Ultrasound-assisted one-pot synthesis of α-oxycarbanilinophosphonates via a three-component condensation of an aldehyde, diethyl phosphite and an isocyanate under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2011.06.057

An efficient one-pot method has been developed for the synthesis of α-oxycarbanilinophosphonates via a one-pot reaction of an aldehyde with diethyl phosphite in the presence of magnesium oxide followed by reaction with an isocyanate under solvent-free conditions using ultrasonic irradiation. This method is simple, rapid and good yielding.

Full text of DOI:10.1016/j.tetlet.2011.06.057

Tetrahedron Letters 52 (2011) 4346–4348
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Tetrahedron Letters
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Ultrasound-assisted one-pot synthesis of
a-oxycarbanilinophosphonates via
a three-component condensation of an aldehyde, diethyl phosphite and
an isocyanate under solvent-free conditions
⇑
Babak Kaboudin , Maryam Fallahi
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45137-66731, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot method has been developed for the synthesis of a-oxycarbanilinophosphonates via a
Received 1 May 2011
Revised 29 May 2011
Accepted 13 June 2011
Available online 2 July 2011
one-pot reaction of an aldehyde with diethyl phosphite in the presence of magnesium oxide followed by
reaction with an isocyanate under solvent-free conditions using ultrasonic irradiation. This method is
simple, rapid and good yielding.
Ó 2011 Elsevier Ltd. All rights reserved.
Organophosphorus compounds have found a wide range of
application in the areas of industrial, agricultural and medicinal
chemistry owing to their biological and physical properties, as well
O
O
R
P(OEt)2
R
P(OEt)2
H
as their utility as synthetic intermediates.1
a
-Functionalized phos-
phonic acids are valuable intermediates for the preparation of
medicinal compounds and synthetic intermediates,2–4 with
-oxy-
carbanilinophosphonates and -hydroxyphosphonates being
important examples that exhibit a variety of interesting and useful
properties. In recent years, the preparation of -oxycarbanilino-
and -hydroxyphosphonates has attracted significant attention,
OH
O
N
R'
O
a
α-hydroxyphosphonates
α−oxycarbanilinophosphonates
a
Scheme
1. Structures
of
a
-oxycarbanilinophosphonates
and
a-
a
hydroxyphosphonates.
a
due to their potential biological activities and broad applications
as enzyme inhibitors or as dinucleotide analogues having antiviral
properties (Scheme 1).5
O
H
O
N
P(OEt)2
In contrast to the widely studied
derivatives,1,6,7 relatively few papers have reported on the chemis-
try of
-oxycarbanilinophosphonates.8 Many effective methods for
the preparation of -hydroxyphosphonates have been developed,
but, to the best of our knowledge, only one synthetic route to
oxycarbanilinophosphonates has been reported. The method in-
volves prolonged heating (3 days) of -hydroxyphosphonates with
a
-hydroxyphosphonic acid
R'
N C O + H P(OEt)2
R'
O
a
a
Scheme 2. Reaction of the isocyanate with diethyl phosphite.
a
-
The development of simple and general synthetic routes for
widely used organic compounds from readily available reagents
is a major challenge in organic synthesis. Surface-mediated solid
phase reactions are of growing interest9 because of their advanta-
ges including ease of set up, mild conditions, rapid reactions, selec-
tivity, increased yields of the products and low cost compared with
their homogeneous counterparts. The application of ultrasound en-
ergy to accelerate organic reactions is of increasing interest and of-
fers several advantages over conventional techniques.10 Syntheses
which normally require long reaction times can be achieved conve-
niently and very rapidly under ultrasonic irradiation. As part of our
efforts to explore the utility of solid phase reactions for the synthe-
sis of organophosphorus compounds,11 we report a new method
a
phenyl isocyanate at 50 °C in the presence of tin octanoate as a cat-
alyst.8 However, the method has drawbacks, including harsh reac-
tion conditions, low yields, long reaction times, use of Lewis acid
and yields side products. In the absence of tin octanoate as catalyst,
isocyanurate was obtained as the major product. The key step in
the one-pot synthesis of
nucleophilic addition of diethyl phosphite to an aldehyde followed
by reaction of the isocyanate with the resulting -hydroxyphos-
a-oxycarbanilinophosphonate is the
a
phonate. Therefore, formation of a carbamoylphosphonate fre-
quently accompanies the synthesis (Scheme 2).
⇑
Corresponding author. Tel.: +98 241 4153220; fax: +98 241 4214949.
E-mail address: kaboudin@iasbs.ac.ir (B. Kaboudin).
for the one-pot synthesis of
a-oxycarbanilinophosphonates from
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.057

B. Kaboudin, M. Fallahi / Tetrahedron Letters 52 (2011) 4346–4348
4347
Table 1
Reaction of aldehydes with diethyl phosphite in the presence of magnesium oxide followed by reaction with isocyanates under solvent-free conditions using ultrasound
Entry
R
R0
Product 3
Reaction time (h)
Yield%a
1
2
3
1
2
3
4
5
6
7
8
C6H5
p-FC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3-Cl,4-MeC6H3
3-Cl,4-MeC6H3
Cyclohexyl
Cyclohexyl
PhCH2
3a
3b
3c
3d
3e
3f
3g
3h
3i
1
1
2
3
2
2
2
1
1
2
3
2
62
56
80
60
60
77
74
60
50
63
62
60
p-MeC6H4
p-MeSC6H4
p-MeOC6H4
o-O2NC6H4–CH@CH
2-Thienyl
2,4-Cl2C6H3
p-O2NC6H4
C6H5
9
10
11
12
3j
3k
3l
C6H5–CH@CH
a
-Naphthyl
a
Yield (over two steps, based on aldehyde) refers to total isolated yield after column chromatography.
the reaction of diethyl phosphite with aldehydes followed by reac-
tion with isocyanates in the presence of magnesium oxide under
solvent-free conditions and ultrasonic irradiation, producing good
Naphthalenecarbaldehyde, polynuclear aldehyde, reacted with a
mixture of benzyl isocyanate and diethyl phosphite in the presence
of magnesium oxide, to give compound 3l in 60% isolated yield. Thus,
the three-component condensation reaction reported herein toler-
ates a wide variety of aldehydes and isocyanates for the synthesis
yields of
a-oxycarbanilinophosphonates.
We have previously reported the synthesis of
a-hydrox-
yphosphonates by the reaction of aldehydes with diethyl phos-
phite in the presence of magnesium oxide.12 Initially, we carried
out the reaction of benzaldehyde (1a) with diethyl phosphite in
the presence of magnesium oxide to afford a solid mixture after
30 min. When phenyl isocyanate (2a) was added to the solid mix-
ture, the reaction failed to give the desired product and only the
of
a
-oxycarbanilinophosphonates.
In summary, we have developed a simple and practical method
for the synthesis of -oxycarbanilinophosphonates via a three-
a
component one-pot reaction of aldehydes, diethyl phosphite and
isocyanates using ultrasonic irradiation in the presence of magne-
sium oxide in moderate to good yields. The simple work-up, mild
conditions and clean reactions with no tar formation are advanta-
ges of this method.13
corresponding
a-hydroxyphosphonate was obtained in 90% yield.
Surprisingly, we found that, when the first step was carried out un-
der ultrasonic irradiation for 30 min, the reaction mixture did not
solidify. Following addition phenyl isocyanate (2a) to the reaction
Acknowledgement
mixture, the corresponding
a-oxycarbanilinophosphonate 3a was
obtained in 62% isolated yield under ultrasonic irradiation for
1 h. The reaction of benzaldehyde with diethyl phosphite and
phenyl isocyanate without magnesium oxide under solvent-free
conditions using ultrasonic irradiation, gave only the correspond-
The authors gratefully acknowledge support from the Institute
for Advanced Studies in Basic Sciences (IASBS), Research Council
under Grant No. G20109IASBS120.
ing
a-hydroxyphosphonate in 25% yield after 5 h.
Supplementary data
These results prompted us to extend this process to other alde-
hydes and isocyanates (Table 1 and Scheme 3). Various substituted
benzaldehydes reacted with diethyl phosphite in the presence of
magnesium oxide followed by reaction with phenyl isocyanate to
give the desired compounds 3b–e in good yields. Treatment of 2-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.057.
References and notes
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nyl-2-carbaldehyde with diethyl phosphite followed by reaction
with phenyl isocyanate gave 74% yield of product 3g. The reaction
of substituted phenyl isocyanate with a mixture of aldehyde and
diethyl phosphite gave the corresponding a-oxycarbanilinophosph-
onates 3h and i in moderate yields. The reaction of cyclohexyl isocy-
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cinnamaldehyde in the presence of diethyl phosphite gave the
desired products 3j and k in 63% and 62% yield, respectively. 1-
O
O
C
O
R
P(OEt)2
MgO,
R
H + R'
N
C
O + H P(OEt)2
H
N
1-3 h, rt
O
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1
2
O
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3
Scheme 3. One-pot synthesis of a-oxycarbanilinophosphonates.

4348
B. Kaboudin, M. Fallahi / Tetrahedron Letters 52 (2011) 4346–4348
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13. Aldehyde (10 mmol) was added to a mixture of diethyl phosphite (10 mmol)
and MgO (0.2 g). The reaction mixture was irradiated with ultrasound for
30 min. The isocyanate (10 mmol) was then added and the mixture irradiated
for 1–3 h (a BANDELN-SONOREX ultrasonic bath with intense frequency of
35 KHz was used in all experiments). The mixture was chromatographed on
silica gel (n-hexane:EtOAc = 40/60) to give the pure product in 50–80% yield.
All products gave satisfactory spectral data in accord with the assigned
structures. Spectral data for the representative examples: Diethyl[(3-chloro-4-
methylanilinocarbonyl)oxy](2,4-dichlorophenyl)methyl phosphonate (3h): mp
146–148 °C (n-hexane-EtOAc). 1H NMR (CDCl3, 400 MHz): d = 1.24 (3H, t,
J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz) 2.31 (3H, S), 3.90–4.25 (4H, m), 6.59 (1H, d,
JHP = 14.4 Hz), 7.11 (1H, d, J = 8.0 Hz), 7.22 (1H, d, J = 8.0 Hz), 7.28 (1H, d, J =
7.6 Hz), 7.46 (s, 2H), 7.71 (1H, d, J = 7.6 Hz), 8.54 (1H, br s, NH); 13C NMR
7. (a) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry 1993, 4,
1779–1782; (b) Yokomatsu, T.; Yoshida, Y.; Shibuya, S. J. Org. Chem. 1994, 59,
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(CDCl3, 100 MHz): d = 16.3, 16.5, 19.3, 63.7 (d, JPC
= 6.9 Hz), 63.9 (d,
JPC = 6.9 Hz), 66.8 (d, JPC = 174.9 Hz), 116.8, 119.2, 127.6 (d, J = 2.0 Hz), 129.4
(d, J = 2.0 Hz), 130.5, 130.6, 130.7, 130.9, 134.3, 134.4, 135.4 (d, J = 3.0 Hz),
136.7, 151.7 (d, JPC = 13.0 Hz) 117.6, 118.7, 129.5, 130.4, 131.5, 131.7, 133.6,
137.6, 152.3; 31P NMR (CDCl3/H3PO4, 162 MHz): d = 16.94. Anal. Calcd for
C
19H21NCl3O5P: C, 47.60; H, 4.42; N, 2.92. Found: C, 47.48; H, 4.28; N, 2.81.
Diethyl[(cyclohexylaminocarbonyl)oxy]-3-phenylallyl phosphonate (3k): mp 108–
110 °C (n-hexane-EtOAc). 1H NMR (DMSO-d6, 250 MHz): d = 0.84–1.92 (16H,
m), 3.74 (1H, s), 4.14–4.21 (4H, m), 4.15 (1H, br s, NH), 5.73 (1H, m), 6.26 (1H,
m), 6.74 (1H, m), 7.27–7.37 (5H, m); 13C NMR (DMSO-d6, 62.9 MHz): d = 16.4,
16.4, 24.7, 25.4, 33.2, 48.83, 63.1 (d, JPC = 6.9 Hz), 63.3 (d, JPC = 6.9 Hz), 69.5 (d,
JPC = 170.5 Hz), 120.7, 126.8, 128.2, 128.6, 134.7, 134.8, 135.9; 31P NMR (CDCl3/
H3PO4, 101 MHz): d = 17.90. Anal. Calcd for C20H32NO5P: C, 60.42; H, 8.12; N,
3.52. Found: C, 60.35; H, 8.00; N, 5.42.
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