Surface-mediated solid phase reactions: A simple and new method for the synthesis of α-aminophosphonates under solvent-free conditions

Article abstract of DOI:10.1246/cl.2001.880

Alumina-supported ammonium formate was found to be an efficient reagent for the synthesis of 1-aminophosphonates from aldehydes and diethyl phosphite. This method is an easy, rapid and high-yielding reaction for the synthesis of 1-aminophosphonates.

Full text of DOI:10.1246/cl.2001.880

880
Chemistry Letters 2001
Surface-Mediated Solid Phase Reactions: A Simple and New Method for the Synthesis of
α-Aminophosphonates under Solvent-Free Conditions
Babak Kaboudin
Institute for Advanced Studies in Basic Sciences (IASBS), P. O. Box 45195-159, Gava Zang, Zanjan, Iran
(Received June, 1, 2001; CL-010519)
Alumina-supported ammonium formate was found to be an
efficient reagent for the synthesis of 1-aminophosphonates from
aldehydes and diethyl phosphite. This method is an easy, rapid
and high-yielding reaction for the synthesis of 1-aminophospho-
nates.
In recent years, considerable interest has been focused on the
synthesis of phosphonic acids, particularly the α-substituted
analogs that are an important class of compounds with applica-
tions as antibiotics, antiviral agents and enzyme inhibitors.
Among the α-functionalized phosphonic acids, α-aminophospho-
nic acid derivatives are gaining in interest in medicinal chem-
istry. α-Aminophosphonic acids are analogues of naturally
occurring α-amino acids in biological systems. Extensive inves-
tigations over the last twenty years have shown they are of partic-
ular importance in biological and medicinal research.1 In this
connection, the uses of α-aminoalkylphosphonates as enzyme
inhibitors,2 antibiotics and pharmacological agents,3 herbicides,4
and haptens of catalytic antibodies5 are well documented.
Although there are many classical methods for synthesizing α-
aminophosphonic acids, these involve either long reaction times,
expensive reagents, or the use of conditions which are amenable
to aliphatic aminophosphonic acids rather than aromatic
aminophosphonic acids.6 The most typical procedure is a
Strecker-type reaction7 which involves the treatment of an alde-
hyde with ammonia and dialkyl phosphite. This method, howev-
er, is not high yielding nor suitable for large-scale production
since the reaction is performed in a sealed vessel with heating at
100 °C.
Surface-mediated solid phase reactions are of growing
interest8 because of their advantages of ease of set up, mild con-
ditions, rapid reactions, selectivity, increased yields of the prod-
ucts and low cost compared with their homogeneous counter-
parts. As a part of our efforts to explore the use of surface-
mediated reactions for the synthesis of organophosphorus com-
pounds,9–12 in this report, a new method for the synthesis of α-
aminophosphonates on a solid surface is described. It was
found that acidic alumina supported ammonium formate under
solvent-free conditions is capable of the synthesis of α -
aminophosphonates from aldehydes and diethyl phosphite
under mild reaction conditions (Scheme 1, Table 1).
The aldehyde 1 is treated with diethyl phosphite in the pres-
ence of acidic alumina-supported ammonium formate, giving
imine derivatives of 1-aminoalkylphosphonate 2 (Scheme 1). 1H
NMR spectrum of 2 exhibits a doublet at 8.25 ppm due to cou-
pling constant, which is indicative for the coupling HC–P (JHP = 5
Hz) moiety in the molecule.13 The reaction of 2 with p-toluene-
sulfonic acid monohydrate in ether and followed neutralization of
ammonium salt 3, gave the desired 1-aminoalkylphosphonates
(4). The overall yields of these reactions are shown in Table 1.
As shown in Table 1, aliphatic aldehydes with diethyl
phosphite, in the presence of alumina supported ammonium for-
mate, afford the desired products in excellent yields (4a–4c).
The o-, m- and p-substituted benzaldehydes also react with
diethyl phosphite in the presence of alumina supported ammo-
nium formate with microwave irradiation, to give the desired
compounds in high yields (4d–4j). The reactions also proceed
with good yields with cinnamaldehyde as an α,β−unsaturated
aldehyde and furfural as a heterocyclic aldehyde (4k, 4l).
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
881
Polynuclear aromatic aldehydes also afford the 1-aminoalkyl-
phosphonates in good yields (4m, 4n).
Atherton, M. J. Hall, C. H. Hassal, R. W. Lambert, W. J.
Lloyd, and P. S. Ringrose, Antimicrob. Agents Chemother.,
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a) J. Emsley and E. D. Hall, “The Chemistry of
Phosphorus,” Harper and Row, London (1976). b) A.
Barder, Aldrichimica Acta, 21, 15 (1988).
The reactions were clean with no tar formation and inter-
estingly, no product from the 1-hydroxyphosphonate was
observed.14 Indeed, a wide range of aldehydes were converted
to corresponding 1-aminoalkylphosphonates using this reaction.
Neutral and basic aluminas and magnesium oxide are not
effective as acidic alumina and usually give low yields of the
corresponding amine since they produce 1-hydroxyphospho-
nates as the major product instead.
This solvent-free reaction method is operationally simple.
The reagent (30 mmol) was prepared by the combination of
ammonium formate (30 mmol, finely ground) and alumina
(Al2O3, acidic, 5.75 g) in a mortar and pestle by grinding them
together until a fine, homogeneous powder is obtained (5–10
min). The aldehyde (60 mmol) is added to this reagent (solid
aldehydes need to be grained before adding the diethyl phos-
phite). Diethyl phosphite was added to this mixture and the
whole was irradiated by microwave for 3–6 min using 720 W
(A kitchen-type microwave was used in all experiments). The
reaction mixture is washed with diethyl ether (200 mL). p-
TsOH·H2O (30 mmol) was added to the ethereal solution with
stirring. After completion of the reaction (1 h), the solid was
filtered and neutralized with NaOH (10%). Chromatography
through a plug of silica gel with EtOAc/n-hexane (1:9) and
evaporation of the solvent under reduced pressure gave the pure
product as oil in 63–78% yields.15
4
5
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6
7
8
In summary, the simple work-up, low consumption of sol-
vent, relatively fast reaction rate, mild reaction conditions, good
yields and selectivity of the reaction make this method an
attractive and a useful contribution to present methodologies.
The Institute for Advanced Studies in Basic Sciences
(IASBS) is thanked for supporting this work.
References and Notes
9
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3
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15 All products gave satisfactory spectral data in accord with
1
the assigned structures. For 4d as an example H NMR
(CDCl3/TMS): δ 1.15 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J =
7.1), 2.75 (2H, br, –NH2); 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),
4.88 (1H, d, J = 17.8 Hz), 7.45 (5H, m); IR (neat): 3377,
3295 (–NH2), 1237 (P=O), 1103–997 (P–O–Et) cm–1.