Chemoselective synthesis of 5-amino-7-bromoquinolin-8-yl sulfonate derivatives and their antimicrobial evaluation

Article abstract of DOI:10.1080/10426507.2018.1488714

A series of new 5-amino-7-bromoquinolin-8-ol sulfonate derivatives 5(a–j) were synthesized from 8-hydroxyquinoline through multi-step process with high yields using mild, efficient and conventional methods. Chemoselectivity was observed during the transfo

Full text of DOI:10.1080/10426507.2018.1488714

Phosphorus, Sulfur, and Silicon and the Related Elements
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Chemoselective synthesis of 5-amino-7-
bromoquinolin-8-yl sulfonate derivatives and their
antimicrobial evaluation
Palaa Krishna
To cite this article: Palaa Krishna (2018): Chemoselective synthesis of 5-amino-7-
bromoquinolin-8-yl sulfonate derivatives and their antimicrobial evaluation, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI: 10.1080/10426507.2018.1488714
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PHOSPHORUS, SULFUR, AND SILICON
https://doi.org/10.1080/10426507.2018.1488714
Chemoselective synthesis of 5-amino-7-bromoquinolin-8-yl sulfonate derivatives
and their antimicrobial evaluation
Palaa Krishna
Department of Chemistry, Geethanjali Institute of Science and Technology, Nellore, India
ABSTRACT
ARTICLE HISTORY
Received 1 January 2018
Accepted 7 June 2018
A series of new 5-amino-7-bromoquinolin-8-ol sulfonate derivatives 5(a–j) were synthesized from 8-
hydroxyquinoline through multi-step process with high yields using mild, efficient and conventional
methods. Chemoselectivity was observed during the transformation of 5-amino-7-bromoquinolin-8-
ol to 5-amino-7-bromoquinolin-8-ol sulfonate with various sulfonylchlorides exclusively to afford
sulfonate derivatives. Also, the products were investigated for their in vitro antimicrobial activities
and compared with the standard drugs. Among all the synthesized compounds 5-amino-7-
bromoquinolin-8-yl biphenyl-4-sulfonate (5b) and 5-amino-7-bromoquinolin-8-yl 2-hydroxy-5-
nitrobenzenesulfonate (5g) have showed potent antibacterial activity, whereas 5-amino-7-bromo-
quinolin-8-yl biphenyl-4-sulfonate (5b) and 5-amino-7-bromoquinolin-8-yl 2-hydroxy-5-nitrobenze-
nesulfonate (5g) possessed potent antifungal activities among all the tested pathogens.
KEYWORDS
8-Hydroxy quinoline;
5-amino-7-bromoquinolin-8-
ol; chemoselectivity;
sulfonation; antimicrobial
activity
GRAPHICAL ABSTRACT
NH2
N
Br
N
O
S
R
OH
O
O
1
5(a-j)
Introduction
8-Hydroxyquinoline (8HQ) is a quinoline derivative
originating from plants as well as from synthesis and it is
known as simple fungicidal compound since the 1920s.[11]
The derivatives of 8HQ are widely used as analytical
reagents due to their ability to form stable complexes with
many metal ions.[12] In addition they have also use in bio-
logical applications such as for example, antimicrobial,[13–15]
antimalarial,[16–18] antiviral,[19] antitubercular[20] and
antidental plaque activities.[21,22] Another derivative of 8HQ,
Clioquinol (5-chloro-7-iodo-8-hydoxyquinoline) which has
found use as an antifungal and antiprotozoal drug with
metal-binding properties.[23–26]
Sulfonates are known as important intermediates in
organic synthesis and precursors of sulfonamides. They act
as alkylating agents and leaving groups in substitution
reactions.[27] On the other hand, compounds containing aryl
sulfonate moiety have received considerable attention during
last two decades due to their biological activities such as
papillomavirus microbicidal,[28] anti-HIV-1,[29] antineo-
plastic[30] and anticancer activity.[31,32] In addition, various
sulfonate derivatives of quinoline exhibit interesting
pharmacological activities.[33] To the best of our knowledge,
Quinoline derivatives are the most important antimalarial
drugs (quinine, chloroquine and amodiaquine) constantly
used historically and these scaffolds are precursors in a wide
variety of pharmacologically active synthetic and natural
compounds.[1] In recent years, the synthesis of quinoline
and its derivatives have been of interest for chemists because
of its various applications in fields like medicine, food,
catalysts, dye materials, refineries and electronics were well
established. In addition, these derivatives possess attractive
ionophoric properties towards a variety of metal ions.
Quinolones and aminoquinolines are the group of synthetic
quinolines used as antimicrobials for the treatment of many
infections[2] and have been considered as pivotal constituents
in a number of pharmaceutically important compounds.[3]
In particular, aminoquinoline derivatives possess potent
biological activities including antiviral,[4] anticancer,[5]
antibacterial,[6]
antifungal,[7]
antiobesity,[8]
antiin-
flammatory[9] and antimalarial activity. It is reported that
many antimalarial compounds have shown antiprion activity
because of the incorporation of the quinoline rings.[10]
CONTACT Palaa Krishna
krshnreddy31@gmail.com
Department of Chemistry, Geethanjali Institute of Science and Technology, Gangavaram, Nellore, India
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/10426507.2018.1488714.
ß 2018 Taylor & Francis Group, LLC

2
P. KRISHNA
no reports were found on sulfonate derivatives of 5-amino- sulfonates by treating with an appropriated sulfonyl chloride
in the presence of a base.[37,38] According to Da Silva et al.,
7-bromoquinolin-8-ol.
Led by the above facts, we focused on the synthesis of the sulfonyl chloride group was chemoseletively[39] attacked
5-amino-7-bromoquinolin-8-ol sulfonate 5(a–j) derivatives by OH group instead of NH2 group exclusively to get sul-
fonate derivatives. This can be attributed to the conjugation
and resonance delocalization of the lone pair electrons of
the amino group nitrogen atom with the aromatic ring
enhancing the nucleophilicity of the quinolinic nitrogen.[39]
It plays the role of nucleophilic catalyst to transfer the
arylsulfonyl moiety to the phenol oxygen atom via intramo-
lecular nucleophilic attack. Here, triethylamine act as a base
to deprotonate the pyridine nitrogen after re-aromatization
of the product molecule.
from 8-hydroxy quinoline (1) in excellent yields through a
multi-step reaction process. All the newly synthesized
5-amino-7-bromoquinolin-8-ol sulfonate derivatives 5(a–j)
were screened for their antibacterial and antifungal
activities.
Results and discussion
Chemistry
In the present study, we have investigated that com-
pounds having a bromo substitution at ortho-position to
hydroxy group show high chemoselectivity to obtain the
quinoline sulfonate 5(a–j) (Figure 1) instead of the forma-
tion of sulfonamides under the conditions of triethylamine
at 0 ꢀC to room temperature (RT). In 1H NMR spectros-
copy, NH2 peak was appeared as a singlet in the region d
5.68–6.18 ppm designated for 2 protons, which clearly
indicates that the formed products are sulfonates.
We have synthesized a series of new 5-amino-7-bromoqui-
nolin-8-ol sulfonate derivatives 5(a–j) from 8-hydroxy
quinoline (1) in four steps bromination, nitrosation, reduc-
tion and sulfonation with high yields (86–93%) (Scheme 1).
Compound (1), on reaction with N-bromosuccinimide in
chloroform,[34] afforded 7-bromoquinolin-8-ol (2), which
upon nitrosation[35] with conc. HCl and NaNO2 in water
yielded 7-bromo-5-nitrosoquinolin-8-ol (3). Compound (3)
was reduced to amino[36] derivative 5-amino-7-bromoquino-
lin-8-ol (4) by reaction with Na2S2O4 in 1:1 THF and water.
Finally, sulfonate derivatives 5(a–j) were achieved from
compound (4) by reaction with various sulfonyl chlorides in
All the newly synthesized compounds were characterized
by IR, NMR (1H and 13C), mass spectra and elemental ana-
lysis spectral data and were presented in experimental data.
In IR spectrum, the two absorption bands were observed in
dry THF in the presence of triethylamine (TEA) to chemo- the region of 3337–3500 cmꢁ1 corresponds to the stretching
selectively afford sulfonate derivatives.
vibrations of N-H for all the title compounds. The absorp-
tion bands in the region 1370–1405 and 560–645 cmꢁ1
In general, primary amines and alkyl/aryl alcohols were
converted to their corresponding sulfonamides and correspond to the stretching vibrations of S¼O and C–Br
NO
CHCl3
NaNO2
NBS
0-40 °C
18 h
Conc. HCl
0 °C-RT
N
N
Br
N
Br
OH
OH
OH
3
1
2
THF
0 °C-RT
Na2S2O4
NH2
NH2
TEA
RSO2Cl
THF
0 °C-RT
N
Br
OSO2R
5(a-j)
N
Br
OH
4
Compound
R
R
R
Compound
(5d)
Compound
(5g)
HO
NO2
Br
(5a)
(5b)
NO2
(5h)
(5i)
(5j)
(5e)
(5f)
F
F
F
Cl
F
(5c)
S
Scheme 1. Chemoselective synthesis of 5-amino-7-bromoquinolin-8-ol sulfonate derivatives 5(a–j).

PHOSPHORUS, SULFUR, AND SILICON
3
13
Antifungal activity
NH2
10
The in vitro antifungal activity was screened for the
compounds which have shown good antibacterial activity
(5b, 5c, 5f, 5g and 5h) against two fungal strains such as
Aspergillus niger and Penicillium spinulosum by the poison
plate technique42 using Fluconazole Fu10 (SD 114, Himedia)
as a standard drug.
Among the tested compounds, 5b and 5g have exhibited
potent antifungal activity against Aspergillus niger and
Pencillium spinulosum, might be due to the presence of
biphenyl, 2-nitro 5-hydroxy benzene ring on sulfonyl group.
However, compounds 5c and 5f have shown good antifungal
activity due to the presence of fluorine and chlorine
substituent in the aromatic ring against all tested pathogens.
Compound 5h possessed moderate activity against
Aspergillus niger (Table S2, Supplemental Materials)
6
1
2
9
5
4
8
12
Br
25
N
7
3
14
S
O
O
O
11
26
15
20
24
21
23
16
22
17
19
18
Figure 1. Structure and numbering of sulfonate derivative 5(a–j).
1
respectively. In the H NMR spectra, the chemical shift val-
ues observed in the region d 5.68–6.18, 6.66–7.35, 7.49–8.07,
8.55–9.12 ppm are assigned to NH2, H1, H9 and H2 protons
respectively. In 13C NMR spectra, the chemical shift
values resonated in the region d 106.2–110.0, 117.6–146.4,
119.1–121.6, 121.6–123.8, 136.9–141.4, 139.8–148.9 and
149.6–153.0 ppm corresponds to C9, C15, C1, C8, C10, C7
and C2 carbon atoms. The chemical shift values were
observed in the region d 127.3, 129.4, 129.4, 137.8, 155.2
and 165.3 ppm corresponds to C–Br, C–Cl, C–OH, C–CH3,
C–NO2 and C–F respectively.
Experimental
All chemicals were purchased from Sigma-Aldrich, Merck
and Lancaster, and were used without further purification.
Compound (1) was purchased from Avra laboratory,
Hyderabad. All solvents used for spectroscopic and other
physical studies were reagent grade and were further puri-
fied by literature methods. Melting points were determined
using a calibrated thermometer by Guna digital melting
point apparatus. IR Spectra were recorded as KBr discs on a
Nicolet 380 FT-IR spectrophotometer. 1H and 13C NMR
spectra were recorded as solutions in DMSO-d6 on a Bruker
Biological activity
1
AMX 400 MHz spectrometer operating at 400 MHz for H
NMR, 100 MHz for 13C NMR. The H NMR and 13C NMR
Antibacterial activity
1
chemical shifts were referenced to internal standards using
tetramethylsilane. Chemical shifts were reported in ppm (d)
and the signals are described as singlet (s), doublet (d),
triplet (t), quartet (q), broad (br), broad singlet (br s) and
multiplet (m). The model structure and numbering of
5-amino-7-bromoquinolin-8-ol sulfonate derivatives is given
in Figure 1. The Supplemental Materials contains sample
1H and 13C NMR spectra for 5a (Figures S4–S5).
The in vitro antibacterial activity of the newly synthesized
compounds 5(a–j) were tested against two bacterial strains
such as Staphylococcus aureus, Bacillus megaterium (Gram
positive bacteria), Klebsiella pneumoniae, Pseudomonas
aeruginosa (Gram negative bacteria); two Gram negative
antibiotic resistant E. coli bacterial strains such as Mutant
E. coli (Streptomycin resistant) and Donor E. coli (Rifampin
resistant) bacteria by agar well diffusion method[40,41] using
Amoxiclav Ac[30] (SD063, Himedia) as a standard drug.
Among the synthesized compounds 5a, 5b and 5h have
shown potent activity against donor E. coli bacteria.
Compound 5b has shown potent activity against
Staphylococcus aureus and mutant E. coli bacteria due to
biphenyl, compounds 5c and 5j showed potent activity
against Bacillus megaterium might be due to the presence of
fluorine and sulfur. Compounds 5h has shown potent
activity against Klebsiella pneumonia might be due to the
presence of 4-methoxy benzene whereas, compounds 5c and
5g have shown potent activity against Pseudomonas
Synthesis of 7-bromoquinolin-8-ol (2)
To a stirred solution of quinolin-8-ol (1) (5 g, 1 mmol) in
chloroform (10 mL), N-bromo succinimide (6.13 g, 1 mmol)
was added portion wise at 0 ꢀC, slowly raising the tem-
perature to 40 ꢀC and stirred for 18 h. The progress of
the reaction was monitored by TLC using ethyl acetate and
hexane as an eluent (1:9).
After completion of the reaction, the reaction mixture
aeruginosa might be due to the presence of fluorine and was evaporated under vacuum and washed with water to
nitro substituents. Compounds, 5b and 5h have shown good give the crude 7-bromoquinolin-8-ol (2) (6.53 g), which was
antibacterial activity against all the tested pathogens, might then washed with hexane and diethyl ether to yield
be due to the presence of biphenyl and 4-methoxy benzene 7-bromoquinolin-8-ol as a white solid in 85% yield. m.p:
on the sulfonyl group (Table S1, Supplemental Materials).
138–143 ꢀC; EI-MS: m/z (%): 224 (Mþ H (100)), 145 (32).

4
P. KRISHNA
Synthesis of 7-bromo-5-nitrosoquinolin-8-ol (3)
NH2), 7.21 (dd, J ¼ 4.4, 4.0 Hz, 1 H, H1), 7.68 (s, 1 H, H9),
7.79–7.81 (m, 2 H, H23,24), 8.15–8.25 (m, 5 H, H6,16,17,18,21),
8.38 (d, J ¼ 2.40 Hz, 1 H, H24), 8.79 (d, J ¼ 1.6 Hz, 1 H, H2);
13C NMR (DMSO-d6, 100 MHz): d 108.1 (C9), 119.1 (C1),
121.6 (C8), 122.6 (C5), 123.7 (C17), 127.5 (C22), 127.9 (C16),
128.9 (C21,23), 129.4 (C24), 129.5 (C20), 131.0 (C6), 131.6
(C18), 133.2 (C19), 135.8 (C4), 139.8 (C10), 141.4 (C15), 146.7
(C7), 151.1 (C2); EI-MS: m/z (%): 429 (Mþ H (10)), 262
(44), 239 (100), 192 (34), 167 (16), 127 (13). Anal. Calcd.
for C19H13BrN2O3S C, 53.16; H, 3.05; N, 6.53; Found: C,
53.10; H, 3.23; N, 6.42.
To 7-bromoquinolin-8-ol (6.53 g, 1 mmol) (2) in minimum
amount of conc. HCl (3 mL), NaNO2 (2.02 g, 1 mmol) in
water was added drop wise through dropping funnel at 0 ꢀC
and stirred for 30 min at room temperature. Formation of
7-bromo-5-nitrosoquinolin-8-ol (3) was confirmed by TLC
(ethyl acetate and hexane, 2:8). After completion, the reac-
tion mixture was poured into ice water and filtered by wash-
ings with water to get the residue, which was purified by
washings with hexane and diethyl ether to obtain an orange
red solid 7-bromo-5-nitrosoquinolin-8-ol (6.05g) (3) with
1
82% yield. m.p: 230–233 ꢀC; H NMR (400 MHz, DMSO-d6)
Biological activity
d: 7.98 (dd, 1H, J ¼ 4.4, 3.6 Hz, H1), 8.38 (s, 1H, H9), 8.78
(dd, 1H, J ¼ 4.4, 4.0 Hz, H6), 9.10 (d, 1H, J ¼ 5.2 Hz, H2),
13.8 (s, 1H, OH); EI-MS: m/z (%): 254 (Mþ H (32)), 236
(21), 157 (100), 149 (46), 131 (21).
Antibacterial activity
Antibacterial activity of the newly synthesized sulfonate
derivatives of 5-amino-7-bromoquinolin-8-ol 5(a–j) was
assayed against Gram positive bacteria Staphylococcus aureus
and Bacillus Megaterium; Gram negative bacteria Klebsiella
pneumoniae and Pseudomonas aeruginosa and Gram
negative antibiotic resistant E. coli bacterial strains Mutant
E. coli (Streptomycin resistant) and Donor E. coli (Rifampin
resistant) by agar well diffusion method. The results are
presented in Table S1 (Supplemental Materials).
Synthesis of 5-amino-7-bromoquinolin-8-ol (4)
To a solution of 7-bromo-5-nitrosoquinolin-8-ol (3) (6.05 g,
1 mmol) in a 1:1 THF and water (10 mL), was added
Na2S2O4 (4.2 g, 1 mmol) in portions at 0 ꢀC and resulting
mixture was stirred for 1 h. Formation of the 5-amino-7-
bromoquinolin-8-ol (4) was ascertained by TLC using ethyl
acetate and hexane (2:8) as an eluent. The reaction mixture
was quenched with saturated sodium bicarbonate solution to
remove unreacted Na2S2O4 and extracted with ethyl acetate
(200 mL). The organic layer was washed with water for sev-
eral times, it was separated and concentrated under vacuum
to give the crude compound, which was purified by silica
gel column chromatography, using ethyl acetate/hexane
(1:4, v/v) as eluent to obtain 5-amino-7-bromoquinolin-8-ol
(4.45g) (4) as white solid with 78% yield.m.p: 237–240 ꢀC;
1H NMR (400 MHz, DMSO-d6) d: 5.31 (s, 2H, NH2), 7.31
(dd, 1H, J ¼ 4.4, 3.6 Hz, H3), 7.46 (s, 1H, H7), 8.18 (dd, 1H,
J ¼ 4.4, 4.0 Hz, H4), 8.72 (d, 1 H, J ¼ 5.2 Hz, H2), 9.39 (s,
1 H, OH); 13C NMR (DMSO-d6, 100 MHz): d 108.1 (C9),
120.1 (C1), 122.6 (C8), 122.9(C5), 130.3(C6), 136.1(C4),
139.8(C10), 141.4 (C7), 150.8 (C2); EI-MS: m/z (%): 239 (Mþ
H (100)), 196 (8), 160 (37), 131 (10).
Antifungal activity
The compounds which have shown good antibacterial
activity were tested for antifungal activity against the fungal
strains like Aspergillus niger and Penicillium spinulosum by
the poison plate technique. The results are presented in
Table S2 (Supplemental Materials).
Conclusion
In this study, we have synthesized a series of new 5-amino-
7-bromoquinolin-8-ol sulfonate derivatives containing
biologically potent groups through mild, efficient and con-
venient synthetic methods & evaluated their antimicrobial
activity. In the final step, the chemoselectivity was observed
to exclusively afford 5-amino-7-bromoquinolin-8-ol sulfon-
ate derivatives. The in vitro antimicrobial activity results
revealed that compounds 5b and 5h exhibited potent
antibacterial activity, whereas, 5b and 5g possessed potent
antifungal activity compared with the remaining synthesized
compounds against all pathogens in tested doses. It is
concluded that, the chemoselective synthetic process might
be useful to the researchers for the synthesis of biologically
active organic compounds. Incorporation of the sulfonyl
group on quinoline enhanced the pharmacological effect,
and hence they are suited for further modifications to obtain
efficient antimicrobial agents.
General procedure for the preparation of 5-amino-7-
bromoquinolin-8-ol sulfonate derivatives 5(a–j) is
illustrated by the synthesis of compound (5a)
To a mixture of 5-amino-7-bromoquinolin-8-ol (4) (1 mmol,
0.5 g) and TEA (2 mmol, 0.385 mL) in dry THF (10 ml) at
0 ꢀC, naphthalene-1-sulfonyl chloride (1 mmol, 0.47g) in dry
THF was added drop wise and stirred for 6 h at room
temperature. After completion, the reaction mixture was
evaporated under vacuum to obtain the residue, which was
purified by washings with n-hexane and diethyl ether
to obtain pure product 5-amino-7-bromoquinolin-8-yl
naphthalene-1-sulfonate (0.79g) (5a).
Acknowledgments
The authors are highly thankful to Department of Chemistry and
Department of Biochemistry for providing lab and biological activity
facilities. Authors are also thankful to B. V. K. Prasad and S.
Yield: 88%, White solid, m.p.: 187–189 ꢀC. IR (KBr,
cmꢁ1): 3500, 3450 (-N-H, str), 1405 (-S ¼ O, str), 620 (-C-
Br, str); 1 H NMR (DMSO-d6, 400 MHz): d 5.89 (s, 2 H, Mallikarjun Reddy for their technical assistance.

PHOSPHORUS, SULFUR, AND SILICON
5
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140–144.
ORCID
Palaa Krishna
http://orcid.org/0000-0001-8556-3678
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