Calcium chloride as an efficient lewis base catalyst for the one-pot synthesis of α-aminophosphonic esters

Article abstract of DOI:10.1246/cl.2008.540

A simple, efficient, and general method has been developed for the one-pot synthesis of α-aminophosphonic esters, under solvent-free conditions, with the use of CaCl₂ as a Lewis base catalyst. The esters were obtained under mild conditions and

Full text of DOI:10.1246/cl.2008.540

540
Chemistry Letters Vol.37, No.5 (2008)
Calcium Chloride as an Efficient Lewis Base Catalyst for the One-pot Synthesis
of ꢀ-Aminophosphonic Esters
Babak Kaboudinꢀ and Hazegh Zahedi
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS),
Gava Zang, Zanjan 45195-1159, Iran
(Received February 15, 2008; CL-080176; E-mail: kaboudin@iasbs.ac.ir)
A simple, efficient, and general method has been developed
O
O
O
C
H
C
for the one-pot synthesis of ꢀ-aminophosphonic esters, under
solvent-free conditions, with the use of CaCl2 as a Lewis base
catalyst. The esters were obtained under mild conditions and
in high yield (80 to 96%) and purity. They were synthesized
by the reaction of diethyl phosphite with a mixture of aldehydes
and amines, in the presence of CaCl2, and under solvent-free
conditions. Major advantages of this protocol are: high yields,
inexpensive method, making use of a non-toxic catalyst and
finally mild and solvent-free conditions.
NH +
Ph
P(OEt)2
H
P(OEt)2
Ph
H + Ph
2
NH
Ph
1a
2a
3a
Scheme 1.
Table 1. Three-component reaction of benzaldehyde (1a),
aniline (2a), and diethyl phosphite using calcium chloride as
catalyst
Entry 1a:2a:DEP:CaCl2 Solvent Reaction time/h Yield/%a,b
3
ꢀ-Functionalized phosphonic acids are valuable intermedi-
ates for the preparation of medicinal compounds and synthetic
intermediates.1 ꢀ-Aminophosphonic acids could be used as
substitutes for the corresponding ꢀ-amino acids in biological
systems.2 Indeed a number of potent antibiotics,3 enzyme inhib-
itors,4 and pharmacological agents5 are ꢀ-aminophosphonic
esters or their peptide analogues. ꢀ-Aminophosphonic esters
are also found as constituents of natural products. Many different
methods for the preparation of ꢀ-aminoalkylphosphonic esters
have been developed so far and the Kabachnik–Fields6 synthetic
method, using an acid or base as catalyst, is the most convenient
method. Nucleophilic addition of an amine to a carbonyl com-
pound, followed by reacting with a dialkyl or a diaryl phosphite
and resulting an imine, is the key step in the Kabachnik–Fields
synthesis of ꢀ-aminophosphonic esters. Frequently formation
of 1-hydroxyphosphonates or its rearrangement product accom-
panies the formation of ꢀ-aminophosphonic esters.7 Lewis acids
1
2
1:1:1.2:—
1:1:1.2:1
—
24
2
43
96
96
78
91
73
73
78
71
71
92
—
3
1:1:1.2:0.1
1:1:1.2:0.1
1:1:1.2:0.1
1:1:1.2:0.1
1:1:1.2:0.1
1:1:1.2:0.1
1:1:1.2:0.1
1:1:1.2:0.1
1:1:1.2:0.1
—
3
4
CH2Cl2
CH3CN
DMSO
DMF
THF
24c
24
24
24
24
24
24
6
5
6
7
8
9
EtOH
MeOH
H2O
10
11
a31P NMR yields. bReactions carried out at 60 ꢁC. cReflux condition.
tally benign, and high yielding method for a three-component,
one-pot synthesis of ꢀ-aminophosphonic esters using CaCl2 as
catalyst.
.
such as SnCl2, SnCl4, BF3 Et2O, ZnCl2, MgBr2, and InCl3 have
Three-component reaction system of benzaldehyde (1a),
aniline (2a), and diethyl phosphite was selected as a model for
the one-pot synthesis of ꢀ-aminophosphonic esters using calci-
um chloride as catalyst (Scheme 1 and Table 1). In the absence
of any catalyst and for 24 h duration, corresponding ꢀ-amino-
phosphonic ester 3a was obtained with 43% yield (Entry 1).
Addition of an equimolar amount of CaCl2 completed the
reaction in 2 h and a quantitatively yield of 3a was achieved.
A catalytic amount of CaCl2 was enough to attain high reaction
efficiency (Entry 3, Table 1). The CaCl2-promoted reaction was
strongly affected by the solvent (Entries 4–11). The reaction
proceeded smoothly in DMSO, while with the use of THF, in
which CaCl2 was hardly dissolved, resulted in a moderate yield
of 3a. The homogeneous reaction in MeOH and EtOH gave
adduct 3a in good yield. Although water was surprisingly
effective solvent, substrates did not dissolve well in it (Entry 11).
The above results prompted us to use CaCl2 as a catalyst for
one-pot synthesis of ꢀ-aminophosphonic esters. As shown in
Scheme 2 and Table 2, a mixture of aniline (2a) and benzalde-
hyde (1a) with diethyl phosphite, in the presence of CaCl2 as
catalyst, afforded the desired product 3a in 90% yield. Other
been used as catalysts in these transformations.8 However, these
reactions could not be carried out in one-step in a reaction
mixture consisting of a carbonyl compound, an amine, and a
dialkyl phosphite since the Lewis acids catalysts could be
decomposed or deactivated in the presence of amines and water
during imine formation. In order to alleviate this problem there
has been recently a number of reports about the use of metal
triflates9 and perchlorates10,11 as catalysts instead of above
Lewis acids. However, these new developments also suffer from
stoichiometric amounts of reagents such as molecular sieves,
MgSO4, etc. Hence, there is still a need to develop a more
efficient, practical, and environmentally benign method for the
synthesis of ꢀ-aminophosphonic esters.
In recent years, there has been considerable interest in devel-
oping more economical and environmental-friendly conversion
processes. CaCl2 is an inexpensive, and commercially available
reagent, and as it has been shown recently, a very good catalyst
in organic reactions.12 In continuation of our interest in develop-
ing novel methodologies for the synthesis of organophosphorous
compounds,13 we report here an efficient, practical, environmen-
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.5 (2008)
541
esters. We also found that ꢀ-hydroxyphosphonate could be
converted to ꢀ-aminophosphonic esters in the presence of ani-
line and CaCl2 as catalyst. All NMR data could be assigned
and they were in good agreement with the characteristic prod-
ucts.16
O
O
O
C
CaCl2(0.1 equiv)
H
C
R
P(OEt)2
NH2+ H P(OEt)2
R
H + R'
60 °C
NH
R'
Scheme 2.
The Institute for Advanced Studies in Basic Sciences
(IASBS) is thanked for supporting this work.
Table 2. One-pot synthesis of ꢀ-aminophosphonic esters using
CaCl2 as catalyst under solvent-free condition
References and Notes
Product R
R0
Reaction time/h Yield/%a
1
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3a
3b
3c
3d
3e
3f
C6H5–
p-CH3C6H4–
C6H5–
C6H5–
3
3
2
2
3
3
3
3
3
2
4
3
90
93
92
90
96
85
87
94
90
83
80
88
p-(CH3)2CHC6H4– C6H5–
p-CH3OC6H4–
p-NO2C6H4–
Ph–CH=CH–
C6H5–
C6H5–
2
3
4
5
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C6H5–
C6H5–
3g
3h
3i
m-NO2C6H4–
m-NO2C6H4–
p-CH3C6H4–
p-(CH3)2CHC6H4– m-NO2C6H4–
3j
p-CH3OC6H4–
C6H5–
m-NO2C6H4–
Cyclohexyl
Cyclohexyl
3k
3l
6
7
M. Horiguchi, M. Kandatsu, Nature 1959, 184, 901.
a) V. P. Kukhar, H. R. Hudson, in Aminophosphonic and
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Ph–CH=CH–
aYield refers to isolated yield by column chromatography.
O
O
P
H
C
H
C
CaCl2(0.1 equiv)
Ph
P
OEt+PhNH2
OEt
Ph
OEt
8
9
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OEt
OH
NH
Ph
4a
3a
Scheme 3.
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mixtures of amines and aldehydes also reacted with diethyl
phosphite, in the presence of catalytic amounts of CaCl2, to give
desired compounds in good yields (Table 2).
Lewis base activity of CaCl2 has recently been reported in
literature.12 We found that LiCl- and NaCl-promoted reactions
of 2a with 1a, for 8 h, gave 3a in high yields. However, shorten-
ing the reaction time revealed that the rate-accelerating ability of
NaCl and LiCl was lower than that of CaCl2 (96% yield of 3a
after 2 h). Interestingly, we also found that Bu4NCl could be
used instead of a metal salt (71% yield of 3a after 12 h). Chloride
ion also accelerated the reaction in the presence of no solvent.
It was detected that 1-hydroxyphosphonates or a product of
its rearrangement was not produced in the formation of 1-amino-
alkylphosphonates. These results prompted us to examine
the conversion of 1-hydroxyalkylphosphonates to 1-aminoalkyl-
phosphonates in the presence of amines, using CaCl2 as catalyst
(Scheme 3).14 Interestingly we found that diethyl 1-hydroxy-
phenylmethylphosphonate (4a) could be converted to diethyl
1-aminophenylmethylphosphonate (3a) in the presence of
aniline and CaCl2 as catalyst, after 24 h (20% yield, 60 ꢁC,
Scheme 3).15 The reaction yield was increased to 65% with
the addition of one equivalent diethyl phosphite to the reaction
mixture.
13 a) B. Kaboudin, Chem. Lett. 2001, 880. b) B. Kaboudin,
Tetrahedron Lett. 2002, 43, 8713. c) B. Kaboudin, R. Nazari,
Tetrahedron Lett. 2001, 42, 8211. d) B. Kaboudin, A.
Rahmani, Synthesis 2003, 2705. e) B. Kaboudin, F. Saadati,
Synthesis 2004, 1249. f) B. Kaboudin, A. Rahmani, Org.
Prep. Proced. Int. 2004, 36, 82. g) B. Kaboudin, K. Moradi,
Tetrahedron Lett. 2005, 46, 2989. h) B. Kaboudin, H.
Haghighat, Tetrahedron Lett. 2005, 46, 7955. i) B. Kaboudin,
H. Haghighat, T. Yokomatsu, J. Org. Chem. 2006, 71, 6604.
j) B. Kaboudin, M. Karimi, Bioorg. Med. Chem. Lett. 2006,
16, 5324. k) B. Kaboudin, F. Farjadian, Beilstein J. Org.
Chem. 2006, 2, 4. l) B. Kaboudin, K. Moradi, Tetrahedron
Lett. 2005, 46, 2989. m) T. Yamagishi, T. Kusano, B.
Kaboudin, T. Yokomatsu, C. Sakuma, S. Shibuya, Tetra-
hedron 2003, 59, 767. n) B. Kaboudin, K. Moradi, Synthesis
2006, 2339. o) B. Kaboudin, E. Jafari, Synthesis 2006, 3063.
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14 1-Hydroxyphosphonates synthesized using known methods:
A. R. Sardarian, B. Kaboudin, Synth. Commun. 1997, 27, 543.
15 B. Kaboudin, Tetrahedron Lett. 2003, 44, 1051.
16 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
In conclusion, in all reactions reported in this paper, the
cleavage of Et–O–P bond was not detected and the conversion
of substrates to their corresponding ꢀ-aminophosphonic esters
was clean. It was revealed that CaCl2 could be an effective
Lewis base catalyst for one-pot synthesis of ꢀ-aminophosphonic
Published on the web (Advance View) April 12, 2008; doi:10.1246/cl.2008.540