Synthesis of aryl-hydrazones via ultrasound irradiation in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2007.12.103

The synthesis of aryl-hydrazones from aromatic aldehydes/ketones and hydrazides (semicarbazide, thiosemicarbazide and aminoguanidine) is described using aqueous medium (acid conditions) under ultrasound irradiation with short reaction times (20-30 min), t

Full text of DOI:10.1016/j.tetlet.2007.12.103

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1538–1541
Synthesis of aryl-hydrazones via ultrasound irradiation
in aqueous medium
Ana Cristina Lima Leite *, Diogo Rodrigo de M. Moreira, Lucas Cunha Duarte Coelho,
*
´
Frederico Duarte de Menezes, Dalci Jose Brondani
LabSINFA—Laboratory for the Planning, Synthesis and Evaluation of Pharmaceutical Products, Department of Pharmaceutical Science,
Centre for Health Science, Federal University of Pernambuco, 50740-520 Recife, PE, Brazil
Received 11 November 2007; revised 15 December 2007; accepted 18 December 2007
Abstract
The synthesis of aryl-hydrazones from aromatic aldehydes/ketones and hydrazides (semicarbazide, thiosemicarbazide and amino-
guanidine) is described using aqueous medium (acid conditions) under ultrasound irradiation with short reaction times (20–30 min), the
reactions occurring at room temperature and giving rise to good to excellent yields of the products, along with the diastereoselectivities.
The procedure is also simple and clean.
Ó 2007 Published by Elsevier Ltd.
Keywords: Hydrazones; Aqueous medium; Ultrasound irradiation; Condensation
Aryl-hydrazones, such as semicarbazones, thiosemicar-
bazones and guanyl hydrazones, are important compounds
for drug design,1 as possible ligands for metal complexes,2
organocatalysis3 and also for the preparation of hetero-
cyclic rings.4
carbonyl compounds bear a strong electron-withdrawing
group.14 Improvements in yields of the aryl-hydrazones
synthesis have been achieved when MW-irradiation at sol-
vent-free conditions were used.15 In some cases, a mixture
of isomers (Z and E) is reported, mainly for reaction pro-
cedures that are only possible at high temperatures or for
prolonged reaction periods.16
At the same time, many addition/condensation reactions
have been demonstrated to occur in aqueous media (such
as: Barbier and Mannich-type reactions, Diels–Alder cyclo-
addition, and Knoevenagel condensation).17 Water is the
cheapest and safest solvent available, and in the presence
of reactive functional groups, protection and deprotec-
tion processes are often unnecessary. In fact, total solubility
is required for efficient reaction in water, and thus,
either organic co-solvents or heating are almost always
employed.18 Although Schiff and colleagues have reported
that the presence of water is a disadvantage in imine synthe-
sis, three works have shown that such reactions can be
effective in completely aqueous media under mild condi-
tions.19 More recently, a protocol for the synthesis of
aryl- and heterocyclic-hydrazones from aryl-hydrazine
At present a broad range of methods for synthesizing
imines5 in the presence of catalysts are available: ZnCl2,6
TiCl2,7 K-10,8 MgSO4-PPTL,9 Mg(ClO4)2
and also
10
SiO2–NaHSO4 (under MW irradiation condition).11 More
recently, ultrasound irradiation has been used to give rise
to the formation of a series of Schiff bases (aryl–aryl and
aryl–alkyl), under solvent-free conditions12 or using SiO2
as a catalyst in ethanol,13 with short reaction times (10–
20 min) and high yields.
For aryl-hydrazones, most reaction methods described
to date involve the use of methanol as a solvent without
catalysts at reflux, although ethanol and acid catalysis (or
p-toluenesulfonic acid in dried toluene) are required if the
*
Corresponding authors. Tel./fax: +55 81 2126 8511 (A.C.L.L.).
E-mail addresses: ana.leite@pq.cnpq.br (A. C. L. Leite), dalci@ufpe.br
(D. J. Brondani).
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.12.103

A. C. L. Leite et al. / Tetrahedron Letters 49 (2008) 1538–1541
1539
Table 1
and aldehydes/ketones has been described with excellent
yields using polystyrene sulfonic acid as a catalyst under
MW irradiation (100 °C) in water.20 However, the literature
does not report the general synthesis of aryl-hydrazones
(such as thiosemicarbazones, semicarbazones, or guanyl
hydrazones) in aqueous media using ultrasound irradiation,
nor the diastereoselectivities for these compounds.
Taking into account its application to studies of medic-
inal chemistry and its use for obtaining metal complexes,
we describe here an efficient and rapid aryl-hydrazone syn-
thesis process using ultrasound irradiation in an aqueous
medium (Scheme 1).
The reactions were carried out in parallel on a micro-
scale: 2 mL of water, 1 mmol of amine, 1 mmol of aryl-alde-
hyde/ketone and irradiated with ultrasound (low intensity)
for 20–30 min at rt (30 °C), and the precipitate was then
filtered and washed (in H2O or EtOH).
First, the reaction of p-methoxybenzaldehyde (1a) and
thiosemicarbazide (2a) was used as the model reaction in
the simplest manner, by mixing the amines and the alde-
hydes directly in water, without adding any co-solvent or
catalyst, at rt and irradiating for 20–30 min with ultra-
sound (Table 1). However, the yield was only 45% under
these conditions (entry 1). When the reaction was run
between 40 and 60 °C, the yields only improved to 55%
and 65%, respectively (entries 2 and 3), and no improve-
ment was observed in the case of solid aldehydes/ketones.
The effect of acidity is very important in this reaction, as
it protonates the carbonyl carbon in the first step to produce
the formation of imines.5 Subsequently, acetic acid and
inorganic salts were tested. KHSO4 and NH4Cl showed
good yields comparable to acetic acid, and thus the use of
acid conditions proved to be crucial, because of the effect
of acidity and also in helping to produce total solubility
of the carbonyl compounds. By contrast, under basic condi-
tions, only a moderate yield was detected (entry 11). The
addition of water-miscible co-solvents (0.5 mL, MeOH or
EtOH) brought about a considerable improvement, mainly
in the case of more lipophilic aldehydes/ketones.
Aqueous medium-promoted condensation of 4-methoxybenzaldehyde (1a)
with thiosemicarbazide (2a) via ultrasound irradiation
Entry
Catalyst
Co-solvent
Temp (°C)
Yielda (%)
1
2
3
4
5
6
7
8
9
None
None
None
HOAcc
HOAc
None
None
None
None
None
None
EtOHd
EtOHd
None
EtOHd
None
None
None
30
40
60
30
60
60
30
60
30
60
30
30
45b
55b
65b (68)g
98
98
75 (78)g
98
HOAc
NH4Cle
NH4Cl
90
95
85
65
f
10
11
12
a
KHSO4
NaOAc
SiO2 (5 equiv)
80 (85)h
Determined as isolated products after 20 min.
The starting materials were mostly recovered.
Five drops (0.1 mL).
A mixture (5:1) of water and co-solvent.
Saturated solution (pH 5.0).
Solution at 10% wt (pH 4.5).
After 30 min.
b
c
d
e
f
g
h
Using ethanol.
(20–30 min) compared to the traditional stirring for 4–6 h
for the reaction between aldehyde 1a and hydrazide 2a
(at rt).
The reaction can be carried out effectively with a wide
variety of aldehydes/ketones and hydrazides using the opti-
mal condition described in entry 4. Excellent results were
obtained in most cases, with the formation of crystalline
products and the same diastereoselectivity (only one isomer
isolated).21 Aromatic ketones proved to be less reactive and
did not furnish the best yields, these being only moderate to
good. Low yield (>20%) was obtained in the condensation
reaction with benzophenone (showing reduced electrophi-
licity of the carbonyl carbon under powerful resonance)
under the conditions of entry 5 (Table 1), even after 1 h.
In the case of cinnaldehyde and arylthioacetaldehyde the
use of a co-solvent (0.5 mL EtOH) or a large amount of
acetic acid (0.5 mL) provided better results than the use
of a complete aqueous medium. Furthermore, cinnalde-
hyde derivatives did not precipitate at the end of reaction,
and had to be isolated by freezing them overnight and then
filtering.
When activated SiO2 was used as catalyst13 in water or
ethanol (Table 1, entry 12), the yield was comparable with
that produced using acetic acid, but generated more prob-
lems due to the precipitation accompanying the product,
and, in this case, it was necessary to use toluene or ethyl
acetate to separate aryl-hydrazone (3a) of the SiO2. We
observed that the application of ultrasound irradiation
significantly increased the reaction rates and yields
Similarly, the use of semicarbazide (chloridrate) or amino-
guanidine 22 (carbonate) also furnished the desired products
under the reaction conditions at good to excellent yields
R
R
X
X
))), H2O
catalyst
+ H2N
N
H
N
N
H
R1
N
H
H
O
R1
N
H
H
2a-c
2a: X=S thiosemicarbazide
2b: X = O semicarbazide
2c: X = NH aminoguanidine
Scheme 1. Synthetic route for aryl-hydrazones.

1540
A. C. L. Leite et al. / Tetrahedron Letters 49 (2008) 1538–1541
Table 2
Table 3
Synthesis of aryl-hydrazones
Comparative study of the reaction between aldehyde 1a and hydrazide 2a
by microwave irradiation
Conditionsa
Entry
Aldehyde/ketone
Hydrazides
Time
(min)
Yield
(%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
18
19
20
21
22
23
24
25
26
27
a
p-Methoxybenzaldehyde
p-Methoxybenzaldehyde
2-Furaldehyde
2-Furaldehyde
2-Furaldehyde
3,4-Di-chlorobenzaldehyde
3,4-Di-chlorobenzaldehyde
3,4-Di-chlorobenzaldehyde
p-Bromobenzaldehyde
p-Bromobenzaldehyde
p-Bromobenzaldehyde
Cinnaldehyde
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
20
20
20
20
20
30
30
30
20
20
20
20
20
20
20
20
20
20
20
20
30
30
30
20
20
30
95
98
95 (92)a
90
98
85
90
88
2 min, Tmax = 100 °C, solvent free
4 min, Tmax = 100 °C, solvent free
4 min, Tmax = 100 °C, DMF (five drops)
4 min, Tmax = 150 °C, solvent free
40
60
60
70
78
75
c
4 min, Tmax = 150 °C, NaHSO4–SiO2
4 min, Tmax = 150 °C, DMF (five drops)d
a
Using a domestic microwave oven.
After recrystallization.
As described in Ref. 11
As described in Ref. 30.
b
85
92
c
d
84 (80)a
90
Cinnaldehyde
Cinnaldehyde
94 (90)a
90
uration involving the thiocarbonyl carbon of the thiosemi-
carbazide when it was microwave heated, as described by
Siemion and co-workers.24 However, it was difficult to
make the correct assignments of this by-product, which
we hope will be reported elsewhere in the future. Thus,
the use of MW-assisted reactions show extraordinary abil-
ity to achieve the aryl-hydrazones synthesis from hydrazine
hydrate or phenyl hydrazine as previously described15,20
and in the case of the aryl-thiosemicarbazones synthesis
is still much more problematic due to the different reactiv-
ity and feasible degradation for the thiosemicarbazide.
The experimental procedures for the synthesis25 and the
full assignment of NMR and IR spectra for the new com-
pounds are provided in Refs. 28,29.
In conclusion, we have discovered a practical, mild, and
rapid procedure for ultrasound-accelerated synthesis of
aryl-hydrazones from aromatic aldehydes/ketones and
hydrazides in the presence of an aqueous medium (under
acid conditions) at room temperature. This method fur-
nishes the products very quickly with good to excellent
yields, compatible with the commonly-used amine/car-
bonyl protecting groups, simplifies the work-up and does
not harm the environment.
p-Hydroxybenzaldehyde
p-Hydroxybenzaldehyde
p-Hydroxybenzaldehyde
Arylthioacetaldehyde
Arylthioacetaldehyde
Arylthioacetaldehyde
Acetophenone
Acetophenone
Acetophenone
p-Chloroacetophenone
p-Chloroacetophenone
p-Chloroacetophenone
80b
95b
85b
90
90
85
80
85
80
85
88
75
Scale-up of 10 mmol, using 15 mL of water and 0.4 mL of acetic acid.
After the filtration, the water from the reaction was extracted with
b
dichloromethane three times and the combined organic extracts were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo.
(Table 2). Moreover, the reactions proceeded normally even
when 2 equiv of enolizable aldehyde was used, and no aldol
adducts were observed as possible by-products.23 We tried
the condensation of N1-(tert-butyloxycarbonyl)thiosemicar-
bazide with aldehyde 1a, but aryl-hydrazone 3a was not
obtained under these conditions. No reaction was detected
for arylthioacetaldehyde diethyl acetal with hydrazide 2a,
and acetal was collected unaltered after prolonged reaction
time (1 h). Subsequently, the reactions described in entries
3, 11, and 13 (Table 2) were shown to be efficient on a
10 mmol scale.
One crucial feature of this reaction procedure was the
total solubilization of the hydrazide starting material in
water when sonicated for 2 min and hence, the aldehyde/
ketone was added dropwise to the mixture and resulted
in an initially homogenous reaction mixture that was
smoothly precipitated during the reaction.
Acknowledgments
We would like to thank the Brazilian National Research
Council (CNPq) for financial support. F.D.M. and
L.C.D.C. also received a CNPq grant and D.R.M.M. is a
fellow of CAPES. Our thanks are also due to the Depart-
ment of Fundamental Chemistry, UFPE, for recording
1
the H, 13C NMR and IR spectra of all compounds and
to Professor R. M. Srivastava (DQF-UFPE) for helpful
discussions.
Finally, we decided to compare the MW irradiation con-
ditions for obtaining aryl-thiosemicarbazone 3a. As sum-
marized in Table 3, the use of MW-irradiation led to
good yield of product 3a in 4 min of reaction when
NaHSO4–SiO2 was used as catalyst, and moderate yields
were achieved at solvent-free conditions or with five drops
of DMF, but the presence of a by-product was unfortu-
nately also observed in all these reactions. This probably
occurred as a result of some kind of degradation or desulf-
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7.56–7.73 (d, 2H, Ar); 7.62 (s, 1H, NH2); 7.90 (d, J = 7.0 Hz, 1H,
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Compound N-(3-phenylethylidene)semicarbazone: mp: 127–8 °C
(from ethanol); 1H NMR (DMSO-d6, 300 MHz): d 6.31 (s, 2H,
NH2); 6.86–6.89 (m, 2H, CH); 7.26–7.39 (m, 3H, Ar); 7.51–7.54 (d,
J = 10 Hz, 2H, Ar); 7.69 (d, J = 5 Hz, 1H, CH@N); 10.22 (s, 1H,
NH); 13C NMR (DMSO-d6, 75.5 MHz): d 125.58; 125.67; 126.67;
128.44; 128.87; 136.16; 141.84 (CH@N); 156.48 (C@O). IR (KBr,
cmÀ1) m 3435 (NH2). 3188 (NH); 1640 (C@O); 1601 (C@N).
Compound N-(3-phenylethylidene)aminoguanidine: mp: 139 °C
(from ethanol); 1H NMR (DMSO-d6, 300 MHz): d 6.51 (s, 1H,
NH2); 6.79 (d, J = 12 Hz, 1H, CH); 7.50 (m, 1H, CH); 7.90–8.11 (m,
5H, Ar and 1H of NH2); 8.12 (d, J = 8 Hz, CH@N); 11.93 (s, 1H,
NH). 13C NMR (DMSO-d6, 75.5 MHz): d 125.07; 126.58; 127.01;
129.04; 128.87; 136.19; 141.84 (CH@N); 159.87 (C@NH). IR (KBr,
cmÀ1) m 3409 (NH2). 3257 (NH); 1619 (C@N).
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