Synthesis of symmetrical and asymmetrical azines encompassing naphtho[2,1-b]furan by a novel approach

Article abstract of DOI:10.1155/2011/784932

The starting material 3-nitro-2-acetylnaphtho[2,1-b]furan (2) was obtained by nitration of 2-acetylnaphtho[2,1-b] furan (1), under mild condition. The compound 1 was synthesized by the reaction of 2-hydroxy-1-naphthaldehyde with chloroacetone, where in both condensation and cyclization took place in single step. The reaction of 3-nitro-2-acetylnaphtho[2,1-b]furan (2) with hydrazine hydrate produced corresponding hydrazone (3) in excellent yield, which on treatment with various aromatic aldehydes under different reaction conditions resulted in the formation of symmetrical azines (4a-e) and unsymmetrical azines (5a-e). All the newly synthesized compounds have been characterized by analytical and spectral studies and were screened for antibacterial antibacterial activity against Bacillus subtilus and Alcaligenes fecalies and antifungal activity against Aspergillus nidulans, Aspergillus parasiticus and Aspergillus terrus. The Second Harmonic Generation (SHG) efficiency of some of the synthesized compounds was measured by powder technique using Nd:YAG laser.

Full text of DOI:10.1155/2011/784932

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(1), 354-360
http://www.e-journals.net
Synthesis of Symmetrical and Asymmetrical
Azines Encompassing Naphtho[2,1-b]furan
by a Novel Approach
K. VEENA, M. RAMAIAH§, G.K. VANITA,
T.S.AVINASH¶ and V. P. VAIDYA*
Department of Chemistry
Maharani’s Science College for Women, Bangalore- 560 001, India
§Department of Chemistry
NMKRV College for Women, Bangalore- 560011, India
¶Department of Studies in Microbiology
Mysore University, Mysore-570006, India
*Department of Chemistry
Kuvempu University, Shankaraghatta- 5777411, India
vaidyavijaya@hotmail.com
Received 1 June 2010; Accepted 1 August 2010
Abstract: The starting material 3-nitro-2-acetylnaphtho[2,1-b]furan (2) was
obtained by nitration of 2-acetylnaphtho[2,1-b] furan (1), under mild condition.
The compound 1 was synthesized by the reaction of 2-hydroxy-1-naphthaldehyde
with chloroacetone, where in both condensation and cyclization took place in
single step. The reaction of 3-nitro-2-acetylnaphtho[2,1-b]furan (2) with hydrazine
hydrate produced corresponding hydrazone (3) in excellent yield, which on
treatment with various aromatic aldehydes under different reaction conditions
resulted in the formation of symmetrical azines (4a-e) and unsymmetrical azines
(5a-e). All the newly synthesized compounds have been characterized by
analytical and spectral studies and were screened for antibacterial antibacterial
activity against Bacillus subtilus and Alcaligenes fecalies and antifungal activity
against Aspergillus nidulans, Aspergillus parasiticus and Aspergillus terrus. The
Second Harmonic Generation (SHG) efficiency of some of the synthesized
compounds was measured by powder technique using Nd:YAG laser.
Keywords: Naphthofurans, Azines, Antibacterial activity, Antifugal activity, NLO
Introduction
Naphtho[2,1-b]furans are associated with wide spectrum of pharmacological and biological
activities. Encouraged by these findings, synthesis of various derivatives of naphtho[2,1-b] furan

Synthesis of Symmetrical and Asymmetrical Azines
355
was taken up as a major research project in our laboratory1-4. Azines are organic compounds
derived from condensation of an aldehyde or a ketone with hydrazine. They can be
considered as 2,3-diaza analogues of butadiene. Enormous research work has been carried
out on different kinds of azines, both symmetrical and asymmetrical, concerning their
application in diverse fields. Azines undergo various types of cyclo addition reactions5,6.
Azines, both symmetrical and asymmetrical, which are difficult to synthesize, are known to
exhibit various activities and find application as Non Linear Optical (NLO) materials.
Polyazines are significantly used as non-linear optical (NLO) materials because of their
optical transparency7. These non-linear optical materials are of particular importance in the
development of light based technology for communication and computing8.
Introduction of nitro group in organic molecules, some times, enhances the activity of
the compounds many folds. The fact that naphtho[2,1-b]furans are associated with wide
spectrum of biological and pharmacological activities9-12 and importance of azines
stimulated our interest to synthesize symmetrical and asymmical azines involving naphtha
[2,1-b] furan, especially with nitro substituent on furan ring of naphthofuran moiety.
Experimental
Melting points were recorded in open capillaries and are uncorrected. The IR spectra were
recorded on a FT-IR Research Spectrophotometer Schimadzu 8201 PC (4000-400 cm-1) and
NMR on Bruker DRX-300 (300MHz-FT-NMR with low and high temperature facility -900
to +800). Standard chemical shifts are given in δ ppm values. All the reactions were
monitored by thin layer chromatographic method. TLC was run on silica gel using ethyl
acetate and petroleum ether (10:90) as eluent. The newly synthesized compounds were
separated and purified by column chromatography using silica gel (60-120 mesh).
Synthesis of 2-acetylnaphtho[2,1-b] furan (1)
2-Hydroxy-1-naphthaldehyde(5.16 g, 0.03 mol), chloroacetone(4.11 mL, 0.03 mol) and
anhydrous potassium carbonate (41.5 g, 0.03 mol) were heated under reflux temperature for
24 h in dry acetone (50 mL). The reaction mixture was filtered and potassium carbonate was
washed with acetone. Evaporation of the solvent from the filtrate yielded the product, 2-
acetylnaphtho[2,1-b] furan 1 which was recrystallised from ethanol. Mixed melting point
1
with authentic sample did not show any depression. The IR and H NMR spectra of this
compound superimposed with known sample.
Synthesis of 3-nitro-2-acetylnaphtho[2,1-b] furan (2)
A cooled nitrating mixture of concentrated nitric acid and concentrated sulphuric acid in the
ratio 1:2 (13 mL : 26 mL) was added very slowly to a cooled solution of 2-acetylnaphtho
[2,1-b]furan (2.24 g, 0.01 mol) in glacial acetic acid (4 mL) and the mixture was stirred for
about 30 min at 5-15 0C. The stirring was continued for 3 h at the same temperature and the
reaction mixture was poured on to crushed ice. The product which was separated as solid
was collected, dried recrystallised from aqueous ethanol.
Synthesis of 3-nitro-2-acetylnaphtho[2,1-b]furanhydrazone (3)
A mixture of 3-nitro-2-acetylnaphtho[2,1-b]furan (2.5 g, 0.01 mol), hydrazine hydrate (1 mL,
0.01 mol), concentrated hydrochloric acid (3-4drops) in ethanol (30 mL) was heated on a
water bath for 6 h. The reaction mixture was poured in to ice water and neutralized with
aqueous sodium hydroxide (5%) The product that separated as solid was collected by
filtration, dried and recrystallised from ethanol.

356
V. P. VAIDYA et al.
Synthesis of Symmetrical azines (4a-e)
Method A
A
mixture of 3-nitro-2-acetylnaphtho[2,1-b]furanhydrazone (1.39 g, 0.005 mol),
benzaldehyde (0.6 mL, 0.005 mol) in ethanol (60 mL) and concentrated hydrochloric acid
(3-4 drops) was refluxed on a water bath for 8 h. The reaction mixture was poured in to ice
water and neutralized with aqueous sodium hydroxide (5%), solid thus separated was
collected by filtration and dried. The crude product was a mixture of two compounds, as
observed by TLC, having Rf values 0.85 and 0.2. These compounds were separated by
column chromatography using silica gel 60-120 mesh size. One product was identified as
condensed symmetrical azine (4a) and another as the regenerated 3-nitro-2-acetyl-
naphthofuran which was eluted using ethyl acetate. Similar procedure was adopted to obtain
the compounds 4b-e from 3 using substituted benzaldehydes.
Method B
To a solution of 3-nitro-2-acetylnaphtho[2,1-b]furanhydrazone (1.39 g, 0.005 mol) and
benzaldehyde (1.0.mL, 0.01 mol) in ethanol (60 mL) and concentrated hydrochloric acid
(3-4 drops) were added and refluxed on a water bath for 8 h. The reaction mixture was
poured in to ice water and neutralized with aqueous sodium hydroxide (5%). Solid thus
separated was collected by filtration and dried. The crude product was a mixture of two
compounds, as observed by TLC, having Rf values 0.85 and 0.2. One product was identified
as condensed symmetrical azine (4a) and another as the regenerated 3-nitro-2 acetyl-
naphthofuran which was eluted using ethyl acetate. Similar procedure was adopted to obtain
the compounds 4b-e from 3 using substituted benzaldehydes.
Synthesis of asymmetrical azines (5 a-e)
A mixture of 3-nitro-2-acetylnaphtho[2,1-b]furanhydrazone (1.39 g, 0.005 mol) and
benzaldehyde (0.6 mL, 0.005 mol) in ethanol (60 mL) were refluxed on water bath for 6 h,
The reaction mixture was poured in to ice water and neutralized with aqueous sodium
hydroxide (5%), the solid thus separated was collected by filtration and dried. The product
was identified as condensed asymmetrical azine (5a). Similar procedure was repeated to get
5b-e from 3 by using appropriate aromatic aldehydes.
Antimicrobial activity
Antibacterial activity was carried out by using Bacillus subtilus, Alcaligenes fecalies and
antifungal activity was carried out using Aspergillus terius, Aspergillus nidulans, Aspergillus
parasiticus.
All the bacterial cultures maintained on nutrient agar media (NA), were inoculated into
nutrient broth to get 36 h old bacterial culture and incubated at 35 2 ºC on a rotary shaker
(Labline biotech) at 100 rmp. The concentration was adjusted to 1×108 cfu/mL using UV-
visible spectrophotometer (Hitachi U-2000 Japan) by reading the OD of solution to 0.45
13
(A610nm ) .
Fungal colonies were cultured on potato dextrose agar (PDA) and incubated at 35 ºC for
5-7 days to induce sporulation. Stock inoculum suspensions were prepared in 2 mL of sterile
distilled water. To obtain spore and mycelium pieces in a sterile tube. After standing for 5
min the thicker particles settle supernatant was placed in another tube shaken in a vortex for
15s and the OD of solution adjusted to 0.09 to 0.11 (A530nm) using spectrophotometer
(Hitachi U-2000 Japan)14.

Synthesis of Symmetrical and Asymmetrical Azines
357
Antimicrobial assay
The test was performed according to NCCL, (National Committee for Clinical
Laboratory Standards)15 by employing the paper disc diffusion method. The spore
suspensions were spread on sterile PDA for fungi and NA plates using the sterile cotton
swabs. The sterile paper discs (Whatmann #1, 6mm diameter) were loaded with the
known concentration (2.5 mg extract per disc) of the extract in acetone. The discs were
dried and placed on pre-seeded PDA(potato dextrose agar) and nutrient agar plates. The
sterile disc loaded with the respective solvents were used as negative control and the
discs loaded with nystatin were used as the positive control for fungi and discs loaded
0
with Gentamicin is used as control for bacteria. The plates were incubated at 4 C for
0
4 hours to ensure complete diffusion and then incubated at 25 3 C for 72 hours. The
plates were observed for the inhibition after the incubation and the diameter of the
inhibition zones were measured by using the metric scale.
Second harmonic generation measurements
Nd:YAG laser of fundamental wavelength 1064 nm was used as the source of light for
second harmonic generation (SHG) experiment. The beam from the laser was passed
through a couple of high energy laser mirrors (Melles Griot, 99.9% reflection) and a long
pass colored glass filter (RG 645, to reject the light from the flash lamp of laser) before be
focused. The energy of the laser beam was kept at 2.60 mJ / pulse. The incident beam power
was measured using a power meter (Scientech Vector H410). The beam was focused into a
glass capillary, using a converging lens of 200 mm focal length. The incoherently scattered
SH photons were collected in the transverse direction using a combination of a
monochromator (Triax 550, Jobin Yvon, 0.024 nm resolution, 1 mm entrance and exit slit
widths) and a photomultiplier tube The second harmonic signal was then sampled, averaged
over 512 shots and was recorded in a digital storage oscilloscope
Results and Discussion
The starting material i.e. 2-acetylnaphtho[2,1-b]furan (1), was synthesized in two steps, the
first step involved Reimer-Tiemann reaction of 2-naphthol with chloroform and sodium
hydroxide, which resulted in the formation of 2-hydroxy-1-naphthaldehyde and the second
step involved conversion of 2-hydroxy-1-naphthaldehyde to 2-acetylnaphtho[2,1-b]furan (1),
which was accomplished by treatment of 2-hydroxy-1-naphthaldehyde with chloroacetone, in
presence of weak base, potassium carbonate. In the second step condensation and cyclization
occurred in single step and the product was obtained in good yield. It underwent smooth
nitration with concentrated nitric acid and concentrated sulphuric acid at low temperature using
acetic acid as a solvent and produced 3-nitro-2-acetylnaphtho[2,1-b] furan (2). The structure of
compound 1 was established by recording its IR and 1H NMR spectra and comparing the same
with an authentic sample10. The reaction of 2 with hydrazine hydrate in ethanol was straight
forward and produced corresponding hydrazone 3, in excellent yield. The IR spectrum of 3
showed strong absorption band at 1623 cm-1 due to carbonyl and broad band at 3446 cm-1due
1
to NH2 group and at 1527 cm-1due to NO2 group. The H NMR and 13C NMR of this
compound confirmed the assigned structure. The hydrazone 3 served as an excellent
intermediate for the synthesis of symmetrical azines (4a-e) and unsymmetrical azines (5a-e).
Thus, very interesting results were obtained when hydrazone (3), was treated with various
aromatic aldehydes under different reaction conditions. Different types of compounds were
obtained, when the reaction was carried in different ratio of reactants and in presence of
hydrochloric acid as catalyst as well as in absence of catalyst.

358
V. P. VAIDYA et al.
Thus, the acid catalyzed reaction of 2-acetyl-3-nitronaphtho[2,1-b]furanhydrazone (3)
with benzaldehyde, 4-methoxybenzaldehyde, 3-nitrobenzaldehyde, 4-chlorobenzaldehye and
2-chlorobenzaldehyde in 1:1 mol ratio at reflux temperature in ethanol produced a mixture
of two compounds. These compounds were separated by column chromatography and
identified as symmetrical azines (4a-e) and 2-acetyl-3- nitronaphtho[2,1-b]furan (2). It has
been presumed that, the originally formed mixed azines underwent hydrolysis, under acidic
condition and recombined to form symmetrical azines. These were isolated and
characterized on the basis of spectral data.
The IR spectrum of 4a exhibited the absorption band at 1623 due to C=N. In its 1H NMR
spectrum (CDCl3) singlet at 8.8 for two CH protons and multiplet at 7.2-8.3 for aromatic protons
were observed. The 1H NMR spectra of compounds 4b-e were consistent with their structures.
Similar reaction was carried out using 3 with respective aldehydes in the molar ratio 1:2
in the presence of an acid. In this case also two products were obtained which were
identified as symmetrical azines and regenerated 2-acetyl -3- nitronaphtho [2,1-b]furan.
On the other hand the condensation of 3 with these aldehydes in 1:1 mol ratio in the
absence of hydrochloric acid at reflux temperature in ethanol gave a single product. The
products thus formed in each case were identified as asymmetrical azines (5a-e) of 2-acetyl-
3-nitronaphtho[2,1-b]furanhydrozone. The IR spectrum of 5b exhibited the absorption band
at 1605 cm_1due to C = N. The 1H NMR spectra of 5b exhibited a singlet at 3.8 due to OCH3
group and multiplet at 7.0-8.4 for aromatic protons. The characterization data of the
synthesized compounds are as shown in Table 1.
Table 1. Analytical data of the synthesized compounds
M.P Yield
oC
Molecular
formula
Compound
R
Found (calculated) %
%
82
94
57
60
70
62
72
68
70
80
60
65
64
-
-
104
180
155
184
C14H10O2
C14H9NO4
80.1(80.0)
4.71(4.76)
3.40(3.50)
3.50(3.90)
-
1
65.0(65.8)
60.0(60.2)
79.0(80.7)
71.0(71.6)
63.0(63.1)
60.0(60.6)
60.0(60.6)
70.0(70.3)
67.5(68.0)
62.0(62.5)
64.0(64.1)
64.0(64.1)
5.0(5.4)
14.9(15.0)
2
-
C 14H 11 N 3O3
C14H12N2
3
H
5.60(5.76) 13.0 (13.4)
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
4-OCH3 178
3-NO2 ›250
C16H16N2O2
C14H10N4O2
C14H10N2Cl2
C14H10N2Cl2
C21H16N303
C22H18N3O4
C21H15N4O5
C21H15N3O3Cl
C21H15N3O3Cl
5.01(5.97)
3.01(3.75)
3.60(3.61)
3.60(3.61)
4.40(4.46)
4.60(4.63)
3.50(3.70)
3.70(3.80)
3.70(3.80)
10.0(10.4)
20.0(20.2)
10.0(10.1)
10.0(10.1)
11.0(11.7)
10.8(10.8)
13.5(13.8)
10.4(10.6)
10.4(10.6)
4-Cl
2-Cl
H
152
196
204
4-OCH3 170
3-NO2 ›250
4-Cl
2-Cl
153
220
Antibacterial activity
All the newly synthesized compounds were tested for their antibacterial activity against -
Bacillus subtilus, Alcaligenes fecalies and antifungal activity against Aspergillus terius,
Aspergillus nidulans, Aspergillus parasiticus by paper disc diffusion method. The
antibacterial results (Table 2) indicate that among the tested compounds 4a showed the
maximum inhibition 12 mm inhibition to Bacillus subtilus and 4d showed 8 mm inhibition
to Bacillus subtilus compared to standard control gentamycin.

Synthesis of Symmetrical and Asymmetrical Azines
359
Antifungal activity
The antifungal screening results indicate that among the tested compounds 4c showed higher
degree of antifungal activity against Aspergillus nidulans i.e. 4 mm inhibition compared to
nystatin which shows 3 mm inhibition. Compounds 4a, 5a, 5b and 5c showed almost same
degree of activity compared to standard drug.
Table 2. Antimicrobial activity of the synthesized compounds
Zone of inhibition in mm
Antibacterial Activity
Antifungal Acitivity
Compound
Bacillus
subtilus
Alcaligenes
fecalies
Aspergillus
nidulans
Aspergillus
parasiticus
Aspergillus
terius
5
-
2
-
-
-
-
-
-
-
-
-
3
-
2
-
-
-
-
-
-
-
-
-
-
-
2
-
-
4b
5b
8
-
2
-
4d
-
5d
12
-
3
3
4
2
-
3
-
4a
5a
-
4
6
-
4c
-
5c
-
4e
-
-
-
5e
Control
28
3
24
Not active, Control: For antibacterial: Gentamicin (10 µg), For antifungal : Nystatin (10 µg) NLO
Studies
The Second harmonic generation (SHG) efficiency of these compounds was measured
by powder technique using Nd:YAG laser with Beam Energy 2.51 mJ/pulse. Among tested
compounds, 5d exhibited NLO property with SHG conversion efficiency 2.5 times that of
urea and compound 4a exhibited NLO property with SHG conversion efficiency almost near
to potassium dihydrogen phosphate (KDP)
Conclusion
The present work gives a novel and simple approach for synthesis of symmetrical and
asymmetrical azines, which are otherwise difficult to synthesize. Some of the compounds
exhibited good antibacterial and antifungal activity. Second harmonic generation efficiency
of the tested compounds showed that the compound 5d has 2.5 times more efficiency that
urea. And the compound 4a exhibited NLO property with SHG efficiency almost equal to
potassium dihydrogen phosphate.
Acknowledgement
The authors are thankful to The Principal, NMKRV College Bangalore for providing
laboratory facilities and are also thankful to the Head, Sophisticated Instrumentation
Facility, IISC, Bangalore, for providing the spectral data.

360
V. P. VAIDYA et al.
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