Fast synthesis of N-acylhydrazones employing a microwave assisted neat protocol

Article abstract of DOI:10.1021/cc9001444

A variety of N-acylhydrazones were synthesized under microwave irradiation within 2.5-10 min, starting from benzo, salicyloyl, and isonicotinic hydrazides. The protocol developed employs microwave irradiation in the absence of solvents and catalysts, lead

Full text of DOI:10.1021/cc9001444

J. Comb. Chem. 2010, 12, 245–247
245
Fast Synthesis of N-Acylhydrazones Employing a Microwave Assisted
Neat Protocol
Marta M. Andrade* and Maria Teresa Barros
REQUIMTE, CQFB, Departamento de Qu´ımica, Faculdade de Cieˆncias e Tecnologia, UniVersidade
NoVa de Lisboa, 2829-516 Caparica, Portugal
ReceiVed September 11, 2009
A variety of N-acylhydrazones were synthesized under microwave irradiation within 2.5-10 min, starting
from benzo, salicyloyl, and isonicotinic hydrazides. The protocol developed employs microwave irradiation
in the absence of solvents and catalysts, leading to high yields. The results are reproducible in a 500 mg to
5 g scale.
N-acylhydrazones have been widely employed in organic
and analytical chemistry, mainly in terms of metal ligands.1
They coordinate strongly with a variety of transition metal
ions, forming complexes of varied biological and pharma-
ceutical activities.2-8 The N-acyl group often plays important
roles in controlling stereochemistry for metal calalysis.9
In the field of organic chemistry, their use as electrophiles
in reactions with nucleophiles has recently made some
important advances as they act as stable imine surrogates.10,11
The hydrazide products can be transformed into various
nitrogen containing compounds by cleavage of the N-N
bond. It is expected that new stereoselective reactions that
take advantage of N-acylhydrazones will be developed and
that the use of N-acylhydrazones as imine equivalents will
be expanded to the chemical and pharmaceutical industries.9,12
N-acylhydrazones are usually obtained by condensation
of aldehydes or ketones with acylhydrazines, in the presence
of an acid catalyst, in reaction times varying from 30 min to
several hours.9,13,14 Their purification can be accomplished
by simple recrystallization, and they are stable at ambient
temperature.
aliphatic ketones (cyclohexanone, 2; cyclopentanone, 3),
linear aliphatic ketones (butan-2-one, 4; pentan-3-one, 5,
4-methylpentan-2-one, 6), aromatic ketones (acetophenone,
7; isobutyrophenone, 8) and heteroaromatic ketones (2-
acetylfurane, 9; 2-acetylthiophene, 10; 2-acetylpyridine, 11).
The protocol employed consists in placing equivalent
amounts of hydrazide and ketone in a quartz tube, which
was then subjected to microwave irradiation (Figure 2)with
the power and times indicated in Table 1. After completion,
the reaction mixture was allowed to cool down to room
temperature, and the product was washed with ethyl ether.
In most cases, purification was not needed since the
hydrazone was pure enough for possible subsequent reaction
steps, although recrystallization can be easily performed with
ethanol for most cases. In this context, the synthesis was
carried out minimizing the use of organic solvents and
unnecessary purification steps.
The results shown in Table 1 demonstrate that the protocol
developed by us provides N-acylhydrazones in 90% to
quantitative yields (with exception to the moderate yield
obtained in entries 7 and 22).
In general, reactions with salicyloyl hydrazide were faster
than those with benzo or isonicotinic hydrazides, because
of the better stability of the resulting hydrazone, owing to
an OH group in ortho position, which can form intramo-
lecular hydrogen bonding with the nitrogen (Figure 3).17
This fact is also visible in the IR spectra of salyciloylhy-
drazones, showing a characteristic low-frequency shift of the
CdO band (see Supporting Information).
We have developed a friendly method for the synthesis
of a library of N-acylhydrazones, based on microwave
radiation. With this protocol, one can avoid the use of
solvents and catalysts, and the products are obtained in short
reaction times and in very good yields.
Both hydrazides and hydrazones are well-known for their
pharmacological activities, such as antitubercular, antima-
larial, and antibacterial agents, fungicides, and also anticon-
vulsant properties, among other applications.15,16 In the
present study, benzhydrazide (1a), salicyloylhydrazide (1b),
and isonicotinic hydrazide (1c) were used to react with a
wide range of ketones and aldehydes (Figure 1). The method
is simple and economical since all the compounds are cheap
and readily available.
Reaction times were much faster than for similar reactions
under conventional heating. For example, synthesis of
To investigate the generalization of the method, we have
tested the protocol with several types of ketones: cyclic
Figure 1. Structures of benzhydrazide (1a), salicyloylhydrazide
(1b), and isonicotinic hydrazide (1c).
* To whom correspondence should be addressed. E-mail: marta.andrade@
dq.fct.unl.pt. Phone: +351 212948300. Fax: +351 2948550.
10.1021/cc9001444  2010 American Chemical Society
Published on Web 01/05/2010

246 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Andrade and Barros
Figure 2. Library of N-acylhydrazones synthesized under neat microwave irradiation.
Table 1. Microwave Promoted Synthesis of N-acylhydrazones,
Starting from Ketones
power time T final P final
entry hydrazide ketone product (W) (min) (°C)
(bar) yield (%)
1
2
3
4
5
6
7
8
9
10
2
3
4
5
6
7
8
9
10
11
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
200
200
200
200
200
200 10
300
100 10
5
3
4
5
152
143
202
210
5.0 quantitative
2.8 quantitative
12.8 quantitative
9.6 90
3.9 93
11.8 92
4.0 70
4.7 90
6.4 93
7.0 90
2.5 159
1a
262
258
175
231
216
4
Figure 4. N-acylhydrazones synthesized by reaction with aldehydes
under neat microwave irradiation.
200
200
5
4
11
12
13
14
15
16
17
18
19
20
2
3
4
5
6
7
8
9
10
11
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
200
200
200
200
200
200
200
200
200
200
4
5
3
5
137
114
95
2.5 quantitative
1.9 quantitative
2.1 98
11.2 91
4.5 90
6.8 96
6.1 90
6.2 quantitative
4.3 96
or hexane (with acetic acid as catalyst), whereas under MW
irradiation the same product is achieved in 10 min (entry
6).19,20
The intramolecular hydrogen bonding mentioned before
is more pronounced for salyciloylhydrazones with a high
degree of electron delocalization,17 explaining the shorter
reaction times observed with aromatic and heteroaromatic
hydrazones when changing from benzo or isonicotinic to
salyciloyl hydrazide (entries 6, 8, 9 compared with entries
16, 18, 19, 23).
208
1b
1c
2.5 161
4
5
2.5 194
3
5
218
229
211
?
?
90
21
22
23
24
3
8
10
11
13c
18c
20c
21c
200
300
200
200
6
4
182
262
5.3 94
7.1 68
8.0 quantitative
5.5 97
4.5 247
208
5
Reaction between benzhydrazide (1a) or isonicotinic
hydrazide (1c) and isobutyrophenone (8) (entries 7 and 22)
were more difficult than all the others because of the
bulkiness of the starting ketone. Different powers were tested,
and the best result was obtained at 300W, leading to 70%
of hydrazone 18a and 67% of hydrazone 18c, recovering
20% and 15% of starting hydrazides, respectively. Neverthe-
less, the here described protocol for the synthesis of 18a
represents an improvement to the procedure described in the
literature that required 12 h in refluxing methanol in the
presence of acetic acid to afford 18a in 68% yield.20
To broaden the scope of the protocol, some examples of
reactions between hydrazides and representative aldehydes
(3-methyl-butanal, 22; benzaldehyde, 23, and 2-pyridein-
ecarboxaldehyde, 24), were tested (Figure 4). The results
obtained are shown in Table 2 and demonstrate that the
methodology is valid also for aldehydes.
hydrazone 12a is accomplished in 6 h using refluxing
methanol and acetic acid as catalyst,18 while under MW
irradiation the same product can now be obtained in only 5
min with quantitative yield (entry 1); hydrazone 17a was
previously obtained in 4 to 12 h using refluxing methanol
Figure 3. Electronic delocalization and intramolecular hydrogen
bonding observed for salicyloyl hydrazides.

Fast Synthesis of N-Acylhydrazones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 247
Table 2. Microwave Promoted Synthesis of N-acylhydrazones,
References and Notes
Starting from Aldehydesa
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reaction times, avoiding the use of solvents and catalyst. The
reactions were reproducible from 500 mg to 5 g scale and
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General Procedure for Microwave Synthesis. Five
grams of hydrazide and 1 equiv of ketone or aldehyde (and
a magnetic stirring bar) were placed in a quartz tube, which
was introduced in the microwave oven inside the reactor
equipped with temperature and pressure probes. Reaction
times and power were applied according to Tables 1 and 2.
After completion, the system was allowed to cool down to
room temperature, resulting in crystallization of the hydra-
zones obtained. Ethyl ether was added to the quartz tube
and the product was filtrated under reduced pressure and
washed with ethyl ether.
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Supporting Information Available. Characterization data,
microwave output graphics and spectra of all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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CC9001444