Iron-catalyzed aryl-aryl cross coupling route for the synthesis of 1-(2-amino)-phenyl)dibenzo[b,d]furan-2-ol derivatives and their biological evaluation

Article abstract of DOI:10.1039/c3ra43345e

Naturally occurring dibenzofuran motifs represent promising lead structures for the development of novel antimycobacterial agents. Prompted by our recent development of cross dehydrogenative coupling using iron catalysis, we extended our strategy to synthesize 14 novel anilinodibenzofuranols and they were explored for anti-tubercular and cytotoxic activities. Consistent with our hypothesis, DBF-3, 14 and 16 exhibited promising activity against two strains (M. tuberculosis H37Rv and the clinical S, H, R, and E resistant isolate), while DBF-13, 18 exhibited selective inhibitory activity only against the clinical S, H, R and E resistant isolate. However, the compounds DBF-4 and DBF-8 showed promising and selective antitumor activity against the tested cancer cell lines. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra43345e

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Page 1 of 32
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Iron-Catalyzed Aryl-Aryl Cross Coupling Route for the
Synthesis of 1-(2-Amino)-phenyl)dibenzo[b,d]furan-2-ol
Derivatives and their Biological Evaluation
a, 1
a
b
b
Barreddi Chiranjeevi , Ganesh Koyyada , S. Prabusreenivasan , Vanaja Kumar , Pombala
c
c
d
e
a,
Sujitha ,C. Ganesh Kumar , B. Sridhar , Saida Shaik , Malapaka Chandrasekharam *
a
c
Inorganic and Physical Chemistry Division Medicinal Chemistry and Phormacology Division
d
e
Center for Xꢀray Crystallography Analytical Division CSIRꢀIndian Institute of Chemical
Technology, Uppal Road, Tarnaka, Hyderabadꢀ500 007, India
b
Tuberculosis Research Centre, V.R. Ramanathan Road, Chennai 600 031, India
Abstract
Naturally occurring dibenzofuran motifs represent promising lead structures for the development
of novel antimycobacterial agents. Prompted by our recent development in cross
dehydrogenative coupling using iron catalysis, we extended our strategy to synthesize 14 novel
anilinodibenzofuranols and were explored for antiꢀtubercular and cytotoxic activities. Consistent
with our hypothesis, DBFꢀ3, 14 and 16 exhibited promising activity against both the strains (M.
tuberculosis H37Rv and the clinical S, H, R, and E resistant isolate), while DBFꢀ13, 18 exhibited
selective inhibitory activity only against the clinical S, H, R and E resistant isolate. However, the
compounds DBFꢀ4 and DBFꢀ8 showed promising and selective antitumor activity against the
tested cancer cell lines
.
Introduction
Tuberculosis (TB), a contagious infectious disease caused by Mycobacterium tuberculosis, has
affected mankind for over 5000 years, and still continues to be a leading cause of morbidity and
1
mortality. This dreaded disease, accounting millions of deaths globally for the past few decades,
2
has been acknowledged as a global health problem, by WHO. Now it ranks second, after human
1

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3
immunodeficiency virus (HIV), for the highest number of deaths registered in the recent times.
One third of the global population are known to have latent TB, but are asymptomatic. It is very
likely that 10% of those latently infected population eventually develop active disease during
their lifeꢀtime. Although most of the M. tuberculosisꢀinfected individuals remain asymptomatic,
4
they serve as a reservoir for the pathogen, making control of this disease a significant challenge.
With the advent of HIV, which allows the latent TB to become active and with the emergence of
its new virulent strains like multidrugꢀresistant TB (MDRꢀTB) and extensively drugꢀresistant TB
(XDRꢀTB) that are virtually untreatable with the existing drugs, the epidemic has further surged
5
to alarming levels. Unfortunately most of the standard drugs used to cure this disease today were
developed 40 or more years ago. Of late, it was found that selfꢀrenewing stem cells in the bone
marrow have properties such as natural drug resistance, infrequent division and a privileged
6
immune status that make them resistant to these standard drugs. The challenge of meeting all
these facts necessitated an urgent need to the development of fast acting secondꢀline antiꢀ
tubercular agents with diverse and unique structural features, and also with the mechanism of
action possibly different from that of existing drugs.
In the recent years, structurally diverse new molecules inspired by natural products have
7
played a major role in drug discovery. The lichen dibenzofuranꢀderived secondary metabolite,
usnic acid, seemed to have displayed interesting antiꢀtubercular activity, but its weak potency
8
had hampered its deployment for the treatment of TB. Later developments in this area showed
that dibenzofuran analogues exhibited very good in vitro and in vivo antimycobacterial activity
(Figure 1). In particular, new hybrid heterocycles with a dibenzofuran ring, such as CGSꢀ35066
7b
and CGSꢀ34043, were developed as potent endothelinꢀconverting enzyme (ECEꢀ1) inhibitors.
8
,9
Better activities resulting from molecular engineering performed on these pharmacophores
2

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combined with the elegant progress made in these class of compounds for antiꢀmycobacterial
activities in the recent times instilled in us an immense interest to further synthesize various
structurally diverse dibenzofuran derivatives and to investigate their biological activities.
Arylꢀaryl bond formation reaction has been practiced for more than a century and is one
of the first reactions using a transition metal. Biaryls resulting from these reactions have drawn
immense attention for decades, discovering novel molecules that find applications in medicinal
1
0
and material chemistry. The pressing need to develop nonꢀresistant antiꢀmycobacterial drugs
combined with our expertise in the area of developing structurally varied biaryls by direct
oxidative cross coupling of anilines to polynuclear phenols using environmentally benign iron
1
1a
11bꢀd
catalyst
and our interest in synthesis of biologically interesting molecules
prompted us to
discover new antiꢀmycobacterial scaffolds. This not only extends the scope of our work, but also
helps us to solve the medicinal challenges. Thus we successfully coupled 2ꢀdibenzofuranol
(DBF) with N, Nꢀdialkyl anilines and developed novel dibenzofuranol analogues, named
anilinodibenzofuranols. These compounds contain diverse structural features and were further
tested for different biological activities like antiꢀtubercular and cytotoxicity. The aforementioned
synthetic pathway for the construction of biaryls involved iron (III) as a catalyst and tꢀbutyl
hydroperoxide (TBHP) (5ꢀ6 M in decane) as a coꢀoxidant (Scheme 1). We synthesized 14
anilinodibenzofuranols, which showed moderate to good antiꢀmycobacterial activity. Among
them, DBFꢀ14 exhibited promising activity against TB. In addition, the compounds DBFꢀ4 and
DBFꢀ8 showed promising and selective antitumor activity against the tested cancer cell lines
.
3

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RESULTS AND DISCUSSION
Chemistry: A toluene solution of 4ꢀmethyl N, Nꢀdi methyl aniline, 2ꢀdibenzofuranol, iron (III)
catalyst and TBHP (5ꢀ6 M in decane) oxidant were stirred for about 24 h under open air
atmosphere yielded the desired coupled product. Based on this result, we opted to extend the
scope of this work by coupling to various substituted anilines. The starting N, Nꢀdialkyl anilines
were prepared by reductive methylation of anilines whereas the synthesis of 2ꢀdibenzofuranol
(DBF) was performed in three step process involving FriedelꢀCrafts acylation of dibenzofuran,
9
a
followed by BaeyerꢀVilliger oxidation and finally basic hydrolysis. The detailed synthetic route
is depicted in Scheme 2.
To expand the substrate scope (see Table 1), the crossꢀcoupling reaction of
dibenzofuranol was carried out with 4ꢀalkylated N, Nꢀdimethyl anilines 1a-5a and 7a that
proceeded smoothly affording good yields (Table 1, entries 1ꢀ5 and 7) of the product. 3, 4ꢀ
th
dimethyl N, Nꢀdimethyl aniline underwent coupling with 8a at less crowded 6 position, rather
nd
than 2 position (Table 1, entry 8). 4ꢀmethoxy N, Nꢀ dimethyl aniline 12a underwent coupling to
give very poor yields of the product and produced complex mixtures (Table 1, entry 15). Unlike
1
1a
2
ꢀnaphthol, which underwent coupling reaction with all halogenated anilines, 2ꢀdibenzofuranol
in exception to fluoro aniline 11a (Table 1, entry 13), failed to couple with other halo substituted
N, Nꢀdialkylanilines. Instead, homoꢀcoupled products were formed, with traces of desired crossꢀ
coupled product. It might be the larger size of DBF compared to 2ꢀnaphthol, that might have
dampened its reactivity. Attempts were made to couple N, Nꢀdialkyl aniline possessing electron
withdrawing nitro group at para position 13a which did not proceed and the substrate was
completely recovered (Table 1, entry 16). Attempts were also made to explore the product
variation by altering the substitution at the nitrogen site. Thus the cross coupling reaction of
4

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dibenzofuranol with 4ꢀsubstituted aniline derivatives 6a, 9a and 10a proceeded smoothly to
obtain the desired products (Table 1, entries 6, 9 and 10). Keeping in mind the presence of free –
NH group in antimicrobial active molecules, we debenzylated the DBFꢀ15 using palladium
catalyst, to give DBFꢀ18 (Table 1, entry 11). The efforts made to couple heterocyclic anilines
met with failure, as the reaction performed with N, Nꢀdimethylaminopyridine did not proceed.
Treatment of DBF with 2ꢀmethoxy N, Nꢀdimethyl aniline ended up with no reaction, revealing
the necessity of the presence of free ortho site. Oꢀalkylation and Oꢀbenzylation of DBFꢀ13 and
DBFꢀ7 using K CO as a base afforded DBFꢀ19 and DBFꢀ21, respectively, in very good yields
2
3
(Table 1, entries 12 and 14). The regioselectivity in the formation of the coupling product is
arising from the Hꢀbond between nitrogen of aniline and oxygen of 2ꢀdibenzofuranol, which is
unambiguously confirmed through the crystal structure of DBF-4 (Figure 2) and also from the
broad peaks encountered from IR data. All the newly synthesized compounds were fully
1
13
characterized by H and C NMR, mass (ESIꢀMS), HRMS and IR spectral data.
This reaction is chemoselective, as it selectively underwent coupling at the ring leaving
1
3
11a
the Nꢀmethyl site intact. In accordance with the previously suggested mechanism, it might
involve the oxidation of aniline by iron (III) catalyst generating a radical cation, which on
coupling to nucleophillic 2ꢀdibenzofuranol generates an adduct. Rearomatization of 2ꢀ
dibenzofuranol and further oxidation of aniline produces a cation which on deprotonation finally
generates crossꢀcoupled product. The reduced iron catalyst is reoxidized back to iron (III) with
the help of the coꢀoxidant TBHP (Scheme 3).
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Antimycobacterial activity
Antiꢀmycobacterial activity of the synthesized new compounds was evaluated by the luciferase
1
4
reporter phage (LRP) assay with some modifications against M. tuberculosis H37Rv and
clinical S, H, R, and E resistant M. tuberculosis (MDRꢀTB) isolate at two different
concentrations (25 and 50 ꢁg/mL) using DMSO as a vehicle solvent. Fifty microliter bacterial
suspension equivalent to MacFarlands No.2 standard was added to 400 ꢁl of G7H9 with and
without the test compound. For each sample, two drugꢀfree controls and two drug concentrations
were prepared and this set up was incubated for 72 h at 37 ºC. After incubation 50 ꢁl of the high
titer of luciferase reporter phage (phAE129) and 40 ꢁl of 0.1 M CaCl were added to all the vials
2
and this setup was incubated at 37 ºC for 4 h. After incubation, 100 ꢁl of the mixture was taken
from each tube into a luminometer cuvette and equal amount of working Dꢀluciferin (0.3 mM in
0.05 M sodium citrate buffer, pH 4.5) solution was added. The RLU was measured after 10 s of
integration in the Luminometer (Monolight 2010). Duplicate readings were recorded for each
sample and the mean was calculated. The percentage reduction in the RLU was calculated for
each test sample and compared with control. The experiment was repeated when the mean RLU
of the control was less than 1000.
The antiꢀtubercular activity results of the synthesized compounds are compiled in Table
2. Among the tested compounds, DBFꢀ14, DBFꢀ16, and DBFꢀ3 proved to be good against M.
tuberculosis H37Rv at both the assayed concentrations, whereas DBFꢀ13, DBFꢀ18, and DBFꢀ9
were effective only at high concentration (50 ꢁg/mL) against M. tuberculosis H37Rv. Eight
(DBFꢀ18, DBFꢀ14, DBFꢀ3, DBFꢀ13, DBFꢀ16, DBFꢀ5, DBFꢀ9, and DBFꢀ19) out of 14 tested
compounds exhibited promising inhibitory activity against the clinical S, H, R and E resistant
6

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isolate when compared with the standard, Isoniazid. It is reported that a relationship exists
1
5,16
between % inhibition and Clog P.
Percentage inhibition increased with increase in Clog P.
Lipinski’s rule stated that Clog P is an indication of the lipophilicity of molecules, and more
1
7
lipophilic molecules can easily enter the lipidꢀenriched mycobacterial cell wall.
Analyzing the structure–activity relationship we first investigated the effect of
,
substitution pattern on the aryl partner of the aniline. In case of alkyl substitutions (Table 2,
entries 1ꢀ5, 7 and 8), DBFꢀ14 and DBFꢀ3 exhibited good activity against both the strains with
relatively low lipophillicity (Table 2, entries 8 and 1). From this it can be concluded that an
elongation of the carbon chain length on aryl ring might dampen its activity, which is probably
due to the increased hydrophobicity that makes them ineffective towards the target sites.
Surprisingly DBFꢀ13 with cyclohexyl group on the aniline ring was found to be promising at
higher concentrations against both the strains, and this discrepancy might be due to the
possibility of interaction of these moieties to more than one target site. Keeping electron
withdrawing substituents like fluorine in place of alkyl chain was not worthy, as it further
deactivated the ring and produced less activity (Table 2, entry 13). Interesting results were
observed when one of the methyl groups on nitrogen was replaced by benzyl and allyl groups.
Allyl in place of methyl group enhanced the activity, whereas with benzyl substitution,
suppressed activity was found (Table 2, entries 9 and 10). The low activity observed with the
benzyl substitution was either due to its increased lipophilicity or it might interrupt the
hydrophilic –OH group through nonꢀbonded interactions. When hydrophilic hydroxyl group of
the DBF was protected, decline in the activities were observed, that could be due to the
decreased interaction of the moiety towards the hydrophilic partner of the target site (Table 2,
entries 12 and 14). From this it is clear that, polar hydrophilic –OH group played a vital role in
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binding to the target site. Increased activity with increased hydrophilicity was observed in case
of DBFꢀ18, when one of Nꢀmethyl was deprotected, which is a clear indication that this group
along with –OH group were binding to the target site (Table 2, entry 11). Though the target site
specificity is not clear, it can be concluded from the above results, that the tubercular activity of
the compounds obtained by embedding a dialkyl aniline moiety on the Cꢀring of 2ꢀ
dibenzofuranol was steered by electronic and steric factors. The moieties are much more
promising, when the lipophillicity is maintained normal by not increasing the alkyl chain length
and also by enhancing the polarity through appropriate or no substitution on nitrogen, provided
the basic –OH group of the 2ꢀdibenzofuranol is kept intact. In brief, DBFꢀ3, 14 and 16 were
found to show promising activity against both the strains at both the concentrations, where as
DBFꢀ13 and 18 exhibited selective inhibitory activities against the clinical S, H, R and E
resistant isolate.
Cytotoxicity assay
Cytotoxicity of all the 14 synthesized compounds was determined on the basis of measurement
of in vitro growth inhibition of tumor cell lines in 96 well plates by cellꢀmediated reduction of
tetrazolium salt to water insoluble formazan crystals using doxorubicin as a standard. The
cytotoxicity as assessed against a panel of four different human tumor cell lines: A549 derived
from human alveolar adenocarcinoma epithelial cells (ATCC No. CCLꢀ185), HeLa derived from
human cervical cancer cells (ATCC No. CCLꢀ2), MDAꢀMBꢀ231 derived from human breast
adenocarcinoma cells (ATCC No. HTBꢀ26) and MCF7 derived from human breast
1
8
adenocarcinoma cells (ATCC No. HTBꢀ22) using the MTT assay. The IC50 values (50%
inhibitory concentration) were calculated from the plotted absorbance data for the doseꢀresponse
curves. IC values (in ꢂM) are indicated as means ± SD of three independent experiments.
5
0
8

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Being aware of the cytotoxicity produced by the dibenzofuran pharmacophores, we
1
9,9d
also subjected these compounds for antitumor activity.
The cytotoxicity of all the synthesized
compounds was tested using the MTT assay and the results obtained are shown in Table 3. It was
observed that among all the tested compounds, DBFꢀ4 (Table 3, entry 2) showed promising
activity against all the aforementioned cell lines. Interestingly, DBFꢀ8 (Table 3, entry 5) showed
selective activity against A549 cell line. It is noteworthy to mention that the compounds DBFꢀ4
and DBFꢀ8 with cytotoxicity were inactive towards M. tuberculosis whereas the compounds that
were most active for antiꢀmycobacterial activity (Table 2, entries 1, 8, and 10) were inactive
towards the cancer cell lines indicating that these compounds showed very specific activity.
Conclusion
We have successfully synthesized hither to unknown novel anilinodebenzofuranols, using iron
(
III) catalyzed crossꢀdehydrogenative CꢀC coupling. The products were assayed for their antiꢀ
tubercular and cytotoxic activities. These moieties produced moderate to good activity and were
very specific. The results obtained in this platform spur a quest in us in developing reliable
methods of CꢀC bond formation, leading to products that have promising biological applications.
To the best of our knowledge, there have been no previous reports of anilinodibenzofuranols as
antiꢀtubercular agents and further studies on the structureꢀactivity relation of these compounds
would give more insight into the design of more active candidates. In view of the specificity
showed by most of these active compounds towards antiꢀtubercular activity as well as
cytotoxicity, further studies are under way.
Experimental Section
General Considerations
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All commerciallyꢀavailable chemicals were used as received. tꢀBuOOH in 5ꢀ6 M in decane was
purchased from SigmaꢀAldrich Chemicals. Thinꢀlayer chromatography plates were visualized by
exposure to ultraviolet light (UV)/Iodine and/or by immersion in an acidic staining solution of
1
phosphomolybdic acid followed by heating on a hot plate. H spectra were obtained on 300
1
3
MHz, 500 MHz spectrometers and C NMR spectra were obtained on 75 MHz and 100 MHz
spectrometers with tetramethylsilane and chloroformꢀd1, respectively, as the internal standard.
1
Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ = 7.26 for H
1
3
1
NMR and δ = 77.0 for C NMR). Data for H NMR were reported as follows: chemical shift
(
multiplicity, coupling constant, number of hydrogens). Multiplicity is abbreviated as follows: s
singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), m (multiplet). IR spectra were
(
recorded on a PerkinꢀElmer 1800 series FTIR spectrometer and samples were analyzed as thin
films on KBr plates. Mass spectra were carried out using Quattro LC tripleꢀquadrupole mass
spectrometer (Micromass, Manchester, UK). Highꢀresolution mass spectra were determined
using Quadrupole timeꢀofꢀflight (QꢀTOF) mass spectrometer (QSTARXL, Applied
Biosystems/MDS Sciex, Foster city, USA).
General procedure for CDC reaction of N, N-dialkyl anilines with 2-dibenzofuranol
A 10 mL round bottomed flask was charged with N, Nꢀdialkyl aniline (1.0 mmol), dibenzofuranol
(1.0 mmol) and toluene. To the resulting mixture was then added FeCl .6H O (20 molꢀ%) and TBHP
3 2
(3.0 mmol) via syringe drop wise under atmospheric air. The resulting solution was allowed to stir at
room temperature under open air for 24 h. The resulting mixture obtained was celite filtered, washed
with ethyl acetate and water. The combined organic layers were dried over Na SO (s) and solvent
2
4
10

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was evaporated under reduced pressure. The crude product was purified by column chromatography
100ꢀ200 /60ꢀ120 mesh) using hexaneꢀethyl acetate as eluent to afford the product.
(
General procedure for the synthesis of N, N-dimethyl Anilines from various substituted
anilines
Ex: Synthesis of N, N, 4ꢀtrimethylaniline (1a): To a solution of pꢀtoluidine (1.00 g, 9.33 mmol) in
glacial acetic acid (50 mL) under inert atmosphere was added paraformaldehyde (2.74 g, 91.43
mmol) and sodium cyanoborohydride (2.75 g, 43.86 mmol). The addition of
sodiumcyanoborohydride caused vigorous bubbling. After stirring overnight, the reaction mixture
was poured into a water/ice mixture (~100 mL) containing NaOH (40 g). The addition was
exothermic, and more ice was added to bring the total volume of the quench mixture to ~300 mL.
This mixture which had a pH of 14 was extracted with CH Cl (350 mL). The combined organic
2
2
layers were dried over Na SO (s), filtered, and concentrated under reduced pressure, and was
2
4
purified by column chromatographic technique to yield a yellowish liquid (1.06 g, 7.85 mmol, 84%).
General procedure for the synthesis of 2-dibenzofuranol
To a solution of dibenzofuran (1) (5.0 g, 29 mmol) in chloroform (50 mL), was added a mixture
of AlCl (4.76 g, 35.7 mmol) and acetyl chloride (2.80 g, 35.6 mmol) in chloroform (50 mL).
3
After stirring the reaction mixture for 45 min at room temperature, it was poured into ice water
(100 mL) and 1N HCl (50 mL). The aqueous layer was washed with chloroform (2 × 30 mL);
combined organic layer was dried over Na SO (s) and concentrated under vacuum. The crude
2
4
residue was purified over silica gel column chromatography to yield 2ꢀacetyldibezofuran 2 (5.90
g, 95%) as white solid.
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°
2
ꢀAcetyldibezofuran (2) (1.0 g, 4.7 mmol) in CH Cl (20 ml) at 0 C was added trifluoroacetic
2 2
°
acid (1.47 mL, 19.1 mmol) and mꢀCPBA (1.64 g, 9.5 mmol) slowly at 0 C. After stirring at
room temperature for 3 days, the reaction mixture was quenched with ferrous sulphate, washed
with water; organic layer was separated, dried over Na SO (s) and concentrated over rotary
2
4
evaporator. The crude residue was dissolved in methanol (15 mL); sodium methoxide (0.76 g,
4.1 mmol) was added and stirred at room temperature for one hour. The reaction mixture was
1
quenched with 2.0 N HCl (5 mL) and solvent was removed under vacuum. It was then treated
with water, extracted with chloroform (2 × 30 mL), combined organic layers was dried over
anhyd. Na SO and concentrated under vacuum. Purification of residue over silica gel column
2
4
chromatography yielded compound 2ꢀdibenzofuranol (3) (0.69 g, 79%) as pale yellow solid.
Procedure for the synthesis of DBF-19
A 10 mL round bottomed flask equipped with mechanical stirrer, was charged with 3 mL of N,
Nꢀdimethylformamide and 0.107 g (0.78 mmol) of anhydrous potassium carbonate. To the
rapidly stirred mixture was then added 0.100 g. (0.259 mmol) of DBFꢀ13 followed by the
addition of 0.064 g (0.39 mmol) of 1ꢀBromohexane. The mixture was stirred for 12 hr.; after the
addition was completed, the mixture was poured into ice water, extracted with ethyl acetate, and
dried over Na SO (s). The solvent was removed on a rotary evaporator, affording 0.120 g (88%)
2
4
of colorless liquid.
Procedure for the synthesis of DBF- 21
A 10 mL round bottomed flask equipped with mechanical stirrer, was charged with 3 mL of N,
Nꢀdimethylformamide and 0.124 g (0.90 mmol) of anhydrous potassium carbonate. The rapidly
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stirred mixture was then added 0.100 g (0.3 mmol) of DBFꢀ7 followed by the addition of 0.048
mL (0.39 mmol) of 4ꢀfluoro benzyl bromide. The mixture was then stirred for 12 h; after the
addition was completed, the mixture was poured into ice water, extracted with ethyl acetate, and
dried over Na SO (s). The solvent was removed on a rotary evaporator, affording 0.109 g (83%)
2
4
of colorless liquid.
Procedure for the synthesis of DBF- 18
Palladium (Pd), 5% on carbon, 0.108 g (10 mol %) was placed in a 10ꢀml round bottomed flask
under N and carefully wetted with 3 ml of denatured ethanol (EtOH). A slurry of 0.200 g of DBFꢀ
2
15 (0.51 mmol) in denatured EtOH (3 mL) was also added. After the system was purged with
nitrogenꢀhydrogen (N /H ), the reaction was stirred at room temperature for 4 h. The catalyst was
2
2
then filtered over a Celite pad and rinsed with ethanol (EtOH). The filtrate was concentrated under
reduced pressure and dried to afford 0.130 g (84%) of the product as a colorless liquid.
General procedure for the monomethylation of anilines (6)
Sodium methoxide (5.0 mol) was made into a paste with methanol. To this aniline (5) (1.0 mol),
dissolved in methanol, was added and the resulting hot solution poured into a suspension of
paraformaldehyde (1.5 mol) in methanol (20 mL). The mixture was stirred under inert atmosphere at
room temp for 5 h and then NaBH (1.0 mol) was added. The resulting solution was heated under
4
reflux for 2ꢀ3 h. The crude then obtained was concentrated under reduced pressure to remove
methanol, followed by quenching with cold aq. NH Cl gives residue, which on extraction with ethyl
4
acetate, drying over Na SO (s), followed by column purification yields the desired product (6) in
2
4
good yields.
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Procedure for the synthesis of N-allyl/benzyl, N-methyl aniline from various substituted N-
methyl anilines (6)
To the ethanolic solution of the aniline (6) (1.0 mol), K CO (3.0 mol), allyl/benzyl bromide (1.2
2
3
mol) were added at room temperature and the resulting mixture was allowed to stir for 12 hrs at
room temperature under inert atmosphere. The resulting mixture thus obtained was first ethanol
concentrated, and then extracted with ethyl acetate and was purified by column chromatographic
technique.
Procedure for the synthesis of 4-p-tolylmorpholine (8)
A 100 ml round bottomed flask equipped with mechanical stirrer, was charged with 30 mL of N, Nꢀ
dimethylformamide and 3.87 g (28.05 mmol) of anhydrous potassium carbonate. To the rapidly
stirred mixture was then added 1.0 g (9.35 mmol) of pꢀtoluidine (7) followed by the addition of 2.60
g (11.22 mmol) of 1ꢀbromoꢀ2ꢀ(2ꢀbromoethoxy) ethane. The mixture was stirred for 12 h.; after the
addition was completed, the mixture was poured into ice water, extracted with ethyl acetate, and
dried Na SO (s). The solvent was removed on a rotary evaporator, affording 1.30 g (79%) of brown
2
4
1
colored solid. H NMR (300 MHz, CDCl ) δ: 7.11 (d, J = 8.50 Hz, 2H), 6.85 (d, J = 8.50 Hz, 2H),
3
1
3
3
.88ꢀ3.84 (m, 4H), 3.12ꢀ3.09 (m, 4H), 2.28 (s, 3H). C NMR (75MHz,CDCl ) δ: 149.1, 129.6,
3
129.5, 116.0, 66.9, 49.9, 20.4.
Characterization data of the compounds
1-(2-(dimethylamino)-5-methylphenyl)dibenzo[b,d]furan-2-ol (DBF-3)
Isolated by column chromatography. The title compound was a red colored liquid (138 mg, 59%
-1
Yield). FTIR (cm ): 3339, 2980, 2929, 1674, 1633, 1497, 1445, 1389, 1363, 1303, 1261, 1183,
14

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1
1
7
1
3
070, 861, 752; H NMR (ppm) δ: 7.57ꢀ7.54 (m, 1H), 7.49ꢀ7.46(m, 2H), 7.42ꢀ7.35 (m, 2H),
1
3
.20ꢀ7.07 (m, 3H), 6.92ꢀ6.88 (m, 1H), 2.70 (s, 6H), 2.32 (s, 3H); C NMR (ppm) δ: 151.3,
34.5, 129.6, 128.8, 126.5, 122.1, 121.7, 118.6, 118.0, 111.6, 111.5, 43.9, 26.3 MS(ESI) m/z:
+
+
18 (M+H) , 319; HRMS (ESI) calcd. for C H NO (M+H) : 318.14886; found: 318.14840.
2
1
20
2
1-(2-(dimethylamino)-5-ethylphenyl)dibenzo[b,d]furan-2-ol (DBF-7)
Isolated by column chromatography. The title compound was a cream colored solid (124 mg,
°
-1
5
1
7
2
1
1
6% Yield); mp 134 C. FTIR (cm ): 3450, 2955, 2866, 2796, 1605, 1496, 1496, 1469, 1439,
1
412, 1300, 1259, 1209, 1182, 1155, 929, 888, 834, 805, 748, 734, 611; H NMR (ppm) δ: 7.56ꢀ
.47 (m, 3H), 7.42ꢀ7.28 (m, 3H), 7.24ꢀ7.21 (m, 1H), 7.18ꢀ7.15 (m, 1H), 7.10ꢀ7.05 (m, 1H),
1
3
.71(s, 6H), 2.66ꢀ2.58 (q, J = 7.55, 2H), 1.23ꢀ1.18jb (t, J = 7.55, 3H); C NMR (ppm) δ: 156.9,
51.3, 150.5, 147.0, 139.4, 133.6, 130.0, 128.5, 126.5, 124.5, 122.2, 121.6, 118.5, 118.0, 111.5,
+
11.4, 43.9, 28.1, 15.6; MS (ESI) m/z: 332 (M+H) , 333; HRMS (ESI) calcd. for C H NO
2
2
22
2
+
(
M+H) : 332.16451; found: 332.16382.
1-(5-iso-propyl-2-(dimethylamino)phenyl)dibenzo[b,d]furan-2-ol (DBF-4)
Isolated by column chromatography. The title compound was a colorless solid (116 mg, 55%
°
-1
Yield); mp 170 C. FTIR (cm ): 3445, 2958, 2870, 1623, 1498, 1468, 1442, 1409, 1303, 1261,
1
1
213, 1187, 932, 890, 810, 751, 625; H NMR (ppm) δ: 7.56ꢀ7.47 (m, 3H), 7.41ꢀ7.31 (m, 3H),
1
3
7
.25ꢀ7.15 (m, 2H), 7.09ꢀ7.04 (m, 1H), 2.95ꢀ2.85 (m, 1H), 2.72 (s, 6H), 1.24ꢀ1.20 (m, 6H); C
NMR (ppm) δ: 156.9, 151.3, 150.5, 147.2, 143.7, 132.2, 129.9, 127.1, 126.6, 124.5, 122.5,
22.4, 122.2, 121.5, 118.5, 117.9, 111.5, 111.4, 43.9, 33.5, 24.0, 23.7; MS (ESI) m/z: 346
1
+
+
(
M+H) , 347; HRMS (ESI) calcd. for C H NO (M+H) : 346.18016; found: 346.17993.
23 24 2
1-(5-tert-butyl-2-(dimethylamino)phenyl)dibenzo[b,d]furan-2-ol (DBF-5)
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Isolated by column chromatography. The title compound was a cream colored solid (111 mg,
-
1
5
1
7
7
1
4
3
5% Yield); mp 173 °C. FTIR (cm ): 3447, 2959, 2904, 2870, 1623, 1499, 1470, 1441, 1422,
1
395, 1260, 1193, 932, 894, 811, 753, 617; H NMR (ppm) δ: 7.68ꢀ7.67 (d, J = 2.45 Hz, 1H),
.56ꢀ7.53 (m, 1H), 7.51ꢀ7.50 (m, 1H), 7.48ꢀ7.47 (m, 1H), 7.40ꢀ7.34 (m, 2H), 7.23ꢀ7.16 (m, 2H),
1
3
.08ꢀ7.04 (m, 1H), 2.72 (s, 6H), 1.28 (s, 9H); C NMR (ppm) δ: 156.8, 151.3, 150.5, 146.7,
45.9, 131.4, 129.5, 126.6, 125.8, 124.4, 122.6, 122.4, 122.2, 121.4, 118.5, 117.7, 111.5, 111.4,
+
+
3.8, 34.3, 31.2; MS (ESI) m/z: 360 (M+H) , 361; HRMS (ESI) calcd. for C H NO (M+H) :
24
26
2
60.19581; found: 360.19559.
1-(5-butyl-2-(dimethylamino)phenyl)dibenzo[b,d]furan-2-ol (DBF-8)
Isolated by column chromatography. The title compound was a colorless solid (117 mg, 58%
-1
Yield); mp 159 °C. FTIR (cm ): 3445, 2955, 2928, 2853, 2794, 1624, 1583, 1497, 1471, 1439,
1
1
7
7
1
1
2
410, 1300, 1259, 1209, 1184, 1039, 1012, 889, 833, 748, 734, 681, 611; H NMR (ppm) δ:
.57ꢀ7.54 (m, 1H), 7.50ꢀ7.46 (m, 2H), 7.41ꢀ7.35 (m, 2H), 7.30ꢀ7.27 (m, 1H), 7.26ꢀ7.21 (m, 1H),
.19ꢀ7.16 (m, 1H), 7.09ꢀ7.04 (m, 1H), 2.73 (s, 6H), 2.61ꢀ2.55 (m, 2H), 1.63ꢀ1.59 (m, 2H), 1.39ꢀ
1
3
.33 (m, 2H), 0.93ꢀ0.88 (m, 3H); C NMR (ppm) δ: 156.9, 151.3, 150.5, 147.0, 143.1, 132.5,
29.8, 127.5, 126.5, 124.5, 122.4, 122.2, 121.5, 118.5, 117.9, 111.5, 111.4, 60.3, 43.8, 34.5, 34.0,
+
6.7., 25.9, 20.9, 14.1; MS (ESI) m/z: 360 (M+H) , 361, 362; HRMS (ESI) calcd. for C H NO
2
4
26
2
+
(
M+H) : 360.19581; found: 360.19568.
1-(2-(dimethylamino)-4,5-dimethylphenyl)dibenzo[b,d]furan-2-ol (DBF-14)
Isolated by column chromatography. The title compound was a cream colored solid (118 mg,
-1
5
3% Yield); mp 147 °C. FTIR (cm ): 2923, 1847, 1729, 1611, 1500, 1447, 1393, 1258, 1190,
1
1
039, 875, 805, 757; H NMR (ppm) δ: 7.56ꢀ7.53 (m, 1H), 7.47ꢀ7.35 (m, 4H), 7.17ꢀ7.06 (m,
16

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1
3
3
H), 2.70 (s, 6H), 2.39 (s, 3H), 2.23 (s, 3H); C NMR (ppm) δ: 152.9, 150.5, 147.0, 134.8,
127.3, 127.1, 126.7, , 122.2, 121.6, 118.4, 111.5, 111.1, 43.9, 19.9, 18.7; MS (ESI) m/z: 332
+
+
(
M+H) , 333; HRMS (ESI) calcd. for C H NO (M+H) : 332.16451; found: 332.16354.
22 22 2
1-(5-cyclohexyl-2-(dimethylamino)phenyl)dibenzo[b,d]furan-2-ol (DBF-13)
Isolated by column chromatography. The title compound was a colorless solid (111 mg, 59%
-1
Yield); mp 163 °C. FTIR (cm ): 3418, 3016, 2920, 2865, 2792, 1589, 1459, 1401, 1330, 1298,
1
1
2
1
1
1
3
234, 1202, 1149, 922, 819, 752, 669, 621; H NMR (ppm) δ: 7.57ꢀ7.54 (m, 1H), 7.50ꢀ7.47 (m,
H), 7.41ꢀ7.36 (m, 2H), 7.33ꢀ7.29 (m, 1H), 7.26ꢀ7.23 (m, 1H), 7.19ꢀ7.16 (m, 1H) 7.09ꢀ7.04 (m,
1
3
H), 2.72 (s, 6H), 2.55ꢀ2.44 (m, 1H), 1.90ꢀ1.66 (m, 6H), 1.41ꢀ1.25 (m, 4H); C NMR (ppm) δ:
56.9, 151.3, 150.5, 147.0, 143.1, 132.5, 129.8, 127.5, 126.5, 124.5, 122.4, 122.2, 121.5, 118.5,
+
17.9, 111.5, 111.4, 60.3, 43.8, 34.5, 34.0, 26.7., 25.9, 20.9, 14.1; MS (ESI) m/z: 386 (M+H) ,
+
87; HRMS (ESI) calcd. for C H NO (M+H) : 386.21146; found: 386.21140.
2
6
28
2
1-(2-(dimethylamino)-5-fluoro phenyl)dibenzo[b,d]furan-2-ol (DBF-20)
Isolated by column chromatography. The title compound was a colorless solid (115 mg, 50%
-1
Yield); mp 210 ºC. FTIR (cm ): 3424, 3067, 2970, 2873, 2791, 1855, 1733, 1494, 1471, 1406,
1
1
7
1
1
338, 1302, 1262, 1207, 1182, 1144, 1115, 817, 757; H NMR (ppm) δ: 7.57ꢀ7.49 (m, 2H), 7.43ꢀ
1
3
.34 (m, 3H), 7.29 (s, 1H), 7.21ꢀ7.10 (m, 3H), 2.71 (s, 6H) ; C NMR (ppm) δ: 159.5, 157.0,
51.4, 150.5, 145.7, 132.2, 126.8, 124.0, 122.0, 121.0, 120.5, 120.3, 119.5, 118.8, 115.6, 115.5,
+
+
12.2, 111.7, 44.1; MS (ESI) m/z: 322 (M+H) , 344 (M+Na) ; HRMS (ESI) calcd. for
+
C H NO F (M+H) : 322.12378; found: 322.12387.
20
17
2
1-(2-(benzyl(methyl)amino)-5-methylphenyl)dibenzo[b,d]furan-2-ol (DBF-15)
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Isolated by column chromatography. The title compound was a red colored liquid (83 mg, 45%
-1
Yield). FTIR (cm ): 3409, 2922, 2853, 1632, 1446, 1260, 1215, 1178, 1113, 1068, 920, 812,
1
7
52; H NMR (ppm) δ: 7.56ꢀ7.49 (m, 3H), 7.43ꢀ7.36 (m, 2H), 7.22ꢀ7.09 (m, 5H), 6.99ꢀ6.96 (m,
2H), 6.92ꢀ6.88 (d, J = 10.19, 1H), 6.25ꢀ6.20 (d, J = 10.19, 1H), 3.97ꢀ3.85 (m, 2H), 2.69 (s, 3H),
1
3
2
.35 (s, 3H); C NMR (ppm) δ: 151.4, 150.2, 146.4, 135.5, 134.4, 133.2, 130.1, 129.7, 129.5,
129.3, 128.8, 128.2, 127.5, 126.6, 122.6, 122.3, 121.9, 121.8, 119.5, 118.5, 111.6, 61.8, 38.8,
+
+
2
6.2; MS (ESI) m/z: 394 (M+H) , 395; HRMS (ESI) calcd. for C H NO (M+H) : 394.18016;
27 24 2
found: 394.18052.
1-(2-(allyl(methyl)amino)-5-ethylphenyl)dibenzo[b,d]furan-2-ol (DBF-16)
Isolated by column chromatography. The title compound was a red colored liquid (89 mg, 44%
-1
Yield). FTIR (cm ): 3450, 2964, 2928, 2858, 1671, 1632, 1453, 1366, 1259, 1197 1102, 1063,
1
1
008, 752; H NMR (ppm) δ: 7.55ꢀ7.53 (d, J=8.23, 1H), 7.48ꢀ7.47 (m, 2H), 7.38ꢀ7.36 (m, 2H),
7.29ꢀ7.28 (m, 1H), 7.21ꢀ7.16 (m, 2H), 7.08ꢀ7.05 (m, 1H), 5.69ꢀ5.59 (m, 1H), 5.07ꢀ5.06 (d,
J=9.26, 1H), 5.01ꢀ4.98(m, 1H), 3.45ꢀ3.34 (m, 2H), 2.77 (s, 3H), 2.65ꢀ2.60 (m, 2H), 1.22ꢀ1.19
13
(
m, 3H); C NMR (ppm) δ: : 156.9, 150.4, 146.4, 139.3, 133.5, 132.9, 129.9, 128.4, 126.5,
122.2, 121.6, 119.4, 119.0, 118.6, 111.5, 80.0, 71.9, 60.4, 37.4, 29.3, 26.3, MS (ESI) m/z: 358
+
+
(
M+H) ; HRMS (ESI) calcd. for C H NO (M+H) : 358.18016; found: 358.18044.
24 24 2
1-(5-methyl-2-(methylamino)phenyl)dibenzo[b,d]furan-2-ol (DBF-18)
Isolated by column chromatography. The title compound was a colorless liquid (64 mg, 84%
-1
Yield). FTIR (cm ): 3363, 2963, 2926, 2858, 1709, 1602, 1570, 1451, 1305, 1261, 1183, 1062,
1
1
012, 955, 882, 813, 750; H NMR (ppm) δ: 7.56ꢀ7.54 (d, J = 7.99, 1H), 7.49ꢀ7.46 (m, 2H),
.39ꢀ7.36 (m, 1H), 7.33ꢀ7.29 (m, 3H), 7.20ꢀ7.18 (d, J = 7.99, 1H), 7.09ꢀ7.06 (m, 1H), 2.83 (s,
7
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1
3
3
H), 2.34 (s, 3H); C NMR (ppm) δ: 156.8, 151.7, 150.7, 146.6, 129.7, 127.3, 127.0, 124.8,
+
1
24.2, 122.3, 120.5, 115.3, 113.3, 111.9, 111.6, 106.2, 31.3, 20.3; MS (ESI) m/z: 304 (M+H) ;
+
HRMS (ESI) calcd. for C H NO (M+H) : 304.13321; found: 304.13367.
2
0
18
2
4-cyclohexyl-2-(2-(hexyloxy)dibenzo[b,d]furan-1-yl)-N,N-dimethylaniline (DBF-19)
Isolated by column chromatography. The title compound was a greenish solid (107 mg, 88%
-1
Yield); mp 85 °C. FTIR (cm ): 2924, 2853, 2777, 1604, 1504, 1467, 1422, 1250, 1190, 1142,
1
1
097, 1605, 1013, 943, 867, 795, 747, 622; H NMR (ppm) δ: 7.50ꢀ7.31(m, 5H), 7.15ꢀ6.91 (m,
H), 4.02ꢀ3.89 (m, 2H), 2.44 (s, 7H), 1.90ꢀ1.68 (m, 6H), 1.38ꢀ1.22 (m, 12H), 0.86ꢀ0.81 (m, 3H);
C NMR (ppm) δ: 151.9, 150.9, 130.4, 129.0, 128.6, 127.2, 126.6, 122.5, 122.3, 121.9, 117.5,
13.5, 111.1, 111.0, 110.6, 109.8, 70.2, 43.6, 34.6, 34.5, 31.4, 29.4, 26.8, 26.1, 25.6, 22.5, 13.9,
4
1
3
1
0
4
+
+
.9; MS (ESI) m/z: 470 (M+H) ; HRMS (ESI) calcd. for C H NO (M+H) : 470.30536; found:
3
2
40
2
70.30447.
4-Ethyl-2-(2-(4-fluoro benzyloxy)dibenzo[b,d]furan-1-yl)-N,N- dimethylaniline (DBF-21)
Isolated by column chromatography. The title compound was a colorless liquid (110 mg, 83%
-1
Yield). FTIR (cm ): 2962, 2932, 2865, 2828, 2779, 1605, 1508, 1419, 1252, 1225, 1191, 1066,
1
8
2
1
4
4
23, 748; H NMR (ppm) δ: 7.52ꢀ7.45 (m, 2H), 7.38ꢀ7.33 (m, 2H), 7.22ꢀ6.93(m, 9H), 5.06 (s,
1
3
H), 2.66ꢀ2.59 (m, 2H), 2.44 (s, 6H), 1.246ꢀ1.19 (m, 3H); C NMR (ppm) δ: 158.9, 151.3,
31.6, 131.4, 129.8, 128.7, 128.6, 127.6, 122.3, 122.2, 122.1, 115.2, 115.0, 114.2, 111.2, 71.3,
+
+
3.7, 29.6, 15.8; MS (ESI) m/z: 440 (M+H) ; HRMS (ESI) calcd. for C H NO F (M+H) :
29
27
2
40.20203; found: 440.20087.
1
ꢀ
(
5
ꢀ
m
e
t
h
y
l
ꢀ
2
ꢀ
m
o
r
p
h
o
l
i
n
o
p
h
e
n
y
l
)
d
i
b
e
n
z
o
[
b
,
d
]
f
u
r
a
n
ꢀ
2
ꢀ
o
l
1
-(5-methyl-2-morpholinophenyl)dibenzo[b,d]furan-2-ol (DBF-9)
19

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Isolated by column chromatography. The title compound was a brown colored solid (85 mg, 42%
-1
Yield); mp 125 °C. FTIR (cm ): 3417, 2922, 2852, 1446, 1260, 1215, 1178, 1113, 1068, 920,
1
8
12, 751; H NMR (ppm) δ: 7.57ꢀ7.30 (m, 6H), 7.21ꢀ7.07 (m, 3H), 3.77ꢀ3.65(m, 4H), 3.14ꢀ2.89
1
3
(
m, 4H), 2.42 (s, 1H), 2.33 (s, 2H); C NMR (ppm) δ: 156.9, 149.6, 145.9, 134.6, 133.6, 130.0,
129.8, 126.7, 122.7, 122.2, 122.0, 121.8, 120.6, 118.6, 118.1, 112.0, 106.1, 66.7, 52.4, 20.5; MS
+
+
(
ESI) m/z: 360 (M+H) , 361; HRMS (ESI) calcd. for C H NO (M+H) : 360.15942; found:
23 22 3
360.15973.
X-ray data
The intensity data were collected at room temperature using a Bruker Smart Apex CCD
diffractometer with graphite monochromated MoKα radiation (λ=0.71073Å) by the ωꢀscan
method [1]. Preliminary lattice parameters and orientation matrices were obtained from four sets
of frames. Unit cell dimensions were determined using 8434 reflections in the range of 2.65 < θ
<
26.90°. Integration and scaling of intensity data were accomplished using the program SAINT
[
1]. The structures were solved by direct methods using SHELXS97 [2] and refinement was
carried out by fullꢀmatrix leastꢀsquares technique using SHELXL97 [2]. Anisotropic
displacement parameters were calculated for all nonꢀhydrogen atoms. The Oꢀbound H atom was
located in a difference Fourier density map and refined isotropically. All other H atoms were
positioned geometrically and treated as riding on their parent C atoms, with CꢀH = 0.93ꢀ0.96 Å,
and with U (H) = 1.5U (C) for methyl H and 1.2U (c) for other H atoms.
iso
eq
eq
20

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3
Crystal data for AO80: C H NO , M = 345.42, colorless needle, 0.18 × 0.11 × 0.08 mm ,
23
23
2
orthorhombic, space group P2 2 2 (No. 19), a = 7.8847(5), b = 11.3771(7), c = 20.8098(13) Å,
1
1 1
3
3
V = 1866.7(2) Å , Z = 4, D = 1.229 g/cm , F = 736, CCD Area Detector, MoKα radiation, λ =
c
000
0
.71073 Å, T = 294(2)K, 2θmax = 50.0º, 18068 reflections collected, 1908 unique (R = 0.0232).
int
Final GooF = 1.067, R1 = 0.0307, wR2 = 0.0821, R indices based on 1805 reflections with
2
ꢀ1
I>2σ(I) (refinement on F ), 243 parameters, 0 restraints,
has been deposited for compound AO80 with the Cambridge Crystallographic Data Centre
CCDC No. 933432]. Copies of the data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre
CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0) 1223 336 033; email:
ꢀ = 0.078 mm . Crystallographic data
[
(
deposit@ccdc.cam.ac.uk].
HPLC Procedure
The chromatographic separation was achieved on InertsilꢀODS3VꢀC18 (4.6mm×250mm i.d.;
particle size 5 ꢁm) analytical column using different compositions of acetonitrile and 20 mM
ammonium acetate as a mobile phase in an isocratic elution mode at a flow rate 1.0 mL/min at 25
°
C. The column effluents were monitored by a photo diode array detector.
ACKNOWLEDGMENTS
B. C. (SRF) and K. G. (JRF) are thankful to CSIR for fellowships. This article is dedicated to
th
Professor Goverdhan Mehta on the eve of his 70 birth day.
21

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References
1
. S. Menon, S. Dharmshale, C. Chande, A. Gohil, S. Lilani, S. Mohammad, A. Joshi, A.
Chowdhary, and R. Bharadwaj, Lung India, 2012, 29, 227ꢀ231.
2
3
4
5
. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980871/
. http://www.who.int/mediacentre/factsheets/fs104/en/
. Handbook of AntiꢀTuberculosis Agents, 2008, 88, 85ꢀ170.
. (a) R. P. Tripathi, N. Tewari, N. Dwivedi, and V. K. Tiwari, Med. Res. Rev. 2005,
2
5, 93 – 131 ; (b) http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5803a1.htm
6
. http://www.stemcellcafe.com/tag/toronto
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. (a) M. Yan, and S. Ma, ChemMedChem., 2012, 7, 2063 – 2075; (b) B. B. Mishra, and V.
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DOI: 10.1039/C3RA43345E
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Chem., 2011, 76, 10229ꢀ10235. (b) S. Partha Sarathi, S. Naveen Kumar, M.
Chandrasekharam, L. PicaꢀMattoccia, D. Cioli and
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DOI: 10.1039/C3RA43345E
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Table legends:
Table 1. Substrate Scope.
Table 2. Antiꢀtubercular activity of the synthesized compounds.
Table 3. Cytotoxicity evaluation of the synthesized compounds on different cancer cell lines.
24

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DOI: 10.1039/C3RA43345E
Table 1.
Reaction
time
Entry
Substrate
Product
MP (°C)
Yield (%)
N
N
R
OH
R
O
DBFꢀ3
ꢀ
59
1
R= 4ꢀMethyl, 1a
R=4ꢀIsopropyl, 2a
R= 4ꢀt-Butyl, 3a
R= 4ꢀEthyl, 4a
12 hr
24 hr
30 hr
24 hr
2
3
4
DBFꢀ4
DBFꢀ5
170
173
134
55
55
DBFꢀ7
DBFꢀ8
56
58
5
R= 4ꢀn-Butyl, 5a
24 hr
159
O
N
6
(6a)
42
30 hr
DBFꢀ9
125
7
8
R=4ꢀCyclohexyl, 7a
R=3,4ꢀdimethyl, 8a
DBFꢀ13
DBFꢀ14
163
147
59
53
3
6 hr
24 hr
N
Ph
(
9
12 hr
DBFꢀ15
45
ꢀ
9a)
N
ꢀ
(10a)
10
12 hr
DBFꢀ16
ꢀ
44
1
1
1
DBFꢀ15
DBFꢀ13
4 hr
12 hr
30 hr
12 hr
DBFꢀ18
DBFꢀ19
DBFꢀ20
DBFꢀ21
DBFꢀ1
NR
ꢀ
84
88
2
85
13
R= 4ꢀFluoro, 11a
DBFꢀ7
212
50
83
1
4
5
ꢀ
ꢀ
1
R=4ꢀMethoxy, 12a
R=4ꢀNitro, 13a
traces
ꢀ
12 hr
1
6
7
ꢀ
ꢀ
36 hr
36 hr
1
ꢀ
R=2ꢀMethoxy, 14a
NR
Substituted Nꢀalkyl aniline (1 equiv), 2ꢀnaphthol (1 equiv), TBHP (3 equiv), and [Fe] (20 mol %): otherwise
are mentioned. Reported yields are based on Nꢀalkyl aniline. NR = no reaction. TBHP used is a 5ꢀ6M
solution in decane.
25

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Table 2.
%
Reduction in RLU
Clinical isolate: S, H, R and E resistant M. tuberculosis
S.No Name of the
Compound
M. tuberculosis H37Rv
2
5 ꢀg/mL
50 ꢀg/mL
25 ꢀg/mL 50 ꢀg/mL
Clogp
1
2
DBFꢀ3
DBFꢀ4
51.54
00
62.28
00
55.47
18.50
76.75
26.69
5.471
6.399
3
4
5
6
7
8
9
DBFꢀ5
DBFꢀ7
DBFꢀ8
DBFꢀ9
DBFꢀ13
DBFꢀ14
DBFꢀ15
DBFꢀ16
DBFꢀ18
DBFꢀ19
DBFꢀ20
DBFꢀ21
32.41
22.96
00
43.45
46.88
61.52
32.28
64.27
35.36
43.09
34.02
30.83
55.82
57.43
61.52
42.26
67.99
56.33
44.51
16.03
00
30.24
52.60
58.61
41.60
51.75
56.54
64.81
27.59
39.10
61.54
63.66
71.98
47.95
58.64
78.12
6.798
6.000
7.058
5.126
7.592
5.920
7.239
6.774
4.805
1
0
1
2
3
1
1
1
42.24
34.23
00
54.37
37.10
00
27.30
10.56
19.35
65.42
38.17
44.77
10.783
5.303
8.457
14
isoniazid(0.2ꢁg/ml)
82.04
38.64
Antimycobacterial activity is indicated by fifty percent reduction in relative units (RLU) in the presence of
compound in comparision with the compound free control. Vehicle solvent used is Dimethyl sulfoxide and
the method used is Luciferase reporter phage (LRP) assay.
Table 3.
IC50 in ꢀM
S.No.
Test Compound
DBFꢀ3
A549
ꢀ
HeLa
MDAꢁMBꢁ231
MCFꢁ7
ꢀ
ꢀ
ꢀ
1
2
DBFꢀ4
0.91±0.021
1.81±0.025
1.95±0.032
2.75±0.021
3
DBFꢀ5
DBFꢀ7
DBFꢀ8
14.89±0.054
16.79±0.048
44.79±0.065
33.91±0.052
4
5
ꢀ
ꢀ
ꢀ
ꢀ
5.44±0.027
ꢀ
ꢀ
ꢀ
ꢀ
6
7
8
DBFꢀ9
17.89±0.032
ꢀ
36.79±0.044
ꢀ
14.91±0.036
ꢀ
DBFꢀ13
DBFꢀ14
DBFꢀ15
DBFꢀ16
36.00±0.045
15.90±0.039
30.90±0.052
ꢀ
ꢀ
ꢀ
9
ꢀ
ꢀ
ꢀ
1
1
1
1
1
0
1
2
3
4
15.78±0.038
ꢀ
78.91±0.069
22.89±0.047
14.71±0.043
DBFꢀ18
DBFꢀ19
DBFꢀ20
DBFꢀ21
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
33.98±0.058
38.91±0.062
ꢀ
ꢀ
ꢀ
ꢀ
19.97±0.046
0.459±0.021
15
Doxorubicin
0.509±0.011
0.91±0.021
1.07±0.026
"ꢀ" Indicates No activity
A549 ꢀ Human alveolar adenocarcinoma cell line; HeLa ꢀ Human cervical cancer cell line; MCFꢁ7
Human breast adenocarcinoma cell line; MDAꢁMBꢁ231 ꢀ Human breast adenocarcinoma cell line.
26

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DOI: 10.1039/C3RA43345E
Figure legends:
Figure 1. Bioactive hybrids of Dibenzofuran.
Figure 2. Ortep diagram of DBFꢀ4.
R
O
Figure 1.
N
N
O
OH
O
N
OH
HO
O
O
O
O
Usnic acid
Dibenzofuran clubbed 1, 2, 3ꢀtriazole
O
O
P
HO
O
HO
N
H
O
OH
NH
N
N
N
Ruscodibenzofuran
CGSꢀ34043
H CO
3
OH
OR
O
O
HO
P
N
COOMe
H
O
HO
O
CGSꢀ35066
R=H; Lucidafuran
R=CH3; Eribofuran
O
Benzofurobenzopyran
Figure 2.
27

RSC Advances
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Scheme legends:
Scheme 1. ArylꢀAryl coupling.
Scheme 2. Synthetic Route.
Scheme 3. Plausible Mechanism.
Scheme 1.
R
OH
N
FeCl (20 mol%)
TBHP (3 eq)
3
N
OH
toluene
r.t, open air
O
R
C
A
2
4 hr
B
O
2
ꢀDibenzofuranol
28

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RSC Advances
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Scheme 2.
O
OH
CH COCl
2
i) mꢀCPBA, TFA, CH Cl2
3
RT, 3ꢀ4 days
AlCl3
ii) NaOCH , 1 N HCl
o
3
CHCl , 0 CꢀRT
3
2ꢀ3 h, r.t
O
O
O
2
h
(1)
Dibenzofuranol (DBF)
3)
(2)
(
NH2
NaBH CN
N
3
(
CH O)n
2
Br
CH COOH
3
R
R
Overnight, r.t
R
N
F
N atm
2
F
(
4)
(5)
K CO
O
2
3
R
DMF; N
r.t, 12hr
atm
2
OH
N
FeCl (20 mol%)
TBHP (3 eq)
O
3
N
When R =4ꢀethyl; DBFꢀ21
R
toluene
r.t, open air
O
OH
R
C
K2CO
6
H
13Br
N
O
12ꢀ 36 hr
3
2
ꢀDibenzofuranol
O
(
5)
DMF; N atm
r.t, 12hr
2
C H
6
13
When R =4ꢀ methyl; DBFꢀ3
R =4ꢀisopropyl; DBFꢀ4
R =4ꢀtꢀbutyl; DBFꢀ5
O
R =4ꢀethyl; DBFꢀ7
When R =4ꢀcyclohexyl; DBFꢀ19
R =4ꢀnꢀbutyl; DBFꢀ8
R =4ꢀcyclohexyl; DBFꢀ13
R =3, 4ꢀdimethyl; DBFꢀ14
R =4ꢀFluoro; DBFꢀ20
R
R
(
i) CH ONa/CH OH
HN
RI
DBF
3
3
RI
NH2
N
(
CH O)n
K
RIꢀX
2
CO
3
FeCl (20 mol%)
N
Pd/C
NH
OH
2
3
CH OH; N2 atm
TBHP (3 eq)
H (Balloon)
2
3
OH
toluene
r.t, open air
12ꢀ36 hr
Ethanol, N2
atm, 12h, r. t
(
ii) NaBH /CH OH
Ethanol; r.t
hr
4
3
R
R
4
reflux, 4ꢀ5 hr
R
O
O
(
4)
(
6)
Where RI = Allyl/Benzyl
When R =4ꢀmethyl; DBFꢀ18
When
RI = Allyl, R =4ꢀethyl; DBFꢀ16
Benzyl, R =4ꢀmethyl; DBFꢀ15
=
O
DBF
NH2
Br
Br
N
O
O
3
FeCl (20 mol%)
N
3
K CO
2
TBHP (3 eq)
OH
toluene
r.t, open air
DMF; N atm
r.t, 12hr
2
4ꢀ24 hr
O
(
7)
(8)
DBFꢀ9
29