A convenient synthesis of 1-aminophosphonates from 1-hydroxyphosphonates

Article abstract of DOI:10.1016/S0040-4039(02)02727-2

A simple, efficient, and general method has been developed for the synthesis of 1-aminophosphonates from 1-hydroxyphosphonates under solvent-free conditions using microwave irradiation. 1-Aminophosphonates were obtained in high yield and mild conditions b

Full text of DOI:10.1016/S0040-4039(02)02727-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1051–1053
A convenient synthesis of 1-aminophosphonates from
1-hydroxyphosphonates
Babak Kaboudin*
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-159, Iran
Received 18 August 2002; revised 16 November 2002; accepted 29 November 2002
Abstract—A simple, efficient, and general method has been developed for the synthesis of 1-aminophosphonates from 1-hydrox-
yphosphonates under solvent–free conditions using microwave irradiation. 1-Aminophosphonates were obtained in high yield and
mild conditions by reaction of diethyl 1-hydroxyalkylphosphonates with amines in the presence of acidic alumina. © 2003 Elsevier
Science Ltd. All rights reserved.
1-Aminophosphonic acids are probably the most
important substitutes for the corresponding amino
acids in biological systems.1–4 Indeed a number of
potent antibiotics,5 enzyme inhibitors,6 and pharmaco-
logical agents7 are 1-aminophosphonic acids as well as
their derivatives, notably peptides. Aminophosphonic
acids are also found as constituents of natural products.
These important compounds have been synthesized by
various routes: (a) addition of P–H function to imines
and enamines,8 (b) addition of P–H function to
nitriles,9 (c) Arbuzov and Michaelis–Beacker reac-
tions,10 (d) condensation of X-NH2 with acyl phospho-
rus species,11 (e) Curtius and Hoffmann rearrangement
of substituted phosphonoacetic esters12 and (f) alkyla-
tion of nucleophilic precursors such as Schiff bases.13
Despite this wide range of synthetic methods for syn-
thesis of 1-aminophosphonates, little attempt has been
made to convert readily accessible 1-hydroxyphospho-
nates to 1-aminophosphonates.14,15 Surface-mediated
solid-phase reactions are of growing interest16 because
of their ease of set up and work-up, mild reaction
conditions, rate of reaction, selectivity, high yields, lack
of solvent and the low cost of the reactions in compari-
son with their homogeneous counterparts. The applica-
tion of microwave energy to accelerate organic
reactions is of increasing interest and offers several
advantages over conventional techniques.17 Syntheses
which normally require long periods, can be achieved
conveniently and very rapidly in a microwave oven. As
a part of our efforts to explore the utility of surface-
mediated reactions for the synthesis of organophospho-
rus compounds,18–21 we report here a new method for
the preparation of 1-aminophosphonates from 1-
hydroxyphosphonates in the presence of a mixture of
an amine and acidic alumina under solvent-free condi-
tions using microwave irradiation producing high yields
of 1-aminophosphonates (Scheme 1, Table 1).
As shown in Table 1, the reaction of a mixture of
aniline, diethyl 1-hydroxyphosphonates22 in the pres-
ence of acidic alumina under microwave irradiation,
afforded the desired products in good yields (2a–2e).
m-Nitroaniline also reacted to give the desired com-
pounds in good yields (2f–2h). The reactions also pro-
ceeded with good yields with cyclohexylamine (2i–2k).
The reaction of (S)-(−)-phenylethylamine with diethyl
1-hydroxyphenyl methylphosphonate gave the desired
compound in good yield. The reactions were clean with
no tar formation.23 The reactions failed after 48 h
without microwave irradiation.
In summary, a simple work-up, low consumption of
solvent, fast reaction rates, mild reaction conditions,
good yields, relatively clean reactions with no tar for-
mation make this method an attractive and a useful
contribution to present methodologies. Indeed, a wide
range of 1-hydroxyphosphonates were converted to the
corresponding 1-aminophosphonates using this method.
* Tel.: +98 241 4242239; fax: +98 241 4249023; e-mail: kaboudin@
iasbs.ac.ir
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02727-2

1052
B. Kaboudin / Tetrahedron Letters 44 (2003) 1051–1053
Table 1. Reaction of a mixture of amine and diethyl 1-hydroxyphosphonates in the presence of acidic alumina under
microwave irradiation
1
R
R%
Reaction time (min)
Yield (%)a
2
a
b
c
d
e
f
g
h
i
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
5
5
4
3
5
7
7
7
5
5
5
6
55
62
65
57
50
53
55
56
60
58
60
65b
p-CH3C6H4-
C6H5-CHꢀCH-
p-NO2C6H4-
n-C4H9-
C6H5-
C6H5-
m-O2NC6H4-
m-O2NC6H4-
m-O2NC6H4-
Cyclohexyl
Cyclohexyl
Cyclohexyl
(S)-(−)-1-Phenylethyl-
p-CH3C6H4-
C6H5-CHꢀCH-
C6H5-
p-CH3C6H4-
C6H5-CHꢀCH-
C6H5-
j
k
l
a Isolated yields.
b Diastereomeric ratio is 65:35 based on 31P NMR.
Further investigations of the mechanism of this reac-
tion are now in progress.
13. (a) Genet, J. P.; Uziel, J.; Port, M.; Touzin, A. M.;
Roland, S.; Thorimbert, S.; Tanier, S. Tetrahedron Lett.
1992, 33, 7; (b) Qian, C.; Huang, T. J. Org. Chem. 1998,
63, 4125; (c) Ranu, B. C.; Hajira, A.; Jana, U. Org. Lett.
1999, 1, 1141; (d) Manabe, K.; Kobayashi, S. Chem.
Commun. 2000, 669; (e) Chanderasekhar, S.; Prakash, S.
J.; Jagadeshwar, V.; Narsihmulu, C. Tetrahedron Lett.
2001, 42, 5561.
Acknowledgements
The Institute for Advanced Studies in Basic Sciences
(IASBS) is thanked for supporting this work.
14. Gajda, T.; Matusiak, M. Synthesis 1992, 367.
15. Chakraborty, S.; Engel, R. Synth. Commun. 1991, 21,
1039.
16. (a) Fadel, A.; Yefash, R.; Saluan, J. Synthesis 1987, 37;
(b) Rosini, G.; Galarini, R.; Marotta, E.; Righi, R. J.
Org. Chem. 1990, 55, 781; (c) Kodomari, M.; Sakamoto,
T.; Yoshitomi, S. J. Chem. Soc., Chem. Commun. 1990,
701; (d) Kropp, P. J.; Daus, K. A.; Crawford, S. D.;
Tubergren, M. W.; Kepler, K. D.; Craig, S. L.; Wilson,
V. P. J. Am. Chem. Soc. 1990, 112, 7433; (e) Hondrogian-
nis, G.; Pagni, R. M.; Kabalka, G. W.; Anisoki, P.; Kurt,
R. Tetrahedron Lett. 1990, 31, 5433; (f) Pantney, H. K.
Tetrahadron Lett. 1991, 32, 2259; (g) Pauter, F.; Daudon,
M. Tetrahedron Lett. 1991, 32, 1457.
17. (a) Caddick, S. Tetrahedron 1995, 55, 10403–10432; (b)
Zlotorzynsky, A. Crit. Rev. Anal. Chem. 1995, 25, 43; (c)
Varma, R. S. Green Chem. 1999, 43; (d) Lidstrom, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9227; (e) Perreux, L.; Loupy, A. Tetrahedron 2001, 57,
9199.
18. Sardarian, A. R.; Kaboudin, B. Synth. Commun. 1997,
27, 543.
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38, 2543.
20. Kaboudin, B. Tetrahedron Lett. 2000, 41, 3169.
21. Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42,
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References
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Giannousi, P. P.; Bartlett, P. A. J. Med. Chem. 1987, 30,
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Chem. Soc., Perkin Trans. 1 1984, 2445; (e) Hilderbrand,
R. L. The Role of Phosphonates in Living Systems; CRC
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193; (b) Kukhar, V. P.; Hudson, H. R. Aminophosphonic
and Aminophosphinic Acids; John Wiley & Sons, 2000.
3. Hanessian, S.; Bennani, Y. L. Synthesis 1995, 1272.
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22. Procedure for the preparation of 1-hydroxyphosphonates:
Magnesium oxide (2 g) was added to a stirred mixture of
diethyl phosphite (0.02 mol) and aldehyde (0.02 mol) at
rt. After 2 h the mixture was washed with dichloro-
methane (4×50 mL), dried with CaCl2, and solvent
evaporated to give the crude products. Products were
crystallized from CH2Cl2/n-hexane (1:2) or distilled under
reduced pressure. All products gave satisfactory
9. Gancarz, R.; Wieczorek, J. S. Synthesis 1978, 625.
10. Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem.
1971, 36, 1379.
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B. Kaboudin / Tetrahedron Letters 44 (2003) 1051–1053
1053
spectral data in accord with the assigned structures. For
microwaves for 3–7 min at 720 W (a kitchen-type
microwave was used in all experiments). The mixture
(including alumina) was chromatographed through a plug
of silica gel with EtOAc/n-hexane and evaporation of the
solvent under reduced pressure gave the pure product in
50–65% yields. All products gave satisfactory spectral
data in accord with the assigned structures. For 2a as an
1c as an example: White crystals (82%); mp 105–106°C
1
(n-hexane/CH2Cl2); H NMR (CDCl3/TMS): 1.15 (3H, t,
J=7.1 Hz), 1.28 (3H, t, J=7.1), 3.94 (1H, ddq, J=7.1,
11.2, 8.1 Hz), 4.09 (1H, ddq, J=7.1, 8.1, 11.2 Hz), 4.18
(2H, m), 4.3 (1H, br, OH), 4.4 (1H, dd, JHP=18, JHH=6
Hz), 6.08 (1H, dd, J=6, 16 Hz), 6.4 (1H, d, J=16),
6.9–7.4 (5H, m); 31P NMR (CDCl3/H3PO4): 19.49; IR
1
example H NMR (CDCl3/TMS-500 MHz): 1.12 (3H, t,
(KBr): 3250 (-OH), 1230 (PꢀO), 1045 (P-O-Et) cm−1
.
J=7.1 Hz), 1.29 (3H, t, J=7.1), 3.68 (1H, ddq, J=7.1,
11.2, 8.1 Hz), 3.95 (1H, ddq, J=7.1, 8.1, 11.2 Hz), 4.14
(2H, m), 4.75 (1H, br, -NH), 4.78 (1H, d, J=17.9 Hz),
6.61 (2H, d, J=8.5 Hz), 6.70 (1H, t, J=7.4), 7.11 (2H, t,
J=7.4), 7.27 (1H, m), 7.34 (2H, t, J=7.4), 7.49 (2H, m);
IR (neat): 3295 (-NH), 1233 (PꢀO), 1103–997 (P-O-Et)
23. This solvent-free reaction method is operationally simple.
1-Hydroxyphosphonate (2 mmol) was combined with
alumina (Al2O3, acidic, 1.5 g) in a mortar and pestle by
grinding them together until a fine, homogeneous powder
was obtained (5–10 min). Amine (3 mmol) was added to
this mixture and the mixture was irradiated by
cm−1
.