Synthesis and antimicrobial evaluation of amide derivatives of benzodifuran-2-carboxylic acid

Article abstract of DOI:10.1016/j.ejmech.2014.01.026

We have synthesized various amide derivatives of benzodifuran-2-carboxylic acid from resorcinol. Reaction of 7-hydroxy-4-methylcoumarin with chloroacetone in anhydrous K₂CO₃ and dry acetone gave ether derivative of 7-hydroxy-4-methyl

Full text of DOI:10.1016/j.ejmech.2014.01.026

European Journal of Medicinal Chemistry 75 (2014) 77e81
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimicrobial evaluation of amide derivatives
of benzodifuran-2-carboxylic acid
*
Jigar N. Soni, Shubhangi S. Soman
Department of Chemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have synthesized various amide derivatives of benzodifuran-2-carboxylic acid from resorcinol. Re-
action of 7-hydroxy-4-methylcoumarin with chloroacetone in anhydrous K2CO3 and dry acetone gave
ether derivative of 7-hydroxy-4-methylcoumarin 3 which on reaction with N-bromosuccinimide in
chloroform gave corresponding 3-bromo derivative 4. Cyclization of bromo derivative in 10% ethanolic
KOH gave benzodifuran-2-carboxylic acid 5. This acid was converted into acid chloride using oxalyl
chloride and then substituted with different amines in presence of base, triethylamine to give amide
derivatives of benzodifuran-2-carboxylic acid 6. All compounds were screened for antimicrobial activity
against two Gram positive bacteria Staphylococus aureus and Bacillus subtilis, two Gram negative bacteria
E. coli and P. aeruginosa and one fungus Candida albicans.
Received 12 September 2013
Received in revised form
8 January 2014
Accepted 14 January 2014
Available online 28 January 2014
Keywords:
Difuran
Amide
Cyclization
Antimicrobial activity
Ó 2014 Elsevier Masson SAS. All rights reserved.
1. Introduction
In order to overcome the threat of wide spread multi drug
resistance in Gram positive and Gram negative bacterial strains as
The incidence of bacterial and fungal infections have increased
significantly in the past 25 years. The evolution of antibacterial
resistance in bacterial strains against the currently available anti-
bacterial agents is an increasing concern in recent years. For
instance Gram positive bacterial pathogens such as Staphylococus
aureus (S. aureus) is resistant to Methicillin, Streptococcus pneu-
moniae and Enterococci are resistant to Penicillin and Vancomycin
well as fungi, there is ongoing demand for new antimicrobial
agents.
Furan and its derivatives show wide range of activity. Benzofu-
rans having various amide, ester, ether and thioether derivatives
with varying functional groups show antifungal activity [3e6]. 3-
substituted benzofuran-2-amide derivatives are reported as
cysteine protease inhibitors [7] and anti proliferative agents against
lung cancer cell lines [8]. Benzofuran and benzothiophene de-
rivatives substituted with amide effectively inhibits ischemic
cell death and can be useful in many other diseases [9]. Various 2-
substituted amide derivatives of benzofuran are reported as potent
orexin receptor antagonist [10] and anti hyperlipidemic agents [11].
Various 2-substituted benzofuran amide derivatives and 2, 3-
substituted benzofuran derivatives are reported to show good
antimicrobial activity [12,13]. Ethyl ester derivatives of 4-hydroxy-
3-methyl-6-phenylbenzofuran-2-carboxylic acid have been re-
ported as antitumor agents [14]. Various 2-substituted vinyl ester
derivatives of benzofuran and benzodifuran have been reported as
angiogenesis inhibitors [15]. Benzofuran-2-biphenyl sulfonamide
derivatives are useful in treatment of osteoarthritis [16].
Substituted benzofuran-1, 3-diazepin derivatives are reported to
show CNS depressant effect [17].
respectively [1] while Gram negative bacteria are resistant to
b
lactams, quinolones and macrolides [2]. Since Candida albicans
(C. albicans) and Aspergillus fumigatus (A. fumigatus) are the main
causative fungi of the systemic mycosis, antifungal drugs for
treating patients of deep mycosis should have a broad antifungal
spectrum including at least these microorganisms. Currently only
four classes of antifungal drugs, polyene macrolides (amphotericin
B), azoles (fluconazole, miconazole, itraconazole and voriconazole)
flucytosine and candins (caspofungin acetate and micafungin) are
available for treatment of systemic micosis. Unfortunately none of
them is ideal in terms of efficacy, antifungal spectrum or safety.
Although amphotericin B is efficacious against both candidiasis and
aspergillosis, it shows severe renal toxicity. The antifungal spectra
of fluconazole and flucytosine are narrow (mainly against
C. albicans) and they are prone to develop drug resistance.
Literature survey reveals that various benzofuran amide de-
rivatives show antimicrobial as well as CNS activities, while little
work is reported on benzodifuran derivatives. In continuation of
our work on search for antimicrobial agents [18,19] we report
* Corresponding author. Tel.: þ91 265 2795552.
E-mail address: shubhangiss@rediffmail.com (S.S. Soman).
0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2014.01.026

78
J.N. Soni, S.S. Soman / European Journal of Medicinal Chemistry 75 (2014) 77e81
herein synthesis and antimicrobial evaluation of series of amide
derivatives of benzodifuran carboxylic acid.
group at C-5 and C-3 respectively. The doublet at
proton with J ¼ 1.6 Hz indicated proton at C-6 and two singlets at
7.84 and 7.92 for one proton each confirmed the linear ring fusion.
d 7.82 for one
d
In mass spectrum of 5, the peak at m/z at 231 indicated [M þ 1]þ
peak thus confirmed the formation of 5. Various amide derivatives
of benzodifuran carboxylic acid 6 were prepared by converting acid
5 into corresponding acid chloride by using oxalyl chloride and
then substituting it with various amines in presence of base like
triethylamine. The amides 6 now insoluble in NaHCO3 indicated the
2. Result and discussion
2.1. Chemistry
Pechmann reaction of resorcinol with ethyl acetoacetate in
presence of sulfuric acid gave 7-hydroxy-4-methyl-coumarin [20] 2
which was condensed [21] with chloroacetone in presence of
anhydrous K2CO3 and dry acetone gave 4-methyl-7-(2-
oxopropoxy)-coumarin 3. Bromination [22] of 3 using N-bromo-
succinimide in dry chloroform gave unexpected product 3-bromo-
4-methyl-7-(2-oxopropoxy)-coumarin 4. Cyclization [21] of 4 in
10% alkaline ethanol gave 3,5-dimethylbenzo[1,2-b:5,4-b0]difuran-
2-carboxylic acid 5 as major product. Acid 5 was converted into acid
chloride using oxalyl chloride and DMF in dry dichloromethane
which on substitution reaction with different amines in dry
dichloromethane in presence of base triethylamine gave corre-
sponding amides as shown in Scheme 1.
formation of 6 which was further confirmed by their IR, 1H NMR, 13
C
NMR, mass spectra and elemental analyses.
2.2. Biological evaluation
All the synthesized compounds were screened by Broth dilution
method [23] for their antibacterial activity against two Gram pos-
itive bacteria S. Aureus and B. Subtilis, two Gram negative bacteria
E. coli and P. Aeruginosa. They were also evaluated for their in vitro
antifungal activity against C. Albicans. Concentration of compounds
was ranging from 40 mg to 600 mg. The lowest concentrations of the
All the compounds were characterized by IR, 1H NMR, 13C NMR,
Elemental analyses and Mass spectra. IR spectrum of 3 exhibited
bands at 1710 and 1736 cmꢀ1 for ketone carbonyl and lactone
compounds that prevented visible growth are given in Table 1. It
was determined that the solvent had no antibacterial or antifungal
activities against any of the test microorganisms. Ciprofloxacin and
Flucanazole were used as standard drugs also tested under the
similar conditions for comparison. The results are summarized in
Table 1.
The minimum inhibitory concentration (MIC) of the synthesized
compounds against highly inhibited organisms is reported in
Table 1. Compounds 6c, 6h and 6j showed moderate effects against
Gram positive bacteria S. aureus while compound 6a, 6b, 6d, 6e, 6g
and 6k showed moderate activity against Gram positive bacteria
B. subtilis. Only compound 6e showed moderate activity against
Gram negative bacteria E. coli while all these compounds found less
group respectively. In 1H NMR of 3 doublet at
d
2.32 and triplet at
d
2.42 for three protons each confirmed the presence of CH3 group
at C-4 and COCH3 group. Singlet at
d
4.66 for two protons indi-
6.17 for one proton at C-3
confirmed the formation of 3. After bromination, in 1H NMR of 4,
the disappearance of peak at 6.17 indicated the presence of Br at
cated CH2 group and doublet at
d
d
C-3 which was further confirmed by its mass spectrum which
showed Mþ and [M þ 2]þ peaks at m/z 310 and 312 of equal
intensity.
In IR spectrum of 5, the bands at 3428 and 1680 cmꢀ1 indicated
presence of COOH group which was further confirmed by solubility
of 5 in saturated NaHCO3 solution and reprecipitation of it by HCl. In
active against P. aeruginosa (MIC 600 mg/ml).
It was observed that methyl or methoxy group at p- position of
amine showed moderate activity while pyrrolidine ring also
showed moderate activity against Gram positive bacteria S. aureus,
the 1H NMR spectrum of 5, the doublet at
d
2.27 (J ¼ 1.6 Hz) and
singlet at
d 2.60 for three protons each indicated presence of CH3
Scheme 1. Condition: (i) ethyl acetoacetate, H2SO4, 12 h (ii) chloroacetone, K2CO3, dry acetone, 6h (iii) N-bromosuccinimide, chloroform, 6 h (iv) 10% KOH in ethanol, 3 h (v)
dichloromethane, DMF, oxalyl chloride, 4 h (vi) dichloromethane, triethylamine, various amines, 12 h.

J.N. Soni, S.S. Soman / European Journal of Medicinal Chemistry 75 (2014) 77e81
79
Table 1
MIC determination of antibacterial and antifungal agent (
4.1.2. 4-Methyl-7-(2-oxopropoxy)-2H-chromen-2-one 3
m
g).
To the solution of 2 (5 g, 0.0289 mol) in dry acetone (50 ml) and
anhydrous potassium carbonate (13.98 g, 0.1011 mol), chlor-
oacetone (2.54 ml, 0.0318 mol) was added very slowly. Reaction
mixture refluxed for 6 h in water bath. Reaction mass poured into
crushed ice to obtain brown solid product, which was filtered, dried
and crystallized using ethanol to afford light brown solid (3.22 g,
49%); mp: 155e158 ꢁC (Lit. 157 ꢁC [21]); IR (KBr): 1736 (lactone),
Sr. no.
MIC (
S. aureus
(gm þve bacteria)
mg)
B. subtilis
E. coli
P. aeruginosa
C. albicans
(gm ꢀve bacteria)
(Fungi)
6a
6b
6c
6d
6e
6f
6g
6h
200
600
160
600
400
600
400
160
400
160
400
5
200
160
400
200
200
400
200
400
200
400
160
2
ꢂ600
400
ꢂ600
600
200
600
600
400
600
400
ꢂ600
15
ꢂ600
600
ꢂ600
ꢂ600
ꢂ600
600
ꢂ600
ꢂ600
ꢂ600
600
ꢂ600
600
ꢂ600
ꢂ600
ꢂ600
600
1710 (>C]O) cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 2.32 (3H, d,
J ¼ 2.4 Hz, CH3), 2.42 (3H, t, J ¼ 1.2, 2 Hz, CH3), 4.66 (2H, s, CH2), 6.17
(1H, d, J ¼ 1.2 Hz, ArH), 6.77 (1H, t, J ¼ 2.8, 4 Hz, ArH), 6.90 (1H, dd,
J ¼ 2.4, 8.8 Hz, ArH), 7.54 (1H, t, J ¼ 3.2, 5.6 Hz, ArH); 13C NMR
ꢂ600
600
(400 MHz, CDCl3):
d 18.7, 26.6, 72.9, 101.8, 112.3, 112.5, 114.4, 125.9,
6i
6j
6k
ꢂ600
600
600
152.4, 155.1, 160.5, 161.0, 203.7; MS m/z 177.0 [M þ 1e70]þ and 175
[M ꢀ 1e70]þ.
ꢂ600
Ciprofloxacin
Flucanazole
7.5
e
e
e
e
e
5
4.1.3. 3-Bromo-4-methyl-7-(2-oxopropoxy)-2H-chromen-2-one 4
Compound 3 (5 g, 0.0216 mol) dissolved in chloroform (50 ml)
and N-bromosuccinimide (4.24 g, 0.0238 mol) added in the re-
action flask. Reaction mixture refluxed for 6 h in water bath.
Excess solvent distilled under reduced pressure to obtain solid
which was washed with hot water thrice, filtered, dried and
crystallized using glacial acetic acid to obtain pale yellow solid
(4.21 g, 63%); mp: 189e193 ꢁC; IR (KBr): 1710 (>C]O), 1681
while all other amines except 6c, 6f, 6h and 6k when used showed
moderate activity against Gram positive bacteria B. subtilis.
All these amide derivatives of benzodifuran carboxylic acid
showed high MIC values (600 mg/ml) against Gram negative bac-
teria E. coli and P. aeruginosa, as well as fungus C. albicans.
(lactone) cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 2.33 (3H, s, CH3),
3. Conclusion
2.62 (3H, s, CH3), 4.67 (2H, s, CH2), 6.78 (1H, s, ArH), 6.94 (1H, d,
J ¼ 8.8 Hz, ArH), 7.61 (1H, d, J ¼ 8.8 Hz, ArH); 13C NMR (400 MHz,
In conclusion, eleven benzodifuran amides were synthesized
and screened for their antimicrobial activity as well as their MIC
against all test organisms. The presence of electron withdrawing
group at para position of amine showed moderate activity against
Gram positive bacteria B. subtilis (6b, 6d, 6e and 6g) while presence
of electron releasing group at para position of amine showed
moderate activity against S. aureus. All the synthesized amide de-
rivatives of benzodifuran carboxylic acid showed higher MIC values
DMSO-d6):
d 19.8, 26.6, 72.8, 101.7, 109.1, 113.5, 113.6, 127.6, 152.3,
153.4, 156.9, 161.5, 203.5; MS m/z 311 [M]þ, 312.9 [M þ 2]þ and
310.7 [M ꢀ 1]þ.
4.1.4. 3,5-Dimethylbenzo[1,2-b:5,4-b0]difuran-2-carboxylic acid 5
Compound 4 (5 g, 0.0161 mol) was dissolved in 50 ml 10%
ethanolic potassium hydroxide solution and refluxed for 3 h in
water bath. Excess ethanol distilled under reduced pressure and
reaction mixture poured into crushed ice, concentrated hydro-
chloric acid was slowly added until pH 2. The solid obtained was
filtered, dissolved in saturated solution of sodium bicarbonate,
filtered and reprecipitated with concentrated HCl. Then it was
filtered and dried. The crude product was purified using column
chromatography by using pet. ether:ethyl acetate (7:3) as eluent
gave light brown solid (1.55 g, 42%); mp: 260e264 ꢁC; IR (KBr):
3428 (OH), 3091, 3061, 2925, 2863, 2828 (CH3, CH), 1680 (>C]O)
(600
mg/ml) against Gram negative bacteria P. aeruginosa, and
fungus C. albicans. These compounds can also be explored for
orexin receptor antagonist activity.
4. Experimental
4.1. Chemistry
Reagent grade chemicals and solvents were purchased from
commercial supplier and used without purification. TLC was per-
formed on silica gel F254 plates (Merck). Silica gel (100e200 mesh)
was used for column chromatographic purification. Melting points
are uncorrected and were measured in open capillary tubes, using a
Rolex melting point apparatus. IR spectra were recorded as KBr
pellets on Perkin Elmer RX 1 spectrometer. 1H NMR and 13C NMR
spectral data were recorded on Advance Bruker 400 spectrometer
(400 MHz) with CDCl3 or DMSO-d6 as solvent and TMS as internal
standard. J values are in Hz. Elemental analyses were recorded on
Thermosinnigan Flash 11-12 series EA. Mass spectra were deter-
mined by ESI/MS, using a Shimadzu LCMS 2020 apparatus.
cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
2.59 (3H, s, CH3), 7.82 (1H, d, J ¼ 1.6 Hz, ArH), 7.84 (s, 1H, ArH), 7.92
d
2.27 (3H, d, J ¼ 1.2 Hz, CH3),
(1H, s, ArH); 13C NMR (400 MHz, DMSO-d6):
d
8.1, 9.7, 94.9, 111.2,
115.6, 125.2, 125.8, 126.9, 141.8, 155.4, 161.5; MS m/z 231.0 [M þ 1]þ
and 228.9 [M ꢀ 1]þ.
4.1.5. General procedure for 6
Compound 5 (0.5 g, 0.0022 mol) dissolved in dichloromethane
(25 ml) and 3-4 drops of DMF slowly added in reaction flask. Oxalyl
chloride (0.75 ml, 0.0088 mol) was added slowly in the reaction
mixture and stirred at room temperature for 3 h. Solvent distilled
under reduced pressure and dried under high vacuum to remove
oxalyl chloride. Reaction mass was dissolved in dichloromethane
(30 ml) and amine (1.1 eq.) along with catalytic amount of trie-
thylamine (0.64 ml, 0.0046 mol) were added and allowed to stir at
room temperature for overnight. Reaction mixture was washed
with saturated sodium bicarbonate (20 ml) and then with 10%
concentrated hydrochloride solution (20 ml). Solvent passed
through Na2SO4 and removed under reduced pressure to give solid.
Crude solid product was purified using column chromatography by
using Pet. Ether:Ethyl acetate (9:1) as eluent.
4.1.1. 7-Hydroxy-4-methyl-2H-chromen-2-one 2
Compound 1 (10 g, 0.0908 mol) was dissolved in ethyl acetoa-
cetate (12 ml, 0.095 mol) with constant shaking in reaction flask.
Concentrated sulfuric acid (20 ml) was added in 3e4 portions and
reaction mixture was kept overnight at room temperature. Reaction
mass poured into crushed ice to obtain pale yellow colored solid
which was filtered, dried and recrystallized using ethanol gave
yellow crystalline product (11.81 g, 74%); mp: 190e193 ꢁC (Lit.
185 ꢁC [20]).

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J.N. Soni, S.S. Soman / European Journal of Medicinal Chemistry 75 (2014) 77e81
4.1.5.1. 3,5-Dimethyl-N-(p-tolyl)benzo[1,2-b:5,4-b0]difuran-2-
carboxamide 6a. This compound obtained as white solid (0.24 g,
35%); mp: 192e194 ꢁC; IR (KBr): 3421 (NH), 3133, 3032, 2956, 2924
(2H, dd, J ¼ 0.4, 1.2 Hz, ArH), 8.39 (1H, s, NH); 13C NMR (400 MHz,
CDCl3):
d 8.1, 9.3, 94.4, 110.0, 115.6, 119.9, 124.0, 124.5, 126.3, 126.9,
129.1, 137.5, 142.3, 142.5, 151.7, 155.5, 158.1; Ele. Ana. for C19H15NO3
% Cal. C, 74.74; H, 4.95; N, 4.59, Found C, 74.84; H, 5.15; N, 4.65; MS
m/z 306.0 [M þ 1]þ.
(CH3, CH), 1670 (>C]O) cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 2.34
(3H, d, J ¼ 1.6 Hz, CH3), 2.37 (3H, s, CH3), 2.77 (3H, s, CH3), 7.23 (2H,
d, J ¼ 8 Hz, ArH), 7.48 (1H, d, J ¼ 1.2 Hz, ArH), 7.58 (1H, d, J ¼ 0.4 Hz,
ArH), 7.63 (2H, d, J ¼ 8.4 Hz, ArH), 7.68 (1H, s, ArH), 8.34 (1H, s, NH);
4.1.5.7. (3,5-Dimethylbenzo[1,2-b:5,4-b0]difuran-2-yl)(morpholino)
methanone 6g. This compound obtained as white solid (0.26 g,
40%); mp: 136e140 ꢁC; IR (KBr): 3059, 2955, 2917, 2859 (CH3, CH2,
13C NMR (400 MHz, CDCl3):
d 8.0, 9.2, 20.9, 94.4, 110.0, 115.5, 119.9,
123.7, 126.4, 126.8, 129.6, 134.1, 135.0, 142.3, 142.6, 151.7, 155.4,
158.0; Ele. Ana. for C20H17NO3 % Cal. C, 75.22; H, 5.37; N, 4.39, Found
C, 75.43; H, 5.28; N, 4.27; MS m/z 320.0 [M þ 1]þ.
CH), 1623 (>C]O) cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 2.32 (3H, d,
J ¼ 1.2 Hz, CH3), 2.56 (3H, s, CH3), 3.83 (8H, s, CH2), 7.46 (1H, d,
J ¼ 1.2 Hz, ArH), 7.53 (1H, d, J ¼ 0.4 Hz, ArH), 7.63 (1H, s, ArH); 13
C
4.1.5.2. 4-(3,5-Dimethylbenzo[1,2-b:5,4-b0]difuran-2-carboxamido)
benzoic acid 6b. This compound obtained as yellow solid (0.08 g,
9%); mp: > 300 ꢁC; IR (KBr): 3676 (OH),1694 (>C]O),1684 (>C]O)
NMR (400 MHz, CDCl3): d 8.1, 9.3, 67.1, 94.4, 109.4, 115.5, 122.2,
125.6, 126.6, 142.1, 143.7, 151.9, 155.0, 161.0; Ele. Ana. for C17H17NO4
% Cal. C, 68.21; H, 5.72; N, 4.68, Found C, 68.54; H, 5.67; N, 4.85; MS
m/z 300.0 [M þ 1]þ.
cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
2.28 (3H, s, CH3), 2.66 (3H, s,
CH3), 7.83 (2H, t, J ¼ 1.2, 2.8 Hz, ArH), 7.92e7.99 (5H, m, ArH), 10.69
(1H, s, COOH); 13C NMR (400 MHz, DMSO-d6):
8.1, 9.6, 95.0, 111.1,
d
4.1.5.8. (3,5-Dimethylbenzo[1,2-b:5,4-b0]difuran-2-yl)(pyrrolidin-1-
yl)methanone 6h. This compound obtained as yellowish solid
(0.235 g, 38%); mp: 108e110 ꢁC; IR (KBr): 3097, 2961, 2919, 2887
115.7, 120.2, 123.9, 126.1, 126.2, 127.0, 130.6, 143.0, 143.1, 143.5, 151.7,
155.2,158.6,167.4; Ele. Ana. for C20H15NO5 % Cal. C, 68.76; H, 4.33; N,
4.01, Found C, 68.43; H, 4.33; N, 3.69; MS m/z 252.9 [M þ 1e98]þ.
(CH3, CH2, CH), 1617 (>C]O) cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
1.99 (4H, s, CH2), 2.32 (3H, d, J ¼ 1.2 Hz, CH3), 2.66 (3H, s, CH3),
3.85 (4H, t, CH2), 7.45 (1H, d, J ¼ 1.2 Hz, ArH), 7.51 (1H, d, J ¼ 0.4 Hz,
ArH), 7.64 (1H, s, ArH); 13C NMR (400 MHz, CDCl3):
8.1, 9.5, 23.8,
4.1.5.3. N-(4-methoxyphenyl)-3,5-dimethylbenzo[1,2-b:5,4-b0]
difuran-2-carboxamide 6c. This compound obtained as light brown
solid (0.31 g, 43%); mp: 178e180 ꢁC; IR (KBr): 3419 (NH), 1671
d
26.6, 46.9, 48.0, 94.2, 109.4, 115.5, 122.4, 125.8, 126.4, 142.0, 151.9,
155.0; Ele. Ana. for C17H17NO3 % Cal. C, 72.07; H, 6.05; N, 4.94, Found
C, 71.89; H, 6.03; N, 5.14; MS m/z 284.0 [M þ 1]þ.
(>C]O) cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
2.33 (3H, d, J ¼ 1.2 Hz,
CH3), 2.76 (3H, s, CH3), 3.84 (3H, s, eOCH3), 6.95 (2H, dd, J ¼ 2,
6.8 Hz ArH), 7.48 (1H, d, J ¼ 1.2 Hz, ArH), 7.57 (1H, d, J ¼ 0.4 Hz, ArH),
7.64 (1H, d, J ¼ 2.4 Hz, ArH), 7.65 (1H, d, J ¼ 2 Hz, ArH), 6.67 (1H, s,
4.1.5.9. (3,5-Dimethylbenzo[1,2-b:5,4-b0]difuran-2-yl)(piperidin-1-
yl)methanone 6i. This compound obtained as yellowish solid
(0.215 g, 33%); mp: 110e112 ꢁC; IR (KBr): 3106, 2942, 2857 (CH3,
ArH), 8.30 (1H, s, NH); 13C NMR (400 MHz, CDCl3):
d 8.1, 9.2, 55.5,
94.4, 109.9, 114.2, 115.5, 121.7, 123.5, 126.4, 126.8, 130.6, 142.2, 142.7,
151.7, 155.4, 156.5, 158.0; Ele. Ana. for C20H17NO4 % Cal. C, 71.63; H,
5.11; N, 4.18, Found C, 71.40; H, 5.04; N, 4.04; MS m/z 336.0
[M þ 1]þ.
CH2, CH), 1635 (>C]O) cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 1.71
(6H, t, CH2), 2.32 (3H, d, J ¼ 1.2 Hz, CH3), 2.51 (3H, s, CH3), 3.69 (4H,
m, CH2), 7.45 (1H, d, J ¼ 1.6 Hz, ArH), 7.53 (1H, d, J ¼ 0.4 Hz, ArH),
7.60 (1H, s, ArH); 13C NMR (400 MHz, CDCl3):
d 8.1, 9.1, 24.7, 94.4,
4.1.5.4. N-(4-hydroxyphenyl)-3,5-dimethylbenzo[1,2-b:5,4-b0]
difuran-2-carboxamide 6d. This compound obtained as yellowish
solid (0.27 g, 39%); mp: 244e246 ꢁC; IR (KBr): 3418 (NH), 3372
109.1, 115.4, 120.0, 125.7, 126.4, 142.0, 144.7, 152.0, 154.7, 161.0; Ele.
Ana. for C18H19NO3 % Cal. C, 72.71; H, 6.44; N, 4.71, Found C, 72.44;
H, 6.29; N, 5.02; MS m/z 298.0 [M þ 1]þ.
(OH), 1644 (>C]O) cmꢀ1 1H NMR (400 MHz, DMSO-d6):
; d 2.28
(3H, d, J ¼ 1.2 Hz, CH3), 2.63 (3H, s, CH3), 6.74 (2H, dd, J ¼ 2.4, 6.8 Hz,
ArH), 7.58 (2H, dd, J ¼ 2, 6.8 Hz, ArH), 7.82 (2H, dd, J ¼ 0.4, 1.6 Hz,
ArH), 7.91 (1H, s, ArH), 9.38 (1H, s, NH), 10.19 (1H, s, OH); 13C NMR
4.1.5.10. N,N-Diethyl-3,5-dimethylbenzo[1,2-b:5,4-b0]difuran-2-
carboxamide 6j. This compound obtained as brown viscous liquid
(0.318 g, 51%); IR (Neat): 3108, 3062, 2973, 2932 (CH3, CH2, CH),
(400 MHz, DMSO-d6):
d
8.2, 9.5, 94.9,110.8,115.4,115.7,122.3,122.9,
1627 (>C]O) cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
1.30 (6H, t, J ¼ 7.2
126.4, 126.8, 130.3, 143.4, 143.7, 151.6, 154.3, 155.0, 158.0; Ele. Ana.
for C19H15NO4 % Cal. C, 71.02; H, 4.71; N, 4.36, Found C, 71.19; H,
4.69; N, 4.00; MS m/z 322.0 [M þ 1]þ and 319.8 [M-1]þ.
Hz, CH3), 2.33 (3H, d, J ¼ 1.2 Hz, CH3), 2.54 (3H, s, CH3), 3.56 (4H, q,
CH2), 7.45 (1H, d, J ¼ 1.2 Hz, ArH), 7.52 (1H, d, J ¼ 0.4 Hz, ArH), 7.61
(1H, d, J ¼ 0.8 Hz, ArH); 13C NMR (400 MHz, CDCl3):
d 8.1, 9.2, 94.3,
109.1, 115.5, 120.6, 125.8, 126.4, 141.9, 145.0, 151.8, 154.8, 161.6; MS
4.1.5.5. N-(4-chlorophenyl)-3,5-dimethylbenzo[1,2-b:5,4-b0]difuran-
2-carboxamide 6e. This compound obtained as yellowish solid
(0.38 g, 51%); mp: 190e192 ꢁC; IR (KBr): 3389 (NH), 1684 (>C]O)
m/z 286.0 [M þ 1]þ.
4.1.5.11. (3,4-Dihydroisoquinolin-2(1H)-yl)(3,5-dimethylbenzo[1,2-
b:5,4-b0]difuran-2-yl)methanone 6k. This compound obtained as
yellowish solid (0.235 g, 31%); mp: 96e98 ꢁC; IR (KBr): 3063, 3023,
2921, 2854 (CH3, CH2, CH), 1628 (>C]O) cmꢀ1; 1H NMR (400 MHz,
cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
2.34 (3H, d, J ¼ 1.2 Hz, CH3), 2.76
(3H, s, CH3), 7.37 (2H, dd, J ¼ 2, 6.8 Hz, ArH), 7.49 (1H, d, J ¼ 1.2 Hz,
ArH), 7.58 (1H, d, J ¼ 0.8 Hz, ArH), 7.69e7.72 (3H, m, ArH), 8.38 (1H,
s, NH); 13C NMR (400 MHz, CDCl3):
d
8.0, 9.3, 94.4, 110.1, 115.6, 121.1,
CDCl3):
d
2.33 (3H, d, J ¼ 1.6 Hz, CH3), 2.55 (3H, d, CH3), 3.06 (2H, S,
124.3, 126.2, 127.0, 129.1, 129.4, 136.1, 142.3, 142.4, 151.7, 155.6,
158.0; Ele. Ana. for C19H14ClNO3 % Cal. C, 67.16; H, 4.15; N, 4.12,
Found C, 66.89; H, 4.33; N, 3.98; MS m/z 340.0 [M þ 1]þ and 337.8
[M ꢀ 2]þ.
CH2), 3.98 (2H, d, CH2), 4.91 (2H, d, CH2), 7.22 (4H, d, J ¼ 3.6 Hz,
ArH), 7.47 (1H, d, J ¼ 1.6 Hz, ArH), 7.56 (1H, s, ArH), 7.64 (1H, s, ArH);
13C NMR (400 MHz, CDCl3):
d 8.1, 9.3, 94.5, 109.3, 115.5, 121.7, 125.7,
126.5, 126.7, 142.1, 144.3, 152.0, 154.9; Ele. Ana. for C22H19NO3 % Cal.
C, 76.50; H, 5.54; N, 4.06, Found C, 76.37; H, 5.61; N, 4.20; MS m/z
346.0 [M þ 1]þ.
4.1.5.6. 3,5-Dimethyl-N-phenylbenzo[1,2-b:5,4-b0difuran-2-
carboxamide 6f. This compound obtained as white solid (0.28 g,
42%); mp: 182e184 ꢁC; IR (KBr): 3421 (NH), 1669 (>C]O) cmꢀ1; 1H
Acknowledgments
NMR (400 MHz, CDCl3):
CH3), 7.17e7.20 (1H, m, ArH), 7.41 (2H, m, ArH), 7.48 (1H, d,
J ¼ 1.6 Hz, ArH), 7.59 (1H, d, J ¼ 0.4 Hz, ArH), 7.69 (1H, s, ArH), 7.75
d
2.34 (3H, d, J ¼ 1.6 Hz, CH3), 2.77 (3H, s,
The authors are thankful to The Head, Department of Chemistry,
Faculty of Science, The M.S. University of Baroda for providing

J.N. Soni, S.S. Soman / European Journal of Medicinal Chemistry 75 (2014) 77e81
81
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Appendix A. Supplementary data
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files and InChIKeys of the most important compounds described in
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