Synthesis of functionalized benzo[f]2H-chromenes and evaluation of their antimicrobial activities

Article abstract of DOI:10.1134/S1068162017020054

Knoevenagel cyclocondensations of α-hydroxy naphthaldehyde with β-oxodithioesters and ketene dithioacetals yielded 2H-benzo[f]chromene-2-thiones and 2H-benzo[f]chromen-2-ones, respectively, in high yields. The newly synthesized compounds were evaluated fo

Full text of DOI:10.1134/S1068162017020054

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2017, Vol. 43, No. 2, pp. 177–185. © Pleiades Publishing, Ltd., 2017.
Synthesis of Functionalized Benzo[f]2H-Chromenes and Evaluation
of Their Antimicrobial Activities1
Irom Harimala Chanua, Laishram Ronibala Devib, Nonibala Khumanthemc, N. Irabanta Singhc,
Dalip Kumard, and Okram Mukherjee Singha, 2
aDepartment of Chemistry, Manipur University, Canchipur, 795003 India
bDepartment of Basic Science and Humanities, NIT Manipur, 795004 India
cDepartment of Life Science, Manipur University, Canchipur, 795003 India
dDepartment of Chemistry, Birla Institute of Technology and Science, Pilani, 333031 India
Received May 11, 2016; in final form, October 8, 2016
Abstract—Knoevenagel cyclocondensations of α-hydroxy naphthaldehyde with β-oxodithioesters and
ketene dithioacetals yielded 2H-benzo[f]chromene-2-thiones and 2H-benzo[f]chromen-2-ones,
respectively, in high yields. The newly synthesized compounds were evaluated for antifungal and anti-
bacterial activities. Among them, compounds (2-furyl)(3-thioxo-3H-benzo[f]chromen-2-yl)metha-
none and phenyl(3-oxo-3H-benzo[f]chromen-2-yl)methanone exhibited excellent antifungal activity
against tested fungi Curvularia lunata and Fusarium moniliforme. The highest antibacterial activity
against the tested bacteria Escherichia coli and Staphylococcus aureus was observed for (4-chlorophe-
nyl)(3-oxo-3H-benzo[f]chromen-2-yl)methanone. The results of antimicrobial screening demonstrate
that (2-furyl)(3-thioxo-3H-benzo[f]chromen-2-yl)methanone, phenyl(3-oxo-3H-benzo[f]chromen-2-
yl)methanone, and (4-chlorophenyl)(3-oxo-3H-benzo[f]chromen-2-yl)methanone are promising as
antimicrobial drugs.
Keywords: chromene, piperidine, antimicrobial activity, β-oxodithioesters, cyclocondensation
DOI: 10.1134/S1068162017020054
INTRODUCTION
and α-oxoketenedithioacetals, have not been intro-
duced yet in the family of these starting materials.
Recently, we have reported the radical scavenging
potential of some 3-heteroaroyl-2H-chromene-2-thi-
ones synthesized from β-oxodithioesters and salicylal-
dehyde toward the stable free radical 2,2-diphenyl-1-
picrylhydrazyl (DPPH) [14].
Chromenes constitute a major class of naturally
occurring heterocyclic compounds that display a wide
range of biological and therapeutic properties [1–5].
They are also used as additives in food, perfumes, cos-
metics, optical brighteners, and dispersed fluorescent
and laser dyes, antitumor and anti-HIV therapy, and
as CNS stimulants [6–8].
In continuation of our interest in the synthesis of bioac-
tive heterocycles using these new synthons [14–17], here
we report a facile synthesis of 2H-benzo[f]chromene-2-
thiones and 2H-benzo[f]chromen-2-ones from β-oxo-
dithioesters and α-oxoketenedithioacetals, respec-
tively, by the domino Knoevenagel cyclocondensa-
tions (Scheme 1). A critical report on their antimicro-
bial activities against the Staphylococcus aureus
(MTCC-7443) and Escherichia coli (MTCC-725) and
two fungal species, namely Curvularia lunata
(MTCC-2605) and Fusarium moniliforme (MTCC-
278), is also presented.
Though classical condensation processes like
Pechmann, Perkin, Reformatsky, Wittig, and Knoev-
enagel reactions are available for the synthesis of cou-
marinyl derivatives [1, 9], many improved methodol-
ogies have been introduced to make the classical
routes more efficacious [10–13]. A limitation of these
classical routes is the confinement to certain starting
materials, such as methyl- and ethylacetoacetate,
malononitrile, and Meldrums acid. Surprisingly,
newly established synthons, like β-oxodithioesters
1
The article is published in the original.
2
Corresponding author: e-mail: ok_mukherjee@yahoo.co.in.
177

178
IROM HARIMALA CHANU et al.
O
S
O
SMe
SMe
O
S
O
O
Ar
SMe
Ar
CHO
IIa−i
IVa−i
Ar
Ar
Piperidine,
Ethanol
reflux
Piperidine,
Ethanol
reflux
O
OH
O
(IIIa−i)
(I)
(Va−i)
Scheme 1. Synthesis of 2H-benzo[f]chromene-2-thiones and 2H-benzo[f]chromen-2-ones from β-oxodithioesters
and α-oxoketenedithioacetals.
RESULTS AND DISCUSSION
model substrates for the cyclocondensation reaction.
By simply refluxing their molar equivalent mixture in
ethanol at 95°C with piperidine as a catalyst, the
desired product 3-(benzoyl)-2H-benzo[f]chromene-
Chemistry
In our initial investigation, we have chosen 2-
hydroxy-1-naphthaldehyde (Ia) and β-oxodithioester
(IIa) (methyl-3-oxo-3-phenylpropanedithioate) as 2-thione (IIIa) was obtained in 93% yield (Scheme 2).
O
O
S
Piperidine
CHO
OH
C6H5
C6H5
Ethanol, reflux
+
MeS
S
O
(I)
(IIa)
(IIIa)
Scheme 2. Synthesis of 3-(benzoyl)-2H-benzo[f]chromene-2-thione (IIIa).
The condensation of starting compound (I) with tion took longer time (4 h) and the yields were poorer
in comparison with piperidine.
compound (II) to generate chromene (IIIa) was inves-
tigated under a variety of conditions and the results are
presented in Table 1. In ethanol, the condensation
took place even with a catalytic amount of piperidine
(0.2 mmol; entry 1, Table 1), whereas no product was
obtained in aqueous medium. A control experiment in
After optimization of the reaction conditions, the
generality and scope of the condensation reaction were
evaluated. The process was successfully extended to a
wide range of β-oxodithioesters (IIb–i) and 2-hydroxy-
1-naphthaldehyde to afford the corresponding
the absence of the catalyst provided no product. Other chromenes (IIIb–i) in excellent yields (Table 2).
bases, like triethylamine, were also tested in ethanol
with negligible yield of product, even though they
afforded 40% yield in combination of other solvents,
e.g. DMF and THF. We further carried out the same
condensation reaction using various metal salt cata-
lytic systems. Among them, cupric chloride and alu-
In order to evaluate the further scope of the reac-
tion, we used α-oxoketene dithioacetals instead of β-
oxodithioester. Interestingly, the cyclocondensation
reacitons of 2-hydroxy-1-naphthaldehyde (I) with α-
oxoketenedithioacetals (IVa–i) were also found suc-
cessful affording 2H-benzo[f]chromen-2-ones (Va–i)
minum chloride gave good yields, however, the reac- (Table 2).
Table 1. Evaluation of different catalytic systems in optimization of the chromene synthesis
Entry
Catalyst (equiv.)
Solvent
Yield, %
1
2
3
4
5
6
7
Piperidine (0.2 mmol)
Piperidine (0.1 mmol)
Piperidine
No catalyst
Et3N (0.2 mmol)
CuCl2
EtOH
EtOH
Water
–
93
90
No reaction
No reaction
THF/DMF
40
70
68
–
–
AlCl3
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SYNTHESIS OF FUNCTIONALIZED BENZO[f]2H-CHROMENES
Table 2. Piperidine-catalyzed synthesis of coumarins (IIIa–i) in ethanola
179
O
O
CHO
OH
Ar
Piperidine
Ar
MeS
(IIa−i)
+
Ethanol, reflux
O
S
S
(I)
(IIIa−i)
Entry
Ar
Products
Yields
1
2
3
4
5
C6H5
(IIIa)
(IIIb)
(IIIc)
(IIId)
(IIIe)
93
95
94
90
93
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
6
7
(IIIf)
(IIIg)
85
80
S
O
8
9
4-FC6H4
2,4-Cl2C6H3
IIIh
IIIi
86
92
a
Reaction conditions: (I) (2.5 mmol), (II) (2.5 mmol), piperidine (0.2 mmol), 95°C, 10–15 min.
Thus, in the presence of catalytic amount of piper- structure of which was confirmed by spectral and ana-
idine, α-oxoketenedithioacetal (IVa) was heated with
2-hydroxy-1-naphthaldehyde (Ia) at 95°C with etha-
nol. The progress of the reaction was monitored by
TLC and complete transformation was observed in
1 h. The reaction mixture was then poured into
crushed ice and the solid product was separated, fil-
tered, and recrystallized from ethanol. The reaction
went very smoothly and the yellow crystal of coumarin
lytical data. The reaction was also extended to differ-
ent α-oxoketenedithioacetals (IVb–i) to afford cou-
marins (Vb–i) in good-to-excellent yield. The
thiomethyl groups were replaced by the naphthyl
hydroxyl and during the cyclization the subsequent
dethiomethylation process led to the sulfur-free
chromene compound (V) as shown in the plausible
(Va) were obtained in 80% yield (Table 3, entry 1), the mechanism (Scheme 3).
O
O−
OH
O
O
O
H
CHO
OH
Ar
+
Ar
Ar
SMe
SMe
SMe
SMe
MeS
SMe
O
(I)
(IV)
−H2O, −SMe
O
O
O
Ar
O
Ar
OH
Ar
SMe
−MeSH
O
O
O
+
SMe
(V)
H2O
Scheme 3. Plausible mechanism for the formation of benzo[f]chromene (V).
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180
IROM HARIMALA CHANU et al.
Table 3. Piperidine catalyzed synthesis of chromenes (Va–f)a
O
O
CHO
Ar
Piperidine
O
SMe
+
Ar
Ethanol, reflux
O
SMe
OH
(I)
(IVa−i)
(IIIa−i)
Entry
Arya
Products
Yields
1
2
3
4
5
6
4-FC6H5
4-MeC6H4
4-BrC6H4
4-ClC6H4
C6H5
(Va)
(Vb)
(Vc)
(Vd)
(Ve)
(Vf)
80
87
82
83
88
86
4-MeOC6H4
7
(Vg)
79
S
8
9
(Vh)
(Vi)
75
82
O
2,4-Cl2C6H3
a
Reaction conditions: (I) (2.5 mmol), (IV) (2.5 mmol), piperidine (2 mmol), 90°C, 1–2 h.
Pharmacology
Antifungal activities of 18 compounds were tested
against two fungal strains Curvularia lunata and Fusar-
being more or similar to that of the antifungal activity
of standard antifungal agent fluconazole.
Antibacterial activity. Among the 18 compounds
ium moniliforme. There were variations in mycelia tested, only 4 compounds (IIIc), (IIIe), (IIIf), and
growth inhibition (%) with varying concentration of (Vd) showed efficient antibacterial activity against the
the compounds. Compounds (IIIe) (3-(4-bromoben- bacteria Escherichia coli and Staphylococcus aureus at
zoyl)-2H-benzo[f]chromene-2-thione), (IIIf) (3- 500 µg/mL concentration (Fig. 3). Negligible antibac-
thienyl-2H-benzo[f]chromene-2-thione), (IIIg) (3- terial activity was observed at lower concentrations
(2-furyl)-2H-benzo[f]chromene-2-thione), (Vb) (3- (100 and 200 µg/mL). Compound (Vd) showed high-
(4-methylbenzoyl-2H-benzo[f]chromen-2-one), and est antibacterial activity (zone of inhibition of 15 mm
(Vd) (3-(4-chlorobenzoyl-2H-benzo[f]chromen-2- for E. coli and 19 mm for S. aureus were quite reason-
one) were effective against fungus C. lunata (the results able as compared to the standard drug streptomycin).
are shown in Fig. 1). Significant mycelial growth inhibi-
tion of 90% and above was found for compounds (IIIe),
EXPERIMENTAL
(IIIf), (IIIg), and (Ve) at 500 µg/mL concentration.
Compound (IIIg) had very efficient antifungal activity
(98% mycelia inhibition even at 200 µg/mL).
Chemistry
The melting points were determined on a Mel-
temp II laboratory device and are uncorrected. 1H and
13C NMR spectra were recorded on a Bruker FT-
NMR-DRX300 (300 and 75.5 MHz, respectively) in
CDCl3 and chemical shifts are reported in parts per mil-
lion (δ, ppm) and signals are quoted as s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet), and dd (dou-
blet of doublets). The FT-IR spectra (νmax, cm–1) were
recorded on a Perkin-Elmer FT-IR spectrometer
(KBr). Elemental analyses were recorded using a Per-
Among the compounds tested for antifungal activ-
ity against F. moniliforme, compounds (IIIa), (IIIe),
(IIIf), and (Ve) showed significant activity as depicted
in Fig. 2. There was increase in the inhibition of myce-
lia growth at higher concentration (500 µg/mL) as
compared to lower concentrations (100 and
200 µg/mL). Mycelial inhibition of 90% and above
was found for compounds (IIIe), (IIIf), and (Ve).
Also, 100% mycelium inhibition of F. moniliforme was
shown by compound (Ve).
Compounds (IIIg) and (Ve) showed excellent anti- kin-Elmer 2400 analytical instrument. Mass spectra
fungal activity, the % inhibition of the tested fungi (ESI-MS) were recorded on a Waters Q-TOF LC-MS
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SYNTHESIS OF FUNCTIONALIZED BENZO[f]2H-CHROMENES
181
100 µg/mL
200 µg/mL
500 µg/mL
120
100
80
60
40
20
0
(IIIa)
(IIIe)
(IIIf)
(IIIg)
(Vb)
(Vd) Fluconazole
Compounds
Fig. 1. Inhibition of C. lunata mycelium growth (%) by the synthesized compounds.
100 µg/mL
200 µg/mL
500 µg/mL
100
80
60
40
20
0
(IIIa) (IIIe) (IIIf) (IIIg) (Vb)
(Vc)
(Ve) Fluconazole
Compounds
Fig. 2. Inhibition of F. moniliforme mycelium growth (%) by the synthesized compounds.
spectrometer. Analytical thin layer chromatography
General Procedure for the Synthesis
of Chromenes (IIIa–i)
To a stirred solution of 2-hydroxynapthaldehyde (I)
(2.2 mmol) and β-oxodithioesters (IIa–i) (2.2 mmol)
(TLC) was carried out using pre-coated silica gel glass
plates (E. Merck, Kiesegel 60F254). β-Oxodithio-
esters were prepared by known procedures [14–16].
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182
25
IROM HARIMALA CHANU et al.
3-(4-Methylbenzoyl)-2H-benzo[f]chromene-2-thi-
S. aureus
E. coli
1
one (IIIc). Yellow solid, mp 264–265°C. H NMR:
2.43 (s, 3H, CH3), 7.27 (d, J = 10.8 Hz, 2H, ArH),
7.75–7.61 (m, 3H, ArH), 7.89 (d, J = 8.1 Hz, 2H,
ArH), 7.96 (d, J = 8.1 Hz, 1H, ArH), 8.11 (d, J = 9.3
Hz, 1H, ArH), 8.24 (d, J = 8.1 Hz, 1H, ArH), 8.36 (s,
1H, ArH). 13C NMR: 192.6, 192.3, 157.0, 145.1, 139.1,
134.6, 133.2, 130.6, 129.9, 129.7, 129.5, 129.2, 128.9,
128.8, 127.0, 121.6, 116.5, 115.2, 21.8. MS, m/z: 330
(M+). Anal. calcd. for C21H14O2S: C, 76.34; H, 4.20.
Found C, 76.33; H, 4.19.
20
15
10
5
3-(4-Chlorobenzoyl)-2H-benzo[f]chromene-2-thi-
one (IIId). Yellow crystals, mp 272–273°C. 1H NMR:
7.47 (d, J = 8.4 Hz, 2H, ArH), 7.66–7.69 (m, 2H,
ArH), 7.74–7.79 (m, 1H, ArH), 7.92–8.01 (m, 3H,
ArH), 8.15 (d, J = 9 Hz, 1H, ArH), 8.27 (d, J = 8.1 Hz,
1H, ArH), 8.42 (s, 1H, ArH); 13C NMR: 115.2, 116.5,
121.7, 127.1, 128.9, 129.1, 129.2, 129.3, 130.4, 130.7,
131.0, 134.3, 135.0, 138.5, 140.4, 157.9, 191.6, 192.4;
IR: 1259, 1558, 1666, 3083; MS, m/z: 350 (M+). Anal.
calcd. for C20H11ClO2S: C, 68.47; H, 3.16; S, 9.14.
Found: C, 68.49; H, 3.11; S, 9.19.
0
(IIIc)
(IIIe)
(IIIf)
Compounds
(Vd) Streptomycin
Fig. 3. Antibacterial activity of the synthesized com-
pounds.
in EtOH, piperidine (0.22 mmol) was added at room
temperature. The reaction mixture was heated at
refluxing temperature in a preheated oil bath (95°C)
for 10–15 min for completion of the reaction (TLC; hex-
ane–EtOAc, 8 : 2). The reaction mixture was then
diluted with ethylacetate (25 mL) and the organic solu-
tion was washed sequentially with water (3 × 25 mL) and
brine (2 × 10 mL) and dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure in
a rotavapor and the resulted crude was subjected to
column chromatography on SiO2. Separation was
done using increasing amounts of ethyl acetate in hex-
ane as eluent.
3-(Benzoyl)-2H-benzo[f]chromene-2-thione (IIIa).
Yellow crystals, mp 200–201°C. 1H NMR: 7.50–7.56
(m, 3H, ArH), 7.61–7.69 (m, 2H, ArH), 7.73–7.78
(m, 1H, ArH), 7.94–8.02 (m, 3H, ArH), 8.13 (d, J =
9 Hz, 1H, ArH), 8.26–8.30 (m, 1H, ArH), 8.40 (s,
1H, ArH); 13C NMR: 112.7, 116.5, 121.5, 125.4, 126.5,
128.7, 128.9, 129.4, 129.7, 129.9, 130.7, 134.8, 135.4,
138.9, 141.8, 157.8, 192.1, 192.7; IR: 1265, 1560, 1654,
3056; MS, m/z: 316 (M+). Anal. calcd. for C20H12O2S:
C, 75.93; H, 3.82; S, 10.14. Found: C, 75.95; H, 3.85;
S, 10.11.
3-(4-Methoxybenzoyl)-2H-benzo[f]chromene-2-
thione (IIIb). Yellow crystals, mp 218–219°C.
1H NMR: 3.80 (s, 3H, OCH3), 6.87 (d, J = 6.6 Hz,
2H, ArH), 7.54–7.65 (m, 3H, ArH), 7.87–7.89 (m,
3H, ArH), 8.03 (d, J = 6.9 Hz, 1H, ArH), 8.15 (d, J =
6.6 Hz, 1H, ArH), 8.27 (s, 1H, ArH); 13C NMR:
113.91, 114.12, 115.26, 121.53, 127.06, 128.81, 128.91,
128.95, 129.22, 129.25, 129.35, 129.65, 130.68, 134.65,
139.16, 157.64, 164.34, 191.29, 192.73; MS, m/z: 346
(M+). Anal. calcd. for C21H14O3S: C, 72.81; H, 4.07; S,
9.26. Found: C, 72.79; H, 4.05; S, 9.29.
3-(4-Bromobenzoyl)-2H-benzo[f]chromene-2-thi-
one (IIIe). Yellow crystals, mp 269–270°C. 1H NMR:
7.64 (d, J = 8.3 Hz, 2H, ArH), 7.67–7.7 (m, 2H,
ArH), 7.72–7.76 (m, 1H, ArH), 7.91–8.08 (m, 3H,
ArH), 8.14 (d, J = 9 Hz, 1H, ArH), 8.28 (d, J = 8.1 Hz,
1H, ArH), 8.10 (s, 1H, ArH); 13C NMR: 114.6, 116.1,
121.4, 127.3, 128.4, 129.7, 129.9, 130.3, 130.5, 130.7,
131.5, 133.9, 134.6, 137.9, 140.1, 157.4, 191.1, 193.2;
IR: 1270, 1601, 1672, 3071; MS, m/z: 350 (M+). Anal.
calcd. for C20H11BrO2S: C, 60.77; H, 2.81. Found: C,
60.75; H, 2.80.
3-(2-Thienyl)-2H-benzo[f]chromene-2-thione (IIIf).
1
Yellow crystals, mp 250–251°C. H NMR: 7.17–7.28
(m, 2H, ArH), 7.65–7.80 (m, 4H, ArH), 7.97 (d, J =
7.8 Hz, 1H, ArH), 8.13 (d, J = 9 Hz, 1H, ArH), 8.25
13
(d, J = 8.1 Hz, 1H), 8.40 (s, 1H, ArH); C NMR:
115.0, 116.5,121.7, 127.1, 128.5, 128.9, 129.3, 129.4,
130.7, 134.9, 135,1, 135.6, 138.6, 142.9, 157.7, 174.4,
184.7, 192.3; IR: 1271, 1558, 1637, 3055; MS, m/z: 322
(M+). Anal. calcd. for C18H10O2S2: C, 67.06; H, 3.13;
S, 19.89. Found: C, 67.09; H, 3.15; S, 19.83.
3-(2-Furyl)-2H-benzo[f]chromene-2-thione (IIIg).
Yellow crystals, mp 252–253°C. 1H NMR: 6.61–6.59
(m, 1H, ArH) 7.33 (d, J = 3.6 Hz, 1H, ArH), 7.76–
7.62 (m, 4H, ArH), 7.96 (d, J = 7.8 Hz, 1H, ArH), 8.11
(d, J = 9.0 Hz, 1H, ArH), 8.25 (d, J = 8.1 Hz, 1H,
ArH), 8.39 (s, 1H, ArH); 13C NMR: 112.8, 115.0,
116.4, 120.1, 121.6, 127.0, 127.0, 128.8, 129.0, 129.2,
130.0, 130.6, 134.9, 137.7, 147.5, 151.8, 157.7, 179.9,
192.3; IR: 1641, 1558, 1462, 1284, 1170; MS, m/z: 307
(M+). Anal. calcd. for C18H10O3S: C, 70.57; H, 3.29.
Found: C, 70.59; H, 3.31.
3-(4-Fluorobenzoyl)-2H-benzo[f]chromene-2-thione
(IIIh). Yellow crystals, mp 269–270°C. 1H NMR: 6.47
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SYNTHESIS OF FUNCTIONALIZED BENZO[f]2H-CHROMENES
183
(s, 1H, ArH); 13C NMR: 21.8, 112.7, 116.7, 121.5,
125.6, 126.5, 128.9, 129.2, 129.3, 129.4, 129.8, 130.3,
133.8, 135.2, 141.4, 144.8, 155,3, 158.6, 191.7; IR:
3063, 2953, 1703, 1651; MS, m/z: 314 (M+). Anal.
calcd. for C21H14O3: C, 80.24; H, 4.49; O, 15.27.
Found: C, 80.25; H, 4.48; O, 15.29.
3-(4-Bromobenzoyl)-2H-benzo[f]chromen-2-one
(Vc). Yellow crystals, mp 243–244°C. 1H NMR: 6.43
(d, J = 8.7 Hz, 2H, ArH), 7.62 (d, J = 9.1 Hz, 1H,
ArH), 7.64 (t, J = 7.8 Hz, 1H, ArH), 7.69 (t, J = 7.3
Hz, 1H, ArH), 7.76 (d, J = 8.4 Hz, 2H, ArH), 7.85 (d,
(d, J = 8.4 Hz, 2H, ArH), 7.65–7.69 (m, 2H, ArH),
7.67–7.68 (m, 1H, ArH), 7.91–8.10 (m, 3H, ArH),
8.13 (d, J = 9 Hz, 1H, ArH), 8.18 (d, J = 8.1 Hz, 1H,
ArH), 8.23 (s, 1H, ArH); 13C NMR: 116.2, 116.5,
122.5, 126.5, 127.9, 128.8, 129.6, 129.8, 130.5, 130.9,
132.0, 135.1, 134.9, 138.7, 140.8, 156.8, 190.4, 193.5;
IR: 1263, 1543, 1665, 3070; MS, m/z: 334.4 (M+).
Anal. calcd. for C20H11FO2S: C, 71.84; H, 3.32.
Found: C, 71.82; H, 3.30.
3-(2,4-Dichlorobenzoyl)-2H-benzo[f]chromene-2-
thione (IIIi). Yellow crystals, mp 275–276°C.
1H NMR: 7.47 (d, J = 8.4 Hz, 2H, ArH), 7.66–7.69 J = 8.2 Hz, 1H, ArH), 7.93 (d, J = 8.3 Hz, 1H, ArH),
(m, 2H, ArH), 7.74–7.78 (m, 1H, ArH), 7.87–7.96 8.12 (d, J = 8.4 Hz, 1H, ArH), 8.34 (s, 1H, ArH);
13C NMR: 112.3, 116.5, 121.7, 124.7, 126.5, 127.7,
(m, 2H, ArH), 8.22 (d, J = 9 Hz, 1H, ArH), 8.28 (d,
13
J = 8.1 Hz, 1H, ArH), 8.83 (s, 1H, ArH); C NMR: 129.4, 129.6, 129.8, 130.6, 130.8, 132.3, 134.6, 141.1,
114.2, 115.8, 120.8, 125.1, 126.9, 128.6, 129.4, 129.7, 142.7, 148.6, 154.6, 190.0; IR: 3034, 2921, 1712, 1665;
MS, m/z: 379 (M+). Anal. calcd. for C20H11BrO3: C,
63.35; H, 2.92; Found: C, 63.34; H, 3.33.
130.8, 131.4, 131.9, 133.3, 134.6, 137.5, 139.4, 149.7,
190.1, 192.8; IR: 1280, 1579, 1664, 3028; MS, m/z: 350
(M+). Anal. calcd. for C20H10Cl2O2S: C, 68.47; H,
3.16; S, 9.14. Found: C, 68.49; H, 3.11; S, 9.19.
3-(4-Chlorobenzoyl)-2H-benzo[f]chromen-2-one
1
(Vd). Yellow crystals, mp 231–232°C. H NMR: 7.47
(d, J = 8.8 Hz, 2H, ArH), 7.52 (d, J = 9.3 Hz, 1H,
ArH), 7.63 (t, J = 7.9 Hz, 1H, ArH), 7.75 (t, J = 7.3
Hz, 1H, ArH), 7.86 (d, J = 8.8 Hz, 2H, ArH), 7.96 (d,
J = 8.3 Hz, 1H, ArH), 8.13 (d, J = 8.8 Hz, 1H, ArH),
8.28 (d, J = 8.3 Hz, 1H, ArH), 8.97 (s, 1H, ArH);
13C NMR: 112.7, 116.7, 121.5, 124.7, 126.7, 128.9,
129.1, 129.3, 129.4, 130.3, 130.9, 134.8, 135.8, 140.2, 142.6,
155.6, 158.6, 191.0; IR: 3069, 2951, 1707, 1655; MS, m/z:
334 (M+). Anal. calcd. for C20H11ClO3: C, 71.76; H, 3.31;
O, 14.34. Found: C, 71.77; H, 3.33; O, 14.33.
3-(Benzoyl)-2H-benzo[f]chromen-2-one (Ve). Yel-
low crystals. mp 215–216°C. 1H NMR: 7.45–7.51 (m,
3H, ArH), 7.57–7.65 (m, 2H, ArH), 7.7 (t, J = 7.3 Hz,
1H, ArH), 7.89–7.94 (m, 3H, ArH), 8.08 (d, J = 9.3
Hz, 1H, ArH), 8.24 (d, J = 8.4 Hz, 1H, ArH), 8.89 (s,
1H, ArH); 13C NMR: 112.6, 116.7, 121.5, 125.4, 126.5,
128.5, 128.9, 129.2, 129.4, 129.6, 130.3, 133.6, 135.3,
136.5, 141.7, 155.4, 158.5, 192.1; IR: 3102, 2959, 1700,
1654; MS, m/z: 300 (M+). Anal. calcd. for C20H12O3:
C, 79.99; H, 4.03; O, 15.98. Found: C, 79.95; H, 4.02;
O, 15.99.
General Procedure for Synthesis of Chromenes (Va–i)
To a stirred solution of 2-hydroxynapthaldehyde (I)
(2.2 mmol) and α-oxoketenedithioacetal (IIa–i)
(2.2 mmol) in EtOH (30 mL), piperidine (0.22 mmol)
was added at room temperature. The reaction mixture
was heated at reflux in a preheated oil bath (95°C) for
1–1.5 h for completion of the reaction (TLC; hexane–
EtOAc, 8 : 2). The reaction mixture was then diluted
with ethylacetate (25 mL), and the organic solution
was washed sequentially with water (3 × 25 mL) and
brine (2 × 10 mL) and dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure in
a rotavapor and the resulted crude was subjected to
column chromatography on SiO2. Separation was
done using increasing amounts of ethyl acetate inhex-
ane as eluent.
3-(4-Flurobenzoyl)-2H-benzo[f]chromen-2-one (Va).
Yellow crystals, mp 229–230°C. 1H NMR: 7.67 (d, J =
8.2 Hz, 2H, ArH), 7.76 (d, J = 9.1 Hz, 1H, ArH), 7.89
(t, J = 7.8 Hz, 1H, ArH), 7.63 (t, J = 7.4 Hz, 1H,
ArH), 7.92 (d, J = 8.9 Hz, 2H, ArH), 7.99 (d, J = 8.1
3-(4-Methoxybenzoyl)-2H-benzo[f]chromen-2-one
1
Hz, 1H, ArH), 8.26 (d, J = 8.9 Hz, 1H, ArH), 8.76 (d, (Vf). Yellow crystals, mp 231–232°C. H NMR: 3.82
J = 8.8 Hz, 1H, ArH), 8.93 (s, 1H, ArH); 13C NMR:
111.4, 114.2, 123.4, 125.1, 126.7, 128.3, 129.4, 129.6,
(s, 3H, OCH3), 6.89 (d, J = 8.3 Hz, 2H, ArH), 7.51 (d,
J = 9.3 Hz, 1H, ArH), 7.57 (br t, J = 7.8 Hz, 1H,
129.9, 130.6, 130.9, 134.3, 135.5, 140.7, 141.5, 155.9, ArH), 7.67 (br t, J = 7.3 Hz, 1H, ArH), 7.85 (d, J = 8.3
Hz, 2H, ArH), 7.91 (d, J = 8.3 Hz, 1H, ArH), 8.07 (d,
J = 9.3 Hz, 1H, ArH), 8.19 (d, J = 8.8 Hz, 1H, ArH),
8.79 (s, 1H, ArH); 13C NMR: 55.6, 112.7, 113.9, 116.7,
121.5, 125.9, 126.5, 128.9, 129.1, 129.2, 129.3, 130.3,
132.2, 135.1, 141.2, 155.2, 158.8, 164.2, 190.5; IR:
3065, 2950, 1706, 1656; MS, m/z: 330 (M+). Anal.
calcd. for C21H14O4: C, 76.35; H, 4.27; O, 19.37.
Found: C, 76.37; H, 4.26; O, 19.39.
158.1, 190.0, IR: 3050, 2986, 1718, 1655; MS, m/z: 318
(M+). Anal. calcd. for C20H11FO3: C, 75.46; H, 3.48.
Found: C, 75.44; H, 3.47.
3-(4-Methylbenzoyl)-2H-benzo[f]chromen-2-one
(Vb). Yellow crystals, mp 191–192°C. 1H NMR: 2.45
(s, 3H, CH3), 7.29 (d, J = 8.3 Hz, 2H, ArH), 7.51 (d,
J = 9.3 Hz, 1H, ArH), 7.61 (br t, J = 7.8 Hz, 1H, ArH),
7.71 (br t, J = 7.3 Hz, 1H, ArH), 7.83 (d, J = 8.3 Hz,
2H, ArH), 7.94 (d, J = 8.3 Hz, 1H, ArH), 8.11 (d, J =
3-(2-Thienylbenzoyl)-2H-benzo[f]chromen-2-one
9.3 Hz, 1H, ArH), 8.25 (d, J = 8.8 Hz, 1H, ArH), 8.90 (Vg). Yellow crystals, mp 240–241°C. 1H NMR: 7.17–
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 43 No. 2 2017

184
IROM HARIMALA CHANU et al.
7.28 (m, 2H, ArH), 7.65–7.80 (m, 4H, ArH), 7.97 (d, solutions of tested compounds were prepared in ace-
J = 7.8 Hz, 1H, ArH), 8.13 (d, J = 9 Hz, 1H, ArH), tone (10 mg/mL). Each compound was added to the
8.25 (d, J = 8.1 Hz, 1H, ArH), 8.40 (s, 1H, ArH); molten sterilized PDA medium in conical flasks sepa-
13C NMR: 115.0, 116.5,121.7, 127.1, 128.5, 128.9,
129.3, 129.4, 130.7, 134.9, 135,1, 135.6, 138.6, 142.9,
150.5, 157.7, 174.4, 192.3; IR: 1271, 1558, 1637, 3055;
MS, m/z: 322 (M+). Anal. calcd. for C18H10O3S: C,
70.57; H, 3.29. Found: C, 69.09; H, 3.25.
rately to get a final concentration of 100, 200, and 500
µg/mL, respectively. Each PDA medium (25 mL)
containing the compounds of the three different con-
centrations was mixed thoroughly and poured into 90
mm Petri plate. Petri plate without any chemical com-
pounds served as control. In each case, three replicates
were taken. PDA containing fluconazole at a concen-
tration of 200 µg/mL served as a standard antifungal
agent. The Petri plates after solidification were inocu-
lated separately with mycelial disc (9 mm) of test fun-
gus taken from 4-days pure cultures aseptically and
incubated at 37°C in B.O.D incubator till the mycelial
growth in the control reached the maximum growth.
The radial growth of the test fungus recorded after 5
days by measuring the colony diameter, in comparison
with the control, were taken as a measure of fungitox-
icity. All the tests were performed in triplicate and the
average was taken as final reading.
3-(2-Furylbenzoyl)-2H-benzo[f]chromen-2-one
1
(Vh). Yellow crystals, mp 240–241°C. H NMR:
6.61–6.59 (m,1H, ArH), 7.33 (d, J = 3.6 Hz, 1H,
ArH), 7.76–7.62 (m, 4H, ArH), 7.96 (d, J = 7.8 Hz,
1H, ArH), 8.11 (d, J = 9.0 Hz, 1H, ArH), 8.39 (s, 1H,
ArH), 8.25 (d, J = 8.1 Hz, 1H, ArH); 13C NMR: 112.8,
115.0, 116.4, 120.8, 121.9, 127.7, 129.0, 129.6, 129.9,
130.6, 131.0, 135.2, 137.8, 147.6, 156.5, 157.7, 170.8,
189.9; IR: 1291, 1555, 1632, 3050; MS, m/z: 290.06
(M+). Anal. calcd. for C18H10O4: C, 74.48; H, 3.47.
Found: C, 74.39; H, 3.45.
3-(2,4-Dichlorobenzoyl)-2H-benzo[f]chromen-2-one
(Vi). Yellow crystals, mp 255–256°°C. 1H NMR: 7.47
Antibacterial bioassay. The antibacterial assay was
(d, J = 8.4 Hz, 2H, ArH), 7.66–7.69 (m, 2H, ArH), assessed by agar well diffusion method using 20 mL of
7.74–7.78 (m, 1H, ArH), 7.87–7.96 (m, 2H, ArH), sterile MHA for testing the bacterial activity [20]
(Perez et al, 1990). Standard inoculums (106 CFU/mL)
8.22 (d, J = 9 Hz, 1H, ArH), 8.28 (d, J = 8.1 Hz, 1H,
ArH), 8.83 (s, 1H, ArH); 13C NMR: 114.2, 115.8, were introduced onto the surface of the sterile agar
120.8, 125.1, 126.9, 128.6, 129.4, 129.7, 130.8, 131.4, plates, and a sterile glass spreader was used for even
131.9, 133.3, 134.6, 136.1, 137.5, 139.4, 149.7, 190.1; distribution of the inoculums.
IR: 1280, 1579, 1664, 3028; MS, m/z; 350 (M+). Anal.
calcd. for C20H10Cl2O3: C, 65.06; H, 2.73. Found: C,
65.49; H, 2.61.
Sterile 8-mm diameter cork borers were pierced in
the agar in each plate. The stock solution of each
chemical was prepared by dissolving 10 mg in 1 mL of
acetone. From this stock solution, serial dilutions of
the compounds (500, 200, and 100 µg/mL) were pre-
pared. Then the well in each plate was inoculated with
the test compound with varying concentrations.
Streptomycin (5 mg/mL) was used as positive control
and acetone as negative control. The plates were incu-
bated for 24 h at 37°C and the antimicrobial activity
was assessed by measuring the diameter of the inhibi-
tion zone around the well. All the tests were performed
in triplicate and the average was taken as final reading.
Biology
Antimicrobial effects of compounds (IIIa–i) and
(Va–i) were visualized in bioassays using selected
microorganisms as test organisms.
Test microorganisms. The microorganisms used in
the bioassays were purchased from the Institute of
Microbial Technology (IMTECH), Chandigarh,
India. Two bacteria namely, Staphylococcus aureus
(MTCC-7443) and Escherichia coli (MTCC-725),
and two fungal species, namely Curvularia lunata
(MTCC-2605) and Fusarium moniliforme (MTCC-
278), were used for the study. Bacterial strains were
inoculated on Mueller Hinton agar (MHA) and incu-
bated at 37°C for 24 h. The fungal strains were inocu-
lated on potato dextrose agar (PDA) and incubated at
30°C. Besides, the antimicrobial activity of the com-
pounds was compared with standard antibiotic (strep-
tomycin) and fungicide (fluconazole).
Antifungal bioassay. Poison food technique [18, 19]
(Grover and Moore, 1962, Mohana and Raversha,
2007) was used for an in vitro study of antifungal activ-
ities. The effect of different concentrations of couma-
rins on the radial growth of test fungi C. lunata and
F. moniliforme were assessed by amending the com-
CONCLUSIONS
Compounds (IIIg) and (Ve) exhibited excellent
antifungal activity against the test fungi Curvularia
lunata and Fusarium moniliforme. Highest antibacte-
rial activity against the test bacteria Escherichia coli
and Staphylococcus aureus was shown by compound
(Vd). The results of antimicrobial screening of the
organic compounds lead to the conclusion that the
compounds (IIIg), (Vd), and (Ve) are promising anti-
microbial drug candidates.
ACKNOWLEDGMENTS
O.M.S.
is
thankful
to
DBT,
India
pounds in potato dextrose agar (PDA) medium. Stock (BT/278/NE/TBP/2011) for financial assistance.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 43
No. 2
2017

SYNTHESIS OF FUNCTIONALIZED BENZO[f]2H-CHROMENES
185
11. Dittmer, D.C., Li, Q., and Avilov, D.V., J. Org. Chem.,
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