Microwave-assisted synthesis of novel benzodifuran-based bis(N-(het)arylthiazol-2-amine) derivatives and their antibacterial and antimycobacterial activities

Article abstract of DOI:10.1007/s10593-018-2323-x

[Figure not available: see fulltext.] A new series of 4,4'-(3,5-diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)bis(N-(het)arylthiazol-2-amine) derivatives have been synthesized from 1,1'-(3,5-diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)diethanone O,O'-

Full text of DOI:10.1007/s10593-018-2323-x

DOI 10.1007/s10593-018-2323-x
Chemistry of Heterocyclic Compounds 2018, 54(6), 658–663
Microwave-assisted synthesis of novel benzodifuran-based
bis(N-(het)arylthiazol-2-amine) derivatives
and their antibacterial and antimycobacterial activities
N. H. Kumar Baba1,2, Dongamanti Ashok3*, Boddu Ananda Rao3,
Madderla Sarasija4, Nandula Y. S. Murthy5
1 Department of Chemistry, Jawaharlal Nehru Technological University,
Hyderabad-500085, Telangana, India; e-mail: nandurihanu@gmail.com
2 Chemveda Life Sciences India Pvt. Ltd., I.D.A. Uppal,
Hyderabad-500039, Telangana, India
3 Green and Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University,
Hyderabad-500007, Telangana, India; e-mail: ashokdou@gmail.com
4 Department of Chemistry, Satavahana University,
Karimnagar-505001, Telangana, India; e-mail: lionsarasija@gmail.com
5 Department of Chemistry, Anurag Group of Institutions,
Hyderabad-500088, Telangana, India; e-mail: nysrim@yahoo.co.in
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(6), 658–663
Submitted January 18, 2018
Accepted March 17, 2018
A new series of 4,4'-(3,5-diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)bis(N-(het)arylthiazol-2-amine) derivatives have been synthe-
sized from 1,1'-(3,5-diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)diethanone O,O'-diacetyl dioxime and substituted isothiocyanates
under conventional and microwave irradiation conditions. The obtained products were subjected to in vitro antibacterial and
antimycobacterial activity tests. Some of the compounds exhibited noteworthy antibacterial activity against Bacillus subtilis (+ve) and
Pseudomonas aeruginosa (-ve) strains and antimycobacterial activity against Mycobacterium bovis strain.
Keywords: benzodifuran, thiazole, antibacterial, antimycobacterial, microwave irradiation.
Benzofurans are a significant class of oxygen-containing
heterocyclic compounds that have potential biological
activities, such as antibacterial,1 antimicrobial,2 antitumor,3
antiproliferative,4 and antimalarial5 activity. In addition,
benzofurans with variously substituted heterocyclic rings
connected directly at the C-2 position demonstrate sub-
stantial biological activities.6 Heterocyclic compounds
having nitrogen and sulfur atoms play an important role in
medicinal chemistry, for example, derivatives of such five-
membered heterocycles have shown an appreciable range
of biological activities.7 Additional studies on thiazole
molecule have been conducted in organic and pharma-
ceutical chemistry.8 Particularly, compounds based on
thiazol-2-amine structure exhibit significant antimyco-
bacterial9 and antibacterial10 activities. Mycobacterium
tuberculosis complexes (MTC) include a set of myco-
bacterial strains like M. tuberculosis, M. bovis,
M. africanum, etc. Drug-resistant M. tuberculosis has
become a matter of concern for the public health due to the
lack of newer antibacterial agents for the treatment of
tuberculosis. Therefore, it is indispensable to discover a
new lead compound against these drug-resistant strains.
Research on antimicrobial agents is a herculean task, as the
microorganisms continuously develop resistance to
0009-3122/18/54(6)-0658©2018 Springer Science+Business Media, LLC
658

Chemistry of Heterocyclic Compounds 2018, 54(6), 658–663
O
Scheme 1
Cl
Me
K2CO3
PhCHO
KOH
HO
Me
OH
O
HO
O
OH
O
HO
O
OH
O
H2, Pd/C
Me
Ph
Ph
Ph
Ph
EtOAc, rt, 3 h
95%
Acetone, , 6 h
EtOH, rt, 12 h
90%
O
1
2
3
Me
O
Me
O
HON
Me
NOH
Me
AcON
Me
NOAc
Me
O
O
O
O
O
O
Ac2O
NH2OH·HCl
EtOH, MW
100°C, 30 min
92%
EtOH, MW
100°C, 30 min
96%
Ph
Ph
Ph
Ph
Ph
Ph
4
5
6
ArN=C=S
7a h
–
Method II
F
Method I
1,4-Dioxane
, 1218 h
7080%
1,4-Dioxane
MW
15–25 min
7990%
CuI
(20 mol %)
Cs2CO3
8a Ar =
, 8b Ar =
, 8c Ar =
, 8d Ar =
Cl
F
F
O
O
Me
S
S
Br
Ar
Ar
N
N
N
H
N
H
8e Ar =
, 8f Ar =
, 8g Ar =
, 8h Ar =
Me
N
O
N
N
Ph
Ph
8a–h
Table 1. Yields of the synthesized compounds 8a–h*
antimicrobial compounds and infections caused by
M. tuberculosis strains are rare and often incurable.
Investigation of the interaction of biologically active
molecules with DNA is a critical step in the development
of new medicines,11 and various DNA-targeting com-
pounds are presently available as approved antimicrobial
drugs.12 However, major unpleasant effects and high
clinical expenditure associated with these drugs have
encouraged investigations of new antimicrobial agents.13
As a part of green chemistry, microwave-assisted organic
synthesis (MAOS) has gained attention in organic and
medicinal chemistry. Furthermore, advantages of the
synthesis of thiazol-2-amine derivatives via copper-catalyzed
oxidative coupling of oxime acetates and variously
substituted isothiocyanates have been demonstrated in
comparison to conventional synthetic methods.14
In view of the pharmacological importance of thiazol-
2-amine derivatives and in continuation of our previous
efforts,15 we planned to perform a symmetrical construction
of thiazole ring at each C-2 position of benzodifuran using
4,6-diacetylresorcinol (DAR) (1) as the starting material
(Scheme 1). Herein, we present the synthesis of novel
4,4'-(3,5-diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)bis-
(N-(het)arylthiazol-2-amine) derivatives 8a–h by both
conventional and microwave-assisted methods and investi-
gation of their in vitro antibacterial and antimycobacterial
activities.
Method I**
Method II***
Com-
pound
Time, h
Yield, %
78
Time, min
Yield, %
86
15
18
16
16
12
18
16
16
15
20
20
20
15
25
20
20
8a
8b
8c
8d
8e
8f
76
82
74
84
72
79
80
90
70
85
75
86
8g
8h
77
89
* Reaction conditions: O,O-diacetyl dioxime 6 (560 mg, 1 mmol),
isothiocyanate 7a–h (2 mmol), CuI (39 mg, 20 mol %), Cs2CO3 (163 mg,
0.5 mmol), 1,4-dioxane (10 ml).
** Reflux.
*** Microwave irradiation, 100°C.
material 1 was treated with two equivalents of benz-
aldehyde in 50% aq KOH solution. Furthermore, the
resulting bis(chalcone) 2 was hydrogenated using 10% Pd/C in
EtOAc to obtain product 3 which was then treated with
chloroacetone in acetone in the presence of K2CO3. The
resulting compound 4 was used in reaction with
NH2OH·HCl in EtOH under microwave irradiation (MW)
to afford dioxime 5, which was subsequently treated with
Ac2O in EtOH under MW. Reaction of the respective
O,O-diacetyl dioxime 6 and substituted isothiocyanates 7a–h
in the presence of Cs2CO3 and 20 mol % CuI in
1,4-dioxane under MW ensured the formation of the
Compounds 8a–h were prepared from DAR (1) which,
in turn, was synthesized according to a previously
described procedure16 (Scheme 1). First, the starting
659

Chemistry of Heterocyclic Compounds 2018, 54(6), 658–663
desired final compounds 8a–h in high yields (method II).
The use of conventional heating for the same reaction
(method I) resulted in lower yields of the products (Table 1).
The structures of the newly synthesized compounds 3–6
and 8a–h were established by spectroscopic (FTIR, 1H and
13C NMR spectroscopy, mass spectrometry) and elemental
analysis. The FTIR spectrum of compound 8a revealed
three bands at 3380 (N–H), 1600 (C=N), and 1535 cm–1
1
(C=C). The H and 13C NMR spectra of the representative
compound 8a contained characteristic signals of thiazole
ring proton at 7.24 ppm and the respective carbon at
105.1 ppm. Finally, the mass spectrum of product 8a exhi-
bited a peak at 715, which corresponded to its [M+H]+ ion.
The in vitro antimicrobial activities of the synthesized
novel products 8a–h at the concentration of 50 µg/ml were
investigated by the cup-plate agar diffusion method against
four pathogenic representative microorganisms: Staphylo-
coccus aureus (MTCC 737), Escherichia coli (MTCC
443), Bacillus subtilis (MTCC 441), and Pseudomonas
aeruginosa (MTCC 741) using norfloxacin and ofloxacin
as the standard drugs. It was found that difuran derivatives
8b,e,g (inhibition zone >10 mm) showed excellent growth
inhibition against Gram-positive B. subtilis strain compared
to norfloxacin (10 mm) (Fig. 1). Compounds 8b,e contain
ortho-substituted aromatic rings with electronegative F and
Br atoms, respectively. Thereby, electron-withdrawing
groups at ortho position increased the activity of the
investigated compounds. In the case of compound 8g,
which also exhibited high activity, pyridine was substituted
at the C-2 position with a methyl group. Among other
difuran derivatives 8a–g and standard ofloxacin, compound
8h with electron-donating methyl group at the C-4 position
of the pyridine ring was exceedingly potent against Gram-
negative bacteria strain P. aeruginosa. Furthermore, the
antibacterial effects of the remaining compounds 8a,c,d,f
on the growth inhibition of the tested bacterial strains were
moderate to low. Product 8e also exhibited excellent in
vitro antimycobacterial activity against M. bovis strain,
while compound 8g showed a moderate zone of inhibition
in comparison with the standard drugs (isoniazid +
rifampicin) (Fig. 2).
Figure 1. A graphical comparison of the antibacterial activity of
the newly synthesized compounds 8a–h and standard drugs nor-
In conclusion, novel symmetrical benzodifuran-based
bis(N-(het)arylthiazol-2-amine) derivatives have been synthe-
sized in copper-catalyzed oxidative coupling of 1,1'-(3,5-di-
phenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)diethanone
O,O-diacetyl dioxime and variously substituted isothio-
cyanates under both conventional and microwave irra-
diation conditions. The application of microwave irradia-
tion allowed to reduce the reaction time and increase the
yield of products, as well as promoted the two-step
synthesis of the starting material O,O-diacetyl dioxime.
The obtained benzodifuran-based bis(N-(het)arylthiazol-
2-amine) derivatives were evaluated for their antibacterial
and antimycobacterial activities. Some of these compounds
showed noteworthy activity against B. subtilis (+ve) and
P. aeruginosa (–ve) strains and antimycobacterial activity
against M. bovis strain. The presence of F and Br atoms at
ortho position of aromatic rings increased the antimyco-
bacterial and antibacterial activity of the investigated
Figure 2. A graphical comparison of the antimycobacterial activi-
ty of the newly synthesized compounds 8a–h and standard drugs
compounds against M. bovis and B. subtilis strains,
respectively, and the compound with a methyl group at the
C-4 position of the pyridine ring was exceedingly potent
against P. aeruginosa strain. The results of these studies
will likely provide a basis for the design of a new series of
promising benzodifuran-based thiazole derivatives. Further
development of novel benzodifuran-based bis(N-(het)-
arylthiazol-2-amine) analogs and investigation of their
biological activities are in progress.
Experimental
IR spectra were recorded on a Shimadzu FTIR-8400S
1
spectrometer. H and 13C NMR spectra (300 and 75 MHz,
respectively) were acquired on a Bruker Avance 300
spectrometer in CDCl3 (compounds 3 and 4) or DMSO-d6
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Chemistry of Heterocyclic Compounds 2018, 54(6), 658–663
(compounds 5, 6, and 8a–h) using tetramethylsilane (TMS)
subjected to microwave irradiation at 100°C for 30 min.
The reaction mixture was then quenched with crushed ice.
The resulting solid was filtered off, washed with Et2O
(10 ml), and dried under reduced pressure. Yield 441 mg
(92%), off-white solid, mp 216–218°С. IR spectrum, ν, cm–1:
3095 (C–H Ar), 3027 (O–H), 2927 (CH3), 1673 (C=N),
1579 (C=C). 1Н NMR spectrum, δ, ppm (J, Hz): 2.19 (6H,
s, CH3); 2.90 (4H, t, J = 7.6, CH2CH2Ph); 3.20 (4Н, t,
J = 7.6, CH2CH2Ph); 7.13–7.20 (2Н, m, H Ar); 7.24–7.32
(8H, m, H Ar); 7.41 (1Н, s, H-8); 7.74 (1H, s, H-4); 11.61
(2H, s, OH). 13C NMR spectrum, δ, ppm: 11.5; 25.6; 34.9;
93.8; 109.5; 117.1; 125.8; 126.1; 128.0; 128.5; 141.6;
148.0; 148.2; 151.6. Mass spectrum, m/z (Irel, %): 481
[M+H]+ (100). Found, %: C 74.94; H 5.83; N 5.85.
C30H28N2O4. Calculated, %: C 74.98; H 5.87; N 5.83.
1,1'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)-
diethanone O,O-diacetyl dioxime (6). A solution of
1,1'-(3,5-diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)di-
ethanone dioxime (5) (480 mg, 1 mmol) and Ac2O
(0.19 ml, 2 mmol) in EtOH (10 ml) was placed into a
microwave tube and subjected to microwave irradiation at
100°C for 30 min. The reaction mixture was then quenched
with crushed ice. The resulting solid was filtered off,
triturated with MeOH (10 ml), repeatedly filtered off, and
dried under reduced pressure. Yield 540 mg (96%), white
solid, mp 192–194°С. IR spectrum, ν, cm–1: 3018 (C–H Ar),
2920 (CH3), 1767 (C=O), 1622 (C=N), 1579 (C=C).
1Н NMR spectrum, δ, ppm (J, Hz): 2.30 (6H, s, CH3CO2);
2.40 (6H, s, CH3); 2.99 (4H, t, J = 7.6, CH2CH2Ph); 3.33
(4Н, t, J = 7.6, CH2CH2Ph); 7.13–7.20 (2Н, m, H Ar); 7.21
(1H, s, H-8); 7.23–7.31 (8H, m, H Ar); 7.50 (1Н, s, H-4).
13C NMR spectrum, δ, ppm: 13.4; 19.8; 26.8; 35.4; 94.1;
110.6; 122.0; 126.0; 126.6; 128.2; 128.8; 141.9; 146.0; 153.5;
156.5; 168.4. Mass spectrum, m/z (Irel, %): 565 [M+H]+
(25), 505 (100). Found, %: C 72.28; H 5.67; N 4.98.
C34H32N2O6. Calculated, %: C 72.32; H 5.71; N 4.96.
Synthesis of benzodifuran derivatives 8a–h (General
method). Substituted isothiocyanate 7a–h (2 mmol), CuI
(39 mg, 20 mol %), and Cs2CO3 (163 mg, 0.5 mmol) were
added to a stirred solution of 1,1'-(3,5-diphenethylbenzo-
[1,2-b:5,4-b']difuran-2,6-diyl)diethanone O,O-diacetyl di-
oxime (6) (560 mg, 1 mmol) in 1,4-dioxane (10 ml). The
reaction was performed according to method I or II. After
completion of the reaction, the reaction mixture was con-
centrated under reduced pressure, and the obtained residue
was subjected to column chromatography (basic alumina,
gradient elution with EtOAc–hexane, 30–40%).
as an internal standard. Mass spectra were recorded on a
Shimadzu LCMS-2020 spectrometer/Agilent Technologies
6420 Triple Quad LC/MS (ESI). Elemental analyses were
performed on a Carlo Erba EA1106 elemental analyzer.
Melting points were determined in open capillary tubes on
a Stuart SMP3 melting point apparatus and are uncorrected.
Microwave reactions were carried out in an Anton Paar
Monowave 300 microwave reactor (2.45 GHz) with a
maximum delivered power of 850 W in 10 W increments
(pulsed irradiation). TLC was performed on silica gel-
60
coated Merck
F
plates, and visualization was achieved
254
by exposure to I2 vapor and UV light (254 nm).
All chemicals were purchased from Sigma-Aldrich, TCI,
and Alfa Aesar. Substituted isothiocyanates 7a–h17 and
compound 218 were synthesized as described previously.
1,1'-(4,6-Dihydroxy-1,3-phenylene)bis(3-phenylpropan-
1-one) (3). 10% Pd/C (400 mg, 20%) was added to a stirred
solution of bis(chalcone) 2 (2.00 g, 5.40 mmol) in EtOAc
(20 ml) in Parr hydrogenation bottle, and the bottle was
charged with H2 (30 psi). The reaction mixture was shaken
at room temperature for 3 h. The catalyst was then filtered
off using a Celite pad. The filtrate was concentrated, and
the residue was purified by flash column chromatography
(silica gel, gradient elution with EtOAc–hexane, 10–20%).
Yield 1.92 g (95%), white solid, mp 88–90°C. IR spectrum,
1
ν, cm–1: 3023 (O–H), 1653 (C=O). Н NMR spectrum,
δ, ppm (J, Hz): 3.04 (4Н, t, J = 7.4, CH2CH2CO); 3.19 (4Н,
t, J = 7.4, CH2CH2CO); 6.42 (1Н, s, H-5); 7.20–7.34 (10H,
m, H Ar); 8.04 (1H, s, H-2); 12.98 (2H, s, OH). 13C NMR
spectrum, δ, ppm: 30.2; 39.6; 105.0; 113.1; 126.5; 128.4;
128.7; 134.6; 140.4; 168.7; 203.5. Mass spectrum, m/z (Irel, %):
375 [M+H]+ (100), 130 (30). Found, %: C 76.94; H 5.89.
C24H22O4. Calculated, %: C 76.99; H 5.92.
1,1'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)-
diethanone (4).
A mixture of 1,1'-(4,6-dihydroxy-
1,3-phenylene)bis(3-phenylpropan-1-one) (3) (3.74 g,
10 mmol), chloroacetone (1.8 ml, 22 mmol), and K2CO3
(4.14 g, 30 mmol) in dry acetone (50 ml) was refluxed for
6 h. The reaction mixture was then quenched with crushed
ice and extracted with EtOAc (2×50 ml). The combined
organic layers were dried over anhydrous Na2SO4,
concentrated, and purified by column chromatography
(silica gel, gradient elution with EtOAc–hexane, 20–30%).
Yield 4.05
g (90%), white solid, mp 138–140°C.
IR spectrum, ν, cm–1: 3087 (C–H Ar), 2923 (CH3), 1670
1
(C=O), 1571 (C=C). Н NMR spectrum, δ, ppm (J, Hz):
2.62 (6H, s, CH3); 2.95 (4Н, t, J = 7.9, CH2CH2Ph); 3.36
(4Н, t, J = 7.9, CH2CH2Ph); 7.16–7.27 (11H, m, H Ar);
7.56 (1H, s, H-4). 13C NMR spectrum, δ, ppm: 26.4; 27.8;
35.6; 94.9; 113.6; 126.2; 126.4; 127.8; 128.3; 128.6; 141.3;
148.8; 154.3; 190.8. Mass spectrum, m/z (Irel, %): 451
[M+H]+ (100). Found, %: C 79.94; H 5.78. C30H26O4.
Calculated, %: C 79.98; H 5.82.
1,1'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)-
diethanone dioxime (5). A solution of 1,1'-(3,5-di-
phenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)diethanone (4)
(450 mg, 1 mmol) and NH2OH·HCl (139 mg, 2 mmol) in
EtOH (10 ml) was placed into a microwave tube and
Method I. The reaction mixture was refluxed for 12–18 h
(Table 1).
Method II. The reaction mixture was placed into a
microwave tube and subjected to microwave irradiation at
100°C for 15–25 min (Table 1).
4,4'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-
diyl)bis(N-phenylthiazol-2-amine) (8a). Off-white solid,
mp 170–172°С. IR spectrum, ν, cm–1: 3380 (N–H), 1600
1
(C=N), 1535 (C=C), 1350 (C–N), 748 (C–S). Н NMR
spectrum, δ, ppm (J, Hz): 2.96–3.10 (4H, m, CH2CH2Ph);
3.48–3.64 (4Н, m, CH2CH2Ph); 6.90 (2H, t, J = 7.4, H Ar);
7.14 (4Н, t, J = 7.4, H Ar); 7.18–7.37 (14H, m, H thiazole,
661

Chemistry of Heterocyclic Compounds 2018, 54(6), 658–663
H Ar); 7.39 (1Н, s, H-8); 7.67 (2H, d, J = 7.4, H Ar); 7.72
solid, mp 206–208°С. IR spectrum, ν, cm–1: 3379 (N–H),
1590 (C=N), 1535 (C=C), 1353 (C–N), 744 (C–S).
1Н NMR spectrum, δ, ppm (J, Hz): 2.91 (4H, t, J = 7.4,
CH2CH2Ph); 3.37–3.48 (4Н, m, CH2CH2Ph); 6.97 (2H, t,
J = 7.6, H Ar); 7.08 (2H, t, J = 7.6, H Ar); 7.18–7.23 (10H,
m, H Ar); 7.28 (2H, s, H thiazole); 7.34 (1H, s, H-8); 7.65
(2H, t, J = 7.6, H Ar); 7.70 (1H, s, H-4); 8.18 (2H, d,
J = 7.6, H Ar); 9.69 (2H, s, NH). 13C NMR spectrum,
δ, ppm: 24.9; 35.5; 93.4; 106.5; 109.1; 113.7; 115.6; 122.3;
124.4; 125.7; 126.3; 128.0; 128.2; 128.4; 132.8; 138.6;
141.6; 141.8; 146.6; 151.8; 164.5. Mass spectrum, m/z (Irel, %):
873 [M]+ (100). Found, %: C 60.51; H 3.66; N 6.44.
C44H32Br2N4O2S2. Calculated, %: C 60.56; H 3.70; N 6.42.
4,4'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-
diyl)bis[N-(morpholin-4-ylphenyl)thiazol-2-amine] (8f).
Off-white solid, mp 218–220°С. IR spectrum, ν, cm–1:
3293 (N–H), 1601 (C=N), 1537 (C=C), 1350 (C–N), 746
(1H, s, H-4); 10.38 (2H, s, NH). 13C NMR spectrum,
δ, ppm: 24.6; 35.5; 93.4; 105.1; 109.1; 115.6; 116.7; 121.1;
125.8; 126.3; 128.1; 128.4; 128.8; 140.8; 141.5; 142.3;
146.7; 151.8; 163.6. Mass spectrum, m/z (Irel, %): 715
[M+H]+ (100). Found, %: C 73.88; H 4.74; N 7.86.
C44H34N4O2S2. Calculated, %: C 73.92; H 4.79; N 7.84.
4,4'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-
diyl)bis[N-(2-fluorophenyl)thiazol-2-amine] (8b). Off-
white solid, mp 108–110°С. IR spectrum, ν, cm–1: 3434 (N–H),
1620 (C=N), 1542 (C=C), 1349 (C–N), 745 (C–S).
1Н NMR spectrum, δ, ppm (J, Hz): 2.94–3.06 (4H, m,
CH2CH2Ph); 3.44–3.56 (4Н, m, CH2CH2Ph); 6.76 (2H, t,
J = 7.9, H Ar); 6.82–7.01 (2H, m, H Ar); 7.16–7.37 (15Н,
m, H thiazole, H Ar); 7.70 (1H, s, H-4); 8.42 (2H, t, J = 7.9,
H Ar); 10.20 (2H, s, NH). 13C NMR spectrum, δ, ppm
2
(J, Hz): 24.6; 35.5; 93.4; 106.3; 109.1; 115.0 (d, JCF = 18.6,
3
1
C Ar); 115.5; 121.9 (d, JCF = 6.5, C Ar); 124.3; 125.7 (d,
(C–S). Н NMR spectrum, δ, ppm (J, Hz): 2.85–2.99 (4H,
2JCF = 18.6, C Ar); 125.8; 126.3; 128.0; 128.2 (d, 3JCF = 12.6,
m, CH2CH2Ph); 3.05–3.11 (8Н, m, NCH2CH2O); 3.48–
3.63 (4H, m, CH2CH2Ph); 3.68–3.79 (8H, m, NCH2CH2O);
6.59 (4H, d, J = 7.7, H Ar); 7.13–7.38 (12H, m, H thiazole,
H Ar); 7.43 (1H, s, H-8); 7.51 (4H, d, J = 7.7, H Ar); 7.70
(1H, s, H-4); 10.13 (2H, s, NH). 13C NMR spectrum,
δ, ppm: 24.0; 35.3; 49.2; 66.0; 93.4; 105.1; 109.1; 115.2;
115.8; 117.9; 124.8; 125.7; 128.1; 128.3; 130.4; 133.6;
141.6; 142.3; 145.8; 151.8; 163.9. Mass spectrum, m/z (Irel, %):
885 [M+H]+ (30), 668 (100). Found, %: C 70.52; H 5.42;
N 9.50. C52H48N6O4S2. Calculated, %: C 70.56; H 5.47;
N 9.49.
4,4'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-
diyl)bis[N-(6-methylpyridin-2-yl)thiazol-2-amine] (8g).
Off-white solid, mp 160–162°С. IR spectrum, ν, cm-1: 3259
(N–H), 1608 (C=N), 1537 (C=C), 1328 (C–N), 734 (C–S).
1Н NMR spectrum, δ, ppm (J, Hz): 2.56 (6H, s, CH3); 3.01
(4H, t, J = 7.2, CH2CH2Ph); 3.54 (4H, t, J = 7.2,
CH2CH2Ph); 6.82 (2H, d, J = 7.7, H pyridine); 6.99 (2H, d,
J = 7.7, H pyridine); 7.15 (2H, t, J = 7.4, H Ar); 7.26 (4H,
d, J = 7.4, H Ar); 7.31 (2H, s, H thiazole); 7.35 (4H, d,
J = 7.4, H Ar); 7.42 (1H, s, H-8); 7.61 (2H, t, J = 7.7,
H pyridine); 7.73 (1H, s, H-4); 11.31 (2H, s, NH).
13C NMR spectrum, δ, ppm: 23.4; 25.0; 35.4; 93.7; 107.6;
108.3; 109.2; 115.1; 115.3; 125.8; 126.3; 128.1; 128.6;
138.2; 140.9; 141.6; 147.1; 151.3; 153.3; 155.1; 159.9.
Mass spectrum, m/z (Irel, %): 745 [M+H]+ (100). Found, %:
C 70.90; H 4.83; N 11.30. C44H36N6O2S2. Calculated, %:
C 70.94; H 4.87; N 11.28.
4,4'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-
diyl)bis[N-(4-methylpyridin-2-yl)thiazol-2-amine] (8h).
Brown solid, mp 184–186°С. IR spectrum, ν, cm–1: 3200
(N–H), 1616 (C=N), 1536 (C=C), 1303 (C–N), 744 (C–S).
1Н NMR spectrum, δ, ppm (J, Hz): 2.30 (6H, s, CH3); 3.01
(4H, t, J = 7.6, CH2CH2Ph); 3.53 (4H, t, J = 7.6,
CH2CH2Ph); 6.81 (2H, d, J = 5.1, H pyridine); 7.01 (2H, s,
H pyridine); 7.15 (2H, t, J = 7.4, H Ar); 7.24 (4H, d,
J = 7.4, H Ar); 7.28 (2H, s, H thiazole); 7.35 (4H, d,
J = 7.4, H Ar); 7.42 (1H, s, H-8); 7.72 (1H, s, H-4); 8.19
(2H, t, J = 5.1, H pyridine); 11.30 (2H, s, NH). 13C NMR
spectrum, δ, ppm: 20.7; 25.1; 35.4; 93.4; 108.2; 109.1;
110.7; 115.3; 117.6; 125.8; 126.3; 128.1; 128.6; 140.9;
1
C Ar); 141.2; 141.5; 141.9; 146.6; 151.5 (d, JCF = 243.7,
C Ar); 151.8; 163.6. Mass spectrum, m/z (Irel, %): 751
[M+H]+ (48), 102 (100). Found, %: C 70.33; H 4.27;
N 7.48. C44H32F2N4O2S2. Calculated, %: C 70.38; H 4.30;
N 7.46
4,4'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-
diyl)bis[N-(4-fluorophenyl)thiazol-2-amine] (8c). Off-white
solid, mp 102–104°С. IR spectrum, ν, cm–1: 3389 (N–H),
1614 (C=N), 1538 (C=C), 1349 (C–N), 753 (C–S).
1Н NMR spectrum, δ, ppm (J, Hz): 3.03 (4H, t, J = 7.2,
CH2CH2Ph); 3.54 (4Н, t, J = 7.2, CH2CH2Ph); 6.82 (4H, t,
J = 8.5, H Ar); 7.22–7.32 (12H, m, H thiazole, H Ar); 7.43
(1H, s, H-8); 7.64 (4H, dd, J = 8.5, J = 4.7, H Ar); 7.71
(1H, s, H-4); 10.39 (2H, s, NH). 13C NMR spectrum,
δ, ppm (J, Hz): 24.2; 35.3; 93.4; 105.0; 109.2; 115.3 (d,
2JCF = 9.9, C Ar); 115.7; 118.2 (d, 3JCF = 7.1, C Ar); 125.8;
4
126.3; 128.1; 128.3; 137.3 (d, JCF = 2.2, C Ar); 141.6;
1
142.2; 146.6; 151.8; 156.7 (d, JCF = 237.6, C Ar); 163.6.
Mass spectrum, m/z (Irel, %): 751 [M+H]+ (100). Found, %:
C 70.34; H 4.26; N 7.49. C44H32F2N4O2S2. Calculated, %:
C 70.38; H 4.30; N 7.46.
4,4'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-
diyl)bis[N-(3-chloro-4-fluorophenyl)thiazol-2-amine] (8d).
Off-white solid, mp 140–142°С. IR spectrum, ν, cm–1:
3384 (N–H), 1604 (C=N), 1535 (C=C), 1349 (C–N), 745
1
(C–S). Н NMR spectrum, δ, ppm (J, Hz): 2.98 (4H, t,
J = 7.2, CH2CH2Ph); 3.44–3.53 (4Н, m, CH2CH2Ph); 6.99
(2H, t, J = 9.1, H Ar); 7.13–7.22 (10H, m, H Ar); 7.24 (2H,
s, H thiazole); 7.46–7.58 (3H, m, H Ar); 7.61 (1H, s, H-4);
7.94 (2H, t, J = 6.4, H Ar); 10.54 (2H, s, NH). 13C NMR
spectrum, δ, ppm (J, Hz): 24.5; 35.5; 93.1; 105.3; 109.0;
2
3
115.6; 116.6 (d, JCF = 21.4, C Ar); 117.9 (d, JCF = 6.7,
3
2
C Ar); 119.1 (d, JCF = 7.7, C Ar); 124.4 (d, JCF = 18.7,
C Ar); 125.7; 127.9; 128.3; 137.9; 141.4; 141.7; 142.2;
1
146.4; 151.7; 151.8 (d, JCF = 239.8, C Ar); 163.1. Mass
spectrum, m/z (Irel, %): 819 [M]+ (30), 232 (100). Found, %:
C 64.43; H 3.67; N 6.85. C44H30Cl2F2N4O2S2. Calculated, %:
C 64.47; H 3.69; N 6.83.
4,4'-(3,5-Diphenethylbenzo[1,2-b:5,4-b']difuran-2,6-diyl)-
bis[N-(2-bromophenyl)thiazol-2-amine] (8e). Off-white
662

Chemistry of Heterocyclic Compounds 2018, 54(6), 658–663
5. Yu, Z.; Brannigan, J. A.; Moss, D. K.; Brzozowski, A. M.;
141.6; 146.0; 147.1; 148.5; 151.7; 151.8; 160.0. Mass
spectrum, m/z (Irel, %): 745 [M+H]+ (80), 373 (100).
Found, %: C 70.89; H 4.82; N 11.29. C44H36N6O2S2.
Calculated, %: C 70.94; H 4.87; N 11.28.
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Antibacterial activity assay.19 P. aeruginosa (Gram-
negative), E. coli (Gram-negative), B. subtilis (Gram-
positive), and S. aureus (Gram-positive) were obtained
from the Microbial Type Culture Collection. The microbes
were inoculated in an autoclaved Lysogeny broth media
and incubated overnight at 37°C in a shaker for bacterial
growth. An aliquot (0.2 ml) of the bacterial culture was
taken and inoculated on freshly prepared autoclaved agar
plates (Petri dishes) using spreader. After drying of the
plates, 5 mm sample discs, dissolved in DMSO (50 µg/ml),
were put on the microbial plate along with the standard
drugs – norfloxacin and ofloxacin. The samples were
incubated overnight at 37°C in Biochemical Oxygen
Demand incubator and zone of inhibition was then
measured by a measuring scale.
Antimycobacterial activity assay. Isolated single
colonies of M. bovis, Middlebrook 7H10 agar plates, and
7H9 medium were used. The activity was assayed by the
turbidimetry method20 using isoniazid + rifampicin as the
standard.
1
The Supplementary information file, containing IR, H
NMR, 13C NMR, and mass spectral data of compounds 3–6
and 8a–h, is available at the journal website at http://
link.springer.com/journal/10593.
The authors are grateful to the Head of Department of
Chemistry, Osmania University, Hyderabad and IICT,
Hyderabad for providing analytical and biological
facilities. D. Ashok is also thankful to DST, PURSE-II
programme, Osmania University for the financial
assistance. Ananda Rao thanks CSIR, New Delhi, India for
the research associate fellowship.
The authors are thankful to Chemveda Life Sciences Pvt.
Ltd., IDA, Uppal, and Hyderabad for providing laboratory
facilities.
17. (a) Huang, R.-Z.; Zhang, B.; Huang, X.-C.; Liang, G.-B.;
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2017, 7, 8866. (b) Wong, R.; Dolman, S. J. J. Org. Chem.
2007, 72, 3969. (c) Liu, P.; Li, C.; Zhang, J.; Xu, X. Synth.
Commun. 2013, 43, 3342.
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