Efficient synthesis via azide-alkyne Huisgen [3+2] cycloaddition reaction and antifungal activity studies of novel triazoloquinolines

Article abstract of DOI:10.1007/s11164-014-1638-1

New functionalized 1,2,3-triazoloquinolines were achieved by intramolecular azide-alkyne Huisgen [3+2] cycloaddition. These derivatives were synthesized via the key Baylis-Hillman adduct under mild, neutral conditions in short duration and consistently go

Full text of DOI:10.1007/s11164-014-1638-1

Res Chem Intermed
DOI 10.1007/s11164-014-1638-1
Efficient synthesis via azide–alkyne Huisgen [3+2]
cycloaddition reaction and antifungal activity studies
of novel triazoloquinolines
•
Nagarajan Saravanan
Maruthapillai Arthanareeswari
•
•
Palanisamy Kamaraj Bitragunta Sivakumar
Received: 4 January 2014 / Accepted: 25 March 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract New functionalized 1,2,3-triazoloquinolines were achieved by
intramolecular azide–alkyne Huisgen [3?2] cycloaddition. These derivatives were
synthesized via the key Baylis–Hillman adduct under mild, neutral conditions in short
duration and consistently good yield. The structures of final compounds were char-
acterized by spectral analysis. Antifungal activities of these analogues against Trich-
ophyton mentagrophytes, Candida albicans, and Aspergillus niger were also assayed.
Keywords Huisgen cycloaddition ꢀ Baylis–Hillman reaction ꢀ Triazoles ꢀ
Quinolines
Introduction
Triazoles are important five-membered heterocyclic compounds containing three
nitrogen atoms in the five-membered ring, showing various medicinal properties
such as antimalarial [1], antimicrobial [2], antiinflammatory [3], anticonvulsant [4],
and antineoplastic activity [5]. Substituted 1,2,4-triazoles find many useful
applications. Some of them are used as analytical reagents for determination of
boron [6], antimony [7], and cobalt [8]. Other triazoles find many synthetic uses as
halogenating agents or as activating polymeric reagents [9]. In recent years, 1,2,3-
triazole derivatives have been widely used as antiproliferative [10] and anticancer
agents [11]. In medicinal chemistry, great attention has been paid to synthesis of
1,2,3-triazoles fused with other heterocycles and investigation of their biological
activity [12–14].
The basic core formed from a quinoline ring results in greater antifungal strength
compared with aromatic systems. The additional presence of the triazole motif
N. Saravanan (&) ꢀ M. Arthanareeswari ꢀ P. Kamaraj ꢀ B. Sivakumar
Department of Chemistry, SRM University, Kattankulathur, Chennai 603203, India
e-mail: npss82@gmail.com
123

N. Saravanan et al.
further increases the potency to a higher level. Introduction of halogens such as
fluorine or chlorine atom into these compounds could alter their pharmacological
activity [1]. The azole class of drugs are b-lactamase inhibitors [15] and exhibit a
wide range of therapeutic activities. In recent years, study of their synthesis and
pharmacology has gained in importance among scholars. Some 1,2,3-triazoles are
used as DNA cleaving agents [10] and potassium channel activators [16].
Cycloaddition reactions are one of the most important classes of reactions in
synthetic chemistry. Within this class, the 1,3-dipolar cycloaddition reaction has
found extensive use as a high-yielding, efficient, regio- and stereocontrolled method
for synthesis of many different heterocyclic compounds. 1,3-Dipolar cycloaddition
[17] is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-
membered ring. Mechanistic investigation and synthetic application were estab-
lished through the work of Rolf Huisgen. Hence, this reaction is sometimes referred
to as Huisgen cycloaddition (a term used to describe specifically 1,3-dipolar
cycloaddition between an organic azide and an alkyne to generate a 1,2,3-triazole).
The intramolecular alkyne–azide Huisgen [3?2] cycloaddition reaction has been
studied as a ‘‘click chemistry’’ reaction without a metal catalyst under aerobic
conditions. Our method can provide extension of the preparation of triazoles and
their uses in synthetic organic chemistry. Azide–alkyne cycloaddition (AAC) to
produce 1,2,3-triazoles has been extensively developed since the Cu catalyst
conditions (CuAAC) were reported [18, 19]. Due to their numerous applications,
especially in chemical biology [20, 21], ligand/material design [22], and pharma-
ceuticals [23], many groups have reported mild, rapid, and Cu-free triazolations
[24]. Recently, triazoles have found extensive use in the developing field of material
and agrochemical research.
Chemistry
As part of our ongoing research, synthesis of triazoloquinolines [25] was achieved
through intramolecular 1,3-dipolar cycloaddition with Baylis–Hillman adducts. a-
Methylene-b-hydroxy esters are easily prepared by the Baylis–Hillman reaction
[26–29], being used as vital building blocks for construction of triazoloquinolines.
2-Chloro-3-formylquinolines were obtained by subjecting the suitable acetanilide to
Vilsmeier reagent [POCl3/dimethylformamide (DMF)] [30]. Compound 1 under-
goes Sonogashira coupling reaction with terminal acetylenes in the presence of
Pd(PPh3)2Cl2, CuI/Et3N to yield compound 2 [31]. Further, the quinoline skeleton
was achieved through Baylis–Hillman reaction by treating 2 with ethyl acrylate in
the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO). Having in hand the
internal activated alkynes 3, we turned our attention to synthesis of azide–alkyne
Huisgen [3?2] cycloadducts 5. First, we tried the reaction of 3 with sodium azide at
room temperature to obtain the intermediate 4, but found no reaction. The same
reaction was heated to 80 °C, achieving cycloadducts through elimination followed
by in situ azide–alkyne Huisgen [3?2] cycloaddition [32]. These reactions were
carried out in anhydrous DMF and afforded new triazoloquinolines in good yields.
123

Efficient synthesis and antifungal activity of novel triazoloquinolines
O
O
NH
(a)
R
N
Cl
N
O
(b)
2
1
R
2(a-g)
R = H, 3-Cl, 3-F, 4-F, 3-Me, 4-Me, 4-t-Bu
OH
O
O
O
(d)
(c)
O
N
N
N3
3
3(a-g)
4
R
R
O
O
N
N
N
N
5
R
5a R = H
5d R = 4-F
5g R = 4-t-Bu
5b R = 3-Cl 5e R = 3-Me
5c R = 3-F 5f R = 4-Me
Scheme 1 a POCl3, DMF, 90 °C; b Pd(PPh3)2Cl2, CuI, triethylamine, THF; c Ethyl acrylate, DABCO;
d NaN3, DMF, 80 °C
1
The formation of cycloadducts was confirmed by H nuclear magnetic resonance
(NMR) and mass spectroscopy (Scheme 1; Table 1).
Experimental
Tetrahydrofuran (THF) was freshly distilled from sodium/benzophenone, DMF
from CaO and distilled POCl3. All reactions were performed under nitrogen
1
atmosphere. All products were confirmed by their spectral data. H and 13C NMR
spectra were recorded on a Bruker Biospin spectrometer at 400 MHz. Mass spectra
were recorded on an Agilent mass spectrometer. Flash column chromatography was
performed on Merck silica gel (230–400 mesh).
123

N. Saravanan et al.
Synthesis of 2-chloroquinoline-3-carbaldehyde (1)
At 0 °C to a stirred solution of POCl3 (39.6 g, 259 mmol) and anhydrous DMF (8 g,
111 mmol) was added acetanilide (5 g, 37 mmol). The mixture was then heated to
65 °C, and the progress of the reaction was monitored by thin-layer chromatography
(TLC) analysis. After 8 h the reaction mixture was cooled to room temperature and
added cautiously into ice-cold water. The precipitated solid was collected by
filtration to isolate compound 1a as yellow solid. Yield 6.2 g (87 %), yellow solid.
1H NMR (400 MHz, CDCl3): d 10.58 (s, 1H), 8.78 (s, 1H), 8.10 (m, 1H), 8.01 (m,
1H), 7.91 (m, 1H), 7.67 (m, 1H); LCMS: m/z 192.0 (M?).
General procedure for synthesis of substituted quinoline carbaldehydes 2a–g
At 0 °C to a solution of 2-chloroquinoline-3-carbaldehyde (0.2 g, 0.1 mmol) in
anhydrous THF (5 mL) were added tetrakis(triphenylphosphine)palladium (0.012 g,
0.01 mmol), CuI (0.02 g, 0.01 mmol), phenylacetylene (0.1 g, 0.1 mmol), and
triethylamine (0.42 g, 0.4 mmol). The reaction mixture was allowed to stir at room
temperature for 1 h. After completion of the reaction, the reaction mixture was
diluted with water, and extracted with ethyl acetate (2 9 15 mL). The organic layer
was separated, dried over sodium sulfate, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography to yield compound
1
2 as pale-brown solid. Yield 0.21 g (77 %). H NMR (400 MHz, CDCl3): d 10.84
(s, 1H), 8.79 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.92 (m,
1H), 7.74 (m, 2H), 7.72 (m, 1H), 7.45 (m, 3H). LCMS: m/z 258.2 (M?).
General procedure for synthesis of substituted a-methylene-b-hydroxy esters
3a–g
To a mixture of compound 2 (0.2 g, 0.7 mmol) in ethyl acrylate (0.3 g, 3.1 mmol)
was added 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.1 mmol), followed by standing
at room temperature for 48 h. The crude product was purified by silica-gel column
1
chromatography to afford compound 3 (0.22 g, 82 %) as colorless liquid. H NMR
(400 MHz, CDCl3): d 8.40 (s, 1H), 8.17 (m, 1H), 7.84 (m, 1H), 7.75 (m, 1H), 7.58
(m, 3H), 7.37 (m, 3H), 6.40 (s, 1H), 6.30 (s, 1H), 5.70 (s, 1H), 3.76 (s, 3H). LCMS:
m/z 344.2 (M?).
General procedure for synthesis of triazoloquinoline derivatives 5a–g
To a solution of compound 3 (0.05 g, 0.14 mmol) in anhydrous DMF (5 mL) was
added sodium azide (0.019 g, 0.29 mmol), and the reaction mixture was heated to
80 °C for 1 h. After completion of the reaction, the reaction mixture was cooled to
room temperature and diluted with water (10 mL), and the contents were extracted
with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and
concentrated under reduced pressure. The crude material thus obtained was purified
by flash column chromatography to yield the title compound 5.
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Efficient synthesis and antifungal activity of novel triazoloquinolines
Table 1 Yields of triazoloquinoline derivatives
Compound
Product
Time (h)
1
Yield (%)
75
5a
O
O
N
N
N
N
5b
5c
5d
1
1
1
77
82
75
O
O
N
N
N
N
Cl
O
O
N
N
F
N
N
O
O
N
N
N
N
F
123

N. Saravanan et al.
Table 1 continued
Compound
Product
Time (h)
1
Yield (%)
84
5e
O
O
N
N
N
N
5f
1
78
O
O
N
N
N
N
5g
1
80
O
O
N
N
N
N
Methyl 1-phenyl-5H-[1,2,3]triazolo[10,50:1,2]azepino[3,4-b]quinoline-6-
carboxylate (5a)
1
Yield: 0.04 g (75 %) as brown solid. HRMS: 368.8 (M). H NMR (400 MHz,
CDCl3): d 8.36 (s, 1H), 8.14 (s, 1H), 7.97 (m, 2H), 7.85 (m, 3H), 7.69 (m, 1H), 7.34
(m, 3H), 5.47 (s, 2H), 3.96 (s, 3H). 13C NMR (400 MHz, CDCl3): 164.8, 147.8,
144.7, 140.4, 131.9, 129.5, 128.7, 126.7, 52.9, 45.1.
123

Efficient synthesis and antifungal activity of novel triazoloquinolines
Methyl 1-(3-chlorophenyl)-5H-[1,2,3]triazolo[10,50:1,2]azepino[3,4-b]quinoline-
6-carboxylate (5b)
1
Yield: 0.045 g (77 %) as white solid. HRMS: 402.6 (M). H NMR (400 MHz,
CDCl3): d 8.35 (s, 1H), 8.20 (s, 1H), 8.12 (m, 2H), 7.96 (m, 1H), 7.80 (m, 1H), 7.65
(m, 3H), 7.22 (m, 1H), 5.47 (s, 2H), 3.96 (s, 3H). 13C NMR (400 MHz, CDCl3): d
165.5, 159.6, 152.3, 142.6, 141.2, 135.7, 132.2, 128.9, 125.5, 124.5, 122.2, 119.6,
116.6, 44.6.
Methyl 1-(3-fluorophenyl)-5H-[1,2,3]triazolo[10,50:1,2]azepino[3,4-b]quinoline-
6-carboxylate (5c)
1
Yield: 0.046 g (82 %) as viscous liquid. HRMS: 386.8 (M). H NMR (400 MHz,
CDCl3): d 8.37 (s, 1H), 8.14 (s, 1H), 8.05 (m, 2H), 7.96 (m, 1H), 7.87 (m, 1H), 7.71
(m, 3H), 7.30 (m, 1H), 5.47 (s, 2H), 3.96 (s, 3H). 13C NMR (400 MHz, CDCl3): d
166.4, 160.4, 154.3, 146.2, 141.2, 137.6, 133.4, 129.4, 125.3, 122.2, 121.2, 116.6,
45.8.
Methyl 1-(4-fluorophenyl)-5H-[1,2,3]triazolo[10,50:1,2]azepino[3,4-b]quinoline-
6-carboxylate (5d)
1
Yield: 0.042 g (75 %) as viscous liquid. HRMS: 386.8 (M). H NMR (400 MHz,
CDCl3): d 8.34 (s, 1H), 8.20 (s, 1H), 7.96 (m, 1H), 7.84 (m, 2H), 7.73 (m, 2H), 7.30
(m, 3H), 5.46 (s, 2H), 3.96 (s, 3H). 13C NMR (400 MHz, CDCl3): d 166.4, 162.3,
155.4, 145.3, 143.6, 142.2, 139.9, 135.6, 129.8, 127.5, 124.3, 121.2, 117.6, 45.3.
Methyl 1-(m-tolyl)-5H-[1,2,3]triazolo[10,50:1,2]azepino[3,4-b]quinoline-6-
carboxylate (5e)
1
Yield: 0.046 g (84 %) as off-white solid. HRMS: 382.5 (M). H NMR (400 MHz,
CDCl3): d 8.50 (s, 1H), 8.34 (m, 1H), 7.95 (m, 1H), 7.84 (m, 2H), 7.75 (m, 2H), 7.52
(m, 1H), 7.32 (m, 2H), 5.47 (s, 2H), 3.95 (s, 3H), 2.43 (s, 3H). 13C NMR (400 MHz,
CDCl3): d 168.6, 154.3, 145.4, 144.3, 138.3, 135.4, 128.4, 125.3, 129.6, 123.2,
120.1, 45.6, 22.2.
Methyl 1-(p-tolyl)-5H-[1,2,3]triazolo[10,50:1,2]azepino[3,4-b]quinoline-6-
carboxylate (5f)
1
Yield: 0.044 g (78 %) as white solid. HRMS: 382.5 (M). H NMR (400 MHz,
CDCl3): d 8.50 (s, 1H), 8.32 (m, 1H), 7.93 (m, 1H), 7.73 (m, 2H), 7.56 (m, 3H), 7.19
(m, 2H), 5.43 (s, 2H), 3.95 (s, 3H), 2.32 (s, 3H). 13C NMR (400 MHz, CDCl3): d
168.6, 156.6, 143.3, 141.2, 138.6, 135.4, 130.2, 125.3, 121.2, 119.9, 45.3, 22.2.
123

N. Saravanan et al.
Methyl 1-(4-(tert-butyl)phenyl)-5H-[1,2,3]triazolo[10,50:1,2]azepino[3,4-
b]quinoline-6-carboxylate (5g)
1
Yield: 0.049 g (80 %) as viscous oil. HRMS: 424.9 (M). H NMR (400 MHz,
CDCl3): d 8.77 (s, 1H), 8.25 (s, 1H), 8.09 (m, 1H), 7.94 (m, 1H), 7.85 (m, 1H), 7.71
(m, 1H), 7.64 (m, 2H), 7.38 (m, 2H), 5.51 (s, 2H), 3.95 (s, 3H), 1.33 (s, 9H). 13C
NMR (400 MHz, CDCl3): d 164.3, 163.2, 153.2 145.3, 143.6, 140.2, 139.9, 135.6,
128.8, 126.5, 123.2, 121.2, 117.6, 45.2, 25.4.
Antifungal assay
The agar well diffusion method was used to evaluate the antifungal potency of the
final analogues. Each fungal isolate was suspended in brain–heart infusion (BHI)
broth and diluted to approximately 105 colony-forming units (CFU) per mL. They
were flood-inoculated onto the surface of BHI agar and then dried. Dimethyl
sulfoxide (DMSO) was used as solvent control. Compound (5 lg) in 500 lL DMSO
was used as stock solution. Five-millimeter-diameter wells were cut from the agar
using a sterile cork-borer, and 30 lL of sample solution was poured into the wells.
The plates were incubated for 18 h at room temperature for fungi. Antifungal
activity was evaluated by measuring the zone of inhibition in millimeters against the
test microorganisms. Ketoconazole was used as reference antifungal agent. The tests
were carried out in triplicate.
Antifungal activity
All synthesized triazoloquinoline compounds were assayed for antifungal (Trich-
ophyton mentagrophytes, Candida albicans, and Aspergillus niger) activities using
the disc diffusion method [33]. The results for the antifungal effect of all the tested
compounds are reported as the zone of inhibition in millimeters in Table 2. The
results revealed that most of the newly synthesized derivatives exhibit moderate
Table 2 Antifungal activity of
triazoloquinoline derivatives
Compound
Candida
albicans
Aspergillus
niger
Trichophyton
mentagrophytes
5a
5b
5c
5d
5e
5f
NZ
NZ
NZ
NZ
NZ
NZ
NZ
23
NZ
NZ
NZ
NZ
NZ
NZ
NZ
10
8
5
5
7
5
5
5
9
5g
Experiments used 5 lg
compound in 500 lL DMSO
Ketoconazole
(reference)
NZ no zone of activity
123

Efficient synthesis and antifungal activity of novel triazoloquinolines
antifungal activity against Trichophyton mentagrophytes except two compounds (5a
and 5g) with zone of inhibition nearly matching that of the standard ketoconazole.
In vitro evaluation of antifungal activity was carried out for the analogues, and
the results are summarized in the table. The zone of inhibition of triazoles 5a–
g against the mentioned fungal strains was investigated. The derivatives revealed
inhibitory efficiency against Trichophyton mentagrophytes in the range of 5–8 mm,
being moderate to equipotent compared with the standard drug ketoconazole. The
activity of the final analogues towards the fungal strains remained unchanged
irrespective of the presence of either electron-withdrawing or electron-donating
groups.
Conclusions
We synthesized triazoloquinoline derivatives via azide–alkyne Huisgen [3?2]
cycloaddition reaction in good yields. The advantages of the present procedure are
experimental simplicity, easy workup procedure, mild reaction conditions, and no
requirement for any catalyst. All synthesized compounds showed moderate
antifungal activity invariably.
Acknowledgments The authors are grateful to the Department of Chemistry, SRM University for
providing the laboratory facilities to carry out the research work. The authors are also grateful to Dr.
Suresh for his valuable suggestions.
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