5
6
6g
82
1h
o-Cl-C H5
6
6h
6i
58
1i
m-Cl-C H5
6
89
1
1
1
1
1
1
0
1
2
3
4
5
1j
p-F-C H5
6j
65
6
1k
β-Naphthyl
6k
6l
82
1l
m-OH-C H5
6
69
1m
1n
p-OH-C H5
6
6m
6n
6o
67
p-CH -C H
5
96
3
6
1o
o-Br-C H5
6
55
a
Reaction conditions: 1a (5mmol), 2 (5mmol), catalyst (30 mol% NH OAc), Solvent (10 mL) Stirred at room
4
temperature then added 3 (5 mmol) dissolved in 10 mL solvent and refluxed.
b
Isolated yield in hot reaction mixture.
2
.1. Structure Elucidation
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Synthesis and structure of 8-hydroxyquinoline derivatives were confirmed by using different
1
13
techniques like FTIR, H-NMR, C-NMR, MALDI-TOF-MS and EI-MS.
-1
-1
FTIR spectra of all synthesized compounds were recorded in 4000cm to 600cm domain and
all spectra have prominent peaks characteristic of synthesized quinoline derivatives (6a-6o)
(
Figures S1-S15) such as NH , NH, OH, C≡N, C=C, C-N and C-O peaks in the vibrational
2
-
1
range of 3500-1000 cm . NH stretching vibrations give rise to two bands in the region of
2
-1
3
500-3300 cm one for asymmetric stretch at higher frequency and other for symmetric stretch
at lower frequency while NH bending vibrations appears as strong band in the region of 1600-
2
-1 [75]
-1
1
500 cm
and NH peaks appear in the region of 3390 ± 60 cm while C≡N showed peaks in
-1
the region of 2200-2100 cm and stretching of OH attached with aromatic rings give rise to a
-
1 [76]
broad peak from 3500-3000 cm
are in accordance with the literature and proposed structure of quinoline derivatives
compounds showed two peaks for NH stretching vibrations that is for asymmetric stretching
. In all spectra of compounds 6a-o all corresponding peaks
[
77-80]
. All
2
-1
band appear in the region of 3500-3400 cm and symmetric stretching peak appear in the range
-1
of 3400-3300 cm while for NH there was a single peak in all spectra in the region of 3400-3300
-1
cm except 6a (Figure 2), 6h and 6m where NH peak is overlapped with NH and OH peaks
2
respectively. Aromatic C−H stretching vibrations are expected to appear in the region of 3200-
-1
[81, 82]
3
000 cm which is characteristic region for C−H stretching vibrations
. The aromatic C-H
stretching bands of synthesized compounds are appeared in the expected region and is in good
[
81, 82]
agreement with literature values
. Most important peak for structure elucidation of
carbonitrile compounds is C≡N as this group is present in target compounds so showed a strong
-1
and sharp peak in the region of 2200-2100 cm which confirms the presence of this group in
synthesized quinoline derivatives. C−N vibration are very difficult to interpret as there are a
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[
77-79]
number of possible band in this region. However by taking the help of literature
C−N
-1
bands are assigned to the bands in the range of 1165-1185 cm . The FTIR peak observed in the
-
1
-
range of 1640-11400 cm assigned to C=C vibrations while bands in the range of 1525-1508 cm
1
to corresponding peak of NH bending vibrations. C−O stretching vibration of C−OH bond
2
-1
appeared in the region of 1051-1025 cm . C−X (where X = Cl, Br and F) also observed in their
-1
respective region that is C−F peak in 6j appeared at 1231.29cm while peak at 1093.80 and
-1
1
125.52 cm appointed to C−Cl stretching vibrations in compounds 6g and 6h and C−Br peak
-1
in compounds 6d and 6o appeared at 1125.87 and 1125.89 cm respectively. NO group show
2
-1
two distinct peaks at 1550 and 1350 cm assigned to asymmetric stretching and symmetric
[
76]
stretching vibration . In reported compounds 6e and 6f asymmetric stretching band of NO2
seems to be overlapped with NH deformation band while NO symmetric stretch is assigned to
2
2
-1
the peak appeared at 1344.97 and 1353.47cm respectively. All the corresponding peaks of
[
75-78, 82]
synthesized 8-hydroxy-1,2-dihydroquinoline derivatives are in accordance with literature
.
1
13
In H-NMR and C-NMR spectra of all synthesized compounds (6a-6o) (Figures S16-S45) all
required signals conforming the respective proton and carbon nuclei of suggested structures are
observed at agreeing chemical shifts (ppm) values which helped in unambiguous characterization
1
of 8-hydroxy-4-phenyl-1,2-dihydroquinoline derivatives. H-NMR spectra allows us to identify
different proton’s chemical shift values, as in our synthesized compounds CH present next to NH
of quinoline ring showed a singlet peak in the region of 5.0-4.0 ppm while NH protons appeared
2
as singlet of integral two in the region of 5.5.5-5.1 ppm. Proton Hb showed a doublet (d) while
Ha and Hc appeared as multiplet (m) signal in the range of 7.0-6.0 ppm, NH and OH groups
appeared as overlapped broad peak at 6.8-6.6 ppm while aromatic protons of aldehyde benzene
1
ring showed signals in the region of chemical shift value of 8.0-7.0 ppm for example, in H-
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NMR spectrum of 6a (Figure 3A) it is clear that there is a peak of H at 4.5ppm while H due to
d
b
coupling with neighboring ortho protons(H , H ) showed a doublet with J= 8.1Hz at 6.65 ppm.
a
c
Signals of protons H , H and H due to the presence of ortho as well as meta protons appeared
a
c
e-g
as multiplet in the range of 6.32-6.26 ppm and 7.32-7.15 ppm respectively. NH peak appeared
2
as singlet at 5.23 ppm while NH and OH as overlapped broad peak at 6.79 ppm. In all
synthesized quinoline derivatives carbon bonded to NH (C2) group resonated at chemical shift
2
value of 60-55 ppm while carbon atom attached with nitrile group is evident in the region of 102-
1
00 ppm and carbon bonded to OH group which is C7 appeared in the region of 149-150 ppm. In
addition, carbon C6 that is attached to nitrogen of pyridine ring also resonate at 149-150 ppm.
Carbon of nitrile group (C12) appear at 129-136 ppm while C14 aldehyde ring carbon attached
to quinoline ring showed a signal in the region of 142-148 ppm. Carbon of OCH group (C21) in
3
compounds 6b and 6c showed a signal at 55.5 and 55.4 ppm while carbon attached to methoxy
group in these compounds resonated at 158.3 and 160.9 ppm respectively. Signals at 21.1 ppm in
1
3
C NMR spectra of compounds 6n confirm the presence of CH carbon nuclei while carbon
3
attached to CH group appear at 136.0 ppm. C−F carbon in compounds 6j showed a doublet with
3
[
83]
coupling constant 240.75 ppm which is in accordance to literature
. C−F of compound 6j
showed two signals at 162.96 and 159.75 ppm. In exemplary C-NMR spectrum of 6a (Figure
B) C≡N signal appeared at 129.9 ppm while carbons attached with NH , CN and OH groups
1
3
3
2
showed peaks at 56.9, 100.5 and 149.4 ppm respectively.
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Figure 2: FTIR spectrum of 6a
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1
13
Figure 3: A) HNMR spectrum of 6a B) CNMR spectrum of 6a
Mass of the synthesized compounds were determined by MALDI-TOF-MS by using Alpha-
Cyano-4-hydroxycinnamic acid (α-CHCA) as matrix in positive ion, reflectron mode and EI-MS
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by using positive ion mode. MALDI-TOF uses soft ionization method to generate ions and is
[
84]
well known as a high throughput technique . Previously it was mostly used for compounds
with higher molecular weight but now a days it is also employed for compounds with low
[
85, 86]
+
+∙
+
+
molecular weight with great success
. Surprisingly [M-H] , M , [M-H ] , and [M-H-H ]
2 2
+
peaks also produced in addition to [M+H] peaks in almost all investigated compounds(Table 4)
+
(
Figures S46-S60). [M-H-H ] peak observed as most intense peak in most of the spectra which
2
+
+
may appear due to the removal of hydrogen molecule from [M-H] ion and [M-H] ion may be
produced due to; a) transfer of hydrogen atom from radical cation of analyte or b) by hydride
removal from neutral molecule of analyte, or c) removal of H from protonated molecule of
2
[
87-90]
+∙
analyte
. M ion may be observed due to removal of electron from parent molecule by
+
photoionization process and [M-H ] by removal of H from molecular ion. All these
2
2
[
91]
mechanisms may occur simultaneously or not depending on the structure of analyte molecule
.
+
MALD-TOF-MS spectrum of 6a (Figure 4A) showed [M-H] peak at 262.72 m/z while EI-MS
+
∙
spectrum of 6a (Figure 4B) showed molecular ion (M ) peak at 263.2 m/z ratio which
confirmed the mass of 6a.
Table. 4: Observed MALDI-TOF-MS peaks of compounds 6a-o
+
∙
+
+
+
+
Compound
M
[M+H]
[M-H]
[M-H2]
[M-H-H2]
260.69
-
6
a
-
-
-
-
262.72
292.36
292.72
340.42
307.66
-
261.75
291.23
291.05
-
6
b
293.24
-
6
c
290.71
338.39
305.66
305.76
294.67
-
6
d
341.46
308.61
308.19
297.17
-
342.25
6
e
-
-
6
f
-
-
306.68
295.06
-
6
g
-
6
h
298.23
296.22
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6
i
297.05
281.41
-
298.11
296.58
280.42
312.09
-
294.54
-
6
j
-
-
6
k
-
311.04
310.72
2276.37
276.43
274.78
338.87
6
l
279.23
279.49
277.38
341.21
280.24
-
6
m
-
-
-
277.44
6
n
276.03
340.61
-
-
6
o
342.53
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Figure 4: Mass spectra of 6a A) MALDI-TOF-MS B) EI-MS
.1. Proposed mechanism
Based on the experimental results and previous literature
2
[
74, 92, 93]
a proposed mechanism of the
reaction was shown in Scheme 2. According to proposed mechanism acetate ion facilitate the
removal of H from 2 to yield I(i) while ammonium ion catalyzed the formation of iminium ion
(I(ii)) which due to higher reactivity than carbonyl group expedite the Knoevenagel condensation
between I(i) and I(ii) followed by elimination of ammonium ion to yield
benzylidenemalononitrile (I(iii)). Then benzylidenemalononitrile through Michael addition with
intermediate I(iv) produced I(v) which by imine-enamine tautomerization and cyclization
yielded I(vi) and I(vii) respectively. Intermediate I(vii) might exhibit in three possible
tautomeric forms out of which 6b is the most stable as indicated by NMR and mass spectral
analysis.
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N
H
O
N
+
-
H N
2
OOCCH3
–
+NH4
H
CH
+H
N
2
R
N
I(i)
I(ii)
R
1
+
-
NH4
N
H
R
I(iii)
N
H
N
–
CH
H
R
Michael addition
NH2
NH –
3
NH
OH
N
I(iv)
HO
I(v)
OH
R
R
N
R
H
H
N
N
Cyclization
–
NH
N
–
N
NH
NH NH
OH
H
OH
H
I(vii)
HO
I(vi)
6
a
R
N
Most stable tautomer
N
H
b
NH2
OH
6
Scheme 2: Proposed mechanism for the synthesis of compound 6
3
. Conclusion
In summary, we successfully synthesized 8-hydroxy-4-phenyl-1,2-dihydroquinoline derivatives
6a-o) by a convenient one pot, three component reaction in 55-98% yield. The reaction proceed
(
though Knoevenagel condensation, Michael addition, rearrangements and cyclization. It is worth
mentioning that this protocol proceeded without the use of toxic solvents, co-catalysts, precious
metals, inert atmosphere and harsh reaction conditions. This one pot atom economic method
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furnished excellent yield of corresponding products with a wide range of substituted aldehydes
and thus provided high substrate scope under mild reaction conditions. Furthermore, all
1
synthesized compounds were characterized by various techniques including FTIR, H-NMR,
1
3
C-NMR, MALDI-TOF-MS and EI-MS which confirmed their synthesis. Additionally,
significance of this protocol to a variety of substrates and bio screening of synthesized
compounds are in progress in our laboratory.
Acknowledgements
The authors are very grateful for The Department of Chemistry, The Islamia University of
Bahawalpur for providing the necessary research facilities.
Abbreviations
8
-HQ = 8-Hydroxyquinoline
MAO = Monoamineoxidase
Raji cells = Cell line derived from a human B cell lymphoma
HIV = Human immunodeficiency virus
Mtb = Mycobacterium tuberculosis
S. aureus = Staphylococcus aureus
MIC = Minimal inhibitory concentration
IC = Half maximal inhibitory concentration
5
0
4
. Experimental
General information
All reagents were from Sigma Aldrich, Merck, Alfa Aesar and BDH and were used without
further purification. Melting points were on Stuart SMP10 and are uncorrected. Silica gel plates
were used to monitor the progress of reaction by TLC using acetone: n-hexane solvent system
This article is protected by copyright. All rights reserved.

(7:3) which were visualized under UV. FTIR spectra were recorded on Bruker Tensor 27 FTIR
1
13
spectrophotometer using KBr discs. H-NMR and C-NMR spectra were recorded on Bruker
DMZ NMR spectrophotometer operating at 300 MHz. Mass spectra were recorded by MALDI-
TOF-MS
technique on Shimadzu Biotech Axima Performance mass spectrometer using Alpha-Cyano-4-
hydroxycinnamic acid (α-CHCA) as matrix in positive ion, reflectron mode. EI-MS spectra were
recorded in positive ion mode using JEOL-600H-1 mass spectrometer.
General procedure for the synthesis of 8-hydroxy-4-phenylquinoline derivatives (6a-o)
To a 10 ml solution of malononitrile 2 (0.33g, 5.0 mmol) and ammonium acetate (0.116g, 30 mol
%) in ethanol, respective benzaldehyde 1 (5.0 mmol) was added and stirred at room temperature
for 5-10 minutes. Intermediate benzylidenemalononitrile was obtained as solid product which
was then heated at 70℃ which helped to dissolve intermediate in ethanol. After getting clear
solution of reaction mixture, solution of 2-amino phenol (0.545g, 5.0 mmol) in 10 mL ethanol
was added in it and refluxed for 15-120 minutes. The solid thus obtained was filtered and washed
with hot ethanol to obtain highly pure corresponding product 6a-o in 55-98% yield.
2
-amino-8-hydroxy-4-phenyl-1,2-dihydroquinoline-3-carbonitrile (6a)
°
Dark yellow solid, Yield: 98%, m.p: 218-220 C, Rf: 0.64 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3429.76, 3353.01 (NH , NH stretch), 3500-31 (OH), 3169.98 (Ar CH), 3024.74 (Ar
2
CH), 2197.70 (C≡N), 1644.41 (C=C), 1507.95 (NH bend), 1406.24 (C=C), 1171.98 (C−N),
2
1
1
041.90 (C−O), H-NMR (300 MHz, DMSO-d ) δ 7.32-7.15 (m, 5H, He, Hf, Hg), 6.79 (s, 2H,
6
NH, OH), 6.65 (d, J = 8.1 Hz, 1H, Hb), 6.32-6.26 (m, 2H, Ha, Hc), 5.23 (s, 2H, NH ), 4.54 (s,
2
1
3
1
1
H, Hd), C-NMR (75 MHz, DMSO-d ) δ 160.9 (C4), 149.4 (C7), 149.2 (C6), 147.2 (C14),
6
29.9 (C12), 129.0 (C16, C18), 127.8 (C15, C19), 127.0 (C17), 121.4 (C5, C10), 111.7 (C9),
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+
+
1
10.6 (C8), 100.5 (C3), 56.9 (C2), MALDI-TOF-MS m/z: [M-H] , required for C H N O :
16 12 3
+
∙
+∙
2
62.097, found: 262.72 EI-MS m/z: M required for C H N O : 263.11, found: 263.2.
1
6
13
3
2
-amino-8-hydroxy-4-(4-methoxyphenyl)-1,2-dihydroquinoline-3-carbonitrile (6b)
°
Dark yellow solid, Yield: 74%, m.p: 214-216 C, Rf: 0.69 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3447.91, 3366.47, 3314.98 (NH , NH stretch), 3229.85, 3187.3196, 3036.44 (Ar
2
CH), 3012.07, 2955.86, 2903.02 (CH stretch), 2188.67 (C≡N), 1636.15 (C=C), 1510.03 (NH
3
2
1
bend), 1414.22 (C=C), 1250.27 (C−N), 1031.74 (C−O), H-NMR (300 MHz, DMSO-d ) δ 7.07
6
(d, J = 8.5 Hz, 2H, He), 6.85 (d, J = 8.5 Hz, 2H, Hf), 6.73 (s, 2H, NH, OH), 6.61 (d, J = 8.3 Hz,
1
H, Hb), 6.30-6.23 (m, 2H, Ha, Hc), 5.22 (s, 2H, NH ), 4.48 (s, 1H, Hd), 3.71 (s, 3H, OCH ),
2
3
1
3
C-NMR (75 MHz, DMSO-d ) δ 160.7 (C4), 158.3(C17), 149.3 (C7), 149.1(C6), 139.3 (C14),
6
1
29.9 (C12), 128.9 (C15, C19), 121.5 (C10), 115.7 (C5), 114.3 (C16, C18), 111.6 (C9), 110.9
+
(
C8), 100.4 (C3), 57.2 (C2), 55.5 (C21), MALDI-TOF-MS m/z: [M-H] , required for
+
C H N O : 292.11, found: 292.63.
17
14
3
2
2
-amino-8-hydroxy-4-(3-methoxyphenyl)-1,2-dihydroquinoline-3-carbonitrile (6c)
°
Yellow solid, Yield: 83%, m.p: 188-190 C, Rf: 0.61 (Acetone: n-hexane (7:3)), FTIR (KBr disc,
-1
cm ): 3460.94, 3377.73, 3337.81 (NH , NH stretch), 3009.90 (Ar CH), 2941.36, 2903.02 (CH
2
3
stretch), 2192.05 (C≡N), 1638.99 (C=C), 1511.91 (NH bend), 1407.62 (C=C), 1270.5110
2
1
(
C−N), 1044.98 (C−O), H-NMR (300 MHz, DMSO-d ) δ 7.21 (t, J = 8.1 Hz, 1H, Hf), 6.78-6.65
6
(
m, 6H, He, Hg, Hh, Hb, NH, OH), 6.30-6.22 (m, 2H, Ha, Hc), 5.24 (s, 2H, NH ), 4.49 (s, 1H,
2
1
3
Hd), 3.74 (s, 3H, OCH ), C-NMR (75 MHz, DMSO-d ) δ 160.9 (C18), 159.8(C4), 149.4 (C7),
3
6
1
1
49.2 (C6), 148.8 (C14), 130.1 (C12), 129.8 (C16), 121.4 (C5, C10), 120.0 (C15), 113.9 (C17),
11.8 (C19), 111.6 (C9), 110.4 (C8), 100.4 (C3), 56.7 (C2), 55.4 (C21), MALDI-TOF-MS m/z:
+
+
[
M-H] , required for C H N O : 292.11, found: 292.72.
17 14 3 2
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2
-amino-4-(3-bromophenyl)-8-hydroxy-1,2-dihydroquinoline-3-carbonitrile (6d)
°
Off white solid, Yield: 86%, m.p: 220-223 C, Rf: 0.65 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3461.42, 3378.56, 3336.89(NH , NH stretch), 3242.74, 3190.21, 3068.68 (Ar CH),
2
2
192.58 (C≡N), 1639.21 (C=C), 1513.09 (NH bend), 1413.58 (C=C), 1174.24 (C−N), 1125.87
2
1
(
C−Br) 1035.80 (C−O), H-NMR (300 MHz, DMSO-d ) δ 7.39 (d, J = 8.1 Hz, 1H, Hg), 7.32-
6
7
6
1
.24 (m, 2H, He, Hf), 7.19 (s, 1H, Hh), 6.88 (s, 2H, NH, OH), 6.65 (d, J = 8.3 Hz, 1H, Hb), 6.32-
1
3
.24 (m, 2H, Ha, Hc), 5.29 (s, 2H, NH ), 4.58 (s, 1H, Hd), C-NMR (75 MHz, DMSO-d ) δ
2
6
61.0 (C4), 150.0 (C7), 149.5 (C6), 149.4 (C14), 131.3 (C12), 130.4 (C17), 129.9 (C15), 129.9
(C18), 127.0 (C19), 122.3 (C16), 121.2 (C10), 111.7 (C9), 109.7 (C8), 100.4 (C3), 56.3 (C2),
+
+
MALDI-TOF-MS m/z: [M-H] , required for C H BrN O : 340.00, found: 340.42.
1
6
11
3
2
-amino-8-hydroxy-4-(4-nitrophenyl)-1,2-dihydroquinoline-3-carbonitrile (6e)
°
Yellow solid, Yield: 78%, m.p: 195-197 C, Rf: 0.64 (Acetone: n-hexane (7:3)), FTIR (KBr disc,
-1
cm ): 3478.24, 3433.18, 3386.56, 3338.31 (NH , NH stretch), 3108.20 (Ar CH), 2189.28
2
(
C≡N), 1643.83 (C=C), 1573.82 (NO asym. stretch), 1514.42 (NH bend), 1412.37 (C=C),
2
2
1
1
344.97 (NO sym. stretch), 1174.53 (C−N), 1122.60 (C−N), 1043.36 (C−O), H-NMR (300
2
MHz, DMSO-d ) δ 8.18 (d, J = 8.3 Hz, 2H, Hf), 7.43 (d, J = 8.3 Hz, 2H, He), 6.95 (s, 2H, NH,
6
OH), 6.63 (d, J = 8.3 Hz, 1H, Hb), 6.30-6.26 (m, 2H, Ha, Hc), 5.31 (s, 2H, NH ), 4.75 (s, 1H,
2
1
3
Hd), C-NMR (75 MHz, DMSO-d ) δ 161.0 (C4), 154.7 (C17), 149.7 (C7), 149.4 (C6), 146.6
6
(C14), 129.9 (C12), 129.1 (C15, C19), 124.5 (C16, C18), 121.0 (C10), 111.7 (C9), 109.0 (C8),
+
+
1
3
2
00.5 (C3), 55.7 (C2), MALDI-TOF-MS m/z: [M-H] , required for C H N O : 307.08, found:
16 11 4 3
07.66 .
-amino-8-hydroxy-4-(3-nitrophenyl)-1,2-dihydroquinoline-3-carbonitrile (6f)
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°
Yellow solid, Yield: 85%, m.p: 235-237 C, Rf: 0.71(Acetone: n-hexane (7:3)), FTIR (KBr disc,
-1
cm ): 3456.25, 3407.14, 3360.42 (NH , NH stretch), 3219.53, 3102.23, 3049.04 (Ar CH),
2
2
1
182.19 (C≡N), 1648.94(C=C), 1578.20 (NO asym. stretch), 1523.17, 1448.58 (NH bend),
2 2
1
401.14 (C=C), 1353.47 (NO sym. stretch), 1176.40 (C−N), 1051.95 (C−O), H-NMR (300
2
MHz, DMSO-d ) δ 8.06-8.01 (m, 2H, Hg, Hh), 7.62 (dd, J = 20.7, 7.9 Hz, 2H, He, Hf), 6.98 (s,
6
2
H, NH, OH), 6.68 (d, J = 8.1 Hz, 1H, Hb), 6.36-6.33 (m, 2H, Ha, Hc), 5.31 (s, 2H, NH ), 4.82
2
1
3
(
s, 1H, Hd), C-NMR (75 MHz, DMSO-d ) δ 161.1 (C4), 149.6 (C18), 149.5 (C7), 149.4 (C6),
6
1
48.4 (C14), 134.7 (C12), 130.6 (C15), 130.0 (C16), 122.2 (C17, C19), 121.2 (C10), 111.9 (C9),
+
+
1
09.3 (C8), 100.6 (C3), 56.1 (C2), MALDI-TOF-MS m/z: [M] , calcd for C H N O : 308.09,
16 12 4 3
found: 308.19.
2
-amino-4-(4-chlorophenyl)-8-hydroxy-1,2-dihydroquinoline-3-carbonitrile (6g)
°
Light yellow solid, Yield: 82%, m.p: 228-231 C, Rf: 0.70 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3446.95, 3367.26, 3314.64 (NH , NH stretch), 3229.62, 3187.99, 3040.58 (Ar CH),
2
2
1
7
2
1
1
189.90 (C≡N), 1634.8708 (C=C), 1514.58 (NH bend), 1414.14 (C=C), 1185.70 (C−N),
2
1
093.80 (C−Cl), 1026.53 (C−O), H-NMR (300 MHz, DMSO-d ) δ 7.34 (d, J = 8.3 Hz, 2H, Hf),
6
.18 (d, J = 8.3 Hz, 2H, He), 6.85 (s, 2H, NH, OH), 6.62 (d, J = 8.3 Hz, 1H, Hb), 6.32-6.27 (m,
1
3
H, Ha, Hc), 5.26 (s, 2H, NH ), 4.58 (s, 1H, Hd), C-NMR (75 MHz, DMSO-d ) δ 160.9(C4),
2
6
49.3 (C7, C6), 146.1 (C14), 131.6 (C12), 129.9 (C17), 129.7 (C16, C18), 128.9 (C15, C19),
+
21.3 (C10), 111.7 (C9), 110.0 (C8), 100.5 (C3), 56.5 (C2), MALDI-TOF-MS m/z: [M] ,
+
required for C H ClN O : 297.07, found: 297.17.
1
6
12
3
2
-amino-4-(2-chlorophenyl)-8-hydroxy-1,2-dihydroquinoline-3-carbonitrile (6h)
°
White solid, Yield: 58%, m.p: 196-199 C, Rf: 0.66 (Acetone: n-hexane (7:3)), FTIR (KBr disc,
-1
cm ): 3477.12, 3378.93 (NH stretch), 3219.14, 3051.65 (Ar CH), 2182.67 (C≡N), 1647.30
2
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(
C=C), 1511.02 (NH bend), 1401.93 (C=C), 1177.08 (C−N), 1125.52 (C−Cl), 1038.82 (C−O),
2
1
H-NMR (300 MHz, DMSO-d ) δ 7.39 (d, J = 7.7 Hz, 1H, Hh), 7.30-7.16 (m, 3H, He, Hf, Hg),
6
6
.87 (s, 2H, NH, OH), 6.61 (d, J = 8.3 Hz, 1H, Hb), 6.30 (dd, J = 10.5, 2.0 Hz, 2H, Ha, Hc), 5.27
1
3
(
s, 2H, NH ), 5.09 (s, 1H, Hd), C-NMR (75 MHz, DMSO-d ) δ 161.2 (C4), 149.54 (C7),
2
6
1
1
49.46 (C6), 143.7 (C14), 132.3 (C12), 131.1 (C19), 130.1 (C17), 129.2 (C18), 128.8 (C15),
28.2 (C16), 121.1 (C10), 111.7 (C9), 109.4 (C8), 100.5 (C3), 55.5 (C2), MALDI-TOF-MS m/z:
+
+
[
M-H] , required for C H ClN O : 296.06, found: 296.22.
16 11 3
3
.4.9. 2-amino-4-(3-chlorophenyl)-8-hydroxy-1,2-dihydroquinoline-3-carbonitrile (6i)
°
Off white solid, Yield: 89%, m.p: 222-224 C, Rf: 0.67 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3461.95, 3378.58, 3332.95 (NH , NH stretch), 3232.42, 3188.15, 3072.15 (Ar CH),
2
2
193.12 (C≡N), 1637.79 (C=C), 1513.14 (NH bend), 1414.94 (C=C), 1174.52 (C−N), 1125.91
2
1
(
C−Cl), 1034.60 (C−O), H-NMR (300 MHz, DMSO-d ) δ 7.34-7.13 (m, 4H, He, Hf, Hg, Hh),
6
6
.88 (s, 2H, NH, OH), 6.66 (d, J = 8.3 Hz, 1H, Hb), 6.34-6.28 (m, 2H, Ha, Hc), 5.28 (s, 2H,
1
3
NH ), 4.60 (s, 1H, Hd), C-NMR (75 MHz, DMSO-d ) δ 161.0 (C4), 149.7 (C7), 149.43 (C6),
2
6
1
1
49.40 (C14), 133.6 (C12), 130.9 (C18), 129.9 (C16), 127.5 (C17), 127.0 (C19), 126.6 (C15),
+
21.2 (C10), 111.8 (C9), 109.8 (C8), 100.5 (C3), 56.3 (C2), MALDI-TOF-MS m/z: [M-H] ,
+
+∙
+∙
calcd for C H ClN O : 296.06, found: 296.58 EI-MS m/z: M required for C H ClN O :
1
6
11
3
16 12
3
2
97.07, found: 297.2.
2
-amino-4-(4-fluorophenyl)-8-hydroxy-1,2-dihydroquinoline-3-carbonitrile (6j)
°
Off white solid, Yield: 65%, m.p: 215-218 C, Rf: 0.69(Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3450.07, 3368.91, 3317.09 (NH , NH stretch), 3232.29, 3189.48, 3050.86 (Ar CH),
2
2
189.07 (C≡N), 1637.51 (C=C), 1509.25 (NH bend), 1414.28 (C=C), 1231.29 (C−F), 1176.64
2
1
(
C−N), 1030.38 (C−O), H-NMR (300 MHz, DMSO-d ) δ 7.22-7.08 (m, 4H, He, Hf), 6.81 (s,
6
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2
4
1
H, NH, OH), 6.63 (d, J = 8.1 Hz, 1H, Hb), 6.29 (t, J = 8.7 Hz, 2H, Ha, Hc), 5.24 (s, 2H, NH2),
1
3
.58 (s, 1H, Hd), C-NMR (75 MHz, DMSO-d ) δ 163.0 (C17, J= 242.66), 160.8 (C4),
6
59.8(C17, J= 242.66), 149.4 (C7), 149.3 (C6), 143.38 (C14), 143.35 (C5), 129.9 (C12), 129.7
(C15), 129.6 C19), 121.3 (C10), 15.5 (C16, C18), 111.7 (C9), 110.4 (C8), 100.5 (C3), 56.9 (C2),
+
+
MALDI-TOF-MS m/z: [M-H] , required for C H FN O : 280.09, found: 280.42.
1
6
11
3
2
-amino-8-hydroxy-4-(naphthalen-2-yl)-1,2-dihydroquinoline-3-carbonitrile (6k)
°
Off white solid, Yield: 82%, m.p: 260-262 C, Rf: 0.67 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3447.88, 3366.88, 3313.35 (NH , NH stretch), 3227.30, 3184.84, 3051.86 (Ar CH),
2
2
188.97 (C≡N), 1636.44 (C=C), 1509.66 (NH bend), 1413.05 (C=C), 1168.79 (C−N), 1032.80
2
1
(
C−O), H-NMR (300 MHz, DMSO-d ) δ 7.90-7.82 (m, 3H, Hf, Hh), 7.74 (s, 1H, He), 7.50-7.46
6
(m, 2H, Hg), 7.25 (dd, J = 8.5, 1.7 Hz, 1H, Hi), 6.85 (s, 2H, NH, OH), 6.65 (d, J = 9.0 Hz, 1H,
1
3
Hb), 6.27 (dd, J = 5.7, 2.1 Hz, 2H, Ha, Hb), 5.26 (s, 2H, NH ), 4.72 (s, 1H, Hd), C-NMR (75
2
MHz, DMSO-d ) δ 160.8 (C4), 149.4 (C7), 149.3 (C6), 144.4 (C14), 133.3 (C12), 132.5 (C17),
6
1
1
30.1 (C22), 129.9 (C18), 128.9 (C21), 128.1 (C15), 128.0 (C16), 126.7 (C19), 126.5 (C20),
26.2 (C23), 125.8 (C5), 121.4 (C10), 111.7 (C9), 110.2 (C8), 100.5 (C3), 56.8 (C2), MALDI-
+
+
TOF-MS m/z: [M-H] , required for C H N O : 312.11, found: 312.09.
2
0
14
3
2
-amino-8-hydroxy-4-(3-hydroxyphenyl)-1,2-dihydroquinoline-3-carbonitrile (6l)
°
Off white solid, Yield: 69%, m.p: 217-220 C, Rf: 0.67(Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3414.20, 3353.32 (NH , NH stretch), 3138.79, 3037.49 (Ar CH), 2182.38 (C≡N),
2
1
643.03 (C=C), 1512.23, 1479.26 (NH bend), 1409.92 (C=C), 1169.48 (C−N), 1045.31 (C−O),
2
1
H-NMR (300 MHz, DMSO-d ) δ 7.08 (t, J = 7.8 Hz, 1H, Hf), 6.76 (s, 2H, NH, OH), 6.67-6.54
6
(
m, 4H, He, Hg, Hh, Hb), 6.31-6.23 (m, 2H, Ha, Hc), 5.22 (s, 2H, NH ), 4.42 (s, 1H, Hd), 3.52,
2
1
3
C-NMR (75 MHz, DMSO-d ) δ 160.8 (C16), 157.9 (C4), 149.4 (C7), 149.2 (C6), 148.7 (C14),
6
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1
1
2
2
29.8 (C18, C12), 121.5 (C10), 118.6 (C19), 114.5 (C17), 114.1 (C15), 111.6 (C9), 110.7 (C8),
+
+
00.4 (C3), 56.9 (C2), MALDI-TOF-MS m/z: [M] , required for C H N O : 279.10, found:
1
6
13
3
2
79.23.
-amino-8-hydroxy-4-(4-hydroxyphenyl)-1,2-dihydroquinoline -3-carbonitrile (6m)
°
Light yellow solid, Yield: 67%, m.p: 264-266 C, Rf: 0.65 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3454.63, 3396.53, 3325.57 (NH , NH stretch), 3200.75, 3103.26, 3042.21(Ar CH),
2
2
182.58 (C≡N), 1651.23 (C=C), 1509.34 (NH bend), 1398.19 (C=C), 1168.60 (C−N), 1036.17
2
1
(
C−O), H-NMR (300 MHz, DMSO-d ) δ 9.32 (s, 1H, OH), 6.97 (d, J = 8.3 Hz, 2H, He), 6.72-
6
6
.61 (m, 5H, Hf, NH, OH, Hb), 6.31-6.23 (m, 2H, Ha, Hc), 5.19 (s, 2H, NH ), 4.43 (s, 1H, Hd),
2
1
3
C-NMR (75 MHz, DMSO-d ) δ 160.7 (C17), 156.4 (C4), 149.3 (C7), 149.0 (C6), 137.7 (14),
6
1
29.9 (C12), 128.8 (C15, C19), 121.5 (C10), 115.9 (C5), 115.7 (C16, C18), 111.6 (C9), 111.3
+
+
(
C8), 100.4 (C3), 57.4 (C2), MALDI-TOF-MS m/z: [M] , required for C H N O : 279.10,
16 13 3 2
found: 279.29.
2
-amino-8-hydroxy-4-(4-methylphenyl)-1,2-dihydroquinoline-3-carbonitrile (6n)
°
Light orange solid, Yield: 96%, m.p: 216-218 C, Rf: 0.70 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3453.1240, 3453.1240, 3371.9891, 3317.5286 (NH , NH stretch), 3231.94, 3187.58,
2
3
1
1
2
034.65 (Ar CH), 2922.98 (CH stretch), 2190.15 (C≡N), 1637.29 (C=C), 1512.01 (NH bend),
3 2
1
412.23 (C=C), 1174.58 (C−N), 1031.78 (C−O), H-NMR (300 MHz, DMSO-d ) δ 7.07 (dd, J =
6
5.4, 8.1 Hz, 4H, He, Hf), 6.76 (s, 2H, NH, OH), 6.62 (d, J = 8.3 Hz, 1H, Hb), 6.28 (td, J = 8.3,
13
.1 Hz, 2H, Ha, Hc), 5.04-5.42 (2H, NH ), 4.49 (s, 1H, Hd), 2.25 (s, 3H, CH ), C-NMR (75
2
3
MHz, DMSO-d ) δ 160.8 (C4), 149.4 (7), 149.1 (C6), 144.3 (C14), 136.0 (C12), 129.9 (C5),
6
1
29.5 (C15, C19), 127.7 (C16, C18), 121.4 (C10), 111.6 (C9), 110.8 (C8), 100.4 (C3), 57.1 (C2),
This article is protected by copyright. All rights reserved.

+
+
2
1.1 (C21) MALDI-TOF-MS m/z: [M-H] , required for C H N O : 276.11, found: 276.03 EI-
17 14 3
+∙
+∙
MS m/z: M required for C H N O : 277.12, found: 277.2.
17
15
3
2
-amino-4-(2-bromophenyl)-8-hydroxy-1,2-dihydroquinoline-3-carbonitrile (6o)
°
Off white solid, Yield: 55%, m.p: 195-197 C, Rf: 0.72 (Acetone: n-hexane (7:3)), FTIR (KBr
-1
disc, cm ): 3461.54, 3378.56, 3336.85 (NH , NH stretch), 3233.97, 3189.03, 3068.35 (Ar CH),
2
2
192.58 (C≡N), 1639.28 (C=C), 1513.09 (NH bend), 1413.49 (C=C), 1174.30 (C−N), 1035.17
2
1
(
C−O), H-NMR (300 MHz, DMSO-d ) δ 7.56 (d, J = 7.5 Hz, 1H, Hh), 7.30-7.11 (m, 3H, He,
6
Hf, Hg), 6.88 (s, 2H, NH, OH), 6.63 (d, J = 7.5 Hz, 1H, Hb), 6.32 (d, J = 7.7 Hz, 2H, Ha, Hc),
1
3
5
.20 (d, J = 43.3 Hz, 3H, NH2, Hd), C-NMR (75 MHz, DMSO-d ) δ 161.1 (C4), 149.5 (C7,
6
C6), 145.5 (C14), 133.2 (C12), 131.4 (C16), 129.2 (C19), 129.1 (C18), 128.8 (C17), 122.8
(C15), 121.0 (C10), 111.8 (C9), 109.6 (C8), 100.6 (C3), 55.9 (C2), MALDI-TOF-MS m/z:
+
+
[
M+H] , required for C H BrN O : 340.00, found: 340.61.
16 11 3
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