Microwave-Assisted synthesis of 30-indolyl substituted 4H-chromenes catalyzed by DMAP and their antimicrobial activity

Article abstract of DOI:10.1007/s00044-011-9861-4

A new series of indole-based chromene derivatives 4a-4p has been synthesized by one pot cyclocondensation reaction of 2-phenyl-1H-indole-3- carbaldehyde 1a-1h; malononitrile 2; and 1,3-cyclohexanedione/dimedone 3a/b under microwave irradiation catalyzed by an organocatalyst 4-(N,N-dimethylamino) pyridine. Easy experimental procedure, high yield, selectivity, and shorter reaction time are the imperative features of this method. All the compounds were screened against a representative panel of bacteria and fungi. Some of the compounds are found to be equipotent or more potent than that of standard drugs as evident from SAR study. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9861-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3406–3416
DOI 10.1007/s00044-011-9861-4
ORIGINAL RESEARCH
Microwave-assisted synthesis of 30-indolyl substituted
4H-chromenes catalyzed by DMAP and their antimicrobial
activity
•
Harshad G. Kathrotiya Manish P. Patel
Received: 23 July 2011 / Accepted: 31 October 2011 / Published online: 19 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A new series of indole-based chromene deriv-
atives 4a–4p has been synthesized by one pot cyclocon-
densation reaction of 2-phenyl-1H-indole-3-carbaldehyde
1a–1h; malononitrile 2; and 1,3-cyclohexanedione/dime-
done 3a/b under microwave irradiation catalyzed by an
organocatalyst 4-(N,N-dimethylamino) pyridine. Easy
experimental procedure, high yield, selectivity, and shorter
reaction time are the imperative features of this method.
All the compounds were screened against a representative
panel of bacteria and fungi. Some of the compounds are
found to be equipotent or more potent than that of standard
drugs as evident from SAR study.
2009), cytotoxic agent (Raj et al., 2010; Sabry et al., 2011),
antidyslipidemic agent (Sashidhara et al., 2008), antile-
ishmanial (Nazarian et al., 2010), anti inflametory (Geb-
hardt et al., 2007), antihelicobacter pylori agent (Chimenti
et al., 2007), and TNF-a inhibitor (Cheng et al., 2003).
On the other hand, indole derivatives have been a topic
of substantial research interest in contemporary heterocy-
clic and medicinal chemistry due to their great significance
in the view of their (i) occurrence in nature as a prominent
sub-structure of a large number of alkaloids (Tanaka et al.,
2006; Frederich et al., 2008) and (ii) wide-ranging bio-
logical activities which includes antimicrobial (Al-Qa-
wasmeh et al., 2010; Tiwari et al., 2006; Harnden et al.,
1978), antitubercular (Karthikeyan et al., 2009; Guzel
et al., 2008), ghrelin receptor (Demange et al., 2007),
anticancer (Singh et al., 2009; Shi et al., 2007), antioxidant
(Lakshmi et al., 2010), antiviral (Giampieri et al., 2009;
Fonseca et al., 2004), and antimalarial (Kgokong et al.,
2005; Agarwal et al., 2005). Literature survey manifests
that the number of 4H-chromene derivatives have been
synthesized using various aldehydes (Thumar and Patel,
2009a, 2011b; Mungra et al., 2011b) but there is not a
single report where 2-phenyl-1H-indole-3-carbaldehyde is
used.
Keywords 4H-Chromene ꢀ Indole ꢀ DMAP ꢀ
Microwave irradiation ꢀ MCR ꢀ
In vitro antimicrobial activity
Introduction
The chromene ring system is considered to be one of the
most imperative heterocycle in nature as it has the dis-
tinction of being the parent ring in countless derivatives of
biological relevance. The current interest in 4H-chromene
derivatives arises from their potential application as anti-
microbial (Kuarm et al., 2011; Rai et al., 2010), anti-HIV
(Bhavsar et al., 2011; Park et al., 2008), anti tubercular
(Kamdar et al., 2010), antioxidant (Singh et al., 2010),
anticancer (Raju et al., 2011), antitumor (Huang et al.,
The molecular manipulation of promising lead com-
pounds is still a chief approach to widen an area of med-
icine research. It involves an idea to merge the separate
pharmacophoric groups of analogous activity into one
compound, thus, making structural changes in the biolog-
ical activity. An attempt has been through to undertake the
synthesis of chromene derivatives with the assumption that
the assimilation of more than one bioactive moiety into a
single scaffold may produces novel heterocycles with fas-
cinating antimicrobial activities to combat the infections of
microbial pathogens.
H. G. Kathrotiya ꢀ M. P. Patel (&)
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar 388120, Gujarat, India
e-mail: patelmanish1069@yahoo.com
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Med Chem Res (2012) 21:3406–3416
3407
In the radiance of the aforementioned facts, and as a
prolongation of our investigation on the synthesis of bio-
logically active heterocyclic compounds (Thumar and
Patel, 2009a, b, 2011a, b, c, d; Shah and Patel, 2011;
Makawana et al., 2011a, b; Shah et al., 2001; Sangani
2011; Mungra et al., 2009, 2011a, b; Ladani et al., 2009a,
b, 2010, 2011; Nirmal et al., 2009, 2010; Shah et al.,
2009a, b), we were provoked to synthesize new indole-
based 4H-chromene derivatives and evaluate them as
antimicrobial agents.
antimicrobial activity against eight human pathogens, of
which three are Gram-positive bacteria (Streptococcus
pneumonia, Clostridium tetani, and Bacillus subtilis), three
are Gram-negative bacteria (Salmonella typhi, Vibrio
cholerae, and Escherichia coli), and two fungi (Aspergillus
fumigatus, Candida albicans) using broth microdilution
MIC (minimum inhibitory concentration) method (NCCLS
2002).
The conventional procedures are not found to be satis-
factory with regard to operational simplicity, effectiveness,
and yield. An alternative synthetic approach is microwave
irradiation (Mungra et al., 2011a, b; Jing et al., 2006; Rao
et al., 2004). In recent years, microwave irradiation has
been demonstrated not only to dramatically accelerate
many organic reactions, but also to improve yield and
selectivity.
Results and discussion
Chemistry
The required 2-phenyl-1H-indole-3-carbaldehyde 1a–1h
was prepared by Vilsmeier-Haack reaction according to
literature procedure (Qu et al., 2009) (Scheme 1, 2).
In this study, a series of 4H-chromene derivatives 4a–4p
have been synthesized by one-pot three-component cyclo-
condensation reaction of 2-phenyl-1H-indole-3-carbalde-
hyde 1a–1h; malononitrile 2; and 1,3-cyclohexanedione/
dimedone 3a/3b under microwave irradiation catalyzed by
an organocatalyst DMAP. The above mixture in refluxing
ethanol gives moderate to good yield, i.e., 69–86%.
According to the mechanism suggested in literature
(Khan et al., 2011), the formation of the chromene deriva-
tives may occurs via an in situ initial formation of the
DMAP derives its remarkable ability to catalyze not just
from its strong base characteristic but from its unique
structure. In connection with our earlier study on DMAP
catalysis with microwave irradiation (Nirmal et al., 2009),
we attempted same strategy to achieve novel 4H-chromene
derivatives of indole.
The constitutions of all the products were confirmed
1
using H NMR, 13C NMR, FTIR and elemental analysis.
All synthesized compounds were screened for in vitro
Scheme 1 Synthetic pathway for the intermediates 1a–1h
Scheme 2 Synthetic pathway
for the synthesis of 4H-
chromene derivatives of
2-phenyl-1H-indole 4a–4p
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Med Chem Res (2012) 21:3406–3416
Scheme 3 Plausible
mechanistic pathway for the
synthesis of 4H-chromene
derivatives
heterylidenenitrile in the presence of DMAP, containing the
electron-poor C=C double bond, from the Knoevenagel
condensation between 2-phenyl-1H-indole-3-carbaldehyde
1a–1h and malononitrile 2 by loss of water molecules.
Finally, Michael addition of 3a/3b to the initially formed
unsaturated nitrile in the presence of DMAP, i.e., nucleo-
philic attack of hydroxyl moiety to the cyano moiety affords
cyclized 4H-chromene derivatives 4a–4p (Scheme 3).
The structures of all the new synthesized compounds
two methyl protons as well as multiplet at d 1.97–2.60 ppm
is assigned to two methylene protons of chromene ring. 13
C
NMR of 4h exhibited a distinctive signal at d 27.00 and
27.10 ppm for two methyl of chromene ring as well as d
29.03 ppm for C 4 of the chromene ring. All the aromatic
carbons of 4h showed signals at d 112.42–136.71 ppm in
the 13C NMR spectra. Moreover, distinctive signals at d
196.76 ppm assigned to carbonyl carbon C 5 of chromene
ring, d 162.52 ppm for C 2, d 158.54 ppm for C 8a, d
112.08 ppm for C 4a, d 58.38 ppm for C 3, d 50.64 ppm
for C 6, d 32.29 ppm for C 8, and d 32.00 ppm for C 7 of
chromene ring in the 13C NMR spectra confirms the
structure 4h.
1
were established by H NMR, 13C NMR, FTIR, elemental
analysis, and molecular weight of some selected com-
pounds were confirmed by mass spectrometry. In 1H NMR,
(DMSO-d6) spectrum of compound 4h indicated the pres-
ence of one singlet peak at d 4.65 ppm of –CH proton and
the disappearance of a singlet from d 10.50 ppm of –CHO
clearly confirm the cyclization of Knoevenagel intermedi-
ate. The singlet at d 6.88 ppm exhibit NH2 protons of the
chromene ring. Aromatic protons of 4h resonate as multi-
plets at d 6.94–7.91 ppm and a deshielded aromatic singlet
at d 11.24 ppm stands for secondary amine of the indole
ring. A singlet at d 0.84 ppm and d 1.02 ppm stands for
The IR spectrum of compound 4h exhibited character-
istic absorption band at 3,430 and 3,360 cm-1 (asym. and
sym. str.) for –NH2 and 2,195 cm-1 for –CN functionality.
The presence of band at 1,210 cm-1 of cyclic ether linkage
and 1,685 cm-1 of carbonyl (C=O) functional group sup-
ports the formation of title compounds 4h. Further, the
structures of selected compounds 4b, 4c, and 4h were
confirmed by its mass spectral studies. The mass spectra
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Med Chem Res (2012) 21:3406–3416
3409
detected the expected molecular ion signals corresponding
to respective molecular formula of synthesized compounds.
Mass spectra of compound 4h gave molecular ion peak at
444.6 (M ? 1) corresponding to molecular formula
C26H22ClN3O2. All spectroscopic data have been given in
experimental section.
activity (MIC 62.5 lg/mL) as compared to the standard
ampicillin (MIC 100 lg/mL). Compounds 4e (R1 = OCH3,
R2 = H), 4m (R1 = SO2CH3, R2 = H) (MIC 100 lg/mL)
and 4n (R1 = SO2CH3, R2 = CH3) (MIC 125 lg/mL)
against C. tetani while compound 4l (R1 = F, R2 = CH3)
(MIC 100 lg/mL) against B. subtilis were found signifi-
cantly active upon comparison with ampicillin (MIC 250
lg/mL). Compounds 4b (R1 = H, R2 = CH3), 4i (R1 = Br,
R2 = H), 4l (R1 = F, R2 = CH3) and 4p (R1 = NO2,
R2 = CH3) against C. tetani as well as compounds 4b
(R1 = H, R2 = CH3), 4g (R1 = Cl, R2 = H), 4i (R1 = Br,
R2 = H), 4j (R1 = Br, R2 = CH3) and 4k (R1 = F,
R2 = H) against B. subtilis were found to possess better
activity (MIC 200 lg/mL) than that of ampicillin (MIC
250 lg/mL).
Antimicrobial activity
All the glass apparatus used were sterilized before use.
Antimicrobial activity of all the synthesized compounds
was carried out by broth microdilution method. Mueller–
Hinton broth was used as nutrient medium to grow and
dilute the compound suspension for the test bacteria and
Sabouraud Dextrose broth used for fungal nutrition. Inoc-
ulum size for test strain was adjusted to 108 CFU [Colony
Forming Unit] per milliliter by comparing the turbidity.
The strains used for the activity were procured from
[MTCC—microbial type culture collection] Institute of
Microbial Technology, Chandigarh. Each synthesized
compound was diluted obtaining 2,000 lg/mL concentra-
tion, as a stock solution. The results are recorded in the
form of primary and secondary screening. The compounds
4a–4p were screened for their antibacterial activity against
Streptococcus pneumoniae (MTCC 1936), Clostridium te-
tani (MTCC 449), Bacillus subtilis (MTCC 441), Salmo-
nella typhi (MTCC 98), Vibrio cholerae (MTCC 3906),
and Escherichia coli (MTCC 443) as well as for antifungal
activity against Aspergillus fumigatus (MTCC 3008) and
Candida albicans (MTCC 227) at concentrations of 1000,
500, and 250 lg/mL as primary screening. DMSO was
used as vehicle to get desired concentrations of compounds
to test upon microbial strains. The compounds found to be
active in the primary screening were further screened in a
second set of dilution at concentrations of 200, 100, 62.5,
and 50 lg/mL. Ten microliter suspensions from each well
were further inoculated and growth was noted after 24 and
48 h. The lowest concentration, which showed no visible
growth (turbidity) after spot subculture was considered as
MIC for each compound. In this study, ampicillin and
norfloxacin were used as standard antibacterial drugs,
whereas griseofulvin was used as standard antifungal
drugs. The protocols are summarized in Table 1.
Moreover, against fungal pathogen C. albicans, com-
pounds 4d (R1 = CH3, R2 = CH3), 4p (R1 = NO2,
R2 = CH3) (MIC 200 lg/mL) and compound 4n (R1 =
SO2CH3, R2 = CH3) (MIC 250 lg/mL) displayed excel-
lent activity upon comparison with griseofulvin (MIC
500 lg/mL).
Compounds 4d (R1 = CH3, R2 = CH3), 4h (R1 = Cl,
R2 = CH3) and 4o (R1 = NO2, R2 = H) were found to be
equipotent to ampicillin (MIC 250 lg/mL) as well as
compounds 4e (R1 = OCH3, R2 = H) and 4m (R1 =
SO2CH3, R2 = H) were equally active to ciprofloxacin
(MIC 100 lg/mL) in case of inhibiting C. tetani. Against
B. subtilis, compounds 4d (R1 = CH3, R2 = CH3), 4e
(R1 = OCH3, R2 = H), 4h (R1 = Cl, R2 = CH3), 4n
(R1 = SO2CH3, R2 = CH3), and 4o (R1 = NO2, R2 = H)
displayed parallel results than that of ampicillin (MIC
250 lg/mL), while compound 4l (R1 = F, R2 = CH3)
showed comparable activity to norfloxacin (MIC 100
lg/mL) as well as compound 4i (R1 = Br, R2 = H) was
found to possess similar activity to ampicillin (MIC
100 lg/mL) toward S. pneumonia.
Further, compounds 4g (R1 = Cl, R2 = H) and 4h
(R1 = Cl, R2 = CH3) against V. cholerae as well as com-
pound 4m (R1 = SO2CH3, R2 = H) against S. typhi have
been found equipotent to ampicillin (MIC 100 lg/mL),
while compounds 4e (R1 = OCH3, R2 = H), 4g (R1 = Cl,
R2 = H), 4m (R1 = SO2CH3, R2 = H) and 4n (R1 =
SO2CH3, R2 = CH3) were found equipotent as compared to
ampicillin (MIC 100 lg/mL) against E. coli. Whereas,
compounds 4d (R1 = CH3, R2 = CH3), 4e (R1 = OCH3,
R2 = H), 4f (R1 = OCH3, R2 = CH3) and 4i (R1 = Br,
R2 = H) were found to have equal activity with griseofulvin
(MIC 500 lg/mL) against C. albicans. Unfortunately, none
of the synthesized compounds were found sufficiently potent
to inhibit fungal pathogen A. fumigatus.
The examination of the data (Table 1) revealed that
majority of the compounds showed good antibacterial and
antifungal activity when compared with standard drugs.
Compounds 4e (R1 = OCH3, R2 = H), 4h (R1 = Cl,
R2 = CH3), 4i (R1 = Br, R2 = H), and 4n (R1 = SO2CH3,
R2 = CH3) were found to be exceedingly potent against
most of the employed strains.
The investigation of the structure–activity relationship
of antibacterial screening revealed that the compounds with
4-bromo phenyl ring at the 2-position of the indole nucleus
In particular, against Gram-negative bacteria E. coli,
compound 4h (R1 = Cl, R2 = CH3) has shown outstanding
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Med Chem Res (2012) 21:3406–3416
Table 1 Antimicrobial activity of the compounds 4a–p
Compound
Minimum inhibitory concentration (MIC, lgL-1
)
Gram-positive bacteria
Gram-negative bacteria
Fungi
S.P.
MTCC
1,936
C.T.
MTCC
449
B.S.
MTCC
441
S.T.
MTCC
98
V.C.
MTCC
3,906
E.C.
MTCC
443
A.F.
MTCC
3,008
C.A.
MTCC
227
4a (R1 = H, R2 = H)
4b (R1 = H, R2 = CH3)
4c (R1 = CH3, R2 = H)
4d (R1 = CH3, R2 = CH3)
4e (R1 = OCH3, R2 = H)
4f (R1 = OCH3, R2 = CH3)
4g (R1 = Cl, R2 = H)
4h (R1 = Cl, R2 = CH3)
4i (R1 = Br, R2 = H)
4j (R1 = Br, R2 = CH3)
4k (R1 = F, R2 = H)
4l (R1 = F, R2 = CH3)
4m (R1 = SO2CH3, R2 = H)
4n (R1 = SO2CH3, R2 = CH3)
4o (R1 = NO2, R2 = H)
4p (R1 = NO2, R2 = CH3)
Ampicillin
500
200
500
200
200
500
200
250
100
125
200
200
500
500
250
250
100
10
500
200
500
250
100
500
500
250
200
500
500
200
100
125
250
200
250
50
500
200
500
250
250
500
200
250
200
200
200
100
500
250
250
500
250
100
50
500
500
250
250
200
500
125
200
200
250
500
250
100
200
500
500
100
10
250
200
250
500
200
500
100
100
200
500
250
500
500
500
500
250
100
10
500
500
200
500
100
500
100
62.5
125
200
500
200
100
100
500
250
100
10
500
500
1,000
1,000
1,000
500
1,000
1,000
1,000
[1,000
1,000
[1,000
500
500
500
[1,000
[1,000
500
200
1,000
500
1,000
250
1,000
1,000
250
1,000
500
500
200
250
200
–
–
Norfloxacin
–
–
Ciprofloxacin
50
100
–
25
25
25
–
–
Griseofulvin
–
–
–
–
–
100
500
Nystatin
–
–
–
–
–
–
100
100
Bold values indicate the active compounds
S.P., Streptococcus pneumoniae; C.T., Clostridium tetani; B.S., Bacillus subtilis; S.T., Salmonella typhi; V.C., Vibrio cholerae; E.C., Escherichia
coli; A.F., Aspergillus fumigatus; C.A., Candida albicans
‘–’ represents ‘not tested’
gave equivalent results against S. pneumoniae. Whereas,
toward C. tetani, compounds with 4-methoxy, bromo, flu-
oro, methylsulfonyl, nitro phenyl, and unsubstituted phenyl
ring substitutions were found to be highly active as well as
compounds with 4-methyl, chloro and nitro phenyl ring
showed equal activity as that of ampicillin. Against
B. subtilis, compounds carrying 4-chloro, bromo, fluoro
phenyl, and unsubstituted phenyl ring were found to be
more potent as well as compounds with 4-methyl, meth-
oxy, chloro, methylsulfonyl, and nitro phenyl ring gave
equal results than ampicillin. Compound having 4-meth-
ylsulfonyl phenyl ring displayed equivalent activity against
S. typhi. Moreover, against V. cholerae, compound con-
taining 4-chloro phenyl ring revealed similar inhibitory
action. Whereas, toward E. coli, compound with 4-chlo-
rophenyl ring was found to be significantly active as well
as compounds with 4-methoxy and methylsulfonyl phenyl
ring were shown analogous results than that of ampicillin.
Antifungal evaluation showed that 4-methylsulfonyl and
nitro phenyl ring containing compounds are the most
potent, while compounds with 4-methyl, methoxy, bromo,
and fluoro phenyl ring displayed similar activity to gris-
eofulvin against fungal species C. albicans.
Interestingly, compounds carrying 4-methoxy, chloro,
bromo, and methylsulfonyl phenyl ring bearing 1H-indole
and 4H-chromene nuclei are found to be the most effective
antimicrobial members of this series. Compounds with
4-methoxy, bromo, and methylsulfonyl phenyl ring hav-
ing (R2 = H) were found to be active against C. tetani,
B. subtilis and C. albicans. Compounds with 4-methyl,
chloro, fluoro, methylsulfonyl, and unsubstituted phenyl
ring having (R2 = CH3) substitution displayed good activity
against C. tetani and B. subtilis as well as compounds with
4-methyl, methoxy, methylsulfonyl, and nitro phenyl ring
carrying (R2 = CH3) substitution displayed promising
activity against fungal pathogen C. albicans. Specifically,
compound 4g (R1 = Cl, R2 = H) was found to have activity
MIC 100 lg/mL but upon replacing R2 = H by R2 = CH3,
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Med Chem Res (2012) 21:3406–3416
3411
resulted compound 4h (R1 = Cl, R2 = CH3) have been
found to possess increased potency MIC 62.5 lg/mL toward
E. coli. Compound having (R1 = SO2CH3, R2 = H) is
inactive (MIC 1,000 lg/mL) but upon replacing R2 = H by
R2 = CH3, resulted compound 4n (R1 = SO2CH3, R2 =
CH3) exhibited significant activity (MIC 250 lg/mL)
against fungal pathogen C. albicans. Compound 4i (R1 =
Br, R2 = H) have been found to possess better activity but
upon replacing R2 = H by R2 = CH3, decrease the potency
of resulted compound 4j (R1 = Br, R2 = CH3) against
S. pneumonia, C. tetani and C. albicans. Compound 4c
(R1 = CH3, R2 = H) has been found totally inactive against
a representative panel of bacteria and fungi but upon
replacing R2 = H by R2 = CH3, resulted compound 4d
(R1 = CH3, R2 = CH3) showed better activity against
C. tetani, B. subtilis and C. albicans.
Elmer, USA) and all compounds are within 0.4% of theory
specified. The IR spectra were recorded in KBr on a Perkin-
Elmer Spectrum GX FT-IR Spectrophotometer (Perkin-
Elmer, USA) and only the characteristic peaks are reported
1
in cm-1. H NMR and 13C NMR spectra were recorded in
DMSO-d6 on a Bruker Avance 400F (MHz) spectrometer
(Bruker Scientific Corporation Ltd., Switzerland) using
solvent peak as internal standard at 400 and 100 MHz,
respectively. Chemical shifts are reported in parts per mil-
lion (ppm). Mass spectra were scanned on a Shimadzu
LCMS 2010 spectrometer (Shimadzu, Tokyo, Japan).
General procedure for the synthesis of 2-amino-7,7-
(un)-substituted-5-oxo-4-(2-(4-(un)-substitutedphenyl)-
1H-indol-3-yl)-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile 4a–p
Reviewing and comparing the activity data, it is worthy
to mention that the antimicrobial activity of the target
compounds depends not only on the bicyclic heteroaro-
matic pharmacophore appended through aryl ring but also
on the nature of the peripheral substituents and may also
upon their spatial relationship and positional changes.
A mixture of an appropriate 2-phenyl-1H-indole-3-carbal-
dehyde 1a–1h (5 mmol), malononitrile 2 (5 mmol), 1,3-
cyclohexanedione/dimedone 3a/3b (5 mmol), and DMAP
(10 mol %) were thoroughly mixed in ethanol (10 mL).
The mixture was irradiated for 6–7 min at 350 W of output
power. After the completion of reaction (checked by TLC),
the reaction mixture was cooled to room temperature and
the solid separated was filtered and washed with equimolar
mixture of chloroform and methanol to obtain the pure
compounds 4a–4p. The physicochemical and spectroscopic
characterization data of the synthesized compounds 4a–4p
are given below.
Experimental
Chemistry
General procedures
Required acetophenone, phenyl hydrazine, polyphosphoric
acid, and phosphorous oxychloride were obtained com-
mercially. Moreover, 1,3-cyclohexanedione and dimedone
were obtained from Sigma-Aldrich and were used without
further purification. Solvents were purified and dried before
being used. The microwave assisted reactions are conducted
in a ‘‘RAGA’s Modified Electromagnetic Microwave Sys-
tem’’ whereby microwaves are generated by magnetron at a
frequency of 2,450 MHz having an adjustable output power
levels, i.e., 10 levels from 140 to 700 Watts and with an
individual sensor for temperature control (fiber optic is used
as a individual sensor for temperature control) with attach-
ment of reflux condenser with constant stirring (thus,
avoiding the risk of high pressure development). All melting
points were taken in open capillaries and are uncorrected.
Thin-layer chromatography (TLC, on aluminum plates
precoated with silica gel, 60F254, 0.25 mm thickness)
(Merck, Darmstadt, Germany) was used for monitoring the
progress of all reactions, purity and homogeneity of the
synthesized compounds; eluent-hexane:ethyl acetate: (5:5).
UV radiation and/or iodine were used as the visualizing
agents. Elemental analysis (% C, H, N) was carried out by
Perkin-Elmer 2400 series-II elemental analyzer (Perkin-
2-Amino-5-oxo-4-(2-phenyl-1H-indol-3-yl)-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4a)
Off white solid, yield: 75%. m.p. 205 °C. Anal.Calcd. for
C24H19N3O2 (381.15): C 75.57, H 5.02, N 11.02%. Found: C
75.32, H 4.93, N 11.18%. IR (KBr, m, cm-1): 3,430 and
3,300 (asym. and sym. str. of –NH2), 2,210 (–C:N str.),
1,680 (C=O str. of cyclic ketone), 1,235 (asym. str. of cyclic
ArC–O–C ether). 1H NMR (400 MHz, DMSO-d6) dH
(ppm): 1.74–2.52 (6H, m, 3 9 CH2), 4.62 (s, 1H, chromene
H4), 6.86 (s, 2H, NH2), 6.92–7.69 (m, 9H, Ar–H), 11.18 (s,
1H, indole NH). 13C NMR (100 MHz, DMSO-d6) dC (ppm):
20.51 (CH2), 26.82 (CH2), 27.18 (chromene C 4), 37.13
(CH2–CO), 58.57 (C–CN), 111.85 (chromene C 4a), 113.41,
113.59, 118.55, 119.31, 120.63, 121.29, 127.13, 129.43,
129.51, 130.72, 136.19, 136.42, 137.44 (Ar–C), 158.54
(chromene C 8a), 164.23 (chromene C 2), 196.72 (C=O).
2-Amino-7,7-dimethyl-5-oxo-4-(2-phenyl-1H-indol-3-yl)-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4b)
Off white solid, yield 81%, m.p. 208–210 °C, Anal. Calcd.
for C26H23N3O2 (409.18): C 76.26, H 5.66, N 10.26%
123

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Found: C 75.98, H 5.71, N 10.08%. IR (KBr, m, cm-1):
3,420 and 3,295 (asym. and sym. str. of –NH2), 2,210
(–C:N str.), 1,685 (C=O str. of cyclic ketone), 1,255
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 0.84 (s, 3H, CH3), 1.01 (s, 3H, CH3),
1.95–2.59 (4H, m, 2 9 CH2), 4.69 (s, 1H, chromene H4),
6.85 (s, 2H, NH2), 6.93–7.89 (m, 9H, Ar–H), 11.16 (s, 1H,
indole NH). 13C NMR (100 MHz, DMSO-d6) dC (ppm):
27.02 (CH3), 29.14 (CH3), 30.05 (chromene C 4), 32.24
(C(CH3)2), 40.46 (CH2), 50.61 (CH2–CO), 57.38 (C–CN),
112.01 (chromene C 4a), 113.11, 114.35, 118.63, 119.28,
119.75, 120.32, 121.65, 126.23, 128.59, 131.05, 132.77,
134.67, 136.69 (Ar–C), 158.32 (chromene C 8a), 162.38
(chromene C 2), 196.58 (C=O). MS: (M ? 1) 410.0.
120.63, 122.03, 126.35, 130.35, 130.91, 133.25, 136.37
(Ar–C), 158.59 (chromene C 8a), 162.56 (chromene C 2),
196.21 (C=O).
2-Amino-4-(2-(4-methoxyphenyl)-1H-indol-3-yl)-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4e)
Off white solid, yield 69%, m.p. 206–208 °C, Anal. Calcd.
for C25H21N3O3 (411.16): C 72.98, H 5.14, N 10.21%
Found: C 72.89, H 4.93, N 10.07%. IR (KBr, m, cm-1):
3,400 and 3,285 (asym. and sym. str. of –NH2), 2,195
(–C:N str.), 1,700 (C=O str. of cyclic ketone), 1,235
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 1.69–2.42 (6H, m, 3 9 CH2), 3.82
(s, 3H, OCH3), 4.95 (s, 1H, chromene H4), 6.84 (s, 2H,
NH2), 7.03–7.60 (m, 8H, Ar–H), 11.11 (s, 1H, indole NH).
13C NMR (100 MHz, DMSO-d6) dC (ppm): 21.01 (CH2),
27.81 (CH2), 28.25 (chromene C 4), 36.57 (CH2–CO),
55.69 (OCH3), 57.31 (C–CN), 111.76 (chromene C 4a),
113.06, 114.22, 117.82, 119.69, 120.85, 122.01, 127.33,
129.49, 129.68, 130.95, 136.33, 136.51, 137.09 (Ar–C),
159.51 (chromene C 8a), 161.32 (chromene C 2), 196.24
(C=O).
2-Amino-5-oxo-4-(2-(4-methylphenyl)-1H-indol-3-yl)-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4c)
Light yellow solid, yield 78%, m.p. 211 °C, Anal. Calcd.
for C25H21N3O2 (395.16): C 75.93, H 5.35, N 10.63%
Found: C 75.98, H 5.01, N 10.39%. IR (KBr, m, cm-1):
3,455 and 3,290 (asym. and sym. str. of –NH2), 2,200
(–C:N str.), 1,680 (C=O str. of cyclic ketone), 1,230
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 1.70–2.59 (6H, m, 3 9 CH2), 2.40
(s, 3H, CH3), 4.71 (s, 1H, chromene H4), 6.82 (s, 2H,
NH2), 6.95–7.75 (m, 8H, Ar–H), 11.21 (s, 1H, indole NH).
13C NMR (100 MHz, DMSO-d6) dC (ppm): 20.40 (CH2),
21.36 (CH3), 26.92 (CH2), 27.01 (chromene C 4), 37.03
(CH2–CO), 58.69 (C–CN), 111.90 (chromene C 4a),
113.53, 113.57, 118.37, 119.26, 121.28, 127.05, 129.36,
129.44, 130.81, 136.04, 136.48, 137.36 (Ar–C), 158.43
(chromene C 8a), 164.10 (chromene C 2), 196.61 (C=O).
MS: (M ? 1) 396.0.
2-Amino-4-(2-(4-methoxyphenyl)-1H-indol-3-yl)-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4f)
Light yellow solid, yield 71%, m.p. 209–210 °C, Anal.
Calcd. for C27H25N3O3 (439.19): C 73.78, H 5.73, N 9.56%
Found: C 73.82, H 5.78, N 9.33%. IR (KBr, m, cm-1):
3,425 and 3,325 (asym. and sym. str. of –NH2), 2,205
(–C:N str.), 1,695 (C=O str. of cyclic ketone), 1,250
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 0.88 (s, 3H, CH3), 1.04 (s, 3H, CH3),
1.78–2.45 (4H, m, 2 9 CH2), 3.84 (s, 3H, OCH3), 4.99 (s,
1H, chromene H4), 6.93 (s, 2H, NH2), 6.96–7.91 (m, 8H,
Ar–H), 11.44 (s, 1H, indole NH). 13C NMR (100 MHz,
DMSO-d6) dC (ppm): 27.51 (CH3), 28.18 (CH3), 28.85
(chromene C 4), 31.56 (C(CH3)2), 40.25 (CH2), 50.77
(CH2–CO), 55.81 (OCH3), 58.17 (C–CN), 112.13 (chro-
mene C 4a), 113.07, 114.28, 118.89, 119.05, 120.39,
121.55, 121.98, 125.36, 133.24, 133.86, 134.28, 135.01,
137.52 (Ar–C), 157.79 (chromene C 8a), 162.33 (chromene
C 2), 196.56 (C=O).
2-Amino-7,7-dimethyl-5-oxo-4-(2-(4-methylphenyl)-1H-
indol-3-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(4d)
Light yellow solid, yield 82%, m.p. 213–215 °C, Anal.
Calcd. for C27H25N3O2 (423.19): C 76.57, H 5.95, N 9.92%
Found: C 76.43, H 5.81, N 10.03%. IR (KBr, m, cm-1):
3,435 and 3,350 (asym. and sym. str. of –NH2), 2,190
(–C:N str.), 1,690 (C=O str. of cyclic ketone), 1,240
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 0.99 (s, 3H, CH3), 1.02 (s, 3H, CH3),
1.84–2.46 (4H, m, 2 9 CH2), 2.38 (s, 3H, CH3), 4.79 (s,
1H, chromene H4), 6.88 (s, 2H, NH2), 6.91–7.88 (m, 8H,
Ar–H), 11.28 (s, 1H, indole NH). 13C NMR (100 MHz,
DMSO-d6) dC (ppm): 21.59 (CH3), 27.36 (CH3), 28.11
(CH3), 29.18 (chromene C 4), 31.89 (C(CH3)2), 40.05
(CH2), 51.09 (CH2–CO), 58.25 (C–CN), 111.98 (chromene
C 4a), 112.53, 113.32, 117.69, 118.06, 118.96, 119.89,
2-Amino-4-(2-(4-chlorophenyl)-1H-indol-3-yl)-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4g)
White solid, yield 81%, m.p. 218–220 °C, Anal. Calcd. for
C24H18ClN3O2 (415.11): C 69.31, H 4.36, N 10.10%
Found: C 69.49, H 4.05, N 9.98%. IR (KBr, m, cm-1):
3,410 and 3,320 (asym. and sym. str. of –NH2), 2,200
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Med Chem Res (2012) 21:3406–3416
3413
2-Amino-4-(2-(4-bromophenyl)-1H-indol-3-yl)-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4j)
(–C:N str.), 1,690 (C=O str. of cyclic ketone), 1,245
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 1.76–2.38 (6H, m, 3 9 CH2), 4.99
(s, 1H, chromene H4), 6.86 (s, 2H, NH2), 6.89–7.93 (m,
8H, Ar–H), 11.43 (s, 1H, indole NH). 13C NMR (100 MHz,
DMSO-d6) dC (ppm): 20.66 (CH2), 26.97 (CH2), 27.19
(chromene C 4), 37.21 (CH2–CO), 59.08 (C–CN), 111.99
(chromene C 4a), 112.18, 113.59, 118.66, 118.98, 120.88,
122.31, 126.97, 129.68, 130.11, 131.25, 132.58, 134.75,
135.94 (Ar–C), 158.93 (chromene C 8a), 163.05 (chromene
C 2), 196.43 (C=O).
Light yellow solid, yield 80%, m.p. 225 °C, Anal. Calcd.
for C26H22BrN3O2 (487.09): C 63.94, H 4.54, N 8.60%
Found: C 64.22, H 4.37, N 8.41%. IR (KBr, m, cm-1):
3,400 and 3,295 (asym. and sym. str. of –NH2), 2,185
(–C:N str.), 1,690 (C=O str. of cyclic ketone), 1,245
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 0.97 (s, 3H, CH3), 1.06 (s, 3H, CH3),
2.01–2.59 (4H, m, 2 9 CH2), 4.58 (s, 1H, chromene H4),
6.85 (s, 2H, NH2), 7.01–7.93 (m, 8H, Ar–H), 11.33 (s, 1H,
indole NH). 13C NMR (100 MHz, DMSO-d6) dC (ppm):
27.81 (CH3), 28.01 (CH3), 28.97 (chromene C 4), 31.93
(C(CH3)2), 40.16 (CH2), 50.83 (CH2–CO), 57.59 (C–CN),
112.15 (chromene C 4a), 112.63, 114.38, 118.82, 119.69,
120.58, 121.93, 127.08, 129.05, 129.88, 131.98, 132.89,
134.33, 136.83 (Ar–C), 158.36 (chromene C 8a), 162.19
(chromene C 2), 196.89 (C=O).
2-Amino-4-(2-(4-chlorophenyl)-1H-indol-3-yl)-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4h)
Off white solid, yield 86%, m.p. 222 °C, Anal. Calcd. for
C26H22ClN3O2 (443.92): C 70.34, H 5.00, N 9.47% Found:
C 70.11, H 4.82, N 9.58%. IR (KBr, m, cm-1): 3,430 and
3,360 (asym. and sym. str. of –NH2), 2,195 (–C:N str.),
1,685 (C=O str. of cyclic ketone), 1,210 (asym. str. of
2-Amino-4-(2-(4-fluorophenyl)-1H-indol-3-yl)-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4k)
1
cyclic ArC–O–C ether). H NMR (400 MHz, DMSO-d6)
dH (ppm): 0.84 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.97–2.60
(4H, m, 2 9 CH2), 4.65 (s, 1H, chromene H4), 6.88 (s, 2H,
NH2), 6.94–7.91 (m, 8H, Ar–H), 11.24 (s, 1H, indole NH).
13C NMR (100 MHz, DMSO-d6) dC (ppm): 27.00 (CH3),
27.10 (CH3), 29.03 (chromene C 4), 32.00 (C(CH3)2),
40.28 (CH2), 50.64 (CH2–CO), 58.38 (C–CN), 112.08
(chromene C 4a), 112.42, 114.26, 118.72, 119.32, 120.37,
121.78, 126.67, 128.91, 131.23, 132.45, 132.90, 134.56,
136.71 (Ar–C), 158.32 (chromene C 8a), 162.38 (chromene
C 2), 196.76 (C=O). MS: (M ? 1) 444.6.
Pale yellow solid, yield 71%, m.p. 217 °C, Anal. Calcd. for
C24H18FN3O2 (399.14): C 72.17, H 4.54, N 10.52% Found:
C 72.09, H 4.63, N 10.81%. IR (KBr, m, cm-1): 3,415 and
3,305 (asym. and sym. str. of –NH2), 2,190 (–C:N str.),
1,695 (C=O str. of cyclic ketone), 1,215 (asym. str. of
1
cyclic ArC–O–C ether). H NMR (400 MHz, DMSO-d6)
dH (ppm): 1.73–2.57 (6H, m, 3 9 CH2), 4.98 (s, 1H,
chromene H4), 6.91 (s, 2H, NH2), 7.09–8.07 (m, 8H, Ar–
H), 11.25 (s, 1H, indole NH). 13C NMR (100 MHz,
DMSO-d6) dC (ppm): 21.24 (CH2), 27.06 (CH2), 28.09
(chromene C 4), 36.88 (CH2–CO), 59.28 (C–CN), 111.96
(chromene C 4a), 112.55, 114.11, 119.87, 120.01, 120.98,
122.22, 128.08, 129.98, 130.56, 134.28, 134.99, 136.86,
138.25 (Ar–C), 158.31 (chromene C 8a), 164.32 (chromene
C 2), 197.32 (C=O).
2-Amino-4-(2-(4-bromophenyl)-1H-indol-3-yl)-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4i)
Off white solid, yield 76%, m.p. 221–223 °C, Anal. Calcd.
for C24H18BrN3O2 (459.06): C 62.62, H 3.94., N 9.13%
Found: C 62.84, H 3.78, N 9.25%. IR (KBr, m, cm-1):
3,420 and 3,345 (asym. and sym. str. of –NH2), 2,190
(–C:N str.), 1,700 (C=O str. of cyclic ketone), 1,240
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 1.81–2.55 (6H, m, 3 9 CH2), 5.00
(s, 1H, chromene H4), 6.83 (s, 2H, NH2), 7.01–7.98 (m,
8H, Ar–H), 11.36 (s, 1H, indole NH). 13C NMR (100 MHz,
DMSO-d6) dC (ppm): 21.13 (CH2), 27.38 (CH2), 27.46
(chromene C 4), 38.09 (CH2–CO), 57.55 (C–CN), 112.03
(chromene C 4a), 113.12, 114.05, 119.28, 119.73, 120.56,
121.63, 127.25, 130.01, 130.88, 132.19, 133.25, 135.32,
137.49 (Ar–C), 158.89 (chromene C 8a), 162.91 (chromene
C 2), 195.93 (C=O).
2-Amino-4-(2-(4-fluorophenyl)-1H-indol-3-yl)-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4l)
Yellowish solid, yield 74%, m.p. 219–221 °C, Anal. Calcd.
for C26H22FN3O2 (427.17): C 73.05, H 5.19, N 9.83%
Found: C 72.82, H 5.31, N 9.92%. IR (KBr, m, cm-1):
3,405 and 3,335 (asym. and sym. str. of –NH2), 2,180
(–C:N str.), 1,685 (C=O str. of cyclic ketone), 1,210
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 1.02 (s, 3H, CH3), 1.10 (s, 3H, CH3),
1.89–2.48 (4H, m, 2 9 CH2), 4.86 (s, 1H, chromene H4),
6.98 (s, 2H, NH2), 7.04–8.06 (m, 8H, Ar–H), 11.19 (s, 1H,
123

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Med Chem Res (2012) 21:3406–3416
indole NH). 13C NMR (100 MHz, DMSO-d6) dC (ppm):
27.53 (CH3), 27.97 (CH3), 28.25 (chromene C 4), 32.14,
(C(CH3)2), 41.05 (CH2), 50.65 (CH2–CO), 58.33 (C–CN),
111.93 (chromene C 4a), 112.51, 113.26, 117.88, 119.35,
120.39, 121.28, 121.93, 129.35, 129.98, 130.33, 133.45,
134.05, 136.56 (Ar–C), 158.46 (chromene C 8a), 162.35
(chromene C 2), 196.71 (C=O).
67.48, H 4.33, N 12.98%. IR (KBr, m, cm-1): 3,395 and
3,320 (asym. and sym. str. of –NH2), 2,215 (–C:N str.),
1,700 (C=O str. of cyclic ketone), 1,215 (asym. str. of cyclic
ArC–O–C ether). 1H NMR (400 MHz, DMSO-d6) dH
(ppm): 1.68–2.60 (6H, m, 3 9 CH2), 4.83 (s, 1H, chromene
H4), 6.88 (s, 2H, NH2), 6.99–8.05 (m, 8H, Ar–H), 11.09 (s,
1H, indole NH). 13C NMR (100 MHz, DMSO-d6) dC (ppm):
21.63 (CH2), 26.83 (CH2), 27.15 (chromene C 4), 38.22
(CH2–CO), 58.35 (C–CN), 111.87 (chromene C 4a), 113.01,
113.82, 115.63, 120.05, 120.59, 124.32, 124.89, 126.52,
126.93, 129.15, 129.86, 133.84, 136.44 (Ar–C), 158.81
(chromene C 8a), 163.67 (chromene C 2), 198.21 (C=O).
2-Amino-4-(2-(4-(methylsulfonyl)phenyl)-1H-indol-3-yl)-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4m)
Pale yellow solid, yield 72%, mp 210–212 °C, Anal. Calcd.
for C25H21N3O4S (459.13): C 65.34, H 4.61, N 9.14%
Found: C 65.56, H 4.81, N 9.01%. IR (KBr, m, cm-1): 3,455
and 3,310 (asym. and sym. str. of –NH2), 2,195 (–C:N str.),
1,695 (C=O str. of cyclic ketone), 1,225 (asym. str. of cyclic
ArC–O–C ether). 1H NMR (400 MHz, DMSO-d6) dH
(ppm): 1.70–2.51 (6H, m, 3 9 CH2), 3.35 (s, 3H, SO2CH3),
5.07 (s, 1H, chromene H4), 6.86 (s, 2H, NH2), 7.12–8.09 (m,
8H, Ar–H), 11.39 (s, 1H, indole NH). 13C NMR (100 MHz,
DMSO-d6) dC (ppm): 20.53 (CH2), 27.18 (CH2), 27.33
(chromene C 4), 37.79 (CH2–CO), 39.99 (CH3–SO2), 59.22
(C–CN), 112.13 (chromene C 4a), 112.91, 113.32, 116.57,
120.32, 121.11, 123.25, 127.63, 127.94, 129.88, 131.56,
131.96, 135.38, 137.88 (Ar–C), 159.39 (chromene C 8a),
165.02 (chromene C 2), 196.65 (C=O).
2-Amino-7,7-dimethyl-4-(2-(4-nitrophenyl)-1H-indol-3-yl)-
5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4p)
Yellow solid, yield 74%, m.p. 213–215 °C, Anal. Calcd.
for C26H22N4O4 (454.16): C 68.71, H 4.88, N 12.33%
Found: C 68.83, H 4.64, N 12.25%. IR (KBr, m, cm-1):
3,405 and 3,310 (asym. and sym. str. of –NH2), 2,195
(–C:N str.), 1,685 (C=O str. of cyclic ketone), 1,215
(asym. str. of cyclic ArC–O–C ether). 1H NMR (400 MHz,
DMSO-d6) dH (ppm): 0.86 (s, 3H, CH3), 1.04 (s, 3H, CH3),
1.72–2.55 (4H, m, 2 9 CH2), 4.99 (s, 1H, chromene H4),
6.88 (s, 2H, NH2), 6.87–7.98 (m, 8H, Ar–H), 11.18 (s, 1H,
indole NH). 13C NMR (100 MHz, DMSO-d6) dC (ppm):
27.22 (CH3), 27.99 (CH3), 30.13 (chromene C 4), 32.35
(C(CH3)2), 40.11 (CH2), 50.39 (CH2–CO), 57.45 (C–CN),
112.13 (chromene C 4a), 112.88, 114.15, 117.67, 118.05,
120.71, 121.42, 121.89, 126.9, 131.83, 132.19, 133.87,
136.14, 137.67 (Ar–C), 158.21 (chromene C 8a), 162.59
(chromene C 2), 196.43 (C=O).
2-Amino-7,7-dimethyl-4-(2-(4-(methylsulfonyl)phenyl)-1H-
indol-3-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4n)
Light brown solid, yield 77%, m.p. 214 °C, Anal. Calcd. For
C27H25N3O4S (487.16): C 66.51, H 5.17, N 8.62% found: C
66.32, H 5.02, N 8.48%. IR (KBr, m, cm-1): 3,400 and 3,290
(asym. and sym. str. of –NH2), 2,205 (–C:N str.), 1,690
(C=O str. of cyclic ketone), 1,230 (asym. str. of cyclic ArC–
O–C ether). 1H NMR (400 MHz, DMSO-d6) dH (ppm): 0.94
(s, 3H, CH3), 1.03 (s, 3H, CH3), 1.77–2.52 (4H, m,
2 9 CH2), 3.41 (s, 3H, SO2CH3), 4.59 (s, 1H, chromene
H4), 6.89 (s, 2H, NH2), 7.9–8.10 (m, 8H, Ar–H), 11.43 (s,
1H, indole NH). 13C NMR (100 MHz, DMSO-d6) dC (ppm):
27.35 (CH3), 28.15 (CH3), 28.79 (chromene C 4), 31.25
(C(CH3)2), 39.78 (CH3–SO2), 40.13 (CH2), 51.13 (CH2–
CO), 58.09 (C–CN), 112.07 (chromene C 4a), 113.15,
114.35, 118.46, 118.98, 120.48, 121.31, 121.91, 125.20,
132.28, 132.77, 134.55, 136.45, 137.78 (Ar–C), 158.19
(chromene C 8a), 162.45 (chromene C 2), 196.47 (C=O).
Conclusion
In this article, we report the synthesis and antimicrobial
activity of two structurally correlated heterocyclic candi-
dates, i.e., 2-phenyl-1-H-indoles and their 4H-chromene
derivatives. The engaged synthetic strategy allows the
construction of relatively complicated nitrogen and oxygen
carrying heterocyclic system as well as the introduction of
various (hetero) aromatic substitutions into 4-position of
4H-chromene system. It can be concluded from antimi-
crobial screening against a panel of human pathogens that
most of the synthesized 4H-chromene derivatives were
found to be highly active compared to the standard drugs,
against bacterial pathogens. It is worth mentioning that
minor changes in molecular configuration of these com-
pounds profoundly influence the activity. This study throws
light on the identification of this new structural class as
antimicrobials which can be of interest for further detailed
preclinical investigations.
2-Amino-4-(2-(4-nitrophenyl)-1H-indol-3-yl)-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4o)
Yellow solid, yield 69%, m.p. 209–211 °C, Anal. Calcd. for
C24H18N4O4 (426.13): C 67.60, H 4.25, N 13.14% Found: C
123

Med Chem Res (2012) 21:3406–3416
3415
Acknowledgments The authors are thankful to Department of
Chemistry, Sardar Patel University for providing research facilities.
We are also thankful to Vaibhav Analytical Laboratory, Ahmedabad
for the FTIR and Sophisticated Instrumentation Centre for Applied
Research and Training (SICART), Vallabh Vidyanagar for elemental
analysis. As well as Oxygen Healthcare Research Pvt. Ltd., Ahme-
dabad for providing mass spectrometry facilities and Dhanji P. Ra-
jani, Microcare Laboratory, Surat for antimicrobial screening of the
compounds reported herein. One of the authors is grateful to UGC,
New Delhi for a Research Fellowship in Sciences for Meritorious
Students.
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