Microwave-assisted one-step synthesis of fenamic acid hydrazides from the corresponding acids

Article abstract of DOI:10.3390/molecules16053544

A facile and efficient method for synthesis of fenamic acid hydrazides from their acids in one-step reaction under microwave irradiation and solvent-free conditions was developed. Compared with the two-step conventional heating method, the process was simple, the reaction time was very short and the yields were almost quantitative.

Full text of DOI:10.3390/molecules16053544

Molecules 2011, 16, 3544-3551; doi:10.3390/molecules16053544
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Microwave-Assisted One-Step Synthesis of Fenamic Acid
Hydrazides from the Corresponding Acids
Tarek Aboul-Fadl 1,*, Hatem A. Abdel-Aziz 1, Adnan Kadi 1, Ahmed Bari 1, Pervez Ahmad 1,
Tilal Al-Samani 1 and Seik Weng Ng 2
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box
2457, Riyadh 11451, Saudi Arabia
2
Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
* Author to whom correspondence should be addressed; E-Mail: fadl@ksu.edu.sa;
Tel.: +966-1-467-7341; Fax: +966-1-467-6220.
Received: 21 February 2011; in revised form: 30 March 2011 / Accepted: 2 April 2011 /
Published: 28 April 2011
Abstract: A facile and efficient method for synthesis of fenamic acid hydrazides from their
acids in one-step reaction under microwave irradiation and solvent-free conditions was
developed. Compared with the two-step conventional heating method, the process was
simple, the reaction time was very short and the yields were almost quantitative.
Keywords: fenamic acids; fenamic acid hydrazides; microwave irradiation; solvent-free
reaction
1. Introduction
Flufenamic acid (FFA), N-(α,α,α-trifluoro-m-tolyl)anthranilic acid, mefenamic acid (MFA),
N-(2,3-xylyl)anthranilic acid and meclofenamic acid (MCFA), N-(2,6-dichloro-3-methylphenyl)
anthranilic acid are derivatives of N-phenylanthranilic acid (fenamates). They are non-steroidal
anti-inflammatory drugs (NSAIDs) used as potent analgesic and anti-inflammatory agents in the
treatment of osteoarthritis, rheumatoid arthritis and other painful musculosketal illnesses [1-5]. The
fenamates exhibit pharmacologic actions similar to those of aspirin. They are potent inhibitors of
cyclooxygenase, thereby inhibiting the release of prostaglandins [5]. Furthermore, in vitro and in vivo
antimycobacterial activities of some NSAIDs such as diclofenac and its derivatives have been also

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reported [6]. Diclofenac is structurally related to fenamic acids suggesting that these NSAIDs may
inhibit a new target in M. tuberculosis. On the other hand, hydrazides are important key intermediates
in the synthesis of many series of biologically active heterocycles, and their synthesis has attracted
significant attention due to their utility as building blocks [7-11] and aroused our interest in
exploring the utility of hydrazides as versatile precursors for the synthesis of a variety of substituted
heterocycles [12-20].
In view of the above facts and as a part of our ongoing project directed to develop new isatin
hydrazone anti-TB agents using combinatorial chemistry and microwave-assisted synthesis
technologies [21], an efficient, fast and high yielding method for preparing hydrazide building blocks
for the design of combinatorial libraries is urgently needed. The current work describes a direct,
microwave assisted, one-pot synthesis of some fenamic acid hydrazides from their corresponding
fenamic acids.
2. Results and Discussion
Over the last few years, there has been growing interest in the synthesis of organic compounds
using green chemistry tools such as microwave irradiation because of increasing environmental
consciousness. The feasibility of microwave assisted synthesis has been demonstrated in various
transformations whose main features are enhanced reaction rates, greater selectivity and experimental
ease of manipulation leading to efficient, environmentally friendly in addition to cost effective
synthetic pathways to several compounds [22,23]. Moreover, the use of microwave irradiation in this
regard is now a well-established procedure in MORE (microwave induced organic reaction
enhancement) chemistry [24]. In the present study, a direct microwave-assisted one-step synthesis of
some fenamic acid hydrazides from their corresponding acids was developed. The obtained results
were compared with the conventional two-step method. In the latter, esters 2a-c are obtained in
80-85% yield by esterification of the corresponding fenamic acids, 1a-c, with methanol, in the
presence of sulfuric acid, under reflux for 12-18 h [25-27,29]. The second step involves production in
80-96% yield of hydrazides 3a-c by the reaction of methyl esters 2a-c with hydrazine hydrate under
reflux for 1.5-12 h. However, the combined reaction times of the latter two steps were 15-28 h, with
overall yields being 64-86% [27-29] (Scheme 1, Table 1). It is worth mention that direct reaction of the
fenamic acids, 1a-c, with hydrazine hydrate to synthesize the hydrazides 3a-c with the conventional
heating method was unsuccessful.
Scheme 1. Conventional synthesis of fenamic hydrazides 3a-c.
H
N
O
O
O
HO
O
Me
R
H2N
R
R
H
N
H
N
H
N
R1
R1
R1
(I)
(II)
R2
R2
R2
2a-c
3a-c
1a-c
a
, R = H, R1 = CF3, R2 = H
b,
R = Me, R1 = Me, R2 = H
c, R = Cl, R1 = Me, R2 = Cl
Reagents and conditions: (I) MeOH/H2SO4, reflux 12-18 h, 80-85%; (II) NH2NH2xH2O, reflux 1.5-12 h, 80-96%.

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Table 1. Reaction times and yield of conventional (2 steps) and microwave-assisted
3546
synthesis.
Conventional synthesis
MW-assisted synthesis
Comp.
Time of 2 step route (h)
Overall yield (%)
Time (min)
Yield (%)
3a
3b
3c
15
28
17
80
64
86
4
12
5
96
82
85
Interestingly, compounds 3a-c were obtained directly in excellent yields from the reaction of acids
1a-c with hydrazine hydrate in absence of organic solvents under microwave irradiation (300W, 250 °C)
for 4-12 min (Scheme 2, Table 1). Spectral analyses of the synthesized hydrazides 3a-c are consistent
with the proposed structures and with those reported [27-29].
Scheme 2. Microwave-assisted one-step synthesis of fenamic hydrazides 3a-c.
H
HO
O
N
O
R
H2N
R
H
N
H
N
R1
MWI
R1
R2
R2
1a-c
3a-c
Reagents and conditions: NH2NH2xH2O, MWI, 300W (250 °C), 4-12 min, 82-96%.
X-Ray diffraction of hydrazide 3c (Figure 1) [30] showed a network of hydrogen bonds. Two
molecules of the dimmer are linked by intermolecular hydrogen bonds (N5—H5·····O1 and
N1—H1·····N4). Besides the latter intermolecular H-bonds, there are two intramolecular H-bonds, one
in each molecule of the dimmer, N3–H3·····O1 and N6–H6·····O2 (Figure 2).
Figure 1. X-ray structure of hydrazide 3c.

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Figure 2. Crystal packing of hydrazide 3c.
3. Conclusions
A microwave-assisted one-step synthesis of some fenamic acid hydrazides by reaction of their
corresponding acids with hydrazine hydrate under solvent-free conditions was developed and
described. In this method, the reaction times were very short (4-12 min), the yields were excellent
(82-96%) and the manipulations were simple compared to the conventional heating method.
4. Experimental
4.1. General
Fenamic acids were purchased from the Sigma-Aldrich Company (St. Louis, MO, USA). All other
chemicals are of commercially available research-grade. Melting points were determined on a
Gallenkamp melting point apparatus, and are uncorrected. NMR Spectra were scanned in DMSO-d6 on
1
a Bruker NMR spectrophotometer operating at 500 MHz for H and 125.76 MHz for 13C at the
Research Center, College of Pharmacy, King Saud University, Saudi Arabia. Chemical shifts are
expressed in δ-values (ppm) relative to TMS as an internal standard and D2O was added to confirm the
exchangeable protons. Mass spectra were measured on Agilent Triple Quadrupole 6410 QQQ LC/MS
with ESI (Electrospray ionization) source. The X-ray diffraction measurements of compound 3c were
done using Bruker SMART APEX diffractometer. The microwave irradiations were carried out using
an Explorer-48 microwave reactor (CEM, USA).
4.2. Conventional Synthesis of Fenamic Acid Hydrazides 3a-c
4.2.1. Step 1
A solution of the appropriate fenamic acid 1a-c (10 mmol), absolute methanol (10 mL) and
concentrated sulfuric acid (1 mL) was heated under reflux for the appropriate time (Table 1). The
solvent was evaporated under reduced pressure, the remaining contents cooled to room temperature,

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neutralized with a concentrated solution of sodium carbonate, then the aqueous solution extracted with
ether (3 times × 20 mL). The combined ether extracts were dried, and the solvent is removed under
reduced pressure to yield the corresponding ester 2a-c in 80-85% yield (Table 1).
4.2.2. Step 2
A solution of hydrazine hydrate (99.9%, 5 mmol) and the appropriate methyl ester 2a-c (1 mmol)
was brought to a gentle reflux for the appropriate time (Table 1), then cooled to room temperature, The
solid formed was filtered (ice/water mixture was added in some cases to complete precipitation),
washed with several portions of water and dried by suction. Crystallization from EtOH afforded the
corresponding fenamic acid hydrazides 3a-c in 80-96% yield (Table 1). The reactions time of the latter
two steps was 15-28 h, with overall yields of 64-86%
4.3. Microwave Irradiation Synthesis of Fenamic Acid Hydrazides 3a-c
A mixture of hydrazine hydrate (99.9%, 2.5 mmol) and the appropriate fenamic acid 1a-c
(1 mmol) was irradiated, in closed vessel, under microwave irradiation at 300W and 250 °C, with 250 psi
maximum pressure, for the appropriate time (Table 1). The reaction mixture was cooled; the separated
solid was filtered, dried and crystallized from EtOH to give the corresponding hydrazides 3a-c in
82-96% yields (Table 1).
4.3.1. 2-(3-(Trifluoromethyl)phenylamino)benzohydrazide (3a)
White fibers; Mp: 136-138 °C (reported [28] 134-136 °C). 1H-NMR δ: 4.59 (br. S, D2O exch., 2H,
NH2), 6.94-7.21 (m, 2H, ArH), 7.29-7.47 (m, 5H, ArH), 7.62-7.63 (m, 1H, ArH), 9.56 (s, D2O exch.,
1H, NH), 9.91 (s, D2O exch., 1H, NH). 13C-NMR δ: 113.80, 116.72, 116.91, 119.93, 120.84, 121.29,
123.01, 125.18, 128.58, 129.80-130.55 (m, -CF3), 131.55, 142.15, 143.10, 167.71. MS m/z (%):
295 (M+-1).
4.3.2. 2-(2,3-Dimethylphenylamino)benzohydrazide (3b)
1
White powder; Mp: 118-120 °C (reported [27] 118-120°C). H-NMR δ: 2.13 (s, 3H, CH3), 2.27
(s, 3H, CH3), 4.38 (br. S, D2O exch., 2H, NH2), 6.72-6.91 (m, 3H, ArH), 7.10-7.23 (m, 3H, ArH),
6.62-7.63 (m, 1H, ArH), 9.53 (s, D2O exch., 1H, NH), 9.88 (s, D2O exch., 1H, NH). 13C-NMR δ:
13.47, 20.24, 113.87, 116.04, 116.86, 119.47, 124.97, 125.80, 128.17, 129.22, 131.73, 137.62, 139.28,
145.91, 168.45. MS m/z (%): 255 (M+-1).
4.3.3. 2-(2,6-Dichloro-3-methylphenylamino)benzohydrazide (3c)
1
White fibers; Mp: 155-157 °C (reported [29] 158-160 °C). H-NMR δ: 2.38 (s, 3H, CH3), 4.57
(s, D2O exch., 2H, NH2), 6.21 (d, 1H, J = 8 Hz, ArH), 6.77 (t, 1H, J = 7 Hz, ArH), 7.22 (t, 1H, J = 7 Hz,
ArH), 7.29 (d, 1H, J = 8 Hz, ArH), 7.48 (d, 1H, J = 8 Hz, ArH), 7.62 (d, 1H, J = 8 Hz, ArH), 9.74
13
(s, D2O exch., 1H, NH), 9.89 (s, D2O exch., 1H, NH). C NMR δ: 20.13, 113.29, 115.82, 117.62,
127.87, 128.06, 128.34, 129.27, 131.60, 132.36, 135.21, 136.39, 144.65, 168.16. MS m/z (%):
310 (M+).

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Acknowledgement
This research project is supported by “NPST program by King Saud University”, Project Number
MED598-02-08.
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Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box
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