A simple and convenient procedure for the synthesis of 1-aminophosphonates from aromatic aldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.03.037

A simple, efficient, possible industrial process has been developed for the synthesis of 1-aminophosphonic acids from simple starting materials. As described below, treatment of aromatic aldehydes with ammonia and reaction with diethyl phosphite gives die

Full text of DOI:10.1016/j.tetlet.2005.03.037

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2989–2991
A simple and convenient procedure for the synthesis of
1-aminophosphonates from aromatic aldehydes
Babak Kaboudin* and Khavar Moradi
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
Received 28 December 2004; revised 1 March 2005; accepted 7 March 2005
Available online 22 March 2005
Abstract—A simple, efficient, possible industrial process has been developed for the synthesis of 1-aminophosphonic acids from
simple starting materials. As described below, treatment of aromatic aldehydes with ammonia and reaction with diethyl phosphite
gives diethyl N-(arylmethylene)-1-aminoaryl methylphosphonates, which can be easily hydrolyzed to diethyl 1-aminoaryl-
methylphosphonates. This method is easy, rapid, and good yielding for the synthesis of 1-aminoalkylphosphonates from simple
starting materials.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Organophosphorus compounds have found a wide
range of applications in the areas of industrial, agricul-
tural, and medicinal chemistry owing to their biological
and physical properties as well as their utility as syn-
thetic intermediates.1 a-Functionalized phosphonic
acids are valuable intermediates for the preparation of
medicinal compounds and synthetic intermediates.2–4
Among a-functional phosphonic acids, 1-aminophos-
phonic acids are an important class of compounds that
exhibit a variety of interesting and useful properties.
The 1-aminophosphonic acids are important substitutes
for the corresponding a-amino acids in biological sys-
tems.5 Indeed a number of potent antibiotics,6 enzyme
inhibitors,7 and pharmacological agents8 are 1-amino-
phosphonic acids or peptide analogues thereof. Amino-
phosphonic acids are also found as constituents of
natural products. A number of synthetic methods for
the synthesis of 1-aminoalkyl phosphonates have been
developed during the past 20 years.9 Of these methods,
the Kabachnik-Fieldꢀs10–14 synthesis of 1-aminoalkyl
phosphonates, catalyzed by a base or an acid, is the
most convenient. The key step in the Kabachnik-Fieldꢀs
synthesis of 1-aminoalkyl phosphonates is the nucleo-
philic addition of an amine to a carbonyl compound
followed by the addition of a dialkyl or diaryl phosphite
to the resulting imine. However, the formation of
1-hydroxyphosphonates or a product of its rearrange-
ment frequently accompanies the formation of 1-amino-
alkyl phosphonates.15 Lewis acids such as SnCl2, SnCl4,
BF3ÆEt2O, ZnCl2, MgBr2, and InCl3 have been used as
catalysts. However, these reactions cannot be carried
out in a one-step operation using the carbonyl com-
pound, amine and dialkyl phosphite because the amines
and water that exist during imine formation can decom-
pose or deactivate the Lewis acids.16 A typical procedure
is a Strecker-type reaction,17 which involves the treat-
ment of an aldehyde with ammonia and a dialkyl phos-
phite. This method, however, is not high yielding and is
unsuitable for large-scale production since the reaction
is performed in a sealed vessel at 100 ꢁC. As a part of
our efforts to introduce novel methods for the synthesis
of organophosphorus compounds,18 in this letter, a new
method for the synthesis of a-aminophosphonates is
described.
We have found that reaction of aromatic aldehydes with
ammonia solution followed by reaction with diethyl
phosphite, gives 1-aminophosphonates in good yields
(Scheme 1). Thus the reaction of benzaldehyde, chosen
as the model compound, was studied. As described be-
low, treatment of benzaldehyde (1a) with ammonia fol-
lowed by treatment with diethyl phosphite, gave diethyl
N-(phenylmethylene)-1-aminophenyl methylphospho-
1
nate (2a) (92%) (Scheme 1). The H NMR spectrum of
Keywords: 1-Aminophosphonates; Aldehydes; Ammonia; Diethyl-
phosphite.
2a exhibited a doublet at d 8.42 indicative of HC ꢀ P
coupling (4JHP = 4.7 Hz). Hydrolysis of 2a with p-tolu-
enesulfonic acid and neutralization of the sulfonate salt,
*
Corresponding author. Tel.: +98 241 4153220; fax: +98 241
4249023; e-mail: kaboudin@iasbs.ac.ir
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.037

2990
B. Kaboudin, K. Moradi / Tetrahedron Letters 46 (2005) 2989–2991
O
O
O
H
C
H
C
H
C
1) NH4OH(aq)
1) NH4OH(aq)
2) Diethyl phosphite
p-TsOH.H2O
Ph
P(OEt)2
PhCHO
Ph
P(OEt)2
Ph
P(OEt)2
NH2
N
NH3.OTs
CH
Ph
2a
4a
1a
3a
Scheme 1.
Table 1. Synthesis of 1-aminophosphonates from aldehydes
Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004,
104, 6177; (e) Palacios, F.; Alonso, C.; de los Santos, J. M.
Curr. Org. Chem. 2004, 8, 1481.
Ar
1
Reaction time (h)
Yielda (%)
4
2. Dingwall, J. G.; Campell, C. D.; Baylis, E. K. UK Patent
Appl. 1,542,938, 1979. Chem. Abstr. 1979, 88, 105559j.
3. Kafarski, P.; Lejczak, B.; Tyka, R.; Koba, L.; Pliszczak,
E.; Wieczorek, P. J. Plant Growth Regul. 1995, 14, 199.
4. Ishiguri, Y.; Yamada, Y.; Kato, T.; Sasaki, M.; Mukai, K.
Eur. Patent Appl. EP 82-301905, 1982. Chem. Abstr. 1983,
98, 102686u.
5. (a) Gancarz, R.; Chakraborty, S. Synthesis 1977, 625; (b)
Giannousi, P. P.; Bartlett, P. A. J. Med. Chem. 1987, 30,
1603; (c) Maier, L.; Lea, P. J. Phosphorus Sulfur 1983, 17,
1; (d) Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J.
Chem. Soc., Perkin Trans. 1 1984, 2445; (e) Hilderbrand,
R. L. The Role of Phosphonates in Living Systems; CRC:
Boca Raton, FL, 1982.
a
b
c
d
e
f
C6H5–
p-ClC6H4–
4
2
5
5
3
2
3
5
5
5
61
76
66
70
81
79
68
51
53
p-(CH3)2CHC6H4–
p-MeOC6H4–
p-BrC6H4–
m-ClC6H4–
m-MeC6H4–
1-Naphthyl
2-Naphthyl
g
h
i
b
j
n-C6H13
–
—
a Isolated yields.
b Unknown products.
6. Atherton, F. R.; Hassal, C. H.; Lambert, R. W. J. Med.
Chem. 1987, 30, 1603.
7. Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J.
M. J. Med. Chem. 1989, 32, 1652.
8. Hassal, C. H. In Antibiotics; Hahn, F. E., Ed.; Springer:
Berlin, 1983; Vol. VI, pp 1–11.
9. Kukhar, V. P.; Hudson, H. R. Aminophosphonic
and Aminophosphinic Acids; John Wiley & Sons: Chiches-
ter, 2000.
1) NH4OH (aq)/reflux/5 h
2) Diethyl phosphite/70°C/2-5 h
3) p-TsOH.H2O/THF/0°C/2 h
4) NH4OH
O
H
C
Ar
P(OEt)2
NH2
ArCHO
1
4
Scheme 2.
10. Hyun-Joon, H.; Gong-Sil, N. Synth. Commun. 1992, 22,
1143.
11. Gancarz, R.; Wieczorek, J. S. Synthesis 1978, 625.
12. Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem.
1971, 36, 1379.
13. Worms, K. H.; Schmidt-Dunker, M. In Organic Phospho-
rus Compounds; Kosolapoff, G. M., Maier, L., Eds.; John
Wiley & Sons: New York, 1976; Vol. 7, p 1.
14. Barycki, J.; Mastalers, P. Tetrahedron Lett. 1970, 36, 3147.
15. Gajda, T. P.; Matsiak, M. Synth. Commun. 1992, 22, 2193.
16. Genet, J. P.; Uziel, J.; Port, M.; Touzin, A. M.; Roland,
S.; Thorimbert, S.; Tanier, S. Tetrahedron Lett. 1992, 33,
7.
gave 1-(aminophenylmethyl)phosphonate (4a) (Scheme
1). This process was successfully applied to other aro-
matic aldehydes as summarized in Table 1. As shown,
substituted benzaldehydes react with ammonia followed
by reaction with diethyl phosphite to afford the desired
1-aminophosphonates in good yields (4b–g). Naphthal-
ene carbaldehydes also reacted with diethyl phosphite
in the presence of ammonia to give the desired 1-amino-
phosphonates in good yields (4h and 4i) (Scheme 2).
In summary, this method is an attractive and useful
contribution to present methodology. A wide range of
aromatic aldehydes was converted to the corresponding
1-aminophosphonic acids using this method. Reac-
tion of aliphatic aldehydes with diethylphosphite in
the presence of ammonia gave unidentified mixed
products.19
17. (a) Chalmers, M. E.; Kosolapoff, G. M. J. Am. Chem. Soc.
1953, 75, 5278; (b) Takahashi, H.; Yoshioka, M.; Imai, N.;
Onimura, K.; Kobayashi, S. Synthesis 1994, 763.
18. (a) Sardarian, A. R.; Kaboudin, B. Tetrahedron Lett.
1997, 38, 2543; (b) Kaboudin, B. Chem. Lett. 2001, 880; (c)
Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42,
8211; (d) Kaboudin, B.; Nazari, R. Synth. Commun. 2001,
31, 2241; (e) Kaboudin, B.; Balakrishna, M. S. Synth.
Commun. 2002, 31, 2773; (f) Kaboudin, B. Tetrahedron
Lett. 2002, 43, 8713; (g) Kaboudin, B. Tetrahedron Lett.
2003, 44, 1051; (h) Kaboudin, B.; Rahmani, A. Synthesis
2003, 2705; (i) Kaboudin, B.; Saadati, F. Synthesis 2004,
1249.
19. The aldehyde (15 mmol) was added to ammonium
hydroxide (30%, 15 mL) and the solution was stirred for
5 h at reflux. During this time, a white precipitate formed.
The precipitate was removed by filtration and dried.
Diethyl phosphite (6 mmol) was added to this solid and
the resulting solution was stirred for 2–5 h at 70 ꢁC.
p-Toluenesulfonic acid (6 mmol) in 50 mL THF was
added to the reaction mixture, which was stirred for 2 h
Acknowledgements
The Institute for Advanced Studies in Basic Sciences
(IASBS) is thanked for supporting this work.
References and notes
1. (a) Engel, R. Chem. Rev. 1977, 77, 349; (b) Hiratake, J.;
Oda, J. Biosci. Biotechnol. Biochem. 1997, 61, 211; (c)
Schug, K. A.; Lindner, W. Chem. Rev. 2005, 105, 64; (d)

B. Kaboudin, K. Moradi / Tetrahedron Letters 46 (2005) 2989–2991
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at 0 ꢁC. The precipitate was removed by filtration and
washed with THF (20 mL). The precipitate was added to
15 mL aqueous ammonium hydroxide (10%) and stirred
for 30 min at room temperature. Extraction with ether
(3 · 50 mL), evaporation of the solvent, and chromato-
graphy on silica gel with EtOAc/n-hexane (9:1) gave the
pure products as oils in 51–81% yields. All products gave
satisfactory spectral data in accord with the assigned
structures and literature reports.18,20
20. Green, D.; Geeta, P.; Elgendy, S.; Baban, J. A.; Claeson,
G.; Kakkar, V. V.; Deadman, J. Tetrahedron 1994, 50,
5099.