Development of practical methodologies for the synthesis of novel 3(4-oxo-4H-chromen-3-yl)acrylic acid hydrazides

Article abstract of DOI:10.1016/j.ultsonch.2010.11.001

We report a new environmentally-benign, convenient and facile methodology for the synthesis of new series of 3(4-oxo-4H-chromen-3-yl)acrylic acid hydrazides derivatives designed by exploring the molecular hybridization approach between isoniazide and 3(4-

Full text of DOI:10.1016/j.ultsonch.2010.11.001

Ultrasonics Sonochemistry 18 (2011) 735–738
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Development of practical methodologies for the synthesis of novel
3(4-oxo-4H-chromen-3-yl)acrylic acid hydrazides
⇑
Ratnadeep S. Joshi, Priyanka G. Mandhane, Pravin V. Badadhe, Charansingh H. Gill
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a new environmentally-benign, convenient and facile methodology for the synthesis of new
series of 3(4-oxo-4H-chromen-3-yl)acrylic acid hydrazides derivatives designed by exploring the molec-
ular hybridization approach between isoniazide and 3(4-oxo-4H-chromen-3-yl)acrylic acids by using
EDCl/HOBt under ultrasound irradiation in very short reaction time. Utilization of easy reaction condi-
tions, isolation and purification makes this manipulation very interesting from an economic perspective.
Ó 2010 Elsevier B.V. All rights reserved.
Received 9 September 2010
Received in revised form 31 October 2010
Accepted 3 November 2010
Available online 11 November 2010
Keywords:
Isoniazide
Acyl hydrazide
Chromones
Peptide coupling
EDCl/HOBt
Ultrasound
1
. Introduction
Chromones are naturally occurring compounds which shows
tuberculosis. The increase in activity was even observed with drug
resistant isolates [9].
Isoniazide (INH) is widely applied as first-line drugs for the
treatment of tuberculosis, usually in combination with other drugs.
Modifying either of these molecules has been a challenge taken up
by several research groups [10]. INH prevents a mycolic acid bio-
synthesis by inhibiting a 2-trans-enoyl-acyl carrier protein reduc-
tase (InhA) that belongs to the FAS-II (fatty acid synthetase II)
system [11].
Ultrasound accelerated chemical reactions which are well
known and proceed via the formation and adiabatic collapse of
transient cavitation bubbles [12]. Ultrasound irradiation has been
demonstrated as an alternative energy source for organic reactions
ordinarily accomplished by heating. Many homogeneous and het-
erogeneous reactions which can be conducted smoothly by sonica-
tion to provide improved yields and increased selectivities.
interesting biological and pharmacological activities coupled with
low toxicity [1]. Chromones having heterocyclic substituents at
2
nd and 3rd position have been reported to possess antiallergic
activity [2], muscular relaxation effect and antimicrobial activity
3]. On the other hand, flavones and their derivatives are com-
[
monly used as precursors for pharmaceutical product such as anti-
cancer agents [4]. It is also well recognized that incorporation of
tetrazole into the chromone skeleton significantly enhances the
antiallergic activity [5].
Condensation reactions of 3-formylchromones with compounds
containing active methylene group have been extensively studied.
Such kind of condensation reactions are achieved by using either
acid or base catalyst. Similarly, the condensation reactions of
3
-formylchromones with hydrazine, monosubstituted hydrazine,
hydroxylamine, guanidine and substituted pyrazoles have also
been reported [6].
2
. Experimental
Acrylic acid derivatives have wide range of therapeutically
importance such as, antitumor activity [4], antioxidant activity
Melting points were determined on a Veego apparatus and are
uncorrected. Infrared spectra were recorded on a Bruker spectro-
photometer in a KBr disc and the absorption bands are expressed
[
5] and antibacterial activity [7]. Promising results have been
shown by Rastogi et al. [8] reported the synergistic activity of
acrylic acid in drug combinations with isoniazide, rifampicin and
other known antimycobacterial agents against mycobacterium
À1
1
in cm
.
H NMR spectra were recorded on a Varian AS 400 MHz
/DMSO-d , chemical shifts (d) are in ppm rel-
spectrometer in CDCl
3
6
ative to TMS and coupling constants (J) are expressed in Hertz (Hz).
Mass spectra were taken on a macro mass spectrometer (Waters)
by electro-spray method (ES). Bandelin Sonorex (with a frequency
of 40 kHz and a nominal power 100 W) ultrasonic bath was used
⇑
Corresponding author. Tel.: +91 240 2403311; fax: +91 240 2400491.
E-mail address: prof_gill@rediffmail.com (C.H. Gill).
1
350-4177/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2010.11.001

7
36
R.S. Joshi et al. / Ultrasonics Sonochemistry 18 (2011) 735–738
for ultrasonic irradiation. Built-in heating, 30–80 °C thermostati-
cally adjustable. The reaction vessel placed inside the ultrasonic
bath containing water.
condensation of 3-formyl chromones and malonic acid in the pres-
ence of pyridine at reflux condition (Scheme 1). This acid was
clubbed with isoniazide using EDC.HCl, HOBt in DMF under ultra-
sound irradiation at ambient temperature which furnished the de-
sired products in excellent yields (Table 1).
3
. General procedure
The coupling reaction was carried out according to reported
method [9]. 3(4-oxo-4H-chromen-3-yl)acrylic acid was treated
with thionyl chloride in the presence of 4-nitrophenol in toluene
at reflux condition which gave the labile ester of acid. This ester re-
acted with isoniazide under different conditions, but surprisingly
the reactions gave mixture of products. So the reaction was carried
out by using coupling reagent EDC.HCl and HOBt which gave de-
sired product. In this reaction of 3(4-oxo-4H-chromen-3-yl)acrylic
acid and isoniazide in the presence of EDC.HCl and HOBt under
ultrasound irradiation to yield the desired product in single step
with excellent yield as shown in (Scheme 1).
3
.1. General procedure for the synthesis of 3(4-oxo-4H-chromen-3-yl)
acrylic acid 2(a–h)
A mixture of 3-formyl chromone (10 mmol) and malonic acid
(
5
20 mmol), in the presence of pyridine (5 ml) was refluxed in
0 ml round bottom flask for 30–45 min with vigorous stirring.
After completion of reaction (monitored by TLC), the reaction mix-
ture was cooled to room temperature, the pH was adjusted to 1.0
with conc. HCl and the reaction mass was again stirred for
3
0 min. The yellow coloured solid thus obtained was filtered and
Initially, we have studied the influence of catalyst concentration
on the reaction time and percentage yield on the typical reaction
washed with 15 ml  2 1 N HCl and dried.
(
Table 1 entry 3a). The elevated amount of catalyst can improve
3
.2. General procedure for the synthesis of 3(4-oxo-4H-chromen-3-
the reaction yields and shorten the reaction time. However in the
absence of catalyst, the reaction did not proceed even after extend-
ing reaction time and gave the mixture of the product.
yl)acrylic acid hydrazide 3(a–h)
A mixture of acrylic acid (0.248 mol), HOBt (0.248 mol) and
EDC.HCl (0.337 mol) was stirred in 5 ml of DMF for 5 min. at
We have studied the different reaction conditions on reaction.
The result revealed that, when the reaction was carried at room tem-
perature it gave lower yield of product even after prolonged reaction
time. But at the same time the reaction was carried out under ultra-
sonication, we got the excellent yields of product in short span. It
was foundthat the ultrasonic irradiationwas very simple and conve-
nient for the synthesis of 3(4-oxo-4H-chromen-3yl)acrylic acid
hydrazide using ultrasonic cleaner with a frequency of 40 kHZ and
a nominal power 100 W. In experiment the ultrasonic technique
represented a better procedure in terms of time and yields (Table 1).
The proposed mechanism for the formation of acyl hydrazide is
shown in the Fig. 1. Firstly, 3(4-oxo-4H-chromen-3-yl)acrylic acid
0
°C, further the solution of isoniazide (0.225 mol) was added and
the reaction mixture was irradiate under ultrasound for
0–45 min at ambient temperature. The progress of the reaction
3
was monitored by TLC. After completion of reaction, reaction mix-
ture was poured on ice cold water (20 ml) and the yellow product
thus obtained was filtered, dried and recrystallized in ethyl acetate.
The structure of products 3(a–h) were confirmed by, IR, 1H NMR,
mass spectra and melting points.
4
. Results and discussion
2
forms the unstable amine reactive intermediate 2a with EDC.HCl
In continuation of research work to synthesized the bioactive
heterocycles [13,14], Herewith, we report the synthesis of
(4-oxo-4H-chromen-3-yl)acrylic acid hydrazides. The design con-
cepts of these compounds explore the introduction of the
chromone containing acrylic acid moiety into isoniazide core
structure aiming to boost its activity. Synthesis of 3(4-oxo-
and HOBt. Further reaction with amines/hydrazide results in the
formation of desired product. It has become increasingly popular
to include catalytic auxiliary nucleophiles in acylation mixtures
the most commonly used additive is l-hydroxbenzotriazole (HOBt),
these are introduced in EDC.HCl mediated couplings to reduce
possible side reactions, including racemisation and to increase
reaction rate by using active esters. In addition it is also used to
3
4
H-chromen-3-yl)acrylic acid was made by simple knoevenagel
R1
R1
R2
R3
O
O
R2
R3
O
O
COOH Pyridine
COOH
Reflux
O
OH
O
1(a-h)
2(a-h)
CONHNH2
N
EDC.HCl, HOBt
DMF, ))))))
R1
R2
R3
O
O
H
N
N
H
O
O
N
3
(a-h)
Scheme 1. Synthesis of acyl hydrazides.

R.S. Joshi et al. / Ultrasonics Sonochemistry 18 (2011) 735–738
737
Table 1
Characterization data of compounds 3(a–h).
Sr. No.
R
1
R
2
R
3
With USa
Without USb
M.P. (°C)
Time (min)
Yieldc (%)
Time (min)
Yieldc (%)
3
3
3
3
3
3
3
3
a
b
c
d
e
f
H
H
H
CH
H
H
Cl
H
H
H
CH
H
H
CH
H
H
H
CH
H
CH
Cl
Cl
Cl
Br
35
40
30
35
38
42
45
40
90
85
92
90
86
89
91
92
150
180
135
150
165
180
155
180
74
78
76
74
78
71
68
65
160–162
221–223
178–180
118–120
242–244
145–147
170–172
218–220
3
3
3
3
3
g
h
a
b
c
Reaction of 3(a–h) with isonicotinohydrazide in presence of EDC.HCl/HOBt in DMF at ultrasound irradiation.
Reaction of 3(a–h) with isonicotinohydrazide in presence of EDC.HCl/HOBt in DMF at room temperature.
Isolated yield.
Fig. 1. Proposed mechanism for acyl hydrazide.
provide excellent leaving groups; all these additives are capable of
acting as proton acceptors aiding deprotonation of the ammonium
ion intermediate and thereby gently increase the reaction rate.
Although added in equimolar quantities to the acylating compo-
nent, the additive is catalytic and therefore remains in essentially
a fixed concentration throughout the coupling step. This ensures
that the highly activated isourea derivative is short lived.
olefinic protons having coupling constant (J = 14.4 Hz) this confirm
the trans double bond and one singlet was observed at d 7.65 ppm
of C carbon of chromone ring and aromatic range of protons at d
2
7.1–7.41 ppm and the labile acidic proton which was highly
deshielding and was observed at 9.1 ppm. The IR (3a) characteristic
À1
frequencies of acyl hydrazide bond observed at 1646 cm
the
absence of acid stretching frequency. Ketone carbonyl frequency
À1
The synthesized compounds were confirmed by physical and
spectral study. The structures of the compounds were established
at 1676 cm appears due to conjugation in chromone ring. The
1
H NMR spectrums of the two hydrazine protons appear as two
1
by means of their IR, H NMR and mass spectral studies. Assign-
singlets in the region of the d 13.43 ppm apart from the signals
due to acyl hydrazide. The structure of the compounds were
determined by their spectroscopic method [15].
ment of selected characteristic IR bands provides significant indi-
cations for the formation of 3(4-oxo-4H-chromen-3-yl)acrylic
acid analogues. 3(4-oxo-4H-chromen-3-yl)acrylic acid give charac-
À1
teristic frequency at 1719 cm and the absence of the aldehyde
stretching frequency but the characteristic band gives the lower
frequency because of conjugation in the chromone ring. ketone
carbonyl frequency at 1675 cm . The H NMR spectrum of acrylic
5. Conclusion
À1
1
In conclusion, we have described that EDC.HCl and HOBt
were found to be mild and effective catalyst for synthesis of
acid (2a) showed the doublet observed at d 6.48, 6.76 of the two

7
38
R.S. Joshi et al. / Ultrasonics Sonochemistry 18 (2011) 735–738
3
(4-oxo-4H-chromen-3-yl)acrylic acid hydrazide. This method
[14] (a) R.S. Joshi, P.G. Mandhane, S.D. Diwakar, C.H. Gill, Ultrason. Sonochem. 17
2010) 298;
b) P.G. Mandhane, R.S. Joshi, D.R. Nagargoje, C.H. Gill, Tett. Lett. 51 (2010)
490;
c) P.G. Mandhane, R.S. Joshi, D.R. Nagargoje, C.H. Gill, Tett. Lett. 51 (2010)
138.
15] (2a) IR in KBr: 3305 (–COOH); 2951(C@C–H); 1719 (–COOH); 1675 (–C@O)
(
(
1
(
provides clean, conversion, greater selectivity and easy workup
make this protocol practical and economically attractive (Table 1).
3
Acknowledgements
[
À1
1
cm
3
; H NMR (400 MHz CDCl ): d ppm 6.48(d, J = 14.4 Hz, 1H); 6.76 (d,
The authors are thankful to University Grants Commission, New
Delhi, for awarding the fellowship and to The Head, Department of
Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, for valuable support and laboratory facility.
J = 14.4 Hz, 1H); 7.11 (t, J = 7.4 Hz, 2H); 7.41 (d, J = 4.54 Hz, 2H); 7.65 (s,
J = 7.4 Hz, 1H); 9.1 (s, 1H); EI-MS. 250 (M+); (3a) IR in KBr: 1676 (–CO–);
À1
1
1646 (–CO–NH–); 1608 (–C@N–) cm
; H NMR (400 MHz, DMSO): d ppm
7.145 (d, J = 15.96 Hz, 1H, vinylic proton); 7.241 (d, J = 15.60 Hz, 1H, vinylic
proton); 7.499–7.531 (m, 3H, Ar–H); 7.720 (d, J = 8.24, 2H, Ar–H); 8.789 (s,
H, chromone ring C
H); 8.893 (s, 2H, pyridine rings); 13.436 (s, 2H, 2Â NH);
Mass (m/z): 334. (MÀ1); (3b) IR in KBr: 3167 (CO–NH–NH–CO); 1694 (–CO–
1
2
References
À1 1
)
; 1665 (–CO–NH–); 1616 (–C@N–) cm
; H NMR (400 MHz, DMSO): d ppm
2
.163 (s, 3H, Ar–CH ); 7.215 (d, J = 15.3 Hz, 1H, vinylic proton); 7.351–7.475
3
[
1] (a) F.M. Dean, Naturally Occurring Oxygen Ring Compounds, Butterworths,
London, 1963, p. 281;
(m, 3H, Ar–H); 7.575 (d, J = 15.2 Hz, 1H, vinylic proton); 7.717–7.937 (m, 2H,
Ar–H); 8.023 (s, 1H, chromone ring C H); 8.653 (s, 2H, pyridine rings);
10.291 (s, 1H, –NH); 10.654 (s, 1H, –NH; Mass (m/z): 350.0 (M+1): (3c) IR in
KBr: 3141 (CO–NH–NH–CO); 1681 (–CO–); 1618 (–CO–NH–); 1490 (–C@N–)
cm ; H NMR (400 MHz, DMSO): d ppm 2.499 (s, 3H, Ar–CH ); 7.145 (d,
3
J = 15.72 Hz, 1H, vinylic proton); 7.486 (d, J = 15.96 Hz, 1H, vinylic proton);
7.659 (m, 4H, Ar–H); 7.799–7.943 (dd, J = 1.84 and 5.22 Hz, 1H, Ar–H); 8.729
(d, J = 5.22 Hz, 2H, pyridine rings); 8.828 (s, 1H, chromone ring C H); 10.554
(s, 1H, –NH); 10.654 (s, 1H, –NH); Mass (m/z): 350.0 (M+1); (3d) IR in KBr:
3056 (CO–NH–NH–CO); 1698 (–CO–); 1647 (–CO–NH–); 1602 (–C@N–)
cm
J = 14.56 Hz, 1H, vinylic proton); 7.214–7.325 (m, 3H, Ar–H); 7.459 (d,
J = 14.56 Hz, 1H, vinylic proton); 7.845–7.954 (m, 1H, Ar–H); 8.325 (s, 1H,
chromone ring C H); 8.881 (s, 2H, pyridine rings); 10.546 (s, 2H, –NH); Mass
(m/z): 364.1 (M+1); (3e) IR in KBr: 3056 (CO–NH–NH–CO); 1702 (–CO–);
1668 (–CO–NH–); 1614 (–C@N–) cm ; H NMR (400 MHz, DMSO): d ppm
6.458 (d, J = 15.80 Hz, 1H, vinylic proton); 7.145–7.245 (m, 3H, Ar–H); 7.394
(d, J = 15.80 Hz, 1H, vinylic proton); 7.784–7.947 (m, 2H, Ar–H); 8.124 (s, 1H,
chromone ring C H); 8.789 (s, 2H, pyridine rings); 10.147 (s, 2H, –NH);
Mass (m/z): 370.1 (M+1), 372.3 (M+3); (3f) IR in KBr: 2910 (C@C–H); 1687
(–C@O); 1640 (–CONH–) cm
Ar–CH ), 6.221 (d, J = 15.32 Hz, 1H), 6.815 (d, J = 15.32 Hz, 1H); 7.237 (t,
J = 6.9 Hz, 3H); 7.43–8.10 (m, 2H, Ar–H); 8.944 (d, 2H, pyridine rings); 10.515
(s, 2H, –NH); EI-MS. 383 (M+), 385 (M+2); (3g) IR in KBr: 3056 (CO–NH–NH–
CO); 1702 (–CO–); 1668 (–CO–NH–); 1614 (–C@N–) cm
(400 MHz, DMSO): d ppm 6.584 (d, J = 16.20 Hz, 1H, vinylic proton); 7.012–
7.231 (m, 3H, Ar–H); 7.412 (d, J = 16.40 Hz, 1H, vinylic proton); 7.689–7.934
(m, 1H, Ar–H); 8.245 (s, 1H, chromone ring C H); 8.784 (s, 2H, pyridine
rings); 10.548 (s, 2H, –NH); Mass (m/z): 404.1 (M+1), 406.1 (M+3); (3h) IR in
KBr: 2923 (C@C–H); 1680 (–C@O); 1610 (–CONHNH–CO–) cm ; H NMR
(400 MHz, CDCl ): 6.454 (d, J = 14.12 Hz, 1H), 6.697 (d, J = 14.12 Hz, 1H);
7.291 (t, J = 7.2 and 8.52 Hz, 2H, Ar–H); 7.656 (s, 1H, –NH); 7.801–8.108 (m,
3H, Ar–H); 8.946 (s, 2H, pyridine ring); 10.224 (s, 1H, NH); EI-MS.414 (M+),
416 (M+2).
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