A greener procedure for the synthesis of α-ureidophosphonates under ultrasound irradiation. An X-ray crystallographic study

Article abstract of DOI:10.1039/c5ra19886k

An efficient, eco-sustainable and greener procedure for the synthesis of α-ureidophosphonates via a one-pot three-component reaction of aldehydes, urea/thiourea and triethylphosphite or diethylphosphite using ultrasonic irradiation under solvent- and cata

Full text of DOI:10.1039/c5ra19886k

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DOI: 10.1039/C5RA19886K
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A greener procedure for the synthesis of α-ureidophosphonates
under ultrasound irradiation. X-ray crystallographic study
Received 00th January 20xx,
Accepted 00th January 20xx
Abdeslem Bouzinaa, Malika Berredjema*, Sofiane Bouacidab,c, Hocine Merazigc and Nour-eddine
Aoufa
DOI: 10.1039/x0xx00000x
An efficient, eco-sustainable and greener procedure for the synthesis of α-ureidophosphonates via a one-pot three-
component reaction of aldehyde, urea/thiourea and triethylphosphite or diethylphosphite using ultrasonic irradiation
under solvent- and catalyst-free conditions at 75°, is developped. The desired products were obtained in excellent yields
within short reaction times (15-30 min). Crystals of Diethyl [α-ureido-(4-methylphenyl)]methyl phosphonate suitable for X-
ray study have been obtained after recrystallization in mixture of diethyl ether and n-hexane. The detailed analysis of
molecular and crystal structure is presented.
www.rsc.org/
connect economic features with the green concerns is performing
organic reactions under ultrasound irradiation19-23 and solvent-free
conditions24-27. This powerful technique became extremely efficient
and attractive in synthetic organic chemistry, and is able to activate
many reactions due to cavitational collapse. Ultrasound irradiation
provides higher yields and selectivities, shorter reaction times and
milder reaction conditions, nontoxic, environmentally friendly
Introduction
The synthesis of α-aminophosphonates has attracted much
attention in organic synthesis due to their structural analogy to α-
amino acids1 and α-aminophosphonic acids2. These compounds
possess diverse biological and pharmacological properties. Among
them, α-ureidophosphonates continue to attract the attention of
chemists because they have been used as precursor for the
synthesis of chiral α-aminophosphonates3.α-ureidophosphonates
have gained diverse biological activities in pharmaceutical as fungal
solvent, in
a one-step reaction, without isolation of any
intermediate thus reducing time, saving money, energy and raw
materials.
pathogens4,enzyme
inhibitors5,
antibiotics6,pharmacological
They also display
In addition, Multi-component reactions (MCRs) constitute one of
the best tools for modern organic synthesis because they can use
most of the constituent atoms of several reactant molecules to
form a product molecule. Such reactions present remarkable
advantages for library synthesis aimed at carrying out structure-
activity relationship (SAR) studies of drug-like compounds, in a
single procedural step such as; high degree of atom economy,
reduction in reaction steps and the number of workup, reduction in
energy consumption28-30. In the present research, we wish to
describe a new and eco-friendly method for the preparation of α-
agents7,peptidomimetics8andantitumor9.
powerful antiviral activities against TMV10. Metal chelating ability11,
and these compounds used as active ingredients in pesticides
especially insecticides and acaricides12. Because of their chemical
and biological importance, many procedures for the synthesis of α-
ureidophosphonates and α-amidophosphonates derivatives have
been developed. Generally, these methods could be fulfilled in the
catalysis such as; BF3 (OEt)213, 3, (H2N–SO3H, PhSO3H, CH3SO3H)14,
LiClO415 andInCl316, in the solvent THF17at 50 °C or toluene18 at 50 °C.
However there are some problems associated with these methods
including harsh reaction conditions, long reaction times and side
reactions.On the other hand, one of the powerful tools used to
ureidophosphonates through
a one-pot reaction of three
component condensation of aldehyde with urea/thiourea and
triethylphosphite or diethylphosphite under catalyst- and solvent-
free conditions using ultrasonic irradiation at 75 °c.
a.Laboratory of Applied Organic Chemistry, Synthesis of biomolecules and
molecular modelling Group, Sciences Faculty, Chemistry Department, Badji-
Mokhtar - Annaba University, Box 12, 23000 Annaba, Algeria. *Corresponding
author. Email: malika.berredjem@univ-annaba.org, mberredjem@yahoo.fr
Results and discussion
In continuation of our investigations on the use of ultrasound
b.Département sciences de la matière, université Oum El Bouaghi, 04000 Oum El
Bouaghi, Algérie.
irradiation for fine chemical preparation of α-amidophosphonates
derivatives31-33
.
c. Unité de Recherche de Chimie de l’Environnement et Moléculaire Structurale,
Université Constantine 1. Constantine 25000, Algérie.
The α-ureidophosphonates (b) were obtained by the one-pot three
component condensation of aldehyde with urea/thiourea and
triethylphosphite or diethylphosphite under ultrasonic irradiation at
†
Spectral data and crystallographic data for the synthesis of α-
ureidophosphonatesprepared in this work are available in the supporting
information joined to this manuscript DOI: 10.1039/x0xx00000x
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75 °C and solvent-, catalyst-free conditions in excellent yields
(Scheme 1).
To evaluate the feasibility of α-ureidophosphonates (b), a modal
View Article Online
reaction involving urea, benzaldehyde and DtrOieI:t1h0y.1lp0h3o9/sCp5hRitAe19w88e6rKe
carried out at different temperatures (r.t, 30, 50 and 75 °C) in the
presence of different solvents or without solvent under ultrasonic
irradiation (table1).
O
X
Et
O
O
H
R
P
Et
O
one o
t
,
p
*
))))
t t 75°
Et
O
+
R
P
Et
O
+
H2N
NH2
ea
N
=
C
,
HN
NH2
Et
O
a
b
X
=
=
an
d
S
X
R
O
A
r
l Alk l
,
y
y
Scheme 1 One-pot synthesis of α-ureidophosphonates under
ultrasound irradiation.
Table 1 Optimization of reaction time and solvent for the synthesis of α−ureidophosphonate.
Entry
Solvent
No solvent
EtOH
Time (min)
Temperature °C
Yields %
85
1
2
3
4
5
6
7
18
75
75
75
75
75
75
75
60
58
MeOH
CH3CN
CH2Cl2
THF
60
55
120
23
120
25
100
50
DMF
100
56
At room temperature in ethanol, product formation was not optimistic conditions (ultrasonic irradiation, catalyst-, solvent-free,
observed after 3h working time, at 30 °C we obtained a low yield
(10-15%) after 2h, but when the temperature increases until 50 °C
the yield is improved. Under ultrasonic irradiation at 75°C, We have
obtained a good yield in short reaction time (15-30 min). At these
and 75 °C), a series of α-ureidophosphonates (b) were obtained by
various aromatic aldehyde and urea/thiourea. The results of these
studies are presented in Table 2.
Table 2 Multicomponent synthesis of α-ureidophosphonates under ultrasound irradiation.
Entry
R
Product
Time /min
Yield%
M.p. 0C
O
P
Et
O
1b
18
85
197-199
Et
NH2
O
HN
O
O
P
Et
O
2b
3b
20
22
78
83
184-186
202-204
Et
NH2
O
HN
O
O
P
Et
O
Et
NH2
O
l
C
HN
l
C
O
l
l
C
O
P
Et
O
l
C
4b
21
77
196-198
C
Et
O
HN
NH2
l
C
O
2 | J. Name., 2012, 00, 1-3
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F
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DOI: 10.1039/C5RA19886K
O
P
Et
O
5b
25
81
198-200
F
Et
O
HN
HN
HN
HN
HN
NH2
O
F
3C
O
P
Et
O
F
3C
Et
O
6b
7b
8b
26
28
23
75
79
85
186-188
188-190
203-205
NH2
O
r
B
O
P
Et
O
r
B
Et
O
NH2
O
N
O2
O
P
Et
O
N
O2
Et
O
NH2
O
l
C
O
P
Et
O
l
C
Et
O
9b
25
30
80
76
201-203
199-201
NH2
O
O
P
Et
O
10b
Et
NH2
O
HN
O
N
O
P
Et
O
N
11b
12b
20
15
85
81
192-194
190-192
Et
NH2
O
HN
O
O
P
Et
O
OEt
NH2
HN
O
O
P
Et
O
13b
25
85
197-199
Et
O
HN
NH2
O
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H
3CO
View Article Online
DOI: 10.1039/C5RA19886K
O
P
Et
O
Et
NH2
O
14b
20
78
204-206
HN
H
3CO
O
O
P
Et
O
F
Et
O
HN
NH2
15b
20
17
80
83
199-201
198-200
O
F
O
P
Et
O
Et
NH2
O
HN
16b
17b
S
l
C
O
P
Et
O
23
81
201-203
Et
O
HN
NH2
l
C
S
Scheme
ureidophosphonates.
2 Mechanistic proposal for the synthesis of α-
The structures of the synthesized compounds are confirmed by
1
elemental analysis as well as by IR and H, 13C, 31P NMR spectral
X-ray analysis of the Diethyl [α-ureido-(4-isopropylphenyl)]
methylphosphonate: The formation of compound 13b was
furtherconfirmed by single crystal X-ray diffraction analyses; the
ORTEP-334 diagram of complex is shown in Fig. 1.
data and MS.
Mechanistic proposal
The ultrasonic energy applying to the reaction generates the
acoustic cavitation mechanical effect when sonic waves propagate
through the medium. Vibrations of molecules generate
compressions and rarefactions which give rise to the phenomenon
of bubble formation and collapse in the reaction mixture
urea/thiourea, aldehyde and triethylphosphite or diethylphosphite
to facilitate the nucleophilic attack of the amino functional
(urea/thiourea) on the carbonyl group (aldehyde). During
cavitation, the chemical bonds break, and water eliminated for
imine formation, the last one undergo to nucleophilic attack of
triethylphosphite or diethylphosphite and formation to water in the
reaction and EtOH eliminated for the α-ureidophosphonates
formation according to the mechanism below.
X
R
X
O
H
H2N
H2N
O
X
+
H2N
N
O
R
H2N
N
H
R
H
H
H
Figure 1 ORTEP for diethyl [α-ureido-(4-
isopropylphenyl)]methylphosphonate.
H
H
-
H2O
O
t
OE
t
X
OE
H2N
N
P
t
OE
NH2
The reported structure was solved by direct methods with SIR2002
to locate all the non-H atoms which were refined anisotropically
P
EtO
t
OE
+
N
35
EtO
X
H
R
R
with SHELXL9736 using full-matrix least-squares on F2 procedure
from within the WinGX34 suite of software used to prepare material
for publication. All the H atoms were placed in the calculated
positions and constrained to ride on their parent atomsCCDC
1424911 contains the supplementary crystallographic data for
O
H
H
O
O
R
P
O
Et
H
*
t
OE
t
t
OE
OE
-
EtOH
H2N
N
P
H2N
N
P
OEt
NH2
t
OE
t
HN
t
OE
OE
X
R
X
R
X
=
an
d
S
r
an
A l
d Alk l
y
X
O
=
R
y
4 | J. Name., 2012, 00, 1-3
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compound 13b. These data can be obtained free of charge from The was crystallized to 6° C overnight. The product was finally filtered
View Article Online
DOI: 10.1039/C5RA19886K
Cambridge
Crystallographic
Data
Centre
via and dried.
www.ccdc.cam.ac.uk/data_request/cif.
Conclusions
Experimental
In conclusion we have developed
multicomponent method for the synthesis of α-
ureidophosphonates under ultrasound irradiation and solvent-
a simple and new
General data
All chemicals and solvents were purchased from common catalyst-free conditions at 75°C, the derivatives of α-
commercial sources and were used as received without any further ureidophosphonates were obtained by condensation of
purification. All reactions were monitored by TLC on silica Merck 60 aldehyde with urea/thiourea and triethylphosphite or
F254 percolated aluminum plates and were developed by spraying diethylphosphite in excellent yields. This new protocol has
with ninhydrin solution. Column chromatography was performed advantages such as; the use of cheap, short reaction times
with Merck silica gel (230-400 mesh). Proton nuclear magnetic (15–30 min), high yields (75–85%), easy of product
resonance (1H NMR) spectra were recorded on a Brücker or Jeol isolation/purification, Solvent- and catalyst-free.
spectrometer at 250, or 400 MHz. Chemical shifts is reported in δ
Acknowledgments
units (ppm) with TMS as reference (δ 0.00). All coupling constants
(J) are reported in Hertz. Multiplicity is indicated by one or more of
the following: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet). Carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on a Brücker or Jeol at 60, 75 or 100 MHz. Chemical
shifts are reported in δ units (ppm) relative to CDCl3 (δ 77.0).
Phosphorus nuclear magnetic resonance (31P NMR) spectra were
recorded on a Brücker or Jeol at 75, 100 or 161 MHz. Infrared
spectra were recorded on a Perkin Elmer 600 spectrometer.
Elemental analysis was recorded on a EURO E.A 3700. Melting
points were recorded on a Büchi B-545 apparatus in open capillary
tubes. Ultrasound assisted reactions were carried out using a
FUNGILAB ultrasonic bath with a frequency of 40 kHz and a nominal
power of 250 W. The reactions were carried out in an open glass
tube (diameter: 25 mm; thickness: 1 mm; volume: 20 mL) at 75°C.
This work was supported financially by The General Directorate for
Scientific Research and Technological Development (DG-RSDT),
Algerian Ministry of Scientific Research, Applied Organic Laboratory
(FNR 2000). We also thank Pr. Jacques Lebreton from the University
of Nantes, Dr. Zouhair Bouaziz and Pr. Marc Le Borgne from the
university Claude Bernard Lyon for their help in the identification
for all products in NMR and MS.
Notes and references
‡Spectral data and crystallographic for the synthesis of
ureidophosphonates, prepared in this work are available in the
supporting information joined to this manuscript.
α-
1
2
3
4
5
6
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In a glass tube (diameter: 25 mm; thickness: 1 mm; volume: 20
mL)taken a mixture of aldehyde (1 mmol) and urea/thiourea (1
mmol) at 750 C, then the triethylphosphite or diethylphosphite (1
mmol) was added. The reaction mixture was subjected to the
ultrasonication with a frequency of 40 kHzfor appropriate time.
After completion of the reaction, as indicated by TLC, silica gel;
dichloromethane:methanol (9:1), a (6:4) mixture of diethyl ether
and n-hexane was added to the reaction mixture and pure product
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